ORGANIC

LETTERS

Benzazoles from Aliphatic Amines and 2012

Vol. 14, No. 23
o‑Amino/Mercaptan/Hydroxyanilines: 5948–5951

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
[email protected]
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Received October 17, 2012

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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 because sulfur is readily available, nontoxic, and stable
and is also present in a variety of biologically active and under normal conditions. In contrast to oxygen, which is a
therapeutically useful compounds.1 Development of new biradical in the ground state, sulfur is less reactive. Conse-
methods for its construction is therefore highly desirable. quently, the reactions using sulfur present a low risk of
A simple and efficient transformation using readily avail- explosion, show different and interesting reactivities and
able reagents under solvent-free and metal-free condi- selectivities even without metal catalyst, and do not require
tions is considered as a key solution for pollution problems pressurized reactors. In connection with our interest in
generated by large-scale reactions. In this context, solvent- C N bond formation, we sought to explore oxidation
and metal-free redox reactions promoted by elemental reactions of aliphatic amine using elemental sulfur as a
sulfur in organic syntheses appear to be highly desirable convenient alternative to oxygen under solvent-free and
to maximize atom economy and to avoid expensive com- catalyst-free conditions.2
plex metal catalysts. In particular, the elemental sulfur- The interaction between sulfur and amines has been the
mediated oxidation represents a useful alternative to other subject of several studies.3 When an aliphatic amine, such
oxidation reactions using its lighter congener, oxygen, as benzylamine 1a, was heated with sulfur, thiobenzamide
3 was obtained as a result of a cascade reaction (Scheme 1).3
†
Institut de Chimie des Substances Naturelles. The synthetic utility of this reaction has received little
‡
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.; (2) (a) Nguyen, T. B.; Sorres, J.; Tran, M. Q.; Ermolenko, L.;
Jennings, S. A.; Vishnuvajjala, B. R.; Westwell, A. D.; Stevens, M. F. G. Al-Mourabit, A. Org. Lett. 2012, 14, 3202. (b) Nguyen, T. B.; Ermolenko,
J. Med. Chem. 2001, 44, 744. (c) Carpenter, R. D.; Andrei, M.; Aina, L.; Al-Mourabit, A. Heterocycles 2012 DOI: 10.3987/COM-12-S(N)53.
O. H.; Lau, E. Y.; Lightstone, F. C.; Liu, R.; Lam, K. S.; Kurth, M. J. (3) (a) Davis, R. E.; Nakshbendi, H. F. J. Am. Chem. Soc. 1962, 84,
J. Med. Chem. 2008, 51, 14. (d) Wang, X.; Sarris, K.; Kage, K.; Zhang, 2085. (b) Hodgson, W. G.; Buckler, S. A.; Peters, G. J. Am. Chem. Soc.
D.; Brown, S. P.; Kolasa, T.; Surowy, C.; El Kouhen, O. F.; Muchmore, 1963, 85, 543. (c) Thomson, J. W.; Nagashima, K.; Macdonald, P. M.;
S. W.; Brioni, J. D.; Stewart, A. O. J. Med. Chem. 2008, 51, 170. (e) Ozin, G. A. J. Am. Chem. Soc. 2011, 133, 5036. (d) McMillan, F. H.
Aiello, S.; Wells, G.; Stone, E. L.; Kadri, H.; Bazzi, R.; Bell, D. R.; J. Am. Chem. Soc. 1948, 70, 868. Mechanistic study of the room tempera-
Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.; Westwell, A. D. ture reaction of sulfur with benzylamine: (e) Sasaki, Y.; Olsen, F. P. Can.
J. Med. Chem. 2008, 51, 5135. (f) Alamgir, M.; Black, D. S. C.; Kumar, J. Chem. 1971, 49, 283. (f) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit,
N. Top. Heterocycl. Chem. 2007, 9, 87. (g) Bradshaw, T. D.; Westwell, A. Org. Lett. 2012, 14, 4274. (g) Aghpoor, K.; Darabbi, H. R.; Tabar-
A. D. Curr. Med. Chem. 2004, 11, 1009. Heydar, K. Phosphorus, Sulfur Silicon 2002, 177, 1183.

10.1021/ol302856w r 2012 American Chemical Society

Published on Web 11/21/2012
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, Table 1. Reaction Conditions Screeninga
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 conversion (%)b
work,3f by using an aliphatic amine such as 2-phenethyl-
1a:2a temp time
amine which is less oxidizable than 1a, we obtained selec- entrya (mmol/mmol) (° C) (h) 3 4aa
tively cross-coupled thiobenzamides. By applying this one-
1 5:0 150 8 100
pot transformation to aromatic amines, activation energy
2 5:0 120 8 100
of the trans-thioamidation step should be higher because 3 0:5 150 8 0c
aromatic amines are less nucleophilic. This difficulty could 4 5:5 150 8 <5 >95
be overcome by using an aniline ortho-substituted by a 5 7.5:5 130 20 ndd >95 (92)f
cyclizable group such as amino, hydroxy or mercaptan. 6 7.5:5 120 20 ndd 80 (71)f
The fomation of benzazoles in this case would be consider- a
Sulfur (15 mmol, 480 mg). b Determined by 1H NMR spectroscopy.
ably facilitated by both energetically favored processes: c
2a recovered unchanged. d Not determined. f Isolated yield.
cyclization and aromatization.
The scope of the reaction with respect to o-phenylene-
diamines and aliphatic amines was next investigated (Table 2).
Scheme 1. Sulfur-Mediated Cross-Coupling Reaction of Two Under the optimized reaction conditions, various substi-
Amines 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 1 5, Table 2).
When R1 or/and R2 = Me, volatile (di)methylamine was
released during the course of the reaction (entries 2 3,
Table 2), while when R1 or/and R2 = Bn, evolved
Herein, we report a chemoselective method for an (di)benzylamine was further oxidized and condensed with
oxidative coupling reaction of alkylamines with o-amino/ o-phenylenediamine (entries 4 and 5, Table 2). Other
mercaptan/hydroxyanilines for the formation of benzimi- benzylamines substituted at the para position gave the
dazoles, benzothiazoles, and benzoxazoles. corresponding benzoxazoles in 85 90% yield (entries
At the start of our studies, we investigated the reaction of 6 8, Table 2). Indeed, there is no sharp difference in
benzylamine 1a with o-phenylenediamine 2a as a model reactivity between the strongly electron-donating 4-meth-
system under solvent-free conditions (Table 1). First, the oxy group (entry 8, Table 2) with the slightly electron-
reactivity of 1a and 2a with sulfur was investigated sepa- donating 4-methyl group (entry 6, Table 2) and the
rately. Compound 1a reacted readily and cleanly with electron-deficient 4-chloro group (entry 7, Table 2). In
sulfur to yield homocoupled thioamide 3a (entry 1, Table 1) particular, R-methylbenzylamine gave the rearranged
as the only observable product even at moderate tempera- coupled product (entry 9, Table 2).3f Interestingly, when
ture (entry 2, Table 1). On the contrary, 2a was stable in the aliphatic amines other than benzylamines such as triethyl-
presence of sulfur, even at high temperature (entry 3, amine, tri-n-propylamine, and dibutylamine (entries
Table 1). Next, we decided to heat an equimolar mixture 10 12, Table 2) were used, the corresponding benzimi-
of both amines 1a and 2a at 150 °C. Gratifyingly, these dazoles were obtained in high yields. Similarly, three
conditions afforded benzimidazole 4aa in excellent yield picolinamines 1i k gave the benzimidazoles 4ai ak in
(entry 4, Table 1). The reaction temperature could be preparative yields (entries 13 15, Table 2). It should be
lowered by using a slight excess of 1a. Interestingly, even noted that in the case of 2- and 4-picolinamines (entries
in the absence of solvent, the reaction mixture was homo- 14 15, Table 2), higher conversions could be achieved
geneous and 4aa was progressively crystallized out from even at lower temperature compared to 3-picolinamine
the liquid reaction mixture. Compound 4aa could be (entry 13, Table 2) and benzylamine (entry 1, Table 2).
isolated in high yield and purity by washing the reaction The efficacy of the reaction in the former cases could be
mixture with toluene to remove excess sulfur and other explained by the efficient conjugative effect of the hetero-
products. cycle nitrogen atom in the 2- and 4-positions.
To further investigate the substrate scope, reactions
(4) Schlatter, M. J. J. Am. Chem. Soc. 1942, 64, 2722. using various o-phenylenediamine substrates were carried
Org. Lett., Vol. 14, No. 23, 2012 5949
Table 2. Sulfur-Mediated Cross-Coupling Reaction of o-Phenylenediamines with Aliphatic Aminesa

a
Reaction conditions: o-phenylenediamine 2a e (5 mmol), amine 1a k (7.5 mmol), and sulfur (15 mmol, 32 g/mol).

out. o-Phenylenediamines bearing alkyl or halogen sterically demanding substrate, the oxidation condensation
substituents were successful substrates in this reac- process was successfully carried out with both ben-
tion and gave the corresponding benzimidazoles in zylamine 1a and triethylamine 1f (entries 19 and 20,
about 80% yields (entries 16 18). Although 2e is a highly Table 2).
5950 Org. Lett., Vol. 14, No. 23, 2012
 oligosulfur chain, the first step of the cascade reaction
could be the formation of trisulfide 5. Trisulfide 5 could
Table 3. Reaction with o-Aminothiophenol and o-Aminophe- also oxidize alkylamines in the subsequent steps.5 Indeed,
nola
when 2f was mixed with elemental sulfur, evolution of H2S
was observed even at rt (Scheme 2).
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 1 6, 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-
Scheme 2. Reaction of 2-Aminothiophenol 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.

Acknowledgment. Financial support from CNRS and

The reaction pathway for 2f is, however, slightly differ- ICSN is gratefully acknowledged.
ent. Because of the propensity of thiophenols to form the
Supporting Information Available. Experimental pro-
(5) Tweit, R. C. J. Heterocycl. Chem. 1970, 7, 687.
(6) (a) Su, F. Z.; Antonietti, M.; Wang, X.; Mathew, S. C.; Moehlmann, cedures, product characterization, and copies of the 1H
L.; Blechert, S. Angew. Chem., Int. Ed. 2011, 50, 657. (b) Blacker, and 13C NMR spectra. This material is available free of
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. charge via the Internet at http://pubs.acs.org
J. Org. Chem. 2011, 5791. (d) Endo, Y.; B€ackvall, J. E. Chem.;Eur. J.
2012, 18, 13609. The authors declare no competing financial interest.

Org. Lett., Vol. 14, No. 23, 2012 5951