A sequential Pummerer-Diels-Alder route for the generation and trapping of furo[3,4-c]pyridines: Synthesis of heterocyclic analogues of 1-arylnaphthalene lignans

Article abstract of DOI:10.1021/jo0344081

The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an α-thio-carbocation, the interception of which by a neighboring keto functionality produces an α-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latt

Full text of DOI:10.1021/jo0344081

A Sequ en tia l P u m m er er -Diels-Ald er Rou te for th e Gen er a tion
a n d Tr a p p in g of F u r o[3,4-c]p yr id in es: Syn th esis of Heter ocyclic
An a logu es of 1-Ar yln a p h th a len e Lign a n s
Tarun K. Sarkar,* Niranjan Panda, and Sankar Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India
tksr@chem.iitkgp.ernet.in
Received March 30, 2003
The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an R-thio-
carbocation, the interception of which by a neighboring keto functionality produces an R-thio-
substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels-Alder
cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by
aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue
of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and
the entire sequence can be run in one pot. The facility of the sequential Pummerer-Diels-Alder
reaction hinges on the experimental conditions, the best results being obtained with heptafluo-
robutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-
toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather
unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible
with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are
unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield
cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer-Diels-Alder reaction is
further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via
oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration
of the resulting hydoxylated isoquinoline derivative.
In tr od u ction
pyridines, furo[3,4-c]pyridines, furo[3,4-d]pyridazines,
furo[3,4-d]quinoxalines, and furo[3,4-c]cinnolines.3 Dur-
ing the course of our studies on heteroisobenzofurans,
we have recently reported the synthesis of a remarkably
stable furo[3,4-c]pyridine intermediate4 and established
the unique advantages of intramolecular Diels-Alder
reactions of furo[3,4-c]pyridines in the synthesis of con-
formationally restricted analogues of nicotine and ana-
basine.5 The utility of heteroisobenzofurans as potential
building blocks for the construction of polycyclic het-
eroaromatics is critically dependent on their availability
as appropriate dienes. The methods so far reported for
the generation of furo[3,4-c]pyridines include (i) thermal
retro-Diels-Alder reactions of 1,4-epoxides,6 (ii) lithiation
and subsequent o-silylation of pyridine-phthalides,7 and
(iii) the Hamaguchi-Ibata reaction of o-aminodiazocar-
bonyl precursors.4,5 As part of our continuing interest in
the chemistry of azaisobenzofurans, we were particularly
interested in the generation of thio-substituted furo[3,4-
c]pyridines by a Pummerer-based route and their ap-
Isobenzofurans have for a long time served as an
interesting class of reactive intermediates in organic
synthesis. As functional analogues of o-xylylenes, they
take part in both inter- and intramolecular Diels-Alder
reactions leading to a variety of polycyclic ring systems
including natural products of biological significance.1 In
contrast, heteroanalogues of isobenzofurans have re-
ceived much less attention, although this situation is
rapidly changing in recent years.2,3 The heteroaromatic
isobenzofurans reported to date include furo[3,4-b]furans,
thieno[2,3-c]furans, furo[3,4-d]oxazoles, furo[3,4-d]isoox-
azoles, furo[3,4-d]thiazoles, furo[3,4-b]benzofurans, benzo-
[4,5]thieno[2,3-c]furans, furo[3,4-b]indoles, furo[3,4-b]-
* Corresponding author.
(1) For reviews see: (a) Friedrichsen, W. Adv. Heterocycl. Chem.
1999, 73, 1. (b) Traulsen, T.; Friedrichsen, W. Targets in Heterocyclic
Systems: Chemistry and Properties; Societa Chimica Italiana: Roma,
Italy, 1998; Vol. 2, p 59. (c) Wege, D. Aust. J . Chem. 1998, 51, 1. (d)
Peters, O.; Friedrichsen, W. Trends Heterocycl. Chem. 1995, 4, 217.
(e) Friedrichsen, W. In Methoden der Organischen Chemie (Houben-
Weyl); Kreher, R., Ed.; Thieme: New York, 1994; Vol. E6b1, pp 163.
(f) Rickborn, B. In Advances in Theoretically Interesting Molecules;
Thummel, R. P., Ed.; J AI Press: Greenwich, CT, 1989; Vol. 1, pp
1-134. (g) Rodrigo, R. Tetrahedron 1988, 44, 2093-2135. (h) Wiersum,
U. E. Aldrichim. Acta 1981, 14, 53. (i) Friedrichsen, W. Adv. Heterocycl.
Chem. 1980, 26, 135. (j) Haddadin, M. J . Heterocycles 1978, 9, 865.
(2) Padwa, A. Chem. Commun. 1998, 1417.
(4) (a) Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow, T. J .
Tetrahedron Lett. 1999, 40, 397. (b) Sarkar, T. K.; Ghosh S. K.; Chow,
T. J . J . Org. Chem. 2000, 65, 3111.
(5) (a) Sarkar, T. K.; Basak, S.; Ghosh S. K. Tetrahedron Lett. 2000,
41, 759. (b) Sarkar, T. K.; Basak, S.; Slanina, Z.; Chow, T. J . J . Org.
Chem. 2003, 68, 4206-4214.
(6) Wiersum, U. E.; Eldred C. D.; Vrijhof, P.; Ven der Plas, H. C.
Tetrahedron Lett. 1977, 1741-1742.
(3) For a review on heteroisobenzofurans, see: Basak, S.; Ghosh S.
K.; Sarkar T. K. J . Indian Inst. Sci. 2001, 81, 431-452.
(7) Iwao, M.; Inoue, H.; Kuraishi, T. Chem. Lett. 1984, 1263.
10.1021/jo0344081 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/14/2003
J . Org. Chem. 2003, 68, 6919-6927
6919

Sarkar et al.
SCHEME 1
In this paper we report the full details of our efforts in
this area including inter alia synthesis of some nitrogen-
containing heterocyclic analogues of 1-arylnaphthalene
lignans.
Resu lts a n d Discu ssion s
Our studies began with nitrile 9, which was prepared
following a slightly modified method as reported by
Bobbitt and Scola for the synthesis of 4-methyl-3-
substituted pyridines.10 Thus, condensation of ethyl
4-(phenylthio)acetoacetate11 with cyanoacetamide in the
presence of potassium hydroxide and acidification of the
resulting monopotassium salt gave 8 (Scheme 2). Conver-
sion of 8 to the corresponding nitrile 9 was then ac-
complished by exposure to phosphorus oxychloride at an
elevated temperature.
Reduction of 9 with diisobutylaluminum hydride
(DIBAL-H) in CH2Cl2 gave aldehyde 10, which on oxida-
tion with sodium periodate in methanol yielded the
corresponding sulfoxide 11 (Scheme 3). In addition, a
series of other pyridine-containing sulfoxide precursors
18-20 was synthesized from their corresponding keto-
sulfides 15-17 by oxidation with NaIO4. The main
drawback in NaIO4-mediated oxidation of sulfides 15-
17 is long reaction time, i.e., 15-20 days are required to
obtain sulfoxides in acceptable yields. For rapid access
to these sulfoxides we subsequently found that 70%
conversion of pyridine-containing keto-sulfoxides 18-20
could be achieved by treatment of sulfides 15-17 with
peracetic acid for a brief period (cf. 30 min). The synthesis
of the desired keto-sulfides 15-17 was accomplished by
the treatment of aldehyde 10 with an aryl-Grignard
reagent in THF and subsequent oxidation of the resultant
alcohols 12-14 under Swern/PCC conditions. It should
be mentioned here that alcohol 14 did not undergo clean
oxidation under Swern oxidation conditions and best
results (96% yield) were obtained by treatment with PCC
in CH2Cl2.
SCHEME 2
plications in the synthesis of heterocyclic analogues of
1-arylnaphthalene lignans of biological significance.
Our strategy toward arylisoquinoline lignans 5-7 is
based on the pioneering work of Padwa et al. as outlined
in Scheme 1.8 This involves generation of R-thiocarboca-
tion 2 from sulfoxide 1 and its interception by a neigh-
boring carbonyl group to give furo[3,4-c]pyridine 3; the
latter should undergo a Diels-Alder reaction with an
added dienophile to give 4, which is readily convertible
to heterolignans 5-7. In a preliminary communication,9
we reported the Pummerer-based generation of furo[3,4-
c]pyridines using heptafluorobutyric anhydride as a
modified triggering agent and their subsequent trapping.
SCHEME 3
6920 J . Org. Chem., Vol. 68, No. 18, 2003

Heterocyclic Analogues of 1-Arylnaphthalene Lignans
SCHEME 4
20 smoothly gave the bridged cycloadducts 25-27 with
improved yields as shown in Scheme 5. This improvement
is either due to the poorer nucleophilicity of “counterion”
toward Pummerer intermediate (cf. 2) generated in the
reaction medium, thereby preventing the formation of
sulfides of type 28, or due to better leaving group ability
of the same “counterion” from 28.
In the absence of a dienophile the Pummerer reaction
of sulfoxide 20 generates the R-thio-substituted furo[3,4-
c]pyridine 24 as a yellow oil. This intermediate is quite
unstable and undergoes aerial decomposition attended
with disappearance of color in a few hours. However, we
were able to isolate and characterize it by 1H NMR
spectroscopy. It may be noted that azaisobenzofuran 24
also undergoes Diels-Alder reaction with less reactive
dienophiles. Thus, exposure of sulfoxide 20 to the Pum-
merer-Diels-Alder reaction protocol in the presence of
methyl acrylate as dienophile gave a 4:1 mixture (1H
NMR) of cycloadducts, the major of which was identified
as 30 on the basis of single-crystal X-ray crystallogra-
phy;13 the minor product is tentatively assigned as 31
(Scheme 6).
To test the viability of the proposed sequential Pum-
merer-Diels-Alder process, we first treated simple
sulfoxide 11 with a suitable dienophile under standard
Pummerer reaction conditions developed by Padwa et al.8
Thus, exposure of 11 to a mixture of acetic anhydride,
dimethyl maleate, and a catalytic amount of p-toluene-
sulfonic acid (p-TsOH) in refluxing toluene for 30 min
gave 21 in 44% yield as a white crystalline solid (Scheme
4). In this case, the [4+2]-adduct (cf. 4) underwent
spontaneous ring cleavage followed by dehydration.
However, when keto-sulfoxide 18 was used, the se-
quential Pummerer-Diels-Alder reaction proceeded as
expected, but here the bridged product 25 was obtained
in only 17% yield (Scheme 5). The stereochemistry of 25
is tentatively assigned on the basis of the Alder endo rule.
Similarly, keto-sulfoxides 19 and 20 gave 26 and 27 in
only 18% and 20% yields, respectively. Here the stereo-
chemistry of 26 was fully supported by an X-ray crystal
structure determination.12 The above route turned out
to be less efficient in all cases in view of the formation of
major products, e.g. acetoxy sulfides of type 28 and
miscellaneous other side products, which were not further
characterized (Scheme 5). For example, in the Pummerer
reaction of 20 the acetoxy sulfide 29 was isolated as a
white crystalline compound. Even using trifluoroacetic
anhydride8 in place of acetic anhydride did not help in
improving yields of these products, e.g. 26. This prompted
us to develop a modified triggering protocol to achieve
acceptable yields of the desired bridged cycloadducts.
After considerable efforts with a variety of Pummerer
promoters, we overcame this difficulty simply by replac-
ing acetic anhydride by heptafluorobutyric anhydride. In
this modified protocol (conditions B), keto-sulfoxides 18-
The regio- and stereoselectivity in the cycloaddition of
24 with methyl acrylate may be rationalized by FMO
theory.14 This is a normal demand π4 + π2 process with
s
s
a HOMO-LUMO gap of 4.8 eV between the HOMO of 24
and LUMO of methyl acrylate. The atomic coefficients
of the interacting orbitals, e.g., 0.314 (phenylthio-
substituted carbon) and 0.23 (anisyl carbon) of the π4
system, e.g., 24, match with 0.63 and 0.464 of the π2
acrylate system to provide the product 30, and the
secondary orbital interaction, which leads to endo addi-
tion, is also favorable.15
The Pummerer-based route for the generation and
trapping of R-thiosubstituted furo[3,4-c]pyridines can also
be extended to intramolecular cases (Scheme 7). Toward
this end tethered sulfoxides 36 and 37 were prepared in
a similar fashion as described before simply by changing
the aryl Grignard reagent by an alkenyl Grignard
reagent and then oxidation of alcohols 32 and 33 with
PCC followed by further oxidation of the resulting
sulfides 34 and 35 (Scheme 7). Subjection of 36 and 37
SCHEME 5a
a
Conditions: (A) Ac2O, p-TsOH, dimethyl maleate, PhMe, reflux, 1 h; (B) (C3F7CO)2O, p-TsOH, dimethyl maleate, PhMe, reflux, 1 h.
J . Org. Chem, Vol. 68, No. 18, 2003 6921

Sarkar et al.
SCHEME 6
toluene to give 44-46 in 45-55% yields (Scheme 8).The
structure of one of these products, 44, was fully estab-
lished by X-ray crystallography.19 Incidentally, initial
attempts for the ring opening of 25-27 with a variety of
other reagents, e.g. MeOH/HCl, p-TsOH in refluxing
toluene, and CF3COOH, were unsuccessful. The synthesis
of these compounds, e.g. 46, also can be conducted in one
pot by exposing keto-sulfoxide 20 to the Pummerer
conditions (conditions B) and then adding DBU to the
reaction mixture. Compounds 44-46 may be looked upon
as heterocyclic analogues of potentially bioactive 1-aryl-
naphthalene lignans.20 The usefulness of the sequential
Pummerer-Diels-Alder reaction was also demonstrated
through the synthesis of a heterolignan20 with a built-in
lactone ring via oxidation of the initial [4+2]-cycloadduct
followed by extrusion of phenyl sulfinate and elaboration
of the resulting hydoxylated isoquinoline derivative.
Thus, the phenylsulfanyl group present in 26 was
to the modified Pummerer conditions (heptafluorobutyric
anhydride/p-TsOH) led to polycyclic ring systems 42 and
43 in one pot with good yields. The need for our new
triggering agent for initiating the Pummerer reaction is
best exemplified in these intramolecular series. For
example, when keto-sulfoxide 36 was subjected to the
other Pummerer conditions8 (Ac2O/p-TsOH in refluxing
toluene) only the acetoxy product (cf. 28) was obtained;
no trace of product resulting from an intramolecular
Diels-Alder reaction could be detected in the crude
reaction mixture by TLC. The high-yielding intramolecu-
lar [4+2]-cycloaddition reaction of 38 and 39 is obviously
related to entropic factors which place the tethered
double bond in close proximity to the diene system.
Since thiol groups can be released from appropriately
substituted precursors at tumors, namely by bioreduc-
tion16 or by antibody-directed enzyme catalysis,17 azai-
sobenzofuran Diels-Alder adducts, e.g. 25-27, with
bridgehead sulfide groups may be looked upon as poten-
tial antitumor prodrugs where cleavage of a sulfide
linkage can lead to aromatization of the oxanorbornyl
ring system.18 Chemically, we have been able to ac-
complish aromatization of 25-27 with DBU in refluxing
21
oxidized by using NaIO4 in the presence of a catalytic
amount of RuCl3 to give sulfone 47. Ring opening followed
by extrusion of phenylsulfinate was done by exposure of
47 to DBU in refluxing toluene to give the hydroxy
isoquinoline derivative 48 (Scheme 9). Selective reduction
of the ester group proximal to the phenolic hydroxy group
in 48 with NaBH4 as reported in the analogous naph-
thalene series,22 however, failed. We overcame this
problem by prior methylation of the hydroxy group and
DIBAL-H reduction of the resulting methyl ether 49 to
give heterolignan 50 directly. The position of the lactone
carbonyl in 50 was determined by NOE experiment,
which showed significant enhancement of the OMe signal
upon irradiation of the adjacent CH2 singlet. The selec-
tivity in the ester reduction stems from the fact that the
tolyl group that is orthogonal to the plane of the iso-
quinoline ring effectively shields the adjacent car-
bomethoxy group.
In conclusion, we have demonstrated that the sequen-
tial Pummerer-Diels-Alder reaction sequence is suited
SCHEME 7
6922 J . Org. Chem., Vol. 68, No. 18, 2003

Heterocyclic Analogues of 1-Arylnaphthalene Lignans
SCHEME 8
an all tandem fashion. Our results clearly indicate that
this methodology provides rapid entry into heteroaro-
matic o-quinodimethanes.
Exp er im en ta l Section
All melting points are uncorrected. Unless otherwise noted,
all reactions were carried out under inert atmosphere in flame-
dried flasks. Solvents and reagents were dried and purified
by distillation before use as follows: Tetrahydrofuran and
toluene from sodium benzophenone ketyl, dichloromethane
and acetonitrile from P2O5, DMSO from CaH2, Et3N and
pyridine from solid KOH, and methanol from Mg. After drying,
organic extracts were evaporated under reduced pressure and
the residue was flash chromatographed on silica gel (Acme’s,
particle size 230-400 mesh), using an ethyl acetate-petroleum
ether (60-80 °C) mixture as eluent unless specified otherwise.
2,6-Dich lor o-4-[(p h en ylth io)m eth yl]n icotin on itr ile (9).
A mixture containing cyanoacetamide (5.06 g, 60.21 mol) and
ethyl 4-(phenylthio)acetoacetate11 (14.33 g, 60.21 mol) in 50
mL of methanol was warmed to attain solution and potassium
hydroxide (4.14 g, 73.82 mol) dissolved in 20 mL of methanol
was added dropwise with stirring. The mixture was heated at
reflux; after 2 h a brown precipitate formed and heating was
continued for an additional 5 h. Then the reaction mixture was
cooled and 2,6-dihydroxy-4-[(phenylthio)methyl]nicotinonitrile
monopotassium salt so formed was separated by filtration,
dissolved in warm water, cooled, and acidified with concen-
trated hydrochloric acid. The product was separated by filtra-
tion, washed with cold methanol, dried in air, and finally
further dried at 120-130 °C in vacuo for 5 h to give 8.4 g (55%)
of 2,6-dihydroxy-4-[(phenylthio)methyl]nicotinonitrile (8) as an
off-white solid: chars at 268 °C, mp 275-278 °C; IR (KBr)
3100, 2221 cm-1; 1H NMR (200 MHz, CDCl3:DMSO-d6) δ 3.98
(s, 2H), 5.68 (s, 2H), 7.10-7.43 (m, 6H); 13C NMR (50 MHz,
CDCl3, DMSO-d6) δ 36.1 (t), 89.2 (s), 92.1 (d), 116.0 (s), 126.7
(d), 128.8 (d), 129.7 (d), 134.1 (s), 159.0 (s), 161.3 (s), 161.8 (s).
A mixture containing 8 (4 g, 15.5 mmol) and POCl3 (5.8 mL,
62.0 mmol) was heated in a sealed tube at 150 °C for 9 h. It
was then cooled to room temperature and transferred into 100
mL of ice cold water. The mixture was filtered with repeated
washings with water. The residue was dissolved in hot
methanol, heated for 10 min with activated charcoal, filtered,
and concentrated. The resulting brown oil was purified by
chromatography (EtOAc:petroleum ether 1:99) to give 2.45 g
(54%) of 9 as a yellow solid. An analytical sample was obtained
by recrystallization from petroleum ether to give colorless
needles: mp 118-119 °C; IR (KBr) 2231, 1567, 1530, 1336
SCHEME 9
to efficient synthesis of a variety of heterocyclic ring
systems including the potentially bioactive heterolignans.
The key intermediates in this cascade process are R-thio-
substituted furo[3,4-c]pyridines, which in some cases can
be isolated and independently reacted with a suitable
dienophile to give [4+2]-cycloadducts. However, we found
it to be most convenient to carry out these reactions in
1
cm-1; H NMR (200 MHz, CDCl3) δ 4.12 (s, 2H), 7.13 (s, 1H),
7.32 (br s, 5H); 13C NMR (50 MHz, CDCl3) 37.5 (t), 109.2 (s),
112.6 (s), 123.1 (d), 128.6 (d), 129.3 (d), 131.9 (s), 132.5 (d),
152.5 (s), 153.6 (s), 156.3 (s). FAB MS m/z (rel intensity) 295
([M+H]+, 46), 242 (4), 186 ([M - SC6H5]H+, 4), 165 (8); HRMS
(FAB) calcd for C13H9Cl2N2S (M+H)+ m/ z 294.9863, found
294.9856. Anal. Calcd for C13H8Cl2N2S: C, 52.89; H, 2.72; N,
9.48. Found: C, 52.68; H, 2.81; N, 9.39.
2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]n icot in a ld eh yd e
(10). To a stirred solution of 9 (4 g, 13.56 mmol) in 60 mL of
CH2Cl2 cooled to -78 °C was added 15 mL of DIBAL-H (1.0
M solution in toluene) dropwise over a period of 1 h. The
resulting mixture was allowed to attain room temperature.
After 2 h of stirring at room temperature the solution was
quenched with saturated aqueous NH4Cl at 0 °C, stirred for
another 1 h at that temperature, and then acidified with 3 N
(8) For generation of thieno[2,3-c]furans and furo[3,4-c]indoles via
a Pummerer reaction: (a) Kappe, C. O.; Cochran, J . E.; Padwa, A.
Tetrahedron Lett. 1995, 36, 9285. (b) Kappe, C. O.; Padwa, A. J . Org.
Chem. 1996, 61, 6166.
(9) Sarkar, T. K.; Basak, S.; Panda, N. Tetrahedron Lett. 2002, 43,
1341.
(10) Bobbitt, J . M.; Scola, D. A. J . Org. Chem. 1960, 25, 560.
(11) Compaigne, E.; Homfeld, E. J . Heterocycl. Chem. 1979, 16, 1321.
(12) Professor H. K. Fun (Malaysia) kindly carried out the X-ray
structure determination (unpublished results).
(13) Usman, A.; Sarkar, T. K.; Panda, N.; Fun, H. K. Acta Crystal-
logr. 2002, E58, 1404.
(14) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(15) The atomic coefficients were calculated with GAMESS.HF/3-
21 G*. Schmidt, M. W.; Baldridge, K. K.; Boatz, J . A.; Elbert, S. T.;
Gordon, M. S.; J ensen, J . H.; Koseki, S.; Matsunaga, N.; Nguyen, N.;
Su, S. J .; Windus, T. L.; Dupuis, M.; Montgomery, J . A. J . Comput.
Chem. 1993, 14, 1347.
(16) Nicolaou, K. C. Chem. Br. 1994, 30, 33.
(17) Shepherd, T. A.; J ungheim, L. N.; Meyer, D. L.; Starling, J . J .
Bioorg. Med. Chem. Lett. 1991, 1, 21.
(20) (a) For a review on heterolignans, see: Ramos, A. C.; deClairac,
R. P.-L.; Medarde, M. Heterocycles 1999, 51, 1443. (b) Kuroda, T.;
Takahashi, M.; Ogiku, T.; Ohmizu, H.; Nishitani, T.; Kondo, K.;
Iwasaki, T. J . Org. Chem. 1994, 59, 7353.
(18) Bailey, J . H.; Coulter, C. V.; Pratt, A. J .; Robinson, W. T. J .
Chem. Soc., Perkin Trans. 1 1995, 589.
(19) Fun, H. K.; Usman, A.; Razak, I. A.; Chantrapromma, S.;
Sarkar, T. K.; Basak, S.; Panda, N. Acta Crystallogr. 2002, E58, 215.
(21) Padwa, A.; Cochran, J . E.; Kappe, C. O. J . Org. Chem. 1996,
61, 3706.
(22) Arnold, B. J .; Mellows, S.; Sammes, P. G. J . Chem. Soc., Perkin
Trans. 1 1973, 1266.
J . Org. Chem, Vol. 68, No. 18, 2003 6923

Sarkar et al.
HCl. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). The combined organic
fractions were washed with saturated aqueous NaHCO3 and
brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude residue was purified by chroma-
tography (EtOAc:petroleum ether 1:99) to give 2.5 g (62%) of
aldehyde 10 as a white crystalline solid: mp 61-62 °C; IR
(KBr) 1688, 1565, 1526, 1317 cm-1; 1H NMR (200 MHz CDCl3:
CCl4 7:3) δ 4.36 (s, 2H), 7.00 (s, 1H), 7.28 (br s, 5H), 10.42 (s,
1H); 13C NMR (50 MHz, CDCl3) δ 36.2 (t), 124.9 (s), 125.0 (d),
128.0 (d), 129.1 (d), 132.2 (d), 133.3 (s), 153.4 (s), 154.2 (s),
154.4 (s), 190.2 (d). Anal. Calcd for C13H9Cl2NOS: C, 52.36;
H, 3.03; N, 4.69. Found: C, 52.23; H, 3.19; N, 4.68.
134.4 (s), 134.5 (s), 138.0 (d), 148.3 (s), 148.9 (s), 151.7 (s). Anal.
Calcd for C18H19Cl2NOS: C, 58.71; H, 5.19; N, 3.80. Found:
C, 58.93; H, 5.31; N, 3.49.
1-{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}-
h ep t-6-en -1-ol (33) was prepared by a similar method starting
from aldehyde 10 (440 mg, 1.47 mmol) and 6-bromo-1-hexene
in 32% yield as a yellow oil: IR (CHCl3) 3308, 1568, 1533, 1307
1
cm-1; H NMR (200 MHz, CDCl3:CCl4 70:30) δ 1.28-2.15 (m,
8H), 2.47 (br s, 1H), 4.27 (d, 1H, J AB ) 13.4 Hz), 4.44 (d, 1H,
J AB ) 13.4 Hz), 4.90-5.05 (m, 2H), 5.21-5.45 (m, 1H), 5.65-
5.85 (m, 1H), 7.04 (s, 1H), 7.27-7.40 (m, 5H); 13C NMR (50
MHz, CDCl3:CCl4 7:3) δ 25.5 (t), 28.4 (t), 33.5 (t), 36.1 (t), 36.4
(t), 71.1 (d), 114.5 (t), 125.3 (d), 127.7 (d), 128.9 (d), 131.6 (d),
134.4 (s), 134.6 (s), 138.5 (d), 148.2 (s), 148.9 (s), 151.7 (s).
{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}(4-
m eth ylp h en yl)m eth a n ol (13). To a stirred solution of alde-
hyde 10 (1 g, 3.5 mmol) in 20 mL of dry THF was added
dropwise a tolylmagnesium bromide solution (16.8 mL, 0.4 M)
[prepared from p-bromotoluene (1.23 mL, 10 mmol) and Mg
(480 mg, 20 mmol) in 24 mL of THF] over a period of 10 min
at -78 °C. During addition a blood red color was formed. After
1 h of stirring the mixture was slowly warmed to 0 °C and
then quenched with saturated aqueous NH4Cl. The organic
layer was separated and the aqueous layer was extracted with
diethyl ether (3 × 10 mL). The combined organic layer was
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and purified by chromatography (EtOAc:petroleum
ether 10:90) giving 950 mg (73%) of 13 as a white crystalline
{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}(4-
m eth ylp h en yl)m eth a n on e (16). To a stirred solution of 13
(2 g, 5.12 mmol) in 20 mL of dry CH2Cl2 was added PCC (1.7
g, 7.7 mmol) at room temperature. After 1.5 h of stirring the
solution was filtered over a short Celite pad. The yellow
solution was then concentrated under reduced pressure and
purified by chromatography (EtOAc:petroleum ether 5:95) to
give 1.55 g (78%) of 16 as a white solid: mp 105-107 °C; IR
(KBr) 1658, 1602, 1565, 1325 cm-1; 1H NMR (200 MHz, CDCl3:
CCl4 7:3) δ 2.42 (s, 3H), 3.90 (s, 2H), 7.05-7.35 (m, 8H), 7.64
(d, 2H, J ) 8.0 Hz); 13C NMR (50 MHz, CDCl3:CCl4 7:3) δ 21.9
(q), 35.6 (t), 123.6 (d), 127.5 (d), 129.1 (d), 129.7 (d), 129.8 (d),
130.8 (d), 133.0 (s), 133.4 (s), 133.6 (s), 145.7 (s), 146.7 (s), 150.6
(s), 150.9 (s), 192.0 (s). Anal. Calcd for C20H15Cl2NOS: C, 61.87;
H, 3.89; N, 3.60. Found: C, 62.09; H, 3.97; N, 3.83.
solid: mp 129-131 °C; IR (KBr) 3371, 1575, 1524, 1104 cm-1
;
1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.36 (s, 3H), 3.46 (s,
1H), 3.84 (d, 1H, J AB ) 15.3 Hz), 4.26 (d, 1H, J AB ) 15.3 Hz),
6.57 (br s, 1H), 6.82-7.41 (m, 10H); 13C NMR (50 MHz, CDCl3:
CCl4 7:3) δ 21.1 (q), 35.4 (t), 70.9 (d), 125.0 (d), 125.2 (d), 127.0
(d), 129.0 (d), 129.3 (d), 130.1 (d), 134.3 (s), 134.4 (s), 137.2
(s), 137.6 (s), 149.5 (s), 149.8 (s), 152.9 (s). FAB MS m/z (rel
intensity) 390 ([M + H]+, 100), 372 ([M - H2O]H+, 26), 279
(31), 264 (42), 227 (10), 219 (5), 188 (4), 120 (10); HRMS (FAB)
calcd for C20H18Cl2NOS (M+H)+ m/ z 390.0486, found 390.0486.
Anal. Calcd for C20H17Cl2NOS: C, 61.56; H, 4.38; N, 3.58.
Found: C, 61.34; H, 4.19; N, 3.85.
{2,6-Dich lor o-4-[(p h e n ylt h io)m e t h yl]p yr id in -3-yl}-
(p h en yl)m eth a n on e (15). To a stirred solution of oxalyl
chloride (0.278 mL, 3.13 mmol) in 10 mL of CH2Cl2 cooled at
-60 °C was added DMSO (0.453 mL, 6.39 mmol) in 5 mL of
CH2Cl2 dropwise via dropping funnel in 15 min under argon
atmosphere. The mixture was stirred for 30 min followed by
addition of 12 (800 mg, 2.13 mmol) in 10 mL of CH2Cl2 over a
period of 10 min. After 30 min of stirring Et3N (1.5 mL, 10.65
mmol) was added and the reaction mixture was allowed to
attain room temperature and stirred for 1 h. Then 100 mL of
cold H2O was added to the mixture. The organic layer was
separated and washed with 1% HCl and brine. Finally the
organic fraction was concentrated in vacuo and purified by
chromatography (EtOAc:petroleum ether 5:95) to give 670 mg
of 15 in 84% yield: IR (KBr) 1666, 1602, 1555, 1332 cm-1; 1H
NMR (200 MHz CDCl3:CCl4 7:3) δ 3.90 (s, 2H), 7.00-7.85 (m,
11H); 13C NMR (50 MHz CDCl3:CCl4 7:3) δ 35.7 (t), 123.7 (d),
127.6 (d), 128.9 (d), 129.2 (d), 129.6 (d), 130.9 (d), 132.7 (s),
133.5 (s), 134.5 (d), 135.8 (s), 146.7 (s), 150.8 (s), 151.1 (s), 192.5
(s).
{2,6-D i c h lo r o -4-[(p h e n y lt h i o )m e t h y l]p y r i d i n -3-
yl}(p h en yl)m eth a n ol (12) was prepared by a similar method
starting from aldehyde 10 (820 mg, 2.75 mmol) and bromoben-
zene in 77% yield as a white crystalline solid: mp 146-148
°C; IR (KBr) 3506, 1605, 1571, 1326, 1066 cm-1; 1H NMR (200
MHz, CDCl3:CCl4 7:3) δ 3.2 (br s, 1H), 3.80 (d, 1H, J AB ) 15.2
Hz), 4.23 (d, 1H, J AB ) 15.2 Hz), 6.62 (s, 1H), 6.98-7.45 (m,
11H); 13C NMR (50 MHz, CDCl3) δ 35.5 (t), 70.9 (d), 125.0 (d),
125.1 (d), 127.1 (d), 127.5 (d), 128.5 (d), 129.0 (d), 130.3 (d),
133.9 (s), 134.0 (s), 140.4 (s), 149.5 (s), 149.9 (s), 152.6 (s). Anal.
Calcd for C19H15Cl2NOS: C, 60.66, H, 4.01; N, 3.72. Found:
C, 60.61; H, 3.91; N, 3.85.
{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}(4-
m eth oxyp h en yl)m eth a n on e (17) was obtained by the PCC
oxidation of alcohol 14 (400 mg, 0.98 mmol) in 96% yield as a
yellow oil. IR (KBr) 1660, 1595, 1564, 1343 cm-1; 1H NMR (200
MHz, CDCl3:CCl4 7:3) δ 3.88 (s, 3H), 3.90 (s, 2H), 6.90 (d, 2H,
J ) 9.1 Hz), 7.12-7.28 (m, 6H), 7.70 (d, 2H, J ) 8.6 Hz); 13C
NMR (50 MHz, CDCl3:CCl4 7:3) δ 35.6 (t), 55.4 (q), 114.2 (d),
123.4 (d), 127.5 (d), 128.9 (s), 129.1 (d), 130.8 (d), 132.0 (d),
133.0 (s), 133.7 (s), 146.7 (s), 150.5 (s), 150.7 (s), 164.6 (s), 190.7
(s). Anal. Calcd for C20H15Cl2NO2S: C, 59.41; H, 3.74; N, 3.46.
Found: C, 59.22; H, 3.63; N, 3.59.
{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}(4-
m eth oxyp h en yl)m eth a n ol (14) was prepared by a similar
method starting from aldehyde 10 (450 mg, 1.51 mmol) and
p-bromoanisol in 69% yield as a white crystalline solid: mp
1
116-118 °C; IR (KBr) 3351, 1569, 1525, 1098 cm-1; H NMR
(200 MHz, CDCl3:CCl4 7:3) δ 3.50 (br s, 1H), 3.78 (s, 3H), 3.86
(d, 1H, J AB ) 15.3 Hz), 4.27 (d, 1H, J AB ) 15.2 Hz), 6.56 (br s,
1H), 6.72-7.35 (m, 10H); 13C NMR (50 MHz, CDCl3:CCl4 7:3)
δ 35.5 (t), 55.3 (q), 70.8 (d), 114.1 (d), 125.1 (d), 126.6 (d), 127.2
(d), 129.1 (d), 130.3 (d), 132.6 (s), 134.3 (s), 149.5 (s), 149.8 (s),
152.9 (s), 159.1 (s). Anal. Calcd for C20H17Cl2NO2S: C, 59.13;
H, 4.21; N, 3.44. Found: C, 59.41; H, 4.31; N, 3.19.
1-{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}-
h ex-5-en -1-on e (34) was obtained by the PCC oxidation of
32 (170 mg, 0.462 mmol) in 83% yield as a yellow oil. IR
1-{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}-
h ex-5-en -1-ol (32) was prepared by a similar method starting
from aldehyde 10 (400 mg, 1.34 mmol) and 5-bromo-1-pentene
in 36% yield: 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 1.31-
2.18 (m, 6H), 2.88 (br s, 1H), 4.25 (d, 1H, J AB ) 13.3 Hz), 4.43
(d, 1H, J AB ) 13.3 Hz), 4.89-5.08 (m, 2H), 5.27-5.37 (m, 1H),
5.62-5.91 (m, 1H), 7.01 (s, 1H), 7.19-7.40 (m, 5H); 13C NMR
(50 MHz, CDCl3:CCl4 70:30) δ 25.4 (t), 33.3 (t), 35.8 (t), 36.4
(t), 71.1 (d), 115.1 (t),125.4 (d), 127.7 (d), 129.2 (d), 131.7 (d),
(CHCl3) 1707, 1565, 1530, 1325 cm-1 1H NMR (200 MHz,
;
CDCl3:CCl4 7:3) δ 1.68-1.97 (m, 2H), 2.08-2.19 (m, 2H), 2.87
(t, 2H, J ) 7.3 Hz), 3.88 (s, 2H), 4.97-5.12 (m, 2H), 5.67-5.91
(m, 1H), 6.99 (s, 1H), 7.13-7.42 (m, 5H); 13C NMR (50 MHz,
CDCl3:CCl4 7:3) δ 22.3 (t), 32.8 (t), 36.1 (t), 43.4 (t), 115.6 (t),
123.9 (d), 128.2 (d), 129.4 (d), 131.9 (d), 133.3 (s), 134.8 (s),
137.5 (d), 145.7 (s), 149.7 (s), 150.3 (s), 202.7 (s). DCI-MS m/z
(rel intensity) 366 ([M + H]+, 100), 383 ([M + NH4]+, 82);
6924 J . Org. Chem., Vol. 68, No. 18, 2003

Heterocyclic Analogues of 1-Arylnaphthalene Lignans
HRMS (FAB) calcd for C18H18Cl2NOS (M + H)+ m/z 366.0486,
keto sulfide 34 (90 mg, 0.246 mmol) by NaIO4 in 85% yield as
found 366.0500.
a yellow oil: IR (CDCl3) 1702, 1530, 1328, 1123, 1085 cm-1
1H NMR (200 MHz, CDCl3) δ 1.78-1.95 (m, 2H), 2.12-2.27
(m, 2H), 2.96-3.02 (m, 2H), 3.71 (d, 1H, J ) 12.8 Hz), 4.12 (d,
1H, J ) 12.9 Hz), 4.99-5.11 (m, 2H), 5.71-5.88 (m, 1H), 6.83
(s, 1H), 7.42-7.58 (m, 5H); 13C NMR (50 MHz, CDCl3:CCl4 7:3)
δ 22.6 (t), 32.7 (t), 43.6 (t), 59.0 (t), 115.5 (t), 123.9 (d), 125.3
(d), 129.5 (d), 132.0 (d), 136.0 (s), 137.6 (d), 141.7 (s), 142.0
(s), 146.0 (s), 150.3 (s), 203.4 (s). Anal. Calcd for C18H17Cl2-
NO2S: C, 56.56; H, 4.47; N, 3.66. Found: C, 56.69; H, 4.53;
N, 3.51.
;
1-{2,6-Dich lor o-4-[(p h en ylt h io)m et h yl]p yr id in -3-yl}-
h ep t-6-en -1-on e (35) was obtained by PCC oxidation of 33
(110 mg, 0.29 mmol) in 82% yield as a yellow oil: IR (CHCl3)
1702, 1567, 1532, 1329 cm-1; 1H NMR (200 MHz, CDCl3:CCl4
7:3) δ 1.38-1.61 (m, 2H), 1.65-1.85 (m, 2H), 1.92-2.21 (m,
2H), 2.86 (t, 2H, J ) 7.2 Hz), 3.87 (s, 2H), 4.92-5.13 (m, 2H),
5.72-5.91 (m, 1H), 6.99 (s, 1H), 7.16-7.41 (m, 5H); 13C NMR
(50 MHz, CDCl3:CCl4 7:3) δ 22.7 (t), 28.2 (t), 33.5 (t), 36.1 (t),
43.9 (t), 115.0 (t), 124.0 (d), 128.2 (d), 129.4 (d), 131.9 (d), 133.3
(s), 134.9 (s), 138.1 (d), 145.6 (s), 149.7 (s), 150.3 (s), 202.8 (s).
1-{2,6-Dich lor o-4-[(p h en ylsu lfin yl)m et h yl]p yr id in -3-
yl}h ep t-6-en -1-on e (37) was obtained by similar oxidation
of keto sulfide 35 (100 mg, 0.263 mmol) by NaIO4 in 77% yield
as yellow oil: IR (CHCl3) 1702, 1633, 1563, 1392, 1094, 1048
cm-1; 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 1.38-2.19 (m, 6H),
2.81-3.09 (m, 2H), 3.72 (d, 1H, J ) 12.9 Hz), 4.11 (d, 1H, J )
12.9 Hz), 4.89-5.16 (m, 2H), 5.69-5.91 (m, 1H), 6.85 (s, 1H),
7.41-7.82 (m, 5H); 13C NMR (50 MHz, CDCl3:CCl4 7:3) δ 22.9
(t), 28.2 (t), 33.6 (t), 43.7 (t), 57.7 (t), 114.9 (t), 126.2 (d), 128.4
(d), 129.7 (d), 134.7 (d), 136.5 (s), 138.2 (s), 138.3 (d), 139.2
(s), 146.5 (s), 150.6 (s), 203.3 (s). Anal. Calcd for C19H19Cl2-
NO2S; C, 57.57; H, 4.82; N, 3.53. Found: C, 57.80; H, 5.01; N,
3.51.
{2,6-Dich lor o-4-[(p h en ylsu lfin yl)m eth yl]p yr id in -3-yl}-
(4-m eth ylp h en yl)m eth a n on e (19). To a slurry of 16 (430
mg, 1.10 mmol) in a 1:1 mixture of CH3OH and H2O (6 mL)
was added NaIO4 (246 mg, 1.15 mmol) at 0 °C; then the
mixture was warmed to room temperature. After 15-20 days
5 mL of CH2Cl2 was added. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layer was dried over anhydrous Na2-
SO4 and concentrated under reduced pressure. The crude mass
was purified over chromatography (EtOAc:petroleum ether 20:
80) to give 380 mg (85%) of sulfoxide 19 as a white solid: mp
162-164 °C; IR (KBr) 1668, 1603, 1570, 1532, 1327, 1085, 1045
cm-1; 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.45 (s, 3H), 3.79
(d, 1H, J ) 12.8 Hz), 3.92 (d, 1H, J ) 12.8), 7.15-7.85 (m,
10H); 13C NMR (50 MHz, CDCl3:CCl4 7:3) δ 21.8 (q), 60.4 (t),
123.7 (d), 125.2 (d), 129.3 (d), 129.7 (d), 129.9 (d), 131.7 (d),
133.4 (s), 133.5 (s), 142.5 (s), 143.5 (s), 145.9 (s), 147.0 (s), 150.7
(s), 191.9 (s). DCI-MS m/z (rel intensity) 404 ([M + H]+, 100),
421 ([M + NH4]+, 84); HRMS (FAB) calcd. for C20H16Cl2NO2S
Gen er a l P r oced u r e for P u m m er er -Diels-Ald er Rea c-
tion . Con d ition s A: A mixture containing acetic anhydride
(10 mmol), appropriate dienophile (4 mmol), and a catalytic
amount of p-toluenesulfonic acid in dry toluene (10 mL) was
heated at reflux under argon. To this mixture was added a
toluene solution of keto-sulfoxide (1 mmol) dropwise over a
period of 10 min. After addition was complete the yellow
mixture was heated at reflux for an additional 1 h. The reddish
yellow solution was cooled and washed with saturated aqueous
NaHCO3 solution. The organic layer was concentrated and
purified by preparative layer chromatography.
(M + H)+ m/z 404.0279, found 404.0262. Anal. Calcd for C20H15
-
Cl2NO2S: C, 59.43; H, 3.73; N, 3.46. Found: C, 59.29; H, 3.78;
N, 3.52.
{2,6-Dich lor o-4-[(p h en ylsu lfin yl)m eth yl]p yr id in -3-yl}-
(p h en yl)m eth a n on e (18) was obtained by similar oxidation
of sulfide 15 (640 mg, 1.71 mmol) in 68% yield as a yellow oil:
Con d ition s B: A mixture containing heptafluorobutyric
anhydride (10 mmol), appropriate dienophile (4 mmol), and a
catalytic amount of p-toluenesulfonic acid was heated at reflux
under argon. To this mixture was added keto-sulfoxde (1 mmol)
in dry toluene dropwise over a period of 10 min. After complete
addition, the yellow mixture was heated at reflux for an
additional 1 h. The reddish yellow solution was cooled and
washed with saturated NaHCO3 solution. The organic layer
was concentrated and purified by preparative layer chroma-
tography.
1
IR (KBr) 1665, 1605, 1577, 1532, 1333, 1085, 1045 cm-1; H
NMR (200 MHz CDCl3:CCl4 7:3) δ 3.74 (d, 1H, J ) 12.9 Hz),
3.90 (d, 1H, J ) 12.9 Hz), 7.18 (s, 1H), 7.22-7.92 (m, 10H);
13C NMR (50 MHz, CDCl3:CCl4 7:3) δ 60.1 (t), 123.7 (d), 125.3
(d), 129.0 (d), 129.3 (d), 129.7 (d), 131.8 (d), 133.3 (s), 134.8
(d), 135.8 (s), 142.5 (s), 143.7 (s), 147.0 (s), 150.9 (s), 192.4 (s).
Anal. Calcd for C19H13Cl2NO2S: C, 58.48; H, 3.35; N, 3.58.
Found: C, 58.19; H, 3.13; N, 3.68.
{2,6-Dich lor o-4-[(p h en ylsu lfin yl)m eth yl]p yr id in -3-yl}-
(4-m eth oxyp h en yl)m eth a n on e (20) was obtained by the
oxidation of keto sulfide 17 (390 mg, 0.96 mmol) in 91% yield
as a white crystalline solid: mp 142-143 °C; IR (KBr) 1687,
1595, 1324, 1153, 1041 cm-1; 1H NMR (200 MHz, CDCl3:CCl4
7:3) δ 3.73 (d, 1H, J ) 12.9 Hz), 3.84 (s, 3H), 3.87 (d, 1H, J )
12.9 Hz), 6.90 (d, 2H, J ) 8.9 Hz), 7.14 (s, 1H), 7.24-7.58 (m,
5H), 7.72 (d, 2H, J ) 8.69); 13C NMR (50 MHz, CDCl3:CCl4
7:3) δ 55.5 (q), 60.4 (t), 114.3 (d), 123.7 (d), 125.1 (d), 128.9 (s),
129.3 (d), 131.6 (d), 132.2 (d), 133.7 (s), 142.7 (s), 143.5 (s),
146.9 (s), 150.5 (s), 164.8 (s), 190.5 (s).
Dim eth yl 1,3-Dich lor o-5-(p h en ylth io)isoqu in olin e-6,7-
d ica r boxyla te (21) was prepared following conditions A from
sulfoxide 11 (100 mg, 0.32 mmol) in the presence of dimethyl
maleate (0.15 mL, 1.27 mmol) in 44% yield as a white
crystalline solid: mp 109-111 °C; IR (KBr) 1706, 1569, 1530,
1327 cm-1; 1H NMR (200 MHz, CDCl3) δ 3.98 (s, 3H), 4.01 (s,
3H), 7.30-7.07 (m, 5H), 8.21 (d, 1H, J ) 0.9 Hz), 9.10 (d, 1H,
J ) 0.9 Hz); 13C NMR (50 MHz, CDCl3) δ 53.0 (q), 53.2 (q),
118.9 (d), 125.5 (s), 127.0 (d), 127.2 (s), 128.5 (d), 128.9 (s),
129.4 (d), 131.9 (d), 134.9 (s), 142.8 (s), 144.5 (s), 147.8 (s),
152.9 (s), 164.0 (s), 167.0 (s). Anal. Calcd for C19H13Cl2NO4S:
C, 54.03; H, 3.09; N, 3.31. Found: C, 53.89; H, 3.25; N, 3.42.
2,6-Dic h lor o-4-[(p h e n ylsu lfin yl)m e t h y l]n ic ot in a l-
d eh yd e (11) was obtained by similar oxidation of sulfide 10
(90 mg, 0.3 mmol) by NaIO4 in 76% yield as a white solid: mp
Dim eth yl 3,5-Dich lor o-1-(4-m eth ylph en yl)-8-(ph en ylth -
io)-11-oxa -4-a za tr icyclo[6.2.1.02,7]u n d eca -2,4,6-tr ien e-9,-
10-d ica r boxyla te (26) was prepared by the treatment of keto-
sulfoxide 19 (100 mg, 0.247 mmol) with dimethyl maleate
(0.124 mL, 1 mmol) under conditions B in 37% yield as a
yellowish white solid: mp 199-200 °C; IR (KBr) 1742, 1633,
1
150-152 °C; IR (KBr) 1705, 1564, 1527, 1327, 1035 cm-1; H
NMR (200 MHz, CDCl3:CCl4 7:3) δ 4.08 (d, 1H, J ) 11.8), 4.75
(d, 1H, J ) 11.9 Hz), 7.05 (s, 1H), 7.50 (br s, 5H), 10.26 (s,
1H); 13C NMR (50 MHz, CDCl3:CCl4 7:3) δ 59.1 (t), 124.0 (d),
125.6 (s), 127.1 (d), 129.1 (d), 131.5 (d), 142.4 (s), 145.0 (s),
153.6 (s), 154.0 (s), 190.1 (d). FAB MS m/z (rel intensity) 626
(2M+, 9), 314 ([M + H]+, 100), 273 (6), 188 ([M - C6H5SO]+,
28), 165 (6); HRMS (FAB) calcd for C13H10Cl2NO2S (M+H)+
m/ z 313.9809, found 313.9819. Anal. Calcd for C13H9Cl2-
NO2S: C, 49.70; H, 2.88; N, 4.45. Found: C, 49.81; H, 2.93;
N, 4.29.
1
1595, 1336 cm-1; H NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.41
(s, 3H), 3.56 (s, 6H), 3.58 (d, 1H, J ) 11 Hz), 4.14 (d, 1H, J )
11 Hz), 7.19-7.69 (m, 10H); 13C NMR (50 MHz, CDCl3:CCl4
7:3) δ 21.4 (q), 52.0 (q), 52.4 (q), 52.6 (d), 53.6 (d), 90.0 (s),
93.7 (s), 118.0 (d), 128.1 (d), 129.2 (d), 129.6 (d), 131.1 (s), 135.5
(d), 137.8 (s), 139.4 (s), 143.8 (s), 148.8 (s), 157.5 (s), 167.7 (s),
169.0 (s). FAB MS m/z (rel intensity) 530 ([M + H]+, 11), 386
(3), 273 (3), 235 (6), 165 (4);HRMS (FAB)calcd for C26H22Cl2NO5S
1-{2,6-Dich lor o-4-[(p h en ylsu lfin yl)m et h yl]p yr id in -3-
yl}h ex-5-en -1-on e (36) was obtained by similar oxidation of
J . Org. Chem, Vol. 68, No. 18, 2003 6925

Sarkar et al.
(M+H)+ m/ z 530.0596, found 530.0589. Anal. Calcd for C26H21
-
(q), 55.3 (q), 90.4 (s), 92.8 (s), 113.8 (d), 114.9 (d), 125.9 (s),
129.0 (d), 129.1 (d), 129.3 (s), 130.0 (d), 134.2 (d), 136.7 (s),
143.7 (s), 149.6 (s), 160.0 (s), 160.4 (s), 170.9 (s).
Cl2NO5S: C, 58.88; H, 3.98; N, 2.64. Found: C, 58.65; H, 3.94;
N, 2.87.
When the reaction was conducted in one pot (cf. conditions
B), the overall yield of products 30 and 31 was higher (46%).
1,3-Dich lor o-5-(p h en ylth io)-8,9-d ih yd r o-7H-cyclop en -
ta [h ]isoqu in olin e (42) was prepared in a similar manner
(conditions B) from keto-sulfoxide 36 (50 mg, 0.13 mmol) in
67% yield as a white crystalline solid: mp 109-110 °C; IR
(KBr) 1577, 1538, 1278, 1177 cm-1; 1H NMR (200 MHz, CDCl3)
δ 2.20 (quint, 2H, J ) 7.6 Hz), 3.03 (t, 2H, J ) 7.7 Hz), 3.74 (t,
2H, J ) 7.5 Hz), 7.01-7.45 (m, 5H), 7.78 (s, 1H), 8.20 (s, 1H);
13C NMR (50 MHz, CDCl3) δ 24.3 (t), 33.3 (t), 36.4 (t), 118.4
(d), 124.9 (s), 126.8(d), 128.1 (s), 129.2 (d), 129.3 (d), 134.3 (s),
135.5 (d), 140.3 (s), 141.5 (s), 142.7 (s), 146.0 (s), 149.9 (s). Anal.
Calcd for C18H13Cl2NS: C, 62.42; H, 3.78; N, 4.04. Found: C,
62.24; H, 3.55; N, 4.29.
Dim eth yl 3,5-Dich lor o-1-p h en yl-8-(p h en ylth io)-11-oxa -
4-a za tr icyclo[6.2.1.02,7]u n d eca -2,4,6-tr ien e-9,10-d ica r box-
yla te (25) was prepared in a similar manner (conditions B)
from keto sulfoxide 18 (100 mg, 0.26 mmol) in 33% yield as a
1
yellowish white solid: mp 174-175 °C; H NMR (200 MHz,
CDCl3:CCl4 7:3) δ 3.57 (s, 6H), 3.61 (d, 1H, J ) 11.2 Hz), 4.16
(d, 1H, J ) 11.2 Hz), 7.25-7.70 (m, 11H); 13C NMR (50 MHz,
CDCl3:CCl4 7:3) δ 51.9 (q), 52.3 (q), 52.5 (d), 53.5 (d), 89.8 (s),
93.7 (s), 117.9 (d), 127.7 (s), 127.9 (s), 128.0 (d), 128.4 (d), 129.1
(d), 129.4 (d), 129.5 (d), 133.9 (s), 135.3 (d), 137.7 (s), 148.7
(s), 157.2 (s), 167.6 (s), 168.9 (s). Anal. Calcd for C25H19Cl2-
NO5S: C, 58.15; H, 3.70; N, 2.71. Found: C, 58.45; H, 3.38;
N, 2.91.
Dim et h yl 3,5-Dich lor o-1-(4-m et h oxyp h en yl)-8-(p h e-
n ylth io)-11-oxa-4-azatr icyclo[6.2.1.02,7]u n deca-2,4,6-tr ien e-
9,10-d ica r boxyla te (27) was prepared in a similar manner
(conditions B) from keto sulfoxide 20 (110 mg, 0.26 mmol) in
40% yield as a white solid: mp 164-166 °C; IR (KBr) 1743,
1596, 1339, 1246 cm-1; 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ
3.55 (s, 3H), 3.56 (s, 3H), 3.57 (d, 1H, J ) 10.9 Hz), 3.89 (s,
3H), 4.13 (d, 1H, J ) 10.9 Hz), 6.89-7.62 (m, 10H); 13C NMR
(50 MHz, CDCl3:CCl4 7:3) δ 51.9 (q), 52.3 (q), 52.5 (d), 53.5
(d), 55.0 (q), 89.7 (s), 93.4 (s), 113.8 (d), 117.9 (d), 125.8 (s),
128.0 (s), 129.1 (d), 129.4 (d), 129.5 (d), 135.4 (d), 137.6 (s),
143.7 (s), 148.7 (s), 157.3 (s), 160.4 (s), 167.5 (s), 168.9 (s). Anal.
Calcd for C26H21Cl2NO6S: C, 57.15; H, 3.87; N, 2.56. Found:
C, 56.98; H, 3.97; N, 2.43.
[2,6-Dich lor o-3-(4-m eth oxyben zoyl)p yr id in -4-yl](p h en -
ylth io)m eth yl a ceta te (29) was obtained along with 27 via
a Pummerer reaction of keto-sulfoxide 20 under conditions A
as a white crystalline solid: mp 123-124 °C; IR (KBr) 1763,
1573, 1661, 1569, 1318 cm-1; 1H NMR (200 MHz, CDCl3:CCl4
7:3) δ 1.98 (s, 3H), 3.88 (s, 3H), 6.75-7.91 (m, 11H); 13C NMR
(50 MHz, CDCl3:CCl4 7:3) δ 20.6 (q), 55.5 (q), 77.4 (d), 114.2
(d), 120.6 (d), 128.8 (s), 129.2 (d), 129.5 (d), 129.9 (s), 130.7
(s), 132.3 (d), 134.6 (d), 147.2 (s), 149.7 (s), 150.7 (s), 164.8 (s),
168.3 (s), 189.9 (s). FAB MS m/z (rel intensity) 461 (M+, 1),
446 ([M - CH3]+; 12), 434 ([M - CO]H+, 10), 386 (12), 364 (4),
336 (2), 273 (2), 235 (3), 165 (3). Anal. Calcd for C22H17Cl2-
NO4S: C, 57.15; H, 3.70; N, 3.02. Found: C, 57.29; H, 3.58;
N, 2.97.
1,3-Dich lor o-5-(p h en ylth io)-7,8,9,10-tetr a h yd r oben zo-
[h ]isoqu in olin e (43) was prepared from keto sulfoxide 37 (40
mg, 0.1 mmol) by similar methodology in 56% yield: IR (KBr)
1574, 1539, 1333, 1112, 1025 cm-1; 1H NMR (200 MHz, CDCl3:
CCl4 7:3) δ 1.78-1.98 (m, 4H), 2.79-3.05 (m, 2H), 3.45-3.63
(m, 2H), 7.01-7.41 (m, 5H), 7.60 (s, 1H), 8.17 (s, 1H); 13C NMR
(50 MHz, CDCl3:CCl4 7:3) δ 21.7 (t), 23.2 (t), 31.1 (t), 31.2 (t),
118.3 (d), 126.8 (d), 127.3 (s), 127.9 (s), 129.0 (d), 129.4 (d),
135.7 (s), 136.1 (s), 138.5 (s), 140.8 (d), 141.0 (s), 142.8 (s) 149.0
(s). FAB MS m/z (rel intensity) 360 ([M + H]+, 21), 273 (3),
235 (6), 165 (5); HRMS (FAB) calcd for C19H16Cl2NS (M+H)+
m/ z 360.0380, found 360.0381. Anal. Calcd for C19H15Cl2NS:
C, 63.34; H, 4.19; N, 3.88. Found: C, 62.98; H, 4.35; N, 4.29.
Dim eth yl 1,3-Dich lor o-8-(4-m eth ylp h en yl)-5-(p h en yl-
th io)isoqu in olin e-6,7-d ica r boxyla te (45). To a stirred solu-
tion of oxa-bridged diester 26 (80 mg, 0.15 mmol) in 5 mL of
toluene was added DBU (0.22 mL, 1.5 mmol) dropwise at room
temperature. The mixture was heated at reflux for 1.5 h giving
a reddish yellow solution, cooled, washed with 10% HCl, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatographic purification (EtOAc:petroleum
ether 10:90) gave 42 mg (55%) of 45 as a yellow crystalline
solid: mp 160-161 °C; IR (KBr) 1735, 1585, 1363, 1333, 1062
cm-1; 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.44 (s, 3H), 3.47
(s, 3H), 3.87 (s, 3H), 7.08-7.40 (m, 9H), 8.36 (s, 1H); 13C NMR
(50 MHz, CDCl3:CCl4 7:3) δ 21.5 (q), 52.5 (q), 53.0 (q), 118.9
(d), 125.0 (s), 127.1 (d), 127.8 (s), 128.6 (d), 128.7 (d), 129.5
(d), 133.5 (s), 134.3 (s), 135.2 (s), 138.5 (s), 141.4 (s), 141.6 (s),
142.8 (s), 146.0 (s), 151.8 (s), 166.6 (s), 166.9 (s). FAB MS m/z
(rel intensity) 512 ([M + H]+, 21), 480 ([M - OCH3]+, 9), 412
(2), 273 (3), 235 (6), 165 (5). Anal. Calcd for C26H19Cl2NO4S:
C, 60.95; H, 3.73; N, 2.73. Found: C, 60.92; H, 3.85; N, 2.89.
Dim et h yl 1,3-Dich lor o-8-p h en yl-5-(p h en ylt h io)-iso-
qu in olin e-6,7-d ica r boxyla te (44) was prepared similarly by
treatment of 25 (150 mg, 0.29 mmol) with DBU in 53% yield:
Meth yl 3,5-Dich lor o-1-(4-m eth oxyp h en yl)-8-(p h en ylth -
io)-11-oxa -4-a za tr icyclo[6.2.1.02,7]u n d eca -2,4,6-tr ien e-10-
ca r boxyla te (30). To a mixture of heptafluorobutyric anhy-
dride(0.47mL,1.9mmol)anda catalyticamount ofp-toluenesulfonic
acid in 5 mL of toluene heated at reflux was added a toluene
solution of keto-sulfoxide 20 (80 mg, 0.19 mmol) over a period
of 10 min under argon atmosphere. The bright yellow mixture
was allowed to reflux for an additional 1 h, concentrated under
reduced pressure, and purified by chromatography (EtOAc:
petroleum ether 5:95) quickly. The intermediate 4,6-dichloro-
3-(4-methoxyphenyl)-1-(phenylthio)furo[3,4-c]pyridine (24) (40
mg, 52% yield) was obtained as a yellow oil: IR (CDCl3) 1604,
mp 178-179 °C; IR (KBr) 1737, 1584, 1375, 1316, 1062 cm-1
;
1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 3. 43 (s, 3H), 3.88 (s,
3H), 7.15-7.32 (m, 6H), 7.35-7.48 (m, 4H), 8.37 (s, 1H); 13C
NMR (50 MHz, CDCl3:CCl4 7:3) δ 52.5 (q), 53.0 (q), 119.0 (d),
124.8 (s), 127.2 (d), 127.9 (d), 128.0 (s), 128.6 (d), 128.8 (d),
129.5 (d), 129.6 (d), 133.4 (s), 135.0 (s), 137.3 (s), 141.1 (s),
141.6 (s), 142.7 (s), 146.2 (s), 151.7 (s), 166.6 (s), 166.9 (s).
Dim eth yl 1,3-Dich lor o-8-(4-m eth oxyp h en yl)-5-(p h en -
ylth io)isoqu in olin e-6,7-d ica r boxyla te (46) was prepared
by similar treatment of 27 (60 mg, 0.11 mmol) with DBU in
45% yield as a white crystalline solid: mp 190-192 °C; IR
(KBr) 1740, 1554, 1365, 1332, 1062 cm-1; 1H NMR (200 MHz,
CDCl3) δ 3.51 (s, 3H), 3.87 (s, 6H), 6.91-7.01 (m, 2H), 7.12-
7.34 (m, 7H), 8.38 (s, 1H). Anal. Calcd for C26H19Cl2NO5S: C,
59.10; H, 3.62; N, 2.65. Found: C, 59.32; H, 3.59; N, 2.55.
Dim eth yl 3,5-Dich lor o-1-(4-m eth ylp h en yl)-8-(p h en yl-
su lfon yl)-11-oxa-4-azatr icyclo[6.2.1.02,7]u n deca-2,4,6-tr ien e-
9,10-d ica r boxyla te (47). To a mixture of oxa-bridged diester
26 (140 mg, 0.264 mmol) and NaIO4 (240 mg, 1.12 mmol) in a
10 mL mixture of CH3CN, CCl4, H2O (1:1:3) was added a
1
1508, 1259 cm-1; H NMR (200 MHz, CDCl3) δ 3.88 (s, 3H),
7.01 (d, 2H, J ) 8.8 Hz), 7.11-7.35 (m, 5H), 7.75 (d, 2H, J )
8.8 Hz). To a well-stirred toluene (5 mL) solution of 24 (40
mg, 0.099 mmol) was added methyl acrylate (0.068 mL, 0.76
mmol) and the mixture was heated at reflux for 1 h under
argon. The resulting yellow solution was triturated with 5 mL
of ether, washed with H2O, and concentrated under reduced
pressure. Purification of the crude product by preparative layer
chromatography yielded a mixture of two isomers (23 mg, 46%
yield) which on crystallization gave 30 as the major isomer
1
(mp 117-119 °C): IR (KBr) 1736, 1575, 1320, 1220 cm-1; H
NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.12 (dd, 1H, J 1 ) 12.2 Hz,
J 2 ) 4.2 Hz), 2.58 (dd, 1H, J 1 ) 12.2 Hz, J 2 ) 10.2 Hz), 3.57
(s, 3H), 3.86 (s, 3H), 3.91 (dd, 1H, J 1 ) 10.2 Hz, J 2 ) 4.2 Hz),
6.91-7.10 (m, 2H), 7.16 (s, 1H), 7.25-7.39 (m, 3H), 7.51-7.68
(m, 4H); 13C NMR (50 MHz, CDCl3) δ 39.8 (t), 47.7 (d), 52.4
6926 J . Org. Chem., Vol. 68, No. 18, 2003

Heterocyclic Analogues of 1-Arylnaphthalene Lignans
catalytic amount of RuCl3‚xH2O. The solution was stirred at
room temperature for 2 h and then diluted with 5 mL of CH2-
Cl2. The resulting two layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL). The combined
organic layer was dried over anhydrous Na2SO4 and concen-
trated. The crude black residue was diluted with 20 mL of
diethyl ether and filtered through a short column of silica gel,
which on concentration gives 140 mg (94%) of 47 as a white
crystalline solid: mp 202-203 °C; IR (KBr) 1750, 1591, 1333,
1164 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.36 (s, 3H), 3.58 (s,
3H), 3.66 (s, 3H), 4.21 (d, 1H, J ) 11.2 Hz), 4.29 (d, 1H, J
)11.2 Hz), 7.12 (s, 4H), 7.51-7.99 (m, 5H), 7.93 (s, 1H);13C
NMR (50 MHz, CDCl3) δ 21.3 (q), 50.8 (d), 52.6 (q), 53.0 (d),
91.8 (s), 98.0 (s), 118.3 (d), 127.8 (d), 129.2 (d), 129.3 (d), 129.8
(s), 130.2 (d), 134.7 (s), 135.1 (d), 137.6 (s), 140.0 (s), 144.5 (s),
149.2 (s), 152.8 (s), 167.2 (s), 168.4 (s). DCI-MS m/z (rel
intensity) 562 ([M + H]+, 100), 579 ([M + NH4]+, 14); HRMS
(FAB) calcd for C26H22Cl2NO7S (M + H)+ m/z 562.0494, found
562.0507.
(s, 3H), 3.93 (s, 3H), 4.07 (s, 3H), 7.09 (d, 2H J ) 8.0 Hz), 7.17
(d, 2H, J ) 8.0 Hz), 8.03 (s, 1H); 13C NMR (50 MHz, CDCl3:
CCl4 7:3) δ 21.4 (q), 52.2 (q), 53.0 (q), 63.7 (q), 115.0 (d), 124.1
(s), 125.4 (s), 128.3 (d), 130.0 (d), 134.1 (s), 134.4 (s), 134.6 (s),
136.5 (s), 137.9 (s), 144.9 (s), 151.3 (s), 153.0 (s), 165.4 (s), 167.0
(s). Anal. Calcd for C21H17Cl2NO5: C, 58.09; H, 3.94; N, 3.22.
Found: C, 58.19; H, 3.89; N, 3.41.
5,7-Dich lor o-9-m eth oxy-4-(4-m eth ylp h en yl)fu r o[3,4-g]-
isoqu in olin -3(1H)-on e (50). To a stirred solution of 49 (50
mg, 0.11 mmol) in 10 mL of CH2Cl2 cooled to -78 °C was added
0.25 mL of DIBAL-H (1.0 M solution in toluene) dropwise
under argon. The resulting mixture was stirred for 30 min at
the same temperature and then allowed to warm to 0 °C. The
reaction mixture was quenched with 2 mL of saturated
aqueous NH4Cl solution and stirred for 30 min, then it was
acidified with 20% HCl and two layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
concentrated under reduce pressure and on preparative layer
chromatographic purification gave 40 mg (90%) of 50 as a
white crystalline solid: mp 252-254 °C; IR (KBr) 1779, 1573,
Dim eth yl 1,3-Dich lor o-5-h yd r oxy-8-(4-m eth ylp h en yl)-
isoqu in olin e-6,7-d ica r boxyla te (48). To a stirred solution
of sulfone 47 (140 mg, 0.25 mmol) in 10 mL of toluene was
added DBU (0.075 mL, 0.5 mmol) at room temperature and
the mixture was then heated to reflux for 1 h under argon.
The reddish yellow solution was washed with 10% HCl, dried
over anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue on chromatographic purification (EtOAc:
petroleum ether 30:70) gave 80 mg (77%) of 48 as a white
crystalline solid: mp 209 °C; IR (KBr) 3441, 3018, 1732, 1612,
1
1460, 1333 cm-1; H NMR (200 MHz, CDCl3) δ 2.45 (s, 3H),
4.19 (s, 3H), 5.59 (s, 2H), 7.01-7.35 (m, 4H), 8.14 (s, 1H); 13
C
NMR (50 MHz, CDCl3) δ 21.5 (q), 59.9 (q), 65.8 (t), 114.8 (d),
124.5 (s), 125.7 (s), 128.5 (d), 129.0 (s), 129.3 (d), 131.7 (s),
137.0 (s), 137.7 (s), 138.2 (s), 145.3 (s), 147.8 (s), 152.5 (s), 167.3
(s). FAB MS m/z (rel intensity) 374 ([M + H]+, 8), 329 ([M -
CO2]+, 3) 273 (6), 242 (5), 165 (6); HRMS (FAB) calcd for
C
19H14Cl2NO3 (M+H)+ m/ z 374.0351, found 374.0351. Anal.
1
1558, 1199 cm-1; H NMR (200 MHz, CDCl3) δ 2.40 (s, 3H),
Calcd for C19H13Cl2NO3: C, 60.98; H, 3.49; N, 3.74. Found: C,
60.71; H, 3.32; N, 3.85.
3.47 (s, 3H), 3.97 (s, 3H), 7.08 (d, 2H, J ) 8.1 Hz), 7.17 (d, 2H,
J ) 8.0 Hz), 8.31 (s, 1H), 12.42 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 21.4 (q), 51.9 (q), 53.6 (q), 106.0 (s), 116.2 (d), 126.4
(s), 128.2 (d), 128.7 (s), 130.8 (d), 133.4 (s), 134.3 (s), 137.9 (s),
143.7 (s), 144.4 (s), 150.4 (s), 167.7 (s), 169.3 (s). DCI-MS m/z
(rel intensity) 420 ([M + H]+, 100), 437 ([M + NH4]+, 7); HRMS
(FAB) calcd for C20H16Cl2NO5 (M + H)+ m/z 420.0406, found
420.0410.
Ack n ow led gm en t . Financial support from CSIR,
Government of India, is gratefully acknowledged. We
are also thankful to Prof. H. K. Fun (Malaysia), Dr. S.
Djuric (Abbott, Chicago, IL), Prof. T. Gallagher (Bristol,
UK), Prof. T. J . Chow (Academia Sinica, Taipei, Tai-
wan), Dr. C. Fehr (Firmenich, Geneva), and Dr. A.
Sarkar (NCL, Pune) for continuing help and support.
Mr. F. J aipuri (U.S.A.) is thanked for some computa-
tional work. N.P. and S.B. thank the CSIR, Government
of India, for a senior research fellowship.
Dim eth yl 1,3-Dich lor o-5-m eth oxy-8-(4-m eth ylp h en yl)-
isoqu in olin e-6,7-d ica r boxyla te (49). Diazomethane gener-
ated from N-nitroso N-methyl urea (236 mg, 2.29 mmol) and
40% aqueous KOH in diethyl ether was added to 120 mg (0.28
mmol) of 48 at 0 °C. After vigorous hand stirring the ice bath
was removed and the reaction mixture was left at room
temperature overnight. Ether was removed under reduced
pressure and the residue on chromatographic purification
(EtOAc: petroleum ether 20:80) gave 110 mg (89%) of 49 as a
white solid: mp 135-137 °C; IR (KBr) 1740, 1560, 1338, 1208
cm-1; 1H NMR (200 MHz, CDCl3:CCl4 7:3) δ 2.41 (s, 3H), 3.44
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 8, 9, 16, 19, 26, 30, 32, 34, 42, 45, 47,
49, and 50. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0344081
J . Org. Chem, Vol. 68, No. 18, 2003 6927