Tri- and tetrasubstituted functionalized vinyl sulfides by radical allylation

Article abstract of DOI:10.1021/ol403103u

2-Fluoropyridinyl-6-oxy- precursors derived from phenyl vinyl sulfide react with radicals generated from xanthates via an addition-elimination process to furnish the corresponding vinyl sulfides in good yields. This convergent method is operationally simp

Full text of DOI:10.1021/ol403103u

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6250–6253
Tri- and Tetrasubstituted Functionalized
Vinyl Sulfides by Radical Allylation
ꢀ
Laurent Debien, Marie-Gabrielle Braun, Beatrice Quiclet-Sire, and Samir Z. Zard*
ꢁ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique,
91128 Palaiseau Cedex, France
Zard@poly.polytechnique.fr
Received October 29, 2013
ABSTRACT
2-Fluoropyridinyl-6-oxy- precursors derived from phenyl vinyl sulfide react with radicals generated from xanthates via an additionꢀelimination
process to furnish the corresponding vinyl sulfides in good yields. This convergent method is operationally simple and enables a straightforward
synthesis of the difficult to access tetrasubstituted vinyl sulfides. Vinyl sulfides were used as more robust enol ether surrogates in highly
stereoselective reactions with N-acylium cations leading to nitrogen-containing polycyclic structures.
Vinyl sulfides are versatile building blocks that have
been widely used asmore robust surrogates for enol ethers1
in reactions involving thionium ions,2 in cycloadditions,3
or in carbometalation processes.4 This structural motif has
also found applications in material science5 and is featured
in some biologically active compounds.6 Not unexpect-
edly, vinyl sulfides have attracted continuing interest from
the synthetic community, and a variety of methods have
been reported for their preparation. The main approaches
include the free radical,7 base,8 or metal9 mediated hydro-
thiolation of alkynes, the cross-coupling10 of thiols with
functionalized vinylic reagents, and the reaction of unsa-
turated compounds with electrophilic sulfur reagents.11
(1) See, for example: (a) Garst, M. E.; Spencer, T. A. J. Am. Chem.
Soc. 1973, 95, 250. (b) Sasmal, P. K.; Maier, M. E. Org. Lett. 2002, 4,
1271. (c) Sasmal, P. K.; Maier, M. E. J. Org. Chem. 2003, 68, 824. For
applications in total synthesis, see: (d) Bratz, M.; Bullock, W. H.;
Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958. (e)
Paquette, L. A.; Sun, L.-Q.; Watson, T. J. N.; Friedrich, D.; Freeman,
B. T. J. Org. Chem. 1997, 62, 8155.
(2) For synthetic applications, see: (a) Schneebeli, S.; Kamenestka,
M.; Foss, F.; Vazquez, H.; Skouta, R.; Hybertsen, M.; Venkataraman,
L.; Breslow, R. Org. Lett. 2010, 12, 4114. (b) Cui, Y.; Floreancig, P. E.
Org. Lett. 2012, 14, 1720. (c) Trost, B. M.; Lavoie, A. C. J. Am. Chem.
Soc. 1983, 105, 5075.
(3) For selected examples, see: (a) Pearson, W. H.; Lee, I. Y.; Mi, Y.;
Stoy, P. J. Org. Chem. 2004, 69, 9109. (b) Kouznetsov, V. V. Tetrahedron
2009, 65, 2721. (c) Shaikh, A. K.; Cobb, A. J. A.; Varvounis, G. Org.
Lett. 2012, 14, 584. (d) Dittami, J. P.; Nie, X. Y.; Nie, H.; Ramanathan,
H.; Buntel, T.; Rigatti, S. J. Org. Chem. 1992, 57, 1151.
(4) (a) Krief, A.; Kenda, B.; Remacle, B. Tetrahedron Lett. 1995, 36,
7917. (b) Cohen, T.; Sherbine, J. P.; Mendelson, S. A.; Myers, M.
Tetrahedron Lett. 1985, 26, 2965. (c) Yamato, S.-y.; Yamamura, G.-H.;
Komatsu, M.; Arai, M.; Fukuyama, T.; Ryu, I. Org. Lett. 2005, 7, 2489.
(d) Trost, B. M.; Tanigawa, Y. J. Am. Chem. Soc. 1979, 101, 4743.
(5) (a) Abe, A. Macromolecules 1980, 13, 546. (b) Ahmed, E.; Kim,
F. S.; Xin, H.; Jeneke, S. A. Macromolecules 2009, 42, 8615. (c) Hoyle,
E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49, 1540.
(7) See, for example: (a) Ichinose, Y.; Wakamatsu, K.; Nozaki, K.;
Birbaum, J.-L. Chem. Lett. 1987, 1647. (b) Benati, L.; Capella, L.;
Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1995,
1035. (c) Lo Conte, M.; Pacifico, S.; Chambery, A.; Marra, A.; Dondoni,
A. J. Org. Chem. 2010, 75, 4644.
(8) For recent examples, see: (a) Waters, M. S.; Cowen, J. A.;
McWilliams, J. C.; Maligres, P. E.; Askin, D. Tetrahedron Lett. 2000,
41, 141. (b) Yu, A. H.; Qiu, R. H.; Tan, N. Y.; Peng, L. F.; Xu, X. H.
Chin. Chem. Lett. 2011, 22, 687. (c) Kondoh, A.; Takami, K.; Yorimitsu,
H.; Oshima, K. J. Org. Chem. 2005, 70, 6468.
(9) Many metals can trigger this transformation; for a review, see:
(a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
ꢀ
See, also: (b) Di Giussepe, A.; Castarlenas, R.; Perez-Torrente, J. J.;
Crucianelli, M.; Polo, V.; Sancho, R.; Lahoz, F. J.; Oro, L. A. J. Am.
Chem. Soc. 2012, 134, 8171.
(10) For a recent review, see: (a) Beletskaya, I. P.; Ananikov, V. P.
Chem. Rev. 2011, 111, 1596. See, also: (b) Lin, Y.-Y.; Wang, Y.-J.; Lin,
C.-H.; Cheng, J.-H.; Lee, C.-F. J. Org. Chem. 2012, 77, 6100. (c) Kao,
H. L.; Lee, C. F. Org. Lett. 2011, 13, 5204.
(6) For selected examples, see: (a) Dvorak, C. A.; Schmitz, W. D.;
Poon, D. J.; Pryde, D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I.
ꢀ
ꢀ
Angew. Chem., Int. Ed. 2000, 39, 1664. (b) Szilagyi, A.; Fenyvesi, F.;
ꢀ
ꢀ
ꢀ
ꢀ
Mayercsik, O.; Pelyvas, I. S.; Bacskay, I.; Feher, P.; Varadi, J.;
ꢀ
Vecsernyes, M.; Herczegh, P. J. Med. Chem. 2006, 49, 5626. (c) Sader,
H. S.; Johnson, D. M.; Jones, R. N. Antimicrob. Agents Chemother.
2004, 48, 53.
r
10.1021/ol403103u
Published on Web 11/23/2013
2013 American Chemical Society

Paradoxically, despite the plethora of transformations avail-
able,12 only a handful of methods allow for the construc-
tion of tetrasubstituted vinyl sulfides.13 Furthermore, these
methods are generally limited in scope by the use of electro-
philic sulfur reagents and/or strong bases and nucleophiles.
Recently, we reported a mild and stereoselective synth-
esis of the least stable isomeric (Z)-alkenes relying on the
radical allylation of xanthates 3 with phenyl vinyl sulfones
1 (Scheme 1, n = 2).14 In the course of this study we
observed in one experiment that the corresponding phenyl
vinyl sulfide 2a was also a competent substrate in this
transformation (Scheme 1, n = 0).
Scheme 1. Experiments at the Origin of Our Study
Figure 1. Scope of the radical allylation for the synthesis of
trisubstituted vinyl sulfides. Reaction conditions: olefin 2
(2 equiv), xanthate 3 (1 equiv); lauroyl peroxide was added in
20 mol %/h portions (with respect to the xanthate). 5h was
obtained as a mixture of diastereo- and geometric isomers, but
the Z/E ratio could not be determined by 1H NMR analysis. For
5j, lauroyl peroxide was added in 30 mol %/h portions.
Recognizing that our radical allylation could provide
access to tetrasubstituted vinyl sulfides while at the same
time overcoming the regioselectivity and functional group
tolerance limitations encountered with established methods,15
we decided to study the scope of the reaction. Our results
are reported herein.
We believe that the preferential formation of the (Z)-
isomer is due to the relative smallness of the SPh substi-
tuent compared to standard alkyl groups.17 As suggested
by the remarkably high yielding formation of vinyl sulfides
5dand 5hand by our recentstudyon polareffects inradical
fragmentations,18 theeliminationstepissignificantlyfaster
in the case of vinyl sulfides than in the case of vinyl
sulfones.19 This comparatively rapid elimination may also
account for the modest selectivities observed by preventing
the intermediate adduct radical from completely adopting
its most stable conformation prior to fragmentation.
The robustness of this radical allylation is further de-
monstrated by the gram scale synthesis of vinyl sulfides 5a
and 5f (Scheme 2). Indeed, the procedure routinely used on
the 0.5ꢀ1.0 mmol scale delivered 5a and 5f in nearly
identical yields when applied on the 5 and 8 mmol scale
respectively.
We were encouraged by these first results to further
expand this radical additionꢀelimination process to tetra-
substituted thio-enol ethers. Indeed, tetrasubstituted vinyl
sulfides could be assembled in good yield and moderate
(Z)-selectivity as shown by examples displayed in Table 2.
The formation of vinyl sulfides bearing acid sensitive func-
tions such as a masked unsaturated aldehyde 5l or ketal 5n
as well as the tolerance for insaturations (alkenes 5d, 5h,
and 5o, enone 5x, Figures 1 and 2) and base/nucleophile
We first examined the synthesis of trisubstituted vinyl
sulfides by reacting various fluoropyridyl ethers 2, derived
from aldehydes and phenyl vinyl sulfide, with electro- and
nucleophilic radicals (Figure 1).16
The reaction proved general, and in all cases, the tar-
geted trisubstituted vinyl sulfides 5 were obtained in good
yields, albeit with moderate stereoselectivities (Figure 1).
(11) For a recent review, see: Zyk, N. V.; Beloglazkina, E. K.; Belova,
M. A.; Dubiniba, N. S. Russ. Chem. Rev. 2003, 9, 769.
(12) For other approaches, see: (a) Rao, S. A.; Knochel, P. J. Am.
Chem. Soc. 1991, 113, 5735. (b) Comasseto, J. V.; Menezes, P. H.;
Stefani, H. A.; Zeni, G.; Braga, A. L. Tetrahedron 1996, 52, 9687. (c)
Fujimoto, T.; Hotei, Y.; Takeuchi, H.; Tanaka, S.; Ohta, K.; Yamamoto,
I. J. Org. Chem. 1991, 56, 4799. (d) De Lucchi, O.; Modena, G. J. Chem.
Soc., Chem. Commun. 1982, 914.
(13) For such methods, see: (a) Rao, S. A.; Knochel, P. J. Am. Chem.
Soc. 1991, 113, 5735. (b) Dunst, C.; Metzger, A.; Zaburdaeva, E. A.;
Knochel, P. Synthesis 2011, 3453. (c) Masaki, Y.; Sakuma, K.; Kaji, K.
Chem. Lett. 1979, 1235. (d) Debuigne, A.; Gerard, J.; Hevesi, L.
Tetrahedron Lett. 1999, 40, 5943. (e) Gerard, J.; Hevesi, L. Tetrahedron
2004, 60, 367.
(14) Braun, M. G.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc.
2011, 133, 15954.
(15) Despite recent progress, hydrothiolation methods still suffer
from the lack of regioselectivity. Cross-coupling reactions are severely
limited by the poor access to the vinylic partner. Reactions involving
electrophilic sulfur reagents are not compatbile with the presence of
other insaturations in the substrate.
(16) The fluoropyridyl ethers 2 were easily prepared by addition of
the lithium anion derived from phenyl vinyl sulfide to aldehydes or
ketones followed by nucleophilic aromatic substitution of 2,6-difluor-
opyridine. See Supporting Information for details.
(17) Measures of the energies necessary for monosubstituted cyclo-
hexanes to equilibrate between their most stable and their least stable
conformations are reported in the literature; see: Eliel, E. L.; Wilen,
S. H.; Doyle, M. P. Basic Organic Stereochemistry; John Wiley & Sons,
Inc.: New York, NY, 2001; p 443. These “A” values can be considered as an
approximate representation of the steric bulk of a given group. For
(18) Debien, L.; Zard, S. Z. J. Am. Chem. Soc. 2013, 135, 3808.
(19) For instance, no competing 5-exo-trig cyclization of the inter-
mediate adduct radical was observed in the case of 5d and 5h. Further-
more, the reaction of analogs of the olefin used to prepare 5d and 5h,
bearing an electron-withdrawing CF3 or SOPh substituent instead of the
electron-donating SPh group, gave complex mixtures.
instance A(SPh) = 0.8 kcal molꢀ1 < A(Me) = 1.70 kcal molꢀ1
.
3
3
Org. Lett., Vol. 15, No. 24, 2013
6251

Scheme 2. Robustness of the Radical Allylation
sensitive groups such as enones, ketones, esters, phtali-
mides, or succinimides testify to the mildness of this
approach. Such functional groups would typically not be
compatible with previous literature methods.13 Vinyl sul-
fides 5p and 5w were prepared by combining our earlier
results with trifluoromethyl alkenes20 with the present
work. The synthesis of thio-enol ether 5w nicely highlights
the convergence of this route since the xanthate involved
was itself made by an intermolecular addition of the
S-(1-cyano-1-methyl)ethyl xanthate to N-vinylphthalimide
(Figure 2).21 Complex structures may also be efficiently
constructed in one step as shown by the formation of
cortisone derived adduct 5x in 68% isolated yield
(Figure 2). Finally, as mentioned earlier, the process is
easily scalable. Thus, tetrasubstituted vinyl sulfide 5m
could be obtained in 74% isolated yield on the gram scale
(8.0 mmol, 2.3 g isolated).
It is important to note that the radical additionꢀ
elimination is in competition with the Claisen rearrange-
ment of the substrates.22 This sigmatopic rearrangement is
especially effective with 2-fluoropyridyl ethers derived
from tertiary allylic alcohols and occurs even in refluxing
ethyl acetate, as illustrated by the near-quantitative con-
version of 2b into 7 (Scheme 3).
Figure 2. Scope of the radical allylation for the synthesis of
tetrasubstituted vinyl sulfides. Reaction conditions: olefin 2
(2 equiv), xanthate 3 (1 equiv), lauroyl peroxide was added in
20 mol %/h portions (with respect to the xanthate). For 5p, 5s,
5u, 5v, 5w, and 5x, lauroyl peroxide was added in 40 mol %/h
portions.
When the xanthate partner contains an R-carbonyl,
then, the additionꢀfragmentation of the corresponding
radical constitutes a formal synthesis of 1,4-dicarbonyls,24
since vinyl sulfides are known to undergo hydrolysis upon
Normally, the rearrangement of 2-allyloxypyridines re-
quires much higher temperatures and furnishes mixtures of
regioisomers.23 We were fortunate that, in our case, this
Claisen rearrangement was not too fast so as to prevent the
radical process from taking place. In this respect, we found
that shortening the reaction time by adding the peroxide
in larger portions allows producing the desired tetrasub-
stituted thio-enol ethers in comparable yield to the less
substituted analogs (Figure 2 vs 1).
treatment with various Lewis25 or Bronsted26 acids.
€
The products are in fact extremely useful as regioselectively
monoprotected 1,4-dicarbonyls. For example, Cohen27 used
γ-keto vinyl sulfides to prepare exo-cyclopentenes derivatives
and Hua exploited the cyclization of the thionium ions
derived therefrom in the total synthesis of (þ)-pentalene28
and (þ)-hirsutene.29
(20) Debien, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2012, 14, 5118.
(21) Quiclet-Sire, B.; Revol, G.; Zard, S. Z. Tetrahedron 2010, 66,
6656.
(25) (a) Corey, E. J.; Shulman, J. I. J. Org. Chem. 1970, 35, 777. (b)
Mukaiyama, T.; Kamio, K.; Kobayashi, S.; Takei, H. Bull. Chem. Soc.
Jpn. 1972, 45, 3723.
(22) Charrier, N.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc.
2008, 130, 8898.
(23) Only the rearrangement of crotyl substituted pyridines has been
studied: (a) Dinan, F. J.; Tieckelmann, H. J. Org. Chem. 1964, 29, 892.
(b) Brooke, G. M.; Matthews, R. S.; Robson, N. S. J. Chem. Soc., Perkin
Trans. 1 1980, 102.
(24) We previsoulsy reported that 1,4-dicarbonyls can be synthesized
by radical allylation with enol ethers followed by hydrolysis; see: Debien,
L.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2011, 13, 5676.
(26) (a) Sato, T.; Okazaki, H.; Otera, J.; Nozaki, H. J. Am. Chem.
Soc. 1988, 110, 5209. (b) Choppin, S.; Gros, P.; Fort, Y. Tetrahedron
1999, 55, 9261.
(27) (a) Cohen, T.; Zhang, B.; Cherkauskas, J. P. Tetrahedron 1994,
50, 11569. (b) Deng, K.; Bensari, A.; Cohen, T. J. Am. Chem. Soc. 2002,
124, 12106. (c) Deng, K.; Bensari-Bouguerra, A.; Whetstone, J.; Cohen,
T. J. Org. Chem. 2006, 71, 2360. (d) Chen, W.; Zhao, X.; Lu, L.; Cohen,
T. Org. Lett. 2006, 8, 2087.
(28) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835.
6252
Org. Lett., Vol. 15, No. 24, 2013

Table 2. Cyclization of Vinyl Sulfides on N-Acylium Ionsa
Scheme 3. Claisen Rearrangement of Precursor 2b
substrate ZIE
time
yield 9
dr 9
yield 10
dr 10
8b 95:5 12 h
(cis)-9a: 62% g95:5 10a: ꢀ
ꢀ
(Z)-8d g95:5 2 days (cis)-9b: ꢀ
(E)-8d e95:5 2 days (trans)-9b:
70%
ꢀ
(cis)-10b: 61% 95:5
g95:5 (trans)-10b: ꢀ
ꢀ
Table 1. Chemoselective Reduction of Succinimide and
Phthalimide Containing Vinyl Sulfides
8e
8eb
ꢀ
7 days 9c: 61%
10 min 9c: 20%
ꢀ
ꢀ
10c: ꢀ
ꢀ
ꢀ
ꢀ
10c: 48%
a Compounds 8 were dissolved in pure formic acid and stirred in an
open to air flask. b Reaction ran in DCM with 4 A molecular sieves.
However, hemiaminals 8b, 8d, and 8e respectively derived
from phthalimides 5f, 5p, and 5s smoothly underwent
cyclization to furnish tricyclic ketones 9 and/or vinyl
sulfides 10 (Table 2). These reactions proved efficient for
both tri- and tetrasubstituted vinyl sulfides, even those
bearing a bulky or an electron withdrawing CF3 group.
They also turned out to be highly stereoselective, as shown
by examples (cis)-9a, (cis)-10b, and (trans)-9b. Amusingly,
trifluoromethyl alkene (Z)-8d selectively gave vinyl sulfide
(cis)-10b32 while (E)-8d furnished ketone (trans)-9b arising
from hydrolysis of the corresponding (trans)-thio-enol
ether. In the case of hemiaminal 8e we also found that
prolonged exposure to formic acid provided ketone 9c
while a short treatment with formic acid in the presence
of 4 A molecular sieves gave vinyl sulfide 10c as the major
product.
In conclusion, we have developed a flexible, mild, and
operationally simple synthesis of regio-defined tri- and
tetrasubstituted vinyl sulfides. The ability to rapidly bring
together various functional groups that could then be
made to react with the thio-enol ether is illustrated by
the assembly of polycyclic nitrogen heterocycles through
cyclization with in situ generated N-acycilium species.
Numerous other variations and modifications can be readily
conceived and hopefully eventually implemented.
substrate
R1
R2 substituent
yield
ZIEa
5d
5fb
5g
5pc
5s
cyclohex-3-en
dihydrocinnamyl
cyclopropyl
CF3
H
H
H
succinimide 8a: 95% 60:40
phthalimide 8b: 90% 95:5
succinimide 8c: 80% 65:35
Me phthalimide 8d: 93% 80:20d
phthalimide 8e: 96%
cycloheptyl
ꢀ
a Z/E ratios of 5 and 8 were identical. b 5f was obtained in a Z/E =
95:5 ratio by recrystallization of the Z/E = 65:35 mixture originally
obtained. c The reaction was run in a 3:1 mixture of MeOH/DCM. d The
(Z) and (E) isomers were separated by silica gel column chromatography.
In contrast, and to the best of our knowledge, vinyl
sulfideshave neverbeen used asπ-nucleophilesinreactions
with the well-known and strongly electrophilic N-acylium
cations.30 Since our technology allows the ready assembly
of the required substrates necessary for such transforma-
tions, we examined briefly this interesting synthetic exten-
sion. Thus, hemiaminals 8aꢀe were prepared in good yield
by reduction with NaBH4 according to literature proce-
dures (Table 1).31
We first subjected succinimide derived hemiaminals 8a
and 8c to formic acid but only obtained complex mixtures.
(29) Hua, D. H.; Venkataraman, S.; Ostrander, R. H.; Sinai-Zingde,
G.; McCann, P. J.; Coulter, M. J.; Xu, M. R. J. Org. Chem. 1988, 53, 507.
(30) For reactions involving Lewis acids, see: (a) Komeyama, K.;
Igawa, R.; Morimoto, T.; Takaki, K. Chem. Lett. 2009, 38, 724. (b)
Mooiweer, H. H.; Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N.
Tetrahedron Lett. 1987, 28, 3285. (c) Pin, F.; Comesse, S.; Garrigues, B.;
Acknowledgment. We thank the ANR for financial
support. This manuscript is dedicated with respect and
admiration to Professor Theodore Cohen (University of
Pittsburgh).
Marchalin, S.; Daıch, A. J. Org. Chem. 2007, 72, 1181. For reactions
involving Bronsted acids, see: (d) Speckamp, W. N.; Hiemstra, H.
¨
€
Tetrahedron 1985, 41, 4367. (e) Shoemaker, H. E.; Dijkink, J.; Speckamp,
W. N. Tetrahedron 1977, 34, 163. (f) Chiurato, M.; Routier, S.; Troin, Y.;
Guillaumet, G. Eur. J. Org. Chem. 2009, 3011.
(31) (a) Hucher, N.; Decroix, B.; Daıch, A. J. Org. Chem. 2001, 66,
¨
4695. (b) Fardis, M.; Jin, H.; Jabri, S.; Cai, R. Z.; Mish, M.; Tsiang, M.;
Supporting Information Available. Experimental proce-
dures and characterization spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Kim, C. H. Biorg. Med. Chem. Lett. 2006, 16, 4031.
(32) (cis)-10b proved remarkably robust and remained intact upon
exposure to strong acids such as H2SO4 or HCl.
The authors declare no competing financial interest.
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