Discovery of bifunctional thiourea/secondary-amine organocatalysts for the highly stereoselective nitro-Mannich reaction of α-substituted nitroacetates

Article abstract of DOI:10.1002/chem.200801170

The readily accessible bifunctional thiourea/secondary-amine organocatalysts for the highly stereoselective Nitro-Mannich reaction of simple esters of α-substituted nitroacids and N-Boc imines were reported. The enantioselectivity of the isomer is found to increase and the N-H group plays a crucial role in the catalytic transition state other than acting as Bronsted base. Good enantioselectivity could be obtained catalyzed by urea-secondary amine and the enantiomeric excess (ee) value is found to decrease in the absence of 4A molecular sieves. In case of methyl 2-nitropropanoiate, excellent diastereo- and enantioselectivities are observed for aryl imines nearing diverse electron-withdrawing or donating substitutions. The nitro-Mannich products resulting from α-phenyl nitroacetate and N-Boc benzaldimine, are found to be labile at ambient temperature due to its crowded structure.

Full text of DOI:10.1002/chem.200801170

DOI: 10.1002/chem.200801170
Discovery of Bifunctional Thiourea/Secondary-Amine Organocatalysts for
the Highly Stereoselective Nitro-Mannich Reaction of a-Substituted
Nitroacetates
Bo Han,[a] Qing-Ping Liu,[b] Rui Li,*[c] Xu Tian,[a] Xiao-Feng Xiong,[a]
Jin-Gen Deng,[b] and Ying-Chun Chen*[a, c]
The nitro-Mannich reaction (or aza-Henry reaction) is a
Bifunctional thiourea/tertiary-amines have been fruitfully
utilized in a number of 1,2- or 1,4-addition reactions.[8,9] Un-
fortunately, our initial studies with the diversely structured
catalysts 1a–1d for the reation of ethyl 2-nitropropanoinate
À
versatile C C bond-forming process that can deliver valua-
ble nitrogen-containing building blocks such as 1,2-diamines
and a-amino carbonyl compounds.[1] Its asymmetric variant
has provoked much interest in the last years. Good stereo-
control has been achieved in the reactions of simple nitroal-
kanes and nitroacetates with various imines, since the pio-
neering work of Shibasaki and Jørgensen, either utilizing
metal-based[2] or organic catalysts.[3] However, despite these
important advances, the applications of a-substituted nitroa-
cetates[4] in this field, in which adjacent quaternary and terti-
ary chiral centers must be constructed concurrently,[5] are
rarely explored,[6] and good results have been presented
only very recently with bulky esters.[7] Here we would like
to report the discovery of readily accessible thiourea/secon-
dary-amine organocatalysts for the highly stereoselective
nitro-Mannich reaction of simple esters of a-substituted ni-
troacids and N-Boc imines.
[a] B. Han, X. Tian, X.-F. Xiong, 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
2a with N-Boc imine 3a catalyzed failed to give significant
chiral induction (Table 1, entries 1–4), though excellent en-
antiomeric excess (ee) values have been achieved in the con-
struction of a quaternary stereocenter with analogous a-
substituted cyanoacetates.[10] Nevertheless, one apparently
different feature of nitro group from cyano functionality is
that the former possesses more preferable binding sites for
hydrogen-bonding interactions. A low ee was also obtained
Sichuan University, Chengdu, 610041 (China)
Fax : (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Dr. Q.-P. Liu, Prof. Dr. J.-G. Deng
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences, Chengdu, 610041 (China)
[c] Dr. R. Li, Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy
West China Hospital, Sichuan University
Chengdu, 610041 (China)
by catalysis with
a simple thiourea/primary-amine 1e
(entry 5). To our gratification, the enantioselectivity of the
major isomer 4a was dramatically increased with 1 f, with a
secondary amine moiety, although the diastereoselectivity
E-mail: lirui@scu.edu.cn
was still not satisfying (entry 6).[11] The N H group of 1 f
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801170.
plays a crucial role in the catalytic transition state other
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Chem. Eur. J. 2008, 14, 8094 – 8097

COMMUNICATION
Table 1. Screening studies of organocatalytic nitro-Mannich reaction of
tained in the reaction of methyl 2-nitropropanoinate 2b and
imine 3a (entry 21).
2-nitropropanoinate 2a and N-Boc benzaldimine 3a.[a]
With the optimal catalytic conditions in hand, the reaction
scope for a-substituted nitroacetates and N-Boc imines were
investigated. The results were summarized in Table 2. In
Entry
Cat.
Solvent
Yield [%][b]
dr[c]
1.7:1
ee [%][d]
Table 2. Stereoselective nitro-Mannich reaction of a-substituted nitroace-
tates 2 and N-Boc aldimines 3.[a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
toluene
4a-50/5a-30
4a-49/5a-31
4a-51/5a-26
4a-51/5a-23
4a-52/5a-25
4a-53/5a-30
4a-70/5a-23
4a-62/5a-17
4a-72/5a-19
4a-74/5a-23
4a-72/5a-23
4a-60/5a-26
4a-57/5a-31
4a-48/5a-28
4a-68/5a-28
4a-62/5a-26
4a-57/5a-28
4a-54/5a-31
4a-60/5a-23
4a-84/5a-7
4b-86/5b-5
10
25
46
23
32
85
94
93
96
96
94
80
63
10
84
92
67
55
89
97
96
1.6:1
2.0:1
2.2:1
2.1:1
1.8:1
3.0:1
3.6:1
3.8:1
3.2:1
3.1:1
2.3:1
1.8:1
1.7:1
2.2:1
2.4:1
2.0:1
1.7:1
2.6:1
12.0:1
17.2:1
Entry
R
R1
Yield [%][b]
dr[c]
ee [%][d]
1
2Me
3
4
5
Me
Ph
4b-86 (5)
4c-78 (8)
4d-83 (8)
4e-79 (10)
4 f-86 (6)
4g-85 (5)
4h-85 (10)
4i-75 (20)
4j-68 (9)
4k-38 (7)
–
17.2:1
9.8:1
10.4:1
7.9:1
14.3:1
17.0:1
8.5:1
3.8:1
7.6:1
5.4:1
–
96
96
95
91[e]
96
94
95
91
93
96
–
p-FC6H4
m-ClC6H4
o-ClC6H4
p-MeC6H4
m-MeC6H4
2-furyl
2-thienyl
Ph
Me
Me
Me
Me
Me
Me
PhCH2
iPr
10
11
12
13
14
15
16
17
18
19[e]
20[f]
21[f,g]
1j
1k
1 L
1m
1n
1o
1j
1j
1j
1j
1j
6
7
8
9
10[f]
11
Ph
Ph
DCM
THF
m-xylene
m-xylene
m-xylene
Ph
[a] Unless noted otherwise, reactions were performed with 2a
(0.15 mmol), 3a (0.23 mmol), 1 (10 mol%) and 4 Š MS (40 mg) in m-
xylene (0.5 mL) at À208C for 72h. [b] Isolated yield; data in parenthesis
is related to the isolated minor isomer 5. [c] Calculated from the isolated
4 and 5. [d] Based on HPLC analysis on chiral column. [e] The absolute
configuration of 4e was determined by X-ray analysis (Figure 1),[13] and
other products were assigned by analogy. [f] Ethyl ester of a-isopropylni-
troacid was used.
1j
[a] Unless noted otherwise, reactions were performed with 2a
(0.15 mmol), 3a (0.23 mmol), 1 (10 mol%) and 4 Š MS (40 mg) in sol-
vent (0.5 mL) at 5–108C for 48 h. [b] Isolated yield of pure 4a and 5a.
[c] Calculated from the isolated isomers 4a and 5a. [d] Determined by
HPLC analysis on chiral column; low ee (<20%) was observed for 5a in
all the tested reactions. [e] Without adding 4 Š MS. [f] At À208C for
72h. [g] 2b was used.
general the major chiral isomers 4 could be directly isolated
in pure form in good to high yields. The solid-state structure
of 4e, as derived from X-ray crystallography, is shown in
Figure 1. For methyl 2-nitropropanoinate 2b, excellent dia-
stereo- and enantioselectivities were observed for aryl
imines bearing diverse electron-withdrawing or -donating
substitutions (Table 2, entries 1–6). Good results were also
obtained for heteroaryl imines (entries 7 and 8).[12] Other a-
substituted nitroacetates were also studied; the a-benzyl de-
rivative gave rise to high stereoselectivity in the reaction
with N-Boc benzaldimine (entry 9). Even the bulky sub-
than merely acting as a Brønsted base, in contrast with that
of tertiary-amine group. Moreover, superior stereocontrol
could be attained with catalyst 1g bearing chiral 1,2-diphe-
nylethylenediamine (DPEN) scaffold (entry 7). Consequent-
ly, an array of thiourea/secondary-amines containing DPEN
were devised. Similar data was obtained for catalysts 1h–1k
with arylmethyl substitutions (entries 8–11); however, much
lower ee values were obtained for catalysts 1l and 1m bear-
ing alkyl groups (entries 12and 13). In contrast, a tertiary
amine, N-benzyl-N-methyl catalyst 1n, still provided poor
enantioselectivity in the model reaction, which further
À
proved that an N H group was essential for the stereocon-
trol (entry 14 vs. 7). In addition, good enantioselectivity
could be obtained catalyzed by urea-secondary amine 1o
(entry 15). Other solvents were also screened in the pres-
ence of 1j, and reduced enantioselectivities were generally
observed (entries 16–18). Moreover, the ee value was slight-
ly decreased in the absence of 4 Š molecular sieves, proba-
bly a trace amount of water would affect the hydrogen-
bonding interaction (entry 19). It was pleasing to find that
the diastereomeric ratio (dr) ratio could be improved with-
out affecting the high conversion by lowering the reaction
temperature to À208C, while the time was extended to 72h
(entry 20). In addition, excellent ee and dr ratio were at-
Figure 1. X-ray structure of enantiopure 4e.
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Nevertheless, the nitro-Mannich products resulting from a-
phenyl nitroacetate and N-Boc benzaldimine were found to
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As illustrated in Scheme 1, the nitro-Mannich adducts
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the reduction with NaBH4/NiCl2.[7,14] Interestingly, the hy-
droxylamino derivative 7 could be chemoselectively ob-
tained by the mild hydrogenation with Pd/C/H2 (1 atm).
Moreover, the a-nitro group of 4b could be stereoselectively
removed under a radical reduction conditions to give com-
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In conclusion, we have presented the highly stereoselec-
tive nitro-Mannich reaction of simple esters of a-substituted
nitro-acetic acids and N-Boc aldimines by employing novel
bifunctional thiourea/secondary-amine catalysts. Some bio-
logically important chiral amino acid derivatives with dense
functionalizations could be readily attained. Currently an in-
vestigation into the catalytic mechanism[16] and expansion of
the new bifunctional organocatalysts in other asymmetric
transformations are in progress.
[7] During the preparation of this paper, Shibasaki et al. reported the
nitro-Mannich reaction of tert-butyl esters of a-substituted nitroace-
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Matsunaga, M. Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170–
2171; Johnston et al. presented the same reaction of bulky 2,6-
iPr2C6H3 esters of a-substituted nitroacetic acids in syn-stereoselec-
tivity with proton catalysis, see: b) A, Singh, J. N. Johnston, J. Am.
Chem. Soc. 2008, 130, 5866–5867.
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We are grateful for the financial support from NSFC (20502018 and
20772084), Ministry of Education (NCET-05-0781), and Sichuan Province
Government (07ZQ026-027).
Keywords: amines · hydrogen bonds · nitroacetate · nitro-
Mannich reaction · organocatalysis · thiourea
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COMMUNICATION
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slowly isomerize to the corresponding enamides.
[13] CCDC-693595 (4e) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.
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[16] For preliminary catalytic mechanism exploration by a DFT compu-
tational study, see Supporting Information.
Received: June 15, 2008
Published online: July 24, 2008
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