2017, Vol. 28 
Organic azides are important precursors for the synthesis of N-containing structural motifs in organic synthesis [1] and their applications in click chemistry have also attracted intensive attentions in fields of pharmaceutical chemistry, supramolecular chemistry and material science [2]. As such, mild and efficient methods for their synthesis are of increasing importance and aza-Micahel addition of azide ion to unsaturated carbonyl compounds represents one of the most straightforward approaches for the synthesis of organic azides [3]. The resulted β-azido carbonyls could be readily converted into β-amino acids [4], an intriguing structural motif widely distributed in biologically and pharmacologically active compounds [5]. In this context, the asymmetric hydroazidation of unsaturated carbonyl compounds is highly desirable [6]. In 1999, Jacobsen and coworkers reported that chiral (salen)Al(Ⅲ) complexes could effectively promote the enantioselective addition of hydrazoic acid to unsaturated imides [6b]. Subsequently, the first organocatalytic enantioselective hydroazidation of Michael acceptors was reported by Miller and co-workers by using a small peptide as the catalyst [6c-d]. Nitroalkenes have also been attempted as Michael acceptors in reaction with azide for the synthesis of optically enriched β-nitro azides, but unfortunately with limited success [6g-h]. Recently, Jang and co-workers reported a tandem reaction of enals with azide in the presence of chiral aminocatalyst and iron complex for the asymmetric synthesis of β-amino α-hydroxy aldehydes [7]. Most of these studies utilized β-substituted Michael acceptors, however, the reactions with β-unsubstituted vinyl carbonyls have not been achieved so far (Scheme 1). The most difficulty associated with this type of substrates comes from the challenging α-stereogenic protonation step.
|
Download:
|
| Scheme 1. Asymmetric Michael addition of trimethylsilylazide to enones. | |
Recently, we have developed chiral primary aminocatalysis for asymmetric conjugate addition to α-substituted acroleins and vinyl ketones with a wide range of nucleophiles [8]. These reactions feature enamine protonation as the key stereogenic step [9] and our detail mechanistic studies have disclosed a Curtin-Hammett stereocontrol for the reactions of α-substituted vinyl ketones [8f]. To further explore the potentials of this reaction, we have examined other types of nucleophiles such as azide in the reaction with α-substituted vinyl ketones. Following the established mechanistic scenario, the targeted reaction would provide a straightforward access of chiral β-azido ketones with promising enantioselectivity [8f]. In this communication, we wish to present the unprecedented stereoselective addition of azide to α-substituted vinyl ketones catalyzed by a simple chiral primary-tertiary diamine catalyst derived from L-phenylalanine.
2. Results and discussionOur studies on this asymmetric Michael addition-protonation reaction with azide were carried out using TMSN3 as the azide source. Using EtOH as the proton source, a preliminary result indicated that the vicinal primary-tertiary diamine catalyst 1 could promote the targeted reaction, with not unexpectedly low activity, but fortunately with a promising enantioselectivity (Table 1, entry 1). Further investigation led to the identification of 3a/TfOH as the optimum catalyst system (Table 1, entries 2-9). In the presence of 10 mol% 3a/TfOH, the reaction gave the desired product 5a in 52% isolated yield and with 42% ee (Table 1, entry 3). The screening of reaction mediums demonstrated that the solvents had an obvious effect on both of the yield and stereocontrol. As can be seen from Table 1, the use of chlorinated solvent, especially 1, 2-dichloroethane (DCE), could greatly improve the reaction outcome, affording the desired product in 63% isolated yield and 57% ee (Table 1, entry 10). Interestingly, when tetrahydrofuran was employed as solvent nearly no product could be detected (Table 1, entry 13).
|
Table 1 Screening of catalysts and solvents.a |
Bearing in mind the dramatic effect of proton donors in enantioselective enamine protonation reactions [8], we next examined a range of proton donors, such as alcohols, water and phenols, in order to further improve the activity and stereoselectivity (Table 2). In general, the use of alcohol additives led to better results but have no significant effect on the stereocontrol and, the use of methyl alcohol afforded the product with the best yield outcome (Table 2, entry 1). Moreover, we disclosed that the drop-wise addition of TNSN3 in one hour could greatly increase the enantioselectivity to 69% ee (Table 2, entry 10). Extensive efforts to improve the enantioselectivity were all in vain, reflecting the difficulties in controlling a stereogenic enamine protonation in this context. Nevertheless, the current results represent the best for this hydroazidation reaction with vinyl ketones. Finally, 10 mol% of 3a as catalyst, 4.0 equipment of methyl alcohol as proton source and 1, 2-dichloroethane as the solvent were chosen as the optimal conditions for our subsequent scope examination.
|
|
Table 2 Screening of proton sources.a |
Under the optimal conditions, the substrate scope of the reaction was next explored. As shown in Table 3, α-substituted vinyl ketones are well tolerated in this reaction. Aromatic α-substituted vinyl ketones were identified as one class of preferred substrates, and para-substitution on the phenyl group bearing either electron-rich or electron-deficient substituents are equally applicable, giving the desired adducts with moderate to good enantioselectivity (Table 3, entries 2-7). Unfortunately, meta-substitution on the phenyl group, especially the incorporation of the elemental fluorine seems somehow detrimental to the reaction (Table 3, entries 8-11). We also found that a more bulky α-substituted group could lead to a sharp drop of the enantioselectivity (Table 3, entries 13-15).
|
|
Table 3 Substrate scope.a |
To evaluate the practicality of this methodology, the Staudinger reduction procedure was performed to furnishe the α-chiral β-amino ketone 5a in good isolated yield, and erosion of the enantioselectivity was observed, likely a result of the subsequent non-optimized basic reaction conditions (Scheme 2). Meanwhile, the click reaction between 5a and 7 can also be readily achieved, affording the benzotriazole addition product 8 in excellent yield.
|
Download:
|
| Scheme 2. Transformations of the azido adducts. | |
3. Conclusion
In summary, we have developed the first example of asymmetric conjugate addition-protonation reactions of trimethylsilylazide to α-substituted vinyl ketones by chiral primary amine catalysis. The reaction proceeds under very mild reaction conditions and further synthetic modification of the products could provide chiral β-amino ketones or related compounds easily in one step.
4. ExperimentalGeneral procedure for chiral primary amine catalyzed asymmetric hydroazidation of α-substituted vinyl ketones: Catalyst 3a/TfOH (10 mol%), α-substituted vinyl ketone 4 (0.2 mmol) and methanol (0.4 mmol) in 0.5 mL 1, 2-dichloroethane at 35 ℃. To the mixture, trimethylsilylazide (0.1 mmol) was added in 0.5 mL DCE to this tube in 1 h and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was directly separated by flash column chromatography on silica gel eluting with a mixture of petrol ether and EtOAc (PE/EA: 20/1). Collected fractions were concentrated under vacuum to afford the desired product.
The characterization data of the products are summarized in the Supporting information.
AcknowledgmentsWe thank National Natural Science Foundation of China (NSFC Nos. 21390400, 21521002 and 21502198) and the Ministry of Science and Technology, Chinese Academy of Sciences (No. QYZDJSSW-SLH023) for generous financial support. S. L. is supported by National Program for Support of Top-notch Young Professionals, CAS Youth Innovation Promotion Association and CAS onehundred talented program (D).
Appendix A. Supplementary dataSupplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2017.01.014.
| [1] |
(a) S. Brase, C. Gil, K. Knepper, et al. , Organic azides: an exploding diversity of a unique class of compounds, Angew. Chem. Int. Ed. 44(2005) 5188-5240; (b) M. Minozzi, D. Nanni, P. Spagnolo, From azides to nitrogen-centered radicals: applications of azide radical chemistry to organic synthesis, Chem. Eur. J. 15(2009) 7830-7840; (c) D. Lubriks, I. Sokolovs, E. Suna, Indirect C-H azidation of heterocycles via copper-catalyzed regioselective fragmentation of unsymmetrical λ3-iodanes, J. Am. Chem. Soc. 134(2012) 15436-15442; (d) C. Tang, N. Jiao, Copper-catalyzed C-H azidation of anilines under mild conditions, J. Am. Chem. Soc. 134(2012) 18924-18927; (e) Q. H. Deng, T. Bleith, H. Wadepohl, L. H. Gade, Enantioselective iron-catalyzed azidation of β-keto esters and oxindoles, J. Am. Chem. Soc. 135(2013) 5356-5359; (f) F. Xie, Z. Qi, X. Li, Rhodium(Ⅲ)-catalyzed azidation and nitration of arenes by C-H activation, Angew. Chem. Int. Ed. 52(2013) 11862-11866; (g) P. Klahn, H. Erhardt, A. Kotthaus, et al. , The synthesis of α-azidoesters and geminal triazides, Angew. Chem. Int. Ed. 53(2014) 7913-7919; (h) H. Yin, T. Wang, N. Jiao, Copper-catalyzed oxoazidation and alkoxyazidation of indoles, Org. Lett. 16(2014) 2302-2305; (i) Y. Fan, W. Wan, G. Ma, et al. , Room-temperature Cu(Ⅱ)-catalyzed aromatic C-H azidation for the synthesis of ortho-azido anilines with excellent regioselectivity, Chem. Commun. 50(2014) 5733-5736; (j) A. Sharma, J. F. Hartwig, Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization, Nature 517(2015) 600-604; (k) X. Huang, T. M. Bergsten, J. T. Groves, Manganese-catalyzed late-stage aliphatic C-H azidation, J. Am. Chem. Soc. 137(2015) 5300-5303; (l) X. Huang, J. T. Groves, Taming azide radicals for catalytic C-H azidation, ACS Catal. 6(2016) 751-759; (m) W. E. Fristad, T. A. Brandvold, J. R. Peterson, et al. , Conversion of alkenes to 1, 2-diazides and 1, 2-diamines, J. Org. Chem. 50(1985) 3647-3649; (n) Y. A. Yuan, D. F. Lu, Y. R. Chen, et al. , Iron-catalyzed direct diazidation for a broad range of olefins, Angew. Chem. Int. Ed. 55(2016) 534-538; (o) B. Zhang, A. Studer, Stereoselective radical azidooxygenation of alkenes, Org. Lett. 15(2013) 4548-4551; (p) L. Zhu, H. Yu, Z. Xu, et al. , Copper-catalyzed oxyazidation of unactivated alkenes: a facile synthesis of isoxazolines featuring an azido substituent, Org. Lett. 16(2014) 1562-1565; (q) H. C. Kolb, M. G. Finn, K. B. Sharpless, Click chemistry: diverse chemical function from a few good reactions, Angew. Chem. Int. Ed. 40(2001) 2004-2021; (r) V. V. Rostovtsev, L. G. Green, V. V. Fokin, et al. , A stepwise huisgen cycloaddition process: copper(Ⅰ)-catalyzed regioselective ligation of azides and terminal alkynes, Angew. Chem. Int. Ed. 41(2002) 2596-2599; (s) P. Wu, A. K. Feldman, A. K. Nugent, et al. , Efficiency and fidelity in a clickchemistry route to triazole dendrimers by the copper(Ⅰ)-catalyzed ligation of azides and alkynes, Angew. Chem. Int. Ed. 43(2004) 3928-3932. |
| [2] |
(a) D. Thirumurugan, Click chemistry for drug development and diverse chemical-biology applications, Chem. Rev 113(2013) 4905-4979; (b) M. Grammel, H. C. Hang, Chemical reporters for biological discovery, Nat. Chem. Biol. 9(2013) 475-484; (c) C. J. Hawker, V. V. Fokin, M. G. Finn, et al. , Bringing efficiency to materials synthesis: the philosophy of click chemistry, Aust. J. Chem. 60(2007) 381-383; (d) C. Chu, R. Liu, Application of click chemistry on preparation of separation materials for liquid chromatography, Chem. Soc. Rev. 40(2011) 2177-2188; (e) W. H. Binder, R. Sachsenhofer, 'Click' chemistry in polymer and materials science, Macromol. Rapid Commun. 28(2007) 15-54; (f) C. Barner-Kowollik, F. E. D. Prez, P. Espeel, et al. , Clicking polymers or just efficient linking: what is the difference? Angew. Chem. Int. Ed. 50(2011) 60-62. |
| [3] |
(a) J. Wang, P. Li, P. Y. Choy, et al. , Advances and applications in organocatalytic asymmetric aza-Michael addition, ChemCatChem 4(2012) 917-925; (b) D. Enders, C. Wang, J. X. Liebich, Organocatalytic asymmetric aza-Michael additions, Chem. Eur. J. 15(2009) 11058-11076; (c) P. R. Krishna, A. Sreeshailam, R. Srinivas, Tetrahedron 65(2009) 9657-9672; (d) L. W. Xu, C. G. Xia, A catalytic enantioselective aza-Michael reaction: novel protocols for asymmetric synthesis of β-amino carbonyl compounds, Eur. J. Org. Chem. (2005) 633-639. |
| [4] |
(a) D. C. Cole, Recent stereoselective synthetic approaches to β-amino acids, Tetrahedron 50(1994) 9517-9582; (b) M. Liu, M. P. Sibi, Recent advances in the stereoselective synthesis of β-amino acids, Tetrahedron 58(2002) 7991-8035; (c) J. A. Ma, Recent developments in the catalyticasymmetric synthesis of α-and β-amino acids, Angew. Chem. Int. Ed. 42(2003) 4290-4299; (d) B. Weiner, W. Szymanski, D. B. Janssen, et al. , Recent advances in the catalytic asymmetric synthesis of β-amino acids, Chem. Soc. Rev. 39(2010) 1656-1691. |
| [5] |
(a) H. X. Ding, K. K. C. Liu, S. M. Sakya, et al. , Synthetic approaches to the 2011 new drugs, Bioorg. Med. Chem. 21(2013) 2795-2825; (b) K. K. C. Liu, S. M. Sakya, C. J. O'Donnell, et al. , Synthetic aroaches to the 2009 new drugs, Bioorg. Med. Chem. 19(2011) 1136-1154; (d) A. Kumar, I. Ahmad, B. S. Chhikara, et al. , Synthesis of 3-phenylpyrazolopyrimidine-1, 2, 3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities, Bioorg. Med. Chem. Lett. 21(2017) 1342-1346; (e) K. K. C. Liu, S. M. Sakya, C. J. O'Donnell, et al. , Synthetic approaches tothe 2009 new drugs, Bioorg. Med. Chem. 19(2011) 1136-1154; (f) A. Kumar, I. Ahmad, B. S. Chhikara, et al. , Synthesis of 3-phenylpyrazolopyrimidine-1, 2, 3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities, Bioorg. Med. Chem. Lett. 21(2011) 1342-1346. |
| [6] |
(a) D. J. Guerin, T. E. Horstmann, S. J. Miller, Amine-catalyzed addition of azide ion to a, β-unsaturated carbonyl compounds, Org. Lett. 1(1999) 1107-1109; (b) J. K. Myers, E. N. Jacobsen, Asymmetric synthesis of β-amino acid derivatives via catalytic conjugate addition of hydrazoic acid to unsaturated imides, J. Am. Chem. Soc. 121(1999) 8959-8960; (c) T. E. Horstmann, D. J. Guerin, S. J. Miller, Asymmetric conjugate addition of azide to a, β-unsaturated carbonyl compounds catalyzed by simple peptides, Angew. Chem. Int. Ed. 39(2000) 3635-3638; (d) D. J. Guerin, S. J. Miller, Asymmetric azidation-cycloaddition with open-chain peptide-based catalysts. A sequential enantioselective route to triazoles, J. Am. Chem. Soc. 124(2002) 2134-2136; (e) L. W. Xu, L. Li, C. G. Xia, et al. , The first ionic liquids promoted conjugate addition of azide ion to a, β-unsaturated carbonyl compounds, Tetrahedron Lett. 45(2004) 1219-1221; (f) M. S. Taylor, D. N. Zalatan, A. M. Lerchner, et al. , Highly enantioselective conjugate additions to a, β-unsaturated ketones catalyzed by a (Salen)Al complex, J. Am. Chem. Soc. 127(2005) 1313-1317; (g) M. Nielsen, W. Zhuang, K. A. Jørgensen, Asymmetric conjugate addition of azide to a, β-unsaturated nitro compounds catalyzed by cinchona alkaloids, Tetrahedron 63(2007) 5849-5854; (h) T. Bellavista, S. Meninno, A. Lattanzi, et al. , Asymmetric hydroazidation of nitroalkenes promoted by a secondary amine-thiourea catalyst, Adv. Synth. Catal. 357(2015) 3365-3373; (i) Z. Liu, J. Liu, L. Zhang, et al. , Silver(Ⅰ)-catalyzed hydroazidation of ethynyl carbinols: synthesis of 2-azidoallyl alcohols, Angew. Chem. Int. Ed. 53(2014) 5305-5309; (j) X. Sun, X. Li, S. Song, et al. , Mn-catalyzed highly efficient aerobic oxidative hydroxyazidation of olefins: a direct approach to β-azido alcohols, J. Am. Chem. Soc. 137(2015) 6059-6060. |
| [7] | Shyam P.K., Jang H.Y.. Metal-organocatalytic tandem azide addition/oxyamination of aldehydes for the enantioselective synthesis of β-amino α-hydroxy esters. Eur. J. Org. Chem. (2014) 1817–1822. |
| [8] |
(a) L. Zhang, S. Luo, Bio-inspired chiral primary amine catalysis, Synlett 23(2012) 1575-1589; (b) L. Zhang, N. Fu, S. Luo, Pushing the limits of aminocatalysis: enantioselective transformations of α-branched β-ketocarbonyls and vinyl ketones by chiral primary amines, Acc. Chem. Res. 48(2015) 986-997; (c) J. Li, X. Li, P. Zhou, et al. , Chiral primary amine-polyoxometalate acid hybrids as asymmetric recoverable iminium-based catalysts, Eur. J. Org. Chem. (2009) 4486-4493; (d) J. Li, N. Fu, L. Zhang, et al. , Chiral primary amine catalyzed asymmetric epoxidation of α-substituted acroleins, Eur. J. Org. Chem. (2010) 6840-6849; (e) N. Fu, L. Zhang, J. Li, et al. , Chiral primary amine catalyzed enantioselective protonation via an enamine intermediate, Angew. Chem. Int. Ed. 50(2011) 11451-11455; (f) N. Fu, L. Zhang, S. Luo, et al. , Chiral primary-amine-catalyzed conjugate addition to α-substituted vinyl ketones/aldehydes: divergent stereocontrol modes on enamine, Chem. Eur. J. 19(2013) 15669-15681; (g) N. Fu, L. Zhang, S. Luo, et al. , Chiral primary amine catalysed asymmetric conjugate addition of azoles to α-substituted vinyl ketones, Org. Chem. Front. 1(2014) 68-72; (h) N. Fu, L. Zhang, S. Luo, et al. , Asymmetric sulfα-Michael addition to α-substituted vinyl ketones catalyzed by chiral primary amine, Org. Lett. 16(2014) 4626-4629; (i) N. Fu, L. Zhang, S. Luo, Chiral primary amine catalyzed asymmetric Michael addition of malononitrile to α-substituted vinyl ketone, Org. Lett. 17(2015) 382-385; (j) N. Fu, Y. Guo, L. Zhang, et al. , Chiral primary amine catalyzed asymmetric tandem reduction-Michael addition-protonation reaction between alkylidene meldrum's acid and α-substituted vinyl ketones, Synthesis 47(2015) 2207-2216. |
| [9] |
(a) A. Yanagisawa, H. Yamamoto, Protonation of enolates, in: E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds. ), Comprehensive asymmetric catalysis, vol. Ⅲ, Springer, Heidelberg, 1999, pp. 1295-1306; (b) L. Duhamel, P. Duhamel, J. C. Plaquevent, Enantioselective protonations: fundamental insights and new concepts, Tetrahedron: Asymmetry 15(2004) 3653-3691; (c) C. Fehr, Enantioselective protonation of enolates and enols, Angew. Chem. Int. Ed. 35(1996) 2566-2587; (d) J. Blanchet, J. Baudoux, M. Amere, et al. , Asymmetric malonic and acetoacetic acid syntheses-a century of enantioselective decarboxylative protonations, Eur. J. Org. Chem. (2008) 5493-5506; (e) J. T. Mohr, A. Y. Hong, B. M. Stoltz, Enantioselective protonation, Nat. Chem. 1(2009) 359-369; (f) S. Oudeyer, J. F. Briere, V. Levacher, Progress in catalytic asymmetric protonation, Eur. J. Org. Chem. (2014) 6103-6119. |