Copper-catalysed N-arylation of arylsulfonamides with aryl bromides and aryl iodides using KF/Al2O3

Article abstract of DOI:10.1007/s12039-010-0015-x

An efficient synthesis of N-arylsulfonamides with a variety of aryl bromides, aryl iodides and heteroaryl bromides using KF/Al₂O ₃ as a suitable base, CuI as an inexpensive catalyst and N,N′dimethylethylenediamine (N,N′-DMEDA) as an effective ligand is described. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0015-x

J. Chem. Sci., Vol. 122, No. 2, March 2010, pp. 143–148. © Indian Academy of Sciences.
Copper-catalysed N-arylation of arylsulfonamides with aryl bromides
and aryl iodides using KF/Al O3
2
a, a
RAHMAN HOSSEINZADEH *, MAHMOOD TAJBAKHSH , MARYAM MOHADJERANI
b
a,c
and MOHAMMAD ALIKARAMI
a
Department of Organic Chemistry, Faculty of Chemistry, Mazandaran University,
Babolsar 47416-95447, Iran
b
Department of Biology, Faculty of Science, Mazandaran University, Babolsar 47416-95447, Iran
c
Islamic Azad University, Ilam, Iran
e-mail: r.hosseinzadeh@umz.ac.ir
MS received 3 May 2009; accepted 19 August 2009
Abstract. An efficient synthesis of N-arylsulfonamides with a variety of aryl bromides, aryl iodides
and heteroaryl bromides using KF/Al
as a suitable base, CuI as an inexpensive catalyst and N,N′-
dimethylethylenediamine (N,N′-DMEDA) as an effective ligand is described.
2 3
O
2
Keywords. N-Arylsulfonamides; copper catalyst; N-arylation; KF/Al O3; N,N′-dimethylethylenediamine.
1
. Introduction
ligands were used in the coupling reaction of sul-
8
–10
fonamides with aryl halides.
However, many of
Formation of C(aryl)–N bond plays an important reported procedures have drawbacks such as long
role in organic synthesis. Among the compounds reaction time, harsh reaction conditions, use of
possessing this bond, N-arylsulfonamides are impor- hygroscopic Cs CO as base and carrying out reac-
2
3
tant target molecules in pharmaceutical research. A tion in a sealed tube. The application of KF/Al O to
2 3
number of these sulfonamides have been reported to organic synthesis has provided new methods for a
11
show significant biological activity, e.g. non- wide array of organic reactions . The strongly basic
1
nucleotide reverse transcriptase inhibitors, class III nature of KF/Al O has allowed it to replace organic
2
3
2
antiarrhythmic agents HIV-1 protease inhibitors
3
12
bases in a number of reactions.
and non-peptidic vasopressin V1a receptor antago-
4
nists. The vast majority of sulfonamides are pre-
2
. Experimental
pared from the reaction of a sulfonyl chloride with
ammonia or primary or secondary amines or via
All yields refer to isolated products. Analytical TLC
5
related transformations. Because of difficulties in
was performed on Merck precoated 60 F254 silica gel
the preparation of sulfonyl chloride intermediate,
sulfonamides are now mostly prepared through the
direct formation of the aryl-nitrogen bond, using
simple copper salt, copper metal or palladium com-
1
plates. The H NMR spectra were recorded on a
Bruker DRX- 500 MHz Avance, Bruker 400 MHz
Avance and Bruker DRX-300 MHz spectrometer in
3 6
CDCl or DMSO-d using TMS as internal standard.
6
plexes as a catalyst. In 2003, Wu reported the CuI-
catalysed N-arylation of sulfonamides with aryl
bromides and aryl iodides under microwave irradia- 2.1 General procedure for the N-arylation of
7
tion. Although no ligand was used in their study, the arylsulfonamides
synthesis required a prolonged reaction time (2–4 h
of microwave irradiation at 195°C) and the yields of To a solution of aryl halide (1 mmol) and arylsul-
the coupling products were modest (54–90%). To fonamide (1⋅5 mmol) in dioxane (5 mL) under argon
improve the efficiency of these methods, many atmosphere were added CuI (20 mol%) and N,N′-
1
3
DMEDA (20 mol%) followed by KF/Al
2 3
O
(
5 equiv.). The reaction mixture was stirred at 100–
*
For correspondence
1
43

1
44
Rahman Hosseinzadeh et al
1
1
10°C for the specified time (table 2). The reaction CH
3
). Entry 23: A solid, H NMR (400 MHz,
): δ = 11⋅87 (br s, 1H, NH), 8⋅01 (br s,
ture was cooled to room temperature. Ethyl acetate 1H, Het-H), 7⋅76 (d, 2H, J = 7⋅6 Hz, Ar-H), 7⋅70 (t,
50–60 mL) was added and filtrated. The filtrate was 1H, J = 7⋅6 Hz, Het-H), 7⋅33 (d, 2H, J = 7⋅6 Hz, Ar-
concentrated under vacuum and the residue sub- H), 7⋅14 (br d, 1H, J = 7⋅6 Hz, Het-H), 6⋅86 (br s,
was monitored by TLC. At the end of reaction, mix- DMSO-d
6
(
1
jected to column chromatography on silica gel using 1H, Het-H), 2⋅33 (s, 3H, CH
hexane: ethylacetate (70 : 30) as eluent to afford the NMR (400 MHz, DMSO-d
3
). Entry 24: A solid, H
6
): δ = 10⋅58 (br s, 1H,
pure coupled product. The spectroscopic data and NH), 8⋅43 (br s, 1H, Het-H), 7⋅77 (d, 2H, J = 7⋅2 Hz,
melting points for known products agreed well with Ar-H), 7⋅64–7⋅51 (m, 6H, Ar-H and Het-H), 7⋅36 (br
the reported data (table 2). Entry 1: A solid, H s, 1H, Het-H). Entry 26: A solid, H NMR
1
1
NMR (500 MHz, CDCl ): δ = 7⋅79–7⋅77 (m, 2H, (400 MHz, CDCl ): δ = 7⋅70 (d, 2H, J = 8⋅0 Hz,
3 3
Ar-H), 7⋅50 (t, 1H, J = 7⋅4 Hz, Ar-H), 7⋅41 (t, 2H, Ar-H) 7⋅38 (br s, 1H, NH), 7⋅24 (d, 2H, J = 8⋅0 Hz,
J=7⋅4 Hz, Ar-H), 7⋅22 (t, 2H, J = 7⋅8 Hz, Ar-H), Ar-H), 7⋅17 (dd, 1H, J = 5⋅2 and 3⋅2 Hz, Het-H),
7
⋅09–7⋅06 (m, 4H, Ar-H and NH)⋅ Entry 3: A solid, 6⋅89–6⋅86 (m, 2H, Het-H), 2⋅39 (s, 3H, CH
3
).
1
H NMR (500 MHz, CDCl
3
): δ = 7⋅77–7⋅75 (m, 2H,
Ar-H), 7⋅50–7⋅47 (m, 1H, Ar-H), 7⋅41–7⋅38 (m, 2H,
3
. Results and discussion
Ar-H), 7⋅10 (br s, 1H, NH), 7⋅00–6⋅94 (m, 4H,
1
). Entry 4: A solid, H NMR In our procedure we have used a stable and suitable
Ar-H), 2⋅23 (s, 3H, CH
3
(
300 MHz, CDCl
3
): δ = 7⋅64 (d, 2H, J = 8⋅3 Hz, base, KF/Al
2 3
O
, for N-arylation of arylsulfonamides
Ar-H), 7⋅22 (d, 2H, J = 8⋅0 Hz, Ar-H), 7⋅03 (d, 2H, with aryl bromides, aryl iodides and heteroaryl bro-
J = 8⋅3 Hz, Ar-H), 6⋅97–6⋅93 (m, 2H, Ar-H), 6⋅62 mides (scheme 1).
(
br s, 1H, NH), 2⋅38 (s, 3H, CH
3
), 2⋅27 (s, 3H, CH
Entry 8: A solid, H NMR (300 MHz, CDCl
δ = 7⋅58 (d, 2H, J = 8⋅2 Hz, Ar-H), 7⋅22 (d, 2H, fonamide with KF/Al
J = 8⋅2 Hz, Ar-H), 6⋅99–6⋅94 (m, 2H, Ar-H), 6⋅79– in the presence of different ligands such as 1,10-
⋅74 (m, 2H, Ar-H), 6⋅32 (br s, 1H, NH), 3⋅76 (s, phenanthroline, L-proline, N,N′-dibenzylethylene-
3
).
): we have treated 4-iodotoluene with benzenesul-
, CuI (20 mol%) in dioxane
In order to find the optimum reaction conditions
1
3
2
O
3
6
1
3
H, OCH
3
), 2⋅39 (s, 3H, CH
3
). Entry 10: A solid, H diamine, N,N′-dimethylethylenediamine, glycine,
NMR (300 MHz, CDCl
3
): δ = 7⋅82–7⋅79 (m, 2H, Ar-
H), 7⋅60–7⋅55 (m, 1H, Ar-H), 7⋅38-7⋅34 (m, 2H,
Ar-H), 7⋅32–7⋅27 (m, 2H, Ar-H), 6⋅98 (br s, 1H,
NH). Entry 12: A solid, H NMR (300 MHz,
Table 1. The coupling of 4-iodotoluene with benzene-
sulfonamide in the presence of different ligands.
1
Entry
Ligand
Yield (%)
3
CDCl ): δ = 7⋅83–7⋅73 (m, 5H, Ar-H), 7⋅51–7⋅34 (m,
H, Ar-H), 6⋅81 (br s, 1H, NH). Entry 16: A solid,
7
1
H NMR (300 MHz, CDCl
⋅2 Hz, Ar-H), 7⋅22 (d, 2H, J = 8⋅2 Hz, Ar-H), 7⋅10
t, 1H, J = 7⋅8 Hz, Ar-H), 6⋅98 (br s, 1H, NH), 6⋅89
t, 3H, J = 6⋅8 Hz, Ar-H), 2⋅37 (s, 3H, CH ), 2⋅26 (s,
). Entry 19: A solid, H NMR (300 MHz,
): δ = 11⋅18 (s, 1H, NH), 8⋅11 (d, 2H,
J = 9⋅1 Hz, Ar-H), 7⋅74 (d, 2H, J = 8⋅2 Hz, Ar-H),
⋅37 (d, 2H, J = 8⋅2 Hz, Ar-H), 7⋅29 (d, 2H,
J = 9⋅1 Hz, Ar-H), 2⋅32 (s, 3H, CH ). Entry 20: A
): δ = 7⋅85 (d, 4H,
J = 8⋅6 Hz, Ar-H), 7⋅57 (t, 1H, J = 6⋅0 Hz, Ar-H),
⋅47 (t, 2H, J = 7⋅1 Hz, Ar-H), 7⋅16 (d, 2H,
J = 8⋅6 Hz, Ar-H), 7⋅12 (br s, 1H, NH), 2⋅53 (s, 3H,
3
): δ = 7⋅70 (d, 2H, J=
1
45
8
N
N
(
(
3
2
3
55
20
1
N
COOH
3
H, CH
3
H
CDCl
3
NH NH
7
3
1
4
5
90
40
H C N
3
N CH
solid, H NMR (300 MHz, CDCl
3
3
H
H
CH COOH
2
H N
2
7
NH
2
1
COCH
DMSO-d
J = 8⋅4 Hz, Ar-H), 7⋅70 (d, 2H, J = 7⋅9 Hz, Ar-H),
⋅35 (d, 2H, J = 7⋅9 Hz, Ar-H), 7⋅19 (d, 2H,
J = 8⋅4 Hz, Ar-H), 2⋅44 (s, 3H, COCH ), 2⋅31 (s, 3H,
3
). Entry 21: A solid, H NMR (300 MHz,
6
7
15
30
HO
CH
OH
OH
6
): δ = 10⋅77 (br s, 1H, NH), 7⋅81 (d, 2H,
3
7
N
H C
3
NH
2
3

Copper-catalysed N-arylation of arylsulfonamides with aryl bromides and aryl iodides using KF/Al
2
O
3
145
2 3
Table 2. The copper-catalysed N-arylation of arylsulfonamides in the presence of KF/Al O .
Aryl halide
or Het-Br
M.p. (°C) Observed
(reported)
Yield
b
(%)
a
15
Entry
Sulfonamide
Product
Time (h)
O
1
5a
I
S
N
9
109–112 (111–112)
91
1
1
H
O
O
1
5b
I
Me
S
N
9
9
97–99 (102–103)
93
90
2
3
2
1
H
O
O
S
H C
3
I
15c
N
Me
118–120 (117–119)
H
O
O
H C
3
I
Me
S
N
Me
15b
H
8
117–118 (115)
92
15
15
4
5
6
2
1
2
O
I
Me
CH
O
S
3
15d
13
120–122 (122–123)
N
H
O
I
Me
CH
O
3
15e
13
105–107 (107–109)
Me
S N
H
O
O
1
5f
7
8
MeO
MeO
I
I
1
2
S
N
H
OMe
11
10
93–94⋅5 (88–89)
75
86
O
O
I
1
5g
Me
S
N
H
OMe
112–114 (114)
O
MeO
OMe
O
1
5h
9
1
1
2
13
87–89 (88–89)
42
88
88
S
N
H
O
CF
3
CF
3
O
1
5i
1
0
5
72⋅5–74 (88–89)
I
S N
H
O
CF
3
CF
3
O
1
5j
1
1
5
94⋅5–96⋅5 (94–95⋅5)
I
Me
S N
H
O
I
1
68–170
O
1
2
1
12
15k
40
S
N
H
(170⋅5–171⋅5)
O
O
S
1
5a
Br
N
H
11
11
109–112 (111–112)
80
84
1
1
3
4
1
2
O
O
1
5b
Br
Me
S
N
97–99 (102–103)
H
O
Me
H C
3
O
S
1
5l
1
5
1
12
94⋅5–95⋅5 (95)
86
Br
N
H
O
(
Contd…)

1
46
Rahman Hosseinzadeh et al
Table 2. (Contd…)
Aryl halide
M.p. (°C) Observed
(reported)
Yield
b
(%)
a
15
Entry
or Het-Br
Sulfonamide
Product
Time (h)
Me
H C
3
O
1
5m
1
6
2
12
114–115⋅5 (114)
86
Br
Me
S
N
H
O
Br
Me
CH
O
15e
3
1
7
2
13
105–107 (107–109)
15
Me
S
N
H
O
Br
OMe
O
S
79⋅5–81⋅5
1
1
8
9
1
2
13
66
96
MeO
N
H
15d
(
82⋅5–83⋅5)
O
O
1
5n
O
N
Br
Me
S
N
NO
2
6
193–196 (189–191)
2
H
O
O
O
O
S
H C
3
Br
15o
2
0
1
N
H
Me
11
258–260 (262)
90
O
O
O
O
2
04–206
H C
3
Br
2
1
2
Me
S
N
Me
10
15p
94
H
(204⋅5–205)
O
O
1
5q
2
2
2
2
2
3
4
5
1
2
1
2
S
N
4
4
171–173 (171–172)
214–216 (215–216)
98
90
85
85
H
N
N
Br
O
O
1
5r
Me
S
N
H
N
N
N
Br
O
N
Br
O
S
1
91–193
N
12
12
15s
H
(188⋅1–189⋅1)
O
N
Br
O
1
92–194
Me
S
N
H
15t
O
N
(190⋅5–191⋅5)
Br
O
1
5v
2
6
2
Me
S
N
S
13
106–108 (105–106)
75
H
O
S
a
Reactions performed using 20 mol% of N,N′-DMEDA as ligand, 1.0 equiv. of aryl halide or heteroaryl bromide,
b
1
⋅5 equiv. of arylsulfonamides and 5 equiv. of KF/Al
products were characterized by H NMR and melting points
2
O
3
as base in dioxane as solvent at 100–110°˚C. Isolated yields;
1
2 3
Scheme 1. N-Arylation of arylsulfonamides catalysed by CuI and KF/Al O .
tris(hydroxymethyl)aminomethane and N,N-dimethyl- N and C–O bond formation in arylation of amide,
1
4
ethylenediamine and the results are presented in alcohols, phenols and diazoles. To test the general-
table 1. The best yield of the cross-coupling product ity of this procedure, we have examined the cou-
was obtained with N,N′-DMEDA (table 1, entry 4). pling of different aryl iodides, aryl bromides and
KF/Al as a base in the presence of CuI was heteroaryl bromides with benzene and p-toluene-
chosen as we have recently used this system for C– sulfonamides and results are shown in table 2.
2
O
3

Copper-catalysed N-arylation of arylsulfonamides with aryl bromides and aryl iodides using KF/Al
2
O
3
147
3
. Turner S R, Strohbach J W, Tommasi R A, Aristoff P
When iodobenzene was treated with sulfonamides
under optimal reaction conditions, a high yield of
the coupling products was obtained (table 2, entries
A, Johnson P D, Skulnick H I, Dolak L A, Seest E P,
Tomich P K, Bohanon M J, Horng M M, Lynn J C,
Chong K T, Hinshaw R R, Watenpaugh K D,
Janakiraman M N and Thaisrivongs S J 1998 J. Med.
Chem. 41 3467
1
and 2). Similarly, para- methyl and para-methoxy
iodobenzene with sulfonamides gave the corre-
sponding N-arylsulfonamides in high yield (table 2,
entries 3, 4 and 7, 8). However, when ortho-methyl,
ortho-methoxy iodobenzenes or 1-iodonaphtalene
were used, the yield of the products were low (table
4. Serradeil-Le Gal C, Wagnon J, Garcia C, Lacour C,
Guiraudou P, Christophe B, Villanova G, Nisato D
and Maffrand J P 1993 J. Clin. Invest. 92 224
5
. (a) Cremlyn R 1996 Organosulfur Chemistry: An In-
troduction (New York: John Wiley and Sons); (b)
Anderson K K 1979 In Sulfonic acid and their de-
rivatives in comrehensive organic chemistry (eds) D
H R Barton, W D Ollis and D N Jones (Oxford: Per-
gamon Press) vol 3; (c) Massah A R, Azadi D, Aliyan
H, Momeni A R, Javaherian Naghash H and Kazemi
F 2008 Monatshefte fure chemie 139 233
2
, entries 5, 6 and 9, 12). Longer reaction time and
caring out the reaction in a solvent at a high tem-
perature did not improve the yield. On the other
hand, when electron withdrawing groups are present
on the aryl iodide the reaction was faster and the
yield of the coupled product high (table 2, entries 10
and 11). We have tried to extend this protocol to
aryl bromides and aryl chlorides. Aryl bromides un-
der the same reaction conditions when treated with
sulfonamides, gave the same results (table 2, entries
6
. (a) Coutts I G C and Hamblin M 1975 J. Chem. Soc.,
Perkin Trans 1 2445; (b) Yin J and Buchwald S L
2002 J. Am. Chem. Soc. 124 6043
7
. He H and Wu Y J 2003 Tetrahedron Lett. 44 3385
. Steinhuebel D, Palucki M, Askin D and Dolling U
8
2
004 Tetrahedron Lett. 45 3305
. Lam P Y S, Vincent G, Clark C G, Deudon S and
Jadhav P K 2001 Tetrahedron Lett. 42 3415
recovered unchanged. Interestingly, the reaction of 10. Deng W, Liu L, Zhang C Liu M and Guo Q X 2005
Tetrahedron Lett. 46 7295
1
3–21), but aryl chlorides did not give satisfactory
9
results and in most cases the reaction material was
heteroaryl bromides such as 2-bromopyridine, 3-
bromopyridine, or 3-bromothiophen with benzene or
p-toluene sulfonamides gave the corresponding N-
heteroaryl)benzenesulfonamide in good yields
table 2, entries 22–26).
1
1
1. Blass B E 2002 Tetrahedron 58 9301
2. (a) Yamawaki J, Ando T and Hanafusa T 1981 Chem.
Lett. 1143; (b) Yadav V K and Kapoor K K 1996 Tet-
rahedron 52 3659; (c) Alloum B A and Villemin D
1989 Synth. Commun. 19 2567; (d) Kabalka G W,
Wang L, Namboodiri V and Pagni R M 2000 Tetra-
hedron Lett. 41 5151; (e) Kabalka G W, Pagni R M
and Hair C M 1999 Org. Lett. 1 1423
(
(
4
. Conclusion
1
1
3. Schmittling E A and Sawyer J S 1991 Tetrahdron
Lett. 32 7207
In summary, we have developed a simple and effi-
cient method for the copper-catalysed coupling of a
variety of aryl iodides, aryl bromides and heteroaryl
bromides with benzene and p-toluene sulfonamides
4. (a) Hosseinzadeh R, Tajbakhsh M, Mohadjerani M
and Mehdinejad H 2004 Synlett. 1517; (b) Hossein-
zadeh R, Tajbakhsh M, Mohadjerani
M and
Alikarami M 2005 Synlett. 1101; (c) Hosseinzadeh R,
Tajbakhsh M and Alikarami M 2006 Tetrahdron Lett.
47 5203; (d) Hosseinzadeh R, Tajbakhsh M and
Alikarami M 2006 Synlett 2124; (e) Hosseinzadeh R,
Tajbakhsh M, Alikarami M and Mohadjerani M 2008
J. Het. Chem. 45 1815; (f) Hosseinzadeh R, Sarrafi
Y, Mohadjerani M and Mohammadpourmir F 2008
Tetrahdron Lett. 49 840; (g) Hosseinzadeh R, Gol-
choubian H and Masoudi M 2008 J. Chin. Chem. Soc.
55 649; (h) Hosseinzadeh R, Tajbakhsh M, Mohad-
jerani M Rezaei P and Alikarami M 2008 Synth.
Commun. 38 3021; (i) Hosseinzadeh R, Tajbakhsh M,
Mohadjerani M and Ghorbani E 2008 Chin. J. Chem.
26 2120
using KF/Al
2
O
3
, CuI and N,N′-DMEDA. Potassium
) provides
CO
fluoride supported on alumina (KF/Al
2
O
3
a viable alternative to bases such as Cs
2
3
.
Acknowledgement
Financial support for this work from the Research
Council of Mazandaran University is gratefully
acknowledged.
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