Asymmetrie imino aza-enamine reaction catalyzed by axially chiral dicarboxylic acid: Use of arylaldehyde N,N-dialkylnydrazones as acyl anion equivalent

Article abstract of DOI:10.1021/ja802704j

Synthetic utility of arylaldehyde N,N-dialkylhydrazones as a practical acyl anion equivalent could be exploited for the first time in the asymmetric imino aza-enamine reaction catalyzed by axially chiral carboxylic acid. Copyright

Full text of DOI:10.1021/ja802704j

Published on Web 05/21/2008
Asymmetric Imino Aza-enamine Reaction Catalyzed by Axially Chiral
Dicarboxylic Acid: Use of Arylaldehyde N,N-Dialkylhydrazones as Acyl Anion
Equivalent
Takuya Hashimoto, Maya Hirose, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received April 13, 2008; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Aza-enamine Property of N,N-Dialkylhydrazone
The use of an acyl anion equivalent generated by the reactivity
umpolung1 of aldehydes provides a distinctive opportunity for the
expedient C-C bond formation, as represented by well-established
dithiane chemistry.2 Aldehyde N,N-dialkylhydrazone, which can
be easily prepared by the condensation of the corresponding
aldehyde and N,N-dialkylhydrazine, is also known as a class of
acyl anion equivalent due to its aza-enamine structure.3 The
synthetic utility of such hydrazones has been explored in the past
four decades, taking advantage of their ready availability and ease
of removal after the reaction (Scheme 1).4 However, their applica-
tion in the field of asymmetric synthesis has been limited only to
the use of formaldehyde N,N-dialkylhydrazone bearing no sub-
stituent at the azomethine carbon atom of the hydrazone (R ) H,
Scheme 1). This limitation has long been considered a result of
the poor nucleophilicity of aryl or aliphatic aldehyde N,N-
dialkylhydrazones, thereby requiring a highly electrophilic reaction
partner, such as sulfonyl isocyanates,5 Vilsmeier reagent,6 or
trifluoroacetic anhydride.7
Table 1. (R)-1-Catalyzed Asymmetric Addition of Formaldehyde
N,N-Dialkylhydrazone to N-Boc Iminesa
entry
R1
R′
solvent
% yieldb
% eec
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
(CH2)4
(CH2)4
(CH2)4
CH3
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
CH2Cl2
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
82
53
89
23
80
76
83
70
76
86
82
81
93
96
87
93
99
93
97
97
89
95
We here wish to report that axially chiral dicarboxylic acid (R)-
1, which has been recently developed in our laboratory as a new
class of chiral Brønsted acid,8,9 has a unique ability to catalyze the
unprecedented asymmetric addition of arylaldehyde N,N-dialkyl-
hydrazones to N-Boc imines. This novel transformation provides a
facile access to enantiomerically enriched R-amino ketones.10,11
Concerning the catalytic asymmetric reaction of formaldehyde
N,N-dialkylhydrazone to N-Boc imines, there have been two reports
to date, wherein the reaction was accomplished by chiral Brønsted
acid using binaphthol12 or phosphoric acid13 as the hydrogen-bond
donor.14 However, the enantiomeric excesses of the products
remained at moderate to good levels. Moreover, the use of aryl or
aliphatic aldehyde N,N-dialkylhydrazones was completely unex-
plored. We initiated our study on the renovation of this reaction
by resorting to the distinctive acidity and chiral efficiency of
dicarboxylic acid catalyst (R)-1.
3-MeC6H4
2-Np
4-MeOC6H4
4-ClC6H4
2-BrC6H4
2-furyl
9
10
11d
Ph
a Reactions were performed with arylaldehyde N-Boc imine (0.10
mmol) and formaldehyde N,N-dialkylhydrazone (0.12 mmol) in the
presence of
5 mol %
of (R)-1 (0.005 mmol). b Isolated yield.
c Determined by chiral HPLC analysis. d Performed with 2 mol % of
(R)-1 for 24 h.
property of the aryl moiety, the products could be obtained in good
yields with excellent enantioselectivities. The reaction with het-
eroarylaldehyde N-Boc imine was also feasible, although the
enantioselectivity decreased slightly (entry 10). The catalyst loading
could be further reduced to 2 mol % uneventfully, although the
longer reaction time was required (entry 11).
Encouraged by the remarkable efficiency realized by the use of
chiral dicarboxylic acid (R)-1, our attention has been focused on a
yet-unsolved task: use of arylaldehyde N,N-dialkylhydrazones in
asymmetric synthesis. As a preliminary experiment, the reaction
of benzaldehyde N,N-tetramethylenehydrazone 4 (R2 ) Ph) and
benzaldehyde N-Boc imine was conducted under the identical
reaction conditions described above to give the desired adduct in
low yield with the promising asymmetric induction of 92% ee
(Table 2, entry 1).15
In the early stage of this investigation, we were pleased to find
the unexpectedly high catalytic activity of (R)-1 compared to that
of previously utilized chiral Brønsted acids.12,13 The reaction of
benzaldehyde N-Boc imine 2 (R1 ) Ph) and formaldehyde N,N-
tetramethylenehydrazone 3 (R′ ) (CH2)4) catalyzed by 5 mol %
of (R)-1 in CH2Cl2 was complete within 4 h at -20 °C (Table 1,
entry 1). After a brief screening of the solvent, the use of chloroform
was found to be optimal to attain high asymmetric induction, giving
the adduct in 89% yield with 96% ee. Use of N,N-dimethylhydra-
zone 3 (R′ ) CH3) was found to deteriorate both the yield and
enantioselectivity (entry 4). In all experiments, molecular sieves
were added to scavenge the adventitious water, which would cause
the undesired hydrolysis of N-Boc imine. The scope of the reaction
with various arylaldehyde N-Boc imines was then surveyed (entries
5-9). Irrespective of the substituent pattern and the electronic
After slight modification of the reaction parameters, including
the use of lower temperature, prolonged reaction time, and 3 equiv
9
7556 J. AM. CHEM. SOC. 2008, 130, 7556–7557
10.1021/ja802704j CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. (R)-1-Catalyzed Asymmetric Addition of Arylaldehyde
N,N-Tetramethylenehydrazones to Benzaldehyde N-Boc Iminea
Scheme 2. Transformation of R-Amino Hydrazone to the
Corresponding R-Amino Ketone by Ozonolysis
entry
R2
conditions (°C, h)
% yieldb
% eec
1d
2
3
4
5
Ph
Ph
3-tolyl
2-Np
4-MeOC6H4
4-ClC6H4
-20, 4
16
66
51
56
55
60
92
95
92
92
92
91
ceeded as well, giving the product in 67% yield with 91% ee (entry
7). At this moment, the use of N-Boc imines and hydrazones derived
from aryl aldehydes is considered to be inevitable.
-30, 96
-30, 96
-30, 96
-30, 96
-30, 96
Optically active R-amino hydrazones thus obtained can be easily
transformed into the corresponding R-amino ketones as exemplified
in Scheme 2. The removal of the hydrazone moiety of the R-amino
hydrazone 5 could be facilitated by ozonolysis, giving the corre-
sponding R-amino ketone in good yield without a deleterious effect
on enantioselectivity. Absolute configuration of the adduct 5 was
deduced from this R-amino ketone by comparison of the optical
rotation of the same R-amino ketone derived from (R)-phenylgly-
cine.
6
a Reactions were performed with benzaldehyde N-Boc imine (0.10
mmol) and arylaldehyde N,N-tetramethylenehydrazone (0.30 mmol) in
the presence of 5 mol % of (R)-1 (0.005 mmol). b Isolated yield.
c Determined by chiral HPLC analysis. d Performed with 0.12 mmol of
benzaldehyde N,N-tetramethylenehydrazone.
Table 3. (R)-1-Catalyzed Asymmetric Addition of Arylaldehyde
N,N-Tetramethylenehydrazones to N-Boc Iminesa
In summary, we have succeeded in the development of asym-
metric imino aza-enamine reaction of aldehyde hydrazones to N-Boc
imines catalyzed by axially chiral dicarboxylic acid (R)-1. To the
best of our knowledge, this is the first example employing
arylaldehyde N,N-dialkylhydrazones as practical acyl anion equiva-
lent in asymmetric synthesis.
entry
R1
R2
% yieldb
% eec
1
2
3
4
5
6
7
3-tolyl
Ph
Ph
Ph
Ph
Ph
55
51
35
54
77
73
67
91
92
84
91
90
89
91
2-Np
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.H. thanks a
Grant-in-Aid for Young Scientists (Start-up).
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reactions were performed with arylaldehyde N-Boc imine (0.10
mmol) and arylaldehyde N,N-tetramethylenehydrazone (0.30 mmol) in
the presence of 5 mol % of (R)-1 (0.005 mmol). b Isolated yield.
c Determined by chiral HPLC analysis.
References
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