Synthesis of 1(11)H-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole starting from benzimidazole-2-sulfonic acid. Intramolecular cyclization of 2-(δ-chlorobutylamino)benzimidazole

Article abstract of DOI:10.1007/s11172-007-0366-8

The intramolecular cyclization of 2-(δ-chlorobutylamino)benzimidazole (3c) follows the unusual pathway involving the predominant attack on the exocyclic amino group rather than on the much more nucleophilic endocyclic nitrogen atom. This reaction affords 2-pyrrolidinobenzimidazole and 1(11)H-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole as the major product and the by-product, respectively. The cyclization can be directed exclusively toward the annulation of the diazepine ring only after the acetylation of the amino group of compound 3c. According to the quantum chemical calculations, the unusual regioselectivity of the cyclization of chloramine 3c is associated primarily with a substantially less steric strain and the higher entropy of pyrrolidine transition states compared to diazepine transition states.

Full text of DOI:10.1007/s11172-007-0366-8

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2315—2322, November, 2007
2315
Synthesis of 1(11)Hꢀ2,3,4,5ꢀtetrahydro[1,3]diazepino[1,2ꢀa]benzimidazole
starting from benzimidazoleꢀ2ꢀsulfonic acid.
Intramolecular cyclization of 2ꢀ(δꢀchlorobutylamino)benzimidazole
V. A. Anisimova,ꢀ V. V. Kuz´menko, T. A. Kuz´menko, and A. S. Morkovnik
†
Institute of Physical and Organic Chemistry, Southern Federal University,
1
94/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4028. Eꢀmail: anis@ipoc.rsu.ru, asmork2@ipoc.rsu.ru
The intramolecular cyclization of 2ꢀ(δꢀchlorobutylamino)benzimidazole (3c) follows the
unusual pathway involving the predominant attack on the exocyclic amino group rather than
on the much more nucleophilic endocyclic nitrogen atom. This reaction affords 2ꢀpyrꢀ
rolidinobenzimidazole and 1(11)Hꢀ2,3,4,5ꢀtetrahydro[1,3]diazepino[1,2ꢀa]benzimidazole as
the major product and the byꢀproduct, respectively. The cyclization can be directed exclusively
toward the annulation of the diazepine ring only after the acetylation of the amino group of
compound 3c. According to the quantum chemical calculations, the unusual regioselectivity of
the cyclization of chloramine 3c is associated primarily with a substantially less steric strain and
the higher entropy of pyrrolidine transition states compared to diazepine transition states.
Key words: 2ꢀ(δꢀchlorobutylamino)benzimidazole, 1(11)Hꢀ2,3,4,5ꢀtetrahydro[1,3]diꢀ
azepino[1,2ꢀa]benzimidazole, 2ꢀpyrrolidinobenzimidazole, quantum chemical calculations,
2
ꢀ(δꢀchlorobutylamino)imidazole, transition states, activation energies, steric effects.
Many derivatives of fused heterocycles containing the
guanidine fragment in the ring, including 1(9)Hꢀ2,3ꢀdiꢀ
hydroimidazoꢀ (1a) and 1(10)Hꢀ1,2,3,4ꢀtetrahydropyriꢀ
mido[1,2ꢀa]benzimidazoles (1b) studied by us, efficiently
by the transformation of amino alcohol 2c into chloroꢀ
butylamine 3c and its thermal cyclization. In the case of
chloroethyl(propyl)ꢀsubstituted compounds 3a,b, the
intramolecular S 2ꢀlike Nꢀalkylation as the last step of
N
1
—7
decrease the blood sugar level and inhibit thrombosis.
this procedure proceeds exclusively at the most nucleoꢀ
philic endocyclic nitrogen atom in 2ꢀaminobenzimidꢀ
A comparison of the properties of bicyclic guanidines
containing the hydrogenated imidazole, pyrimidine, and
diazepine rings showed that the imidazo[1,2ꢀa][1,3]diꢀ
azepine derivative exhibits the highest hypoglycemic acꢀ
tivity.3
1
2,13
azoles.
Results and Discussion
This prompted us to undertake the present study in
order to develop a preparative procedure for the synthesis
of the sevenꢀmembered analog of compounds 1a,b, viz.,
Our investigations showed that amino alcohol 2c and
chloro derivative 3c are formed in high yields without any
complications. However, the subsequent cyclization of
compound 3c occurs predominantly at the exocyclic
amino group to form 2ꢀpyrrolidinobenzimidazole (4) (in
1
(11)Hꢀ2,3,4,5ꢀtetrahydro[1,3]diazepino[1,2ꢀa]benzꢀ
imidazole (1c). Earlier, compound 1c has been syntheꢀ
sized by the thermal rearrangement of difficultly accesꢀ
7
0—80% yield), whereas the cyclization at the endocyclic
8
sible 1ꢀcyanoꢀ2ꢀphenyltetrahydropyridazine. The syntheꢀ
nitrogen atom giving rise to diazepine 1c (15—25% yield)
is the minor process. This is rather unexpected from the
theoretical point of view because fiveꢀmembered hydroꢀ
genated rings are more strained per ring unit than sevenꢀ
sis of the 9ꢀnitro derivative of this compound in moderate
yield by the cyclization of 2ꢀ(3ꢀnitrophenylimino)ꢀ
2
,3,4,5,6,7ꢀhexahydroꢀ1Hꢀ1,3ꢀdiazepine was docuꢀ
9
mented.
In our opinion, the more promising procedure for the
synthesis of diazepine 1c, by analogy with the formation
of tricyclic compounds 1a,b,1
1
4
membered rings and the side amino group in comꢀ
pound 3c is much less nucleophilic than the endocyclic
nitrogen atom. The regioselectivity of the reaction is virꢀ
tually independent of the nature of the solvent (refluxing
0,11
(Scheme 1) could inꢀ
volve the replacement of the sulfo group in benzimidꢀ
azoleꢀ2ꢀsulfonic acid with 4ꢀaminobutanꢀ1ꢀol followed
in H O, EtOH, MeCN, toluene, xylene, or DMF) and
2
remains the same in the reaction performed in a melt at
130—135 °C; however, exclusively pyrrolidine 4 is formed
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2237—2243, November, 2007.
066ꢀ5285/07/5611ꢀ2315 © 2007 Springer Science+Business Media, Inc.
1

2316
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Anisimova et al.
Scheme 1
1
—3: n = 2 (a), 3 (b), 4 (c)
in the presence of NaOH due, apparently, to the involveꢀ
ment of the Nꢀanion of the substrate in the reaction.
Isomers 4 and 1c were identified by comparing their
aminobenzimidazoles and 3ꢀacylꢀ1ꢀalkylꢀ2ꢀaminobenzꢀ
imidazolium salts, respectively, which rather readily unꢀ
dergo thermal acylotropic isomerization to thermodyꢀ
namically more stable 2ꢀacylaminobenzimidazoles by the
interꢀ or intramolecular mechanism. Hence, heating in
1
H NMR spectra. In pyrrolidine 4, the tetramethylene
fragment is symmetrical and is characterized by two fourꢀ
proton multiplets of the βꢀ and αꢀpyrrolidine protons at
δ 1.90—1.96 and 3.40—3.46, respectively, whereas the
unsymmetrical tetramethylene group in compound 1c is
characterized by three multiplets, viz., one fourꢀproton
multiplet (C(3)H and C(4)H ) and two twoꢀproton mulꢀ
Ac O, most likely, leads to the rearrangement of comꢀ
2
pound 5 into its isomer 6. The latter was not isolated
because of the rapid cyclization to 1ꢀacetyldiazepine 7
(94% yield). The immediate heating of a solution of 3c in
Ac O to boiling results in the formation of pyrrolidine 4 as
2
2
2
tiplets (C(2)H and C(5)H ) at δ 1.93—1.99, 3.21—3.28,
a byꢀproduct. Compound 7 is smoothly transformed into
diazepine 1c by acid hydrolysis.
2
2
and 3.96—4.04, respectively. The validity of the structural
assignments was additionally confirmed by the indepenꢀ
dent synthesis of compound 4 from benzimidazoleꢀ2ꢀsulꢀ
fonic acid and pyrrolidine.
To protect the secondary amino group from the unꢀ
desired alkylation and to direct the cyclization toward the
predominant diazepine ring closure, compound 3c was
The formation of 2ꢀ[Nꢀ(4ꢀacetoxybutyl)ꢀNꢀaceꢀ
tyl]amine 8 by refluxing amino alcohol 2c in Ac O is
2
circumstantial evidence for the migration of the acetyl
group in compound 5. The IR spectrum of amine 8 shows
absorption bands of the NCOMe, OCOMe, and NH
–
1
groups at 1645, 1705, and 3340 cm , respectively. The
1
acylated with Ac O at 20—25 °C. Under these conditions,
H NMR spectrum contains, along with other signals,
2
the acetylation appeared to proceed at the imidazole ring
to form 1ꢀacetylꢀsubstituted derivative 5, which is rather
stable at room temperature. The structure of compound 5
was unambiguously confirmed by the H NMR spectrum,
which shows a strong spinꢀspin coupling between the proꢀ
singlets for the protons of these groups at δ 2.05, 2.45,
and 11.5 and two triplets of the methylene groups (δ 4.15
and 4.23), which is indicative of the absence of a considꢀ
erable spinꢀspin coupling between the protons of the
NH fragment and the methylene group.
1
tons of the exocyclic NH group and the adjacent methylꢀ
An alternative mechanism of the formation of
1ꢀacetyldiazepine 7 involving the cyclization of 1ꢀacetyl
derivative 5 directly to 11ꢀacetylꢀsubstituted diazepine 1c
followed by the isomerization to the final product is unꢀ
likely because of the expected considerable decrease in
ene fragment (J = 6.4 Hz). Earlier,1
5—19
it has been
demonstrated that primary 2ꢀaminobenzimidazoles and
their 1ꢀalkylꢀsubstituted derivatives are acylated at low
temperature at the imidazole ring to form 1ꢀacylꢀ2ꢀ

Tetrahydro[1,3]diazepino[1,2ꢀa]benzimidazole
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2317
the nucleophilicity of the endocyclic nitrogen atom in
compound 5 under the influence of the electronꢀwithꢀ
drawing acetyl group.
Therefore, the regioselectivity of thermal cyclization
can be efficiently influenced by introducing the acetyl
protection of the amino group in chlorobutylamine 3c,
which allows the synthesis of tricyclic compound 1c in
high yield.
It should also be noted that earlier,20 with the aim of
studying pharmacologically active 11ꢀacylmethylꢀ2,3,4,5ꢀ
tetrahydro[1,3]diazepino[1,2ꢀa]benzimidazoles, we have
synthesized 1ꢀacetyl derivative 7 according to an analoꢀ
gous scheme but by the oneꢀpot reaction starting from
potassium benzimidazoleꢀ2ꢀsulfonate and an equimolar
amount of 4ꢀaminobutanol without isolation of intermeꢀ
diates 2c, 3c, and 5. However, this reaction is accompaꢀ
nied by considerable resinification, and the total yield of
compound 7 is at most 48%.
To reveal the factors responsible for the observed
regioselectivity of the thermal cyclization of chloroꢀ
butylamine 3c, we performed the quantum chemical study
of this reaction and the analogous transformation of the
simpler model compound, 2ꢀ(δꢀchlorobutylamino)imidꢀ
azole (9), by the density functional theory method
The cyclization of the amino forms for each chloroꢀ
butylamino derivative involves the same set of transition
states, including, in particular, two diazepine conformer
states TS5, in which the sevenꢀmembered ring adopts a
distorted boat or chair conformation. These transition
states ensure the preliminary formation of two correꢀ
sponding conformers of diazepine 1c. In addition, four
pyrrolidineꢀtype transition states (TS6) containing the
pyrrolidine ring in the envelope conformation with the
βꢀcarbon atom of the δꢀchlorobutyl group at the flap are
formed. These states differ by the N(1)—C(2)—NPyr—Cδ
dihedral angle characterizing the degree of twist of the
pyrrolidinyl group with respect to the imidazole ring and
the mutual arrangement of the diazolyl group and the
βꢀcarbon atom (see Scheme 2). The latter can be either
on the same side (ZꢀTS) or different sides (EꢀTS) of the
plane passing through the other atoms of the pyrrolidine
ring (see Table 1). The structures of selected transition
states for the cyclization of amino forms of substrates 3c
and 9 are presented in Fig. 1.
In the case of the cyclization to diazepine, the boatꢀ
like transition states TS5 have the lowest energy; the total
–
1
energy of these state is 0.5—0.7 kcal mol lower than the
energy of their chairꢀlike analogs. In the case of the cyꢀ
clization to pyrrolidine, the E conformations of the tranꢀ
(
B3LYP/6ꢀ31G**). In addition, to gain a better underꢀ
standing of the results, we studied the ring and nonꢀring
sition states TS6 with the N(1)—C(2)—NPyr—C dihedral
δ
Nꢀmethylation of 2ꢀmethylaminoimidazole (10a) and
angles of 43 (3c) and 34° (9) serve this function; these
states are ~1 kcal mol more favorable than the highestꢀ
energy transition states ZꢀTS6 (see Table 1).
In the first approximation, the regioselectivity of cyꢀ
clization of unsolvated chlorobutylamines 3c and 9 is deꢀ
termined by the difference between the total energies of
the pyrrolidine and diazepine transition states
–
1
2
ꢀmethylaminobenzimidazole (10b) with methyl chloride
and the analogous reactions of their tautomeric imino
forms (the transitions states for these four processes are
denoted as TS1, TS2 and TS3, TS4, respectively). These
reactions were chosen because they are similar in the
mechanism to the cyclization of compounds 3c and 9 and
taking into account that they are sterically uncomplicated
bimolecular transformations proceeding with the involveꢀ
ment of structurally similar substrates. The transition states
TS1—TS8 were located for all monoꢀ and bimolecular
transformations under consideration. These transition
states are highly polar with µcalc of about 10—16 D. The
characteristics of the reagents and the transition states,
including their total energies, the activation energies in
∆
Etot
= Etot
– Etot
= ∆∆E≠TS5,TS6,
TS5
TS5,TS6
TS6
which is –4.0 and –6.2 kcal mol–1, respectively (calcuꢀ
lated at the B3LYP/6ꢀ31G** level). This indicates that
the pathway giving rise to diazepine is somewhat more
favorable with respect to this parameter. However, this
–
1
parameter is 4.0—4.5 kcal mol lower in magnitude than
the analogous (and also negative) difference ∆∆E≠
TS1,TS2
≠
tot
tot
the absence of solvation (∆E = E
– E reag), the
characterizing the selectivity of the sterically uncompliꢀ
cated Nꢀmethylation of the amino forms of 2ꢀmethylꢀ
aminodiazoles 10a,b with methyl chloride. The higherꢀ
TS
≠
Gibbs free energies (∆G ) in EtOH, and the imaginary
vibrational frequencies are given in Table 1.
The intramolecular cyclization of 2ꢀ(δꢀchloroꢀ
butyl)amines 3c and 9 to diazepines 1c and 11 and
pyrrolidines 4 and 12, respectively, like the methylation
of amines 10a,b, can follow four pathways involving the
analogous but monomolecular trigonalꢀbipyramidal tranꢀ
sition states TS5—TS8 corresponding to the formation of
each cyclic product from amino and imino forms of comꢀ
pounds 3c and 9 (Scheme 2). However, the transition
states can exist as different conformers because of the
conformational diversity of the reagents containing the
chlorobutyl fragment.
level calculations (MP2/6ꢀ311G**) give an even smaller
tot
energy difference ∆E
for chlorobutylamine 9
TS5,TS6
–
1
(–1.7 kcal mol ; see Table 1). In spite of a certain differꢀ
ence in the values, both methods show that the cyclizaꢀ
tion of chlorobutylamines 3c and 9 is characterized by the
substantially smaller difference between the activation
≠
energies ∆E of the electrophilic attack on the ring and on
the exocyclic atoms compared to the bimolecular Nꢀalkyꢀ
lation.
It should be emphasized that the transformation of
amines 3c and 9 into diazepines is more hindered than the

2318
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Anisimova et al.
Table 1. Results of calculations at the B3LYP/6ꢀ31G** level of theory for the reagents and transition states of the cyclization and
Nꢀmethylation involving compounds 3c, 9, and 10a,b and their tautomeric imino forms
TS and reagentsa
Conformer
TSb
–Etot/Hartree
∆E≠
(EtOH))
52
kcal mol
µcalc
/D
C—Nс
C—Cl
Angle
N—С—Cl
/deg
νi
/cm–1
(∆G≠
/
с
3
Å
–
1
MeCl
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
499.978024
500.031228
1051.430735
897.911874
897.935190
897.904347
897.897962
1051.423227
820.525263
974.042178
820.512229
974.024694
820.522736
974.040969
820.517462
974.038365
897.862380
896.457916
897.861921
1051.379015
1051.377883
897.855964
896.455201
897.855436
897.855537
896.455236
897.853410
1051.369050
1051.368599
1051.368650
1051.366817
897.824880
1051.346346
897.861102
1051.383258
—
—
—
—
—
—
—
—
25.9
27.2
34.1
38.1
48.2
55.7
22.3
24.5
2.1
2.1
5.5
5.6
11.6
7.7
5.7
4.4
14.7
14.4
9.6
11.1
16.1
16.1
13.7
13.5
14.6
14.1
14.1
14.5
13.8
10.0
8.5
—
—
—
—
1.47
1.53
—
1.80
1.78
1.83
1.83
—
—
—
133.7
136.5
—
—
—
—
—
—
—
—
—
471.8
480.3
411.8
376.4
405.9
407.2
479.5
482.3
437.3
—
442.9
442.1
448.9
329.3
—
MeCld
3
9
1
1
1
1
c
3a
4a
5a
5b
—
—
1.83
1.83
2.42
2.43
2.49
2.54
2.57
2.57
2.38
2.40
2.51
2.39
2.49
2.52
2.51
2.59
2.40
2.63
2.61
2.44
2.64
2.64
2.66
2.64
2.67
2.69
2.70
2.45
2.46
148.3
149.5
178
176
172
175
178
178
178
178
166
169
163
166
163
166
169
168
164
169
169
165
168
163
168
161
162
169
170
—
TS1 (Im)
TS1 (Bzm)
TS2 (Im)
TS2 (Bzm)
TS3 (Im)
TS3 (Bzm)d
TS4 (Im)
1.88
1.89
1.83
1.79
1.74
1.73
1.93
1.91
1.95
1.91
1.95
1.94
1.94
1.83
1.88
1.80
1.85
1.88
1.81
1.79
1.78
1.82
1.80
1.81
1.80
1.98
1.96
d
TS4 (Bzm)
TS5 (DI)
—
Distorted boat
Distorted boate
Distorted chair
Distorted boat
Distorted chair
E (34 )
E (33 )e
E (132)
Z (41)
31.1 (13.6)
—
31.3 (14.5)
32.5 (15.8)
33.2 (17.2)
35.1 (12.9)
—
35.4 (14.2)
35.4 (15.3)
—
36.7 (13.6)
38.7 (18.8)
40.0 (17.8)
40.1 (18.8)
41.0 (20.8)
45.9 (23.8)
48.2 (25.8)
23.1 (8.2)
25.1 (10.6)
TS5 (DB)
TS6 (PI)
11.7
10.3
9.9
308.7
344.5
—
Z (52)e
Z (139)
E (43)
E (129)
Z (46)
Z (126)
—
—
11.8
10.9
12.0
10.8
12.4
13.0
13.0
13.3
13.0
340.9
296.4
278.6
323.5
315.7
366.4
403.6
479.5
424.1
TS6 (PB)
TS7 (DI)
TS7 (DB)
TS8 (PI)
TS8 (PB)
—
—
a
The corresponding heterosystems are given in parentheses after the notations of TS: Im and Bzm are imidazole and benzimidazole,
respectively; DI and DB are diazepinoimidazole and diazepinobenzimidazole, respectively; PI and PB are pyrrolidylimidazole and
pyrrolidylbenzimidazole, respectively. The transition states TS1 and TS2 correspond to the attack of 2ꢀmethylaminoazoles 10a,b on
the exocyclic and endocyclic nitrogen atoms, respectively; the transition states TS3 and TS4 correspond to the analogous attack of the
corresponding imino tautomers.
b
For the pyrrolidine transition state, the N(1)—C(2)—NPyr—C dihedral angle is given in parentheses.
For the nitrogen atom involved in the reaction.
The calculation at the BHHLYP/6ꢀ31G(d,p) level.
The calculation at the MP2/6ꢀ311G** level.
δ
c
d
e
Nꢀmethylation of methylaminoꢀsubstituted derivatives
0a,b with methyl chloride at the heterocyclic ring, which
has the same direction of the electrophilic attack taking
(∆∆E≠
< 1.0 kcal mol–1) (see Table 1). These data
TS2,TS6
1
indicate that the diazepine transition states are higher in
energy than the pyrrolidine transition states. This can be
attributed to their higher steric strain, the lower entropy
due to higher rigidity of these systems, and, apparently,
less efficient solvation. The higher strain of TS5 is evident
from the following structural features: first, the deviation
≠
–1
into account that ∆∆E
is larger than 5 kcal mol .
TS1,TS5
Unlike this reaction, the cyclization of chlorobutylamines
to pyrrolidines proceeds almost as easily as the methylaꢀ
tion of compounds 10a,b at the exocyclic amino group

Tetrahydro[1,3]diazepino[1,2ꢀa]benzimidazole
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2319
Scheme 2
, 11, 12, 13a—15a: R1 = R = H;
2
9
1
1
2
c, 3c, 4, 13b—15b: R R = —CH=CH—CH=CH—
of the electrophilic attack from the most favorable direcꢀ
tion along the axis of the lone electron pair of the nitrogen
atom subjected to the attack, which is more pronounced
in chairꢀlike transition states; second, an elongation of
the C—N bond in the reaction center by 0.07 Å compared
to the unstrained transition states TS1, which is, eviꢀ
dently, a consequence of the steric hindrance to the optiꢀ
mal proximity between the reaction centers; and finally,
Cl
a
b
H
2
.52
H
H
C
H
N
H
H
H
C
C
C
H
C
C
C
C
C
H
H
NPyr
1
.94
C
H
H
H
C
C(2)
H
N
1.79
Cδ
C
H
H
C
C
H
C
N(1)
C
H
N
H
H
H
H
H
H
C
C
H
2
.64
N
C
H
C
H
Cl
H
Fig. 1. Diazepine transition state TS5 (distorted boat) (a) and the pyrrolidine transition state EꢀTS6 (the N(1)—C(2)—NPyr—Cδ
dihedral angle is 43°) (b) for the cyclization of chlorobutylaminobenzimidazole 3c (calculations at the B3LYP/6ꢀ31G** level). The
C—N and C—Cl bond lengths in the reaction centers are given (in Å).

2320
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Anisimova et al.
the substantially larger total deviation of the bond angles
of the tetramethylene bridge from the optimal tetrahedral
angles compared to that in the pyrrolidine transition states
Experimental
The progress of the reactions and the individuality of the
reaction products were monitored by TLC on alumina plates
(Brockmann activity III) using CHCl3 as the eluent; spots were
(
see Table 1).
The difference between the entropies of the transition
1
visualized by exposure to iodine vapor in a wet box. The H NMR
states TS5 and TS6 with the minimum energy for each
–
1
–1
spectra were recorded on a Varian XLꢀ300 instrument. The
IR spectra were measured on a Specordꢀ75 IR spectrometer in
Nujol mulls.
chlorobutylamine is ~3 kal mol
К , which is responꢀ
–1
sible for an additional increase (by more than 1 kcal mol
)
in the free activation energy of the cyclization to diazepine
compared to the cyclization to pyrrolidine at the reaction
temperature.
The quantum chemical calculations were carried out with
21
the use of the PC GAMESS 6.4 version of the GAMESS (US)
22
quantumꢀchemical program package and by the DFT method
All together these factors lead to the fact that the
pyrrolidine transition states TS6 for the imidazole are
formed in solution with somewhat lower free activation
energies ∆G than the corresponding diazepine transiꢀ
tion states,ꢀ as was demonstrated by the calculations
(B3LYP/6ꢀ31G**).
The firstꢀ and secondꢀorder stationary points were identified
by calculations of their force matrices and the frequencies corꢀ
responding to normal vibrational modes. In addition, the calcuꢀ
lations by the intrinsic reaction coordinate (IRC) method were
carried out for the transition states. Since this method requires a
large volume of calculations, most of calculations were performed
at the RHF/6ꢀ31G level (sometimes, at the B3LYP/6ꢀ31G**
level). Of a large set of conformations of the starting compounds
≠
at the B3LYP/6ꢀ31G** level of theory in terms of the
PCM solvation model (EtOH) (see Table 1). For the
benzimidazole transition states, the inverse ratio of
the Gibbs free energies of the transition states was estiꢀ
mated by this method, but the energy difference is small
3
c and 9 with similar energies, one most stable conformation
was chosen for each type of cyclization. Then the geometry of
these structures was optimized by the DFT method with the
6ꢀ31G** basis set. The total energies were used in the calculaꢀ
(
1.6 kcal mol–1).
It should be noted that the contribution of the minor
≠
tions of ∆E . The calculations were carried out with the zeroꢀ
imino forms of substrates 15a,b to both types of the cyꢀ
clization of compounds 3c and 9 can be ignored. In parꢀ
ticular, the formation of diazepines 1c and 11 from imiꢀ
point energy (ZPE) correction. In the calculations at the
B3LYP/6ꢀ31G(d,p) level, the scaling coefficient of 0.961
2
3
was used.
ꢀ(4ꢀHydroxybutylamino)benzimidazole (2c). A mixture of
nes is virtually impossible due to the very high activation
2
energies (∆E≠
> 45 kcal mol ). The fact that the
–1
TS7
benzimidazoleꢀ2ꢀsulfonic acid (4 g, 20 mmol) and 4ꢀaminoꢀ
butanol (4.6 mL, 50 mmol) was heated with stirring to
150—155 °C and kept at this temperature for 1.5 h. After compleꢀ
tion of the reaction, the melt was cooled to ~90 °C and treated
with water (25 mL). After 2—3 h, the precipitate was filtered off
and washed with ice water (3×10 mL). The yield was 3.48 g
(85%), slightly yellowish flakes, m.p. 161—162 °C (from MeCN).
Found (%): C, 64.29; H, 7.2; N, 20.56. C H N O. Calcuꢀ
cyclization of imines to pyrrolidines is nonꢀcompetitive
is attributed to the fact that the corresponding total
expenditure of energy by this reaction channel, including
≠
∆
E
and the energy of tautomerization of the amino
TS8
tot
tot
forms, E
activation energies ∆E
– E
is substantially higher than the
for the direct cyclization of
imino
amino
≠
TS6
1
1
15
3
amino forms 3c and 9 (see Table 1).
–
1
lated (%): C, 64.37; H, 7.37; N, 20.47. IR, ν/cm : 1620 (C=N);
An analysis of the results of quantum chemical calcuꢀ
lations shows that the activation energies for all imidazole
substrates are, on the whole, lower than those for their
benzimidazole analogs, which is, evidently, a consequence
of the higher nucleophilicity of the imidazole heteroꢀ
system.
Therefore, the thermal cyclization of 2ꢀ(δꢀchloroꢀ
butylamino)benzimidazole 3c, unlike the cyclization of
shorterꢀchainꢀlength 2ꢀ(ωꢀchloroalkylamino)benzimidꢀ
azoles, is characterized by the predominant attack on the
lowꢀnucleophilic nitrogen atom and, consequently, the
qualitatively different regioselectivity. The aboveꢀconsidꢀ
ered data suggest that this is also typical of imidazole
analogs of compounds 3c.
1
3
1
5
000—3200 (NH, OH); 3400 (NH). H NMR (CDCl ), δ:
.48—1.72 (m, 4 H, βꢀCH , γꢀCH ); 3.30 (q, 2 H, NCH , J =
.3 Hz); 3.45 (t, 2 H, OCH , J = 6.0 Hz); 6.26 (t, 1 H, NH, J =
3
2
2
2
2
5.3 Hz); 6.73—6.87 (m, 2 H, H(5), H(6)); 7.00—7.11 (m, 2 H,
H(4), H(7)); 11.40 (br.s, 1 H, NH).
2
ꢀ(4ꢀChlorobutylamino)benzimidazole (3c). Freshly distilled
SOCl (1.08 mL, 15 mmol) was slowly added to a suspension of
2
amino alcohol 2c (2.05 g, 10 mmol) in dry CHCl (30 mL) at a
3
temperature no higher than 35 °C. The reaction solution was
refluxed for 1 h and concentrated. The residue was treated with
acetone. Hydrochloride 3c was filtered off and washed with
acetone until the washing liquid became colorless and then with
petroleum ether. The yield of hydrochloride 3c was 2.4 g (93%),
m.p. 140—141 °C (from MeCN). Found (%): C, 50.69; H, 5.74;
Cl, 27.18; N, 16.35. C H Cl N . Calculated (%): C, 50.78;
1
1
15
2
3
–
1
+
H, 5.81; Cl, 27.26; N, 16.15. IR, ν/cm : 1660 (C=N H);
3000—3200 (NH). H NMR (DMSOꢀd ), δ: 1.73—1.94 (m,
ꢀ
1
It should be noted that the cyclization to pyrrolidine is more
6
favorable even in spite of substantially higher stability of
4 H, C(2)H , C(3)H ); 3.50 (q, 2 H, NCH , J = 6.3); 3.66 (t,
2
2
2
diazepinobenzimidazolium cations 13 compared to cations 14
2 H, CH Cl, J = 6.1 Hz); 7.08—7.18 (m, 2 H, H(5), H(6));
2
tot
(
for the imidazole pair of cations 13a and 14a, ∆E is higher
7.32—7.43 (m, 2 H, H(4), H(7)); 9.23 (t, 1 H, 2ꢀNHCH , J =
2
–
1
than 19 kcal mol (see Table 1)).
6.3 Hz); 12.97 (br.s, 2 H, 2 NH).

Tetrahydro[1,3]diazepino[1,2ꢀa]benzimidazole
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2321
The resulting hydrochloride (1.3 g, 5 mmol) was dissolved in
water (10 mL) at room temperature. The solution was carefully
made alkaline with concentrated NH OH. The precipitate of
4
compound 7 was filtered off and washed with water. The yield
was 2.1 g (92%), m.p. 154—155 °C (from C H ). Found (%):
made alkaline with concentrated NH OH to pH 8—9. The oil
4
6
6
that formed rapidly crystallized to give colorless crystals. After
C, 68.04; H, 6.72; N, 18.43. C H N O. Calculated (%):
13 15 3
–
1
0
.5 h, the crystals were filtered off, washed with water, and dried
C, 68.10; H, 6.59; N, 18.33. IR, ν/cm : 1618, 1602 (C=C);
1
in air. The yield was 1.1 g (98%), m.p. 115—116 °C. Found (%):
1668 (C=N); 1675 (C=O). H NMR (DMSOꢀd ), δ: 1.90—1.98
6
C, 58.95; H, 6.30; Cl, 15.70; N, 18.96. C H ClN . Calcuꢀ
(m, 4 H, C(3)H , C(4)H ); 2.20 (s, 3 H, COMe); 3.72—3.88
(m, 2 H, C(5)H ); 4.10—4.18 (m, 2 H, C(2)H ); 7.27—7.35
2 2
(m, 3 H, H(7)—H(9)); 7.73 (dd, 1 H, H(10), J1 = 6.3 Hz,
J2 = 2.0 Hz).
B. Compound 5 (0.27 g, 1 mmol) was heated at 80 °C for
10 min. The melt was cooled and treated with a 22% ammonia
solution. The precipitate was filtered off and washed with water.
The yield was 0.22 g (96%). The compound is identical to that
synthesized according to the method A.
1
1
14
3
2
2
–
1
lated (%): C, 59.06; H, 6.31; Cl, 15.85; N, 18.78. IR, ν/cm
630 (C=N); 2500—2750 (NH); 3400 (NH).
Thermal cyclization of 2ꢀ(4ꢀchlorobutylamino)benzimidazole
3c). A melt of chlorobutylamine 3c (0.5 g, 2.2 mmol) was kept
:
1
(
at 130—135 °C for 10 min. After cooling, the melt was treated
with concentrated NH OH (2 mL). The precipitate consisting
4
of 2ꢀpyrrolidinobenzimidazole 4 (R 0.35) and diazepinoꢀ
f
benzimidazole 1c (R 0.35) (TLC data) was filtered off and
f
washed with water. The yield was 0.39 g (95%). According to the
1(11)Hꢀ2,3,4,5ꢀTetrahydro[1,3]diazepino[1,2ꢀa]benzimidꢀ
azole (1c). Compound 7 (2.29 g, 10 mmol) was refluxed in
concentrated HCl (20 mL) for 1 h. Then the reaction solution
1
H NMR spectra, compounds 4 and 1c were obtained in a ratio
1
of ~3 : 1. The H NMR spectra of individual compounds 4 and
1
c are given below. The selectivity of cyclization in the reactions
performed in solutions is virtually the same.
ꢀPyrrolidinobenzimidazole (4). A. A suspension of hydroꢀ
was cooled and made alkaline with concentrated NH OH to
4
pH 9—10. After 2 h, the precipitate that formed was filtered off
and washed with water. The yield was 1.73 g (93%), colorless
needleꢀlike crystals, m.p. 199—200 °C (from C H ) (cf. lit.
2
chloride 3c (0.26 g, 1 mmol) was refluxed in a 5% NaOH soluꢀ
tion (4 mL) for 2 h. After cooling, the precipitate was filtered off
and washed with water. The yield was 0.17 g (91%), m.p.
6
6
1
1
data : m.p. 192 °C). Found (%): C, 70.63; H, 7.05; N, 22.56.
C H N . Calculated (%): C, 70.56; H, 7.00; N, 22.44. IR,
1
1
13
3
–
1
1
3
34—335 °C (from EtOH, with decomp.). Found (%): C, 70.45;
ν/cm : 1585, 1600, 1629 (C=C, C=N); 3218 (NH). H NMR
(DMSOꢀd ), δ: 1.93—1.99 (m, 4 H, C(3)H , C(4)H );
H, 7.22; N, 22.56. C H N . Calculated (%): C, 70.56; H, 7.00;
N, 22.24. IR, ν/cm–1: 1633 (C=N); 3000—3100 (NH). H NMR
1
1
13
3
6
2
2
1
3.21—3.28 (m, 2 H, C(2)H ); 3.96—4.04 (m, 2 H, C(5)H );
2
2
(
4
DMSOꢀd ), δ: 1.90—1.96 (m, 4 H, (CH ) ); 3.40—3.46 (m,
H, N(CH ) ); 6.83—6.89 (m, 2 H, H(5), H(6)); 7.11—7.14
2 2
5.47 (br.s, 1 H, NH); 7.06—7.17 (m, 3 H, H(7)—H(9)); 7.44 (d,
1 H, H(10), J = 8.4 Hz).
6
2 2
(
m, 2 H, H(4), H(7)); 11.08 (br.s, 1 H, NH).
2ꢀ[Nꢀ(4ꢀAcetoxybutyl)ꢀNꢀacetylamino]benzimidazole (8).
B. A mixture of benzimidazoleꢀ2ꢀsulfonic acid (2.0 g,
A solution of amino alcohol 2c (0.4 g, ~2 mmol) in Ac O (3 mL)
2
1
0 mmol) and pyrrolidine (2.5 mL, 30 mmol) was heated in a
was refluxed for 1.5 h, cooled, and poured into water (20 mL).
Acetic anhydride was quenched, and the reaction mixture
sealed tube at 140—150 °C for 1.5 h. After cooling, the reaction
mixture was treated with water (20 mL). The precipitate was
filtered off, washed with water, and recrystallized from ethanol
containing activated carbon. The yield was 1.27 g (68%), m.p.
was carefully made alkaline with concentrated NH OH. The
4
reaction product was extracted with CHCl3 (3×7 mL), and
the extract was passed through a layer of Al O (CHCl3 as
2
3
3
34—335 °C (with decomp.). A mixture of compound 4 and the
the eluent). The yield was 0.53 g (91%), m.p. 101—102 °C
(from light petroleum ether). Found (%): C, 62.35; H, 6.78;
N, 14.75. C H N O . Calculated (%): C, 62.27; H, 6.62;
sample prepared according to the procedure A showed no meltꢀ
ing point depression.
1
5
19
3
3
–
1
1
ꢀAcetylꢀ2ꢀ(4ꢀchlorobutylamino)benzimidazole (5). A soluꢀ
N, 14.52. IR, ν/cm : 1645 (NCOMe); 1705 (OCOMe); 3340
1
tion of chloramine 3c (0.22 g, 1 mmol) in Ac O (4 mL) was kept
(NH). H NMR (CDCl ), δ: 1.75—1.96 (m, 4 H, C(2)H ,
2
3
2
at 20—25 °C for ~24 h. The progress of the reaction was moniꢀ
tored by TLC (R (3c) 0.15, R (5) 0.95). Then Ac O was concenꢀ
C(3)H ); 2.05 (s, 3 H, NCOMe); 2.45 (s, 3 H, OCOMe); 4.15
2
(t, 2 H, NCH2 or OCH , J = 6.5 Hz); 4.23 (t, 2 H, OCH
f
f
2
2
2
trated to dryness at 30—35 °C in vacuo. The residue was treated
or NCH , J = 7.8 Hz); 7.15—7.28 (m, 2 H, H(5), H(6)); 7.38
2
with diethyl ether, filtered off, and dried in air. The yield was
(d, 1 H, H(4), J = 8.0 Hz); 7.65 (d, 1 H, H(7), J = 7.8 Hz);
0
.25 g (94%), m.p. 62 °C. Found (%): C, 58.68; H, 6.10;
11.50 (s, 1 H, NH).
Cl, 13.22; N, 15.96. C H ClN O. Calculated (%): C, 58.75;
1
3
16
3
–
1
H, 6.07; Cl, 13.34; N, 15.81. IR, ν/cm : 1640 (C=N); 1700
C=O); 3370 (NH). H NMR (DMSOꢀd ), δ: 1.67—1.81 (m,
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ96804)
and the Administration of the Rostov Region.
1
(
6
4
H, C(2)H , C(3)H ); 2.74 (s, 3 H, Me); 3.46 (q, 2 H, NCH ,
2 2 2
J = 6.3 Hz); 3.67 (t, 2 H, CH Cl, J = 6.3 Hz); 6.99 (t, 1 H, H(5)
2
or H(6), J = 7.7 Hz); 7.15 (t, 1 H, H(6) or H(5), J = 7.6 Hz);
7
7
.24 (d, 1 H, H(7), J = 7.8 Hz); 7.53 (d, 1 H, H(4), J = 8.0 Hz);
.89 (t, 1 H, NH, J = 6.3 Hz).
References
1
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in acetic anhydride (20 mL) was kept at 20—25 °C until the
complete acetylation of the amino group was achieved (see the
synthesis of compound 5). Then the reaction mixture was reꢀ
fluxed for 2 h, cooled, and poured into water (50 mL). Excess
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Received June 26, 2007;
in revised form September 14, 2007