The thermal instability of 2,4 and 2,6-N-alkylamino-disubstituted and 2-N-alkylamino-substituted nitrobenzenes in weakly alkaline solution: Sec-amino effect

Article abstract of DOI:10.1002/jhet.2154

We report herein the preparation of two families of secondary amines by the reactions of two equivalents of monoamines with either 2,4 or 2,6-difluoronitrobenzenes in N,N-dimethylacetamide in the presence of anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N-nitrosamines. In both instances, these compounds could be prepared in quantitative yield when the reaction temperature was held below 130°C. Above this reaction temperature, an unexpected cyclization reaction between the nitro and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed.

Full text of DOI:10.1002/jhet.2154

May 2015
The Thermal Instability of 2,4 and 2,6-N-Alkylamino-disubstituted and
2-N-Alkylamino-substituted Nitrobenzenes in Weakly Alkaline Solution:
sec-Amino Effect
681
Christopher Walczak,a Thomas J. Payne,b Colin B. Wade,b Matthew Yonkey,c Melissa Scheid,b Alec Badour,b
b
*
and Dilip K. Mohanty
aDepartment of Biochemistry, University of Michigan, Ann Arbor, Michigan 48109
bDepartment of Chemistry, Central Michigan University, Mt. Pleasant, Michigan 48858
cDow Chemical Company, Midland, Michigan 48642
*
E-mail: Mohan1dk@cmich.edu
Additional Supporting Information may be found in the online version of this article.
Received August 13, 2013
DOI 10.1002/jhet.2154
Published online 29 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
We report herein the preparation of two families of secondary amines by the reactions of two equivalents
of monoamines with either 2,4 or 2,6-difluoronitrobenzenes in N,N-dimethylacetamide in the presence of
anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N-nitrosamines.
In both instances, these compounds could be prepared in quantitative yield when the reaction temperature
was held below 130°C. Above this reaction temperature, an unexpected cyclization reaction between the nitro
and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings
in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed.
J. Heterocyclic Chem., 52, 681 (2015).
INTRODUCTION
6-DFNB) with homologous aliphatic primary amines (from
n-hexyl to n-decyl amines) [5]. The low molecular weight
secondary amines were prepared in N,N-dimethylacetamide
(DMAc) at 120°C in the presence of anhydrous potassium
carbonate. Any one of these reactions at reaction temperatures
above 130°C failed to yield the desired products in high yield.
Analysis of the reaction mixture by TLC and GC–MS
showed the presence of the desired product, and numerous
other compounds along with one major component. The
presence of the disubstituted secondary amine in the complex
reaction mixture indicated the following: the secondary
amine forms at a lower temperature and then decomposes
at elevated temperatures. In addition, the molecular
weight of each major side product was 34 Da less than
its corresponding starting material, indicative of the loss
of a molecule of hydrogen peroxide.
Nitric oxide (NO), a small diatomic gaseous molecule,
produced in vivo, plays a critical role in cell signaling [1].
We have reported the preparation of a variety of low and high
molecular weight exogenous NO donors, N-nitrosoamines,
and their effects on the proliferations of human aortic smooth
muscle cells. These N-alkyl-N-aryl nitrosamines release NO in
a slow and sustained manner. This NO release pattern is in
contrast to the commercially available NO donors, which re-
lease NO in a single burst of high concentration. Furthermore,
the synthesized NO donors exhibit longer half-lives ranging
from 60 to 140 h, significantly longer than the commercial
materials [2–5]. In the course of our investigations, we were
successful in preparing low molecular weight secondary
amines as precursors to N-nitrosoamines, by the reactions
of 2,4 and 2,6-difluoronitrobenzenes (2,4-DFNB and 2,
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In order to understand the possible origin of these side
expected, the molecular weights of these cyclized species were
products, lower molecular weight secondary amines, N,N
′-diethyl-4-nitrobenzene-1,3-diamine (1) and N,N′-diethyl-
2-nitrobenzene-1,3-diamine (2), were prepared under
carefully controlled reaction conditions, by the reactions
of each of the two dihalides, 2,4-DFNB and 2,6-DFNB,
via nucleophilic substitution with ethylamine, respectively
(Scheme 1). In this report, we propose a possible reaction
pathway leading to the formation of the unexpected
products via the formation of a nitrene intermediate,
based upon the structural elucidation of the major isolable
side product.
34 Daltons less than the respective starting materials.
Furthermore, the mass spectral analyses of the starting materials,
(1) and (2), revealed the formation of fragments ((M–H3O2)+.);
m/z values 35 units less than the m/z of the molecular ions. It is
important to point out that in the absence of anhydrous
potassium carbonate compounds (1) and (2) remained
unaffected.
From an examination of Scheme 2, there appears to be a
reaction between the secondary amino group (ortho to the
nitro group) and the adjacent methylene unit reacts with
the nitro group. This results in the formation of an imidaz-
ole ring with the concurrent loss of hydrogen peroxide, as
the major side product in addition to a series of other
compounds, which were not identified. To the best of our
knowledge, this is the first instance where such a reaction
has been observed. It is important to point out that this
cyclization reaction is somewhat similar to the cyclization
observed in the case of nitrobenzenes with ortho-substituted
tertiary N-alkylamine moieties. This known cyclization
reaction, called “tert-Amino Effect”, was reported as far
back as 1895 by Pinnow [6,6b),6c),6d),6e),6f),7–9], and
served as an influence to name the observed cyclization
(Scheme 2), the “sec-Amino Effect”. Essentially all reac-
tions falling under tert-amino-effect, proceed through ionic
intermediates. For example, 2-nitrophenyl sarcosine is
transformed to N-hydroxyquinoxaline-2-3-dione in aque-
ous alkaline medium [6e]. N,N-Dialkyl-2-nitroanilines
cyclize thermally to form 1,2-disubstituted benzimidazoles or
their N-oxides depending on the reaction conditions [7].
Formation of the cyclized products were observed during mass
spectral analyses of these N,N-dialkyl-2-nitroanilines [6f].
RESULTS AND DISCUSSIONS
In order to identify unambiguously the major component
formed at elevated temperature, (1) and (2) were dissolved
in N-methylpyrrolidinone (NMP) and DMAC, respectively.
These solutions were heated with potassium carbonate and
toluene to simulate the reaction conditions used for the
formation of the secondary amines (Scheme 2). The major com-
ponent from each of these two reactions, 5-N-ethylamino-2-
methyl-1H-benzimidazole (4) and 4-N-ethylamino-2-methyl-
1H-benzimidazole (5), were isolated and identified. As
Scheme 1. Preparation of (1)–(3).
1
The IR, H-NMR and the 13C-NMR spectra of (5) are
displayed in Figure 1a, b, and c, respectively. The X-ray
diffraction data of (5) has been reported earlier [10]. From
an examination of the IR spectrum (Fig. 1a), the broad
band centered around 3366 cmÀ1 illustrates the acidic
nature of the hydrogen atom attached to one of the nitrogen
atoms located in the ring of (5) and is confirmed further by
the absence of an absorbance due to this hydrogen atom in
1
the H-NMR [11]. The absorbances due to the various
Scheme 2. Thermal cyclization of (1)–(3).
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Alkylamino-substituted Nitrobenzenes in Weakly Alkaline Solution: sec-Amino Effect
1
Figure 1. (a) IR (neat) spectrum of (5). (b) H-NMR (CDCl3) spectrum of (5). (c) 13C-NMR (CDCl3) spectrum of (5).
carbon atoms in the 13C spectrum are consistent with the
calculated values from chemical shifts contributions [12].
As mentioned in the experimental section, the benzimid-
azoles derived from (1) and (2) were the only compounds
that could be isolated from the myriad of other products.
This suggests the formation of a reactive intermediate with
the ability to produce a variety of products. It is well
known that aromatic nitro groups can be converted to
nitrenes either thermally [13,14] or in the presence of cata-
lysts including triethyl phosphite and tributyl phosphine
[14–16]. Proposed in the succeeding text is a possible reac-
tion pathway (Scheme 3) for the cyclization reactions of (1)
and (2) (pathway for (2) is shown) involving a nitrene
intermediate with the concurrent loss of a molecule of
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Scheme 3. Proposed reaction pathway for the formation of benzimidazole derivative.
hydrogen peroxide. The nitrene intermediate forms by the
intra-molecular reaction between the nitro group and the
N-ethylamino moiety in either ortho or para orientation.
This reactive nitrene group then inserts into the C–H bond
of the methylene unit α to the remaining ortho ethylamine
group to form a five-membered ring [17]. Nitrenes are
known to insert into a secondary α-ethereal C–H bond as
well, akin to what is observed in the present instance
[18]. The stability of the nitrene intermediate is enhanced
by the presence of a secondary amine group in para and
ortho orientations for (1) and (2), respectively. The
positioning of substituents in (2) enhances the probability
of ring closure leading to the formation of (5) at 160°C
and (4) at 180°C.
An examination of Scheme 3 indicates the proposed
involvement of two N-ethylamino substituents. Therefore,
the question arises as to how the cyclization reaction would
progress in the presence of only one N-ethylamino substit-
uent. In order to address this issue, 2-nitro-N-ethylaniline,
(3), was prepared from the reactions of ethylamine and
2-fluoronitrobenzene (Scheme 1) and was subjected to
the thermal cyclization reaction conditions (Scheme 2).
The 1H-NMR of the cyclized product, quinoxaline,
obtained from (3) in approximately 5% yield (after column
chromatographic separation), was identical to that of the
1H-NMR spectrum of commercially available material.
The progress of this reaction was monitored by GC–MS
analyses, which indicated the concomitant formation of a
species with molecular weight 2 amu higher than that of
quinoxaline in addition to residual starting material and a
host of other products. The higher molecular weight
species co-eluted with the starting material when hexane
was used as the eluent during chromatographic separation.
We speculate this compound to be 1,4-dihydro-2H-
quinoxaline, the precursor to quinoxaline formation. These
observations suggest that the nitrene intermediate (formed
after the loss of hydrogen peroxide) inserts into a C–H
bond of the methyl group α to the –N═CH– moiety
(Scheme 4) to form 1,4-dihydro-2H-quinoxaline, which
subsequently aromatizes to quinoxaline. The lack of
formation of quinoxaline during the cyclization reactions
of (1) and (2) can be explained by a significantly lower heat
of formation of benzimidazoles, 83.1 kJ/mole [19] com-
pared with that of quinoxaline, 240.3 kJ/mole [20]. These
observations lend further credence to the proposed electron
deficient nitrene intermediate for the cyclization reactions.
We are presently investigating the possible inhibitory
effects of electron withdrawing substituents including nitro
and nitrile groups on the cyclization reactions of 2-nitro-N-
ethylaniline in different orientations with respect to the
nitro group. Theoretical quantum mechanical modeling
studies in support of the proposed mechanism involving a
nitrene intermediate will be reported elsewhere.
In summary, we have identified a possible reaction path-
way through which 2,4 and 2,6-di-N-alkylamino as well as
2-N-alkylamino substituted nitrobenzenes decompose at
elevated reaction temperatures in a weakly basic dipolar
aprotic solvent medium. The formation of a nitrene inter-
mediate is proposed for compounds with N-alkylamino
substituent(s) containing at least two carbon atoms.
EXPERIMENTAL
General.
Dimethylacetamide, NMP (Aldrich), and toluene
(Fisher) were dried over calcium hydride and distilled at reduced
pressure. All other reagents were used as received. NMR spectra
were recorded on a Varian Mercury 300 MHz spectrometer and a
Varian INOVA 500 MHz spectrometer with CDCl3 (7.26 ppm for
1H-NMR), CDCl3 (77.0 ppm for 13C-NMR). TMS was used as
the internal standard for these measurements. Chemical shifts are
expressed in δ (ppm) values, and coupling constants are expressed
in hertz (Hz). Standard abbreviations for NMR spectra are:
s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. IR
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Alkylamino-substituted Nitrobenzenes in Weakly Alkaline Solution: sec-Amino Effect
Scheme 4. Proposed reaction pathway for the formation of quinoxaline from 2-nitro-N-ethylaniline.
spectra were recorded on a Nicolet 20DXB FTIR spectrometer,
covering the range of 500–4000cmÀ1. IR samples were prepared
by depositing a thin film of sample on a sodium chloride plate.
Mass spectra were obtained using a Waters GCT Premier 7890
GC–MS with an ionization potential of 70eV. All mass spectral
data is reported in Daltons.
The synthesis of the isomeric form, N,N’-diethyl-2-nitrobenzene-
1,3-diamine, (2), was conducted in a similar manner. Crystals
suitable for X-ray diffraction were obtained by recrystallization
from ethanol/dichloromethane, (2): Yield: 2.01 g, 65%; mp
63–65°C. 1H-NMR (300 MHz, CDCl3): δ = 8.6 (br s, 2H), 7.1
(t, J = 8.7 Hz, 1H), 5.9 (d, J = 9.60Hz, 2H), 3.2 (q, J = 8.40, 4H),
1.3 (t, J = 7.20Hz, 6H), ppm. 13C-NMR (75MHz, CDCl3):
148.51, 137.06, 121.01, 98.01, 38.34,14.42 ppm. IR (NaCl, v
1400 cmÀ1): v = 3347, 2980, 2860, 1582, 1515,1472 cmÀ1. HRMS
m/z Calcd for C10H15N3O2 209.1161, found 209.1165 (TOF MS
EI), 174.1032 (100%).
Syntheses of N,N′-diethyl-4-nitrobenzene-1,3-diamine (1)
and N,N′-diethyl-2-nitrobenzene-1,3-diamine (2). Anhydrous
potassium carbonate (5.09g, 0.036mol) and a solution of
ethylamine (11.34 g, 0.253mol; 70% in water) in DMAc (8 mL)
were combined in a 100mL three-necked round-bottom flask
fitted with a nitrogen inlet, thermometer, magnetic stirring bar,
and a Dean-Stark trap fitted with a condenser. To the stirring
solution, 2,4-difluoronitrobenzene (2.35 g, 0.0148 mol) in DMAc
(5mL) was added. Additional DMAc (8mL) was used to wash
the transfer container and this was added to the reaction mixture,
followed by toluene (20 mL). The color of the reaction mixture
turned orange within a minute. The reaction was allowed to stir at
room temperature for 4 h, while the temperature of the reaction
mixture was gradually increased to 120°C over a 2-h span. Water,
the by-product of the reaction, was removed via azeotropic
distillation with toluene. On completion of the reaction, the
reaction mixture was allowed to cool to room temperature and
diluted with dichloromethane (30 mL). The reaction mixture was
then filtered through celite under reduced pressure to remove
remaining potassium carbonate. The filtrate was then transferred
to a rotary evaporator to remove dichloromethane. The residual
DMAc was then removed by short path distillation, at reduced
pressure and at a temperature below 100°C using a hot oil bath as
the heat source. The red crude product was dissolved in
dichloromethane (30 mL), transferred to a separatory funnel and
washed repeatedly with deionized water. The organic layer was
collected, dried over anhydrous magnesium sulfate, filtered, and the
filtrate was evaporated using a rotary evaporator to yield a bright
yellow solid, (1): Yield: 2.17 g, 70%; mp 108–110°C. 1H-NMR
(300 MHz, CDCl3): δ = 8.4 (br s, 1H), 8.0 (d, J= 9.60 Hz, 1H), 5.9
(dd, J1 =9.60Hz, J2 = 2.40 Hz, 1H), 5.6 (d, J= 2.18 Hz, 1H), 4.4
(br s, 1H), 3.3 (two overlapping q, 4H), 1.34 (t, J= 7.20 Hz, 3H),
1.28 (t, J= 7.20 Hz, 3H) ppm. 13C-NMR (75 MHz, CDCl3):
δ = 200.59, 154.52, 148.70, 129.47, 104.90, 90.10, 38.10, 37.76,
14.61, 14.42 ppm. IR (NaCl, v> 1400 cmÀ1): v= 3340, 3307,
2973, 1623,1551, 1460 cmÀ1. HRMS m/z Calcd for C10H15N3O2
209.1161, found 209.1176 (TOF MS EI), 174.1033 (98%).
Synthesis of 2-nitro-N-ethylaniline (3). The reaction vessel
consisted of a 100 mL, three-necked round-bottomed flask fitted
with thermometer, a magnetic stirrer, and Dean-Stark apparatus
fitted with a condenser. The reaction vessel was charged with
2-fluoronitrobenzene (0.94g, 0.0066 mol), 70% aqueous solution
of ethylamine (3mL, excess), anhydrous potassium carbonate
(3.53 g, excess), DMAc (10 mL), and toluene (10mL). The
reaction vessel was heated with an external oil bath, and the
reaction was allowed to continue under reflux for 1 h. An
additional 2 mL of ethylamine solution was added and the
reaction was allowed to continue for an additional 1.5 h. Water
was continuously removed via the Dean-Stark apparatus. At
the completion of the reaction, the reaction mixture was
diluted with dichloromethane (20 mL) and filtered.
Dichloromethane, residual ethylamine, and toluene were
removed from the filtrate using a rotary evaporator at reduced
pressure. The residue was subjected to high vacuum
distillation to remove DMAc. The residue was dissolved in
dichloromethane, washed with water twice, and the organic
layer was dried over anhydrous magnesium sulfate.
Dichloromethane was removed from the filtrate using a rotary
evaporator. The residue was distilled using high vacuum to
obtain the pure desired compound (3). Yield: 0.80 g, 73%; bp
125–127°C/0.9 mmHg. 1H-NMR (300 MHz, CDCl3): δ = 8.2
(dd, J1 = 8.70 Hz, J2 = 1.50 Hz, 1H); 8.0 (br s, 1H); 7.4(m, 1H)
6.8 (dd, J1 = 8.70 Hz, J2 = 1.20 Hz, 1H); 6.6 (m, 1H); 3.4 (dq,
J1 = 5.45 Hz, J2 = 9.21 Hz, 2H); 1.4 (t, J = 8.40 Hz, 3H) ppm.
13C-NMR (75MHz, CDCl3): δ = 14.57; 37.87; 113.99; 115.30;
127.01, 131.72, 136.45, 145.70 ppm. IR (NaCl, v > 1400cmÀ1):
v = 3382; 2974; 2873; 1617; 1573; 1441cmÀ1. HRMS m/z Calcd
for C8H10N2O2 166.0730, found 166.0732 (TOF MS EI),
151.0494 (100).
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1H-NMR (300 MHz, CDCl3): δ = 7.1 (t, J = 9.00 Hz, 1H), 6.7
(dd, J1 = 10.50 Hz, J2 = 1.50 Hz, 1H), 6.3 (d, J = 7.50 Hz, 1H),
3.3 (q, J = 6.90 Hz, 2H), 2.6 (s, 3H), 1.3 (t, J = 7.50 Hz, 3H)
ppm. 13C-NMR (75 MHz, CDCl3): δ = 148.81, 139.63, 134.31,
131.14, 124.11, 101.88, 100.53, 38.56, 15.06 ppm. IR (NaCl,
v > 1400 cmÀ1): v = 3366, 2961, 1607, 1540, 1422 cmÀ1. HRMS
m/z Calcd for C10H13N3 175.1107, found 175.1108 (TOF MS
EI), 160.0879 (100).
5-N-ethylamino-2-methyl-1H-benzimidazole (4). A three-
necked, 50 mL, round-bottomed flask containing a magnetic stir
bar and fitted with a nitrogen inlet, a thermometer and a
condenser was used as the reaction vessel. The reaction vessel
was charged with anhydrous potassium carbonate (0.65 g,
0.0046 mol). (1) (0.66 g, 0.003 mol), was weighed into a one-
dram glass vial, dissolved in NMP (5 mL) and then transferred
to the reaction vessel. The vial was subsequently washed with
12 mL of NMP, which was then added to the reaction vessel to
ensure complete transfer. The reaction mixture was stirred,
while the vessel was heated using an external temperature-
controlled oil bath. The reaction was allowed to continue at
180°C for 14 h. Upon the extraction process, (4) was found in
the aqueous layer. The aqueous layer was filtered through a
celite bed to remove all solids, and the filtrate was cooled in a
dry-ice/acetone bath and was then lyophilized for 48 hours
using a Labconco Freeze Dry System. The crude residue was
dissolved in methanol, mixed with silica gel (60–100 mesh), and
then dried to remove methanol. The desired compound, 5-
ethylamino-2-methyl-1H-benzimidazole was eluted with ethanol/
ethyl acetate (10/90 v/v) on a silica gel column. GC–MS
analysis indicated a pure product. However, in spite of repeated
attempts, we were unable to recrystallize this compound to
obtain crystals of sufficient quality for X-ray diffraction studies.
(4), Yield: 0.8 g, ~15%. mp 122–124°C. 1H-NMR (300 MHz,
CDCl3): δ = 7.3 (d, J = 8.40 Hz, 1H), 6.7 (d, J = 2.40 Hz, 1H), 6.5
(dd, J1 = 8.10 Hz, J2 = 2.40 Hz, 1H), 3.1 (q, J = 8.10 Hz 2H), 2.5
(s, 3H), 1.2 (t, J = 8.70 Hz, 3H) ppm. 13C-NMR (75 MHz,
CDCl3): δ = 150.29, 145.05, 138.76, 132.95, 116.03, 111.21,
96.05, 39.67, 15.08, 14.84 ppm. IR (NaCl, v > 1400 cmÀ1):
v = 3349, 3199, 2969, 1637, 1593, 1456, 1408 cmÀ1. HRMS m/z
Calcd for C10H13N3 175.1107, found 175.1101 (TOF MS EI),
160.0867 (100).
Acknowledgment. The work was supported by National Institute
of Health (NIH) Award Number R15HL106600 from the
National Heart, Lung and Blood Institute (NHLBI). The content
is solely the responsibility of the authors and does not represent
the official views of NHLB or NIH.
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4-N-ethylamino-2-methyl-1H-benzimidazole (5).
The
cyclization reaction was carried out similar to that of compound
(1). DMAc, instead of NMP was used as the solvent in the
presence of anhydrous potassium carbonate. The dark-red
reaction mixture was stirred, while the vessel was heated using
an external temperature-controlled oil bath. The reaction was
allowed to continue at 160°C for 24 h. During this period,
multiple aliquots were withdrawn from the reaction mixture at
increasing time intervals to monitor the progress of the reaction
using GC–MS analyses. Upon the conclusion of the reaction,
the reaction mixture turned black and opaque. The external
heating source was removed and the reaction was allowed to
cool to room temperature. The reaction mixture was diluted
with dichloromethane (30 mL) and filtered through a celite bed
to remove potassium carbonate and other residual solids. The
filtrate was distilled at reduced pressure to remove all solvents.
The crude product mixture was dissolved in a minimal amount
of dichloromethane and transferred to a separatory funnel, and
washed three times with deionized water. The organic layer was
collected, dried over magnesium sulfate, and filtered. The
filtrate was evaporated using a rotary evaporator at reduced
pressure to yield a sticky dark brown solid. 4-Ethylamino-2-
methyl-1H-benzimidazole, (5), the major component of the
mixture, was identified by GC–MS and isolated using an
alumina column with dichloromethane and ethyl acetate (70:30
v/v) as the eluent. The solution was evaporated at reduced
pressure and the blue-green solid residue was recrystallized
using dichloromethane. (5), Yield: 0.5 g, 10%. mp 63–65°C.
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