Asymmetric suzuki cross-couplings of activated secondary alkyl electrophiles: Arylations of racemic α-chloroamides

Article abstract of DOI:10.1021/ja105148g

A nickel-catalyzed stereoconvergent method for the enantioselective Suzuki arylation of racemic α-chloroamides has been developed. This process provides a unique example of an asymmetric arylation of an α-haloamide, an enantioselective arylation of an α-chlorocarbonyl compound, and an asymmetric Suzuki reaction with an activated alkyl electrophile or an arylboron reagent. The method is also applicable to the corresponding enantioselective cross-coupling of α-bromoamides. The coupling products can be transformed without racemization into enantioenriched α-arylcarboxylic acids and primary alcohols. A modest kinetic resolution of the α-chloroamide was observed; a mechanistic study indicated that the selectivity may reflect discrimination by the chiral catalyst of the two enantiomeric α-chloroamides in an irreversible oxidative-addition process.

Full text of DOI:10.1021/ja105148g

Published on Web 07/27/2010
Asymmetric Suzuki Cross-Couplings of Activated Secondary Alkyl
Electrophiles: Arylations of Racemic r-Chloroamides
Pamela M. Lundin and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 12, 2010; E-mail: gcf@mit.edu
Table 1. Effect of Some Reaction Parameters on the Asymmetric
Suzuki Arylation of a Racemic R-Chloroamidea
Abstract: A nickel-catalyzed stereoconvergent method for the
enantioselective Suzuki arylation of racemic R-chloroamides has
been developed. This process provides a unique example of an
asymmetric arylation of an R-haloamide, an enantioselective
arylation of an R-chlorocarbonyl compound, and an asymmetric
Suzuki reaction with an activated alkyl electrophile or an arylboron
reagent. The method is also applicable to the corresponding
enantioselective cross-coupling of R-bromoamides. The coupling
products can be transformed without racemization into enan-
tioenriched R-arylcarboxylic acids and primary alcohols. A modest
kinetic resolution of the R-chloroamide was observed; a mecha-
nistic study indicated that the selectivity may reflect discrimination
by the chiral catalyst of the two enantiomeric R-chloroamides in
an irreversible oxidative-addition process.
entry
variation from the “standard” conditions
ee (%)
yield (%)b
1
2
3
4
5
6
7
8
none
no NiBr2 ·diglyme
no (S,S)-1
92
-
89
<2
8
-
no i-BuOH
-
8
water instead of i-BuOH
(S,S)-2 instead of (S,S)-1
r.t.
91
85
82
91
-
25
74
84
78
6
4% NiBr2 ·diglyme, 5% (S,S)-1
9
X ) NBnPh
Enantioenriched R-arylcarboxylic acids that bear a tertiary R
stereocenter, including arylpropionic acids such as naproxen, serve
as important therapeutics as well as useful intermediates in organic
synthesis.1,2 Although the cross-coupling of enolates with aryl
electrophiles has not yet proved to be a viable route to the generation
of such compounds,3 a few reports have described the umpolung
approach, i.e., the coupling of an R-halocarbonyl compound with
an aryl nucleophile. Whereas organozinc,4 organosilicon,5 and
organomagnesium6 reagents have been employed in such processes
(with R-bromoketones and R-bromoesters), organoboron compounds
have not.7-10 In this report, we establish that a chiral nickel catalyst
can achieve asymmetric cross-couplings of arylboron reagents with
racemic R-haloamides to generate tertiary R-arylcarbonyl com-
pounds in good ee (eq 1).
10
11
12
13
14
X ) NPh2
-
4
X ) NEt2
76
<5
26
50
19
84
82
74
X ) NMe(OMe)
X ) NHMe
X ) OEt
a All data are averages of two experiments. b The yield was
determined by GC or 1H NMR analysis versus an internal standard.
In the absence of NiBr2 ·diglyme, essentially no carbon-carbon
bond formation is observed (entry 2 of Table 1), and, in the absence
of ligand 1, the cross-coupling proceeds very slowly (entry 3). If
i-BuOH is omitted, the reaction is also sluggish (entry 4), and, if
water is used in place of i-BuOH, the product is generated with
good enantioselectivity but modest yield (entry 5). The cross-
coupling occurs with somewhat lower ee if ligand 2 is employed
rather than ligand 1 (entry 6) or if it is conducted at room
temperature (entry 7). Use of less catalyst leads to a slightly
diminished yield (entry 8). A variety of other R-chloroamides (both
tertiary and secondary) as well as an R-chloroester are less suitable
cross-coupling partners than the indolinylamide (entries 9-13).
Cross-couplings that illustrate the scope of this new stereocon-
vergent method for the synthesis of R-arylcarboxylic acid derivatives
are provided in Table 2.13 Functional groups such as an olefin and
a silyl ether (entries 3 and 4), as well as ꢀ-branching (entry 5), are
tolerated in the alkyl side chain of the electrophile. For the
nucleophile, a meta (entries 6 and 7) or para (entries 8 and 9)
substituent can be present, and it can be electron-withdrawing (entry
6) or electron-donating (entries 7 and 8). This asymmetric Suzuki
cross-coupling proceeds with comparable efficiency on a gram scale,
and the product amide can be recrystallized to >99% ee (entry 2 of
After surveying an array of reaction parameters, we determined
that NiBr2 ·diglyme/1 can catalyze the cross-coupling of an R-chlo-
robutyramide with Ph-(9-BBN) in good ee and yield (entry 1 of
Table 1). The cross-coupling illustrated in entry 1 is noteworthy in
part because there are no previous examples of enantioselective
arylations of R-haloamides, asymmetric Suzuki reactions of acti-
vated alkyl electrophiles or arylboron11 reagents, or enantioselective
arylations of R-chlorocarbonyl compounds.12 Both NiBr2 ·diglyme
and ligand 1 are commercially available.
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J. AM. CHEM. SOC. 2010, 132, 11027–11029 11027

C O M M U N I C A T I O N S
Table 2. Asymmetric Suzuki Arylations of R-Chloroamides
catalyst, or it could result from excellent discrimination but some
reversibility in the oxidative addition to nickel.17
(see eq 1)a
yield (%)b
In order to gain insight into this issue, we examined the Suzuki
arylation of the individual enantiomers of the R-chloroamide (eqs
6 and 7). In each of these cross-couplings, the ee of the unreacted
electrophile at partial conversion is essentially unchanged, consistent
with irreversible oxidative addition under the reaction conditions.
Consequently, the ee observed in eq 5 for the recovered R-chlo-
roamide likely reflects the inherent selectivity of the chiral catalyst
toward the two enantiomers of the electrophile in the oxidative-
addition step of the catalytic cycle (selectivity factor ≈ 1.8).
entry
R
Ar
ee (%)
1
2
3
4
5
6c
7
8
9
Et
Me
Ph
Ph
Ph
Ph
Ph
92
87
90
84
85
92
92
90
94
78
88
80
80
84
76
84
80
70
CH2CHdCH2
CH2CH2OTBS
i-Bu
Et
Et
3-ClC6H4
3-MeC6H4
4-OMeC6H4
4-FC6H4
Et
Et
a All data are averages of two experiments. b Yield of purified
product. c Using 10% NiBr2 ·diglyme and 12.5% (S,S)-1.
Table 2: 92% ee and 88% yield before recrystallization; >99% ee
and 70% yield after recrystallization).
This method for catalytic enantioselective carbon-carbon
bond formation was developed and optimized for Suzuki
arylations of R-chloroamides. Nevertheless, it can be applied
without modification to a racemic R-bromoamide, providing
comparable results (eq 2).
The data in eqs 6 and 7 illustrate that NiBr2 ·diglyme/(S,S)-1
transforms each enantiomer of the R-chloroamide into the same
enantiomer of the product in essentially identical ee. This confirms
the dominant role played by the chirality of the catalyst rather than
the substrate in determining the ee of the product.
The products of these asymmetric cross-coupling reactions can
be reduced to primary alcohols (83%; eq 3) or converted into
R-arylcarboxylic acids (e.g., an arylpropionic acid; eq 4). No
racemization is observed.
In conclusion, we have developed a nickel-catalyzed stereocon-
vergent method for the enantioselective Suzuki arylation of racemic
R-chloroamides that employs commercially available catalyst
components (NiBr2 ·diglyme and ligand 1). This process represents
the first example of an asymmetric arylation of an R-haloamide,
an enantioselective arylation of an R-chlorocarbonyl compound,
and an asymmetric Suzuki reaction with an activated alkyl
electrophile or an arylboron reagent. The method is also applicable
to the corresponding enantioselective cross-coupling of R-bromo-
amides. The coupling products can be transformed without rac-
emization into useful enantioenriched R-arylcarboxylic acids and
primary alcohols. An unprecedented (and modest) kinetic resolution
of the R-chloroamide has been observed; a mechanistic study
indicated that the selectivity likely reflects the discrimination by
the chiral catalyst of the two enantiomeric R-chloroamides in an
irreversible oxidative-addition process. Further efforts to develop
catalytic asymmetric methods for cross-coupling alkyl electrophiles,
as well as additional mechanistic studies, are underway.
As for the other nickel-catalyzed enantioselective cross-couplings
of alkyl electrophiles that have been described to date,4-6,8a,14 this
new asymmetric Suzuki reaction is also stereoconvergent: both
enantiomers of the racemic starting material are preferentially
converted into the same enantiomer of the product. However, in
contrast to all of the other processes, in these Suzuki arylations the
unreacted electrophile is kinetically resolved15 with a significant
ee (eq 5).16
Acknowledgment. We thank Dr. Francisco Gonza´lez-Bobes for
preliminary studies. Support was provided by the National Institutes
of Health (National Institute of General Medical Sciences, Grant
R01-GM62871), Eli Lilly (fellowship to P.M.L.), Novartis (fel-
lowship to P.M.L.), and the Merck Research Laboratories.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Our observation that the recovered R-chloroamide is not racemic
indicates that the enantiopure catalyst has the ability to differentiate
between the two enantiomers of the starting material. The moderate
ee of the unreacted electrophile even at high conversion could be
due to modest differentiation of the enantiomers by the chiral
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