S8-Mediated Cyclization of 2-Aminophenols/thiophenols with Arylmethyl Chloride: Approach to Benzoxazoles and Benzothiazoles

Article abstract of DOI:10.1002/asia.201600355

A metal-free approach to benzazoles from arylmethyl chlorides and 2-mercaptan/2-hydroxyanilines using elemental sulfur as a traceless oxidizing agent has been developed. The reactions proceeded in good to excellent yields, exhibiting good functional groups tolerance and gram-scale ability. A key mechanistic investigation indicated that the key intermediate trisulfide 6, which was characterized by NMR, HRMS and crystal X-ray crystallography, was separated in the reaction prior to the formation of the product.

Full text of DOI:10.1002/asia.201600355

DOI: 10.1002/asia.201600355
Communication
Synthetic Methods
S8-Mediated Cyclization of 2-Aminophenols/thiophenols with
Arylmethyl Chloride: Approach to Benzoxazoles and
Benzothiazoles
Haifeng Gan,[a] Dazhuang Miao,[a] Qiang Pan,[a] Renhe Hu,[a] Xiaotong Li,[a] and
Shiqing Han*[a, b]
Abstract: A metal-free approach to benzazoles from aryl-
methyl chlorides and 2-mercaptan/2-hydroxyanilines using
elemental sulfur as a traceless oxidizing agent has been
developed. The reactions proceeded in good to excellent
yields, exhibiting good functional groups tolerance and
gram-scale ability. A key mechanistic investigation indicat-
ed that the key intermediate trisulfide 6, which was char-
acterized by NMR, HRMS and crystal X-ray crystallography,
was separated in the reaction prior to the formation of
the product.
2-Substituted benzazoles are important heterocyclic scaffolds
in organic electronic materials, biologically active natural prod-
ucts, and particularly pharmaceutical compounds due to their
high biological activities, such as antitumor, antimicrobial, and
antiviral properties.[1,2] The development of a promising strat-
egy for the synthesis of benzazoles has attracted much atten-
tion in the past decades. Common methods involve the con-
densation reactions of 2-aminophenols/thiophenols with alde-
hydes, carboxylic acids, or a-ketone acids under oxidative con-
ditions (Scheme 1a),[3] a transition-metal-catalyzed intramolecu-
lar cyclization of 2-haloanilides/analogues (Scheme 1b),[4] and
a copper-catalyzed oxidative decarboxylative intermolecular
arylation of benzothiazoles with phenylacetic acids
(Scheme 1c).[5] However, these methods have one or more
shortcomings, such as prefunctionalization of the starting ma-
terials, employing transition-metals or excess oxidants, harsh
reaction conditions, and so forth.
Scheme 1. Recent strategy for the synthesis of benzazoles.
ranging from À2 to +6, and can form products with a homolo-
gous sulfur chain.[6] In recent years, sulfur-mediated/catalyzed/
participated reactions have attracted a great deal of attention
in organic synthesis for the construction of CÀC and CÀX
bonds.[7] Nguyen[8] and Guntreddi[9] group independently de-
veloped S8-catalyzed cyclization of 2-aminophenols/thiophe-
nols with benzylamines or arylacetic acid (Scheme 1d). Even
so, to explore a new protocol for the synthesis of 2-substituted
benzazoles from simple and readily available starting materials
is highly urgent. As a continuation of our interest in sulfur-
mediated reactions,[10] we disclose a simple and efficient ap-
proach to benzazoles by S8-mediated cyclization of 2-amino-
phenols/thiophenols with arylmethyl chlorides under metal-
free conditions (Scheme 1e).
Element sulfur is readily available, nontoxic, stable under
normal conditions, and exists in numerous oxidation states,
[a] Dr. H. Gan, D. Miao, Q. Pan, R. Hu, X. Li, Prof. Dr. S. Han
College of Biotechnology and Pharmaceutical Engineering
Nanjing Tech University
Nanjing, Jiangsu, 211816 (P. R. China)
Fax: (+86)25-58139369
E-mail: hanshiqing@njtech.edu.cn
We initiated our investigation by using 2-aminothiophenol
(1a) with benzyl chloride (2a) as model substrates (Table 1).
Different parameters were screened. The use of inorganic
bases, such as NaHCO3, Na2CO3, and K2CO3, in DMSO gave less
product (entries 1–3), and other organic bases, such as trime-
thylamine (TEA), N-methylmorpholine, and N-methylpiperidine,
also performed poorly (entries 4–6). Then, we used pyridine as
[b] Prof. Dr. S. Han
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry, CAS
Shanghai, 200032 (P. R. China)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600355.
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donor, was obtained in 90% yield. 3,4-Dimethoxylbenzyl chlo-
ride gave the desired product 3av in good yield. Furthermore,
we have explored different substituted aminothiophenol 1b–
1e and found that they were tolerated in the present reaction
conditions. Methylbenzothiazole 3be, a precursor of an imag-
ing agent for amyloid plaques in Alzheimer disease,[1c] was ob-
tained in 81% yield, and fluorinated benzothiazole 3ew (PMX
610), which has a potent and selective inhibitory activity
against lung, colon, and breast cancer cell lines,[11] was ob-
tained in 54% yield. Both 3be and 3ew could be obtained in
a single step from commercially available starting materials. To
explore the efficiency of our reaction, a gram-scale experiment
was also carried out. 3af could still be achieved at 5 mmol
scale in 80% isolated yield (1.16 g).
Table 1. Optimization of conditions.[a]
Entry
Base
Solvent
T [8C]
Yield [%][b]
1
2
3
4
NaHCO3 (3 equiv)
Na2CO3 (3 equiv)
K2CO3 (3 equiv)
TEA
DMSO
DMSO
DMSO
–
130
130
130
130
130
130
130
150
110
130
130
130
130
130
130
130
130
130
84
69
41
31
79
75
92
92
5
NMM
–
6
7
8
N-methyl piperidine
Pyridine
Pyridine
–
–
–
9
Pyridine
–
35
10
11
12
13
14
15
16
17
18
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
K2S
Na2S2O3
–
–
–
–
–
–
92[c]
81[d]
85[e]
90[f]
92[g]
43[h]
74
To further establish the general utility of these transforma-
tions, 2-aminothiophenol was replaced with 2-aminophenol for
the synthesis of benzoxazoles (Table 3). To our delight, 2-phe-
nylbenzoxazole (5aa) was obtained in 56% isolated yield
under the standard conditions. Benzyl chlorides with an elec-
tron-donating group in the para-position afforded 5ab–5ad,
and 5ai in moderate to good yields, whereas halogen-substi-
tuted benzyl chlorides (2e–2g) offered relatively low yield
(5ae–5ag). Benzyl chlorides with meta-position substituents,
such as methyl group (2j), methoxy group (2k), and halogens
group (2e–2g), provided 5aj–5an in 54–60% yields. Moderate
electron-withdrawing substituents at the para-position (2h)
gave 5ah in 52% yield. Besides, different substituted amino-
phenols 4b–4e were tolerated in the present reaction condi-
tions. 5-Methyl-2-aminophenol (4b) afforded 5ba in 75% yield,
whereas 4-methyl-2-aminophenol (4c) afforded 5ca in 51%
yield. Halogen-substituted aminophenols 4d and 4e provided
5da and 5ea, respectively, in moderate yields.
In order to gain an opinion on the reaction mechanism, we
conducted some control experiments as following: Treatment
of 1a or 4a with 2a in pyridine (2 mL) at 1308C for 20 h did
not give the desired product 3aa or 5aa (Scheme 2). Element
sulfur with 4a in pyridine (2 mL) at 1308C for 20 h provided tri-
sulfide 6, which was confirmed by crystal X-ray crystallogra-
phy[12] (Figure 1), in 75% isolated yield and was subsequently
subjected to the standard conditions to afford 3aa in 89% iso-
lated yield. Furthermore, 2a was reacted with pyridine (2 mL)
at 1308C for 4 h, and then 4a was added and reacted for an-
other 20 h to afford intermediate I in 56% isolated yield. Final-
Pyridine
Pyridine
Pyridine
14
trace
Na2SO3
[a] Conditions: 1a (1.0 mmol), 2a (1.2 mmol), sulfur (3.0 mmol), solvent
(2.0 mL), 1308C, 20 h under nitrogen atmosphere. [b] Isolated yield.
[c] BnCl (1.5 mmol). [d] BnCl (1.0 mmol). [e] Sulfur (2.0 mmol). [f] Sulfur
(4.0 mmol). [g] BnBr (1.2 mmol). [h] Under air atmosphere. NMM=N-
methylmorpholine. Bn=benzyl chloride
base and solvent to explore the reaction. To our delight, the
product was obtained in 92% yield at 1308C for 20 h (entry 7).
Increasing the reaction temperature to 1508C did not enhance
the yield of the product (entry 8), whereas decreasing the tem-
perature to 1108C decreased the yield dramatically (entry 9).
Furthermore, changing the equivalent of BnCl and sulfur did
not improve the reaction (entries 10–13). In addition, replacing
BnCl with BnBr performed equally (entry 14). Conducting the
reaction under air restrained the result (entry 15). Finally, differ-
ent sulfurating reagents, such as K2S, Na2S2O3, and Na2SO3,
gave less product too (entries 16–18). The optimal reaction
conditions were obtained with 2-aminothiophenol (1.0 equiv),
BnCl (1.2 equiv), and element sulfur (3.0 equiv) in pyridine
(2 mL) at 1308C for 20 h.
With the optimized conditions in hand, the scope and versa-
tility of substituted benzyl chlorides and 2-aminothiophenols
was then examined. The results are summarized in
Table 2. Benzyl chlorides possessing electron-donat-
ing or weak to moderate electron-withdrawing
groups on the aromatic rings gave the desired prod-
ucts 3ab–3ao in 84–96% yields. Notably, the posi-
tion of the substituents on aromatic rings of benzyl
chlorides had little effect (3ab–3ao), with only o-sub-
stitution giving slightly inferior yields to m- and p-
substitution (3ak, 3ap), probably as a result of steric
hindrance. Besides, 1-naphthylmethyl chloride react-
ed well to give 3aq in 73% yield. Heteroaromatic
methyl chlorides also worked well under the standard
conditions and offered 3ar–3au in moderate to
good isolated yield, especially 3as, a dinitrogen Scheme 2. Control experiments.
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6 because of its propensity to form polysulfur chain.
Meanwhile, 2a can easily react with pyridine to give
1-benzylpyridinium chloride 7. Then, trisulfide 6 can
oxidize 7 to afford disulfide 8 and thiobenzaldehyde
9, which undergoes a nucleophilic addition/elimina-
tion reaction to give intermediate 10 followed by an
intramolecular cyclization to afford 11. Finally, dehy-
drogenation of 11 forms the desired product 3aa.[14]
Indeed, when 1a was mixed with elemental sulfur,
evolution of H2S was observed even at room temper-
ature. Compound 4a is alkylated with 1-benzylpyridi-
nium chloride 7 to generate intermediate I, which is
oxidized by elemental sulfur to give thioamide II fol-
lowed by the cyclization to afford the desired prod-
uct 5aa. Related data are showed in the Supporting
Information. Notably, the hydroxy group in 4a ren-
ders the o-amino group less nucleophilic, and thus
less effective for the trans-thioamidation step, which
results in lower yield of benzoxazole 5aa compared
to its thio analogues (3aa).
Table 2. Substrate scope I.[a,b]
In summary, a metal-free approach to benzazoles
from arylmethyl chlorides and 2-mercaptan/2-hydrox-
yanilines using elemental sulfur as a traceless oxidiz-
ing agent has been developed. The reactions pro-
ceeded in good to excellent yields, exhibiting good
functional groups tolerance and gram-scale ability.
Primary mechanistic investigations indicated that the
key intermediate trisulfide 6, which was characterized
by NMR, HRMS, and crystal X-ray crystallography, was
separated in the reaction prior to the formation of
the product. The reaction is free from the use of
metal and external oxidant, which makes the process
attractive and practical. A research on the scope, de-
tailed reaction mechanism, extension to other hetero-
aromatic substrates of this protocol is currently un-
derway in our laboratory.
Experimental Section
Typical procedure for the synthesis of benzazoles
[a] Conditions: 1a (1.0 mmol), 2a (1.2 mmol), sulfur (3.0 mmol), solvent (2.0 mL),
1308C, 20 h under nitrogen atmosphere. [b] Isolated yield. [c] The starting material are
4-(chloromethyl)pyridine hydrochloride and 2-(chloromethyl)pyridine hydrochloride,
respectively.
A mixture of 2-aminothiophenol 1a (1.0 mmol), benzyl
chloride 2a (1.2 mmol), elemental sulfur (3.0 mmol), and
pyridine (2 mL) was placed in a sealed pressure vessel
(25 mL) containing a magnetic stirring bar and then
capped and stirred at 1308C for 20 h under nitrogen at-
mosphere. After the reaction was completed (TLC), the mixture
was cooled to room temperature, diluted with methanol (2 mL)
and ethyl acetate (10 mL), evaporated in vacuum and purified by
silica gel column chromatography using petroleum ether and ethyl
acetate as eluent (200:1) to afford the related product 3aa as
a light yellow solid (194 mg, 92% yield).
ly, intermediate I was treated with sulfur in pyridine (2 mL) at
1308C for 20 h to provide 5aa in 61% yield.
Based on the above experiments and related literatures,[8,13]
a plausible mechanism is outlined in Scheme 3. In the presence
of elemental sulfur and a base, 1a is oxidized to form trisulfide
Acknowledgements
We are grateful to the National High Technology Research and
Development Program of China (No. 2012AA02A701 and
2013AA031901) for their financial support.
Figure 1. X-ray crystallography of 6. The probability of atoms is 50%.
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Scheme 3. Proposed mechanisms.
Table 3. Substrate scope II.[a,b]
16, 2430–2440; c) K. Serdons, C. Terwinghe, P. Vermaelen,
K. Van Laere, H. Kung, L. Mortelmans, G. Bormans, A. Ver-
bruggen, J. Med. Chem. 2009, 52, 1428–1437; d) M. M. M.
Raposo, M. C. R. Castro, M. Belsley, A. M. C. Fonseca, Dyes
Pigm. 2011, 91, 454–465; e) A. Banerjee, S. K. Santra, S.
Guin, S. K. Rout, B. K. Patel, Eur. J. Org. Chem. 2013, 1367–
1376; f) Q. Ding, C. Ye, S. Pu, B. Cao, Tetrahedron 2014, 70,
409–416; g) M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr.
Top. Med. Chem. 2016, 16, 1200–1216.
[2] a) T. Hisano, M. Ichikawa, K. Tsumoto, M. Tasaki, Chem.
Pharm. Bull. 1982, 30, 2996; b) I. H. Leaver, B. Milligan, Dyes
Pigm. 1984, 5, 109–144; c) M. R. Deluca, S. M. Kerwin, Tetra-
hedron Lett. 1997, 38, 199–202; d) Y. Sato, M. Yamada, S.
Yoshida, T. Soneda, M. Ishikawa, T. Nizato, K. Suzuki, F.
Konno, J. Med. Chem. 1998, 41, 3015–3021; e) S. Sato, T.
Kajiura, M. Noguchi, K. Takehana, T. Kobayashi, T. Tsuji, J.
Antibiot. 2001, 54, 102–104; f) M. L. McKee, S. M. Kerwin,
Bioorg. Med. Chem. 2008, 16, 1775–1783; g) S. M. Johnson,
S. Connelly, I. A. Wilson, J. W. Kelly, J. Med. Chem. 2008, 51,
260–270; h) J. Boyer, E. Arnoult, M. Mdebielle, J. Guille-
mont, J. Unge, D. Jochmans, J. Med. Chem. 2011, 54, 7974–
7985.
[3] a) H. Sharma, N. Singh, D. O. Jang, Green Chem. 2014, 16,
4922–4930; b) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y.
Lan, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 502–506;
Angew. Chem. 2014, 126, 512–516.
[4] a) P. Saha, T. Ramana, N. Purkait, A. M. Ashif, R. Paul, T. Pun-
niyamurthy, J. Org. Chem. 2009, 74, 8719–8725; b) D. Yang,
H. Fu, L. Hu, Y. Jiang, Y. Zhao, J. Org. Chem. 2008, 73,
7841–7844; c) J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X.
Wang, Y. Wang, C. Chen, J. Org. Chem. 2011, 76, 716–719;
d) T. Itoh, T. Mase, Org. Lett. 2007, 9, 3687–3689; e) D. Ma,
S. Xie, P. Xue, X. Zhang, J. Dong, Y. Jiang, Angew. Chem. Int.
Ed. 2009, 48, 4222–4225; Angew. Chem. 2009, 121, 4286–
4289.
[a] Conditions: 4a (1.0 mmol), 2a (1.2 mmol), sulfur (3.0 mmol), solvent (2.0 mL),
1308C, 20 h under nitrogen atmosphere. [b] Isolated yield.
[5] Q. Song, Q. Feng, M. Zhou, Org. Lett. 2013, 15, 5990–5993.
[6] H. Liu, X. Jiang, Chem. Asian J. 2013, 8, 2546–2563.
[7] For selective examples, see: a) Y. Huang, X. He, X. Lin, M. Rong, Z.
Weng, Org. Lett. 2014, 16, 3284–3287; b) T. B. Nguyen, L. Ermolenko, A.
Al-Mourabit, J. Am. Chem. Soc. 2013, 135, 118–121; c) T. B. Nguyen, L.
Ermolenko, A. Al-Mourabit, Org. Lett. 2013, 15, 5238–5241; d) R. Vanjari,
T. Guntreddi, S. Kumar, K. N. Singh, Chem. Commun. 2015, 51, 366–369;
Keywords: arylmethyl
benzoxazoles · cyclization · sulfur
chlorides
·
benzothiazoles
·
[1] a) W. S. Saari, J. M. Hoffman, J. S. Wai, T. E. Fisher, C. S. Rooney, A. M.
Smith, C. M. Thomas, M. E. Goldman, J. A. O’Brien, J. Med. Chem. 1991,
34, 2922–2925; b) A. A. Weekes, A. D. Westwell, Curr. Med. Chem. 2009,
Chem. Asian J. 2016, 11, 1770 – 1774
www.chemasianj.org
1773
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
e) T. B. Nguyen, M. Q. Tran, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2014,
16, 310–313; f) T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit,
Angew. Chem. Int. Ed. 2014, 53, 13808–13812; Angew. Chem. 2014, 126,
14028–14032; g) T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett. 2015, 17,
976–978.
[12] CCDC 1450794 (6) contain the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[13] a) T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2012, 14, 4274–
4277; b) I. S. Young, A. Ortiz, J. R. Sawyer, D. A. Conlon, F. G. Buono, S. W.
Leung, J. L. Burt, E. W. Sortore, Org. Process Res. Dev. 2012, 16, 1558–
1565; c) M. Scheunemann, L. Hennig, U. Funke, J. Steinbach, Tetrahedron
2011, 67, 3448–3456.
[8] T. B. Nguyen, L. Ermolenko, W. A. Dean, A. Al-Mourabit, Org. Lett. 2012,
14, 5948–5951.
[9] T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett. 2014, 16, 3624–3627.
[10] Y. Tong, Q. Pan, Z. Jiang, D. Miao, X. Shi, S. Han, Tetrahedron Lett. 2014,
55, 5499–5503.
[14] a) R. C. Tweit, J. Heterocycl. Chem. 1970, 7, 687–688; b) H. Deng, Z. Li, F.
Ke, X. Zhou, Chem. Eur. J. 2012, 18, 4840–4843.
[11] a) C. G. Mortimer, G. Wells, J.-P. Crochard, E. L. Stone, T. D. Bradshaw,
M. F. G. Stevens, A. D. Westwell, J. Med. Chem. 2006, 49, 179–185; b) S.
Aiello, G. Wells, E. L. Stone, H. Kadri, R. Bazzi, D. R. Bell, M. F. G. Stevens,
C. S. Matthews, T. D. Bradshaw, A. D. Westwell, J. Med. Chem. 2008, 51,
5135–5139.
Manuscript received: March 17, 2016
Revised: April 12, 2016
Accepted Article published: April 28, 2016
Final Article published: May 24, 2016
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