Reinvestigation of the noncatalyzed coupling of aryllithium with haloarene: A novel aromatic nucleophilic substitution pathway

Article abstract of DOI:10.1002/chem.200204373

Noncatalyzed coupling reactions of aryllithiums and haloarenes proceed not only through the well-known aryne route but also, in some cases, through a novel addition-elimination pathway. Indeed, ortho-chloro- and ortho-bromomethoxyarenes lead selectively to the corresponding ortho-biaryls through a chelation-driven aromatic nucleophilic substitution pathway. Contrary to common belief, such noncatalyzed coupling reactions often proceed with high regioselectivity and high yield. These results underline the potency of such simple reactions and open up a straightforward access to a wide range of biaryl structures; this also appears particularly useful for large-scale and biaryl building-block syntheses, as only cheap and readily available substrates are involved.

Full text of DOI:10.1002/chem.200204373

FULL PAPER
Reinvestigation of the Noncatalyzed Coupling of Aryllithium with Haloarene:
A Novel Aromatic Nucleophilic Substitution Pathway
Jean-Michel Becht, Arnaud Gissot, Alain Wagner,* and Charles Mioskowski*[a]
Abstract: Noncatalyzed coupling reactions of aryllithiums and haloarenes proceed
not only through the well-known aryne route but also, in some cases, through a novel
addition elimination pathway. Indeed, ortho-chloro- and ortho-bromomethoxyar-
enes lead selectively to the corresponding ortho-biaryls through a chelation-driven
aromatic nucleophilic substitution pathway. Contrary to common belief, such
noncatalyzed coupling reactions often proceed with high regioselectivity and high
yield. These results underline the potency of such simple reactions and open up a
straightforward access to a wide range of biaryl structures; this also appears
particularly useful for large-scale and biaryl building-block syntheses, as only cheap
and readily available substrates are involved.
Keywords: aromatic substitution
arynes biaryls metalation
nucleophilic substitution
¥
¥
¥
¥
classical mechanism involving arynes, another mechanism
operates through competing halogen displacement and halo-
gen metal exchange processes. The reaction of phenyllithi-
um, for example, with a 4-halotoluene leads to the formation
of a complex mixture of the two possible meta and para
isomers along with homocoupling reaction products arising
from metal halogen exchange side reactions.[11]
These complex results proved discouraging for further
synthetic developments, and stimulated no additional inves-
tigations or research in the field despite publication of three
interesting reports. In 1983 Meyers succeeded in controlling
the regioselectivity of the reaction by using an aryne precursor
bearing a phenyloxazolidine substituent, which acts as a
strong ortho-directing and chelating group.[12] More recently,
Schulte and Laschat found that 3,3',4,4'-tetraalkoxybiphenyl
was obtained regioselectively by treatment of 4-bromo-1,2-
dimethoxybenzene with 0.5 equiv of n-butyllithium in THF at
À788C.[13]
Introduction
Biaryls are found in important biologically active molecules[1]
such as the naturally occurring terprenin[1f] or in synthetic
i]
anti-HIV derivatives[1g and are used as core structures for
molecular recognition devices,[2] organic semiconductors,
material for nonlinear optics, and metal ligands for catalysts.[3]
Several powerful synthetic methods are available for their
preparation,[4] including long-known reactions such as Ull-
mann[4] or Gomberg Bachmann Hey couplings,[6] or more
modern reactions such as Stille,[7] Suzuki Pd-catalyzed, and
Ni-catalyzed cross-coupling reactions.[8] Although these reac-
tions make it possible to prepare complex, polyfunctionalized
biaryl structures under mild conditions, more efficient and
simpler approaches are still suitable.
Based on this analysis, we reinvestigated the noncatalyzed
reaction of aryllithiums with haloarenes. Surprisingly, this
reaction has only been little studied and very sparsely used in
organic synthesis. The mechanism generally proposed in the
literature proceeds via the in-situ formation of a highly
reactive aryne intermediate[9] that reacts with the aryllithium,
leading to the biaryl structure. The mixture of regioisomers
formed in the process is due to the two electrophilic positions
present on the aryne intermediate.[10, 11] In addition to the
These results prompted us to reinvestigate the potential of
this interesting transformation. We found that, in many cases,
the reaction proceeds with high and predictable regioselec-
tivity, making the transformation of interest for synthetic
purposes. The substitution pattern of the haloarenes directs
the formation of the biaryl structures, which are always
obtained in good to moderate yields.
[a] Dr. A. Wagner, Dr. C. Mioskowski, J.-M. Becht, A. Gissot
¡
¬
Laboratoire de Synthese Bioorganique, UMR 7514 associee au CNRS,
¬
Faculte de Pharmacie
Results and Discussion
74 Route du Rhin, 67400 Illkirch (France)
Fax : (‡33)3-90-24-43-06
To evaluate the scope and limitations of this cross-coupling
reaction we investigated the reactivity of several haloarenes
E-mail: wagner@bioorga.u-strasbg.fr
mioskowski@bioorga.u-strasbg.fr
Chem. Eur. J. 2003, 9, 3209 3215
DOI: 10.1002/chem.200204373
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Wagner, and C. Mioskowski et al.
FULL PAPER
with different aryllithiums. In a first set of experiments we
used 1,3-dimethoxybenzene as the anion precursor and
chlorobenzene as the aryne source. Addition of n-butyllithi-
um to a mixture of 1,3-dimethoxybenzene and chlorobenzene
in various solvents (hexane, diethyl ether, THF, THF/HMPA)
at various temperatures did not afford the desired biaryl
structure. In contrast, good results were obtained when
chlorobenzene was added to a solution of 2-lithio-1,3-dimeth-
oxybenzene in THF or DME and the resulting mixture was
heated overnight at 608C. Under these conditions, the desired
biaryl was obtained in 95% yield (Table 1, entry 2). At room
temperature only poor yields are obtained. Notably, when the
reaction was carried out on a 1.0 mol scale under the
optimized conditions, the biaryl structure was obtained in a
quantitative yield.
To access a larger panel of biaryl structures, other
aryllithiums were then generated by metal halogen ex-
change (Table 3).
[15]
Table 3. Reaction of aryllithiums generated by metal/halogen exchange.
Entry
R1
R2
X
Yield [%]
1
2
3
2-OMe
4-OMe
H
H
Cl
F
F
57
70
42
À
À
O
3,4-O CH2
2-Lithioanisole was generated by bromine lithium ex-
change from 2-bromoanisole by using metallic lithium (en-
try 1).[16] Reaction with chlorobenzene led to the desired
biaryl in 57% yield. 4-Bromoanisole treated with tert-
butyllithium gave the biaryl in 70% yield. 4-Lithio-1,2-
benzodioxole generated from 4-bromo-1,2-benzodioxole re-
acted with fluorobenzene to afford the coupling product in
42% yield (entry 3).
Table 1. Reaction of 2-lithio-1,3-dimethoxybenzene with halobenzene.
X
Yield [%]
F
> 95
Cl
Br
I
95
82
To extend the scope of this reaction, anions generated from
a-metalated heterocycles were tested (Scheme 1).
no reaction
Next, we varied the nature of the halogen. The order of
reactivity, F > Cl > Brꢀ I, is in accordance with a mechanism
involving a transient aryne, the hydrogen abstraction being
14]
the rate-determining step.[11
Interestingly, with iodoben-
zene no biaryl structure could be detected in the crude
mixture by 1H NMR analysis. The reaction was then extended
to other aryllithiums generated under classical ortho-metal-
ation conditions (Table 2).
Scheme 1. Reaction of a-metalated heterocycles and chloro- or fluoro-
Compared with 1,3-dimethoxybenzene (entry 2), the lower
yields observed in the case of mono-stabilized anions (en-
tries 1, 3) might be due to the lower thermal stability of the
2-lithio anion. In accordance 1,2-dimethoxybenzene, which
readily decomposes upon metallation, gave only traces of
product (<10%). With phenyloxazoline, N,N-dimethylbenza-
mide and N-tert-butylbenzamide ortho anions, we observed a
comparable lack of reactivity.
benzene.
In both cases, only fluorobenzene allowed the reaction to
proceed; coupling products were isolated in moderate 69%
and low 22% yield.
In this preliminary study, since only chloro- or fluoroben-
zene was used as the aryne precursor, the regioselectivity issue
was avoided. To address this issue, we employed functional-
ized haloarenes for which random aryne formation and/or
subsequent random nucleophilic attack are expected to lead
to a mixture of isomers (Scheme 2).
Table 2. Reaction of various aryllithiums and chloro- or fluorobenzene
Reaction of 2-, 3-, and 4-haloanisoles with 2-lithio-1,3-
dimethoxybenzene (Table 4) was studied first. The ortho/
meta/para-biaryl ratios were determined by GC analysis of the
crude mixtures. The ortho and para isomers were identified
unambiguously by comparison with reference samples syn-
thesized by classical Pd coupling reactions.[8] The structures of
the meta isomers were assessed by X-ray analysis. Reaction of
2-lithio-1,3-dimethoxybenzene with 2-chloroanisole gave the
ortho-biaryl in 80% yield and 82% selectivity (entry 1),
whereas 3-chloroanisole led predominantly to the meta
isomer with 97% selectivity and 82% overall yield (entry 4).
Entry
R1
R2
X
Yield [%]
1
2
3
4
5
6
H
H
H
H
H
5-OMe
H
F
Cl
F
Cl or F
F
F
48
95
52
3-OMe
4-OMe
2-OMe
3-OMe
5-Me
55
41
3210
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, 3209 3215

Aryllithium Haloarene Coupling
3209 3215
Scheme 2. Possible products formed through random aryne formation and
subsequent random nucleophilic attack.
Scheme 3. Possible mechanism for the reaction of 2- and 3-chloroanisole.
tion took over and the ortho isomer was obtained in 75%
yield (entry 3).
4-Chloroanisole afforded a 1:1 mixture of the two possible
meta and para isomers, as a result of formation of the 3,4-
aryne and subsequent random nucleophilic attack at posi-
tions 3 and 4 (entry 5).
Table 4. Reaction of 2-lithio-1,3-dimethoxybenzene with substituted
chloro- and fluorobenzene.
To check whether this regioselectivity was specific for the
anion of 1,3-dimethoxybenzene, we carried out experiments
under similar conditions using phenyllithium. 2-Chloroanisole
afforded the ortho-biaryl in 78% isolated yield and 3-chloro-
anisole the meta isomer in 80% isolated yield. These results
indicate clearly that the selectivity is mainly governed by the
substitution pattern and the nature of the haloarenes.
Other substrates, such as 2-chloro- and 3-chloro-N,N-
dimethylanilines (entries 6, 7), afforded exclusively meta-
biphenyl in 40% and 47% yield respectively. Replacement
of the chlorine atom by a less acidifying bromine atom
(entry 8) did not change the selectivity, but resulted in a
dramatic drop in the yield. Similar results were obtained with
phenyllithium.
Results observed with the halotoluenes (entries 9 14) are
in total accordance with the aryne pathway and with an early
report by Chlebowski.[11] Here again, the increase in yield by
switching from chloro- to fluorotoluene indicates that a-
hydrogen abstraction is a determining step in the mechanism
(Table 1). The slight deviation from the statistical ratio of the
possible regioisomers might be explained by the steric
hindrance of the methyl group, which disfavors the nucleo-
philic addition at the 2-position.
3-Chlorotrifluoromethylbenzene gave a mixture of meta
and para isomers in a 7:3 ratio (entry 15), which differs from
the ratio obtained with 3-chlorotoluene (entry 12). The better
ortho-stabilizing effect of the trifluoromethyl group accounts
for this result. 4-Chlorotrifluoromethylbenzene gave a stat-
istical mixture of meta- and para-biaryls (entry 16).
To prove the ipso nucleophilic substitution pathway, we
synthesized 2-chloro-3-deuteroanisole. meta-Anisidine was
first converted into 2-chloro-3-aminoanisole,[17a], which was
diazotized[17b] and reduced with sodium borodeuteride[17d] to
afford the desired deuterated substrate. The latter was
employed in an anionic cross-coupling reaction (Scheme 4).
As expected, 2-chloro-3-deuteroanisole leads to the cou-
pling product with less than 5% of deuterium loss, showing
Entry R1
X
ortho [%] meta [%] para [%] Yield [%]
1
2
3
4
5
2-OMe
Cl
F
Br 90
Cl
Cl
82
18
> 95
10
80
80
75
2-OMe
2-OMe
3-OMe
4-OMe
97
3
82
50
50
53
6
7
8
2-NMe2 Cl
3-NMe2 Cl
2-NMe2 Br
> 90
> 85
> 90
64
63
60
54
55
51
70
40
47
10
72
30
< 20
40
84
96
9
2-Me
2-Me
2-Me
3-Me
3-Me
4-Me
3-CF3
4-CF3
F
Cl
I
Cl
F
Cl
Cl
Cl
36
37
40
9
10
11
12
13
14
15
16
37
34
49
30
55
11
30
60
45
Exclusive formation of a transient 2,3-aryne, followed by
addition of the aryllithium specifically at the 3-position, leads
to the most stabilized anionic intermediate. This set of steps
accounts for the formation of the meta-biaryl obtained from
3-chloroanisole. According to this mechanism, 2-chloroani-
sole is expected to give the same 2,3-aryne intermediate and
thus the same reaction product. Instead, the observed
formation of the ortho-biaryl isomer, in total contradiction
of the classical aryne-based mechanism, suggests a novel
aromatic nucleophilic substitution pathway (Scheme 3). To
support this hypothesis, substitution of 2-chloroanisole by
2-fluoroanisole reversed the reaction selectivity (entry 2). The
strong ortho-acidifying effect of the fluorine atom favors
hydrogen abstraction and thus the aryne pathway. In accord-
ance with this, 2-fluoroanisole yielded the meta isomer
cleanly. In contrast, since the bromine atom has little or no
acidifying effect, with 2-bromoanisole nucleophilic substitu-
Chem. Eur. J. 2003, 9, 3209 3215
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A. Wagner, and C. Mioskowski et al.
FULL PAPER
Scheme 4. Ipso substitution reaction on deuterated substrate.
that no hydrogen abstraction occurs. This result clearly
demonstrates that, for this isomer, the biaryl structure is
formed through an ipso nucleophilic substitution mechanism.
Next, we tested the hypothesis that the selectivity could result
from the chelation of the lithium cation by the oxygen atom of
the methoxy group. Addition of HMPA, which is known to
disrupt the lithium chelation, resulted in the reversal of
selectivity with formation of the meta isomer in 68% yield.
Similarly, when the reaction was carried out in the presence of
LiClO4 both the ortho and the meta isomers were obtained in
a 55:45 ratio. It thus appears that lithium chelation has a
predominant role in directing the ipso substitution. Such
chelation-driven selectivity also accounts for the experimental
results obtained with 2-haloaniline (Table 4, entries 6 8), for
which the biaryl formation proceeds through the aryne
pathway since the nitrogen atom has weak lithium chelation
ability.
Scheme 5. Summary of the substrate substitution reaction pathways.
adduct. For haloarenes bearing substituents which do not
stabilize the anionic adduct, a statistical mixture of the
possible isomers is obtained. For substrates bearing two
stabilizing groups, the regioselectity is governed by the
strongest directing group.
These noncatalyzed reactions give a straightforward access
to a wide range of useful biaryl structures. As only cheap and
readily available substrates are involved, our process appears
to be of special interest for large-scale synthesis of basic biaryl
building blocks.
To pioneer a novel type of aromatic chemistry, such
chelation-driven substitution might be extendable to other
carbanionic nucleophiles. Studies are currently being under-
taken in that direction.
Even though a chelation-driven addition of phenylmagne-
sium bromide to ortho-methoxyphenyloxazoline was de-
scribed recently,[18] to the best of our knowledge this unusual
mechanistic pathway has been neither studied nor exploited in
organic synthesis. To extend its scope further, we considered
haloarenes bearing two directing groups (Table 5).
Experimental Section
Table 5. Reaction of 2-lithio-1,3-dimethoxybenzene with di-substituted
chloro- and fluorobenzene derivatives.
1
General: H and 13C NMR spectra in CDCl3 were recorded using either a
200 MHz or a 300 MHz instrument. Chemical (d) shifts are reported in
parts per million downfield from TMS. Gas chromatography was per-
formed on a Carlo Erba 6000 Vega equipped with a flame ionization
detector using a 25 m BPX5 fused silica column. The GC conditions for
isomer analysis were: pressure of carrier 20 kPa; injection of the sample at
1708C kept constant for 3 min then increased to 2408C at 408CminÀ1 for
17 min. Tetrahydrofuran (THF) was distilled from sodium/benzophenone.
Dimethoxyethane (DME) was dried with molecular sieves. All biaryl
syntheses by our methodology were performed in flame-dry glassware
under an argon atmosphere. Since the descriptions of the various biaryl
structures are dispersed and incomplete in the literature, we give full
characterizations of all the synthesized compounds.
Entry
R1
R2
X
ortho [%]
> 95
meta [%]
Yield [%]
1
2
3
4
5
3-OMe
3-OMe
3,4-O CH2O
2-OMe
2-Me
5-OMe
4-OMe
Cl
F
Cl
Cl
Cl
> 95
> 95
> 95
40
66
38
60
62
General procedure for synthesis of the biaryls in Tables 1, 4, and 5: n-
Butyllithium (1.6m solution in hexane, 3.9 mL, 6.3 mmol) was added
dropwise at RTto a solution of 1,3-dimethoxybenzene (6.3 mmol) in THF
(5 mL). After 1 h a solution of aryl halide (2.9 mmol) in THF (2 mL) was
added dropwise. The resulting mixture was stirred for another hour at RT
and then heated at 608C for 12 h. The reaction mixture was cooled to RT
and quenched by addition of H2O (40 mL). The aqueous layer was
extracted twice with Et2O (total 60 mL), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under vacuum. The
residue was purified by silica gel flash chromatography with Et2O/hexane.
If they were still colored after chromatographic purification, the products
were filtered on charcoal.
5-Me
5-OMe
> 95
These results indicate that the rules governing the reaction
pathways are perfectly understood and predictable. The
nucleophilic substitution is preferred when possible; if it is
not possible, the major isomer arises from the most stable
anion adduct (Scheme 5).
In conclusion, we have shown that noncatalyzed coupling of
aryllithiums with haloarene often proceeds with high selec-
tivity. ortho-Chloro- and ortho-bromomethoxyarenes give the
corresponding ortho-biaryls through chelation-driven aromat-
ic nucleophilic substitution. For other substrates the biaryl
comes from the addition of the aryllithium to an aryne
intermediate at the position leading to the most stable anionic
2,6-Dimethoxybiphenyl (Table 1 and Table 2, entry 2): White solid, m.p.
898C; Rf ˆ 0.5 (10% Et2O/hexane); 1H NMR (200 MHz, [D1]CHCl3,
208C): d ˆ 3.83 (s, 6H; 2OCH3), 6.76 (d, 3J(H,H) ˆ 8.8 Hz, 2H; 3,5-H), 7.39
(t, 3J(H,H) ˆ 8.8 Hz, 1H; 4-H), 7.49 7.59 ppm (m, 5H; 5-H'); 13C NMR
(50 MHz, [D1]CHCl3, 208C): d ˆ 55.8, 104.1, 119.4, 126.7, 127.6, 128.5, 130.8,
134.1, 157.6 ppm; IR (CHCl3): nÄ ˆ 3054, 2946, 1584, 1470, 1427, 1242,
‡
‡
1103 cmÀ1; MS (NH4 ): m/z: 232 [M‡NH4] ; elemental analysis calcd (%)
3212
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Chem. Eur. J. 2003, 9, 3209 3215

Aryllithium Haloarene Coupling
3209 3215
'
3
for C14H14O2 (214.26): C 78.48, H 6.58, O 14.94; found: C 78.32, H 6.56, O
14.89.
OCH3 ), 6.70 (d, J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 6.90 7.10 (m, 3H; 3',5',6'-
H), 7.25 7.35 ppm (m, 2H; 4,4-H); 13C NMR (75 MHz, [D3]CH3CN, 208C):
d ˆ 56.1, 56.4, 105.2, 112.1, 121.1, 124.9, 129.4, 129.9, 133.0, 158.6,
2-Methoxybiphenyl (Table 2, entry 1): After a solution of 2-bromoanisole
(15 mmol) in Et2O (16.8 mL) had been added dropwise at RTto a
suspension of lithium wires (400 mg, 58 mmol) in Et2O (16.8 mL), the
medium was stirred for 2 h at RT, then a portion (16.8 mL) of this solution
was diluted with THF (8 mL). A solution of fluorobenzene (2.4 mmol) in
THF (2 mL) was added dropwise at RT. The reaction mixture was stirred
for 1 h at RTand refluxed to 60 8C for 12 h. The reaction mixture was
allowed to cool to RTand quenched by addition of water (40 mL). The
aqueous layer was extracted twice with Et2O (total 100 mL), then the
combined organic layers were dried over MgSO4, filtered, concentrated in
vacuo, and purified by flash chromatography on silica gel with hexane as
eluent. Yield 250 mg (57%).
159.0 ppm; IR (CHCl3): nÄ ˆ 3008, 2938, 1591, 1504, 1471, 1250, 1111 cmÀ1
;
‡
‡
MS (NH4 ): m/z: 245 [M‡H] ; elemental analysis calcd (%) for C15H16O3
(244.29): C 73.75, H 6.60, O 19.65; found: C 73.71, H 6.61, O 19.61.
2,6,3'-Trimethoxybiphenyl (Table 4, entries 2, 4): White solid, m.p. 708C;
Rf ˆ 0.2 (5% Et2O/hexane); GC retention time ˆ 11.16 min; 1H NMR
(200 MHz, [D1]CHCl3, 208C): d ˆ 3.75 (s, 6H; 2OCH3), 3.83 (s, 3H;
3
OCH3'), 6.66 (d, J(H,H) ˆ 7.8 Hz, 2H; 3,5-H), 6.85 6.97 (m, 3H; 2',4',6'-
H), 7.25 7.38 ppm (m, 2H; 4,5'-H); 13C NMR (75 MHz, [D1]CHCl3, 208C):
d ˆ 55.1, 55.9, 104.2, 112.4, 113.2, 116.6, 123.3, 128.5, 131.9, 135.5, 157.7,
159.0 ppm; IR (CHCl3): nÄ ˆ 3050, 2953, 1587, 1468, 1243, 1106 cmÀ1; MS
‡
‡
(NH4 ): m/z: 245 [M‡H] ; elemental analysis calcd (%) for C15H16O3
(244.29): C 73.75, H 6.60, O 19.65; found: C 73.66, H 6.62, O 19.59.
2-Methoxybiphenyl (Table 2, entry 1): Colorless oil; Rf ˆ 0.5 (10% AcOEt/
1
hexane); H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.98 (s, 3H; OCH3),
2,6,4'-Trimethoxybiphenyl (Table 4, entry 5): White solid, m.p. 1228C; Rf ˆ
0.2 (5% AcOEt/hexane); GC retention time ˆ 11.83 min; 1H NMR
(200 MHz, [D1]CHCl3, 208C): d ˆ 3.79 (s, 6H; 2OCH3), 3.88 (s, 3H;
OCH3'), 6.69 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 6.99 (d, 3J(H,H) ˆ 9.0 Hz,
2H; 3',5'-H), 7.26 7.35 ppm (m, 3H; 4,2',6'-H); 13C NMR (75 MHz,
[D1]CHCl3, 208C): d ˆ 55.0, 55.8, 104.2, 113.2, 119.1, 126.1, 128.3, 131.9,
157.7, 158.2 ppm; IR (CHCl3): nÄ ˆ 3015, 2954, 1588, 1519, 1471, 1247,
7.15 7.26 (m, 2H; 3,5-H), 7.52 7.79 ppm (m, 7H; 4,6-H, 5H'); 13C NMR
(50 MHz, [D1]CHCl3, 208C): d ˆ 56.2, 112.0, 121.6, 127.7, 128.8, 129.4, 130.3,
131.4, 131.6, 139.4, 157.2 ppm; IR (CHCl3): nÄ ˆ 3060, 2926, 1599, 1499, 1482,
1258, 1025 cmÀ1; MS (NH4 ): m/z: 202 [M‡NH4] ; elemental analysis calcd
(%) for C13H12O (184.24): C 84.75, H 6.56, O 8.68; found: C 84.56, H 6.54, O
8.71.
‡
‡
1112 cmÀ1; MS (NH4 ): m/z: 245 [M‡H] ; elemental analysis calcd (%) for
‡
‡
General procedure for the synthesis of biaryls (Table 3): The bromoaryl
(5.4 mmol) was added at À788C to a solution of tBuLi (1.7m in pentane,
6.4 mL, 10.8 mmol). The reaction mixture was warmed to RT for 30 min.
After it had been cooled to 08C, DME (3 mL) and THF (3 mL) were added
successively. Halobenzene (1.5 mmol) was diluted in DME (2.5 mL), and
the resulting solution was heated at 708C; a solution of aryllithium
(10.4 mL) was added quickly at 708C. The reaction mixture was stirred at
this temperature for 12 h. After cooling to RT, the reaction was quenched
by addition of water (40 mL). The aqueous layer was extracted twice with
Et2O (total 100 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel.
C15H16O3 (244.29): C 73.75, H 6.60, O 19.65; found: C 73.47, H 6.59, O 19.68.
(2',6'-Dimethoxybiphenyl-3-yl)dimethylamine (Table 4, entries 6 8):
White solid, m.p. 1188C; Rf ˆ 0.3 (30% Et2O/hexane); GC retention
time ˆ 12.30 min; 1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 2.97 (s, 6H;
NMe2), 3.76 (s, 6H; 2OCH3), 6.68 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3',5'-H), 6.70
6.77 (m, 3H; 2,4,6-H), 7.26 7.33 ppm (m, 2H; 5,4'-H); 13C NMR (50 MHz,
[D1]CHCl3, 208C): d ˆ 40.6, 55.8, 104.1, 111.3, 115.4, 119.3, 120.4, 128.2,
128.3, 134.7, 150.0, 157.7 ppm; IR (CHCl3): nÄ ˆ 3054, 2989, 1604, 1471, 1266,
1112 cmÀ1; MS (NH4 ): m/z: 258 [M‡H] ; elemental analysis calcd (%) for
C16H19NO2 (257.33): C 74.68, H 7.44, O 12.43; found: C 74.48, H 7.45, O
12.46.
‡
‡
2,5-Dimethoxybiphenyl (Table 2, entry 3): Colorless oil; Rf ˆ 0.4 (10%
Et2O/hexane); 1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 3.77 (s, 3H;
OCH3), 3.83 (s, 3H; OCH3), 6.84 6.96 (m, 3H; 3,4,6-H), 7.34 7.61 ppm
(m, 5H; 5H'); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.8, 56.3, 112.7,
113.1, 116.7, 127.1, 128.0, 129.4, 131.7, 138.4, 150.8, 153.8 ppm; IR (CHCl3):
2,6-Dimethoxy-3'-methylbiphenyl (Table 4, entries 9 14): Colorless oil;
Rf ˆ 0.5 (10% AcOEt/hexane); GC retention time ˆ 8.75 min; 1H NMR
(300 MHz, [D1]CHCl3, 208C): d ˆ 2.41 (s, 3H; CH3), 3.76 (s, 6H; 2OCH3),
3
6.67 (d, J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.13 7.37 ppm (m, 5H; 4-H, 4H');
13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 21.6, 56.1, 104.6, 120.3, 127.6,
127.7, 128.0, 128.6, 131.7, 134.2, 137.1, 158.0 ppm; IR (CHCl3): nÄ ˆ 3048,
‡
nÄ ˆ 3069, 2944, 1601, 1505, 1488, 1216, 1040 cmÀ1; MS (NH4 ): m/z: 232
‡
‡
‡
2930, 1606, 1589, 1466, 1242, 1110 cmÀ1; MS (NH4 ): m/z: 229 [M‡H] ;
elemental analysis calcd (%) for C15H16O2 (228.29): C 78.92, H 7.06, O
14.02; found: C 78.71, H 7.05, O 14.06.
[M‡NH4] ; elemental analysis calcd (%) for C14H14O2 (214.26): C 78.48, H
6.58, O 14.93; found: C 78.39, H 6.60, O 14.89.
2,4,6-Trimethoxybiphenyl (Table 2, entry 5): White solid, m.p. 1528C; Rf ˆ
1
0.4 (20% Et2O/hexane); H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 3.74
2,6-Dimethoxy-4'-methylbiphenyl (Table 4, entries 12 14): White solid,
m.p. 868C; Rf ˆ 0.5 (10% AcOEt/hexane); GC retention time ˆ 9.15 min;
1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 2.41 (s, 3H; CH3), 3.75 (s, 6H;
2OCH3), 6.67 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.21 7.32 ppm (m, 5H;
4-H, 4H'); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 21.4, 56.1, 104.7,
120.1, 128.6, 128.7, 130.9, 131.3, 136.3, 158.1 ppm; IR (CHCl3): nÄ ˆ 3053,
(s, 6H; 2OCH3), 3.89 (s, 3H; OCH3), 6.26 (s, 2H; 3,5-H), 7.28 7.44 ppm (m,
5H; 5H'); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.3, 55.9, 90.9, 126.4,
127.6, 130.9, 131.2, 134.1, 158.3, 160.5 ppm; IR (CHCl3): nÄ ˆ 3020, 2930,
‡
‡
1607, 1484, 1461, 1211, 1127 cmÀ1; MS (NH4 ): m/z: 245 [M‡H] ; elemental
analysis calcd (%) for C15H16O3 (244.29): C 73.75, H 6.60, O 19.65; found: C
73.98, H 6.57, O 19.70.
‡
‡
2986, 1653, 1589, 1469, 1264, 1110 cmÀ1; MS (NH4 ): m/z: 229 [M‡H] ;
elemental analysis calcd (%) for C15H16O2 (228.29): C 78.92, H 7.06, O
14.02; found: C 78.71, H 7.04, O 13.98.
2-Methoxy-5-methylbiphenyl (Table 2, entry 6): Colorless oil; Rf ˆ 0.5 (4%
Et2O/hexane); 1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 2.43 (s, 3H;
3
CH3), 3.85 (s, 3H; OCH3), 6.96 (d, J(H,H) ˆ 8.4 Hz, 1H; 3-H), 7.19 7.27
2,6-Dimethoxy-4'-trifluoromethylbiphenyl (Table 4, entries 15, 16): White
solid, m.p. 828C; Rf ˆ 0.5 (10% AcOEt/hexane); GC retention time ˆ
7.71 min; 1H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.76 (s, 6H;
2OCH3), 6.68 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.38 (t, 3J(H,H) ˆ 8.3 Hz,
(m, 2H; 4,6-H), 7.39 7.64 ppm (m, 5H; 5H'); 13C NMR (75 MHz,
[D1]CHCl3, 208C): d ˆ 20.4, 55.7, 111.3, 126.8, 127.9, 128.8, 129.5, 129.9,
130.5, 131.6, 138.6, 154.4 ppm; IR (CHCl3): nÄ ˆ 3025, 2936, 1603, 1508, 1490,
‡
‡
1236, 1029 cmÀ1; MS (NH4 ): m/z: 216 [M‡NH4] ; elemental analysis calcd
(%) for C14H14O (198.26): C 84.81, H 7.11, O 8.08; found: C 84.67, H 7.10, O
8.05.
3
3
1H; 4-H) , 7.48 (d, J(H,H) ˆ 8.0 Hz, 2H; 2',6'-H), 7.66 ppm (d, J(H,H) ˆ
8.3 Hz, 2H; 3',5'-H); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.8,
104.2, 118.0, 124.5, 124.5 (q, 1J(C,F) ˆ 270 Hz), 127.9, 129.4, 131.4, 138.1,
157.5 ppm; IR (CHCl3): nÄ ˆ 3059, 2924, 1664, 1592, 1469, 1248, 1113 cmÀ1
;
4-Methoxybiphenyl (Table 3, entry 2): White solid, m.p. 898C; Rf ˆ 0.3
(hexane); 1H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.90 (s, 3H; OCH3),
7.03 (d, 3J(H,H) ˆ 8.8 Hz, 2H; 3,5-H), 7.31 7.66 ppm (m, 7H; 2,6-H, 5H');
13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.2, 114.1, 126.6, 126.7, 128.1,
128.7, 133.7, 140.8, 159.1 ppm; IR (CHCl3) nÄ ˆ 3050, 2958, 1606, 1516, 1485,
‡
‡
MS (NH4 ): m/z: 300 [M‡NH4] ; elemental analysis calcd (%) for
C15H13F3O2 (282.26): C 63.83, H 4.64, O 11.34; found: C 64.01, H 4.63, O
11.30.
2,6-Dimethoxy-3'-trifluoromethylbiphenyl (Table 4, entries 15, 16): Color-
less oil; Rf ˆ 0.5 (10% AcOEt/hexane); GC retention time ˆ 7.37 min;
1H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.81 (s, 6H; 2OCH3), 6.73 (d,
3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.34 (t, 3J(H,H) ˆ 8.4 Hz, 1H; 4-H), 7.51
7.78 ppm (m, 4H; 4H'); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 56.3,
104.6, 118.3, 124.0, 125.0 (q, 1J(C,F) ˆ 270 Hz), 128.5, 129.8, 130.0, 130.7,
134.9, 135.3, 157.9 ppm; IR (CH2Cl2): nÄ ˆ 3011, 2955, 1589, 1467, 1239,
‡
‡
1272, 1037 cmÀ1; MS (NH4 ): m/z: 185 [M‡H] ; elemental analysis calcd
(%) for C13H12O (184.24): C 84.75, H 6.56, O 8.68; found: C 84.99, H 6.54, O
8.65.
2,6,2'-Trimethoxybiphenyl (Table 4, entries 1, 3): White solid, m.p. 1418C;
Rf ˆ 0.2 (10% AcOEt/hexane); GC retention time ˆ 9.29 min; 1H NMR
(200 MHz, [D3]CH3CN, 208C): d ˆ 3.67 (s, 6H; 2OCH3), 3.70 (s, 3H;
Chem. Eur. J. 2003, 9, 3209 3215
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3213

A. Wagner, and C. Mioskowski et al.
FULL PAPER
1111 cmÀ1; MS (NH4 ): m/z: 300 [M‡NH4] ; elemental analysis calcd (%)
for C15H13F3O2 (282.26): C 63.83, H 4.64, O 11.34; found: C 63.75, H 4.63, O
11.31.
1-(2,6-Dimethoxyphenyl)naphthalene: White solid, m.p. 1088C; Rf ˆ 0.3
‡
‡
1
(4% AcOEt/hexane); H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.69 (s,
6H; 2OCH3), 6.76 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.34 7.54 (m, 6H;
naphthalene H), 7.59 (t, 3J(H,H) ˆ 8.3 Hz, 1H; 4-H), 7.88 7.98 ppm (m,
2H; naphthalene H); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.9,
104.2, 125.3 125.4, 126.0, 127.4, 128.0, 128.1, 129.1, 132.6, 133.5, 158.4 ppm;
Biphenyl-3-yldimethylamine: Colorless oil; Rf ˆ 0.6 (10% Et2O/hexane);
1H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.08 (s, 6H; NMe2), 6.75 7.08
(m, 3H; 2,4,6-H), 7.32 7.69 ppm (m, 6H; 5'-H, 5H'); 13C NMR (75 MHz,
[D1]CHCl3, 208C): d ˆ 40.6, 111.5, 111.6, 115.8, 127.0, 127.3, 128.5, 129.4,
IR (CHCl3): nÄ ˆ 3025, 2952, 1596, 1529, 1472, 1214, 1113 cmÀ1; MS (NH4 ):
‡
‡
m/z: 265 [M‡H] ; elemental analysis calcd (%) for C18H16O2 (264.32): C
142.2, 150.9 ppm; IR (CHCl3): nÄ ˆ 3008, 2884, 1601, 1568, 1487, 1214 cmÀ1
;
81.79, H 6.10, O 12.11; found: C 82.01, H 6.08, O 12.15.
‡
‡
MS (NH4 ): m/z: 198 [M‡H] ; elemental analysis calcd (%) for C14H15N
(197.28): C 85.24, H 7.66; found: C 85.51, H 7.65.
2-(2,6-Dimethoxyphenyl)naphthalene: White solid, m.p. 838C; Rf ˆ 0.3
1
(4% AcOEt/hexane); H NMR (200 MHz, [D1]CHCl3, 208C): d ˆ 3.80 (s,
3-Methoxybiphenyl: Colorless oil; Rf ˆ 0.3 (10% AcOEt/hexane); GC
retention time ˆ 7.15 min; 1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 3.90
(s, 3H; OCH3), 6.93 (dd, 3J(H,H) ˆ 8.3 Hz, 4J(H,H) ˆ 5.5 Hz, 2H; 2-H),
7.17 7.26 (m, 2H; 4,6-H), 7.38 7.66 ppm (m, 6H, 5-H; 5H'); 13C NMR
(75 MHz, [D1]CHCl3, 208C): d ˆ 55.2, 112.6, 112.9, 119.7, 127.2, 127.4, 128.7,
129.7, 141.1, 142.7, 159.9 ppm; IR (CHCl3): nÄ ˆ 3054, 2959, 1599, 1479, 1266,
6H; 2OCH3), 6.75 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.38 (t, 3J(H,H) ˆ
8.3 Hz, 1H; 4-H), 7.46 7.57 (m, 3H; naphthalene H), 7.84 8.00 ppm (m,
4H; naphthalene H); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.9,
104.3, 119.5, 125.5, 126.9, 127.7, 128.1, 128.8, 129.3, 129.7, 131.7, 132.5, 133.3,
157.9 ppm; IR (CHCl3): nÄ ˆ 3003, 2941, 1585, 1496, 1274, 1105 cmÀ1; MS
‡
‡
1220 cmÀ1; MS (NH4 ): m/z: 185 [M‡H] ; elemental analysis calcd (%) for
‡
‡
(NH4 ): m/z: 265 [M‡H] ; elemental analysis calcd (%) for C18H16O2
(264.32): C 81.79, H 6.10, O 12.11; found: C 81.97, H 6.11, O 12.09.
C13H12O (184.24): C 84.75, H 6.56, O 8.68; found: C 84.52, H 6.58, O 8.65.
2-Phenylthiophene (Scheme 1): A solution of n-butyllithium (1.6m solution
in hexane, 6.9 mL, 11 mmol) was added dropwise at À408C to a solution of
thiophene (11 mmol) in THF (8.2 mL). The mixture was stirred for 1 h at
À308C, then cooled at À408C, and a solution of fluorobenzene (5 mmol) in
THF (3.2 mL) was added dropwise. The resulting mixture was warmed to
RTfor 1 h and heated to 60 8C for 12 h. The reaction mixture was allowed
to cool to RTand quenched by addition of water (40 mL). The aqueous
layer was extracted with Et2O (60 mL). The organic phase was dried over
MgSO4, filtered, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel using hexane as eluent. Yield 552 mg
(69%) of white solid, m.p. 358C; Rf ˆ 0.5 (hexane); 1H NMR (300 MHz,
[D1]CHCl3, 208C): d ˆ 7.11 7.16 (m, 1H; 5-H), 7.31 7.70 ppm (m, 7H; 3,4-
H, 5H'); 13C NMR (50 MHz, [D1]CHCl3, 208C): d ˆ 123.0, 124.8, 125.9,
127.4, 128.0, 128.9, 134.3, 144.4 ppm; IR (CHCl3): nÄ ˆ 3065, 3014, 1596,
2,6,3',5'-Tetramethoxybiphenyl (Table 5, entry 1): White solid, m.p. 1228C;
Rf ˆ 0.3 (10% AcOEt/hexane); GC retention time ˆ 17.23 min; 1H NMR
(200 MHz, [D1]CHCl3, 208C): d ˆ 3.79 (s, 6H; 2OCH3), 3.84 (s, 6H;
2OCH3), 6.50 (t, 4J(H,H) ˆ 2.2 Hz, 1H; 4'-H), 6.55 (d, 4J(H,H) ˆ 2.2 Hz,
2H; 2',6'-H), 6.69 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 7.32 ppm (t, 3J(H,H) ˆ
8.3 Hz, 1H; 4-H); 13C NMR (50 MHz, [D1]CHCl3, 208C): d ˆ 55.7, 56.4,
99.7, 104.6, 109.4, 119.9, 129.2, 136.5, 158.1, 160.5 ppm; IR (CHCl3): nÄ ˆ
‡
3094 , 2944, 1598, 1450, 1253, 1194, 1149 cmÀ1; MS (NH4 ): m/z: 275
‡
[M‡H] ; elemental analysis calcd (%) for C16H18O4 (274.31): C 70.06, H
6.61, O 23.33; found: C 69.81, H 6.63, O 23.41.
2,6,3',4'-Tetramethoxybiphenyl (Table 5, entry 2): White needles, m.p.
1488C; Rf ˆ 0.5 (30% Et2O/hexane); 1H NMR (200 MHz, [D1]CHCl3,
208C): d ˆ 3.79 (s, 6H; 2OCH3), 3.90 (s, 3H; OCH3À), 3.96 (s, 3H; OCH3'),
6.70 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3,5-H), 6.93 6.99 (m, 3H; 2',5',6'-H),
‡
‡
1523, 1486 cmÀ1; MS (NH4 ): m/z: 161 [M‡H] ; elemental analysis calcd
3
7.29 ppm (t, J(H,H) ˆ 8.3 Hz, 1H; 4-H); 13C NMR (50 MHz, [D1]CHCl3,
(%) for C10H8S (160.24): C 74.96, H 5.03; found: C 74.68, H 5.04.
208C): d ˆ 55.7, 55.8, 55.9, 104.2, 110.5, 114.3, 119.2, 123.1, 126.4, 128.4,
147.7, 148.1, 157.8 ppm; IR (CHCl3): nÄ ˆ 3012 , 2935, 1587, 1523, 1470, 1292,
2-Phenylbenzofuran (Scheme 1):
A solution of n-butyllithium (1.6m
1247, 1106, 1024 cmÀ1; MS (NH4 ): m/z: 275 [M‡H] ; elemental analysis
calcd (%) for C16H18O4 (274.31): C 70.06, H 6.61, O 23.33; found: C 70.31, H
6.62, O 23.39.
‡
‡
solution in hexane, 3.3 mL, 5.3 mmol) was added dropwise at À108C to a
solution of benzofuran (5.3 mmol) in THF (10 mL). The reaction mixture
was stirred at À108C for 1 h and warmed to 08C; then a solution of
fluorobenzene (2.4 mmol) in THF (1.6 mL) was added dropwise. After the
reaction mixture had been stirred for 1 h at RT, it was heated to 608C for
12 h, then allowed to cool to RT, and quenched by addition of water
(40 mL). The aqueous layer was extracted with Et2O (50 mL), dried over
MgSO4, and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel using hexane as eluent. Yield 102 mg (22%)
of a white solid, m.p. 1238C; Rf ˆ 0.3 (hexane); 1H NMR (200 MHz,
[D1]CHCl3, 208C): d ˆ 7.08 (s, 1H; 3-H), 7.20 7.70 (m, 8H), 7.88 7.97 ppm
(m, 2H; 2H'); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 101.3, 111.2,
120.9, 122.9, 124.2, 124.9, 128.5, 128.8, 129.2, 130.5, 154.9, 155.9 ppm; IR
5-(2,6-Dimethoxyphenyl)benzo[1,3]dioxole (Table 5, entry 3): White solid,
m.p. 908C; Rf ˆ 0.2 (5% Et2O/hexane); 1H NMR (300 MHz, [D1]CHCl3,
3
208C): d ˆ 3.76 (s, 6H; 2OCH3), 5.99 (s, 2H; OCH2O), 6.65 (d, J(H,H) ˆ
8.1 Hz, 2H; 3,5-H), 6.80 6.90 (m, 3H; 3,4,6-H), 7.27 ppm (t, 3J(H,H) ˆ
8.1 Hz, 1H; 4-H); 13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 55.9, 100.8,
104.2, 107.9, 111.5, 119.1, 124.2, 127.5, 128.5, 146.3, 147.0, 157.8 ppm; IR
‡
(CHCl3): nÄ ˆ 3025, 2997, 1590, 1500, 1467, 1214 cmÀ1; MS (NH4 ): m/z: 276
‡
[M‡NH4] ; elemental analysis calcd (%) for C15H14O4 (258.27): C 69.76, H
5.46, O 24.78; found: C 70.01, H 5.48, O 24.84.
(CHCl3): nÄ ˆ 3020, 1615, 1510, 1492 cmÀ1; MS (NH4 ): m/z: 195 [M‡H] ;
elemental analysis calcd (%) for C14H10O (194.23): C 86.57, H 5.19, O 8.24;
found: C 86.81, H 5.17, O 8.26.
‡
‡
2,2',6'-Trimethoxy-5-methylbiphenyl (Table 5, entry 4): White solid, m.p.
1148C; Rf ˆ 0.3 (20% Et2O/hexane); 1H NMR (300 MHz, [D1]CHCl3,
208C): d ˆ 2.37 (s, 3H; CH3), 3.77 (s, 3H; OCH3), 3.78 (s, 6H; 2OCH3'),
6.69 (d, 3J(H,H) ˆ 8.3 Hz, 2H; 3',5'-H), 6.93 (d, 3J(H,H) ˆ 8.3 Hz, 1H;
3-H), 7.04 (d, 4J(H,H) ˆ 1.9 Hz, 1H; 6-H), 7.16 (dd, 3J(H,H) ˆ 8.3 Hz,
4J(H,H) ˆ 1.9 Hz, 1H; 4-H), 7.32 ppm (t, 3J(H,H) ˆ 8.3 Hz, 1H; 4'-H);
13C NMR (75 MHz, [D1]CHCl3, 208C): d ˆ 18.7, 55.2, 55.9, 104.0, 112.8,
116.2, 118.9, 128.7, 129.4, 130.2, 157.1, 157.7 ppm; IR (CHCl3): nÄ ˆ 2991,
2-Chloro-1-methoxy-3-deuterobenzene: Colorless liquid; Rf ˆ 0.5 (hex-
ane); 1H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 3.92 (s, 3H; OCH3), 6.92
(m, 2H; 4,6-H), 7.24 ppm (t, 3J(H,H) ˆ 7.8 Hz, 1H; 5-H); 13C NMR
(75 MHz, [D1]CHCl3, 208C): d ˆ 56.0, 112.0, 121.1, 122.3, 127.7, 129.9 (t,
1J(C,H) ˆ 24.5 Hz, C,D), 155.0 ppm; IR (CHCl3): nÄ ˆ 3069, 2922, 1583,
‡
2931, 1607, 1586, 1507, 1250, 1109, 1040 cmÀ1; MS (NH4 ): m/z: 259
‡
‡
1474, 1434, 1272, 1047 cmÀ1; MS (NH4 ): m/z: 145 [M‡H] ; elemental
analysis calcd (%) for C7H6ClOD (143.58): C 58.56, H 4.21, O 11.14; found:
C 58.37, H 4.22, O 11.10.
‡
[M‡H] ; elemental analysis calcd (%) for C16H18O3 (258.32): C 74.39, H
7.02, O 18.58; found: C 74.67, H 7.04, O 18.52.
5,2',6'-Trimethoxy-2-methylbiphenyl (Table 5, entry 5): White solid, m.p.
998C; Rf ˆ 0.2 (20% Et2O/hexane); 1H NMR (300 MHz, [D1]CHCl3,
208C): d ˆ 2.04 (s, 3H; CH3), 3.77 (s, 6H; 2OCH3), 3.83 (s, 3H; OCH3), 6.69
(d, 3J(H,H) ˆ 8.3 Hz, 2H; 3',5'-H), 6.76 (d, 4J(H,H) ˆ 2.9 Hz, 1H; 6-H),
6.86 (dd, 3J(H,H) ˆ 8.3 Hz, 4J(H,H) ˆ 2.9 Hz, 1H; 4-H), 7.22 (d, 3J(H,H) ˆ
8.3 Hz, 1H; 3-H), 7.35 ppm (t, 3J(H,H) ˆ 8.3 Hz, 1H; 4'-H); 13C NMR
(75 MHz, [D1]CHCl3, 208C): d ˆ 20.5, 55.9, 104.1, 111.2, 116.3, 123.2, 128.5,
128.9, 132.6, 155.4, 158.0 ppm; IR (CHCl3): nÄ ˆ 3005, 2935, 1607, 1590, 1500,
2,6,2'-Trimethoxy-6'-deuterobiphenyl (Scheme 4): White solid, m.p. 1408C;
Rf ˆ 0.2 (10% AcOEt/hexane); 1H NMR (300 MHz, [D3]CH3CN, 208C):
d ˆ 3.68 (s, 6H; 2OCH3), 3.70 (s, 3H; OCH3'), 6.70 (d, 3J(H,H) ˆ 8.1 Hz,
2H; 3,5-H), 6.93 7.09 (m, 2H; 3',5'-H), 7.25 7.36 ppm (m, 2H; 4,4'-H);
2H NMR (300 MHz, [D1]CHCl3, 208C): d ˆ 7.40 ppm (6'-D); 13C NMR
(125 MHz, [D3]CH3CN, 208C) d ˆ 56.2, 56.4, 105.2, 112.1, 112.2, 121.0, 124.0
(d, 1J(C,D) ˆ 10.3 Hz), 129.5, 129.9, 133.0, 158.6, 159.1 ppm; IR (CHCl3):
‡
‡
‡
1468, 1246, 1111 cmÀ1; MS (NH4 ): m/z: 259 [M‡H] ; elemental analysis
calcd (%) for C16H18O3 (258.32): C 74.39, H 7.02, O 18.58; found: C 74.21, H
7.01, O 18.61.
nÄ ˆ 3053, 2930, 1656, 1589, 1499, 1264, 1110 cmÀ1; MS (NH4 ): m/z: 263
‡
[M‡NH4] ; elemental analysis calcd (%) for C15H15O3D (245.29): C 73.46,
H 6.57, O 19.57 found C 73.71, H 6.58, O 19.51.
3214
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 3209 3215

Aryllithium Haloarene Coupling
3209 3215
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We thank the Ministere de la Recherche et de l×Enseignement for financial
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Revised: March 7, 2003 [F4373]
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3215