A palladium-catalyzed enantioselective addition of arylboronic acids to cyclic ketimines

Article abstract of DOI:10.1002/anie.201302861

Sly as Nicox: A palladium-catalyzed addition of arylboronic acids to ketimines has been developed to efficiently provide products in up to 99 % yield and 96 % ee. The reactions could be run under aerobic conditions and with unpurified trifluoroethanol (TFE). A pyrrolidine compound bearing a chiral α-tertiary amine was synthesized in several steps without loss of enantioselectivity. TFA=trifluoroacetate. Copyright

Full text of DOI:10.1002/anie.201302861

Angewandte
Chemie
Communications
Asymmetric Catalysis
G. Yang, W. Zhang*
&&&& — &&&&
A Palladium-Catalyzed Enantioselective
Addition of Arylboronic Acids to Cyclic
Ketimines
Sly as Nicox: A palladium-catalyzed
oethanol (TFE). A pyrrolidine compound
addition of arylboronic acids to ketimines
has been developed to efficiently provide
products in up to 99% yield and 96% ee.
The reactions could be run under aerobic
conditions and with unpurified trifluor-
bearing a chiral a-tertiary amine was
synthesized in several steps without loss
of enantioselectivity. TFA=trifluoroace-
tate.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201302861
Asymmetric Catalysis
A Palladium-Catalyzed Enantioselective Addition of Arylboronic
Acids to Cyclic Ketimines**
Guoqiang Yang and Wanbin Zhang*
The construction of chiral quaternary stereocenters by
asymmetric catalysis remains a challenging proposition for
chemists.[1,2] Chiral a-tertiary amines reside within a wide
assortment of potent drugs and bioactive natural products,
therefore considerable effort has been directed toward their
asymmetric synthesis.[2] Among reactions involving the con-
struction of chiral a-tertiary amines,[3–9] asymmetric addition
to ketimines is a powerful strategy. Organocatalytic and chiral
Lewis acid catalyzed nucleophilic additions to ketimines have
been reported for the synthesis of chiral a-tertiary amines.[4,5]
Another convenient method involves the transition metal
catalyzed enantioselective addition of organometallic nucle-
ophiles. Despite the great advances in asymmetric transition
metal catalyzed additions of organometallic reagents to
imines,[10,11] the development of such reactions towards the
construction of chiral a-tertiary amines has had limited
success because of the steric and electronic factors.[2,6–9]
Several reports have described the copper- or zirconium-
catalyzed asymmetric addition of allylboronates or dialkyl-
zinc reagents to ketimines.[7] Alternatively, Hayashi and co-
workers pioneered rhodium-catalyzed asymmetric additions
for several kinds of ketimines and arylboron reagents with
various functional groups.[8,9] Although valuable progress has
been made, the asymmetric addition of arylboron reagents to
ketimines to give chiral a-diaryl alkyl amines (important
components of potent drugs)[12] suffers from limited substrate
scope.[8a,b] The asymmetric addition of arylboronic acids to
ketimines, is therefore still highly desired.
carbene palladium catalysts have shown excellent catalytic
activity.[14e] However, there are still no reports concerning the
palladium-catalyzed addition of arylboronic acids to keti-
mines (including the reaction producing racemic products),
and this may be due to the less nucleophilic nature of the
arylpalladium species compared with that of the arylrhodium
species.[15] Herein, we report the first ligand- and solvent-
assisted palladium-catalyzed addition of arylboronic acids to
ketimines, thus representing a practical enantioselective
synthesis of chiral a-diaryl alkyl amines under either an air
or oxygen atmosphere.
Recently, saccharin-derived cyclic ketimines bearing aryl
or carboxy substituents have been studied in the rhodium-
catalyzed addition of arylboron reagents because of the stable
[8c,d]
=
geometry and low electron density of the C N bond.
However, the addition of boronic acids to the slightly
electron-donating, alkyl-substituted, saccharin-derived cyclic
ketimines has never been explored. Additionally the sultam
products are an intriguing class of synthetic targets.[16] Thus,
the alkyl-substituted ketimine 1 was chosen as the substrate
for our palladium-catalyzed addition reaction. Using the n-
butyl-substituted 1a as the standard substrate, reaction
conditions for the palladium-catalyzed enantioselective addi-
tion of phenylboronic acid to the cyclic ketimine were
investigated (Table 1). Initial solvent screening showed that
catalysis in MeOH provided the most promising result
(entry 1; and see the Supporting Information). This may be
due to the beneficial effect MeOH has on the rate of the
transmetalation and protonation steps of the catalytic
cycle.[13m,p] Palladium black was formed in most of the other
tested solvents. Subsequently, different chiral pyridine-oxazo-
line-type ligands were screened (entries 1–8). iPr-Pyrox
provided the best results compared to iPr-Quinox and iPr-
Pyrim (entry 1 versus entries 2 and 3). The highest enantio-
selectivity was achieved when a tBu substituent was attached
to the oxazoline ring of Pyrox (92% ee), however reaction
yield was poor because of the steric hindrance (entry 7 versus
entries 1 and 4–6). It has been reported that an electron-
deficient ligand may improve palladium-catalyzed addition
reactions.[13q,14d] Therefore, tBu-Nicox was tested and a slightly
higher ee value and yield were obtained (entry 8).[17] Consid-
ering the formation of palladium black was due to the low rate
of the addition reaction and high rate of homocoupling, two
simple methods were considered to resolve this problem. One
method involved using oxygen to oxidize the Pd0 species to
regenerate the catalyst PdII with the help of a pyridine-
oxazoline-type ligand.[3i,18] The other method involved per-
forming the catalysis in the more polar and protic solvent,
TFE, which can stabilize the intermediates and transition
state of addition by decreasing the charge density, and
Palladium catalysis is a very attractive area for both
academia and industry. Although it has been applied to
conjugate addition reactions involving arylboron reagents,[13]
the palladium-catalyzed addition of arylboronic acids to
imines has become feasible only recently.[14] Subsequently,
several asymmetric approaches have been developed for
aldimine substrates,[14c–h] and chiral bidentate N-heterocyclic
[*] Dr. G. Yang, Prof. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
Homepage: http://wanbin.sjtu.edu.cn
[**] We thank Prof. Tsuneo Imamoto and Dr. Masashi Sugiya for helpful
discussion. This work was partially supported by the National
Natural Science Foundation of China (Nos. 21172143 and
21232004) and Science and Technology Commission of Shanghai
Municipality (No. 09JC1407800), and Nippon Chemical Industrial
Co., Ltd. Our thanks also go to the Instrumental Analysis Center of
Shanghai Jiao Tong University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302861.
2
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope of arylboronic acids.[a]
Entry
Sol.
L*
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TFE
iPr-Pyrox
iPr-Quinox
iPr-Pyrim
Bn-Pyrox
iBu-Pyrox
Ph-Pyrox
tBu-Pyrox
tBu-Nicox
tBu-Nicox
tBu-Nicox
tBu-Pyrox
tBu-Nicox
tBu-Nicox
48
48
48
48
48
48
48
48
48
1
96
47
56
94
95
89
26
35
67
99
78
99
99
70
À9
69
70
73
76
92
94
94
92
89
96
95
Entry
Ar
T [8C]
t []h
Yield [%][b]
ee [%][c]
1
2
Ph
40
40
40
40
60
60
60
80
40
40
60
60
80
80
40
40
40
80
24
24
12
24
26
16
24
48
12
18
48
24
48
48
12
12
24
24
99
99
98
95
99
99
95
94
90
95
94
94
94
93
95
95
92
95
87
–
4-MeC6H4
4-MeOC6H4
4-PhC6H4
4-ClC6H4
4-FC6H4
4-MeO2CC6H4
4-CF3C6H4
3-MeC6H4
3-MeOC6H4
3-ClC6H4
3[d]
4
7[d]
8[d]
9[d,e]
10[e]
11[e]
12[e,f]
13[f,g]
5
6
7
59 (78)[e]
95
TFE
TFE
TFE
24
24
24
8[e,f]
9
99
99
87
10[d]
11[e]
12
[a] Reactions were carried out in air on a 0.20 mmol scale using 10 mol%
[Pd(TFA)2], 15 mol% ligand in purified solvent (2.0 mL) and PhB(OH)2
(0.40 mmol) at 808C in a sealed tube. [b] Yield of isolated product.
[c] Determined by HPLC using a chiral Daicel column. [d] Palladium
black was formed. [e] Charged with oxygen. [f] Using 5 mol% Pd(TFA)2,
7.5 mol% ligand and 1.5 equiv of PhB(OH)2 at 408C. [g] In a test tube
which was opened to air. TFA= trifluoroacetic acetate, TFE=trifluor-
oethanol.
3-MeO2CC6H4
2-FC6H4
69 (84)[e]
47
13[e,f,g]
14[f,g]
15
2-MeOC6H4
3,5-Me2C6H3
3,4-(OCH2O)C6H3
2-naphthyl
3-thienyl
ca. 15[h]
99
95
93
96
90
16[d]
17
99
74 (87)[e]
89
18[e]
[a] Reactions were carried out in air on a 0.20 mmol scale using 5 mol%
Pd(TFA)2, 7.5 mol% ligand and ArB(OH)2 (0.30 mmol) in unpurified TFE
(2.0 mL) at a certain temperature in a test tube which was opened to air.
[b] Yield of isolated product. [c] Determined by HPLC using a chiral
Daicel column. [d] With 1.8 equiv of ArB(OH)2. [e] Sealed tube charged
with oxygen. [f] Using 10 mol% Pd(TFA)2 and 15 mol% ligand. [g] With
2.0 equiv of ArB(OH)2. [h] Determined by 1H NMR spectroscopy.
improve the protonation step. Both of these improved the
reaction outcome (entries 9 and 10). In TFE, the importance
of the electron-deficient nature of tBu-Nicox was observed
(entry 10 versus 11). Furthermore, the effects of TFE and tBu-
Nicox were so strong that the catalysis could be carried out at
408C with lower catalyst and phenylboronic acid loading
(5 mol% cat., 1.5 equiv of PhB(OH)2) (entry 12). Notably,
the reaction was insignificantly affected by performing the
catalysis in unpurified TFE under “open to air” conditions
(entry 13 versus 12).
Excellent yields were obtained for most of the reactions using
electron-rich and electron-deficient arylboronic acids
(entries 1–12). However, a decrease in reaction rate was
observed when electron-deficient arylboronic acids were used
(entries 5, 7, 8, 11, and 12). ortho-Substituents on the
arylboronic acids dramatically decreased the enantioselectiv-
ity and catalytic activity (entries 13 and 14), and arylboronic
acids possessing two substituents gave good results (entries 15
and 16). Fused-ring aryl or heteroaryl boronic acids could also
be used as the nucleophiles, thus providing the a-tertiary
amines in high ee values, albeit with slightly lower yields
(entries 17 and 18).
The catalyst loading could be lowered to 1 mol% by the
sequential addition of phenylboronic acid [Eq. (1)]. A one-
The ketimine substrate scope was also investigated
(Table 3). A range of ketimines possessing alkyl substituents
were tolerable to the enantioselective palladium-catalyzed
addition reaction (2aa–ga, 2 fb, 2 fc, 2gb, 2ha–ja). All of the
substrates with linear alkyl groups, including alkoxy-function-
alized substituents, gave excellent yields and good ee values
(2aa–ga, 2 fb, 2 fc, 2gb). The catalytic additions involving 5-
methyl-substituted ketimine gave the corresponding products
in high ee values (2ga and 2gb). The ee values and yields of
the catalysis involving substrates with branched and cyclic
alkyl substituents decreased (2ha–ja). Interestingly, the
reaction of phenyl-substituted substrates provided products
in good results (2ka and 2kb). Finally, the more electron-rich
portion addition of 1.2 equivalents of phenylboronic acid
resulted in the formation of palladium black on trace amounts
of product.
Having identified the catalytic system, a variety of
arylboronic acids were examined for addition to substrate
1a (Table 2). Electron-rich and electron-deficient arylboronic
acids had little influence on enantioselectivity (entries 1–12).
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Table 3: Scope of arylboronic acids.[a]
substrates remain a challenge for our catalytic system. The
electron-withdrawing alkyl group CF3 could improve the
reactivity of the substrate, thus giving the product in better
yield (72% under O2, 51% open to air), but has no effect on
the enantioselectivity (2na versus 2ma).
The stereochemical outcome can be explained using
a model shown in Figure 1. The nucleophilic aryl group
Figure 1. Stereochemical model.
bound to the Pd center is cis to the pyridine of Nicox, and the
imine is trans to the pyridine. The sterically favored inter-
mediate B, wherein the substrate coordinates to the palladium
with the -SO2- group oriented upward, (re-face) away from
the tert-butyl group of Nicox, leads to the optically major
product being the one we obtained.
A short synthesis of the chiral pyrrolidine compound 4
was also conducted (Scheme 1). The enantioselective cata-
Scheme 1. Transformations of chiral product. Boc=tert-butoxycar-
bonyl, DIAD=diisopropylazodicarboxylate, DMAP=4-(dimethylami-
no)pyridine, DME=1,2-dimethoxyethane, THF=tetrahydrofuran.
[a] Reactions were carried out in air on a 0.20 mmol scale using 5 mol%
Pd(TFA)2, 7.5 mol% ligand and ArB(OH)2 (0.30 mmol) in unpurified TFE
(2.0 mL) at 408C in a test tube for 24 h which was opened to air. [b] Yield
of isolated product. The ee values were determined by HPLC using
a chiral Daicel column. [c] 36 h. [d] 18 h. [e] 808C. [f] 608C. [g] Sealed
tube charged with oxygen. [h] With 1.8 equiv of ArB(OH)2 for 12 h.
[i] Using 10 mol% Pd(TFA)2 and 15 mol% ligand. [j] 48 h. [k] Another
1.5 equiv of PhB(OH)2 was added after 24 h. [l] The absolute config-
urations of 2ka and 2kb were determined to be R by comparison of its
optical rotation and HPLC retention time with the literature value.[8c,d]
The others were proposed according to this result.
lytic addition of piperonylboronic acid to substrate 1e
provided the product 2eb with good ee value and in 99%
yield. The chiral polycyclic compound 3, an analogue of
selective non-nucleoside HIV-1 reverse transcriptase inhib-
itors[12a] and agents for treating diabetes,[12b] was obtained by
benzyl removal from 2eb and subsequent Mitsunobu reac-
tion. No loss of enatiomeric purity was observed. This product
could be further transformed in moderate overall yield to the
pyrrolidine structure 4, thus bearing a chiral a-tertiary amine
motif (93% ee) through removal of the SO2 group and
installation of the Boc group.
ketimine substrates, the products of which also may be
synthetically useful, showed lower reactivity but provided
high enantioselectivities (2la and 2ma). These kinds of
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Morimoto, S. Matsunaga, M. Shibasaki, Angew. Chem. 2011, 123,
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In summary, we have developed the first catalytic system
of the palladium-catalyzed addition of arylboronic acids to
ketimines. The catalysis is highly efficient with good enantio-
seletivities and yields (up to 96% ee and 99% yield).
Additionally, the majority of the reactions could be per-
formed in open air and with unpurified TFE solvent. A wide
range of cyclic N-sufonyl ketimines and arylboronic acids are
tolerated under the reaction conditions.
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Received: April 6, 2013
Published online: && &&, &&&&
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Keywords: amines · asymmetric catalysis · enantioselectivity ·
heterocycles · palladium
.
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