The expedient and regioselective metalation of unprotected biphenyl-2-, -3-, and -4-carboxylic acids

Article abstract of DOI:10.1002/ejoc.200500469

Unprotected biphenyl-2-carboxylic acid can be cleanly metalated with sec-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution. The remote C2′-position is attacked by the superbasic

Full text of DOI:10.1002/ejoc.200500469

FULL PAPER
DOI: 10.1002/ejoc.200500469
The Expedient and Regioselective Metalation of Unprotected Biphenyl-2-, -3-,
and -4-carboxylic Acids
[a]
[a,b]
[a]
[b]
David Tilly, Subhendu S. Samanta,
Anne-Sophie Castanet, Asish De, and
Jacques Mortier*[
a]
Dedicated to the memory of Subhendu S. Samanta[†]
Keywords: ortho-Lithiation / Unprotected benzoic acids / Organolithium compounds / Schlosser–Lochmann superbase /
9
H-Fluoren-9-one
Unprotected biphenyl-2-carboxylic acid can be cleanly meta-
lated with sec-butyllithium at the position adjacent to the
carboxylate and can then be subjected to site-selective elec-
trophilic substitution. The remote C2Ј-position is attacked by
the superbasic mixture of n-butyllithium and potassium tert-
butoxide (LICKOR, 3.5 equiv.) in THF or benzene at 20–
60 °C. The resulting dianion cyclizes to give the fluorenone
skeleton. The metalation reactions of biphenyl-3- and -4-car-
boxylic acids are also described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
systems.[5,6] In recent work[7] we have reported the metal-
ation of meta-anisic acid (1) at the doubly activated position
by lithium 2,2,6,6-tetramethylpiperidide (LTMP); in con-
trast, nBuLi/tBuOK (LICKOR) at low temperature prefer-
Introduction
Nonpeptidic compounds containing biphenylcarboxylic
acid groups inhibit HIV-1 protease, with IC values of 3.4–
5
0
[
1]
7
4 μm. The structure/inhibitory activity relationship dem-
[8]
entially deprotonates the C4-position.
onstrates the necessity of the biphenylcarboxylic acid group
for inhibition. Losartan, one of the most prominent mod-
ern antihypertensive drugs, is a (biphenyl-2-yl)tetrazole de-
The metalation of 4-fluoro- and 4-chlorobenzoic acids
2a, 2b results in exclusive reaction ortho to the carboxylate
with sBuLi, sBuLi/TMEDA, or tBuLi, but LTMP selec-
[
2]
rivative that antagonizes the angiotensin II AT receptor.
[9]
1
tively metalates the C3-positions. These results corrobo-
Their importance as precursors of biologically active
molecules notwithstanding, very little attention has been
paid to the synthesis of biphenyl-2-carboxylic acid deriva-
tives through lithiation reactions. Treatment of tertiary bi-
phenyl-2-carboxamides and biphenyl-2-yloxazolines with
LDA or tBuLi affords the fluorenone skeleton directly by
remote metalation,[3,4] with alkyllithium metalation occur-
ring exclusively ortho to the amide group. The carbonyl
group is invariably protected prior to metalation
rate the concept of the achievement of regiocontrol in hy-
Regioselective lithiation of biphenylcarboxylic acids is a
new challenge because of the previously demonstrated ortho
directing effect of the carboxylic acid group in benzenoid
[
a] Université du Maine and CNRS, Unité de Chimie Organique
Moléculaire and Macromoléculaire (UMR, 6011), Faculté des
Sciences,
Avenue Olivier Messiaen,
72085 Le Mans Cedex 9, France
Fax: +33-2-43833902
E-mail: jacques.mortier@univ-lemans.fr
b] Department of Organic Chemistry, Indian Association for the
Cultivation of Science,
[
[
7
00 032 Jadavpur, Kolkata, India
†] Our colleague and friend passed away at the age of 36 years on
April 17, 2005. He is sadly missed by all of us.
174
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 174–182

Metalation of Unprotected Biphenyl-2-, -3-, and -4-carboxylic Acids
FULL PAPER
drogen/metal exchange processes through mechanism-based Table 1. Metalations of biphenyl-2-carboxylic acid (3). Preparation
of compounds 6 and 7 (Scheme 1).[
a]
matching of substituents and reagents.[
10]
Here we report on the reactivity of biphenyl-2-, -3-, and
4-carboxylic acids 3–5 towards sterically hindered lithium
amides, alkyllithiums, and LICKOR. The results obtained
Cpd.
EX/E
O/D
MeI/Me
EtI/Et
6 (A)
99[b]
7 (B)
7 (C)
70[b]
7 (D)
-
a
b
c
d
e
f
g
h
i
D
2
–
95
88
82
96
92
91
0
–
54
58
0
–
–
0
–
–
–
80
63
72
71
73
81
98
10
–
30
48
43
49
–
–
–
–
show that although the CO Li group does activate neigh-
2
C
C
2
Cl
Br
6
/Cl
Cl
boring positions towards metalation, the effect remains rel-
atively weak, enabling regioflexibility since most other elec-
tronegative substituents outperform a competing carboxyl-
ate group through their superior ortho-directing capabilities.
2
2
4
/Br
I
2
/I
Me
Me SiCl/Me Si
2
S
2
/MeS
3
3
Sn
[c]
nBu
DMF/CHO
PhCHO/PhCH(OH)
3
Sn/nBu
3
65[
–
–
–
d]
e]
j
k
80
93[
–
Results and Discussion
[a] Yields of recrystallized or chromatographed materials. [b] The
1
isotope ratio was determined by H NMR and FIMS: 6a (reac-
Biphenyl-2-carboxylic acid (3) undergoes regiospecific tion A, 1d :1d 30:70), 7a (reaction C, 1d :1d 0:100). [c] Recovered
0
1
0
1
metalation ortho to the carboxylate substituent (C3) when as the ester tri-n-butyltin 3-(tri-n-butylstannyl)biphenyl-2-carboxyl-
ate (6iЈ). [d] Compound 6j was not isolated but was converted di-
treated with sec-butyllithium (sBuLi) in THF at –78 °C
rectly into 3-hydroxy-7-phenylisobenzofuran-1(3H)-one (14) by
(Scheme 1). Trapping of the stable lithium 3-lithiobiphenyl-
acid treatment upon workup. [e] Compound 6k was not isolated
2-carboxylate (8) with a variety of electrophiles (see Table 1)
but was converted directly into 3,7-diphenylisobenzofuran-1(3H)-
afforded diversely 3-substituted biphenyl-2-carboxylic acids one (15) by acid treatment upon workup.
Scheme 1.
Eur. J. Org. Chem. 2006, 174–182
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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175

D. Tilly, S. S. Samanta, A.-S. Castanet, A. De, J. Mortier
FULL PAPER
6
a–k (reaction A).[11] D O gave 6a, in which 70% of the quence allows the introduction of a broader range of sub-
2
deuterium was incorporated at the carbon C3. Treatment stituents at the C1-position than is achievable by these
with nBu SnCl gave the ester 6iЈ (68%, Figure 1), which was methods. The fluorenone skeleton occurs in a wide range
3
[
12]
[18]
transformed into meta-terphenyl-2Ј-carboxylic acid (13)
by the Stille reaction (59%) (Figure 1; see Experimental lysates,
Section). Acids 6j and 6k, the results of treatment of the mington petroleum.
dianion 8 with DMF and with benzaldehyde, were con- function as photoinitiators in various photochemical reac-
verted directly into 3-hydroxy-7-phenylisobenzofuran- tions.
(3H)-one (14) and 3,7-diphenylisobenzofuran-1(3H)-one With LICKOR (3.5 equiv.) in THF or benzene at 20–
15), respectively, during the acidic workup.
of substrates, including marine sediments, kerogen pyro-
[
19]
weathered surface retorted oil shales, and Wil-
[
20]
Fluorenones are also known to
[
21]
1
(
[
22]
60 °C, biphenyl-2-carboxylic acid (3) gave the fluorenone
skeleton 7 (E = H; Scheme 1), arising from the metalation
[
23]
of the remote C2Ј site (reaction C).
The unstable C2Ј-
metalated species 10 has a short lifetime and rapidly cy-
clizes to give the doubly charged geminal dimetalo dialk-
oxide group 11. The equilibrium between the C3-metalated
species and the C2Ј-metalated species is shifted to the right
by Le Châtelier’s principle. Deuterolysis experiments have
shown that both ortho (C3) and remote (C2Ј) positions are
[
23]
metalated under these conditions.
1
The H NMR spectrum of the residue prior to hydrolysis
in [D ]THF displays broad signals with poor resolution in
8
the aromatic region, probably due to the presence of aggre-
gates that prevent simple structural elucidation. The dialk-
oxide 11 is not trappable by electrophiles: treatment with
iodomethane or dimethyl sulfate gave the fluorenone 7 even
when hydrolysis of the reaction mixture with water was
[
23]
omitted.
When 2 equiv. of nBuLi were added to the mixture com-
posed of 3 and LICKOR (3.5 equiv.) in benzene at 60 °C,
quenching with D O produced isotopically pure 1-deuterio-
2
9
H-fluoren-9-one 7a (E = D, 70%, 100% 1d ). The doubly
1
Figure 1. Functionalization of unprotected biphenyl-2-carboxylic charged dimetalo dialkoxide group C(OM) of 11 presum-
2
acid (3).
ably directs a second metalation in the adjacent position
(C1) to afford the stable 1-metalo-9H-fluoren-9,9-dimetalo
dialkoxide (12), which can be trapped by D O after acidic
2
In this reaction, the alkyllithium presumably approaches workup. 1-Substituted 9H-fluoren-9-ones 7b–k were ob-
the benzoate in the initial step through strong coordination tained successfully with a variety of electrophiles (see
with the highly electron-rich π-system of the carboxylate, Table 1).
producing a pre-lithiation complex [Complex-Induced
1-Substituted 9H-fluoren-9-ones (7) were also prepared
Proximity Effect (CIPE) process].[ The directing and ac- by anionic cyclization of 3-substituted biphenyl-2-carbox-
celerating effect of the carboxylate might be due to the sta- ylic acids 6, but results in this case were less satisfactory
bilization both of the initial complex and of the transition (reaction D, Scheme 1). Thus, treatment of 6b or 6c (R =
13]
[
14]
structure. The coordination by the carboxylate could be Me, Et) with LICKOR (3.5 equiv.) in benzene at 60 °C gave
[
7]
stronger in the transition state than in the initial complex;
the fluorenones 7b or 7c after acidic workup (54% and
as a result, complexation could increase the rate of reaction 58%, respectively). Consequently the remote metalation at
by providing a new mechanism with a smaller activation C2Ј and cyclization is faster than the lateral metalation of
energy (Ea).
the chain of the substrate. Notably, reaction C gave 7b in
Intramolecular Friedel–Crafts acylation by treatment of lower yield (10%). Because of the drastic reaction condi-
3
-substituted biphenyl-2-carboxylic acids (6b–g) with meth- tions used, the corresponding reactions of 6d–g failed. For
[15]
anesulfonic acid at 50–60 °C
afforded the fluorenones the preparation of 1-substituted fluorenones, the sequence
7
b–g in good yields after column chromatography (reac- A + B is thus to be preferred.
tion B). 1-Phenyl-9H-fluoren-9-one (16) was prepared from We next embarked on an investigation of the deproton-
the teraryl carboxylic acid 13 under the same reaction con- ation of biphenyl-3- and -4-carboxylic acids (4 and 5) by
ditions (41%, Figure 1). varying the base, the solvent, the metalation temperature,
In the literature, fluorenones containing aryl substituents and the exposure times (Scheme 2). Whereas acid 4 in prin-
at their C1-positions have been prepared either by radical ciple offers selection of either of the two possible ortho sub-
[
16]
procedures
or through fluorenone-1-boronic acid coup- stitutions (C2 and C4), 5 can be metalated only in the C3
[17]
ling with the corresponding aryl halides.
The A + B se- position for symmetry reasons. Biphenyl-3- and -4-carbox-
176
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Metalation of Unprotected Biphenyl-2-, -3-, and -4-carboxylic Acids
FULL PAPER
1
1
ylic acid moieties are present in numerous biologically (1.00± 0.05 unit/1 H). The two-dimensional COSY H- H
[
24,25]
active molecules.
The acids 4 and 5 were prepared by spectra of 4 and 18 confirmed the correct deuterium regi-
Suzuki coupling between phenylboronic acid and 3- or 4- ochemistry of the reaction products. Quenching with hexa-
bromobenzoic acids in the presence of Pd/C (10%) and tri- chloroethane afforded 4-chlorobiphenyl-3-carboxylic acid
phenylphosphane (0.2 equiv.) (65% and 85% yield, respec- (19), which was isolated in 22% yield after column
[
26]
tively).
chromatography and recrystallization.
The acid 4, LTMP, and Me SiCl did not react under in
3
[
27]
situ quench conditions.
With LICKOR (3.5 equiv.) in
benzene at 20 °C, (biphenyl-3-yl)(phenyl)methanone (20)
was the only product formed (36%). It has been reported
in the literature that benzene is metalated by the superbasic
n-butyllithium/tBuOK mixture, affording phenyl potassium
(
C H K), the purity of which was reported to be highly
6 5
[
28]
dependent on reaction conditions.
potassium are weakly nucleophilic,
Since alkyl and aryl-
PhLi must be the
[
29,30]
reactive nucleophilic species that reacts with the lithium salt
of 4 to give 20.
Alkyllithium bases (nBuLi, sBuLi, and tBuLi) and
LTMP are not suitable to metalate 4. Nucleophilic addition
of RLi to the carboxylate again provided the 1,2-addition
[
31]
products 21. Furthermore, addition of HMPA, TMEDA,
or PMDTA at –78 °C was virtually without effect.
Biphenyl-4-carboxylic acid (5) was also subjected to a
series of bases (Scheme 4). Alkyllithiums are again too nu-
cleophilic, whereas LICKOR and LTMP do not react. It
was found that the 1:1 sBuLi/TMEDA complex (2.2 equiv.)
was able to metalate the acid 5 regioselectively, affording
Scheme 2.
Metalation of 4 was achieved with LICKOR (3.5 equiv.) the dilithio dianion 22. Subsequent deuterolysis with D O
2
in THF for 2 h at –78 °C (Scheme 3). Trapping of the di- gave 23 (57%) with 60% deuterium incorporation (evalu-
anion 17 with D O at –78 °C [external quench (EQ) condi- ated by NMR). The 3d /3d isotope ratio was determined
2
0
1
tions] gave 18 in which 59% of the deuterium was incorpo- to be 39.4:60.4 by FIMS of chromatographed material.
1
rated at the C4 carbon (89%) (determined by H NMR Complexation of the carboxylate by the alkyllithium base
and FIMS). The percentage of deuterium was defined as is presumably once again the predominant factor that gov-
absolute regioselectivity of the metalation. It was assigned erns the reaction rate. The 1,2-addition is competitive, since
as decreased intensity of the signal in relation to the 1-(biphenyl-4-yl)-2-methylbutan-1-one (24) was also iso-
averaged intensities of the unaffected positions: 2, 5, and 6 lated in 36% yield.
Scheme 3.
Eur. J. Org. Chem. 2006, 174–182
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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177

D. Tilly, S. S. Samanta, A.-S. Castanet, A. De, J. Mortier
FULL PAPER
Scheme 4.
ref.[34,35] 132–133 °C, 4.29 g, 80%]. H NMR (400 MHz, CDCl
1
): δ
Experimental Section
3
=
2
10.50 (s, 1 H), 7.39–7.32 (m, 6 H), 7.20 (m, 1 H), 7.19 (d, J =
.4 Hz, 1 H), 2.43 (s, 3 H, CH ) ppm. C NMR (50 MHz, CDCl ):
3 3
δ = 175.2, 140.6, 140.2, 135.4, 132.1, 129.7, 129.2 (2 C), 128.3 (3
C), 127.5, 127.5, 19.9 ppm. IR (KBr): ν˜ = 2951–2643 (br), 1699,
General: For standard working practices, see ref.[32,33]. Metalation
reactions were carried out under argon in oven-dried glassware.
Tetrahydrofuran was dried from sodium benzophenone ketyl. Ben-
zene was distilled from calcium hydride. NMR spectra were re-
corded on 200 or 400 MHz spectrometers. 13C NMR spectra were
obtained with broadband proton decoupling. For spectra recorded
13
–1
1
12 2
458, 1284 cm . C14H O (212.24): calcd: C 79.23, H 5.70; found
C 79.44, H 5.72.
3
-Ethylbiphenyl-2-carboxylic Acid (6c): This compound was pre-
pared as described in the General Procedure, with quenching with
iodoethane (6 mL, 75.6 mmol) to give 6c as a white solid
recrystallization heptane/ethyl acetate, m.p. 140–141 °C, 3.60 g,
3
): δ = 7.47–7.35 (m, 6 H), 7.26–
.20 (m, 2 H), 2.76 (dd, J = 7.9 Hz and J = 7.4 Hz, 2 H), 1.28 (t,
in CDCl
3
, chemical shifts are recorded relative to the internal TMS
]DMSO and [D ]ace-
(tetramethylsilane) reference signal. For [D
6
6
tone used as solvents, chemical shifts are given relative to the sol-
vent signals.
[
6
1
3%]. H NMR (400 MHz, CDCl
3-Substituted Biphenyl-2-carboxylic Acids 6a–k from Biphenyl-2-
7
carboxylic Acid (3). General Procedure (Reaction A): sBuLi (1.3 m
in cyclohexane, 44 mL, 57.2 mmol) was added dropwise under ar-
gon at –78 °C − over a period of ca. 30 min − to a vigorously
stirred solution of biphenyl-2-carboxylic acid (3, 5 g, 25.22 mmol)
in anhydrous THF (180 mL). A deep red-orange coloration ap-
peared during addition of the organolithium. After 2.5 h stirring
at –78 °C, the mixture was treated with an excess of the appropriate
electrophile. The solution was then allowed to warm overnight to
ambient temperature, and water (30 mL) was added. The aqueous
phase was washed twice with diethyl ether (40 mL) and shaken,
and was then acidified with HCl (4 m, pH 1). The aqueous phase
was extracted with diethyl ether (4×20 mL). The combined ether
13
J = 7.4 Hz, 3 H) ppm. C NMR (50 MHz, CDCl
3
): δ = 175.1,
41.5, 140.6, 140.0, 131.7, 129.8, 128.4 (2 C), 128.3 (2 C), 127.6,
27.5, 127.5, 26.8, 15.7 ppm. IR (KBr): ν˜ = 2969, 1689, 1588, 1463,
1
1
1
–1
14 2
286, 1253 cm . C15H O (226.27): calcd: C 79.62, H 6.24; found
C 79.57, H 6.21.
3
-Chlorobiphenyl-2-carboxylic Acid (6d): This compound was pre-
pared as described in the General Procedure, with quenching with
hexachloroethane (17.9 g, 75.6 mmol) to give 6d as a white solid
recrystallization heptane/ethyl acetate, m.p. 184–185 °C, ref.
[
36]
[
1
1
84–186 °C, 4.23 g, 72%]. H NMR (400 MHz, CDCl
3
): δ = 7.41–
.35 (m, 6 H), 7.32–7.28 (m, 2 H) ppm. C NMR (100 MHz,
): δ = 175.2, 168.9, 142.9, 141.3, 135.9, 132.2, 132.0, 130.3,
30.3 (2 C), 130.0 (2 C), 129.8 ppm. IR (KBr): ν˜ = 3025–2786 (br),
1
3
7
CDCl
3
4
phases were washed with water (2×25 mL) and dried with MgSO .
1
1
Filtration and concentration in vacuo gave the crude acids 6a–k,
which were purified by recrystallization for characterization in each
case.
–
1
699, 1560, 1455, 1294 cm .
3
-Bromobiphenyl-2-carboxylic Acid (6e): This compound was pre-
3
-Deuteriobiphenyl-2-carboxylic Acid (6a): This compound was pre-
pared as described in the General Procedure, with quenching with
Br Cl (24.6 g, 75.6 mmol) to give 6e as a white solid [recrystalli-
pared as described in the General Procedure, with quenching with
D
C
2
2
4
1
O (3.8 mL, 210 mmol) to give 6a as a white solid (4.98 g, 99%). zation heptane/ethyl acetate, m.p. 185–186 °C, 4.97 g, 71%].
H
2
1
The isotope ratio determined by H NMR (doublet at δ = 7.94 ppm
attributed to H3) and FIMS was found to be 3d :3d 30:70.
): δ = 10.63 (s, 1 H, COOH), 7.94 (d,
J = 7.3 Hz, 0.3 H), 7.56–7.55 (m, 1 H), 7.46–7.26 (m, 7 H).
NMR (400 MHz, [D
6
]acetone): δ = 11.30 (s, 1 H), 7.71–7.59 (m, 1
1
3
6
H), 7.45–7.30 (m, 7 H) ppm. C NMR (50 MHz, [D ]acetone): δ
0
1
1
H NMR (200 MHz, CDCl
3
= 169.5, 143.0, 141.2, 131.5, 130.7, 128.8, 128.5 (2 C), 128.3 (3
C), 128.2, 119.3 ppm. IR (KBr): ν˜ = 3029–2801 (br), 1699, 1552,
–
1
1
456 cm .
3-Methylbiphenyl-2-carboxylic Acid (6b): This compound was pre-
pared as described in the General Procedure, with quenching with
iodomethane (4.7 mL, 75.6 mmol) to give 6b as a white solid
3-Iodobiphenyl-2-carboxylic Acid (6f): This compound was pre-
pared as described in the General Procedure, with quenching with
iodine (19.19 g, 75.2 mmol) to give 6f as a white solid [recrystalli-
[recrystallization heptane/ethyl acetate, m.p. 133.4–134.4 °C,
178
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Metalation of Unprotected Biphenyl-2-, -3-, and -4-carboxylic Acids
FULL PAPER
zation heptane/ethyl acetate, m.p. 169–170 °C, 5.97 g, 73%]. 1
NMR (400 MHz, [D
.9 Hz and J = 1.0 Hz, 1 H), 7.47–7.38 (m, 6 H), 7.28–7.25 (m, 1
H
7.57 (m, 3 H), 7.52–7.45 (m, 4 H), 7.42–7.25 (m, 6 H), 6.37 (s, 1
1
3
6
6
]acetone): δ = 11.91 (s, 1 H), 7.94 (dd, J = H) ppm. C NMR (50 MHz, [D ]DMSO): δ = 169.2, 151.0, 142.6,
7
136.6, 136.2, 134.0, 131.0, 129.5, 129.1 (2 C), 128.9, 128.3 (3 C),
13
H) ppm. C NMR (50 MHz, [D
6
]acetone): δ = 170.9, 142.7, 142.3,
127.9, 126.9 (2 C), 121.6 (2 C), 121.4 ppm. IR (KBr): ν˜ = 3057,
–
1
1
41.7, 139.9, 132.4, 131.5, 130.3, 130.2 (2 C), 129.8 (2 C), 93.7 ppm.
1765, 1013 cm . C20
C 83.84, H 4.95.
14 2
H O (286.32): calcd: C 83.90, H 4.93; found
–1
9 2
IR (KBr): ν˜ = 2903, 1688, 1552, 1287 cm . C13H IO (324.11):
calcd: C 48.17, H 2.80; found C 48.25, H 2.80.
meta-Terphenyl-2Ј-carboxylic Acid (13): Triphenylphosphane
(95 mg, 0.34 mmol), bistriphenylphosphane dichloropalladium
(127 mg, 0.17 mmol), and iodobenzene (0.75 mL, 6.88 mmol) were
successively added, under argon, to a solution of 6iЈ (2.69 g,
3.44 mmol) in xylene (25 mL). After having been heated at reflux
for 24 h, the mixture was allowed to cool to room temp., filtered,
and extracted with aq. NaOH (2 m). The aqueous layer was washed
3-(Methylthio)biphenyl-2-carboxylic Acid (6g): This compound was
prepared as described in the General Procedure, with quenching
with dimethyl disulfide (6.8 mL, 77 mmol) to give 6g as a white
solid [recrystallization heptane/ethyl acetate, m.p. 115–116 °C,
5
.0 g, 81%]. 1H NMR (400 MHz, CDCl
3
): δ = 11.26 (s, 1 H,
COOH), 7.45–7.35 (m, 7 H), 7.21 (dd, J = 7.2 Hz and J = 0.8 Hz,
1
1
1
1
H), 2.51 (s, 3 H, SCH
73.2, 140.8, 139.9, 136.6, 132.6, 130.2, 128.4 (2 C), 128.3 (2 C), 4 mL), and extracted with diethyl ether (2×60 mL). The combined
27.7, 127.4, 126.8, 17.6 ppm. IR (KBr): ν˜ = 3035–2905 (br), 1685, ether layers were dried with MgSO , filtered, and concentrated in
) ppm. 13C NMR (50 MHz, CDCl
): δ = twice with diethyl ether (40 mL), acidified with aq. HCl (4 m,
3 3
4
–1
596, 1450, 1404, 1132 cm . C14
H
12
O
2
S (244.31): calcd: C 68.83, vacuo to give a residue, which was recrystallized (heptane/ethyl ace-
H 4.95; found C 69.03, H 4.85.
tate). The product 13 was isolated as a white solid (m.p. 188–
89 °C, ref.[
37]
191–193 °C, 0.56 g, 59%). H NMR (200 MHz,
): δ = 7.56–7.25 (m, 13 H) ppm. C NMR (50 MHz,
): δ = 174.5, 140.3 (2 C), 131.7, 129.6, 128.9 (2 C), 128.4 (4
1
1
3-(Trimethylsilyl)biphenyl-2-carboxylic Acid (6h): This compound
1
3
CDCl
CDCl
3
was prepared as described in the General Procedure, with quench-
ing with chlorotrimethylsilane (8.20 g, 75.2 mmol) to give 6h as a
3
C), 128.3 (4 C), 128.1, 127.6 (2 C) ppm.
white solid [recrystallization heptane/ethyl acetate, m.p. 143–
1
1
44 °C, 6.69 g, 98%]. H NMR (400 MHz, CDCl
3
): δ = 7.60 (d, J
1-Substituted 9H-Fluoren-9-ones 7b–g by Intramolecular Friedel–
Crafts Acylation of Acids 6b–g (Reaction B). General Procedure:
The appropriate compound (6b–g, 9.4 mmol) was dissolved in
methanesulfonic acid (Ϸ 50 equiv.) in a round-bottomed flask with
a magnetic stirrer, and the reaction mixture was warmed to 60 °C.
A dark red color appeared rapidly. The reaction was followed by
TLC until total conversion of the starting acid was observed. The
mixture was then poured into water (25 mL) at 0 °C. The aqueous
layer was extracted with ethyl acetate (2×20 mL). The organic layer
=
7.4 Hz, 1 H), 7.46 (dd, J = 7.9 Hz and J = 7.3 Hz, 1 H), 7.37–
.34 (m, 6 H), 0.32 (s, 9 H) ppm. 13C NMR (50 MHz, [D
]acetone):
δ = 177.7, 140.9, 140.1, 138.7, 137.1, 133.5, 130.7, 129.3, 128.3 (4
7
6
C), 127.3, 0.0 (3 C). C16
found C 71.11, H 6.81.
18 2
H O Si (270.4): calcd: C 71.07, H 6.71;
Tributylstannyl 3-(Tributylstannyl)biphenyl-2-carboxylate (6iЈ):
Treatment of biphenyl-2-carboxylic (3, 1.0 g, 5.06 mmol) and sBuLi
(
1.3 m in cyclohexane, 8.6 mL, 11.1 mmol) in THF (30 mL) was
followed by quenching with excess tri-n-butyltin chloride (4 mL,
5.16 mmol). After the system had been allowed to warm to room
temperature and the solvents had been removed in vacuo, heptane
15 mL) was added to the residue. The insoluble component was
was washed successively with water (2×15 mL), satd. NaHCO
15 mL), and water (15 mL), and was then dried with MgSO , fil-
3
(
4
1
tered, and concentrated in vacuo to give a residue, which was
recrystallized (heptane/ethyl acetate).
(
filtered off and the filtrate was concentrated with a rotavap. Vola-
tiles were removed under vacuum (4 mbar) at 200 °C and the re-
sulting orange residue was chromatographed on neutral alumina
1-Methyl-9H-fluoren-9-one (7b): This compound was prepared
from 6b as described in the General Procedure given above. Yellow
solid (m.p. 98–99 °C, ref.[ 97–98 °C, 1.73 g, 95%). H NMR
38]
1
(
cyclohexane/ethyl acetate 8:2) to give 6iЈ as a colorless oil (13.33 g,
(400 MHz, CDCl
7.4, J = 6.9, J = 7.9 Hz, 2 H), 7.34–7.29 (m, 2 H), 7.24 (m, 1 H),
7.03 (m, 1 H), 2.60 (s, 3 H) ppm. C NMR (50 MHz, CDCl ): δ
3
3
): δ = 7.59 (d, J = 7.4 Hz, 1 H), 7.43 (ddd, J =
1
6
8%). H NMR (CDCl
J = 20.2 Hz, 1 H), 7.39 (m, 1 H), 7.32–7.19 (m, 5 H), 7.24 (dd, J
7.4 Hz and J = 7.9 Hz, 1 H), 1.38–1.61 (m, 12 H), 1.21–1.37 (m, = 195.0, 144.7, 143.8, 139.4, 134.3, 133.9, 131.8, 130.8, 128.8, 123.7,
3
, 400 MHz): δ = 7.57 (dd, J = 7.4 Hz and
1
3
=
1
3
2 H), 1.00–1.16 (m, 12 H), 0.88 (t, 18 H, CH
3
) ppm. 1 C NMR 119.9 (2 C), 117.8, 17.7 ppm.
(
1
1
CDCl , 100 MHz): δ = 174.6, 147.2, 144.5, 143.2, 137.8, 135.5,
30.8, 129.2, 128.4, 127.5, 126.2, 29.3, 27.7, 27.5, 27.1, 16.3, 13.8,
3.6, 11.5 ppm.
3
1
-Methyl-9H-fluoren-9-one (7b) was also prepared from 6b by met-
alation with LICKOR (reaction D), 6b (0.54 g, 2.52 mmol) in dry
THF (20 mL) being added dropwise to a solution of LICKOR
(5.54 mmol, preparation: see reaction C, General Procedure) in dry
benzene (10 mL) at 60 °C. The mixture was stirred for 4–5 h at
60 °C, after which water (20 mL) was added. The reaction mixture
was extracted with ethyl acetate, the combined organic layers were
3
-Hydroxy-7-phenylisobenzofuran-1(3H)-one (14): This compound
was prepared as described in the General Procedure, with quench-
ing with freshly distilled DMF (5.87 mL, 75.6 mmol) to give 14 (via
6
1
7
7
j) as a white solid [recrystallization heptane/ethyl acetate, m.p.
1
45–147 °C, 4.57 g, 80%]. H NMR (400 MHz, [D
.75 (dd, J = 7.9, J = 7.3 Hz, 1 H), 7.61 (d, J = 7.3 Hz, 1 H), 7.53– the residue was chromatographed (cyclohexane/ ethyl acetate) to
.49 (m, 3 H), 7.46–7.40 (m, 3 H), 6.60 (s, 1 H), 6.53 (s, 1 H) ppm. give 7b (0.27 g, 54%).
6 4
]acetone): δ = washed with brine, dried (MgSO ), and concentrated in vacuo, and
1
3
C NMR (50 MHz, [D
6
]acetone): δ = 167.6, 148.1, 142.0, 136.2,
1
6
-Ethyl-9H-fluoren-9-one (7c): This compound was prepared from
c as described in the General Procedure given above. Yellow solid
1
34.1, 132.1, 129.3, 128.2 (2 C), 127.8, 122.8 (2 C), 122.1, 96.1 ppm.
–1
IR (KBr): ν˜ = 2883, 1693, 1551, 1442, 1286, 1145 cm . C14
(
H
10
O
3
[39]
1
(
m.p., 93.6–94.4 °C, ref.
91–93 °C, 1.72 g, 88%). H NMR
226.23): calcd: C 74.33, H 4.46; found C 74.53, H 4.56.
(400 MHz, CDCl ): δ = 7.61 (d, J = 7.4 Hz, 1 H), 7.48–7.43 (m, 2
3
3
,7-Diphenylisobenzofuran-1(3H)-one (15): This compound was pre-
H), 7.36–7.32 (m, 2 H), 7.26 (dd, J = 1.5 Hz and J = 7.4 Hz, 1 H),
7.08 (dd, J = 1.5 Hz and J = 6.9 Hz, 1 H), 3.07 (q, J = 7.5 Hz, 2
pared as described in the General Procedure, with quenching with
freshly distilled benzaldehyde (7.72 mL, 75.6 mmol) to give 15 (via
1
3
H), 1.25 (t, J = 7.5 Hz, 3 H) ppm. C NMR (50 MHz, CDCl
= 194.8, 146.0, 144.9, 143.8, 134.2 (2 C), 130.1 (2 C), 128.8, 123.8
3
): δ = 7.69– (2 C), 119.9, 117.9, 24.5, 14.7 ppm.
3
): δ
6
9
k) as a white solid [recrystallization diethyl ether/heptane, m.p.
1–92 °C, 6.72 g, 93%]. 1H NMR (400 MHz, CDCl
Eur. J. Org. Chem. 2006, 174–182
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
179

D. Tilly, S. S. Samanta, A.-S. Castanet, A. De, J. Mortier
FULL PAPER
Compound 7c was also prepared from 6c (2.52 mmol) by metal-
ation with LICKOR (reaction D) (304 mg, 58%). See second prep-
aration of 6b.
1
70%). The isotope ratio was determined by H NMR and FIMS:
1
1d
0
:1d
1
0:100. H NMR (CDCl
3
, 400 MHz): δ = 7.63 (d, 1 H, J =
7.4 Hz), 7.46 (m, 4 H), 7.27 (m, 2 H) ppm.
1
-Chloro-9H-fluoren-9-one (7d): This compound was prepared from
d as described in the General Procedure given above. Yellow solid
1-Methyl-9H-fluoren-9-one (7b): Quenching with iodomethane gave
7b as a yellow solid (39 mg, 10%). See above for spectroscopic and
analytical characterization.
6
(
(
m.p., 138–139 °C, ref.[40] 137–137.8 °C, 1.65 g, 82%). 1H NMR
400 MHz, CDCl
3
): δ = 7.63 (d, J = 7.4 Hz, 1 H), 7.47 (d, J =
.9 Hz, 2 H), 7.39–7.36 (m, 2 H), 7.30 (m, 1 H), 7.17 (d, J = 7.4 Hz,
H) ppm. 13C NMR (50 MHz, CDCl
): δ = 190.7, 146.4, 142.4,
1-Chloro-9H-fluoren-9-one (7d): Quenching with hexachloroethane
3
1
1
1
gave 7d (130 mg, 30%). See above for spectroscopic and analytical
characterization.
3
35.1, 134.6, 133.7, 132.6, 130.8, 129.6, 129.3, 124.3, 120.3,
18.6 ppm.
1-Bromo-9H-fluoren-9-one (7e): Quenching with C
251 mg, 48%). See above for spectroscopic and analytical charac-
terization.
2 2 4
Br Cl gave 7e
(
1
6
-Bromo-9H-fluoren-9-one (7e): This compound was prepared from
e as described in the General Procedure given above. Yellow solid
m.p. 132.5–133.5 °C, ref.[40] 134–134.3 °C, 2.34 g, 96%). H NMR 1-Iodo-9H-fluoren-9-one (7f): Quenching with elemental iodine gave
1
(
(
400 MHz, CDCl
3
): δ = 7.64 (d, J = 7.4 Hz, 1 H), 7.46 (m, 2 H),
.43 (d, J = 7.4 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.26–2.30 (m, acterization.
H) ppm. 13C NMR (50 MHz, CDCl
): δ = 190.9, 146.8, 142.2,
7f (266 mg, 43%). See above for spectroscopic and analytical char-
7
2
1
1
3
1-Methylthio-9H-fluoren-9-one (7g): Quenching with dimethyl di-
35.2, 134.7, 134.1, 133.6, 131.0, 129.5, 124.3, 120.4, 119.1,
18.6 ppm.
sulfide gave 7g (224 mg, 49%). See above for spectroscopic and
analytical characterization.
1
-Iodo-9H-fluoren-9-one (7f): This compound was prepared from 6f
Biphenyl-3-carboxylic Acid (4) and Biphenyl-4-carboxylic Acid (5):
as described in the General Procedure given above. Yellow solid
3-Bromobenzoic acid or 4-bromobenzoic acid (3.5 g, 17.4 mmol),
m.p. 147–148.5 °C, ref.[ 144–145 °C, 2.65 g, 92%). 1H NMR
400 MHz, CDCl ): δ = 7.67 (m, 2 H), 7.50–7.47 (m, 3 H), 7.28 (m,
H), 7.31 (m, 1 H), 7.12 (dd, J = 7.9 Hz and J = 7.4 Hz, 1 H) ppm.
40]
(
(
phenylboronic acid (2.7 g, 20.9 mmol), Pd/C (907 mg, 0.86 mmol,
3
1
3
0% weight, 3230H type), triphenylphosphane (808 mg,
.08 mmol) and dimethoxyethane (60 mL) were stirred under argon
1
1
3
3
C NMR (50 MHz, CDCl ): δ = 191.6, 147.0, 141.7, 140.4, 134.9,
34.9, 134.9, 129.5, 124.5, 120.0 (2 C), 119.9, 91.5 ppm.
2 3
for 20 min at room temperature. Aqueous Na CO (2 m, 33 mL)
1
was added and the mixture was stirred at 85 °C for 24 h. After the
mixture had cooled to room temp., diethyl ether was added. After
filtration through celite, the filtrate was washed with water
(3×100 mL), and the aqueous layer was acidified with aq. HCl
(4 m) until the pH reached 1. The aqueous layer was washed with
1
-(Methylthio)-9H-fluoren-9-one (7g): This compound was pre-
pared from 6g as described in the General Procedure given above.
Yellow solid (m.p. 167–168 °C, 1.94 g, 91%). H NMR (400 MHz,
CDCl ): δ = 7.62 (d, J = 7.4 Hz, 1 H), 7.48–7.43 (m, 2 H), 7.37
3
1
(
dd, J = 7.4 Hz and J = 7.9 Hz, 1 H), 7.27 (m, 1 H), 7.22 (d, J = diethyl ether (6×50 mL), the combined ether layer was dried with
1
3
7
.4 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 2.05 (s, 3 H) ppm.
): δ = 193.1, 145.4, 143.1, 141.4, 134.4,
34.1, 129.1, 128.8, 123.8 (2 C), 120.2, 115.7, 13.6 ppm.
C
4
MgSO and concentrated in vacuo, and the residue was recrys-
tallized (heptane/ethyl acetate) to give the product.
NMR (50 MHz, CDCl
1
3
Biphenyl-3-carboxylic acid (4) was obtained as white crystals (m.p.
112–114 °C, ref.[ 112–114 °C, 2.24 g, 65%). H NMR (200 MHz,
41]
1
1
1
-Phenyl-9H-fluoren-9-one (16): This compound was prepared from
3 as described in the General Procedure given above. Yellow solid
3
CDCl ): δ = 10.68 (s, 1 H), 8.37 (s, 1 H), 8.11 (d, J = 7.8 Hz, 1 H),
17]
119–120 °C, 0.99 g, 41%). 1H NMR 7.85 (d, J = 7.8 Hz, 1 H), 7.54–7.51 (m, 6 H) ppm. C NMR
13
(
(
m.p. 119–120 °C, ref.[
200 MHz, CDCl
3
3
): δ = 7.68–7.37 (m, 10 H), 7.30–7.13 (m, 2 (50 MHz, CDCl ): δ = 172.2, 141.6, 140.0, 132.4, 129.8, 128.9 (2
13
H) ppm. C NMR (50 MHz, CDCl
42.1, 137.3, 134.6, 134.4, 134.1, 131.4, 129.0 (2 C), 128.7, 127.7 (2
C), 124.2, 123.9, 120.2, 119.9, 119.1 ppm.
3
): δ = 193.0, 145.3, 143.4,
C), 128.9 (2 C), 128.8, 127.8, 127.1 (2 C) ppm.
1
Biphenyl-4-carboxylic acid (5) was recrystallized from chloroform
[41]
1
(
m.p. 224–225 °C, ref.
227–229 °C, 2.93 g, 85%). H NMR
1
-Substituted 9H-Fluoren-9-ones 7a, 7b, 7d–g from Biphenyl-2-car-
boxylic Acid (3) (Reaction C). General Procedure: n-Butyllithium
4.5 mL, 7.8 mmol) was added at ambient temperature to a suspen-
sion of potassium tert-butoxide (792 mg, 7.0 mmol) in benzene
10 mL). After the mixture had been stirred for 5 min, the
(200 MHz, [D
6
]DMSO): δ = 8.05 (d, J = 8.2 Hz, 2 H), 7.75–7.73
1
3
6
(m, 4 H), 7.47–7.45 (m, 3 H) ppm. C NMR (50 MHz, [D ]
DMSO): δ = 167.1, 144.3, 139.0, 129.9 (2 C), 129.6, 129.0 (2 C),
128.2, 126.9 (2 C), 126.8 (2 C) ppm.
(
(
4-Deuteriobiphenyl-3-carboxylic Acid (18): n-Butyllithium (3.52 mL,
LICKOR base was transferred into a round flask containing bi-
phenyl-2-carboxylic acid (3, 400 mg, 2.02 mmol) in benzene (5 mL).
Stirring at 60 °C was maintained for an hour. The system was al-
lowed to cool to room temp., nBuLi (2.5 mL, 4.05 mmol) was
added dropwise, and the mixture was stirred at 60 °C for an ad-
ditional 2 hours. After gradually cooling to room temp., the solu-
tion was quenched with the electrophile (40.4 mmol) in benzene
6.1 mmol) was added at –78 °C to a suspension of potassium tert-
butoxide (627 mg, 5.54 mmol) in dry THF (10 mL). After the mix-
ture had been stirred for 5 min, biphenyl-3-carboxylic acid (4,
5
00 mg 2.52 mmol) in dry THF (20 mL) was added dropwise
at –78 °C to the LICKOR superbase. Vigorous stirring was main-
tained for 2 h, and D O (150 μL, 8.3 mmol) in dry THF (4 mL)
2
was added at –78 °C. The mixture was stirred overnight at room
temp. and water (20 mL) was added. The aqueous layer was washed
with diethyl ether (2×20 mL) and acidified (pH 1) with aq. HCl
(
(
6 mL). The yellow mixture was stirred overnight, after which water
30 mL) was added. The aqueous layer was extracted with ethyl
acetate (3×30 mL), acidified with aq. HCl (2 m), and extracted
with ethyl acetate (3×30 mL). After concentration in vacuo, the
crude 1-substituted 9H-fluoren-9-ones 7a, 7b, 7d–g were purified
by chromatography on silica gel (cyclohexane/ethyl acetate, 90:10).
(
(
2 m). The aqueous layer was extracted with diethyl ether
3×20 mL). The combined ether layer was dried (MgSO ) and con-
4
centrated in vacuo, and the residue was recrystallized (heptane/
ethyl acetate) to give 18 as a white solid. The isotope ratio deter-
1
1
-Deuterio-9H-fluoren-9-one (7a):
Quenching
with
D
2
O
mined by H NMR (multiplet at δ = 8.11 ppm attributed to H4)
1
(40.4 mmol) gave 7a as a yellow solid (m.p. 80–82 °C, 256 mg,
was found to be 4d
0
:4d
1
41:59. H NMR (400 MHz, CDCl
3
): δ =
180
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 174–182

Metalation of Unprotected Biphenyl-2-, -3-, and -4-carboxylic Acids
FULL PAPER
8
7
.37 (m, 1 H), 8.11 (m, 0.41 H, residual H4), 7.86 (m, 1 H), 7.69–
.38 (m, 6 H) ppm.
[2] See inter alia: a) H. Ji, M. Leung, Y. Zhang, K. J. Catt, K.
Sandberg, J. Biol. Chem. 1994, 269, 16533–16536; b) V. Nirula,
W. Zheng, K. Krishnamurthi, K. Sandberg, FEBS Lett. 1996,
4-Chlorobiphenyl-3-carboxylic Acid (19): Biphenyl-3-carboxylic
3
94, 361–364.
3] J.-M. Fu, B.-P. Zhao, M. J. Sharp, V. Snieckus, J. Org. Chem.
991, 56, 1683–1685.
F. Ciske, W. D. Jones Jr., Synthesis 1998, 1195–1198.
acid (3, 375 mg 1.9 mmol) in dry THF (5 mL) was added dropwise
at –78 °C to a solution of LICKOR (5.7 mmol, see preparation
above) in dry THF (7 mL). After the mixture had been vigorously
stirred at –30 °C for 1.5 h, hexachloroethane (2.689 g, 11.4 mmol)
in dry THF (5 mL) was added. Similar workup followed by
chromatography (cyclohexane/ethyl acetate 9:1) and recrystalli-
zation (heptane/ethyl acetate) gave 4-chlorobiphenyl-3-carboxylic
[
1
[4]
[5] J. Mortier, J. Moyroud, B. Bennetau, P. A. Cain, J. Org. Chem.
1994, 59, 4042–4044.
[6] Lithiation reactions of unprotected 2-halobenzoic acids: a) F.
Gohier, A.-S. Castanet, J. Mortier, Org. Lett. 2003, 5, 1919–
1922; 3-halobenzoic acids: b) F. Gohier, J. Mortier, J. Org.
Chem. 2003, 68, 2030–2033; naphthalene-1-carboxylic acid: c)
D. Tilly, A.-S. Castanet, J. Mortier, Chem. Lett. 2005, 34, 446–
1
acid (19) as a white solid (m.p. 192 °C, 97 mg, 22%). H NMR
(400 MHz, [D
6
]acetone): δ = 8.16 (d, J = 2.5 Hz, 1 H), 7.84 (dd, J
=
2, J = 8.4 Hz, 1 H), 7.71–7.73 (m, 2 H), 7.63 (d, J = 8.4 Hz, 1
4
47; application for the synthesis of novel 6-substituted 2-chlo-
1
3
H), 7.52–7.50 (m, 2 H), 7.44 (d, J = 6.4 Hz, 1 H) ppm. C NMR
50 MHz, [D ]DMSO): δ = 166.6, 139.0, 138.0, 131.9, 131.5, 130.8,
29.0, 128.7, 128.1, 126.7, 126.6 ppm. HRMS calcd for
robenzoic acids: d) F. Gohier, A.-S. Castanet, J. Mortier, Synth.
Commun. 2005, 35, 799–806.
(
1
C
6
[7] T. H. Nguyen, N. T. T. Chau, A.-S. Castanet, K. P. P. Nguyen,
35
13 9 2
H ClO : calcd: 232.0291; found 232.0292.
J. Mortier, Org. Lett. 2005, 7, 2445–2448.
Biphenyl-3-yl)(phenyl)methanone (20):[42] n-Butyllithium (3.52 mL,
.1 mmol) was added at 20 °C to a suspension of potassium tert-
butoxide (627 mg, 5.54 mmol) in dry benzene (10 mL). After the
[8] See also: S. Sinha, B. Mandal, S. Chandrasekaran, Tetrahedron
Lett. 2000, 41, 3157–3160.
(
6
[
[
[
[
9] F. Gohier, A.-S. Castanet, J. Mortier, J. Org. Chem. 2005, 70,
1501–1504.
mixture had been stirred for 5 min, biphenyl-3-carboxylic acid (4,
10] M. Schlosser, Eur. J. Org. Chem. 2001, 3975–3984 and refer-
500 mg 2.52 mmol) in dry THF (20 mL) was added dropwise to
ences cited therein.
the LICKOR superbase. Vigorous stirring was maintained for 2 h
and water was added. Conventional workup gave 20 as a white
11] See our preliminary communication: D. Tilly, S. S. Samanta, F.
Faigl, J. Mortier, Tetrahedron Lett. 2002, 43, 8347–8350.
12] Review on teraryls, oligoaryls and polyaryls: S. P. Stanforth,
Tetrahedron 1998, 54, 263–303.
solid (m.p. 94 °C) after chromatography on silica gel (234 mg,
1
3
6%). H NMR (400 MHz, CDCl
3
): δ = 8.38 (s, 1 H), 8.22–8.08
(
m, 3 H), 7.97–7.89 (m, 3 H), 7.88–7.77 (m, 4 H), 7.74–7.68 (m, 1
H), 7.68–7.56 (m, 2 H).
-Deuteriobiphenyl-4-carboxylic Acid (23): Biphenyl-4-carboxylic
[13] a) P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356–363;
b) M. N. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew.
Chem. Int. Ed. 2004, 43, 2206–2225.
3
[
14] a) W. Bauer, P. v. R. Schleyer, J. Am. Chem. Soc. 1989, 111,
acid (5, 500 mg, 2.52 mmol) dissolved in dry THF (10 mL), was
added dropwise under argon at –78 °C − over a period of 30 min −
to a vigorously stirred solution of a 1:1 sBuLi/TMEDA complex
7
191–7198; b) N. J. R. Van Eikema Hommes, P. v. Ragué Schle-
yer, Angew. Chem. Int. Ed. Engl. 1992, 31, 755–758; c) N. J. R.
Van Eikema Hommes, P. v. Ragué Schleyer, Tetrahedron 1994,
(
5.54 mmol) in anhydrous THF (10 mL). After 2 hours stirring at
50, 5903–5916.
–78 °C, the mixture was treated with an excess of D
2
O (150 μL,
[
15] S. Aki, Y. Haraguchi, M. Sakikawa, M. Ishigami, T. Fujioka,
T. Furuta, J. Minamikawa, Org. Process Res. Dev. 2001, 5, 535–
538.
8.3 mmol). The resulting solution was allowed to warm to ambient
temperature and water (20 mL) was added. The aqueous layer was
washed with diethyl ether (2×20 mL), shaken, and then acidified
with HCl (2 m, pH 1). The aqueous layer was extracted with diethyl
ether (3×20 mL). The combined organic layers were dried with
MgSO . Filtration and concentration in vacuo gave the crude car-
4
boxylic acid 23, which was purified by chromatography (cyclohex-
[16] M. Stilles, A. J. Libbey Jr., J. Org. Chem. 1947, 22, 1243–1246.
[17] A. Demeter, G. Timári, A. Kotschy, T. Bérces, Tetrahedron
Lett. 1997, 38, 5219–5222.
[
[
18] P. Fernandez, J. M. Bayona, J. Chromatogr. 1992, 625, 141–149.
19] G. Van Graas, J. W. De Leeuw, P. A. Schenck, J. Haverkamp,
Geochim. Cosmochim. Acta 1981, 45, 2465–2474.
ane/ethyl acetate 9:1) (286 mg, 57%). The isotope ratio determined
1
[20] W. E. Pereira, C. E. Rostad, T. R. Steinheimer, S. M. Johnson,
by H NMR (multiplet at δ = 8.05 ppm attributed to H
3
-H3Ј) was
J. Environ. Sci. Health, Sect. A 1981, 16, 571–587.
found to be 3d
to be 39.4:60.4 by FIMS of chromatographed material. H NMR
400 MHz, CDCl ): δ = 8.05 (m, 1.4 H, residual H3–H3Ј), 7.97–
.71 (m, 4 H), 7.59–7.39 (m, 3 H) ppm.
0 1 0 1
:3d 40:60. The 3d /3d isotope ratio was determined
[
21] H. F. Mark, D. F. Othmer, C. G. Overberger, G. T. Seaberg, En-
cyclopedia of Chemical Technology, 1982, vol. 17, p. 703.
22] Reviews on reactions of organolithium compounds with alkali
metal alkoxides and reactions of superbases: a) L. Lochmann,
Eur. J. Inorg. Chem. 2000, 1115–1126; b) See also ref. 10.
1
(
3
[
7
1
3
7
1
-(Biphenyl-4-yl)-2-methylbutan-1-one (24):[ White solid (216 mg,
43]
1
6%). H NMR (200 MHz, CDCl
3
): δ = 8.10–8.01 (m, 2 H), 7.87–
.69 (m, 4 H), 7.56–7.36 (m, 3 H), 3.56 (m, 1 H), 1.71 (m, 1 H),
.12–1.10 (m, 3 H), 1.42 (m, 1 H), 0.85 (t, 3 H) ppm.
[23] D. Tilly, S. S. Samanta, A. De, A.-S. Castanet, J. Mortier, Org.
Lett. 2005, 7, 827–830.
[
24] 3-Chloro-, 3-methyl-, and 3-ethylbiphenyl-4-carboxylic acids,
for instance, display interesting herbicidal and pharmaceutical
properties: a) M. Shinoda, E. Emori, F. Matsuura, T. Kaneko,
N. Ohi, S. Kasai, H. Yoshitomi, K. Yamazaki, S. Miyashita, T.
Hibara, H. Seiki, R. Clark, H. Harada, Wo. Pat. 0125181 A1,
Acknowledgments
2
001; b) H. Ogawa, K. Kondo, H. Yamashita, K. Suga, N.
This research was supported by the CNRS, the Université du
Maine, and the Institut universitaire de France. DT would like to
thank the CNRS and the “Région Pays-de-la-Loire” (France) for
a doctoral fellowship.
Matsuzaki, T. Shinohara, Y. Tanada, M. Kurimura, M. Tomin-
aga, Y. Yabuuchi, Wo. Pat. 95345401, 1995; c) I. Sircar, K. S.
Gudmundsson, R. Martin, Wo. Pat. 9936393 A1, 1999; d) A. F.
Hawkins, I. Jones, T. Lewis, US Pat. 784638, 1980.
25] Biphenyl-4-carboxylic acid derivatives display interesting prop-
erties in liquid crystals: N. K. Sanyal, M. Roychoudhury, S. N.
Tiwari, S. Shukla, Mol. Cryst. Liq. Cryst. Sci. Technol. 1985,
128, 211–218.
[
[
1] P. J. Tummino, D. Ferguson, C. M. Jacobs, B. Tait, L. Hupe,
E. Lunney, D. Hupe, Arch. Biochem. Biophys. 1995, 316, 523–
528.
Eur. J. Org. Chem. 2006, 174–182
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
181

D. Tilly, S. S. Samanta, A.-S. Castanet, A. De, J. Mortier
FULL PAPER
[
26] G. Marck, A. Villiger, R. Buchecker, Tetrahedron Lett. 1994,
5, 3277–3280.
[33] a) B. Bennetau, J. Mortier, J. Moyroud, J.-L. Guesnet, J. Chem.
Soc., Perkin Trans. 1 1995, 1265–1271; b) R. Cantegril, J. Mort-
ier, D. Croisat, R. Peignier, Wo. Pat. 9602138, 1996; c) D. Cro-
isat, P. Desbordes, F. Guigues, J. Mortier, R. Peignier, J.-P. Vors,
U. S. Pat. 5945382, 1999.
3
[
27] a) F. Marsais, B. Laperdrix, T. Güngör, M. Mallet, G. Quégu-
iner, J. Chem. Res. Miniprint 1982, 2863; b) T. D. Krizan, J. C.
Martin, J. Am. Chem. Soc. 1983, 105, 6155–6157; c) B. H. Lip-
shutz, M. R. Wood, C. W. Lindsley, Tetrahedron Lett. 1995, 36,
[34] W. Carruthers, R. Poornamorthy, J. Chem. Soc., Perkin Trans.
4
385–4388.
28] a) L. Lochmann, Collect. Czech. Chem. Commun. 1987, 52,
710–2716; b) M. Schlosser, J. H. Choi, S. Takagishi, Tetrahe-
1
1974, 2405–2409.
[
[
[
[
[
35] R. D. Haworth, P. B. Tinker, J. Chem. Soc. 1955, 911–915.
36] J. R. E. Hoover, J. Med. Chem. 1964, 7, 245–251.
37] D. H. Jones, W. R. Wragg, J. Chem. Soc. (C) 1968, 2154–2155.
2
dron 1990, 46, 5633–5648.
29] a) M. Schlosser, J. Organomet. Chem. 1967, 8, 9–16; b) C. L.
Mioskowski, S. Manna, J. R. Falck, Tetrahedron Lett. 1984, 25,
[38] a) S. M. Gannon, J. G. Krause, Synthesis 1987, 10, 915–917; b)
W. C. Lothrop, P. A. Goodwin, J. Am. Chem. Soc. 1943, 65,
363–367.
5
5
19–522; c) C. Prandi, P. Venturello, J. Org. Chem. 1994, 59,
458–5462; d) A. Deagostino, C. Prandi, P. Venturello, Tetrahe-
dron 1996, 52, 1433–1442.
[39] H. Tomioka, H. Kawasaki, N. Kobayashi, K. Hirai, J. Am.
Chem. Soc. 1995, 117, 4483–4498.
[40] E. H. Huntress, K. Pfister, K. H. T. Pfister, J. Am. Chem. Soc.
1942, 64, 2845–2849.
[41] N. E. Leadbeater, S. M. Resouly, Tetrahedron 1999, 55, 11889–
11894.
[42] B. H. Lipshutz, P. A. Blomgren, Org. Lett. 2001, 3, 1869–1871.
[43] Y. Yano, S. Oonishi, H. Kimura, T. Sone, JP8176057, 1996.
Received: June 27, 2005
[
30] Reviews: a) M. Schlosser, Mod. Synth. Methods 1992, 6, 227–
271; b) A. Mordini, in: Advances in Carbanion Chemistry (Ed.:
V. Snieckus), J. A. Press Inc., Greenwich CT, 1992, Vol. 1, p. 1;
c) M. Schlosser, F. Faigl, L. Franzini, H. Geneste, G. Kat-
soulos, G.-F. Zhong, Pure Appl. Chem. 1994, 66, 1439–1446.
31] a) M. J. Jorgenson, Org. React. 1970, 18, 1–97; b) T. Ahn, T.
Cohen, Tetrahedron Lett. 1994, 35, 203–206.
[
[
32] M. Schlosser, Organometallics in Synthesis. A Manual; Wiley,
nd
Chichester, 2 ed., 2002.
Published Online: October 31, 2005
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 174–182