Access to N-thioalkenyl and N-(o-thio)aryl-benzimidazol-2-ones by ring opening of thiazolobenzimidazolium and benzimidazobenzothiazolium salts and C-O bond cleavage of an alkoxide

Article abstract of DOI:10.1021/acs.joc.5b00221

We report herein the synthesis of highly functionalized 1,3-dihydro-2H-benzimidazol-2-ones via a ring opening of thiazolo[3,2-a]benzimidazolium or benzimidazo[2,1-b][1,3]benzothiazol-6-ium salts and an unusual C-O bond cleavage of an alkoxide. A large variety of benzimidazolones bearing an original N-thioalkenyl or N-(o-thio)aryl group was obtained in high yields. The developed chemistry provides efficient and rapid access to the privileged benzimidazol-2-one scaffold.

Full text of DOI:10.1021/acs.joc.5b00221

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Article
Access to N-thioalkenyl and N-(o-thio)aryl-Benzimidazol-2-
ones by Ring Opening of Thiazolobenzimidazolium and
Benzimidazobenzothiazolium Salts and C-O Bond Cleavage of an Alkoxide
Federico Andreoli, Radia Kaid-Slimane, Fabien Coppola,
Daniel Farran, Christian Roussel, and Nicolas Vanthuyne
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00221 • Publication Date (Web): 27 Feb 2015
Downloaded from http://pubs.acs.org on March 2, 2015
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Access to N-thioalkenyl and N-(o-thio)aryl-Benzimidazol-2-ones
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by
Ring
Opening
of
Thiazolobenzimidazolium
and
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Benzimidazobenzothiazolium Salts and C-O Bond Cleavage of an
Alkoxide
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Federico Andreoli,† Radia KaidꢀSlimane,‡ Fabien Coppola,† Daniel Farran,*,† Christian
Roussel,*,† Nicolas Vanthuyne†
†Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille,
France
‡ Laboratoire de synthèse organique appliquée, Département de Chimie, Faculté des
Sciences, université d’Oran (Es Sénia), B.P. 1524, El M’naouer Oran, Algérie
* Corresponding authors’ e-mail address : christian.roussel@univ-amu.fr;
daniel.farran@univ-amu.fr
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Scheme of abstract:
4
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R4
S
R2
O
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9
S
X
S
-
R2
R3
R2
N
N
R3-X
R4O Na+
N
N
N
N
R1
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R3
R1
R1
17 examples
up to 100 %
R5
R4
S
X
S
S
R5
R5
-
R3
N
R3-X
R4O Na+
N
N
N
N
O
N
R3
7 examples
up to 100 %
Abstract: We report herein the synthesis of highly functionalized 1,3ꢀdihydroꢀ2Hꢀ
benzimidazolꢀ2ꢀones via ring opening of thiazolo[3,2ꢀa]benzimidazolium or
a
benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium salts and an unusual CꢀO bond cleavage of an
alkoxide. A large variety of benzimidazolones bearing an original Nꢀthioalkenyl or Nꢀ(oꢀ
thio)aryl group was obtained in high yields. The developed chemistry provides efficient and
rapid access to the privileged benzimidazolꢀ2ꢀone scaffold.
Introduction
Benzimidazolꢀ2ꢀone is a common molecular framework which belongs to privileged
structures, i.e. compounds able of providing useful ligands for more than one type of receptor
or enzyme target by judicious structural modifications.1 Indeed, 1,3ꢀdihydroꢀ2Hꢀ
benzimidazolꢀ2ꢀone derivatives exhibit a broad scope of pharmacological properties,
including opioid receptorꢀlike agonists2 and antagonists,3 reverse transcriptase inhibitors,4 p38
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kinase inhibitors,5 respiratory syncytial virus fusion inhibitors6 and progesterone receptor
antagonists.7 A survey of recent literature indicates that investigations in these fields remain
an active and crucial area of research.8 Furthermore, besides all these biological activities, this
class of compounds also constitute attractive building blocks in crystal engineering9 as well as
thermoplastic10 and conducting11 polymers.
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Conventional synthesis of benzimidazolꢀ2ꢀones bearing two different substituents on each
nitrogen atom requires multiꢀstep manipulations, and three pathways can be envisioned. The
first strategy involves the formation of the benzimidazole core followed by regioselective
alkylation of either nitrogen atom.7b,12 The requirement of protecting groups is mandatory in
such method. Another typical approach consists in the nucleophilic displacement of 2ꢀ
fluoronitrobenzenes with primary amines, subsequent reduction and cyclization using 1,1’ꢀ
carbonyldiimidazole5a,13 or triphosgene.14 In this case, the scarce commercially availability of
diversely substituted starting material represents a limitation. Finally, alternative procedures
have been reported by cyclization of oꢀhaloarylureas using palladium15 or copper catalysis.16
Although these methodologies offer certain advantages, each suffers from some drawback
(e.g. low yield, reaction sequence not straightforward, only few described examples, harsh
conditions) and generates a single functionalized nitrogen atom.
Access to new therapeutic entities depends greatly on the discovery of original and pertinent
scaffolds, connected with the development of innovative synthetic reactions. In this paper, we
report a straightforward synthesis of unsymmetrically N,N’ꢀdisubstituted 1,3ꢀdihydroꢀ2Hꢀ
benzimidazolꢀ2ꢀones 1 and 2 via ring opening of thiazolo[3,2ꢀa]benzimidazolium 3 and
benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium 4 quaternary salts respectively (Figure 1).17 The
strategy described here allows modulation of four substituents on the benzimidazole scaffolds.
Interestingly, this work represents the first example of installation of a Nꢀthioalkenyl or Nꢀ(oꢀ
thio)aryl substituent on these relevant nitrogenꢀcontaining heterocycles and only two synthetic
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pathways to Nꢀalkenylꢀbenzimidazolꢀ2ꢀones, simpler structures, are described in the
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literature.18
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R4
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S
S
X
R3
S
R2
O
R2
R2
N
N
N
N
N
N
R1
R1
R1
R3
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3
5
R5
R4
S
S
X
R3
S
R5
R5
N
N
N
N
N
N
R3
R1
O
R1
R1
2
4
6
Figure 1. Synthesis of Nꢀthioalkenyl and Nꢀ(oꢀthio)aryl benzimidazolꢀ2ꢀones starting from
thiazolobenzimidazole and benzo[d]imidazoꢀ[2,1ꢀb]benzothiazole respectively
Results and Discussion
1,3ꢀDihydroꢀ2Hꢀbenzimidazolꢀ2ꢀones 1 were prepared using thiazolo[3,2ꢀa]benzimidazoles 5
as starting materials. Several thiazolobenzimidazoles 5 are commercially available or can be
obtained from 2ꢀmercaptobenzimidazoles.19 In this work, heterocycles 5 were efficiently
synthesised using a one pot procedure starting from Nꢀ(2ꢀaminophenyl)ꢀthiazolineꢀ2ꢀthiones
as we have previously reported.20 This protocol led to a broad structural diversity: R1
represents a hydrogen, a fluorine or a trifluoromethyl group, and R2 can be an alkyl or an aryl
substituent.21
With compounds 5 in hand, we first examined the sequence leading to benzimidazolꢀ2ꢀone 1a
(Scheme 1). The simplest thiazolobenzimidazole 5a (R1 = H; R2 = Me) was easily converted
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into its corresponding quaternary salt 3a using methyl iodide in acetone. After solubilisation
in methanol, this salt was reacted with sodium methoxide at room temperature and we were
delighted to observe a ring opening generating the 1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone 1a as
a white powder in 71% overall isolated yield.
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Scheme 1. Synthesis of benzimidazolꢀ2ꢀone 1a via ring opening of thiazolobenzimidazolium
salt 2a
S
S
S
I
MeI
N
N
MeONa
N
N
N
N
O
Acetone, r.t.
MeOH, r.t.
5a
3a (89%)
1a (80%)
Compound 1a is remarkable for the simplicity of the synthesis route and for the
unprecedented access to (thio)vinyl substituent in benzimidazolꢀ2ꢀone series. The formation
of 1a emphasizes also an uncommon phenomenon: the H3CꢀO bond of the alkoxide is cleaved
to provide the oxygen of the benzimidazolone core and the CH3 group bonded to the sulphur
atom. It means that, in this process, the methoxide anion acts as a source of methyl group and
oxygen atom.
Benzimidazolꢀ2ꢀone 1a was isolated as a single isomer and a NOESY experiment was carried
out in order to establish the stereochemistry of C=C double bond.21 This 2D NMR spectrum
revealed that the vinylic hydrogen atom is close to those belonging to the methyl group
located on the double bond. It clearly indicates that both heteroatoms are on the same side of
the C=C bond, i.e. a Z configuration issuing from the thiazole moiety.
The study was then directed towards the access to a focused library of benzimidazolꢀ2ꢀones 1
with the aim to extend the scope of our methodology (Table 1). Heterocycles 5 were allowed
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to react with a range of halogenated derivatives R3ꢀX (iodomethane, iodoethane, 1ꢀ
iodoheptane, benzyl chloride, 3,5ꢀbis(trifluoromethyl)benzyl chloride or 4ꢀnitrobenzyl
chloride) to furnish the corresponding Nꢀalkylated salts 3 in 68ꢀ100% yield after a simple
filtration.
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In the presence of MeONa or BnONa, 3 underwent a ring opening and we obtained single
stereomers of 1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀones 1 (R4 = Me) with good to excellent
overall yields (Table 1, entries 1ꢀ5 and 9ꢀ17). This unprecedented sequence enabled the
preparation of a large series of Nꢀthioalkenyl benzimidazolones 1 with control of four
substituents on the heterocyclic ring. Pure products were isolated without tedious purification
since the workꢀup consisted in an extraction in dichloromethane sometimes followed by a
quick filtration on a pad of silica. It is noteworthy that the protocol utilizes cheap chemicals
and allows high atom efficiency.
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Table 1. Synthesis of benzimidazolꢀ2ꢀones 1 starting from thiazolobenzimidazoles 5a
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R4
S
R2
S
X
S
R2
R2
N
N
(i)
R3
(ii)
N
N
N
N
R1
O
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R3
R1
R1
5
3
1
b
b
Entry
Entry
1
1
S
S
N
N
1j (68%)
O
N
N
CF3
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10
1b (62%)
O
CF3
S
S
N
N
N
N
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3
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12
1c (81%)
O
1k (100%)
O
n-C7H15
S
F
S
N
1d (85%)
N
O
1l (97%)
O
N
N
S
Cl
S
N
1e (69%)
O
N
CF3
N
4
13
1m (98%)
O
N
CF3
S
OMe
S
N
N
N
1f (86%)
O
5
6
7
14
15
16
1n (100%)
O
N
NO2
S
S
N
O
N
N
N
1o (95%)
O
1g1 (50%)
S
S
S
N
O
N
+
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N
N
N
O
1p (67%)
O
F
1g1 (26%)
1g2 (20%)
S
N
S
S
F3C
N
N
N
8
9
17
+
O
1q (83%)
O
O
N
N
1h1 (27%)
1h2 (36%)
S
N
1i (100%)
O
N
a Reagents and conditions: (i) R3ꢀX, acetone (entries 1, 3, 5ꢀ8 and 11ꢀ17) or none solvent (entries 2 and 9) or acetonitrile (entries 4 and 10),
reflux (entries 1ꢀ8 and 10ꢀ15) or 100°C (entry 9) or room temperature (entries 16 and 17); (ii) MeONa, MeOH, r.t. (entries 1ꢀ5 and 9ꢀ16) or
BnOH/Na, r.t. (entry 6) or BnOH, NaOH, reflux (entries 7ꢀ8) or MeONa, MeOH, reflux (entry 17). b Overall isolated yield between brackets.
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In order to confirm the cleavage of the alkoxide species, salt 3d (R1 = H, R2 = Me, R3 = Bn)
were treated at room temperature by a freshly prepared solution of sodium benzylate (Table 1,
entry 6). As expected, addition of BnOꢀ provided the anticipated cis benzimidazolone with
subsequent transfer of the benzyl group to sulfur. This unambiguously demonstrates that the
R4 moiety and the oxygen of the carbonyl on the final heterocycle come from the same
alkoxide anion. Furthermore, salts 3d (R1 = H, R2 = Me, R3 = Bn) and 3a (R1 = H, R2 = Me,
R3 = Me) were allowed to react with BnOH/NaOH at reflux (Table 1, entries 7ꢀ8).
Interestingly, the two geometric isomers of 1g and 1h have been obtained in a 45/55 (Z/E)
ratio (determined by 1H NMR on the crude material). We assume that the occurrence of both
isomers probably resulted from isomerisation of the double bond during heating. However,
they were easily separated by column chromatography so that this procedure provided access
to the trans stereomer of benzimidazolone.
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Compound 1k was crystallised and a suitable crystal was used for Xꢀray diffraction.21 The
chemical structure of the isolated benzimidazolꢀ2ꢀones and the stereochemistry of C=C
double bond were confirmed. Some insight at the solid state can be gleaned from this
analysis: the conformation adopted is characterized by a dihedral angle of 126° between the
plane containing the original Nꢀthioalkenyl substituent and the plane containing the
heterocyclic ring. In addition, the crystal packing revealed the presence of two frozen
atropisomers about NꢀCvinylic bond axis. During HPLC analysis, neither plateau nor peak
separation were observed, meaning that the exchange between these atropisomeric forms is
fast in solution.
During the development of this work, novel efficient methodologies to generate
benzo[d]imidazo[2,1ꢀb]thiazoles 6 have been published in literature.22 These structures are
similar to thiazolobenzimidazoles 5 and this encouraged us to perform a parallel treatment in
these series, i.e. synthesis of the corresponding quaternary salts 4, followed by a ring opening
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promoted by an alkoxide (Table 2). This sequence would lead to Nꢀaryl benzimidazolꢀ2ꢀones
2 which belong to a class of molecules possessing pharmacological activities such as heat
shock protein 90 inhibitors,23 serotonin 5ꢀHT ligands,24 farnesyltransferase inhibitors13a and
maxiꢀK channel openers.25
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Table 2. Synthesis of benzimidazolꢀ2ꢀones 2 starting from benzo[d]imidazoꢀ[2,1ꢀ
b]benzothiazoles 6a
R5
R4
S
X
S
S
R5
R5
(i)
R3
(ii)
N
N
R3
N
N
N
N
O
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4
2
b
b
Entry
1
Entry
5
2
2
Cl
S
S
N
N
N
O
2e (100%)
O
N
2a (45%)
Cl
S
N
S
N
N
2
3
6
7
O
O
N
2f (89%)
Cl
2b (69%)
Cl
Cl
S
S
N
N
N
N
2g (33%)
O
O
2c (63%)
n-C7H15
Cl
S
4
N
N
O
2d (74%)
a Reagents and conditions: (i) R3ꢀX, pentanꢀ3ꢀone (entries 1ꢀ4 and 7) or none solvent (entries 5 and 6), reflux (entries 1ꢀ4 and 7) or 90°C
(entries 5 and 6); (ii) MeONa/MeOH (entries 1ꢀ3, 5 and 7) or EtOH/Na (entries 4 and 6), 40°C (entries 1, 2 and 7) or reflux (entries 3 and 5)
or room temperature (entries 4 and 6). b Overall isolated yield between brackets.
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6a (R5 = H) and 6c (R5 = Cl) were directly obtained according to a reported protocol from 2ꢀ
mercaptobenzimidazole which is commercially available.22c Nꢀ(pꢀchloro)benzyl 4b (R3 = pꢀ
ClꢀBn, R5 = H), Nꢀbenzyl 4e (R3 = Bn, R5 = Cl) and Nꢀheptyl 4g (R3 = nꢀC7H15, R5 = Cl)
quaternary salts were then prepared using analogous procedures to that described for
compounds 3. Interestingly, the treatment of 6a and 6c with methyl iodide did not proceed
quantitatively, even under harsh conditions (large excess of reagent; heating). TLC of the
crude revealed the presence of a significant amount of starting material indicating a reversible
reaction. We hypothesized that this was probably due to the lower basicity of the involved
nitrogen atom and/or to the nucleophilicity of the iodine counterion which could provide a
demethylation reaction.26 To tackle this issue, methyl pꢀtoluenesulfonate was chosen as
alkylating agent and the desired salts 4a (R3 = Me, R5 = H) and 4c (R3 = Me, R5 = Cl) were
isolated in 77% and 87% yield respectively after purification.
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Sodium methoxide was then allowed to react with [3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ
6ꢀium 4a-c, 4e and 4g (Table 2, entries 1ꢀ3, 5 and 7 respectively) leading to the corresponding
Nꢀaryl benzimidazolones 2 with good to excellent yields, excepting 2g for which we were not
able to optimize the purification step on column chromatography. Moreover, sodium ethoxide
was tested on derivatives 4c (Table 2, entry 4) and 4e (Table 2, entry 6). Preliminary attempt
on 4c was carried out at 70°C and furnished a mixture of 2c (R3 = Me, R4 = Me, R5 = Cl) and
2d (R3 = Me, R4 = Et, R5 = Cl). We postulated that the formation of compound 2c probably
resulted from a demethylation of the starting quaternary salts. Consequently, the ring opening
was performed at room temperature yielding the sole compound 2d. Similar experimental
conditions were used for the synthesis of 2f which was isolated in very good yield.
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Scheme 2. Possible mechanism for the ring opening
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R4
R4
O
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R2
O
S
S
R5
R5
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R3
R3
X
R2
R2
N
N
Na+
-O-R4
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3 / 5
1 / 2
A plausible mechanism of this unprecedented ring opening is depicted in Scheme 2. In a first
step, the nucleophilic alcoholate species attacks the quaternary sp2 carbon bonded to three
heteroatoms. The R4ꢀO bond of the alcoholate is then cleaved to provide the oxygen atom of
the benzimidazolone core and R4 bonded to the sulphur atom. Based on the observed results,
scheme 2 provides a postulated mechanism as a concerted process. However, depending on
the actual bond breaking, the formation of thiolate and oxonium as an intimate ionꢀpair can be
also envisioned. Further studies are underway to trace the occurrence of disulfide moieties
which would indicate a stepwise process accompanying the concerted one.
Conclusion
In summary, we have developed and exemplified a powerful sequence for accessing
unprecedented Nꢀthioalkenyl and Nꢀ(oꢀthio)aryl 1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀones. The
process involves a ring opening of a quaternary salt (thiazolo[3,2ꢀa]benzimidazolium or
benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium) and a concomitant CꢀO bond cleavage of the
addition product. Taking into account that the 1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone scaffold
belongs to the few privileged structures, this study opens the way to an unexplored chemical
space for future biological screenings.
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Experimental section
General information
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Commercially reagent grade chemicals were used as received without additional purification.
All reactions were followed by TLC (Kieselgel 60 Fꢀ254). TLC spots were visualized with
UV light and/or by staining with potassium permanganate or phosphomolybdic acid solution
followed by heating. Column chromatography was performed on silica gel (60ꢀ200 mesh).
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Melting points are uncorrected. Chemicals shifts in H NMR and 13C NMR spectra are
reported as part per million downshift from tetramethylsilane and coupling constants are
reported in hertz. When necessary, resonances were assigned using twoꢀdimensional
experiments (COSY, HMBC, HSQC). HRMS (ESI) were recorded on a TOF mass
spectrometer.
Synthesis of 3-(2-aminophenyl)-1,3-thiazole-2(3H)-thione 7
General procedure for compounds 7k-o: Triethylamine (20 mmol) was added dropwise to a
suspension of 1,2ꢀdiaminobenzene (10 mmol) in CS2 (23 mL). After 2 hours, the precipitate
was filtered, washed with Et2O and dried to yield quantitatively the dithiocarbamate salt. This
solid was then suspended in ethanol (30 mL) and a solution of αꢀhalogenated ketone (10
mmol; 2ꢀbromoacetophenone for 7k; 2ꢀbromoꢀ4’ꢀfluoroacetophenone for 7l; 2ꢀbromoꢀ4’ꢀ
chloroacetophenone for 7m; 2ꢀbromoꢀ4’ꢀmethoxyacetophenone for 7n; 2ꢀbromoꢀ2'ꢀ
acetonaphthone for 7o) in ethanol (30 mL) was added dropwise at 0°C, followed by an
addition of HCl 37% (3 mL) dropwise at 0°C. The mixture was then heated at reflux for 1
hour whereupon water (100 mL) was added. The mixture was then extracted with
dichloromethane (3 x 100 mL) and the organic layer was washed with water (3 x 100 mL),
dried on MgSO4 and evaporated under reduced pressure. The desired compound was then
isolated after crystallisation in ethanol.
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3ꢀ(2ꢀAminophenyl)ꢀ4ꢀphenylꢀ1,3ꢀthiazoleꢀ2(3H)ꢀthione 7k. Yield: 86% (2.620 g); White
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solid; Mp = 189°C; H NMR (400 MHz, DMSOꢀd6) δ 5.12 (2H, br s, NH2), 6.42ꢀ6.47 (1H,
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m, arom), 6.70ꢀ6.76 (2H, m, arom), 6.99ꢀ7.05 (1H, m, arom), 7.17 (1H, s, H5), 7.21ꢀ7.31 (5H,
m, arom); 13C NMR (100 MHz, DMSOꢀd6) δ 110.3, 116.0, 116.2, 122.9, 128.1 (2C), 128.4
(2C), 129.0, 129.2, 129.8, 130.6, 144.5, 145.0, 188.5; HRMS m/z calcd C15H13N2S2 [M+H]+:
285.0514; found: 285.0514.
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3ꢀ(2ꢀAminophenyl)ꢀ4ꢀ(4ꢀfluorophenyl)ꢀ1,3ꢀthiazoleꢀ2(3H)ꢀthione 7l. Yield: 77% (2.477 g);
White solid; Mp = 139°C; 1H NMR (400 MHz, DMSOꢀd6) δ 5.09 (2H, br s, NH2), 6.44ꢀ6.49
(1H, m, arom), 6.70ꢀ6.76 (2H, m, arom), 6.77ꢀ6.81 (2H, m, arom), 7.00ꢀ7.09 (2H, m,
arom+H5), 7.15ꢀ7.21 (2H, m, arom); 13C NMR (100 MHz, DMSOꢀd6) δ 109.3, 113.5, 113.8,
116.0, 116.2, 122.9, 129.2, 129.8, 129.9 (2C), 130.5, 144.4, 145.0, 159.6, 188.4; HRMS:
ionization of the sample under various conditions failed.
3ꢀ(2ꢀAminophenyl)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ1,3ꢀthiazoleꢀ2(3H)ꢀthione 7m. Yield: 61% (2.730 g);
White solid; Mp = 231°C; 1H NMR (400 MHz, DMSOꢀd6) δ 5.15 (2H, br s, NH2), 6.44ꢀ6.50
(1H, m, arom), 6.72 (1H, dd, J = 8.2, J = 1.2, arom), 6.77 (1H, dd, J = 7.9, J = 1.5, arom),
7.01ꢀ7.07 (1H, m, arom), 7.22 (1H, s, H5), 7.24ꢀ7.36 (4H, m, arom); 13C NMR (100 MHz,
DMSOꢀd6) δ 110.9, 116.0, 116.2, 122.5, 128.2 (2C), 129.2, 129.4, 130.0, 130.3 (2C), 133.8,
143.2, 145.0, 188.6; HRMS m/z calcd C15H12N2S2Cl [M+H]+: 319.0124; found: 319.0126.
3ꢀ(2ꢀAminophenyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1,3ꢀthiazoleꢀ2(3H)ꢀthione 7n. Yield: 75% (6.660
1
g); White solid; Mp = 164°C; H NMR (400 MHz, DMSOꢀd6) δ 3.69 (3H, s, OCH3), 5.09
(2H, br s, NH2), 6.43ꢀ6.50 (1H, m, arom), 6.70ꢀ6.75 (2H, m, arom), 6.77ꢀ6.82 (2H, m, arom),
7.00ꢀ7.06 (1H, m, arom), 7.07 (1H, s, H5), 7.16ꢀ7.21 (2H, m, arom); 13C NMR (100 MHz,
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DMSOꢀd6) δ 55.1, 109.3, 113.5 (2C), 116.0, 116.2, 122.9 (2C), 129.2, 129.8, 129.9 (2C),
144.4, 145.0, 159.6, 188.4; HRMS m/z calcd C16H15N2OS2 [M+H]+: 315.0620; found:
315.0622.
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3ꢀ(2ꢀAminophenyl)ꢀ4ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,3ꢀthiazoleꢀ2(3H)ꢀthione 7o. Yield: 49% (3.900 g);
White solid; Mp = 163°C; 1H NMR (400 MHz, DMSOꢀd6) δ 5.20 (2H, br s, NH2), 6.39ꢀ6.45
(1H, m, arom), 6.73 (1H, dd, J = 8.2, J = 1.2, arom), 6.79 (1H, dd, J= 7.8, J = 1.4, arom),
6.97ꢀ7.03 (1H, m, arom), 7.31 (1H, dd, J = 8.6, J = 1.7, arom), 7.31 (1H, s, H5), 7.48ꢀ7.55
(2H, m, arom), 7.76 (1H, d, J = 12.4, arom), 7.76ꢀ7.87 (2H, m, arom), 7.90 (1H, s, arom);
13C NMR (100 MHz, DMSOꢀd6) δ 110.8, 116.1, 116.2, 122.9, 125.5, 126.6, 127.0, 127.5
(2C), 128.1 (2C), 128.1, 129.2, 129.9, 132.2, 132.6, 144.5, 145.1, 188.6; HRMS m/z calcd
C19H15N2S2 [M+H]+: 335.0671; found: 335.0669.
Synthesis of [1,3]thiazolo[3,2-a]benzimidazole 5
General procedure: Compound 7 (2 mmol) was solubilised in acetone (10 mL) and methyl
iodide (20 mmol) was added. After 12 hours, the solvent was removed under reduced pressure
to afford quantitatively the corresponding thiazolium iodide. The residue was heated at reflux
for 12ꢀ24 hours in methanol (20 mL) whereupon the solvent was removed under reduced
pressure to afford quantitatively the corresponding thiazolo[3,2ꢀa]benzimidazolium iodide.
The crude was then treated with a saturated solution of NaHCO3 (20 mL). The mixture was
extracted with dichloromethane (3 x 10 mL) and the organic layer was dried on MgSO4 and
evaporated to give the desired compound.
3ꢀPhenyl[1,3]thiazolo[3,2ꢀa]benzimidazole 5k. Yield: 69% (603 mg); White solid; Mp =
147°C; 1H NMR (400 MHz, CDCl3) δ 6.70 (1H, s, H5), 7.08ꢀ7.14 (1H, m, arom), 7.23 (1H, d,
J = 8.2, arom), 7.34ꢀ7.40 (1H, m, arom), 7.56ꢀ7.69 (5H, m, arom), 7.82 (1H, d, J = 8.2, arom);
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13C NMR (100 MHz, CDCl3) δ 108.3, 112.1, 118.8, 121.2, 124.2, 129.0, 129.1 (2C), 129.2
(2C), 129.7, 130.5, 134.6, 146.7, 156.8; HRMS m/z calcd C15H11N2S [M+H]+: 251.0637;
found: 251.0638.
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3ꢀ(4ꢀFluorophenyl)[1,3]thiazolo[3,2ꢀa]benzimidazole 5l. Yield: 91% (300 mg); White solid;
Mp = 152°C; 1H NMR (400 MHz, CDCl3) δ 6.76 (1H, s, H5), 7.12ꢀ7.20 (2H, m, arom), 7.27ꢀ
7.34 (2H, m, arom), 7.37ꢀ7.43 (1H, m, arom), 7.63ꢀ7.69 (2H, m, arom), 7.85 (1H, d, J = 8.3,
arom); 13C NMR (100 MHz, CDCl3) δ 109.3, 111.9, 116.5, 116.7, 118.5, 121.7, 124.7, 124.9,
129.4, 131.2, 131.3, 133.6, 145.4, 156.3, 164.1 (d, J = 251); HRMS m/z calcd C15H10N2SF
[M+H]+: 269.0543; found: 269.0543.
3ꢀ(4ꢀChlorophenyl)[1,3]thiazolo[3,2ꢀa]benzimidazole 5m. Yield: 86% (160 mg); White solid;
Mp = 200°C; 1H NMR (400 MHz, CDCl3) δ 6.85 (1H, s, H5), 7.16ꢀ7.25 (2H, m, arom), 7.41ꢀ
7.47 (1H, m, arom), 7.58ꢀ7.65 (4H, m, arom), 7.87 (1H, d, J = 8.3, arom); 13C NMR
(100 MHz, CDCl3) δ 110.3, 112.2, 118.1, 122.2, 125.2, 126.9, 129.0, 129.8 (2C), 130.5 (2C),
131.5, 133.7, 137.2, 156.1; HRMS m/z calcd C15H10N2SCl [M+H]+: 285.0247; found:
285.0248.
3ꢀ(4ꢀMethoxyphenyl)[1,3]thiazolo[3,2ꢀa]benzimidazole 5n. Yield: 55% (450 mg); White
solid; Mp = 153°C; 1H NMR (400 MHz, CDCl3) δ 3.92 (3H, s, OCH3), 6.58 (1H, s, H5), 7.06ꢀ
7.11 (3H, m, arom), 7.24 (1H, d, J = 8.2, arom), 7.32ꢀ7.37 (1H, m, arom), 7.55ꢀ7.60 (2H, m,
arom), 7.80 (1H, d, J = 8.2, arom); 13C NMR (100 MHz, CDCl3) δ 55.6, 107.1, 111.9, 114.6
(2C), 118.9, 120.9, 121.4, 123.9, 129.9, 130.5 (2C), 134.4, 147.4, 156.9, 161.2; HRMS m/z
calcd C16H13N2OS [M+H]+: 281.0743; found: 281.0743.
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3ꢀ(Naphthalenꢀ2ꢀyl)[1,3]thiazolo[3,2ꢀa]benzimidazole 5o. Yield: 33% (300 mg); White solid;
Mp = 164°C; 1H NMR (400 MHz, CDCl3) δ 6.78 (1H, s, H5), 7.03ꢀ7.09 (1H, m, arom), 7.24
(1H, d, J = 8.2, arom), 7.33ꢀ7.38 (1H, m, arom), 7.59ꢀ7.67 (2H, m, arom), 7.83 (1H, dd, J =
8.4, J = 1.8, arom), 7.83 (1H, d, J = 8.5, arom), 7.91ꢀ8.01 (2H, m, arom), 8.05 (1H, d, J = 8.5,
arom), 8.16 (1H, s, arom); 13C NMR (100 MHz, CDCl3) δ 108.5, 112.2, 118.8, 121.2, 124.1,
125.7, 126.4, 127.4, 127.7, 128.2, 128.5, 128.9, 129.1, 129.9, 133.1, 134.0, 134.6, 147.0,
156.9; HRMS m/z calcd C19H13N2S [M+H]+: 301.0794; found: 301.0794.
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Synthesis of [1,3]thiazolo[3,2-a]benzimidazol-9-ium 3
Experimental procedures and characterization data for compounds 3a-f and 3p-q: see
reference 17.
9ꢀBenzylꢀ3ꢀtertꢀbutyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium chloride 3i. A solution of 3ꢀtertꢀ
butylꢀthiazolo[3,2ꢀa]benzimidazole 5i (349 mg, 1.52 mmol) in benzyl chloride (2 mL) was
stirred at 100°C for 24 hours. The crude was purified by column chromatography (eluent:
CH2Cl2/MeOH 9:1) providing the desired compound (540 mg). Yield: 100%; Pale orange
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solid; Mp = 177°C; H NMR (400 MHz, CD3OD) δ 1.69 (9H, s, CH3), 5.86 (2H, s, NCH2),
7.36 (1H, s, H5), 7.48 (3H, s, arom), 7.61 (2H, s, arom), 7.75ꢀ7.87 (2H, m, arom), 8.18 (1H,
br d, J = 6.1, arom), 8.44 (1H, br d, J = 6.2, arom); 13C NMR (100 MHz, CD3OD) δ 29.0,
34.8, 51.9, 111.7, 114.2, 118.0, 126.3, 128.5, 129.0, 130.5 (2C), 130.8 (3C), 132.5, 137.9,
147.7, 157.8; HRMS m/z calcd C20H21N2S+ [M]+: 321.1420; found: 321.1415.
9ꢀ[3,5ꢀBis(trifluoromethyl)benzyl]ꢀ3ꢀtertꢀbutyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium
chloride 3j. To a solution of 3ꢀtertꢀbutylꢀthiazolo[3,2ꢀa]benzimidazole 5i (273 mg, 1.19
mmol) in acetonitrile (3 mL), 3,5ꢀbis(trifluoromethyl)benzyl chloride (935 mg, 3.56 mmol)
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was added and the mixture was stirred at reflux for 24 hours. The crude was purified by
column chromatography (eluent: CH2Cl2/MeOH 9:1) providing the desired compound (395
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mg). Yield: 68%; White solid; Mp = 161°C; H NMR (400 MHz, CD3OD) δ 1.71 (9H, s,
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CH3), 6.04 (2H, s, NCH2), 7.34 (1H, s, H5), 7.75ꢀ7.84 (2H, m, arom), 8.03ꢀ8.06 (1H, m,
arom), 8.11 (1H, s, arom), 8.23 (2H, s, arom), 8.43ꢀ8.47 (1H, m, arom); 13C NMR (150 MHz,
CD3OD) δ 29.0 (3C), 35.0, 50.5, 111.3, 113.9, 118.3, 124.3 (m), 124.5 (2C, q, J = 272),
126.5, 128.6, 129.4, 130.9 (2C, m), 133.7 (2C, q, J = 34), 136.6, 137.9, 148.5, 158.6; HRMS
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m/z calcd C22H19N2SF6 [M]+: 457.1168; found: 457.1165.
General procedure for compounds 3k-o: To a solution of the corresponding compound 5 (1
mmol) in acetone (3 mL), methyl iodide (10 mmol) was added and the mixture was stirred at
reflux (3 hours for 3k and 3o; 5 hours for 3l-n). The desired compound was then isolated by
filtration.
9ꢀMethylꢀ3ꢀphenyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium iodide 3k. Yield: 100% (87 mg);
White solid; Mp = 202°C; 1H NMR (400 MHz, CD3OD) δ 4.24 (3H, s, NCH3), 7.35 (1H, d, J
= 8.4, arom), 7.48 (1H, td, J = 8.4, J = 0.9, arom), 7.65 (1H, s, H5), 7.69ꢀ7.87 (6H, m, arom),
8.01 (1H, d, J = 8.5, arom); 13C NMR (100 MHz, CD3OD) δ 33.7, 113.8, 114.7, 114.8, 125.9,
128.4, 128.7, 130.6 (2C), 130.8, 130.9 (2C), 132.6, 137.7, 138.5, 156.9; HRMS m/z calcd
C16H13N2S+ [M]+: 265.0793; found: 265.0793.
3ꢀ(4ꢀFluorophenyl)ꢀ9ꢀmethyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium iodide 3l. Yield: 97%
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(159 mg); White solid; Mp = 264°C; H NMR (400 MHz, CD3OD) δ 4.11 (3H, s, NCH3),
7.20 (1H, d, J = 8.4, arom), 7.31ꢀ7.41 (3H, m, arom), 7.53 (1H, s, H5), 7.60ꢀ7.65 (1H, m,
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arom), 7.73ꢀ7.79 (2H, m, arom), 7.88 (1H, d, J = 8.4, arom); C NMR (75 MHz, CD3OD) δ
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156.9, 166.0 (d, J = 250.5); HRMS m/z calcd C16H12N2SF+ [M]+: 283.0699; found: 283.0700.
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3ꢀ(4ꢀChlorophenyl)ꢀ9ꢀmethyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium iodide 3m. Yield: 98%
(73 mg); White solid; Mp = 276°C; 1H NMR (400 MHz, CD3OD) δ 4.24 (3H, s, NCH3), 7.39
(1H, d, J = 8.5, arom), 7.53 (1H, t, J = 7.6, arom), 7.69 (1H, s, H5), 7.73ꢀ7.87 (5H, m, arom),
8.02 (1H, d, J = 8.5, arom); 13C NMR (75 MHz, CD3OD) δ 33.6, 113.8, 114.7, 115.4, 126.1,
127.0, 128.5, 130.9 (2C), 131.7, 132.5 (2C), 136.6, 138.4, 138.9, 157.0; HRMS m/z calcd
C16H12N2SCl+ [M]+: 299.0404; found: 299.0404.
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3ꢀ(4ꢀMethoxyphenyl)ꢀ9ꢀmethyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium iodide 3n. Yield:
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100% (163 mg); Pale brown solid; Mp = 216°C; H NMR (400 MHz, CD3OD) δ 3.97 (3H, s,
OCH3), 4.22 (3H, s, NCH3), 7.22ꢀ7.28 (2H, m, arom), 7.38 (1H, d, J = 8.5, arom), 7.46ꢀ7.52
(1H, m, arom), 7.54 (1H, s, H5), 7.71ꢀ7.77 (3H, m, arom), 8.01 (1H, d, J = 8.4, arom);
13C NMR (75 MHz, CD3OD) δ 33.6, 56.2, 113.7, 113.9, 114.7, 115.9 (2C), 120.1, 125.9,
128.4, 128.7, 132.4 (2C), 137.9, 138.4, 156.8, 163.6; HRMS m/z calcd C17H15N2OS+ [M]+:
295.0899; found: 295.0900.
9ꢀMethylꢀ3ꢀ(naphthalenꢀ2ꢀyl)[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium iodide 3o. Yield: 100%
(91 mg); Pale brown solid; Mp = 193°C; 1H NMR (400 MHz, CD3OD) δ 4.25 (3H, s, NCH3),
7.30 (1H, d, J = 8.5, arom), 7.42 (1H, t, J = 8.3, arom), 7.65ꢀ7.76 (4H, m, arom+H5), 7.85
(1H, dd, J = 8.5, J = 1.7, arom), 8.01 (1H, d, J = 8.4, arom), 8.07 (2H, t, J = 7.3, arom), 8.20
(1H, d, J = 8.5, arom), 8.38 (1H, s, arom); 13C NMR (100 MHz, CD3OD) δ 33.7, 113.8, 114.8,
115.0, 125.5, 125.9, 126.8, 128.4, 128.7, 128.7, 129.2, 129.3, 129.6, 130.4, 131.2, 134.4,
135.7, 137.8, 138.4, 157.0; HRMS m/z calcd C20H15N2S+ [M]+: 315.0950; found: 315.0950.
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Synthesis of benzo[d]imidazo-[2,1-b]benzothiazoles 4
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General procedure for compounds 4a-c and 4g: To a solution of the corresponding compound
6 (1 mmol) in pentanꢀ3ꢀone (1ꢀ4 mL), alkylating reagent (for 4a and 4c: 10 mmol of methyl
pꢀtoluenesulfonate; for 4b: 8 mmol of pꢀchlorobenzyl chloride; for 4g: 12 mmol of 1ꢀ
iodoheptane) was added and the mixture was stirred at reflux (for 4a: 20 hrs; for 4b: 24 hrs;
for 4c: overnight; for 4g: 48 hrs). The desired compound was then isolated by filtration and
washed with acetone (for 4b: before this filtration, excess of pꢀchlorobenzyl chloride was
removed under vacuum).
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6ꢀmethyl[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium 4ꢀmethylbenzenesulfonate 4a.
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Yield: 58% (2.354 g); White solid; Mp = 245ꢀ247°C; H NMR (400 MHz, CD3OD) δ 2.38
(3H, s, CH3 tos), 4.25 (3H, s, NCH3), 7.23 (2H, d, J = 8.0, arom), 7.70 (2H, d, J = 8.1, arom),
7.78 (1H, t, J = 7.8, arom), 7.82ꢀ7.89 (2H, m, arom), 7.94 (1H, t, J = 7.8, arom), 8.05ꢀ8.11
(1H, m, arom), 8.31 (1H, d, J = 8.2, arom), 8.61ꢀ8.68 (2H, m, arom); 13C NMR (100 MHz,
CD3OD) δ 21.3, 34.0, 114.0, 114.7, 116.4, 126.7, 126.9 (2C), 127.3, 128.4, 128.5, 128.9,
129.7, 129.8 (2C), 130.2, 133.9, 137.9, 141.6, 143.6, 156.6; HRMS m/z calcd C14H11N2S+
[M]+: 239.0637; found: 239.0639.
6ꢀ(4ꢀchlorobenzyl)[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium chloride 4b. Yield: 70%
1
(457 mg); Pale brown solid; Mp = 240°C (decomposition); H NMR (400 MHz, CD3OD) δ
5.87 (2H, s, NCH2), 7.54 (2H, d, J = 8.5, arom), 7.63 (2H, d, J = 8.4, arom), 7.71 (1H, t, J =
7.9, arom), 7.82ꢀ7.87 (2H, m, arom), 7.89 (1H, t, J = 7.9, arom), 8.10ꢀ8.16 (1H, m, arom),
8.18 (1H, d, J = 8.2, arom), 8.61ꢀ8.67 (2H, m, arom); 13C NMR (100 MHz, CD3OD) δ 51.3,
114.3, 114.9, 116.5, 126.5, 127.6, 128.6 (2C), 129.2, 130.1, 130.2, 130.8 (2C), 131.1, 132.7
(2C), 133.6, 137.3, 137.5, 156.0; HRMS m/z calcd C20H14N2SCl+ [M]+: 349.0561; found:
349.0564.
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2ꢀchloroꢀ6ꢀmethyl[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium 4ꢀmethylbenzenesulfonate
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4c. Yield: 87% (785 mg); White solid; Mp = 247°C (decomposition); H NMR (400 MHz,
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CD3OD) δ 2.32 (3H, s, CH3), 4.21 (3H, s, NCH3), 7.14 (2H, d, J = 8.0, arom), 7.60 (2H, d, J =
8.2, arom), 7.74 (1H, dd, J = 8.8, J = 1.8, arom), 7.78ꢀ7.86 (2H, m, arom), 8.01ꢀ8.06 (1H, m,
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arom), 8.24 (1H, d, J = 8.8, arom), 8.59ꢀ8.64 (1H, m, arom), 8.67 (1H, d, J = 1.8); C NMR
(100 MHz, CD3OD) δ 21.3, 33.9, 114.0, 114.8, 116.7, 126.8 (2C), 127.5, 127.8, 128.3, 128.6,
128.7, 128.8, 129.7 (2C), 134.7, 136.3, 137.8, 141.5, 143.6, 157.4; HRMS m/z calcd
C14H10N2SCl+ [M]+: 273.0248; found: 273.0251.
2ꢀchloroꢀ6ꢀheptyl[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium iodide 4g. Yield: 65% (583
1
mg); White solid; Mp = 255°C; H NMR (400 MHz, CD3OD) δ 0.87ꢀ0.93 (3H, m, CH3),
1.28ꢀ1.57 (8H, m, 4CH2), 2.05ꢀ2.16 (2H, m, CH2), 4.69 (2H, t, J = 7.3, NCH2), 7.77 (1H, dd,
J = 8.8, J = 1.8, arom), 7.80ꢀ7.87 (2H, m, arom), 8.09ꢀ8.15 (1H, m, arom), 8.30 (1H, d, J =
8.8, arom), 8.64ꢀ8.69 (1H, m, arom), 8.72 (1H, d, J = 1.8, arom); 13C NMR (100 MHz,
CD3OD) δ 14.4, 23.6, 27.7, 29.1, 29.9, 32.8, 49.0, 114.2, 115.1, 116.9, 127.6, 127.9, 128.3,
128.7, 128.8, 129.1, 134.8, 136.4, 137.3, 156.7; HRMS m/z calcd C20H22N2SCl+ [M+H]+:
357.1187; found: 357.1184.
6ꢀbenzylꢀ2ꢀchloro[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium bromide 4e. A solution of
2ꢀchlorobenzo[d]benzo[4,5]imidazo[2,1ꢀb]thiazole 6c (128 mg, 0.49 mmol) in benzyl
bromide (2 mL, 16.92 mmol) was added and the mixture was stirred at 90°C for 4 hours.
After cooling at room temperature, diethylether (10 mL) was added and the desired compound
was then isolated by filtration (210 mg).Yield: 100%; White solid; Mp = 246°C
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(decomposition); H NMR (400 MHz, CD3OD) δ 5.97 (2H, s, NCH2), 7.52ꢀ7.73 (6H, m,
arom), 7.82ꢀ7.89 (2H, m, arom), 8.07ꢀ8.19 (2H, m, arom), 8.65ꢀ8.72 (2H, m, arom); 13C NMR
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(100 MHz, CD3OD) δ 52.2, 103.8, 114.3, 115.0, 116.7, 127.5, 127.7, 128.8, 129.1, 130.8
(2C), 131.5 (3C), 131.9, 134.2, 136.3, 137.5, 156.5; HRMS m/z calcd C20H14N2SCl+ [M]+:
349.0561; found: 349.0561.
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Synthesis of benzimidazol-2-one 1
Experimental procedures and characterization data for compounds 1a-h and 1p-q: see
reference 17.
Procedure to access to compound 1g1 as a single isomer (Table 1, entry 6): To a solution of 9ꢀ
benzylꢀ3ꢀmethyl[1,3]thiazolo[3,2ꢀa]benzimidazolꢀ9ꢀium chloride 3d (65 mg, 0.21 mmol) in
benzyl alcohol (3 mL), 1.5 mL of a freshly prepared solution of sodium benzylate (prepared
by addition of sodium [22 mg, 0.96 mmol] in 5 mL of benzyl alcohol) was added at room
temperature and the mixture was stirred for 24 hours. The solvent was then evaporated, water
was added (25 mL) and the mixture was extracted with dichloromethane (3 × 25 mL). The
organic layer was dried on MgSO4 and evaporated under reduced pressure providing the
desired compound (45 mg, 56%). Characterization data are consistent with reference 17.
General procedure for compounds 1i-o: To a solution of the corresponding compound 3 (1
mmol) in methanol (60 mL), purchased sodium methoxide (4 mmol) was added and the
mixture was stirred at r.t. for 48 hours. The solvent was then evaporated, water was added (25
mL) and the mixture was extracted with dichloromethane (3 × 25 mL). The organic layer was
dried on MgSO4 and evaporated under reduced pressure providing the desired compound.
1ꢀBenzylꢀ3ꢀ[(1Z)ꢀ3,3ꢀdimethylꢀ1ꢀ(methylsulfanyl)butꢀ1ꢀenꢀ2ꢀyl]ꢀ1,3ꢀdihydroꢀ2Hꢀ
benzimidazolꢀ2ꢀone 1i. Yield: 100% (239 mg); Pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
1.22 (9H, s, CH3), 2.21 (3H, s, SCH3), 5.02 (1H, d, JAB = 15.8, CH2), 5.15 (1H, d, JAB = 15.9,
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CH2), 6.40 (1H, s, H5), 6.78ꢀ6.86 (2H, m, arom), 6.91ꢀ7.01 (2H, m, arom), 7.17ꢀ7.32 (5H, m,
arom); 13C NMR (100 MHz, CDCl3) δ 16.6, 29.5, 38.8, 44.9, 108.5, 109.4 (2C), 121.3, 121.5,
127.4 (2C), 127.6, 128.8 (2C), 129.2, 129.6, 136.5, 137.9, 153.5; HRMS m/z calcd
C21H24N2OS+ [M+H]+: 353.1682; found: 353.1684.
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1ꢀ[3,5ꢀBis(trifluoromethyl)benzyl]ꢀ3ꢀ[(1Z)ꢀ3,3ꢀdimethylꢀ1ꢀ(methylsulfanyl)butꢀ1ꢀenꢀ2ꢀyl]ꢀ
1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone 1j. Yield: 100% (313 mg); White solid; Mp = 143°C; 1H
NMR (400 MHz, CDCl3) δ 1.27 (9H, s, CH3), 2.25 (3H, s, SCH3), 5.05 (1H, d, JAB = 16.3,
CH2), 5.41 (1H, d, JAB = 16.2, CH2), 6.45 (1H, s, H5), 6.81ꢀ6.84 (1H, m, arom), 6.91ꢀ6.94
(1H, m, arom), 7.01ꢀ7.10 (2H, m, arom), 7.77 (1H, s, arom), 7.80 (2H, s, arom); 13C NMR
(150 MHz, CDCl3) δ 16.4, 29.4 (3C), 38.7, 43.9, 107.8, 109.9, 121.8, 121.9, 122.1, 123.3 (2C,
q, J = 273), 127.6 (2C), 128.9, 129.6, 130.0, 132.2, (2C, q, J = 33), 138.0, 139.4, 153.4;
+
HRMS m/z calcd C23H22N2OSF6 [M+H]+: 489.1430; found: 489.1432.
1ꢀMethylꢀ3ꢀ[(Z)ꢀ2ꢀ(methylsulfanyl)ꢀ1ꢀphenylethenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone
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1k. Yield: 100% (43 mg); White crystals; Mp = 168°C; H NMR (300 MHz, CDCl3) δ 2.41
(3H, s, SCH3), 3.51 (3H, s, NCH3), 6.73 (1H, d, J = 7.8, arom), 6.97ꢀ7.32 (9H, m, arom+H5);
13C NMR (75 MHz, CDCl3) δ 17.3, 27.6, 107.8, 109.5, 121.6, 122.0, 124.7 (2C), 128.0,
128.1, 128.4, 128.9 (2C), 130.6, 130.7, 135.5, 152.7; HRMS m/z calcd C17H17N2OS+ [M+H]+:
297.1056; found: 297.1056.
1ꢀ[(Z)ꢀ1ꢀ(4ꢀFluorophenyl)ꢀ2ꢀ(methylsulfanyl)ethenyl]ꢀ3ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀ
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benzimidazolꢀ2ꢀone 1l. Yield: 100% (51 mg); Colourless oil; H NMR (300 MHz, CDCl3) δ
2.40 (3H, s, SCH3), 3.50 (3H, s, NCH3), 6.72 (1H, d, J = 7.7, arom), 6.91ꢀ7.28 (8H, m,
arom+H5); 13C NMR (75 MHz, CDCl3) δ 17.3, 27.6, 107.9, 109.4, 115.8, 116.1, 121.6, 122.1,
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126.5, 126.6, 127.3, 128.2, 130.3, 130.6, 131.9, 152.6, 162.7 (d, J = 250.6); HRMS m/z calcd
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C17H16N2OSF+ [M+H]+: 315.0961; found: 315.0962.
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1ꢀ[(Z)ꢀ1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ(methylsulfanyl)ethenyl]ꢀ3ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀ
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benzimidazolꢀ2ꢀone 1m. Yield: 100% (49 mg); Yellow oil; H NMR (300 MHz, CDCl3) δ
2.41 (3H, s, SCH3), 3.51 (3H, s, NCH3), 6.71 (1H, d, J = 7.7, arom), 6.98ꢀ7.29 (8H, m,
arom+H5); 13C NMR (75 MHz, CDCl3) δ 17.3, 27.6, 107.9, 109.4, 121.7, 122.1, 126.0 (2C),
127.0, 128.1, 129.1 (2C), 130.6, 131.5, 133.8, 134.1, 152.5; HRMS m/z calcd C17H16N2OSCl+
[M+H]+: 331.0666; found: 331.0666.
1ꢀ[(Z)ꢀ1ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀ(methylsulfanyl)ethenyl]ꢀ3ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀ
benzimidazolꢀ2ꢀone 1n. Yield: 100% (61 mg); Pale brown oil; 1H NMR (300 MHz, CDCl3) δ
2.38 (3H, s, SCH3), 3.50 (3H, s, NCH3), 3.77 (3H, s, OCH3), 6.72 (1H, d, J = 7.6, arom), 6.76ꢀ
7.21 (8H, m, arom+H5); 13C NMR (75 MHz, CDCl3) δ 17.3, 27.5, 55.4, 107.7, 109.5, 114.3
(2C), 121.5, 121.9, 126.1 (2C), 128.0, 128.2, 128.3, 128.5, 130.6, 152.7, 159.6; HRMS m/z
calcd C18H19N2O2S+ [M+H]+: 327.1161; found: 327.1161.
1ꢀMethylꢀ3ꢀ[(Z)ꢀ2ꢀ(methylsulfanyl)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ethenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀ
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benzimidazolꢀ2ꢀone 1o. Yield: 95% (21 mg); Pale brown oil; H NMR (300 MHz, CDCl3) δ
2.45 (3H, s, SCH3), 3.55 (3H, s, NCH3), 6.74 (1H, d, J = 7.7, arom), 6.95ꢀ7.82 (11H, m,
arom+H5); 13C NMR (75 MHz, CDCl3) δ 17.4, 27.6, 107.8, 109.5, 121.6, 122.0, 122.7, 123.6,
126.3, 126.6, 127.7, 128.2, 128.4, 128.5, 128.7, 130.7, 131.3, 132.8, 133.1, 133.6, 152.7;
HRMS m/z calcd C21H19N2OS+ [M+H]+: 347.1212; found: 347.1212.
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General procedure for compounds 2a and 2e: To a solution of the corresponding compound 4
(1 mmol) in methanol (for 2a: 50 mL; for 2e: 70 mL), purchased sodium methoxide (for 2a:
1.1 mmol; for 2e: 5 mmol) was added and the mixture was stirred (for 2a: 40°C for 5 hours;
for 2e: reflux for 3 hours). The solvent was then evaporated, water was added (25 mL) and the
mixture was extracted with dichloromethane (3 × 25 mL). The organic layer was dried on
MgSO4 and evaporated under reduced pressure providing the desired compound.
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1ꢀmethylꢀ3ꢀ[2ꢀ(methylsulfanyl)phenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone 2a. Yield: 77%
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(50 mg); Pale brown solid; Mp = 127ꢀ129°C; H NMR (400 MHz, CD3OD) δ 2.39 (3H, s,
SCH3), 3.50 (3H, s, NCH3), 6.64 (1H, d, J = 7.9, arom), 7.06 (1H, t, J = 7.7, arom), 7.15ꢀ7.25
(2H, m, arom), 7.31ꢀ7.39 (2H, m, arom), 7.51ꢀ7.58 (2H, m, arom); 13C NMR (100 MHz,
CDCl3) δ 15.5, 27.5, 107.7, 108.9, 121.5, 122.0, 126.0, 126.8, 129.6, 129.8, 129.9, 130.4,
132.0, 139.2, 153.5; HRMS m/z calcd C15H15N2OS + [M+H]+: 271.0900; found: 271.0900.
1ꢀbenzylꢀ3ꢀ[5ꢀchloroꢀ2ꢀ(methylsulfanyl)phenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone
2e.
Yield: 100% (163 mg); White solid; Mp = 159°C; 1H NMR (400 MHz, CDCl3) δ 2.40 (3H, s,
SCH3), 5.11 (1H, d, JAB = 15.8, CH2), 5.21 (1H, d, JAB = 15.8, CH2), 6.69ꢀ6.72 (1H, m, arom),
6.91ꢀ6.94 (1H, m, arom), 6.99ꢀ7.07 (2H, m, arom), 7.27ꢀ7.42 (7H, m, arom), 7.46 (1H, dd, J =
8.5, J = 2.3, arom); 13C NMR (100 MHz, CDCl3) δ 15.7, 45.2, 108.8, 108.9, 121.7, 122.3,
127.6 (2C), 127.9, 128.0, 128.9 (2C), 129.5, 129.6, 129.9, 130.1, 131.4, 132.9, 136.2, 138.1,
153.2; HRMS m/z calcd C21H18N2OSCl+ [M+H]+: 381.0823; found: 381.0823.
General procedure for compounds 2b-c and 2g: To a solution of the corresponding compound
4 (1 mmol) in methanol (for 2b and 2c: 40 mL; for 2g: 146 mL), purchased sodium methoxide
(for 2b: 2.4 mmol; for 2c: 5 mmol; for 2g: 2 mmol) was added and the mixture was stirred
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(for 2b: 40°C, overnight; for 2c: reflux for 4 hours; for 2g: 40°C for 1 hour). The solvent was
then evaporated and the crude was purified by column chromatography (eluent:
CH2Cl2/AcOEt 10:0 → 9:1) providing the desired compound.
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1ꢀ(4ꢀchlorobenzyl)ꢀ3ꢀ[2ꢀ(methylsulfanyl)phenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone
2b.
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Yield: 98% (95 mg); White solid; Mp = 154°C; H NMR (400 MHz, CDCl3) δ 2.41 (3H, s,
SCH3), 5.07 (1H, d, JAB = 15.8, NCH2), 5.99 (1H, d, JAB = 15.9, NCH2), 6.68ꢀ6.71 (1H, m,
arom), 6.87ꢀ6.91 (1H, m, arom), 6.99ꢀ7.07 (2H, m, arom), 7.29ꢀ7.43 (7H, m, arom), 7.46ꢀ7.51
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(1H, m, arom); C NMR (100 MHz, CDCl3) δ 15.5, 44.4, 108.4, 109.0, 121.7, 122.0, 126.0,
126.9, 129.0 (2C), 129.1 (2C), 129.2, 129.6, 129.9, 130.0, 131.7, 133.6, 134.9, 139.2, 153.3;
HRMS m/z calcd C21H18N2OSCl+ [M+H]+: 381.0823; found: 381.0825.
1ꢀ[5ꢀchloroꢀ2ꢀ(methylsulfanyl)phenyl]ꢀ3ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone
2c.
Yield: 72% (110 mg); Pale yellow oil; Mp = 184°C; 1H NMR (400 MHz, CDCl3) δ 2.38 (3H,
s, SCH3), 3.51 (3H, s, NCH3), 6.70 (1H, br d, J = 8.3, arom), 7.03ꢀ7.07 (2H, m, arom), 7.14ꢀ
7.18 (1H, m, arom), 7.31ꢀ7.34 (1H, m, arom), 7.35 (1H, d, J = 2.0, arom), 7.44 (1H, dd, J =
8.6, J = 2.2, arom); 13C NMR (100 MHz, CDCl3) δ 15.7, 27.6, 107.9, 108.9, 121.7, 122.3,
127.9, 129.4, 129.8, 130.1, 130.4, 131.3, 132.9, 138.0, 153.2; HRMS m/z calcd
C15H14N2OSCl+ [M+H]+: 305.0510; found: 305.0506.
1ꢀ[5ꢀchloroꢀ2ꢀ(methylsulfanyl)phenyl]ꢀ3ꢀheptylꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone
2g.
Yield: 50% (80 mg); White solid; Mp = 75°C; 1H NMR (400 MHz, CDCl3) δ 0.87 (3H, br t, J
= 6.9, CH3), 1.24ꢀ1.46 (8H, m, 4CH2), 1.77ꢀ1.86 (2H, m, CH2), 3.89ꢀ4.01 (2H, m, NCH2),
6.70 (1H, d, J = 7.7, arom), 7.04 (1H, t, J = 7.6, arom), 7.07 (1H, d, J = 8.2, arom), 7.14 (1H,
t, J = 7.6, arom), 7.32 (1H, d, J = 8.6, arom), 7.36 (1H, d, J = 2.1, arom), 7.44 (1H, dd, J =
8.5, J = 2.2, arom); 13C NMR (100 MHz, CDCl3) δ 14.2, 15.7, 22.7, 26.9, 28.4, 29.1, 31.9,
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41.5, 108.1, 108.9, 121.4, 122.1, 128.0, 129.5, 129.8, 129.9, 130.0, 131.3, 133.0, 138.1, 153.0;
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HRMS m/z calcd C21H26N2OSCl+ [M+H]+: 389.1449; found: 389.1452.
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1ꢀ[5ꢀchloroꢀ2ꢀ(ethylsulfanyl)phenyl]ꢀ3ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone 2d. To a
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solution
of
2ꢀchloroꢀ6ꢀmethyl[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium
4ꢀ
methylbenzenesulfonate 4c (238 mg, 0.54 mmol) in ethanol (5 mL), 5 mL of a freshly
prepared solution of sodium ethoxide (prepared by addition of sodium [25.6 mg, 1.11 mmol]
in 10 mL of ethanol) was added at 0°C. The mixture was allowed to warm to room
temperature overnight. The solvent was then evaporated, water was added (25 mL) and the
mixture was extracted with dichloromethane (3 × 25 mL). The organic layer was dried on
MgSO4 and evaporated under reduced pressure providing the desired compound (145
1
mg).Yield: 81%; White solid; Mp = 101°C; H NMR (400 MHz, CDCl3) δ 1.21 (3H, t, J =
7.4, CH3), 2.78ꢀ2.91 (2H, m, SCH2), 3.51 (3H, s, NCH3), 6.67ꢀ6.71 (1H, m, arom), 7.02ꢀ7.08
(2H, m, arom), 7.13ꢀ7.18 (1H, m, arom), 7.34ꢀ7.37 (1H, m, arom), 7.40ꢀ7.43 (2H, m, arom);
13C NMR (100 MHz, CDCl3) δ 14.0, 27.4, 27.5, 107.8, 108.8, 121.6, 122.2, 129.9 (2C),
130.2, 130.3, 132.0, 134.1, 136.5, 153.3; HRMS m/z calcd C16H16N2OSCl+ [M+H]+:
319.0666; found: 319.0665.
1ꢀbenzylꢀ3ꢀ[5ꢀchloroꢀ2ꢀ(ethylsulfanyl)phenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone 2f. To a
solution of 6ꢀbenzylꢀ2ꢀchloro[3,1]benzimidazo[2,1ꢀb][1,3]benzothiazolꢀ6ꢀium bromide 4e
(100 mg, 0.23 mmol) in ethanol (40 mL), 7 mL of a freshly prepared solution of sodium
ethoxide (prepared by addition of sodium [73 mg, 1.11 mmol] in 40 mL of ethanol) was
added at 40°C. The mixture was allowed to cool to room temperature overnight. The solvent
was then evaporated, water was added (25 mL) and the mixture was extracted with
dichloromethane (3 × 25 mL). The organic layer was dried on MgSO4 and evaporated under
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reduced pressure providing the desired compound (81 mg).Yield: 89%; Yellow oil; H NMR
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(400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.3, CH3), 2.79ꢀ2.92 (2H, m, CH2), 5.11 (1H, d, JAB
=
7
8
9
15.6, NCH2), 5.22 (1H, d, JAB = 15.6, NCH2), 6.70 (1H, d, J = 7.1, arom), 6.92 (1H, d, J =
7.1, arom), 6.98ꢀ7.07 (2H, m, arom), 7.27ꢀ7.47 (8H, m, arom); 13C NMR (100 MHz, CDCl3) δ
14.0, 27.6, 45.2, 108.8, 108.9, 121.7, 122.2, 127.7 (2C), 127.9, 128.9 (2C), 129.5, 129.8,
129.9, 130.0, 130.6, 132.1, 134.3, 136.3, 136.6, 153.3; HRMS m/z calcd C22H20N2OSCl+
[M+H]+: 395.0979; found: 395.0975.
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Supporting Information Available
Copies of 1H NMR and 13C NMR spectra for all new compounds and compounds described in
reference 17. XꢀRay analysis of 1k. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgments
We gratefully acknowledge OSEO (A0607008UAT), AixꢀMarseille University and the CNRS
(iSm2 – UMR 7313) for funding this research. We thank W. Bergachi and S. Aboudou for
synthesis of starting materials and Dr. M. Giorgi (Spectropole) for Xꢀray structures.
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