This thesis (chapters II, III, IV and V) deals with the synthesis and formation of

fused dihydro oxazolo derivatives from suitable precursors by reductive cyclization with
lithium aluminum hydride. Hence, the Introduction (Chapter I) to this thesis has been
described into two parts: the first part deals with reactions of LAH and the second part
deals with synthesis and formation of fused oxazolo derivatives by ring closure methods.

35
1.1 REDUCTION:
1.1.1 GENERAL
Reduction, one of the most widely used fundamental organic reactions, can be
accomplished by several brand methods including addition of hydrogen and/or electrons,
or hydride ions to a molecule or removal of oxygen or the other electronegative
substituents. The most important reducing agents from a synthetic point of view are of
two types, viz non-hydride reducing agents and hydride reducing reagents.1
1.1.2 Types of Reducing Agents
1.1.2 (a) Non-Hydride Reducing Agents
Catalytic hydrogenation: This reaction involves addition of the elemental H2
across a double bond as shown in Equation – 1.1.

H2 C CH2 + H H H3 C CH3

(I) (II)
Equation – 1.1
Dissolving metal reductions: In general, this method is useful for the reduction
conjugated systems, enones, or aromatics. For saturated carbonyl compounds, hydride
reductions are better. The commonly used metals are Li, Na, K, Zn, Mg, Sn and Fe and
the commonly used solvents are NH3, HMPA, THF, DME and Crown ethers.
Electrochemical reductions: This reaction involves electrolysis at a mercury, lead
or cadmium cathode and tetramethylammonium chloride as catalyst.
Various non-hydridic procedures were developed for the reduction of organic
functional groups prior to the discovery of hydride reagents.1 Reduction of aldehydes to
the corresponding alcohols was achieved by zinc dust - acetic acid, sodium amalgam -
acetic acid, sodium in toluene - acetic acid or iron - acetic acid,2 as shown in Equation –
1.2.
2(H)
CHO CH2OH
Fe / AcOH, Water (IV)
(III)
6.0 h, 100 oC, 75 - 80 %

36
 Equation – 1.2
Simple ketones were reduced to the corresponding alcohol using sodium in
ethanol,3 as shown in Equation – 1.3
O OH
Na/EtOH

(V) (VI)
65 %
Equation – 1.3
Equation 1.4 describes that the diaryl ketones were reduced to the alcohols by
using zinc and sodium hydroxide mixture in ethanol.4
2 (H)
Ph Ph
O OH
Ph Zn/2NaOH/EtOH Ph
(VII) 70oC, 3.0 h, 96 % (VIII)

Equation – 1.4
Aldehydes were reduced to corresponding carbinols using aluminum ethoxide in
ethanol or aluminum ethoxide in isopropyl alcohol.6 This method has been applied to a
5

variety of aldehydes and ketones popularly known as “Meerwein- Ponndorf-Verley

reduction”. (Equation – 1.5)
Al/iPrOH CH2OH
CHO

(IX) 8 - 9 hrs, 110 oC (X)

60 %

Ph
O
Al (iPrO)3 Ph
OH
Ph Ph
Reflux/1.0 h (VIII)
(VII) 99 %
Equation – 1.5
Carboxylic acid esters were reduced to the corresponding alcohols by sodium in
ethanol which is known as Bouveault and Blanck reduction.7 (Equation -1.6)
Na/EtOH
nC11H23CO2Et nC11H23CH2OH
(XI) Steam bath, 65 - 75 % (XII)

37
 Equation – 1.6
The non-hydridic reductive procedures often require elevated temperature, long
reaction time and are associated with low yields. However, the discovery of metal
hydrides and complex metal hydrides has dramatically changed the situation, not only for
the reduction of carbonyl groups, but also for the reduction of a wide variety of many
other functional groups.
1.1.2 (b) Hydride Reducing Agents
The first hydride-reducing agent is diborane, which was discovered in 1930s, the
structure of which was subject to considerable study and speculation.8 Professor H. I.
Schlesinger at University of Chicago was studied the reactions of diborane. The methods
available for the preparation of diborane were not satisfactory for large scale
preparations.
Hence, sodium borohydride was started to be used as a reducing agent,9 and
improved methods were available for preparing sodium borohydride.10 The alkaline
metal hydride route was successfully extended for the synthesis of the corresponding
aluminum derivatives.
1.2 Lithium aluminum hydride:
1.2.1 Synthesis & Physical Properties
Lithium aluminum hydride was synthesized in 1945 by the reaction of lithium
hydride and aluminum chloride in ether solution.11
4LiH + AlCl3 LiAlH4 + LiCl
3LiAlH4 + AlCl3 4AlH3 + 3LiCl
4AlH3 + 4LiH 4LiAlH4
The discovery of sodium borohydride in 1942 and of lithium aluminum hydride in
1945 brought a revolutionary change in procedures for the reduction of functional groups
in organic synthesis.12 As first described by W. G. Brown et al. 12 Lithium aluminum
hydride is an exceedingly powerful reducing agent and capable of reducing practically all
functional groups.

38
 Consequently, it was quite difficult to apply this reagent for the selective
reduction of multifunctional molecule. Lithium aluminum hydride is capable of reducing
almost all of the organic functional groups rapidly to the lowest reduced state.13 It can
hydroaluminate double and triple bonds14 and can function as a base15 It is soluble in
variety of ethereal solvents such as ethyl ether (15.0 gm in 100 mL), tetrahydrofuran
(13.0 gm in 100 mL), monoglyme, diglyme , triglyme and reacts violently with water and
other protic solvents.
1.2.2 Reactivity & Synthetic Applications
Exploratory study of the reactivity of this reagent towards representative organic
functional groups is summarized below.16
Table – 1.1: Reactivity of various functional groups with LAH.
S.No. Reactant Product
1. Aldehyde Alcohol
2. Ketone Alcohol
3. Acid Chloride Alcohol / Aldehyde
4. Lactone Alcohol (diol)
5. Epoxide Alcohol
6. Ester Alcohol
7. Carboxylic acid Alcohol
8. Carboxylic acid salt Alcohol
9. tert.Amide Amine / Aldehyde
10. Nitrile Amine
11. Nitro Amino / Azo
12. Olefin No reaction.

The general mechanisms for reduction of some important class of carbonyl

compounds are shown as below:-
For Ketones:-

39
 Li
H3Al OLi Li R
H H O
Al H3Al O
H H R H R
R R R
R
O
R

OH 4H O R Li R
2
LiOH, Al(OMe) + LiAl O H2Al O
R R R 4 R 2

Scheme – 1.1
For Carboxylic esters:-
Li
H3Al OLi Li OR
O R H
H H H3Al O
Al
H H R H R -ROAlCH3 O
R OR OR

R H
H+
O AlH2OR R OH
H R O

ROAlH2

Scheme – 1.2
For Carboxamides:-
Li
H3Al OLi Li NH2
H H O R H
H3Al O
Al
H H R H H R NH2
R NH2 NH2

R H
H+
NH2 AlH2 O- R NH2
H R N
H2
-OAlH
2

Scheme – 1.3
The powerful hydride transfer properties of this reagent is the reason for the high
reactivity with aldehydes, ketones, esters, lactones, carboxylic acids, anhydrides, and

40
epoxides to give alcohols, and with amides, iminum ions, nitriles, and aliphatic nitro
compounds to give amines. Several methods are available for the workup procedure of
these reductions. A strongly recommended option16 involves a careful and successive
drop wise addition of n mL of 15 % NaOH solution, and 3n mL of water to the mixture
containing n grams of LiAlH4. These conditions provide a dry granular inorganic
precipitate that is easy to rinse and filter. Alternatively, solid Glauber’s salt
(Na2SO4.10H2O) can be added portion wise until the salts become white.17 In certain
instances, an acidic workup (10 % H2SO4) may prove advantageous because the
inorganic salts become solubilized in the aqueous phase.18
LAH can be used in dimerization of acetals and ketals along with titanium tetra
chloride (Equation 1.7).19 Allylic or benzylic alcohols can be symmetrically coupled by
treatment with LAH & TiCl4 (Equation 1.8). 20 Dehalogenation has been accomplished
with LAH (Equation 1.9).21 Oximes and imines have been converted to the corresponding
aldehyde or ketone by treatment with LAH-HMPA (Equation 1.10),22 episulfides can be
converted into olefins (Equation 1.11).23 Five membered cyclic sulfones can be
converted to cyclobutenes by treatment with BuLi followed by LAH (Equation 1.12),24
ethers are stable with LAH but THF when treated with LAH-AlCl3 gives 1- butanol.
LAH opens an epoxide (Equation 1.13),25 alcohols can also be reduced indirectly i.e. by
converting it to a sulfonate followed by the reduction of that compound, the two reactions
26
can be carried out without isolation of the sulfonate (Equation 1.14). Fluorine
containing amide when treated with LAH alone results in amine, but when the reagent
was used in combination with AlCl3, fluorine is also displaced by hydrogen. (Equation
1.15)27
1.2.1Table – I
Eq. No. SCHEME Ref:
1.7 EtO 19
OEt LAH/TiCl4

OEt 85 % OEt
(XIII) (XIV)

41
 1.8 HO Ph LAH/TiCl4 20
Ph Ph
Ph OH
Cis & Trans
(XV) (XVI)

1.9 x 21
LAH
x
(XVII) (XVIII)
1.10 LAH 22
+ W-NH2
N HMPA O
W
(XIX) (XX)

1.11 LAH 23
S
(XXI) (XVIII)

1.12 24
O BuLi
S 47
O LAH

(XXII) (XXIII)

1.13 LAH / AlCl3 25

OH
O
(XXIV) (XXV)

1.14 26
N N
1)TsCl

OH 2) LAH
O O

(XXVI) (XXVII)

1.15 O 27
O H H LAH O H
N LAH/AlCl3 O N N
O O O

(XXIX) (XXVIII) F (XXX) F F

F

The reduction of N,N-disubstituted amides with LAH leads to aldehydes where

amines are also formed as other products (Equation 1.16),28 Synthesis of Aziridines from

42
β-iodo azides by reductive cyclization with LAH (Equation 1.17),29 were reported in the
literature. 1 Molar equiv of LAH with 0.25 molar equiv of TiCl4 in THF is extremely
effective in reducing bromohydrins to olefins in high yields (Equation 1.18).30 Several
carboxylic esters and lactones were reduced to ether derivatives employing a reagent
prepared from LAH & BF3-Et2O (Equation 1.19).31 Aromatic aldehydes, ketones, acids
and esters were converted to corresponding halides in one pot operation with LAH
followed by treatment with HBr (Equation 1.20).32 Cyclohexene epoxides are
preferentially reduced by an axial approach of the nucleophile.33 Aromatic bromides are
reduced quite rapidly and quantitatively to the corresponding hydrocarbons by LAH in
THF (Equation 1.21).34 LAH was used for the stereospecific reduction of acetylenes
(Equation 1.22).35

1.2.1Table – I
Eq. No. SCHEME Ref:
1.16 CHO NHMe 28
O LAH

N Et2O,
Me 58 % (Aldehyde)

(XXXII) (XXXIII)
(XXXI)

1.17 N3 29
LAH N
I
Et2O,

(XXXIV) (XXXV)

1.18 Br 30
LAH
OH
THF, 93 %
(XXXVI) (XXXVII)

43
 1.19 O O 31
O
LAH
BF3.Et2O

(XXXVIII)
(XXXIX)

1.20 COR 1) LAH / Et2O CH2Br 32

2) HBr, 99 %
(XL) (XLI)
R = H, OH, OCH3

1.21 Br 34
LAH
THF, 90 %
(XLII) (XLIII)

1.22 LAH 35

diglyme
96 % (XLV)
(XLIV)

1.3. Cyclization methods:

In a cyclization process the ring is made by the formation of one new bond in an
intramoleculor fashion. Typical “Building Blocks” for cyclization reactions are as
follows.
O
O
O
Me . . H
. . .
Me
Cl
Me . Me
O H (XLVIII)
(XLVII)
(XLVI)
eg.
. . Me N 2 N

Me2N
. N
. +
NMe2 X-
NH OH2 NMe2
N Ref. 95
(XLIX) O
(L)
Bis-electrophiles

44
 . .
. . . . . NH2 OH
MeNH2 MeNHNHMe PhNHOH
. . .
NH2
(LII) (LIII) (LIV) (LV)
(LI)

Bis-nucleophiles
O O
.
CHO
.

.
NC CN O
.

.
(LVI) NH2
(LVII)
(LVIII)

Nucleophile + electrophile combinations

There is a vast range of simple building blocks, of which only a few are
illustrated. Carbonyl groups are the most common electrophilic components, and
carbanions, nitrogen, oxygen and sulfur act as the most common nucleophilic
components.
Saturated heterocycles can be synthesized by intramoleculor cyclization by using
sodiumhydride, to give three membered ring or four membered ring.36 (Equation 1.23)
Cl Cl Ar1 Cl
Ar1 Ar2
. K2CO3 Cl
N. .
NH . OMs 60 - 78 % Ar2
(LIX) (LX)

Equation 1.23
Or five membered ring. (Equation 1.24)
.. NHOH .
NHBOC n
. HN
OMs ..
MsO n . .
n=1 2 3 NHBOC
(LXI) 60 62 53 % (LXII)

Equation 1.24
Pyrrole derivatives can be prepared by a cyclization method (Paal-Knorr
Synthesis), in which carbonyl components act as electrophiles.37 (Equation 1.25)

45
 Ph CONHPh
Ph CONHPh RCH2NH2

O CHMe2 75.0 % Ar N CHMe2

Ar O
R
(LXIII) (LXIV)

Equation 1.25
The formation of indole derivative by intramolecular cyclization of an N-
acyl-o-toluidine with strong bases at high temperatures38 is known as Madelung indole
synthesis. (Equation 1.26)
-
O NaOEt O H+
R
H2O
N R 360 C o N R N
H H H
(LXVII)
(LXV) (LXVI)

Equation 1.26
Recently some ring systems were created by the addition of bis (nucleophile) +
bis (electrophile) combination.39 (Equation 1.27)

CO2But O N NHBOC
NH2OH.HCl
EtOH, Reflux
O NHBOC
62 % CO2But
(LXVIII) (LXIX)

Equation 1.27
Iodocyclization can be used to prepare heterocycles40 (Equation 1.28).
Intramoleculor aza Wittig reaction is also another useful method for the preparation
variety of heterocycles.41 (Equation 1.29).
I
R
I2, K2CO3

Ts 45 - 82 %
MeO2C R
MeO2C N N
H
(LXX) Ts (LXXI)

Equation 1.28

46
 N3
P(OEt)3, 90 oC N
O

87.0 % Ph Me
Ph O Me O

(LXXII) (LXXIII)

Equation 1.29
Cyclization on to arenes is useful for making some benzo fused
heterocycles.42 (Equation 1.30).
R
R OH
KNH2, NH3

NH2
Br N
H
(LXXIV) (LXXV)

Equation 1.30
43
Example for preparation of heterocycle derivative by radical cyclization,
(Equation 1.31) cyclization of radicals on to imines.44 (Equation 1.32)
H

Br
Bu3SnH

N AIBN, 86 % N
CO2Et

(LXXVII)
(LXXVI)
CO2Et

Equation 1.31

N NH

R
(LXXVIII) (LXXIX) R

Equation 1.32
Another cyclization method for preparation of heterocycles is via ring closing
metathesis (RCM).45 (Equation 1.33)

47
 R4 R4
R3

O O R2

R2 (LXXXI)

(LXXX) R3

Equation 1.33

1.4 Introduction of Oxazoles:

Oxazole (LXXXII) is a five membered heterocycle that contains one oxygen and
one nitrogen as heteroatoms in 1 and 3 positions. The oxazolo moiety is frequently found
to be an integral part of many biologically active molecules and natural products.46 - 64
2
3N O1
4 5
(LXXXII)
Oxazole moiety is also found in fusion with other heterocycles such as pyridines,
piperidines, indoles, quinolines, benzoxazines, pyrimidines, naphthyridines, quinazolines
etc. A number of such structures and their use in different therapeutic areas have been
listed below.
O
O
CN N O N
N OH

Ph Ph O
(LXXXIII) (LXXXIV) (LXXXV)
Atisine Alkaloid 46 Natural Product 47 HIV-1 inhibitor 48

48
 O
O
Ph
O
N
N N
O N NBn
N O
O O H
(LXXXVI) (LXXXVII) (LXXXVIII)
Antitumor agent 49 Antihypertensive agent 50 Anti viral Agent 51
O
O
O
F CO2H S
N
S
N

N N N N O
O
(XC) N O
N
(XC1)
(LXXXIX)
Antibacterial agent 52 Gastric Antisecretory agents 53

O
EtO2C
N
O
N O
N
Ph O
O O O
CO2Et N O
(XCI)
Used in the Treatment (XCII) (XCIII)
of Congenital Disorders 54 Antihypertensive Drug 55
Synthetic biproduct 56
O O
N N N
Ph
N
O OH O N O
(XCIV) (XCV) (XCVII) O
(XCVI)
Synthetic important Synthetic important Synthetic important Synthetic important
product 57 product 58 product 59 product 60
R1 R2
O

N O
O2N Ar
N O N
NH N
(XCVIII) R O Ph
Ph (XCIX) O (C)
(CI) O
Synthetic important Synthetic important Synthetic important (R)-(+) Salsolidine
product 61 product 62 product 63 Starting material 64

49
 O O
N
S
N N
O2N Ph
O
NH2 N O Synthetic importent
Synthetic importent product
product Gastric Antisecretory agents

O O
O
N N
N O O Ph
O O O
O
Used in the Treatment Ph (R)-(+) Salsolidine
of Congenital Disorders Synthetic importent Starting material
product

O O
N O
S
N N
O Ph
N O O N O
(R)-(+) Salsolidine
Gastric Antisecretory agents Starting material
Synthetic biproduct

O O O

S O
N N N
O2N Ph
O O O
N O NH2
Used in the Treatment Synthetic importent
Gastric Antisecretory agents of Congenital Disorders product
EtO2C
N EtO2C
N N
O
Ph O
Ph O
CO2Et Ph
Antihypertensive Drug Synthetic importent CO2Et
product Antihypertensive Drug
O
N O
S N
N
N O
N O
O Synthetic importent
Synthetic biproduct product
Gastric Antisecretory agents

50
Synthesis of some known Oxazoles:
3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile (LXXXIV)47 was
prepared by condensation of phenylglycinol (CII) with glutaraldehyde (CII) in the
presence of potassium cyanide to give compound LXXXIV via piperidine intermediate
(CIII). (Equation – 1.34)
Ph
OH CHO CHO
KCN
NH2
NC N O NC N O
(CII) (CIII)
Ph Ph
(CIV) (LXXXIV)

Equation 1.34
Substituted 2,3-dihydrooxazolo [2,3-a] isoindol-5 (9bH) –one (LXXXV) was
synthesized, starting from substituted 2-aminobenzophenone (CV). Compound CV was
converted to the carboxylic acid (CVI) via diazotization, cyanation and hydrolysis. CVI
was then reacted with 2-aminoethanol followed by cyclization to give the target
compound LXXXV48 in the presence of catalytic amount of toluene-4-sulfonic acid in
toluene. (Equation – 1.35)
O O
O
Ph NH2CH2CH2OH
Ph 1. NaNO2 / NaCN
N
PTSA, Toluene
NH2 2. Conc. H2SO4 COOH
and H2O Ph O
(CV) (LXXXV)
(CVI)
Equation 1.35
Oxazolo[3,2-a][1,8]naphthyridine derivatives (LXXXIX), were synthesized
starting from ethyl 3-(2,6-dichloro-5-fluoro-3-pyridyl)-3-oxopropionate (CVII) which
was treated with carbon disulfide in the presence of sodium hydride in DMA to give
CVIII. The latter on treatment with substituted 2-aminoethanol in the presence of
triethylamine in toluene gives CIX. Compound CIX on cyclization in the presence of
potassium tert-butoxide in dioxane gives the oxazolo derivative CX, which on treatment
with N-methylpiperzine in ethanol gives CXI. Hydrolysis of CXI yields the target
compound LXXXIX52 (Equation – 1.36)

51
 O R
O SMe
F CO2Et O HN
F
SMe F
O
Cl N Cl CS2/ MeI/ NaH CO2Et NH2CH(R)CH2OH
Cl N Cl CO2Et
(CVII) Cl N Cl
(CVIII)
(CIX)

O O O
t F CO2Et F CO2Et F CO2H
BuO-K+

Cl N N O N N N O N N N O
N N
(CX) R R R
(CXI) (LXXXIX)

Equation 1.36
Synthesis of compound XCI was achieved starting from Sesamol (i.e. 5-hydroxy
2,3-benzodioxole, (CXII). Reacting it with carbon dioxide in the presence of sodium
hydride in diglyme gave 3,4-methylenedioxysalisylic acid (CXIII), which was then
treated with 2-aminoethanol in the presence of carbonyldiimidazole in dichloromethane
yielding the amino ethanol derivative CXIV. Compound CXIV was treated with
trimethyl orthoformate and formic acid in chloroform to give the final compound XCI54
(Equation – 1.37)
CDI /
O OH CO / NaH O OH NH2CH2CH2OH
2

O O CHCL3 / 79 %
Diglyme/ 68 % COOH
(CX11) (CXIII)

OH

O OH CH(OMe)3 O O O
O NH O N
HCO2H, CHCl3
51 %
(XCI) O
(CXIV) O

Equation 1.37
Substituted oxazolo [3,2-a] pyridine carboxylate (CXII)55 was synthesized
starting from (2R) or (2S)-1-amino-2-propanol and ethyl acetoacetate to give the chiral

52
enamines CXVIII-R or CXVIII-S, which on reaction with acetyl phenylpropanoate
(CXVII), give oxazolopyridines (CXII-R) or (CXII-S). (Equation – 1.38)

HO O O O O HO
+
+ Me
H2N Me
OEt OEt H2N
(CXVI) (CXV - S)
(XCV - R) (XCVI)

O O
O
RO RO (CXVIII- S)
(CXVIII - R) MeO2C
HN HN
(CXVII)
OH OH

EtO2C N EtO2C N
O O

CO2R CO2R

(CXII - R) (CXII - S)

Equation – 1.38
1.5 References:
01. Herbert C. Brown and Krishnamurthy, S., Tetrahedron,; 1979, 35, 567-607.
02. (a) Bouis, J and Carlet, H., Libegs Ann. Chem, 1976, 124, 23; (b) Schorlemmer,
C., Ibid. 1975, 177, 303; (c) Hill, A. J and E. H. Nason, J. Am. Chem. Soc. 1924,
46, 2236; (d) Clarke, H. T and Dreeger, E. E., Org. Synth. Coll. 1941, 1, 304.
03. Thoms, H and Mannich, C., Ber. Dtsch. Chem. Ges, 1903, 36, 2544.
04. Wiseloge, F. Y and H. Sonneborn, Org. Synth. Coll, 1941, 1, 90.
05. (a) Verly, Bull. Soc. Chim. Fr. 1925, 37, 537. (b) Meerwin, H and Schmidt, R.,
Liebigs Ann. Chem. 1925, 444, 221.
06. Pondorf, W. Z. Angew. Chem, 1926, 39, 138.
07. Buveault, L and Blanck, Bull. Soc. Chim. Fr. 1974, 31, 674.

53
08. Stock, A., Hydrides of Boron and silicon, Cornell University press, Ithaca, New
Yark.
09. Schlesinger, H. I., Brown, H. C., Hoekstra, H. R and Rapp, L. R., J. Am. Chem.
Soc. 1953, 75, 199.
10. Schlesinger, H. I., Brown, H. C. and. Finholt, A. E., J. Am. Chem. Soc. 1953, 75,
205.
11. Finholt, A. E., Bond, Jr, A. C and Schlesinger, H. I., J. Am. Chem. Soc.1947, 69,
1199.
12. (a) Gaylord, N. G. Reduction with complex metal hydrides. Interscience, New
York (1956); (b) Wakar, E. R. H., Chem. Soc. Rev. 1976, 5, 23; (c) Brown, W.
G. Org.React. 1951 6, 469, (1951).
13. W. G. Brown, Org. React. 1951, 6, 469.
14. Ziegler. K., Bond. A. C., Schesinger, H. I. ; J. Am. Chem. Soc. 1947, 69, 1199.
15. Bates. R. B., Buchi. G., Matsuura, T., Shaffer, R. R.; J. Am. Chem. Soc. 1960, 82,
2327.
16. (a) Brown, H. C and Wiseman, P. M.; J. Am. Chem. Soc. 1966, 88, 1458. (b)
Fieser, L. F; Fieser, M.; F F, 1957, 1, 584.
17. Paquette, L. A., Gardlik, J. M., McCullough, K. J., Samodral, R., J. Am. Chem.
Soc. 1983, 105, 7649.
18. Sroog, C. E., Woodburn, H. M., Org. Synth. Coll. 4, 1963, 271.
19. Ishikawa; Mukaima; Bull. Chem. Soc. Jpn. 1978, 51, 2059.
20. Mc Murry, Silvestri, Fleming, J. Org. Chem. 1978, 43, 3249.
21. Larak, Text book functional group transformations: 1989, 151-152.
22. Wang, Sukenik, J. Org. Chem. 1985, 50, 5448.
23. Latif, Mishriky,Zeid J. Prakt. Chem. 1970, 312, 421.
24. Photis, Paquette, J. Am. Chem. Soc. 1974, 96, 4715.
25. Bailey, Marktscheffel, J. Org. Chem. 1960, 25, 1797.
26. (a) Bonner; J. Am. Chem. Soc. 1951, 73, 2872. (b) Corey, E. J and Achiwa;
J. Org. Chem. 1969, 34, 3667.

54
27. Pinder, Synthesis, 1980, 425-452.
28. Brown, Tsukamols, J. Am. Chem. Soc. 1964, 86, 1089.
29. Hassner, Mathews, J. Am. Chem. Soc., 1969, 91, 5046.
30. Mc Murry, Hoj, J. Org. Chem. 1975, 40, 3797.
31. (a) Pettit, Ghatak, Green, J. Org. Chem.,1961, 26, 1685. (b) Pettit; J. Org. Chem.
1960, 25, 875.
32. Bilger; Royer; Synthesis, 1988, 902.
33. Rickborn, B and Quartucci, J., Pettit, J. Org. Chem. 1964, 29, 3185.
34. Brown, H. C and Krishnamurthy, S., J. Org. Chem. 1969, 34, 3918.
35. Mangoon, E. F and Slaugh, L. H., Tetrahedron, 1967, 23, 4509.
36. Norbert De Kimpe, Altermann, W., J. Org. Chem., 1998, 63 ,6-11.
37. Kelvin L. B, Donald E. Butler., Tetrahedron Lett., 1992, 33,(17), 2283.
38. M.Madelung, Ber., 1912, 45, 1128.
39. Adlington, Baldwin., J. Chem. Soc. (P1), 2000, 303.
40. Knight., Synthetic letters, 1988, 731.
41. Hisato Takeuchi, Shun-ichi Yanagida.; J. Org. Chem., 1989, 54 ,431.
42. Peter Stanetty and Barbara Krumpak; J. Org. Chem., 1996, 61, 5130.
43. Eun Lee, Tae Seop Kang, Beom Jun Joo; Tetrahedron Lett., 1995, 36, 417-420.
44. Aldabbagh and Bowman; Org. Synth., 1997, 4, 267.
45. Sukbok Chang, Robert H. Grubbs J. Org. Chem., 1998, 63 ,864.
46. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496.
(b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761.
(c) Pellettier, S. W., Parthasarathy, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777.
(d) Naresh V. Mody, Pellettier, S. W., Tetrahedron; 1978, 34, 2421. (e) Pellettier,
S. W., Naresh V. Mody, Haridutt K. Desai, Janet Finer-Moore, Jacek Nowacki,
and Balawant S. Joshi. J. Org. Chem., 1983, 48 (11), 1787.
47. (a) Lue Guerrier, Jacques Royer, David S. Grierson and Henri-Philippe Husson.
J. Amer. Chem. Soc. 1983, 105, 7754. (b) Bonin M. Royer J. Grierson D.S and
Husson H. P., Tetrahedron Lett., 1986, 27 (14), 1569. (c) Jean-Charles Quirion,

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 David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron
Letters; 1988, 29 (27), 3311. (d) Naoki YYamazaki, Toshimasa Ito and Chihiro
Kibayashi, Syn. Lett., 1999, 1, 37. (e) Teran, J. L. Gnecco, D. Galindo, A. Juarez,
J. Bernes, S. and Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357. (f) Luis
F. Roa, Dino Gnecco, Alberto Galindo, Jorge Juarez and Sylvan Bernes,
Analytical Sciences, 2003, 19, 1223. (g) Mercedes Amat, Nuria Llor, Carmen
Escolano, Marta Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron
Asymmetry; 2003, 14, 293.
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Hans, S.; Ulrike, L.; Herbert, L. J. Med. Chem. 1993, 36 (17), 2526.
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Sakamoto, T., Sugimoto, M., Tabata, K.; JP 1989242587.
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Manuel Medarde, Lourdes Moran del Prado and Arturo San Feliciano,
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57
58
2.1 INTRODUCTION:
The oxazolo moiety is found in many biologically active compounds and
synthetically important intermediates some of which were mentioned earlier in the first
chapter.
2.2 Present Work:
A survey of literature revealed that different oxazole derivatives showed various
types of pharmacological activities. However, not much work has been done on the
synthesis of fused oxazolo compounds. It was considered desirable to study the synthesis
of oxazolothiazines. It is conceivable that these oxazolothiazines can be synthesized from
2-aminothiophenol by ring closure with chloroacetic acid to obtain benzothiazines in the
first step. These benzothiazines can be used as building blocks for the synthesis of fused
oxazolo ring units.
2.3 Results and Discussion
Commercially available 2-aminothiophenol (1) was treated with chloroacetic
acid in the presence of sodium hydroxide to obtain 1,4-benzothiazine-3(4H)-one (2a, i.e.
24, R = R1 = H) in 76 % yield (equation – 2.1). 2a is a compound known1 in literature.
However, it was further characterized in the present work by spectral and analytical data.
Thus, its IR (KBr) spectrum (Fig. 2.1) showed a peak at 3440 cm-1, which may be
–1
assigned to –NH- stretching vibration, and a strong peak at 1663 cm in the carbonyl
region which may be assigned to the amide carbonyl grouping. Its 1H NMR (in CDCl3)
showed (Fig. 2.2) signals at δ 8.87 (bs, 1H, D2O exchangeable, amide proton), three
aromatic signals at 7.33 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.0 Hz,
2H), 6.88 (d, J = 7.8 Hz, 1H) and S – CH2 at 3.43 (s, 2H). Its mass spectrum (Fig. 2. 3)
showed the molecular ion peak at 166 (M+ +1, 100 %), as base peak.
SH ClCH2CO2H, NaOH, Water S

100 °C, 6.0 h, 76.0 %

NH2 N O
H
(1) (2a)
Equation – 2.1

59
 In addition to the method given above, several other methods have also been
reported in the literature for the preparation of benzothiazinones. Thus, for example,
condensation2 of 2-aminothiophenol and ethyl 2-halo-2-alkylacetate at 150 °C, or the
addition of 2-bromo-2-alkylacetic acid esters in the presence of sodium ethoxide to
ethanol (multistep), or in the presence of glacial acetic acid and hydrochloric acid, 3 from
2-(2-nitro-phenylsulfanyl)-propionic acid4 at 240 °C for 2.0 hrs, from 2-aminobenzothiol
5 °
and 2-haloethyl acetate in DMF at 90 – 95 C, from 2-bromomethyl – 4H-
benzo[1,4]thiazine-3-one in the presence of tributyltin hydride and AIBN in benzene,6 by
reaction7 of 2-aminobenzothiol and 2-bromoalkylacetic acid at 125 °
C, 2-
8
aminobenzothiol and 2-chloroalkylacetic acid amide in the presence of potassium
carbonate in acetone for 16.0 hrs, from 2-(1-chloroethyl)-benzothiazole in presence of
potassium tert butoxide in isopropanol,9 from bis-(2-nitro phenyl)-disulfane in the
presence10 of samarium (II) iodide in THF (two steps), from 2,2-dimethyl-2,3-dihydro-
benzothiazole in presence of potassium carbonate,11 from 2-chloro-N-(2-
methylsulfanylphenyl)-2-aryl/alkyl acetamide at 195 °C under pressure,12 from 2,2,2-
trichloro-1-aryl-ethanol & 2-amino benzothiol in presence of KOH, methanol,13 from 2-
acetoxy-4H-benzo[1,4]thiazine-3-one in presence of trifluroacetic acid,14 from 2,2I-
disulfonediyl-bis-aniline in presence of sodium hydride in DMF15 from 2-chloro-4H-
benzo[1,4]thiazin-3-one with arenes in presence of aluminum chloride.16 All these
reported methods involve more than one step, which are environmentally harmful with
fairly long reaction times. Therefore, there is always need for the development of an
improved or alternative procedure for the synthesis of substituted benzothiazines.

Table – 2.1: Some known methods to prepare compounds 2a - h

S.No. Reactant Product Conditions Ref:
1. SH S CH3CH(Br)COOH, 2
Zuletzt, 150 oC
NH2 N O
H

60
2. SH S 1. CH3CH(Br)COOEt, in 3
AcOH
NH2 N O
H 2. Con. HCl
3. HO2C R S 240 oC, 2.0 hrs 4
S ii) NaBH4, Pd-C, Dioxane,
N O
H Water, 72 hrs
NH2
4. SH S R RCH(X)COOEt 5
DMF, 90 – 95 oC
NH2 N O
H R = CH3, Ph
5. S S (Bu)3SnH, AIBN, 6
Br
Benzene, Reflux
N O
H N O
H
6. SH S CH3CH(Br)COOH 7
120 – 125 oC
NH2 N O
H
7. SH S CH3CH(Cl)CONH2 8
K2CO3, Acetone, Refluxed for
NH2 N O
H 16.0 hrs
8. N S tBuO K 9
tBuOH, 64 %
S Cl N O
H
9. O2N S R 1) SmI, THF 10
S 2) RCH(Br)COOH
S
N O
H R = CH3, Ph
NO2
10. H S R K2CO3, Ether 11
N

S N O
H

61
11. SMe S Ph 195 °oC, 12

NH Pressure
N O
O Cl H
12. SH S Ph KOH, Methanol, 2,2,2 – 13
trichloro-1-phenyl
NH2 N O
H
13. S OAc S Ph Benzene, TFA, Refluxed 14

N O N O
H H
14. H2N S Ph PhCH2CO2Et, NaH, DMF, 100 15
°o
S C, 86.0 %
S
N O
NH2 H

15. S OAc S Ar ArH, AlCl3, 10 min, 16

50 oC
N O N O
H H
16. SH S CH3CH(Cl)CO2H 17
NaOH, Water
NH2 N O
H Refluxed for 4.0 hrs
17. SH S Ph PhCH(Br)COOH, 18
Zuletzt, 150 oC
NH2 N O
H
18. SH S Ph 1) PhCH(Br)COOMe, KI 19
2) NaOMe, C6H6, 80 ° oC
NH2 N O
H
19. SH S Ph 1) PhCH(Cl)COOH, 20
NaOH.
NH2 N O
H

62
 20. S CO2R S NaBH4, Pd-C, Dioxane, 21
Water, 72 hrs
NO2 N O
H
21. SH S (CH3)2C(Br)COOH 22
KOH, EtOH
NH2 N O
H
22. SH S (CH3)2C(X)COOEt 23
1) K2CO3
NH2 N O 2) Con. HCl
H
23. S S CH3I 24
LDA
N O N O
H H

Keeping this in view, two simple but new methods were developed for the
synthesis of benzothiazinones. In the first method, 2-aminothiophenol was reacted with
°
ethyl bromoacetate in aqueous sodium hydroxide at 80 C for 1.0 hr, which resulted in the
formation of 2a in 94 % yield. In the other method, 2-aminothiophenol was treated with
ethyl 2-bromoacetate in the presence of microwaves using microwave oven for 5.0 min,
to yield 2a in 80 % yield. (Equation 2.2)

63
 BrCH2CO2Et, NaOH,

Water, 80 oC, 1.0 hr, 94 % S

SH

N O
NH2 H
(1) BrCH2CO2Et, NaOH, (2a)

Water, MW, 4 - 5 min, 80 %

Equation – 2.2

Substituted 1,4-benzothiazine-3(4H)-ones (2) were prepared in the above two

methods and also all derivatives 2a-h were prepared simultaneously in one lot by using
parallel synthesizer. The structures for these products were assigned on the basis of
analogy and on the basis of analytical and spectral data. (Table –2.2)

BrRR1CCO2Et, NaOH, Water, R

SH S
MW, 4 - 5 min, Parallel
R1
NH2 (7 Reactions at a time) 65 - 89 %
N O
H
(1) (2a-h)

Equation – 2.3

Table –2.2: Synthesis of 2 (a-h) from 1 and its data

1
H NMR (200 MHz, CDCl3); IR (KBr) / cm-1.
IR: 3196(-NH- Band), 1665(- CO - Stretching);
1
H NMR: (CDCl3) δ 9.25 (bs, 1H, D2O
Exchangeable, NH), 7.29 (d, J = 7.52 Hz, 1H),

64
7.15 (d, J = 7.52 Hz, 1H), 7.03 (t, J = 7.52 Hz,
1H), 6.93 (t, J = 7.52 Hz, 1H), 3.60 – 3.50 (q, J =
6.98 Hz, 1H, SCH), 1.49 (d, J = 6.99 Hz, 3H,
SCHCH3); Mass: 180 (M++1, 100 %).
IR: 3422(-NH- Band), 1667 (- CO - Stretching);
1
H NMR: (CDCl3) δ 10.57 (bs, 1H, D2O
Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, ),
7.18 (d, J = 7.81 Hz, 1H, ), 7.00 (d, J = 7.82 Hz,
2H, ), 1.34 (s, 6H, C(CH3)2; Mass: 194 (M+ +1,
100 %).
IR: 3195 (-NH- Band), 1662 (- CO - Stretching);
1
H NMR: (CDCl3) δ 10.56 (bs, 1H, D2O
Exchangeable, NH), 7.31 (d, J = 7.81 Hz, 1H, ),
7.16 (d, J = 7.81 Hz, 1H, ), 7.00 – 6.94 (m, 2H, ),
3.45 – 3.38 (dd, J = 5.86 & 8.31 Hz, 1H, SCH),
1.81 – 1.70 (m, 1H, SCHCH2CH3), 1.54 – 1.39
(m, 1H, SCHCH2CH3), 0.96 (t, J = 7.33 Hz, 3H,
SCHCH2CH3); Mass: 194 (M++1, 100 %).
IR: 1670 (- CO - Stretching); 1H NMR: (CDCl3)
δ 10.56 (bs, 1H, D2O Exchangeable, NH), 7.31
(d, J = 7.81 Hz, 1H), 7.16 (m, 1H, ), 7.00 – 6.94
(m, 2H), 3.52 – 3.45 (d, J = 7.81 Hz, 1H, SCH),
1.77 – 1.67 (m, 1H, SCHCH2CH2), 1.52 – 1.33
(m, 3H, SCHCH2CH2 & SCHCH2CH2), 0.89 –
0.83 (t, J = 7.33 Hz, 3H, SCHCH2CH3); Mass:
208 (M++1, 100 %).
IR: 3412 (-NH- Band), 1685 (- CO - Stretching);
1
H NMR: δ 9.17 (bs, 1H, D2O Exchangeable,
NH), 7.30 (d, J = 7.82 Hz, 1H), 7.16 (t, J = 7.81

65
Hz, 1H), 6.99 (t, J = 7.33 Hz, 1H), 6.88 (d, J =
7.81 Hz, 1H), 3.11 (d, J = 8.79 Hz, 1H, SCH),
1.97 – 1.90 (m, 1H, SCHCH(CH3)2), 1.05 (d, J =
6.83 Hz, 6H, SCHCH(CH3)2); Mass: 208 (M++1,
100 %).
IR: 1663 (- CO - Stretching); 1H NMR: (CDCl3)
δ 9.10 (bs, 1H, D2O Exchangeable, NH), 7.30 (d,
J = 7.33 Hz, 1H), 7.17 (t, J = 7.33 Hz, 1H), 7.00
(t, J = 7.81 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H),
3.39 (t, J = 7.08 Hz, 1H, SCH), 1.93 – 1.84 (m,
1H, SCHCH2), 1.66 – 1.50 (m, 1H, SCHCH2),
1.25 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.82
(m, 3H, SCHCH2 (CH2)4CH3; Mass: 250 (M+
+1, 100 %).
IR: 3430 (-NH- Band), 1677 (- CO - Stretching);
1
H NMR (DMSOd6, 200 MHz): δ 10.43 (bs, 1H,
D2O Exchangeable, NH), 7.33 – 7.26 (m, 6H),
7.17 – 7.09 (m, 1H), 7.02 – 6.91 (m, 2H), 4.62 (s,
1H, Ph CH); Mass: 242 (M+ +1, 100 %), 241
(M++1, 20 %).

66
 1,4-benzothiazine-3(4H)-one (2a) was treated with ethyl 2-bromoacetate in the
presence of potassium hydroxide in acetone at 60 °C for 30 min. Processing of the
reaction mixture gave a product which was found to be 3a (Equation 2.8) by comparison
of its physical constants with those reported in literature.25 Compound 3a has been further
characterized by spectral methods. Its IR spectrum showed no absorption above 3000 cm-
1
indicating absence of –NH- grouping. However, the IR spectrum showed (Fig. 2.4) two
strong sharp bands, one at 1744 cm-1 and the other at1680 cm-1. The former has been
assigned to ester carbonyl grouping and the other assigned to amide carbonyl grouping.
Thus, its 1H NMR spectrum (Fig. 2.5) displayed signals at δ 7.38 (d, J = 6.84 Hz, 1H, Ar
- H), 7.21 (t, J = 7.33 Hz, 1H, Ar - H), 7.05 (d, J = 7.33 Hz, 1H, Ar - H), 6.87 (d, J = 8.30
Hz, 1H, Ar - H), 4.65 (s, 2H, N-CH2), 4.27 (q, J = 7.33 Hz, 2H, O – CH2), 3.46 (s, 2H, S
– CH2), 1.28 (t, J = 7.33 Hz, 3H, O – CH3) while the mass spectrum showed (Fig. 2.6)
m/z 252 (M++1, 100 %) and other peak at 206 (10 %) etc.

S
S KOH / BrCH2CO2Et

o N O
N O acetone, 60 C, 30 min
H (3a) OEt
(2a)
O
Equation – 2.4

Subsequently, it has been found that 3a could also be prepared from 2a by

reaction in DMF using K2CO3 as base at 80°°C for 12 hrs. (Equation 2.9)
S
S K2CO3, BrCH2CO2Et

o N O
N ODMF 80 C, 12 hrs
H OEt
(3a)
(2a)
O
Equation – 2.5

40
2-Substituted-3,4-dihydro-3-oxo-2H-1,4-benzothiazine–4-acetic acid ethyl esters could
also be prepared using the above method. Structures of all products (3a – h) have been
assigned on the basis of analogy and on the basis of spectral & analytical data (Table –
2.3).
S R
S R
K2CO3, BrR1CHCO2Et
N O
N O DMF 80 0C, 12.0 hrs
H OEt
R1
(2a - h) (3a - j) O

Equation – 2.6
Table – 2.3: Synthesis of 3 (a-h) from 2 (a-j) and Data:
1
Structure H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

IR1732 (ester- CO – Stretching), 1678 (amide- CO – Stretching); 1H

NMR: δ 7.37 (d, J = 7.32 Hz, 1H), 7.21 (t, J = 7.81 Hz, 1H ), 6.86
(d, J = 8.31 Hz, 1H), 4.75 – 4.54 (dd, J = 17.58 & 22.96 Hz, 2H,
NCH2), 4.30 – 4.19 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.58 – 3.50 (q,
J = 7.32 Hz, 1H SCHCH3), 1.47 (d, J = 6.84 Hz, 3H, SCHCH3), 1.28
(t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 266 (M+ +1, 100 %).
IR: 1750 (ester- CO – Stretching), 1672 (amide- CO – Stretching);
1
H NMR: δ 7.36 (d, J = 7.82 Hz, 1H), 7.24 (t, J = 7.32 Hz, 1H),
7.05 (t, J = 7.33 Hz, 1H ), 6.83 (d, J = 8.30 Hz, 1H), 4.66 (s, 2H,
NCH2), 4.31 – 4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 1.47 (s, 6H),
1.29 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 280 (M+ +1, 100 %).
IR: 1749(ester- CO – Stretching), 1674 (amide- CO – Stretching).
1
H NMR: δ 7.38 (d, J = 7.33 Hz, 1H), 7.23 (t, J = 7.81 Hz, 1H),
7.04 (t, J = 7.32 Hz, 1H), 6.83 (d, J = 8.31 Hz, 1H), 4.90 (d, J =
17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.25 (q, J

41
= 7.30 Hz, 2H, OCH2CH3), 3.39 (t, J = 7.57 Hz, 1H, SCHCH2CH3),
2.00 – 1.86 (m, 1H, SCHCH2CH3), 1.68 - 1.54 (m, 1H,
SCHCH2CH3), 1.29 (t, J = 7.33 Hz, 3H, OCH2CH3), 1.05 (t, J = 7.32
Hz, 3H, SCHCH2CH3); Mass: 280 (M+ +1, 100 %).
IR: 1748 (ester- CO – Stretching), 1674 (amide- CO – Stretching);
1
H NMR: δ 7.37 (d, J = 7.33 Hz, 1H), 7.23 (t, J = 7.81 Hz, 1H),
7.04 (t, J = 7.81 Hz, 1H), 6.83 (d, J = 7.82 Hz, 1H), 4.88 (d, J =
17.09 Hz, 1H, NCH2), 4.45 (d, J = 17.58 Hz, 1H, NCH2), 4.31 –
4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.47 (t, J = 7.33 Hz, 1H,
SCH), 1.89 – 1.83 (m, 1H, SCHCH2), 1.65 – 1.42 (m, 3H, SCHCH2
& SCHCH2CH2), 1.29 (t, J = 7.32 Hz, 3H, OCH2CH3), 0.91 (t, J =
6.83 Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+ +1, 100 %).
IR: 1748 (ester- CO – Stretching), 1674 (amide- CO – Stretching);
1
H NMR: δ 7.36 (d, J = 7.33 Hz, 1H), 7.25 (t, J = 7.81 Hz, 1H),
7.02 (t, J = 7.81 Hz, 1H), 6.80 (d, J = 7.82 Hz, 1H), 5.09 (d, J =
17.58 Hz, 1H, NCH2), 4.30 – 4.17 (q, J = 7.33 Hz, 2H, OCH2CH3),
3.10 (d, J = 9.77 Hz, 1H), 2.90 (d, J = 14.65 Hz, 1H), 1.87 – 1.75
(m, 1H, SCH), 1.28 (t, J = 7.33 Hz, 1H, OCH2CH3), 1.03 (t, J = 6.83
Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+ +1, 100 %).
IR: 1749 (ester- CO – Stretching), 1673 (- CO - Stretching); 1H
NMR: (CDCl3) δ 7.36 (d, J = 7.33 Hz, 1H), 7.25 (t, J = 7.33 Hz,
1H), 7.02 (t, J = 7.81 Hz, 1H), 6.82 (d, J = 7.81 Hz, 1H), 4.44 (d, J =
17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.29 –
4.18 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.43 (t, J = 7.08 Hz, 1H,
SCH), 1.91 – 1.81(m, 1H, SCHCH2), 1.70 – 1.30 (m, 1H, SCHCH2),
1.27 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.84 (m, 3H, SCHCH2
(CH2)4CH3); Mass: 236 (M+ +1, 100 %).
IR: 1746 (ester- CO – Stretching), 1673 (amide- CO – Stretching);
1
H NMR: δ 7.43 – 7.35 (m, 2H, ), 7.31 – 7.17 (m, 5H), 6.98 (t, J =

42
7.32 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H), 4.97 (d, J = 17.58 Hz, 1H,
NCH2CO), 4.77 (s, 1H, SCHPh), 4.50 (d, J = 17.58 Hz, 1H,
NCH2CO), 4.34 – 4.23 (q, J = 7.33 Hz, OCH2CH3), 1.31 (t, J = 7.33
Hz, 3H, OCH2CH3); Mass: 328 (M+ +1, 100 %).
IR: 1739 (ester- CO – Stretching), 1676 (amide- CO – Stretching).
1
H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23 (d, J = 7.79 Hz, 1H, ),
7.17 – 6.97 (m, 2H), 5.15 – 5.08 (dd, J = 5.37 & 9.94 Hz, 1H, NCH
CO), 4.28 – 4.14 (m, 2H, OCH2CH3), 3.41 (s, 2H, SCH2 ), 2.27 –
2.17 (m, 1H, NCHCH2CH3), 2.11 – 1.90 (m, 1H, NCHCH2CH3),
1.23 (t, J = 7.25 Hz, 3H, OCH2CH3), 0.82 (t, J = 7.25 Hz, 3H,
NCHCH2CH3); Mass: 281 (M+ +2, 15 %), 280 (M+ +1, 100 %), 234
(10 %).
IR: 1740 (ester- CO – Stretching), 1678 (amide- CO – Stretching);
1
H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23(d, J = 8.06 Hz, 1H), 7.17
– 6.97 (m, 2H), 5.25 – 5.18 (dd, J = 5.38 & 9.14 Hz, 1H, NCHCO),
4.28 – 4.16 (m, 2H, OCH2CH3), 3.40 (s, 2H, SCH2), 2.16 – 2.00 (m,
2H, NCHCH2), 1.27 – 1.16 (m, 5H, OCH2CH3 & NCHCH2CH2),
0.82 (t, J = 7.25 Hz, 3H, OCH2CH3); Mass: 295 (M+ +1, 30 %), 294
(100 %) and 248 (10 %).

43
 It was considered desirable to study the effect of substituents in the cyclization
reaction yielding oxazolothiazines. All the compounds reported in Table 2.4 contain
hydrogen/alkyl groups at R1. It would be interesting to study the course of cyclisation if
R1 is substituted with aryl moiety having electron releasing / withdrawing groups.
Therefore, 3k and 3l, needed to build oxazolothiazines were prepared as follows:-
Commercially available phenylacetic acid (4) was refluxed in absolute ethanol in the
presence of conc. H2SO4 to give 5, which with N-bromosuccinimide in the presence of
catalytic amount of benzoyl peroxide gave 6.26 The latter was then reacted with 1,4-
benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate to give 3k (Scheme
2.1).

CO2H CO2Et Br CO2Et

Ethanol, NBS(1.05 eq),
Con.H2SO4 (cat.), Benzoylperoxide (Cat)
8 0 °C, 4.0 hrs CCl4, 3.0 hrs
(4) (5) (6)

Br CO2Me

S S
K2CO3, DMF
+
N O 80 °C, 12.0 hrs N O
H
(6) (2a) (3k)
Ph CO2Me
Scheme – 2.1
The structure of the compound 3k is supported by its spectral and analytical
data. Thus, its IR (KBr) showed peaks at 1748 (ester- CO – Stretching), 1676 (amide-
CO – Stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.41 – 7.28 (m, 7H,
ArH), 7.10 – 6.95 (m, 2H, ArH), 6.23 (s, 1H, PhCH), 3.83 (s, 3H, COOCH3), 3.53 (s,
2H, SCH2). Its mass spectrum showed peaks at m/z 313 (M+ +1, 25 %), 281 (100 %),

54
 226 (60 %), 211 (75 %), 121 (60 %). Elemental Analysis: Mol. F: C17H15NO3S, Cal. C:
65.160, H: 4.829, N: 4.473; Experimental, C: 64.685, H: 5.032, N: 4.236.

S S
S (i) Morpholine, Sulfur,
AcCl, AlCl3, 100 °C, 12.0 hrs SOCl2, Ethanol
CH2Cl2,
(ii) Aq. HCl, 100 °C, 0 - 80 °C, 6.0hrs
0 - r.t, 3.0 hrs 12.0 hrs
(7)
O HO2C (9)
(8)
O O
S S S
O NBS(1.05 eq) O
Oxone, Acetone Benzoylperoxide (Cat),

water, r.t., 6.0 hrs CCl4, 3.0 hrs

EtO2C EtO2C EtO2C Br

(10) (11) (12)

O S
S
O
S
K2CO3, DMF, N O
+ O
80 °C, 12.0 hrs
N O
H
O
EtO2C Br S
(10) O O (3l)
(2a)

Scheme – 2. 2

In order to prepare the intermediate 3l, thioanisole (7) was treated with acetyl
chloride in the presence of aluminum chloride to obtain 8,27 which on Willgerodt reaction
using morpholine and sulfur gave 4-methylthiophenylacetic acid (9).28 Compound 9 was
converted to ethyl ester 10 in the presence of thionyl chloride in ethanol.29 The
methylthio group of 10 was oxidized with oxone to obtain 4-methylsulfonylphenylacetic

55
acid (11). 11 was treated with N-bromosuccinimide in the presence of benzoyl peroxide
as a catalyst to give Bromo-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (12)30
which was reacted with 1,4-benzothiazine-3(4H)-one (2a) in the presence of potassium
carbonate to yield 3l. (Scheme 2.2)

The structure of the compound 3l is supported by its spectral and analytical data.
Thus, its IR (KBr) showed peaks at 1742 cm-1 (ester carbonyl stretching) and at 1664 cm-
1
(amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.92 (d, J =
8.31 Hz, 2H, ArH), 7.57 (d, J = 8.31 Hz, 2H, ArH), 7.44 – 7.40 (m, 1H, ArH), 7.33 – 7.14
(m, 2H, ArH), 7.11 – 6.97 (m, 2H, ArH), 6.89 – 6.82 (m, 1H, ArH), 6.16 (s, 1H, ArCH),
4.28 – 4.21 (m, 2H, CO2CH2CH3), 3.43 (s, 2H, SCH2), 3.04 (s, 3H, SO2CH3), 1.19 (t, J =
7.33 Hz, 3H, CO2CH2CH3). Its mass spectrum showed peaks at m/z 405 (M+ +1, 30 %),
359 (100 %), 304 (95 %), 165 (70 %) and 136 (80 %).

COOH CO2Et Br CO2Et

Thionyl chloride NBS(1.05 eq)
Ethanol Benzoylperoxide (Cat)

0 - 80 oC, 6.0 hrs CCl4, 3.0 hrs

OMe OMe OMe
(13) (14) (15)

S
Br CO2Et

S K2CO3, DMF N O
+ O
80 oC, 12.0 hrs
N O
H O
OMe MeO
3m
(15) (2a)
Scheme – 2. 3

56
 To prepare 3m, commercially available 4-methoxyphenylacetic acid (13), was
esterified with thionyl chloride in ethanol followed by bromination with N-
bromosuccinimide in the presence of benzoyl peroxide as catalyst to obtain ethyl 2-
bromo-2-(4-methoxyphenyl)acetate (15).31 compound 15 was reacted with 1,4-
benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate as base in dry
dimethylformamide resulting in ethyl 2-(4-methoxyphenyl)-2-(3-oxo-3,4-dihydro-2H-
benzo[b][1,4]thiazin-4-yl) acetate (3m). (Scheme – 2.3) The structure of the compound
3m is supported by its spectral and analytical data. Thus, its IR (KBr) showed peaks at
1742 cm-1 (ester carbonyl stretching) and at 1674 cm-1 (amide carbonyl stretching). Its 1H
NMR (in CDCl3) showed signals at δ 7.38 – 7.30 (m, 1H, ), 7.23 (d, J = 9.13 Hz, 2H, ),
7.05 – 6.90 (m, 2H, ), 6.83 (d, J = 8.86 Hz, 2H, ), 6.17 (s, 1H, Benzylic H), 4.31 – 4.18
(m, 2H), 3.77 (s, 3H), 3.50 (s, 2H), 1.20 (t, J = 7.3 Hz, 3H). Its mass spectrum showed
peaks at m/z 358 (M+1, 10 %), 357 (M+, 10 %), 193 (100 %).

Reductions with Lithium Aluminum Hydride (LAH):

Treatment of 3a with 1.1 eq. of LAH in THF45 followed by simple processing
gave a product, which was obtained as a syrupy liquid. The compound was found to be
homogenous on TLC. Its IR spectrum (Fig. 2.7) (Neat) did not show any diagnostic peaks
due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed signals (Fig. 2.8) at δ 7.14
(t, J = 7.81 Hz, 1H, Ar - H), 7.03 (d, J = 7.81 Hz, 1H, Ar - H), 6.66 (t, J = 7.32 Hz, 1H,
Ar - H), 6.52 (d, J = 8.30 Hz, 1H, Ar - H), 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H, O
CH CH2), 4.3 – 4.21(m, 1H, O CH2), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H, O CH2),
3.5 (m, 2H, N CH2), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H, S CH2), 2.70 – 2.60 (dd,
J = 9.28 and 11.72 Hz, 1H, S CH2). Its mass spectrum showed peaks (Fig. 2.9) at m/z194
(M+ +1, 100 %)and other peaks at 162 (30 %), 136 40%). Elemental Composition
(EIHRMS) Cal Mass: 193.05613, Exp. Mass: 193.056520, DBE: 6, C: 10, H: 11, N: 1,
O:1, S:1. Based on this data, the product was assigned as 1,2,3a,4-
tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine (16a). (Equation – 2.7)

57
 S
S
LAH
N O THF, 0 °C - r.t
N O
OEt 1 hr
(3a)
O (16a)
Equation – 2.7
It may be mentioned here that the product of LAH reduction in the above
reaction was expected to be 17, which was, however, not found to be formed. (Equation
– 2.8)
S
S
LAH
N X
O N
THF, 0 - r.t OH
OEt
1 hr
(3a)
O (17)
Equation – 2.8

The above reaction of 3a yielding 16a seems to be general one. It has been
extended to other N-substituted benzothiazinones (3) yielding (17). (Equation – 2.9)

S R
S R
LAH
N O THF, 0 °C - r.t
N O
OEt 1.0 hr
R1
R1
O
(3a -m) (16a- m)
Equation – 2.9
Structure confirmation: To further confirm the structure of the product 16 its
single crystal X-ray diffraction study was undertaken. For single crystal X-ray diffraction
study to be carried out, it is essential that the compound should be solid crystalline
substance as a first pre-requisite. Since the product 16a obtained in the present study was

58
a syrupy liquid and others being low melting solids, nitration of 16a was prepared hoping
that the nitro derivative of 16a would be a solid amenable to X-ray studies. Thus,
nitration of 16a with nitric acid in acetic anhydride yielded a product, which was
assigned 7-nitro-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine (18)
structure on the basis of its spectral data and analytical data.
S HNO3 O2N S
Ac2O
N O N O
16a) (18)
Equation –2.10

5 4
6 Hb
O2 N 9 S
3 Ha
2 H
7
8 10 1
N O 13
11
Ha
12 Hb
Hb Ha
(18)
Thus, its IR (KBr) spectrum (Fig 2.10) showed peaks indicating absence of any
specific functional groups; Its 1H NMR (400 MHz, in CDCl3) showed signals (Fig 2.11)
at δ 5.07 (dd, J = 8.40 & 4.40 Hz, 2H, protons from carbon 2), Ha is 3.62 (dd, J = 10.0 &
8.40 Hz), 3 Hb is 3.19 (dd, J = 10.0 & 8.40 Hz), 8.04 (d, 2.4 Hz, 1H, from 7 position),
7.94 (dd, J = 8.80 & 2.40 Hz, 1H, from 8 position), 6.43 (d, J = 8.80 Hz, 1H), 3.60 (dt, J
= 7.60 & 8.80 Hz, 11Ha), 3.52 (ddd, J = 7.60, 6.40 & 2.80 Hz, 11Hb) and 4.36 (dt, J =
6.4 & 8.80 Hz, 12 Ha), 4.09 (ddd, J = 7.60, 6.40 & 2.80 Hz, 12Hb). In table 2.5 are
explained the Carbon 13, COSY and gHSQC.
In the steady state 1D nOe experiment on irradiation, the C-8 proton at 6.57
ppm showed the enhancement of signals at 3.7 and 3.5 ppm corresponding to C-11 Ha
and Hb protons respectively. From these results, aromatic C-8 proton was fixed at 6.57

59
ppm. The splitting of C-8 proton as doublet is due to coupling with C-7 proton. Hence,
the position of nitro group is assigned at C-6.

Table –2.4 Carbon 13, COSY and gHSQC of compound 18

13
Position COSY C DEPT gHSQC
(Fig: 2.15) (Fig: 2.12) (Fig: 2.13) (Fig: 2.14)
2 (3Ha, 3.36) 85.82 CH (1H, 4.88)
(3Hb, 4.61)
3 (2H, 4.88) 26.82 CH2 (2Ha, 3.36)
(2H, 4.88) (2Hb, 4.61)
5 123.39 CH (5H, 7.78)
6 145.62
7 (8H, 6.57) 123.39 CH (7H, 7.87)
8 (7H, 7.87) 110.27 CH (8H, 6.57)
9 115.09
10 137.61
11 (12Ha, 4.12) 46.32 CH2 (11Ha, 3.49)
(12Hb, 4.32)
(11Hb, 3.72)
(12Ha, 4.12) (11Hb, 3.72)
(12Hb, 4.32)
(11Hb, 3.49)
12 (11Ha, 3.49) 65.26 CH2 (12Ha, 4.12)
(11Hb, 3.72)
(12Hb, 4.32)
(11Ha, 3.49) (12Ha, 4.32)
(11Hb, 3.72)
(12Hb, 4.12)

60
 The possible major fragmentation pattern for 18 is deduced from Chemical
ionization mass spectrum (C I M S) is shown below (Fig. 2.16) Scheme – 2.4. And from
thermal analysis melting point is 160.04 °C (Fig. 2.17).
O2N S + O2N
+
- 46 +
- 32
N O N O
-S - NO2 N O
(19)
(18) (20)

m/z = 239 M+1, 100 % m/z = 207, M+, 10 % m/z = 161, 2.0 %

- 25 +
- 14 +
- CH2CH2 N OH
H -N OH
(22)
(21)

m/z = 136, 8.0 % m/z = 122, 2.0 %

Scheme – 2.4
Point of attack: Having confirmed the structure of 18, it was considered
desirable to study the mechanism of formation of 16a (or 18) from its precursor 3a. For
that it is essential to know which of the two oxygens present in 3a would end up in 16a.
This was decided on the basis of the following sets of experiments: 3a was treated with
Lawsson’s reagent in dioxane to obtain thioamide derivative 3n (analytical data, Fig.
2.18, 1.19 & 2.20), which was reduced with LAH (1.1 equiv.) to obtain the tricyclic
oxazolo compound 16a instead of thiazolo compound (23). This result clearly indicates
that oxygen from amide was not involved in the cyclization, but that of ester carbonyl was
involved in the cyclization to produce tricyclic oxazolo compound 16a. Scheme – 2.5

61
 S

LAH (1.2 eq) N S

X (23)
S S
Lawsson's Reagent,

N O N S
dioxane, 100 °C, 6.0 h
(3n)
(3a) CO2Et CO2Et
S
LAH (1.2 eq)
N O

(16a)

Scheme – 2.5
Table –2.5: Synthesis of 16 (a-m) from 3 (a-m) by reduction with LAH:
Structure Analytical Data: (IR cm-1), 1H NMR (δppm) (CDCl3, 200
MHz)
S IR: Did not show any diagnostic peaks due to –NH- and -CO-
groups; 1H NMR: (CDCl3, 200 MHz): δ 7.14 (t, J = 7.81 Hz, 1H),
7.03 (d, J = 7.81 Hz, 1H), 6.66 (t, J = 7.32 Hz, 1H), 6.52 (d, J =
N
O 8.30 Hz, 1H, 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H), 4.3 –
4.21(m, 1H), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H), 3.5 (m,
2H), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H), 2.70 – 2.60 (dd,
3a J = 9.28 and 11.72 Hz, 1H). Mass: m/z: 194 (M+ +1, 100 %)and
other peaks at 162 (30 %), 136 40%). EIHRMS: Cal Mass:
193.05613, Exp. Mass: 193.056520,
S IR: Did not show any diagnostic peaks due to –NH- and -CO-
groups; 1H NMR: (CDCl3, 200 MHz): δ 7.11 (d, J = 7.81Hz, 1H),
7.00 (t, J = 7.81 Hz, 1H), 6.65 (t, J = 7.57 Hz, 1H), 6.51 – 6.45
N
O (dd, J = 3.41 and 8.01 Hz, 1H), 4.62 (d, J = 8.06 Hz, 1H), 4.31 –
4.13 (m, 1H), 4.10 – 3.98 (q, J = 8.30 Hz, 1H), 3.50 – 3.42 (m,
2H), 2.81 – 2.74 (dd, J = 7.81 Hz, 1H), 1.43 (d, J = 6.59 Hz, 3H);
3b
Mass: m/z 208 (M+ +1, 100 %). 56 % YIELD

62
 S IR: Did not show any diagnostic peaks due to –NH- and -CO-
groups; 1H NMR: (CDCl3, 200 MHz): δ 7.09 – 7.00 (m, 2H), 6.64
(t, J = 7.32 Hz, 1H), 6.49 – 6.45 (dd, J = 7.81 Hz, 1H), 4.88 (s,
N 1H), 4.29 – 4.22 (m, 1H), 4.12 – 4.00 (m, 1H), 3.53 - 3.47 (m,
O
2H), 1.41 – 1.40 (m, 1H), 1.44 – 1.41 (s, 6H); Mass: m/z 222 (M+
+1, 100 %).
3c
IR: Did not show any diagnostic peaks due to –NH- and -CO-
groups; 1H NMR: (CDCl3, 200 MHz): δ 7.16 – 7.00 (m, 2H), 6.65
(t, J = 7.1 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.68 (d, J= 8.06 Hz,
1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.00 Hz, 1H), 3.45 (t,
J = 7.3 Hz, 2H), 2.74 – 2.63 (m, 1H), 2.21 – 2.08 (m, 1H), 1.62 –
1.30 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H); Mass: 222 (M+1, 100 %).
3e IR: Did not show any diagnostic peaks due to –NH- and -CO-
16e groups; 1H NMR: (CDCl3, 200 MHz): δ 7.15 – 7.00 (m, 2H), 6.65
Pr (t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.70 – 4.66 (d, J= 6.3
H Hz, 1H), 4.26 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.3 Hz, 1H), 3.46
54 (t, J = 6.9 Hz, 2H), 2.75 – 2.71 (m, 1H), 2.05 (m, 1H), 1.66 – 1.54
(m, 1H), 1.51 – 1.43 (m, 2H), 1.00 – 0.85 (m, 3H); Mass: 236 (M+
+1, 100 %).
3f IR: Did not show any diagnostic peaks due to –NH- and -CO-
16f groups; 1H NMR: (CDCl3, 200 MHz): δ 7.16 (d, J = 7.6 Hz, 1H),
i
Pr 7.04 (t, J = 7.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 8.0
H Hz, 1H), 4.83 (d, J= 8.5 Hz, 1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97
49 (q, J = 7.8 Hz, 1H), 3.48 – 3.42 (dd, J = 5.6 and 7.4 Hz, 2H), 2.80
– 2.74 (dd, J = 3.2 and 8.6 Hz, 1H), 2.50 – 2.35 (m, 1H), 1.14 (d, J
= 7.1 Hz, 3H), 1.05 (d, J = 7.1 Hz, 3H); Mass: 236 (M+ +1, 100
%).
3g IR: Did not show any diagnostic peaks due to –NH- and -CO-

63
16g groups; 1H NMR: (CDCl3, 200 MHz): δ 7.15 – 6.98 (m, 2H), 6.65
Hex (t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 4.67 (d, J= 8.1 Hz,
H 1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 7.3 Hz, 1H), 3.49 –
52 3.42 (m 2H), 2.78 – 2.70 (m, 1H), 2.07 – 2.04 (m, 1H), 1.69 – 1.30
(m, 9H), 0.88 – 0.85 (m, 3H); Mass: 278 (M+ +1, 100 %).
3h IR: Did not show any diagnostic peaks due to –NH- and -CO-
16h groups. 1H NMR: (CDCl3, 200 MHz): δ 7.39 (s, 5H, ), 7.20 (d, J
Ph = 8.79 Hz, 1H, ), 7.12 (t, J = 7.33 Hz, 1H, ), 6.71 (t, J = 7.33 Hz,
H 1H, ArH), 6.60 (d, J = 7.81 Hz, 1H, ), 5.13 (d, J = 8.31 Hz, 1H,
63 NCHO), 4.29 – 4.19 (m, 1H, SCHPh), 4.06 – 3.94 (dd, 8.30 &
15.63 Hz, 1H, OCH2CH2N), 3.73 (d, J = 8.30 Hz, 1H,
OCH2CH2N), 3.54 (t, J = 7.32 Hz, 2H, NCH2CH2O). Mass: 270
(M+ +1, 100 %).
3i IR: Did not show any diagnostic peaks due to –NH- and -CO-
16i groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,
H ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.11 (dd, J= 3.7 and 9.1
Et Hz, 1H), 4.23 – 4.02 (m, 2H), 3.79 – 3.72 (m, 1H), 3.09 – 3.01
71 (dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.48 (dd, J = 6.3 and 12.0 H,
1H), 1.96 – 1.71 (m, 1H), 1.56 – 1.43 (m, 1H), 0.99 – 0.91 (m,
3H); Mass: 222 (M+ +1, 100 %).
3j IR: Did not show any diagnostic peaks due to –NH- and -CO-
16j groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,
H ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.10 (dd, J= 3.7 and 9.1
Pr Hz, 1H), 4.20 – 4.04 (m, 2H), 3.94 – 3.82 (m, 1H), 3.86 – 3.71 (m,
61 1H), 3.09 – 3.01 (dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.47 (dd, J =
6.3 and 12.0 H, 1H), 1.88 – 1.72 (m, 1H), 1.59 – 1.32 (m, 5H),
0.98 (t, J = 7.1 Hz, 3H); Mass: 236 (M+ +1, 100 %).
3k IR: Did not show any diagnostic peaks due to –NH- and -CO-
16k groups. 1H NMR: (CDCl3, 200 MHz): δ 7.34 (s, 3H, ), 7.31 (d, J

64
H = 3.9 Hz, 2H, ), 7.21 – 7.17 (dd, J = 1.5 & 7.8 Hz, 1H, ), 6.92 –
Ph 6.84 (m, 1H, ArH), 6.60 (d, J = 7.31 Hz, 1H, ), 6.33 (d, J = 8.31
46 Hz, 1H, NCHO), 5.48 – 4.41 (dd, J = 3.9 & 9.3 Hz, 1H), 4.82 (t, J
= 7.8 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 3.76 (t, J = 8.3 Hz, 1H),
3.20 – 3.12 (dd, J = 3.5 % 12.1 Hz, 1H), 2.66 – 2.55 (dd, J = 9.2 &
12.2 Hz, 1H); Mass (m/z): 270 (M+ +1, 100 %).
3l IR: Did not show any diagnostic peaks due to –NH- and -CO-
16l groups. 1H NMR: (CDCl3, 200 MHz): δ 7.95 (d, J = 8.3 Hz, 2H,
H ArH), 7.56 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 6.90 (t, J = 8.2 Hz,
* 1H), 6.67 (t, J = 8.2 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 5.49 – 5.42
39 (dd, J = 4.0 & 9.2 Hz, 1H), 4.9 (t, J = 6.8 Hz, 1H), 4.57 (t, J = 9.3
Hz, 1H), 3.74 (t, J = 7.8 Hz, 1H), 3.32 – 3.14 (m, 1H), 3.07 (s,
3H), 2.67 – 2.56 (dd, J = 9.3 & 18.0 Hz, 1H); Mass: 347 (M+ +1,
100 %), 304 (60 %).
3m IR: Did not show any diagnostic peaks due to –NH- and -CO-
16m groups. 1H NMR: (CDCl3, 200 MHz): δ 7.26 (m, 4H, ArH), 6.89
H (d, J = 8.3 Hz, 2H), 6.62 (t, J = 7.5 Hz, 1H), 6.36 (d, J = 8.1 Hz,
** 1H, ArH), 5.47 – 5.40 (dd, J = 4.0 & 9.0 Hz, 1H), 4.77 (t, J = 7.5
41 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 3.80 – 3.74 (m, 4H), 3.29 (d, J =
4.3 Hz, 1H), 3.19 – 3.11 (dd, J = 4 & 11 Hz, 1H), 2.65 – 2.54 (dd,
J = 9.4 & 12.0 Hz, 1H).Mass: 300 (M+, 100%)
* =, 4 – methylsulfonyl phenyl, ** = 4 –methoxy phenyl

65
2.4 POSSIBLE MECHANISM OF REDUCTIVE CYCLIZATION:
(i) Addition of LAH: Addition of the LAH in both the ways, that is normal
addition (substrate was added to the LAH) or reversible addition (LAH was
added to the substrate). In the both the ways, same product (16a) was
obtained.
(ii) Use of more than 1.1 equivalents of LAH leads to alcohol (17a) as the
product. Once the cyclized product is formed, it is stable and no further
reduction occurs with LAH. After isolating product by using 1.1 eq. of LAH
and aq. sodium sulfate workup it was treated with 3.0 eq to 4.0 eq of LAH, no
reaction was took place. Even same thing was done before work up it lead to
alcohol 17a. Compound 17a is more stable with LAH, once it cyclizes.

S 2 - 4 eq. of LAH S

O THF N
N OH
OEt (17a)
(3a)
O

1.1 eq. of LAH

S 2 - 4 eq. of LAH S

X N
N O
(16a) (16a)
OH

Scheme 2.6
Formation of tricyclic compound 16a can be rationalized through initial reduction
of 3a to amino alcohol 24 which may instantaneously cyclize to the cyclic compound 25.
In contrast, compound 24 may react with excess of LAH to form the diol 26 which may
reduce further with LAH to give amino alcohol 17a or get cyclized to afford 16a. In the
presence of excess of LAH, therefore, the yield of 16a decreases as the yield of alcohol
25 increases. In order to substantiate this mechanism as well as to develop a new method

66
to synthesize the hitherto unknown fused 1,3-oxazolo tricyclic compound 16a, reactions
were carried out as shown below (Scheme – 2.7).

S
THF, LAH(1.1 eq) S S
N O
O OM
OEt r.t, 1.0 h N N O
(3a) OH
O (24) (25)

S LAH S S

N N OM N O
OH OH
(17a) (16a)
(26)

Scheme – 2.7

Optimization:

With a view to optimize conditions, the reactions of 3a with LAH were studied
under different conditions and different equivalents of LAH gave a mixture of 16a and
17a and in certain conditions almost zero yields of 16a. These results are shown in
Table- 2.6
S S S
LAH

N O N O N OH
OEt
(3a) (16a) (17a)
O
Equation – 2.11

Table – 2.6: Reduction of 3a with different equivalents of LAH

67
 S.No. LAH a eq. Ratio of products b (%)
3a 16a 17a
01. 0.5 60 40 0
02. 1.0 4 96 0
03. 1.1 0 100 0
04. 2.0 0 97 0
05. 4.0 0 91 9
06. 6.0 0 72 28

a
All reactions were carried out in dry THF under inert atmosphere at room temperature
(ca, 25 °C) for 0.45 hrs, bproduct ratios were determined by HPLC; column: Inertsil ODS;
mobile phase: 0.01M KH2PO4 and ACN (30:70); λmax. 235 nm; retention time: 3a, 4.37
min.; 17a, 8.2 min.

Results from above experiments indicate that only 1.1 eq. of LAH are needed for
to get desired oxazolo product.
The above reaction was also been studied with reducing agents other than LAH.
These experiments showed some interesting results which are given in Table 2.7. The
expected product 16a was not formed in these reductions.
The compound 3a was treated with sodium metal (4.0 equivalents) in ethanol in
order to obtain 16a. However, the product obtained was 2-(3-oxo-3,4-dihydro-2H-
benzo[b][1,4]thiazin-4-yl)acetic acid (27). Equation –2.12

S S
Na / EtOH

N O 80 °C, 6.0 h N O
(3a) OEt OH
(27)
O O
Equation – 2.12

68
The structure of compound 27 is supported by its spectral and analytical data. Thus, its
IR (KBr) spectrum showed peaks at 1732 cm-1 (acid carbonyl stretching), at 1671 cm-1
(amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.39 (d, J = 7.7
Hz, 1H), 7.29 – 7.26 (m, 1H), 7.06(t, J = 7.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.23 (bs,
1H, D2O exchangeable), 4.70 (s, 2H), 3.48 (s, 2H); while mass spectrum showed m/z 224
(M+1, 25 %) molecular ion at 223 (M+, 50 %) and other peaks at 178 (25 %), 150 (100
%), 136 (60 %) etc.
Compound 3a was reacted with sodium borohydride and borane dimethyl sulfide
(2.2 equivalents) in THF at 50 oC to yield 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)-
1-ethanol (17a) instead of 16a. (Equation –2.13) 17a was confirmed by its spectral and
analytical data. Thus, its IR (KBr) showed peak at 3396 cm-1 due to alcohol stretching,
and no peaks at carbonyl stretching frequency. Its 1H NMR (in CDCl3) showed signals at
δ 7.07 – 6.96 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.69 (m, 1H), 3.84 (t, J = 6.0 Hz, 2H),
3.66(t, J = 6.0 Hz, 2H), 3.47(m, 2H), 3.05 (t, J = 6.0 Hz, 2H); mass spectrum showed m/z
at 196 (M+1 60 %), 195 (M+, 60 %) and other peaks at 164 (90 %), 136 (100 %).
S S
NaBH4 / BMS

N O N
OEt OH
(3a) (17a)
O
Equation –2.13
When 3a was reacted with borane (2.2 equivalents) for 24 hrs in THF, it gave
ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)acetate (28). (Equation –2.14) 28 was
characterized by its spectral data. Thus, its IR (KBr) showed peak at 1744 cm-1 due to
ester carbonyl stretching. Its 1H NMR (CDCl3, 200 MHz): showed signals at δ 7.06 –
6.91 (m, 2H), 6.63 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 8.3,1H), 4.24 – 4.14 (q, J = 7.0 Hz,
2H), 4.00 (s, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.06(t, J = 6.4 Hz, 2H), 1.25 (t, J = 7.0 Hz,
2H); mass spectrum showed peaks at m/z 238 (M+1 75 %) and other peaks at 237 (M+, 60
%), 64 (100 %), 136 (80 %). All these experiments was explained in the following

69
 Table – 2.7
S S
BH3 (2.2 eq)

N O r.t., 24 h
N
OEt OEt
(3a) (28)

O O
Equation –2.14
Table –2.7: Reaction of 3a with different reducing reagents, reaction conditions
and results.
S.No. Reagent Conditions Results
Name Equalents Solvent Temp. Time 3a 16a 17a
(°C) (hrs)
1. Na 4.0 EtOH 80 6.0 *
2. Na 8.0 EtOH 80 6.0 *
3. NaBH4 1.1 Diglyme 80 6.0 √
4. NaBH4 2.2 Diglyme 80 6.0 √
5. NaBH4 AlCl3 1.1 / 0.4 Diglyme r.t 12.0 √
6. NaBH4 / AlCl3 2.2 / 0.8 Diglyme r.t 12.0 √
7. NaBH4 / AlCl3 2.2 / 0.8 Diglyme 75 12.0 √
8. NaBH4 / LiCl 1.1 /1.1 THF r.t 12.0 √
9. NaBH4 / I2 1.1 / 0.4 THF r.t 4.0 √
10. NaBH4 / NiCl2 1.1 / 1.1 MeOH r.t 4.0 √
11. NaBH3 / H2SO4 2.4 / 1.2 THF 40 12.0 √
12. BMS / NaBH4 1.1 / 0.5 THF r.t 6.0 √
13. BMS 1.1 THF r.t 6.0 √
14. BMS 1.1 THF 50 6.0 √
15. BMS 2.4 THF 50 6.0 √
16. L-Selectride 1.1 THF r.t 4.0 Not clean

70
 17. 9 BBN 1.1 THF r.t 6.0 √
18. BH3 1.1 THF r.t 6.0 √
19. BH3 2.2 THF r.t 24.0 **
20. DIBAL-H 1.1 THF r.t 24.0 √
* Ester was hydrolyzed, ** only amide keto was reduced.

Experimental procedure:
i) Preparation of 2a:
To a solution of 2-aminothiophenol (1) (50.0 gms, 400 mmol) in aq.
sodium hydroxide (8 %, 200 mL) at 15 oC was added a solution of chloroacetic acid (37.8
g gms, in 100 ml of water, 400 mmol) while the temperature was kept below 40 oC. Oil
starts separating out from the solution in about 60 min, time, and the resulting mixture
was stirred and refluxed for 4 hrs, during which time the oil changes to granular solid.
Then the mixture was cooled to room temperature, the solid was filtered and washed with
cold water. The solid was triturated with acetonitrile on the filter funnel and dried to
obtain 2a as colorless solid (50.0 g, 76 %).
ii) Preparation of 2a - h (General procedure):
First method: To a solution of 2-aminothiophenol (1) (5.0 g, 40.0 mmol) in water was
added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl acetate
(1.2 eq) at room temperature. The reaction mixture was stirred for one hr at room
temperature and then poured into dil. HCl (100 mL, 50 % v/v). The separated solid was
filtered, washed with water and dried to obtain 2a-h (Table-2.3).
Second method: To a solution of 2-aminothiophenol (0.250 g, 2.0 mmol) in water was
added of sodium hydroxide (0.12 g, 3.0 mmol), followed by ethyl 2-bromo-2-alkyl
acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using
household microwave oven for 5.0 min. The mixture was cooled and stirred with cold dil.
HCl (100 mL, 50 % v/v). The separated solid was filtered, washed with water and dried
to obtain 2a-h (Table-2.3).

71
iii) Preparation of 3a – j (General procedure): To a solution of 2a – h (1.0 eq) and
potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2-
alkyl acetate (1.2 eq) drop wise at room temperature. After stirring for 24 hrs the mixture
was poured in to water and extracted with ethyl acetate. The organic layer was washed
with water, dried and concentrated under reduced pressure to obtain 3a – o as crude
product, which was purified through column chromatography yielding pure compounds
3a – j (Table 2.2)
iv) Preparation of 5: A mixture of 4 (20.0 gms, 147 mmol) in ethanol (200 mL) was
refluxed for 3.0 hrs in the presence of a trace of con. H2SO4 (catalytic amount). Then the
solvent was removed from the reaction mixture under reduced pressure and the residue
was dissolved in ethyl acetate (200 mL). The ethyl acetate layer was washed with aq.
NaHCO3 solution followed by water (2 X100 mL), dried over Na2SO4 and concentrated
under reduced pressure to give 5 (24.0 g, 99 %) as thick liquid.
v) Preparation of 6: To a solution of 5 (20.0 gms, 122 mmol) in carbon tetrachloride
(200 mL), was added N-bromosuccinimide (23.8 gms, 134 mmol) and catalytic amount
of benzoyl peroxide. The mixture was stirred for 24.0 hrs at 60 oC. Then, the mixture was
filtered, washed with CCl4 and filtrate was concentrated under reduced pressure to yield a
crude residue which was dissolved in ethyl acetate. The ethyl acetate layer was washed
with water, dried over Na2SO4 and concentrated under vacuum, to obtain 6 (25.0 gms, 86
%) as gummy solid.

vi) Preparation of 3k: A solution of 2a (2.0 gms, 12.12 mmol), 6 (3.33 gms, 14.54
mmol) and anh. potassium carbonate (2.5 gms, 18.18 mmol) was stirred in DMF at 80 oC
for 12 hrs. At the end of this period, the reaction mixture was cooled to room temperature
and poured in to water. The mixture was extracted with ethyl acetate. The ethyl acetate
layer was washed with water, dried and concentrated under reduced pressure to obtain the
crude product, which was purified through column chromatography to yield a pure low-
melting solid of 3k (1.2 gms, 32 %).

72
vii) Preparation of 8: To a suspension of aluminum chloride (25.7 gms, 193.5 mmol) in
methylene chloride (150 mL) was added acetyl chloride (15.2 mL, 193.5 mmol) slowly at
0°C. The reaction mixture was then stirred at 25° oC until clear solution was obtained. A
solution of 7 (20.0 gms, 161.0 mmol) in dichloromethane (50 mL) was added slowly to
this mixture at 25 oC with vigorous stirring. The stirring was continued for 4.0 hrs at 25
o
C, then the mixture was poured into crushed ice (200 g) and extracted with chloroform
(3X100 mL). Combined organic layer was washed with water (2X100 mL), dried over
anhydrous Na2SO4 and concentrated under vacuum to give 8 (24.0 gms, 92 %) as pale
yellow powder.
viii) Preparation of 9: A mixture of 8 (22.0 gms, 132 mmol), elemental sulfur (5.0
gms, 159 mmol) and morpholine (13.8 gms, 159 mmol) was stirred for 24 hrs at 130 °C.
The reaction mixture was cooled to 25 °C followed by slow addition of 6N HCl (100 mL)
and then allowed to proceed for 24 hrs at 140 °C with vigorous stirring. After cooling to
room temperature the reaction mixture was poured into water (100 mL) and extracted
with ethyl acetate (3 X100 ml) followed by the extraction of the combined organic layer
with 10 % sodium hydroxide solution (2X100 mL). The aqueous layer was collected,
combined and acidified with 6N HCl. The separated solid was filtered, washed with
water and dried under vacuum to give 9 (17.0 gms, 71 %) as brown colour powder.
ix) Preparation of 10: A solution of 9 (16.0 gms, 87.9 mmol) in ethanol (200 mL) was
refluxed in the presence of con. H2SO4 (catalytic amount) for 4 hrs. At the end of this
period, the solvent was removed from the reaction mixture and the residue was dissolved
in ethylacetate (200 mL). The ethyl acetate layer was washed with aq. NaHCO3 solution
followed by water (100 mL X2), dried over Na2SO4 and concentrated under vacuum to
give 10 (18.0 g, quantitative) as thick liquid.
x) Preparation of 11: To a solution of 10 (6.0 gms, 28.57 mmol) in acetone (50 mL),
°
was added Oxone (36.89 gms, 59.99 mmol in 30 mL of water) at 25 C. The mixture was
stirred for 4.0 hrs at 25 oC Acetone was removed from the reaction mixture under
vacuum; the residue was neutralized with aq. NaHCO3 solution and extracted with ethyl

73
acetate. The ethyl acetate layer was washed with water, it was dried and concentrated to
obtain 11 (6.2 g, 90 %) as low-melting solid.
xi) Preparation of 12: To a solution of 11 (6.0 gms, 24.79 mmol) in carbon tetrachloride
(60 mL), was added N-bromosuccinimide (4.65 gms, 27.27 mmol) and catalytic amount
°
of benzoyl peroxide. The resulting mixture was stirred for 24.0 hrs at 60 C. Then the
mixture was filtered, washed with CCl4 and filtrate was concentrated under reduced
pressure. The crude residue was dissolved in ethyl acetate. The ethyl acetate layer was
washed with water, dried over Na2SO4 and concentrated under vacuum, to yield 12 (6.3 g,
80 %) as low-melting solid.
Analytical data:
IR (Neat): 1738 cm-1 (ester carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.96
– 7.92 (d, J = 8.30 Hz, 2H), 7.77 – 7.73 (d, J = 8.3 Hz, 2H), 5.36 (s, 1H), 4.31 – 4.19 (m,
2H), 3.06 (s, 3H), 1.32 –1.25 (t, J = 7.8 Hz, 3H); MS: m/z 321 (M+, 10 %), 250 (50 %),
241 (70 %), 185 (70 %), 170 (100 %), 162 (40 %), 107 (80 %), 90 (50 %).
xii) Preparation of 3l: A mixture of 2a (2.0 gms, 12.12 mmol), 12 (4.7 gms, 14.5 mmol)
°
and anh. potassium carbonate (2.5 gms, 18.18 mmol) in DMF was stirred at 80 C for 24

hrs. The reaction mixture was cooled to room temperature and poured into water (100
ml). The mixture was extracted with ethyl acetate (3 x 50 mL). Ethyl acetate layer was
washed with water, dried and concentrated under reduced pressure to yield a crude
product, which was purified through column chromatography giving the pure product 3l
(0.25 gms, 5 %) as low-melting solid.
xiii) Preparation of 14: To a cooled solution of 4-methoxyphenylacetic acid (35) (5.0 g,
30.12 mmol) in ethanol (60 mL), was added thionyl chloride (45.0 mL, 60.24 mmol)
°
dropwise at 0 C. Then the reaction mixture was refluxed for four hours and the solvent
removed under low pressure. The crude residue was dissolved in ethyl acetate and
washed with aq. NaHCO3 solution (100 mL of 10 % in water) followed by water (300
ml). The organic layer was dried and concentrated under reduced pressure to yield 14 (5.7
g, 98 %).

74
xiv) Preparation of 15: To a solution of ethyl 4-methoxyphenylacetate (5.0 g, 25.77
mmol) in carbon tetrachloride, was added N-bromosuccinimide (5.0 g, 28.35 mmol) and
the mixture was refluxed for three hours using electric bulb in the presence of catalytic
amount of benzoyl peroxide. Then the mixture was diluted with some more CCl4 and
washed with water, it was dried and concentrated to obtain 15 (6.8 gms, 97 %).
xv) Preparation of 3 m: To a mixture of 2a (0.5 gms, 3.03 mmol) potassium carbonate
(1.25 gms, 9.09 mmol), dry dimethylformamide (10 mL), was added 16 (0.99 gms, 3.63
mmol) in DMF (5.0 mL) drop wise at room temperature. After stirring at 60 oC, for 12
hrs, the mixture was poured in to water (50 ml) at room temperature. The separated solid
was filtered, washed with water and dried to obtain 3m ( 69 %).
xvi) Preparation of 16a – m (General procedure): To a solution of 3a - o (2.0 mmol) in
dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several
portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The resulting
mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was
filtered and the filtrate concentrated. The crude product was purified by column
chromatography using ethyl acetate and pet. ether (5:95) to give 16a – m (Table-2.6).
xvii) Preparation of 18: To an ice cold solution of 16a (5.0 g, 25.77 mmol) in acetic
anhydride (80 mL) was added fuming nitric acid (1.78 g, 28.34 mmol) drop wise at –5
o
C, and the mixture was stirred for 3 hrs at 0 °C. The reaction mixture was poured in to
crushed ice, the separated solid was filtered, washed with water and dried. The crude
product was purified through column chromatography by using ethyl acetate in petroleum
ether to obtain 18 (1.0 gms, 18 %) as yellowish crystalline solid.
xviii) Preparation of 3n: Method A: To a solution of 3a (1.0 g, 3.95 mmol) in dioxane
was added Lawsson’s reagent [2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-
dithiadiphosphetane) (0.8 g, 1.97 mmol) and the mixture was refluxed for 6 hrs. The
solvent was removed and the crude residue was purified through column
chromatography, to give 3n as yellow solid (1.0 g, 95 %).
xiv) Reduction of 3n with LAH: To a solution of 3n (0.534 g, 2.0 mmol) in dry THF
(10 mL) at 0 °C, lithium aluminumhydride (0.0836 g, 2.2 mmoles) was added in several

75
portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The resulting
mixture was then quenched with aq. sodium sulfate solution. The mixture was filtered
and the filtrate concentrated. The crude product was purified by column chromatography
using ethyl acetate and pet. ether (5:95) to obtain 16p.
xv) Experimental procedures of reactions which are explained in Table – 2.8:
a) (i) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.092
g, 4.0 mmol) in of dry toluene (20 mL) and the mixture was heated until sodium melted.
Then, the mixture was cooled to 60 °C and this was added 25a (0.25 g, 1.0 mmol) in
ethanol (5.0 ml), followed by more ethanol (20 mL) as rapidly as possible. The reaction
mixture was refluxed for 6.0 hrs, and the solvent was removed by distillation. The crude
residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water; it
was dried and concentrated under reduced pressure to give 27 (0.17 g, 81 %).
(ii) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.184 g, 4.0
mmol) in dry toluene (20 mL) and was heated until sodium melted. Then the mixture was
cooled to 60 °C and to this was added 3a (0.25 g, 1.0 mmol) in ethanol (5.0 ml), followed
by more ethanol (20 mL) as rapidly as possible. The reaction mixture was refluxed for
6.0 hours, and the solvent was removed by distillation. The crude residue was dissolved
in ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated
under reduced pressure to obtain 27. (0.180 g, 86 %)
b) Reduction of 3a with Sodium borohydride: To a stirred solution of 3a (0.251 g, 1.0
mmol) in diglyme (10.0 mL), was added sodium borohydride (0.041 g, 1.1 mmol) pinch
by pinch at room temperature. The mixture was stirred for six hours at 80 °C. Then the
reaction mixture was quenched with ice-cold water (5 ml) and extracted with ethyl
acetate (2X25 mL), It was washed with satd. sodium chloride solution, dried and
concentrated. Instead of expected product, starting material was recovered. The same
reaction was done with 2.2 eq. of sodium borohydride yet no product could be isolated.
c) Reduction of 3a with sodium borohydride and aluminum chloride:
First Method: To a solution of sodium borohydride (0.041 g, 1.1 mmol) in diglyme
(11 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and

76
aluminum chloride (0.053 g, 0.4 mmol, 2.0 ml of 2M solution in diglyme) was added
through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at
room temperature.
Second Method: To a solution of sodium borohydride (0.083 g, 2.2 mmol) in diglyme
(22 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and
aluminum chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added
through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at
room temperature.
Third Method: To a solution of sodium borohydride (0.083 g, 2.2 mmol) in diglyme (22
mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and aluminum
chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added through
dropping funnel at room temperature. The mixture was stirred for 12.0 hours at 75 °C.
In all the above methods, no product could be isolated and starting material was
recovered unchanged.
d) Reduction of 3a with Sodium borohydride and Lithium chloride: To a solution of
sodium borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0
mmol). Vigorous stirring was initiated and lithium chloride (0.046 g, 1.1 mmol) was
added at room temperature. The mixture was stirred for 12.0 hours at room temperature.
No product could be isolated and starting material was recovered unchanged.
e) Reduction of 3a with sodium borohydride and iodine: To a solution of sodium
borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0 mmol).
Vigorous stirring was initiated and iodine (0.101 g, 1.1 mmol) in THF (10 ml) was added
through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at
room temperature. Processing the reaction mixture gave back starting material was
unchanged.
f) Reduction of 3a with Sodium borohydride and Nickel chloride: To a solution of
25a (0.251g, 1.0 mmol) in methanol (15 mL) was added sodium borohydride (0.041 g,
1.1 mmol) at 0 °C, and followed by nickel chloride (0.262 g, 1.1 mmol) at same

77
temperature. The mixture was stirred for 12.0 hours at room temperature. On processing
the reaction mixture, starting material was recovered unchanged.
g) Reduction of 3a with sodium borohydride and sulfuric acid: To a solution of 3a
(0.251 g, 1.0 mmol) in THF (15 mL), was added sodium borohydride (0.120 g, 2.4 mmol)
at 0 °C, followed by sulfuric acid (0.117 g, 1.2 mmol) at the same temperature. The
mixture was stirred for 12 hrs at 40 °C. On processing the reaction mixture, starting
material was recovered unchanged.
h) Reduction of 3a with borane dimethylsulfide complex and Sodium borohydride:
To a solution of 3a (0.251 g, 1.0 mmol) in toluene (15 mL) was added dropwise borane
dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. After 30 min of stirring,
sodium borohydride (0.019 g, 0.5 mmol) was added in parts at 0 °C. The mixture was
stirred for 6.0 hours at room temperature. Reaction mixture was quenched by adding
methanol and solvent was removed from the mixture. The crude residue was purified
through column chromatography to give reduced product i.e. alcohol 3a (0.175 g, 89 %).
i) Reduction of 3a with borane dimethylsulfide complex:
First Method: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop
wise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture
was stirred for 6.0 hours at room temperature. On processing the reaction mixture,
starting material was recovered unchanged.
Second Method: To a solution 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop
wise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture
was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol
and solvent was removed from the mixture. The crude residue was purified through
column chromatography to give reduced product i.e. alcohol 17a (0.155 g, 79 %).
Third Method : To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop
wise borane dimethylsulfide complex (2.0 ml of 10 M, 2.2 mmol) at 20 °C. The mixture
was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol
and solvent was removed from the mixture. The crude was purified through column
chromatography to obtain reduced product i.e. alcohol 17a. (0.150 g, 77 %)

78
j) Reduction of 3a with Selectride: To a solution of ethyl 2-(3,4 dihydro-3oxo-2H-
benzo[b][1,4]thiazin –4-yl)acetate (3a) (0.251 g, 1.0 mmol) in THF (15 mL) was added
drop wise L- selectride(1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for
4 hrs at room temperature. On processing the reaction mixture, starting material was
recovered unchanged.
k) Reduction of 3a with 9BBN: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL)
was added drop wise 9BBN (2.2 ml of 0.5 M, 1.1 mmol) at 20 °C. The mixture was
stirred for 6.0 hours at room temperature. Reaction mixture was quenched with methanol
and water. Then, the mixture was extracted with ethyl acetate. Ethyl acetate layer was
washed with water, dried and concentrated to yield alcohol product i.e. 3a (0.165 g, 86
%).
l) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in THF
(15 mL) was added dropwise borane in THF (1.1 ml of 10 M, 1.1 mmol) at 20 °C. The
mixture was stirred for 6.0 hours at room temperature. On processing the reaction
mixture, starting material was recovered unchanged.
m) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in
THF (15 mL) was added dropwise borane in THF (2.2 ml of 10 M, 2.2 mmol) at 20 °C.
The mixture was stirred for 24.0 hours at room temperature. Reaction mixture was
quenched with methanol and water. Then, the mixture was extracted with ethyl acetate.
Ethyl acetate layer was washed with water, dried and concentrated to give 28. (0.190 g,
80 %)
n) Reduction of 3a with DIBAL-H: To a solution of 3a (0.251 g, 1.0 mmol) in THF
(15 mL) was added drop wise DIBAL - H in THF (1.0 ml of 10 M, 1.1 mmol) at 20 °C.
The mixture was stirred for 24.0 hours at room temperature. On processing the reaction
mixture, starting material was recovered unchanged.
REFERENCE
01. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc., 1982,
74, 1321.
02. Unger, G. Chem. Ber.; 1897, 40, 2496.

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03. Koos, M., Monatsh. Chem.; 1994, 125 (8/9) 1011.
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07. Hiroshi, S.; Norihiro, U.; Tadashi, K.; Mikio, H. Chem. Pharm. Bull. 1984, 42
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08. Nair, M. D.; David, J.; Nagarajan, K. Indian. J. Chem. Sect. B, 1985, 24, 940.
09. Saverio, F.; Vito, C.; Gennara, C.; Tetrahedron; 1997, 54 (16), 5849.
10. Zhong, W.; Zhang, Y. Tetrahedron Lett. 2001, 42 (17), 4125.
11. Mikio, H.; Tadashi, K.; Hiroshi, S.; Yutaka, I. Chem. Pharm. Bull. 1979, 27 (9),
1973.
12. Takamizawa, A., Chem. Pharm. Bull., 1972, 20, 892.
13. Wilkins, R.; Rohert, W. C. III. Can. J. Chem. 1979, 57, 444.
(Chem. Abstr. 1979, 90: 186884).
14. Norio, K.; Yuichi, H.; Koichi, S. Heterocycles. 1984, 22 (2), 277.
(Chem. Abstr. 1984, 100: 191811)
15. Niels, J.; Hans; Kolind, A. Synthesis. 1990, 10, 911.
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599.
17. Babudri, F.; Florio, S.; Indelicati, G.; Trapani, G. J. Org. Chem. 1983, 48 (22),
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18. Unger, G. Chem. Ber. 1897, 40, 2496, (1897). (Ref: 12)
19. Olagbemiro, T. O.; Nyakutse, C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E.
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21. Coutts, R. T., Sharon, J. M., Mah, E. and Pound, N. J.; Can. J. Chem. 1970, 48,
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22. Langlet, B.; Till, S. Vet – Akd. Handlingar, 22, II, No 1, S 17.
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Bull. 1990, 48 (5), 1248.
24. Shimizu, H.; Ueda, N.; Kataoka, T.; Hori, Mikio. Chem. Pharm. Bull. 1984,
42(7), 2571. (Chem. Abstr. 1984, 108:229556.
25. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc. 1952, 74,
321.
26. Bergmann; Ikan. J. Amer. Chem. Soc. 1958, 80, 3135.
27. Rahim Abdur, M.; Rao Praveen, P. N.; Knwas Edward, E. Bioorg. Med. Chem.
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28. Reichardt, C.; Schaefer, G.; Milart, P. Collect. Czech. Chem. Commun. 1990, 55
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29. (a) Joseph, W. C.; Reuben G. J.; Quentin F. S.; Calvert W. W.; Otto K. B. J.
Amer. Chem. Soc. 1948, 70, 2837. (b) Charles, D. H.; Gene, L. O. J. Amer.
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30. Davies, l. W.; Marcoux, Jean F.; Corley, E. G.; Journet, M.; Cai Dong, W.;
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81
31. (a) Harry, H. Wasserman.; Dennis, J. H.; Temper, A. W.; James, S. W. J.
Org. Chem. 1981, 46 (15), 2999. (b) Nacci, V.; Fironi, I.; Garofalo, A.; Cagnotto,
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82
 CHAPTER – III
STUDIES ON SYNTHESIS OF
“OXAZOLO OXAZINES”

3.1 Introduction:
Oxazolooaxzines were not very well documented in literature. Survey of literature
shows that not much work seems to have been done i.e. hexahydrooxazolo[2,3-
c][1,4]oxazine (29) as byproduct was reported by Jean-Charless Quirion, David S.
Grierson et. al. in Tetrahedron Letters.1
O
O Ph
N
N
Ph
OH O O HO
(29)
Compound (29) was prepared by condensation of phenylglycinol with
glutaraldehyde to give piperidine intermediate which was reacted with second molecule
of glutaraldehyde to give compound 29. (Equation – 3.1)

83
 Ph
OH
(30) CHO CHO
NH2 O
+
N N
CHO CHO O Ph
OH O
(31) Ph
(32) (29)

Equation – 3.1
Apart from above another oxazolooxazine (33) was reported by Kukharev, B. F.
Stankevich, V. K. et. al. in Arkivoc (it’s an online journal), 2003.2 It was prepared by the
condensation of N-(2-hydroxybenzylidine)-1,2-aminoethanol (34) with
paraformaldehyde. Equation – 3.2
O

O
(33)

N O NH
OH O
OH OH + CH2O
N

(34) (35) (33) O

Equation – 3.2

3.2 Present Work:

The survey of literature revealed that synthesis of oxazolo oxazines is a
difficult task to accomplish. Therefore, it was considered worth while to attempt the
synthesis of new compounds containing oxazolooxazines. It is conceivable that the
oxazolo moieties can be synthesized from 2-nitrophenol on reaction with ethyl 2-bromo-
2-alkyl/aryl and followed by ring closure in the presence of 10 % palladium carbon and
hydrogen under pressure to obtain benzooxazines in the first step. These benzooxazines
can be used as building blocks for the synthesis of fused oxazolo ring units.
3.3 Results and Discussion:

84
 Commercially available o-nitrophenol (36a i.e. R = R1 = H) was treated with
ethyl 2-bromoacetate in the presence of potassium carbonate to obtain ethyl 2(2-nitro
phenoxy) acetate (37a, i.e. R = R1 = H) in quantitative yield (Equation 3.2). Compound
37a is a compound known in literature.3 However, it was further characterized in the
present work by its spectral and analytical data. Thus, its IR (neat) spectrum showed (Fig
3.1) the absence of any peak above 3000 cm-1 indicating the disappearance of –OH group
of starting material. Further, the IR showed a peak at 1737 cm-1 assignable to ester
carbonyl stretching in the product 37a. It’s 1H NMR (in CDCl3) showed signals (Fig 3.2)
at δ 7.84 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), O – CH2 at
4.77 (s, 2H), 4.28 – 4.18 (q, J = 7.3 Hz, 2H, -CH2CH3-), 1.25 (t, J = 7.3 Hz, 3H, -
CH2CH3-). Its mass spectrum (Fig 3.3) showed peaks at m/z 266 (M+1, 100%) and other
peaks at m/z 179 (10 %), 152 (10 %) etc.
The above reaction of 36a with ethyl 2-bromoacetate has been found to be a
general and has been extended to other phenols 37b-e and the products obtained have
been assigned structures 37b-e on the basis of their spectral and analytical data (Table
3.1).

R OH ethyl bromoacetate, R OCH2CO2Et

R1 NO2 K2CO3, DMF, R1 NO2

(36a - e) 80 °C, 4 h (37 a -e)
Equation – 3.3

85
Table –3.1: Synthesis of 37 (b-e) from 36 (b-e) and their spectral data.
S. No. R R1 Yield Spectral Data: 1H NMR (200 MHz, CDCl3); IR
(KBr / Neat) / cm-1.
37b F H 93.0 % IR (Neat): Absence of any absorption due to –OH
group and a strong band at 1748 cm-1 due to ester
carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ
8.01 – 7.94 (dd, J = 5.8 and 8.8 Hz, 1H), 6.84 – 6.75
(ddd, J = 2.44, 7.33 and 11.24 Hz, 1H), 6.71 – 6.55
(dd, J = 2.45 – 9.77 Hz, 1H), 4.76 (s, 2H), 4.33 – 4.22
(q, J = 7.32 Hz, 2H), 1.33 – 1.25 (t, J = 7.32 Hz, 3H);
Mass: m/z 244 (M+ +1, 100 %), 170 (30 %).
37c Me H 92.0 % IR (Neat): Absence of any absorption due to –OH
group and a strong band at 1745 cm-1 due to ester
carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ
7.81 (d, J = 7.82 Hz, 1H), 6.88 (d, J = 8.30 Hz, 1H),
6.77 (s, 1H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.32 Hz,
2H), 2.39 (s, 3H), 1.32 – 1.24 (t, J = 7.32 Hz, 3H);
Mass: m/z 240 (M+ +1, 100 %), 166 (40 %).
37d H Me 91.0 % IR (Neat): Absence of any absorption due to –OH
group and a strong band at 1757 cm-1 due to ester
carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ
7.67 (s, 1H), 7.32 (d, J = 8.79 Hz, 1H), 6.91 (d, J =
8.31 Hz, 1H), 4.74 (s, 2H), 4.31 – 4.22 (q, J = 7.32
Hz, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.3 2Hz, 3H);
Maas: m/z 240 (M+ +1, 100 %), 166 (30 %).
37e MeS H 87.0 % IR (Neat): Absence of any absorption due to –OH
group and a strong band at 1727 cm-1 due to ester
carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ

85
7.88 (d, J = 8.31 Hz, 1H), 6.88 (d, J = 8.31 Hz, 1H),
6.75 (s, 3H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.33 Hz,
2H), 2.50 (s, 3H), 1.32 – 1.25 (t, J = 7.33 Hz, 3H);
Maas: m/z 272 (M+ +1, 100 %), 266 (40 %), 197 (20
%) etc.

86
 The compound 37e, referred in Table 3.1, above is not known in literature. It was
needed in the present work and it was prepared as follows:- Commercially available 3-
fluro-5-nitro phenol (36b, i.e. R = F, R1 = H), was reacted with sodium thiomethoxide in
HMPA to give 5-methylsulfanyl-2-nitrophenol (36e). Structure of 36e was confirmed by
spectral and analytical data. Thus, its IR (KBr) showed a band at 3419 cm-1 indicating
the presence of a hydroxy group. Its 1H NMR (in CDCl3) showed signals at δ 10.89 (s,
1H, D2O exchangeable), 8.00 – 7.84 (dd, J = 2.44 and 8.79 Hz, 1H), 6.86 – 6.76 (m, 2H),
2.53 (s, 3H). Its mass spectrum showed peaks at m/z 186 (M+1, 100 %). Compound 36e
was reacted with ethyl 2-bromoacetate in the presence of potassium carbonate to yield
37e as a yellow solid. (Equation – 3.4)

F OH NaSMe MeS OH

NO2 HMPA, r.t, NO2

(36b) 5h (36e)

ethylbromoacetate, MeS OCH2CO2Et

K2CO3, DMF, 80 oC, NO2

4.0 h (37e)
Equation – 3.4
Reduction of 37a (i.e. R = R1 = H) with iron powder in acetic acid4 gave 3-oxo,
2H 1,4-benzoxazine (38a i.e. R = R1 = H) in 63 % yield. This compound could also be
prepared from 37a by reduction with hydrogen in the presence of 10 % palladium carbon5
in 72 % yield. The structure of 38a was confirmed from its analytical and spectral data.
Thus, its IR (KBr) showed (Fig 3.4) peak at 1704 cm-1 due to the amide carbonyl
stretching vibration as distinct from the absorption at 1756 cm-1 in 37a due to the ester
carbonyl function. The –NH- stretching vibration of the product appeared at 3430 cm-1.
Its 1H NMR (in CDCl3) showed signals (Fig 3.5) at δ 9.6 (s, 1H, D2O Exchangeable,

87
NH), 6.98 - 6.89 (m, 4H, Ar - H), 4.6 (s, 2H, O – CH2). Its mass spectrum (Fig 3.6)
showed peaks at 151 (M+1, 20 %), 150 (M+, 100 %). (Equation – 3.5)

Fe / AcOH

R OCH2CO2Et R O

R1 NO2 R1 N O
H
(36)
(38)
10 % Pd /C
H2 Pressure

Equation – 3.5
The formation of 38a from 37a is probably due to the reduction of the nitro group to
amino group followed by intramoleculor cyclization leading to cyclic amide formation
with the alcohol moiety as shown below.

R OCH2CO2Et R OCH2CO2Et R O

R1 NO2 R1 NH2 R1 N O
(37) (37l) H
(38)
Equation – 3.6
In the above reaction involving formation of 38 from 37, 37l is an intermediate.

88
Table – 3.2 Syntheses of 37 (b-e) from 38 (b-e) and their spectral data:
Sub. Pdt R R1 Yield (%) Spectral Data: 1H NMR (200 MHz, CDCl3); IR
(KBr / Neat) / cm-1.
37b 38b F H 65.0 IR (KBr): 3429 cm-1 (amide –NH- stretching) 1694
cm-1 (amide carbonyl stretching); 1H NMR (in DMSO
d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 -
6.76 (m, 4H, Ar - H), 4.56 (s, 2H, O – CH2); Mass: m/z
(M+1, 20 %), 168 (M+ +1, 100 %).
37c 38c Me H 59.0 IR (KBr): 3043 cm-1 (amide –NH- stretching) 1702
cm-1 (amide carbonyl stretching); 1H NMR (in DMSO
d6) δ 10.52 (s, 1H, D2O Exchangeable, NH), 6.73 (s,
3H, Ar - H), 4.49 (s, 2H, O – CH2), 2.18 (s, 3H,
ArCH3; Mass: m/z (M+1, 20 %), 164 (M+, 100 %).
37d 38d H Me 57.0 IR (KBr): 3436 cm-1 (amide –NH- stretching) 1699
cm-1 (amide carbonyl stretching); 1H NMR (in DMSO
d6) δ 10.61 (s, 1H, D2O Exchangeable, NH), 6.81 (m,
1H, Ar - H), 6.77 – 6.66 (m, 2H, Ar - H), 4.47 (s, 2H,
O – CH2), 2.18 (s, 3H, ArCH3; Mass: m/z 164 (M+1,
100 %), 163 (M+, 50 %).
37e 38e SMe H 53.0 IR (KBr): 3455 cm-1 (amide –NH- stretching) 1684
cm-1 (amide carbonyl stretching); 1H NMR (in DMSO
d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 –
6.84 (m, 3H, Ar - H), 4.55 (s, 2H, O – CH2), 2.42 (s,
3H, ArCH3; Mass: m/z 196 (M+ +1,100 %), 195 (M+,
60 %).

89
 Apart from compounds 38a – e, compound 38f, an additional derivative in the
present series, was prepared from compound 38e by oxidation of sulfanyl group with
oxone reagent. It is versatile oxidizing agent used for oxidizing sulfanyl to sulfonyl
groups and used in place of hydrogen peroxide in acetone – water solution. (Equation
– 3.7) The structure of 38f was confirmed from its analytical and spectral data. Thus, its
IR (KBr) showed diagnostic peak at 1697 cm-1 due to amide carbonyl stretching and
twin peaks at 1299 cm-1 due to sulfonyl group. Its 1H NMR (in DMSO d6) signals
showed at δ 11.14 (s, 1H, D2O Exchangeable, NH), 7.53 – 7.48 (dd, J = 1.47 and 8.30
Hz, 1H, ArH), 7.45 (s, 1H, ArH), 7.07 (d, J = 7.91 Hz, 1H), 4.69 (s, 2H, O – CH2), 3.1
(s, 3H, SCH3). Its mass spectrum showed peaks at m/z 228 (M+, 100 %).
O
S O Oxone, acetone S O
O
N O methanol, r.t, 3.0 h N O
H H
(38e) (38f)
Equation – 3.7
Another intermediate 38g required in the present work, was prepared from
commercially available 2-amino-5-nitrophenol (39) by reacting it with chloroacetyl
chloride in the presence of triethylamine in dichloromethane yielding N1-(2-hydroxy-4-
nitrophenyl)-2-chloroacetamide (40) followed by cyclization with aq.
sodiumhydroxide in the presence of catalytic amount of tetrabutyl ammonium hydrogen
sulfate (TBAHS) giving 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one (38g).
(Equation – 3.7) The structure of 38g is supported by its analytical and spectral data.
Thus, its IR (KBr) showed diagnostic amide carbonyl band at 1696 cm-1. Its 1H NMR
(in DMSO d6) showed signals at δ 11.34 (s, 1H, D2O Exchangeable, NH), 7.93 – 7.87
(dd, J = 1.96 and 8.79 Hz, 1H, ArH), 7.76 (s, 1H, ArH), 7.06 (d, J = 8.30 Hz, 1H), 4.73
(s, 2H, O – CH2). Its mass spectrum showed peaks at m/z 195 (M+, 100 %).

90
 O2N OH ClCH2COCl O2N OH
O
Cl
NH2 Et3N, CH2Cl2 N
r.t 6.0 h H
(39)
(40)

aq. NaOH, TBAHS O 2N O

CH2Cl2 r.t, 2.0 h N O

H
(38g)
Equation – 3.7
The compound 38a was treated with ethyl 2-bromoacetate in the presence of
potassium carbonate6 in DMF at 80 °C. Processing of the reaction mixture gave a product
which was found to be 3,4 dihydro-3-oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester
(41a, i.e. 341, R = R = H) (Equation – 3.9). 41a had been characterized by spectral and
analytical methods. Thus, its IR (KBr) spectrum showed no absorption above 3000 cm-1
indicating absence of –NH- group. However, IR spectrum showed (Fig 3.7) two
diagnostic sharp strong bands, one at 1739 cm-1 (ester carbonyl stretching) and 1681 cm-1
(amide carbonyl stretching). Its 1H NMR (CDCl3, 200 MHz): showed signals (Fig 3.8) at
δ 7.02 – 7.01 (m, 3H, Ar - H), 6.77 – 6.73 (m, 1H, Ar - H), 4.67(s, 2H, O- CH2 - CO),
4.65 (s, 2H, N – CH2), 4.29 – 4.19 (q, J = 7.1 Hz, 2H, O – CH2 – CH3),1.31 – 1.24 (t, J =
7.1 Hz, 3H, O – CH2 – CH3). Its mass spectrum (Fig 3.9) showed peaks at m/z 236 (M+
+1, 100 %) and at 190 (10 %) when recorded in the Q+1 mode
R O K2CO3, BrCHCO2Et R O

R1 N O DMF 80 °C, 12.0 hrs R1 N O

H OEt
(38) (41)
O
Equation – 3.9
6 or 7 substituted 3,4-dihydro-3oxo-2H-1,4-benzoxazine –4-acetic acid ethyl esters could
also be prepared using the above method. Apart from 41a – g, 41h was synthesized by
the reduction of nitro group of 41g with sodium borohydride in the presence of nickel (II)

91
chloride (to enhance speed of the reaction) in methanol leading to 7-nitro-3,4 dihydro-3-
oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester (41h) (Equation – 3.10).
O2N O H2N O
NaBH4, NiCl2

N O N O
MeOH, r.t 4.0 h
OEt OEt
(41h)
(41g) O
O
Equation – 3.10
Structures of all products (41a – h) were assigned based on spectral and analytical data
(Table 3.3).

92
 Table – 3.3: Synthesis of 41from 38 by alkylation.
Sub. Pdt. R R1 R2 Yield (%) Spectral Data: 1
HNMR (200 MHz,
CDCl3); IR (KBr/Neat)/cm-1.
38b 41b F H H 74.0 IR (KBr): 1741 cm-1 (ester carbonyl
stretching) and 1688 cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
6.78 – 6.64 (s, 3H), 4.68 (s, 2H), 4.63 (s, 2H),
4.29 – 4.19 (q, J = 7.25 Hz, 2H),1.31 – 1.24
(t, J = 7.25 Hz, 3H); Mass: m/z 254 (M+ +1,
100 %), 152 (30 %). Elemental Analysis:
Mol. F: C12H12NO4F, Cal. C: 56.900, H:
4.779, N: 5.533; Experimental, C: 56.551, H:
4.940, N: 5.403.
38c 41c Me H H 74.0 IR (KBr): 1744 cm-1 (ester carbonyl
stretching) and 1681 cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
6.82 – 6.77 (m, 2H), 6.64 – 6.60 (d, J = 7.82
Hz, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 4.27 –
4.17 (q, J = 7.32 Hz, 2H), 2.27 (s, 3H), 1.33 –
1.26 (t, J = 7.32 Hz, 3H); Mass: m/z 250 (M+
+1, 100 %), 249 (M+, 75 %), 204 (40 %), 148
(40 %).
38d 41d H Me H 72.0 IR (KBr): 1742 cm-1 (ester carbonyl
stretching) and 1685 cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
6.89 (d, J = 8.30 Hz, 1H), 6.80 (d, J = 8.30
Hz, 1H), 6.53 (s, 1H), 4.62 (s, 4H), 4.30 –
4.19 (q, J = 7.33 Hz, 2H), 2.29 (s, 3H), 1.31 –
1.24 (t, J = 7.33 Hz, 3H); Mass: m/z 250

93
 (M+1, 100 %), 204 (40 %), 176 (50 %), 148
(80 %).
38e 41e SMe H H 69.0 IR (KBr): 1739 cm-1 (ester carbonyl
stretching) and 1676 cm-1 (amide carbonyl
stretching); 1H NMR (DMSO d6, 200 MHz):
δ 7.00 – 6.99 (m, 3H), 4.70 (s, 4H), 4.16 –
4.13(q, J = 7.32 Hz, 2H), 2.45 (s, 3H), 1.24 –
1.17 (t, J = 7.32 Hz, 3H); Mass: m/z 282
(M+1, 100 %), 281 (M+1, 80 %), 236 (30 %),
180 (30 %).
38f 41f SO2Me H H 76.0 IR (KBr): 1747 cm-1 (ester carbonyl
-1
stretching) and 1700 cm (amide carbonyl
stretching); 1H NMR (DMSO d6, 200 MHz):
δ 7.60 – 7.55 (m, 2H), 7.35 (d, J = 8.30 Hz,
1H), 4.85 (s, 2H), 4.80 (s, 2H), 4.22 – 4.11
(q, J = 7.33 Hz, 2H), 3.22 (s, 3H), 1.25 – 1.18
(t, J = 7.32 Hz, 3H); Mass: m/z 314 (M+ +1,
100 %), 212 (30 %).
38g 41g NO2 H H 75.0 IR (KBr): 1736 cm-1 (ester carbonyl
-1
stretching) and 1694 cm (amide carbonyl
stretching); 1H NMR (DMSO d6, 200 MHz):
δ 7.96 (d, J = 1.95 Hz, 1H, Ar - H), 7.90 (d, J
= 1.96 Hz, 1H), 6.84 (d, J = 8.79 Hz, 1H),
4.78 (s, 2H), 4.71 (s, 2H), 4.32 – 4.21 (q, J =
7.33 Hz, 2H), 1.30 (t, J = 7.32 Hz, 3H); Mass:
m/z 281 (M+ +1, 100 %), 179 (30 %).
38g 41h NH2 H H IR (KBr): 1744 cm-1 (ester carbonyl
stretching) and 1689 cm-1 (amide carbonyl
stretching); 1H NMR (DMSO d6, 200 MHz):

94
 δ 6.56 – 6.52 (d, J = 8.30 Hz, 1H), 6.36 – 6.28
(m, 2H), 4.61 (s, 2H), 4.58 (s, 2H), 4.27 –
4.17 (q, J = 7.33 Hz, 2H), 1.30 – 1.23 (t, J =
7.32 Hz, 3H); Mass: m/z 251 (M+ +1, 100 %),
177 (25 %) .
38a 41i H H Et IR (KBr): 1740 cm-1 (ester carbonyl
stretching) and 1692 cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
7.07 – 6.90 (m, 3H), 6.87 – 6.80 (m, 1H), 5.37
– 5.29 (dd, J = 5.37 & 9.94 Hz, 1H), 4.72 –
4.53 (dd, 15.04 & 21.21 Hz, 2H), 4.28 – 4.12
(m, 2H), 2.37 – 2.19 (m, 1H), 2.17 – 1.91 (m,
1H), 1.23 – 1.16 (t, J = 7.25 Hz, 3H), 0.93 –
0.86 (t, J = 7.52 Hz, 3H); Mass: m/z 264 (M+
+1, 100 %).
38a 41j H H Pr IR (KBr): 1740 cm-1 (ester carbonyl
stretching) and 1692 cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
7.07 – 6.90 (m, 3H, Ar H ), 6.87 – 6.80 (m,
1H, Ar H), 5.37 – 5.34 (dd, J = 5.37 & 9.94
Hz, 1H, NCH), 4.72 – 4.53 (dd, 15.04 &
21.21 Hz, 2H, OCH2CO), 4.28 – 4.12 (m, 2H,
OCH2CH3), 2.37 –1.91 (m, 2H,
NCHCH2CH2), 1.3 (t, J = 7.52 Hz, 2H,
NCHCH2CH2), 1.23 – 1.21 (t, J = 7.25 Hz,
3H, OCH2CH3), 0.98 – 0.88 (t, J = 7.52 Hz,
3H, NCHCH2CH2CH3); Mass: m/z 278 (M+
+1, 100 %).
38a 41l H H Ph 58.0 IR (KBr): 1746 cm-1 (ester carbonyl

95
 stretching) and 1681cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
7.36 – 7.31 (m, 5H, Ar H), 7.03 – 6.92 (m,
2H, Ar H), 6.80 – 6.70 (m, 2H, Ar H), 6.40 (s,
1H, Benzylic H), 4.76 (dd, J = 15.04 & 19.87
Hz, 2H, OCH2CO), 4.33 – 4.17 (m, 2H, OCH2
CH3), 1.19 (t, J = 7.2 Hz, 3H, OCH2 CH3);
Mass: m/z 312 (M+ +1, 100 %).
38a 41m H H Ar 71.0 IR (KBr): 1744 cm-1 (ester carbonyl
stretching) and 1691cm-1 (amide carbonyl
stretching); 1H NMR (CDCl3, 200 MHz): δ
7.31 (d, J = 8.60 Hz, 2H, Ar H), 6.98 (d, J =
8.00 Hz, 2H, Ar H), 6.91 – 6.80 (m, 4H, Ar
H), 6.31 (s, 1H, Benzylic H), 4.79 – 4.61 (dd,
J = 15.05 & 20.95 Hz, 2H, OCH2 CO), 4.29 –
4.19 (m, 2H, OCH2 CH3), 3.78 (s, 3H), 1.19
(t, J = 7.3 Hz, 3H, OCH2 CH3); Mass: m/z
342 (M+ +1, 10 %) and 193 (100 %).
Ar = 4-methoxy phenyl

96
Reductions with Lithium Aluminum Hydride (LAH):
Treatment of 41a (41, R = R1 = H) with 1.1 eq. of LAH in THF followed by usual
workup gave a product as syrupy liquid. The compound was found to be homogenous on
TLC and different from the starting material. Its IR spectrum (Neat) did not show any
diagnostic peaks due to the presence of –NH- and -CO- groups (Fig 3.10). Its 1H NMR
(in CDCl3) showed signals (Fig 3.11) at δ 6.98 – 6.88 (m, 2H, Ar - H), 6.79 – 6.72 (m,
2H, Ar - H), 4.89 – 4.84 (dd, J= 3.42 and 6.84 Hz, 1H, O CH), 4.44 – 4.37 (dd, J= 2.93
and 10.75 Hz, 1H, OCH2), 4.14 – 3.94 (m, 2H, O CH2 & N CH2), 3.74 – 3.56 (m, 2H, O
CH2 & N CH2), 3.50 – 3.42 (m, 1H, O CH2). Its mass spectrum (Fig 3.12) showed
molecular ion peak at m/z 178 (M+ +1, 100 %). Elemental Analysis: Mol. F: C10H11NO2,
Cal. C: 67.766, H: 6.261, N: 7.908; Experimental, C: 67.763, H: 6.694, N: 8.179. Based
on this data, the product was assigned as 1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-
d][1,4]oxazine (42a). (Equation – 3.11)

R O R O
LAH
R1 N O THF, 0 - r.t R1 N O
OEt 1.0 hr
R2
R2
O
(41) (42)
Equation – 3.11
It is noteworthy that the product expected from LAH reduction in the above
reaction was 43, which however, did not form. (Equation – 3.12)

O O
LAH
N O N OH
THF, 0 - r.t
OEt 1.0 min
(41a)
(43)
O
Equation – 3.12
The above reaction (Equation – 3.11) of 41a yielding 42a is general one. It has
been extended to other N-substituted benzoxazinones (41) yielding (42). Structures of all

97
these compounds have assigned on analogy and on the basis of spectral and analytical
data (Table 3.4).
Structure confirmation: To confirm the structure of the compound 42 further
especially its stereochemistry, single crystal X-ray diffraction study was carried out.7 For
single crystal X-ray diffraction study to be carried out, it is essential that the compound
should be solid crystalline substance. Since the product 42a obtained in the present study
was a syrupy liquid and other analogs also had low melting points, compound 42a was
nitrated hoping that the resulting derivative 44a would be a solid amenable for X-ray
studies. Nitration of 42a with nitric acid in acetic anhydride yielded 7-nitro-1,2,3a,4-
tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]oxazine (44). (Equation – 3.13)
O
HNO3 O2N O

N Ac2O N
O O
(42a) (44)
Equation –3.13

5 4
Hb
O2N 6 9 O
3
Ha
2 H
7
8 101N O 13
11
Ha
12 Hb
Hb Ha
(44)
Thus, its IR (KBr) spectrum (Fig. 3.13) showed the absence of any diagnostic
peaks due to –NH- and -CO- groups. Its 1H NMR (CDCl3, 200 MHz) showed signals
(Fig. 3.14) at δ 7.89 – 7.84 (dd, J = 8.8 and 2.4 Hz, 1H, ArH), 7.77 (d, J = 2.4 Hz, 1H,
ArH), 6.56 (d, J = 8.8 Hz, 1H, ArH), 4.92 – 4.86 (dd, J = 8.4 and 3.4 Hz, 1H), 4.63 – 4.56
(dd, J = 10.0 and 4.0 Hz, 1H), 4.35 – 4.25 (dd, J = 9.0 and 3.2 Hz, 1H), 4.15– 4.03 (dt, J
= 6.4 and 8.8 Hz, 1H), 3.75 – 3.70 (m, 1H), 3.56 – 3.30 (m, 2H). The data of 400 MHz
1
H NMR depicted in Table – 3.4. Carbon 13 and COSY data is also shown in Table 3.4.

98
The mass spectrum of 44 showed the molecular ion peak at 223 (M+1, 100 %) in Q+1
mode.
In the steady state 1D nOe experiment on irradiating the C-8 proton at 6.57 ppm.
The spectrum showed enhancement of signals at 3.72 and 3.49 ppm corresponding to C-
11 Ha and Hb protons respectively. With this information, the position of the aromatic C-
8 proton was fixed at 6.57 ppm. The splitting of C-8 proton is doublet due to C-7 proton
coupling. Hence the position of Nitro group is fixed at C-6. NMR assignments of (44)
are listed in the following page

Table 3.4: The NMR assignments of (44)

1
Position H δ (ppm) J (Hz)# COSY 13
C DEPT
(Fig. 3.17) (Fig. 3.15) (Fig. 3.16)
2 1H 4.88 dd, 8.4, 4.4 (3Ha, 3.36) 82.34 CH
(3Hb, 4.61)
3 Ha 3.36 dd, 10.0, 8.4 (2H, 4.88) 65.70 CH2
Hb 4.61 dd, 10.0, 4.4 (2H, 4.88)
5 1H 7.78 d, 2.4 112.13 CH
6 138.19
7 1H 7.87 dd, 8.8, 2.4 (8H, 6.57) 119.82 CH
8 1H 6.57 d, 8.8 (7H, 7.87) 111.07 CH
9 139.11
10 141.58
11 Ha 3.49 dt, 7.6, 8.8 (12Ha, 4.12) 46.73 CH2
(12Hb, 4.32)
(11Hb, 3.72)

99
 Hb 3.72 ddd, 7.6,6.4,2.8 (12Ha, 4.12)
(12Hb, 4.32)
(11Hb, 3.49)
12 Ha 4.12 dt, 6.4, 8.8 (11Ha, 3.49) 65.92 CH2
(11Hb, 3.72)
(12Hb, 4.32)
Hb 4.32 ddd, 7.6,6.4,2.8 (11Ha, 3.49)
(11Hb, 3.72)
(12Hb, 4.12)

The possible major fragments produced in the e.i mass spectrum (Fig.
3.20) of 44 are shown below:-
O2 N O O2N + O

N O N O N O
(45) (46) (47)

m/z = 223 m/z = 206 m/z = 177

Melting point (150 °C) was confirmed by thermal analysis (Fig. 3.21)
Single crystal X-ray diffraction study: Single Crystal suitable for X-ray
diffraction have been grown from the recrystallisation of 44 in the mixture of solvents
such as ethyl acetate and petroleum ether. The compound crystallizes as yellow flakes in
monoclinic space group P21/c with cell dimensions a = 12.164 (2), b = 22.079 (2), c =
7.374 (2), β = 100.82 (2) A0 and V = 1945.2 0
(6), Z = 8. There are independent
molecules in the asymmetric unit. Molecule –A adopted envelope conformation while
molecule-B assumed half chair conformation. The molecules inside the lattice are
stabilized by Van der wall interactions. The intensity data was collected on Rigaku AFC-
7S single crystal diffractometer using Cu Kα (λ = 1.5405 A0). The structure has been
solved with direct methods and refined using the TEXSAN software. The final R factors
are: R (Rw) = 0.067 (0.076) with 2683 observed reflections (I>1.50\σ(I)). All the bond

100
parameters were normal. The results from the various physicochemical techniques
confirm the molecular structure.

Crystal Photograph of Compound 44

101
Crystal Structure of Compound 44

102
Table – 3.4 Synthesis of 41 (a-i) from 42 (a-i) by reduction with LAH:
Sub Pdt R R1 R2 Yield (%) Spectral Data : 1H NMR (200 MHz,
CDCl3); IR (KBr / Neat) / cm-1.
41b 42b F H H 99.0 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups. H
NMR: δ 6.76 – 6.60 (m, 3H), 4.85 –
4.80 (dd, J= 3 and 6 Hz, 1H), 4.38 –
4.31 (dd, J= 3 and 11 Hz, 1H), 4.07 –
3.90 (m, 2H), 3.75 – 4.60 (m, 2H), 3.49
– 3.34 (m, 1H); MS: m/z 196 (M+ +1,
100 %), 195 (80%). Elemental
Analysis: Mol. F: C10H10FNO2, Cal. C:
61.517, H: 5.166, N: 7.179;
Experimental, C: 60.221, H: 5.468, N:
6.924.
41d 42d Me H H 86.0 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR: δ 6.71 – 6.49 (m, 3H), 4.85 –
4.81 (dd, J= 3 and 6 Hz, 1H), 4.40 –
4.29 (dd, J= 2.9 and 11 Hz, 1H), 4.02 –
3.88 (m, 3H), 3.69 – 3.59 (m, 1H), 3.46
– 3.45 (m, 1H), 2.23 (s, 3H); MS: m/z
192 (M+ +1, 95 %), 191 (M+, 100 %).
41e 42e H Me H 94.0 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR: δ 6.74 (d, J = 7.8 Hz, 1H), 6.56
– 6.52 (m, 2H), 4.85 – 4.78 (dd, J= 3
and 7 Hz, 1H), 4.38 – 4.31 (dd, J= 2.9
and 11 Hz, 1H), 4.08 – 3.90 (m, 2H),

103
 3.69 – 3.52 (m, 2H), 3.46 – 3.34 (m,
1H), 2.26 (s, 3H); MS: m/z 192 (M+ +1,
95 %), 191 (M+, 100 %).
41f 42f SMe H H 99.0 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR: δ 6.93 – 6.88 (m, 2H), 6.71 –
6.67 (m, 1H), 4.85 – 4.81 (dd, J= 3 and
8 Hz, 1H), 4.40 – 4.34 (dd, J= 3.0 and
11 Hz, 1H), 4.13 – 3.91 (m, 2H), 3.70 –
3.55 (m, 2H), 3.45 – 3.37(m, 1H), 2.41
(s, 3H); MS: (m/z) 224 (M+ +1, 80 %),
223 (M+, 100 %).
41g 42g SO2Me H H 39.0 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR: δ 7.45 – 7.40 (dd, J = 1.9 & 8.4
Hz, 1H), 7.36 – 7.35 (d, J = 1.9 Hz, 1H),
6.65 – 6.61 (d, J = 8.4 Hz, 1H), 4.83 –
4.77 (dd, J = 3.8 & 8.0 Hz, 1H), 4.55 –
4.48 (dd, J = 4 & 10 HZ, 1H), 4.21 –
4.16 (m,1H), 4.08 – 4.00 (m, 1H), 3.67 –
3.61 (m, 1H), 3.44 – 3.24 (m, 2H), 2.94
(s, 3H); MS: m/z 256 (M+ +1, 100 %).
41j 42j H H Et 45 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR (CDCl3, 200 MHz): δ 6.95 – 6.71
(m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.69
& 4.88 Hz, 1H), 4.35 – 4.28 (dd, J =
2.68 and 11.23 Hz, 1H), 4.10 – 4.03 (dd,
J = 6.35 and 7.57 Hz, 1H), 3.91 – 3.83

104
 (dd, J = 5.12 and 11.47 Hz, 1H), 3.76 –
3.70 (dd, J = 4.39 & 6.59 Hz, 1H), 3.69
– 3.59 (dd, J = 4.15 and 7.81 Hz, 1H),
1.87 – 1.76 (m, 1H), 1.71 – 1.57 (m,
1H), 1.11 – 1.04 (t, J = 7.33 Hz, 3H);
MS: m/z 206 (M+ +1,100 %), 136 (10
%).
41k 42k H H Pr 42 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR (CDCl3, 200 MHz): δ 6.96 – 6.71
(m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.68
& 4.88 Hz, 1H), 4.35 – 4.28 (dd, J =
2.68 and 11.48 Hz, 1H), 4.10 – 4.02 (dd,
J = 7.24 and 11.48 Hz, 1H), 3.93 –
3.85(dd, J = 4.88 and 11.48Hz, 1H),
3.82 – 3.73 (m, 1H), 3.63 – 3.57 (dd, J =
4.15 and 7.81 Hz, 1H), 1.82 – 1.70 (m,
1H), 1.59 – 1.41 (m, 3H), 1.07 – 1.00 (t,
J = 7.33 Hz, 3H); MS: m/z 206 (M+
+1,100 %), 136 (10 %).
41l 42l H H Ph 48 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; H
NMR (CDCl3, 200 MHz): δ 7.42 – 7.32
(m, 5H, Ar H), 6.96 – 6.91 (dd, J = 1.88
& 6.25 Hz, 1H, Ar H), 6.81 – 6.67 (ddd,
J = 1.88, 6.98 & 9.13 Hz, 2H, Ar H),
6.50 – 6.45 (dd, J = 1.88 & 7.52 Hz, 1H,
Ar H), 5.25 – 5.19 (dd, J = 2.76 & 7.52
Hz, 1H, OCH2CHO), 4.73 (t, J = 7.26

105
 Hz, 1H, N CH Ph), 4.56 – 4.47 (m, 2H,
O CH2CH), 3.79 (t, J = 8.06 Hz, 1H,
OCH2CHN), 3.61 – 3.52 (dd, J = 7.52 &
2.90 Hz, 1H, OCH2CHN); MS: m/z 254
(M+ +1,100 %). Elemental Analysis:
Mol. F: C16H15NO2, Cal. C: 75.856, H:
5.973, N: 5.532; Experimental, C:
75.721, H: 6.659, N: 5.258.
41m 42m H H Ar 39 IR: Did not show any diagnostic peaks
1
due to –NH- and -CO- groups; ; H
NMR (CDCl3, 200 MHz): δ 7.34 (d, J =
8.59 Hz, 2H, Ar H), 6.93 (d, J = 8.59
Hz, 2H, Ar H), 6.78 – 6.69 (ddd, J =
1.88, 7.52 & 9.67 Hz, 2H, Ar H), 6.51 –
6.47 (dd, J = 1.88 & 7.25 Hz, 1H, Ar H),
5.23 – 5.18 (dd, J = 3.76 & 7.52 Hz, 1H,
NCHO), 4.67 (t, J = 7.52 Hz, 1H,
Benzylic H), 4.55 - 4.42 (ddd, J = 4.03,
10.30 & 14.50 Hz, 2H, OCH2CHO),
3.82 (s, 3H, OCH3), 3.80 – 3.72 (dd, J =
6.17 & 8.05 Hz, 1H, CHCH2O), 3.59 –
3.50 (dd, J = 7.52 & 10.48 Hz, 1H,
CHCH2O); MS: m/z 284 (M+ +1,100
%), 151 (30%). Elemental Analysis:
Mol. F: C17H17NO3, Cal. C: 72.054, H:
6.051, N: 4.946; Experimental, C:
70.797, H: 5.763, N: 6.028.
Ar = 4-methoxy phenyl

106
 It was considered desirable to study the effect of substitution on the cyclization
reaction yielding oxazolooxazines. All the compounds reported in Table 3.5 have
substitutions at 1, 7 and 8 positions. It would be interesting to study the course of
cyclization if there are substitutions with aryl moiety at position 3. Therefore,
preparation of 42j, which was needed in the present work, was carried out as follows:-
Br CO2Me
OH K2CO3, Acetone O CO2Me
10 % Pd /C
NO2 Ph AcOH / H2gas
NO2
60 °C, 12 hrs
(36a) (37g)

O Ph ethylbromoacetate, O Ph O Ph
LAH / THF
N O K2CO3, DMF, r.t, N O r.t, 60 min N
H O
12 h O
(38i) (41j) (42j)
O
Scheme – 3.1
Commercially available 2-nitrophenol (36a) was reacted with 4 in the presence of
potassium carbonate as base in acetone to give ethyl 2- (2-nitrophenoxy)-2 –
phenylacetate (37g), which was characterized by its spectral and analytical data. Thus, its
IR (Neat) showed a diagnostic peak at 1737 cm-1 due to ester carbonyl stretching. Its 1H
NMR (in CDCl3) showed signals at δ 7.91 – 7.86 (dd, J = 1.07 & 8.32 Hz, 2H, Ar H),
7.64 – 7.59 (m, 5H, Ar H), 7.52 – 7.38 (m, 4H), 7.08 (t, J = 7.79 Hz, 1H, Ar H), 6.98 (d, J
= 8.3 Hz, 1H, Ar H), 5.76 (s, 1H), 3.71 (s, 3H). Its mass spectrum showed peaks at 288
(M+, 20 %), 149 (M-1, 100 %). 37g was cyclized in the presence of 10 % palladium
charcoal under hydrogen atmosphere in acetic acid to give 2-phenyl -3,4-dihydro-2H-
benzo[b][1,4]oxazin-3-one (38i). This was confirmed by analytical and spectral data.
Thus, its IR (KBr) showed peaks at 1681cm-1 indicating amide carbonyl stretching. Thus,
its 1H NMR (CDCl3) showed signals at δ 9.25 (bs, 1H, D2O exchangeable, NH), 7.45 –
7.43 (m, 2H), 7.35 – 7.32 (m, 3H), 7.04 – 6.91 (m, 3H), 6.89 – 6.78 (m, 1H), 5.69 (s, 1H).
Its mass spectrum showed the molecular ion peaks at m/z 226 (M+1, 100 %) in Q+1

108
mode. The compound 38i was N- alkylated with ethyl 2-bromoacetate in the presence of
potassium carbonate as a base in DMF at room temperature to give 41j. The structure of
41j was assigned based on following spectral data. Thus, its IR (KBr) showed peaks at
1748 cm-1 indicating ester carbonyl stretching as diagnostic peak. Its 1H NMR (CDCl3)
showed signal at δ 7.45 – 7.42 (m, 2H, Ar H), 7.34 – 7.21 (m, 3H, Ar H), 6.96 – 6.91 (m,
3H, Ar H), 6.71 – 6.67 (m, 1H, Ar H), 5.74 (s, 1H, Benzylic H), 4.90 (d, J = 17.46 Hz,
1H, NCH2CO), 4.42 (d, J = 17.46 Hz, 1H, NCH2CO), 4.26 – 4.15 (q, J = 7.25 Hz, 2H,
OCH2CH3), 1.22 (t, J = 7.25 Hz, 3H, OCH2CH3). Its mass spectrum showed peaks at 312
(M+1, 100 %), 311 (10 %) when spectrum used in the Q+1 mode. The compound 41j was
reduced with lithium aluminumhydride in THF followed by simple processing to obtain a
product as syrupy liquid. The compound was found to be homogenous on TLC. Its IR
spectrum (Neat) did not show any diagnostic peaks due to –NH- and -CO- groups. Its 1H
NMR (in CDCl3, 400 MHz) showed signals at δ 7.51 – 7.47 (m, 2H, ArH), 7.44 – 7.35
(m, 3H, ArH), 7.02 – 6.96 (dd, J = 7.80 and 12.55 Hz, 2H, ArH), 6.77 – 6.75 (d, J = 7.80
Hz, 2H, ArH), 4.72 – 4.70 (d, J = 7.32 Hz, 1H), 4.26 – 4.22 (m, 1H), 4.15 – 4.13 (d, J =
7.32 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.80 – 3.76 (m, 1H), 3.45 – 3.39 (m, 1H). Its mass
spectrum showed the molecular ion peak at m/z 254 (M+., 100 %). Based on this data, the
product was assigned as by 4-phenyl-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-
d][1,4]oxazine structure 42j. (Scheme – 3.1)
3.4 Experimental Section
i) Preparation of 37a-f (General procedure): To a suspension of 36 a-e (30 mmol) and
potassium carbonate (12.4 gms, 90.0 mmol) in dry dimethyl formamide (80 mL) was
added ethyl bromoacetate (4.0 mL, 36.0 mmol) at 25 °C and the mixture was stirred for
4.0 hrs at 80 °C. The reaction mixture was cooled to room temperature and water (200
mL) was added. The mixture was extracted with ethyl acetate (3 X 50 mL). The organic
layer was washed with water, dried over sodium sulfate and the solvent was evaporated
under reduced pressure yielding 37a-f. (Table-3.1)

109
ii) Preparation of 36f: To a solution of 5-fluoro-2-nitro phenol (40b) 5.0 g (31.80 mmol)
in HMPA (50 mL) was added sodium thiomethoxide (4.68 g, 66.87 mmol) at 25 °C and
the mixture was stirred for 12.0 hrs at room temperature. The reaction mixture was
poured into water (200 mL) acidified with cold 6N HCl (100 mL). The separated solid
was filtered washed with water and dried to obtain 36f. Yield = 5.6 gms (95 %).

iii) Preparation 38a: To a solution of 37a (5.0 gms, 22.22 mmol) in dioxane (60 mL)
was added 10 % palladium-carbon (1.0 g). The reaction mixture was stirred under 60 psi
of hydrogen pressure at room temperature for 6 hrs. The mixture was then filtered
through a bed of Celite and the bed was washed with dioxane. The combined filtrates
were concentrated under reduced pressure to give 38 a. Yield = 2.5 gms (75 %).

iv) Preparation of 38a – h (General procedure): To a solution of 37a - h in methanol

(10 mL / 1 gm) was added acetic acid (15 eq.) followed by iron powder (5.0 eq). Then
the reaction mixture was refluxed for 5 hrs at 80 °C. Solvent was removed from the
reaction mixture by distillation and the crude residue was neutralized with NaHCO3
solution. The mixture was extracted with ethyl acetate & combined organic layers were
washed with water. Finally, the organic layer was dried and concentrated under reduced
pressure to obtain 38 a-h. (Table-3.2)

v) Preparation of 38 g: To a solution of 38 f (2.5 gms, 12.82 mmol) in acetone (30 mL)

was added oxone (15.74 Gms, 25.6 mmol in 50 mL water) at 25 °C and the mixture was
stirred for 3.0 hrs at room temperature. Acetone was removed from the reaction mixture
by the distillation and residual water layer was diluted with more water. The separated
solid was filtered, washed and dried to obtain 38 g yield = 2.2 gms (76 %).

vi) Preparation of 38 h: To an ice cold solution of 2-amino-5-nitro-phenol (39) (10 g,

64.93 mmol), in dichloromethane (100 mL), was added triethylamine (18.0 mL, 129.86
mmol) followed by chloroacetylchloride (8.8 g, 77.92 mmol) at 0 °C. The mixture was

110
stirred for 6 hrs at room temperature and then made basic (to pH = 14) with aqueous
sodium hydroxide solution. The resulting mixture was stirred for 6.0 hours at room
temperature and acidified with dil hydrochloric acid; the separated solid was filtered,
washed with ethanol and dried to obtain 38 h as brown solid. Yield = 6.0 gms (48 %).

vii) Preparation of 41a-g (General procedure): To a suspension of 38 a-g and

potassium carbonate (3.0 eq) in dry dimethyl formamide (10 mL / 1.0 gm) was added
ethyl bromoacetate (1.2 eq) at 25 °C and the mixture was stirred for 12.0 hrs at room
temperature. The reaction mixture was poured into cold water; the separated solid was
filtered, washed and then dried to obtain 41 a-g. (Table-3.3).

viii) Preparation of 41h: To a suspension of 41g (2.0 gms, 7.1 mmol) in methanol (40
mL) was added nickel chloride (5.06 gms, 21.3 mmol) at 0 °C and followed by pinch by
pinch of sodiumborohydride (1.08 gms, 28.57 mmol) at 0 °C. The reaction mixture was
stirred for 4 hrs at room temperature, then the solvent was removed from the mixture
under reduced pressure. Then the crude residue was dissolved in ethyl acetate, and
organic layer was washed with water dried and concentrated to give 41h.

ix) Preparation of 42a-h (General Procedure): To a solution of 41a-h (2.0 mmol) in

dry THF (10 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several
portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The reaction
mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was
filtered and the filtrate concentrated. The crude residual product was purified by column
chromatography using ethyl acetate and pet. ether (5:95) to give 42a-h. (Table-3.4).

x) Preparation of 44: To an ice cold solution of 47a (6.0 g, 33.8 mmol) in acetic
anhydride (100 mL) was added fuming nitric acid (2.34 g, 37.18 mmol) drop wise at –5
°
C, and the mixture was stirred for three hours at 0 °C. The reaction mixture was poured
in to crushed ice; the separated solid was filtered, washed with water and dried well. The

111
crude was purified through column chromatography using ethyl acetate & petroleum
ether to give 44 as yellowish crystalline solid, Yield: 1.5 g (44 %).

xi) Preparation of 37f: To a solution of 2-nitrophenol (36f) (4.0 g, 28.7 mmol) and
potassium carbonate (12.0 g) in acetone was added ethyl α-bromo phenylacetate (7.9 g,
34.5 mmol) at room temperature and the mixture was refluxed for 12.0 hrs. Then the
reaction mixture was filtered, washed with acetone and filtrate was concentrated under
reduced pressure. Crude residue was dissolved in ethyl acetate and washed with water.
Ethyl acetate layer was dried and concentrated under reduced pressure to give 37f in 82
% yield.

xii) Preparation of 38h: Palladium carbon (3.0 gm of 10 % ) was charged in 1000 mL

hydrogenation flask, made wet with acetic acid (50 mL) and to this 37f (15.0 gm, in150
mL of acetic acid) was added at room temperature. Then the flask was arranged for Parr
hydrogenation for 6.0 hrs at 60 psi H2 pressure. The reaction mixture was filtered
through a pad of Celite to remove palladium carbon and the filter bed washed with acetic
acid. The filtrate was stirred with 2000 mL of water and the separated white solid was
filtered, washed with water and dried to obtain 38h. (8.0 gms, 67 %)

xiii) Preparation of 41i: To a solution of 38h(1.0 gm, 4.42 mmol) and potassium
carbonate (1.8 gm, 13.2 mmol), in 20 mL of dry dimethylformamide was added ethyl
bromoacetate (0.6 mL, 5.3 mmol) drop wise at room temperature. After 12.0 hrs stirring
the mixture was poured in to water and the separated solid was filtered, washed with
water and dried to give 83 % of 41i.

xiv) Preparation of 42i: To a solution of 41i (2.0 mmol) in dry THF (10 mL) at 0 °C,
lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 20
min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with
aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate

112
concentrated. The crude product was purified by column chromatography using ethyl
acetate and pet. ether (5:95) to give 42i.

3.5 Reference:
01. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe
Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques Royer,
David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc. 1983, 105,
7754.
02. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A.
I. Arkivoc, 2003, xiii, 166.
03. (a) Sicker Dieter, Praetotius Birgitt, Mann Gerhard, Meyer Lutz.; Synthesis; 1989, 3,
211. (b) Atkinson, J. Morand Peter, Arnason John T, Niemeyer Harmann M., Bavo
Hector R., J. Org. Chem., 1990, 56 (5), 1788. (c) Banzatti Carlo, Heidempergher

113
 Franco, Melloni Piero; J. Heterocycl. Chem.; 1983, 20, 259. (d) Sicker, Dieter;
Praetorius, Birgitt; Mann, Gerhard; Meyer, Lutz; Synthesis; 1988, 3, 211.
04. Finger, J. Amer. Chem. Soc.; 1959, 81, 94.
05. (a) Schlaeger, Leeb. Monatsh. Chem., 1950, 81, 714. (b) Blout, Silverman, J.
Amer. Chem. Soc., 1944, 66, 1442.
06. (a) Hogale, M. B.; Nikam, B. P. J. Indian Chem. Soc. 1988, 60 (10), 735. (b)
Caliendo, G.; Grieco, P.; Perissutti, E.; Santagada, V.; Santini, A. Eur. J. Med.
Chem. Ther. 1975, 33 (12), 957. (c) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, Akira,;
Takayama, Kazuhisa.; Yoden, T. Chem. Pharm. Bull. 1996, 44 (1), 103.
07. S. Vishnu Vardhan Reddy, A. Sivalakshmidevi, K. Vyas. Venugopal Rao
Veeramaneni, Koteswar Rao Yeleswarapu, A. Venkateswarlu and P. K. Dubey.
Acta Cyrstallographia Section E, 2003, E59, 0369.

CHAPTER – IV

STUDIES ON SYNTHESIS OF
“OXAZOLO [3,2-a]QUINOXALINES”

114
4.1 Introduction:
Oxazolo quinoxalines are not well documented in literature. Not much work have been
done in this area. One oxazolo quinoxaline, i.e. N, N’-[(4”, 5”-dimethyl)-1”, 2”-
phenylene]-2,2’-dimethyl-bisoxazolidine (49) seems to be well-known.1

N O

N O

(49)
2,3-Butanedione (50) was condensed with ethanol amine (52) in benzene1 for 5 hrs at
room temperature. Processing of the reaction mixture and separation of products gave 49
along with 52, 53 and 54. (Equation 4.1)

O H HO
(50) N O N N OH N O
Benzene OH NH
O CH3
Room OH O OH N
N N O O
H CH3
OH temperature (52) (53) (54) (49)
H2N 5.0 hrs
(51)

Equation – 4.1
4.2 Present Work:
Survey of literature revealed that preparation of oxazoloquinoxalines has not been
carried out very extensively. Therefore, it was considered desirable to prepare new
compounds containing oxazoloquinoxalines. It is conceivable that these oxazolo
moieties can be synthesized from 1,2-diaminobenzene by ring closure with chloroacetic

115
acid to obtain quinoxalin-2-one in the first step. The latter can be used as a building block
for the synthesis of fused oxazolo ring units.

4.3 Results and Discussion:

Commercially available o-phenylenediamine (55a) was treated with ethyl 2-
bromoacetate in the presence of triethylamine2 as a base in dichloromethane and
tetrahydrofuran as solvent to obtain 1,2,3,4-tetrahydro-2-quinoxalinone (56a R = H) in
67.0 % yield. (Equation – 4.2)
H
NH2 BrCH2CO2Et N

NH2 TEA, CH2Cl2 N O

THF H
(55)
(56a)

Equation – 4.2
Compound 56a is known in literature. However, it was further characterized in
the present work by analytical and spectral data. Thus, its IR (KBr) spectrum showed
(Fig 4.1) a peak at 3367 cm-1 (due to –NH stretching) and at 1681 cm-1 (due amide
carbonyl stretching) as diagnostic peaks. Its 1H NMR (DMSO d6): showed signals (Fig
4.2) at δ 10.21 (bs, 1H, D2O Exchangeable, NH), 6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H,
D2O Exchangeable, NH), 3.34 (s, 2H, NCH2CO), and its mass spectrum (Fig 4.3) showed
the molecular ion peak at m/z 149 (M++1, 100 % ) as the base peak in the spectrum.
In addition to the method given above, several other methods have also been
reported in literature for the preparation of 2-quinoxalinones. Thus, for example,
condensation3 of o-phenylenediamine and ethyl 2-halo-2-alkylacetate in the presence of
zinc dust, or the addition4 of chloroacetic acid in the presence of ammonia, or the
addition5 of 2-chloroacetamide in the presence of aqueous sodium hydroxide at 100 °C,
from N-(2-nitrophenyl)glycine in the presence of tin hydrochloride,6 o-phenylenediamine
and chloro acetic acid in the presence of sodium carbonate.7and from other methods.8
Table – 4.1: Some known methods to prepare compounds 56a - g

116
S.No Reactant Conditions Product Ref:
1. NH2 Ethyl 2-bromo acetate, H 2
N

NH2 Triethylamine, THF

N O
H
2. NH2 Chloro acetic acid, H 3
N

NH2 Diluted Ammonia

N O
H
3. NH2 Chloro acetamide H 4
N

NH2 Diluted Ammonia

N O
H
4. NH2 Bromo acetic acid H 5
N

NH2 Zinc dust, HCl

N O
H
5. NH2 Ethyl 2-bromo-2,21- H 6
N

NH2 dimethyl acetate

N O
H
6. NH2 Trichloromethane H 7
N

NH2 Acetone, NaOH, PTS

N O
H
7. NH2 1,1,1-trichloro-2- H 7
N

NH2 methylpropan-2-ol,
N O
NaOH, PTS H

8. NH2 1,1,1-trichloro H 8
N

NH2 compound, KOH

N O
H
9. NH2 3-phenyloxirane-2,2- H 9
N Ph
NH2 dicarbonitrile, ethanol
N O
H

117
 10. NH2 Ethyl α-bromo phenyl H 10
N Ph
NH2 acetate, K2CO3, KI,
N O
NaOEt H

11. NH2 Ethyl bromo acetae H 11

N

NH2 Pot. tert. butoxide

N O
H
12. O Tin, HCl H 12
H N
N
OH
N O
NO2 H
13. O H2 Pressure / 10 % H 2
H N
N
OEt Palladium Carbon.
N O
NO2 H
14. H Pd(dba)2, Carbon H 13
N N
monoxide.
NO2 N O
H
15. N Ph Palladium carbon, H 14
N Ph

N O
Hydrogen pressure
N O
H H

Keeping this in view two simple but new methods were developed for the
synthesis of quinoxalines. In the first method o-phenylenediamine was treated with ethyl
2-bromo acetate in DMF in the presence of microwave irradiation for 5.0 min to obtain
56a in 72 % yield. (Equation – 4.3)

118
 BrCH2CO2Et, NaOH,

Water, 80 °C, 1.0 hr, H

N
NH2

N O
NH2 H
(55) BrCH2CO2Et, DMF (56a)

4 - 5 min

Equation – 4.3
Substituted 1,2,3,4-tetrahydro-2-quinoxalinone (56a-i) were prepared in the above
two methods. The structures for these products were assigned on the basis of analogy
and on the basis of analytical and spectral data. (Table –4.2)
H R
NH2 N R1

NH2 N
H O

(55) (56 a-i)

Equation – 4.4

119
 Table – 4.2: Synthesis of 56 (a-h) from o-phenylenediamine.
S. No. R R1 Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat)
/ cm-1.
56a H H 72 IR (KBr): 3367 (Amide NH band), 1681 cm-1 (Amide Keto). 1H
NMR (In DMSO d6): δ 10.21 (bs, 1H, D2O Exchangeable, NH),
6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H, D2O Exchangeable,
NH), 3.38 (s, 2H, NCH2CO); Mass: 149 (M+ +1, 100%).
56b. H Me 69 IR (KBr): 1665 cm-1 (Amide Keto); 1H NMR (In DMSO d6): δ
12.17 (bs, 1H, D2O Exchangeable, NH), 7.72 (d, J = 7.81 Hz,
1H, ArH), 7.5), 7.70 – 7.21 (m, 3H, ArH), 2.95 (m, 1H,
NHCHCH3), 2.55 (s, 3H, CHCH3); Mass: 162 (M+, 10%), 161
(100 %).
56c. Me Me 73 IR (KBr): 3422 cm-1 (amide NH band), 1667 cm-1 (Amide
carbonyl stretching); 1H NMR (CDCl3, 200 MHz): 10.57 (bs,
1H, D2O Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, Ar H),
7.18 (d, J = 7.79 Hz, 1H, Ar H), 7.00 (d, J = 7.79 Hz, 2H, Ar H),
1.34 (s, 6H, C(CH3)2; Mass: m/z 194 ((M+ +1, 20 %).
56d. H Et 65 IR (KBr): 3440 cm-1 (amide NH band), 1659 cm-1 (Amide
1
carbonyl stretching); H NMR (In CDCl3): δ 11.99 (bs, 1H,
D2O Exchangeable, NH), 8.10 (d, J = 7.81 Hz, 1H, ArH), 7.78 –
7.71 (m, 1H, ArH), 7.59 – 7.52 (m, 2H, ArH), 3.32 – 2.21 (m,
1H, CHCH2CH3), 1.72 – 1.56 (m, 2H, CHCH2CH3), 1.44 – 1.36
(t, = 7.33 Hz, 3H, CH2CH3); Mass: 177 ((M+ +1, 10 %), 175
(M+, 100 %).
56e. H Pr 68 IR (KBr): 3384 (amide NH band), 1668 cm-1 (Amide carbonyl
1
stretching); H NMR (In DMSO d6): δ 12.16 (bs, 1H, D2O
Exchangeable, NH), 7.70 (d, J = 7.82 Hz, 1H, ArH), 7.45(t, J =
7.81 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 2.75 (t, J = 7.33
Hz, 1H, CHCH2CH2CH3), 2.53 (t, J = 5.36 Hz, 2H,

122
 CHCH2CH2CH3), 1.73 (t, J = &.32 Hz, 2H, CHCH2CH2CH3),
0.95 (t, J = 7.32 Hz, 3H, CHCH2CH2CH3); Mass: 191 (M+1, 50
%), 189 (M+, 100 %).
i
56f. H Pr 59 IR (KBr): 3433 (amide NH band), 1665cm-1 (Amide carbonyl
1
stretching); H NMR (In DMSO d6): δ 11.92 (bs, 1H, D2O
Exchangeable, NH), 7.71 (d, J = 7.82 Hz, 1H, ArH), 7.45(d, J =
7.33 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 3.49 – 3.42 (m,
1H, CH(CH3)2), 1.23 (s, 3H, CH(CH3)2), 1.19 (s, 3H,
CH(CH3)2); Mass: 191 (M+1, 10 %), 189 (M+, 100 %), 188 (40).
56g. H Ph 63 IR (KBr): 3425 (amide NH band), 1664cm-1 (Amide carbonyl
1
stretching); H NMR (In DMSO d6): δ 12.57 (bs, 1H, D2O
Exchangeable, NH), 8.32 – 8.27 (m, 2H, ArH), 8.29 – 8.27 (d, J
= 7.33 Hz, 1H, ArH), 7.59 –7.49 (m, 4H, ArH), 7.74 (d, J = 7.81
Hz, 1H, ArH), 7.51 (s, 3H, CHPh); Mass: 224 ((M+ +1, 10 %),
223 (M+, 100 %), 194 (10).

123
Compound 56a was treated with benzyl bromide in the presence of sodium carbonate in
aq.ethanol15 to give 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a). (Equation 4.5)

CH2Ph
H
N N
PhCH2Br
Na2CO3 N O
N O
H aq. EtOH H
(56a) 80 °C, 12 hrs (57a)
Equation – 4.5

Substituted 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinones (57b and 57c) were prepared

in the above method. (General Equation 4.6) The structures for these products were
assigned on the basis of analogy and on the basis of analytical and spectral data. (Table –
4.3)
Bn
H N R
N R BnBr
Na2CO3 N O
N O aq. EtOH H
H
(56b &c)
(56c & h)
Equation – 4.6

124
 Table – 4.3: Synthesis of 57 from 56
Sub. Pdt. R Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat)
/ cm-1.
56a 57a H 79.0 IR (KBr): (Fig 4.4) 3438 (NH band stretching), 1684 cm-1
(Amide carbonyl stretching); 1H NMR (in CDCl3): (Fig 4.5) δ
9.29 (bs, 1H, D2O Exchangeable, NH), 7.31- 7.25 (m, 5H, Ar
H), 6.94 – 6.82 (m, 1H, Ar H), 6.79 – 6.72 (m, 3H, Ar H), 4.41
(s, 2H, PhCH2), 3.81 (s, 2H, NCH2); Mass: m/z (Fig 4.6) 239
(M+1, 100 %) and 238((M+ +1, 30 %).
56h 57b Ph 59 IR (KBr): 3431 (NH band stretching), 1682 cm-1 (Amide
carbonyl stretching); 1H NMR (in CDCl3): δ 8.69 (bs, 1H, D2O
exchangeable, NH proton), 7.29 – 7.17 (m, 10H, ArH), 6.96 –
6.92 (m, 1H, ArH), 6.77 – 6.71 (m, 3H, ArH), 4.97 (s, 1H, NCH
(Ph)), 4.67 (d, J = 15.62 Hz, 1H, NCH2Ph), 4.09 (d, J = 15.62
Hz, 1H, NCH2Ph); Mass: 315 ((M+ +1, 100 %).
56c 57c DiMe 74.0 % IR (KBr): 3445 (NH band stretching), 1680 cm-1 (Amide
carbonyl stretching); 1H NMR (in CDCl3): δ 8.06 (bs, 1H, D2O
Exchangeable, NH), 7.32- 7.21 (m, 5H, Ar H), 6.82 – 6.78 (m,
1H, Ar H), 6.71 (d, J = 3.43 Hz, 2H, Ar H), 6.51 (d, J = 7.79 Hz,
1H, Ar H), 4.51 (s, 2H, PhCH2), 1.51 (s, 6H, NC(CH3)2); Mass:
m/z 267 ((M+ +1, 100 %).

125
 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a) was treated with ethyl 2-
bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for 12 hrs. (Equation
4.7) Processing of the reaction mixture gave a product which was found to be ethyl 2-(4-
benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58a) which was characterized by
spectral methods. Thus, in its IR spectrum (Fig 4.3.1) peaks were found at 1749 cm-1
(due to ester carbonyl stretching) and at 1678 cm-1 (due to amide carbonyl stretching)
were observed. Its 1H NMR (In CDCl3) showed (Fig 4.3.2) signals at δ 7.32 (m, 5H,
ArH), 6.98 (t, J = 7.33 Hz, 1H), 6.87 – 6.70 (m, 3H), 4.67 (s, 2H), 4.38 (s, 2H), 4.29 –
4.18 (q, J = 7.33 Hz, 2H), 3.81 (s, 2H), 1.28 (t, J = 7.33 Hz, 3H). Its mass spectrum (Fig
4.3.3) showed peaks at m/z 325 (M+1, 100 %) and at 324 (M+, 30 %) in the Q+1 mode.
Bn
Bn
N
N K2CO3 / BrCHCO2Et

DMF 80 0C, 12.0 hrs N O

N O
H (58a) OEt
(57a)
O
Equation – 4.7
Substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl) acetates
could also be prepared using the above method. Structures of all the products (58a – h)
have been assigned on the basis of analogy and on the basis of spectral & analytical data
(Table – 4.4).
Bn Bn
N R N R
K2CO3, BrR1CHCO2Et

N DMF 80 0C, 12.0 hrs N O

H O
OEt
R1
(57a - h)
O
(58a - i)
Equation – 4.8

126
 Table – 4.4: Synthesis of 58 (a-h) from 57 (a-c)
Sub. Pdt. R R1 Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr /
Neat) / cm-1.
57a 58a H H 78 IR (KBr): 1749 (Ester carbonyl stretching), 1677 cm-1
(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m,
5H, ArH), 6.98 (t, J = 7.33 Hz, 1H, ArH), 6.87 – 6.70 (m,
3H, ArH), 4.67 (s, 2H, NCH2Ph), 4.38 (s, 2H, NCH2CON),
4.29 – 4.18 (q, J = 7.33 Hz, 2H, CO2CH2CH3), 3.81 (s, 2H,
NCH2CO2Et), 1.28 (t, J = 7.33 Hz, 3H, CO2CH2CH3);
Mass: 325 (M+1, 100 %), 324 (M+, 10 %).
57b 58b Ph H 81 IR (KBr): 1749 (Ester carbonyl stretching), 1679 cm-1
1
(Amide carbonyl stretching); H NMR (CDCl3): δ 7.98 –
7.16 (m, 10H, ArH), 7.02 – 6.94 (m, 2H, ArH), 6.88 – 6.71
(m, 2H), 5.15 (s, J = 1H, NCHPh), 5.05 (m, 2H, NCH2Ph),
4.64 (d, J = 15.14 Hz, 1H, NCH2CO2Et), 4.40 (d, J = 17.10
Hz, 1H, NCH2CO2Et), 4.28 – 4.06 (m, 2H, CO2CH2CH3),
1.15 (t, J = 7.33 Hz, 3H, CO2CH2CH3); Mass: 401 ((M+ +1,
100 %), 309 (10 %).
57a 58c H Me 63 IR (KBr): 1741 (Ester carbonyl stretching), 1682 cm-1
(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m,
5H, ArH), 7.21 – 6.95 (m, 2H, ArH), 6.89 – 6.79 (m, 2H,
ArH), 5.49 – 5.56 (m, 2H, NCH2Ph), 5.28 – 5.25 (m, 2H,
NCH2CON), 4.26 – 4.13 (m, 2H, CO2CH2CH3), 3.73 – 3.72
(m, 2H, NCH2CO2Et), 1.75 (d, J = 8.0 Hz, 3H, CHCH3), 1.30
– 1.16 (m, 3H, CO2CH2CH3); Mass: 339 (M+1, 100 %), 338
(M+, 30 %).
57a 58d H Et 57 IR (KBr): 1739 (Ester carbonyl stretching), 1683 cm-1
1
(Amide carbonyl stretching ); H NMR (In CDCl3): δ 7.31
(m, 5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.77 (m, 3H,

127
 ArH), 5.36 – 5.28 (m, 1H, NCHCH2CH3), 4.49 – 4.42 (d, J =
15.44 Hz, 1H, NCH2Ph), 4.32 – 4.24 (d, J = 15.44 Hz, 1H,
NCH2Ph), 4.22 – 4.13 (m, 2H, CO2CH2CH3), 3.75 (s, 2H,
NCH2CON), 2.32 – 2.22 (m, 1H, NCHCH2CH3), 2.14 – 2.03
(m, 1H, NCHCH2CH3), 1.19 (t, J = 7.33 Hz, 3H,
CO2CH2CH3), 0.89 (t, J = 7.33 Hz, 3H, NCHCH2CH3);
Mass: 261 (M+ -1, 100 %).
57a 58e H Hex 49 IR (KBr): 1740 (Ester carbonyl stretching), 1685 cm-1
(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.31 (m,
5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.76 (m, 3H,
ArH), 5.48 (s, 1H), 4.36 (d, J = 15.44 Hz, 1H, NCH2Ph),
4.27 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.25 – 4.14 (m, 2H,
CO2CH2CH3), 3.75 (s, 2H, NCH2CON), 2.23 – 2.03 (m, 1H,
NCHCH2CH3), 1.23 – 1.16 (m, 11H), 0.82 (m, 3H); Mass:
407 (M+, 100 %).
57a 58f H Ph 56 IR (KBr): 1748 (Ester carbonyl stretching), 1683 cm-1
(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.34 –
7.31 (m, 10H), 6.97 – 6.79 (m, 2H), 6.75 – 6.68 (m, 2H),
6.24 (s, 1H), 4.54 – 4.30 (m, 2H), 3.86 – 3.82 (m, 2H), 3.77
(s, 3H); Mass: m/z 387 (M+1, 100 %) and 253 (10 %).
57b 58g Ph Ph 61 IR (KBr): 1744 (Ester carbonyl stretching), 1678 cm-1
1
(Amide carbonyl stretching); H NMR (CDCl3): δ 7.35 –
7.08 (m, 15H, ArH), 6.99 – 6.91 (m, 1H, ArH), 6.83 – 6.80
(m, 1H), 6.76 – 6.64 (m, 2H), 6.06 (s, 1H), 5.14 (d, J = 7.60
Hz, 1H, NCHPh), 4.83 – 4.70 (dd, J = 10.8 & 15.1 Hz, 1H,
NCH2CO2Et), 4.22 (t, J = 5.1 Hz, 1H, NCH2CO2Et), 3.82 (s,
3H), 3.60 (s, 1H); Mass: 463 ((M+ +1, 100 %), 371 (20 %),
265 (30 %).
57c 58h DiMe H 65 IR (KBr): 1739 (Ester carbonyl stretching), 1678 cm-1

128
(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.33-
7.21 (m, 5H, Ar H), 6.87 – 6.80 (m, 4H, Ar H), 4.69 (s, 2H,
NCH2), 6.71 – 6.59 (m, 2H), 4.53 (s, 2H, PhCH2), 4.30 –
4.19 (q, J = 7.32 Hz, 2H, OCH2CH3), 1.51 (s, 6H,
NC(CH3)2), 1.25 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: m/z
353 ((M+ +1, 100 %), 337.

129
Reductions with Lithium Aluminum Hydride (LAH):
Treatment of 58a with 1.1 eq. of LAH in THF followed by simple processing
gave a product, which was obtained as a syrupy liquid. The compound was found to be
homogenous on TLC. Its IR spectrum (Neat) (Fig 4.10) did not show any diagnostic
peaks due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed (Fig 4.11) signals
at δ 7.32 (m, 5H, ArH), 6.95 – 6.61 (m, 4H, ArH), 4.90 – 4.84 (dd, J = 3.90 & 7.32 Hz,
1H), 4.61 – 4.53 (d, J = 15.63 Hz, 1H), 4.33 – 4.26 (d, J = 15.13 Hz, 1H), 4.21 – 4.11 (m,
1H), 4.06 – 3.94 (m, 2H), 3.66 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J = 7.33 & 10.74 Hz, 1H).
Its mass spectrum (Fig 4.12) showed peaks at m/z 267 ((M+ +1, 90 %) and m/z 266 (M+,
100 %) in the Q+1 mode. Based on this data, the product was assigned as 5-benzyl-
1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59a). (Equation – 4.9)

Bn
Bn
N
N
LAH
N O THF, 0 °C
N O
OEt to r.t
1.0 hr
O
(58a) (59a)

Equation – 4.9
The above reaction of 58a yielding 59a general. It has been extended to other
substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetates (58a-h)
yielding (59a-h). (Equation – 4.10)

130
 Bn Bn
N R N R
LAH
N O THF, 0 - r.t N O
OEt 1.0 min
R1
R1
O
(58a-h) (59a-h)

Equation – 4.10
Table –4.5: Synthesis of 59 (a-h) from 58 (a-h) with LAH was explained by data:
Sub. Pdt. Yiel Analytical Data: (IR cm-1), 1H NMR (δppm) (CDCl3,
S.No R R1 d 200 MHz) & Mass
%
58a 59a H H 75 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H), 6.95 –
6.61 (m, 4H), 4.90 – 4.84 (m, 1H), 4.61 – 4.26 (dd, J =
15.63 and 15.13 Hz, 2H), 4.21 – 4.11 (m, 1H), 4.03 –
3.94 (m, 2H), 3.65 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J =
7.33 and 10.74 Hz, 1H); Mass (m/z): 267 ((M+ +1, 90
%), 266 (M+, 100 %).
8b 59b Ph H 69 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.33 – 7.14 (m, 10H), 6.81 –
6.71 (m, 2H), 6.63 – 6.56 (m, 2H), 5.02 (d, J = 3.90 Hz,
1H), 4.89 – 4.51 (m, 2H), 4.30 – 3.96 (m, 3H), 3.66 –
3.34 (m, 3H); Mass: (m/z) 343 ((M+ +1, 90 %), 342 (M+,
100 %).

131
58c 59c H Me 54 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H, Ar H),
6.82 – 6.63 (m, 4H, Ar H), 5.03 – 4.97 (dd, J = 4.36 and
7.24 Hz, 1H), 4.60 – 4.45 (m, 2H), 4.26 – 4.13 (m, 2H),
4.03 – 3.91 (m, 2H), 3.57 – 3.41 (m, 2H), 2.68 – 2.59
(m, 1H), 1.39 (d, J = 6.17 Hz, 3H); Mass: (m/z) 281
((M+ +1, 90 %), 280 (M+, 100 %).
58d 59d H Et 66 IR: Did not show any diagnostic peaks due to –NH- and
1
-CO- groups. H NMR: δ 7.34 – 7.25 (m, 5H, Ar H),
6.81 – 6.64 (m, 4H, Ar H), 5.00 – 4.94 (dd, J = 4.36 and
6.75 Hz, 1H), 4.55 (d, J = 15.08 Hz, 1H), 4.25 (d, J =
15.08 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.85 – 3.75 (m, 1H),
3.67 – 3.60 (m, 2H), 3.49 – 3.41 (dd, J = 4.0 and 11.0
Hz, 1H), 2.72 – 2.63 (dd, J = 6.99 and 11.01 Hz, 1H),
1.90 – 1.71 (m, 1H), 1.68 – 1.56 (m,1H), 1.02 (t, J = 7.30
Hz, 3H); Mass: (m/z) 295 ((M+ +1, 90 %), 294 (M+, 100
%).
58e 59e H Hex 49 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.34 – 7.25 (m, 5H, Ar H),
6.81 – 6.63 (m, 4H, Ar H), 4.99 – 4.94 (dd, J = 4.31 and
6.71 Hz, 1H), 4.58 – 4.51 (d, J = 15.04 Hz, 1H), 4.24 (d,
J = 15.04 Hz, 1H), 4.06 (d, J = 7.52 Hz,1H), 3.85 – 3.82
(m, 1H), 3.64 – 3.58 (dd, J = 4.83 and 7.79 Hz, 2H), 3.48
– 3.41 (dd, J = 4.30 and 11.02 Hz, 1H), 2.72 – 2.63 (dd, J
= 16.98 and 10.98 Hz, 1H), 1.83 – 1.64 (m, 1H), 1.55 –
1.47 (m,1H), 1.32 – 1.26 (m, 8H), 0.98 – 0.88 (m, 3H);
Mass: (m/z) 351 ((M+ +1, 90 %), 350 (M+, 100 %).

132
58f 59f H Ph 58 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.41 – 7.25 (m, 12H, Ar H),
6.77 – 6.56 (m, 2H, Ar H), 6.41 – 6.37 (m, 1H), 5.27 –
5.21 (dd, J = 11.57 and 7.79 Hz, 1H), 4.77 (t, J = 8.32
Hz, 1H), 4.23 (d, J = 14.77 Hz, 1H), 3.72 (t, J = 8.33 Hz,
1H), 3.58 – 3.51 (dd, J = 4.60 and 15.31 Hz, 1H), 2.67 –
2.58 (dd, J = 7.74 and 10.48 Hz, 1H); Mass: (m/z) 343
(M+ +1, 90 %), 342 (M+, 100 %).
58g 59g Ph Ph 49 IR: Did not show any diagnostic peaks due to –NH- and
-CO- groups. 1H NMR: δ 7.41 – 7.16 (m, 19H, Ar H),
6.65 – 6.44 (m, 2H, Ar H), 5.30 (d, J = 6.45 Hz, 1H),
4.88 (m, 1H), 4.53 – 4.43 (m, 2H), 4.05 (d, J = 16.65 Hz,
1H), 3.84 (d, J = 6.45 Hz, 1H), 3.69 (t, J = 8.06 Hz, 1H);
Mass: (m/z) 419 ((M+ +1, 90 %), 418 (M+, 100 %).
58h 59h Di H 63 IR: Did not show any diagnostic peaks due to –NH- and
Me -CO- groups. 1H NMR: δ 7.32 – 7.19 (m, 5H, Ar H),
6.65 (m, 1H, Ar H), 6.52 (t, J = 7.3 Hz, 2H, Ar H), 6.37
(d, J = 7.2 Hz, 1H, Ar H), 4.62 (d, J = 14 Hz, 2H), 4.29 –
4.09 (m, 2H), 3.61 – 3.49 (m, 2H), 0.97 (s, 6H); Mass:
(m/z) 295 ((M+ +1, 50 %), 294 (M+, 100 %), 223 (90
%).

133
 It was considered desirable to study the effect of substitution in the cyclization
reaction yielding oxazolooxazines. All the compounds which are N-benzyl derivatives
are reported in Table 4.5. It would be interesting to study the course of cyclisation in N-
ethyl substituted derivatives instead of N-benzyl substituted derivatives. Therefore,
preparation of 59i, was needed in the present work was carried as follows: - Compound
56a was treated with ethyl bromide in the presence of sodium carbonate in aq.ethanol8 to
give 4-ethyl-1,2,3,4-tetrahydro-2-quinoxalinone (57d) and its structure was confirmed
from spectral and analytical data. Thus, its IR (KBr) showed a peak at 3443 cm-1
indicating presence of – NH – group and another at 1686 cm-1 indicating presence of
amide carbonyl group. Its 1H NMR (In CDCl3) showed signals at δ 10.32 (bs, 1H, D2O
exchangeable Amide NH proton), 6.89 – 6.60 (m, 4H), 3.82 (s, 2H), 3.67 (s, 2H), 3.32 –
3.22 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). Its mass spectrum showed peaks at m/z
177 (M+1, 100 %) and at m/z 176 (M+, 10 %) in the Q+1 mode. Compound 57d was
treated with ethyl 2-bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for
12.0 hrs. Processing of the reaction mixture gave a product which was found to be ethyl
2-(4-ethyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58i) characterized by spectral
methods. Thus, its IR showed peaks at1748 cm-1 due to carbonyl carbon stretching and
another peak at 1684 cm-1 due to amide carbonyl stretching. Its 1H NMR (In CDCl3)
showed signals at δ 7.04 – 6.90 (m, 2H), 6.83 – 6.67 (m, 3H), 4.65 (s, 2H), 4.30 – 4.21
(m, 2H), 3.83 (s, 2H), 3.37 – 3.27 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.21 (t, J =
7.0 Hz, 3H). Its mass spectrum showed peaks at 277 (M+1, 100 %) in the Q+1 mode.
Treatment of compound 58i with 1.1 eq. of LAH in THF yielded syrupy product. The
compound was found to be homogenous on TLC. Its IR spectrum (Neat) did not show
any diagnostic peaks due to of –NH- and -CO- groups. Its 1H NMR (in CDCl3) show
signals at δ 6.77 – 6.65 (m, 3H), 6.63 – 6.57 (m, 1H), 4.90 – 4.84 (dd, J = 4.0 and 8.7 Hz,
1H), 4.17 – 4.09 (m, 1H), 4.05 – 3.93 (q, J = 7.3 Hz, 2H), 3.64 – 3.24 (m, 3H), 2.72 –
2.63 (dd, J = 7.3 and 10 Hz, 1H), 1.17 (t, J = 7.3 Hz, 3H). Based on this data, the product
was assigned as 5-ethyl-1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59i).

135
 H N Ethyl bromoacetate
N EtBr

Na2CO3 N O K2CO3, DMF

N O aq. EtOH H
H 80 °C
(57d)
(56a)

N LAH N

N O N O
THF
O
(58i) (59i)
O
Scheme – 4.1
When N-ethyl derivative 58i was subjected to reduction with LAH it gave the
final product 59 in lower yield than the corresponding N-benzyl derivatives. This
indicates that for good yields N-benzyl protection is preferable than N-ethyl protection.
Another advantage with N-benzyl derivatives is that it is easy to remove the benzyl group
from tricyclic oxazolo quinoxaline to yield the parent ring system which can be utilized
for further chemical reactions.

4.4 Experimental procedure:

i) Preparation of 56a - h (General procedure):
Method A: To a solution of o-phenylenediamine (55, 5.0 gms, 46.0 mmol) in
water was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl
acetate (1.2 eq) at room temperature. The reaction mixture was stirred for one hour at 80
°
C, cooled to room temperature and neutralized with aq. HCl (50 %, v/v). The separated
solid was filtered, washed with water and dried to obtain 56a-h (Table-4.1).

136
 Method B: To a solution of o-phenylenediamine (55, 0.5 gms, 4.6 mmol) in DMF
was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl
acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using
household microwave oven for 5.0 min. Then, the mixture was cooled, and neutralized
with aq. HCl (50 %, v/v). The separated solid was filtered, washed with water and dried
to obtain 56a-h (Table-4.1).

ii) Preparation of 57a - c (General procedure): To a solution of compounds 57a -h and

sodium carbonate (2.0 eq) in aqueous ethanol (10 mL ethanol: 1.0 mL water for 1.0 gm
of substrate) was added benzyl bromide (1.2 eq.) and the mixture refluxed for 12 hrs.
The reaction mixture was cooled to room temperature and poured into water. The
separated solid was filtered, washed with water and dried to obtain 57a-c (Table-4.2).

iii) Preparation of 57d: To a solution of compounds 56a (2.0 gms, 13.51 mmol) and
sodium carbonate (2.75 gms, 27.07 mmol) in aqueous ethanol (20 mL ethanol: 2.0 mL
water) was added ethyl bromide (1.26 mL, 16.21 mmol) and refluxed for 12 hrs. The
reaction mixture was cooled to room temperature and poured into water. The separated
solid was filtered, washed with water and dried to obtain 57d (1.78 gm, 75 %).

iv) Preparation of 58a – i (General procedure): To a solution of 57 a – d (1.0 eq) and

potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2-
alkyl acetate (1.2 eq) drop wise at room temperature. After 12.0 hrs stirring at 80 °C, the
mixture was poured in to water. The separated solid was filtered, washed with water and
dried to give 58a –i (Table-4.3).

v) Preparation of 59a – i (General procedure): To a solution of 58a - i (2.0 mmol) in

dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several
portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The reaction
mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was

137
filtered and the filtrate concentrated. The separated crude product was purified by column
chromatography using ethyl acetate and pet. ether (5:95) to give 59a – m (Table-4.4).

4.5 References:
01. Noberto Farfan, Rosa Santillan, Julian Guzaman, Belinda Castillo and Aurelio
Ortiz. Tetrahedron; 1994, 50 (33), 9951.
02. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B.
Carter, J. Med. Chem., 1994, 37, 758.
03. Motylewski, et. al. Chem. Ber. 41, 800 (1908).
04. Perkin, Riley, J. Chem. Soc., 1923, 123, 2406.
05. Holley, J. Amer. Chem. Soc., 1952, 74, 3069.
06. Ploechl; Chem. Ber.; 1886, 19, 10.
07. Borthakur N, Bhattacharyya A. K., Rastogi R. C., Indian J. Chem. Sect. B., 1981,
20 (9), 822.
08. (a) Harsanyi k et. al; Chem. Ber.; 1972, 105, 805. (b) Cuiban F; Bull. Soc. Chim.
Fr.; 1963, 356. (c) Taylor, Thompson; J. Org. Chem.; 1961, 26, 3511. (d) Bell,
Childress; J. Org. Chem.; 1964, 29, 506. (e) Heller.; J. Prakt. Chem.; 1925, 111,
19. (f) Hinsberg, Justus Liebigs Ann Chem., 1896, 292, 246. (g) Lai John T.,
Synthesis.; 1982, 1, 72. (h) Clark – Lewis. Aust J Chem.; 1970, 23, 1249. (i) Clark –
Lewis.; Aust J Chem.; 1964, 17, 877. (j) Soederberg Bjoern C. G., Wallace Jeffery
M, Tamariz Joaquin; Org. Lett.; 2002, 4 (8), 1339. (k) Taylor Edward C.,
Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem., 1980, 45 (12), 2512. (l)

138
 Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.
Soc. Chim. Belg., 1987, 96 (6), 473. (m) De La Fuente, Julio R., Canete Alvaro,
Zanocco Antonio L., Saitz Claudio, Jullian Carolina., J. Org. Chem., 2000, 65 (23),
7949.
09. Taylor Edward C., Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem.,
1980, 45 (12), 2512.
10. Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.
Soc. Chim. Belg., 1987, 96 (6), 473.
11. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B.
Carter, J. Med. Chem., 1994, 37, 758.
12. Ploechi; Chem. Ber., 1886, 19, 10.
13. Bjorn C. G. Sederberg, Jeffery M. Wallace and Joaquin Tamariz; Org. Lett.;
2002, 4 (28), 1339.
14. De La Fuente, Julio R., Canete Alvaro, Zanocco Antonio L., Saitz Claudio, Jullian
Carolina., J. Org. Chem., 2000, 65 (23), 7949.
15. (a) Laurinvicius Valdas, Krutinatiene Bogumila, Liauksminas Virgnijus,
Puodziunatie Benedikta Janciene., Monatsh Chem., 1999, 130 (10), 1269.
(b) Smith., J. Org. Chem., 1959, 24, 205.

139
 CHAPTER –V
STUDIES ON SYNTHESIS OF
“OXAZOLO QUINOLINES”

5.1 INTRODUCTION:
Hexahydro-oxazolo[3,2-a]pyridine (60) or tetrahydro-oxazolo[3,2-a]pyridine (61)
is a fused heterocycle, in which piperidine or tetrahydropyridine is fused with 1.3-oxazole
in an angular fashion. These moieties are frequently found to be an integral part of many
biologically active molecules, synthetically important compounds and natural products.1-8

N O N O

(60) (61)

140
 A number of such structures and their use in different therapeutic areas have been
listed below in Table – 5.1. Hexahydro-oxazolo[3,2-a]pyridine (60) is an integral part of
Atisine (62),1 which is a natural product (aconite alkaloid). Oxazole derivative 64 was
used as starting material for synthesis of Salsolidine9 which is an isoquinoline alkaloid
found to posses anti tumor activity.
Table – 5.1: Some known Oxazolopyridines / Isoquinolines.
S.No. Structure of derivative Importance Ref.
1. OH Atisine Alkaloid 1

N O

(62)
2. 2
N

O
(63)
3. O Starting material for 3
N (R)-(+) Salsolidine
O Ph
O Anti tumor
(64)
4. CO2Et 4

HO N O

Ph
(65)
5. 5
N

O
(66)

141
 6. 6
N O

Ph
(67)
7. (-)-Pumiltoxin 7
NC N O
Natural product

Ph
(68)

Oxazolo[2,3-a]tetrahydroisoquinoline (64) was synthesized starting from 6,7-

dimethoxy-1-methyl-isochroman (69) which gives 70 in the presence of bromine in CCl4.
The latter on stirring with D-phenylglycinol (71) in the presence of triethylamine as base
at -78 °C gives compound 64.3 This compound 64 is useful as key intermediate for the
synthesis of isoquinoline alkaloid i.e. Saisolidine (72). (Equation - 5.1)
NH2
O Br2, CCl4
O Br OH (13)
Ph
O 80°
O O CHO Et3N
(70)
(69)

O O

N NH
O Ph O
O Me
(64) (72)
(R)-(+) Saisolidine

Equation - 5.1
3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile (68)6-7 was prepared
by condensation of phenylglycinol (71) with glutaraldehyde (73) in the presence of
potassium cyanide to give compound 68 via piperidine intermediate (681). (Equation -
5.2)

142
 Ph
OH CHO CHO
KCN
NH2
NC N O NC N O
(71) (73)
Ph Ph (68)
(681)

Equation - 5.2
Synthesis of compound 65 was achieved starting from 68. Reacting it with
alumina (Al2O3) and DEAD (diethyl acetylenedicaboxylate) in ethanol was refluxed to
give 8-Hydroxy-1-phenyl-1,2,4,5-tetrahydro-3aH-oxazolo[3,2-a]quinoline-6-carboxylic
acid ethyl ester (65).4 (Equation - 5.3)

Ph Ph CO2Et
NC N O HCN N OH Al2O3

DEAD HO N O
(65)
(68) (74)
Ph
Equation - 5.3

5.2 Present Work:

Survey of literature thus, revealed that different oxazolo isoquinolines have
shown diverse types of biological activities and these are used in synthesis of some other
natural products. Therefore, it was considered desirable to prepare new compounds
containing oxazolo quinolines. Not much information is found in literature in the area of
oxazolo quinolines. It is conceivable that these oxazolo moieties can be synthesized from
2-nitro benzaldehyde by condensation with phenylacetic acid and followed by reductive
cyclization in the presence of hydrogen gas over palladium carbon to yield quinolines in
the first step. These can be used as building blocks for the further structural modification
leading to fused oxazolo ring units.
5.3 Results and Discussion:

143
 Commercially available 2-nitrobenzaldehyde (75) was reacted with
triphenylphosphine ylide (76) in benzene to obtain ethyl (E)-3-(2-nitrophenyl)-2-
propenoate (77 a, i.e. R = H) in 90.0 % yield (Equation – 5.4). 77a is a compound
known9 in literature. However, it was further characterized in the present work by
spectral and analytical data. Thus, its IR spectrum the absence of absorption at 1650 cm-1
typical of the aromatic aldehyde group. However, the IR spectrum showed (Fig 5.1) a
peak at 1716 cm-1, which was assigned to ester carbonyl stretching. Its 1H NMR (in
CDCl3) showed signals (Fig 5.2) at δ 8.14 – 8.02 (m, 2H), 7.65 – 7.63 (m, 1H), 7.58 –
7.49 (m, 2H), 6.36 (d, J = 15.7 Hz, 1H), 4.34 – 4.23 (q, J = 7.30 Hz, 2H), 1.31 (t, J = 7.30
Hz, 3H). Its mass spectrum (Fig 5.3) showed the molecular ion peak at 222 ((M+ +1, 100
%), and other peaks at m/z 192 (30 %), 176 (40 %, indicative of loss of ethoxy).
O
CHO Benzene
+ Ph3P=CHCO2Et OEt
NO2 80 0C, 6.0 hrs NO2
(75) (76)
(77a)
Equation – 5.4
In order to prepare the intermediate 77b, 2-nitrobenzaldehyde (75) was reacted
with phenylacetic acid (4) in the presence of triethylamine and acetic anhydride10 to give
(E)-2-phenyl-3-(2-nitrophenyl)-2-propenoic acid (77b) in 65.0 % yield. (Equation – 5.5)
The structure of 77b was confirmed by its analytical and spectral data. Thus, its IR
showed a peak at 1683 cm-1 indicative of carbonyl group, which has been assigned to
COOH group. Its 1H NMR (in DMSO d6) showed signals at 12.96 (bs, 1H, D2O
exchangeable), 8.10 - 8.05 (m, 1H, Ar H), 7.47 – 7.43 (m, 1H, Ar H), 7.20 (s, 1H), 7.08 –
7.07 (m, 1H, Ar H), 6.97 – 6.93 (m, 1H, Ar H). Its mass spectrum showed peaks at 254
(M+ +1) and 240 (100 %).

144
 CO2H

CHO Ac2O, Et3N

+
CO2H
NO2 NO2
(75) (4) (77b)

Equation – 5.5

In order to prepare another intermediate 77c, 2-nitrobenzaldehyde (75) was

reacted with 4-methoxyphenylacetic acid (13) in the presence of triethylamine and acetic
anhydride to give (E)-2-(4-methoxyphenyl)-3-(2-nitrophenyl)-2-propenoic acid (77c) in
65.0 % yield. (Equation – 5.6) The structure of 77c was confirmed by its analytical and
spectral data. Thus, its IR showed peak at 1686 cm-1 due to the carbonyl stretching. Its
1
H NMR (in DMSO d6) showed signals at 8.17 (s, 1H, Ar H), 8.10 – 8.08 (dd, J = 2.42 &
5.37 Hz, 1H, Ar H), 7.37 - 7.33 (m, 2H, ArH), 7.07 (d, J = 8.86 Hz, 2H, ArH), 6.99 –
6.95 (m, 1H, Ar H), 6.76 (d, J = 8.60 Hz, 2H, ArH), 3.76 (s, 3H). Its mass spectrum
showed peak at 300 (M+1, 100 %).
CO2H OMe

CHO Ac2O, Et3N

+
CO H
NO2 NO2 2
OMe
(75) (77c)
(13)

Equation – 5.6
Ethyl (E)-3-(2-nitrophenyl)-2-propenoate (77 a) was reduced with hydrogen gas
over 10 % palladium on charcoal in acetic acid at room temperature11 to give 1,2,3,4-
tetrahydro-2-quinolinone (78a) in 97.0 % yield, (Equation – 5.7) which was characterized
by analytical and spectral data. Thus, its IR (KBr) spectrum showed (Fig 5.4) a peak at
3440 cm-1 which may be assigned to –NH- stretching vibration, and a strong peak at 1680
cm –1 in the carbonyl region which may be assigned to the amide carbonyl grouping. Its
1
H NMR (in CDCl3) showed (Fig 5.5) three aromatic signals at δ 8.79 (bs, 1H, D2O
exchangeable), 7.14 (d, J = 7.0 Hz, 2H), 6.99 (d, J = 7.0 Hz, 1H), 6.81 (d, J = 7.0 Hz,

145
 1H), and other signals at 2.97 (t, J = 7.0 Hz, 2H), 2.68 (d, J = 7.0 Hz, 2H). Its mass
spectrum (Fig 5.6) showed peaks at m/z 148 (M+ +1, 100 %).
10 % Pd-C
CO Et N O
NO2 2 H2, 60 PSI H
(77a) (78a)
Equation – 5.7
Substituted 2-quinolinones (78 b and c) were prepared in the similar manner as
above.12 The structures for these products were assigned on the basis of analogy and on
the basis of analytical and spectral data. (Table –5.2)

R R

10 % Pd-C
CO H H2, 60 PSI N O
NO2 2 H
(77b-c) (78b-c)

Equation – 5.8
Table 5.2: Synthesis of 78 from 77 and their spectral Data:
Sub. Pdt. R Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr) /
cm-1.
77b 78b H 65.0 IR (KBr): 3210 cm-1 (amide –NH- band), 1680 cm-1 (amide
1
carbonyl stretching); H NMR (DMSO d6, 200 MHz):
δ10.31 (bs, 1H, D2O exchangeable, NH), 7.23 – 7.14 (m, 7H,
Ar H), 6.90 – 6.87 (m, 2H, Ar H), 3.80 (t, J = 7.3 Hz, 1H,
PhCH), 3.15 (d, J = 7.30 Hz, 2H, Ph CH2); Mass: m/z 224
(M+1, 100 %).
77c 78c OMe 67.0 IR (KBr): 3208 cm-1 (amide –NH- band), 1678 cm-1 (amide
carbonyl stretching); 1H NMR (DMSO d6, 200 MHz): δ 8.39
(bs, 1H, D2O exchangeable, NH), 7.18 – 7.15 (m, 5H, Ar
H),7.03 – 6.95 (m, 1H), 6.87 – 6.75 (m, 2H, Ar H), 3.85 –
3.72 (m, 1H, PhCH), 3.77 (s, 3H, OMe), 3.23 (d, J = 7.70

146
 Hz, 2H, Ph CH2); Mass: m/z 254 (M+1, 100 %).

1,2,3,4-tetrahydro-2-quinolinone (78a) was treated with ethyl 2-bromoacetate in

the presence of potassium carbonate in DMF at 80 °C for 9 hrs. Processing of the reaction
mixture gave a product (68 %) which was found to be 79a in 50 % yield (Equation 5.9) it
was characterized by spectral methods. Thus, its IR spectrum showed no absorption
above 3000 cm-1 indicating absence of any –NH- grouping. However, the IR spectrum
(Fig 5.7) showed two strong sharp bands, one at 1743 cm-1 and the other at1688 cm-1.
The former has been assigned to ester carbonyl grouping and other assigned to amide
carbonyl grouping. Thus, its 1H NMR spectrum (Fig 5.8) displayed signals at δ 7.21-
17(m, 2H, Ar - H), 7.03 (d, J = 7.3 Hz, 1H, Ar-H), 6.75 (d, J = 7.3 Hz, 1H), 4.66 (s, 2H,
N-CH2), 4.27 – 4.16 (q, J = 7.30 Hz, 2H, O – CH2CH3), 2.95 (t, J = 6.4 Hz, 2H), 2.72 (t, J
= 6.4 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H, O – CH2CH3) while the mass spectrum (Fig 5.9)
showed m/z 234 (M+ +1, 100 %).

BrR1CHCO2Et
N O
N O K2CO3
H
CO2Et
(78a) (79a)

Equation – 5.9

147
 Substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl esters (79a-k)
could also be prepared using the above method. Structures of all products 79a – k
(Equation 5.10) have been assigned on the basis of analogy and on the basis of spectral &
analytical data (Table – 5.3).
R
R
BrR1CHCO2Et
N O
N O K2CO3
H R1 CO2Et
(78a-c) (79a-k)
Equation – 5.10
Table 5.3 Synthesis of 79 (a-k) from 78 (a-c) and data:
Sub. Pdt. R R1 Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR
(KBr) / cm-1.
78b 79b Ph H 54 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1748 cm-1 and amide carbonyl appeared at 1681 cm-1;
1
H NMR (CDCl3): δ 7.26 (s, 5H), 7.17 (d, J = 10 Hz,
2H), 7.01 (t, J = 7.32 Hz, 1H), 6.80 (d, J = 8.10 Hz,
1H), 4.84 – 4.61 (q, J = 17.46 Hz, 2H), 4.28 – 4.18 (q,
J = 7.25 Hz, 2H), 3.96 (t, J = 6.72 Hz, 1H), 1.25 (t, J =
7.25 Hz, 3H); Mass: m/z 310 (M+ +1, 100 %).
78b 79c Ph Me 49 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1742 cm-1 and amide carbonyl appeared at 1677 cm-1;
1
H NMR (CDCl3): δ 7.30 – 6.79 (m, 9H), 5.07 – 4.97
(m, 1H), 4.26 – 4.08 (m, 2H), 3.80 – 3.74 (m, 1H), 3.39
– 3.20 (m, 1H), 3.18 – 3.04 (m, 1H), 1.57 – 1.43 (m,
3H), 1.28 – 1.12 (m, 3H); Mass: m/z 324 (M+1, 100
%).
78b 79d Ph Et 51 IR (KBr): no absorption above 3000 cm-1 indicating

150
 absence of –NH- grouping. Ester carbonyl appeared at
1738 cm-1 and amide carbonyl appeared at 1676 cm-1;
1
H NMR (CDCl3): δ 7.28 – 6.78(m, 9H), 5.15 – 5.08
(m, 1H), 4.28 – 4.10 (m, 2H), 3.91 – 3.83 (m, 1H), 3.33
– 2.88 (m, 1H), 2.35 – 2.19 (m, 1H), 2.15 – 2.00 (m,
1H), 1.28 – 1.20 (m, 3H), 1.10 – 0.97 (m, 3H); Mass:
m/z 338 (M+ +1, 100 %).
78c 79f Ar H 57 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1735 cm-1 and amide carbonyl appeared at 1678 cm-1;
1
H NMR (CDCl3): δ 7.26 – 7.16 (m, 5H, ArH), 7.05 –
7.01 (m, 1H), 6.85 – 6.77 (m, 2H), 4.84– 4.59 (q, J =
17.46 Hz, 2H, NCH2), 4.28 – 4.17 (q, J = 6.98 Hz, 2H,
O – CH2CH3), 3.95 – 3.88 (m, 1H), 3.75 (s, 3H, OCH2),
3.25 – 3.20 (m, 2H), 1.25 (t, J = 6.98 Hz, 3H, O –
CH2CH3); Mass: m/z 340 (M+, 100 %).
78c 79g Ar Me 56 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1739 cm-1 and amide carbonyl appeared at 1670 cm-1;
1
H NMR (CDCl3): δ 7.26 – 7.08 (m, 5H, ArH), 7.03 –
6.74 (m, 4H), 5.38 – 5.31 (m, 1H), 4.27 – 4.10 (m, 2H,
O – CH2CH3), 3.95 – 3.89 (m, 1H), 3.73 (s, 3H, OCH2),
3.35 – 3.03 (m, 2H), 1.69 – 1.62 (m, 3H), 1.26 (t, J =
7.33 Hz, 3H, O – CH2CH3); Mass: m/z 354 (M+, 100
%).
78c 79h Ar Et 62 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1737 cm-1 and amide carbonyl appeared at 1676cm-1;
1
H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.06 –

151
 7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H),
4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H,
OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.20
(t, J = 6.98 Hz, 3H, O – CH2CH3), 0.88 (t, J = 7.3 Hz,
3H); Mass: m/z 368 (M+, 100 %).
78c 79i Ar Pr 49 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1737 cm-1 and amide carbonyl appeared at 1676cm-1;
1
H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.05 –
7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H),
4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H,
OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.21
– 1.18 (t, J = 6.98 Hz, 3H, O – CH2CH3), 0.92 – 0.85
(m, 3H); Mass: m/z 411 (M+, 100 %).
78c 79j Ar Hex 46 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1737 cm-1 and amide carbonyl appeared at 1677cm-1;
1
H NMR (CDCl3): δ 7.26 – 7.10 (m, 4H, ArH), 7.05 –
7.02 (m,1H), 6.91 – 6.74 (m, 3H), 5.53 – 5.46 (m, 1H),
4.27 – 4.10 (m, 2H, O – CH2CH3), 3.98 – 3.81 (m, 1H),
3.73 (s, 3H, OCH2), 3.36– 3.12 (m, 2H), 2.34 – 2.05
(m, 2H), 1.23 – 1.14 (m, 11), 0.98 – 0.84 (m, 3H);
Mass: m/z 424 (M+, 100 %).
78c 79k Ar Ph 49 IR (KBr): no absorption above 3000 cm-1 indicating
absence of –NH- grouping. Ester carbonyl appeared at
1747 cm-1 and amide carbonyl appeared at 1667 cm-1;
1
H NMR (CDCl3): δ 7.34 – 7.26 (m, 5H, ArH), 7.22 –
7.06 (m, 4H, ArH), 7.02 – 6.86 (m, 2H, ArH), 6.83 –
6.72 (m, 2H, ArH), 3.86 – 3.83 (m, 1H), 3.80 (s, 3H),

152
 3.75 (s, 3H), 3.40 – 3.20 (m, 2H). Mass: m/z 402 (M+
100 %), 369 (20 %), 342 (20 %)
Ar = 4-methoxyphenyl

153
Reductions with Lithium Aluminum Hydride (LAH):
Treatment of 79a with 1.1 eq. of LAH in THF followed by simple processing
gave a product, which was obtained as a syrupy liquid. The compound was found to be
homogenous on TLC. Its IR spectrum (Neat) did not show any diagnostic peaks due to
of –NH- and -CO- groups (Fig 5.10). Its 1H NMR (400 MHz, in CDCl3) showed (Fig
5.11) signals at δ 7.12 – 7.10 (m, 1H), 7.08 – 6.99 (m, H), 6.68 – 6.64 (m, 1H), 6.52 –
6.50 (d, J = 7. 0 Hz, 1 H), 4.850 – 4.82 (dd, J = 1.9 & 7.9 Hz, 1H), 4.22 – 4.17 (m, 1H),
4.01 – 3.95 (m, 1H), 3.51 – 3.46 (m, 1H), 3.38 – 3.34 (m, 1H), 2.84 – 2.74 (m, 1H), 2.29
– 2.23 (m, 1H), 1.69 – 1.43 (m, 2H). Its mass spectrum showed (Fig 5.12) peaks at m/z
175 (M+, 30 %), 174 (40 %), 149 (70 %), 135 (40 %), 125 (75 %), 97 (100 %). Based on
this data, the product was assigned as 1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-
a]quinoline (80a). (Equation – 5.11)
LAH, THF
N O 0 °C - r.t, 1.0 hr N O
CO2Et
(79a) (80a)
Equation – 5.11
The above reaction of 79a yielding 80a seems to be general one. It has been
extended to other substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl
esters (79a-k) yielding 80a-k. (Equation – 5.12)
R R
LAH, THF
N O 0 °C - r.t, 1.0 hr N O
R1 CO2Et R1
(79a-k) (80a-k)
Equation – 5.12

154
 Table 5.3 Synthesis of 80 (a-k) from 79 (a-k) by reduction with LAH and their spectral
characteristics.
Sub. Pdt. R R1 Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR
(KBr / Neat) / cm-1.
79c 80c Ph Me 65 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.43 – 7.21
(m, 5H, ArH), 7.17 – 6.99 (m, 2H, ArH), 6.70 (t, J =
7.32 Hz, 1H, ArH), 6.56 (d, J = 7.81 Hz, 1H, ArH),
4.92 (d, J = 8.79 Hz, 1H), 4.27 (t, J = 6.83 Hz, 1H),
4.03 – 3.90 (m, 1H), 3.57 (t, J = 5.86 Hz, 1H), 3.43 (t,
J = 7.81 Hz, 1H), 3.19 – 2.93 (m, 1H), 2.87 – 2.69
(m, 1H), 1.44 (s, 3H); Mass: m/z 266 (M+, 100 %).
79d 80d Ph Et 52 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.37 – 7.26
(m, 5H), 7.16 – 7.01 (m, 2H), 6.98 – 6.83 (m, 1H),
6.67 – 6.59 (m, 1H), 5.00 – 4.87 (m, 1H), 4.26 – 4.22
(m, 1H), 3.85 – 3.81 (m, 1H), 3.65 – 3.61 (m, 1H),
3.38 (m, 1H), 3.07 – 3.00 (m, 1H), 2.88 – 2.75 (m,
1H), 1.89 – 1.86 (m, 1H), 1.64 – 1.61 (m, 1H), 1.00 –
0.85 (m, 3H); Mass: m/z 280 (M+, 100 %).
79f 80f Ar H 58 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.26 – 7.17
(m, 4H), 7.07 (d, J = 7.52 Hz, 1H), 6.93 (d, J = 8.3
Hz, 1H), 6.69 (t, J = 7.30 Hz, 1H), 6.55 (d, J = 7.82
Hz, 1H), 4.86 (d, J = 8.79 Hz, 1H), 4.31 – 4.23 (m,
1H), 3.99 – 3.90 (m, 1H), 3.82 (s, 3H), 3.57 – 3.52
(m, 1H), 3.46 – 3.34 (m, 1H), 3.5 (d, J = 13.70 Hz,
1H), 2.91 (d, J = 3.90 Hz, 1H), 2.75 – 2.64 (m, 1H);
Mass: m/z 282 (M+, 100 %), 270 (30 %), 240 (20 %)

155
 and 216 (30 %).
79g 80g Ar Me 49 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.30 – 7.17
(m, 4H), 7.09 – 7.02 (m, 1H), 6.95 – 6.78 (m, 2H),
6.72 – 6.57 (m, 1H), 4.97 – 4.92 (d, J = 9.80 Hz, 1H),
4.32 (t, J = 7.4 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.94 –
3.88 (m, 1H), 3.82 (s, 3H), 3.55 – 3.57 (m, 1H), 3.34
– 3.23 (m, 1H), 3.09 – 3.01 (m, 1H), 2.98 – 280 (m,
1H), 2.77 – 2.65 (m, 1H), 1.41 – 1.27 (m, 3H); Mass:
m/z 296 (M+, 100 %).
79h 80h Ar Et 52 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.34 – 7.14
(m, 4H), 7.09 – 7.03 (m, 1H), 6.96 – 6.84 (m, 2H),
6.73 – 6.60 (m, 1H), 4.96 – 4.80 (m, 2H), 4.28 (t, J =
7.8 Hz, 1H), 4.03 – 3.87 (m, 1H), 3.82 (s, 3H), 3.77 –
3.59 (m, 1H), 3.48 – 3.38 (m, 1H), 3.09 – 3.01 (m,
1H), 2.99 – 266 (m, 2H), 1.98 – 1.81 (m, 1H), 1.77 –
1.46 (m, 1H), 1.02 – 0.95 (m, 3H); Mass: m/z 310
(M+, 100 %).
79j 80j Ar Hex 45 IR: Did not show any diagnostic peaks due to –NH-
and -CO- groups. 1H NMR (CDCl3): δ 7.34 – 7.18
(m, 4H), 7.14 – 7.05 (m, 1H), 7.02 – 6.80 (m, 2H),
6.72 – 6.59 (m, 1H), 4.95 – 4.85 (m, 2H), 4.26 – 4.23
(m, 1H), 3.81 (s, 3H), 3.61 (t, J = 7.8 Hz, 1H), 3.42 –
3.34 (m, 1H), 3.27 – 3.04 (m, 1H), 2.97 – 271 (m,
2H), 1.86 – 1.79 (m, 1H), 1.58 – 1.55 (m, 1H), 1.34
(m, 6H), 0.93 – 0.81 (m, 3H); Mass: m/z 366 (M+,
100 %).
Ar = 4-methoxyphenyl

156
157
 5.4 Experimental procedure:
i) Preparation of 77a: A mixture of 2-nitrobenzaldehyde (75, 5.0 gms, 33 mmol) and
triphenylphosphine ylid (76, 13.8 gms, 39 mmol) in benzene (150 mL) was refluxed for
24 hours at 80 °C. Then the mixture was cooled to r.t, adsorbed over silica gel and
purified through column chromatography to give pure 77a as thick liquid (5 gms, 71 %).

ii) Preparation of 77b and c (General procedure): A mixture of 2-nitrobenzaldehyde

(75, 20.0 gms, 131.11 mmol), phenylacetic acid (197.35 mmol of 4 or 13), acetic
anhydride (67.0 mL, 657 mmol) and triethylamine (18.0 mL, 131.11) were refluxed at 90
°
C for 15 min. The solution was cooled, the separated solid was filtered and washed with
mixture of water-acetic acid to give 77a & b, yield of 77a 28 gms (79 %); yield of 77b
32 gms (82 %)

iii) Preparation of 78a-c (General procedure): 10 % palladium carbon (1.0 gm/10.0

gms of substrate) was charged in hydrogenation flask, made wet with acetic acid (10
mL/1.0 gm of substrate) and to this 78a-c (1.0 gm, in10 mL of acetic acid) was added at
room temperature. Then the flask was arranged for parr hydrogenation for 6 hrs at 60 psi
H2 pressure. The reaction mixture was filtered through a pad of Celite to remove
palladium carbon and the filter bed washed with acetic acid. The filtrate was stirred with
water (100 ml/1.0 gm substrate) and the separated white solid was filtered, washed with
water and dried to give 78a-c. (Table-5.1)

iv) Preparation of 79a-k (General procedure): To a solution of 78 a – c (1.0 eq) and

potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2-
alkyl acetate (1.2 eq) drop wise at room temperature. After 24.0 hrs stirring, the mixture
was poured in to water and the separated solid was filtered, washed with water and dried
to give 79a-k. (Table-5.2)

158
v) Preparation Of 80a – k (General procedure): To a solution of 79a – k (2.0 mmol) in
dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several
portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The reaction
mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was
filtered and the filtrate concentrated. The crude product was purified by column
chromatography using ethyl acetate and pet. Ether (5:95) to give 80a – k (Table-5.3).

5.5 References:
01. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496.
(b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761.
(c) Pellettier, S. W., Parthasarathi, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777.
(d) Pellettier, S. W., Naresh V. M., Haridutt K. D., Janet Finer-Moore, Jacek
Nowacki, and Balawant S. J., J. Org. Chem., 1983, 48 (11), 1787. (e) Naresh V.
M., Pellettier, S. W., Tetrahedron; 1978, 34, 2421.(f) Pellettier, S. W. and
Walter A. J., J. Amer. Chem. Soc. 1956, 78, 4144.
02. Crist N. Filer, Felix E. Granchelli, Albert H. Soloway and John L. Neumeyer.
J. Org. Chem., 1978, 43 (4), 672.

159
03. (a) Spath, E.; Dengel, F. Chem. Ber., 1938, 71B, 113. (b) Masatoshi, Y.;
Kuniko, H.; Shigetaka, I. and Nazmul, Q. Tetrahedron Letters; 1988, 29 (52),
6949.
04. (a) Trevor, A. Crabb and Asmita V. Patel. Heterocycles. 1994, 37 (1), 431.
(b) Marie-Christine Lallemand; Mathieu Gaillard; Nicole Kunesch and Henri-
Philippe Husson. Heterocycles. 1998, 47 (2), 747. (c) Kukharev, B. F.;
Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc,
2003, xiii, 166.
05. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.;
Albanov, A. I. Arkivoc, 2003, xiii, 166.
06. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe
Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques
Royer, David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc.
1983, 105, 7754. (c) Mercedes Amat, Nuria Llor, Carmen Escolano, Marta
Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron Asymmetry;
2003, 14, 293. (d) Teran, J. L. Gnecco, D. Galindo, A. Juarez, J. Bernes, S. and
Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357.
07. (a) Mercedes, A.; Nuria, L.; Carmen, E.; Marta, H.; Maria, P.; Elies, M and
Joan, B.; Tetrahedron Asymmetry; 2003, 14, 293. (b) Jean-Charles, Q.; David S.
G.; Jacques, R and Henri-Philippe H.; Tetrahedron Letters; 1988, 29 (27), 3311.
(c) Lue, G.; Jacques, R.; David S. G and Henri-Philippe Husson. . J. Amer.
Chem. Soc. 1983, 105, 7754.
08. (a) Martin, E.; Asuncion M.; Lusia, M. M.; Luis S. R.; Pilar, P. P.; Manual, M.;
Esther, C. and Arturo S. F. Bioorg Med Chem Lett. 2000, 10 (4), 419. (b)
Esther C.; Pilar P. P.; Manual M. and Arturo S. F.; Tetrahedron; 1993, 49 (44),
10079. (c) Esther C.; Pilar, P. P.; Mar, S.; Manuel, M.; Lourdes, M.; and Arturo
S. F.; Tetrahedron Asymmetry; 1996, 7 (7), 1985. (d) Esther C.; Pilar, P. P.; Mar
S.; Miguel, A. S.; Garcia-Granda and Arturo S. F.; J. Org. Chem., 1996, 61 (9),
1890.

160
09. Mali R. S., Yadav V. J., Synthesis, 1984, 10, 862.
10. Bakunin, Peccerillo, Gazz. Chim. Ital.; 1935, 65, 1145. (ii) Org. Synth. Coll.
vol.; 1963, V, 730
11. (a) Schlaeger, Leeb. Monatsh. Chem., 1950, 81, 714. (b) Blout, Silverman, J.
Amer. Chem. Soc., 1944, 66, 1442.
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Yasutaka, Uno, Hiyoshi.; Chem. Pharm. Bull.; 1987, 35 (7), 2819.
CONCLUSIONS & HIGHLITS

A simple method has been developed for the synthesis of Novel tricyclic oxazolo
or oxazine derivatives,
This method represents a good example of reductive cyclization with lithium
aluminumhydride.
The oxazolo compounds are structural mimics of some known biologically active
molecules.
Preparation of starting materials (benzothiazin-3-ones and quinoxaline-2-ones) in
this work was made by the method of high-speed parallel synthesizer using
microwaves and water as solvent.
Intense use has been made of chromatographic methods to isolate products in a
state of high purity.
Intense use has been made of spectroscopic methods and X-ray diffraction
technique to assign structures for products to the highest accuracy and detail.

161
 APPENDIX – LIST OF PUBLICATIONS
1. Novel Method for the preparation of Tricyclic [6:6:5] systems by Reductive
Cyclization with Lithium Aluminum Hydride (LAH).
B. B. Lohray, V. B. Lohray, A. Sekar Reddy, V. Venugopal Rao.
Indian .J. Chem., Vol. 39B, April 2000, pp. 297 – 299.
2. 7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new
heterocycle.
S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas. Venugopal Rao
Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and
Pramod Kumar Dubey.
32nd National Seminar on Crystallography, October 24 – 26, 2002. Jammu,
INDIA. (Poster Presentation)
3. 7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new
heterocycle. S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
Acta Cyrstallographia E, 2003, E359
4. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2H-
benzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
Pharmacophore, January 16-17, 2004, Hyderabad. INDIA.
(Poster Presentation)
5. Novel method for the preparation of poly cyclic [6:6:5], [6:6:6] and [6:6:7:6]
systems by reductive cyclization with LAH.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
IUPAC – BNP – 2004. January 26 – 31, 2004, New Delhi, INDIA.

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 (Poster Presentation)
6. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2H-
benzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
(J. Org. Chem., Will be communicated)
7. Novel method for the preparation of tri cyclic [6:6:5] oxazolooxazines,
oxazolothiazines, oxazoloquinoxalines and oxazoloquinolines by reductive
cyclization with LAH.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
(J. Org. Chem., Will be communicated)
8. Novel method for the preparation of poly cyclic [6:6:6] [6:7:5]and [6:6:7:6]
systems by reductive cyclization with LAH.
Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu
Akella and Pramod Kumar Dubey.
(J. Org. Chem., Will be communicated)

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