A convenient synthesis of benzannelated diazacycloalkanes by reductive cleavage of 1,2-polymethylenebenzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2013.11.025

A facile procedure for the synthesis of benzannelated diazacycloalkanes 3 is elaborated on the basis of reductive cleavage of 1,2- polymethylenebenzimidazoles 2 with DIBAL-H. The reduction of the corresponding salts prepared by treatment of 1,2-polymethylenebenzimidazoles 2 with methyl iodide proceeded differently affording exclusively o-phenylenediamines 10. The limitations and scope of the method were established, and a tentative mechanism proposed.

Full text of DOI:10.1016/j.tetlet.2013.11.025

Accepted Manuscript
A convenient synthesis of benzannelated diazacycloalkanes by reductive cleav-
age of 1,2-polymethylenebenzimidazoles
Tatyana Shvidenko, Kostiantyn Nazarenko, Konstantin Shvidenko, Aleksandr
Kostyuk
PII:
S0040-4039(13)01961-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.025
TETL 43820
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 September 2013
16 October 2013
7 November 2013
Please cite this article as: Shvidenko, T., Nazarenko, K., Shvidenko, K., Kostyuk, A., A convenient synthesis of
benzannelated diazacycloalkanes by reductive cleavage of 1,2-polymethylenebenzimidazoles, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.025
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A convenient synthesis of benzannelated diazacycloalkanes by reductive cleavage
of 1,2-polymethylenebenzimidazoles
Tatyana Shvidenko, Kostiantyn Nazarenko, Konstantin Shvidenko, Aleksandr Kostyuk
H
N
N
DIBAL-H
n = 1-4
N
(CH2)n
(CH2)n
N
H

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A convenient synthesis of benzannelated diazacycloalkanes by reductive cleavage of
1,2-polymethylenebenzimidazoles
Tatyana Shvidenko, Kostiantyn Nazarenko, Konstantin Shvidenko, Aleksandr Kostyuk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv-94, 02660, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile procedure for the synthesis of benzannelated diazacycloalkanes 3 is
elaborated on the basis of reductive cleavage of 1,2-polymethylenebenzimidazoles 2
with DIBAL-H. The reduction of the corresponding salts prepared by treatment of 1,2-
polymethylenebenzimidazoles 2 with methyl iodide proceeded differently affording
exclusively o-phenylenediamines 10. The limitations and scope of the method were
established, and a tentative mechanism proposed.
Available online
Keywords:
Benzimidazoles
o-phenylenediamine
polyazacycloalkanes
dihydrobenzimidazoles
DIBAL-H
2009 Elsevier Ltd. All rights reserved.
One of the methods for the synthesis of medium-sized ring
compounds and macrocycles bearing two or more nitrogen atoms
is reductive cleavage of bi- and polycyclic systems possessing an
amidine fragment common to both rings. Typical reagents used
for the reduction are BH3 and complex metal hydrides. For
example, the method was successfully applied to the synthesis of
macrocyclic spermine and spermidine alkaloids, with the key
step being reductive ring-expansion (internal bond cleavage) of
bicyclic derivatives of a 4-oxotetrahydropyrimidine with sodium
Another example is the synthesis of bi- and
polyazacycloalkanes by reductive ring-expansion of bicyclic
amidines and aminals.2 Among the many available methods, the
selective reductive cleavage of the C-N bond in amidines by
diisobutylaluminium hydride (DIBAL-H) developed by
Yamamoto and Maruoka should be mentioned.3 The reaction of
bicyclic amidines and bisamidines with DIBAL-H opens the way
to macrocyclic polyamines, which have found application mainly
as polydentate ligands (Scheme 2).4
O
O
N
NaBH3CN
NH N
H
N
N
DIBAL-H
N
N
H
H
AcOH
toluene, reflux
N HN
Ph
N
Ph
N
N
H
cyclen
O
Scheme 2. Synthesis of the macrocyclic polyamine, cyclen
N
NR
H
Yamamoto and Maruoka showed that DIBAL-H easily
cleaves the C-N bond, not only in amidines, but also in aromatic
heterocycles containing the N-C=N fragment. To date, the only
example of the reductive opening of the imidazole nucleus in
benzimidazoles is provided by the reduction of 1-benzyl-2-
methylbenzimidazole (1) with DIBAL-H to give N-benzyl-N`-
ethyl-1,2-phenylenediamine in 97% yield. Easy opening of the
imidazole nucleus combined with high regioselectivity suggests
Ph
N
H
Scheme 1. Example of the utilization of reductive ring-expansion
cyanoborohydride in acetic acid (Scheme 1).1
———
 Corresponding author. Tel.: +38067-2099273; e-mail: a.kostyuk@yahoo.com

2
Tetrahedron Letters
that applying this approach to fused benzimidazole 2 opens up
opportunities for the synthesis of benzannelated medium-sized
compounds and macrocycles containing two or more
(Scheme 4 path 1). At the same time the reductive cleavage of
the C=N bond resulting in intermediates 6 may be implemented
by a double attack at the same nitrogen atom to form aluminum
imides 7 (Scheme 4, path 2), which are usually less energetically
favorable compared to intermediates 6. Therefore, the lack of
selectivity in the case of 2a and 2b testifies to hindrance to
electrophilic attack by DIBAL-H at the bridgehead nitrogen atom
in intermediates 5 (n = 1, 2). At the same time, the greater
conformational flexibility of 7- and 8-membered ring systems
favors path 1, as in the case of benzimidazole 1.
3
heteroatoms in the saturated ring (Figure 1). Continuing the
research on the synthesis of fused partially saturated nitrogen-
containing heterocycles,5 we proposed to extend this work by
using model compounds such as 1,2-polymethylene
benzimidazole derivatives 2 [X = (CH2)n, n = 3-6] as well as their
quaternary salts 8. It should be noted that available methods for
the synthesis of macrocycles 3 are multi-step, low-yielding
procedures.5
(CH2)n
H
N
N
N
N
N CH2
i-Bu2Al
N
Me
X
3
N
X
NH
path 1
(CH2)n
N
AlBu-i2
Ph
1
2
3
DIBAL-H
6
N
2
AlBu-i2
Figure 1. Starting benzimidazoles 1and 2 and target
macrocycles 3
(CH2)n
N
4
5
(AlBu-i )
N
path 2
2 2
For our studies, 1,2-polymethylene benzimidazole derivatives
2a-e, readily prepared from the corresponding cyclic amidines
via a copper-catalyzed intramolecular arylation, were used as the
starting compounds.6 The reduction was carried out in toluene
using a six-fold excess of DIBAL-H. The reaction mixture was
refluxed for 16 hours and then treated successively with NaF and
water to provide the target macrocycle (Scheme 3).7 It was found
that under these conditions, complete reductive opening of the
imidazole nucleus occurred, but the regioselectivity depended on
the size of the saturated cycle. Thus, the only products of the
reduction of compounds 2c-e were the target diazacycloalkanes
3c-e, resulting from cleavage of the original single C-N bond.
These compounds were isolated by flash chromatography in 87 -
92% yields (Table 1). On decreasing the size of the saturated ring
in the starting benzimidazoles to five- and six-membered
examples the regioselectivity was completely lost. Reduction of
2a led to the formation of approximately an equimolar mixture of
3a (cleavage of the original C-N bond) and o-phenylenediamine
derivative 4a (cleavage of the original C=N bond). It is worth
noting that the reduction of 2b afforded predominantly
diazacycloalkane 3b (52%) plus o-phenylenediamine derivative
4b (21%), thus highlighting the tendency of 1,2-polymethylene
benzimidazole derivatives 2 to afford diazacycloalkanes 3 on
increasing the saturated ring size.
7
Scheme 4. Tentative routes for the reduction
Quaternary salts 8 prepared by alkylation of benzimidazoles 2
were readily reduced by DIBAL-H under the conditions
described for 2. However, in this case, the reductive cleavage
occurred at the C(2)-N(3) bond to form only o-phenylenediamine
derivatives 10a-d, regardless of the size of the saturated cycle. It
can be assumed that in this case the reaction proceeded via
intermediate dihydrobenzimidazole derivatives 9, which
determined the direction of further reductive cleavage.
Compounds 9a-e8 were isolated and characterized by treatment
of salts 8 with sodium borohydride in methanol.9 Further
reduction of compounds 9a-e with DIBAL-H proceeded
selectively with cleavage of the C-NMe bond affording
compounds 10a-d.
(CH2)n
2a-d
N
N
Me
1
MeI
Despite the similarity of the H NMR spectra of compounds 3
and 4, they are easily discriminated by the number of aromatic
carbon signals in the 13C NMR spectra: 3 signals for compounds
3 and 6 signals for 4. Compounds 3 and 4 were readily separated
by chromatography.7
NaBH4
9a-d
Yields
DIBAL-H
(CH2)n
(CH2)n
(CH2)n
(CH2)n
NH
(CH2)n
N
DIBAL-H
N
N
N
+
N
HN
N
DIBAL-H
NH2
+
Me
NHMe
10a-d
8a-d
a (n=1), b (n=2), c (n=3), d (n=4)
2 a-e
3 a-e
4 a,b
Scheme 3. Reduction of compounds 2 with DIBAL-H
Scheme 5. Reduction of salts 8
The formation of compounds 3 can be easily rationalized by
the reduction mechanism of amidines with DIBAL-H proposed
by Yamamoto and Maruoka which includes a sequential
electrophilic attack of DIBAL-H at the two nitrogen atoms
In conclusion, we have found that the reductive cleavage of
1,2-polymethylenebenzimidazoles 2 with DIBAL-H can serve as

3
a
convenient method for the synthesis of benzannelated
quaternary salts 8 or dihydrobenzimidazole derivatives 9 under
the same conditions led exclusively to o-phenylenediamines 10.
diazacycloalkanes 3. The reactions proceeded regioselectively for
derivatives 2 with n = 3, 4. At the same time, reduction of
Table 1. Yields and product compositions of the reduction of compounds 2 with DIBAL-H
Entry
1
Starting benzimidazole
Product (yield, %)
NH2
N
H
N
N
N
N
H
3a (35)
4a (43)
2a
N
NH2
H
N
2
3
N
N
N
H
3b (52)
4b (21)
2b
N
H
N
N
N
H
3c (92)
2c
N
H
N
4
5
N
N
H
3d (88)
2d
N
HN
H
N
N
3e (87)
2e
50, 3078–3086; (b) Khan, A.; Silversides, J. D.; Madden, L.;
Greenman J.; Archibald, S. J. Chem. Commun., 2007, 416–418;
(c) Weisman, G. R.; Rogers, M. E.; Wong, E. H.; Jasinski, J.P.;
Paight, E. S. J. Am. Chem. Soc. 1990, 112, 8604-8605; (d) Wong,
E.H.; Weisman, G. R.; Hill, D. C.; Reed, D. P.; Rogers, M. E.;
Condon, J. S.; Fagan, M. A.; Calabrese, J. C.; Lam, K-Ch.; Guzei,
I. A.; Rheingold, A.L. J. Am. Chem. Soc. 2000, 122, 10561-10572;
(e) Lewis E. A., Boyle, R.W.; Archibald, S.J. Chem. Commun.,
2004, 2212-2213.
References and notes
1. (a) Wasserman, H. H. ; Brunner, R. K.; Buynak, J. D.; Carter, C.
G.; Oku, T.; Robinson, R.P. J. Am. Chem. Soc. 1985, 107, 519-
521; (b) Kuehne, P.; Linden, A.; Hesse M. Helv. Chem. Acta
1996, 79, 1085 – 1094; (c) Wasserman, H. H.; Brunner, R. K.;
Carter, C. G. J. Am. Chem. Soc. 1983, 105, 1697-1698; (d)
Wasserman, H. H.; Matsuyama, H.; Robinson, R. P. Tetrahedron
2002, 58, 7177-7190; (e) Matsuyama, H.; Kobayashi, M.;
Wasserman, H. H. Heterocycles 1987, 26, 85-90; (f) Matsuyama,
H.; Kurosawa, A.; Takei, T.; Ohira, N.; Yoshida, M.; Iyoda, M.
Chem. Lett. 2000, 1104.
3. Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc.1981, 103, 4186-
4194.
4. (a) Croker, S. J.; Loeffler, R. S. T.; Smith, T. A. Tetrahedron Lett.
1983, 24, 1559-1560; (b) Weisman, G.; Reed, D. J. Org. Chem.
1996, 61, 5186-5187; (c) Alder, R.; Heilbronner, E.; Honegger, E.;
McEwen, A.; Moss, R.; Olefirowicz, E.; Petillo, P.; Sessions, R.;
Weisman, G.; White, J.; Yangs, Z.Z. J. Am. Chem. Soc. 1993, 115,
6580-6591
2. (a) Odendaal, A.Y.; Fiamengo, A. L.; Ferdani, R.; Wadas, T. J.;
Hill, D. C.; Peng, Y.; Heroux, K.J.; Golen, J. A.; Rheingold, A.L.;
Anderson, C. J.; Weisman, G. R.; Wong E. H. Inorg. Chem. 2011,

4
Tetrahedron
5. (a) Hayward, R. J.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans.
1 1975, 212–219.; (b) Fielden, R.; Meth-Cohn, O. ; Suschitzky,
H. J. Chem. Soc., Perkin Trans. 1 1973, 705–711.
6. (a) Liubchak, K.; Nazarenko, K.; Tolmachev, A. Tetrahedron
2012, 68, 2993-2930; (b) Liubchak, K.; Tolmachev, A.;
Grygorenko, O. O.; Nazarenko, K. Tetrahedron 2012, 68, 8564-
8571; (c) Cherepakha, A.; Kovtunenko, V. O.; Tolmachev, A.;
Lukin, O.; Nazarenko, K. G. Synth. Commun. 2011, 41, 1977-
1989; (d) Khodachenko, A.N., Shivanyuk, A.N., Shishkina, S.V.;
Shishkin O.V.; Nazarenko, K. G.; Tolmachev, A.A. Synthesis
2010, 2588-2598.
7. General procedure for the reduction of compounds 2 with DIBAL-
H. To a solution of 2 (3.17 mmol) in toluene (10 mL) was added
a solution of DIBAL-H (2.7 g, 19 mmol) in toluene (6 mL),
dropwise with stirring at 0 0С. The reaction mixture was stirred for
7 h, and then refluxed for 16 h. After cooling to r.t., benzene (40
mL) was added. The mixture was cooled to 0 0С and NaF (3.19 g)
was added, and then H2O (1.03 g) was added dropwise. The
suspension formed was stirred for 20 min at r.t. to produce an
amorphous precipitate, which was filtered and washed with
CH2Cl2 (2x30 mL). The solvents were evaporated to give an oil
which was purified by flash chromatography. 1,2,3,4,5,6-
Hexahydro-benzo[b][1,4]diazocine (3a) Yield 35%, mp 71 °С
(lit.5a 74 °С), light beige crystals, purified by silica gel column
chromatography (EtOAc : hexane = 1:1), Rf 0.36. 1Н NMR (400
МHz, CDCl3):  1.71 (s, 4H), 3.32 (s, 4H), 3.40 (br, 2H), 6.76-
6.78 (m, 2H), 6.81-6.84 (m, 2H). 13С NMR (125 МHz, CDCl3): 
28.58, 48.74, 122.15, 122.17, 141.23. IR (KBr): 3348, 2926, 1593,
1501, 1262, 1108, 745 cm-1. Anal. Calcd for C10H14N2: C, 74.03;
H, 8.70; N, 17.27. Found C, 73.92; H, 8.58; N, 17.38. 2-
Pyrrolidin-1-yl-phenylamine (4a) Yield 43%, red oil, purified by
column chromatography (ethylacetate: hexane = 1:1), Rf 0.73. 1Н
NMR (400 МHz, CDCl3):  1.96 (s, 4H), 3.09 (s, 4H), 3.87 (br.s,
2H), 6.77 (t, J = 7.8 Hz, 2Н), 6.93 (t, J = 7.8 Hz, 1Н), 7.03 (d, J =
7.8 Hz, 1Н). 13С NMR (125 МHz, CDCl3):  24.15, 50.19, 115.45,
118.59, 118.65, 123.44, 137.73, 141.36. IR (thin film): 3440,
2970, 2820, 1611, 1501, 1197, 1059 cm-1. Anal. Calcd for
C10H14N2: C, 74.03; H, 8.70; N, 17.27. Found C, 74.22; H, 8.81;
N, 17.19.
8. Dihydrobenzimidazoles of type 9 were previously prepared by
cyclization of various substituted 1-phenylazacycloalkanes (t-
amino effect), see for example: (a) Ryabukhin, S. V.; Plaskon,
A.S.; Volochnyuk, D.M.; Shivanyuk, A.N.; Tolmachev A.A. J.
Org. Chem. 2007, 72, 7417-7419; (b) Garner, R.; Garner, G.V.;
Suschitzky, H. 1970, J. Chem. Soc. (C), 825-829; (c) Grantham,
R. K.; Meth-Cohn, O.; Naqui, M. A. J. Chem. Soc. (C), 1969,
1438-1443; (d) Grantham, R. K.; Meth-Cohn, O. J. Chem. Soc.
(C), 1969, 1444-1448.
9. General procedure for the preparation of 9a-d. To a solution of
8а (0.2 g, 0.67 mmol) in MeOH (2 mL) was added NaBH4
portionwise (0.1 g, 2.5 mmol) with stirring under ice-cooling. The
resulting solution was stirred for 1 h and H2O (20 mL) was added.
The resulting oil was extracted with CH2Cl2 (30 mL), and the
organic layer washed with H2O (3  30 mL), and dried over
Na2SO4. Evaporation of the solvent gave 9a (0.1 g), 86% as a pale
yellow oil. 4-Methyl-2,3,3a,4-tetrahydro-1H-benzo[d]pyrrolo[1,2-
a]imidazole 9a. Yield 86%, light yellow oil. 1Н NMR (400 МHz,
CDCl3):  1.80-1.87 (m, 3H), 1.97-2.03 (m, 1H), 2.76 (s, 3H),
3.13-3.19 (m, 1H), 3.32-3.38 (m, 1H), 4.93-4.95 (m, 1H), 6.32 (d,
J = 7.8 Hz, 1Н), 6.60-6.62 (m, 2H), 6.75-6.79 (m, 1H). 13С NMR
(125 МHz, C6D6):  23.80, 31.13, 32.51, 54.84, 88.47, 105.28,
111.90, 118.50, 121.63, 144.66, 145.34. IR (thin film): 3433,
2890, 1691, 1518, 1414, 1306, 1169 cm-1. Anal. Calcd for
C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found C, 75.76; H, 8.15;
N, 16.02.
Supplementary Material

H
N
N
N
DIBAL-H
n = 1-4
(CH2)n
(CH2)n
N
H