The sulfone linker in solid-phase synthesis: Preparation of 3,5-disubstituted cyclopent-2-enones

Article abstract of DOI:10.1021/jo0256843

The preparation of functionalized 3,5-disubstituted cyclopent-2-enones via a solid-phase sulfone linker strategy is described. Polystyrene/divinylbenzene sulfinate 1 underwent S-alkylation followed by α,α-dialkylation with cis-1,4-dichloro-2-butene to form polymer-bound 3-phenylsulfonylcyclopentenes 8. Subsequent epoxidation of the cyclopentene moiety in 8 was accomplished by treatment of mCPBA, and the resulting oxirane ring in resin 9 was opened with various nucleophiles, i.e., Grignard and cuprate reagents, azide ion, and amines. To complete the sulfone-based linker strategy, Swern or TPAP oxidation of 10 gave a transient γ-ketosulfone, which underwent sulfinate elimination, thus cleaving the sulfone linker. Eleven 3,5-disubstituted cyclopent-2-enones (11) were prepared with this five-step process in 18-40% overall yield from solid-phase benzene sulfinate 1.

Full text of DOI:10.1021/jo0256843

VOLUME 67, NUMBER 13
J UNE 28, 2002
© Copyright 2002 by the American Chemical Society
Articles
Th e Su lfon e Lin k er in Solid -P h a se Syn th esis: P r ep a r a tion of
3,5-Disu bstitu ted Cyclop en t-2-en on es
Wei-Chieh Cheng and Mark J . Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616-5295
mjkurth@ucdavis.edu
Received March 5, 2002
The preparation of functionalized 3,5-disubstituted cyclopent-2-enones via a solid-phase sulfone
linker strategy is described. Polystyrene/divinylbenzene sulfinate 1 underwent S-alkylation followed
by R,R-dialkylation with cis-1,4-dichloro-2-butene to form polymer-bound 3-phenylsulfonylcyclo-
pentenes 8. Subsequent epoxidation of the cyclopentene moiety in 8 was accomplished by treatment
of mCPBA, and the resulting oxirane ring in resin 9 was opened with various nucleophiles, i.e.,
Grignard and cuprate reagents, azide ion, and amines. To complete the sulfone-based linker strategy,
Swern or TPAP oxidation of 10 gave a transient γ-ketosulfone, which underwent sulfinate
elimination, thus cleaving the sulfone linker. Eleven 3,5-disubstituted cyclopent-2-enones (11) were
prepared with this five-step process in 18-40% overall yield from solid-phase benzene sulfinate 1.
Sulfinate-functionalized resins1 have been efficiently
prepared and utilized in solid-phase organic synthesis
(SPOS), and the resulting sulfone linker has been found
to be both a robust and a versatile linker.2 As an
extension of our research involving sulfone linkers, we
report here the preparation of functionalized 3,5-disub-
stituted cyclopent-2-enone via a sulfone-based solid-phase
linker strategy. Our preparation of 3,5-disubstituted-2-
cyclopentenones 11a -k from sulfinate-functionalized
resin 1 (Figure 1) proceeds via a five-step protocol
F igu r e 1. Five-step route for PS/1%DVB-SO2-M+ f cyclpen-
tenones.
Fuchs cyclopentenone-chemistry,6 (v) oxidation with con-
consisting of (i) sulfinate S-alkylation, (ii) sulfone R,R-
comitant â-elimination of sulfinate7 to release target
molecules from the solid support (Scheme 4). The result-
ing cyclopentenones may prove useful as molecular
dialkylation,2a,b,3 (iii) epoxidation4 (see Scheme 2), (iv)
epoxide-ring opening5 (see Scheme 3), and modifying
(1) (a) Farrall, M. J .; Frechet, J . M. J . Org. Chem. 1976, 41, 3877.
(b) Fyles, T. M.; Leznoff, C. C. Can J . Chem. 1978, 56, 1031.
(2) (a) Halm, C.; Evarts, J . B.; Kurth, M. J . Tetrahedron Lett. 1997,
38, 7709. (b) Cheng, W.-C.; Halm, C.; Evarts, J . B.; Olmstead, M. M.;
Kurth, M. J . J . Org. Chem. 1999, 64, 8557. (c) Cheng, W.-C.; Olmstead,
M. M.; Kurth, M. J . J . Org. Chem. 2001, 66, 5528
(4) (a) Eisch, J . J .; Galle, J . E. J Org. Chem. 1979, 44, 3277. (b)
McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895.
(5) Calvani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron
1994, 50, 12999.
(6) Nantz, M. H.; Radisson, X.; Fuchs, P. L. Synth. Commun. 1989,
17, 55.
(3) Eisch, J . J .; Dua, S. K.; Behrooz, M. J . Org. Chem. 1985, 50,
3674.
(7) Yoshida, T.; Saito, S. Chem. Lett. 1982, 165.
10.1021/jo0256843 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

4388 J . Org. Chem., Vol. 67, No. 13, 2002
Cheng and Kurth
Sch em e 1. Solu tion -P h a se Syn th esis of
3-P h en yl-5-a llyl-2-cyclop en ten on ea
Sch em e 2. Solid -P h a se Syn th esis of Oxir a n e 9a
a
Reagents and conditions: (f) R1CH2X, THF/DMF, 80 °C. (g)
nBuLi (10 equiv), THF, rt; cis-1,4-dichloro-2-butene (10 equiv),
THF. (h) mCPBA, CHCl3, 60 °C.
Sch em e 3. Solid -P h a se Nu cleop h ilic Ep oxid e
Op en in g 9 f 10a
a
Reagents and conditions: (a) benzyl bromide, THF/DMF, 80
°C (90%). (b) nBuLi (2.2 equiv), cis-1,4-dichloro-2-butene (1.3 equiv),
THF, 0 °C f rt (76%). (c) mCPBA, CHCl3, 60 °C (75%). (d)
allylmagnesium bromide, THF, 0 °C (69%). (e) Swern oxidation
(88%).
a
Reagents and conditions: (i) (a) LiN3 (14.7 equiv), DMF, 80
scaffolds for library production, as cyclopentenone-
containing compounds are both prevalent in nature and
useful as building blocks for further transformations.8
Preliminary solution-phase experiments were under-
taken to survey the requisite reaction conditions and
establish modifications required for SPOS. To begin our
investigation, cyclopentene 3 was prepared from sodium
benzenesulfinate (2) in two steps, S-alkylation and sul-
fone R,R-dialkylation, in an overall yield of 68%. Treat-
ment of 3 with mCPBA in CHCl3 at 60 °C for 6 h
delivered oxirane 4 as one diastereomer9 in 75% yield.
In contrast, epoxidation of 3 in CH2Cl2 at room temper-
ature was sluggish. Subsequent nucleophilic ring open-
ing10 of the epoxide moiety in 4 was achieved by treat-
ment with allylmagnesium bromide at 0 °C and afforded
cyclopentanol 5. Cleavage of the sulfone C,S-bond would,
on solid-phase, constitute a release of substrate from the
resin. Our plan was to take advantage of sulfinate
elimination to effect this transformation, and to that end,
the hydroxyl moiety of 5 was oxidized using the Swern
procedure11 to the corresponding ketone. To our delight,
γ-ketosulfone 6 was not isolated upon reaction workup.
Rather, the basic conditions of the Swern oxidation
promoted the concomitant â-elimination of sulfinate
leading directly to 5-allyl-3-phenyl-2-cyclopentenone (11b;
Scheme 1). The success of these solution-phase transfor-
mations encouraged us to explore this protocol on solid
phase.
°C, 16 h; (b) allylmagnesium bromide (7.2 equiv), THF, -20 f 0
°C, 4 h; (c) benzylmagnesium chloride (7.2 equiv), THF, -20 f 0
°C, 4 h.
With a solution-phase route in hand, attention was
next directed at development of a solid-phase protocol,
and work began with step i, the S-alkylation of the
sulfinate moiety of resin 1 (sulfinate loading ) 0.5 mmol/
n
g) with benzyl bromide, ethyl iodide, and butyl iodide.
While step i was amenable to FTIR monitoring (e.g.,
disappearance of sulfinate absorption at 1028 cm-1
;
appearance of sulfone absorptions at ∼1320 and ∼1130
cm-1), it was not possible to monitor step ii consisting of
sulfone R,R-dialkylation with cis-1,4-dichloro-2-butene to
construct the cyclopentene moiety (7 f 8)6 or step iii
consisting of epoxidation of the alkene with mCPBA in
CHCl3 at 60 °C for 12 h to deliver oxirane-functionalized
resin 9 (Scheme 2).
Although a number of reagents could be employed to
open the epoxide ring of 9 (step iv, Scheme 3), we chose
lithium azide12 as our first nucleophile, thinking that an
azido absorption peak in the product FTIR would provide
evidence that step ii and step iii had proceeded as
anticipated. Indeed, treatment of oxirane resin 9a with
lithium azide in DMF at 80 °C for 10 h gave cyclopentanol
resin 10a as evidenced by the appearance of a new
absorption peak at 2101 cm-1 in the IR spectrum of 10a .
Likewise, Grignard reagents allylmagnesium bromide
and benzylmagnesium chloride reacted with oxirane 9a ,
delivering cyclopentanols 10b and 10c, respectively.
(8) (a) Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2, 1601. (b)
Belanger, D. B.; O’Mahony, D. J . R., Livinghouse, T. Tetrahedron Lett.
1998, 39, 7637. (c) Tanikawa, M.; Yamada, K.; Tominaga, K.; Moriski,
H.; Kaneko, Y.; Ileda, K.; Suzuki, M.; Kiho, T.; Tomokiyo, K.; Furuta,
K.; Noyori, R.; Nakanishi, M. J . Biol. Chem. 1998, 273, 18522. (d)
Weidler, M.; Rether, J .; Anke, T.; Erkel, G.; Sterner, O. J . Antibiot.
2001, 54, 679. (e) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903.
(9) On the basis of literature precedent, we have assigned 4 the
stereochemistry as depicted in Scheme 1. See: (a) Blake, A. J .; Cooke,
P. A.; Kendall, J . D.; Simpkins, N. S.; Westaway, S. M. J . Chem. Soc.,
Perkin Trans. 1 2000, 153. (b) Fuchs, P. L.; Nantz, M. H. J . Org. Chem.
1987, 52, 5298.
The stage was now set for oxidation (CHOH f CdO)
with concomitant sulfinate elimination to deliver the
target cyclopentenone (11). As illustrated in Scheme 4,
Swern oxidation of cyclopentanols 10a -c indeed deliv-
ered the target 3,5-disubstituted cyclopent-2-enones 11a-c
in 35-38% overall isolated yield (including purification
by column chromatography to remove trace impurities)
(10) (a) Smith, J . G. Synthesis 1984, 629. (b) Rao, A. S. Tetrahedron
1983, 39, 2323.
(11) Mancuso, A.; Huang, S. L.; Swern, D. J . Org. Chem. 1978, 43,
2480.
(12) Tanner, D.; Tedenborg, L.; Almario, A.; Pettersson, I.; Csoregh,
I.; Kelly, N. M.; Andersson, P. G.; Hohberg, T. Tetrahedron 1995, 51,
6071.

3,5-Disubstituted Cyclopent-2-enones
J . Org. Chem., Vol. 67, No. 13, 2002 4389
Ta ble 2. P S/1%DVB-SO2-M+ f Cyclop en ten on es
Sch em e 4. Cyclop en ten on es by Solid -P h a se
Oxid a tion /Elim in a tion a
Dem on str a tion Libr a r y
11
step i
step iv
step v
overall yield
a
b
c
d
e
f
g
g
h
i
BnBr
BnBr
BnBr
BnBr
BnBr
EtI
LiN3
allyl-MgBr
see Table 1
see Table 1
see Table 1
Swern
Swern
Swern
Swern
TPAP/NMO
Swern
Swern
Swern
see Table 1
see Table 1
see Table 1
30%
20%
35%
40%
38%
18%
33%
a
Reagents and conditions: (j) (a) Method A: Swern, CH2Cl2,
benzyl-MgCl
nBu2Cu(CN)Li2
piperidine/LiOTf
LiN3
benzyl-MgCl
benzyl-MgCl
piperidine/LiOTf
allyl-MgBr
-60 °C, 3 h; (b) Method B: SO3/pyridine (6 equiv), Et3N (10 equiv),
DMSO, rt, 8 h; (c) Method C: TPAP (15 mol %), NMO (3 equiv),
CH2Cl2, rt, 12 h.
Ta ble 1. Com p a r a tive Meth od s for Solid -p h a se
Oxid a tion /Su lfin a te Elim in a tion
EtI
EtI
EtI
oxidation methoda/yieldb
nBuI
nBuI
nBuI
nBuI
cyclopentenone
product
R2
N3
allyl
benzyl
A
B
C
j
j
k
benzyl-MgCl
benzyl-MgCl
nBu2Cu(CN)Li2
32%
39%
20%
TPAP/NMO
Swern
11a
11b
11c
35%
35%
38%
19%
20%
25%
36%
38%
36%
pentenone oxidation, provide ready access to the resin-
free target. Moreover, the solid-phase synthetic route
presented here benefits from the fact that, aside from
trace unidentified impurities, only molecules having
successfully negotiated the entire reaction sequence
(steps i-v) can be released from the solid support. The
preparation of cyclopentenones with two functional groups
has been developed and is suitable for library generation.
a
Oxidation method: A ) Swern oxidation (-60 °C), B )
b
DMSO‚SO3/pyridine (rt), C ) TPAP/NMO (rt), Et3N. Overall
yield from starting resin 1; after column chromatography.
from starting resin 1. That equates to an average yield
per step of ca. 81-82% for the five solid-phase reactions.
Although cyclopentenones 11a -c were successfully
liberated from the solid support via this Swern oxidation,
the inconvenience of low temperature for the oxidation13
prompted us to consider other oxidation methods. Switch-
ing to the DMSO‚SO3/pyridine complex14 allowed us to
perform the oxidation at room temperature, but the
cyclopentenone yields were lower than those achieved
with Swern conditions (see Table 1). We next tried the
TPAP/NMO15 method in CH2Cl2 (rt, 8 h) followed by
addition of Et3N (rt, 3 h) and obtained cyclopentenones
11a -c in yields similar to those obtained with the Swern
oxidation, but with the distinct advantage that this
oxidation/â-elimination sequence is run at room temper-
ature.
With the results of Schemes 2-4 in hand, we set out
to prepare a small library of cyclopentenones. As il-
lustrated in Table 2, we employed three different 1°-alkyl
halides in step i, allyl and benzyl Grignard, nBu2Cu(CN)-
Li2,16 azide, and piperidine17 in step iv, and both Swern
and TPAP/NMO conditions for step v. The five-step
overall yields of cyclopentenones 11a -k ranged from 18%
to 40%, which translates to average per step yields of 71-
83%. We believe some of the lower overall yields are a
consequence of product volatility in the workup and
isolation of step v.
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 purification. Analytical
TLC was carried out on precoated plates (silica gel 60, F254)
and visualized with UV light. Flash column chromatography
was performed with silica (70-230 mesh). NMR spectra (1H
at 300 MHz, 13C at 75 MHz) were recorded in CDCl3 as solvent,
and chemical shifts are expressed in parts per million related
to internal TMS. CC refers to column chromatography; con-
centration refers to rotary evaporation.
3-P h en ylsu lfon yl-3-p h en ylcyclop en ten e (3). To an ice-
bath-cooled solution of benzyl phenyl sulfone (2.0 g, 8.6 mmol)
n
in THF (50 mL) was added BuLi (1.6 M, 2.2 equiv, 19.0 mmol,
12 mL). After 40 min, cis-1,4-dichloro-2-butene (1.2 equiv, 1.1
mL) was added slowly to the mixture under ice-bath cooling,
and the reaction was allowed to stir for 30 min. The reaction
was quenched with 10% HCl (30 mL) and extracted with ether
(3×). The combined organic solution was washed with brine,
dried (MgSO4), and concentrated. The resulting compound was
purified by CC (25% EtOAc in hexanes) to give 3 (1.8 g, 6.5
mmol) as a white solid in 76% yield: 1H NMR δ 3.08 (d, 2H,
J ) 16.2 Hz), 3.65 (d, 2H, J ) 16.2 Hz), 5.67 (s, 2H), 7.20-
7.59 (m, 10H); 13C NMR δ 137.5, 135.2, 133.2, 130.1, 130.0,
128.24, 128.22, 128.0, 127.7, 76.7, 41.1.
In summary, this work further demonstrates the
durability and chemical versatility of the sulfone moiety
as a linker for SPOS. The mild cleavage conditions, base-
mediated â-elimination during cyclopentanol to cyclo-
3-B e n z e n e s u lfo n y l-3-p h e n y l-6-o x a b ic y c lo [3,1,0]-
h exa n e (4). A mixture of 3 (0.8 g, 2.8 mmol) and mCPBA
(80%, 2 equiv, 1.2 g) in CHCl3 (15 mL) was stirred at 60 °C
for 6 h. The reaction was quenched with water (30 mL) and
extracted with CHCl3 (3×), and the combined organic solution
was washed with saturated NaHCO3 (5×), dried (MgSO4), and
concentrated. The resulting compound was purified by CC
(50% EtOAc in hexanes) to give 4 (0.63 g, 2.1 mmol) as a white
solid in 75% yield: 1H NMR δ 2.75 (d, 2H, J ) 15.0 Hz), 3.06
(d, 2H, J ) 15.0 Hz), 3.65 (s, 2H), 7.04-7.51 (m, 10H); 13C
NMR δ 136.6, 134.7, 133.4, 129.7, 128.6, 128.0, 127.9, 127.6,
76.4, 57.3, 35.6.
(13) (a) Smith, A. B., III; Liu, H.; Okumura, H.; Favor, D. A.;
Hirschmann, R. Org. Lett. 2000, 2, 2041. (b) Cheng, W.-C.; Wong, M.;
Olmstead, M. M.; Kurth, M. J . Org. Lett. 2002, 4, 741.
(14) Parikh, J . R.; Doering, W. v E. J . Am. Chem. Soc. 1967, 89,
5505.
(15) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(16) (a) Lipshutz, B. H.; Kozlowski, J .; Wilhelm, R. S. J . Am. Chem.
Soc. 1982, 104, 2305. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski,
J . A. Tetrahedron 1984, 40, 5005.
2-Allyl-4-ben zen esu lfon yl-4-p h en ylcyclop en ta n ol (5).
Allylmagnesium bromide (1.0 M, 5.0 equiv, 3.35 mmol, 3.4 mL)
was added to a THF (5 mL) solution of 4 (0.2 g, 0.67 mmol) at
(17) Auge, J .; Leroy, F. Tetrahedron Lett. 1996, 37, 7715.

4390 J . Org. Chem., Vol. 67, No. 13, 2002
Cheng and Kurth
0 °C. After 1 h, the reaction mixture was allowed to warm to
room temperature with stirring (3 h) and then cooled to 0 °C
and quenched with saturated aqueous NH4Cl (20 mL). The
mixture was extracted with ether (3×), and the combined
organic solution was washed with brine, dried (Mg2SO4), and
concentrated. The resulting residue was purified by CC (50%
EtOAc in hexanes) to give 5 (0.16 g, 0.46 mmol) as a white
solid in 69% yield: 1H NMR δ 1.81-1.90 (m, 1H), 2.03 (s, 1H),
2.28 (dd, 1H, J ) 14.1, 8.1 Hz), 2.40-2.49 (m, 1H), 2.57-2.61
(m, 2H), 3.06 (dd, 1H, J ) 14.1, 7.2 Hz), 4.27-4.35 (m, 1H),
5.04 (d, 1H, J ) 10.2 Hz), 5.14 (d, 1H, J ) 17.1 Hz), 5.79-
5.88 (m, 1H), 7.11-7.51 (m. 10 H); 13C NMR δ 137.6, 136.5,
134.7, 133.3, 129.9, 129.1, 128.2, 128.0, 127.7, 116.4, 76.2, 73.9,
45.9, 42.5, 37.0, 36.6. Anal. Calcd for C20H22O3S/0.3 H2O: C,
69.05; H, 6.56. Found: C, 69.38; H, 6.84.
reaction was heated at 80 °C for 16 h and quenched with
aqueous HCl (10%, 15 mL). Resin 10a was collected by
filtration, washed with THF/H2O (4:1, 3×), THF, MeOH (2×),
THF (2×), and dried: IR (single bead reflectance) ca. 2101
cm-1. Resins 10a and 10f were prepared in similar fashion.
Gen er a l P r oced u r e for Ep oxid e Op en in g w ith Gr ig-
n a r d Rea gen ts. The resin 9a (1 g, 0.47 mmol) was swollen
in THF (10 mL) at -20 °C, and allylmagnesium bromide (3.4
mL, 3.4 mmol, 1 M) was added. The reaction was stirred at 0
°C for 4 h and quenched with 10% aqueous HCl (15 mL). Resin
10b was collected by filtration, washed with THF/H2O (4:1,
3×), THF (2×), MeOH, THF (2×), and dried. Resins 10b, 10c
(benzylmagnesium chloride was used in place of allylmagne-
sium bromide), 10g (benzylmagnesium chloride was used in
place of allylmagnesium bromide), 10i, and 10j (benzylmag-
nesium chloride was used in place of allylmagnesium bromide)
were prepared in similar fashion.
Gen er a l P r oced u r e for Ep oxid e Op en in g w ith Cu -
p r a te Rea gen ts. A mixture of CuCN (0.22 g, 2.48 mmol) and
nBuLi (3.12 mL, 5.0 mmol,1.6 M) in THF (10 mL) was stirred
at -78 °C for 40 min, and the resulting solution was trans-
ferred to a THF (8 mL) suspension of polymer 9a (1.2 g, 0.56
mmol). This reaction was stirred at -78 °C for 2 h and warmed
to -20 °C. After an additional 2 h, the reaction was quenched
with aqueous HCl (10%, 20 mL). Resin 10d was collected by
filtration and washed with THF/H2O (4:1, 3×), THF, MeOH
(2×), THF (2×), and dried. Resins 10d and 10k were prepared
in similar fashion.
5-Allyl-3-p h en ylcyclop en t-2-en on e (11b). Compound 5
(0.20 g, 0.58 mmol) was oxidized via the normal Swern
oxidation procedure11 (oxalyl chloride, 1.3 equiv), DMSO (2.5
equiv), and Et3N (5 equiv) in CH2Cl2 at -60 °C (4 h). The crude
product was purified by CC (33% EtOAc in hexanes) to give
11b (0.10 g, 88%) as a colorless oil: 1H NMR δ 2.19-2.24 (m,
1H), 2.57-2.76 (m, 3H), 3.15 (dd, 1H, J ) 18.0, 6.6 Hz), 5.02-
5.13 (m, 2H), 5.72-5.85 (m, 1H), 6.53 (s, 1H), 7.40-7.45 (m,
3H), 7.62-7.65 (m, 2H); 13C NMR δ 210.1, 172.3, 135.1, 133.6,
131.0, 128.6, 126.6, 126.3, 116.7, 45.2, 35.6, 34.4. Anal. Calcd
for C14H14O: C, 84.81; H, 7.12. Found: C, 84.67; H, 7.18.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olym er -
Bou n d Alk yl P h en yl Su lfon es (7). Sp ecific for P olym er -
Bou n d P h en yl Ben zyl Su lfon e (7a ). Polymer-bound ben-
zenesulfinate 12 (10 g, 5 mmol; sulfinate loading ) 0.5 mmol/
g) was swollen in DMF/THF (1:1, 60 mL), benzyl bromide (20
mL) was added, and the mixture was gently stirred at 60 °C
for 24 h. The resin was collected by filtration, washed with
THF (2×), THF/H2O (4:1, 2×), THF (2×), and ether, and dried
to afford polymer-bound benzyl sulfone 7a as yellow beads:
IR (single bead reflectance) 1598, 1492, 1450, 1322(s), 1133-
Gen er a l P r oced u r e for Ep oxid e Op en in g w ith P ip er i-
d in e. Lithium triflate (0.25 g, 1.6 mmol) was added to a
suspension of polymer 9a (1.1.g, 0.52 mmol) in THF/CH3CN
(1:1, 10 mL), and the mixture was stirred for 30 min.
Piperidine (0.27 g, 3.2 mmol) was then added, and the
temperature was raised to 70 °C for 12 h. The reaction was
neutralized with aqueous HCl (10%, 8 mL). Resin 10e was
collected by filtration, washed with THF/H2O (4:1, 2×), THF,
MeOH, THF, MeOH, and dried. Resins 10e and 10h were
prepared in similar fashion.
(s), 1029 cm-1
.
P olym er -Bou n d P h en yl Eth yl Su lfon e (7b). As with 7a ,
polymer 7b was prepared from resin 1, except S-alkylation was
accomplished using ethyl iodide: IR (single bead reflectance)
Gen er a l P r oced u r e for th e P r ep a r a tion of Cyclop en -
ten on es 11a -k . Sp ecific for Azid o-3-p h en ylcyclop en t-2-
en on e (11a ). Meth od A (Sw er n oxid a tion ).11 The solution-
phase preparation of 11b was modified as follows to give 11a .
Polymer 10a (0.4 g, 0.18 mmol), DMSO (8 equiv), oxalyl
chloride (4 equiv), Et3N (10 equiv), and CC (20% EtOAc in
hexanes) gave 11a (13 mg, 35%). Meth od B (DMSO-SO3/
p yr id in e). To a DMSO (8 mL) suspension of polymer 10a (0.55
g) was added SO3/pyridine complex (6 equiv) and dry Et3N (10
equiv). The mixture was stirred at ambient temperature for 8
h, and the resin was removed by filtration and washed with
CH2Cl2 (2×), MeOH, CH2Cl2 (2×), and ether. The filtrate and
washings were concentrated to remove organic solvent, and
the residue was purified by CC (25% EtOAc in hexanes) to
give 11a (10 mg, 19%) as a pale yellow oil. Meth od C (TP AP /
NMO). To a CH2Cl2 (6 mL) suspension of polymer 10a (0.5 g)
was added TPAP(15 mol %, 12 mg) and NMO (3 equiv, 80 mg).
The reaction mixture was stirred at ambient temperature for
12 h, at which time the mixture was treated with Et3N (5
equiv). After an additional 4 h, the polymer was removed by
filtration and washed with CH2Cl2 (2×), ether, CH2Cl2 (2×),
and ether. The filtrate and washings were concentrated to
remove organic solvent, and the residue was passed through
a short silica gel column, which was washed with CH2Cl2 to
give 11a as a pale yellow oil in 36% yield: IR (CDCl3) 2103,
1601, 1492, 1451, 1300(s), 1138(s) cm-1
.
P olym er -Bou n d P h en yl Bu tyl Su lfon e (7c). As with 7a ,
polymer 7c was prepared from resin 1 except S-alkylation was
accomplished using n-butyl iodide: IR (single bead reflectance)
1600, 1492, 1452, 1305(s), 1135(s) cm-1
.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olym er -
Bou n d P h en ylsu lfon yl Cyclop en ten e Der iva tives 8. Sp e-
cific for 3-(P S/DVB su lfon yl)-3-p h en ylcyclop en ten e (8a ).
nBuLi (16 mL, 24 mmol, 1.6 M) was added to a THF (40 mL)
suspension of resin 7a (5 g, 2.44 mmol) at 0 °C. The mixture
was warmed to ambient temperature and stirred for 1 h.
Excess nBuLi/THF was removed by anhydrous filtration, and
dry THF (20 mL) was added under N2. cis-1,4-Dichloro-2-
butene (3 g, 24 mmol) was added dropwise to the reaction at
0 °C, and the mixture was allowed to stir for 40 min. The
mixture was neutralized with 10% HCl, and the resin was
collected by filtration and washed with THF (2×), THF/H2O
(4:1, 3×), THF (2×), and ether (2×) to give resin 8a : IR (single
bead reflectance) 1599, 1492, 1451, 1296(s), 1135(s) cm-1
.
Resins 8b and 8c were prepared in similar fashion.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olym er -
Bou n d P h en yl Su lfon yl Oxir a n es 9. Sp ecific for 3-(P S/
DVB su lfon yl)-3-p h en yl-6-oxa bicyclo[3,1,0]h exa n e (9a ).
Resin 8a (3 g, 1.42 mmol) was swollen in CHCl3 (30 mL),
mCPBA (2.4 g, 14 mmol, 80%) was added at ambient temper-
ature, and the mixture was then heated at 60 °C for 12 h.
Filtration to collect the resin followed by washing with THF
(2×), THF/H2O (4:1, 2×), MeOH (2×), CH2Cl2 (2×), and ether
gave 9a (yellow beads), which was dried by storage in a
desiccator overnight: IR (single bead reflectance) 1600, 1492,
1451, 1300(s), 1136(s) cm-1. Resins 9b and 9c were prepared
in similar fashion.
1
1701 cm-1; H NMR δ 2.82 (dd, 1H, J ) 18, 3.3 Hz), 3.37(dd,
1H, J ) 18, 7.2 Hz), 4.23(dd, 1H, J ) 7.2, 3.3 Hz); 13C NMR δ
203.5, 171.4, 132.8, 132.0, 128.9, 126.9, 124.4, 60.2, 35.1.
5-Allyl-3-p h en ylcyclop en t-2-en on e (11b). Methods A, B,
and C were used to prepare 11b: yields ) 35% (A), 20% (B),
and 38% (C).
5-Ben zyl-3-p h en ylcyclop en t-2-en on e (11c). Methods A,
B, and C were used to prepare 11c: yields ) 38% (A), 25%
(B), and 36% (C); 1H NMR δ 2.61 (dd, 1H, J ) 13.8, 10.5 Hz),
2.67-2.75 (m, 1H, J ) 18), 2.85-2.93 (m, 1H), 3.03 (dd, 1H, J
) 18, 6.9 Hz), 3.32 (dd, 1H, J ) 13.8, 4.2 Hz), 6.55 (s, 1H),
7.22-7.59 (m, 10 H); 13C NMR δ 209.7, 172.3, 139.3, 133.5,
Gen er a l P r oced u r e for Ep oxid e Op en in g w ith Azid e
An ion . Polymer 9a (1 g, 0.47 mmol) was swollen in DMF (15
mL), and lithium azide (0.34 g, 6.9 mmol) was added. The

3,5-Disubstituted Cyclopent-2-enones
J . Org. Chem., Vol. 67, No. 13, 2002 4391
131.0, 128.6, 128.3, 126.6, 126.1, 126.1, 47.5, 37.1, 34.5. Anal.
Calcd for C18H16O/0.1 H2O: C, 86.43; H, 6.54. Found: C, 86.59;
H, 6.54.
5-Allyl-3-p r op ylcyclop en t-2-en on e (11i). Method C gave
1
11i (33%): IR (CDCl3) 2967, 1704(s), 1616 cm-1; H NMR δ
0.94 (t, 3H, J ) 7.2 Hz), 1.59 (m, 2H, J ) 7.2 Hz), 2.08-2.56
(m, 6H), 2.67 (dd, 1H, J ) 18.3, 6.6 Hz), 4.98-5.08 (m, 2H),
5.65-5.78 (m, 1H), 5.89 (s, 1H); 13C NMR δ 211.0, 181.6, 135.2,
128.5, 116.5, 45.2, 37.3, 35.5, 20.3, 13.8.
5-Bu tyl-3-p h en ylcyclop en t-2-en on e (11d ). Method C
gave 11d (30%): 1H NMR δ 0.98 (t, 3H, J ) 7.0 Hz), 1.33-
1.36 (m, 5H), 1.84-1.87 (m, 1H), 2.50-2.54 (m, 1H), 2.88 (d,
1H, J ) 18.3 Hz), 3.18 (dd, 1H, J ) 18.3, 6.6 Hz), 6.50 (s, 1H),
7.40-7.44 (m, 3H), 7.60-7.65 (m, 2H); 13C NMR δ 211.1, 172.0,
133.8, 130.9, 128.6, 126.6, 126.5, 46.1, 35.3, 31.3, 29.4, 22.7,
14.0. Anal. Calcd for C15H18O/0.1H2O: C, 83.36; H, 8.50.
Found: C, 83.09; H, 8.37.
5-Ben zyl-3-p r op ylcyclop en t -2-en on e (11j). Methods A
1
(32%) and C (39%) gave 11j: IR (CDCl3) 1701 cm-1; H NMR
δ 0.88 (t, 3H, J ) 7.2 Hz), 1.53 (2H, m, J ) 7.2 Hz), 2.46-2.32
(m, 3H), 2.50-2.73 (m, 3H), 3.20 (dd, 1H, J ) 13.8, 3.9 Hz),
5.91(s, 1H), 7.15-7.28(m, 5H); 13C NMR δ 210.7, 181.6, 139.3,
128.6, 128.4, 128.2, 126.0, 47.4, 37.3, 36.9, 35.4, 20.3, 13.7;
HRMS for C15H19O (M + H) 215.1436, found 215.1498.
5-Bu tyl-3-pr opylcyclopen t-2-en on e (11k). Method C gave
11k (20%): IR (CDCl3) 1700(s), 1617 cm-1; 1H NMR δ 0.82 (s,
br, 3H), 0.89 (t, 3H, J ) 7.5 Hz), 1.24 (m, br, 6H), 1.54 (m, 2H,
J ) 7.5 Hz), 1.71 (s, br, 1H), 2.17 (d, 1H, J ) 18.5 Hz), 2.28-
2.32 (m, 2H), 2.66 (dd, 1H, J ) 18.5 Hz), 5.82 (br s,1H); 13C
NMR δ 211.7, 181.0, 128.4, 46.0, 38.1, 35.3, 31.0, 29.3, 22.5,
20.2, 13.8, 13.7.
3-P h en yl-5-(p ip er id in -1-yl)cyclop en t -2-en on e (11e).
Method C gave 11e (20%): IR (CDCl3) 1695, 1598, 1571 cm-1
;
1H NMR δ 1.44-1.46 (m, 2H), 1.60 (m, 4H), 2.52-2.76 (m, 4H),
3.00 (d, 1H, J ) 17.7 Hz), 3.13 (dd, 1H, J ) 17.7, 6.6 Hz), 3.59-
3.62 (m, 1H), 6.54 (s, 1H), 7.47-7.67 (m, 5H); 13C NMR δ 208.3,
171.0, 133.7, 131.3, 128.8, 126.8, 126.7, 68.3, 50.2, 30.4, 26.1,
24.3.
5-Azid o-3-m eth yl-cyclop en t-2-en on e (11f). Method C
1
gave 11f (35%): IR (CDCl3) 2103, 1710 cm-1; H NMR δ 2.11
(s, 3H), 2.34 (d, 1H, J ) 17.7 Hz), 2.85 (dd, 1H, J ) 17.7,6.9
Hz), 4.01 (dd, 1H, J ) 6.9, 3.0 Hz), 5.92 (s, 1H); 13C NMR δ
204.1, 176.8, 128.0, 60.4, 39.1, 19.6.
Ack n ow led gm en t. We thank the National Science
Foundation and Cystic Fibrosis Foundation for financial
support of this research. The 400 and 300 MHz NMR
spectrometers used in this study were funded in part
by a grant from NSF (CHE-9808183).
5-Ben zyl-3-m eth yl-cyclop en t-2-en on e (11g). Methods A
(40%) and C (38%) gave 11g: IR (CDCl3) 1705 cm-1; 1H NMR
δ 2.06 (s, 3H), 2.29 (d, 1H, J ) 18.6 Hz), 2.50-2.62 (m, 2H),
2.69-2.75 (m, 1H), 3.22 (dd, 1H, J ) 13.8, 4.0 Hz), 5.92 (s,
1H), 7.17-7.30 (m, 5H); 13C NMR δ 210.6, 177.4, 139.4, 129.6,
128.6, 128.2, 126.1, 48.0, 39.0, 36.9, 19.5.
3-Met h yl-5-(p ip er id in -1-yl)cyclop en t -2-en on e (11h ).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3, 4, and 11a ,e-k . This material is
available free of charge via the Internet at http://pubs.acs.org.
Method C gave 11h (18%): IR (CDCl3) 1698, 1619 cm-1 1H
;
NMR δ 1.41 (m, 2H, J ) 5.7 Hz), 1.57 (m, 4H, J ) 5.7 Hz),
2.10 (s, 3H), 2.38-2.65 (m, 6H), 3.41 (m, 1H), 5.90 (s, 1H); 13
NMR δ 208.7, 176.2, 130.3, 68.6, 50.1, 34.4, 25.9, 24.1, 19.8.
C
J O0256843