A General Approach to Quaternary Center Construction from Couplings of Unactivated Alkenes and Acyl Xanthates

Article abstract of DOI:10.1021/acs.orglett.7b00882

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.

Full text of DOI:10.1021/acs.orglett.7b00882

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.
5
6
he construction of all-carbon quaternary centers remains
the primary challenge when synthesizing compounds
disubstituted olefins or from derivatives of tertiary alcohols
7
T
or carboxylic acids. An important limitation of these reactions to
date is the requirement of activated alkenes electronically suitable
for additions involving tertiary radicals.
containing this moiety. A limited number of reactions are
suitable for this task, especially involving intermolecular
8
,9
1
processes. Radical reactions are particularly effective for this
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
purpose, as they proceed via early transition states with long
forming bonds and are less sensitive to steric factors than ionic
2
processes. For example, Barton esters can generate tertiary
radicals that participate in highly efficient group-transfer
3
10
additions to alkenes (Figure 1). Recently, a number of studies
pioneered by Zard. These processes benefit from the high
have targeted the development of unique radical-mediated,
intermolecular processes for the construction of quaternary
centers. These transformations proceed via the addition of
nucleophilic tertiary radicals produced from fundamental
synthetic building blocks such as trisubstituted or 1,1-
effective lifetime of the radical intermediate, facilitating couplings
11
with otherwise challenging unactivated alkenes. 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
4
12
approach. 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
13
limited. We hypothesized that tertiary acyl xanthates could
unlock a general approach to quaternary centers via decarbon-
ylative 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 radical-
mediated 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 infra). 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
14
quaternary center in 62% isolated yield (entry 1). Notably,
these couplings were successful in the presence of a variety of
Figure 1. Quaternary center constructions from tertiary carboxylic acids
and derivatives.
Received: March 24, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Quaternary Center Construction via Coupling of a
Tertiary Acyl Xanthate with Unactivated Terminal Alkenes
Table 2. Couplings of Tertiary Acyl Xanthates with Allyl
a
a
Acetate
a
Reactions were performed with [substrate]0 = 1.0 M and 1−3
b
c
additions of 10 mol % DLP. Isolated yields. NMR yield with
hexamethyldisiloxane (HMDS) as internal standard.
a
Reactions were performed with [substrate]0 = 1.0 M and 1−2
b
additions of 10 mol % DLP. Isolated 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.
good yield (82% and 71%, respectively) from decarbonylative 5-
exo 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 five-
membered ring synthesis; acyl xanthate 31 provided cyclohexane
We next sought to evaluate the potential for quaternary center
construction using a number of cyclic and acyclic acyl xanthates
32 in good yield, although minor amounts of cycloheptane 33
(
Table 2). The successful transformations of substituted
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,
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
1
7 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, afforded coupling product 22 from the less-hindered
face of the polycyclic system.
1
5
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
the tertiary alkyl xanthate 34 is formed in high yield (70%) from
substrate 13, with only partial conversion to addition product 14;
B
DOI: 10.1021/acs.orglett.7b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Construction of Quaternary Centers via Cyclizations
a
of Unsaturated Tertiary Acyl Xanthates
Figure 2. Molecular diversification of the xanthate coupling products.
See Supporting Information for reaction details.
23
of a deuterium atom, which can render compounds useful for
metabolic studies and bestow enhanced pharmacokinetic
24
properties. Additional transformations of the xanthate group
21
are also available.
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 carbodifunctionaliza-
tions. 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
Supporting Information
■
a
b
c
See Table 1 for conditions. Isolated yields. NMR yield with
*
S
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.
in the absence of an olefin acceptor, tertiary acyl xanthates are
known to undergo decarbonylation to afford tertiary alkyl
Experimental procedures and spectral data for all new
compounds (PDF)
1
7
xanthates. 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
AUTHOR INFORMATION
Corresponding Author
■
*
11
E-mail: eja@email.unc.edu.
followed by subsequent alkene addition.
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 decom-
ORCID
Erik J. Alexanian: 0000-0002-0256-2133
Author Contributions
†
These authors contributed equally to this work.
18
12a,19a
position of diazo compounds, conjugate addition,
and in
Notes
19b
situ formation from a tertiary alkyl halide,
although this
The authors declare no competing financial interest.
approach suffers from the instability of the starting materials and
the use of a tin-based manifold.
ACKNOWLEDGMENTS
This work was supported by UNC Chapel Hill.
■
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
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,
2
431.
(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,
2
0
21
1304. (b) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.;
Qin, T.; Gutierrez, 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.
partner. Using conditions we previously developed, 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
́
(
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.
2
2
product. Finally, the xanthate group permits facile introduction
C
DOI: 10.1021/acs.orglett.7b00882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
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) Quiclet-
Sire, 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,
5, 953.
12) For examples of alkene addition using tertiary alkyl xanthates
(
(
2
(
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,
5
0% 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) Muller, 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.; Muller, 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,
967.
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,
540.
21) Czaplyski, W. L.; Na, C. G.; Alexanian, E. J. J. Am. Chem. Soc. 2016,
38, 13854.
22) Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 1998,
7, 2864.
23) Allais, F.; Boivin, J.; Nguyen, V. T. Beilstein J. Org. Chem. 2007, 3,
6.
24) Harbeson, S. L.; Tung, R. D. Annu. Rep. Med. Chem. 2011, 46, 403.
(
(
(
̈
̈
(
1
(
(
(
(
1
(
1
(
3
(
4
(
D
DOI: 10.1021/acs.orglett.7b00882
Org. Lett. XXXX, XXX, XXX−XXX