- Email: [email protected]
An efficient method for the preparation of mono α-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC)
Tetrahedron Letters 53 (2012) 1060–1062
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
An efficient method for the preparation of mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC) Manoranjan Behera a, R. Venkat Ragavan a,⇑, M. Sambaiah a, Balaiah Erugu a, J. Rama Krishna Reddy a,b, K. Mukkanti b, Satyanarayana Yennam a a b
Chemistry services, GVK Biosciences Pvt. Ltd, Plot No. 28, IDA, Nacharam, Hyderabad 500 076, A.P., India Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, A.P., India
a r t i c l e
i n f o
Article history: Received 17 November 2011 Revised 15 December 2011 Accepted 16 December 2011 Available online 24 December 2011
a b s t r a c t An efficient method for the synthesis of mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC) has been described. Using this method many sterically hindered and highly substituted mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate were synthesized in high yield. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Ethyl-1-imidazole carbamate LiHMDS Mono-a-aryl derivatives of diethyl malonate and ethyl cyanoacetate
The century old alkylation chemistry of diethyl malonate and related compounds continue to see wide use in organic synthesis.1 a-Aryl malonates have been used as effective modulators in mammalian cell membranes and as enzyme inhibitors.2 For the synthesis of highly functionalized compounds containing quaternary centers3; malonate chemistry remains the method of choice. A broad range of synthetically valuable materials is derived from a-aryl malonates.4–7 For example, a-aryl malonates have a notable potential in the synthesis of a-aryl carboxylic acids.8 a-Aryl carboxylic acids and acid derivatives comprise an important class of organic molecules. There has been much interest in these molecules because of their occurrence in a myriad of natural products and wide applications in pharmaceutical chemistry.9 a-Aryl acetic acids (e.g., indomethancin, sulindac, ibufenca, dicofenac) and a-aryl propionic acids (e.g., ibuprofen, naproxen, ketoprofen) are two main categories of nonsteroidal anti-inflammatory drugs (NSAIDS).10 Aryl cyanoacetates can be used to generate a variety of nitrogen containing products such as amino alcohols11 and b-amino acids12 while also being valuable as chiral shift reagents.13 Among the many methods available14 for the synthesis of a-aryl compounds, a great deal of attention has been given to the palla-
dium-catalyzed coupling of enolates with aryl halides.15 Another important protocol involves arylation of activated methylene compounds mediated by copper salts.16 Recently, proline has also been used along with CuI for c-arylation of diethyl malonate.17 But some of the methods suffer from serious drawbacks and limitations viz. long reaction times, the high cost of Pd catalyst and the need for stoichiometric amounts of copper salts.18 Hartwig reported that di-alkyl malonate did not react with pyridyl halides or halobenzonitriles in the presence of palladium catalysts.19 Among other reagents for arylation of diethyl malonate, Jeff’s group has used ethyl cyanoformate and phenyl acetic acid ester to prepare the a-aryl malonate.20 Recently, the same method has been used for the preparation of 1,3-porpane diamine derivatives21 But it was not generalized for various substrates. Also there are few reports using diethyl carbonate. But the main disadvantage is that one has to use large excess of diethyl carbonate and base.22
COOEt
N
N COOEt
EtOOC
COOEt
2 ⇑ Corresponding author. Tel.: +91 6628 1348; fax: +91 6628 1505. E-mail addresses: (R. Venkat Ragavan).
[email protected],
[email protected]
1a
LiHMDS, THF
Scheme 1. Synthesis of diethyl 2-phenyl malonate (2a). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.12.067
3a
1061
M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
During our research program on preparation of heterocycles we needed to synthesize number of a-aryl compounds with various degrees of substituent on aromatic ring. Intrigued by the finding of Saprong et al23 that methyl imidazole carbamate (MImC) can be used for the esterification and amidation of carboxylic acids, we ventured to explore the potential use of ethyl imidazole carbamate (EImC) for the preparation of a-aryl malonate derivatives. Herein, we wish to report that EImC24 can be used efficiently for the preparation of a-aryl diethyl malonate and ethyl cyanoacetate starting from the phenyl acetic acid ester (Scheme 1). Ethyl-1imidazole carbamate (EImC) 2 was prepared by treating ethyl chloroformate with imidazole in the presence of triethylamine in DCM in very good yield. Initially, phenyl acetic acid ethyl ester 1a was chosen as model substrate. Thus, when compound 1a was reacted with EImC in the presence of LiHMDS in THF at 0 °C for 6 h, the compound 3a was obtained with 44% yield along with some unwanted product. When we repeated the same reaction at 78 °C, better yield was obtained and no by product was observed. 1H NMR of compound 3a clearly shows the characteristic peak at 4.6 as singlet besides ester and aromatic peaks. To optimize the reaction conditions, various bases and solvents were screened whose results are summarized in Table 1. Among the bases screened we found that LiHMDS produced the best yield, while KHMDS gave 67% yield. Use of sodium hydride and potassium tert-butoxide resulted in poor yield and also 10–20% of unreacted phenyl acetic acid ethyl ester was recovered in both the cases. Among the solvents screened we observe that both the solvents viz. THF and toluene are good for these reactions. Once the reaction condition was standardized, various highly substituted phenyl acetic acid ethyl esters were reacted with EImC (2) to give the compounds 3a–p (Table 2)25 The required phenyl acetic acid ethyl esters were either commercially available or prepared from corresponding acids by esterification with EtOH in the presence of cat. H2SO4. All compounds 4–17 were well characterized by 1H NMR, IR and 13 C NMR (for unknown compounds). The purity of all compound were measured by LC–MS analysis. It is noteworthy to mention here that previously inaccessible pyridine analogues and benzonitrile analogues were synthesized in very good yield (entries 14–16). As indicated in Table 2, sterically hindered analogues (entries 1, 3 and 6) and substrates having the strong electron withdrawing groups (entries 5, 10 and 15) gave the products in very good yield without any difficulties. We did not observe the self condensed products of phenyl acetic acid ethyl esters in any of the cases. Using the condition above, ortho-substitution is tolerated to give the products in good yield. Similar approach was adapted to synthesize26 the mono a-aryl derivatives of ethyl cyanoacetate (Scheme 2) and the results are given in Table 3. All the substrates reacted well under these conditions and did not produce any by products. Also, we did not observe the hydrolysis of cyano group in this condition. In conclusion, we developed an efficient and simple method to synthesize the mono a-aryl diethyl malonates and mono a-aryl ethyl cyanoacetates in good yield using LiHMDS and EImC.
Table 2 Synthesis of mono a-aryl diethyl malonates Entry
Substrate
COOEt
EtOOC COOEt
1a COOEt
3a EtOOC COOEt
1b OCH3 COOEt F Cl 1c COOEt
OCH3 EtOOC COOEt F Cl 3c EtOOC COOEt
81
1
2
3
4
1d OCF3 COOEt
5
1e F
6
7
F COOEt Cl Cl 1f Cl COOEt F F 1g COOEt
8
9
COOEt 10
CF3 COOEt
a b
Yielda (%)
1 2 3 4 5 6
LiHMDS (1 M in THF) KHMDS (1 M in THF) LiHMDS (1 M in THF) NaH t-BuOK LiHMDS (1 M in THF)
THF THF THF THF THF Toluene
81 67 44b 42 33 78
Isolated yield. Reaction performed at 0 °C.
3e F F EtOOC COOEt Cl Cl 3f Cl EtOOC COOEt F F 3g EtOOC COOEt 3h
3i EtOOC
3j EtOOC
CF3 COOEt
EtOOC
3k COOEt F 3l
1l Br COOEt F
Br EtOOC COOEt F
1m Cl COOEt 1n
3m
72
77
78
65
75
3n
N
EtOOC COOEt F 3o
CN COOEt
CN EtOOC COOEt
N
1p
82
75
Cl EtOOC COOEt
COOEt F 1o
16
Isolated yield.
78
COOEt
F
12
a
69
80
1k COOEt
15
75
Cl EtOOC COOEt
11
13
76
OCF3 EtOOC COOEt
1j
N Solvent
3d
1i
14
Base
3b
1h Cl COOEt
Table 1 Effect of solvent and base on the yield of 3a Entry
Yielda (%)
Product
N
3p
84
72
79
1062
M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
N
CN
EtOOC
N COOEt
CN
2 F
6.
LiHMDS, THF
4a
F
5a 7.
Scheme 2. Synthesis of ethyl 2-cyano-2-(4-fluorophenyl) acetate (5a).
8. 9.
Table 3 Synthesis of mono a-aryl ethyl cyanoacetates S. No
Substrate
CN
Yielda (%)
Product
EtOOC
CN
4a
1
5a F
F CN
EtOOC
F 4b
2
Br CN
Cl CN
CN F 5b
EtOOC
F 4c
3
71
Br CN F 5c
14. 15.
73 16.
Cl EtOOC CN 81
4
4d CN 5
a
68
10. 11. 12. 13.
EtOOC
5d CN
4e
5e
OMe
OMe
17. 78
Isolated yield.
Acknowledgments We are grateful to GVK Biosciences Pvt. Ltd for the financial support and analytical data. We thank Dr. Balram Patro for his encouragement and motivation. Supplementary data
18.
19. 20. 21.
22.
23. 24. 25.
Supplementary data (copies of 1H NMR & 13C NMR and LC–MS of the compounds) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.12.067. References and notes 1. (a) Cope, A. C.; Holmes, H. L.; House, H. O. Org. React. 1957, 9, 107; (b) Gorssman, R. B.; Varner, M. A. J. Org. Chem. 1997, 62, 5235. 2. (a) Beyer, J.; Jensen, B. S.; Strobaek, D.; Christophersen, P.; Teuber, L. WO Patent 00/37422, 2000.; (b) Gao, Y.; Burke, T. R. Synlett 2000, 134; (c) Gao, Y.; Yao, Z. J.; Guo, R.; Zou, H.; Kelly, J.; Voigt, J. H.; Yang, D.; Burke, T. R. J. Med. Chem. 2000, 41, 911; (d) Roedern, E. G.; Grams, F.; Brandstetter, H.; Moroder, L. J. Med. Chem. 1998, 41, 339. 3. (a) Fuji, K. Chem. Rev. 1993, 93, 2037; (b) Canet, J. L.; Fadel, A.; Salaun, J. J. Org. Chem. 1992, 57, 3463; (c) Martin, S. F. Tetrahedron 1980, 36, 419. 4. Matoishi, K.; Hanzawa, S.; Kakidani, H.; Sugai, T.; Ohta, H. Chem. Commun. 2000, 1519. 5. (a) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769; (b) Toone, E. J.; Jones, J. B. Tetrahedron: Asymmetry 1991, 2, 1041; (c) Shunsaku, S.;
26.
Okada, H.; Nakamata, K.; Yamamoto, T.; Sekine, F. Heterocycles 1996, 43, 1031; (d) Patel, R.; Banerjee, A.; Chu, L.; Brozozowski, D.; Nanduri, V.; Laszlo J. Am. Oil. Chem. Soc. 1998, 75, 1473; (e) Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1. (a) Narisano, E.; Riva, R. Tetrahderon: Asymmetry 1999, 10, 1223; (b) Guanti, G.; Narisano, E.; Riva, R. Tetrahderon: Asymmetry 1859, 1998, 9; (c) Chenevert, R.; Desjardins, M. Can. J. Chem. 1994, 72, 2312. (a) Knabe, J.; Buch, H. P.; Kirsch, G. A. Arch. Pharm. 1987, 320, 323; (b) Meester, P. D.; Jovanovic, M. V.; Chu, S. S. C.; Biehl, E. R. J. Heterocycl. Chem. 1986, 32, 337. Carey, F. A.; Sunderberg, R. J. Advanced Organic Chemistry Part B: Reaction and Synthesis; Plenum Press: New York, 1990. pp 13–16. (a) Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D. H.; Smith, G. A. Nature 1978, 271, 223; (b) Takeda, T.; Gonda, R.; Hatano, K. Chem. Pharm. Bull. 1997, 45, 697; (c) Kong, F.; Andersen, R. J. J. Org. Chem. 1993, 58, 6924; (d) Hedge, V. R.; Dai, P.; Patel, M.; Gullo, V. P. Tetrahedron Lett. 1998, 39, 5683; (e) Kimura, Y.; Nishibe, M.; Nakajima, H.; Hamasaki, T. Agric. Biol. Chem. 1991, 55, 1137. Rieu, J. P.; Boucherle, A.; Cousse, H.; Mouzine, G. Tetrahedron 1986, 42, 4095. Knabe, J.; Buch, H. P.; Kirsch, G. A. Arch. Pharm. 1985, 318, 593. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1. (a) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728; (b) Takeuchi, Y.; Iwashita, H.; Yamada, K.; Gotaishi, M.; Kurose, N.; Koizumi, T.; Kabuto, K.; Kometani, T. Chem. Pharm. Bull. 1995, 43, 1668; (c) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani, T.; Kirk, K. L. Chem. Commun. 1998, 365. (a) Grossman, R. B.; Varner, M. J. Org. Chem. 1997, 62, 5235; (b) Piorko, A.; AbdEl-Aziz, A. S.; Lee, C. C.; Sutherland, R. G. J. Chem. Soc., Perkin Tarns. I 1989, 469. (a) Culkin, D. A.; Hatrwig, J. F. Acc. Chem. Res 2003, 36, 234; (b) Aramendia, M. A.; Bprau, V.; Jimenez, C.; Marinas, J. R. R.; Ruiz, J. R.; Urbano, F. J. Tetrahedron Lett. 2002, 43, 2847; (c) Djakovitch, L.; Kohler, K. J. Organomet. Chem. 2000, 60, 101; (d) Hennesy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. & references cited therein. (a) Okura, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 7606; (b) Suzuki, H.; Kobayashi, T.; Osuka, A. Chem. Lett. 1983, 12, 589; (c) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469; (d) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem. 2004, 6, 215; (e) Kidwai, M.; Bhardwaj, S.; Poddar, R.; Belstein J. Org. Chem. 2010, 6, 35; (f) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. (a) Setsune, J. I.; Matsukawa, K.; Wakemoto, H.; Kitao, T. Chem. Lett. 1981, 10, 367; (b) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693; (c) Buchwald, Z. Org. Lett. 2005, 7, 4693. (a) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731; (b) Fox, J. M.; Huang, X.; Chieff, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360; (c) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816. Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541. Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948. (a) Busto, E.; Gotor-Fernandez, V.; Montejo-Bernado, J.; Garcia-Granda, S.; Gotor, V. Org. Lett. 2007, 9, 4203; (b) Rios-Lambodia, N.; Busto, E.; GarciaUrdiales, E.; Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2009, 74, 2571. (a) Richon, A. B.; Maragoudakis, M. E.; Wasvary, J. S. J. Med. Chem. 1982, 25, 745; (b) Shiotani, S.; Okada, H.; Nakamat, K.; Yamamoto, T.; Sekine, F. Heterocycles 1996, 43, 1031. Heller, S. T.; Sarpong, R. Org. Lett. 2010, 12, 4572. Heller, S. T.; Sarpong, R. Tetrahedron 2011, 67, 8851. Typical experimental for preparation of compound 3a: To a stirred solution of phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at 78 °C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at 78 °C and stirred at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 4% ethyl acetate/pet ether gave the pure compound 3a (1.1 g, 81% yield) as a colorless liquid. Typical experimental for preparation of compound 5a: To a stirred solution of compound 4a (700 mg, 5.18 mmol) in THF (10 mL) was added LiHMDS (6.2 ml, 1 M sol. in THF, 6.2 mmol) at 0 °C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (870 mg, 6.22 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at 0 °C and stirred at rt for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 10% ethyl acetate/pet ether gave the pure compound 5a (720 mg, 68% yield) as a colorless liquid.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
An efficient method for the preparation of mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC) Manoranjan Behera a, R. Venkat Ragavan a,⇑, M. Sambaiah a, Balaiah Erugu a, J. Rama Krishna Reddy a,b, K. Mukkanti b, Satyanarayana Yennam a a b
Chemistry services, GVK Biosciences Pvt. Ltd, Plot No. 28, IDA, Nacharam, Hyderabad 500 076, A.P., India Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, A.P., India
a r t i c l e
i n f o
Article history: Received 17 November 2011 Revised 15 December 2011 Accepted 16 December 2011 Available online 24 December 2011
a b s t r a c t An efficient method for the synthesis of mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC) has been described. Using this method many sterically hindered and highly substituted mono a-aryl derivatives of diethyl malonate and ethyl cyanoacetate were synthesized in high yield. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Ethyl-1-imidazole carbamate LiHMDS Mono-a-aryl derivatives of diethyl malonate and ethyl cyanoacetate
The century old alkylation chemistry of diethyl malonate and related compounds continue to see wide use in organic synthesis.1 a-Aryl malonates have been used as effective modulators in mammalian cell membranes and as enzyme inhibitors.2 For the synthesis of highly functionalized compounds containing quaternary centers3; malonate chemistry remains the method of choice. A broad range of synthetically valuable materials is derived from a-aryl malonates.4–7 For example, a-aryl malonates have a notable potential in the synthesis of a-aryl carboxylic acids.8 a-Aryl carboxylic acids and acid derivatives comprise an important class of organic molecules. There has been much interest in these molecules because of their occurrence in a myriad of natural products and wide applications in pharmaceutical chemistry.9 a-Aryl acetic acids (e.g., indomethancin, sulindac, ibufenca, dicofenac) and a-aryl propionic acids (e.g., ibuprofen, naproxen, ketoprofen) are two main categories of nonsteroidal anti-inflammatory drugs (NSAIDS).10 Aryl cyanoacetates can be used to generate a variety of nitrogen containing products such as amino alcohols11 and b-amino acids12 while also being valuable as chiral shift reagents.13 Among the many methods available14 for the synthesis of a-aryl compounds, a great deal of attention has been given to the palla-
dium-catalyzed coupling of enolates with aryl halides.15 Another important protocol involves arylation of activated methylene compounds mediated by copper salts.16 Recently, proline has also been used along with CuI for c-arylation of diethyl malonate.17 But some of the methods suffer from serious drawbacks and limitations viz. long reaction times, the high cost of Pd catalyst and the need for stoichiometric amounts of copper salts.18 Hartwig reported that di-alkyl malonate did not react with pyridyl halides or halobenzonitriles in the presence of palladium catalysts.19 Among other reagents for arylation of diethyl malonate, Jeff’s group has used ethyl cyanoformate and phenyl acetic acid ester to prepare the a-aryl malonate.20 Recently, the same method has been used for the preparation of 1,3-porpane diamine derivatives21 But it was not generalized for various substrates. Also there are few reports using diethyl carbonate. But the main disadvantage is that one has to use large excess of diethyl carbonate and base.22
COOEt
N
N COOEt
EtOOC
COOEt
2 ⇑ Corresponding author. Tel.: +91 6628 1348; fax: +91 6628 1505. E-mail addresses: (R. Venkat Ragavan).
[email protected],
[email protected]
1a
LiHMDS, THF
Scheme 1. Synthesis of diethyl 2-phenyl malonate (2a). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.12.067
3a
1061
M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
During our research program on preparation of heterocycles we needed to synthesize number of a-aryl compounds with various degrees of substituent on aromatic ring. Intrigued by the finding of Saprong et al23 that methyl imidazole carbamate (MImC) can be used for the esterification and amidation of carboxylic acids, we ventured to explore the potential use of ethyl imidazole carbamate (EImC) for the preparation of a-aryl malonate derivatives. Herein, we wish to report that EImC24 can be used efficiently for the preparation of a-aryl diethyl malonate and ethyl cyanoacetate starting from the phenyl acetic acid ester (Scheme 1). Ethyl-1imidazole carbamate (EImC) 2 was prepared by treating ethyl chloroformate with imidazole in the presence of triethylamine in DCM in very good yield. Initially, phenyl acetic acid ethyl ester 1a was chosen as model substrate. Thus, when compound 1a was reacted with EImC in the presence of LiHMDS in THF at 0 °C for 6 h, the compound 3a was obtained with 44% yield along with some unwanted product. When we repeated the same reaction at 78 °C, better yield was obtained and no by product was observed. 1H NMR of compound 3a clearly shows the characteristic peak at 4.6 as singlet besides ester and aromatic peaks. To optimize the reaction conditions, various bases and solvents were screened whose results are summarized in Table 1. Among the bases screened we found that LiHMDS produced the best yield, while KHMDS gave 67% yield. Use of sodium hydride and potassium tert-butoxide resulted in poor yield and also 10–20% of unreacted phenyl acetic acid ethyl ester was recovered in both the cases. Among the solvents screened we observe that both the solvents viz. THF and toluene are good for these reactions. Once the reaction condition was standardized, various highly substituted phenyl acetic acid ethyl esters were reacted with EImC (2) to give the compounds 3a–p (Table 2)25 The required phenyl acetic acid ethyl esters were either commercially available or prepared from corresponding acids by esterification with EtOH in the presence of cat. H2SO4. All compounds 4–17 were well characterized by 1H NMR, IR and 13 C NMR (for unknown compounds). The purity of all compound were measured by LC–MS analysis. It is noteworthy to mention here that previously inaccessible pyridine analogues and benzonitrile analogues were synthesized in very good yield (entries 14–16). As indicated in Table 2, sterically hindered analogues (entries 1, 3 and 6) and substrates having the strong electron withdrawing groups (entries 5, 10 and 15) gave the products in very good yield without any difficulties. We did not observe the self condensed products of phenyl acetic acid ethyl esters in any of the cases. Using the condition above, ortho-substitution is tolerated to give the products in good yield. Similar approach was adapted to synthesize26 the mono a-aryl derivatives of ethyl cyanoacetate (Scheme 2) and the results are given in Table 3. All the substrates reacted well under these conditions and did not produce any by products. Also, we did not observe the hydrolysis of cyano group in this condition. In conclusion, we developed an efficient and simple method to synthesize the mono a-aryl diethyl malonates and mono a-aryl ethyl cyanoacetates in good yield using LiHMDS and EImC.
Table 2 Synthesis of mono a-aryl diethyl malonates Entry
Substrate
COOEt
EtOOC COOEt
1a COOEt
3a EtOOC COOEt
1b OCH3 COOEt F Cl 1c COOEt
OCH3 EtOOC COOEt F Cl 3c EtOOC COOEt
81
1
2
3
4
1d OCF3 COOEt
5
1e F
6
7
F COOEt Cl Cl 1f Cl COOEt F F 1g COOEt
8
9
COOEt 10
CF3 COOEt
a b
Yielda (%)
1 2 3 4 5 6
LiHMDS (1 M in THF) KHMDS (1 M in THF) LiHMDS (1 M in THF) NaH t-BuOK LiHMDS (1 M in THF)
THF THF THF THF THF Toluene
81 67 44b 42 33 78
Isolated yield. Reaction performed at 0 °C.
3e F F EtOOC COOEt Cl Cl 3f Cl EtOOC COOEt F F 3g EtOOC COOEt 3h
3i EtOOC
3j EtOOC
CF3 COOEt
EtOOC
3k COOEt F 3l
1l Br COOEt F
Br EtOOC COOEt F
1m Cl COOEt 1n
3m
72
77
78
65
75
3n
N
EtOOC COOEt F 3o
CN COOEt
CN EtOOC COOEt
N
1p
82
75
Cl EtOOC COOEt
COOEt F 1o
16
Isolated yield.
78
COOEt
F
12
a
69
80
1k COOEt
15
75
Cl EtOOC COOEt
11
13
76
OCF3 EtOOC COOEt
1j
N Solvent
3d
1i
14
Base
3b
1h Cl COOEt
Table 1 Effect of solvent and base on the yield of 3a Entry
Yielda (%)
Product
N
3p
84
72
79
1062
M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
N
CN
EtOOC
N COOEt
CN
2 F
6.
LiHMDS, THF
4a
F
5a 7.
Scheme 2. Synthesis of ethyl 2-cyano-2-(4-fluorophenyl) acetate (5a).
8. 9.
Table 3 Synthesis of mono a-aryl ethyl cyanoacetates S. No
Substrate
CN
Yielda (%)
Product
EtOOC
CN
4a
1
5a F
F CN
EtOOC
F 4b
2
Br CN
Cl CN
CN F 5b
EtOOC
F 4c
3
71
Br CN F 5c
14. 15.
73 16.
Cl EtOOC CN 81
4
4d CN 5
a
68
10. 11. 12. 13.
EtOOC
5d CN
4e
5e
OMe
OMe
17. 78
Isolated yield.
Acknowledgments We are grateful to GVK Biosciences Pvt. Ltd for the financial support and analytical data. We thank Dr. Balram Patro for his encouragement and motivation. Supplementary data
18.
19. 20. 21.
22.
23. 24. 25.
Supplementary data (copies of 1H NMR & 13C NMR and LC–MS of the compounds) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.12.067. References and notes 1. (a) Cope, A. C.; Holmes, H. L.; House, H. O. Org. React. 1957, 9, 107; (b) Gorssman, R. B.; Varner, M. A. J. Org. Chem. 1997, 62, 5235. 2. (a) Beyer, J.; Jensen, B. S.; Strobaek, D.; Christophersen, P.; Teuber, L. WO Patent 00/37422, 2000.; (b) Gao, Y.; Burke, T. R. Synlett 2000, 134; (c) Gao, Y.; Yao, Z. J.; Guo, R.; Zou, H.; Kelly, J.; Voigt, J. H.; Yang, D.; Burke, T. R. J. Med. Chem. 2000, 41, 911; (d) Roedern, E. G.; Grams, F.; Brandstetter, H.; Moroder, L. J. Med. Chem. 1998, 41, 339. 3. (a) Fuji, K. Chem. Rev. 1993, 93, 2037; (b) Canet, J. L.; Fadel, A.; Salaun, J. J. Org. Chem. 1992, 57, 3463; (c) Martin, S. F. Tetrahedron 1980, 36, 419. 4. Matoishi, K.; Hanzawa, S.; Kakidani, H.; Sugai, T.; Ohta, H. Chem. Commun. 2000, 1519. 5. (a) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769; (b) Toone, E. J.; Jones, J. B. Tetrahedron: Asymmetry 1991, 2, 1041; (c) Shunsaku, S.;
26.
Okada, H.; Nakamata, K.; Yamamoto, T.; Sekine, F. Heterocycles 1996, 43, 1031; (d) Patel, R.; Banerjee, A.; Chu, L.; Brozozowski, D.; Nanduri, V.; Laszlo J. Am. Oil. Chem. Soc. 1998, 75, 1473; (e) Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1. (a) Narisano, E.; Riva, R. Tetrahderon: Asymmetry 1999, 10, 1223; (b) Guanti, G.; Narisano, E.; Riva, R. Tetrahderon: Asymmetry 1859, 1998, 9; (c) Chenevert, R.; Desjardins, M. Can. J. Chem. 1994, 72, 2312. (a) Knabe, J.; Buch, H. P.; Kirsch, G. A. Arch. Pharm. 1987, 320, 323; (b) Meester, P. D.; Jovanovic, M. V.; Chu, S. S. C.; Biehl, E. R. J. Heterocycl. Chem. 1986, 32, 337. Carey, F. A.; Sunderberg, R. J. Advanced Organic Chemistry Part B: Reaction and Synthesis; Plenum Press: New York, 1990. pp 13–16. (a) Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D. H.; Smith, G. A. Nature 1978, 271, 223; (b) Takeda, T.; Gonda, R.; Hatano, K. Chem. Pharm. Bull. 1997, 45, 697; (c) Kong, F.; Andersen, R. J. J. Org. Chem. 1993, 58, 6924; (d) Hedge, V. R.; Dai, P.; Patel, M.; Gullo, V. P. Tetrahedron Lett. 1998, 39, 5683; (e) Kimura, Y.; Nishibe, M.; Nakajima, H.; Hamasaki, T. Agric. Biol. Chem. 1991, 55, 1137. Rieu, J. P.; Boucherle, A.; Cousse, H.; Mouzine, G. Tetrahedron 1986, 42, 4095. Knabe, J.; Buch, H. P.; Kirsch, G. A. Arch. Pharm. 1985, 318, 593. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1. (a) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728; (b) Takeuchi, Y.; Iwashita, H.; Yamada, K.; Gotaishi, M.; Kurose, N.; Koizumi, T.; Kabuto, K.; Kometani, T. Chem. Pharm. Bull. 1995, 43, 1668; (c) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani, T.; Kirk, K. L. Chem. Commun. 1998, 365. (a) Grossman, R. B.; Varner, M. J. Org. Chem. 1997, 62, 5235; (b) Piorko, A.; AbdEl-Aziz, A. S.; Lee, C. C.; Sutherland, R. G. J. Chem. Soc., Perkin Tarns. I 1989, 469. (a) Culkin, D. A.; Hatrwig, J. F. Acc. Chem. Res 2003, 36, 234; (b) Aramendia, M. A.; Bprau, V.; Jimenez, C.; Marinas, J. R. R.; Ruiz, J. R.; Urbano, F. J. Tetrahedron Lett. 2002, 43, 2847; (c) Djakovitch, L.; Kohler, K. J. Organomet. Chem. 2000, 60, 101; (d) Hennesy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. & references cited therein. (a) Okura, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 7606; (b) Suzuki, H.; Kobayashi, T.; Osuka, A. Chem. Lett. 1983, 12, 589; (c) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469; (d) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem. 2004, 6, 215; (e) Kidwai, M.; Bhardwaj, S.; Poddar, R.; Belstein J. Org. Chem. 2010, 6, 35; (f) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. (a) Setsune, J. I.; Matsukawa, K.; Wakemoto, H.; Kitao, T. Chem. Lett. 1981, 10, 367; (b) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693; (c) Buchwald, Z. Org. Lett. 2005, 7, 4693. (a) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731; (b) Fox, J. M.; Huang, X.; Chieff, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360; (c) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816. Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541. Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948. (a) Busto, E.; Gotor-Fernandez, V.; Montejo-Bernado, J.; Garcia-Granda, S.; Gotor, V. Org. Lett. 2007, 9, 4203; (b) Rios-Lambodia, N.; Busto, E.; GarciaUrdiales, E.; Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2009, 74, 2571. (a) Richon, A. B.; Maragoudakis, M. E.; Wasvary, J. S. J. Med. Chem. 1982, 25, 745; (b) Shiotani, S.; Okada, H.; Nakamat, K.; Yamamoto, T.; Sekine, F. Heterocycles 1996, 43, 1031. Heller, S. T.; Sarpong, R. Org. Lett. 2010, 12, 4572. Heller, S. T.; Sarpong, R. Tetrahedron 2011, 67, 8851. Typical experimental for preparation of compound 3a: To a stirred solution of phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at 78 °C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at 78 °C and stirred at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 4% ethyl acetate/pet ether gave the pure compound 3a (1.1 g, 81% yield) as a colorless liquid. Typical experimental for preparation of compound 5a: To a stirred solution of compound 4a (700 mg, 5.18 mmol) in THF (10 mL) was added LiHMDS (6.2 ml, 1 M sol. in THF, 6.2 mmol) at 0 °C and the reaction mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (870 mg, 6.22 mmol) in dry THF (3 ml) was added drop wise to the reaction mixture at 0 °C and stirred at rt for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 10% ethyl acetate/pet ether gave the pure compound 5a (720 mg, 68% yield) as a colorless liquid.