Dithiocarbamate and DBU-promoted amide bond formation under microwave condition

Article abstract of DOI:10.1016/j.tetlet.2009.11.127

Dithiocarbamate and DBU-promoted amide bond formation under microwave condition has been reported. The versatility of this synthetic protocol has been demonstrated with various carboxylic acids and different dithiocarbamates. The products thus obtained ha

Full text of DOI:10.1016/j.tetlet.2009.11.127

Tetrahedron Letters 51 (2010) 899–902
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dithiocarbamate and DBU-promoted amide bond formation under
microwave condition
Katari Naresh Kumar a, Kintali Sreeramamurthy b, Sadananda Palle a, Khagga Mukkanti a,
Parthasarathi Das b,
*
a Institute of Science and Technology, JNTU-Hyderabad, Hyderabad 500 085, AP, India
b Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Dithiocarbamate and DBU-promoted amide bond formation under microwave condition has been
reported. The versatility of this synthetic protocol has been demonstrated with various carboxylic acids
and different dithiocarbamates. The products thus obtained have been characterized by mp, IR, 1H NMR,
and mass spectroscopy.
Received 23 October 2009
Revised 23 November 2009
Accepted 27 November 2009
Available online 4 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Dithiocarbamate
Microwave
The stable amide bond is not only common in naturally occur-
ring materials like peptides and proteins but is also found in many
synthetic substances.1 This makes the amide function important to
synthetic chemists especially in peptides and lactam synthesis, in
which the formation of amide bond is crucial. Some derivatives
of amides exhibit biological properties such as anticancer, antihis-
tamine, antifungal, and antibacterial.2–5 Recently, it has been ob-
served that many potent kinase inhibitors contain N-aryl amide
bonds and this kind of bond plays a crucial role for enzyme inhibi-
tion as observed in the cases of Imatinib and ZM-447439 (Fig. 1).6,7
In connection with a drug discovery program, we needed an effi-
cient route to the synthesis of various N-phenyl amides.
In the last decade, microwaves (MWs) have been used to sim-
plify and improve reaction conditions for many classic organic
reactions. Microwave irradiation often leads to a remarkable de-
crease in reaction time, increased yields, and easier workup match-
ing with green chemistry protocols.8–10
The microwave-assisted syntheses of amides had already been
investigated.11 However, in these studies a limited number of
amines and carboxylic acids were combined to afford the corre-
sponding amides.
Only acids and amines with no additional functionality were
used. In short, the chemical diversity covered in the amides gener-
ated was rather poor.
tuted amides.12 The major drawback of these reactions is the use
of toxic isocyanate. Apart from handling these toxic agents, the
synthesis of isocyanates requires handling of highly toxic phos-
gene. Moreover, the disadvantage with isocyanates is that they
are unstable if stored for a longer period. Following our studies to-
ward the development of a new route for the synthesis of organic
compounds, our interest remains in dithiocarbamate-mediated
reactions.13 Herein, we report a highly efficient microwave-as-
sisted one-pot synthesis of amides using various substituted acids
and substituted dithiocarbamates (Scheme 1). These dithiocarba-
mates are easy to synthesize in larger quantities by using readily
available anilines.14
The initial experiment was performed with commercially avail-
able 4-fluoro benzoic acid and S-methyl-N-aryl dithiocarbamate by
using DBU as a base in DMF at 60 °C for 3 min in microwave. The
desired N-phenylbenzamide was isolated in good yield (entry1).
Several organic bases like pyridine, DABCO, and DMAP as well as
inorganic bases were screened to optimize the methodology. But
it was observed that the DMF and DBU combination gave the best
results under microwave conditions.
With this efficient transformation under mild conditions, we
successfully explored this methodology with respect to different
acids and dithiocarbamates (Table 1). This reaction was quite suc-
cessful in the cases of aromatic, alicyclic, and heterocyclic acids.
In summary, we have reported an efficient synthesis of an
amide bond formation via microwave condition employing dithio-
carbamate as an amine source.
The condensation reaction between isocyanates and carboxylic
acids is a well-known method for practical synthesis of N-substi-
General procedure: To the solution of acid (1 mmol) in 2 ml of
DMF were added the corresponding dithiocarbamate (1.1 mmol)
* Corresponding author. Tel.: +91 40 23046677; fax: +91 40 23045438.
E-mail address: parthads@yahoo.com (P. Das).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.127

900
K. N. Kumar et al. / Tetrahedron Letters 51 (2010) 899–902
H
N
O
N
HN
N
H
N
H
O
O
N
N
N
N
N
O
N
N
ZM-447439
Aurora kinase inhibitor
O
Imatinib (Gleevec)
Bcr-Abl kinase inhibitor
Figure 1. Kinase inhibitor with N-phenyl amide bond.
and DBU (1 mmol) and were irradiated in a CEM microwave sys-
H
N
O
O
SMe
tem (300 W) using a 10 mL vial that contained a stir bar at 60 °C
for 3 min. The reaction mixture was cooled to rt and the reaction
was quenched with cold water. The solid obtained was filtered,
washed with water, and dried under vacuum to obtain the corre-
sponding pure amide. The physical data of these synthesized com-
pounds are reported below.
DBU/DMF
+
R
N
H
R
OH
MW, 3 min
S
60 oC
15 examples
60-92% yield
R = aryl, heterocyclic, alicyclic
Scheme 1.
Table 1
Synthesis of N-phenyl amides
Entry
Acid
Dithiocarbamate
Amide
Yield (%)
92
O
H
O
N
SMe
OH
1
N
H
S
F
F
OH
O
H
N
H
SMe
SMe
N
2
3
88
82
S
S
O
O
H
N
O
OH
N
H
O
H
N
O
SMe
SMe
O
O
4
5
76
68
OH
HN
S
S
O
O
O
O
H
N
O
OH
N
H
NH2
OH
NH2
O
H
N
H
N
SMe
SMe
6
7
78
70
S
S
O
H
N
O
OH
OH
N
H
H
N
H
N
SMe
SMe
8
9
72
76
O
S
O
S
S
S
O
O
O
H
N
H
N
OH
O
OH
H
N
H
N
O
SMe
O
10
83
O
S
O
O
O

K. N. Kumar et al. / Tetrahedron Letters 51 (2010) 899–902
901
Table 1 (continued)
Entry
Acid
Dithiocarbamate
Amide
Yield (%)
O
H
O
O
O
N
SMe
11
12
76
78
OH
O
O
N
H
S
O
H
N
F
O
SMe
SMe
OH
N
H
S
F
O
H
Cl
O
N
OH
13
14
60
78
N
H
S
Cl
O
N
O
N
OH
H
NH
S
N
SMe
SMe
O
O
O
O
O
O
O
O
NH
S
O
O
O
OH
15
72
O
N
O
H
O
4-Fluoro-N-phenylbenzamide (entry 1): mp: 180–181 °C (Lit15
180–181 °C); IR (KBr, cmÀ1): 3340, 3055, 2918, 1651, 1597, 1529,
1504; 1H NMR (400 MHz, DMSO-d6): d = 10.16 (s, 1H, NH), 8.04–
7.9 (m, 2H), 7.77–7.70 (m, 2H), 7.39–7.34 (m, 4H), 7.12–7.09 (m,
1H); Mass (ESI) = 216 [M+H]+.
N-Phenylfuran-2-carboxamide (entry 8): mp: 130–132 °C (Lit21
125–126 °C); IR (KBr, cmÀ1): 3280, 3140, 3059, 1656, 1598, 1581,
1529; 1H NMR (400 MHz, DMSO-d6): d = 10.13 (s, 1H, NH), 7.92 (s,
1H), 7.75–7.72 (m, 2H), 7.35–7.31 (m, 3H), 7.11–7.07 (m, 1H),
6.70–6.69 (m, 1H); Mass (ESI) = 188 [M+H]+.
N,2-Diphenylacetamide (entry 2): mp: 116–117 °C (Lit16 116–
118 °C); IR (KBr, cmÀ1): 3282, 3194, 3136, 1957, 1815, 1658; 1H
NMR (400 MHz, DMSO-d6): d = 10.12 (s, 1H. NH), 7.58 (m, 2H),
7.33–7.22 (m, 7H), 7.05–7.02 (m, 1H), 3.6 (s, 2H); Mass (ESI) = 212
[M+H]+.
N-Phenylthiophene-2-carboxamide (entry 9): mp: 136–138 °C
(Lit22 139–140 °C); IR (KBr, cmÀ1): 3305, 3084, 1631, 1595, 1535,
1514; 1H NMR (400 MHz, DMSO-d6): d = 10.19 (s, 1H, NH). 8.02–
8.01 (m, 1H), 7.85–7.84 (m, 1H), 7.71–7.68 (m, 2H), 7.73–7.70 (m,
2H), 7.37–7.21 (m, 1H), 7.12–7.10 (m, 1H); Mass (ESI) = 204 [M+H]+.
N-(3,4-Dimethoxyphenyl)-2-phenylacetamide (entry 10): mp:
148–149 °C (Lit23 147 °C); IR (KBr, cmÀ1): 3284, 3062, 3026, 2993,
2968, 2835, 1658, 1519; 1H NMR (400 MHz, DMSO-d6): d = 9.99 (s,
1H, NH), 7.32–7.30 (m, 5H), 7.25–7.22 (m, 1H), 7.08–7.05 (m, 1H),
6.86–6.82 (m, 1H), 3.70 (s, 6H), 3.59 (s, 2H); Mass (ESI) = 272 [M+H]+.
N-(3,4-Dimethoxyphenyl)cyclohexanecarboxamide (entry 11):
mp: 146–147 °C; IR (KBr, cmÀ1): 3302, 3162, 2924, 2848, 1651,
1604, 1529, 1514; 1H NMR (400 MHz, DMSO-d6): d = 9.60 (s, 1H,
NH), 7.05–7.03 (m, 1H), 6.89–6.86 (m, 1H), 6.82–6.80 (d, J = 8 Hz,
1H), 3.73 (s, 6H), 2.25–2.20 (m, 1H), 1.78–1.63 (m, 5H), 1.40–1.18
(m, 5H); Mass (ESI) = 264 [M+H]+.
N-(4-Fluorophenyl)-4-methylbenzamide (entry 12): mp: 185–
186 °C (Lit24 186–188 °C); IR (KBr, cmÀ1): 3265, 3104, 3030,1693,
1531; 1H NMR (400 MHz, DMSO-d6): d = 10.20 (s, 1H, NH), 7.95–
7.93 (m, 2H), 7.80–7.78 (m, 2H), 7.35–7.30 (m, 2H), 7.20–7.15 (m,
2H), 2.40 (s, 3H); Mass (ESI) = 230[M+H]+.
N-(4-Chlorophenyl)nicotinamide (entry 13): mp: 171–172 °C
(Lit25 169.5–170 °C); IR (KBr, cmÀ1): 3217, 3132, 3061, 3035, 1718,
1695, 1530; 1H NMR (400 MHz, DMSO-d6): d = 10.50 (s, 1H, NH),
8.75–8.72 (m, 1H), 8.16–8.14 (m, 1H), 8.07–8.05 (m, 1H), 7.96–
7.92 (m, 2H), 7.70–7.67 (m, 1H), 7.42–7.38 (m, 2H); Mass (ESI) =
233 [M+H]+.
N-Phenylcyclohexanecarboxamide (entry 3): mp: 136–137 °C
(Lit17 137–139 °C); IR (KBr, cmÀ1): 3275, 3190, 2931, 2850, 1658,
1597; 1H NMR (400 MHz, DMSO-d6): d = 9.76 (s, 1H, NH), 7.59 (m,
2H), 7.26 (m, 2H), 7.0–6.98 (m, 1H), 2.34–2.28 (m, 1H), 1.80–1.63
(m, 5H), 1.45–1.31 (m, 2H), 1.31–1.18 (m, 3H); Mass (ESI) = 204
[M+H]+.
3,4-Dimethoxy-N-phenylbenzamide (entry 4): mp: 175–176 °C; IR
(KBr, cmÀ1): 3317, 3271, 2960, 2939, 1647, 1598 cmÀ1 1H NMR
;
(400 MHz, DMSO-d6): d = 10.03 (s, 1H, NH), 7.74 (m, 2H), 7.62 (m,
2H), 7.34 (m, 2H), 7.10–7.07 (m, 2H), 3.84 (s, 6H); Mass (ESI) = 258
[M+H]+.
2-Amino-N-phenylbenzamide (entry 5): mp: 255–256 °C (Lit18
255 °C); IR (KBr, cmÀ1): 3331, 3244, 3097, 2929, 1892, 1685; 1H
NMR (400 MHz, DMSO-d6): d = 13.03 (s, 1H, NH), 7.95–7.85 (m,
2H), 7.49–7.24 (m, 9H); Mass (ESI) = 213 [M+H]+.
N-Phenyl-1-naphthamide (entry 6): mp: 164–165 °C (Lit19
165 °C); IR (KBr, cmÀ1): 3286, 3047, 2960, 2862, 1653, 1595, 1525,
1500; 1H NMR (400 MHz, DMSO-d6): d = 10.54 (s, 1H, NH), 8.19–
8.17 (m, 1H), 8.07–8.05 (m, 1H), 8.03–8.01 (m, 1H), 7.81–7.78 (m,
2H), 7.74–7.70 (m, 1H), 7.63–7.60 (m, 3H), 7.37–7.34 (m, 2H),
7.12–7.10 (m, 1H); Mass (ESI) = 248 [M+H]+.
N-Phenylcyclopentanecarboxamide (entry 7): mp: 147–148 °C
(Lit20 152 °C); IR (KBr, cmÀ1): 3280, 3250, 3192, 3078, 2962,
2866, 1948, 1654, 1541; 1H NMR (400 MHz, DMSO-d6): d = 9.80
(s, 1H, NH), 7.59–7.56 (m, 2H), 7.29–7.25 (m, 2H), 8.03–8.00 (m,
1H), 2.80–2.72 (m, 1H), 1.87–1.50 (m, 8H); Mass (ESI) = 190
[M+H]+.
N-(Benzo[d][1,3]dioxol-5-yl)-2-phenyl acetamide (entry 14): mp:
141–143 °C(Lit26 146 °C); IR (KBr, cmÀ1): 3263, 3028, 2914, 1654,
1537, 1504; 1H NMR (400 MHz, DMSO-d6): d = 10.04 (s, 1H, NH),
7.32–7.21 (m, 6H), 6.96–6.94 (m, 1H), 6.83–6.80 (m, 1H), 5.96 (s,
2H), 3.58 (s, 2H); Mass (ESI) = 256 [M+H]+.

902
K. N. Kumar et al. / Tetrahedron Letters 51 (2010) 899–902
7. (a) Druker, B. J.; Sawyers, C. L.; Kantarjian, H.; Resta, D. J.; Reese, S. F.; Ford, J.
N-(Benzo[d][1,3]dioxol-5-yl)-3,4-dimethoxybenzamide (entry 15):
M.; Capdeville, R.; Talpaz, M. N. Eng. J. Med. 2001, 344, 1038; (b) Asaki, T.;
Sugiyama, Y.; Hamamoto, T.; Higashioka, M.; Umehara, M.; Naito, H.; Niwa, T.
Bioorg. Med. Chem. Lett. 2006, 16, 1421.
mp: 159–161 °C; IR (KBr): 3280, 3001, 2879, 2837, 1645, 1600; 1H
NMR (400 MHz, DMSO-d6): d = 9.95 (s, 1H, NH), 7.58–7.55 (m, 1H),
7.50–7.48 (m, 1H), 7.42–7.40 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.06–
7.02 (m, 1H), 6.88–6.85 (m, 1H), 6.0 (s, 2H), 3.83 (s, 6H); Mass
(ESI) = 302 [M+H]+.
8. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe, D.
Synthesis 1998, 1213.
9. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
10. Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863.
11. (a) Vasquez-Tato, M. P. Synlett 1993, 506; (b) Perrux, L.; Loupy, A.; Volatron, F.
Tetrahedron 2002, 58, 2155; (c) Gelens, E.; Smeets, L.; Sliedregt, L. A. J. M.;
Steen, B. J. V.; Kruse, C. G.; Lurs, R.; Orru, R. V. A. Tetrahedron Lett. 2005, 46,
3751.
12. (a) Schuemacher, A. C.; Hoffmann, R. W. Synthesis 2001, 243; (b) Gurtler, C.;
Denielmeier, K. Tetrehedron Lett. 2004, 45, 2515.
Acknowledgments
K.N.K. and S.P. are thankful to JNTU-Hyderabad and CSIR, New
Delhi, respectively, for their fellowships. We thank the Analytical
Department of Dr. Reddy’s Laboratories Ltd. for recording spectral
data.
13. Das, P.; Kirankumar, C.; Nareshkumar, K.; Innus, Md.; Iqbal, J.; Srinivas, N.
Tetrehedron Lett. 2008, 49, 992.
14. (a) Azizi, N.; Ebrahimi, F.; Aakbari, E.; Aryansab, F.; Saidi, M. R. Synthesis 2007,
2797; (b) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org.
Chem. 2006, 71, 3634; (c) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8,
5275; (d) Wang, Y.-Q.; Ge, Z.-M.; Hou, X.-L.; Cheng, T.-M.; Li, R.-T. Synthesis
2004, 675; (e) Salvatore, R. N.; Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001, 42,
2055.
15. Kim, S.-H.; Rieke, R. D. Synth. Commun. 1998, 28, 1065.
16. Johnson, T. B. J. Am. Chem. Soc. 1906, 28, 1454.
17. Minami, T.; Yamataka, Y.; Ohshiro, Y.; Agawa, T.; Yasuoka, N.; Kasai, N. J. Org.
Chem. 1972, 37, 3810.
18. Stavropoulos, G.; Theodoropoulos, D. J. Heterocycl. Chem. 1977, 14, 1139.
19. Smith, P. A. S.; Antoniades, E. P. Tetrahedron 1960, 9, 210.
20. Hoberg, H.; Nohlen, M. J. Organomet. Chem. 1990, 382, C6–C10.
21. Toda, F.; Miyamoto, H.; Kanemoto, K.; Tanaka, K.; Takahashi, Y.; Takenaka, Y. J.
Org. Chem. 1999, 64, 2096.
22. Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
23. Gazit, A.; App, H.; McMahon, G.; Chen, J.; Levitzki, A.; Bohmer, F. D. J. Med.
Chem. 1996, 39, 2170.
References and notes
1. (a) Hudson, D. J. Org. Chem. 1988, 53, 617; (b) Beckwith, A. L. J. In The Chemistry
of Amides: Synthesis of Amides; Zabicky, J., Ed.; Interscience: New York, 1970; p
96; (c) Trost, B. M.; Fleming, I.. In Comprehensive Organic Synthesis; Winterfeld,
E., Ed.; Pergamon: Oxford, 1991; Vol. 6, (d) Ghose, A. K.; Viswanadhan, V. N.;
Vendol, J. J. J. Comb. Chem. 1999, 1, 55; (e) Montalbetti, C. A. G. N.; Falque, V.
Tetrahedron 2005, 61, 10827.
2. Mrozik, H.; Jones, H.; Friedman, J.; Schwartzkopf, G.; Schardt, R. A.; Patchett, A.
A.; Holff, D. R.; Yakstis, J. J.; Riek, R. F.; Ostlind, D. A.; Plischker, G. A.; Butler, R.
W.; Cuckler, A. C.; Campbell, W. C. Experientia 1996, 883.
3. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 2337.
4. (a) White, G. A. Pestic. Biochem. Physiol. 1989, 34, 255; (b) Yalcin, I.;
Kaymakcioglu, B. K.; Oren, I.; Sener, E.; Temiz, O.; Akin, A.; Altanlar, N.
Farmaco 1997, 52, 685.
5. Kobayashi, I.; Muraoka, H.; Hasegawa, M.; Saika, T.; Nishida, M.; Kawamura,
M.; Ando, R. J. Antimicrob. Chemother. 2002, 50, 129.
24. Blatter, H. M.; Lukaszewski, H. J. Org. Chem. 1966, 31, 722.
25. Baxter, J. N.; Cymerman-Craig, J. J. Chem. Soc. 1953, 1490.
26. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1931, 53, 1536.
6. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat. Rev. Drug Disc.
2002, 1, 493.