HETEROCYCLES

Communication | Regular issue | Vol. 83, No. 12, 2011, pp. 2773-2778
Received, 17th September, 2011, Accepted, 14th October, 2011, Published online, 20th October, 2011.
DOI: 10.3987/COM-11-12363

■ Efficient and Mild Procedure for the Decarboxylative Cyanomethyl Esterification of Arylmalonic Acids Using ClCH2CN/1,8-Diazabicyclo[5.4.0]undec-7-ene

Niiha Sasakura, Tomoyuki Yamauchi, Keiji Nakano, Yoshiyasu Ichikawa, and Hiyoshizo Kotsuki*

Laboratory of Natural Products Chemistry, Faculty of Science, Kochi University, 2-5-1, Akebono-cho, Kochi 780-8520, Japan

Abstract

An efficient and mild procedure for the decarboxylative cyanomethyl esterification of arylmalonic acids has been developed. The reaction can be performed at room temperature by using chloroacetonitrile and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene, and the desired arylacetic acid cyanomethyl esters are obtained in high yields within a short period of time.

Malonic ester synthesis is one of the most fundamental techniques for the chain elongation of carboxylic acids based on a carbon-carbon bond-forming strategy.1 This procedure can usually be performed through a three-step process, i.e., alkylation of malonic esters, hydrolysis to free dicarboxylic acids, and decarboxylation by heating (Scheme 1). In this synthetic sequence, the final step of decarboxylation requires rather high temperatures, although alternative methods have been reported to avoid this difficulty.2

In our separate work on organocatalytic asymmetric synthesis,3 we needed to prepare a variety of arylacetic acid derivatives using malonic ester synthesis in a quite simple methodology. Unexpectedly, however, we found that the treatment of arylmalonic acid intermediate 1 with chloroacetonitrile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a strong amidine base in THF gave the corresponding monoester 2 accompanied by unusual decarboxylation.4 Very recently, Lafrance et al. reported a closely related work on the N,N’-carbonyldiimidazole-directed decarboxylation of malonic acids.5 This result prompted us to report our independent findings in this field.
First, several organic bases were examined to optimize the conditions (Table 1). Pyridine showed no activity, and Et3N rather weakly promoted the desired reaction compared with DBU, while no reaction was observed in the absence of a base (Table 1, Entries 1-4). At least 1.5 equiv. of both chloroacetonitrile and DBU were necessary to achieve high yield, and a reduction to stoichiometric amounts compromised the reactivity (Table 1, compare Entries 4 and 5). Next, we found that there was a significant solvent effect: THF, CH2Cl2, DMF, MeCN, and MeNO2 were tested, but they were less effective than toluene (Table 1, Entries 5-10). The solvent-free system was somewhat complicated and 2 was recovered in 65% yield (Table 1, Entry 11). Thus, the best conditions were as follows: ClCH2CN (1.5 equiv.), DBU (1.5 equiv.), in toluene.

With the optimized reaction conditions in hand, we then investigated the general scope of this chemistry by using various substituted malonic acids as substrates (Table 2).

As expected, a variety of aromatic and heteroaromatic malonic acids underwent decarboxylative esterification in good to high yields (Table 2, Entries 1-8). The reaction was also successful with the rigid tetralin system (Table 2, Entry 6). One notable limitation of this method is that alkyl-group-substituted malonic acids were less reactive, and the corresponding diesters were formed exclusively (Table 2, Entries 9 and 10).6
It is well known that cyanomethyl esters are stable but useful as mildly activated functionalities.7 Accordingly, we examined their utility in amidation and transesterification by the action of piperidine and cyclohexanol as typical N- and O-nucleophiles. The results are summarized in Table 3.

In all cases, the desired reactions proceeded cleanly to afford the corresponding piperidinyl amides and cyclohexyl esters in good to high yields. Thus, the overall process starting from malonic acid precursors provides a new entry to derive pharmaceutically important arylacetic acid derivatives.8
In our decarboxylative esterification, the best solvent was determined to be toluene, where the reaction took place in a two-phase system. In this case, arylacetates formed by decarboxylation should be smoothly transferred to the less polar toluene phase prior to contamination with venomous side-reactions. In contrast, the same components in an aprotic polar solvent such as THF or DMF became a clear homogeneous solution, which led to inevitable interference from excess reagents or by-products formed in situ. A plausible mechanism to account for the present decarboxylation is shown in Scheme 2. Mono-esterification followed by decarboxylation produced the anionic intermediate that is stabilized by virtue of the electron-withdrawing nature of a cyanomethyl group.

In conclusion, we have developed an efficient and mild procedure for the decarboxylative esterification of arylmalonic acids using ClCH2CN and DBU. This method is useful for preparing a variety of arylacetic acid cyanomethyl esters with a very simple strategy. Interestingly, the overall process resembles arylmalonate decarboxylase (AMDase) catalysis.9 This suggests that we may be able to extend this approach to asymmetric organocatalysis, and further studies along these lines are now in progress in our laboratory.

Experimental Section
General procedure: To a suspension of dicarboxylic acids (1.0 mmol) in toluene (2.0 mL) were added at rt DBU (1.5 mmol) and ClCH2CN (1.5 mmol), and the mixture was stirred until the reaction was complete. The mixture was then diluted by the addition of AcOEt, washed with H2O and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel column chromatography (elution with CH2Cl2) to afford the pure ester.

Amidation of cyanomethyl ester: To a solution of cyanomethyl ester (1.0 mmol) in dry MeCN (2.0 mL) were added piperidine (2.0 mmol) and DBU (2.0 mmol) at rt. After completion, the mixture was diluted by the addition of AcOEt, washed with H2O and brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (elution with hexane/ AcOEt) to afford the pure amide.
Transesterification of cyanomethyl ester: To a solution of cyclohexanol (1.0 mmol) in THF (2.0 mL) was added n-BuLi (1.2 mmol) at –40 °C under Ar. After stirring for 10 min, the solution was introduced to a solution of cyanomethyl ester in THF (2.0 mL) via cannula at 0 °C. After completion, the mixture was quenched by the addition of sat. aq. NH4Cl and extracted with AcOEt. The combined extracts were washed with H2O and brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (elution with hexane/AcOEt) to afford the pure ester.

ACKNOWLEDGEMENTS
The present work was supported in part by the Yamada Science Foundation. One of the authors (N. S.) is grateful for a Sasakawa Scientific Research Grant from the Japan Science Society.

References

1. L. Kürti and B. Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Amsterdam, 2005, pp. 272–273.
2. Reviews: a) A. P. Krapcho, ARKIVOC, 2007, (ii) 1; b) A. P. Krapcho, ARKIVOC, 2007, (ii) 54.
3. Y. Inokoishi, N. Sasakura, K. Nakano, Y. Ichikawa, and H. Kotsuki, Org. Lett., 2010, 12, 1616. CrossRef
4. The evolution of CO2 was confirmed by a positive CaCO3 test.
5. D. Lafrance, P. Bowles, K. Leeman, and R. Rafka, Org. Lett., 2011, 13, 2322. CrossRef
6. Under the standard conditions (1.5 equiv. of ClCH2CN, 1.5 equiv. of DBU, in toluene, rt), the reactants were recovered almost completely and the diester was obtained in only 15% yield after 12 h: compare with Table 2, Entry 10.
7. For example, see: (a) S. A. Robertson, J. A. Ellman, and P. G. Schultz, J. Am. Chem. Soc., 1991, 113, 2722; CrossRef (b) H. M. Hugel, K. V. Bhaskar, and R. W. Longmore, Synth. Commun., 1992, 22, 693; CrossRef (c) W. Fitz and C.-H. Wong, J. Org. Chem., 1994, 59, 8279; CrossRef (d) S. Findlow, P. Gaskin, P. A. Harrison, J. R. Lenton, M. Penny, and C. L. Willis, J. Chem. Soc., Perkin Trans. 1, 1997, 751; CrossRef (e) R. Shen, C. T. Lin, and J. A. Porco, Jr., J. Am. Chem. Soc., 2002, 124, 5650; CrossRef (f) R. Shen, C. T. Lin, E. J. Bowman, B. J. Bowman, and J. A. Porco, Jr., J. Am. Chem. Soc., 2003, 125, 7889; CrossRef (g) Q. Su and J. S. Panek, J. Am. Chem. Soc., 2004, 126, 2425; CrossRef (h) C. Bouillon, G. Quéléver, and L. Peng, Tetrahedron Lett., 2009, 50, 4346; CrossRef (i) C. Bouillon, A. Tintaru, V. Monnier, L. Charles, G. Quéléver, and L. Peng, J. Org. Chem., 2010, 75, 8685. CrossRef
8. G. Dannhardt and W. Kiefer, Eur. J. Med. Chem., 2001, 36, 109. CrossRef
9. For example, see: K. Okrasa, C. Levy, M. Wilding, M. Goodall, N. Baudendistel, B. Hauer, D. Leys, and J. Micklefield, Angew. Chem. Int. Ed., 2009, 48, 7691, and references cited therein. CrossRef