Intramolecular aminocyanation of alkenes by cooperative palladium/boron catalysis

Article abstract of DOI:10.1021/ja4122632

A cooperative palladium/triorganoboron catalyst to accomplish the intramolecular aminocyanation of alkenes through the cleavage of N-CN bonds is reported. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) is found to be crucial as a ligand for palladium to effectively catalyze the transformation with high chemo- and regioselectivity. A range of substituted indolines and pyrrolidines with both tetra- or trisubstituted carbon and cyano functionalities are readily furnished by the newly developed cyanofunctionalization reaction. A preliminary example of enantioselective aminocyanation is also described.

Full text of DOI:10.1021/ja4122632

Communication
pubs.acs.org/JACS
Intramolecular Aminocyanation of Alkenes by Cooperative
Palladium/Boron Catalysis
Yosuke Miyazaki,† Naoki Ohta,† Kazuhiko Semba,† and Yoshiaki Nakao*,†,‡
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
‡ACT-C, Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
A key to realizing aminocyanation is the activation of N−CN
bonds of cyanamides by metal catalysts. Indeed, the catalytic
cleavage of N−CN bonds has been reported only very recently,10
whereas the reactivity of cyanamides and their use in synthetic
organic chemistry have been studied extensively,11 wherein very
harsh reaction conditions are required for the cleavage of the
unreactive N−CN bonds.12 We have demonstrated that the use
of Lewis acid cocatalysts significantly affects the rate of nickel-
catalyzed carbocyanation13 and palladium-catalyzed oxycyana-
tion8 reactions, possibly by promoting the oxidative addition of
C−CN14 and O−CN bonds through coordination of a cyano
group to a Lewis acid catalyst in an η1 fashion. Therefore, we
examined the reaction of N-cyano-N-[2-(2-methylallyl)phenyl]-
acetamide (1a)15 to ascertain the viability of the aminocyanation
reaction through N−CN bond activation by taking advantage of
cooperative catalysis. Screening of several combinations of metal
ABSTRACT: A cooperative palladium/triorganoboron
catalyst to accomplish the intramolecular aminocyanation
of alkenes through the cleavage of N−CN bonds is
reported. 4,5-Bis(diphenylphosphino)-9,9-dimethylxan-
thene (Xantphos) is found to be crucial as a ligand for
palladium to effectively catalyze the transformation with
high chemo- and regioselectivity. A range of substituted
indolines and pyrrolidines with both tetra- or trisubstituted
carbon and cyano functionalities are readily furnished by
the newly developed cyanofunctionalization reaction. A
preliminary example of enantioselective aminocyanation is
also described.
yanofunctionalization reactions across unsaturated car-
Cbon−carbon bonds have been studied extensively because complexes, ligands, and Lewis acids led us to find that reaction
conditions very similar to those for the intramolecular oxy-
cyanation8 employing CpPd(allyl) (10 mol %), 4,5-bis-
(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)16 (10
mol %), and BEt3 (40 mol %) allowed the intramolecular
insertion of the double bond of 1a into the N−CN bond in a 5-
exo-trig manner to give 2-(1-acetyl-2-methylindolin-2-yl)-
acetonitrile (2a) in 82% yield after 3 h in toluene at 80 °C
(reaction scheme in Table 1). BPh3 also showed good activity. As
in the case of oxycyanation, the Pd/Xantphos/triorganoboron
catalysts are exceptionally effective; poor to modest yields were
obtained with the related bisphosphine ligands DPEphos (entry
1) and Nixantphos (entry 2), whereas other mono- and
diphosphanes gave no trace amounts of 2a. In many cases,
modest to good conversions of 1a were noted; however, reaction
quenching by filtration through a silica gel pad resulted mainly in
protodecyanation of 1a. The use of other Lewis acids such as
B(C6F5)3 (entry 3) and AlEt3 (entry 4) and the absence of a
Lewis acid catalyst (entry 5) were futile. Nevertheless, the
prolonged reaction with B(C6F5)3 in the absence of CpPd(allyl)
at a higher temperature gave a small amount of 2a (entry 6),
while BPh3 alone did not show any detectable amount of product
(entry 7). The preliminary but interesting reactivity observed
with B(C6F5)3 would be an issue for further investigation. Other
palladium sources were far less effective than CpPd(allyl)
(entries 8−11). Palladium(II) sources such as PdCl2 and
Pd(OAc)2 are reluctant to be reduced to palladium(0) species
under these reaction conditions, partly because of the inability of
of their utility in accessing highly functionalized nitriles, which
are found in a number of pharmaceutical drugs, agrochemicals,
and optoelectronic materials as well as synthetic intermediates
for carboxylic acids, esters, amides, and amines. Starting from
simple and readily available substrate sets, silylcyanation,1
germylcyanation,2 stannylcyanation,3 borylcyanation,4 carbocya-
nation,5 thiocyanation,6 bromocyanation,7 and most recently
oxycyanation8 of alkynes and/or alkenes have been realized by
metal catalysis to give nitriles having a functional group at the
position β to the cyano group. We report herein the
intramolecular aminocyanation of alkenes through N−CN
bond activation by cooperative palladium/boron catalysis. We
also demonstrate the first catalytic enantioselective amino-
cyanation reaction. Aminocyanation had never been achieved
until the very recent report on the three-component coupling of
alkenes, N-fluorobenzenesulfonimide, and Me3SiCN by copper
catalysis to achieve net aminocyanation.9 The transformation
serves as an ideal protocol to directly give β-aminonitriles, which
function as synthetic precursors for highly important building
blocks such as β-amino acids and 1,3-diamines (Scheme 1).
Scheme 1. Aminocyanation of Unsaturated Compounds
Received: December 2, 2013
Published: February 28, 2014
© 2014 American Chemical Society
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Table 1. Intramolecular Aminocyanation of Alkenes with 1a:
Effect of Reaction Parameters
Table 2. Intramolecular Aminocyanation of Alkenes
Catalyzed by Pd/BR3
a
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
DPEphos instead of Xantphos (with BPh3)
Nixantphos instead of Xantphos (with BPh3)
B(C6F5)3 instead of BR3
6
45
1
AlEt3 instead of BR3
<1
2
without BR3
bc
,
6
7
B(C6F5)3 instead of BR3 without CpPd(allyl)
without CpPd(allyl) (with BPh3)
11
<1
<1
<1
19
24
1
8
[PdCl(allyl)]2 instead of CpPd(allyl) (with BPh3)
PdCl2 instead of CpPd(allyl) (with BPh3)
Pd(OAc)2 instead of CpPd(allyl) (with BPh3)
Pd(dba)2 instead of CpPd(allyl) (with BPh3)
Ni(cod)2 instead of CpPd(allyl) (with BPh3)
9
10
11
12
bd
,
a
b
c
Yields estimated by GC. Run on a 0.10 mmol scale. Run at 80 °C
d
for 39 h and then at 120 °C for 47 h. Run for 16 h.
the triorganoboranes to achieve the reduction in the absence of
nucleophilic and/or basic additives. Although Pd(OAc)2 could
be reduced by Xantphos, this would give oxidized ligands, leading
to an insufficient amount of an active catalyst species and thus
resulting in poor conversion. On the other hand, CpPd(allyl) has
been known to undergo reductive elimination of the Cp and allyl
groups upon coordination of phosphorus ligands to give a
palladium(0) species.17 The observed poor activity of Pd(dba)2
can be ascribed to the dibenzylideneacetone (dba) ligand, which
inhibits the reaction in a manner yet to be identified. The
reaction under the optimized reaction conditions with BEt3 in
the presence of added dba (20 mol %) gave 2a in 29% yield after
6 h. Finally, a nickel catalyst was completely ineffective (entry
12).
The standard reaction conditions on a 1.0 mmol scale for 6 h
gave 2a in 93% yield, even with a decreased amount of the
catalysts (5 mol % Pd/Xantphos; 20 mol % BEt3), after
purification by medium-pressure column chromatography on
silica gel (Table 2, entry 1). N-Boc variant 1b underwent the
reaction in even higher yield when BPh3 was used (entry 2).
Substituents on the double bond in 1 can be varied; ethyl (entry
3) and (tert-butyldimethylsilyloxy)methyl (entry 4) were
tolerated, whereas the aminocyanation across a conjugated
double bond was sluggish (entry 5).18 Unlike oxycyanation,8 the
cyclization of N-(2-allylphenyl)-N-cyanoacetamide (1f) and its
Boc variant 1g proceeded smoothly to give 2f and 2g having a
trisubstituted carbon (entries 6 and 7), without possible β-
hydride elimination (vide infra). 4-Methoxy-, 4-chloro-, and 2-
methyl-substituted variants 1h−j also underwent the amino-
cyanation (entries 8−10). While a range of 2,2-disubstituted and
2-monosubstituted indolines were successfully accessed by the
present protocol, 2-substituted tetrahydroquinoline 2k was
obtained in modest yield through a seemingly reluctant 6-exo-
trig cyclization (entry 11). On the other hand, the use of BPh3 as
a
b
c
Isolated yields. Run on a 0.30 mmol scale. Run on a 0.50 mmol
d
e
f
scale. 82% conversion of 1e. Run on a 0.20 mmol scale. 91%
conversion of 1k. 91% conversion of 1n.
g
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the Lewis acid allowed the N−CN bond activation of cyanamides
derived from aliphatic amines to afford variously substituted
pyrrolidines in modest to good yields (entries 12−14). We found
that decyanation competed as a byproduct-forming process,
resulting in modest yields of the aminocyanation products
(entries 5, 11, and 14). In addition, a mixture of cyclic products
lacking a cyano group, which were likely derived from β-hydride
elimination before C−CN bond-forming reductive elimination
(vide infra), was also noted (entries 11 and 14).
Although detailed mechanistic studies have yet to be
undertaken, the reaction would be initiated by oxidative addition
of the N−CN bond in 1, which is coordinated to the boron Lewis
acid catalyst through a cyano group, to a Pd(0)−Xantphos
complex (Scheme 2). Syn aminopalladation19 in an exo-trig
not proceed at all in the absence of BPh3 under the same reaction
conditions even after 22 h. Thus, the coordination of a cyano
group to a Lewis acidic boron center is likely to induce the N−
CN bond activation. Coordination of the aminocarbonyl
functionality to a palladium center would be rather important
to suppress competitive β-hydride elimination of alkylpalladium
intermediate 5 (R2 = H), which is the case with oxycyanation
because of the lack of such O substituents.8 The C(sp3)−CN
bond-forming reductive elimination can also be effected by the
coordination of a cyano group to the Lewis acid23 as well as the
bidentate phosphorus ligand with a large bite angle.16
In view of the importance of chiral β-amino acids and
indolines, the development of an enantioselective amino-
cyanation was sought. Although most known chiral bidentate
ligands were ineffective in terms of reactivity, we identified
(R,R,R)-Ph-SKP, which was recently developed by Wang and
Ding,24 as a promising lead for the enantioselective amino-
cyanation. Thus, the reaction of 1b using the aforementioned
chiral ligand instead of Xantphos allowed the cyclization to
proceed in a highly enantioselective manner to give optically
active indoline 2b in good yield (eq 2). The use of (R,R,R)-Tol-
Scheme 2. Plausible Catalytic Cycle
fashion is followed by C−CN bond-forming reductive
elimination to give boron-bound 2, and transfer of the boron
catalyst to unreacted 1 regenerates the catalytically active
palladium and 1−boron complexes. Coordination of the
aminocarbonyl functionality in 1 to a boron catalyst cannot be
ruled out to justify the pronounced effect of the Lewis acid.
Indeed, N-benzyl and N-unsubstituted variants of 1a did not
undergo the cyclization. On the other hand, we have previously
shown that a cyano group coordinates to a Lewis acid
preferentially over an aminocarbonyl moiety in the oxidative
adduct derived from cyanoformamides, Ni(cod)2, and BPh3.20
To gain insights into the oxidative addition step, stoichiometric
reactions were examined.21 Gratifyingly, the reaction of Ph(Ac)-
N−CN, Pd(PPh3)4, and BPh3 in benzene at 80 °C gave oxidative
adduct 6, which was characterized by NMR spectroscopy and X-
ray crystallography (eq 1).22 The observed oxidative addition did
SKP also allowed the enantioselective aminocyanation of 1g to
give a modest yield of 2g having a chiral trisubstituted carbon (eq
2). (R,R,R)-Ph-SKP gave a lower yield of 2g (∼20%) but with
very similar enantioselectivity (er 89:11).
In summary, we have developed an intramolecular amino-
cyanation of alkenes by palladium/boron catalysis.25 The
transformation allows for simultaneous installation of a tetra-
or trisubstituted carbon and a cyano group through N−CN bond
activation to afford variously substituted indolines and
pyrrolidines, including optically active examples, which can be
of interest as synthetic building blocks. Synthetically, the
aminocyanation demonstrated herein can be a CO- and/or
oxidant-free alternative to alkene aminocarbonylation and other
aminofunctionalization reactions catalyzed by palladium.26
Current efforts are directed toward further development of the
enantioselective aminocyanation and more detailed mechanistic
studies.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, including spectroscopic and
analytical data, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
nakao.yoshiaki.8n@kyoto-u.ac.jp
■
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(18) The reactions of substrates bearing 1,2-disubstituted and
trisubstituted double bonds were unsuccessful, giving decyanation
products in modest yields.
Notes
The authors declare no competing financial interest.
(19) (a) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644.
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review of migratory insertion of alkenes into metal−nitrogen bonds, see:
Hanley, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 8510.
(20) Hirata, Y.; Yada, A.; Morita, E.; Nakao, Y.; Hiyama, T.; Ohashi,
M.; Ogoshi, S. J. Am. Chem. Soc. 2010, 132, 10070.
(21) The attempted reactions of CpPd(allyl) or Pd(PPh3)4 with
Xantphos, Ph(Ac)N−CN, and BPh3 were sluggish.
(22) The use of PPh3 (20 mol %) instead of Xantphos under the
optimized reaction conditions with 1a gave no trace amount of 2a.
(23) Huang, J.; Haar, C. M.; Nolan, S. P.; Marcone, J. E.; Moloy, K. G.
Organometallics 1999, 18, 297.
ACKNOWLEDGMENTS
■
We thank Profs. Seijiro Matsubara and Keisuke Asano for their
assistance in chiral HPLC analysis and Profs. Yasushi Tsuji and
Tetsuaki Fujihara for generous use of their X-ray diffraction
instrument and their assistance in X-ray crystallographic analysis.
This work was financially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” (22105003) from
MEXT, the ACT-C Program of JST, The Uehara Memorial
Foundation, and The Asahi Glass Foundation.
(24) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012,
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