An expeditious, highly efficient, catalyst-free and solvent-free synthesis of nitroamines and nitrosulfides by Michael addition

Article abstract of DOI:10.1039/c0gc00830c

A simple, atom economical, fast and highly efficient green protocol has been developed for the synthesis of nitroamines and nitrosulfides by the Michael addition of amines and thiols to nitroolefins by simple mixing or grinding. This catalyst-free and solvent-free green approach provided the addition products in quantitative yield within minutes at room temperature. This procedure does not require any water quenches, solvent separations and purification steps such as recrystallization and column chromatography.

Full text of DOI:10.1039/c0gc00830c

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An expeditious, highly efficient, catalyst-free and solvent-free synthesis of
nitroamines and nitrosulfides by Michael addition†
Garima Choudhary and Rama Krishna Peddinti*
Received 19th November 2010, Accepted 30th November 2010
DOI: 10.1039/c0gc00830c
A simple, atom economical, fast and highly efficient
green protocol has been developed for the synthesis of
nitroamines and nitrosulfides by the Michael addition
of amines and thiols to nitroolefins by simple mixing
or grinding. This catalyst-free and solvent-free green ap-
proach provided the addition products in quantitative yield
within minutes at room temperature. This procedure does
not require any water quenches, solvent separations and
purification steps such as recrystallization and column
chromatography.
Nitroamines are typically synthesized by addition of nitro
compounds to an azomethine function by an aza-Henry reaction
mechanism6 (Scheme 1; Method-I). Several reports are available
in the literature7–18 on direct addition of amines and thiols to
nitroolefins for the synthesis of nitroamines and nitrosulfides
(Scheme 1; Method-II). Owing to the importance of this reac-
tion, these transformations were investigated under the catalytic
activity of zirconium tetrakis(dodecylsulfate),7 samarium(III)
triflate,8 tin(II) chloride,9 triethylamine in acetonitrile,10 L-proline
in ionic liquid [bmim]PF6,11 copper(II) and nickel(II) chelates,12
ammonium chloride,13 sodium acetate,14 TMAF.15 Catalyst free
procedures in water are also known but they failed to carry
out reactions with secondary aliphatic amines like morpholine.16
This method requires longer reaction times and involves work
up followed by purification through recrystallization or column
chromatography. The yields of the adducts with nitroolefins
bearing groups such as chlorine are low and the transformations
require longer reaction times.17 A catalyst-free and solvent-free
procedure for the synthesis of nitrothiols from liquid samples
of nitrostyrenes and thiols was also reported.18 However, this
procedure requires stirring of the reaction mixture, column
chromatographic purification of the products and it is not
applicable for solid-solid reactants.
Introduction
With the growing awareness in industry and academia for
sustainable development, the international chemical community
is under increasing pressure to alter current working practices
and to find greener alternatives. As a result, green chemistry
has been promoted worldwide by an increasing number of
research groups because it provides transformations that are
environmentally benign.1,2 A green protocol can be considered
as a series of reductions such as costs, waste, energy use, materials
consumption, risks and hazards, and non-renewables.3
The Michael reaction, being an atom economical reaction,
fulfills the condition of incorporating all the constituents of
the starting materials into the final product, required for a
green protocol. The conjugate Michael addition of carbon
nucleophiles to the electron deficient nitroalkenes is particularly
interesting and challenging as it involves the generation of two
chiral centres in a single step. The adducts, nitroamines and
nitrosulfides, are versatile buildings blocks for the preparation
of natural products and pharmacologically important targets
and are used extensively in various organic reactions.4 Because
of the presence of the nitro group, these products can be readily
transformed into a variety of functionalities e.g., they can be
reduced to 1,2-diamines, which are an important structural motif
in medicinal chemistry, or oxidized to a-amino acids by the Nef
reaction.5
Scheme 1 Methods for the synthesis of nitroamines and nitrosulfides.
As part of our ongoing research work on the development
of green approaches in organic synthesis, herein we report our
results for a near absolute green protocol for the synthesis of
nitroamines and nitrothiols by Michael addition of aromatic
amines and aromatic thiols to nitroolefins under solvent-free
and catalyst-free conditions. This method proceeds with simple
mixing or grinding of stoichiometric amounts of the reactants
to provide the pure addition products in quantitative yield.
Department of Chemistry, Indian Institute of Technology, Roorkee, 247
667, Uttarakhand, India
† Electronic supplementary information (ESI) available: Characteriza-
tion data for all products. See DOI: 10.1039/c0gc00830c
276 | Green Chem., 2011, 13, 276–282
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It was also found that the nature of the substitution on
Results and discussion
the aromatic nucleus of the nitroolefin as well as on the
aniline had great influence on the reaction. The electron
withdrawing group on the arene moiety of the nitroolefin and
electron donating group on aniline drive the reaction very
fast. For instance, the reaction between m-nitro-nitrostyrene
and p-anisidine reached completion within a minute. Similarly,
the nitro-substituted b-nitrostyrenes reacted with morpholine
within a minute. In contrast, the reaction between 4-hydroxy-
nitrostyrene with aniline and the reaction between nitrostyrene
with p-nitroaniline did not reach completion under the reaction
conditions, and provided the corresponding adducts in 30%
yield.
Reaction between amines and nitroolefins
As a prelude to this objective, we carried out the reaction
between liquid-solid reactants. Thus, equimolar amounts of
aniline (1a) and nitrostyrene (2a)19 were taken in a pre-weighed
petri dish and mixed with spatula for two min and then the
mixture was allowed to stand for five min. The progress of
the reaction was monitored by thin layer chromatography.
During this period, complete conversion from the reactants
to the Michael adduct took place. After completion of the
reaction, the weight of the petri dish along with the product
was taken and found that the yield of the addition product
3a was quantitative. The purity of the product was good
enough for spectroscopic analysis. Similarly, the mixing of 3,5-
dimethylaniline (1b) with nitrostyrene (2a) provided the Michael
adduct 3b in quantitative yield. Subsequently, the reaction of
solid reactants p-methoxyaniline (1c) and nitrostyrene (2a) was
performed in a mortar and pestle by grinding the mixture
for one minute at room temperature. Again in this case the
yield of the pure product 3c was found to be quantitative
(Scheme 2).
Reaction between aromatic thiols and nitroolefins
Inspired by above results we extended the grinding protocol
for the synthesis of nitrosulfides in quantitative yields by using
thiol as the nucleophile in place of aniline, with nitroolefins. A
stoichiometric molar ratio of benzenethiol 4a and nitroolefin
2a were taken in a petri dish and mixed with a spatula for
two minutes. The progress of the reaction was monitored by
thin layer chromatography, and a new product was formed
immediately. This reaction mixture was allowed to stand
at room temperature for five minutes to reach completion.
Thus the desired adduct 5a was obtained in quantitative
yield.
To further explore this method, a series of nitrothiols 5b–
r have been synthesized (Scheme 3) and results are sum-
marized in Table 2. This method is applicable to various
thiols i.e. benzenethiol, phenylmethanethiol, naphthalene-2-
thiol, 4-methoxybenzenethiol, 4-bromobenzenethiol and 4-
methylbenzenethiol with various nitroolefins. A wide variety of
nitroolefins bearing groups such as 4-bromo, 4-chloro, 2-nitro
and 3-nitro participated in the current protocol. In all these
cases, the reaction proceeded smoothly to produce the adducts
in quantitative yield.
Scheme 2 Synthesis of nitroamines.
After a successful attempt with aromatic amines we fur-
ther explored the reaction of nitrostyrene with morpholine,
a secondary aliphatic amine. An exothermic reaction started
immediately after mixing equimolar ratio of the reactants 1e
and 2a with concomitant liquidification of the contents followed
by solidification of the product 3d. A perfect solid product was
obtained in excellent yield of 95%. However, when the reaction
was carried out with slight excess (1.1 equiv) of morpholine,
the Michael adduct 3d was obtained in quantitative yield. The
adduct is quite stable and no back-conversion to the reactants
was observed unlike the products of nitrostyrene with secondary
amines obtained from the reaction in water.16
To expand the scope of the current green protocol, a series
of reactions between variously substituted nitrostyrenes and
selected anilines and morpholine were carried out. The products
are shown in Table 1. All the reactions were performed under
neat conditions without using any solvent or catalyst. In
the course of our investigations, the solid-liquid combination
reactions were carried out by simple mixing of stoichiometric
molar ratios of both reactants with a spatula in a petri dish and
allowing the contents to stand for five minutes if required. In
the case of solid-solid combination reactions, the solid mixture
was ground in mortar with pestle for one to three minutes and
the contents were allowed to stand for five minutes if required to
afford the pure products 3c, 3i, and 3j (Table 1, entries 3, 9 and
10). The reactions of morpholine with nitrostyrenes reached
completion within one minute of mixing to afford the solid
products.
Scheme 3 Synthesis of nitro sulfides.
We have not noticed any incidents during grinding reactions
under the reaction scale studied. The handling of highly reactive
low volatile aromatic nitroolefins in an open petri dish or
mortar would not be an apprehension on safety issue since
nitroolefins are known to possess antibacerial and antitumor
activites.21 However, care needs to be taken in handling these
materials.
Conclusion
In conclusion, we have demonstrated a simple, atom economy,
fast and highly efficient, solvent-free green protocol for synthesis
of nitroamines and nitrosulfides. To the best of our knowledge,
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Table 1 Synthesis of nitroamine derivativesa
Entry
1
Nitroalkene
Nucleophile
Methodb/Time (min)
Product
Yieldc (%)
99
Method A/2 + 5
2
2a
Method A/1 + 5
100
3
4
5
2a
2a
Method B/1 + 0
Method A/1 + 0
Method A/1 + 5
100
100
100
6
2b
Method A/1 + 5
100
7
8
Method A/1 + 5
Method A/1 + 5
100
100
2c
9
2c
2c
Method B/1 + 0
Method B/3 + 5
100
98
10
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Table 1 (Contd.)
Entry
11
Nitroalkene
2c
Nucleophile
Methodb/Time (min)
Product
Yieldc (%)
100
Method A/1 + 0
12
13
Method A/1 + 0
Method A/1 + 5
100
100
14
15
2e
Method A/1 + 0
Method A/1 + 5
100
100
a All reactions were carried out with an equimolar (2 mM) ratio of donor and acceptor. 2.2 mM (1.1 equiv) of morpholine (1e) was used in entries 4,
11, 12, and 14. b Method A: mixing of reactants with a spatula in a petri dish for 1–2 min followed by allowing the mixture for standing for 5 min if
necessary. Method B: grinding of reactants with a mortar and pestle for 1–3 min followed by allowing the mixture for standing for 5 min if necessary.
c Yield of pure Michael adduct.
this green protocol was not known to synthesize aforementioned
Michael adducts. The current environmentally benign procedure
is a near absolute green protocol since it: (i) does not require
the use of solvents (organic or aqueous), catalysts, energy,
and purification steps such as column chromatography or
crystallization; (ii) requires less time to obtain the products; (iii)
incorporates the reactants into the final product to a maximum
possible extent without side products; and (iv) stands as the
cheapest methodology so far. The success for this technique
relies on the selection of Michael donors and acceptors of the
reaction. The current novel protocol is a step towards achieving
chirality through a green asymmetric approach. Studies in this
direction are underway in our laboratory.
in a petri dish to form a homogeneous paste and then the
mixture was allowed to stand for 5 min if required. The adducts
3a,b,d,e,f,g,h,k,l,m,n,o were obtained in this way.
Solid-solid combinations: in the case of 1c, the mixture was
subjected to mechanical grinding in a mortar with pestle for
one min at room temperature to afford adducts 3c,i. The reaction
of 1d and 2c was carried out by 3 min of grinding and five min
standing at room temperature to get the adduct 3j. Completion
of reaction in all the above cases was monitored by TLC.
Reaction between thiols and nitroolefins
A nitrostyrene (2 mmol) and a thiol (2 mmol) were mixed
together thoroughly with either (i) a spatula in a petri dish or
with (ii) mechanical grinding by a mortar with pestle, for solid-
solid reactants for 1–2 min to form a paste. Then the reaction
mixture was allowed to stand at room temperature for 5 min.
Completion of the reaction was monitored by TLC. The adducts
thus obtained, (i) 5a,b,e,f,h,j,k,n,p,q and (ii) 5c,d,g,i,l,m,o,r, were
characterized by 1H (500 MHz) and 13C (125 MHz) NMR
spectroscopy.
Experimental
Reaction between amines and nitroolefins
Solid-liquid combinations: a nitrostyrene (2a–f, 2 mmol) and
an aniline (1a–d, 2 mmol) or morpholine (1e, 2.2 mmol) were
mixed together thoroughly with a spatula for one to two minutes
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Table 2 Synthesis of nitrosulfide derivativesa
Entry
1
Nitroalkene
Nucleophile
Methodb/Time (min)
Product
Yieldc (%)
98
Method A/2 + 5
2
3
2a
2a
Method A/1 + 5
Method B/2 + 5
100
99
4
5
2a
Method B/1 + 5
Method A/1 + 5
100
100
6
7
2b
2b
Method A/1 + 5
Method B/1 + 5
100
100
8
2b
2b
Method A/1 + 5
Method B/1 + 5
Method A/1 + 5
100
100
99
9
10
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Table 2 (Contd.)
Entry
11
Nitroalkene
Nucleophile
Methodb/Time (min)
Product
Yieldc (%)
100
2c
Method A/1 + 5
12
13
2c
Method B/1 + 5
Method B/1 + 5
100
100
2c
14
15
16
Method A/1 + 5
Method B/1 + 5
Method A/1 + 5
100
100
100
2d
17
18
2e
2e
Method A/1 + 5
Method B/1 + 5
100
100
a All reactions were carried out with an equimolar (2 mM) ratio of donor and acceptors. b Method A: mixing of reactants with a spatula in a petri
dish for 1–2 min followed by allowing the mixture for standing for 5 min. Method B: grinding of reactants with a mortar and pestle for 1–2 min
followed by allowing the mixture for standing for 5 min. c Yield of pure Michael adduct.
Dekker, New York, 2001; (d) M. Lancaster, in Green Chemistry:
Acknowledgements
An Introductory Text, Royal Society of Chemistry, Cambridge, UK,
2002.
GC thanks CSIR, New Delhi for a research fellowship.
2 (a) Green Chemistry: Theory and Practice, ed. P. T. Anastas and
J. C. Warner, Oxford University Press, Oxford, UK, 1998; (b) M.
Lancaster, in Handbook of Green Chemistry and Technology, ed.
J. H. Clark and D. J. Macquarrie, Blackwell Publishing, Abingdon,
2002; (c) A. Bruckmann, A. Krebs and C. Bolm, Green Chem., 2008,
10, 1131–1141; (d) I. T. Horva´th, Green Chem., 2008, 10, 1024–1028;
(e) Handbook of Green Chemistry, R. H. Crabtree and P. T. Anastas,
2009, Wiley-VCH.
References
1 (a) C. Baird, Environmental Chemistry, New York, 1999; (b) P.
Anastas, L. G. Heine and T. C. Williamson, in Green Chemical
Syntheses and Processes, Oxford University Press, New York,
2000; (c) A. S. Matlack, Introduction to Green Chemistry, Marcel
This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 276–282 | 281
©

View Article Online
3 P. T. Anastas, L. B. Bartlett, M. M. Kirchhoff and T. C. Williamson,
Catal. Today, 2000, 55, 11–22.
12 V. M. Potapov, E. G. Solozhenko and G. V. Panova, Zhurnal Obshchei
Khimii, 1984, 54, 662–665.
13 W. Chen and L. Shi, Catal. Commun., 2008, 9, 1079–1081.
14 C. B. Ranu and T. Mandal, Aust. J. Chem., 2007, 60, 223–227.
15 M. Menand and V. Dalla, Synlett, 2005, 95–98.
16 A. Ziyaei-Halimehjani and R. M. Saidi, Tetrahedron Lett., 2008, 49,
1244–1248.
17 L. F. Cason and C. C. Wanser, J. Am. Chem. Soc., 1951, 73, 142–145.
18 C.-M. Chu, Z. Tu, P. Wu, C.-C. Wang, J.-T. Liu, C.-W. Kuo, Y.-H.
Shin and C.-F. Yao, Tetrahedron, 2009, 65, 3878–3885.
19 b-Nitrostyrenes have been synthesized using a modified procedure
(Ref. 20). In a typical procedure, a mixture of 3-nitrobenzaldehyde
(2.267 g, 15 mM), nitromethane (6 mL, 110 mM) and ammonium
acetate (0.4 g, 5.2 mM) in glacial acetic acid (40 mL) was heated
under reflux for 8 h. Then the hot solution was poured into 400 mL
of ice-cold water in a beaker. Immediately the product began to
precipitate out. To get the complete precipitation, the beaker was
kept in refrigerator for 4 h. The precipitate was filtered under reduced
pressure, washed with water and dried under vacuum to afford 2.84 g
(97.6%) of pure 3-nitro-b-nitrostyrene (2b).
20 (a) X. A. Dominguez, J. Slim and A. Elizondo, J. Am. Chem. Soc.,
1953, 75, 4581–4582; (b) J.-T. Liu and C.-F. Yao, Tetrahedron Lett.,
2001, 42, 6147–6150.
21 (a) O. Dann and E. F. Holler, Chem. Ber., 1949, 82, 76; (b) O. Schales
and H. A. Graefe, J. Am. Chem. Soc., 1952, 74, 4486; (c) K. Zee-
Cheng and C. Cheng, J. Med. Chem., 1969, 12, 157; (d) G. W. Kabalka
and R. S. Varma, Org. Prep. Proced. Int., 1987, 19, 283–328.
4 (a) B. M. Trost and A. C. Lavoie, J. Am. Chem. Soc., 1983, 105, 5075–
5090; (b) R. D. Miller and R. Hassig, Tetrahedron Lett., 1985, 26,
2395–2398; (c) H. Mizuno, K. Domon, K. Masuya, K. Tanino and
I. Kuwajima, J. Org. Chem., 1999, 64, 2648–2656; (d) D. Enders and
U. Reinhold, Tetrahedron: Asymmetry, 1997, 8, 1895–1946; (e) A.
Cordova, Acc. Chem. Res., 2004, 37, 102–112.
5 (a) D. Lucet, T. Le Gall and C. Mioskowski, Angew. Chem., Int.
Ed., 1998, 37, 2580–2627; (b) D. Lucet, L. Toupet, T. Le Gall
and C. Mioskowski, J. Org. Chem., 1997, 62, 2682–2683; (c) P. H.
O’Brien, D. R. Sliskovic, C. J. Blankley, B. Roth, M. W. Wilson,
K. L. Hamelehle, B. R. Krause and R. L. Stanfield, J. Med. Chem.,
1994, 37, 1810–1822.
6 (a) F. Fini, V. Sgarzani, D. Pettersen, R. P. Herrera, L. Bernardi and
A. Ricci, Angew. Chem., Int. Ed., 2005, 44, 7975–7578; (b) E. Foresti,
G. Palmieri, M. Petrini and R. Profeta, Org. Biomol. Chem., 2003,
1, 4275–4281; (c) R. Ballini and M. Petrini, Tetrahedron, 2004, 60,
1017–1047; (d) H. W. Pinnick, Org. React., 1990, 38, 655–792.
7 M. Jafarpour, A. Rezaeifard and M. Aliabadi, Letters in Organic
Chemistry, 2009, 6, 94–99.
8 J. S. Yadav, A. R. Reddy, Y. G. Rao, A. V. Narsaiah and B. V. S.
Reddy, Synthesis, 2007, 22, 3447–3450.
9 A. S. Mahasneh, Basic Sci. Engg., 2004, 13, 79–86.
10 P. A. Sarathi, C. Gnanasekaran and A. Shunmugasundaram, Bull.
Korean Chem. Soc., 2008, 29, 790–794.
11 P. Kotrusz and B. Toma, Molecules, 2006, 11, 197–205.
282 | Green Chem., 2011, 13, 276–282
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The Royal Society of Chemistry 2011
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