Catalytic enantioselective decarboxylative cyanoalkylation of imines by using palladium pincer complexes with C2-symmetric chiral Bis(imidazoline)s

Article abstract of DOI:10.1002/chem.201203782

Manifold products: The enantioselective decarboxylative Mannich-type reaction of cyanoacetic acid with N- (2-pyridinesulfonyl)imines catalyzed by chiral 1,3-bis(imidazolin-2-yl)benzene (Phebim)-Pd^II complexes afforded products with good enantioselectivity (see scheme). The reaction was applied to a wide range of imines with good yield and enantioselectivity. The obtained products can be converted into various compounds without the loss of enantiopurity. Copyright

Full text of DOI:10.1002/chem.201203782

DOI: 10.1002/chem.201203782
Catalytic Enantioselective Decarboxylative Cyanoalkylation of Imines by
Using Palladium Pincer Complexes with C2-Symmetric Chiral
Bis(imidazoline)s
Kengo Hyodo, Masaru Kondo, Yasuhiro Funahashi, and Shuichi Nakamura*[a]
Optically active b-aminonitriles are very important chiral
building blocks, because they can be easily converted into
either b-aminocarboxylic acids or 1,3-diamino compounds.[1]
Furthermore, b-aminonitriles are important structural motifs
in biologically active compounds such as ruxolitinib,[2] isoin-
doline derivatives,[3] and alkyl nitrile quinolones.[4]
metal catalysts and an enantioselective reaction with imines
has been reported.[7,8] On the other hand, there is only one
study on the enantioselective decarboxylative addition reac-
tion of a-cyanoacetic acids as cyanoalkylating reagents to
imines.[9,10] Shibasaki et al. reported the pioneering work for
the highly enantioselective decarboxylative addition of acti-
vated benzylic a-cyano carbanions to imines by using (R)-
(À)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphi-
no]-4,4’-bi-1,3-benzodioxole (DTBM-SEGPHOS)–CuOAc
as catalyst to give b-aminonitriles having a quaternary ster-
eocenter with high enantioselectivity.[11] Despite the impres-
sive progress achieved in catalytic enantioselective reaction
of benzylic a-cyano carbanions with imines, the enantiose-
lective reaction of more simple alkylnitriles remains un-
solved probably due to their low acidity and the low steric
hindrance of alkylnitriles. Therefore, expanding the scope of
enantioselective decarboxylative reactions of simple alkylni-
triles by using novel catalyst systems with acceptable catalyt-
ic activity and stereoselectivity would be highly desirable.
Recently, we developed the highly enantioselective reaction
of benzylnitriles with imines by using palladium pincer com-
plexes with 1,3-bis(imidazolin-2-yl)benzene (Phebim).[7b,12,13]
Herein, our ongoing interest was extended to an enantiose-
lective decarboxylative reaction of a-cyanoacetic acids with
imines by using bis(imidazoline)-palladium pincer com-
plexes (Figure 1). The coordination of palladium to cyanide
Therefore, the catalytic enantioselective synthesis of
chiral b-aminonitriles has received considerable attention.
One of the most efficient methods for the preparation of
chiral b-aminonitriles is the catalytic enantioselective reac-
tion of imines with a-cyano carbanions. Although the prepa-
ration of a-cyano carbanions from a-cyano esters, a-sulfonyl
nitriles, malononitriles, a-aryl- or a-allylnitriles is easy, the
generation of a-cyano carbanions from simple alkylnitriles
is not a trivial task due to the low acidity of the a protons
for alkyl nitriles (CH3CN: pKa =31.3 and 28.9 in DMSO and
in water, respectively) in comparison with a-aryl- or a-allyl-
nitriles (PhCH2CN: pKa =21.9 in DMSO).[5] The in situ gen-
eration of a-cyano carbanions from simple alkyl nitriles gen-
erally requires strong bases, such as lithium diisopropyl-
ACHTUNGTRENNUNGamide (LDA) or phosphazenes, which place a severe limita-
tion on the chemoselective activation in a catalytic manner.
Therefore, the development of an easy preparation of a-
cyano carbanions is highly desired.[6] Recently, the enhance-
ment of the acidity of alkylnitriles by using chiral transition-
Figure 1. Enantioselective decarboxylative cyanoalkylation of a-cyano-
acetic acids with imines by using chiral palladium complexes.
in a-cyanoacetic acids enhances the stability of the a-cyano
carbanions, followed by the Mannich-type reaction of the a-
cyano carbanions with imines, giving b-aminonitriles.
We first examined the enantioselective decarboxylative
Mannich-type reaction of cyanoacetic acid (2a) (3.0 equiv)
with the various imines 1a–e (1.0 equiv) by using 5 mol% of
the palladium catalysts 4a–e at room temperature. The re-
sults are shown in Table 1.
[a] K. Hyodo, M. Kondo, Prof. Y. Funahashi, Prof. S. Nakamura
Department of Frontier Materials
Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax : (+81)52-735-5245
E-mail: snakamur@nitech.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203782.
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Chem. Eur. J. 2013, 19, 4128 – 4134

COMMUNICATION
Table 1. Enantioselective reaction of cyanoacetic acid (2a) with the vari-
ous imines 1a–e by using catalysts 4a–e.[a]
Table 2. Enantioselective reaction of cyanoacetic acid (2a) with various
imines 1e–o using catalyst 4b.[a]
Entry
Ar
Product
t [h]
Yield [%]
ee [%]
1
2
Ph (1e)
3e
3 f
3g
3h
3i
3j
3k
3l
96
36
36
36
168
90
168
168
168
168
168
82
82
79
70
83
73
78
80
60
62
78
88
85
87
80
84
84
72
75
80
90
90
3-ClC6H4 (1 f)
3-BrC6H4 (1g)
3-FC6H4 (1h)
3-MeOC6H4 (1i)
1-naphthyl (1j)
2-naphthyl (1k)
2-furyl (1l)
3-furyl (1m)
2-thienyl (1n)
3-thienyl (1o)
3[b]
4
5
6[b]
7
Entry
Imine
Catalyst
t [h]
Yield [%]
ee [%][b]
8
9
10
11
3m
3n
3o
1
2[c]
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4b
4b
168
168
168
168
96
48
24
48
69
17
–
66
9
–
[a] Py=pyridyl. [b] KOTf (10 mol%) was added.
–
–
77
81
81
76
19
49
82
69
71
72
73
68
49
46
88
90
11).[16] To the best of our knowledge, this is the first report
on the highly enantioselective decarboxylative Mannich-
type reaction of cyanoacetic acid.
Next, we examined the reaction of imine 1e with the sub-
stituted a-cyanoacetic acids 2b and 2c (Scheme 1). Al-
though the reaction of 2-cyano-2-methylpropionic acid (2c)
with imine 1e by using complex 4b and AgOTf did not
afford a product, the reaction of 2-cyanopropionic acid (2b)
with imine 1e gave product 3p in moderate yield with high
enantioselectivity but with low diastereoselectivity.
168
168
96
10
11[d]
12[d,e]
90
[a] Boc=tert-butoxycarbonyl. [b] ee=enantiomeric excess. [c] The reac-
tion was carried out without AgOTf. [d] The reaction was carried out at
08C by using 2.0 equivalents of cyanoacetic acid. [e] KOTf (OTf=tri-
flate) (10 mol%) was added.
Although the reaction of imine 1a with 2a by using cata-
lyst 4a only afforded product 3a in low yield, the reaction
by using 5 mol% of 4a and AgOTf afforded 3a in high
yield with moderate enantioselectivity (Table 1, entries 1
and 2). The reaction of N-diphenylphosphonyl imine (1b) or
N-Boc imine (1c) did not afford products (Table 1, entries 3
and 4). We also tried to use the N-(heteroarenesulfonyl)-
imines 1d and 1e (Table 1, entries 5 and 6).[14] The reactivity
can be improved by a pyridyl group in the reaction of N-(2-
pyridinesulfonyl)imine (1e). To improve the enantioselectiv-
ity, we next optimized the structure of the catalysts. After
fine-tuning the various substitutions on the nitrogen atom,
the bis(imidazoline) having an acetyl group (R1) and phenyl
groups (Ar) was found to be the best catalyst (Table 1, en-
tries 7–10).[15] When the reaction was carried out at a lower
temperature, the enantioselectivity was slightly improved
(Table 1, entry 11). The addition of KOTf also slightly im-
proved the enantioselectivity of the reaction (Table 1,
entry 12).
Scheme 1. Reaction of imine 1e with a-substituted 2-cyanoacetic acids by
using complex 4b and AgOTf as catalyst.
On the other hand, the reaction of 1e with ethyl cyano-
AHCTUNGTREGaNNNU cetate by using 4b and AgOTf afforded the a,b-unsaturat-
ed a-cyano ester 5, which was obtained by the elimination
reaction of pyridinesulfonamide from the addition product
(Scheme 2). This result clearly shows the superiority of the
reaction by using cyanoacetic acid as a cyanomethylating re-
agent over the reaction that uses cyanoacetate.
With these optimized conditions, the reaction of cyano-
acetic acid (2a) with a series of imines 1e–o by using
5 mol% of catalyst 4b and AgOTf was examined (Table 2).
The reaction with both electron-donating and electron-with-
drawing imines (i.e., imines 1e–i) gave products 3e–i in
good yield with good enantioselectivity (Table 2, entries 1–
5). Naphthyl and heteroaryl imines afforded products 3j–o
in good yield with high enantioselectivity (Table 2, entries 6-
Scheme 2. Reaction of imine 1e with ethyl cyanoacetate by using com-
plex 4b and AgOTf as catalyst.
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S. Nakamura et al.
The products 3 are versatile intermediates in organic syn-
thesis and can be readily converted into important chiral
building blocks (Scheme 3). For example, hydrolysis of the
cyano group in N-(2-pyridinesulfonyl)aminonitrile (3e) by
using 50% H2O2 and K2CO3 in DMSO afforded the b-ami-
noamide 6 in high yield without any racemization.[7c]
tion of cyanoacetic acid undergoes the formation of a palla-
dium ketenimide complex, which reacts with imines, and
2) the deprotonation of the a-proton of the cyano group of
cyanoacetic acid and the nucleophilic reaction of the keten-
AHCTUNGTREGiNNNU mide to imines precedes the decarboxylation (Figure 2).
Figure 2. Reaction pathways for the decarboxylative Mannich-type reac-
tion.
In order to clarify the reaction pathway, we performed at-
mospheric-pressure chemical ionization (APCI) mass spec-
troscopic analysis of the reaction mixture of cyanoacetic
acid (2a) with pyridinesulfonylimine 1e in THF. The APCI
mass spectra showed the a-cyano-b-aminopropionic acid in-
termediate (cation mode, m/z calcd for C15H14N3O4S: 332.1;
found: 332.2). On the other hand, the reaction of the a,a-
disubstituted a-cyanoacetic acid 2c with imine 1e did not
afford a product (Scheme 1). Furthermore, the treatment of
cyanoacetic acid (2a) with complex 4b and AgOTf without
imine did not allow the decarboxylation reaction of cyano-
acetic acid to proceed. These results indicate that the first
reaction step would be a nucleophilic reaction of the a-
cyano carbanion of cyanoacetic acid to the imines, followed
by decarboxylation from the addition product (Figure 2,
path b).
Scheme 3. Transformation of the optically active b-aminonitrile 3e.
Product 3e could be converted to the enantiomerically
enriched b-amino acid 7 through hydrolysis by using HCl.[17]
On the other hand, the reduction of the cyano group in 3e
was carried out by using NiCl2·6H2O, NaBH4, and (Boc)2O
to give the chiral diamine 8.[18]
Furthermore, we also synthesized the key intermediates
for the PDE-4 inhibitor (Scheme 4). The deprotection of the
pyridinesulfonyl group from N-(2-pyridinesulfonyl)aminoni-
The proposed catalytic cycle for the generation of the a-
cyano carbanion and the reaction with the imines are shown
in Figure 3. The addition of AgOTf causes the exchange re-
action of bromide in 4b to triflate (complex A). The ligand
exchange reaction of triflate to cyanoacetic acid gave com-
plex B. Complex B can be deprotonated by a weak base,
such as triflate or pyridine in imine 1e, due to the stabiliza-
tion of the ketenimide from cyanoacetic acid by the biden-
tate coordination to palladium, to give the palladium keten-
AHCTUNGTRENNUNG
imide (complex C).[20,21] The next step is the nucleophilic re-
Scheme 4. Synthesis of the key intermediate of the PDE4 inhibitor.
action of complex C with the imine to give complex D,
which subsequently undergoes protonation and decomplexa-
tion to give product 3e and regenerates complex A. In
order to clarify the assumed reaction mechanism, we per-
formed an APCI mass spectroscopic analysis for the reac-
tion mixture of cyanoacetic acid (2a) with pyridinesulfonyl-
trile (3e) by using magnesium in methanol afforded the b-
aminonitrile 9. The imide formation reaction of 9 with 3-ni-
trophthalic anhydride gave the key intermediate for the op-
tically active PDE-4 inhibitor 10 without a loss of enantio-
purity.[3] On the other hand, the absolute configuration of 9
was assigned as R after conversion to the N-tosylated b-ami-
nonitrile,[19] and the stereochemistry of other products was
tentatively assumed by analogy.
AHCTUNGTREGiNNUN mine 1e. Complex B could be observed in this reaction
mixture (cation mode, m/z calcd for C43H36N5O4Pd as com-
plex [B+H+]: 792.2; found: 792.2). This signal supports our
proposed reaction mechanism.
Two possible reaction pathways can be expected in the re-
action of cyanoacetic acid with imines: 1) the decarboxyla-
We also confirmed the structures of the palladium pincer
complex 4b by X-ray crystal structure analysis (Figure 4).
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Catalytic Enantioselective Decarboxylative Cyanoalkylation of Imines
COMMUNICATION
LANL2DZ level (Figure 5).[23]
The calculation showed that
the carboxyl group in cyano-
acetic acid coordinated to pal-
ladium, and the cyano group in
cyanoacetic acid also coordi-
nated to palladium (see the
Supporting Information). The
natural bond orbital (NBO)
analysis[24] for complex
C
shows interaction between the
CN group of the ketenimide
and the palladium cation. The
stabilization energy for this in-
teraction was estimated to be
6.1 kcalmolÀ1. Based on the
absolute configuration of the
products, the proposed transi-
tion state for the enantioselec-
tive reaction of the palladium
ketenimide with imine 1e is
shown in Figure 5. By avoiding
steric repulsion, imine 1e ap-
proaches from the Re face of
the imine to react with the pal-
ladium ketenimide to give the
(R) isomer.[25] Further studies
Figure 3. Proposed catalytic cycle for the decarboxylative Mannich-type reaction.
are required to fully elucidate
the mechanistic detail of the
reaction.
In conclusion, we developed the first highly enantioselec-
tive decarboxylative Mannich-type reaction of cyanoacetic
acid with N-sulfonylimines by using chiral palladium pincer
complexes of 1,3-bis(imidazolin-2-yl)benzene to give prod-
ucts with good enantioselectivity. A range of imines can be
tolerated in the process. This process offers a simple and ef-
ficient route for the synthesis of b-aminonitriles and their
derivatives. Further experiments are in progress to study the
scope of this process and the potential application of the bis-
(imidazoline)-palladium pincer catalyst to other reactions.
Figure 4. X-ray crystal structure of complex 4b·2CHCl3. Hydrogen atoms
and chloroform molecules have been omitted for clarity.
The bis(imidazoline) ligand is
coordinated to the PdII center
through two nitrogen atoms in
the imidazoline and one
carbon atom of the aryl group
in a tridentate manner. The
palladium pincer complex 4b
possesses an approximate C2
symmetry. The complex 4b
features a nearly square planar
PdII center.
Based on this structure, we
next examined the molecule
orbital (MO) calculation of
complex C between complex
4b and cyanoacetic acid by
Figure 5. MO calculation of complex C by using Gaussian 09 B3LYP/LANL2DZ and assumed transition state
for the reaction. Hydrogen atoms have been omitted for clarity.
using a Gaussian 09[22] B3LYP/
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S. Nakamura et al.
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Experimental Section
Typical procedure for the reaction of a-cyanoacetic acids with N-(2-pyri-
dinesulfonyl)imines catalyzed by chiral Phebim–PdII complexes
(R)-2-(2-Pyridinesulfonyl)amino-2-phenylpropionitrile: Compound 2a
(40.1 mg, 0.472 mmol) and N-sulfonylimine 1e (58.1 mg, 0.236 mmol)
were added to a mixture of AgOTf (3.0 mg, 11.8 mmol), complex 4b
(9.3 mg, 11.8 mmol), and molecular sieves 4 ꢁ (90 mg) in THF (1.5 mL)
at 08C. After disappearance of the N-sulfonylimine monitored by TLC,
the reaction was quenched by adding a saturated aqueous solution of
NaHCO3. The crude mixture was filtered through celite and washed with
AcOEt (Ac=acyl, 10 mL). The aqueous layer was extracted with
AcOEt, the combined organic layers were washed with brine, and dried
over Na2SO4. Filtration and removal of solvent under reduced pressure
gave a residue, which was purified by column chromatography (benzene/
CH3CN=90:10) giving product 3e (55.4 mg, 82%) as a white solid.
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Acknowledgements
This work was supported by the Teijin Pharma Award in Synthetic Or-
ganic Chemistry, Japan and a Sasagawa Scientific Research Grant from
the Japan Science Society. We thank Prof. Norio Shibata at Nagoya Insti-
tute of Technology for unrestricted access to analytical facilities.
Keywords: asymmetric catalysis
·
decarboxylation
·
imidazolines · nitriles · palladium · pincer complexes
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Catalytic Enantioselective Decarboxylative Cyanoalkylation of Imines
COMMUNICATION
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Received: October 23, 2012
Published online: February 27, 2013
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Chem. Eur. J. 2013, 19, 4128 – 4134