Letter pubs.acs.org/OrgLett
A General Approach to Quaternary Center Construction from Couplings of Unactivated Alkenes and Acyl Xanthates Ernest N. Jenkins,† William L. Czaplyski,† and Erik J. Alexanian* Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States S Supporting Information *
ABSTRACT: A general, radical-mediated approach to quaternary center construction using unactivated alkenes as coupling partners is reported. In this strategy, acyl xanthates, readily accessed from carboxylic acids, serve as precursors to tertiary radicals. This strategy leverages the unique reactivity of xanthates to participate in efficient radical-mediated additions to unactivated alkenes, expanding the scope of quaternary center construction.
T
disubstituted olefins5 or from derivatives of tertiary alcohols6 or carboxylic acids.7 An important limitation of these reactions to date is the requirement of activated alkenes electronically suitable for additions involving tertiary radicals.8,9 The ability to construct all-carbon quaternary centers via intermolecular radical couplings of carboxylic acid derivatives with unactivated alkenes would significantly expand the power of this approach. Alkyl xanthates undergo efficient additions to unactivated alkenes in a variety of synthetic contexts, as pioneered by Zard.10 These processes benefit from the high effective lifetime of the radical intermediate, facilitating couplings with otherwise challenging unactivated alkenes.11 Moreover, alkyl xanthates have been used to form quaternary centers in select contexts, but the significant challenge of synthesizing tertiary alkyl xanthates greatly limits the generality of this approach.12 Acyl xanthates, which are readily accessible from carboxylic acids, have been studied in a number of radical reactions, but direct applications in alkene additions are rather limited.13 We hypothesized that tertiary acyl xanthates could unlock a general approach to quaternary centers via decarbonylative couplings with unactivated alkenes in a single step. Herein, we demonstrate achievement of this goal in the development of a unique, general strategy for the radicalmediated construction of quaternary centers. Our studies commenced with the intermolecular coupling of simple acyclic tertiary acyl xanthate 1 with a diverse array of unactivated alkenes to construct quaternary centers (Table 1). These reactions were performed at 85 °C in dichloroethane with portionwise addition of 10 mol % dilauroyl peroxide (DLP) every 2 h until complete consumption of the tertiary xanthate intermediate (vide inf ra). For example, the coupling of acyl xanthate 1 with 2 equiv of allyl acetate using 10 mol % DLP delivered product xanthate 2 containing a newly formed quaternary center in 62% isolated yield (entry 1).14 Notably, these couplings were successful in the presence of a variety of
he construction of all-carbon quaternary centers remains the primary challenge when synthesizing compounds containing this moiety. A limited number of reactions are suitable for this task, especially involving intermolecular processes.1 Radical reactions are particularly effective for this purpose, as they proceed via early transition states with long forming bonds and are less sensitive to steric factors than ionic processes.2 For example, Barton esters can generate tertiary radicals that participate in highly efficient group-transfer additions to alkenes (Figure 1).3 Recently, a number of studies have targeted the development of unique radical-mediated, intermolecular processes for the construction of quaternary centers.4 These transformations proceed via the addition of nucleophilic tertiary radicals produced from fundamental synthetic building blocks such as trisubstituted or 1,1-
Figure 1. Quaternary center constructions from tertiary carboxylic acids and derivatives. © 2017 American Chemical Society
Received: March 24, 2017 Published: April 13, 2017 2350
DOI: 10.1021/acs.orglett.7b00882 Org. Lett. 2017, 19, 2350−2353
Letter
Organic Letters Table 1. Quaternary Center Construction via Coupling of a Tertiary Acyl Xanthate with Unactivated Terminal Alkenesa
Table 2. Couplings of Tertiary Acyl Xanthates with Allyl Acetatea
a
Reactions were performed with [substrate]0 = 1.0 M and 1−3 additions of 10 mol % DLP. bIsolated yields. cNMR yield with hexamethyldisiloxane (HMDS) as internal standard.
a
Reactions were performed with [substrate]0 = 1.0 M and 1−2 additions of 10 mol % DLP. bIsolated yields.
common molecular functionality as demonstrated in Table 1. Furthermore, the reaction requires only a simple radical initiator to facilitate the chain process. While these reactions are consistently efficient across a range of substrates, we attribute the moderate yields to the initiator-derived undecyl radicals forming a primary alkyl xanthate byproduct and minor decomposition of the secondary xanthate products under the reaction conditions. We next sought to evaluate the potential for quaternary center construction using a number of cyclic and acyclic acyl xanthates (Table 2). The successful transformations of substituted cyclohexyl substrate 11 and N-tosyl piperidine acyl xanthate 13 demonstrated the capability of the reaction to form cyclic quaternary centers. Acyl xanthate 15 with β-OAc disubstitution provided coupling product 16 in 68% yield. Decalin acyl xanthate 17 reacted with allyl acetate to deliver 18 in 50% yield, constructing a quaternary center at a ring fusion site. The acyl xanthate 19, originating from the cholesterol-lowering agent gemfibrozil, delivered coupling product 20 in 68% yield. Acyl xanthate 21, derived from the bioactive natural product isosteviol,15 afforded coupling product 22 from the less-hindered face of the polycyclic system.16 We were also keenly interested in examining intramolecular variants of the reaction for the construction of cyclic quaternary centers. The ability of our approach to use unactivated alkenes unlocks this powerful application for complex synthesis. An initial survey is presented in Table 3. Acyclic substrates 23 and 25 deliver cyclopentyl and tetrahydrofuranyl products 24 and 26 in
good yield (82% and 71%, respectively) from decarbonylative 5exo cyclization. Notably, although 6-exo ring-closure by the acyl radical intermediate is possible, no such cyclohexanone products are observed. The construction of spirocyclic frameworks is also possible using this approach, as demonstrated in the synthesis of N-tosyl piperidine and tetrahydropyran products 28 and 30. It is also worth noting that the reaction is not limited to fivemembered ring synthesis; acyl xanthate 31 provided cyclohexane 32 in good yield, although minor amounts of cycloheptane 33 were also observed. In order to glean insight into the reaction mechanism, we performed the reactions in eqs 1 and 2. At short reaction times,
the tertiary alkyl xanthate 34 is formed in high yield (70%) from substrate 13, with only partial conversion to addition product 14; 2351
DOI: 10.1021/acs.orglett.7b00882 Org. Lett. 2017, 19, 2350−2353
Letter
Organic Letters Table 3. Construction of Quaternary Centers via Cyclizations of Unsaturated Tertiary Acyl Xanthatesa
Figure 2. Molecular diversification of the xanthate coupling products. See Supporting Information for reaction details.
of a deuterium atom,23 which can render compounds useful for metabolic studies and bestow enhanced pharmacokinetic properties.24 Additional transformations of the xanthate group are also available.21 In conclusion, we have developed a general approach to the construction of quaternary centers using easily accessed acyl xanthates and unactivated alkenes as coupling partners. This transformation is efficient in both inter- and intramolecular contexts and tolerates a range of common molecular functionality. The product alkyl xanthates offer a wealth of attractive opportunities in formal alkene carbodifunctionalizations. We anticipate that the practicality of this approach and the unique bond constructions involved will lead to applications in a variety of synthetic contexts.
■
ASSOCIATED CONTENT
S Supporting Information *
a
See Table 1 for conditions. bIsolated yields. cNMR yield with hexamethyldisiloxane (HMDS) as internal standard.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00882. Experimental procedures and spectral data for all new compounds (PDF)
in the absence of an olefin acceptor, tertiary acyl xanthates are known to undergo decarbonylation to afford tertiary alkyl xanthates.17 When tertiary xanthate 34 is resubjected to the reaction conditions, product 14 is obtained in good yield. Therefore, we hypothesize that the reaction initially involves decarbonylation and formation of tertiary alkyl xanthates followed by subsequent alkene addition.11 The direct, decarbonylative addition of tertiary acyl xanthates to unactivated alkenes has not previously been reported. Furthermore, tertiary alkyl xanthates have seen limited use in alkene additions, likely owing to a lack of general strategies for their preparation. Reported methods include radical decomposition of diazo compounds,18 conjugate addition,12a,19a and in situ formation from a tertiary alkyl halide,19b although this approach suffers from the instability of the starting materials and the use of a tin-based manifold. The xanthate functionality present in the product structures offers opportunities in molecular diversification not available with alternative approaches that use electron-poor alkenes, in which the resulting carbon-centered radical is trapped with an H atom source or reduced for subsequent protonation. Capitalizing on the synthetic versatility of the xanthate functionality leads to a diverse array of formal alkene carbodifunctionalization processes. For example, following the intermolecular coupling of gemfibrozil derivative 19 with N-Boc-allylamine (61% yield on gram-scale), the xanthate moiety can be transformed into several different groups in a single synthetic step (Figure 2). Simple aminolysis affords the thiol, which can participate in the bioorthogonal thiol-ene click reaction with a suitable olefin partner.20 Using conditions we previously developed,21 the xanthate product may also be transformed to a ketone, representing the net coupling of a tertiary radical at a carbonyl α-position. Radical group transfer as developed by Zard facilitates C−C bond formation and was used to access an allylated product.22 Finally, the xanthate group permits facile introduction
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Erik J. Alexanian: 0000-0002-0256-2133 Author Contributions †
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS This work was supported by UNC Chapel Hill. REFERENCES
(1) (a) Christoffers, J.; Baro, A. Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181. (2) Damm, W.; Giese, B.; Hartung, J.; Hasskerl, T.; Houk, K. N.; Hueter, O.; Zipse, H. J. Am. Chem. Soc. 1992, 114, 4067. (3) (a) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. C. Tetrahedron 1995, 51, 1867. (b) Barton, D. H. R.; Liu, W. Tetrahedron Lett. 1997, 38, 2431. (4) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49, 1578. (5) (a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304. (b) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484. (6) (a) Togo, H.; Matsubayashi, S.; Yamazaki, O.; Yokoyama, M. J. Org. Chem. 2000, 65, 2816. (b) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 15342. (c) Lackner, G. L.; Quasdorf, K. W.; Pratsch, G.; Overman, L. E. J. Org. Chem. 2015, 80, 6012. 2352
DOI: 10.1021/acs.orglett.7b00882 Org. Lett. 2017, 19, 2350−2353
Letter
Organic Letters (d) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 2015, 137, 11270. (7) (a) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401. (b) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 10886. (c) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015, 80, 6025. (d) Chinzei, T.; Miyazawa, K.; Yasu, Y.; Koike, T.; Akita, M. RSC Adv. 2015, 5, 21297. (8) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (b) Zhang, W. Tetrahedron 2001, 57, 7237. (c) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377. (9) For additional examples using activated alkynes as coupling partners or electrophilic tertiary radicals, see: (a) Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y. Chem. Commun. 2015, 51, 5275. (b) Gao, C.; Li, J.; Yu, J.; Yang, H.; Fu, H. Chem. Commun. 2016, 52, 7292. (c) Huan, F.; Chen, Q.-Y.; Guo, Y. J. Org. Chem. 2016, 81, 7051. (10) (a) Quiclet-Sire, B.; Zard, S. Z. Chem. - Eur. J. 2006, 12, 6002. (b) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2010, 83. (c) QuicletSire, B.; Zard, S. Z. Beilstein J. Org. Chem. 2013, 9, 557. (11) For detailed discussion on the mechanism of alkyl xanthate addition to unactivated olefins, see: Zard, S. Z. J. Phys. Org. Chem. 2012, 25, 953. (12) For examples of alkene addition using tertiary alkyl xanthates derived from enones, see: (a) Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard, S. Z. Synlett 2003, 3, 382. For an example of alkene addition using a tertiary benzylic cyclopropyl xanthate, see: (b) Heinrich, M. R.; Zard, S. Z. Org. Lett. 2004, 6, 4969. (13) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (14) When 1 equiv of allyl acetate is used under the same conditions, 50% yield of coupling product is observed. (15) Brahmachari, G.; Mandal, L. C.; Roy, R.; Mondal, S.; Brahmachari, A. K. Arch. Pharm. 2011, 344, 5. (16) Overman observed the same stereochemical outcome in syntheses of the trans-clerodanes bearing a similar fused ring system: (a) Müller, D. S.; Untiedt, N. L.; Dieskau, A. P.; Lackner, G. L.; Overman, L. E. J. Am. Chem. Soc. 2015, 137, 660. (b) Slutskyy, Y.; Jamison, C. R.; Lackner, G. L.; Müller, D. S.; Dieskau, A. P.; Untiedt, N. L.; Overman, L. E. J. Org. Chem. 2016, 81, 7029. (17) Barton, D. H. R.; George, M. V.; Tomoeda, M. J. Chem. Soc. 1962, 1967. (18) Bouhadir, G.; Legrand, N.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 277. (19) (a) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201. (b) Boivin, J.; Camara, J.; Zard, S. Z. J. Am. Chem. Soc. 1992, 114, 7909. (20) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49, 1540. (21) Czaplyski, W. L.; Na, C. G.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 13854. (22) Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 1998, 37, 2864. (23) Allais, F.; Boivin, J.; Nguyen, V. T. Beilstein J. Org. Chem. 2007, 3, 46. (24) Harbeson, S. L.; Tung, R. D. Annu. Rep. Med. Chem. 2011, 46, 403.
2353
DOI: 10.1021/acs.orglett.7b00882 Org. Lett. 2017, 19, 2350−2353
