Novel access to 1-substituted-benzimidazoles via benzotriazole-mediated synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.10.094

A one-pot good-yielding synthesis of 1-(alcoxymethyl)-1H-benzimidazoles and 1-((1H-benzimidazol-1-yl)methyl)-1H-benzotriazole from N¹,N²-bis((1H-benzotriazol-1-yl)methyl)benzene-1,2 -diamine (3) and alcohols is described. The synthesis of 3 from macrocyclic aminal 6H,13H-5:12,7:14-dimethanedibenzo-[d,i][1,3,6,8]tetraazecine (DMDBTA, 1) and benzotriazole is also described. Both these methods are simple, isolation of the products from the reaction mixtures is easy, and the yields are good.

Full text of DOI:10.1016/j.tetlet.2009.10.094

Tetrahedron Letters 51 (2010) 102–104
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel access to 1-substituted-benzimidazoles via
benzotriazole-mediated synthesis
*
Augusto Rivera , Mauricio Maldonado, Jaime Ríos-Motta, Miguel Angel Navarro, Diego González-Salas
Departamento de Química, Universidad Nacional de Colombia, Ciudad Universitaria, Carrera 30 No. 45-03, Bogotá DC, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot good-yielding synthesis of 1-(alcoxymethyl)-1H-benzimidazoles and 1-((1H-benzimidazol-1-
yl)methyl)-1H-benzotriazole from N1,N2-bis((1H-benzotriazol-1-yl)methyl)benzene-1,2-diamine (3)
Received 21 August 2009
Revised 16 October 2009
Accepted 19 October 2009
Available online 23 October 2009
and alcohols is described. The synthesis of
3 from macrocyclic aminal 6H,13H-5:12,7:14-dim-
ethanedibenzo-[d,i][1,3,6,8]tetraazecine (DMDBTA, 1) and benzotriazole is also described. Both these
methods are simple, isolation of the products from the reaction mixtures is easy, and the yields are good.
Ó 2009 Elsevier Ltd. All rights reserved.
6H,13H-5:12,7:14-Dimethanedibenzo[d,i][1,3,6,8]tetraazecine
(DMDBTA, 1), which was prepared for the first time by the end of
the 19th-century by condensation of o-phenylenediamine with
formaldehyde,1 belongs to a class of nitrogen-containing heterocy-
cles having a cage-adamanzanes-type structure. Now, it is worth
pointing out that during our continuous research program about
the reactivity of 1,2–4 the reaction between 1 and benzotriazole
in dioxane yielding bis-1,3(benzotriazol-yl-methyl)-2,3-dihydro-
benzil imidazole (2) resulted in moderate yield.4 In order to im-
prove the yield of 2 we used ethyl acetate as a solvent instead of
dioxane due to the major stability of 1 in this solvent. Under these
conditions an unexpected compound called N1,N2-bis((1H-ben-
zotriazol-1-yl)methyl)benzene-1,2-diamine (3) was obtained in
good yields.5 It should be noted that 3 is an interesting compound
because it possesses two benzotriazolyl groups, and it is structur-
N
N
N
N
N
N
N
N
N
N
N
N
1
2
N
N
N
R1
N
NH HN
N
N
N
R2
N
N
N
4
3
OH
HO
R
R
H
H
N
ally related to compounds such as N-(
a-amino substituted)-benzo-
N
triazoles (4) which constitute an interesting class of aminals that
react by nucleophilic substitution of the benzotriazolyl group with
a variety of O-, S-, and C-nucleophiles.6
The molecular structure of 3, which to the best of our knowl-
edge is previously unreported, became evident from NMR spectral
measurements in DMSO-d6. The 1H NMR spectrum of 35 showed
two set of signals for the aromatic protons which were unequivo-
cally assigned to protons of the benzotriazolyl and o-phenylenedi-
amine rings, based on their chemical shifts and correlation in the
2D-COSY spectrum.
5
Single-crystal X-ray diffraction analysis7 revealed that 3 is com-
posed of discrete monomeric molecules with the two benzotriazol-
yl moieties arranged in a face-to-face manner. The bond angles
around the benzylic carbon are close to normal tetrahedral bond
angles. The bond angles around atoms N4 and N5 are close to
P
sp2-hybridization [
a
ffi 360°]. Interestingly, the two benzotriaz-
An X-ray analysis confirmed the structure of 3.7 The molecular
diagram is shown in Figure 1, and relevant bond lengths and angles
are given in Table 1.
olyl–methylene bonds are different (C20–N3 and C19–N6, Table
1). This observation is explained in terms of a strong anomeric ef-
fect of the nN5?
rꢀC19—N6. Such stereoelectronic interactions might
cause a lengthening of the C19–N6 bond.8
Next, our attention was initially focused on the presumption
that 3 can undergo double amino-alkylation with phenols to give
the corresponding di-Mannich bases 5. However, attempts to pre-
pare target compounds 5 by treating 3 with phenols in 2-propanol
* Corresponding author. Tel.: +57 1 3165000x14464; fax: +57 1 3165220.
E-mail address: ariverau@unal.edu.co (A. Rivera).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.094

A. Rivera et al. / Tetrahedron Letters 51 (2010) 102–104
103
Table 2
Reactions of compound 3 with alcohols a–h
Entry
Alcohol
Time (h)
Yield (%)
6a–c
8
7
a
b
c
d
e
f
MeOH
EtOH
i-PrOH
PrOH
ButOH
PentOH
HexOH
t-BuOH
36
34
26
30
24
9
64.2
49.0
16.7
—
—
—
—
—
—
24.8
29.6
49.0
41.6
38.2
19.7
22.4
68.4
59.1
48.6
21.8
45.1
51.3
g
h
5
26
—
—
to explore the scope and generality of this reaction using alcohols
of different sizes (Scheme 1).11 During the work, however, we
found unexpected results; with the smaller-sized alcohols such
as methanol and ethanol, the respective 1-(alcoxy methyl)-1H-
benzimidazoles (6a–b) were obtained in yields of 64.2% and
49.0%, respectively (Table 2, entries a and b), but with propanol,
butanol, pentanol, hexanol, and 1,1-dimethyl-ethanol, none of
the 1-(alcoxymethyl)-1H-benzimidazoles (6) were produced as
stated by TLC, and the reactions instead afforded benzotriazole, 7
and the compound 1-((1H-benzimidazol-1-yl)methyl)-1H-benzo-
triazole (8) in good yields (see Table 2).
Figure 1. The molecular structure of 3. Displacement ellipsoids are drawn at the
50% probability level, and H atoms are shown as small spheres.
Table 1
Selected bond lengths (Å) and bond angles (°) for 3
Bond lengths
Bond angles
The structures of the compounds 6a–c and 8 were established
through rigorous spectroscopic analysis.11 The structure of 8 was
initially determined using an array of NMR experiments. These
NMR data, together with LR–MS (m/z 249.0 [M+]) confirmed the
suggested structure of compound 8. Satisfactory elemental analy-
ses were obtained for compounds 6a–c and 8.11
C1–N4
1.404(3)
1.417(4)
1.458(4)
1.402(3)
1.429(4)
1.478(4)
N5–C19–N6
N4–C20–N3
115.0(2)
113.9(2)
C20–N4
C20–N3
C2–N5
C19–N5
C19–N6
This singular behavior of 3 was attributed to the strong ten-
dency of 3 to undergo a ring-closing reaction to yield 8, due to
the presence of a strong anomeric effect, which assisted the facile
loss of the one benzotriazole moiety,8 and the additional stability
of benzimidazole ring (8) over the expected product. Although a
more in-depth study of the reaction mechanism is required, the
results provide evidence that 3 undergoes a rearrangement process
under the given reaction conditions, followed by fast oxidation of
the resulting 1-((2,3-dihydro-1H-benzimidazol-1-yl)methyl)-1H-
benzotriazole (9) with atmospheric oxygen to form 1-((1H-ben-
as the solvent according to known procedures9,10 were unsuccess-
ful. The only substances that could be isolated from this reaction
were the starting phenol and the unexpected products 1-(isoprop-
oxymethyl)-1H-benzimidazole (6c) and 1-methyl-benzimidazole
(7). It is noteworthy that parallel reactions carried out in the ab-
sence of phenol always gave compounds 6c (yield 16.7%) and 7
(yield 68.4%). On the basis of these interesting results, we decided
NH HN
NH HN
N
N
N
N
N
N
pathway A
-Btz
N
N
N
3
10
-Btz
N
N
HN
N
N
N
R
O
R-OH
-Btz
N
N
N
Redox
-Btz
2
N
N
N
8
9
+
6 a-c
a: R = -CH3
b: R = -CH2-CH3
CH3
N
N
c
: R = -CH-(CH3)2
7
Scheme 1. Proposed pathways to the formation of 6a–c, 7, and 8.

104
A. Rivera et al. / Tetrahedron Letters 51 (2010) 102–104
4. Rivera, A.; Maldonado, M.; Núñez, M. E.; Joseph-Nathan, P. Heterocycl. Commun.
2004, 10, 77–80.
zimidazol-1-yl)methyl)-1H-benzotriazole (8) (Scheme 1), which
has been reported for the preparation of benzimidazole
derivatives.12,13
5. Preparation of N1,N2-bis((1H-benzotriazol-1-yl)methyl)-benzene-1,2-diamine (3):
A
mixture of 1 g (3.79 mmol) of DMDBTA and 0.9 g (7.58 mmol) of
benzotriazole in 5 mL of ethyl acetate was stirred for 12 h at room
temperature. The precipitated solid was collected by filtration and was
washed with ethyl acetate and dried in vacuo: yield 85%, mp 156–158 °C. 1H
NMR (400 MHz, DMSO-d6): d 6.17 (d, J = 6.84 Hz, 4H), 6.51 (t, J = 6.84 Hz, 2H, –
NH), 6.48 (m, 2H), 6.75 (m, 2H), 7.34 (t, J = 7.88 Hz, 2H, Bt), 7.47 (t, J = 7.88 Hz,
2H), 7.98 (d, J = 7.88 Hz, 4H).13C NMR (100 MHz, DMSO-d6) d: 57.3, 111.0,
112.5, 119.0, 119.2, 123.9, 127.1, 132.2, 133.1, 145.4.
There are two plausible reaction pathways that would explain
the selective elimination of one benzotriazolyl moiety (Btz) of 3
to produce 8. The first one (pathway A in Scheme 1) involves a
stepwise mechanism with a rate-limiting expulsion of the benzo-
triazolate leaving group to give the cationic intermediate (10),
which undergoes an intramolecular cyclization. The second pro-
posed pathway (B in Scheme 1) may be explained by the presump-
tion that the preferred conformation of the molecule acts as an
organic template which induces pre-organization to favor its sub-
sequent cyclization to the benzimidazole ring, involving a con-
certed mechanism with simultaneous bond formation and fission
in which the leaving group is expelled as an anion.
6. Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409–548.
7. Crystal data for compound 3, C20H18N8, were collected using a Siemens Smart
CCD diffractometer, M = 370.42, monoclinic, P2(1)/c, a = 10.302(1),
b = 17.565(2), c = 10.662(1) Å, V = 1816.4(4) Å3, Z = 4, Dcalcd = 1.355 g/cmꢁ3, X-
ray source Mo K
a (radiation), k = 0.71073 Å, F(0 0 0) = 776, colorless prism
0.50 ꢂ 0.29 ꢂ 0.25 mm. The structure solution was obtained by direct methods
and was refined with anisotropic thermal parameters using full-matrix least
squares procedures on F2 to give R = 0.064, wR = 0.220 for 5303 independent
observed reflections and 261 parameters. Crystallographic data (excluding
structure factors) for the given structure in this Letter have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 745159. Copies of these data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44(0) 1223 336033 or email: deposit@ccdc.cam.ac.uk).
Finally, in order to investigate the reaction mechanism, we used
density functional theory (DFT) calculations to analyze the trans-
formation of 3–8. The structure of 3, the transition states, and
intermediates were further optimized using density functional the-
ory (DFT) at the B3LYP level and a 6-31G(d) basis set.14 Both tran-
sition states were characterized with vibrational frequency
analyses performed at the same theoretical level, which showed
only one imaginary frequency in each transition state.15 All the cal-
culations were carried out using the GAUSSIAN 98W program pack-
age.16 The gas-phase energy barrier at the B3LYP/6-31G* level for
the bimolecular mechanism is only 1.4 kcal/mol higher in energy
than unimolecular mechanism. However, inclusion of the solvent
effect, performed through single-point calculations on the gas-
phase optimized structures using the polarizable continuum model
(PCM),17–19 increases the free-energy barrier for the unimolecular
mechanism by 13.6 kcal molꢁ1, which indicates that the formation
of pentacoordinated transition state is thermodynamically favored.
Due to the relatively low nucleophilicity of alcohols compared
to amines and the tendency of 3 to undergo spontaneous cycliza-
tion to afford 1-((1H-benzimidazol-1-yl)methyl)-1H-benzotriazole
(8) (Scheme 1), we believe that 8 would be an obvious precursor to
6a–c. Thus, the intermediate 8, formed by oxidation, reacts by sub-
sequent nucleophilic substitution by small alcohols (Scheme 1),
whereas the observed unreactivity of the other alcohols (Table 2,
entries d–h) was expected on the basis of the mechanistic hypoth-
esis due to the lower nucleophilicity of these bulky alcohols.20 To
confirm the latter, we carried out the reactions between 8 and
the cited alcohols, but the results were similar to those previously
obtained with 3, thus we concluded that 8 was the compound
undergoing the substitution reaction. Further investigations on
the synthetic applications of N1,N2-bis((1H-benzotriazol-1-yl)-
methyl)-benzene-1,2-diamine (3) and 1-((1H-benzimidazol-1-yl)-
methyl)-1H-benzotriazole (8) are in progress.
8. Katritzky, A. R.; Steel, P. J.; Denisenko, S. N. Tetrahedron 2001, 57, 3309–3314.
9. Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E.; Steel, P. J.; Schall, O. F.;
Gokel, G. W. J. Org. Chem. 1996, 61, 7585–7592.
10. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Belyakov, S. A.;
Ghiviriga, I.; Steel, P. J. J. Org. Chem. 1999, 64, 6071–6075.
11. Reaction of N1,N2-bis((1H-benzotriazol-1-yl)methyl)-benzene-1,2-diamine with
alcohols: In a typical reaction, the appropriate alcohol and N1,N2-bis((1H-
benzotriazol-1-yl)methyl)-benzene-1,2-diamine were heated to reflux for
different times, ranging from 5 to 36 h. The solution was concentrated by
rotary-evaporator, and the residue was purified by column chromatography on
silica gel (eluted with benzene/ethyl acetate, 8:2) to afford: 1-(methoxymethyl)-
1H-benzimidazole (6a): 1H NMR (400 MHz, CDCl3): d 3.28 (s, 3H), 5.49 (s, 2H),
7.33 (m, 2H), 7.52 (d, J = 8 Hz, 1H), 7.81 (d, J = 8 Hz, 1H), 7.98 (s, 1H). 13C NMR
(100 MHz, CDCl3) d: 56.3, 76.0, 110.2, 120.4, 122.8, 123.6, 133.6, 143.1, 144.0
(CG–MS) m/z 162 (M+). Elemental Anal. Calcd for C9H10N2O: C, 66.6 7; H, 6.17;
N, 17.28. Found: C, 66.59; H, 6.21; N, 17.24. 1-(Ethoxymethyl)-1H-benzimidazole
(6b): 1H NMR (400 MHz, CDCl3): d 1.14 (t, J = 7 Hz, 3H), 3.43 (q, J = 7 Hz, 2H),
5.53 (s, 2H), 7.31 (t, J = 6 Hz, 2H,), 7.53 (d, J = 6.2 Hz, 1H), 7.80 (d, J = 6.5 Hz, 1H),
7.97 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 14.1, 64.3, 75.5, 110.1, 120.3, 122.6,
123.4, 133.6, 143.0, 143.9 (CG–MS) m/z 176 (M+). Elemental Anal. Calcd for
C10H12N2O: C, 68.18; H, 6.82; N, 15.91. Found: C, 68.13; H, 6.86; N, 115.87. 1-
(Isopropoxymethyl)-1H-benzimidazole (6c): 1H NMR (400 MHz, CDCl3): d 1.14 (d,
J = 6.4 Hz, 6H), 3.66 (h, J = 6.4 Hz, 6H), 5.57 (s, 2H), 7.31 (t, J = 6.2 Hz, 2H), 7.54
(d, J = 6.2 Hz, 1H), 7.81 (d, J = 6.2 Hz, 1H), 7.98 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 21.9, 69.8, 72.4, 110.3, 120.4, 122.7, 123.4, 133.4, 142.8, 142.8 (CG–
MS) m/z 190 (M+). Elemental Anal. Calcd for C11H14N2O: C, 69.47; H, 7.37; N,
14.74. Found: C, 69.42; H, 7.41; N, 14.71. 1-(1H-Benzimidazol-1-yl-methyl)-1H-
1,2,3-benzotriazole (8): 1H NMR (400 MHz, CDCl3): d 6.95 (s, 2H), 7.31 (t,
J = 7.6 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.50 (d, J = 8.1 Hz,
1H), 7.52 (t, J = 8.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 8.08
(d, J = 8.1 Hz, 1H), 8.25 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 55.7, 108.6, 110.0,
120.7, 120.8, 123.4, 124.3, 124.7, 128.7, 131.9, 132.9, 142.2, 143.9, 146.4 (CG–
MS) m/z 249 (M+). Elemental Anal. Calcd for C14H11N5: C, 67.47; H, 4.42; N,
28.08. Found: C, 67.41; H, 4.46; N, 28.03.
12. (a) Ivanova, N. V.; Sviridov, S. I.; Stepanov, A. E. Tetrahedron Lett. 2006, 47,
8025–8027; (b) Vojtech, M.; Petrušová, M.; Sláviková, E.; Bekešová, S.; Petruš,
L. Carbohydr. Res. 2007, 342, 119–123.
13. Gallant, A. J.; Patrick, B. O.; MacLachlan, M. J. J. Org. Chem. 2004, 69, 8739–8744.
14. Finley, J. W.; Stephens, P. J. J. Mol. Struct. (Theochem) 1995, 357, 225–235.
15. Foresman, J. B., Frish, A. E. Exploring Chemistry with Electronic Structure Methods;
Gaussian: Pittsburgh, PA, 1993.
16. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A. Jr.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M.
C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.;
Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.;
Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko,
A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
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M.; Replogle, E. S.; Pople, J. A. GAUSSIAN 98, Revision A.9, Gaussian, Inc.:
Pittsburgh, PA, 1998.
In this Letter, we introduce N1,N2-bis((1H-benzotriazol-1-
yl)methyl)benzene-1,2-diamine (3) as a new starting material for
the synthesis of 1-substituted-1H-benzo[d]imidazoles. This meth-
odology represents a valid alternative to the existing procedures
especially for 1-alkylsubstituted benzimidazoles.
Acknowledgments
The authors acknowledge the Division de Investigaciones Bo-
gotá (DIB) and the Universidad Nacional de Colombia, for financial
support. M.A.N. and D.G.-S. acknowledge Colciencias for their
fellowships.
17. Tomasi, J.; Cammi, R.; Mennucci, B.; Cappeli, C.; Corni, S. Phys. Chem. Chem.
Phys. 2002, 4, 5697–5712.
18. Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327–
335.
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