Novel and efficient synthesis of symmetrical functionalized biaryls using zinc and triethylammonium formate

Article abstract of DOI:10.1055/s-2004-817783

Reductive homocoupling of aryl halides in the presence of commercial zinc dust and triethylammonium formate in methanol produces biaryls in good to excellent yields. Aryl halides having either electron-donating or electron-withdrawing groups underwent smooth coupling to afford the corresponding symmetrical biaryls. The reductive coupling did not occur without triethylammonium formate. Addition of one equivalent of sodium hydroxide enhanced the coupling reaction rate. The commercial zinc dust is inexpensive, widely available and can be used without any auxiliary catalysts such as Pd(0) and/or Ni(0).

Full text of DOI:10.1055/s-2004-817783

LETTER
877
Novel and Efficient Synthesis of Symmetrical Functionalized Biaryls Using
Zinc and Triethylammonium Formate
N
ovel and Efficien
.
t
S
ynthesis
o
A
f
Symmetrical
F
u
b
nctionalized
iBiarylsraj, G. R. Srinivasa, D. Channe Gowda*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, 570 006, India
Fax +91(821)2421263; fax +91(821)2518835; E-mail: dcgowda@yahoo.com
Received 6 October 2003
nents of the system, i.e. transition metal, electron source,
and solvent.
Abstract: Reductive homocoupling of aryl halides in the presence
of commercial zinc dust and triethylammonium formate in metha-
nol produces biaryls in good to excellent yields. Aryl halides having
either electron-donating or electron-withdrawing groups underwent
smooth coupling to afford the corresponding symmetrical biaryls.
The reductive coupling did not occur without triethylammonium
formate. Addition of one equivalent of sodium hydroxide enhanced
the coupling reaction rate. The commercial zinc dust is inexpensive,
widely available and can be used without any auxiliary catalysts
such as Pd(0) and/or Ni(0).
In 1978, Bamfield et al.12 performed the homocoupling
of aryl halides using a heterogeneous mixture of palla-
dium on carbon as the catalyst together with a sodium
formate solution as the ultimate reductant. This approach
is highly advantageous as it involves mild reaction condi-
tions, easy bulk management, minimal effluents, and
facile product separation. Accordingly, various organic
reducing agents such as 2-propanol,13a 2-propanol/tet-
raalkylammonium salt,13b hydroquinone,13c molecular
hydrogen,13d sodium formate,13e amines,13f and tet-
rakis(dimethylamino)ethylene13g have been used in palla-
dium-catalyzed reductive homocoupling of aryl halides.
However, in the presence of an organic reducing agent
and a powerful catalyst like palladium, aryl halides are
prone to undergo hydrodehalogenation rather than cou-
pling reaction resulting in low yields of the biaryls. Thus,
there still remains a great demand for the development of
alternative catalysts and reducing agents to promote
highly selective, cost-effective and efficient reductive
coupling of aryl halides.
Key words: aryl halides, homocoupling, zinc, triethylammonium
formate, biaryls
Biaryls are recognized as an important class of com-
pounds in organic synthesis because of their numerous po-
tential applications. Biaryls exhibit a large variety of
physical and chemical properties and can be used as
monomers for the synthesis of conductive polymers,1 for
the synthesis of important biaryl natural products such as
steganone,2 supramolecules,3 as ligand catalysts and re-
ceptor macrocyclic molecules.4 As a consequence, over
the last 10 years more than 700 articles have dealt with
new results in the area of aryl-aryl bond formation.5
We report here the zinc-catalyzed facile synthesis of sym-
metrical biaryls using base and triethylammonium for-
mate in methanol at reflux. The zinc/triethylammonium
formate system effectively promotes the reductive homo-
coupling of aryl halides 1a–n having either electron-do-
nating or electron-withdrawing groups to give the
corresponding symmetrical biaryls 2a–n (Scheme 1).
Various palladium and/or nickel catalyzed cross-coupling
reactions of aryl halides with aryl nucleophiles have been
developed for the synthesis of symmetrical and unsym-
metrical biaryls. Aryl boronic acids,6 aryl stannanes,7 and
aryl zinc8 derivatives as well as aryl Grignard reagents9
are frequently used as aryl nucleophiles. On the other
hand, the synthesis of symmetrical biaryls via reductive
dimerization of aryl halide is considered to be a more con-
venient and straightforward method as it bypasses the syn-
thesis of aryl nucleophiles, which sometimes requires two
steps. Historically, the Ullmann coupling has been used
for this purpose.10 However, the Ullmann coupling con-
sumes more than a stoichiometric amount of copper, and
proceeds only under forcing conditions resulting in limit-
ed applications to the synthesis of functionalized biaryls.
Zinc has been widely used as auxiliary reducing agent
(electron source) in conjunction with transition metals
(electron-transfer catalyst) for the reductive homocou-
pling of aryl halides.11 In these multi-metal redox systems,
reactivity and selectivity depend highly on the compo-
Scheme 1
The experimental procedure is very simple. A mixture of
aryl halide (5 mmol), zinc dust (5 mmol; particle size <45
mm), triethylammonium formate (10 mmol) and sodium
hydroxide (5 mmol) in methanol (15 mL) was stirred un-
der reflux for the specified time under a nitrogen atmo-
sphere (Table 1). After consumption of the starting
material, as monitored by TLC, the reaction mixture was
filtered through Celite. The filtrate was evaporated under
vacuum and the residue was taken into chloroform or di-
ethyl ether and the organic phase was washed successive-
ly with brine and water and then dried (Na2SO4).
SYNLETT 2004, No. 5, pp 0877–0879
0
2.
0
4.
2
0
0
4
Advanced online publication: 24.02.2004
DOI: 10.1055/s-2004-817783; Art ID: D24503ST
© Georg Thieme Verlag Stuttgart · New York

878
K. Abiraj et al.
LETTER
Evaporation of the solvent followed by purification by both electron-donating and electron-withdrawing substit-
silica gel chromatography produced the homocoupled uents allow efficient coupling with no significant differ-
ence in reaction rate. Similar reductive coupling proceed
smoothly with 1-iodonaphthalene and 2-iodopyridine
(Table 1, entries 13 and 14). This procedure is found to
be compatible with several sensitive functionalities such
as -OH, -OMe, -CO2Me, -COOH, -CN. However, the
reductive coupling of an aryl halide containing nitro or
carbonyl group is very difficult because these two func-
tionalities undergo reduction very easily.
product.
A wide range of structurally varied aryl halides underwent
coupling by this procedure to furnish the corresponding
biaryls. The results are summarized in Table 1. All the bi-
aryls synthesized were characterized by comparison of
their physical properties and spectroscopic data with au-
thentic samples. Addition of one equivalent of sodium hy-
droxide enhanced the coupling rate significantly. The
reactions are, on the whole, reasonably fast and high
yielding. The relative reactivity of aryl halides decreases
in the order I>Br>Cl (Table 1, entries 1–3). Generally,
Reductive coupling was also attempted using an alkaline
solution of iodobenzene with zinc but without triethyl-
ammonium formate. Even after prolonged reflux (48 h),
Table 1 Reductive Homocoupling of Aryl Halides Using Zinc/Triethylammonium Formate
Entry
Aryl Halide
Producta
Time (h)b
Yield (%)c
1
2
3
1a
1b
1c
2 (5)
4 (11)
7 (17)
95
94
91
2a–c13c
X = I
X = Br
X = Cl
4
5
1d
1e
2d13c
5 (11)
3 (10)
84
90
2e13c
6
7
1f
2f13g
2g13g
2h13g
2i18
1.5 (4)
3 (7)
96
95
94
81
90
92
93
85
1g
1h
1i
8
6 (12)
3.5 (9)
5 (6.5)
4.5 (8)
4 (9.5)
5 (9)
9
10
11
12
13
1j
2j18
1k
1l
2k19
2l19
1m
2m13c
14
1n
2n13c
2.5 (6)
92
a All of the products are known and the isolated products gave TLC, melting points, IR spectra and 1H NMR spectra (AMX-400 MHz
spectrometer: CDCl3; TMS as internal standard) in agreement with authentic samples.
b Time in parenthesis corresponds to coupling reaction time without sodium hydroxide.
c Yields of isolated pure products.
Synlett 2004, No. 5, 877–879 © Thieme Stuttgart · New York

LETTER
Novel and Efficient Synthesis of Symmetrical Functionalized Biaryls
879
the starting material was recovered quantitatively. This
result reveals two important facts; i) the mechanism of
coupling does not proceed via the formation of radical
anion {[C6H5X]–} as the aryl halides are effective electron
acceptors in the presence of donors such as alkali metals,
carbanions, and various organometals to form radical an-
ions.13e,14 ii) the coupling does not involve the initial in
situ formation of aryl zinc halide intermediate.15 A plausi-
ble mechanism of the zinc/triethylammonium formate
promoted reductive homocoupling reaction of aryl halides
is shown in Scheme 2. The initial step in the homo-
coupling reaction would be the formation of zinc hydride
(ZnH–) species by the reaction of Zn(0) with HCOO–.16
Addition of aryl halide Ar-X in the presence of HNEt3+ to
thus formed ZnH– could form Ar-Zn-H. Subsequent reac-
tion of aryl zinc hydride Ar-Zn-H with Ar-X would afford
Ar-Zn-Ar. Finally, reductive elimination of Ar-Zn-Ar
would produce biaryl Ar-Ar and Zn(0) to complete the
catalytic cycle.17 The exact role played by the base in this
system is unclear. Addition of base may facilitate the
coupling reaction by neutralizing the acid produced in the
reduction cycle.
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Scheme 2 A Plausible mechanism of the zinc/triethylammonium
formate promoted reductive homocoupling of aryl halides
In conclusion, the triethylammonium formate mediated
synthesis of symmetrical functionalized biaryls via reduc-
tive homocoupling of aryl halides can be achieved in the
presence of commercial zinc dust. In the zinc/triethylam-
monium formate system, the coupling of aryl halides pro-
ceeds efficiently to furnish corresponding biaryls in high
yields and the competitive reduction reaction (hydrodeha-
logenation) is less probable. Moreover zinc dust is inex-
pensive, widely available and can be used without any
expensive auxiliary catalysts such as palladium and/or
nickel. The ease of product separation, safe reaction me-
dium, high selectivity and low cost of the reagents pro-
mote this method as a promising alternative to other
existing transition metal catalyzed coupling techniques.
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initial formation of PdH-species was proposed as a plausible
mechanism, see: Rajgopal, S.; Anwer, M. K.; Spatola, A. F.
In Peptides: Design, Synthesis, and Biological Activity;
Basava, C.; Anantharamaiah, G. M., Eds.; Birkhauser:
Boston, 1994, 11.
Acknowledgment
(17) For zinc/nickel catalyst-promoted reaction, reductive
elimination of Ar2Ni affording Ar2 was proposed as a
plausible mechanism.11
(18) The spectra were compared to those of a commercial sample.
(19) Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261.
We gratefully acknowledge financial support from the University
Grants Commission, New Delhi, India. K. A. is also thankful to
the Lady Tata Memorial Trust, Mumbai, India for a research
fellowship.
Synlett 2004, No. 5, 877–879 © Thieme Stuttgart · New York