Catalytic asymmetric synthesis of secondary nitriles via stereoconvergent negishi arylations and alkenylations of racemic α-bromonitriles

Article abstract of DOI:10.1021/ja303442q

The first method for the stereoconvergent cross-coupling of racemic α-halonitriles is described, specifically, nickel-catalyzed Negishi arylations and alkenylations that furnish an array of enantioenriched α-arylnitriles and allylic nitriles, respectively. Noteworthy features of this investigation include: the highly enantioselective synthesis of α-alkyl-α-aryl nitriles that bear secondary α-alkyl substituents; the first examples of the use of alkenylzinc reagents in stereoconvergent Negishi reactions of alkyl electrophiles; demonstration of the utility of a new family of ligands for asymmetric Negishi cross-couplings (a bidentate bis(oxazoline), rather than a tridentate pybox); in the case of arylzinc reagents, carbon-carbon bond formation at a remarkably low temperature (-78 °C), the lowest reported to date for an enantioselective cross-coupling of an alkyl electrophile; a mechanistic dichotomy between Negishi reactions of an unactivated versus an activated secondary alkyl bromide.

Full text of DOI:10.1021/ja303442q

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Synthesis of Secondary Nitriles via
Stereoconvergent Negishi Arylations and Alkenylations of Racemic
α-Bromonitriles
Junwon Choi and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
(sulfonyl)nitriles in the presence of an achiral palladium
catalyst.7c In the case of two enantioenriched electrophiles (one
ABSTRACT: The first method for the stereoconvergent
cross-coupling of racemic α-halonitriles is described,
specifically, nickel-catalyzed Negishi arylations and alke-
nylations that furnish an array of enantioenriched α-
arylnitriles and allylic nitriles, respectively. Noteworthy
features of this investigation include: the highly
enantioselective synthesis of α-alkyl-α-aryl nitriles that
bear secondary α-alkyl substituents; the first examples of
the use of alkenylzinc reagents in stereoconvergent Negishi
reactions of alkyl electrophiles; demonstration of the utility
of a new family of ligands for asymmetric Negishi cross-
couplings (a bidentate bis(oxazoline), rather than a
tridentate pybox); in the case of arylzinc reagents,
carbon−carbon bond formation at a remarkably low
temperature (−78 °C), the lowest reported to date for
an enantioselective cross-coupling of an alkyl electrophile;
a mechanistic dichotomy between Negishi reactions of an
unactivated versus an activated secondary alkyl bromide.
unhindered and one doubly activated), he established that
carbon−carbon bond formation proceeds with inversion of
stereochemistry with little or no erosion in ee; on the other
hand, Falck did not describe the stereochemical outcome for
Suzuki couplings of electrophiles that bear a secondary alkyl
substituent. In this report, we provide a complementary
approach wherein a chiral catalyst achieves stereoconvergent
Negishi cross-couplings of racemic electrophiles with aryl, as
well as with alkenyl, nucleophiles (eq 1).
any bioactive compounds bear a cyano group attached
Negishi reactions are an especially attractive family of cross-
coupling processes, due to the compatibility of organozinc
reagents with a wide range of functional groups and the typical
lack of a need for a stoichiometric quantity of a Brønsted-basic
additive.8 In previous studies, we determined that several
classes of activated electrophiles are suitable coupling partners
in asymmetric Negishi alkylations or arylations; in every
instance, nickel with a pybox ligand proved to be the catalyst of
choice.9,10 Unfortunately, however, when we applied any of the
arylation methods to the phenylation of an α-bromonitrile, we
obtained disappointing results (<40% ee).
We decided to look beyond tridentate pybox ligands, and
after substantial effort we determined that the Negishi
phenylation of an α-bromonitrile can be achieved in good ee
and yield in the presence of NiCl2·glyme and a new, readily
available bis(oxazoline) ligand11 (94% ee, 98% yield; Table 1,
entry 1).12 The reaction proceeds at −78 °C, which is, to the
best of our knowledge, the lowest temperature that has been
employed for a cross-coupling of an alkyl electrophile.13
As illustrated in Table 1, essentially no cross-coupling of the
α-bromonitrile is observed in the absence of NiCl2·glyme
(entry 2) or of bis(oxazoline) L (entry 3), as well as when an
M
to a stereogenic carbon.1 Furthermore, nitriles serve as
versatile precursors to a diverse array of molecules, including
heterocycles, aldehydes, ketones, amides, carboxylic acids, and
amines.2 Enantioenriched α-alkyl-α-arylnitriles are particularly
noteworthy targets, since they can be transformed into α-aryl
carboxylic acids such as α-arylpropionic acids, which are widely
used as nonsteroidal anti-inflammatory drugs (e.g., naproxen).3
A variety of methods have been described for the catalytic
asymmetric synthesis of α-alkyl-α-arylnitriles.4−6 For example,
nickel-catalyzed hydrocyanation of vinylarenes can generate α-
methyl-α-arylnitriles with excellent ee; however, there have
been no reports of corresponding highly enantioselective
hydrocyanations of substituted styrenes to produce nitriles
that bear α-alkyl substituents larger than methyl. The conjugate
addition of H−CN to β-aryl-α,β-unsaturated carbonyl com-
pounds provides an alternate route to α-alkyl-α-arylnitriles,
although current methods generally only furnish products with
α-alkyl groups that are primary.
We have been interested in exploring the catalytic
asymmetric synthesis of secondary α-arylnitriles through the
reaction of an aryl nucleophile with a nitrile that bears a leaving
group geminal to the cyano substituent; to the best of our
knowledge, there is no precedent for this transformation using a
chiral catalyst.7 However, while our study was underway, Falck
reported an important investigation of Suzuki arylations of α-
Received: April 10, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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Table 1. Stereoconvergent Negishi Phenylation of a Racemic
α-Bromonitrile: Effect of Reaction Parameters
Table 2. Stereoconvergent Negishi Phenylations of Racemic
α-Bromonitriles
a
a
b
entry
variation from the “standard″ conditions
ee (%)
yield (%)
1
none
94
−
<2
90
4
98
<2
3
2
no NiCl2·glyme
no L
3
4
PhZnX, instead of Ph2Zn
r.t., instead of −78 °C
1, instead of L
6
5
16
89
88
32
25
48
68
6
84
8
7
2, instead of L
8
3, instead of L
8
9
4, instead of L
32
93
93
10
11
0.6 equiv Ph2Zn
5% NiCl2·glyme, 6.5% (S,S)-L
a
b
All data are the average of two experiments. Yield determined by
GC analysis versus a calibrated internal standard.
arylzinc halide is employed as the nucleophilic reaction partner
(entry 4). The reaction proceeds in poor ee and yield when
conducted at room temperature (entry 5), and ligands other
than L provide modestly (bis(oxazoline) 1; entry 6) or
substantially (bis(oxazoline) 2, pybox 3, and 1,2-diamine 4
(entries 7−9)) inferior results. Use of less Ph2Zn (entry 10) or
less catalyst (entry 11) leads to a decrease in yield, but no loss
in enantioselectivity.
a
b
All data are the average of two experiments. Yield of purified
c
d
product. Reaction temperature: −60 °C. Yield determined by GC
analysis versus a calibrated internal standard.
Table 3. Stereoconvergent Negishi Arylations of Racemic
Bromonitriles
a
With our optimized method, asymmetric Negishi cross-
couplings of Ph2Zn with a range of racemic α-bromonitriles
proceed efficiently, furnishing α-phenylnitriles in good ee and
yield (Table 2).14 A wide variety of functional groups are
compatible with the reaction conditions, including an ether
(entry 5), a carbamate (entry 6), an amide and a heterocycle
(entry 7), a sulfonamide (entries 8 and 9), an unactivated alkyl
chloride (entry 9), and an alkene (entries 11 and 12). In view of
the limitations of other methods for generating highly
enantioenriched α-alkyl-α-arylnitriles in the case of branched
alkyl groups (e.g., via asymmetric hydrocyanation; vide supra),
our high ee’s for Negishi cross-couplings of hindered
electrophiles (entries 1−9) are particularly noteworthy.
This process for the Negishi arylation of α-bromonitriles is
not limited to phenylation reactions. Thus, we can cross-couple
with a range of nucleophiles in uniformly high ee and yield
(Table 3), regardless of whether the aryl group is electron-rich
(entries 1−3) or electron-poor (entry 4).15
a
b
All data are the average of two experiments. Yield of purified
Although we have previously described examples of stereo-
convergent Negishi reactions of activated electrophiles with
alkyl- and arylzinc reagents, we have never been able to achieve
corresponding cross-couplings with alkenylzinc reagents.9 We
c
product. Reaction temperature: −60 °C.
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were therefore pleased to determine that we can apply the
conditions (except reaction temperature16) that we developed
for enantioselective Negishi arylations (Table 3) of α-
bromonitriles to alkenylations (Table 4).17 Thus, as depicted
Table 4. Stereoconvergent Negishi Alkenylations of Racemic
a
α-Bromonitriles
Negishi reaction of the electrophile illustrated in eq 4. If radical
cyclization is occurring, but the acyclic radical preferentially
proceeds to the cross-coupling product (Curtin−Hammett
scenario), then the Z stereochemistry of the starting material
would not be preserved in the acyclic product. However, we
observe only the Z isomer, which suggests that radical
cyclization is not occurring in this Negishi reaction of an α-
bromonitrile, in contrast to our previous studies of cross-
couplings of unactivated secondary alkyl bromides.21
a
b
All data are the average of two experiments. Yield of purified
product.
In summary, we have developed the first method for the
stereoconvergent cross-coupling of racemic α-halonitriles,
specifically, nickel-catalyzed Negishi arylations and alkenyla-
tions that generate a variety of useful enantioenriched
secondary α-arylnitriles and allylic nitriles, respectively. With
regard to accessing secondary α-alkyl-α-arylnitriles, this work
complements other prominent approaches, which are most
effective for the synthesis of products in which the alkyl group
is methyl (hydrocyanation of olefins) or a primary alkyl
substituent (conjugate addition of HCN). For the first time for
studies of asymmetric Negishi cross-couplings, an alkenylzinc
reagent can serve as an effective nucleophilic partner, and a
ligand other than a tridentate pybox is the ligand of choice; this
latter observation is significant for future explorations of
enantioselective Negishi reactions. Couplings with arylzinc
reagents occur at a remarkably low temperature (−78 °C), the
lowest temperature reported to date for such asymmetric
carbon−carbon bond-forming processes. Finally, a mechanistic
study provides a contrast between nickel-catalyzed Negishi
reactions of unactivated versus activated secondary alkyl
bromides. An array of additional investigations of enantiose-
lective cross-couplings of alkyl electrophiles are underway.
in Table 4, we can accomplish an array of asymmetric
alkenylations with good ee, thereby providing ready access to
enantioenriched allylic nitriles.18 No racemization or isomer-
ization (to the conjugated nitrile) of the allylic nitrile is
observed under these mild conditions.
The enantioenriched allylic nitriles are suitable substrates for
stereoselective functionalizations. For example, osmium-cata-
lyzed dihydroxylation proceeds with good diastereoselectivity
(eq 2).
We have previously proposed that a radical intermediate may
be involved in the oxidative-addition step of certain nickel-
catalyzed cross-couplings of unactivated secondary alkyl
halides.19 One observation consistent with this hypothesis is
the stereochemistry of cyclization/cross-couplings of electro-
philes that bear pendant olefins. We have now determined that,
as for Hiyama and Suzuki reactions,20 Negishi reactions of
secondary bromides 5 and 6 proceed with the same
diastereoselectivities as observed for reductive cyclizations of
these substrates by Bu3SnH, which is consistent with a common
intermediate (I) in the cyclization step for all of these processes
(eq 3).
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.
In this regard, it is interesting to note that the substrates
depicted in entries 11 and 12 of Table 2, which have the
potential to cyclize/cross-couple to furnish five-membered
rings, afford only acyclic coupling products. To gain insight into
whether cyclization of a radical intermediate might be
occurring, but reversibly, in enantioselective cross-couplings
of α-bromonitriles that bear pendant olefins, we examined the
AUTHOR INFORMATION
■
Corresponding Author
gcf@mit.edu
Notes
The authors declare no competing financial interest.
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(13) For enantioselective Kumada reactions of α-haloketones that
proceed at −60 °C, see: Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
1264−1266.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01−
GM62871) and the Kwanjeong Educational Foundation
(fellowship to J.C.). We thank Dr. Ashraf Wilsily for assistance
in the preparation of substrates.
(14) Under our standard conditions: on a gram-scale, the asymmetric
Negishi reaction illustrated in entry 8 of Table 2 proceeds in 90% ee
and 93% yield; if PhMgBr is employed as the nucleophile (Table 2,
entry 2), Kumada coupling occurs in 88% ee and 6% yield; there is no
erosion in the enantiomeric excess of the product during the course of
a cross-coupling; an α-chloronitrile and an α-iodonitrile cross-couple
in significantly lower ee (chloride) and/or yield (chloride and iodide);
diethylzinc and alkylzinc halides are not suitable cross-coupling
partners.
(15) Under our standard reaction conditions, essentially no cross-
coupling is observed when (o-tol)2Zn is employed as the nucleophile.
(16) The cross-coupling proceeds in high ee, but somewhat slowly, at
−78 °C.
(17) Under our standard reaction conditions, divinylzinc cross-
couples in 55% ee and 80% yield.
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