Copper-catalyzed domino one-pot synthesis of 2-(arylselanyl)arylcyanamides

Article abstract of DOI:10.1002/ejoc.201100785

Domino C-Se cross-coupling of 2-(iodoaryl)selenoureas with aryl iodides has been accomplished in the presence of a copper(I)-1,1-phenanthroline complex at moderate temperature. The reactions involve intra- and intermolecular C-Se cross-coupling to give th

Full text of DOI:10.1002/ejoc.201100785

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100785
Copper-Catalyzed Domino One-Pot Synthesis of 2-(Arylselanyl)arylcyanamides
Tamminana Ramana[a] and Tharmalingam Punniyamurthy*[a]
Keywords: Copper / Selenium / Heterocycles / Cross-coupling / Domino reactions
Domino C–Se cross-coupling of 2-(iodoaryl)selenoureas with
aryl iodides has been accomplished in the presence of a cop-
per(I)–1,1-phenanthroline complex at moderate temperature.
The reactions involve intra- and intermolecular C–Se cross-
coupling to give the substituted 2-(arylselanyl)arylcyan-
amides. Aryl iodides having electron-donating and -with-
drawing substituents are compatible, affording the target
selanyl ethers in high yield.
Introduction
Results and Discussion
First, the reaction conditions were optimized with N-(2-
iodo-4-methylphenyl)selenourea and iodobenzene as model
substrates (Table 1). Among the set of ligands examined,
The cross-coupling reactions of aryl halides with hetero-
atom nucleophiles using transition metal catalysts are
powerful tools for the construction of carbon–heteroatom
bonds that are important in biological, materials, and phar-
maceutical sciences.[1] Recently, the formation of C–N, C–
O, and C–S bonds have made considerable progress. Sub-
sequently, a few studies have focused on the construction of
C–Se bonds, as this moiety is present in many biologically
and pharmaceutically active compounds.[2,3] Selenides also
play an important role in synthetic chemistry as versatile
reagents for synthesis.[4] Similarly, cyanamides have at-
tracted much attention in biological and pharmaceutical
sciences because of their unique structure.[5,6] For example,
cyanamides serve as important intermediates for the synthe-
sis of minoxidil[7] and herbicides.[8] They also find use as
tumor inhibitors.[9] The development of methods for the
synthesis of compounds having these two aforementioned
moieties will be thus useful in organic synthesis. In this con-
tribution, we wish to report a novel copper(I)-catalyzed
one-pot domino C–Se cross-coupling reaction of 2-
(iodoaryl)selenoureas with aryl iodides to afford substituted
2-(arylselanyl)arylcyanamides at moderate temperature in
high yield. The reactions are efficient and take place via
intra- and intermolecular C–Se cross-coupling reactions.
Aryl iodides having electron donating and -withdrawing
substituents are compatible. To the best of our knowledge,
this is the first example available for the synthesis of 2-(aryl-
selanyl)arylcyanamides.
Table 1. Optimization of the reaction conditions.
Entry
[Cu]
Ligand
Solvent
X
Time % Yield[a,b]
Source
[h]
A
B
C
1
2
3
CuSO4·5H2O
CuI
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
1
3
1
3
3
3
1
1
3
1
3
3
3
3
4
4
3
3
1
6
6
–
95
–
30 20 45
95
43 15 37
53 16 26
49 15 35
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L7
L7
L7
L7
L7
L7
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
–
–
4[c]
5[d]
6
7
8
9
toluene
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
–
94
94
–
–
45 15 35
92
10
11
12
13
14
15[e]
16[f]
17[g]
18
19
20
21
–
–
25 25 45
37 23 35
25 10 60
35 18 45
62
49
50
–
–
–
33
46
45
CuBr
Cu2O
CuI
I
I
Br
Cl
55 15 25
–
20
–
95
–
–
–
75
94
CuI
[a] Department of Chemistry,
Indian Institute of Technology Guwahati,
Guwahati 781039, India
[a] Substrate (0.5 mmol), copper source (5 mol-%), L1–7 (5 mol-%),
Cs2CO3 (0.75 mmol), and iodobenzene (0.5 mmol) were stirred in
solvent (1 mL) at 90 °C. [b] Isolated yield. [c] K2CO3 used.
[d] K3PO4 used. [e] T = 80 °C. [f] Cs2CO3 (1 equiv.) used. [g] Cata-
lyst (2.5 mol-%) used.
Fax: +91-361-2690762
E-mail: tpunni@iitg.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100785.
4756
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4756–4759

Cu-Catalyzed One-Pot Synthesis of 2-(Arylselanyl)arylcyanamides
1,10-phenanthroline (L7) afforded the best results, giving Table 2. The cross-coupling of N-(2-iodo-4-methylphenyl)-
selenourea with substituted aryl iodides.[a]
selectively product A in 99% yield (Table 1, Entry 3). In
contrast, ethylene diamine (L1), ethylene glycol (L2), l-pro-
line (L3), 2,2Ј-bipyridine (L4), 8-hydroxyquinoline (L5),
and dibenzoylmethane (L6) were found to be less selective,
giving B or C or both as byproducts along with target mole-
cule A. Recrystallization of A in MeOH gave single crystals
whose X-ray analysis is presented in Figure 1. A control
experiment confirmed that a mixture of A, B, and C were
detected without the aid of ligand L7 (Table 1, Entry 2).
The catalytic activity of different copper sources was evalu-
ated, and CuI was found to be superior to CuBr, Cu2O, and
CuSO4·5H2O. DMSO was found to be the solvent of
choice, whereas DMF, toluene, and 1,4-dioxane gave in-
ferior results. Of the screened bases, K2CO3, K3PO4, and
Cs2CO3, Cs2CO3 gave the best results. Reaction tempera-
ture was another important factor that affected the results,
and 90 °C was found to be the optimum temperature. A
blank reaction run without a copper salt gave B as the sole
product and the formation of A was not observed. This
result suggests that, in the absence of a copper(I) complex,
the base-promoted deselenization takes place to afford cy-
anamide B.
Figure 1. ORTEP diagram of 2-(phenylselanyl)-4-methylphenylcy-
anamide with 50% ellipsoids.[10] H atoms are omitted for clarity.
The reactivities of other aryl halides were further com-
pared. The reactions with bromobenzene and chlorobenz-
ene gave C as the only product. Likewise, reaction of N-(2-
bromo-4-methylphenyl)selenourea with iodobenzene gave a
4:15 mixture of 2-bromo-4-methylphenylcyanamide and C
in Ͼ99% yield, whereas N-(2-chloro-4-methylphenyl)sele-
nourea did not undergo any cross-coupling with iodo-
benzene and afforded 2-chloro-4-methylphenylcyanamide
as the sole product in Ͼ99% yield. In summary, the optimal
conditions in DMSO consist of the combination of CuI
(0.5 mmol), CuI (5 mol-%), 1,10-phenanthroline (5 mol-%), and
(5 mol-%) and L7 (5 mol-%) along with the presence of
[a] N-(2-Iodo-4-methylphenyl)selenourea (0.5 mmol), aryl iodide
Cs2CO3 (0.75 mmol) were stirred at 90 °C in DMSO (1 mL) in air.
[b] Isolated yield.
Cs2CO3 (1.5 equiv.) at 90 °C for 1 h.
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4757

T. Ramana, T. Punniyamurthy
SHORT COMMUNICATION
Next, to reveal the scope of the procedure, the reaction tramolecular followed by intermolecular C–Se domino
of a series of substituted aryl iodides was explored with N- cross-coupling reactions (Scheme 3). Thus, the selenourea
(2-iodo-4-methylphenyl)selenourea (Table 2). Aryl iodides may undergo chelation followed by oxidative addition with
having 2-Cl, 2-OMe, 3-NO2, 4-NH2, 4-Cl, 4-OMe, and 4- copper(I)–1,10-phenanthroline to give metallocycle b,
NO2 substituents readily participated in the C–Se domino which could lead to the formation of F by reductive elimi-
cross-coupling reaction to give 2-(aryl selanyl)arylcyan- nation. The cross-coupling of F with c may afford interme-
amides in 1–2 h with yields ranging from 75 to 95%. Simi- diate d, which could complete the catalytic cycle by re-
larly, aryl iodides with 2,4-Me, 2,5-Me, and 2,6-Me groups ductive elimination of target molecule D.
and 1-naphthyl iodide gave the corresponding 2-(aryl-
selanyl)arylcyanamides in high yield.
Finally, the reactions of the substituted N-(2-iodo-4-
methylphenyl)selenoureas with aryl iodides were studied
(Table 3). For example, N-(2-iodo-4-methylphenyl)seleno-
urea having 4-Cl, 4-Me, and 4,5-Me substituents underwent
domino C–Se cross-coupling with 1-iodo-4-methylbenzene
Scheme 1.
to afford the respective substituted 2-(arylselanyl)-
arylcyanamides in 1 h with 90–95% yields. These results
clearly suggest that the present protocol can be used for the
one-pot synthesis of 2-(arylselanyl)arylcyanamides.
Table 3. The cross-coupling of substituted selenoureas with 1-iodo-
4-methylbenzene.[a]
Scheme 2.
[a] N-(2-Iodoaryl)selenourea (0.5 mmol), 1-iodo-4-methylbenzene
(0.5 mmol), CuI (5 mol-%), L7 (5 mol-%), and Cs2CO3 (0.75 mmol)
were stirred at 90 °C for 1 h in DMSO (1 mL). [b] Isolated yield.
Regarding the mechanism, control experiments were pur-
sued. The cyclization of (2-iodo-4-methylphenyl)selenourea
was studied with 0.5 equiv. of Cs2CO3 in the absence of an
Scheme 3. Proposed catalytic cycle.
aryl iodide (Scheme 1). The cyclization occurred to give 2-
aminobenzoselenazole F in 0.5 h with 100% selectivity.
Next, the reaction of F was studied with iodobenzene in the
presence of 1 equiv. of Cs2CO3 (Scheme 2). Benzoselenazole
Conclusions
F underwent reaction in the presence of CuI–1,10-phen-
anthroline to give D in quantitative yield. The intramolecular
In conclusion, a novel copper-catalyzed domino C–Se
cyclization was found to be faster than the intermolecular cross coupling of (2-iodoaryl)selenoureas with aryl iodides
reaction. These results suggest that the process involves in- has been developed to afford the substituted (2-selanylaryl)-
4758
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Eur. J. Org. Chem. 2011, 4756–4759

Cu-Catalyzed One-Pot Synthesis of 2-(Arylselanyl)arylcyanamides
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Experimental Section
General Procedure for the Synthesis of 2-(Arylselanyl)arylcyan-
amides: To a stirred solution of 1,10-phenanthroline (5 mol-%) and
CuI (5 mol-%) in DMSO (1 mL) was added the N-(2-iodoaryl)-
selenourea (0.5 mmol), aryl iodide (0.5 mmol), and Cs2CO3
(244 mg, 0.75 mmol) at ambient temperature, and the mixture was
allowed to stir at 90 °C for the appropriate time. Progress of the
reaction was monitored by TLC (ethyl acetate/hexane). The reac-
tion mixture was then cooled to room temperature and diluted with
ethyl acetate (10 mL). The solution was washed successively with
1 n HCl (1ϫ3 mL) and water (3ϫ3 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue that was purified by silica
gel column chromatography (ethyl acetate/hexane) to afford the 2-
(arylselanyl)arylcyanamide in analytically pure form.
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Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and copies of the 1H and 13C NMR
spectra of the 2-(arylselanyl)arylcyanamides.
Acknowledgments
We thank the Department of Science and Technology, New Delhi,
and the Council of Scientific and Industrial Research, New Delhi,
for generous financial support.
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amide in MeOH afforded single crystals whose X-ray data were
collected with a Bruker SMART APEX equipped with a CCD
area detector using Mo-Kα radiation in the scan range 1.20–
28.31°. C14H12N2Se, Mw = 287.22, orthorhombic; space group
Pna21, a = 8.0688(3) Å, b = 19.6845(9) Å, c = 15.9556(7) Å; α
= 90°, β = 90°, γ = 90°, V = 2534.23(19) Å3, Z = 8, ρcalcd.
=
1.506 mg/m3;
T
=
296(2) K,
crystal
dimension
0.3ϫ0.2ϫ0.2 mm3; 3786 reflections; F(000)= 1152.0, Final
[IϾ2σ(I)]; R1 = 0.0636, wR2 = 0.1617, R Indices (all data) R1
= 0.0771, WR2 = 0.1721, GOF (on F2) = 0.905. CCDC-779997
contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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A. Hallberg, T. Hogberg, Adv. Drug Res. 1996, 28, 65–180; d)
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2125–2179.
[3] For some recent examples, see: a) D. Alves, C. G. Santos,
M. M. Paixao, L. C. Soares, D. De Souza, O. E. D. Rodrigues,
Received: June 2, 2011
Published Online: July 26, 2011
Eur. J. Org. Chem. 2011, 4756–4759
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4759