Radical [n + 1] annulations with sulfur dioxide

Article abstract of DOI:10.1021/jo052035t

A new methodology for [n + 1] radical annulation using sulfur dioxide as a geminal radical acceptor/donor is presented. This methodology provides a novel route to the formation of five-, six-, and seven-membered cyclic sulfones utilizing a radical chain m

Full text of DOI:10.1021/jo052035t

Radical [n + 1] Annulations with Sulfur Dioxide
Anna Tsimelzon and Rebecca Braslau*
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California, 95064
braslau@chemistry.ucsc.edu
Received September 28, 2005
A new methodology for [n + 1] radical annulation using sulfur dioxide as a geminal radical acceptor/
donor is presented. This methodology provides a novel route to the formation of five-, six-, and
seven-membered cyclic sulfones utilizing a radical chain mechanism under very mild conditions.
Introduction
Radical chain reactions are highly efficient processes:
generation of a small amount of an initiating radical can
effect conversion of a large amount of substrate. Further
efficiency is obtained if the reaction is convergent. Most
radical acceptors are double-bond systems, which gener-
ate a new radical on the atom adjacent to the site of
addition. Not surprisingly, the first convergent annula-
tions were [3 + 2] systems in which a three-atom unit
undergoes a tandem addition cyclization sequence with
an olefin to form a five-membered ring1 (Scheme 1).
FIGURE 1. [n + 1] Radical annulation.
donor/acceptor. Using a slightly different strategy, Kim6
accomplished [4 + 1] radical annulations using bissul-
fonyl oxime ethers as a 2-fold one-atom radical acceptor.
We now report [n + 1] annulations using sulfur dioxide
as a radical acceptor/donor. Heterocyclic compounds
containing SO2 as part of the ring are of particular
SCHEME 1. [3 + 2] Radical Annulation
(3) (a) Du, W.; Curran, D. P. Synlett 2003, 1299-1302. (b) Josien,
H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem.-Eur. J. 1998, 4, 67-83.
(c) Curran, D. P.; Liu, H.; Josien, H.; Ko, S. B. Tetrahedron 1996, 52,
11385-11404. (d) Curran, D. P.; Ko, S. B.; Josien, H. Angew. Chem.,
Int. Ed. Engl. 1996, 34, 2683-2684.
(4) (a) Zhang, Q. S.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc.
2002, 124, 5774-5781. (b) Zhang, W.; Luo, Z. Y.; Chen, C. H. T.;
Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450.
(5) Ryu, I.; Kusano, K.; Hasegawa, M.; Kambe, N.; Sonoda, N. J.
Chem. Soc., Chem. Commun. 1991, 1018-1019. (b) For reviews, see:
Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999,
99, 1991-2069. Also, see ref 2b and 2c.
(6) Kim, S.; Yoon, J. Y. J. Am. Chem. Soc. 1997, 119, 5982-5983.
(7) (a) Koteva, K. P.; Cantin, A. M.; Neugebauer, W. A.; Escher, E.
Can. J. Chem. 2001, 79, 377-387. (b) Balsamo, A.; Cercignani, G.;
Gentili, D.; Lapucci, A.; Macchia, M.; Orlandini, E.; Rapposelli, S.;
Rossello, A. Eur. J. Med. Chem. 2001, 36, 185-193. (c) Alpegiani, M.;
Bissolino, P.; Corigli, R.; Del Nero, S.; Perrone, E.; Rizzo, V.; Sacchi,
N.; Cassinelli, G.; Franceschi, G.; Baici, A. J. Med. Chem. 1994, 37,
4003-4019. (d) Finke, P. E.; Ashe, B. M.; Knight, W. B.; Maycock, A.
L.; Navia, M. A.; Shah, S. K.; Thompson, K. R.; Underwood, D. J.;
Weston, H.; Zimmerman, M.; Doherty, J. B. J. Med. Chem. 1990, 33,
2522-2528. (e) Buynak, J. D. Curr. Med. Chem. 2004, 11, 1951-1964.
(f) Van der Steen, F. H.; Van Koten, G. Tetrahedron 1991, 47, 7503-
7524.
There are only a few functional groups that undergo
radical addition resulting in the formation of a new
radical at the same atom as the initial addition: geminal
radical acceptor/donors (Figure 1). In 1991, Curran2
introduced methodology for radical [n + 1] annulation
using isonitriles as the one-atom radical acceptor/donor
1. This was developed into a very efficient entry to the
campotothecins3 and mappicines.4 Ryu5 extended this
strategy to the use of carbon monoxide as the radical
(1) Rheault, T. R.; Sibi, M. P. Synthesis 2003, 803-819.
(2) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127-
2132. (b) For reviews, see: McCarroll, A. J.; Walton, J. C. J. Chem.
Soc., Perkin Trans. 1 2001, 3215-3229. (c) Ryu, I.; Sonoda, N.; Curran,
D. P. Chem. Rev. 1996, 96, 177-194.
10.1021/jo052035t CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/17/2005
10854
J. Org. Chem. 2005, 70, 10854-10859

Radical [n + 1] Annulations with Sulfur Dioxide
SCHEME 2. Radical Addition to SO2 Using the
Thiohydroxamic Ester System
SCHEME 4. Example of Aryl Sulfonyl
Radical-Mediated Cyclization
SCHEME 5. Sulfonyl Radical Cyclization
SCHEME 3. Bis Addition of Perfluorinated
Nitroxide to SO2
sulfonyl radical chain reactions are less common and
sometimes proceed with SO2 extrusion13 to generate
reactive alkyl radicals that can be harnessed for atom
abstraction or other chain-carrying roles. Walton14 dem-
onstrated sulfonyl radical cyclizations from sulfonyl
chloride substrates (Scheme 5). For example, chlorine
radical abstraction from sulfonyl chloride precursor 10
gives predominantly 6-endo-trig closure. This 6-endo
closure may be an inherent kinetic preference, or it may
be the result of equilibration via a reversible cyclization
step. Johnson15 demonstrated radical annulations with
SO2 utilizing cobaloxime chemistry in 1984. For example,
pent-4-enylcobaloxime 11 was irradiated in the presence
of tricholoromethanesulfonyl chloride 12 to produce sul-
folane 13 (Scheme 6). The mechanism is as follows:
trichloromethyl radical 14 adds to pent-4-enylcobaloxime
11 to produce secondary carbon radical 15, which adds
to SO2. Cyclization via an SHi mechanism (substitution
homolytic intramolecular) produces sulfolane 13 and
cobalt-centered radical 16. Abstraction of chloride from
trichloromethanesulfonyl chloride followed by SO2 extru-
sion regenerates trichloromethyl radical 14 and SO2.
Cyclizations using R,ω dienes were also examined using
cobaloximes as catalysts.
interest because of the presence of this structural motif
in the cephalosporins7 as well as in other pharmaceuti-
cally active compounds, such as TRUSOPT (dorzolamide
hydrochloride).8
Carbon radicals add readily to the sulfur lone pair of
sulfur dioxide. For example, Barton and Zard9 used their
thiohydroxamic ester system to trap SO2 in a radical
chain sequence (Scheme 2). Photolysis of thiohydroxamic
ester 2 in dichloromethane saturated with SO2 gas
results in homolytic cleavage of the oxygen-nitrogen
bond. The acyloxy radical 3 undergoes decarboxylation
to afford carbon radical 4, which adds to SO2. The sulfur-
centered radical 5 adds to the thiocarbonyl of the starting
material, affording product 6 and perpetuating the radi-
cal chain. Primary, secondary, and tertiary radicals were
shown to add to SO2 in good yields. This work clearly
demonstrates that SO2 behaves as a one-atom radical
acceptor/donor in a fashion similar to that of isonitriles
and carbon monoxide. In fact, radical polymerizations
10
between olefin monomers and SO2 have been known
since Kharash’s work in the 1940s. In another example,
Smith has shown that SO2 can act as a 2-fold geminal
radical acceptor in the bis addition of persistent perflu-
Results and Discussion
As outlined above, the precedent exists for both carbon
radical addition to SO2 and sulfonyl radical cyclization
onto a tethered olefin. Thus, a convergent [n + 1]
cyclization with SO2 was pursued, beginning with thio-
hydroxamic ester 17 (Scheme 7). Photolysis of ester 17
in dichloromethane saturated with sulfur dioxide formed
an inseparable 3:1 mixture of products 18 and 19
11
orinated nitroxides such as 7 to neat SO2 (Scheme 3).
Aryl sulfonyl radicals are common intermediates in
synthetic methodology, often participating as the chain-
carrying species. A representative example is the cycliza-
tion of bisallylic ether 8, mediated by an aryl sulfonyl
radical to afford bicyclic product 9 (Scheme 4).12 Alkyl
SCHEME 6. Cobaloxime-Mediated SO2 Radical Annulation
J. Org. Chem, Vol. 70, No. 26, 2005 10855

Tsimelzon and Braslau
SCHEME 7. [n + 1] SO2 Radical Annulation Using the Thiohydroxamic Ester System
SCHEME 8. Reductive Desulfurization of [n + 1] Annulation Products 18 and 19
SCHEME 9. Reactions of 1,5-Hexadiene with SO2 Mediated by a Phenylthiyl Radical
resulting from both 6-endo and 5-exo cyclization in a
combined 30% yield. In addition, product 20 was formed
from the direct addition of the carbon radical to the
starting material 17. In a separate experiment without
SO2, thiohydroxyamic ester 17 rearranged upon heating
to produce sulfide 20,16 providing an authentic sample
for spectroscopic identification in the crude reaction
mixture containing cyclic sulfones 18 and 19.
To determine the identity of the major product, the
mixture of cyclic sulfones 18 and 19 was reduced with
nickel boride17 generated in situ to produce the known
unsubstituted cyclic sulfones 21 and 22 (Scheme 8). The
major product was the 6-endo derived material 21
isolated in 25% yield.
With this encouraging example of [5 + 1] cyclization
using the parent 4-pentenyl radical, additional substrates
23-25 (Figure 2) were prepared and subjected to similar
reaction conditions. Disappointingly, none of the desired
cyclization products were obtained: only direct trapping
products analogous to compound 20 were isolated, in
addition to recovered starting material.
Because of the limited success of the substrates based
on thiohydroxamic ester chemistry, an alternative initia-
tion/termination approach was investigated. Simple thiyl
radical addition to olefins is a reversible method for the
generation of carbon radicals. Treatment of 1,5-hexadiene
with diphenyl disulfide in dichloromethane saturated
with SO2 under photolysis gave no detectable cyclization
products, but produced a white insoluble polymer10
(Scheme 9). The use of catalytic disulfide and 1 equiv of
allyl phenyl sulfide gave a complex mixture of products
in low yield in addition to a significant amount of
insoluble polymeric material. 1H NMR and mass spectral
data suggested the formation of products incorporating
both one and two molecules of SO2, tentatively assigned
as structures 26-29.
(8) Tsai, J.-C.; Chang, H.-W. J. Ocul. Pharmacol. Ther. 2001, 17,
499-504.
(9) Barton, D. H. R.; Lacher, B.; Misterkiewicz, B.; Zard, S. Z.
Tetrahedron 1988, 44, 1153-1158.
(10) (a) Kharasch, M. S.; Friedlander, H. N. J. Org. Chem. 1948,
13, 882-885. (b) Hwang, J. S.; Tsonis, C. P. J. Polym. Sci., Part A:
Polym. Chem. 1993, 31, 1417-1421. (c) Tsai, J. Y.; Shevlin, P. B. J.
Org. Chem. 1998, 63, 3230-3234.
(11) Arfaei, A.; Smith, S. J. Chem. Soc., Perkin Trans. 1 1984, 1791-
1794.
(12) Smith, T. A. K.; Whitham, G. H. J. Chem. Soc., Perkin Trans.
1 1989, 319-325.
(13) (a) For a review, see: Bertrand, F.; Le Guyader, F.; Liguori,
L.; Ouvry, G.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Compt. Rend.
2001, 4, 547-555 and references therein. (b) Montermini, F.; Lacote,
E.; Malacria, M. Org. Lett. 2004, 6, 921-923. (c) Panchaud, P.;
Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud, P.; Zigmantas, S.
Chem.-Eur. J. 2004, 10, 3606-3614. (d) Kim, S.; Lim, C. J. Bull.
Korean Chem. Soc. 2003, 24, 1219-1222. (e) Ouvry, G.; Zard, S. Z.
Chem. Commun. 2003, 778-779. (f) Andraos, J.; Barclay, G. G.;
Medeiros, D. R.; Baldovi, M. V.; Scaiano, J. C.; Sinta, R. Chem. Mater.
1998, 10, 1694-1699.
To avoid incorporation of a second equivalent of SO2,
a rapid termination step was needed following the desired
[n + 1] cyclization. Thus, substrate 30 bearing an allylic
sulfide was prepared. In addition to providing a clean
final step for the cyclization, substitution on the allylic
sulfide trap can be used to direct the endo/exo regiose-
lectivity of the cyclization. Upon irrradiation of substrate
30 in the presence of catalytic diphenyl disulfide in
(14) Culshaw, P. N.; Walton, J. C. Tetrahedron Lett. 1990, 31, 6433-
6436. Culshaw, P. N.; Walton, J. C. J. Chem Soc., Perkin Trans. 2 1991,
1201-1208.
(15) Ashcroft, M. R.; Bougeard, P.; Bury, A.; Cooksey, C. J.; Johnson,
M. D.; Hungerford, J. M.; Lampman, G. M. J. Org. Chem. 1984, 49,
1751-1761.
(16) Okano, T.; Ishihara, H.; Takakura, N.; Tsuge, H.; Eguchi, S.;
Kimoto, H. J. Org. Chem. 1997, 62, 7192-7200.
(17) Back, T. G.; Yang, K.; Krouse, H. R. J. Org. Chem. 1992, 57,
1986-1990.
10856 J. Org. Chem., Vol. 70, No. 26, 2005

Radical [n + 1] Annulations with Sulfur Dioxide
SCHEME 10. [5 + 1] 6-Endo-Trig Radical
of thiyl radical. The thiyl radical adds to the monosub-
stituted olefin of substrate 30 to afford carbon radical
33 that is captured by SO2 to form sulfonyl radical 34.
This sulfur-centered radical cyclizes in a 6-endo fashion
onto the olefin of the allylic sulfide; rapid fragmentation
produces the desired product 31 and generates another
thiyl radical that perpetuates the chain. Note that in this
cyclization, the thiyl radical is the chain-carrying species.
Addition of a thiyl radical to the monosubstituted olefin
initiates the cyclization sequence. However, addition of
a thiyl radical to the allylic sulfide also occurs but is a
degenerate reaction.18
Annulation
SCHEME 11. Mechanism of the [5 + 1]
6-Endo-Trig Radical Annulation
Encouraged by this extremely clean and efficient
reaction, a number of substrates were prepared incorpo-
rating both olefins and acetylenes and using linear or
branched allylic sulfides as the terminating functionality.
Retrosynthetically, the requisite allylic sulfides were
prepared from the corresponding allylic alcohols. These
were prepared either by a metalation-alkylation se-
quence or by olefination and reduction. The synthesis of
substrates 30, 38, 42, 46, and 50 is depicted in Scheme
12. Thus, methallyl alcohol 35 was doubly deprotonated
with 2.1 equiv of n-BuLi in the presence of N,N,N,N-
tetramethylethylenediamine followed by C-alkylation
with either allyl or propargyl bromides to obtain com-
pounds 36 or 37.19 Allylic alcohol 41 was assembled by
Horner-Wadsworth-Emmons olefination of aldehyde 39
to give the R,â-unsaturated ester 40; DIBAL-H reduction
afforded alcohol 41.20 Similarly, yne-enol 4521 was pre-
pared by Swern oxidation of 4-pentyn-1-ol 43, followed
by olefination and reduction. The synthesis of dienol 49
began with an SN2 reaction between 5-bromopentene 47
and deprotonated methyl diethylphosphonoacetate, fol-
lowed by a Horner-Wadsworth-Emmons olefination
with formaldehyde to afford R,â-unsaturated ester 48.
Reduction with DIBAL-H afforded allylic alcohol 49.22
The allylic sulfide cyclization substrates were prepared
dichloromethane saturated with SO2, cyclization took
place exclusively in the 6-endo mode to afford the desired
product 31 in 92% yield (Scheme 10). The reaction
product was extremely clean, containing only the cata-
lytic diphenyl disulfide as an impurity.
The mechanism of this reaction is illustrated in
Scheme 11. Diphenyl disulfide 32 undergoes homolytic
cleavage upon photolysis to produce a catalytic amount
FIGURE 2. Failed annulation substrates.
SCHEME 12. Preparation of Radical Annulation Substrates 30, 38, 42, 46, and 50
J. Org. Chem, Vol. 70, No. 26, 2005 10857

Tsimelzon and Braslau
TABLE 1. [n + 1] SO2 Radical Annulations
decoupling experiments. Irradiation of the peak at δ 7.35
ppm resulted in simplification of the two peaks at δ 2.22
and δ 2.01 ppm, corresponding to the diastereotopic
allylic methylene protons in the ring. Conversely, ir-
radiation at δ 2.22 ppm caused the doublet of doublets
at δ 7.35 ppm to collapse to a doublet. Likewise, irradia-
tion at δ 2.01 ppm also resulted in a doublet at δ 7.35
ppm.
The formation of five- and six-membered rings by
radical cyclization is well precedented. However, the
formation of larger rings is more challenging because of
substantially slower cyclization rates.25 Pleasingly, sub-
strate 50 underwent [6 + 1] cyclization to give exclusively
the 7-endo product 54. The 1H NMR analysis of the crude
reaction mixture showed only the product and diphenyl
disulfide. Purification by preparative TLC afforded 50%
of the pure product on a small scale.
Summary
The ability to form five-, six-, and seven-membered
cyclic sulfones by this [n + 1] radical annulation strategy
demonstrates a new convergent approach to these het-
erocycles under very mild conditions. The exo vs endo
selectivity can be tuned by selection of either a linear or
a branched allylic sulfide terminating group. In addition,
the phenyl sulfide group in the final products provides a
functional handle that can be utilized in subsequent steps
for further elaboration of the cyclized material. This [n
+ 1] radical annulation strategy should be amenable to
other substrates capable of rapid fragmentation as the
cyclization terminating step. In summary, this work
demonstrates the use of SO2 as a one-atom geminal
acceptor/donor in radical [n + 1] annulations to prepare
five- to seven-membered cyclic sulfones under extremely
mild conditions.
according to the procedure of Castro:23 allylic alcohols
were treated with hexamethylphosphorus triamide and
carbon tetrachloride to form the allylic alkyloxyphospho-
nium chlorides, which are stable at -70 °C. These were
displaced in situ by thiolate.
With the substrates in hand, a series of [n + 1]
cyclizations were examined (Table 1). The acetylenic
branched allylic sulfide 38 underwent [5 + 1] cyclization
to afford the 6-endo product 51 as a single isomer in 18%
yield on a 42 mg scale after purification by preparative
thin-layer chromatography (TLC). The ACD24 simulation
1
of the H NMR spectra of the E and Z isomers of vinyl
sulfide 51 predicted a chemical shift for the vinylic sulfide
proton of δ 7.28 ppm for the E isomer and δ 5.79 ppm for
the Z isomer. Product 51 displayed a singlet at δ 7.52
ppm, indicating that the cyclization product possessed
Experimental Section
Cyclization to Form 3-(2′-Pyridylsulfide)-1,1-dioxythia-
cyclohexane 18 and 2-Methyl-(2′-pyridylsulfide)-1,1-di-
oxythiacyclopentane 19. In a 50 mL quartz tube was put
22 mL of CH2Cl2 cooled to -40 °C; the solvent was saturated
with SO2 gas until the volume increased by 30%. Hex-5-enoic
acid 2-thioxo-2H-pyridin-1-yl ester 17 (300 mg, 1.31 mmol),
dissolved in 1 mL of CH2Cl2, was added to the saturated SO2
solution. The tube was closed with a glass stopper, and the
resulting yellow solution was irradiated with a 250 W tung-
sten-halogen lamp until the color disappeared (about 1 h).
The solvent was removed in vacuo, and the crude mixture was
analyzed by 1H NMR. The ratio of the two cyclization products
was determined to be 3:1. The crude mixture was dissolved in
a minimal amount of CH2Cl2, and hexanes were added. The
product immediately formed a precipitate that was filtered and
dried to afford 195 mg (0.80 mmol, 61% yield) of a white solid.
1
the E configuration. The H NMR of the crude product
showed only the desired product and diphenyl disulfide
as an impurity, implying that the yield should be
substantially higher on a larger scale. Although the thiyl
radical is expected to add more quickly to the unsubsti-
tuted sp2 hybridized olefin compared to the sp hybridized
acetylenic terminus, only the latter leads to the consump-
tion of starting material and the formation of the product
whereas the former is a degenerate reaction.
Linear allylic sulfide 42 underwent [4 + 1] cyclization
to form the 5-exo-sulfolane 52 in 92% yield as an
inseparable mixture of diastereomers in a 1:1 ratio, as
1
determined by H NMR. Similarly, the acetylenic ana-
logue substrate 46 cyclized in the expected [4 + 1] mode
to afford the 5-exo product 53 as a single isomer in 20%
yield after 63 h. The reaction did not go to completion;
the ratio of the starting material to the product was 2:1.
However, extended reaction times did not enhance the
yield but instead afforded complex mixtures. The E
configuration of the vinyl sulfide was again assigned by
(18) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 1997, 69, 645-
650.
(19) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421-9438.
(20) Crandall, J. K.; Mayer, C. F. J. Org. Chem. 1970, 35, 3049-
3053.
(21) Huang, H.-L.; Liu, R.-S. J. Org. Chem. 2003, 68, 805-810.
(22) Schomaker, J. M.; Borhan, B. Org. Biomol. Chem. 2004, 2, 621-
624.
(23) Castro, B.; Selve, C. Bull. Soc. Chim. Fr. 1971, 2296-2298.
(24) Advanced Chemistry Development (ACD/Labs) Software So-
laris, version 2.0; Advanced Chemistry Development, Inc.: Toronto,
Ontario, Canada, 1994-2005; http://www.acdlabs.com/.
(25) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941.
1
examination of the H NMR spectrum. Experimentally,
the sp2 hydrogen of the vinylic sulfide came at δ 7.35
ppm; ACD24 predicted a chemical shift of δ 7.39 ppm for
the E isomer and δ 6.07 ppm for the Z isomer. The
identity of this peak was confirmed by homonuclear
10858 J. Org. Chem., Vol. 70, No. 26, 2005

Radical [n + 1] Annulations with Sulfur Dioxide
1H NMR indicated that the ratio of the two cyclization products
after precipitation was enhanced to 9:1. The major isomer was
further characterized by DEPT, COSY, and HETCOR experi-
ments (see Supporting Information).
disulfide (4.0 mg, 0.02 mmol) were dissolved in 6 mL of
dichloromethane and placed into a 15 mL heavy-walled glass
pressure vessel. The solution was cooled to -78 °C, and 6 mL
of SO2 gas was condensed into the reaction mixture using a
dry ice condenser. The mixture became yellow in color. The
dry ice condenser was removed, and the pressure vessel was
sealed and irradiated with a 450 W Hg lamp for 17 h. During
the photolysis, the solution turned brown in color. The mixture
was cooled to -78 °C, and the pressure vessel was slowly
opened to the air and left standing in the hood at room
temperature until all of the SO2 gas had evaporated. Volatiles
were removed in vacuo to give 101 mg (0.36 mmol, 92% yield)
of the title compound as a brown oil.
TLC: 5:1 hexanes/ethyl acetate; UV; I2; Rf ) 0.36. IR
(CDCl3): 2962, 1711, 1440, 1364, 899, 748 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.40-7.26 (m, 5H), 5.11 (s, 1H), 5.05 (s, 1H),
3.80 (dd, J ) 13.5 Hz, 2.2 Hz, 1H), 3.71 (d, J ) 13.5 Hz, 1H),
3.62 (d, J ) 13.5 Hz, 1H), 3.02 (tt, J ) 11.5 Hz, 3.0 Hz, 1H),
2.87 (dd, J ) 14.2 Hz, 11.2 Hz, 1H), 2.55-2.50 (m, 2H), 2.15-
2.11 (m, 1H), 1.81-1.74 (m, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δ 136.8, 134.1, 129.5, 129.4, 127.0, 117.7, 60.6, 60.2,
32.7, 29.1, 27.5 ppm. HRMS calcd for C13H17O2S2, 269.0670;
found, 269.0665.
A. Major Isomer. TLC: 1:1 hexanes/ethyl acetate; UV; Rf
) 0.13. IR (CDCl3): 3155, 1572, 1469, 1332, 1135, 706 cm-1
.
1H NMR (500 MHz, CDCl3): δ 8.69 (ddd, J ) 1.0 Hz, 2.0 Hz,
5.0 Hz, 1H), 7.83 (td, J ) 7.5 Hz, 2.0 Hz, 1H), 7.74 (dt, J ) 1.0
Hz, 7.5 Hz, 1H), 7.44 (ddd, J ) 1.0 Hz, 5.0 Hz, 7.5 Hz, 1H),
4.26 (tt, J ) 2.5 Hz, 12.5 Hz, 1H), 3.79-3.76 (m, 1H), 3.28 (t,
J ) 13.0 Hz, 1H), 3.13 (dq, J ) 14.5 Hz, 2.75 Hz, 1H), 2.98
(td, J ) 13.5 Hz, 2.5 Hz, 1H), 2.63 (br d, J ) 15.0 Hz, 1H),
2.36-2.32 (m, 1H), 2.13 (qt, J ) 12.5 Hz, 4.0 Hz, 1H), 1.84
(qd, J ) 13.5 Hz, 3.5 Hz, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δ 151.2, 150.2, 138.5, 131.9, 125.4, 66.4, 51.0, 50.9,
24.4, 21.9 ppm. HRMS (M + 1) calcd for C10H14NO2S2,
244.0469; found, 244.0461.
Direct Trapping Product 4-(2-Pyridinothio)-1-pen-
tene16 (20). 1H NMR (250 MHz, CDCl3): δ 8.42 (m, 1H), 7.47-
7.45 (m, 1H), 7.18-7.14 (m, 1H), 6.97-6.94 (m, 1H), 5.82-
5.73 (m, 1H), 5.08-4.96 (m, 2H), 3.16 (t, J ) 7.5 Hz, 2H), 2.21-
2.12 (m, 2H), 1.86-1.71 (m, 2H) ppm.
Reduction to Prepare Tetrahydrothiopyran 1,1-Diox-
ide 2114b and 2-Methyltetrahydrothiophene 1,1-Dioxide
22. On the basis of the procedure of Back,17 the mixture of
compounds 18 and 19 (100 mg, 0.41 mmol) was dissolved in
10 mL of THF. To this solution was added NiCl2‚H2O (684 mg,
2.88 mmol) dissolved in 6 mL of methanol. The resulting
mixture was cooled to 0 °C, and NaBH4 (326 mg, 8.61 mmol)
was added in portions. The reaction mixture was stirred for
15 min, and then the solvent was evaporated. The resulting
black solid was resuspended in a 1:1 methanol/chloroform
mixture and was filtered through Celite. Purification by flash
column chromatography using 50:1 methylene chloride/
methanol gave 14 mg (0.10 mmol, 25% yield) of tetrahydrothio-
pyran 1,1-dioxide 21.
Acknowledgment. We thank the National Science
Foundation (CHE-0078852) and Research Corporation
(RA0336) in addition to equipment grants from the NSF
(BIR-94-19409) (NMR) and a supplement grant from
NIH (CA52955) (ESITOFMS) for providing financial
support for this project. We also thank Professor Yian
Shi for helpful discussions on the synthesis of 2-meth-
ylenehex-5-en-1-ol 36.
Supporting Information Available: General experimen-
tal; detailed experimental procedures for the preparation of
compounds 17, 30, 36-38, 40-42, 44-46, and 48-54; and
TLC: 99:1 methylene chloride/methanol; PAA stain; Rf )
1
0.5. H NMR (500 MHz, CDCl3): δ 3.00-2.98 (m, 4H), 2.11-
1
the H NMR and 13C NMR spectra of compounds 18, 31, and
2.09 (m, 4H), 1.64 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3):
δ 52.2, 24.3, 23.9 ppm.
51-54 along with HETCOR and COSY spectra of 18. Ad-
ditionally, HETCOR, COSY, and NOESY spectra for compound
52 are also available. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Procedure for SO2 Cyclization. The prepara-
tion of 5-methylene-2-phenylsulfanylmethyltetrahydrothiopyran
1,1-dioxide 31 is a representative example: (2-Methylenehex-
5-enylsulfanyl)benzene 30 (80 mg, 0.39 mmol) and diphenyl
JO052035T
J. Org. Chem, Vol. 70, No. 26, 2005 10859