Construction of quaternary stereocenters: Asymmetric α-amination of branched aldehydes catalyzed by monoimide substituted cyclohexane-1,2-Diamines

Article abstract of DOI:10.1002/chir.22203

A highly efficient enantioselective α-amination of branched aldehydes catalyzed by chiral imide monosubstituted 1,2-diamine derivatives was reported to afford the quaternary stereogenic centers in excellent yields (up to 99%) and enantioselectivities (up to 97% ee). Chirality 25:668-672, 2013. 2013 Wiley Periodicals, Inc α-Amination of branched aldehydes with azadicarboxylate was efficiently promoted by monoimide substituted cyclohexane-1,2-diamines, and the chiral quaternary amino aldehydes were successfully achieved in excellent yields (up to 99%) and enantioselectivities (up to 97% ee).

Full text of DOI:10.1002/chir.22203

CHIRALITY 25:668–672 (2013)
Construction of Quaternary Stereocenters: Asymmetric a-Amination
of Branched Aldehydes Catalyzed by Monoimide Substituted
Cyclohexane-1,2-Diamines
1
1
JI-YA FU,1,2 QI-LIN WANG,1,3 LIN PENG,1 YONG-YUAN GUI,1,3 XIAO-YING XU, AND LI-XIN WANG
*
*
1Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences, Chengdu, P.R. China
2College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan, P.R. China
3University of Chinese Academy of Sciences, Beijing, P.R. China
ABSTRACT
A highly efficient enantioselective a-amination of branched aldehydes catalyzed
by chiral imide monosubstituted 1,2-diamine derivatives was reported to afford the quaternary
stereogenic centers in excellent yields (up to 99%) and enantioselectivities (up to 97% ee).
Chirality 25:668–672, 2013. © 2013 Wiley Periodicals, Inc
KEY WORDS: asymmetric amination; branched aldehydes; primary amine
INTRODUCTION
ligand,28–32 and chiral thioureas.33–35 Imide monosubstituted-
1,2-diamines, the key intermediates in the preparation of those
chiral molecules, have drawn our attention and were
successfully applied to asymmetric double Michael reaction36
and enantioselective Diels-Alder reaction of anthrone with
maleimide.37 On the other hand, our group is interested in
developing new methods to construct substituted amino
aldehydes and successfully applied chiral thioureas, amino
acids in the amination of aldehydes with excellent results.16,
Asymmetric amination is one of the most important
methods for the direct asymmetric formation of C-N bonds
and widely applied in organic synthesis.1–4 In particular, a-
amination of branched aldehydes is an efficient method to
access optically active nitrogen-containing compounds with
chiral quaternary stereogenic centers, which are versatile
synthetic motifs for the preparation of biologically active
natural products and pharmaceuticals.5–8 Typically, a,a-
disubstituted amino aldehydes are important building blocks
and key intermediates to construct a-amino alcohols and
unnatural a-amino acids.9,10 Since Bräse and colleagues
reported the first example of amination of branched aldehyde
in moderate enantioeslectivities,11 several asymmetric
protocols have been reported.12–15 However, there were still
no efficient and satisfactory asymmetric methods until our
group reported a highly effective a-amination of branched
aldehydes promoted by chiral proline-derived amide thiourea
bifunctional catalysts in excellent yields (up to 99%) and
enantioselectivities (up to 97% ee).16 After that, an ion pair
catalyst of 9-amino(9-deoxy)epi-quinine and (-)-CSA was
applied in this transformation.17 And in 2011, our group
disclosed that the simple primary amino acid of 3-(1-naphthyl)
alanine may catalyze the amination of branched aldehydes
with high enantioselectivities.18 Even so the direct
enantioselective preparations of unnatural chiral a-amino
acids, especially chiral quaternary amino acids, are still
challenges. Considering asymmetric a-amination of branched
aldehydes, easily and cheaply available, may be one of the
most efficient and direct means to fulfill this goal and for
further and deep understanding and expanding this useful
asymmetric transformation, it is still desirable to develop
simple, easily available catalysts for various multifunctional
preparations of optically active chiral a,a-disubstituted
amino compounds.
18, 15j
Based on these achievements and our continuing
interests in asymmetric synthesis promoted by chiral amine
catalysis,16,18,38–42 herein we report the asymmetric a-amination
of branched aldehydes with azodicarboxylates catalyzed by
simple chiral imide monosubstituted 1,2-diamine derivatives in
excellent enantioselectivities.
In the course of our deep and systematic study on asymmetric
amination of aldehydes, we found that the imide
monosubstituted and unsymmetric chiral cyclohexane 1,2-di-
amine 1a, not the C2 symmetric counterpart 1i, showed high
reactivity and enantioselectivity in this transformation, which
might be attributed to the introduction of bulkier substituents.
Encouraged by the primary outstanding results, imide
monosubstituted-1,2-diamines catalysts 1a-1f bearing different
chiral diamine skeletons were synthesized,34,35,43,44 and primary
thiourea bifunctional catalysts 1g, 1h, and 1,2-diaminocyclo-hex-
ane were also chosen as the counterparts (Fig. 1). 2-Phenyl-
propionaldehyde (2a) and diethyl azadicarboxylate (DEAD)
(3a) were used as the model substrates and the results were
summarized in Table 1.
All the cases gave the desired amination products 4a in
moderate to excellent yields (61–99%) and poor to good
enantioselectivities (29–89% ee; Table 1, entries 1–9). Catalysts
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant number: 21272230.
RESULTS AND DISCUSSION
*Correspondence to: X.-Y. Xu or L.-X. Wang, Key Laboratory of Asymmetric
Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu 61004, P.R.
China. E-mail: wlxioc@cioc.ac.cn or xuxy@cioc.ac.cn
Received for publication 19 April 2013; Accepted 24 May 2013
DOI: 10.1002/chir.22203
Chiral amines have emerged as powerful tools in asymmetric
catalysis.19–24 Among them, 1,2-diphenylethane-1,2-diamine
and cyclohexane-1,2-diamine are widely used as starting
materials for the preparation of chiral reagents, ligands, and
catalysts, such as Jacobsen’s salen ligands,25–27 Trost’s
© 2013 Wiley Periodicals, Inc.
Published online 16 July 2013 in Wiley Online Library
(wileyonlinelibrary.com).

CONSTRUCTION OF QUATERNARY STEREOCENTERS
669
Fig. 1. Screened primary amine catalysts.
1a-1f afforded the a,a-disubstituted amino compounds in
moderate to excellent yields and enantioselectivities (61–99%
yield, 49–89% ee; Table 1, entries 1–6). Catalyst 1d with a
cyclohexanediamine chiral scaffold afforded better yield and
enantioselectivity than 1f with a diphenyldiamine scaffold,
and it seemed that introduction of a bulkier group or more
conjugated aromatic ring would be beneficial to the reaction.
Catalyst 1c with a bulkier group gave better enantioselectivity
than 1b, which revealed that the catalytic activities and
enantioselectivities are highly dependent on steric hindrances
of imide monosubstituted groups (Table 1, entry 2 vs. 3).
When catalyst 1e with naphthyl group was employed, an
obvious increase in enantioselectivity was observed
(Table 1, entry 5).
To further optimize the reaction conditions, a number of
solvents and additives were also examined in the presence of
20 mol% 1d or 1e at 25ꢀC, and the results are described in
Table 2. The reaction media significantly affected the yields
and enantioselectivities. Almost all the solvents gave moderate
to good yields and enantioselectivities (up to 90% ee). Less polar
solvents gave high yields and enantioselectivities (Table 2,
entries 4–7), whereas a polar solvent such as DMF afforded poor
yield and enantioselectivity (Table 2, entry 10). Chlorinated sol-
vents were found to be more suitable for both 1d and 1e (Table 2,
entries 4–7). Especially 1,2-dichloroethane (DCE) afforded the
best results (99% yield, 90% ee; Table 2, entry 6) in the
presence of catalyst 1e, and was chosen as the optimal solvent.
To further increase the enantioselectivities, a series of acid
additives and the reaction temperature were evaluated (Table 2,
entries 12–16). As shown in Table 2, TFA was the most
favorable additive. the reaction temperature slightly affected
the enantioselectivities, and lower temperatures had almost
no effect on the enantioselectivity, while dramatically
decreasing the yield and reaction rate (Table 2, entries 6, 17,
18); better yields and enantioselectivities were observed at
25ꢀC. Subsequently, the amount of additive and catalyst was
also examined. Better results were obtained when 20 mol%
additive was added (99% yield and 90% ee; Table 2, entry 6),
as well as when the catalyst loadings were reduced to 10 mol
% (91% ee) (Table 2, entry 21). Based on the comprehensive
screenings, the optimal reaction conditions were established as
shown in Table 2, entry 21.
Under the optimized conditions, various azodicarboxylates
and branched aldehydes were also examined and the results
are summarized in Table 3. Substituents on azodicarboxylates
and branched aldehydes were well tolerated, affording the
desired adducts in moderate to excellent yields (up to 99%)
and excellent enantioselectivities (up to 97% ee). Basically, the
steric hindrance of azodicarboxylates had no obvious effects
on the enantioselectivities and yields, and all the cases gave
good results (91–96% yield and 88–93% ee; Table 3, entries
1–4). A range of substituted aromatic aldehydes were also
studied, and the substituents on the phenyl ring showed no
evident effects on the yields and enantioselectivities (Table 3,
entries 5–13). Both electron-withdrawing and -donating
substituents afforded poor to excellent yields (38–99% yields;
Table 3, entries 5–13) and good to excellent enantioselectivities
(81–97% ee; Table 3; entries 5, 6, 8–13) except 4-nitrophenyl
Chirality DOI 10.1002/chir
TABLE 1. Reaction of 2-phenyl-propionaldehyde with DEAD
catalyzed by 1a-1i a
Entry
Cat.
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
2
2
1
2
1
16
30
4
88
98
96
99
85
61
65
76
87
78
56
80
86
89(R)
49
40
66
29
4
aUnless otherwise specified, all reactions were carried out with 2-phenyl-
propionaldehyde (2a, 0.30 mmol), diethyl azodicarboxylate (3a, 0.20 mmol),
the catalyst (20 mol%) and TFA (20 mol%) in CH2Cl2 (1.0 mL) at 25ꢀC.
bIsolated yield.
cDetermined by HPLC with a Chiralpak-AS column and the absolute configu-
ration of 4a was assigned as R.5h

670
FU ET AL.
Chirality DOI 10.1002/chir

CONSTRUCTION OF QUATERNARY STEREOCENTERS
671
TABLE 3. Asymmetric amination of branched aldehydesa
Entry
R1
R2
Et
i-Pr
t-Bu
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Bn
Time (h)
Product
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
5
4
4
(+)-4a
(+)-4b
(+)-4c
(+)-4d
(+)-4e
(+)-4f
(+)-4g
(+)-4h
(+)-4i
(+)-4j
(+)-4k
(-)-4l
96
94
92
91
88
38
94
>99
62
38
94
47
95
75
90
77
91
93
90
88
91
97
54
95
93
81
89
78
93
76
90
57
1.5
48
155
48
3
18
144
3
24
3
48
2
4-CH3OPh
4-CH3Ph
4-NO2Ph
4-BrPh
4-FPh
4-ClPh
3-ClPh
2-ClPh
2-naphthyl
2-CH3Ph
3-CH3OPh
n-Pr
9
10
11
12
13
14
15
16
(+)-4m
(-)-4n
(+)-4o
(+)-4p
3
aUnless otherwise specified, all reactions were carried out with branched aldehydes (2, 0.30 mmol), azodicarboxylate (3, 0.20 mmol), 1e (10 mol%) and TFA (10 mol%),
ClCH2CH2Cl (1.0 mL) at 25ꢀC.
bIsolated yield.
cDetermined by HPLC with a Chiralpak column.
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amino aldehydes in excellent yields (up to 99%) and
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ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (No. 21272230).
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Chirality DOI 10.1002/chir