Cyclization Cascade of 1,6-Enynes for the

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Radical Borylation/Cyclization Cascade of 1,6-Enynes for the Synthesis of Boron-Handled Hetero- and Carbocycles Shi-Chao Ren,‡ Feng-Lian Zhang,‡ Jing Qi, Yun-Shuai Huang, Ai-Qing Xu, Hong-Yi Yan, and Yi-Feng Wang* Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China S Supporting Information *

Scheme 1. Synthetic Applications of N-Heterocyclic Carbene−Boryl Radicals

ABSTRACT: A synthetic method to construct boronhandled cyclic molecules was developed based on a radical borylation/cyclization cascade of 1,6-enynes. The process was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene−boryl radical to an alkene or alkyne, followed by ring closure to afford boronsubstituted cyclic skeletons. Further molecular transformations of the cyclic products to synthetically useful building blocks were also demonstrated.

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rganoboron compounds have been extensively applied in modern synthetic chemistry.1 Although many borylation methods have been developed,2 exploration of conceptually distinct approaches to the synthesis of complex organoboron compounds with predictable stereo- and regio-control remains challenging. Boron-centered radicals (boryl radicals), in particular, those that are Lewis base ligated, have been involved as key intermediates in various organic transformations.3 For example, the seminal work by Roberts revealed that amine−boryl radicals could facilitate radical hydrogen transfer reactions through polarity reversal catalysis.3c Recently, Fensterbank, Lacôte, Malacria, and Curran discovered that N-heterocyclic carbene (NHC)−boryl radicals4 could be generated by hydrogen atom abstraction of NHC−BH3 complexes.5 Significantly, these NHC−boryl radicals have shown versatile reactivities to enable a range of radical reactions (Scheme 1a), including radical deoxygenation of xanthates,4,6 reduction of organic halides7 and alkyl nitriles,8 radical polymerization of electron-deficient alkenes,9 and homolytic substitution of disulfides.10 Very recently, Li, Zhu, and Jiao disclosed that pyridine-ligated boryl radicals, produced by homolysis of the B−B bond in pyridine-coordinated diboranes,11 could induce the catalytic reduction of diazo compounds11 and the radical borylation of aryl halides.12 Despite these advances, the reactions of boryl radicals with alkenes and alkynes, which deliver versatile alkyl and alkenyl boron compounds,13 have rarely been documented.14 Herein, we report unprecedented chemo- and regiocontrolled radical borylation/cyclization cascades of 1,6-enynes, which can access alkyl or alkenyl boron-handled cyclic scaffolds through the divergent addition of an NHC−boryl radical to either an alkene or alkyne moiety (Scheme 1b). Radical cascade reactions represent a powerful strategy to assemble cyclic frameworks with the concomitant installation of © 2017 American Chemical Society

various functionalities.15 We envisioned that a boryl radicalmediated radical cascade process would provide a new route to make high-value boron-tethered cyclic molecules, which have been hardly accessed because of the limited number of synthetic methods.16 To achieve this goal, the following challenges were anticipated: (i) identification of a boryl radical species that can react with unsaturated C−C bonds while being compatible with other functional groups, (ii) precise control over the chemo- and regioselective cascade processes, and (iii) exploitation of a reaction system that maintains an efficient radical chain.17 We commenced our study by investigating the reaction of 1,6-enyne 1a with various boryl radical precursors.18 Extensive screening of the reaction conditions revealed that employment of 1,3-dimethylimidazol-2-ylidene borane (2) as the boryl radical precursor and 2,2-azobis(isobutyronitrile) (AIBN) as the radical initiator could promote the radical domino process of 1a, furnishing 3-methylenepiperidine 3a19 in 20% yield as a single diastereomer with 4,5-trans stereochemistry along with 61% recovery of 2 (Table 1, entry 1). The yield of 3a was enhanced when thiophenol (PhSH) (entry 2) or tertdodecanethiol (entry 3), which might act as polarity reversal catalysts,7c,20 was used as an additive. Switching the solvent to CH3CN led to an 84% isolated yield of 3a (entry 4). A comparable result was obtained when di-tert-butyl hyponitrite Received: February 22, 2017 Published: April 12, 2017 6050

DOI: 10.1021/jacs.7b01889 J. Am. Chem. Soc. 2017, 139, 6050−6053

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general, 1,6-enynes possessing a radical-stabilizing aryl group as R1 at the alkene end could afford the cyclized products 3 in moderate to good yields. Remarkably, only a trans-diastereomer was formed in all cases. Benzene rings bearing various functional groups were compatible, regardless of their electronic nature and substitution pattern (for 3b−g), except for a susceptible bromine substituent (for 3h). Both naphthyl (for 3i) and quinoline (for 3j) motifs could also be installed. In place of an aryl group, a methoxycarbonyl group could be used as the substituent R1 (for 3m) while maintaining good selectivity and efficiency. The present method allowed for the construction of tetrahydropyran (for 3k) and cyclohexane (for 3l) scaffolds. Notably, no detrimental effect was detected when methyl (1n), hydroxymethyl (1o), and allyl (1p) groups were incorporated at the alkyne end. However, no reaction occurred when R1 was a hydrogen (for 1q) or methyl group (for 1r and 1s). In addition, the reaction of 1t gave a complex mixture without the detection of the desired product. Interestingly, the reaction of 1u provided 3-benzylidenepiperidine 3u and tetrahydropyridine 5u in 35% and 34% yield (eq 1), respectively. The formation of 5u should occur via the

Table 1. Optimization of the Radical Borylation/Cyclization Reaction of 1,6-Enynea

entry

initiator

additive

solvent

3a yield (%)b

1 2 3 4 5 6e 7

AIBN AIBN AIBN AIBN TBHN Et3B/O2 −

− PhSH C9H19C(CH3)2SH C9H19C(CH3)2SH C9H19C(CH3)2SH C9H19C(CH3)2SH C9H19C(CH3)2SH

PhCH3 PhCH3 PhCH3 CH3CN CH3CN CH3CN CH3CN

21 (61)c 33 (20)c 58 (13)c 84d 80 0 (90)c 0 (98)c

a

Reaction conditions: 2 (0.2−0.3 mmol), 1a (1.2 equiv), initiator (20 mol %), additive (50 mol %), solvent (2 mL), 80 °C for 12 h. bNMR yield using tetrachloroethane as an internal standard. cRecovery yield of 2 is shown in parentheses. dIsolated yield. eThe reaction was run at room temperature under an air atmosphere.

(TBHN) was utilized as the radical initiator (entry 5), whereas use of Et3B/O2, which can initiate the generation of an NHC− boryl radical,4,5a was unable to induce the present reaction (entry 6).21 No reaction occurred in the absence of radical initiator (entry 7), suggesting that a radical mechanism is involved in this transformation. Using the optimized reaction conditions, we examined the generality of this radical borylation/cyclization of enynes 1 for the synthesis of borylated cyclic products 3 (Table 2). In

addition of B· to the phenyl-substituted alkyne motif. Such a finding led us to develop another cascade process of 1,6-enynes bearing aryl-tethered alkynes. To this end, a simple alkene unit was requisite to preclude competitive initiation. As depicted in Table 3, the radical domino process initiated from the alkyne portion of the 1,6-enyens 4 proceeded smoothly to form the products 5 in moderate to good yields.

Table 2. Scope of the Radical Boryaltion/Cyclization of 1,6Enynes 1a

Table 3. Scope of the Radical Boryaltion/Cyclization Reaction Initiated from Alkynesa

a Reaction conditions: 1 (0.2−0.3 mmol), 2 (1.5 equiv), AIBN (20 mol %), C9H19C(CH3)2SH (50 mol %), CH3CN (2−3 mL), 80 °C for 2− 11 h. bThe NMR yield was recorded. cFour portions of AIBN (20 mol % x 4) were added successively in 9 h. dTwo portions of AIBN (20 mol %) were added in 2 h. eThe structure was secured by X-ray crystallographic analysis; see Supporting Information. fA complex mixture was obtained.

a Reaction conditions: 2 (0.2−0.3 mmol), 1 (1.2 equiv), AIBN (20 mol %), C9H19C(CH3)2SH (50 mol %), CH3CN (2−3 mL), 80 °C for 12 h. bC18H37SH (50 mol %) was used. cThe structure was secured by Xray crystallographic analysis; see Supporting Information. dRecovery yield of 2 is shown in parentheses. eA complex mixture was obtained.

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DOI: 10.1021/jacs.7b01889 J. Am. Chem. Soc. 2017, 139, 6050−6053

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reaction. On the other hand, for the reaction of 4a, boryl radical II adds selectively to the phenyl-substituted alkyne moiety, which is followed by 6-exo-trig ring closure and hydrogen atom transfer, affording product 5a with the propagation of the radical chain reaction. The synthetic utility of the NHC−borane-tethered products was demonstrated (Scheme 3). Treatment of 3a and 5h with 2

A borylated carbocyclic compound 5e could be assembled. However, the reaction became messy when a methyl group was installed at the internal carbon of the alkene moiety (for 4f). A number of bicyclic N-containing heterocycles (for 5g−5n) with an alkenyl-boron substituent were constructed as well. The different reactivity of 2 with 1,6-enynes 1 and 4 indicated that the B· derived from 2 could add specifically to alkenes or alkynes, where a functional group could stabilize the resulting alkyl or vinyl radical species. Such a reactivity bias ensured the exclusive chemo- and regioselectivity in the initiation step of the present cascade process. It should be noted that the reactions of phenyl-substituted 1,7-enynes did not give the desired cyclic products, although some alkenyl boron compounds derived from radical hydroboration of phenylactivated alkynes were formed in low yields.22 To verify the radical cascade processes, two radical probe experiments were conducted using 1v and 4o, in which a cyclopropyl radical clock23 was installed at the alkynyl or alkenyl end, respectively. As a result, two cyclopropane ringopening products 3v and 5o were isolated in good yields. These results strongly supported the existence of the cyclopropyl carbinyl radical intermediates A and B in the reaction sequence. Based on these observations and previous findings for NHC− boryl radical chemistry,4,5 plausible mechanisms for the formation of 3a and 5a were outlined in Scheme 2b. Boryl

Scheme 3. Transformations of Borylated Productsa

a

Reagents and conditions: (a) aq. HCl (2 M, 2.6 equiv), pinacol (2−3 equiv), CH3CN, 30 °C, 3.5 h; (b) Selectfluor (2.7 equiv), CH3CN, rt, 2 h; (c) Selectfluor (2.2 equiv), CH3CN, −20 °C, 6 h; (d) H2O2 (30%, 8.0 equiv), NaOH (aq., 4.6 equiv), MeOH/CH3CN, 40 °C, 15 h; (e) (1) aq. HCl (2 M, 2.6 equiv), CH3CN, 30 °C, 3 h, (2) NaBO3 (3 equiv), THF/H2O, 30 °C, 1 h.

Scheme 2. Mechanistic Studies and Plausible Mechanisms of the Formation of 3a and 5a

M HCl25 in the presence of pinacol afforded alkyl (6) and alkenyl (9) pinacol boronic esters in 82% and 83% yields, respectively. Alternatively, NHC−difluoroboranes 7 and 10, which could be utilized as organoboronic acid derivatives, could be accessed following Curran’s protocol.26 Eventually, the oxidation of 3a and 5h gave the alcohol 8 and ketone 1119 in 86% and 81% yields, respectively. In conclusion, we have developed an NHC−boryl radicalinduced boylation/cyclization cascade of 1,6-enynes to prepare alkyl or alkenyl boron-handled cyclic molecules. Remarkable chemo- and regioselectivity were achieved by tuning the substitution nature of the alkene and alkyne functionalities. The resulting boron-containing compounds could be derivatized to useful synthons. We expect that these controllable radical borylation/cyclization processes will provide new routes to construct boron-containing cyclic scaffolds with versatile uses in synthetic and medicinal applications.

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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/jacs.7b01889. Detailed experimental procedures and characterization of new compounds (PDF) Crystallographic data (CIF, ZIP)

radical II is initially generated by hydrogen abstraction from 2.5 For the reaction of 1a, boryl radical II adds specifically to the phenyl-substituted alkene, affording a resonance-stabilized radical III.14 The subsequent 6-exo-dig cyclization with a pendant alkyne acceptor 24 leads to the vinyl radical intermediate IV with the construction of the 3-methylenepiperidine framework. Excellent trans stereochemistry (referring to the phenyl and boron substituents) is also obtained in this ring-closure step. Hydrogen atom abstraction of IV from tert-dodecanethiol7c gives product 3a. The resulting sulfur radical (RS·), in turn, abstracts a hydrogen atom from 2 to regenerate RSH and II,7c thus propagating the radical chain

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Yi-Feng Wang: 0000-0003-1360-8931 Author Contributions ‡

S.-C.R. and F.-L.Z. contributed equally.

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DOI: 10.1021/jacs.7b01889 J. Am. Chem. Soc. 2017, 139, 6050−6053

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Int. Ed. 2014, 53, 5418. (c) Taniguchi, T.; Curran, D. P. Angew. Chem., Int. Ed. 2014, 53, 13150. (d) Pan, X.; Boussonnière, A.; Curran, D. P. J. Am. Chem. Soc. 2013, 135, 14433. (e) Boussonnière, A.; Pan, X.; Geib, S. J.; Curran, D. P. Organometallics 2013, 32, 7445. (f) Toure, M.; Chuzel, O.; Parrain, J.-L. J. Am. Chem. Soc. 2012, 134, 17892. (g) Prokofjevs, A.; Boussonnière, A.; Li, L.; Bonin, H.; Lacôte, E.; Curran, D. P.; Vedejs, E. J. Am. Chem. Soc. 2012, 134, 12281. (h) Scheideman, M.; Wang, G.; Vedejs, E. J. Am. Chem. Soc. 2008, 130, 8669. (i) Scheideman, M.; Shapland, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 10502. (14) (a) Walton, J. C.; Brahmi, M. M.; Monot, J.; Fensterbank, L.; Malacria, M.; Curran, D. P.; Lacôte, E. J. Am. Chem. Soc. 2011, 133, 10312. (b) Yoshimura, A.; Takamachi, Y.; Han, L.-B.; Ogawa, A. Chem. - Eur. J. 2015, 21, 13930. (c) Yoshimura, A.; Takamachi, Y.; Mihara, K.; Saeki, T.; Kawaguchi, S.-i.; Han, L.-B.; Nomoto, A.; Ogawa, A. Tetrahedron 2016, 72, 7832. (d) Watanabe, T.; Hirose, D.; Curran, D. P.; Taniguchi, T. Chem. - Eur. J. 2017, DOI: 10.1002/ chem.201700689. (15) For selected recent reviews, see: (a) Baralle, A.; Baroudi, A.; Daniel, M.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.; Larraufie, M.H.; Maestri, G.; Malacria, M.; Ollivier, C. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons, Ltd: Chichester, U.K., 2012. (b) Wille, U. Chem. Rev. 2013, 113, 813. (c) Albert, M.; Fensterbank, L.; Lacôte, E.; Malacria, M. Top. Curr. Chem. 2006, 264, 1. (d) Dhimane, A.-L.; Fensterhank, L.; Malacria, M. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2008; pp 350−382. (16) For a leading review on borylative cyclization reactions, see: Buñuel, E.; Cárdenas, D. J. Eur. J. Org. Chem. 2016, 2016, 5446. (17) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58. (18) For detailed optimization table, see Supporting Information. (19) The structures of 3a and 11 were secured by X-ray crystallographic analysis. See Supporting Information. (20) (a) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114, 2587. (b) Newcomb, M.; Choi, S.-Y.; Horner, J. H. J. Org. Chem. 1999, 64, 1225. (c) Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. J. Am. Chem. Soc. 1989, 111, 268. (21) The NHC−boryl radical can react with O2 rapidly; see ref 9b. (22) For detailed results of 1,7-enynes, see Supporting Information. (23) (a) Newcomb, M. Tetrahedron 1993, 49, 1151. (b) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317. (24) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513. (25) Solovyev, A.; Chu, Q.; Geib, S. J.; Fensterbank, L.; Malacria, M.; Lacôte, E.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 15072. (26) Nerkar, S.; Curran, D. P. Org. Lett. 2015, 17, 3394.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21672195) and Recruitment Program of Global Experts. F.-L.Z. is grateful for the grant from the China Postdoctoral Science Foundation (2016M602014). We thank Prof. Shunsuke Chiba (NTU, Singapore) for valuable discussions.

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