Combined directed ortho metalation - Intramolecular Friedel-Crafts connections. Regiospecific route to 1-substituted fluoren-9-ones

Article abstract of DOI:10.1016/S0040-4039(02)01976-7

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.

Full text of DOI:10.1016/S0040-4039(02)01976-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8347–8350
Combined directed ortho metalation—intramolecular
Friedel–Crafts connections. Regiospecific route to 1-substituted
fluoren-9-ones
a
a
b
a,
David Tilly, Subhendu S. Samanta, Ferenc Faigl and Jacques Mortier *
a
Universit e´ du Maine and CNRS, Unit e´ de chimie organique mol e´ culaire et macromol e´ culaire (UMR 6011), Facult e´ des sciences,
avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
b
Department 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
classes of alkaloids, physiologically active agents, and
environmental pollutants. Fluorenones are also known
derivatives via lithiation reactions. Treatment of ter-
tiary 2-biphenylcarboxamides and 2-biphenyloxazolines
with LDA or t-BuLi affords the fluorenone skeleton
1
10,11
to function as photoinitiators in various photochemical
directly by remote metalation,
alkyllithium metala-
2
reactions. The most useful syntheses of fluoren-9-ones
tion occuring exclusively ortho to the amide group.
Unvariably, the carbonyl group is protected prior to
metalation.
include Friedel–Crafts closures of biarylcarboxylic acids
3
and derivatives, intramolecular [4+2] cycloaddition
4
reactions of conjugated enynes, and oxidation of
5
fluorenes. Fluoren-9-ones have been recently synthe-
Regioselective lithiation of biphenyl carboxylic acids is
a new challenge because of the previously demonstrated
sized by palladium-catalyzed cyclization of 2-
6
iodobenzophenones
and by p7alladium-catalyzed
ortho directing effect of the carboxylic acid group in
12,13
cyclocarbonylation of 2-halobiaryls.
benzenoid systems.
In order to shed light on more
details of the role of the carboxylic acid group in
metalation, we have studied the reactivity of 2-biphenyl
carboxylic acid (1) toward strong bases.
On the other hand, non peptidic compounds that con-
tain a biphenyl carboxylic acid group have been shown
to inhibit HIV-1 protease, with IC50 values in the range
8
3
.4–74 mM. The structure–inhibitory activity relation-
All the optimization reactions were carried out using
commercially available 2-biphenyl carboxylic acid (1)
under argon and THF as the solvent (Table 1). The
intermediates were trapped in each case with
ship demonstrates the necessity of the biphenyl car-
boxylic acid group for inhibition. Losartan (Merck,
Sharpe & Dohme trademarks: Cozaar, Lozaar), one of
the most prominent modern antihypertensive drugs, is a
1
iodomethane. The product ratio was determined by H
2
-biphenyl tetrazole derivative that, by behaving as a
NMR after acidification and extraction with ether of
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
selectivity and the efficiency of the metalation reactions.
‘
G-protein coupled receptors-needle’, antagonizes the
angiotensin II AT receptor.
9
1
In view of their tremendous importance as precursors
of biologically active molecules, very little attention has
been paid to the synthesis of 2-biphenyl carboxylic acid
10
In contrast to tertiary biarylamides, 2-biphenyl car-
boxylic acid (1) was unreactive toward LDA or lithium
2
,2,6,6-tetramethylpiperidide (LTMP) in the interval of
temperature −78“0°C in THF (entries 1–3). Treatment
with t-BuLi (2.2 equiv.) in THF at −78°C led to the
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01976-7

8
348
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
Basea,b
Equiv.
T (°C)
1:3a:5
c
Entry
1
2
3
4
5
6
7
8
9
LDA
LDA
LTMP
t-BuLi
t-BuLi
n-BuLi
n-BuLi/TMEDA
s-BuLi
s-BuLi/TMEDA
2.2
3.5
2.2
2.2
3.5
2.2
2.2
2.2
2.2
−78
0
−78
−78
25
−78
−78
−78
−78
100:0:0
100:0:0
100:0:0
50:50:0
5:0:95
20:80:0
40:60:0
10:90:0
65:35:0
d
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
2
by adding n-BuLi (1 equiv.) to diisopropylamine (1 equiv.) and 2,2,6,6-tetramethylpiperidine (1 equiv.), respectively, in THF at −20°C.
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.).
After acidication with 4 M HCl and extraction with ether, the molar ratio of the crude reaction mixture was determined by 1H NMR.
R=t-Bu.
b
c
d
ortho methylated acid 3a albeit in moderate yield (entry
acid 1 afforded 3a,b efficiently (entries 1 and 2). Chlori-
nation, bromination, iodination, and methylsulfenyla-
tion gave 3c–f in good recrystallized yields. The smooth
4
). When 3.5 equiv. of t-BuLi was used at 25°C, ketone
5
was the only product identified (Table 1).
Acid 1 was found to be deprotonated smoothly ortho to
the carboxylate by n-BuLi (2.2 equiv.) at −78°C.
Quenching the orange lithium ortho lithiobenzoate 2
with iodomethane led to 3a in good yield (entry 6).
High conversion was achieved with s-BuLi at −78°C
and high-yield reaction of chlorotrimethylsilane afford-
ing 3g is indoubtedly related to its in situ compatibility
16
with alkyllithiums and finds further utility in regimens
associated with protection of kinetically reactive
1
7
anionic sites and ipso desilylation. n-Bu SnCl gave 3h,
3
(
90%, entry 8). NMR analysis of the crude reaction
a precursor of teraryl carboxylic acid 6 via the Stille
18,19
mixture shows that the product alkylated in ortho of the
acid group was the only formed isomer. N,N,N%,N%-Tet-
ramethyl-1,2-ethylenediamine (TMEDA) is known as
an accelerator of metalation reactions due to its disag-
reaction (59%).
The regioselectivity of the reaction
was ascertained with DMF and benzaldehyde: 3i and 3j
underwent cyclization to hydroxyphthalide 7 and lac-
tone 8, respectively, upon acidic work-up.
14
gregation effect on butyllithium oligomers. Neverthe-
less, its use with either n-BuLi or s-BuLi was
detrimental to the reaction, with the yield dropping
from 80 and 90% to 60 and 35%, respectively (entries 7
and 9).
3-Substituted 2-biphenyl carboxylic acids 3a–g were
2
0
then reacted with methanesulfonic acid at 50–60°C.
After completion of the reaction, the mixture was
poured into water at 0°C and extracted with ethyl
acetate. The extract was washed with water and concen-
trated in vacuo. Fluoren-9-ones 4a–f were isolated in
good yield after column chromatography (heptane/
ethyl acetate). In the literature, 1-substituted
By employing the optimized conditions found in entry 8
with various electrophiles, acid 1 afforded the 3-substi-
1
5
tuted 2-biphenyl carboxylic acids 3a–j (Table 2).
2
1
Methylation and ethylation of 2-biphenyl carboxylic
fluorenones are prepared either by radical procedures

D. Tilly et al. / Tetrahedron Letters 43 (2002) 8347–8350
8349
Table 2. Preparation of 3-substituted 2-biphenyl carboxylic acids 3a–j and 1-substituted fluoren-9-ones 4a–f
Electrophile
E
Product
Yield (%)a
Mp (°C)
Product
Yield %a
Mp (°C)
MeI
EtI
Me
Et
Cl
Br
I
MeS
3a
3b
3c
3d
3e
3f
80
63
72
71
73
81
98
65
80
93
133–134b
140–141
184–185
185–186
169–170
115–116
143–144
56–57
4a
4b
4c
4d
4e
4f
4g
–
95
88
82
96
92
91
98–99f
93.5–94.5
138–139
132.5–133.5
147–148.5
167–168
g
c
h
C Cl6
2
i
C Br Cl
2
2
4
j
I2
Me2S2
k
Me SiCl
Me Si
3g
3h
0
–
–
–
–
3
3
n-Bu SnCl
DMF
PhCHO
n-Bu Sn
CHO
PhCH(OH)
–
–
–
3
3
d
3i
3j
145–147
91–92
–
–
e
a
Yield of recrystallized or chromatographed (heptane/ethyl acetate) materials.
b
c
d
e
f
Lit. mp 132°C (Carruthers W.; Poornamorthy, R. J. Chem. Soc., Perkin Trans. 1 1974, 2405–2409).
Lit. mp 184–186°C (Hoover, J. R. E. J. Med. Chem. 1964, 7, 245–251).
Not isolated but converted directly into the hydroxyphthalide 7 by acid treatment upon work-up.
Not isolated but converted directly into the lactone 8 by acid treatment upon work-up.
Lit. mp 97–98°C (Lothrop, W. C.; Goodwin, P. A. J. Am. Chem. Soc. 1943, 65, 363).
Lit. mp 91–93°C (Tomioka, H; Kawasaki, H.; Kobayashi, N.; Hirai, K. J. Am. Chem. Soc. 1995, 117, 4483–4498).
Lit. mp 137–138°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849).
Lit. mp 134–134.5°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849).
Lit. mp 144–145°C (Huntress, E. H.; Pfister, K.; Pfister, K. H. T. J. Am. Chem. Soc. 1942, 64, 2845–2849).
Fluorenone 9 was formed exclusively.
g
h
i
j
k
or by palladium(0)-catalyzed cross-coupling reactions
2. Mark, H. F.; Othmer, D. F.; Overberger, C. G.; Seaberg,
G. T. Encyclopedia Chem. Technol. 1982, 17, 703.
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1
1
of aryl bromides/triflates with arylboranes. The direct
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22
ent fluorenone has also been reported. The Si and Sn
groups were not resistant to the acidic conditions used
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the corresponding 2-biphenyl carboxylic acids by a
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BuOK mixture (the Schlosser base). This work will be
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Acknowledgements
This work was supported by the CNRS, Universit e´ du
Maine and Institut universitaire de France.
9
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5. The preparation of 3a is representative: at −78°C, s-BuLi
1.3 M in cyclohexane, 2.2 equiv., 55.4 mmol, 42.6 mL)
(
was added dropwise—over a period of 30 min—to a
vigorously stirred solution of 2-biphenyl carboxylic acid
(
1) (25.2 mmol, 5.0 g) in THF (180 mL) under an argon
atmosphere. After 2.5 h at −78°C, the mixture was
treated with iodomethane (75.6 mmol, 4.7 mL) in THF
(40 mL). The resulting solution was allowed to warm up
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33–134°C. H NMR (400 MHz, CDCl ) l 10.5 (1H, br,
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13
J=2.4 Hz), 2.43 (3H, s). C NMR (100 MHz, CDCl ) l
3
1
74.43, 139.91, 134.66, 131.43, 128.92, 128.42, 127.70,