DMAP-promoted multicomponent reaction of cyanoacetylene, MBH carbonate and water: a facile access to functional quaternary carbon

Abstract

An efficient method for the synthesis of highly functionalized products containing cyanide-substituted quaternary carbon centers via DMAP-promoted multicomponent reactions of cyanoacetylene, Morita–Baylis–Hillman (MBH) carbonate and water was developed. The reactions could be achieved under simple and mild conditions.

---

Efficient construction of complicated molecules with chemical and biological importance is a challenging point and has received considerable attention in recent years. Among various synthetic methods, the multicomponent reaction has emerged as a powerful tool to generate molecular complexity from easily available starting materials, and the advantages of this process are synthetic efficiency, atom economy, generating less waste, minimizing the excessive handling.¹ Recently, electron-deficient alkyne is one kind of the most important intermediates and has served as a key building block in the preparation various multifunctional molecules.² Furthermore, above compounds through conjugate addition with N- and P-nucleophiles have covered many interesting reactions, such as isomerization,³ addition reaction,⁴ cycloaddition,⁵ chemical bond cleavage,⁶ and ring opening reaction,⁷ etc. Apart from above reactions, the multicomponent reaction of electron-deficient alkynes also has been studied intensively and numerous synthetic methods have been developed for the synthesis of various densely functional molecules.⁸

Traditional organic base catalyzed or promoted organic reactions were using dialkyl acetylene dicarboxylates, terminal alkynoates or alkynyl ketones as electron-deficient alkynes.⁹ But there are a few reports about the applications of cyanoacetylenes as electron-deficient alkynes to form zwitterionic adducts in the presence of tertiary phosphines or amines.¹⁰ On the other hand, water has been widely used for organic reactions due to its inherent advantages, such as non-toxicity, cheap cost, and non-flammability.¹¹ Generally, water was used as catalyst in proton shift process in some tertiary phosphines or amines catalyzed or promoted reactions on the basis of the electron-deficient alkynes.^7,12 However, a few reports about water used as starting materials in the above described reactions.¹³ Herein, we wish to report a novel DMAP-promoted multicomponent reaction of cyanoacetylene, MBH carbonate and water to construct densely functional quaternary carbon center under simple and mild reaction conditions.

As an initial experiment, a model reaction of 3-phenylpropiolonitrile (1a), methyl 2-(((tert-butoxycarbonyl)oxy)methyl)acrylate (2a) and water in the presence of 20 mol% of DMAP in CH₂Cl₂ at room temperature for 72 h, to our delight, the product dimethyl 4-benzoyl-4-cyano-2,6-dimethyleneheptanedioate (3a) was obtained in 12% yield. This interesting preliminary result encouraged us to optimize the reaction conditions for improvement of the yield of 3a and the results could be seen from Table 1. The amount of DMAP has an obviously effect on the reaction. The yield of desired product 3a was improved with increasing the amount of DMAP until using 0.5 equiv. of DMAP in the reaction (Table 1, entries 1−5). Next, we examined the influence of the solvent and the base on the model reaction. Among the solvents tested, CH₃CN was found to be the best one. The product yields of 3a were obtained in 18% and 15% respectively when acetone and toluene were used as solvents. Other solvents, such as 1,4-dioxane, THF, CHCl₃ and CCl₄ were harmful to this reaction, and EtOAc, ether, and DMF were infeasible (Table 1, entries 6−15). Further screening of organic base revealed that DMAP was the optimal base. Only a trace amount of the desired product was detected by TLC when DABCO was used as promoter. No reaction was occurred when the reaction was carried out in the presence of Et₃N. Further with the utilization of pyridine, DBU and PPh₃, no desired product 3a was detected (Table 1, entries 16−20).

Table 1 Optimization of reaction conditions for the multicomponent reaction of 3-phenylpropiolonitrile (1a), methyl 2-(((tert-butoxycarbonyl)oxy)methyl)acrylate (2a) and water^a

Entry	Solvent	Base	Yield (%)^b
a Reaction conditions: 1a (0.20 mmol), 2a (0.60 mmol), H2O (0.20 mmol), base (0.1 mmol), solvent (2.0 mL), room temperature, in air, 72 h.b Isolate yields.c 0.2 equiv. of DMAP was used.d 0.3 equiv. of DMAP was used.e 0.4 equiv. of DMAP was used.f 1.0 equiv. of DMAP was used.g NR = No reaction was occurred.h ND = No desired product was detected. DMAP = 4-dimethylaminopyridine, DABCO = 1,4-diazabicyclo[2.2.2]-octane, DBU = diaza(1,3)bicyclo[5.4.0]undecane.
1	CH2Cl2	DMAP	12^c
2	CH2Cl2	DMAP	20^d
3	CH2Cl2	DMAP	28^e
4	CH2Cl2	DMAP	41
5	CH2Cl2	DMAP	38^f
6	CH3CN	DMAP	57
7	Acetone	DMAP	18
8	Toluene	DMAP	15
9	1,4-Dioxane	DMAP	Trace
10	THF	DMAP	Trace
11	CHCl3	DMAP	Trace
12	CCl4	DMAP	Trace
13	EtOAc	DMAP	NR^g
14	Ether	DMAP	NR^g
15	DMF	DMAP	Complicated
16	CH3CN	DABCO	Trace
17	CH3CN	Et3N	NR^g
18	CH3CN	Pyridine	ND^h
19	CH3CN	DBU	ND^h
20	CH3CN	PPh3	ND^h

---

After establishing the optimized multicomponent reaction conditions for the synthesis of densely functional quaternary carbon centers, several cyanoacetylenes and MBH carbonates containing different substituents were synthesized and applied to explore the scope of multicomponent reaction under present optimized conditions. As can see from the Table 2, 3-phenylpropiolonitrile (1a), water and MBH carbonates (2) bearing different ester groups afforded the corresponding products in moderate to good yields. Moreover, the size of the ester group in 2 had no obviously effect on the yield of this cascade multicomponent reaction (3a and 3b vs 3c and 3d). It should be noted that larger iso-octyl ester group in substrate 2e generated the desired product 3e in 50% yield. On the other hand, cyanoacetylenes with both electron-donating and electron-withdrawing functionalities, such as methyl, propyl, tert-buty, and fluoro groups, also proceeded the reactions to afford the corresponding products (3f–n) in 35–69% yields. It is obvious that the substituents on the aromatic cyanoacetylenes had no effect on the yields of the reactions.

Table 2 DMAP-promoted multicomponent reactions of cyanoacetylene (1), MBH carbonate (2) and water^a,b

a Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), H₂O (0.20 mmol), DMAP (0.10 mmol), CH₃CN (2.0 mL), rt, in air, 72 h.b Isolated yields.

---

Up till now, the detailed mechanism of the DMAP-promoted above multicomponent reactions has not been clarified. However, on the basis of our experimental results and previous literature,¹⁴ we proposed a mechanism for this reaction as shown in Scheme 1. The reaction could be triggered by the nucleophilic addition of DMAP to 3-phenylpropiolonitrile (1a) to produce zwitterion A, which reacted with 2a via an addition–elimination process to form ammonium salts B. Then water was deprotonated by the in situ generated tert-butyloxide anion to afford hydroxyl anion, which underwent a nucleophilic attack B to give intermediate C, which changed into D through a similar process with changing procedure of A to B. Subsequently, the intermediated D was deprotonated by another generated tert-butyloxide anion to form intermediate E, which afforded the desired product 3a through an elimination of DMAP.

Scheme 1 A plausible mechanism for the multicomponent reactions.

Conclusions

In summary, we have developed a novel multicomponent reaction of cyanoacetylene, MBH carbonate and water promoted by DMAP under simple and mild reaction conditions. The reaction generated highly functionalized products containing cyanide-substituted quaternary carbon centers in moderate to good yields. An extended investigation about using the obtained products to explore new reaction and the detailed reaction mechanism are currently underway.

Acknowledgements

This work was financially supported by the National Science Foundation of China (nos 21372095, 21172092) and the Anhui Provincial Natural Science Foundation (1208085QB40).

Notes and references

1. (a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) A. de Meijere, P. von Zezschwitz and S. Bräse, Acc. Chem. Res., 2005, 38, 413; (c) A. Dömling, Chem. Rev., 2006, 106, 17; (d) L. F. Tietze, T. Kinzel and C. C. Brazel, Acc. Chem. Res., 2009, 42, 367; (e) M. B. Gawande, V. D. B. Bonifácio, R. Luque, P. S. Branco and R. S. Varma, Chem. Soc. Rev., 2013, 42, 5522.
2. For recent reviews, see: (a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535; (b) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37, 1140; (c) V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash and A. T. Biju, Acc. Chem. Res., 2006, 39, 520.
3. (a) B. M. Trost and U. Kazmaier, J. Am. Chem. Soc., 1992, 114, 7933; (b) C. Cao and X. Lu, J. Chem. Soc., Perkin Trans. 1, 1993, 1921.
4. For selected examples, see: (a) L.-G. Meng, K. Tang, H.-F. Liu, J. Xiao and S. Xue, Synlett, 2010, 1833; (b) B. M. Trost and G. R. Dake, J. Am. Chem. Soc., 1997, 119, 7595; (c) M. Hanédanian, O. Loreau, F. Taran and C. Mioskowski, Tetrahedron Lett., 2004, 45, 7035; (d) S. Xue, Q.-F. Zhou and X.-Q. Zheng, Synth. Commun., 2005, 35, 3027; (e) H. Liu, Q. Zhang, L. Wang and X. Tong, Chem. – Eur. J., 2010, 16, 1968; (f) J. Inanaga, Y. Baba and T. Hanamoto, Chem. Lett., 1993, 241; (g) B. M. Trost and G. R. Drake, J. Am. Chem. Soc., 1997, 119, 5670; (h) J. Sun and G.-C. Fu, J. Am. Chem. Soc., 2010, 132, 4568; (i) M.-J. Fan, G.-Q. Li and Y.-M. Liang, Tetrahedron, 2006, 62, 6782; (j) Q.-F. Zhou, Q.-F. Wu and S. Xue, Tetrahedron Lett., 2008, 49, 7027.
5. For selected examples, see: (a) M. Adib, M. H. Sayahi, S. Mahernia and L.-G. Zhu, Tetrahedron Lett., 2008, 49, 945; (b) W. Zhang and T. M. Swager, J. Am. Chem. Soc., 2007, 129, 7714; (c) K. Nozaki, N. Sato, K. Ikeda and H. Takaya, J. Org. Chem., 1996, 61, 4516; (d) H. Waldmann, V. Khedkar, H. Duckert, M. Schurmann, I. M. Oppel and K. Kumar, Angew. Chem., Int. Ed., 2008, 47, 6869; (e) H. Kuroda, I. Tomita and T. Endo, Org. Lett., 2003, 5, 129; (f) S. Gabillet, D. Lecerclé, O. Loreau, M. Carboni, S. Dézard, J.-M. Gomis and F. Taran, Org. Lett., 2007, 9, 3925; (g) D. Tejedor, A. Santos-Expósito and F. García-Tellado, Chem. Commun., 2006, 2667; (h) M. Fan, Z. Yang, W. Liu and Y. Liang, J. Org. Chem., 2005, 70, 8204; (i) Q.-F. Zhou, F. Yang, Q.-X. Guo and S. Xue, Synlett, 2007, 215; (j) L.-G. Meng, P. Cai, Q. Guo and S. Xue, J. Org. Chem., 2008, 73, 8491.
6. (a) L.-G. Meng, B. Hu, Q.-P. Wu, M. Liang and S. Xue, Chem. Commun., 2009, 6089; (b) V. Nair, A. R. Sreekanth and A. U. Vinod, Org. Lett., 2001, 3, 3495; (c) V. Nair, A. R. Sreekanth and A. U. Vinod, Org. Lett., 2001, 4, 2807; (d) V. Nair, A. N. Pillai, R. S. Menon and E. Suresh, Org. Lett., 2005, 7, 1189.
7. L.-G. Meng and L. Wang, Chem. Commun., 2012, 48, 3242.
8. (a) Y. Matsuya, K. Hayashi and H. Nemoto, Chem. – Eur. J., 2005, 11, 5408; (b) Y. Matsuya, K. Hayashi, A. Wada and H. Nemoto, J. Org. Chem., 2008, 73, 187; (c) Y.-G. Wang, S.-L. Cui and X.-F. Lin, Org. Lett., 2006, 8, 1241; (d) D. Tejedor, S. López-Tosco, S. González-Platas and F. García-Tellado, J. Org. Chem., 2007, 72, 5454; (e) L.-G. Meng, K. Tang, Q.-X. Guo and S. Xue, Tetrahedron Lett., 2008, 49, 3885.
9. For selected examples, see: (a) C.-Q. Li and M. Shi, Org. Lett., 2003, 5, 4273; (b) R. Weiss, M. Bess, S. M. Huber and F. W. Heinemann, J. Am. Chem. Soc., 2008, 130, 4610; (c) S. Ngwerume and J. E. Camp, J. Org. Chem., 2010, 75, 6271; (d) R. C. F. Jones, J. N. Martin, P. Smith, T. Gelbrich, M. E. Light and M. B. Hursthouse, Chem. Commun., 2000, 1949; (e) X. Jiang, D. Fu, X. Shi, S. Wang and R. Wang, Chem. Commun., 2011, 47, 8289; (f) H. Liu, Q. Zhang, L. Wang and X. Tong, Chem. Commun., 2010, 46, 312; (g) Q. Zhang, T. Fang and X. Tong, Tetrahedron, 2010, 66, 8095; (h) D. Tejedor, F. García-Tellado, J. J. Marrero-Tellado and P. Armas, Chem. – Eur. J., 2003, 9, 3122.
10. (a) H. Duckert, V. Khedkar, H. Waldmann and K. Kumar, Chem. – Eur. J., 2011, 17, 5130; (b) B. A. Trofimov, L. V. Andriyankova, K. V. Belyaeva, A. G. Mal’kina, L. P. Nikitina, A. V. Afonin and I. A. Ushakov, J. Org. Chem., 2008, 73, 9155; (c) B. A. Trofimov, L. V. Andriyankova, K. V. Belyaeva, A. G. Mal’kina, L. P. Nikitina, O. A. Dyachenko, O. N. Kazheva and G. G. Alexandrov, Tetrahedron Lett., 2011, 67, 1288.
11. For recent reviews, see: (a) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (b) R. Breslow, Acc. Chem. Res., 2004, 37, 471; (c) C.-J. Li, Chem. Rev., 2005, 105, 3095; (d) C.-J. Li and L. Chen, Chem. Soc. Rev., 2006, 35, 68; (e) M. B. Gawande and P. S. Branco, Green Chem., 2011, 13, 3355; (f) M. B. Gawande, V. D. B. Bonifácio, R. Luque, P. S. Branco and R. S. Varma, ChemSusChem, 2013 DOI:10.1002/cssc.201300485.
12. (a) Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y. Li and Z.-X. Yu, J. Am. Chem. Soc., 2007, 129, 2470; (b) Y. Liang, S. Liu, Y. Xia, Y. Li and Z.-X. Yu, Chem. – Eur. J., 2008, 14, 4361; (c) Y. Liang, S. Liu and Z.-X. Yu, Synlett, 2009, 905; (d) E. Mercier, B. Fonovic, C. Henry, O. Kwon and T. Dudding, Tetrahedron Lett., 2007, 48, 3617.
13. (a) J. Tae and K.-O. Kim, Tetrahedron Lett., 2003, 44, 2125; (b) A. W. Mcculloch and A. G. Mcinnes, Can. J. Chem., 1974, 52, 3569.
14. P. Xie, Y. Huang and R. Chen, Org. Lett., 2010, 12, 3768.

---

Footnote

† Electronic supplementary information (ESI) available: General information, detailed experimental procedures, deuterium labeling experiment results and characterization data for all products. See DOI: 10.1039/c3ra47105e

---