A mild and practical synthesis of biphenyl compounds

Article abstract of DOI:10.3184/174751912X13419099572319

A mild and practical synthetic route for biphenyls is established. Isopropyl nitrite was prepared from sodium nitrite, isopropanol and hydrochloric acid. The biphenyl compounds were obtained from the diazotisation of aniline derivatives with the generated isopropyl nitrite and the coupling reaction with benzene derivatives in the presence of CuCl as a catalyst in good yields.

Full text of DOI:10.3184/174751912X13419099572319

JOURNAL OF CHEMICAL RESEARCH 2012
SEPTEMBER, 555–556
RESEARCH PAPER 555
A mild and practical synthesis of biphenyl compounds
Shuang Liang, Xiaohui Cao, Xilong Yan* and Ligong Chen
School of Chemical Engineering andTechnology, Tianjin University, Tianjin, 300072, P. R. China
A mild and practical synthetic route for biphenyls is established. Isopropyl nitrite was prepared from sodium nitrite,
isopropanol and hydrochloric acid. The biphenyl compounds were obtained from the diazotisation of aniline deriva-
tives with the generated isopropyl nitrite and the coupling reaction with benzene derivatives in the presence of CuCl
as a catalyst in good yields.
Keywords: biphenyls, aniline derivative, isopropyl nitrite, diazotisation
The biphenyl group is one of the most important substructures
in a number of bioactive and functional molecules. It is used in
many pharmaceutically active ingredients such as antibiotics,
anti-inflammatory, antihypertensive, anticancer, antihistaminic
in the generated isopropyl nitrite and the diazonium salt may
transfer into the aqueous phase, which was negative for the
coupling reaction, the organic phase containing isopropyl
nitrite was separated from the reaction liquid and used in the
next coupling reaction. Using the same molar ratio as above,
the isolated yield of the improved experiment was increased to
64%.
1
–4
and infertility treatments. Moreover, the benzene–benzene
bond is present in numerous natural products as well as in bio-
5
logically active agrochemicals. As a result, they have attracted
considerable interest. There are numbers of synthetic routes
for biphenyl compounds, and a wide variety of applications of
these methods have been reviewed. Among these methods,
the classical Ullmann reaction is well known as constructing
biphenyl frameworks from aryl halides in the presence of
copper, but it requires harsh reaction conditions and has
To demonstrate the generality of this benzene–benzene
coupling reaction, a number of aniline derivatives with elec-
tron releasing and electron withdrawing groups at different
positions 1a–j were chosen for this reaction. The results are
summarised in Table 1. It is clear that all of aniline derivatives
except for 1g and 1i proceed effectively to obtain desired prod-
ucts in moderate or good yields. The steric hindrance can be
the main reason that contributed to the failure of synthesising
the corresponding target biphenyl compounds from 1g and 1i.
In addition, it is attractive that the yields of aniline derivatives
with electron-withdrawing groups are higher than those of
aniline derivatives with electro-releasing groups.
In summary, we established a mild and practical method for
synthesising biphenyl compounds using isopropyl nitrite to
diazotise aniline derivatives at room temperature. In addition,
numbers of biphenyl compounds were obtained with moderate
to good yields by this method. This synthetic route has many
advantages including mild conditions, simplified work-ups
and low cost.
6
–10
1
1–18
reputation for erratic yields.
are also well known in biphenyl synthesis, such as Kharasch,
Catalytic coupling reactions
19
20
21
22
Negishi, Stille and Suzuki reactions. Some of these syn-
thetic methods have been applied in the industrial production.
Nevertheless, there are some limitations to these synthetic
methods, e.g. complex work-ups, dangerous or expensive and
instable catalysts.
Recently, our group has focused on the synthesis of 2-fluoro-
-bromobiphenyl, which is a versatile and functional interme-
4
diate for synthesising flurbiprofen from 2-fluoro-4-bromoaniline
2
3
and benzene (Scheme 1). We found that 2-fluoro-4-bromobi-
phenyl can be generated in good (75.4%) yield by using
isopropyl nitrite as the diazotising reagent. Compared with
the traditional method of using sodium nitrite as the diazotis-
ing reagent, which was initially used to achieve the target
molecule, the route reported here has several advantages such
as mild conditions, simplified work-ups and low cost. This has
triggered our interest in investigating the applicability of iso-
propyl nitrite as the diazotising reagent in the benzene–benzene
coupling reaction. The obtained results are summarised and
reported here.
Experimental
Reagents and solvents were obtained from commercial suppliers.
All reactions were carried out in air and monitored by TLC using
commercial aluminium-backed silica gel plates. Melting points were
observed on YRT-3 Melting Point Tester and are uncorrected. NMR
Results and discussions
As isopropyl nitrite is volatile and potentially explosive, it
should be used immediately after preparation. The isopropyl
nitrite was obtained from the reaction of isopropanol, sodium
nitrite and hydrochloric acid in water at 0–5 °C.The aniline
derivative 1a was diazotised with the generated isopropyl
nitrite, followed by the coupling reaction with 1,4-dimethyl-
benzene in the presence of CuCl as a catalyst at room tempera-
ture to yield the corresponding biphenyl compound 2a in
moderate (46%) yield. Considering that there was some water
Scheme 2 Reaction of aniline derivatives with isopropyl
in 1, 4-dimethylbenzene.
Table 1 Reactions of aniline derivatives with isopropyl nitrite
in 1,4-dimethylbenzene
Entry
R=
Product
1
2
3
4
5
6
7
8
9
1a H
1b 2-F
1c 4-Cl
1d 4-Br
1e 4-F
2a
2b
2c
2d
2e
2f
1f 4-CH
1g 2-CH
3
Scheme 1 Reaction of 2-fluoro-4-bromoaniline with
3
2g
2h
2i
isopropyl nitrite in benzene.
1h 4-OCH
1i 2-OCH
1j 4-NO
3
3
10
2
2j
*
Correspondent. E-mail: yan@tju.edu.cn

5
56 JOURNAL OF CHEMICAL RESEARCH 2012
spectra were recorded on Varian Inova-400/500 MHz NMR spectro-
meter with TMS as an internal reference. IR spectra were recorded as
KBr pellets on a Bruker-Tensor 27 spectrometer. HRMS were recorded
on an Autoflex tof/tof III mass spectrometer. Silica gel (200–300
mesh) was used to isolate the products.
135.95, 134.73, 131.71, 129.95, 129.80, 128.65, 128.31, 127.35,
19.85, 19.67 and 18.82.
31
4′-Methoxy-2,5-dimethyl-1,1′- biphenyl (2h) : Colourless oil,
3
1
1
63.7% (lit. 24%). H NMR (400 MHz, CD
1s, CH ), 2.27 (3H, 1s, CH ), 3.78 (3H, 1s, OCH
m, ArH7). C NMR (100 MHz, CD OD), δ(ppm): 158.60 (C–OCH ),
OD), δ(ppm): 2.16 (3H,
3
) and 6.90–7.16 (7H,
3
3
3
13
3
3
Synthesis of isopropyl nitrite
Concentrated hydrochloric acid (12.0 mL, 120 mmol) was dropped
into the magnetically stirred mixture of sodium nitrite (6.21 g,
141.37, 134.75, 134.49, 131.81, 130.06, 129.83, 127.25, 113.12,
54.30, 19.70 and 18.90.
27
4′-Nitro-2,5-dimethyl-1,1′-biphenyl (2j) : Light yellow solid,
27
28
1
9
0
0 mmol), isopropanol (13.8 mL, 180 mmol) and water (8.0 mL) at
–5 °C by means of ice bath. After the addition, this reaction was
5.16g, 75.8% (lit. 58%). m.p. 83–84 °C (lit. 86–87 °C). H NMR
(400 MHz, CD OD), δ(ppm): 2.23 (3H, 1s, CH ), 2.34 (3H, 1s, CH
and 7.06–8.315 (7H, m, ArH ). C NMR (100 MHz, CDCl ), δ(ppm):
149.04 (C–NO ), 139.47, 135.67, 131.90, 130.70, 130.09, 129.31,
29.20, 123.48, 123.36, 20.86, and 19.80.
)
3
3
3
13
stirred for 1 h at 0–5 °C. Then isopropyl nitrite, the organic layer, was
obtained after separating the aqueous layer.
7
3
2
1
Synthesis of biphenyl products
The mixture solution of aniline derivatives (30 mmol) and 1,4-methyl-
bezene (40.0 mL) was added dropwise into a mixture of 1,4-dimethyl-
benzene (20.0 mL), isopropyl nitrite, as prepared above, and CuCl
Received 16 May 2012; accepted 2 July 2012
Paper 1201317 doi:10.3184/174751912X13419099572319
Published online: 28 August 2012
(
1.00 g, 10mmol). The reaction was mechanically stirred for 3 h at
room temperature. The mixture was filtered to remove CuCl. The
solvent was evaporated and the residue purified by column chroma-
tography using PE as the eluent. 2-Fluoro-4-bromobiphenyl was
prepared by the same method.
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3

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