21

CHAPTER-2

SYNTHESIS OF ARYL UREA DERIVATIVES FROM ARYL AMINES AND

ARYL ISOCYANATES

2.1 INTRODUCTION

The present chapter describes the synthesis of novel diaryl urea

derivatives obtained from aryl amine 1 and aryl isocyanates 2. The

synthesized compounds are analogues of sorafenib [4-{4-[({4-chloro-3-

(trifluromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-

2-carboxamide] .

In the contemporary literature on these functionalized aryl ureas,

phenoxy pyridyl moiety in the final compounds has been modified by

introducing different substituents and chloro-trifluoromethyl phenyl

moiety remains the same. In our strategy, we designed different types of

aryl urea derivatives 3 by replacing chloro and CF3 groups with other

functional variants and synthesized new analogues. The synthetic

scheme for novel analogues of sorafenib is discussed under “Results &

Discussion” (Scheme 2.1).

R1
R1 O CONHCH3
O CONHCH3 O
Acetone, rt N
N + N N
H 2N R2 H H
NCO
R2

(1) (2) (3)

Scheme 2.1
 22

2.2 LITERATURE SURVEY

Due to the important biological activities [74] of substituted ureas,

they are much attracted by researchers. In 1773 the French chemist

H.Rouelle discovered urea in human urine. Urea was synthesized by the

German chemist Friedrich Wohler in 1828 and was the first organic

compound to be synthesized from inorganic starting materials ie..

treating silver isocyanate (AgNCO) with ammonium chloride (NH4Cl). In

1870, urea was produced by heating ammonium carbamate in a sealed

vessel. This was the first time an organic compound was synthesized in

the laboratory from inorganic starting materials, without the involvement

of living organisms. The result of this experiment implicitly discredited

vitalism; the theory that the chemicals of living organisms are

fundamentally different from inanimate matter. This insight was

important for the development of organic chemistry. Wohler is

considered by many as The father of modern organic chemistry.

In 1922, the first process was developed for manufacture of urea

by Bosch-Meiser by heating under pressure the mixture of the two gases,

carbon dioxide (CO2) and ammonia (NH3) in about required proportions.

Urea and its derivatives have attracted attention of the chemists

for a long time because of their use in syntheses and useful biological

activities. Some of the substituted ureas having biological activity are

shown below in Table 2.1.

 23

Table 2.1

S.No Compound structure IUPAC name Common name Activity

H3C
Br H H N-[(acetylamino)carbonyl]-2-
1. H 3C N N CH3 Acecarbromal Sedative, hypnotic.
bromo-2-ethylbutanamide.
O O O

O O
O
S N-Acetyl-N-[(cyclohexyl amino)
N N
2. H H Acetohexamide Antidiabetic.
H3C
carbonyl]benzenesulfonamide.
O

CH3

H H N-[(Acetylamino)carbonyl]-α-
3. N N CH3 Acetylpheneturide Anticonvulsant.
ethyl benzeneacetamide.
O O O

H
H2N N N O OH [(2,5-Dioxo-4-imidazolidinyl)-
Al
4. Aldioxa Antiulcerative.
O N OH
H ureato]dihydroxyaluminum.
O

N N
O
N, N’-Bis(4-amino-2-methyl-6-
5. N N Aminoquinuride. Antiseptic.
H H quinolinyl)urea.
NH2 NH2
 24

O
Cl Cl
6. N N N,N’-Bis(2-chloroethyl)-N-nitroso Carmustine Antineoplastic.
H
N
O urea.

Cl N-[[(4-chlorophenyl)amino]
F O O

7. N N carbonyl]-2,6- Diflubenzuron Insecticide.

H H
F difluorobenzamide.

F Cl N-[[[2,5-Dichloro-4-(1,1,2,3,3,3-
O O O F
CF3 hexafluoropropoxy) phenyl]
8. F F Lufenuron Ectoparasiticide.
N N amino] carbonyl] -2,6-
H H
Cl F
diflurobenzamide.

H H
O 2N S N N CH3
9. N-Ethyl-N’-(5-nitro-2-thiazolyl) Nithiazide Antiprotozoal
N O
urea.

NO2
O
10. N N N N-(4-Nitrophenyl)-N’-(3-pyridinyl Pyriminil Rodenticide.
H H
methyl)urea.
 25

2-(4-chlorophenoxy)-2-methyl-N-
O O
11. O [[(4-morpholinylmethyl)amino] Plafibride Antithrombotic
N N N
H H
H3C CH3 O carbonyl]propanamide.
Cl

O O O
S 4’-(carbomoylsulfamoyl)-N-
O N N OH
H H
12. (hydroxylmethyl)phthalanilic Sulfaloxic Acid Anti bacterial.
N
H
acid.
COOH

H H (±)-N-Cyclohexyl-N’-[4-[3-[(1,1-
N N
Antihypertensive,
13. (H3C)3C O dimethylethyl)amino]-2-hydroxy Talinolol.
N O Antiarrhythmic.
H
OH propoxy] phenyl]urea.

[4-{4-[({4-chloro-3-(trifluro meth

CF3 yl) phenyl]amino} carbonyl)

14 Cl O CONHCH3 Sorafenib Antineoplastic
O
amino]phenoxy}-N-
N
N N
H H
methylpyridine-2-carbox amide]
 26

These observations and our continued interest in the synthesis of anti

neoplastic compounds prompted us to prepare various urea derivatives

as sorafenib analogues.

General preparations of isocyanates:

Richter and Ulrich [75] reported that the reaction of primary

amines 4 with phosgene (5) leads to chloroformamides 6 which on

heating above 500C eliminate HCl to give isocyanates (7). This useful

reaction constitutes a general method for isocyanate synthesis (Scheme

2.2).

-HCl -HCl
RNH2 + COCl2 RNHCOCl RN=C=O
2

(4) (5) (6) (7)

Scheme 2.2

Cotarca et al [76] (Scheme 2.3) reported that triphosgene (8) reacts with

primary alkyl-and arylamines or their salts to yield

trichloromethylcarbamates 9, which can readily form isocyanates 7. The

existence of trichloromethylcarbamate (9) intermediate as the isocyanate

precursor, analogoues to carbamoyl chloride in the classical

phosgenation, has been suggested by kinetic and mechanistic studies.

 27

-HCl
R-NH2 + Cl3CO-CO-OCCl3 R-NH-CO-OCCl3 RN=C=O

(4) (8) (9) (7)

Scheme 2.3

Staab and his co workers [77] (Scheme 2.4) reported that primary

imidazole-N-carboxamides (11) are obtained from primary amines (4)

and carbonyl diimidazole (10) are dissociated into isocyanates (7) and

imidazole (12), even at room temperature. This dissociation forms the

basis for a simple method of preparing isocyanates from aliphatic,

alicyclic and aromatic amines.

O O
20oC, N N
R-NH2 + N N N N RHN N + RN=C=O +
THF N N
N
H H

(4) (10) (11) (12) (7) (12)

Scheme 2.4

According to Stern and Spector [78] (Scheme 2.5), primary aliphatic or

aromatic amines react with carbon monoxide in the presence of PdCl2.

The reaction proceeds readily under mild conditions and is accompanied

by reduction of PdCl2 to palladium metal.

 28

RNH2 + CO + PdCl2 RN=C=O + Pd + 2HCl

(4) (7)

Scheme 2.5

Carbonylation of aromatic nitroso compounds 13 were reported by

Unverferth et al [79] (Scheme 2.6) by using rhodium and iridium

carbonyls.

RNO2 + 2CO RN=C=O + CO2

(13) (7)
Scheme 2.6

General prepartions of urea derivatives:-

The simplest and direct synthesis of substituted ureas is described

by Shriner et al [80] (Scheme 2.7).

O RNH2 O
RNCO
X X' -HX RHN X' -HX'

(14) (15) (7)

R'NH2 R'NH2
O

RHN NR'H

(16)

Scheme 2.7
 29

The process essentially involves two steps; (i) reaction of the selected

amine with the reagent 14 containing the carbonyl group to form the

intermediate 15 still possessing a leaving group linked to the cabonyl; (ii)

further reaction of the intermediate 15 with the same amine or with a

different amine to form the symmetrical or the unsymmetrical

substituted urea 16 directly or through the more reactive isocyanate 7.

Izdebski and Pawlak [81] reported that bis (4-nitrophenyl) carbonate

(17), a very stable reagent can be converted into carbamates (18) (44-

78% yield) by reaction with equimolecular amounts of primary aliphatic

or aromatic amines within 2h in dichloromethane. The carbamate

intermediates 18 react further with different primary amines giving rise

to the unsymmetrical ureas 16 in good yields (scheme 2.8). The second

step is considerably slower than the first and requires a longer reaction

time of ca. 4h necessitating reacting 17 with an excess of amine (1:2

ratio).

H
O O RNH2 R'NH2
N O O
R
O
O2N NO2 O RHN NR'H
NO2

(17) (18) (16)

Scheme 2.8

One application is reported by Lamothe et al [82] (Scheme 2.9) for di-

tert-butyldicarbonate (19) [(BOC)2O], a well-known reagent utilised for

protecting the amino group giving N-BOC-primary amines (20) with high
 30

yield and selectivity. The reagent 20 can be converted into

unsymmetrically substituted ureas 16 by reaction with a second amine.

The reaction requires the use of strong bases such as alkyllithiums,

which convert 20 into the isocyanate 7 capable of undergoing fast

addition of a second amine affording the final unsymmetrical urea 16.

O O
O RNH2 BuLi
R N OBu' R N OBu'
Bu'O OBu'
H Li

(19) (20) (21)

-Bu'OLi
O
R R'NH2
R' RNCO
N N
H H

(16) (7)

Scheme 2.9

Batey et. al [83] (Scheme 2.10) reported that N,Nl-carbonyldiimidazole

(22) (CDI) is utilized as starting reagent for the general synthesis of

unsymmetrical tetra substituted ureas. The intermediate carbonyl

imidazole 23 is first obtained by reaction of CDI with a secondary amine.

Compound 23 is successively converted into the more reactive and

resonance-stabilized imidazolinium salt 24 by N-alkylation of the

imidazole moiety. Addition of a different secondary amine to 24 furnishes

N, N, N', N'-unsymmetrical tetrasubstituted ureas (25) in high yield

(Scheme 2.10).
 31

O O
O O
N N RR'NH R MeI
N N R R''R'''NH R R''
N N N N
N N R' N Et3N
R' N+ R' R'''
Me
I-

(22) (23) (24) (25)

Scheme 2.10

In a similar way Katritzky [84] (Scheme 2.11) and his co-workers

reported that N, N'-carbonyldibenzotriazole (26) can be utilized to

synthesise N, N, N', N'-unsymmetrical tetra substituted ureas (25) by

one-pot reaction with the first amine to produce the carbonyl

benzotriazole intermediate 27 that can react under more forceful

conditions with a second amine giving the final urea 25 in satisfactory to

good yield.

O O O
R''R'''NH R R''
RR'NH R N N
N N N N
N N R' N N R' R'''
N N

(26) (27) (25)

Scheme 2.11

Thavonekham [85] reported that disubstituted ureas 16 including some

chiral compounds are efficiently synthesized by reaction of amines with

carbamates 29, which in turn are prepared from phenyl chloroformate

(28) (Scheme 2.12)

 32

O O R'NH2 O
RNH2
Ph Ph
O Cl DMSO O NHR DMSO R'HN NHR

(28) (29) (16)

Scheme 2.12

The synthesis of N, N, N', N'-tetrasubstitutedureas 31 by

carbonylation of lithium amides 30 with carbon monoxide at

atmospheric pressure under mild conditions has been reported by

Nudelman et al [86] (Scheme 2.13) The advantages of this method are

the short reaction time and use of molecular oxygen as oxidant.

R' R' R' R' R'

R' O2
CO N N
N N Li N N
R R R R R
R Li
LiO OLi O
O

(30) (31)

Scheme 2.13

Nomura and his co-workers [87] (Scheme 2.14) reported that the

catalyst Ph3SbO/P4S10 utilised in the molar ratio amine/ Ph3SbO/P4S10

40/1.0/2.0 is highly effective for the carbonylation of both amines and

diamines giving linear and cyclic ureas at 80-150oC for 12h with CO2.

Monitoring the reaction by 13C NMR spectroscopy revealed that the

reaction course constitutes thiolation of the carbamic acid 32 to an

 33

intermediate antimony carbamate species followed by aminolosis of the

carbamothioic acid thus formed.

H H
CO2 RNH2 H H
RNH2 N OH N S NH2R Ph3SbO
R R N N
Ph3SbO/P4S10 R R
O O
O

(4) (32) (33)

Scheme 2.14

McGhee et al [88] (Scheme 2.15) reported that carbamate esters

34 could be synthesized by reaction of amines with carbon dioxide and

alkyl halides in the presence of bases.

H H H
CO2/base R'NH2
RNH2 N OR" N N
R"Cl R R R'
O O

(4) (34) (16)

Scheme 2.15

2.3 PRESENT WORK

The present chapter describes the design and preparation of a

series of aryl ureas as novel analogues of sorafenib and their

characterization aspects. The novel analogues of sorafenib of present

work consist of urea derivatives having functional variants in the aryl

fragment other than the phenoxy pyridyl moiety.

 34

The analogues of sorafenib [4-{4-[({4-chloro-3-(trifluoromethyl)

phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-

carboxamide] are designated as 3a - 3o and the synthetic scheme for the

preparation of these compounds is depicted in Scheme 2.1

The process consists of coupling of amine 1 and isocyanate 2 in

acetone medium at room temperature to afford the required product in

good yield and purity. The Physico-chemical properties of the synthesized

analogues of sorafenib are described in experimental section. The key

intermediates, isocyanates 2, were prepared from the reaction of

triphosgene (8) and appropriate amine 35 in methylene chloride at reflux

temperature (Scheme 2.16)

R1 R1
(8)

CH2Cl2, reflux
NH2 R2 NCO
R2

(35) (2)

Scheme2.16

Purity of isocyanates was estimated by HPLC via derivatization to

methyl carbamates due to the inherent instability of isocyanates. Yield

and purity of the synthesized isocyanates are given in experimental

section.
 35

The intermediate 4-(2-(N-methyl carbamoyl)-4-pyridyloxy) aniline

(1) has been prepared from the known process [89] in three steps from 2-

picolinicacid (36) as shown below (Scheme 2.17).

Cl
Cl
SOCl2 MeOH aq.CH3NH2

70-75oC 5-10oC
N CO2H N COOCH3
N COCl
.HCl
HCl

(36) (37)

Cl H2N OH (39) O CONHCH3

Potassium t-butoxide N
80-90oC, 2-3h H2N
N CONHCH3

(38) (1)

Scheme 2.17

2.4 DOCKING STUDIES

We proposed total fifteen analogs of sorafenib and these

compounds were screened by molecular docking using Computer-Aided

Drug Design (CADD) technique to design sorafenib analogues based on

structure based drug designing studies.

CADD is an existing and diverse discipline where different aspects

of applied and basic research merge and stimulate each other [90]. All

the world’s major pharmaceutical and biotechnology companies use

computational design tools. The growing number of chemical and

biological databases and an explosion in currently available software

tools are providing a much-improved basis for design of ligands and

inhibitors with desired specificity. The phrase Computer-Aided Drug

 36

Design implies that drug discovery lies in the hands of computational

scientists who are able to manipulate molecules on their computer

screens [91]. The drug discovery process is actually a complex and

interactive one, involving scientists from many disciplines working

together to provide many types of information.

To evaluate the docking study of above series of compounds by

CADD, we employed 1UWH from protein data bank (PDB) ID [92]. 1UWH

is the protein responsible for kinase inhibitors. The docking study of

novel analogues of sorafenib of current work was carried out along with

sorafenib as reference molecule.

Docking Studies of sorafenib Analogues

Computational Details

The Docking process was carried out by using Ligandfit program of

Discovery Studio2.1 [93]. Software validation was performed in ligandfit

using PDB protein 1UWH[94]. To ensure that the ligand orientation and

the position obtained from the docking studies were likely to represent

valid and reasonable binding modes of the inhibitors, docking

parameters had to be first validated for the crystal structure used PDB

ID –1UWH[94].

The ligand sorafenib found in the crystal structure, was extracted and

docked back to the corresponding binding pocket, to determine the

ability of Docking method to reproduce the orientation and position of

the inhibitor observed in the crystal structure.

 37

Molecular Docking

To gain better insight for interaction between various compounds

and target, Ligandfit program was employed to dock the designed list of

sorafenib analogues. Ligandfit program requires molecules in sd, mol or

mol2 format. All given structures were prepared by using Prepare Ligand

program. For each run, maximum of 20,000 Monte Carlo run was used

in the docking experiment. The distance for hydrogen bonding was set at

2.5 Å. All docking runs were performed by using PLP force field [95-96].

Details of docking study of the novel analogues of sorafenib of current

work are tabulated in the Table 2.2.

Scoring functions

The docked conformations were further scored using different

scoring functions available with Ligandfit. The LigandFit algorithm uses

an internal scoring function, DockScore, to select and return dissimilar

poses for each compound. DockScore is a simple force field based scoring

function, which estimates the energy of interaction by summing the

ligand/protein interaction energy and the internal energy of the ligand.

CFF force field was used to resolve the van der Waals parameters for

DockScore. The top DockScore pose was used for post docking scoring.

Scoring was performed using a set of scoring functions as implemented

in Ligandfit. These included LigScore1, LigScore2, PLP1, PLP2 and

DockScore available from the docking process [97]. The putative 3D

poses and score results were then stored as an SD file.

 38

Table 2.2 - Scoring table

Molecule PLP1 PLP2 DOCK Lig 2

Sorafenib 153.93 141.33 133.92 7.82

3a 134.61 130.2 124.22 7.62

3b 132.13 122.53 118.086 7.35

3c 110.74 105.75 116.221 6.99

3d 158.2 142.73 133.79 7.9

3e 132.5 123.04 122.54 7.44

3f 136.88 124.34 119.31 7.05

3g 140.07 128.01 130.25 7.63

3h 133.39 126.86 122.21 7.22

3I 131.92 123.15 121.993 7.23

3j 128.05 126.39 119.753 7.04

3k 128.42 122.3 119.49 6.72

3l 138.66 131.1 13.917 7.81

3m 136.56 129.39 125.889 7.78

3n 132.53 123.7 118.32 6.61

3o 140.25 128.78 125.58 7.61

Docking pictures

Super imposed structures of the docked molecules with reference

molecule are given below.

 39

Superimposed structure of 3 d (grey) with sorafenib (yellow)

H-bond interaction of 3d with B-Raf protein (PDB ID –1UWH)

Represented as green dots.

 40

Superimposed structure of 3m (grey) with Sorafenib (yellow)

H-bond interaction of 3m with B-Raf protein (PDB ID –1UWH)

represented as green dots.

 41

Superimposed structure of 3o(grey) with Sorafenib (yellow)

H-bond interaction of 3o with B-Raf protein (PDB ID –1UWH)

Novel analogues of sorafenib of present work are designated as 3 (a-o).

 42

Docking Results

According to docking studies which is based on binding affinity, H-

bond interaction and scoring value, it was revealed that out of fifteen

docked analogues four compounds 3d, 3g, 3m, and 3o are found to be

good fits in terms of the docking scores.

2.5 RESULTS AND DISCUSSION

The primary amine, 4-nitroaniline (35o, ie 35, R1=4-NO2, R2=H)

on reaction with triphosgene (Cl3CO-CO-OCCl3, 8) in dichloromethane at

reflux temperature gave 4-nitrophenyl isocyanate (2o, ie 2, R1=4-NO2,

R2=H), which is characterized on the basis of spectral data (Scheme

2.16). Thus, its IR (neat) (Fig. 2.1) showed a very sharp band of strong

intensity in the region 2262cm-1 assignable to –N=C=O stretching and

absence of amine (35) -NH2 peaks at the 3481 and 3360cm-1 indicating

the complete conversion of amine to isocyanate. Its 1H NMR (CDCl3

/TMS) (Fig. 2.2) showed signals at δ 7.24(d, J= 8.8, 2H aryl protons); δ

8.22 (d, J = 8.8, 2H aryl protons). The 13C NMR spectrum of 4-

nitrophenyl isocyanate (Fig. 2.3) exhibited that the aromatic carbon

atoms from δ 125.2 to 140 ppm. The isocyanate carbon resonates at

about δ145ppm. The mass spectrum (CI method) of this compound (2o)

has shown the molecular ion peak at 163.9 (Fig 2.4) as base peak. The

fragment ion at 136.84 shown the loss of neutral molecule, carbon

monoxide from the product.

 43

R1 R1
(8)

CH2Cl2, reflux
NH2 R2 NCO
R2

(35) (2)

Scheme 2.16

Entry R1 R2 Entry R1 R2

a 4-Br H i 2-Me 4-Me

b 2-Cl H j 2-Me 5-Me

c 2-Cl 6-Me k 2-Me 6-Me

d 4-Cl-3-CF3 6-NO2 l 3-Me 4-Me

e 4-F H m 3-Me 5-Me

f 4-F 2-NO2 n 3-NO2 H

g 3-CF3 H o 4-NO2 H

h 2-Me 3-Me

The above reaction was found to be a general one and has been

observed to be facile with a variety of arylamines 35 as tabulated above.

The structures of the isocyanate products 2, thus obtained were

confirmed on the basis of spectral and analytical data (Experimental

Section).

2-Picolinic acid (36) was reacted with thionyl chloride in toluene

medium at 70-75 ºC to obtain 4-chloropicolinyl chloride hydrochloride.

This acid chloride, when reacted in situ with methanol, afforded methyl

4-chloro-2-picolinate hydrochloride (37). The IR spectrum showed ester

 44

carbonyl peak at 1742 cm-1shifted from acid carbonyl peak at 1718 cm-1

and absence of O-H str peak at about 3100 cm-1. The compound 37 on

reaction with aqueous methylamine in toluene gave 4-chloro-N-methyl-2-

pyridine carboxamide (38). Its IR spectrum exhibited the amide carbonyl

peak at 1686 cm-1. 38 was reacted with 4-aminophenol (39) in DMF in

the presence of potassium t-butoxide at 80 ºC to afforded the ether

derivative, 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (1), which has

been characterized by its spectral data. Thus, its IR spectrum showed

amide carbonyl peak with sharp and strong intensity at1658 cm-1. Sharp

peak with medium intensity at 3337 cm-1 assignable to N-H str. Its 1H

NMR (DMSO) showed signals at δ 2.77(d, J=4.7, 3H) assignable to methyl

protons, δ 5.1 (s, 2H) assignable to NH2 protons. The aromatic protons

appeared in the aromatic region at about δ 8.0. Its Mass spectrum (ESI,

m/z) showed the [M+H]+ ion peak at 244 corresponding to the molecular

mass of 243 (Scheme 2.17).

Treatment of 1 with 2-Chloro-6-methylphenylisocyanate (2c) in

acetone medium for 3-4h at 40 ºC afforded the aryl urea derivative of

Sorafenib analog, 4-{4-[({2-Chloro-6-methyl}phenyl)amino}carbonyl)

amino]phenoxy}-N-methylpyridine-2-carboxamide (3c) (Scheme2.1),

which has been characterized on the basis of spectral and other

analytical data. The IR (KBr) spectrum (Fig. 2.5) of 3c showed sharp

peaks at 3403 cm-1 and at 3296 cm-1 corresponding two NH absorptions

of urea derivative. And showed amide C=O str band at 1687 cm-1. The
 45

urea carbonyl peak observed at 1646 cm-1. Its 1H NMR spectrum (CDCl3

/TMS) (Fig. 2.6) showed signal at δ 2.28(s, 3H, -NHCH3), at δ 2.79(s, 3H,

aryl CH3), δ 7.1-7.3 (complex m, 7H, two aryl and three pyridyl ring

protons), δ 7.6(d, J=8.88, 2H, aryl protons), δ 8.02 (s, 1H, D2O

exchangeable -NH-), δ 8.5 (d, J=5.6,1H, aryl proton), δ 8.8(d, 1H, J=4.8) δ

9.08(s, 1H, D2O exchangeable -NH-). Its 13C NMR (400MHZ, DMSO d6)

spectrum (Fig. 2.7) showed signals at δ 18.74(Ar-CH3), 26.22(-NH-CH3),

108.91, 114.15, 119.90, 120.00, 121.67, 127.05, 127.59, 129.32,

132.12, 134.02, 138.03, 138.85, 147.54, 150.60, 152.52, 153.09,

164.17(-N-CO-), 166.28(-N-CO-N-). Its Mass spectrum (ESI, m/z) (Fig.

2.8) showed the [M+H]+ ion peak at 411 corresponding to the molecular

mass of 410. Fig 2.9, Fig 2.10 showed HPLC chromatograms of 3c and

3d respectively.

R1 R1
O CONHCH3 O CONHCH3
O
+
Acetone, rt N
N
NCO H2N N N
R2 R2 H H

(2) (1) (3)

Scheme 2.1

The above reaction was found to be a general one and has been

found to lead to other derivatives of 3 [3a to 3o]. The structures of the

products 3, thus obtained were confirmed on the basis of spectral data

(Experimental Section).
 46

Scheme for the formation of isocyanates as given below:-

heating
Cl3CO-CO-OCCl3 3COCl2

(8) (5)

COCl2 + RNH2 RN=C=O + 2HCl

(5) (4) (7)

Possible mechanism for the formation of aryl urea derivatives as

given below:-

H H H
+
..
R N + R' N C O R N C O R N C O H

H H N R' N R'

H H
+
R N C O H R N C O

N R' N R'
H

O CONHCH3
R =
N
H 2N
 47

2.6 EXPERIMENTAL SECTION

37 [98]: To a stirred solution of thionylchloride (483g, 4.0mole) and DMF

(10ml) was added 36 (100g, 0.81mole) in lots at 40-45 ºC. The reaction

mass was maintained at 70-75 ºC for 16h. Excess thionyl chloride was

distilled off keeping the mass temperature at 75-80 ºC. Finally toluene

(2x200ml) was added and the mixture co-distilled to remove toluene

along with traces of thionyl chloride. The reaction mass was cooled and

added to pre cooled (0-5 ºC) mixture of toluene (100ml) and methanol

(39ml). The reaction mass was maintained at 0-10 ºC for 2h and filtered.

The solid mass was washed with toluene (100ml) and chilled (5-10 ºC)

acetone (250ml). The material was dried at 60-65 ºC for 1-2h to get the

methyl 4-chloro-2-picolinate hydrochloride (37, 121g) and directly used

for further work.

38: To a stirred solution of aq. methylamine (124.1g, 4.0mole) in toluene

(200ml) was added 37 (115g, 0.56mole) in lots below 5 ºC within 30-

45min. The reaction mass was maintained at 5-10 ºC for 2h. Aliquots

were followed by TLC. After completion of the reaction, the mixture was

allowed to cool to room temperature and extracted with toluene

(3x200ml). The toluene layer was washed with saturated sodium chloride

solution (5%, 2x200ml). Carbon treatment was given for the toluene

layer. Toluene was distilled off at 75-85 ºC using rotavapour to obtain the

residue of 38 (94.3g). This material was used for further work.

 48

1: To a stirred solution of 39 (38.4g, 0.35moles) in DMF (280ml) was

added potassium t-butoxide (41.4g, mole) in lots keeping the mass

temperature below 40 ºC under nitrogen atmosphere. The reaction was

maintained at 25-30 ºC for 2h. A solution of 38 (50.0g, 0.25mole)

obtained from the above reaction) in DMF (50ml) was added to the

reaction mass. Potassium carbonate (22.3g) and potassium iodide (2.5g)

were added in succession to the reaction mass. The reaction mass was

maintained at 80-90 ºC for 2-3h. Aliquots were followed by TLC. After

completion of the reaction by TLC, reaction mass was cooled to room

temperature. The reaction mass was poured into DM water (1.0L)

keeping the mass temperature 25-30 ºC. The product was extracted with

toluene (4x500ml) and the toluene layer was washed with 5% aq.sodium

hydroxide solution (2x400ml) until absence of 39 was indicated in the

toluene layer. Carbon treatment was given for toluene layer at 70-80 ºC.

The filtrate was concentrated under vacuum at 75-85ºC, the residue was

cooled to –5 to 5 ºC under stirring and maintained for 45-60min. The

reaction was filtered and washed the wet solid with chilled (0-5 ºC)

toluene (100ml). The wet material (59.5g) was dried in the oven at 60-65

ºC for 2h (till constant wt is obtained) to obtain the product 1 (57.5g). The

purity (HPLC) of this material was checked and used for further work.
 49

General procedure for the preparation of isocyanates (2):

To a stirred solution of the amine (35, 0.01mole) in

dichloromethane (50ml) was added 8 (0.005mole) in lots at 15-20 ºC. The

condenser was provided with cold water circulation during the addition

of 8, and carbon (1.0g) was added to the reaction mass. The reaction

mass was maintained at room temperature for 2h, raised to reflux and

maintained for 5-6h. Aliquots were followed by IR for confirmation of

isocyanate formation by observing the peak at 2250-2275 cm-1 and

absence of characteristic peak of primary amine at about 3200 cm-1.

After completion of the reaction by IR, the reaction mass was cooled and

filtered. Then filtrate was concentrated under reduced pressure. Finally,

the residual mass was azeotroped with toluene (3x10ml) under vacuum

to remove the traces of 8. The obtained crude aryl isocyanate 2 was

dissolved in acetone and taken to next step.

2a). (i.e., 2, R1 = 4-Br, R2 = H). Yield 1.7g (85%). Purity (HPLC): 95%. IR

(neat, cm-1): 2273 (–N=C=O vib), 1618, 1520, 1457, 1049, 736.

1H-NMR (400MHz, CDCl3) δ: 7.22 (d, J=10, 2H, Ar-H), δ: 7.76 (d, J=10.8,

2H, Ar-H).

2b). (i.e., 2, R1 = 2-Cl, R2 = H) yield1.33g (87%). Purity (HPLC): 93%. IR

(neat, cm-1): 2257 (–N=C=O vib), 1646, 1591, 1517, 1450, 1053, 751.

1H-NMR (400MHz, CDCl3) δ: 7.29-7.53 (complex m, 4H, Ar-H)

 50

2c). (i.e., 2, R1 = 2-Cl, R2 = 6-Me) Yield 1.67g(91%.) Purity (HPLC): 97%.

IR (neat, cm-1): 2270 (–N=C=O vib), 1601, 1519, 1470, 1047, 764.

1H-NMR (400MHz, CDCl3) δ: 2.34 (s, 3H, -CH3), 7.19-7.55 (complex m,

3H, Ar-H)

2d). (i.e., 2, R1 = 4-Cl-3-CF3, R2 = 6-nitro) Yield 1.82g (68%). Purity

(HPLC): 89%. IR (neat, cm-1): 2274 (–N=C=O vib), 1625, 1577, 1527,

1369, 1345, 1304, 1263, 1152, 909, 827, 761.

1H-NMR (400MHz, CDCl3) δ: 7.92(s, 1H, Ar-H), 8.23 (d, J=9.6 Ar-H).

2e). (i.e., 2, R1= 4-F, R2 = H) Yield 1.25g (92%). Purity (HPLC): 91%. IR

(neat, cm-1): 2280(–N=C=O vib), 1735, 1522, 1231, 1151, 1094, 1014,

834.

1H-NMR (400MHz, CDCl3) δ: 7.29-7.36 (complex m, 4H, Ar-H).

2f) (i.e., 2, R1= 4-F, R2 = 2-NO2) Yield 1.82g (86%). Purity (HPLC): 93%.

IR (neat, cm-1): 3472, 3356, 3096, 2267 (–N=C=O vib), 1730, 1543, 1342,

1132, 944, 879, 814, 731, 565.

1H-NMR (400MHz, CDCl3) δ: 7.62-8.23 (complex m, 3H, Ar-H).

2g). (i.e., 2, R1 = 3-CF3, R2 = H) Yield 1.74g(94%). Purity (HPLC): 92%.

IR (neat, cm-1): 2270(–N=C=O vib), 1617, 1596, 1325, 1179, 1134, 1067,

944, 820, 696, 525.

 51

1H-NMR (400MHz, CDCl3) δ: 7.27-7.29(complex m, 1H, Ar-H), 7.35 (bs.

1H, Ar-H), 7.46 (d, J=4.8, 2H, Ar-H), MS (ES): 186 [M-1]

13C-NMR: δ 121.6, 122.48, 124.73, 125.23, 128.03, 130.16, 132.2,

134.28.

MS (CI): m/z 186 [M-H]+.

2h). (i.e., 2, R1 = 2-Me, R2 = 3-Me) Yield1.37g (93%). Purity (HPLC): 97%.

IR (neat, cm-1): 2272 (–N=C=O vib), 1705, 1499, 1086, 864, 776, 566.

1H-NMR (400MHz, CDCl3) δ: 2.37(s, 6H, 2x CH3), 6.9 (d, J=8.4, 1H, Ar-

H), 7.21-7.34 (m, 2H, Ar-H).

2i). (i.e., 2, R1 = 2-Me, R2 = 4-Me) Yield1.35g (92%). Purity (HPLC): 98%.

IR (neat, cm-1): 2278 (–N=C=O vib), 1756, 1521, 1080, 814, 562.

1H-NMR (400MHz, CDCl3) δ: 2.34 (s, 6H, 2x CH3), 6.93 (d, J=8.8, 1H, Ar-

H), 7.02 -7.18 (m, 2H, Ar-H).

2j). (i.e., 2, R1 = 2-Me, R2 = 5-Me) Yield1.33g (91%). Purity (HPLC): 97%.

IR (neat, cm-1): 2922, 2273(–N=C=O vib), 1617, 1518, 1079, 810, 559.

1H-NMR (400MHz, CDCl3) δ: 2.28 (d, J=2.8, 6H, 2x CH3), 6.88-7.25

(complex, m, 3H, Ar-H). 13C-NMR: δ 17.57, 20.47, 125.39, 126.45,

128.09, 128.90, 129.47, 131.93, 136.62; MS (ES); MS (CI): m/z 147(M)+.

 52

2k). (i.e., 2, R1 = 2-Me, R2 = 6-Me) Yield 1.4g (95%). Purity (HPLC): 99%.

IR (neat, cm-1): 2919, 2275(–N=C=O vib), 1609, 1510, 845, 571.

1H-NMR (400MHz, CDCl3) δ: 2.36 (s, 6H, 2x CH3), 7.04-7.43 (complex m,

3H, Ar-H).

2l). (i.e., 2, R1 = 3-Me, R2 = 4-Me) Yield 1.38g(94%). Purity (HPLC): 94%.

IR (neat, cm-1): 2918, 2269(–N=C=O vib), 1607, 899, 839, 567. 7.08-7.26

(m, 3H, Ar-H).

1H-NMR (400MHz, CDCl3) δ: 2.28(s, 6H, 2x CH3), 6.7 (s, 2H, Ar-H), 7.41

(s, 1H, Ar-H).

2m). (i.e., 2, R1= 3-Me, R2 = 5-Me) Yield 1.32g (90%). Purity (HPLC):

92%.

IR (neat, cm-1): 2921, 2266(–N=C=O vib), 1609, 900, 843, 682, 551.

1H-NMR (400MHz, CDCl3) δ: 2.32 (s, 6H, 2x CH3), 6.9 (s, 2H, Ar-H), 7.16

(bs, 1H, Ar-H).

2n). (i.e., 2, R1 = 3-NO2, R2 = H)Yield 1.44g (88%). Purity (HPLC): 89%.

IR (neat, cm-1): 2269 (–N=C=O vib), 1594, 1515, 1340, 847, 753.

1H-NMR (400MHz, CDCl3) δ: 7.42-8.0 (complex m, 4H, Ar-H).

2o). (i.e., 2, R1 = 3-NO2, R2 = H) Yield 1.32g (79%). Purity (HPLC): 96%.

IR (neat, cm-1): 2262 (–N=C=O vib), 1596, 1518, 1344, 855, 749.

1H-NMR (400MHz, CDCl3) δ: 6.93 (d, J=10.8, 2H, Ar-H), 8.14 (d, J=10.4,

2H, Ar-H)
 53

General procedure for the preparation of urea derivative (3):

To a stirred solution of 1 (0.01mole) in acetone (50ml) was added 2

(0.01mole) in acetone (10ml) keeping the temperature below 40 ºC. The

reaction mass was maitained at room temperature for 3-4 h followed by

TLC. After completion of reaction the product was filtered from the

reaction mass, washed with acetone (5ml) and dried at 60-65 ºC for 2h to

obtain crude 3.

3a). (i.e., 3, R1 = 4-Br, R2 = H). Yield 4.14g (94%). Pure 3a (Acetone).

M.F: C20H17BrN4O3; Purity (HPLC): 97.5%; m.p: 229.6 ºC. HCl salt : 192.6

ºC; PTs salt :145.2 ºC.

IR (KBr, cm-1): 3391, 3256, 1677, 1654, 15931545, 1538, 1504, 1487,

1463, 1406, 1391, 1296, 1222, 1199, 1073, 993, 928, 828, 785, 766,

556, 505.

1H-NMR (400MHz, DMSO d6) δ: 8.91(s, 2H), 8.79 (d, J=4.8 1H), 8.51(d,

J=5.6 1H), 7.58 (d, J=8.8 2H), 7.46 (s, 4H), 7.38 (d, J=2.4 1H), 7.18 (m,

3H); 2.80 (d, 3H).

13C NMR (DMSO d6) δ (ppm): 26.04, 108.72, 113.31, 113.96, 120.11,

120.18, 121.47, 131.53, 137.42, 139.12, 147.56, 150.29, 152.40,

152.47, 1638, 166.04;

MS (CI): m/z 443.4 [M+2H]+.

 54

3b). (i.e., 3, R1 = 2-Cl, R2 = H) yield 3.83g (97%). Pure 3b (Acetone).

Purity (HPLC): 99.2%; M.F: C20H17ClN4O3; m.p: 213.8 ºC. HCl salt: 150.0

ºC; PTs salt: 146.5 ºC.

IR (KBr, cm-1): 3296, 1687, 1646, 1591, 1560, 1530, 1505, 1471, 1441,

1407, 1297, 1222, 922, 847, 739.

1H-NMR (400MHz, CDCl3) δ: 8.55 (s, 1H, exch with D2O); 8.42 (d, J=5.6

1H), 8.26-8.28 (dd, 2H), 7.66(d, J=19.6 2H), 7.45 (d, J=9.2 2H), 7.25-

7.32 (m, 2H), 7.07- 7.09 (q, 1H), 6.99 (d, J=8.8 3H). 3.05 (s, 3H);

13C NMR (DMSO d6) δ (ppm): 26.40, 109.09, 114.71, 121.14, 121.62,

122.84, 123.35, 127.44, 128.98, 135.60, 136.90, 148.30, 149.73,

151.40, 152.86, 165.16, 166.81;

MS (CI): m/z 397.5 [M+H]+.

Elemental analysis: C H N O

Found 60.69 4.32 14.14 12.23

Cal 60.60 4.29 14.14 12.12

3c). (i.e., 3, R1 = 2-Cl, R2 = 6-Me) Yield 3.56g (87%). Pure 3c (Acetone).

Purity (HPLC): 99.6%; M.F: C21H19ClN4O3; m.p: 184.6 ºC. HCl salt: 153.9

ºC; PTs salt: not formed.

IR (KBr, cm-1): 3264, 3244, 1642, 1593, 1505, 1469, 1409, 1239.5,

1203.5, 928.5, 773, 667.2.

1H-NMR (400MHz, DMSO d6) δ: 9.09 (s, 2H, exch with D2O), 8.79 (s, 1H),

8.02 (s, 1H, exch with D2O), 7.59(d, J=8.8 2H), 7.38 (d, J=2.4 1H) 7.35 (s,

1H), 7.13-7.26 (m, 5H), 2.78 (d, J=4.8 3H), 2.28 (s, 3H);
 55

13C NMR (DMSO d6) δ (ppm): 18.74, 26.22, 108.91, 114.15, 119.90,

120.00, 121.67, 127.05, 127.59, 129.32, 132.12, 134.02, 138.03,

138.85, 147.54, 150.60, 152.52, 153.09, 164.17, 166.28.

MS (CI): m/z 411.16 [M+H]+

Elemental analysis: C H N O

Found 61.48 4.65 13.71 12.0

Cal 61.46 4.63 13.65 11.7

3d). (i.e., 3, R1 = 4-Cl-3-CF3, R2 = 6-NO2) Yield 4.6g (91%). Pure 3d

(Acetone). Purity (HPLC): 99.6%; M.F: C21H15ClF3N5O5; m.p: 208.4 ºC.

HCl salt: 213.8 ºC; PTs salt: 216.2 ºC.

IR (KBr, cm-1): 3371, 3303, 3077, 1714, 1654, 1558, 1489, 1448, 1411,

1302, 1175, 1148, 1033, 922, 907, 836, 735, 714, 672, 610, 510, 459.

1H-NMR (400MHz, DMSO d6) δ: 10.20(s, 1H), 9.79(s, 1H), 8.92(s, 1H),

8.79(d, J=4.8 1H), 8.51(d, J=5.6 1H), 8.41(s, 1H), 7.62(d, J=8.8 2H), 7.38

(d, J=2.8 1H), 7.15-7.22(dd, 3H), 2.78 (d, J=4.8 3H);

13C NMR (DMSO d6) δ (ppm): 25.97, 108.77, 114.01, 120.65, 121.52,

121.81, 121.87, 122.10, 123.24, 128.06, 130.53, 130.84, 131.15,

131.46, 134.12, 136.52, 139.10, 148.31, 150.36, 151.62, 152.46,

163.76, 165.85.

MS (CI): m/z 510.6 [M+1]+

3e). (i.e., 3, R1 = 4-F, R2 = H) Yield 3.53g(93%). Pure 3e (Acetone). Purity

(HPLC): 93.4%; M.F: C20H17FN4O3; m.p: 221.5 ºC. HCl salt: 233.7 ºC; PTs

salt: 141.0 ºC
 56

IR (KBr, cm-1): 3395, 3328, 3270, 1672, 1600, 1557, 1504, 1466, 1410,

1298, 1228, 1202, 931, 860, 835, 600, 556, and 511.

1H-NMR (400MHz, DMSO d6) δ: 8.84 (s, 1H), 8.77 (bs, 2H), 8.50 (d,

J=5.6 1H), 7.57 (d, J=8.8 2H), 7.45-7.48 (q, 2H), 7.37 (d, J=2.8 1H), 7.13-

7.17 (m, 5H), 2.78 (d, J=4.8 3H);

13C NMR (DMSO d6) δ (ppm): 26.01, 108.70, 113.96, 115.18, 115.40,

120.02, 120.09, 121.45, 135.98, 137.59, 147.46, 150.31, 152.40,

152.70, 156.22, 158.58, 163.81, 166.06; MS (CI): m/z 381.5 [M+H]+.

Elemental analysis: C H N O

Found 63.19 4.47 14.72 12.61

Cal 63.15 4.47 14.7 12.63

3f) (i.e., 3, R1 = 4-F, R2 = 2-NO2) Yield 4.1g(96%). Pure 3f (Acetone).

Purity (HPLC): 97.8%; M.F: C20H16FN5O5; m.p: 226.6 ºC. HCl salt: 209.3

ºC; PTs salt: 215.5 ºC

IR (KBr, cm-1): 3330, 3092, 1709, 1660, 1557, 1500, 1453, 1409, 1340,

1296, 1186, 1133, 942, 922, 850.

1H-NMR (400MHz,DMSO d6) δ: 9.96 (s, 1H), 9.53 (s, 1H), 8.80 (d, J=4.8

1H), 8.51(d, J=5.2 1H), 8.25-8.29 (q, 1H), 7.98-8.01(q, 1H), 7.60-7.70 (m,

3H), 7.38 (d, J=2.4 1H); 7.152-7.21 (m, 3H), 2.79 (s, 3H);

13C NMR (DMSO d6) δ (ppm): 26.19, 109.03, 111.96, 112.23, 114.25,

120.69, 121.76, 122.56, 122.78, 125.18, 125.26, 131.55, 137.19,

138.31, 138.39, 148.24, 150.68, 152.26, 152.52, 154.95, 157.37,

164.14, 164.21, 166.17.

 57

MS (CI): m/z 426.2 [M+H]+

3g). (i.e., 3, R1 = 3-CF3, R2 = H) Yield3.51g (82%). Pure 3g (Acetone).

Purity (HPLC): 99.1%; M.F: C21H17F3N4O3; m.p: 187.6 ºC. HCl salt: 179.9

ºC; PTs salt: 212.5 ºC.

IR (KBr, cm-1): 3358, 3090, 1708, 1654, 1568, 1541, 1505, 1465, 1407,

1338, 1300, 1228, 1195, 1170, 1126, 1096, 1072, 993, 926, 879, 846,

786, 702, 661, 564, 510, 487.

1H-NMR (400MHz,CDCl3) δ: 8.46 (d, J=5.2 1H), 8.36 (d, J=5.2 1H),

8.33(s, 1H), 8.11(s, 1H), 7.70 (s, 1H) 7.65 (d, J=8 1H), 7.56 (d, J=2.4 1H),

7.36 (d, J=8.8 3H), 7.24 (s, 1H), 7.15-7.17 (q, 1H), 6.98 (d, J=8.8 2H),

3.05 (s, 3H);

13C NMR (DMSO d6) δ (ppm): 25.66, 109.41, 113.42, 114.64, 118.13,

120.18, 120.90, 121.11, 122.31, 125.01, 128.87, 130.36, 130.68,

136.55, 139.76, 148.00, 149.27, 152.52, 164.16, 166.11.

MS (CI): m/z 431.6 [M+H]+.

Elemental analysis: C H N O

Found 58.63 4.00 13.15 11.21

Cal 58.60 3.95 13.02 11.16

3h). (i.e., 39, R1 = 2-Me, R2 = 3-Me) Yield 3.78(97%). Pure 3h (Acetone).

Purity (HPLC): 99.3%; M.F: C22H22N4O3; m.p: 194.1 ºC. HCl salt: 162.9

ºC; PTs salt: 185.6 ºC.

IR (KBr, cm-1): 3412, 3284, 1681, 1643, 1604, 1567, 1534, 1506, 1466,

1406, 1295, 1230, 1200, 1099, 925, 856, 686, 593, 546, 509.
 58

1H-NMR (400MHz,DMSO d6) δ: 9.11(s, 1H, exch with D2O), 8.76-8.79 (q,

1H), 8.50 (d, J=5.6 1H), 8.01(s, 1H), 7.52-7.60(dd, 3H), 7.39 (d, J=2.4

1H), 7.13-7.16 (m, 3H), 7.02-7.06 (t, 1H), 6.91(d, J=7.6 1H), 2.79 (d,

J=4.8 3H), 2.26 (s, 3H), 2.15(s, 3H);

13C NMR (DMSO d6) δ (ppm): 13.64, 20.33, 26.01, 108.72, 113.93,

119.64, 120.55, 121.45, 125.02, 125.24, 127.67, 136.59, 136.90,

137.97, 147.19, 150.21, 152.29, 152.98, 163.72, 166.17.

MS (CI): m/z 391.6 [M+H]+.

3i). (i.e., 39, R1= 2-Me, R2 = 4-Me) Yield 3.82g (98%). Pure 3i (Acetone).

Purity (HPLC): 94.3%; M.F: C22H22N4O3; m.p: 181.5 ºC. HCl salt: 216.2

ºC; PTs salt: 177.6 ºC.

IR (KBr, cm-1): 3288, 1686, 1646, 1601, 1557, 1505, 1467, 1297, 1197,

928, 829, 784, 691, 545, 510.

1H-NMR (400MHz,DMSO d6) δ: 9.13 (s, 1H), 8.77-8.8 (q, 1H), 8.50(d,

J=5.6 1H), 7.91 (s, 1H), 7.57-7.65 (dd, 3H), 7.39 (d, J=2.8 1H), 7.15 (d,

J=8.8 3H), 6.70 (s, 1H), 6.95-6.97 (d, J=8.4 1H), 2.79 (d, J=4.8 3H), 2.23

(s, 3H), 2.21(s, 3H).

13C NMR (DMSO d6) δ (ppm): 17.84, 20.33, 26.02, 108.81, 113.95,

119.63, 121.44, 121.67, 126.59, 128.07, 130.73, 131.81, 134.67,

137.96, 147.19, 150.13, 152.17, 152.86, 163.65, 166.25;

MS (CI): m/z 391 [M+H]+.

 59

3j). (i.e., 39, R1 = 2-Me, R2 = 5-Me) Yield 3.66g (94%). Pure 3j (Acetone).

Purity (HPLC): 98.7; M.F: C22H22N4O3; m.p: 186.4 ºC. HCl salt: 154.9 ºC;

PTs salt: 193.8 ºC.

IR (KBr, cm-1): 3298, 1640, 1555, 1537, 1505, 1406, 1288, 1227, 1196,

996, 922, 833, 799, 668, 563.

1H-NMR (400MHz, DMSO d6) δ: 9.16 (s, 1H, exch with D2O), 8.78 (d,

J=4.8 1H), 8.51(d, J=5.6 1H), 7.90 (s, 1H), 7.67 (s, 1H), 7.59 (d, J=9.2

2H), 7.38 (d, J=2.8 1H), 7.16(d, J= 8.8 3H), 7.05(d, J=2 1H), 6.78(d,

J=7.2 1H), 2.79 (d, J=4.8 3H), 2.23 (d, J=20.8 6H);

13C NMR (DMSO d6) δ (ppm): 17.44, 20.89, 25.98, 30.61, 108.73, 113.93,

119.71, 121.42, 121.86, 123.48, 124.61, 129.98, 135.10, 137.09,

137.82, 147.36, 150.30, 152.45, 152.72, 163.84, 166.06;

MS (CI): m/z 391 [M+H]+.

3k). (i.e., 3, R1 = 2-Me, R2 = 6-Me) Yield 3.74g (96%). Pure 3k (Acetone).

Purity (HPLC): 99.5%; M.F: C22H22N4O3; m.p: 220.7 ºC. HCl salt: 197.5 ºC;

PTs salt: not formed.

IR (KBr, cm-1): 3310, 2918,1673, 1641, 1590,1557, 1503, 1468, 1405,

1295, 1259, 1227,1199,1147.9, 921.8, 831, 768, 701.7, 563.5, 482

1H-NMR (400MHz,DMSO d6) δ: 8.93 (s, 1H), 8.79 (d, J=8.8 1H), 8.49 (d,

J=5.6 1H), 7.77 (s, 1H), 7.58 (d, J=9.2 2H), 7.37 (d, J=2.4 1H), 7.12-7.14

(m, 3H), 7.07 (s, 3H), 2.78 (d, J=4.8 3H), 2.22 (s, 6H);
 60

13C NMR (DMSO d6) δ (ppm): 18.43, 26.21, 108.87, 114.14, 119.88,

121.62, 126.32, 127.97, 135.35, 135.86, 138.37, 147.31, 150.59,

152.51, 153.47, 164.18, 166.32;

MS (CI): m/z 391 [M+H]+.

3l). (i.e., 3, R1= 3-Me, R2 = 4-Me) Yield 3.7g (95%). Pure 3l (Acetone).

Purity (HPLC): 95.6%; M.F: C22H22N4O3; m.p: 190.9 ºC. HCl salt: 199.6 ºC;

PTs salt: not formed.

IR (KBr, cm-1): 3317.2, 1673.5, 1642.3, 1591.2, 1556.7, 1503.6, 1405.5,

1295.4, 1227.3, 1199.5, 921.7, 768.

1H-NMR (400MHz,DMSO d6) δ: 8.81 (bs, 2H), 8.55 (s, 1H), 8.51 (d,

J=16.8 1H), 7.58 (d, J=7.5 2H), 7.38 (d, J=2.4 1H), 7.24 (bs, 1H), 7.14-

7.20 (m, 4H), 7.03 (d, J=8 1H) 2.79 (d, J=4.8 3H), 2.17 (d, J=14.8 6H);

13C NMR (DMSO) δ (ppm): 18.96, 19.92, 26.22, 109.07, 114.29, 116.24,

120.01, 120.25, 121.76, 130.02, 130.12, 136.79, 137.35, 147.70,

150.69, 152.49, 152.89, 164.26, 166.41;

MS (CI): m/z 391 [M+H]+.

3m). (i.e., 3, R1 = 3-Me, R2 = 5-Me) Yield 3.74g (96%). Pure 3m (Acetone).

Purity (HPLC): 98.3%; M.F: C22H22N4O3; m.p: 212.1 ºC. HCl salt: 178.4 ºC;

PTs salt: 220.9 ºC

IR (KBr, cm-1): 3300, 1651, 1551, 1504, 1467, 1296, 1234, 1205, 922,

834, 686, 562.

 61

1H-NMR (400MHz, DMSO d6) δ: 8.78 (s, 2H), 8.55 (s, 1H), 8.5 (d, J=5.6

1H) 7.57 (d, J=8.8 2H), 7.38 (d, J=2.4 1H), 7.08-7.16 (m, 5H), 6.62 (s,

1H), 2.78 (d, J=4.8 3H), 2.23 (s, 6H);

13C NMR (DMSO) δ (ppm): 21.13, 26.00, 108.66, 113.96, 116.01, 119.85,

121.44, 123.53, 137.66, 137.73, 139.45, 147.35, 150.33, 152.41,

152.52, 163.78, 166.06;

MS (CI): m/z 391 [M+H]+.

3n). (i.e., 3, R1 = 3-NO2, R2 = H) Yield 3.5g (86%). Pure 3n (Acetone).

Purity (HPLC): 92.5%;

M.F: C20H17N5O5; m.p: 199.6 ºC. HCl salt: 194.7 ºC; PTs salt: 218.3 ºC

IR (KBr, cm-1): 3361, 1720, 1654, 1600, 1560, 1504, 1405, 1347, 1299,

1233, 1193, 1163, 931, 880, 833, 735, 672, 567, 511, 483.

1H-NMR (400MHz,DMSO d6) δ: 9.41 (s, 1H, exch with D2O), 9.13 (s, 1H,

exch with D2O), 8.83 (d, J=4.4 1H), 8.58 (s, 1H), 8.52 (d, J=5.6 1H), 7.84

(d, J=8.4 1H), 7.74 (d, J=8 1H), 7.58-7.63 (t, 3H), 7.41(s, 1H), 7.19(d,

J=9.2 3H), 2.79 (d, J= 4.4 3H);

13C NMR (DMSO d6) δ (ppm): 26.24, 109.29, 112.43, 114.36, 116.73,

120.74, 121.74, 124.58, 130.36, 137.26, 141.08, 148.10, 148.40,

150.37, 152.04, 152.69, 163.93, 166.61;

MS (CI): m/z 408 [M+H]+.

3o). (i.e., 3, R1 = 4-NO2, R2 = H) Yield 3.7g(91%). Pure 3o (Acetone).

Purity (HPLC): 97%;

M.F: C20H17N5O5; m.p: 242.2 ºC. HCl salt: 248.3 ºC; PTs salt: 233.5 ºC
 62

IR (KBr, cm-1): 3391.8, 3335.0, 3247.6, 1682, 1654, 1552.9, 1531.5,

1495.1, 1415.1, 1335.2, 1197.8, 1115.1, 857.3, 753.3.

1H-NMR (400MHz, DMSO d6) δ: 9.51 (s, 1H, exch with D2O), 9.09 (s, 1H,

exch with D2O), 8.78(d, J=4.4 1H), 8.51(d, J=5.6 1H), 8.21(d, J=9.2 2H),

7.71 (d, J =9.2 2H), 7.61 (d, J= 8.8 2H), 7.39 (d, J=2.4 1H), 7.15-7.21 (m,

3H), 2.79 (d, J=4.8 3H);

13C NMR (DMSO d6) δ (ppm): 26.04, 108.68, 114.05, 117.53, 120.50,

121.57, 125.19, 136.91, 141.04, 146.37, 147.96, 150.39, 152.05,

152.44, 163.81, 165.97.

MS (CI): m/z 408 [M+H]+.

Elemental analysis: C H N O

Found 67.70 5.61 14.32 12.31

Cal 67.69 5.64 14.35 12.30