Stereospecific Ni-catalyzed cross-coupling of potassium alkenyltrifluoroborates with alkyl halides

Article abstract of DOI:10.1021/ol500408a

A general method for the alkenylation of alkyl electrophiles using nearly stoichiometric amounts of the air- and moisture-stable potassium organotrifluoroborates has been developed. Various functional groups were tolerated on both the nucleophilic and electrophilic partner. Reactions of highly substituted E- and Z-alkenyltrifluoroborates, as well as vinyl- and propenyltrifluoroborates, were successful, and no loss of stereochemistry or regiochemistry was observed.

Full text of DOI:10.1021/ol500408a

Letter
pubs.acs.org/OrgLett
Stereospecific Ni-Catalyzed Cross-Coupling of Potassium
Alkenyltrifluoroborates with Alkyl Halides
Gary A. Molander* and O. Andreea Argintaru†
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A general method for the alkenylation of alkyl electrophiles using nearly stoichiometric amounts of the air- and
moisture-stable potassium organotrifluoroborates has been developed. Various functional groups were tolerated on both the
nucleophilic and electrophilic partner. Reactions of highly substituted E- and Z-alkenyltrifluoroborates, as well as vinyl- and
propenyltrifluoroborates, were successful, and no loss of stereochemistry or regiochemistry was observed.
he stereoselective synthesis of olefins has long attracted
have been reported. Additionally, similar to most heteroaryl-
and alkylboronic acids, alkenylboronic acids are prone to rapid
protodeboronation when stored on the benchtop,9 and a large
excess is required to achieve good yields.10 More recently, the
Fe-catalyzed Suzuki−Miyaura cross-coupling of alkenyl pinacol
boronate esters with alkyl halides was reported.11 Although
these organoborons are more stable than their boronic acid
equivalents, the substrate scope of the nucleophile remains
limited (a silyl protected alcohol was the only functional group
tolerated on the nucleophile), in addition to the inconvenience
associated with the lack of atom economy of pinacol boronates.
A major drawback in the reported Fe-catalyzed Suzuki−
Miyaura alkenylation is the requirement to use super-
stoichiometric amounts of t-BuLi.
We envisioned that the aforementioned limitations (stability
of the nucleophiles and of other reagents such as t-BuLi, large
excess of organoborons, and pinacol waste) could be overcome
by the use of potassium alkenyltrifluoroborates in a Ni-
catalyzed Suzuki−Miyaura cross-coupling with various alkyl
electrophiles. Alkenyltrifluoroborates are indefinitely air- and
moisture-stable, and various stereochemically pure, highly
substituted and functionalized structures (containing alkyl
halides, esters, nitriles, ketones, etc.) can be easily accessed.12
Encouragingly, the use of alkenyltrifluoroborates as an
alternative to other organoborons in C(sp2)−C(sp2) cross-
couplings has been successfully demonstrated,12 as well as the
Ni-catalyzed cross-coupling of a wide array of potassium aryl-
and heteroaryltrifluoroborates with alkyl halides.13
T
the attention of the organic chemistry community.1
Although since their discovery transition metal catalyzed
cross-coupling reactions have focused mainly on C(sp2)−
C(sp2) bond formation, recent advances have also been made
in the important field of C(sp2)−C(sp3) coupling.2,3 Among
these, alkenylations of alkyl electrophiles have been of high
interest because they allow rapid access to a broad array of
highly substituted and sterically hindered olefins.2b,3 With a
wide variety of structurally diverse, functionalized, alkyl halides
being commercially available or readily accessible, the challenge
of the transformation remains the alkenyl nucleophile.3
Previous studies have described the cross-coupling of alkenyl
nucleophiles with primary iodides and bromides catalyzed by
Pd, but most frequently Ni and Fe complexes are used because
of their capacity to cross-couple secondary electrophiles
without the undesired β-hydride elimination.3 Despite remark-
able advances in the field, the existing methods still present
limitations. For example, the Kumada4 or Negishi5 stereo-
specific cross-couplings of alkenyl nucleophiles with secondary
bromides and iodides were successfully achieved, but these
transformations suffer from the instability of the organometallic
nucleophile, along with a lack of functional group compatibility.
The functional group tolerance and stability issues were solved
by developing Stille alkenylations of alkyl iodides and bromides.
However, the high toxicity of organostannanes makes the Stille
cross-coupling a less desirable transformation.6 Pd-7 and Ni-
catalyzed8 Suzuki−Miyaura alkenylations were developed, and
they present advantages over the aforementioned methods
because of the stability, low toxicity, and functional group
compatibility of organoborons. However, only isolated
examples of Pd-7 and Ni-catalyzed8 cross-coupling of
unhindered E-alkenylboronic acids with alkyl electrophiles
Received: February 8, 2014
Published: March 25, 2014
© 2014 American Chemical Society
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The success of our group in using parallel microscale high-
throughput experimentation (HTE) for rapid reaction opti-
mization13,14 prompted us to apply it to the Ni-catalyzed cross-
coupling of alkyl halides with potassium alkenyltrifluoroborates.
Using 1-bromo-3-phenylpropane as the model electrophile and
stoichiometric amounts of either (E)-2-styryltrifluoroborate or
(E)-5-phenyl-pent-1-en-1-yltrifluoroborate as nucleophiles, a
wide variety of catalyst/ligand combinations, solvents, and
bases were screened at 60 and 80 °C (Scheme 1).
The increase in temperature did not lead to any significant
difference in terms of yields, and unless otherwise noted, the
reactions were run at 60 °C to ensure smoother conditions.
Although several ligands showed reactivity to a certain extent,
we observed that bathophenthroline (L1) was the top ligand,
especially when the reaction was scaled to 1 mmol and when
the best conditions applied to other classes of halides and
alkenyltrifluoroborates were used. Interestingly, bathophenan-
throline, 2-acetyl pyridine (L10), and 2-acetyl pyrrole (L11)
also provided the desired compound in good yields. NiBr2·
glyme and Ni(COD)2 showed similar reactivity for the model
substrates, but because Ni(COD)2 is air-sensitive and needs to
be stored in the freezer in the glovebox, the more stable NiBr2·
glyme was preferred. For proof of concept, some reactions were
set up outside of the glovebox, and similar overall average yields
were obtained (see Table 1, entries 2 and 4, and Table 2,
entries 3, 4, and 11).
Scheme 1. Model Substrates and Catalytic Systems Tested
via Parallel Microscale High-Throughput Experimentation
(HTE)
Table 1. Substrate Scope for the Ni-Catalyzed Cross-
Coupling of Potassium Alkenyltrifluoroborates
During the HTE, it was observed that the counterion on the
base was significant for the outcome of the reaction. LiHMDS
provided the desired compound in good yields; however, the
yields using NaHMDS were superior. KHMDS, on the other
hand, resulted in very low reactivity. NaHMDS in t-BuOH
provided similar yields to those using t-BuONa, and the HMDS
formed seems to have no role in the reaction. However, for the
ease of the HTE screenings setup, LiHMDS, NaHMDS, or
KHMDS was used in combination with various protic solvents
to generate a wide range of alkoxides in situ. As expected,15 the
hydrolysis of the potassium organotrifluoroborates was depend-
ent on the amount and the nature of the base, as well as the
protic solvent. It was found that at least 3 equiv of base were
necessary to achieve good yields, probably to achieve a fast
enough rate of hydrolysis of the potassium organotrifluoro-
borate. Also, it was observed that methoxides and ethoxides
provide very low yields, and mostly protodeboronation of the
trifluoroborate was observed. Use of a nonprotic solvent
(CPME, THF, toluene) in combination with a secondary or
tertiary alcohol reduced the undesired protodeboronation and
increased the yield of the desired cross-coupled product.
a
Reaction using 2-acetylpyridine instead of bathophenanthroline.
b
Reaction using 2-acetylpyrrole instead of bathophenanthroline.
c
d
Reaction run at 80 °C. Product ratio Z/E = 95/5 from starting
e
material potassium propen-1-yltrifluoroborate Z/E = 95/5. Product
f
ratio Z/E > 98/2. Reaction set up outside the glovebox, using t-
BuONa instead of NaHMDS.
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Organic Letters
Letter
would not be compatible with the use of t-BuLi.11 Transition
metal catalyzed Suzuki−Miyaura cross-coupling of vinyl or
propenylboronic acids or boronate esters has never been
reported. Under the conditions developed, vinyltrifluoroborate
and various propenyltrifluoroborates smoothly underwent the
reaction in good yields (Table 1, entries 10−13), overcoming
the limitations and disadvantages encountered with the boronic
acid analogues.11,12 It is important to notice the stereo-
specificity of the transformation, as both the (E)- and (Z)-
isomers of the same trifluoroborates underwent the reaction
with retention of stereochemistry about the olefin (Table 1,
entries 1−4 and entries 10−11).
Table 2. Substrate Scope for the Ni-Catalyzed Alkenylation
of Various Bromide and Iodide Electrophiles
The scope of alkyl electrophiles was then extensively
expanded (Table 2). In terms of functional group tolerance,
acetals (Table 2, entry 1), benzyl ethers (Table 2, entry 2), a
distal olefin (Table 2, entry 3), a nitrile (Table 1, entry 5), and
in modest yields an alcohol (Table 2, entry 4) were tolerated.
Alkyl bromides and iodides reacted chemoselectively, leaving
the alkyl chlorides intact and available for further functionaliza-
tion (Table 2, entries 6 and 7). Additionally, the chemo-
selectivity of the C(sp3)−Br bond in the presence of the
C(sp2)−Br bond on the same electrophile was observed,
another important observation in terms of bidirectional
functionalization (Table 2, entry 8). Secondary cyclic iodides
(Table 2, entry 9) and bromides (Table 2, entry 10) were
successfully coupled. Although 4-bromoheptane cross-coupled
without any branched/linear isomerization (Table 2, entry 11),
3-bromobutane provided the major desired product, along with
∼15% isomerization products (Table 2, entry 12).
Although we were pleased to observe the chemoselectivity of
alkyl iodides and bromides over alkyl chlorides, it became clear
that the initial reaction conditions developed could not be
applied to the cross-coupling of alkyl chlorides. Various
bromides and iodide salts (KI, LiI, LiBr, CuBr, CuI) were
tested as additives in various ratios to initiate the cross-coupling
of alkyl chlorides, but all turned out to be unsuccessful. Inspired
by previously developed conditions for the Ni-catalyzed cross-
coupling of alkyl electrophiles,13 the catalytic system was
switched to Ni(COD)2 (10 mol %) and L-prolinol (20 mol %)
at 80 °C. Under these conditions, increasing the amount of
trifluoroborate (1.3 equiv) and base (3.5 equiv) provided the
desired products in moderate to good yields (Table 3).
In conclusion, a method has been developed for the Ni-
catalyzed alkenylation of alkyl bromides and iodides using
a
Potassium trifluoro(1,4-dioxaspiro[4,5]dec-7-en-8-yl)borate was used
1
to facilitate the purification of the describe product. Similar crude H
NMR yields were obtained when using potassium (E)-2-styryltrifluoro-
borate and potassium (E)-(5-phenylpent-1-en-1-yl)trifluoroborate.
b
Reaction setup outside the glovebox, using t-BuONa instead of
c
NaHMDS, ran at 80 °C. Isomerization linear/branched observed by
1H NMR in a ratio: (E)-(3-ethylhept-1-en-1-yl)benzene/(E)-(3-
methyloct-1-en-1-yl)benzene (E)-non-1-en-1-ylbenzene = 85/10/5.
As a result of the HTE screenings, the best conditions were
found to be 10 mol % NiBr2·glyme, 10 mol % bathophenan-
throline, and 3 equiv of NaHMDS as the base in a mixture of t-
BuOH/CPME = 1:1. Some examples were performed using t-
BuONa to establish the equivalency of NaHMDS in t-BuOH
and t-BuONa (see Table 1, entries 2 and 4, and Table 2, entries
3, 4, and 11).
Table 3. Ni-Catalyzed Cross-Coupling of Alkyl Chlorides
with Potassium Alkenyltrifluoroborates
Because the published alkenylation methods are limited,
especially in terms of substrate scope and functional group
compatibility of the nucleophilic partner,4,5,11 the conditions
found were first applied to the cross-coupling of various
stereochemically pure potassium alkenyltrifluoroborates (1.05
equiv) with 3-phenyl-1-bromopropane or 3-(4-biphenyl)-1-
bromopropane (Table 1).
Reasonable functional group tolerance on the nucleophilic
partner was observed, including substrates containing acetals
(Table 1, entry 5), amines (Table 1, entries 8 and 9), alkyl
nitriles (Table 1, entry 6), and notably alkyl chlorides (Table 1,
entry 7), which could not be present on Grignard reagents and
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Letter
42, 5079−5082. (c) Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem.
Soc. 2005, 127, 510−511.
virtually stoichiometric amounts of the air and moisture stable
nucleophile. An increase in temperature and a slight excess of
nucleophile were required to achieve moderate to good yields
for the cross-coupling of alkyl chlorides. The transformation
showed reasonable functional group tolerance and a very broad
structural diversity of both coupling partners. Crucially, the
reaction was stereospecific, leading to highly substituted alkenes
without loss of stereochemistry. Additionally, cross-coupling of
branched secondary electrophiles was performed in good yields
without any branched/linear isomerization.
(7) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662−13663.
(8) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340−1341.
(9) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. J. Am. Chem. Soc. 2009,
131, 6961−6963. (b) Vinylboronic acid is known to undergo rapid
polymerization: Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228−
4233.
(10) (a) Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org.
Chem. 2004, 1075−1082. (b) For a review on various alkenyl
nucleophiles, see: Denmark, S. E.; Butler, C. R. Chem. Commun. 2009,
20−33.
(11) Hashimoto, T.; Hatakeyama, T.; Nakamura, M. J. Org. Chem.
2012, 77, 1168−1173.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Molander, G. A.; Barcellos, T.; Traister, K. M. Org. Lett.
2013, 15, 3342−3345. (b) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424−8429. (c) Molander, G. A.; Rivero, M. R. Org.
Lett. 2002, 4, 107−109. (d) Molander, G. A.; Felix, L. A. J. Org. Chem.
2005, 70, 3950−3956. (e) Molander, G. A.; Brown, A. R. J. Org. Chem.
2006, 71, 9681−9686.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
Present Address
(13) Molander, G. A.; Argintaru, O. A.; Aron, I.; Dreher, S. D. Org.
Lett. 2010, 12, 5783−5785.
(14) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G.
A. J. Am. Chem. Soc. 2008, 130, 9257−9259. (b) Dreher, S. D.; Lim, S.-
E.; Sandrock, D. L.; Molander, G. A. J. Org. Chem. 2009, 74, 3626−
3631.
(15) (a) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012,
134, 7431−7441. (b) Amatore, C.; Jutand, A.; Duc, G. L. Chem.Eur.
J. 2011, 17, 2492−2503.
†Novartis Institute for Biomedical Research, 100 Technology
Square, Cambridge, Massachusetts 02139.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Frontier Scientific for a generous gift of boronic
acids, pinacol boronates, and potassium organotrifluoroborates.
Financial support has been provided by the NIH (NIGMS R01
GM081376). Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for obtaining HRMS data. DaWeon Ryu is
acknowledged for assistance with some spectroscopic analysis
for the preparation of the Supporting Information.
REFERENCES
■
(1) (a) Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; pp 729−817. (b) Prepara-
tion of Alkenes; Williams, J. M. J., Ed.; Oxford University: Oxford, 1996.
́
(c) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in
̈
Organic Synthesis; Academic Press/Elsevier Science: Amsterdam, 2005.
(2) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002. (b) Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2004. (c) Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004.
(3) (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346,
1525−1532. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005,
44, 674−688. (c) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed.
2009, 48, 2656−2670.
(4) (a) Hatakeyama, T.; Nakagawa, N.; Nakamura, M. Org. Lett.
́
2009, 11, 4496−4499. (b) Guerinot, A.; Reymond, S.; Cossy, J. Angew.
Chem., Int. Ed. 2007, 119, 6641−6644. (c) Cahiez, G.; Duplais, C.;
Moyeux, A. Org. Lett. 2007, 9, 3253−3254. (d) Ohmyia, H.; Yorimitsu,
H.; Oshima, K. Org. Lett. 2006, 8, 3093−3096.
(5) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527−
12530. (b) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2004,
126, 82−83. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
12527−12530. (d) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 82−83.
(6) (a) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718−
3719. (b) Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
1907
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