Tetrahedron Letters 43 (2002) 8347–8350
Combined directed ortho metalation—intramolecular Friedel–Crafts connections. Regiospecific route to 1-substituted fluoren-9-ones
David Tilly,a Subhendu S. Samanta,a Ferenc Faiglb and Jacques Mortiera,*
aUniversite´ du Maine and CNRS, Unite´ de chimie organique mole´culaire et macromole´culaire (UMR 6011), Faculte´ des sciences,
avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
bDepartment of Organic Chemical Technology, Technical University of Budapest, 1521 Budapest, Hungary
Received 5 July 2002; revised 10 September 2002; accepted 13 September 2002
Abstract—ortho-Substituted-2-biphenyl carboxylic acids of the type 3a–j were prepared by the tandem metalation sequence from 2-biphenyl carboxylic acid 1 with sec-butyllithium in THF at −78°C followed by quenching with electrophiles. The carboxylic acids 3a–f were converted into 1-substituted fluorenones 4a–f upon treatment with methanesulfonic acid. 2002 Elsevier Science Ltd. All rights reserved.
The fluoren-9-one skeleton is found in significant
derivatives via lithiation reactions. Treatment of ter-
classes of alkaloids, physiologically active agents, and
tiary 2-biphenylcarboxamides and 2-biphenyloxazolines
environmental pollutants.1 Fluorenones are also known
with LDA or t-BuLi affords the fluorenone skeleton
to function as photoinitiators in various photochemical
directly by remote metalation,10,11 alkyllithium metala-
reactions.2 The most useful syntheses of fluoren-9-ones
tion occuring exclusively ortho to the amide group.
include Friedel–Crafts closures of biarylcarboxylic acids
Unvariably, the carbonyl group is protected prior to
and derivatives,3 intramolecular [4+2] cycloaddition
reactions of conjugated enynes,4 and oxidation offluorenes.5 Fluoren-9-ones have been recently synthe-
Regioselective lithiation of biphenyl carboxylic acids is
a new challenge because of the previously demonstrated
ortho directing effect of the carboxylic acid group in
benzenoid systems.12,13 In order to shed light on moredetails of the role of the carboxylic acid group in
On the other hand, non peptidic compounds that con-
metalation, we have studied the reactivity of 2-biphenyl
tain a biphenyl carboxylic acid group have been shown
carboxylic acid (1) toward strong bases.
to inhibit HIV-1 protease, with IC50 values in the range3.4–74 mM.8 The structure–inhibitory activity relation-
All the optimization reactions were carried out using
ship demonstrates the necessity of the biphenyl car-
commercially available 2-biphenyl carboxylic acid (1)
boxylic acid group for inhibition. Losartan (Merck,
under argon and THF as the solvent (Table 1). The
Sharpe & Dohme trademarks: Cozaar, Lozaar), one of
the most prominent modern antihypertensive drugs, is a
iodomethane. The product ratio was determined by 1H
2-biphenyl tetrazole derivative that, by behaving as a
NMR after acidification and extraction with ether of
‘G-protein coupled receptors-needle’, antagonizes the
the crude reaction mixture. Since the recovered starting
acid 1 and non-acidic products were also identified in these conditions, the product distribution represents the
In view of their tremendous importance as precursors
selectivity and the efficiency of the metalation reactions.
of biologically active molecules, very little attention has
In contrast to tertiary biarylamides,10 2-biphenyl car-
been paid to the synthesis of 2-biphenyl carboxylic acid
boxylic acid (1) was unreactive toward LDA or lithium 2,2,6,6-tetramethylpiperidide (LTMP) in the interval of temperature −780°C in THF (entries 1–3). Treatment
with t-BuLi (2.2 equiv.) in THF at −78°C led to the
0040-4039/02/$ - see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 0 - 4 0 3 9 ( 0 2 ) 0 1 9 7 6 - 7
D. Tilly et al. / Tetrahedron Letters 43 (2002) 8347–8350
Table 1. Reactions of 2-biphenyl carboxylic acid (1) with strong bases (MeI quench) in THF
a n-BuLi 1.6 M in hexanes. s-BuLi 1.3 M and 1.4 M in cyclohexane. TMEDA was distilled from CaH before use. LDA and LTMP were prepared
by adding n-BuLi (1 equiv.) to diisopropylamine (1 equiv.) and 2,2,6,6-tetramethylpiperidine (1 equiv.), respectively, in THF at −20°C.
b Alkyllithiums (entries 4–9): normal addition. Lithium amides (entries 1–3): reverse addition (see: Mortier, J.; Vaultier, M.; Cantegril, R.; Dellis,
P. Aldrichimica Acta 1997, 30, 34). The mixture was stirred for 2 h before addition of iodomethane (4 equiv.).
c After acidication with 4 M HCl and extraction with ether, the molar ratio of the crude reaction mixture was determined by 1H NMR. d R=t-Bu. ortho methylated acid 3a albeit in moderate yield (entry
acid 1 afforded 3a,b efficiently (entries 1 and 2). Chlori-
4). When 3.5 equiv. of t-BuLi was used at 25°C, ketone
nation, bromination, iodination, and methylsulfenyla-
5 was the only product identified (Table 1).
tion gave 3c–f in good recrystallized yields. The smooth
Acid 1 was found to be deprotonated smoothly ortho to
and high-yield reaction of chlorotrimethylsilane afford-
the carboxylate by n-BuLi (2.2 equiv.) at −78°C.
ing 3g is indoubtedly related to its in situ compatibility
Quenching the orange lithium ortho lithiobenzoate 2
with alkyllithiums16 and finds further utility in regimens
with iodomethane led to 3a in good yield (entry 6).
High conversion was achieved with s-BuLi at −78°C
anionic sites and ipso desilylation.17 n-Bu SnCl gave 3h,
(90%, entry 8). NMR analysis of the crude reaction
a precursor of teraryl carboxylic acid 6 via the Stille
mixture shows that the product alkylated in ortho of the
reaction (59%).18,19 The regioselectivity of the reaction
acid group was the only formed isomer. N,N,N%,N%-Tet-
was ascertained with DMF and benzaldehyde: 3i and 3j
ramethyl-1,2-ethylenediamine (TMEDA) is known as
underwent cyclization to hydroxyphthalide 7 and lac-
an accelerator of metalation reactions due to its disag-
tone 8, respectively, upon acidic work-up.
gregation effect on butyllithium oligomers.14 Neverthe-less, its use with either n-BuLi or s-BuLi was
3-Substituted 2-biphenyl carboxylic acids 3a–g were
detrimental to the reaction, with the yield dropping
then reacted with methanesulfonic acid at 50–60°C.20
from 80 and 90% to 60 and 35%, respectively (entries 7
After completion of the reaction, the mixture was
poured into water at 0°C and extracted with ethylacetate. The extract was washed with water and concen-
By employing the optimized conditions found in entry 8
trated in vacuo. Fluoren-9-ones 4a–f were isolated in
with various electrophiles, acid 1 afforded the 3-substi-
good yield after column chromatography (heptane/
tuted 2-biphenyl carboxylic acids 3a–j (Table 2).15
Methylation and ethylation of 2-biphenyl carboxylic
fluorenones are prepared either by radical procedures21
D. Tilly et al. / Tetrahedron Letters 43 (2002) 8347–8350
Table 2. Preparation of 3-substituted 2-biphenyl carboxylic acids 3a–j and 1-substituted fluoren-9-ones 4a–f
a Yield of recrystallized or chromatographed (heptane/ethyl acetate) materials. b Lit. mp 132°C (Carruthers W.; Poornamorthy, R. J. Chem. Soc., Perkin Trans. 1 1974, 2405–2409). c Lit. mp 184–186°C (Hoover, J. R. E. J. Med. Chem. 1964, 7, 245–251). d Not isolated but converted directly into the hydroxyphthalide 7 by acid treatment upon work-up. e Not isolated but converted directly into the lactone 8 by acid treatment upon work-up. f Lit. mp 97–98°C (Lothrop, W. C.; Goodwin, P. A. J. Am. Chem. Soc. 1943, 65, 363). g Lit. mp 91–93°C (Tomioka, H; Kawasaki, H.; Kobayashi, N.; Hirai, K. J. Am. Chem. Soc. 1995, 117, 4483–4498). h Lit. mp 137–138°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849). i Lit. mp 134–134.5°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849). j Lit. mp 144–145°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849). k Fluorenone 9 was formed exclusively.
or by palladium(0)-catalyzed cross-coupling reactions
2. Mark, H. F.; Othmer, D. F.; Overberger, C. G.; Seaberg,
of aryl bromides/triflates with arylboranes.11 The direct
G. T. Encyclopedia Chem. Technol. 1982, 17, 703. ortho lithiation of the aminoalkoxide derived from par-
3. (a) Olah, G. A.; Mathew, T.; Farnia, M.; Prakash, S.
ent fluorenone has also been reported.22 The Si and Sn
Synlett 1999, 1067–1068; (b) Yu, Z.; Velasco, D. Tetra-
groups were not resistant to the acidic conditions used
hedron Lett. 1999, 40, 3229–3232.
and the parent fluorenone 9 was formed in both cases.
4. Danheiser, R. L.; Gould, A. E.; Pradilla, R. F.; Helga-
son, A. L. J. Org. Chem. 1994, 59, 5514–5515.
The fluoren-9-one skeleton can also be obtained from
5. (a) Nikalje, M.; Sudalai, A. Tetrahedron 1999, 55, 5903–
the corresponding 2-biphenyl carboxylic acids by a
5908; (b) Murahashi, S.-I.; Komiya, N.; Oda, Y.;
process involving the ‘superbasic’ n-butyllithium/t-
Kuwabara, T.; Naota, T. J. Org. Chem. 2000, 65, 9186–
BuOK mixture (the Schlosser base). This work will be
6. Qabaja, G.; Jones, G. B. Tetrahedron Lett. 2000, 41,
7. Campo, M. A.; Larock, R. C. Org. Lett. 2000, 2, 3675– Acknowledgements
8. Tummino, P. J.; Ferguson, D.; Jacobs, C. M.; Tait, B.;
This work was supported by the CNRS, Universite´ du
Hupe, L.; Lunney, E.; Hupe, D. Arch. Biochem. Biophys.
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9. See inter alia: (a) Ji, H.; Leung, M.; Zhang, Y.; Catt, K.
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127.56, 126.74, 126.40, 19.10 (CH ). Anal. calcd for
C H O : C, 79.23; H, 5.70. Found: C, 79.44; H, 5.72%.
14. (a) Schlosser, M. In Organometallics in Synthesis: A Man-
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15. The preparation of 3a is representative: at −78°C, s-BuLi
J. Synlett 1993, 171–176 and references cited therein.
(1.3 M in cyclohexane, 2.2 equiv., 55.4 mmol, 42.6 mL)
18. Teraryls, oligoaryls and polyaryls are used as building
was added dropwise—over a period of 30 min—to a
blocks for host–guest complexes, natural products, poly-
vigorously stirred solution of 2-biphenyl carboxylic acid
mers, advanced materials, liquid crystals, catalysts in
(1) (25.2 mmol, 5.0 g) in THF (180 mL) under an argon
asymmetric transformations, enzyme mimics, ligands for
atmosphere. After 2.5 h at −78°C, the mixture was
homogeneous catalysis, and molecules of medicinal inter-
treated with iodomethane (75.6 mmol, 4.7 mL) in THF
est. Review: Stanforth, S. P. Tetrahedron 1998, 54, 263–
(40 mL). The resulting solution was allowed to warm up
to ambient temperature, after which water was added.
19. For a recent preparation of methyl-polyheterocycles, see:
The aqueous layer was washed with diethyl ether, and
Mathieu, J.; Gros, P.; Fort, Y. Tetrahedron Lett. 2001,
shaken, and then acidified with 4 M HCl. The mixture
was diluted with diethyl ether and the organic layer was
20. Aki, S.; Haraguchi, Y.; Sakikawa, M.; Ishigami, M.;
separated and dried with MgSO . Filtration and concen-
Fujioka, T.; Furuta, T.; Minamikawa, J. Org. Process
tration in vacuo followed by recrystallization (heptane–
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ethylacetate) gave 3a as white crystals (4.30 g, 80%). Mp
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133–134°C. 1H NMR (400 MHz, CDCl ) l 10.5 (1H, br,
s), 7.39–7.32 (6H, m), 7.20 (1H, d, J=2 Hz), 7.19 (1H, d,
22. (a) Commins, D. L. Synlett 1992, 615; (b) Demeter, A.; J=2.4 Hz), 2.43 (3H, s). 13C NMR (100 MHz, CDCl ) l
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