Efficient preparation of polysubstituted naphthyl phenyl and dinaphthyl ketones from naphthalenic esters by anionic homo-Fries rearrangement

Article abstract of DOI:10.1055/s-2002-35601

The anionic homo-Fries rearrangement of naphthalenic esters can be effected in good yield to provide regiocontrolled access to complex diaryl ketones.

Full text of DOI:10.1055/s-2002-35601

2
086
LETTER
Efficient Preparation of Polysubstituted Naphthyl Phenyl and Dinaphthyl
Ketones from Naphthalenic Esters by Anionic Homo-Fries Rearrangement
E
A
fficient
P
reparati
r
on of Po
n
lysubstituted
a
Naphthyl
P
u
henyl and
D
d
inaphthyl
K
etonesPiettre, Christine Massardier, Emmanuel Chevenier, Yves Gimbert,* Andrew E. Greene*
Chimie Recherche (LEDSS), Université Joseph Fourier, BP 53X, 38041 Grenoble, France
Fax +(33)476514494; E-mail: Yves.Gimbert@ujf-grenoble.fr; E-mail: Andrew.Greene@ujf-grenoble.fr
Received 20 August 2002
forming the products into xanthones (e.g., Scheme 2). The
homo-Fries rearrangement, which is distinguished from
the Fries by an additional carbon in the halide portion of
the ester (Scheme 1, n = 1), has also found synthetic
application, most notably in balanol-related work.6
Abstract: The anionic homo-Fries rearrangement of naphthalenic
esters can be effected in good yield to provide regiocontrolled
access to complex diaryl ketones.
4
Key words: Homo-Fries rearrangement, naphthyl phenyl ketone,
dinaphthyl ketone, xanthone
F
OH
O
O
base
In the context of a program on the synthesis of the new to-
1
,2
100%
poisomerase I inhibitor hypoxyxylerone (Figure 1) and
3
derivatives, the potential of the anionic homo-Fries rear-
OMe
O
OMe
OMe
OMe
rangement of naphthyl-phenyl and naphthyl-naphthyl es-
ters for regioselective xanthone formation seemed worth
investigating.
Scheme 2
In this paper we present the results of a study of the an-
ionic homo-Fries rearrangement of naphthyl-phenyl and
naphthyl-naphthyl esters, which has been found to afford
effectively naphthyl phenyl and dinaphthyl ketones, key
intermediates for the synthesis of variously substituted
tetra- and pentacyclic xanthones.
HO
OH
HO
O
OH
O
7
OH
The naphthyl-phenyl esters 1a,b on exposure to n-BuLi
Hypoxyxylerone
under carefully studied conditions suffered homo-Fries
rearrangement to give the naphthyl phenyl ketones 2a,b in
ca. 50% yield (Scheme 3). THF in the absence of addi-
tives such as HMPA or 12-crown-4 proved to be the most
suitable milieu for these reactions. The amount of n-BuLi
was found to be critical, with the use of over 1.1 equiva-
lents leading to butylated products. Ester concentration
was also found to be an important parameter, the highest
yields being achieved with a concentration of 0.25 M. At
lower concentrations, the yields decreased; at 0.06 M
there was little conversion. These results are consistent
with the formation of an intermediate dimeric species, as
proposed by Horne and Rodrigo.5
Figure 1
In its simplest form, the anionic Fries rearrangement in-
volves halogen-metal exchange in an ortho-halophenyl
benzoate, which is followed by intramolecular carbonyl
attack by the carbanion to produce the corresponding
benzophenone (Scheme 1, n = 0). This rearrangement,
which is usually more efficient when a methoxyl substit-
4
5
uent is present ortho to the ester carbonyl, has enjoyed
use in synthesis due, in part, to the better yields that can
usually be realized relative to the intermolecular variant
and the possibility of easily and regioselectively trans-
X
Li
RLi
O
O
(
)n
( )n
O
O
O
( )n
OH
n = 0 Fries
n = 1 homo-Fries
Scheme 1
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2086,2088,ftx,en;G24102ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Efficient Preparation of Polysubstituted Naphthyl Phenyl and Dinaphthyl Ketones
2087
R2
R1
R2
R2
MeO
R1 Br
MeO
n-BuLi, THF
O
O
R2
–78 °C, ca. 1 h
2a, 52%; 2b, 50%
OMe OMe
OMe OMe
O
OH
1
2
1
2
1
1
a, R =OMe; R =OBn
2a, R =OMe; R =OBn
1
2
1
2
b, R =OBn; R =OMe
2b, R =OBn; R =OMe
Scheme 3
That the naphthyl-phenyl anionic homo-Fries rearrange- In summary, we have demonstrated that the anionic
ment is not particularly sensitive to the sense of the reac- homo-Fries rearrangement can be extended to different
tion was shown through treatment of ester 3a (Scheme 4) naphthyl-phenyl and naphthyl-naphthyl systems to pro-
with n-butyllithium, which produced naphthyl phenyl duce in synthetically useful yields naphthyl phenyl and di-
ketone 4a in comparable yield (41%).
naphthyl ketones, key intermediates for the preparation of
complex xanthones.9
A dramatic increase in yield was observed, however, in
the transformation of fluoride 3b into ketone 4b (85%), a
result that can be understood on the basis of both steric
Acknowledgment
5
and electronic effects. Coupled with the clean, regiose-
We thank Professor Y. Vallée for his interest in our work and Mr.
D. Monchaud for his capable experimental assistance. Financial
support from the CNRS (UMR 5616) and Aventis and fellowship
awards (to C.M. and E.C.) from Aventis are gratefully acknow-
ledged.
lective ring closure that is possible with an ortho-fluoro
substituent (F vs OMe, Scheme 2), this type of anionic
homo-Fries rearrangement should allow particularly effi-
cient formation of complex, polycyclic xanthones.
The naphthyl-naphthyl esters 5a,b were also examined
under the above rearrangement conditions (Scheme 5). To
our satisfaction, these first examples of naphthyl-naphthyl
anionic homo-Fries rearrangements proceeded smoothly
and highly reproducibly (300-mg scale), in spite of the rel-
ative complexity of the systems, to furnish the corre-
sponding dinaphthyl ketones 6a,b. Dinaphthyl ketone 6a,
References
(
1) For reviews on topoisomerase, see: (a) Wang, J. C. Annu.
Rev. Biochem. 1996, 65, 635. (b) Bailly, C. Curr. Med.
Chem. 2000, 7, 39. (c) Long, B. H.; Balasubramanian, B. N.
Expert Opin. Ther. Pat. 2000, 10, 635.
(2) Edwards, R. L.; Fawcett, V.; Maitland, D. J.; Nettleton, R.;
8
obtained in 55% yield (65% brsm), has been converted
Shields, L.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun.
1991, 1009.
into a potential xanthone intermediate for the synthesis of
hypoxyxlerone by methylation, debenzylation, and base-
3
induced cyclization.
OMe Oi-Pr
MeO
OMe
Oi-Pr R1
Br
R1
n-BuLi, THF
O
–78 °C, ca. 1 h
MeO
4a, 41%; 4b, 85%
O
OMe
O
OMe
HO
1
1
3
3
a, R =OMe
4a, R =OMe
1
1
b, R =F
4b, R =F
Scheme 4
R2
MeO
OMe
OMe
R1
R2
MeO
R1 Br
O
MeO
n-BuLi, THF
OMe –50 °C, ca. 2 h
6a, 55%; 6b, 50%
OMe OMe
O
OMe OMe O
OH
1
2
1
2
5
5
a, R =OBn; R =OMe
6a, R =OBn; R =OMe
1
2
1
2
b, R =OMe; R =Oi-Pr
6b, R =OMe; R =Oi-Pr
Scheme 5
Synlett 2002, No. 12, 2086–2088 ISSN 0936-5214 © Thieme Stuttgart · New York

2
088
A. Piettre et al.
LETTER
(
3) (a) Gimbert, Y.; Chevenier, E.; Greene, A. E.; Massardier,
C.; Piettre, A. EP 014025514, 2001. (b) Piettre, A.;
Chevenier, E.; Massardier, C.; Gimbert, Y.; Greene, A. E.
Org. Lett. 2002, 4, 3139.
4) Miller, J. A. J. Org. Chem. 1987, 52, 322; and references
cited therein.
mixture was treated with sat. aq NH Cl solution, allowed to
4
warm to 20 °C, and diluted with EtOAc. The crude product
was isolated with EtOAc in the usual manner and purified by
radial thin-layer chromatography (hexane in EtOAc, 9:1 to
1:1) to give 43 mg (16%) of recovered starting material, 32
mg (13%) of debrominated starting material, and 130 mg
(55%, 65% brsm) of dinaphthyl ketone 6a as a white solid.
Ketone 6a: Mp 220–224 °C (cyclohexane–
(
(
5) (a) Horne, S.; Rodrigo, R. J. Org. Chem. 1990, 55, 4520.
(
1
b) See also: Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986,
9, 356.
–
1 1
dichloromethane); IR(neat): 3454, 1619, 1573 cm ; H
(
6) (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem.
Soc. 1994, 116, 8402. (b) Lampe, J. W.; Hugues, P. F.;
Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.Chem. 1996, 61,
NMR (200 MHz, CDCl ): = 3.41 (s, 3 H), 3.57 (s, 3 H),
3
3.83 (s, 3 H), 3.87 (s, 3 H), 3.90 (s, 6 H), 4.55 (d, J = 6.8 Hz,
2 H), 5.03 (s, 2 H), 6.37 (d, J = 2.4 Hz, 1 H), 6.45 (d, J = 2.4
Hz, 1 H), 6.60 (d, J = 2.1 Hz, 1 H), 6.70 (d, J = 2.1 Hz, 1 H),
4
572. (c) Lampe, J. W. et al. J. Med. Chem. 2002, 45, 2624.
d) See also: Couture, A.; Deniau, E.; Lebrun, S.;
Grandclaudon, P. J. Chem. Soc., Perkin Trans. 1 1999, 789.
e) Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G.
1
3
(
6.87 (s, 1 H), 7.05–7.35 (m, 5 H), 7.41 (s, 1 H); C NMR
(75.4 MHz, CDCl3): = 55.3 (CH ), 55.4 (CH ), 56.0 (CH ),
3
3
3
(
63.9 (CH ), 64.0 (CH ), 64.1 (CH ), 64.7 (CH ), 70.2 (CH ),
3 3 3 2 2
Eur. J Org. Chem. 2001, 12, 2221.
97.4 (CH), 98.7 (CH), 99.3 (CH), 103.2 (CH), 111.1 (C),
(
7) (a) Esters 1a,b, 3a,b, 5a,b were prepared by coupling under
Mitsunobu conditions. See: Mitsunobu, O. Synthesis 1981,
114.7 (C), 124.4 (CH), 125.4 (C), 127.4 (2 CH), 127.8 (CH),
128.3 (2 CH), 131.3 (C), 136.3 (C), 139.3 (C), 139.5 (C),
155.1 (C), 156.0 (C), 157.6 (C), 157.8 (C), 159.4 (C), 159.6
1. (b) See also: Hughes, D. L. Org. React. 1992, 42, 335.
+
(
c) For the preparation of the naphthalenic precursors, see
(C), 198.6 (C); MS (DCI): m/z (%) = 599 (50) [MH ], 279
3
ref.
(100); Anal. Calcd for C H O : Mr, 598.2203. Found: Mr
3
5
34
9
(
8) Anionic Homo-Fries Reaction of Ester 5a: A solution of
ester 5a (269 mg, 0.397 mmol) in THF (1.59 mL, from
which residual water had been eliminated with n-BuLi and
o-phenanthroline) under argon was cooled to –55 to –45 °C
and treated dropwise with n-BuLi (0.203 mL, 0.437 mmol).
After being stirred for 2 h at this temperature, the reaction
(mass spectrum, EI), 598.2211.
(9) For recent references to biologically active xanthones, see:
(a) Lin, C.-N.; Liou, S.-J.; Lee, T.-H.; Chuang, Y.-C.; Won,
S.-J. J. Pharm. Pharmacol. 1996, 48, 532. (b) Wang, L.-
W.; Kang, J.-J.; Chen, I.-J.; Teng, C.-M.; Lin, C.-N. Bioorg.
Med. Chem. 2002, 10, 567; and references cited therein.
Synlett 2002, No. 12, 2086–2088 ISSN 0936-5214 © Thieme Stuttgart · New York