N-Alkylation of benzimidazoles with ketonic Mannich bases and the reduction of the resulting 1-(3-oxopropyl)benzimidazoles

Article abstract of DOI:10.2478/s11532-012-0062-x

Benzimidazole, benzimidazoles diversely substituted at position 2, and 5,6-dimethylbenzimidazole have been alkylated at N¹ with ketonic Mannich bases derived from acetophenones, acetylnaphthalenes, 2-acetylthiophene and 1-tetralone to afford a

Full text of DOI:10.2478/s11532-012-0062-x

Cent. Eur. J. Chem. • 10(5) • 2012 • 1516-1526
DOI: 10.2478/s11532-012-0062-x
Central European Journal of Chemistry
N-Alkylation of benzimidazoles with ketonic
Mannich bases and the reduction
of the resulting 1-(3-oxopropyl)benzimidazoles*
Research Article
Gheorghe Roman#
Petru Poni Institute of Macromolecular Chemistry, Iaşi 700487, Romania
Received 29 December 2011; Accepted 19 April 2012
1
Abstract:
Benzimidazole, benzimidazoles diversely substituted at position 2, and 5,6-dimethylbenzimidazole have been alkylated at N with
ketonic Mannich bases derived from acetophenones, acetylnaphthalenes, 2-acetylthiophene and 1-tetralone to afford a series of novel
1-(3-oxopropyl)benzimidazoles. The reduction of these transamination products with NaBH4 in methanol produced the corresponding
1-(3-hydroxypropyl)benzimidazoles in excellent yields.
Keywords: Benzimidazole • Mannich bases • N-alkylation • Reduction
© Versita Sp. z o.o.
1. Introduction
the N-alkylation of benzimidazole with Mannich bases
derived from cycloalkanones, α,β-unsaturated ketones
The ability of Mannich bases to alkylate structurally and acetophenones in ethanol reported modest yields
diverse substrates is a feature of particular interest in of β-keto N-substituted benzimidazoles as reaction
the chemistry of these compounds [2,3]. For instance, products [5,6]. Analogous N-alkylated benzimidazoles
Mannich bases derived from ketones, phenols, or indoles were described in patent literature and were claimed
have been shown to C-alkylate ketones, phenols, or to posses interesting biological activities [7,8]. In
heterocycles such as furan, pyrrole, indole, whereas continuation of our work on the N-alkylation of NH-
thiols and thiocarbamates can act as sulfur-containing heterocycles with Mannich bases [9,10], the current
substrates in an S-alkylation reaction by Mannich paper reports the transamination of ketonic Mannich
bases. N-Alkylation of amines or NH-heterocycles bases and benzimidazoles and their subsequent
with Mannich bases (also known as amine exchange reduction of the resulting to the corresponding alcohols.
reaction, or transamination) is also well documented. In In addition, these ketones with an azole moiety have a
particular, N-alkylation of NH-heterocycles (especially huge potential as intermediates for the synthesis of novel
azoles and their benzo-fused congeners) with ketonic heterocycles such as benzisoxazoles [11] or isoxazoles
Mannich bases, phenolic Mannich bases, or indole and pyrazoles [12], or may present interesting biological
Mannich bases represents an effective approach activities [13,14].
for the synthesis of heterocycles 1, 2, or 3 having at the
nitrogen atom a 3-oxopropyl group, or a 2-hydroxybenzyl
2. Experimental procedure
group, or
a
indol-3-ylmethyl group, respectively
(Scheme 1).
Despite the fact that the scope and the limitation
of this reaction were examined briefly by Tramontini
et al. over 40 years ago [4], a close inspection of the
literature revealed that more comprehensive studies on
this topic are still scarce. A couple of studies presenting
Melting points were taken on a Mel-Temp II apparatus
and are uncorrected. Elemental analysis was conducted
in-house on a PerkinElmer 2400 Series II CHNS/O
1
system. H and 13C NMR spectra were recorded on a
BrukerAvance 400 MHz spectrometer. The signals owing
# E-mail: gheorghe.roman@icmpp.ro
1516
* This communication is Part 22 in the series “Synthesis and reactivity of Mannich bases”; for Part 21, see [1]

G. Roman
Scheme 1. N-Alkylation of NH-azoles with ketonic, phenolic or indole Mannich bases.
to residual protons in the deuterated solvents were (61%), mp 104–105°C (lit. mp 102–103°C [4]); 1H NMR
used as internal standards for the 1H NMR spectra. The (CDCl3): δ 3.51 (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.4 Hz,
chemical shifts for the carbon atoms are given relative to 2H), 7.25–7.34 (m, 2H), 7.40–7.46 (m, 3H), 7.53–7.58
deuteriochloroform (δ = 77.16 ppm) or dimethyl sulfoxide (m, 1H), 7.78–7.82 (m, 1H), 7.88 (d, J = 7.6 Hz, 2H), 8.04
d6 (δ = 39.52 ppm).
(s, 1H); 13C NMR (CDCl3): δ 38.2, 39.5, 109.4, 120.7,
2-Ethylbenzimidazole [15], 2-benzylbenzimidazole 122.3, 123.1, 128.1, 128.9, 133.6, 133.9, 136.2, 143.8,
[16], 2-(1-naphthylmethyl)benzimidazole [17] and 144.0, 196.8; Anal. Calcd. for C16H14N2O: C, 76.78; H,
2-(phenoxymethyl)benzimidazole [18] were prepared 5.64; N, 11.19. Found: C, 76.54; H, 5.81; N, 11.36.
through the Phillips benzimidazole synthesis involving
3-(2-Methyl-1H-benzimidazol-1-yl)-1-phenyl-
the condensation of the appropriate carboxylic acid and 1-propanone (16). Off-white crystals (2-propanol–
ortho-phenylenediamine in 4N HCl. The ketonic Mannich hexanes), yield 605 mg (46%), mp 99–100°C; 1H NMR
bases required in this study were synthesized from the (CDCl3): δ 2.67 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 4.60 (t,
corresponding ketone through an adaptation of the J = 7.2 Hz, 2H), 7.20–7.26 (m, 2H), 7.30–7.37 (m, 1H),
procedure reported [19] for the direct aminomethylation 7.44 (t, J = 7.6 Hz, 2H), 7.54–7.60 (m, 1H), 7.65–7.72 (m,
of acetophenone with paraformaldehyde and 1H), 7.88 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3): δ 14.1,
dimethylamine hydrochloride, and the identity of 38.0, 38.8, 109.1, 119.4, 122.1, 122.3, 128.1, 128.9,
compounds 4–14 was confirmed by comparing their 133.9, 134.9, 136.2, 143.0, 151.7, 197.1; Anal. Calcd.
melting point and NMR data with those reported in for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
the literature [20-31]. All other chemical reagents were 76.92; H, 5.84; N, 10.50.
obtained from Sigma–Aldrich and were used without
3-(5,6-Dimethyl-1H-benzimidazol-1-yl)-1-phenyl-
prior purification.
1-propanone (17). Tan crystals (2-propanol–hexanes),
1
General procedure for the N-alkylation of yield 710 mg (51%), mp 114–115°C; H NMR (CDCl3):
benzimidazoles with hydrochlorides of ketonic δ 2.37 (s, 3H), 2.40 (s, 3H), 3.50 (t, J = 6.8 Hz, 2H),
Mannich bases. The solution of Mannich base 4.61 (t, J = 6.8 Hz, 2H), 7.20 (s, 1H), 7.40–7.48 (m,
hydrochloride (5 mmol) and benzimidazole (5 mmol) in 2H), 7.53–7.60 (m, 2H), 7.86–7.94 (m, 3H); 13C NMR
a mixture of ethanol–water (12 mL, 1:1 v/v) was heated (CDCl3): δ 20.3, 20.7, 38.4, 39.5, 109.6, 120.7, 128.1,
underrefluxfor1h.Thereactionmixturewascooledinan 128.9, 131.1, 132.1, 132.2, 133.8, 136.3, 142.7, 143.0,
ice–water bath under vigorous stirring until crystallization 196.9; Anal. Calcd. for C18H18N2O: C, 77.67; H, 6.52; N,
occurred. The resulting solid was filtered, washed with 10.06. Found: C, 77.49; H, 6.31; N, 10.27.
a mixture of ethanol–water, and recrystallized from the
3-(1H-Benzimidazol-1-yl)-1-(4-chlorophenyl)-
appropriate solvent(s). In the case of compound 50, the 1-propanone (18). Colorless crystals (ethanol), yield
supernatant was removed with a pipette at the end of 955 mg (67%), mp 132–133°C; 1H NMR (CDCl3): δ 3.48
the reaction time, and the remaining oil was dissolved in (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.4 Hz, 2H), 7.26–7.36 (m,
ethyl acetate (15 mL). The organic solution was washed 2H), 7.38–7.47 (m, 3H) 7.77–7.86 (m, 3H), 8.03 (s, 1H);
with water (30 mL), dried over anhydrous Na2SO4, and 13C NMR (CDCl3): δ 38.2, 39.4, 109.3, 120.7, 122.4,
then the solvent was removed under reduced pressure. 123.1, 129.2, 129.4, 133.5, 134.4, 140.4, 143.8, 144.0,
Subsequent column chromatography of the oily residue 195.6; Anal. Calcd. for C16H13ClN2O: C, 67.49; H, 4.60;
afforded the pure compound 50.
N, 9.84. Found: C, 67.72; H, 4.40; N, 10.04.
3-(1H-Benzimidazol-1-yl)-1-phenyl-1-propanone
1 - ( 4 - C h l o r o p h e n y l ) - 3 - ( 2 - m e t h y l - 1 H -
(15). Colorless crystals (2-propanol), yield 760 mg benzimidazol-1-yl)-1-propanone
(19).
Colorless
1517

N-Alkylation of benzimidazoles with ketonic Mannich bases
and the reduction of the resulting 1-(3-oxopropyl)benzimidazoles
1
crystals (ethanol), yield 925 mg (62%), mp 157–158°C; mg (78%), mp 160–161°C; H NMR (CDCl3): δ 3.56 (t,
1H NMR (CDCl3): δ 2.66 (s, 3H), 3.43 (t, J = 7.2 Hz, 2H), J = 7.0 Hz, 2H), 4.70 (t, J = 7.0 Hz, 2H), 7.26–7.36 (m,
4.58 (t, J = 7.2 Hz, 2H), 7.20–7.26 (m, 2H), 7.29–7.35 2H), 7.37–7.50 (m, 4H), 7.57–7.62 (m, 2H), 7.66 (d, J
(m, 1H), 7.41 (dd, J = 2.0 and 8.8 Hz, 2H), 7.65–7.71 = 8.8 Hz, 2H), 7.79–7.84 (m, 1H), 7.96 (d, J = 8.4 Hz,
(m, 1H), 7.81 (dd, J = 1.8 and 8.4 Hz, 2H); 13C NMR 2H), 8.07 (s, 1H); 13C NMR (CDCl3): δ 38.4, 39.6, 109.4,
(CDCl3): δ 14.1, 37.9, 38.7, 109.0, 119.4, 122.2, 122.3, 120.8, 122.3, 123.1, 127.4, 127.5, 128.6, 128.7, 129.1,
129.2, 129.5, 134.5, 134.8, 140.4, 143.0, 151.7, 195.9; 133.7, 134.9, 139.7, 143.8, 144.1, 146.6, 196.4; Anal.
Anal. Calcd. for C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38. Calcd. for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found:
Found: C, 68.55; H, 4.89; N, 9.62.
C, 80.70; H, 5.78; N, 8.39.
1-(4-Chlorophenyl)-3-(5,6-dimethyl-1H-
1-(Biphenyl-4-yl)-3-(2-methyl-1H-benzimidazol-
benzimidazol-1-yl)-1-propanone (20). Tan crystals 1-yl)-1-propanone (25). Colorless crystals (ethanol),
(ethanol), yield 1330 mg (85%), mp 162–163°C; yield 1325 mg (78%), mp 141–142°C; 1H NMR (CDCl3):
1H NMR (CDCl3): δ 2.36 (s, 3H), 2.40 (s, 3H), 3.46 δ 2.69 (s, 3H), 3.50 (t, J = 7.2 Hz, 2H), 4.62 (t, J =
(t, J = 6.6 Hz, 2H), 4.60 (t, J = 6.6 Hz, 2H), 7.18 (s, 7.2 Hz, 2H), 7.21–7.28 (m, 2H), 7.33–7.50 (m, 4H),
1H), 7.40 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 7.82 (d, J = 7.57–7.63 (m, 2H), 7.63–7.73 (m, 3H), 7.96 (d, J =
8.8 Hz, 2H), 7.90 (s, 1H); 13C NMR (CDCl3): δ 20.3, 20.7, 8.4 Hz, 2H); 13C NMR (CDCl3): δ 14.1, 38.0, 38.9, 109.1,
38.4, 39.4, 109.5, 120.7, 129.2, 129.5, 131.2, 132.1, 119.4, 122.1, 122.3, 127.4, 127.5, 128.6, 128.7, 129.1,
132.3, 134.6, 140.4, 142.6, 143.0, 195.7; Anal. Calcd. 134.9, 135.0, 139.7, 143.0, 146.6, 151.7, 196.7; Anal.
for C18H17ClN2O: C, 69.12; H, 5.48; N, 8.96. Found: C, Calcd. for C23H20N2O: C, 81.15; H, 5.92; N, 8.23. Found:
69.38; H, 5.30; N, 9.11.
C, 81.34; H, 6.20; N, 8.03.
3-(1H-Benzimidazol-1-yl)-1-(4-bromophenyl)-1-
1-(Biphenyl-4-yl)-3-(5, 6-dimethyl-1H-
propanone (21). Tan crystals (ethanol), yield 1250 mg benzimidazol-1-yl)-1-propanone (26). Tan crystals
1
(76%), mp 145–146°C; H NMR (CDCl3): δ 3.48 (t, J = (ethanol), yield 1345 mg (76%), mp 188–189°C; 1H NMR
6.8 Hz, 2H), 4.66 (t, J = 6.8 Hz, 2H), 7.26–7.35 (m, 2H), (CDCl3): δ 2.38 (s, 3H), 2.41 (s, 3H), 3.54 (t, J = 6.6 Hz,
7.41–7.46 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.74 (d, 2H), 4.64 (t, J = 6.6 Hz, 2H), 7.22 (s, 1H), 7.36–7.50
J = 8.8 Hz, 2H), 7.78–7.83 (m, 1H), 8.04 (s, 1H); 13C (m, 3H), 7.55–763 (m, 3H), 7.66 (d, J = 8.4 Hz, 2H),
NMR (CDCl3): δ 38.3, 39.4, 109.3, 120.8, 122.4, 123.2, 7.93 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3):
129.2, 129.6, 132.2, 133.5, 134.9, 143.8, 144.0, 195.8; δ 20.3, 20.7, 38.5, 39.6, 109.6, 120.7, 127.4, 127.5,
Anal. Calcd. for C16H13BrN2O: C, 58.38; H, 3.98; N, 8.51. 128.5, 128.7, 129.1, 131.2, 132.2, 132.3, 135.0, 139.7,
Found: C, 58.61; H, 4.19; N, 8.28.
1 - ( 4 - B r o m o p h e n y l ) - 3 - ( 2 - m e t h y l - 1 H - C, 81.33; H, 6.26; N, 7.90. Found: C, 81.09; H, 6.15; N,
benzimidazol-1-yl)-1-propanone (22). Off-white 8.14.
crystals (ethanol), yield 1305 mg (76%), mp 172–173°C; 3-(1H-Benzimidazol-1-yl)-1-(naphthalen-1-yl)-1-
142.7, 143.0, 146.5, 196.5; Anal. Calcd. for C24H22N2O:
1H NMR (CDCl3): δ 2.67 (s, 3H), 3.43 (t, J = 7.0 Hz, 2H), propanone (27). Colorless crystals (ethanol–hexanes),
4.58 (t, J = 7.2 Hz, 2H), 7.21–7.26 (m, 2H), 7.30–7.35 yield 1125 mg (75%), mp 106–107°C; 1H NMR (CDCl3):
(m, 1H), 7.58 (dd, J =1.8 and 8.4 Hz, 2H), 7.66–7.71 (m, δ 3.61 (t, J = 6.4 Hz, 2H), 4.72 (t, J = 6.4 Hz, 2H), 7.23–
1H), 7.74 (dd, J =2.4 and 8.4 Hz, 2H);13C NMR (CDCl3): 7.35 (m, 2H), 7.36–7.62 (m, 4H), 7.76 (dd, J = 1.0 and
δ 14.1, 37.9, 38.7, 109.0, 119.5, 122.2, 122.3, 129.2, 7.4 Hz, 1H), 7.79–7.88 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H),
129.6, 134.8, 134.9, 143.0, 151.7, 196.1; Anal. Calcd. 8.09 (s, 1H), 8.62 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3):
for C17H15BrN2O: C, 59.49; H, 4.41; N, 8.16. Found: C, δ 39.9, 41.2, 109.5, 120.7, 122.3, 123.1, 124.3, 125.7,
59.22; H, 4.66; N, 7.92.
126.8, 128.4, 128.5, 128.6, 130.2, 133.6, 133.8, 134.1,
1-(4-Bromophenyl)-3-(5,6-dimethyl-1H- 134.4, 143.8, 144.1, 200.4; Anal. Calcd. for C20H16N2O:
benzimidazol-1-yl)-1-propanone (23). Tan crystals C, 79.98; H, 5.37; N, 9.33. Found: C, 80.21; H, 5.09; N,
(ethanol), yield 1465 mg (82%), mp 174–175°C; 1H NMR 9.17.
(CDCl3): δ 2.37 (s, 3H), 2.40 (s, 3H), 3.46 (t, J = 6.6 Hz,
2H), 4.61 (t, J = 6.6 Hz, 2H), 7.18 (s, 1H), 7.52–7.61 (naphthalen-1-yl)-1-propanone
(m, 3H), 7.74 (d, J = 8.8 Hz, 2H), 7.90 (s, 1H); 13C NMR crystals (2-propanol–hexanes), yield 925 mg (59%), mp
3 - ( 2 - M e t h y l - 1 H - b e n z i m i d a z o l - 1 - y l ) - 1 -
(28). Colorless
1
(CDCl3): δ 20.4, 20.8, 38.3, 39.4, 109.5, 120.7, 129.1, 113–114°C; H NMR (CDCl3): δ 2.70 (s, 3H), 3.57 (t, J
129.6, 131.3, 132.0, 132.2, 132.3, 135.0, 142.6, 143.0, = 6.8 Hz, 2H), 4.66 (t, J = 6.8 Hz, 2H), 7.20–7.26 (m,
196.0; Anal. Calcd. for C18H17BrN2O: C, 60.52; H, 4.80; 2H), 7.34–7.45 (m, 2H), 7.50–7.63 (m, 2H), 7.67–7.76
N, 7.84. Found: C, 60.80; H, 5.03; N, 8.05.
(m, 2H), 7.86 (dd, J = 1.2 and 8.4 Hz, 1H), 7.99 (d, J =
3-(1H-Benzimidazol-1-yl)-1-(biphenyl-4-yl)-1- 8.4 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3):
propanone (24). Colorless crystals (ethanol), yield 1270 δ 14.1, 39.2, 40.9, 109.2, 119.4, 122.1, 122.3, 124.4,
1518

G. Roman
125.7, 126.8, 128.5, 128.6, 128.7, 130.2, 133.8, 134.1, crystals (acetone), yield 590 mg (42%), mp 239–240°C;
134.5, 134.9, 143.0, 151.7, 200.6; Anal. Calcd. for 1H NMR (d6-DMSO): δ 2.58 (s, 3H), 3.46 (t, J = 7.2 Hz,
C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.01; 2H), 4.50 (t, J = 7.2 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),
H, 5.98; N, 9.14.
7.08–7.19 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.54 (d, J =
3-(5,6-Dimethyl-1H-benzimidazol-1-yl)-1- 7.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 10.39 (br s, 1H);
(naphthalen-1-yl)-1-propanone (29). Tan crystals 13C NMR (d6-DMSO): δ 13.5, 37.0, 38.7, 110.0, 115.2,
1
(2-propanol), yield 675 mg (41%), mp 151–152°C; H 118.1, 121.1, 121.3, 127.9, 130.6, 134.9, 142.4, 151.8,
NMR (CDCl3): δ 2.37 (s, 3H), 2.40 (s, 3H), 3.60 (t, J = 162.2, 195.8; Anal. Calcd. for C17H16N2O2: C, 72.84; H,
6.4 Hz, 2H), 4.68 (t, J = 6.4 Hz, 2H), 7.21 (s, 1H), 7.40– 5.75; N, 9.99. Found: C, 72.55; H, 5.92; N, 10.12.
7.46 (m, 1H), 7.50–7.62 (m, 3H), 7.77 (dd, J = 1.2 and
1-(4-Hydroxyphenyl)-3-(5,6-dimethyl-1H-
7.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.94–8.01 (m, 2H), benzimidazol-1-yl)-1-propanone (34). Tan crystals,
1
8.62 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3): δ 20.3, 20.7, yield 1075 mg (73%), mp 268–269°C; H NMR (d6-
39.9, 41.3, 109.7, 120.7, 124.4, 125.7, 126.8, 128.3, DMSO): δ 2.29 (s, 3H), 2.33 (s, 3H), 3.52 (t, J = 6.8 Hz,
128.5, 128.6, 130.2, 131.2, 132.2, 132.3, 133.7, 134.1, 2H), 4.51 (t, J = 6.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H),
134.6, 142.7, 143.0, 200.6; Anal. Calcd. for C22H20N2O: 7.39 (s, 1H), 7.42 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 8.06
C, 80.46; H, 6.14; N, 8.53. Found: C, 80.71; H, 6.33; N, (s, 1H), 10.37 (s, 1H); 13C NMR (d6-DMSO): δ 19.8, 20.1,
8.40.
37.4, 39.7, 110.5, 115.2, 119.4, 127.9, 129.6, 130.5,
3-(1H-Benzimidazol-1-yl)-1-(naphthalen-2- 130.8, 132.2, 142.0, 143.3, 162.3, 195.7; Anal. Calcd.
yl)-1-propanone (30). Tan crystals (ethanol), yield for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C,
1195 mg (80%), mp 160–161°C; 1H NMR (CDCl3): δ 3.67 73.16; H, 5.95; N, 9.26.
(t, J = 6.6 Hz, 2H), 4.73 (t, J = 6.6 Hz, 2H), 7.24–7.38 (m,
3-(1H-Benzimidazol-1-yl)-1-(2-hydroxyphenyl)-1-
2H), 7.46–7.63 (m, 3H), 7.79–7.92 (m, 4H), 7.97 (dd, propanone (35). Colorless crystals (methanol–water),
J = 2.0 and 8.4 Hz, 1H), 8.12 (s 1H), 8.37 (s, 1H); 13C yield 1115 mg (84%), mp 133–134°C; 1H NMR (CDCl3):
NMR (CDCl3): δ 38.4, 39.8, 109.5, 120.7, 122.4, 123.2, δ 3.48 (t, J = 6.4 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 6.76–
123.5, 127.1, 127.9, 128.9, 129.0, 129.7, 130.0, 132.5, 6.80 (m, 1H), 6.90–6.93 (m, 1H), 7.22–7.42 (m, 5H),
133.5, 133.6, 135.9, 143.7, 143.8, 196.7; Anal. Calcd. 7.51–7.53 (dd, J = 1.5 and 8.0 Hz, 1H), 7.76–7.78 (dd,
for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, J = 1.5 and 7 Hz, 1H); 7.99 (s, 1H); 11.94 (s, 1H);
80.18; H, 5.56; N, 9.11.
3 - ( 2 - M e t h y l - 1 H - b e n z i m i d a z o l - 1 - y l ) - 1 - 119.0, 120.3, 122.1, 122.9, 129.3, 133.2, 136.8, 143.5,
(naphthalen-2-yl)-1-propanone (31). Colorless 143.6, 162.1, 202.2; Anal. Calcd. for C16H14N2O2: C,
13C NMR (CDCl3): δ 37.5, 38.8, 109.1, 118.4, 118.8,
crystals (2-propanol–hexanes), yield 925 mg (59%), mp 72.16; H, 5.30; N, 10.52. Found: C, 72.33; H, 5.61; N,
130–131°C; 1H NMR (CDCl3): δ 2.69 (s, 3H), 3.61 (t, J = 10.66.
7.2 Hz, 2H), 4.65 (t, J = 7.2 Hz, 2H), 7.21–7.30 (m, 2H),
7.36–7.42 (m, 1H), 7.51–7.64 (m, 2H), 7.67–7.74 (m, benzimidazol-1-yl)-1-propanone
1 - ( 2 - H y d r o x y p h e n y l ) - 3 - ( 2 - m e t h y l - 1H -
(36). Off-white
1H), 7.83–7.90 (m, 3H), 7.97 (dd, J = 2.4 and 4.8 Hz, crystals (methanol–water), yield 1150 mg (82%), mp
1H), 8.34 (s, 1H); 13C NMR (CDCl3): δ 14.1, 38.0, 39.0, 145–146°C; 1H NMR (CDCl3): δ 2.65 (s, 3H), 3.48 (t, J =
109.2, 119.4, 122.2, 122.3, 123.5, 127.2, 127.9, 128.9, 6.8 Hz, 2H), 4.56 (t, J = 6.8 Hz, 2H), 6.78–6.89 (m, 1H),
129.0, 129.7, 130.1, 132.5, 133.6, 134.9, 135.9, 143.0, 6.90–7.02 (m, 1H), 7.16–7.25 (m, 2H), 7.30–7.74 (m,
151.7, 197.1; Anal. Calcd. for C21H18N2O: C, 80.23; H, 4H), 11.97 (s, 1H); 13C NMR (CDCl3): δ 14.3, 37.9, 38.8,
5.77; N, 8.91. Found: C, 80.47; H, 5.55; N, 9.16.
109.3, 119.1, 119.4, 119.6, 119.7, 122.5, 122.7, 129.9,
3-(1H-Benzimidazol-1-yl)-1-(4-hydroxyphenyl)-1- 135.0, 137.4, 143.2, 151.9, 162.8, 203.1; Anal. Calcd.
propanone (32). Off-white crystals (2-butanone), yield for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
1
880 mg (66%), mp 233–234°C; H NMR (d6-DMSO): 73.08; H, 5.42; N, 10.21.
δ 3.56 (t, J = 6.8 Hz, 2H), 4.58 (t, J = 6.8 Hz, 2H), 6.82
(d, J = 8.8 Hz, 2H), 7.15–7.28 (m, 2H), 7.63 (d, J = 8.0 benzimidazol-1-yl)-1-propanone
1-(2-Hydroxyphenyl)-3-(5,6-dimethyl-1H-
(37). Off-white
Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, crystals (acetone), yield 1160 mg (79%), mp 186–187°C;
2H), 8.24 (s, 1H), 10.39 (s, 1H); 13C NMR (d6-DMSO): 1H NMR (CDCl3): δ 2.36 (s, 3H), 2.39 (s, 3H), 3.53 (t,
δ 37.4, 39.6, 110.5, 115.2, 119.3, 121.4, 122.2, 127.9, J = 6.6 Hz, 2H), 4.59 (t, J = 6.6 Hz, 2H), 6.82–6.86 (m,
130.5, 133.7, 143.3, 144.2, 162.3, 195.7; Anal. Calcd. 1H), 6.96 (dd, J = 0.7 and 8.4 Hz, 1H); 7.18 (s, 1H),
for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 7.43–7.47 (m, 1H), 7.55 (s, 1H), 7.59 (dd, J = 1.5 and
71.93; H, 5.39; N, 10.39.
1 - ( 4 - H y d r o x y p h e n y l ) - 3 - ( 2 - m e t h y l - 1H - δ 20.2, 20.6, 37.8, 39.0, 109.3, 118.6, 118.9, 119.1,
benzimidazol-1-yl)-1-propanone (33). Off-white 120.5, 129.4, 131.1, 131.8, 132.2, 136.9, 142.4, 142.7,
8 Hz, 1H), 7.90 (s, 1H), 11.97 (s, 1H); 13C NMR (CDCl3):
1519

N-Alkylation of benzimidazoles with ketonic Mannich bases
and the reduction of the resulting 1-(3-oxopropyl)benzimidazoles
162.3, 202.5; Anal. Calcd. for C18H18N2O2: C, 73.45; H, 1H); 13C NMR (CDCl3): δ 20.2, 37.9, 39.0, 63.2, 109.4,
6.16; N, 9.52. Found: C, 73.69; H, 5.99; N, 9.77.
1-(2-Hydroxyphenyl)-3-(2-phenoxymethyl-1H- 129.2, 129.6, 135.0, 137.9, 142.3, 149.2, 157.6, 160.2,
benzimidazol-1-yl)-1-propanone (38). Colorless 202.8; Anal. Calcd. for C24H22N2O3: C, 74.59; H, 5.74; N,
114.6, 118.2, 118.5, 120.2, 121.6, 122.5, 123.4, 128.2,
crystals (methanol), yield 1545 mg (83%), mp 131– 7.25. Found: C, 74.83; H, 5.48; N, 7.47.
1
132°C; H NMR (CDCl3): δ 3.54 (t, J = 7.3 Hz, 2H),
3-(2-Ethyl-1H-benzimidazol-1-yl)-1-(2-hydroxy-5-
4.74 (t, J = 7.3 Hz, 2H), 5.46 (s, 2H), 6.77–6.81 (m, methylphenyl)-1-propanone (43). Colorless crystals
1
1H), 6.95–7.06 (m, 4H), 7.24–7.34 (m, 4H), 7.39–7.50 (methanol), yield 1340 mg (87%), mp 160–161°C; H
(m, 3H), 7.80–7.82 (m, 1H), 12.02 (s, 1H); 13C NMR NMR (CDCl3): δ 1.45 (t, J = 7.5 Hz, 3H), 2.16 (s, 3H),
(CDCl3): δ 37.9, 39.1, 63.3, 109.4, 114.6, 118.5, 118.8, 2.90 (q, J = 7.5 Hz, 2H), 3.43 (t, J = 7.1 Hz, 2H), 4.52
119.1, 120.3, 121.7, 122.5, 123.4, 129.5, 129.7, 135.0, (t, J = 7.1 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 7.21–7.32
136.8, 142.3, 149.2, 157.6, 162.3, 203.0; Anal. Calcd. (m, 5H), 7.70–7.73 (m, 1H), 11.83 (s, 1H); 13C NMR
for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, (CDCl3): δ 11.6, 20.5, 20.2, 37.5, 38.0, 108.8, 118.2,
73.92; H, 5.59; N, 7.30.
118.5, 119.2, 121.8, 122.9, 128.2, 129.1, 134.5, 137.9,
3-(1H-Benzimidazol-1-yl)-1-(2-hydroxy-5- 142.6, 155.8, 160.1, 202.6; Anal. Calcd. for C19H20N2O2:
methylphenyl)-1-propanone (39). Colorless crystals C, 74.00; H, 6.54; N, 9.08. Found: C, 73.74; H, 6.28; N,
(ethanol), yield 1305 mg (93%), mp 172–174°C; 1H NMR 9.31.
(CDCl3): δ 2.21 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 4.62
(t, J = 6.4 Hz, 2H), 6.83–8.01 (m, 8H), 11.77 (s, 1H); 13
3-(1H-Benzimidazol-1-yl)-1-(thiophen-2-yl)-1-
propanone (44). Colorless crystals (2-propanol), yield
C
NMR (CDCl3): δ 20.4, 37.7, 39.1, 109.2, 118.4, 118.5, 995 mg (77%), mp 114–115°C; 1H NMR (CDCl3): δ 3.35
120.6, 122.2, 123.0, 129.0, 133.3, 138.1, 143.6, 143.8, (t, J = 6.4 Hz, 2H), 4.64 (t, J = 6.4 Hz, 2H), 7.07 (dd,
160.3, 202.2; Anal. Calcd. for C17H16N2O2: C, 72.84; H, J = 4.0 and 4.8 Hz, 1H), 7.24–7.35 (m, 2H), 7.44 (dd,
5.75; N, 9.99. Found: C, 72.66; H, 5.87; N, 10.18.
1-(2-Hydroxy-5-methylphenyl)-3-(2-methyl-1H- 1H), 7.63 (dd, J = 1.0 and 4.8 Hz, 1H), 7.79 (dd, J =
benzimidazol-1-yl)-1-propanone (40).
Colorless 1.2 and 7.2 Hz, 1H), 8.01 (s, 1H); 13C NMR (CDCl3):
J = 1.2 and 7.6 Hz, 1H), 7.60 (dd, J = 1.0 and 4.0 Hz,
crystals (methanol–water), yield 1280 mg (87%), mp δ 38.9, 39.5, 109.4, 120.7, 122.3, 123.1, 128.4, 132.4,
1
134–135°C; H NMR (CDCl3): δ 2.16 (s, 3H), 2.60 (s, 133.6, 134.6, 143.3, 143.7, 144.0, 189.5; Anal. Calcd.
3H) 3.43 (t, J = 7 Hz, 2H), 4.50 (t, J = 7 Hz, 2H), 6.83 (d, for C14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C,
J = 8.4 Hz, 1H), 7.19–7.32 (m, 5H), 7.65–7.67 (m, 1H), 65.33; H, 4.98; N, 11.08.
11.82 (s, 1H); 13C NMR (CDCl3): δ 13.7, 20.2, 37.3, 38.3,
3-(2-Methyl-1H-benzimidazol-1-yl)-1-(thiophen-2-
108.8, 118.1, 118.5, 119.0, 121.9, 122.0, 128.2, 129.0, yl)-1-propanone (45). Colorless crystals (2-propanol–
134.4, 137.9, 142.6, 151.3, 160.0, 202.4; Anal. Calcd. hexanes), yield 945 mg (70%), mp 100–101°C; 1H NMR
for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, (CDCl3): δ 2.65 (s, 3H), 3.39 (t, J = 7.0 Hz, 2H), 4.57
73.21; H, 6.37; N, 9.64.
(t, J = 7.2 Hz, 2H), 7.07 (dd, J = 4.0 and 4.8 Hz, 1H),
1-(2-Hydroxy-5-methylphenyl)-3-(5,6-dimethyl- 7.19–7.27 (m, 2H), 7.31–7.38 (m, 1H), 7.57 (dd, J =
1H-benzimidazol-1-yl)-1-propanone (41). Tan crystals 0.8 and 4.0 Hz, 1H), 7.64 (dd, J = 0.8 and 4.8 Hz, 1H),
1
(acetone), yield 1245 mg (81%), mp 184–185°C; H 7.63–7.71 (m, 1H); 13C NMR (CDCl3): δ 14.0, 38.6, 38.8,
NMR (CDCl3): δ 2.23 (s, 3H), 2.36 (s, 3H), 2.40 (s, 3H), 109.1, 119.4, 122.1, 122.3, 128.5, 132.5, 134.7, 134.8,
3.52 (t, J = 6.6 Hz, 2H), 4.60 (t, J = 6.6 Hz, 2H) 6.87 (d, 143.0, 143.4, 151.7, 189.8; Anal. Calcd. for C15H14N2OS:
J= 8.4 Hz, 1H) 7.19 (s, 1H), 7.26 (dd, J= 1.5 and 8.8 Hz, C, 66.64; H, 5.22; N, 10.36. Found: C, 66.91; H, 5.02;
1H), 7.35 (d, J = 1.5 Hz, 1H), 7.56 (s, 1H), 7.91 (s, 1H), N, 10.58.
11.80 (s, 1H); 13C NMR (CDCl3): δ 20.2, 20.4, 20.6, 37.9,
3-(5,6-Dimethyl-1H-benzimidazol-1-yl)-1-
39.1, 109.4, 118.4, 118.6, 120.5, 128.3, 129.1, 131.1, (thiophen-2-yl)-1-propanone (46). Tan crystals
131.8, 132.2, 138.0, 142.8, 160.3, 202.4; Anal. Calcd. (ethanol), yield 1035 mg (73%), mp 147–148°C;
for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 1H NMR (CDCl3): δ 2.36 (s, 3H), 2.40 (s, 3H), 3.43 (t,
73.81; H, 6.33; N, 9.29.
J = 6.4 Hz, 2H), 4.59 (t, J = 6.4 Hz, 2H), 7.08 (t,
1 - ( 2 - H y d r o x y - 5 - m e t h y l p h e n y l ) - 3 - ( 2 - J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.54 (s, 1H), 7.60
phenoxymethyl-1H-benzimidazol-1-yl)-1-propanone (d, J = 3.6 Hz, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.88 (s,
(42). Colorless crystals (methanol), yield 1735 mg (90%), 1H); 13C NMR (CDCl3): δ 20.3, 20.7, 39.0, 39.5, 109.6,
1
mp 148–149°C; H NMR (CDCl3): δ 2.19 (s, 3H), 3.53 120.6, 128.4, 131.2, 132.0, 132.3, 132.4, 134.6, 142.6,
(t, J = 7.3 Hz, 2H), 4.73 (t, J = 7.3 Hz, 2H), 5.46 (s, 2H), 142.9, 143.4, 189.7; Anal. Calcd. for C16H16N2OS: C,
6.88 (d, J = 8.4 Hz, 1H), 6.97–7.06 (m, 3H), 7.24–7.32 67.58; H, 5.67; N, 9.85. Found: C, 67.85; H, 5.48; N,
(m, 6H), 7.40–7.43 (m, 1H), 7.80–7.82 (m, 1H), 11.86 (s, 10.04.
1520

G. Roman
3-(2-Phenylmethyl-1H-benzimidazol-1-yl)-1-
2-(5,6-Dimethyl-1H-benzimidazol-1-ylmethyl)-
(thiophen-2-yl)-1-propanone (47). Off-white crystals 3,4-dihydronaphthalen-1(2H)-one (51). Tan crystals
(ethanol), yield 1160 mg (64%), mp 131–132°C; (2-propanol–hexanes), yield 1005 mg (66%), mp
1H NMR (d6-DMSO): δ 3.26 (t, J = 7.2 Hz, 2H), 4.37 144–145°C; 1H NMR (CDCl3): δ 1.75–1.89 (m, 1H),
(s, 2H), 4.50 (t, J = 7.2 Hz, 2H), 7.13–7.23 (m, 4H), 1.97–2.08 (m, 1H), 2.89–2.97 (m, 2H), 2.97–3.07 (m,
7.26–7.32 (m, 4H), 7.54–7.61 (m, 2H), 7.73 (dd, J = 1H), 4.33 (dd, J = 8.0 and 14.8 Hz, 1H), 4.86 (dd, J =
1.2 and 3.6 Hz, 1H), 7.98 (dd, J = 1.0 and 5.0 Hz, 1H); 4.4 and 14.8 Hz, 1H), 7.17–7.24 (m, 2H), 7.33 (t, J =
13C NMR (d6-DMSO): δ 33.0, 37.9, 38.5, 110.2, 118.5, 7.0 Hz, 1H), 7.45–7.52 (m, 1H), 7.57 (s, 1H), 7.86 (s,
121.3, 121.7, 126.5, 128.5, 128.6, 128.7, 133.4, 134.9, 1H), 8.07 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3): δ 20.4,
135.0, 136.9, 142.4, 143.1, 153.3, 190.5; Anal. Calcd. 20.8, 27.2, 28.7, 44.8, 48.0, 110.0, 120.6, 127.0, 127.6,
for C21H18N2OS: C, 69.59; H, 5.01; N, 7.73. Found: C, 128.9, 131.2, 132.1, 132.4, 132.6, 134.0, 142.6, 143.3,
69.34; H, 4.79; N, 7.97.
3-(2-(Naphthalen-1-ylmethyl)-1H-benzimidazol-1- 6.62; N, 9.20. Found: C, 78.68; H, 6.45; N, 9.46.
yl)-1-(thiophen-2-yl)-1-propanone (48). Tan crystals General procedure for the reduction of
(ethanol), yield 1210 mg (61%), mp 183–184°C; benzimidazole–ketones. To the solution of
143.9, 197.5; Anal. Calcd. for C20H20N2O: C, 78.92; H,
1H NMR (d6-DMSO): δ 3.34 (t, J = 7.2 Hz, 2H), 4.58 (t, benzimidazole–ketone (3 mmoles) in methanol
J = 7.2 Hz, 2H), 4.84 (s, 2H), 7.11–7.23 (m, 3H), 7.33 (20 mL), NaBH4 (342 mg, 9 mmoles) was added in small
(d, J = 6.8 Hz, 1H), 7.39–7.45 (m, 1H), 7.47–7.55 (m, portions, under good stirring, at room temperature.
3H), 7.60 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 3.6 Hz, 1H), The reaction mixture was then stirred at room
7.82 (d, J = 8.0 Hz, 1H), 7.90–7.96 (m, 1H), 7.99 (d, temperature overnight. The solvent was removed under
J = 5.2 Hz, 1H), 8.18–8.25 (m, 1H); 13C NMR (d6-DMSO): reduced pressure, and the residue was partitioned
δ 31.0, 38.0, 38.7, 110.2, 118.5, 121.3, 121.8, 124.3, between water (30 mL) and ethyl acetate (15 mL). The
125.5, 125.8, 126.1, 126.9, 127.3, 128.4, 128.7, 131.8, aqueous phase was further extracted with ethyl acetate
133.1, 133.4, 133.6, 135.0, 135.1, 142.3, 143.2, 153.2, (15 mL), then the organic phases were combined
190.7; Anal. Calcd. for C25H20N2OS: C, 75.73; H, 5.08; and dried over anhydrous Na2SO4. The solvent was
N, 7.07. Found: C, 75.50; H, 4.91; N, 6.96.
removed under reduced pressure to give a residue that
2 - ( 1 H - B e n z i m i d a z o l - 1 - y l m e t h y l ) - 3 , 4 - was crystallized from the appropriate solvent.
dihydronaphthalen-1(2H)-one (49). Off-white crystals
(±)-3-(1H-Benzimidazol-1-yl)-1-(4-chlorophenyl)-
1
(2-propanol), yield 925 mg (67%), mp 144–145°C; H 1-propanol (52). Colorless crystals (2-propanol–
NMR (CDCl3): δ 1.77–1.91 (m, 1H), 2.03–2.13 (m, 1H), hexanes), yield 455 mg (53%), mp 168–169°C; 1H
2.88–3.08 (m, 3H), 4.43 (dd, J = 7.2 and 14.8 Hz, 1H), NMR (CDCl3): δ 2.10–2.28 (m, 2H), 4.25–4.34 (m, 1H),
4.88 (dd, J = 4.8 and 14.8 Hz, 1H), 7.21 (d, J = 7.6 Hz, 4.38–4.46 (m, 2H), 4.49–4.60 (m, 1H), 7.19–7.32 (m,
1H), 7.25–7.36 (m, 3H), 7.41–7.51 (m, 2H), 7.79–7.84 6H), 7.40 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H),
(m, 1H), 7.99 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H); 13C NMR 7.93 (s, 1H); 13C NMR (CDCl3): δ 38.3, 41.7, 69.3, 109.9,
(CDCl3): δ 27.4, 28.8, 44.9, 48.2, 109.8, 120.7, 122.3, 120.3, 122.4, 123.2, 127.2, 128.8, 133.5, 133.6, 143.1,
123.2, 127.1, 127.7, 128.9, 132.1, 134.1, 134.2, 143.9, 143.6; Anal. Calcd. for C16H15ClN2O: C, 67.02; H, 5.27;
144.0, 144.1, 197.3; Anal. Calcd. for C18H16N2O: C, N, 9.77. Found: C, 67.25; H, 5.08; N, 9.98.
78.24; H, 5.84; N, 10.14. Found: C, 78.04; H, 6.02; N,
10.31.
(±)-1-(4-Chlorophenyl)-3-(5,6-dimethyl-1H-
benzimidazol-1-yl)-1-propanol (53). Colorless crystals
2-(2-Methyl-1H-benzimidazol-1-ylmethyl)-3,4- (2-propanol–hexanes), yield 547 mg (58%), mp 130–
1
dihydronaphthalen-1(2H)-one (50). Yellowish oil after 131°C; H NMR (CDCl3): δ 2.06–2.26 (m, 2H), 2.26 (s,
column chromatography (silicagel, ethyl acetate), yield 3H), 2.35 (s, 3H), 4.17–4.27 (m, 1H), 4.31 (dd, J = 3.6
1145 mg (79%), Rf 0.23 (ethyl acetate); 1H NMR (CDCl3): and 10.0 Hz, 1H), 4.46–4.57 (m, 1H), 4.98 (br s, 1H),
δ 1.85–2.02 (m, 2H), 2.64 (s, 3H), 2.85–2.95 (m, 2H), 7.13 (s, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4
3.00–3.11 (m, 1H), 4.18 (dd, J = 9.6 and 15.2 Hz, 1H), Hz, 2H), 7.84 (s, 1H); 13C NMR (CDCl3): δ 20.2, 20.7,
4.99 (dd, J = 4.4 and 15.2 Hz, 1H), 7.19–7.26 (m, 3H), 38.1, 41.6, 68.9, 110.0, 120.2, 127.3, 128.7, 131.3,
7.28–7.38 (m, 2H), 7.46–7.53 (m, 1H), 7.67–7.74 (m, 132.0, 132.4, 133.3, 142.1, 143.0, 143.5; Anal. Calcd.
1H), 8.07 (dd, J = 1.2 and 8.0 Hz, 1H); 13C NMR (CDCl3): for C18H19ClN2O: C, 68.67; H, 6.08; N, 8.90. Found: C,
δ 14.3, 27.4, 28.8, 44.0, 47.9, 109.4, 119.4, 122.1, 68.90; H, 5.83; N, 9.22.
122.3, 127.1, 127.6, 129.0, 132.1, 134.1, 135.4, 142.9,
(±)-3-(1H-Benzimidazol-1-yl)-1-(4-bromophenyl)-
143.9, 152.0, 197.5; Anal. Calcd. for C19H18N2O: C, 1-propanol (54). Colorless crystals (2-propanol), yield
1
78.59; H, 6.25; N, 9.65. Found: C, 78.25; H, 5.97; N, 845 mg (85%), mp 175–176°C; H NMR (CDCl3): δ
9.93.
2.10–2.23 (m, 2H), 4.25–4.34 (m, 1H), 4.40 (dd, J = 4.0
1521

N-Alkylation of benzimidazoles with ketonic Mannich bases
and the reduction of the resulting 1-(3-oxopropyl)benzimidazoles
and 10.0 Hz, 1H), 4.48 (br s, 1H), 4.48–4.60 (m, 1H), 8.24 (s, 1H); 13C NMR (d6-DMSO): δ 38.8, 41.4, 69.6,
7.16 (d, J = 8.4 Hz, 2H), 7.20–7.25 (m, 1H), 7.26–7.31 110.3, 119.5, 121.4, 122.2, 123.9, 124.4, 125.6, 126.1,
(m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 127.5, 127.7, 132.3, 132.8, 133.8, 142.9, 143.5, 144.1;
2H), 7.56 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H); 13C NMR Anal. Calcd. for C20H18N2O: C, 79.44; H, 6.00; N, 9.26.
(CDCl3): δ 38.2, 41.7, 69.3, 109.9, 120.3, 121.6, 122.4, Found: C, 79.61; H, 6.17; N, 9.03.
123.2, 127.5, 131.8, 133.6, 143.5, 143.6; Anal. Calcd.
for C16H15BrN2O: C, 58.02; H, 4.56; N, 8.46. Found: C, (naphthalen-2-yl)propan-1-ol (59). Colorless crystals
57.81; H, 4.69; N, 8.60. (2-propanol), yield 625 mg (66%), mp 179–180°C;
(±)-3-(2-Methyl-1H-benzimidazol-1-yl)-1-
(±)-1-(4-Bromophenyl)-3-(5,6-dimethyl-1H- 1H NMR (CDCl3): δ 2.01–2.23 (m, 2H), 2.53 (s, 3H),
benzimidazol-1-yl)-1-propanol (55). Colorless crystals 4.23–4.40 (m, 2H), 4.69–4.77 (m, 1H), 5.71 (d, J =
1
(2-propanol), yield 646 mg (60%), mp 154–155°C; H 4.8 Hz, 1H), 7.09–7.20 (m, 2H), 7.42–7.54 (m, 5H), 7.83
NMR (CDCl3): δ 2.03–2.29 (m, 2H), 2.25 (s, 3H), 2.34 (s, 1H), 7.84–7.91 (m, 3H); 13C NMR (CDCl3): δ 13.4,
(s, 3H), 4.18–4.31 (m, 2H), 4.47–4.59 (m, 1H), 7.08 (s, 38.4, 40.3, 69.6, 109.7, 118.2, 121.1, 121.4, 123.9,
1H), 7.12 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.43 (d, J 124.4, 125.6, 126.1, 127.5, 127.7, 132.3, 132.8, 135.0,
= 8.4 Hz, 2H), 7.85 (s, 1H); 13C NMR (CDCl3): δ 20.2, 142.4, 142.9, 151.7; Anal. Calcd. for C21H20N2O: C,
20.7, 38.0, 41.6, 68.8, 110.0, 120.1, 121.3, 127.7, 131.3, 79.72; H, 6.37; N, 8.85. Found: C, 79.94; H, 6.60; N,
131.6, 131.9, 132.4, 142.0, 143.0, 144.1; Anal. Calcd. 8.61.
for C18H19BrN2O: C, 60.18; H, 5.33; N, 7.80. Found: C,
59.95; H, 5.55; N, 8.02.
(±)-3-(1H-Benzimidazol-1-yl)-1-(thiophen-2-
yl)-1-propanol (60). Colorless crystals (2-propanol),
1
(±)-3-(1H-Benzimidazol-1-yl)-1-(naphthalen-1-yl) yield 465 mg (60%), mp 127–128°C; H NMR (CDCl3):
propan-1-ol (56). Colorless crystals (2-propanol), yield δ 2.32–2.45 (m, 2H), 4.11 (s, 1H), 4.30–4.38 (m, 1H),
1
752 mg (83%), mp 173–174°C; H NMR (d6-DMSO): δ 4.47–4.57 (m, 1H), 4.80 (dd, J = 5.6 and 8.0 Hz, 1H),
2.04–2.16 (m, 1H), 2.26–2.38 (m, 1H), 4.39–4.49 (m, 6.94 (d, J = 3.6 Hz, 1H), 6.97 (dd, J = 3.6 and 4.8 Hz,
1H), 4.52–4.63 (m, 1H), 5.23 (d, J = 9.6 Hz, 1H), 5.69 (d, 1H), 7.26–7.32 (m, 3H), 7.44 (d, J = 7.6 Hz, 1H), 7.72
J = 3.6 Hz, 1H), 7.19–7.35 (m, 3H), 7.42–7.53 (m, 2H), (d, J = 7.6 Hz, 1H), 7.92 (s, 1H); 13C NMR (CDCl3): δ
7.58 (dd, J = 1.2 and 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 38.6, 41.6, 66.1, 109.9, 120.3, 122.4, 123.2, 123.9,
2H), 7.79 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 124.8, 126.9, 133.7, 143.5, 143.7, 148.5; Anal. Calcd.
8.27 (s, 1H); 13C NMR (d6-DMSO): δ 38.4, 41.7, 66.3, for C14H14N2OS: C, 65.09; H, 5.46; N, 10.84. Found: C,
110.4, 119.5, 121.5, 122.3, 122.7, 125.4, 125.5, 125.8, 65.32; H, 5.19; N, 11.07.
127.2, 128.7, 129.6, 133.2, 133.8, 141.0, 143.6, 144.2;
(±)-3-(2-Methyl-1H-benzimidazol-1-yl)-1-
Anal. Calcd. for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. (thiophen-2-yl)-1-propanol (61). Colorless crystals
Found: C, 79.69; H, 5.78; N, 9.50.
(2-propanol–hexanes), yield 555 mg (68%), mp 146–
1
(±)-3-(2-Methyl-1H-benzimidazol-1-yl)-1- 147°C; H NMR (CDCl3): δ 2.31–2.38 (m, 2H), 2.58 (s,
(naphthalen-1-yl)propan-1-ol (57). Colorless crystals 3H), 3.64 (br s, 1H), 4.24–4.33 (m, 1H), 4.35–4.45 (m,
(2-propanol), yield 758 mg (80%), mp 176–177°C 1H), 4.95 (t, J = 6.4 Hz, 1H), 6.94–7.01 (m, 2H), 7.20–
(softening at 165°C); 1H NMR (CDCl3): δ 1.95–2.07 (m, 7.31 (m, 3H), 7.33–7.40 (m, 1H), 7.62–7.68 (m, 1H); 13
C
1H), 2.19–2.31 (m, 1H), 2.56 (s, 3H), 4.30–4.40 (m, 1H), NMR (CDCl3): δ 13.8, 38.9, 40.4, 66.8, 109.4, 119.0,
4.45–4.55 (m, 1H), 5.23 (d, J = 9.6 Hz, 1H), 5.68 (d, 122.1, 122.2, 124.1, 125.1, 127.0, 135.2, 142.6, 148.0,
J = 3.6 Hz, 1H), 7.11–7.19 (m, 2H), 7.26–7.33 (m, 1H), 151.8; Anal. Calcd. for C15H16N2OS: C, 66.15; H, 5.92;
7.39–7.57 (m, 4H), 7.64 (d, J = 8.8 Hz, 1H), 7.69 (d, J = N, 10.29. Found: C, 66.39; H, 6.09; N, 10.08.
8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz,
4-(3-(2-Methyl-1H-benzimidazol-1-yl)-1-
suspension of
1H); 13C NMR (CDCl3): δ 13.4, 38.0, 40.5, 66.1, 109.8, hydroxypropyl)phenol (62).
A
118.2, 121.1, 121.4, 122.6, 122.7, 125.4, 125.5, 125.7, benzimidazole–ketone 33 (840 mg, 3 mmol) in methanol
127.2, 128.7, 129.5, 133.2, 135.0, 141.1, 142.5, 151.8; (20 mL) was treated with NaBH4 (570 mg, 15 mmol) in
Anal. Calcd. for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. small portions under efficient stirring. The mixture is
Found: C, 79.44; H, 6.14; N, 9.09.
stirred at room temperature overnight, and then the
(±)-3-(1H-Benzimidazol-1-yl)-1-(naphthalen-2- solvent is removed under reduced pressure to give a
yl)propan-1-ol (58). Colorless crystals (2-propanol– sticky residue. Upon treatment with an excess of 10%
hexanes), yield 660 mg (73%), mp 123–124°C; 1H NMR HCl, this residue gradually dissolves in water (30 mL).
(d6-DMSO): δ 2.10–2.31 (m, 2H), 4.30–4.47 (m, 2H), The solution is filtered, cooled in an ice-bath, and treated
4.64–4.74 (m, 1H), 5.69 (d, J = 2.8 Hz, 1H), 7.17–7.29 dropwise with 28% NH4OH under efficient stirring until
(m, 2H), 7.43–7.53 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), pH reaches 8. The solid is filtered, washed thoroughly
7.66 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.84–7.91 (m, 3H), with water, air-dried, and recrystallized from 2-propanol
1522

G. Roman
to give colorless crystals (565 mg, 67%), mp 200– derived from 4′-hydroxyacetophenone, owing to its rapid
1
201°C; H NMR (d6-DMSO): δ 1.91–2.07 (m, 2H), 2.52 separation from the reaction mixture while being heated
(s, 3H), 4.17–4.31 (m, 2H), 4.41–4.49 (m, 1H), 5.35 (d, under reflux. Reaction times longer than 4 hours were
J = 4.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 7.09–7.21 (m, preferred for the synthesis of Mannich base 8 derived
4H), 7.42 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), from 1-acetylnaphthalene, as an attempt to improve the
9.30 (br s, 1H); 13C NMR (d6-DMSO): δ 13.3, 38.6, 40.3, low yields reported in literature [23]. Additionally, the
69.2, 109.7, 114.8, 118.2, 121.1, 121.4, 126.9, 135.0, aminomethylation of 4′-phenylacetophenone in ethanol
135.7, 142.4, 151.7, 156.3; Anal. Calcd. for C17H18N2O2: was revisited, despite previous reports of failure [22]. In
C, 72.32; H, 6.43; N, 9.92. Found: C, 72.11; H, 6.09; N, contrast to this, the classical procedure ensured good
10.20.
yields of the desired compound 7 after 48 h, and a pure
2-(3-(1H-Benzimidazol-1-yl)-1-hydroxypropyl)- sample, in which the corresponding acrylophenone by-
4-methylphenol (63). The solution of benzimidazole– product could not be detected, was obtained after one
ketone 39 (840 mg, 3 mmol) in methanol (20 mL) was recrystallization of the crude product.
treated with NaBH4 (570 mg, 15 mmol) in small portions
Two experimental approaches for the amine
under vigorous stirring at room temperature, and then exchange reaction involving ketonic Mannich bases
the reaction mixture was stirred at room temperature and NH-azoles are available in the literature [4]. The
overnight. The solvent was removed under reduced difference between the two sets of conditions rests with
pressure and the residue was dissolved in water the nature of the solvent employed (aprotic or protic),
(30 mL). Dropwise addition of 10% acetic acid until pH which in turn determines the form of the Mannich base
reaches 7 yielded a colorless solid, which was removed (free base or salt, respectively) used in the reaction.
by filtration, washed thoroughly with water, air-dried, and Because there appears to be no significant difference
recrystallized from ethanol to afford colorless crystals between the yields for the isolated reaction products
(755 mg, 89%), mp 169–170°C; 1H NMR (CDCl3): in both sets of conditions for ketonic Mannich bases
δ 1.96–2.05 (m, 1H), 2.13–2.24 (m, 1H), 2.20 (s, 3H), as substrates in the amine exchange reaction [4],
3.76 (br s, 1H), 4.38 (t, J = 7.2 Hz, 2H), 4.85–4.87 (m, and because the intermediate ketonic Mannich bases
1H), 6.66 (d, J = 8.0 Hz, 1H); 6.84 (d, J = 8.0 Hz, 1H), are usually isolated as hydrochlorides, the approach
7.18–7.28 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H), 7.67 (d, employing protic solvents has been favored in this
J = 7.6 Hz, 1H), 8.26 (s, 1H), 9.20 (br s, 1H); 13C NMR study. Provided that both reactants are water-soluble,
(CDCl3): δ 20.5, 37.4, 41.6, 64.4, 110.4, 114.8, 119.4, the replacement of the amine moiety in Mannich bases
121.6, 122.3, 126.7, 127.2, 127.8, 131.2, 133.9, 143.2, with an NH-azole in a protic medium is best conducted
144.0, 151.2. Anal. Calcd. for C17H18N2O2: C, 72.32; H, in water. Besides being an environmentally friendly
6.43; N, 9.92. Found: C, 72.59; H, 6.22; N, 10.12.
solvent, water also presents the advantage of a simple
separation of the transamination product, which is
usually water-insoluble. However, a mixture of water
and ethanol is desirable as protic medium in the amine
exchange reaction leading to the benzimidazole-derived
compounds, owing to the limited solubility of some
benzimidazoles in water at low temperatures. In this
case, the resulting benzimidazole–ketones separate
from the cold reaction mixtures in most cases as almost
pure solids, and they can be subsequently isolated
by filtration. Commercially available benzimidazole,
3. Results and discussions
The aim of this study is to explore extensively the
amine exchange reaction between benzimidazoles
and ketonic Mannich bases derived from several
common alkyl aryl ketones. Commercially available
acetophenones substituted in the aromatic ring were
the typical substrates in the synthesis of these ketonic
Mannich bases, and 1- and 2-acetylnaphthalene,
2-acetylthiophene and 1-tetralone were chosen as
substrates for aminomethylation with the aim to
illustrate the behavior of structurally more diverse
ketonic Mannich bases in the N-alkylation reaction of
NH-azoles. The ketonic Mannich bases 4–14 required
as intermediates in this study were obtained through
the direct aminoalkylation of an alkyl aryl ketone in
ethanol or 2-propanol [19]. The standard reaction time
was 4 hours; however, the reaction time was shortened
to 2 hours for the sparingly soluble Mannich base 10
2-methyl-1H-benzimidazole,
and
5,6-dimethyl-1H-
benzimidazole were commonly employed for the
displacement of the amine moiety in the ketonic Mannich
base 4–14; 2-ethyl-1H-benzimidazole, 2-benzyl-1H-
benzimidazole,
and 2-(naphthalen-1-ylmethyl)-1H-benzimidazole
were the NH-azole counterpart in the amine exchange
reaction in limited number of examples only
2-phenoxymethyl-1H-benzimidazole,
a
(Scheme 2). The benzimidazoles 15–51 alkylated at N1
with residues derived from ketonic Mannich bases were
generally obtained in good to excellent yields using this
1523

N-Alkylation of benzimidazoles with ketonic Mannich bases
and the reduction of the resulting 1-(3-oxopropyl)benzimidazoles
Scheme 2. Synthesis of benzimidazole–ketones 15–51 and their reduction to the corresponding alcohols 52–63. Reagents and conditions:
a) substituted benzimidazoles, ethanol–water (1:1, v/v), reflux, 1 h; b) NaBH4, methanol, rt, overnight.
approach. It is worth mentioning that compounds derived 33 has a very low solubility in cold methanol. Whereas
from 2-methylbenzimidazole and 2-ethylbenzimidazole all other benzimidazole–ketones are reduced swiftly
were frequently difficult to purify by recrystallization, and quantitatively in a homogenous system by three
as they have a tendency to separate as oils from their equivalents of NaBH4, the reduction of benzimidazole–
concentrated solutions, even upon slow cooling. Also, ketone 33 is limited by the rate of dissolution of the
the purification of benzimidazoles N1-alkylated with a substrate, which is in turn determined by the formation
moiety derived from the Mannich base of 1-tetralone was of the corresponding more soluble sodium salt. Because
often troublesome, and 2-(2-methyl-1H-benzimidazol-1- the sodium salt of the substrate is formed slowly and
ylmethyl)-3,4-dihydronaphthalen-1(2H)-one 50 was the gradually in the reaction with sodium methoxide
only benzimidazole derivative in this study that could not resulted from the methanolysis of the reducing agent,
be obtain as a solid.
it is conceivable that significant amounts of NaBH4 are
The reduction of selected 1-(3-oxopropyl) consumed without any actual reduction of the substrate
benzimidazoles with NaBH4 in methanol at room taking place. Indeed, when compound 33 was reduced
temperature occurred at the carbonyl function to produce usingthreeequivalentsofreducingagent, aTLCanalysis
1-(3-hydroxypropyl)benzimidazoles 52–63 (Scheme 2). showed the presence of the starting material at the end
The reducing agent (an excess of three equivalents) of the reaction time, and the NMR analysis of an aliquot
was added in small portions to the solution of the confirmed the presence of approximately 30% unreacted
benzimidazole–ketone, and then the reaction mixture benzimidazole–ketone 33 in the reaction mixture.
was stirred overnight. The isolation of the reaction However, when 5 equivalents of NaBH4 were used, the
product involves the removal of the solvent under conversion of the starting material 33 into benzimidazole-
reduced pressure, followed by addition of water with the alcohol 62 was complete. The isolation of compound 62
view to dissolve the inorganics. The resulting secondary required also particular attention, due to the presence
alcohol usually solidifies after some time, and is filtered of an acidic phenolic group and a benzimidazole moiety
off; in a small number of cases, extraction with ethyl capable of forming water-soluble salts in the presence
acetate was necessary in order to isolate the reaction of acids. The sticky semi-solid resulted after the removal
products, owing to their reluctance to crystallize even of methanol, presumably a mixture of the sodium salt
after having been stirred for up to one day. Under these of 63 and inorganic by-products of the reaction, did
experimental conditions, the isolated benzimidazole– not dissolve well in water, but formed readily a solution
alcohols are devoid of any starting material, and the upon treatment with dilute HCl. The solution was
yields are almost quantitative. The analytical samples filtered, cooled in an ice-bath, and rendered basic with
were however purified by recrystallization, usually concentrated NH4OH, when benzimidazole-alcohol 62
accompanied by filtration to remove small amounts precipitated as a crystalline solid. Despite its significantly
of fine particles (presumably inorganics incorporated higher solubility in methanol compared to compound 33,
within the crystals upon solidification). Because these five equivalents of NaBH4 were employed also in the
benzimidazole–alcohols are quite soluble in inferior case of benzimidazole–ketone 39, and the TLC analysis
alcohols, the solvent of choice for purification was either proved the complete reduction of the substrate at the
2-propanol or its mixture with hexanes, but, even under end of the reaction time. The isolation of benzimidazole–
these conditions, the recovery was sometimes poor.
alcohol 63 was straightforward, as the residue obtained
The reduction of benzimidazole–ketones 33 and 39 after the removal of methanol was completely soluble
derived from hydroxyacetophenones is particular due to in water. Careful treatment with dilute acetic acid under
the presence of the phenolic group. First of all, compound strict monitoring of pH provided the compound 63 as
1524

G. Roman
a crystalline solid; at lower pH, the amount of isolated by the occasional aliphatic carbon atoms present in the
precipitate decreased, as benzimidazole–alcohol 63 structure of benzimidazole–ketones 15–51, two signals,
dissolved partially in the acidic solution.
falling in the range from 37 to 41 ppm, are detectable
All ofthe synthesized compounds were characterized always in the aliphatic region of the carbon spectra of
by NMR spectroscopy. The representative feature in the these compounds; these signals are correlated with
1H NMR spectra of benzimidazole–ketones 15–48 is the carbon atoms in the two methylene groups of the
the pair of well-defined triplets at approximately 3.5 and linker. Upon reduction of benzimidazole–ketones to
4.5 ppm, which are associated with the protons of the benzimidazole–alcohols, the chemical shift of these two
methylenegroupsinthelinkerbetweenthebenzimidazole carbon atoms does not change much, but the presence
moiety and the aromatic ring originating from the initial of a third signal at about 65–70 ppm, and the absence
Mannich base. In the case of benzimidazole–ketones of the signal appearing at about 190–200 ppm in the
49–51 derived from 1-tetralone, the substitution at the carbon spectra of benzimidazole–ketones are indicative
carbon atom adjacent to the carbonyl group destroys for the conversion of the carbonyl group into a hydroxyl
the pattern observed in aliphatic region of proton spectra function.
of their analogs 15–48 and creates two diastereotopic
protons. Consequently, the typical feature in the 1H
NMR spectra of benzimidazole–ketones 49–51 is the 4. Conclusions
pair of double doublets around 4.5 ppm engendered
by the protons in the methylene group attached to the The exploration of the scope of the N-alkylation of
benzimidazole ring. The transformation of the carbonyl benzimidazoles with ketonic Mannich bases has
groupintoasecondaryalcoholfunctionthroughreduction shown that azole substrates having various substitution
also alters significantly the appearance of the aliphatic patterns and a wide range of the aforementioned
region of the proton spectra of benzimidazole–alcohols alkylating agents derived from acetophenones,
52–63. The protons in the methylene group adjacent to acetonaphtones, 2-acetothienone or 1-tetralone are
the hydroxyl function appear as two multiplets between amenable to this reaction. The use of a variety of
2 and 2.5 ppm that overlay one another to some extent benzimidazoles and ketonic Mannich bases allowed
in several cases. The remaining protons (two from the the facile creation of a small library of structurally
methylene group next to the benzimidazole moiety diverse 1-(3-oxopropyl)benzimidazoles that were fully
and one attached to the carbon atom of the secondary described and characterized. This library was used to
alcohol function) usually give three multiplets in the range generate a second set of compounds that comprises
of 4 to 5 ppm whose peaks are often superimposed. 1-(3-hydroxypropyl)benzimidazoles by means of the
A broad singlet or a doublet with a coupling constant reduction of the carbonyl group with NaBH4. The
within the range of 3 to 5 Hz that can be associated antimicrobial activity of selected compounds from these
with the proton of the hydroxyl group is noticeable collections will be investigated.
also in the proton spectra of benzimidazole–alcohols
52–63.
The transformation of benzimidazole–ketones into
benzimidazole–alcohols is reflected also in the 13C NMR
Acknowledgement
spectra. Again, the carbon atoms in the linker bridging
the two aromatic moieties in the structures of these
compounds are responsible for the distinctive features in
their carbon spectra. Aside from other peaks produced
The research leading to these results has received
funding from the European Union’s Seventh Framework
Programme (FP7/2007-2013) under grant agreement
n°264115 – STREAM.
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