Oxazoline-thiourea as a bifunctional organocatalyst: Enantioselective aza-Henry reactions

Article abstract of DOI:10.1055/s-2007-984916

Bifunctional oxazoline-thiourea-based organocatalysts were synthesized and applied to the aza-Henry reactions between N-Boc aryl imines and nitromethane in high ee and chemical yields at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984916

LETTER
2283
Oxazoline–Thiourea as a Bifunctional Organocatalyst: Enantioselective
aza-Henry Reactions
E
nantioselective az
u
a-Henry
R
e
-
a
Department of Chemistry, Hezuo Minorities Teachers’ College, Hezuo 747000, P. R. of China
Fax +86(941)8252686; E-mail: changyuwei@hzmtc.edu.cn
b
Yizheng Chemical Fiber Co, Ltd Chemical Plant, Yangzhou 211900, P. R. of China
Received 22 March 2007
nitronate, followed by deprotonation by the neighboring
tertiary amino group (Scheme 1).11 In addition, the oxazo-
line N is a much stronger base than a tertiary N due to the
resonance effect of the neighboring O, which favors the
deprotonation of the nitronate.
Abstract: Bifunctional oxazoline–thiourea-based organocatalysts
were synthesized and applied to the aza-Henry reactions between
N-Boc aryl imines and nitromethane in high ee and chemical yields
at room temperature.
Key words: oxazoline, thiourea, aza-Henry reactions, organocata-
lyst
In this communication, we present a successful applica-
tion of such new chiral bifunctional organocatalysts to-
wards the enantioselective aza-Henry reaction. To the best
of our knowledge, this is the first example of enantioselec-
tive organocatalytic Henry reaction catalyzed by oxazo-
line–thiourea bifunctional catalyst.
The addition of a nitroalkane across the C=N bond of an
imine (known as aza-Henry reaction) has attracted much
attention because it is an important C–C bond-forming
process.1 The resulting 1,2-nitroamine adducts can be
transformed into 1,2-diamines2 by reduction3 as well as to
a-amino acids by a Nef oxidation.4
S
chiral
scaffold
N
H
N
H
Recently, the development of catalytic asymmetric ver-
sions of the nitro-Mannich reaction has become a topic of
interest. Shibasaki reported the reaction of nitro com-
pounds with N-phosphinoyl imines derived from aromatic
aldehydes using binaphthoxide-based heterobimetallic
complexes of ytterbium and aluminum as catalysts.5
Jørgensen reported the reaction of silyl nitronates with
amino esters catalyzed by copper bis(oxazoline) com-
plexes.6 Palomo also described the use of complexes of
ZnII and N-methylephedrine as catalysts of the reaction of
nitromethane and N-Boc aryl imines,7 thus providing a
new entry to enantioenriched diamines and aryl glycines.
N
Figure 1
S
S
Ar
Ar
N
H
N
H
O
N
H
O
N
R
R
H
O
O
+
O
N
O
N
N
N
H
Ph
H
Ph
H
H
H
H
Scheme 1
In the last decade, asymmetric organocatalysis has proven
to be a robust and valid alternative to traditional metal-
based catalysis for a number of reactions.8 High enantio-
meric excesses have been achieved in the reaction be-
tween nitroalkanes and imines (aza-Henry reaction) using
chiral, enantiopure organic catalysts. Remarkable results
were obtained in particular by Takemoto9 and Jacobsen,10
who employed thioureas as organocatalysts.
R
R
LiOH
O
THF–MeOH–H2O
r.t. 12 h
O
CO2H
CO2Me
O
N
N
3
2
R
R
O
NaBH4, I2
Boc2O
Encouraged by these results, we explored the structure of
the above organocatalysts and found that they contained a
thiourea moiety and a neighboring tertiary amino group in
their structure (Figure 1). We envisaged that the combina-
tion of oxazoline with thiourea may promote the asym-
metric aza-Henry reaction, since the thiourea moiety can
activate the nitroalkane to produce the corresponding
O
N
N
THF
NH4HCO3
NH2
NH2
5
4
R
1a: R = H, Ar = 4-MeC6H4
1b: R = Me, Ar = 4-MeC6H4
1c: R = Me, Ar= 4-NO2C6H4
1d: R = Me, Ar= 2-NO2C6H4
O
N
SCNAr
CH2Cl2
S
HN
1e: R = Me, Ar= 3,5-(CF3)2C6H3
HN
Ar
1
SYNLETT 2007, No. 14, pp 2283–2285
Advanced online publication: 20.07.2007
0
3
.0
9
.2
0
0
7
Scheme 2
DOI: 10.1055/s-2007-984916; Art ID: W05207ST
© Georg Thieme Verlag Stuttgart · New York

2284
Y.-w. Chang et al.
LETTER
The desired organic catalysts were successfully synthe-
sized according to Scheme 2. Initially, compound 212 was
hydrolyzed in the presence of lithium hydroxide to
provide the carboxylic acid 3 in 96% yield. Compound 3
was then reacted with ammonium hydrogen carbonate in
Table 1 Aza-Henry Reaction Catalyzed by Bifunctional Organo-
catalystsa
Boc
Boc
N
1e (10 mol%)
HN
MeNO2
+
NO2
Ph
6a
THF r. t.
Ph
the presence of Boc2O to afford 4 in 80% yield.13
A
7a
subsequent reduction was performed using NaBH4 and I2
in THF to obtain compound 5 in 70% yield. The target
compounds were easily generated through the reaction
of compound 5 with different aryl isothiocyanates in
96–97% ee and 78–92% yield.
Entry
1
Cat.
Solvent
THF
Time (h) Yield (%)b ee (%)c
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
48
48
48
48
48
12
48
12
12
12
12
48
48
89
92
86
90
93
86
64
80
90
83
88
72
80
44
38
70
82
88
14
31
10
5
2
THF
The organocatalysts were screened for their efficiency in
the aza-Henry reaction (Table 1). The reaction between
N-Boc phenyl imines and nitromethane was carried out in
THF at room temperature in the presence of 10 mol% of
the catalyst. It was found that catalysts 1a and 1b exhibit-
ed poor activity (Table 1, entries 1 and 2). In contrast,
compounds 1c–e afforded promising results (entries 3–5).
Under the same reaction conditions, catalyst 1e gave the
corresponding adduct in high enantioselectivity (88% ee).
It was noted that the substituent of the isothiocyanate part
played an important role in the catalytic process. All reac-
tions were completed in 48 hours at room temperature.
Further investigation on catalyst 1e in different solvents
such as DMF, methanol, and chloroform revealed that
more polar solvents gave lower product enantioselec-
tivity. This finding suggested a destruction of hydrogen-
bonding interactions between the thiourea and the nitro
group in the substrate in strongly H-bonding-acceptor sol-
vents. Similar reaction runs in nitromethane, toluene, and
dichloromethane essentially gave no better enantioselec-
tivity. It was also noted that lowering the temperature did
not provide higher enantioselectivity (Table 1, entry 12).
3
THF
4
THF
5
THF
6
DMF
7
MeOH
CHCl3
MeNO2
CH2Cl2
Toluene
THFd
THFe
8
9
10
11
12
13
9
4
89
87
a Reactions were carried out with 6a (1 mmol), MeNO2 (10 mmol),
and catalyst (0.1 mmol) in 2 mL of solvent.
b Yield of isolated product.
c Determined by HPLC analysis.
d Reactions were performed at 0 °C.
e Amount of catalyst was 5 mol%.
With optimized reaction conditions in hand, the scope of
the reaction was explored (Table 2). The aza-Henry reac-
tion of nitromethane with a variety of N-Boc aryl imines
was probed.14 The results showed that, in general, the re-
actions took place efficiently (68–97% yield) with high
levels of enantioselectivity (73–92% ee) for N-Boc phenyl
imines bearing either electron-donating or electron-with-
drawing substituents. In order to examine the diastereo-
selectivity of this reaction, we investigated the reaction of
other nucleophiles such as 1-nitropropane and nitroethane
with N-Boc phenyl imines. Interestingly, under the same
catalyst constitutes an important step towards the design
of new catalysts in this field. Further investigations aimed
at the understanding of the mechanism and scopes of this
reaction are currently under way.
Acknowledgment
The financial support by financial support from the department of
science and technology of Hezuo Minorities Teachers’ College and
reaction conditions, the reactions proceeded smoothly to Yizheng Chemical Fiber Co, Ltd. Chemical Plant is gratefully
acknowledged. We thank Professor Hong-ming We from Peking
University for his comments to the manuscript.
afford the corresponding products 7j in 2.5:1 dr and 87%
ee and 7k in 3.2:1 dr and 90% ee, respectively (Table 2,
entries 11 and 12). There was no observable effect of the
substituted groups on nitroalkanes on the efficiency of the
aza-Henry reactions.
References and Notes
(1) Westermann, B. Angew. Chem. Int. Ed. 2003, 42, 151.
(2) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int.
Ed. 1998, 37, 2580.
(3) (a) O’Brien, P. H.; Sliskovic, D. R.; Blankley, C. J.; Roth,
B.; Wilson, M. W.; Hamelehle, K. L.; Krause, B. R.;
Stanfield, R. L. J. Med. Chem. 1994, 37, 1810. (b) Adams,
H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org.
Chem. 1998, 63, 9932.
In summary, we have developed a new class of bifunc-
tional oxazoline–thioureas 1, which serve as efficient
organocatalysts for the asymmetric aza-Henry reaction of
nitromethane to N-Boc phenyl imines. To the best of our
knowledge, this is the first example of a highly enantio-
selective aza-Henry reaction catalyzed by oxazoline–
thiourea organocatalysts. We believe this kind of organo-
Synlett 2007, No. 14, 2283–2285 © Thieme Stuttgart · New York

LETTER
Enantioselective aza-Henry Reactions
2285
Table 2 Aza-Henry Reaction of N-Boc Imines with Nitroalkanes Catalyzed by Bifunctional Organocatalysta
Boc
Boc
R1
N
HN
1e (10 mol%)
+
CH2NO2
R1
NO2
R
THF r.t.
R
6a–k
7a–k
Entry
1
Substrate
R
R1
H
Time (h)
48
Yield (%)b
eec (%, dr)d
6a
6b
6c
6c
6d
6e
6f
Ph
93
84
93
94
86
92
95
97
75
68
94
93
88
2
2-MeC6H4
H
48
90
3
4-MeC6H4
4-MeC6H4
H
48
74
4
H
63
73
5
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-F3CC6H4
3-NO2C6H4
4-NO2C6H4
Ph
H
48
78
6
H
48
88
7
H
48
92
8
6g
6h
6i
H
48
83
9
H
48
89
10
11
12
H
48
80
6j
Me
Et
48
87 (2.5:1d)
90 (3.2:1d)
6k
Ph
48
a Reactions were carried out with 6a–k (1 mmol), MeNO2 (10 mmol), and 1e (0.1 mmol) in 2 mL of THF at r.t.
b Isolated yield.
c The ee was determined by HPLC.
d The dr was determined by 1H NMR.
(4) (a) Pinnick, H. W. Org. React. 1990, 38, 655. (b) Ballini,
R.; Petrini, M. Tetrahedron 2004, 60, 1017. (c) Foresti, E.;
Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol. Chem.
2003, 1, 4275.
(5) (a) Yamada, K.; Harwood, S. J.; Gröger, H.; Shibasaki, M.
Angew. Chem. Int. Ed. 1999, 38, 3504. (b) Yamada, K.;
Moll, G.; Shibasaki, M. Synlett 2001, 980.
(6) (a) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K.
V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
(b) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2001, 40, 2992.
(c) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem.
2005, 3, 1362.
(9) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625. (b) Xu, X.; Furukawa, T.; Okino, T.;
Miyabe, H.; Takemoto, Y. Chem. Eur. J. 2006, 12, 466.
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(14) Representative Procedure
To a stirred solution of N-Boc phenyl imines (1 mmol) and
the catalyst (0.1 mmol) in THF (2 mL) was added MeNO2
(10 mmol), and the mixture was stirred for 24 h at r.t. Then
the reaction mixture was condensed under reduced pressure,
and the obtained residue was purified by column chromatog-
raphy on silica gel to afford desired product 6a (93% yield).
(7) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; López, R.
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Synlett 2007, No. 14, 2283–2285 © Thieme Stuttgart · New York

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