Synthesis and structural features of new cyclofunctionalized benzimidazoles

Article abstract of DOI:10.3987/COM-99-8784

The synthesis of new tricyclic derivatives having sulfur-containing six or seven-membered rings fused to the <> edge of benzimidazole system, is reported. The stereochemical characteristics of thiazino- and thiazepinobenzimidazoles (4-7) are described

Full text of DOI:10.3987/COM-99-8784

HETEROCYCLES, Vol. 53, No. 3, 2000, pp. 613 - 620, Received, 18th October, 1999
SYNTHESIS
AND
STRUCTURAL
FEATURES
OF
NEW
CYCLOFUNCTIONALIZED BENZIMIDAZOLES
Alba Chimirri, * a Anna Maria Monforte,b Pietro Monforte,a Francesco Nicolò,c
Angela Rao,a and Maria Zappalàa
aDipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168
b
Messina, Dipartimento di Scienze Farmacobiologiche, Università di Catanzaro
c
"Magna Græcia", 88021 Roccelletta di Borgia (CZ), Dipartimento di Chimica
Inorganica, Chimica Analitica e Chimica Fisica, Università di Messina, Vill.S.
Agata, 98166 Messina, Italy
Abstract - The synthesis of new tricyclic derivatives having sulfur-containing six
or seven-membered rings fused to the «a» edge of benzimidazole system, is
reported.
The
stereochemical
characteristics
of
thiazino-
and
thiazepinobenzimidazoles (4-7) are described and comparative NMR data are
discussed. The synthetic approach to new benzo- or pyridothiazinobenzimidazole
tetracyclic systems (8) is also reported.
INTRODUCTION
The benzimidazole system is present in numerous compounds of biological interest and plays an
important role in medicinal chemistry research.1
Over the past years, the introduction of an additional ring on the benzimidazole system has been
increasing attention in the expectation that such changes could potentially affect the interaction of the
molecules with biological targets.2,3 In particular, in our research, the introduction of a thiazole nucleus
on the «a» edge of benzimidazole has been investigated as an approach to the discovery of anti-HIV
(human immunodeficiency virus) agents. This effort has resulted in the preparation of several 1H,3H-
thiazolo[3,4-a]benzimidazoles (TBZs), some of which were found to be potent inhibitors of HIV-1 induced
cytopathicity and virus replication.4-12
Moreover, in our previous papers,13-15 the introduction of a pyrrole nucleus on benzimidazole system
resulted in generally active compounds endowed with anticonvulsant properties better than that of
valproate and comparable to that of phenytoin.
In connection with these studies on the chemistry of cyclofunctionalized benzimidazoles as potential
pharmacological agents, we have extended the research to the study of new tricyclic and tetracyclic
systems in which sulfur-containing six or seven-membered rings are fused at the «a» edge of the
benzimidazole moiety.
Email:
FAX: +39 090 355613

As far as we know very limited data on thiazino- or thiazepinobenzimidazole derivatives as well as on
benzo- or pyridothiazinobenzimidazole ones have appeared in literature.16-17 The structural features of
the newly synthesized compounds have been unambiguously assigned by means of spectroscopic
measurements.
RESULTS AND DISCUSSION
A multi-step procedure (Schemes 1-3) was employed for the synthesis of thiazinobenzimidazoles (4 and
6) and thiazepinobenzimidazoles (5 and 7).
The appropriate 1,2-phenylenediamine hydrochloride (1a-c) was alternatively treated with
mercaptoacetic acid (2a) or with 2- or 3-mercaptopropionic acid (2b or 2c) to afford, after treatment with
NH4OH, mercaptoalkylbenzimidazoles (3a-f)18-20 as intermediate compounds (Scheme 1).
H
O
R2
R1
NH2
NH2
R2
R1
N
1. H2O, ∆
SH
n
SH
+
HO
n
2. NH4OH
N
R3
R3
3a-f
R1 R2 R3
2a-c
R3
1a-c
R1 R2
n
n
1a
1b Cl
H
H
H
2a
2b Me
2c
H
1
1
2
3a
3b
H
H
H
H
H
H
Me
H
1
1
1
1
2
2
1c Me Me
H
3c Cl
3d Me Me
3e
3f Me Me
H
H
H
H
H
Scheme 1
The subsequent reaction of 3a-d with a suitable dibromoalkane in phase-transfer catalysis (PTC)
conditions afforded, after conventional work-up, 3,4-dihydro-1H-[1,4]thiazino[4,3-a]benzimidazoles (4a-e)
and 4,5-dihydro-1H,3H-[1,4]thiazepino[4,3-a]benzimidazoles (5a-c) (Scheme 2).
S
R2
R1
N
N
R1 R2 R3
R3
4a
4b
H
H
H
H
H
Me
H
H
N
Br(CH2)2Br
R2
R1
4a-e
4c Cl
4d
H
SH
DMF/NaOH
PTC
H
Cl
H
N
R3
4e Me Me
H
Br(CH2)3Br
5a
5b
H
H
H
H
H
3a-d
R2
R1
N
Me
H
S
5c Me Me
N
R3
5a-c
Scheme 2

Similarly, the reactions in which derivatives (3e,f) were used as substrates, gave 3,4-dihydro-1H-
[1,3]thiazino[3,4-a]benzimidazoles (6a-d) and 1,2,4,5-tetrahydro[1,4]thiazepino[4,5-a]benzimidazoles
(7a,b) (Scheme 3).
R3
S
R2
N
R1 R2 R3
N
R1
6a
H
H
H
R3CHBr2
H
N
6a-d
6b Me Me
H
R2
R1
DMF/NaOH
PTC
6c
6d
7a
H
H
H
H
H
H
Ph
SH
3-FC6H4
N
Br(CH2)2Br
S
R2
7b Me Me
N
3e,f
N
R1
7a,b
Scheme 3
The synthesis of tetracyclic derivatives 6H-benzo[e][1,3]thiazino[3,4-a]benzimidazole (8a) and 11H-
pyrido[2’,3’:6,5][1,3]thiazino[3,4-a]benzimidazole (8b) (Scheme 4) was derived from reaction of
dibromomethane with 2-(2’-mercaptoaryl)benzimidazoles (3g,h) previously obtained by condensation of
1,2-phenylenediamine (1a) with 2-mercaptobenzoic acid (2d) or 2-mercaptonicotinic acid (2e),
respectively.
H
N
HS
S
NH2
HS
O
X
DMF/NaOH
PTC
X
N
N
X
PPA
+
250°C
HO
BrCH2Br
NH2
N
8a,b
1a
2d,e
3g,h
X
2d, 3g, 8a CH
2e, 3h, 8b N
Scheme 4
The structures of the synthesized compounds were deduced from spectral data and supported by
satisfactory elemental analysis (Table 1).
The 1H-NMR spectra (Table 2) are characterized for the aliphatic region by resonance patterns, such as
A2 or A2B2 systems, that are indicative of a conformational mobility of the heterocycle fused on the «a»
edge of the benzimidazole system in solution at room temperature. In derivatives (4b, 5b, 6c and 6d), in
which a substituent is present on the thiazino or thiazepino nucleus, the alicyclic bridge gives rise to a
more complex resonance pattern, which can be explained on the basis both of a reduced conformational
mobility and of the presence of a chiral center.

Table 1. Tricyclic and tetracyclic benzimidazoles
Compound
Yield
(%)
mp (°C)a
Solventb
Formula
Analysis
Calculated/Found (%)
H
C
N
4a
4b
4c
4d
4e
5a
5b
5c
6a
6b
6c
6d
7a
7b
8a
8b
24
60
47
45
60
25
38
88
55
30
12
16
15
32
20
22
145-148
127-130
214 (dec)
202 (dec)
218 (dec)
158-160
177-179
215-218
204-207
200-202
165-168
146-149
132-135
229-232
123-125
170-173
-
C10H10N2S
C11H12N2S
C10H9N2SCl
C10H9N2SCl
C12H14N2S
C11H12N2S
C12H14N2S
C13H16N2S
C10H10N2S
C12H14N2S
C16H14N2S
C16H13N2SF
C11H12N2S
C13H16N2S
C14H10N2S
C13H9N2S
63.13
63.21
5.30
5.42
14.72
14.63
C
D
D
-
64.67
64.98
5.92
5.63
13.71
13.55
53.45
53.59
4.04
4.16
12.47
12.21
53.45
53.22
4.04
4.14
12.47
12.68
66.02
66.37
6.46
6.32
12.83
12.77
A
-
64.67
64.35
5.92
5.61
13.71
13.95
66.02
66.21
6.46
6.15
12.83
12.74
-
67.20
67.54
6.94
7.07
12.06
12.32
-
63.13
63.47
5.30
5.55
14.72
14.52
C
C
C
A
A
B
B
66.02
66.09
6.46
6.59
12.83
12.66
72.15
72.45
5.30
5.49
10.52
10.29
67.58
67.42
4.61
4.86
9.85
9.64
64.67
64.73
5.92
5.72
13.71
13.90
67.20
67.31
6.94
6.85
12.06
12.22
70.56
70.22
4.23
4.48
11.75
11.33
65.62
65.28
3.79
3.95
17.56
17.49
aCrystallization solvents were: EtOAc for 4a and 6a; EtOH for 4b-e, 5a, 6b-d, 7a,b and 8a,b; Et2O/EtOH for 5b,c
bSolvent for column chromatography: CHCl3/MeOH 97:3 (A), 96:4 (B), 95:5 (C), CHCl3/EtOAc 6:4 (D).

The characterization of the position isomers (4c) and (4d) was obtained by a careful examination of the
resonance pattern of the aromatic moiety, considering that the imine nitrogen exerts a deshielding effect
on the proximal aromatic proton.
MS spectra and 13C-NMR data of selected compounds are reported in Table 3. MS spectra show correct
molecular ion and fragmentations that are in agreement with the proposed structures. 13C-NMR spectra
give conclusive evidence for the structural assignment of the synthesized compounds.
In conclusion, by reacting 1,2-phenylenediamine with easily available synthones, we have developed a
simple strategy for the synthesis of a variety of cyclofunctionalized benzimidazole derivatives of potential
pharmacological interest.
Table 2. 1H NMR spectral data of tricyclic and tetracyclic benzimidazole derivatives
Compound 1H NMR (CDCl3/TMS) δ, J (Hz)
4a
4b
3.17 (t, 2H, J=5.7, H-3), 4.10 (s, 2H, H-1), 4.34 (t, 2H, J=5.7, H-4), 7.27-7.72 (m, 4H, ArH)
1.85 (d, 3H, J=6.9, Me-1), 3.19-3.25 (m, 2H, H-3), 4.29-4.38 (m, 3H, H-4 and H-1), 7.27-7.76 (m,
4H, ArH)
4c
4d
4e
5a
5b
5c
3.19 (t, 2H, J=5.8, H-3), 4.10 (s, 2H, H-1), 4.34 (t, 2H, J=5.8, H-4), 7.23 (m, 2H, H-6 e H-7), 7.69
(d, 1H, J=1.8, H-9)
3.19 (t, 2H, J=5.7, H-3), 4.10 (s, 2H, H-1), 4.32 (t, 2H, J=5.7, H-4), 7.25 (dd, 1H, J=1.9 and 8.5, H-
8), 7.31 (d, 1H, J=1.9, H-6), 7.61 (d, 1H, J=8.5, H-9)
2.37 and 2.39 (2s, 6H, Me), 3.16 (t, 2H, J=5.8, H-3), 4.10 (s, 2H, H-1), 4.30 (t, 2H, J=5.8, H-4),
7.07 (s, 1H, H-6), 7.46 (s, 1H, H-9).
2.15 (quintet, 2H, H-4), 3.02 (t, 2H, J=5.4, H-3), 4.04 (s, 2H, H-1), 4.27 (t, 2H, J=5.0, H-5), 7.23-
7.74 (m, 4H, ArH)
1.84 (m, 1H, HA-4), 1.89 (d, 3H, J=7.2, Me), 2.32 (m, 1H, HB-4), 2,93 (m, 1H, HA-3), 3.15 (m, 1H,
HB-3), 4,08 (m, 1H, HA-5), 4.26 (q, 1H, J=7.2, H-1), 4.52 (m, 1H, HB-5), 7.22-7.79 (m, 4H, ArH).
2.12 (quintet, 2H, H-4), 2.37 and 2.39 (2s, 6H, Me), 2.99 (t, 2H, J=5.0, H-3), 4.01 (s, 2H, H-1),
4.22 (t, 2H, J=5.0, H-5), 7.05 (s, 1H, H-7 ), 7.46 (s, 1H, H-10 ).
6a
6b
3.12 (t, 2H, J=6.1, H-3), 3.47 (t, 2H, J=6.1, H-4), 5.10 (s, 2H, H-1), 7.27-7.72 (m, 4H, ArH).
2.37 and 2.39 (2s, 6H, Me), 3.10 (t, 2H, J=6.05, H-3), 3.43 (t, 2H, J=6.05, H-4), 5.03 (s, 2H, H-1),
7.07 (s, 1H, H-9 ), 7.46 (s, 1H, H-6).
6c
6d
7a
2.92-3.10 (m, 2H, H-3), 3.47-3.63 (m, 2H, H-4), 6.46 (s, 1H, H-1), 6.81-7.74 (m, 9H, ArH).
2.93-3.09 (m, 2H, H-3), 3.46-3.63 (m, 2H, H-4), 6.43 (s, 1H, H-1), 6.75-7.75 (m, 8H, ArH).
2.86 (t, 2H, J=5.7, H-4), 2.88 (t, 2H, J=4.4, H-2), 3.59 (t, 2H, J=5.7, H-5), 4.60 (t, 2H, J=4.4, H-1),
7.27-7.73 (m, 4H, ArH).
7b
2.37 and 2.39 (2s, 6H, Me), 2.83 (t, 2H, J=5.3, H-4), 2.85 (t, 2H, J=4.7, H-2), 3.55 (t, 2H, J=5.3,
H-5), 4.54 (t, 2H, J=4.7, H-1), 7.04 (s, 1H, H-10), 7.46 (s, 1H, H-7).
8a
8b
5.33 (s, 2H, CH2), 7.27-8.38 (m, 8H, ArH).
5.41 (s, 2H, CH2), 7.22-8.54 (m, 7H, ArH).

Table 3. MS and 13C NMR spectral data of selected tricyclic and tetracyclic benzimidazole derivatives
Compound MS m/z (%)
190 (M+, 100), 157 (13), 144 (53), 26.43 (C-3), 26.691 (C-1), 45.22 (C-4) 109.31 (C-6), 119.48
13C NMR (CDCl3/TMS) δ
4a
4b
4c
4d
5a
5b
6a
7a
8a
117 (12), 77 (10).
(C-9), 123.11 (C-7), 123.46 (C-8), 135.05 (C-5a), 141.22 (C-
9a), 147.10 (C-10a).
204 (M+, 68), 189 (100), 157 (15), 20.15 (Me-1), 25.31 (C-3), 34.84 (C-1) 45.48 (C-4), 109.53 (C-
144 (9), 102 (9), 77 (11).
6), 119.53 (C-9), 123.26 (C-7), 123.51 (C-8), 135.02 (C-5a),
140.10 (C-9a), 151.93 (C-10a).
224 (M+, 100), 189 (46), 178 (46), 25.86 (C-3), 26.59 (C-1) 44.83 (C-4), 109.44 (C-6), 119.08 (C-
152 (14), 151 (14), 112 (6), 89 (5), 9), 122.77 (C-7), 128.16 (C-8), 133.50 (C-5a), 142.35 (C-9a),
75 (11).
147.93 (C-10a).
224 (M+, 100), 189 (60), 178 (59), 25.91 (C-3), 26.56 (C-1) 44.87 (C-4), 108.98 (C-6), 120.08 (C-
152 (30), 151 (24), 112 (14), 89 9), 123.27 (C-8), 128.14 (C-7), 135.54 (C-5a), 140.04 (C-9a),
(19), 75 (35).
147.53 (C-10a).
204 (M+, 100), 175 (11), 171 (39), 30.09 (C-4), 30.15 (C-1), 34.74 (C-3), 44.52 (C-5), 109.33 (C-
157 (27), 131 (13), 118 (10), 77 7), 119.85 (C-10), 122.77 (C-8), 123.33 (C-9), 135.92 (C-6a),
(14).
141.53 (C-10a), 155.72 (C-11a).
218 (M+, 100), 203 (58), 185 (36), 18.20 (Me-1), 29.48 (C-4), 33.98 (C-3) 37.37 (C-1), 44.06 (C-
171 (35), 157 (37), 131 (14), 118 5), 109.10 (C-7), 120.10 (C-10), 122.55 (C-8), 123.19 (C-9),
(15), 90 (15), 77 (80), 65 (16).
190 (M+, 100), 157 (14), 144 (91), 25.61 (C-3), 28.73 (C-4), 43.93 (C-1), 109.09 (C-9), 119.39
135.84 (C-6a), 141.82 (C-10a), 158.63 (C-11a).
118 (15), 77 (19).
(C-6), 122.99 (C-8), 123.33 (C-7), 134.29 (C-9a), 141.15 (C-
6a), 150.20 (C-5a).
204 (M+, 63), 171 (18), 158 (25), 27.86 (C-4), 30.85 (C-2) 34.70 (C-5), 48.72 (C-1), 109.30 (C-
102 (100), 90 (52), 77 (54), 63 10), 119.57 (C-7), 122.98 (C-9), 123.39 (C-8), 135.76 (C-10a),
(18).
141.29 (C-6a), 155.82 (C-5a).
238 (M+, 100), 237 (73), 119 (11), 42.47 (C-6), 109.48 (C-8), 120.22 (C-11), 123.72 (C-9),
77 (16).
123.72 (C-9), 123.94 (C-10), 126.51 (C-4a), 127.15, 127.65,
127.91, 130.34 (C-1, C-2, C-3, C-4), 131.40 (C-12b), 133.77
(C-7a), 143.28 (C-11a), 148.11 (C-12a).
8b
239 (M+, 100), 238 (80), 120 (10), 42.47 (C-11), 109.76 (C-9), 120.27 (C-6), 122.35 (C-8),
77 (9).
123.07 (C-4a), 124.17 (C-7), 124.65 (C-3), 133.87 (C-9a),
135.24 (C-4), 143.95 (C-5a), 147.26 (C-4b), 151.48 (C-2),
155.20 (C-12a).
EXPERIMENTAL
Melting points were determined on a Kofler hot stage apparatus and are uncorrected. Elemental
analyses (C, H, N) were carried out on a C. Erba Model 1106 Elemental Analyzer. Column
chromatography was performed with Merck silica gel (63-200 µm). The following mixtures of solvents
were used as eluents: CHCl3/MeOH 97:3 (A), 96:4 (B), 95:5 (C), CHCl3/EtOAc 6:4 (D). 1H- and 13C-NMR
spectra were measured with a Varian Gemini-300 instrument in CDCl3 as solvent. Chemical shifts are
expressed in δ (ppm) relative to TMS as internal standard and coupling constants (J) in Hz. MS spectra
were recorded with a QP5050A Shimadzu mass spectrometer.

General procedure for the synthesis of mercaptoalkylbenzimidazoles (3a-f)
To a solution of the suitable 1,2-phenylenediamine hydrochloride (0.01 mol) in H2O (7 mL) was added
mercaptoacetic, 2-mercaptopropionic or 3-mercaptopropionic acid (0.03 mol). The reaction mixture was
refluxed for 1-2 h then cooled and treated with concd NH4OH to afford a crude product which was
purified by recrystallization from EtOH.
General procedure for the synthesis of 2-(2’-mercaptoaryl)benzimidazoles (3g-h)
A mixture of 1,2-phenylenediamine (0.01 mol) and 2-mercaptosalicylic or 2-mercaptonicotinic acid (0.01
mol) in 20 g of PPA was heated until 250°C under stirring and then maintained at this temperature for 4
h. The mixture was allowed to cool to 100°C and then poured into H2O (60 mL) and neutralized with a
solution of 50% aq. NaOH. The precipitate obtained was filtered and recrystallized from EtOH.
General procedure for the synthesis of cyclofunctionalized benzimidazoles (4a-e, 5a-c, 6a-d, 7a-b
and 8a-b)
The suitable mercaptoalkylbenzimidazole (0.005 mol) and a catalytic amount of benzyltriethylammonium
chloride were added to a solution of 50% aq. NaOH (10 mL). The resulting mixture was treated with a
solution of the appropriate dibromoalkane (0.01 mol) in 80 mL of DMF and stirred at rt until completion of
the reaction. After separation of inorganic salts, the reaction mixture was diluted with H2O and extracted
with CHCl3. The combined organic solution was dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The oily residue was recrystallized to afford compounds (4a, 4e, 5b-c and 6a)
or purified by column chromatography as reported in Table 1.
AKNOWLEDGEMENT
This work was supported by the Ministero dell’Università e della Ricerca Scientifica e Tecnologica
(MURST).
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