Simple and efficient TiCl4-mediated synthesis of biaryls via arylmagnesium compounds

Article abstract of DOI:10.1016/S0040-4020(00)00929-7

Oxidative self-coupling reactions of various arylmagnesium bromides with TiCl₄ affords the corresponding symmetric biaryls in moderate to good yields at 0°C or lower. Tributylmagnesate-induced halogen-magnesium exchange of aryl halides followed by the coupling reaction provides biaryls in good yields under mild conditions. This method can achieve a one-pot synthesis of biaryls containing functional groups such as esters, amides, or nitriles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00929-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9601±9605
Simple and Ef®cient TiCl4-Mediated Synthesis of Biaryls via
Arylmagnesium Compounds
*
Atsushi Inoue, Kazuya Kitagawa, Hiroshi Shinokubo and Koichiro Oshima
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 11 September 2000; accepted 4 October 2000
AbstractÐOxidative self-coupling reactions of various arylmagnesium bromides with TiCl4 affords the corresponding symmetric biaryls in
moderate to good yields at 08C or lower. Tributylmagnesate-induced halogen±magnesium exchange of aryl halides followed by the coupling
reaction provides biaryls in good yields under mild conditions. This method can achieve a one-pot synthesis of biaryls containing functional
groups such as esters, amides, or nitriles. q 2000 Elsevier Science Ltd. All rights reserved.
Biaryls are recognized as an important class of compounds
in organic synthesis because of their versatility in both
ligand chemistry and materials chemistry. Biaryls are also
found in various types of natural products which show
unique biological activity. The synthesis of biaryls via
coupling reactions has been the subject of numerous past
and current investigations.1 Biaryls are often prepared from
aryl halides either by the classical Ullmann-type reaction2,3
or by the transition metal-catalyzed coupling reaction of
aryl halides with arylmetals.4 Self-coupling reaction of aryl-
metallic reagents with oxidants such as Co(II), Cu(II) or
V(V) also provides a convenient method for the synthesis
of symmetric biaryls.5,6
workup and puri®cation by silica gel column chromato-
graphy gave biphenyl (2a) in 82% yield (Scheme 2). The
use of THF as a solvent is essential for successful coupling.
The use of ether instead of THF provided biphenyl in lower
yield (22%).
Various arylmagnesium bromides can be easily prepared
from the corresponding aryl bromides and metallic magne-
sium. A one-pot synthesis of biaryls from aryl bromides has
been developed. The results are shown in Table 1.
As shown in Table 1, 3,3- and 4,40-disubstituted biaryls
could be obtained in moderate to good yields (entries
2±5). In contrast, ortho-substituted arylmagnesium bromide
gave 2,20-disubstituted biaryl only in low yield (entry 6). In
this reaction, the major product was anisole (50%), which
was generated from hydrolysis of the starting Grignard
reagent. In this case, however, an inverse-addition pro-
cedure was found to improve the yield of the desired biaryl.
Thus, the addition of a THF solution of 2-methoxyphenyl-
magnesium bromide, prepared from the reaction of
2-bromoanisole with magnesium, to a solution of TiCl4 in
1,2-dimethoxyethane provided 2,20-dimethoxybiphenyl in
58% yield (Scheme 3).
Phenyltrichlorotitanium is known to decompose thermally
to form biphenyl and titanium(III) chloride (Scheme 1).7
However the yield of biphenyl was low and the synthetic
application of this reaction has not yet been fully investi-
gated. Herein we wish to report a simple procedure for
coupling of various arylmagnesium compounds using
titanium(IV) chloride as an oxidant. The coupling reaction
can proceed under conditions so mild that this method can
be successfully applied to the coupling of functionalized
arylmagnesium reagents.
Titanium(IV) chloride was added dropwise at 08C to a solu-
tion of phenylmagnesium bromide (1a) in THF and the
reaction mixture was stirred for 30 min at 08C. Aqueous
We have also developed an alternative coupling method
starting from aryl halides. Recently we reported the
halogen±magnesium exchange reaction8 of aryl bromides
and aryl iodides with lithium trialkylmagnesate
(R3Mg2Li1).9 This exchange reaction can generate an
Scheme 1.
Keywords: biaryls; coupling reactions; titanium(IV) chloride; arylmag-
nesium compound; aryl halides.
* Corresponding author. Tel.: 181-75753-5523; fax: 181-75753-4863;
e-mail: oshima@fm1.kuic.kyoto-u.ac.jp
Scheme 2.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00929-7

9602
A. Inoue et al. / Tetrahedron 56 (2000) 9601±9605
Table 1. The coupling reaction of arylmagnesium bromides prepared from aryl bromides and magnesium
arylmagnesium ate-complex which would be a promising
precursor for the oxidative coupling reaction. Indeed, the
addition of TiCl4 to the resulting arylmagnesium species
provided biaryls in good yields. The results of this alterna-
tive one-pot procedure are summarized in Table 2. Both aryl
bromides and aryl iodides can be converted to the corre-
sponding biaryls ef®ciently. In the case of dibromobenzene,
one of two bromines could be selectively metallated with
tributylmagnesate to give 4,40-dibromobiphenyl or 3,30-
dibromobiphenyl in good yield (entries 5 and 6).
nitrile, the inverse-addition technique (vide supra) improved
the yields of the corresponding biaryls (Scheme 5). We
suppose that biaryls arise from aryltitanium species via
the transmetallation between magnesium ate-complex 5
and TiCl4. Butylated products could not be found in the
reaction mixture, although butyl group might be on the
titanium species after the transmetallation.
This new coupling method can be successfully applied to
intramolecular reactions. Treatment of substrates such as 6
with trialkylmagnesate followed by an addition of TiCl4
afforded the desired coupling product 7 in moderate yields
(Scheme 6).
It is worth noting that the exchange procedure has an advan-
tageous feature: the exchange reaction with magnesate
reagent proceeds at low temperatures to furnish function-
alized arylmagnesium species ef®ciently. Thus, the subse-
quent TiCl4-induced coupling reaction at low temperatures
provided biaryls bearing functional groups such as an ester
or amide (Scheme 4). In the case of p- or m-bromobenzo-
In conclusion, we have found that TiCl4-induced self-
coupling reaction of arylmagnesium species proceeds
ef®ciently in THF under mild conditions and at low
temperatures. This method can be successfully applied to
the preparation of functionalized biaryls starting from aryl
halides having various functional groups using the halogen±
magnesium exchange reaction.
Experimental
Instrumentation and materials
1H NMR (300 MHz) and 13C NMR (75.3 MHz) spectra
were taken on a Varian GEMINI 300 spectrometer, CDCl3
Scheme 3.

A. Inoue et al. / Tetrahedron 56 (2000) 9601±9605
9603
Table 2. The coupling reaction of arylmagnesium compounds prepared by halogen±magnesium exchange
Scheme 4.
Scheme 5.

9604
A. Inoue et al. / Tetrahedron 56 (2000) 9601±9605
Scheme 6.
was used as a solvent, and chemical shifts are given in d
with tetramethylsilane as an internal standard. IR spectra
were determined on a JASCO IR-810 spectrometer. TLC
analyses were performed on commercial glass plates bear-
ing 0.25 mm layer of Merk Silica gel 60F254. Silica gel
(Wakogel 200 mesh) was used for column chromatography.
The analyses were carried out at the Elemental Analysis
Center of Kyoto University.
benzamide (3j, 0.51 g, 2.0 mmol) in THF (3 mL) was
added dropwise. The mixture was stirred for 0.5 h. TiCl4
(0.33 mL, 3.0 mmol) was added and the reaction mixture
was warmed to 08C gradually. The reaction mixture was
poured into saturated aqueous NH4Cl and extracted with
ethyl acetate (3£10 mL). The organic layers were dried
over Na2SO4 and concentrated in vacuo. Puri®cation by
silica gel column chromatography (ethyl acetate) gave
N,N,N0,N0-tetraethylbiphenyl-4,40-dicarboxamide (2j, 0.23 g,
0.65 mmol) in 65% yield: IR (nujol) 1624, 1287, 1099, 845,
754 cm21; 1H NMR (CDCl3) d 1.15 (bs, 3H), 1.24 (bs, 3H),
3.31 (bs, 3H), 3.55 (bs, 3H), 7.45 (d, Jˆ8.4 Hz, 4H), 7.61 (d,
Jˆ8.4 Hz, 4H); 13C NMR (CDCl3) d 12.82, 14.12, 39.16,
43.21, 126.98, 127.17, 136.58, 141.22, 171.11. Found: C,
74.79; H, 8.07%. Calcd for C22H28N2O2: C, 74.97; H,
8.01%.
Diethyl ether was dried over a slice of sodium. Tetrahydro-
furan (THF) and 1,2-dimethoxyethane (DME) were freshly
distilled from sodium benzophenone ketyl before use.
Titanium(IV) chloride was distilled and stored under
argon. All reactions were carried out under an argon
atmosphere.
General procedure for TiCl4-mediated coupling reaction
of aryl Grignard reagents
Dibutyl biphenyl-4,40-dicarboxylate (2k). IR (nujol) 1722,
1
1267, 1103, 846, 756 cm21; H NMR (CDCl3) d 0.99 (t,
Jˆ7.2 Hz, 6H), 1.49 (tq, Jˆ7.4, 7.2 Hz, 4H), 1.77 (tt,
Jˆ6.6, 7.4 Hz, 4H), 4.35 (t, Jˆ6.6 Hz, 4H), 7.68 (d,
Jˆ8.1 Hz, 4H), 8.12 (d, Jˆ8.1 Hz, 4H); 13C NMR
(CDCl3) d 13.64, 19.17, 30.69, 64.94, 127.28, 130.14,
130.24, 144.42, 166.53. Found: C, 74.37; H, 7.54%. Calcd
for C22H26O4: C, 74.55; H, 7.39%.
Magnesium turnings (51 mg, 2.1 mmol) and THF (3 mL)
were placed in a ¯ask under argon atmosphere. 3-Bromo-
anisole (3d, 0.37 g, 2.0 mmol) was added and stirred for
0.5 h at room temperature. THF (7 mL) was added and the
mixture was cooled to 2788C. TiCl4 (0.33 mL, 3.0 mmol)
was added dropwise and the reaction mixture was stirred for
0.5 h at 08C. The reaction mixture was poured into saturated
aqueous NH4Cl and extracted with ethyl acetate (3£10 mL).
The organic layers were dried over Na2SO4 and concen-
trated in vacuo. Puri®cation by silica gel column chromato-
graphy provided 3,30-dimethoxybiphenyl (2d, 0.15 g,
0.71 mmol) in 71% yield.
Procedure for the synthesis of biphenyldicarbonitrile
To a solution of butylmagnesium bromide (1.0 mL, 1.0 M
THF solution, 1.0 mmol) in THF (5 mL) was added butyl-
lithium (1.3 mL, 1.6 M hexane solution, 2.0 mmol) at 08C
and the mixture was stirred for 10 min. The solution was
cooled to 2408C and a solution of 4-bromobenzonitrile (3l,
0.36 g, 2.0 mmol) in THF (3 mL) was added dropwise. The
mixture was stirred for 0.5 h. In another ¯ask was placed
THF (10 mL) and cooled to 2408C. TiCl4 (0.33 mL,
3.0 mmol) was added and the mixture was stirred for
10 min. To this suspension was added dropwise the THF
solution of arylmagnesate prepared above. The reaction
mixture was stirred for 0.5 h at 2408C and then poured
into saturated aqueous NH4Cl and extracted with ethyl
acetate (3£10 mL). The organic layers were dried over
Na2SO4 and concentrated in vacuo to give a white solid.
Washing this solid with hexane gave biphenyl-4,40-dicarbo-
nitrile (2l, 0.13 g, 0.62 mmol) in 62% yield: IR (nujol) 2222,
Procedure for the synthesis of 2,20-disubstituted biaryl
A THF solution of 2-methoxyphenylmagnesium bromide,
which was prepared from 2-bromoanisole (3f, 0.37 g,
2.0 mmol) and magnesium (51 mg, 2.1 mmol) as above,
was added to a precooled solution of TiCl4 (0.33 mL,
3.0 mmol) in DME (15 mL) at 2788C and the mixture
was stirred for 0.5 h at 08C. The reaction mixture was
poured into saturated aqueous NH4Cl and extracted with
ethyl acetate (3£10 mL). The organic layers were dried
over Na2SO4 and concentrated in vacuo. Puri®cation by
silica gel column chromatography (hexane/ethyl acetateˆ
10/1) provided 2,20-dimethoxybiphenyl (2f, 0.12 g,
0.58 mmol) in 58% yield.
1
1605, 817 cm21; H NMR (CDCl3) d 7.68 (d, Jˆ8.7 Hz,
4H), 7.78 (d, Jˆ8.7 Hz, 4H); 13C NMR (CDCl3) d 112.50,
118.45, 128.01, 132.97, 143.63. Found: C, 82.08; H, 3.79%.
Calcd for C14H8N2: C, 82.34; H, 3.95%.
One-pot procedure for the synthesis of functionalized
biaryl
To a solution of butylmagnesium bromide (1.0 mL, 1.0 M
THF solution, 1.0 mmol) in THF (5 mL) was added butyl-
lithium (1.3 mL, 1.6 M hexane solution, 2.0 mmol) at 08C
and the mixture was stirred for 10 min. The solution was
cooled to 2408C and a solution of 4-bromo-N,N-diethyl-
Biphenyl-3,30-dicarbonitrile (2m). IR (nujol) 2224, 786,
1
685 cm21; H NMR (CDCl3) d 7.60 (dd, Jˆ7.8, 7.8 Hz,
2H), 7.71 (d, Jˆ7.8 Hz, 2H), 7.79 (d, Jˆ7.8 Hz, 2H), 7.84
(s, 2H); 13C NMR (CDCl3) d 113.58, 118.38, 130.13,

A. Inoue et al. / Tetrahedron 56 (2000) 9601±9605
9605
130.75, 131.50, 131.90, 140.29. Found: C, 82.07; H, 3.85%.
Calcd for C14H8N2: C, 82.34; H, 3.95%.
Science, Sports and Culture, Government of Japan. A. I. is
grateful to Research Fellowships of the Japan Society for
the Promotion of Science for Young Scientists.
Procedure for the intramolecular coupling
To a solution of butylmagnesium bromide (1.0 mL, 1.0 M
solution in THF, 1.0 mmol) in THF (2 mL) was added butyl-
lithium (1.3 mL, 1.6 M hexane solution, 2.0 mmol) at 08C
and the mixture was stirred for 10 min. A solution of 1,2-
bis(2-bromophenyl)ethane (6a, 0.34 g, 1.0 mmol) in THF
(3 mL) was added at 08C and the mixture was stirred for
0.5 h at the temperature. TiCl4 (0.33 mL, 3.0 mmol) was
added dropwise at 08C. The reaction mixture was stirred
for further 0.5 h. The mixture was then poured into saturated
aqueous NH4Cl and extracted with ethyl acetate (3£10 mL).
The organic layers were dried over Na2SO4 and concen-
trated in vacuo. Puri®cation by silica gel column chromato-
graphy (hexane/ethyl acetateˆ20/1) afforded 9,10-
dihydrophenanthrene (7a, 0.11 g, 0.63 mmol) in 63% yield
along with dibenzyl (0.05 g, 0.29 mmol) in 29% yield.
References
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(CDCl3) d 5.20 (s, 2H), 6.88 (ddd, Jˆ1.5, 7.5, 7.8 Hz,
1H), 6.96 (dd, Jˆ1.5, 8.1 Hz, 1H), 7.19 (ddd, Jˆ1.5, 7.5,
7.5 Hz, 1H), 7.27 (ddd, Jˆ1.5, 7.8, 8.1 Hz, 1H), 7.37 (ddd,
Jˆ1.5, 7.5, 7.8 Hz, 1H), 7.58 (dd, Jˆ1.5, 7.8 Hz, 1H), 7.59
(dd, Jˆ1.5, 7.5 Hz, 1H), 7.72 (dd, Jˆ1.5, 7.5 Hz, 1H); 13C
NMR (CDCl3) d 69.97, 112.43, 113.74, 121.64, 122.45,
127.77, 128.59, 128.60, 129.23, 132.51, 133.58, 135.94,
154.79. Found: C, 45.53; H, 2.86%. Calcd for
C13H10Br2O: C, 45.65; H, 2.95%.
9,10-Dihydro-9-oxaphenanthrene (7b). IR (neat) 2840,
1607, 1487, 1440, 1245, 1198, 1018, 810, 753, 724, 651,
1
614 cm21; H NMR (CDCl3) d 5.13 (s, 2H), 7.01 (dd,
6. For recent reports of oxidative coupling by oxovanadium
species, see: (a) Ishikawa, T.; Ogawa, A.; Hirao, T. J. Am.
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A. J. Org. Chem. 2000, 65, 1511.
Jˆ1.2, 8.1 Hz, 1H), 7.07 (ddd, Jˆ1.5, 7.5, 7.8 Hz, 1H),
7.16 (dd, Jˆ1.5, 7.5 Hz, 1H), 7.25 (ddd, Jˆ1.5, 7.5,
8.1 Hz, 1H), 7.29 (ddd, Jˆ1.5, 7.5, 7.5 Hz, 1H), 7.39
(ddd, Jˆ1.5, 7.5, 7.8 Hz, 1H), 7.71 (dd, Jˆ1.5, 7.8 Hz,
1H), 7.75 (dd, Jˆ1.5, 7.8 Hz, 1H); 13C NMR (CDCl3) d
68.43, 117.44, 122.07, 122.21, 123.01, 123.36, 124.73,
127.73, 128.51, 129.53, 130.19, 131.50, 154.89. Found: C,
85.73; H, 5.55%. Calcd for C13H10O: C, 85.69; H, 5.53%.
7. (a) Boustany, K. S.; Bernauer, K.; Jacot-Guillarmod, A. Helv.
Chim. Acta. 1967, 50, 1080. (b) Boustany, K. S.; Bernauer, K.;
Jacot-Guillarmod, A. Helv. Chim. Acta. 1967, 50, 1305.
 Ã
8. (a) Rottlander,M.; Boymond, L.; Berillon, L.; Lepretre, A.;
È
Â
Varchi, G.; Avolio, S.; Laaziri, H.; Queguiner, G.; Ricci, A.;
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È
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Knochel, P. J. Org. Chem. 2000, 65, 4618.
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This work was supported by Grant-in-Aid for Scienti®c
Research (No. 10208208) from the Ministry of Education,