Novel bifunctional chiral thiourea catalyzed highly enantioselective aza-henry reaction

Article abstract of DOI:10.1021/ol8003035

A novel blfunctional chlral thiourea organocatalyst bearing a glycosyl scaffold and a tertiary amino group was synthesized starting from readily available alpha-D-glucose. This thiourea was proven to be an effective organocatalyst for the asymmetric aza-H

Full text of DOI:10.1021/ol8003035

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1707-1710
Novel Bifunctional Chiral Thiourea
Catalyzed Highly Enantioselective
aza-Henry Reaction†
Chungui Wang, Zhenghong Zhou,* and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic
Chemistry, Nankai UniVersity, Tianjin 300071, PRC
z.h.zhou@nankai.edu.cn
Received February 11, 2008
ABSTRACT
A novel bifunctional chiral thiourea organocatalyst bearing a glycosyl scaffold and a tertiary amino group was synthesized starting from
readily available alpha-D-glucose. This thiourea was proven to be an effective organocatalyst for the asymmetric aza-Henry reaction between
N-Boc imines and nitromethane. The corresponding adducts were obtained in good to excellent yields with excellent enantioselectivities (up
to 99.8% ee). In addition, the reaction of nitroethane also proceeded smoothly with excellent enantioselectivity, albeit with low to good
diastereoselectivities.
The nucleophilic addition of nitroalkanes to the CdN bond
of imines, known as the aza-Henry (or nitro-Mannich)
reaction, is a useful carbon-carbon bond-forming process
in organic synthesis.1 The resulting ꢀ-nitroamine derivatives
can be readily transformed into valuable building blocks or
biologically active compounds, such as vicinal diamines via
reduction of the nitro group2 and R-amino acids by means
of the Nef reaction.2,3 As a result, much attention has been
paid to the aza-Henry reaction, especially for the catalytic
asymmetric version of this reaction, during the past several
years.4,5 In 1999, Shibasaki reported the first example of a
catalytic asymmetric aza-Henry reaction using a heterobi-
metallic catalyst [YbK3(binaphthoxide)3], in which up to 91%
ee was obtained.4a Thereafter, significant progress has been
(4) (a) Yamada, K.-i.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504. (b) Yamada, K.-i.; Moll, G.; Shibasaki, M.
Synlett 2001, 980. (c) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (d) Knudsen,
K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am.
Chem. Soc. 2001, 123, 5843. (e) Knudsen, K. R.; Jørgensen, K. A. Org.
Biomol. Chem. 2005, 3, 1362. (f) Anderson, J. C.; Blake, A. J.; Howell,
G. P.; Wilson, C. J. J. Org. Chem. 2005, 70, 549. (g) Anderson, J. C.;
Howell, G. P.; Lawrence, R. M.; Wilson, C. J. J. Org. Chem. 2005, 70,
5665. (h) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lo´pez, R. Angew.
Chem., Int. Ed. 2006, 45, 117. (i) Trost, B. M.; Lupton, D. W. Org. Lett.
2007, 9, 2023. (j) Gao, F.; Zhu, J.; Tang, J. Y.; Deng, M.; Qian, C. Chirality
2006, 18, 741. (k) Lee, A.; Kim, W.; Lee, J.; Hyeon, T.; Kim, B. M.
Tetrahedron: Asymmetry 2004, 15, 2595.
† Dedicated to professor Chuchi Tang on the occasion of his 70th
birthday.
(1) For recent advances on this reaction, see: (a) Westermann, B. Angew.
Chem., Int. Ed. 2003, 42, 151. (b) Ting, A.; Schaus, S. E. Eur. J. Org.
Chem. 2007, 5797.
(5) (a) Okino, T.; Nakamura, A.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625. (b) Xu, X. N.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto,
Y. Chem.-Eur. J. 2006, 12, 466. (c) Yoon, T. P.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2005, 44, 466. (d) Bernardi, L.; Fini, F.; Herrera, R. P.;
Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375. (e) Bode, C. M.; Ting,
A.; Schaus, S. E. Tetrahedron 2006, 62, 11499. (f) Nugent, B. M.; Yoder,
R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. (g) Singh, A.;
Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466.
(h) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 15110. (i) Palomo, C.; Oiarbide, M.; Laso, A.; Lo´pez, R. J. Am. Chem.
Soc. 2005, 127, 17622. (j) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera,
R. P.; Bernadi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975.
(2) (a) Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986, 51, 4294. (b)
Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29, 5733. (c)
Sturgess, M. A.; Yarberry, D. J. Tetrahedron Lett. 1993, 34, 4743. (d)
Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem.
1998, 63, 9932. (e) Bernadi, L.; Bonini, B. F.; Capito`, E.; Dessole, G.;
Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168.
(3) For a recent review on the Nef reaction, see: (a) Ballini, R.; Petrini,
M. Tetrahedron 2004, 60, 1017. (b) Foresti, E.; Palmieri, G.; Petrini, M.;
Profeta, R. Org. Biomol. Chem. 2003, 1, 4275. (c) Matt, C.; Wagner, A.;
Moiskowski, C. J. Org. Chem. 1997, 62, 234
.
10.1021/ol8003035 CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society

witnessed for chiral metallic catalyst promoted enantiose-
lective aza-Henry reaction.4 However, besides these metal-
catalyzed variants, the organocatalytic version remained
unexplored until two reports of enantioselective organocata-
lytic aza-Henry reaction appeared in 2004. Takemoto has
developed a bifunctional thiourea catalyst that results in
moderate stereoselectivity in the addition of nitromethane
to a variety of aromatic N-phosphinoyl imines,5a and
Johnston has documented a chiral bisamidine triflate salt that
provides up to 95% ee in the diastereo- and enantioselective
addition of nitroethane to a range of N-Boc imines.5f
Although only moderate ee values were observed for the
thiourea 1a catalyzed reaction between N-phosphinoyl imines
and nitromethane,5a high stereoselectivity (up to 98% ee)
was obtained when N-Boc imines were employed instead of
N-phosphinoyl imines as the substrates.5b Using thiourea 1b,
Jacobsen developed another variation of the aza-Henry
reaction of N-Boc imines, in which moderate de values and
excellent ee values were attained.5c Most recently, Ricci5d
and Schaus5e independently screened a variety of cinchona-
based thiourea organocatalysts to catalyze the addition of
nitromethane to acyl imines, in which satisfactory yields and
enantiomeric excesses were provided. In addition, chiral
proton catalysis,5g chiral urea catalysis,5h and chiral phase-
transfer catalysis5i,j based on quinine or cinchonidine derived
quaternary ammonium salts effecting the asymmetric aza-
Henry reaction have also been described and gave rise to
good diastereo- and enantioselectivities. As aforementioned,
bifunctional thioureas have proven to be an efficient type of
organocatalyst for the asymmetric aza-Henry reaction. There-
fore, the development of new bifunctional thiourea catalysts
is still in great demand. Carbohydrates are in general very
attractive scaffolds because of their availabilty and well-
defined stereocenters. Hence, a novel type of bifunctional
thiourea 2 bearing a saccharide scaffold and a tertiary amino
group was synthesized and employed as the catalyst in the
asymmetric aza-Henry reaction. Herein, we report the
discovery that thiourea 2a efficiently promotes the aza-Henry
reaction of nitromethane with N-Boc imines with excellent
levels of enantioselectivity.
through monoamino protection with phthalic anhydride, N,N-
dimethylation, and subsequently deprotection starting from
(R,R)-cyclohexane-1,2-diamine.7 Consequently, coupling of
3 and 4 afforded the desired bifunctional thiourea catalyst
2a in good yield. Following the same procedure, thiourea
catalysts 2b and 2c were also synthesized from galactose
and lactose, respectively (in a yield of 67% for 2b and 73%
for 2c).
Scheme 1. Synthesis of Novel Thiourea 2
With these novel catalysts in hand, we initially screened
several imines with different N-protecting groups (PG) in
the presence of 2a (15 mol %) and nitromethane in methylene
chloride at 0 °C (Table 1).
Table 1. Enantioselective aza-Henry Reaction of Different
Imines with Nitromethane
entry
PG
time (h)
yield (%)a
ee (%)b
8
1
2
3
4
5
6
Ts
4.5
48
48
16
24
24
79
Ph2P(S)
Ph2P(O)
Boc
CO2Et
CO2Bn
trace
NRc
85
77
71
90
85
86
a Yield of the isolated product after chromatography on silica gel.
b Determined chiral HPLC analysis. c NR means no reaction occurred.
Figure 1. Thiourea organocatalysts.
Among the imines examined, N-alkoxycarbonylimines
tended to provide the desired adducts with good enantiose-
lectivities compared with other imines (Table 1, entries 1-6),
and the best result was obtained for N-Boc imine in terms
of chemical yield and enantiomeric excess (Table 1, entry
4, 95% yield, 90% ee). Although N-tosyl imine exhibited
the best reactivity, an almost racemic product was attained
Starting from commercially available R-D-glucopyranose,
glucosyl isothiocyanate 3 was prepared via acetylation,
bromination, and nucleophilic substitution reactions.6 (R,R)-
N,N-Dimethyl cyclohexane-1,2-diamine 4 was synthesized
(6) (a) Deng, X. J.; Wan, Q. H. Fine Chem. 2005, 22, 307. (b) Yu,
J. X.; Liu, F. M.; Lu, W. J.; Li, Y. P.; Tian, L. L.; Liu, Y. T. Chem. J. Chin.
UniV. 1999, 20, 1233.
(7) Kaik, M.; Gawron´ski, J. Tetrahedron: Asymmetry 2003, 14, 1559.
Org. Lett., Vol. 10, No. 9, 2008
1708

(Table 1, entry 1). In the case of N-(thio)phosphinoyl imines,
the reactions were quite sluggish even after a prolonged
reaction time (Table 1, entries 2 and 3).
In further experiments, other factors, such as solvent,
catalyst loading, and reaction temperature, influencing the
reaction were thoroughly investigated employing 2 as the
catalyst and the reaction between tert-butyl benzylidenecar-
bamate and nitromethane as the model. The results are listed
in Table 2.
With the optimal reaction conditions in hand (15 mol %
of 2a as the catalyst, at -78 °C in methylene chloride), we
investigated the scope and limitations of this asymmetric aza-
Henry reaction. The results are summarized in Table 3.
Table 3. Chiral Thiourea 2 Catalyzed Asymmetric Addition of
Nitromethane to N-Boc Iminesa
Table 2. Optimization of the Reaction Conditions
entry
Ar group
Ph (5a)
4-MeOC6H4 (5b)
4-MeC6H4 (5c)
4-ClC6H4 (5d)
3-FC6H4 (5e)
4-FC6H4 (5f)
2-ClC6H4 (5g)
1-naphthyl (5h)
2-furyl (5i)
4-F3CC6H4 (5j)
2-F3CC6H4 (5k)
6
time (h) yield (%)b,c ee (%)d
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
60
66
68
60
39
65
42
65
62
64
61
86
94
93(70)
93
87
91
85
95
86(69)
85
>99
94
entry 2 (mol %) solvent temp (°C) yield (%)a ee (%)b
83(>99)
>99
>99
>99
92
>99
90(97)
94
1
2
3
4
5
6
7
8
2a (15)
2a (15)
2a (15)
2a (15)
2a (15)
2a (15)
2a (10)
2a (20)
2b (15)
2c (15)
2a (15)
2a (15)
2a (15)
CH2Cl2
MePh
THF
0
0
0
0
0
0
0
0
0
85
87
87
90
trace
88
77
78
89
89
87
86
86
90
85
67
80
CHCl3
MeOH
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
91
85
87
85
78
93
96
>99
j
k
84
96
a The absolute configurations of the major isomer of the aza-Henry
adducts 6 were assigned as R by comparison to the literature value of optical
rotation in refs 5c, 5e, 5i, and 5j. b Yield of the isolated product after
chromatography on silica gel. c Data in parentheses were obtained through
a simple recrystallization from ethyl acetate/petroleum ether. d Determined
by chiral HPLC analysis.
9
10
11
12
13
0
-40
-60
-78
a Yield of the isolated product after chromatography on silica gel.
b Determined chiral HPLC analysis.
As shown in Table 3, in all cases, the corresponding aza-
Henry adducts were obtained in satisfactory chemical yields
within acceptable reaction times. Excellent enantioselectivi-
ties can be obtained for the substrates bearing electron-
withdrawing substituents (5d-g, 5j,k) and imine derived
from 1-naphthyl aldehyde, and in most cases, almost perfect
enantiocontrol was realized. The reaction of the electron-
donating methoxy group substituted imine (5b) also pro-
ceeded smoothly to afford the desired product in excellent
stereoselectivity. Although a slight decrease in ee value was
observed for methyl-substituted imine (5c) and electron-rich
heteroaromatic aldehyde-derived substrate (5i), the optical
purity of the product can be significantly improved via a
simple recrystallization (99.7% and 97.2% ee, respectively).
Solvent evaluation revealed that all the tested solvents
except for methanol, which probably inhibits hydrogen-
bonding interaction between nitromethane and the thiourea
moiety of 2, afforded the desired product in good yield and
ee values (Table 2, entries 1-6). The best results were
observed when methylene chloride and acetonitrile were used
(Table 2, entries 1 and 6, 90% and 91% ee, respectively).
Since acetonitrile has a relatively higher freezing point (-48
°C), it is not applicable for low-temperature tests; therefore,
we chose methylene chloride as the favorable solvent for
this reaction. Although bifunctional thiourea catalysts 2b,c
can also promote this reaction, a moderate decrease in
enantioselectivtiy was observed, which affords the desired
adduct with 85% and 78% ee, respectively (Table 1, entries
9 and 10). Adjusting the catalyst loading (2a) demonstrated
little influence on the ee value of the reaction. For example,
the use of a larger or smaller amount of thiourea organo-
catalyst resulted in only a slight loss of stereocontrol (Table
2, entry 8, 87% ee and entry 7, 85% ee). Moreover, the
reaction temperature was found to be an essential factor to
the enantioselectivity of this reaction. Generally, lowering
the temperature improved the enantiomeric excess of the
reaction (Table 2, entries 1 and 11-13). It is worth noting
that almost perfect enantiocontrol was realized with good
chemical yield when the reaction was performed at -78 °C
(Table 2, entry 11, >99% ee).
In addition, aza-Henry reactions with other nitro alkanes
were preliminarily investigated. Nitroethane proved to be
considerably less reactive under the standard conditions but
underwent smooth reaction at an elevated temperature (-60
°C) to provide adducts 7 in excellent enantioselectivities with
low to good diastereoselectivities. For example, benzade-
hyde-derived imine (5a) underwent reaction with excellent
enantioselectivity (97.0% ee for syn-isomer) and provided
products with synthetically useful levels of diastereoselec-
tivity (syn/anti ) 9.3/1). Although a low syn/anti ratio (1.2/
1) was attained in the case of 3-fluorobenzaldehyde-based
imine (5e), it was gratifying that high enantioselectivity was
Org. Lett., Vol. 10, No. 9, 2008
1709

obtained for the separable anti-isomer. Reaction with the
more sterically challenging 2-nitropropane did not proceed
at all.
with excellent enantioselectivity. In addition, the reaction of
nitroethane was also effective to provide the corresponding
adducts with high enantioselectivities, albeit with low to good
diastereoselectivities. Further investigation on the diastereo-
selective aza-Henry reaction and application of this novel
catalyst in other asymmetric reactions are ongoing in our
laboratory.
Scheme 2
.
Chiral Thiourea 2a Catalyzed Asymmetric Addition
of Nitroethane to N-Boc Imines
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (No. 20472033, 20772058) for
generous financial support for our programs.
Supporting Information Available: Experimental pro-
1
cedures, characterization of the catalyst and copies of H
In conclusion, we have developed a readily available novel
bifunctional chiral thiourea organocatalyst bearing a glycosyl
scaffold and a tertiary amino group. The high effectiveness
of this novel organocatalyst was demonstrated by catalysis
of the aza-Henry reaction of nitromethane with N-Boc imines
NMR spectra, and chiral HPLC spectra of the aza-Henry
adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8003035
1710
Org. Lett., Vol. 10, No. 9, 2008