Catalytic Enantioselective Synthesis of N,N-Acetals from α-Dicarbonyl Compounds Using Chiral Imidazoline-Phosphoric Acid Catalysts

Article abstract of DOI:10.1002/adsc.202001128

The enantioselective synthesis of chiral N,N-acetals derived from α-dicarbonyl compounds has been achieved. Good yields and enantioselectivities were observed for the reaction with various α-dicarbonyl compounds with 2-aminobenzamides using chiral bis(imidazoline)-phosphoric acid catalysts. Based on these experimental investigations, a possible transition state is proposed to explain the origin of the asymmetric induction. (Figure presented.).

Full text of DOI:10.1002/adsc.202001128

Title: Catalytic Enantioselective Synthesis of N,N-Acetals from α-
Dicarbonyl Compounds Using Chiral Imidazoline-Phosphoric Acid
Catalysts
Authors: Shuichi Nakamura, Tatsumi Wada, Tsunayoshi Takehara,
and Takeyuki Suzuki
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001128
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10.1002/adsc.202001128
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Enantioselective Synthesis of N,N-Acetals from α-
Dicarbonyl Compounds Using Chiral Imidazoline-Phosphoric
Acid Catalysts
Shuichi Nakamura,*,a,b Tatsumi Wada,b Tsunayoshi Takehara,c Takeyuki Suzukic
a
Department of Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Frontier Research Institute for Material Science, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-
b
8555 (Japan)
c
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047
(Japan)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Their broad utility has prompted considerable interest
to develop asymmetric methods for their preparation.
Therefore, there are several reports on the
enantioselective synthesis of chiral N,N-acetals
prepared from aldehydes,[10] aldimines[11,12] or
enamines.[13] However, the electrophilic substrates in
enantioselective N,N-acetal formation reactions were
mainly restricted to aldehyde or imines, but the
enantioselective reaction using ketones is still not
Abstract. The enantioselective synthesis of chiral N,N-
acetals derived from α-dicarbonyl compounds has been
achieved.
Good yields and enantioselectivities were
observed for the reaction with various α-dicarbonyl
compounds with 2-aminobenzamides using chiral
bis(imidazoline)-phosphoric acid catalysts. Based on these
experimental investigations, a possible transition state is
proposed to explain the origin of the asymmetric induction.
Keywords: Enantioselectivity; N,N-Acetals; Imidazoline;
Organic catalysis, Ketimines
fruitful.
The first enantioselective N,N-acetal
formation reaction with ketones was reported by List
and co-workers, who used isatin, as a ketone, together
with
2-aminobenzamide
to
give
The family of chiral N,N-acetals and their derivatives
spirodihydroquinazolinone with 84% ee.[10a] After
this pioneering work, enantioselective N,N-acetal
syntheses of 2-aminobenzamide with isatins were
reported by Shi[14] and Wang’s groups.[15] Recently,
Smith and co-workers reported the enantioselective
includes
important
compounds
active,
that
such
are
as
pharmacologically
bendroflumethiazide,[1] thiabutazide,[2] palcernuine,[3]
baloxavir
saxitoxine,[6] as well as chiral catalysts or chiral
auxiliary (Figure 1).[7]
Furthermore, 2,3-
marboxil,[4]
physostigmine,[5]
and
intramolecular
N,N-acetal
formation
of
trifluoromethyl alkyl ketimines with a pyrrole moiety
to give products with up to 98% ee.[16] The
enantioselective reactions of 2H-azirine as a ketimine
with pyrazole or indoline-2-one were reported by
Zhang,[17] and Liu and Feng’s group.[18] Wang and
co-workers reported the enantioselective tandem
cyclization of alkyne, amine, and indole using chiral
phosphoric acid catalysts.[19] Lin and Duan[20] and Li
and co-workers[21] independently reported the
enantioselective formation of N,N-acetals between
ketimines derived from isatins with amines or
triazoles using chiral thiourea catalysts. The first
highly enantioselective N,N-acetal formation reaction
with acyclic ketones was reported by Zhou and co-
workers, they examined the reaction of 2-(1H-
indolyl)anilines and trifluoromethyl ketones.[22] On
dihydroquinazolinone backbones, such as aquamox,
are important structure motifs in compounds that also
exhibit bioactivities, such as antitumor, analgesic,
antifibrillatory, antibiotic, antispermatogenic, and
vasodilatory efficacy.[2,8] In addition, the enantiomers
of some 2,3-dihydroquinazolinone compounds show
different bioactivities.[8h,9]
the
other
hand,
we
recently
developed
enantioselective C-O, C-S, and C-C bond formations
to ketimines giving chiral N,O-acetals,[23] N,S-
acetals[24] and amines having tetra-substituted carbon
Figure 1. Examples of biologically active N,N-acetals
1
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10.1002/adsc.202001128
Advanced Synthesis & Catalysis
centers,[25] and novel chiral imidazoline-phosphoric
acid catalysts.[26] Herein, our ongoing interest was
extended to the catalytic N,N-acetal formation
reaction of acyclic ketones with 2-aminobenzamide
using chiral imidazoline-phosphoric acid catalysts
(Figure 2).
an ethanesulfonyl group to a tosyl or a 1-
naphthalenesulfonyl group (Table 1, entries 2 and 3).
Mono-imidazoline-phosphoric acid catalyst 3d
showed low enantioselectivity (Table 1, entry 4). We
also examined commercially available chiral
phosphoric acid catalysts 3e,f having triphenylsilyl or
a 3,5-bis(trifluoromethyl)phenyl group to afford 4aa
with low enantioselectivity (Table 1, entries 5 and
6).[27] To improve enantioselectivity, we optimized
the structure of α-ketoesters 2a-e (Table 1, entries 7-
10). As a result, the reaction using α-ketoester 2e
having a benzhydryl group gave product 4ae with
high enantioselectivity but in moderate yield (Table 1,
entry 10). To our delight, the reaction using 3.0
equivalent of α-ketoester at a lower temperature
improved the yield and enantioselectivity of the
product (Table 1, entry 11).
Figure 2. Enantioselective formation of N,N-acetals by the
reaction of ketones with 2-aminobenzamides
We first examined the enantioselective reaction of 2-
aminobenzamide 1a (1.0 equiv.) with various α-
ketoesters 2a-e (1.2 equiv.) using 10 mol% of chiral
phosphoric acid catalysts 3a-f. The results are shown
in Table 1. The reaction of 1a with 2a using chiral
bis(imidazoline)-phosphoric
acid
catalyst
3a
Next, we examined the reaction of various
aminobenzamides 1a-e with α-ketoesters 2e-q using
catalyst 3c (Table 2). The reaction of 2e with 1b
having an electron-donating methyl group showed
good enantioselectivity and yield of product (Table 2,
entry 2). The reaction of 1c-e bearing electron-
proceeded to give product 4aa in good yield albeit
with low enantioselectivity (Table 1, entry 1). The
enantioselectivity was improved by changing the
substituent on nitrogen in imidazoline catalysts from
Table 1. Optimization of the reaction of various α-
ketoesters 2a-e with 2-aminobenzamide 1a using chiral
catalysts 3a)
Table 2. The reaction of various 2-aminobenzamides 1a-e
with various α-ketoesters 2e-q using 3ca)
Entry
1
2
Product Time Yield Ee
(h)
(%)
99
88
84
79
77
90
91
93
77
87
81
95
88
85
77
95
88
(%) b)
92
82
96
93
95
93
93
91
92
92
93
85
86
95
93
76
89
1
160
120
120
160
240
140
140
140
140
140
210
168
190
140
90
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2e
2e
2e
2e
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
4ae
5
6
7
8
2 b)
3 b)
4 b)
5 b)
6
Entry
2
3
Temp
(oC)
70
70
70
70
70
70
70
70
70
70
rt
Time Yield Ee
(h)
72
72
72
72
72
72
72
72
72
72
160
(%)
73
88
75
74
14
91
71
70
91
52
99
(%) b)
38
64
70
27
9
9
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
3a
3b
3c
3d
3e
3f
3c
3c
3c
3c
3c
7 b)
8 b)
9
10
11
10
11
12
13
14
15
16
17
18
19
20
1
12 b,c)
13 b)
14 b)
15 b)
16 c,d)
17 b,c)
74
23
70
89
92
9
10
11 c)
48
15
a)
Reaction conditions: The reaction was carried out using
a) Reaction conditions: The reaction was carried out using 1
(0.1 mmol), 2 (3.0 equiv.), and 3c (10 mol%) in 1,2-
1a (0.1 mmol), 2 (1.2 equiv.), and 3 (10 mol%) in 1,2-
o
b)
dichloroethane (0.1 M) at 70 C. Enantiomer excess was
determined by HPLC analysis using chiral column. c) 2e
(3.0 equiv.) was used.
dichloroethane (0.1 M) at rt. b) 2 (5.0 equiv.) was used.
c)
The reaction was carried out using 20 mol% of 3c. d) The
reaction was carried out at 0 oC.
2
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10.1002/adsc.202001128
Advanced Synthesis & Catalysis
withdrawing groups, such as a fluoro, chloro, and
bromo groups, also gave products 6-8 in high yield
with high enantioselectivity (77-84%, 91-96% ee,
Table 2, entries 3-5).[28] The reaction of 1a with 2f,g
having a methyl group in the meta or para position
gave products 9,10 in high yield with high
enantioselectivity (93% ee, Table 2, entries 6 and 7).
The reaction with 2h-m bearing an electron-
withdrawing group in ortho, meta, and para positions
gave products 11-16 in high yield with high
enantioselectivity (75-95%, 85-93% ee, Table 2,
entries 8-13). 2-Naphthyl and 3-thienyl α-ketoesters
2n and 2o gave products 17,18 with high
enantioselectivity (Table 2, entries 14 and 15).
Furthermore, the reaction of alkyl-substituted α-
ketoesters 2p or 2q with 1a gave products 19,20 in
good yield with high enantioselectivity (Table 2,
entries 16 and 17).
absolute configuration of 24 was determined as (R)
by X-ray crystallographic analysis,[29] and the
configuration of other products was tentatively
assumed by analogy. The amidation of 4ae in NH3
afforded amide 25 in high yield without the loss of
enantiopurity.
Scheme 3. Transformation of N,N-acetals to chiral
alcohols 24 and amide 25
We also examined the enantioselective synthesis of
N,N-acetals by the reaction of N-benzyl isatin 2r as a
cyclic α-ketoamide compound, benzil 2s as an acyclic
diketone, or benzaldehyde 2t with 2-aminobenzamide
1a. The reaction using 3c afforded products 21-23 in
high yield with good enantioselectivity (91-93% ee,
Scheme 1). The absolute stereochemistry of products
21 and 23 were determined to assigned to be S in
comparison with the value of the specific rotation
reported in the literature.[10d,14]
The assumed catalytic cycle for the reaction of α-
ketoesters 2 with aminobenzamides 1 is shown in
Figure 3.
Catalyst 3c makes intramolecular
hydrogen-bonding between phosphoric acid and
imidazoline,[26] it activates α-ketoester 2 by a
hydrogen-bonding interaction, then aminobenzamide
1
reacts to α-ketoester
2
to afford an o-
iminobenzamide intermediate. The intramolecular
nucleophilic addition of an amide group in o-
iminobenzamide to the imine moiety gives chiral
N,N-acetals.
We checked the retro-N,N-acetal
formation reaction of product 4ae using catalyst 3c
and the cross- N,N-acetal formation reaction of
product 4ae with 1b using 3c. These reactions did
not change the structure or enantiopurity of products.
Therefore, the stereoselectivity of the reaction is
kinetically controlled.
Scheme 1. Enantioselective reaction of N-benzylisatin 2r,
benzil 2s, or benzaldehyde 2t with 2-aminobenzamide 1a
The gram-scale synthesis of N,N-acetal 4ae via the
reaction of 0.4 g of 1a with 2e using catalysts 3c
successfully proceed to afford 1.2 g of 4ae (Scheme
2).
Figure 3. Proposed reaction cycle of the reaction of α-
ketoesters 2 with 2-aminobenzamides 1 using catalyst 3
Scheme 2. Gram-scale synthesis of N,N-acetal 4ae by the
reaction of 1a with 2e using catalyst 3c.
Furthermore, we also examined the reaction of α-
ketoester 2e and 2-amino-N-methylbenzamide 1f, but
the reaction did not afford any product (Scheme 4).
This result implies the importance of the activation of
the intermediate imine with a chiral phosphoric acid
catalyst.
We next examined the transformation of N,N-acetals.
Reduction of the ester group in product using sodium
borohydride in THF/EtOH gave corresponding
primary alcohol 24 in high yield (Scheme 3). The
3
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10.1002/adsc.202001128
Advanced Synthesis & Catalysis
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Scheme 4. Reaction of 2-amino-N-methylbenzamide 1f
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In conclusion, we developed the highly
enantioselective synthesis of N,N-acetals derived
from
α-dicarbonyl
compounds
and
2-
aminobenzamides using chiral bis(imidazoline)-
phosphoric acids catalysts. Various α-ketoesters and
2-aminobenzamides can be applied in the process.
Further studies are in progress to the synthesize chiral
cyclic compounds having a tetra-substituted carbon
center.
Experimental Section
2-Aminobenzamide 1a (13.6 mg, 0.1 mmol) was
added to a solution of bis(imidazoline)-phosphoric
acid catalyst 3c (11.7 mg, 10 mol%) and α-ketoester
2e (94.9 mg, 0.3 mmol) in dichloroethane (1.0 mL) at
r.t. After stirred for 160 h, the mixture was purified
over silica gel column chromatography (hexane/ethyl
acetate=70:30) to give 4ae (43.2 mg, 99%, 92% ee).
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4
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Advanced Synthesis & Catalysis
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10.1002/adsc.202001128
Advanced Synthesis & Catalysis
COMMUNICATION
Catalytic Enantioselective Synthesis of N,N-
Acetals from α-Dicarbonyl Compounds Using
Chiral Imidazoline-Phosphoric Acid Catalysts
Adv. Synth. Catal. Year, Volume, Page – Page
Shuichi Nakamura,*,a,b Tatsumi Wada,b Tsunayoshi
Takehara,c Takeyuki Suzukic
6
This article is protected by copyright. All rights reserved.