Nickel-catalyzed enantioselective C-C bond formation through C sp 2 -O cleavage in aryl esters

Article abstract of DOI:10.1002/anie.201412051

We report the first enantioselective C-C bond formation through C-O bond cleavage using aryl ester counterparts. This method is characterized by its wide substrate scope and results in the formation of quaternary stereogenic centers with high yields and asymmetric induction.

Full text of DOI:10.1002/anie.201412051

Angewandte
Chemie
DOI: 10.1002/anie.201412051
Synthetic Methods
À
Nickel-Catalyzed Enantioselective C C Bond Formation through
Csp2 O Cleavage in Aryl Esters**
À
Josep Cornella, Evan P. Jackson, and Ruben Martin*
À
Abstract: We report the first enantioselective C C bond
À
formation through C O bond cleavage using aryl ester
counterparts. This method is characterized by its wide substrate
scope and results in the formation of quaternary stereogenic
centers with high yields and asymmetric induction.
À
O
ver the past decade, C O electrophiles have gained
momentum as powerful alternatives to aryl halides in the
cross-coupling arena.[1] Such popularity is largely due to the
availability and lack of toxicity of phenols compared to
organic halides, representing a significant step forward for
their utilization in cross-coupling techniques. Among the
phenol series, the utilization of aryl sulfonates, particularly
aryl triflates, has become routine due to their high reactivity,
À
low barrier for C O oxidative addition, and the lack of
À
regioselectivity issues for C O bond cleavage (Scheme 1, top
À
Scheme 1. C C bond formation with ester counterparts.
left).[1] In sharp contrast, the employment of simpler and
À
cheaper aryl esters as C O electrophiles still poses formida-
ble challenges due to the higher activation energy required for
À
the cleavage of the rather unreactive Csp2 O bond, the site
atives remains largely undeveloped. In recent years, elegant
stereoselective transformations have recently been reported
by the groups of Jarvo[4] and Watson[5] (Scheme 1, path a)
using ester counterparts; unfortunately, these methods are
restricted to the formation of tertiary stereocenters, requiring
the installation of a preexisting stereogenic center. In sharp
À
selectivity among multiple C O bonds and their inherent
tendency for hydrolysis under basic conditions (Scheme 1, top
right).[1] Not surprisingly, a rather limited number of C C
À
bond-forming reactions have been reported using aryl ester
counterparts; importantly, the vast majority of these process-
es employ stoichiometric and well-defined organometallic
species, thus constituting a drawback from a practical stand-
point (Scheme 1, top right).[2,3]
À
contrast, an enantioselective C C bond formation through
À
Csp2 O bond cleavage with prochiral nucleophilic entities that
obviates the need for organometallic reagents and results in
the rather elusive quaternary stereogenic centers has not yet
been described in the literature.[6] Unquestionably, the ability
to promote such a reaction would not only dramatically
Despite the advances realized,[1] the development of
asymmetric C O bond cleavage reactions using ester deriv-
À
À
expand the utility of C O electrophiles, but would also open
up new and unconventional strategies for preparing valuable
[*] J. Cornella, E. P. Jackson, Prof. R. Martin
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢀsos Catalans 16, 43007, Tarragona (Spain)
E-mail: rmartinromo@iciq.es
and enantioenriched complex molecules. As part of our
[7]
À
ongoing studies in C O bond cleavage reactions, we
summarize our investigations aimed at the development of
Prof. R. Martin
À
the first metal-catalyzed enantioselective C C bond forma-
tion of aryl esters through Csp2 O bond cleavage (Scheme 1,
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluꢀs Companys, 23, 08010, Barcelona (Spain)
À
path b).[8] This transformation utilizes in situ-generated pro-
chiral ketone enolates and replaces commonly employed
organic halides or activated aryl sulfonates by simpler aryl
esters derived from phenol.[9,10] This method is distinguished
by a high asymmetric induction and wide scope, including the
coupling of rather challenging nonextended p-systems.
We began our study by examining the reactivity of 2-
methyl-1-indanone (1a) with 2-naphthyl pivalate (2a), and
the effects of the metal catalyst, ligand, base, and solvent
employed were systematically investigated (Scheme 2).[11]
Initial evaluation of a number of metal complexes identified
Ni(cod)2 as a competent catalyst in combination with NaOtBu
[**] We thank the ICIQ foundation, the European Research Council
(ERC-277883), MINECO (CTQ2012-34054 & Severo Ochoa Excel-
lence Accreditation 2014-2018; SEV-2013-0319), and the CELLEX
Foundation through the CELLEX-ICIQ high-throughput experimen-
tation platform for financial support. Johnson Matthey, Umicore,
and Nippon Chemical Industrial are acknowledged for a gift of
metal and ligand sources. We thank Eduardo Escudero for the X-ray
crystallographic data. J.C. thanks the European Union (FP7-
PEOPLE-2012-IEF-328381) for a fellowship. E.P.J. thanks Rackham
Graduate School for funding. Azu is gratefully acknowledged for
inspiring the development of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412051.
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Scheme 2. Enantioselective a-arylation of ketones with aryl esters.
Reaction conditions: 1a (0.25 mmol), 2a (0.40 mmol), Ni(cod)2
(10 mol%), L (10 mol%), NaOtBu (0.40 mmol), toluene (0.17m) at
808C for 12 h. Yields were determined by GC using decane as internal
standard. Enantiomeric ratios (e.r.) were determined by HPLC of the
crude mixtures on a chiral stationary phase. [a] (R)-3a was formed.
Scheme 3. Scope of naphthyl pivalates. Reaction conditions: 1a
(0.25 mmol), 2a–2i (0.40 mmol), Ni(cod)2 (10 mol%), L2 (10 mol%),
NaOtBu (0.40 mmol), PhMe (0.17m) at 808C for 12 h. Yields are of
isolated products; average of at least two independent runs. Enantio-
meric ratios (e.r.) were determined by HPLC on a chiral stationary
phase. [a] LiHMDS (0.25 mmol) was used as the base.
as the base in toluene at 808C. After a judicious screening of
the available chiral ligands,[11] we observed a promising
asymmetric induction when operating under a L1 regime. A
similar pattern was found for L3 and L5,[10d] reinforcing the
notion that a chiral bidentate ligand bearing a biaryl axis was
critical for success. In line with these results, we found little
reactivity, if any, and low asymmetric induction for L4 and L6.
Intriguingly, the inclusion of more electron-rich and sterically
demanding ligands had a detrimental impact on the reaction
outcome.[11] Similarly, we found that subtle changes on the
biaryl backbone of the ligand employed had a marked
influence on enantioselectivity. After considerable experi-
mentation, we found that commercially available L2 provided
the best results, obtaining 3a in 88% yield and with an
excellent asymmetric induction (99:1 e.r.). The absolute
configuration of 3a was unambiguously determined by X-
ray crystallographic analysis,[12] thus concluding that S-con-
figured 3a was obtained when the reaction was performed
with (S)-Tol-BINAP (L2). As anticipated, control experi-
ments showed that all reaction components were critical for
obtaining 3a in high yield and asymmetric induction.[13]
With the optimized conditions, we sought to examine the
Equally interesting is the ability to couple carbazole motifs in
good yields and without an erosion in enantioselectivity (2h).
In light of these results, we anticipated that site selectivity
À
would be within reach with similarly reactive C O bonds. As
shown for 2i, this was indeed the case, obtaining a single
regioisomer with excellent yield and asymmetric control.
A close inspection of literature data indicates that the use
of extended p-systems has typically been a requisite in a wide
[14]
À
number of catalytic C O bond cleavage processes. Most
likely, the ease for h2-coordination to the metal center and the
intermediacy of Meisenheimer-type complexes makes
extended p-systems several orders of magnitude more
reactive than regular arenes.[15,16] Therefore, it was unclear
À
whether a Ni-catalyzed enantioselective C C bond formation
À
through C O bond cleavage could ever be conducted with
less activated and rather challenging phenyl pivalates. Grat-
ifyingly, this turned out to be the case (Scheme 4). As shown,
the coupling of a host of challenging phenyl pivalates could be
conducted under otherwise similar reaction conditions to
those in Scheme 3. These results reinforce the perception that
our protocol based upon Ni/L2 represents a general technique
for preparing a-arylated compounds with quaternary stereo-
genic centers from simple aryl ester coupling partners.
Although aryl pivalates afforded significantly lower reaction
rates than naphthyl pivalates (Scheme 3), excellent enantio-
selectivities were found in all substrates analyzed (Scheme 4).
As judged by the results in Scheme 4, it becomes evident that
the outcome of the a-arylation event was largely insensitive to
electronic changes at the para and meta positions on the
aromatic ring. Unfortunately, ortho-substituted phenyl piv-
alates could not be employed as substrates. Notably, amines
À
scope and the generality of our enantioselective C C bond
À
formation through C O bond cleavage. As shown in
Scheme 3, the Ni-catalyzed ketone a-arylation of naphthyl
pivalates turned out to be widely applicable when utilizing
a diverse set of naphthyl derivatives. Interestingly, substrates
with pyrazoles (2d), quinolines (2c), silanes (2e), silyl ethers
(2 f), amides (2g), and esters (2i) posed no problems and
remained intact under our optimized reaction conditions. Of
particular interest is the fact that nitrogen-containing hetero-
cycles do not interfere (2c, 2d), indicating that these motifs do
not compete with L2 for substrate binding at the Ni center.
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that medium-sized rings other than indanone can be equally
effective. As anticipated, the inclusion of functional groups
such as silyl ethers (6c) posed no problems. Particularly
noteworthy was the observation that a pivalate motif in the
indanone core does not interfere (6 f), resulting in the
À
selective C O bond cleavage of 2b when employing
NaHMDS as the base.[17] Taken together, we believe that
the results in Schemes 3–5 will not only have broader
implications for the utilization of rather unconventional aryl
À
esters as C O electrophiles in cross-coupling reactions, but
will also lead to the implementation of new enantioselective
[18]
À
protocols based on C O bond cleavage.
À
In summary, we have described the first asymmetric C C
bond forming reaction utilizing aryl esters as C O electro-
À
philes and in situ-generated prochiral ketone enolates. The
transformation is distinguished by its wide substrate scope,
high asymmetric induction, and diverse set of substitution
patterns. We anticipate that our study will lead to the
foundation of new asymmetric protocols when utilizing
Scheme 4. Scope of aryl pivalates. Reaction conditions: 1a
(0.25 mmol), 4a–4i (0.40 mmol), Ni(cod)2 (10 mol%), L2 (10 mol%),
NaOtBu (0.40 mmol), PhMe (0.17m) at 1108C for 12 h. Yields are of
isolated products; average of at least two independent runs. Enantio-
meric ratios (e.r.) were determined by HPLC on a chiral stationary
phase. [a] 4 (0.75 mmol).
À
simpler C O electrophiles. Further investigations along
these lines are currently underway in our laboratories.
Received: December 16, 2014
Published online: && &&, &&&&
(4c), nitrogen-containing heterocycles (4e), acetals (4i), and
aryl fluorides (4 f) were all well accommodated, thus illus-
trating the chemoselectivity and robustness of our protocol.
Next, we turned our attention to explore the reactivity of
differently substituted aryl ketones in our Ni-catalyzed
enantioselective reaction (Scheme 5). As shown, aryl ketones
containing ethyl or even bulkier isopropyl substituents in the
a-position (6a and 6b) did not significantly hamper the
reactivity and the targeted products were obtained in good
yields and high enantioselectivities. The successful prepara-
tion of benzofuranone 7d and tetralone 7e tacitly indicates
Keywords: aryl esters · C-O cleavage · C-O electrophiles ·
.
nickel catalysis
[1] For recent reviews, see: a) J. Cornella, C. Zarate, R. Martin,
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À
[2] For selected C C bond forming reactions using aryl ester
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Scheme 5. Scope of aryl ketone counterparts. Reaction conditions: 6a–
6i (0.25 mmol), 2a,b (0.40 mmol), Ni(cod)2 (10 mol%), L2
(10 mol%), NaOtBu (0.40 mmol), PhMe (0.17m) at 808C for 12 h.
Yields are of isolated products; average of at least two independent
runs. Enantiomeric ratios (e.r.) were determined by HPLC on a chiral
stationary phase. [a] Using 2b. [b] Ni(cod)2 (20 mol%). [c] Using 2a.
[d] NaHMDS (0.25 mmol) was used as the base.
[4] Selected references using benzyl ester derivatives: a) E. J.
Tollefson, D. D. Dawson, C. A. Osborne, E. R. Jarvo, J. Am.
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Chem. Soc. 2014, 136, 14951; b) H. M. Wisniewska, E. C. Swift,
E. R. Jarvo, J. Am. Chem. Soc. 2013, 135, 9083; c) M. R. Harris,
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Buchwald, J. Am. Chem. Soc. 2002, 124, 1261.
[11] See the Supporting Information for details of the optimization,
including the use of other ligands and bases. We found than
simpler acetates could not be employed as substrates, invariably
resulting in phenol formation.
[5] Selected references using benzyl or allylic ester derivatives:
a) H. D. Srinivas, Q. Zhou, M. P. Watson, Org. Lett. 2014, 16,
3596; b) W. Chen, M. Chen, J. F. Hartwig, J. Am. Chem. Soc.
2014, 136, 15825; c) Q. Zhou, H. D. Srinivas, S. Dasgupta, M. P.
Watson, J. Am. Chem. Soc. 2013, 135, 3307.
[6] For excellent reviews dealing with the formation of quaternary
stereogenic centers, see: a) J. Christoffers, A. Mann, Angew.
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[7] a) C. Zarate, R. Martin, J. Am. Chem. Soc. 2014, 136, 2236; b) Y.
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c) A. Correa, T. Leon, R. Martin, J. Am. Chem. Soc. 2014, 136,
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Alvarez-Bercedo, R. Martin, J. Am. Chem. Soc. 2010, 132, 17352.
[8] While this manuscript was under preparation, the Itami group
reported an elegant Ni-catalyzed cross-coupling of aryl ketones
with aryl pivalates for preparing racemic a-arylated products
containing tertiary stereogenic centers: R. Takise, K. Muto, J.
Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2014, 53, 6791;
Angew. Chem. 2014, 126, 6909.
[9] For reviews dealing with a-arylation of carbonyl compounds,
see: a) P. Novꢀk, R. Martin, Curr. Org. Chem. 2011, 15, 3233;
b) C. C. C. Johansson, T. J. Colacot, Angew. Chem. Int. Ed. 2010,
49, 676; Angew. Chem. 2010, 122, 686; c) F. Bellina, R. Rossi,
Chem. Rev. 2009, 110, 1082; d) A. C. Butoloso, Synlett 2009, 320;
e) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234.
[10] For a selection of enantioselective a-arylation methodologies
utilizing activated aryl sulfonates or aryl halides, see: a) Z.
Huang, L. H. Lim, Z. Chen, Y. Li, F. Zhou, H. Su, J. Zhou,
Angew. Chem. Int. Ed. 2013, 52, 4906; Angew. Chem. 2013, 125,
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16330; d) X. Liao, Z. Weng, J. F. Hartwig, J. Am. Chem. Soc.
[12] The use of Mo Ka radiation allowed for the absolute structure
determination of enantiopure light-atom molecules: E. C. Escu-
dero-Adꢀn, J. Benet-Buchholz, P. Ballester, Acta Crystallogr.
Sect. B 2014, 70, 660. CCDC 1039400 ((R)-3a) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] Aryl carbonates could not be employed as coupling partners,
resulting in the recovery of the corresponding starting materials.
A similar reaction outcome was observed when using aryl
pivalates as substrates with weaker bases such as K3PO4 or
related.
[14] Selected references: a) B. L. H. Taylor, E. C. Swift, J. D. Waet-
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[15] Unlike regular arenes, extended p-systems bind strongly the Ni
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[16] For a hypothesis based on Meisenheimer-type complexes, see:
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scenarios dealing with the intermediacy of dearomatized prod-
ucts, see: Ref. [7f].
[17] No reaction took place under our optimized reaction conditions
when employing aliphatic or nonfused aromatic ketone counter-
parts.
[18] Whether these results indicate a direct oxidative addition into
À
the targeted Csp2 O bond or if there are other mechanistic
implications via the intermediacy of Ni0-ate complexes is the
subject of ongoing mechanistic studies in our laboratory.
4
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Synthetic Methods
J. Cornella, E. P. Jackson,
R. Martin*
&&& — &&&
Aryl ester electrophiles are used in an
ligand, allowing the formation of enan-
À
À
Nickel-Catalyzed Enantioselective C C
enantioselective C C bond formation
tioenriched quaternary stereocenters.
This protocol is characterized by its high
asymmetric induction and remarkable
wide scope.
À
À
Bond Formation through Csp2 O Cleavage
through C O bond cleavage. This reac-
in Aryl Esters
tion proceeds under nickel catalysis by
means of an axially chiral bidentate
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