Microwave assisted high-speed parallel synthesis of N-phenyl

malonamic acid esters under solvent free condition†

Venugopal Rao Veeramaneni,§ Koteswar Rao Yeleswarapu§* and

Venkateswarlu Akella*

§Discovery Chemistry, Discovery Research-Dr. Reddy’s Laboratories Ltd. Bollaram

Road, Miyapur, Hyderabad 500 049, India, Dr. Reddy’s Research Foundation,

Miyapur, Hyderabad 500049, India.

Abstract: A novel microwave-assisted synthesis of malonamic acid esters under solvent

free conditions has been developed. These compounds are useful building blocks in the

synthesis of pharmacologically important scaffolds.

Key Words: Malonamic acid esters, quinolinone heterocycles, microwave-assisted

synthesis.

† DRL Publication No. 436

Corresponding Address:

Tel: 91-40-23045439, Fax: 91-40-23045438

E-mail: venugopalrv@drreddys.com, venkata@drreddys.com

N-Phenyl malonamic acid esters (Fig – 1 I) are useful intermediates in the synthesis of

pharmacologically active compounds which are used as potent inhibitors of plasminogen

activator inhibitor-1 (PAI-1, Fig. 2, II),1a cytostatic agent (breast cancer BT-549 cell line,

colon cancer HCT-15 cell line, non-small cell lung NCI-H23 cell line, Fig. 2, III),1b

glycine NMDA receptor antagonists (Fig. 2, IV),1c antibacterial agents, -lactam class of

compounds,1d and serotonin (5HT3) receptor antagonists.1e In addition, N-phenyl

malonamic acid esters have been found to serve as key intermediates in the synthesis of

novel heterocycles. 2

I

Fig - 1

II III IV

Fig – 2

Due to their enormous importance in chemical as well as pharmaceutical research, a

number of methods are reported in literature for the synthesis of (I). The existing

methods consist of the use of anilines and dimethylmalonate in benzene,3 addition of

chlorocarbonyl acetic acid ethyl ester to anilines in presence of base,4 malonic acid mono

methyl ester and anilines in presence of DCC/EDC.5 Apart from these, they are also

obtained as side product from different reactions.6 However, all these methods require

carcinogenic organic solvents such as benzene, heating for a long time, and utilize

expensive reagents such as EDC, CDI etc. Therefore, there is a need for an improved and

alternative procedure for synthesis of (I). The solvent free reactions are useful in organic

synthesis and in particular, use of microwave irradiation has been well documented in the

literature.7-9 In continuation of our interest in microwave assisted reactions, we applied

this technique for the synthesis of N-phenylmalonamic acid methyl esters. Herein, we

report for the first time, microwave enhanced formation of N-phenyl malonamic acid

esters from substituted anilines and malonic ester using solvent free conditions and

without any supported reagents. The present work was an observation during the

preparation of tricyclic oxazolo compounds.10 Optimization of reaction conditions was

performed using 4-fluoroaniline and dimethyl malonate (entry 7 in Table 1). Optimal

conditions for this synthesis were found to be 10 min reaction time using 40%

Microwave oven level (1000 W), from the house hold Microwave oven. These optimal

conditions were then applied for the synthesis of a range of 2,3 and 4 substituted N-

phenyl malonamic acid esters, as depicted in Table -1. It is interesting to note that the

electron withdrawing containing anilines also worked well and afforded good yields. Our

synthetic procedure involves irradiation of mixture of aniline compound (substituted

anilines) and dimethyl malonate in house hold Microwave oven. The reactions were

carried out in open vessel so as to enable escape of ethanol formed during the reaction.

Table-1. Reaction products and the spectral data obtained from substituted anilines and dimethyl malonate.

Entry Product R Yield (%)1. 2a H 922. 2b 3,4-Dimethoxy 923. 2c 2,4-Dimethoxy 964. 2d 2-Methoxy 905. 2e 4-Methoxy 956. 2f 3-Fluoro 937. 2g 4-Fluoro 968. 2h 4-Acetyl 899. 2i 2-Methyl 8510. 2j 4-Carboxy 91

We extended this work to prepare 2-amino pyridine and 2-amino pyrimidine derivatives

(Scheme -2), out of which 2-amino pyrimidine derivative (6) was reported as an anti

inflammatory (carrageenin-induced Paw edema in Rats) molecule.10

Typical procedure for the synthesis of N-phenyl malonamic acid methyl esters.

Preparation of (I): A solution of 3,4-dimethoxy aniline (3.0 g, 19.6 mmol) and dimethyl

malonate (6.75 mL, 58.82 mmol) in 100 ml flat bottomed round flask, was irradiated in

the house hold Microwave oven for 10 min at 40 % power level . Cooled the reaction

mixture and stirred with n-hexane at 0 0C for 10 min. The light brown solid product was

filtered, washed with hexane and dried to furnish 2a – 2j.

Parallel Synthesis of malonamic esters. The appropriate anilines (1.0 g, Table 1) and

dimethyl malonate (3.0 eq) were placed in six individual 100 ml flat bottomed round

flasks. These all reaction flasks were irradiated in the house hold Microwave oven for 10

min at the 40 % power level. A similar work-up as described above, provided excellent

yields of the desired products (Table 1).

All the products were characterized from their spectral (IR, 1H NMR and MS) data. The

spectral data of the all compounds are given below.

N-Phenylmalonamic acid methyl ester (2a, Entry 1)

Solid; mp 49-51 °C.

IR (KBr) 3271, 1867, 1741, 1601, cm-1.

1H NMR (CDCl3, 200 MHz) 9.11 (bs, 1H, D2O exchangeable), 7.53 (s, 2H), 7.32 (m,

2H), 7.12 (s, 1H), 3.8 (s, 3H), 3.48 (s, 2H).

MS (CI Method): m/z = 194 [100%, (M+1)+].

N-(3,4-Dimethoxyphenyl)-malonamic acid methyl ester (2b, Entry 2)

Solid; mp: 103 – 105 °C.

IR (KBr): 3268, 2951, 1752, 1649 cm-1.

1H NMR: 9.16 (bs, 1H, D2O exchangeable), 8.20 (d, J = 9.0 Hz, 1H), 6.48 – 6.43 (m,

2H), 3.88 (s, 3H), 3.79 (s, 6H), 3.48 (s, 2H).

MS (CI Method): m/z = 254 (100) [M+1] 253 (30) [M+].

N-(2,4-Dimethoxyphenyl)-malonamic acid methyl ester (2c, Entry 3)

Solid; mp: 112 – 114 °C.

IR (KBr): 3270, 2954, 1748, 1647 cm-1.

1H NMR: 9.16 (bs, 1H, D2O exchangeable), 8.20 (d, J = 9.0 Hz, 1H), 6.48 – 6.43 (m,

2H), 3.88 (s, 3H), 3.79 (s, 6H), 3.48 (s, 2H).

MS (CI Method): m/z = 254 (100) [M++1], 253 (30 %) [M+].

N-(2-methoxyphenyl) malonamic acid methyl ester (2d, Entry 4)

Solid; mp: 162 – 164 °C.

IR (KBr): 3342, 2955, 1740, 1688 cm-1.1H NMR: 9.36 (bs, 1H, D2O exchangeable), 8.33 (d, J = 7.3 Hz, 1H), 7.08 – 6.86 (m,

3H), 3.89 (s, 3H), 3.78 (s, 3H), 3.73 (s, 2H).

MS (CI Method): m/z = 209 (100), 163, 121.

N-(4-methoxyphenyl) malonamic acid methyl ester (2e, Entry 5)

Solid; mp: 190 – 192 °C.

IR(KBr): 3274, 2925, 1744, 1645 cm-1.1H NMR: 9.00 (bs, 1H, D2O exchangeable), 7.45 (d, J = 8.66 Hz, 2H), 6.87 (d, J = 8.60

Hz, 2H), 3.79 (s, 6H), 3.47 (s, 2H).

MS (CI Method): m/z = 224 [M++1].

N-(3-fluorophenyl) malonamic acid methyl ester (2f, Entry 6)

Solid; mp: 152 – 154 °C.

IR(KBr): 3317, 3088, 2957, 1744, 1676 cm-1.

1H NMR: 9.30 (bs, 1H D2O Exchangeable), 7.53 (d, J = 11.2 Hz, 1H), 7.28 – 7.16 (m,

2H), 6.82 (t, J = 7.8 Hz, 1H), 3.8 (s, 3H), 3.49 (s, 2H).

MS (CI Method): m/z = 212 (100) [M++1].

N-(4-fluorophenyl) malonamic acid methyl ester (2g, Entry 7)

Solid; mp: 124 – 126 °C.

IR (KBr): 3301, 3102, 2924, 1731, 1659 cm-1.

1H NMR: 9.18 (bs, 1H D2O Exchangeable), 7.55 – 7.48 (m, 2H), 7.02 (d, J = 8.3 Hz,

2H), 3.81 (s, 3H), 3.48 (s, 2H).

MS (CI Method): m/z = 212 (M++1, 100%).

N-(4-acetylphenyl) malonamic acid methyl ester (2h, Entry 8)

Solid; mp: 220 – 222 °C.

IR (KBr): 3300, 3195, 2954, 1738, 1672 cm-1.

1H NMR: 9.49 (bs, 1H D2O Exchangeable), 7.95 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.8

Hz, 2H), 3.82 (s, 3H), 3.51 (s, 2H), 2.36 (s, 3H).

MS (CI Method): m/z = 236 (100) [M++1].

N-(2-methylphenyl) malonamic acid methyl ester (2i, Entry 9)

Solid; mp: 132 – 134 °C.

IR (KBr): 3266, 3037, 2954, 1737 cm-1.

1H NMR: 9.21 (bs, 1H D2O Exchangeable), 7.95 (d, J = 8.8 Hz, 1H), 7.17 (m, 3H),

3.81 (s, 3H), 3.52 (s, 2H), 2.32 (s, 3H).

MS (CI Method): m/z = 208 (100) [M++1].

N-(4-carboxyhenyl) malonamic acid methyl ester (2j, Entry 10)

Solid; mp: 249 – 251 °C.

IR (KBr): 3271, 1867, 1741 cm-1.1H NMR: 9.11 (bs, 1H D2O Exchangeable), 7.53 (s, 2H), 7.32 (m, 2H), 7.12 (s, 1H), 3.8

(s, 3H), 3.48 (s, 2H).

MS (CI Method): m/z = 194 (100) [M++1].

Methyl 2-(2-pyridylcarbamoyl)acetate (4):

Solid; mp: 185 – 187 °C,

IR (KBr): 3310, 2955, 1744, 1696 cm-1.

1H NMR (CDCl3, 200 MHz): 9.53 ( bs, 1H D2O exchangeable), 8.29 (d, J = 4.0 Hz,

1H), 8.16 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 7.0 Hz, 1H), 7.05 (t, J = 5.0 Hz, 1H), 3.78 (s,

3H), 3.5 (s, 2H).

MS (CI Method): m/z = 195 (100) [M++1], 163, 121, 94. Yield: 43 %.

Methyl 2-(2-pyrimidinylcarbamoyl) acetate (6)

Solid; mp: 216 – 218 °C.

IR (KBr): 3143, 3073, 2953, 2921, 1731, 1681 cm-1.

1H NMR (CDCl3, 200 MHz): 10.81 (s, 1H, D2O exchangeable), 8.64 (d, J = 4.88 Hz,

2H), 7.18 (t, J = 4.88 Hz, 1H), 3.71 (s, 2H), 3.63 (s, 3H).

MS (CI Method): m/z =196 (100) [M++1), 164 (75).

In conclusion, we described here a reagent free rapid and practical procedure for the

synthesis of N-phenyl malonamic acid esters from substituted anilines and malonic acid

methyl ester under microwave condition.

Acknowledgement:

The authors would like to thank analytical department for the spectral support.

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