Copper catalyzed/mediated synthetic methodology for ebselen and related isoselenazolones

Article abstract of DOI:10.1016/j.tet.2011.09.141

Scope of the copper catalyzed/mediated selenium-nitrogen coupling reaction has been studied for the synthesis of isoselenazolones. It is noticed that the 2-chloro, 2-bromo-, and 2-iodo-aryl amides substrates can be exploited in the selenium-nitrogen coupling reaction by employing 25-100 mol % of CuI/1,10-phenanthroline (L) and potassium carbonate as a base in DMF. Furthermore, electron rich 2-chloro-arylamides also underwent selenium-nitrogen coupling reaction to give biologically important selenium-nitrogen heterocycles. Also, copper-catalyzed selenium-nitrogen coupling reaction has been meticulously applied for the synthesis of diaryl diselenides having methoxy, amine, and amide functionality from respective aryl iodides in the presence of stoichiometric amount of succinimide as an external Se-N coupling partner.

Full text of DOI:10.1016/j.tet.2011.09.141

Tetrahedron 67 (2011) 9565e9575
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper catalyzed/mediated synthetic methodology for ebselen and related
isoselenazolones
*
Shah Jaimin Balkrishna, Bhagat Singh Bhakuni, Sangit Kumar
Department of Chemistry, Indian Institute of Science Education and Research Bhopal (IISER), Bhopal, MP 462 023, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2011
Received in revised form 29 September 2011
Accepted 30 September 2011
Available online 6 October 2011
Scope of the copper catalyzed/mediated selenium-nitrogen coupling reaction has been studied for the
synthesis of isoselenazolones. It is noticed that the 2-chloro, 2-bromo-, and 2-iodo-aryl amides sub-
strates can be exploited in the seleniumenitrogen coupling reaction by employing 25e100 mol % of CuI/
1,10-phenanthroline (L) and potassium carbonate as a base in DMF. Furthermore, electron rich 2-chloro-
arylamides also underwent seleniumenitrogen coupling reaction to give biologically important sele-
niumenitrogen heterocycles. Also, copper-catalyzed seleniumenitrogen coupling reaction has been
meticulously applied for the synthesis of diaryl diselenides having methoxy, amine, and amide func-
tionality from respective aryl iodides in the presence of stoichiometric amount of succinimide as an
external SeeN coupling partner.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
RNH2
Cl
Ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3-(2H)-one, 1)
having SeeN bond exhibits significant antioxidant activity and
therefore is a promising mimic of glutathione peroxidase antioxi-
dant selenoenzyme.1,2 As a result, ebselen is a benchmark com-
pound in many hydroperoxides and organic peroxides
decomposing assays and exhibits a broad spectrum of biological
activities, namely anti-inflammatory, anti-atherosclerotic, and
cytoprotective.3 Hydroperoxides and organic peroxides decom-
posing activity of ebselen and related isoselenazolones has also
been studied as oxygen transfer reagent in many organic reactions.4
In view of its biological applications, particularly hydroperoxides
and organic peroxides decomposing antioxidant activity and min-
imal toxicity, synthesis of several related aryl/alkyl iso-
selenazolones comprising SeeN bond, have been reported.1a,5
Ebselen was first synthesized by Lesser and Weiss in 1924.6 After
that several synthetic routes have been developed to prepare
organoseleniumenitrogen heterocycles.7e16 Literature survey on
the synthetic methods for ebselen and related isoselenazolones, is
depicted in Schemes 1 and 2 (Eqs. 1e8).
(1)
(2)
1
SeCl
SOCl2
O
O
O
NaNO2
HCl, KOH
Na2 Se2
RNH2
NHR
NH2NH2 or
(PhCO2)2
OH
OH
-
1
-
Se)2
NH2
Se)2
NaBH4
Benz-X/
CH3I
O
N
ONa
S
(1) COCl2, (2)
R' = Benz
NHR
SeR'
PCl5, R' = Me
(3)
(4)
1
1
Scheme 1. Synthetic methods for ebselen and related isoselenazolones.
the lengthy nature, this method is commonly used for the con-
struction of ebselen analogues due to its broad substrate scope,
particularly, for the synthesis of ebselen analogues containing
various NdR (R¼alkyl, aryl) substituents.1g,l,8,9 A broad range of
ebselen analogues has been synthesized by this method in which
treatment of ortho-benzoyl chloride selenenyl chloride occurs with
various amines (ammonia, alkyl amines, substituted aryl amines).
Lithiation route, which was developed by Engman et al., is an
expeditious and also widely used method for the construction of
SeeN heterocycles.11e13 In this method, lithiation of benzanilide is
occurred by the use of n-butyllithium, subsequent reaction with
selenium powder, and finally ring closure by copper dibromide
gave ebselen in one pot (Eq. 5). The obtained yield was 63%. Further
Synthesis of ebselen and related isoselenazolones mainly de-
pends on two routes; bis(ortho-benzoic acid) diselenide and ortho-
lithiation of benzanilide. Bis(ortho-benzoic acid) diselenide route is
a conventional method, in which anthranilic acid is converted into
SeeN heterocycle by a series of reactions (Eq. 1, Scheme 1).7 Despite
* Corresponding author. E-mail address: sangitkumar@iiserbhopal.ac.in
(S. Kumar).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.141

9566
S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
Table 1
Optimization of seleniumenitrogen coupling reaction on 2-halo-aryl amide
substrates
Entry Substrates CuI/La
Base
Solvent Time (h) 1b (%) 2b (%)
1
2
3
AreCl
AreCl
AreCl
AreCl
AreI
CuI/L, 20 mol % K2CO3 DMF
CuI/L, 50 mol % K2CO3 DMF
CuI/L, 75 mol % K2CO3 DMF
24c,d
24c,d
24c,d
36c,d
8,c 12d
47
54
55
53
83
83
4
None
CuI/L
CuI/L
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
None None
84
5e
6e
94
91
AreBr
16,c 26d 78
a
CuI/1,10-phenanthroline (L) (20 mol %) was used otherwise noticed.
Isolated yield otherwise mentioned.
Reaction time for N-phenyl substrates.
Reaction time for N-benzyl substrates.
Reaction conditions included for comparison purpose (see Ref. 19).
b
c
d
e
Scheme 2. Reported ortho-lithiation routes for the synthesis of ebselen and related
isoselenazolones.
improvement in the yield was made by employing lithium diiso-
propylamide and n-butyllithium as lithiating reagent and sub-
sequently ebselen was isolated in better yield (76%).12
Having optimization condition on 2-chloro substrates and earlier
optimized condition on bromo and iodo substrates (entries 2, 5, and
6, Table 1) in hand, a series of isoselenazolones 1e15 have been
synthesized from 2-chloro-, 2-bromo-, 2-iodo-arylamide substrates
(entries 1e10, Table 2). Readers are suggested to follow our earlier
Although, other methods for the synthesis of aryl iso-
selenazolones have been reported, these methods depend on either
the bis(ortho-benzoic acid)diselenide route (Eqs. 2e4) or the Eng-
man method (Eqs. 6 and 7).10,14b,15 Despite the several reports on the
construction of ebselen and related analogues, synthesis of SeeN
heterocycles remains challenging. In this regard, of particular in-
terest is the synthesis of substituted ebselen analogues and hetero-
aromatic isoselenazolones. Moreover, catalytic route to synthesize
aryl isoselenazolones has not been described in the literature.
Transition metal catalyzed synthesis of organochalcogens (S, Se,
and Te) are benign methods, which offer several advantages over
the conventional methods, such as broad substrate scope, mild re-
action conditions, and need catalytic amount of reagents to ac-
complish the transformations. As a result of this, in recent time
several groups have explored transition metal catalyzed synthesis of
organochalcogens.17,18 Our research group has described a copper
catalyzed synthesis of ebselen analogues from 2-iodo-, 2-bromo-,
and activated 2-chloro-arylamide substrates in a preliminary com-
munication (Eq. 9).19 In this paper, we present the detail study on
copper-catalyzed SeeN coupling reaction which includes the com-
patibility of non-activated 2-chloro-arylamides and synthesis of
electron rich isoselenazolones. Also Cu-catalyzed SeeN coupling
reaction is applied to the synthesis of diaryl diselenides.
communication for the synthesis of
a diverse series of iso-
selenazolones from respective 2-iodo- and 2-bromo-arylamides.19
Isoselenazolones 1 and 2 were obtained in 54 and 83% yield from
respective chloro substrates (entries 1e3, Table 2). A small amount of
byproduct presumably respective monoselenide was also formed
along with the formation of 1. However, respective monoselenides
were not observed in the case of isoselenazolones 2e15. In our
preliminary study, difficulty was encountered in the purification of
2-bromo-substituted isoselenazolone 6. In this study, iso-
selenazolones substituted with fluoro, chloro, bromo, and methoxy
groups were isolated in pure form by using copper catalyzed cou-
pling reaction at 90 ꢀC (entries 4e6, Table 2). The next set of sub-
strates was electron rich and readily accessible 2-chloro/bromo-
arylamides, which we explored for the SeeN coupling reaction
(entries 8e12, Table 2). It is worth mentioning that despite the
theoretical investigation on the antioxidant activity of methoxy
substituted ebselen analogues and promising hydroperoxides and
organic peroxides decomposing activity of methoxy substituted
diaryl diselenides, synthesis of methoxy substituted iso-
selenazolones has not been well documented.15,20 Moreover, scarce
availability of electron rich 2-bromo- and 2-iodo-aryloic acids made
the synthesis even difficult. 2-Chloro/bromo-3-methoxy-arylamide
substrates gave desired isoselenazolones in 57e76% yield in the
copper-catalyzed SeeN coupling reaction. It follows that SeeN
coupling reaction could not be observed for the electron rich chloro-
aryl substrate in the presence of 20e25 mol % of CuI/L under stan-
dard conditions and substrate was recovered in 87% yield (entry 8,
Table 2). Interestingly, SeeN coupling took place in the electron rich
chloro substrates by employing 50 mol % of CuI/L catalyst. Under the
same conditions, the chloro substrate with two methoxy groups
reacted to give the corresponding isoselenazolone 11. Similarly,
chloro substrate with methylthio functionality was transformed into
isoselenazolone 12. Although isolated yield is moderate to good for
electron rich aryl isoselenazolones 8e12, this could possibly be the
best method to construct electron rich isoselenazolones from readily
available chloro-arylamide substrates.
2. Results and discussion
To achieve the compatibility of 2-chloro-arylamides in the cop-
per-catalyzed SeeN coupling reaction and also as suggested by one
of the reviewers of our preliminary communication, it was of the
interest to study the effect of CuI/1,10-phenanthroline (L) complex
loading versus SeeN product formation in the coupling reaction.
We have hereby chosen two substrates; 2-chloro-N-phenyl- and
2-chloro-N-benzylbenzamide for this purpose. It is evident from
the Table 1 that high CuI/L catalyst loading (20e50 mol %) gave
good yield of SeeN coupled products from chloro substrates. High
CuI/L loading from 50 to 75 mol % produced nearly same yield of
isoselenazolones. Other parameters, such as increase in tempera-
ture from 110 to 150 ꢀC and change in base potassium tert-butoxide
and sodium hydroxide were ineffective for chloro substrates in the
SeeN coupling reaction and mainly lead to side products, despite
the complete consumption of substrates.
For the synthesis of pyridyl isoselenazolones, readily accessible
chloro nicotinamide substrates were under taken for SeeN cou-
pling (entries 13e15, Table 2).

S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
9567
Table 2
Construction of isoselenazolones from 2-halo-arylamides by copper iodide catalyzed/mediated SeeN coupling reaction
Entry
Substrate
Product yield in %
1
1
3
R¼Phenyl, X¼Cl
1 R¼Phenyl (54)a
R¼Benzyl, X¼Cl
R¼n-Butyl, X¼I
2 R¼Benzyl (83)a
3 R¼n-Butyl (72)b
4
5
6
7
X/R¼F
4 X/R¼F (71)b
5 X/R¼Cl (82)b
6 X/R¼Br (93)b
7 X/R¼OMe (86)b
X/R¼Cl
X/R¼Br
X/R¼OMe
8
9
R¼Ph (57)
8 R¼Ph (57)a
R¼Benzyl (67)
9 R¼Benzyl (67)a
10
10 (76)b
11
12
11 (44)a
12 (39)a
13
14
15
R¼Benzyl
13 R¼Benzyl (50)c
14 R¼Cyclohexyl (64)c
15 R¼n-Butyl (55)c
R¼Cyclohexyl
R¼n-Butyl
a
Isolated yield by employing 50 mol % of CuI/1,10-phenanthroline (L) from chloro substrate, otherwise noted.
Yield obtained from 2-bromo-arylamide, and 25 mol % of CuI/L was used.
CuI/L (100 mol %) was used.
b
c

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S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
It is worth mentioning here that construction of pyridyl iso-
Preparation of thiophenyl and alkyl isoselenazolones was un-
successful under optimized conditions developed for electron rich
isoselenazolones and also by using 100 mol % CuI/L. Chloro-
alkylamides gave respective four-membered lactams 19 and 20
quantitatively under optimized reaction conditions instead of alkyl
SeeN heterocycles (Scheme 4). It seems that the formation of
copperesubstrate complex (RNeCuLn) is not feasible in chloro-
alkylamides as we have proposed for the 2-iodo-arylamide sub-
strates. Since formation of lactam 19 was observed without the
addition of CuI/L complex in the presence of K2CO3, it is reasonable
to assume that intramolecular coupling of alkyl carbon and nitro-
selenazolones has proven to be difficult by an earlier reported
method (Scheme 3, see products 16e18).9c Reported synthesis for
pyridyl isoselenazolones, involves 2-chloronicotinoyl chloride as
the precursor, which undergoes multi-step reactions: protection,
selenation, deprotection, chlorination, and amination. Among
these multi-steps, two of them: selenation in which reaction of
dilithium diselenide occurs with tert-butyl 2-chloronicotinate; and
deprotection of bis 2-(tert-butyl nicotinate) diselenide 16 into
bis(nicotinic acid) diselenide 17 require 72
h and 12 days,
respectively.
Scheme 3. Synthetic methods for the construction of pyridyl isoselenazolones.
Chloro-nicotinamide substrates were subjected for SeeN cou-
gen is faster than the formation of RNeCuLn complex and thus may
not facilitate the formation of alkyl isoselenazolones.
pling reaction by using 50 mol % of catalyst as established for the
synthesis of 1e4 from corresponding chloro substrates. However,
SeeN product formation was not observed even after 72 h. By
exploiting stoichiometric amount of copper iodide/1,10-
phenanthroline, pyridyl SeeN heterocycles were obtained in
50e64% yield from readily accessible 2-chloro-nicotinamide sub-
strates. The obtained yield from pyridyl substrates are moderate
and also high loading of CuI/L (100 mol %) complex is required.
Nonetheless, the pyridyl isoselenazolones are obtained from easily
accessible 2-chloro-nicotinamide in one pot and in 22e48 h. The
structure of pyridyl isoselenazolone 13 was established by single
crystal X-ray crystallography in addition to NMR and IR spectral
characterization (Fig. 1).
Next, we were able to study that the copper-catalyzed SeeN
coupling reaction could be used for the synthesis of diaryl dis-
elenides, which are the key precursors in organoselenium chem-
istry, from aryl iodides. For this purpose, we set to use
stoichiometric amount of sec-amide [RC(O)NHR] as an external
SeeN coupling partner in the copper catalyzed reaction (Table 3).
N-Benzyl-, N-butyl-, and N-phenyl-benzamides were studied as
the external SeeN coupling partner for the synthesis of diaryl
diselenides. None of the sec-amides gave satisfactory results under
optimized condition for CuI/L catalyzed SeeN coupling reaction.
The use of succinimide as a SeeN coupling partner provided diaryl
diselenides in moderate to good yield.
A small amount of
Fig. 1. ORTEP view of 13 with 50% ellipsoidal probability.

S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
9569
shown that copper-catalyzed seleniumenitrogen coupling reaction
can be applied not only for 2-iodo- and 2-bromo-arylamides but
also 2-chloro-arylamides substrates. This has been established by
the synthesis of methoxy and methylthio substituted electron rich
phenyl isoselenazolones and pyridyl isoselenazolones from re-
spective 2-chloro-arylamides. It is indeed noteworthy that the
copper-catalyzed SeeN coupling reaction has been constructively
utilized for the synthesis of diaryl diselenides from the respective
aryl iodides.
5. Experimental section
5.1. General experimental details
All NMR experiments were carried out on 400 or 500 MHz
spectrometers in DMSO-d6 or CDCl3 and NMR chemical shifts are
reported in parts per million referenced to the solvent peaks of
CDCl3 (7.26 ppm for 1H and 77.0 (ꢁ0.1) ppm for 13C, respectively) or
DMSO-d6 (2.50 ppm for 1H and 39.50 ppm for 13C, respectively).
High resolution mass spectra (HRMS) are reported for ions of 80Se.
Mass analysis is performed on quadruple-time of flight (Q-TOF)
mass spectrometer equipped with an ESI source (þve). Infrared (IR)
spectra were recorded as a pellet in KBr with an FTIR machine.
Melting points are uncorrected. DMF with sure seal septa, selenium
powder (60 mesh size), copper iodide, and 1,10-phenanthroline
were used as received from Aldrich. Grinded anhydrous K2CO3
powder was used which was grinded using mortar, dried in oven at
160 ꢀC for 6 h and stored in a desiccator. Seleniumenitrogen cou-
pling reactions were carried out under nitrogen atmosphere.
Substituted benzoyl chlorides were prepared from respective
benzoic acids by refluxing with excess of thionyl chloride otherwise
prepared according to reported procedure. Excess of thionyl chlo-
ride was removed under vacuo and resulted residue was used for
amide preparation without further purification. Silica gel
(60e120 mesh size) was used for column chromatography. TLC
analysis of reaction mixtures was performed using silica gel plates.
Scheme 4. Attempted synthesis of thiophenyl and alkyl isoselenazolones.
byproducts presumably respective triselenides was also observed
in the case of diselenides 21e28. It turns out that the succinimide
offers many advantages, such as easy availability, facile hydrolysis
of SeeN bond (vide infra), which in turns facilitate diaryl diselenide
formation, and easy removal of succinimide from reaction mixture.
These features make succinimide a better SeeN external coupling
partner for the synthesis of diaryl diselenides. Copper-catalyzed
SeeN coupling occurred smoothly with aryl iodides, succinimide,
and selenium powder under the optimized conditions as described
for the synthesis of isoselenazolones. Aqueous hydrolysis of the
reaction mixture afforded diaryl diselenides 21e28 from respective
aryl iodides (Table 3). Diaryl diselenides 23e25 having eNH2,
eNHCOR, and eCONR2 functional groups are difficult to access by
conventional methods and either involves protection and depro-
tection strategy and/or require excess of reagents. Diaryl dis-
elenides 23e25 were obtained in 45e84% by this SeeN coupling
reaction using easily available CuI/1,10-phenanthroline catalyst in
the presence of potassium carbonate base under mild reaction
conditions. Also hetero-aryl; thiophenyl and pyridyl diselenides (26
and 27) were accessible by copper catalyzed reaction.
5.1.1. Representative copper-catalyzed SeeN coupling procedure for
the preparation of isoselenazolones; synthesis of ebselen (1). Copper
iodide (82 mg, 0.4 mmol) and 1,10-phenanthroline (78 mg,
0.4 mmol) were added into DMF (3 mL) in a single neck flask.
Resulted brownish solution was stirred for 15 min and then 2-
chloro-N-phenylbenzamide22 (0.20 g, 0.86 mmol), selenium pow-
der (81 mg, 1.0 mmol), and potassium carbonate powder (178 mg,
1.3 mmol) were added sequentially to same reaction flask. Brown
colored reaction mixture was refluxed at 110 ꢀC using refluxing
condenser under nitrogen atmosphere. Progress of reaction was
monitored by TLC. Reaction mixture was refluxed for 24 h. After
this, reaction mixture was poured into brine solution (50 mL) and
stirred for 3 h. Product was precipitated as white solid, which was
collected by filtration over Buchner funnel, washed with water
(15 mLꢂ3), dried in air, dissolved in ethyl acetate, and concentrated
over rotary evaporator. The resulted brown solid was purified by
column chromatography using hexane/ethyl acetate (8:2) over
silica gel. Yield 128 mg (54%). Characterization data (mp, 1H NMR,
Mass, and IR) is in accordance with reported one.19
3. Mechanistic consideration
In the mechanistic considerations, plausible reaction pathway is
depicted in Scheme 5 based on the control experiments, related
reported copper catalyzed amidation of aryl halides, and copper
amide complexes.21 We believe that this is a base promoted re-
action which proceeds by CueN bond formation intermediate. As
the formation of selenazolones was not observed in the absence of
base and in the presence of 100 mol % of catalyst, the base may
facilitates the formation of LnCueN complex intermediate. In-
sertion of selenium in to CueN bond might lead to the NeSeeCuLn
intermediate and this intermediate could react intramolecularly to
ortho halogen and then followed by reductive elimination lead to
form desired SeeN heterocycle and concomitant regeneration
CuLnX catalyst. Although the isolation of proposed NeSeeCuLn
intermediate was unsuccessful, the formation of diaryl diselenides
from aryl iodide in the presence of stoichiometric amount of suc-
cinimide in this copper catalyzed reaction supports the proposed
mechanism.
5.1.2. 2-Benzylbenzo[d][1,2]selenazol-3(2H)-one (2). Synthesis of 2
from 2-chloro-N-benzylbenzamide23 (0.4 g, 1.6 mmol) was carried
out at 1.6 mmol scale using CuI (154 mg, 0.8 mmol), 1,10-
phenanthroline (146 mg, 0.8 mmol), selenium powder (0.15 g,
1.9 mmol), and K2CO3 (0.34 g, 2.46 mmol) in DMF (4 mL). Reaction
mixture was refluxed for 24 h at 110 ꢀC. After this reaction mixture
was poured into brine solution, stirred for 3 h, reaction mixture
together with brine solution (30 mL) extracted with ethyl acetate
(15 mLꢂ4). Ethyl acetate layer washed with water (15 mL), dried
4. Conclusion
In summary, scope of copper-catalyzed SeeN coupling reaction
has been studied with respect 2-halo-aryl/alkylamides. We have

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S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
Table 3
Synthesis of diaryl diselenide from aryl iodide by using CuI/L catalyst and succinimide
Entry
Substrate
Product (% yield)a
1
2
3
4
5
6
7
a
Isolated yield by employing 15e25 mol % of CuI/1,10-phenanthroline (L), 1.2 equiv of Se powder, and 1.5 equiv of K2CO3.

S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
9571
O
I
Dried over Na2SO4 (5 g), concentrated under vacuo, purification by
column chromatography using DCM as an eluent yielded white
crystalline product. Rf (2% DCM/MeOH) 0.5. Yield 2.47 g, 92%, mp
O
I
-HI
NHR
NR
CuLn
139e141 ꢀC, 1H NMR (400 MHz, CDCl3)
d
8.57 (d, J¼8.2 Hz, 1H),
+
K2CO3
7.99e7.96 (m, 2H), 7.58 (d, J¼7.6 Hz, 1H), 7.48 (t, J¼7.5 Hz, 1H), 7.44
(dd, J¼8.1, 1.4 Hz, 1H), 7.37 (t, J¼8.0 Hz, 1H), 7.20 (td, J¼7.6, 1.6 Hz,
1H), 7.14 (td, J¼7.6 Hz, 1.5 Hz, 1H). 13C NMR (100 MHz, CDCl3)
Se
CuILn
d
167.2, 141.8, 140.4, 134.3, 131.8, 129.2, 128.45, 128.41, 127.4, 125.3,
123.3, 121.9, 92.4. IR (plate): 3263, 2920, 2852, 1654, 1581, 1523,
1478, 1438, 1307, 1057, 750 cmꢃ1. HRMS (ESI) m/z 379.9327 (calcd
for C13H9Cl1I1N1O1þNa: 379.9310).
O
I
O
NR
SeCuLn
N
Se
R
5.1.6. 2-(2-Chlorophenyl)benzo[d][1,2]selenazol-3(2H)-one
(5). Compound 5 was prepared at 1.2 mmol scale from 2-iodo-N-
(2-chlorophenyl)benzamide (0.50 g, 1.4 mmol), CuI (66 mg,
0.35 mmol), 1,10-phenanthroline (63 mg, 0.35 mmol), selenium
powder (0.13 g, 1.7 mmol), and K2CO3 (0.29 g, 2.1 mmol) in 5 mL of
DMF. Resulted reaction mixture was refluxed at 90 ꢀC for 14 h and
then poured into brine solution (100 mL) and stirred for 2 h.
Resulted aqueous layer together with brown precipitate was
extracted with ethyl acetate (30 mLꢂ4), organic layer washed with
water (120 mL), dried over Na2SO4, concentrated under vacuo to
obtain brown solid, which was purified by column chromatography
on silica gel using hexane/ethyl acetate (8:2). Rf (20% hexanes/
EtOAc) 0.3. Yield 354 mg (82%), mp 194 ꢀC (decomposed). 1H NMR
Scheme 5. Proposed reaction pathway for the copper-catalyzed SeeN coupling.
over Na2SO4, evaporated on rotary evaporator. The resulted yel-
lowish liquid product was chromatographed over silica gel using
CH2Cl2 and yielded crystalline solid (0.39 g, 83%). Characterization
data (mp, 1H NMR, Mass, and IR) is in accordance with reported
one.19
5.1.3. 2-Butylbenzo[d][1,2]selenazol-3(2H)-one (3). Compound 3 was
prepared from 2-iodo-N-butylbenzamide24 (700 mg, 2.4 mmol) and
selenium powder (220 mg, 2.8 mmol) using CuI (110 mg,
0.58 mmol), 1,10-phenanthroline (104 mg, 0.58 mmol), and K2CO3
(0.48 g, 3.5 mmol) in 5.0 mL of DMF. Resulted reaction mixture was
refluxed at 110 ꢀC for 10 h. Standard workup and column chroma-
tography as mentioned for isoselenazolone 2 yielded white liquid,
which solidified on standing. Yield 423 mg (72%), mp 92 ꢀC (92 ꢀC).10
(400 MHz, DMSO-d6)
1H), 7.71 (m, 1H), 7.63 (m, 1H), 7.53e7.50 (m, 2H), 7.48e7.44 (m,
2H). 13C NMR (100 MHz, DMSO-d6)
166.1, 140.9, 136.7, 133.1, 132.7,
131.6, 130.65, 130.25, 128.56, 128.47, 127.3, 126.6, 126.5. IR (plate):
d
8.11 (d, J¼8.0 Hz, 1H), 7.91 (dd, J¼7.8, 1.5 Hz,
d
2920, 1666, 1585, 1510, 1480, 1431, 1303, 1242, 1026, 748 cmꢃ1
.
HRMS (ESI) m/z 331.9350 (calcd for C13H8Cl1N1O810Se1þNa:
1H NMR (500 MHz, CDCl3)
d
8.04 (d, J¼7.7 Hz, 1H), 7.63 (d, J¼7.9,
331.9355).
1.0 Hz, 1H), 7.57 (dt, J¼7.8, 1.0 Hz, 1H), 7.42 (t, J¼7.7 Hz, 1H), 3.86 (t,
J¼7.2 Hz, 2H), 1.71 (p, J¼7.3 Hz, 2H), 1.42 (sextet, J¼7.3 Hz, 2H), 0.96
5.1.7. 2-(2-Bromophenyl)benzo[d][1,2]selenazol-3(2H)-one
(6)19. Compound 6 was prepared at 1.0 mmol scale from 2-iodo-N-
(2-bromophenyl)benzamide19 (0.40 g, 1.0 mmol), CuI (47 mg,
0.25 mmol), 1,10-phenanthroline (45 mg, 0.25 mmol), selenium
powder (94 mg, 1.2 mmol), and K2CO3 (0.20 g, 1.5 mmol) in 5 mL of
DMF. Resulted reaction mixture was refluxed at 90 ꢀC for 20 h and
then poured into brine solution (100 mL) and stirred for 2 h. Resulted
aqueous layer together with brown precipitate was extracted with
ethyl acetate (25 mLꢂ4), organic layer washed with water (100 mL),
dried over Na2SO4, concentrated under vacuo to obtain brown solid,
which was purified by column chromatography on silica gel using
hexane/ethyl acetate (8:2). Yield 327 mg (93%), 1H NMR (400 MHz,
(t, J¼7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 167.2, 138.1, 131.7, 128.5,
127.7, 126.0, 124.3, 44.4, 32.5, 19.8, 13.6. HRMS (ESI) m/z 256.0249
(calcd for C11H13N1O1 80Se1 þ Hþ: 256.0235).
5.1.4. 2-(2-Fluorophenyl)benzo[d][1,2]selenazol-3(2H)-one
(4). Compound 4 was prepared at 1.2 mmol scale from 2-iodo-N-
(2-fluorophenyl)benzamide25 (0.30 g, 0.9 mmol), CuI (41 mg,
0.22 mmol), 1,10-phenanthroline (40 mg, 0.22 mmol), selenium
powder (83 mg, 1.05 mmol), and K2CO3 (0.18 g, 1.3 mmol) in 5 mL of
DMF. Resulted reaction mixture was refluxed at 90 ꢀC for 16 h and
then poured into brine solution (100 mL) and stirred for 2 h.
Resulted aqueous layer together with brown precipitate was
extracted with ethyl acetate (25 mLꢂ4), organic layer washed with
water (100 mL), dried over Na2SO4, concentrated under vacuo to
obtain brown solid, which was purified by column chromatography
on silica gel using hexane/ethyl acetate (7:3). Rf (30% hexanes/
EtOAc) 0.5. Yield 182 mg (71%), mp 160e161 ꢀC (165e167 ꢀC).7 1H
CDCl3)
d
8.11 (d, J¼8.0 Hz, 1H), 7.71e765 (m, 3H), 7.49e7.47 (m, 2H),
7.40 (t, J¼7.8 Hz, 1H), 7.28 (d, J¼7.8 Hz, 1H). HRMS (ESI) m/z:
353.9032(C13H8Br1N1O1 80Se1þHþ: 353.9033)
5.1.8. 2-(2-Methoxyphenyl)benzo[d][1,2]selenazol-3(2H)-one
(7). Compound 7 was prepared at 0.9 mmol scale from 2-iodo-N-
(2-methoxyphenyl)benzamide26 (0.30 g, 0.85 mmol), CuI (40 mg,
0.20 mmol), 1,10-phenanthroline (38 mg, 0.21 mmol), selenium
powder (80 mg, 1.0 mmol), and K2CO3 (0.18 g, 1.3 mmol) in 4 mL of
DMF. Resulted reaction mixture was refluxed at 90 ꢀC for 18 h and
then poured into brine solution (100 mL) and stirred for 2 h.
Resulted aqueous layer together with brown precipitate was
extracted with ethyl acetate (25 mLꢂ4), organic layer washed with
water (100 mL), dried over Na2SO4, concentrated under vacuo to
obtain brown solid, which was purified by column chromatography
on silica gel using hexane/ethyl acetate (5:5). Rf (50% hexanes/
EtOAc) 0.6. Yield 220 mg (86%), mp 172e174 ꢀC. 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
J¼8.0 Hz, 1H), 7.92 (dd, J¼7.8, 1.0 Hz, 1H), 7.71 (m, 1H), 7.54e7.29(m,
5H). 13C NMR (100 MHz, DMSO-d6)
166.0, 159.4, 156.9, 140.8,
d d 8.11 (d,
1H NMR (400 MHz, DMSO-d6)
d
132.8, 130.7, 130.00, 129.92, 128.4, 127.3, 126.90, 126.77, 126.69,
126.52, 125.41, 125.38, 117.1, 116.9. HRMS (ESI) m/z 315.9649 (calcd
for C13H8F1N1O820Se1þNa: 315.9648).
5.1.5. 2-Iodo-N-(2-chlorophenyl)benzamide (substrate for iso-
selenazolone 5). 2-Chloroaniline (1.15 g, 9.0 mmol) and triethyl
amine (3.1 mL, 22.0 mmol) in DCM (30 mL) was added drop wise to
a cold solution of 2-iodo-benzoyl chloride (2.00 g, 7.5 mmol) in
DCM (40 mL). The resulted reaction mixture was stirred at 0 ꢀC for
1 h and 3 h at room temperature. After this reaction mixture was
poured into water (200 mL) and 50 mL of DCM was added. Organic
layer was separated, washed with 10% (v/v) aqueous HCl solution.
DMSO-d6)
d
8.08 (d, J¼8.0 Hz, 1H), 7.88 (dd, J¼7.8, 1.0 Hz, 1H), 7.67
(m, 1H), 7.47 (t, J¼7.6 Hz, 1H), 7.40e7.35 (m, 2H), 7.16 (d, J¼8.0 Hz,
1H), 7.03 (dt, J¼7.8, 1.0 Hz, 1H), 3.78 (s, 3H). 13C NMR (100 MHz,
DMSO-d6)
d 166.2, 155.7, 140.8, 132.4, 130.2, 129.6, 128.3, 127.79,

9572
S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
127.67, 126.35, 126.28, 121.0, 113.1, 56.2. IR (plate): 2920, 1670, 1634,
1496, 1442, 1342, 1269, 1246, 1107, 1045, 1022, 741 cmꢃ1. ESMS (ESI)
m/z: 306 (MþHþ). HRMS (ESI) m/z 306.0040 (calcd for
C14H11N1O820Se1þHþ: 306.0033).
7.36e7.32 (m, 5H), 7.19 (dd, J¼8.5, 3.0 Hz, 1H), 5.00 (s, 2H), 3.88 (s,
3H). 13C NMR (125 MHz, CDCl3)
166.9, 158.7, 137.1, 129.1, 128.6,
128.29, 128.26, 128.01, 124.9, 121.6, 110.5, 55.5, 48.6. IR (plate):
d
2925, 1603, 1470, 1342, 1274, 1230, 1126, 1150, 1022, 700 cmꢃ1
.
HRMS (ESI) m/z 320.0194 (C15H13N1O2 80Se1þHþ: 320.0184).
5.1.9. 2-Chloro-3-methoxy-N-phenylbenzamide (substrate for Iso-
selenazolone 8). 2-Chloro-3-methoxybenzoyl chloride (0.95 g,
5.0 mmol) was dissolved in dry CH2Cl2 (15 mL) in a single neck flask
and cooled to 0 ꢀC. Aniline (0.95 g,10.1 mmol) in 10 mL of CH2Cl2 was
slowly added to this solution by dropping funnel. Resulted reaction
mixture was stirred for 1 h at 0 ꢀC and 12 h at room temperature.
After this, water (50 mL) was added to the reaction flask and stirred
for 30 min. Organic layer was extracted with CH2Cl2 (50 mLꢂ3) and
water layer separated by separating funnel. Organic layer was
washed with 10% aqueous HCl (25 mL), with water (25 mL), dried
over Na2SO4, and evaporated on rotary evaporator under vacuo. The
resulted white solid was passed through silica gel using CH2Cl2 to
obtain pure amide. Rf (3% DCM/MeOH) 0.6. Yield 1.26 g (95%), mp
5.1.13. 6,7-Dimethoxy-2-phenylbenzo[d][1,2]selenazol-3(2H)-one
(11). 6,7-Dimethoxy isoselenazolone 11 was prepared from 2-
chloro-3,4-dimethoxy-N-phenylbenzamide23 (0.5 g, 1.7 mmol),
copper iodide (164 mg, 0.9 mmol), 1,10-phenanthroline (154 mg,
0.9 mmol), selenium powder (0.16 g, 2.0 mmol), and potassium
carbonate (0.94 g, 6.8 mmol). The reaction mixture was refluxed for
24 h. Workup and purification procedures are similar as described
for compound 2. Yield 252 mg, 44%, mp 139e141 ꢀC (139e141 ꢀC).15
1H NMR (500 MHz, CDCl3)
2H), 7.42 (t, J¼8.5 Hz, 2H), 7.26 (m, 1H), 7.09 (d, J¼8.5 Hz, 1H), 4.003
(s, 3H), 3.997 (s, 3H). 13C NMR (125 MHz, CDCl3)
165.8,154.7,142.2,
139.5, 131.3, 129.3, 126.5, 125.3, 125.2, 121.3, 112.7, 60.5, 56.3. IR
d
7.82 (d, J¼8.5 Hz, 1H), 7.61 (d, J¼8.5 Hz,
d
140e142 ꢀC. 1H NMR (500 MHz, CDCl3)
d
7.83 (br s, 1H), 7.63 (d,
(plate): 2925, 2853, 1664, 1599, 1492, 1441, 1281, 1040, 744 cmꢃ1
.
J¼8.0 Hz, 2H), 7.37 (t, J¼7.5 Hz, 2H), 7.31 (t, J¼8.0 Hz, 1H), 7.27e7.25
HRMS (ESI) m/z 336.0134 (C15H13N1O3 80Se1þHþ: 336.0133).
(m,1H), 7.16 (t, 7.5 Hz,1H), 7.02 (dd, J¼8.0,1.2 Hz,1H), 3.93 (s, 3H).13C
NMR (125 MHz, CDCl3)
d
164.7, 155.3, 137.6, 137.1, 129.0, 127.8, 124.7,
5.1.14. 2-Benzyl-5-(methylthio)benzo[d][1,2]selenazol-3(2H)-one
(12). Heterocycle 7 was prepared from copper iodide (82 mg,
0.4 mmol), 1,10-phenanthroline (77 mg, 0.4 mmol), 2-chloro-5-
(methylthio)-N-benzylbenzamide28 (0.50 g, 1.7 mmol), selenium
powder (0.16 g, 2.1 mmol), and potassium carbonate (0.94 g,
6.8 mmol) in DMF (8 mL). Resulted reaction mixture was heated for
36 h at 110 ꢀC. Reaction workup procedure is similar to 2. Purifi-
cation was carried out by using hexane/ethyl acetate (8:2) on silica
gel. Rf (20% Hexane/EtOAc) 0.6. Yield (223 mg, 39%), mp
121.2,120.1,119.4,113.6, 56.4. IR (plate): 3282, 3071, 3011, 2929,1655,
1599, 1495, 1440, 1326, 1273, 1054, 754 cmꢃ1
.
5.1.10. 7-Methoxy-2-phenylbenzo[d][1,2]selenazol-3(2H)-one
(8). Isoselenazolone was synthesized using CuI (76 mg,
8
0.4 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), 2-chloro-3-
methoxy-N-phenylbenzamide (0.21 g, 0.8 mmol), selenium pow-
der (0.07 g, 0.9 mmol), and K2CO3 (0.42 g, 3.0 mmol) in DMF (3 mL).
Reaction mixture was heated at 110 ꢀC for 24 h. Workup and pu-
rification for this compound is similar to the isoselenazolone 2. Rf
(100% DCM) 0.4. Yield 137 mg, 57%, mp 138e141 ꢀC (139e140 ꢀC).15
139e141 ꢀC. 1H NMR (500 MHz, CDCl3)
J¼8.5 Hz, 1H), 7.44 (d, J¼8.5 Hz, 1H), 7.38e7.34 (m, 5H), 5.00 (s, 2H),
2.56 (s, 3H). 13C NMR (100 MHz, CDCl3)
166.7, 137.7, 137.1, 134.4,
d 7.91 (s, 1H), 7.47 (d,
d
1H NMR (500 MHz, CDCl3)
2H), 7.44 (q, J¼7.5 Hz, 3H), 7.28 (t, J¼7.5 Hz, 1H), 7.07 (d, J¼8.0 Hz,
1H), 3.97 (s, 3H). 13C NMR (125 MHz, CDCl3)
165.9, 154.1, 139.4,
d
7.71 (d, J¼3.0 Hz, 1H), 7.63 (d, J¼8.5 Hz,
130.9, 128.9, 128.5, 128.3, 128.1, 125.4, 124.2, 48.7, 15.9. IR (plate):
2918, 1590, 1543, 1449, 1337, 1079, 816, 761, 695 cmꢃ1. HRMS (ESI)
m/z 335.9968 (C15H13N1O1S1 80Se1þHþ: 335.9956).
d
129.3, 128.87, 128.26, 126.84, 126.62, 125.3, 121.1, 112.2, 56.0. IR
(plate): 2922, 1640, 1590, 1454, 1299, 1270, 1135, 733 cmꢃ1. HRMS
(ESI) m/z 306.0055 (C14H11N1O2 80Se1þHþ: 306.0027).
5.1.15. 2-Benzyl[1,2]selenazolo[5,4-b]pyridin-3(2H)-one
(13). Isoselenazolone 13 containing pyridine moiety was con-
structed from N-benzyl-2-chloronicotinamide29 (0.4 g, 1.6 mmol),
CuI (310 mg, 1.6 mmol), 1,10-phenanthroline (292 mg, 1.6 mmol),
selenium powder (0.19 g, 2.4 mmol), and K2CO3 (0.45 g, 3.2 mmol)
in DMF (5 mL). Resulted reaction mixture was refluxed for 22 h at
110 ꢀC. Workup was carried out by pouring reaction mixture into
saturated NaHCO3 aqueous solution followed by extraction with
EtOAc (25 mLꢂ5). Crude product obtained after evaporating EtOAc
layer and purified by column chromatography on silica gel using
CH2Cl2 and EtOAc (8:2). Rf (20% DCM/EtOAc) 0.5 afforded a white
crystalline solid. X-ray quality crystals were obtained by using
CH2Cl2 and hexane (9:1) solvent mixture. 0.234 g (50%), mp:
5.1.11. 2-Benzyl-7-methoxybenzo[d][1,2]selenazol-3(2H)-one
(9). Isoselenazolone 9 was prepared by following similar method
as described for 3 from 2-chloro-3-methoxy-N-benzylbenzamide23
(0.30 g, 1.1 mmol), CuI (104 mg, 0.5 mmol), 1,10-phenanthroline
(98 mg, 0.5 mmol), selenium powder (0.10 g, 1.3 mmol), and
K2CO3 (0.61 g, 4.4 mmol) in DMF (5 mL). The resulted reaction
mixture was stirred for 24 h at 110 ꢀC. Workup procedure is similar
to 2. Compound 9 was purified by column chromatography using
silica gel and eluent hexane/ethyl acetate (8:2). Rf (20% Hexane/
EtOAc) 0.2. Yield 232 mg, 67%, mp 66e68 ꢀC. 1H NMR (500 MHz,
CDCl3)
d
7.69 (d, J¼8.0 Hz, 1H), 7.41 (t, J¼8.0 Hz, 1H), 7.62e7.32 (m,
162e164 ꢀC. 1H NMR (500 MHz, CDCl3)
d
8.68 (d, J¼5.0 Hz, 1H), 8.28
5H), 6.99 (t, J¼8.0 Hz, 1H), 5.00 (s, 2H), 3.91 (s, 3H). 13C NMR
(d, J¼8.0 Hz, 1H), 7.39 (d, J¼5.0 Hz, 1H), 7.38e7.36(m, 5H), 5.03(s,
2H). 13C NMR (100 MHz, CDCl3): 165.3, 162.1, 152.9, 151.1, 136.9,
136.6, 128.9, 128.6, 128.5, 121.5, 48.5 IR (plate): 2921, 2853, 1648,
1579, 1388, 1324, 1228, 1081, 749, 698 cmꢃ1. HRMS (ESI) m/z
291.0037 (C13H10N2O180Se1þHþ: 291.0031).
(125 MHz, CDCl3) d 167.4, 154.3, 137.3, 128.78, 128.51, 128.23, 127.92,
127.80, 127.33, 120.6, 111.7, 55.9, 48.7. IR (plate): 3030, 2926, 1644,
1578, 1479, 1270, 1071, 740 cmꢃ1. HRMS (ESI) m/z 320.0196
(C15H13N1O2 80Se1þHþ: 320.0184).
5.1.12. 2-Benzyl-5-methoxybenzo[d][1,2]selenazol-3(2H)-one
(10). 5-Methoxybenzyl isoselenazolone 10 was prepared from 2-
bromo-5-methoxy-N-benzylbenzamide27 (0.50 g, 1.6 mmol), cop-
per iodide (74 mg, 0.4 mmol), 1,10-phenanthroline (71 mg,
0.4 mmol), selenium powder (0.15 g, 1.9 mmol), and potassium
carbonate (0.32 g, 2.3 mmol). The reaction mixture was refluxed for
22 h. Workup and purification procedures are similar as described
for compound 2. Yield 380 mg, 76%, mp 124e126 ꢀC. 1H NMR
5.1.16. 2-Cyclohexyl[1,2]selenazolo[5,4-b]pyridin-3(2H)-one
(14). For the preparation of cyclohexyl containing SeeN hetero-
cycle 14, reaction was carried in a similar manner as described for
13 by using N-cyclohexyl-2-chloronicotinamide30 (0.7 g, 2.9 mmol),
CuI (560 mg, 2.9 mmol), 1,10-phenanthroline (530 mg, 2.9 mmol),
selenium powder (0.34 g, 4.3 mmol), and K2CO3 (3.0 g, 21.7 mmol)
in DMF (7 mL) and resulted reaction mixture was refluxed for 48 h
at 110 ꢀC. Standard workup as described for 13, and purification by
column chromatography on silica gel using CH2Cl2 and EtOAc (8:2)
(500 MHz, CDCl3)
d
7.57 (d, J¼3.0 Hz, 1H), 7.43 (d, J¼8.5 Hz, 1H),

S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
9573
afforded a white crystalline solid. Yield 0.528 g (64%), mp:
181e183 ꢀC (183e187 ꢀC).9c 1H NMR (500 MHz, CDCl3)
8.71 (d,
dimethylpropanoyl chloride (0.42 g, 2.7 mmol) was dissolved in
dry CH2Cl2 (15 mL) in a single neck flask and cooled to 0 ꢀC. 3,5-
Dimethoxyaniline (0.63 g, 4.1 mmol) in 10 mL of CH2Cl2, was
slowly added to 3-chloro-2,2-dimethylpropanoyl chloride solution
by dropping funnel. Resulted reaction mixture stirred for 1 h at 0 ꢀC
and 12 h at room temperature. After this water (50 mL) was added
to reaction flask and stirred for 30 min. Dichloromethane (50 mL)
was added to reaction mixture and water layer separated by sep-
arating funnel. Dichloromethane layer was washed with 10% HCl
(25 mL), and then with water (25 mL). Dichloromethane layer dried
over Na2SO4, evaporated on rotary evaporator under vacuo.
Resulted white solid was passed through silica gel using CH2Cl2 to
obtain pure amide. Rf (2% DCM/MeOH) 0.6. Yield 0.34 g (46%), mp
d
J¼4.5 Hz,1H), 8.24 (d, J¼8.0 Hz,1H), 7.37 (dd, J¼4.5, 8.0 Hz,1H), 4.51
(m, 1H), 2.12 (m, 2H), 1.87 (m, 2H), 1.73 (m, 1H), 1.53e1.38 (m, 4H),
1.29e1.16 (m, 1H). 13C NMR (125 MHz, CDCl3)
d 164.3, 161.9, 151.9,
136.4,124.8,121.3, 53.5, 34.1, 25.5, 25.2. IR (plate): 2953, 2844,1638,
1586, 1390, 1364, 1069, 892, 743 cmꢃ1. HRMS (ESI) m/z 283.0354
(C12H14N2O180Se1þHþ: 283.0344).
5.1.17. 2-Butyl[1,2]selenazolo[5,4-b]pyridin-3(2H)-one (15). For the
preparation of heterocycle 15, reaction was carried in a similar
manner as described for 13 by using N-n-butyl-2-chloronicotina-
mide31 (0.55 g, 2.6 mmol), CuI (493 mg, 2.6 mmol), 1,10-
phenanthroline (466 mg, 2.6 mmol), selenium powder (0.31 g,
3.9 mmol), and K2CO3 (1.7 g,12.3 mmol) in DMF (6 mL) and refluxed
for 48 h at 110 ꢀC. Standard workup as described for 13 and puri-
fication by column chromatography on silica gel using CH2Cl2 and
EtOAc (8:2) afforded a white crystalline solid. Rf (20% DCM/EtOAc)
0.5. Yield 0.363 g (55%), mp 120e122 ꢀC. 1H NMR (500 MHz, CDCl3)
116e118 ꢀC. 1H NMR (500 MHz, CDCl3)
J¼2.5 Hz, 2H), 6.26 (t, J¼2.5 Hz, 1H), 3.78 (s, 6H), 3.69 (s, 2H), 1.40 (s,
6H). 13C NMR (125 MHz, CDCl3)
173.1, 161.0, 139.2, 98.4, 97.2, 55.3,
52.6, 45.0, 23.6. IR (plate): 3337, 2935, 2838, 1664, 1618, 1559, 1453,
1418, 1197, 1153, 1068, 828 cmꢃ1
d 7.42 (br s, 1H), 6.78 (d,
d
.
d
8.73 (dd, J¼1.5, 4.5 Hz, 1H), 8.24 (dd, J¼1.5, 8.0 Hz, 1H), 7.39 (dd,
5.1.21. 1-(3,5-Dimethoxyphenyl)-3,3-dimethylazetidin-2-one
(20). Lactam 20 was obtained by following similar procedure as
described for 19 by using 3-chloro-N-(3,5-dimethoxyphenyl)-2,2-
dimethylpropanamide (0.23 g, 0.85 mmol), CuI (40 mg,
0.2 mmol), 1,10-phenanthroline (38 mg, 0.2 mmol), selenium
powder (78 mg, 1.0 mmol), and K2CO3 (0.17 g, 1.2 mmol) in DMF
(5 mL) and refluxing for 8 h at 110 ꢀC. Standard workup and puri-
fication as described for 19 afforded a brown crystalline solid. Rf
(20% Hexane/EtOAc) 0.5. Yield 0.198 g (98%), mp 58e60 ꢀC. 1H NMR
J¼4.5, 8.0 Hz, 1H), 3.89 (t, J¼7.5 Hz, 2H), 1.73 (p, J¼7.5 Hz, 2H), 1.44
(sextet, J¼7.5 Hz, 2H), 0.97 (t, J¼7.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3)
d 165.0, 161.7, 152.1, 136.6, 123.9, 121.4, 44.2, 32.5, 19.9, 13.7.
IR (plate): 2960, 2925, 2857, 1633, 1582, 1463, 1392, 1190, 753 cmꢃ1
.
HRMS (ESI) m/z 257.0193 (C10H12N2O180Se1þHþ: 257.0188).
5.1.18. 3-Chloro-N-(4-methoxyphenyl)-2,2-dimethylpropanamide
(substrate for azetidine 19). 3-Chloro-2,2-dimethylpropanoyl chlo-
ride (0.6 g, 3.7 mmol) was dissolved in dry CH2Cl2 (15 mL) in
a single neck flask and cooled to 0 ꢀC. 4-Methoxyaniline (0.7 g,
5.5 mmol) in 10 mL of CH2Cl2 was slowly added to 3-chloro-2,2-
dimethylpropanoyl chloride solution by dropping funnel. Resulted
reaction mixture stirred for 1 h at 0 ꢀC and 12 h at room temper-
ature. After this, water (50 mL) was added to the reaction flask and
stirred for 30 min. Dichloromethane (50 mL) was added to the re-
action mixture and water layer separated by separating funnel.
Dichloromethane layer was washed with 10% aqueous HCl (25 mL),
and then with water (25 mL). Dichloromethane layer dried over
Na2SO4, evaporated on rotary evaporator under vacuo. Resulted
white solid was passed through silica gel using CH2Cl2 to obtain
pure 3-chloro-N-(4-methoxyphenyl)-2,2-dimethylpropanamide. Rf
(2% DCM/MeOH) 0.6. Yield 0.8 g (90%), mp 94e96 ꢀC. 1H NMR
(500 MHz, CDCl3)
d
6.54 (d, J¼2.5 Hz, 2H), 6.20 (t, J¼2.5 Hz,1H), 3.78
(s, 6H), 3.40 (s, 2H), 1.39 (s, 6H). 13C NMR (125 MHz, CDCl3)
d
171.1,
161.2, 140.3, 96.1, 94.8, 55.3, 53.5, 49.6, 21.3. IR (plate): 2962, 1598,
1482, 1334, 1272, 1207, 115, 1091, 830 cmꢃ1. HRMS (ESI) m/z
236.1115 and 258.1098 (calcd for C12H15N1O2þHþ: 236.1281 and for
C13H17N1O3þNa: 258.1100).
5.2. Preparation of bisphenyl diselenide (21); representative
copper catalyzed procedure for the synthesis of diaryl
diselenides
To a DMF solution (5 mL), CuI (233 mg, 1.2 mmol) and 1,10-
phenanthroline (221 mg, 1.2 mmol) was added sequentially under
N2 atmosphere and stirred for 15 min. To this red colored solution
of CuI/L, succinimide (0.48 g, 5.9 mmol), benzene iodide (0.55 mL,
4.9 mmol), selenium powder (0.46 g, 5.9 mmol), and potassium
carbonate (2.03 g, 14.7 mmol) were added in same order and the
resulted reaction mixture was heated at 110 ꢀC for 8 h (progress of
reaction was monitored by TLC continuously. For TLC, an aliquot of
reaction mixture was poured into brine solution (2.0 mL) and
mixed well with brine. After this, ethyl acetate was added, shaken
well, and organic layer was used for TLC). After this, reaction
mixture was poured into a beaker containing brine solution (80 mL)
and resulted solution stirred for 2 h in air. Reaction mixture was
extracted with ethyl acetate (25 mLꢂ3). Combined organic layer
was washed with water (50 mL), dried over Na2SO4 and evaporated
under vacuo to provide resulted yellowish residue. Column chro-
matography of crude product using hexane gave yellowish oil.
Crystallization by n-hexane at 0 ꢀC gave yellow colored bisphenyl
diselenide. Yield 0.497 g (65%), mp 58e60 ꢀC (60e62 ꢀC).33 1H NMR
(500 MHz, CDCl3)
(s, 3H), 3.69 (s, 2H), 1.40 (s, 6H), signal due to NH proton is not
visible in the spectrum. 13C NMR (125 MHz, CDCl3)
173.0, 156.7,
130.5, 122.5, 114.0, 55.4, 52.8, 44.7, 23.6. IR (plate): 3320, 2962,
1654, 1512, 1239, 1180, 1034, 830 cmꢃ1
d
7.41 (d, J¼8.5 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H) 3.79
d
.
5.1.19. 1-(4-Methoxyphenyl)-3,3-dimethylazetidin-2-one (19). Lactam
19 was obtained from 3-chloro-N-(4-methoxyphenyl)-2,2-dimethyl-
propanamide (0.3 g, 1.2 mmol), CuI (60 mg, 0.3 mmol), 1,10-
phenanthroline (56 mg, 0.3 mmol), selenium powder (0.12 g,
1.5 mmol), and K2CO3 (0.26 g, 1.9 mmol) in DMF (4 mL) and refluxing
for 8 h at 110 ꢀC. Standard workup is similar to isoselenazolone 2 and
crude product was purified by column chromatography on silica gel
using hexane and ethyl acetate (8:2) afforded a brown crystalline
solid. Rf (20% Hexane/EtOAc) 0.5. Yield 0.238 g (97%), mp 63e65 ꢀC
(69e70 ꢀC).32 1H NMR (500 MHz, CDCl3)
d
7.29 (d, J¼8.5 Hz, 2H), 6.87
(d, J¼8.5 Hz, 2H) 3.78 (s, 3H), 3.39 (s, 2H), 1.39 (s, 6H). 13C NMR
(500 MHz, CDCl3)
d
7.62 (dd, J¼7.5, 1.5 Hz, 4H), 7.29e7.25 (m, 6H). IR
(125 MHz, CDCl3)
d
170.4, 161.2, 132.3, 117.5, 114.3, 55.5, 53.3, 49.8,
(plate): 3070, 2929, 1571, 1473, 1435, 1067, 733, 686 cmꢃ1
.
21.4. IR (plate): 2962,139,1514, 1397, 1295,1246,1154,1033, 830 cmꢃ1
.
HRMS (ESI) m/z 206.1059 and 228.1007 (calcd for C12H15N1O2þHþ:
206.1176 and for C12H15N1O2þNa: 228.0995).
5.2.1. Bis-(2-methoxyphenyl)diselenide (22). Diselenide 22 was
synthesized from 2-iodo anisole (0.9 g, 3.8 mmol), N-succinimide
(0.38 g, 3.8 mmol), CuI (190 mg, 1.0 mmol), 1,10-phenanthroline
(180 mg, 1.0 mmol), selenium powder (0.36 g, 4.6 mmol), and
K2CO3 (1.6 g, 11.6 mmol) in DMF (7 mL) by following similar
5 . 1. 2 0 . 3 - C h l o r o - N - ( 3 , 5 - d i m e t h o x y p h e n y l ) - 2 , 2 -
dimethylpropanamide (substrate for azetidine 20). 3-Chloro-2,2-

9574
S.J. Balkrishna et al. / Tetrahedron 67 (2011) 9565e9575
procedure as described for 21. Reaction mixture was refluxed for
24 h at 110 ꢀC. Standard workup as described for 21 and purification
by column chromatography on silica gel using hexane as mobile
phase afforded a yellow thick oil, which converted into crystalline
orange solid upon cooling. Yield 0.601 g (84%), mp 83e85 ꢀC
solid. Yield 82 mg, 54%. 1H NMR (400 MHz, CDCl3)
d 8.48 (dm,
J¼4.8 Hz, 2H), 7.82 (dt, J¼8.1, 1.0 Hz, 2H), 7.56 (td, J¼8.0, 2.0 Hz, 2H),
7.10 (ddd, J¼7.50, 4.8,1.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 154.4,
149.6, 137.5, 123.6, 121.3. ESMS m/z 338.9 (C10H8N2Se2þNa). IR
(plate): 3060, 2960, 2920, 1565, 1555, 1444, 1408, 1105, 1076, 1041,
(85e87 ꢀC).34 1H NMR (500 MHz, CDCl3)
d
7.57 (dd, J¼8.0, 1.0 Hz,
987, 741, 689 cmꢃ1
.
1H), 7.29e7.25 (m, 1H), 7.23e7.17 (m, 2H), 6.92e6.81 (m, 4H), 3.91
(s, 6H). IR (plate): 3060, 3003, 2933, 2834, 1576, 1472, 1270, 1054,
5.2.6. Bis-2-thiophenyl diselenide (27). Synthesis of diselenide 27
was carried out at 2.4 mmol using 2eiodo-thiophene (500 mg,
2.38 mmol), succinimide (236 mg, 2.38 mmol), CuI (113 mg, 0.6
mmo1), 1,10-phenanthroline (107 mg, 0.6 mmol), selenium powder
(207 mg, 2.6 mmol), and K2CO3 (0.493 mg, 3.57 mmol) in DMF
(6 mL). Reaction mixture was refluxed at 110 ꢀC for 3 h. Workup and
column chromatography on silica gel using hexane as an eluent
1022, 748 cmꢃ1
.
5.2.2. Bis-2-(aniline) diselenide (23). Diselenide 23 was prepared
by following similar procedure as described for 21 using 2-iodo
aniline (1.0 g, 4.6 mmol), N-succinimide (0.45 g, 4.5 mmol), CuI
(217 mg, 1.1 mmol), 1,10-phenanthroline (205 mg, 1.1 mmol), sele-
nium powder (0.43 g, 5.5 mmol), and K2CO3 (1.9 g, 13.7 mmol) in
DMF (7 mL). Resulted reaction mixture was refluxed for 12 h at
110 ꢀC. Standard workup followed as mentioned for 21. Crude
product obtained after evaporating ethyl acetate layer was purified
by column chromatography on silica gel using hexane and ethyl
acetate as mobile phase (8:2) afforded a yellow thick oil, which
converted into crystalline orange solid on standing. Yield 0.351 g
yielded
a
white solid. Yield 251 mg (65%), mp 55e57 ꢀC
(57e59 ꢀC).39 1H NMR (400 MHz, CDCl3)
d
7.51 (dd, J¼5.3, 1.2 Hz,
2H), 7.26 (dd, J¼3.5,1.2 Hz, 2H), 7.03 (dd, J¼5.3, 3.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3)
d 136.9, 132.9, 128.1, 125.6.
Acknowledgements
(45%), mp 80e83 ꢀC (83 ꢀC).35 1H NMR (500 MHz, CDCl3)
d 7.35 (dd,
S.K. thanks Department of Science and Technology (DST) New
Delhi for financial support. S.J.B. and B.S.B. thank IISER Bhopal for
research fellowship. S.K. thanks Professor Vinod K. Singh, Dr. Pra-
deep K. Singh, and Mr. Suresh Allu (Department of Chemistry, IIT
Kanpur) for HRMS data. We heartedly thank Professor T.N. Guru
Row and Dr. Susanta Kumar Nayak for data collection on the CCD
facility at IISc, Bangalore.
J¼8.0 Hz, 2H), 7.18e7.12 (m, 2H), 6.72 (d, J¼8.5 Hz, 2H), 6.56 (t,
J¼7.5 Hz, 2H), 4.27 (br s, 4H). IR (plate): 3435, 3353, 2924, 2859,
1603, 1467, 1440, 1304, 1257, 1158, 1013, 742 cmꢃ1. HRMS (ESI) m/z
344.9416 (calcd for C12H12N820Se2þHþ: 344.9403).
5.2.3. Bis[2-(N-acetylaniline)] diselenide (24). Preparation of dis-
elenide 24 carried out at 2.9 mmol from 2-iodoacetanilide (0.75 g,
2.9 mmol), N-succinimide (0.28 g, 2.8 mmol), CuI (137 mg,
0.7 mmol), 1,10-phenanthroline (130 mg, 0.7 mmol), selenium
powder (0.27 g, 3.4 mmol), and K2CO3 (1.2 g, 8.6 mmol) in DMF
(6 mL) by following similar procedure as described for 21 and
refluxed for 12 h at 110 ꢀC. Standard workup similar to 21 and crude
product was purified by flash column chromatography on silica gel
using hexane and ethyl acetate (7:3) afforded a brown colored solid.
Yield 0.367 g (60%), mp 160e162 ꢀC (164 ꢀC).36 1H NMR (500 MHz,
Supplementary data
Additional experimental details, copies of spectra for com-
pounds and crystallographic data, CIF file for 13 (CCDC No. 808789)
are available. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2011.09.141.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
CDCl3)
d
8.31 (d, J¼8.0 Hz, 1H), 7.83 (s, 2H), 7.57 (d, J¼7.5 Hz, 2H),
7.38 (t, J¼7.5 Hz, 2H), 6.99 (t, J¼7.5 Hz, 2H), 1.94 (s, 6H). IR (plate):
3263, 2926, 1667, 1579, 1519, 1470, 1296, 1028, 754 cmꢃ1. HRMS
(ESI) m/z 428.9624 (C16H16N2O2 80Se2þHþ: 428.9615).
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.
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