LETTER
611
Efficient and General Synthesis of 3-Aryl Coumarins Using Cyanuric Chloride1 Synthesi of3-ArylCoumarins Koneni V. Sashidhara,* Gopala Reddy Palnati, Srinivasa Rao Avula, Abdhesh Kumar Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226 001, India Fax +91(522)2623405; E-mail:
[email protected]; E-mail:
[email protected] Received 22 December 2011
Key words: synthesis, 3-aryl coumarins, cyanuric chloride, 2hydroxy benzaldehyde
Coumarins are an important class of compounds, which occupy a special role in nature.2,3 The diverse biological and pharmaceutical properties of natural and synthetic coumarins as anti-HIV,4 anticoagulant,5 antibacterial,6 antioxidant,7 and anticancer agents8 are well known. In the last few years our research group has been engaged in the synthesis of new biologically active coumarins.9 In particular, the 3-phenylcoumarin scaffold has been the focus of our most recent studies with some compounds exhibiting significant antidepressant activity10 and coumestrol (3phenylcoumarin) being one of the most important known phytoestrogens. Furthermore, some 3-phenylcoumarins have been demonstrated to play an important role in monoamino oxidase inhibition.11 Different synthetic strategies are known in the literature for the synthesis of substituted 3-aryl coumarins derivatives. The well-known Knoevenagel condensation,12,13 Wittig,14 Pechmann,15,16 and Perkin reactions,17–21 are some of the synthetic routes commonly used to synthesize 3-aryl coumarins derivatives. Besides these routes, 3-aryl coumarins were also prepared using DCC, DDQ, NaOH, POCl3, and the Mukaiyama reagent (2-chloro-1-meth-
ylpyridinium iodide).16,22 Very recently, Matos et al. have developed a Pd-catalyzed cross-coupling reaction for the synthesis of substituted 3-aryl coumarins.23 Most of the methods for the synthesis of the 3-aryl coumarins suffer from low yields and/or long reaction times. Therefore, in spite of the present methodologies, there is still a need to explore a versatile synthetic methodology for the construction of a chemical library of 3-substituted coumarin derivatives. Cyanuric chloride (2,4,6-trichloro-1,3,5-triazine or TCT) has received considerable attention for the preparation of alkyl chlorides,24 Beckmann rearrangement products,25 isonitriles,26 bis(indolyl)methanes,27 thiiranes,28 dihydropyridines,29 14-aryl and alkyl-14-H-dibenzo[a,j]xanthenes,30 alcohols,31 diazocarbonyl,32 acyl azides,33 hydroxamic acids,34 and acyl chlorides.35 Recently, cyanuric chloride has also been used in the Friedel–Craft acylation for the formation of carbonyl compounds in excellent yield.36 In this paper, we wish to report a very simple and highly efficient method for the synthesis of 3aryl coumarin derivatives, using 2-hydroxy benzaldehydes and phenylacetic acid derivatives in the presence of cyanuric chloride. To the best our knowledge, this is the Table 1 Effect of Reaction Conditions on the Cyanuric Chloride Mediated Reaction of 1a and 1b Entry
Base (mmol)
Solvent
Time (min)
Temp (°C)
Yield (%)a
1
pyridine (3.0)
DMF
180
110
30
2
piperidine (3.0)
DMF
180
110
45
3
Et3N (3.0)
DMF
180
110
40
4
K2CO3 (3.0)
DMF
180
110
30
5
NMM (3.0)
DMF
180
110
95
6
NMM (1.5)
DMF
180
110
95
7
NMM (1.0)
DMF
180
110
83
8
NMM (1.5)
DMF
30
110
95
9
NMM (1.5)
DMF
45
r.t.
0
10
NMM (1.5)
DMF
45
60
25
11
NMM (1.5)
DMF
45
90
75
12
NMM (1.5)
MeCN
60
100
46
OH O
OH CHO
cyanuric chloride
+ 1a
O
O
O
base, solvent temp, time O 1b
1c
Scheme 1 Reaction between 2-hydroxy benzaldehyde (1a) and 4-methoxy phenyl acetic acid (1b) promoted by TCT
SYNLETT 2012, 23, 611–621 x.x201 Advanced online publication: 10.02.2012 DOI: 10.1055/s-0031-1290344; Art ID: D25011ST © Georg Thieme Verlag Stuttgart · New York
a
Yields after purification by column chromatography.
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Abstract: An efficient and general protocol for a rapid synthesis of different substituted 3-aryl coumarins is reported. A series of different substituted phenyl acetic acids have been successfully reacted with different substituted 2-hydroxy benzaldehydes in the presence of cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) and N-methyl morpholine to afford 3-aryl coumarins in good to excellent yields.
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K. V. Sashidhara et al.
diverse 2-hydroxybenzaldehydes and a variety of phenylacetic acids, and representative examples are summarized in Table 2. 2-Hydroxybenzaldehydes bearing either electron-withdrawing or electron-donating groups were converted into the corresponding 3-aryl coumarins in very short reaction times and in excellent yields (90–99%, Table 2, entries 1–14). To generalize our reagent system to more complex systems, we examined several chalconesubstituted 2-hydroxybenzaldehydes 15a–20a (derived from the reaction of 4a with appropriate acetophenones),9d which readily underwent smooth conversion under the optimized conditions to afford a wide range of 3aryl coumarins 15c–22c, Table 2, entries 15–22) in good to excellent yields, indicating that this reaction is quite general and has very broad substrate scopes.
first example of a cyanuric chloride mediated synthesis of substituted 3-aryl coumarins. Thus, we demonstrated that 3-aryl coumarin derivative 1c can be easily synthesized from 2-hydroxy benzaldehyde (1a) and 4-methoxy phenyl acetic acid (1b), by employing TCT (use of 1.0 mmol molar ratio gave best results, Scheme 1). Different sets of conditions (reaction times, temperatures, base molar ratios, and solvents) were tried to investigate the efficacy and selectivity of cyanuric chloride (Table 1). From Table 1, it is clear that N-methylmorpholine at 1.5 mmol promotes the reaction to produce the desired product 3-aryl coumarin 1c in 95% yield (Table 1, entry 8) in 30 minutes. In a brief solvent screen, DMF gave best yields at a temperature of 110 °C. With the optimized reaction conditions in hand, we explored the generality and scope of the reaction by using General Synthesis of Substituted 3-Aryl Coumarins
R4 R3
O OH
R2
O
CHO a R1 1a–6a R3
O
OH
O CHO
CHO
a
CHO
c
O
R2
O
OH a
b
R5
O
CHO 4a
X
R6
X
O
R3
1c–14c OH
R2
O
R4
R1
R4
R5
O
R7 15a–18a
19a–20a
R6 R7
21c–22c
Entry
15c–20c
Substrate a
Substrate b
Product
O OH
O
OH
1a
Yield (%)
45
95
60
90
O
O
CHO
1
Time (min)
O
1c
1b O
O
OH OH
CHO
O
O
2 Br O
2a 1b Synlett 2012, 23, 611–621
Br
2c © Thieme Stuttgart · New York
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Table 2
LETTER Table 2
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Synthesis of 3-Aryl Coumarins
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1
R4
R1 1a–6a
O
OH
CHO CHO
2
O
R
a
CHO
a
b
X
R5
O
CHO 4a
R6
X
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH c
O O
O
OH
R3
R3
1c–14c
Substrate a
Substrate b
Product
O OH CHO
3
O
3a
Yield (%)
40
97
30
96
45
98
85
90
O
O
OH
Time (min)
O
3c
1b O OH
CHO
O
O
OH O
4 CHO O
4a
CHO
1b
4c O
O
OH OH
CHO
O
O
5 CHO O
5a
CHO
1b
5c O
OH
O OH
CHO
O
6
O
6a 1b
© Thieme Stuttgart · New York
O
6c
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R4
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Table 2
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1
R4
R1 1a–6a
O
OH
CHO CHO
2
O
R
CHO
c
O
a
b
X
R5
O
CHO 4a
R6
X
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
a
O
O
OH
R3
R3
1c–14c
Substrate a
Substrate b
Product
O
Time (min)
Yield (%)
40
93
35
95
45
98
30
98
O
OH OH
CHO
7
O
1a 2b
7c O O
OH
O OH
CHO
O
8 O
CHO
4a
CHO
3b 8c
O O OH
O OH
CHO
O
9 CHO
O
5a
CHO
3b 9c
O
O OH
O
OH
CHO
O
10 CHO
O
O O
4a
CHO
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R4
LETTER Table 2
615
Synthesis of 3-Aryl Coumarins
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1
R4
R1 1a–6a
O
OH
CHO CHO
2
O
R
CHO
c
O
a
b
X
R5
O
CHO 4a
R6
X
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
a
O
O
OH
R3
R3
1c–14c
Substrate a
Substrate b
Product
Yield (%)
50
98
90
92
40
99
90
93
O
O OH
O
O
OH
CHO
Time (min)
O
11 O
CHO
O
5a
CHO
4b 11c O
O
O
OH
OH
CHO
O
O
12 O O
6a
12c
4b
O
O OH CHO
O
O
OH
O
O
13 O
CHO
O O
4a
CHO
5b 13c
O
O OH
O
OH
CHO
O
14 O
O
O O
6a 5b © Thieme Stuttgart · New York
O
14c Synlett 2012, 23, 611–621
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R4
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K. V. Sashidhara et al.
Table 2
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1 1a–6a
CHO CHO
R
a
CHO
c
a
b
R6
X
O
R5
O
CHO 4a
X
O
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
Substrate a
Substrate b
Product
O
O O
Yield (%)
90
87
80
89
O
O
O
O
Time (min)
O
O OH
15
O O O
1b 15c
7a
O
O
OH O
CHO
O
O OH
16 O O
O O
4b 7a 16c
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O
O
OH
2
R3
1c–14c OH
R3
O
R4
R1
R4
LETTER Table 2
617
Synthesis of 3-Aryl Coumarins
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1 1a–6a
CHO CHO
R
a
CHO
c
O
a
b
X
R5
O
CHO 4a
R6
X
O
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
Substrate a
Substrate b
Product
Time (min)
Yield (%)
75
92
80
90
O OH
O
O O
CHO
O
O
OH
17 O
O
O
O
5b
O
7a 17c O
O OH O
O
CHO
OH
18 O O
8a
O
1b
O O
18c
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O
O
OH
2
R3
1c–14c OH
R3
O
R4
R1
R4
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Table 2
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1 1a–6a
CHO CHO
R
a
CHO
c
O
a
b
X
R5
O
CHO 4a
R6
X
O
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
Substrate a
Substrate b
Product
CHO
85
92
90
94
O
O
O
Yield (%)
O
O
OH
Time (min)
OH
19 O
O O
O
O
4b
O
O O
9a 19c
O OH
O
O CHO
O
O
O
OH
20 O
O
O
O O
O O
O
O
5b O
10a
O
20c
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O
O
OH
2
R3
1c–14c OH
R3
O
R4
R1
R4
LETTER Table 2
619
Synthesis of 3-Aryl Coumarins
General Synthesis of Substituted 3-Aryl Coumarins (continued) R4 R3
O OH
R2
O
CHO a R1
R4
R1 1a–6a
O
OH
CHO CHO
2
O
R
CHO
c
O
a
b
X
R5
O
CHO 4a
R6
X
R5
O
R7 15a–18a
19a–20a
R6 R7 15c–20c
21c–22c
Entry
R2
O
OH
a
O
O
OH
R3
R3
1c–14c
Substrate a
Substrate b
Product
O
CHO
Yield (%)
85
91
90
92
O
O
OH
Time (min)
O
O OH
21 O O O
O O
4b
11a
O
21c O
O
OH O
CHO
O
O OH
22 O O S
12a
O O
4b
S
22c a
Reaction conditions: Phenylacetic acid 1b–5b, cyanuric chloride, NMM, DMF, 110 °C, 30–90 min. Reaction conditions: Appropriate acetophenone, concd HCl, dioxane, reflux, 2–3 h. c Reaction conditions: 2-Acetylthiofuran/2-acetyl furan, concd HCl, dioxane, reflux, 2–3 h. b
As shown in Table 2, all the substrates participated very efficiently in the reaction to afford the desired products in very short times (30–90 min only) and better yields than those reported by earlier methods.21 All compounds were characterized through 1H, 13C NMR, MS, and IR spectroscopic studies.37
© Thieme Stuttgart · New York
A plausible mechanism for the formation of 3-aryl coumarin derivatives is given in Scheme 2. It is postulated that an initial reaction of cyanuric chloride33,36 with N-methylmorpholine generates adduct (I), which upon the nucleophilic attack of the carboxyl group of phenyl acetic acid (2b), leads to the formation of ester (II), that subsequently reacts with 2-hydroxybenzaldehyde (1a) to form
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R4
620
LETTER
K. V. Sashidhara et al. O Cl O N Cl
O
+
N Me
Me
N N
N
N Cl
DMF r.t.
Cl
Cl–
OCOBn
HO N
N Cl
Cl
N I
N Cl
N
2b
II OH CHO
1a O
O O
O
CHO
Scheme 2
III
Plausible mechanism of cyanuric chloride mediated reaction of 2-hydroxy benzaldehydes and phenyl acetic acid
ester (III), which, on consequent intramolecular cyclization–dehydration, furnishes the 3-aryl coumarin 7c. In summary, we have developed a simple and efficient method for the synthesis of substituted 3-aryl coumarins in good to excellent yields using cyanuric chloride. The important features of this methodology are shorter reaction times and higher yields compared to previously known methods and simple experimental procedure.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. They include spectral data of all the compounds associated with this article. Acknowledgment The authors thank the SAIF Division for providing the spectroscopic and analytical data. The authors are grateful to Dr Tushar K. Chakraborty (Director, CDRI) for his constant support and encouragement. G.R.P, A.S.R and A.K are thankful to CSIR, New Delhi, India for financial support. This is CDRI communication number 8169.
References and Notes (1) Part VIII in the series ‘Studies on Novel Synthetic Methodologies’. (2) Kennedy, R. O.; Thornes, R. D. Coumarins: Biology, Applications and Mode of Action; Wiley: New York., 1997. (3) Hoult, J. R. S.; Paya, M. Gen. Pharmacol. 1996, 27, 713. (4) Ma, T.; Liu, L.; Xue, H.; Li, L.; Han, C.; Wang, L.; Chen, Z.; Liu, G. J. Med. Chem. 2008, 51, 1432. (5) Kidane, A. G.; Salacinski, H. A.; Tiwari, K. R.; Bruckdorfer, A. M. Biomacromolecules 2004, 5, 798. (6) Appendino, G.; Mercalli, E.; Fuzzati, N.; Arnoldi, L.; Stavri, M.; Gibbons, S.; Ballero, M.; Maxia, A. J. Nat. Prod. 2004, 67, 2108. (7) Kontogiorgis, C. A.; Hadjipavlou, L. D. Bioorg. Med. Chem. Lett. 2004, 14, 611.
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(8) Go, M. L.; Wu, X.; Liu, X. L. Curr. Med. Chem. 2005, 12, 483. (9) (a) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sonkar, R.; Bhatia, G.; Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 4248. (b) Sashidhara, K. V.; Rosaiah, J. N.; Kumar, A.; Bhatia, G.; Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 3065. (c) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Srivastava, A.; Puri, A. Bioorg. Med. Chem. Lett. 2010, 20, 6504. (d) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem. Lett. 2010, 20, 7205. (e) Sashidhara, K. V.; Rosaiah, J. N.; Kumar, M.; Gara, R. K.; Nayak, L. V.; Srivastava, K.; Bid, H. K.; Konwar, R. Bioorg. Med. Chem. Lett. 2010, 20, 7127. (f) Sashidhara, K. V.; Rosaiah, J. N.; Bhatia, G.; Saxena, J. K. Eur. J. Med. Chem. 2008, 2592. (10) Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem. Lett. 2011, 21, 1937. (11) (a) Santana, L.; González-Díaz, H.; Quezada, E.; Uriarte, E.; Yáñez, M.; Viña, D.; Orallo, F. J. Med. Chem. 2008, 51, 6740. (b) Matos, M. J.; Viña, D.; Quezada, E.; Picciau, C.; Delogu, G.; Orallo, F.; Santana, L.; Uriarte, E. Bioorg. Med. Chem. Lett. 2009, 19, 3268. (c) Matos, M. J.; Viña, D.; Picciau, C.; Orallo, F.; Santana, L.; Uriarte, E. Bioorg. Med. Chem. Lett. 2009, 19, 5053. (12) Bogdal, D. J. Chem. Res. Synop. 1998, 468. (13) Mali, R. S.; Tilve, S. G. Synth. Commun. 1990, 20, 1781. (14) Mali, R. S.; Joshi, P. P. Synth. Commun. 2001, 31, 2753. (15) (a) Ming, Y.; Boykin, D. W. Heterocycles 1987, 26, 3229. (b) Vilar, S.; Quezada, E.; Santana, L.; Uriarte, E.; Yanez, M.; Fraiz, N.; Alcaide, C.; Cano, E.; Orallo, F. Bioorg. Med. Chem. Lett. 2006, 16, 257. (16) (a) Hans, N.; Singhi, M.; Sharma, V.; Grover, S. K. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1996, 11, 1159. (b) Santana, L.; González-Díaz, H.; Quezada, E.; Uriarte, E.; Yáñez, M.; Viña, D.; Orallo, F. J. Med. Chem. 2008, 51, 6740. (17) Khiri, C.; Ladhar, F.; El Gharbi, R.; Le Bigot, Y. Synth. Commun. 1999, 29, 1451. (18) Mohanty, S.; Makrandi, J. K.; Grove, S. K. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1989, 28, 766.
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7c
(19) Langmuir, M. E.; Yang, J. R.; Moussa, A. M.; Laura, R.; Lecompte, K. A. Tetrahedron Lett. 1995, 36, 3989. (20) Mashraqui, S.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129. (21) Kabeya, L. M.; de Marchi, A. A.; Kanashiro, A.; Lopes, N. P.; da Silva, C. H. Bioorg. Med. Chem. 2007, 15, 1516. (22) (a) Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem. 2003, 687, 425. (b) Bäuerle, P.; Schiedel, M. S. WO 2001068635, 2001. (23) Matos, M. J.; Vazquez-Rodriguez, S.; Borges, F.; Santana, L.; Uriarte, E. Tetrahedron Lett. 2011, 52, 1225. (24) Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553. (25) Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272. (26) Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org. Chem. 2005, 70, 2361. (27) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. Tetrahedron Lett. 2004, 45, 7729. (28) Bandgar, B. P.; Joshi, N. S.; Kamble, V. T. Tetrahedron Lett. 2006, 47, 4775. (29) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R. Synthesis 2006, 55. (30) Bigdeli, M. A.; Heravi, M. M.; Mahdavinia, G. H. Catal. Commun. 2007, 8, 1595. (31) Falorni, M.; Porcheddu, A.; Tadei, M. Tetrahedron Lett. 1999, 40, 4395. (32) Forbes, D. C.; Barrett, E. J.; Lewis, D. L.; Smith, M. C. Tetrahedron Lett. 2000, 41, 9943. (33) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2002, 43, 3413.
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Synthesis of 3-Aryl Coumarins
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(34) Giacomelli, G.; Porcheddu, A.; Salaris, M. Org. Lett. 2003, 5, 2715. (35) (a) Luo, G.; Xu, L.; Poindexter, G. S. Tetrahedron Lett. 2002, 43, 8909. (b) Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1979, 20, 3037. (36) (a) Kangani, C. O.; Day, B. W. Org. Lett. 2008, 10, 2645. (b) Mahdi, J.; Ankati, H.; Gregory, J.; Tenner, B.; Biehl, E. R. Tetrahedron Lett. 2011, 52, 2594. (37) Representative Experimental Procedure for the Synthesis of 3-(4¢-Methoxy Phenyl) Coumarin (1c) A mixture of cyanuric chloride (377 mg, 1.0 mmol), NMM (331 mg, 1.5 mmol), and 4-methoxyphenylacetic acid (1b, 340 mg, 1 mmol) in DMF (5 mL) was stirred at r.t. for 10 min. After this time 2-hydroxybenzaldehyde (1a, 250 mg, 1 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 45 min. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with H2O (10 mL) and extracted 3 times with EtOAc (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Al2O3, 70–230 mesh, neutral, hexane–CH2Cl2) to provide pure 1c [3-(4¢-methoxyphenyl)coumarin] as a colorless crystalline solid; yield 95%; mp 146–148 °C. IR (KBr): 3033, 1705, 1633, 1020 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.75 (s, 1 H), 7.68 (d, J = 8.8 Hz, 2 H), 7.53–7.47 (m, 2 H), 7.36–7.28 (m, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 160.8, 160.2, 153.3, 138.5, 131.0, 129.9, 127.9, 127.8, 127.1, 124.5, 119.9, 116.4, 113.9, 55.4. ESI-MS: m/z = 252 [M + H]+.
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