Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A Robust One-Step Approach to Ynamides Yongliang Tu,†,§ Xianzhu Zeng,†,§ Hui Wang,† and Junfeng Zhao*,†,‡ †
Key Laboratory of Chemical Biology of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *
ABSTRACT: A robust one-step synthetic strategy for ynamide with cheap and easily available stock chemicals vinyl dichlorides and electron deficient amides as the starting material is described. In the absence of transition-metal catalyst, the reaction proceeds under mild reaction conditions in open air and thus rendering a convenient operation. This strategy is not only suitable for both terminal and internal ynamide synthesis but also amenable for large-scale preparation. Broad substrate scopes with respect to vinyl dichloride as well as electron-deficient amide were observed.
Y
hypervalent iodine reagents are difficult to prepare, and expensive and strong basic lithium reagents are used. To address such disadvantages, alkyne reagents including alkynyl bromides,8 alkynes,9 copper acetylides,10 potassium alkynyltrifluoroborates,11 propiolic acid derivatives12 (Scheme 1, eq 2), and vinyl dibromides (Scheme 1, eq 3)13 have been employed as the alkyne component for ynamide synthesis via coppercatalyzed cross-coupling reactions. However, all of these strategies are limited to internal ynamides, and coppercatalyzed homocoupling of the alkyne component is a notorious issue for these strategies. A highly efficient synthetic strategy for ynamides, especially for terminal ynamides,14 is still a great challenge for organic chemists. Herein, we report a robust transition-metal-free approach to both terminal and internal ynamides from easily available stock chemicals in one simple operation (Scheme 1, eq 4). Ynamine could be synthesized via the nucleophilic substitution of alkynyl chloride with amine.15 It is attractive but challenging to apply this strategy for ynamide synthesis because of the low nucleophilicity of amide. On the other hand, vinyl halides are cheap and easily available alkyne surrogates.16 We hypothesized that it would be possible to use vinyl dichlorides, which could release alkynyl halides in situ under basic reaction conditions, as the masked alkyne halide. If successful, a one-step synthesis of terminal as well as internal ynamides would be expected (Scheme 1, eq 4). The cheap, commercially available, and nonlachrymatory 1,1-dichloroethylene was chosen as a model substrate to test the validity of our proposal. Preliminary study disclosed that this proposal was feasible, but the reaction efficiency was sensitive to the reaction conditions (for details of reaction condition optimization, see Table S1). To our delight, the terminal ynamide 3a could be obtained in 96% yield from 1,1dichloro-ethylene and N,4-dimethylbenzenesulfonamide with
namides, bearing an additional electron-withdrawing group on the nitrogen atom, display many advantages such as thermal stability, synthetic accessibility, and easy handling over their ynamine congeners due to the optimal balance between stability and reactivity. However, ynamides have not received much attention since they were introduced in 1972 by Viehe,1 which might be attributed to their insufficient synthetic availability. Decades later, Hsung,2 Evano,3 and others4 reinvestigated ynamides and facilitated the renaissance of ynamide chemistry. Thanks to these efforts, ynamides have evolved as versatile functionalities finding wide use in an increasing array of organic transformations. Meanwhile, a series of synthetic strategies have been developed for various ynamides. Elimination of haloenamides is the earliest and reliable approach to ynamides.1,5 However, tedious multisynthetic steps are required for haloenamides.6 The first one-step synthesis of ynamide was accomplished by employing the direct coupling of electron-deficient amides with alkynyliodonium salts (Scheme 1, eq 1).7 However, the Scheme 1. One-Step Strategy for Ynamide Synthesis
Received: November 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03665 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
the standard reaction conditions of terminal ynamide. Interestingly, excellent yield could be obtained with slight modification of the reaction conditions by replacing NaH with Cs2CO3 as the base. The substrate scope with respect to amide moiety was investigated, and the results are summarized in Scheme 3. Various alkyl sulfonamides reacted smoothly to
NaH as the base. With the optimized reaction conditions in hand, the substrate scope of the transition-metal-free, one-step terminal ynamide synthetic strategy was examined. As shown in Scheme 2, a broad range of N-alkylsulfonamides proceeded Scheme 2. Substrate Scope for the Terminal Ynamidesa
Scheme 3. Substrate Scope for Internal Ynamidesa
a
Reaction conditions: Unless otherwise specified, the reactions were carried out with 1 (0.2 mmol), 2 (0.4 mmol), and NaH (5.0 equiv) in DMSO (1.0 mL) at 70 °C. b10 mmol scale. c100 °C.
smoothly to give the target terminal ynamides in good to excellent yields. Terminal ynamides derived from aniline sulfonamides, difficult substrates for other ynamide synthetic methodologies, could also be prepared efficiently with 1,1dichloroethylene as the alkyne surrogate (3f−m). The presence of a weak electron-donating group (3g−j) on the phenyl ring of aniline sulfonamides has little effect on the reaction efficiency. However, strong electron-donating (3k) and -withdrawing groups (3l, 3m) have some deleterious effects on the reaction efficacy. Oxazolidinone demonstrated to be viable substrate for this transformation (3o). It is noted that N-alkynylation of aromatic azacycles such as indole and carbazole could also be accomplished to give terminal ynamines in excellent yields (3p−r). Additionally, the biynamide could be synthesized efficiently by this method (3s). With the success on the synthesis of terminal ynamides, we went further for the synthesis of internal ynamides with (2,2dichloroethenyl)benzene 4 as the model substrate. However, only moderate yield of internal ynamide was obtained under
a
Reaction conditions: Unless otherwise specified, the reactions were carried out with 1 (0.2 mmol), 4 (0.4 mmol), and Cs2CO3 (5.0 equiv) in DMSO (1.0 mL) at 70 °C. b10 mmol scale. c100 °C.
furnish the internal ynamides in good to excellent yields (Scheme 4). The steric hindrance of the alkyl group was tolerated, albeit longer reaction times were required for bulky sulfonamides (5f−k). The aniline sulfonamide was a poor substrate for internal ynamides synthesis (5l). Other Nmethylbenzenesulfonamides with electron-donating and -withdrawing groups on the phenyl group were compatible (5m−p). Acyclic carbonates as well as oxazolidinones were valid substrate for this reaction, although a higher reaction temperature was required to obtain good yields (5q−s). Similar to that of terminal ynamines, the alkynylation aromatic azacycles proceeded smoothly to furnish the internal ynamines in excellent yields (5t−w). The potential application of this strategy was further showcased by the synthesis of a biynamide 5x in excellent yield. B
DOI: 10.1021/acs.orglett.7b03665 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. . Substrate Scope for Internal Ynamidesa
contrary, β-position addition of nitrogen nucleophile and protonation would produce β-chloroenamide VI (path b). The substituent R2 plays an important role for the selection between path a and path b. The ynamide was obtained when R2 is an aryl group which can stabilize the minus charge of intermediate II. On the contrary, path b is preferred to give βchloroenamide when R2 is an alkyl group. In conclusion, we have developed a robust transition-metalfree synthetic method for ynamides with nonlachrymatory and inexpensive vinyl dichloride as the alkyne surrogate. Both internal and terminal ynamides could be synthesized efficiently via such one-step strategy with commercially available or easily prepared chemicals as the starting material. A broad range of functional groups and substituents are compatible for both coupling partners. No transition-metal catalyst was used, thus avoiding the homocoupling side reaction of alkyne reagents encountered in other copper-catalyzed synthetic strategies. Undoubtedly, this highly efficient strategy will find broad application in ynamide synthesis and facilitate the application of ynamide chemistry in other research fields.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03665. Experimental procedures, compounds characterization data, and NMR spectra (PDF)
■
a
Reaction conditions: Unless otherwise specified, the reactions were carried out with 1a (0.2 mmol), 6 (0.4 mmol), and Cs2CO3 (5.0 equiv) in DMSO (1.0 mL) at 70 °C.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Next, the generality of the reaction regarding to vinyl dichlorides was also investigated. A variety of 2-arylvinyl dichlorides reacted smoothly with N,4-dimethylbenzenesulfonamide to afford the corresponding internal ynamides in good to excellent yields (7a−o). Both the electron-donating and electron-withdrawing groups were compatible on the phenyl ring of 2-arylvinyl dichlorides. Heterocyclic aryl groups such as thiophene and benzo[b]thiophene were also tolerated (7j−l). However, no target ynamide but β-chloroenamides 7p and 7q were obtained when 2-alkylvinyl dichlorides 6p and 6q were employed as the substrates. A plausible reaction mechansim was proposed to rationalize the experimental outcome (Scheme 5). The alkynyl chloride intermediate II would be formed in situ upon elimination of HCl under the basic reaction conditions. The direct α-position nucleophilic substitution of alkynyl chloride II by nitrogen nucleophile would furnish the ynamide IV (path a). On the
ORCID
Junfeng Zhao: 0000-0003-4843-4871 Author Contributions §
T.Y. and Z.X. contributed equally
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS The National Natural Science Foundation of China (21462023, 21778025) and the Education Department of Jiangxi Province (150297) are acknowledged for support of this research.
■
REFERENCES
(1) Janousek, Z.; Collard, J.; Viehe, H. G. Angew. Chem., Int. Ed. 1972, 11, 917−918. (2) (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L. L. Tetrahedron 2001, 57, 7575−7606. (b) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417−2420. (c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064−5106. (d) Wang, X. N.; Yeom, H. S.; Fang, L. C.; He, S.; Ma, Z. X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560−578. (3) (a) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17−26. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840−2859. (c) Evano, G.; Theunissen, C.; Lecomte, M. Aldrichimica Acta 2015, 48, 59. (d) Evano, G.; Blanchard, N.; Compain, G.; Coste, A.; Demmer, C. S.; Gati, W.; Guissart, C.; Heimburger, J.; Henry, N.; Jouvin, K.; Karthikeyan, G.; Laouiti, A.; Lecomte, M.; Martin-Mingot,
Scheme 5. Proposed Reaction Mechanism
C
DOI: 10.1021/acs.orglett.7b03665 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters A.; Métayer, B.; Michelet, B.; Nitelet, A.; Theunissen, C.; Thibaudeau, S.; Wang, J.; Zarca, M.; Zhang, C. Chem. Lett. 2016, 45, 574−585. (4) (a) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802− 3803. (b) Pirwerdjan, R.; Becker, P.; Bolm, C. Org. Lett. 2015, 17, 5008−5011. (c) Shu, C.; Wang, Y. H.; Zhou, B.; Li, X. L.; Ping, Y. F.; Lu, X.; Ye, L. W. J. Am. Chem. Soc. 2015, 137, 9567−9570. (d) Lecomte, M.; Evano, G. Angew. Chem., Int. Ed. 2016, 55, 4547− 4551. (e) Patil, D. V.; Kim, S. W.; Nguyen, Q. H.; Kim, H.; Wang, S.; Hoang, T.; Shin, S. Angew. Chem., Int. Ed. 2017, 56, 3670−3674. (f) Pirwerdjan, R.; Priebbenow, D. L.; Becker, P.; Lamers, P.; Bolm, C. Org. Lett. 2013, 15, 5397−5399. (g) Hu, L.; Xu, S.; Zhao, Z.; Yang, Y.; Peng, Z.; Yang, M.; Wang, C.; Zhao, J. J. Am. Chem. Soc. 2016, 138, 13135−13138. (5) (a) Wei, L. L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459−466. (b) Rodriguez, D.; Castedo, L.; Saa, C. Synlett 2004, 2004, 783−786. (c) Rodriguez, D.; Martinez-Esperon, M. F.; Castedo, L.; Saa, C. Synlett 2007, 2007, 1963−1965. (d) Couty, S.; Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005, 2005, 905−910. (e) Bruckner, D. Tetrahedron 2006, 62, 3809−3814. (f) Bruckner, D. Synlett 2000, 2000, 1402−1404. (6) (a) Joshi, R. V.; Xu, Z. Q.; Ksebati, M. B.; Kessel, D.; Corbett, T. H.; Drach, J. C.; Zemlicka, J. J. Chem. Soc., Perkin Trans. 1 1994, 1089−1098. (b) Mansfield, S. J.; Campbell, C. D.; Jones, M. W.; Anderson, E. A. Chem. Commun. 2015, 51, 3316−3319. (c) Brandsma, L.; Mal’kina, A. G.; Trofimov, B. A. Synth. Commun. 1994, 24, 2721− 2724. (d) van der Heiden, R.; Brandsma, L. Synthesis 1987, 1987, 76− 77. (7) (a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489−492. (b) Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1994, 1255−1256. (8) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L. C.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368−2369. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011−4014. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151−1154. (d) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820−1821. (e) Chen, X. Y.; Wang, L.; Frings, M.; Bolm, C. Org. Lett. 2014, 16, 3796−3799. (9) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833−835. (b) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6−9. (c) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F. F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 3478−3480. (d) Wang, H.; Cheng, Y.; Becker, P.; Raabe, G.; Bolm, C. Angew. Chem., Int. Ed. 2016, 55, 12655−12658. (10) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756− 760. (11) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272− 3275. (12) (a) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000−2003. (b) Priebbenow, D. L.; Becker, P.; Bolm, C. Org. Lett. 2013, 15, 6155−6157. (13) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48, 4381−4385. (14) Cook, A. M.; Wolf, C. Tetrahedron Lett. 2015, 56, 2377−2392. (15) Viehe, H. G.; Reinstein, M. Angew. Chem., Int. Ed. 1964, 3, 506−506. (16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769− 3772.
D
DOI: 10.1021/acs.orglett.7b03665 Org. Lett. XXXX, XXX, XXX−XXX
