Benzazoles from aliphatic amines and o -amino/mercaptan/hydroxyanilines: Elemental sulfur as a highly efficient and traceless oxidizing agent

Article abstract of DOI:10.1021/ol302856w

A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.

Full text of DOI:10.1021/ol302856w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Benzazoles from Aliphatic Amines and
o‑Amino/Mercaptan/Hydroxyanilines:
Elemental Sulfur as a Highly Efficient
and Traceless Oxidizing Agent
Thanh Binh Nguyen,*,† Ludmila Ermolenko,† William A. Dean,‡ and Ali Al-Mourabit†
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles,
CNRS, 91198 Gif-sur-Yvette Cedex, France
nguyen@icsn.cnrs-gif.fr
Received October 17, 2012
ABSTRACT
A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines
using elemental sulfur as traceless oxidizing agent has been developed.
Benzazole moiety plays an important role in chemistry
and is also present in a variety of biologically active and
therapeutically useful compounds.1 Development of new
methods for its construction is therefore highly desirable.
A simple and efficient transformation using readily avail-
able reagents under solvent-free and metal-free condi-
tions is considered as a key solution for pollution problems
generated by large-scale reactions. In this context, solvent-
and metal-free redox reactions promoted by elemental
sulfur in organic syntheses appear to be highly desirable
to maximize atom economy and to avoid expensive com-
plex metal catalysts. In particular, the elemental sulfur-
mediated oxidation represents a useful alternative to other
oxidation reactions using its lighter congener, oxygen,
because sulfur is readily available, nontoxic, and stable
under normal conditions. In contrast to oxygen, which is a
biradical in the ground state, sulfur is less reactive. Conse-
quently, the reactions using sulfur present a low risk of
explosion, show different and interesting reactivities and
selectivities even without metal catalyst, and do not require
pressurized reactors. In connection with our interest in
CÀN bond formation, we sought to explore oxidation
reactions of aliphatic amine using elemental sulfur as a
convenient alternative to oxygen under solvent-free and
catalyst-free conditions.2
The interaction between sulfur and amines has been the
subject of several studies.3 When an aliphatic amine, such
as benzylamine 1a, was heated with sulfur, thiobenzamide
3 was obtained as a result of a cascade reaction (Scheme 1).3
The synthetic utility of this reaction has received little
† Institut de Chimie des Substances Naturelles.
‡ Present address: Harvard University, Cambridge, MA 02138.
(1) For examples, see: (a) Jain, A. K.; Paul, A.; Maji, B.; Muniyappa,
K.; Bhattacharya, S. J. Med. Chem. 2012, 55, 2981. (b) Hutchinson, I.;
Jennings, S. A.; Vishnuvajjala, B. R.; Westwell, A. D.; Stevens, M. F. G.
J. Med. Chem. 2001, 44, 744. (c) Carpenter, R. D.; Andrei, M.; Aina,
O. H.; Lau, E. Y.; Lightstone, F. C.; Liu, R.; Lam, K. S.; Kurth, M. J.
J. Med. Chem. 2008, 51, 14. (d) Wang, X.; Sarris, K.; Kage, K.; Zhang,
D.; Brown, S. P.; Kolasa, T.; Surowy, C.; El Kouhen, O. F.; Muchmore,
S. W.; Brioni, J. D.; Stewart, A. O. J. Med. Chem. 2008, 51, 170. (e)
Aiello, S.; Wells, G.; Stone, E. L.; Kadri, H.; Bazzi, R.; Bell, D. R.;
Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.; Westwell, A. D.
J. Med. Chem. 2008, 51, 5135. (f) Alamgir, M.; Black, D. S. C.; Kumar,
N. Top. Heterocycl. Chem. 2007, 9, 87. (g) Bradshaw, T. D.; Westwell,
A. D. Curr. Med. Chem. 2004, 11, 1009.
(2) (a) Nguyen, T. B.; Sorres, J.; Tran, M. Q.; Ermolenko, L.;
Al-Mourabit, A. Org. Lett. 2012, 14, 3202. (b) Nguyen, T. B.; Ermolenko,
L.; Al-Mourabit, A. Heterocycles 2012 DOI: 10.3987/COM-12-S(N)53.
(3) (a) Davis, R. E.; Nakshbendi, H. F. J. Am. Chem. Soc. 1962, 84,
2085. (b) Hodgson, W. G.; Buckler, S. A.; Peters, G. J. Am. Chem. Soc.
1963, 85, 543. (c) Thomson, J. W.; Nagashima, K.; Macdonald, P. M.;
Ozin, G. A. J. Am. Chem. Soc. 2011, 133, 5036. (d) McMillan, F. H.
J. Am. Chem. Soc. 1948, 70, 868. Mechanistic study of the room tempera-
ture reaction of sulfur with benzylamine: (e) Sasaki, Y.; Olsen, F. P. Can.
J. Chem. 1971, 49, 283. (f) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit,
A. Org. Lett. 2012, 14, 4274. (g) Aghpoor, K.; Darabbi, H. R.; Tabar-
Heydar, K. Phosphorus, Sulfur Silicon 2002, 177, 1183.
r
10.1021/ol302856w
XXXX American Chemical Society

attention. We reasoned that if another amine stable to sulfur-
mediated oxidation is added to the reaction mixture and is
capable of participating in the trans-thioamidation with 3,
a cross-coupled product could be obtained. The driving
force of this transformation is obviously the consumption
of released benzylamine 1a. In contrast to transamidation
which required high temperature and/or catalytic condi-
tions, trans-thioamidation is likely to proceed at lower
temperature even without added catalyst.4 In our previous
work,3f by using an aliphatic amine such as 2-phenethyl-
amine which is less oxidizable than 1a, we obtained selec-
tively cross-coupled thiobenzamides. By applying this one-
pot transformation to aromatic amines, activation energy
of the trans-thioamidation step should be higher because
aromatic amines are less nucleophilic. This difficulty could
be overcome by using an aniline ortho-substituted by a
cyclizable group such as amino, hydroxy or mercaptan.
The fomation of benzazoles in this case would be consider-
ably facilitated by both energetically favored processes:
cyclization and aromatization.
Table 1. Reaction Conditions Screeninga
conversion (%)b
1a:2a
temp
time
(h)
entrya
(mmol/mmol)
(° C)
3
4aa
1
2
3
4
5
6
5:0
5:0
150
120
150
150
130
120
8
8
100
100
0:5
8
0c
5:5
8
<5
>95
7.5:5
7.5:5
20
20
ndd
ndd
>95 (92)f
80 (71)f
a Sulfur (15 mmol, 480 mg). b Determined by 1H NMR spectroscopy.
c 2a recovered unchanged. d Not determined. f Isolated yield.
The scope of the reaction with respect to o-phenylene-
diamines and aliphatic amines was next investigated (Table 2).
Under the optimized reaction conditions, various substi-
tuted aliphatic amines reacted with o-phenylenediamines to
yield the corresponding benzimidazoles in good yields.
Benzylamines N-mono- and disubstituted by methyl or
benzyl groups work well as substrates for the oxidative
condensation reaction and were readily transformed into
2-phenylbenzimidazole in high yields (entries 1À5, Table 2).
When R1 or/and R2 = Me, volatile (di)methylamine was
released during the course of the reaction (entries 2À3,
Table 2), while when R1 or/and R2 = Bn, evolved
(di)benzylamine was further oxidized and condensed with
o-phenylenediamine (entries 4 and 5, Table 2). Other
benzylamines substituted at the para position gave the
corresponding benzoxazoles in 85À90% yield (entries
6À8, Table 2). Indeed, there is no sharp difference in
reactivity between the strongly electron-donating 4-meth-
oxy group (entry 8, Table 2) with the slightly electron-
donating 4-methyl group (entry 6, Table 2) and the
electron-deficient 4-chloro group (entry 7, Table 2). In
particular, R-methylbenzylamine gave the rearranged
coupled product (entry 9, Table 2).3f Interestingly, when
aliphatic amines other than benzylamines such as triethyl-
amine, tri-n-propylamine, and dibutylamine (entries
10À12, Table 2) were used, the corresponding benzimi-
dazoles were obtained in high yields. Similarly, three
picolinamines 1iÀk gave the benzimidazoles 4aiÀak in
preparative yields (entries 13À15, Table 2). It should be
noted that in the case of 2- and 4-picolinamines (entries
14À15, Table 2), higher conversions could be achieved
even at lower temperature compared to 3-picolinamine
(entry 13, Table 2) and benzylamine (entry 1, Table 2).
The efficacy of the reaction in the former cases could be
explained by the efficient conjugative effect of the hetero-
cycle nitrogen atom in the 2- and 4-positions.
Scheme 1. Sulfur-Mediated Cross-Coupling Reaction of Two
Amines
Herein, we report a chemoselective method for an
oxidative coupling reaction of alkylamines with o-amino/
mercaptan/hydroxyanilines for the formation of benzimi-
dazoles, benzothiazoles, and benzoxazoles.
Atthe start of our studies, weinvestigatedthe reaction of
benzylamine 1a with o-phenylenediamine 2a as a model
system under solvent-free conditions (Table 1). First, the
reactivity of 1a and 2a with sulfur was investigated sepa-
rately. Compound 1a reacted readily and cleanly with
sulfurtoyieldhomocoupledthioamide3a(entry1,Table1)
as the only observable product even at moderate tempera-
ture (entry 2, Table 1). On the contrary, 2a was stable in the
presence of sulfur, even at high temperature (entry 3,
Table 1). Next, we decided to heat an equimolar mixture
of both amines 1a and 2a at 150 °C. Gratifyingly, these
conditions afforded benzimidazole 4aa in excellent yield
(entry 4, Table 1). The reaction temperature could be
lowered by using a slight excess of 1a. Interestingly, even
in the absence of solvent, the reaction mixture was homo-
geneous and 4aa was progressively crystallized out from
the liquid reaction mixture. Compound 4aa could be
isolated in high yield and purity by washing the reaction
mixture with toluene to remove excess sulfur and other
products.
To further investigate the substrate scope, reactions
using various o-phenylenediamine substrates were carried
(4) Schlatter, M. J. J. Am. Chem. Soc. 1942, 64, 2722.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Sulfur-Mediated Cross-Coupling Reaction of o-Phenylenediamines with Aliphatic Aminesa
a Reaction conditions: o-phenylenediamine 2aÀe (5 mmol), amine 1aÀk (7.5 mmol), and sulfur (15 mmol, 32 g/mol).
out. o-Phenylenediamines bearing alkyl or halogen
substituents were successful substrates in this reac-
tion and gave the corresponding benzimidazoles in
about 80% yields (entries 16À18). Although 2e is a highly
sterically demanding substrate, the oxidationÀcondensation
process was successfully carried out with both ben-
zylamine 1a and triethylamine 1f (entries 19 and 20,
Table 2).
Org. Lett., Vol. XX, No. XX, XXXX
C

oligosulfur chain, the first step of the cascade reaction
could be the formation of trisulfide 5. Trisulfide 5 could
also oxidize alkylamines in the subsequent steps.5 Indeed,
when 2f was mixed with elemental sulfur, evolution of H2S
was observed even at rt (Scheme 2).
Table 3. Reaction with o-Aminothiophenol and o-Aminophe-
nola
Benzoxazole 4ga was obtained in lower yield compared
to its aza and thia analogues (4aa and 4fa). This observa-
tion could be understood by the fact that, in 2g, the
hydroxy group renders its o-amino group less nucleophilic
and thus less effective for the trans-thioamidation step,
which is also the rate-determining step of benzazole for-
mation (Scheme 3).
When 1j was used with 2g (Table 3, entry 8), the yield of
4gj was significantly higher. In this case, the trans-thio-
amidation step is favored by the easy oxidation of 1j which
acted as a leaving group in this determining step.
In general, our method is more convenient than other
known methods for conversion of alkylamine into 2-sub-
stituted benzazoles which inevitably required in all cases
expensive/complex catalysts,6 under high pressure,6a
irradiation,6a high temperature conditions,6c,d or expen-
sive oxidizing agent6b with limited scope.6b,c Moreover,
unlike almost reactions involving elemental sulfur and
amines which result the incorporation of sulfur in the final
products, in the present case, sulfur played the role of a
traceless oxidizing agent.
a Reaction conditions: aniline 2f,g (5 mmol), amine 1 (7.5 mmol), and
sulfur (15 mmol, 32 g/mol).
Scheme 3. Reaction of 2-Aminophenol
Finally, we investigated this reaction to prepare thia-
and oxa- analogues of benzimidazoles: benzothiazoles and
benzoxazoles (Table 3) whose structures are found in
various bioactive molecules. In all cases investigated for
2-aminothiophenol 2f, the desired benzothiazoles were
obtained in high yields (entries 1À6, Table 3).
Overall, in view of the availability of all reaction com-
ponents including sulfur, and the remarkably simple and
catalyst-free reaction conditions at moderate temperature,
the present method may possess a highly valuable advan-
tage. The method constitutes a straightforward and effi-
cient proceeding for the large scale synthesis of various
biologically active targets without metallic contaminants.
Further studies of reaction mechanism and applications
are in progress.
Scheme 2. Reaction of 2-Aminothiophenol
Acknowledgment. Financial support from CNRS and
ICSN is gratefully acknowledged.
The reaction pathway for 2f is, however, slightly differ-
ent. Because of the propensity of thiophenols to form the
Supporting Information Available. Experimental pro-
1
cedures, product characterization, and copies of the H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org
(5) Tweit, R. C. J. Heterocycl. Chem. 1970, 7, 687.
(6) (a) Su, F. Z.; Antonietti, M.; Wang, X.; Mathew, S. C.; Moehlmann,
L.; Blechert, S. Angew. Chem., Int. Ed. 2011, 50, 657. (b) Blacker,
A. J.; Farah, M. M.; Marsden, S. P.; Saidi, O.; Williams, J. M. J.
Tetrahedron Lett. 2009, 50, 6106. (c) De Luca, L.; Porcheddu, A. Eur.
€
J. Org. Chem. 2011, 5791. (d) Endo, Y.; Backvall, J. E. Chem.;Eur. J.
2012, 18, 13609.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX