An Expedient Route for the Stereoselective Construction of Bridged Polyheterocyclic Ring Systems Using the Tandem "Pincer" Diels-Alder Reaction

Article abstract of DOI:10.1021/jo9701593

The tandem "pincer" Diels-Alder reaction, consisting of two consecutive [4 + 2] cycloadditions between two dienes and an acetylenic bis-dienophile, has been applied toward the rapid construction of bridged polyoxacyclic ring systems when furan derivatives are used as the diene components. The study has demonstrated the stereoselectivity (exo-exo adduct), the chemoselectivity ("pincer" vs "domino"), as well as the regioselectivity of the reaction. The reaction has been successfully applied to a variety of 2-substituted furans and tethered bis-furans in combination with mono-activated and diactivated dienophiles. The synthesis of unsymmetrical cycloadducts starting from the aza- and oxanorbornadiene-type intermediate has also been realized.

Full text of DOI:10.1021/jo9701593

4418
J . Org. Chem. 1997, 62, 4418-4427
An Exp ed ien t Rou te for th e Ster eoselective Con str u ction of
Br id ged P olyh eter ocyclic Rin g System s Usin g th e Ta n d em
“P in cer ” Diels-Ald er Rea ction
Mark Lautens* and Eric Fillion
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
Received J anuary 28, 1997X
The tandem “pincer” Diels-Alder reaction, consisting of two consecutive [4 + 2] cycloadditions
between two dienes and an acetylenic bis-dienophile, has been applied toward the rapid construction
of bridged polyoxacyclic ring systems when furan derivatives are used as the diene components.
The study has demonstrated the stereoselectivity (exo-exo adduct), the chemoselectivity (“pincer”
vs “domino”), as well as the regioselectivity of the reaction. The reaction has been successfully
applied to a variety of 2-substituted furans and tethered bis-furans in combination with mono-
activated and diactivated dienophiles. The synthesis of unsymmetrical cycloadducts starting from
the aza- and oxanorbornadiene-type intermediate has also been realized.
Sch em e 1
In tr od u ction
The Diels-Alder reaction is among the most powerful
C-C bond-forming processes and one of the most widely
used and studied transformations in organic chemistry.1
Its widespread application arises from the versatility and
the predictability of the stereochemical as well as the
regiochemical outcome of the reaction based on well-
defined rules.2 The development of a variety of elegant
strategies using tandem Diels-Alder cycloadditions has
allowed the construction of multiple carbon-carbon
bonds generating an array of complex polycyclic struc-
tures in a single chemical step with control of multiple
stereocenters.3 We were interested in the applicability
of the “pincer” Diels-Alder reaction of furan derivatives
as the diene component directed toward the rapid con-
struction of bridged polyoxacyclic ring systems.4-6 The
latter are valuable and important intermediates arising
from their ability to be ring-opened to highly function-
alized cyclohexane derivatives.
The tandem “pincer” Diels-Alder reaction consists of
two consecutive Diels-Alder cycloadditions between two
dienes and an acetylenic dienophile, which acts as a bis-
dienophile. The sequence is called a tandem “domino”
Diels-Alder reaction when the second cycloaddition
occurs at the newly formed double bond of the cyclohexa-
diene intermediate (Scheme 1).6 The tandem “pincer”
and “domino” Diels-Alder reactions have served as the
cornerstone in Paquette’s classic synthesis of dodeca-
hedrane6 and Prinzbach’s synthesis of pagodane,7 respec-
tively. Despite these successful examples, the synthetic
potential of the tandem “domino” and “pincer” Diels-
Alder reactions remains underutilized in organic syn-
thesis.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) For recent reviews on the Diels-Alder reaction, see: (a) Carru-
thers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon
Press: New York, 1990. (b) Intermolecular Diels-Alder reactions:
Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, p 315. (c) Heterodienophile
additions to dienes: Weinreb, S. M. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p
401. (d) Heterodiene additions: Boger, D. L. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p
451. (e) Intramolecular Diels-Alder reactions: Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 5, p 513. (f) Retrograde Diels-Alder reactions:
Sweger, R. W.; Czarnik, A. W. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 551.
(2) For a critical survey on the mechanistic aspect of Diels-Alder
reactions, see: Sauer, J .; Sustmann, R. Angew. Chem., Int. Ed. Engl.
1980, 19, 779.
(3) For recent reviews on tandem Diels-Alder cycloadditions: (a)
Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (b) Winkler,
J . D. Chem. Rev. 1996, 96, 167. (c) Ho, T.-L. Tandem Organic Reactions;
J ohn Wiley and Sons: New York, 1992.
(4) (a) For a recent review on aromatic heterocycles as intermediates
in synthesis, see: Shipman, M. Contemp. Org. Synth. 1995, 2, 1. (b)
For the synthesis of a symmetrical dioxapentacycle and its enantio-
selective desymmetrization, see: Marchionni, C.; Vogel, P.; Roversi,
P. Tetrahedron Lett. 1996, 37, 4149.
The dioxacyclic compounds obtained from the “pincer”
Diels-Alder reaction between 2 equiv of furan derivative
and 1 equiv of acetylenic dienophile have been known
for 65 years.8 However, they have essentially remained
a chemical “curiosity”, and no substantial progress has
been made in optimizing their preparation. As far as
their utilization in synthesis is concerned, it has been
limited to very few examples.9 In the cases reported to
date, the diene counterparts were limited to furan,10,11
1,3-diphenylisobenzofuran,12 and a few other symmetrical
furan derivatives.13 The dienophiles generally used were
(5) (a) For recent reviews on the ring opening of oxabicyclic systems,
see: Woo, S.; Keay, B. Synthesis 1996, 669. (b) Chiu, P.; Lautens, M.
Topics in Current Chemistry; Springer-Verlag: Berlin, in press. (c)
Lautens, M. Synlett 1993, 177. (d) Lautens, M.; Chiu, P.; Ma, S.; Rovis,
T. J . Am. Chem. Soc. 1995, 117, 532. (e) Lautens, M.; Klute, W. Angew.
Chem., Int. Ed. Engl. 1996, 35, 442.
(6) (a) For the first use of the terms “pincer” and “domino” Diels-
Alder, see: Paquette, L. A.; Wyvratt, M. J .; Berk, H. C.; Moerck, R. E.
J . Am. Chem. Soc. 1978, 100, 5845. (b) Paquette, L. A.; Balogh, D. W.
J . Am. Chem. Soc. 1982, 104, 774.
(7) Fessner, W.-D.; Sedelmeier, G.; Spurr, P. R.; Rihs, G.; Prinzbach,
H. J . Am. Chem. Soc. 1987, 109, 4626.
(8) Diels, O.; Alder, K. J ustus Liebigs Ann. Chem. 1931, 490, 243.
(9) (a) Tochtermann, W.; Malchow, A.; Timm, H. Chem. Ber. 1978,
111, 1233. (b) Lin, C.-T.; Chou, T.-C. Synthesis 1988, 628.
S0022-3263(97)00159-X CCC: $14.00 © 1997 American Chemical Society

Construction of Bridged Polyheterocyclic Ring Systems
J . Org. Chem., Vol. 62, No. 13, 1997 4419
dimethyl acetylenedicarboxylate (DMAD) (1) and acetyl-
enedicarboxylic acid (2). The conditions used for their
synthesis have generally led, in modest yields, to mix-
tures of stereo- and regioisomers (“pincer” vs “domino”
adducts) and to the formation of mono, bis, and tris
cycloadducts. Very reactive dienophiles as well as Lewis
acids14a or high-pressure conditions15 did not enhance the
yield or the selectivity of the reaction. Finally, dioxa-
cycles have been isolated as side products in the Diels-
Alder reaction between a furan derivative and an acet-
ylenic dienophile,16 especially when the reaction was
carried out in the presence of highly reactive fluorinated
acetylenes.17 The problem encountered in the synthesis
of this family of compounds is mainly due to the revers-
ibility of the cycloaddition reaction.14a
permutations can be envisioned for the rapid construction
of a large variety of bridged polycycles by varying the
furans and/or the dienophiles.
In this paper, we have addressed the issue of regio-,
chemo-, and stereocontrol in the tandem Diels-Alder
reaction and shown that the starting materials are
readily available. The dioxacycles thus obtained can be
utilized as precursors to a wide variety of fused polycyclic
compounds as we reported in a preliminary communica-
tion.18
Ba ck gr ou n d
In 1931, Diels and Alder incorrectly proposed that the
“pincer” adduct 3 was produced when an excess of furan
was reacted with dimethyl acetylenedicarboxylate (1) at
elevated temperature.8 In 1940, Diels and Olsen carried
out the previous experiment at room temperature and
characterized a 2:1 cycloadduct that they proved to have
structure 3. In fact, the earlier experiment was shown
to give the adduct 4.10a,f In both experiments, the
monoadduct 5 and some tris cycloadducts were also
isolated.
Our overall plan relies on the “pincer” Diels-Alder
reaction between 2 equiv of a substituted furan compo-
nent and 1 equiv of an acetylenic dienophile (eq 1). Many
(10) Furan and diactivated dienophile: (a) Diels, O.; Olsen, S. J .
Prakt. Chem. 1940, 156, 285. (b) Stockman, H. J . Org. Chem. 1961,
26, 2025. (c) Weis, C. D. J . Org. Chem. 1963, 28, 74. (d) Kallos, J .;
Deslongchamps, P. Can. J . Chem. 1966, 44, 1239. (e) Gandhi, R. P.;
Chadha, V. K. J . Chem. Soc., Chem. Commun. 1968, 552. (f) Slee, J .
D.; LeGoff, E. J . Org. Chem. 1970, 35, 3897. (g) Weber, G.; Menke, K.;
Hopf, H. Chem. Ber. 1980, 113, 531. (h) Maier, G.; J ung, W. A.
Tetrahedron Lett. 1980, 21, 3875. (i) Maier, G.; J ung, W. A. Chem. Ber.
1982, 115, 804. (j) Gorgues, A.; Stephan, D.; Belyasmine, A.; Khanous,
A.; Le Coq, A. Tetrahedron 1990, 46, 2817.
(11) Furan and monoactivated dienophile: (a) Gelin, R.; Debard, A.
Bull. Soc. Chim. Fr. 1966, 144. (b) McCulloch, A. W.; Smith, D. G.;
McInnes, A. G. Can. J . Chem. 1974, 52, 1013. (c) McCulloch, A. W.;
McInnes, A. G. Can. J . Chem. 1975, 53, 1496. (d) For an example of a
regioselective Diels-Alder reaction of 2-methylfuran with an unsym-
metrical diactivated acetylenic dienophile, see: Gorgues, A.; Simon,
A.; Le Coq, A.; Hercouet, A.; Corre, F. Tetrahedron 1986, 42, 351. (e)
Lasne, M.-C.; Ripoll, J .-L. Bull. Soc. Chim. Fr. 1986, 766.
It was not until 1970 that Slee and LeGoff determined
the configurations of the cycloadducts 3 and 4 reported
1
by Diels, Alder, and Olsen using H NMR spectroscopy
(Scheme 2).10f At low temperature, the double bond
substituted with carbomethoxy groups acts as a dieno-
phile (“pincer” mode),19 whereas at high temperature,
equilibration occurred to give reaction at the less sub-
stituted but less activated double bond (“domino” mode).
These observations were explained by the thermal lability
of the furan Diels-Alder adducts.20 Exclusive attack of
the incoming diene on the exo face of the oxanorborna-
diene intermediate 5 was a key feature of these reactions.
(12) (a) Berson, J . A. J . Am. Chem. Soc. 1953, 75, 1240. (b) Sasaki,
T.; Kanematsu, K.; Iizuka, K. Heterocycles 1975, 3, 109.
(13) (a) Kapicak, L. A.; Battiste, M. A. J . Chem. Soc., Chem.
Commun. 1973, 930. (b) Hall, R. H.; Harkema, S.; den Hertog, H. J .;
van Hummel, G. J .; Reinhoudt, D. N. Rec. Trav. Chim. Pays-Bas 1981,
100, 312. (c) Halverson, A.; Keehn, P. M. J . Am. Chem. Soc. 1982, 104,
6125. (d) Wollenweber, M.; Fritz, H.; Rihs, G.; Prinzbach, H. Chem.
Ber. 1991, 124, 2465.
Sch em e 2
(14) (a) For a detailed study on the Diels-Alder reaction between
furan and dimethyl acetylenedicarboxylate, see: McCulloch, A. W.;
Smith, D. G.; McInnes, A. G. Can. J . Chem. 1973, 51, 4125. (b) An
explanation of the stereoselective cycloaddition of furan with oxanor-
bornadienomaleimide and oxanorbornadiene anhydride intermediates
based on semiempirical molecular orbital calculations has been
reported; see: Warrener, R. N.; Elsey, G. M.; Maksimovic, L.; J ohnston,
M. R.; Kennard, C. H. L. Tetrahedron Lett. 1995, 42, 7753.
(15) J urczak, J .; Belniak, S.; Kozluk, T.; Pikul, S.; Salanski, P. Bull.
Pol. Acad. Sci., Chem. 1984, 32, 135.
(16) (a) Iten, P. X.; Eugster, C. H. Helv. Chim. Acta 1978, 61, 1134.
(b) Smith, J . G.; Dibble, P. W.; Sandborn, R. E. J . Org. Chem. 1986,
51, 3762. (c) Suzuki, T.; Kubomura, K.; Fuchii, H.; Takayama H. J .
Chem. Soc., Chem. Commun. 1990, 1687. (d) Suzuki, T.; Kubomura,
K.; Fuchii, H.; Takayama, H. J . Chem. Soc., Chem. Commun. 1991,
204. (e) Suzuki, T.; Kubomura, K.; Takayama, H. Heterocycles 1994,
38, 961. (f) Takeshita, H.; Mori, A.; Kato, N.; Kurahashi, Y.; Ito, M.
Bull. Chem. Soc. J pn. 1995, 68, 2669.
(17) (a) Russell, R. A.; Longmore, R. W.; Weerasuria, K. D. V.;
Warrener, R. N. Aust. J . Chem. 1991, 44, 1341. (b) Nezis, A.; Fayn, J .;
Cambon, A. J . Fluorine Chem. 1991, 53, 285. (c) Barlow, M. G.;
Tajammal, S.; Tipping, A. E. J . Fluorine Chem. 1993, 62, 95. (d)
Barlow, M. G.; Pritchard, R. G.; Tajammal, S.; Tipping, A. E. Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 1993, C49, 2151. (e)
Barlow, M. G.; Suliman, N. N. E.; Tipping, A. E. J . Fluorine Chem.
1995, 70, 59. (f) Barlow, M. G.; Suliman, N. N. E.; Tipping, A. E. J .
Fluorine Chem. 1995, 70, 95. (g) Barlow, M. G.; Suliman, N. N. E.;
Tipping, A. E. J . Fluorine Chem. 1995, 70, 109.
(18) Lautens, M.; Fillion, E. J . Org. Chem. 1996, 61, 7994.
(19) Slee and LeGoff reported a 15:1 ratio of exo-endo vs exo-exo,
which was shown to be erroneous by McInnis and co-workers (ref 14a).
We observed a 3:1 ratio in accordance with the results of McInnis.
(20) (a) For an example of “pincer” Diels-Alder using a tethered
bis-pyrrole see: Visnick, M.; Battiste, M. A. J . Chem. Soc., Chem.
Commun. 1985, 1621. (b) The exo addition of furan on the oxanorbor-
nadiene intermediate, yielding predominantly the exo-endo adduct, was
explained by Slee and LeGoff in terms of the bulk of the methyl esters
(ref 10f).

4420 J . Org. Chem., Vol. 62, No. 13, 1997
Lautens and Fillion
Resu lts a n d Discu ssion
Sch em e 3
P r ep a r a tion of th e Dien es. Bis-furans 6 and 7 were
prepared by trapping 2 equiv of 2-lithiofuran with 1 equiv
of 1,3-diiodopropane and 1,4-diiodobutane, respectively.
The preparation of 1,2-bis(2-furyl)ethane (9) was per-
formed according to Wenkert’s procedure29 starting from
furoin (8).
In 1961, Cram and co-workers reported21 the first and
only example of a “pincer” Diels-Alder reaction using a
tethered bis-furan to give a hexacyclic adduct of exo-exo22
stereochemistry (Scheme 3). Deslongchamps and Kallos
in 1966 established that the “pincer” cycloadduct pos-
sessing the exo-exo stereochemistry is formed exclusively
when acetylenedicarboxylic acid (2) is used as the dieno-
phile instead of DMAD (1) at room temperature.10d,23
McInnes and co-workers rationalized Deslongchamps and
Kallos’ observation on the basis of a selective crystalliza-
tion of the exo-exo product and confirmed the reversible
nature of the Diels-Alder reactions.14a The exo-endo
adduct is the major product after a few hours, whereas
the exo-exo adduct becomes predominant in solution over
time and starts to crystallize, thus driving the equilib-
rium toward its further formation. This study also
revealed that the molar ratio of diene and dienophile, the
temperature, and the reaction time are the important
factors in controlling the final ratio of products.14b
3-(2-Furyl)-1-chloropropane (10)30 was deprotonated
with n-BuLi and coupled with 3-(2-furyl)-1-iodopropane
(11),30 providing the tethered bis-furan 12 in 48% yield
(eq 2).
The heteroatom-substituted tethered bis-furans 13-
15 were synthesized in one step from furfuryl bromide
(prepared from furfuryl alcohol and PBr3 in Et2O31). The
latter was subsequently condensed with furfuryl alcohol
to give the ether 13 in 85% yield and in the same manner
with furfuryl amine, yielding the secondary amine 14 in
36% yield.32 The treatment of 2 equiv of furfuryl bromide
with 1 equiv of p-anisidine gave the p-methoxyphenyl
(PMP)-protected bis-furan 15 in 34% yield. The second-
ary amine 14 was converted to its tertiary benzyl 16 and
p-methoxybenzyl (PMB) 17 derivatives under standard
conditions.
Since the mid-1960’s interest in the dioxacycles has
been minimal. It is only recently that these compounds
have been “rediscovered” and used as templates for the
construction of belt and cavity molecules24 as well as cage
molecules25 and ladder polymers.26
In some cases, the “intermediate” aza- and oxanorbor-
nadiene-type systems can be isolated in good yields by
careful control of the reaction conditions.27,28 The isola-
tion of “mixed” dioxatetracyclic compounds starting from
an isolated oxanorbornadiene system and reaction with
a second and different diene have been reported by
Weis10c and Slee and LeGoff.10f
(21) (a) Cram, D. J .; Knox, G. R. J . Am. Chem. Soc. 1961, 83, 2204.
(b) Cram, D. J .; Montgomery, C. S.; Knox, G. R. J . Am. Chem. Soc.
1966, 88, 515.
(22) Some authors refer to this stereochemistry as endo-endo (refs
10a,b,e, 11b, and 14a).
(23) Stockman was the first to perform this experiment (ref 10b)
but incorrectly assigned the stereochemistry as exo-endo.
(24) (a) Warrener, R. N.; Butler, D. N.; Liao, W. Y.; Pitt, I. G.;
Russell, R. A. Tetrahedron Lett. 1991, 32, 1889. (b) Warrener, R. N.;
Maksimovic, L. Tetrahedron Lett. 1994, 35, 2389. (c) Warrener, R. N.;
Maksimovic, L.; Butler, D. N. J . Chem. Soc., Chem. Commun. 1994,
1831. (d) Warrener, R. N.; Wang, S.; Maksimovic, L.; Tepperman, P.
M.; Butler, D. N. Tetrahedron Lett. 1995, 36, 6141. (e) Warrener, R.
N.; Maksimovic, L.; Pitt, I. G.; Mahadevan, I.; Russell, R. A.; Tiekink,
E. R. T. Tetrahedron Lett. 1996, 36, 3773.
(25) Pollmann, M.; Mu¨llen, K. J . Am. Chem. Soc. 1994, 116, 2318.
(26) (a) Luo, J .; Hart, H. J . Org. Chem. 1988, 53, 1343. (b) Blatter,
K.; Godt, A.; Vogel, T.; Schlu¨ter, A.-D. Makromol. Chem. Macromol.
Symp. 1991, 44, 265. (c) Packe, R.; Enkelmann, V.; Schlu¨ter, A.-D.
Makromol. Chem. 1992, 193, 2829. (d) Schu¨rmann, B. L.; Enkelmann,
V.; Lo¨ffler, M.; Schlu¨ter, A.-D. Angew. Chem., Int. Ed. Engl. 1993, 32,
123.
The synthesis of tetrahydrobenzofuran (19) commenced
with the preparation of benzofuranone 18 as described
by Hammond.33 The latter was reductively deoxygenated
with a 1:1 mixture of LiAlH4 and AlCl3 to give 4,5,6,7-
tetrahydro-4-benzofuran (19) in 50% yield (eq 3).34
P r ep a r a t ion of t h e Acet ylen ic Un sym m et r ica l
Bis-Dien op h iles. 3-(Benzenesulfonyl)prop-2-ynoic acid
methyl ester (21) was synthesized using Schultz’s pro-
(27) (a) Kitzing, R.; Fuchs, R.; J oyeux, M.; Prinzbach, H. Helv. Chim.
Acta 1968, 51, 888. (b) Bansal, R. C.; McCulloch, A. W.; McInnes, A.
G. Can. J . Chem. 1969, 47, 2391. (c) Bansal, R. C.; McCulloch, A. W.;
McInnes, A. G. Can. J . Chem. 1970, 48, 1472. (d) For a recent review
on the synthesis of azabicyclic systems see: Chen, Z.; Trudell, M. L.
Chem. Rev. 1996, 96, 1179.
(28) (a) McCulloch, A. W.; Stanovnik, B.; Smith, D. G.; McInnes, A.
G. Can J . Chem. 1969, 47, 4319. (b) Anderson, W. K.; Dewey, R. H. J .
Med. Chem. 1977, 20, 306. (c) Xing, Y. D.; Huang, N. Z. J . Org. Chem.
1982, 47, 140. (d) For the asymmetric synthesis of oxanorbornadiene
intermediates see: Sha, C.-K.; Shen, C.-Y.; Lee, R.-S.; Lee, S.-R.; Wang,
S.-L. Tetrahedron Lett. 1995, 36, 1283.
(29) Wenkert, E.; Guo, M.; Lavilla, R.; Porter, B.; Ramachandran,
K.; Sheu, J .-H. J . Org. Chem. 1990, 55, 6203.
(30) Rogers, C.; Keay, B. A. Can. J . Chem. 1992, 70, 2929.
(31) Zanetti, J . E. J . Am. Chem. Soc. 1927, 49, 1065.
(32) Zanetti, J . E.; Beckmann, C. O. J . Am. Chem. Soc. 1928, 50,
2031.
(33) Zambias, R. A.; Caldwell, C. G.; Kopka, I. E.; Hammond, M. L.
J . Org. Chem. 1988, 53, 4135.
(34) (a) Nystrom, R. F.; Berger, C. R. A. J . Am. Chem. Soc. 1958,
80, 2896. (b) Scharf, H.-D.; Wolters, E. Chem. Ber. 1978, 111, 639. (c)
Buxton, S. R.; Holm, K. H.; Skattebøl, L. Tetrahedron Lett. 1987, 28,
2167.

Construction of Bridged Polyheterocyclic Ring Systems
J . Org. Chem., Vol. 62, No. 13, 1997 4421
give 30. The latter was submitted to the Diels-Alder
reaction under Prinzbach’s conditions27a in the presence
of DMAD to give the azanorbornadiene derivative 31 in
33% yield (Scheme 6).
Sch em e 6
tocol35 starting from methyl propiolate (20) (Scheme 4).
After a quick purification, the unstable dienophile was
immediately used in the cycloaddition reaction. 4-Oxo-
pent-2-ynoic acid methyl ester (22) was prepared via a
modification of J ones and co-workers’ procedure.36 Meth-
yl propiolate (20) was deprotonated with LDA and treated
with acetaldehyde. The resulting propargylic alcohol was
oxidized using J ones reagent to yield the ketoester 22 in
30% overall yield (Scheme 4).
The synthesis of 4-(benzenesulfonyl)but-3-yn-2-one (26)
started with the tetrahydropyranyl ether of 3-butyn-2-
ol (23).37 Deprotonation of the latter mixture of diaster-
eomers using n-BuLi and trapping of the resulting
organolithium species with diphenyl disulfide gave a
mixture of (phenylthio)alkynes that were deprotected to
provide the free alcohol 24 in 84% yield for the two
operations. Sequential oxidation of the alcohol38 and of
the sulfide gave the keto sulfone 26. The latter was not
purified due to its instability (rapid polymerization) and
was used directly in the cycloaddition reaction (Scheme
5).
Stu d y of th e Ta n d em “P in cer ” Diels-Ald er Cyclo-
a d d it ion . The feasibility of the regio- and stereo-
controlled “pincer” Diels-Alder reaction was first ex-
plored using 2-methylfuran (27) as the diene counterpart.
A solution of acetylenedicarboxylic acid (2) and 2 equiv
of 2-methylfuran (27) in ether was allowed to stand for
3 weeks at room temperature, during which time the
“pincer” cycloadduct 33 slowly crystallized out of the
solution (eq 5).10d The only product isolated of the 16
Sch em e 4
possible isomers was identified as the C2-symmetrical
exo-exo adduct 33 bearing the two bridgehead methyl
groups in an “anti” relationship as readily confirmed by
13C NMR spectroscopy. To the best of our knowledge,
this is the first example of a regioselective “pincer” Diels-
Alder reaction controlled solely by steric factors. Steric
repulsion between the methyl group on the oxanorbor-
nadiene intermediate 32 and the methyl group on the
incoming 2-methylfuran (27) in the transition state of the
second cycloaddition must be responsible for the produc-
Sch em e 5
tion of the “anti” product.
A
1H NMR study of the
ethereal solution showed that the oxanorbornadiene
intermediate 32 is the predominant component in the
reaction mixture. The cycloadduct 33 is found in low
concentration in solution possibly due to its insolubility
in ether and its rapid crystallization as soon as it is
formed. The “anti” dimethyl exo-endo cycloadduct was
also detected, but no trace of the “syn” dimethyl cyclo-
adducts was observed. The stereoselectivity (exo vs endo)
as well as the chemoselectivity (“pincer” vs “domino”) of
2-methylfuran (27) toward the ambident dienophile 32
are in agreement with Deslongchamps and Kallos’ ob-
servation on the reactivity of furan with acetylenedicar-
boxylic acid.10d The stereoselectivity may be driven by
crystal packing forces that cause selective crystallization
of the symmetrical exo-exo product, whereas the chemo-
selectivity of 2-methylfuran (27) toward the tetrasubsti-
tuted olefin of the ambident dienophile 32 is due to
kinetic control in the tandem Diels-Alder reaction.20a In
a single step, two new rings, four C-C bonds, and six
stereocenters have been formed.
Syn th esis of th e Aza - a n d Oxa n or bor n a d ien e-
Typ e Ad d u cts. The oxanorbornadiene intermediate 28
was prepared in one step from 2-methylfuran (27) and
DMAD (1) (eq 4).28b,c
Three steps were necessary to access the azanorbor-
nadiene intermediate 31. Pyrrole was tosylated,39 depro-
tonated40 with t-BuLi, and then alkylated with MeI to
In order to verify the hypothesis of the steric interac-
tion between the methyl groups in the regioselective
formation of 33, the experiment described above was
repeated using the unsymmetrical diactivated dienophile
21 (eq 6). The highly activated dienophile 21 has been
shown to react in a highly regioselective manner with
an unsymmetrical diene where the methoxycarbonyl
(35) Shen, M.; Schultz, A. G. Tetrahedron Lett. 1981, 22, 3347.
(36) J ones, E. R. H.; Shen, T. Y.; Whiting, M. C. J . Chem. Soc. 1950,
236.
(37) Larock, R. C.; Liu, C.-L. J . Org. Chem. 1983, 48, 2151.
(38) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(39) Papadopoulos, E. P.; Haidar, N. F. Tetrahedron Lett. 1968, 9,
1721.
(40) Hasan, I.; Marinelli, E. R.; Chang Lin, L.-C.; Fowler, F. W.;
Levy, A. B. J . Org. Chem. 1981, 46, 157.

4422 J . Org. Chem., Vol. 62, No. 13, 1997
Lautens and Fillion
Ta ble 1. Un sym m etr ica l “P in cer ” [4 + 2] Cycloa d d u cts
group was the directing group.35 After a few minutes at
room temperature, the dienophile 21 and 2-methylfuran
(27) reacted to give the oxanorbornadiene intermediate
34. However, even after standing for 3 weeks with an
excess of 2-methylfuran (27), no trace of the dioxatetra-
cyclic adducts 35 bearing the two methyl groups in a
a
[4 + 2] cycloaddition, details in the Experimental Section.
b
Isolated yield of analytically pure product.
1
“syn” relationship was detected by H NMR analysis of
perature. None of the other seven possible isomers was
observed. A H NMR analysis of the reaction mixture
the crude mixture. The only product present in the
reaction mixture was the oxanorbornadiene intermediate
34, which illustrates the significance of the steric interac-
tion in the inhibition of the formation of the “syn”
dimethyl cycloadduct in the reaction between acetylene-
dicarboxylic acid (2) and 2-methylfuran (27).
1
showed the absence of the oxanorbornadiene intermedi-
ate. This suggests that the intramolecular cycloaddition
is much faster than the reaction with a second mole of
furan and that the second step (intramolecular cyclo-
addition) is significantly faster than the first one (inter-
molecular Diels-Alder). Also, no trace of the exo-endo
cycloadduct was detected in the reaction mixture. The
formation of three new rings and six stereocenters was
performed in a single step.
The scope of the reaction has been fully defined by
using a variety of bis-furans and reacting them with
acetylenedicarboxylic acid (2) or DMAD (1) to give the
exo-exo cycloadducts in yields ranging from 63% to 79%
(entries 3-8, Table 2). 2,5-Substitution of the bis-diene
moiety 12 did not interfere with the course of the
cycloaddition, and the cycloadduct 41 was obtained in
good yield (entry 3, Table 2). Interestingly, the protecting
group on the amine had no effect on the reactivity of the
bis-diene (entries 5-7, Table 2) except in the case of 15
(entry 5, Table 2) where the reaction had to be performed
neat in order to proceed.
The generalization of this observation was achieved by
the synthesis of unsymmetrical dioxatetracycles and
“mixed” azaoxatetracycle starting from the aza- and
oxanorbornadiene intermediates 28 and 31 (Table 1).
Under the mild conditions previously used, the hetero-
norbornadiene dienophiles were unreactive. This dif-
ficulty was overcome by utilizing the lithium perchlorate-
mediated Diels-Alder reaction developed by Grieco41 and
successfully employed in the recent synthesis of a N-
siloxyazanorbornadiene derivative.42 In a typical experi-
ment, the heteronorbornadiene dienophile and the diene
were dissolved in a 5 M LiClO4 solution in ether and
stirred for 6 weeks at room temperature. The dienophile
28 reacted with 10 and 19 to give the dioxacyclic
compounds 36 and 37, respectively, in modest yield,
entries 1 and 2, Table 1. The azaoxatetracycle 38 was
prepared by treatment of the dienophile 31 with 2-
methylfuran (27) in 26% yield, entry 3, Table 1.43
Analysis of the crude reaction mixtures by 1H NMR
indicated that the exo-exo adducts bearing the bridgehead
substituents in an “anti” relationship were the only
products. The structural assignments of the cycloadducts
The unsymmetrical diactivated dienophiles 21 and 26
gave the exo-exo cycloadducts 48 and 49 as single
regioisomers (entries 9 and 10, Table 2).11d The only
exception was with the keto ester 22, which gave a 4:1
mixture of regioisomers (50 and 51) in favor of the
product where the methyl ketone was the dominant
directing group (entry 11, Table 2). The lower yield can
be attributed to the fact that the major isomer did not
crystallize out of the solution to drive the reaction to
completion. The keto sulfone 26 gave a lower yield of
the cycloadduct probably due to its fast polymerization
(entry 10, Table 2). In the case of the very reactive
dienophiles 21 and 26, the reactions were complete after
a few minutes but it took several hours before the product
began to crystallize out of the solution. The structure of
1
were made by examination of the H NMR spectra and
NOE results. In the case of 38, the stereochemistry has
been confirmed by X-ray crystallography of a diol deriva-
tive formed by reduction with LiAlH(OMe)3.44 In all the
examples, the remaining products were predominantly
the unreacted diene and dienophile.
In order to access the isomeric substrates with “syn”
substituents, the tethered bis-furan 6 was reacted with
acetylenedicarboxylic acid (2) and DMAD (1) to give the
cycloadducts 39 and 40 in good yields, entries 1 and 2,
Table 2. The symmetrical structure of the adducts was
48 was proven by X-ray crystallography.44 The H NMR
1
spectrum showed that the chemical shift of the bridge-
head proton moved upfield due to the presence of the
nearby phenyl group. A similar observation was noted
for 49. Finally, the structure of the major isomer 50 was
determined by X-ray crystallography.44
The reaction with the monoactivated dienophiles had
to be performed in an ethereal solution of LiClO4 (entries
12 and 13, Table 2). The reactions were highly regio-
selective, and the structures of the cycloadducts 52 and
54 were determined by NOE experiments. It is note-
worthy that the methoxycarbonyl group is a stronger
directing group than the phenylsulfonyl substituent
(entry 9 vs 12, Table 2) even if the latter is reported to
be a better activating group of the triple bond (entry 12
vs 13, Table 2).35,45
1
readily ascertained by H NMR spectroscopy. Reaction
of acetylenedicarboxylic acid (2) with 6 under the previ-
ously described conditions was significantly faster than
the one of 2-methylfuran (27) and provided the exo-exo
dioxapentacyclic adduct 39 after 1 week at room tem-
(41) (a) Grieco, P. A.; Nunes, J . J .; Gaul, M. D. J . Am. Chem. Soc.
1990, 112, 4595. (b) Forman, M. A.; Dailey, W. P. J . Am. Chem. Soc.
1991, 113, 2761.
(42) Heard, N. E.; Turner J . J . Org. Chem. 1995, 60, 4302.
(43) For the synthesis of an azaoxabicyclic system from the reaction
of furo[2,3-c]pyrroles with 2 equiv of DMAD, see: Sha, C.-K.; Lee, R.-
S.; Wang, Y. Tetrahedron 1995, 51, 193.
(44) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Construction of Bridged Polyheterocyclic Ring Systems
J . Org. Chem., Vol. 62, No. 13, 1997 4423
Ta ble 2. “P in cer ” [4 + 2] Cycloa d d ition
Sch em e 7
(55 and 57) came from the reaction of 1 equiv of DMAD
with the bis-furans without subsequent intramolecular
cycloaddition and the minor ones (56 and 58) from the
reaction of 2 equiv of DMAD (1) with the bis-furans.47 In
this case, a mixture of stereoisomers is expected even if
their presence was not detected by 1H NMR. In both
cases, 19% of the unreacted starting material was
isolated.
Con clu sion
In conclusion, we have described a regio- and stereo-
controlled approach for the simple and expedient syn-
thesis of bridged polyheterocyclic ring systems. The
flexibility of the “pincer” Diels-Alder reaction in terms
of dienes and dienophiles has been demonstrated. We
are currently delineating the scope of the ring opening
reaction of these compounds18 and utilizing the reaction
in synthesis.
a
Exp er im en ta l Section
[4 + 2] cycloaddition, details in the Experimental Section.
Isolated yield of analytically pure product. c Furfuryl sulfide is
b
The following includes general experimental procedures,
specific details for representative reactions, and isolation and
spectroscopic information for the compounds prepared.
Gen er a l P r oced u r e for th e Alk yl-Teth er ed Bis-F u r a n
P r ep a r a tion : 1,3-Bis(2-fu r yl)p r op a n e (6). A solution of
n-butyllithium (200 mL, 2.5 M solution in hexanes, 500 mmol)
was added dropwise to a solution of furan (37 mL, 509 mmol)
in THF (300 mL) at 0 °C. The mixture was stirred for 1 h at
0 °C and an additional 1 h at rt. The reaction was then cooled
to 0 °C prior to the dropwise addition of 1,3-diiodopropane (25
g, 84.5 mmol). After the addition was complete, stirring was
continued at rt for an additional 15 h. The reaction was
quenched by the addition of water (10 mL), and the solvent
was removed in vacuo. The residue was filtered over silica
gel and the product eluted with hexanes (1000 mL). The
filtrate was concentrated, and a bulb-to-bulb distillation (0.20
mmHg, 50-60 °C) of the residual oil yielded 6 (5.5 g, 37%) as
a colorless oil: Rf ) 0.33 on silica gel (100% hexanes); IR (neat)
3114, 2945, 1595, 1511, 1462 cm-1; 1H NMR (200 MHz, CDCl3)
δ 7.33 (2H, s), 6.31-6.30 (2H, m), 6.04-6.03 (2H, m), 2.70 (4H,
t, J ) 7.5 Hz), 2.02 (2H, quintet, J ) 7.5 Hz); 13C NMR (50
MHz, CDCl3) δ 155.5, 140.8, 110.0, 105.0, 27.3, 26.5. Anal.
Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 74.70; H,
6.56.
d
commercially available. The overall yield includes the oxidation
of the sulfide 25 to the sulfone and the cycloaddition. e Obtained
as a 4:1 mixture of regioisomers 50 and 51. f Ethynyl p-tolylsulfone
is commercially available.
We have also shown that the presence of a weakly
electron-donating methyl group present on the mono-
activated dienophile deactivates the alkyne and inhibits
the formation of the cycloadduct even in the presence of
LiClO4 (eq 7).
Finally, we attempted the synthesis of dioxapentacyclic
systems by changing the length of the tether separating
the furans. When 7 and 9 were treated with DMAD (1)
under the same conditions as used previously for the
three-carbon tether bis-furan 6, mixtures of two cyclo-
adducts were obtained (Scheme 7). The major adducts
1,4-Bis(2-fu r yl)bu ta n e (7). The reaction was carried out
as in the general procedure using n-butyllithium (134 mL, 2.5
M solution in hexanes, 335 mmol), furan (24.2 mL, 333 mmol),
and 1,4-diiodobutane (7.4 mL, 56 mmol). Bulb-to-bulb distil-
lation (0.20 mmHg, 60-70 °C) provided 7 (10.7 g, 100%) as a
colorless oil: Rf ) 0.25 on silica gel (100% hexanes); IR (neat)
3150, 3140, 2930, 2860, 1596, 1507, 1462, 1438 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.28 (2H, m), 6.26 (2H, dd, J ) 3.2, 2.1
(45) A similar observation has been noted by Danishefsky in his
work with â-(phenylsulfinyl)-R,â-unsaturated carbonyl dienophiles.
Danishefsky, S.; Harayama, T. J .; Singh, R. K. J . Am. Chem. Soc. 1979,
101, 7008.
(46) (a) Commercially available. (b) Truce, W. E.; Onken, D. W. J .
Org. Chem. 1975, 40, 3200.
(47) For the synthesis of 2,2′-bifuryl-DMAD adducts, see: Grigg, R.;
Roffey, P.; Sargent, M. V. J . Chem. Soc. C 1967, 2327.

4424 J . Org. Chem., Vol. 62, No. 13, 1997
Lautens and Fillion
Hz), 5.96 (2H, dd, J ) 3.1, 0.9 Hz), 2.64 (4H, t, J ) 6.8 Hz),
1.68 (4H, quintet, J ) 7.3 Hz); 13C NMR (50 MHz, CDCl3) δ
155.9, 140.6, 110.0, 104.7, 27.6, 27.4; HRMS calcd for C12H14O2
[M]+ 190.0994, found 190.0999.
°C for the dropwise addition of benzyl bromide (358 mL, 3.01
mmol). The mixture was stirred for 2 h at rt. The reaction
was quenched by the addition of water (10 mL), and the solvent
was removed in vacuo. The residue was dissolved in water
and extracted (3×) with Et2O. The combined organic layers
were dried over MgSO4, filtered, and concentrated. Flash
chromatography purification yielded 16 as a colorless oil (463
mg, 72%): Rf ) 0.49 on silica gel (hexanes-EtOAc 9:1); IR
5-(3-Ch lor op r op yl)-1,3-bis(2-fu r yl)p r op a n e (12). A so-
lution of n-butyllithium (7.26 mL, 2.5 M solution in hexanes,
18.15 mmol) was added dropwise to a solution of 3-(2-furyl)-
1-chloropropane30 (10) (2.50 g, 17.29 mmol) in THF (30 mL)
at 0 °C. After the mixture was stirred for 2 h at 0 °C, a
solution of 3-(2-furyl)-1-iodopropane30 (11) (4.08 g, 17.28 mmol)
in THF (20 mL) was added dropwise, and the resulting mixture
was stirred for an additional 15 h at rt. The reaction was
quenched by the addition of water (10 mL), and the solvent
was removed in vacuo. The aqueous layer was extracted (3×)
with Et2O. The combined organic layers were dried (MgSO4),
filtered, and concentrated. Purification of the residual oil by
flash chromatography (100% hexanes) yielded 12 as a colorless
oil (2.11 g, 48%): Rf ) 0.09 on silica gel (100% hexanes); IR
(neat) 3114, 2952, 1433, 732 cm-1; 1H NMR (200 MHz, CDCl3)
δ 7.32 (1H, s), 6.32-6.29 (1H, m), 6.03 (1H, d, J ) 2.3 Hz),
5.95-5.90 (2H, m), 3.58 (2H, t, J ) 7.7 Hz), 2.81-2.61 (6H,
m), 2.17-1.91 (4H, m); 13C NMR (50 MHz, CDCl3) δ 155.5,
154.0, 152.4, 140.7, 109.9, 105.9, 105.4, 104.9, 44.1, 31.0, 27.4,
27.3, 26.5, 25.2. Anal. Calcd for C14H17O2Cl1: C, 66.53; H,
6.78. Found: C, 66.71; H, 6.47.
(neat) 3112, 3053, 3030, 2928, 2830, 1598, 1497, 1455 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (7H, m), 6.33 (2H,
dd, J ) 2.9, 1.8 Hz), 6.23 (2H, d, J ) 2.9 Hz), 3.66 (4H, s),
3.62 (2H, s); 13C NMR (100 MHz, CDCl3) δ 152.4, 141.9, 138.9,
128.9, 128.2, 126.9, 110.0, 108.7, 57.1, 49.3. Anal. Calcd for
C17H17N1O2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.75; H,
6.51; N, 5.16.
Bis(fu r a n -2-ylm eth yl)(4-m eth oxyben zyl)a m in e (17). A
solution of 14 (3.0 g, 16.9 mmol) in THF (20 mL) was added to
a suspension of NaH (745 mg, 18.6 mmol, 80% in oil) and KH
(194 mg, 1.7 mmol, 35% in oil) (washed three times with
pentane) in THF (30 mL) and DMF (5 mL). The mixture was
stirred for 3 h at rt. A solution of p-methoxybenzyl bromide
(3.7 g, 18.6 mmol) in THF (10 mL) was added dropwise, and
the mixture was stirred for an additional 15 h at rt. The
reaction was quenched by the addition of water, and the
solvent was removed in vacuo. The residue was dissolved in
water and extracted (3×) with Et2O. The combined organic
layers were dried over MgSO4, filtered, and concentrated.
Purification by flash chromatography (hexanes-EtOAc 9:1)
gave 17 (4.43 g, 88%) as a colorless oil: Rf ) 0.44 on silica gel
(hexanes-EtOAc 9:1); IR (neat) 3062, 3032, 2999, 2951, 2928,
2830, 1611, 1509, 1454, 1245 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.39 (2H, dd, J ) 1.8, 0.7 Hz), 7.30-7.26 (2H, m), 6.87-6.83
(2H, m), 6.32 (2H, dd, J ) 3.0, 1.9 Hz), 6.21 (2H, m), 3.78 (3H,
s), 3.63 (4H, s), 3.54 (2H, s); 13C NMR (100 MHz, CDCl3) δ
158.6, 152.4, 141.9, 130.8, 130.0, 113.6, 110.0, 108.7, 56.4, 55.2,
49.1; HRMS calcd for C18H19NO3 [M]+ 297.1365, found 297.1358.
4,5,6,7-Tetr a h yd r o-4-ben zofu r a n (19).34b,c A solution of
LiAlH4 (100 mL, 1.0 M in Et2O, 100 mmol) was placed in a
three-necked flask equipped with a dropping funnel, a reflux
condenser, and a large vent. A solution of AlCl3 (13.3 g, 100
mmol) in Et2O (100 mL) was added dropwise. The formation
of a white precipitate was observed. A solution of 4,5,6,7-
tetrahydro-4-benzofuranone33 18 (13.6 g, 100 mmol) in Et2O
(200 mL) was added at a rate such as to produce a gentle
reflux. After the addition was complete, the reaction mixture
was stirred for an additional 2 h at rt. The reaction was
quenched by the addition of water (20 mL) followed by 6N
H2SO4 (50 mL) and extracted with Et2O (3×). The combined
organic layers were washed with water (1×) followed by brine
(1×), dried over Na2SO4, filtered, and concentrated in vacuo.
Vacuum distillation (∼10 mmHg, 95 °C) using a water pump
produced 19 (5.93 g, 50%) as a colorless oil: Rf ) 0.81 on silica
gel (hexanes-EtOAc 10:1); IR (neat) 3114, 2931, 2854, 1631,
1560, 1511, 1448, 1300, 1223, 1103, 1033 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.26 (1H, d, J ) 1.8 Hz), 6.22 (1H, d, J ) 1.8
Hz), 2.61 (2H, t, J ) 5.7 Hz), 2.49-2.42 (2H, m), 1.91-1.68
(4H, m); 13C NMR (100 MHz, CDCl3) δ 151.2, 140.6, 117.1,
110.9, 23.6 (2C), 22.6 (2C).
Gen er a l P r oced u r e for th e Heter oa tom -Su bstitu ted
Tet h er ed Bis-F u r a n P r ep a r a t ion : Di-r-fu r fu r yl et h er
(13).31 A solution of phosphorus tribromide (5.0 g, 18.5 mmol)
in Et2O (5 mL) was added over 20 min to a solution of freshly
distilled furfuryl alcohol (5.0 g, 51.0 mmol) in Et2O (25 mL) at
0 °C. The mixture was allowed to stand for 30 min at rt and
then decanted into an Erlenmeyer flask. The solution was
cooled to 0 °C and treated cautiously with a 40% KOH solution
(15 mL). The ether layer was decanted into a round-bottom
flask and treated with excess solid KOH (10 g). Furfuryl
alcohol (4.0 g, 40.8 mmol) was added to the furfuryl bromide
solution, and the solvent was boiled off. The remaining residue
was dissolved in water and extracted with Et2O (3×). The
combined organic layers were washed with brine (2×), dried
(MgSO4), filtered, and concentrated. Purification by flash
chromatography (hexanes-EtOAc 9:1) gave 13 (6.2 g, 85%)
as a colorless oil: Rf ) 0.50 on silica gel (hexanes-EtOAc 9:1);
1
IR (neat) 3149, 3121, 2910, 2861, 1504, 1068 cm-1; H NMR
(200 MHz, CDCl3) δ 7.41-7.40 (2H, m), 6.34-6.32 (4H, m),
4.47 (4H, s); 13C NMR (50 MHz, CDCl3) δ 151.2, 142.5, 110.0,
109.3, 63.1.
Bis(fu r a n -2-ylm eth yl)a m in e (14).32 The reaction was
carried out as in the general procedure using phosphorus
tribromide (5.0 g, 18.5 mmol), furfuryl alcohol (5.0 g, 51.0
mmol), and furfurylamine (4.0 g, 41.2 mmol). Purification by
flash chromatography (hexanes-EtOAc 1:1) gave 14 (2.63 g,
36%) as a colorless oil: Rf ) 0.43 on silica gel (hexanes-EtOAc
1:1); IR (neat) 3339, 3276, 3114, 2924, 2833, 1602 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 7.30 (2H, dd, J ) 1.8, 0.9 Hz), 6.24
(2H, dd, J ) 3.2, 1.8 Hz), 6.12 (2H, dd, 3.3, 0.7 Hz), 3.70 (4H,
s), 1.72 (1H, bs); 13C NMR (50 MHz, CDCl3) δ 153.2, 141.5,
109.8, 106.8, 44.7.
Bis(fu r a n -2-ylm et h yl)(4-m et h oxyp h en yl)a m in e (15).
The reaction was carried out as in the general procedure using
phosphorus tribromide (12.0 g, 44.1 mmol), furfuryl alcohol
(12.0 g, 121.8 mmol), and p-anisidine (5.0 g, 40.6 mmol).
Purification by flash chromatography (hexanes-EtOAc 9:1)
gave 15 (3.9 g, 34%) as a colorless oil: Rf ) 0.47 on silica gel
(hexanes-EtOAc 9:1); IR (neat) 3117, 3047, 2993, 2935, 2906,
2833, 1513, 1454, 1244, 1183, 1149, 1042, 1009 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.34 (2H, dd, J ) 1.9, 0.9 Hz), 6.88-6.85
(2H, m), 6.81-6.78 (2H, m), 6.28 (2H, dd, J ) 3.2, 1.7 Hz),
6.13 (2H, bs), 4.37 (4H, s), 3.73 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 152.5, 152.2, 143.0, 141.8, 116.3, 114.4, 110.2, 107.6,
55.5, 48.3; HRMS calcd for C17H17NO3 [M]+ 283.1208, found
282.1210.
4-Oxop en t-2-yn oic Acid Meth yl Ester (22).36 A solution
of n-butyllithium (25.0 mL, 2.5 M solution in hexanes, 62.5
mmol) was added dropwise to a solution of diisopropylamine
(8.6 mL, 59.5 mmol) in THF (300 mL) at 0 °C. The mixture
was stirred for 15 min at -78 °C and 15 min at 0 °C. The
reaction was cooled to -78 °C prior to the dropwise addition
of a solution of methyl propiolate (20) (5.0 g, 59.5 mmol) in
THF (25 mL). The mixture was stirred for 1 h at -78 °C, and
a solution of acetaldehyde (4.0 mL, 75.56 mmol) in THF (25
mL) was added. The mixture was stirred for an additionnal
2 h at -78 °C. The reaction was quenched by the addition of
saturated aqueous NH4Cl. THF was removed in vacuo, and
the residue was extracted with Et2O (3×). The combined
organic layers were dried over MgSO4, filtered, and concen-
trated.
Ben zylbis(fu r a n -2-ylm eth yl)a m in e (16). A solution of
n-butyllithium (1.06 mL, 2.5 M solution in hexanes, 2.65 mmol)
was added dropwise to a solution of 14 (426 mg, 2.41 mmol)
in THF (5 mL) at -78 °C. The mixture was stirred for 10 min
at -78 °C and 10 min at 0 °C. The mixture was cooled to -78
The crude alcohol was dissolved in acetone (150 mL) and
carefully treated with a solution of J ones’ reagent at 0 °C until
the solution remained a dark brown color. The mixture was

Construction of Bridged Polyheterocyclic Ring Systems
J . Org. Chem., Vol. 62, No. 13, 1997 4425
stirred for an additional 15 min at 0 °C prior to the addition
of NaHCO3 (5.0 g) and MgSO4. The mixture was filtered over
silica gel and the solid washed several times with Et2O. The
filtrate was concentrated and the residue purified by flash
chromatography (hexanes-EtOAc 5:1) to give 22 (2.22 g, 30%)
as a colorless oil: Rf ) 0.51 on silica gel (hexanes-EtOAc 4:1);
1-Met h yl-7-p -t olyl-7-a za b icyclo[2.2.1]h ep t a -2,5-d ien e
(31). A solution of 30 (4.29 g, 18.25 mmol) and DMAD (12.95
g, 91.13 mmol) in xylenes (30 mL) was heated at reflux for 7
h. The solvent was removed in vacuo, and the residue was
purified by flash chromatography (hexanes-EtOAc 2:1) to
yield 31 (2.25g, 33%) as a white crystalline solid: Rf ) 0.28
on silica gel (hexanes:EtOAc 2:1); mp 112-115 °C (CH2Cl2);
IR (KBr) 3100, 3002, 2945, 2847, 1724, 1700, 1635, 1439, 1345,
IR (neat) 3009, 2966, 2847, 2362, 2341, 1729, 1694, 1265 cm-1
;
1H NMR (200 MHz, CDCl3) δ 3.83 (3H, s), 2.41 (3H, s); 13C
NMR (50 MHz, CDCl3) δ 182.1, 152.3, 80.8, 77.1, 53.1, 32.0.
1
1161 cm-1; H NMR (200 MHz, CDCl3) δ 7.59 (2H, d, J ) 8.4
Hz), 7.26 (2H, d, J ) 8.2 Hz), 7.06 (1H, dd, J ) 5.2, 2.9 Hz),
6.78 (1H, d, J ) 5.5 Hz), 5.46 (1H, d, J ) 2.9 Hz), 3.72 (3H, s),
3.68 (3H, s), 2.40 (3H, s), 1.87 (3H, s); 13C NMR (50 MHz,
CDCl3) δ 164.1, 161.6, 155.8, 148.5, 148.0, 143.7, 143.5, 135.4,
129.6, 128.3, 79.0, 69.0, 52.1 (2C), 21.5, 13.6. Anal. Calcd for
C18H19NO6S: C, 57.28; H, 5.07; N, 3.71. Found: C, 57.18; H,
5.13; N, 3.73.
4-(P h en ylsu lfen yl)bu t-3-yn -2-ol (24). A solution of n-
butyllithium (9.53 mL, 2.5 M solution in hexanes, 23.83 mmol)
was added dropwise to a solution of 2-[(1-methylprop-2-ynyl)-
oxy]tetrahydropyran37 (23) (3.50 g, 22.70 mmol) in THF (75
mL) at -78 °C. After the mixture was stirred for 1 h at -78
°C, a solution of phenyl disulfide (5.20 g, 23.82 mmol) in THF
(25 mL) was added dropwise. After the addition was complete,
the mixture was warmed to rt, and stirring was continued for
an additional 2 h. The reaction was quenched by the addition
of water and diluted with Et2O. The organic layer was washed
with a 5 M NaOH solution (4×) and brine (1×), dried (MgSO4),
filtered, and concentrated.
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction in
E t 2O. Met h od A. exo,exo-1,6-Dim et h yl-11,12-d ioxa -
t et r a cyclo[6.2.1.13,6.02,7]d od eca -4,9-d ien e-2,7-d ica r b ox-
ylic Acid (33). Acetylenedicarboxylic acid (15 g, 132 mmol)
and 2-methylfuran (28 mL, 310 mmol) were dissolved in Et2O
(75 mL), and the solution was left for 3 weeks at rt with daily
stirring, during which time the product crystallized out. The
crystals were isolated by filtration and washed with Et2O to
yield the cycloadduct 33 (22.6 g, 62%) as a white solid: mp
141-143 °C (Et2O); IR (KBr) 3459-2453, 1750, 1729 cm-1; 1H
NMR (200 MHz, CD3OD) δ 6.66 (2H, dd, J ) 5.5, 1.7 Hz), 6.38
The residual oil was dissolved in MeOH (300 mL), treated
with p-TsOH (432 mg, 2.27 mmol), and stirred at rt for 5 h.
The reaction was quenched by adding 300 mL of a saturated
solution of NaHCO3 and extracted with CH2Cl2 (3×). The
combined organic layers were washed with brine (2×), dried
over MgSO4, filtered, and concentrated. Purification by flash
chromatography (hexanes-EtOAc 4:1) yielded the alcohol 24
(3.40 g, 84%) as a colorless oil: Rf ) 0.34 on silica gel
(hexanes-EtOAc 4:1); IR (neat) 3543, 3339, 3058, 2981, 2875,
(2H, d, J ) 5.5 Hz), 5.07 (2H, d, J ) 1.8 Hz), 1.64 (6H, s); 13
C
NMR (50 MHz, CD3OD) δ 173.9, 143.8, 140.1, 91.5, 81.9, 75.2,
15.1. Anal. Calcd for C14H14O6: C, 60.43; H, 5.07. Found:
C, 60.19; H, 5.34.
1
2184, 1581, 1370, 1124, 1075, 688 cm-1; H NMR (200 MHz,
3-(Ben zen esu lfon yl)-1-m eth yl-7-oxabicyclo[2.2.1]h epta-
2,5-d ien e-2-ca r boxyxlic Acid Meth yl Ester (34). Freshly
prepared 2135 (513 mg, 2.29 mmol) and 27 (1.0 mL, 11.08
mmol) in Et2O (5 mL) were stirred at rt for 15 h. The solvent
was removed in vacuo, and the residue was purified by flash
chromatography (hexanes-EtOAc 3:1) to give the cycloadduct
34 (432 mg, 62%) as a colorless oil: Rf ) 0.26 on silica gel
(hexanes-EtOAc 3:1); IR (neat) 3066, 2988, 2953, 1730, 1631,
1443, 1311, 1262, 1160, 1089 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.94-7.90 (2H, m), 7.68-7.64 (1H, m), 7.58-7.55 (2H, m),
7.06 (1H, dd, J ) 5.2, 1.9 Hz), 6.93 (1H, d, J ) 5.1 Hz), 5.48
(1H, d, J ) 1.9 Hz), 3.82 (3H, s), 1.74 (3H, s); 13C NMR (100
MHz, CDCl3) δ 163.3, 158.5, 155.6, 145.0, 143.8, 138.4, 134.1,
129.3, 128.0, 95.0, 83.5, 52.6, 14.8; HRMS calcd for C15H14O5S
[M]+ 306.0562, found 306.0570.
CDCl3) δ 7.45-7.18 (5H, m), 4.75 (1H, q, J ) 6.7 Hz), 2.66
(1H, bs), 1.54 (3H, d, J ) 6.6 Hz); 13C NMR (50 MHz, CDCl3)
δ 132.3, 129.1, 126.5, 126.1, 100.6, 70.9, 59.1, 24.1; HRMS calcd
for C10H10O1S1 [M]+ 178.0452, found 178.0449.
4-(P h en ylsu lfen yl)bu t-3-yn -2-on e (25). Oxalyl chloride
(2.83 mL, 32.40 mmol) was added dropwise to a solution of
DMSO (3.07 mL, 43.20 mmol) in CH2Cl2 (125 mL) at -78 °C.
After the addition was complete, the reaction was stirred at
-78 °C for 30 min. A solution of the alcohol 24 (3.85 g, 21.60
mmol) in CH2Cl2 (25 mL) was then added dropwise, and after
the addition was complete, the reaction was stirred at -78 °C
for an additional 30 min. Et3N (15.00 mL, 108.62 mmol) was
added and the mixture stirred for an additional 15 min at -78
°C. The reaction was poured into CH2Cl2, and the organic
layer was washed with a 1 M HCl solution (2×) and brine (1×),
dried (MgSO4), filtered, and concentrated. Purification by
flash chromatography (hexanes-EtOAc 9:1) yielded 25 (3.23
g, 85%) as a colorless oil: Rf ) 0.47 on silica gel (hexanes-
EtOAc 9:1); IR (neat) 3065, 3002, 2924, 2137, 2095, 1667, 1580,
1479, 1441, 573 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.48-7.25
(5H, m), 2.37 (3H, s); 13C NMR (50 MHz, CDCl3) δ 181.2, 129.2,
127.5, 126.6, 100.6, 84.6, 31.2; HRMS calcd for C10H8O1S1 [M]+
176.0296, found 176.0301.
Gen er a l P r oced u r e for th e Diels-Ald er Rea ction in 5
LiClO4/E t 2O. Met h od B. Cycloa d d u ct 36. The
M
cycloadduct28b,c 28 (900 mg, 4.01 mmol) and the furan deriva-
tive30 10 (580 mg, 4.01 mmol) were dissolved in a solution of
5 M LiClO4 in Et2O (5 mL) and allowed to stand at rt for 6
weeks in a sealed flask with daily stirring. The mixture was
diluted with EtOAc (100 mL), and the organic layer was
washed (3×) with water and brine (1×), dried (MgSO4),
filtered, and concentrated. Purification by flash chromatog-
raphy (hexanes-EtOAc 3:1) yielded the cycloadduct 36 (503
mg, 34%) as a pale yellow oil: Rf ) 0.13 on silica gel (hexanes-
EtOAc 3:1); IR (neat) 3095, 3014, 2953, 2873, 1716, 1457, 1436,
1387, 1242, 1083 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.62 (2H,
dd, J ) 5.5, 1.4 Hz), 6.34 (1H, d, J ) 5.5 Hz), 6.28 (1H, d, J )
5.5 Hz), 5.12 (1H, d, J ) 1.8 Hz), 5.11 (1H, d, J ) 1.8 Hz),
3.65-3.48 (2H, m), 3.60 (3H, s), 3.59 (3H, s), 2.17-1.95 (3H,
m), 1.89-1.78 (1H, m), 1.62 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 170.5, 170.4, 142.4, 140.8, 139.2, 139.0, 93.1, 90.0,
80.5(2C), 74.6, 74.3, 52.0, 51.9, 45.0, 28.0, 26.4, 14.9; HRMS
calcd for C18H21ClO6 [M]+ 368.1027, found 368.1021.
2-Meth yl-1-p-tolyl-1H-p yr r ole (30). A solution of tert-
butyllithium (14.6 mL, 1.7 M solution in pentane, 24.86 mmol)
was added dropwise to a solution of 1-p-tolyl-1H-pyrrole39 (29)
(5.0 g, 22.60 mmol) in THF (120 mL) at -78 °C. The mixture
was stirred for 10 min at -78 °C, 10 min at 0 °C, and 20 min
at rt. The mixture was cooled to 0 °C prior to the slow addition
of iodomethane (7.0 mL, 112 mmol). After the addition was
complete, the mixture was stirred for 1 h at rt, and the reaction
was quenched by the addition of a saturated aqueous NH4Cl
solution. The aqueous layer was extracted with ether (3×),
and the combined organic layers were dried over MgSO4,
filtered, and concentrated. The residue was recrystallized from
MeOH to yield 30 as a white solid (4.29 g, 81%): Rf ) 0.43 on
silica gel (hexanes-EtOAc 9:1); mp 87-88 °C (MeOH); IR
(KBr) 3142, 3107, 2966, 2924, 1595, 1490, 1455, 1358, 1174
Cycloa d d u ct 37. The reaction was carried out as in the
general procedure B using the dienophile 28 (918 mg, 4.09
mmol) and 4,5,6,7-tetrahydro-4-benzofuran (19) (500 mg, 4.09
mmol) in a solution of 5 M LiClO4 in Et2O (5 mL) for 6 weeks.
Purification by flash chromatography (hexanes-EtOAc 1:1)
yielded the cycloadduct 37 (702 mg, 50%) as a white solid: Rf
) 0.44 on silica gel (hexanes-EtoAc 1:1); mp 107-110 °C
(Et2O); IR (neat) 3016, 2945, 2861, 1742, 1715, 1435, 1241
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.67 (2H, d, J ) 8.5 Hz),
7.31-7.26 (3H, m), 6.16 (1H, t, J ) 3.3 Hz), 5.96-5.93 (1H,
m), 2.41 (3H, s), 2.29 (3H, s); 13C NMR (50 MHz, CDCl3) δ
144.7, 136.2, 130.7, 129.8, 126.8, 121.9, 113.0, 111.1, 21.5, 13.5.
Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95.
Found: C, 61.25; H, 5.79; N, 5.85.
1
cm-1; H NMR (400 MHz, CDCl3) δ 6.56 (1H, dd, J ) 5.5, 1.8
Hz), 6.26 (1H, d, J ) 5.5 Hz), 6.25-6.23 (1H, m), 5.12 (1H, d,

4426 J . Org. Chem., Vol. 62, No. 13, 1997
Lautens and Fillion
J ) 1.8 Hz), 4.93 (1H, d, J ) 1.8 Hz), 3.57 (6H, s), 2.48-2.34
(2H, m), 1.97-1.57 (4H, m), 1.52 (3H, s), 1.32-1.03 (2H, m);
13C NMR (100 MHz, CDCl3) δ 170.6, 169.5, 150.7, 143.4, 137.7,
132.3, 90.0, 80.5, 78.7, 77.2, 73.4, 72.9, 51.7, 51.5, 27.6, 26.7,
23.7, 22.5, 14.6. Anal. Calcd for C19H22O6: C, 65.88; H, 6.40.
Found: C, 65.79; H, 6.36.
Cycloa d d u ct 43. The reaction was carried out as in the
general procedure A using DMAD (1.7 g, 11.7 mmol) and 15
(3.0 g, 10.6 mmol) without solvent for 6 weeks to yield the
cycloadduct 43 (2.82g, 63%) as a white solid: Rf ) 0.40 on silica
gel (hexanes-EtOAc 1:2); mp 128-131 °C (Et2O); IR (neat)
3077, 2997, 2891, 2836, 1716, 1513, 1444, 1399, 1265, 1183,
1
1070 cm-1; H NMR (400 MHz, CDCl3) δ 7.02-6.98 (2H, m),
Cycloa d d u ct 38. The reaction was carried out as in the
general procedure B using the dienophile 31 (2.70 g, 7.16
mmol) and 2-methylfuran (3.23 mL, 35.80 mmol) in a solution
of 5 M LiClO4 in Et2O (25 mL) for 6 weeks. Purification by
flash chromatography (CH2Cl2-EtOAc 9:1) yielded the cy-
cloadduct 38 (840 mg, 26%) as a white solid: Rf ) 0.45 on silica
gel (CH2Cl2-EtOAc 9:1); mp 44-46 °C (CH2Cl2); IR (neat)
3094, 2988, 2952, 2847, 1743, 1716, 1599, 1436, 1348, 1160
6.82-6.78 (2H, m), 6.65 (2H, dd, J ) 5.5, 1.9 Hz), 6.49 (2H, d,
J ) 5.5 Hz), 5.13 (2H, d, J ) 1.8 Hz), 3.90 (2H, d, J ) 13.6
Hz), 3.74 (3H, s), 3.61 (3H, s), 3.59 (3H, s), 3.58 (2H, d, J )
13.5 Hz); 13C NMR (100 MHz, CDCl3) δ 170.3, 170.3, 154.0,
145.2, 139.7, 139.2, 119.6, 114.2, 88.1, 83.8, 71.9, 67.6, 55.5,
52.1 (2C), 49.9; HRMS calcd for C23H23NO7 [M]+ 425.1475,
found 425.1457.
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.68 (2H, d, J ) 8.4 Hz),
Cycloa d d u ct 44. The reaction was carried out as in the
general procedure A using DMAD (234 mg, 1.65 mmol) and
16 (400 mg, 1.50 mmol) in Et2O (5 mL) for 6 weeks to yield
the cycloadduct 44 (443 mg, 72%) as a white solid: Rf ) 0.40
on silica gel (hexanes-EtOAc 1:1); mp 162-165 °C (Et2O); IR
(KBr) 3030, 3000, 2950, 2850, 2790, 1735, 1708, 1465, 1437
7.21 (2H, d, J ) 8.4 Hz), 6.61 (1H, dd, J ) 5.5, 1.8 Hz), 6.35
(1H, dd, J ) 5.1, 2.2 Hz), 6.24 (1H, d, J ) 5.5 Hz), 5.95 (1H,
d, J ) 5.5 Hz), 5.11 (1H, d, J ) 2.2 Hz), 5.00 (1H, d, J ) 1.8
Hz), 3.59 (3H, s), 3.56 (3H, s), 2.37 (3H, s), 1.64 (6H, s); 13C
NMR (100 MHz, CDCl3) δ 170.0, 169.7, 143.1, 142.8, 142.5,
139.5, 138.2, 137.7, 129.3, 127.9, 90.3, 80.4, 76.5, 74.9, 72.6,
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.34-7.20 (5H, m), 6.57
65.7, 52.1, 52.0, 21.5, 14.8, 13.6. Anal. Calcd for C23H25
-
(2H, dd, J ) 5.5, 1.8 Hz), 6.41 (2H, d, J ) 5.5 Hz), 5.11 (2H,
d, J ) 1.9 Hz), 3.77 (2H, s), 3.58 (3H, s), 3.53 (3H, s), 3.29
(2H, d, J ) 13.2 Hz), 2.96 (2H, d, J ) 12.9 Hz); 13C NMR (100
MHz, CDCl3) δ 170.5, 170.4, 139.7, 139.1, 136.9, 129.3, 128.2,
127.1, 88.4, 83.7, 72.0, 67.8, 62.5, 52.0, 51.9, 50.8. Anal. Calcd
for C23H23N1O6: C, 67.47; H, 5.66; N, 3.42. Found: C, 67.08;
H, 5.80; N, 3.67.
NO7S: C, 60.12; H, 5.48; N, 3.05. Found: C, 60.10; H, 5.37;
N, 3.25.
Cycloa d d u ct 39. The reaction was carried out as in the
general procedure A using acetylenedicarboxylic acid (325 mg,
2.85 mmol) and 6 (500 mg, 2.84 mmol) in Et2O (1.5 mL) for 1
week to yield the cycloadduct 39 (608 mg, 74%) as a white
solid: mp 156-160 °C (Et2O); IR (KBr) 3416-2488, 2988,
Cycloa d d u ct 45. The reaction was carried out as in the
general procedure A using DMAD (2.3 g, 16.4 mmol) and 17
(4.4 g, 14.9 mmol) in Et2O (15 mL) for 6 weeks to yield the
cycloadduct 45 (4.26 g, 65%) as a white solid: Rf ) 0.14 on
silica gel (hexanes-EtOAc 1:1); mp 159-163 °C (acetone); IR
(CCl4) 3066, 3000, 2952, 2936, 2836, 2786, 1723, 1558, 1458,
1436, 1248, 1103, 1085, 1042, 1007 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.26-7.22 (2H, m), 6.84-6.80 (2H, m), 6.57 (2H, dd,
J ) 5.5, 1.9 Hz), 6.41 (2H, d, J ) 5.5 Hz), 5.10 (2H, d, J ) 1.5
Hz), 3.77 (3H, s), 3.71 (2H, bs), 3.59 (3H, s), 3.53 (3H, s), 3.28
(2H, d, J ) 13.2 Hz), 2.92 (2H, d, J ) 13.2 Hz); 13C NMR (100
MHz, CDCl3) δ 170.5, 170.4, 158.7, 139.8, 139.0, 130.6, 128.9,
113.6, 88.5, 83.7, 72.0, 67.8, 61.9, 55.2, 52.0, 51.9, 50.7. Anal.
Calcd for C24H25N1O7: C, 65.59; H, 5.73; N, 3.19. Found: C,
65.50; H, 5.84; N, 3.15.
Cycloa d d u ct 47. The reaction was carried out as in the
general procedure A using DMAD (2.19 g, 15.4 mmol) and
furfuryl sulfide (46) (3.00 g, 15.4 mmol) in Et2O (10 mL) for 3
weeks to yield the cycloadduct 47 (3.68 g, 71%) as a white
solid: Rf ) 0.33 on silica gel (hexanes-EtOAc 1:2); mp 191-
194 °C (Et2O); IR (KBr) 2997, 2958, 1740, 1705, 1440, 1430,
1278, 1010, 685 cm-1; 1H NMR (200 MHz, CDCl3) δ 6.57 (2H,
dd, J ) 5.5, 1.8 Hz), 6.41 (2H, d, J ) 5.5 Hz), 5.09 (2H, d, J )
1.7 Hz), 3.58 (3H, s), 3.57 (3H, s), 3.52 (2H, d, J ) 15.1 Hz),
2.87 (2H, d, J ) 15.1 Hz); 13C NMR (50 MHz, CDCl3) δ 170.2,
170.0, 141.3, 138.9, 87.1, 83.3, 73.4, 67.2, 52.1, 52.0, 27.1.
Anal. Calcd for C16H16O6S1: C, 57.13; H, 4.79. Found: C,
57.43; H, 4.80.
Cycloa d d u ct 48. The reaction was carried out as in the
general procedure A using freshly prepared 2135 (424 mg, 1.89
mmol) and 6 (366 mg, 2.08 mmol) in Et2O (10 mL) for 15 h.
Recrystallization from CH2Cl2 yielded the cycloadduct 48 (525
mg, 69%) as a white solid: Rf ) 0.38 on silica gel (hexanes-
EtOAc 1:1); mp 181-183 °C (CH2Cl2); IR (KBr) 3002, 2952,
2931, 1715, 1574, 1448, 1321, 1279, 1152 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.86-7.83 (2H, m), 7.71-7.67 (1H, m), 7.63-
7.59 (2H, m), 6.54 (4H, bs), 4.73 (2H, bs), 3.70 (3H, s), 2.21-
2.08 (4H, m), 1.92-1.80 (1H, m), 1.68-1.61 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 169.6, 142.1, 140.5, 138.6, 134.0, 129.4,
128.6, 91.5, 91.3, 83.4, 71.2, 52.3, 25.7, 16.7. Anal. Calcd for
C21H20O6S1: C, 62.99; H, 5.03. Found: C, 62.73; H, 4.81.
Cycloa d d u ct 49. A solution of 25 (500 mg, 2.84 mmol) in
CH2Cl2 (35 mL) was treated with m-CPBA 50% (2.94 g, 8.52
mmol) at 0 °C and stirred for 3 h at rt. The mixture was
diluted with CH2Cl2, washed with a saturated solution of
NaHCO3 (1×), a 5 M solution of NaOH (2×), and brine (1×),
dried (MgSO4), filtered, and concentrated. The crude keto
sulfone 26 was dissolved in Et2O (3 mL) and treated with 6
2938, 1721, 1384 cm-1 1H NMR (200 MHz, CD3OD) δ 6.58
;
(2H, dd, J ) 5.5, 1.7 Hz), 6.47 (2H, d, J ) 5.6 Hz), 5.00 (2H,
d, J ) 1.7 Hz), 2.37-2.22 (2H, m), 2.08-1.79 (3H, m), 1.71-
1.60 (1H, m); 13C NMR (50 MHz, CD3OD) δ 173.8, 173.7, 142.9,
139.6, 91.3, 84.7, 74.4, 69.7, 26.5, 18.1. Anal. Calcd for
C15H14O6: C, 62.07; H, 4.86. Found: C, 61.95; H, 4.79.
Cycloa d d u ct 40. The reaction was carried out as in the
general procedure A using DMAD (500 mg, 2.63 mmol) and 6
(444 mg, 3.12 mmol) in Et2O (2.0 mL) for 3 weeks to yield the
cycloadduct 40 (644 mg, 71%) as a white solid: Rf ) 0.39 on
silica gel (hexanes-EtOAc 1:1); mp 151-153 °C (CH2Cl2); IR
(KBr) 3002, 2959, 2924, 2861, 1736, 1708, 1434, 1272 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.50 (2H, dd, J ) 5.5, 1.8 Hz),
6.42 (2H, d, J ) 5.5 Hz), 4.99 (2H, d, J ) 1.5 Hz), 3.56 (3H, s),
3.55 (3H, s), 2.13-2.10 (4H, m), 1.98-1.86 (1H, m), 1.65 (1H,
dquintet, J ) 13.6, 3.5 Hz); 13C NMR (100 MHz, CDCl3) δ
170.8, 170.5, 142.0, 138.1, 89.9, 83.4, 73.3, 68.5, 51.9, 51.8, 25.6,
17.0. Anal. Calcd for C17H18O6: C, 64.14; H, 5.70. Found:
C, 63.72; H, 5.80.
Cycloa d d u ct 41. The reaction was carried out as in the
general procedure A using acetylenedicarboxylic acid (453 mg,
4.0 mmol) and 12 (1.00 g, 4.0 mmol) in Et2O (5 mL) for 6 weeks
to yield the cycloadduct 41 (1.15 g, 79%) as a white solid: mp
186-189 °C (acetone); IR (KBr) 3416-2545, 2959, 1727, 1695,
1683, 1408, 699 cm-1; 1H NMR (400 MHz, CD3OD) δ 6.65 (1H,
dd, J ) 5.5, 1.9 Hz), 6.47-6.43 (2H, m), 6.37 (1H, d, J ) 5.5
Hz), 5.12 (1H, d, J ) 1.8 Hz), 3.67-3.57 (2H, m), 2.39 (1H, td,
J ) 14.0, 4.9 Hz), 2.23-1.86 (8H, m), 1.68-1.64 (1H, m); 13C
NMR (100 MHz, CD3OD) δ 174.1, 173.8, 142.7, 142.4, 142.1,
140.5, 93.8, 91.4, 90.6, 82.1, 76.2, 72.6, 45.9, 29.6, 27.5, 26.6
(2), 18.1. Anal. Calcd for C18H19O6Cl1: C, 58.94; H, 5.22.
Found: C, 58.67; H, 5.17.
Cycloa d d u ct 42. The reaction was carried out as in the
general procedure A using DMAD (2.31 g, 16.25 mmol) and
13 (2.63 g, 14.77 mmol) in Et2O (20 mL) for 3 weeks. The
filtrate was concentated and the residue purified by flash
chromatography (hexanes-EtOAc 1:2) to yield the cycloadduct
42 in a combined yield of 76% (3.59 g) as a white crystalline
solid: Rf ) 0.33 on silica gel (hexanes-EtOAc 1:2); mp 178-
181 °C (Et2O); IR (KBr) 3012, 2966, 1736, 1727, 1717, 1428,
1255, 1080 cm-1; 1H NMR (400 MHz, CD3OD) δ 6.67 (2H, dd,
J ) 5.7, 1.7 Hz), 6.43 (2H, d, J ) 5.5 Hz), 5.14 (2H, d, J ) 1.5
Hz), 4.25 (2H, d, J ) 13.2 Hz), 4.13 (2H, d, J ) 13.2 Hz), 3.60
(3H, s), 3.58 (3H, s); 13C NMR (100 MHz, CD3OD) δ 171.6,
171.5, 141.4, 138.5, 89.0, 85.1, 72.4, 68.5, 65.7, 52.6, 52.5.
Anal. Calcd for C16H16O7: C, 60.00; H, 5.04. Found: C, 59.61;
H, 4.94.

Construction of Bridged Polyheterocyclic Ring Systems
J . Org. Chem., Vol. 62, No. 13, 1997 4427
(500 mg, 2.84 mmol). The mixture was stored for 24 h at rt,
during which time the product crystallized out. The crystals
were isolated by filtration and washed with Et2O to yield the
cycloadduct 49 (327 mg, 30%) as a white solid: Rf ) 0.38 on
silica gel (hexanes-EtOAc 1:1); mp 138-142 °C (CH2Cl2); IR
(KBr) 3065, 2952, 1684, 1574, 1306 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.88-7.85 (2H, m), 7.76-7.72 (1H, m), 7.68-7.64 (2H,
m), 6.80 (2H, dd, J ) 5.5, 1.8 Hz), 6.64 (2H, d, J ) 5.5 Hz),
4.65 (2H, d, J ) 1.5 Hz), 2.32 (3H, s), 2.18-2.05 (4H, m), 1.86-
1.74 (1H, m), 1.64-1.59 (1H, m); 13C NMR (100 MHz, CDCl3)
δ 206.6, 142.4, 140.1, 139.3, 134.3, 129.7, 128.0, 92.0, 88.9, 83.2,
80.5, 32.3, 25.8, 16.6. Anal. Calcd for C21H20O5S1: C, 65.61;
H, 5.24. Found: C, 65.28; H, 5.23.
a white solid (44 mg, 16%). Cycloadduct 55: Rf ) 0.43 on silica
gel (hexanes-EtOAc 3:1); IR (neat) 3037, 3002, 2952, 2854,
1715, 1638, 1509, 1436, 1271, 1229, 1009 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.29 (1H, d, J ) 1.8 Hz), 7.16 (1H, dd, J ) 5.2,
1.9 Hz), 6.93 (1H, d, J ) 5.1 Hz), 6.26 (1H, dd, J ) 3.3, 1.9
Hz), 5.99 (1H, m), 5.64 (1H, d, J ) 1.8 Hz), 3.82 (3H, s), 3.76
(3H, s), 2.82-2.70 (2H, m), 2.55-2.48 (2H, m); 13C NMR (100
MHz, CDCl3) δ 164.8, 162.7, 155.6, 154.6, 151.8, 144.6, 144.5,
141.0, 110.1, 105.2, 96.8, 83.4, 52.4, 52.3, 27.5, 23.4; HRMS
calcd for C16H16O6 [M]+ 304.0947, found 304.0943. Cyclo-
adduct 56: Rf ) 0.46 on silica gel (hexanes-EtOAc 1:1); mp
189-192 °C (Et2O); IR (KBr) 3093, 3016, 2959, 2854, 1739,
1710, 1650, 1440, 1429, 1279, 1261, 1112 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.16 (2H, dd, J ) 5.1, 1.8 Hz), 6.95 (2H, d, J )
5.1 Hz), 5.62 (2H, d, J ) 2.2 Hz), 3.81 (6H, s), 3.76 (6H, s),
2.36-2.24 (4H, m); 13C NMR (100 MHz, CDCl3) δ 164.7, 162.7,
155.5, 151.9, 144.8, 144.6, 97.0, 83.5, 52.4, 52.3, 24.3; HRMS
calcd for C22H22O10 [M]+ 446.1213, found 446.1238.
Cycloa d d u cts 50 a n d 51. The reaction was carried out
as in the general procedure A using 22 (250 mg, 2.0 mmol)
and 6 (352 mg, 2.0 mmol) in Et2O (5 mL) for 2 weeks. The
solvent was removed in vacuo, and the residue was purified
by flash chromatography (hexanes:EtOAc 1:1) to yield a
mixture of cycloadduct 50 (284 mg) and 51 (76 mg) in a 4:1
ratio as white solids in a combined yield of 60%. Cycloadduct
50: Rf ) 0.43 on silica gel (hexanes-EtOAc 1:1); mp 146-
148 °C (CH2Cl2); IR (KBr) 3023, 3002, 2959, 2931, 2868, 1738,
1-(4-F u r a n -2-ylbu t yl)-7-oxa b icyclo[2.2.1]h ep t a -2,5-d i-
en e-2,3-d ica r boxylic Acid Dim eth yl Ester (57) a n d Cy-
cloa d d u ct 58. The reaction was carried out as in the general
procedure A using DMAD (411 mg, 2.89 mmol) and 1,4-bis(2-
furyl)butane (7) (500 mg, 2.63 mmol) in Et2O (2 mL) for 3
weeks. The solvent was removed in vacuo, and the residue
was purified by flash chromatography (hexanes-EtOAc 3:1)
to yield the cycloadduct 57 (330 mg, 38%) as a colorless oil
and the unreacted starting material 7 (93 mg, 19%). Further
elution with hexanes-EtOAc (1:1) gave the cycloadduct 58 as
a clear oil (270 mg, 22%). Cycloadduct 57: Rf ) 0.40 on silica
gel (hexanes-EtOAc 3:1); IR (neat) 3009, 2952, 2861, 1718,
1639, 1508, 1437, 1272, 1231, 1201, 1006 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.25 (1H, dd, J ) 1.8, 0.7 Hz), 7.14 (1H, dd, J
) 5.2, 1.9 Hz), 6.95 (1H, d, J ) 5.5 Hz), 6.23 (1H, dd, J ) 2.9,
1.8 Hz), 5.94 (1H, dd, J ) 3.3, 0.7 Hz), 5.60 (1H, d, J ) 1.8
Hz), 3.79 (3H, s), 3.74 (3H, s), 2.60 (2H, mt, J ) 7.5 Hz), 2.22-
2.08 (2H, m), 1.68 (2H, quintet, J ) 7.5 Hz), 1.55-1.37 (2H,
m); 13C NMR (100 MHz, CDCl3) δ 165.1, 162.6, 156.1, 155.8,
151.3, 144.9, 144.5, 140.6, 110.0, 104.7, 97.6, 83.2, 52.3, 52.2,
28.5, 28.0, 27.6, 24.3; HRMS calcd for C18H20O6 [M]+ 332.1260,
found 332.1263. Cycloadduct 58: Rf ) 0.53 on silica gel
(hexanes-EtOAc 1:1); IR (neat) 3093, 3002, 2952, 2868, 1745,
1717, 1641, 1561, 1437, 1378, 1122, 1084 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.14 (2H, dd, J ) 5.3, 2.0 Hz), 6.95 (2H, d, J )
5.1 Hz), 5.61 (2H, d, J ) 1.8 Hz), 3.81 (6H, s), 3.75 (6H, s),
2.19-2.08 (4H, m), 1.58-1.41 (4H, m); 13C NMR (100 MHz,
CDCl3) δ 165.1, 162.7, 156.2, 151.4, 144.9, 144.6, 97.6, 83.3,
52.3, 52.2, 28.6, 25.0; HRMS calcd for C24H26O10 [M]+ 474.1526,
found 474.1526.
1
1680 cm-1; H NMR (200 MHz, CDCl3) δ 6.55-6.49 (4H, m),
5.04 (2H, bs), 3.60 (3H, s), 2.20-1.75 (5H, m), 1.82 (3H, s),
1.69-1.57 (1H, m); 13C NMR (50 MHz, CDCl3) δ 207.4, 171.1,
142.8, 138.4, 90.3, 83.2, 76.0, 71.2, 52.0, 31.9, 25.5, 16.9. Anal.
Calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.25; H,
5.94. Cycloadduct 51: Rf ) 0.26 on silica gel (hexanes-EtOAc
1:1); mp 139-141 °C (CH2Cl2); IR (KBr) 3002, 2945, 2924,
2861, 1726, 1704 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.59 (2H,
d, J ) 5.5 Hz), 6.42 (2H, dd, J ) 5.7, 1.9 Hz), 5.04 (2H, d, J )
1.8 Hz), 3.59 (3H, s), 2.17-2.04 (4H, m), 2.01-1.89 (1H, m),
1.98 (3H, s), 1.70-1.63 (1H, m); 13C NMR (100 MHz, CDCl3) δ
204.3, 171.5, 144.6, 135.9, 90.5, 83.5, 82.6, 67.0, 52.0, 29.7, 25.6,
17.2. Anal. Calcd for C17H18O5: C, 67.54; H, 6.00. Found:
C, 67.14; H, 5.97.
Cycloa d d u ct 52. The reaction was carried out as in the
general procedure B using methyl propiolate (20) (716 mg, 8.52
mmol) and 6 (1.0 g, 5.68 mmol) in a solution of 5 M LiClO4 in
Et2O (7 mL) for 8 weeks. Purification by flash chromatography
(hexanes-EtOAc 1:1) yielded the cycloadduct 52 (846 mg, 57%)
as a white solid: Rf ) 0.27 on silica gel (hexanes-EtOAc 1:1);
mp 119-121 °C (CH2Cl2); IR (KBr) 3065, 3009, 2952, 2917,
2847, 1715 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.56 (2H, dd, J
) 5.7, 1.7 Hz), 6.12 (2H, d, J ) 5.5 Hz), 4.82 (2H, d, J ) 1.5
Hz), 3.55 (3H, s), 2.56 (1H, s), 2.35 (2H, dt, J ) 14.0, 4.5 Hz),
2.11 (2H, dt, J ) 14.2, .3.1 Hz), 1.99 (1H, qt, J ) 13.4, .3.9
Hz), 1.75-1.68 (1H, m); 13C NMR (100 MHz, CDCl3) δ 172.1,
140.5, 139.5, 87.4, 80.8, 63.8, 55.5, 51.9, 24.8, 17.3. Anal. Calcd
for C15H16O4: C, 69.22; H, 6.20. Found: C, 68.86; H, 6.01.
Cycloa d d u ct 54. The reaction was carried out as in the
general procedure A using ethynyl p-tolylsulfone (53) (200 mg,
1.11 mmol) and 6 (235 mg, 1.33 mmol) in a solution of 5 M
LiClO4 in Et2O (3 mL) for 4 weeks. Purification by flash
chromatography (hexanes-EtOAc 1:1) yielded the cycloadduct
54 (328 mg, 83%) as a white solid: Rf ) 0.32 on silica gel
(hexanes-EtOAc 1:1); mp 165-167 °C (CH2Cl2); IR (KBr)
Ack n ow led gm en t. The E.W.R. Steacie Memorial
Fund, Natural Science and Engineering Research Coun-
cil (NSERC) of Canada, the Merck Frosst Centre for
Therapeutic Research, and the University of Toronto are
thanked for financial support. E.F. thanks the FCAR
(Que´bec) (1993-1996) and the Government of Ontario
(OGS) (1996-1997) for fellowships. Dr. Alan Lough,
University of Toronto, is thanked for the X-ray structure
determinations. Dr. Sophie Kumanovic is gratefully
acknowledged for the synthesis of 19.
3092, 3070, 2977, 2938, 1590, 1282, 1293, 1144, 1125 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.53 (2H, d, J ) 8.0 Hz), 7.21
(2H, d, J ) 8.4 Hz), 6.86 (2H, d, J ) 5.5 Hz), 6.38 (2H, dd, J
) 5.5, 1.8 Hz), 4.64 (2H, d, J ) 1.8 Hz), 2.62 (2H, dt, J ) 14.0,
4.5 Hz), 2.39 (3H, s), 2.26 (2H, dt, J ) 14.2, 3.1 Hz), 2.00 (1H,
tq, J ) 13.5, 4.1 Hz), 1.84 (1H, s), 1.83-1.76 (1H, s); 13C NMR
(100 MHz, CDCl3) δ 145.0, 144.2, 137.8, 137.2, 129.2, 129.0,
89.8, 83.5, 81.1, 64.0, 26.3, 21.6, 17.1. Anal. Calcd for
C20H20O4S1: C, 67.40; H, 5.66. Found: C, 67.27; H, 5.60.
1-(2-Fu r an -2-yleth yl)-7-oxabicyclo[2.2.1]h epta-2,5-dien e-
2,3-d ica r b oxylic Acid Dim et h yl E st er (55) a n d Cyclo-
a d d u ct 56. The reaction was carried out as in the general
procedure A using DMAD (105 mg, 0.74 mmol) and 1,2-bis(2-
furyl)ethane29 (9) (100 mg, 0.62 mmol) in Et2O (1 mL) for 3
weeks. The solvent was removed in vacuo, and the residue
was purified by flash chromatography (hexanes-EtOAc 3:1)
to give the cycloadduct 55 (70 mg, 38%) as a colorless oil and
the unreacted starting material 9 (19 mg, 19%). Further
elution with hexanes-EtOAc (1:1) gave the cycloadduct 56 as
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawings
and details of the data acquisition are available for compounds
48 and 50 and for the derivative of 38 (8 pages). This material
is contained in libraries on microfiche, 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 O9701593