Enantio-and diastereoselective nitro-Mannich reactions with in situ generated N-Boc-imines catalyzed by a bifunctional thiourea-guanidine catalyst

Article abstract of DOI:10.1055/s-0031-1289885

The asymmetric nitro-Mannich reactions of nitroalkanes and in situ generated N-Boc-imines were achieved with a new type of thiourea-guanidine bifunctional organocatalyst. The novel transformations exhibited good diastereoselectivities, and the adducts bearing adjacent chiral centers were generally obtained in moderate to high enantioselectivities (up to 94% ee). This reaction provides a concise and alternative route converting readily accessible and stable N-carbamate amido sulfones into optically active 1,2-diamino compounds. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289885

LETTER
2981
Enantio- and Diastereoselective Nitro-Mannich Reactions with in situ
Generated N-Boc-imines Catalyzed by a Bifunctional Thiourea–Guanidine
Catalyst
E
nantio- and
D
iastereos
e
i
ro-MannichR
H
eactions uang,a Cheng Peng,*a,b Li Guo,a Rong Hu,b Bo Han*a
a
b
Received 22 August 2011
and efficient solutions for the stereocontrolled assembly
of 1,2-diamino compounds and their derivatives.2 As a re-
sult, great strides have been made over the last several
years with both chiral metal3 and organic catalysts4 for the
Abstract: The asymmetric nitro-Mannich reactions of nitroalkanes
and in situ generated N-Boc-imines were achieved with a new type
of thiourea–guanidine bifunctional organocatalyst. The novel trans-
formations exhibited good diastereoselectivities, and the adducts
bearing adjacent chiral centers were generally obtained in moderate catalytic asymmetric version of this reaction. In the re-
to high enantioselectivities (up to 94% ee). This reaction provides a
ported literature, N-carbamate-activated imines, derived
concise and alternative route converting readily accessible and sta-
from aryl, heteroaryl, and aliphatic aldehydes, are the
ble N-carbamate amido sulfones into optically active 1,2-diamino
commonly used electrophiles. However, the preparation
compounds.
of these imines requires harsh reaction conditions and
their purification and storage are rather troublesome be-
Key words: organocatalysis, nitro-Mannich reaction, thiourea–
guanidine catalyst, in situ generated imines
cause of their inherent instability. It is noteworthy that a-
amido sulfone is a useful and stable precursor for the in
situ preparation of the imine acceptor.5 Thus, practically
Optically active 1,2-diamino compounds and their deriv-
and environment-friendly organocatalytic asymmetric
atives – acids, esters, and amides –, have attracted a great
Mannich-type reactions using a-amido sulfone have been
investigated, for example, with chiral phase-transfer cata-
deal of attention among organic chemists and biochemists
through the years due to the ubiquitous nature of 1,2-di-
lysts, cinchona alkaloids, and proline-type catalysts,
though with limited success so far.6
amines as key structural fragments of biologically active
compounds (Figure 1).1 Additionally, the synthesis of
these enantiopure materials has also represented a chal-
lenge for synthetic organic chemists due to the structural
complexity of molecules with two vicinal chiral centers.
Thiourea-based organic molecules have become the most
prominent hydrogen-bond-donor catalysts in a wide vari-
ety of organic reactions.7 Despite their tremendous utility,
these bifunctional catalysts are derived from a very limit-
ed range of chiral structural scaffolds, including cyclohex-
O
O
OH
ane-1,2-diamine,
1,1¢-binaphthyl-2,2¢-diamine,
and
HN
O
N
OH
cinchona alkaloids. Very recently, Nagasawa and co-
workers have developed the thiourea–guanidine catalyst8
and applied it to aza-Henry reactions with easily hydro-
lyzable N-carbamate imines and unsubstituted linear ni-
troalkanes.8e This new type of bifunctional catalyst is
expected to be applicable to a wide range of asymmetric
reactions. To our knowledge, the direct and practical
asymmetric nitro-Mannich reactions with in situ genera-
tion of carbamate-protected imines and functionalized ni-
troalkanes catalyzed by thiourea–guanidine catalysts have
not yet been reported. Herein, we describe our contribu-
tions to the development of practical and efficient synthe-
ses of the diversified chiral 1,2-diamino compounds.
Me3N
O2HC
dysibetaine
O
O
NH2
N
H
L-quisqualic acid
used in Chinese medicine
isolated from the marine sponge
O
O
H2N
O
OH
N
N
H
H
NH2
dapdiamide A
natural tripeptide antibiotics
O
Figure 1
Among various synthetic approaches, catalytic asymmet-
ric nitro-Mannich (or aza-Henry) reactions are elegant
We envisaged that the imine acceptor could be easily gen-
erated from the corresponding a-amido sulfone under
proper alkaline conditions. Meanwhile, nucleophilic car-
banion from nitroalkane might be produced under the
same conditions as well. Then the guanidinium group and
SYNLETT 2011, No. 20, pp 2981–2984
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289885; Art ID: W18611ST
© Georg Thieme Verlag Stuttgart · New York

2982
W. Huang et al.
LETTER
thiourea group selectively coordinated to the nucleophile
(nitroalkane) and the electrophile (imine) through ionic
and hydrogen-bonding interaction, respectively, and the
chiral induction was controlled by the chiral skeleton.
Table 1 Screening Studies of Organocatalytic Nitro-Mannich Reac-
tion of Nitroacetate 2a and a-Amido Sulfone 3aa
Boc
(S,S)-1 (5 mol%)
Boc
NH
base (4 equiv )
Bn
NO2
2a
HN
Bn
+
Ph
As a model reaction we chose to study the reaction of ni-
troethane 2a bearing an aromatic group with the stable a-
amido sulfone derived from benzaldehyde 3a (Table 1).
We focused our catalyst-screening efforts on thiourea–
guanidine catalyst 1a–i and performed the reaction in the
presence of four equivalents K2CO3 in dichloromethane at
0 °C (Table 1, entries 1–6). Catalysts 1a and 1b with
monosubstituted guanidines failed to afford significant
chiral induction, though good yields could be achieved in
two hours (Table 1, entries 1 and 2). Gratifyingly, system-
atic variation of the catalyst structure revealed that bis-
substituted guanidine 1c provided promising enantio- and
diastereoselectivity (Table 1, entry 3). Moreover, superior
stereocontrol (86% ee and dr = 4.0:1) could be attained
with catalyst 1d bearing a cyclic amine-substituted guani-
dine (Table 1, entry 4). The absolute configuration of 4a
solvent, 0 °C, 2 h
Ph
SO2Ph
NO2
4a
3a
R1
R2
Cl–
N+
H
H
H
H
N
N
N
N
R3
N
H
N
H
R3
S
R4
R4
S
1a R1 = n-Bu, R2 = H, R3 = 3,5-(CF3)2C6H3, R4 = Bn
1b R1 = i-Pr, R2 = H, R3 = 3,5-(CF3)2C6H3, R4 = Bn
1c R1 = n-Bu, R2 = n-Bu, R3 = 3,5-(CF3)2C6H3, R4 = Bn
1d R1–R2 = CH2Me)2CH2, R3 = 3,5-(CF3)2C6H3, R4 = Bn
1e R1–R2 = CH2(Me)2CH2, R3 = 4-ClC6H4, R4 = Bn
1f R1–R2 = CH2(Me)2CH2, R3 = 4-MeC6H4, R4 = Bn
1g R1–R2 = CH2(Me)2CH2, R3 = 3,5-(CF3)2C6H3, R4 = Me
1h R1–R2 = CH2(Me)2CH2, R3 = 3,5-(CF3)2C6H3, R4 = i-Pr
+
N
R5
Cl–
F3C
F3C
H
H
1
N
N
was determined by comparison of the H NMR data and
N
N
H
the HPLC retention time with that of literature data.4c,i
Consequently, replacing the 3,5-bis(trifluoromethyl)phe-
nyl group with other aryl groups decreased the enantiose-
lectivities as a result of weak hydrogen-bonding abilities
(Table 1, entries 5 and 6). Attempts to optimize R4 on the
chiral skeleton through the preparation of derivatives 1g–
h failed. Neither linear nor branch alkyl groups could af-
ford good stereoselectivity (Table 1, entries 7 and 8). The
catalysts 1i and 1j with only one thiourea unit were capa-
ble of promoting the reaction efficiently, but unfortunate-
ly, providing inferior chiral induction (Table 1, entries 9
and 10). Other solvents and inorganic bases were also
screened in the presence of 1d (Table 1, entries 11–15).
Among the solvents tested, toluene was proven to be the
best one in terms of both chemical yield and stereocontrol
(Table 1, entry 12). Adjusting the inorganic base demon-
strated little influence on the ee value of the reaction
(Table 1, entries 14 and 15). When the reaction was initi-
ated at lower temperature, a small decrease in conversion
was noted compared to the reaction at 0 °C, without im-
proving the ee values dramatically (Table 1, entry 16).
H
S
Bn
1i R5 = OMe
1j R5 = CF3
Entry Cat.
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
toluene
THF
Base
Yield (%)b drc
ee (%)d,e
<10
<10
56
1
2
1a
1b
1c
1d
1e
1f
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
CsOH
K2CO3
43 (41)
38 (39)
62 (20)
68 (17)
52 (30)
49 (36)
50 (33)
55 (26)
50 (28)
52 (32)
64 (20)
76 (14)
43 (17)
56 (13)
65 (19)
56 (14)
1:1
1:1
3
3.1:1
4.0:1
1.7:1
1.3:1
1.5:1
2.1:1
1.8:1
1.6:1
3.2:1
5.4:1
2.5:1
4.3:1
3.4:1
4.0:1
4
86
5
62
6
46
7
1g
1h
1i
35
8
40
9
61
10
11
12
13
14
15
1j
65
1d
1d
1d
1d
1d
1d
64
Then we examined the scope of the reaction under the op-
timized conditions. Results obtained in the addition of di-
versified nitroalkanes 2 to a variety of a-amido sulfones 3
are summarized in Table 2. All of the reactions were con-
ducted in toluene at 0 °C in the presence of 1d as a cata-
lyst. In all cases, the major chiral isomers 4 could be
directly isolated in pure form in good to high yields. Intro-
90
75
toluene
toluene
toluene
88
85
duction of electron-donating or electron-withdrawing 16f
groups on the aromatic ring of imines had limited influ-
ences on the stereo outcome, and satisfactory data were
generally attained (Table 2, entries 1–3). When a-amido
sulfone 3d possessing a heteroaromatic ring was used as
substrate, the ee value and dr of the adduct 4d slightly de-
creased (Table 2, entries 4). Next, we examined other
functionalized nitroalkanes as reaction partners (Table 2,
entries 5–8). These types of nucleophiles would be more
89
a Reaction conditions: 2a (0.2 mmol), 3a (0.1 mmol), 1 (5 mol%), sol-
vent (1 mL), 0 °C, 2 h.
b Isolated yield of pure diastereomer. Data in parentheses are related
to the isolated minor isomer.
c Calculated from the isolated yield of 4a and its isomer.
d Determined by chiral HPLC analysis.
e The absolute configuration was determined by comparison of the
HPLC retention time with that of literature data.
f At –20 °C for 12 h.
Synlett 2011, No. 20, 2981–2984 © Thieme Stuttgart · New York

LETTER
Enantio- and Diastereoselective Nitro-Mannich Reactions
2983
promising from the viewpoint of utility of the correspond- el methodology provides facile access to 1,2-diamino
ing products as synthetic intermediates. To synthesize the compounds and their derivatives with two adjacent chiral
2,3-diamino alcohol, benzyl-protected 2-nitroethanol was centers. Further investigations on the application of this
treated with a-amido sulfone 3a, and this provided the de- novel bifunctional organocatalyst in other asymmetric
sired product with good enantioselectivity and diastereo- transformations are under way in our laboratory.
selectivity (Table 2, entry 5). Similarly, high stereo-
selectivities were consistently obtained in the reaction
with several nitroalkanol derivatives bearing longer car-
bon chains (Table 2, entries 6–8). Finally, we investigated
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
the reaction of commonly employed linear alkyl nitroal-
kanes with a-amido sulfones. Under the same reaction
conditions, the reactions proceeded smoothly to afford the
products 4i in 90% ee and 4j in 92% ee, respectively
(Table 2, entries 9 and 10). These results demonstrated
that there was no observable effect of the substituted
groups of nitroalkanes on the efficiency of the nitro-Man-
nich reactions. It was also noteworthy that alkyl a-amido
sulfone also worked well in this reaction with nitroethane,
while the diastereoselectivity somewhat decreased
(Table 2, entry 11).
Acknowledgment
We thank the Scientific Research Fund of SiChuan Provincial Edu-
cation Department (2006B020) and Technology Department of
Chendu University of Traditional Chinese Medicine
(ZRYB2007032 and ZRYB2007030) for financial support.
References and Notes
(1) Review on a,b-diamino compounds: Viso, A.; de la Pradilla,
R. F.; Tortosa, M.; Garcia, A.; Flores, A. Chem. Rev. 2011,
111, PR1; and references cited therein.
(2) For a review on the synthesis of a,b-diamino compounds by
using Mannich reaction strategies, see: Arrayas, R. G.;
Carretero, J. C. Chem. Soc. Rev. 2009, 38, 1940.
In summary, we have successfully presented the stereose-
lective nitro-Mannich reaction of diversified nitroalkanes
and readily accessible and stable N-carbamate amido sul-
fones by employing bifunctional thiourea–guanidine cat-
alyst.9 In general, good diastereo- and enantioselectivities
could be obtained with a spectrum of substrates. This nov-
(3) (a) Yamada, K.; Harwood, S. J.; Gröger, H.; Shibasaki, M.
Angew. Chem. Int. Ed. 1999, 38, 3504. (b) Yamada, K.;
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4340.
Table 2 Asymmetric Nitro-Mannich Reaction of Functionalized
Nitroalkanes 2 and a-Amido Sulfones 3a
Boc
(S,S)-1d (5 mol%)
Boc
NH
R2
NO2
K2CO3 (4 equiv)
HN
R1
R2
NO2
+
R1
toluene, 0 °C, 2 h
SO2Ph
3
2
4
Entry R1
R2
Yield (%)b
drc
ee (%)d
1
2
Ph
4-MeC6H4
Bn
Bn
4a 76 (14)
4b 78 (15)
4c 71 (11)
4d 52 (16)
4e 80 (12)
5.4:1
5.2:1
6.5:1
3.3:1
6.7:1
5.2:1
5.1:1
5.8:1
4.2:1
4.9:1
2.3:1
90
94
89
78
92
90
87
88
90
92
84
3
4-F3CC6H4 Bn
4
3-pyridyl
Ph
Bn
5
CH2OBn
6
Ph
(CH2)2OBn 4f 78 (15)
(CH2)3OBn 4g 72 (14)
7
Ph
8
Ph
(CH2)3OTf
Me
4h 75 (13)
4i 77 (18)
4j 69 (14)
4k 55 (24)
9
Ph
10
11
Ph
C5H11
Me
i-Bu
a Reaction conditions: 2 (0.2 mmol), 3 (0.1 mmol), 1d (5 mol%), tol-
uene (1 mL), 0 °C, 2 h.
b Isolated yield of pure diastereomer. Data in parentheses are related
to the isolated minor isomer.
c Calculated from the isolated yield of 4 and its isomer.
d Determined by chiral HPLC analysis.
Synlett 2011, No. 20, 2981–2984 © Thieme Stuttgart · New York

2984
W. Huang et al.
LETTER
(5) (a) Petrini, M. Chem. Rev. 2005, 105, 3949. (b) Petrini, M.;
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(9) Typical Procedure for the Asymmetric Nitro-Mannich
Reaction for the Synthesis of Compound 4a
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Commun. 2007, 1620. (e) Los, S.; Dai, P.; Schaus, S. E.
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G.; Jiang, H.; Liu, H. J. Org. Chem. 2007, 73, 8563.
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Melchiorre, P. Angew. Chem. Int. Ed. 2008, 47, 8700.
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2009, 351, 345.
To a mixture of a-amido sulfone 3a (0.1 mmol), chiral
catalyst (S,S)-1d (0.005 mmol, 5 mol%), and K2CO3 (0.4
mmol) in toluene (1.0 mL) at 0 °C was added nitroalkane 2a
(0.2 mmol) in one portion. The resulting mixture was stirred
at 0 °C for 2 h. Then, a sat. aq NH4Cl solution was added,
and the organic layer was extracted with EtOAc. The
extracts were dried over MgSO4, filtered, and concentrated
in vacuo. Compound 4a was obtained as a white solid in
76% yield after flash column chromatography (PE–EtOAc =
50:1), and the ee was determined to be 86% by HPLC on
Chiralpak AD-H column (15% 2-PrOH–n-hexane, 1 mL/
min), l = 220 nm, tR (major) = 15.9 min, tR minor) = 17.8
min; mp 189–190 °C. 1H NMR (500 MHz, CDCl3):
d = 7.33–7.41 (m, 3 H), 7.26–7.31 (m, 4 H), 7.12–7.25 (m, 3
H), 5.19–5.30 (m, 2 H), 4.99–5.10 (br s, 1 H), 3.25–3.35 (m,
1 H), 3.13–3.20 (dd, J = 3.5, 14.8 Hz, 1 H), 1.46 (s, 9 H)
ppm. 13C NMR (125 MHz, CDCl3): d = 155.0, 136.4, 135.5,
129.2, 129.0, 128.9, 128.8, 127.5, 127.0, 92.7, 80.8, 57.3,
36.2, 28.2 ppm. ESI-HRMS: m/z calcd for C20H24N2O4 + Na:
379.1634; found: 379.1636.
Synlett 2011, No. 20, 2981–2984 © Thieme Stuttgart · New York

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