Professional Documents
Culture Documents
By
RONG JIANG
Copyright 2005
by
Rong Jiang
This document is dedicated to my family, my father De-ji Jiang, my mother Tang Qin,
and my sister Ying Jiang.
ACKNOWLEDGMENTS
It is a great pleasure to acknowledge the assistance I have received from people
around me.
My deepest gratitude goes to my supervisor, Professor Alan R. Katritzky, whose
guidance, support and encouragement is essential in my chemistry journey. I greatly
thank my committee members, Dr. William R. Dolbier, Dr. Jon Stewart, Dr. Ronald
Castellano, Dr. Fazil Najafi for their time and help. Particularly, I thank Dr. Dolbier for
his teaching to write mechanism and Dr. Stewart who helped me out in the maintenance
of GC/MS in our group.
I greatly appreciate my parents and my sister for their consistent support and
endless love.
Specially, I thank my friends, who make my life as colorful as summer flowers.
iv
TABLE OF CONTENTS
page
ACKNOWLEDGMENTS ................................................................................................. iv
LIST OF TABLES............................................................................................................. ix
LIST OF SCHEMES............................................................................................................x
LIST OF FIGURES ......................................................................................................... xiii
ABSTRACT..................................................................................................................... xiv
CHAPTER
1
2.4.3 General procedure for reduction of N-benzotriazolylmethyl-1,2,3,4tetrahydroisoquinolines 6ab with NaBH4. .....................................................18
2.4.4 Procedure for the preparation of chiral -amino amides 9a,b from NBoc-Phe (2.8). ..................................................................................................18
2.4.5 Preparation of N-Boc group. -Amino amide 2.10a, b..............................19
2.4.6 General procedure for the preparation of Bt intermediates 2.11ac. .........20
2.4.7 General procedure for the preparation of chiral 3-substituted-1,2,3,4tetrahydroisoquinolines 2.12ac via annulation of 2.11ac. ...........................22
2.4.8 General procedure for the nucleophilic substitution of 6a with Grignard
reagents. ...........................................................................................................23
2.4.9 Procedure for the nucleophilic substitution of 6a with a silyl enol ether. ..24
2.4.10 Procedure for the nucleophilic substitution of 2.6a with triethyl
phosphate. ........................................................................................................25
3
vi
vii
LIST OF REFERENCES.................................................................................................105
BIOGRAPHICAL SKETCH ...........................................................................................123
viii
LIST OF TABLES
Table
page
ix
LIST OF SCHEMES
page
Scheme
xii
LIST OF FIGURES
page
Figure
62
71 Examples of biologically active molecules containing fragments of - and amino acid derivatives..............................................................................................89
xiii
xiv
chapter 7, I report the novel syntheses of - and -amino acids from aspartic acid and
glutamic acid, respectively, via N-aminoacylbenzotriazoles.
Benzotriazole shows both electron-donor and electron-acceptor properties; because
of this, N-substituted derivatives of benzotriazole possess many interesting properties.
For example, compounds in which a nitrogen atom and a N-linked benzotriazole group
are attached to the same carbon atom can ionize to form an iminium cation and
benzotriazole anion. The chemistry of chapter 2 and chapter 3 is based on the formation
of iminium cations, which undergo intramolecular nucleophilic cyclization to produce
various N-heterocycles.
Examples of the activation of the CN bond of substituents attached to
benzotriazole nitrogen due to the good leaving ability of benzotriazole are demonstrated
in chapter 4 and chapter 5.
Recently, our group has extensively studied N-acylbenzotriazoles as powerful
neutral acylation reagents. In a further extension of this methodology, I have now applied
N-aminoacylbenzotriazoles in the synthesis of various precursors for biologically active
compounds. Chapter 6 describes a novel method to prepare chiral -aminoalkyl
heterocyclic ketones from N-protected N-aminoacylbenzotriazoles without racemization.
In chapter 7, novel syntheses of chiral - and -amino acid derivatives utilizing Naminoacylbenzotriazoles from aspartic acid and glutamic acid has been discussed.
xv
CHAPTER 1
GENERAL INTRODUCTION
Interest in benzotriazole chemistry stems from the advantages of benzotriazole as a
synthetic auxiliary in organic synthesis. Since the commencement of work concerning
benzotriazole chemistry in our group, the novel and useful aspects of benzotriazole
methodology have aroused extensive study of N-substituted derivatives of benzotriazole.
Generally, N-substituted derivatives of benzotriazole can be obtained by
replacement of a halogen in alkyl or acyl halides and of an alkoxy group in acetals or
ketals. Other important methods include: (i) additions of benzotriazole to aldehydes and
both electron-rich and -deficient olefins; (ii) Mannich type of condensation reaction of
benzotriazole with carbonyl compound and an NH derivative [98CV409] (Fig. 11).
By Substitution
By Addition
R-Bt
RX + Bt
BtH =
RCOX + Bt
R
R1
N
RCOBt
OR2
+ BtH
OR3
N
N
H
R
R
OR
Bt
R
BtH +
R1
2
3
O + R N R
H
R1
R Bt R2
N
R1
R3
BtH
R Bt R2
R1
O
R3
R2
R1
NH2
R1
O
R3
By Condensation
R2
R
N
BtH
R Bt R2
R1
BtH
R Bt R
NH
R1
NH2
2
The N-substituted derivatives of benzotriazole have many interesting properties.
Because benzotriazole possesses both electron-donor and electron-acceptor properties,
compounds with a heteroatom attached to a carbon adjacent to benzotriazole nitrogen can
ionize in two ways. The loss of the heteroatom substituent can give 1.1 when X is a
halogen. More commonly, when the heteroatom is N, O or S, the formation of a
benzotriazole anion provides an immonium, oxonium or thionium cation 1.2. The active
specie 1.2 can participate in nucleophilic substitution, elimination or hydrolysis to afford
various compounds (Fig. 12) [98CV409].
N
X +
N
H
1.1
N
N X
R
H
N
N
N
X
R
H
1.2
X = N, O or S
3
R3
R3
R1
Bt
R2
AlCl3/CH2Cl2, reflux
Bt -
Bt
Bt
R1
R4
COR1
HOOC
N
+
NH2
n
N
n
p-TsOH
R2
N+
R1
_ H+
Dean-Stark
R2
PhH
n N
R1
R2
2
R2
R2
n= 1 or 2
A
Br2 Br
R
Bt
R1R2NH
Br
DMF/H2O
O
R
NR1R2
O
Bt
PPh3, CCl4
H
THF
H
Bt
Bt
LiNp/Nu
Nu
ii)Electrophiles
R1
PG
N
H
AlCl3
Bt
N
R2
CH2Cl2, 20 C
PG
N
H
N
R2
5
O
O
n
H2N
OH
O
OH
i) SOCl2/MeOH
ii) CF3COOEt
iii) BtH, SOCl2
Tfa
N
H
OMe
n
O
Bt
O
TiCl4
Tfa
Aromatics
n
N
H
Ar
O
OMe NaBH
4
O
H3O
Tfa
n
N
H
OH
Ar
n=1 -amino acids derivatives
n=2 -amino acids derivatives
Figure. 18. - and -Amino acids from L-aspartic acid and L-glutamic acid
CHAPTER 2
SUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES AND CHIRAL 3CARBOXYL ANALOGUES FROM N-BENZOTRIAZOLYLMETHYL-NPHENETHYLAMINES
2.1 Introduction
Many alkaloids contain 1,2,3,4-tetrahydroisoquinoline (THIQ) skeletons and
derivatives of THIQ play an important role in medicinal chemistry due to their significant
biological and physiological activities such as inhibition of diazepam binding to rat
cerebral cortical membranes in vitro [85CBIA213], [72IACP] [84JMC564], [96JMC556].
Also, a number of selective inhibitors of phenylethanolamine N-methyltransferase
(PNMT, an enzyme that is involved in the biosynthesis of epinephrine in the central
nervous system) contain the THIQ nucleus 2.1 (Fig. 21) [99JMC1982]. Therefore,
syntheses of substituted 1,2,3,4-tetrahydroisoquinolines continue to attract much interest
[00OL2185], [00JOC5469], [00OL3901], [98JOC10018], [98CPB918], [01TL2111],
[01TL4503].
R
NH
R = H, CH3, CH2CH3
CH2OH, COOH
COOCH3, CONH2
2.1
7
CH2O, HCl
NH
NH2
43%
+
Ar
O
+ BtH
HN
R1
AlCl3 or H2SO4
Bt
Ar
Ar
2.2
TiCl4 or AlCl3
BtH, RCHO
R
Toluene, PTSA
- Bt
N
HN
Bt
O
O
R
2.3
O
O
NH
R1
- Bt
NH2
EtOH
R1
R3
R1
R3
R3
R3
AlCl3
N
Bt
R1
NaBH4
N
Bt
R1
CH3
Bt
SCHEME 23. Locher and Peerzadas method for the preparation of N-methyl-1,2,3,4tetrahydroisoquinolines
8
2.2 Results and Discussion
2.2.1 Preparation of N-benzotriazolylmethyl-N-phenethylamines 2.5ac and their
cyclizations in the presence of AlCl3.
Our group has intensively investigated Mannich reactions of benzotriazole, amines
and formaldehyde (as well as other aldehydes) [98CV409], [89S66], [90JOC3205],
[96JOC3117], [90CJC446]. Two methods were generally used for the condensation: A)
reactions of amines with benzotriazole and formaldehyde (37% aqueous solution); B)
reactions of amines with Bt1CH2OH (Scheme 24). Generation of
mono(benzotriazolylmethyl) products in good yields from primary amines requires
hindered amines with a substituent at the -position [90CB1443], [90JCS(PT1)541].
Reactions of unhindered primary amines with 2 equivalents of BtH and formaldehyde
give bis(benzotriazolylmethyl) products[89JCS(PT1)225].
1eq. BtH/R2CHO
or 1eq. BtCH2OH
(for R2 = H)
R2
R1
N
H
Bt
R1NH2
2
R2
R1
R2
Bt
Bt
9
Bt1CH2OH in the presence of sodium sulfate gave bis(benzotriazolylmethyl)
intermediates 2.5b and 2.5c in 95% and 97% yields, respectively.(Scheme 25)
R3
R3
Compd
R2
i
NH2
R1
R1
Bt
2.5a-c
2.4a-c
Bt
a
R1
R2
R3
Ya (%) of 2.5
MeO
92
MeO
MeO
95
Ph
97
Isolated yield.
N
N
N
Bt1 = benzotriazol-1-yl
Bt2 = benzotriazol-2-yl
10
changed to 5:1, 7:1 and 4:1, respectively. This is consistent with previous reports that
both Bt1 and Bt2 groups are good leaving groups in the presence of Lewis acids, such as
AlCl3, ZnBr2, BF3, etc [91T2683], [98JOC6699], [00JOC3683], [00JOC4364],
[01JOC148]. For 2.6a and 2.6b, I report the individual 1H NMR and 13C NMR (using
attached proton test technique) data for each of their Bt1 and Bt2 isomers. The chemical
shifts of the carbons attached to the benzotriazol-2-yl group appear at a lower field (76.7
ppm, for both 2.6a and 2.6b) compared to those of the carbons attached to the
benzotriazol-1-yl group (68.9 ppm, for both 2.6a and 2.6b) [90CJC446].
R3
R3
AlCl3/CH2Cl2, reflux
R1
Bt
2.5a-c
H+
Bt -
R1
Bt
Bt
R2
Bt
2.6a-c
Compd
R1
R2
R3
Ya (%) of 2. 6
MeO
86
MeO
MeO
89
Ph
82
Isolated yield.
11
R3
R2
NaBH4
R3 = H
R1
Bt
2.6a-b
R2
MeO
Me
2.7a, R2 = H
2.7b, R2 = MeO
12
electrophilic substitution on the tethered phenyl ring to furnish optically active 3substituted-1,2,3,4-tetrahydroisoquinolines 2.12ac. The optical activity of 2.12c ([]25D
= 126) matches the literature reported value ([]22D = 124) [97LA533] indicating that
no racemization occurred for all of the above transformations under the mild reaction
conditions employed. This method is advantageous in comparison to an earlier reported
method that involved the reaction of phenylalanine with formaldehyde in the presence of
concentrated hydrochloric acid to afford 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic
acid. The enantiopure phenylalanine was partially racemized under the strong acidic
conditions [99JMC1982].
O
COOH
Ph
Boc
Ph
Boc
2.8
ii
Ph
#
a, R = N
R
2.10a-b
O
O
R
NH2
Ph
NH2
2.9a-b
2.10a-c
O
R
iii
Ph
Bt
R
N
AlCl3
2.11a-c
H
H
2.12a-c
O ; b, R = N(C4H9-n)2; c, R = OMe
2.10a and 2.10c (from Aldrich) were used as their hydrochloride salts.
Therefore, one equivalent of NaOH was used in step iii).
13
2.2.3 Nucleophilic substitution of 2-benzotriazolylmethyl-7-methoxy-1,2,3,4tetrahydroisoquinoline (2.6a) with Grignard reagents, a silyl enol ether or
triethyl phosphate.
Nucleophilic substitution of 2.6a with 2 equivalents of Grignard reagents (phenyl,
n-pentyl or phenylethynyl magnesium bromide) in dry THF generated novel Nsubstituted-1,2,3,4-tetrahydroisoquinolines 2.13ac (Scheme 29). The structures of
2.13ac were clearly supported by their 1H, 13C NMR spectra and microanalysis or
HRMS results. The success of nucleophilic substitution of 2.6a with various Grignard
reagents leaded us to the further investigation of the nucleophilic substitution of 2.6a with
other nucleophiles such as a silyl enol ether and triethyl phosphate. The reaction of 2.6a
with silyl enol ether in the presence of BF3Et2O gave 2.14 in 63% yield. Likewise,
treatment of 2.6a with 1.2 equivalents of triethyl phosphite in the presence of ZnBr2
furnished diethyl [7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]methylphosphonate (2.15)
in 80% yield. (Scheme 29)
RMgBr
N
MeO
MeO
Bt
2.6a
OTMS
Ph
BF3 Et2O
P(OEt)3
ZnBr2
MeO
2.13a, R = Ph
2.13b, R = n-C5H11
2.13c, R = C6H5C C
O
P
OEt
MeO
N
O
OEt
2.15
Ph
2.14
Scheme 29. Nucleophilic substitution of 2.6a with Grignard reagents, a silyl enol ether
and triethyl phosphite.
14
2.3 Conclusion
In summary, a simple and efficient approach to 1,2,3,4-tetrahydroisoquinolines has
been reported by the treatment of N-benzotriazolylmethyl-N-phenethylamines 2.5ac and
2.11ac with aluminum chloride. No racemization was observed when chiral
phenethylamines 2.10ac were used as starting materials. Reduction of 2.6ab with
sodium borohydride easily replaces the benzotriazolyl group with hydrogen and
nucleophilic substitutions of 2.6a with Grignard reagents, silyl enol ether and triethyl
phosphite furnish novel N-substituted-1,2,3,4-tetrahydroisoquinolines 2.13ac, 2.14 and
2.15 in good yields.
2.4 Experimental Section
Melting points were determined using a Bristoline hot-stage microscope and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
Gemini 300 NMR spectrometer in CDCl3 (with TMS for 1H and chloroform-d for 13C as
the internal reference), unless otherwise stated. HRMS were measured on an AEI-30
mass spectrometer. Optical rotation values were measured on a Perkin-Elmer 341
polarimeter with the use of the sodium D line. Column chromatography was performed
on silica gel (200425 mesh). All of the reactions were carried out under N2.
2.4.1 General procedure for the syntheses of bis(benzotriazolylmethyl) intermediates
2.5ac.
Method A: Benzotriazole (2.38 g, 20 mmol) and an appropriate primary amine 4
(10 mmol) were stirred in MeOH (30 mL)/H2O (5 mL) at 25 C for 10 minutes.
Formaldehyde (1.62 g, 20 mmol) was added to the vigorously stirred mixture. After 4 h, a
thick suspension was filtered and the precipitate was washed with cool MeOH to give the
desired product.
15
Method B: A mixture of an appropriate amine 2.4 (10 mmol), Bt1CH2OH (20
mmol) and Na2SO4 (anhydrous, 4 g) was stirred in MeOH (40 mL) at 25 C for 10 h. The
solid was filtered off and the solvent was evaporated in vacuo to give the desired product.
Bis(benzotriazolylmethyl) intermediates 2.5ac can be used for the subsequent
cyclization without further purification. For microanalysis purpose, the solid formed was
recrystallized from appropriate solvents or the sticky oil was purified by column
chromatography.
N,N-Bis(benzotriazolylmethyl)-N-(4-methoxyphenethyl)amine (2.5a). Method
A; mixture of Bt1 and Bt2 isomers in 22:1 ratio; colorless needles (from CHCl3/Et2O);
yield, 92%; mp 9697 C; 1H NMR (Bt1) 8.07 (d, J = 8.1 Hz, 2H), 7.547.36 (m, 6H),
6.90 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 5.61 (s, 4H), 3.74 (s, 3H), 3.11 (t, J =
6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H); 13C NMR (Bt1) 158.0, 146.0, 133.1, 130.6, 129.4,
127.7, 124.1, 119.9, 113.8, 109.8, 64.4, 55.1, 52.3, 33.0. Anal. Calcd for C23H23N7O: C,
66.81; H, 5.61; N, 23.71. Found: C, 66.65; H, 5.63; N, 23.79.
N,N-Bis(benzotriazolylmethyl)-N-(3,4-dimethoxyphenethyl)amine
(2.5b).
Method B; mixture of Bt1 and Bt2 isomers in 4:1 ratio; sticky oil; yield, 95%; 1H NMR
(Bt1) 8.07 (d, J = 8.3 Hz, 2H), 7.557.36 (m, 6H), 6.656.52 (m, 2H), 6.43 (d, J = 1.7 Hz,
1H), 5.64 (s, 4H), 3.80 (s, 3H), 3.49 (s, 3H), 3.13 (t, J = 7.0 Hz, 2H), 2.73 (t, J = 7.0 Hz,
2H); 13C NMR (Bt1) 148.6, 147.3, 145.8, 132.9, 131.1, 127.7, 124.1, 120.3, 119.8, 109.7,
64.6, 55.6, 55.5, 52.2, 33.5. Anal. Calcd for C24H25N7O2: C, 65.00; H, 5.68; N, 22.11.
Found: C, 64.64; H, 6.04; N, 21.71.
N,N-Bis-(1H-1,2,3-benzotriazol-1-ylmethyl)-2,2-diphenyl-1-ethanamine (2.5c).
Method B; colorless flakes (from CHCl3/hexanes); yield, 97%; mp 120121C; 1H NMR
16
8.04 (d, J = 8.2 Hz, 2H), 7.417.33 (m, 4H), 7.317.25 (m, 2H), 7.167.11 (m, 6H),
7.097.02 (m, 4H), 5.54 (s, 4H), 4.26 (t, J = 8.1 Hz, 1H), 3.46 (d, J = 8.1 Hz, 2H); 13C
NMR 146.0, 141.5, 133.0, 128.4, 127.8, 127.7, 126.6, 124.1, 119.8, 109.8, 64.7, 55.3,
49.1. Anal. Calcd for C28H25N7: C, 73.18; H, 5.48; N, 21.34. Found: C, 72.95; H, 5.29; N,
21.42.
2.4.2 Preparation of N-benzotriazolylmethyl-1,2,3,4-tetrahydroisoquinolines 2.6ac
via annulation of bis(benzotriazolylmethyl) intermediates 2.5ac.
To a stirred solution of 2.5ac (4 mmol) in dry CH2Cl2 (30 mL), AlCl3 (2.13 g, 16
mmol) was added. The reaction mixture was refluxed for 10 h. After cooling, 2 M NaOH
(20 mL) was added. The separated aqueous phase was extracted with CH2Cl2. The
combined organic fractions were washed with 2 M NaOH, brine and dried over
anhydrous MgSO4. Removal of solvents in vacuo gave a solid, which was recrystallized
from appropriate solvents to afford the pure products 2.6a,b.
2-Benzotriazolylmethyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.6a).
Mixture of Bt1 and Bt2 isomers in 5:1 ratio; colorless prisms (from CH2Cl2/Et2O); yield,
86%; mp 127129 C; 1H NMR (Bt1) 8.05 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),
7.48 (dd, J = 7.2, 7.2 Hz, 1H), 7.35 (dd, J = 7.6, 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H),
6.66 (dd, J = 8.4, 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.58 (s, 2H), 3.79 (s, 2H), 3.71 (s,
3H), 2.92 (t, J = 5.3 Hz, 2H), 2.81 (t, J = 5.4 Hz, 2H), [ (Bt2) 7.907.85 (m, 2H),
7.407.34 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.5 Hz, 1H), 6.53 (d, J =
2.5 Hz, 1H), 5.73 (s, 2H), 3.88 (s, 2H), 3.71 (s, 3H), 3.01 (t, J = 5.3 Hz, 2H), 2.83 (t, J =
5.4 Hz, 2H)]; 13C NMR (Bt1): 157.5 (q), 145.8 (q), 134.5 (q), 133.7 (q), 129.5, 127.4,
125.4 (q), 123.8, 119.7, 112.7, 110.9, 109.9, 68.9 (Bt1CH2), 55.1 (OCH3), 52.3, 48.6,
17
28.2, [ (Bt2) 157.5 (q), 144.1 (q), 134.8 (q), 126.3, 125.5 (q), 118.1, 112.5, 110.8, 109.9,
76.7 (Bt2CH2), 55.1 (OCH3), 51.7, 48.4, 28.5]. Anal. Calcd for C17H18N4O: C, 69.37; H,
6.16; N, 19.03. Found: C, 69.34; H, 6.02; N, 19.16.
2-Benzotriazolylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2.6b).
Mixture of Bt1 and Bt2 isomers in 7:1 ratio; colorless needles (from CH2Cl2/Et2O); yield,
89%; mp 136137 C; 1H NMR (Bt1) 8.06 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H),
7.50 (dd, J = 7.2, 7.2 Hz, 1H), 7.36 (dd, J = 7.5, 7.5 Hz, 1H), 6.55 (s, 1H), 6.47 (s, 1H),
5.61 (s, 2H, Bt1CH2), 3.81 (s, 3H), 3.79 (s, 3H), 3.76 (s, 2H), 2.94 (t, J = 5.5 Hz, 2H),
2.82 (t, J = 5.3 Hz, 2H), [ (Bt2) 7.917.88 (m, 2H), 7.407.37 (m, 2H), 6.55 (s, 1H),
6.50 (s, 1H), 5.74 (s, 2H, Bt2CH2), 3.84 (s, 3H), 3.83 (s, 2H), 3.81 (s, 3H), 3.03 (t, J = 5.9
Hz, 2H), 2.82 (t, J = 5.3 Hz, 2H)]; 13C NMR (Bt1) 147.4 (q), 147.1 (q), 145.7 (q), 133.6
(q), 127.3, 125.1 (q), 125.0 (q), 123.7, 119.5, 111.1, 109.9, 109.1, 68.9 (Bt1CH2), 55.7,
51.8, 48.4, 28.6, [ (Bt2) 147.3 (q), 147.1 (q), 144.0 (q), 126.3, 125.5 (q), 125.1 (q),
118.1, 109.9, 109.1, 76.7 (Bt2CH2), 55.7, 51.1, 48.2, 28.9]. Anal. Calcd for C18H20N4O2:
C, 66.65; H, 6.21; N, 17.27. Found: C, 66.52; H, 6.45; N, 17.53.
2-(Benzotriazolylmethyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline (2.6c).
Mixture of Bt1 and Bt2 isomers in 4:1 ratio; sticky oil; yield, 82%; 1H NMR (Bt1) 8.04
(d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 7.2, 7.2 Hz, 1H), 7.34 (dd, J =
7.3, 7.3 Hz, 1H), 7.267.20 (m, 3H), 7.207.00 (m, 5H), 6.86 (d, J = 7.5 Hz, 1H), 5.55 (s,
2H), 4.274.21 (m, 1H), 3.94 (d, J = 5.6 Hz, 2H), 3.25 (dd, J = 11.5, 5.1 Hz, 1H), 2.98
(dd, J = 11.5, 6.4 Hz, 1H). 13C NMR (Bt1) 145.9, 144.4, 136.5, 133.9, 129.6, 128.9,
128.2, 127.5, 126.5, 126.4, 126.3, 126.2, 123.9, 119.8, 118.3, 110.0, 69.2, 56.6, 52.7,
45.6. Anal. Calcd for C22H20N4: C, 77.62; H, 5.92. Found: C, 77.39; H, 6.24.
18
2.4.3 General procedure for reduction of N-benzotriazolylmethyl-1,2,3,4tetrahydroisoquinolines 6ab with NaBH4.
A mixture of 2.6a or 2.6b (2 mmol) and NaBH4 (0.16 g, 4 mmol) was stirred in dry
THF (15 mL) at 25 C overnight. The reaction mixture was quenched with water and
extracted with Et2O. The combined organic layers were dried over anhydrous Na2SO4.
After removal of the solvents in vacuo, the residue was purified by column
chromatography with hexanes/EtOAc (2:1) as an eluent to give N-methyl-1,2,3,4tetrahydroisoquinolines 2.7ab.
7-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (2.7a). Colorless flakes;
yield, 83%; mp 5051 C (lit.14 bp 126 C/8 mmHg; mp 5051 C); 1H NMR 7.09 (d, J
= 8.6 Hz, 1H), 6.80 (dd, J = 8.4, 2.3 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 4.21 (d, J = 12.3
Hz, 1H), 3.81 (d, J = 12.3 Hz, 1H), 3.78 (s, 3H), 3.20 (t, J = 8.4 Hz, 2H), 2.93 (t, J = 6.2
Hz, 2H), 2.62 (s, 3H, NCH3); 13C NMR 148.2, 147.9, 122.4, 121.8, 110.9, 109.1, 61.0,
56.3, 55.7, 46.6, 23.9.
6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (2.7b). Colorless flakes;
yield, 87%; mp 8384 C (lit.15 mp 8384 C); 1H NMR 6.66 (s, 1H), 6.50 (s, 1H), 4.16
(d, J = 16.0 Hz, 1H), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.77 (d, J = 16.0 Hz, 1H),
3.17 (t, J = 6.2 Hz, 2H), 2.91 (t, J = 6.1 Hz, 2H), 2.62 (s, 3H, NCH3); 13C NMR 148.1,
147.9, 122.4, 121.8, 110.9, 109.1, 61.0, 56.3, 55.8 (OCH3), 55.7 (OCH3), 46.6, 23.9.
2.4.4 Procedure for the preparation of chiral -amino amides 9a,b from N-Boc-Phe
(2.8).
To a cold solution (15 C) of (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)3-phenylpropanoic acid (2.8) (2.65 g, 10 mmol) and 4-methylmorpholine (1.01 g, 10
mmol) in dry THF (30 mL), iso-butyl chloroformate (1.36 g, 10 mmol) in THF (5 mL)
19
was added dropwise in 15 min. After stirring for another 15 min, morpholine (0.87 g, 10
mmol) or N,N-dibutylamine (1.29 g, 10 mmol) was added. Then, the reaction mixture
was stirred at rt for 2 h. After evaporation of the solvent in vacuo, the residue was diluted
with EtOAc (80 mL) and the organic phase was washed with 10% Na2CO3, 0.1 M HCl
and brine and dried over anhydrous MgSO4. Evaporation of the solvent in vacuo gave
2.9a,b, which was used for the subsequent step without further purification.
tert-Butyl N-[(1S)-1-benzyl-2-morpholino-2-oxoethyl]carbamate (2.9a)
[00TL37]. Colorless oil; yield, 92%; 1H NMR 7.327.19 (m, 5H), 5.49 (d, J = 8.6 Hz,
1H), 4.844.76 (m, 1H), 3.673.38 (m, 5H), 3.333.25 (m, 1H), 3.062.84 (m, 4H), 1.43
(s, 9H); 13C NMR 170.2, 155.0, 136.3, 129.5, 128.5, 127.0, 79.7, 66.4, 66.0, 50.7, 45.9,
42.1, 40.4, 28.3.
tert-Butyl N-[(1S)-1-benzyl-2-(dibutylamino)-2-oxoethyl]carbamate (2.9b).
Colorless oil; yield, 89%; []25D = + 6.0 (c 1.84, CHCl3); 1H NMR 7.277.19 (m, 5H),
5.35 (d, J = 8.9 Hz, 1H), 4.784.70 (m, 1H), 3.473.38 (m, 1H), 3.072.85 (m, 5H), 1.41
(s, 9H), 1.351.81 (m, 8H), 0.950.83 (m, 6H); 13C NMR 171.0, 154.8, 136.6, 129.4,
128.2, 126.6, 79.2, 51.3, 47.3, 45.9, 40.3, 30.8, 29.4, 28.1, 20.0, 19.8, 13.7, 13.6. Anal.
Calcd for C22H36N2O3: C, 70.18; H, 9.64; N, 7.44. Found: C, 69.97; H, 9.31; N, 7.62.
2.4.5 Preparation of N-Boc group. -Amino amide 2.10a, b.
To a stirred solution of 2.9a,b (10 mmol) in EtOAc (30 mL), HCl in EtOAc (ca 1
M, 20 mL) was added. The mixture was stirred at rt until TLC showed disappearance of
the starting material (about 15 h). For 2.10a, the precipitate formed was filtered and
washed with ether to give its hydrochloride salt. For 2.10b, the clear solution was washed
with 1 M NaOH, brine, dried over anhydrous K2CO3 and evaporated to give 2.10b.
20
(2S)-1-Morpholino-1-oxo-3-phenyl-2-propanaminium chloride (2.10a).
Colorless needles (from EtOH); yield, 87%; mp 231233 C; []25D = + 69.5 (c 1.73,
EtOH); 1H NMR (DMSO-d6) 8.65 (br s, 3H), 7.377.24 (m, 5H), 4.644.59 (m, 1H),
3.493.22 (m, 7H), 2.962.87 (m, 2H), 2.712.68 (m, 1H); 13C NMR (DMSO-d6)
166.9, 134.7, 129.8, 128.6, 127.3, 65.6, 65.3, 49.4, 45.6, 42.0, 37.0. Anal. Calcd for
C13H19ClN2O2: C, 57.67; H, 7.07; N, 10.35. Found: C, 57.28; H, 7.20; N, 10.04.
(2S)-2-Amino-N,N-dibutyl-3-phenylpropanamide (2.10b). Colorless oil; yield,
92%; []25D = + 50.7 (c 1.81, EtOH); 1H NMR 7.327.18 (m, 5H), 3.81 (t, J = 7.0 Hz,
1H), 3.503.43 (m, 1H), 3.102.85 (m, 4H), 2.76 (dd, J = 13.2, 7.3 Hz, 1H), 1.78 (s, 2H),
1.521.32 (m, 4H), 1.321.17 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H);
13
C NMR 174.2, 137.8, 129.2, 128.3, 126.5, 52.9, 47.0, 46.0, 42.9, 31.2, 29.6, 20.1,
19.9, 13.7, 13.6. Anal. Calcd for C17H28N2O: C, 73.87; H, 10.21; N, 10.13. Found: C,
73.92; H, 10.36; N, 9.97.
2.4.6 General procedure for the preparation of Bt intermediates 2.11ac.
To a solution of benzotriazole (0.36 g, 3 mmol), hydrochloride salt 2.10a,c (3
mmol) and NaOH (0.12 g, 3 mmol) in MeOH/H2O (20/10 mL), formaldehyde (0.24 g, 3
mmol, 37% aqueous solution) was added. The mixture was stirred at rt for 5 h. For
2.11a,c, the precipitate formed was filtered, washed with cool H2O and EtOH, and
recrystallized from appropriate solvents. For 2.11b, the clear solution was concentrated,
extracted with CH2Cl2, and dried over anhydrous Na2SO4. Evaporation of solvents in
vacuo afforded 2.11b, which was used directly for the subsequent reaction.
(2S)-2-[(Benzotriazolylmethyl)amino]-1-morpholino-3-phenyl-1-propanone
(2.11a). Mixture of Bt1 and Bt2 isomers in 6:1 ratio; colorless flakes (from EtOAc); yield,
21
91%; mp 9192 C; []25D = + 151 (c 2.39, EtOH); 1H NMR (Bt1) 8.01 (d, J = 8.2 Hz,
1H), 7.60 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 7.2, 7.2 Hz, 1H), 7.36 (dd, J = 7.5, 7.5 Hz,
1H), 7.287.13 (m, 3H), 7.107.02 (m, 2H), 5.50 (s, 2H), 3.903.78 (br s, 1H, NH),
3.353.00 (m, 6H), 2.912.82 (m, 2H), 2.772.59 (m, 3H); 13C NMR (Bt1) 171.4
(C=O), 146.0, 136.6, 132.2, 129.2, 128.3, 127.3, 126.8, 124.0, 119.3, 109.8, 65.8, 65.4,
61.9, 55.9, 45.1, 41.6, 41.0. Anal. Calcd for C20H23N5O2: C, 65.73; H, 6.34; N, 19.16.
Found: C, 66.05; H, 6.48; N, 19.20.
(2S)-2-[(Benzotriazolylmethyl)amino]-N,N-dibutyl-3-phenylpropanamide
(2.11b). Mixture of Bt1 and Bt2 isomers in 8:1 ratio; light yellow oil; yield, 93%; []25D =
+ 47.7 (c 1.70, CHCl3); 1H NMR (Bt1) 8.00 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.3 Hz,
1H), 7.42 (dd, J = 7.3, 7.3 Hz, 1H), 7.34 (dd, J = 7.3, 7.3 Hz, 1H), 7.217.15 (m, 3H),
7.07 (d, J = 7.5 Hz, 2H), 5.43 (br s, 2H), 3.803.74 (m, 1H), 3.20 (br s, 1H, NH),
3.103.04 (m, 1H), 3.002.93 (m, 1H), 2.872.82 (m, 2H), 2.792.74 (m, 2H), 1.191.08
(m, 4H), 0.950.87 (m, 4H), 0.82 (t, J = 7.7 Hz, 6H); 13C NMR (Bt1) 172.4 (C=O),
146.3, 137.5, 132.4, 129.1, 128.2, 127.2, 126.5, 123.9, 119.6, 110.2, 62.1, 56.6, 47.1,
46.1, 40.6, 30.7, 29.4, 20.1, 20.0, 13.7, 13.6. Anal. Calcd for C24H33N5O: C, 70.73; H,
8.16. Found: C, 70.74; H, 8.48.
Methyl (2S)-2-[(1H-1,2,3-benzotriazol-1-ylmethyl)amino]-3-phenylpropanoate
(2.11c). Colorless needles (from CHCl3); yield, 92%; mp 9697 C; []25D = + 18.3 (c
2.17, EtOH); 1H NMR 8.03 (d, J = 8.3 Hz, 1H), 7.427.38 (m, 2H), 7.387.32 (m, 1H),
7.197.13 (m, 3H), 7.027.00 (m, 2H), 5.565.41 (m, 2H), 3.703.60 (m, 1H), 3.46 (s,
3H), 2.97 (dd, J = 13.7, 5.2 Hz, 1H), 2.79 (dd, J = 13.6, 8.1 Hz, 1H), 2.69 (br s, NH, 1H);
13
C NMR 173.6 (C=O), 146.1, 136.4, 132.4, 128.9, 128.3, 127.3, 126.7, 123.9, 119.8,
22
109.4, 61.4, 59.4, 51.9, 39.2. Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05.
Found: C, 65.77; H, 6.22; N, 18.13.
2.4.7 General procedure for the preparation of chiral 3-substituted-1,2,3,4tetrahydroisoquinolines 2.12ac via annulation of 2.11ac.
A mixture of 2.11ac (4 mmol) and AlCl3 (2.13 g, 16 mmol) was refluxed in dry
CH2Cl2 (30 mL) for 10 h. After cooling, 2 M NaOH (20 mL) was added. The separated
aqueous phase was additionally extracted with CH2Cl2. The combined organic phase was
washed with 2 M NaOH, brine and dried over anhydrous MgSO4. After removal of the
solvent in vacuo, the residue was purified by column chromatography with
hexanes/EtOAc/Et3N (2:1:0.005) as an eluent to give 2.12ac.
Morpholino[(3S)-(1,2,3,4-tetrahydro-3-isoquinolinyl)]methanone (2.12a).
Colorless needles; yield, 70%; mp 113114 C; []25D = 89.4 (c 2.03, EtOH); 1H NMR
7.167.07 (m, 3H), 7.047.01 (m, 1H), 4.08 (s, 2H), 3.87 (dd, J = 11.1, 4.4 Hz, 1H),
3.803.42 (m, 6H), 3.623.49 (m, 2H), 2.98 (dd, J = 16.3, 11.2 Hz, 1H), 2.76 (dd, J =
16.4, 4.2 Hz, 1H), 1.99 (br s, 1H, NH); 13C NMR 171.3 (C=O), 135.2, 133.4, 129.2,
126.2, 126.1, 125.6, 66.7, 66.6, 53.0, 47.2, 45.8, 42.1, 31.3. Anal. Calcd for C14H18N2O2:
C, 68.27; H, 7.37; N, 11.37. Found: C, 68.63; H, 7.73; N, 11.37.
(3S)-N,N-Dibutyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (2.12b).
Colorless oil; yield, 80%; []25D = 53.2 (c 1.76, CHCl3); 1H NMR 7.187.03 (m, 4H),
4.11 (s, 2H), 3.83 (dd, J = 10.8, 3.9 Hz, 1H), 3.403.25 (m, 4H), 3.01 (dd, J = 16.5, 10.8
Hz, 1H), 2.74 (dd, J = 16.5, 3.6 Hz, 1H), 1.89 (br s, 1H, NH), 1.601.53 (m, 4H),
1.371.26 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H); 13C NMR 172.4, 135.4, 133.9, 129.2,
23
126.1, 126.0, 125.6, 53.0, 47.4, 47.3, 45.8, 31.7, 31.6, 29.7, 20.1, 20.0, 13.8, 13.7. Anal.
Calcd for C18H28N2O: C, 74.95; H, 9.78; N, 9.71. Found: C, 74.64; H, 10.07; N, 9.61.
Methyl (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylate (2.12c). Light yellow
oil; yield, 72%; []25D = 126 (c 1.28, CH2Cl2), {lit.13 []22D = 124 (c 1.28, CH2Cl2)};
1
H NMR 7.157.06 (m, 3H), 7.066.98 (m, 1H), 4.08 (d, J = 3.3 Hz, 2H), 3.76 (s, 3H),
3.72 (dd, J = 10.1, 4.8 Hz, 1H), 3.182.90 (m, 2H), 2.20 (br s, 1H, NH); 13C NMR
173.4 (C=O), 134.7, 132.9, 129.0, 126.1, 126.0, 125.9, 55.7, 52.0, 47.2, 31.5; MS (EI):
191 (M+, 3), 176 (M+CH3, 3), 132 (M+COOMe, 100). Anal. Calcd for C11H13NO2: C,
69.09; H, 6.85. Found: C, 69.10; H, 6.69.
2.4.8 General procedure for the nucleophilic substitution of 6a with Grignard
reagents.
To a cold solution (40 C) of 2-benzotriazolylmethyl-7-methoxy-1,2,3,4tetrahydroisoquinoline (2.6a) (0.88 g, 3 mmol) in dry THF (30 mL), an appropriate
Grignard reagent (6 mmol) was added and then the mixture was stirred at 40 C for 2 h
and at rt for another 10 h. The reaction mixture was washed with 2 M NaOH, and the
aqueous phase was extracted with Et2O. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. After removal of solvents in vacuo, the residue
was purified by column chromatography with hexanes/EtOAc (3:1) as an eluent to afford
2.13ac.
2-Benzyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.13a). Colorless oil; yield,
63%; 1H NMR 7.407.26 (m, 5H), 6.99 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H),
6.51 (s, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 3.59 (s, 2H), 2.81 (t, J = 5.3 Hz, 2H), 2.74 (t, J =
5.4 Hz, 2H); 13C NMR 157.5, 138.3, 135.8, 129.5, 129.1, 128.3, 127.1, 126.4, 112.6,
24
111.1, 62.6, 56.2, 55.2, 50.8, 28.2. Anal. Calcd for C17H19NO: C, 80.59; H, 7.56; N, 5.53.
Found: C, 80.65; H, 7.74; N, 5.77.
2-Hexyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.13b). Colorless flakes;
yield, 59%; mp 4041 C; 1H NMR 6.99 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 8.4, 2.7 Hz,
1H), 6.56 (d, J = 2.4 Hz, 1H), 3.76 (s, 3H), 3.61 (s, 2H), 2.84 (t, J = 5.7 Hz, 2H), 2.73 (t,
J = 5.7 Hz, 2H), 2.50 (t, J = 7.8 Hz, 2H), 1.631.52 (m, 2H), 1.401.22 (m, 6H), 0.89 (t,
J = 6.6 Hz, 3H); 13C NMR 157.5, 135.7, 129.5, 126.4, 112.5, 111.2, 58.4, 56.3, 55.2,
51.1, 31.8, 28.0, 27.3, 27.0, 22.6, 14.0; HRMS Calcd for C16H26NO 248.2014 (M+1),
found 248.2006.
7-Methoxy-2-(3-phenyl-2-propynyl)-1,2,3,4-tetrahydroisoquinoline (2.13c).
Colorless oil; yield, 74%; 1H NMR 7.457.42 (m, 2H), 7.317.28 (m, 3H), 7.03 (d, J =
8.4 Hz, 1H), 6.72 (dd, J = 8.7, 2.7 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 3.82 (s, 2H), 3.77 (s,
3H), 3.73 (s, 2H), 2.90 (s, 4H); 13C NMR 157.6, 135.6, 131.7, 129.5, 128.2, 128.1,
125.9, 123.1, 112.6, 111.3, 85.5, 84.3, 55.3, 54.7, 50.1, 47.5, 28.4. Anal. Calcd for
C19H19NO: N, 5.05. Found: N, 5.21. HRMS Calcd for C19H20NO 278.1545 (M+1), found
278.1542.
2.4.9 Procedure for the nucleophilic substitution of 6a with a silyl enol ether.
To a solution of 6a (0.59 g, 2 mmol) in dry THF (30 mL) at 0 C, 1-phenylvinyl
trimethylsilyl ether (0.58 g, 3 mmol ) and BF3Et2O (2 mmol, 0.28 g) were added. The
mixture was stirred at 0 C for 2 h and at room temperature for other 10 h. The reaction
mixture was washed with 2 M NaOH, brine and the aqueous phase was extracted with
Et2O. The combined organic layers were dried over anhydrous Na2SO4. After removal of
25
the solvent in vacuo, the residue was purified by column chromatography with
hexanes/EtOAc (2:1) as an eluent to afford 2.14.
3-[7-Methoxy-3,4-dihydro-2(1H)-isoquinolinyl]-1-phenyl-1-propanone (2.14).
Pale yellow oil; yield, 63%; 1H NMR 7.98 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H),
7.45 (dd, J = 7.6, 7.6 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.70 (dd, J = 8.4, 2.7 Hz, 1H),
6.56 (d, J = 2.1 Hz, 1H), 3.75 (s, 3H), 3.67 (s, 2H), 3.30 (t, J = 7.2 Hz, 2H), 3.00 (t, J =
8.1 Hz, 2H), 2.842.79 (m, 4H); 13C NMR 199.0, 157.5, 136.9, 135.5, 133.0, 129.5,
128.5, 128.0, 126.2, 112.5, 111.2, 56.2, 55.2, 52.8, 51.3, 36.7, 28.2. Anal. Calcd for
C19H21NO2: N, 4.74. Found: N, 4.79. HRMS Calcd for C19H22NO2 296.1651 (M+1),
found 296.1655.
2.4.10 Procedure for the nucleophilic substitution of 2.6a with triethyl phosphate.
To a solution of 2.6a (0.59 g, 2 mmol) in dry THF (20 mL) at 0 C, ZnBr2 (0.90 g,
4 mmol) was added. The solution was stirred for 20 min before triethyl phosphite (0.40 g,
2.4 mmol) was added dropwise. After stirring at room temperature for 10 h, most of the
THF was evaporated. The residue was diluted with EtOAc, and the solution was washed
with 2 M NaOH, water and dried over Na2SO4. After removal of solvent in vacuo, the
residue was purified by column chromatography with hexanes/EtOAc (3:11:1) as an
eluent to afford 2.15.
Diethyl [7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]methylphosphonate
(2.15). Light yellow oil; yield, 80%; 1H NMR 7.00 (d, J = 8.4 Hz, 1H), 6.71 (dd, J =
8.4, 2.7 Hz, 1H), 6.55 (d, J = 2.7 Hz, 1H), 4.224.15 (m, 4H), 3.82 (s, 2H), 3.76 (s, 3H),
2.982.94 (m, 4H), 2.82 (t, J = 7.2 Hz, 2H), 1.33 (t, J = 7.0 Hz, 6H); 13C NMR 157.5,
135.4, 129.5, 125.9, 112.6, 111.1, 62.1 (d, J = 6.8 Hz), 57.4 (d, J = 10.8 Hz), 55.2, 53.5
26
(d, J = 162.8 Hz), 52.6 (d, J = 10.3 Hz), 27.9, 16.5 (d, J = 5.7 Hz). Anal. Calcd for
C15H24NO4P: C, 57.50; H, 7.72; N, 4.47. Found: C, 57.84; H, 8.02; N, 4.68.
CHAPTER 3
CONVENIENT SYNTHESES OF DIHYDROPYRROLO[2',1':3,4]PYRAZINO- AND
DIHYDROPYRROLO[2',1':3,4][1,4]DIAZEPINO-[2,1-A]ISOINDOLONES
3.1 Introduction
Isoindoles and derivatives represent valuable active substances in medications for
the therapy and prophylaxis of diseases, for example, pyrazinoisoindoles are
antihypertensive [81US115606f]. Likewise, [1,4]diazaheterocycles such as
pyrrolo[1,4]benzodiazepines are biologically active compounds which exhibit antitumor
and antibiotic activities [97B2478], [86B3021], [88CRT258], [94JMC4329] and
cytotoxicity [99JMC1951]. Consequently, the synthesis of polycyclic nitrogen
heterocycles containing isoindole and [1,4]diaza skeletons will enrich the families of
isoindoles and [1,4]diaza systems which are potentially biologically active.
Among known polycyclic systems containing isoindoles and [1,4]diaza skeletons,
isoindolopyrroloquinoxaline (3.2a), isoindolopyrrolo[1,4]benzodiazepines (3.2b, c) and
isoindolopyrrolo2,5]benzodiazocine (3.2d), were previously prepared in three steps from
the condensation of substituted anilines or benzylamines with phthalic anhydride to
afford phthalimides which reacted with NaBH4 or EtMgI to give hydroxylactam
intermediates 3.1. Further treatment of 3.1 with trifluoroacetic acid or thionyl chloride in
dichloromethane furnished the synthesis of pentacyclic compounds 3 (Scheme 31)
[00H273]. Similarly, indolodiazepinoisoindolone 3.4 was obtained in three steps from 1(3-aminopropyl)-3-methylindole and phthalic anhydride through the formation of
phthalimide 3.3 (Scheme 32) [77C362].
27
28
O
H2N
O
NaBH4
or EtMgI
n
HO R
m
N
3.2a, n = 0, m = 0
3.2b, n = 0, m = 1
3.2c, n = 1, m = 0
3.2d, n = 1, m = 1
3.1
3.2a-d
R = H or Et
N
O
1) LiAlH4
2) AlCl3
NH2
N
O
3.3
3.4
29
[2001JOC148] .[2001TL1511], [98JOC1144], [2001TL3943], [2000JOC235],
[97T2449].
CHO
COOH
R
R4
R2
4
R1
NH2
R3
BtH
R2
R1
N
O
TiCl4
R1
R
+
-H
R3
Bt
3.5
BtH = Benzotriazole
3.6
3.7
30
H
N
+ Cl
NH3 Cl
n
NaOH/CH3CN/TBAS
NH2
n
3.8a, n = 2
3.8b, n = 3
Me
N
H
Me
+ Cl
NH3 Cl NaOH/CH3CN/TBAS
N
NH2
3.9
C NMR spectra and microanalysis. The 1H NMR spectra show NCH-pyrrole singlet
signals for 3.11a and 3.11b at 5.74 and 5.65 ppm, respectively. The reaction pathway is
believed to involve the formation of transient hydroxylactam intermediates and
subsequent generation of N-acyliminium cations A, which undergo intramolecular
pyrrole cyclization to furnish 3.11ac. Therefore, three new bonds are formed in one step
to generate the tetracyclic ring system.
31
HOOC
N
NH2
PhH
3.10 R1
R2
Me
N+
R1
_ H+
OMe
N
R1
Dean-Stark
R2
N
p-TsOH
R2
3.8
COR1
R
R2
R2
R2
A
3.11
R1
R2
OMe 81
Me
Y (%)
76
79
32
COR1
HOOC
N
NH2
O
p-TsOH
R2
R2
3.8b
3.10
a
b
c
R1
H
H
Me
Dean-Stark
PhCH3
or
Hb (4.69 ppm,d)
R2
a
Hc H (5.17 ppm,d)
NOE
R2
R2
H
OMe
H
when R1 = H
when R1 = Me
3.12a, R2 = H, 76%
3.12b, R2 = OMe, 66%
3.13, 66%
Me
+
N
HOOC
CHO
PhH
NH2
Me
3.9
3.10a
3.14, 82%
33
3.4 Experimental Section
1
H (300 MHz), 13C (75 MHz) NMR and NOE spectra were recorded on a Gemini
300 NMR spectrometer in CDCl3 (with TMS for 1H and chloroform-d for 13C as the
internal reference). Column chromatography was performed on silica gel (200425
mesh). All of the reactions were carried out under N2.
Typical Procedure: A mixture of the primary amine 3.8a, 3.8b or 3.9 (1.2 mmol),
2-formylbenzoic acids 3.9a, b or 2-acetylbenzoic acid 3.9c (1 mmol) and pMeC6H4SO3HH2O (0.02 g, 0.1 mmol) was refluxed in benzene (for 3.11ac and 3.14) or
toluene (for 3.12a, b and 3.13) for 816 h using a Dean-Stark apparatus. After being
cooled, most of the solvent was evaporated in vacuo and the residue was diluted in
EtOAc. The organic phase was washed with 1 M NaOH, brine and dried over anhydrous
Na2SO4. After removal of solvents in vacuo, the residue was purified by column
chromatography with hexanes/EtOAc (4:1 to 2:1) to give the final product. The melting
points are: 3.11a, 129.5130 C; 3.11b, 143144 C; 3.11c, 158.5159 C; 3.12a,
106107 C; 3.12b, 205 C (decomposition); 3.13, colorless oil; 3.14, 173 C
(decomposition).
5,6-Dihydropyrrolo[2',1':3,4]pyrazino[2,1-a]isoindol-8(12bH)-one 3.11a.
Obtained as hydrate; colorless needles; yield, 76%; 1H NMR 2.01 (br s, for hydrate),
3.60 (ddd, J = 13.5, 10.5, 5.1 Hz, 1H), 3.944.08 (m, 2H), 4.68 (ddd, J = 13.2, 4.5, 2.1
Hz, 1H), 5.74 (s, 1H), 6.19 (t, J = 3.0 Hz, 1H), 6.27 (br s, 1H), 6.61 (br s, 1H), 7.48 (t, J =
7.4 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H);
13
C NMR 37.6, 44.2, 56.2, 104.0, 108.6, 119.9, 122.9, 123.8, 125.4, 128.5, 131.6,
34
132.1, 144.3, 167.8. Anal. Calcd for C14H12N2O H 2O: C, 69.40; H, 5.82; N, 11.56.
Found: C, 69.31; H, 5.69; N, 11.48.
9,10-Dimethoxy-5,6-dihydropyrrolo[2',1':3,4]pyrazino[2,1-a]isoindol-8(12bH)one 3.11b. Colorless microcrystals; yield, 81%; mp 143144 C; 1H NMR 3.55 (ddd, J
= 13.5, 9.9, 6.0 Hz, 1H), 3.89 (s, 3H), 3.994.03 (m, 2H), 4.07 (s, 3H), 4.66 (ddd, J =
13.5, 4.5, 2.1 Hz, 1H), 5.65 (s, 1H), 6.19 (t, J = 3.0 Hz, 1H), 6.23 (br s, 1H), 6.61 (br s,
1H), 7.16 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H); 13C NMR 37.6, 44.1, 55.1, 56.8,
62.5, 103.9, 108.6, 117.0, 118.0, 119.8, 124.0, 126.1, 137.8, 147.3, 152.7, 166.1. Anal.
Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.20; H, 5.69; N, 9.67.
12b-Methyl-5,6-dihydropyrrolo[2',1':3,4]pyrazino[2,1-a]isoindol-8(12bH)-one
3.11c. Colorless needles; yield, 79%; mp 158.5159.0 C; 1H NMR 1.80 (s, 3H), 3.57
(ddd, J = 13.5, 10.8, 5.7 Hz, 1H), 3.914.03 (m, 2H), 4.70 (ddd, J = 13.5, 5.7, 1.5 Hz,
1H), 6.15 (t, J = 3.0 Hz, 1H), 6.25 (dd, J = 3.6, 1.5 Hz, 1H), 6.53 (t, J = 2.1 Hz, 1H), 7.45
(t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz,
1H); 13C NMR 28.8, 35.2, 44.3, 61.7, 104.0, 108.4, 119.4, 121.9, 123.8, 128.3, 130.2,
130.5, 132.4, 150.8, 167.9. Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76.
Found: C, 75.51; H, 5.86; N, 11.86.
6,7-Dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[2,1-a]isoindol-9(13bH)-one
3.12a. Colorless flakes; yield, 76%; 1H NMR 1.851.98 (m, 1H), 2.102.18 (m, 1H),
3.25 (td, J = 13.2, 3.3 Hz, 1H), 4.25 (t, J = 4.5 Hz, 2H), 4.76 (dt, J = 14.1, 3.6 Hz, 1H),
5.59 (s, 1H), 5.87 (s, 1H), 5.96 (t, J = 3.0 Hz, 1H), 6.65 (s, 1H), 7.52 (t, J = 7.4 Hz, 1H),
7.62 (t, J = 7.2 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H); 13C NMR
29.0, 43.2, 49.1, 58.8, 106.2, 108.5, 123.3, 124.0, 124.1, 128.7, 128.9, 131.3, 132.5,
35
142.4, 167.9. Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.53;
H, 6.03; N, 11.68.
10,11-Dimethoxy-6,7-dihydro-5H-pyrrolo[2',1':3,4][1,4]diazepino[2,1a]isoindol-9(13bH)-one 3.12b. Colorless microcrystals; yield, 66%; mp 205 C
(decomposition); 1H NMR 1.821.96 (m, 1H), 2.082.15 (m, 1H), 3.19 (td, J = 13.2,
3.0 Hz, 1H), 3.93 (s, 3H), 4.08 (s, 3H), 4.204.24 (m, 2H), 4.71 (dt, J = 14.4, 3.3 Hz,
1H), 5.48 (s, 1H), 5.88 (s, 1H), 5.97 (t, J = 3.2 Hz, 1H), 6.65 (s, 1H), 7.15 (d, J = 8.2 Hz,
1H), 7.30 (d, J = 8.2 Hz, 1H); 13C NMR 28.9, 43.1, 49.0, 56.6, 57.7, 62.5, 106.0, 108.2,
115.9, 119.0, 123.2, 124.5, 129.5, 135.5, 147.3, 152.6, 166.0. Anal. Calcd for
C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.16; H, 6.04; N, 9.07.
3-Methylene-2-[3-(1H-pyrrol-1-yl)propyl]-1-isoindolinone 3.13. Colorless oil;
yield, 66%; 1H NMR 2.16 (tt, J = 7.0, 7.0 Hz, 2H), 3.78 (t, J = 7.1 Hz, 2H), 3.97 (t, J =
6.9 Hz, 2H), 4.69 (d, J = 2.7 Hz, 1H, Hb), 5.17 (d, J = 2.4 Hz, 1H, Ha), 6.16 (t, J = 2.0 Hz,
2H), 6.71 (t, J = 1.8 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.68 (d, J
= 7.5 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H); 13C NMR 30.1, 36.7, 47.0, 88.7, 108.3, 119.9,
120.5, 123.1, 129.1, 129.6, 132.0, 136.3, 141.5, 167.2; GC-MS (EI): 252 (M+), 185, 159,
130, 107, 81 (base). Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C,
76.03; H, 6.43; N, 11.23.
10-Methyl-3,4-dihydroisoindolo[1',2':3,4]pyrazino[1,2-a]indol-1(10bH)-one
3.14. Colorless microcrystals; yield, 82%; mp 173 C (decomposition); 1H NMR 2.64
(s, 3H), 3.39 (ddd, J = 13.5, 12.0, 4.2 Hz, 1H), 3.98 (td, J = 11.7, 4.2 Hz, 1H), 4.14 (dd, J
= 11.7, 3.3 Hz, 1H), 4.81 (dd, J = 13.2, 3.3 Hz, 1H), 6.09 (s, 1H), 7.107.20 (m, 3H),
7.48 (t, J = 7.5 Hz, 1H), 7.547.61 (m, 2H), 7.89 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 7.5 Hz,
36
1H); 13C NMR 10.7, 38.7, 42.1, 57.3, 106.9, 108.8, 118.4, 119.6, 121.9, 123.8, 124.0,
127.6, 128.5, 128.6, 131.8, 132.2, 135.9, 145.2, 169.1. Anal. Calcd for C19H16N2O: C,
79.14; H, 5.59; N, 9.72. Found: C, 78.77; H, 5.69; N, 9.38.
.
CHAPTER 4
ONE-CARBON HOMOLOGATION OF ARYL AND ALKYL ALDEHYDES TO
AMIDES VIA VINYL BENZOTRIZOLES
4.1 Introduction
Homologation of carbonyl compounds by one carbon is of great importance in
organic and medicinal chemistry. Previous methods for the one-carbon homologation of
aldehydes to amides have mostly involved the one-carbon homologation of aldehydes 4.1
to carboxylic acids 4.3 followed by a functional group transformation to amides. The
classical intermediates developed for the preparation of one-carbon homologated
carboxylic acids 4.3 include: cyanohydrins 4.2a, nitriles 4.2b, glycidic esters 4.2c,
epoxides 4.2d, enol ethers 4.2e, thioenol ethers 4.2f, enamines 4.2g, ketene thioacetals
4.2h, ,-unsaturated sulfones 4.2i, or ,-unsaturated phosphonates 4.2j (Scheme 41).
Even though the homologation of aldehydes to carboxylic acids offers an attractive
alternative, the practical process is difficult and has limited applications. Syntheses of
intermediates 4.2a-j and subsequent conversion to carboxylic acids 4.3 often require
harsh conditions that are incompatible with sensitive functional groups. Reports of low
yields using these intermediates and lack of sufficient examples indicate a limited scope
[02OL1315].
Previously, our group reported a one-pot procedure for the preparation of onecarbon homologated carboxylic acids from 1-(benzotriazol-1-yl)-1-methoxyalk-1-enes
4.2k which was obtained by Peterson olefination of aldehydes and ketones with
trimethylsily(methoxy)benzotriazole-1-ylmethane. (Scheme 42) [96S1425]
37
38
Unfortunately no method of directly conversion of aldehydes to one-carbon homologated
amide has been investigated in our group.
CN
R
X
4.2a,b
O
R
X
R
OH
4.3
4.2c,d
X
4.2e-j
(4.2a) X = OH; (4.2b) X = H; (4.2c) X = H, Y = COOR; (4.2d) X = Y = H; (4.2e) X = H,
Y = OMe, OPh; (4.2f) X = H, Y = SPh; (4.2g) X = H, Y = N(CH2)4; (4.2h) X, Y = SMe,
SPh, S(CH2)3S; (4.2i) X = SO2Ph, Y = NHCHO; (4.2j) X = PO(OEt)2, Y = NMe2;
SiMe3
Bt
OMe
1) n-BuLi
2) RR'C=O
R
R'
2) H3O+
R
R'
OH
O
4.2k
39
and aryl amines and uses carcinogenic carbon tetrabromide (Scheme 43) [02OL1315],
[02T9925].
R
O
O
+ (EtO)2P
R1
CN
NaH
Ot-Bu
CN
R1
ZnCl2
H
CN R2 N R3
R1
OAc
R1
Ar
N R3
2
4.2l
CBr4, PPh3
Ar
H
N
Br
R2
Br
DMF/H2O
R1
4.2m
Ar
O
N R1
2
40
dibromoalkanes were obtained in quantitative yields and could be directly used in the
next step without further purification.
BtCH2P+Ph3Cl4.5
Bt
n-BuLi
RCHO
Br2
CH2Cl2
4.6a-d, 32-80%
Br
Bt
Br
4.7a-d, 83-100%
Bt
Br
R
4.7a-d
R1R2NH
DMF/H2O
O
R
NR1R2
4.8a-r
32-95%
41
applicability of this method and allows the preparation of one-carbon homologated
amides from aryl or alkyl aldehydes and various amines.
Table 41. Preparation of one-carbon homologated amides 4.8ar
R2
Yield (%)a
Entry
R
R1
1
Ph
Ph(CH2)2
H
4.8a (47)
2
Ph
CH3(CH2)3
H
4.8b (58)
3
Ph
(CH2)5
4.8c (61)
4
Ph
Ph
H
4.8d (72)
5
Ph
t-Bu
H
4.8e (68)
6
Ph
2-Pyridyl
H
4.8f (85)
7
Ph
1-Pyrimidyl
H
4.8g (80)
8
2-thienyl
Ph(CH2)2
H
4.8h (52)
9
2-thienyl
CH3(CH2)3
H
4.8i (92)
10
2-thienyl
(CH2)5
4.8j (88)
11
i-Pr
(CH2)5
4.8k (50)
12
Et
CH3(CH2)3
H
4.8l (84)
13
Et
(CH2)2N(CH3)2
H
4.8m (32)
14
Et
(CH2)2O(CH2)2
4.8n(54)
15
Et
(CH2)2N(CH3)(CH2)2
4.8o (62)
16
Et
Ph
H
4.8p (95)
17
Et
4-Pyridyl
H
4.8q (82)
18
Et
H
4.8r (68)
-Napthyl
4.3 Conclusion
In summary, we have developed a general method for the preparation of onecarbon homologated amides from aldehydes via easily accessible 1,2-dibromobenzotriazolylalkanes.
4.4 Experimental Section
Melting points were determined on a MEL-TEMP capillary melting point apparatus
equipped with a Flucke 51 digital thermometer. 1H NMR (300 MHz) and 13C NMR (75
MHz) spectra were recorded on a Gemini 300 NMR spectrometer in CDCl3 (with TMS
for 1H and chloroform-d for 13C as the internal reference). Elemental analyses were
performed on a Carlo Erba-1106 instrument. THF was distilled from
sodium/benzophenone prior to use. All of the reactions with air sensitive compounds
42
were carried out under N2. Column chromatography was performed on silica gel 200425
mesh.
4.4.1 Procedure for the preparation of benzotriazolyl alkenes 4.6a-d
To a solution of 1-(1H-1,2,3-benzotrazolyl)-1-triphenyl methane chloride (21.7 g,
0.05 mol) in DMSO, n-BuLi (1.6 M, 31 mL, 0.05 mol) was added under nitrogen at
25C. One hour later aldehyde (0.06 mol, 5.9 g) was added dropwise. After stirring for 12
h, the mixture was poured into 150 mL water, followed by extraction with CHCl3 (450
ml). The combined extracts were washed with brine and dried with MgSO4. After
removing the solvent, the crude compound was purified by chromatography (ethyl
acetate: hexane = 10:1).
1-[(E)-2-Phenylethenyl]-1H-1,2,3-benzotriazole (4.6a): white microcrystals; mp
115116 C; yield, 50%; 1H NMR 7.287.62 (m, 8H), 7.74 (d, J = 8.25 Hz, 1H), 7.92
(d, J = 14.6 Hz, 1H), 8.09 (d, J = 8.25 Hz, 1H); 13C NMR 110.0, 120.4, 121.0, 121.7,
124.6, 126.5, 128.2, 128.4, 128.9, 131.4, 134.3, 146.3.
1-[(E)-2-(3-Thienyl)ethenyl]-1H-1,2,3-benzotriazole (4.6b): yellow powder; mp
80.082.0 C; yield, 68%. 1H NMR 7.077.12 (m, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.33
(d, J = 3.6 Hz, 1H), 7.48 (t, J = 3.6 Hz, 1H), 7.607.88 (m, 4H), 8.15 (d, J = 8.4 Hz, 1H);
13
C NMR 109.9, 114.9, 120.5, 120.6, 124.7, 125.3, 127.6, 127.9, 128.3, 128.5, 138.6,
146.3. Anal. Calcd for C12H9N3S: C, 63.41; H, 3.99; N, 18.49. Found: C, 63.65; H, 3.87;
N, 17.89.
1-[(E)-3-Methyl-1-butenyl]-1H-1,2,3-benzotriazole (4.6c): colorless oil; yield,
60%. 1H NMR 1.10 (d, J = 6.3 Hz, 1H), 1.21 (d, J = 6.9 Hz, 5H), 2.602.65 (m, 1H),
6.51 (t, J = 6.9 Hz, 1H), 7.27 (d, J = 14.1 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.52 (t, J =
43
6.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR 22.3, 22.6,
26.9, 29.5, 103.3, 109.4, 110.0, 117.9, 119.9, 120.1, 121.0, 124.2, 127.6, 127.8, 130.3,
131.4, 136.8, 146.1. Anal. Calcd for C11H13N3: C, 70.56; H, 7.00; N, 22.44. Found: C,
70.73; H, 7.16; N, 23.08.
1-[(E)-1-Butenyl]-1H-1,2,3-benzotriazole (4.6d): yellow oil; yield, 50%. 1H
NMR 1.01 (t, J = 7.5 Hz, 3H, one isomer), 1.11 (t, J = 7.5 Hz, 3H, other isomer), 2.27
(q, J = 7.5 Hz, 2H, one isomer), 2.35 (q, J = 7.5 Hz, 2H, other isomer), 5.75 (q, J = 7.2
Hz, 1H, one isomer), 6.47 (q, J = 7.2 Hz, 1H, other isomer), 6.90 (d, J = 8.0 Hz, 1H),
7.197.32 (m, 3H), 7.407.45 (m, 3H), 7.57 (d, J = 8.4 Hz, 1H), 7.968.00 (m, 1H); 13C
NMR 13.4, 13.7, 21.1, 23.4, 109.6, 110.0, 119.6, 119.8, 120.0, 122.3, 124.0, 124.2,
125.0, 127.6, 127.8, 131.1, 131.4, 132.8, 145.1, 146.0. Anal. Calcd for C10H11N3: C,
69.34; H, 6.40; N, 24.26. Found: C, 69.47; H, 6.58; N, 23.87.
4.4.2 Procedure for the preparation of 1,2-dibromo-benzotriazolyl alkanes 4.7a-d.
To a solution of vinylbenzotriazole 4.6 (5 mmol) in dry dichloromethane was added
bromine (0.26 mL, 5 mmol) at 0oC. The mixture was maintained at this temperature for
30 min and then was allowed to warm up to room temperature. The mixture was stirred
for 2 h and dichloromethane was evaporated under vacuum to give 1,2-dibromobenzotriazolyl alkanes 4.7 in quantitative yield which can be used directly in the next step
without further purification.
1-(1,2-Dibromo-2-phenylethyl)-1H-1,2,3-benzotriazole (4.7a): light yellow
solid; mp 7475 C; 1H NMR 6.21 (d, J = 11.4 Hz, 1H), 7.25 (d, J = 5.4 Hz, 1H),
7.447.53 (m, 4H), 7.607.69 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H);
44
13
C NMR 52.8, 60.9, 110.0, 120.9, 125.1, 128.2, 128.7, 129.2, 129.8, 131.7, 137.5,
146.6.
1-[1,2-Dibromo-2-(3-thienyl)ethyl]-1H-1,2,3-benzotriazole (4.7b): This
compound was obtained as a mixture of isomers. Yellow powder; mp 120121 C; yield,
96%. 1H NMR 6.99 (d, J = 3.9 Hz, 1H), 7.07 (d, J = 3.9 Hz, 1H), 7.107.14 (m, 1H),
7.26 (d, J = 3.9 Hz,1H), 7.35 (d, J = 3.9 Hz, 1H), 7.477.89 (m, 3H), 8.17 (d, J = 8.1 Hz,
1H). 13C NMR 109.8, 109.9, 112.7, 114.1, 114.9, 120.4, 120.5, 120.8, 124.7, 124.8,
125.3, 127.7, 127.8, 127.9, 128.3, 128.5, 130.8, 131.4, 139.9, 146.2.
1-(1,2-Dibromo-3-methylbutyl)-1H-1,2,3-benzotriazole (4.7c): Light yellow
solid; mp 6667 C; yield, 100%. 1H NMR 1.10 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.6
Hz, 3H), 2.69 (dq, J = 6.3, 2.1 Hz, 1H), 5.27 (dd, J = 9.9, 2.1 Hz, 1H), 6.92 (d, J = 11.1
Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 8.19
(d, J = 8.4 Hz, 1H); 13C NMR 15.1, 15.9, 22.2, 30.6, 60.3, 62.6, 63.2, 65.1, 103.2,
110.7, 110.8, 119.4, 120.0, 125.9, 126.5, 129.2, 129.5, 131.7, 143.7. Anal. Calcd for
C11H13N3: C, 38.07; H, 3.78; N, 12.11. Found: C, 37.85; H, 3.41; N, 11.74.
1-(1,2-Dibromobutyl)-1H-1,2,3-benzotriazole (4.7d): brown oil; yield, 83%. 1H
NMR 1.24 (t, J = 7.2 Hz, 3H), 2.17 (q, J = 7.4 Hz, 2H), 2.51-2.60 (m, 1H), 5.23 (dt, J
=8.1, 2.7 Hz, 1H), 6.89 (d, J = 10.4 Hz, 1H), 7.46 (t, J = 6.9 Hz, 1H), 7.61 (t, J = 8.1 Hz,
2H), 7.70 (d, J = 8.3Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H); 13C NMR 10.5, 29.3, 55.6, 61.0,
110.1, 120.4, 125.0, 128.5, 146.0. Anal. Calcd for C10H11Br2N3: C, 36.07; H, 3.33; N,
12.62. Found: C, 36.22; H, 3.34; N, 12.31.
45
4.4.3 Procedure for the preparation of amides 4.8a-r.
To a solution of 1,2-dibromo-benzotriazolyl alkane 4.7 (1 mmol) dissolved in
DMF/H2O (3 mL/1 mL) was added amine (5 mmol). The mixture was heated at 80 C for
4 h till the starting material disappeared. Ethyl acetate (30 mL) was added and the diluted
mixture was washed with water (310 mL) followed by 1M NaOH (10 mL). The organic
phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude
product was triturated in ether and filtered to give the desired amide 4.8 in 3295% yield.
N-Phenethyl-2-phenylacetamide (4.8a): pale yellow solid; mp: 117118C (Lit
mp: 117119C) [02T2155]; yield: 47%; 1H NMR 2.71 (t, J = 6.6 Hz, 2H), 3.44 (dd, J
= 12.9, 6.9 Hz, 2H), 3.57 (s, 2H), 5.50 (brs, 1H), 7.19 (d, J = 6.0 Hz, 2H), 7.157.31 (m,
8H); 13C NMR 35.4, 40.6, 43.7, 126.3, 127.2, 128.5, 128.6, 128.9, 129.3, 134.7, 138.6,
170.8.
N-Butyl-2-phenylacetamide (4.8b) [41JA2965]: yellow oil ; yield 58%; 1H NMR
0.87 (t, J = 6.9 Hz, 3H), 1.211.31 (m, 2H), 1.351.45 (m, 2H), 3.29 (dd, J = 13.5, 6.9
Hz, 2H), 3.55 (s, 2H), 5.66 (brs, 1H), 7.247.34 (m, 5H); 13C NMR 13.6, 19.8, 31.4,
39.3, 43.7, 127.1, 128.8, 129.3, 135.0, 170.9.
2-Phenyl-1-piperidino-1-ethanone (4.8c): yellow solid; mp: 8283C (Lit mp:
8486C) [20AC148]; yield: 61%; 1H NMR 1.331.37 (m, 2H), 1.521.60 (m, 4H),
3.37 (t, J = 5.7 Hz, 2H), 3.58 (t, J = 4.8 Hz, 2H), 3.74 (s, 2H), 7.227.34 (m, 5H); 13C
NMR 24.3, 25.4, 26.1, 41.1, 42.8, 47.2, 126.6, 128.5, 128.6, 135.3, 169.3.
N,2-Diphenylacetamide (4.8d): white powder; mp 117 C; (Lit mp: 117.0119.0
C) [02T2155]; yield: 72%; 1H NMR 3.72 (s, 2H), 7.087.43 (m, 11H); 13C NMR
44.8, 119.9, 124.5, 127.6, 128.9, 129.2, 129.5, 134.5, 137.6, 169.3.
46
N-(tert-Butyl)-2-phenylacetamide (4.8e): yellow powder; mp 113115 C; (Lit
mp: 115.0116.0 C) [85JOC5507]; yield: 68%; 1H NMR 1.28 (s, 9H), 3.48 (s, 2H),
5.20 (brs, 1H), 7.237.37 (m, 5H); 13C NMR 28.6(3C), 44.8, 51.2, 127.1, 128.7, 128.9,
129.2, 129.3, 135.6, 170.4.
2-Phenyl-N-(2-pyridinyl)acetamide (4.8f): orange crystals; mp 9395 C; (Lit.
mp 124125 C) [73YZ1034]; yield: 85%; 1H NMR 3.71 (s, 2H), 6.99 (td, J = 7.0, 2.0
Hz, 1H), 7.247.33 (m, 5H), 7.66 (td, J = 7.0, 2.0 Hz, 1H), 8.208.27 (m, 2H), 8.24 (brs,
1H); 13C NMR 44.3, 114.3, 119.6, 127.2, 129.1, 134.0, 138.3, 147.3, 151.5, 169.7.
Anal. Calcd for C13H12N2O: C, 73.57; H, 5.70; N, 13.20. Found: C, 73.54; H, 5.80; N,
13.08.
2-Phenyl-N-(2-pyrimidinyl)acetamide (4.8g): white powder; mp 195 C; (Lit mp:
193.0196.0 C) [75AF1477]; yield: 80%; 1H NMR 4.08 (s, 2H), 6.99 (t, J = 4.8 Hz,
1H), 7.277.36 (m, 5H), 8.62 (d, J = 4.8 Hz, 2H), 9.12 (brs, 1H); 13C NMR 44.4, 116.4,
127.3, 128.8, 129.6, 134.4, 157.5, 158.4.
N-Phenethyl-2-(2-thienyl)acetamide (4.8h): Brown oil; yield: 52%; 1H NMR
2.74 (t, J = 6.9 Hz, 2H), 3.46 (q, J = 6.9 Hz, 3H), 3.72 (s, 2H), 5.76 (brs, 1H), 6.83 (d, J =
3.3 Hz, 1H), 6.95 (t, J = 5.4 H z, 1H), 7.08 (d, J = 6.6 Hz, 1H), 7.197.28 (m, 5H); 13C
NMR 35.4, 37.5, 40.8, 125.6, 126.5, 127.4, 127.5, 128.6, 128.7, 136.0, 138.6, 169.9.
N-Butyl-2-(2-thienyl)acetamide (4.8i): brown oil; yield: 92%; 1H NMR 0.89 (t,
J = 7.2 Hz, 3H), 1.241.31 (m, 2H), 1.381.45 (m, 2H), 3.22 (q, J = 7.2 Hz, 2H), 3.78 (s,
2H), 5.67 (brs, 1H), 6.937.01 (m, 2H), 7.25 (dd, J = 5.1, 1.2 Hz, 1H); 13C NMR 13.7,
19.9, 31.4, 37.5, 39.5, 125.6, 127.3, 127.4, 136.3, 169.9.
47
1-Piperidino-2-(2-thienyl)-1-ethanone (4.8j) [96S1425]: brown oil; yield: 88%;
1
H NMR 1.381.54 (m, 6H), 3.37 (t, J = 5.7 Hz, 2H), 3.50 (t, J = 5.7 Hz, 2H), 3.84 (s,
2H), 6.826.88 (m, 2H), 7.12 (dd, J = 5.1, 1.2 Hz, 1H); 13C NMR 24.3, 25.3, 26.1, 35.1,
43.0, 47.4, 124.5, 125.8, 126.7, 136.7, 168.3.
2-Methyl-1-piperidino-1-propanone (4.8k) [67BCJ2706]: yellow oil; 1H NMR
0.90 (d, J = 6.6 Hz, 6H), 1.23 (d, J = 6.6 Hz, 1H), 1.521.56 (m, 6H), 2.20 (d, J = 6.6 Hz,
2H), 3.41 (m, 2H), 3.56 (m, 2H); 13C NMR 17.9, 22.6, 24.4, 25.5, 25.7, 26.5, 42.0, 42.4,
46.8, 170.7.
N-Butylbutanamide (4.8l) [56JOC1072]: colorless oil; yield: 82%; 1H NMR
0.89 (m, 6H), 1.30 (m, 2H), 1.46 (m, 2H), 1.62 (m, 2H), 2.15 (m, 2H), 3.18 (m, 2H), 6.54
(brs, 1H); 13C NMR 13.5 (2C), 19.1, 19.9, 31.4, 38.3, 39.1, 173.4. Anal. Calcd for
C8H17N1O: C, 67.09; H, 11.96; N, 9.78. Found: C, 66.82; H, 12.46; N, 9.65.
N-[2-(Dimethylamino)ethyl]butanamide (4.8m) [53MC349]: colorless oil; yield:
32%; 1H NMR 0.87 (t, J = 7.2 Hz, 3H), 1.581.60 (m, 4H), 2.07 (t, J = 7.8 Hz, 2H),
2.16 (s, 6H), 2.31 (t, J = 7.8Hz, 2H), 3.23 (t, J = 5.7 Hz, 2H), 3.69 (brs, 1H); 13C NMR
13.6, 18.9, 26.0, 38.5, 38.6, 45.0, 58.0, 173.0.
1-Morpholino-1-butanone (4.8n) [36BSF143]: colorless oil; yield: 50%; 1H NMR
0.97 (t, J = 7.5 Hz, 3H), 1.66 (m, 2H), 2.31 (t, J = 7.5 Hz, 2H), 3.48 (t, J = 3.6 Hz, 2H),
3.623.69 (m, 6H); 13C NMR 13.7, 18.3, 34.7, 41.5, 45.7, 66.4, 66.6, 171.3.
1-(4-Methylpiperazino)-1-butanone (4.8o) [68CA105246K]: colorless oil; yield:
62%; 1H NMR 0.97 (t, J = 7.2 Hz, 3H), 1.621.69 (m, 2H), 2.28-2.43 (m, 9H), 3.50 (t, J
= 4.8 Hz, 2H), 3.63 (t, J = 4.8 Hz, 2H); 13C NMR 13.4, 18.2, 34.6, 40.7, 45.4, 54.2,
48
54.6, 170.9. Anal. Calcd for C9H18N2: C, 63.49; H, 10.66; N, 16.45. Found: C, 62.56; H,
10.97; N, 16.19.
N-Phenylbutanamide (4.8p): white powder; mp 8284 C; (Lit mp: 92 C)
[31JA1063]; yield: 95%; H NMR 0.98 (t, J = 7.2 Hz, 3H), 1.75 (m, 2H), 2.32 (t, J = 7.2
Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.70
(brs, 1H); 13C NMR 13.8, 19.1, 39.6, 119.9, 124.2, 128.9, 138.1, 171.7. Anal. Calcd for
C10H13N1O: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.49; H, 8.31; N, 8.60.
N-(4-Pyridinyl)butanamide (4.8q): white powder; mp 136138 C; yield: 95%;
1
H NMR 0.99 (t, J = 7.5 Hz, 3H), 1.721.79 (m, 2H), 2.38 (t, J = 7.5 Hz, 2H), 7.54 (d, J
= 6.3 Hz, 2H), 8.45 (d, J = 6.3 Hz, 2H), 8.58 (brs 1H); 13C NMR 13.6, 18.7, 39.5,
113.6, 145.6, 150.3, 172.5. Anal. Calcd for C9H12N2: C, 65.83; H, 7.37; N, 17.06. Found:
C, 65.45; H, 7.66; N, 15.97.
N-(1-Naphthyl)butanamide (4.8r): violet powder; mp 113115 C (Lit mp: 120
C) [69JA5614]; yield: 68%; 1H NMR 1.05 (t, J = 7.2 Hz, 3H), 1.81 (q, J = 7.2 Hz,
2H), 2.45 (t, J = 7.2 Hz, 2H), 7.437.87 (m, 8H); 13C NMR 13.6, 19.1, 38.8, 121.3,
121.7, 125.3, 125.7, 125.8, 127.7, 128.2, 132.4, 133.9, 172.5. Anal. Calcd for C14H15N1O:
C, 78.84; H, 7.09; N, 6.57. Found: C, 78.80; H, 7.24; N, 6.63.
CHAPTER 5
A CONVENIENT SYNTHESIS OF BENZOTRIAZOLYLACETYLENES AND
SUBSTITUTED ACETYLENES FROM N-2,2-DICHLOROVINYLBENZOTRIAZOLE
5.1 Introduction
Alkynes play a significant role as building blocks in synthetic organic
chemistry.Ynamines, created by the direct linking of amino nitrogen atom with alkyne,
are very useful functionalized alkynes; the electron donating ability of the nitrogen atom
makes them synthetically effective due to their high regioselectivity in reactions with a
variety of electrophiles. The preparation and synthetic utility of ynamines in organic and
related fields have been extensively explored recently.[76T1449], [01T7575] However,
the synthetic applications of ynamines have remained relatively limited because of the
difficulty experienced in preparation and handling of ynamines due to their high
reactivity and sensitivity toward hydrolysis. [01T7575] Therefore, the balance of
reactivity and stability is important for the extension of ynamines synthetic utility. Some
advances have been made in exploring the electron-deficient ynamines including
ynamines with electron-withdrawing group on nitrogen and push-pull ynamines. (Fig. 51)
Ph
Ph
F3C
R1
CF3
R1
CF3
push-pull
49
R2
R1
R2
50
The N-substituted benzotriazoles possess both electron-donor and electron-acceptor
properties which can potentially activate the adjacent unsaturated bond attached to the
benzotriazole nitrogen without decreasing stability. Thus, benzotriazolylacetylenes with
CC-triple bond on the nitrogen atom of 1H-benzotriazole seem to hold promise as an
important class of compounds in the family of ynamines.
Previously, our group has reported the direct introduction of a CC-triple bond on
the nitrogen atom of 1H-benzotriazole by (i) use of hypervalent iodine chemistry;
[96CRV1123], [87JA228] in reactions of alkynylphenyliodonium tosylates with
potassium benzotriazolate [00H303], [98TL3787] or (ii) base treatment of benzotriazolyl
enol triflates. (Scheme 51) [00OL3789], [01JOC5606] The first method requires
preparation of hypervalent iodine salts 5.1 [87JA228] and is limited to the preparation of
N-arylethynylbenzotriazoles 5.2; attempted preparations of N-alkylethynylbenzotriazoles
are reported to give mixtures of (E)- and (Z)-1-vinyl-1H-benzotriazoles 5.3a and (Z)-2vinyl-2H-benzotriazole 5.3b as the main products. [00H303] The second method
proceeds through 1-trimethylsilylmethylbenzotriazole (5.4) and N-acylbenzotriazoles 5.5
which on further reaction with triflic anhydride give the corresponding benzotriazolyl
enol triflates 5.6. [01JOC5606]
Corey and Fuchs introduced the well-known conversion of aldehydes to alkynes in
1972, and the method has been widely utilized in many synthetic protocols since then
(Scheme 52) [72TL3769]. Now, I report a new application of this method to the direct
preparation of N-ethynylbenzotriazoles, via novel dichlorovinylbenzotriazole (5.7)
obtained in one-step from commercially available 1-formylbenzotriazole, and the
lithiation-electrophilic substitution of 5.7 to give a variety of benzotriazolylacetylenes
51
5.8a-h. Treatment of propynylbenzotriazole 5.8b with lithium naphthalenide and
electrophiles gave substituted acetylenes. Using this protocol, I have prepared propargyl
alchohols 5.9a,b by the reaction of 5.8b with aromatic ketones.
PhI(OAc)2
HO
CH3CN
TsOH.H2O
PhI
OTs
CH2Cl2
_
+
Bt K
Bt1
R
5.2
_
+
I PhO Ts
R
THF/t-BuOH/CH2Cl2
5.1
R = aryl
_
+
Bt K
R
Bt1
H
5.3a
THF/t-BuOH/CH2Cl2
R
Bt2
Ot-Bu
5.3b
Ot-Bu
R = alkyl
_
TMSCH2Cl
TMSCH2Bt
Bt Na+
RCOCl
Bt
5.4
5.5
Tf2O 2,6-lutidine
Bt1
NaOMe
R
Bt
OTf
R = alkyl or aryl
5.6
O
R
Br
CBr4, PPh3
H
80-90%
Br
2eq. n-BuLi
Li
CO2
COOH
52
5.2 Results and Discussion
5.2.1 Preparation of benzotriazolylacetylenes 5.8.
Reaction of 1-formylbenzotriazole with triphenylphosphine and tetrachloromethane
under Corey-Fuchs conditions [72TL3769] gave 1-(2,2-dichlorovinyl)benzotriazole (5.7)
in 78% yield as a white crystalline solid. The 1H NMR spectrum of 5.7 showed the
vinylic proton at 7.68 ppm as a singlet in addition to the four protons of benzotriazolyl
moiety. The 13C NMR spectrum of 5.7 showed the disappearance of carbonyl signal at
159.7 ppm and the appearance of additional signals at 125.1 and 121.4 ppm due to the
incorporation of the vinylic moiety. Subsequent treatment of 5.7 with 2 equiv of n-BuLi
at 78 oC in THF for 1 h and reaction with a variety of electrophiles gave the
corresponding benzotriazolylacetylenes 5.8ah in 32-84% yields (Scheme 53) (Table
51).
O
Bt
PPh3, CCl4
H
THF, 60C, 4h
Bt
Cl
n-BuLi, THF
Cl
-78C, 1h, E+
Bt
E
5.8a-h
5.7, 78%
53
All of the benzotriazolylacetylenes 5.8ah, except 5.8b, are novel compounds and
were characterized by their 1H and 13C NMR spectra and elemental analysis. As
expected, the 1H NMR spectra showed the disappearance of the vinylic proton at 7.69
ppm and the appearance of additional signals from the newly attached substituent. In the
13
C NMR spectra the signals from vinylic carbons at 121.4 and 125.1 ppm were replaced
by new signals corresponding to the acetylenic carbons at 66.7 and 76.1 ppm,
respectively. The signals from benzotriazolyl moiety in all of the
benzotriazolylacetylenes 5.8ah experienced a negligible change in the chemical shift
values from those in the 1H and 13C NMR spectra of the precursor
dichlorovinylbenzotriazole (5.7).
5.2.2 Preparation of substituted acetylenes 5.9 from benzotriazolylacetylenes 5.8.
Benzotriazolylacetylenes, with a CC-triple bond on the nitrogen atom of 1Hbenzotriazole, can be precursors for many chemical transformations. For example, our
group have reported the syntheses of disubstituted acetylenes by replacement of
benzotriazole group of a benzotriazolylacetylenes (when R is aryl) with a variety of alkyl
or aryl groups using Grignard reagents (Scheme 54) [02JOC7526]. Also, the treatment
of benzotriazolylacetylenes with p-TSA and TBAF or NaOMe followed by hydrolysis
replaces the benzotriazolyl group and results in the formation of substituted carboxylic
acids or esters (Scheme 54) [00OL3789] [01JOC5606].
54
N N
R = alkyl
N
N
R1MgBr
R1
R
5.8
R = aryl
R1
p-TSA/CH3CN
OTs N N
N
TBAF or OH
OH
R
O
Me
5.8b
LiNp/RCOR
R OH
Y (%)
Me
R
5.9
5.9a Ph
47
5.9b p-MeOPh 16
55
5.4 Experimental Section
Melting points were determined using a Bristoline hot-stage microscope and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
Gemini 300 NMR spectrometer in CDCl3 (with TMS for 1H and chloroform-d for 13C as
the internal reference). Elemental analyses were performed on a Carlo Erba-1106
instrument. HRMS were measured on an AEI-30 mass spectrometer. THF was distilled
from sodium/benzophenone prior to use. All of the reactions were carried out under N2.
Column chromatography was performed on silica gel 200425 mesh.
5.4.1 Procedure for the Preparation of 1-(2,2-Dichlorovinyl)-1H-1,2,3-benzotriazole
(5.7).
1-Formylbenzotriazole (1.0 g, 6.80 mmol) and PPh3 (5.35 g, 20.4 mmol) were
dissolved in THF (70 mL). Carbon tetrachloride (7 mL, 68 mmol) was added slowly at 60
o
C and the mixture was heated under reflux for 6 h. After stirring for an additional hour,
the mixture was diluted with ethyl acetate. Aqueous work-up with satd. NaHCO3 and
purification by flash chromatography on silica gel using hexanes/EtOAc (9.5/0.5)
afforded the product 5.7 in 68% yield.
1-(2,2-Dichlorovinyl)-1H-1,2,3-benzotriazole (5.7): white cubes (from hexanes);
mp 88-90 oC; yield, 68%; 1H NMR 7.45 (t, J = 8.1 Hz, 1H), 7.53-7.62 (m, 2H), 7.69
(s, 1H), 8.12 (d, J = 8.4 Hz, 1H); 13C NMR 110.1, 120.4, 121.4, 124.7, 125.1, 128.5,
132.2, 145.2. Anal. Calcd for C8H5Cl2N3: C, 44.89; H, 2.35; N, 19.28. Found: C, 45.09;
H, 2.25; N, 19.28.
56
5.4.2 General Procedure for the Preparation of Benzotriazolylacetylenes 5.8a-h by
Lithiation- Electrophilic Substitution of 5.7.
To a solution of 7 (0.22 g, 1 mmol) in dry THF (20 mL) at -78 C, was added nBuLi (1.33 mL, 2.1 mmol). The mixture was stirred at -78 C for 1 h and an appropriate
electrophile (1.0 mmol) was added. The the reaction mixture was allowed to warm to 25
o
C and quenched by adding water. The aqueous layer was extracted with Et2O and the
combined organic phase was dried over MgSO4. After removal of the solvent in vacuo,
the residue was purified by flash column chromatography with hexanes/EtOAc (9:1) as
eluent to afford 5.8a-h.
1-Ethynyl-1H-1,2,3-benzotriazole (5.8a): yellow prisms (from hexanes); mp 7172 oC; yield, 73%; 1H NMR 3.86 (s, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.61-7.69 (m, 2H),
8.11 (d, J = 8.3 Hz, 1H); 13C NMR 68.6, 69.4, 109.8, 120.5, 125.4, 129.5, 134.2, 143.6.
1-(1-Propynyl)-1H-1,2,3-benzotriazole (5.8b): colorless oil; yield, 84%; 1H NMR
2.22 (s, 3H), 7.40 ( t, J = 7.8 Hz, 1H), 7.54-7.64 (m, 2H), 8.06 (d, J = 8.2 Hz, 1H); 13C
NMR 3.3, 66.7, 76.1, 109.8, 120.0, 124.8, 128.8, 134.1, 143.4.
1-(1-Butynyl)-1H-1,2,3-benzotriazole (5.8c): white powder; yield, 58%; 1H NMR
1.35 (t, J = 7.5 Hz, 3H), 2.62 (q, J = 7.8 Hz, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.58-7.68
(m, 2H), 8.10 (d, J = 8.2 Hz, 1H); 13C NMR 12.4, 13.5, 110.1, 120.4, 125.0, 129.0.
1-[2-(Trimethylsilyl) ethynyl]-1H-1,2,3-benzotriazole (5.8d): yellow oil; yield
82%; 1H NMR 0.48 (s, 9H), 7.57 (dt, J = 8.1, 1.5 Hz, 1H), 7.68-7.86 (m, 2H), 8.21 (d,
J = 8.4 Hz, 1H); 13C NMR -1.3, -0.4, 83.6, 87.3, 110.0, 110.7, 120.1, 120.3, 124.6,
125.2, 128.6, 129.3, 129.8, 132.2.
57
3-(1H-1,2,3-Benzotriazol-1-yl)-1,1-diphenyl-2-propyn-1-ol (5.8e): white needles
(from EtOAc/hexanes); mp 125-126 oC; yield, 84%; 1H NMR 3.72 (s, 1H), 7.30-7.39
(m, 7H), 7.53 (brs, 2H), 7.69-7.71 (m, 4H), 8.02 (d, J = 8.10 Hz, 1H). 13C NMR 73.9,
74.8, 82.9, 109.9, 120.3, 125.3, 126.0, 128.0, 128.4, 129.4, 134.2, 143.5, 144.0. Anal.
Calcd for C21H15N3O: C, 77.52; H, 4.65; N, 12.91. Found: C, 77.29; H, 4.69; N, 12.82.
4-(1H-1,2,3-Benzotriazol-1-yl)-2-methyl-3-butyn-2-ol (5.8f): light yellow oil;
yield, 71%; 1H NMR 1.59 (d, J = 1.2 Hz, 6H), 2.90 (s, 1H), 7.47 ( t, J = 6.8 Hz, 1H),
7.57-7.65 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H). 13C NMR 28.3, 31.3, 65.6, 69.7, 84.4,
110.0, 120.5, 125.3, 129.4, 134.2, 143.8.
(E)-5-(1H-1,2,3-Benzotriazol-1-yl)-1,3-diphenyl-1-penten-4-yn-3-ol (5.8h): light
yellow solid; yield, 43%; 1H NMR 3.34 (brs, 1H), 6.52 (d, J = 15.8 Hz, 1H), 7.07 (d, J
= 15.9 Hz, 1H), 7.23-7.45 (m, 10 H), 7.60( t, J = 6.8 Hz, 1H), 7.77-7.80(m, 2H), 8.10 (d,
J = 8.2 Hz, 1H); 13C NMR 73.3, 74.3, 81.3, 110.0, 120.5, 125.4, 125.7, 127.0, 128.2,
128.4, 128.6, 128.6, 129.5, 130.0, 131.8, 134.3, 135.7, 142.5, 143.8.
5.4.3 General Procedure for the Preparation of Propargyl Alcohols 5.9.
To a suspension of Li (0.035 g, 5 mmol) in dry THF was added naphthalene (0.65
g, 5 mmol) at 25 oC and the suspension was stirred for 1 h until the color changed to
dark green. After cooling to -78 C 8b (1.0 mmol) was added and the mixture was stirred
at -78 C for 1 h. An appropriate electrophile (1.0 mmol) was added and the reaction
mixture was allowed to warm to 25 oC and quenched by saturated ammonium chloride.
The aqueous layer was extracted by Et2O and the combined organic phase was dried over
MgSO4. After removal of the solvent in vacuo, the residue was purified by flash column
58
chromatography with hexanes/EtOAc (10:1) as eluent to afford propargyl alcohols 5.9a,
b.
1,1-Diphenyl-2-butyn-1-ol (5.9a): colorless oil; yield, 47%; 1H NMR 1.93 (s,
3H), 2.81 (s, 1H), 7.19-7.32 (m, 6H), 7.57-7.60 (m, 4H); 13C NMR 3.7, 74.4, 82.1,
83.6, 126.0, 126.8, 127.4, 128.1, 128.2, 128.3, 128.5, 129.3, 129.5, 146.4
1,1-Bis(4-methoxyphenyl)-2-butyn-1-ol (5.9b): light yellow oil; yield, 16%; 1H
NMR 1.26 (s, 1H), 1.96 (s, 3H), 3.78 (s, 6H), 6.83 (dd, J = 6.9, 1.8 Hz, 4H), 7.48 (dd, J
= 6.6, 2.1 Hz, 4H); 13C NMR 3.8, 55.2, 69.8, 73.8, 82.5, 83.2, 113.3, 113.4, 113.7,
126.7, 127.3, 128.0, 130.1, 131.3, 138.0, 158.9.
CHAPTER 6
N-TFA AND FMOC-(-AMINOACYL)BENZOTRIAZOLES AS CHIRAL CACYLATING REAGENTS UNDER FRIEDEL-CRAFTS REACTION CONDITIONS
6.1 Introduction
Chiral N-protected -amino ketones are useful precursors to many biologically
active compounds including chiral -amino alcohols [85JOC325], [95JOC4838],
[91AG1531], pharmaceutically important chiral heterocycles [96CV1825],
[04BMCL2867], [03OPRD839], and diamines [91AG1531], [82S605]. Preparations of
-amino aliphatic ketones and -amino aryl ketones have been thoroughly investigated
[03S1653], but much less attention has been directed toward the synthesis of aminoalkyl heterocyclic ketones and to our knowledge, no general method has been
reported. Previous syntheses of chiral -amino ketones utilized N-protected -amino
acids, esters and amides (i) with organometallic reagents for nucleophilic substitution
[98S1013], [02T10167], [01OL1519], [83JOC2260], [03HAC603], [84JA1095] (Scheme
61) or (ii) with AlCl3 for Friedel-Crafts acylations [81JA6157], [81JOC2431],
[84JOC4107], [85JOC3481], [01JOC7002] (Scheme 62). The methods using
organometallic reagents, though well established, sometimes suffer from drawbacks such
as tedious purification [98S1013] and competition between nucleophilic addition and
nucleophilic substitution [02T10167.] Moreover, N-protected -amino acid chlorides are
often unstable, and are prone to racemization [79The Peptides].
N-Acylbenzotriazoles, which are easily prepared from carboxylic acids by (i)
thionyl chloride and 1H-benzotriazole at 20 C [03S2795] or (ii) BtSO2Me in the
59
60
O
RMgX,CuI
PG
YR
or RLi
O
1
NH
PG
R
NH
Y = O or N
PCl5
PG
OH
NH
O
1
PG
Cl
NH
AlCl3
Ar
Aryl
PG
NH
BtSO2CH3, Et3N
OH or BtH, SOCl2
Lewis Acids
Bt
Heterocycles
Het
61
6.2 Results and Discussion
6.2.1 Preparation of N-(Tfa- and Fmoc--aminoacyl)benzotriazoles.
The amino group of L-alanine and L-phenylalanine were protected with Ntrifluoroacetyl (Tfa) group using ethyl trifluoroacetate in the presence of Et3N in
methanol to generate the N-Tfa--amino acids [79JOC2805]. The N-Tfa-protected amino
acids were treated with thionyl chloride and 4 equivalents of benzotriazole to give N(Tfa--aminoacyl)benzotriazoles 6.1a and 6.1b (Scheme 64). Racemic N-(Tfa-aminoacyl)benzotriazoles 6.1i and 6.1j were prepared similarly from DL-alanine and DLphenylalanine, respectively. N-(Fmoc--aminoacyl)benzotriazoles 6.1ch were prepared
by the above method from commercially available N-Fmoc-L-phenylalanine, Ltryptophan and L-methionine [05S397]. The Z-protected aminoacylbenzotriazole 6.1k
was prepared by a previously reported method [UP-1406].
R1
PG
N
H
R1
OH
BtH, SOCl2
PG
THF, 20 C
N
H
Bt
O
6.1a-k
N
N
N
Bt = benzotriazol-1-yl
O
PG: Fmoc = 9H-fluorenylmethoxycarbonyl
O
Z = benzyloxycarbonyl
F3C
62
similar conditions also gave the corresponding amino ketones 6.3ae (Scheme 65,
Table 61). The C-acylations occurred specifically at C-2, and no 3-acylated products
were observed.
When compounds with Fmoc group and bulky aromatic side-chains such as FmocPhe-Bt (6.1c) and Fmoc-Trp-Bt (6.1d) were used, the corresponding ketones were
obtained in lower yields than the ketones with aliphatic side-chains. For the reaction of
6.1d with N-methylpyrrole, the 45% yield was not improved even when the reaction time
was extended to 24 h.
R1
R1
PG
N
H
AlCl3
Bt
PG
CH2Cl2, 20 C
N
2
R
N
H
N
R2
6.2a-e; R2 = H
6.3a-e; R2 = Me
6.1a-e
Reactant
From Pyrrole
Tfa-Phe-Bt (6.1a)
Tfa-Ala-Bt (6.1b)
Fmoc-Phe-Bt (6.1c)
Fmoc-Trp-Bt (6.1d)
Fmoc-Met-Bt (6.1e)
a
Isolated yield
6.2a (82)
6.2b (78)
6.2c (72)
6.2d (52)
6.2e (66)
From N-Methylpyrrole
6.3a (78)
6.3b (75)
6.3c (56)
6.3d (45)
6.3e (60)
Furthermore, this methodology was extended to the preparation of the bis(acyl)pyrrole 6.4 by using N-(Fmoc-aminodiacyl)benzotriazole 6.1h (prepared from N-Fmocglutamic acid) in 35% yield (Scheme 66). The yield of the aminodiketone 6.4 was not as
good as those from the mono-acylation reactions, presumably due to the lack of solubility
63
of 6.1h in CH2Cl2. Mono-acylated compounds were not observed during the purification
of 6.4 by column chromatography.
However, the attempted C-acylation of pyrrole with Z-Ala-Bt (6.1k) resulted in the
loss of the Z group as indicated by their crude NMR spectra and no desired product was
isolated.
HN
O
Fmoc
N
H
Bt
Bt
O
O
H
N
AlCl3
CH2Cl2, 20 C
Fmoc
N
H
N
H
6.1h
6.4 (35%)
64
N
H
R
N
R1
PG
Bt
AlCl3
CH2Cl2, 20 C
6.1a-e
PG
N
H
R3
N
6.5a-e; R3 = H
6.6a-j; R3 = Me
65
Tfa
N
H
Bt
AlCl3
CH2Cl2, 20 C
6.1b
Tfa
N
H
O
6.7 (63%)
66
acylation of Fmoc-L-Ala-Bt (6.1f) with N-methylindole. A similar process was used to
prepare the other diastereomer 6.11. (Scheme 6-9) The methyl group of the alanine
moiety in a diastereomer 6.9 (L-Phe-L-Ala) displays a single doublet at 1.51 ppm, while
6.11 (L-Phe-D-Ala) exhibited a single doublet at 1.39 ppm. No trace was found of methyl
peaks characteristic of 6.11 in the 1H NMR spectrum of 6.9 and also nothing of 6.9 in the
NMR of 6.11. (Fig. 61)
Fmoc
N
H
OH
CH3
N
BtH, SOCl2
THF, 20 C
Fmoc
N
H
Fmoc-L-Ala-OH
Bt
AlCl3, N-methylindole
Fmoc
CH2Cl2, 20 C,
O
N
H
6.1f
O
6.6f (85%)
morpholine
CH3
N
O
Ph
Tfa
NH
CH2Cl2, 20 C
N
H
CH3
N
Tfa-L-Phe-Bt (1a)
H2N
O
6.8 (75%)
6.9 (80%)
CH3
N
Fmoc
N
H
OH
O
BtH, SOCl2
Fmoc
THF, 20 C
Fmoc-D-Ala-OH
Bt
N
H
AlCl3, N-methylindole
CH2Cl2, 20 C
Fmoc
N
H
6.1g
O
6.6g (75%)
morpholine
CH3
N
O
Ph
Tfa
NH
CH3
N
Tfa-L-Phe-Bt (1a)
N
H
CH2Cl2, 20 C
6.11 (80%)
H2N
O
6.10 (75%)
67
Figure. 61. 1H NMR of methyl group of the alanine in diastereomer 6.9 (L-Phe-L-Ala)
and 6.11 (L-Phe-D-Ala)
6.2.6 Intramolecular Cyclization of 6.1a and 6.1d.
The lower yields of -amino ketones 6.2d (52%), 6.3c (41%), and 6.6d (45%)
obtained from aromatic side-chains containing aminoacylbenzotriazoles 6.1c and 6.1d (as
compared to those from aminoacylbenzotriazoles 6.1a, b, e containing alphatic sidechains), suggested a competing intramolecular acylation reaction of the aromatic sidechains in 6.1a and 6.1d. Reactions of the two compounds 6.1a and 6.1d under the
68
conditions used for the preparation of 6.5 and 6.6 but in the absence of indole, and
generated the cyclized products 6.12, 6.13 in 57% and 62% yield, respectively (Scheme
610). The 1H NMR spectra of 6.12, 6.13 showed the disappearance of Bt signals in
aromatic region indicating the loss of the benzotriazolyl group during the reaction. The
13
C NMR spectrum of 6.12 showed a signal at 201.2 ppm corresponding to the carbonyl
group of the cyclized ketone and the disappearance of the signal at 168.8 ppm belonging
to the carbonyl group at position of the benzotriazolyl group in the starting material.
Likewise, the 13C NMR spectrum of 6.13 showed a signal for the cyclized ketone at 191.3
ppm and the disappearance of the signal of the carbonyl group of the benzotriazolyl
group at 172.2 ppm. The cyclization also was confirmed in 1H NMR spectrum by the
observation of four protons in aromatic region of 6.12 due to the loss of one aromatic
proton from the starting material. Furthermore, the splitting patterns of the two protons at
the position to the phenyl ring of 6.1a and cyclized ketone 6.12 were different.
Regarding 6.1a, one of the two protons appeared at 3.37 ppm (dd, J = 13.8, 7.2 Hz) and
the other one at 3.59 ppm (dd, J = 13.8, 5.1 Hz). In the 1H NMR spectrum of 6.12, one
proton was observed at 3.05 ppm (dd, J = 16.8, 5.7 Hz) and the other at 3.89 ppm (dd, J =
16.8, 5.1 Hz). The difference of chemical shifts of the two protons (0.84 ppm) in 6.12
was much larger than that of the two protons (0.22 ppm) in 6.1a, which can be
rationalized by the formation of a 5-membered ring system.
69
Tfa
AlCl3
N
H
Tfa
CH2Cl2, 20 C
Bt
6.1a
N
H
6.1d
6.12 (57%)
NH
Fmoc
N
H
AlCl3
Fmoc
CH2Cl2, 20 C
NH
N
H
Bt
6.13 (62%)
70
coupling of amine 6.8 and Tfa-L-Phe-Bt (6.1a), it is reasonable to conclude that the
racemization probably took place in the stage of the cleavage of Fmoc group (from 6.13
to 6.14) due to the acidic proton at the position to the carbonyl group of the
cyclopentenone which can be easily deprotonated to form an enol (Scheme 612)
ii
NH
Fmoc
N
H
Tfa
H
N
NH
N
H
NH
H2N
O
iii
6.14 (71%)
6.13 (62%)
Tfa
H
N
NH
N
H
H
+
N
Tfa
NH
N
H
O
6.17 (30%)
6.16 (30%)
i) Morpholine; ii) Tfa-DL-Ala-Bt (6.1i); iii) Tfa-L-Ala-Bt (6.1b)
Fmoc
NH
N
H
Morpholine
NH
NH
H2N
H2N
OH
6.13 (62%)
O
6.14 (71%, Racemized)
71
enantiomerically pure -amino ketones containing heterocyclic moieties offers facile
access to potentially valuable biological and pharmacological compounds.
72
6.4 Experimental Section
6.4.1 General Procedure for the Preparation of N-protected (aminoacyl)
benzotriazoles (6.1al).
Thionyl chloride 10 mmol (0.73 mL) was added to the 1H-benzotriazole 40 mmol
(4.76 g) dissolved in anhydrous THF (30 mL) and the solution was heated at 40 C for 30
min. After cooling to 0 C, a solution of N-protected amino acid (10 mmol) in anhydrous
THF was added and the mixture was stirred at 20 C for 2 h. The white precipitate was
filtered off and the filtrate was concentrated and diluted with dichloromethane followed
by washing with saturated sodium carbonate (50 mL3), water (50 mL) and drying with
anhydrous MgSO4. Evaporation of the solvent gave products 6.1al in 6383% yields,
which were recrystallized from CHCl3/Hexanes for CHN analysis. Compounds 6.1d, 6.1e
and 6.1k have been previously reported and fully characterized.
N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-oxoethyl]-2,2,2trifluoroacetamide (Tfa-L-Phe-Bt, 6.1a): colorless needles; yield, 83%; mp 136137
o
C; []23D = + 49.7 (c 1.6, CHCl3); 1H NMR (CDCl3) 3.37 (dd, J = 14.4, 7.2 Hz, 1H),
3.59 (dd, J = 14.1, 5.1 Hz, 1H), 6.31 (dd, J = 12.9, 7.5 Hz, 1H), 7.047.09 (m, 3H),
7.267.29 (m, 3H), 7.60 (t, J = 8.1 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 8.19 (d, J = 7.3 Hz,
1H), 8.22 (d, J = 7.4 Hz, 2H); 13C NMR (CDCl3) 38.5, 54.2, 114.7, 115.5 (q, J = 288.0
Hz), 120.6, 127.0, 127.9, 128.9, 129.1, 130.8, 131.2, 133.8, 146.1, 156.7 (q, J = 38.4 Hz),
168.8. Anal. Calcd for C17H13F3N4O2: C, 56.36; H, 3.62; N, 15.46. Found C, 56.55; H,
3.53; N, 15.34.
N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-methyl-2-oxoethyl]-2,2,2trifluoroacetamide (Tfa-L-Ala-Bt, 6.1b): colorless needles; yield, 76%; mp 115116
73
o
C; []23D = 106.4 (c 1.6, CHCl3); 1H NMR (CDCl3) 1.82 (d, J = 7.2 Hz, 3H), 6.04
(quintet, J = 7.5 Hz, 1H), 7.29 (d, J = 5.4 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.73 (t, J =
7.5 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3) 19.1,
49.8, 114.4, 115.8 (q, J = 285.7 Hz), 120.8, 127.2, 131.2, 131.4, 146.3, 156.9 (q, J= 38.2
Hz), 170.5. Anal. Calcd for C11H9F3N4O2: C, 46.16; H, 3.17; N, 19.57. Found: C, 46.33;
H, 3.05; N, 19.27.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-benzotriazol-1-yl-2-oxoethyl]
carbamate (Fmoc-L-Phe-Bt, 6.1c): colorless flakes; yield, 83%; mp 136137 oC; []23D
= +35.6 (c 1.6, DMF); 1H NMR (DMSO-d6) 3.20 (dd, J = 13.8, 8.1 Hz, 1H), 3.47 (dd, J
= 13.8, 4.5 Hz, 1H), 4.15 (t, J = 7.2 Hz, 1H), 4.294.42 (m, 2H), 5.86 (d, J = 7.4 Hz, 1H),
6.066.11 (m, 1H), 7.127.27 (m, 8H), 7.34 (t, J = 7.5 Hz, 2H), 7.447.54 (m, 3H), 7.60
(t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 7.8 Hz,
1H); 13C NMR (DMSO-d6) 25.7, 38.9, 55.8, 68.0, 114.4, 120.0, 120.4, 125.1, 126.6,
127.1, 127.4, 127.8, 128.8, 129.4, 130.9, 131.1, 135.3, 141.3, 143.7, 146.1, 155.8, 171.0.
Anal. Calcd for C30H24N4O3: C, 73.75; H, 4.95; N, 11.47. Found: C, 73.53; H, 5.07; N,
11.24.
9H-Fluoren-9-ylmethyl N-[(1S)-2-(1H-1,2,3-benzotriazol-1-yl)-1-methyl-2oxoethyl]carbamate (Fmoc-L-Ala-Bt, 6.1f): colorless microcrystals; yield, 85%; mp
160161 oC; []23D = 96.8 (c 1.6, DMF); 1H NMR (DMSO-d6) 1.59 (d, J = 7.2 Hz,
3H), 4.27 (t, J = 6.6 Hz, 1H), 4.38 (d, J = 6.9 Hz, 2H), 5.45 (quintet, J = 6.9 Hz, 1H),
7.347.47 (m, 4H), 7.65 (t, J = 7.8 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.7 Hz,
1H), 7.82 (t, J = 7.5 Hz, 1H), 7.92 (d, J = 7.2 Hz, 2H), 8.258.37 (m, 3H); 13C NMR
(DMSO-d6) 16.8, 46.6, 50.1, 65.9, 114.0, 120.1, 120.2, 125.2, 126.7, 127.1, 127.7,
74
130.6, 131.1, 140.8, 143.7, 145.3, 156.1, 172.5. Anal. Calcd for C24H20N4O3: C, 69.89; H,
4.89; N, 13.58. Found: C, 69.48; H, 4.94; N, 13.41.
9H-Fluoren-9-ylmethyl N-[(1R)-2-(1H-1,2,3-benzotriazol-1-yl)-1-methyl-2oxoethyl]carbamate (Fmoc-D-Ala-Bt, 6.1g): colorless microcrystals; yield, 85%; mp
161 oC; []23D = +95.6 (c 1.6, DMF). 1H NMR and 13C NMR are the same with Fmoc-LAla-Bt (1f).
9H-Fluoren-9-ylmethyl N-[(1S)-4-benzotriazol-1-yl-1-(benzotriazol-1-ylcarbonyl)-4-oxobutyl]carbamate (Fmoc-Glu-Di-Bt, 6.1h): colorless flakes; yield, 63%;
mp 166167 oC; []23D = 19.7 (c 1.6, DMF); 1H NMR (DMSO-d6) 2.402.64 (m, 2H),
3.71 (t, J = 6.6 Hz, 2H), 4.23 (t, J = 6.9 Hz, 1H), 4.34 (d, J = 6.9 Hz, 2H), 5.675.73 (m,
1H), 7.32 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.587.90 (m, 8H), 8.16 (d, J = 8.1
Hz, 1H), 8.248.28 (m, 3H), 8.46 (d, J = 6.6 Hz, 1H); 13C NMR (DMSO-d6) 24.9, 31.4,
46.6, 53.5, 65.9, 113.9, 114.0, 120.0, 120.1, 120.2, 125.2, 126.4, 126.8, 127.1, 127.6,
130.5, 130.7 (2C), 131.1, 140.7, 143.7, 145.3, 145.4, 156.2, 171.3, 171.5. Anal. Calcd for
C30H24N4O3: C, 67.24; H, 4.41; N, 17.15. Found: C, 67.09; H, 4.23; N, 17.12.
N-[(1R,S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-methyl-2-oxoethyl]-2,2,2trifluoroacetamide (Tfa-DL-Ala-Bt, 6.1i): colorless needles; yield, 80%; mp 110112
o
C. 1H NMR and 13C NMR are the same with Fmoc-L-Phe-Bt (1b).
N-[(1R,S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-oxoethyl]-2,2,2-
C. 1H NMR and 13C NMR are the same with Fmoc-L-Phe-Bt (1a).
75
6.4.2 General Procedure for the Acylations of Nitrogen Heterocycles.
AlCl3 (0.4 g, 3 mmol) was added to the mixture of nitrogen-heterocycle (2.4 mmol)
and 6.1 (2 mmol) dissolved in anhydrous CH2Cl2 (20 mL) at 0 C. After removing the
ice-bath, the reaction mixture was stirred at room temperature for 3 h, and then quenched
by MeOH (1 mL). Removal of CH2Cl2 under reduced pressure gave the crude product,
which was purified by column chromatography (EtOAc/Hexanes = 4:1) to give the
desired products 6.2, 6.3, 6.5, 6.6, 6.7 in 4090 % yields, which were futher
recrystallized from CHCl3/hexane for CHN analysis.
N-[(1S)-1-Benzyl-2-oxo-2-(1H-pyrrol-3-yl)ethyl]-2,2,2-trifluoroacetamide
(6.2a): white needles; yield, 82%; mp 171172 C; []23D = +44.3 (c 1.6, CHCl3); 1H
NMR (CDCl3) 3.18 (dd, J = 13.5, 5.1 Hz, 1H), 3.35 (dd, J = 13.5, 5.1 Hz, 1H), 5.47 (q,
J = 7.5 Hz, 1H), 6.336.36 (m, 1H), 6.977.01 (m, 3H), 7.13 (s, 1H), 7.237.25 (m, 4H),
9.40 (br s, 1H); 13C NMR (CDCl3) 39.8, 55.2, 111.8, 115.7 (q, J = 287.8 Hz), 118.4,
126.7, 127.4, 128.5, 128.9, 129.4, 134.7, 156.4 (q, J = 37.8 Hz), 184.8. Anal. Calcd for
C15H13F3N2O2: C, 58.07; H, 4.22; N, 9.03. Found: C, 57.85; H, 4.16; N, 8.84.
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]acetamide
(6.2b): colorless needles; yield: 78%;. mp 142143 C; []23D = 2.0 (c 1.6, CHCl3); 1H
NMR (CDCl3) 1.57 (d, J = 6.9 Hz, 3H), 5.28 (quintet, J = 6.9 Hz, 1H), 6.38 (quintet, J
= 1.8 Hz, 1H), 7.07 (s, 1H), 7.16 (s, 1H), 7.58 (br s, 1H), 9.80 (br s, 1H); 13C NMR
(CDCl3) 20.6, 50.8, 112.0, 115.9 (q, J = 285.2 Hz), 118.5, 127.0, 128.4, 156.7 (q, J =
37.6 Hz), 186.5. Anal. Calcd for C9H9F3N2O2: C, 46.16; H, 3.87; N, 11.96. Found: C,
46.39; H, 3.77; N, 11.80.
76
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]
carbamate (6.2c): colorless needles; yield: 72%; mp 186187 C; []23D = +16.7 (c 1.6,
DMF); 1H NMR (DMSO-d6) 3.09 (dd, J = 13.8, 6.0 Hz, 1H), 3.26 (dd, J = 13.5, 6.0 Hz,
1H), 4.19 (t, J = 6.9 Hz, 1H), 4.29 (t, J = 6.9 Hz, 1H), 4.44 (dd, J = 10.2, 7.2 Hz, 1H),
5.29 (dd, J = 14.1, 6.6 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 3.3 Hz, 1H), 6.99 (s,
1H), 7.05 (d, J = 2.4 Hz, 2H), 7.20 (d, J = 6.3 Hz, 3H), 7.29 (t, J = 7.5 Hz, 2H), 7.39 (t, J
= 7.2 Hz, 2H), 7.56 (t, J = 4.5 Hz, 2H), 7.76 (d, J = 7.5 Hz, 2H), 9.60 (br s, 1H); 13C
NMR (DMSO-d6) 40.4., 47.4, 56.6, 67.1, 111.6, 118.0, 120.2, 125.4, 126.1, 127.1,
127.2, 127.9, 128.6, 129.7, 136.2, 141.5, 144.0, 144.1, 155.8, 187.2. Anal. Calcd for
C28H24N2O3: C, 77.04; H, 5.54; N, 6.42. Found: C, 76.79; H, 5.70; N, 6.29.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-oxo-2-(1H-pyrrol-2yl)ethyl]carbamate (6.2d): white plates; yield, 52%; mp 196197 C; []23D = +32.5 (c
1.6, DMF); 1H NMR (DMSO-d6) 3.04 (dd, J = 14.7, 9.3 Hz, 1H), 3.22 (dd, J = 14.7, 5.1
Hz, 1H), 4.184.21 (m, 3H), 4.975.04 (m, 1H), 6.216.23 (m, 1H), 6.99 (t, J = 7.2 Hz,
1H), 7.047.09 (m, 2H), 7.13 (s, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.257.43 (m, 5H), 7.57
(d, J = 7.8 Hz, 1H), 7.67 (d, J = 6.6 Hz, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.92 (s, 1H), 10.85
(s, 1H), 11.90 (s, 1H); 13C NMR (DMSO-d6) 27.7, 46.6, 56.4, 65.7, 110.0, 110.2, 111.4,
116.8, 118.1, 118.4, 120.1, 120.9, 123.8, 125.3, 126.1, 127.0, 127.2, 127.6, 129.9, 136.1,
140.7, 143.8, 155.7, 188.2. Anal. Calcd for C30H25N3O3: C, 75.77; H, 5.30; N, 8.84.
Found: C, 75.55; H, 5.18; N, 8.76.
9H-Fluoren-9-ylmethyl N-[(1S)-3-(methylsulfanyl)-1-(1H-pyrrol-2-ylcarbonyl)
propyl]carbamate (6.2e): colorless plates; yield, 66%; mp 163164 C; []23D = 5.9 (c
1.6, DMF); 1H NMR (DMSO-d6) 1.922.01 (m, 1H), 2.06 (s, 3H), 2.142.26 (m, 1H),
77
2.512.60 (m, 2H), 4.21 (t, J = 6.9 Hz, 1H), 4.354.56 (m, 2H), 5.21 (dd, J = 9.3, 8.1 Hz,
1H), 5.83 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 3.3 Hz, 1H), 7.08 (s, 1H), 7.12 (s, 1H), 7.28 (t,
J = 7.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 7.8 Hz,
2H), 9.80 (br s, 1H); 13 C NMR (DMSO-d6) 15.6, 30.2, 34.2, 47.2, 54.6, 67.0, 111.5,
118.2, 120.0, 125.1, 126.3, 127.1, 127.7, 129.4, 141.3, 143.9, 156.1, 187.7. Anal. Calcd
for C24H24N2O3S: C, 68.55; H, 5.75; N, 6.66. Found: C, 68.26; H, 5.85; N, 6.74.
N-[(1S)-1-Benzyl-2-(1-methyl-1H-pyrrol-2-yl)-2-oxoethyl]-2,2,2trifluoroacetamide (6.3a): colorless needles; yield, 78%; mp 109110 C; []23D =
+43.6 (c 1.6, CHCl3); 1H NMR (CDCl3) 3.17 (dd, J = 13.8, 4.8 Hz, 1H), 3.31 (dd, J =
13.8, 6.6 Hz, 1H), 3.68 (s, 3H), 5.32 (dd, J = 12.6, 6.0 Hz, 1H), 6.62 (d, J = 1.5 Hz, 2H),
7.007.03 (m, 2H), 7.197.26 (m, 4H), 7.36 (br s, 1H); 13C NMR (CDCl3) 36.8, 39.3,
56.4, 109.9, 115.9 (q, J = 287.3 Hz), 122.3, 124.3, 127.3, 128.3, 128.5, 129.7, 135.4,
156.5 (q, J = 37.2 Hz), 190.1. Anal. Calcd for C16H15F3N2O2: C, 59.26; H, 4.66; N, 8.64.
Found: C, 59.17; H, 4.62; N, 8.47.
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-(1-methyl-1H-pyrrol-2-yl)-2-oxoethyl]acetamide (6.3b): colorless needles; yield, 75%; mp 120121 C; []23D = 7.4 (c 1.6,
CHCl3); 1H NMR (CDCl3) 1.53 (d, J = 7.2 Hz, 3H), 3.73 (s, 3H), 5.13 (quintet, J = 6.3
Hz, 1H), 6.616.60 (m, 2H), 7.40 (t, J = 1.8 Hz, 1H), 7.73 (br s, 1H); 13C NMR (CDCl3)
19.9, 36.7, 51.4, 109.7, 115.7 (q, J = 286.4 Hz), 121.2, 124.1, 127.8, 156.2 (q, J = 37.0
Hz), 191.3. Anal. Calcd for C10H11F3N2O2: C, 48.39; H, 4.47; N, 11.29. Found: C, 48.70;
H, 4.38; N, 11.15.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-(1-methyl-1H-pyrrol-2-yl)-2oxoethyl]carbamate (6.3c): colorless needles; yield, 56%; mp 172173 C; []23D = +9.9
78
(c 1.6, DMF); 1H NMR (DMSO-d6) 3.05 (dd, J = 13.8, 6.3 Hz, 1H), 3.25 (dd, J = 13.8,
5.7 Hz, 1H), 3.89 (s, 3H), 4.20 (t, J = 7.2 Hz, 1H), 4.29 (dd, J = 10.5, 7.5 Hz, 1H), 4.43
(dd, J = 10.2, 7.2 Hz, 1H), 5.31(q, J = 6.3 Hz, 1H), 5.68 (d, J = 8.4 Hz, 1H), 6.15 (q, J =
2.7 Hz, 1H), 6.87 (s, 1H), 7.037.05 (m, 3H), 7.217.23 (m, 3H), 7.30 (t, J = 7.5 Hz,
2H), 7.40 (t, J = 7.2 Hz, 2H), 7.57 (t, J = 6.6 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H); 13C NMR
(DMSO-d6) 37.7, 40.5, 47.2, 56.7, 66.9, 108.8, 120.0, 120.5, 125.2, 125.3, 126.9, 127.1,
127.7, 128.3, 129.5, 132.3, 136.3, 141.3, 144.0, 155.6, 187.5. Anal. Calcd for
C29H26N2O3: C, 77.31; H, 5.82; N, 6.22. Found: C, 76.93; H, 5.76; N, 6.21.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-methyl1H-pyrrol-2-yl)ethyl]carbamate (6.3d): grey microcrystals; yield, 45%; mp 154155
C; []23D = +35.6 (c 1.6, DMF); 1H NMR (DMSO-d6) 3.28 (dd, J = 14.1, 5.1 Hz, 1H),
3.41 (dd, J = 14.7, 6.6 Hz, 1H), 3.56 (s, 3H), 4.20 (t, J = 7.2 Hz, 1H), 4.294.42 (m, 2H),
5.25 (q, J = 6.3 Hz, 1H), 5.84 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H), 6.60 (s, 1H),
6.86 (d, J = 1.8 Hz, 1H), 7.057.10 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.8 Hz,
3H), 7.39 (t, J = 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz, 3H), 7.75 (d, J = 7.5 Hz, 2H), 8.00 (s,
1H); 13C NMR (DMSO-d6) 30.1, 36.8, 47.4, 57.0, 67.1, 109.9, 111.2, 119.1, 119.8,
120.1 (2C), 122.2, 123.1, 123.9, 125.4, 125.5, 127.3, 127.8 (2C), 128.0, 136.2, 141.5,
144.2, 156.1, 193.0. HRMS Calcd for C31H27N3O3 (M+H)+ : 490.2125, found : 490.2151.
9H-Fluoren-9-ylmethyl N-[(1S)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-3(methylsulfanyl)propyl]carbamate (6.3e): light yellow needles; yield, 60%; mp
109110 C; []23D = 17.3 (c 1.6, DMF). 1H NMR (DMSO-d6) 1.862.00 (m, 1H),
2.06 (s, 3H), 2.142.25 (m, 1H), 2.442.63 (m, 2H), 3.66 (s, 3H), 4.21 (t, J = 6.3 Hz,
1H), 4.37 (d, J = 6.9 Hz, 2H), 5.075.13 (m, 1H), 5.84 (d, J = 8.4 Hz, 1H), 6.59 (t, J =
79
2.4 Hz, 1H), 6.65 (s, 1H), 7.267.32 (m, 2H), 7.38 (t, J = 6.0 Hz, 3H), 7.60 (d, J = 7.2
Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H); 13C NMR (DMSO-d6) 15.7, 30.3, 34.2, 36.9, 47.3,
55.6, 67.0, 110.0, 120.1, 122.8, 124.1, 125.3, 127.2, 127.8, 128.0, 141.4, 143.9, 156.2,
192.7. Anal. Calcd for C25H26N2O3S: C, 69.10; H, 6.03; N, 6.45. Found: C, 69.11; H,
5.98; N, 6.46.
9H-Fluoren-9-ylmethyl N-[(1S)-4-oxo-4-(1H-pyrrol-2-yl)-1-(1H-pyrrol-2ylcarbonyl)butyl]carbamate (6.4): light violet microcrystals; yield, 35%; mp
140141C; []23D = + 12.2 (c 1.6, DMF); 1H NMR (DMSO-d6) 1.801.92 (m, 1H),
2.092.20 (m, 1H), 2.803.03 (m, 2H), 4.224.27 (m, 3H), 4.83 (quintet, J = 7.5 Hz, 1H),
6.20 (d, J = 17.1 Hz, 2H), 6.94 (s, 1H), 7.10 (d, J = 16.8 Hz, 2H), 7.29 (s, 1H), 7.34 (t, J
= 7.5 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.73 (t, J = 6.9 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H),
7.89 (d, J = 7.5 Hz, 2H), 11.86 (d, J = 9.6 Hz, 2H); 13C NMR (DMSO-d6) 27.2, 33.8,
46.6, 55.4, 65.6, 109.7, 109.9, 116.3, 116.9, 120.1, 125.3, 125.9, 127.1, 127.6, 129.6,
131.5, 140.7, 143.7, 143.9, 156.1, 188.4, 188.8. Anal. Calcd for C28H25N3O4: C, 71.93; H,
5.39; N, 8.99. Found: C, 72.11; H, 5.41; N, 8.91.
N-[(1S)-1-Benzyl-2-(1H-indol-3-yl)-2-oxoethyl]-2,2,2-trifluoroacetamide (6.5a):
grey needles; yield, 85%; mp 198199 C; []23D = +22.0 (c 1.6, CHCl3); 1H NMR
(CDCl3) 3.22 (dd, J = 13.5, 5.1 Hz, 1H), 3.31 (dd, J = 13.5, 6.3 Hz, 1H), 5.47 (dd, J =
12.9, 7.2 Hz, 1H), 7.05 (t, J = 3.6 Hz, 2H), 7.207.22 (m, 3H), 7.337.44 (m, 3H), 7.55
(d, J = 7.2 Hz, 1H), 7.64 (d, J = 3.0 Hz, 1H), 8.338.35 (m, 1H), 8.83 (br s, 1H); 13C
NMR (CDCl3) 39.8, 56.4, 111.7, 115.2, 115.7 (q, J = 285.8 Hz), 122.2, 123.5, 124.5,
125.3, 127.3, 128.5, 129.5, 132.5, 135.2, 136.2, 156.6 (q, J = 37.0 Hz), 190.1. Anal.
Calcd for C13H11F3N2O2: C, 63.33; H, 4.20; N, 7.77. Found: C, 62.98; H, 4.08; N, 7.75.
80
2,2,2-Trifluoro-N-[(1S)-2-(1H-indol-3-yl)-1-methyl-2-oxoethyl]acetamide
(6.5b): colorless microcrystals; yield, 79%; mp 189190 C; []23D = 7.0 (c 1.6,
CHCl3); 1H NMR (CDCl3) 1.61 (d, J = 6.9 Hz, 3H), 5.31 (quintet, J = 6.9 Hz, 1H), 7.23
(br s, 1H), 7.337.45 (m, 2H), 7.447.48 (m, 1H), 7.97 (d, J = 3.3 Hz, 1H), 8.35 (t, J =
5.4 Hz, 1H), 8.89 (br s, 1H); 13C NMR (CDCl3) 20.4, 51.5, 111.7, 114.2, 115.7 (q, J =
286.4 Hz), 122.3, 123.5, 124.5, 125.5, 132.0, 136.4, 156.5 (q, J = 37.6 Hz), 191.5. Anal.
Calcd for C13H11F3N2O2: C, 54.93; H, 3.90; N, 9.86. Found: C, 54.98; H, 3.91; N, 9.85.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-benzyl-2-oxo-2-(1H-indol-3-yl)ethyl]
carbamate (6.5c): yellow flakes; yield, 63%; mp 101102 C; []23D = 18.3 (c 1.6,
DMF). 1H NMR (DMSO-d6) 3.08 (dd, J = 13.8, 6.0 Hz, 1H), 3.23 (dd, J = 13.8, 6.3 Hz,
1H), 4.114.17 (m, 1H), 4.244.30 (m, 1H), 4.384.44 (m, 1H), 5.25 (dd, J = 14.7, 6.3
Hz 1H), 6.00 (d, J = 7.1 Hz, 1H), 7.067.39 (m, 14 H), 7.52 (t, J = 7.2 Hz, 2H), 7.73 (d, J
= 7.2 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 9.30 (br s, 1H); 13C NMR (DMSO-d6) 40.3,
47.3, 57.8, 67.3, 119.3, 115.6, 120.1, 122.3, 123.2, 124.2, 125.3, 125.7, 127.0, 127.3,
127.9, 128.6, 129.7, 132.8, 136.5, 136.6, 141.4, 143.9, 156.2, 192.8. Anal. Calcd for
C32H26N2O3: C, 78.99; H, 5.39; N, 5.76. Found: C, 78.78; H, 5.65; N, 6.20.
9H-Fluoren-9-ylmethyl-N-[(1S)-2-(1H-indol-3-yl)-1-(1H-indol-3-ylmethyl)-2oxoethyl]carbamate (6.5d): To a solution of Fmoc-Trp-Bt (1d) 1.06g (2 mmol) and NTMS-indole13 0.58g (3 mmol) in CH2Cl2 (30 mL), TiCl4 (1M CH2Cl2 solution) 4 mL (4
mmol) was added quickly at 0 oC. The reaction mixture was stirred for 15 min at the
temperature, and quenched with MeOH (2 mL). The solution was directly subjected to
column chromatography (EtOAc:Hexanes = 1:2) to give the desired product 5d in 0.9g
(87%), which was further recrystallized in CHCl3/hexanes to provide brown
81
microcrystals; yield, 87%; mp 194195 oC; []23D = +28.3 (c 1.6, DMF). 1H NMR
(DMSO-d6) 3.12 (dd, J = 14.6, 8.7 Hz, 1H), 3.29 (dd, J = 14.7, 5.5 Hz, 1H), 4.20 (s,
3H), 5.16 (dd, J = 14.0, 8.2 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.0 Hz, 1H),
7.217.51 (m, 9H), 7.627.68 (m, 3H), 7.86 (d, J = 7.4 Hz, 2H), 7.96 (d, J = 8.3 Hz, 1H),
8.248.33 (m, 2H), 10.8 (s, 1H), 12.0 (s, 1H); 13C NMR (DMSO-d6) 21.7, 46.6, 56.9,
65.7, 110.4, 111.3, 112.2, 114.4, 118.3, 120.0, 120.8, 121.4, 121.9, 123.0, 123.7, 125.3,
125.8, 127.0, 127.3, 127.6, 133.8, 136.1, 136.5, 140.6, 143.8, 155.8, 193.7. Anal. Calcd
for C34H27N3O3: C, 77.70; H, 5.18; N, 7.99. Found: C, 77.47; H, 5.28; N, 7.90.
9H-Fluoren-9-ylmethyl N-[(1S)-1-(1H-indol-3-ylcarbonyl)-3-(methylsulfanyl)propyl]carbamate (6.5e): colorless plates; yield, 83%; mp 128129 C; []23D = 51.2
(c 1.6, DMF); 1H NMR (DMSO-d6) 1.902.01 (m, 2H), 2.05 (s, 3H), 2.542.62 (m,
2H), 4.204.30 (m, 3H), 4.965.03 (m, 1H), 7.227.28 (m, 2H), 7.30 (t, J = 7.5 Hz, 2H),
7.40 (td, J = 6.9, 2.1 Hz, 2H), 7.507.52 (m, 1H), 7.23 (t, J = 6.9 Hz, 2H), 7.85 (s, 1H),
7.89 (d, J = 7.5 Hz, 2H), 8.22 (d, J = 6.6 Hz, 1H), 8.42 (d, J = 3.0 Hz, 1H), 12.05 (s, 1H);
13
C NMR (DMSO-d6) 14.6, 30.1, 31.9, 46.7, 55.7, 65.6, 112.2, 113.9, 120.1, 121.3,
121.9, 123.0, 125.3, 125.7, 127.0, 127.6, 133.8, 136.5, 140.7, 143.8, 156.0, 193.6 Anal.
Calcd for C28H26N2O3S: C, 71.46; H, 5.57; N, 5.95. Found: C, 71.16; H, 5.89; N, 5.55.
N-[(1S)-1-Benzyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-2,2,2trifluoroacetamide (6.6a): colorless needles; yield, 62 %; mp 176177 C; []23D =
+32.9 (c 1.6, CHCl3); 1H NMR (CDCl3) 3.24 (d, J = 2.1 Hz, 1H), 3.26 (d, J = 3.3 Hz,
1H), 3.75 (s, 3H), 5.43 (q, J = 6.3 Hz, 1H), 7.077.10 (m, 2H), 7.197.22 (m, 3H),
7.347.38 (m, 3H), 7.51 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 8.328.35 (m, 1H); 13C NMR
(CDCl3) 33.5, 39.8, 56.4, 109.9, 115.4 (q, J = 285.7 Hz), 113.4, 122.3, 123.3, 124.0,
82
126.2, 127.1, 128.4, 129.6, 135.6., 136.9, 137.5, 156.5 (q, J = 37.0 Hz), 189.5. Anal.
Calcd for C20H17F3N2O2: C, 64.17; H, 4.58; N, 7.48. Found: C, 64.36; H, 4.41; N, 7.46.
2,2,2-Trifluoro-N-[(1S)-1-methyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]
acetamide (6.6b): colorless needles; yield, 75 %; mp 161162 C; []23D = 84.2 (c 1.6,
CHCl3); 1H NMR (CDCl3) 1.60 (d, J = 6.9 Hz, 3H), 3.90 (s, 3H), 5.29 (quintet, J = 6.9
Hz, 1H), 7.357.40 (m, 3H), 7.77 (d, J = 5.4 Hz, 1H), 7.88 (s, 1H), 8.308.34 (m, 1H);
13
C NMR (CDCl3) 20.7, 34.1, 51.6, 110.3, 112.7, 116.0 (q, J = 287.8 Hz), 122.6, 123.6,
124.3, 126.5, 136.5, 137.9, 156.7 (q, J = 37.8 Hz), 191.1. Anal. Calcd for C14H13F3N2O2:
C, 56.38; H, 4.39; N, 9.39. Found: C, 56.44; H, 4.33; N, 9.31.
9H-Fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-(1-methyl-1H-indol-3-yl)-2oxoethyl]carbamate (6.6c): colorless needles; yield, 40%; mp 153154 C; []23D =
+13.1 (c 1.6, DMF); 1H NMR (DMSO-d6) 3.16 (dd, J = 13.5, 5.7 Hz, 1H), 3.23 (dd, J =
13.8, 7.2 Hz, 1H), 3.74 (s, 3H), 4.20 (t, J = 7.2 Hz, 1H), 4.30 (dd, J = 10.2, 7.2 Hz, 1H),
4.42 (dd, J = 10.2, 7.2 Hz, 1H), 5.25 (dd, J = 14.4, 6.9 Hz, 1H), 5.97 (d, J = 8.4 Hz, 1H),
7.117.44 (m, 12 H), 7.53 (s, 1H), 7.57 (t, J = 5.1 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H),
8.378.39 (m, 1H); 13C NMR (DMSO-d6) 33.6, 40.5, 47.2, 57.7, 67.0, 109.8, 114.2,
120.0, 120.9, 122.6, 123.1, 123.8, 125.2, 125.3, 126.7, 127.1, 127.7, 128.3, 129.7, 136.8,
137.5, 141.3, 143.9, 155.8, 191.9. Anal. Calcd for C33H28N2O3: C, 79.18; H, 5.64; N,
5.60. Found: C, 78.98; H, 5.81; N, 5.79.
9H-Fluoren-9-ylmethyl-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-methyl1H-indol-2-yl)ethyl]carbamate (6.6d): colorless microcrystals; yield, 45%; mp 191192
C; []23D = +32.9 (c 1.6, DMF); 1H NMR (DMSO-d6) 3.11 (dd, J = 14.7, 9.0 Hz, 1H),
3.27 (dd, J = 14.4, 5.4 Hz, 1H), 3.83 (s, 3H), 4.184.23 (m, 3H), 5.13 (dd, J = 14.1, 8.4
83
Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.217.42 (m, 8H), 7.54 (d, J =
7.2 Hz, 1H), 7.66 (t, J = 6.6 Hz, 3H), 7.867.92 (m, 3H), 8.26 (d, J = 7.2 Hz, 1H), 8.32
(s, 1H), 10.84 (s, 1H); 13C NMR (DMSO-d6) 27.8, 33.2, 46.6, 57.0, 65.7, 110.4, 110.6,
111.3, 113.2, 118.3, 120.0, 120.8, 121.5, 122.2, 123.0, 123.6. 125.3 (2C), 126.2, 127.0,
127.3, 127.6, 136.0, 137.2, 137.4, 140.6, 143.8, 155.8, 193.3. Anal. Calcd for
C35H29N3O3: C, 77.90; H, 5.42; N, 7.79. Found: C, 77.70; H, 5.48; N, 7.61.
9H-Fluoren-9-ylmethyl N-[(1S)-1-[(1-methyl-1H-indol-3-yl)carbonyl]-3(methylsulfanyl)propyl]carbamate (6.6e): colorless microcrystals; yield, 90%; mp
140141 C; []23D = 41.5 (c 1.6, DMF); 1H NMR (DMSO-d6) 1.952.05 (m, 1H),
2.08 (s, 3H), 2.192.29 (m, 1H), 2.492.69 (m, 2H), 3.85 (s, 3H), 4.22 (t, J = 7.2 Hz,
1H), 4.344.44 (m, 2H), 5.27 (dd, J = 10.2, 8.1 Hz, 1H), 5.94 (d, J = 6.9 Hz, 1H), 7.30 (t,
J = 7.8 Hz, 2H), 7.347.41 (m, 5H), 7.59 (t, J = 7.2 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H),
8.00 (s, 1H), 8.39 (d, J = 6.0 Hz, 1H); 13C NMR (DMSO-d6) 15.8, 30.5, 34.0, 34.3,
47.4, 55.3, 61.2, 110.1, 114.0, 120.2, 122.7, 123.3, 124.1, 125.3, 126.7, 127.2, 127.9,
136.9, 137.8, 141.5, 144.0, 156.4, 192.6. Anal. Calcd for C29H28N2O3S: C, 71.87; H,
5.82; N, 5.78. Found: C, 71.48; H, 5.76; N, 6.31.
9H-Fluoren-9-ylmethyl N-[(1S)-1-methyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]carbamate (6.6f): colorless needles; mp 144145 C; yield, 85%; []23D = 60.1 (c
1.6, DMF); 1H NMR (DMSO-d6) 1.52 (d, J = 6.9 Hz, 3H), 3.85 (s, 3H), 4.23 (t, J = 7.2
Hz, 1H), 4.38 (d, J = 7.2 Hz, 2H), 5.10 (quintet, J = 7.2 Hz, 1H), 6.00 (d, J = 4.8 Hz, 1H),
7.277.42 (m, 7H), 7.61 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.86 (s, 1H),
8.348.39 (m, 1H); 13C NMR (DMSO-d6) 21.1, 33.9, 47.4, 52.4, 67.1, 110.0, 113.5,
120.2, 122.7, 123.3, 124.0, 125.4, 126.7, 127.3, 127.9, 136.3, 137.8, 141.5, 144.1, 155.9,
84
193.5. Anal. Calcd for C27H24N2O3: C, 76.40; H, 5.70; N, 6.60. Found: C, 76.52; H, 5.71;
N, 6.61.
N-[(1R,S)-1-Benzyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-2,2,2trifluoroacetamide (6.6j): colorless needles; yield, 64 %; mp 170172 C. 1H NMR and
13
2,2,2-trifluoroacetamide (6.6a).
6.4.3 Procedure for C-Acylations of Benzene.
AlCl3 (0.4 g, 3 mmol) was added to 6.1d (2 mmol) dissolved in benzene (20 mL) at
0 C. After removing ice-bath, the reaction mixture was stirred at room temperature for 3
h and then quenched by MeOH (1 mL). Removal of solvent under reduced pressure gave
the crude product, which was directly purified by column chromatography
(EtOAc:Hexane = 1:10) to give product 7 in 63 % yield.
N-[(1S)-1-Benzyl-2-oxo-2-phenylethyl]-2,2,2-trifluoroacetamide (6.7): colorless
needles; mp 6465 C (lit.7c mp 6263 C); yield, 63 %; 1H NMR (CDCl3) 1.57 (d, J =
7.2 Hz, 3H), 5.13 (quintet, J = 7.2 Hz, 1H), 6.70 (br s, 1H), 7.297.40 (m, 5H); 13C NMR
(CDCl3) 21.2, 50.0, 116.0 (q, J = 287.3 Hz), 126.4, 128.3, 129.2, 141.1, 156.6 (q, J =
37.0 Hz), 195.1.
6.4.4 Procedure for preparation of amines 6.8, 6.10 and 6.14 by cleavage of Fmoc
protecting group.
Carbamate 6.6f or 6.6g 0.42 g (1 mmol) was dissolved in morpholine 10 mL (10
mmol). After stiring for 30 mins 300 mL of water was added. After the mixture was
extracted with hexane until the TLC showed the disappearance of first spot indicating the
elimination of 9-methylene-9H-fluorene, the water phase was further extracted with
EtOAc. Then organic phase EtOAc was dried with MgSO4 and the evaporation of solvent
85
gave crude product (2S)-2-amino-1-(1-methyl-1H-indol-3-yl)-1-propanone (6.8) [or (2R)2-amino-1-(1-methyl-1H-indol-3-yl)-1-propanone (6.10) from 6.6g] in 75% yield (75%
from 6.10 as well) which can be used for the next step without further purification. The
cleavage of 9H-fluoren-9-ylmethyl N-[(2S)-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl]carbamate (6.13) following the same procedure gave racemic 2-amino-1,2dihydrocyclopenta[b]indol-3(4H)-one (6.14) in 71% yield. We used these three
compounds as crude staring materials for next coupling reaction without purification.
Therefore, we did not provide their characterization.
6.4.5 Procedure for the preparation of diastereomers 6.9 and 6.11.
Amine 6.8 (or 6.10) 0.21 g (1 mmol) was stirred with Tfa-L-Phe-Bt (6.1a) 0.36g (1
mmol) in CH2Cl2 (20 mL) at 20 C for 1 h. Evaporation of solvent gave crude product
which can be purified by column chromatography (EtOAc:Hexane = 1:6).
(2S)-N-[(1S)-1-Methyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-3-phenyl-2[(2,2,2-trifluoroacetyl) amino]propanamide (6.9): colorless needles; mp 212214 C;
yield, 80 %; []23D = 12.1 (c 1.6, DMF); 1H NMR (CDCl3) 1.50 (d, J = 6.9 Hz, 3H),
3.14 (d, J = 6.9 Hz, 2H), 3.87 (s, 3H), 5.01 (q, J = 7.2 Hz, 1H), 5.37 (quintet, J = 7.2 Hz,
1H), 7.15 (s, 5H), 7.337.40 (m, 3H), 7.49 (d, J = 6.9 Hz, 1H), 8.04 (s, 1H), 8.348.37
(m, 1H); 13C NMR (CDCl3) 21.0, 33.6, 38.8, 51.0, 54.7, 109.9, 112.9, 115.8 (q, J =
285.7 Hz), 122.5, 123.2, 123.9, 126.5, 127.3, 128.6, 129.2, 135.3, 136.9, 137.7, 156.7 (q,
J = 37.6 Hz), 168.8, 192.4. Anal. Calcd for C23H22F3N3O3: C, 62.02; H, 4.98; N, 9.43.
Found: C, 61.95; H, 4.91; N, 9.34.
(2S)-N-[(1R)-1-Methyl-2-(1-methyl-1H-indol-3-yl)-2-oxoethyl]-3-phenyl-2[(2,2,2-trifluoroacetyl) amino]propanamide (6.11): colorless needles; mp 212214 C;
86
yield, 80 %; []23D = 14.0; 1H NMR (CDCl3) 1.39 (d, J = 6.6 Hz, 3H), 3.24 (d, J = 7.2
Hz, 2H), 3.75 (s, 3H), 5.24 (q, J = 7.2 Hz, 1H), 5.38 (quintet, J = 7.2 Hz, 1H), 7.01 (t, J =
7.2 Hz, 1H), 7.227.34 (m, 8H), 7.86 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 8.328.34 (m,
1H); 13C NMR (CDCl3) 20.7, 33.6, 39.6, 51.5, 54.7, 110.1, 112.9, 115.8 (q, J = 285.7
Hz), 122.5, 123.2, 123.9, 126.7, 127.2, 128.8, 129.3, 136.0, 137.8, 156.7 (q, J = 37.6,
Hz), 169.4, 192.9. Anal. Calcd for C23H22F3N3O3: C, 62.02; H, 4.98; N, 9.43. Found: C,
61.95; H, 4.91; N, 9.34.
6.4.6 Procedure for the Intramolecular Acylations of 6.1a and 6.1d.
AlCl3 0.4 g (3 mmol) was added to 6.1a (or 6.1d) (2 mmol) dissolved in anhydrous
CH2Cl2 (20 mL) at 0 C. After removing of ice-bath, the reaction mixture was stirred at
room temperature for 3 h and then quenched by MeOH (1 mL). Removal of solvent under
reduced pressure gave the crude product, which was purified by column chromatography
(EtOAc:Hexanes = 6:1) to give the intramolecular acylated products 6.12 (6.13 from
6.1d). They were futher recrystallized from CHCl3/hexanes for CHN analysis.
2,2,2-Trifluoro-N-[(2S)-1-oxo-2,3-dihydro-1H-inden-2-yl]acetamide (6.12):
white flakes; yield, 57%; mp 207208 C; []23D = 3.2 (c 1.6, DMF). 1H NMR (DMSOd6) 3.05 (dd, J = 16.8, 5.4 Hz, 1H), 3.55 (dd, J = 16.8, 8.4 Hz, 1H), 4.614.68 (m, 1H),
7.45 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.697.76 (m, 2H), 9.96 (d, J = 7.8 Hz,
1H); 13C NMR (DMSO-d6) 32.1, 54.6, 115.8 (q, J = 286.9 Hz), 123.5, 126.8, 127.8,
134.6, 135.6, 151.4, 156.3 (q, J = 36.5 Hz), 201.2. Anal. Calcd for C11H8F3NO2: C,
54.33; H, 3.32; N, 5.76. Found: C, 54.31; H, 3.24; N, 5.70.
9H-Fluoren-9-ylmethyl N-[(2S)-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indol-2yl]carbamate (6.13): white flakes; yield, 62%; 235 C (Dec.); []23D = 4.3 (c 1.6,
87
DMF). 1H NMR (DMSO-d6) 2.88 (dd, J = 16.2, 3.0 Hz, 1H), 3.51 (dd, J = 16.2, 6.9 Hz,
1H), 4.244.38 (m, 3H), 4.53 (quintet, J = 6.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H),
7.337.48 (m, 6H), 7.72 (d, J = 7.5 Hz, 4H), 7.908.01 (m, 2H), 11.76 (s, 1H); 13C NMR
(DMSO-d6) 28.1, 46.7, 59.6, 65.6, 113.6, 120.1, 121.4, 122.8, 127.8, 125.9, 126.9,
127.1, 127.6, 136.6, 140.7, 140.9, 143.4, 143.8, 155.9, 191.3. Anal. Calcd for
C26H20N2O3: C, 76.45; H, 4.94; N, 6.86. Found: C, 76.24; H, 4.88; N, 6.72.
6.4.7 Procedure for the preparation of diastereomers 6.15 (6.16 and 6.17).
Amine 6.14 0.17 g (1 mmol) was stirred with Tfa-DL-Ala-Bt (1i) or Tfa-L-Ala-Bt
(1b) 0.28g (1 mmol) in CH2Cl2 (20 mL) at 20 C for 1 h. Evaporation of solvent gave the
corresponding crude product which can be purified by column chromatography
(EtOAc:Hexane = 1:3).
N-(1-Oxo-1,2,3,8-tetrahydrocyclopenta[a]inden-2-yl)-2-[(2,2,2trifluoroacetyl)amino]propanamide (6.15): white plates; yield, 52%; mp 257258 C.
1
H NMR (DMSO-d6) (diastereomeric mixture) 1.49 (d, J = 7.0 Hz, 3H), 1.50 (d, J = 7.0
Hz, 3H), 2.933.03 (m, 2H), 3.12 (br s, 2H), 3.573.66 (m, 2H), 4.584.79 (m, 2H),
4.764.92 (m, 2H), 7.16 (t, J = 6.9 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.73 (d, J = 8.1 Hz,
2H), 8.018.08 (m, 2H), 8.58 (br s, 2H), 10.8 (s, 2H); 13C NMR (DMSO-d6)
(diastereomeric mixture) 17.4, 17.5, 28.4, 28.5, 49.3 (2C), 59.0, 59.3, 113.6, 116.2 (q, J
= 285.2 Hz), 120.5, 120.6, 121.5, 123.5, 127.2 (2C), 136.8, 136.9, 143.9(2C), 156.4 (q, J
= 40.0 Hz), 170.9, 190.0, 190.1. HRMS Calcd for C17H15F3N2O3 (M+2H)+ : 354.1191,
found: 354.1185.
CHAPTER 7
NOVEL SYNTHESES OF CHIRAL - AND -AMINO ACID DERIVATIVES
UTILIZING N-(PROTECTED AMINOACYL)BENZOTRIAZOLES FROM ASPARTIC
ACID AND GLUTAMIC ACID
7.1 Introduction
Non-natural - and -amino acids have gained considerable attention due to their
roles in the design and synthesis of bioactive molecules as well as in the study of
biomimetic polymers that contain both secondary and tertiary structure analogous to
those of natural proteins. For example, -amino acid derivatives are key components of a
variety of biologically active molecules including the antitumor agent taxol [91PT35],
[04OL3553], antifungal jasplakinolide [86TL2797], antibiotics [89TL4349], and the
enzyme inhibitor bestatin (Fig. 71a) [01TL3563]. -Amino acids are also of high
interest as precursors for peptidomimetics [02CMC811], [01CV3219] and -lactams
[92CL], [93OCL]. Likewise, -amino acids represent important roles in the structure of
natural products with antitumor activity such as Hapalosin [99SL1118], [99TL9309],
[94JOC7219], Dolastatin [94JOC6287] Caliculins [86JA2780], [91Tl5983], and of
various enzyme inhibitor GABA-analogues (Fig. 71b) [97TL5503]. In addition, they are
attractive starting materials for the formation of peptides with helical secondary
structures [98JA8569] [98HCA983].
88
89
(a) -amino acid derivatives in biologically active compounds
AcO
BzHN
OH
O
O
O
OH
OH
BzO
AcO
H2N
OH
O
OH
Taxol
Bestatin
OH
O
O
HN
Br
O
O
HN
N
H2N
O
O
O
OH
NH
OH
OH
N
H
Amastatin
O
Jasplakinolide
(b) -amino acid derivatives in biologically active compounds
R3
OH O
O
MeO
OO
HO
nC7H15
OH
N
H
O
HO OH
O P
O
O
O
Hapalosin
OH
OMe
OH
H
N
OH
O
N
N
OMe O
MeO
O
NH
R2
S
N
Dolastatin
Calyculins
R1
Figure. 71. Examples of biologically active molecules containing fragments of - and amino acid derivatives
90
Given this significance of - and -amino acids, the development of efficient
methods for the synthesis of enantiomerically pure - and -amino acids is important.
Among many previously reported methodologies for -amino acids [02T7990], perhaps
the most common method uses -amino acids as starting materials due to their ready
availability, low cost, and high enantiomeric purity. The direct homologation of -amino
acids to prepare -amino acids following the Arndt-Eistert procedure has been
extensively studied (Scheme 71) [96HCA913], [98HCA187], [97JA11777],
[97JCS(PT1)1969], [98S837]. However, the Arndt-Eistert homlogation protocol is not
suitable for large scale synthesis due to the high cost of the silver catalyst and difficult
handling of the hazardous reagent CH2N2 [02T7991]. Although Longobarbos
modification provided a method to avoid using the silver catalyst and CH2N2, the
procedure took four steps [95T12337].
R
PG
N
H
OH
O
i) i-BuOCOCl, NMM PG
N
ii) CH2N2, Et2O
H
Et3N, THF/H2O
N2
O
R
PG
Cat. CF3COOAg
N
H
O
OH
NMM = N-Methylmorpholine
Scheme 71. -Amino acids by direct homologation of -amino acids via Arndt-Eistert
reaction
Naturally occurring aspartic acid, possessing a -amino carboxylic acid fragment,
is an attractive precursor for the preparation of -amino acids. In the literature, synthesis
of -amino acids was demonstrated by the stereoselective ring-opening of either lactones
or oxazolidinones prepared in four steps from L-aspartic acid [96HCA1203],
[96TL3165], [00JOC1298] and the nucleophilic substitution of organocuprates
[92S1104] or organozinc reagents (Scheme 72) [99JOC7579].
91
PG
PG
PG
NH
NH
NH
Ac2O
HOOC
COOH
O
PG
Me3SiI
i) NaBH4
ii) PhH, TsOH
O
EtOH
NH
EtOOC
I
R2CuLi, THF
or Zn, RI, Pd2(dba)3
NH2
HOOC
deprotection
R
PG
PG
K2CO3
NH
HOOC
MeOH/H2O
EtOOC
NH
R
Scheme 72. Literature methods of synthesis of -amino acids from L-aspartic acid
Three methods for the synthesis of -amino acids from natural -amino acids have
been reported, which has relatively fewer examples compared to -amino acids: (i) The
double Arndt-Eistert homlogation [69RC299], [77HCV2747]. (ii) The Wittig reaction
with Ph3P=CHCO2Et of aldehyde from natural -amino acids followed by reduction
[97TL163]. (iii) the alkylation of diethylmalonate by substituted N-tosyl aziridines
prepared in situ from N,O-ditosylates of amino alcohols derived from -amino acids
(Scheme 73) [77CPB29]. The Wittig protocol is limited to -alkyl -amino acid
derivatives [97TL163]. The alkylation method is incompatible with sensitive
functionality because of harsh conditions (17 h reflux in 47% HBr to remove the N-tosyl
protecting group) [77CPB29]. Recently, Smreina et al. reported the synthesis of substituted -amino acid via N-Boc-5-substituted pyrrolidinones, but this procedure
required five steps (Scheme 74) [97T12867].
92
R
P
OH
N
H
R
P
3) H2O/Ag2O
OMe
NH P
Ph
H2N
CH2N2
OH
R1
Base
OR2
H2N
Ph
E+/THF
cat. Ag+ P
OR2
NH
P
OH
N
H
1) diethyl potassiomalonate
K2CO3 Ph
Pyridine HN
OH
Tos
N2
N
H
NH P
TosCl
O
1
Ph
OH
N
H
1) DIBALH, then
Ph3P=CHCO2R2
O
1
1) SOCl2
2) CH2N2
OTos
Ph
N
2) 47% HBr, reflux, 17 hr
Tos
OH
NH2
Scheme 73. Literature methods of synthesis of -amino acids from -amino acids
R
OH
BocHN
O
Meldrum's acid
DCC, DMAP, CH2Cl2
NaBH4
O
BocHN
O
AcOH, CH2Cl2
O
O
BocHN
O
Toluene, reflux
R
R
BocHN
COOH
NaOH
acetone, water
BocN
O
93
(a) From organocuprates
O
HO
OR
PG
HO
ii) NaBH4
NH
OR
PG
i) TsCl/Py
i) ClCO2Et
1
NH
ii) NaI
OR1
I
PG
NH
R2Cu/THF
O
O
R2
i) Hydrolysis
OH
R2
ii) Deprotection
PG
NH2
OR
NH
HO
PG
O
OR
NHS, DCC
NH
N O
OR1
PG
NaBH4
OR1
HO
NH
PG
NH
O
Ar
NH2
ii) Hydrolysis
ii) Deprotection
OR1
I
PG
NH
Scheme 75. Literature methods of synthesis of -amino acid from glutamic acids
Our group has developed N-acylbenzotriazoles as an efficient acylating agents for
N-, [00JOC8210], [98S153], [02ARK134], [02BMC1809], [04S2645], [04ARK14], C-,
[00JOC3679], [03JOC1443], [03JOC4932], [04JOC6617], [03JOC5720], [04CCA175]
O-, [04JOC6617], [99JHC777], [96LA881] and S-acylation reactions [04S1806]. In
particular, N-acylbenzotriazoles, which are advantageously stable towards moisture and
storable for a long period of time, are efficient for the C-acylation of reactive
heterocycles such as indoles, pyrroles [03JOC5720], furan, and thiophene [04CCA]
under Friedel-Crafts conditions. Recently, we have extended our work to the preparation
of N-Tfa- and Fmoc--amino ketones by C-acylation of pyrroles and indoles with chiral
N-protected (-aminoacyl)benzotriazoles [02ARK134], [04S2645], [05S297] in the
presence of AlCl3 with preservation of chirality as demonstrated by configurational
analysis [05JOCASAP].
94
Now, a novel and practical method for the synthesis of - and -amino acids and
their derivatives with preservation of the chirality by the reduction of - and -amino
ketones is reported. The - and -amino ketones are obtained by the Friedel-Crafts type
reaction of aromatics with chiral N-protected (-aminoacyl)benzotriazoles 7.4 and 7.8,
readily available from L-aspartic acid and L-glutamic acid.
7.2 Results and Discussion
7.2.1 Preparation of N-(Tfa--aminoacyl)benzotriazoles 7.4 and 7.8.
L-Aspartic acid (7.1) was reacted with methanol and thionyl chloride to form the mono methyl ester 7.2 selectively in 80% yield [01CC1710]. Ester 7.2 was protected with
N-trifluroacetyl (Tfa) group using ethyl trifluoroacetate in the presence of 2 equivalents
Et3N in methanol to generate N-Tfa-aspartic ester 7.3. [72JOC2805]. On treatment with
thionyl chloride and 4 equivalents of benzotriazole ester 7.3 gave Tfa-Asp(OMe)-Bt (7.4)
in 91% yield. Similarly, Tfa-Glu(OMe)-Bt (7.8) was synthesized in 66% overall yield
from L-glutamic acid 7.5 via 7.6 and 7.7. (Scheme 76)
O
O
OH
O
H2N
OH
7.1
SOCl2
MeOH
80%
Cl H3N
OMe
CF3COOEt
O
Et3N, MeOH
OH
87%
7.2
Tfa
N
H
7.3
OMe
BtH, SOCl2
O
CH2Cl2
OH
91%
Tfa
OMe
O
N
H
Bt
Tfa-Asp(OMe)-Bt (7.4)
OH
OMe
SOCl2
O
H2N
OH
7.5
MeOH
80%
Cl H3N
OH
7.6
OMe
CF3COOEt
Et3N, MeOH
89%
Tfa
N
H
7.7
O
OH
O
BtH, SOCl2
CH2Cl2
93%
Tfa
N
H
OMe
O
Bt
Tfa-Glu(OMe)-Bt (7.8)
Tfa = CF3CO
Bt = benzotriazol-1-yl
95
7.2.2 Syntheses of -keto--amino esters 7.9.
Previously, we reported the synthesis of -amino ketones from Friedel-Crafts
acylations of N-heterocycles utilizing chiral N-protected (-aminoacyl)benzotriazoles in
presence of AlCl3. Unfortunately, when this method was extended to the preparation of keto--amino esters 7.9 by acylation of aromatics with Tfa-Asp(OMe)-Bt (7.4) under the
same reaction conditions, starting material 7.4 decomposed in one hour and the desired
product was not isolated. The results from Lewis Acids screening led me to TiCl4
(starting materials were recovered when BF3 or ZnBr2 was used). The reaction of TfaAsp(OMe)-Bt (7.4) with 1.1 equivalent of aromatics in the presence of 1.5 equivalent
TiCl4 at 20 C for 1 hour generated the corresponding amino -keto--amino esters
7.9af in 4589% yield (Scheme 77).
O
Tfa
N
H
O
OMe
O
Bt
OMe
O
TiCl4
Tfa
Aromatics
Tfa-Asp(OMe)-Bt (7.4)
N
H
Ar
7.9 (45-89%)
indole
82
N-methylindole
89
N-methylpyrrole
65
pyrrole
54
1,3-(MeO)2C6H4
45
1,3,5-(MeO)3C6H3
45
96
7.2.3 -Aryl--amino esters 7.10 from the reduction of -keto--amino esters 7.9.
When 7.9b and 7.9e were reduced by the combination of chlorodimethylsilane
(Me2SiClH) and a catalytic amount of indium chloride (InCl3) the corresponding -aryl amino esters 7.10b and 7.10e were isolated in 56% and 80% yield respectively. (Scheme
78) [99SL182] However, the attempted reduction of 7.9c and 7.9d failed under various
conditions (combination of Me2SiClH and InCl3; BH3; Pd/C hydrogenation; Et3SiH in
CF3COOH). The harsh condition (LiAlH4) used previously [89US4826869]-31 for the
reduction of 1H-pyrrol-2-yl-propanone caused decomposition of starting material in our
case.
O
Tfa
N
H
OMe
O
InCl3\Me2SiClH
CH2Cl2
Ar
7.9b
7.9e
OMe
Tfa
N
H
Ar
7.10b (Y: 56%)
7.10e (Y: 80%)
Scheme 78. -Aryl--amino esters 7.10 from the reduction of -keto--amino esters 7.9
7.2.4 -Hydroxyl--amino ester 11 from the reduction of -keto--amino esters 7.9.
The first attempt to reduce the -keto--amino esters 7.9 was to use sodium
borohydride (NaBH4) in ethanol as a reducing reagent. However, all the reductions with
NaBH4 gave us two diastereomers: the syn- and the anti-products (major). Selectivity
could be improved by decreasing temperature from 0 C (Anti:Syn = 60:40) to -15 C
(Anti:Syn = 80:20). When temperature was lower than -20 C there was no reaction and
the starting material was recovered. When DIBALH was used in THF at -20 C, the crude
NMR of the corresponding -hydroxyl--amino ester 7.11b showed only one
diastereomer present (Scheme 79)
97
O
O
Tfa
N
H
NaBH4
OMe
O
Tfa
MeOH
Ar
N
H
Ar
83%
O
DIBALH
7.9b
OMe
OH
OMe
OH
THF
Tfa
N
H
or
Tfa
Ar
N
H
OMe
OH
Ar
7.11b
Scheme 79. -Hydroxyl--amino ester 7.11 from the reduction of -keto--amino esters
7.9
7.2.5 -Aryl--amino acids 12 from the reduction of -keto--amino esters 7.9.
When the reaction was carried out with NaBH4 in DMF/H2O (3/1) (4 equiv.), the aryl--amino acids 7.12 were generated in 5476% yield. (Scheme 710)
O
Tfa
N
H
O
OMe
O
Ar
NaBH4
DMF/H2O
OH
Tfa
N
H
7.9
Ar
7.12
Scheme 710. -Aryl--amino acids 7.12 from the reduction of -keto--amino esters 7.9
Table 72 -Aryl--amino acids 7.12 from the reduction of -keto--amino esters 7.9
Entry Aryl
-Aryl--amino acids 7.12 (%)
a
indole
72
b
N-methylindole
76
c
N-methylpyrrole
54
7.2.6 Syntheses of -keto--amino esters 7.13.
Following the method developed for the preparation of -keto--amino esters 7.9,
the reaction of Tfa-Glu(OMe)-Bt (7.8) with 1.1 equivalent of aromatics in the presence of
1.5 equivalent TiCl4 at 20 C for 1 hour generated the corresponding -keto--amino
esters 7.13 in 4888% yield. (Scheme 711)
98
O
OMe
OMe
TiCl4
Tfa
N
H
Bt
Tfa
Aromatics
N
H
Ar
7.13 (48-88%)
Tfa-Glu(OMe)-Bt (7.8)
indole
80
N-methylindole
88
N-methylpyrrole
69
pyrrole
50
1,3-(MeO)2C6H4
48
1,3,5-(MeO)3C6H3
46
13
Gemini 300 NMR spectrometer in CDCl3 or DMSO-d6 (with TMS as the internal
references). Elemental analyses were performed on a Carlo Erba-1106 instrument. HPLC
analyses were performed on Beckman system gold programmable solvent module 126
using Chirobiotic T column (4.6250 mm), detection at 254 nm, flow rate of 1.0 mL/min
and MeOH as an eluting solvent. Fmoc-Amino acids purchased from Fluka and amino
acids purchased from Across, were used without further purification. THF was distilled
from sodium/benzophenone prior to use. All of the reactions were carried out under N2.
Column chromatography was performed on silica gel 200425 mesh.
99
7.3.1 General Procedure for the Preparation of N-Tfa-(aminoacyl)benzotriazoles 7.4
and 7.8.
To a solution of BtH 0.95 g (8 mmol) in CH2Cl2, SOCl2 0.24 g (2 mmol) was
added, and the reaction mixture was refluxed for 30 min. Then, the reaction mixture was
cooled to 0 C, and Tfa-Asp(OMe)-OH 0.486g (2 mmol) in CH2Cl2 (10 mL) was added
dropwise. The reaction mixture was stirred at 23 C for 2 hours, and then it was washed
with water, Na2CO3 until BtH was completely removed, and dried on MgSO4. Removing
the solvent gave the white solid, which was recrystallized from CHCl3/hexanes to give
the desired products. When Tfa-Glu(OMe)-OH 0.51g (2 mmol) was used Tfa-Glu(OMe)Bt 7.8 was isolated in 93% yield.
Methyl
(3S)-4-(1H-1,2,3-benzotriazol-1-yl)-4-oxo-3-[(2,2,2-trifluoroacetyl)
amino] butanoate (7.4): colorless needles; yield, 91% yield; mp 68.070.0C; 1H NMR
(CDCl3) 3.30 (dd, J = 17.3, 4.9 Hz, 1H), 3.53 (dd, J = 17.3, 5.1 Hz, 1H), 3.69 (s, 3H),
6.086.14 (m, 1H), 7.58 (apparent t, 1H), 7.73 (apparent t, 1H), 7.88 (br s, 1H), 8.17 (d, J
= 8.2 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H);
13
115.5 (q, J = 288 Hz), 120.6, 127.0, 131.1, 131.3, 146.0, 157.0 (q, J = 38 Hz), 167.4,
170.3. Anal. Calcd for C13H11F3N4O4: C, 45.36; H, 3.22; N, 16.28. Found: C, 45.48; H,
3.23; N, 15.91.
Methyl
(4S)-5-(1H-1,2,3-benzotriazol-1-yl)-5-oxo-4-[(2,2,2-trifluoroacetyl)
amino]pentanoate (7.8): colorless needles; yield, 93%; 1H NMR (CDCl3) 2.02.37 (m,
2H), 2.442.55 (m, 2H), 3.71 (s, 3H), 5.986.04 (m, 1H), 7.29 (s, 1H), 7.59 (t, J = 8.0
Hz, 1H), 7.99 (t, J = 8.0Hz, 1H), 8.05 (d, J = 3.2 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H); 13C
NMR (CDCl3) . Anal. Calcd for C14H13F3N4O4: C, 46.93; H, 3.66; N, 15.64. Found: C,
46.95; H, 3.64; N, 14.91.
100
7.3.2 General Procedure for the Preparation of -keto--amino esters 7.9.
To a solution of Tfa-Asp(OMe)-Bt (7.4) (0.34 g, 1 mmol) and aromatics (1.1
mmol) in anhydrous CH2Cl2 (10 mL) was added TiCl4 (1.5 mL, 1.5 mmol) at 0 C. The
mixture was stirred at room temperature for 1 hr and purified by chromatography (dry
loading method, EtOAc/Hexane = 1/3)
Methyl (3S)-4-(1H-indol-3-yl)-4-oxo-3-[(2,2,2-trifluoroacetyl)amino]butanoate
(7.9a): colorless crystals; yield, 82%; mp 136137 C; []23D = 78.3o (c 1.66, CHCl3);
1
H NMR (CDCl3) 2.86 (dd, J = 15.9, 5.9 Hz, 1H), 3.00 (dd, J = 15.9, 5.4 Hz, 1H), 3.71
(s, 3H), 5.625.68 (m, 1H), 7.307.34 (m, 2H), 7.427.45 (m, 1H), 7.99 (d, J = 8.0Hz,
1H), 8.15 (d, J = 3.2 Hz, 1H), 8.308.33 (m, 1H), 9.29 (s, 1H); 13C NMR (CDCl3) 37.2,
51.5, 52.4, 111.8, 114.1, 115.7 (q, J = 287 Hz), 122.1, 123.4, 124.5, 125.6, 133.2, 136.5,
156.9 (q, J = 38 Hz), 171.3, 188.9. Anal. Calcd for C15H13F3N2O4: C, 52.64; H, 3.83; N,
8.18. Found: C, 52.50; H, 3.71; N, 7.98.
Methyl
(3S)-47.-(1-methyl-1H-indol-3-yl)-4-oxo-3-[(2,2,2-trifluoroacetyl)
13
C NMR (CDCl3) 34.0, 37.3, 51.5, 52.5, 110.2, 112.9, 115.9 (q, J = 286.3
Hz), 122.6, 123.6, 124.3, 126.7, 137.4, 137.9, 156.9 (q, J = 37.6 Hz), 171.2, 188.7. Anal.
Calcd for C16H15F3N2O4: C, 55.14; H, 4.63; N, 4.63. Found: C, 55.04; H, 4.61; N, 7.44.
Methyl
(3S)-4-(1-methyl-1H-pyrrol-3-yl)-4-oxo-3-[(2,2,2-trifluoroacetyl)
101
3.94 (s, 3H), 5.515.57 (m, 1H), 6.21 (dd, J = 2.4, 4.2 Hz, 1H), 6.95 (s, 1H), 7.15 (dd, J =
1.5, 4.2 Hz, 1H), 7.73 (d, J = 6.3 Hz, 1H); 13C NMR (CDCl3) 37.7 (d, J = 8.6 Hz), 51.2,
52.2 (d, J = 2.9 Hz), 109.3, 115.7 (q, J = 286.3 Hz), 121.0, 27.2, 133.3, 156.5 (q, J = 38.1
Hz), 170.4, 183.8. Anal. Calcd for C12H13F3N2O4: C, 47.07; H, 4.28; N, 9.15. Found: C,
46.91; H, 4.21; N, 9.24.
(S)-Methyl
3-(2,2,2-trifluoroacetamido)-4-oxo-4-(1H-pyrrol-3-yl)butanoate
(7.9d): colorless needles; yield, 54%, mp 135.0136.0 C; 1H NMR (CDCl3) 2.88 (dd, J
= 5.4, 16.2 Hz, 1H), 2.99 (dd, J = 5.4, 16.2 Hz, 1H), 3.69 (s, 3H), 5.515.58 (m, 1H),
6.356.38 (m., 1H), 7.137.16 (m, 1H), 7.85 (d, J = 7.8 Hz, 1H), 9.74 (br s, 1H);
13
NMR (CDCl3) 37.0, 50.7, 52.3 (q, J = 2.85 Hz), 111.9, 115.6 (q, J = 285.8 Hz), 118.5,
127.0, 128.4, 156.7 (q, J = 37.5 Hz), 170.6, 183.6. Anal. Calcd for C11H11F3N2O4: C,
45.21; H, 3.79; N, 9.59. Found: C, 45.44; H, 3.76; N, 9.24.
Methyl
(3S)-4-(2,4-dimethoxyphenyl)-4-oxo-3-[(2,2,2-trifluoroacetyl)amino]
3-(2,2,2-trifluoroacetamido)-4-(2,4,6-trimethoxyphenyl)-4-
102
3.80 (s, 6H), 3.84 (s, 3H), 5.375.43 (m, 1H), 6.10 (s, 2H), 7.70 (d, J = 7.8 Hz, 1H); 13C
NMR (CDCl3) 34.8, 51.9, 55.4, 55.8, 55.9 (2C), 90.6, 108.0, 115.7 (q, J = 286.3 Hz),
156.5 (q, J = 37.0 Hz), 159.3, 163.7, 170.6, 196,6. Anal. Calcd for C16H18F3NO7: C,
48.86; H, 4.61; N, 3.56. Found: C, 48.72; H, 4.57; N, 3.51.
(R)-Methyl
3-(2,2,2-trifluoroacetamido)-4-(1-methyl-1H-indol-3-yl)butanoate
(7.10b): colorless needles; yield, 56%, mp 115116 C; []23D = 20.8o (c 1.66, CHCl3);
1
H NMR (CDCl3) 2.59 (d, J = 5.1 Hz, 2H), 3.03 (dd, J = 14.7, 8.1Hz, 1H), 3.15 (dd, J =
14.4, 5.7 Hz, 1H), 3.70 (s, 3H), 3.76 (s, 3H), 4.534.61 (m, 1H), 6.88 (s, 1H), 7.117.16
(m, 1H), 7.227.32 (m, 3H), 7.61 (d, J = 8.1 Hz, 1H);
13
35.9, 47.5, 52.0, 108.9, 109.4, 115.8 (q, J = 286.4 Hz), 118.7, 119.3, 122.0, 127.5, 127.7,
137.0, 156.6 (q, J = 36.5 Hz), 172.0. Anal. Calcd for C16H17F3N2O3.: C, 56.14; H, 5.01;
N, 8.18. Found: C, 56.38; H, 5.02; N, 8.08.
(R)-Methyl
3-(2,2,2-trifluoroacetamido)-4-(2,4-dimethoxyphenyl)butanoate
(7.10e): colorless needles; yield, 80%, mp 8788 C; 1H NMR (CDCl3) 2.52 (dd, J =
6.6, 16.5 Hz, 1H), 2.65 (dd, J = 4.5, 16.2 Hz, 1H), 2.852.98 (m, 2H), 3.71 (s, 3H), 3.80
(s, 3H), 3.82 (s. 3H), 4.39 (q, J = 4.5 Hz), 6.436.47 (m, 2H), 7.01 (d, J = 8.7 Hz, 1H),
7.61 (d, J = 6.9 Hz, 1H);
13
104.6, 115.8 (q, J = 286.3 Hz), 117.0, 131.8, 156.9 (q, J = 36.5 Hz), 158.0, 160.2, 171.7.
Anal. Calcd for C15H18F3NO5: C, 51.58; H, 5.19; N, 4.01. Found: C, 51.38; H, 5.18; N,
3.92.
(3R)-4-(1H-Indol-3-yl)-3-[(2,2,2-trifluoroacetyl)amino]butanoic acid (7.12a):
pale yellow microcrystal; yield, 72%; mp 157.0158.0C; []23D = +2.678.3o (c 1.75,
DMF); 1H NMR (DMSO-d6) 2.502.57 (m, 2H), 2.882.97 (m, 2H), 4.344.46 (m,
103
1H), 6.977.14 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 HZ, 1H), 9.39 (d, J =
8.2 Hz, 1H), 10.89 (s, 1H), 12.15 (br s, 1H);
13
110.1, 111.4, 115.9 (q, J = 289 Hz), 118.2, 118.4, 121.0, 123.5, 127.3, 136.2, 155.7 (q, J
= 36 Hz), 172.2. Anal. Calcd for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C,
53.25; H, 4.29; N, 8.64.
2,2,2-Trifluoro-N-{(1R)-3-hydroxy-1-[(1-methyl-1H-pyrrol-3yl)methyl]propyl} acetamide (7.12c): colorless microcrystals; yield, 54%; mp
145.0146.0C; 1H NMR (CDCl3) 2.24 (d, J = 5.7 Hz, 2H), 2.72 (d, J = 6.6 Hz, 2H),
3.54 (s, 3H), 4.11 (quintet, J = 6.0 Hz, 1H), 5.735.74 (m, 1H), 5.84 (t, J = 3.0 Hz, 1H),
10.3 (br s, 1H);
13
C NMR (CDCl3) 27.6, 33.1, 47.6, 50.2, 106.2, 107.1, 116.0 (q, J =
4-(2,2,2-trifluoroacetamido)-5-(1H-indol-3-yl)-5-oxopentanoate
C NMR (CDCl3) 29.6, 30.3, 34.0, 52.1, 54.3, 110.2, 112.9, 116.0 (q, J = 286.3 Hz),
104
122.5, 123.5, 124.2, 126.6, 137.6, 137.8, 157.5 (q, J = 37.1 Hz), 173.6, 190.2. Anal.
Calcd for C17H17F3N2O4: C, 55.14; H, 4.63; N, 7.56. Found: C, 55.04; H, 4.61; N, 7.44.
Methyl (4S)-5-(1-methyl-1H-pyrrol-3-yl)-5-oxo-4-[(2,2,2-trifluoroacetyl)amino]
pentanoate (7.13c): colorless needles; yield, 69%; mp 131.0132.0C; 1H NMR (CDCl3)
1.892.04 (m, 1H), 2.362.49 (m, 3H), 3.70 (s, 3H), 3.95 (s, 3H), 2.375.44 (dt, J =
3.0, 8.1 Hz,1H), 6.226.24 (m, 1H), 6.95 (s, 1H), 7.29 (d, J = 3.9 Hz, 1H), 7.59 (d, J =
6.0 Hz, 1H); 13C NMR (CDCl3) 29.6, 29.9, 52.0, 53.9, 109.6, 116.0 (d, J = 286.3 Hz),
121.7, 127.6, 135.5, 157.2 (d, J = 37.0 Hz), 173.2, 185.6.
(S)-methyl
4-(2,2,2-trifluoroacetamido)-5-oxo-5-(1H-pyrrol-2-yl)pentanoate
13
C NMR
(CDCl3) 29.5, 29.6, 52.0, 53.5, 111.9, 115.7 (q, J = 285.7 Hz), 118.9, 126.9, 128.6,
157.2 (q, J = 37.0 Hz), 173.3, 185.1. Anal. Calcd for C12H13F3N2O4: C, 47.07; H, 4.28; N,
9.15. Found: C, 46.91; H, 4.19; N, 8.75.
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BIOGRAPHICAL SKETCH
Rong Jiang was born in December 9th 1974 in Sichuan, China. She received her
Bachelor of Science in polymer material engineering in July 1996 from Xian Jiaotong
University. Under the supervision of Professor Alan R. Katritzky, she commenced her
Ph.D study in chemistry department of University of Florida in January 2001.
123