Highly effective and enantioselective α-amination of aldehydes promoted by chiral proline amide-thiourea bifunctional catalysts

Article abstract of DOI:10.1016/j.tetlet.2010.07.042

A series of secondary amine-thiourea catalysts derived from l-proline and chiral diamine were prepared and first applied to highly enantioselective amination of unmodified aldehydes with various azodicarboxylates in excellent yields (up to 99%) and enanti

Full text of DOI:10.1016/j.tetlet.2010.07.042

Tetrahedron Letters 51 (2010) 4870–4873
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Highly effective and enantioselective
a
-amination of aldehydes promoted by
chiral proline amide–thiourea bifunctional catalysts
a,
Ji-Ya Fu a,b, Qing-Chun Huang a, Qiao-Wei Wang a, Li-Xin Wang a, , Xiao-Ying Xu
*
*
a Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610 041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100 039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of secondary amine–thiourea catalysts derived from
L-proline and chiral diamine were prepared
Received 13 May 2010
Revised 7 July 2010
Accepted 9 July 2010
Available online 13 July 2010
and successfully applied to the highly effective and enantioselective
hydes with various azodicarboxylates in excellent yields (up to 99%) and enantioselectivities (up to
99% ee) within a few minutes.
a
-amination of unmodified alde-
Ó 2010 Elsevier Ltd. All rights reserved.
The formation of carbon–nitrogen bond is a straightforward
method to access optically active nitrogen-containing compounds,
which has been widely applied to the preparation of natural prod-
Recently, bifunctional activations, which simultaneously acti-
vate both acceptors and donors, have been regarded as an impor-
tant strategy in asymmetric small molecular catalysis.18 As a
typical and effective activation model, chiral thiourea catalysts
have been widely used due to their effective activation of carbonyl
and nitro groups through double hydrogen-bonding interactions,19
ucts and pharmaceuticals of biological activities.1
a
-Amination of
aldehydes is one of the most powerful and efficient methods for
carbon–nitrogen bond formation and can afford -amino alde-
hydes which are potentially important building blocks for a variety
a
and secondary amines, especially L-proline and L-prolic amides,
of valuable synthetic intermediates such as
a
-amino alcohols,
a
-
have been well identified as powerful catalysts to activate alde-
hydes or ketones via enamine or imine transition state.20 Holding
the concept of bifunctional activations, we expected that the kind
amino acids.2
Over the past years, great progresses have been made on
asymmetric -amination of aldehydes. In 2002, Jørgensen and
co-workers3 and List4 almost simultaneously reported the first
example of -amination of aldehydes catalyzed by -proline in high
yields and excellent enantioselectivities. Since then, -amination
a
O
a
L
H
a
N
H
linker
N
S
(S)
of aldehydes with azodicarboxylates has received considerable
attention in recent years. After that, Adolfsson reported the same
amination catalyzed by chiral mono-sulfonyl-2-aminopyrrolidines
N
H
HN
thiourea skeleton
in moderate yields and enantioselectivities.5 Except
L
-proline3,4,6
L-prolic skeleton
CF3
and its structural analogs,5,7,8 Chen and co-workers recently devel-
F3C
oped a series of mono-sulfonyl-2-aminopyrrolidines with camphor
O
(S)
O
(R)
scaffold for the direct a-amination of simple aldehydes in excellent
(S)
N
(R)
yields and high enantioselectivities.9 For a broader range of this
reaction, asymmetric amination of ketones,10,11 cyanoacetates,12,13
alkylidene cyanoacetates,14 and 2-oxindoles15–17 have also been
reported. Up to the present, a considerable amount of effort has
been made on the discovery of chiral organocatalysts for this direct
asymmetric conversion, however, to the best of our knowledge,
(S)
N
H
H
N
H
(S)
HN
N
H
HN
S
S
HN
HN
Ar
Ar
1b
1a
Ph
O
Ph
(S)
O
(R)
(S) Ph
N
there have been only
a limited number of chiral catalysts
(R) Ph
HN
N
H
H
(S)
available3–8 for excellent enantioselectivities. It is still highly
challenging and desirable to develop new, efficient catalytic sys-
tems for this reaction.
N
H
(S)
HN
N
H
S
S
HN
HN
Ar
Ar
Ar = 3,5-bis(trifluoromethyl)benzene
Figure 1. Secondary amine–thiourea catalysts.
1c
1d
* Corresponding authors. Tel./fax: +86 28 85255208 (L.-X.W).
E-mail addresses: wlxioc@cioc.ac.cn (L.-X. Wang), xuxy@cioc.ac.cn (X.-Y. Xu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.042

J.-Y. Fu et al. / Tetrahedron Letters 51 (2010) 4870–4873
4871
Table 1
Screening of catalysts 1a–d and solventsa
O
O
O
solvent, 0 ºC
1.cat 1. (20 mol %),
HO
N
O
N
N
CHO
*
NH
+
º
2. NaBH4 (1.5 eq), MeOH,
0 C
O
O
O
O
2a
4a
3a
Entry
Cat.
Solvent
Timeb (min)
Yieldc (%)
eed (%)
1f
2f
3
4
5
6
7
8
9
10
11
12
13
14e
1a (1c)
1b (1d)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a (1c)
1a
CH3CN
CH3CN
40 (20)
35 (240)
25 (25)
25 (25)
40 (50)
30 (270)
23 (20)
25 (144)
40 (180)
35 (35)
660 (540)
18 (20)
330 (600)
10
71 (98)
70 (70)
76 (99)
79 (64)
89 (91)
80 (82)
92 (85)
88 (89)
90 (97)
75 (86)
45 (53)
93 (95)
18 (48)
89
89 (94)(R)
81 (76)(R)
91 (81)
96 (83)
99 (94)
95 (87)
95 (94)
96 (91)
90 (92)
97 (95)
97 (79)
92 (89)
54 (16)
93
n-Hexane
Cyclohexane
o-Xylene
Toluene
DCE
DCM
CHCl3
Et2O
THF
CH3CN
MeOH
o-Xylene
a
b
c
Adding sequence: catalyst 1 (20 mol %), solvent (0.8 mL), isovaleral (0.3 mmol) and azodicarboxylate (0.2 mmol).
Time of amination.
Isolated yield.
The ee value was determined by GC and the absolute configuration of 4a was assigned as R (see Supplementary data).
The reaction was carried out at 25 °C.
d
e
Table 2
Reaction of 2a with azodicarboxylates 3 catalyzed by 1aa
R1
O
R1
O
O
1. cat 1a. (20 mol %),
o-xylene,
º
0
C
HO
R1
O
N
O
N
N
CHO
+
NH
*
º
2. NaBH4 (1.5 eq), MeOH,
0 C
R1
O
O
O
3
2a
4
Entry
R1
2a:3 (mol:mol)
Cat. loading (Âmol %)
Timeb(min)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
i-Pr (3a)
Bn (3b)
Et (3c)
i-Pr (3a)
i-Pr (3a)
Et (3c)
Et (3c)
Et (3c)
Et (3c)
1.5:1.0
1.5:1.0
1.5:1.0
1.0:1.0
1.0:1.5
1.5:1.0
1.5:1.0
1.5:1.0
1.5:1.0
20
20
20
20
20
15
10
5
40
10
5
80
80
5
50
320
1800
4a 89
4b 70
4c 97
4a 87
4a 93
4c 93
4c 94
4c 92
4c 90
99
98e
>99
96
90
>99
>99
>99
>99
2
a
b
c
Reactions performed with isovaleral, catalyst 1a (20 mol %), and azodicarboxylate in o-xylene (0.8 mL).
Time of amination.
Isolated yield.
The ee value was determined by GC.
The ee value was determined by HPLC.
d
e
of catalysts bearing both
L
-proline and thiourea functional moieties
a-amination of aldehydes with azodicarboxylates in excellent
linked by a suitable chiral linker might simultaneously activate
both a nucleophile and an electrophile in the same asymmetric
reaction. Typically, the secondary amine–thiourea catalysts 1a–d
(Fig. 1) in our hands, synergistically combining two catalytic sites
yields and enantioselectivities. The whole scheme and strategies
for these catalysts are illustrated in Figure 1.
Chiral catalysts 1a–d may be similarly prepared as in the re-
ported procedures.21 To determine the optimal asymmetric reac-
of chiral thiourea and
ough attentions.21 We regarded that these bifunctional organocat-
alysts may catalyze the asymmetric -amination of aldehydes and
the reactivity and enantioselectivity may be enhanced by double
activation, mutual stereo-compatibility and chiral recognition.
As a part of our continuing interests in asymmetric synthesis,22
herein, we wish to report the example of these chiral proline
amide–thiourea bifunctional catalysts promoted enantioselective
L
-prolic amide skeleton haven’t drawn en-
tion conditions, a-amination of isovaleral (2a) with diisopropyl
azadicarboxylate (DIAD) (3a) was used as a model reaction and
chiral catalysts 1a–d were initially screened, and the results were
summarized in Table 1. As expected, each reaction was success-
fully carried out in CH3CN at 0 °C in the presence of 20 mol % cat-
alysts (1a–d) and gave the corresponding primary alcohol 4a after
reduction with sodium borohydride in excellent overall yields (70–
98%) and enantioselectivities (76–99% ee). Comparatively, catalysts
a

4872
J.-Y. Fu et al. / Tetrahedron Letters 51 (2010) 4870–4873
Table 3
Direct a
-amination of various unmodified aldehydes with amine sourcesa
R1
O
R1
O
O
1. cat 1a. ( 20 mol % ),
º
o-xylene,
0 ºC
0 C
R2
CHO
+
N
O
O
N
N
R1
O
HO
NH
2. NaBH4 (1.5 eq),
*
MeOH,
R2
R1
O
O
2
3
4
Entry
R1
R2
Timeb (min)
Yieldc (%)
eed (%)
1
2
3
4
5
i-Pr (3a)
Bn (3b)
Bn (3b)
Bn (3b)
Bn (3b)
Bn (3b)
Et (3c)
Et (3c)
Et (3c)
Et (3c)
i-Pr (2a)
i-Pr (2a)
Me (2b)
Et (2c)
40
10
4a 89
4b 70
4d 82
4e 73
4f 88
4g 68
4h 89
4c 96
4c 97
4i 65
99e
98
91
97
85
540
540
540
660
2
570
1
7
n-Pr (2d)
6
n-C5H11 (2e)
Me (2b)
i-Pr (2a)
i-Pr (2a)
Bn (2f)
88
7
96e
99e
99e
77
8f
9
10
a
b
c
d
e
f
Reactions performed with aldehyde (0.3 mmol), catalyst 1a (20 mol %), and azodicarboxylate (0.2 mmol) in o-xylene (0.8 mL).
Time of amination reaction.
Isolated yield.
The ee value was determined by HPLC.
The ee value was determined by GC.
Reactions performed with isovaleral (0.3 mmol), catalyst 1a (20 mol %), and diethyl azodicarboxylate (0.2 mmol) in o-xylene (2.0 mL)
1a and 1c gave better yields and enantioselectivities (Table 1, en-
tries 1 versus 2). It is probably due to the compatibility of the
two catalytic chiral centers. The less incompatible chiral centers
in 1b and 1d probably exert no synergic or negative effects on
the enantioselectivity. So, both catalysts 1a and 1c, bearing a R,
R-linker, affording the desired products in almost the same
enantioselectivity (Table 1, entry 1), were chosen for further
optimization. After that, a range of solvents were screened for
the model reaction catalyzed by 1a or 1c at 0 °C. As shown in
Table 1, the enantioselectivities and yields are highly variable with
different solvents. In all the aprotic solvents such as n-hexane,
o-xylene, CHCl3, both 1a and 1c delivered excellent yields (up to
99%) and enantioselectivities (up to 99% ee) (Table 1, entries 2–
12). Comparatively, when the reaction was carried out in MeOH,
only poor to moderate yields (18–48%) and disappointing enanti-
oselectivities (16–54% ee) (Table 1, entry 13) were obtained. Partic-
ularly, the highest enantioselectivity (99% ee) was obtained in
o-xylene in the presence of 20 mol % 1a (Table 1, entry 5). To fur-
ther optimize the results, the reaction temperature was raised to
room temperature, while no significant improvement in yield
was observed (Table 1, entry 14). Those results indicated that 1a
was the promising catalyst and o-xylene was the suitable candi-
date solvent for this reaction (Table 1, entry 5).
and enatioselecitvities (77–99% ee). All the aldehydes gave satisfy-
ing yields and excellent enantioselectivities (Table 3, entries 1–9),
except that 3-phenylpropionaldehyde (2f) gave a relatively lower
yield (65%) and moderate enantioselectivity (77% ee) (Table 3, en-
try 10). Particularly, when DEAD was used as an acceptor, 1a
showed excellent and extraordinary reactivity and enantioselectiv-
ity for propanal and isovaleral, and the reaction finished almost in
no time (within only two minutes) after the addition of the reac-
tants (Table 3, entries 7 and 9).
Based on the experimental results and the absolute configura-
tion of the products, we suggested a plausible bifunctional catalytic
mechanism involving hydrogen binding and enamine formation as
shown in Figure 2. The azodicarboxylate might be directed and
activated by hydrogen binding interaction with the thiourea moi-
ety and thus enhances its electrophilicity, and the pyrrolidine
group activated isovaleral by the formation of enamine intermedi-
ate. The excellent reactivity and enantioselectivity may be attrib-
uted to the double activation, mutual stereo-compatibility and
chiral recognition.
In summary, we have successfully applied the newly developed
secondary amine–thiourea bifunctional catalysts 1a–d with two
catalytic sites of chiral thiourea and
L-prolic amide skeleton to pro-
mote the direct asymmetric -amination of various aldehydes with
a
To obtain better results, various azodicarboxylates 3 and cata-
lyst loadings were also screened and the results were listed in
Table 2. The reaction was performed smoothly, catalyzed by
20 mol % 1a in excellent results regardless of azodicarboxylate
3a, 3b or 3c as acceptor. The molar ratio of 2a to 3 was also studied,
however, no significant improvement was observed (Table 2, en-
tries 1, 4, 5). Further decrease of the catalyst loading of 1a from
20 to 2 mol %, the conversion was still completed within a few
hours in excellent enantioselectivities and yields (Table 2, entries
3 and 6–9). Through extensive screening, the optimized reaction
conditions were found to be 20 mol % of catalyst 1a, diethyl azodi-
carboxylate (DEAD) 3c used as donor, and 1.5 equiv isovaleral in
o-xylene at 0 °C (Table 2, entry 3).
azodicarboxylates in excellent yields (up to 99%) and enantioselec-
tivities (up to 99% ee). Further applications of those catalysts in
other reactions are currently underway in our laboratory.
O
(S)
HN
N
(R)
CO2R
(R)
N
H
N
N
S
RO2C
N
H
Under the optimized conditions, the scopes of this amination of
various aldehydes (2a–f) with azodicarboxylates (3a–c) were fur-
ther studied and the results were summarized in Table 3. All the
reactions were performed smoothly in o-xylene at 0 °C with
20 mol % 1a and afforded moderate to excellent yields (65–97%)
CF3
F3C
Figure 2. Proposed Transition State Model.

J.-Y. Fu et al. / Tetrahedron Letters 51 (2010) 4870–4873
4873
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.042.
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