Letter pubs.acs.org/OrgLett
Stereospecific Nucleophilic Substitution of Enantioenriched Tertiary Benzylic Amines via in Situ Activation with Benzyne Yang Gui and Shi-Kai Tian* Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China S Supporting Information *
ABSTRACT: A one-pot protocol has been developed for sequential benzyne activation and nucleophilic substitution of enantioenriched tertiary benzylic amines. In the presence of 2(trimethylsilyl)phenyl triflate and CsF, a range of enantioenriched tertiary benzylic amines were substituted by various nucleophiles, delivering structurally diverse benzylic compounds in moderate to excellent yields with excellent retention of enantiopurity. Importantly, this operationally simple protocol permitted formation of various chiral C−S, C−Se, C−C, and C−N bonds with excellent enantiopurity under metal-free conditions.
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Scheme 1. Stereospecific Transformations of Enantioenriched Tertiary Benzylic Amines and BenzynePromoted Ring-Opening of Enantioenriched Aziridines
hile enantioenriched benzylic amines are readily accessible and widely employed as nitrogen nucleophiles in chemical synthesis,1 they have rarely served as carbon electrophiles in stereospecific nucleophilic substitution reactions. Owing to the poor leaving ability of amino groups, it is necessary to activate benzylic amines to enhance electrophilicity by modifying amino groups in advance. Although enantioenriched primary benzylic amines can be substituted by nucleophiles after being transformed into diazonium compounds,2 diazotates,3 or pyridinium salts4 or after introduction of electron-withdrawing groups to their amino groups,2,5 the enantiopurity has decreased dramatically, and in many cases, even racemic products have been obtained. In contrast, effective chirality transfer has been achieved when transforming enantioenriched tertiary benzylic amines into quaternary ammonium salts, which can be substituted by an electrochemically generated phosphide6 and undergo nickel-catalyzed crosscouplings with boron reagents (Scheme 1).7 Moreover, a onepot protocol has been disclosed for activation and substitution of an enantioenriched benzylic amine with a chlorotriazine, delivering an enantioenriched benzylic chloride.8 To expand the scope and facilitate the process for stereospecific substitution of enantioenriched benzylic ammonium salts, alongside our interests in exploring asymmetric C−N bond cleavage,5a,9 we have developed a new strategy by generating the ammonium salts in situ from enantioenriched tertiary benzylic amines and benzyne (Scheme 1). Importantly, this one-pot protocol has permitted a variety of nucleophiles to participate in stereospecific substitution with enantioenriched tertiary benzylic amines under metal-free conditions. The one-pot protocol to sequential activation and substitution of enantioenriched tertiary benzylic amines was designed according to previous studies on the nucleophilic addition of tertiary amines to arynes, particularly those generated in situ from 2-(trimethylsilyl)aryl triflates under mild conditions.10−13 It is noteworthy that two examples were reported on the use of benzyne to promote the ring-opening © XXXX American Chemical Society
reaction of enantioenriched aziridines with nucleophiles (acetonitrile and trifluoroacetic acid), wherein the relief of ring strain is a driving force (Scheme 1).12a,c Inspired by these reports, we envisioned that the zwitterions generated from tertiary benzylic amines and benzyne would undergo substitution in an SN2 manner to afford optically active benzylic compounds with inversion of configuration. Of course, care should be taken to minimize or even obviate side reactions Received: February 4, 2017
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DOI: 10.1021/acs.orglett.7b00365 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters such as addition of nucleophiles to benzyne.10 Using 2(trimethylsilyl)phenyl triflate as a benzyne precursor and CsF as a fluoride source, we examined the model reaction of amine 1a (99% ee) with thiophenol (2a) at 50 °C for 8 h in a number of solvents, such as toluene, 1,2-dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, N,Ndimethylformamide, and dimethyl sulfoxide (eq 1), and found
Table 1. Scope of Enantioenriched Tertiary Benzylic Aminesa,b
that the reaction conducted in untreated acetonitrile (containing 0.3 wt % water) afforded chiral thioether 3a with the best results: 87% yield and 99% ee.14 It is noteworthy that the reaction was performed open to air, and increasing the scale from 0.20 to 2.0 mmol gave a slightly lower yield (81%). To our surprise, a much lower yield (18%) was obtained from a control experiment performed in dry acetonitrile under nitrogen. Replacing CsF with KF or Bu4NF led to a sluggish reaction. Moreover, a lower yield (81%) was obtained when the reaction temperature was lowered to 25 °C and the reaction time was prolonged from 8 to 24 h. A range of enantioenriched tertiary benzylic amines were successfully substituted by thiophenol (2a) with inversion of configuration in the presence of 2-(trimethylsilyl)phenyl triflate and CsF, delivering structurally diverse benzylic thioethers in moderate to excellent yields with excellent retention of enantiopurity (Table 1). The reaction efficiency is very sensitive to the substituents on the phenyl group of benzylic amines, and the substrate bearing an electron-withdrawing group gave a higher yield and better retention of enantiopurity relative to the one bearing an electron-donating group (Table 1, entries 2−5). Moreover, a sluggish reaction was observed with a benzylic amine bearing a strong electron-donating group, such as a methoxy group, at the para-position, probably owing to the inferior electrophilicity of the corresponding benzylic ammonium salt intermediates. The reaction conditions were also suitable for the ring-opening of enantioenriched six-membered cyclic dibenzylic amine 1i, albeit with significant erosion of enantiopurity (Table 1, entry 9). Nevertheless, very low conversion (99% deuterium incorporation at both C-2 and C-6 of the Nphenyl group (eq 3).11b Furthermore, no deuterium incorporation was observed for the reaction with PhSD (71% D) (eq 4). These results suggest that the zwitterion generated from an amine and benzyne (Scheme 1) can abstract a proton from B
DOI: 10.1021/acs.orglett.7b00365 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 2. Scope of Nucleophilesa−c
both water and the solvent. The successful substitution of ammonium triflate rac-4a with thiophenol (2a) further confirms that the nucleophile can participate in substitution without deprotonation in advance (eq 5). Moreover, the use of the phenyl group to activate the amino group in a tertiary benzylic amine proved crucial for the substitution reaction when compared to the control experiment with benzyltrimethylammonium triflate rac-4b, substitution of which with thiophenol (2a) did not occur at all. In line with the results shown in entries 9 and 10 of Table 2, ammonium triflate rac-4a was smoothly substituted by alkyl thiolate 2k but not by alkyl thiol 2j (eq 6). According to the above experimental results and previous relevant studies, we propose the following reaction pathways as depicted in Scheme 2 for the nucleophilic substitution of tertiary benzylic amines. Nucleophilic addition of amine 1 to benzyne, generated in situ from 2-(trimethylsilyl)phenyl triflate in the presence of CsF affords zwitterion 5,11 which deprotonates water or the solvent (acetonitrile) and suba Reaction conditions: 1a (0.20 mmol), 2 (0.22 mmol), 2(trimethylsilyl)phenyl triflate (0.24 mmol), CsF (0.40 mmol), acetonitrile (0.50 mL), 50 °C (oil bath), 8 h. bThe ee values were determined by chiral HPLC analysis. cThe absolute configuration of compounds 3n, 3p, and 3v was assigned according to the literature and that of the rest of products shown in Tables 1 and 2 was assigned by analogy.14 dIsolated yield. eThe reaction was run for 12 h. f1d (99% ee) was used instead of 1a.
Scheme 2. Proposed Reaction Pathways
Figure 2. Nucleophiles 2s−v.
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DOI: 10.1021/acs.orglett.7b00365 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(6) Millauer, H.; Brungs, P. Eur. Pat. Appl. EP 0754695, 1997. (7) (a) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 280. (b) ShackladyMcAtee, D. M.; Roberts, K. M.; Basch, C. H.; Song, Y.-G.; Watson, M. P. Tetrahedron 2014, 70, 4257. (c) Hu, J.; Sun, H.; Cai, W.; Pu, X.; Zhang, Y.; Shi, Z. J. Org. Chem. 2016, 81, 14. (d) Basch, C. H.; Cobb, K. M.; Watson, M. P. Org. Lett. 2016, 18, 136. (8) Kolesiñska, B.; Kamiñski, Z. Pol. J. Chem. 2008, 11, 2115. (9) For recent examples, see: (a) Wang, Y.; Li, M.; Ma, X.; Liu, C.; Gu, Y.; Tian, S.-K. Chin. J. Chem. 2014, 32, 741. (b) Wang, Y.; Xu, J.K.; Gu, Y.; Tian, S.-K. Org. Chem. Front. 2014, 1, 812. (c) Wang, T.-T.; Wang, F.-X.; Yang, F.-L.; Tian, S.-K. Chem. Commun. 2014, 50, 3802. (d) Zhou, M.-G.; Zhang, W.-Z.; Tian, S.-K. Chem. Commun. 2014, 50, 14531. (e) Wang, Y.; Xu, Y.-N.; Fang, G.-S.; Kang, H.-J.; Gu, Y.; Tian, S.-K. Org. Biomol. Chem. 2015, 13, 5367. (f) Xu, J.-K.; Wang, Y.; Gu, Y.; Tian, S.-K. Adv. Synth. Catal. 2016, 358, 1854. (g) Zhang, J.; Chen, Z.-X.; Du, T.; Li, B.; Gu, Y.; Tian, S.-K. Org. Lett. 2016, 18, 4872. (10) For reviews, see: (a) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (b) Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199. (c) Kitamura, T. Aust. J. Chem. 2010, 63, 987. (d) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (e) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (f) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (11) For examples, see: (a) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.; Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199. (b) Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Org. Lett. 2013, 15, 5452. (c) Bhojgude, S. S.; Baviskar, D. R.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2015, 17, 6270. (d) Varlamov, A. V.; Guranova, N. I.; Borisova, T. N.; Toze, F. A. A.; Ovcharov, M. V.; Kristancho, S.; Voskressensky, L. G. Tetrahedron 2015, 71, 1175. (e) Hirsch, M.; Dhara, S.; Diesendruck, C. E. Org. Lett. 2016, 18, 980. (f) Bhojgude, S. S.; Roy, T.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2016, 18, 5424. (g) Roy, T.; Thangaraj, M.; Kaicharla, T.; Kamath, R. V.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2016, 18, 5428. (12) For the ring-opening of aziridines activated by arynes, see: (a) Stephens, D.; Zhang, Y.; Cormier, M.; Chavez, G.; Arman, H.; Larionov, O. V. Chem. Commun. 2013, 49, 6558. (b) Tang, C.-Y.; Wang, G.; Yang, X.-Y.; Wu, X.-Y.; Sha, F. Tetrahedron Lett. 2014, 55, 6447. (c) Roy, T.; Baviskar, D. R.; Biju, A. T. J. Org. Chem. 2015, 80, 11131. (13) For the ring-opening of azetidines activated by arynes, see: (a) Aoki, T.; Koya, S.; Yamasaki, R.; Saito, S. Org. Lett. 2012, 14, 4506. (b) Reference 12c.. (14) For details, see the Supporting Information.
sequently participate in anion exchange to afford ammonium triflate 4.11e SN2 substitution of ammonium triflate 4 with a nucleophile affords benzylic compound 3 with inversion of configuration. A minor reaction pathway is SN1 substitution of ammonium triflate 4 via benzyl cation 6 to afford racemic product rac-3, which accounts for the erosion of enantiopurity in some cases shown in Tables 1 and 2. In summary, we have developed a new strategy for the stereospecific nucleophilic substitution of enantioenriched tertiary benzylic amines via in situ activation with benzyne to generate the corresponding ammonium salts. A range of enantioenriched tertiary benzylic amines were successfully substituted by various nucleophiles in the presence of 2(trimethylsilyl)phenyl triflate and CsF, delivering structurally diverse benzylic compounds in moderate to excellent yields with excellent retention of enantiopurity. Importantly, this operationally simple protocol permitted formation of various chiral C−S, C−Se, C−C, and C−N bonds with excellent enantiopurity under metal-free conditions. This study extends the scope for the use of enantioenriched benzylic amines as carbon electrophiles in stereospecific nucleophilic substitution reactions.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00365. Experimental procedures, characterization data, and 1H, 13 C, and 19F NMR spectra and HPLC traces (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shi-Kai Tian: 0000-0002-2938-7013 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21472178 and 21232007), the National Key Basic Research Program of China (2014CB931800), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00365 Org. Lett. XXXX, XXX, XXX−XXX
