Allylic Sulfones in Solid-Phase Synthesis: Preparation of Cyclobutylidenes

Article abstract of DOI:10.1021/jo990954b

Polymer-bound allyl sulfones (cf. 9) were utilized in geminal cycloalkylations with epichlorohydrin to generate a cis-phenylsulfonylcyclobutanol derivative (cf. 11) in one step. In the final step of this solid-phase synthetic sequence, cuprate, organomolybdenum, and organopalladium reagents were screened to obtain an optimal protocol for "traceless" cleavage of cyclobutylidene products from the resin. Among these, palladium-catalyzed allylic alkylation was the most efficient. In addition, highly regioselective nucleophilic attack at the less hindered terminus of the allyl fragment (i.e., overall S_N2′ sulfinate displacement) was observed. Cyclobutylidene diversification was demonstrated by incorporating different allylic substituents, O-functionalizations, and C-nucleophiles to prepare a demonstration library of eight cyclobutylidene derivatives (i.e., derivatives of 4) in four steps and 30-38% overall yield from lithium polystyrene/divinylbenzene sulfinate.

Full text of DOI:10.1021/jo990954b

J . Org. Chem. 1999, 64, 8557-8562
8557
Allylic Su lfon es in Solid -P h a se Syn th esis: P r ep a r a tion of
Cyclobu tylid en es
Wei-Chieh Cheng, Chris Halm, J erry B. Evarts, Marilyn M. Olmstead, and Mark J . Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616-5295
Received J une 14, 1999
Polymer-bound allyl sulfones (cf. 9) were utilized in geminal cycloalkylations with epichlorohydrin
to generate a cis-phenylsulfonylcyclobutanol derivative (cf. 11) in one step. In the final step of this
solid-phase synthetic sequence, cuprate, organomolybdenum, and organopalladium reagents were
screened to obtain an optimal protocol for “traceless” cleavage of cyclobutylidene products from
the resin. Among these, palladium-catalyzed allylic alkylation was the most efficient. In addition,
highly regioselective nucleophilic attack at the less hindered terminus of the allyl fragment (i.e.,
overall SN2′ sulfinate displacement) was observed. Cyclobutylidene diversification was demonstrated
by incorporating different allylic substituents, O-functionalizations, and C-nucleophiles to prepare
a demonstration library of eight cyclobutylidene derivatives (i.e., derivatives of 4) in four steps
and 30-38% overall yield from lithium polystyrene/divinylbenzene sulfinate.
In tr od u ction
a palladium-catalyzed SN2′ sulfinate displacement.10 The
resulting cyclobutanes may prove useful as a molecular
scaffold for library production11 as cyclobutane-containing
compounds are both prevalant in nature and useful as
building blocks for further transformations.12 The conver-
sion of sulfinate-functionalized resin 3 to cyclobutylidene
4 (Scheme 1) which is presented here proceeds by a four-
step procedure consisting of (i) sulfinate S-allylation (see
Scheme 3), (ii) CR-sulfone R,R-dialkylation with epichlo-
rohydrin (see Scheme 4), (iii) O-alkylation (or O-acylation)
(see Scheme 5), and (iv) SN2′ sulfinate displacement with
carbon nucleophiles (see Scheme 5). Reagent variation
in steps i, iii, and iv has been demonstrated, and the
overall protocol appears suitable for library generation.
The construction of small organic molecules on polymer
support,1 which generally proceeds by chemical modifica-
tion of insoluble resins2,3 (solid-phase organic synthesis,
SPOS),4 has allowed organic chemists to generate a wide
variety of compound classes with high efficiency. An
important continuing objective in SPOS is the develop-
ment of strategies and chemistries applicable to combi-
natorial techniques, but where reactions are not limited
by the tether and where the target can be efficiently
cleaved from the resin by a specialized reagent or
transformation. In this regard, one of our goals has been
to examine new tethering strategies for the attachment
of small-molecule building blocks to insoluble resins and
to explore new applications of these tethers in SPOS.5
We recently reported the preparation of a sulfinate-
functionalized resin6 from styrene/2% divinylbenzene
copolymer beads (PS/DVB ) b). Subsequent conversion
of this resin to solid-phase allyl sulfone 1 followed by
copper-mediated Grignard displacement of sulfinate7
delivered trisubstituted olefin 2.6
Resu lts a n d Discu ssion
Solu tion -P h a se Syn th esis of Cyclobu tylid en ol 8.
With the continuing evolution of SPOS13 comes a growing
appreciation for the importance of linker technology,14
which ideally must accommodate a wide variety of
Herein, we report modification of this chemistry to
accommodate cyclobutane formation by sulfone dianion
alkylation8 and subsequent “traceless” resin release9 by
(9) (a) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-
7. (b) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem. Soc.
1995, 117, 11999-12000. (c) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703-6. (d) Lorsbach, B. A.; Miller, R. B.;
Kurth, M. J . J . Org. Chem. 1996, 61, 8716-17.
(1) (a) Ellman, J . A. Acc. Chem. Res. 1996, 29, 132-43. (b) Balk-
enhohl, F.; Von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2289-337.
(2) (a) Labadie, J . W. Curr. Opin. Chem. Biol. 1998, 2, 346-52. (b)
Fruchtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-
42. (c) Blackburn, C. Biopolymers 1999 (volume date 1998), 47, 311-
51.
(3) Alternatively, soluble resins can be used. See: Harwig, C. W.;
Gravert, D. J .; J anda, K. D. Chemtracts 1999, 12, 1-26.
(4) (a) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees,
D. C. Tetrahedron 1998, 54, 15385-15443. (b) Brown, R. D. J . Chem.
Soc., Perkin Trans. 1 1998, 3293-320. (c) Yan, B. Acc. Chem. Res. 1998,
31, 621-30. (d) Kantorowski, E. J .; Kurth, M. J . Mol. Diversity 1997,
2, 207-16.
(10) (a) Gil, R.; Fiaud, J . Bull. Soc. Chim. Fr. 1994, 131, 584-9. (b)
Trost, B.; Verhoeven, T. J . Am. Chem. Soc. 1977, 99, 3867-8. (c) Trost,
B.; Verhoeven, T. J . Am. Chem. Soc. 1976, 98, 630-2.
(11) (a) Fauchere, J . L.; Henlin, J . M.; Boutin, J . A. Analysis 1997,
25, 97-101. (b) Neustadt, B. R.; Smith, E. M.; Nechuta, T.; Zhang, Y.
Tetrahedron Lett. 1998, 39, 5317-20. (c) Pryor, K. E.; Shipps, W., J r.;
Skyler, D. A.; Rebek, J ., J r. Tetrahedron 1998, 54, 4107-24. (d) del
Fresno, M.; Alsina, J .; Royo, M.; Barany, G.; Albericio, F. Tetrahedron
Lett. 1998, 39, 2639-42.
(12) (a) Nemoto, H.; Fukumoto, K. Synlett 1997, 863-75. (b) Okuma,
K.; Tsubakihara, K.; Tanaka, Y.; Koda, G. Tetrahedron Lett. 1995, 36,
5591-4. (c) Frimer, A.; Weiss, J .; Gottlieb, H.; Wolk, J . J . Org. Chem.
1994, 59, 780-92. (d) Dzhemilev, U. M.; Khusnutdinov, R. I.; Tolstikov,
G. A. J . Organomet. Chem. 1991, 409, 15-65. (e) D. T. Hurst, D. T. In
Rodd’s Chemistry of Carbon Compounds; Sainsbury, M., Ed.; Else-
vier: Amsterdam 1992; Chapter 3, Second Supplement to IIA/IIB. (f)
Lee, T. V. Gen. Synth. Methods 1989, 11, 518-46. (g) Bellus, D.; Ernst,
B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797-827. (h) Lee-Ruff, E.
Adv. Strain Org. Chem. 1991, 1, 167-213. (i) Oppolzer, W. Acc. Chem.
Res. 1982, 15, 135-41.
(5) (a) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res.
1996, 29, 144-54. (b) Terrett N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51, 8135-73.
(6) (a) Halm, C.; Evarts, J .; Kurth, M. J . Tetrahedron Lett. 1997,
38, 7709-12. (b) Fre´chet, J . M. J . Tetrahedron 1981, 37, 663-83.
(7) J ulia, M.; Righini-Tapie, A.; Verpeaux, J . Tetrahedron 1983, 39,
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(13) Lorsbach, B. A.; Kurth, M. J . Chem. Rev. 1999, 99, 1549-81.
10.1021/jo990954b CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

8558 J . Org. Chem., Vol. 64, No. 23, 1999
Cheng et al.
Sch em e 3. P r ep a r a tion of Solid -P h a se Allyl
Sch em e 1. Su lfon e-Ba sed SP OS Lin k er
P h en yl Su lfon e
Sch em e 2. Solu tion -P h a se Su lfon e
r,r-Dia lk yla tion a n d SN2′ Disp la cem en t
Sch em e 4. Solid -P h a se Cyclobu ta n ol F or m a tion
(Step ii)
P r ep a r a tion of Solid -P h a se Allyl P h en yl Su lfon e.
With a solution-phase route to cyclobutylidene 8 from
benzenesulfinate in hand, we turned to development of
a solid-phase protocol which began with the preparation
of polymer-bound benzenesulfinate. In parallel with
Leznoff’s strategy for PS/2% DVB functionalization,18
commercially available PS/2% DVB copolymer (bC6H5)
was metalated with n-BuLi/TMEDA (1:1 molar ratio) in
cyclohexane (60 °C, 10 h) (Scheme 3). After the orange
suspension of bC6H4Li was washed at 0 °C with dry THF
to remove excess n-BuLi, sulfur dioxide gas was bubbled
through it, giving polymer 3 (pale yellow). The benzene-
sulfinate loading (1 mmol/g) of these beads was deter-
mined by titration of a THF suspension of the corre-
sponding sulfinic acid with standardized aqueous
NaOH.
S-Allylation of this benzenesulfinate was accomplished
by treatment of a THF-swollen suspension of 3 with
allyl bromide, giving resin-bound allyl phenyl sulfone
9. This transformation could be monitored by FTIR
[bArsSO2Li (1600, 1497, 1458, 1200, 1028, 980 cm-1) f
bArsSO2CH2CHdCH2 (1600, 1492, 1452, 1320, 1139
cm-1)]. Other allylic alkylating agents can be used in the
S-allylation step: for example, use of methallyl bromide
in the reaction with 3 gives sulfone 10.
Solid -P h a se Syn th esis of Cyclobu tylid en ol 8. Even
though a hydroxyl moiety is introduced in 9 f 11
(Scheme 4), this R,R-dialkylation reaction proved impos-
sible to monitor by FTIR since residual moisture after
reaction workup and resin washing rendered the hy-
droxyl region of the IR spectrum unreliable. Therefore,
the resin 11 obtained upon treatment of 9 with n-BuLi
(8 equiv) and epichlorohydrin (10 equiv) in THF (0 °C f
room temperature, 24 h) was employed without further
purification in the next transformation.
In contrast to our experience with the straightforward
solution-phase preparation of 8, our efforts to effect the
solid-phase variant of this reaction began with 13 unsuc-
cessful attempted protocols for 11 f 8 consisting of
various reaction temperatures and solvents as well as
synthetic transformations and yet allow for ready product
cleavage in the final solid-phase transformation. R,R-
Dialkylated allyl sulfones of generalized structure 1
appear to be ideally suited for SPOS linker application
where the allylic C-S bond serves as the substrate-resin
tether.
Preliminary solution-phase experiments were con-
ducted as outlined in Scheme 2. Allylation of benzene-
sulfinate with allyl bromide in THF furnished allyl
phenyl sulfone in 85% yield. Higher yields were obtained
using MeOH, but we chose to utilize solvents in these
solution-phase studies that could be anticipated to swell
PS/DVB so that the resulting protocol would be readily
adaptable to SPOS. Lithiation15 of allyl phenyl sulfone
(5)16 using n-BuLi and subsequent alkylation17 with
epichlorohydrin proceeded smoothly to give a single
cyclobutanol product (75%) as evidenced by 1H NMR. The
p-nitrobenzoyl derivative 7 (55% yield) of this cyclobu-
tanol was submitted for single-crystal X-ray analysis,
establishing that the hydroxyl and phenylsulfonyl moi-
eties are cis-arranged in 6. Interestingly, the epoxy
mesylate analogue of epichlorohydrin (i.e., -OMs replac-
ing -Cl) gives a mixture of 6 and its hydroxyl epimer.
Finally, treating allylic sulfone 6 with CuI and isopro-
pylmagnesium chloride in THF delivered cyclobutylidenol
8 in 56% yield.
(14) (a) Doerner, B.; Steinauer, R.; White, P. Chimia 1999, 53, 11-
17. (b) Morphy, J . R. Curr. Opin. Drug Discovery Dev. 1998, 1, 59-65.
(c) Wustrow, D. J .; J in, S.; Holub, D. P. Tetrahedron Lett. 1998, 39,
3651-4. (d) Backes, B. J .; Ellman, J . A. Curr. Opin. Chem. Biol. 1997,
1, 86-93. (e) Ellman, J . A.; Thompson, L. A. Chem. Rev. 1996, 96, 555-
600. (f) Ellman, J . A.; Backes, B. J . J . Am. Chem. Soc. 1994, 116,
11171-2.
(15) Houston, T.; Koreeda, M. Synth. Commun. 1994, 24, 393-8.
(16) Commercially available from Aldrich: Catalog No. 31,
771-3.
(17) (a) Trost, B.; Merlic, C. J . Am. Chem. Soc. 1988, 110, 5216-8.
(b) Trost, B.; Schmuff, N. J . Am. Chem. Soc. 1985, 107, 396-405.
(18) For the preparation of bC6H4CO2H from bC6H5, see: Fyles, T.
M.; Leznoff, C. C. Can. J . Chem. 1976, 54, 935-42.

Allylic Sulfones in Solid-Phase Synthesis
J . Org. Chem., Vol. 64, No. 23, 1999 8559
Sch em e 5. Solu tion -P h a se Mo- or P d -Med ia ted
Sch em e 6. Solid -P h a se O-F u n ction a liza tion (step
iii) a n d P d -Med ia ted SN2′ Disp la cem en t of P h en yl
Su lfin a te (Step iv)
SN2′ Disp la cem en t of P h en yl Su lfin a te
addition techniques. We were about to conclude that
perhaps conversion of 9 to 11 had failed. Fortunately, in
our 14th attempt, we were finally able to partially mimic
solution results and isolate cyclobutylidenol 8, albeit in
low yield (∼10%), by cannulating a premade cuprate
solution (CuI, isopropylmagnesium chloride, THF) into
THF-swollen polymer 11 at -30 °C f room temperature
(stirring for 7 h).
Solu tion -P h a se Mo- or P d -Ca ta lyzed SN2′ Dis-
p la cem en t of P h en yl Su lfin a te. In addition to being
low yielding, we felt this release strategy (11 f 8) lacked
generality and was also severely limited by the cleavage
conditions (copper-assisted Grignard or cuprate condi-
tions would preclude the incorporation of many electro-
philic functional groups). We therefore reverted to the
solution phase to investigate other metal-catalyzed allylic
alkylations strategies for substrate release.
Drawing on the molybdenum [Mo(CO)6]19 and pal-
ladium [Pd(PPh3)4]20 catalyzed allylic alkylation studies
of Trost, we investigated the SN2′ sulfinate displacement
reaction of cyclobutanol 6. While the palladium-mediated
transformation on this free hydroxyl-containing substrate
was successful, the yield was low (30%). We found that
O-blocked substrates not only improved the yield of this
transformation, but also increased the diversity poten-
tial of the target cyclobutylidene. For example, O-
alkylation of the hydroxyl functional group in cyclobu-
tanol 6 (sodium hydride and benzyl bromide in THF) gave
benzyl ether 12 in 95% yield, which then underwent
metal-mediated conversion 12 f 13 (see Scheme 5). We
found that palladium catalysis was uniformly more
effective than molybdenum catalysis,21 and in all cases,
no competing SN2 sulfinate displacement product was
detected.22
treating resin 10 with n-BuLi in THF followed by
addition of epichlorohydrin) were O-alkylated (f 15 and
16, respectively, n-BuLi in THF, BnBr) or O-acylated (f
17 and 18, respectively, BzCl/pyridine in THF). In the
case of these O-acylations, we were pleased to obtained
FTIR confirmation (an ester CdO signal was observed
at 1718 cm-1) that solid-phase R,R-dialkylative cyclobu-
tanol formation (9/10 f 11/14) had been successful.
With these solid-phase substrates in hand, we were
delighted to find that addition of the sodium salt of
diethyl methylmalonate to a THF suspension of benzyl
ether 15 containing 5-10 mol % Pd(PPh3)4 delivered
cyclobutylidene 13a (Scheme 6). Reaction workup con-
sisted of addition of saturated aqueous NH4Cl, removal
of the polymer by filtration, extraction with ether, wash-
ing with brine, and drying (MgSO4). This delivered the
targeted cyclobutylidene contaminated primarily with
excess nucleophile (neutral A-C) and triphenylphos-
phine. Purification by column chromatography gave 13a
in 38% overall isolated yield from bC6H5. This equates
to an ∼83% yield per step for sulfinate formation,
S-allylation, R,R-dialkylation, O-alkylation, and SN2′
sulfinate displacement and was achieved on a scale which
delivered 400 mg of 13a .
Likewise, treatment of a THF suspension of benzoate
17 with the sodium salt of 2-acetylcyclopentanone and
Pd(PPh3)4 delivered cyclobutylidene 19 in 34% overall
yield, establishing that this solid-phase SN2′ sulfinate
displacement transformation is mild enought to accom-
modate an ester moiety. In this way, reaction of 15-18
with the sodium salts of diethyl methylmalonate, ethyl
cyanoacetate, and 2-acetylcyclopentanone and Pd(PPh3)4
in refluxing THF provided alkylation products 13a -c and
Solid -P h a se P d -Ca ta lyzed SN2′ Disp la cem en t of
P h en yl Su lfin a te. Returning to the solid phase, cy-
clobutanols 11 and 14 (obtained as in 9 f 11 but by
(19) (a) Trost, B. M.; Lautens, M. J . Am. Chem. Soc. 1983, 105,
3343-4. (b) Trost, B. M.; Lautens, M. J . Am. Chem. Soc. 1987, 109,
1469-78. (c) Trost, B. M.; Merlic, G. A. J . Org. Chem. 1990, 55,
1127-9.
(20) (a) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J . Org. Chem. 1985, 50, 1523-9. (b) Trost, B. M.;
Schmuff, N. R.; Miller, M. J . J . Am. Chem. Soc. 1980, 102, 5979-81.
(c) Trost, B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1977, 99,
3867-8.
(21) (a) Kocovsky, P.; Malkov, A. V.; Baxendale, I.; Mansfield, D. J .
Tetrahedron Lett. 1997, 38, 4895-7. (b) Trost, B. M. Bull. Chem. Soc.
J pn. 1988, 61, 107-24.
(22) (a) Trost, B. M.; Hung, M.-H. J . Am. Chem. Soc. 1984, 106,
6837-9. (b) de Meijere, A.; Salaun, J .; Atlan, V.; Racouchot, S.;
Rubin, M.; Bremer, C.; Ollivier, J . Tetraherdon: Asymmetry 1998, 9,
1131-5. (c) de Meijere, A.; Stolle, A.; Salaun, J . Tetrahedron 1990,
31, 4593-6.

8560 J . Org. Chem., Vol. 64, No. 23, 1999
Cheng et al.
133.7, 129.7, 128.6, 120.4, 61.2, 60.3, 38.3. Anal. Calcd for
C12H14O3S: C, 60.48; H, 5.92. Found: C, 60.41; H, 5.79.
3-(3-Meth ylbu tylid en yl)cyclobu ta n ol (8). Isopropylmag-
nesium chloride (10 mL, 20 mmol, 2.0 M in THF) was added
dropwise to a suspension of CuI (0.2 g, 1.1 mmol) in THF (20
mL) at -30 °C. After 20 min, a solution of 6 (0.1 g, 0.42 mmol)
in THF (10 mL) was added, and the mixture was stirred for
an additional 6 h with warming to 0 °C. Saturated aqueous
NH4Cl was added, and following standard workup, cyclobu-
tylidene 8 (30 mg, 51%) was isolated as a colorless oil after
CC (17% EtOAc in hexanes): IR (CDCl3) 3300, 1101 cm-1; 1H
NMR δ 5.22 (m, 1H), 4.38 (m, 1H), 2.96 (m, 2H), 2.58 (m, 2H),
2.22 (s, 1H), 1.78 (m, 2H), 1.58 (m, 1H, J ) 6 Hz), 0.85 (d, 6H,
J ) 6 Hz);13C NMR δ 130.6, 121.4, 64.0, 42.2, 40.4, 37.9, 28.6,
22.3.
19-23 in the yields listed in Scheme 5. In contrast to
the limitation imposed when either cuprate- or copper-
mediated Grignard reactions are employed in the SN2′
sulfinate displacement transformation, the mild condi-
23
tions employed with catalytic Pd(PPh3)4 allow for
diverse substrate functionality. The eight-compound
demonstration library constructed in this study embraces
two different O-functionalizations (R1 in 4), two different
S-allylating reagents (R2 in 4), and three different
nucleophiles (R3 in 4).
Su m m a r y
We have developed a route to cyclobutylidenes with
three points of diversification (R1, R2, and R3 in 4) which
incorporates two C,C bond-forming transformations (steps
iii and iv). The key to successfully executing this solid-
phase protocol was utilization of a palladium catalyst in
the SN2′ sulfinate displacement step, which results in
resin release and allows for functional diversity in the
targeted cyclobutylidenes. Other experiments established
complete diastereoselectivity in the cyclobutanol-forming
sulfone R,R-dialkylation step. The solid-phase preparation
of eight diverse cyclobutylidenes demonstrates the gen-
erality of this four-step protocol.
Allyl P S/DVB Su lfon e (9). Polymer 3 (10 g) was swollen
in THF (50 mL) and allyl bromide (12 mL) was added at reflux
under nitrogen (24 h). The resin was collected by filtration
using a medium sintered glass fritted Buchner funnel, washed
with THF (2 × 15 mL), THF/H2O (4:1, 2 × 20 mL), THF (2 ×
20 mL), and ether (2 × 10 mL), and dried overnight in a
vacuum oven (35 °C, 5 mmHg), affording polymer-bound allyl
sulfone 9 as yellow beads: IR (single bead reflectance) 1600,
1492, 1452, 1320, 1139 cm-1
.
Meth a llyl P S/DVB Su lfon e (10). Likewise, polymer 10
was prepared from lithium sulfinate polymer 3 except allyla-
tion was accomplished using 3-chloro-2-methylpropene in THF
at reflux for 24 h: IR (single bead reflectance) 1600, 1497,
1450, 1317, 1150, 1129 cm-1
.
3-(P S/DVBsu lfon yl)-3-vin ylcyclobu ta n ol (11). Polymer
9 (10 g, 10 mmol) was swollen in THF (200 mL) at 0 °C, and
n-BuLi (50 mL, 80 mmol, 1.6 M) was added, turning the yellow
suspension to dark orange. An excess of epichlorohydrin (9.44
g, 102 mmol) was added slowly over 30 min, and the reaction
was stirred at room temperature for 24 h. The reaction was
quenched with aqueous HCl (1 N, 20 mL), and polymer 11 was
filtered out and washed with THF (2 × 20 mL), THF/H2O (4:
1, 2 × 25 mL), THF (2 × 20 mL), and ether (2 × 10 mL) and
dried overnight in a vacuum oven (35 °C, 5 mmHg): IR (single
Exp er im en ta l Section
Gen er a l P r oced u r es. All chemicals were obtained from
commercial suppliers and used without further purification.
Analytical TLC was carried out on precoated plates (Merck
silica gel 60, F254) and visualized with UV light. Flash column
chromatography was performed with silica (Merck, 70-230
mesh). NMR spectra (1H at 300 MHz, 13C at 75 MHz) were
recorded in CDCl3 solvent, and chemical shifts are expressed
in parts per million relative to internal TMS. CC refers to
column chromatography. Concentration refers to rotoevapo-
ration.
bead reflectance) 1600, 1492, 1452, 1294, 1132 cm-1
.
Ben zyl 3-(P h en ylsu lfon yl)-3-vin ylcyclobu tyl Eth er (12).
Benzyl bromide (0.6 g, 3.5 mmol) was added to a solution of
NaH (1 g, 25 mmol, 60% in mineral oil) and 6 (0.83 g, 3.5
mmol) in THF at -20 °C, and the mixture was stirred for 3 h.
When no starting material could be visualized by TLC,
saturated aqueous NH4Cl was added, and the organic layer
was extracted with ether, dried over MgSO4, and concentrated.
The crude product was purified by CC (33% EtOAc in hexanes)
to give 12 (1.09 g, 95%) as a yellow solid: IR (CDCl3) 1446,
Lith iu m P S/DVB Su lfin a te (3). Cyclohexane (400 mL)
was distilled directly into a flask containing PS/DVB (40 g).
Under an argon atmosphere, TMEDA (60 mL, 0.4 mol) was
introduced, the mixture was cooled to 0 °C with gentle stirring
(overhead mechanical), and n-BuLi (1.6 M, 250 mL, 0.4 mol)
was added. The resin changed from an off-white color to an
orange color after being refluxed overnight, the resulting
lithiated PS/DVB was washed with anhydrous THF (3 × 50
mL) and cooled to -78 °C, and SO2(g) was bubbled through
the THF-swollen polymer for 1 h using a fritted glass bubbler.
The reaction was quenched by addition of H2O (1 h), and the
polymer was washed with THF, THF/H2O (80:20), THF, and
ether and collected by filtration. The polymer was dried in a
vacuum oven overnight at 30 °C. This lithium sulfinate
polymer proved to be stable and not air-sensitive: IR 1600,
1
1303, 1139, 908 cm-1; H NMR δ 2.31-2.37 (m, 2H, J ) 9.0,
6.0 Hz), 2.82-2.89 (m, 2H, J ) 9.0, 6.0 Hz), 3.88 (t, 1H, J ) 9
Hz), 4.38 (s, 2H), 5.00 (d, 1H, J ) 18 Hz), 5.27 (d, 1H, J ) 12
Hz), 5.88 (dd, 1H, J ) 12, 18 Hz), 7.21-7.77 (m, 10H); 13C
NMR δ 137.5, 135.6, 133.4, 129.4, 128.2, 128.5, 127.5, 120.2,
70.1, 66.3, 59.6, 35.4. Anal. Calcd for C19H20O3S: C, 69.48; H,
6.14. Found: C, 69.42; H, 6.17.
Dieth yl (2-(3-Ben zyloxycyclobu tylid en e)eth yl)m eth -
ylm a lon a te (13a ). A suspension of diethyl methylmalonate
(290 mg, 1.7 mmol) and NaH (66 mg, 1.65 mmol, 60% in
mineral oil) in toluene (8 mL) was stirred for 40 min at 0 °C.
The resulting mixture was then added to a solution of 12 (180
mg, 0.55 mmol) and Mo(CO)6 (21 mg, 0.08 mmol, 15 mol %) in
toluene (8 mL). The reaction was refluxed for 22 h and
monitored by TLC. After neutralization with saturated aque-
ous NH4Cl, the reaction mixture was extracted with ether. The
combined organic extracts were dried (MgSO4) and concen-
trated, and the residue was purified by CC (25% EtOAc in
hexanes) to give 13a (130 mg, 68%) as a clear oil: IR (neat)
1497, 1458, 1200(s), 1028(s), 980(s) cm-1
.
cis-3-P h en ylsu lfon yl-3-vin ylcyclobu tan ol (6). Allyl phen-
yl sulfone (5) (6.0 g, 30 mmol) was dissolved in THF and cooled
to 0 °C, and n-BuLi (43 mL, 68 mmol, 1.6 M) was added
dropwise with stirring for 1 h. Epichlorohydrin (3.6 g, 39 mmol)
was added to the yellow solution, and the mixture was allowed
to warm to room temperature for 12 h. Water was added, and
the organic fraction was separated, washed with brine, dried
(MgSO4), and concentrated to give a yellow oil which was
purified by CC (25% EtOAc in hexanes) to give 6 (5.35 g,
75%): IR (CDCl3) 3469, 1446, 1284 (s), 1128(s), 1083 cm-1
;
1H NMR δ 2.54-2.58 (m, 2H, J ) 6.9 Hz), 2.78-2.82 (m, 2H,
J ) 6.9 Hz), 3.06 (s, 1H), 4.16 (t, 1H, J ) 6.9 Hz), 5.03 (d, 1H,
J ) 17.1 Hz), 5.32 (d, 1H, J ) 10.5 Hz), 5.93 (dd, 1H, J )
17.1, 10.5 Hz), 7.48-7.75 (m, 4H); 13C NMR δ 135.3, 133.5,
1
1727(s), 1240, 1197, 1103 cm-1; H NMR δ 1.21 (t, 6H, J ) 9
Hz); 1.35 (s, 3H), 2.25 (d, 2H, J ) 7.5 Hz), 2.59 (m, 2H), 2.81
(m, 2H), 4.04 (t, 1H, J ) 6 Hz), 4.15 (q, 4H, J ) 9 Hz), 4.43 (s,
2H), 5.12 (m, 1H), 7.32 (m, 5H); 13C NMR δ 171.4, 137.7, 134.8,
127.9, 127.3, 127.2, 115.9, 69.9, 68.8, 60.6, 53.3, 39.0, 37.2, 34.5,
19.3, 13.6. Anal. Calcd for C21H28O5: C, 69.98; H, 7.83.
Found: C, 70.04; H, 7.86.
(23) (a) Schurer, S.; Blechert, S. Synlett 1998, 166-8. (b) Flegelova´,
Z.; Pa´tek, M. J . Org. Chem. 1996, 61, 6735-8.

Allylic Sulfones in Solid-Phase Synthesis
J . Org. Chem., Vol. 64, No. 23, 1999 8561
Under similar solution-phase conditions, but employing Pd-
(PPh3)4 (80 mg, 0.07 mmol, 5 mol %) as catalyst and THF as
solvent, 12 (500 mg, 1.5 mmol) and diethyl methylmalonate
(923 mg, 5.3 mmol) gave 13a (380 mg, 72%). Solid-phase
preparation from polymer 15 (3.0 g), diethyl methylmalonate
(2.83 g, 16 mmol), and Pd(PPh3)4 (170 mg, 0.15 mmol, 5 mol
%) in THF (reflux, 2 d) gave 13a (400 mg, 38% overall yield
from polymer 3).
and washed with THF (2 × 10 mL) and ether (2 × 10 mL): IR
(single bead reflectance) 1718, 1450, 1299, 1270, 1114, 757,
696 cm-1
.
3-(P S/DVBsu lfon yl)-3-(1-m eth ylvin yl)cyclobu tyl Ben -
zoa te (18). The preparation of polymer 17 was modified as
follows to give polymer 18. Pyridine (5 mL), benzoyl chloride
(700 mg, 5 mmol), and THF (5 mL) gave 18: IR (single bead
reflectance) 1718, 1492, 1450, 1299, 1270, 1114 cm-1
.
Eth yl (2-(3-ben zyloxycyclobu tylid en e)eth yl)cya n o-
a ceta te (13b). The solution-phase, Mo(CO)6-catalyzed prepa-
ration of 13a was modified as follows: 12 (180 mg, 0.55 mmol),
ethyl cyanoacetate (190 mg, 1.7 mmol), NaH (66 mg, 1.65
mmol, 60% in mineral oil), dry toluene (16 mL), Mo(CO)6 (25
mg, 0.09 mmol, 17 mol %), and CC (17% EtOAc in hexanes)
gave 13b (30 mg, 18%) as a clear oil: IR (neat) 1750(s), 1202,
2-Act eyl-(2-(3-b en zoyloxycyclob u t ylid en e)et h yl)cy-
clop en ta n on e (19). 2-Acetylcyclopentanone (688 mg, 5.4
mmol) was added to a suspension of NaH (210 mg, 5.2 mmol,
60% in mineral oil) in THF (6 mL), and the mixture was stirred
for 40 min at 0 °C. The resulting mixture was added to a THF
(10 mL) suspension of polymer 17 (1.5 g) containing Pd(PPh3)4
(120 mg, 0.10 mmol, 7 mol %). The orange mixture was
refluxed (60 h), neutralized with saturated aqueous NH4Cl,
and filtered to remove the polymer. This polymer was washed
with ether (3 × 30 mL), and the resulting washings were
combined with the collected filtrate, which was then dried
(MgSO4) and concentrated. The residue was purified by CC
(20% EtOAc in hexanes) to give 19 (170 mg, 34% overall yield
from polymer 3) as a pale yellow oil: IR (neat) 1716(s), 1270,
1
1103, 1026 cm-1; H NMR δ 1.20 (t, 3H, J ) 9.4 Hz), 2.42 (t,
2H, J ) 6 Hz), 2.59 (m, 2H), 2.83 (m, 2H), 3.39 (q, 1H, J ) 6.3
Hz), 4.01 (t, 1H, J ) 6.6 Hz), 4.14 (q, 2H, J ) 9.4 Hz), 4.36 (s,
2H), 7.24 (m, 5H); 13C NMR δ 165.5, 137.7, 137.3, 128.2, 127.6,
127.5, 116.2, 115.1, 70.3, 68.8, 62.8, 39.2, 37.5, 37.4, 29.1, 13.8.
Anal. Calcd for C18H21O3N: C, 72.22; H, 7.07; N, 4.68. Found:
C, 72.11; H, 7.08; N, 4.61.
Under similar solution-phase conditions, but employing Pd-
(PPh3)4 (120 mg, 0.11 mmol, 7 mol %) as catalyst and THF as
solvent, 12 (500 mg, 1.5 mmol) and ethyl cyanoacetate (380
mg, 3.3 mmol) gave 13b (280 mg, 63%). Solid-phase prep-
aration from polymer 15 (3.0 g), ethyl cyanoacetate (1.73
g, 15 mmol), and Pd(PPh3)4 (170 mg, 0.15 mmol, 5 mol %) in
THF (reflux, 3 d) gave 13b (300 mg, 34% overall yield from
polymer 3).
1
1110, 1069, 711 cm-1; H NMR δ 1.70-1.90 (m, 4H), 2.19 (s,
3H), 2.28 (m, 2H), 2.48-2.60 (m, 2H), 2.84 (m, 2H), 3.15 (m,
2H), 5.07 (s, 1H), 5.22 (t, 1H, J ) 6 Hz), 7.40-8.01 (m, 5H);
13C NMR δ 215.3, 203.8, 165.9, 135.0, 132.9, 129.7, 128.2,
116.9, 68.4, 65.8, 39.4, 38.5, 37.8, 33.9, 30.3, 25.9, 19.2. Anal.
Calcd for C20H22O4: C, 73.59; H, 6.79. Found: C, 73.33; H,
6.78.
Dieth yl (2-(3-Ben zyloxycyclobu tylid en e)-2-m eth yleth -
yl)m et h ylm a lon a t e (20). Diethyl methylmalonate (1.80 g,
10.4 mmol) was added to a suspension of NaH (0.40 g, 10.0
mmol, 60% in mineral oil) in THF (8 mL) and stirred for 40
min at 0 °C. This mixture was added to a suspension of
polymer 16 (2.0 g) and Pd(PPh3)4 (120 mg, 0.10 mmol, 5 mol
%) in dry THF (10 mL), which was refluxed for 48 h. The
reaction was cooled to room temperature, and a solution of
saturated aqueous NH4Cl was added. The polymer was
removed by filtration and washed with ether (3 × 30 mL). The
combined filtrate and washings were dried (MgSO4) and
concentrated. The residue was purified by CC (20% EtOAc in
hexanes) to give 270 mg of 20 (270 mg, 35% overall yield
from polymer 3) as a pale yellow oil: IR (neat) 1741, 1265,
2-Acet yl-2-(2-(3-b en zyloxycyclob u t ylid en e)et h yl)cy-
clop en ta n on e (13c). The solution-phase, Pd(PPh3)4-catalyzed
preparation of 13a was modified as follows: 12 (500 mg, 1.5
mmol), 2-acetylcyclopentanone (630 mg, 5.0 mmol), NaH (200
mg, 5.0 mmol, 60% in mineral oil), dry THF (15 mL), Pd(PPh3)4
(100 mg, 0.08 mmol, 5.7 mol %), and CC (33% EtOAc in
hexanes) gave 13c (280 mg, 59%) as a clear oil: IR (neat) 1735-
1
(s), 1701, 1112 cm-1; H NMR δ 1.65 (m, 2H), 1.80 (m, 2H),
2.14 (s, 3H), 2.22 (m, 2H), 2.46-2.64 (m, 4H), 2.81 (m, 2H),
4.04 (t, 1H, J ) 6 Hz), 4.39 (s, 2H), 4.97 (m, 1H), 7.28 (m, 5H);
13C NMR δ 215.1, 203.6, 137.7, 135.2, 128.0, 127.4, 127.3,
115.9, 70.0, 68.7, 68.2, 34.0, 38.3, 37.3, 33.8, 29.9, 25.7, 19.0.
Anal. Calcd for C20H24O3: C, 76.89; H, 7.74. Found: C, 76.68;
H, 7.72.
1084, 732 cm-1 1H NMR δ 1.30 (t, 6Η, J ) 9 Hz), 1.40 (s,
;
Solid-phase preparation from polymer 15 (3.0 g), 2-acetyl-
cyclopentanone (1.89 g, 15 mmol), and Pd(PPh3)4 (170 mg, 0.15
mmol, 5 mol %) in THF (reflux, 3 d) gave 13c (335 mg, 36%
overall yield from polymer 3).
3H), 1.49 (s, 3H), 2.60-2.67 (m, 4H), 2.91 (m, 1H), 4.11 (t,
1H, J ) 6.5 Hz), 4.22 (q, 4H, J ) 9 Hz), 4.50 (s, 2H), 7.40 (m,
5H); 13C NMR δ 172.5, 138.1, 129.6, 128.4, 127.6, 127.8, 123.4,
70.4, 68.5, 61.2, 53.4, 38.6, 37.9, 37.6, 19.7, 17.3, 14.0. Anal.
Calcd for C22H30O5: C, 70.56; H, 8.07. Found: C, 70.62; H,
8.08.
3-(P S/DVBsu lfon yl)-3-(1-m eth ylvin yl)cyclobu tan ol (14).
The preparation of polymer 11 from polymer 9 was modified
as follows to give polymer 14. Polymer 10 (10 g, 10 mmol),
n-BuLi (50 mL, 80 mmol, 1.6 M), and epichlorohydrin (9.46 g,
102 mmol) gave polymer 14: IR (single bead reflectance) 1450,
Eth yl (2-(3-Ben zyloxycyclobu tylid en e)-2-m eth yleth yl)-
cya n oa ceta te (21). The preparation of 20 was modified as
follows to give 21. Polymer 16 (2.0 g), ethyl cyanoacetate
(1.15 g, 10.2 mmol), NaH (0.40 g, 10.0 mmol, 60% in mineral
oil), Pd(PPh3)4 (150 mg, 0.13 mmol, 7 mol %), 60 h of re-
flux, and CC (20% EtOAc in hexanes) gave 21 (180 mg, 30%):
1403, 1295, 1132 cm-1
.
Ben zyl 3-(P S/DVBsu lfon yl)-3-vin ylcyclob u t yl E t h er
(15). n-BuLi (12.5 mL, 20 mmol, 1.6 M in hexanes) was added
to polymer 11 (5 g) in THF (20 mL) at -20 °C. After 40 min,
benzyl bromide (3.5 g, 21 mmol) was added at 0 °C, and the
reaction was stirred for 10 h. Water was added, and polymer
15 was isolated by filtration and washed with THF (2 × 30
mL) and ether (2 × 20 mL): IR (KBr) 1492, 1460, 1295, 1128,
1
IR (neat) 1741, 1244, 1203, 1083, 1026 cm-1; H NMR δ 1.31
(t, 3H, J ) 7.2 Hz), 1.58 (s, 3H), 2.54-2.64 (m, 4H), 2.89 (m,
2H), 3.56 (t, 1H, J ) 8.1 Hz), 4.08 (m, 1H, J ) 6.9 Hz), 4.24
(q, 2H, J ) 7.2 Hz), 4.43 (s, 2H), 7.33 (m, 5H); 13C NMR δ
166.0, 137.9, 130.7, 128.3, 127.8, 127.6, 121.6, 116.4, 70.4, 68.4,
62.7, 37.6, 37.4, 36.2, 33.8, 16.1, 13.9. Anal. Calcd for
696 cm-1
.
Ben zyl 3-(P S/DVBsu lfon yl)-3-(1-m eth ylvin yl)cyclobu -
t yl E t h er (16). The preparation of polymer 15 was modi-
fied as follows to give polymer 16. n-BuLi (3.1 mL, 5 mmol,
1.6 M in hexanes), polymer 14 (1 g), THF (7 mL), and benzyl
bromide (850 mg, 5 mmol) gave polymer 16 after the polymer
was washed with THF (2 × 15 mL) and ether (2 × 10
mL): IR (single bead reflectance) 1452, 1295, 1128, 1085, 1047
C19H23O3N: C, 72.82; H, 7.39; N, 4.47. Found: C, 72.79; H,
7.44; N, 4.53.
2-Acetyl-(2-(3-ben zyloxycyclobu tylid en e)-2-m eth yleth -
yl)cyclop en ta n on e (22). The preparation of 20 was modified
as follows to give 22. Polymer 16 (3.0 g), 2-acetylcyclopen-
tanone (1.89 g, 15.0 mmol), NaH (0.60 g, 15.0 mmol, 60% in
mineral oil), Pd(PPh3)4 (150 mg, 0.13 mmol, 5 mol %), 65 h of
reflux, and CC (20% EtOAc in hexanes) gave 22 (340 mg,
cm-1
.
3-(P S/DVBsu lfon yl)-3-vin ylcyclob u t yl Ben zoa t e (17).
Pyridine (5 mL) and benzoyl chloride (700 mg, 5.0 mmol) were
added to polymer 11 (1 g) in THF (5 mL) at 0 °C. The reaction
was warmed to room temperature with stirring over 24 h.
Water was added, and polymer 17 was isolated by filtration
32%): IR (neat) 1735(s), 1698, 1453, 1100 cm-1 1H NMR δ
;
1.37 (s, 3H), 2.52-2.61 (m, 4H), 2.83 (m, 2H), 4.04 (t, 1H, J )
6 Hz), 1.66-1.84 (m, 4 H), 2.28-2.42 (m, 2H), 2.21 (s, 3H),
4.43 (s, 2H), 7.33 (m, 5H); 13C NMR δ 220.0, 204.1, 138.0, 129.6,
128.5, 127.8, 127.6, 123.9, 70.4, 68.4, 68.4, 38.2, 37.6, 37.8, 30.1,

8562 J . Org. Chem., Vol. 64, No. 23, 1999
Cheng et al.
29.9, 25.9, 19.3, 17.4. Anal. Calcd for C21H26O3: C, 77.27; H,
8.02. Found: C, 77.18; H, 8.09.
25.7, 19.1, 17.2. Anal. Calcd for C21H24O4: C, 74.09; H, 7.10.
Found: C, 74.00; H, 7.20.
2-Acet yl-(2-(3-b en zoyloxycyclob u t ylid en e)-2-m et h yl-
eth yl)cyclop en ta n on e (23). The preparation of 19 was
modified as follows to give 23. Polymer 18 (1.5 g), 2-acetylcy-
clopentanone (0.94 g, 7.5 mmol), NaH (0.30 g, 7.5 mmol, 60%
in mineral oil), Pd(PPh3)4 (100 mg, 0.08 mmol, 6 mol %), 60 h
of reflux, and CC (20% EtOAc in hexanes) gave 23 (175 mg,
35%): IR(neat) 1701(s), 1451, 1356, 1273, 1110 cm-1; 1H NMR
δ 1.37 (s, 3Η), 2.75 (m, 2H), 3.07 (m, 2H), 5.16 (t, 1H, J ) 6
Hz), 2.19 (s, 3H), 1.62-1.86 (m, 4H), 2.22-2.64 (m, 4H), 7.37-
7.98 (m, 5H); 13C NMR δ 215.3, 203.5, 165.8, 132.7, 129.7,
129.2, 128.6, 128.1, 124.5, 68.6, 65.0, 37.9, 37.7, 37.5, 29.9, 29.7,
Ack n ow led gm en t. We are grateful to the National
Science Foundation for financial support of this re-
search.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for 7 and 1H NMR and 13C NMR spectra for
compound 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O990954B