Catalytic asymmetric umpolung reactions of imines

Article abstract of DOI:10.1038/nature14617

The carbon-nitrogen double bonds in imines are fundamentally important functional groups in organic chemistry. This is largely due to the fact that imines act as electrophiles towards carbon nucleophiles in reactions that form carbon-carbon bonds, thereby

Full text of DOI:10.1038/nature14617

LETTER
doi:10.1038/nature14617
Catalytic asymmetric umpolung reactions of imines
Yongwei Wu1, Lin Hu1, Zhe Li1 & Li Deng1
The carbon–nitrogen double bonds in imines are fundamentally rarely reported11–14. Aiming at the realization of highly efficient cata-
important functional groups in organic chemistry. This is largely lytic asymmetric umpolung reactions of imines, we embarked on a
due to the fact that imines act as electrophiles towards carbon search for catalysts to both promote the formation of carbanions from
nucleophiles in reactions that form carbon–carbon bonds, thereby imines and direct the carbanions thus formed to react with carbon
serving as one of the most widely used precursors for the formation electrophiles to generate chiral amines in an asymmetric fashion.
of amines in both synthetic and biosynthetic settings1–5. If the
We recently reported that modified cinchona alkaloids such as the
carbon atom of the imine could be rendered electron-rich, the
imine could react as a nucleophile instead of as an electrophile.
Such a reversal in the electronic characteristics of the imine
functionality would facilitate the development of new chemical
transformations that convert imines into amines via carbon–carbon
bond-forming reactions with carbon electrophiles, thereby creating
new opportunities for the efficient synthesis of amines. The develop-
ment of asymmetric umpolung reactions of imines (in which the
imines act as nucleophiles) remains uncharted territory, in spite of
the far-reaching impact such reactions would have in organic
synthesis. Here we report the discovery and development of new
chiral phase-transfer catalysts that promote the highly efficient
asymmetric umpolung reactions of imines with the carbon electro-
phile enals. These catalysts mediate the deprotonation of imines
and direct the 2-azaallyl anions thus formed to react with enals in a
highly chemoselective, regioselective, diastereoselective and enantio-
selective fashion. The reaction tolerates a broad range of imines
and enals, and can be carried out in high yield with as little as
0.01 mole per cent catalyst with a moisture- and air-tolerant opera-
tional protocol. These umpolung reactions provide a conceptually
new and practical approach to chiral amino compounds.
Umpolung reactions create new activities by reversing the inherent
polarity of common organic functionalities such as carbonyls and
consequently allow the development of new reactions of distinct bond
connections6. The successful development of numerous C–C bond-
forming umpolung reactions with carbonyls as acyl anion equivalents
has greatly expanded the repertoire of organic synthesis7–9. The power
of carbonyl umpolung reactions has been tapped for asymmetric syn-
thesis through the successful development of efficient chiral catalysts
for enantioselective Stetter reactions and other asymmetric reactions10.
In contrast, C–C bond-forming umpolung reactions of imines are
quinine-derived (Q) catalyst Q-2 could promote highly enantioselec-
tive isomerization of trifluoromethyl imines such as 1 (Fig. 1)15,16. This
reaction presumably proceeds through the initial formation of the
2-azaallyl anion 3, and then a highly enantioselective protonation
of 3. This discovery prompted us to postulate that, if the 2-azaallyl
anion 3 could be made to react with carbon electrophiles in a stereo-
selective manner, novel C–C bond-forming asymmetric reactions
transforming imines 1 into enantioenriched amines could be realized
(Fig. 1). Although numerous catalytic asymmetric C–C bond-forming
reactions with enolates derived from glyoxylateimines14 and
glycine imines17 have been documented for the synthesis of amino
acids, only two catalyticasymmetric C–Cbond-forming reactionswith
2-azaallyl anions have been reported18,19. The palladium-catalysed
cross-coupling of 2-azaallyl anions with aryl halides and triflates
remains the sole example of highly enantioselective C–C bond-form-
ing reactions with 2-azaallyl anions18.
Guided by these considerations, we investigated quinine- and qui-
nidine-derived (QD) organocatalysts Q-2, QD-11 and QD-12 for the
reaction of imine 1A and crotonaldehyde (8a) (Table 1). None of them
was active towards the desired C–C bond-forming reaction; only
the isomerized imine 4A was detected. These catalysts promoted the
deprotonation of trifluoromethyl imine 1A to form the 2-azaallyl
anion 3, but were unable to direct the conjugate addition of 3 to
crotonaldehyde. Presumably, the protonated cinchona alkaloids
formed on deprotonation of 1A rapidly protonate 3 to form 4A. As
the 2-azaallyl anion 3 was shown to engage in protonation in the
presence of a proton donor, we surmise that a novel class of catalysts
must be developed to afford the required chemoselectivity in favour of
the C–C bond formation over the protonation.
We decided to explore chiral phase-transfer catalysts20. Under
phase-transfer catalysis conditions, stronger bases could be explored
Discovery
CF3
CF3
Protonation
HCl
N
R
Q-2,
(10 mol%)
NO2
N
H2N
H
R
OMe
N
O2
N
O2
R
CF3
4
5 (80–94% e.e.)
1
OH
OMe
N
H
δ
Postulation
Et
C3
OH
N
X
F
3C
N
R
X
δ
Carbon
F
3C
R
N
electrophiles
HCl
C1
R
CF3
Et
Cl
N
*
N
R′
H2N
*
3
*
X
2
Q-
*
R′
N
O2
C–C bond formation
R′
7
6
Cl
Figure 1
|
Design of a catalytic C–C bond-forming umpolung reaction of imines. See text for details.
1Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.
2 3 J U L Y 2 0 1 5
| V O L 5 2 3 | N A T U R E | 4 4 5
G
2015 Macmillan Publishers Limited. All rights reserved

RESEARCH LETTER
Table 1
|
Experiments with chiral base catalysts
Ar
Ar
CHO
Ar
δ
Ar
Ar
CHO
N
CHO
Base
N
8a
N
N
N
+
+
PhMe
δ
H
3C
Ar = 4-NO2Ph
H
3C
10Aa
CF3
H
3C
CF3
H
CF3
3C
H
CF3
3C
F
3C
3A
1A
9Aa
4A
OMe
N
OMe
N
OH
Et
OPHN
Et
OH
OH
N
N
N
Et
=
PHN
N
O
Q-2
QD-11
QD-12
Cl
Entry
T ( uC)
Catalyst
Conversion (%)
9/4
1
2
3
RT
RT
RT
Q-2
QD-11
QD-12
84
32
9
0/100
0/100
0/100
Conditions: room temperature (RT), 10 mol% catalyst, 16 h.
for the deprotonation of imine 1 to form 2-azaallyl anion 3. anion, is noteworthy. However, amine 9Aa was formed with moderate
Furthermore, in the absence of a protonated cationic species, 3 should diastereoselectivity and poor enantioselectivity.
be less prone to protonation and therefore more likely to engage in the
addition to 8a. A cinchonine-derived (C) phase-transfer catalyst C-13
was first investigated to promote the reaction of 1A and 8a in toluene
and aqueous KOH at room temperature. The desired amine 9Aa was
formed, albeit in minuscule amounts (entry 1, Table 2). Importantly,
the chemoselectivity for the C–C bond formation could be improved
with catalyst C-14 bearing PYR, a bulky heteroaryl group (see Table 2
for details), although both the reaction conversion and the chemos-
electivity remained poor (entry 2, Table 2). Subsequently, we found
that a reaction at lower temperature afforded significantly improved
conversion and chemoselectivity. The absence of 10Aa, which would
be formed by conjugate addition from the other end of the 2-azaallyl
Introducing an additional interaction between a conformationally
well-defined phase-transfer catalyst and the anionic nucleophile has
proven to be a useful strategy to enhance catalytic selectivity21. We
hypothesized that a cinchonine-derived phase-transfer catalyst bear-
ing a properly located aromatic group with suitable electronic prop-
erties might interact with 2-azaallyl anion 3A via both ionic and p–p
interactions22–24, thereby mediating the model umpolung reaction in
a highly chemo-, regio-, diastereo- and enantioselective fashion.
Analogues C-15 and C-16 bearing electron-withdrawing and elec-
tron-donating N-benzyl substituents, respectively, were examined.
We found that C-16 afforded only improved conversion whereas
C-15 was worse than C-14 (entries 4 and 5, Table 2). Interestingly,
Table 2
|
Screening and optimization of chiral phase-transfer catalysts
Ph
R1
=
OPYR
O
N
N
Br
R1
N
Br
N
N
F3C
CF3 MeO
OMe
N
Ph
Ph
Ph
PYR:
C-14
C-15
C-16
C-17
C-13
Cl
C-14 to 21b
R1
=
F3C
CF3
4
3
5
OMe
OTBS
MeO
OMe
C-18
C-19
C-20
C-21a
C-21b
CF3
CF3
Entry
T ( uC)
Catalyst
Conversion (%)
9/4; 9/10
d.r. of 9
e.e. of 9 (%)
1
2
3
4
5
6*
7*
8*
9*
10*
11*
12*
13{
14*
RT
RT
C-13
C-14
C-14
C-15
C-16
C-16
C-17
C-18
C-19
C-20
C-21a
C-21b
C-21b
TBAB
41
18
58
54
84
41
14
40
39
66
88
99
97
31
2/98; ND
11/89; ND
ND
ND
ND
ND
39
18
40
39
68
77
55
85
91
96
95
ND
220
220
220
220
220
220
220
220
220
220
220
220
37/63; .95/5
36/64; .95/5
34/66; .95/5
32/68; .95/5
67/33; .95/5
74/26; .95/5
45/55; .95/5
68/32; .95/5
94/6; .95/5
99/1; .95/5
99/1; .95/5
4/96; ND
82/18
67/33
76/24
74/26
87/13
86/14
96/4
91/9
91/9
93/7
93/7
ND
Conditions: 10 mol% catalyst, 10 mol% KOH(aq.), 16 h. TBAB, tetra-n-butylammonium bromide. ND, not determined; d.r., diastereomeric ratio; e.e., enantiomeric ratio.
*1.0 mol% catalyst, 10 mol% KOH(aq.), 2 h.
{0.2 mol% of C-21b used, 5 h.
4 4 6
|
N A T U R E
|
V O L 5 2 3
|
2 3 J U L Y 2 0 1 5
G
2015 Macmillan Publishers Limited. All rights reserved

LETTER RESEARCH
we observed that a decrease in the loading of C-16 did not affect the substituent in a position not causing obstructive steric interference
catalytic selectivities negatively (entry 6 versus 5, Table 2). We there- between the catalyst and 2-azaally anion 3. Gratifyingly, C-21a not
fore decreased the catalyst loading from 10 mol% to 1 mol% in our only turned out to be much more active, but also afforded 9Aa with
subsequent catalyst screening and optimization studies. We next synthetically useful chemo-, regio-, diastereo- and enantioselectivity
turned to C-17, an analogue containing a biphenyl group. C-17 (entry 11, Table 2). Catalyst C-21b with a more electron-donating and
afforded substantially improved chemo-, diastereo- and enantioselec- bulky tert-butyldimethylsilyl ether (OTBS) group was more active and
tivity, thereby allowing amine 9Aa to be formed as the major product selective; a loading of only 0.2 mol% produced imine 9Aa rapidly with
(entry 7 versus 6, Table 2).
almost complete chemoselectivity and excellent stereoselectivity
(entry 13, Table 2). We attributed the superiority of C-21b over
C-21a to two factors resulting from the substitution of the 4-methoxy
with the 4-OTBS group: (1) the terphenyl moiety is more electron rich
due to the presence of the more electron-donating 4-OTBS group;
(2) the terphenyl moiety has less conformational flexibility due to
Assuming the improved catalysis resulted from a p–p interaction
between the biaryl moiety of C-17 and 3A, we designed and synthe-
sized catalyst C-18 (Table 2). We reasoned that the presence of the
C2-symmetric terphenyl moiety could render C-18 a more efficient
catalyst than C-17. This working hypothesis received support from the
superior performance of C-18 in catalytic activity as well as chemo- steric hindrance of the rotation of the 3,5-phenyl rings by the bulky
4-OTBS group. Both factors could reinforce the p–p interaction
terphenyl moiety was initially attempted by introducing electron- between 3A and the catalyst C-21b.
and enantioselectivity (entry 8 versus 7, Table 2). Further tuning of the
withdrawing and electron-donating groups on the 3- and 5-phenyl
groups. Catalyst C-20 (entry 10, Table 2) bearing an electron-rich
terphenyl group performed better than C-19 (entry 9), which con-
tained an electron-deficient terphenyl moiety. However, C-20 furn-
ished higher stereoselectivity but lower chemoselectivity than those
produced by C-18 (entry 10 versus 8, Table 2).
Only a trace of 9Aa was formed from 1A and 8a using tetrabuty-
lammonium bromide (TBAB) as the quaternary ammonium salt
(entry 14, Table 2), which confirmed that the structural characteristics
of C-21b were responsible for both the catalytic activity and the select-
ivity observed for the umpolung reaction between imine 1A and enal
8a. To ascertain that 2-azaallyl anion 3 originated only from imine 1
We next examined catalyst C-21a (Table 2) which was designed to rather than also from the isomerized imine 4, we established that no
create an electron-rich terphenyl moiety with an electron-donating reaction occurred between 4A and 8a under the optimized conditions.
Table 3
|
Substrate scope for umpolung reactions of trifluoromethyl imines with enals
Ar
Ar
NH
CH2OH
Ar
NaBH4 HOAc
,
Ar
0.2 mol% C-21b
10 mol%KOH(aq.)
Ar
CHO
R1
F3C
N
CHO
N
22, R1 = Alkyl
CHO
+
R2
+
+
N
N
0.1 M
R1
F3C
PhMe,
–20 ºC
R2
R1
CF3
R2
R1
CF3
NH2 CH2OH
R1
=
Ar 4-NO2Ph
R2
1) NaBH4
2) HCl
CF3
1
8
4
10
R1
F3C
9
23, R1 = Aryl
or Alkenyl
Scope of imines in reactions with crotonaldehyde (8a, R2 5 Me)
Entry
R1
Time (h); conversion (%)
9/4; 9/10
d.r. of 9
93/7
91/9
Yield (%)*
81 (22Aa)
84 (22Ba)
e.e. (%){
95
1
5; 99
5; 97
.95/5; .95/5
.95/5; .95/5
H3C
1A
1B
2
94
3
4
5
6
1C
1D
1E
5; 98
5; 99
.95/5; .95/5
.95/5; .95/5
.95/5; .95/5
91/9; .95/5
91/9
91/9
91/9
93/7
83 (22Ca)
75 (22Da)
72 (22Ea)
54 (22Fa)
96
96
96
95
Br
BnO
7; 94
12; 98
1F
Cy
Scope of b-substituted enals in reactions with imine 1A
Entry
R2
Time (h); conversion (%)
9/4; 9/10
d.r. of 9
Yield (%)*
e.e. (%){
7
8
9
CH3CH2; 8b
CH3(CH2)5; 8c
Ph; 8d
5; 99
12; 93
8; 93
89/11; .95/5
86/14; .95/5
.95/5; 68/32
.95/5
.95/5
.95/5
64 (22Ab)
51 (22Ac)
51 (22Ad)
95
96
91
Scope of imines in reactions with acrolein (8e, R2 5 H)
Entry
R1
Time (h); conversion (%)
9/4; 9/10
Yield (%)*
e.e. (%){
H3C
1A
1B
10{
11{
12{
13{
14
3; 95
3; 99
3; 97
3; 99
3; 99
3; 94
3; 99
1; 99
.95/5; .95/5
.95/5; .95/5
.95/5; .95/5
.95/5; .95/5
94/6; .95/5
92/8; .95/5
88/12; .95/5
.95/5; .95/5
89 (22Ae)
82 (22Be)
84 (22De)
90 (22Fe)
71 (23Ge)
67 (23He)
78 (23Ie)
90 (23Je)
92
91
91
92
94
94
92
93
1D
Br
1F
Cy
Ph; 1G
15
p-MeOC6H4; 1H
p-CF3C6H4; 1I
16
1J
17
Ph
Conditions: imine 1 (0.2 mmol), aldehyde 8 (0.4 mmol), C-21b (0.2 mol%), KOH (2.2 ml, 50 wt% aq., 10 mol%), PhMe (2.0 ml). Conversion, regioselectivity (9/10) and d.r. of 9 were determined by 1H NMR analysis of
the crude umpolung reaction mixture. Chemoselectivity (9/4) was determined by 19F NMR analysis.
*Overall yield for the transformation of imine 1 to either 22 or 23.
{e.e. of 22 or 23, determined by HPLC analysis.
{Reaction was performed at 210 uC.
2 3 J U L Y 2 0 1 5
| V O L 5 2 3 | N A T U R E | 4 4 7
G
2015 Macmillan Publishers Limited. All rights reserved

RESEARCH LETTER
Ar
a
Ar
Ar
Ar
CHO
C-21b
1) Citric acid
(0.6 mg, 0.01 mol%)
CHO
H
3C
CHO
2.0 equiv.
8a
N
+
N
+
N
N
+
2) NaBH4
3) HCl
N
25 mol% KOH(aq.)
PhMe, 0 ºC, 24 h
Cl
H
3C
F
F
3C
H
CF3
3C
H
CF3
H
CF3
3C
3C
H
H
3C
1.0 equiv.
24Aa HCl
62%yield, 96% e.e.
∙
9Aa
4A
10Aa
1A
24Aa HCl
∙
9Aa/4A = 96/4, 9Aa/10Aa > 95/5,
(6.0 mmol, 1.5 g)
d.r. of 9Aa = 93/7, 93% e.e.
Ar
NH2
1) NaBH4
HN
10% Pd/C
cyclohexene
6h, 94% yield
OH
H
3C
2)
HOAc
OH
F
3C
H
3C
F
3C
22Aa
23Aa
Ar
Ar
b
0.2 mol% C-21b
10 mol% KOH(aq.)
CHO
2.0 equiv.
8e
N
+
N
Ph
HCl
1) Citric acid
2) NaBH4
N
H
PhMe, –20 ºC, 3 h
F
3C
Ph
Ph
CF3
CHO
CF3
9Ge
1.0 equiv.
1G
24Ge
24Ge HCl
∙
74% yield, 95%e.e.
Figure 2
|
Gram-scale reaction and synthetic applications. a, Highly efficient gram-scale catalytic asymmetric umpolung reaction of imine 1A (1.5 g) with 0.01
mol% of C-21b (0.6 mg) and its application for the syntheses of aminoalcohol 23Aa and pyrrolidine 24Aa. b, Synthetic application of catalytic asymmetric
umpolung reaction of imine 1G for the syntheses of amine 9Ge and pyrrolidine 24Ge.
It should be noted that amine 9Aa may also form via a [312] cycload- desirable amine 9Ad and the regioisomer 10Ad. Nonetheless, 9Ad was
dition between 1A and 8a followed by a retro-Mannich reaction. produced with high chemo-, diastereo- and enantioselectivity in syn-
However, we did not detect the formation of the [312] adduct when thetically useful yield (entry 9, Table 3).
monitoring the reaction by 1H and 19F NMR analyses.
We next examined the reactions of trifluoromethylated imines 1
Our investigation of the substrate scope began with the reaction of with acrolein (8e). We found that at 210 uC the reaction between
1A and 8a with 0.2 mol% of C-21b (entry 1, Table 3). The reaction 1A and 8e proceeded cleanly and in a highly enantioselective fashion
proceeded to full conversion within 5 h with excellent chemo-, regio-, to furnish the corresponding amine 9Ae as the only detectable product
diastereo- and enantioselectivities. The optically active amine 9Aa was by NMR analysis of the crude reaction mixture. The reactions of
then converted to the more stable N-benzyl aminoalcohol 22Aa by acrolein (8e) with trifluoromethyl imines 1 bearing a variety of alkyl,
reducing first the aldehyde with NaBH4 and then the imine with aryl and alkenyl substituents were equally successful, affording the
NaBH4 and acetic acid, which could be readily isolated as a single corresponding trifluoromethylated amines 9 containing a tetrasubsti-
diastereomer in good yield. Reactions of 8a with a series of trifluor- tuted stereocentre25,26 in high optical purity (entries 11–17, Table 3).
omethyl imines (1B–E, Table 3) bearing simple and functionalized Alkyl trifluoromethylated amines (9Ae–Fe) were converted to
linear alkyl substituents consistently proceeded in high yield and excel- N-benzyl aminoalcohols 22 (entries 10–13, Table 3). Aryl and alkenyl
lent chemoselectivity and stereoselectivity. The reaction tolerated an amines 9Ge–Je were converted to aminoalcohols 23 by reduction of
imine bearing a b-branched alkyl substituent (1F). The reaction the aldehyde with NaBH4 and hydrolysis of the imine with aqueous
accepted larger b-alkyl groups on the enal (entries 7 and 8, Table 3). HCl (entries 14–17, Table 3). In all these cases, the aminoalcohols 22
Cinnamaldehyde (8d) reacted with 1A to give a 68:32 mixture of the and 23 were obtained in good yields and high optical purity.
Ar
Ar
Ar
a
Ar
δ
δ
3
N
N
N
N
3
δ
δ
δ
R
H
R
Ar
H
R
H
R
H
3′
1
1
=
=
Ph
4-NO2
Ar 4-NO2Ph
25
26
27
28
Ar
Ar
Ar
Ar
CHO
1.5 mol% cat.
δ
b
10 mol%KOH(aq.)
8e
N
H
CHO
3
N
N
δ
N
+
PhMe, RT, 30 min
Ph
Ph
H
CHO
Ph
H
1
Ph
H
=
Ar
Ph
4-NO2
25A
26A
29Ae
30Ae
OPYR
Br
R1
Entry Cat. Conv. (%) 29/30 e.e. (%) Entry Cat. Conv. (%) 29/30
e.e. (%)
=
N
1
2
C-21b
C-21c
80
>95/5
>95/5
92
93
3* C-21c
4 TBAB
100
52
>95/5
44/56
95
-
R1
N
100
OtBu
C-21c
N
PYR
Ph
Cl
Ph
N
*Reaction was performed with 2.5 mol% C-21c at 0 ºC for 8 h.
Figure 3
|
Asymmetric umpolung reactions of aryl and unsaturated aldimines. a, Left, 2-azaallyl anion 26 derived from deprotonation of phenyl imine
25; right, 2-azaallyl anion 28 derivedfrom deprotonation ofalkenylimine 27. b, Catalyst optimization for theumpolung reaction ofphenylimine25Awithenal 8e.
4 4 8
|
N A T U R E
|
V O L 5 2 3
|
2 3 J U L Y 2 0 1 5
G
2015 Macmillan Publishers Limited. All rights reserved

LETTER RESEARCH
Table 4
|
Substrate scope for umpolung reactions of aryl aldimines with acrolein (8e)
Ar
Ar
Ar
Boc
R
21c
2.5 mol% C-
NH
H
CH2OH
10 mol KOH
%
1) NaBH4
(aq.)
CHO
N
H
N
N
+
CHO
+
2) NH4Cl,
(Boc)2O
PhMe, 0 ºC
=
R
R
H
CHO
R
H
Ar
Ph
4-NO2
31Ae–He
25A–H
8e
29Ae–He
30Ae–He
Entry
R
Time (h)
29/30
Yield of 31 (%)*
e.e. of 31 (%){
1
2
3{
4
5{
6
Ph; 25A
8
8
8
8
5
5
8
18
.95/5
.95/5
90/10
.95/5
.95/5
.95/5
83/17
.95/5
55
51
54
53
52
56
53
45
93
94
94
95
95
95
90
95
o-CH3C6H4; 25B
2-Naphthyl; 25C
2-Thienyl; 25D
p-BrC6H4; 25E
o-BrC6H4; 25F
7{
81
p-MeO2CC6H4; 25G
p-MeOC6H4; 25H
Conditions: reactions were performed with 25 (0.20 mmol), 8e (0.40 mmol), C-21c (2.5 mol%) and KOH (2.2 ml, 50 wt% aq., 10 mol%) in PhMe (2.0 ml) until full conversion. Regioselectivity (29/30) was
determined by 1H analysis of the crude umpolung reaction mixture.
*Overall yield for the transformation of imine 25 to 31.
{Determined by HPLC analysis.
{Reaction was performed in PhMe/CH2Cl2 5 2/1 solution (3.0 ml).
15.0 mol% C-21c used.
A gram-scale reaction of 1A with 8a with 0.01 mol% of C-21b went 2-azaallyl anion 26A, which is flanked by the phenyl and the 4-nitro-
to completion without deterioration in selectivity (Fig. 2a). This phenyl rings (Fig. 3b). Thus, there is an inherent electronic bias for an
remarkable catalytic efficiency indicates the utility of this new reaction electrophile to react with 26A by attacking preferentially the more
in preparative-scale organic synthesis27. To demonstrate the synthetic electron-rich C328. Nonetheless, the remarkable catalytic efficiency of
versatility of this reaction, we converted chiral aminoaldehyde 9Aa to C-21b made us hopeful that it could provide powerful catalytic activity
aminoalcohol 23Aa and pyrrolidine 24Aa as shown in Fig. 2a. and selectivity to overcome this undesirable substrate bias while still
Similarly, the phenyl substituted product 9Ge was converted to pyr- affording the required stereoselectivity for an efficient asymmetric
rolidine 24Ge (Fig. 2b). The absolute configurations of 24Aa and 24Ge imine umpolung reaction.
were determined by X-ray crystallography.
Accordingly, we investigated the reaction of phenyl imine 25A with
We are interested in extending the scope to simple imines, which acrolein (8e) applying the conditions established with trifluoromethyl
would greatly expand the reach of this asymmetric umpolung reaction imines 1. As expected, 25A was far less reactive than 1A; only a trace
in organic synthesis. However, 2-azaallyl anions 26 derived from aryl amount of the desired product 29Ae was detected. With a substantially
imines 25 (Fig. 3a) are substantially less stable than those derived increased catalyst loading (entry 1, Fig. 3b), the reaction progressed to
from the corresponding trifluoromethyl imines 1. Furthermore, regios- high conversion and in excellent enantioselectivity. A new catalyst
electivity control for the electrophilic reaction with an unsymmetrically bearing a 4-OtBu group (C-21c) was found to be more active and
substituted 1,3-diaryl-2-azaallyl anion 26 might prove difficult afforded better enantioselectivity (entry 2, Fig. 3b); this allowed a clean
(Fig. 3a). For example, deprotonation of phenyl imine 25A should form and complete reaction to occur at 0 uC in excellent enantioselectivity
Table 5
|
Substrate scope for umpolung reactions of alkenyl aldimines with acrolein (8e)
Ar
Ar
Ar
Boc
Boc
R2
N
2.5 mol%C-
21c
10 mol%KOH(aq.)
CH2OH
CH2OH
NH
H
NH
H
CHO
N
N
H
1) NaBH4
H2
CHO
+
+
R1
H
Alkenyl
Alkenyl
Pd/C
PhMe,0 ºC
2) NH4Cl,
(Boc)2O
H
CHO
Alkenyl
Alkenyl
R3
=
Ar 4-NO2Ph
27A–F
8e
32Ae–Fe
33Ae–Fe
34Ae–Fe
35Ae: 94% yield, 92% e.e.
Entry
1
Alkenyl
Time (h)
32/33
Yield of 34 (%)*
e.e. of 34 (%){
16
16
86/14
51
92
27A
Ph
Me
2
95/5
50
46
92
95
27B
27C
Ph
Ph
3{
24
82/18
Me
4
12
24
77/23
83/17
44
41
92
90
6H4
-BrC
27D
27E
p
5{
6H4
Me
-MeOC
p
6{
6
95/5
371
90
27F
Br
Conditions: reactions were performed with 27 (0.20 mmol), 8e (0.40 mmol), C-21c (2.5 mol%) and KOH (2.2 ml, 50 wt% aq., 10 mol%) in PhMe (2.0 ml) until full conversion. Regioselectivity (32/33) was
determined by 1H analysis of the crude umpolung reaction mixture.
*Overall yield for the transformation of imine 27 to 34.
{Determined by HPLC analysis.
{5.0 mol% C-21c used.
1Overall yield for a four-step transformation of (E )-3-bromobut-2-enal to 34Fe, see Supplementary Information for details.
2 3 J U L Y 2 0 1 5
| V O L 5 2 3 | N A T U R E | 4 4 9
G
2015 Macmillan Publishers Limited. All rights reserved

RESEARCH LETTER
10. Vora, H. U. & Rovis, T. Asymmetric N-heterocyclic carbene (NHC) catalyzed acyl
anion reactions. Aldrichim. Acta 44, 3–11 (2011).
11. Reich, B. J. E., Justice, A. K., Beckstead, B. T., Reibenspies, J. H. & Miller, S. A.
Cyanide-catalyzed cyclizations via aldimine coupling. J. Org. Chem. 69,
1357–1359 (2004).
12. Ogle, J. W., Zhang, J., Reibenspies, J. H., Abboud, K. A. & Miller, S. A. Synthesis of
electronically diverse tetraarylimidazolylidene carbenes via catalytic aldimine
coupling. Org. Lett. 10, 3677–3680 (2008).
13. Liu, X., Gao, A., Ding, L., Xu, J. & Zhao, B. Aminative umpolung synthesis of aryl
vicinal diamines from aromatic aldehydes. Org. Lett. 16, 2118–2121 (2014).
14. Matsumoto, M., Harada, M., Yamashita, Y. & Kobayashi, S. Catalytic imine-imine
cross-coupling reactions. Chem. Commun. 50, 13041–13044 (2014).
15. Wu, Y. & Deng, L. Asymmetric synthesis of trifluoromethylated amines via catalytic
enantioselective isomerization of imines. J. Am. Chem. Soc. 134, 14334–14337
(2012).
with 2.5 mol % of C-21c (entry 3, Fig. 3b). Amine 29Ae was converted
to the Boc-protected aminoalcohol 31Ae in high optical purity and
good yield in three steps (entry 1, Table 4). Subsequently, we estab-
lished that the umpolung reaction tolerated a broad range of aryl and
heteroaryl aldimines of varying steric and electronicproperties (entries
2–8, Table 4). Electron-rich arylimines such as 25H appeared to be less
active, but the umpolung reaction with C-21c still went to completion
with high chemoselectivity, regioselectivity and enantioselectivity.
Owing to the synthetic versatility of the olefin and amine function-
alities, chiral allylic amines are highly valuable chiral building blocks29.
If we could extend the substrate scope to a,b-unsaturated imines 27
(Fig. 3a), the impact of the imine umpolung reactions would be further
enlarged. However, the 2-azaallyl anions 28 derived from a,b-unsat-
urated imines 27 were expected to be even less stable than those
derived from arylaldimines30. Furthermore, the conjugation of an
azaallyl anion with an olefin renders 28 a more challenging nucleo-
phile from the viewpoint of achieving catalytic control of regioselec-
tivity (Fig. 3a). Gratifyingly, C-21c provided highly selective catalysis
to efficiently promote the umpolung reaction of 27A and 8e (entry 1,
Table 5). Importantly, the efficiency of C-21c remained undiminished
for reactions involving a variety of a,b-unsaturated imines bearing di-
and trisubstituted olefins (entries 2–6, Table 5). As allylic amines could
be readily hydrogenated to the corresponding aliphatic amines
(Table 5), these results established this imine umpolung reaction as
a useful method for the asymmetric synthesis of both chiral allylic and
aliphatic amines.
16. Liu, M., Li, J., Xiao, X., Xie, Y. & Shi, Y. An efficient synthesis of optically active
trifluoromethyl aldimines via asymmetric biomimetic transamination. Chem.
Commun. 49, 1404–1406 (2013).
17. Jakubowska, A. & Kulig, K. Progress in the glycine equivalent based a-amino acids
synthesis. Curr. Org. Synth. 10, 547–563 (2013).
18. Zhu, Y. & Buchwald, S. L. Ligand-controlled asymmetric arylation of aliphatic
a-amino anion equivalents. J. Am. Chem. Soc. 136, 4500–4503 (2014).
19. Qian, X. et al. Palladium-catalyzed decarboxylative generation and asymmetric
allylation of a-imino anions. Org. Lett. 16, 5228–5231 (2014).
20. Shirakawa, S. & Maruoka, K. Recent developments in asymmetric phase-transfer
reactions. Angew. Chem. Int. Ed. Engl. 52, 4312–4348 (2013).
21. Ooi, T., Ohara, D., Tamura, M. & Maruoka, K. Design of new chiral phase-transfer
catalysts with dual functions for highly enantioselective epoxidation of a,b-
unsaturated ketones. J. Am. Chem. Soc. 126, 6844–6845 (2004).
22. Dolling, U. H., Davis, P. & Grabowski, E. J. J. Efficient catalytic asymmetric
alkylations. 1. Enantioselective synthesis of (1)-indacrinone via chiral phase-
transfer catalysis. J. Am. Chem. Soc. 106, 446–447 (1984).
23. Bandini, M., Bottoni, A., Eichholzer, A., Miscione, G. P. & Stenta, M. Asymmetric
phase-transfer-catalyzed intramolecular N-alkylation of indoles and pyrroles: a
combined experimental and theoretical investigation. Chem. Eur. J. 16,
12462–12473 (2010).
We have identified a new class of tunable chiral phase-transfer
catalysts and demonstrated their unique ability to promote C–C
bond-forming reactions with 2-azaallyl anions in a highly chemose-
lective, regioselective, diastereoselective and enantioselective fashion.
This discovery releases the potential of imines as nucleophiles, thereby
allowing the realization of catalytic asymmetric umpolung reactions of
imines, and providing a fundamentally new approach towards chiral
amino compounds. With a simple operational protocol and low cata-
lyst loading, this transformation also provides a practical method for
organic synthesis.
24. Knowles, R. R., Lin,S. & Jacobsen, E. N. Enantioselectivethiourea-catalyzed cationic
polycyclizations. J. Am. Chem. Soc. 132, 5030–5032 (2010).
25. Fu, P., Snapper, M. L. & Hoveyda, A. H. Catalytic asymmetric alkylations of
ketoimines. Enantioselective synthesis of N-substituted quaternary carbon
stereogenic centers by Zr-catalyzed additions of dialkylzinc reagents to aryl-,
alkyl-, and trifluoroalkyl-substituted ketoimines. J. Am. Chem. Soc. 130,
5530–5541 (2008).
26. Nie, J., Guo, H.-C., Cahard, D. & Ma, J.-A. Asymmetric construction of stereogenic
carbon centers featuring a trifluoromethyl group from prochiral
trifluoromethylated substrates. Chem. Rev. 111, 455–529 (2011).
27. Giacalone, F., Gruttadauria, M., Agrigento, P. & Noto, R. Low-loading asymmetric
organocatalysis. Chem. Soc. Rev. 41, 2406–2447 (2012).
Received 23 February; accepted 21 May 2015.
28. Bordwell, F. G., Algrim, D. & Vanier, N. R. Acidities of anilines and toluenes. J. Org.
Chem. 42, 1817–1819 (1977).
1. Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications
(Wiley-VCH, 2010).
2. Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-
butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010).
3. Kobayashi, S., Mori, Y., Fossey, J. S. & Salter, M. M. Catalytic enantioselective
formation of C2C bonds by addition to imines and hydrazones: a ten-year update.
Chem. Rev. 111, 2626–2704 (2011).
4. Silverio, D. L. et al. Simple organic molecules as catalysts for enantioselective
synthesis of amines and alcohols. Nature 494, 216–221 (2013).
5. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach 3rd edn (Wiley &
Sons, 2009).
6. Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Ed. Engl. 18,
239–258 (1979).
29. Hartwig, J. F. & Stanley, L. M. Mechanistically driven development of iridium
catalysts for asymmetric allylic substitution. Acc. Chem. Res. 43, 1461–1475
(2010).
30. Jaun, B., Schwarz, J. & Breslow, R. Determination of the basicities of benzyl, allyl,
and tert-butylpropargyl anions by anodic oxidation of organolithium compounds.
J. Am. Chem. Soc. 102, 5741–5748 (1980).
Supplementary Information is available in the online version of the paper.
Acknowledgements We are grateful for financial support from the National Institute of
General Medical Science (NIH, GM-61591). We thank M. Bezpalko and B. Foxman for
X-ray crystallographic characterizations of structures. C. Fei and B. Hu are
acknowledged for the help in substrate preparation.
7. Seebach, D. & Corey, E. J. Generation and synthetic applications of 2-lithio-1,3-
dithianes. J. Org. Chem. 40, 231–237 (1975).
8. Smith, A. B. & Adams, C. M. Evolution of dithiane-based strategies for the
construction of architecturally complex natural products. Acc. Chem. Res. 37,
365–377 (2004).
9. Brehme, R., Enders, D., Fernandez, R. & Lassaletta, J. M. Aldehyde
N-dialkylhydrazones as neutral acyl anion equivalents: umpolung of the imine
reactivity. Eur. J. Org. Chem. 5629–5660 (2007).
Author Contributions Y.W., L.H. and Z.L. performedthe experimentsand analysed data.
Y.W. and L.D. conceived the idea and prepared this manuscript with feedback from L.H.
and Z.L.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to L.D. (deng@brandeis.edu).
4 5 0
|
N A T U R E
|
V O L 5 2 3
|
2 3 J U L Y 2 0 1 5
G
2015 Macmillan Publishers Limited. All rights reserved