Study on the influence of a sustainable medium for the design of multistep processes: Three-component synthesis of 2-Nitroamines

Article abstract of DOI:10.1055/s-0033-1339898

An environmentally benign method was developed for the three-component, one-pot synthesis of 2-nitroamines by heating a solution of an aldehyde, an aromatic amine, and a nitroalkane in 20% water–methanol at 60 °C for five hours in the absence of a catalys

Full text of DOI:10.1055/s-0033-1339898

2596▌
LETTER
lSettteur dy on the Influence of a Sustainable Medium for the Design of Multistep
Processes: Three-Component Synthesis of 2-Nitroamines
Three-Component Synthesis of 2-Nitroamines
Calogero G. Piscopo,a Giovanni Sartori,a José A. Mayoral,b Daniela Lanari,c Luigi Vaccaro,c Raimondo Maggi*a
a
Clean Synthetic Methodology Group, Dipartimento di Chimica dell’Università, Viale G. P. Usberti 17A, 43124 Parma, Italy
Fax +39(0521)905472; E-mail: raimondo.maggi@unipr.it
b
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón and Instituto Universitario de Catálisis Homogénea,
Facultad de Ciencias, Calle Pedro Cerbuna 12, Universidad de Zaragoza, 50009 Zaragoza, Spain
c
Laboratory of Green Synthetic Organic Chemistry (CEMIN), Dipartimento di Chimica dell’Università, Via Elce di Sotto 8, 06123 Perugia,
Italy
Received: 23.07.2013; Accepted after revision: 05.09.2013
rapidly to produce an intermediate that subsequently un-
Abstract: An environmentally benign method was developed for
dergoes a second reaction to afford a final product.
the three-component, one-pot synthesis of 2-nitroamines by heating
a solution of an aldehyde, an aromatic amine, and a nitroalkane in
20% water–methanol at 60 °C for five hours in the absence of a cat-
alyst.
On the basis of these results, and taking into account the
well-documented possibility that synthetic processes in-
volving aliphatic nitro compounds can be performed in
aqueous media,5 we planned to investigate the synthesis
of N-(2-nitro-1-phenylethyl)aniline (5aaa) by a three-
component reaction of benzaldehyde (1a), aniline (2a),
and nitromethane (4a) in water (Scheme 1).
Key words: coupling, Mannich bases, multicomponent reactions,
Schiff bases, solvent effects
Multicomponent reactions (MCRs) are powerful tools in
organic synthesis because, by changing the reaction con-
ditions or by adding further reagents, libraries of products
can be prepared through formation of several bonds in a
single operation without isolation of intermediates.1 In ad-
dition to their usefulness in synthetic chemistry, MCRs
provide more environmentally benign methods for syn-
theses of complex molecules, as they involve simple op-
erations with minimal production of waste materials and
minimal energy consumption.2 The eco-efficiency of a
given MCR can be further enhanced by performing the
reaction without a solvent or in a green solvent, such as
water or an alcohol, and in the absence of any added cata-
lyst.3
CHO
NH2
N
+
+ H2O
a)
1a
2a
3aa
HN
3aa + MeNO2
b)
NO2
4
5aaa
Scheme 1 Three-component synthesis of N-(2-nitro-1-phenyle-
thyl)aniline (5aaa)
Usually the steps of an MCR involve well-known reac-
tions, the novelty of the process lying in the sequential
combination of various reactions under the same (prefer-
ably green) experimental conditions to give the final prod-
uct in a one-pot process, saving time, energy, and raw
materials, with consequential economic and environmen-
tal benefits.
We assumed that a fast initial condensation between benz-
aldehyde (1a) and aniline (2a) should give the intermedi-
ate imine 3aa, which would then undergo addition of
nitromethane (4a) to give the nitro amine 5aaa by a typi-
cal nitro-Mannich process6 in the presence of a convenient
catalyst or, better still, without an additional promoter.
In earlier studies, we reported that multistep and multi-
component reactions involving a dehydration step (the
production of an imine from a carbonyl compound and an
amine) can be performed efficiently in water in the pres-
ence of a solid catalyst or without a catalyst.4 We surmised
that this reaction might provide an intriguing first step for
a three-component reaction. According to the general
rules of the MCR strategy,1 the first step must proceed
The addition of nitroalkanes to imines to give 2-nitro
amines can be achieved by using several promoters, such
as a Brönsted acid,7 a stoichiometric amount of a Lewis
acid,8 or the nitrogen-containing superbase 1,1,3,3-tetra-
methylguanidine.6d An elegant three-component synthesis
under solvent-free conditions catalyzed by 4-(imidazoli-
um-1-yl)butane sulfonate has also recently been report-
ed.9 Moreover, in recent decades a great deal of attention
has been devoted to the development of protocols for per-
forming enantioselective aza-Henry reactions.10
SYNLETT 2013, 24, 2596–2600
Advanced online publication: 16.10.2013
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DOI: 10.1055/s-0033-1339898; Art ID: ST-2013-D0688-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Three-Component Synthesis of 2-Nitroamines
2597
Initially, to facilitate analysis of the progress of the syn-
thetic process, we disconnected the two steps of the three-
component reaction. The first goal was to synthesize the
intermediate imine 3aa in water under mild conditions. To
this end, we examined the model reaction shown in step
(a) of Scheme 1, taking into account a procedure previous-
ly adopted by our research group,4a and the results report-
ed by Tanaka and co-workers.11 As expected, imine 3aa
could be synthesized in high yield (92%) by treating benz-
aldehyde (1a; 1 mmol) with aniline (2a; 1 mmol) in water
(5 mL) at 60 °C for five hours under biphasic conditions
without a catalyst. It is worth underlining that this reaction
represents an example of a high-yielding dehydration pro-
cess that occurs in the presence of water.12
Figure 1 Yield and selectivity of product 5aaa versus time. Re-
agents and conditions: benzaldehyde (1 mmol), aniline (1 mmol), ni-
tromethane (10 mmol), H2O (5 mL), 60 °C.
Our second goal was to perform the nitro-Mannich reac-
tion between the intermediate imine 3aa and nitromethane
(4a) [Scheme 1, step (b)] to obtain the desired product
5aaa with maximum yield and selectivity under condi-
tions that were as similar as possible to those of the first
step. The reaction between imine 3aa (1 mmol) and nitro-
methane (4a; 10 mmol) was therefore performed in water
and in a range of organic solvents (5 mL) without added
catalyst. The most significant results are summarized in
Table 1.
As can be seen from Figure 1, the reaction performed in
water reaches a high yield (~60%) in a relatively short
time (two hours). This is followed by a slow but continu-
ous rise in yield to a maximum of 92% after 20 hours.
To check the possible activation effect of water13 and the
contributions of hydrophobicity and micellar catalysis14 to
this process, two series of reactions were performed with
increasing amounts of water under biphasic conditions
and with water–methanol mixtures of various molar ratios
under homogeneous conditions. Figure 2 shows the ef-
fects of increasing the amount of water from 0 to 5 mL on
the yield and selectivity of product 5aaa in the model re-
action.
Within the range of concentrations explored, the medium
had a marked effect on the efficiency of the process. The
reaction gave the product 5aaa in good yield and very
high selectivity when performed in the absence of an add-
ed catalyst in protic media such as water (68% yield, 96%
selectivity) or methanol (77% yield, 95% selectivity) (Ta-
ble 1, entries 1 and 2). The use of polar or nonpolar aprotic
media, however, gave in only traces of product 5aaa (en-
tries 3–5), whereas solvent-free conditions gave product
5aaa in 10% yield (entry 6). To the best of our knowledge,
this is the first example of a nitro-Mannich reaction that is
promoted by a protic solvent (water or methanol).
The solvent-free reaction gave product 5aaa in modest
yield (10%), but addition of 0.5 mL of water to the reac-
tion mixture produced a dramatic increase in reactivity,
and product 5aaa was obtained in 65% yield. The maxi-
mum yield of 72% was achieved when 1.5 mL of water
was added and this value remained unchanged upon addi-
tion of larger amounts of water. A very high selectivity of
about 95% was observed during all experiments.
On the basis of these results, the optimal protocol for di-
rect one-pot, three-component synthesis of nitro amine
5aaa involves simply mixing benzaldehyde (1a; 1 mmol)
with aniline (2a; 1 mmol) and nitromethane (4a; 10
mmol) in water (5 mL) at 60 °C with vigorous stirring.
Product 5aaa was obtained in 92% yield and 95% selec-
tivity after 20 hours (Figure 1).
Similar accelerating effects of water in various chemical
reactions have previously been reported.13–15 The increase
in reaction rate and selectivity is frequently ascribed to
hydrophobic effects when insoluble organic reagents re-
act in water.16 Some of these reactions have been termed
Table 1 The Nitro-Mannich Reaction of Benzaldimine 3aa and Nitromethane (4a) in Various Media or under Solvent-Free Conditions without
an Added Catalyst
Entry
Medium
Conversion (%) of 3aa
Yield (%) of 5aaa
Selectivity (%) of 5aaa
1
2
3
4
5
6
H2O
71
81
~4
~3
~5
11
68
77
~3
~3
~4
10
96
95
–
MeOH
toluene
2-methyltetrahydrofuran
–
MeCN
–
–
95
a Reaction conditions: benzaldimine 3aa (1 mmol), MeNO2 (4a; 10 mmol), medium (5 mL), 60 °C, 5 h.
© Georg Thieme Verlag Stuttgart · New York
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C. G. Piscopo et al.
LETTER
aprotic polar or apolar media, undergoes a dramatic rate
acceleration when performed in the presence of water or,
better, in a water–methanol mixture.19 The possible cata-
lytic role of traces of both the amine and imine cannot be
excluded; nevertheless, the above results provide evi-
dence of a remarkable influence of the reaction medium,
whose ‘catalytic behavior’ might be related to some pecu-
liar properties, such as polarity/polarizability (water:
1.09; methanol: 0.60) or hydrogen-bond donor (water:
1.17; methanol: 0.98) or acceptor (water: 0.47; methanol:
0.66) abilities. The fact that the optimum yield was ob-
tained with a particular water–methanol mixture might be
due to a solubility effect or to an optimal combination of
acid–base properties. Stabilization of the transition state
by hydrogen bonding probably also has a comparable pos-
itive effect.13,20 Indeed, some preliminary studies have
shown that neither the first step (production of imine 3aa)
nor the complete three-component reaction show any rate
enhancement when performed in the presence of a salting-
out agent such as lithium chloride, which is known to in-
crease the hydrophobic effect.21
Figure 2 Effects of addition of water on the yield and selectivity of
product 5aaa. Reagents and conditions: benzaldehyde (1 mmol), an-
iline (1 mmol), nitromethane (10 mmol), 60 °C, 5 h.
‘on-water’ reactions, because the reactants are located at a
water–emulsion surface.17 However, it has been clearly
stated by Breslow18 that, ‘… the simple observations of an
increase of the reaction rate in water does not inevitably
establish that a hydrophobic effect and a micellar cataly-
sis are involved.’
With the aim of increasing the sustainability of the pro-
cess, we attempted to reduce the amount of the nitroalkane
required. A good yield (87%) and excellent selectivity
(96%) can be obtained by reducing the amount of nitro-
methane from 10 mmol to 5 mmol per mmol of benzalde-
hyde and aniline; further decreases gave lower yields of
product 5aaa.
To gain further information on the physicochemical pa-
rameters that control the process, we performed the model
reaction in the presence of mixtures of water and metha-
nol containing enough methanol to render the reactions
homogeneous. For comparison, the reaction was per-
formed in pure water and in pure methanol. The results are
shown in Figure 3.
We then extended the procedure to various aromatic
amines, aliphatic or aromatic aldehydes, and nitrometh-
ane (Table 2). The reaction proceeded efficiently with
benzaldehyde (1a) or aryl aldehydes 1b–e carrying either
electron-withdrawing and electron-releasing groups (Ta-
ble 2, entries 1–6). A lower reactivity was observed with
the aliphatic aldehyde 1f (entry 7). With aliphatic amines,
the corresponding imines were obtained and no traces of
the nitro amines were detected. Noticeably, the Henry by-
product, formed by attack of nitromethane on the alde-
hyde, was not observed; this selectivity was ascribed to
the rate of the first step (imine formation) being higher
than that of the Henry reaction.
Finally, we examined the effect of the length and branch-
ing of the alkyl moiety of the nitroalkane. A marked de-
crease in yield was observed in going from nitromethane
(87% yield) to nitroethane (43%), 1-nitropropane (21%),
and 2-nitropropane (traces). This behavior can be ascribed
to a combination of steric hindrance and a decrease in the
stability of the nitroalkane carbanion.22
Figure 3 Effects of the water–methanol ratio on the yield and selec-
tivity of product 5aaa. Reagents and conditions: benzaldehyde (1
mmol), aniline (1 mmol), nitromethane (10 mmol), medium (1 mL),
60 °C, 5 h.
As already shown, good yields of product 5aaa were ob-
tained when the reaction was performed in pure methanol
(77%) or pure water (68%). Interestingly, the addition of
water to methanol, still under homogeneous conditions,
resulted in an increase in the yield in comparison with that
observed in pure methanol, and a maximal yield of 93%
was obtained in 20% water–methanol. A similar trend was
observed with nitroethane.
In summary, we have developed a new design and meth-
odology for the three-component, one-pot synthesis of 2-
nitroamines. The process is efficiently performed by heat-
ing a solution of an aldehyde, an aromatic amine, and a ni-
troalkane at 60 °C for five hours without any added
catalyst in 20% water–methanol. It should be underlined
that, from the eco-sustainable standpoint, it would be pref-
erable to use pure methanol to carry out the process. A se-
ries of experimental observations showed that the
All the above results confirm that the model three-compo-
nent reaction shown in Scheme 1, which proceeds very
poorly under solvent-free conditions or in the presence of
Synlett 2013, 24, 2596–2600
© Georg Thieme Verlag Stuttgart · New York

LETTER
Three-Component Synthesis of 2-Nitroamines
2599
(c) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168.
Table 2 Preparation of Various Substituted 2-Nitroamines 5
R2
NH2
(2) von Wangelin, A. J.; Neumann, H.; Gördes, D.; Klaus, S.;
Strübing, D.; Beller, M. Chem. Eur. J. 2003, 9, 4286.
(3) (a) Henderson, R. K.; Jimènez-González, C.; Constable, D.
J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood,
J.; Binksa, S. P.; Curzons, A. D. Green Chem. 2011, 13, 854.
(b) Strauss, C. R. Aust. J. Chem. 1999, 52, 83.
R3
20% H2O–MeOH
R1CHO +
1a–f
+
NO2
4a–d
HN
R1
60 °C, 5 h
R4
NO2
R4
R2
R3
2a,b
(4) (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem.
1999, 64, 1033. (b) Sartori, G.; Bigi, F.; Maggi, R.;
Mazzacani, A.; Oppici, G. Eur. J. Org. Chem. 2001, 2513.
(c) Maggi, R.; Bigi, F.; Carloni, S.; Mazzacani, A.; Sartori,
G. Green Chem. 2001, 3, 173. (d) Soldi, L.; Ferstl, W.;
Loebbecke, S.; Maggi, R.; Malmassari, C.; Sartori, G.;
Yadab, S. J. Catal. 2008, 258, 289.
5
Entry R1
R2
R3
R4
Product Yield Selectivity
(%) (%)
1
2
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5aaa
5baa
5caa
5daa
5eaa
5aba
5faa
5aab
5aac
87
88
87
78
83
90
96
97
98
97
98
97
4-ClC6H4
3-ClC6H4
H
(5) Ballini, R.; Barboni, L.; Fringuelli, F.; Palmieri, A.; Pizzo,
F.; Vaccaro, L. Green Chem. 2007, 9, 823.
3
H
(6) (a) Baer, H. H.; Urbas, L. In The Chemistry of the Nitro and
Nitroso Groups; Patai, S., Ed.; Interscience: New York,
1970, Part 2 117. (b) Nishiwaki, N.; Knudsen, K. R.;
Gothelf, K. V.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2001, 40, 2992. (c) Qian, C.; Gao, F.; Chen, R. Tetrahedron
Lett. 2001, 42, 4673. (d) Singh, A.; Yoder, R. A.; Shen, B.;
Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466.
(e) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887.
(7) (a) Stacy, G. W.; Morath, R. J. J. Am. Chem. Soc. 1952, 74,
3885. (b) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A.
M. K. J. Org. Chem. 1998, 63, 9932.
(8) Anderson, J. C.; Peace, S.; Pih, S. Synlett 2000, 850.
(9) Kundu, D.; Debnath, R. K.; Majee, A.; Hajra, A.
Tetrahedron Lett. 2009, 50, 6998.
(10) Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P.
Eur. J. Org. Chem. 2009, 2401.
4
4-O2NC6H4
H
5
4-MeOC6H4
H
6
Ph
Et
OMe
H
H
7
H
64a 91
43b 96
21b 97
trace –
8
Ph
Ph
Ph
H
Me
Et
9
H
10
H
Me Me 5aad
a Reaction carried out for 16 h.
b Sum of diastereoisomers.
(11) Tanaka, K.; Shiraishi, R. Green Chem. 2000, 2, 272.
(12) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 11971.
(13) (a) Klijn, J. E.; Engberts, J. B. F. N. Nature 2005, 435, 746.
(b) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.;
Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005,
44, 3275.
(14) (a) Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem.
1983, 48, 3137. (b) Breslow, R.; Maitra, U. Tetrahedron
Lett. 1984, 25, 1239.
(15) (a) Li, C.-J. Chem. Rev. 1999, 93, 2023. (b) Li, C.-J.; Chen,
L. Chem. Soc. Rev. 2006, 35, 68. (c) Lubineau, A.; Augé, J.;
Queneau, Y. Synthesis 1994, 741. (d) Bonollo, S.; Lanari,
D.; Vaccaro, L. Eur. J. Org. Chem. 2011, 2587.
optimum yield and selectivity are obtained by using a
20% water–methanol mixture as a result of a synergistic
combination of the solubility effect and optimal acid–base
properties.
In a typical experiment, a solution of the appropriate alde-
hyde 1 (1 mmol), amine 2 (1 mmol), and nitroalkane 4 (5
mmol) in 20% H2O–MeOH (1 mL) was heated in a closed
reactor at 60 °C with stirring for five hours. The mixture
was cooled to room temperature, water (5 mL) was added,
and the mixture was extracted with ethyl acetate (2 × 5
mL). The combined extracts were dried (Na2SO4), fil-
tered, and concentrated by distillation. The 2-nitroamines
523 was isolated by column chromatography (silica gel,
hexane–ethyl acetate).
(16) Lindström, U. M.; Andersson, F. Angew. Chem. Int. Ed.
2006, 45, 548; and references cited therein.
(17) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
(18) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(19) A method for synthesizing imines from amines and
aldehydes in aqueous suspension has been previously
reported; see ref. 11. However, this solvent-free approach
gave a poor yield (~20%) of the model product 5aaa when
applied to the present three-component reaction described in
Scheme 1.
(20) (a) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002,
124, 3220. (b) Hayashi, Y. Angew. Chem. Int. Ed. 2006, 45,
8103. (c) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem. Int. Ed. 2006, 45, 8100. (d) Huang, J.; Zhang,
X.; Armstrong, D. W. Angew. Chem. Int. Ed. 2007, 46, 9073.
(21) PhCHO (1a; 1 mmol) and PhNH2 (2a; 1 mmol) were stirred
in H2O (5 mL) or 1 M aq LiCl (5 mL) at 60 °C for 10 min to
give imine 3aa in 75 and 78% yield, respectively. In a
second experiment, PhCHO (1a; 1 mmol), PhNH2 (2a; 1
mmol), and MeNO2 (4a; 10 mmol) were stirred in H2O (5
Acknowledgment
This work was supported by the Ministero dell’Università e della
Ricerca (MIUR), Italy, the University of Parma (National Project
Sintesi organiche ecosostenibili mediate da nuovi sistemi catalitici)
and the University of Perugia (financing programmes PRIN 2008
and FIRB-Futuro in Ricerca). The Centro Interdipartimentale Misu-
re (CIM) at the Parma University is acknowledged for the use of
NMR instruments.
References
(1) (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187. (b) Ugi, I.; Heck,
S. Comb. Chem. High Throughput Screening 2001, 4, 1.
© Georg Thieme Verlag Stuttgart · New York
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C. G. Piscopo et al.
LETTER
mL) or 1 M aq LiCl (5 mL) at 60 °C for 30 min to give nitro
amine 5aaa in 37 and 39% yield, respectively.
2008, 49, 1244. (b) Petersen, S.; Mitrowsky, A. GB 771566,
1957. (c) Mahasneh, A. S. Abhath Al-Yarmouk, Basic Sci.
Eng. 2004, 13, 79. (d) Shoemaker, G. L.; Keown, R. W.
Trans. Ky. Acad. Sci. 1955, 16, 85. (e) Ai, X.; Wang, X.; Liu,
J.-m.; Ge, Z.-m.; Cheng, Z.-m.; Li, R.-t. Tetrahedron 2010,
66, 5373. (f) Leonard, N. J.; Leubner, G. W.; Burk, E. H. Jr.
J. Org. Chem. 1950, 15, 979.
(22) (a) Henry, L. C. R. Acad. Sci., Ser. C 1895, 126. (b) Henry,
L. Bull. Soc. Chim. Fr. 1895, 13, 999. (c) Rosini, G. In
Comprehensive Organic Synthesis II; Vol. 2; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 321.
(23) All 2-nitroamines 5 synthesized are known compounds, see:
(a) Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett.
Synlett 2013, 24, 2596–2600
© Georg Thieme Verlag Stuttgart · New York