1,3-Dipolar cycloadditions of acetylenic sulfones in solution and on solid supports

Article abstract of DOI:10.1021/jo801621d

(Chemical Equation Presented) Several representative acetylenic sulfones were immobilized on a polymer support derived from Merrifield resin by means of ester linkers that were used to couple free carboxylic acid groups on the solid support with benzylic hydroxyl functions on the arylsulfonyl moieties of the acetylenes. Several examples of reversed ester linkers, using Merrifield resin directly, were also successfully prepared. The 1,3-dipolar cycloadditions of the solid-supported acetylenic sulfones were investigated with a series of 1,3-dipoles, including benzyl azide, ethyl diazoacetate, diazomethane, as well as representative nitrile oxides, nitrile imines, nitrile ylides, nitrones, azomethine imines, azomethine ylides, munchnones, and sydnones. In general, analogous cycloadditions were also performed with acetylenic sulfones in solution phase for comparison. The cycloadditions typically afforded good to excellent yields of the desired products in both solution and solid phase, although the latter reactions sometimes required more vigorous conditions. Except in the case of benzyl azide and diazo compounds, where mixtures of regioisomers were obtained, the other 1,3-dipoles reacted with high regioselectivity and afforded essentially unique regioisomers. Cleavage of the products from the resin was smoothly effected by alkaline hydrolysis, while several attempts at reductive desulfonylation with sodium amalgam or samarium diiodide-HMPA resulted in N-O or C-O scission, in addition to cleavage from the polymer. The method provides access to a number of important classes of heterocycles, including variously substituted and functionalized triazoles, pyrazoles, 1,2-oxazoles, pyrroles, as well as their dihydro and bicyclic analogues. The success of the cycloadditions on polymer supports paves the way to future investigations of sequential transformations leading to libraries of useful heterocycles.

Full text of DOI:10.1021/jo801621d

1,3-Dipolar Cycloadditions of Acetylenic Sulfones in Solution and on
Solid Supports
Detian Gao, Huimin Zhai, Masood Parvez, and Thomas G. Back*
Department of Chemistry, UniVersity of Calgary, Calgary, AB, Canada, T2N 1N4
tgback@ucalgary.ca
ReceiVed July 22, 2008
Several representative acetylenic sulfones were immobilized on a polymer support derived from Merrifield
resin by means of ester linkers that were used to couple free carboxylic acid groups on the solid support
with benzylic hydroxyl functions on the arylsulfonyl moieties of the acetylenes. Several examples of
reversed ester linkers, using Merrifield resin directly, were also successfully prepared. The 1,3-dipolar
cycloadditions of the solid-supported acetylenic sulfones were investigated with a series of 1,3-dipoles,
including benzyl azide, ethyl diazoacetate, diazomethane, as well as representative nitrile oxides, nitrile
imines, nitrile ylides, nitrones, azomethine imines, azomethine ylides, munchnones, and sydnones. In
general, analogous cycloadditions were also performed with acetylenic sulfones in solution phase for
comparison. The cycloadditions typically afforded good to excellent yields of the desired products in
both solution and solid phase, although the latter reactions sometimes required more vigorous conditions.
Except in the case of benzyl azide and diazo compounds, where mixtures of regioisomers were obtained,
the other 1,3-dipoles reacted with high regioselectivity and afforded essentially unique regioisomers.
Cleavage of the products from the resin was smoothly effected by alkaline hydrolysis, while several
attempts at reductive desulfonylation with sodium amalgam or samarium diiodide-HMPA resulted in
N-O or C-O scission, in addition to cleavage from the polymer. The method provides access to a
number of important classes of heterocycles, including variously substituted and functionalized triazoles,
pyrazoles, 1,2-oxazoles, pyrroles, as well as their dihydro and bicyclic analogues. The success of the
cycloadditions on polymer supports paves the way to future investigations of sequential transformations
leading to libraries of useful heterocycles.
Introduction
conjugate additions of various types of nucleophiles.5 It also
stabilizes adjacent carbanions,6 thus making it possible to carry
out combinations of conjugate additions and intramolecular
Acetylenic sulfones are a readily available class of compounds
that provide the opportunity for a broad range of synthetically
useful transformations.1-3 The strongly electron-withdrawing
sulfone group activates an adjacent alkyne moiety toward
Diels-Alder and related cycloadditions,4 as well as toward
(4) For selected examples, see: (a) Veniard, L.; Bena¨ım, J.; Pourcelot, G. C. R.
Acad. Sci. (Ser. C) 1968, 266, 1092–1094. (b) Davis, A. P.; Whitham, G. H.
J. Chem. Soc., Chem. Commun. 1980, 639, 640. (c) De Lucchi, O.; Lucchini,
V.; Zamai, M.; Modena, G.; Valle, G. Can. J. Chem. 1984, 62, 2487–2497. (d)
Paquette, L. A.; Browne, A. R.; Doecke, C. W.; Williams, R. V. J. Am. Chem.
Soc. 1983, 105, 4113–4115. (e) Paquette, L. A.; Fischer, J. W.; Browne, A. R.;
Doecke, C. W. J. Am. Chem. Soc. 1985, 107, 686–691. (g) Back, T. G.; Parvez,
M.; Zhai, H. J. Org. Chem. 2006, 71, 5254–5259.
* To whom correspondence should be addressed. T. G. Back, Tel.: (403)
220-6256. Fax: (403) 289-9488.
(1) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford,
1993.
(2) The Chemistry of Sulphones and Sulphoxides; Patai, S., Rappoport, Z.,
Stirling, C., Eds.; Wiley: Chichester, 1988.
(5) A wide range of O, N, S, halide, carbanion, and organometallic
nucleophiles are known to react with acetylenic sulfones by conjugate addition;
see ref 3.
(3) For a review of acetylenic and allenic sulfones, see: Back, T. G.
Tetrahedron 2001, 57, 5263–5301.
(6) Block, E. Reactions of Organosulfur Compounds; Academic Press: New
York, 1978; Chapter 2.
10.1021/jo801621d CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8057–8068 8057

Gao et al.
alkylations or acylations.7 The removal of the sulfone group
from the product can be achieved by several types of reductive,
oxidative or alkylative desulfonylations.8 The combination of
conjugate addition, intramolecular alkylation or acylation and
desulfonylation has been employed in the synthesis of a variety
of alkaloids, including (-)-pumiliotoxin C,7a (-)-indolizidines
167B, 207A, 209B, and 209D,7b ent-(-)-julifloridine,9 (-)-
lasubine II,10 (()-myrtine,10 and 4-quinolone alkaloids derived
from the medicinal plant Ruta chalepensis.11 The conjugate
additions of cyclic tertiary R-vinyl amines to acetylenic sulfones
afford zwitterions that undergo facile aza-Cope rearrangements,
resulting in ring-expansions that have been utilized in the
synthesis of the marine natural products motuporamine A and
B.12 Acetylenic sulfones also undergo cycloadditions with
several types of 1,3-dipoles, including diazo compounds,13
azides,13b,14 nitrones,15 pyridine N-oxides,16 nitrile oxides,13b,17
nitrile imines,17a certain mesoionic compounds,17a,18a,b and
others.18c,d These general transformations are summarized in
Scheme 1. We recently reported the first preparation of
acetylenic sulfones on solid supports and a few of their
representative reactions.19 Several earlier examples of the
reactions of vinyl sulfones on solid supports have also ap-
peared.20 The utility of 1,3-dipolar cycloadditions21 in the
preparation of diverse heterocyclic products and the special
SCHEME 1
advantages of solid phase organic synthesis22 have prompted
us to examine a wider range of 1,3-dipoles for this purpose.
We now report the results of these cycloadditions both on solid
supports and, for comparison, in solution.
Results and Discussion
Of several methods that were investigated for the preparation
of acetylenic sulfones on solid supports,19 the one shown in
Scheme 2 proved the most generally applicable. Thus, sulfo-
nylhydrazide 1 was converted into the corresponding selenos-
ulfonate 2 by oxidation with benzeneseleninic acid.23 Several
representative acetylenes 3a-3c were then subjected to free-
radical selenosulfonation24 with 2, followed by esterification25
of the resulting adducts 4 with the polymer-supported carboxylic
acid 5 to afford the corresponding ester-linked products 6a-
(7) (a) Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566–6571. (b)
Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543–4552.
(8) For a review of desulfonylations, see: Na´jera, C.; Yus, M. Tetrahedron
1999, 55, 10547–10658.
(9) Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3853–3858.
(10) Back, T. G.; Hamilton, M. D.; Lim, V. J. J.; Parvez, M. J. Org. Chem.
2005, 70, 967–972.
(11) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68, 2223–
2233.
(12) Weston, M. H.; Nakajima, K.; Back, T. G. J. Org. Chem. 2008, 73,
4630–4637.
(21) For selected reviews and key references for 1,3-dipolar cycloadditions,
see: (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984; Vols. 1 and 2. (b) Synthetic Applications of 1, 3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley: Hoboken NJ, 2003. (c) Little, R. D. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5,Ch. 3.1, pp 239-270. (d) Padwa, A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol.
4,Ch. 4.9, pp 1069-1109. (e) Wade, P. A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, Ch. 4.10,
pp 1111-1168. (f) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–598.
(g) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633–645. (h) Huisgen, R.
J. Org. Chem. 1976, 41, 403–419. (i) Firestone, R. A. Tetrahedron 1977, 33,
3009–3039. (j) Padwa, A. Angew. Chem., Int. Ed. Engl. 1976, 15, 123–136. (k)
Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George, J. K. J. Am.
Chem. Soc. 1973, 95, 7287–7301. (l) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus,
L. J. J. Am. Chem. Soc. 1973, 95, 7301–7315. (m) Fleming, I. Frontier Orbitals
and Organic Chemical Reactions, Wiley: Chichester, 1976; pp 148-161. (n)
Sustmann, R. Tetrahedron Lett. 1971, 2717–2720. (o) Gothelf, K. V.; Jørgensen,
K. A. Chem. ReV. 1998, 98, 863–909. (p) Namboothiri, I. N. N.; Hassner, A.
Top. Curr. Chem. 2001, 216, 1–49. (q) Pellissier, H. Tetrahedron 2007, 63, 3235–
3285.
(22) For selected recent reviews, see: (a) Solid-Phase Organic Syntheses;
Czarnik, A. W., Ed.; Wiley, New York, 2001; Vol. 1. (b) Do¨rwald, F. Z. Organic
Synthesis on Solid Phase: Supports, Linkers, Reactions, 2nd ed.; Wiley-VCH:
Weinheim, 2002. (c) Booth, S. E.; Dreef-Tromp, C. M.; Hermkens, P. H. H.;
deMan, J. A. P. A.; Ottenheijm, H. C. J. In Combinatorial Chemistry; Jung, G.,
Ed.; Wiley-VCH: Weinheim, 1999; pp 35-76. (d) Handbook of Combinatorial
Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH:
Weinheim, 2002; Vols. 1 and 2. (e) Ley, S. V.; Baxendale, I. R.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer,
R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815–4195. (f)
Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217–1239. (g)
Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549–1582. (h) Sammelson,
R. E.; Kurth, M. J. Chem. ReV. 2001, 101, 137–202. (i) Kantorowski, E. J.;
Kurth, M. J. Mol. DiVersity 1997, 2, 207–216. (j) Harju, K.; Yli-Kauhaluoma,
J. Mol. DiVersity 2005, 9, 187–207. For previous reports of solid-supported
ꢀ-benzoyloxyalkyl and γ-hydroxyalkyl sulfones in Julia-Lythgoe olefinations
and in the preparation of trisubstituted pyridones, see: (k) D′herde, J. N. P.; De
Clercq, P. J. Tetrahedron Lett. 2003, 44, 6657–6659. (l) Li, W.; Chen, Y.; Lam,
Y. Tetrahedron Lett. 2004, 45, 6545–6547.
(13) (a) Massa, F.; Hanack, M.; Subramanian, L. R. J. Fluorine Chem. 1982,
19, 601–615. (b) Back, T. G.; Bethell, R. J.; Parvez, M.; Taylor, J. A.; Wehrli,
D. J. Org. Chem. 1999, 64, 7426–7432. (c) Guillerm, G.; L’Honore´, A.; Veniard,
L.; Pourcelot, G.; Benaim, J. Bull. Soc. Chim. Fr. 1973, 2739–2746. (d) Padwa,
A.; Wannamaker, M. W. Tetrahedron 1990, 46, 1145–1162. (e) Padwa, A.;
Wannamaker, M. W. Tetrahedron Lett. 1986, 27, 2555–2558. (f) Padwa, A.;
Wannamaker, M. W.; Dyszlewski, A. D. J. Org. Chem. 1987, 52, 4760–4767.
(g) Padwa, A.; Wannamaker, M. W. Tetrahedron 1991, 47, 6139–6156. (h)
Padwa, A.; Krumpe, K. E.; Terry, L. W.; Wannamaker, M. W. J. Org. Chem.
1989, 54, 1635–1642. (i) Franck-Neumann, M.; Lohmann, J.-J. Angew. Chem.,
Int. Ed. Engl. 1977, 16, 323–324. (j) Benati, L.; Calestani, G.; Nanni, D.;
Spagnolo, P.; Volta, M. Tetrahedron 1997, 53, 9269–9278. (k) Bourissou, D.;
Bertrand, G. Tetrahedron Lett. 1999, 40, 883–886.
(14) (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184–6189.
(b) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith, S. C.;
Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559–1561.
(15) (a) Padwa, A.; Carter, S. P.; Chiacchio, U.; Kline, D. N. Tetrahedron
Lett. 1986, 27, 2683–2686. (b) Padwa, A.; Bullock, W. H.; Kline, D. N.;
Perumattam, J. J. Org. Chem. 1989, 54, 2862–2869. (c) Parpani, P.; Zecchi, G.
J. Org. Chem. 1987, 52, 1417–1421. (d) Broggini, G.; Diliddo, D.; Zecchi, G.
J. Heterocycl. Chem. 1991, 28, 89–91. (e) Moriyama, S.; Valle´e, Y. Synthesis
1998, 393–404.
(16) (a) Matsuoka, T.; Hasegawa, T.; Harano, K.; Hisano, T. Heterocycles
1992, 33, 179–188. (b) Matsuoka, T.; Hasegawa, T.; Eto, M.; Harano, K.; Hisano,
T. J. Chem. Soc., Perkin Trans. 2 1993, 1859–1865.
(17) (a) Dalla Croce, P.; La Rosa, C.; Zecchi, G. J. Chem. Soc., Perkin Trans.
1 1985, 2621–2624. (b) Bruche´, L.; Gelmi, M. L.; Zecchi, G. J. Org. Chem.
1985, 50, 3206–3208.
(18) (a) Berk, H. C.; Franz, J. E. Synth. Commun. 1981, 11, 267–271. (b)
Dalla Croce, P.; Gariboldi, P.; La.Rosa, C. J. Heterocycl. Chem. 1987, 24, 1793–
1797. (c) Yamago, S.; Ejiri, S.; Nakamura, E. Angew. Chem., Int. Ed. Engl.
1995, 34, 2154–2156. (d) Acheson, R. M.; Ansell, P. J. J. Chem. Soc., Perkin
Trans. 1 1987, 1275–1281.
(19) Preliminary communication: Back, T. G.; Zhai, H. Chem. Commun.
2006, 326–328.
(20) For previous reports of synthesis with solid-supported vinyl sulfones,
see: (a) Connors, R. V.; Zhang, A. J.; Shuttleworth, S. J. Tetrahedron Lett. 2002,
43, 6661–6663. (b) Kroll, F. E. K.; Morphy, R.; Rees, D.; Gani, D. Tetrahedron
Lett. 1997, 38, 8573–8576. (c) Wang, G.; Mahesh, U.; Chen, G. Y. J.; Yao,
S. Q. Org. Lett. 2003, 5, 737–740. (d) Wang, G.; Yao, S. Q. Org. Lett. 2003, 5,
4437–4440.
(23) Back, T. G.; Collins, S.; Krishna, M. V. Can. J. Chem. 1987, 65, 38–
42.
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1,3-Dipolar Cycloadditions of Acetylenic Sulfones
SCHEME 2
SCHEME 3
6c.26 The carboxylic acid 5 was in turn obtained from Merrifield
resin by the method of Kurth et al.27 Finally, oxidation and
selenoxide syn-elimination produced the desired acetylenic
sulfones 7a-7c, while hydrolysis of 7c afforded the terminal
acetylene 7d. When the selenoxide elimination was performed
in solution phase with adducts 4, prior to attachment to the
polymer-supported carboxylic acid 5, the final products were
generally less pure, with lower loadings. The loadings in 7a
and 7c were determined gravimetrically, while those in 7b and
7d were determined by hydrolysis of the ester linkers with
lithium hydroxide solution and isolation of 1-[(p-hydroxym-
ethyl)benzenesulfonyl]-2-phenylethyne and (p-hydroxymeth-
yl)phenyl methyl sulfone (formed by cleavage of the corre-
sponding ꢀ-keto sulfone), respectively. The loading of 5 was
determined gravimetrically after conversion into the correspond-
ing cesium carboxylate. The presence of the acetylenic sulfone
moieties on the polymer supports was confirmed by strong IR
thermodynamically favored acetylenic isomers, and acid-
catalyzed hydrolysis of the methyl ester groups. The free
carboxylic acid functions of 10 and 11 were then coupled with
Merrifield resin 12 and oxidation of the sulfide products28
afforded the corresponding solid-supported sulfones 13 and 14
respectively. Moreover, oxidation of 10 to the sulfone 15 and
coupling of the latter with Wang resin 16 provided an alternative
route to 13.
Cleavage of the products from the supports was accomplished
by alkaline hydrolysis of the ester linkers. When acetylenic
sulfones 7 were employed in the cycloadditions, the polymer-
supported carboxylic acid 5 could be recovered after the
cleavage of the cycloadducts from the resin was complete. The
recycled 5 was converted back to 7a and 7b, which were
employed in several cycloadditions with comparable results to
those obtained starting with fresh carboxylic acid 5.
Alternatively, cleavage by reductive desulfonylation with
either 5% sodium amalgam29 or samarium(II) iodide in the
presence of HMPA30 proved less successful because of other
competing reduction pathways.
absorptions at ca. 2200 cm-1
.
A different approach to the preparation of solid-supported
acetylenic sulfones by means of a reversed ester linker is shown
in Scheme 3. Acetylenic sulfides 10 and 11 were obtained from
the corresponding thiols 8 and 9, respectively, via alkylation
with propargyl bromide, followed by the base-catalyzed isomer-
ization of the initially formed propargylic sulfides to their
(24) (a) Back, T. G.; Collins, S.; Kerr, R. G. J. Org. Chem. 1983, 48, 3077–
3084. For a review of selenosulfonation, see: (b) Back, T. G. In Organoselenium
Chemistry - A Practical Approach; Back, T. G., Ed.; Oxford University Press:
Oxford, 1999; pp 175-178.
(25) The esterification of 5 was performed by a similar method to one used
for the preparation of esters from bromomethyl Wang resin and a benzoic acid
derivative: (a) Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org. Chem.
1998, 63, 1172–1177.
(28) (a) Truce, W. E.; Markley, L. D. J. Org. Chem. 1970, 35, 3275–3281.
(b) Truce, W. E.; Onken, D. W. J. Org. Chem. 1975, 40, 3200–3208.
(29) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. Tetrahedron
Lett. 1976, 3477–3478.
(26) Selenosulfonates attached to a polystyrene support via their selenium
atoms have also been recently reported. :Qian, H.; Huang, X. Tetrahedron Lett.
2002, 43, 1059–1061.
(27) Beebe, X.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1995, 60, 4196–
4203.
(30) Ku¨nzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R. Tetrahedron Lett. 1991,
32, 1949–1952.
J. Org. Chem. Vol. 73, No. 20, 2008 8059

Gao et al.
CHART 1
SCHEME 4
respectively, in refluxing toluene solution (Table 1, entry 1).
Attempts were made to perform the reaction under Cu(I)-
catalyzed conditions in order to improve the regioselectivity.42
Unfortunately, decomposition of the acetylenic sulfone competed
with cycloaddition in the presence of Cu(I) and neither 29 nor
30 was isolated in useful amounts. Azide 17 and the immobilized
n-butyl-substituted acetylenic sulfone 7a produced the analogous
products 31 and 32 in similar yields (entry 2), after cleavage
from the polymer by ester hydrolysis with lithium hydroxide,
whereas the phenyl derivative 7b afforded a slight excess of
the opposite regioisomer 34, along with 33 (entry 3). An X-ray
structure of the minor product 32 made it possible to assign the
regiochemistry of 31 and 32 unequivocally, while similar
assignments to 29 and 30, as well as to 33 and 34, were based
on a comparison of their spectroscopic properties with those of
the solid phase analogues 31 and 32.
In general, an excess of the 1,3-dipole was employed in the
The solution-phase reaction of ethyl diazoacetate (18a) with
the n-butyl-substituted acetylenic sulfone 28a afforded pyrazoles
35 and 36 in 55% yield in the ratio of 4:1 (entry 4). Surprisingly,
when performed on solid phase under similar conditions, a
highly regioselective cycloaddition of the n-butyl-substituted
acetylenic sulfone 7a with 18a was observed, affording only
pyrazole 37 in 53% yield (entry 5). In contrast, the analogous
reaction of the phenyl derivative 7b with 18a failed under a
variety of conditions. The structure of the major solution product
35 was confirmed by X-ray crystallography and the structures
of the compounds 36 and 37 were assigned by comparison of
their spectra with those of 35. When the more nucleophilic
diazomethane (18b) was employed, the opposite cycloaddition
regiochemistry predominated and N-methylation was observed.
Thus, diazomethane reacted with 7a to afford 38 as the minor
cycloaddition regioisomer, along with an inseparable mixture
of 39a and 39b, produced by the further N-methylation of the
two respective nitrogen atoms of the major cycloaddition
regioisomer (entry 6). The phenyl derivative 7b produced only
the single cycloaddition regioisomer as a similar mixture of
N-methylated isomers 40a and 40b (entry 7). The identification
of individual isomers in entries 6 and 7 was based on NOE
experiments, and is tentative. Thus, irradiation of the N-methyl
group of 38 enhanced the signal of the allylic methylene protons
of the n-butyl substituent. On the other hand, irradiation of the
pyrazole C-H protons in 39a,b and 40a,b enhanced the signals
of protons from the n-butyl and phenyl substituents, respectively.
The remaining dipoles 19-27 provided highly regioselective
reactions, generally producing essentially unique (i.e., >95:5)
regioisomers of the products. Thus, 1,2-oxazole 41 was obtained
in 79% yield as a single regioisomer from the solution-phase
reaction of nitrile oxide 19 with 28b (entry 8). Similarly, 1,2-
oxazoles 42-46 were obtained from the solid-phase reactions
of 19 with acetylenic sulfones 7a, 7b, 7d, 13 and 14, respectively
(entries 9-13). Cleavage of the products from their polymer
supports was achieved by hydrolysis with aqueous lithium
cycloaddition step and the yields of the isolated products were
calculated from their weights and the loadings of the solid-
supported acetylenic sulfones. The representative dipoles that
were investigated (Chart 1) include benzyl azide (17),31 ethyl
diazoacetate (18a), diazomethane (18b), nitrile oxide 19,32 nitrile
imine 20,17a,33 nitrile ylide 21,34 nitrone 22,35 azomethine imine
23,36 azomethine ylides 2437 and 25,38 munchnones 26,39 and
sydnone 27.40
In most cases, we first investigated the reactions of dipoles
17-27 with representative acetylenic sulfones 28a and/or 28b
in solution phase in order to compare them with analogous
cycloadditions performed with the polymer-supported reagents
7a, and 7b or, in several instances, with the terminal acetylene
7d or the reversed ester derivatives 13 and 14. Compounds 28a
and 28b are readily available from the selenosulfonation and
selenoxide syn-elimination of 1-hexyne7,41 and 1-phenylacety-
lene,24a respectively (Scheme 4). The results of the cycloaddi-
tions and the yields of products 29-71 are summarized in
Table 1.
Thus, benzyl azide 17 and sulfone 28a afforded the two
regioisomeric triazoles 29 and 30 in 57 and 28% yield,
(31) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413–414.
(32) Grundmann, C.; Richter, R. J. Org. Chem. 1968, 33, 476–478.
(33) (a) Paulvannan, K.; Chen, T.; Hale, R. Tetrahedron 2000, 56, 8071–
8076. (b) Patel, H. V.; Vyas, K. A.; Pandey, S. P.; Fernandes, P. S. Tetrahedron
1996, 52, 661–668.
(34) (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C.-H. J. Am. Chem.
Soc. 1996, 118, 10150–10155. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 9260–9266. (c) Larionov, O. V.; de Meijere, A.
Angew. Chem., Int. Ed. 2005, 44, 5664–5667.
(35) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383–2386.
(36) (a) Allen, C. F. H.; Magder, E. W. J. Heterocycl. Chem. 1969, 6, 349–
360. (b) The following general method was used to prepare 23: Turk, C.; Svete,
J.; Stanovnik, B.; Golic, L.; GolicGrdadolnik, S.; Golobic, A.; Selic, L. HelV.
Chim. Acta 2001, 84, 146–156.
(37) (a) Na´jera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150.
(b) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–
10175.
(38) Silva, A. M. G.; Tome´, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Cavaleiro, J. A. S. J. Org. Chem. 2005, 70, 2306–2314.
(39) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer, F. C. Angew. Chem.,
Int. Ed. Engl. 1964, 3, 136–137.
(40) Ranganathan, D.; Bamezai, S. Tetrahedron Lett. 1983, 24, 1067–1070.
(41) Back, T. G.; Krishna, M. V. J. Org. Chem. 1987, 52, 4265–4269.
(42) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
8060 J. Org. Chem. Vol. 73, No. 20, 2008

1,3-Dipolar Cycloadditions of Acetylenic Sulfones
TABLE 1. 1,3-Dipolar Cycloadditions of Acetylenic Sulfones
J. Org. Chem. Vol. 73, No. 20, 2008 8061

Gao et al.
TABLE 1. Continued
a ∆ ) reflux; RT ) room temperature. b Ts ) p-toluenesulfonyl; Mes ) 2,4,6-trimethylphenyl (mesityl);
c Performed in solution; no cleavage step required. d Ratios were determined by NMR integration and refer to unseparated products.
hydroxide (entries 9-11) or by transesterification with sodium
methoxide in methanol (entries 12-13). Alternatively, the
product obtained from the cycloaddition of 19 and 7b was
cleaved from its support by reductive desulfonylation with 5%
sodium amalgam, resulting in concomitant N-O cleavage to
produce 47 as a mixture of equilibrating tautomers (entry 14).
8062 J. Org. Chem. Vol. 73, No. 20, 2008

1,3-Dipolar Cycloadditions of Acetylenic Sulfones
SCHEME 5
SCHEME 7
SCHEME 6
SCHEME 8
The formation of the latter confirms the regiochemistry of
product 43 in entry 10, and by analogy that of the other
cycloadducts obtained from nitrile oxide 19.
The nitrile imine 20 was generated in situ by dehydrochlo-
rination of hydrazonyl chloride 72,33 as shown in Scheme 5.
Its solution phase cycloadditions with 28a and 28b afforded
the pyrazoles 48 and 49 (entries 15 and 16), with the same
regiochemistry (i.e., 4-sulfonyl) as the major isomers 35 and
37 obtained with ethyl diazoacetate (18a) in entries 4 and 5
and the minor isomer 38 formed with diazomethane (18b) in
entry 6. Similar cycloadditions of 20 with 1-(phenylsulfonyl)-
propyne and 1-phenyl-2-(phenylsulfonyl)ethyne were reported
previously17a with the same regiochemistry corresponding to
that of 48-49 in entries 15-16. The reaction of 20 with solid-
supported acetylenic sulfones 7a and 7b produced the analogous
products 50 and 51, respectively. The structures of 48 and 51
were confirmed unequivocally by X-ray crystallography. Com-
pound 49 has been prepared previously by a different method.43
Nitrile ylide 21 was also generated in situ. Methyl N-
formylglycinate was dehydrated to the corresponding isocyanide
73,34a which was in turn treated with catalytic Cu2O (10 mol
%) to generate 21,34b,c as shown in Scheme 6. Its cycloaddition
with 28a and 28b proceeded smoothly to afford trisubstituted
pyrrole products 52 and 53, respectively (entries 19 and 20).
The corresponding reactions with solid-supported sulfones 7a
and 7b required harsher conditions, longer reaction times and
excess Cu2O, but again afforded unique regioisomers of pyrroles
54 and 55 after cleavage from the support by alkaline hydrolysis
(entries 21 and 22). The structure of 54 was confirmed by X-ray
crystallography and those of the other pyrrole products 52, 53,
and 55 were inferred by analogy and from the similarity of their
spectra.
the butyl substituent at δ 2.90 and 2.66 ppm. Moreover,
reduction of 56 with zinc in acetic acid resulted in cleavage of
the N-O bond, followed by fragmentation to the corresponding
known44 ꢀ-keto sulfone 74 (Scheme 7).
The solution phase cycloadditions of azomethine imine 2336b
with 28a and 28b proceeded slowly and afforded poor yields
of cycloadducts in refluxing THF, toluene, xylenes or in DMF
at 120 °C. The best results were obtained in refluxing anisole,
affording the 1,5-diaza[3.3.0]bicyclooctane 59b from the n-butyl
derivative 28a, after isomerization of the alkene double bond
of the initial cycloadduct 59a to the exocyclic position (entry
27). With shorter reaction times, 59a could be isolated in low
yield (entry 26). Single regio- and diastereoisomers of both 59a
and 59b were isolated, but their exact stereochemistry could
not be determined (the E isomer of 59b is shown in the Table
arbitrarily). In contrast, the phenyl-substituted acetylenic sulfone
28b afforded pyrazole 60, the product of lactam hydrolysis and
elimination of p-toluenesulfinic acid from the initial cycloadduct
corresponding to 59a in the butyl series.45 When the cycload-
dition was performed on solid phase with either 7a or 7b, a
similar hydrolysis and elimination afforded 61 and 60, respec-
tively (entries 29 and 30). The structure of 61 was confirmed
by X-ray crystallography, while that of 60 was based on a
comparison of its spectra with those of 61. The structure
assignment of 61 in turn verified the structure of the initial
cycloadduct 59a, obtained in solution phase.
Padwa et al.15a,b reported that the cycloadditions of several
acyclic nitrones with 1-(benzenesulfonyl)propyne afforded the
corresponding 4-sulfonyl-substituted dihydro-1,2-oxazoles as the
principal or sole products. The solution-phase cycloaddition of
nitrone 2235 with acetylenic sulfone 28a proceeded rapidly in
dichloromethane and similarly afforded dihydro-1,2-oxazole 56
as the only isolable product (entry 23). The solid-supported
sulfones 7a and 7b also reacted regioselectively with 22, but
required a considerably longer reaction time. After cleavage by
hydrolysis, products 57 and 58 were obtained in yields of 67%
and 72% (entries 24 and 25). The regiochemistry was confirmed
in 56 by an HMBC correlation between the R-carbon of the
vinyl ether moiety at δ 169.2 ppm and the allylic protons of
Azomethine ylides 24a, 24b, and 24c were prepared by the
condensation of the methyl esters of glycine, phenylalanine and
serine with benzaldehyde, followed by treatment with the metal
halides, acetates, or triflates shown in Scheme 8.37 Unfortu-
nately, attempts to react these stabilized ylides with acetylenic
sulfones 28a and 28b in solution under a variety of conditions
resulted either in the recovery of unreacted 28a and 28b, or in
extensive decomposition. On the other hand, the nonstabilized
(44) Iwata, N.; Morioka, T.; Kobayashi, T.; Asada, T.; Kinoshita, H.; Inomata,
K. Bull. Chem. Soc. Jpn. 1992, 65, 1379–1388.
(45) Under rigorously anhydrous conditions, the reaction of 23 with the
phenyl-substituted acetylenic sulfone 28b afforded the expected initial cycload-
duct analogous to 59a. It was formed in the ratio of 5:1, in a combined yield of
89%, with a minor regio- or diastereomer that could not be identified with
certainty and could not be separated from the main product.
(43) Padmavathi, V.; Reddy, A. V. B.; Sumathi, R. P.; Padmaja, A.; Reddy,
D. B. Indian J. Chem. 1998, 37B, 1286–1289.
J. Org. Chem. Vol. 73, No. 20, 2008 8063

Gao et al.
SCHEME 9
decarboxylation, proceeded in an analogous fashion to that of
munchnones 26a and 26b, affording 68 and 69, respectively,
in excellent yield (entries 38 and 39). The corresponding
reactions with the solid-supported sulfones 7a and 7b provided
cycloadducts 70 and 71 in slightly diminished yields after
removal from the support by alkaline hydrolysis (entries 40 and
41). The reductive cleavage of the product obtained from 7a
with samarium diiodide in the presence of HMPA resulted in
benzylic C-O fission, as observed previously in the munchnone
series in entry 37, to afford 68 (entry 42). An X-ray crystal
structure of cycloadduct 70 confirmed its regiochemistry and
the structures of the other products 68, 69, and 71 were inferred
by comparison of their spectra with those of 68.
In general, the strongly electron-withdrawing sulfone group
of acetylenic sulfones enhances dipole HOMO-dipolarophile
LUMO interactions, leading to the high regioselectivities
observed in most of the examples shown in Table 1, where only
one regioisomer was isolated. Only in the case of azide 17
(entries 1-3 in Table 1) and diazo compounds 18a (entry 4)
and 18b (entry 6) were significant amounts of both regioisomers
formed. Moreover, a comparison of the relatively electrophilic
diazo ester 18a (entries 4 and 5) with that of the more
nucleophilic diazomethane (18b) (entries 6 and 7) reveals a
reversal of regioselectivity. This may be attributed to dipole
HOMO control in the case of 18b, as expected in reactions with
electron-deficient dipolarophiles, while dipole LUMO control
predominates with the ester-substituted dipole 18a.
SCHEME 10
azomethine ylide 25, which was generated in situ from sarcosine
and paraformaldehyde,38 reacted successfully with 28a and 28b
in refluxing toluene to afford the corresponding dehydropyrro-
lidines 62 and 63 (entries 31 and 32). However, it failed to
undergo cycloaddition with the solid-supported acetylenic
sulfones 7a and 7b.
Summary and Conclusions
Mesoionic compounds such as munchnones and sydnones are
also capable of undergoing 1,3-dipolar cycloadditions with
activated acetylenes, followed by loss of carbon dioxide.46 Thus,
munchnones 26a and 26b were prepared in situ from proline
and pipecolinic acid, respectively39 and allowed to react with
acetylenic sulfone 28a in refluxing acetic anhydride (Scheme
9). Slightly better yields of products 64 and 65 were obtained
with DMF as a cosolvent (entries 33 and 34). When munchnones
26a and 26b were similarly generated in the presence of solid-
supported acetylenic sulfones 7a and 7b, the more strained
analogue 26a failed to undergo cycloaddition and appeared to
decompose to unknown products. In complete contrast, the
homologue 26b afforded cycloadducts 66 and 67 smoothly and
in high yield after the usual hydrolysis of the ester linker (entries
35 and 36). When an attempt was made to cleave the product
obtained from 26b and 7a from the solid support by reductive
desulfonylation instead of by alkaline hydrolysis,47 reduction
of the ester linker at the benzylic position occurred instead,
affording the p-toluenesulfonyl derivative 65 (entry 37). The
structure of product 66 was established unequivocally by X-ray
crystallography, while the regiochemistry of 64, 65, and 67 was
inferred by comparison of their spectra with those of 66.
Sydnone 2740 was prepared from N-nitrosoproline via cy-
clodehydration with trifluoroacetic anhydride (Scheme 10). Its
cycloaddition to acetylenic sulfones 28a and 28b, followed by
Only a few examples of 1,3-dipolar cycloadditions of
acetylenic sulfones in solution have been investigated to date
and, to our knowledge, there are no previous reports of such
processes with nitrile ylides, azomethine imines and azomethine
ylides. Furthermore, acetylenic sulfones immobilized on solid
supports had not been reported until our preliminary com-
munication,19 in which only one type of dipolar cycloaddition,
with nitrile oxide 19, was described. The reactions listed in Table
1 indicate that diverse 1,3-dipolar cycloadditions of acetylenic
sulfones can be carried out easily, both in solution and on
polymer supports. The majority of the products are formed with
high regioselectivity, often in good to excellent yield. The
regiochemistry and yields of these processes in solution and on
solid phase are generally similar, although reactions conducted
on polymer supports often required longer reaction times. These
cycloadditions provide facile access to a host of variously
substituted and functionalized triazoles, pyrazoles, 1,2-oxazoles,
pyrroles, as well as their dihydro and bicyclic analogues. These
are common ring systems which are found in many types of
natural products and medicinal compounds. Further transforma-
tions of the immobilized cycloadducts on polymer supports are
under investigation, with the objective of ultimately producing
small libraries of these important classes of nitrogen heterocycles.
Experimental Section
(46) See the following and references cited therein: Coppola, B. P.; Noe,
M. C.; Schwartz, D. J.; Abdon, R. L.; Trost, B. M. Tetrahedron 1994, 50, 93–
116.
(47) It is doubtful that direct reductive cleavage of the polymer-supported
cycloadduct occurred with sodium amalgam, as penetration of the polymer beads
by the reagent under the two-phase conditions of the reaction is unlikely.
However, it is possible that the relatively basic conditions resulted in prior
hydrolysis of the ester linker, followed by reduction of the liberated benzyl alcohol
moiety in a subsequent step. The same product 65 was obtained in 53% yield
when samarium diiodide-HMPA was employed as the reductant.
All NMR spectra were recorded in deuteriochloroform and all
mass spectra were obtained by electron impact unless otherwise
indicated. “Chromatography” refers to flash chromatography on
silica-gel (230-400 mesh).
The following general procedure was used for the workup and
alkaline cleavage of the products from the resin for cycloadditions
performed on solid phase. After completion of the cycloaddition,
the reaction mixture was filtered and the resulting resin was washed
8064 J. Org. Chem. Vol. 73, No. 20, 2008

1,3-Dipolar Cycloadditions of Acetylenic Sulfones
three times alternatively with each of dichloromethane and metha-
nol. The resin was air-dried and then dried under vacuum overnight.
The resin (ca. 0.5 g) was stirred in THF (25 mL) for 30 min,
followed by the addition of 5% aqueous LiOH solution (1.0 mL,
2.1 mmol). The reaction mixture was stirred at room temperature
for 1-3 d, the resin was filtered and washed three times alternatively
with each of THF and methanol. The combined filtrate was
neutralized with 5% HCl, evaporated under reduced pressure and
triturated with dichloromethane (20 mL). The mixture was filtered,
the filtrate was concentrated under reduced pressure and the residue
was separated by flash chromatography on silica gel.
The experimental details for the preparation of acetylenic sulfones
on polymer supports (7a-7d) and for the preparation and charac-
terization of compounds 42-44 and 47 were reported in the
Supporting Information of our preliminary communication.19
Representative procedures and characterization of products from
Table 1 are provided below, while the preparation of solid-supported
acetylenic sulfones 13 and 14, as well as the remaining procedures
and characterization data from Table 1 are given in the Supporting
Information.
2 H), 7.42-7.30 (m, 3 H), 7.23-7.05 (m, 2 H), 5.48 (s, 2 H), 4.78
(d, J ) 4.9 Hz, 2 H), 2.87 (t, J ) 7.7 Hz, 2 H), 2.40 (t, J ) 5.4 Hz,
1 H), 1.39-1.21 (m, 4 H), 0.84 (t, J ) 6.9 Hz, 3 H);13C NMR (75
MHz) δ 147.4, 144.6, 140.21, 139.7, 133.7, 129.1, 128.8, 128.0,
127.3, 127.1, 64.1, 52.5, 30.8, 22.6, 22.55, 13.5; MS (m/z, %) 385
(M+, 0.5), 279 (22), 91 (100); HRMS calcd for C20H23N3O3S (M+):
385.1460; found: 385.1427. Anal. Calcd for C20H23N3O3S: C, 62.31;
H, 6.01; N, 10.90. Found C, 62.31; H, 6.20; N, 10.54. The ORTEP
diagram and X-ray crystallographic data for structure 32 are
provided in the Supporting Information.
Ethyl 5-n-Butyl-4-(p-toluenesulfonyl)-1H-pyrazole-3-carboxy-
late (35) and Ethyl 4-n-Butyl-5-(p-toluenesulfonyl)-1H-pyrazole-
3-carboxylate (36). A solution of acetylenic sulfone 28a (59 mg,
0.25 mmol) and ethyl diazoacetate 18a (32 mg, 0.28 mmol) in
dichloromethane (5 mL) was stirred in the dark for 3 d. The reaction
mixture was concentrated in vacuum. The crude mixture was
chromatographed (5% methanol-chloroform) to afford 48 mg (55%)
of an unseparated 4:1 mixture of pyrazoles 35 and 36 as a pale-
yellow oil that crystallized from ethyl acetate-hexanes to afford
pure 35: mp 104-105 °C; IR (KBr) 3204, 1743, 1700, 1322, 1230,
1161 cm-1; 1H NMR (300 MHz) δ 11.61 (s, 1 H), 7.91 (d, J ) 8.4
Hz, 2 H) 7.32 (d, J ) 8.2 Hz, 2 H), 4.39 (q, J ) 7.1 Hz, 2 H), 2.95
(t, J ) 7.6 Hz, 2 H), 2.42 (s, 3 H), 1.57-1.31 (m, 7 H), 0.91 (t, J
) 7.0 Hz, 3 H); 13C NMR (75 MHz) δ 159.3, 150.6, 144.9, 138.1,
133.2, 129.9, 128.2, 127.4, 62.0, 33.3, 23.2, 23.0, 21.8, 14.3, 13.9;
MS (m/z, %) 350 (M+, 18), 308 (60), 275 (72), 262 (86), 91 (100);
HRMS calcd for C17H22N2O4S (M+): 350.1300; found: 350.1279.
Anal. Calcd for C17H22N2O4S: C, 58.26; H, 6.33; N, 7.99. Found:
C, 58.01; H, 6.07; N, 7.77. The ORTEP diagram and X-ray
crystallographic data for structure 35 are provided in the Supporting
Information.
1-Benzyl-4-n-butyl-5-p-toluenesulfonyl-1H-1,2,3-triazole (29)
and 1-Benzyl-5-n-butyl-4-p-toluenesulfonyl-1H-1,2,3-triazole (30).
A solution of acetylenic sulfone 28a (59 mg, 0.25 mmol) and benzyl
azide (17) (50 mg, 0.38 mmol) in toluene (25 mL) was refluxed
for 3 d. The solution was washed with water and brine. The organic
phase was dried, filtered, and concentrated in vacuo. The crude
mixture was chromatographed (25% ethyl acetate-hexanes) to
afford 52 mg (57%) of triazole 29 as a pale-yellow oil: IR (film)
1
1343, 1161, 1087, 817 cm-1; H NMR (300 MHz) δ 7.32-6.94
(m, 9 H), 5.81 (s, 2 H), 2.84 (t, J ) 7.6 Hz, 2 H), 2.27 (s, 3 H),
1.74-1.56 (m, 2 H), 1.44-1.25 (m, 2 H), 0.87 (t, J ) 8.6 Hz, 3
H);13C NMR (75 MHz) δ 151.6, 145.2, 137.3, 134.5, 131.9, 129.8,
128.7, 128.1, 127.6, 127.0, 53.6, 31.0, 25.5, 22.5, 21.5, 13.8; MS
(CI, m/z, %) 370 (M+ + 1, 100); HRMS calcd for C13H16N3 (M+-
Ts): 214.1344; found: 214.1339.
The filtrate contained a mixture of 35 and 36, from which 36
could not be separated completely free of 35. Isomer 36 had distinct
1H NMR signals at δ 4.28 (q, J ) 7.1 Hz) and 3.07 (t, J ) 7.8
Hz).
Further elution (35% ethyl acetate-hexanes) provided 26 mg
Ethyl 5-n-Butyl-4-[4-(hydroxymethyl)benzenesulfonyl]-1H-
pyrazole-3-carboxylate (37). The solid-supported acetylenic sul-
fone 7a (0.50 g, 0.67 mmol/g) was stirred in dichloromethane (50
mL) for 30 min. Ethyl diazoacetate (190 mg, 1.67 mmol) was added
and the reaction mixture was stirred at room temperature for 4 days
in the dark. The cycloadduct was cleaved from the support with
LiOH. The resulting yellow oil was purified by chromatography
(3% methanol-chloroform) to afford pyrazole 37 as a pale-yellow
oil (65 mg, 53%): IR (film) 3274, 1713, 1309, 1148 cm-1; 1H NMR
(300 MHz) δ 11.66 (s, 1 H), 7.99 (d, J ) 8.2 Hz, 2 H), 7.54 (d, J
) 8.1 Hz, 2 H), 4.84 (s, 2 H), 4.43 (q, J ) 7.1 Hz, 2 H), 2.99 (t,
J ) 7.7 Hz, 2 H), 1.58-1.31 (m, 7 H), 0.95 (t, J ) 7.1 Hz, 3 H);
13C NMR (75 MHz) δ 158.9, 150.5, 147.2, 139.7, 133.0, 128.2,
127.4, 127.0, 64.2, 61.8, 33.2, 23.0, 22.8, 14.1, 13.8; MS (m/z, %)
366 (M+, 16), 320 (45), 42 (100); HRMS calcd for C17H22N2O5S
(M+): 366.1249; found: 366.1252.
5-n-Butyl-4-[(p-hydroxymethyl)benzenesulfonyl]-1-methylpyra-
zole (38), 4-n-Butyl-5-[(p-hydroxymethyl)benzenesulfonyl]-1-
methylpyrazole (39a), and 4-n-Butyl-3-[(p-hydroxymethyl)ben-
zenesulfonyl]-1-methylpyrazole (39b). A solution of diazomethane
(2.0 mmol) in 6 mL of ether was added dropwise at 0 °C to a
suspension of resin 7a (400 mg, 0.65 mmol/g) in 10 mL of ether
and the mixture was stirred at room temperature for 26 h. The excess
diazomethane was quenched with acetic acid. The cycloadducts
were cleaved from the resin with LiOH and the crude product was
purified by chromatography (40% hexanes-ethyl acetate) to afford
(28%) of cycloadduct 30 as a yellow oil that crystallized from ethyl
acetate-hexanes: mp 102-103 °C; IR (film) 1330, 1152, 817 cm-1
;
1H NMR (300 MHz) δ 7.93 (d, J ) 8.3 Hz, 2 H), 7.37-7.28 (m,
5 H), 7.20-7.09 (m, 2 H), 5.47 (s, 2 H), 2.86 (t, J ) 7.7 Hz, 2 H),
2.39 (s, 3 H), 1.40 - 1.11 (m, 4 H), 0.81 (t, J ) 6.9 Hz, 3 H);13C
NMR (75 MHz) 145.0, 144.9, 140.2, 138.2, 134.0, 130.0, 129.3,
128.9, 128.0, 127.5, 52.6, 30.9, 22.8, 22.7, 21.8, 13.7; MS (m/z,
%) 369 (M+, 1), 263 (14), 234 (10), 91 (100); HRMS calcd for
C20H23N3O2S (M+): 369.1511; found: 369.1492. Anal. Calcd for
C20H23N3O2S: C, 65.01; H, 6.27; N, 11.38. Found: C, 64.88; H,
6.37; N, 11.27.
[4-(1-Benzyl-4-n-butyl-1H-1,2,3-triazol-5-ylsulfonyl)phenyl]-
methanol (31) and [4-(1-Benzyl-5-n-butyl-1H-1,2,3-triazol-4-
ylsulfonyl)phenyl]methanol (32). The solid-supported acetylenic
sulfone 7a (0.50 g, 0.67 mmol/g) was stirred in toluene for 0.5 h.
Benzyl azide 17 (67 mg, 0.50 mmol) was added and the mixture
was refluxed for 7 d. The cycloadduct was cleaved from the support
with LiOH and chromatographed (ethyl acetate-hexanes, 2:1) to
afford 71 mg (55%) of product 31 as a yellow oil that crystallized
from ethyl acetate-hexanes: mp 82-84 °C; IR (film) 3391, 1330,
1148, 809 cm-1; 1H NMR (300 MHz) δ 7.36 (d, J ) 8.5 Hz, 2 H),
7.32-7.22 (m, 5 H), 7.07 (d, J ) 7.8 Hz, 2 H), 5.86 (s, 2 H), 4.68
(s, 2 H), 2.87 (t, J ) 7.3 Hz, superimposed on br s, 3 H), 1.81-1.55
(m, 2 H), 1.38 (m, 2 H), 0.92 (t, J ) 7.3 Hz, 3 H); 13C NMR (75
MHz) 151.8, 147.9, 138.9, 134.4, 131.7, 128.8, 128.3, 127.6, 127.1,
127.0, 63.8, 53.8, 31.0, 25.5, 22.5, 13.8; MS (CI, m/z, %) 386 (M+
+ 1, 63); HRMS calcd for C20H23N3O3S (M+): 385.1460; found:
385.1451. Anal. Calcd for C20H23N3O3S: C, 62.31; H, 6.01; N,
10.90. Found C, 62.14; H, 6.11; N, 10.44.
11 mg (14%) of the less polar regioisomer 38 as a colorless oil: IR
1
(film) 3399, 1312, 1156, 1119 cm-1
; H NMR (300 MHz) δ 7.87
(d, J ) 8.2 Hz, 2 H), 7.55 (d, J ) 8.2 Hz, 2 H), 7.35 (s, 1 H), 4.81
(s, 2 H), 4.02 (s, 3 H), 2.77 (t, J ) 7.2 Hz, 2 H), 1.90 (br, s, 1 H),
1.70-1.55 (m, 2 H), 1.50-1.35 (m, 2 H), 0.95 (t, J ) 7.2 Hz, 3
H); 13C NMR (75 MHz) δ 147.2, 140.3, 138.4, 134.8, 128.0, 127.3,
127.2, 64.1, 39.5, 32.6, 23.9, 22.5, 13.9; MS (m/z, %) 308 (M+,
Further elution with the same solvent provided 37 mg (29%) of
32 as a yellow oil that crystallized from ethyl acetate-hexanes:
1
mp 111.5-112 °C; IR (KBr) 3365, 1335, 1148, 1061 cm-1; H
NMR (300 MHz) δ 8.00 (d, J ) 8.4 Hz, 2 H), 7.51 (d, J ) 8.3 Hz,
J. Org. Chem. Vol. 73, No. 20, 2008 8065

Gao et al.
6), 266 (56), 95 (100); HRMS calcd for C15H20N2O3S: 308.1195;
found 308.1196.
399.1140; found: 399.1161. Anal. Calcd for C21H21NO5S: C, 63.14;
H, 5.30; N, 3.51. Found: C, 62.70; H, 5.17; N, 3.40.
5-n-Butyl-1,3-diphenyl-4-(p-toluenesulfonyl)-1H-pyrazole (48).
Hydrazonyl chloride 7233 (87 mg, 0.38 mol) and diisopropylethyl-
amine (245 mg, 1.9 mmol were added to a solution of acetylenic
sulfone 28a (59 mg, 0.25 mmol) in chloroform (20 mL) and the
mixture was refluxed for 6 h. The solution was washed with water
and brine. The organic phase was dried, filtered and concentrated.
The crude product was purified by chromatography (30% chloroform-
hexanes to 3% methanol-chloroform) to afford 72 mg (67%) of
pyrazole 48 as a pale-yellow oil that crystallized from ethyl
Further elution (25% hexanes-ethyl acetate) afforded 34 mg
(42%) of the more polar regioisomer as an inseparable 2:1 mixture
of 39a and 39b, obtained as a colorless oil, which solidified upon
1
standing; IR (film) 3383, 1308, 1160, 1117 cm-1; H NMR (300
MHz, both isomers) δ 7.89 (d, J ) 8.2 Hz, 2 H), 7.84 (s, 1 H,
major isomer), 7.81 (s, 1 H, minor isomer), 7.50 (d, J ) 7.7 Hz, 2
H), 4.79 (s, 2 H), 3.86 (s, 3 H, major isomer), 3.78 (s, 3 H, minor
isomer), 2.82 (t, J ) 7.7 Hz, 2 H, minor isomer), 2.67 (d, J ) 7.7
Hz, 2 H, major isomer), 2.02 (br s, 1 H), 1.59-1.23 (m, 4 H), 0.91
(t, J ) 6.7 Hz, 3 H, minor isomer), 0.88 (t, J ) 7.7 Hz, 3 H, major
isomer); 13C NMR (75 MHz, both isomers) 152.3, 146.3, 146.2,
145.1, 142.2, 141.8, 139.3, 134.0, 127.8, 127.2, 127.1, 127.0, 126.9,
120.8, 64.2, 39.3, 36.7, 30.8, 30.5, 26.3, 24.0, 22.6, 22.5, 13.8, 13.7;
MS (m/z, %) 308 (M+, 9), 266 (52), 95 (100); HRMS calcd for
C15H20N2O3S: 308.1195; found 308.1199.
5-[(p-Hydroxymethyl)benzenesulfonyl]-1-methyl-4-phenylpyra-
zole (40a) and 3-[(p-Hydroxymethyl)benzenesulfonyl]-1-methyl-
4-phenylpyrazole (40b). The cycloaddition of diazomethane with
7b was performed as with 7a, followed by cleavage with LiOH in
the usual manner. Chromatography (40% hexanes-ethyl acetate)
afforded an inseparable 2:1 mixture of 40a and 40b as a colorless
oil in 56% yield; IR (film) 3397, 1307, 1165, 1140 cm-1; 1H NMR
(300 MHz) δ 8.01 (s 1 H, minor isomer), 7.99 (s, 1 H, major
isomer), 7.64-7.15 (m, 9 H), 4.67 (s, 2 H, major isomer), 4.66 (s,
2 H, minor isomer), 3.94 (s, 3 H, minor isomer), 3.64 (s, 3 H, major
isomer), 2.45 (br, s, 1 H); 13C NMR (75 MHz, both isomers) δ
150.4, 146.4, 146.3, 143.9, 141.0, 140.7, 139.3, 135.3, 130.6, 130.2,
130.1, 129.2, 129.0, 128.5, 128.1, 127.21, 127.15, 126.6, 126.5,
122.3, 121.8, 64.00, 63.97, 39.5, 37.5; MS (m/z, %) 328 (M+, 75),
105 (47), 89 (48), 77 (100); HRMS calcd for C17H16N2O3S:
328.0882; found: 328.0897.
3-Mesityl-4-(p-toluenesulfonyl-5-phenyl-1,2-oxazole (41). Acet-
ylenic sulfone 28b (102 mg, 0.400 mmol) and nitrile oxide 19 (161
mg, 1.00 mmol) were stirred in dichloromethane at room temper-
ature for 20 h. The solvent was evaporated under vacuum and the
resulting yellow oil was chromatographed (20% ethyl acetate-
hexanes), to provide 132 mg (79%) of 1,2-oxazole 41 as a pale
yellow oil. Recrystallization from ethyl acetate-hexanes afforded
colorless needles: mp 167-168 °C; IR (film): 1380, 1161, 1124
cm-1; 1H NMR (400 MHz) δ 8.01 (d, J ) 6.8 Hz, 2 H), 7.68-7.51
(m, 3 H), 7.25 (d, J ) 8.3 Hz, 2 H), 7.06 (d, J ) 8.1 Hz, 2 H),
6.86 (s, 2 H), 2.367 (s, 3 H), 2.373 (s, 3 H), 1.87 (s, 6 H); 13C
NMR (100 MHz) δ 172.5, 160.6, 144.7, 139.7, 138.1, 137.4, 131.8,
130.1, 129.3, 128.4, 128.1, 127.9, 126.0, 123.1, 118.6, 21.6, 21.3,
20.0; MS (CI, m/z) 418 (M+ + 1); HRMS calcd for C25H24NO3S
(M++ 1), 418.1477; found, 418.1495. Anal. Calcd for: C25H23NO3S:
C, 71.92; H, 5.55; N, 3.35. Found: C, 71.56; H, 6.04; N, 3.12.
acetate-hexanes: mp 128-129 °C; IR (film) 1313, 1148, 761 cm-1
;
1H NMR (300 MHz) δ 7.90-7.21 (m, 12 H), 7.09 (d, J ) 8.1 Hz,
2 H), 3.06 (t, J ) 7.9 Hz, 2 H), 2.34 (s, 3 H), 1.86-1.50 (m, 2 H),
1.46-1.10 (m, 2 H), 0.84 (t, J ) 7.3 Hz, 3 H);13C NMR (75 MHz)
δ 151.5, 147.8, 143.4, 140.0, 138.5, 131.4, 130.1, 129.4, 129.3,
129.1, 128.8, 127.7, 127.0, 126.4, 118.4, 32.0, 25.0, 22.6, 21.5,
13.5; MS (m/z, %) 430 (M+, 7), 275 (25), 233 (100); HRMS calcd
for C26H26N2O2S (M+): 430.1715; found: 430.1714. Anal. Calcd
for C26N2H26O2S: C, 72.53; H, 6.09; N, 6.51. Found: C, 72.47; H,
6.09; N, 6.33. The ORTEP diagram and X-ray crystallographic data
for structure 48 are provided in the Supporting Information.
5-n-Butyl-4-[p-(hydroxymethyl)benzenesulfonyl]-1,3-diphen-
yl-1H-pyrazole (50). Polymer resin 7a (0.50 g, 0.67 mmol/g) was
stirred in chloroform (50 mL) for 30 min, followed by the addition
of hydrazonyl chloride 72 (117 mg, 0.507 mmol) and diisopropy-
lethylamine (328 mg, 2.54 mmol). The reaction mixture was
refluxed 16 h. The resulting solid-supported cycloadduct was
cleaved by LiOH in the usual manner. The resulting yellow oil
was purified by chromatography (4% methanol-chloroform) to
afford 91 mg (61%) of pyrazole 50 as a pale-yellow oil that
crystallized from ethyl acetate-hexanes: mp 114-115 °C; IR (film)
3422, 1317, 1143 cm-1; 1H NMR (300 MHz,) δ 7.73-7.04 (m, 14
H), 4.61 (s, 2 H), 3.04 (t, J ) 7.9 Hz, 2 H), 2.33 (s, 1 H), 1.79-1.50
(m, 2 H), 1.40-1.20 (m, 2 H), 0.83 (t, J ) 7.3 Hz, 3 H); 13C NMR
(75 MHz) δ 151.9, 148.2, 146.2, 141.5, 138.4, 131.3, 130.1, 129.5,
129.4, 128.9, 127.7, 127.1, 126.4, 118.1, 64.0, 32.0, 25.0, 22.6,
13.5; MS (m/z, %) 446 (M+, 5), 275 (24), 233 (100); HRMS calcd
for C26H26N2O3S (M+): 446.1664; found: 446.1646. Anal. Calcd
for C26H26N2O3S: C, 69.93; H, 5.87; N, 6.27; Found: C, 69.90; H,
6.08; N, 6.14.
Methyl 3-n-Butyl-4-(p-toluenesulfonyl)-1H-pyrrole-2-carbox-
ylate (52). Isocyanide 7334a (99 mg, 1.0 mmol) and cuprous oxide
(9 mg, 0.06 mmol) were added successively to a solution of
acetylenic sulfone 28a (59 mg, 0.25 mmol) in DMF (20 mL). The
mixture was heated at 85 °C for 3 h. The solution was filtered,
diluted with water and extracted with ethyl acetate. The organic
phase was washed with 5% ammonium hydroxide solution, water
and brine. It was dried, filtered, concentrated in vacuo and purified
by chromatography (35% ethyl acetate-hexanes) to afford 60 mg
(72%) of pyrrole 52 as a pale-yellow oil that crystallized from ethyl
acetate-hexanes: mp 149-150 °C; IR (film) 3300, 1713, 1257,
1157, 1096 cm-1; 1H NMR (300 MHz) δ 9.79 (br s, 1 H), 7.81 (d,
J ) 8.2 Hz, 2 H), 7.58 (d, J ) 3.4 Hz, 1 H), 7.30 (d, J ) 8.3 Hz,
2 H), 3.86 (s, 3 H), 2.81 (t, J ) 7.5 Hz, 2 H), 2.44 (s, 3 H),
1.36-1.17 (m, 4 H), 0.85 (t, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz);
161.2, 143.8, 140.0, 132.1, 129.8, 127.4, 126.2, 125.7, 121.4, 51.9,
33.0, 24.6, 23.1, 21.6, 13.9; MS (m/z, %) 335 (M+, 42), 293 (100);
HRMS calcd for C17H21NO4S (M+): 335.1191; found: 335.1178.
Anal. Calcd for C17H21NO4S: C, 60.87; H, 6.31; N, 4.18. Found:
C, 60.90; H, 6.79; N, 3.85.
Methyl 3-n-Butyl-4-[p-(hydroxymethyl)benzenesulfonyl)]-1H-
pyrrole-2-carboxylate (54). Resin 7a (0.50 g, 0.67 mmol/g) was
stirred in DMF (40 mL) for 30 min. Isocyanide 73 (280 mg, 2.85
mmol) and cuprous oxide (75 mg, 0.50 mmol) were added and the
reaction mixture was heated at 95 °C for 16 h. Cleavage of the
product from the support was effected with LiOH in the usual
manner, followed by chromatography (65% ethyl acetate-hexanes)
to afford 67 mg (57%) of pyrrole 54 as a pale-yellow oil: IR (film)
3-Mesityl-4-[(p-methoxycarbonyl)benzenesulfonyl]-5-methyl-
1,2-oxazole (45). A suspension of nitrile oxide 19 (98 mg, 0.61
mmol) and resin 13 (400 mg, 0.87 mmol/g) in 10 mL of ether was
stirred for 48 h and filtered. The resin was washed with ether and
then with dichloromethane, methanol, and ether, followed by drying
under reduced pressure. The product was cleaved from the resin
by refluxing it in 10 mL of methanol-THF (1:2) containing sodium
methoxide (81 mg, 1.5 mmol) overnight. The resin was removed
by filtration and was washed with methanol-THF (1:1), THF,
methanol, and ether. The filtrate was evaporated to dryness,
triturated with dichloromethane, dried, filtered, evaporated, and
chromatographed (25% hexanes-ethyl acetate) to give 74 mg (54%)
of 45 as a white solid: mp 98-101 °C (from ethyl acetate-hexanes);
1
IR (KBr) 1729, 1333, 1278, 1167 cm-1; H NMR (300 MHz) δ
7.98 (d, J ) 8.2 Hz, 2 H), 7.46 (d, J ) 8.2 Hz, 2 H), 6.84, (s, 2 H),
3.97 (s, 3 H), 2.93 (s, 3 H), 2.35 (s, 3 H), 1.69 (s, 6 H); 13C NMR
(75 MHz) δ 174.5, 165.4, 159.7, 144.2, 140.0, 137.9, 134.6, 129.9,
128.1, 127.8, 122.4, 117.5, 52.7, 21.2, 19.6, 13.3; MS (m/z, %)
399 (M+, 4), 104 (48), 43 (100); HRMS calcd for C21H21NO5S:
8066 J. Org. Chem. Vol. 73, No. 20, 2008

1,3-Dipolar Cycloadditions of Acetylenic Sulfones
1
3304, 1717, 1304, 1139 cm-1; H NMR (300 MHz) δ 9.58 (br s,
424 (M+, 12), 347 (100), 218 (70); HRMS calcd for C24H28N2O3S
(M+): 424.1821; found: 424.1816.
1 H), 7.86 (d, J ) 8.3 Hz, 2 H), 7.53 (d, J ) 3.5 Hz, 1 H), 7.48 (d,
J ) 8.2 Hz, 2 H), 4.77 (s, 2 H), 3.85 (s, 3 H), 2.78 (t, J ) 7.6 Hz,
2 H), 2.19 (s, 1 H), 1.46-1.06 (m, 4 H), 0.83 (t, J ) 7.0 Hz, 3 H);
13C NMR (100 MHz, CDCl3-DMSO-d6) δ 161.1, 147.4, 141.4,
131.5, 126.8, 126.62, 126.57, 123.9, 121.2, 63.3, 51.2, 32.8, 24.3,
22.8, 13.7; MS (m/z, %) 351 (M+, 35), 309 (100), 246 (30); HRMS
calcd for C17H21NO5S (M+): 351.1140; found: 351.1144. Anal.
Calcd for C17H21NO5S: C, 58.10; H, 6.02; N, 3.99. Found: C, 58.04;
H, 6.18; N, 3.56. The ORTEP diagram and X-ray crystallographic
data for structure 54 are provided in the Supporting Information.
2-n-Butyl-3-(p-toluenesulfonyl)-4,5,6,7-tetrahydro-3aH-isox-
azolo[2,3-a] pyridine (56). Acetylenic sulfone 28a (59 mg, 0.25
mmol) was added to a solution of nitrone 22 (10 mL, 0.5 M) in
dichloromethane at room temperature and the reaction mixture was
stirred for 10 min. The solvent was evaporated and the product
was chromatographed (25% ethyl acetate-hexanes) to give 65 mg
(78%) of cycloadduct 56 as a pale-yellow oil: IR (film) 1617, 1317,
1161, 1148 cm-1;1H NMR (300 MHz) δ 7.77 (d, J ) 8.3 Hz, 2
H), 7.35 (d, J ) 8.0 Hz, 2 H), 4.26 (br s, 1 H), 3.15 (br s, 1 H),
3.06-2.82 (m, 2 H), 2.66 (dt, J ) 13.8, 7.0 Hz, 1 H), 2.46 (s, 3
H), 2.21-1.75 (m, 2 H), 1.73-1.20 (m, 8 H), 0.99 (t, J ) 7.3 Hz,
3 H); 13C NMR (75 MHz) δ 169.2, 143.4, 139.5, 129.9, 126.4,
109.8, 64.3, 51.6, 28.9, 25.8, 22.7, 21.5, 19.5, 13.9; MS (m/z, %)
335 (M+, 40), 334 (100); HRMS Calcd for C18H25NO3S (M+):
335.1555; found: 335.1524. Anal. Calcd for C18H25NO3S: C, 64.44;
H, 7.51; N, 4.18. Found: C, 64.31; H, 7.60; N, 4.62.
Cycloadduct 56 (100 mg, 0.30 mmol) was treated with 0.5 g of
zinc powder in 5 mL of acetic acid at 65 °C until TLC analysis
indicated consumption of the starting material. The mixture was
filtered and the resulting solution was diluted with water and
extracted with ethyl acetate. The organic solution was washed with
saturated sodium bicarbonate solution, water and brine, and then
dried. The solvent was evaporated and the residue was purified by
chromatography (25% ethyl acetate-hexanes) to afford 36 mg
(43%) of ꢀ-keto sulfone 74.44
2-n-Butyl-3-[(p-hydroxymethyl)benzenesulfonyl]-4,5,6,7-tet-
rahydro-3aH-isoxazolo[2,3-a]pyridine (57). The resin 7a (0.50
g, 0.67 mmol/g) was stirred in dichloromethane (50 mL) for 30
min. Nitrone 22 in dichloromethane (20 mL, 0.5 M) was added
and the reaction mixture was stirred at room temperature for 16 h.
The resulting solid-supported cycloadduct was cleaved with LiOH
in the usual manner and the crude product was purified by
chromatography (50% ethyl acetate-hexanes) to afford 78 mg
(67%) of 57 as a pale-yellow oil: IR (film) 3417, 1617, 1309, 1148
cm-1;1HNMR (300 MHz) δ 7.86 (d, J ) 8.3 Hz, 2 H), 7.55 (d, J
) 8.4 Hz, 2 H), 4.83 (s, 2 H), 4.40-4.19 (m, 1 H), 3.26-3.06 (m,
1 H), 3.07-2.51 (m, 3 H), 2.19-1.24 (m, 11 H), 0.99 (t, J ) 7.3,
3 H);13C NMR (75 MHz,) δ 169.5, 146.2, 141.6, 127.0, 126.8,
109.9, 64.2, 64.1, 51.7, 29.1, 26.0, 25.8, 22.5, 19.6, 13.7; MS (m/
z, %) 351 (M+, 17), 350 (35), 155 (63), 42 (100); HRMS Calcd
for C18H25NO4S (M+): 351.1504; found: 351.1484.
7-Butylidene-3-methyl-5-phenyl-6-(p-toluenesulfonyl)-tetrahy-
dro-pyrazolo[1,2-a]pyrazol-1-one (59b). Product 59b was prepared
by the same procedure as 59a, except that a longer reaction time
of 2 h was employed. The crude product was chromatographed
(5% methanol-chloroform) to afford 60 mg (57%) of product 59b
as a pale-yellow oil that crystallized from ethyl acetate-hexanes:
mp 103-105 °C; IR (film) 1717, 1317, 1148 cm-1; 1H NMR (300
MHz) δ 7.77 (d, J ) 8.3 Hz, 2 H), 7.51-7.29 (m, 7 H), 4.60 (d,
J ) 3.3 Hz, 1 H), 4.53 (t, J ) 7.4 Hz, 1 H), 3.92 (d, J ) 3.0 Hz,
1 H), 3.77-3.53 (m, 1 H), 2.70 (dd, J ) 15.9, 7.6 Hz, 1 H), 2.57
(dd, J ) 15.9, 11.3 Hz, 1 H), 2.46 (s, 3 H), 2.34-2.06 (m, 2 H),
1.49-1.21 (m, 2 H), 1.16 (d, J ) 6.3 Hz, 3 H), 0.83 (t, J ) 7.3
Hz, 3 H); 13C NMR (75 MHz) δ 167.2, 145.4, 140.9, 132.5, 130.1,
129.6, 128.8, 128.0, 126.8, 124.6, 123.9, 77.4, 65.6, 61.2, 41.6,
31.7, 22.4, 21.7, 19.4, 13.7; MS (m/z, %) 424 (M+, 23), 347 (100);
HRMS calcd for C24H28N2O3S (M+): 424.1821; found: 424.1797.
3-(3,5-Diphenyl-1H-pyrazol-1-yl)butanoic acid (60). Product
60 was prepared by a similar procedure to that of 59a, except that
a longer reaction time of 4 h was employed. After chromatography
(2-5% methanol-chloroform), 60 was obtained in 88% yield and
was identical to the product obtained from 23 and 7b (see
Supporting Information).
3-(3-n-Butyl-5-phenyl-1H-pyrazol-1-yl)butanoic acid (61).
Resin 7a (0.50 g, 0.67 mmol/g) was stirred in anisole (30 mL) for
30 min. The azomethine imine 23 (126 mg, 0.67 mmol) was added
and the reaction mixture was refluxed for 2 h. The resulting solid-
supported cycloadduct was treated with LiOH in the usual manner.
The resulting yellow oil was chromatographed (2% methanol-
chloroform) to afford 35 mg (37%) of pyrazole 61 as a yellow oil
that crystallized from ethyl acetate-hexanes: mp 98-99 °C; IR
(film) 3500-2300, 1713, 765 cm-1; 1H NMR (400 MHz) δ 11.90
(s, 1 H), 7.50-7.34 (m, 5 H), 6.08 (s, 1 H), 4.71 (m, 1 H), 3.04
(dd, J ) 16.1, 7.1 Hz, 1 H), 2.92 (dd, J ) 16.1, 4.1 Hz, 1 H), 2.66
(t, J ) 7.6 Hz, 2 H), 1.66 (m, 2 H), 1.49 (d, J ) 6.8 Hz, 3 H,),
1.47-1.33 (m, 2 H), 0.95 (t, J ) 7.3 Hz, 3 H); 13C NMR (100
MHz) δ 173.5, 152.8, 144.3, 130.2, 128.9, 128.8, 128.7, 104.9,
50.1, 41.6, 31.4, 27.5, 22.4, 20.7, 13.8; MS (m/z, %) 286 (M+, 4),
244 (67), 158 (100); HRMS calcd for C15H17N2O2 (M+ - C2H5):
257.1290; found: 257.1282. Anal. Calcd for C17H22N2O2: C, 71.30;
H, 7.74; N, 9.78. Found: C, 71.12; H, 7.93; N, 9.82. The ORTEP
diagram and X-ray crystallographic data for structure 61 are
provided in the Supporting Information.
3-n-Butyl-1-methyl-4-(p-toluenesulfonyl)-2,5-dihydro-1H-pyr-
role (62). Sarcosine (67 mg, 0.75 mmol) and paraformaldehyde
(43.5 mg) were added to a solution of acetylenic sulfone 28a (59
mg, 0.25 mmol) in toluene (20 mL) in a flask equipped with a
Dean-Stark trap and the solution was refluxed for 24 h. It was
then washed with water and brine, dried, filtered, and concentrated
in vacuo. The crude product was chromatographed (25% ethyl
acetate-hexanes) to afford 56 mg (76%) of dihydropyrrole 62 as
a pale-yellow oil: IR (film) 1670, 1304, 1147 cm-1; 1H NMR (300
MHz) δ 7.73 (d, J ) 8.2 Hz, 2 H), 7.29 (d, J ) 8.3 Hz, 3 H), 3.57
(t, J ) 3.4 Hz, 2 H), 3.53 (t, J ) 3.7 Hz, 2 H), 2.60 (t, J ) 7.2 Hz,
2 H), 2.39 (s, 3 H), 2.33 (s, 3 H), 1.41-1.27 (m, 4 H), 0.89 (t, J
) 7.0 Hz, 3 H); 13C NMR (75 MHz) δ 154.8, 144.2, 138.1, 132.2,
129.8, 127.3, 65.8, 61.8, 42.0, 30.0, 26.8, 22.7, 21.5, 13.8; MS (m/
z, %) 293 (M+, 10), 249 (15), 95 (100); HRMS calcd for
C16H23NO2S: (M+): 293.1450; found: 293.1461.
7-n-Butyl-5-methyl-6-(p-toluenesulfonyl)-2,3-dihydro-1H-pyr-
rolizine (64). Acetylenic sulfone 28a (59 mg, 0.25 mmol), proline
(70 mg, 0.61 mmol), and acetic anhydride (325 mg, 3.2 mmol)
were refluxed in DMF (10 mL) for 30 min. The solution was diluted
with water and extracted with ethyl acetate. The organic phase was
washed with saturated NaHCO3 solution, water, and brine. The
organic phase was dried, filtered, and concentrated. The crude
product was chromatographed (35% ethyl acetate-hexanes) to
afford 73 mg (88%) of product 64 as a pale-yellow oil: IR (film)
7-n-Butyl-3-methyl-5-phenyl-6-(p-toluenesulfonyl)-2,3-dihy-
dro-5H-pyrazolo[1,2-a]pyrazol-1-one (59a). Azomethine imine 23
(47 mg, 0.25 mmol) was added to a solution of acetylenic sulfone
28a (59 mg, 0.25 mmol) in anisole (20 mL) and the reaction mixture
was refluxed for 15 min. The solution was washed with water and
brine, dried, filtered, evaporated under vacuum, and chromato-
graphed (20-35% ethyl acetate-hexanes) to afford 34 mg (32%)
of product 59a as a pale-yellow oil: IR (film) 1721, 1324, 1151
cm-1; H NMR (300 MHz) δ 7.21-7.04 (m, 5 H), 6.99 (d, J )
1
8.4 Hz, 2 H), 6.92 (d, J ) 8.3 Hz, 2 H), 5.09 (s, 1 H), 3.49 - 3.18
(m, 2 H), 3.13-2.95 (m, 1 H), 2.65 (dd, J ) 16.4, 6.5 Hz, 1 H),
2.51 (dd, J ) 16.4, 12.5 Hz, 1 H), 2.28 (s, 3 H), 1.80-1.68 (m, 1
H), 1.65-1.51 (m, 1 H), 1.50-1.38 (m, 2 H), 0.94 (t, J ) 7.4 Hz,
3 H), 0.85 (d, J ) 6.1 Hz, 3 H); 13C NMR (75 MHz) δ 165.5,
147.2, 143.3, 138.84, 138.81, 129.1, 129.0, 128.0, 126.9, 118.6,
73.8, 62.7, 43.7, 30.8, 24.3, 22.7, 21.5, 17.4, 13.9; MS (m/z, %)
J. Org. Chem. Vol. 73, No. 20, 2008 8067

Gao et al.
1300, 1130, 1086, 816 cm-1; 1H NMR (300 MHz) δ 7.72 (d, J )
8.2 Hz, 2 H), 7.22 (d, J ) 8.1 Hz, 2 H), 3.76 (t, J ) 7.1 Hz, 2 H),
2.70 (t, J ) 7.3 Hz, 2 H), 2.54 (t, J ) 7.6 Hz, 2 H), 2.48 (s, 3 H),
2.47-2.39 (m, 2 H), 2.38 (s, 3 H), 1.49-1.17 (m, 4 H), 0.85 (t, J
) 7.2 Hz, 3 H); 13C NMR (75 MHz) δ 142.37, 142.35, 132.8, 129.3,
128.2, 126.3, 118.9 114.5, 44.5, 32.7, 26.8, 25.0, 23.7, 22.7, 21.5,
14.0, 11.7; MS (CI, m/z, %) 332 (M+ + 1) 100); HRMS calcd for
C19H25NO2S (M+): 331.1606; found: 331.1593.
in anisole (5 mL). The solution was washed with water and brine,
dried, filtered, and concentrated under vacuum. The crude product
was chromatographed (25% ethyl acetate-hexanes) to afford 72
mg (90%) of product 68 as a pale yellow oil that crystallized from
ethyl acetate-hexanes: mp 103-105 °C; IR (film) 1596, 1317, 1135
1
cm-1; H NMR (300 MHz) δ 7.76 (d, J ) 8.3 Hz, 2 H), 7.27 (d,
J ) 8.3 Hz, 2 H), 4.07 (t, J ) 7.7 Hz, 2 H,), 3.08 (t, J ) 7.4 Hz,
2 H), 2.70 (t, J ) 7.7 Hz, 2 H), 2.65-2.49 (m, 2 H), 2.39 (s, 3 H),
1.67-1.42 (m, 2 H), 1.40-1.19 (m, 2 H), 0.86 (t, J ) 7.3 Hz, 3
H); 13C NMR (75 MHz) δ 156.9, 149.8, 143.7, 140.8, 129.8, 126.8,
114.1, 48.5, 31.0, 27.3, 25.5, 24.3, 22.7, 21.6, 13.9; MS (m/z, %)
318 (M+, 7), 276 (100), 211 (88); HRMS calcd for C17H22N2O2S
(M+): 318.1402; found: 318.1384.
1-n-Butyl-2-[(p-hydroxymethyl)benzenesulfonyl]-3-methyl-
5,6,7,8-tetrahydroindolizine (66). Resin 7a (0.50 g, 0.67 mmol/
g) was stirred in 40 mL of DMF for 30 min. Pipecolinic acid (129
mg, 1.00 mmol) and acetic anhydride (520 mg, 5.10 mmol) were
added and the reaction mixture was refluxed for 30 min. The
resulting yellow resin was filtered and washed with dichloromethane
and methanol. The solid-supported cycloadduct was cleaved in
the usual manner with LiOH and the product was chromatographed
(65% ethyl acetate-hexanes) to afford 94 mg (78%) of cycloadduct
66 as a pale-yellow oil that crystallized from ethyl acetate-hexanes:
2-n-Butyl-3-[(p-hydroxymethyl)benzenesulfonyl]-5,6-dihydro-
4H-pyrrolo[1,2-b]pyrazole (70). Similarly, resin 7a (0.50 g, 0.67
mmol/g) was stirred in anisole (30 mL) for 30 min. Sydnone 27
(63 mg, 0.50 mmol was added and the reaction mixture was refluxed
for 2 h. The resulting solid-supported cycloadduct was cleaved with
LiOH in the usual manner. The resulting yellow oil was chro-
matograped (50% ethyl acetate-hexanes) to afford 92 mg (82%)
of product 70 as a yellow oil that crystallized from ethyl
acetate-hexanes: mp 106-107.5 °C; IR (KBr) 3339, 1596, 1322,
mp 124.5-125.5 °C; IR (KBr) 3478, 1396, 1274, 1152, 1130 cm-1
;
1H NMR (300 MHz) δ 7.78 (d, J ) 8.3 Hz, 2 H), 7.40 (d, J ) 8.1
Hz, 2 H), 4.72 (d, J ) 5.9 Hz, 2 H), 3.71 (t, J ) 6.1 Hz, 2 H), 2.58
(t, J ) 6.3 Hz, 2 H), 2.54-2.39 (m, 3 H), 2.45 (s, 3 H), 1.92 (m,
2 H), 1.77 (m, 2 H), 1.42- 1.16 (m, 4 H), 0.85 (t, J ) 6.9 Hz, 3
H); 13C NMR (75 MHz) δ 145.2, 144.1, 131.6, 126.7, 126.3, 126.1,
118.3, 116.0, 64.3, 43.2, 33.3, 24.0, 23.3, 22.9, 21.8, 20.4, 13.9,
10.5; MS (m/z, %) 361 (M+, 100), 318 (90); HRMS calcd for
C20H27NO3S (M+): 361.1712; found: 361.1678. Anal. Calcd for
C20H27NO3S: C, 66.45; H, 7.53; N, 3.87. Found: C, 66.37; H, 7.43;
N, 3.79. The ORTEP diagram and X-ray crystallographic data for
structure 66 are provided in the Supporting Information.
1
1130, 1052 cm-1; H NMR (300 MHz) δ 7.84 (d, J ) 8.3 Hz, 2
H), 7.48 (d, J ) 8.3 Hz, 2 H), 4.76 (d, J ) 5.1 Hz, 2 H), 4.09 (t,
J ) 7.2 Hz, 2 H), 3.10 (t, J ) 7.5 Hz, 2 H), 2.70 (t, J ) 8.2 Hz,
2 H), 2.65-2.55 (m, 2 H), 2.32 (t, J ) 5.2 Hz, 1 H), 1.77-1.44
(m, 2 H), 1.42-1.15 (m, 2 H), 0.88 (t, J ) 7.3 Hz, 3 H); 13C NMR
(75 MHz) δ 157.1, 150.0, 146.4, 142.5, 127.1, 127.0, 113.8, 64.3,
48.5, 31.0, 27.3, 25.5, 24.4, 22.7, 14.0; MS (m/z, %) 334 (M+,
20), 305 (90), 292 (100); HRMS calcd for C17H22N2O3S (M+):
334.1351; found: 334.1324. Anal. Calcd for C17H22N2O3S: C, 61.05;
H, 6.63; N, 8.38. Found: C, 61.03; H, 6.80; N, 8.26. The ORTEP
diagram and X-ray crystallographic data for structure 70 are
provided in the Supporting Information.
The above cycloaddition was repeated and cleavage of the resin
was effected by reduction with sodium-amalgam29 as follows. The
resin (0.55 g) was stirred 30 min in 34 mL of DMF before the
addition of 222 mg (1.56 mmol) of Na2HPO4, 7.4 g of 5% sodium
amalgam (15 mmol) and 4.2 mL of methanol at room temperature.
The reaction mixture was stirred vigorously overnight and filtered
through a pad of celite. The filtrate was diluted with water and
extracted with ethyl acetate. The organic solution was washed with
water and brine, dried, and evaporated. The resulting residue was
purified by chromatography (35% ethyl acetate-hexanes) to afford
65 in 67% yield.
The reduction of the cycloadduct obtained from sydnone 27 and
the solid-supported acetylenic sulfone 7a with samarium diiodide
was carried out as in the case of the cycloadduct formed between
dipole 26b and 7a (Vide supra) to afford 68 in 77% yield.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada and Merck Frosst
(Canada) Inc. for financial support.
Alternatively, reduction with samarium diiodide30 was carried
out as follows. The polymer (0.55 g) was stirred for 30 min in dry
THF at room temperature. The solution was cooled to -78 °C and
228 mg of HMPA was added under argon, followed by 15 mL of
0.1 M samarium diiodide in dichloromethane via syringe. The
reaction mixture was stirred at room temperature overnight. It was
then filtered through a pad of celite, the filtrate was evaporated,
and the resulting residue was chromatographed (35% ethyl
acetate-hexanes) to produce the same compound 65 in 53% yield.
2-n-Butyl-3-(p-toluenesulfonyl)-5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazole (68). A mixture of acetylenic sulfone 28a (59 mg, 0.25
mmol) and sydnone 2740 (47 mg, 0.38 mmol) was refluxed 30 min
Supporting Information Available: Procedures for the
preparation of 13, 14, 33, 34, 40a,b, 46, 49, 51, 53, 55, 58, 60,
63, 65, 67, 69, and 71; 1H and 13C NMR spectra of new
compounds; ORTEP diagrams and cif files for the X-ray
structures of compounds 32, 35, 48, 51, 54, 61, 66, and 70.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801621D
8068 J. Org. Chem. Vol. 73, No. 20, 2008