Mild Michael addition of glycine imines to aromatic nitroalkenes catalyzed by DBU with LiOTf as an additive

Article abstract of DOI:10.1055/s-0028-1088210

A mild Michael addition of glycine imines to aromatic-nitroalkenes catalyzed by 10 mol% DBU with LiOTf as an additive was developed. In most cases, the products could be obtained in good yields (up to 96%) with moderate to good diastereoselectivities (up

Full text of DOI:10.1055/s-0028-1088210

LETTER
925
Mild Michael Addition of Glycine Imines to Aromatic Nitroalkenes Catalyzed
by DBU with LiOTf as an Additive
Michael
Addition of
G
ly
e
cine Imine
i
s
toAromatic
L
N
itroalkenes i,a Han Liu,a Da-Ming Du*a,b
a
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. of China
Fax +86(10)68914985; E-mail: dudm@pku.edu.cn
b
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, P. R. of China
Received 23 September 2008
acrylates and acrylamides,4 unsaturated nitriles,4e,h,i,l,m,5
linear and cyclic enones,4e,i,4l–4o,5a,6 and vinyl phenyl sul-
fone,4m,5a have been applied as Michael acceptors. Good
chemical and optical yields can be obtained by the cataly-
Abstract: A mild Michael addition of glycine imines to aromatic-
nitroalkenes catalyzed by 10 mol% DBU with LiOTf as an additive
was developed. In most cases, the products could be obtained in
good yields (up to 96%) with moderate to good diastereoselectivi-
ties (up to 10:1). The selectivity for syn adduct can be reversed to sis of chiral phase-transfer catalysts derived from natural
anti when the R group of glycine imines was changed from methyl
or ethyl to tert-butyl.
alkaloids or other chiral sources, chiral bisoxazoline com-
plexes, and chiral guanidine compounds. On the contrary,
Key words: Michael addition, nitroalkene, catalysis, amino acids,
DBU
Michael addition of benzophenone-derived glycine im-
ines to nitroalkenes has been rarely developed,7 though
nitroalkenes are very important building blocks in organic
synthesis.8 In 1992, Rowley et al. reported the addition of
The chemistry of peptide is one of the most important sub- glycine imine to nitrostyrene mediated by LDA and the
jects on the boundary of synthetic chemistry, biochemis- application of the adduct in the synthesis of 4-substituted
try, and pharmaceutical chemistry. The design and analogue of the glycine/NMDA antagonist HA-966.9 In
synthesis of novel unnatural amino acids, especially in 1994, de Meijere et al. reported n-BuLi-mediated tandem
enantiopure form, is one basis of peptide chemistry.1 Dur- Michael addition–intramolecular substitution of glycine
ing the past century, a plethora of methodologies have imine with 3-bromo-1-nitroalkene for the preparation of
been exploited for the synthesis of amino acids through cyclopropyl containing amino acids.10 In 1998 and 2000,
different kinds of chemical bond formation, such as C–H Cossío et al. reported the product of the Michael addition
bond formation, C–N bond formation, and C–C bond for- of 3 to nitroalkene 4c under the catalysis of LiClO4 and
mation.2 Compared with the former two methods, the for- Et3N in MeCN as an intermediate of 1,3-dipolar cycload-
mation of C–C bond at the a-position is more efficient in dition.11 A recent example was published by Dougherty et
terms of reaction and product diversity.
al. in 2007.12 In their synthesis of agonists for nicotinic
acetylcholine receptor, nitroethene was use as Michael ac-
ceptor combined with LDA. Considering the air- and
moisture-sensitivity of the base used and the low reaction
temperature, milder conditions for this transformation are
still in demand. As part of our project on the chemistry of
nitroalkenes13 for their high reactivity and potent diverse
transformation of nitro group,14 we would like to docu-
ment the addition of glycine imines 1–3 to aromatic
nitroalkenes 4 under the catalysis of DBU in the presence
of LiOTf as an additive.
The benzophenone-protected glycine derivatives (glycine
imines) 1–3 are widely used as glycine anion equivalent in
the synthesis of amino acids with one or two different
kinds of substitutions on the a-position through C–C bond
formation.2e From the first publication about these com-
pounds in 1978,3 many efficient transformations have
been developed from these readily available starting ma-
terials. Generally, the introduction of a-substitutions can
be facilitated in two ways, nucleophilic substitution of
alkyl or phenyl halides, and Michael addition to unsatur-
ated systems. In the Michael addition of glycine imines,
Ph
O
Ph
O
O
O2N
O2N
catalyst (10 mol%)
OEt
OEt
Ph
N
NO2
+
+
OEt
Ph
Ph
N
Ph
N
additive
solvent, r.t.
Ph
Ph
syn
Ph
4a
1
anti
5a'
5a
Scheme 1 Michael addition of glycine imine to nitrostyrene
SYNLETT 2009, No. 6, pp 0925–0928
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088210; Art ID: W15208ST
© Georg Thieme Verlag Stuttgart · New York

926
W. Li et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
Additiveb Solvent Yield (%)c syn/antid
the diastereoselectivity was mainly kinetically controlled,
while the slight epimerization of the stereocenter under
the reaction conditions also provided some contributions.
Entry Catalyst
1
2
3
4
5
6
7
8e
TMG
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
–
THF
THF
THF
THF
54
23
58
82
8.5:1
1:1
Table 2 Michael Addition of glycine imines to nitroalkenesa
–
Entry
1
R
Ar
Product15 Yield (%)b syn/antic
–
20:1
Et
Et
Et
Et
Et
Et
Et
Et
Ph
5a,a¢
5b,b¢
5c,c¢
5d,d¢
5e,e¢
5f,f¢
90
84
89
83
96
94
86
93
94
85
84
88
91
99
89
10.4:1
5.0:1
6.0:1
4.3:1
4.1:1
4.9:1
3.1:1
4.8:1
1:7.0
1:6.7
1:2.1
3.1:1
3.7:1
4.6:1
2.3:1
LiOTf
LiOTf
LiOTf
LiOTf
LiOTf
8.9:1
1:2.2
1:3.8
8.8:1
10.4:1
2
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
CH2Cl2 80
CHCl3 62
toluene 62
THF 90
3
4
5
6
a The reaction was conducted in 0.25 mmol scale at r.t. for 24 h. Un-
less otherwise noted, the amount of nitrostyrene was equimolar with
that of glycine imine.
7
3,4-(MeO)2C6H3 5g,g¢
b The amount of 10 mol% LiOTf was used.
8
2-naphthyl
5h,h¢
6a,a¢
6b,b¢
6c,c¢
6d,d¢
7a,a¢
7b,b¢
7c,c¢
c Determined by 1H NMR using DMSO as internal standard.
d Determined by 1H NMR of crude product.
9
t-Bu Ph
e Molar ratio of nitrostyrene to glycine imine = 1.2:1.
10
11
12
13
14
15
t-Bu 4-MeOC6H4
t-Bu 4-ClC6H4
t-Bu 2-naphthyl
At the beginning of our work, we chose 1 and 4a as model
substrates (Scheme 1). Different organic bases were test-
ed as catalysts in THF at room temperature. As shown in
Table 1, Et3N was not efficient in this transformation.
Only 23% conversion of material was obtained (entry 2).
When TMG and DBU with stronger basicity were used,
the yields were improved significantly (entries 1 and 3),
while higher syn selectivity was achieved in the later case.
The relative configuration of the product was determined
through comparison of the 1H NMR with published spec-
tral data. Considering lithium enolate was generated in
former publications,9–12 we added 10 mol% of LiOTf as
an additive for further improvement. As we expected, the
yield increased from 58% to 82%, though the diastereo-
selectivity decreased to 8.9:1 (entry 4). Higher yields may
be ascribed to the stabilization of the anion by lithium cat-
ion through chelation. Other solvents such as CH2Cl2,
CHCl3, and toluene, did not give better results (entries 5–
7). When the amount of nitrostyrene increased from 1.0
equivalent to 1.2 equivalents, slightly better yield and se-
lectivity could be achieved (entry 8). If the reaction time
was shortened to 6 hours, the desired product was ob-
tained in lower yield for the incomplete conversion, with
7.6:1 diastereoselectivity. The lower selectivity compared
to the value obtained after 24 hours reaction indicated that
Me
Me
Me
Ph
4-MeOC6H4
4-ClC6H4
a The reaction was conducted in 0.5 mmol scale in THF at r.t. for 24
h by the catalysis of 10 mol% DBU/LiOTf.
b Isolated total yield of syn and anti isomers.
c Determined by 1H NMR of crude product.
With the optimized conditions in hand, more substrates
were tested in this reaction (Scheme 2). As shown in
Table 2, good yields were achieved in all cases, though
the diastereoselectivities varied significantly with differ-
ent substitutions on the aromatic system (entries 1–8). The
lack of any reaction trend was difficult to interpret as there
were many interactions between the two substrates, such
as steric repulsion, electrostatic interaction, and p–p
stacking. Interestingly, when the R group was changed
from ethyl to tert-butyl, the anti isomer became the major
product (entries 9–12). Such a phenomenon can be inter-
preted by the different steric repulsion of ethyl and tert-
butyl group, as illustrated in Figure 1. In the case of sub-
Ar
O
Ar
O
O
O2N
O2N
DBU (10 mol%)
OR
OR
NO2
Ph
N
+
+
Ar
OR
LiOTf (10 mol%)
THF, r.t.
Ph
N
Ph
N
Ph
Ph
Ph
syn
anti
R = Et
R = t-Bu
R = Me
1
2
3
4a–h
R = Et
R = t-Bu
R = Me
5a–h
6a–d
7a–c
5a'–h'
6a'–d'
7a'–c'
Scheme 2 Michael addition of glycine imines to different aromatic nitroalkenes by the catalysis of DBU/LiOTf
Synlett 2009, No. 6, 925–928 © Thieme Stuttgart · New York

LETTER
Michael Addition of Glycine Imines to Aromatic Nitroalkenes
927
Ph
O
Ph
O
O2N
O2N
Li
Li
H
O
O
OEt
Ph
Ph
OEt
Ph
Ph
H
N
O
O
Ph
N
Ph
N
N
NO2
O2N
Ph
Ph
Ph
syn
Ph
anti
H
H
disfavored
favored
5a
5a'
Ph
O
Ph
O
O2N
O2N
Li
H
O
Li
O
H
Ph
Ph
Ot-Bu
Ot-Bu
Ph
Ph
O
N
N
O
Ph
N
Ph
N
NO2
Ph
O2N
Ph
Ph
syn
Ph
anti
H
H
disfavored
favored
6a
6a'
Figure 1 Proposed origin of inversed diastereoselectivity with 1 and 2
strate 1 bearing ethyl group, the repulsion between nitro
group and the imine fragment is stronger. The phenyl
group tends to be vicinal to the imine fragment and the syn
product 5a is favored. In the case of 2 bearing the bulky
tert-butyl group, the repulsion between nitro group and
the ester fragment increases and overcomes the repulsion
between nitro group and imine fragment, and the anti
product 6a¢ is favored instead. To get further evidence for
our proposal, a glycine imine 3 in which R is a methyl
group was also tested in this reaction (entries 13–15). As
expected, the smaller methyl ester gave similar diastereo-
selectivities as compared to the ethyl ester, but was very
different from the bulky tert-butyl ester. Such a result that
two products with different relative configurations could
be available under the same reaction conditions through a
slight change of substrate structure could be useful in the
application of this methodology.
References and Notes
(1) (a) Barrett, G. C. Chemistry and Biochemistry of the Amino
Acids; Chapman and Hall: London, 1985. (b) Jones, J. H.
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In conclusion, we developed a mild Michael addition of
glycine imines to aromatic nitroalkenes. In most cases,
good yields and moderate to good diastereoselectivities
can be achieved. Both the syn and anti adducts could be
obtained under the same conditions through slight change
of the substrate structure. This methodology could be ap-
plied in the synthesis of unnatural amino acids with func-
tional group in the side chain. The asymmetric form of
this reaction is under development in our laboratory.
(i) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.;
Yamaguchi, K. Chem. Commun. 2003, 1734. (j) Corey,
E. J.; Noe, M. C. Org. Synth. 2003, 80, 34. (k) Shibuguchi,
T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.;
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(l) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda,
K.; Isobe, T. Chem. Commun. 2001, 245. (m) O’Donnell,
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Tetrahedron: Asymmetry 2001, 12, 821. (n) Tzalis, D.;
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E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
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Ezquerra, J.; Pedregal, C. Tetrahedron 1996, 52, 8365.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This project was partially supported by National Natural Science
Foundation of China (Grant Nos: 20572003, 20772006), the Pro-
gram for New Century Excellent Talents in University (NCET-
07-0011). W. Li thank the support of Innovative Experiment Project
for Undergraduate Students and National Fund for Fostering
Talents of Basic Sciences (JO630421).
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2004, 52, 646. (b) Zhang, F.-Y.; Corey, E. J. Org. Lett.
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Synlett 2009, No. 6, 925–928 © Thieme Stuttgart · New York

928
W. Li et al.
LETTER
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(7) The benzaldehyde derived glycine imines have been widely
used as precursor of 1,3-dipole in [3+2] reactions. For recent
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K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem. Int. Ed.
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mg, 0.1 mmol), and ethyl diphenylmethyleneiminoacetate
(267 mg, 1 mmol) or tert-butyl diphenylmethyleneimino-
acetate (295 mg, 1 mmol) in dry THF (1 mL) was added
DBU (15 mg, 0.1 mmol) in dry THF (1 mL). The mixture
was stirred at r.t. for 24 h. After being quenched by H2O, the
mixture was extracted by CH2Cl2. The organic phase was
separated and dried with Na2SO4. The diastereoselectivity
was determined by NMR analysis of curde product. The
sample for analysis was purified on column chromatography
(SiO2, 200–300 mesh) using PE–EtOAc (20:1) as eluent and
recrystallized from Et2O and PE.
syn-Ethyl 2-Diphenylmethyleneimino-4-nitro-3-phenyl-
butanoate (5a)
According to the general procedure, a white solid was
obtained; mp 84–85 °C. 1H NMR (300 MHz, CDCl3):
d = 1.20 (t, J = 7.2 Hz, 3 H), 4.11–4.16 (m, 2 H), 4.27–4.38
(m, 2 H), 5.14–5.18 (m, 2 H), 6.60–6.62 (d, J = 6.9 Hz, 2 H),
7.14–7.48 (m, 1 1H), 7.64 (d, J = 6.9 Hz, 2 H). IR: 1735,
1551, 1446, 1368, 1316, 1290, 1190, 1024, 695 cm–1. MS
(70 eV, EI): m/z (%) = 416 (3) [M+], 343 (10), 296 (23), 267
(21), 266 (100), 193 (47), 165 (50). Anal. Calcd (%) for
C25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found: C, 71.74; H,
5.83; N, 6.55.2.
(8) For reviews, see: (a) Barrett, A. G. M.; Graboski, G. G.
Chem. Rev. 1986, 86, 751. (b) Berner, O. M.; Tedeschi, L.;
Enders, D. Eur. J. Org. Chem. 2002, 1877.
(9) Rowley, M.; Leeson, P. D.; Williams, B. J.; Moore, K. W.;
Baker, R. Tetrahedron 1992, 48, 3557.
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Chem. Soc. 2000, 122, 6078.
(12) Cashin, A. L.; Torrice, M. M.; McMenimen, K. A.; Lester,
H. A.; Dougherty, D. A. Biochemistry 2007, 46, 630.
(13) (a) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem.
Soc. 2006, 128, 7418. (b) Lu, S.-F.; Du, D.-M.; Xu, J. Org.
Lett. 2006, 8, 2115. (c) Liu, H.; Xu, J.; Du, D.-M. Org. Lett.
2007, 9, 4725. (d) Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M.
Chem. Asian J. 2008, 3, 1111. (e) Zhou, W.-M.; Liu, H.;
Du, D.-M. Org. Lett. 2008, 10, 2817.
syn-Ethyl 2-Diphenylmethyleneimino-3-(4-
methylphenyl)-4-nitrobutanoate (5b)
According to the general procedure, a white solid was
obtained; mp 102–103 °C. 1H NMR (300 MHz, CDCl3):
d = 1.19 (t, J = 6.9 Hz, 3 H), 2.29 (s, 3 H), 4.10–4.15 (m, 2
H), 4.27–4.32 (m, 2 H), 5.10–5.12 (m, 2 H), 6.65 (d, J = 6.0
Hz, 2 H), 7.04 (s, 4 H), 7.27–7.45 (m, 6 H), 7.65 (d, J = 7.5
Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 14.0, 21.0, 46.2,
61.5, 68.7, 76.3, 127.3, 128.0, 128.2, 128.3, 128.6, 128.9,
129.3, 130.9, 134.0, 135.4, 137.4, 138.7, 169.9, 172.6. IR:
1736, 1732, 1619, 1552, 1516, 1446, 1379, 1317, 1288,
1182, 1026, 695 cm–1. MS (70 eV, EI): m/z (%) = 430 (4)
[M+], 413 (3), 357 (7), 310 (17), 267 (27), 266 (100), 238
(22), 193 (69), 165 (61). Anal. Calcd (%) for C26H26N2O4: C,
72.54; H, 6.09; N, 6.51. Found: C, 72.36; H, 6.22; N, 6.35.
(14) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
(15) General Procedure for Michael Addition of Glycine
Imines to Aromatic Nitroalkenes
To a stirred solution of nitroalkene (1.2 mmol), LiOTf (16
Synlett 2009, No. 6, 925–928 © Thieme Stuttgart · New York