An expeditious construction of polycyclic ketals: Synthesis of fused seven-membered rings and substituted naphthalenes

Article abstract of DOI:10.1016/S0040-4039(00)01906-7

Treatment of allylic alcohols 5, easily prepared from dioxene and methoxyacetophenones, with 1-(trimethylsilyloxy)cyclopentene in the presence of a catalytic amount of TMSOTf in acetonitrile, afforded a polycyclic acetal 6 by domino nucleophilic substitution, annulation and intramolecular Friedel-Crafts alkylation reaction sequence. Acid-mediated cleavage of the acetal moiety led to fused seven-membered carbocyclic rings or to substituted naphthalenes.

Full text of DOI:10.1016/S0040-4039(00)01906-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 231–234
An expeditious construction of polycyclic ketals: synthesis of
fused seven-membered rings and substituted naphthalenes
Issam Hanna,a,* Vale´rie Michauta and Louis Ricardb
aLaboratoire de Synthe`se Organique associe´ au CNRS, F-91128 Palaiseau, France
bLaboratoire ‘He´te´roe´le´ments et Coordination’ associe´ au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received 9 October 2000; accepted 25 October 2000
Abstract—Treatment of allylic alcohols 5, easily prepared from dioxene and methoxyacetophenones, with 1-(trimethylsilyl-
oxy)cyclopentene in the presence of a catalytic amount of TMSOTf in acetonitrile, afforded a polycyclic acetal 6 by domino
nucleophilic substitution, annulation and intramolecular Friedel–Crafts alkylation reaction sequence. Acid-mediated cleavage of
the acetal moiety led to fused seven-membered carbocyclic rings or to substituted naphthalenes. © 2000 Elsevier Science Ltd. All
rights reserved.
The development of reactions that efficiently generate
polycyclic molecules from easily accessible starting ma-
terials continues to be an important trend in organic
synthesis. For this purpose, domino reactions offer the
advantage of executing multistep transformations with-
out intermediate workup and therefore can be applied
to the one-pot synthesis of polycyclic ring systems.1 In
recent reports, we have described the behaviour of
allylic alcohols 1, readily prepared by the addition of
dioxenyllithium to ketones and aldehydes, towards
nucleophilic displacement reactions in the presence of
Lewis acids.2 For instance, 1 reacts with various silyl
enol ether such as 1-(trimethylsilyloxy)cyclopentene in
the presence of a catalytic amount of trimethylsilyltri-
fluorosulfonate (TMSOTf) in acetonitrile to afford 2,3-
disubstituted 1,4-dioxenes 2 in high yields (Scheme 1).2b
Oxidation of
2 with m-chloroperbenzoic acid in
methanol followed by nucleophilic addition of allyl-
trimethylsilane in the presence of TiCl4 afforded di-
enes 3, which have been converted to oxabicyclo[4.2.1]
nonenes 4 in excellent yield by an olefin ring-closing
metathesis reaction.2c We have found, and now report
that a nucleophilic substitution reaction at allylic alco-
hols 5 bearing an aromatic substituent such as a
Scheme 1.
Scheme 2.
* Corresponding author. Fax: +33 1 69 33 30 10; e-mail: hanna@poly.polytechnique.fr
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01906-7

232
I. Hanna et al. / Tetrahedron Letters 42 (2001) 231–234
Scheme 3.
Scheme 4.
methoxyphenyl group gave, instead of 2, a polycyclic
acetal 6 by a triple-domino reaction.
absence of an external nucleophile (e.g. the silyl enol
ether), the indene derivative 8 was isolated as the sole
product in nearly quantitative yield.
Allylic alcohols 5 were readily prepared by addition of
dioxenyllithium to corresponding acetophenones.3
Treatment of 5a with 1-(trimethylsilyloxy)cyclopentene
(1.5 equiv.) in the presence of a catalytic amount (10
mol%) of TMSOTf in acetonitrile at −40 to −10°C led
to the pentacyclic ketal 6a4 as a mixture of two
diastereoisomers (2:1 ratio) separated by flash column
chromatography in 77% combined yield (Scheme 2).
These isomers only differ in the configuration of the
benzylic carbon bearing the methyl group. The struc-
tural assignment for 6a was based on its spectral data
and was further confirmed by an X-ray crystal structure
determination of acetal opened derivatives (Scheme 2).
We next investigated the feasibility of the cleavage of
the ether bond in the [3.2.1]oxabicyclic moiety in 6a in
order to generate a seven-membered carbocyclic ring
system. To this end, Lewis acid-mediated nucleophilic
cleavage6,7 was first considered. Treatment of 6a (the
major isomer) with excess triethylsilane (8 equiv.) in the
presence of titanium tetrachloride (TiCl4) (3 equiv.) in
dichloromethane at −70°C afforded 9 as a single
diastereoisomer in 90% yield after flash column chro-
matography. In the same manner, addition of al-
lyltrimethylsilane to 6a gave the tetracyclic compound
10 in 75% yield (Scheme 4). These structures were
The unexpected formation of this novel pentacyclic ring
system can be rationalized as indicated in Scheme 2. We
assume that Lewis acid-catalyzed nucleophilic substitu-
tion of the silyl enol ether at allylic alcohol 5a occurs
first providing 7a. The protonation of the exocyclic
double bond in 7a initiates cyclization and leads to a
tertiary carbocation which undergoes an intramolecular
Friedel–Crafts alkylation.5 This final step is undeniably
assisted by the electron-donating methoxy group. In
fact, in the absence of this group, the reaction is
stopped at the cyclopentanone stage in agreement with
the results of our previous investigations.2
Under the same reaction conditions, allylic alcohol 5b
afforded the same pentacyclic structure 6b as above,
albeit in lower yield (40%), along with the indene
derivative 8b (45%). In contrast, the presence of a third
methoxy group in 5c totally inhibited the aromatic
electrophilic substitution and gave rise to cyclopen-
tanone 7c and indene 8c in equal amounts (Scheme 3).
As anticipated, when the reaction was carried out in the
Figure 1. ORTEP drawing of 9.

I. Hanna et al. / Tetrahedron Letters 42 (2001) 231–234
233
Scheme 5.
Scheme 6.
tions leading to the pentacyclic acetal 6 which can be
transformed into a fused seven-membered ring system
or into naphthalene derivatives in high yields. Work to
apply this reaction to the synthesis of natural products
containing the 5,6,7-fused tricyclic systems is now under
way.
assigned on the basis of an extensive NMR study
(COSY, NOESY and HETCOR spectra) and have been
confirmed by X-ray crystallographic analysis (Fig. 1).8
The formation of 9 and 10 is the overall result of
sequential double addition of the nucleophile (hydride
and allylsilane, respectively) from the same face, syn to
each other.
References
In order to cleave the dioxene ring and release the
oxygenated functionalities, acid hydrolysis of 6a was
undertaken. Treatment of ketal 6a with perchloric acid
in refluxing acetonitrile for three hours furnished the
naphthalene derivative 11 in 95% after flash chromatog-
raphy. This unexpected structure was established on the
1. For a review on domino reactions, see: Tietze, L. F. Chem.
Rev. 1996, 96, 115.
2. (a) Hanna, I.; Ricard, L. Tetrahedron Lett. 1999, 40, 863.
(b) Hanna, I. Tetrahedron Lett. 1999, 40, 2521. (c) Hanna,
I.; Michaut, V. Org. Lett. 2000, 2, 1141.
1
basis of H, 13C NMR, IR and mass spectra. A similar
3. Fe´tizon, M.; Goulaouic, P.; Hanna, I.; Prange´, T. J. Org.
result was obtained when 6a was submitted to
iodotrimethylsilane. Treatment of 6a with excess TMSI,
in situ generated from chlorotrimethylsilane and
sodium iodide in acetonitrile, led the iodomethylnaph-
thalene 12 in 44% yield. This structure was deduced
from its spectroscopic data and confirmed by the fol-
lowing transformation: reduction of 12 with n-trib-
utyltin hydride in the presence of a catalytic amount of
AIBN in refluxing benzene for one hour gave the
dimethylnaphthalene 13 (Scheme 5).
Chem. 1988, 53, 5673.
4. Spectroscopic and analytical data for compound 6a (major
isomer): Colorless crystals, mp 100–101°C. IR wmax 1610,
1579 cm−1 1H NMR (400 MHz, CDCl3) l 7.04 (d, 1H,
.
J=8.4 Hz), 6.74 (d, 1H, J=2.2 Hz), 6.67 (dd, 1H, J=8.4
and 2.2 Hz), 4.16 (td, 1H, J=11.6 and 2.8 Hz), 3.84 (d,
1H, J=7.4 Hz), 3.79 (s, 3H, OMe), 3.77 (d, 1H, J=12.8
Hz), 3.55–3.70 (m, 2H), 2.80 (q, 1H, J=7.0 Hz), 2.30–
2.40 (m, 1H), 2.20–2.30 (m, 1H), 1.95–2.25 (m, 3H),
1.75–1.90 (m, 1H), 1.47–1.66 (m, 1H), 1.35 (d, 3H, J=7.0
Hz) ppm. 13C NMR (100.6 MHz, CDCl3) l 158.4 (C),
141.4 (C), 134.0 (C), 120.9 (CH), 115.0 (CH), 110.8 (CH),
102.4 (C), 89.5 (C), 78.0 (CH), 63.3 (CH2), 61.1 (CH2),
57.6 (CH3, OMe), 55.3 (CH), 42.3 (CH), 32.4 (CH2), 27.2
(CH2), 25.6 (CH2), 18.8 (CH3) ppm. MS (CI, NH3), m/z
303 (M+1), 320 (M+18). Elemental analysis (%) calcd for
C18H22O4: C, 71.50; H, 7.33. Found: C, 71.01; H, 7.33.
5. For a recent example involving intramolecular Friedel–
Crafts alkylation in domino reactions see: Kno¨lker, H.-J.;
Baum, E.; Graf, R.; Jones, P. G.; Spieß, O. Angew. Chem.,
Int. Ed 1999, 38, 2583.
The formation of the naphthalene ring can be rational-
ized as illustrated in Scheme 6. Protonation of the
furane ring occurs first and leads after cleavage of the
ether bond to intermediate B. Acid-mediated opening
of the dioxane moiety is followed by a pinacol-like
rearrangement affording C which leads to 11 after
hydrolysis of the hemiacetal and dehydration. Obvi-
ously, the driving force for this transformation is the
formation of the highly stabilized aromatic system.
In summary, we have found that allylic alcohols 5,
readily prepared from 1,4-dioxene and methoxy-aceto-
phenones, undergo acid-catalyzed triple-domino reac-
6. For a review on Lewis acid-mediated addition to acetals
see: Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043–
1054.

234
I. Hanna et al. / Tetrahedron Letters 42 (2001) 231–234
7. For recent examples on addition of nucleophiles to cyclic
acetals, see: Fujiwara, K.; Amano, A.; Tokiwano, T.;
Murai, A. Tetrahedron 2000, 56, 1065. Wu, H.-S.; Chern,
J.-H. J. Org. Chem. 1997, 62, 3208. Pellissier, H.; Santelli,
M. J. Chem. Soc., Chem. Commun. 1995, 607.
8. Crystallographic data for compounds 9 and 10 have been
deposited with the Cambridge Crystallographic Data
Centre.
.
.