One-pot synthesis of five and six membered N, O, S-heterocycles using a ditribromide reagent

Article abstract of DOI:10.1021/cc100124q

In a one-pot procedure, bromine less brominating reagent 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) has been utilized as an efficient desulfurizing agent for the construction of a library of heterocycles containing N, O, and S starting from aryl/alkyl isothiocyanates. In this approach, aryl/alkyl isothiocyanate reacts with o-phenylenediamine (o-PD), o-aminophenol, and o-aminothiophenol to form their monothiourea which on desulfurization with EDPBT led to the formation of corresponding 2-aminobenzimidazoles, 2-aminobenzoxazoles, and 2-aminobenzothiazoles, respectively. An interesting regioselectivity was observed for unsymmetrical thiourea having a naphthyl moiety on the one side and an ortho amino or an ortho hydroxy phenyl group on the other side giving a completely different product which is mainly dependent on the nature of the nucleophiles (-OH or -NH ₂). Further, the bis-thioureas resulted from the aliphatic 1,2-diamine with 2 equiv of aryl isothiocyanates on treatment with EDPBT gave imidazolidenecarbothioamides, whereas bis-thioureas resulted from aromatic 1,2-diamine yielded benzimidazoles with concurrent expulsion of an isothiocyanate unit. This method is simple and applied to various substrates which are amenable to bromination that reveals the desulfurizing ability of EDPBT predominating over its brominating ability. Finally, the spent reagent EDPDB can be recovered, regenerated, and reused without any loss of activity.

Full text of DOI:10.1021/cc100124q

754
J. Comb. Chem. 2010, 12, 754–763
One-Pot Synthesis of Five and Six Membered N, O, S-Heterocycles
Using a Ditribromide Reagent
Ramesh Yella and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781 039, India
ReceiVed July 6, 2010
In a one-pot procedure, bromine less brominating reagent 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide
(EDPBT) has been utilized as an efficient desulfurizing agent for the construction of a library of heterocycles
containing N, O, and S starting from aryl/alkyl isothiocyanates. In this approach, aryl/alkyl isothiocyanate
reacts with o-phenylenediamine (o-PD), o-aminophenol, and o-aminothiophenol to form their monothiourea
which on desulfurization with EDPBT led to the formation of corresponding 2-aminobenzimidazoles,
2-aminobenzoxazoles, and 2-aminobenzothiazoles, respectively. An interesting regioselectivity was observed
for unsymmetrical thiourea having a naphthyl moiety on the one side and an ortho amino or an ortho hydroxy
phenyl group on the other side giving a completely different product which is mainly dependent on the
nature of the nucleophiles (-OH or -NH2). Further, the bis-thioureas resulted from the aliphatic 1,2-diamine
with 2 equiv of aryl isothiocyanates on treatment with EDPBT gave imidazolidenecarbothioamides, whereas
bis-thioureas resulted from aromatic 1,2-diamine yielded benzimidazoles with concurrent expulsion of an
isothiocyanate unit. This method is simple and applied to various substrates which are amenable to bromination
that reveals the desulfurizing ability of EDPBT predominating over its brominating ability. Finally, the
spent reagent EDPDB can be recovered, regenerated, and reused without any loss of activity.
Introduction
in the ratio of 2:1. The resultant 1,1′-(ethane-1,2-diyl)dipy-
ridinium ditribromide (EDPDB)5a,b salt on treatment with
KBr as the bromide source and Oxone as the oxidizing agent
gave the ditribromide reagent 1,1′-(ethane-1,2-diyl)dipyri-
dinium bistribromide (EDPBT) in excellent yield.5a,b This
reagent also has been employed as catalyst/reagent for
acylation of alcohols,5c regioselective enolate addition to
9-phenyl-9H-xanthene-9-ol,5d,e in the synthesis of various
thiazolidene-2-imine derivatives,5f,g synthesis of 1,4-dithiins
and 1,4-benzodithiins,5i and construction of 1,3-oxathiolan-
2-ylidenes5j and urazole to triazonediones.5k Very recently,
we have utilized this reagent to reveal the formation of an
anti-Hugerschoff product from an aryl-sec-alkyl unsym-
metrical thiourea having a thioamido guanidino moiety6 and
not the expected Hugerschoff product 2-aminobenzothiazole
as has been reported.3a,b
Tandem reactions involving C-N, C-O, and C-S bond
formation are one of the vital tools in combinatorial
chemistry for the construction of a library of small molecules.
Generally, they involve numerous chemical transformations
in one-pot, and the advantages associated with these reactions
are minimal workup and minimization of waste generation.1
The use of molecular bromine is awkward because of its
hazardous nature; thus, special care has to be taken for its
uses, storage, and transport. To overcome this problem,
several bromine less brominating reagents, namely, tribro-
mides, have been developed.2,3 Among various tribromides,
benzyltrimethylammonium tribromide (BTMATB)3a and
3b
[Bmim]Br3 have been employed for the construction of
2-aminobenzothiazoles. Over the past decade, we have
successfully replaced corrosive and toxic molecular bromine
with various organic ammonium tribromides, namely, tet-
rabutylammonium tribromide, for various synthetically useful
organic transformations.2a,b,4 However, the process is ex-
pensive particularly for large scale reactions because of their
inherent phase transfer property and, beside others, recycling
of the spent reagent. To alleviate some of the problem
associated with the existing tribromides, we recently designed
the first ditribromide reagent, 1,1′-(ethane-1,2-diyl)dipyri-
dinium bistribromide (EDPBT)5a,b which is superior to most
tribromides and has several advantages over molecular
bromine and other known tribromides. This reagent can be
easily prepared by heating pyridine and 1,2-dibromoethane
In continuation to our ongoing research in heterocyclic
synthesis, we have been exploring the thiophilic nature of
diacetoxyiodobenzene (DIB) in various organic transforma-
tions.7 In spite of its superiority; the expensive nature of the
hypervalent iodine reagent is the major obstacle for large
scale requirements. As a part of a continuing effort in our
laboratory toward the development of newer methods for
the expeditious synthesis of biologically relevant heterocyclic
compounds,5e-g,6b,7b we became interested in the possibility
of developing a novel and efficient method to construct
various N, O, S heterocycles utilizing the thiophilic property
of EDPBT 3.
Benzimidazoles are important structural motifs in medici-
nal chemistry, which involve nearly one-quarter of the top-
100 selling drugs. Specifically, 2-amino benzimidazoles can
* To whom correspondence should be addressed. E-mail: patel@
iitg.ernet.in.
10.1021/cc100124q  2010 American Chemical Society
Published on Web 08/18/2010

Synthesis of Five and Six Membered N, O, S-Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 755
Figure 1. Bioactive benzofused N, O, S heterocycles.
Scheme 1. Available Synthetic Methods for the Preparation
of 2-Aminobenzimidazole(A-F)12,13
be found in a number of biologically active molecules.8
Several compounds from this class have been used as
anticancer,9a antihistamine,9b and antiviral agents.9c-e Some
examples of pharmaceutically interesting benzofused N, O,
S heterocycles9-11 are shown in Figure 1 (I-IV).
The conventional methods for the preparation of 2-ami-
nobenzimidazoles are by the reaction of arylcarbonimidoyl
dichlorides which in turn are prepared by the chlorination
of aryl isothiocyanate, with o-phenylenediamines in a suitable
solvent A12a (Scheme 1), reductive cyclization of nitrothio-
ureas B12b (Scheme 1), SNAr reaction of chlorobenzimidazole
or methylsulfonyl benzimidazole with an amine nucleophiles
C12c,d (Scheme 1) under solvent-free conditions. The most
commonly adopted method for the synthesis of 2-aminoben-
zimidazole involves the cyclodesulfurization of a preformed
or in situ generated monothioureas D. The reported desulfu-
rizing agents include carbodiimides,13a,b tosylchloride,13c
methyl iodide,13d mercury(II) oxide,13e mercury(II) chlo-
ride,13f and DIB.7b In addition to this, copper(I)/(II) salts have
also been employed for the condensation of dithiocarbamate
E with o-phenylenediamine (o-PD) at high temperature.13g,h
Very recently, Xie et al. reported the synthesis of benzimi-
dazoles from a toxic isoselenocyanates in dimethylformamide
(DMF) at high temperature F.13i
spectrum of biologically active benzofused N, O, S hetero-
cycles and study the regioselectivity of its formation.
Results and Discussion
In an initial experiment, the in situ generated thiourea,
obtained by treating phenyl isothiocyanate 1a7b,14c,d (1 equiv)
with o-phenylenediamine 2a (o-PD) (1 equiv), followed by
the addition of Et3N (3 equiv) and subsequent treatment with
EDPBT 3 (0.5 equiv) in THF afforded the product 2-ami-
nobenzimidazole 4a in 81% yield. A mechanism as shown
As part of our interests in the chemistry of heterocyclic
compounds and development of newer methods by replacing
the toxic reagents with greener reagents,6,14 we herein
disclose the thiophilicity/desulfurizing ability of bromineless
brominating reagent (EDPBT) 3 in the synthesis of a

756 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Yella and Patel
Scheme 2. Proposed Mechanism for the Formation of Benzimidazole/Benzoxazole and Benzothiazole
Table 1. Screening of Different Bromine Equivalents Using
CH3CN Solvent
the formation of the 2-aminobenzimidazole 4a is the
predominant product. On the basis of the overall isolated
yield (Table 1), EDPBT 3 was found to be the best among
the various reagents assessed. In addition to this, the reagent
is a stable crystalline solid, easy to prepare, handle, and
maintain the desired stoichiometry. Further, the advantage
of storage, transport, and recyclability of the spent reagent
makes this reagent superior to toxic, fuming liquid bromine.
Thus, further supporting our argument about the superiority
of the reagent.6c
.
entry
brominating Reagent/time(h)
yielda
1
2
3
4
5
6
7
8
EDPBTb/0.5 h
67
90
79
84
81
86
83
75
EDPBTb,c/0.5 h
[Bmimd]+Br3-/0.5 h
Bu4N+Br3-/0.5 h
Following this protocol a library of benzimidazoles
(4a-4l) were synthesized in good yields as shown in Table
2. It was observed that aryl isothiocyanates having moder-
ately electron withdrawing groups (such as halide groups)
(Table 2, entries 1b-1f) as well as electron donating groups
(such as alkyl groups) (Table 2, entries 1g-1i) reacts
efficiently with various aromatic 1,2-diamines possessing
electron withdrawing substituents (-NO2) (Table 2, entry 2b)
or electron donating (Me)(Table 2, entry 2c) giving corre-
sponding benzimidazoles 4c, 4l, 4e, and 4i in good yields
as shown in Table 2. The success of this strategy mainly
lies on the selective formation of monothiourea resulted from
1 equiv of isothiocyanate 1 and o-phenylenediamine 2.
The successful synthesis of benzimidazoles prompted us
to synthesize another interesting class of compound, namely,
benzoxazole. In particular, 2-aminobenzoxazole moiety is a
popular building block for the construction of pharmaceuti-
cally important compounds10a for instance, as shown in
Figure 1 (entry II). These classes of compounds are vital as
drug candidates, and their use is currently explored for the
treatment of diseases such as HIV, neurodegeneration, and
inflammation.15 The most commonly adopted method for the
synthesis of 2-aminobenzoxazoles is by the cyclodesulfur-
ization of preformed thiourea having an o-phenolic group.
The reported cyclodesulfurization agents includes, NiO,16a
HgO,16b-d AgNO3,17a,b KO218a,b salts of transition metals,18c
and dicyclohexylcarbodiimide (DCC),18d aq H2O2,18e DIB.7b
More recently it has been prepared by the direct amination
of benzoxazoles using Cu-catalyst.18f Because of the toxicity
and high cost associated with reported reagents, they cannot
PhCH2N+Me3Br3-/0.5 h
CH3(CH2)15N+Me3Br3-/0.5 h
CH3CH2Ph3PBr3-/0.5 h
Br2/1 h
a All the reactions performed in 1 mmol scale. Isolated yields. b 2
equiv Et3N used. b,c Because it is a ditribromide reagent, 0.5 equiv of
the reagent was used (all other cases, 1 equiv of the reagents were used).
d Bmim ) 1-butyl-3-methylimidazolium.
in Scheme 2 can be proposed to account for the formation
of the product 4a. The soft sulfur atom of the in situ
generated thiourea first attacks on the thiophilic bromine
forming a S-Br type of species K (Scheme 2).5h An
intramolecular attack of the amino nucleophile (where X )
NH) as shown in path-a (Scheme 2) should yield the
intermediate M which on elimination would give the desired
benzimidazole 4a. Alternatively, a reductive elimination as
shown in path-b to form the intermediate carbodiimide L
cannot be ruled out. Subsequent intramolecular attack of the
o-amino group onto carbodiimide would generate the desired
product 4a.
Among the various solvents tested such as CH2Cl2,
Dioxane, tetrahydrofuran (THF), CH3CN, MeOH, DMF, and
dimethylsulfoxide (DMSO), solvents CH2Cl2 and CH3CN
were found equally effective in giving good yields (86%,
90%) in short reaction time but for convenience CH3CN was
chosen for all other reactions. Further, the efficacy of the
reagent/method was compared with some known tribromides
including molecular bromine (Table 1, entries 3-8) using
Et3N as the base and CH3CN as the solvent. As can be seen
from Table 1, irrespective of the brominating reagents used,

Synthesis of Five and Six Membered N, O, S-Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 757
Table 2. Reaction of o-Phenylenediamine 2 (o-PD) with
Isothiocyanates 1 Using EDPBTa
Figure 2. ORTEP view with the atomic numbering scheme of 6h.19a
Scheme 3. Differential Reactivity of Naphthyl-Phenyl
Thiourea 7 and 10
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR,
and 13C NMR. c Isolated yield.
Table 3. Reaction of o-Aminophenol 5 with Isothiocyanates 1
Using EDPBTa
mechanism is expected to be similar to the above (Scheme
2) proposed mechanism. Several aminobenzoxazole deriva-
tives (6b-6j) have been successfully prepared from the
isothiocyanates 1 substituted with electron-poor (Table 3,
entries 1c, 1e, 1f) and rich substituents (Table 3, entries 1h-
1k) in excellent yields in shorter reaction times as shown in
Table 3. The structure of the N-2-(2,6-dimethylphenyl)-1,3-
benzoxazol-2-amine 6h has been further confirmed by X-ray
crystallography (Figure 2).19a In addition to aryl isothiocy-
anates, reactions of alkyl isothiocyanates for instance, benzyl
isothiocyanate 1l, and cyclohexyl isothiocyanate 1m also
proceeded smoothly to give rise to their corresponding
aminobenzoxazoles 6i and 6j in good yields.
A noteworthy aspect is that the unsymmetrical naphthyl-
hydroxyphenylthiourea 7 generated from the 1-napthyl
isothiocyanate and 2-aminophenol 5, when treated with
EDPBT, gave the 2-(naphtho[1,2-d]thiazol-2-ylamino)phe-
nol 8 as the major product rather than the expected
N-(naphthalen-1-yl)benzo[d]oxazol-2-amine 9 (Scheme 3).
The predominate formation of benzothiazole 8 can be in
part because of the intramolecular electrophilic substitution
of the activated naphthyl ring, and poor nucleophilicity
of sOH group. This observation is analogous to Huger-
schoff reaction known since 1901.20 To ascertain the later
effect, that is, nucleophilicity plays the role in the product
formation, the sOH nucleophile was replaced with a
-NH2 nucleophile by designing the substrate 10. Interest-
ingly, the substrate 10 having an amino group under an
identical condition gave exclusively N-(naphthalen-1-yl)-
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR
and 13C NMR, c Isolated yield.
be applied for large scale reactions. Therefore we explored
the above strategy of benzimidazoles synthesis for the
synthesis of benzoxazole as shown in Table 3.
The in situ generated monothiourea resulted from aryl
isothiocyanate 1a (Scheme 2) and o-amino phenol 5 when
treated with 0.5 equiv of EDPBT 3 gave the desired N-2-
phenyl-1,3-benzoxazol-2-amines 6a in excellent yield. The

758 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Yella and Patel
Table 4. Reaction of o-Aminothiophenol 13 with
Isothiocyanates 1 Using EDPBTa
1H-benzo[d]imidazol-2-amine 12 without giving any
traces of benzothiazole 11 which is further confirmed by
its mass spectra,13a thus supporting our assumption that
nucleophilicity is equally important in deciding the course
of the reaction (Scheme 3).
In another set of experiments, the scope of this strategy
was applied to the synthesis of benzothiazoles. Benzothia-
zoles are privileged organic compounds because of their
recognition in biological and therapeutic activities. Specif-
ically, 2-aminobenzothiazoles are broadly found in bioor-
ganic and medicinal chemistry with applications in drug
discovery and development for the treatment of diabe-
tes,21a epilepsy,21b-d inflammation,22a amyotrophic lateral
sclerosis,22b analgesia,22c tuberculosis,22d and viral infec-
tions.22e Some of representative examples of biologically
important aminobenzothiazoles are shown in Figure 1 (III
and IV).10b-e,11
The Hugherschoff reaction is known to produce 2-ami-
nobenzothiazole from 1,3-diaryl thiourea and liquid bromine
in chloroform.20 This reaction works well for symmetrical
thioureas giving exclusively one product.3a But when the
same reaction is performed using unsymmetrical 1,3-diaryl
thioureas there is always uncertainty as to on which aryl ring
the intramolecular electrophilic substitution would take place
to give aminobenzothiazole. To improve the selectivity in
product formation, intramolecular ligand assisted copper and
palladium catalyzed C-S bond formation between arylhalide
and thiourea functionality has been employed for the
synthesis of aminobenzothiazole.23 So far only two methods
have been reported using desulfurization strategy24 for the
preparation of aminobenzothiazoles.
The in situ generated monothiourea from aryl isothiocy-
anate and o-aminothiophenol 13 (Scheme 2), when treated
with 0.5 equiv of EDPBT 3, afforded the desired aminoben-
zothazole 14a in good yield. The proposed mechanism is
similar to that of benzimidazole and benzoxazole as shown
in Scheme 3. Various benzothiazoles 14b-14f were obtained
under our standard experimental conditions, irrespective of
the nature of the substituents attached to the isothiocyanates
(Table 4, entry 1e, 1g, 1i, 1j, and 1k). Further, the structure
of 14d was confirmed by X-ray crystallography (Figure 3).19b
In addition to aryl isothiocyanates, alkyl isothiocyanate such
as cyclohexyl isothiocyanate 1m (Table 4) also proceeded
smoothly to give product 14g.
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR
and 13C NMR, c Isolated yield.
Figure 3. ORTEP view with the atomic numbering scheme of
14d.19b
Table 5. Reaction of o-Aminobenzyl Alcohol 15 with
Isothiocyanates 1 Using EDPBTa
Benzoxazines are yet another member of the heterocycle
family which have been synthesized by an analogous
desulfurization strategy using expensive DCC18d and DIB7b
as the desulfurizing agent. Another literature method in the
preparation of benzoxazines involves an arduous tandem aza-
Wittig/heterocumulene-mediated annulation strategy.25
A
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR
and 13C NMR. c Isolated yield.
series of these important heterocycles 16a-16f were prepared
under our optimized experimental conditions as shown in
Table 5. The structure of the product 16f has been confirmed
by X-ray crystallography (See Supporting Information).
There exist several possibilities for bis-thiourea when
separated by two carbon spacer. The S-Br form on one side
could be attacked by any one of the two nitrogen nucleophiles
from the adjacent thiourea either giving a five membered or
a seven membered ring. Alternatively, sulfur atom from the
adjacent thiourea can attack to give a seven membered ring
or form an eight membered disulfide ring. However, hyper-
valent iodine mediated reaction of similar substrate gave
1-imidazolidinecarbothioamide as the exclusive product.7b
Thus we were interested to see if the reagent EDPBT behaves
similar to the hypervalent iodine DIB or gives a different
product. The aryl isothiocyanate 1 (2 equiv) was treated with

Synthesis of Five and Six Membered N, O, S-Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 759
Scheme 4. Alternative Mechanism for the Formation of 1-Imidazolidinecarbothioamide
Table 6. Synthesis of Imidazolidenecarbothioamides and
ethylenediamine 17 (1 equiv) to give bis-thiourea which on
reaction with EDPBT gave excellent yield of imidazolidin-
ecarbothioamide 18a (Scheme 4). This is perhaps the most
important part of this methodology since there are few
synthetic methods available for 1-imidazolidinecarbothioa-
mide. Only three methods have been reported so far for the
synthesis of this class of compounds. The first is the
desulfurization strategy of bis-thioureas using toxic mercury
salt26a or expensive hypervalent iodine (DIB)7b and the other
involves the treatment of 2-methylamino-2-imidazoline with
isothiocyanate.26b Because of limited synthetic methods
available these compounds are relatively unexplored in
medicinal chemistry but some are known to be valuable
insecticides, usually for the control of Epilachna varivestis.27
A plausible mechanism for the formation of imidazolidin-
ecarbothioamide involves the attack of the internal nitrogen
of the adjacent thiourea on to the iminium carbon of the other
thiourea displacing S-Br as shown in Scheme 4, eq 2, path
c. This mechanism is similar to the hypervalent iodine
mediated reaction recently reported by us.7b Recently we
have reported the formation of an anti-Hugerschoff product
from an unsymmetrical aryl-alkyl thiourea which is believe
to go via an iminium disulfide intermediate (Scheme 4, eq
1). One of the imine nitrogen then attacks on to the adjacent
iminium carbon with the concurrent expulsion of the
elemental sulfur to give the desired product (Scheme 4, eq
1). This mechanism has been supported by a crossover
experiment.6a Thus, taking cues from the above mechanism,
the following mechanism involving an eight membered
disulfide N intermediate cannot be ruled out (Scheme 4, eq
2). One of the iminium nitrogen undergo protonation which
is attacked by the other imine nitrogen O in an intramolecular
fashion followed by the expulsion of sulfur to yield the stable
product 18a shown in Scheme 4, eq 2.
Benzimidazolea
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR
and 13C NMR, c Isolated yield.
was confirmed by X-ray crystallography (See Supporting
Information).
After successfully synthesizing imidazolidinecarbothioa-
mide, the strategy was applied to electron poor (Table 6,
1b, 1c, 1e, and 1f) and electron rich (Table 6, 1h-1j)
isothiocyanates giving the products 18b-18h in good to
excellent yields, as shown in Table 6. The structure of 18f
We were further interested to see if an aromatic 1,2-
diamine such as o-phenylenediamine 2 (o-PD) behaves
similar to the aliphatic 1,2-diamine 17. Interestingly, the bis-
thiourea obtained by the treatment of o-phenylenediamine 2
(o-PD) and aryl isothiocyanate 1 gave benzimidazole 4 and

760 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Yella and Patel
Scheme 5. Reactivity of Aromatic 1,2-bis-Thiourea with
EDPBT
was collected separately for recycling. The ethyl acetate layer
was washed with a saturated solution of NaHCO3 (5 mL),
dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The pure product was isolated by silica
gel column (1:4 ethylacetate/hexane) to give the product
4a7b,13c,i (377 mg, 90%). Mp 150-152 °C, H NMR (400
1
MHz, CDCl3 + DMSO-d6) δ 6.29 (brs, 1H), 6.92 (t, J )
7.6 Hz, 1H), 7.04 (m, 2H), 7.23 (m, 2H), 7.30 (m, 2H), 7.49
(m, 2H); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 112.7,
118.4, 120.7, 122.0, 129.1, 137.4, 140.0, 151.4; IR (KBr)
3053, 2917, 1635, 1603, 1573, 1531, 1498, 1456, 1270, 1233,
1184, 1045, 898, 754, 743 cm-1; elemental analysis calcd
(%) for C13H11N3: C 74.62, H 5.30, N 20.08; found C 74.66,
H 5.32, N 20.11.
aryl isothiocyanate 1 instead of the expected imidazolidin-
ecarbothioamide. Various bis-thioureas (Table 6, entry
19a-c) were reacted under the present experimental condi-
tion and in each case a benzimidazole 4 (Table 6, 4a, 4c,
and 4i) and an aryl isothiocyanate 1 (Table 6, 1a, 1c, and
1i) were isolated. In this case the intermediate imidazolidi-
necarbothioamide P (Scheme 5) which is non-aromatic in
character rapidly loses a molecule of isothiocyanate 1 giving
benzimidazole 4. The driving force for this reaction seems
to be the gain in the aromatic character of the product
benzimidazole because of loss of an isothiocyanate from the
intermediate Q (Scheme 5).
Spectral Data for Selected Compounds. N-(2-Chlo-
rophenyl)-4-nitro-1H-benzo[d]imidazol-2-amine (4c). Mp
1
213-215 °C, H NMR (400 MHz, CDCl3 + DMSO-d6) δ
4.58 (s, 1H), 7.01 (t, J ) 7.6 Hz, 1H), 7.35 (t, J ) 7.8 Hz,
1H), 7.41 (t, J ) 8.0 Hz, 2H), 8.02 (m, 1H), 8.25 (s, 1H),
8.63 (t, J ) 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3 +
DMSO-d6) δ 108.0, 111.8, 116.6, 119.4, 121.2, 122.3, 127.1,
128.5, 135.3, 141.0, 153.2; IR (KBr) 3374, 3312, 2924, 1609,
1567, 1532, 1468, 1450, 1362, 1324, 1124, 1070, 1026, 869,
820, 737 cm-1; elemental analysis calcd (%) for
C13H9ClN4O2: C 54.09, H 3.14, N 19.41; found C 54.06, H
3.16, N 19.44.
Conclusion
In summary, bromineless brominating reagent EDPBT has
been employed as a thiophilic/desulfurizing reagent for the
efficient construction of a library of five and six membered
N, O, S heterocycles in one-pot. So far, most of the reported
methods were performed in multisteps using toxic heavy
metals or using expensive reagents. The most interesting
aspect of the present report is the regioselective product for
unsymmetrical thiourea having a napthyl moiety in one side
and an o-amino or an o-hydroxyphenyl on the other side
which is dependent on the nature of the nucleophiles (OH
or NH2). Another interesting aspect is the differential
reactivity of bis-thioureas of aliphatic and aromatic 1,2-
diamines, the former giving 1-imidazolidinecarbothioamide
and the later benzimidazole and isothiocyanate. In addition,
the ease of preparation of this reagent, facile isolation of
products, and recyclability of the spent reagent makes this
method more practical over the existing methods in the
literature.
N-(3-Chlorophenyl)-6-methyl-1H-benzo[d]imidazol-2-
1
amine (4e). Mp 95-97 °C, H NMR (400 MHz, CDCl3 +
DMSO-d6) δ 2.41 (s, 3H), 4.62 (brs, 1H), 6.92 (t, J ) 8.0
Hz, 2H), 7.21 (m, 3H), 7.44 (m, 1H), 7.62 (s, 1H); 13C NMR
(100 MHz, CDCl3 + DMSO-d6) δ 21.6, 112.5, 112.8, 116.4,
118.0, 121.8, 122.4, 130.2, 130.9, 134.4, 134.6, 136.1, 141.2,
150.1; IR (KBr) 2921, 1648, 1594, 1558, 1478, 1275, 1094,
912, 856, 798, 770, 678, 594 cm-1; elemental analysis calcd
(%) for C14H12ClN3: C 65.25, H 4.69, N 16.30; found C
65.21, H 4.73, N 16.22.
N-2-(2-Methoxyphenyl)-1,3-benzoxazol-2-amine (6e).
1
Mp 106 °C, H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H),
6.89 (d, J ) 8.0 Hz, 1H), 7.00-7.13 (m, 3H), 7.22 (t, J )
8.0 Hz, 1H), 7.32 (d, J ) 8.0 Hz, 1H), 7.51 (d, J ) 7.6 Hz,
1H,), 7.66 (brs, 1H), 8.41 (d, J ) 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 55.9, 109.1, 110.2, 117.6, 121.5, 122.5,
123.7, 124.3, 127.6, 142.9, 147.5, 147.9, 157.9; IR (KBr)
3388, 2926, 1638, 1606, 1578, 1528, 1456, 1346, 1254, 1242,
1213, 1165, 1115, 982, 740 cm-1; HRMS (ESI) m/z 241.1328
(MH+); elemental analysis calcd (%) for C14H12N2O2: C
69.99, H 5.03, N 11.66; found C 69.94, H 5.07, N 11.61.
Experimental Section
General Procedure for Preparation of N-phenyl-1H-
benzo[d]imidazol-2-amines (4a). To a solution of phenyl
isothiocyanate 1a (270 mg, 2 mmol.) in CH3CN (6 mL) was
added o-phenylenediamine 1a (216 mg, 2 mmol), at room
temperature. Formation of monothiourea was observed within
30 min as judged from thin layer chromatography (TLC).
To this reaction mixture was added triethylamine (835 µL,
6 mmol) followed by portion wise addition of EDPBT (666
mg, 1 mmol) over a period of 10-15 min. The reaction was
kept at room temperature for stirring, and complete conver-
sion to benzimidazole 4a was observed within 30 min with
concomitant precipitation of sulfur as can be judged from
TLC and disappearance of orange color of EDPBT. After
completion of the reaction, the solvent was evaporated and
the reaction mixture was admixed with ethyl acetate (15 mL)
and water 8 mL. The water layer containing the spent reagent
1,1′-(ethane-1,2-diyl)dipyridinium ditribromide (EDPDB)
2-(Naphtho[1,2-d]thiazol-2-ylamino)phenol (8). Mp
1
216-218 °C, H NMR (400 MHz, CDCl3 + DMSO-d6) δ
6.92-6.99 (m, 3H), 7.50-7.65 (m, 3H), 7.74 (t, J ) 7.2
Hz, 1H), 7.90 (t, J ) 7.0 Hz, 1H), 8.12 (d, J ) 7.2 Hz, 1H),
8.52 (t, J ) 7.2 Hz, 1H), 9.41 (brs, 1H), 10.2 (brs, 1H); 13
C
NMR (100 MHz, CDCl3 + DMSO-d6) δ 115.6, 117.8, 118.8,
119.0, 121.4, 122.7, 122.8, 124.1, 124.5, 125.1, 125.4, 127.0,
127.9, 130.9, 146.1, 162.9; IR (KBr) 3418, 2255, 2128, 1649,
1542, 1456, 1393, 1368, 1048, 1025, 1002, 826, 764 cm-1;
HRMS (ESI): m/z 293.3685 (MH+); elemental analysis calcd
(%) for C17H12N2OS:C 69.84, H 4.14, N 9.58, S 10.97; found
C 69.88, H 4.11, N 9.66, S 10.92.

Synthesis of Five and Six Membered N, O, S-Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 761
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Benzothiazol-2-yl-(2,4-dimethyl-phenyl)-amine (14e).
Mp 135 °C, H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H),
1
2.37 (s, 3H), 7.10 (m, 3H), 7.26 (m, 1H), 7.38 (d, J ) 8.0
Hz, 1H), 7.44 (d, J ) 8.0 Hz, 1H), 7.54 (d, J ) 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 18.0, 21.2, 118.9, 121.0,
122.0, 125.2, 126.2, 128.0, 132.2, 133.3, 135.9, 136.9, 152.0,
168.2; IR (KBr) 3063, 2851, 1618, 1607, 1568, 1449, 1268,
1217, 1126, 906 cm-1; elemental analysis calcd (%) for
C15H14N2S:C 70.83, H 5.55, N 11.01, S, 12.61; found C
70.79, H 5.58, N 11.05, S, 12.66.
N-(2,4-dimethylphenyl)-4H-benzo[d] [3,1]oxazin-2-amine
(16f). Mp 163-166 °C, 1H NMR (400 MHz, CDCl3) δ 2.20
(s, 3H), 2.30 (s, 3H), 5.14 (s, 2H), 6.80 (d, J ) 8.0 Hz, 1H),
6.92-6.99 (m, 4H), 7.15 (t, J ) 7.2 Hz, 1H), 7.31 (d, J )
7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.1, 21.0, 67.8,
120.1, 120.6, 122.5,123.8, 124.0, 127.2, 129.2, 130.9, 131.3,
134.1, 135.8, 141.2, 152.5; IR (KBr) 2976, 2917, 2865, 1680,
1650, 1598, 1484, 1457, 1402, 1305, 1268, 1251, 1206, 1251,
1206, 1123, 1031, 908, 831,756 cm-1; HRMS (ESI) m/z
253.1348 (MH+); elemental analysis calcd (%) for
C16H16N2O: C 76.16, H 6.39, N 11.10; C 76.19, H 6.42, N
11.04.
2-(2-Methoxyphenylimino)-N-(2-methoxyphenyl)imida-
zolidine-1-carbothioamide (18f). Mp 153 °C, 1H NMR (400
MHz, CDCl3) δ 3.43 (t, J ) 7.6 Hz, 2H), 3.76 (s, 3H), 3.83
(s, 3H), 4.44 (t, J ) 7.6 Hz, 2H), 4.71 (s, 1H), 6.88 (d, J )
8.0 Hz, 1H), 6.98 (m, 3H), 7.04-7.15 (m, 3H), 8.47 (d, J )
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 38.6, 48.8, 55.9,
56.2, 111.0, 112.5, 120.1, 121.6, 124.5, 124.7, 124.8, 125.9,
128.8, 135.3, 151.3, 151.4, 151.9, 178.2; IR (KBr) 3403,
2938, 2898, 2835, 1669, 1607, 1564, 1495, 1475, 1398, 1371,
1323, 1295, 1247, 1108, 1046, 1026, 910, 748 cm-1; HRMS
(ESI): m/z 379.1217 (M+Na+); elemental analysis calcd (%)
for C18H20N4O2S: C 60.65, H 5.66, N 15.72, S 9.00; found
C 60.60, H 5.60, N 15.77, S 9.09.
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Acknowledgment. B.K.P. acknowledges the support of this
research by the Department of Science and Technology (DST)
(SR/S1/OC-79/2009), New Delhi, and the Council of Scientific
and Industrial Research (CSIR) (01(2270)/08/EMR-II). R.Y.
thanks the CSIR for fellowships. Thanks are due to the Central
Instruments Facility (CIF) IIT Guwahati for Mass and NMR
spectra, and DST-FIST for the XRD facility.
Supporting Information Available. Detailed experimen-
tal procedures, general information, and analytical data of
1
all compounds, and the copies of their H NMR and 13C
NMR, crystallographic information of 16f and 18f. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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shtm.
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(19) (a) Crystallographic description of 6h: Crystal dimension (mm):
0.3 × 0.2 × 0.1; C15H14N2O, Mr ) 238.28; monoclinic, space
group P21/n; a ) 11.0031(4) Å, b ) 17.0388(6) Å, c )
14.9909(5) Å; R ) γ ) 90.00°, ꢀ ) 109.882(2)°, V )
2642.97(16) Å3; Z ) 8; Fcal ) 1.198 mg/m3; µ(mm-1) ) 0.077;
F(000) ) 1008; reflection collected/unique ) 5913/5560; refine-
ment method ) full-matrix least-squares on F2; final R indices
[I > 2σl] R1 ) 0.0786, wR2 ) 0.1842, R indices (all data) R1
) 0.1749, wR2 ) 0.2169; goodness of fit ) 1.062. #CCDC
769692. . (b) Crystallographic description of 14d: Crystal
dimension (mm): 0.3 × 0.2 × 0.1; C14H12N2OS, Mr ) 256.33;
j
triclinic, space group P1; a ) 6.9368(2) Å, b ) 8.9658(3) Å,
c ) 10.6643(4) Å; R ) 78.187(2)°, ꢀ ) 74.508(2)°, γ )
89.919(2)°, V ) 624.62(4) Å3; Z ) 2; Fcal ) 1.363 mg/m3;
µ(mm-1) ) 0.247; F(000) ) 268; reflection collected/unique
) 3074/2329; refinement method ) full-matrix least-squares
on F2; final R indices [I > 2σl] R1 ) 0.0380, wR2 ) 0.0981,
R indices (all data) R1 ) 0.0500, wR2 ) 0.1057; goodness
of fit ) 1.063. #CCDC 769691.
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