Rh(I)-catalyzed intermolecular hydroacylation: Enantioselective cross-coupling of aldehydes and ketoamides

Article abstract of DOI:10.1021/ja504296x

Under Rh(I) catalysis, α-ketoamides undergo intermolecular hydroacylation with aliphatic aldehydes. A newly designed Josiphos ligand enables access to α-acyloxyamides with high atom-economy and enantioselectivity. On the basis of mechanistic and kinetic s

Full text of DOI:10.1021/ja504296x

Article
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Rh(I)-Catalyzed Intermolecular Hydroacylation: Enantioselective
Cross-Coupling of Aldehydes and Ketoamides
Kevin G. M. Kou,†,‡ Diane N. Le,† and Vy M. Dong*,†
†Department of Chemistry, University of California, Irvine, California 92697, United States
‡Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Under Rh(I) catalysis, α-ketoamides undergo inter-
molecular hydroacylation with aliphatic aldehydes. A newly designed
Josiphos ligand enables access to α-acyloxyamides with high atom-
economy and enantioselectivity. On the basis of mechanistic and
kinetic studies, we propose a pathway in which rhodium plays a dual
role in activating the aldehyde for cross-coupling. A stereochemical
model is provided to rationalize the sense of enantioinduction
observed.
coordination of ketone 2 to Rh, followed by oxidative addition
INTRODUCTION
■
of aldehyde 1, would generate coordinatively saturated Rh(III)-
hydride I. Octahedral complex I has a lower propensity to
undergo carbonyl deinsertion, a process that deactivates the
rhodium catalyst.8 Ketone insertion into acyl-Rh(III)-hydride I
would lead to Rh(III)-alkoxide II, followed by reductive
elimination to give ester 3 with concomitant regeneration of
the Rh(I) catalyst. In comparison to conventional approaches
to ester synthesis, this catalytic method obviates the need for
prefunctionalization of the acyl component and is amenable to
enantioselective synthesis of esters.
The catalytic functionalization of aldehyde C−H bonds
represents a mild and atom-economical approach to prepare
esters.1 While there has been much progress in developing
hydroacylation of aldehydes,2−6 the hydroacylation of ketones
is relatively unexplored and warrants attention due to its
potential for constructing chiral esters.4 Our laboratory has
demonstrated intramolecular ketone hydroacylations, including
the first examples of enantioselective lactonizations.7 Due to the
propensity of nonchelating aldehydes to engage in decarbon-
ylation,8−10 Tishchenko dimerizations,5 and aldol condensa-
tions, intermolecular hydroacylations are considerably more
challenging.11−13 Herein, we report the design and develop-
ment of the first enantioselective intermolecular ketone
hydroacylation.
We imagined a novel cross-coupling between a broad range
of aldehydes 1 and ketones bearing a directing group (DG) 2
(Scheme 1). On the basis of previous studies, we proposed that
this functional group would promote preferential ketone
binding to the Rh(I) center and favor chemoselective cross-
coupling over aldehyde dimerization or decarbonylation.9d,e,14
In the presence of a suitable bidentate phosphine ligand,
RESULTS AND DISCUSSION
■
Method Development. To test our hypothesis, we chose
hydrocinnamaldehyde (1a) and α-ketoamide 2a as model
substrates (Chart 1). A number of Rh-bis(phosphine) catalysts
were examined because previous studies in our lab had
demonstrated that these complexes promote intramolecular
ketone hydroacylation.7,15 After studying various ligands, we
found Rh(I)-Josiphos catalysts most promising. Commercially
available ligand L1 provides modest yield and 13% ee.
Changing to ligand L2, which contains a diphenylphosphine
and a dialkylphosphine, results in a small improvement in
enantioselectivity (21% ee). Josiphos L3 containing a more π-
accepting difurylphosphine and a σ-donating di-tert-butyl-
phosphine affords the desired α-acyloxyamide 3a in 46% yield
and 73% ee. We reason that this C1-symmetric ligand may
facilitate the product-determining hydride delivery via the trans
effect; the hydride trans to the electron-rich dialkylphosphine
becomes more hydridic, while the ketone trans to the π-
acceptor becomes more prone to insertion (Scheme 2).16,17
Inspired by L3, we created new Josiphos ligands to study the
steric influence of the phosphine substituents. In comparison to
Scheme 1. Proposed Rh(I)-Catalyzed Cross-Coupling of
Aldehydes and Ketones
Received: April 30, 2014
© XXXX American Chemical Society
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reported for reducing α-ketoamides, although with low
efficiency.24
Chart 1. Evaluation of Ligands for Enantioselective Ketone
Hydroacylation
a
Thus, with Rh-L5 in hand, we studied the coupling of α-
ketoamides 2 with nonchelating aliphatic aldehydes 1 (Table
1). Aryl ketones containing various substituents and sub-
stitution patterns undergo hydroacylation with hydro-
cinnamaldehyde (1a) (entries 1−7) and hexanal (1b) (entries
8−14) in good to high yields (53−98%) and high enantio-
selectivities (84−96%). Sterically demanding 2-methylphenyl
(entries 2 and 9), mesityl (entries 4 and 11), and 1-naphthyl
ketones (entries 5 and 12) tend to give higher conversions and
selectivities even with lower (5 mol %) catalyst loadings,
resulting in 73−98% yields of the α-acyloxyamides with 94−
96% ee. α-Ketoamides bearing smaller aryl groups, such as 3-
methylphenyl (entries 3 and 10), 4-chlorophenyl (entries 6 and
13), and 3,5-difluorophenyl groups (entries 7 and 14), require a
higher catalyst loading to provide the corresponding α-
acyloxyamides in 53−81% yields and 84−90% ee.
Sterically encumbered primary aldehydes (R = i-Bu and
neopentyl, entries 15−17) are effective coupling partners,
providing the desired products in high yields and ee. Using
aldehyde 1d and ketone 2e, we show that the reaction can also
be performed on a larger scale (1.0 mmol, 353 mg product
isolated, 91% yield, 93% ee) at 5 mol % catalyst loading (entry
16). The rhodium loading can be further reduced to 3.5 mol %
at elevated temperature conditions (60 °C), providing
hydroacylation product 3p in 92% yield and 87% ee (entry
17). Transforming α-branched cyclohexanecarboxaldehyde
(entry 18) requires elevated temperatures (50 °C) to proceed
and furnishes the desired α-acyloxyamide 3q in 57% yield and
90% ee. Aryl aldehydes do not participate in hydroacylation to
any appreciable extent under the current reaction conditions
(<5% conversion), perhaps due to a higher barrier to C−H
activation.25 Compared to the N,N′-alkylarylamide, ketones
containing N,N′-diaryl- or dialkylamides are also less effective
(entries 19 and 20) and provide α-acyloxyamides 3r and 3s
with modest yields and enantioselectivities. A cyclic ketoamide
is converted to 3-acyloxyindolinone 3t (entry 21) in 54% yield
and 58% ee. The efficacy of this reaction is improved by
employing L3, which provides heterocycle 3t in 88% yield and
69% ee. The amide motif impacts both reactivity and
enantioselectivity, presumably due to a directing group role.
The absolute configuration of the products was assigned
based on X-ray analysis of α-acyloxyamide 3c (see Supporting
Information).26 The observed S-enantiomer is consistent with a
proposed model that invokes the trans-effect in promoting the
product-determining ketone insertion step (Scheme 2). In this
model, the C1-symmetric ligand cooperatively renders the
hydride more nucleophilic and the ketone more electrophilic
(complex A), and thus substantially favors formation of the S-
stereoisomer in the case of (SP,R)-L5. Conversely, the
alternative complex B is stabilized by the trans-effect which
would result in an increased barrier to migratory insertion.16,17
We propose the acyl group to be situated on the “bottom”
apical position, with the less hindering N,N′-disubstituted
amide carbonyl bound to the “top” apical position. This ligand
arrangement minimizes unfavorable steric interactions between
the acyl group and the substituents on the phosphines and is
supported by DFT calculations.27
a
Conditions: 1a (1.2 equiv), 2a (1 equiv), [Rh(cod)2]BF4 (0.1 equiv),
ligand (0.1 equiv), DCE, rt (23 °C), 24 h.
Scheme 2. Proposed Model for Enantioinduction
commercial L3, ligand L4 bears bulkier adamantyl groups and
shows inferior performance. In contrast, L5 with bulkier π-
accepting dibenzofurylphosphines affords better results than L3
(65% yield, 87% ee). The Rh-L5 catalyst shows excellent
chemoselectivity with no observable aldehyde dimerization.4,5
Scope of Intermolecular Ketone Hydroacylation. This
mild Rh(I)-catalyzed method offers an attractive approach to
enantioenriched esters that are structurally related to those
obtained via the multicomponent Passerini reaction.19−21
A
conventional route to these motifs would involve enantio-
selective ketone reduction followed by an additional acylation
step (which generally requires stoichiometric activating agents)
to obtain the α-acyloxyamides. Moreover, the asymmetric
reduction of α-ketoamides has not been well-studied and
remains limited in scope and/or selectivity. A method featuring
Rh catalysis with bidentate amidophosphine−phosphinite
ligands appears most promising and has been applied to reduce
α-ketoamides with good enantioselectivity for a few aryl-
substituted ketones.22 There is one example of ruthenium-
catalyzed α-ketoamide hydrogenation where excellent ee was
achieved following recrystallization for a bulky tert-butyl-
substituted ketone.23 Biocatalytic methods have also been
We find that morpholine amides direct hydroacylation
effectively to yield cross-coupled products in good yields and
enantioselectivities (Table 2). A similar trend is observed in
which ketones bearing larger aryl groups perform better, both
B
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a b
,
Table 1. Coupling Aldehydes with α-Ketoamides
a
d
j
b
c
Conditions: 0.12 mmol of 1, 0.1 mmol of 2. The catalyst was activated by hydrogenation (see Supporting Information). Isolated yields.
e
f
g
h
i
Enantiomeric excess determined by chiral SFC analysis. See ref 18. At 60 °C. With 1.2 mmol of 1, 1.0 mmol of 2. At 50 °C, 4 days. For 3 days.
L3, 7.5 h.
in terms of isolated yields and enantioselectivities. Phenyl
ketone 4a is hydroacylated with 3,3-dimethylbutanal (1d) to
furnish ester 5a in 67% yield and 80% ee, whereas larger mesityl
and 1-naphthyl ketones give 5b and 5d in 94 and 75% yields,
respectively (95 and 92% ee). Other aldehydes including
cyclohexanecarboxaldehyde, hexanal, and hydrocinnamalde-
hyde are also good coupling partners. The use of the
morpholine amide as a directing group provides a handle for
further chemical manipulations.28
The Rh-L5 catalyst described in this study, however, is not
effective with α-keto-Weinreb amide 2k (Scheme 3). To this
end, we have identified an alternative rhodium catalyst derived
from methoxy-BIPHEP L6, which provides good reactivity and
modest enantioselectivity for this transformation to yield ester
6 (93%, 51% ee).
Investigation of the Kinetics of Intermolecular Hydro-
acylation. We initiated mechanistic studies by examining the
kinetics for the cross-coupling of aldehyde 1d and α-ketoamide
2e by 1H NMR. These particular substrates were chosen
1
because their H NMR signals are distinct and no products of
decomposition were observed over the course of reaction
progress, thus simplifying data analysis. Initial rates for the
hydroacylation of 2e were then measured by varying the
concentrations of 1d, 2e, and rhodium catalyst. These
experiments revealed a first-order dependence of the rate on
both aldehyde 1d (Figure 1) and ketone 2e concentrations
(Figure 2). More intriguing is the observed second-order rate
dependence on catalyst concentration (Figure 3), which
suggests the involvement of two rhodium species in the
turnover-limiting step. A study on the correlation between the
enantiomeric excess of the catalyst and that of the product
C
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Table 2. Ketone Hydroacylation Using Morpholine Amide
a b
,
Directing Group
Figure 1. Plot of initial rates (kobs) with respect to [aldehyde 1d]
showing first-order dependence; [2e] = 0.17 M, [catalyst] = 0.0083 M.
a
b
Conditions: 0.12 mmol of 1, 0.1 mmol of 2. The catalyst was
hydrogenated at rt for 45 min prior to adding substrates (see
c
Supporting Information). At 50 °C, 72 h.
Figure 2. Plot of initial rates (kobs) with respect to [α-ketoamide 2e]
showing first-order dependence; [1d] = 0.20 M, [catalyst] = 0.0083 M.
Scheme 3. Ketone Hydroacylation with Weinreb Amide
a
Directing Group
a
Conditions: 0.12 mmol of 1, 0.1 mmol of 2. The catalyst was
hydrogenated at rt for 45 min prior to adding substrates (see
Supporting Information).
Figure 3. Plot of initial rates (kobs) with respect to [catalyst]2 showing
second-order dependence; [1d] = 0.20 M, [2e] = 0.17 M.
yielded a small, positive nonlinear relationship (Figure 4).29
Such a phenomenon is consistent with the added degree of
complexity in the reaction mechanism as indicated by the
and 1.2 equiv of aldehyde at 25 °C, the initial turnover
frequency is determined to be 4.8 × 10−4 s−1.
Isotope Labeling Study. To gain further insight into the
mechanism, we measured the kinetic isotope effect (KIE) by
running two independent, side-by-side experiments using
protio-1a and deuterated 1a-D (Scheme 4).30 Aldehyde 1a-D
was chosen (over 1d and others) for this study due to ease of
isolation. Examination of the initial rates resulted in a KIE of
kinetic profile.
The rate data obtained from the kinetics experiments allowed
us to calculate initial turnover frequencies. Under standard
catalytic conditions using 5 mol % catalyst, 1.0 equiv of ketone,
D
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Scheme 5. Proposed Mechanism via Rate-Limiting Oxidative
Addition Catalyzed by Two Rhodium Centers
Figure 4. Relationship between the enantioselectivity of the reaction
and the ee of the chiral catalyst. Each data point was run in duplicate.
Scheme 4. KIE Measurement from Two Parallel Reactions
Using Method of Initial Rates
CONCLUSIONS
■
By developing a new Rh-Josiphos catalyst, we achieved the first
enantioselective intermolecular ketone hydroacylation, which
features the rare use of nonchelating aldehydes. Kinetic analysis
reveals a second-order rate dependence on the rhodium catalyst
and, together with a study on nonlinear relationship and the
KIE, points to a unique mechanism involving homobimetallic
oxidative addition as the turnover-limiting step. This work
provides a foundation for understanding C−H activation and
hydroacylation using nonactivated aldehydes which will guide
future studies and applications.
2.6 and supports C−H bond activation to be turnover-limiting.
This value is larger than that previously observed for an
intramolecular ketone hydroacylation where insertion was
implicated as the turnover-limiting step (KIE = 1.79
0.06).7b,31 The absence of a directing group on the aldehyde
in the present system likely increases the barrier to oxidative
addition significantly.32,33
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, X-ray crystallographic data, character-
ization data for new compounds, and chiral chromatographic
analyses. This material is available free of charge via the Internet
at http://pubs.acs.org.
■
S
On the basis of the kinetic analysis and KIE, we propose a
mechanism invoking homobimetallic activation34 of the
aldehyde where one rhodium catalyst acts as a Lewis acid by
coordinating the oxygen atom of the aldehyde and a second
rhodium catalyst participates in the oxidative addition of the
formyl C−H bond to produce acyl-Rh(III)-hydride IV
(Scheme 5).35 A report of cationic rhodium complexes
behaving as Lewis acid catalysts supports this proposal.36 In
addition, Lewis acid additives (i.e., ZnCl2, ZnBr2, ZnI2, etc.)
have been found to be beneficial in a study on intermolecular
alkene hydroacylation, although their role is unclear.37 The
mechanism proceeds with insertion to generate acyl-Rh(III)-
alkoxide V, followed by reductive elimination to furnish the
product and turnover the Rh(I) catalyst. It is possible for the
reaction to occur through bimetallic intermediates following
oxidative addition; however, reactive intermediates were not
observed spectroscopically.38 We believe that rapid coordina-
tion and dissociation of solvent and substrate leads to
broadening of the 31P NMR resonance signals and is thus
consistent with [Rh(diphosphine)(solvent)2]+ III being a
resting state.
AUTHOR INFORMATION
Corresponding Author
dongv@uci.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM105938) for
funding. K.G.M.K. is grateful for an NSERC CGS-D. D.N.L. is
grateful for an NSF Graduate Fellowship. We thank Lauren E.
Longobardi for studies using achiral catalysts, K.B. Schenthal
for entry 18 (Table 1), Van M.-T. Nguyen for preparing
substrate 2a, and Dr. Joseph W. Ziller for X-ray crystallographic
analysis.
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Dornan, P. K.; Kou, K. G. M.; Houk, K. N.; Dong, V. M. J. Am. Chem.
Soc. 2014, 136, 291.
(14) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 16330.
(15) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 15608.
(16) The trans-effect of unsymmetrical bidentate ligands in Pd-
catalyzed allylic substitutions has been reported: Tu, T.; Zhou, Y.-G.;
Hou, X.-L.; Dai, L.-X.; Dong, X.-C.; Yu, Y.-H.; Sun, J. Organometallics
2003, 22, 1255.
(17) Hasanayn, F.; Achord, P.; Braunstein, P.; Magnier, H. J.;
Krough-Jesperson, K.; Goldman, A. S. Organometallics 2012, 31, 4680.
(18) Measures were taken to ensure that the reported ee is
representative of the reaction and not an artifact of self-dispropor-
tionation of enantiomers (see Supporting Information). For an
example of self-disproportionation of enantiomers during achiral
phase silica gel chromatography, see: Soloshonok, V. A. Angew. Chem.,
Int. Ed. 2006, 45, 766.
(36) Dias, E. L.; Brookhart, M.; White, P. S. Chem. Commun. 2001,
423.
(37) Inui, Y.; Tanaka, M.; Imai, M.; Tanaka, K.; Suemune, H. Chem.
Pharm. Bull. 2009, 57, 1158.
(38) Rhodium-catalyzed hydroacylation has been described as a
“black box” due to difficulties in detecting reaction intermediates:
(a) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 946. (b) See ref
4.
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