Reaction control in the organocatalytic asymmetric one-pot, three-component reaction of aldehydes, diethyl α-aminomalonate and nitroalkenes: Toward diversity-oriented synthesis

Article abstract of DOI:10.1002/chem.200801410

A study was conducted to demonstrate diversity-oriented synthesis and reaction control in the organocatalytic asymmetric one-pot and three-component reaction of aldehydes, diethyl α-aminomalonate, and nitroalkenes. The study investigated the reaction of α-imino acetate and nitrostyrene, catalyzed by thiourea-tertiary amine in toluene at ambient temperature. It was found that the introduction of another ethoxycarbonyl group at the α-position of α-imino acetate will facilitate the generation of the azomethine ylide intermediate through tertiary amine activation. A variety of nitroalkene and aldehyde substrates were investigated, to establish the general utility of the catalytic transformation, after finding the favorable reaction conditions. A range of catalysts, bearing an active thiourea moiety were also screened through one-pot, three-component reaction of benzaldehyde, to investigate the predictions.

Full text of DOI:10.1002/chem.200801410

COMMUNICATION
DOI: 10.1002/chem.200801410
Reaction Control in the Organocatalytic Asymmetric One-Pot, Three-
Component Reaction of Aldehydes, Diethyl a-Aminomalonate and
Nitroalkenes: Toward Diversity-Oriented Synthesis
Yan-Kai Liu,[a] Hao Liu,[a] Wei Du,[a] Lei Yue,[a] and Ying-Chun Chen*[a, b]
The demand for enantiomerically enriched compounds is
continuously increasing as a result of the rapid development
of the pharmaceutical industry. Therefore, asymmetric syn-
thesis remains a major focus of organic chemistry over the
past decades. For instance, enormous efforts have been de-
voted to the catalytic stereoselective transformations of
imine derivatives of a-amino esters and a,b-unsaturated
compounds, either by Michael addition[1] or [3+2] dipolar
lyst.[7,8] As outlined in Scheme 1, the tertiary amine group
would activate the in situ formed a-imino esters to produce
azomethine ylides (or enolates). Nitroalkenes would be acti-
vated by the thiourea group, through a double hydrogen-
bonding interaction. Thus the synergistic communication
through bifunctional catalysis would ensure high stereoselec-
tivity in the subsequent Michael addition or dipolar cyclo-
A
A
the efficient synthesis of biologically important unnatural
amino acids, or pyrrolidines with multiple chiral centers.
Most studies in the literature have utilized a-imino esters as
the nucleophilic precursors,[3] and control of the reaction se-
lectivity (Michael addition or cycloaddition) has generally
been poor.[4] In the pursuit of more efficient methods for di-
versity-oriented synthesis,[5] it would be highly desirable that
the Michael adducts or dipolar cycloaddition products could
be selectively obtained from the same three-component re-
action of aldehydes, a-amino esters and activated alkenes
under easily controllable conditions, catalyzed by environ-
mentally benign organic molecules.[6]
Our strategy is based on the following considerations: al-
though a-amino esters might directly coordinate with a
metal cation, which would affect the formation of a-imino
esters with aldehydes and the subsequent reaction with the
activated alkenes, such processes should happen in the pres-
ence of a bifunctional organic thiourea–tertiary amine cata-
Scheme 1. Proposed organocatalytic three-component reaction of a-
amino esters, aldehydes and nitroalkenes. cat. 1=thiourea–tertiary amine
organocatalyst (see Scheme 2)
We first investigated the reaction of a-imino acetate 2a
and nitrostyrene 3a, catalyzed by thiourea–tertiary amine
1a (Scheme 2, 10 mol%) in toluene at ambient temperature.
Unfortunately, no reaction occurred, probably because the
tertiary amine group of 1a could not remove the a-proton
of 2a to generate the azomethine ylide intermediate
[a] Y.-K. Liu, H. Liu, W. Du, L. Yue, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and
Drug Deliver System of Education Ministry
Department of Medicinal Chemistry, West China School of Pharmacy
Sichuan University, Chengdu, 610041 (China)
Fax : (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801410.
Scheme 2. The structures of bifunctional organocatalysts 1a–e.
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9873

(Table 1, entry 1). 5 mol% of LiBr (or AgF with urea cata-
lyst 1b) was added in order to increase the acidity of the
proton by metal-coordination.[11] The dipolar cycloaddition
indeed occurred but only the racemic product 5a (R=H)
a-aminomalonate 7 and nitrostyrene 3a was explored, cata-
lyzed by 1a in the presence of 4 Š molecular sieves to
remove water (a by-product of the reaction). Although a
very low yield was attained when the three reagents were
added together in one vessel, the reaction proceeded much
better when 6a and 7 were previously stirred at 08C for 2h,
before adding 3a.[8] A good yield with excellent enantiose-
lectivity for the Michael adduct 4a was obtained, whereas
the results for cyclic product 5b were still poor (Table 1,
entry 5). Other bifunctional thiourea–tertiary amine cata-
lysts 1c–1e with various chiral scaffolds were also screened,
affording the Michael adduct 4a with inferior enantioselec-
tivities (Table 1, entries 6–8). Pleasingly, the urea catalyst
1b[12] displayed better efficacy and excellent enantioslectivi-
ty (96% ee) with high chemoselectivity for the Michael reac-
tion was obtained (Table 1, entry 9). It should be noted that
poor enantioselectivities for cycloaddition product 5b were
detected in all the screened reactions.
Having found the favourable reaction conditions, we then
examined a variety of nitroalkene and aldehyde substrates
to establish the general utility of the catalytic transforma-
tion.[14] The one-pot, three-component Michael addition of
aldehydes 6, diethyl a-aminomalonate 7 and nitroalkene 3
was commonly performed with 10 mol% of 1b at 08C for
48 h (after prior stirring of 6 and 7 at 08C for 2h). Only
trace amounts of dipolar cycloaddition products were
formed with all the tested substrates. As illustrated in
Table 2, for benzaldehyde 6a, excellent enantioselectivities
and high yields were obtained for nitrostyrenes 3a–h, bear-
ing diverse electron-withdrawing or -donating substituents
(Table 2, entries 1–8). High ee values were also attained for
Table 1. Screening studies of organocatalytic reaction of a-imino esters
and nitrostyrene.[a]
Entry
1[d]
Cat.
1a
Conditions.
A
Yield [%][b]
–
ee [%][c]
–
2[e]
3[f]
4[g]
1a
1b
1a
A
A
A
5a 80
5a 85
5a 0
5a 0
4a 50
5b 20
4a 91
5b 20
5
6
7
8
9
1a
1c
1d
1e
1b
B
B
B
B
B
4a 70
5b 18
4a 93
5b 20
4a 30
5b 65
4a 57
5b 5
4a 81
5b 18
4a 82
5b 14
4a 66
5b 20
4a 90
5b 6
Table 2. Asymmetric one pot, three-component Michael addition of alde-
4a 93
5b 6
4a 96
5b 40
hydes 6, diethyl a-aminomalonate 7 and nitroalkenes 3.[a]
[a] Conditions A: reaction performed with 2 (0.1 mmol), 3a (0.12mmol),
1 (10 mol%), and 4 Š molecular sieves (MS, 50 mg) in toluene (0.8 mL)
at room temperature for 24 h. B: benzaldehyde 6a (0.1 mmol), diethyl a-
aminomalonate 7 (0.1 mmol) and 4 Š MS (80 mg) were stirred at 08C for
2h before adding nitrostyrene 3a (0.12mmol) and catalyst 1 (10 mol%).
The mixture was then stirred for a further 48 h at 08C. 5a: R=H; 4a/5b:
R=COOEt. [b] Yield of isolated product. [c] Determined by HPLC anal-
ysis on chiral column, d.r.>99:1 for cyclic product 5. [d] 2a was used.
[e] 2a was used in addition to 5 mol% of LiBr. [f] 2a was used in addi-
tion to 5 mol% of AgF. [g] 2b was used.
Entry
Ar
Ph
R
Yield [%][b]
ee [%][c,13]
1
2Ph
3
4
5
6
7
8
9
10
11[d]
12[d]
13[d]
14
15
16[e]
Ph
p-ClPh
m-ClPh
o-ClPh
p-BrPh
p-FPh
p-MePh
p-MeOPh
2-thienyl
2-furyl
n-propyl
isopropyl
cyclohexyl
Ph
4a 93
4b 87
4c 93
4d 80
4e 84
4 f 83
4g 95
4h 83
4i 90
4j 89
4k 56
4l 60
4m 48
4n 93
4o 86
4a 90
96
98
98
94
96
98
96
95
96
98
97
98
98
96
97
94
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-FPh
p-MePh
Ph
was isolated (Table 1, entries 2and 3). We envisaged that
the introduction of another ethoxycarbonyl group at the a-
position of 2a would facilitate the generation of the azome-
thine ylide intermediate through tertiary amine activation.[2k]
In this case, employing 2b as the starting material, the
Ph
Ph
A
isolated as a stable compound after 24 h with promising
enantioselectivity (91% ee, Table 1, entry 4). A low yield of
cycloaddition product 5b (20%) was delivered but with very
poor enantioselectivity (20% ee). Subsequently, the poten-
tial three-component reaction of benzaldehyde 6a, diethyl
[a] Unless otherwise noted, reactions were performed with 6 (0.1 mmol),
7 (0.1 mmol), 3 (0.12mmol), 1b (10 mol%), 4 Š MS (80 mg), in toluene
(0.8 mL) at 08C for 48 h. [b] Yield of isolated product. [c] Based on
HPLC analysis on chiral column. [d] At room temperature for 72h.
[e] At 5.0 mmol scale with respect to aldehyde 6, for 60 h.
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Diversity-Oriented Synthesis
COMMUNICATION
nitroalkenes 3i and 3j, with heteroaryl groups (Table 2, en-
tries 9 and 10). Alkyl-substituted nitroalkenes exhibited
lower reactivity, although high enantioselectivities were still
obtained with moderate yields for reactions at ambient tem-
perature for 72h (Table 2, entries 11–13). Furthermore,
other aryl aldehydes could be successfully applied in the
Michael addition reaction (Table 2, entries 14 and 15). This
catalytic reaction could be smoothly scaled up, affording
similar results (Table 2, entry 16). Conversely, aliphatic alde-
hydes failed to afford the desired Michael adducts under the
current catalytic conditions.
As the 1,3-dipolar cycloaddition products were generated
in low yields and enantioselectivities, we investigated wheth-
er these pyrrolidine derivatives could be synthesized in a
more enantioenriched manner. When chiral Michael adduct
4a (96% ee) was treated with various bases (1,8-
Scheme 4. The structures of chiral monofunctional thiourea (urea) cata-
lysts 1 f–m.
Table 3. Asymmetric one-pot, three-component [3+2] cycloaddition of
aldehydes 6, diethyl a-aminomanolonate 7 and nitroalkenes 3.[a]
diazabicyclo
A
ACHTREUNG
(LDA) at À408C), surprisingly, cyclic product 5b was isolat-
ed in its racemic form (Scheme 3). Drawing on the results of
Entry Cat. Conditions
R
R1
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
1 f
1g
1h
1i
1j
1k
1l
1m
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClPh
m-ClPh
o-ClPh
p-FPh
5b 86
5b 88
5b 9257
5b 95
5b 85
5b 88
5b 93
5b 91
5b 70
5b 73
5b 9289
5c 79
5d 83
5e 69
5 f 73
4
0
4
36
65
76
8
70
9[d]
81
10
90[e]
11[f]
12
Scheme 3. Synthesis of [3+2] cycloaddition product 5b.
89
90
84
86
91
91
13
14
15
16
17
18
19
the chiral urea (thiourea)–tertiary amine-catalyzed reaction
(see Table 1), we realized that the cyclic product was not
produced from the Michael-addition intermediate by intra-
molecular cyclization.[15] Instead, a retro-Michael reaction of
chiral 4a would occur in the presence of a strong base, and
the racemic 5b would form in a concerted [3+2] cycloaddi-
tion mechanism. In fact, we found that 5b could be directly
isolated in 61% yield from the three-component reaction of
benzaldehyde, diethyl a-aminomalonate and nitrostyrene
without any catalyst at 08C for 48 h. The Michael addition
product 4a was not detected (Scheme 3).[10] The presence of
a tertiary amine functionality seems to be essential for the
catalytic Michael addition, but not to be cooperative in the
dipolar cycloaddition. Moreover, it has been documented
that a-imino ester 2b can undergo thermal 1,2-prototropy to
produce the active azomethine ylide.[2k] The use of chiral
monofunctional thioureas with bulkier substituents might
aid stereocontrol in the asymmetric 1,3-dipolar cycloaddi-
tion.
p-MeOPh 5g 75
2-furyl
n-propyl
Ph
Ph
Ph
5h 77
5i 6260
5j 90
5k 56
5b 80
Ph
p-ClPh
b-styryl
Ph
86
83
85
20
21[g]
[a] Unless otherwise noted, reactions were performed with 6 (0.1 mmol),
7 (0.1 mmol), 3 (0.12mmol), 4 Š MS (80 mg). Conditions A: with
1
(10 mol%) in toluene (0.8 mL) at 08C for 48 h; Conditions B: with 1l
(20 mol%) in MTBE (0.8 mL) at À208C for 72h. [b] Yield of isolated
product. [c] Based on chiral HPLC analysis. endo-selectivity>99:1.
[d] With 1l (20 mol%) at À208C for 72h. [e] The absolute configuration
of 5b was determined by X-ray crystallographic analysis after some deri-
vation (see Supporting Information). The others were assigned by analo-
gy. [f] With imine 2b. [g] At 3.0 mmol scale with respect to aldehyde 6,
for 120 h.
uct with complete endo-selectivity.[10] Thiourea–pyrrole com-
pound 1l was identified as the optimal catalyst (Table 3,
entry 7). The ee value was improved to 81% at À208C with
20 mol% of 1l (Table 3, entry 9), and even higher ee could
be attained in methyl tert-butyl ether (MTBE, Table 3,
entry 10). The reaction of imine 2b and nitrostyrene 3a was
also tested under the same catalytic conditions, affording
the cycloaddition product 5c in a better yield and with a
To investigate these predictions, a range of catalysts 1 f–
m,[16] bearing only an active thiourea (or urea) moiety
(Scheme 4, 10 mol%), were screened in the one-pot, three-
component reaction of benzaldehyde, diethyl a-aminomalo-
nate and nitrostyrene in toluene at 08C (Table 3, entries 1–
8). Pleasingly, pyrrolidine 5b was isolated as the sole prod-
Chem. Eur. J. 2008, 14, 9873 – 9877
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Y.-C. Chen et al.
similar ee value (Table 3, entry 11). Subsequently, the sub-
strate scope for the one-pot, three-component 1,3-dipolar
cycloaddition was explored. Highly stereoselective reactions
were proceeded using an array of nitrostyrenes with elec-
tron-withdrawing or donating substituents (Table 3, en-
tries 12–16). Excellent enantioselectivity was also gained for
2-furyl-substituted nitroalkene (Table 3, entry 17). The use
of an alkyl-substituted nitroalkene, however, led to more
modest ee values (Table 3, entry 18). The reaction of p-chloro-
benzaldehyde with nitrostyrene 3a afforded good results in
the cycloaddition reaction (Table 3, entry 19). Notably high
enantioselectivity was detected when cinnamaldehyde was
applied (Table 3, entry 20). We also tested the dipolar cyclo-
addition reaction at a larger scale, and a good ee value was
attained (Table 3, entry 21). However, aliphatic aldehydes
again could not be successfully used in the 1,3-dipolar cyclo-
addition.
Based on the absolute configuration of 5b, a plausible cat-
alytic mechanism for the concerted 1,3-dipolar cycloaddition
was proposed. The steric hindrance of the bulky 2,5-diaryl-
pyrrole substituent on the catalyst would lead to the forma-
tion of the aforementioned double hydrogen-bonding inter-
action between the thiourea moiety and nitrostyrene with
the b-phenyl group directed away from the catalyst. Subse-
quently, endo-attack on the in situ-formed azomethine ylide
from the re-face of nitrostyrene would generate the chiral
pyrrolidine product 5b (Scheme 5).
thiourea (urea)-based asymmetric catalysis is currently in
progress in our laboratory.
Acknowledgements
We are grateful for the financial support from NSFC (20502018), Minis-
try of Education (NCET-05-0781) and Chinesisch-Deutsches Zentrum für
Wissenschaftsfçrderung [GZ422 (362/6)].
Keywords: azomethine ylides
· cycloaddition · Michael
addition · nitroalkenes · organocatalysis
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Diversity-Oriented Synthesis
COMMUNICATION
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J. Long, B.-J. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, J. Am. Chem. Soc.
2007, 129, 1878–1879; i) S. J. Zuend, E. N. Jacobsen, J. Am. Chem.
Soc. 2007, 129, 15872–15883; for a recent review on thiourea and
urea catalysis, see: j) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007,
107, 5713–5743.
[11] a) O. Tsuge, S. Kanemasa, M. Yoshioka, J. Org. Chem. 1988, 53,
1384–1391; b) C. Alemparte, G. Blay, K. A. Jørgensen, Org. Lett.
2005, 7, 4569–4572; c) The combination of thiourea–tertiary amine
1a and AgF could not catalyze the dipolar cycloaddition because of
the preferable formation of the thiourea–Ag complex. However,
urea–tertiary amine 1b–AgF promoted the cycloaddition (Table 1,
entry 3).
[12] X. Xu, T. Yabuta, P. Yuan, Y. Takemoto, Synlett 2006, 137–140.
[13] The absolute configuration of 4 has not yet been determined. It was
assigned based on the concerted catalytic mode by Takemoto et al.:
T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119–125. Please see Supporting Information.
[14] The direct Michael addition of diethyl a-aminomalonate to nitroal-
kenes, catalyzed by 1b, could not proceed in the absence of alde-
hydes.
[15] The Michael adducts have been proposed as intermediates in the
[3+2] cycloaddition of azomethine ylides. See ref. 4 and ref. 9.
[16] Thiourea–pyrrole catalysts 1h–m were prepared in a similar proce-
dure to 1g, reported by Taylor and Jacobsen. See: M. S. Taylor,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558–10559.
[8] A thiourea-catalyzed three-component asymmetric acyl-Strecker re-
action has been recently reported, see: S. C. Pan, B. List, Org. Lett.
2007, 9, 1149–1151.
[9] For studies on [3+2] cycloadditions of azomethine ylides and nitro-
alkenes, see: a) S. Vivanco, B. Lecea, A. Arrieta, P. Prieto, I. Morao,
A. Linden, F. P. Cossío, J. Am. Chem. Soc. 2000, 122, 6078–6092;
b) X.-X. Yan, Q. Peng, Y. Zhang, K. Zhang, W. Hong, X.-L. Hou,
Received: July 11, 2008
Published online: October 2, 2008
Chem. Eur. J. 2008, 14, 9873 – 9877
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9877