One-pot preparation of 2-(alkyl)arylbenzoselenazoles from the corresponding N-(acetyl)benzoyl-2-iodoanilines via a microwave-assisted methodology

Article abstract of DOI:10.1016/j.tetlet.2014.07.055

We report here the first example of a one-pot synthesis of 2-(alkyl)arylbenzoselenazoles from N-(acetyl)benzoyl-2-iodoanilines. The reaction was carried out in the presence of Woollins' reagent under microwave irradiation and resulted in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.07.055

Tetrahedron Letters 55 (2014) 5052–5054
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot preparation of 2-(alkyl)arylbenzoselenazoles
from the corresponding N-(acetyl)benzoyl-2-iodoanilines
via a microwave-assisted methodology
⇑
Sébastien Redon, Youssef Kabri, Maxime D. Crozet, Patrice Vanelle
Aix-Marseille Université, UMR CNRS 7273, Institut de Chimie Radicalaire (ICR), Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin,
CS 30064, 13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the first example of
a one-pot synthesis of 2-(alkyl)arylbenzoselenazoles from
Received 13 May 2014
Revised 4 July 2014
Accepted 16 July 2014
Available online 22 July 2014
N-(acetyl)benzoyl-2-iodoanilines. The reaction was carried out in the presence of Woollins’ reagent under
microwave irradiation and resulted in moderate to good yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Woollins’ reagent
Benzoselenazole
Microwave irradiation
Cyclization
The value of the selenium-containing heterocycles has been
demonstrated in medicinal chemistry,1 offering antiviral,2
antihypertensive,3 antifungal,4 and anticancer5 properties. Some
1,3-benzoselenazole derivatives are also useful as precursors of
new materials such as cyanine-type dyes.6 Compared to their
sulfur homologues, selenium compounds exhibit very valuable
antioxidant properties.7 However, synthetic routes remain poorly
explored because of their high cost or low stability in air.
Woollins’ reagent14 (WR) to convert the amides into the corre-
sponding selenoamides. We initially explored the reaction of 1a
with 1.2 equiv of WR under classical heating procedure (reflux of
THF, toluene). Unfortunately, the starting material was entirely
recovered without any trace of the expected product (entries 1
and 2, Table 1). However, this reaction, under reflux of organic base
(pyridine), afforded the 2-methylbenzoselenazole 3a alone with no
trace of selenoamide after 16 h (entry 3). Although the yield was
low, this encouraging result showed that the selenation/cyclization
sequence could be realized under one-pot conditions. With a higher
boiling point solvent (mixture of xylenes), a better though still low
yield was obtained without any trace of intermediate selenoamide
2 (entry 4). With this classical heating procedure, 1a was still pres-
ent after reaction and the yield of 3a remained low, we therefore
investigated whether the selenation/cyclization sequence could
be promoted under microwave irradiation.15 Using pyridine as
the solvent at 160 °C under microwave irradiation, we monitored
the reaction by LCMS. The starting material was completely con-
sumed after 6 h but 2-methylbenzoselenazole 3a was obtained in
moderate yield (entry 5). Variation of the amount of WR (2 equiv)
slightly improved the yield to 41% (entry 6). Next, pyridine was
replaced by NEt3 at the same temperature (160 °C). The reaction
was finished in 3 h and 2-methylbenzoselenazole 3a was obtained
in higher yield (57%) (entry 7). With other base (2 equiv of Cs2CO3 in
xylenes),13 a low yield (<10%) was observed under microwave irra-
diation for 3 h (entry 8). Furthermore, cyclization is less efficient
with other N-acetyl-2-haloanilines with chlorine or bromine atoms.
In continuation of our research program on medicinal chemistry8
we investigate the synthesis of benzoselenazoles as homologues of
benzothiazoles. Among the few existing synthetic routes it should
be notified thecondensation of zinc bis(o-aminoselenoate) withacid
chlorides9a or bis(o-aminophenyl) diselenide with aldehydes pro-
moted by sodium metabisulfite.9b Recently an efficient method
was developed via intermolecular C–Se cross-coupling catalyzed
by transition metal giving 2-aminobenzoselenazole from 2-iodo-
4-methylphenyl)selenourea.10 Sashida improved this method via a
one-pot reaction starting from iodoaniline and isoselenocyanates.11
Kambe reported a copper(I)-catalyzed reaction of 2-bromophenylis-
ocyanide with selenium and heteroatom nucleophiles.12
We focused on an existing benzothiazole synthesis via an intra-
molecular nucleophilic aromatic substitution of o-halo-thiobenza-
nilide (INASOB) promoted by base.13 We used the well-known
⇑
Corresponding author. Tel.: +33 4 9183 5580; fax: +33 4 9179 4677.
E-mail address: patrice.vanelle@univ-amu.fr (P. Vanelle).
http://dx.doi.org/10.1016/j.tetlet.2014.07.055
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Redon et al. / Tetrahedron Letters 55 (2014) 5052–5054
5053
Table 1
One-pot cyclization of N-acetyl-2-haloaniline with Woollins’ reagent
H
N
H
Woollins' reagent
N
N
Solvent
Base
Se
O
Se
X
X
1a-c
2b-c
3a
Entry
X
Compounds
W.R. (equiv)
Conditions
Yielda (%)
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
I
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1.2
1.2
1.2
1.2
1.2
2.0
1.2
1.2
1.2
1.2
THF, 80 °C, 12 h
0
0
Toluene, 110 °C, 16 h
Pyridine, 115 °C, 16 h
Xylenes, 140 °C, 16 h
Pyridine, 160 °C, 6 h
Pyridine, 160 °C, 6 h
NEt3, 160 °C, 3 h
Xylenes, CsCO3 (2 equiv), 3 h
NEt3, 160 °C, 6 h
NEt3, 160 °C, 3 h
<10 (3a)
18 (3a)
27 (3a)
41 (3a)
57 (3a)
<10 (3a)
MW
MW
MW
MW
MW
MW
Br
Cl
35 (2b), 19 (3a)
49 (2c), <10 (3a)
10
a
Isolated yield.
For example, with N-acetyl-2-bromoaniline 1b and N-acetyl-2-
chloroaniline 1c, the reaction gave a mixture of corresponding sele-
noamides 2 and 2-methylbenzoselenazole 3a (entries 9 and 10).
To extend the substrate scope of this one-pot selenation/cycli-
zation, various N-(acetyl)benzoyl-2-iodoanilines were synthe-
sized16 and subjected to the microwave protocol. The results
obtained under the optimized reaction conditions17 are listed in
Table 2 and show that the reaction is efficient with different alkyl,
aryl, and heteroaryl derivatives. Different functional groups includ-
ing electron-withdrawing groups such as chloro and trifluoro-
methyl and electron-donating groups such as methoxy, furan,
thiophene, and pyrrole on the benzoyl moiety showed roughly
the same efficiency. The electron-withdrawing groups such as car-
bonyl,18a cyano,18b amide,18c and sulfone18d on the benzoyl moiety
were not tested because of their well-known good reactivity with
Woollins reagent. The selenation/cyclization process was also
applied with electron-withdrawing groups or electron-donating
groups such as bromo or methoxy in para position of iodo. The cor-
responding yields are similar for the bromo compound 3m (entry
11) and lower for the methoxy compound 3n (entry 12).
work describes for the first time a synthetic pathway in benzosele-
nazole series under microwave irradiation. Under these experimen-
tal conditions, the N-acetylchloro or bromoanilines led to
selenoamide intermediate as the isolated major product and
2-methylselenazole as the isolated minor product. The scope of the
reaction succeeded in moderate to good yields.
Acknowledgments
This work was supported by the CNRS (Centre National de la
Recherche Scientifique) and Aix-Marseille Université. The authors
thank V. Remusat for NMR spectra recording and the Spectropole
team for various analytical measurements.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
07.055.
Insummary, wehavedevelopedanovelmethodofbenzoselenaz-
ole synthesis with Woollins’ reagent under basic conditions and
microwave irradiation via a one-pot reaction from corresponding
N-(acetyl)benzoyl-2-iodoanilines. To the best of our knowledge, this
References and notes
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M.; Jacob, C. J. Med. Chem. 2010, 53, 6954–6963.
Table 2
Scope of the reaction
H
R1
N
R
R1
Woollins' reagent (1.2 equiv), NEt3,
Microwave irradiation, 3 h, 160 °C
N
R
O
Se
I
6. For recent examples: (a) Reis, L. V.; Serrano, J. P. C.; Almeida, P.; Santos, P. F.
Synlett 2002, 1617–1620; (b) Santos, P. F.; Reis, L. V.; Almeida, P.; Oliveira, A. S.;
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Mugesh, G. Chem. Eur. J. 2008, 14, 10603–10614; (d) Bhabak, K. P.; Mugesh, G.
Chem. Asian J. 2009, 4, 974–983; (e) Sharma, B. K.; Manna, D.; Minoura, M.;
Mugesh, G. J. Am. Chem. Soc. 2010, 132, 5364–5374.
8. (a) Crozet, M. P.; Archaimbault, G.; Vanelle, P.; Nouguier, R. Tetrahedron Lett.
1985, 26, 5133–5134; (b) Curti, C.; Laget, M.; Ortiz Carle, A.; Gellis, A.; Vanelle,
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Vanelle, P. Green Chem. 2009, 11, 1736–1742; (d) Verhaeghe, P.; Azas, N.;
Hutter, S.; Castera-Ducros, C.; Laget, M.; Dumetre, A.; Gasquet, M.; Reboul, J.-P.;
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Crozet, M. D.; Botta, C.; Gasquet, M.; Curti, C.; Rémusat, V.; Hutter, S.; Chapelle,
O.; Azas, N.; De Méo, M.; Vanelle, P. Eur. J. Med. Chem. 2009, 44, 653–659.
1
3
Entry Starting material
R
R1
Product Yielda (%0)
1
2
3
4
5
6
7
8
9
1a
1d
1e
1f
1g
1h
1i
1j
1k
1l
–CH3
–CH2CH2C6H5 –H
–C6H5
–H
3a
3d
3e
3f
3g
3h
3i
3j
3k
3l
57
53
59
50
49
48
48
46
45
55
44
21
–H
–H
–H
–H
–H
–H
–H
–H
–Br
–pMeC6H4
–pClC6H4
–pCF3C6H4
–pOMeC6H4
–2-Furanyl
–2-Thienyl
–2-Pyrrolyl
–CH3
10
11
12
1m
1n
3m
–CH3
–OCH3 3n
a
Isolated yield.

5054
S. Redon et al. / Tetrahedron Letters 55 (2014) 5052–5054
9. (a) Bogert, M. T.; Stull, A. J. Am. Chem. Soc. 1927, 49, 2011–2016; (b) Mbuyi, M.;
Evers, M.; Tihange, G.; Luxen, A.; Christiaens, L. Tetrahedron Lett. 1983, 24,
5873–5876; (c) Radatz, S. C.; Alves, D.; Schneider, P. H. Tetrahedron 2013, 69,
1316–1321.
10. Ramana, T.; Punniyamurthy, T. Eur. J. Org. Chem. 2011, 4756–4759.
11. Kaname, M.; Minoura, M.; Sashida, H. Tetrahedron Lett. 2011, 52, 505–508.
12. Fujiwara, S.-I.; Asanuma, Y.; Shin-ike, T.; Kambe, N. J. Org. Chem. 2007, 72,
8087–8090.
J = 32.5 Hz), 128.3, 126.8, 126.2 (q, J = 3.5 Hz), 126.0, 125.4, 125.1, 123.9 (q,
J = 272.6 Hz). LC–MS (ESI+): tR = 4.77 min; m/z [M+H]+: 328.05. HRMS for
C
14H9F3NSe [M+H]+ calcd/found: 327.9847/327.9850.
2-(Furan-2-yl)-1,3-benzoselenazole (3j): White solid (65 mg), yield = 46%, mp
122–124 °C; Rf = 0.46 (ethyl acetate/petroleum ether: 10/90); 1H NMR
(200 MHz, CDCl3, d, ppm) 8.11 (d, J = 8.1, 0.6 Hz, 1H), 7.87 (d, J = 7.8, 0.8 Hz,
1H), 7.62 (d, J = 1.3 Hz, 1H), 7.49 (dd, J = 7.7, 1.2 Hz, 1H), 7.26–7.35 (m, 2), 6.61
(dd, J = 3.5, 1.8 Hz, 1H); 13C NMR (50 MHz, CDCl3, d, ppm) 160.9, 155.1, 151.0,
145.1, 137.4, 126.7, 125.4, 124.9, 124.7, 113.0, 111.4. LC–MS (ESI+):
tR = 3.07 min; m/z [M+H]+: 250.18. HRMS C11H8NOSe [M+H]+ calcd/found:
249.9766/249.9766.
2-(Thiophen-2-yl)-1,3-benzoselenazole (3k): Yellow solid (68 mg), yield = 45%,
mp 107–109 °C; Rf = 0.57 (ethyl acetate/petroleum ether: 10/90); 1H NMR
(200 MHz, CDCl3, d, ppm) 8.07 (dd, J = 8.1 Hz, 1H), 7.87 (dd, J = 7.8 Hz, 1H), 7.60
(d, J = 3.7 Hz, 1H), 7.42–7.52 (m, 2H), 7.24–7.34 (m, 1H), 7.12 (d, J = 5.1, 1.2 Hz,
1H); 13C NMR (50 MHz, CDCl3) d: 164.5, 155.1, 140.1, 137.9, 129.9, 129.8, 128.2,
126.7, 125.5, 124.8, 124.6. LC–MS (ESI+): tR = 3.50 min; m/z [M+H]+: 266.06.
HRMS C11H8NSSe [M+H]+ calcd/found: 265.9537/265.9536.
2-(1H-Pyrrol-2-yl)-1,3-benzoselenazole (3l): White solid (78 mg), yield = 55%;
mp 148–150 °C; Rf = 0.31 (ethyl acetate/petroleum ether: 10/90); 1H NMR
(200 MHz, CDCl3, d, ppm) 10.09 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz,
1H), 7.48 (dt, J = 6.8, 1.1 Hz, 1H), 7.20–7.25 (m, 1H), 7.00–7.05 (m, 1H), 6.80–
6.85 (m, 1H), 6.30–6.35 (m, 1H); 13C NMR (50 MHz, CDCl3, d, ppm) 163.8, 155.0,
136.7, 128.9, 126.5, 124.9, 124.7, 123.3, 122.7, 114.4, 110.9. LC–MS (ESI+):
tR = 3.02 min; m/z [M+H]+: 249.22. HRMS C11H9N2Se [M+H]+ calcd/found:
248.9926/248.9925.
5-Bromo-2-methyl-benzoselenazole (3m): White solid (70 mg), yield = 44%; mp
148–150 °C; Rf = 0.25 (ethyl acetate/petroleum ether: 10/90); 1H NMR
(200 MHz, CDCl3, d, ppm) 8.11 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.39
(dd, J = 8.6, 1.8 Hz, 1H), 2.87 (s, 3H); 13C NMR (50 MHz, CDCl3, d, ppm) 173.6,
155.6, 137.7, 128.0, 126.8, 125.8, 119.7, 23.8. LC–MS (ESI+): tR = 2.96 min; m/z
[M+H]+: 275.92. HRMS C8H7BrNSe [M+H]+ calcd/found: 275.8919/275.8918.
5-Methoxy-2-methyl-benzoselenazole (3n): Orange solid (25 mg), yield = 21%;
mp 88–90 °C; Rf= 0.23 (ethyl acetate/petroleum ether: 10/90); 1H NMR
(200 MHz, CDCl3, d, ppm) 7.68 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 6.92
(dd, J = 9.3, 2.1 Hz, 1H), 3.86 (s, 3H), 2.84 (s, 3H); 13C NMR (50 MHz, CDCl3, d,
ppm) 171.3, 157.0, 128.0, 123.0, 114.5, 112.6, 105.2, 53.7, 27.8. LC–MS (ESI+):
tR = 2.34 min; m/z [M+H]+: 228.19. HRMS C9H10NOSe [M+H]+ calcd/found:
227.9928/227.9923.
13. Bernardi, D.; Ba, L. A.; Kirsch, G. Synlett 2007, 2121–2123.
14. (a) Hua, G.; Woollins, J. D. Angew. Chem., Int. Ed. 2009, 48, 1368–1377; (b)
Madhumita, M.; Sourav, C.; Parasuraman, J. Synlett 2012, 2615–2618.
15. For an example of efficient thionation under microwave irradiation see: Varma,
R. S.; Kumar, D. Org. Lett. 1999, 1, 697–700.
16. The substrates 1 were prepared from the acyl chlorides in toluene.
17. Typical experimental procedure for the synthesis of benzoselenazoles: In a 5 mL
glass vial equipped with a small magnetic stirring bar, the N-(2-iodophenyl)-
acetamide 1a (0.57 mmol, 150 mg), Woollins’ reagent (0.34 mmol, 180 mg,
1.2 equiv) were mixed with dry triethylamine (3 mL) under nitrogen
atmosphere. The vial was tightly sealed with an aluminum/teflon crimp top.
The mixture was then irradiated in a BiotageÒ Initiator microwave reactor for
3 h at 160 °C. After the reaction was complete, the reaction mixture was
evaporated under vacuum. The residue was purified by flash chromatography
on silica gel using petroleum ether/EtOAc (95:5) as the eluent, yielding 3a
(65 mg, 57%). Analysis for compounds 3a, 3e, 3f, and 3i is in agreement with
that reported in the literature.9b,c Data for the new compounds:
2-(2-Phenylethyl)-1,3-benzoselenazole (3d): White solid (87 mg), yield = 53%;
mp 114–116 °C; Rf = 0.35 (ethyl acetate/petroleum ether: 5/95); 1H NMR
(200 MHz, CDCl3, d, ppm) 7.93 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.38 (t,
J = 7.9 Hz, 1H), 7.12–7.27 (m, 6H), 3.39 (t, J = 7.9 Hz, 2H), 3.12 (t, J = 7.9 Hz, 2H);
13C NMR (50 MHz, CDCl3, d, ppm) 174.5, 152.0, 138.0, 136.3, 126.7, 126.6, 124.6,
124.3, 123.2, 123.0, 122.1, 37.2, 33.8. LC–MS (ESI+): tR = 4.02 min; m/z [M+H]+:
288.15. HRMS for C15H14NSe [M+H]+ calcd/found: 288.0291/288.0288.
2-(4-Chlorophenyl)-1,3-benzoselenazole (3g): White solid (82 mg), yield = 49%,
mp 101 °C; Rf = 0.35 (ethyl acetate/petroleum ether: 5/95); 1H NMR (200 MHz,
CDCl3, d, ppm) 8.12 (d, J = 8.1 Hz, 1H), 7.90–8.00 (m, 3H), 7.42–7.55 (m, 3H),
7.33 (dt, J = 7.9, 1.2 Hz, 1H); 13C NMR (50 MHz, CDCl3, d, ppm) 171.2, 155.5,
138.3, 137.3, 134.6, 129.5, 129.3, 126.7, 125.7, 125.0. HRMS for C13H9ClNSe
[M+H]+ calcd/found: 293.9581/293.9584.
2-[4-(Trifluoromethyl)phenyl]-1,3-benzoselenazole (3h): White solid (90 mg),
yield = 48%, mp 143–145 °C; Rf = 0.35 (ethyl acetate/petroleum ether: 5/95);
1H NMR (200 MHz, CDCl3, d, ppm) 8.01–8.06 (m, 3H), 7.95 (d, J = 8.0 Hz, 1H),
7.75 (d, J = 8.4 Hz, 2H), 7.37 (dt, J = 8.2 Hz, 1.2 Hz, 1H), 7.32 (dt, J = 8.0 Hz, 1.2 Hz,
1H); 13C NMR (50 MHz, CDCl3, d, ppm) 170.6, 155.7, 139.3, 138.7, 132.5 (q,
18. (a) Bhattacharyya, P.; Woollins, J. D. Tetrahedron Lett. 2001, 42, 5949–5951; (b)
Hua, G.; Li, Y.; Slawin, A. M. Z.; Woollins, J. D. Org. Lett. 2006, 8, 5251–5254; (c)
Bethke, J.; Karaghiosoff, K.; Wessjohann, L. A. Tetrahedron Lett. 2003, 44, 6911–
6913; (d) Hua, G.; Woollins, J. D. Tetrahedron Lett. 2007, 48, 3677–3679.