Electrophilically activated nitroalkanes in reaction with aliphatic diamines en route to imidazolines

Article abstract of DOI:10.1039/c9ra08630g

A novel synthetic methodology for the assembly of imidazolines via an unusual reaction between nitroalkanes and aliphatic 1,2-diamines in the presence of phosphorous acid is described. In contrast to the related highly efficient preparation of benzimidazoles from aromatic amines, this process represents a major synthetic challenge and for a long time was elusive. Analysis of the method limitations is provided.

Full text of DOI:10.1039/c9ra08630g

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Electrophilically activated nitroalkanes in reaction
with aliphatic diamines en route to imidazolines†
Cite this: RSC Adv., 2019, 9, 39458
a
a
*
Alexander V. Aksenov,
Nicolai A. Aksenov,
Nikolai A. Arutiunov,a
Vladimir V. Malyuga,a Sergey N. Ovcharova and Michael Rubin
ab
*
Received 21st October 2019
Accepted 25th November 2019
A novel synthetic methodology for the assembly of imidazolines via an unusual reaction between
nitroalkanes and aliphatic 1,2-diamines in the presence of phosphorous acid is described. In contrast to
the related highly efficient preparation of benzimidazoles from aromatic amines, this process represents
a major synthetic challenge and for a long time was elusive. Analysis of the method limitations is provided.
DOI: 10.1039/c9ra08630g
rsc.li/rsc-advances
Results and discussion
Introduction
In recent years, our group has developed an expertise in
designing novel acid-mediated multistep cascade trans-
formations of nitroalkenes and nitroalkanes targeting material
science and medicinal chemistry applications. In particular, it
was shown that nitroalkanes 5 dissolved in polyphosphoric acid
(PPA) transform into phosphorylated nitronate 7 showing
strong electrophilic properties. This unusual species can be
used to design a number of one-pot multi-step transformations
involving various carbon-based nucleophiles.17–19 The utiliza-
tion of nucleophilic amines was also demonstrated.20–24 Mech-
anistically, the latter process is related to the classical Nef
reaction,25–27 employing aniline20–23 or hydrazine24 species 8
instead of water. It was proposed, that this reaction initially
provides imidinium ion 9, that can be further employed as
a convenient building block for the synthesis of heterocyclic
Compounds with a ve membered cyclic amidine core isosteric
to peptide bond, play a very important role in medicinal
chemistry. Targeting adrenergic and imidazoline receptors
these small molecules could show regulatory function for the
central nervous system, and have found utility in the develop-
ment of many marketed drugs for the treatment of hyperten-
sion, diabetes, neural disorders, etc.1,2 In addition, ligands with
a 2-imidozaline structure were shown to target adenosine,3
cholecystokinin,4 cyclooxygenase-2,5 estrogen,6 and histamine7
receptors. Also, molecules of this class were studied as inhibi-
tors of DNA topoisomerase,8 proteasome,9 and cholesterol
acyltransferase10 enzymes. Not surprisingly, imidazalines are
oen regarded nowadays as one of the privileged scaffolds for
drug discovery.11,12 Normally, preparation of 2-imidazolines 4 is
very straightforward and involves acylation of 1,2-diamines 2
with carbonyl compounds 1 (acyl, thioacyl, carbamoyl halides,
esters, carboxylic acids, or nitriles) and subsequent cyclo-
condensation of the formed b-aminocarboxamide intermediate
3 (Scheme 1).13–16 For number of years we were interested in
electrophilic activation of nitroalkanes and their reactions with
different nucleophilic species. We pondered if this approach
can be employed to access 2-imidazolines. Indeed, in this case,
the reaction of diamines 2 with nitroalkanes 5 would provide N-
hydroxyamidines 6, which aer cyclization and elimination of
hydroxylamine should afford the same core 4. Herein we wish to
report a full account of this investigation.
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation. E-mail: alexaks05@rambler.ru
bDepartment of Chemistry, University of Kansas, 1567 Irving Hill Road, Lawrence, KS
66045-7582, USA. E-mail: mrubin@ku.edu; Tel: +1-785-864-5071
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra08630g
Scheme 1 Formation of imidazolines.
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ꢀ
compounds: benzoxazoles 10, benzimidazoles 11, diazines 12– the reaction mixture heated at 170 C. Next we tested reaction
13,20–23 and oxadiazoles 14 (ref. 24) (Scheme 2). Evidently, mediated by 80% PPA (an equivalent of relatively strong pyro-
employment of aliphatic 1,2-diamines in this synthetic scheme phosphoric acid, H4P2O7), which also failed to provide imida-
would potentially provide 2-imidazolines 4.
zoline product neat (entry 3) or in the presence of activating
To test this idea, we stirred a mixture of 1-nitropropane (1a) additives: PCl3 (entry 4) or EtOH (entry 5). We also failed to
and N-phenyl-1,2-ethylenediamine (2a) in 86% polyphosphoric observe any reactivity towards formation of 4aa aer heating the
acid (PPA with 86% P2O5 content, an equivalent of polymeric reagents in the presence of PCl3 in boiling xylene (entry 6). Our
metaphosphoric acid) under conditions previously optimized attempts on carrying the reaction in orthophosphoric acid,
for synthesis of benzimidazoles.20 Upsettingly, we failed to either anhydrous (entry 7) or commercial 86% aqueous (entry 8)
observe formation of any imidazolines at 130 ꢀC (Table 1, entry proved to be a total asco as well. Frustrated with this long
1), and only traces of the desired product 4aa were detected in series of failures, we started to test the possibility to cyclize the
imidazoline core in the presence of other strong Brønsted acids,
which ever were used for electrophilic activation of nitroalkanes
or nitroalkenes in our laboratories: formic (entry 9), tosic acid in
protic (entry 10) or aprotic (entry 11) solvents, and even phos-
phomolybdic acid (HPA, entry 12), but the stubborn reaction
newer worked. We saw the light at the end of the tunnel when
one of the test reactions carried out at 170 ꢀC in 86% PPA in the
presence of phosphorous acid additive afforded 56% of the
desired product (entry 13). Further improvement was achieved
aer lowering the reaction temperature. The process took
longer time for completion, but provided improved yield (entry
14). We also noticed, that reaction is being mediated by H3PO3
namely, while molten PPA serves as polar solvent with slight
adverse effect. Indeed, an attempt to reduce the amount of PPA
in the mixture led to the further improvement of the reaction
outcome (entry 15). Finally, we discovered that the process is
best mediated by H3PO3 alone under solvent-free conditions
(entry 16).
Scheme 2 Activation of nitroalkanes towards nucleophilic attack by
amines.
With optimized conditions in hands, we proceeded with
evaluation of preparative value of this reaction. Aer standard
aqueous quench and neutralization of the reaction mixture with
aqueous ammonia, crude 4aa could be routinely extracted and
puried by preparative column chromatography to afford pure
product in 74% yield (Scheme 3, entry 1). Ethylenediamines 2b
and 2c bearing N-p-anisyl and N-benzyl substituents, respec-
tively, were also tested in reaction with 1-nitropropane (1a) to
provide the corresponding products 4ab and 4ac in comparable
yields (entries 2, 3). An attempt to use 1,2-propylenediamine
(2d) possessing two primary amino groups proved more chal-
lenging. In this case yield of product 4ad was quite marginal
(entry 4), probably due to signicant losses of quite volatile
starting material at elevated temperatures despite efficient
reux condenser employed. Another factor affecting the yield
could be a sensitivity of the reaction to the steric hindrance at C-
1. Indeed, in the reaction of non-volatile diamine 2e bearing
even bulkier Ph group at C-1, the yield was also quite low
(entry 5).
It should be pointed out that volatility of the starting mate-
rials escaping the reaction vessel seems to be a major challenge
to be addressed in the design of this process. Although this is
expected to become a less of an issue upon scale up, in
1.0 mmol scale this has an adverse effect on the reaction
performance. Indeed, all reactions involving nitroethane (1b, bp
115 ꢀC) provided consistently lower yields than those carried out
in the presence of 1-nitropropane (1a, bp 132 ꢀC) (Scheme 3,
entries 6–8). This problem becomes a nuisance when trying to
Table 1 Optimization of reaction conditions for cyclocondensation of
1a and 2a to produce imidazoline 4aa
Medium
Temperature Time Yielda
1
2
3
4
5
6
7
8
9
PPA 86% (2 g)
PPA 86% (2 g)
PPA 80% (2 g)
PPA 80% (2 g), PCl3 (0.5 g)
PPA 80% (0.5 g), EtOH (1 mL)
PCl3 (0.5 g), xylene (1 mL)
H3PO4 100% (2 g)
130 ꢀ
170 ꢀ
170 ꢀ
130 ꢀ
C
C
C
C
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
7 h
0%
4%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
56%
90 ꢀC
140 ꢀ
170 ꢀ
170 ꢀ
C
C
C
H3PO4 86% (2 g)
HCOOH (0.5 mL)
170 ꢀC
10 AcOH (0.5 mL), TsOH$H2O (190 mg) 130 ꢀ
C
C
C
C
C
C
C
11 TsOH$H2O (95 mg), PhCl (2 mL)
12 H3PMo12O40 (50 mg), PhCl (2 mL)
13 PPA 86% (1.5 g), H3PO3 (0.5 g)
14 PPA 86% (1.5 g), H3PO3 (0.5 g)
15 PPA 86% (0.5g), H3PO3 (0.5 g)
16 H3PO3 (0.5 g)
140 ꢀ
140 ꢀ
170 ꢀ
160 ꢀ
160 ꢀ
160 ꢀ
12 h 63%
6 h
6 h
73%
78%
a
NMR yield of compound 4aa are shown; test reactions were performed
in 1.0 mmol scale.
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Scheme 4 Mechanistic rationales.
which aer subsequent elimination of phosphorus acid mole-
cule would be transformed into amidine species 17. The latter
would experience 5-exo-trig nucleophilic attack by secondary
amine moiety to produce intermediate triaminomethane 18.
This step is expected to be quite sensitive to steric factors, which
explains poor results obtained in reactions involving reagents
with relatively bulky substituents R,1 R2 and R3. Finally, acid-
assisted elimination of hydroxylamine (in O-phosphorylated
form 19) would yield imidazoline 4.
This rationale, however, cannot explain why orthophos-
phoric acid or PPA, which also are known to stabilize nitronate
form via phosphorylation, did not mediate this cyclization.
Taking into account, that phosphorous acid has distinct
reducing properties, we pondered if this reagent could enable
reduction of nitroalkanes into nitroso-compounds 20
(Scheme 4). Once formed, the later should tautomerize into
oxime 21, which at elevated temperatures in the presence of
acid would loose water to form nitrile (in highly electrophilic
protonated form 22). Subsequent nucleophilic attack by
primary amine group of diamine 2 shall produce amidinium
ion, which exists in equilibrium between forms 23 and 24.
Following 5-exo-trig cyclization 24 would afford cyclic tri-
aminomethane species 25, which aer elimination of ammo-
nium molecule would yield imidazoline 4 (Scheme 4). It should
be pointed out, that H3PO3 indeed seems to be able to reduce
nitroalkanes under the featured reaction conditions. Thus,
Scheme 3 Synthesis of imidazolines.
synthesize imidazoline 4ca non-substituted at C-2 from nitro-
methane (1c, bp 100–102 ꢀC). The yield obtained in this reaction
was extremely poor even when we attempted to offset the loss by
loading large excess (5 equiv.) of the reagent (entry 9). In
contrast, reaction of high boiling nitroalkanes 1d and 1e pro-
ceeded smoothly, providing the corresponding cyclic products
4db, 4dd, and 4ea in moderate yields (entries 10–12).
Unexpectedly, we met a major challenge trying to employ a-
nitrotoluene (1f) as an electrophilic component of the featured
transformation. The reaction was very sluggish, did not proceed
to completion, and afforded very poor yields (Scheme 3, entries
13–14). An attempt to carry out this process under more forcing
conditions did not lead to improvement, as the products
notably decomposed at elevated temperatures. Evidently, in this
case, steric issues become greatly prohibitive.
The mechanistic rationale of the described transformation is
shown in Scheme 4. Initially, under acidic conditions nitro-
alkane 1 produces an aci form, which could be stabilized in
phosphorylated nitronate form 15. As shown previously, both
PPA and H3PO3 enable this step, but diphosphite 15 is less
sterically hindered and usually more reactive than diphosphate
analog derived from PPA.28 Nucleophilic attack by NH2-moiety
of diamine 2 at C-1 of aci-form would rst afford aminal 16,
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nitroethane was converted into acetonitrile, which in the intermediate 30. Aer elimination of water this shall provide
absence of nucleophilic amines was further hydrolyzed into imidazoline product 4, missing carbonyl group in the substit-
acetic acid and ammonia (both detected by mass spectroscopy). uent at C-2. It should be pointed out, that this pathway, provides
Interception of nitrile species the presence of benzylamine (26) an alternative route for installation of bulky substituents at C-2,
afforded acetamide 27 in 80% (NMR yield) (Scheme 5).
Next, we attempted to synthesize 2-acyl-substituted imida- involving direct condensation of diamines with carboxylic acid
zolines employing the featured methodology of electrophilic derivatives. Interestingly, reaction of N-benzyl-1,2-
although it might be less efficient than “normal route”,
activation of nitroalkanes. To this end, a-nitroacetophenone ethylenediamine (2c) with a-nitroacetophenone 1g carried at
(1g) was subjected to the reaction with ethylenediamines 2a and 160 ꢀC was accompanied by competing debenzylation of the
2b under optimized reaction conditions. We were surprised to resulting imidazoline. Aer 12 h this process was complete
nd that imidazolines 4fa and 4 were obtained in these affording heterocycle 4ff as sole product, albeit in modest yield
reactions as sole isolable products (Scheme 6). The yields of (Scheme 5). Benzyl group is removed in a form of benzyl alcohol
these products were quite moderate, but still signicantly better (as detected by GC/MS analysis of the crude reaction mixture),
than in attempted reactions involving electrophilically activated which advocates for SN2-mechanism of this process.
a-nitrotoluene (1f) (Scheme 3, entries 13, 14). Such outcome can
be explained as follows (Scheme 6). Although, formation of
phosphorylated aci-form of nitroalkanes is thermodynamically
Conclusion
favored process, it usually requires quite a long time. With
electrophilic carbonyl group already present in the substrate 1g,
it easily outcompetes the nitronate site, thus, affording hemi-
aminal 28. The latter may undergo extrusion of nitromethane to
yield carboxamide species 29, which can undergo subsequent 5-
exo-trig cyclization via “normal” route, affording cyclic
In conclusion, a new protocol was developed, allowing for an
assembly of imidazolines from aliphatic 1,2-diamines and
electrophilically activated nitroalkanes. Although preparation
of benzimidazoles from aromatic analogs can be performed
routinely, reaction of aliphatic bis-nucleophiles required careful
optimization of the reaction conditions and switching to quite
unusual H3PO3 reaction medium. Reaction provides quite
moderate yields and is very sensitive to steric factors. Several
side processes were studied and the plausible mechanistic
rationales explaining the observed limitations was suggested.
Experimental part
General information
1H and 13C NMR spectra were recorded on a Bruker Avance-III
spectrometer (400 or 100 MHz, respectively) equipped with
a BBO probe in CDCl3 using TMS as an internal standard. High-
resolution mass spectra were registered with a Bruker Maxis
spectrometer (electrospray ionization, in MeCN solution, using
HCO2Na–HCO2H for calibration). Melting points were
measured with a Stuart SMP30 apparatus. All reactions were
performed in oven-dried 5 mL round-bottomed asks equipped
with reux condensers. The reaction progress and purity of
isolated compounds were controlled by TLC on Silufol UV-254
plates, with EtOAc as eluent. Polyphosphoric acids (86% and
80%) were obtained by dissolving of precise amount of P2O5 in
85% orthophosphoric acid according to the published proto-
cols.29,30 All reagents and solvents were purchased from
commercial vendors and used as received.
Scheme 5 Reduction of nitroalkanes with H3PO3.
2-Ethyl-1-phenyl-4,5-dihydro-1H-imidazole (4aa)
Typical procedure: round bottomed ask (5 mL) equipped with
reux condenser and magnetic bar was charged with N-phenyl-
1,2-ethylenediamine (2a) (129 mL, 136 mg, 1.00 mmol), 1-nitro-
propane (1a) (179 mL, 178 mg, 2.00 mmol), and phosphorous
acid (500 mg). The reaction vessel was placed in the oil bath pre-
ꢀ
heated to 160 C and the mixture was stirred for 6 h. Then the
mixture was cooled down, quenched with water (10 mL), and
Scheme 6 Synthesis of imidazolines from a-nitroacetophenone.
basied with 20% aqueous ammonia (10 mL). Crude organic
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material was extracted with dichloromethane (4 ꢁ 15 mL), (3 : 1) to remove impurities following by acetone/20% aq.
concentrated in vacuum and puried with preparative column ammonia to collect the target molecule. The titled compound
chromatography on silica gel eluting with acetone/EtOAc/Et3N was isolated as a yellowish oil, Rf 0.55 (acetone/aq. (20%)
1
(4 : 4 : 0.3). The titled compound was obtained as a yellowish NH4OH, 10 : 2). Yield 42 mg (0.38 mmol, 38%). H NMR (400
oil, Rf 0.40 (acetone/EtOAc/Et3N, 4 : 4 : 0.5), Rf 0.37 (EtOH/ MHz, CDCl3): d ¼ 4.14–3.98 (m, 1H), 3.78 (t, J ¼ 10.7 Hz, 1H),
EtOAc/Et3N, 50 : 30 : 3). Yield 174 mg (0.74 mmol, 74%). 1H 3.24 (dd, J ¼ 11.3, 7.5 Hz, 1H), 2.37 (q, J ¼ 7.6 Hz, 2H), 1.24 (d, J
NMR (400 MHz, CDCl3): d ¼ 7.31 (t, J ¼ 7.9 Hz, 2H), 7.14–7.03 ¼ 6.3 Hz, 3H), 1.19 (t, J ¼ 7.6 Hz, 3H). 13C NMR (101 MHz,
(m, 3H), 3.78 (s, 4H), 2.28 (q, J ¼ 7.4 Hz, 2H), 1.11 (t, J ¼ 7.4 Hz, CDCl3): d ¼ 171.4, 53.5, 52.2, 21.4, 20.4, 10.7. IR (lm,
3H). 13C NMR (101 MHz, CDCl3): d ¼ 166.1, 141.7, 129.3 (2C), NaCl, cmꢂ1): 3239, 2974, 2934, 2886, 1747, 1659, 1563, 1402,
124.6, 123.3 (2C), 52.9, 52.1, 22.2, 11.0. IR (lm, NaCl, cmꢂ1): 1286; HRMS (ES TOF) calculated for C6H13N2 (M + H)+ 113.1073,
3311, 2982, 2938, 1655, 1607, 1503, 1222, 1069; HRMS (ES TOF) found 113.1074 (ꢂ0.3 ppm).
calculated for C11H15N2 (M + H)+ 175.1230, found 175.1232
(ꢂ1.2 ppm).
2-Ethyl-1,5-diphenyl-4,5-dihydro-1H-imidazole (4ae)
This compound was prepared according to the typical proce-
dure employing N-1,1-diphenyl-1,2-ethanediamine (2e), (190 mL,
2-Ethyl-1-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole (4ab)
This compound was prepared according to the typical proce- 212 mg, 1.00 mmol), 1-nitropropane (1a) (179 mL, 178 mg, 2.00
dure employing N-(4-methoxyphenyl)ethylenediamine (2b) (153 mmol), and phosphorous acid (500 mg). The crude material was
mL, 166 mg, 1.00 mmol), 1-nitropropane (1a) (179 mL, 178 mg, puried by preparative column chromatography on silica gel
2.00 mmol), and phosphorous acid (500 mg). The crude mate- eluting with EtOAc/hexanes (1 : 1). The titled compound was
rial was puried by preparative column chromatography on isolated as a yellowish oil, Rf 0.33 (EtOAc/hexanes, 1 : 1). Yield
silica gel eluting with acetone/EtOAc/Et3N (4 : 1 : 0.3). The titled 93 mg (0.37 mmol, 37%). 1H NMR (400 MHz, CDCl3): d ¼ 7.34–
compound was isolated as a yellowish oil, Rf 0.41 (acetone/ 7.19 (m, 7H), 7.13 (t, J ¼ 7.4 Hz, 1H), 6.98 (d, J ¼ 7.6 Hz, 2H), 5.08
EtOAc/Et3N, 4 : 1 : 0.5). Yield 114 mg (0.56 mmol, 56%). 1H (t, J ¼ 10.2 Hz, 1H), 4.36 (dd, J ¼ 13.9, 10.9 Hz, 1H), 3.76 (dd, J ¼
NMR (400 MHz, CDCl3): d ¼ 7.05 (d, J ¼ 8.9 Hz, 2H), 6.88 (d, J ¼ 14.0, 9.7 Hz, 1H), 2.45–2.23 (m, 2H), 1.19 (t, J ¼ 7.5 Hz, 3H). 13
C
8.9 Hz, 2H), 3.80 (s, 3H), 3.86–3.70 (m, 4H), 2.17 (q, J ¼ 7.4 Hz, NMR (101 MHz, CDCl3): d ¼ 167.5, 141.6, 140.2, 129.4 (2C),
2H), 1.10 (t, J ¼ 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3): d ¼ 128.9 (2C), 128.0, 127.2 (2C), 126.4, 125.9 (2C), 69.3, 61.7, 22.2,
167.6, 157.7, 134.7, 126.5 (2C), 114.7 (2C), 55.6, 54.1, 51.9, 21.7, 11.0. IR (lm, NaCl, cmꢂ1): 3375, 2934, 2365, 1603, 1493, 1390,
10.9. IR (lm, NaCl, cmꢂ1): 2985, 2880, 2836, 2368, 1650, 1515, 1222, 1029; HRMS (ES TOF) calculated for C17H19N2 (M + H)+
1240, 1034; HRMS (ES TOF) calculated for C12H17N2O1 (M + H)+ 251.1543, found 251.1550 (ꢂ2.8 ppm).
205.1335, found 205.1340 (ꢂ2.2 ppm).
2-Methyl-1-phenyl-4,5-dihydro-1H-imidazole (4ba)
1-Benzyl-2-ethyl-4,5-dihydro-1H-imidazole (4ac)
This compound was prepared according to the typical proce-
This compound was prepared according to the typical proce- dure employing N-phenyl-1,2-ethylenediamine (2a) (129 mL,
dure employing N-benzyl-1,2-ethylenediamine (2c) (151 mL, 136 mg, 1.00 mmol), nitroethane (1b) (144 mL, 150 mg, 2.00
150 mg, 1.00 mmol), 1-nitropropane (1a) (179 mL, 178 mg, 2.00 mmol), and phosphorous acid (500 mg). The crude material was
mmol), and phosphorous acid (500 mg). The crude material was puried by preparative column chromatography on silica gel
puried by preparative column chromatography on silica gel eluting with acetone/EtOAc/Et3N, (4 : 4 : 0.3). The titled
eluting with acetone/EtOAc/Et3N, 4 : 1 : 0.3. The titled compound was isolated as a yellowish oil, Rf 0.14 (acetone/
compound was isolated as a yellowish oil, Rf 0.29 (acetone/ EtOAc/Et3N, 4 : 4 : 0.5), Rf 0.37 (acetone/EtOAc/Et3N, 4 : 1 : 1).
EtOAc/Et3N, 4 : 1 : 1). Yield 145 mg (0.77 mmol, 77%). 1H NMR Yield 99 mg (0.62 mmol, 62%). 1H NMR (400 MHz, CDCl3): d ¼
(400 MHz, CDCl3): d ¼ 7.34 (t, J ¼ 7.3 Hz, 2H), 7.30–7.19 (m, 3H), 7.30 (t, J ¼ 7.8 Hz, 2H), 7.06 (dd, J ¼ 17.1, 7.7 Hz, 3H), 3.85–3.67
4.28 (s, 2H), 3.69 (t, J ¼ 9.6 Hz, 2H), 3.21 (t, J ¼ 9.7 Hz, 2H), 2.31 (m, 4H), 2.00 (s, 3H). 13C NMR (101 MHz, CDCl3): d ¼ 161.5,
(q, J ¼ 7.3 Hz, 2H), 1.23 (t, J ¼ 7.4 Hz, 3H). 13C NMR (101 MHz, 141.5, 129.2 (2C), 124.1, 122.2 (2C), 52.1, 51.9, 16.0. IR (lm,
CDCl3): d ¼ 168.3, 137.8, 128.8 (2C), 127.5, 127.3 (2C), 52.1, 50.6, NaCl, cmꢂ1): 3291, 3042, 2938, 2862, 1650, 1599, 1402, 1318,
50.4, 21.2, 10.9. IR (lm, NaCl, cmꢂ1): 3307, 2974, 2938, 2882, 1258, 1041; HRMS (ES TOF) calculated for C10H13N2 (M + H)+
1743, 1655, 1563, 1515, 1459, 1382, 1246; HRMS (ES TOF) 161.1073, found 161.1077 (ꢂ2.4 ppm).
calculated for C12H17N2 (M + H)+ 189.1386, found 189.1384 (1.3
ppm).
1-(4-Methoxyphenyl)-2-methyl-4,5-dihydro-1H-imidazole (4bb)
This compound was prepared according to the typical proce-
dure employing N-(4-methoxyphenyl)ethylenediamine (2b) (153
2-Ethyl-5-methyl-4,5-dihydro-1H-imidazole (4ad)
This compound was prepared according to the typical proce- mL, 166 mg, 1.00 mmol), nitroethane (1b) (144 mL, 150 mg, 2.00
dure employing (ꢃ)-1,2-diaminopropane (2d) (82 mL, 74 mg, mmol), and phosphorous acid (500 mg). The crude material was
1.00 mmol), 1-nitropropane (1a) (179 mL, 178 mg, 2.00 mmol), puried by preparative column chromatography on silica gel
and phosphorous acid (500 mg). The crude material was puri- eluting with acetone/EtOAc/Et3N (4 : 1 : 0.3). The titled
ed by preparative column chromatography on silica gel eluting compound was isolated as a yellowish oil, Rf 0.24 (acetone/
rst with acetone/EtOAc/Et3N (40 : 17 : 3) and acetone/Et3N EtOAc/Et3N, 4 : 1 : 0.5). Yield 80 mg (0.42 mmol, 42%). 1H NMR
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(400 MHz, CDCl3): d ¼ 7.06 (d, J ¼ 8.9 Hz, 2H), 6.95–6.86 (m, 1458, 1380, 1244, 1043; HRMS (ES TOF) calculated for
2H), 3.81 (s, 3H), 3.81–3.72 (m, 4H), 1.91 (s, 3H). 13C NMR (101
MHz, CDCl3): d ¼ 163.0, 157.4, 134.6, 125.7 (2C), 114.6 (2C),
55.6, 53.4, 51.8, 15.2. IR (lm, NaCl, cmꢂ1): 3059, 2989, 2836,
2363, 1615, 1506, 1401, 1244, 1183; HRMS (ES TOF) calculated
for C11H15N2O1 (M + H)+ 191.1179, found 191.1174 (2.6 ppm).
C
17H27N2O1 (M + H)+ 275.2118, found 285.2113 (2.0 ppm).
2-Heptyl-5-methyl-4,5-dihydro-1H-imidazole (4dd)
This compound was prepared according to the typical proce-
dure employing (ꢃ)-1,2-diaminopropane (2d) (82 mL, 74 mg,
1.00 mmol), 1-nitrooctane (1d) (346 mL, 318 mg, 2.00 mmol),
and phosphorous acid (500 mg). The crude material was puri-
ed by preparative column chromatography on silica gel eluting
rst with acetone/Et3N (9 : 1) to remove impurities following by
acetone/20% aq. ammonia (6 : 1) to collect the target molecule.
The titled compound was isolated as a yellowish oil, Rf 0.37
1-Benzyl-2-methyl-4,5-dihydro-1H-imidazole (4bc)
This compound was prepared according to the typical proce-
dure employing N-benzyl-1,2-ethylenediamine (2c) (151 mL,
150 mg, 1.00 mmol), nitroethane (1b) (144 mL, 150 mg, 2.00
mmol), and phosphorous acid (500 mg). The crude material was
puried by preparative column chromatography on silica gel
eluting with EtOH/EtOAc/Et3N (5 : 3 : 1). The titled compound
was isolated as a yellowish oil, Rf 0.43 (EtOAc/Et3N, 10 : 1). Yield
103 mg (0.59 mmol, 59%). 1H NMR (400 MHz, CDCl3): d ¼ 7.43–
7.27 (m, 3H), 7.22 (d, J ¼ 7.0 Hz, 2H), 4.33 (s, 2H), 3.72 (t, J ¼
9.8 Hz, 2H), 3.30 (t, J ¼ 9.7 Hz, 2H), 2.10 (s, 3H). 13C NMR (101
MHz, CDCl3): d ¼ 165.1, 136.6, 129.1 (2C), 128.0, 127.4 (2C),
50.7, 50.0, 49.8, 14.0. IR (lm, NaCl, cmꢂ1): 3030, 2870, 2834,
2361, 1619, 1495, 1418, 1274, 1250, 1029; HRMS (ES TOF)
calculated for C11H15N2 (M + H)+ 175.1230, found 175.1232
(ꢂ1.2 ppm).
1
(acetone/Et3N, 10 : 1). Yield 78 mg (0.43 mmol, 43%). H NMR
(400 MHz, CDCl3): d ¼ 4.01–3.84 (m, 1H), 3.70 (t, J ¼ 10.5 Hz,
1H), 3.15 (dd, J ¼ 11.2, 7.3 Hz, 1H), 2.22 (t, J ¼ 7.8 Hz, 2H), 1.57
(dd, J ¼ 14.6, 7.1 Hz, 2H), 1.33–1.21 (m, 8H), 1.18 (d, J ¼ 6.3 Hz,
3H), 0.84 (t, J ¼ 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): d ¼
167.3, 56.7, 56.2, 31.8, 29.4, 29.3, 29.1, 26.8, 22.7, 21.9, 14.2. IR
(lm, NaCl, cmꢂ1): 2938, 2862, 1711, 1559, 1402, 1250, 1009;
HRMS (ES TOF) calculated for C11H23N2 (M + H)+ 183.1856,
found 183.1854 (0.8 ppm).
2-Benzyl-1-phenyl-4,5-dihydro-1H-imidazole (4ea)
1-Phenyl-4,5-dihydro-1H-imidazole (4ca)
This compound was prepared according to the typical proce-
dure employing N-phenyl-1,2-ethylenediamine (2a) (129 mL,
136 mg, 1.00 mmol), 1-phenyl-2-nitroethane (1e) (269 mL,
302 mg, 2.00 mmol), and phosphorous acid (500 mg). The crude
material was puried by preparative column chromatography
on silica gel eluting with EtOAc/hexanes/Et3N (4 : 4 : 0.5). The
titled compound was isolated as a yellowish oil, Rf 0.28 (EtOAc/
hexanes/Et3N, 4 : 4 : 0.5). Yield 97 mg (0.41 mmol, 41%). 1H
NMR (400 MHz, CDCl3): d ¼ 7.31 (t, J ¼ 7.8 Hz, 2H), 7.25–7.13
(m, 4H), 7.11 (d, J ¼ 6.7 Hz, 2H), 7.06–6.99 (m, 2H), 3.93–3.79
(m, 4H), 3.66 (s, 2H). 13C NMR (101 MHz, CDCl3): d ¼ 164.2,
141.2, 136.0, 129.4 (2C), 128.9 (2C), 128.5 (2C), 126.8, 125.6,
124.4 (2C), 53.3, 51.8, 34.6. IR (lm, NaCl, cmꢂ1): 3323, 3042,
2942, 1651, 1603, 1499, 1262; HRMS (ES TOF) calculated for
This compound was prepared according to the typical proce-
dure employing N-phenyl-1,2-ethylenediamine (2a) (129 mL,
136 mg, 1.00 mmol), nitromethane (1c) (269 mL, 305 mg, 5.00
mmol), and phosphorous acid (500 mg). The crude material was
puried by preparative column chromatography on silica gel
eluting with acetone/EtOAc/Et3N (1 : 6 : 0.3). The titled
compound was isolated as a yellowish oil, Rf 0.36 (acetone/
EtOAc/Et3N, 1 : 6 : 0.5). Yield 41 mg (0.28 mmol, 28%). 1H NMR
(400 MHz, CDCl3): d ¼ 8.22 (s, 1H), 7.19 (t, J ¼ 7.9 Hz, 2H), 6.73
(t, J ¼ 7.3 Hz, 1H), 6.63 (d, J ¼ 7.7 Hz, 2H), 3.56 (dd, J ¼ 11.6,
5.9 Hz, 2H), 3.33 (t, J ¼ 5.8 Hz, 2H). 13C NMR (101 MHz, CDCl3):
d ¼ 161.9, 147.9, 129.5 (2C), 118.1, 113.0 (2C), 43.9, 37.9. IR
(lm, NaCl, cmꢂ1): 3351, 3054, 2874, 1663, 1603, 1507, 1386,
1326, 1254, 877, 753; HRMS (ES TOF) calculated for C9H11N2 (M
+ H)+ 147.0917, found 147.0920 (ꢂ2.4 ppm).
C
16H17N2 (M + H)+ 237.1386, found 237.1391 (ꢂ2.2 ppm).
1,2-Diphenyl-4,5-dihydro-1H-imidazole (4fa)
2-Heptyl-1-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole (4db)
This compound was prepared according to the typical proce-
This compound was prepared according to the typical proce- dure employing N-phenyl-1,2-ethylenediamine (2a) (129 mL,
dure employing N-(4-methoxyphenyl)ethylenediamine (2b) (153 136 mg, 1.00 mmol), a-nitrotoluene (1f) (274 mg, 2.00 mmol),
mL, 166 mg, 1.00 mmol), 1-nitrooctane (1d) (346 mL, 318 mg, and phosphorous acid (500 mg). The crude material was puri-
2.00 mmol), and phosphorous acid (500 mg). The crude mate- ed by preparative column chromatography on silica gel eluting
rial was puried by preparative column chromatography on with acetone/EtOAc/Et3N (1 : 8 : 0.3). The titled compound was
silica gel eluting with hexanes/EtOAc/EtOH/Et3N, 10 : 1 : 1 : 1. isolated as a yellowish oil, Rf 0.41 (acetone/EtOAc/Et3N,
1
The titled compound was isolated as a yellowish oil, Rf 0.68 1 : 8 : 0.3). Yield 40 mg (0.18 mmol, 18%). H NMR (400 MHz,
(hexanes/EtOAc/EtOH/Et3N, 6 : 1 : 1 : 1). Yield 145 mg CDCl3): d ¼ 7.51–7.45 (m, 2H), 7.38–7.32 (m, 1H), 7.30–7.24 (m,
(0.53 mmol, 53%). 1H NMR (400 MHz, CDCl3): d ¼ 7.06 (d, J ¼ 2H), 7.16 (t, J ¼ 7.9 Hz, 2H), 6.98 (t, J ¼ 7.4 Hz, 1H), 6.79 (d, J ¼
8.9 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H), 3.92–3.70 (m, 7H), 2.24–2.15 7.6 Hz, 2H), 4.04 (s, 4H). 13C NMR (101 MHz, CDCl3): d ¼ 162.7,
(m, 2H), 1.59–1.49 (m, 2H), 1.30–1.11 (m, 8H), 0.83 (t, J ¼ 6.8 Hz, 143.1, 131.1, 130.1, 128.8 (2C), 128.8 (2C), 128.3 (2C), 123.5,
3H). 13C NMR (101 MHz, CDCl3): d ¼ 167.4, 158.1, 133.8, 126.7 122.7 (2C), 54.1, 53.0. IR (lm, NaCl, cmꢂ1): 3299, 3050, 2946,
(2C), 114.8 (2C), 55.6, 54.06, 50.6, 31.7, 29.4, 28.9, 27.9, 26.6, 2862, 1599, 1495, 1386, 1270; HRMS (ES TOF) calculated for
22.7, 14.2. IR (lm, NaCl, cmꢂ1): 2954, 2871, 2840, 1616, 1511,
C
15H15N2 (M + H)+ 223.1230, found 223.1233 (ꢂ1.2 ppm).
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The same material was obtained employing a-nitro-
acetophenone (1g) (330 mg, 2.00 mmol) instead of a-nitro-
toluene (1f). Yield 80 mg (0.36 mmol, 36%).
Notes and references
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This compound was prepared according to the typical proce-
dure employing N-(4-methoxyphenyl)ethylenediamine (2b) (153
mL, 166 mg, 1.00 mmol), a-nitrotoluene (1f) (274 mg, 2.00
mmol), and phosphorous acid (500 mg). The crude material was
puried by preparative column chromatography on silica gel
eluting with acetone/EtOAc/Et3N (1 : 8 : 0.3). The titled
compound was isolated as a yellowish oil, Rf 0.35 (acetone/
EtOAc/Et3N, 1 : 8 : 0.3); Rf 0.25 (EtOAc/EtOH 1 : 1); Rf 0.57
(acetone/EtOAc/Et3N, 4 : 4 : 0.5). Yield 40 mg (0.16 mmol, 16%).
1H NMR (400 MHz, CDCl3): d ¼ 7.50 (d, J ¼ 7.3 Hz, 2H), 7.37 (t, J
¼ 7.4 Hz, 1H), 7.29 (d, J ¼ 7.7 Hz, 2H), 6.87 (d, J ¼ 8.9 Hz, 2H),
6.76 (d, J ¼ 8.9 Hz, 2H), 4.14–4.05 (m, 4H), 3.75 (s, 3H). 13C NMR
(101 MHz, CDCl3): d ¼ 164.1, 157.4, 134.9, 131.1, 129.2 (2C),
128.53, 128.47 (2C), 125.8 (2C), 114.6 (2C), 55.6, 55.2, 50.4. IR
(lm, NaCl, cmꢂ1): 3002, 2840, 2363, 1615, 1511, 1388, 1248,
1179, 1039; HRMS (ES TOF) calculated for C16H17N2O1 (M + H)+
253.1335, found 253.1339 (ꢂ1.5 ppm).
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The same material was obtained employing a-nitro-
acetophenone (1g) (330 mg, 2.00 mmol) instead of a-nitro-
toluene (1f). Yield 103 mg (0.41 mmol, 41%).
2-Phenyl-4,5-dihydro-1H-imidazole (4ff)
This compound was prepared according to the typical proce-
dure employing N-benzyl-1,2-ethylenediamine (2c) (151 mL,
150 mg, 1.00 mmol), a-nitroacetophenone (1g) (330 mg, 2.00
mmol), and phosphorous acid (500 mg). The crude material was
puried by preparative column chromatography on silica gel
eluting with acetone/EtOAc/Et3N (4 : 4 : 0.3). The titled
compound was isolated as a yellowish oil, Rf 0.35 (acetone/
EtOAc/Et3N, 4 : 4 : 0.5). Yield 55 mg (0.38 mmol, 38%). 1H NMR
(400 MHz, CDCl3): d ¼ 7.78 (d, J ¼ 7.1 Hz, 2H), 7.40 (dt, J ¼ 23.1,
7.2 Hz, 3H), 3.75 (s, 4H). 13C NMR (101 MHz, CDCl3): d ¼ 165.0,
130.9, 130.3, 128.5 (2C), 127.2 (2C), 50.1 (2C). IR (lm,
NaCl, cmꢂ1): 3051, 2875, 2368, 1685, 1598, 1572, 1493, 1380,
1275; HRMS (ES TOF) calculated for C9H11N2 (M + H)+ 147.0917,
found 147.0919 (ꢂ1.5 ppm).
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Conflicts of interest
There are no conicts to declare.
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I. V. Aksenova and M. Rubin, Org. Biomol. Chem., 2015, 13,
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Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (grant #19-03-00308a) and grants from the Ministry of
Education and Science of the Russian Federation #4.1196.2017/
4.6 and #4.4589.2017/6.7.
21 A. V. Aksenov, N. A. Aksenov, D. S. Ovcharov, D. A. Aksenov,
G. Griaznov, L. G. Voskressensky and M. Rubin, RSC Adv.,
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39464 | RSC Adv., 2019, 9, 39458–39465
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RSC Adv., 2019, 9, 39458–39465 | 39465