1,1-Diamino-2-nitroethylenes as excellent hydrogen bond donor organocatalysts in the Michael addition of carbon-based nucleophiles to β-nitrostyrenes

Article abstract of DOI:10.1016/j.tet.2013.08.040

A new class of hydrogen bond donor catalysts based on the 1,1-diamino-2-nitroethylene scaffold has been introduced for the activation of trans-β-nitrostyrenes toward reactions with a range of carbon-based nucleophiles, affording the corresponding adducts

Full text of DOI:10.1016/j.tet.2013.08.040

Tetrahedron xxx (2013) 1e6
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1,1-Diamino-2-nitroethylenes as excellent hydrogen bond donor
organocatalysts in the Michael addition of carbon-based
nucleophiles to b-nitrostyrenes
,
b
a
Rodrigo C. da Silva a, Gustavo P. da Silva a, Diego P. Sangi a , Joao G. de M. Pontes ,
~
a
a,
a,
*
*
^
^
ꢀ
~
Antonio G. Ferreira , Arlene G. Correa , Marcio W. Paixao
a
~
~
Departamento de Química, Universidade Federal de Sao Carlos, Sao Carlos, SP, Brazil
b
^
Instituto de Ciencias Exatas, Universidade Federal Fluminense, 27213-145 Volta Redonda, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of hydrogen bond donor catalysts based on the 1,1-diamino-2-nitroethylene scaffold has
been introduced for the activation of trans- -nitrostyrenes toward reactions with a range of carbon-
based nucleophiles, affording the corresponding adducts in excellent yields. Importantly, this new set
of organocatalysts is easily prepared from commercially available starting materials in mild reaction
conditions.
Received 25 June 2013
Received in revised form 14 August 2013
Accepted 16 August 2013
Available online xxx
b
Ó 2013 Published by Elsevier Ltd.
Keywords:
Organocatalysis
Hydrogen-bond donor
Michael addition
1,1-Diamino-2-nitroethylenes
b
-Nitrostyrenes
1. Introduction
related compounds through double hydrogen-bonding interactions
have emerged as a powerful alternative to metal catalysis. Among
Over the past few years, organocatalysis has been widely stud-
ied, developed, and employed for the synthesis of novel organic
molecules in the fine chemicals industry.1 This new concept has
rapidly become a complementary method to classical strategies
employed in synthetic organic chemistry for the construction of
carbonecarbon and carboneheteroatom bonds.2 Among the range
of reactions promoted by organocatalysts, the conjugate addition of
carbon-based nucleophiles to electron-deficient alkenes is recog-
nized as one of the most powerful and atom-economical synthetic
tools for the construction of densely functionalized compounds
from simple precursors.3 In this context, various electrophilic spe-
cies have been examined, and recent efforts have been devoted to
the application of nitroalkenes as suitable Michael acceptors.4 This
can be rationalized by the strong electron-withdrawing property of
the nitro group, which also represents a highly useful reac-
tive handle for further synthetic manipulations into a variety of
building blocks, such as amines, acids, oximes, and others.5 Small
the series of molecular architectures that have proven to be effec-
tive as hydrogen-bond donors are urea, thiourea, guanidines, and
squaramide-derived catalysts.6 Hence, many useful trans-
formations and elegant reaction sequences have been developed
employing these frameworks.7,8 Very recently, Franz and Mattson
independently introduced a new class of catalyst, namely silane-
diols, which also operates through hydrogen bonding9 (Scheme 1).
molecules capable of activating
a,b-unsaturated carbonyls or
* Corresponding authors. Tel.: þ55 16 33518075; fax: þ55 16 33518350; e-mail
Scheme 1. Hydrogen-bonding catalysts.
^
~
addresses: agcorrea@ufscar.br (A.G. Correa), mwpaixao@ufscar.br (M.W. Paixao).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.08.040
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2
R.C. da Silva et al. / Tetrahedron xxx (2013) 1e6
Table 1
Owing to the success of hydrogen-bonding catalysis, the pursuit
Catalytic Michael addition reaction of indole 4a with trans-
b-nitrostyrene 3a in the
of new and efficient catalytic systems, providing excellent yields at
low catalyst loading and under mild reaction conditions, still stands
as a significant challenge. As part of our ongoing research program
toward the development of practical catalytic synthetic methods,10
herein we disclose the synthesis of a new class of hydrogen-
bonding organocatalysts and their catalytic performance in Mi-
chael additions of C-based nucleophiles to nitroalkenes. Initially,
a series of 1,1-diamino-2-nitroethylene catalysts 2aef was readily
presence of organocatalysts 2aef under different reaction conditionsa
prepared from L,L-bis(methylthio)-2-nitroethene (1) and different
amines, which are commercially available, inexpensive starting
materials, without the need of inert or dry conditions (Scheme 2),11
hence greatly enhancing the applicability of this new type of
organocatalysts.
Entry
Catalyst (10 mol %)
Solvent
Yield (%)b
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
2c
6a
2c
2c
2c
2c
2c
2c
6b
d
2g
2f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
THF
82
79
86
72
79
76
71
58
73
26
85
91
81
45
66
11
13
36
7c
8d
9
Scheme 2. General synthesis of organocatalysts 2aef.
10
11
12
13e
14f
15
16
17
18
CHCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2. Results and discussion
With these novel hydrogen-bond donors in hand, screening
studies were initiated to find a proof of concept for their application
in hydrogen-bonding catalysis. The addition of indole (4a) to trans-
b
-nitrostyrene (3a) was chosen as a model reaction for catalyst
a
Unless otherwise specified, reactions were conducted using: trans-
styrene 3a (0.25 mmol), indole 4a (0.375 mmol) in 0.2 mL of solvent.
b-nitro-
screening in CH2Cl2 at room temperature for 24 h and 10 mol % of
catalyst loading. After screening a variety of hydrogen-bond donor
catalysts based on the 1,1-diamino-2-nitroethylene core, it was
discovered that organocatalyst 2c showed the best activity, leading
to the addition product in 86% yield (entry 3, Table 1). This result
clearly indicates that the CF3 substituent on the aromatic ring is
important for the efficient conversion. Unfortunately, a slight ero-
sion in the chemical yield was observed when decreasing the cat-
alyst loading to 5 mol % (entry 7). By comparing our catalytic system
with conventional thiourea and squaramide catalysts (6aeb), the
superiority of 1,1-diamino-2-nitroethylene 2c was manifested,
providing higher yield of the desired product, after 24 h using
CH2Cl2 and toluene, respectively (86% vs 58% and 66%, entries 3 vs 8
and 15).9d
For further optimization of the reaction conditions, we turned to
address the solvent effect in the catalyst efficacy. From the nonpolar
solvents investigated, which are all generally suitable for hydrogen-
bonding catalysis, it was found that ethereal solvents like THF had
a negative influence on the activity of organocatalyst 2c, whereas
the use of toluene led to an improvement in the reaction yield
(entries 9e12).
b
Yields of the isolated product.
Reaction was performed using 5 mol % of the catalyst 2c.
See Ref. 9d.
c
d
e
Reaction was performed using trans-
b
-nitrostyrene 3a (0.25 mmol), indole 4a
(0.25 mmol) in 0.2 mL of solvent.
f
Reaction was performed using trans-b-nitrostyrene 3a (0.375 mmol), indole 4a
(0.25 mmol) in 0.2 mL of solvent.
In order to investigate the mode of action with this new class of
organocatalyst, the activity of catalysts 2g and 2h was examined. As
expected, when the di-methylated organocatalyst 2g was evalu-
ated, no hydrogen-bonding catalysis can take place, as the chemical
yield matches the background rate (entries 16 vs 17). On the other
hand, organocatalyst 2h, having a single hydrogen bonding capa-
bility, which can also engage in an intramolecular hydrogen bon-
ding,11b exhibits catalytic activity, albeit with lower reactivity
(entry 18). In order to better investigate the mode of action with
nitroethenediamine, we performed an NMR binding study. 1H and
13C NMR spectra of organocatalyst 2e and mixtures (1:1 and 1:2) of
2e with nitroolefin were recorded at ambient temperature in
DMSO-d6 on a 400-MHz liquid NMR spectrometer. We found that
the corresponding 1H NMR spectra of 2e from a 2:1 mixture of 2e
and nitroolefin showed the appearance of two new peaks with
large changes in the chemical shifts for the NH protons. Further-
more, several other signals of the 2e side chain were split due to its
complexation with the nitroolefin (Fig. 1).
Finally, the effect of the reaction stoichiometry was examined.
When equimolar amounts of indole and nitroalkene were used, the
isolated yield dropped from 91% to 81% (entry 12 vs 13). The use of
an excess of Michael acceptor (1.5 equiv) had a negative influence
on the reaction course, furnishing the desired product in 45% yield
(entry 14).
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R.C. da Silva et al. / Tetrahedron xxx (2013) 1e6
3
nitroalkenes bearing either electron-donating or electron-
withdrawing substituents at the aromatic ring were successfully
applied in the nucleophilic addition (entries 2e8) with excellent
results. However, when 4-bromo-b-nitrostyrene was employed,
48 h of reaction were required to achieve high yield (entry 3). In
general, the electronic nature and steric properties of the sub-
stituents at the aromatic ring of the Michael acceptor have little
effect on the reactivity of this catalytic system (entries 5e8). Taking
into account that the indole skeleton is considered a privileged
pharmacophore, widely applied in the pharmaceutical chemistry,
we then turned our attention to the evaluation of a range of indoles
in the presence of this catalytic system. Fortunately, we were able
to demonstrate that the described Michael addition is unbiased
toward substitution on the indole nucleophiles. Having an electron-
donating substituent at the 5-position on the indole ring was well
tolerated, furnishing the desired addition products 5h and 5i in 99%
and 90% yield, respectively (Table 2, entries 9 and 10).
Fig. 1. Expanded region of sections of the 1H NMR spectra in DMSO-d6. (a) Free catalyst
2e; (b) mixture of catalyst 2e and nitroolefin 3a (1:1); (c) mixture of catalyst 2e and
nitroolefin 3a (1:2).
Table 2
The 13C NMR clearly indicates the complex formation in favor of
a two hydrogen-bonding contributor, once both methylene carbon
atoms next to the nitrogen showed a significant downfield shift
over 3 ppm (Fig. 2). Therefore, based on the results obtained using
catalysts 2g and 2h with the NMR studies our hypothesis is that
there are two hydrogen-bonding contributors in the reaction
equilibriums. Although, the single hydrogen-bonding interaction
cannot be fully excluded, the dual hydrogen-bonding interactions
with the substrate seem to be the most effective behavior for this
catalytic system (Scheme 3).
Michael addition of indoles (4aeg) to nitroalkenes (3aeh) catalyzed by organo-
catalyst 2ca
Entry
R1
R2/R3/R4
Product
Yield (%)b
1
Ph
H/H/H
H/H/H
H/H/H
H/H/H
H/H/H
H/H/H
H/H/H
H/H/H
OMe/H/H
Me/H/H
Br/H/H
Cl/H/H
H/H/Me
OMe/H/H
H/H/H
5a
5b
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
91
70
85
91
85
80
73
65
99
90
85
70
99
58
87
2
4-BreC6H4
4-BreC6H4
4-CleC6H4
2-CleC6H4
4-MeOeC6H4
3-MeOeC6H4
2-MeOeC6H4
Ph
Ph
Ph
Ph
Ph
3c
4
5
6
7
8
9
10
11
12
13
14
15
Pent
C8H9
a
Unless otherwise specified, reactions were conducted using trans-b-nitro-
styrene 3aeh (0.25 mmol), indole 4aeg (0.375 mmol) in 0.2 mL of solvent.
b
Yields of the isolated product.
Reaction was conducted for 48 h.
c
Fig. 2. Expanded region of sections of the 13C NMR spectra in DMSO-d6. (a) Free cat-
alyst 2e; (b) mixture of catalyst 2e and nitroolefin 3a (1:1); (c) mixture of catalyst 2e
and nitroolefin 3a (1:2).
Furthermore, electron-deficient nucleophiles in the context of
a 5-halogen (Br and Cl) substituted indole could also be included as
reaction partners; however, a slight variation in terms of yield was
observed (entries 11 and 12). Such halogenated indole adducts
proved to be valuable synthons, as they can be further elaborated
using organometallic technologies. Incorporation of an alkyl sub-
stituent at the C(2)-indole position reveal that electronic and steric
modification of the indole ring can be accomplished with a positive
influence on the reaction performance, giving the corresponding
addition product in 99% yield (entry 13).
To our delight, the reactions of trans-b-nitrostyrene bearing b-al-
kyl substituents (5h and 5i) afforded the product in good to excellent
chemical yield (Table 2, entry 14 and 15). Moreover, the applicability
of this new type of hydrogen-bonding scaffold could be successfully
extended utilizing a set of different carbon-based nucleophiles. Un-
fortunately, under the sameprotocol applied before, theaddition of2-
Scheme 3. The complex formation in favor of a two hydrogen-bonding contributor.
Having established the optimal conditions, the scope of the
Michael addition was explored with a variety of nitroalkenes and
indoles in the presence of organocatalyst 2c. The results shown
in Table 2 demonstrate the versatility of this novel class of
hydrogen bond donor catalyst for this transformation. A number of
hydroxy-1,4-naphthoquinone (10a) to trans-b-nitrostyrene (3a)
completely failed. To circumvent this problem we explored the highly
modular nature and easy synthesis of this new class of hydrogen-
bond donor to fine-tuning the catalytic activity. Therefore, we
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4
R.C. da Silva et al. / Tetrahedron xxx (2013) 1e6
Nu
designed and synthesized a novel bifunctional organocatalyst9 based
NO
Organocatalyst
NO
on the 1,1-diamino-2-nitroethylene core (Scheme 4).12
Solvent, 23 C, 12 h
Nu
O
O
Using 5 mol% of the Organocatalyst gave
99% yield, ee: 44% in CH Cl as solvent
N
H
N
H
N
MeO
CF
Using 10 mol% of the Organocatalyst gave
99% yield, ee: 36% in toluene as solvent
NO
N
N
H
Chiral Organocatalyst based on 1,1-
Diamino-2-Nitroethylene Core
Scheme 6. Preliminary applications of the chiral organocatalyst, based on the 1,1-
diamino-2-nitroethylene core.
Scheme 4. General synthesis of organocatalyst 9.
nitroalkenes, under mild reaction conditions. Remarkably, its
modular nature and easy synthesis allows the preparation of a wide
range of organocatalysts, especially with regard to the chiral envi-
ronment. Ongoing efforts towards the fine-tuning of this chiral
hydrogen bond donor organocatalyst are under evaluation and will
be reported in due course.
We then applied the bifunctional organocatalyst (9) as a pro-
moter in the Michael addition of 2-hydroxy-1,4-naphthoquinone
(10a) to 1-phenyl-2-nitroethene (3a) in toluene as solvent. To our
delight the desired product was afforded in excellent yield (83%).13
Encouraged by these results and the particular importance of
non-natural amino acids,14 the reactivity of oxazolone 10b and
glycine imine 10e with hydrogen-bond donor system was also
evaluated.15 The
a,a-disubstituted and a-monosubstituted amino
4. Experimental section
4.1. General remarks
acids were obtained in good yields and diastereoselectivities (10b:
75% yield, dr¼62:38/10e: 78% yield, dr¼75:25). Furthermore, 1,3-
dicarbonyl compounds16 reacted smoothly with
b-nitrostyrene to
afford the desired product in quantitative yield with
a
di-
Reactions were monitored by thin-layer chromatography using
UV light to visualize the course of reaction. Purification of products
was carried out by flash chromatography on silica gel. Mass spectra
and high-resolution mass spectra (HRMS) were recorded using
electrospray ionization (ESI). Chemical yields refer to pure isolated
substances. 1H and 13C NMR spectra were obtained using deuterated
solvents (CDCl3 and DMSO-d6) in a Bruker Avance III spectrometer.
Chemical shifts are reported in parts per million from tetrame-
thylsilane with the solvent as the internal standard. The following
abbreviations were used to designate chemical shift multiplicities:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, h¼heptet, m¼multiplet,
br¼broad. Reagents were purchased from Aldrich Chemical Com-
pany and used as received.
astereomeric ratio of 88:22. Despite the usefulness and versatility
of oxindoles as building blocks in a number of natural alkaloids and
in many pharmaceuticals,17 the focus was posed on the addition of
this nucleophile. Notably, the oxindole 10c underwent Michael
addition in 80% yield and 85:15 dr (Scheme 5).
4.1.1. General procedure for the synthesis of organocatalysts 2aef. To
a solution of 1,1-bis(methylthio)-2-nitroethylene (1.5 mmol) in
ethanol (5 mL) was added the respective amines (3 mmol). The
reaction was refluxed for 48 h and then the solvent was removed to
give a residue, which was purified by column chromatography on
silica gel (60:40 hexane/EtOAc) to provide the organocatalysts
2aef. Spectral data of the products prepared are listed below.
4.1.1.1. 2-Nitro-N,N0-diphenylethene-1,1-diamine (2a). 85% yield;
Yellow solid; mp 160e161 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
6.31
Scheme 5. Addition of a range of C-based nucleophiles to trans-
b-nitrostyrene (3a).
(s, 1H); 7.19e7.38 (m, 10H); 10.40 (s, 1H); 13C NMR (100 MHz,
Reactions were conducted using trans- -nitrostyrene 3a (0.25 mmol), carbon-based
b
nucleophile (0.375 mmol), organocatalyst 9 (10 mol %) in toluene (0.2 mL).
DMSO-d6)
d 100.5; 124.4; 126.1; 129.3; 136.4; 153.6; HRMS
(C14H13N3O2) [MþH]þ: calcd: 256.1086; found: 256.1079.
Moreover, we turned our attention to the chiral version of this new
class of hydrogen bond donor organocatalyst, based on the 1,1-
diamino-2-nitroethylene core. Preliminary studies have revealed that
cinchona-derived organocatalyst 9b effectively catalyzed the Michael
addition of 2,4-pentanedione and indole (4a) to trans-b-nitrostyrene
(3a), giving the desired products in excellent yields and promising
4.1.1.2. N,N0-Dibenzyl-2-nitroethene-1,1-diamine (2b). 92% yield;
Yellow solid; mp 203e205 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
4.35
(s, 2H); 4.62 (s, 2H); 6.40 (s, 1H); 7.20e7.44 (m, 10H); 8.01 (s, 1H);
10.4 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
44.1; 44.3; 97.8; 126.6
d
(br 2ꢁ); 127.3 (br 4ꢁ); 128.1; 128.6 (br 3ꢁ); 155.8; HRMS
(C16H18N3O2) [MþH]þ: calcd: 284.1399; found: 284.1395.
enantioselectivities (44% and 36% ee), respectively (Scheme 6).
3. Conclusion
4.1.1.3. N,N0-Bis(3,5-bis(trifluoromethyl)benzyl)-2-nitroethene-
1,1-diamine (2c). 77% yield; Yellow solid; mp 97e99 ꢀC; 1H NMR
In summary, a novel class of hydrogen bond donor organo-
catalyst was designed, synthesized, and successfully applied to
promoting the addition of several carbon-based nucleophiles to
(400 MHz, DMSO-d6)
7.75e8.09 (m, 7H); 10.56 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
43.0; 43.3; 97.7; 121.1; 121.8; 124.5; 129.8; 130.1; 130.4; 130.8;
d 4.52 (s, 2H); 4.79 (s, 2H); 6.56 (s, 1H);
d
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R.C. da Silva et al. / Tetrahedron xxx (2013) 1e6
5
141.3; 155.7; HRMS (C20H13F12N3O2) [MþH]þ: calcd: 556.0894;
DMSO-d6) d
3.27 (s, 6H); 6.78 (s, 1H); 6.85e7.38 (m, 10H); 13C NMR
found: 556.0882.
(100 MHz, DMSO-d6) d 54.3; 100.9; 120.9; 124.9; 126.2; 128.8;
144.2; 147.0; 149.3; HRMS (C16H17N3O2) [MþH]þ: calcd: 284.1399;
4.1.1.4. N,N0-Dicyclohexyl-2-nitroethene-1,1-diamine (2d). 61%
yield; Yellow solid; mp 197e199 ꢀC; 1H NMR (400 MHz, DMSO-d6)
found: 284.1403.
d
1.06e1.78 (m, 22H); 6.56 (s,1H); 6.67 (s,1H); 10.30 (s,1H); 13C NMR
4.1.4.2. N-Methyl-2-nitro-N,N0-diphenylethene-1,1-diamine
(100 MHz, DMSO-d6)
d
23.6 (br); 24.4; 24.9; 31.9; 32.4; 97.2; 153.5;
(2h). 11% yield; Yellow oil; 1H NMR (400 MHz, DMSO-d6)
d
3.80 (s,
3H); 6.83 (s, 2H); 6.87e7.02 (m, 6H); 7.25e7.75 (m, 5H); 9.42 (s,
1H); 13C NMR (100 MHz, DMSO-d6)
54.5; 106.9; 119.3; 121.2;
HRMS (C14H25N3O2) [MþH]þ: calcd: 268.2025; found: 268.2026.
d
4.1.1.5. N,N0-Dibutyl-2-nitroethene-1,1-diamine (2e). 99% yield;
122.5; 122.8; 128.6; 128.8; 139.8; 143.7; 148.8; HRMS (C15H15N3O2)
Yellow solid; mp 80e82 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
0.89 (t,
[MþH]þ: calcd: 270.1164; found: 270.1184.
J¼7.4 Hz, 6H); 1.31 (sext, J¼7.4 Hz, 4H); 1.31e1.48 (m, 8H);
3.08e3.20 (m, 4H); 6.49 (s, 1H); 7.14 (s, 1H); 10.08 (s, 1H); 13C NMR
4.1.5. General procedure for diamino-2-nitroethylene catalyzed nu-
cleophilic addition to nitrostyrene. To a vial containing a magnetic
stir bar was added nitrostyrene (0.25 mmol), nucleophile
(0.375 mmol), the catalyst (0.025 mmol), and the solvent (0.2 mL).
After confirming the disappearance of starting material by TLC
analysis, the reaction mixture was straight purified by flash chro-
matography on silica gel using hexane/ethyl acetate to afford the
product. All spectral data match with those previously reported
(see Supplementary data).
(100 MHz, DMSO-d6)
d 13.5; 19.3.7; 30.2; 31.0; 41.2; 96.9; 155.5;
HRMS (C10H22N3O2) [MþH]þ: calcd: 216.1712; found: 216.1707.
4.1.1.6. 5,50-((2-Nitroethene-1,1-diyl)bis(azanediyl))bis(pentan-1-
ol) (2f). 99% yield; Brown liquid; 1H NMR (400 MHz, DMSO-d6)
d
1.31e1.50 (m, 16H); 3.07e3.19 (m, 2H); 6.49 (s, 1H); 7.15 (s, 1H);
10.07 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 22.7; 28.1; 28.8; 32.0;
40.4; 41.5; 97.0; 155.4; HRMS (C12H26N3O4) [MþH]þ: calcd:
276.1923; found: 276.1918.
4.1.5.1. General procedure for the synthesis of (E)-N-(1-(methyl-
thio)-2-nitrovinyl)-3(trifluoromethyl)aniline was the same reported
for the preparation of compound 7. 51% yield; Yellow solid; mp
4.1.2. General procedure for the synthesis of compound 7. To a solu-
tion of 1,1-bis(methylthio)-2-nitroethylene (1) (1.5 mmol) in eth-
anol (3 mL) was added 3,5-bis(trifluoromethyl)benzylamine (6)
(1.5 mmol) and irradiated during 90 min in a CEM DiscoveryÒ fo-
cused microwave oven at 110 ꢀC and 70 W. Then the solvent was
removed to give a residue, which was further purified using column
chromatography on silica gel (75:25 hexane/EtOAc).2
109e110 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.42 (s, 3H); 6.71 (s, 1H);
7.60e7.63 (m, 4H); 11.79 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d
14.7; 108.6; 123.0; 124.7; 129.2; 130.1; 131.8; 132.2; 136.8; 162.6;
HRMS (C10H10F3N2O2S) [MþH]þ: calcd: 279.0415; found: 279.0428.
4.1.6. General procedure for the synthesis of chiral organo-
catalysts. To a solution of (E)-N-(1-(methylthio)-2-nitrovinyl)-3
(trifluoromethyl) aniline (0.36 mmol) in ethanol (8 mL) was added
the respective 9-amino-9-deoxyquinine (0.36 mmol). The reaction
was refluxed for 12 h and then the solvent was removed to give
a residue, which was purified by column chromatography on silica
gel (95:5 EtOAc/MeOH) to provide the organocatalysts in 75% yield;
Yellow solid; mp 188e189 ꢀC; 1H NMR (400 MHz, DMSO-d6)
4.1.2.1. (E)-N-(3,5-Bis(trifluoromethyl)benzyl)-1-(methylthio)-2-
nitroethenamine (7). 91% yield; Yellow solid; Mp 123e124 ꢀC; 1H
NMR (400 MHz, CDCl3)
(s, 1H); 7.77 (s, 2H); 7.86 (s, 1H); 10.79 (s, 1H); 13C NMR (100 MHz,
CDCl3) 14.5; 47.1; 107.5; 121.6; 122.2; 122.3; 122.4; 124.3; 127.4;
d
2.47 (s, 3H); 4.78 (d, J¼6.45 Hz, 2H); 6.62
d
131.9; 132.2; 132.6; 132.9; 138.6; 164.5; HRMS (C12H11F6N2O2)
[MþH]þ: calcd: 360.0367; found: 360.0398.
d
0.99e0.81 (m, 1H); 1.27 (m, 4H); 1.65 (m, 3H); 2.38 (m, 2H); 2.85
4.1.3. General procedure for the synthesis of organocatalysts 9. A
25 mL round-bottomed flask was charged with EtOH (3 mL), and
compounds 7 (1 mmol) and 8 (1 mmol, 0.159 mL) at reflux for 24 h.
After this time, the solvent was removed to give a residue, which
was further purified using column chromatography on silica gel
(75:25 EtOAc/MeOH).
(m, 1H); 3.90 (s, 3H); 5.15e4.88 (m, 2H); 5.92e5.72 (m, 1H); 6.12 (s,
1H); 7.77e7.08 (m, 9H); 7.99 (d, J¼9.2 Hz, 1H); 8.74 (s, 1H); 13C NMR
(100 MHz, DMSO)
d 24.9; 26.1; 26.6; 38.2; 40.5; 54.0; 55.5; 77.1;
100.9; 102.0; 114.8; 121.6; 122.1; 126.3; 131.5; 140.9; 144.1; 147.5;
153.8; 157.5; HRMS (C29H31F3N5O3) [MþH]þ: calcd: 554.2379;
found: 554.2409.
4.1.3.1. (E)-N-(3,5-Bis(trifluoromethyl)benzyl)-2-nitro-N-(3 (pi-
peridinyl)propyl)ethene-1,1-diamine (9). 99% yield; Mp 51e52 ꢀC;
Acknowledgements
dr¼8:2; 1H NMR (400 MHz, CDCl3)
d 1.39 (m, 6H); 1.89 (m, 2H);
The authors gratefully acknowledge FAPESP (09/07281-0) and
2.44 (m, 6H); 3.49 (m, 2H); 4.49 (s, 2H); 6.39 (s, 1H); 7.69 (m, 3H);
ꢀ
CNPq (INCT-Catalise and INBEQMeDI) for financial support. R.C.S.,
9.22 (s, 1H); 10.32 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 23.4; 24.8;
and D.P.S. thanks FAPESP, while J.G.P.M. cordially acknowledge
CNPq for their fellowships.
25.0; 39.4 (br); 43.7 (br); 53.7; 55.1; 98.1; 119.1; 120.9; 121.0; 121.1;
121.8; 124.5; 127.1 (br); 127.2; 131.1; 131.4; 131.8; 132.1; 156.4;
HRMS (C19H25F6N4O2) [MþH]þ: calcd: 455.1882; found: 455.1881.
The NMR data were described to major diastereomer.
Supplementary data
Copies of 1H NMR,13C NMR spectra of allunknowncompoundsare
available as Supplementary data. Supplementary data related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2013.08.040.
4.1.4. General procedure for the synthesis of compound 2g and
2h. To a solution of compound 2a (0.2 mmol) in acetone (3 mL) was
added K2CO3 (1 mmol) and iodomethane (for synthesis of com-
pound 2g was used 1 mmol and for 2h was used 0.2 mmol). After
stirring for 12 h, the reaction mixture was concentrated, and the
residue was purified using column chromatography on silica gel
(85:15 hexane/EtOAc) to afford the product 2g and 2h.
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