Stereoselective synthesis of all-carbon tetrasubstituted alkenes from in situ generated ketenes and organometallic reagents

Article abstract of DOI:10.1021/ol400392r

Stereoselective synthesis of tetrasubstituted alkenes is a challenging problem in chemical synthesis. New protocols to access this important, yet simple, structural motif are of fundamental significance because they are found in many valuable molecules and can be utilized in a variety of important complexity building chemical transformations. The two-step strategy presented herein involves stereoselective generation of an alkenyl pseudohalide followed by a stereospecific metal-catalyzed cross-coupling.

Full text of DOI:10.1021/ol400392r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereoselective Synthesis of All-Carbon
Tetrasubstituted Alkenes from In Situ
Generated Ketenes and Organometallic
Reagents
Wei You, Yan Li, and M. Kevin Brown*
Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47401,
United States
*brownmkb@indiana.edu
Received February 8, 2013
ABSTRACT
Stereoselective synthesis of tetrasubstituted alkenes is a challenging problem in chemical synthesis. New protocols to access this important, yet
simple, structural motif are of fundamental significance because they are found in many valuable molecules and can be utilized in a variety of
important complexity building chemical transformations. The two-step strategy presented herein involves stereoselective generation of an
alkenyl pseudohalide followed by a stereospecific metal-catalyzed cross-coupling.
The alkene moiety is one of the most versatile and
widespread functional groups among small molecules.
Oftentimes, it is necessary to prepare substituted alkenes
with high degrees of stereoselectivity, either because it is
present in an important molecule1 or because subsequent
chemicalreactionsrequire anestablishedgeometry.2 While
many methods have been developed for the stereoselective
synthesis of di- and trisubstituted alkenes,3 stereoselective
synthesis of all-carbon tetrasubstituted alkenes remains a
challenge.4
(Scheme 1B). This method is notable not only for the ease
in which tetrasubstituted alkenes can be prepared but also
the substrate scope.
Traditional methods for the stereoselective synthesis
of all-carbon tetrasubstituted alkenes are based on metal-
catalyzed vicinal-dicarbofunctionalization of alkynes.4
While significant progress has been achieved in this area,
many of these methods rely on the use of directing groups
to control stereoselectivity. This strategy results in inher-
ently less practical processes, as these groups must be first
introduced and later removed.4 An alternative approach
toward stereodefined tetrasubstituted alkenes is outlined
in Scheme 1A. Alkenyl pseudohalides are competent part-
ners for metal-catalyzed cross-coupling.5,6 Therefore, if
these species (II or III) could be generated with control
Herein, we present a two-step strategy to prepare a wide-
range of stereodefined all-carbon tetrasubstituted alkenes
from simple carboxylic esters and organometallic reagents
(1) (a) Yu, H.; Richey, R. N.; Carson, M. W.; Coghlan, M. J. Org.
Lett. 2006, 8, 1685–1688. (b) Anastasia, L.; Dumond, Y. R.; Negishi, E.
Eur. J. Org. Chem. 2001, 3039–3043. (c) Gardner, R. R.; Liang, G. B.;
Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 1806–1816. (d) Takahashi,
A.; Kirio, Y.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1989, 111, 643–647.
(5) For a review regarding Pd-catalyzed cross-coupling with activa-
tion of CÀO bonds, see: Li, B. J.; Yu, D. G.; Sun, C. L.; Shi, Z. J.
Chem.;Eur. J. 2011, 17, 1728–1759.
(2) (a) Woodmansee, D. H.; Pfaltz, A. Chem. Commun. 2011, 47, 7912–
7916. (b) Brandes, B. D.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5123–
5126. (c) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463–8464.
(3) Negishi, E. I.; Huang, Z. H.; Wang, G. W.; Mohan, S.; Wang, C.;
Hattori, H. Acc. Chem. Res. 2008, 41, 1474–1485.
(6) (a) Shiroodi, R. K.; Dudnik, A. S.; Gevorgyan, V. J. Am. Chem.
Soc. 2012, 134, 6928–6931. (b) Chary, B. C.; Kim, S.; Shin, D.; Lee, P. H.
Chem. Commun. 2011, 47, 7851–7853. (c) Gauthier, D.; Beckendorf, S.;
Gogsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2009, 74,
3536–3539. (d) Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron
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(4) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698–4745.
r
10.1021/ol400392r
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of stereochemistry, this would constitute a straightforward
synthesis of stereodefined tetrasubstituted alkenes (Vor VI).
by Tidwell, good selectivities are observed when the size
difference between the ketene substituents is large (e.g.,
Ph/Et ketene, >20:1 dr whereas Ph/i-Pr ketene, 1:4 dr).9
Tidwell’s method, however, remains limited toketenes that
are relatively easy to handle and isolate (e.g., Ph/Et ketene).
When less stable ketenes are used (e.g., Et/Et ketene), low
yields of the desired products are observed and significant
quantities of ketene dimerization adducts are formed.9f
To avoid complications arising from the use of isolated
ketenes, Seebach and co-workers reported that ketenes
could be generated in situ by fragmentation of 2,6-di-
tert-butyl hydroxytoluene (BHT) ester lithium enolates
(VIII f IX f X) (Scheme 1B).10 When the ketenes (X)
are generated in the presence of an alkyllithium reagent
(R3Li), stereoselective addition occurs to provide the
corresponding enol silanes (II, G = SiMe3) after quench
of the lithium enolates with Me3SiCl. These reactions are
limited to only dialkylketenes but do provide the products
with moderate to excellent levels of stereoselectivity (e.g.,
i-Pr/Me ketene, 7:1 dr, and t-Bu/Me ketene, >99:1 dr).
Scheme 1. General Strategy for the Stereoselective Synthesis of
All-Carbon Tetrasubstituted Alkenes
Table 1. Optimization Studiesa
Common strategies for the synthesis of trisubstituted
alkenyl pseudohalides (IIÀIII) generally rely on enoliza-
tion of a ketone (I) and subsequent trap with an appro-
priate electrophile. However, unless specialized substrates/
conditions are utilized that favor formation of one alkene
isomer (e.g., II and not III or IV), low selectivity is ob-
served.7,8,9d To render this straightforward strategy feasi-
ble for the synthesis of stereodefined tetrasubstituted
alkenes, we sought to develop a general method for the
stereoselective synthesis of alkenyl pseudohalides from
enolates.
We were inspired by seminal studies by Tidwell9 and
Seebach10,11 on the stereoselective synthesis of stereode-
fined lithium enolates. Each method relies on the stereo-
selective addition of an organolithium reagent to a
differentially substituted ketene. In general, as established
(7) This strategy has been shown to be effective in one example.
Wallace, D. J.; Campos, K. R.; Shultz, C. S.; Klapars, A.; Zewge, D.;
Crump, B. R.; Phenix, B. D.; McWilliams, J. C.; Krska, S.; Sun, Y.;
Chen, C.; Spindler, F. Org. Process Res. Dev. 2009, 13, 84–90.
(8) (a) Babinski, D.; Soltani, O.; Frantz, D. E. Org. Lett. 2008, 10,
2901–2904. (b) Beccalli, E. M.; Gelmi, M. L.; Marchesini, A. Eur. J. Org.
Chem. 1999, 1421–1426. (c) Crisp, G. T.; Meyer, A. G. J. Org. Chem.
1992, 57, 6972–6975.
a See the Supporting Information for experimental details. b Yield of
isolated product after silica gel column chromatography. c Determined
by 31P NMR (170 MHz) analysis of the unpurified reaction mixture.
(9) (a) Allen, A. D.; Baigrie, L. M.; Gong, L.; Tidwell, T. T. Can. J.
Chem. 1991, 69, 138–145. (b) Allen, A. D.; Gong, L.; Tidwell, T. T.
J. Am. Chem. Soc. 1990, 112, 6396–6397. (c) Seikaly, H. R.; Tidwell,
T. T. Tetrahedron 1986, 42, 2587–2613. (d) Baigrie, L. M.; Seiklay, H. R.;
Tidwell, T. T. J. Am. Chem. Soc. 1985, 107, 5391–5396. (f) Baigrie, L. M.;
Lenoir, D.; Seikaly, H. R.; Tidwell, T. T. J. Org. Chem. 1985, 50, 2105–
2109. (g) Lenoir, D.; Seikaly, H. R.; Tidwell, T. T. Tetrahedron Lett.
1982, 23, 4987–4990.
(10) (a) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, W. B.;
Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403–5409. (b) Haener, R.;
Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107, 5396–5403.
(11) For use of BHT ester enolates, see (a) Barbero, A.; Pulido, F. J.
Synlett 2001, 827–829. (b) Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
1828–1830. (c) Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909–
6911.
To initiate our studies, we attempted the synthesis of 2
starting from phenolic esters (1aÀd) under the conditions
illustrated in Table 1. In line with reports by Seebach,10
aryl/alkyl-substituted ester enolates derived from 1a do
not undergo fragmentation to generate ketenes (Table 1,
entry 1). We reasoned that perhaps the low reactivity of
these ester enolates was due to the poor leaving group
ability of BHT. Therefore, we guided the selection of esters
toevaluate basedontwo characteristics: (1) sufficientsteric
hindrance so as to protect the carbonyl from nucleophilic
addition by the first equivalent of n-BuLi and (2) good
B
Org. Lett., Vol. XX, No. XX, XXXX

leaving group ability (R in Table 1) such that the potentially
unstable ketene is generated readily at low temperatures
(À20 °C) and short reaction time (<2 h). Furthermore, we
initially investigated the formation of enol phosphates (vs
enol triflates) as these compounds are stable. Reactions with
phenylthio ester 1b or a phenyl ester 1c result in competitive
addition of the first equivalent of n-BuLi to the carbonyl as
opposed to deprotonation (Table 1, entries 2 and 3). We
ultimately identified the ester derived from 2,6-dimethyl-
phenol (1d) (Table 1, entry 4) as having an ideal balance
between sufficient steric hindrance to block nucleophilic
addition of the first equivalent of n-BuLi and reasonable
rate of ketene generation at low temperatures (À20 °C, 2 h).
Figure 2. Stereoselective synthesis of various enol triflates and
phosphates. Key: (a) See the Supporting Information for ex-
perimental details. Yield refers to yield of isolated product after
silica gel column chromatography. Z/E ratios determined by
either 1H NMR (400 MHz), 31P NMR (170 MHz), or 19F NMR
(376 MHz) analysis of the unpurified reaction mixture. Relative
configuration determined by analysis of 2D NMR spectra.
(b) After the addition of R3Li the reaction was warmed to 0 °C.
(c) t-BuLi was used instead of n-BuLi for generation of the enolate.
Figure 1. Diastereoselective synthesis of enol triflates and phos-
phates from ester 1d. Key: (a) See the Supporting Information
for experimental details. (b) Yield of isolated product after silica
gel column chromatography. (c) Determined by either 1H NMR
(400 MHz), 31P NMR (170 MHz), or 19F NMR (376 MHz)
analysis of the unpurified reaction mixture. Relative configura-
tion determined by analysis of 2D NMR spectra. (d) After addi-
tion of R3Li, the reaction mixture was allowed to warm to 0 °C.
for most cases, the exception being 12 (2:3, Z/E) where
both the substituents are similar in size.9 (2) Reactions with
esters bearing heteroaryl (16), electron-rich aryl (13 and
14), and sterically hindered aryl groups (15) work well in
this process. Esters that bear an electron-deficient aryl group
undergo competitive arene deprotonation with n-BuLi and
thus lead to a complex mixture of products. (3) Dialkyl
esters undergo reaction with good selectivities (17À19).
With an efficient procedure for the stereoselective synthe-
sis of enol phosphates and enol triflates in hand (Figures 1
and 2) we then focused on establishing conditions for
stereospecific Pd-catalyzed cross-coupling. As illustrated
in Figure 3, we have identified that Pd-catalyzed cross-
coupling of enol phosphates with Grignard reagents pro-
ceeds in good yield with <5% loss in stereochemical
purity.5,6,14,15 Through application of this reaction, a
variety of structurally diverse tetrasubstituted alkenes
(20-27) can be prepared readily (Figure 3).
Withanoptimizedsetofconditionsinhand, weexplored
the substrate scope of the organolithium reagent.12,13 As
illustrated in Figure 1, a variety of organolithium reagents
(alkyl-, aryl-, vinyl-, heteroaryl-based) can be utilized in
this process with uniform success (generally, >65% yield
and >20:1 Z/E). The generated lithium enolate can either
be trapped with Tf2O or ClP(O)(OR)2 (R = Et or Ph) to
provide the alkenyl pseudohalide in good yield and selec-
tivity. In general, formation of the enol phosphate results
in higher yield than the enol triflate primarily due to the
lower stability associated with the enol triflates (compare
Figure 1, compounds 4 and 2).
Use of alkyl Grignard reagents that bear β-hydrogens
(e.g., n-BuMgX), however, led to the formation of the
The method has also been extended to reactions of esters
with various substituents (Figure 2). Several points are
noteworthy: (1) good to excellent selectivities are observed
(14) For select cases, purification of the enol phosphate was compli-
cated due to difficult separation of 9 (G = P(O)(OEt)2 or P(O)(OPh)2)
from the desired product. The cross-coupling reactions presented in
Figure 3, however, are largely unaffected by the presence of 9 (G =
P(O)(OEt)2 or P(O)(OPh)2); thus, its separation from the enol phos-
phates is not crucial. See the Supporting Information for details.
(15) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
(12) Use of Grignard reagents in place of lithium reagents leads to a
complex mixture of products
(13) See the Supporting Information for complete experimental
details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Cross-Coupling with Enol Triflates
Figure 3. Cross-coupling with enol phosphates. Key: see the
Supporting Information for experimental details. Yield refers to
yield of isolated product after silica gel column chromatogra-
phy. Z/E ratios determined by GC/MS analysis of the unpuri-
fied reaction mixtures.
corresponding trisubstituted alkenes through incorpora-
tion of hydrogen. This product presumably arises from
β-hydride elimination of the generated PdÀalkyl inter-
mediate prior to reductive elimination. Therefore, we
directed our efforts toward cross-coupling with alkyl
boron reagents as success has been documented in related
transformations.16 As illustrated in eq 1 (Scheme 2),
Pd-catalyzed cross-coupling with n-Hex-9-BBN and enol
triflate 4 generates 28 in good yield (89%) with excellent
retention of stereochemistry (<2% of the corresponding
trisubstituted alkene is observed) (eq 1, Scheme 2).17 It
should be noted that multialkyl tetrasubstituted alkenes
are difficult to prepare with existing reaction methodology.4
The present method allows for their synthesis via two
distinct routes (e.g., synthesis of 26 and 28).
metal-catalyzed cross-coupling reactions, and there are
undoubtedly other applications of the enol phosphates
and enol triflates prepared in this study.5
In summary, a simple two-step synthesis of a wide range
of stereodefined tetrasubstituted alkenes from readily
available esters and organometallic reagents has been
developed. Furthermore, the synthesis and use of in situ
generated ketenes described herein should be of utility for
the preparation of a variety of other alkenyl systems.
Studies along these lines are currently under investigation.
Acknowledgment. We thank Indiana University (IU)
for financial support. Dr. Maren Pink (IU, X-ray), Dr.
Jonathan A. Karty (IU, Mass Spec), Angela M. Hanson
(IU, Mass Spec), and Dr. Frank Gao (IU, NMR) are
acknowledged for their support.
The enol triflates prepared herein are also amenable
to various other cross-coupling reactions including aryl-
Suzuki and Sonogashira (eqs 2 and 3, respectively,
Scheme 2).18 We have by no means explored all possible
Supporting Information Available. Experimental pro-
cedures, analytical data for all compounds, and crystal-
lographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417–1492.
(17) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
The authors declare no competing financial interest.
(18) Suffert, J.; Bruckner, R. Tetrahedron Lett. 1991, 32, 1453–1456.
D
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