A new multicomponent reaction for direct synthesis of primary γ-nitroamides

Article abstract of DOI:10.1039/c6ra22141f

A new multicomponent reaction for direct synthesis of γ-nitroamides promoted by ammonium carbonate was developed. A series of γ-nitroamides were synthesized in 35-93% yield from Meldrum's acid, aromatic or aliphatic aldehydes, nitromethane and ammonium carbonate. A mechanistic pathway was proposed based on electrospray ionization mass spectrometry (ESI/MS) experiments.

Full text of DOI:10.1039/c6ra22141f

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: C. R. Montes
D'Oca, J. C. Silva, E. P. Guedes, M. G. Montes D'Oca, L. Santos, F. M. Nachtigall and D. Russowsky, RSC
Adv., 2016, DOI: 10.1039/C6RA22141F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 9
View Article Online
DOI: 10.1039/C6RA22141F
RSC Advances
ARTICLE
A new multicomponent reaction for direct synthesis of primary
γ-nitroamides
Received 00th January 20xx,
Accepted 00th January 20xx
Caroline R. Montes D’Oca,a Jessica C. da Silva,a Esthefani P. Guedes,a Marcelo G. Montes D’Oca,b
Leonardo S. Santos;c Fabiane M. Natchigall;d and Dennis Russowskya*
DOI: 10.1039/x0xx00000x
A new multicomponent reaction for direct synthesis of γ-nitroamides promoted by ammonium carbonate was developed.
A series of γ-nitroamides were synthesized in 35-93% yield from Meldrum’s acid, aromatic or aliphatic aldehydes,
nitromethane and ammonium carbonate. A mechanistic pathway was proposed based on electrospray ionization mass
spectrometry (ESI/MS) experiments.
www.rsc.org/
bistratum, both with potent cytotoxic activity. Other compounds as
Introduction
The γ-aminobutyric acid (GABA) is the major inhibitory
amino acid neurotransmitter of the central nervous system
(CNS) of mammalians. It plays important role in a variety of
physiological functions, including motion control, vision,
relaxation and sleep, reducing other neuronal excitabilities of
brain.1-3
Trocade (3, Cipemastat, anti-arthritic)13 or the biologically active
pregabalinamide derivative 4,14 also present the GABA-amide
system in their structures (Figure 2).
H
N
O
O
O
CO2H
H
N
O
HN
H
N
O
N
OH
O
O
H
O
OH
N
Me
O
OH
O
The GABA, activates specific classes of receptors such as:
the GABAA, GABAB and GABAC.4 The GABAA-receptors are
largely expressed in both peripheral and central nervous
Bistramide A 2
O
NH
OH
H
OH
OH
OH
N
N
OMe
H
O
O
HO
Microsclerodermin A 1
NMe
N
system representing
association.5-7
a
therapeutic target for drug
O
O
H
N
N
C(O)NHOH
O
H2
N
Although a variety of modulators of GABA-receptors are
known, there is a continuing interest in developing new drugs
that be able to interact as agonists well as antagonists with
these receptors.8-10 Among them, a less explored class of these
substances have been the GABA-amides (Figure 1).
N
H
Pregabalinamide Derivative 4
Trocade (Cipemastat) 3
Figure 2. Natural and synthetic bioactive GABA-Amides
Other studies have identified a series of functionalized linear
GABA-amides as partial, full, or superagonists of GABAA receptors,
despite their non-zwitterionic structures.15 Nortriptyline-γ-
Aminobutyric acid amide hybrid derivative 5, exhibited significantly
greater antinociceptive activity than their corresponding parent
compound nortriptyline.16 Structurally diverse and orally
bioavailable γ-aminoamide 6 was achieved as Chemokine Receptor
O
O
NH2
NH2
HO
H2N
GABA
GABA-Amide
Figure 1. Structures of GABA and GABA-Amides
The chemical unit γ-aminoamide was found early in cyclic
peptides 1, isolated from marine sponge Microscleroderma sp.11 or
in Bistramide A (2)12 isolated as marine metabolite of Lissoclinum
2 (CCR2) antagonists (Figure 3).17
O
R2N
CF3
N
H
O
ClH3N
CF3
N
Me
F
Nortriptyline GABA Amide derivative 5
GABA amide Chemokine receptor antagonist 6
Figure 3. Superagonists and antagonists GABA-Amides
Several synthetic methods were developed and applied to
prepare the functional γ-amino amide moiety. The functional group
transformation starting from natural malate ester,11 addition of allyl
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 9
View Article Online
DOI: 10.1039/C6RA22141F
ARTICLE
Journal Name
boranes to amino aldehydes,12 desymmetrization of glutaric
From previous investigations about the use of dual
anhydride,14 ring opening of N-Boc butyrolactams,15 amide bond acid/base hydrotalcite like materials in multicomponent
formation from GABA16 or γ,δ-unsaturated carboxylic acid17 are synthesis of -nitroesters,42 we tried to use the ammonium
γ
some of employed strategies. Additionally, the Mannich reaction,18 acetate (4a, NH4OAc) as a dual acid/base specie to promote
the aziridine ring opening by enolate anions,19 Michael addition that new reaction.
reaction of aldehydes to nitroolefins20 are other of successful
For our surprise, we isolated the respective
γ
-nitroamides
examples.
It is noteworthy the recent report of Rubin in which the GABA-
as the major component together with
a mixture of
unidentified products. By this result, we decide to systematize
the optimization of reaction conditions, considering variations
in the solvent, reaction time, temperature, type and amount of
the ammonium salt.
amides were prepared through the one pot nucleophilic addition of
amines to 3,3-disubstituted cyclopropenes.21 Particularly, the one
pot protocol brings many advantages to the organic synthesis
process, once it eliminates the tedious purifications in each step
and avoids the possible losses of mass by handling the
intermediates.22
For this purpose, the first reaction was carried out in a
vessel charged with Meldrum’s acid
(
1,
1.1 mmol),
benzaldehyde (2a, 1.0 mmol) nitromethane (
3
, 4.0 mmol) and
The concepts of green chemistry and atomic economy have
gained much attention in the organic synthesis, not only due to the
simplicity of execution and economic aspects but also, for the
reduction of the wastes discharged on the environment.23,24
The multicomponent reactions are a special class of the one pot
reactions25 and bring further advantages because three or more
reactants are combined in the same vessel to produce, in one-step,
a single product that contain almost all the atoms of the reactants.
This strategy has been applied efficiently in the synthesis of a large
NH4OAc (4a, 2.0 mmol) in EtOH (2.0 mL) under reflux
conditions by 24 hours. The results are shown in the Table 1,
bellow.
Table 1. Screening experimental conditions to synthesis of 5a.
Time
(h)
24
24
24
24
24
8
Temp.
Ammonium
Yield
(%)a,b
25
Enty
Solv.
Equiv.
(ºC)
Salt
1
EtOH
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
reflux
refux
reflux
reflux
reflux
reflux
r.t.
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
NH4HCO2
NH4OAc
NH4OAc
(NH4)2CO3
2
4
2
4
6
4
4
4
4
4
4
4
4
4
4
2
38
number of bioactive small molecules,26 including
a
series of
3
45
heterocyclic compounds27,28 and several other different classes of
compounds with low environmental impact.29-31
4
88
5
90
As an example of sophistication’s level reached by this process
is distinguished synthesis of several bioactive compounds in its
enantiomeric pure forms via multicomponent protocols, making it a
powerful tool in asymmetric organic synthesis.32
6
55
7
24
24
24
24
24
24
24
24
24
CM
CM
93
8
60
9
reflux
60
Additionally, the carboxylic acid amides derivatives constitute
versatile building blocks in synthetic organic chemistry, exhibiting a
wide range of pharmacological interest and industrial
applications.33,34 For this reason, new methods for their synthesis
are always in continuous development.
10
11
12
13
14
15
40
r.t.
CM
43
reflux
reflux
reflux
reflux
76
----
CM
CM
As a part of our ongoing efforts in the field of MCR,35-41 we
----
disclose herein our studies on the development of
a new
[a] Isolated yield. [b] All reactions performed using 4.0 mmol of CH3NO2.
CM= complex mixture
multicomponent approach to direct synthesis of primaries γ-
nitroamides, from the reaction between Meldrum’s acid (1),
aromatic or aliphatic aldehydes 2, nitromethane (3) and ammonium
acetate (4) (Scheme 1). Analogously to the γ-nitroesters, the γ-
nitroamides could be considered as advanced intermediates in the
synthesis of GABA-amide derivatives.42
After this time, the TLC analysis showed the total consume
of Meldrum’s acid. The crude mixture was fractioned by
column chromatography and the γ-nitroamide 5a was isolated
in only 25% yield from a complex mixture (Table 1, entry 1).
Increasing the amount of NH4OAc to 4.0 mmol caused no
improvement in the reaction’s performance (entry 2).
O
O
Next, we decided to use CH3CN as non protic solvent and
the same reagents were submitted to react at reflux condition
using 2.0 mmol of NH4OAc. After 24 hours the consumption of
starting materials was observed by TLC, the crude mixture was
R
H
NH2
NO2
Solvent
Reflux
2
O
O
NH4X
4a-c
R
O
O
CH3NO2
-Nitroamides 5a-l
1
3
purified by column chromatography and the γ-nitroamide 5a
Scheme
1
.
Multicomponent synthesis of primary
γ-
was isolated in yields 45% yield (Table 1, entry 3). In this
condition, the increase of amount of NH4OAc to 4.0 mmol
caused an impressive increase to 88% yield (entry 4). The use
of 6.0 mmol promoted a little improvement to 90% yield (entry
nitroamides.
Results and discussion
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 9
View Article Online
DOI: 10.1039/C6RA22141F
Journal Name
ARTICLE
5). Others experiments by using shorter reaction times or
lower temperatures providing unsatisfactory results as low
yield or complex mixtures (entries 6, 7 and 8, respectively).
Regarding the multicomponent synthesis of γ-nitroamides, the
CG/MS study indicated the presence of two main
intermediates during the multicomponent process.
We tried to use of 4.0 mmol of ammonium carbonate [4b
(NH4)2CO3] instead NH4OAc, proceeded clearly and after 24
hours of reflux conditions, afforded the desired -nitroamide
,
γ
5a in 93% yield, after purification (entry 9). Results performing
the same reaction at lower temperatures were unsatisfactory
(entries 10 and 11).
The use of ammonium formate (4c, NH4HCO2) caused a
decrease in yield (entry 12). The change of solvent to THF was
Table 2. Multicomponent synthesis of γ-nitroamides 5a-l
Entry
Ald.
R
Amide
Yield (%)a
effective to produce the desired product 5a
, however
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
C6H5
4-Cl-C6H4
5a
5b
5c
5d
5e
5f
93
84
89
80
85
87
80
70
65
67
45
35
produced lower yields in the reaction (entry 13). Reactions
under solventless conditions with NH4OAc or (NH4)2CO3 were
unsuccessful (Entries 14 and 15, respectively).
4-Br-C6H4
4-CN-C6H4
4-MeO-C6H4
3,4-MeO-C6H3
3,4,5-MeO-C6H2
3-thiofenyl
3-MeO-C6H4
4-Me-C6H4
Isopentyl
This study permeated to conclude that non protic solvents,
temperatures between 80oC and 90oC and 24 hours of
reaction times are essential for the achieving the best results.
Among the three ammonium salts investigated the (NH4)2CO3
proved to be the most efficient. The optimized condition was
used to evaluate the multicomponent reactional scope
2g
2h
2i
5g
5h
5i
10
11
12
2j
5j
addressed to synthesis of
reactions were performed in the presence of different
aromatic and aliphatic aldehydes 2a , as showed in Table 2
(Scheme 2). According to the results, all tested examples
resulted in the obtainment of -nitroamides 5a under a
multicomponent process. The -aril -nitroamides 5a-j, from
γ-aril or γ-alkyl nitroamides 5a-l, the
2k
2l
5k
5l
Pentyl
-l
[a] Isolated yield.
γ
-l
The first is the benzylidene intermediate
6
, which results
β
γ
from a Knoevenagel like condensation between the Meldrum’s
acid ( ) and benzaldehyde 2a. The second one, is the Michael
adduct formed by the conjugate addition of nitromethane (
to the benzylidene intermediate . Finally, the opening of the
aromatic aldehydes, were isolated in yields 67-93% (Table 2,
1
entries 1-10).
7
3)
6
Meldrum’s acid moiety through a domino process by the
amide bond formation with loss of acetone followed by a
decarboxylation step, affords the γ-nitroamide 5a (Scheme 3).
Scheme 2. Multicomponent synthesis of alkyl and aryl
γ-
nitroamides.
The nature of substituents attached to aromatic aldehydes
do not affect significantly the reactivity, leading to similar
yields of nitroamides 5a-j. However, the use of aliphatic
aldehydes 2k,l resulted in lower yields of β-alkyl-γ-nitroamide
(35%-45%, Table 2, entries 11 and 12 respectively). This
difference was associated with the possible fast auto-
condensation of aliphatic aldehydes.
Scheme 3.
synthesis of
A
mechanistic approach of multicomponent
A mechanistic study by ESI/MS
γ-nitroamides
In
nitroesters, we investigated a possible mechanistic pathway of
analogous multicomponent reaction using Gas
a previous studies regarding the synthesis of γ-
By the monitoring the reaction through the ESI/MS, we
were able to detect several intermediates that permitted to
confirm the suggestion discussed above.
Chromatograpy-Mass Spectra (CG/MS) and Electrospray
ionization Mass Spectrometry (ESI/MS).42,43
For this study, we considered the reaction of Meldrum’s
acid (1.1 mmol), benzaldehyde (1.0 mmol), nitromethane (4.0
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 9
View Article Online
DOI: 10.1039/C6RA22141F
ARTICLE
Journal Name
mmol) and ammonium acetate (2.0 mmol) in MeCN (2.0 mL) and m/z 311 (M+) as the ammonium cation form related to the
under reflux condition. Michael adduct (Figure 4b). The formation of this adduct was
A series of aliquots were taken at different reaction times, suggested as result of the conjugate addition of nitrometane
thus the evolution of the reaction can be monitored path by to the benzylidene intermediate
path. After t=15 min of reaction, we could detect the presence The ESI/MS obtained after 1 hour evidenced earlier, the
of intermediate bezylidene with m/z 250 (M+) as ammonium
7
6.
6
presence of the desired -nitroamide 5a at m/z 209 (M+1) and
γ
cation form and m/z 255 (M+) as the sodium cation form as
shown in Figure 4a. The next aliquot was taken at t= 30 min
and the ESI/MS revealed two new signals at m/z 294 (M+1)
m/z 226 (M+) as the ammonium cation form. The other
intermediaries were still observed and are only fully consumed
only after 24 hours (Figure 4c).
UFRGS_REACAO-NH4_T1H 1 (0.019)
TOF MS ES+
311
811
100
218
255
C
206
294
253
252
209
297
236
237
312
313
256
258
226
219
249
298
210
293
205
276
232
223
270
0
UFRGS_REACAO-NH4_T30 1 (0.019)
100
TOF MS ES+
1.34e3
255
B
311
218
294
252
256
312
313
236
297
207
219
209
232
206
214
250
249
298
276
0
UFRGS_REACAO-NH4_T15 12 (0.222)
100
TOF MS ES+
1.51e3
255
A
250
256
257
260
251
280
280
218
220
0
200
m/z
315
205
210
215
225
230
235
240
245
250
255
265
270
275
285
290
295
300
305
310
Figure 4. ESI mass spectra obtained at t = 15 min. (A); t = 30 min. (B) and t = 60 min. (C) during the multicomponent reaction.
During the monitoring of multicomponent reactions, we Scheme 4. Intermediate species generated from intermediate
also observed other signals at m/z 236, m/z 218, m/z 252, m/z
253 and m/z 235, which have been suggested as intermediates
7.
Additionally, we carried out independent experiments to
8-13, respectively. These intermediates were formed through reinforce the mechanistic suggestion discussed above. First,
the opening of the Meldrum’s moiety on the Michael adduct
before the decarboxylation process (Scheme 4).
7
the intermediate
CH3NO2 in presence of 1 equivalent of 1,8-Diazabicycloundec-
7-ene (DBU) to afford the intermediate in almost
6, prepared independently, was reacted with
7
quantitative yield. The use of NH4OAc or (NH4)CO3 was avoided
due to their incompatibility with the ring Meldrum moiety.
Then, the Michael adduct
7 was treated with 4 equivalents of
(NH4)CO3 in refluxing MeCN for 24 hours. After this time, the
γ
-
nitroamide 2a was isolated in 90% yield, after purification by
column chromatography. This experiment is in accordance
with the results shown by the ESI/MS analysis as well as it
corroborate with the proposed mechanism (Scheme 5).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 5 of 9
View Article Online
DOI: 10.1039/C6RA22141F
Journal Name
ARTICLE
MHz for 13C, respectively. The spectra were internally referenced
to TMS (tetramethylsilane) at zero ppm. Chemical shifts were
reported in parts per million (ppm). IR spectra were recorded on
Varian 640-IR spectrometer and are expressed in cm -1 in the range
of 4000 and 400 cm-1. ESI/MS and ESI-MS/MS experiments in the
positive ion-mode were performed on a high-resolution hybrid
quadrupole (Q) and orthogonal timeof-flight (TOF) mass
Scheme 5. Independent synthesis of intermediate
7 and its
conversion to amide 5a
.
spectrometer (Q-TOF Micro, Waters Micromass, UK) with
a
A
tentative mechanist pathway to understand the
transformation of into 5a was considered through the in situ
formation of ketene derivative or half-amide of malonic acid
intermediate 11
The pathway B, consider the thermal fragmentation of
constant nebulizer temperature of 100 °C and a capillary voltage of
3.0 V. The cone and extractor potentials were set to 15 and 4.5 V,
respectively, with a m/z scan range of 70-1000. Samples were
directly infused into the ESI source at flow rates of 15 µL min-1 by
means of a microsyringe pump.
7
8
.
7
to
the formation of ketene derivative 8, which could be captured
by the NH3 present in the medium, leading the formation of
Typical procedure for multicomponent synthesis of γ-nitroamides
A mixture of aromatic aldehydes (1.0 mmol), Meldrum’s acid (1.1
mmol), nitromethane (4.0 mmol) and ammonium carbonate (4.0
mmol) in acetonitrile (1.0 mL) was stirred at reflux for 24h. After,
the solvent was evaporated under reduced pressure. The resulting
residue was purified by silica gel column chromatography to afford
the γ-nitroamides 5a-l.
half-amide intermediate 11
reaction takes place affording the enol 13, which would
equilibrate to the -nitroamide 5a
. Then, the decarboxylation
γ
.
The second way, the pathway A, consider the opening of
the Meldrum’s acid moiety with lose of acetone by a
conventional partial amylolysis with ammonium acetate as the
nitrogen font, would lead to achievement of transient half-
amide intermediate 11. This event would be aided by the
acetic acid present in the medium, which would act as a
Bronsted acid catalyst, as shown in the Scheme 6 below.
4-nitro-3-phenylbutanamide (5a). Yield 88%; white solid; m.p. 94-
96ºC; NMR 1H (300 MHz, CDCl3): δ 2.60 (dd, 1H, J= 15.0 and 6.0 Hz),
2.70 (dd, 1H, J= 15.0 and 9.0 Hz), 3.98 (quint, 1H, J= 7.5 Hz), 4.66
(dd, 1H, J= 12.0 and 6.0 Hz), 4.81 (dd, 1H, J= 12.0 and 6.0 Hz), 5.57
(s, 1H), 5.83 (s, 1H), 7.21-7.36 (m, 5H); NMR 13C (75 MHz, CDCl3): δ
38.8, 40.3, 79.3, 127.3 (2C), 128.0, 129.1 (2C), 138.4, 172.1; IR
(νmax, cm-1): 3415, 3197, 1656, 1660, 1214, 1216; HRMS calc. for
[C10H12N2O3+Na]: 231.0746; found: 231.0750.
3-(4-chlorophenyl)-4-nitrobutanamide (5b). Yield 84%; yellow oil;
1
NMR H (300 MHz, CDCl3): δ 2.62 (dd, 1H, J= 15.3 and 6.9 Hz), 2.70
(dd, 1H, J= 15.3 and 7.5 Hz), 4.01 (q, 1H, J= 7.2 Hz), 4.68 (dd, 1H, J=
12.7 and 8.4 Hz), 4.83 (dd, 1H, J= 12.6 and 6.3 Hz), 5.53 (s, 1H), 5.71
(s, 1H), 7.20 (d, 2H, J= 8.4 Hz), 7.34 (d, 2H, J= 8.7 Hz); NMR 13C (75
MHz, CDCl3): δ 38.6, 39.7, 79.1, 128.7 (2C), 129.3 (2C), 133.9, 137.0,
171.6; IR (νmax, cm-1): 3456, 3343, 3198, 1667, 1550, 1492; HRMS
calc. for [C10H11N2O3+H]: 243.0536; found: 243.0526.
Scheme 6: A tentative mechanist pathway for transformation
of adduct 7 into the -nitroamide 5a in presence of ammonium
acetate.
3-(4-bromophenyl)-4-nitrobutanamide (5c). Yield 89%; pale yellow
solid; m.p. 90-94°C; NMR 1H (300 MHz, CDCl3): δ 2.56 (dd, 1H, J=
15.0 and 6.0 Hz), 2.67 (dd, 1H, J= 15.0 and 9.0 Hz), 3.96 (quint, 1H,
J= 6.0 Hz), 4.63 (dd, 1H, J = 12.0 and 9.0 Hz), 4.80 (dd, 1H, J= 12.0
and 6.0 Hz), 5.56 (s, 1H), 5.75 (s, 1H), 7.11 (d, 2H, J= 9.0 Hz), 7.45 (d,
2H, J= 9.0 Hz); NMR 13C (75 MHz, CDCl3): δ 38.5, 39.7, 79.0, 121.9,
129.0 (2C), 132.1 (2C), 137.5, 171.6; IR (νmax, cm-1): 3410, 3201,
1657, 1558, 1487, 1381; HRMS calc. for [C10H11BrN2O3+Na]:
308.9851; found: 308.9860.
Experimental
General methods
All commercially available reagents and analytical grade
solvents were used without further purification, unless otherwise
specified. Column chromatography was performed using silica gel
(230–400 mesh, Merck). TLC was performed on glass sheets
precoated with silica gel (Kieselgel 60 PF254, Merck). The melting
points were measured with Olympus BX41 microscopy equipped
with Mettler-Toledo FP82HT hotplate.
3-(4-cyanophenyl)-4-nitrobutanamide (5d). Yield 80%; NMR 1H
(300 MHz, DMSO-d6): δ 2.54 (m, 2H), 3.97 (quint, 1H, J = 7.5 Hz),
4.99 (dd, 1H, J = 15.0 and 9.0 Hz), 5.06 (dd, 1H, J = 12.0 and 6.0 Hz),
6.92 (s, 1H), 7.42 (s, 1H), 7.59 (d, 2H, J = 6.0 Hz), 7.85 (d, 2H, J = 6.0
Hz); NMR 13C (75 MHz, DMSO-d6): δ 37.8, 78.8, 110.1, 118.7, 128.9
The 1H and 13C NMR spectroscopic data were recorded on
Varian VNMRS spectrometer operating at 300 MHz for 1H and 75
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 9
View Article Online
DOI: 10.1039/C6RA22141F
ARTICLE
Journal Name
(2C), 132.4 (2C), 145.9, 171.1; IR (νmax, cm-1): 3457, 2987, 2234,
4-nitro-3-p-tolylbutanamide (5j). Yield 67%; brown solid; m.p. 90-
1724, 1553, 1381; HRMS calc. for [C11H11N3O3+Na]: 256.0698; 93ºC; NMR 1H (300 MHz, CDCl3): δ 2.25 (s, 3H), 2.58 (m, 2H), 3.88
found: 256.0690.
(quint, 1H, J= 6.0 Hz), 4.57 (dd, 1H, J= 15.0 and 9.0 Hz), 4.72 (dd, 1H,
J= 15.0 and 9.0 Hz), 5.39 (s, 1H), 5.48 (s, 1H), 7.06 (m, 4H); NMR 13
C
3-(4-methoxyphenyl)-4-nitrobutanamide (5e). Yield 85%; white
solid; m.p. 102-104°C; NMR 1H (300 MHz, CDCl3): δ 2.57 (dd, 1H, J =
15.0 and 9.0 Hz), 2.66 (dd, 1H, J = 18.0 and 9.0 Hz), 3.95 (s, 3H), 3.95
(quint, 1H, J = 7.5 Hz), 4.62 (dd, 1H, J = 15.0 and 9.0 Hz), 4.80 (dd,
1H, J = 15.0 and 9.0 Hz), 5.75 (s, 1H), 6.37 (s, 1H), 6.85 (d, 2H, J = 9.0
(75 MHz, CDCl3): δ 21.0, 38.9, 40.0, 79.5, 127.1, 127.2, 129.7, 129.9,
135.3, 137.7, 172.4; IR (νmax, cm-1): 3438, 3179, 1657, 1560, 1430,
1374, 815, 515; CHN calc. for [C11H14N2O3]: C 59.45%; H 6.35%; N
12.60%; found: C 59.52%; H 6.34%; N 12.06%.
Hz), 7.16 (d, 2H, J = 9.0 Hz); NMR 13C (75 MHz, CDCl3): δ 38.7, 39.6, 5-methyl-3-(nitromethyl)hexanamide (5k). Yield 45%; yellow oil;
1
55.0, 79.6, 114.1(2C), 128.2(2C), 130.5, 158.8, 172.0; IR (νmax, cm- NMR H (300 MHz, CDCl3): δ 0.84 (m, 6H), 1.20 (m, 2H), 1.61 (hept,
1): 3457, 3318, 3214, 1692, 1650, 1545, 1250; HRMS calc. for 1H J= 6.0 Hz), 2.22 (dd, 1H, J= 15.0 and 6.0 Hz), 2.30 (dd, 1H, J= 9.0
[C11H14N2O4+Na]: 261.0851; found: 261.0860.
and 6.0 Hz), 2.61 (m, 1H), 4.38 (dd, 1H, J= 12.0 and 6.0 Hz), 4.48 (dd,
3-(3,4-dimethoxyphenyl)-4-nitrobutanamide (5f). Yield 87%; white 1H, J= 12.0 and 6.0 Hz), 6.12 (s, 1H), 6.36 (s, 1H); NMR 13C (75 MHz,
solid; m.p. 100-104°C; NMR 1H (300 MHz, CDCl3): δ 2.65 (m, 2H), CDCl3): δ 22.2 (2C), 24.8, 32.2, 37.1, 40.3, 78.6, 173.7; IR (νmax, cm-
3.85 (s, 3H), 3.87 (s, 3H), 3.93 (m, 1H), 4.65 (dd, 1H, J = 12.0 and 6.0 1): 3414, 3195, 2960, 2871, 1657, 1551, 1381, 6445; HRMS calc. for
Hz), 4.79 (dd, 1H, J = 12.0 and 6.0 Hz), 5.53 (s, 1H), 5.74 (s, 1H), [C8H16N2O3+Na]: 211.1059; found 211.1059.
6.75-6.84 (m, 3H); NMR 13C (75 MHz, CDCl3): δ 38.9, 40.1, 55.9, 56.0,
1
79.5, 110.8, 111.6, 119.2, 130.7, 148.7, 149.2, 172.8; IR (νmax, cm-
3-(nitromethyl)octanamide (5l). Yield 35%; pale yellor oil; NMR H
1): 3413, 3206, 2833, 1642, 1552, 1545, 1364, 1251, 1018; HRMS
NMR (300 MHz, CDCl3): δ 0.92 (t, 3H, J= 7.5 Hz), 1.28-1.48 (m, 8H),
2.39 (m, 2H), 2.64 (quint, 1H, J= 6.0 Hz), 4.50 (dd, 1H, J= 12.0 and
calc. for [C12H16N2O5+Na]: 291.0957; found: 291.0953.
6.0 Hz), 4.60 (dd, 1H, J= 12.0 and 6.0 Hz), 5.78 (s, 1H), 5.98 (s, 1H);
4-nitro-3-(3,4,5-trimethoxyphenyl)butanamide (5g). Yield 90%; NMR 13C (75 MHz, CDCl3): δ 13.9, 22.4, 26.2, 31.2, 31.5, 34.5, 37.1,
1
white solid; m.p. 105-109ºC; NMR H (300 MHz, CDCl3): δ 2.60 (dd, 78.3, 172.9; IR (νmax, cm-1): 3388, 3194, 2929, 2853, 1652, 1548,
1H, J= 15.0 and 9.0 Hz), 2.69 (dd, 1H, J= 15.0 and 9.0 Hz), 3.82 (s, 1411, 1382, 1270, 1197, 1104; HRMS calc. for [C9H18N2O3+Na]:
3H), 3.84 (s, 6H), 3.93 (quint, 1H, J= 6.0 Hz), 4.67 (dd, 1H, J= 9.0 and 225.1215; found: 225.1210.
12.0 Hz), 4.82 (dd, 1H, J= 12.0 and 6.0 Hz), 5.39 (sl, 2H), 6.44 (s, 2H);
NMR 13C (75 MHz, CDCl3): δ 38.8, 40.7, 56.1 (2C), 60.7, 79.4, 104.4
Procedure for the synthesis of intermediate 7
(2C), 134.4, 137.4, 153.4 (2C), 172.0; IR (νmax, cm-1): 3453, 3342,
The benzylidene 6 (1 mmol), CH3NO2 (3) (5 mmol) and 1,8-
Diazabicycloundec-7-ene (DBU, 1 mmol) were added into a round
bottom flask. The mixture was submitted to magnetic stirred at
room temperature overnight. After this, the excess of nitromethane
was removed under vacuum, the crude was dissolved in AcOEt and
washed with HCl (5%, 3 x 5 mL). The organics were combined, dried
with MgSO4, filtered and evaporated to afford the intermediate 7 in
yield 98% as a viscous yellow oil.
3268, 2830, 1682, 1549, 1460, 1127. HRMS calc. for
[C13H18N2O6+Na]: 321.1063; found: 321.1060.
4-nitro-3-(thiophen-3-yl)butanamide (5h). Yield 70%; pale yellow
1
solid; m.p. 95-97°C; NMR H NMR (300 MHz, CDCl3): δ 2.65 (d, 2H,
J= 9.0 Hz), 4.14 (quint, 1H, J= 7.5 Hz), 4.65 (dd, 1H, J= 15.0 and 9.0
Hz), 4.83 (dd, 1H, J= 12.0 and 6.0 Hz), 5.83 (sl, 1H), 6.54 (sl, 1H), 7.01
(d, 1H, J= 6.0 Hz), 7.15 (m, 1H), 7.31 (m, 1H); NMR 13C (75 MHz,
CDCl3): δ 35.8, 38.6, 79.1, 122.2 (2C), 126.0, 126.9 (2C), 138.9,
172.4; IR (νmax, cm-1): 3405, 3192, 2846, 1653, 1553, 1428, 1381,
1260, 1159, 776; HRMS calc. for [C8H10N2O3S+Na]: 237.0310; found:
237.0307.
2,2-Dimethyl-5-(2-nitro-1-phenylethyl)-1,3-dioxane-4,6- dione (7)44
1
Yield 27.8 mg, 98%; viscous yellow oil; H NMR (300 MHz, CDCl3): δ
1.39 (s, 3H), 1.72 (s, 3H), 4.05 (d, 1H, J= 3.3 Hz), 4.65 (m, 1H), 5.03
(dd, 1H, J= 14.1 and 6.6 Hz), 5.40 (dd, 1H, J= 13.9 and 8.7 Hz), 7.33
(m, 5H); 13C NMR (75 MHz, CDCl3) δ 27.6, 28.1, 41.9, 48.5, 75.9,
105.9, 128.7, 128.8, 128.9, 129.0, 129.2, 135.1, 163.9, 164.4; IR
(νmax/ cm-1) 2999, 2867, 1781, 1735, 1553, 1329, 1310, 1206,
1110, 758.
3-(3-methoxyphenyl)-4-nitrobutanamide (5i). Yield 65%; brown
gum; NMR 1H (300 MHz, CDCl3): δ 2.60 (dd, 1H, J= 18.0 and 9.0 Hz),
2.67 (dd, 1H, J= 15.0 and 6.0 Hz), 3.78 (s, 3H), 3.95 (quint, 1H, J= 7.5
Hz), 4.67 (dd, 1H, J= 12.0 and 9.0 Hz), 4.77 (dd, 1H, J= 12.0 and 6.0
Hz), 5.62 (s, 1H), 5.72 (s, 1H), 6.79 (m, 3H), 7.25 (m, 1H); NMR 13C
(75 MHz, CDCl3): δ 38.7, 40.3, 55.2, 79.2, 113.0, 113.5, 119.3, 130.1,
139.9, 159.9, 172.3; IR (νmax, cm-1): 3414, 3209, 1642, 1548, 1390,
1269, 1045, 784, 700, 607; HRMS calc. for [C11H15N2O4+]: 239.1032;
found: 239.1040.
Procedure for conversion of intermediate 7 into γ-nitroamide 5a.
A mixture of adduct 7a (1.0 mmol) and ammonium carbonate (4.0
mmol) in acetonitrile (1.0 mL) was stirred at reflux for 24h.
Afterwards, the volatile were removed under vacuum and the crude
purified by column chromatography on silica gel using a gradient of
hexanes and ethyl acetate as eluent to give the γ-nitroamide 5a.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 7 of 9
View Article Online
DOI: 10.1039/C6RA22141F
Journal Name
ARTICLE
16 A. Rephaeli, I. Gil-Ad, A. Aharoni, I. Tarasenko, N. Tarasenko,
Y. Geffen, E. Halbfinger, Y. Nisemblat, A. Weizman, A. J.
Nudelman, J. Med. Chem., 2009, 52, 3010.
Conclusions
The present investigation showed, for the first time, the
development of a new tetracomponent reaction for the direct
17 A. Pasternak, D. Marino, P. P. Vicario, J. M. Ayala, M. A.
Cascierri, W. Parsons, S. G. Mills, M. MacCoss, , L. J. Yang, J.
Med. Chem., 2006, 49, 4801.
synthesis of new γ-nitroamides. By this methodology β-aryl- or
-alkyl- -nitroamides were prepared in one step reaction. The
β
γ
18 G. Lu, H. Morimoto, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed., 2008, 47, 6847.
protocol is based on common and commercially available
starting materials, such as: Meldrum’s acid, nitromethane and
aliphatic or aromatic aldehydes. Ammonium acetate or
ammonium carbonate play a central role as an acid/base
catalyst well as a reactant. The method was more effective by
using aryl aldehydes, affording the desired products in
reasonable to good yields after purification (67%-93%). A
19 J. L. Vicario, D. Badia, L. J. Carrillo, Org. Chem., 2001, 66
,
5801.
20 S. H. Gellman, Y. Chi, L. Guo, United States Patent, N0.2 US
8.637.696 B2, 2014.
21 V. A. Maslivetc, M. Rubina, M. Rubin, Org. Biomol. Chem.,
2015, 13, 8993.
tentative mechanistic pathway to formation of γ-nitroamides
was proposed through monitoring the course of the reaction
22 Y. Hayashi, Chem. Sci., 2016, 7, 866.
23 R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem., 2014, 16
,
by the ESI/MS spectrometry assays. The studies regarding the
2958.
preparation of secondary and tertiary
current investigation.
γ-nitroamides are under
24 J. V. Alegre-Requena, E. Marqués-López, R. P. Herrera in
Multicomponent Reactions: Concepts and applications for
Design and Synthesis, 1st Ed.; R. P. Herrera, E. Marqués-
López, Eds.; John Wiley & Sons, Inc.: Hoboken, New Jersey,
2015; pp. 1-15.
Acknowledgements
The authors would like to acknowledge FAPERGS, CNPq
(Grant Universal No. 455791/2014-7) and CAPES for their
financial support and fellowships (C.R.M.D’O.; J.C.S.; E.P.G.).
Fondecyt (11130086 and 1140642), Anillo Cientifco ACT1107,
PIEI-UTalca, and Chile CORFO (FCR-CSB 09CEII-6991), are
greatly acknowledged.
25 B. B. Touré, D. G. Hall, in Multicomponent reactions, 1st Ed.;
Z. Zhu, H. Bienaymé, Eds.; Willey-VCH: Weinheim, 2005, pp.
342.
26 P. Slobbe, E. Ruijter, R. V. A. Orru, Med. Chem. Commun.,
2012, 3, 1189.
27 R. V. A. Orru, E. Ruijter, in Topics in Heterocyclic Chemistry -
Synthesis of Heterocycles via Multicomponent Reactions I,
Springer-Verlag, Berlinm, 2010, vol. 23.
28 25 R. V. A. Orru, E. Ruijter in Topics in Heterocyclic Chemistry
- Synthesis of Heterocycles via Multicomponent Reactions II,
Springer-Verlag, Berlim, 2010, vol. 25.
Notes and references
1
2
W. Sieghart, Adv. Pharmacol., 2006, 54, 231.
T. Goetz, A. Arslan, W. Wisden, P. Wulff, Prog. Brain Res.
2007, 160, 21.
29 A. Habibi, A. Rahmani, Helv. Chim. Acta, 2011, 94, 1806.
30 A. Dömling, W. Wang, K. Wang, Chem. Rev., 2012, 112, 3083.
31 A. Dömling, Chem. Rev., 2006, 106, 17.
3
4
R. W. Olsen, W. Sieghart, Neuropharmacol., 2009, 56, 141.
32 C. Graaff, E. Ruijter, R. V. A. Orru, Chem. Soc. Rev., 2012, 41
,
M. Chebib, G. A. R. Johnston, Biochem. Soc. Trans. 2009, 37
,
3969.
1317.
33 E. Valeur, M. Bredley, Chem. Soc. Rev., 2009, 38, 606.
34 C. L. Allen, J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405.
5
6
7
J. Bormann, Trends Pharmacol. Sci., 2000, 21, 16.
N. G. Bowery, Curr. Opin. Pharmacol., 2006, 6, 37.
35 M. N. Godoi, H. S. Costenaro, E. Kramer, P. S. Machado, M.
G. M. D’Oca, D. Russowsky, Quim. Nova 2005, 28, 1010.
M. Chebib, G. A. R. J. Johnston, J. Med. Chem., 2000, 43
,
1427.
36 D. Russowsky, E. V. Benvenutti, Roxo, G. S.; F. Grasel, Lett.
8
9
U. Rudolph, H. Möhler, Annu. Rev. Pharmacol. Toxicol., 2004,
44, 475.
Org. Chem., 2007, 4, 39.
37 M. V. Marques, M. Ruthner, L. A. M. Fontoura, D. Russowsky,
J. Braz. Chem. Soc., 2012, 23, 171.
F. Caputo, M. Bernardi, Curr. Pharm. Des., 2010, 16, 2118.
10 K. Gajcy, S. Lochynski, T. Librowski, Curr. Med. Chem., 2010,
17, 2338.
11 T. Shioiri, S. Sasaki, Y. Hamada, ARKIVOC, 2003, ii, 103.
38 R. A. Affeldt, V. Benvenutti, D. Russowsky, New J. Chem.,
2012, 36, 1502.
39 J. S. Costa, J. P. B. Lopes, D. Russowsky, C. L. Petzhold, A. C.
A. Borges, M. A. Ceschi, E. Konrath, C. Batassini, P. S. Lunardi,
C. A. S. Gonçalves, Eur. J. Med. Chem., 2013, 62, 556.
40 H. D. Fontecha-Tarazona, R. C. Brinkerhoff, P. M. Oliveira, S.
B. Rosa, D. C. Flores, C. R. M. D'Oca, D. Russowsky, M. G. M.
12 A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc., 2004,
126, 9546.
13 N. Borkakoti, Biochem. Soc. Trans., 2004, 32, 17.
14 S. Horvat, Z. Hamersak, I. Stipetic, T. Jolas, Eur. J. Med.
Chem., 2010, 45, 1447.
D'Oca, RSC Adv., 2015, 5, 59638.
15 P. R. Carlier, E. S-H. Chow, R. L. Barlowb, J. R. Bloomquist,
Bioorg. Med. Chem. Lett., 2002, 12, 1985.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 8 of 9
View Article Online
DOI: 10.1039/C6RA22141F
ARTICLE
Journal Name
41 T. G. M. Treptow, F. Figueiro, E. H. F. Jandrey, A. M. O.
Battastini, C. G. Salbego, J. B. Hoppe, P. S. Taborda, S. B.
Rosa, L. A. Piovesan, C. R. M. D'Oca, D. Russowsky, M. G. M.
D'Oca, Eur. J. Med. Chem., 2015, 95, 552.
42 F. F. Naciuk, D. Z. Vargas, C. R. M. D’Oca, C, C. Moro, D.
Russowsky, New J. Chem. 2015, 39, 1643.
43 C. R. M. D'Oca, F. F. Naciuk, J. C. Silva, E. P. Guedes, C. C.
Moro, M. G. M. D'Oca, L. S. Santos, F. M. Natchigall, D.
Russowsky, J. Braz. Chem. Soc. 2016 DOI: 10.5935/0103-
5053.20160175.
44 I. Schuster, P. Schuster, Tetrahedron, 1969, 25, 199.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
RSC Advances
View Article Online
DOI: 10.1039/C6RA22141F
Graphical Abstract
A new multicomponent reaction for direct synthesis of γ-nitroamides