Microwave assisted high-speed parallel synthesis of N-phenyl

malonamic acid esters under solvent free condition†

Venugopal Rao Veeramaneni,§ Koteswar Rao Yeleswarapu§* and

Venkateswarlu Akellaφ*

§
Discovery Chemistry, Discovery Research-Dr. Reddy’s Laboratories Ltd. Bollaram
Road, Miyapur, Hyderabad 500 049, India, φ 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, β-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
O O

NH O

I
Fig - 1
O
O
Ar O
N
O NOH

Ar
N N O

O N O
O H

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.
O O

NH2 NH O
Dimethyl malonate
MW, 10 min,
R R 2
1
Scheme -1
 Table-1. Reaction products and the spectral data obtained from
substituted anilines and dimethyl malonate.

Entry Product R Yield (%)

1. 2a H 92
2. 2b 3,4-Dimethoxy 92
3. 2c 2,4-Dimethoxy 96
4. 2d 2-Methoxy 90
5. 2e 4-Methoxy 95
6. 2f 3-Fluoro 93
7. 2g 4-Fluoro 96
8. 2h 4-Acetyl 89
9. 2i 2-Methyl 85
10. 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
O O

NH2 NH O

N Dimethyl malonate N
MW, 10 min,
3 4
O O

NH2 NH O
Dimethyl malonate N N
N N
MW, 10 min,
5 6
Scheme -2

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.
1
H NMR (CDCl3, 200 MHz) δ 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H NMR: δ 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.
1
H NMR (CDCl3, 200 MHz): δ 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.
1
H 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.

References:
[1] (a) Folkes Adrin, Brown S David, Canne Lynne E, Chan Jocelyn, Engelhardt Erin
Bioorg. Med. Chem. Lett., 2002, 12 (7), 1063. (b) Cocco Maria Teresa, Congiu
Cenzo, Onnis Valentina., Farmaco, 2001, 56 (10), 741. (c) (i) Sui Xiong Cai,
Zhang-Lin Zhou, Jin-Cheng Huang, Edward R Whittemore, J. Med. Chem.,
1996,36, 3248. (ii) Kulagowski J.J., Bakar R., Curtius N. R., Leeson P. D., Mawer
I. M., Moseley. A. M., J. Med. Chem. 1994, 37, 1402. (iii) Rowley M., Kulagowski
J.J., Watt A. P., Rathbone D., Stevenson G. I., Carling R. W., Baker R., Marshall G.
R., Kemp J. A., Foster A. C., Grimwood S., Hargreaves R, Hurley R., Leeson P. D.;
J. Med. Chem. 1997, 40, 4053. (d) Lawton Geoffrey, Moody Christopher J,
Pearson Christopher J, J. Chem. Soc. Perkin Trans. 1987, 1, 877. (e) Hayashi H.,
Miwai I., Ichikawa S., Yoda N., Miki I., Ishii A., Kono M., Yasuzawa T., Suzuki F.;
J. Med. Chem. 1993, 36, 617.
[2] (a) Takei Hisashi, Fukuda Yoshimasa, Sugaya Kazuhiro Taguchi, Chem. Lett. 1980,
1307. (b) Casadei Maria Antonietta, Cesa Stefania, Inesi Achille, Morrachi Franco
Micheleti, J. Chem. Res. Miniprint, 1995, 5, 1064. (c) Ukhov S. V, Konshin M. E,
Chem. Heterocycl. Compd (Engl. Transl.) 1992, 28, 78. Khim. Geterotsikl.
Soedin., RU, 1992, 1, 89. (d) Jacobson, Amstutz, J. Org. Chem. 1956, 21, 311. (e)
Wee Andrew G, Liu Baosheng, Tetrahydron, 1994, 50 (3), 609.
[3] (a) Chattaway, Olmsted; J. Chem. Soc. 1910, 97, 939. (b) Balbi et. al. Farmaco
Ed. Sci. 1979, 34, 595. (c) Bhatt, K. N., Dave, A.M., Undavia N.K.,
J. Indian Chem. Soc. 1988, 65, 799.
[4] (a) Lawton Geoffrey, Moody Christopher J, Pearson Christopher J, J. Chem. Soc.
 Perkin Trans. 1987, 1, 877. (b) Ukrainets Igor V, Bezugly Gorokhova Olga V,
Tetrahedron, 1994, 50 (34), 10331. (c) Heath Perry C, Hung Charles Q, Lowe
Richard F, James R, Weigel Leland O, Whitten Jeffery P,; Tetrahydron Lett. 2001,
42 (9) 1607. (d) Suzuki Koji, Wantanabe Kazuhiko, Matsumoto Yukhihiro,
Kobayashi mitsuru; Anal. Chem., 1995, 67 (2) 324. (e) Staudinger, Becker, Chem.
Ber, 1917, 50, 1023. (f) Cai Sui Xiong, Zhou Zhang-Lin, Hung Jin Cheng,
Whittemore Edward R., J. Med. Chem., 1996, 39 (17) 3248.
[5] (a) Wee Andrew G, Liu Baosheng, Tetrahydron, 1994, 50 (3), 609. (b) Plueg
Carsten, Wentrup Curt, Acta Chem. Scand, 1998, 52 (5), 654. (c) Katagi
Toyoshi, Aoki Misako, Kashiwagi Masako, Ohata Katsuya, Kohno Shigekatsu,
Chem. Pharm. Bull, 1985,33 (11), 4878.
[6] (a) Ang Kiah H, Prager Rolf H, Williams Craig M, Aust. J. Chem., 1995, 48 (3),
567. (b) Missio Lauri J, Braibante Hugo S, Braibante Mara F, J. Heterocycl.
Chem., 1996, 33 (4), 1243. (c) Pepino R et. al. Gazz. Chim. Ital., 1976, 106, 1135.
(d) Minami et. al. J. Org. Chem., 1976, 41, 3811. (e) Bosson et. al. Aust. J.
Chem., 1963, 16, 480. (f) Bun, EdEdward et al. Can. J. Chem., 1972, 50, 3730.
[7] Pelle Lidstrom, Jason Tierney, Bernard Wathey and Westman., Tetrahedron, 2001,
57, 9225.
[8] Varma S. V.; Green Chem, 1999, 1, 43.
[9] (a) Bose, A. K., Banik B. K., Lavlinskaia N., Jayaraman M., Manhas M. S.;
Chemtech, 1997, 27, 18. (b) Caddick S.; Tetrahydron, 1995, 51, 10403.
[10] Katagi Toyoshi, Aoki Misako, Kashiwagi Masako, Ohata Katsuya, Kohno
Shigekatsu et al.; Chem. Parm. Bull. 1985, 33 (11), 4878.