A Facile Synthesis of 2-Amino-5-Cyano-4, 6-Disubstitutedpyrimidines under MWI

doi:10.4236/ijoc.2011.12009

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International Journal of Organic Chemistry, 2011, 1, 47-52

doi:10.4236/ijoc.2011.12009 Published Online June 2011 (http://www.SciRP.org/journal/ijoc)

A Facile Synthesis of 2-Amino-5-cyano-4,

6-disubstitutedpyrimidines under MWI

Kishor S. Jain*, Swapnil K. Chaudhari, Nikhil S. More, Kapil D. More, Sachin A. Wakedkar,

M. K. Kathiravan

P. G. Research Centre, Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Pune, India.

E-mail: [email protected]

Received May 21, 2011; revised June 20, 2011; accepted July 1, 2011

Abstract

Microwave Assisted Organic Synthesis (MAOS) is energy efficient and effective tool to speed up the syn-

thesis for drug discovery process. In the present study we report a novel protocol for the rapid, high

throughput synthesis of mononuclear 2-amino-5-cyano-4,6-disubstituted pyrimidines, adaptable to parallel

synthesis for compound libraries. The overall reaction time in hrs has been reduced to 25 - 50 minutes with

improved yields.

Keywords: Microwave Assisted Organic Synthesis (MAOS), 2-Amino-5-Cyano-2, 6-Disubstitutedpyrimidines,

α-Cyanoketene S,S-Acetals

1. Introduction

Mononuclear pyrimidines exhibit a wide range of me-

dicinal activities and are isomeric with two other forms

of diazine. Physiologically important nucleic acids bases

as well as some vitamins are pyrimidine derivatives [1,2].

The major approach to the synthesis of mononuclear

pyrimidines is the principal synthesis, involving the

condensation of N-C-N fragment with an appropriate

functionalized 3-carbon unit [3]. Various synthetic me-

thods and reaction conditions have been employed for

the synthesis of mononuclear pyrimidines in the litera-

ture [4-17].

The reported methods for the syntheses of mononu-

clear pyrimidines have one or the other limitations such

as more number of steps, use of carcinogenic reagents

like benzene, pyridine and lengthy reaction time. In

many syntheses volatile organic solvents are used, which

are detrimental to the environment and are to be recov-

ered.

The generalized method for the synthesis of mononu-

clear pyrimidines is by the cyclocondensation of α-

cyanoketene S,N-acetals with guanidine in DMF under

reflux for 24 - 36 hr. The α-cyanoketene S,N-acetals

were prepared through the nucleophilic displacement of

the 3-methylthio group of the corresponding α-cyanoke-

tene S,S-acetals with various amines [16].

Tominaga et al. [18] have further improved on the

synthesis of mononuclear pyrimidines by direct one pot

synthesis through Multi Component Reaction (MCR) of

α-Cyanoketenes S,S-acetals, appropriate amine and gua-

nidine carbonate (Scheme 1). The solvent employed was

pyridine and overall reaction time was 24 - 36 hr.

Microwave Assisted Organic Synthesis (MAOS) is an

invaluable technology for drug discovery applications as

it dramatically reduces reaction time, which makes it

ideal for rapid reaction scouting and optimization, al-

lowing rapid synthesis of large number of NCEs and

their libraries. It is an efficient synthetic tool and its

benefit has been well documented [19-22]. In continua-

tion to our ongoing work on green chemical techniques

[23], herein we report a novel, hitherto unreported pro-

tocol for the rapid synthesis of mononuclear 2-amino-5-

cyano-4,6-disubstituted-pyrimidines under MWI. (Mic-

rowave Irradiation)

2. Results and Discussion

The α-cyanoketene S,S-acetals such as di-(methylthio)

methylene malononitrile 1 and ethyl-2,2-di(methyl-

thio)methylene cyanoacetate 2 were prepared as per re-

ported method [16]. The α-cyanoketene S,S-acetals 1 and

2 were converted to corresponding S,N-acetals by reacting

with appropriate primary as well as secondary amine in

ethanol under microwave at 80 W (Scheme 2). Secondary

amine being more reactive underwent nucleophilic

K. S. JAIN ET AL.

CNNC

CS SCH

HN R

NNH

24-36 hrs

pyridine

= aryl and cycloalkyl amines.

HCO

HN R

Scheme 1. MCR of α-cyanoketenes S,S-acetals, amine and guanidine carbonate.

OCH

CNX

SMeMeS +CN

SMeN

1, X = CN

2, X = COO C

EtOH

1a-i, X = CN

2a-i, X = COOC

MWI, 80W

5-10 min

Scheme 2. Synthesis of α-cyanoketene S,N-acetals (1a-i, 2a-i)E.

SMeN

1a-i , X = CN

2a-i , X = COOC

DMF

3a-i , X = NH

4a-i , X = OH

MWI, 80W

25-50 minNC

NHH

Scheme 3. Synthesis of target compounds.

substitution with α-cyanoketene S,S-acetals in 5 minutes.

Also the amines possessing substitution like halogens as

well as electron donating groups such as methyl and

methoxy completed the displacement in shorter time (5

minutes) when compared with unsubstituted amine ow-

ing to its resonance effect.

There was not much difference in the reaction rate be-

tween the amines bearing substitution at meta and para

positions. The overall reaction time were 5 - 10 minutes.

The best yields were obtained for 1c, 96%. Over all yields

were in the range of 84% - 96% (Table 1).

In the subsequent step condensation of guanidine with

α-cyanoketene S,N-acetals for the synthesis of title com-

pounds were investigated. The reaction involved one-pot

yclocondensation of functionalized α-cyanoketene c

S,N-acetals with guanidine in the dimethylformamide.

Initially guanidine as a free base was generated in situ

from its salt form by treating with sodium hydride in DMF

under microwave irradiation for 1 minute at 20W. Once

the free base was generated, α-cyanoketene S,N-acetals

was added and subjected to MWI for 25 - 50 minutes at 80

W to afford the title 2-amino-5-cyano-4,6-disubstituted-

pyrimidines (Scheme 3). The reaction was completed in

just few minutes instead of the 18 hrs required under con-

ventional heating. The products were obtained in high

yield (76% - 90%), purity (>95%). (Table 2)

In comparison to the conventional heating method,

microwave heating affords more advantages such as high

yield, reduced reaction time, low cost, and simplicity in

reaction progress, reduced pollution and higher product

K. S. JAIN ET AL.49

Table 1. Physical Data of α-cyanoketene S,N-acetals (1a-i, 2a-i).

XNC

SCH3

R2R1N

Comp.No. X NR1R2 M.P. (˚C) Reaction

time (min)

at 80 WYield Comp.

No X NR1R2 M.P. (˚C) Reaction

time (min)

at 80 W Yield

1a CN C6H5NH 170 - 172 10 90 2a COOC2H5C6H5NH 82 - 83 10 95

1b CN 4-morpholinyl 150 - 152 5 85 2b COOC2H54-morpholinyl 93 - 94 5 91

1c CN 4-CH3OC6H4NH148 - 150 10 96 2c COOC2H54-CH3OC6H4NH 96 - 98 10 86

1d CN 4-CH3C6H4NH 140 - 141 5 94 2d COOC2H54-CH3C6H4NH 112 - 114 10 87

1e CN 4-Br-C6H5NH 122 - 124 10 92 2e COOC2H54-Br-C6H5NH 120 - 121 10 84

1f CN 4-F-C6H4NH 135 - 137 5 88 2f COOC2H5

4-F-C6H4NH 128 - 130 5 95

1g CN 4-Cl-C6H4NH 160 - 162 10 86 2g COOC2H54-Cl-C6H4NH 140 - 142 5 92

1h CN 3-Cl,4-F-C6H5NH139 - 141 5 91 2h COOC2H53-Cl,4-F-C6H5NH 151 - 153 5 90

1i CN 3-CH3C6H4NH 106 - 108 10 88 2i COOC2H5

3-CH3C6H4NH 95 - 96 10 94

purity. Hence, the synthetic methodology reported herein

is a very efficient method for the parallel library synthe-

sis of 2-amino-5-cyano-4,6-disubstitutedpyrimidines.

3. Experimental

All reagents and chemicals used were of LR grade and

purchased from standard vendors and used as received.

Microwave synthesizer; (Questron Technologies Corp.,

Canada; model-ProM) having monomode open-vessel

was used for the synthesis. The 1H NMR spectra were

recorded in CDCl3 using NMR Varian Mercury YH-300

MHz spectrometer and chemical shifts are given in units

as per million, downfield from TMS (tetramethylsilane)

as an internal standard. Mass spectra were obtained on a

Shimadzu GCMS-QP2010 spectrometer. The Ultraviolet

absorption spectra were determined in methanol on

JASCO (Japan) V-530, UV-Visible double beam spec-

trophotometer. The IR spectra of the synthesized com-

pounds were recorded on Perkin Elmer (USA) spectrum

BX.FT-IR in potassium bromide discs.

3.1. The α-Cyanoketene S,S-Acetals were

Prepared as Per Literature Method

3.1.1. Synthesis of α-Cyanoketene S,N-Acetals (1a-i,

2a-i)

A mixture of appropriate α-cyanoketene S,S-acetal 1 or 2

(0.02 mol) and 0.02 mol of aromatic amine in 10 ml of

ethanol was subjected to microwave irradiation at 80 W

for 5 - 10 minutes. The progress of the reaction was

monitored by TLC. Upon completion the mixture was

cooled and the crystals obtained were filtered, washed

with chilled ethanol and air dried. The compounds were

pure for all practical purpose.

3.1.2. Synthesis of 2,4-Diamino-5-Cyano-6-

(Phenylaminopyrimidine (3a-I & 4a-i)

To the benzene washed suspension of sodium hydride

(50%) (0.01 mol) in DMF (10 ml), guanidine nitrate

(0.01 mol) was added and subjected to microwave irra-

diation at 20 W for 1 min. The solution was filtered and

to the filterate α-cyanoketene S,N-acetals (1a-i, 2a-i)

(0.01 mol) was added. The flask was subjected to MWI

at 80 W for 25 - 50 min. The progress of reaction was

monitored by TLC for every 5 minutes. On completion

of reaction, the reaction mixture was cooled to RT and

poured into ice water (50 ml). The solid precipitate ob-

tained was filtered and dried. The crude product was

recrystallized from DMF-ethanol to obtain the desired

product.

3.2. Representative Data of Target Compounds

2,4-Diamino-5-cyano-6-(phenylamino)pyrimidine 3a

1HNMR (400 MHz, DMSO-d6): δ 5.01(2H, s, NH2 at 4);

5.13(2H, s, NH2 at 2); 5.34(1H, s, NH 6); 7.11 - 7.62 (5H,

m, ArH). IR (KBr) cm–1: 3479, 3317[



NH], 2210[



CN]. m/z

K. S. JAIN ET AL.

Table 2. Physical data of 2-amino-5-cyano-4,6-disubstitutedpyrimidines (3a-i, 4a-i).

Com. No. X

Yield (%)M.P. (˚C)

(Solv. of recryst)* Reaction time

(Min) at 80 W

3a NH2 C

6H5NH 84 268 - 270

D - E 25

3b NH2 4-morpholinyl 82 226 - 227

D - E 35

3c NH2 4-CH3OC6H4NH88 259 - 262

D - E 40

3d NH2 4-CH3C6H4NH 78 253 - 254

D - E 45

3e NH2 4-Br C6H5NH 80 249 - 251

D - E 40

3f NH2 4-FC6H4NH 89 245 - 247

D - E 35

3g NH2 4-ClC6H4NH 81 2425 - 244

D - E 30

3h NH2 3-Cl,4F-C6H5N

H 79 227 - 229

D - E 35

3i NH2 3-CH3C6H4NH 76 264 - 266

D - E 30

4a OH C6H5NH 81 280 - 281

D - E 40

4b OH 4-morpholinyl 80 257 - 258

D - E 45

4c OH 4-CH3OC6H4NH84 270 - 272

D - E 50

4d OH 4-CH3C6H4NH 79 276 - 278

D-E 45

4e OH 4-Br C6H5NH 87 266 - 267

D-E 35

4f OH 4-FC6H4NH 88 259 - 261

D - E 30

4g OH 4-ClC6H4NH 85 247 - 250

D - E 45

4h OH 3-Cl,4F-C6H4N

H 82 278 - 280

D - E 35

4i OH 3CH3C6H4NH 90 260 - 263

D - E 35

*Solv.of recryst. D = Dimethylformamide, E = Ethanol.

K. S. JAIN ET AL.51

226 (M+). Anal. Calcd. for C11H10N6: C, 58.40; H, 4.46;

N, 37.15; found C, 58.76; H, 4.76; N, 37.43.

2,4-Diamino-5-cyano-6-(4-morpholinyl)pyrimidine

1HNMR (400 MHz, DMSO-d6): δ 3.54 - 3.76(4H, m,

-NH(CH2-)2); 3.84-4.12 (4H, m, O-(CH2-)2]; 6.51(2H, s,

NH2 at 4); 6.69(2H, s, NH2 at 2). IR (KBr) cm–1: 3466,

3358[



NH], 2216[



CN]. m/z 220(M+). Anal. Calcd. for

C9H12N6O: C, 49.08; H, 5.49; N, 38.16; found C, 49.32;

H, 5.68; N, 38.29.

2,4-Diamino-5-cyano-6-[(4-methoxyphenyl)amino]p

yrimidine 3c

1HNMR (400 MHz, DMSO-d6): δ 3.73(3H, s, OCH3);

4.0 - 4.31(4H, s, NH2 at 2 and 4); 6.85 - 7.33 (4H, m,

Ar-H). IR (KBr) cm–1: 3416, 3374 [



NH], 2208 [



CN]. m/z

256(M+). Anal. Calcd. for C12H12N6O: C, 56.24; H, 4.72;

N, 32.79; found C, 56.35; H, 4.45; N, 32.93.

2,4-diamino-5cyano-6-[(4-methylphenyl)amino]pyri

midine 3d

1HNMR (400 MHz, DMSO-d6): δ 3.4(3H, s, ArCH3 at

6); 6.6(4H, m, NH2 at 2 and 4); 8.4(4H, m, ArH at 6). IR

(KBr) cm–1: 3474, 3289, 3153[



NH], 2188[



CN]. m/z

240(M+). Anal. Calcd. for C12H12N6: C, 59.99; H, 5.03;

N, 34.98 ; found C, 59.84; H, 5.34; N, 34.87.

2,4-diamino-5-cyano-6-[(4-chlorophenyl)amino]pyr

imidine 3g

1HNMR (400 MHz, DMSO-d6): δ 3.4(3H, s, ArCH3 at

6); 6.6(4H, m, NH2 at 2 and 4); 8.4(1H, s, ArH at 6). IR

(KBr) cm–1: 3324, 3178[



NH], 2190[



CN]. m/z 260(M+).

Anal. Calcd. for C11H9N6Cl: C, 50.68; H, 3.48; N, 32.24;

found C, 50.43; H, 3.62; N, 32.26.

2-amino-4-hydroxy-5-cyano-6-(4-morpholinyl)pyri

midine 4b

1HNMR (400 MHz, DMSO-d6): δ 2.9[s, -N(CH2-)2];

3.8[s, O-(CH2-)2]; 6 (2H, s, NH2 at 2); 7.4( s, 1H, OH at

4). IR (KBr) cm–1: 3357, 3115[



NH], 2922[



C-H], 2182[



CN],

1628[



CONH]. m/z 221(M+). Anal. Calcd. for C9H11N5O2: C,

48.86; H, 5.01; N, 31.66; found C, 48.74; H, 5.44; N,

31.34.

2-amino-4-hydroxy-5-cyano-6-[(4-flurophenyl)ami

no]pyrimidine 4f

1HNMR (400 MHz, DMSO-d6): δ 4.2(2H, s, NH2 at 4);

5.07(1H, s, OH); 6.72(5H,m, Ar-H ). IR (KBr) cm–1: 3476,

3296[



NH], 2916.12[



C-H], 2211[



CN] 1654, 1618[



CONH]. m/z

245(M+). Anal. Calcd. for C11H8N5OF: C, 53.88; H, 3.29;

N, 28.56; found C, 53.73; H, 3.08; N, 28.32.

4. Conclusions

We have described a new, rapid and a versatile approach

by MAOS for the synthesis of 2-amino-5-cyano-4,6-

disubstitutedpyrimidines in a highly efficient way. Fur-

ther work is in progress with respect to diversity oriented

synthesis of mononuclear pyrimidines and their biologi-

cal screening.

5. Acknowledgements

The authors acknowledge the contributions of Prof. M. N.

Navale, President, & Dr. (Mrs.) S. M. Navale, Secretary,

Sinhgad Technical Education Society, Pune for provid-

ing facilities to carry out the synthetic work and basic

spectroscopic analysis. The Mass and NMR were done at

Department of Chemistry, Saurashtra University, Rajkot,

India and University of Pune, India, respectively.

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