Copper catalyzed Gomberg-Buchmann-Hey reaction using aryldiazonium tosylate

Article abstract of DOI:10.1016/j.tetlet.2011.07.074

Copper catalyzed modification of Gomberg-Bachmann-Hey reaction to synthesize symmetrical/unsymmetrical biaryls via diazotization of anilines with p-TSA and NaNO₂ system at 50 °C, in aromatic liquids as solvents and second partners was successfully developed. Aniline and 3-nitronaniline gave biphenyl and 3-nitrobiphenyl, respectively, with moderate yields. All para-substituted anilines gave comparatively higher yields while in the other cases including ortho-substituted anilines yields were lower. Except anilines with o-NHCOCH₃ and o-CONH₂ which gave symmetrical biaryls, all others gave selectively unsymmetrical biaryls.

Full text of DOI:10.1016/j.tetlet.2011.07.074

Tetrahedron Letters 52 (2011) 4950–4953
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Tetrahedron Letters
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Copper catalyzed Gomberg–Buchmann–Hey reaction
using aryldiazonium tosylate
Ganesh U. Chaturbhuj a, Krishnacharya G. Akamanchi a,
⇑
a Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.M. Parikh Road, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper catalyzed modification of Gomberg–Bachmann–Hey reaction to synthesize symmetrical/unsym-
metrical biaryls via diazotization of anilines with p-TSA and NaNO2 system at 50 °C, in aromatic liquids as
solvents and second partners was successfully developed. Aniline and 3-nitronaniline gave biphenyl and
3-nitrobiphenyl, respectively, with moderate yields. All para-substituted anilines gave comparatively
higher yields while in the other cases including ortho-substituted anilines yields were lower. Except ani-
lines with o-NHCOCH3 and o-CONH2 which gave symmetrical biaryls, all others gave selectively unsym-
metrical biaryls.
Received 4 May 2011
Revised 14 July 2011
Accepted 17 July 2011
Available online 23 July 2011
Keywords:
Gomberg–Buchmann–Hey reaction
Aryldiazonium tosylate
Cross coupling
Ó 2011 Elsevier Ltd. All rights reserved.
Copper catalyst
Biaryls
Gomberg–Buchmann–Hey (GBH) reaction1a,b is one of the clas-
sical methods for aryl C–C coupling wherein generation of aryl rad-
ical through degradation of aryldiazonium salt in the presence of a
base viz. sodium hydroxide2a,b or sodium acetate3 in aromatic liq-
uids as second partner at 0–5 °C to yield biaryl compounds. This
reaction is well studied mechanistically4 and few improvements
have been made. Despite wide applicability of GBH reaction it is
least preferred for industrial applications because diazotization in
aqueous medium leads to biphasic reaction.
The biaryl scaffold is an important substructure in a number of
bioactive and functional molecules. It is found in many categories
of pharmaceutically active ingredients such as antibiotics,
antiinflammatory, antihypertensive, antifungal, anticancer, antihis-
taminic, and infertility treatment.5–7 Clinically used antihyperten-
sive drugs like candesartan, losartan, valsartan, and telmisartan
contain this scaffold.
Syntheses of biaryls have been the focus of synthetic activity of
chemist for over 100 years.8 There are several methods for aryl C–C
bond formation; the most common one is based on transition me-
tal catalyzed coupling reactions viz. Mizeroki-Heck, Nigishi, Stille,
Suzuki-Miyaura.9–11 Majority of these methods need pre-function-
alization of the coupling reactants with halogen, boronic acid,
silane, mesylate, and triflate and so on. These methods of aryl
C–C bond formation although high yielding with great specificity
require precious metals and specially synthesized ligands.
Biaryls are accessible by classical methods as well as Ullmann
reaction,8 Gatterman reaction,12 GBH reaction and also via decom-
position of biaryl peroxides to generate radical followed by cou-
pling with aromatic counterpart.13 All these methods have
several disadvantages such as low yields, harsher conditions, large
amount of waste generation, and tedious workup procedures.
However, the major advantage is that these reactions require
cheaper catalysts with no additional requirement of ligands. These
advantages have triggered the reinvestigation of the classical
methods and one of these being GBH reaction.
Important modifications in GBH reaction are synthesis of aryldi-
azonium salts in neutral aprotic, homogenous medium by the use
of alkyl nitrites14 or alkyl thionitrites.15 The issue of heterogenicity
was dealt with by the use of phase-transfer catalysts such as
18-Crown-6 with potassium acetate16a as well as with potassium
t-butoxide as bases16b and the methods have also been modified
for intra-molecular ring closure.17 Stable diazonium salts that can
be readily prepared, isolable and nonexplosive in solid state are
reported and these include aryldiazonium tetrafluoroborate,18
O
S
p-TSA / NaNO2
NH
2 TEOF , CuCl
o
N
N O
O
–O
O
50
C
N+
N+
N+
–O
O
–O
O
⇑
Corresponding author. Tel.: +91 22 33611111; fax: +91 22 33611020.
E-mail address: kgap@rediffmail.com (K.G. Akamanchi).
Scheme 1. Copper catalyzed GBH reaction of 4-nitroaniline in benzene as solvent/
reactant.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.074

G. U. Chaturbhuj, K. G. Akamanchi / Tetrahedron Letters 52 (2011) 4950–4953
4951
Table 1
Reaction results of aryldiazonium tosylate with benzene aromatic solvent/reactant (Method A)
p-TSA/NaNO2
TEOF, CuCl
50 0C
O
S
R2
NH2
R2
R1
R1
R1
N
N O
O
R1
R1
1
2
3
Entry
Anilines 1
Product(s) Yielda(%)
Mp °C
Mp °C, lit. (Ref.)
2 (Lit.b)
3
NH2
1
2
2a, 55 (47)
2b, 60 (26)
3a, 0
3b, 0
69–70
82–83
70–7227
84–8728
1a
NH2
H3CO
1b
NH2
3
4
2c, 75 (60)
2d, 70 (67)
3c, 0
3d, 0
72–74
75–7829
Cl
1c
NH2
112–114
114.5–11530
O2N
1d
NH2
5
6
7
2e, 70
2f, 67
2g, 80
3e, 0
3f, 0
3g, 0
215–217
112–114
224–226
218–219.431
115–11632
227–22833
HOOC
1e
NH2
H3COOC
H2NO2S
1f
NH2
1g
NH2
8
2h, 55
3h, 0
3i, 0
3j, 0
3k, 0
Oil
3427
Cl
1h
1i
NH2
9
2i, 40 (33)
2j, 37
Oil
37–3834
113–11435
11536
NO2
NH2
10
11
110–112
112–113
COOH
1j
NH2
2k, 45
COOCH3
1k
O
12
2l, 43c
1l, 0
Oil
––
NH2
1l
NH2
O2N
13
14
2m, 60
2n, 0
3m, 0
60–61
60–6137
1m
NH2
3n, 75
160–162
164–165.538
NHCOCH3
1n
(continued on next page)

4952
G. U. Chaturbhuj, K. G. Akamanchi / Tetrahedron Letters 52 (2011) 4950–4953
Table 1 (continued)
Entry
Anilines 1
Product(s) Yielda(%)
Mp °C
Mp °C, lit. (Ref.)
2 (Lit.b)
2o, 0
3
NH2
CONH2
15
3o, 78
208–210
209–21139
1o
a
Isolated yield.
Yields taken from Ref.15.
29% of 9-fluorenone was formed, by GC.
b
c
2,20-diacetylaminobiphenyl was subjected to hydrolysis while
2,20-biphenyl carboxamide to Hoffmann degradation yielded iden-
tical product, that is, 2,20-diaminobiphenyl.25 As expected in the
case of 2-aminobenzophenone, 9-fluorenone was formed as a by
product due to intramolecular cyclization (Table 1, entry 12).
Selective formation of unsymmetrical biaryls is attributed to ra-
pid generation of aryl radical in dilute solution where solvent plays
a dual role as diluent and reactant. In the two exceptional cases
(Table 1, entries 14 and 15) where only symmetrical biaryls are
formed due to self coupling, it is difficult to give a convincing
explanation. However, it could be postulated that a dimeric Cu-
complex by the participation of nitrogen containing neighboring
groups prior to generation of free radicals is responsible.
o-Tolylbenzonitrile (OTBN) is an important intermediate in the
synthesis of sartan series of drugs such as losartan, candesartan,
and valsartan. Synthesis of OTBN was attempted by Method B26
using p-toluidine and benzonitrile as the solvent/reactant. The
results indicated that the product was a 1:1 mixture of OTBN
and p-tolylbenzonitrile (Table 2, entry 1). In the same way reaction
of aniline with chlorobenzene resulted in the mixture of o, m, and
p-substituted biaryls in the ratio of 46:31:23 (Table 2, entry 2).
In summary a new modification of GBH reaction that can be
conducted in organic solvent at a higher temperature using copper
as catalyst has been successfully developed. Present method is
applicable for the synthesis of symmetrical/unsymmetrical biaryl
with moderate to good yields depending on the substrates.
Table 2
Reaction results of aryldiazonium tosylate with benzonitrile and chlorobenzene
aromatic solvent/reactant (Method B)
O
S
p-TSA / NaNO
2
NH2
R2
R1
N
N
O
O
TEOF , CuCl
R2
50 0
C
R1
R1
Entry
Anilines R1
Aromatic solvent/reactant R2
Biaryl isomer ratioa
o-
m-
p-
1
2
CH3
H
CN
Cl
50
46
—
31
50
24
a
By comparison of retention times with standard and area percent by GC
analysis.
hexafluorophosphate,19 and aryldiazonium o-benzenedisulfona-
mides.20 Similarly, aryldiazonium tosylates Ar1N2þAr2SOꢀ are
3
reported about half a century ago21 and these have been used re-
cently for iodination.22
This inspired us to investigate the use of aryldiazonium tosylate
for aryl C–C coupling. Herein we report the rapid generation and
copper catalyzed coupling of aryldiazonium tosylate in nonaque-
ous conditions with aromatic liquid as solvent/reactant to yield
baryls.
For preliminary experiment 4-nitroaniline was used as a repre-
sentative substrate which was diazotized with p-toluenesulfonic
acid (p-TSA) and NaNO2 in the presence of triethylorthoformate
(TEOF) as water scavenger23 and CuCl as a catalyst in benzene as
aromatic reactant/solvent at 50 °C to yield selectively 4-nitrobi-
phenyl with no detectable amount of symmetrical biaryl
(Scheme 1).
To study the general applicability substrates including anilines
with electron-donating as well as electron-withdrawing substitu-
ents at different positions were selected.
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