Facile access to versatile polyaromatic building blocks: Selectively protected benzocyclobutenedione derivatives via regioselective [2 + 2] cycloaddition of α-alkoxybenzyne and ketene silyl acetal

Article abstract of DOI:10.1002/1522-2675(200211)85:11<3589::AID-HLCA3589>3.0.CO;2-Z

A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the regioselective [2 + 2] cycloaddition of α-alkoxybenzynes and ketene silyl acetals. The cycloadducts could be converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.

Full text of DOI:10.1002/1522-2675(200211)85:11<3589::AID-HLCA3589>3.0.CO;2-Z

Helvetica Chimica Acta Vol. 85 (2002)
3589
Facile Access to Versatile Polyaromatic Building Blocks: Selectively
Protected Benzocyclobutenedione Derivatives via Regioselective [2 ‡ 2]
Cycloaddition of a-Alkoxybenzyne and Ketene Silyl Acetal
by Toshiyuki Hamura, Takamitsu Hosoya, Hiroki Yamaguchi, Yokusu Kuriyama, Mitsujiro Tanabe,
Makoto Miyamoto, Yoshizumi Yasui, Takashi Matsumoto, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology and CREST, Japan Science and Technology
Corporation (JST), O-okayama, Meguro-ku, Tokyo 152-8551
(tel: 81-(0)3-5734-2228; e-mail; ksuzuki@chem.titech.ac.jp)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the
regioselective [2 ‡ 2] cycloaddition of a-alkoxybenzynes and ketene silyl acetals. The cycloadducts could be
converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the
synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of
sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.
Introduction.
Retrosynthetic analysis by considering latent polarity is now a
standard method in planning organic synthesis [1]. Logical disconnection by assigning
donor/acceptor characteristics greatly aids one in systematically recognizing possible
precursor structures that may be well-precedented but might be overlooked, unknown,
or deserve development. The state-of-the-art in current organic synthesis greatly owes
the umpolung concept of Seebach [2], which spurred the development of various
charge-inverted (umpoled) species, providing wider possibilities of synthetic pathways.
As a consequence of rapid advancement along these lines, an ironic situation may well
arise today, such that one might carry out a synthetic transformation even without being
aware of whether it is a natural one or an umpoled one. Another implication is the
concept of synthetic equivalents possessing variable polarities, facilitating the
formulation of versatile reagents or building blocks as a new repertoire for synthetic
transformations.
With respect to these concepts, we wish to describe a regioselective approach to a
set of isomeric compounds I and II. These are the selectively masked forms of an
intriguing species III with multiple potential reactivities, i.e., inherent polarities IIIa or
IIIb and two additional carbonyl groups.
Benzocyclobutene derivatives display unique reactivities arising from their inherent
strain [3], and, among numerous possibilities, the facile pericyclic opening to give o-
quinodimethane species [4] is key to various useful synthetic reactions. Even greater
opportunities can be expected from the congeners with a higher oxidation state, i.e.,
benzocyclobutenones and benzocyclobutenediones. The utility of some of these has
been proven by pioneering studies (for selected examples, see [5]). The progress in this
area, however, is limited by the accessibility to such highly oxidized benzocyclobutene
derivatives.

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Helvetica Chimica Acta Vol. 85 (2002)
OR
OR
OMe
OMe
O
OMe
OMe
O
I
II
OR
OR
O
O
OR
O
O
O
O
+
–
+
•
•
–
IIIa
III
IIIb
In our continuing studies on the synthesis of polyarene structures, we have
established an efficient, divergent access to benzocyclobutenedione derivatives. The
three key features of our approach are illustrated in Scheme 1: a) efficient generation of
benzyne species from o-iodo triflate precursor IV by treatment with butyllithium at low
temperature [6], b) the viability of the [2 ‡ 2] cycloaddition of the a-alkoxybenzyne V,
thus generated, to ketene silyl acetal VI, and c) the rigorous regioselectivity
consistently observed to provide a single adduct VII [7]. Importantly, all of these
aspects proved to be applicable to all substrate combinations tested, including ones
with multiple O-functionalities, thereby allowing direct access to a class of selectively
protected or selectively elaborated alkoxybenzocyclobutenediones. These, in turn,
serve as building blocks for the completed [8] or currently targeted [9] synthesis of the
polyaromatic natural products shown in the Figure.
Scheme 1
RO
RO
RO
OR'
Y
I
R'O
X
OSiMe3
Y
OSiMe3
X
BuLi
OTf
VI
VII
IV
V
Results and Discussion. For the preparation of iodo triflate derivatives 3m and
3b1), two possible routes are shown in Scheme 2. In the three-step method, conversion
of 2-iodoresorcinol (1) [10] to the corresponding bis-triflate (Tf2O, iPr2NEt, CH2Cl2),
followed by the cleavage of one of the two sulfonyl groups by treatment with cesium
carbonate in 1,2-dimethoxyethane, cleanly afforded phenol 2 in virtually quantitative
yield. Subsequent methylation (Me2SO4, K2CO3, acetone) or benzylation (BnBr,
K2CO3, DMF) of 2 produced iodo triflate 3m or 3b in high yield, respectively. This
1
)
Throughout this article, the suffix m or b designates a series of compounds having a methyl or a benzyl
protecting group.

Helvetica Chimica Acta Vol. 85 (2002)
3591
MeO
OH
HO
O
OH
MeO
OH
H
O
O
O
OH
OH
R
HO
O
O
OH
O
Gilvocarcin M (R = Me)
Gilvocarcin V (R = vinyl)
HO
TAN-1085
CO2H
O
NH
Me
O
OH
O
O
HO
HO
O
O
HO
OH
O
HO
HO
MeO
HO
O
O
HO
Aquayamycin
HO
HO
O
O
NH2
HO
HO
Pradimicin C
OH
O
O
HO
HO
OH
O
O
O
O
O
HO
MeO
O
HO
O
O
HO
OH
FD-594
MeO HO
Figure. Polyaromatic natural products synthesized or to be synthesized from alkoxybenzocyclobutenediones
protocol is attractive in terms of simplicity, applicability to large-scale synthesis, and
high yield, excep for the drawback that a molar equivalent of triflate is −wasted×.
An alternative, presumably more economical, five-step route involved dibenzoy-
lation of 1 followed by selective monosaponification to benzoate 4. Methylation or
benzylation of 4 followed by hydrolysis afforded methyl ether 5m or benzyl ether 5b,
which was converted to 3m or 3b, respectively.
Previously, we utilized a directed metallationÀiodination protocol for the synthesis
of this class of compounds (see, e.g., Scheme 3), which had problems of longer steps and
difficulty in scaling up. On the other hand, the ready availability of 2-iodoresorcinol (1)
by direct iodination of resorcinol [10] enabled us to open a more-facile access to the
benzyne precursors.

3592
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
OH
OH
I
OR
I
I
a) b)
c)
OH
OTf
OTf
1
2
3m R = Me
3b R = Bn
d) e)
h)
OH
OR
I
I
f) g)
OBz
OH
4
5m R = Me
5b R = Bn
a) Tf2O, iPr2NEt, CH2Cl2, À788 (99%). b) Cs2CO3, 1,2-dimethoxyethane, 808 (quant.). c) For 2 ! 3m:
(MeO)2SO2, K2CO3, acetone (88%); for 2 ! 3b: BnBr, K2CO3, DMF (82%). d) BzCl, pyridine, N,N-
dimethylpyridin-4-amine (DMAP). e) 2m NaOH, 1,4-dioxane (83%, 2 steps from 1). f) For 4 ! 5m:
(MeO)2SO2, K2CO3, acetone (98%); for 4 ! 5b: BnBr, K2CO3, DMF (99%). g) 1m NaOH, 1,4-dioxane (92%
for 4 ! 5m; 97% for 4 ! 5b). h) Tf2O, iPr2NEt, CH2Cl2, À788 (94% for 5m ! 3m; 90% for 5b ! 3b).
Scheme 3
OBz
OTHP
OBn
OTHP
I
I
BuLi
then I2
OMOM
OH
OR
OMOM
Divergent Access to Isomeric Benzocyclobutenedione Derivatives. The starting point
is the [2 ‡ 2] cycloaddition of an a-alkoxybenzyne to an olefin as exemplified in
Scheme 4 by V‡ 6 ! 7 [7]. Several points deserve comments: a) Ketene silyl acetals
(KSAs), easily available from the enolizationÀsilylation of various esters [11a,b] (KSAs
8, 13, and 20 were prepared by the Yamamoto method [11c]), proved to show excellent
reactivity as an olefinic component, which can be ascribed to the high HOMO level of
KSA. b) The relevant frontier orbital of benzyne is the unusually low-lying LUMO,
which is made even lower by the inductively electron-withdrawing alkoxy group [12].
These two aspects are the origin of excellent reactivities and yields observed for these
reaction partners in comparison with the parent system, i.e., ethylene and benzyne.
Such electronic perturbation in these partners is also the origin of the remarkably
rigorous regioselectivity (see Scheme 4). The cycloaddition gives product 7, in which
the silyl acetal moiety is located near the MeOgroup. The rationale shown in Scheme 4
is based on the two-step mechanism by the Fukui Hoffmann interpretation on this
particular, thermally allowed [2 ‡ 2] process [12]. The site where the primary orbital
interaction occurs for the benzyne side is distal from the ROgroup, and the attack of
the olefinic p-system forms a three-membered ring intermediate VIII that collapses to
the final four-membered ring of 7. Obvious preference in the two canonical forms,
VIIIa over VIIIb, clearly explains the regiochemical outcome. Alternatively, the two
oxy functions may offer cation stabilization sufficient for the direct generation of an

Helvetica Chimica Acta Vol. 85 (2002)
3593
Scheme 4
MeO
MeO
OEt
OSitBuMe2
H
I
EtO
H
OSitBuMe2
BuLi
+
THF, –78°
OTf
3m
7
89%
b
RO
OEt
C
EtO
H
OSiR3
H
–
RO
OSiR3
H
+
7
C
H
VIII
V
6
OEt
OEt
–
RO
–
RO
+ C OSiR3
C
OSiR3
H
+ C
H
C
H
H
VIIIb
VIIIa
open zwitterion VIIIa. However, experiments showed that the (E)/(Z) ratio of KSA is
perfectly reflected in the cis/trans composition in the product [7b], suggesting a short
lifetime of such an open zwitterion if involved2).
Leaving the rationale aside, the key aspect is that the regioselectivity proved to
persist for a variety of oxygenated KSAs, thereby enabling access to various
benzocyclobutenes of synthetic versatility as shown in Scheme 5. Upon treatment of
iodo triflate 3m in the presence of KSA 8 with BuLi (THF, À788), cycloadduct 9m was
immediately formed as a single product by the [2 ‡ 2] cycloaddition of a-alkoxyben-
zyne V and KSA 8. The perfect regioselectivity applied also in the corresponding
reaction of iodo triflate 3b, having a benzyl protecting group, to give cycloadduct 9b.
Amazingly, the more oxygenated KSA 13 also showed complete regioselectivity.
This is an intriguing observation in view of the high symmetry in tetraoxyethene 13,
which, nonetheless, gave a single cycloadduct 14m (Scheme 5). Experimentally, Et2O
(rather than THF) was the solvent of choice for the reaction of fully oxygenated olefin
13. When THF was used, though the regioselectivity remained perfect, giving only 14m,
the yield was lower (56%). Again, for the reaction with the benzyl derivative 3b,
complete regioselectivity was observed to give 14b.
The synthetic implication of these findings is that a pair of cycloadducts 9m and
14m, and their benzyl-protected congeners 9b and 14b, are formally differentially
protected alkoxybenzocyclobutenediones. Such an aspect became obvious by success-
ful conversion of these compounds to a pair of monoprotected derivatives 12m and
2
)
Theoretical calculation showed that these two cases are very close to each other, and the relative stability
delicately depends on molecular geometry as well as on the calculation level (unpublished results of Prof.
Yoshihiro Osamura and Mr. Kazuhiko Sato [13]).

3594
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 5
RO
RO
RO
Me3SiO
MeO
I
Me3SiO
OMe
OMe
OMe
a)
e)
OSitBuMe2
OTf
V
V
8
13
3m R = Me
3b R = Bn
RO
RO
RO
RO
OMe
OSiMe3
OMe
OSiMe3
OMe
OSitBuMe2
9m R = Me
OMe
14m R = Me
14b R = Bn
9b R = Bn
b)
f)
RO
O
O
OMe
OMe
10m R = Me
10b R = Bn
OH
15m R = Me
15b R = Bn
c)
RO
OMe
OMe
OMe
OMe
d)
OH
O
11m R = Me
11b R = Bn
12m R = Me
12b R = Bn
a) 8, BuLi, THF, À788. b) 46% aq. HF soln., MeCN, 0 ! 258 (10m: 68%; 10b: 75%; 2 steps). c) TsOH,
(MeO)3CH, MeOH (11m: 92%; 11b: 96%). d) Et3N, SO3 ¥ pyridine, DMSO( 12m: 94%; 12b: 95%). e) 13, BuLi,
Et2O, À788. f) Sat. aq. KF soln., Bu4NCl, MeCN, 258 (15m: 72%; 15b: 80%; 2 steps).
15m, as well as to their benzyl counterparts, 12b and 15b. Thus, the cycloadduct 14m was
easily converted to the corresponding mono-one 15m by treatment with aqueous KF
solution in MeCN (cat. Bu4NCl, 258). Similarly, the benzyl congener 14b was
hydrolyzed to mono-one 15b in high yield. On the other hand, cycloadducts 9m and 9b
could be converted in high yields to the regioisomeric mono-ones 12m and 12b, by
treatment with aqueous HF solution and MeCN (0 ! 258) ( ! hydroxy ketones 10m, b)
and subsequent acetalization and oxidation (SO3 ¥ pyridine, Et3N, DMSO).
We now have a facile entry into these attractive benzocyclobutene derivatives that
are highly oxygenated, yet selectively protected, and are, therefore, promising building
blocks awaiting synthetic utilization. Indeed, starting from benzocyclobutenone IX, we
have reported pericyclic accesses to various compounds, such as 1-arylnaphthalenes X,
including highly hindered ones [14], dihydronaphthalenes XI [15], and also eight-
membered rings XII [16] as illustrated in Scheme 6.

Helvetica Chimica Acta Vol. 85 (2002)
3595
Scheme 6
RO
RO
O
OMe
OMe
OMe
O
OMe
IX
H–
∆
RO
RO
RO
OR'
∆
MeO
XII
OMe
RO
X
OR'
XI
Synthesis of 3-(Phenylsulfonyl)phthalides. Another synthetic utility of these
selectively protected benzocyclobutene derivatives can be found in relation to the
Hauser reaction, one of the most important annelation reactions in polyaromatic
synthesis [17]. The key was our previous finding that the Baeyer Villiger oxidation of
benzocyclobutenones proceeds regioselectively with the O-insertion into the
C(1)ÀC(2) bond (Path a) rather than the C(1)ÀC(4) bond (Path b) (see Scheme 7,
XIII ! XIV). This is remarkable in view of the general order of migratory aptitude in
this class of anionotropic reaction, aryl > alkyl. This general difference in the migratory
aptitudes is explained by the presence or absence of p-participation at the stage of the
Criegee intermediate [18]. In the present Criegee intermediate XVI, however, p-
participation is inhibited by the geometrical constraints imposed by the bicyclic
structure [19]. Thus, the effect of hybridization becomes decisive, making the benzylic
C-atom (sp3) a better migrator rather than the aromatic C-atom (sp2).
Although we were unsure prior to this study whether such a tendency is valid for the
more-oxygenated benzocyclobutenones, it turned out to be the case. Scheme 8 shows
the facile syntheses of a pair of regioisomeric 3-(phenylsulfonyl)phthalides 19m (and its
benzyl congener 19b) and 23m. Thus, reduction of ketone 15m with NaBH4 followed by
acid hydrolysis gave hydroxy ketone 16m in 94% yield, which was converted to the
corresponding tert-butyldimethylsilyl ether 17m (tBuMe2SiCl, 1H-imidazole, DMF).
Upon treatment with MMPP (magnesium monoperoxyphthalate) in the presence of
Na2HPO4, silyloxy ketone 17m underwent Baeyer Villiger oxidation in a fully
regioselective manner to give phthalide 18m. None of the regioisomeric product, the

3596
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 7
BnO
BnO
O
O
4
MMPP
1
O
2
DMF, H2O
40°, 7 h
XIII
XIV 85%
BnO
CO3H
O
O
MMPP =
Mg•6H2O
–
CO2
2
XV
R
O
BnO
O
b
O
Path a
Path b
O
a
XIV
XV
H
XVI
benzofuran-2(3H)-one, was observed. Replacement of the [(tert-butyl)dimethylsilyl]-
oxy group in 18m by a phenylthio group proceeded smoothly by reaction with PhSH
under acidic conditions, and oxidation of the resulting sulfide with mCPBA afforded 3-
(phenylsulfonyl)phthalide 19m in high yield. In a similar manner, the benzyl congener
15b was also converted to the corresponding phthalide 19b in high overall yield. Two
differences should be noted, a) use of an acetate protection at the stage of 17b, and b)
use of mCPBA as the oxidant for 17b, which gave a better overall yield to phthalide 18b.
For the synthesis of the isomeric sulfonylphthalide 23m, benzocyclobutenone 21m
was used as the starting material, itself prepared by the cycloaddition of a-
methoxybenzyne (vide supra) to KSA 20 followed by acid hydrolysis. Baeyer Villig-
er oxidation of 21m with MMPP proceeded again regioselectively, giving phthalide
22m in 85% yield as a sole product. Treatment of 22m with PhSH under acidic
conditions, followed by oxidation of the resulting sulfide with mCPBA, afforded 3-
(phenylsulfonyl)phthalide 23m in high yield.
Thus, by exploiting the selective protection patterns in the isomeric benzocyclo-
butenedione derivatives, we have developed a facile, divergent access to regioisomeric
(phenylsulfonyl)phthalides, which are versatile intermediates for the synthesis of
polyaromatic compounds via the Hauser annelation reaction [17]. Indeed, these
aspects were fully exploited in the first total synthesis of aquayamycin [8c], the first aryl
C-glycoside antibiotic discovered [20][21], as outlined in Scheme 9. C-Glycosylated
iodo triflate XVII served as the starting point to carry out the synthetic transformations
discussed in this paper [8c], culminating in the long-sought target, aquayamycin
(XVIII), with high total efficiency.
In conclusion, we have developed a facile, divergent access to highly oxygenated
benzocyclobutene derivatives, via the [2 ‡ 2] cycloaddition of a-alkoxybenzynes and

Helvetica Chimica Acta Vol. 85 (2002)
3597
Scheme 8
RO
MeO
O
OSitBuMe2
H
I
MeO
MeO
OMe
OMe
OTf
15m R = Me
15b R = Bn
3m
20
a)
h) i)
RO
RO
RO
MeO
MeO
MeO
OH
O
16m R = Me
16b R = Bn
O
OMe
21m
b) or c)
j)
O
OR'
O
17m R = Me, R' = tBuMe2Si
17b R = Bn, R' = Ac
O
OMe 22m
k) l)
d) or e)
RO
O
OR'
O
SO2Ph
f) g)
O
O
SO2Ph
O
O
18m R = Me, R' = tBuMe2Si
23m
19m R = Me
19b R = Bn
18b R = Bn, R' = Ac
t
a) NaBH4, MeOH, 08, then 2m aq. HCl (16m: 94%; 16b: 92%). b) BuMe2SiCl, 1H-imidazole, DMF (16m !
17m: 95%). c) Ac2O, DMAP, pyridine (16b ! 17b: 99%). d) MMPP (see Scheme 7), Na2HPO4, DMF, H2O , 408
(17m ! 18m: 83%). e) 3-Chloroperbenzoic acid (mCPBA), Na2HPO, CH2Cl2 (17b ! 18b: 85%). f) PhSH,
TsOH, benzene reflux. g) mCPBA, CH2Cl2 (19m: 92% 2 steps from 18m; 19b: 83% 2 steps from 18b. h) BuLi,
THF, À788 (81%). i) Aq. HF soln., MeCN, 258 (93%). j) MMPP, Na2HPO4, DMF, H2O , 408 (85%). k) PhSH,
TsOH, benzene reflux. l) mCPBA, CH2Cl2 (89% 2 steps from 22m).
ketene silyl acetals. The cycloadducts and their derivatives are promising candidates for
the selective synthesis of various classes of compounds, particularly those including
polyaromatic systems. Although we have described only one example of applications in
relation to the Hauser approach, various further possibilities of these compounds would
be uncovered by careful polarity considerations.

3598
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 9
OMe
OMe
OMe
OTMS
OTf
O
O
BnO
BnO
BnO
BnO
I
BnO
BnO
BnO
XVII
O
OH
O
O
HO
O
OH
O
O
BnO
BnO
HO
HO
SO2Ph
HO
O
Aquayamycin
XVIII
Experimental Part
General. Ethereal solvents were distilled from benzophenone ketyl (ˆoxidodiphenylmethyl) immediately
before use. CH2Cl2 was distilled successively from P2O5 and CaH2, and stored over 4-ä molecular sieves. M.p.:
Yanako MP-S3 instrument; uncorrected. Flash column chromatography (FC): silica gel 60 (Art 7734, 70
230 mesh) from Merck. TLC: Merck precoated plates, silica gel 60 F254 (Art 5715, 0.25 mm). Prep. TLC: Merck
silica gel 60 PF254 (Art 7747). 1H- and 13C-NMR Spectra: Jeol JNM-lambda-300; or JNM-lambda-400
spectrometer; d in ppm, J in Hz. IR Spectra: Perkin-Elmer 1600-FT/IR-200 spectrometer; in cmÀ1
.
2-Iodoresorcinol (1) [10]. To a soln. of resorcinol (ˆ benzene-1,3-diol; 66.1 g, 0.600 mol) and I2 (163 g,
0.642 mol) in H2O(450 ml) was slowly added NaHCO (56.5 g, 0.667 mmol) in portions at 08 with vigorous
3
stirring (strong evolution of CO2). After warming to r.t., the mixture was stirred for a further 10 min. The
mixture was extracted with Et2O(3 Â), and the extract dried (Na2SO4) and evaporated. The crude product,
consisting predominantly of 1, was triturated in CHCl3 at À108 for 1 h, and filtered: pure 1 (103 g, 72.3%).
White solid. M.p. 91.2 92.58 ([10]: 107 1098 (H2O)]. 12C-NMR ((D6)acetone): 6.45 (d, J ˆ 8.1, 2 H); 6.99
(t, J ˆ 8.1, 1 H); 8.81 (s, 2 H). 1H-NMR ((D6)acetone): 75.2; 106.9; 130.2; 158.6. IR (KBr): 3546, 3354, 1582,
1490, 1456, 1354, 1304, 1278, 1249, 1185, 1158, 1022, 994, 783. Anal. calc. for C6H5IO2 (236.01): C 30.54, H 2.14;
found: C 30.75, H 2.10.
2-Iodoresorcinol Bis(trifluoromethanesulfonate). To a soln. of 1 (49.3 g, 0.209 mol) in CH2Cl2 (300 ml) were
added iPr2NEt (88 ml, 0.51 mol) and Tf2O(82 ml, 0.49 mol) at À788. After 10 min, the reaction was quenched
with H2O, the mixture extracted with Et2O(2 Â), dried (Na2SO4), and evaporated, and the residue purified by
FC (silica gel, hexane/AcOEt 92 :8): title compound (103 g, 99.0%). Recrystallization from hexane gave a white
1
solid. M.p. 34.3 36.28. H-NMR (CDCl3): 7.38 (d, J ˆ 8.3, 2 H); 7.56 (t, J ˆ 8.3, 1 H). 13C-NMR (CDCl3): 87.6,
118.7 (q, J(C,F) ˆ 320.7); 121.5; 131.0; 151.6. IR (KBr): 3101, 1573, 1447, 1426, 1220, 1141, 970, 880, 800, 758.
Anal. calc. for C8H3F6IO6S2 (545.11): C 19.21, H 0.60, S 12.81; found: C 19.30, H 0.36, S 12.56.
3-Hydroxy-2-iodophenyl Trifluoromethanesulfonate (2). To a soln. of 2-iodoresorcinol bis(trifluorometh-
anesulfonate) (103 g, 0.209 mol) in 1,2-dimethoxyethane (400 ml) was added Cs2CO3 (104 g, 0.319 mol) at r.t.
The mixture was warmed to 808 and stirred further for 3 h. After cooling to r.t., the reaction was quenched with
sat. aq. NH4Cl soln. the mixture extracted with Et2O(2 Â), the extract dried (Na2SO4) and evaporated, and the
residue purified by FC (silica gel, hexane/AcOEt 7:3): 2 (82.2 g, quant.). Colorless oil. 1H-NMR (CDCl3): 6.45
(s, 1 H); 6.90 (d, J ˆ 8.3, 1 H); 6.94 (d, J ˆ 8.3, 1 H); 7.27 (dd, J ˆ 8.3, 8.3, 1 H). 13C-NMR (CDCl3): 81.6; 113.9;
114.6; 118.6 (q, J(C,F) ˆ 320.1); 130.6; 150.2; 157.1. IR (KBr): 3487, 1595, 1571, 1462, 1451, 1418, 1297, 1175, 1137,
1028, 975, 841, 784, 731. Anal. calc. for C7H4F3SIO4 (368.07): C 22.84, H 1.10, S 8.71; found: C 22.98, H 0.94,
S 8.87.
2-Iodo-3-methoxyphenyl Trifluoromethanesulfonate (3m). To a soln. of 2 (82.1 g, 0.223 mol) in acetone
(400 ml) were added dimethyl sulfate (104 g, 0.319 mol) and K2CO3 (63.2 g, 0.457 mmol) at 08. After warming to
r.t., the mixture was further stirred for 1 h. The inorg. material was filtered off. For removal of excess dimethyl

Helvetica Chimica Acta Vol. 85 (2002)
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sulfate, Et2NH (5.5 ml) was added at 08, and the mixture was allowed to stand for 30 min. After addition of 2m
HCl, the mixture was extracted with AcOEt (2Â), the combined org. extract washed with sat. aq. NaHCO3 soln.
and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (silica gel, hexane/AcOEt 8 :2): 3m
(75.0 g, 88.0%). Recrystallization from hexane gave colorless prisms. M.p. 33.2 33.88. 1H-NMR (CDCl3): 3.93
(s, 3 H); 6.82 (dd, J ˆ 8.3, 1.0, 1 H); 6.96 (dd, J ˆ 8.3, 1.0, 1 H); 7.38 (dd, J ˆ 8.3, 8.3, 1 H). 13C-NMR (CDCl3);
57.0; 82.7; 110.1; 114.2; 118.8 (q, J(C,F) ˆ 320.6); 130.4; 151.3; 160.4. IR (KBr) 2960, 1590, 1470, 1425, 1290,
‡
‡
1270, 1230, 1210, 1130, 1060, 1020, 930, 830, 785. HR-MS: 381.8987 (C8H6F3IO4SH , M ; 381.8984).
3-(Benzyloxy)-2-iodophenyl Trifluoromethanesulfonate (3b). To a soln. of 2 (64.9 g, 0.176 mol) in DMF
(200 ml) were added BnBr (28 ml, 0.24 mol) and K2CO3 (32.5 g, 0.235 mol) at 08. The mixture was warmed to r.t.
and stirring was continued for 17 h. For removal of excess BnBr, Et2NH (12 ml) was added at 08, and the mixture
was allowed to stand for 30 min. After addition of H2O, the mixture was extracted with Et2O(2 Â) and the
combined extract washed with 2m HCl, sat. aq. NaHCO3 soln., and brine, dried (Na2SO4), and evaporated. The
residue, almost pure product, was recrystallized from hexane: 3b (66.1 g, 81.8%). White solid. M.p. 84 858.
1H-NMR (CDCl3): 5.18 (s, 2 H); 6.84 (d, J ˆ 8.3, 1 H); 6.96 (d, J ˆ 8.3, 1 H); 7.34 (dd, J ˆ 8.3, 8.3, 1 H); 7.32 7.36
(m, 1 H); 7.38 7.43 (m, 2 H); 7.47 7.50 (m, 2 H). 13C-NMR (CDCl3): 71.5; 83.4; 111.7; 114.4; 118.7 (q, J(C,F) ˆ
320.6); 127.0; 128.2; 128.7; 130.3; 135.7; 151.3; 159.4. IR (KBr): 3080, 2940, 1580, 1500, 1470, 1450, 1420, 1400,
1390, 1295, 1275, 1230, 1210, 1140, 1080, 1060, 1020, 950, 850, 830, 790, 740. Anal. calc. for C14H10F3IO4S
(368.07): C 36.70, H 2.20, S 7.00; found: C 36.81, H 2.14, S 7.30.
Ketene Silyl Acetal 13: Typical Procedure [11c]. To a soln. of tetramethylpiperidine (22.8 g, 1.61 mmol) in
THF (100 ml) was slowly added 1.56m BuLi in hexane (100 ml, 156 mmol) at 08. This mixture was stirred for
15 min and subsequently cooled to À788. Me3SiCl (19.2 g, 177 mmol) in THF (40 ml) was added, and then a
soln. of the ester (18.0 g, 134 mmol) in THF (90 ml) was slowly added over 1.2 h. The mixture was stirred for
10 min at À788 and subsequently was allowed to reach r.t. After stirring for 1 h, the soln. was diluted with
hexane (450 ml). The mixture was filtered through a Celite pad and the filtrate evaporated. Distillation of the
1
residue at 70 758/15 Torr gave 13 (19.9 g, 71.7%). H-NMR ((D6)acetone): 0.18 (s, 9 H); 3.46 (s, 3 H); 3.489
(s, 3 H); 3.493 (s, 3 H). 13C-NMR ((D6)acetone): 0.08; 57.2; 57.4; 58.5; 137.4; 140.2. IR (neat): 2961, 2938, 2834,
1463, 1442, 1237, 1195, 1127, 1049, 999, 955, 878, 848, 758.
8-Hydroxy-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (10m). To a mixture of 3m (6.39 g, 16.7 mmol)
and ketene silyl acetal 8 (6.44 g, 23.3 mmol) in THF (60 ml) was added 1.58m BuLi in hexane (15 ml, 24 mmol)
at À788. After 10 min, the reaction was stopped by adding H2O. Extractive workup (AcOEt) followed by
evaporation gave crude cycloadduct 9m. To a soln. of cycloadduct 9m (9.14 g) in MeCN (60 ml) was added 46%
aq. HF soln. (8.0 ml) at 08. After warming to r.t., the mixture was further stirred for 4 h. The reaction was
stopped by adding sat. aq. NaHCO3 soln., the mixture extracted with AcOEt, the combined org. extract washed
with brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 7 :3): 10m (1.98 g,
72.1%). Recrystallization from hexane/AcOEt gave colorless prisms. M.p. 81.6 82.58. 1H-NMR (CDCl3): 3.46
(d, J ˆ 7.3, 1 H); 4.10 (s, 3 H); 5.74 (d, J ˆ 7.3, 1 H); 6.93 (d, J ˆ 8.3, 1 H); 7.26 (d, J ˆ 7.4, 1 H); 7.54 (dd, J ˆ 7.4,
8.3, 1 H). 13C-NMR (CDCl3): 59.8; 85.1; 115.1; 117.8; 131.7; 138.6; 154.6; 156.4; 187.2. IR (KBr): 3280, 3170,
1771, 1610, 1568, 1484, 1436, 1322, 1284, 1194, 1161, 1124, 943, 812, 778. Anal. calc. for C9H8O3 (164.16): C 65.58,
H 4.90; found: C 65.72, H 4.88.
2,8,8-Trimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol (11m). To a soln. of 10m (545 mg, 3.32 mmol) in MeOH
(34 ml) were added trimethyl orthoformate (3.5 ml, 32 mmol) and TsOH ¥ H2O(63 mg, 0.33 mmol) at r.t. After
4 h, the reaction was quenched with sat. aq. NaHCO3, soln., the mixture extracted with Et2O(3 Â), dried
(Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 7:3): 11m (657 mg, 94.1%).
Recrystallization from hexane/Et2Ogave colorless prisms. M.p. 72.0 72.5 8. 1H-NMR ((D6)acetone): 3.39
(s, 3 H); 3.48 (s, 3 H); 3.84 (s, 3 H); 4.31 (d, J ˆ 10.0, 1 H); 5.01 (d, J ˆ 10.0, 1 H); 6.90 (d, J ˆ 8.3, 1 H); 6.92
(d, J ˆ 7.3, 1 H); 7.34 (dd, J ˆ 7.3, 8.3, 1 H). 13C-NMR ((D6)acetone): 52.1; 52.2; 56.0; 78.9; 108.2; 112.6; 116.2;
131.6; 132.9; 148.9; 154.7. IR (neat): 3426, 2976, 2946, 2839, 1603, 1486, 1464, 1439, 1414, 1344, 1271, 1234, 1172,
1103, 1068, 1043, 1025, 1002, 919, 799, 764, 742, 708. Anal. calc. for C11H14O4 (210.23): C 62.84, H 6.71; found:
C 62.82, H 6.82.
2,8,8-Trimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (12m). To a soln. of 11m (1.07 g, 5.09 mmol) in DMSO
(11.0 ml) were added SO3 ¥ pyridine (2.03 g, 12.7 mmol) and Et3N (3.6 ml, 26 mmol) at r.t., and further stirred
for 2 h. The reaction was quenched with H2O, and the mixture extracted with Et2O(3 Â), dried (Na2SO4), and
evaporated, and the residue purified by FC (hexane/AcOEt 94 :6): 12m (977 mg, 92.2%). Recrystallization
1
from hexane/Et2Ogave colorless prisms. M.p. 33.2 33.8 8. H-NMR (CDCl3): 3.58 (s, 6 H); 3.98 (s, 3 H); 7.06
(d, J ˆ 8.1, 1 H); 7.16 (d, J ˆ 7.6, 1 H); 7.53 (dd, J ˆ 7.6, 8.1, 1 H). 13C-NMR (CDCl3): 53.6; 56.7; 113.3; 117.0;

3600
Helvetica Chimica Acta Vol. 85 (2002)
119.0; 133.9; 145.6; 149.5; 155.4; 191.5. IR (KBr): 2974, 2943, 1771, 1594, 1506, 1489, 1457, 1350, 1272, 1232, 1053,
1018, 948, 904, 826, 808, 756, 715. Anal. calc. for C11H12O4 (208.21): C 63.45, H 5.81; found: C 63.61, H 5.62.
5-(Benzyloxy)-8-hydroxybicyclo[4.2.0]octa-1,3,5-trien-7-one (10b). To a mixture of 3b (27.8 g, 60.7 mmol)
and ketene silyl acetal 8 (21.8 g, 78.8 mmol) in THF (70 ml) was slowly added 1.57m BuLi in hexane (46.5 ml,
73 mmol) at À788 over 40 min. After 20 min, the reaction was stopped by adding pH 7 phosphate buffer.
Extractive workup (Et2O) followed by evaporation gave crude cycloadduct 9b. To a soln. of this material in
MeCN (200 ml) was added 46% aq. HF soln. (13 ml) at 08. After warming to r.t., the mixture was further stirred
for 12 h. After dilution with H2O, the mixture was extracted with Et2O, the combined org. extract washed with
sat. aq. NaHCO3 soln. and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/
AcOEt 8 :2 ! 7:3): 10b (11.0 g, 75.5%). Recrystallization from hexane/Et2Ogave colorless prisms. M.p. 75
788. 1H-NMR (CDCl3): 1.76 1.78 (m, 1 H); 3.36 3.48 (m, 1 H); 5.35 (d, J ˆ 12.2, 1 H); 5.49 (d, J ˆ 12.2, 1 H);
7.01 (d, J ˆ 8.3, 1 H); 7.26 (d, J ˆ 7.0, 1 H); 7.29 7.45 (m, 5 H); 7.54 (dd, J ˆ 7.0, 8.3, 1 H). 13C-NMR (CDCl3):
74.0; 85.0; 115.3; 118.5; 127.8; 128.3; 128.5; 131.9; 136.1; 138.7; 153.4; 156.3; 187.3. IR (KBr): 3372, 1744, 1604,
1567, 1471, 1270, 1131, 756, 702. Anal. calc. for C15H12O3 (240.26): C 74.99, H 5.03; found: C 75.02, H 5.13.
2-(Benzyloxy)-8,8-dimethoxybicyclo[4.2.0]-1,3,5-trien-7-ol (11b). To a soln. of 11b (11.0 g, 7.76 mmol) in
MeOH (500 ml) were added trimethyl orthoformate (90 ml) and TsOH ¥ H2O(880 mg, 4.63 mmol) at r.t. After
6 h, the reaction was quenched with sat. aq. NaHCO3, soln. the mixture extracted with Et2O(4 Â), dried
(Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 8 :2 ! 7:3): 11b (12.1 g, 92.0%).
Recrystallization from hexane/Et2Ogave colorless prisms. M.p. 72.0 72.5 8. 1H-NMR (CDCl3): 2.87 (d, J ˆ 10.5,
1 H); 3.49 (s, 3 H); 3.63 (s, 3 H); 5.14 (d, J ˆ 10.5, 1 H); 5.15 (d, J ˆ 12.2, 1 H); 5.20 (d, J ˆ 12.2, 1 H); 6.85
(d, J ˆ 8.5, 1 H); 7.02 (d, J ˆ 7.3, 1 H); 7.29 7.42 (m, 6 H). 13C-NMR (CDCl3): 52.2; 52.7; 70.4; 76.9; 106.5; 113.4;
116.1; 127.1; 127.9; 128.5; 130.7; 132.4; 136.7; 147.7; 152.7. IR (KBr): 3424, 2941, 1604, 1482, 1454, 1384, 1343,
1273, 1243, 1070, 1028, 763. Anal. calc. for C17H18O4 (286.33): C 71.31, H 7.34; found: C 71.47, H 6.63.
2-(Benzyloxy)-8,8-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (12b). To
a soln. of 11b (12.1 g,
42.3 mmol) in DMSO(110 ml) were added SO 3 ¥ pyridine (16.2 g, 102 mmol) and Et3N (31 ml, 224 mmol) at
r.t., and the mixture was further stirred for 1 h. The reaction was quenched with ice water, the mixture extracted
with Et2O(3 Â), dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 9 :1): 12b
(11.7 g, 97.4%). Recrystallization from hexane/Et2Ogave colorless prisms. M.p. 53 56 8. 1H-NMR (CDCl3): 3.58
(s, 6 H); 5.26 (s, 2 H); 7.10 (d, J ˆ 8.1, 1 H); 7.17 (d, J ˆ 7.6, 1 H); 7.32 7.48 (m, 5 H); 7.50 (dd, J ˆ 7.6, 8.1, 1 H).
13C-NMR (CDCl3): 53.7; 71.6; 113.7; 117.1; 120.7; 127.5; 128.2; 128.6; 133.9; 136.1; 145.8; 149.6; 154.6; 191.8. IR
(KBr): 1766, 1596, 1484, 1277, 1232, 1093, 955, 754, 701. Anal. calc. for C17H16O4 (284.31): C 71.82, H 5.67; found:
C 72.12, H 5.92.
5,8,8-Trimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (15m). To a mixture of 3m (12.9 g, 33.7 mmol) and
ketene silyl acetal 13 (8.34 g, 40.4 mmol) in Et2O(100 ml) was slowly added 1.56 m BuLi in hexane (28 ml,
44 mmol) at À788 over 1 h. After 10 min, the reaction was quenched with pH-7 phosphate buffer. Extractive
workup (Et2O) followed by evaporation gave crude cycloadduct 14m. To a soln. of this material in MeCN
(120 ml) were added sat. aq. KF soln. (4.2 ml) and Bu4NCl (0.94 g, 3.37 mmol) at r.t. After 24 h, the reaction was
stopped by adding sat. aq. NaHCO3 soln. the mixture extracted with Et2O(3 Â), dried (Na2SO4), and
evaporated, and the residue purified by FC (silica gel, hexane/AcOEt 9 :1): 15m (4.95 g, 70.5%).
Recrystallization from hexane gave colorless prisms. M.p. 39.2 39.58. 1H-NMR (CDCl3): 3.59 (s, 6 H); 4.14
(s, 3 H); 6.97 (d, J ˆ 8.3, 1 H); 7.23 (d, J ˆ 7.3, 1 H); 7.53 (d, J ˆ 7.3, 8.3, 1 H). 13C-NMR (CDCl3): 52.6; 59.9;
113.8; 114.9; 118.5; 132.9; 138.1; 155.3; 157.8; 185.8. IR (KBr): 2950, 2840, 1755, 1600, 1565, 1485, 1440, 1360,
1270, 1250, 1125, 1070, 1040, 1015, 980, 890, 800. Anal. calc. for C11H12O4 (208.21): C 63.45, H 5.81; found:
C 63.40, H 5.77.
5-(Benzyloxy)-8,8-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (15b). To
a mixture of 3b (20.8 g,
45.4 mmol) and ketene silyl acetal 13 (14.5 g, 70.2 mmol) in Et2O(170 ml) was slowly added 1.54 m BuLi in
hexane (34.1 ml, 52.5 mmol) at À788 over 30 min. After 10 min, the reaction was quenched by adding pH-7
phosphate buffer. Extractive workup (Et2O) followed by evaporation gave crude cycloadduct 14b. To a soln. of
this material in MeCN (180 ml) were added Bu4NCl (608 mg, 2.19 mmol) and sat. aq. KF soln. (5.5 ml, 87 mmol)
at 08. The mixture was stirred at r.t. for 1.5 h, and sat. aq. NaHCO3 soln. was poured into this mixture at 08.
MeCN was removed by azeotropic distillation with benzene. The mixture was extracted with Et2O(3 Â), the
combined extract washed with sat. aq. NaHCO3 soln. and brine, dried (Na2SO4), and evaporated, and the
residue purified by FC (hexane/AcOEt 95 :5 ! 93 :7 ! 91:9): 15b (10.3 g, 79.8%). Recrystallization from
1
hexane gave colorless needles. M.p. 53.5 54.08. H-NMR (CDCl3): 3.59 (s, 6 H); 5.47 (s, 2 H); 7.05 (d, J ˆ 8.3,
1 H); 7.24 (d, J ˆ 6.9, 1 H); 7.30 7.57 (m, 6 H). 13C-NMR (CDCl3): 52.6; 74.3; 114.0; 114.8; 119.1; 127.9; 128.3;
128.5; 133.0; 136.0; 138.2; 154.0; 157.7; 185.9. IR (KBr): 2940, 2850, 1765, 1600, 1565, 1450, 1415, 1390, 1355,

Helvetica Chimica Acta Vol. 85 (2002)
3601
1260, 1205, 1130, 1055, 1015, 970, 840, 810, 760. Anal. calc. for C17H16O4 (284.31): C 71.81, H 5.67; found: C 71.70,
H 5.79.
5,8-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (21m). To a mixture of 3m (1.21 g, 3.17 mmol) and
ketene silyl acetal 20 (972 mg, 4.45 mmol) in THF (10 ml) was added 1.60m BuLi in hexane (4.0 ml, 6.4 mmol) at
À788. After 10 min, the reaction was stopped by adding pH-7 phosphate buffer. The mixture was extracted with
Et2Oand the combined org. extract washed successively with brine, dried (Na 2SO4), and evaporated. The
residue was purified by FC (hexane/Et2O96 :4): cycloadduct (838 mg, 81.4%). Colorless oil. 1H-NMR (CDCl3):
À0.14 (s, 3 H); 0.04 (s, 3 H); 0.94 (s, 9 H); 3.51 (s, 3 H); 3.56 (s, 3 H); 3.86 (s, 3 H); 4.73 (s, 1 H); 6.84 (d, J ˆ 8.3,
1 H); 6.96 (d, J ˆ 6.8, 1 H); 7.32 (dd, J ˆ 6.8, 8.3, 1 H). 13C-NMR (CDCl3): À4.5; À4.0; 18.5; 25.9; 52.2; 55.5;
57.8; 86.8; 104.9; 112.3; 116.1; 132.1; 132.5; 144.6; 153.4. IR (neat): 3090, 2970, 2950, 2900, 2860, 2850, 1620, 1500,
1480, 1460, 1455, 1420, 1380, 1360, 1290, 1265, 1230, 1180, 1155, 1135, 1100, 1085, 1070, 1030, 990, 970, 935, 890,
‡
‡
860, 830, 820, 800, 785, 770, 745, 710. HR-MS: 323.1677 (C17H28OsSi , M ; calc. 323.1677).
To a soln. of the cycloadduct (161 mg, 0.496 mmol) in MeCN (1.6 ml) was added 46% aq. HF soln. (0.3 ml,
6 mmol) at 08. After warming to r.t., the mixture was further stirred for 1 h. The reaction was stopped by adding
sat. aq. NaHCO3 soln., the mixture extracted with AcOEt the combined org. extract washed successively with
sat. aq. NaHCO3 soln. and brine, dried (Na2SO4), and evaporated, and the residue purified by prep. TLC
(hexane/AcOEt 7:3): 21m (82.6 mg, 93.1%). Colorless oil. 1H-NMR (CDCl3): 3.55 (s, 3 H); 4.13 (s, 3 H); 5.52
(s, 1 H); 6.94 (d, J ˆ 8.3, 1 H); 7.24 (d, J ˆ 6.8, 1 H); 7.52 (dd, J ˆ 6.8, 8.3, 1 H). 13C-NMR (CDCl3): 56.8; 59.8;
92.0; 115.5; 117.8; 132.4; 138.1; 154.3; 155.1; 186.1. IR (neat): 3525, 3050, 3000, 2950, 2825, 1765, 1605, 1580, 1500,
‡
1450, 1430, 1380, 1295, 1220, 1080, 1135, 1070, 1020, 970, 940, 835, 820, 800, 745. HR-MS: 178.0626 (C10H10O3
M ; calc. 178.0628).
,
‡
3,7-Dimethoxyisobenzofuran-1(3H)-one (22m). To a soln. of 21m (76.7 mg, 0.430 mmol) in DMF (3.0 ml)
and H2O(0.5 ml) were added Na 2HPO4 ¥ 12 H2O(369 mg, 1.03 mmol) and MMPP ( ca. 80% purity; 441 mg,
0.71 mmol) at r.t. After warming to 408, the mixture was further stirred for 3 h. The reaction was stopped by
adding 10% aq. Na2S2O3 soln., the mixture extracted with Et2O(3 Â), dried (Na2SO4), and evaporated, and the
residue purified by prep. TLC (hexane/AcOEt 5 :5): 22m (71.0 mg, 84.9%). Recrystallization from hexane/
AcOEt gave colorless needles. M.p. 62.3 63.18. 1H-NMR (CDCl3): 3.60 (s, 3 H); 4.00 (s, 3 H); 6.21 (s, 1 H); 7.02
(d, J ˆ 8.3, 1 H); 7.12 (d, J ˆ 7.8, 1 H); 7.66 (dd, J ˆ 7.8, 8.3, 1 H). 13C-NMR (CDCl3): 56.1; 56.3; 101.7; 112.6;
114.2; 115.0; 136.7; 147.2; 158.3; 166.5. IR (KBr): 3050, 2950, 2875, 1785, 1620, 1500, 1465, 1450, 1390, 1360, 1325,
1300, 1255, 1200, 1135, 1080, 1070, 1040, 995, 970, 945, 880, 840, 805, 780, 700. Anal. calc. for C10H10O4 (194.19):
C 61.80, H 5.20; found: C 61.85, H 5.19.
7-Methoxy-3-(phenylthio)isobenzofuran-1(3H)-one. To a soln. of 22m (27.1 mg, 0.140 mmol) in benzene
(3.0 ml) were added benzenethiol (120 mg, 1.09 mmol) and TsOH ¥ H2O(108 mg, 0.568 mmol) at r.t. The soln.
was heated under reflux in a Dean Stark apparatus for 2 h. The cooled mixture was successively washed with 1m
NaOH and brine, dried (Na2SO4), and evaporated, and the residue purified by prep. TLC (hexane/AcOEt 5 :5):
title compound (35.2 mg, 92.6%). White powder. 1H-NMR ((D6)acetone); 3.91 (s, 3 H); 6.90 (s, 1 H); 7.10
(d, J ˆ 8.8, 1 H); 7.26 (d, J ˆ 7.8, 1 H); 7.30 7.76 (m, 6 H). 13C-NMR ((D6)acetone): 56.4; 85.3; 112.9; 114.3;
116.0; 129.5; 129.9; 131.7; 134.0; 137.4; 149.8; 159.3; 166.6. IR (KBr): 3075, 3000, 2850, 1780, 1605, 1500, 1440,
‡
‡
1300, 1255, 1215, 1195, 1095, 1070, 1020, 970, 835, 780, 745. HR-MS: 272.0496 (C15H12O3S , M ; calc. 272.0505).
7-Methoxy-3-(phenylsulfonyl)isobenzofuran-1(3H)-one (23m). To a soln. of 7-methoxy-3-(phenylthio)-
isobenzofuran-1(3H)-one (132 mg, 0.483 mmol) in CH2Cl2 (2.0 ml) was added mCPBA (ca. 80% (w/w); 302 mg,
1.2 mmol) at r.t. After 1 h, the solid 3-chlorobenzoic acid was removed by filtration, the filtrate was washed with
10% aq. Na2S2O3 soln., sat. aq. NaHCO3 soln., and brine, dried (Na2SO4), and evaporated, and the residue
purified by FC (hexane/AcOEt 5 :5): 23m (136 mg, 92.6%). Recrystallization from hexane/acetone gave
1
colorless prisms. M.p. 187.7 188.08. H-NMR (CDCl3): 3.96 (s, 3 H); 6.10 (s, 1 H); 7.05 (d, J ˆ 8.3, 1 H); 7.50
7.87 (m, 7 H). 13C-NMR (CDCl3): 56.2; 89.8; 113.2; 113.3; 116.5; 129.2; 129.7; 134.6; 134.9; 137.1; 141.6; 158.7;
165.4. IR (KBr): 3200, 2875, 1790, 1600, 1495, 1465, 1450, 1335, 1300, 1245, 1210, 1195, 1160, 1090, 1075, 1040,
‡
1000, 950, 825, 785, 775, 755, 730. HR-MS: 304.0388 (C15H12O5S, M ; calc. 304.0404).
8-Hydroxy-2-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (16m). To a soln. of NaBH4 (116 mg, 3.07 mmol)
in MeOH (1 ml) was added ketone 15m (382 mg, 1.83 mmol) in MeOH (5.0 ml) at 08. After the consumption of
15m (TLC monitoring), 4m HCl (2.2 ml) was added to the mixture at 08. After 20 min, the mixture was
neutralized with sat. aq. NaHCO3 soln., and extracted with AcOEt, the combined org. extract washed
successively with sat. aq. NaHCO3 soln. and brine, dried (Na2SO4), and evaporated, and the residue purified by
FC (hexane/AcOEt 7:3): 16m (281 mg, 93.3%). Recrystallization from hexane/Et2Ogave colorless prisms. M.p.
1
83.0 83.68. H-NMR (CDCl3): 4.00 (d, J ˆ 7.8, 1 H); 4.05 (s, 3 H); 5.87 (d, J ˆ 7.8, 1 H); 7.05 (d, J ˆ 7.8, 1 H);
7.07 (d, J ˆ 7.8, 1 H); 7.47 (dd, J ˆ 7.8, 7.8, 1 H). 13C-NMR (CDCl3): 57.3; 85.6; 113.5; 121.8; 133.4; 141.4; 148.8;

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Helvetica Chimica Acta Vol. 85 (2002)
156.6; 191.7. IR (KBr): 3400, 3100, 3000, 2960, 2860, 1745, 1605, 1590, 1500, 1445, 1350, 1270, 1245, 1180, 1165,
1095, 1060, 1050, 985, 900, 840, 815, 780, 735. Anal. calc. for C9H8O3 (164.16): C 65.58, H 4.90; found: C 65.85,
H 4.91.
8-{[(tert-Butyl)dimethylsilyl]oxy}-2-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (17m). To a soln. of 16m
(102 mg, 0.621 mmol) in DMF (4 ml) were added tBuMe2SiCl (357 mg, 1.30 mmol) and 1H-imidazole (123 mg,
1.81 mmol) at 08. After 40 min, the reaction was stopped by pouring the mixture into pH-7 phosphate buffer at
08. The mixture was extracted with Et2O, the combined org. extract washed with brine, dried (Na2SO4), and
evaporated, and the residue purified by FC (hexane/AcOEt 9 :1): 17m (165 mg, 95.4%). Colorless oil. 1H-NMR
(CDCl3): 0.20 (s, 3 H): 0.21 (s, 3 H); 0.94 (s, 9 H); 4.01 (s, 3 H); 5.85 (s, 1 H); 7.02 (d, J ˆ 7.8, 1 H); 7.06 (d, J ˆ 7.3,
1 H); 7.44 (dd, J ˆ 7.3, 7.8, 1 H). 13C-NMR (CDCl3): À5.0; À4.4; 18.2; 25.7; 57.2; 86.0; 113.3; 121.2; 133.0; 142.2;
148.8; 156.6; 190.7. IR (neat): 2950, 2900, 2870, 1775, 1605, 1580, 1490, 1465, 1440, 1415, 1395, 1355, 1275, 1235,
‡
‡
1195, 1170, 1110, 1060, 1040, 1010, 985, 945, 875, 845, 810, 790. HR-MS: 278.1341 (C15H22O3Si , M ; calc.
278.1337).
3-{[(tert-Butyl)dimethylsilyl]oxy}-4-methoxyisobenzofuran-1(3H)-one (18m). To a soln. of 17m (48.1 mg,
0.173 mmol) in DMF (1.2 ml) and H2O(0.5 ml) were added Na 2HPO4 ¥ 12H2O(185 mg, 0.517 mmol) and
MMPP (ca. 80% purity; 128 mg, 0.21 mmol) at r.t. After 15 min, the reaction was stopped by pouring the
mixture into pH-7 phosphate buffer at 08. The mixture was extracted with Et2O, the combined org. extract
washed successively with sat. aq. Na2S2O3 soln., sat. aq. NaHCO3 soln., and brine, dried (Na2SO4), and
evaporated, and the residue purified by prep. TLC (hexane/AcOEt 8 :2): 18m (42.1 mg, 82.8%). Recrystalliza-
tion from hexane gave colorless prisms. M.p. 75.4 76.28. 1H-NMR (CDCl3): 0.20 (s, 3 H); 0.26 (s, 3 H); 0.96
(s, 9 H); 3.91 (s, 3 H); 6.63 (s, 1 H); 7.11 (d, J ˆ 8.3, 1 H); 7.43 (d, J ˆ 7.3, 1 H); 7.51 (dd, J ˆ 7.3, 8.3, 1 H).
13C-NMR (CDCl3): À5.2; À4.5; 18.1; 25.4; 55.5; 96.7; 115.9; 116.9; 128.7; 132.3; 135.1; 155.2; 168.9. IR (KBr):
2940, 2860, 1790, 1775, 1620, 1500, 1470, 1390, 1360, 1315, 1290, 1280, 1260, 1215, 1190, 1125, 1055, 1010, 965, 905,
860, 845, 815, 790, 755, 710. Anal. calc. for C15H22O4Si (294.42): C 61.19, H 7.53; found: C 61.06, H 7.60.
4-Methoxy-3-(phenylthio)-isobenzofuran-1(3H)-one. To a soln. of 18m (104 mg, 0.354 mmol) in benzene
(3.5 ml) were added benzenethiol (202 mg, 1.84 mmol) and TsOH ¥ H2O(90.1 mg, 0.474 mmol) at r.t., and the
soln. was heated under reflux in a Dean Stark apparatus. After 40 min, the soln. was cooled to r.t., and diluted
with Et2O(15 ml). The org. phase was washed with 1m NaOH, dried (Na2SO4), and evaporated. Purification by
prep. TLC (hexane/AcOEt 6 :4) gave the title compound (93.9 mg, 97.6%). Recrystallization from hexane gave
colorless needles. M.p. 88.2 88.58. 1H-NMR (CDCl3): 4.00 (s, 3 H); 6.66 (s, 1 H); 7.10 (d, J ˆ 7.8, 1 H); 7.19 7.28
(m, 3 H); 7.32 (d, J ˆ 7.3, 1 H); 7.41 7.47 (m, 3 H). 13C-NMR (CDCl3): 55.9; 84.8; 115.7; 117.0; 128.1; 128.9;
128.9; 130.0; 131.9; 133.4; 134.4; 154.3; 169.0. IR (KBr): 3070, 3010, 2950, 2850, 1780, 1610, 1495, 1470, 1440,
1350, 1275, 1230, 1180, 1090, 1065, 1035, 970, 905, 880, 825, 780, 770, 755, 740. Anal. calc. for C15H12O3S (272.32):
C 66.16, H 4.44; found: C 65.95, H 4.59.
4-Methoxy-3-(phenylsulfonyl)isobenzofuran-1(3H)-one (19m). To a soln. of 4-methoxy-1(3H)-isobenzo-
furan-3-(phenylthio)-one (159 mg, 0.585 mmol) in CH2Cl2 (5.0 ml) was added mCPBA (ca. 80% (w/w); 372 mg,
ca. 1.5 mmol) at r.t. After 1.5 h, the reaction was stopped by adding 10% aq. Na2S2O3 soln. The mixture was
extracted with AcOEt, the combined org. extract washed successively with sat. aq. NaHCO3 soln. and brine,
dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 5 :5): 19m (168 mg, 94.5%).
Recrystallization from AcOEt gave colorless prisms. M.p. 185.1 185.38. 1H-NMR (CDCl3): 3.99 (s, 3 H); 6.31
(s, 1 H); 7.24 (d, J ˆ 8.3, 1 H); 7.42 (d, J ˆ 7.3, 1 H); 7.51 7.56 (m, 2 H); 7.59 (dd, J ˆ 7.3, 8.3, 1 H); 7.65 7.70
(m, 1 H); 7.86 7.89 (m, 2 H). 13C-NMR (CDCl3): 56.4; 90.2; 117.0; 117.7; 127.0; 128.3; 129.2; 129.8; 133.5; 134.7;
135.4; 156.0; 167.6. IR (KBr): 3100, 2990, 2890, 1800, 1620, 1590, 1505, 1470, 1450, 1345, 1330, 1305, 1290, 1185,
‡
‡
1170, 1100, 1090, 1040, 1020, 925, 835, 800, 775, 760, 740. HR-MS: 304.0380 (C15H12O5S , M ; calc. 304.0404).
2-(Benzyloxy)-8-hydroxybicyclo[4.2.0]octa-1,3,5-trien-7-one (16b). To soln. of NaBH4 (3.06 g,
a
72.6 mmol) in MeOH (60 ml) was added 15b (10.3 g, 36.2 mmol) in THF (60 ml) at À788 over 20 min. The
mixture was warmed to 08 over 75 min, and stirring was continued for 20 min. After the consumption of 15b
(TLC monitoring), 4m HCl (90 ml) was added at 08, and the mixture was warmed to r.t. After 30 min. sat. aq.
NaHCO3 soln. was poured into this mixture at 08. After MeOH was removed by azeotropic distillation with
benzene, the mixture was extracted with AcOEt (3Â), the combined extract washed with sat. aq. NaHCO3 soln.
and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 76 :24): 16b (8.03 g,
92.3%). Recrystallization from hexane/AcOEt gave white needles. M.p. 94 958. 1H-NMR (CDCl3): 4.03 4.12
(m, 1 H); 5.40 (d, J ˆ 12.2, 1 H); 5.49 (d, J ˆ 12.2, 1 H); 5.76 (d, J ˆ 7.6, 1 H); 7.06 (d, J ˆ 7.6, 1 H); 7.13 (d, J ˆ
8.3, 1 H); 7.31 7.48 (m, 6 H). 13C-NMR (CDCl3): 71.6; 85.7; 113.8; 122.9; 127.2; 128.2; 128.7; 133.4; 136.6; 141.3;
148.7; 155.7; 191.5. IR (KBr): 3346, 3095, 3059, 2923, 1769, 1604, 1568, 1483, 1448, 1384, 1346, 1264, 1231, 1142,
1041, 1028. Anal. calc. for C15H12O3 (240.26): C 74.98, H 5.04; found: C 74.76, H 5.26.

Helvetica Chimica Acta Vol. 85 (2002)
3603
8-(Acetoxy)-2-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one (17b). To a soln. of 16b (8.03 g, 33.5 mmol)
in pyridine (25 ml) were added Ac2O(6.2 ml, 65.6 mmol) and a cat. amount of DMAP (204 mg, 1.68 mmol) at
08. After the mixture was stirred for 15 min, the reaction was quenched by adding a small amount of H2O . The
soln. was diluted with AcOEt, the org. layer washed with sat. aq. CuSO4 soln. and sat. aq. Na2SO4 soln., dried
(Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 8 :2 ! 75 :25): 17b (9.38 g, 99.3%).
1
Colorless oil (solidified in a refrigerator as a white solid). M.p. 43 458. H-NMR (CDCl3): 2.14 (s, 3 H); 5.19
(s, 2 H); 6.77 (s, 1 H); 7.14 (d, J ˆ 7.9, 1 H); 7.17 (d, J ˆ 7.9, 1 H); 7.32 7.41 (m, 5 H); 7.52 (dd, J ˆ 7.9, 7.9, 1 H).
13C-NMR (CDCl3): 20.7; 71.0; 84.2; 113.8; 122.2; 127.0; 128.2; 128.7; 133.9; 135.9; 137.8; 150.1; 155.2; 169.4;
185.3. IR (neat): 2940, 1770, 1735, 1600, 1480, 1210, 1025. Anal. calc. for C17H14O4 (282.30): C 72.33, H 5.00;
found: C 72.06, H 5.28.
3-Acetoxy-4-(benzyloxy)isobenzofuran-1(3H)-one (18b). To a suspension of mCPBA (ca. 80% (w/w);
3.91 g, 18.1 mmol) and Na2HPO4 ¥ 12 H2O(8.34 g, 22.7 mmol) in CH 2Cl2 (17 ml) was added 17b (4.26 g,
15.1 mmol) in CH2Cl2 (30 ml) at 08. After the mixture was stirred for 10 min, 10% aq. Na2S2O3 soln. was added.
The mixture was stirred for 10 min and then diluted with AcOEt. Sat. aq. NaHCO3 soln. was added, the mixture
extracted with AcOEt (3Â), the combined extract washed with 10% aq. Na2S2O3 soln., sat. aq. NaHCO3 soln.
and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 8 :2): 18b (3.81 g,
84.6%). Recrystallization from hexane/AcOEt gave white needles. M.p. 126.5 127.58. 1H-NMR (CDCl3): 2.13
(s, 3 H); 5.21 (s, 2 H); 7.20 (d, J ˆ 8.1, 1 H); 7.34 7.42 (m, 5 H); 7.49 7.59 (m, 3 H). 13C-NMR (CDCl3): 20.6;
70.3; 91.0; 117.50; 117.54; 126.9; 128.3; 128.4; 128.7; 131.9; 133.2; 135.6; 154.1; 167.9; 169.0. IR (KBr): 2945, 1884,
1790, 1758, 1616, 1490, 1393, 1283, 1221, 1052, 1016. Anal. calc. for C17H14O5 (298.30): C 68.45, H 4.73; found:
C 68.51, H 4.65.
4-(Benzyloxy)-3-(phenylthio)isobenzofuran-1(3H)-one. A soln. of 18b (3.72 g, 12.5 mmol), benzenethiol
(6.4 ml, 62 mmol), and TsOH ¥ H2O(387 mg, 2.03 mmol) in benzene (100 ml) was refluxed for 2.2 h in a Dean
Stark apparatus. To this mixture was added TsOH ¥ H2O(600 mg, 3.15 mmol), and the reaction was completed
by stirring for another 50 min under reflux. The soln. was cooled to 08, diluted with Et2O, washed with 0.5m
NaOH and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 8 :2): title
compound (3.87 g, 89.1%). Recrystallization from hexane/AcOEt gave white needles. M.p. 92.5 93.58.
1H-NMR (CDCl3): 5.24 (d, J ˆ 12.2, 1 H); 5.30 (d, J ˆ 12.2, 1 H); 6.69 (s, 1 H); 7.15 7.58 (m, 13 H). 13C-NMR
(CDCl3): 70.4; 85.2; 117.0; 117.2; 127.2; 128.3; 128.3; 128.7; 128.87; 128.90; 130.2; 131.9; 133.8; 134.4; 135.9;
153.2; 169.0. IR (KBr): 3089, 3084, 3025, 2899, 2857, 1760, 1613, 1498, 1466, 1295, 1275, 1089, 1039. Anal. calc. for
C21H16O3S (348.42): C 72.39, H 4.63, S 9.20; found: C 72.14, H 4.84, S 9.09.
4-(Benzyloxy)-3-(phenylsulfonyl)isobenzofuran-1(3H)-one (19b). To a soln. of 4-(benzyloxy)-3-(phenyl-
thio)isobenzofuran-1(3H)-one (3.72 g, 10.7 mmol) in CH2Cl2 (70 ml), mCPBA (ca. 80% (w/w); 6.22 g,
28.9 mmol) was slowly added at 08. The mixture was stirred for 1 h at r.t., and 10% aq. Na2S2O3 soln. was added
at 08. After the mixture was stirred for 5 min and diluted with AcOEt, sat. aq. NaHCO3 soln. was added, the
mixture extracted with AcOEt (3Â), the combined extract washed with 10% aq. Na2S2O3 soln., sat. aq.
NaHCO3 soln., and brine, dried (Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt
7:3 ! 6 :4): 19b (3.77 g, 92.8%). Recrystallization from hexane/AcOEt gave a white solid. M.p. 131 1328.
1H-NMR (CDCl3): 5.26 (d, J ˆ 12.2, 1 H); 5.34 (d, J ˆ 12.2, 1 H); 6.34 (s, 1 H); 7.26 (d, J ˆ 8.3, 1 H); 7.85 7.90
(m, 12 H). 13C-NMR (CDCl3): 70.9; 90.2; 117.8; 118.2; 127.3; 128.3; 128.7; 129.1; 129.8; 133.4; 134.7; 135.2; 135.6;
155.0; 167.5. IR (KBr): 2965, 1780, 1610, 1500, 1335, 1145, 1015. Anal. calc. for C21H16O5S (380.42): C 66.30,
H 4.24, S 8.43; found: C 66.19, H 4.44, S 8.29.
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Received June 7, 2002