Tandem Pummerer-Diels-Alder reaction sequence. A novel cascade process for the preparation of 1-arylnaphthalene lignans

Article abstract of DOI:10.1021/jo960295s

The α-thiocarbocation generated from the Pummerer reaction of an o-benzoyl-substituted sulfoxide is intercepted by the adjacent keto group to produce an α-thio isobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloadditio

Full text of DOI:10.1021/jo960295s

3706
J . Org. Chem. 1996, 61, 3706-3714
Ta n d em P u m m er er -Diels-Ald er Rea ction Sequ en ce. A Novel
Ca sca d e P r ocess for th e P r ep a r a tion of 1-Ar yln a p h th a len e
Lign a n s†
Albert Padwa,* J ohn E. Cochran, and C. Oliver Kappe
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received February 13, 1996X
The R-thiocarbocation generated from the Pummerer reaction of an o-benzoyl-substituted sulfoxide
is intercepted by the adjacent keto group to produce an R-thio isobenzofuran as a transient
intermediate which undergoes a subsequent Diels-Alder cycloaddition with added dienophiles.
Acid-catalyzed ring-opening of the cycloadduct followed by aromatization gave an arylnaphthalene
derivative. With acetylenic dienophiles, the tandem cyclization-cycloaddition sequence provided
tetralones which result from a pinacol-type rearrangement of the primary cycloadducts. The
versatility of the approach is highlighted through the synthesis of taiwanin C and E and justicidin
E. The R-thiocarbocation generated from the Pummerer reaction of benzo[1,3]dioxol-5-yl-[6-
[(ethylsulfinyl)methyl]benzo[1,3]dioxol-5-yl)methanone is intercepted by the adjacent keto group
to produce an R-thioisobenzofuran as a transient intermediate which undergoes a subsequent Diels-
Alder cycloaddition with dimethyl maleate. The initially formed Diels-Alder cycloadduct was
readily converted to 5-benzo[1,3]dioxol-5-yl-8-(ethylthio)naphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic
acid dimethyl ester by loss of water on treatment with p-toluenesulfonic acid. Desulfurization of
the thionaphthalene with Ra/Ni followed by hydrolysis of the less hindered methyl ester afforded
5-benzo[1,3]dioxol-5-ylnaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid 6-methyl ester which was
further transformed into taiwanin C and justicidin E in good yield. Oxidation of the initial Diels-
Alder cycloadduct with NaIO4 in the presence of RuCl3 followed by extrusion of ethyl sulfinate
gave a naphthol derivative which can be converted into taiwanin E.
The Pummerer rearrangement has been widely studied
the Pummerer intermediate.21,22 De Groot and co-work-
ers23 recently developed an efficient procedure for buteno-
lide formation in which the key step involves a Pummerer
induced cyclization of aldehydic sulfoxides of type 1 into
butenolides 3. It was assumed that the neighboring
carbonyl group attacks the initially formed thionium ion
to give an oxy-stabilized cation 2 which loses a proton to
generate a 2-thio-substituted furan24 which is subse-
quently converted to the butenolide upon hydrolysis.
and has received considerable attention as a synthetically
useful process.1-3 R-Acyl thionium ions generated from
R-acyl sulfoxides under Pummerer conditions are power-
ful electrophiles, reacting efficiently with nucleophilic
carbon species. Bimolecular addition of the cation to
various carbon-carbon double bonds is well known.4 In
the realm of natural product synthesis, most success has
been achieved using intramolecular Friedel-Crafts cy-
clization of the Pummerer thionium ion intermediate.5-20
Far fewer examples exist for heteroatom interception of
† This paper is dedicated to Professor Paul Dowd on the occasion of
his 60th birthday.
X Abstract published in Advance ACS Abstracts, May 15, 1996.
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lignans has prompted us to examine various methods for
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S0022-3263(96)00295-2 CCC: $12.00 © 1996 American Chemical Society

Tandem Pummerer-Diels-Alder Reaction Sequence
J . Org. Chem., Vol. 61, No. 11, 1996 3707
Sch em e 1
Sch em e 2
with MnO2 in CH2Cl2 afforded the desired keto sulfide
11 in quantitative yield.
An alternative protocol that was also used for the
preparation of sulfide 11 is shown in Scheme 3. The
readily available 2-(bromomethyl)benzonitrile (12)33 was
converted into nitrile 13 by reaction with ethanethiol in
the presence of DBU.32 Further treatment of 13 with
phenylmagnesium bromide in toluene provided, after
acidic workup, the desired keto sulfide 11 in 95% overall
yield from 12.
In the third method (Scheme 4), commercially available
phthalide was allowed to react with sodium ethanethio-
late in refluxing ethanol which resulted in the formation
of 2-[(ethylthio)methyl]-benzoic acid (15) in 90% yield.34
Conversion of carboxylic acid 15 into the Weinreb amide
16 was accomplished by successive treatment of 15 with
thionyl chloride and N,O-dimethylhydroxylamine in 80%
yield.35 Coupling of amide 16 with phenylmagnesium
bromide under the usual reaction conditions35 produced
keto sulfide 11 in 94% yield. The analogous methyl
ketone 17 was prepared similarly by treating 16 with
methylmagnesium bromide in 96% yield.
the construction of the phenylnaphthyl skeleton.25 In
particular, we have been interested in the internal
trapping of the Pummerer cation with an adjacent
carbonyl group (De Groot protocol23) as a method to
prepare isobenzofurans and subsequently aryl lignans.26-31
The main features of our strategy are illustrated in
Scheme 1. The R-thiocarbocation generated from the
Pummerer reaction of an o-benzoyl-substituted sulfoxide
of type 4 is intercepted by the adjacent keto group to
produce an R-thioisobenzofuran 5 as a transient inter-
mediate which undergoes a subsequent Diels-Alder
cycloaddition. The resulting cycloadduct 6 should be
readily converted to representatives of several arylnaph-
thalene lignans 7. In this paper we describe results
which verify the underlying viability of this approach to
the aryl lignan skeleton.
Resu lts a n d Discu ssion
In order to have ready access to the requisite sulfox-
ides, we have developed three independent routes for
their preparation. In the first method (Scheme 2),
commercially available 2-bromobenzyl bromide (8) was
converted to sulfide 9 using ethanethiol and DBU in
benzene.32 Metal-halogen exchange of bromide 9 with
t-BuLi in THF below -90 °C followed by quenching of
the lithiate with benzaldehyde at low temperature pro-
duced alcohol 10 in 96% yield. It is important to use
these exact experimental conditions since the reaction
with n-BuLi at -78 °C was sluggish and produced
mixtures of starting material, the final product, and
miscellaneous side-products. Oxidation of alcohol 10
This method is particularly useful since carboxylic acid
15 can be prepared in large quantities and can serve as
an intermediate for the preparation of other acid analogs
(i.e. amides, esters) which we have employed in related
Pummerer-based transformations.36 Finally, the oxida-
tion of sulfides 11 and 17 to the desired sulfoxides 18
and 19 was carried out in very high yield using NaIO4
as the oxidizing reagent.37 To test the viability of the
proposed tandem Pummerer-Diels-Alder cascade proc-
ess, sulfoxides 18 and 19 were treated with a suitable
dienophile under standard Pummerer reaction condi-
tions.2 Thus, heating a sample of the sulfoxide at 140
°C with acetic anhydride resulted in the formation of
cycloadducts 21-24 in 64-87% yield as mixtures of
diastereomers. When an unactivated dienophile such as
cyclohexene was used (high lying LUMO), the cyclo-
addition reaction proceeded in low yield. This is presum-
(25) For a preliminary report see: Cochran, J . E.; Padwa, A. J . Org.
Chem. 1995, 60, 3938.
(26) Biftu, T.; Gamble, N. F.; Doebber, T.; Hwang, S. B.; Shen, T.
Y.; Snyder, J .; Sringer, J . P.; Stevenson, R. J . Med. Chem. 1986, 29,
1917.
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F. E.; Williams, M.; Saenz-Renauld, J . A.; Brown, P.; Schmidt, J . M.;
Ellis, P. D. J . Org. Chem. 1984, 49, 4258.
(28) Ayres, D. C. Chemistry of Lignans; Rao, C. B. S., Ed.; Andhra
Univ. Press: India, 1978; pp 123-173.
(29) Gottlieb, O. R. New Natural Products and Plant Drugs with
Pharmacological, Biological, or Therapeutical Activity; Wagner, H.,
Wolf, P., Eds.; Springer-Verlag: Berlin, 1977; p 227.
(30) Wada, K.; Munakata, K. Tetrahedron Lett. 1970, 2017.
(31) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23, 1207.
(32) Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980, 952.
(33) Cassidy, P. E.; Wallace, R. J .; Aminabhavi, T. M. Polymer 1986,
27, 1131.
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1973, 38, 1596.
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a review on the chemistry of Weinreb amides see: Sibi, M. P. Org.
Prep. Proced. Int. 1993, 25, 15.
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(37) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.

3708 J . Org. Chem., Vol. 61, No. 11, 1996
Padwa et al.
Sch em e 3
ably due to a poor FMO-matching of the frontier molec-
ular orbitals. Diels-Alder adducts 21-24 are stable
solids which were isolated and handled in conventional
fashion. Prolonged storage or treatment with acid,
however, resulted in the formation of aromatized prod-
ucts (vide infra).
Sch em e 4
The intermediacy of the highly reactive R-thioiso-
benzofuran 20 in this reaction was established through
the isolation and NMR identification of the phenyl
derivative 20a .38 By employing somewhat more gentle
conditions for triggering the Pummerer reaction (i.e.
toluene-Ac2O-p-TsOH),39 we were able to obtain 20a as
a stable intermediate in toluene solution. Addition of
N-phenylmaleimide to this bright yellow solution at 0 °C
resulted in spontaneous decoloration and formation of
cycloadduct 21 as a single diastereomer (endo) in 82%
isolated yield. Isobenzofuran 20a is sensitive to air and
moisture and reacts with oxygen to form ketone 25.40
to produce the naphthalene derivative 26 in 72% overall
yield from sulfoxide 18.
Since the cycloaddition step of the cascade process
proceeds at 0 °C, we attempted to trigger the Pummerer
reaction at a lower temperature. Indeed, by using
trifluoroacetic anhydride/triethylamine as the Pummerer
promotor,41 we were able to obtain cycloadduct 20a as
the endo diastereomer in 80% yield starting from sulf-
oxide 18 and N-phenylmaleimide at 0 °C. When p-
toluenesulfonic acid was added to the crude reaction
mixture, ring-opening followed by aromatization occurred
(38) For an alternative generation and cycloadditions of R-thio-
isobenzofurans of type 20, see: Bailey, J . H.; Coulter, C. V.; Pratt, A.
J ., Robinson, W. T. J . Chem. Soc., Perkin Trans. 1 1995, 589.
(39) Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kuma-
moto, T. Bull. Chem. Soc. J pn. 1981, 54, 817.
(40) For some reviews on isobenzofurans, see: Friedrichsen, W. Adv.
Heterocycl. Chem. 1981, 26, 135. Rickborn, B. Advances in Theoretically
Interesting Molecules; Thummel, R. P., Ed.; J AI Press: Greenwich, CT,
1989; Vol. 1, p 1. Friedrichsen, W. In Houben-Weyl, Methoden der
Organischen Chemie; Kreher, R., Ed.; Thieme Verlag: Stuttgart, 1994;
Vol. E6b, pp 163-216.
Acetylenic dienophiles did not give the expected cyclo-
adduct 27 but instead afforded the rearranged tetralone
derivative 29 (or 30). Thus, treatment of 18 with acetic
anhydride in the presence of dimethyl acetylenedicar-
boxylate gave tetralone 29 in 38% isolated yield. An
(41) Sharma, A. K.; Swern, D. Tetrahedron Lett. 1974, 1503.

Tandem Pummerer-Diels-Alder Reaction Sequence
J . Org. Chem., Vol. 61, No. 11, 1996 3709
analogous reaction occurred using methyl propiolate
producing tetralone 30 as the exclusive product in 51%
isolated yield. The structure of 30 was assigned on the
basis of its spectral data and was unambiguously estab-
lished by an X-ray crystal analysis.42 The mechanism of
this unusual reaction has not been unequivocally proven,
but one reasonable possibility is outlined below. Here it
is proposed that the cyclization-cycloaddition sequence
40 natural arylnaphthalenes, the majority of which are
lactones of general type 7, are known and represent a
significant subclass of lignans.48 Although a wide variety
of methods have been utilized for the synthesis of this
class of natural products,49-51 the key step for the
construction of the phenylnaphthyl skeleton can be
classified roughly into two methodologies. The first relies
on assembling the B-ring of the naphthalene nucleus via
the annulation of a properly substituted benzene deriva-
tive followed by an aromatization process.52 The second
approach is the joining of the pertinent aryl and naphthyl
units via conjugate addition to a butenolide followed by
reaction with an aldehyde.53 These methods generally
require a number of steps for construction of the 1-aryl-
naphthalene skeleton.
The versatility of the tandem Pummerer-Diels-Alder
cascade approach has been highlighted through the
synthesis of taiwanin C and E and justicidin E, naturally
occurring arylnaphthalene lignans which possess all the
functionality of podophyllotoxin26 around a central aro-
matic ring. The requisite ketosulfoxide 34 was synthe-
sized starting from piperonyl alcohol 31 which was
converted to 6-bromopiperonyl bromide 32 (92%) using
a modified literature procedure.54 The bromide was
treated with ethanethiol and 1,8-diazabicycloundecene
(DBU) in benzene to produce the corresponding ethyl
sulfide in 93% yield. Metal-halogen exchange took place
cleanly with t-BuLi below -90 °C producing an orange
colored lithiate that was quenched with a THF solution
of piperonal to give the expected alcohol 33 in 90% yield.
Oxidation to the benzophenone derivative was accom-
plished using MnO2 in 92% yield. Further oxidation of
the sulfide functionality was carried out with NaIO4 in
the usual manner37 to produce sulfoxide 34 in an overall
yield of 62% (five steps). Heating sulfoxide 34 with
dimethyl maleate in acetic anhydride at reflux following
the standard reaction conditions employed with our
model systems led to a dark brown mixture. Extensive
silica gel chromatography resulted only in a low yield
(<35%) of the aromatized product 36. The cascade
reaction sequence, however, could be dramatically im-
proved by slowly adding an acetic anhydride solution of
sulfoxide 34 to a refluxing solution of dimethyl maleate
in acetic anhydride. Not only were the yields consistently
higher (i.e. 85%), but also only cycloadduct 35 was
obtained and none of the aromatized compound 36 was
formed. Further reaction of 35 with p-toluenesulfonic
acid in CH2Cl2 at 25 °C afforded the R-thio-substituted
produces the expected cycloadduct 27 which then re-
arranges to 29 (or 30) via intermediate 28. The key step
involves oxabicyclic ring opening which is driven by the
lone pair of electrons on the sulfur atom, and this is
followed by a pinacol type rearrangement of 28 proceed-
ing by way of a 1,2-phenyl shift.43 The formation of
adduct 30 as a single regioisomer is consistent with FMO
theory.44 The most favorable FMO interaction is between
the HOMO of the isobenzofuran and the LUMO of methyl
propiolate. The atomic coefficient at the ethylthio-
substituted position in the isobenzofuran ring is larger
than at the phenyl position in the HOMO and this nicely
accommodates the high regioselectivity encountered.45
The model studies described above clearly demonstrate
that the Pummerer reaction of o-benzoyl sulfinylmethyl
aromatics of type 18 represents an effective method for
the preparation of the isobenzofuran ring system. Isoben-
zofurans are highly reactive dienes for Diels-Alder
cycloadditions, and this reactivity has been exploited in
the synthesis of biologically active polycyclic aromatic
compounds.46 In this approach, the oxygen bridge in the
initially formed cycloadduct can be easily cleaved to
produce an aryl naphthalene derivative. Due to their
widespread occurrence in nature and broad range of
biological activity, aryl-substituted naphthalenes have
attracted considerable synthetic attention over the
years.26-31 Much interest has been focused on their
effectiveness as antineoplastic agents, and research in
this area has revealed several modes of action by which
they can regulate the growth of mammalian cells.47 Over
(47) Gonzales, A. G.; Darias, V.; Alonso, G. Planta Med. 1979, 36,
200. Massanet, G. M.; Pando, E.; Rodriguez-Lius, F.; Zubia, E.
Fitotherapia 1989, LX, 3.
(48) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75. Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977.
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Rep. 1987, 503.
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Harrowven, D. C.; Dennison, S. T. Tetrahedron Lett. 1993, 34, 3323.
(51) Epsztajn, J .; J o´zwiak, A.; Szczesniak, A. Tetrahedron 1993, 49,
929. Iwao, M.; Inque, H.; Kuraishi, T. Chem. Lett. 1984, 1263. De Silva,
S. O.; St. Denis, C.; Rodrigo, R. J . Chem. Soc., Chem. Commun. 1980,
354. Kobayashi, K.; Kanno, Y.; Seko, S.; Suginome, H. J . Chem. Soc.,
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Commun. 1980, 995. Takano, S.; Otaki, S.; Ogasawara, K. Tetrahedron
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Commun. 1976, 50. Seko, S.; Tanabe, Y.; Suzukamo, G. Tetrahedron
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(42) The authors have deposited coordinates for structure 30 with
the Cambridge Data Centre. The coordinates can be obtained from the
Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
(43) Rickborn, B. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 3, pp 721-731.
(44) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(53) Meyers, A. I.; Avila, W. B. J . Org. Chem. 1981, 46, 3881. Hattori,
T.; Satoh, S.; Miyano, S. Bull. Chem. Soc. J pn. 1993, 66, 3840. Oi, S.;
Matsunaga, K.; Hattori, T.; Miyano, S. Synthesis 1993, 895. Ogiku,
T.; Seki, M.; Takahashi, M.; Ohmizu, H.; Iwasaki, T. Tetrahedron Lett.
1990, 31, 5487. Harrowven, D. C. Tetrahedron 1993, 49, 9039.
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(45) FMO coefficients were determined with MOPAC 6.0 using the
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(46) Rodrigo, R. Tetrahedron 1988, 44, 2093.

3710 J . Org. Chem., Vol. 61, No. 11, 1996
Padwa et al.
naphthalene 36 in 98% yield. Desulfurization of 36 with
Ra-Ni produced naphthalene 37 (>97%), which on
treatment with KOSiMe3,55 resulted in selective attack
on the less hindered ester functionality giving rise to the
half acid-ester 38 in nearly quantitative yield. Selective
reduction of an ester in the presence of a carboxylic
acid56-59 is usually a facile process. We therefore did not
expect any difficulty in reducing each functionality in 38
selectively to produce the regioisomeric lignans taiwanin
C (39) and justicidin E (40). The carboxylic acid func-
tionality in 38, however, proved to be unusually suscep-
tible to reduction. Thus, treatment of the half acid-ester
38 with LiEt3BH led selectively to the reduction of the
carboxylic acid, which after acidic workup, gave taiwanin
C (39)60 in 68% yield (56% overall yield from 34). The
carboxylic acid could also be reduced by a variety of other
reducing agents including NaBH4 in refluxing dioxane.
On the other hand, LiBH4 in dioxane did reduce the ester
functionality (albeit with low selectivity) but also led to
an over-reduced product (i.e. a diol). Selective reduction
of the ester functionality was ultimately achieved by an
initial deprotonation of 38 using 2 equiv of NaH followed
by the addition of 2 equiv of LiBH4 and subsequent
heating of the mixture at reflux in dioxane for 2 h. This
procedure resulted a 65% yield of a 4:1 mixture of
justicidin E (40) and taiwanin C (39).
The above results prompted us to also investigate the
conversion of cycloadduct 35 into taiwanin E (43). The
selective transformation of cycloadduct 35 to naphthalene
36 is presumably driven by the lone pair of electrons on
the sulfur atom which induces regioselective C-O bond
cleavage and further loss of a molecule of water. It
seemed reasonable to assume that oxidation of the sulfide
group in 35 to the corresponding sulfone (i.e. 41) would
prevent this type of ring-opening and thereby promote
an alternative mode of ring cleavage resulting in the
ejection of ethyl sufinate to give naphthol 42. After some
experimentation we found that the oxidation of sulfide
35 to sulfone 41 could best be achieved using NaIO4
containing a catalytic amount of RuCl3 at 0 °C.61 This
procedure worked exceedingly well for our system pro-
ducing sulfone 41 in essentially quantitative yield.
Treatment of the crude sulfone 41 with p-TsOH in CH2Cl2
promoted the desired elimination to give naphthol 42 in
65% overall yield from sulfoxide 34. The synthesis of
naphthol 42 completes the formal synthesis of taiwanin
E (43), since 42 can be readily converted to the natural
product in one step using NaBH4.62
In conclusion, we have demonstrated that the tandem
Pummerer-Diels-Alder cyclization-cycloaddition se-
quence is well suited for the preparation of a variety of
naturally occurring 1-arylnaphthalene lignans. The
required sulfoxide precursors can be obtained in high
overall yield by several routes and different methods for
triggering the desired Pummerer reaction may be em-
ployed. The combination of these factors makes the
cascade process extremely useful. Further work utilizing
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Trans. 1 1973, 1266.

Tandem Pummerer-Diels-Alder Reaction Sequence
J . Org. Chem., Vol. 61, No. 11, 1996 3711
of 2-bromobenzyl bromide in 100 mL of benzene was added
dropwise. The mixture was stirred overnight at rt, diluted
with benzene, and poured into 5% HCl. The aqueous layer
was extracted with benzene, the resulting solution was dried
over Na2SO4 and concentrated in vacuo, and the residue was
chromatographed on silica gel to give 10.8 g (94%) of 2-[(ethyl-
thio)methyl]bromobenzene (9) as a colorless oil: IR (neat) 3058,
2970, 1569, 1468, 1439 cm-1 1H-NMR (CDCl3, 300 MHz) δ
;
1.25 (t, 3H, J ) 7.4 Hz), 2.50 (q, 2H, J ) 7.4 Hz), 3.84 (s, 2H),
7.09 (td, 1H, J ) 7.7 and 1.6 Hz), 7.25 (ddd, 1H, J ) 7.7, 7.4,
and 1.0 Hz), 7.36 (dd, 1H, J ) 7.4 and 1.6 Hz), and 7.55 (dd,
1H, J ) 7.7 and 1.0 Hz); 13C-NMR (CDCl3, 75 MHz) δ 14.5,
25.6, 36.1, 124.4, 127.3, 128.4, 130.6, 132.0, 138.0. HRMS
Calcd for C9H11BrS: 229.9765. Found: 229.9761.
In a 250 mL, flame-dried, round-bottomed, three-necked
flask equipped with a low temperature thermometer was
dissolved 10.4 g (45.0 mmol) of the above bromide in 70 mL of
THF. The solution was cooled to -90 °C and 40 mL of 1.2 M
t-BuLi solution (66.0 mmol) was added maintaining the
temperature at -90 °C. The solution was stirred for 15 min
at -90 °C, and then a solution of 4.6 mL (45.3 mmol) of
benzaldehyde in 20 mL of THF was added to the mixture. The
solution was stirred overnight at 25 °C, concentrated under
reduced pressure, poured into a 5% HCl solution, and extracted
with CH2Cl2. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was chro-
matographed on silica gel to give 11.18 g (96%) of [2-[(ethyl-
thio)methyl]phenyl]phenylmethanol (10) as a light yellow oil:
IR (neat) 3406, 3062, 1602, 1493, 1451 cm-1; 1H-NMR (CDCl3,
300 MHz) δ 1.20 (t, 3H, J ) 7.4 Hz), 2.44 (q, 2H, J ) 7.4 Hz),
3.23 (d, 1H, J ) 3.4 Hz), 3.67 (d, 2H, J ) 13.0 Hz), 3.74 (d,
2H, J ) 13.0 Hz), 6.20 (d, 1H, J ) 3.4 Hz), 7.18-7.37 (m, 9H);
13C-NMR (CDCl3, 75 MHz) δ 14.4, 25.7, 33.4, 72.4, 126.6, 127.2,
127.5, 127.6, 128.2, 128.6, 130.4, 135.4, 142.1, 142.8. HRMS
(FAB) Calcd for C16H18OS: 265.1238. Found: 265.1233 (M +
Li).
these thioisobenzofuran-derived cycloadducts as low cy-
totoxicity precursors of intercalating agents is in progress,
and the results of these studies will be reported in due
course. We are also investigating the generality of the
cascade process for the construction of aza-polycyclic ring
systems and its further application in target-oriented
synthesis.
In a 250 mL, flame-dried, round-bottomed flask was dis-
solved 9.55 g (40.0 mmol) of the above alcohol in 100 mL of
CH2Cl2. To this solution was added 31.9 g (313 mmol) of
activated MnO2 (85%), and the black slurry was stirred for 3
days. The mixture was filtered through a plug of silica gel,
the filtrate was evaporated under reduced pressure, and the
residue was chromatographed on silica gel to give 8.79 g (93%)
of [2-[(ethylthio)methyl]phenyl]phenylmethanone (11) as a pale
Exp er im en ta l Section
Diethyl ether, tetrahydrofuran, benzene, toluene, and xylene
were distilled from sodium benzophenone ketyl prior to use.
Dichloromethane and triethylamine were distilled from CaH2
prior to use. All reactions were performed under an atmo-
sphere of dried argon unless otherwise noted.
Gen er a l P r oced u r e for Ta n d em P u m m er er Cycliza -
tion Diels-Ald er Cycloa d d ition Sequ en ce. In a 250 mL,
flame-dried, round-bottomed flask, a sample of Weinreb’s
amide 16 (vide infra) was dissolved in THF. The solution was
cooled to 0 °C, and an excess of the appropriate Grignard
reagent in THF was added dropwise. The solution was stirred
overnight, poured into 5% HCl, and extracted with a 50%
mixture of Et2O/CH2Cl2. The organic extract was dried over
MgSO4, concentrated under reduced pressure, and chromato-
graphed on silica gel to give the appropriate thio-substituted
ketone, 11 or 17. This compound was dissolved in methanol,
and the mixture was added to a solution of NaIO4 in H2O at 0
°C. The mixture was stirred for 1 h at 0 °C and then at rt
until the starting material was no longer evident by TLC. The
mixture was poured into H2O and extracted with CH2Cl2. The
organic extract was dried over Na2SO4 and evaporated under
reduced pressure to give the crude sulfoxide. The sulfoxide
was purified by silica gel chromatography. The appropriate
sulfoxide was dissolved in acetic anhydride in a flame-dried,
25 mL, round-bottomed flask. The dienophile was added and
the mixture was heated at reflux under an inert atmosphere.
The solution was cooled and concentrated under reduced
pressure, and the residue was taken up in CH2Cl2 and washed
with a saturated aqueous NaHCO3 solution. The organic layer
was dried over Na2SO4 and concentrated under reduced
pressure, and the resulting crude cycloadduct was chromato-
graphed on silica gel with 1% Et3N added.
1
yellow oil: IR (neat) 3062, 2927, 1665, 1598, 1449 cm-1; H-
NMR (CDCl3, 300 MHz) δ 1.11 (t, 3H, J ) 7.4 Hz), 2.37 (q,
2H, J ) 7.4 Hz), 3.87 (s, 2H), 7.25-7.33 (m, 2H), 7.39-7.47
(m, 4H), 7.55-7.60 (m, 1H), 7.79-7.83 (m, 2H); 13C-NMR
(CDCl3, 75 MHz) δ 14.3, 25.7, 33.1, 126.2, 128.3, 129.2, 130.1,
130.2, 130.5, 133.0, 137.8, 138.4, 138.6, 198.0. HRMS (FAB)
Calcd for C16H16OS: 263.1082. Found: 263.1083 (M + Li).
A sample of sulfide 11 was also prepared from 2-[(ethylthio)-
methyl]benzonitrile (13). A mixture containing 2.83 g (18.0
mmol) of DBU, and 1.12 g (18.0 mmol) of ethanethiol in 10
mL of THF was added to a solution of 2.91 g (14.8 mmol) of
2-(bromomethyl)benzonitrile (12)33 in 20 mL of THF. After
stirring for 5 h, the precipitate that formed was filtered and
the filtrate was passed through a plug of silica gel to give 2.60
g (99%) of 13 as a colorless oil: IR (neat) 3065, 2225, 1598,
1
1485 cm-1; H-NMR (CDCl3) δ 1.25 (t, 3H, J ) 7.4 Hz), 2.49
(q, 2H, J ) 7.4 Hz), 3.90 (s, 2H), 7.32-7.63 (m, 4H); 13C-NMR
(CDCl3) δ 14.1, 25.5, 33.7, 112.1, 117.3, 127.2, 129.7, 132.5,
132.5, 142.6. A solution of phenylmagnesium bromide in 20
mL of ether was prepared from 486 mg (20.0 mmol) of Mg
powder and 3.14 g (20.0 mmol) of bromobenzene. Most of the
solvent was removed under reduced pressure, and this was
followed by the addition of 10 mL of toluene. A solution of
2.46 g (13.9 mmol) of nitrile 13 in 5 mL of toluene was added
to the hot solution, and the mixture was heated at reflux for
15 min. After cooling to rt, 3 mL of H2O followed by 10 mL of
2 N H2SO4 was added, and the mixture was heated at reflux
for 1 h in order to hydrolyze the initially formed imine. The
mixture was extracted with CH2Cl2 and the organic layer was
washed with 2 N NaOH, brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification by flash
chromatography gave 3.42 g (96%) of sulfide 11.
P r ep a r a t ion of [2-[(E t h ylsu lfin yl)m et h yl]p h en yl]-
p h en ylm eth a n on e (18). In a 250 mL, flame-dried, round-
bottomed flask equipped with a dropping funnel was placed
3.90 mL (52.7 mmol) of ethanethiol in 100 mL of benzene. To
this solution was added 7.20 mL (48.1 mmol) of 1,8-diazabicyclo-
[5.4.0]un-dec-7-ene, and then a solution of 12.4 g (49.7 mmol)

3712 J . Org. Chem., Vol. 61, No. 11, 1996
Padwa et al.
A 1.28 g (5.00 mmol) sample of sulfide 11 was treated with
1.18 g (5.51 mmol) of NaIO4 dissolved in 25 mL of CH3OH and
25 mL of water to give 1.55 g (99%) of [2-[(ethylsulfinyl)methyl]-
phenyl]phenylmethanone (18) as a colorless oil: IR (neat)
solution was cooled in an ice-bath, and then 190 mg (1.1 mmol)
of N-phenylmaleimide in 5 mL of toluene was added. The
resulting mixture was stirred for 10 min at 0 °C and was then
immediately washed with a saturated aqueous NaHCO3 solu-
tion. The organic phase was dried over Na2SO4 and evapo-
rated under reduced pressure to give 350 mg (82%) of
1-(ethylthio)-8,11-diphenyl-11-aza-14-oxatetracyclo[6.5.1.02,709,13]-
tetradeca-2,4,6-triene-10,12-dione (21) as a white solid after
chromatographic purification: mp 180-181 °C; IR (neat) 3067,
2948, 1667, 1599, 1450 cm-1 1H-NMR (CDCl3, 300 MHz) δ
;
1.29 (t, 3H, J ) 7.5 Hz), 2.61-2.79 (m, 2H), 4.20 (d, 1H, J )
12.7 Hz), 4.38 (d, 1H, J ) 12.7 Hz), 7.33-7.61 (m, 3H), 7.79
(dd, 1H, J ) 8.1 and 1.2 Hz); 13C-NMR (CDCl3, 75 MHz) δ 6.5,
45.1, 55.1, 127.2, 128.1, 130.0, 130.3, 130.8, 131.0, 132.2, 132.9,
137.5, 137.7, 197.4. HRMS Calcd for C16H16OS: 273.0946.
Found: 273.0934.
1779, 1717, 1598, 1501 cm-1 1H-NMR (CDCl3, 300 MHz) δ
;
1.40 (t, 3H, J ) 7.5 Hz), 2.81-2.98 (m, 2H), 3.96 (d, 1H, J )
8.4 Hz), 4.16 (d, 1H, J ) 8.4 Hz), 6.46-6.49 (m, 2H), 7.04 (d,
1H, J ) 7.3 Hz), 7.23-7.27 (m, 3H), 7.29 (td, 1H, J ) 7.3 Hz
and 1.2 Hz), 7.38 (td, 1H, J ) 7.3 Hz and 0.9 Hz), 7.46-7.53
(m, 4H), 7.93-7.97 (m, 2H); 13C-NMR (CDCl3, 75 MHz) δ 15.4,
24.4, 54.3, 54.8, 90.6, 95.0, 121.2, 121.5, 126.2, 127.0, 128.4,
128.6, 128.6, 128.7, 128.8, 135.9, 140.3, 144.6, 171.4, 172.9.
HRMS (FAB) Calcd for C26H22NO3S: 428.1320. Found:
428.1326 (M + H+).
P r ep a r a t ion of 1-[2-[(E t h ylsu lfin yl)m et h yl]p h en yl]-
eth a n on e (19). In a 1 L round-bottomed flask was placed
22.1 g (165 mmol) of phthalide in 400 mL of 95% ethanol. To
this solution was added 14 g (166 mmol) of sodium ethane-
thiolate, and the mixture was heated at reflux for 3 h. The
solution was concentrated under reduced pressure, and the
resulting solid was dissolved in a saturated NaHCO3 solution
and washed with ethyl acetate. The aqueous layer was
acidified with concentrated HCl, and the solid was filtered,
washed with water, and dried to give 28.3 g (90%) of pure 15
as a white solid: mp 105-106 °C; IR (KBr) 2961, 1674, 1567,
An NMR spectrum of 1-(ethylthio)-3-phenylisobenzofuran
(20a ) could be obtained by subjecting the bright yellow solution
of 20a obtained above to rapid flash chromatogaphy followed
by removal of the solvent under reduced pressure. The
resulting yellow oil (95%) obtained by this procedure can be
stored under an argon atmosphere in solution for several hours
before decomposition occurs: 1H-NMR (CDCl3) δ 1.27 (t, 3H,
J ) 7.2 Hz), 2.83 (q, 2H, J ) 7.2 Hz), 6.97 (m, 2H), 7.28 (dd,
1H, J ) 7.6 Hz), 7.45 (dd, 2H, J ) 7.6 Hz), 7.50 (m, 1H), 7.61
(m, 1H), 7.89 (dd, 2H, J ) 7.6 and 1.2 Hz); 13C-NMR (CDCl3)
δ 15.6, 31.5, 119.6, 119.9, 121.1, 124.9, 125.0, 125.1, 127.2,
128.8, 131.0, 131.4, 136.5, 147.6. On prolonged exposure to
atmospheric conditions, the transient isobenzofuran 20a was
converted into 2-benzoylthiobenzoic acid S-ethyl ester (25).
Purification by flash silica gel chromatography afforded 167
mg (62%) of pure 25 as a colorless oil: IR (CDCl3) 1771, 1665,
1
1389 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.23 (t, 3H, J ) 7.4
Hz), 2.48 (q, 2H, J ) 7.4 Hz), 4.20 (s, 2H), 7.32-7.40 (m, 2H),
7.49 (td, 1H, J ) 7.4 and 1.3 Hz), 8.08 (dd, 1H, J ) 7.2 and
0.9 Hz), 11.85 (br s, 1H); 13C-NMR (CDCl3, 75 MHz) δ 14.4,
25.7, 34.2, 127.0, 128.0, 131.1, 132.0, 132.7, 141.8, 173.2. Anal.
Calcd for C10H12O2S: C, 61.19; H, 6.17. Found: C, 60.97; H,
6.21.
In a 250 mL, flame-dried, round-bottomed flask was placed
a mixture of 9.82 g (50.04 mmol) of the above acid in 100 mL
of benzene, and then 7.3 mL (100.1 mmol) of thionyl chloride
was added and the mixture was stirred at rt for 12 h. The
solvent was removed under reduced pressure, and the result-
ing oil was dissolved in 200 mL of CH2Cl2 and 5.48 g (55.05
mmol) of N,O-dimethylhydroxylamine hydrochloride was added.
The mixture was cooled to 0 °C, and 9.30 g (115.0 mmol) of
pyridine was added dropwise. After stirring at 25 °C for 3 h,
the mixture was extracted with ether and washed with brine.
The organic layer was dried over MgSO4, concentrated under
reduced pressure, and chromatographed on silica gel to give
9.62 g (80%) of N-methoxy-N-methyl 2-[(ethylthio)methyl]-
benzamide (16) as a colorless oil: IR (neat) 2925, 1645, 1595,
1
1282, 1207 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.12 (t, 3H, J
) 7.5 Hz), 2.87 (q, 2H, J ) 7.5 Hz), 7.36-7.97 (m, 9H); 13C-
NMR (CDCl3, 75 MHz) δ 14.3, 23.8, 128.2, 128.3, 128.4, 129.4,
129.8, 132.2, 133.0, 137.0, 137.2, 139.3, 192.0, 196.9. HRMS
(FAB) Calcd for C16H15O2S: 271.0793. Found: 271.0805 (M
+ H+).
P r ep a r a tion of 1-(Eth ylth io)-8-m eth yl-11-p h en yl-11-
a za -14-oxa tetr a cyclo[6.5.1.02,709,13]tetr a d eca -2,4,6-tr ien e-
10,12-d ion e (22). A 526 mg (2.50 mmol) sample of sulfoxide
19 was treated with 433 mg (2.50 mmol) of N-phenylmaleimide
in 3 mL of Ac2O to give 584 mg (64%) of cycloadduct 22 as a
white solid: mp 181-182 °C; IR (neat) 2977, 2933, 1715, 1499,
1385 cm-1; 1H-NMR (CDCl3, 300 MHz), δ 1.32 (t, 3H, J ) 7.5
Hz), 2.07 (s, 3H), 2.80 (m, 2H), 3.63 (d, 1H, J ) 8.4 Hz), 3.81
(d, 1H, J ) 8.4 Hz), 6.39-6.42 (m, 2H), 7.22-7.29 (m, 4H),
7.37 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 15.1, 17.5, 24.2,
54.8, 86.9, 95.1, 120.2, 121.5, 123.9, 126.1, 126.4, 128.3, 128.5,
128.6, 128.7, 129.0, 141.0, 143.7, 171.7, 172.8. HRMS (FAB)
Calcd for C21H20NO3S: 366.1164. Found: 366.1177 (M + H+).
P r ep a r a t ion of 1-(E t h ylt h io)-8-p h en yl-11,14-d ioxa -
t et r a cyclo[6.5.1.02,709,13]t et r a d eca -2,4,6-t r ien e-10,12-d i-
on e (23). A 595 mg (2.18 mmol) sample of sulfoxide 18 was
treated with 217 mg (2.21 mmol) of maleic anhydride in 4 mL
of Ac2O to give 670 mg (87%) of cycloadduct 23 as a white solid
after chromatographic purification: mp 179-180 °C; IR (neat)
1
1445, 1410 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.21 (t, 3H, J
) 7.4 Hz), 2.44 (q, 2H, J ) 7.4 Hz), 3.30 (brs, 3H), 3.55 (br s,
3H), 3.85 (s, 2H), 7.23-7.39 (m, 4H); 13C-NMR (CDCl3, 75
MHz) δ 14.2, 25.5, 32.9, 60.6, 126.3, 126.9, 129.1, 129.8, 134.6,
136.4. HRMS Calcd for C12H17NO2S: 239.0980. Found:
239.0979.
A 2.39 g (10.0 mmol) sample of amide 16 in 70 mL of THF
was treated with 10.0 mL (30.0 mmol) of a 3.0 M MeMgBr
solution to give 1.86 g (96%) of 1-[2-[(ethylthio)methyl]phenyl]-
ethanone (17) as a colorless oil: IR (neat) 3061, 2869, 1681,
1
1595, 1567 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.20 (t, 3H, J
) 7.4 Hz), 2.43 (q, 2H, J ) 7.4 Hz), 2.59 (s, 3H), 4.03 (s, 2H),
7.30-7.38 (m, 3H), 7.65 (d, 1H, J ) 7.4 Hz); 13C-NMR (CDCl3,
75 MHz) δ 14.3, 25.7, 29.6, 33.5, 126.7, 129.1, 130.9, 130.9,
137.7, 138.7, 201.9. HRMS Calcd for C11H14OS: 194.0765.
Found: 194.0775.
A 1.46 g (7.50 mmol) sample of the above sulfide was treated
with 1.76 g (8.21 mmol) of NaIO4 in 40 mL of CH3OH and 40
mL of H2O to give 1.55 g (98%) of 1-[2-[(ethylsulfinyl)methyl]-
phenyl]ethanone (19) as a colorless oil: IR (neat) 2968, 1681,
3068, 1866, 1785, 1461 cm-1 1H-NMR (CDCl3, 300 MHz) δ
;
1.34 (t, 3H, J ) 7.4 Hz), 1.38 (t, 3H, J ) 7.4 Hz), 2.70-2.95
(m, 4H), 3.43 (d, 1H, J ) 6.6 Hz), 3.70 (d, 1H, J ) 6.6 Hz),
4.06 (d, 1H, J ) 8.8 Hz), 4.27 (d, 1H, J ) 8.8 Hz), 7.03 (brd,
1H, J ) 7.1 Hz), 7.21 (brd, 1H, J ) 7.0 Hz), 7.28-7.55 (m,
16H), 7.58-7.62 (m, 2H), 7.80-7.83 (m, 2H); 13C-NMR (CDCl3,
75 MHz) δ 15.1, 15.2, 15.3, 24.5, 24.6, 54.8, 55.1, 55.9, 56.3,
90.8, 91.3, 95.2, 95.7, 91.3, 95.7, 119.9-122.3, 125.0-129.9,
134.9, 139.4, 142.4, 143.7, 146.0, 166.1, 166.7, 166.6. HRMS
(FAB) Calcd for C20H17O4S: 353.0848. Found: 353.0837 (M
+ H+).
1
1595, 1567 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.36 (t, 3H, J
) 7.5 Hz), 2.60 (s, 3H), 2.70-2.85 (m, 2H), 4.00 (d, 1H, J )
12.1 Hz), 4.38 (d, 1H, J ) 12.1 Hz), 7.38-7.50 (m, 3H), 7.86
(d, 1H, J ) 7.4 Hz); 13C-NMR (CDCl3, 75 MHz) δ 6.3, 28.6,
45.0, 56.5, 127.9, 129.9, 130.9, 131.7, 132.7, 136.2, 200.7.
HRMS (FAB) Calcd for C11H14O2S: 211.0793. Found: 211.0796.
Gen er a tion a n d Tr a p p in g of 1-(Eth ylth io)-3-p h en yl-
isoben zofu r a n (20a ). A mixture containing 20 mL of dry
toluene and 1 mL of acetic anhydride containing 2 mg of
p-toluenesulfonic acid was heated at reflux under argon. To
this mixture, was added 272 mg (1 mmol) of sulfoxide 18 in 5
mL of toluene dropwise via syringe over a 10 min period. After
the addition was complete, the yellow solution was heated at
reflux under argon for an additional 20 min. The bright yellow
P r ep a r a tion of 9,10-Bis(p h en ylsu lfon yl)-1-(eth ylth io)-
8-ph en yl-11-oxatr icyclo[6.2.1.02,7]u n deca-2,4,6-tr ien e (24).
A 396 mg (1.45 mmol) sample of sulfoxide 18 was treated with
459 mg (1.49 mmol) of trans-bis(phenylsulfonyl)ethene in 3 mL
of Ac2O to give 559 mg (69%) of a 1:1 mixture of diastereomers.
Recrystallization from CHCl3 provided one of the diastereo-

Tandem Pummerer-Diels-Alder Reaction Sequence
mers as a white solid: mp 144-145 °C; IR (neat) 3066, 1461,
J . Org. Chem., Vol. 61, No. 11, 1996 3713
In a flame-dried 250 mL round-bottomed flask equipped
with an addition funnel, was dissolved 4.4 mL (29.4 mmol) of
1
1449, 1323, 1152 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.34 (t,
3H, J ) 7.5 Hz), 2.83 (t, 2H, J ) 7.5Hz), 4.52 (d, 2H, J ) 4.3
Hz), 4.86 (d, 2H, J ) 4.3 Hz), 7.07-7.71 (m, 17H), 7.03 (m,
2H); 13C-NMR (75 MHz, CDCl3) δ 15.2, 24.4, 71.8, 73.7, 89.3,
93.4, 120.1, 123.7, 126.2, 127.9, 128.0, 128.1, 128.5, 128.6,
128.6, 128.8, 129.1, 133.3, 134.2, 138.7, 139.9, 141.6, 145.1,
148.6. HRMS (FAB) Calcd for C30H26O5S3: 563.1021.
Found: 563.1033 (M + H+).
1,8-diazabicyclo[5.4.0]undec-7-ene in 100 mL of benzene.
A
2.2 mL (29.7 mmol) sample of ethanethiol was added to the
colorless solution. To this mixture was added dropwise a
solution of 8.60 g (29.3 mmol) of dibromide 32 in 50 mL of
benzene which caused the precipitation of the DBU hydro-
bromide salt. The mixture was stirred overnight, diluted with
H2O, and extracted with CH2Cl2. The organic extracts were
washed with 10% NaOH, dried over Na2SO4, and concentrated
under reduced pressure to give 7.90 g (98%) of 5-bromo-6-
ethylthiomethylbenzo[1,3]dioxole as a clear light yellow oil: IR
P r ep a r a tion of 4-(Eth ylth io)-2,9-d ip h en ylben zo[f]iso-
in d ole-1,3-d ion e (26). Cycloadduct 21 was also obtained
using trifluoroacetic anhydride as the Pummerer promotor at
25 °C. To a solution of 1.15 g (4.22 mmol) of sulfoxide 18, 1.06
g (6.12 mmol) of N-phenylmaleimide, and 0.69 g (6.77 mmol)
of triethylamine in 15 mL of CH2Cl2 was added dropwise a
solution of 1.30 g (6.19 mmol) of trifluoroacetic anhydride in
3 mL of CH2Cl2 at 0 °C. After stirring at rt for 1 h, the mixture
was washed successively with 2 N HCl and H2O. The organic
layer was dried (Na2SO4) and concentrated in vacuo to leave
cycloadduct 21 as a single diastereomer. Treatment of a
sample of 21 with 5 mg of p-TsOH in CH2Cl2 for 18 h at rt
resulted in the loss of water producing 4-(ethylthio)-2,9-
diphenylbenzo[f]isoindole-1,3-dione (26) (72%) as pale yellow
solid: mp 169-170 °C; IR (KBr) 3050, 1764, 1718, 1490, 1375
cm-1; 1H-NMR (CDCl3) δ 1.29 (t, 3H, J ) 7.4 Hz), 3.22 (q, 2H,
J ) 7.4 Hz), 7.32-7.83 (m, 13H), 9.13 (d, 1H, J ) 8.4 Hz);
13C-NMR (CDCl3) δ 15.2, 31.5, 124.1, 126.7, 127.9, 128.0, 128.1,
128.4, 128.4, 128.7, 128.9, 129.3, 129.4, 129.6, 131.7, 134.5,
135.6, 138.3, 140.6, 165.6. Anal. Calcd for C26H19NO2S: C,
76.26; H, 4.68; N, 3.42. Found: C, 75.98; H, 4.71; N, 3.32.
P r ep a r a tion of 4-(Eth ylth io)-1-oxo-2-p h en yl-1,2-d ih y-
d r on a p h t h a len e-2,3-d ica r b oxylic Acid Dim et h yl E st er
(29). A 421 mg (1.55 mmol) sample of sulfoxide 18 was treated
with 950 µL (7.73 mmol) of DMAD in 3 mL of Ac2O to give
230 mg (38%) of cycloadduct 29 as a yellow oil: IR (neat) 3064,
1771, 1740, 1719, 1669, 1447 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 1.25 (t, 3H, J ) 7.4 Hz), 2.86 (q, 2H, J ) 7.4 Hz), 3.35 (s,
3H), 3.87 (s, 3H), 7.09 (d, 1H, J ) 7.7 Hz), 7.17 (d, 1H, J ) 7.3
Hz), 7.30-7.55 (m, 5H), 7.80 (d, 1H, J ) 7.7 Hz), 8.45 (d, 1H,
J ) 7.6 Hz); 13C-NMR (CDCl3, 75 MHz) δ 14.5, 30.6, 52.2, 64.6,
68.8, 127.7, 128.1, 128.2, 128.4, 128.6, 129.3, 129.4, 129.5,
130.9, 131.8, 133.8, 134.1, 134.4, 140.1, 166.1, 166.7. HRMS
(FAB) Calcd for C22H21O5S: 397.1110. Found: 397.1108 (M
+ H+).
(neat) 2970, 2925, 1503, 1450, 1231 cm-1 1H-NMR (CDCl3,
;
300 MHz) δ 1.29 (t, 3H, J ) 7.3 Hz), 2.51 (q, 2H, J ) 7.3 Hz),
3.77 (s, 1H), 5.96 (s, 1H), 6.89 (s, 1H), 6.99 (s, 1H); 13C-NMR
(CDCl3, 75 MHz) δ 14.6, 25.6, 36.0, 101.7, 110.1, 112.7, 114.6,
131.1, 147.1, 147.3.
In a flame-dried, 250 mL, three-necked, round-bottomed
flask equipped with a low temperature thermometer and septa
was dissolved 7.51 g (27.3 mmol) of the above sulfide in 50
mL of THF. The solution was cooled below -90 °C using a
liquid N2-Et2O bath, and 34 mL (57.8 mmol) of 1.7 M t-BuLi
solution was added dropwise. In a separate 25 mL, flame-
dried, round-bottomed flask was dissolved 4.10 g (27.3 mmol)
of piperonal in 20 mL of THF. After addition of the t-BuLi
solution to the sulfide was complete, the solution was stirred
for 30 min below -90 °C, and the piperonal solution was added
to the dark reddish-orange lithiate solution. The solution was
stirred overnight, acidified with 5% HCl solution, and ex-
tracted with CH2Cl2. The organic extracts were washed with
a saturated aqueous NaHCO3, brine, dried over Na2SO4, and
concentrated under reduced pressure to give 8.51 g (90%) of
benzo[1,3]dioxol-5-yl-[6-[(ethylthio)methyl]benzo[1,3]dioxol-5-
yl)methanol (33) as a light yellow oil: IR (neat) 3408, 2898,
1
1486, 1241, 1040 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.23 (t,
3H, J ) 7.4 Hz), 2.48 (q, 2H, J ) 7.4 Hz), 2.86 (d, 1H, J ) 3.7
Hz), 3.62 (d, 1H, J ) 13.1 Hz), 3.72 (d, 1H, J ) 13.1 Hz), 5.90
(d, 2H, J ) 1.4 Hz), 5.92 (s, 2H), 6.06 (d, 1H, J ) 3.7 Hz), 6.69
(s, 1H), 6.75 (d, 1H, J ) 8.5 Hz), 6.81 (s, 1H), 6.82-6.84 (m,
2H); 13C-NMR (CDCl3, 75 MHz) δ 14.5, 25.9, 33.5, 71.6, 101.0,
101.1, 107.3, 108.0, 108.6, 110.3, 119.9, 129.0, 136.2, 137.0,
146.7, 147.1, 147.2, 147.7.
In a flame-dried, 500 mL, round-bottomed flask was dis-
solved 8.34 g (24.1 mmol) of alcohol 33 in 75 mL of CH2Cl2. To
the yellow solution was added 10.18 g (117 mmol) of activated
MnO2 (85%). The mixture was stirred at rt for 24 h, filtered
over Celite and concentrated under reduced pressure to give
7.62 g (92%) of benzo[1,3]dioxol-5-yl-[6-[(ethylthio)methyl]-
benzo[1,3]dioxol-5-yl)methanone as a light yellow oil: IR (neat)
2905, 1654, 1603, 1485 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.13
(t, 3H, J ) 7.4 Hz), 2.39 (q, 2H, J ) 7.4 Hz), 3.77 (s, 2H), 6.02
(s, 2H), 6.06 (s, 2H), 6.77 (s, 1H), 6.82 (d, 1H, J ) 8.1 Hz),
6.98 (s, 1H), 7.32 (dd, 1H, J ) 8.1 and 1.7 Hz), 7.35 (s, 1H);
13C-NMR (CDCl3, 75 MHz) δ 14.5, 25.8, 33.1, 101.6, 101.9,
107.7, 109.2, 109.5, 110.6, 127.1, 132.2, 132.6, 133.5, 145.7,
148.0, 149.0, 151.9, 195.2. HRMS (FAB) Calcd for
C18H16O5S: 345.0797. Found: 345.0793.
P r ep a r a tion of 4-(Eth ylth io)-1-oxo-2-p h en yl-1,2-d ih y-
d r on a p h th a len e-2-ca r boxylic Acid Meth yl Ester (30). A
436 mg (1.60 mmol) sample of sulfoxide 18 was treated with
0.8 µL (9.57 mmol) of methyl propiolate in 2 mL of Ac2O to
give 276 mg (51%) of cycloadduct 30 as pale yellow solid: mp
1
99-100 °C; IR (neat) 3064, 1777, 1740, 1593, 1684 cm-1; H-
NMR (CDCl3, 300 MHz) δ 1.39 (t, 3H, J ) 7.4 Hz), 2.94 (q,
2H, J ) 7.4 Hz), 3.76 (s, 3H), 6.35 (s, 1H), 7.27-7.49 (m, 6H),
7.63 (td, 1H, J ) 7.4 and 1.0 Hz), 7.83 (d, 1H, J ) 8.0 Hz),
8.02 (dd, 1H, J ) 8.0 and 1.0 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 13.6, 26.4, 53.2, 65.9, 125.2, 127.1, 127.8, 127.8, 127.9, 128.1,
128.3, 128.4, 129.1, 132.5, 134.7, 136.1, 136.4, 170.2, 193.4.
HRMS (FAB) Calcd for C20H19O3S: 339.1055. Found: 339.1069
(M + H+). Anal. Calcd for C20H18O3S: C, 70.98; H, 5.36.
Found: C, 70.73; H, 5.43. The X-ray structure of 30 was solved
by direct methods using the SHELXTL program.42
In
a 250 mL round-bottomed flask equipped with an
addition funnel was dissolved 12.9 g (60.5 mmol) of NaIO4 in
100 mL of H2O, and the mixture was cooled in an ice-bath. A
19.8 g (57.4 mmol) sample of the above sulfide was dissolved
in 100 mL of 1,4-dioxane and added dropwise to the aqueous
solution which resulted in the eventual precipitation of a white
solid. The ice-bath was removed, and the mixture was stirred
overnight, diluted with water, and extracted with CH2Cl2. The
organic extracts were dried over Na2SO4 and concentrated
under reduced pressure to give 17.47 g (88%) of benzo[1,3]-
diox-ol-5-yl-[6-[(ethylsulfinyl)methyl]benzo[1,3]dioxol-5-yl)-
methanone (34) as a colorless oil: IR (neat) 2910, 1650, 1603,
P r epar ation of Ben zo[1,3]dioxol-5-yl-[6-[(eth ylsu lfin yl)-
m eth yl]ben zo[1,3]d ioxol-5-yl)m eth a n on e (34). In a 100
mL round-bottomed flask was dissolved 5.0 g (3.29 mmol) of
piperonyl alcohol (31) in 10 mL of acetic acid. The flask was
cooled in an ice-bath, and a mixture of 2.0 mL of bromine (38.8
mmol) and 6 mL of acetic acid was added dropwise. The
reaction mixture was stirred at rt overnight during which time
a white solid precipitated. The mixture was filtered, and the
filtercake was washed with water. The solid was dried in
vacuo to give 7.62 g of 5-bromo-6-(bromomethyl)benzo[1,3]-
dioxole (32). The filtrate was extracted with CH2Cl2, and the
extracts were dried over Na2SO4, concentrated, and chromato-
graphed to afford an additional 1.42 g (92% total) of dibromide
1487 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.30 (t, 3H, J ) 7.6
1
Hz), 2.70 (m, 2H), 3.87 (d, 2H, J ) 12.8 Hz), 4.27 (d, 2H, J )
12.8 Hz), 6.04-6.06 (m, 4H), 6.82-6.85 (m, 1H), 6.90 (s, 1H),
6.99, (s, 1H), 7.28-7.33 (m, 2H); 13C-NMR (CDCl3, 75 MHz) δ
6.7, 45.3, 55.5, 101.9, 102.0, 107.7, 109.6, 110.5, 112.2, 126.2,
127.2, 132.1, 132.4, 146.8, 148.0, 149.6, 152.0, 194.8. HRMS
(FAB) Calcd for C18H16O5S: 345.0797. Found: 345.0793.
1
32 as a white solid: mp 88-89 °C (lit.54 91-92 °C); H-NMR
(CDCl3, 300 MHz) δ 4.55 (s, 2H), 5.99 (s, 2H), 6.91 (s, 1H),
7.01 (s, 1H); 13C-NMR (CDCl3, 75 MHz) δ 34.1, 102.1, 110.5,
113.1, 115.6, 129.9, 147.6, 148.8.

3714 J . Org. Chem., Vol. 61, No. 11, 1996
Padwa et al.
P r ep a r a t ion of 5-Ben zo[1,3]d ioxol-5-yl-8-(et h ylt h io)-
n a p h t h o[2,3-d ][1,3]d ioxole-6,7-d ica r b oxylic Acid Di-
m eth yl Ester (36). In a flame-dried, three-necked, 500 mL,
round-bottomed flask was dissolved 5.0 mL (40 mmol) of
dimethyl maleate in 250 mL of Ac2O, and the mixture was
heated at reflux. A 7.11 g (19.7 mmol) sample of sulfoxide 34
was dissolved in 30 mL of Ac2O and this was added dropwise
to the hot Ac2O solution. After all of the sulfoxide solution
had been added, the reaction was heated at reflux for an
additional 30 min. The yellow solution was concentrated
under reduced pressure, and the orange residue was taken up
in CH2Cl2. The organic solution was washed with a saturated
aqueous NaHCO3 solution, dried over Na2SO4, and concen-
trated under reduced pressure to give 8.17 g (85%) of cyclo-
adduct 35. The solid was dissolved in 200 mL of CH2Cl2, and
200 mg (1.05 mmol) of p-toluenesulfonic acid was added. The
reaction was heated overnight at reflux, cooled and washed
with a saturated aqueous NaHCO3 solution, concentrated, and
chromatographed to afford 7.58 g (82%) of naphthalene sulfide
36 as a white solid: mp 219-220 °C; IR (KBr) 1739, 1719,
1H, J ) 8.0 and 1.0 Hz), 6.82 (d, 1H, J ) 1.0 Hz), 6.98 (d, 1H,
J ) 8.0 Hz), 7.13 (s, 1H), 7.20 (s, 1H), 7.69 (s, 1H).
P r ep a r a tion of J u sticid in E (40). In a 50 mL, flame-
dried, round-bottomed flask was dissolved 506 mg of the half
acid-ester 38 in 20 mL of anhydrous 1,4-dioxane. A 202 mg
sample of NaH (8.42 mmol) was added in one portion, then
3.0 mL of LiBH4 (2.0 M in THF, 6.0 mmol) was added, and
the mixture was heated at reflux for 2 h. The solution was
cooled, acidified with 5% HCl, and extracted with CH2Cl2. The
organic extracts were dried over Na2SO4 and concentrated
under reduced pressure to give 560 mg of a white solid that
was shown by 1H-NMR spectroscopy to consist of a 4:1 mixture
of justicidin E (40) and taiwanin C (39). The mixture was
chromatographed on silica gel (90% CH2Cl2:hexane) to afford
233 mg (51%) of justicidin E whose spectral properties were
identical with those previously reported:60 1H-NMR (CDCl3,
300 MHz) δ 5.17 (s, 2H), 6.07 (s, 4H), 6.77 (dd, 1H, J ) 8.0
and 1.0 Hz), 6.82 (d, 1H, J ) 1.0 Hz), 6.98 (d, 1H, J ) 8.0 Hz),
7.10 (s, 1H), 7.32 (s, 1H), 8.27 (s, 1H).
P r epar ation of 5-Ben zo[1,3]dioxol-5-yl-8-h ydr oxyn aph -
th o[2,3-d ][1,3]d ioxole-6,7-d ica r boxylic Acid Dim eth yl Es-
ter (42). In a flame-dried, three-necked, 500 mL, round-
bottomed flask was dissolved 5.0 mL (40 mmol) of dimethyl
maleate in 250 mL of Ac2O, and the mixture was heated at
reflux. A 7.11 g (19.7 mmol) sample of sulfoxide 34 was
dissolved in 30 mL of Ac2O and was added dropwise to the
hot Ac2O solution. After all of the sulfoxide solution had been
added, the reaction was heated at reflux until all of the starting
sulfoxide had been consumed. The resulting yellow solution
was concentrated under reduced pressure, and the orange
residue was taken up in CH2Cl2. The mixture was washed
with a saturated aqueous NaHCO3 solution, dried over Na2SO4,
and concentrated to give 1.53 g of a yellow oil. The oil was
immediately dissolved in 100 mL of 70% mixture of 1,4-
dioxane/CH3CN and added to a solution of 1.51 g (7.0 mmol)
of NaIO4 in H2O. A catalytic amount of RuCl3 (77 mg, 371
µmol) was added, and the mixture was stirred overnight. The
olive green mixture was poured into H2O and extracted with
CH2Cl2. The organic extracts were washed with a saturated
aqueous NaHCO3 solution, dried over Na2SO4, and concen-
trated to give 1.73 g of sulfone 41. This material was dissolved
in 20 mL of CH2Cl2, 200 mg of p-toluenesulfonic acid was
added, and the mixture was stirred for 5 min at rt. The
solution was washed with a saturated aqueous NaHCO3
solution and the organic layer was dried over Na2SO4 and
concentrated under reduced pressure to give 0.82 g (65%) of
naphthol 42 as a pale, yellow solid: mp 172-173 °C; IR (KBr)
3010, 2906, 1737, 1663, 1462 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 3.59 (s, 3H), 3.92 (s, 3H), 6.02 (s, 2H), 6.03 (s, 2H), 6.70-
6.78 (m, 3H), 6.86 (d, 1H, J ) 7.8 Hz), 7.69 (s, 1H), 12.2 (s,
1H); 13C-NMR (CDCl3, 75 MHz) δ 51.9, 52.7, 100.7, 101.1,
101.7, 103.6, 107.9, 111.2, 121.2, 124.1, 128.0, 128.9, 129.7,
130.4, 133.9, 147.1, 147.2, 148.0, 150.9, 159.6, 169.1, 170.3.
Anal. Calcd for C22H16O9: C, 62.26; H, 3.81. Found: C, 62.15;
H, 3.87.
1
1443, 1216, 1038 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.11 (t,
3H, J ) 7.4 Hz), 2.86 (q, 2H, J ) 7.4 Hz), 3.49 (s, 3H), 3.84 (s,
3H), 6.12 (d, 2H, J ) 5.9 Hz), 6.23 (d, 2H, J ) 2.3 Hz), 6.68
(dd, 1H, J ) 7.9 and 1.4 Hz), 6.86 (s, 1H), 6.87 (d, 1H, J ) 1.4
Hz), 7.03 (d, 1H, J ) 7.9 Hz), 7.99 (s, 1H); 13C-NMR (CDCl3,
75 MHz) δ 14.7, 30.7, 52.3, 52.5, 101.4, 102.6, 103.2, 108.3,
110.1, 122.9, 126.9, 127.4, 129.9, 130.1, 130.6, 133.0, 135.7,
138.9, 147.1, 147.3, 149.3, 150.3, 167.3, 167.7. HRMS Calcd
for C18H16O6S: 361.0746. Found: 361.0744.
P r ep a r a tion of 5-Ben zo[1,3]d ioxol-5-yln a p h th o[2,3-d ]-
[1,3]d ioxole-6,7-d ica r boxylic Acid Dim eth yl Ester (37).
In a 250 mL round-bottomed flask was placed 4.35 g (9.28
mmol) of naphthalene 36 in 85 mL of THF. To this mixture
was added 24 g (408 mmol) of wet Ra-Ni, and the mixture
was heated at reflux until the starting material had disap-
peared. The hot mixture was filtered over a pad of SiO2 and
was eluted with THF. Evaporation of the filtrate afforded 3.79
g (100%) of 37 as a white solid: mp 218-219 °C; IR (KBr)
3017, 2948, 2917, 1727, 1713 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 3.66 (s, 3H), 3.93 (s, 3H), 6.03-6.06 (m, 4H), 6.77 (dd, 1H, J
) 8.1 and 1.2 Hz), 6.79 (d, 1H, J ) 1.2 Hz), 6.88 (s, 1H), 6.89
(d, 1H, J ) 7.5 Hz), 7.22 (s, 1H), 8.38 (s, 1H); 13C-NMR (CDCl3,
75 MHz) δ 52.2, 52.5, 101.2, 101.7, 103.3, 104.8, 108.1, 110.8,
122.9, 123.7, 129.8, 129.9, 130.4, 132.3, 137.0, 147.4, 148.7,
150.3, 166.3, 169.5.
P r ep a r a tion of 5-Ben zo[1,3]d ioxol-5-yln a p h th o[2,3-d ]-
[1,3]d ioxole-6,7-d ica r boxylic Acid 6-Meth yl Ester (38). In
a flame-dried, 100 mL, round-bottomed flask was placed 2.26
g (5.55 mmol) of diester 37 in 60 mL of THF. To the mixture
was added 3.14 g (24.5 mmol) of potassium trimethylsilanolate.
The reaction was stirred at rt for 15 min and then acidified
with 5% HCl and extracted with ethyl acetate. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure to give 2.23 g (100%) of the mono-acid ester 38 as a
white solid: mp 243-244 °C; IR (KBr) 3428, 1737, 1690, 1487,
1
1238 cm-1; H-NMR (CDCl3, 300 MHz) δ 3.50 (s, 3H), 6.10-
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26750), DHEW, for gen-
erous support of this work. C.O.K. wishes to thank the
Austrian Science Foundation (FWF) for an Erwin-
Schro¨dinger-Postdoctoral Fellowship. We also thank M.
A. Semones for determining the X-ray crystal structure
of 30, M. D. Weingarten for performing the FMO
calculations, and Bobby L. Williamson for some experi-
mental assistance. Use of the high-field NMR spec-
trometer used in these studies was made possible
through equipment grants from the NIH and NSF.
6.18 (m, 4H), 6.68 (dd, 1H, J ) 7.8 and 1.3 Hz), 6.72 (s, 1H),
6.80 (d, 1H, J ) 1.3 Hz), 7.02 (d, 1H, J ) 7.8 Hz), 7.62 (s, 1H),
8.45 (s, 1H); 13C-NMR (CDCl3, 75 MHz) δ 51.8, 101.2, 102.0,
102.2, 104.9, 108.1, 110.3, 123.3, 123.8, 129.6, 130.1, 131.2,
136.2, 146.9, 147.0, 148.5, 150.1, 166.9, 168.5. Anal. Calcd
for C21H14O8: C, 63.96; H, 3.58. Found: C, 63.79; H, 3.68.
P r ep a r a tion of Ta iw a n in C (39). In a flame-dried 50 mL
round-bottomed flask was placed 550 mg (1.39 mmol) of half
ester-acid 38 in 25 mL of THF. A 5 mL sample of LiEt3BH
(1.0 M solution in THF, 5.0 mmol) was added which resulted
in immediate gas evolution. The mixture was heated at reflux
overnight, cooled, acidified with 5% HCl and then heated to
reflux for 2 h. A white precipitate appeared during the heating
period. The reaction mixture was poured into a 5% NaHCO3
solution, and the aqueous layer was extracted with CH2Cl2.
The organic extracts were dried over Na2SO4 and concentrated
under reduced pressure to give 450 mg (93%) of taiwanin C
(39) as a white solid, mp 272-273 °C, whose spectral charac-
teristics were identical with those previously reported:60 1H-
NMR (CDCl3, 300 MHz) δ 5.38 (s, 2H), 6.07 (s, 4H), 6.78 (dd,
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR and 13C-
NMR spectra for all compounds with high-resolution mass
spectra together with an ORTEP drawing for cycloadduct 30
(17 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O960295S