Intramolecular Cyclizations of o-Acylbenzyllithiums. Formation of Benzocyclobuten-1-ol Derivatives and Their Thermal Isomerization

Article abstract of DOI:10.1021/jo982366o

The formation of benzocyclobutenol derivatives by intramolecular cyclizations of o-acylbenzyllithiums is described. Treatment of o-(trialkylsilylmethyl)phenyl ketones with lithium diisopropylamide (LDA) followed by quenching of the resulting benzylic carb

Full text of DOI:10.1021/jo982366o

J . Org. Chem. 1999, 64, 3557-3562
3557
In tr a m olecu la r Cycliza tion s of o-Acylben zyllith iu m s. F or m a tion of
Ben zocyclobu ten -1-ol Der iva tives a n d Th eir Th er m a l
Isom er iza tion
Kazuhiro Kobayashi,* Masataka Kawakita, Masaharu Uchida, Koichi Nishimura,
Tohru Mannami, Susumu Irisawa, Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami,
Tottori 680-8552, J apan
Received December 2, 1998
The formation of benzocyclobutenol derivatives by intramolecular cyclizations of o-acylbenzyllithiums
is described. Treatment of o-(trialkylsilylmethyl)phenyl ketones with lithium diisopropylamide (LDA)
followed by quenching of the resulting benzylic carbanions with chlorotrialkylsilane resulted in
stereoselective formation of the corresponding 1-trialkylsiloxy-2-(trialkylsilyl)benzocyclobutenes in
good yields. Subsequently, o-acyl-m-methoxybenzyllithiums were found to work well in cyclization
to benzocyclobuten-1-ol derivatives. The reaction of 2-benzoyl-3,4,5-trimethoxybenzyllithium,
generated in situ by deprotonation of 6-methyl-2,3,4-trimethoxybenzophenone with LDA, with
chlorotrimethylsilane afforded the corresponding 1-(trimethylsiloxy)benzocyclobutene. Cyclization
of 2-pivaloyl-3-methoxybenzyllithiums, generated in situ from tert-butyl 2-methyl-6-methoxyphenyl
ketones upon deprotonation with LDA, proceeded spontaneously even at -78 °C to give the
corresponding benzocyclobuten-1-ols. We also describe the results of thermal isomerization of these
1-trimethylsiloxy-2-(trialkylsilyl)benzocyclobutenes.
In tr od u ction
ration of heterocycles7 and other useful compounds.8
Therefore, there has been continuing interest in the
development of new methods for the synthesis of benzo-
cyclobuten-1-ol derivatives, and a number of efficient
methods have been reported, most of which rely on (1)
2+2 cycloaddition of benzynes with alkenes, such as vinyl
acetate,9 1,1-dimethoxyethene,10 or 1,1-dichloroethene,11
followed by the appropriate treatment of the resulting
benzocyclobutene derivatives, (2) photolysis of o-alkyl-
phenyl ketones,5 or (3) intramolecular cyclization of
o-lithiated styrene oxides4a and related compounds.4b,12
The present procedure makes benzocyclobuten-1-ol de-
rivatives available, including those carrying a trialkylsilyl
group at the 2-position. They are potentially useful
intermediates for organic synthesis, but their preparation
is less well described,13 although the preparation of
In our previous reports we have described the use of
reactions of o-acylbenzyllithiums with electrophiles, such
as aldehydes, ketones, ethyl chloroformate, and furan-
2(5H)-one, for preparing heterocycles, such as isocou-
marins,1 3-isochromanones,2 and arylnaphthofuranone
lignans.3 In this paper we wish to describe intramolecular
cyclization reactions of o-acylbenzyllithiums carrying
appropriate substituents, which give a very rapid access
to benzocyclobuten-1-ol derivatives. These derivatives are
being recognized as an important class of compounds
because of their versatility in organic synthesis, e.g., for
use as precursors for the generation of R-oxy-o-quinone-
dimethides,4,5 which are useful intermediates for the
synthesis of polycyclic compounds,4-6 and for the prepa-
* Corresponding author. Fax: +81 857 31 0881. E-mail: kkoba@
bio.tottori-u.ac.jp.
(1) Kobayashi, K.; Konishi, A.; Kanno, Y.; Suginome, H. J . Chem.
Soc., Perkin Trans. 1 1993, 111-115.
(2) Kobayashi, K.; Mannami, T.; Kawakita, M.; Tokimatsu, J .;
Konishi, H. Bull. Chem. Soc. J pn. 1994, 67, 582-585.
(6) Durst, T.; Kozma, E. C.; Charlton, J . L. J . Org. Chem. 1985, 50,
4829-4833. Macdonald, D. I.; Durst, T. J . Org. Chem. 1988, 53, 3663-
3669. Azadi-Ardakani, M.; Wallace, T. W. Tetrahedron 1988, 44, 5939-
5952. Kanai, G.; Miyaura, N.; Suzuki, A. Chem. Lett. 1993, 845-848.
Woo, S. H. Tetrahedron Lett. 1994, 35, 3975-3978, and references
therein.
(3) Kobayashi, K.; Tokimatsu, J .; Maeda, K.; Morikawa, O.; Konishi,
H. J . Chem. Soc., Perkin Trans. 1 1995, 3013-3016. Kobayashi, K.;
Kajimura, Y.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi, H.
Heterocycles 1997, 45, 1593-1600.
(7) Adams, G.; Andreux, J .; Plat, M. Tetrahedron Lett. 1981, 22,
3181-3184. Kobayashi, K.; Itoh, M.; Sasaki, A.; Suginome, H. Tetra-
hedron 1991, 47, 5437-5452. Kobayashi, K.; Kanno, Y.; Seko, S.;
Suginome, H. J . Chem. Soc., Perkin Trans. 1 1992, 3111-3117.
Fitzgerald, J . J .; Pagano, A. R.; Sakoda, V. M.; Olofson, R. A. J . Org.
Chem. 1994, 59, 4117-4121. Fitzgerald, J . J .; Michael, F. E.; Olofson,
R. A. Tetrahedron Lett. 1994, 35, 9191-9194. Becker, D. P.; Flynn, D.
L. Synlett 1996, 57-59.
(4) (a) J ung, M. E.; Lam, P. Y.-S.; Mansuri, M. M.; Speltz, L. M. J .
Org. Chem. 1985, 50, 1087-1105. (b) Macdonald, D. I.; Durst, T. J .
Org. Chem. 1988, 53, 3663-3669. (c) Choy, W.; Yang, H. J . Org. Chem.
1988, 53, 5796-5798. (d) Coltart, D. M.; Charlton, J . L. Can. J . Chem.
1996, 74, 88-94. (e) Hickman, D. N.; Hodgetts, K. J .; Mackman, P. S.;
Wallace, T. W.; Wardleworth, J . M. Tetrahedron 1996, 52, 2235-2260.
(f) Kraus, G. A.; Zhao, G. J . Org. Chem. 1996, 61, 2770-2773.
(5) For a review on early work, see: Sammes, P. G. Tetrahedron
1976, 32, 405-422. For recent examples, see: Charlton, J . L.; Koh,
K., Plourde, G. L. Tetrahedron Lett. 1989, 30, 3279-3282. Coll, G.;
Costa, A.; Deya, P. M.; Saa, J . M. Tetrahedron Lett. 1991, 32, 263-
266. Charlton, J . L.; Koh, K. J . Org. Chem. 1992, 57, 1514-1516.
Tsuno, T.; Sugiyama, K. Tetrahedron Lett. 1992, 33, 2829-2832.
Tomioka, H.; Ichihashi, M.; Yamamoto, K. Tetrahedron Lett. 1995, 36,
5371-5374. Takahashi, Y.; Miyamoto, K.; Sakai, K.; Ikeda, H.;
Miyashi, T.; Ito, Y.; Tabohashi, K. Tetrahedron Lett. 1996, 37, 5547-
5550, and references therein.
(8) Fitzgerald, J . J .; Drysdale, N. E.; Olofson, R. A. J . Org. Chem.
1992, 57, 7122-7126, and references therein.
(9) Wassermann, H. H.; Solodar, J . J . Am. Chem. Soc. 1965, 87,
4002-4003.
(10) Stevens, R. V.; Bisacchi, G. S. J . Org. Chem. 1982, 47, 2393-
2396.
(11) Durr, H.; Nickels, H. J . Org. Chem. 1981, 45, 973-980.
(12) Akgun, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J . Org.
Chem. 1981, 46, 2730-2734. Aidhen, I. S.; Narasimhan, N. S.
Tetrahedron Lett. 1991, 32, 2171-2172.
(13) Part of this paper has been reported as a preliminary com-
munication. Kobayashi, K.; Kawakita, M.; Mannami, T.; Konishi, H.
Tetrahedron Lett. 1995, 36, 733-736.
10.1021/jo982366o CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/16/1999

3558 J . Org. Chem., Vol. 64, No. 10, 1999
Kobayashi et al.
Sch em e 1
Sch em e 2
2-(trimethylsilyl)benzocyclobuten-1-ol has been recorded
by Trahanovsky and Fisher.14 We also examined thermal
isomerization of some of the benzocyclobutenol deriva-
tives prepared. The results have led to considerations on
the mechanism of these cyclization reactions and the
stereochemistry of the products.
methylsilane under conditions similar to those described
above resulted in formation of an intractable mixture of
the products; reactions via intermolecular condensation
of the silylated ketone appeared to take place. This
negative result prompted us to examine the reaction of
an o-methylbenzophenone derivative carrying a methoxy
substituent at the o′-position. The substrate for this
purpose, 2,3,4-trimethoxy-6-methylbenzophenone (5), was
prepared by treatment of 2-lithio-3,4,5-trimethoxytoluene
with benzaldehyde, followed by the PCC oxidation of the
resulting alcohol. We have found that lithiation of 5 with
an equimolar amount of LDA generated 2-benzoyl-3,4,5-
trimethoxybenzyllithium, treatment of which with an
equimolar amount of chlorotrimethylsilane resulted in
formation of 1-(trimethylsilyloxy)benzocyclobutenes 6 and
8 in 19 and 7% yields, respectively, along with silylated
ketone 7 in 65% yield (Scheme 2). These products were
separable from each others by means of preparative TLC
on silica gel. It can be reasonably assumed from this
result that the 3-methoxy group in the benzoylbenzyl-
lithium assists in the ring closure. The stereochemistry
of 8 was established on the basis of the considerations
stated below. Compounds 6 and 8 were obtained from 5
by sequential treatment with 2 molar amounts each of
LDA and chlorotrimethylsilane in 13 and 62% yields,
respectively. Conversion of 7 to 8 was also achieved on
treatment with LDA and then with chlorotrimethylsilane
in 73% yield.
Cycliza tion of ter t-Bu tyl o-Tolyl Keton es Bea r in g
a n o′-Meth oxy Gr ou p , 9 a n d 10, to Ben zocyclobu -
ten ols 11 a n d 12. In view of the success of the above-
mentioned reactions, we next examined the possibility
in cyclization reaction of tert-butyl o-tolyl ketones bearing
an o′-methoxy group, 9 and 10, which were expected to
provide more flexibility in terms of cyclization. tert-Butyl
2-methoxy-6-methylphenyl ketone (9) was prepared by
the PCC oxidation of the alcohol which was prepared by
interaction of 2-methoxy-6-methylbenzaldehyde with tert-
butylmagnesium bromide. A procedure similar to that
described above for the preparation of the trimethoxy-
benzophenone 5, except for the use of pivalaldehyde in
the place of benzaldehyde, gave tert-butyl 2,3,4-tri-
methoxy-6-methylphenyl ketone (10). As expected, the
lithiated intermediates of these ketones were found to
cyclize more readily than those from 1 and 5. Thus,
treatment of 9 with an equimolar amount of LDA in -78
°C resulted immediately in deep-red coloration, which
turned gradually to yellow on stirring for 1 h at the same
Resu lts a n d Discu ssion
Cycliza tion of o-Acylben zyllith iu m s Lea d in g to
Ben zocyclobu ten yl Tr ia lk ylsilyl Eth er s 3, 4, 6, a n d
8. Treatment of tert-butyl o-tolyl ketone (1)1 with an
equimolar amount of LDA in THF at -78 °C, followed
by in situ trapping with chlorotrimethylsilane, afforded
a 58% yield of the expected trimethylsilylated ketone 2,
after simple acidic workup and purification by prepara-
tive TLC on silica gel. In addition to compound 2, an oily
and very mobile product was isolated. The structure of
this product was determined from spectroscopic data. The
mass spectrum and elemental analysis indicated its
molecular formula to be C18H32OSi2. The infrared spec-
trum showed no evidence for the presence of the carbonyl
group. Two singlet signals (9H each) at δ -0.11 and 0.20,
which are assignable to two trimethylsilyl groups, and a
singlet signal (1H) at δ 3.03 were observed in the 1H
NMR spectrum. These results indicated that the product
was 1-(trimethylsiloxy)benzocyclobutene derivative 3,
which appears to result from the further lithiation of the
silylated ketone 2, followed by trapping of the resulting
lithium intermediate with chlorotrimethylsilane. Com-
pound 2 was similarly treated with an equimolar amount
each of LDA and chlorotrimethylsilane to give the ben-
zocyclobutene 3 in 86% yield. In addition, it was found
that, when the o-tolyl ketone 1 was treated successively
with 2 molar amounts each of LDA and chlorotrimeth-
ylsilane, compound 3 was produced in 59% yield. Simi-
larly, treatment of 1 with 2 molar amounts each of LDA
and chlorotriethylsilane resulted in the formation of
1-(triethylsiloxy)benzocyclobutene derivative 4 in 51%
yield. The above-mentioned results are outlined in Scheme
1. The configuration assignments depicted for 3 and 4
rely on the considerations stated below. The production
of these compounds was highly stereoselective, and the
corresponding diastereomers, for example 13, for 3 could
not be obtained.
Our next object was to examine similar transforma-
tions of 2-methylbenzophenone into the corresponding
benzocyclobutenol derivatives. However, lithiation of this
ketone with LDA followed by treatment with chlorotri-
(14) Trahanovsky, W. S.; Fischer, D. R. J . Am. Chem. Soc. 1990,
112, 4971-4972.

Intramolecular Cyclization of o-Acylbenzyllithium
J . Org. Chem., Vol. 64, No. 10, 1999 3559
Sch em e 3
Sch em e 5
Sch em e 4
temperature, indicating that the intramolecular cycliza-
tion was complete. The usual workup gave the expected
benzocyclobutenol 11 in 76% yield. The cyclization reac-
tion of 10 was carried out similarly and gave the
corresponding benzocyclobutenol 12 in 59% yield. These
reactions are outlined in Scheme 3.
Sch em e 6
Th er m a l Isom er iza tion of Tr im eth ylsiloxyben zo-
cyclobu ten es 3 a n d 8. We tried thermal isomerization
of the benzocyclobutenes 3 and 8 in order to examine
thermodynamic behavior of these compounds. The results
obtained are outlined in Scheme 4. When a solution of 3
in p-cymene was heated at reflux temperature for 2.5 h,
an isomerization reaction took place and the stereoisomer
13 was formed in an almost quantitative yield. This
result is intriguing since it indicates that 13 is thermo-
dynamically more stable and sterically less strained than
3. Similarly, a thermal isomerization of compound 8
proceeded smoothly to give the corresponding stereoiso-
mer 14 quantitatively. This leads to a conclusion similar
to that mentioned above for 3 and 13. MM2 calculations
with Chem3D Pro suggest that compound 13 is more
stable (7.48 kcal/mol) than the corresponding stereoiso-
mer 3 and that 14 is more stable (2.08 kcal/mol) than 8.
Deter m in a tion of th e Ster eoch em istr ies of Ben -
zocyclobu ten ol Der iva tives 3, 8, 13, a n d 14. In our
preliminary communication,13 the stereochemistry of 3
was tentatively assigned as depicted in 13. This assign-
ment was based on consideration that the reaction could
proceed via the intermediate 18 (vide infra). However,
since the thermal isomerization experiment coupled with
the MM2 calculations revealed that 3 is thermodynami-
cally less stable than 13, the previous assignment should
be reversed. This revised stereochemistry was supported
by the results of NOE studies of compounds 3 and 13.
Thus, irradiation of the signal at δ 0.20 due to OTMS of
3 resulted in an enhancement (6.3%) of the signal at δ
3.03 due to the cyclobutyl proton, while a large enhance-
ment (23%) of the signal at δ 3.22 due to the cyclobutyl
proton of 13 was observed on irradiation of the signal at
δ 0.95 due to t-Bu. The stereochemistries of 8 and 14 were
also established with the aid of NOE experiments. For
compound 8, irradiation of the signal at δ 0.13 due to
OTMS resulted in an enhancement (11%) of the signal
at δ 3.28 due to the cyclobutyl proton. On the other hand,
an enhancement was observed for the signal at δ 7.27
due to the ortho-protons of Ph (5.5%) of 14 when the
signal at δ 2.84 due to the cyclobutyl proton was irradi-
ated. A considerable upfield shift of the signal due to the
cyclobutyl proton of 14 gives further support to the
stereochemical assignment of 8 and 14.
P r oba ble Mech a n ism s for th e F or m a tion of Ben -
zocyclob u t en ol Der iva t ives a n d Th eir Th er m a l
Isom er iza tion . Although no unambiguous explanation
of the mechanisms of the present cyclizations can be
offered at the present time, the probable pathways to the
products are depicted in Schemes 5-7. The proposed
mechanism for the highly selective formation of the
sterically hindered product 3 is illustrated in Scheme 5.
Thus, interaction of tert-butyl o-[(trimethylsilyl)methyl]-
phenyl ketone (2) with LDA leads to formation of the
lithiated intermediate 15, which is trapped with chlo-
rotrimethylsilane selectively at the oxygen of the R-oxy-
o-quinodimethane type equilibrium form 16 (or 17) not
at the R-carbon of 15 to give the corresponding trimeth-
ylsiloxy-o-quinodimethane, of which conrotatory ring
closure15 gives rise to the product 3. o-[Bis(trimethylsilyl)-
methyl]phenyl tert-butyl ketone was not isolated, indicat-

3560 J . Org. Chem., Vol. 64, No. 10, 1999
Kobayashi et al.
Sch em e 7
equilibrium form 25 of the tert-butyl o-(lithiomethyl)-
phenyl ketone 24 and/or the lithium benzocyclobutenyl
oxide 26, as illustrated in Scheme 7.
We have no clear explanation for the mechanism of the
isomerization of 3 to 13 and 8 to 14. We attempted the
isomerization of 8 to 14 in refluxing toluene. This
temperature is high enough for the ring opening of
benzocyclobutenes bearing an oxy substituent at the
1-position, as described by Oppolzer.17 The isomerization,
however, proceeded very sluggishly, and most of the
starting material remained unchanged after 18 h. This
result would indicate that the isomerization, of course,
does not occur through an o-quinodimethane intermedi-
ate and that this is a concerted reaction.
ing that the introduction of the second trimethylsilyl
group at the oxygen is strongly favored over introduction
at the carbon. The high stereoselectivity of the cyclization
can be understood by comparison of relative stabilities
between the intermediates 16 (or 17) and 18 (or 19). The
formation of the silicate through a intramolecular coor-
dination of the alkoxide to the silicon atom would result
in a stabilization of 16. The intermediacy of 17 would be
supported by the large outward preference of oxy sub-
stituents in the formation of o-quinodimethanes, dem-
onstrated in the work of Houk et al. on the concept of
torquioselectivity.16 It should be noted that no benzocy-
clobutenol derivative was isolated by quenching the
lithiated intermediate 15 with aqueous ammonium chlo-
ride, and the starting ketone 2 was recovered in an
almost quantitative yield. This result indicates that the
corresponding benzocyclobutenoxide was not formed in
the reaction mixture.
Scheme 6 shows the probable pathway to the 1-(tri-
methylsiloxy)benzocyclobutene 6 and 8 from the o-
methoxy-o′-methylbenzophenone 5. Presumably, the R-oxy-
o-quinodimethane type equilibrium form 21 of the o-ben-
zoylbenzyllithium 20 is somewhat stabilized due to the
o′-methoxy group to form the 1-(trimethylsiloxy)benzo-
cyclobutene 6. The formation of 8 can be explained by
considering the chelate-stabilized intermediate 23 (or a
silicate intermediate similar to 16). It is also worth noting
that treatment of the lithiated intermediates 20 and 22
with aqueous ammonium chloride resulted in the almost
quantitative recovery of the starting materials 5 and 7,
respectively.
An alternative path for the formation of these 1-(tri-
methylsiloxy)benzocyclobutenes may be by a chlorotri-
alkylsilane-induced intramolecular nucleophilic attack of
the benzylic carbanions to the carbonyl groups, followed
by trapping of the resulting lithium alkoxides with
chlorotrimethylsilane. Although this possibility cannot
be excluded, it appears even less likely considering that
compounds 3 and 8, which appear to be sterically more
hindered than their corresponding isomers 13 and 14,
were exclusively formed as a single stereoisomer and that
the quenching experiments of the lithiation products from
the ketones 2, 5, and 7 with aqueous ammonium chloride
gave no benzocyclobutenol derivatives.
Exp er im en ta l Section
P h en yl 2,3,4-Tr im eth oxy-6-m eth ylp h en yl Keton e (5).
To a stirred solution of N,N,N′,N′-tetramethylethylenediamine
(TMEDA) (20 mmol, 2.3 g) in Et2O (50 cm3) at 0 °C under argon
was added butyllithium (20 mmol, 1.6 M in hexane) and then
1,2,3-trimethoxy-5-methylbenzene (10 mmol, 1.8 g). The mix-
ture was refluxed for 2 h and then allowed to stand for 12 h
at room temperature. To the cooled (0 °C) suspension was
added benzaldehyde (20 mmol, 2.1 g) dropwise. The resulting
mixture was stirred for an additional 2 h at the same
temperature before it was quenched by adding 5% aqueous
HCl. The organic layer was separated, and the aqueous layer
was extracted with Et2O twice (100 cm3 each). The combined
ether layers were washed with brine and dried (MgSO4). The
solvent was removed under reduced pressure, and the residue
was purified by column chromatography on silica gel to afford
phenyl(2,3,4-trimethoxy-6-methylphenyl)methanol (2.3 g, 81%)
as a pale yellow oil: Rf 0.41 (1:5, EtOAc-hexane); IR (neat)
3470 cm-1; 1H NMR (60 MHz, CCl4) δ 2.26 (3H, s, 6′-Me), 3.33
(3H, s, OMe), 3.5 (1H, br s, OH), 3.74 (3H, s, OMe), 3.82 (3H,
s, OMe), 5.82 (1H, br d, J ) 10 Hz), 6.42 (1H, s, 5′-H), 7.19
(5H, s, ArH); MS (rel intensity) m/z 288 (M+, 100). Anal. Calcd
for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.93; H, 7.06. A
mixture of the foregoing alcohol (2.3 g, 8.0 mmol), pyridinium
chlorochromate (PCC) (5.2 g, 24 mmol), and Celite (5.0 g) in
CH2Cl2 (200 cm3) was stirred for 1 h at room temperature.
After this time, the mixture was filtered. The filtrate was
washed successively with 5% aqueous HCl and brine and dried
(MgSO4). Removal of the solvent gave a residue, which was
introduced at the top of a short silica gel column and eluted
with CH2Cl2. After concentration of the eluent, the residual
solid was recrystallized from hexane to afford the title com-
pound (2.1 g, 92%) as a white solid: mp 93-94.5 °C; IR (neat)
1
1669 cm-1; H NMR (270 MHz, CDCl3) δ 2.12 (3H, s, 6-Me),
3.68 (3H, s, OMe), 3.86 (3H, s, OMe), 3.90 (3H, s, OMe), 6.55
(1H, s, 5-H), 7.35-7.55 (3H, m, 3′, 4′, 5′-H), 7.81 (2H, dd, J )
7.6, 1.5 Hz, 2′, 6′-H); MS (rel intensity) m/z 286 (M+, 71), 285
[(M - 1)+, 100]. Anal. Calcd for C17H18O4: C, 71.31; H, 6.34.
Found: C, 71.05; H, 6.30.
ter t-Bu tyl 2-Meth oxy-6-m eth ylp h en yl Keton e (9). To a
stirred solution of tert-butylmagnesium chloride, prepared in
situ from tert-butyl chloride (0.46 g, 5.0 mmol) and magnesium
turnings (0.15 g, 6.0 mmol) in Et2O (5 cm3), at 0 °C was added
a solution of 2-methoxy-6-methylbenzaldehyde18 (0.50 g, 3.3
mmol) in Et2O (5 cm3). The mixture was allowed to warm
slowly to room temperature and poured into 5% aqueous HCl.
The organic layer was separated, and the aqueous layer was
extracted with Et2O. The combined extracts were washed with
brine, dried (MgSO4), and concentrated. The residue was
purified by preparative TLC on silica gel to give 2,2-dimethyl-
1-(2-methoxy-6-methylphenyl)-1-propanol (0.38 g, 54%) as a
yellow liquid: Rf 0.24 (1:10 EtOAc-hexane); IR (neat) 3542
The ease of the production of the benzocyclobutenols
11 and 12 is noteworthy and is most likely ascribed to
the high stability of the R-oxy-o-quinodimethane type
1
cm-1; H NMR (60 MHz, CCl4) δ 0.91 (9H, s, t-Bu), 2.31 (3H,
(15) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, 1970.
(16) Kirmse, W.; Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
1984, 106, 7989-7991. Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
1985, 107, 2099-2111. Dolbier, W. R., J r.; Koroniak, K.; Houk, K. N.;
Sheu, C. Acc. Chem. Res. 1996, 29, 471-477.
s, 6′-Me), 3.7-4.0 (4H, m including s at 3.78, OMe, OH), 4.47
(17) Oppolzer, W. Synthesis 1978, 793-802.
(18) Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 723-724.

Intramolecular Cyclization of o-Acylbenzyllithium
J . Org. Chem., Vol. 64, No. 10, 1999 3561
(1H, br. d, J ) 11 Hz), and 6.5-7.1 (3H, m, ArH); MS (rel
intensity) m/z 208 (M+, 0.8), 151 [(M - C4H9)+, 100]. Anal.
Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.94; H,
9.70. Oxidation of the alcohol thus obtained (0.35 g, 1.7 mmol)
with PCC (1.1 g, 5.1 mmol) in CH2Cl2 (40 cm3) under conditions
similar to those described above afforded the title compound
(0.30 g, 90%) as a yellow liquid: Rf 0.33 (1:10 EtOAc-hexane);
(0.12 g, 1.1 mmol) in a manner similar to that described above
for the reaction of 1 to give 3 (0.30 g, 86%).
Tr ea tm en t of th e Keton e 1 w ith 2 Mola r Am ou n ts ea ch
of LDA a n d Me3SiCl. Lithiation of 1 (0.17 g, 1.0 mmol) with
LDA (2.0 mmol) in THF (5 cm3), followed by treatment with
Me3SiCl (0.22 g, 2.0 mmol), gave 3 (0.19 g, 59%).
tr a n s-7-ter t-Bu tyl-8-tr ieth ylsilyl-7-(tr ieth ylsiloxy)bicy-
clo[4.2.0]octa -1,3,5-tr ien e (4). Lithiation of 1 (0.17 g, 1.0
mmol) with LDA (2.0 mmol) in THF (5 cm3), followed by
treatment with Et3SiCl (0.30 g, 2.0 mmol), gave the title
compound (0.21 g, 51%) as a colorless oil; Rf 0.75 (hexane); IR
1
IR (neat) 1694 cm-1; H NMR (60 MHz, CCl4) δ 1.16 (9H, s,
t-Bu), 2.14 (3H, s, 6′-Me), 3.79 (3H, s, OMe), 6.63 (1H, d, J )
7.9 Hz, 3′-H), 6.72 (1H, d, J ) 7.3 Hz, 5′-H), 7.09 (1H, dd, J )
7.9, 7.3 Hz, 4′-H); MS (rel intensity) m/z 206 (M+, 1.1), 149
[(M - C4H9)+, 100]. Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.39; H, 8.55.
1
(neat) 1582, 1238, 1069, 1006, 762, 727 cm-1; H NMR (270
MHz, CDCl3) δ 0.41 [6H, q, J ) 7.9 Hz, 8-Si(CH2Me)3], 0.76
[6H, q, J ) 7.9 Hz, OSi(CH2Me)3], 0.84 [9H, t, J ) 7.9, 8-Si-
(CH2Me)3], 0.97 (9H, s, t-Bu), 1.01 [9H, t, J 7.9, OSi(CH2Me)3],
3.16 (1H, s, 8-H), 7.0-7.25 (4H, m); MS (rel intensity) m/z 404
(M+, 8.9), 347 [(M - t-Bu)+, 55], 275 (76), 87 (100). Anal. Calcd
for C24H44OSi2: C, 71.21; H, 10.96. Found: C, 71.07; H, 10.71.
ter t-Bu tyl 2,3,4-Tr im eth oxy-6-m eth ylp h en yl Keton e
(10). Lithiation of 1,2,3-trimethoxy-5-methylbenzene (1.8 g, 10
mmol) with n-BuLi-TMEDA (20 mmol) in Et2O (40 cm3)
followed by treatment of the resulting lithium compound with
2,2-dimethylpropanal (2.4 g, 20 mmol) in THF (8 cm3) was
carried out in a manner similar to that described above for
the preparation of phenyl(2,3,4-trimethoxy-6-methylphenyl)-
methanol to give 2,2-dimethyl-1-(2,3,4-trimethoxy-6-meth-
ylphenyl)-1-propanol (1.6 g, 59%) as a yellow liquid: Rf 0.27
(1:5 EtOAc-hexane); bp 115-117 °C/0.1 Torr; IR (neat) 3541
Lith ia tion of th e Ben zop h en on e 5 a n d Su bsequ en t
Tr ea t m en t of t h e R esu lt in g Ca r b a n ion w it h Me3SiCl.
Lithiation of 5 (0.29 g, 1.0 mmol) with LDA (1.0 mmol) in THF
(5 mL) followed by treatment with Me3SiCl (0.11 g, 1.0 mmol)
was carried out in the same way as described above for the
preparation of 2 and 3 to give 3,4,5-trimethoxy-7-phenyl-7-
(trimethylsilyloxy)bicyclo[4.2.0]octa-1,3,5-triene (6) (a white
solid; 69 mg, 19%), phenyl 2,3,4-trimethoxy-6-(trimethylsilyl-
methyl)phenyl ketone (7) (a yellow oil; 0.23 g, 65%), and trans-
3,4,5-trimethoxy-7-phenyl-8-trimethylsilyl-7-(trimethylsilyloxy)-
bicyclo[4.2.0]octa-1,3,5-triene (8) (a white solid; 30 mg, 7%).
6: Rf 0.30 (1:10 EtOAc-hexane); mp 97.5-98 °C (hexane); IR
(KBr disk) 1252, 841 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.06
(9H, s, SiMe3), 3.28 (1H, d, J ) 14.0 Hz, 8-H), 3.47 (1H, d, J )
14.0 Hz, 8-H), 3.59 (3H, s, OMe), 3.71 (3H, s, OMe), 3.80 (3H,
s, OMe), 6.41 (1H, s, 2-H), 7.1-7.35 (5H, m, ArH); MS (rel
intensity) m/z 358 (M+, 61), 357 [(M - 1)+, 100]. Anal. Calcd
for C20H26O4Si: C, 67.00; H, 7.31. Found: C, 66.94; H, 7.29.
7: Rf 0.27 (1:10 EtOAc-hexane); IR (neat)1668, 1276, 853
1
cm-1; H NMR (60 MHz, CCl4) δ 0.90 (9H, s, t-Bu), 2.25 (3H,
s, 6′-Me), 3.7-4.0 (10H, m including 3s at 3.73, 3.79, 3.93,
3OMe, OH), 4.40 (1H, br d, J ) 10 Hz), 6.33 (1H, s, 5′-H); MS
(rel intensity) m/z 268 (M+, 0.06), 250 [(M - H2O)+, 6.9], 212
[(M - C4H8)+, 100]. Anal. Calcd for C15H24O4: C, 67.14; H, 9.01.
Found: C, 67.19; H, 9.12. Oxidation of the alcohol thus
obtained (2.3 g, 8.0 mmol) with PCC (5.2 g, 24 mmol) in CH2-
Cl2 (200 cm3) afforded the title compound (2.1 g, 92%) as a
pale yellow solid: mp 93-94 °C (hexane); IR (neat) 1694 cm-1
;
1H NMR (60 MHz, CCl4) δ 1.16 (9H, s, t-Bu), 2.07 (3H, s, 6′-
Me), 3.75 (3H, s, OMe), 3.80 (3H, s, OMe), 3.84 (3H, s, OMe),
6.39 (1H, s, 5′-H); MS (rel intensity) m/z 266 (M+, 6.0), 210
[(M - C4H8)+, 100]. Anal. Calcd for C15H22O4: C, 67.64; H, 8.33.
Found: C, 67.93; H, 8.22.
Lith ia tion of ter t-Bu tyl o-Tolyl Keton e (1) w ith a n
Equ im ola r Am ou n t of LDA a n d Su bsequ en t Tr ea tm en t
of th e Resu ltin g Ca r ba n ion w ith a n Equ im ola r Am ou n t
of Me3SiCl. The ketone 11 (0.72 g, 4.1 mmol) was added
dropwise to a stirred solution of LDA (4.1 mmol) in THF (20
cm3) (at -78 °C under argon), which was generated from
n-BuLi (1.6 M in hexane, 4.1 mmol) and diisopropylamine (0.40
g, 4.1 mmol) by the standard method, resulting in the produc-
tion of a characteristic red solution of the carbanion. After 15
min, Me3SiCl (0.44 g,4.1 mmol) was added dropwise, and the
mixture was stirred for an additional 1 h at the same
temperature, whereupon the red color gradually faded to
orange. The resulting mixture was quenched by adding aque-
ous NH4Cl and extracted with Et2O three times (30 cm3 each).
The combined organic layers were washed with brine and dried
(MgSO4). The solvent was removed under reduced pressure,
and the crude products were purified by preparative TLC on
silica gel to afford tert-butyl 2-(trimethylsilylmethyl)phenyl
ketone (2) (a pale yellow oil; 0.59 g, 58%) and trans-7-tert-
butyl-8-trimethylsilyl-7-(trimethylsilyloxy)bicyclo[4.2.0]octa-
1,3,5-triene (3) (a colorless oil; 79 mg, 6.0%). 2: Rf 0.44 (1:20
EtOAc-hexane); IR (neat) 1689, 1248, 851 cm-1; 1H NMR (270
MHz, CDCl3) δ -0.03 (9H, s, SiMe3), 1.25 (9H, s, t-Bu), 1.96
(2H, s, CH2SiMe3), 6.95-7.2 (4H, m, ArH); MS (rel intensity)
m/z 248 (M+, 7.3), 247 [(M - 1)+, 8.9], 233 [(M - CH3)+, 99],
73 (100). Anal. Calcd for C15H24OSi: C, 72.53; H, 9.74. Found:
C, 72.41; H, 9.66. 3: Rf 0.88 (1:20 EtOAc-hexane); IR (neat)
1599, 1583, 1250, 1068, 859 cm-1; 1H NMR (270 MHz, CDCl3)
δ -0.11 (9H, s, 8-SiMe3), 0.20 (9H, s, OSiMe3), 0.97 (9H, s,
t-Bu), 3.03 (1H, s, 8-H), 6.95-7.2 (4H, m, ArH); MS (rel
intensity) m/z 320 (M+, 0.83), 305 [(M - CH3)+, 1.6], 263 [(M
- t-Bu)+, 17], 247 [(M - SiMe3)+, 18], 233 (65), 73 (100). Anal.
Calcd for C18H32OSi2: C, 67.43; H, 10.06. Found: C, 67.50; H,
9.92.
1
cm-1; H NMR (270 MHz, CDCl3) δ 0.05 (9H, s, SiMe3), 1.86
(2H, s, CH2SiMe3), 3.63 (3H, s, OMe), 3.82 (3H, s, OMe), 3.88
(3H, s, OMe), 6.33 (1H, s, 5-H), 7.2-7.55 (3H, m, ArH), and
7.65-7.9 (2H, m, ArH); MS (rel intensity) m/z 358 (M+, 100).
Anal. Calcd for C20H26O4Si: C, 67.00; H, 7.31. Found: C, 66.97;
H, 7.19. 8: Rf 0.31 (1:10 EtOAc-hexane); mp 93-94 °C
1
(hexane); IR (KBr disk) 1252, 840 cm-1; H NMR (270 MHz,
CDCl3) δ -0.30 (9H, s, 8-SiMe3), 0.13 (9H, s, OSiMe3), 3.28
(1H, s, 8-H), 3.60 (3H, s, OMe), 3.70 (3H, s, OMe), 3.86 (3H, s,
OMe), 6.23 (1H, s, 2-H), 7.2-7.35 (5H, s, ArH); MS (rel
intensity) m/z 430 (M+, 5.9), 415 [(M - CH3)+, 100]. Anal. Calcd
for C23H34O4Si2: C, 64.14; H, 7.95. Found: C, 64.35; H, 7.66.
Tr ea tm en t of th e Keton e 5 w ith 2 Mola r Am ou n ts
Ea ch of LDA a n d Me3SiCl. Lithiation of 5 (0.29 g, 1.0 mmol)
with LDA (2.0 mmol) in THF (5 cm3), followed by treatment
with Me3SiCl (0.22 g, 2.0 mmol), gave 6 (47 mg, 13%) and 8
(0.27 g, 62%).
Lith ia tion of th e Silyla ted Ben zop h en on e 7 a n d Su b-
seq u en t Tr ea t m en t of t h e R esu lt in g Ca r b a n ion w it h
Me3SiCl. Lithiation of 7 (0.11 g, 0.32 mmol) with LDA (0.32
mmol) in THF (5 cm3) followed by treatment with Me3SiCl (35
mg, 0.32 mmol) gave 8 (0.10 g, 73%).
7-ter t-Bu tyl-5-m eth oxybicyclo[4.2.0]octa -1,3,5-tr ien -7-
ol (11). After treatment of 9 (0.21 g, 1.0 mmol) with LDA (1.0
mmol) in THF (5 cm3) at -78 °C, the resulting red solution
was allowed to stir for 1 h at the same temperature, where-
upon the color faded. The mixture was worked up as usual
and separated by preparative TLC on silica gel to give the title
compound (0.16 g, 76%) as a pale-yellow oil: Rf 0.13 (1:10
EtOAc-hexane); IR (neat) 3456 cm-1; 1H NMR (60 MHz, CCl4)
δ 0.99 (9H, s, t-Bu), 2.00 (1H, br s, OH), 2.77 (1H, d, J ) 14.3
Hz, 8-H), 3.33 (1H, d, J ) 14.3 Hz, 8-H), 3.75 (3H, s, OMe),
6.56 (1H, d, J ) 7.9 Hz, 4-H), 6.66 (1H, d, J ) 7.3, 2-H), 7.10
(1H, dd, J ) 7.9, 7.3, 3-H); MS (rel intensity) m/z 206 (M+,
12), 191 [(M - CH3)+, 24], 150 [(M - C4H8)+, 70], 149 [(M -
t-Bu)+, 100]. Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.65; H, 9.05.
Lith ia tion of th e Silyla ted Keton e 2 a n d Su bsequ en t
Tr ea t m en t of t h e R esu lt in g Ca r b a n ion w it h Me3SiCl.
Lithiation of 2 (0.26 g, 1.1 mmol) with LDA (1.1 mmol) in THF
(5 cm3) was followed by treatment with chlorotrimethylsilane

3562 J . Org. Chem., Vol. 64, No. 10, 1999
Kobayashi et al.
7-ter t-Bu t yl-3,4,5-t r im et h oxyb icyclo[4.2.0]oct a -1,3,5-
tr ien -7-ol (12). Compound 10 (0.27 g, 1.0 mmol) was treated
with LDA (1 mmol) in THF (5 cm3) under conditions similar
to those described above for the preparation of 11 to give the
title compound (0.16 g, 59%): Rf 0.06 (1:5 EtOAc-hexane);
mp 80-81 °C (hexane); IR (neat) 3482 cm-1; 1H NMR (60 MHz,
CDCl3) δ 0.99 (9H, s, t-Bu), 2.14 (1H, s, OH), 2.66 (1H, d, J )
14.3 Hz, 8-H), 3.29 (1H, d, J ) 14.3 Hz, 8-H), 3.69 (3H, s, OMe),
3.76 (3H, s, OMe), 3.86 (3H, s, OMe), 6.35 (1H, s, 2-H); MS
(rel intensity) m/z 266 (M+, 5.0), 209 [(M - t-Bu)+, 100]. Anal.
Calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.74; H,
8.46.
cis-7-ter t-Bu tyl-8-tr im eth ylsilyl-7-tr im eth ylsiloxybicy-
clo[4.2.0]octa -1,3,5-tr ien e (13). The trimethylsiloxybenzo-
cyclobutene 3 (0.15 g, 0.50 mmol) was dissolved in dry
p-cymene (4 cm3), and the solution was heated at reflux
temperature for 1 h under argon, the reaction being followed
by TLC. The mixture was allowed to cool to room temperature,
and the solvent was removed under reduced pressure. The
residue was purified by preparative TLC to give the title
compound (0.15 g, quantitative) as a colorless oil: Rf 0.80
(hexane); IR (neat) 1250, 1107, 1077, 840 cm-1; 1H NMR (270
MHz, CDCl3) δ 0.05 (9H, s, SiMe3), 0.09 (9H, s, SiMe3), 0.95
(9H, s, t-Bu), 3.22 (1H, s, 8-H), 6.99 (1H, d, J ) 7.3 Hz, ArH),
7.05-7.1 (2H, m, ArH), 7.15-7.2 (1H, m, ArH); MS (rel
intensity) m/z 320 (M+, 5.1), 319 [(M - 1)+, 6.4], 305 [(M -
Me)+, 6.6], 263 [(M - t-Bu)+, 31], 247 [(M - SiMe3)+, 46], 147
(66), 73 (100). Calcd for Anal. C18H32OSi2: C, 67.43; H, 10.06.
Found: C, 67.71; H, 9.92.
cis-3,4,5-Tr im et h oxy-7-p h en yl-8-t r im et h ylsilyl-7-t r i-
m eth ylsiloxybicyclo[4.2.0]octa -1,3,5-tr ien e (14). Isomer-
ization of 8 (0.11 g, 0.25 mmol) in dry p-cymene (3 cm3) was
carried out following a procedure similar to that described
above for 3 to give the title compound (0.11 g, quantitative)
as a white solid; Rf 0.58 (1:10 EtOAc-hexane); mp 83-84 °C
(hexane); IR (KBr disk) 1602, 1251, 1121, 840 cm-1; 1H NMR
(270 MHz, CDCl3) δ -0.09 (9H, s, SiMe3), 0.03 (9H, s, SiMe3),
2.84 (1H, s, 8-H), 3.76 (3H, s, OMe), 3.79 (3H, s, OMe), 3.84
(3H, s, OMe), 6.30 (1H, s, 2-H), 7.15-7.2 (3H, m, Ph), 7.27
(2H, dd, J ) 8.1, 1.6 Hz, Ph); MS (rel intensity) m/z 430 (M+,
1.0), 415 [(M - Me)+, 28], 73 (100). Anal. Calcd for C23H34O4-
Si2: C, 64.14; H, 7.96. Found: C, 64.37; H, 7.75.
Ack n ow led gm en t. We thank Mrs. Miyuki Tan-
matsu of this Department for help in determining the
mass spectra.
J O982366O