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Synlett 2012(4): 611-621  
DOI: 10.1055/s-0031-1290344
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficient and General Synthesis of 3-Aryl Coumarins Using Cyanuric Chloride [¹]

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: sashidhar123@gmail.com; e-Mail: kv_sashidhara@cdri.res.in;

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Publication History

Received 22 December 2011
Publication Date:
10 February 2012 (online)

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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.

Key words

synthesis - 3-aryl coumarins - cyanuric chloride - 2-­hydroxy 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 agents [8] 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 activity [¹0] and coumestrol (3-phenylcoumarin) 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]

Scheme 1 Reaction between 2-hydroxy benzaldehyde (1a) and 4-methoxy phenyl acetic acid (1b) promoted by TCT

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-methylpyridinium 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.

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
a Yields after purification by column chromatography.

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 3-aryl coumarin derivatives, using 2-hydroxy benzaldehydes and phenylacetic acid derivatives in the presence of cyanuric chloride. To the best our knowledge, this is the 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 ­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 chalcone-substituted 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 3-aryl 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.

Table 2 General Synthesis of Substituted 3-Aryl Coumarins (continued)

Entry Substrate a Substrate b Product Time (min) Yield (%)
1

1a

1b

1c 		45 95
2

2a

1b

2c 		60 90
3

3a

1b

3c 		40 97
4

4a

1b

4c 		30 96
5

5a

1b

5c 		45 98
6

6a

1b

6c 		85 90
7

1a

2b

7c 		40 93
8

4a

3b

8c 		35 95
 9

5a

3b

9c 		45 98
10

4a

4b

10c 		30 98
11

5a

4b

11c 		50 98
12

6a

4b

12c 		90 92
13

4a

5b

13c 		40 99
14

6a

5b

14c 		90 93
15

7a

1b

15c 		90 87
16

7a

4b

16c 		80 89
17

7a

5b

17c 		75 92
18

8a

1b

18c 		80 90
19

9a

4b

19c 		85 92
20

10a

5b

20c 		90 94
21

11a

4b

21c 		85 91
22

12a

4b

22c 		90 92
a Reaction conditions: Phenylacetic acid 1b-5b, cyanuric chloride, NMM, DMF, 110 ˚C, 30-90 min.
b 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.

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]

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 chloride [³³] [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 ester (III), which, on consequent intramolecular cyclization-dehydration, furnishes the 3-aryl coumarin 7c.

Scheme 2 Plausible mechanism of cyanuric chloride mediated reaction of 2-hydroxy benzaldehydes and phenyl acetic acid

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.accesdistant.sorbonne-universite.fr/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.

1

Part VIII in the series ‘Studies on Novel Synthetic Methodologies’.

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): δ = 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): δ = 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]+.

1

Part VIII in the series ‘Studies on Novel Synthetic Methodologies’.

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): δ = 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): δ = 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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Scheme 1 Reaction between 2-hydroxy benzaldehyde (1a) and 4-methoxy phenyl acetic acid (1b) promoted by TCT

Scheme 2 Plausible mechanism of cyanuric chloride mediated reaction of 2-hydroxy benzaldehydes and phenyl acetic acid