Cu-catalyzed efficient synthetic methodology for ebselen and related se-N heterocycles

Article abstract of DOI:10.1021/ol102027j

An efficient copper-catalyzed method for the synthesis of biologically important ebselen and related analogues containing a Se-N bond has been developed. This is the first report of a catalytic process of selenation and Se-N bond formation reaction. Copper-catalyzed reaction tolerates functional groups such as amides, hydroxyls, ethers, nitro, fluorides, and chlorides. The best results are obtained by using a combination of potassium carbonate as a base, iodo- or bromo-arylamide substrates, selenium powder, and copper iodide catalyst.

Full text of DOI:10.1021/ol102027j

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5394-5397
Cu-Catalyzed Efficient Synthetic
Methodology for Ebselen and Related
Se-N Heterocycles
Shah Jaimin Balkrishna, Bhagat Singh Bhakuni, Deepak Chopra, and
Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal
(IISER), Bhopal, MP 462 023, India
sangitkumar@iiserbhopal.ac.in
Received August 26, 2010
ABSTRACT
An efficient copper-catalyzed method for the synthesis of biologically important ebselen and related analogues containing a Se-N bond has
been developed. This is the first report of a catalytic process of selenation and Se-N bond formation reaction. Copper-catalyzed reaction
tolerates functional groups such as amides, hydroxyls, ethers, nitro, fluorides, and chlorides. The best results are obtained by using a combination
of potassium carbonate as a base, iodo- or bromo-arylamide substrates, selenium powder, and copper iodide catalyst.
Ebselen (1, 2-phenyl-1,2-benzisoselenazol-3(2H)-one) and
related analogues comprising a Se-N bond have attracted
considerable interest in biology and chemistry in view of
their promising antioxidant function.1-3 Indeed, ebselen is
the first known selenium compound with minimal toxicity
and is in clinical studies for the treatment of inflammatory
diseases and strokes.3b,4 Ebselen and its analogues have also
been used as oxygen transfer catalysts for the synthesis of
organic molecules.5
Despite the clear biological importance, the synthesis of
selenazolones is challenging and mainly relies on two methods:
ortho-lithiation of benzanilide6 and a multistep route which
depends on bis(ortho-benzoic acid) diselenide (Scheme 1, eqs
1 and 2).7 Other synthetic methods for the synthesis of Se-N
heterocycles have also been reported; however, most of them
depend upon their respective diorgano diselenide multistep route
or selenium reagents such as SeBr2 and KSeCN.8,9
In spite of many reported methods on Se-N heterocycles,
the construction of a Se-N bond is an intriguing step.
(1) (a) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. ReV. 2001, 101,
2125, and references therein. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T.
Chem. ReV. 2004, 104, 6255. (c) Sharma, B. K.; Mugesh, G. J. Am. Chem.
Soc. 2005, 127, 11477. (d) Bhabak, K. P.; Mugesh, G. Chem.sEur. J. 2007,
13, 4594. (e) Sharma, B. K.; Mugesh, G. Chem.sEur. J. 2008, 14, 10603.
(f) Bhabak, K. P.; Mugesh, G. Chem. Asian J. 2009, 4, 974. (g) Sharma,
B. K.; Manna, D.; Minoura, M.; Mugesh, G. J. Am. Chem. Soc. 2010, 132,
5364. (h) Bhabak, K. P.; Mugesh, G. Acc. Chem. Res. 2010, DOI: 10.1021/
(4) (a) Muller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem. Pharmacol.
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9, 607.
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H. Eur. J. Org. Chem. 2003, 4329. (b) Freudendahl, D. M.; Santoro, S.;
Shahzad, S. A.; Santi, C.; Wirth, T. Angew. Chem., Int. Ed. 2009, 48, 8409.
(6) Engman, L.; Hallberg, A. J. Org. Chem. 1989, 54, 2964.
(7) European Patent EP 44453. Klaymann, D. L.; Griffin, T. S. J. Am.
Chem. Soc. 1973, 95, 197. Lesser, R.; Wesiss, R. Ber. 1924, 57, 1077.
(8) (a) Fong, M. C.; Schiesser, C. H. Tetrahedron Lett. 1995, 36, 7329.
ar100059g
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(2) (a) Reich, H. J.; Jasperse, C. P. J. Am. Chem. Soc. 1987, 109, 5549.
(b) Back, T. G.; Dyck, B. P. J. Am. Chem. Soc. 1997, 119, 2079. (c) Jacob,
C.; Giles, G. I.; Giles, N. M.; Sies, H. Angew. Chem., Int. Ed. 2003, 42,
4742
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(b) Fong, M. C.; Schiesser, C. H. J. Org. Chem. 1997, 62, 3103.
(3) (a) Glass, R. S.; Farooqui, F.; Sabahi, M.; Ehler, K. W. J. Org. Chem.
1989, 54, 1092. (b) Zhao, R.; Masayasu, H.; Holmgren, A. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 8579. (c) Terentis, A. C.; Freewan, M.; Plaza, T. S. S.;
(9) (a) Erdelmeier, I.; Tailhan-Lomont, C.; Yadan, J.-C. J. Org. Chem.
2000, 65, 8152. (b) Zade, S. S.; Panda, S.; Tripathi, S. K.; Singh, H. B.;
Wolmersha¨user, G. Eur. J. Org. Chem. 2004, 3857. (c) Zade, S. S.; Panda,
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10.1021/ol102027j  2010 American Chemical Society
Published on Web 11/05/2010

Scheme 1
.
Synthetic Routes to Ebselen and Related
Selenazolones
Table 2. Cu-Catalyzed Synthesis of Se-N Heterocycles from
Halo Aryl Amides by Following Equation 3
Furthermore, to the best of our knowledge, there is no
catalytic method available for the synthesis of ebselen and
related selenazolones.
In recent times, transition-metal-catalyzed coupling has
become an important method for the formation of aromatic
carbon-heteroatom bonds. Among this class of reactions,
Cu- and Pd-catalyzed syntheses of organosulfur and -sele-
nium compounds have been explored.10,11 Herein, for the
first time, we report a general, efficient, and catalytic
approach for the synthesis of biologically important Se-N
heterocycles from halo-amides and selenium powder in the
presence of a base (eq 3).
Reaction conditions for the Cu-catalyzed synthesis of
Se-N heterocycles were optimized with 2-iodo-N-phenyl-
benzamide. After extensive screening, the high yield of
product was obtained when iodo-amide was treated with 20
mol % of CuI and 1,10-phenanthroline and selenium powder
in the presence of K2CO3 in DMF (eq 3, Table 1). The Cu-
a Isolated yield obtained from iodo-amide substrates using 20 mol %
of CuI/L and 1.5 equiv of K2CO3 unless otherwise stated. b Yield at 74
mmol scale. c Yields obtained from Ar-Br substrates. d Yields obtained
from Ar-Cl substrates. e 25 mol % of CuI/L, K2CO3 (3 equiv) used.
Table 1. Cu-Catalyzed Formation of 1: Survey of Reaction
Conditionsa
entry
CuI/L, base
solvent temp (°C) time (h)
yield
(2-5) were synthesized in excellent yields. Heterocycles 1
and 2 were also obtained from respective bromo substrates
in nearly the same yield, although, reaction time was longer
than for the iodo substrates (see Supporting Information,
pages S3-S5).
1
2
3
4
5
6
7
CuI/L, K2CO3 THF
CuI/L, K2CO3 DMSO
CuI/L, K2CO3 DMF
CuI/L, K2CO3 DMF
110
110
110
r.t.
110
110
110
12
12
8
24
24
12
48
traceb
none
84%
traceb
40%c
None
traceb
CuI/L, Et3N
CuI/L
DMF
DMF
DMF
d
K2CO3
(10) See references on organosulfur and selenium coupling reactions:
(a) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 6904. (b) Taniguchi,
N. J. Org. Chem. 2006, 71, 7874. (c) Taniguchi, N. Synlett 2006, 1351. (d)
Taniguchi, N. J. Org. Chem. 2007, 72, 1241. (e) Taniguchi, N. Synlett 2007,
1917. (f) Taniguchi, N. Synlett 2008, 849. (g) Taniguchi, N. Tetrahedron
2009, 65, 2782. (h) Alvaro, E.; Hartwig, J. F. J. Am. Chem. Soc. 2009,
131, 7858. (i) Ferna´ndez-Rodr´ıguez, M. A.; Hartwig, J. F. J. Org. Chem.
2009, 74, 1663. (j) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D.
Org. Lett. 2009, 11, 5250. (k) Taniguchi, N. Eur. J. Org. Chem. 2010, 2670.
(11) See references on organosulfur and selenium coupling reactions:
(a) Zhao, X.; Yu, Z.; Yan, S.; Wu, S.; Liu, R.; He, W.; Wang, L. J. Org.
Chem. 2005, 70, 7338. (b) Kumar, S.; Engman, L. J. Org. Chem. 2006, 71,
5400. (c) Braga, A. L.; Barcellos, T.; Paixaˇo, M. W.; Deobald, A. M.; Godoi,
M.; Stefani, H. A.; Cella, R.; Sharma, A. Organometallics 2008, 27, 4009.
(d) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009,
11, 951. (e) Singh, D.; Deobald, A. M.; Camargo, L. R. S.; Tabarelli, G.;
Rodrigues, O. E. D.; Braga, A. L. Org. Lett. 2010, 12, 3288.
a 20 mol % of Cul/1,10-phenanthroline (L) and 1.5 equiv of base used
unless otherwise indicated. b Monitored by TLC. c Isolated yield and 27%
of substrate recovered. d 5 equiv of K2CO3 used.
catalyzed reaction was applied to the synthesis of a series
of Se-N heterocycles (1-28) which were obtained in
moderate to excellent yields (Table 2). Ebselen 1 was
obtained in 84% yield from 2-iodo-amide. On performing
the same reaction at 74 mmol scale, the yield is comparable
with 3 mmol (84 vs 80%, entry 1). Following the same
strategy, N-alkyl, N-benzyl-substituted Se-N heterocycles
Org. Lett., Vol. 12, No. 23, 2010
5395

Interestingly, 2-iodo-benzamide having an additional acidic
proton is compatible with this reaction (entry 6). Similarly,
halo aryl amides with unprotected aliphatic hydroxyl or an
additional -C(O)NHR group coupled to form Se-N het-
erocycles (entries 7-8 and 17-20). Furthermore, activated
chloro amides (entries 9-12 and 23-25) quantitatively
undergo coupling reaction to form Se-N heterocycles. In
an earlier reported method, depicting the synthesis of nitro-
substituted ebselen 9 has proven to be difficult. The obtained
yield is 17% by the reaction of 2-bromo-3-nitrobenzoic acid
with MeSeH followed by subsequent treatment with bro-
mine.12 The present catalytic method is a single-pot reaction
by which a series of nitro-substituted ebselen analogues
(9-12) were synthesized in high yield (77-90%) from
chloro substrates. After exploiting activated chloro substrates
in Se-N coupling reaction, we attempted to use chloro
substrates to synthesize ebselen 1 (entry 1). Indeed, the
reaction gave ebselen; however, the reaction was sluggish,
and 1 was obtained in 47% yield. Substrates with fluoro,
chloro, bromo, ester, methoxy, and methyl functionality were
amenable to the Cu-catalyzed reaction. It is noteworthy that
the Se-N coupling reaction is invariant to the presence of
electron-donating (entries 13 and 21) or -withdrawing (entries
9-12, 14, 15, and 22-25) substituents on both aromatic
rings. Moreover, for the corresponding dibromo substrate
bearing an N-(4-bromo)phenyl ring (entry 14), the Se-N
coupling reaction occurred regioselectively to give hetero-
cycles 14.
Scheme 2
.
Conversion of Se-N Heterocycles to Unsymmetrical
Aryl Selenides and Diaryl Diselenides
As depicted in Scheme 2, we studied the utility of Se-N
heterocycles for the preparation of synthetically important
unsymmetrical diaryl selenides and diaryl diselenides. Ad-
dition of Grignard reagent15 to 5 furnished 29 and 30, and
similarly, reduction and oxidation of 2 and 5 by NaBH4 and
air, respectively, afforded diselenides 31 and 32 quantita-
tively.
To understand the catalytic cycle of Se-N coupling, the
following reactions were investigated: (a) in the absence of
K2CO3; (b) in the absence of CuI/1,10-phenanthroline. None
of the reactions yielded Se-N heterocycle 1. Also 100 mol
% of CuI/ligand in the absence of K2CO3 failed to produce
1 under optimized conditions. However, when the reaction
was heated longer (48 h) in the presence of excess K2CO3,
traces of 1 were observed. In light of these experiments and
reported copper-amide complexes,16 it is reasonable to
assume that this is a base-promoted reaction in which
Cu-amide complex formation would take place followed
by insertion of selenium into the Cu-N bond and finally
reductive elimination of CuILn leading to the formation of
the Se-C bond (Scheme 3).
Synthesis of bis Se-N heterocycle 16 bearing two ebselen
moieties has proven to be problematic and often obtained a
monomer when ortho-(chloroseleno)benzoyl chloride coupled
with 1,6-diamino hexane (eq 2).1d,13 Copper-catalyzed
coupling was successfully extended to the construction of
bis Se-N heterocycle 16.
After obtaining results on benzene-based amides, we
studied the generality of the Cu-catalyzed reaction for other
aromatic substrates: naphthalene-, pyridine-, and thiophene-
amides. As expected, iodo-naphthyl amides were converted
into the corresponding heterocycles 27 and 28 by this
catalytic reaction. However, efforts to synthesize pyridine-
and thiophene-based Se-N heterocycles from easily acces-
sible bromo substrates have been unsuccessful.
Scheme 3
.
Proposed Mechanism for the Se-N Coupling
Reaction
In summary, we have shown that a one-pot Cu-catalyzed
reaction can be applied to synthesize a series of organo Se-N
heterocycles from readily available halo-amides and selenium
powder. Selenazolones with unprotected functional groups
could also be obtained in one pot. Catalytic studies on Se-N
The structure of naphthyl Se-N heterocycle 28 was
established by both spectroscopic and single-crystal X-ray
diffraction techniques (Figure 1).14
(12) Lambert, C.; Christiaens, L. Tetrahedron 1991, 47, 9053.
(13) Osajda, M.; Kloc, K.; Młochowski, J.; Piasecki, E.; Rybka, K. Pol.
J. Chem. 2001, 75, 823.
(14) X-ray quality crystals of 28 were obtained from DCM:hexane (7:
3) solvent mixtures. Crystal data: C18H13NOSe, MW ) 338.25, CCDC
Number: 769448, a ) 12.3938(3) Å, b ) 18.8824(5) Å, c ) 5.9739(2) Å,
V ) 1398.04(1) Å3, Orthorhombic, Pna21, λ ) 0.71073, Mo KR, Z ) 4,
µ ) 2.683, F(000) 679.9; θmin,max ) 2.71, 24.99. No. of unique refls/
parameters: 2459/190; R_obs, wR_obs ) 0.0242, 0.0480; ∆Fmax,min 0.230,
-0.322, GoF 0.887. Selected bond lengths and angles: C-Se, 1.893(3) Å;
Se-N, 1.881(2) Å; CdO, 1.237(3) Å; C(5)-N, 1.356(3) Å; N-Se-C(7),
85.4 (9)°.
Figure 1. ORTEP view of 28 with 50% ellipsoidal probability.
H-atoms are omitted for clarity.
(15) Lisiak, R.; Młochowski, J. Synth. Commun. 2009, 39, 3141.
(16) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 9971.
5396
Org. Lett., Vol. 12, No. 23, 2010

heterocycles and characterization of intermediates involved
in the Se-N coupling reaction are currently in progress in
our laboratory.
Dept., IISc Bangalore), Prof. H. B. Singh and V. P. Singh
(Chemistry Dept., IIT Bombay), Dr. S. Panda (IISER
Kolkata), and Prof. V. K. Singh and P. K. Singh (Chemistry
Dept., IIT Kanpur) for NMR data collection.
Acknowledgment. This study was supported by the
Department of Science and Technology (DST), New Delhi.
S.J.B. and B.S.B. acknowledge IISER Bhopal for the
fellowships. D.C. thanks Dr. S.K. Nayak (SSCU, IISc
Bangalore) for crystal data collection. SK thanks Prof.
Michael R. Detty (Dept. of Chemistry, University at Buffalo)
for help. We thank Prof. G. Mugesh and D. Manna (IPC
Supporting Information Available: Experimental details,
characterization data (NMR and mass) for selected com-
pounds, and CIF file for 28 (CCDC No. 769488). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102027J
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