Palladium-catalyzed alkyne insertion/Suzuki reaction of alkyl iodides

Article abstract of DOI:10.1021/ja307761f

A palladium-catalyzed alkyne insertion/Suzuki reaction with unactivated alkyl iodides is described. Under the reaction conditions, selective migratory insertion of alkynes avoids β-hydride elimination and provides a facile synthesis of stereodefined, tetrasubstituted olefins. The transformation offers broad substrate scope for both the alkyl iodide and boron nucleophile. Mechanistic studies have revealed inversion of the stereocenter for the carbon bearing the iodide.

Full text of DOI:10.1021/ja307761f

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Alkyne Insertion/Suzuki Reaction of Alkyl
Iodides
Brendan M. Monks and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
Scheme 1. Alkyne Migratory Insertion as an Alternative
Reaction Pathway to β-Hydride Elimination in
Alkylpalladium Species
ABSTRACT: A palladium-catalyzed alkyne insertion/
Suzuki reaction with unactivated alkyl iodides is described.
Under the reaction conditions, selective migratory
insertion of alkynes avoids β-hydride elimination and
provides a facile synthesis of stereodefined, tetrasubstituted
olefins. The transformation offers broad substrate scope
for both the alkyl iodide and boron nucleophile.
Mechanistic studies have revealed inversion of the
stereocenter for the carbon bearing the iodide.
synthesis of tetrasubstituted olefins, known to be challenging
targets for organic synthesis.10
To test the viability of the cascade alkyne insertion/cross-
coupling reaction, alkyl iodide 1 was subjected to 10 mol %
Pd(PPh3)4, Cs2CO3, and 1-napthalene boronic acid at 130 °C
in toluene (Scheme 2). Gratifyingly, tetrasubstituted olefin 2
alladium-catalyzed Csp2−Csp2 cross-coupling reactions
Phave had a transformative impact on the field of organic
chemistry.1 They have found widespread use in total synthesis2
and represent the most important carbon−carbon bond-
forming reaction in medicinal chemistry.3 In contrast, Csp3−
Csp2 cross-coupling reactions involving Csp3−halide electro-
philes remain rare.4 When such electrophiles are employed, the
cross-couplings suffer from slow oxidative addition and the
potential for β-hydride elimination of intermediate alkylpalla-
dium species.5 Identification of fundamental organometallic
processes that proceed with rates comparable to β-hydride
elimination allows the incorporation of complexity-building
transformations into Csp3 cross-couplings. As such, our group
has initiated a program aimed at intercepting alkylpalladium
intermediates prior to β-hydride elimination.6 Here we describe
the migratory insertion of internal alkynes into Csp3−palladium
intermediates, providing straightforward access to tetrasubsti-
tuted olefins.
Previous pioneering work has established migratory insertion
as an alternative mechanistic pathway to β-hydride elimination
for alkylpalladium species. For example, carbon monoxide
undergoes rapid migratory insertion into alkylpalladium species
en route to a carbonylative Heck reaction.7 Additionally,
migratory insertion of olefins into alkylpalladium intermediates
has been shown to produce a viable alkyl-Heck reaction.8
However, the reaction conditions that facilitated olefin insertion
required sterically encumbered N-heterocyclic carbenes as
ligands or elevated temperatures (110−130 °C). Since alkynes
have been reported to insert more rapidly than olefins into
acylpalladium bonds,9 we reasoned a tethered alkyne might be
used to intercept a transient alkylpalladium species prior to β-
hydride elimination (Scheme 1). Following migratory insertion
of the alkyne, a new vinyl carbopalladium intermediate would
provide an opportunity for an additional cross-coupling
reaction. Such a process would allow for the regioselective
Scheme 2. Initial Result for Novel Alkyne Insertion/Suzuki
Reaction
was formed in 14% yield along with two expected side
products, terminal olefin 3 (36% yield) and trisubstituted olefin
4 (7% yield). The direct Suzuki cross-coupled product 5 was
not observed.4d,11 Similar tetrasubstituted olefins would be
inaccessible using conventional olefination strategies12 or
alternative palladium-catalyzed reactions.13
Following this initial result, we continued with optimization
efforts to suppress the formation of side products 3 and 4 (see
SI for additional details). Lowering the reaction temperature
and reducing the amount of Cs2CO3 combined to inhibit the β-
hydride elimination pathway leading to terminal olefin 3.
Identifying the hydride source required for the formation of
trisubstituted olefin 4 proved difficult, but changing the solvent
from toluene to benzene at 85 °C dramatically reduced the
amount of 4, while the addition of exogenous water had little
Received: August 5, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja307761f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
effect on the product distribution. Furthermore, the use of
Pd2(dba)3 (commercial or freshly prepared)14 and exogenous
triphenylphosphine led to higher yields than freshly prepared
Pd(PPh3)4, with optimal reaction rates obtained with a
palladium:phosphine ratio of 1:3. Appropriate control reactions
excluding palladium, phosphine, Cs2CO3, and aryl nucleophile
resulted in little to no desired tetrasubstituted olefin 2.
Table 2. Alkyne Insertion/Suzuki Substrate Scope
Further examination of ligands revealed electron-rich
arylphosphines, such as P(4-MePh)3 and P(4-MeOPh)3,
increased the overall reaction rate but compromised the yield
of tetrasubstituted olefin 2 (entries 1 and 2, Table 1). More
a
Table 1. Electronic Effects of the Phosphine Ligand
yield (%)
entry
phosphine
conv (%)
2
3
4
1
2
3
4
5
6
P(4-MePh)3
P(4-MeOPh)3
PPh3
100
100
100
95
74
76
81
84
76
90
6
7
3
2
0
0
12
11
10
8
P(4-FPh)3
P(4-CF3Ph)3
P(4-CIPh)3
87
6
100
8
a
1H NMR yields based on 1,3,5-trimethoxybenzene as an internal
standard.
sterically encumbered, electron-rich alkylphosphines, such as
P(t-Bu)3 or P(t-Bu)2Me, led to fast consumption of starting
iodide 1 without the formation of an appreciable amount of
tetrasubstituted olefin 2, even at lower temperatures. On the
other hand, electron-deficient arylphosphines such as P(4-
ClPh)3, P(4-FPh)3, and P(4-CF3Ph)3 afforded both slower
reaction rates and higher yields of desired tetrasubstituted
olefin 2 (entries 4−6, Table 1). Of these, P(4-ClPh)3 provided
the highest conversion and yield, thereby making it the
preferred ligand for this palladium-mediated cascade reaction.
With optimal reaction conditions achieved, the substrate
scope of alkynyl iodides was evaluated (Table 2). Varying the
electronic properties of the internal alkyne with electron-rich
and -deficient aromatic groups had little effect on the reaction,
providing high yields in all cases (entries 1−5, Table 2).
Alkynes substituted with alkyl groups, regardless of steric bulk,
proceeded cleanly and in high yield (entries 6 and 7, Table 2).
Interestingly, secondary iodide 12 provided the tetrasubstituted
olefin 22 in good yield, even at lower temperature (70 °C, entry
8, Table 2). This constitutes a rare example of oxidative
addition into unactivated secondary halides by palladium.4e
Likewise, the tetrasubstituted enol ether 23 was accessed
through the reaction of alkyl iodide 14 (entry 9, Table 2). The
reaction also proved applicable in the construction of a six-
membered ring in compound 24 (entry 10, Table 2).
Unfortunately, attempts to access four- and seven-membered
rings under the optimized reaction conditions led to
significantly lower yields.
a
b
c
Isolated yield. Reaction time = 48 h. Reaction performed at 70 °C.
Cursory investigation of aryl boronic nucleophiles demon-
strated the expected substrate scope for a competent Suzuki
reaction. For example, electronically neutral aryl substrates
proceeded cleanly with high yields (entries 1−3, Table 3). Aryl
nucleophiles containing electron-rich or -deficient aromatic
groups also provided good yields (entries 4−6, Table 3).
Additionally, the use of a sterically congested, ortho-
disubstituted aryl boronic acid also led to high yield (87%,
entry 5, Table 3). Both catechol esters and free boronic acids
worked well for the cross-coupling reaction. The reaction
proved compatible with functional groups such as aldehydes,
esters, ethers, and aryl chlorides (entries 4−6, Table 3).
Unfortunately, attempts to use aryl nucleophiles bearing nitro,
carboxylic acid, or alcohol functional groups resulted in low
yields of the desired tetrasubstituted olefin.
Oxidative addition at palladium(0) with alkyl halides has
been shown to proceed through both SN24d,8a and radical-
mediated pathways.8b,15 To probe the mechanism of oxidative
addition, deuterium-labeled substrate 25 was prepared and
subjected to standard reaction conditions (Scheme 3).8a Under
these conditions, the formation of a single syn diastereomer 26
B
dx.doi.org/10.1021/ja307761f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Scope of Boron Nucleophile in Alkyne Insertion/
Suzuki Reaction
Scheme 4. (a) Primary Alkyl Iodides Lacking a Pendant
Alkyne Fail To Undergo Oxidative Addition under the
Optimized Reaction Conditions; (b) The Presence of an
Exogenous Alkyne Promotes the Oxidative Addition of Alkyl
Iodides
a
Isolated yield.
Scheme 5. Putative Catalytic Cycles for the Alkyne
Insertion/Suzuki Reaction
Scheme 3. Deuterium Labeling Demonstrates Inversion of
Stereochemistry at the Carbon Electrophile
suggests an SN2 oxidative addition for this reaction.
Furthermore, running the reactions in the presence of 2,6-di-
tert-butyl-4-methylphenol (BHT) or azobisisobutyronitrile
(AIBN) under the standard conditions had little effect on
rate or yield, thereby arguing against free radical initiation of
the reaction.8b
Since the overall transformation reported here occurs at
lower temperatures (70−85 °C) than the previously reported
alkyl Heck reaction with aryl phosphines (110−130 °C),8b we
sought to establish whether the alkyne facilitated oxidative
addition, the putative rate-determining step for the reaction.5a,c
To that end, when substrates 27 and 28 were prepared and
separately subjected to the standard reaction conditions,
quantitative recovery of starting material was observed without
formation of the expected β-hydride elimination products
(Scheme 4a). Additionally, when alkyl iodide 27 was subjected
to the same reaction conditions in the presence of 3-octyne,
terminal olefin 29 was obtained in 10% yield along with 85%
recovered iodide 27 (Scheme 4b). Finally, when a mixture of
internal alkyne 1 and reduced alkyl iodide 27 was subjected to
the standard reaction conditions, clean formation of desired
product 2 was observed along with the recovery of iodide 27
and trace quantities of β-hydride elimination product 29. While
additional experiments are necessary, clearly the presence of the
alkyne promotes oxidative addition, likely through palladium
precoordination to the alkyne.
form Csp3−Pd(II) intermediate 31, migratory insertion of the
tethered alkyne proceeds more rapidly than β-hydride
elimination to give vinylpalladium 32. Transmetallation with
boronic ester provides intermediate 33, which reductively
eliminates to give tetrasubstituted olefin product 26. Studies to
further elucidate the mechanism are underway.
In summary, we have demonstrated that migratory insertion
of alkynes into Csp3−palladium species can out-compete β-
hydride elimination without exotic ligands. This process
allowed the development of a tandem alkyne insertion/Suzuki
reaction of unactivated alkyl iodides. The reaction has broad
substrate scope: applicable to both primary and secondary alkyl
iodides and useful in the construction of both five-membered
and six-membered rings. Cursory mechanistic studies have led
to the proposal of a plausible catalytic cycle. The overall
transformation provides rapid access to regio- and stereo-
defined, unsymmetrical, tetrasubstituted olefins through a
mechanistically unique reaction manifold which complements
existing methods.
With these results, a putative catalytic cycle is proposed in
Scheme 5. Precoordination of the palladium catalyst to the
alkyne promotes an intramolecular SN2 oxidative addition
consistent with the inversion of stereochemistry observed for
deuterated substrate 26. Following the oxidative addition to
C
dx.doi.org/10.1021/ja307761f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sicook@indiana.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for generous financial support by
Indiana University and the Petroleum Research Fund,
administered by the American Chemical Society. We thank
Andrea Patterson for experimental support.
REFERENCES
■
(1) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V.
Angew. Chem., Int. Ed. 2012, 51, 5062.
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
(3) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(4) (a) Sustmann, R.; Lau, J.; Zipp, M. Tetrahedron Lett. 1986, 27,
5207. (b) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett.
1992, 691. (c) Luh, T. Y.; Leung, M. K.; Wong, K. T. Chem. Rev. 2000,
100, 3187. (d) Netherton, M. R.; Dai, C. Y.; Neuschutz, K.; Fu, G. C. J.
Am. Chem. Soc. 2001, 123, 10099. (e) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656 and references therein.
(5) (a) Collman, J. P. Acc. Chem. Res. 1975, 8, 342. (b) Ozawa, F.;
Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102, 6457. (c) Pearson,
R. G.; Figdore, P. E. J. Am. Chem. Soc. 1980, 102, 1541. (d) Ozawa, F.;
Ito, T.; Nakamura, Y.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1981, 54,
1868. (e) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am.
Chem. Soc. 1996, 118, 3626. (f) Huang, M. H.; Liang, L. C.
Organometallics 2004, 23, 2813. (g) Tanaka, D.; Romeril, S. P.; Myers,
A. G. J. Am. Chem. Soc. 2005, 127, 10323.
(6) Gao, P.; Cook, S. P. Org. Lett. 2012, 14, 3340.
(7) (a) Anderson, G. K.; Cross, R. J. Acc. Chem. Res. 1984, 17, 67.
(b) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.;
Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035. (c) Bloome,
K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132, 12823.
(8) (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(b) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc.
2011, 133, 20146.
(9) (a) Samsel, E. G.; Norton, J. R. J. Am. Chem. Soc. 1984, 106,
5505. (b) LaPointe, A. M.; Brookhart, M. Organometallics 1998, 17,
1530.
(10) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(11) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662.
(12) (a) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318.
̈
(b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733. (c) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (d) Julia, M.;
Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833. (e) Boutagy, J.; Thomas,
R. Chem. Rev. 1974, 74, 87. (f) McMurry, J. E.; Fleming, M. P. J. Am.
Chem. Soc. 1974, 96, 4708. (g) Chan, T.-H. Acc. Chem. Res. 1977, 10,
442. (h) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(13) (a) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5,
1579. (b) Zhou, C.; Larock, R. C. Org. Lett. 2005, 7, 259. (c) Zhou, C.;
Larock, R. C. J. Org. Chem. 2006, 71, 3184.
(14) Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31, 2302.
(15) (a) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(b) Stadtmuller, H.; Vaupel, A.; Tucker, C. E.; Studemann, T.;
Knochel, P. Chem.−Eur. J. 1996, 2, 1204.
D
dx.doi.org/10.1021/ja307761f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX