Benzimidazoles and benzoxazoles via the nucleophilic addition of anilines to nitroalkanes

Article abstract of DOI:10.1039/c5ob00131e

PPA-induced umpolung triggers efficient nucleophilic addition of unactivated anilines to nitroalkanes to produce N-hydroxyimidamides. The latter undergo sequential acid-promoted cyclocondensation with ortho-OH or ortho-NHR moieties to afford benzoxazoles

Full text of DOI:10.1039/c5ob00131e

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Benzimidazoles and benzoxazoles via the
nucleophilic addition of anilines to nitroalkanes†
Cite this: DOI: 10.1039/c5ob00131e
Alexander V. Aksenov,*a Alexander N. Smirnov,a Nicolai A. Aksenov,a
Asiyat S. Bijieva,a Inna V. Aksenovaa and Michael Rubin*a,b
Received 22nd January 2015,
Accepted 2nd March 2015
PPA-induced umpolung triggers efficient nucleophilic addition of unactivated anilines to nitroalkanes to
produce N-hydroxyimidamides. The latter undergo sequential acid-promoted cyclocondensation with
ortho-OH or ortho-NHR moieties to afford benzoxazoles and benzimidazoles, respectively.
DOI: 10.1039/c5ob00131e
www.rsc.org/obc
Introduction
It is hard to overstate the importance of benzimidazole and
benzoxazole scaffolds for modern bioorganic and medicinal
chemistry. Out of over 1.2 million and 300 000 benzimidazoles
and benzoxazoles, respectively, listed in the SciFinder data-
base, more than 400 000 were used in biological studies.
Several best-selling drugs, such as antiulcerants Nexium
(esomeprazole),1 Prevacid (lansoprazole),2 and Aciphex (rabe-
prazole);3 antihypertensives Micardis (telmisartan)4 and Bend-
azol;5 anticoagulant agent Pradaxa (dabigartan);6 and
anticancer drug Treanda (bendamustine)7 possess this versa-
tile pharmacophore (Fig. 1).
Classical approaches to imidazoles and oxazoles involve
cyclocondensations of carboxylic acid derivatives (esters, ortho-
esters, acyl chlorides, etc.) with 1,2-phenylenediamines or
2-aminophenols, respectively.8 These approaches rely on the
efficiency of initial nucleophilic attack by the aniline moiety at
an activated carbonyl group. Alternative routes via oxidative
cyclocondensation with aldehydes take advantage of the
enhanced reactivity of these electrophiles.9 Condensations
with less electrophilic carbonyl species, such as carboxylic
acids can also be carried out in concentrated organic or
mineral acids, although the require harsh conditions.10 Herein
we wish to report an alternative efficient approach to benzimi-
dazole and benzoxazole heterocyclic cores employing unusual
electrophilic behaviour of nitroalkanes activated with polyphos-
phoric acid.
Fig. 1 Best-selling drugs with benzimidazole cores.
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation. E-mail: alexaks05@rambler.ru;
Tel: +7 (918) 743-0255
Results and discussion
bDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence,
In our prior research we have studied the behavior of nitro
compounds in polyphosphoric acid (PPA)11 and came across
unusual reactivity of nitroalkanes 1 in reactions with electron-
rich arenes. Treatment of 1 with PPA converted these normally
KS 66045-7582, USA. E-mail: mrubin@ku.edu; Fax: +1 (785) 864-5396;
Tel: +1 (785) 864-5071
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, physico-chemical and spectral data. See DOI: 10.1039/c5ob00131e
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Scheme 2
Scheme 1
sterically demanding methyl substituent in the ortho-position
of the aromatic rings afforded nearly pure tautomer 10db
(Scheme 2).
Having optimized the nucleophilic amination step, we
attempted to incorporate it into a heteroannulation cascade.
Accordingly, substrates 12 or 13 possessing heteroatom-based
nucleophilic ortho- substituents (XH = OH or NH2, Scheme 3)
were subjected to the standard reaction conditions. It was
anticipated that the initially-formed imidamide 14 (in proto-
nucleophilic species into electrophilic phosphorylated aci
forms 2. This umpolung activated nitroalkane towards attack
by electron-rich arene 3. Subsequent elimination of H3PO4 pro-
vided oxime intermediates 4. Aldoximes 4 (R = H) obtained in
reactions with nitromethane typically undergo elimination of a
second molecule of H3PO4 to form nitriles which, after acid-
mediated hydrolysis, provide primary amides 5 or parent car-
boxylic acids (path a, Scheme 1).12 Ketoximes 4 (R = Alk)
resulted from reactions with higher nitroalkanes undergo a
Beckman rearrangement to afford the corresponding anilides
6 (path b, Scheme 1).13 We rationalized that anilines can also
be employed in a similar transformation as nitrogen-based
nucleophiles to produce imidamides 8–9 (Scheme 1), which
can further be employed as convenient building blocks for the
synthesis of heterocyclic compounds.
This idea was realized upon heating a mixture of aniline
(7a) with 5 equiv. of nitromethane (1a) in 86% PPA at 100 °C
for 14 h. The expected transformation proceeded smoothly
affording, after quenching with aqueous ammonia, crystalline
N-phenylformimidamide in good yield. Next, we examined the
reactivity of anilines towards higher nitroalkanes. To this end,
mixtures of anilines 7a–d and nitroethane (1b, 1.25 equiv.)
were stirred in PPA at 105 °C for 5 h. In all these cases the
corresponding N-phenylacetimidamides were obtained in good
to excellent yields as crystalline solids upon simple dilution of
the reaction mixtures with aqueous ammonia (Scheme 2).
Interestingly, NMR spectra of the products in DMSO-d6
showed mixtures of slowly exchanging tautomers 10 and 11
(Scheme 2), which averaged out upon heating of the sample to
110 °C or in the presence of TFA. We also found that the tauto-
meric ratio 10 : 11 was dependent on the electronic properties
of the aromatic ring in the aniline reagent. Thus, the parent
aniline (7a) provided a 1 : 1 tautomeric mixture of 10ba/11ba.
Introduction of electron withdrawing (Br) and electron-donat-
ing (OMe) substituents shifted the equilibria towards tauto-
mers 11 (10bb : 11bb = 39 : 61) or 10 (10cb : 11cb = 68 : 32),
respectively (Scheme 2). Employment of aniline 7d with the
Scheme 3
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nated form) would undergo a nucleophilic ring closure to
furnish cyclic aminal 15, which after subsequent acid-
promoted elimination of hydroxylamine would afford the
corresponding heterocyclic products, benzoxazoles 16 (X = O)
or benzimidazoles 17 (X = NH), respectively (Scheme 3).
This strategy proved to be very fruitful. Thus, the reaction
between 2-aminophenol (12a) and nitromethane (1a) in PPA
produced benzoxazole (16aa) in high yield. 1,2-Diamino-
benzene (13a) afforded benzimidazole (17aa) under the same
conditions (Scheme 3). It should be pointed out that the large
excess of nitromethane (5 equiv.) used in both cases was
necessary to compensate for significant loss of reagent due to
evaporation in the employed reaction set up.14 Less volatile
nitroalkanes were used in only 10% excess, which was
sufficient for ensuring complete conversions. It also allowed
for carrying out the reaction at higher temperatures, which
further improved the reaction efficiency. Treatment of amino-
phenols 12a,b and diaminobenzenes 13a,b with nitroethane
1b afforded the corresponding benzoxazoles 16ba, 16bb and
benzimidazoles 17ba, 17bb in excellent yields (Scheme 3).
Further increase of reaction temperature to 140–150 °C was
necessary to engage of the less reactive, sterically demanding
(nitromethyl)benzene (1c) and (2-nitroethyl)benzene (1d) to
obtain the corresponding 2-phenyl- (16ca, 17ca) and 2-benzyl-
substituted products 16da and bendazole (17da) in high
yields.
Scheme 4
To further showcase the synthetic usefulness of the develo-
ped method and its competitiveness with existing protocols,
we attempted synthesis of N-substituted benzimidazoles. First,
we probed the reaction of nitromethane (1a) and nitroethane
(1b) with N-monomethylated phenylenediamine (13c). Both
reactions afforded N-methylbenzimidazoles (17ac and 17bc) in
high yields (Scheme 3). Under the same conditions a more
sterically hindered 13d efficiently provided the corresponding
N-benzylated product 17bd (Scheme 3).
Interestingly, attempts to synthesize 2-acylsubstituted
azoles by reacting anilines 12a, 13a, and 13c with 2-nitro-
1-phenylethan-1-one (1e) did not provide the expected pro-
ducts 16ea, 17ea, and 17ec. Instead, 2-phenylsubstituted
azoles 16ca, 17ca, and 17cc were obtained in excellent yields
(Scheme 4). We believe that this transformation proceeded via
the initial formation of iminium intermediate 18, followed by
intramolecular nucleophilic attack to give cyclic aminal 19.
The latter further undergoes nucleofugal cleavage of nitro-
methane to produce 16ca and 17ca (Scheme 4). Apparently,
this alternative reactivity results from the superior electrophili-
city of the ketone carbonyl function compared to the aci form
of the nitroalkane.
Scheme 5
yields (Scheme 5), although required extended reaction times
as compared to single-fold cyclizations described above.
Conclusions
We have also explored the possibility of furnishing bis-imi- In conclusion, we demonstrated that PPA-induced umpolung
dazoles 19, potentially useful as precursors for chelating NHC activates the α-carbon of nitroalkanes towards addition of
ligands broadly used in transition metal catalysis and material nitrogen-based nucleophiles. This transformation was used to
science applications.15 Using our methodology these scaffolds design an efficient method for the synthesis of oxazoles and
can be accessed via a double-fold nucleophilic cyclization of imidazoles. The synthetic usefulness of this method was
tethered bis(1,2-phenylenediamines) 18 with 2 equivalents of demonstrated in a concise synthesis of antihypertensive drug
an appropriate nitroalkane (Scheme 5). Indeed, the corres- bendazole (17da). A double-fold cyclization can be employed
ponding tethered bis-imidazoles 19 were isolated in excellent for efficient synthesis of tethered bis-imidazoles.
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(2C), 16.1. 1H NMR (DMSO-d6, CF3COOH) δ, ppm: 10.54 (s,
1H), 7.46–7.43 (m, 2H), 7.36–7.32 (m, 3H), 2.05 (s, 3H); 13C
NMR (DMSO-d6, CF3COOH) δ, ppm: 157.3, 135.9, 129.3 (2C),
Experimental part
General information
1H and 13C NMR spectra were recorded on a Bruker Avance-III 127.2, 126.0 (2C), 14.2; IR, cm−1: 3373, 3312, 3004, 1669, 1631,
spectrometer (400 or 100 MHz, respectively) equipped with 1594, 1494, 1363, 1314, 1236, 1030, 907, 806, 752, 686; HRMS
BBO probe in CDCl3 or DMSO-d6, using TMS as internal calcd for C8H11N2O (M + H)+: 151.0871, found 151.0869.
standard. High-resolution mass spectra were registered with a
N-(4-Bromophenyl)-N′-hydroxyacetimidamide (10bb, 11bb).
Bruker Maxis spectrometer (electrospray ionization, in MeCN This material was obtained as colorless crystalline solid, mp
solution, using HCO2Na–HCO2H for calibration). Melting 143–144 °C (water) in a yield 403 mg (1.76 mmol, 88%); 10bb:
points were measured with a Stuart smp30 apparatus. All reac- 1H NMR (DMSO-d6) δ, ppm: 9.26 (br. s, 1H), 8.21 (br. s, 1H),
tions were performed in oven-dried drum vials open to the 7.45 (d, J = 8.90 Hz, 2H), 7.33 (d, J = 8.90 Hz, 2H), 1.96 (s, 3H);
atmosphere employing overhead stirring. Reaction progress 13C NMR (DMSO-d6) δ, ppm: 151.8, 141.4, 131.0 (2C), 119.4
and purity of isolated compounds were controlled by TLC on (2C), 110.6, 14.1; 11bb: 1H NMR (DMSO-d6) δ, ppm: 9.60 (br. s,
Silufol UV-254 plates, eluting with EtOAc. Flash column 1H), 8.05 (br. s, 1H), 7.40 (d, J = 8.74 Hz, 2H), 7.06 (d, 8.74 Hz,
chromatography was performed on silica gel (32–63 μm, 60 Å 2H), 1.87 (s, 3H); 13C NMR (DMSO-d6) δ, ppm: 146.6, 139.8,
pore size).
131.4 (2C), 123.9 (2C), 114.2, 16.1; IR, cm−1: 3383, 3111, 2976,
Nitroacetophenone (1e),16 2-phenylnitroethane (1d),17 phe- 2360, 1659, 1585, 1543, 1491, 1421, 1387, 1341, 1313, 1299,
nyitromethane (1c),18 1,3-bis(2-aminophenylamino)propane 1275, 1261, 1236, 1212, 1073, 947, 914, 841, 822, 757; HRMS
(18a),19 1,4-bis(2-aminophenylamino)butane (18b),19 and N,N′- calcd for C8H10BrN2O (M + H)+: 228.9977, found 228.9968.
bis(2-aminophenyl)-1,4-benzenedimethanamine (18c)20 were
N′-Hydroxy-N-(4-methoxyphenyl)acetimidamide
(10cb,
synthesized according to published procedures. All other 11cb).23 This material was obtained as colorless crystalline
reagents and solvents were purchased from commercial solid, mp 150–152 °C (water) in a yield 310 mg (1.72 mmol,
1
vendors and used as received.
86%); 10cb: H NMR (DMSO-d6) δ, ppm: 9.30 (br. s, 1H), 7.60
N-Hydroxy-N′-arylformimidamides (10, 11) (general pro- (br. s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.72
cedure). Mixture of aniline (2 mmol) and nitroalkane (s, 3H), 1.73 (s, 3H); 13C NMR (DMSO-d6) δ, ppm: 156.2, 148.5,
(2.5 mmol of nitroethane or 10 mmol of nitromethane) in PPA 133.6, 125.8 (2C), 114.4 (2C), 55.5, 16.2; 11cb: 1H NMR (DMSO-
(4 g, 86% P2O5) was vigorously stirred. Reactions with nitro- d6) δ, ppm: 8.95 (br. s, 1H), 7.77 (br. s, 1H), 7.41 (d, J = 9.00 Hz,
methane and nitroethane were heated for 14 h at 100 °C or for 2H), 6.77 (d, J = 9.0 Hz, 1H), 3.67 (s, 3H), 1.94 (s, 3H); 13C NMR
5 h at 110 °C, respectively. When TLC analysis confirmed con- (DMSO-d6) δ, ppm: 153.2, 152.5, 136.1, 119.4 (2C), 114.1 (2C),
sumption of starting aniline, the mixture was cooled down to 55.6, 14.5; IR, cm−1: 3386, 3314, 3216, 1636, 1560, 1491, 1441,
80 °C and diluted with water (10 mL). The mixture was neutral- 1420, 1370, 1333, 1300, 1260, 1229, 1182, 1034, 825, 811, 763,
ized with 20% aqueous ammonia (to pH ∼ 9, ca. 25 mL), 712; HRMS calcd for C9H13N2O2 (M + H)+: 181.0977, found
heated to reflux, and filtered. The filtrate was then cooled 181.0976.
down to 0 °C, and formed crystalline precipitate was collected
by suction filtration. Analytically pure samples were obtained material was obtained as colorless crystalline solid, mp
by second crystallization from water.
104–105 °C (water) in a yield 240 mg (1.46 mmol, 73%); 1H
N′-Hydroxy-N-(o-tolyl)acetimidamide (10db, 11db). This
N-Hydroxy-N′-phenylformimidamide (10aa, 11aa).21 This NMR (DMSO-d6) δ, ppm: 9.37, (br. s, 1H), 7.60 (br. s, 1H), 7.21
material was obtained as colorless crystalline solid, mp (d, J = 7.4 Hz, 1H), 7.16 (dd, J = 7.4, 6.8 Hz, 1H), 7.08 (d, J = 6.8
127–129 °C (water) in a yield 212 mg (1.56 mmol, 78%); 1H Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 2.20 (s, 3H), 1.64 (s, 3H); 13C
NMR (DMSO-d6) δ, ppm: 9.83 (br. s, 1H), 8.52 (d, J = 10.4 Hz, NMR (DMSO-d6) δ, ppm: 148.5, 139.0, 133.5, 130.8, 126.7,
1H), 7.44 (d, J = 10.4 Hz, 1H), 7.12–7.21 (m, 4H), 6.83 (t, J = 126.6, 125.2, 18.1, 16.1; IR, cm−1: 3366, 3085, 2981, 2794, 1638,
7.1 Hz, 1H); 13C NMR (DMSO-d6) δ, ppm: 147.6, 140.7, 129.1 1610, 1517, 1488, 1432, 1393, 1354, 1314, 1274, 1131, 1032,
(2C), 123.0, 122.7 (2C); NMR spectra are averaged at RT. IR, 931, 830, 807, 707; HRMS calcd for C9H13N2O (M + H)+:
cm−1: 3378, 3312, 3015, 1695, 1635, 1594, 1465, 1363, 1326, 165.1028, found 165.1025.
911, 809, 765; HRMS calcd for C7H9N2O (M + H)+: 137.0715,
found 137.0712.
Synthesis of benzoxazoles 16 (general procedure). A mixture
of o-aminophenol (2 mmol) and nitroalkane (2.5 mmol) in
N′-Hydroxy-N-phenylacetimidamide (10ba, 11ba).22 This PPA (4 g, 86% P2O5) was vigorously stirred and heated to the
material was obtained as colorless crystalline solid, mp specified temperature. The reactions with nitromethane (1a,
114–115 °C (water) in a yield 282 mg (1.88 mmol, 94%); 10ba: 10 mmol) were carried out at 100 °C for 14 h. Reactions with
1H NMR (DMSO-d6) δ, ppm: 9.11 (br. s, 1H), 7.85 (br. s, 1H), nitroethane (1b) were carried at 105–110 °C for 3 h. Reactions
7.25–7.24 (m, 2H), 7.09 (d, J = 7.13 Hz, 2H), 7.00 (t, J = 5.96 Hz, with 1-nitro-2-phenylethane and phenylnitromethane were
1H), 1.86 (s, 1H); 13C NMR (DMSO-d6) δ, ppm: 151.9, 142.1, carried out at 150 °C for 7 h. When TLC analysis confirmed
128.3 (2C), 122.2, 117.5 (2C), 14.1. 11ba: 1H NMR (DMSO-d6) the completion of the reaction the mixture was cooled down to
δ, ppm: 9.49 (br. s, 1H), 7.99 (br. s, 1H), 7.49 (d, J = 7.3 Hz, 80 °C and diluted with water (25 mL) and neutralized with
2H), 7.19–7.15 (m, 2H), 6.78 (t, J = 6.1 Hz, 1H), 1.96 (s, 3H); 13
NMR (DMSO-d6) δ, ppm: 147.1, 140.2, 128.8 (2C), 122.6, 119.5 extracted with CH2Cl2 (4 × 15 mL). Combined organic phases
C
20% aqueous ammonia (to pH ∼ 9, ca. 25 mL), and then
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were dried with CaCl2, filtered, and concentrated in vacuum. IR, cm−1: 2355, 2342, 1460, 1411, 1274, 1245, 753, 745; HRMS
Flash column chromatography on Silica gel eluting with calcd for C7H7N2 (M + H)+: 119.0609, found 119.0619.
mixture of n-hexane and ethyl acetate (gradient from 9 : 1 to
2-Methyl-1H-benzimidazole (17ba).29 This material was
5 : 5) afforded the corresponding product. Physical and spec- obtained as colorless crystals, mp 177–178 °C (ethanol) in a
1
tral properties of all the synthesized materials were identical to yield 240 mg (1.82 mmol, 91%). H NMR (CDCl3) δ, ppm: 7.56
those previously reported in literature.
(dd, J = 5.9, 3.2 Hz, 2H) 7.24 (dd, J = 6.0, 3.2 Hz, 2H), 6.0 (br. s,
Benzoxazole (16aa).24 This material was obtained as color- 1H), 2.68 (3H); 13C NMR (CDCl3) δ, ppm: 151.1, 137.6 (2C),
less oil that solidified upon standing. Yield 210 mg 122.9 (2C), 114.5 (2C), 14.7; IR, cm−1: 2685, 1557, 1446, 1437
(1.76 mmol, 88%); 1H NMR (CDCl3) δ, ppm: 7.30–7.40 (2H, m), 1417, 1387, 1361, 1273, 1218, 1025, 848, 830, 730; HRMS calcd
7.51–7.60 (1H, m), 7.74–7.83 (1H, m); 8.09 (1H, s); 13C NMR for C8H9N2 (M + H)+: 133.0766, found 133.0765.
(CDCl3) δ, ppm: 111.0, 120.6, 124.7, 125.7, 140.0, 150.0, 152.6;
2-Methyl-5-nitro-1H-benzimidazole (17bb).30 This material
was obtained as colorless crystals, mp 198–199 °C (ethanol) in
HRMS calcd for C7H6NO (M + H)+: 120.0449, found 120.0438.
2-Methylbenzoxazole (16ba).25 This material was obtained a yield 329 mg (1.86 mmol, 93%). 1H NMR (CDCl3) δ, ppm:
as colorless oil, yield 242 mg (1.82 mmol, 91%). 1H NMR 8.36 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 8.8, 2.2 Hz, 1H), 7.63 (d,
(CDCl3) δ, ppm: 2.61 (3H, s), 7.20–7.30 (2H, m), 7.39–7.47 (1H, J = 8.8 Hz, 1H), 2.56 (s, 3H); 13C NMR (CDCl3) δ, ppm: 142.1,
m), 7.58–7.66 (1H, m); 13C NMR (CDCl3) δ, ppm: 14.6, 110.3, 117.2, 14.9; IR, cm−1: 3108, 2974, 2784, 1633, 1544, 1514, 1473,
119.5, 124.3, 124.6, 141.4, 151.1, 164.0; HRMS calcd for 1419, 1383, 1337, 1309, 1270, 1220, 1124, 1065, 1028, 947, 879,
C8H8NO (M + H)+: 134.0606, found 134.0600.
822, 738; HRMS calcd for C8H8N3O2 (M + H)+: 178.0617, found
2,5-Dimethylbenzoxazole (16bb).26 This material was 178.0612.
1
obtained as colorless oil, yield 262 mg (1.78 mmol, 89%). H
2-Phenyl-1H-benzimidazole (17ca).31 This material was
NMR (CDCl3) δ, ppm: 2.44 (3H, s), 2.61 (3H, s), 7.08 (1H, d, J = obtained as colorless crystals, mp 296–297 °C (ethanol) in a
8.5 Hz), 7.32 (1H, d, J = 8.5 Hz), 7.43 (1H, s); 13C NMR (CDCl3) yield 322 mg (1.66 mmol, 83%). 1H NMR (DMSO-d6) δ, ppm:
δ, ppm: 14.6, 21.5, 109.7, 119.4, 125.6, 134.1, 141.6, 149.3, 12.91 (br. s, 1H), 8.19 (d, J = 7.35 Hz, 2H), 7.67–7.47 (m, 5H),
164.1; HRMS calcd for C9H10NO (M + H)+: 148.0762, found 7.21 (d, J = 4.3 Hz, 2H); 13C NMR (DMSO-d6) δ, ppm: 151.2
148.0767.
(2C), 130.2 (2C), 130.2, 128.9 (4C), 126.4 (4C); IR, cm−1: 2366,
2-Phenylbenzoxazole (16ca).25 This material was obtained 2342, 1464, 1445, 1410, 1372, 1315, 1276, 1226, 1119, 969, 740,
as colorless oil, yield 335 mg (1.72 mmol, 86%). 1H NMR 701, 684; HRMS calcd for C13H11N2 (M + H)+: 195.0922, found
(DMSO-d6) δ, ppm: 7.37–7.46 (2H, m), 7.57–7.66 (3H, m), 195.0923.
7.75–7.84 (2H, m), 8.16–8.24 (2H, m); 13C NMR (DMSO-d6)
2-Benzyl-1H-benzimidazole
(bendazole,
17da).32 This
δ, ppm: 110.9, 119.8, 124.9, 125.5, 126.4, 127.3 (2C), 129.3 (2C), material was obtained as colorless crystals, mp 186–187 °C
131.9, 141.5, 150.2, 162.2; HRMS calcd for C13H10NO (M + H)+: (benzene) in a yield 350 mg (1.68 mmol, 84%). 1H NMR
196.0762, found 196.0758.
(DMSO-d6) δ, ppm: 12.28 (br. s, 1H), 7.48 (dd, J = 5.2, 3.2 Hz,
2-Benzyl-5-methylbenzoxazole (16db).27 This material was 2H), 7.36–7.29 (m, 4H), 7.25–7.20 (m, 1H), 7.14–7.10 (m, 2H),
obtained as colorless oil, yield 372 mg (1.66 mmol, 83%). H 4.17 (s, 2H); 13C NMR (DMSO-d6) δ, ppm: 153.5 (2C), 137.7
1
NMR (CDCl3) δ, ppm: 2.39 (3H, s), 4.20 (2H, s), 7.02–7.06 (1H, (2C), 128.8 (3C), 128.5 (3C), 126.5, 121.3 (2C), 34.9; IR, cm−1
:
d, J = 8.5 Hz), 7.18–7.34 (6H, m), 7.42 (1H, s); 13C NMR 2360, 2342, 1422, 1268, 1022, 1010, 927, 766, 745, 722, 692,
(CDCl3) δ, ppm: δ 21.6, 35.4, 110.0, 119.7, 126.0, 127.4, 129.0 669; HRMS calcd for C14H13N2 (M + H)+: 209.1079, found
(2C), 129.1 (2C), 134.3, 134.9, 141.2, 149.4, 165.5; HRMS calcd 209.1076.
for C15H14NO (M + H)+: 224.1075, found 224.1067.
1-Methyl-1H-benzoimidazole (17ac). Mp 59–62 °C (hexane);
Synthesis of benzimidazoles 17 (general procedure). A 1H NMR (CDCl3) δ, ppm: 7.72–7.71 (m, 2H), 7.26–7.14 (m, 3H),
mixture of o-phenylenediamine (2 mmol) and nitroalkane 3.63 (s, 3H); 13C NMR (CDCl3) δ, ppm: 143.4, 143.3, 122.8,
(2.5 mmol) in PPA (4 g, 86% P2O5) was vigorously stirred at 122.0, 119.8, 109.3, 30.8; IR, cm−1: 2915, 2851, 1498, 1459,
specified temperature. The reaction progress was monitored by 1424, 1329, 1284, 1249, 1204, 1054, 1003, 886, 775, 739, 719;
TLC. The reactions were carried out for 13 h at 100 °C with HRMS calcd for C8H9N2 (M + H)+: 133.0706, found 133.0761.
nitromethane, for 3 h at 110 °C with nitroethane, for 8 h at
1,2-Dimethyl-1H-benzoimidazole (17bc). Mp 111–112 °C
1
150 °C with phenylnitromethane, and for 11 h at 150 °C with (hexane); H NMR (DMSO-d6) δ, ppm: 7.51 (d, J = 7.5 Hz, 1H),
1-nitro-2-phenylethane. After achieving full conversion the 7.45 (d, J = 7.6 Hz, 1H), 7.19–7.11 (m, 3H), 3.71 (s, 3H), 2. 51 (s,
reaction mixture was cooled down to 80 °C and diluted with 3H); 13C NMR (DMSO-d6) δ, ppm: 152.0, 142.3, 135.8, 121.2,
water (15 mL). Crude mixture was neutralized with 20% 121.0, 118.0, 109.5, 29.6, 13.4; IR, cm−1: 3052, 2941, 1617,
aqueous ammonia (25 mL), cooled down, and the formed 1520, 1511, 1479, 1446, 1396, 1328, 1286, 1234, 1008, 995, 928,
crystalline precipitate was collected by suction filtration.
1H-Benzimidazole (17aa).28 This material was obtained as found 147.0936.
858, 753, 732; HRMS calcd for C9H11N2 (M + H)+: 147.0922,
colorless crystals, mp 170 °C (ethanol) in a yield 203 mg
1-Benzyl-2-methyl-1H-benzoimidazole (17bd). Mp 58–59 °C
(1.72 mmol, 86%). 1H NMR (CDCl3) δ, ppm: 8.31 (br. s, 2H), (petroleum ether); 1H NMR (DMSO-d6) δ, ppm: 7.56 (dd, J =
7.69 (dd, J = 5.9, 3.2 Hz, 2H), 7.31 (dd, J = 6.1, 3.1 Hz, 2H); 13C 5.85, 2.95 Hz, 1H), 7.46 (dd, J = 5.58, 3.27 Hz, 1H), 7.34–7.25
NMR (CDCl3) δ, ppm: 140.5, 136.7 (2C), 123.6 (2C), 115.5 (2C); (m, 3H), 7.16–7.12 (m, 4H), 5.47 (s, 3H), 3.38 (s, 2H); 13C NMR
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(DMSO-d6) δ, ppm: 151.9, 142.4, 137.0, 135.4, 128.9 (2C), 127.5,
1,4-Bis(2-methyl-1H-benzoimidazol-1-yl)butane (19bb). Mp
196–197 °C (diethyl ether); H NMR (CDCl3) δ, ppm: 7.68 (dd,
1
126.6 (2C), 121.6, 121.3, 118.3, 110.0, 46.2, 13.7; IR, cm−1
:
3033, 1619, 1525, 1465, 1452, 1401, 1354, 1330, 1283, 1248, J = 4.6, 1.3 Hz, 1H), 7.24–7.19 (m, 3H), 4.06 (t, J = 4.6 Hz, 2H),
1227, 1154, 1013, 856, 726, 694; HRMS calcd for C15H14N2Na 2.53 (s, H), 1.86–1.83 (m, 2H); 13C NMR (CDCl3) δ, ppm: 151.3,
(M + Na)+: 245.1055, found 245.1053.
142.7, 135.0, 122.3, 122.1, 119.4, 109.0, 43.4, 27.3, 14.1; IR,
Benzoxazoles 16 and benzimidazoles 17 by the reaction with cm−1: 2369, 2336, 1457, 1403, 1360, 1288, 1248, 1008, 787, 738;
nitroacetophenone. A mixture of aniline (12a, 13a, or 13c, HRMS calcd for C20H22N4Na (M + Na)+: 341.1742, found
2 mmol) and nitroacetophenone (1e, 2.2 mmol) in PPA (4 g, 341.1737.
87% P2O5) was vigorously stirred for 3 h at 120 °C monitoring
the reaction progress by TLC. When the reaction was complete,
the mixture was cooled down to 80 °C, diluted with water
(25 mL), and neutralized with 20% aqueous ammonia (25 mL).
Acknowledgements
The resulted solution was cooled down and the formed pre- This work was executed in a frame of the State Assignment to
cipitate was collected by suction filtration. The physical and Higher Education Institutions (Russian Ministry of Education
spectral properties of products 16ca, 17ca obtained in these and Science) and was financially supported by the Russian
experiments were identical to those described above.
Foundation for Basic Research (grant #13-03-00304a).
1-Methyl-2-phenyl-1H-benzoimidazole (17cc). Mp 94–96 °C
1
(hexane); H NMR (CDCl3) δ, ppm: 7.87 (m, 1H), 7.8–7.79 (m,
2H), 7.56–7.50 (m, 3H), 7.42–7.39 (m, 1H), 7.34–7.31 (m, 2H),
3.87 (s, 3H); 13C NMR (CDCl3) δ, ppm: 153.9, 143.1, 136.7,
129.9, 129.6 (2C), 128.8 (2C), 122.9, 122.6, 120.0, 109.7, 31.8;
IR, cm−1: 2365, 2333, 1469, 1440, 1349, 1383, 1278, 1264, 776,
766, 755, 714, 703; HRMS calcd for C14H12N2Na (M + Na)+:
231.0898, found 231.0895.
Notes and references
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136 °C (diethyl ether); H NMR (CDCl3) δ, ppm: 7.89 (s, 1H),
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7.81–7.79 (m, 1H), 7.28–7.23 (m, 3H), 4.16 (t, J = 6.9 Hz, 2H),
2.53–2.46 (m, 1H); 13C NMR (CDCl3) δ, ppm: 143.8 (2C), 142.7,
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(19ab). Mp
174–
175 °C (diethyl ether); 1H NMR (CDCl3) δ, ppm: 7.8 (s, 1H),
7.78–7.76 (m, 1H), 7.29–7.22 (m, 3H), 4.10 (m, 2H), 1.86 (m,
2H); 13C NMR (CDCl3) δ, ppm: 143.9 (2C), 142.8133.6, 123.3
(2C), 122.5 (2C), 120.6 (2C), 109.5 (2C), 44.5, 27.3; IR, cm−1
:
2360, 1495, 1462, 1442, 1384, 1374, 1357, 1333, 1283, 1249,
1196, 1159, 1009, 1002, 880, 771, 752, 742, 736; HRMS calcd
for C18H19N4 (M + H)+: 291.1610, found 291.1608.
1,4-Bis((1H-benzo[d]imidazol-1-yl)methyl)benzene
(19ac).
1
Mp 168–169 °C (diethyl ether); H NMR (CDCl3) δ, ppm: 7.83
(s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.21–7.14 (m, 3H), 7.03 (s, 2H),
5.22 (s, 2H); 13C NMR (CDCl3) δ, ppm: 143.9, 143.1, 135.6,
133.8, 127.7, 123.2, 122.4, 120.5, 109.9, 48.33; IR, cm−1: 2363,
2342, 1489, 1454, 1366, 1352, 1286, 1259, 1169, 777, 766, 744,
740, 731; HRMS calcd for C22H19N4 (M + H)+: 339.1610, found
339.1619.
1,3-Bis(2-methyl-1H-benzoimidazol-1-yl)propane (19ba). Mp
1
226–227 °C (diethyl ether); H NMR (CDCl3) δ, ppm: 7.68 (dd,
J = 4.8, 1.3 Hz, 1H), 7.23–7.18 (m, 3H), 4.05 (t, J = 4.3 Hz, 2H),
2.52 (s, 3H), 1.86–1.83 (m, 1H); 13C NMR (CDCl3) δ, ppm:
151.3, 142.8, 135.0, 122.3, 122.1, 119.4, 109.0, 43.4, 27.3, 14.1;
IR, cm−1: 2948, 1612, 1507, 1457, 1404, 1358, 1332, 1285, 1248,
1159, 1136, 1011, 853, 790, 768, 735; HRMS calcd for C19H21N4
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