Synthesis of sulfur-containing heterocycles through oxidative carbon-hydrogen bond functionalization

Article abstract of DOI:10.1021/ol3002877

Vinyl sulfides react rapidly and efficiently with 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone (DDQ) to form α,β-unsaturated thiocarbenium ions through oxidative carbon-hydrogen bond cleavage. These electrophiles couple with appended π-nucleophiles to yield sulfur-containing heterocycles through carbon-carbon bond formation. Several nucleophiles are compatible with the procedure, and the reactions generally proceed through readily predictable transition states.

Full text of DOI:10.1021/ol3002877

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1720–1723
Synthesis of Sulfur-Containing
Heterocycles through Oxidative
CarbonÀHydrogen Bond Functionalization
Yubo Cui and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States
florean@pitt.edu
Received February 5, 2012
ABSTRACT
Vinyl sulfides react rapidly and efficiently with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form R,β-unsaturated thiocarbenium ions
through oxidative carbonÀhydrogen bond cleavage. These electrophiles couple with appended π-nucleophiles to yield sulfur-containing
heterocycles through carbonÀcarbon bond formation. Several nucleophiles are compatible with the procedure, and the reactions generally
proceed through readily predictable transition states.
Organic sulfides display a remarkable range of proper-
ties in comparison to their oxygen-containing analogs.
They are more nucleophilic, less basic, and less polar,
and they can be oxidized to form sulfoxides and sulfones
that provide additional opportunities for structural diver-
sification. Moreover sulfides can be converted to sub-
strates for [2,3]-sigmatropic rearrangements1 that have
proven to be useful in complex molecule synthesis. Sulfur’s
versatility has been exploited significantly in drug discov-
ery efforts, as evidenced by the fact that several of the 200
top-selling pharmaceutical agents in 20102 contain sulfur
and, in many cases, the sulfur atom is contained in a ring.
Thus developing new methods for the stereoselective
synthesis of sulfur-containing heterocycles is clearly a
worthy objective.
proceeds through an endo-pathway would provide a pre-
parative method for sulfur-containing heterocycles. This
strategy is rarely employed for thia-Prins-type reactions in
which ring formation occurs through carbonÀcarbon
bond formation.4 The limited number of reported exam-
ples of this type of transformation5 and the potential for
preparing sulfur analogs of biologically active tetrahydro-
pyran natural products6 led us to explore the synthesis of
tetrahydrothiopyrans7 through intramolecular additions
of π-nucleophiles into oxidatively generated thiocarbe-
nium ions.8
Our approach was designed to mirror our route to the
formation of oxygen-containing heterocycles,9 whereby
allylic or benzylic ethers react with 2,3-dichloro-5,
Thiocarbenium ions are attractive intermediates for
the synthesis of sulfur-containing compounds.3 The vast
majority of cyclization reactions that proceed through
thiocarbenium ions provide exo-products in which the
sulfur is not contained in a ring. Designing reactions of
thiocarbenium ions in which the nucleophilic addition
(4) For recent reviews of Prins-type cyclization reactions, see:
(a) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron
2010, 66, 413. (b) Pastor, I.; Yus, M. Curr. Org. Chem. 2007, 11, 925.
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739. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S. J.;
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(b) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237.
(7) For recently reported alternate strategies for sulfur-containing
heterocycle synthesis, see: (a) Li, F.; Calabrese, D.; Brichacek, M.;
Lin, I.; Njardarson, J. T. Angew. Chem., Int. Ed. 2012, 51, 1938.
(b) Robertson, F. J.; Wu, J. J. Am. Chem. Soc. 2012, 134, 2775.
(8) For a similar approach to thiocarbenium ion formation, see: Li,
Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. Org. Lett. 2008, 10,
803.
(1) (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
(b) Vedejs, E. Acc. Chem. Res. 1984, 17, 358.
(2) For a list of the top selling drugs in 2010 with structures, see:
http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster.
(3) (a) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J.
Angew. Chem., Int. Ed. 2010, 49, 5832. (b) Feldman, K. S. Tetrahedron
2006, 62, 5003. (c) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401.
r
10.1021/ol3002877
Published on Web 03/15/2012
2012 American Chemical Society

6-dicyano-1,4-benzoquinone (DDQ) to yield oxocarbenium
ions that react with enol acetate nucleophiles (Scheme 1).10
Sulfur is a larger and less electronegative atom than
oxygen, making the relative stabilities of intermediate
thiocarbenium and oxocarbenium ions difficult to predict,
though comparative studies have shown that the energetic
differencebetweenthese species issmall.11 Additionallythe
longer bonds between carbon and sulfur indicate that the
strong preference for the E-geometry of oxocarbenium
ions12 could be eroded for thiocarbenium ions, leading to
lower stereocontrol.
vinyl sulfide substrates. Mechanistic studies in our group
have revealed that oxidation rates are influenced by the
oxidation potential of the substrate and the stability of the
cation.13 Although allyl sulfides and isomeric vinyl sulfides
form the same thiocarbenium ion upon DDQ oxidation,
the lower oxidation potential of vinyl sulfides14 was ex-
pected to provide higher radical cation concentrations and
faster cation formation. This strategy has been shown to be
effective for acyliminium ion formation,15 whereby allylic
amides are unreactive toward DDQ while vinyl amides
react quickly. Vinyl sulfides are attractive substrates for
these processes because of their increasing accessibility
through a number of new metal mediated protocols for
their formation.16
Scheme 1. Heterocycle Synthesis through Oxidative CarbonÀ
Vinyl sulfide 9 was prepared through a sequence in
which the key step was a palladium-mediated coupling
between a thiol and a vinyl iodide.17 Exposing 918 to DDQ
provided 2 in 58% isolated yield within 10 min at 0 °C
through the same thiocarbenium ion that was formed
from allyl sulfide 1 (Scheme 3). Vinyl sulfide 10 also
proceeded through the oxidative cyclization reaction
smoothly, forming 5 with excellent diastereocontrol.
No overoxidation was observed. These results vali-
dated the strategy of employing vinyl sulfides rather
than allyl sulfides as substrates for oxidative thiocar-
benium ion formation.
Hydrogen Bond Cleavage
We demonstrated the viability of allylic sulfide sub-
strates in these reactions (Scheme 2) through the DDQ-
mediated conversion of 1 to 2. This transformation led to
the formation of variable amounts of enone 3 as a result of
the oxidation of 2. The addition of LiClO4 to the reaction
mixture reduced the formation of 3 to 4%, presumably due
to the stabilization of the radical anion that forms from the
initial electron transfer. Secondary sulfide 4 reacted with
DDQ to yield 5 as a satisfactory 10:1 ratio of diastereo-
mers, confirming that the E-thiocarbenium ion is the
dominant reactive species. The product of overoxidation
(6) was also formed in this transformation in 4% yield.
Benzyl sulfide 7 was converted to tetrahydrothiopyrone 8
with excellent stereocontrol. No overoxidation was ob-
served in this reaction. We postulate that the benzylic
carbonÀhydrogen bond in the product does not overlap
the p-orbitals of the aromatic ring, thereby slowing pro-
duct oxidation.
Scheme 3. Cyclizations of Vinyl Sulfide Substrates
(9) (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008,
47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567. (c) Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069.
(d) Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 5894.
(10) For recent examples of carbonÀcarbon bond formation through
DDQ-mediated carbonÀhydrogen bond oxidation, see: (a) Benfatti, F.;
Capdavila, M. G.; Zoli, L.; Benedetto, E.; Cozzi, P. G. Chem. Commun.
2009, 5919. (b) Hayashi, Y.; Itoh, T.; Ishikawa, H. Angew. Chem., Int.
Ed. 2011, 50, 3920. (c) Ghosh, A. K.; Cheng, X. Org. Lett. 2011, 13, 4108.
(d) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2011, 50,
10429. (e) Son, Y. W.; Kwon, T. H.; Lee, J. K.; Pae, A. N.; Lee, J. Y.;
Cho, Y. S.; Min, S.-J. Org. Lett. 2011, 13, 6500. (f) Reddy, B. V. S.;
Borkar, P.; Jadav, J. S.; Reddy, P. P.; Kunwar, A. C.; Sridhar, B.; Gree,
R. Org. Biomol. Chem. 2012, 10, 1349. (g) Park, S. J.; Price, J. R.; Todd,
M. H. J. Org. Chem. 2012, 77, 949.
Scheme 2. Allylic and Benzylic Sulfide Substrates
€
(11) (a) Osapay, K.; Delhalle, J.; Nsunda, K. M.; Rolli, E.; Houriet,
R.; Hevesi, L. J. Am. Chem. Soc. 1989, 111, 5028. (b) Apeloig, Y.; Karni,
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M. J. Chem. Soc., Perkin Trans. 2 1988, 625. (c) Grutzmacher, H.;
Marchand, C. M. Coord. Chem. Rev. 1997, 163, 287.
(12) Broecker, J. L.; Hoffmann, R. W.; Houk, K. N. J. Am. Chem.
Soc. 1991, 113, 5006.
(13) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830.
(14) Directly appending electron donating groups to alkenes results
in a substantial lowering of the oxidation potential. See: Schepp, N. P.;
Johnston, L. J. J. Am. Chem. Soc. 1996, 118, 2872.
(15) (a) Brizgys, G. J.; Jung, H. H.; Floreancig, P. E. Chem. Sci. 2012,
3, 438. (b) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152.
The formation of overoxidized products and our desire
toexpand thescopeofnucleophilicgroupsledustoexplore
Org. Lett., Vol. 14, No. 7, 2012
1721

Increasing the level of substitution in the products
can be achieved by employing substituted nucleophiles.
Controlling the stereochemical outcome of reactions with
highly substituted nucleophiles requires the preparation of
enolate surrogates with a high degree of geometrical con-
trol. The geometry of enol acetates and enolsilanes is
difficult to control, but enol carbamates can be prepared
with the appropriate level of control. The preparation
and cyclization of enol carbamate substrates is shown in
Scheme 4. The isomerization of allyl carbamate 11 with
LDA in the presence of HMPA19 provided (Z)-enol
carbamate 12. The vinyl sulfide was formed through a
sequence of silyl ether cleavage, Mitsunobu displacement
with thioacetic acid,20 and coupling with (E)-1-iodo-1-
hexene using the recently reported conditions from Kao
and Lee21 to yield substrate 13. Although these conditions
were developed for thiols, we observed the useful result
whereby thioesters could be used in the coupling reactions
with equal efficiency to thiols, presumably due to in situ
thioester cleavage. Oxidation of 13 with DDQ resulted in
the smooth conversion to 14 with high stereocontrol.
Branched vinyl sulfide 15 was also an excellent participant
in the reaction, providing 16 in 82% yield as a 25:1:1
mixture of products, with the major product arising from
the expected chair transition state with an (E)-thiocarbe-
nium ion. The minor products can be attributed to a boat
transition state and a transition state with a (Z)-thiocar-
benium ion.
Scheme 4. Cyclization with Enol Carbamate Nucleophiles
predominance of a chair transition state in which the
thiocarbenium ion has an (E)-geometry and the allylsilane
group occupies a pseudoequatorial orientation. The minor
diastereomer can be formed from the (Z)-thiocarbenium
ion, from the allylsilane group occupying a pseudoaxial
orientation, or from a competitive twist boat transition
state.
The (E)-carbamate was accessed by exposing alkynyl
carbamate 17 to Marek’s carbocupration/iodination
sequence22 to form 18. Cyclization substrate 19 was pre-
pared througha straightforward sequence. Oxidation of19
with DDQ provided 2,3-cis-product 20 in 72% yield as a
single stereoisomer. These results demonstrated that com-
plementary stereocontrol can be accessed by the appro-
priate selection of enolate surrogate geometry.
Scheme 5. Ring Closure by Allylsilane Addition
Allylsilanes are also effective nucleophiles for this
reaction,23 as shown by the conversion of 21 to 23 in
Scheme 5. This process required that MeNO2 be used as
the solvent24 since reactions in CH2Cl2 led to the formation
of dienyl sulfide 24 from the deprotonation of thiocarbe-
nium ion 22. The more polar solvent allows for nucleo-
philic addition to be competitive with proton transfer,
presumably by stabilizing the silyl-substituted carboca-
tion intermediate that forms during the carbonÀcarbon
bond forming step. The trans-relationship between the two
alkenyl groups in the product can be attributed to the
Several additional allylsilane substrates were prepared
to probe the transition state of these reactions. The results
are shown in Table 1. Cyclizations of vinyl sulfides that
contain (Z)-allylsilane or trisubstituted allylsilane nucleo-
philes (entries 1 and 2) proceeded with much lower diaster-
eocontrol than the cyclization of 21. Incorporating a
branched alkyl group into the substrate led to the forma-
tion offour diastereomeric products (entries 3À6), with the
(E)-allylsilane substrates again reacting with higher levels
of stereocontrol than the corresponding (Z)-allylsilane
substrates. Tetrahydrothiophenes are also accessible
through allylsilane additions to thiocarbenium ions, as
(16) (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(b) Bichler, P.; Love, J. A. Top. Organomet. Chem. 2010, 31, 39.
(17) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36,
4133.
(18) Please see the Supporting Information for details regarding
substrate syntheses.
€
(19) Hoppe, D.; Hanko, R.; Bronneke, A.; Lichtenberg, F.; van
€
Hulsen, E. Chem. Ber. 1985, 118, 2822.
(20) Mitsunobu, O. Synthesis 1981, 1.
(21) Kao, H.-L.; Lee, C.-F. Org. Lett. 2011, 13, 5204.
(22) Chechik-Lankin, H.; Marek, I. Org. Lett. 2003, 5, 5087.
(23) (a) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293. (b)
Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375.
(24) CAUTION! The flash point of MeNO2 is 35 to 44 °C.
1722
Org. Lett., Vol. 14, No. 7, 2012

of tetrahydrothiophene 35 proceeds cleanly through
(E)-thiocarbenium ion 40. While we do not currently
understand the origin of the effect, a comparison of 39,
40, and the disfavored intermediate 41 infers the potential
for an attractive interaction between the nucleophile and
the vinyl group of the thiocarbenium ion in 39 that would
not be present in 41.
Table 1. Stereocontrol in Allylsilane Addition Reactionsa
Scheme 6. Origins of Minor Products with Allylsilane Nucleo-
philes
We have demonstrated that stabilized thiocarbenium
ions can be prepared through the oxidation of unsaturated
sulfides with DDQ. The oxidations proceed most quickly
for vinyl sulfides due to their lower oxidation potentials.
The oxidatively generated electrophiles react with ap-
pended nucleophiles to form tetrahydrothiopyrans and
tetrahydrothiophenes. In most cases these transformations
proceed with good levels of stereocontrol through transi-
tion states that mirror those of the corresponding oxygen
analogs, although (Z)-allylsilanes react with poor stereo-
control for the formation of six-membered rings. Enol
carbamates were shown to be very effective nucleophiles
for the preparation of highly substituted heterocycles with
excellent stereocontrol.
a Representative procedure: DDQ (1.05 equiv) was added to a
solution of the vinyl sulfide in MeNO2 (∼0.1 M) at 0 °C. The reaction
was stirred for 5 min and then purified by flash chromatography. b Yield
refers to the mixture of isomeric products. c Determined by NOESY
experiments and coupling constants in 1H NMR spectra. d See text for
details.
shown in entry 7 where the (Z)-allylsilane substrate pro-
vides the product with good stereocontrol. The facility
of the unusual 5-endo cyclization can be attributed to
thelongercarbonÀsulfurbondsincomparisontocarbonÀ
oxygen bonds. The origin of the striking differences be-
tween the selectivities of the (E)- and (Z)-allylsilanes is
illustrated in Scheme 6. The most abundant minor product
in the cyclization of substrates 28 and 30 is 36. This
compound most likely arises through transition state 37,
in which the alkyl group occupies a pseudoaxial orienta-
tion. This is reasonable based on the diminished energetic
penalty for axial substituents in sulfur-containing hetero-
cycles in comparison to oxygen-containing heterocycles.25
The most abundant byproduct in the cyclizations of 32 and
33, however, is 38. This arises from cyclization through
(Z)-thiocarbenium ion 39. We note that the formation
Acknowledgment. We thank the National Institutes of
Health (GM062924) for generous support of this work.
Supporting Information Available. Synthetic schemes
for substrate syntheses, experimental procedures for cy-
clization reactions, and characterization data for all new
compounds. This information is available free of charge
via the Internet at http://pubs.acs.org.
(25) Eliel, E. L. Acc. Chem. Res. 1970, 3, 1.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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