Nickel-catalyzed enantioselective cross-couplings of racemic secondary electrophiles that bear an oxygen leaving group

Article abstract of DOI:10.1021/ja300031w

To date, effective nickel-catalyzed enantioselective cross-couplings of alkyl electrophiles that bear oxygen leaving groups have been limited to reactions of allylic alcohol derivatives with Grignard reagents. In this Communication, we establish that, in the presence of a nickel/pybox catalyst, a variety of racemic propargylic carbonates are suitable partners for asymmetric couplings with organozinc reagents. The method is compatible with an array of functional groups and utilizes commercially available catalyst components. The development of a versatile nickel-catalyzed enantioselective cross-coupling process for electrophiles that bear a leaving group other than a halide adds a significant new dimension to the scope of these reactions.

Full text of DOI:10.1021/ja300031w

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Enantioselective Cross-Couplings of Racemic
Secondary Electrophiles That Bear an Oxygen Leaving Group
Alexander J. Oelke, Jianwei Sun, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
cleavage), including nickel-catalyzed carbon−carbon bond-
forming processes.4 In contrast, there are far fewer examples
ABSTRACT: To date, effective nickel-catalyzed enantio-
selective cross-couplings of alkyl electrophiles that bear
oxygen leaving groups have been limited to reactions of
allylic alcohol derivatives with Grignard reagents. In this
Communication, we establish that, in the presence of a
nickel/pybox catalyst, a variety of racemic propargylic
carbonates are suitable partners for asymmetric couplings
with organozinc reagents. The method is compatible with
an array of functional groups and utilizes commercially
available catalyst components. The development of a
versatile nickel-catalyzed enantioselective cross-coupling
process for electrophiles that bear a leaving group other
than a halide adds a significant new dimension to the scope
of these reactions.
of corresponding nickel-catalyzed couplings of alkyl electro-
philes (Csp −O bond cleavage), especially secondary or tertiary
electrophiles. Furthermore, to the best of our knowledge,
enantioselective reactions are limited to a rather narrow set of
allylic electrophiles, and good ee’s and yields are observed only
with highly reactive Grignard reagents.5
We sought to expand the scope of such processes beyond
allylic alcohol derivatives and beyond Grignard reagents as
coupling partners. For some of the nickel-catalyzed cross-
coupling methods that we have developed, we have
hypothesized that oxidative addition proceeds through a two-
step inner-sphere electron-transfer pathway, beginning with
abstraction of the leaving group (X) by nickel (eq 2).6,7
3
uring the past several years, we have pursued the
D
development of nickel-catalyzed asymmetric cross-cou-
pling reactions of racemic secondary alkyl electrophiles.1−3
Although both activated and unactivated electrophiles can serve
as suitable coupling partners, our progress to date has been
limited to substrates in which the leaving group is a halide. Of
course, oxygen-based leaving groups are widely used in organic
chemistry, and the conditions for their synthesis from alcohols
can complement those employed for the generation of halides
(e.g., Brønsted-basic vs Brønsted-acidic). We therefore sought
to add a new dimension to our stereoconvergent cross-coupling
reactions of alkyl electrophiles by developing a method that can
utilize oxygen leaving groups. In this Communication, we
describe the achievement of this objective, specifically, nickel-
catalyzed asymmetric Negishi reactions of racemic propargylic
carbonates (eq 1).
Because SH2 reactions at oxygen are uncommon, we decided to
pursue a Barton−McCombie-like approach8 to achieving C−O
bond cleavage, specifically, the use of acylated alcohols as
substrates, which provides nickel with the opportunity to
initially interact with a carbon−heteroatom double bond and to
cleave the target C−O bond in a subsequent step.
In view of the synthetic utility of alkynes,9 we attempted to
apply a method that we have developed for stereoconvergent
Negishi reactions of propargylic halides10 to the cross-coupling
of an acylated propargylic alcohol (eq 3). Unfortunately, we
obtained virtually none of the desired coupling product.
After considerable effort, we have developed a method that
achieves enantioselective cross-couplings of propargylic electro-
philes that bear an oxygen leaving group. As illustrated in Table
1, whereas a Negishi reaction of a propargylic xanthate
proceeds with very modest ee and yield (entry 1), the
corresponding carbonate couples with promising enantioselec-
tivity (but still unsatisfactory yield; entry 2). Substitution of the
methyl group of the carbonate with a phenyl group leads to a
Oxygen leaving groups are widely employed in cross-
Received: January 2, 2012
Published: February 1, 2012
2
coupling reactions of aryl electrophiles (Csp −O bond
© 2012 American Chemical Society
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Communication
Table 1. Impact of the Structure of the Oxygen Leaving
Group on the Catalytic Asymmetric Cross-Coupling of a
Propargylic Electrophile
Table 2. Catalytic Asymmetric Cross-Couplings of TMS-
Protected Racemic Propargylic Carbonates
a
a
a
b
All data are the average of two experiments. The yield was
determined by GC analysis with the aid of a calibrated internal
standard.
significant improvement in ee and product formation (entry 3),
and, finally, the addition of electron-donating substituents to
the 2, 4, and 6 positions of the aromatic ring results in a small
enhancement in enantioselectivity and a substantial increase in
yield (entries 4−6).
a
All data are the average of two experiments. For reaction conditions,
Table 2 provides a variety of examples of this new
stereoconvergent cross-coupling of organozinc reagents with
propargylic electrophiles via C−O bond cleavage.11,12 Thus, an
array of TMS-substituted propargylic carbonates couple with a
range of arylzinc reagents, including ortho-,13 meta-, and para-
substituted nucleophiles (entries 3−5). The method is
compatible with a diverse set of functional groups, such as
aryl methyl ethers (entries 3−5 and 9),14 acetals (entries 8 and
12), silyl ethers (entry 9), esters (entry 10), aryl chlorides and
fluorides (entry 10),15 olefins (entry 11), alkyl chlorides (entry
12),16 and a Boc-protected nitrogen heterocycle (entry 13).
Both of the catalyst components (NiCl2(PCy3)2 and L*) are
commercially available and air-stable.
b
c
see eq 1 (R = TMS). Yield of purified product. de.
Although this method was optimized for asymmetric cross-
couplings of readily deprotected TMS-substituted alkynes, we
have determined that it can be applied without modification to
other families of alkynes. Thus, regardless of whether the distal
carbon of the propargylic carbonate bears a small or a large
alkyl group, or an aromatic substituent, the stereoconvergent
Negishi reaction proceeds with promising enantioselectivity
and yield (eqs 4−6).
We have applied our method to the synthesis of alkyne B,
which has potential utility for the treatment of allergic and
inflammatory diseases.17 Thus, on a gram-scale, a catalytic
asymmetric Negishi cross-coupling of propargylic carbonate A
with a functionalized arylzinc reagent, followed by desilylation
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Communication
and oxidation, furnishes the target alkyne in 90% ee and 47%
overall yield (three steps; eq 7).
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01-
GM62871) and the Alexander von Humboldt Foundation
(research fellowship for A.J.O.). We thank Dr. Wataru
Muramatsu for a preliminary investigation.
REFERENCES
■
(1) (a) For leading references, see: Zultanski, S. L.; Fu, G. C. J. Am.
Chem. Soc. 2011, 133, 15362−15364. Owston, N. A.; Fu, G. C. J. Am.
Chem. Soc. 2010, 132, 11908−11909. (b) For an initial study, see:
Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594−4595. (c) For
multi-gram reactions, see: Lou, S.; Fu, G. C. Org. Synth. 2010, 87,
317−329. Lou, S.; Fu, G. C. Org. Synth. 2010, 87, 330−338.
(2) For work by others, see: Caeiro, J.; Sestelo, J. P.; Sarandeses, L. A.
Chem.Eur. J. 2008, 14, 741−746.
Although propargylic carbonates are not suitable cross-
coupling partners (<2% ee and 5% yield) using our earlier
procedure for Negishi reactions of propargylic bromides,10 our
new method is fairly versatile, effective not only for propargylic
carbonates (Table 2), but, without modification, also for
propargylic bromides and chlorides (eqs 8 and 9).
(3) For reviews and leading references, see: (a) Rudolph, A.; Lautens,
M. Angew. Chem., Int. Ed. 2009, 48, 2656−2670. (b) Glorius, F. Angew.
Chem., Int. Ed. 2008, 47, 8347−8349.
(4) For a recent review with leading references, see: Rosen, B. M.;
Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N.
K.; Percec, V. Chem. Rev. 2011, 111, 1346−1416.
(5) Enantioselective coupling reactions of secondary allylic electro-
philes: (a) Indolese, A. F.; Consiglio, G. Organometallics 1994, 13,
2230−2234 and references therein. (b) Nomura, N.; RajanBabu, T. V.
Tetrahedron Lett. 1997, 38, 1713−1716. (c) Gomez-Bengoa, E.;
Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 1998, 120, 7649−7650. (d) Nagel, U.; Nedden, H. G. Inorg.
Chim. Acta 1998, 269, 34−42. (e) Chen, H.; Deng, M.-Z. J. Organomet.
Chem. 2000, 603, 189−193. (f) Chung, K.-G.; Miyake, Y.; Uemura, S.
J. Chem. Soc., Perkin Trans. 1 2000, 15−18. Chung, K.-G.; Miyake, Y.;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 2725−2729. (g) Novak,
A.; Fryatt, R.; Woodward, S. Comptes Rendus Chimie 2007, 10, 206−
212.
(6) For suggestions of radical intermediates in nickel-catalyzed cross-
coupling reactions of unactivated alkyl electrophiles, see the following.
(a) Suzuki: Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340−
1341. (b) Hiyama: Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004,
126, 7788−7789. (c) Reference 1a. We expect that the pathway for
oxidative addition will depend on a variety of factors, including the
ligand, the leaving group, and the nature of the electrophile (e.g.,
unactivated vs. activated).
(7) For mechanistic proposals for Ni/terpyridine-catalyzed Negishi
reactions of unactivated alkyl electrophiles, see: (a) Jones, G. D.;
Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.;
Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A.
J. Am. Chem. Soc. 2006, 128, 13175−13183. (b) Lin, X.; Phillips, D. L.
J. Org. Chem. 2008, 73, 3680−3688.
(8) For a review and leading references, see: Mancuso, J. In Name
Reactions for Homologations; Li, J. J., Ed.; John Wiley & Sons:
Hoboken, NJ, 2009; Part 1, pp 614−632.
(9) For leading references to the chemistry of alkynes, see: (a)
Science of Synthesis; Thomas, E. J., Ed.; Thieme: Stuttgart, 2008; Vol.
43. (b) Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski, R.
R., Eds.; Wiley−VCH: New York, 2005.
(10) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645−
12647.
(11) Notes: (a) Under our standard reaction conditions: essentially
no cross-coupling product (<2%) is formed in the absence of
NiCl2(PCy3)2, and very little (∼5%) is generated in the absence of L*;
a propargylic carbonate that includes a terminal alkyne is not a suitable
substrate; an attempt to couple a hindered electrophile (alkyl = i-Pr)
led to the formation of an allene; the corresponding propargylic iodide
cross-couples in lower yield (<30%); there is no kinetic resolution of
the propargylic carbonate during the course of a coupling reaction.
(b) The cross-coupling illustrated in entry 2 of Table 2 proceeds in
91% ee and 48% yield (with 20% unreacted electrophile) in the
presence of 5% NiCl2(PCy3)2 and 6.5% L*. (c) In a preliminary study
In summary, with respect to nickel-catalyzed enantioselective
cross-couplings of alkyl electrophiles that bear oxygen leaving
groups, only reactions of a small set of allylic alcohol derivatives
with Grignard reagents had previously been reported to
proceed in good ee and yield. We have established that a
diverse array of racemic propargylic carbonates are suitable
coupling partners in nickel/pybox-catalyzed asymmetric Negishi
reactions. The method is compatible with a range of functional
groups and employs commercially available catalyst compo-
nents. The development of a versatile nickel-catalyzed
enantioselective cross-coupling process for electrophiles that
bear a leaving group other than a halide adds a significant new
dimension to the scope of these reactions. Further inves-
tigations into the use of non-halide leaving groups, as well as
studies to elucidate the mechanism of this transformation, are
underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
gcf@mit.edu
Notes
The authors declare no competing financial interest.
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under related conditions, a benzylic carbonate couples with an arylzinc
reagent in 64% ee and 72% yield.
(12) Using a nickel catalyst, but with a different leaving group
(alkoxy), a different activating substituent (naphthyl and other
extended aromatic), a different nucleophile (MeMgI), a different
ligand (phosphine), etc., Jarvo has reported cross-couplings that
proceed with inversion of stereochemistry: Taylor, B. L. H.; Swift, E.
C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389−391
and references therein.
(13) In the case of asymmetric Negishi reactions of propargylic
bromides (ref 10), ortho-substituted arylzinc reagents are not suitable
coupling partners (yield <40%).
(14) For examples of nickel-catalyzed cross-couplings of aryl methyl
ethers, see ref 4.
(15) For a recent report of nickel-catalyzed Negishi reactions of aryl
chlorides, see: Liu, N.; Wang, L.; Wang, Z.-X. Chem. Commun. 2011,
1598−1600.
(16) For examples of nickel-catalyzed cross-couplings of unactivated
primary alkyl chlorides, see: Gonzal
Chem. Soc. 2006, 128, 5360−5361.
(17) Christensen, S. B.; Karpinski, J. M.; Frazee, J. S. Substituted-
Pent-4-Ynoic Acids. U.S. Patent 6,037,367, March 14, 2000.
́
ez-Bobes, F.; Fu, G. C. J. Am.
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