Impressive changeover of reaction course in ring expansion of styrylbenzocyclobutenol under alkoxide-forming conditions

Article abstract of DOI:10.1016/j.tetlet.2006.06.079

Impressive changeover of the reaction course was observed in the rearrangement of styrylbenzocyclobutenol derivative 1. While the thermal reaction gave naphthalene 2, the base-promoted reaction gave the isomeric product 3 in high yield.

Full text of DOI:10.1016/j.tetlet.2006.06.079

Tetrahedron Letters 47 (2006) 6677–6679
Impressive changeover of reaction course in ring expansion of
styrylbenzocyclobutenol under alkoxide-forming conditions
Isao Takemura, Takashi Matsumoto and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and SORST, Japan Science and Technology Agency (JST),
2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan
Received 27 April 2006; revised 12 June 2006; accepted 15 June 2006
Available online 28 July 2006
Abstract—Impressive changeover of the reaction course was observed in the rearrangement of styrylbenzocyclobutenol derivative 1.
While the thermal reaction gave naphthalene 2, the base-promoted reaction gave the isomeric product 3 in high yield.
Ó 2006 Elsevier Ltd. All rights reserved.
In relevance to the synthesis of polycyclic aromatic
MeO
OH
toluene
110 °C
natural products, we have described in the preceding
letter an approach for constructing phenylnaphthalene
structures via the ring enlargement of styrylbenzocyclo-
butenols under thermal conditions (Scheme 1).1 Two
isomeric starting materials A and B, differing in the con-
nectivity of the styryl unit (a or b) and the benzocyclo-
butene unit, could be converted to closely related
structures C and C0, which share the same skeleton,
but with complementary protection pattern.
OMe
73%
MeO
MeO
MeO
OH
MeO
2
OMe OMe
MeO
OH
OMe
MeO
1
LDA, THF
then, H3O+
OMe
In contrast to the convergency of this process, described
herein is its divergency, which was unexpectedly found in
continuing studies (Scheme 2; 1!3). Thus, simple heat-
ing of benzocyclobutenol 1 in refluxing toluene gave the
quant
OMe
3
Scheme 2.
RO
OMe
expected phenylnaphthalene 2.2 The same reaction was
attempted under the base-promoted conditions, hoping
to gain rate acceleration effect, if any. Indeed, upon con-
version of 1 to the corresponding lithium alkoxide
(LDA, THF, ꢀ78 °C), the starting material 1 was
smoothly consumed during the warmup to 0 °C in 2 h.
Unexpectedly, however, the product isolated in quanti-
tative yield was isomer 3, after careful quenching with
2 M aqueous hydrochloric acid. The structure of 3 was
assigned by extensive NOE study (Fig. 1).3 Note the dif-
ference in the locations of the aryl groups in 2 and 3.
Herein, we feature the origin of this unexpected result,
involving an intriguing skeletal rearrangement.
OMe
HO
RO
OR'
OR"
A
B
preceding
paper
RO
OH
C : R' = Me, R" = H (from A)
C': R' = H, R" = Me (from B)
OMe
OMe
Scheme 1.
For gaining insight into the reaction mechanism, label-
ing experiments were carried out. Upon subjection of
*
Corresponding author. Tel.: +81 5734 2228; fax: +81 3 5734 2788;
e-mail: ksuzuki@chem.titech.ac.jp
13
the C-labeled substrate 1* to the reaction conditions
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.079

6678
I. Takemura et al. / Tetrahedron Letters 47 (2006) 6677–6679
8.99 ppm (s)
3.67 ppm (s)
4.08 ppm (s)
H3C
O
H3C
O
H
O
H
6.99 ppm
(d, J = 7.8 Hz)
OCH3
H
7.80 ppm
(d, J = 8.5 Hz)
H
O
6.65 ppm (s)
3.87 ppm (s)
CH3
(
: NOE)
Figure 1. NOE study of compound 3.
as stated above, the final location of the labeled carbon
in 3* was as shown in Scheme 3, clearly indicating that
the fission of the C(1)–C(a) bond was involved.2
Figure 2. ORTEP drawing of the X-ray structure of 5.4
Subsequent fate of tricyclic intermediate III depends on
the method of quenching (Scheme 6). In the case of the
acid quenching, phenol 3 was the product, which could
be explained by the acid activation of the dimethyl ace-
tal to induce the cleavage of cyclopropanol as in IV. By
contrast, quenching with water gave acid-sensitive cyclo-
propanol 4, which manifests another key aspect in the
present skeletal rearrangement to 3. Furthermore, it is
interesting to note that quenching with MeOH (0 °C)
gave indanone 6 in quantitative yield. Use of MeOD fur-
nished deuterated 6 as indicated. The diverse modes of
the cyclopropane cleavage are related to the well-known
tautomeric behavior of cyclopropanols under basic con-
ditions.6 Conversion of 4 was also promoted by treat-
ment with Et3N in D2O, giving indanone 6 deuterated
at the benzylic position.
TLC-Monitoring suggested the presence of an interme-
diate in this puzzling reaction. Upon careful quenching
with water, the unstable intermediate was identified
as cyclopropanol 4 (Scheme 4). Since 4 was unstable
toward chromatographic purification (SiO2), we
attempted to trap it as a stable derivative. After some
experimentation, quenching of the reaction with
Me3SiCl, rather than aqueous HCl, enabled us to obtain
silyl ether 5, which gave nice single crystals for X-ray
analysis (Fig. 2).4 Thus, the intermediate was proven
to be tricyclic compound 4, in which the 2,6-dimethoxy-
phenyl group is disposed to the exo direction.
Based on these data, a possible mechanism could be
drawn (Scheme 5). Assuming an ionic mechanism, the
first step would be the alkoxide-induced 1,2-shift of the
acetal carbon, that is C(2), to generate transient benzyl
anion II, which counterattacks the carbonyl group to
give cyclopropanolate III.5
Finally, we examined the generality of this reaction. Ta-
ble 1 shows the comparison of the reactions under ther-
mal/basic conditions for the related substrates 1b–d with
different aromatic moieties (Ar). We found the thermal
MeO
MeO
MeO
MeO
O–
MeO
–
O
β
MeO
MeO
OH
O
β
OH
1
Ar
1
–
Ar
Ar
α
LDA / THF
α
OMe
OMe OMe
2
OMe
then
2 M HCl aq.
2
OMe
H
OMe
OMe
OMe
MeO
II
MeO
III
OMe
I
1*
:
13C-label)
3*
Scheme 5.
6.65 ppm (d,
/acetone-d6
J13C-H = 157.7 Hz)
(
H
–
MeO
MeO
MeO
OH
O
Scheme 3.
O
Ar
Ar
Ar
OMe
H3O+
H2O
MeO
OH
Ar
+
OMe
OMe
MeO
MeO
MeO
H
H
H2O, 0 °C
4
III
IV
OMe
MeO
4
Et3N, D2O
1,4-dioxane
MeOH (MeOD)
1
LDA, THF,
–78 °C rt
MeO
MeO
OH
MeO
O
OSiMe3
H
H
Ar
Ar
H(D)
Ph
Me3SiCl
OMe
–78 °C (77%)
MeO
OMe
MeO
5
OMe
6
3
Scheme 4.
Scheme 6.

I. Takemura et al. / Tetrahedron Letters 47 (2006) 6677–6679
6679
Table 1.
MeO
MeO
O
MeO
OH
MeO
method A
method B
LDA, THF;
then 2 M HCl aq
ii, BuLi
THF, –78 ºC
OH
Ar
toluene, 110 ˚C
OMe
OMe
OMe
MeO
OMe
OMe
7
OMe
9
MeO
1b–d
MeO
H
OMe
MeO
MeO
OH
OH
OH
Ar
LiAlH4
THF
OMe OMe
MeO
12C, 8*:
Ar
OMe
8:
=
=
13C
OMe
OMe
1 92%, 2 steps
3b–d
2b–d
3. Conversion to the corresponding quinone derivative 10 was
Run
1
Ar
Method
Yield (%)
2:3
the additional structure proof.
Me
MeO
O
MeO
A
B
96
90
2b only
2:98
(NH4)2Ce(NO3)6
3
OMe
aq. MeCN, 0 °C
MeO
MeO
10
98%
O
2
3
Aa
B
88
46
2c only
7:93
MeO
OMe
Me
Me
A
B
79
79
2d only
38:63
Me
a See Ref. 7.
10
ORTEP drawing of quinone 10.4
reactions (method A) invariably afforded the expected
products 2b–d, while the base-promoted conditions led
to mixtures of products 3b–d accompanied by variable
amounts of ‘thermal products’ 2b–d.
4. Crystallographic data (excluding structure factors) for the
structures in this letter have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 243852 (for compound 5) and
244793 (for compound 10). Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1 EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
5. Since considerable data have been accumulated for the role
of homolytic processes in the related system, the corre-
sponding radical-based mechanism also could be possible,
including homolysis of the four-membered ring to form a
diradical 11 followed by recombination via 12.
In conclusion, we have described an impressive change-
over of reaction course in the rearrangement of styryl-
benzocyclobutenol derivative 1, which is not only
interesting from mechanistic standpoints, but also have
implication related to the synthesis of polyaromatic nat-
ural products.
O–
MeO
O–
MeO
Acknowledgments
Ar
Ar
Thanks are due to Professors Daisuke Uemura
(Nagoya) and Tohru Fukuyama (Tokyo) for helpful
suggestions. We thank Mr. M. Bando, Otsuka Pharma-
ceutical Co., for X-ray analysis. Partial financial
support by 21st Century COE Program is gratefully
acknowledged.
OMe
OMe
OMe
MeO
12
11
Roth, W. R.; Rekowski, V.; Bo¨rner, S.; Quast, M. Liebigs
Ann. Chem. 1996, 409–430; Paul, T.; Boese, R.; Steller, I.;
Bandmann, H.; Gescheidt, G.; Korth, H.-G.; Sustmann, R.
Eur. J. Org. Chem. 1999, 551–563.
6. Gibson, D. H.; DePuy, C. H. Chem. Rev. 1974, 74, 605–624.
7. Compound 13 was also obtained in 10% yield as a side
product.
References and notes
1. Takemura, I.; Imura, K.; Matsumoto, T.; Suzuki, K., see
preceding paper. Tetrahedron Lett. 2006, 47, doi:10.1016/
j.tetlet.2006.06.078.
MeO
O
OMe
OMe
2. Compound 1 was prepared by reaction of ketone 7 and the
anion from alkyne 8 followed by hydroalumination. 13C-
Labeled substrate 1* was prepared by using the labeled
alkyne 8*.
OMe
OMe OMe
13