Palladium-Catalyzed Stereospecific Decarboxylative Benzylation of Alkynes

Article abstract of DOI:10.1021/acs.orglett.5b02410

Enantioenriched benzyl esters of propiolic acids undergo highly stereospecific decarboxylative coupling to provide 1,1-diarylethynyl methanes. This sp-sp³ coupling does not require strongly basic conditions or preformed organometallics and prod

Full text of DOI:10.1021/acs.orglett.5b02410

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Stereospecific Decarboxylative Benzylation of
Alkynes
Shehani N. Mendis and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
*
S Supporting Information
ABSTRACT: Enantioenriched benzyl esters of propiolic acids undergo highly stereospecific decarboxylative coupling to provide
3
1
,1-diarylethynyl methanes. This sp−sp coupling does not require strongly basic conditions or preformed organometallics and
produces CO as the sole byproduct. Ultimately, this method results in the successful transfer of stereochemical information from
2
secondary benzyl alcohols to generate enantioenriched tertiary diarylmethanes.
ransition-metal-catalyzed cross-coupling reactions that
Scheme 1. Catalytic Stereospecific Arylmethylation
T
generate tertiary stereogenic centers via the alkylation of
3
secondary sp -hybridized reactants are potentially powerful
1
tools for asymmetric synthesis. Despite the significant
advancements made in this area, the asymmetric alkynylation
2
of secondary benzyl electrophiles is scarcely reported. Benzyl
halides are known to undergo Sonogashira coupling as well as
2
,3
related couplings with other organometallic acetylides.
However, these reactions rarely utilize secondary benzyl
electrophiles and they suffer from the use of relatively toxic
benzyl halides. Moreover, the couplings often require
2
,3a−c
cocatalysts or preformed organometallics.
For example,
the nickel-catalyzed enantioselective benzyl-acetylide coupling
2
requires preformed trialkyl indium complexes. In addition,
benzyl-acetylide cross-couplings can result in the formation of
unwanted side products via isomerization of the alkyne under
3
d
3c
basic media, or further coupling of the product alkyne.
Catalytic decarboxylative coupling reactions have emerged as
potentially powerful alternatives to standard cross-coupling
4
reactions. Thus, we envisioned that a wide array of tertiary
diaryl methane motifs that are prevalent in biologically active
5
compounds could be accessed via decarboxylative benzyl-
acetylide couplings of enantioenriched diarylmethanol deriva-
tives (Scheme 1). Decarboxylative coupling reactions are
particularly well suited for the alkynylation of benzyl electro-
philes since the reactions occur under formally neutral
6
conditions. The absence of added base greatly decreases the
7
rate of deprotonation which can lead to racemization of
enantioenriched benzyl alkynes or formation of allene side
are readily available in enantioenriched form, making them
ideal substrates for asymmetric cross-coupling reactions.
3
d
products. Decarboxylative cross-coupling reactions have the
further advantage that they use benzyl alcohol derivatives in lieu
Received: August 20, 2015
2
of more toxic benzyl halides. Lastly, secondary benzyl alcohols
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02410
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Organic Letters
Letter
Legros and others have shown that secondary benzylic
electrophiles derivatives can undergo palladium-catalyzed
stereospecific cross-coupling reactions. These reactions
Table 1. Scope of Stereospecific Decarboxylative Benzylation
of Alkynes
8
proceed via the intermediacy of Pd-π-benzyl complexes that
act as chiral benzyl cation equivalents (Scheme 1).
More recently, Jarvo and Watson have made impressive
progress on the development of nickel-catalyzed stereospecific
cross-coupling reactions of secondary benzylic electrophiles to
9
generate molecules with tertiary stereocenters. Herein we
report the synthesis of enantioenriched 1,1-diarylethynyl
methanes via a highly stereospecific palladium-catalyzed
decarboxylative benzylation strategy. To the best of our
knowledge, this is the first report of a stereospecific
decarboxylative benzylation. Moreover, we are unaware of any
other cross-coupling method for the direct synthesis of
enantioenriched 1,1-diarylethynyl methanes.
To begin, an array of benzylic ester derivatives were prepared
via esterification of propiolic acids with enantioenriched diaryl
methanols. These alcohols were obtained by a slightly modified
(
−)-MIB-catalyzed addition of boronic acids to aldehydes,
7b
originally reported by Braga (Scheme 2). This method
Scheme 2. Synthesis of Enantioenriched Propiolic Esters
produced a wide range of alcohols in high enantiomeric excess;
however, several of the precursor alcohols were obtained in
lower ee (e.g., 1d, 1i, 1o, 1p, Table 1). Nonetheless the Braga
method provided each alcohol in large enough enantiomeric
excess to accurately measure the stereospecificities of
decarboxylative coupling. An additional advantage of this
method for alcohol preparation is that either enantiomer of
the alcohol can be obtained via the appropriate selection of the
aryl boronic acid and the aromatic aldehyde reaction partners.
We then investigated the scope of the stereospecific
decarboxylative benzylation reaction (Table 1). As we and
6b,10
others have noted,
benzylic cross-couplings that proceed
via π-benzyl intermediates are much more facile for benzylic
electrophiles that have extended π-conjugation. For example
phenyl propiolic ester of diphenylmethanol did not show any
reactivity under standard conditions. Therefore, a variety of
substituted benzyl propiolates that contain 1-naphthyl, 2-
naphthyl, or indolyl groups were chosen for initial study. Since
π-benzyl formation is accompanied by partial dearomatization
of the coordinating arene, these aromatic groups that have
relatively low resonance energies more readily form such
complexes. For example, selective coordination of naphthalene
instead of a phenyl group would be expected on the basis of the
lower resonance energy of naphthalene (1b, Figure 1).
Ultimately, the decarboxylative coupling of benzyl ester 1b is
facile and forms the product 2b with a high degree of
stereochemical fidelity, with a conservation of enantiomeric
excess (cee) of 94% [cee = (product ee/reactant ee) × 100]
a
b
Determined by chiral HPLC analysis. Yield of isolated product All
products were stored cold upon isolation to avoid decomposition or
c
d
isomerization. Yield reported using the racemic benzylic ester. Boc
group removed prior to HPLC analysis.
(Table 1). However, oxidative addition is sterically disfavored
by an ortho substituent on the naphthyl ring (1c, Figure 1 and
Table 1), preventing the reaction. Substitution at the ortho
position of the noncoordinating arene (1d, Figure 1) does slow
the coupling; however, the reaction still proceeds with high
enantiospecificity (1d, Table 1). Further substitution of the
benzylic esters with a variety of alkyl (2f, 2h, 2j), alkoxy (2d,
2e, 2l), or halogen (2g, 2k) substituents allowed for highly
B
DOI: 10.1021/acs.orglett.5b02410
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Determination of the Stereochemical Course of
the Reaction
Figure 1. π-Benzyl formation: sterics and favorable coordination of
arenes with extended π-conjugation.
enantiospecific (average cee = 97%) cross-coupling, and the
products were isolated in good to excellent yield. However, a
sulfur donor in the para-position led to partial racemization
during the coupling (2i, Table 1). Furthermore, substitution of
one of the arenes with a strongly electron-withdrawing p-NO2
or p-CN substituent, which substantially acidifies the benzylic
proton, drastically lowered the yield of the reaction and these
products were isolated as the allene isomers (2m, 2n).
Interestingly, heteroaromatic phenyl propiolates (1o−1q) also
underwent stereospecific decarboxylative benzylation with
moderate-to-good stereochemical fidelity.
We also briefly examined the effect of the acetylide coupling
partner on the yields and stereospecificity of the decarbox-
ylative coupling (Table 2). In addition to phenyl propiolates,
7
c,11
prepared.
The alcohol was converted to the highly
enantiomerically enriched phenyl propiolate ester (R)-1k via
PyBop coupling. After the decarboxylative coupling, crystals of
the product were subjected to single crystal X-ray diffraction
analysis which revealed the absolute configuration of 2k to be
Table 2. Scope of Stereospecific Decarboxylative
Benzylation: Alkynes
(
S) (Scheme 3).
The overall inversion of stereochemistry that is observed in
decarboxylative coupling can be mechanistically explained as
follows (Scheme 4). Substrate 1 undergoes oxidative addition
Scheme 4. Proposed Catalytic Cycle for the Decarboxylative
Coupling
a
b
Determined by chiral HPLC analysis. Yield of isolated product. All
c
products were stored cold upon isolation. Isolated yield after 16 h.
3
to Pd to generate an η -benzyl-Pd carboxylate intermediate.
alkyl (1r, 1s) and aryl propiolates (1t−1v) also undergo
decarboxylative benzylation with high stereospecificity. How-
ever, a cyclohexenyl acetylide (1w) did not undergo
decarboxylative benzylation under optimized reaction con-
ditions.
While it was clear that the decarboxylative couplings of most
propiolic esters occur with high stereospecificity, it was
desirable to determine whether the coupling proceeded with
retention or inversion of configuration. With this in mind, an
alcohol [(R)-3k, Scheme 3] of known configuration was
The oxidative addition is expected to proceed with inversion of
12
configuration via S 2-like displacement by palladium.
N
We propose that coordination of the alkyne to Pd, as in
intermediate A, facilitates decarboxylation resulting in the
formation of a benzyl-Pd-acetylide intermediate (B) which
undergoes reductive elimination with retention of stereo-
chemistry to give the cross-coupled product 2 with overall
inversion of stereochemistry. This is similar to Pd-catalyzed
allylic alkylations, where allylation of nonstabilized or “hard”
6a
nucleophiles proceeds with inversion of configuration.
C
DOI: 10.1021/acs.orglett.5b02410
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Organic Letters
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In summary, we have shown that decarboxylative benzylation
of acetylides is highly stereospecific and that the stereochemical
information on a secondary alcohol is successfully transferred to
generate a tertiary stereogenic center. This method provides a
route for the asymmetric coupling of secondary benzylic
electrophiles with alkynes that does not require preformed
organometallics.
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́
(
ASSOCIATED CONTENT
■
1
́
́
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02410.
(9) (a) Yonova, I. M.; Johnson, A. G.; Osborne, C. A.; Moore, C. E.;
Morrissette, N. S.; Jarvo, E. R. Angew. Chem., Int. Ed. 2014, 53, 2422−
2427. (b) Wisniewska, H. M.; Swift, E. C.; Jarvo, E. R. J. Am. Chem.
Soc. 2013, 135, 9083−9090. (c) Taylor, B. L. H.; Harris, M. R.; Jarvo,
E. R. Angew. Chem., Int. Ed. 2012, 51, 7790−7793. (d) Zhou, Q.;
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A.; Sirianni, E. R.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 280−
Experimental procedures, H, 13C NMR data, character-
ization data and HPLC data of all novel products (PDF)
Crystallographic data for 2k (CIF)
1
2
85.
AUTHOR INFORMATION
■
(10) (a) Greene, M. A.; Yonova, I. M.; Williams, F. J.; Jarvo, E. R.
Corresponding Author
Org. Lett. 2012, 14, 4293−4296. (b) Kuwano, R.; Kondo, Y.;
Matsuyama, Y. J. Am. Chem. Soc. 2003, 125, 12104−12105.
*E-mail: tunge@ku.edu.
(11) Li, K.; Hu, N.; Luo, R.; Yuan, W.; Tang, W. J. Org. Chem. 2013,
Notes
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(
5
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1465172)
and the Kansas Bioscience Authority Rising Star program for
financial support. We also thank Dr. Victor Day for X-ray
crystallographic analysis and the NSF-MRI Grant CHE-
0923449 used to purchase the X-ray diffractometer and
software used in this study. Support for the NMR
instrumentation was provided by NSF Academic Research
Infrastructure Grant No. 9512331, NIH Shared Instrumenta-
tion Grant No. S10RR024664, and NSF Major Research
Instrumentation Grant No. 0320648.
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