Chinese Chemical Letters  2019, Vol. 30 Issue (2): 383-385   PDF    
A facile transformation of alkynes into α-amino ketones by an N-bromosuccinimide-mediated one-pot strategy
Ting Weia, Yongming Zenga,b,*, Wei Hea, Lili Genga, Liang Honga     
a Department of Chemistry and Applied Chemistry, Changji University, Changji 831100, China;
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
Abstract: A facile transformation of alkynes into α-amino ketones by an N-bromosuccinimide-mediated one-pot cascade strategy is described. A variety of α-amino ketones are obtained in moderate to good yields under mild conditions. To overcome the multi-step synthesis, N-bromosuccinimide is involved in multiple tasks, playing a key role in the reaction course.
Keywords: α-Amino ketones     N-Bromosuccinimide     Alkynes     One-pot synthesis    

α-Amino ketones are a class of highly valuable molecules that widely exist in natural products and pharmaceuticals [1]. In particular, they have gained much attention due to their roles as key intermediates in the syntheses of biologically active compounds [2]. Various approaches have been developed to construct this class of molecules [3]. All these conventional methods involve the α-bromination of ketones [4] or bromohydroxylation of olefins followed by oxidation [5]. Such processes have been frequently carried out with lachrymatic phenacyl halides [4], toxic bromine [6] and precious metals [7], which hinder their widespread applications due to the chemical toxicity and tedious handling requirements. Recently, halogen-activated organic reactions have provided an attractive approach to this transformation under metal-free conditions, especially the halonium-initiated one-pot cascade [8]. For example, Sudalai reported the direct transformation of alkenes and enol ethers into α-imido carbonyl compounds with the combination of N-bromosuccinimide (NBS) and dimethyl sulfoxide (DMSO) [9]. The Kshirsagar group demonstrated an NBSpromoted one-pot strategy [10]. Liang and co-workers developed the method of simultaneous intramolecular C=O and C-N bond formation of α-amino ketones via halogen activation [11]. However, there have been few reports of the simple and efficient conversion of alkynes into α-amino ketones under metal-free conditions [12]. Addressing the regioselectivity and expanding the substrate scope still remain challenges. Therefore, the development of a novel efficient approach for the rapid chemoselective construction of α-amino ketones directly from various alkynes is highly desired. In this context, we wish to report a facile transformation consisting of N-bromosuccinimide-mediated one-pot cascade under metal-free conditions (Scheme 1).

Scheme 1. One-pot conversion of alkynes to α-amino ketones.

Phenyl acetylene 1a was selected as the test substrate. The model reaction of phenyl acetylene 1a with NIS (2.0 equiv.) in H2O at 80℃ for 1 h, followed by the addition of DBU (3.0 equiv.) and acetone (1 mL) and stirring at room temperature for 2 h, was initially examined. 1-(2-Oxo-2-phenylethyl)pyrrolidine-2, 5-dione (2a) was obtained only in 18% yield (Table 1, entry 1). The use of NCS instead of NIS did not provided the desired product 2a, whereas with NBS, the yield of 2a reached 71% (Table 1, entries 2, 3), indicating that NBS played a key role in the reaction course. The effects of various bases were investigated and we found that other bases, besides DBU, were found to be less effective or even inefficient (Table 1, entries 3–9). Lower yields were obtained when the reaction was performed with THF, MeCN, DCM, DMSO, or DMF as the solvent (Table 1, entries 10–14). To further improve the yield, the reaction conditions, such as the dosage of DBU, reaction temperature and time were also optimized. When the reaction temperature was reduced to 60℃, the yield significantly decreased (53%, Table 1, entry 15). Increasing the reaction temperature did not change the yield (70%, Table 1, entry 16). However, considering energy consumption, 80℃ was selected as the optimal reaction temperature. Additionally, a lower conversion was obtained upon lowering the amount of DBU to 2.0 equiv. (63%, Table 1, entry 17). A similar yield was achieved in the presence of 3.0 equiv. of DBU (71%, Table 1, entry 18). A prolonged reaction time had no effect on the yield (70%, Table 1, entry 19). Studies showed that a combination of NBS (2 equiv.) and DBU (3 equiv.) worked well for the transformation.

Table 1
Optimization of the reaction conditions.a

To evaluate the generality of this protocol, the one-pot cascade reaction was extended to various substituted alkynes under the optimized conditions, providing the corresponding α-amino ketones in 50%–77% yields (Fig. 1). Terminal alkynes containing electron-rich aryl (Fig. 1, 2b, 2c, 2f) and electron-deficient aryl (Fig. 1, 2d, 2e, 2g, 2h) moieties were found to be excellent substrates for the transformation, providing the desired products (Fig. 1, 2a–h). In addition, the scope of the reaction was further explored for 2-naphthyl, 2-pyridyl and 2-thienyl substrates, affording the corresponding products in moderate yields of 65%, 53% and 58%, respectively (Fig. 1, 2j, 2k and 2l). For alkyl alkynes, the transformation also proceeded smoothly, leading to the corresponding products 2i, 2m and 2o in 50%, 63% and 62% yields, respectively. Nevertheless, substrate 1n was ineffective under these conditions. Notably, a variety of internal alkynes were successfully converted into the target products in moderate yields (Fig. 1, 2p, 2q and 2y).

Fig. 1. Scope and limitation for the synthesis of α-imido ketones. Isolated yield.

This highly efficient synthesis of functionalized α-amides ketones permits access to various important α-amino ketones. Treating 2a with dilute sodium hydroxide by hydrolyzing the succinimide gave 2-amino-1-phenylethanone in 89% yield (Supporting information).

To gain insight into the reaction mechanism, control experiments were performed (Scheme 2). To explore the role of NBS in the reaction system, alkyne 1a was treated with NBS in the absence of DBU in H2O, and phenacyl bromide Ⅲ was obtained in 85% yield (Scheme 2, Eq. (1)). Furthermore, the same reactionwas conducted without water, and no corresponding product Ⅲ was observed (Scheme 2, Eq. (2)). This indicated that water was crucial in this step. Phenacyl bromide and succinimide in the presence of DBU in acetone at r.t. for 2h gave the corresponding product 2a in 82% yield (Scheme 2, Eq. (3)), confirming that the reaction proceeded via an intermediate phenacyl bromide. The absence of DBU in the same reaction did not alter the formation of product 2a (Scheme 2, Eq. (4)), demonstrating that DBU promotes the nucleophilic reaction in the reaction system. When alkyne 1a was subjected to the standard conditions in the presence of H218O, 18O-2a was detected (Scheme 2, Eq. (5)), which further indicated that the oxygen atom of benzoyl group originated from water.

Scheme 2. Control experiments.

Based on our experimental results described above and previously reported studies, a plausible mechanism for the α-imidation of ketones is proposed in Scheme 3. Initially, the reaction of alkyne 1a with NBS led to the formation of the bromonium ion intermediate (), which is further regioselectively attacked by water to generate brominated enol (). Subsequently, α-bromoketone () is formed via a rearrangement reaction. Upon nucleophilic substitution by the succinimide anion, α-bromoketone () transforms into the corresponding α-imido ketone 2a.

Scheme 3. Plausible reaction mechanism.

To summarize, a facile efficient transformation of commercially available alkynes into α-amino ketones by an N-bromosuccinimide-mediated one-pot cascade strategy was developed. A variety of α-amino ketones were obtained in moderate to good yields under mild conditions. The reaction was simple and amenable to a number of functional groups, which makes the current process a practical method to prepare α-amino ketones from alkynes. To overcome the multi-step synthesis, NBS was involved in multiple tasks, playing a key role in the reaction course. Further efforts will be devoted to exploring various nucleophiles and expanding the applications of this synthesis strategy.


We are grateful to the Natural Science Foundation of Xinjiang Province (No. 2016D01C009) and the Educational Commission of Xinjiang (No. XJEDU2017S053) for financial support.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at

(a) A.J. Eshleman, K.M. Wolfrum, M.G. Hatfield, et al., Biochem. Pharmacol. 85 (2013) 1803-1815;
(b) B.E. Blough, A. Landavazo, J.S. Partilla, et al., ACS Med. Chem. Lett. 5 (2014) 623-627;
(c) S. Guha, V. Rajeshkumar, S.S. Kotha, G. Sekar, Org. Lett. 17 (2015) 406-409;
(d) R. Kolanos, J.S. Partilla, M.H. Baumann, et al., ACS Chem. Neurosci. 6 (2015) 771-777;
(e) F.I. Carrol, B.E. Blough, P. Abraham, et al., J. Med. Chem. 52 (2009) 6768-6781;
(f) K. Cameron, R. Kolanos, R. Verkariya, L.D. Felice, R.A. Glennon, Psychopharmacology 227 (2013) 493-499.
(a) L. He, J. Pian, J. Shi, G. Du, B. Dai, Tetrahedron 70 (2014) 2400-2405;
(b) F. Carroll, B. Blough, P. Abraham, et al., J. Med. Chem. 52 (2009) 6768-6781;
(c) T. Sehl, Z. Maugeri, D. Rother, J. Mol. Catal. B: Enzym. 114 (2015) 65-71;
(d) L. Frolova, N. Evdokimov, K. Hayden, et al., Org. Lett. 13 (2011) 1118-1121;
(e) W. Wei, Y. Shao, H. Hu, et al., J. Org. Chem. 77 (2012) 7157-7165.
(a) P. Selig, Angew. Chem. Int. Ed. 52 (2013) 7080-7082;
(b) S. Guha, V. Rajeshkumar, S.S. Kotha, G. Sekar, Org. Lett. 17 (2015) 406-409;
(c) S.L. McDonald, Q. Wang, Chem. Commun. 50 (2014) 2535-2538;
(d) F.D. Klingler, Acc Chem. Res. 40 (2007) 1367-1376;
(e) K.A. Dekorver, H. Li, A.G. Lohse, et al., Chem. Rev. 110 (2010) 5064-5106;
(f) S. Hoffmann, A.M. Seayad, B. List, Angew. Chem. Int. Ed. 44 (2005) 7424-7427;
(g) G. Li, Y. Liang, J.C. Antilla, J. Am. Chem. Soc. 129 (2007) 5830-5831;
(h) W. Wen, Y. Zeng, L. Peng, L. Fu, Q. Guo, Org. Lett. 17 (2015) 3922-3925;
(i) M.R. Smith, K.K. Hii, Chem. Rev. 111 (2011) 1637-1656.
(a) J. Tatar, R. Markovic, M. Stojanovic, M. Baranac-Stojanovic, Tetrahedron Lett. 51 (2010) 4851-4855;
(b) K. Morri, Y. Thummala, V.R. Doddi, Org. Lett. 17 (2015) 4640-4643;
(c) H.Y. Choi, D.Y. Chi, Org. Lett. 5 (2003) 411-414;
(d) H.Y. Choi, D.Y. Chi, J. Am. Chem. Soc. 123 (2001) 9202-9203;
(e) C. Wu, X. Xin, Z.M. Fu, et al., Green Chem. 19 (2017) 1983-1989;
(f) W.M. He, L.Y. Xie, Y.Y. Xu, et al., Org. Biomol. Chem. 10 (2012) 3168-3171;
(g) L.Y. Xie, Y.D. Wu, W.G. Yi, et al., J. Org. Chem. 18 (2013) 9190-9195;
(h) Z.W. Chen, D.N. Ye, M. Ye, et al., Tetrahedron Lett. 55 (2014) 1373-1375;
(i) H.X. Zou, W.B. He, Q.Z. Dong, et al., Eur. J. Org. Chem. 2016 (2016) 116-121.
(a) G.L. Fisher, R. Burnett, J. Am. Chem. Soc. 137 (2015) 11614-11617;
(b) Q. Jiang, B. Xu, A. Zhao, et al., J. Org. Chem. 79 (2014) 8750-8756;
(c) Y. Lv, Y. Li, T. Xiong, et al., Chem. Commun. 50 (2014) 2367-2369;
(d) J. Majetich, Tetrahedron Lett. 51 (2010) 6830-6834.
(a) L.H. Huang, X.B. Zhang, Y.H. Zhang, Org. Lett. 4 (2009) 363-366;
(b) R.L. Gao, C.S. Yi, ACS Catal. 1 (2011) 544-547.
(a) F. Minisci, R. Galli, Tetrahedron Lett. 5 (1964) 3197-3200;
(b) J.A. Souto, P.B. Becker, A. Iglesias, K. Muniz, J. Am. Chem. Soc. 134 (2012) 15505-15511;
(c) T. Miura, T. Bitajima, T. Fujii, M. Murakami, J. Am. Chem. Soc. 134 (2012) 194-196;
(d) T. Sueda, A. Kawada, Y. Urashi, N. Teno, Org. Lett. 15 (2013) 1560-1563;
(e) R.E. Evans, J.R. Zbieg, S. Zhu, W. Li, D.W.C. Macmillan, J. Am. Chem. Soc. 135 (2013) 16074-16077;
(f) J.S. Alford, M.L. Davies, Org. Lett. 14 (2012) 6020-6023;
(g) S. Cacchi, G. Fabrizi, E. Filisti, et al., Org. Biomol. Chem. 10 (2012) 4699-4703.
(a) M. Li, H. Yuan, B. Zhao, F. Liang, J. Zhang, Chem. Commun. 50 (2014) 2360-2363;
(b) W. Gao, F. Hu, Y. Huo, et al., Org. Lett. 17 (2015) 3914-3917;
(c) A. Sakakura, A. Ukai, K. Ishihara, Nature 445 (2007) 900-903;
(d) Y. Cai, X. Liu, Y. Hui, et al., Angew. Chem. Int. Ed. 49 (2010) 6160-6164;
(e) S.M. Walter, F. Kniep, E. Herdtweck, S.M. Huber, Angew. Chem. Int. Ed. 50 (2011) 7187-7191;
(f) M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi, Science 332 (2011) 448-451.
P.K. Prasad, R.N. Reddi, A. Sudalai, Org. Lett. 18 (2016) 500-503. DOI:10.1021/acs.orglett.5b03540
M.H. Shinde, U.A. Kshirsagar, Org. Biomol. Chem. 14 (2016) 858-861. DOI:10.1039/C5OB02034D
(a) Y. Wei, S. Lin, F. Liang, J. Zhang, Org. Lett. 15 (2013) 852-855;
(b) Y. Wei, F. Liang, X. Zhang, Org. Lett. 15 (2013) 5186-5189;
(c) Y. Wei, S. Lin, F. Liang, Org. Lett. 14 (2012) 4202-4205.
(a) B. Wang, L. Tang, L.Y. Liu, et al., Green Chem. 19 (2017) 5794-5799;
(b) N. Ren, J. Nie, J.A. Ma, Green Chem. 18 (2016) 6609-6617;
(c) D.Q. Dong, S.H. Hao, H. Zhang, Z.L. Wang, Chin. Chem. Lett. 28 (2017) 1597-1599.