A catalytic asymmetric Ugi-type reaction with acyclic azomethine imines

Article abstract of DOI:10.1002/anie.201201905

An unconventional Ugi: A catalytic asymmetric Ugi-type reaction can be realized by use of N'-alkylbenzohydrazide, instead of a conventional amine, in the presence of an axially chiral dicarboxylic acid. The reaction proceeds through a key acyclic azomethi

Full text of DOI:10.1002/anie.201201905

Angewandte
Chemie
DOI: 10.1002/anie.201201905
Organocatalysis
A Catalytic Asymmetric Ugi-type Reaction With Acyclic Azomethine
Imines**
Takuya Hashimoto, Hidenori Kimura, Yu Kawamata, and Keiji Maruoka*
More than half a century ago, Ugi reported a four-component
reaction consisting of an aldehyde, a primary amine, an
isocyanide and a carboxylic acid.[1] Whereas the ease of
assembling a variety of complex structures in one step has
prompted its widespread application in a range of organic
syntheses,[2] the realization of a catalytic asymmetric Ugi
reaction still remains a largely unsolved issue, owing to its
and the carboxylic acid could be regenerated to enter the next
catalytic cycle.[9]
As
a source of the isocyanide, we opted to use
2-benzoyloxyphenyl isocyanide 3a developed by Pirrung
and co-workers,[10] because of its odorless nature, and more
importantly, its equivalency to a pharmaceutically valuable
benzoxazole unit (see below).[11] Preliminary experiments
using benzaldehyde and N’-benzylbenzohydrazide (2a) in the
presence of the representative chiral dicarboxylic acids (R)-
1a and (R)-1b were rather disappointing in terms of both the
À
logical limitation. Namely, whereas the crucial C C bond
formation between the isocyanide and the imine is thought to
be a carboxylic acid catalyzed process (Scheme 1), the
reactivity and selectivity (Table 1, entries 1 and 2).[7,12]
A
Table 1: Optimization of reaction conditions.[a]
Entry R2
Cat. Solvent
Temp. [8C],
time [h]
Yield
[%][b]
ee
[%][c]
Scheme 1. Ugi-type reaction of imines and acyclic azomethine imines.
1
2
3
4
5
Bn (2a)
1a toluene
1b toluene
1c toluene
1d toluene
1d toluene
0, 24
0, 24
0, 24
0, 24
0, 24
12
10
73
85
94
À7
À6
15
55
82
carboxylic acid is then taken up in the product, thus ruling
out the possibility of using a catalytic amount of chiral
carboxylic acid. The only solution reported to date is the use
of isocyanoacetamides in the presence of chiral phosphoric
acid,[3,4] a strategy that is more successful in the related
Passerini reaction.[5,6]
To provide a completely new solution to this long-standing
problem, we came up with an idea to use acyclic azomethine
imines I, which was recently revealed by us as a novel
prochiral electrophile generated with a catalytic amount of
axially chiral dicarboxylic acid.[7,8] By applying this reaction
system in the Ugi reaction, we envisaged that the interme-
diary nitrilium ion II would be trapped internally by the
oxygen of the hydrazide to give heterocyclic compound III,
2-MeOBn
(2b)
6
7
1d toluene
À20, 24
70
70
88
93
85
89
90
93
1d mesitylene À20, 24
8
1d m-xylene
1d m-xylene
À20, 24
9[d]
À30, 40
[a] Performed with (R)-1 (0.0025 mmol), benzaldehyde (0.06 mmol),
benzohydrazide 2 (0.050 mmol), isocyanide (0.060 mmol), and 4 ꢀ M.S.
(50 mg). [b] Yield of isolated product. [c] Determined by chiral-phase
HPLC analysis. [d] Performed with (R)-1d (0.005 mmol), benzaldehyde
(0.12 mmol), benzohydrazide 2b (0.10 mmol), isocyanide (0.12 mmol),
and 4 ꢀ M.S. (100 mg). Bn=benzyl, Bz=benzoyl, M.S.=molecular
sieves.
[*] Dr. T. Hashimoto, H. Kimura, Y. Kawamata, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
considerable improvement in reactivity was observed by using
catalyst (R)-1c, which bears 3,5-bis(trifluoromethyl)phenyl
groups, although the selectivity remained very low (entry 3).
As a next step, we introduced catalyst (R)-1d, which bears
3,5-dinitrophenyl groups. Through the use of this catalyst, the
enantioselectivity could be dramatically increased to 55% ee
(entry 4). To further improve the enantioselectivity of the
process, we then screened a variety of hydrazides bearing
Sakyo, Kyoto, 606-8502, (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201905.
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Communications
different functionalities. This study revealed a positive effect
from the use of N’-(2-methoxybenzyl)benzohydrazide (2b),
with which the corresponding heterocycle was obtained in
82% ee (entry 5). In the final optimization, solvents and
temperatures were screened (entries 6–8). The optimal con-
ditions were determined to be m-xylene at À308C, which gave
the product in 93% yield with 93% ee (entry 9).
With the optimized reaction conditions in hand, we turned
our attention to the screening of aldehydes (Table 2). Among
Table 2: Catalytic asymmetric Ugi-type reaction using acyclic azome-
thine imines.[a]
Entry
R3
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
93
79
85
55
94
95
99
97
95
93
90
87
59
92
92
90
88
90
85
85
68
42
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-BrC6H4
4-MeOC6H4
3-MeOC6H4
2-naphthyl
cyclohexyl
PhCH2CH2
9[d]
10
11
12[e]
13[f]
4j
4k
4l
98
>99
89
4m
66
[a] Performed with (R)-1d (0.005 mmol), aldehyde (0.12 mmol), benzo-
hydrazide 2b (0.10 mmol), isocyanide 3a (0.12 mmol), and 4 ꢀ M.S.
(100 mg) in m-xylene (1.0 mL). [b] Yield of isolated product. [c] Deter-
mined by chiral-phase HPLC analysis. [d] 96 h. [e] À408C, 48 h.
[f] À408C, 20 h. M.S.=molecular sieves.
Scheme 2. One-pot catalytic asymmetric Ugi-type reaction/ring recon-
struction. i) (R)-1d (0.005 mmol), benzaldehyde (0.12 mmol), benzohy-
drazide 2b (0.10 mmol), isocyanide 3 (0.12 mmol), and 4 ꢀ M.S.
(100 mg) in m-xylene (1.0 mL). ii) K2CO3 (0.30 mmol) and CF3CH2OH
(1.0 mL). Yields reported are of isolated products. Enantiomeric
excesses were determined by chiral-phase HPLC analysis. Bn=benzyl,
Bz=benzoyl, M.S.=molecular sieves.
the variety of substituents on the aromatic ring, both 3- and
4-tolualdehydes could be employed without affecting the
enantioselectivity (Table 2, entries 2 and 3). The use of
2-tolualdehyde led to a decrease in both the reactivity and
selectivity (entry 4). Irrespective of the electronic properties
of aldehydes, the reaction proceeded well, producing hetero-
cycles with ee values ranging from 85–92% (entries 5–10).
2-Naphthaldehyde could also be employed without difficulty
(entry 11). Aliphatic aldehydes like cyclohexanecarbalde-
hyde and hydrocinnamaldehyde showed fairly good reactiv-
ities, but modest selectivities (entries 12 and 13), leaving room
for future improvement. The absolute configuration of the
product was determined to be R by the derivatization of 4a
(see the Supporting Information).
mediated cleavage of the benzoyl moiety derived from the
isocyanide after the Ugi-type reaction, as it generates
a benzoxazole moiety in the product. Accordingly, 2-benzoy-
loxyaryl isocyanides can be regarded as masked benzoxazoles
with a nucleophilic C2 position.
Our experiment determined that treatment of the Ugi-
type reaction solution with K2CO3 and CF3CH2OH was the
method of choice, through which benzoxazole 6a was
obtained in 97% yield and 90% ee in the reaction with
2-benzoyloxyphenyl isocyanide 3a. A mild base was crucial to
prevent racemization of the product. A variety of isocyanides
could be utilized as well, to give the desired products 6b–g in
consistently high yields and enantioselectivities, irrespective
of the electronic properties and the position of the aryl
substituent in the isocyanide employed.
The heterocyclic ring of 4a could be easily hydrolyzed
under acidic conditions to give the corresponding a-hydrazino
amide 5 without loss in the enantioselectivity [Eq. (1); Bn =
benzyl, Bz = benzoyl].
The benzamide moiety of the products can be subse-
À
The successful implementation of this catalytic asymmet-
ric Ugi-type reaction with acyclic azomethine imines gener-
ated in situ then prompted us to focus on the isocyanide part
(Scheme 2). For this study, we devised a one-pot base-
quently removed by SmI2 mediated reductive N N bond
cleavage to give chiral diarylmethylamine 7, which bears
a unique benzoxazole unit, without deterioration in the
enantioselectivity [Eq. (2); Bn = benzyl, Bz = benzoyl].
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[6] a) S. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Eur. J. Org. Chem.
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[7] T. Hashimoto, H. Kimura, Y. Kawamata, K. Maruoka, Nat.
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incorporating a carboxylic acid; see: M. Krasavin, E. Bushkova,
V. Parchinsky, A. Shumsky, Synthesis 2010, 933, and references
therein.
In summary, we have succeeded in developing a new
strategy to implement an Ugi-type reaction in a catalytic
asymmetric manner through the use of an axially chiral
dicarboxylic acid and acyclic azomethine imines generated
in situ. This three-component reaction gave rise to hetero-
cycles with high enantioselectivities, which could be easily
transformed into a variety of chiral molecules.[13]
[10] a) M. C. Pirrung, S. Ghorai, J. Am. Chem. Soc. 2006, 128, 11772;
b) M. C. Pirrung, S. Ghorai, T. R. Ibarra-Rivera, J. Org. Chem.
2009, 74, 4110.
Received: March 10, 2012
Revised: April 3, 2012
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Published online: June 12, 2012
Keywords: azomethine imine · chiral Brønsted acid ·
.
isocyanides · multicomponent reaction · Ugi reaction
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