Rapid assembly of polycyclic structures via sigmatropic rearrangement of S-propargyl xanthates

Article abstract of DOI:10.3987/COM-12-S(N)98

Upon heating in chlorobenzene, propargyl xanthates yield the corresponding 4,5-bis(alkylidene)-1,3-dithiolan-2-ones which are trapped by unactivated olefins in an intramolecular Diels-Alder cycloaddition yielding interesting polycyclic structures.

Full text of DOI:10.3987/COM-12-S(N)98

HETEROCYCLES, Vol. 86, No. 2, 2012
965
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 965 - 971. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 12th July, 2012, Accepted, 24th August, 2012, Published online, 28th August, 2012
DOI: 10.3987/COM-12-S(N)98
RAPID
ASSEMBLY
OF
POLYCYCLIC
STRUCTURES
VIA
SIGMATROPIC REARRANGEMENT OF S-PROPARGYL XANTHATES
Ryan M. Harrington, David Wright, and Samir Z. Zard*
Department of Chemistry, Ecole Polytechnique, CNRS UMR 7652, 91128
Palaiseau, France. zard@poly.polytechnique.fr
Abstract – Upon heating in chlorobenzene, propargyl xanthates yield the
corresponding 4,5-bis(alkylidene)-1,3-dithiolan-2-ones which are trapped by
unactivated olefins in an intramolecular Diels-Alder cycloaddition yielding
interesting polycyclic structures.
We have found over the years that radicals derived from xanthates provide a rich and varied chemistry for
the synthesis of a wide array of molecular architectures.1 In the course of our studies we discovered an
unusual non-radical chemistry of S-propargyl xanthates 1. We observed that, upon heating, S-propargyl
xanthates undergo a [3,3]-sigmatropic rearrangement to give the corresponding allene 2, which exists in
equilibrium with a novel betaine of structure 3 (Scheme 1).2 The equilibrium is almost completely in
favor of allene 2, and evidence for the existence of betaine 3 is indirect and based on chemical
transformations that cannot be rationalized otherwise.3 These transformations hinge for most part on
exploiting the allylic anion character of this species (only two canonical structures 3a and 3b are drawn
for clarity).
R"
R"
OR"
S
O"R
S
O
O
S
S
C
[3,3]-!
S
S
S
S
R
R'
R
R'
R'
R
R'
R
3b
1
3a
2
Scheme 1. An unusual betaine derived from S-propargyl xanthates
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
This paper is dedicated with respect and admiration to Prof. Ei-ichi Negishi, a pioneer in organometallic
chemistry.

966
HETEROCYCLES, Vol. 86, No. 2, 2012
One such process concerns S-propargyl xanthates of general structure 4, which are converted into
4,5-bis(alkylidene)-1,3-dithiolan-2-ones 6 via the corresponding betaines 5 (Scheme 2).4 These highly
reactive rigid cisoid dienes, and especially the parent compound (6a, R = H), readily dimerize into
derivatives 7, but can be captured by strongly electrophilic dienophiles as illustrated by cycloadditions
with dimethyl acetylenedicarboxylate or naphthoquinone to furnish cycloadducts 8 and 9. The latter is
easily oxidized by air to give brown-colored tetracyclic derivative 10 in high overall yield (Scheme 2).4
This method for producing 4,5-bis(alkylidene)-1,3-dithiolan-2-ones 6 was later applied by Gorgues et al.
for functionalizing fullerenes.5
R"
OR"
S
O"R
S
O
O
S
S
C
[3,3]-!
S
S
PhCOO
R
S
S
-PhCOOR"
R'
PhCOO
R'
R'
PhCOO
R'
R
4
R
5
6
R
OR"
S
O
O
S
S
S
S
S
PhCl
PhCOO
R
R'
6a, R = H
6b, R = Me
O
S
reflux
R
R
R
S
7
R
4a, R = H
4b, R = Me
R
naphthoquinone
MeO2C
Me
CO2Me
R'
O
Me
O
Me
S
S
MeO2C
Et3N, air
S
S
S
O
O
O
isopropanol
reflux
S
MeO2C
O
Me
O
Me
Me
9, 80% (from 4b)
8a, R = H, 100%
8b, R = Me, 80%
Scheme 2. Generation and capture of rigid cisoid dienes
In this communication, we report our preliminary results on the generation and capture of the
4,5-bis(alkylidene)-1,3-dithiolan-2-ones with unactivated alkenes. Our attempts involving
6
intermolecular cycloadditions were unfortunately met with failure. Even starting with xanthate 4a, which
gives the most reactive parent diene 6a, and using neat refluxing allyl acetate or propargyl acetate as the
reaction medium did not result in the isolation of any discernable cycloaddition products 10 (Scheme 3).
Clearly, the desired intermolecular cycloaddition with ordinary, unactivated alkenes was unable to
compete with the self-reaction of the diene.
OR"
S
OAc
OAc
or
S
S
S
OAc
O
PhCOO
reflux
4
10
Scheme 3. Failed intermolecular cycloadditions

HETEROCYCLES, Vol. 86, No. 2, 2012
967
More promising were the intramolecular variants. The required precursors were readily prepared by
exploiting the possibility of generating the alkynyllithium from propargyl chloride and capturing it with
various appropriately substituted aldehydes. A first series of diene precursors 13a-j was prepared from
modified salicylaldehydes 11a-j by a simple two-step sequence, as pictured in Scheme 4 (the yields given
are overall yields for the two steps). While it is possible to isolate the intermediate chlorides 12, these
substances readily decompose and it is best to transform them directly without purification into the
corresponding propargyl xanthates 13, which are much more bench stable.
R
R
R'
R'
1. n-BuLi, propargyl chloride,
THF, - 78 °C, then PhCOCl
n
n
O
O
O
12, X = Cl
13, X = SCSOEt
X
H
2. EtOCSSK, acetone
OBz
Cl
11
Me
O
O
O
Cl
O
SCSOEt
SCSOEt
13c, 70%
SCSOEt
SCSOEt
13b, 67%
OBz
13a, 62%
OBz
OBz
13d, 61%
OBz
Br
Me
Ph
O
O
O
O
SCSOEt
13e, 62%
SCSOEt
13g, 72%
SCSOEt
13h, 63%
SCSOEt
OBz
13f, 82%
OBz
OBz
OBz
O
O
SCSOEt
SCSOEt
13i, 69%
OBz
13j, 63%
OBz
Scheme 4. Synthesis of S-propargyl xanthate precursors
Upon heating in refluxing chlorobenzene, S-propargyl xanthates 13a-j underwent the aforementioned
rearrangement to yield intermediary 4,5-bis(alkylidene)-1,3-dithiolan-2-ones 14, which, except for 13j,
were trapped by Diels-Alder cycloaddition to yield new 1,3-dithiol-2-ones 15a-i containing carbon
skeletons with the formation of three new carbocycles (Scheme 5). As expected for a concerted
suprafacial cycloaddition process, the two isomeric chlorides 13c and 13d furnished the corresponding
epimeric cycloadducts 15c and 15d. In the case of S-propargyl xanthates 13b, a slight loss of
stereochemical integrity was observed, perhaps due to partial isomerization of the butenyl group by
adventitious acid. Adduct 15g containing a tertiary bromide was only moderately stable under the reaction
conditions and tended to undergo loss of hydrogen bromide to give olefinic side-products. The acetylenic
precursor 13i furnished diene adduct 15i, which spontaneously aromatized upon standing in air. Partial

968
HETEROCYCLES, Vol. 86, No. 2, 2012
aromatization also occurred during the reaction, causing some variability in the yield. Finally, we were
disappointed to find that 13j did not lead to the seven-membered ring cycloadduct 15j. Recourse to high
dilution or to slow addition of S-propargyl xanthate 13j to refluxing chlorobenzene did not modify the
outcome. This reflected the difficult competition between the desired intramolecular cycloaddition and
the unwanted dimerization of intermediate diene 14. The importance of pre-organization in speeding up
intramolecular Diels-Alder reactions has been noted very recently by Krenske and Houk.6 The longer
tether in 13j is clearly too floppy to ensure the necessary favorable pre-organization speeding access to
the transition state.
R
R
R'
R'
O
n
n
n
S
R
O
O
PhCl
R'
S
OEt
reflux
S
OBz
S
14
15
13
S
O
S
O
O
O
H
O
H
O
H
H
H
H
H
H
Cl
Cl
15d, 78%
Me
15c, 75%
(d.r. 3:5)
15a, 85%
(d.r. 1:1)
15b, 69%
(d.r. 7:6.4:1.8:1)
S
S
S
S
(d.r. 1:3)
S
S
S
S
O
O
O
O
O
O
H
O
O
H
H
Br
H
H
Me
H
Ph
H
15e, 75%
(d.r. >95:5)
15h, 71%
(d.r. >95:5)
15f, 76%
(d.r. 1:1.6)
15g, 62%
(d.r. undetermined)
S
S
S
S
S
S
S
S
O
O
O
O
O
O
15i, 43%
15j, 0%
S
S
S
S
O
O
Scheme 5. Formation of polycyclic structures
Although the salicylaldehyde scaffold was convenient for the purposes of exploring this chemistry on
unactivated olefins, this protocol can be applied in principle to any system in which the propargyl
xanthate is appropriately spaced from the dienophile. Indeed, the approach is not limited to scaffolds
containing a rigid aryl backbone at all, but may be applied to systems containing varied aliphatic and
hetero-aliphatic skeletons. Thus, propargyl xanthates 16a-e shown in Scheme 6 react under similar
conditions to yield tetrahydrofuran, tetrahydropyran, pyrrolidine, and piperidine heterocyclic structures
17a-e in good yields.

HETEROCYCLES, Vol. 86, No. 2, 2012
969
S
S
Ts
H
Ph
O
N
EtO
S
EtO
S
H
H
Ph
PhCl
PhCl
H
reflux
reflux
O
N
S
S
OBz
Ts OBz
S
S
17a, 80%
(d.r. 3:5)
16a
16b
17b, 85%
(d.r. not determined)
O
O
S
S
Ph
O
O
TMS
EtO
S
S
16d
Ph
OEt
H
Ph
PhCl
PhCl
TMS
H
O
O
reflux
reflux
S
S
OBz
OBz
S
S
17d, 48%
16c
17c, 85%
(d.r. 1:3.5)
O
O
Boc
S
Ph
N
EtO
S
H
PhCl
H
N
reflux
Boc
S
17e, 80%
16e
OBz
S
O
Scheme 6. Further syntheses of polycyclic structures
The Diels-Alder reaction is arguably one of the most powerful reactions for organic synthesis.7 The
observation that S-propargyl xanthates, of general structure 4, represent latent, reactive cisoid dienes
opens therefore numerous possibilities for the synthesis of useful compounds. For instance, the examples
of Diels-Alder products displayed in Scheme 4 have chromene-like structures.8 Chromene subunits are
present in several classes of bioactive compounds and are found in numerous plants and edible
vegetables.9 Synthetic analogues are known to be pharmacologically important, having anti-fungal and
anti-microbial activities.10 Furthermore, the 1,3-dithiolen-2-one motifs in the cycloadducts are interesting
in their own right, as they furnish tetrathiafulvenes upon reductive coupling with phosphines or
phosphites.11 Tetrathiafulvenes are known for their charge transfer properties and have found applications
in non-linear optics and as photovoltaics.12 A variety of derivatives are also used as redox switches and
near-IR dyes.13 Furthermore, base induced cleavage yields a 1,2-dithiol moiety, a key bidentate ligand in
many biological molybdenum and tungsten complexes such as the molybdopterin cofactor.14 Many
transition metals may be sequestered by the dithiol ligand and such complexes are being studied for
applications in photographic, lithographic, thermal imaging, and liquid crystal technologies.15
ACKNOWLEDGEMENTS
One of us (R. M. H.) thanks Ecole Polytechnique for a scholarship.

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HETEROCYCLES, Vol. 86, No. 2, 2012
REFERENCES AND NOTES
1. For reviews of the xanthate transfer, see: S. Z. Zard, Angew. Chem., Int. Ed. Engl., 1997, 36, 672; B.
Quiclet-Sire and S. Z. Zard, Top. Cur. Chem., 2006, 264, 201; B. Quiclet-Sire and S. Z. Zard, Chem.
Eur. J., 2006, 12, 6002; S. Z. Zard, Aust. J. Chem., 2006, 59, 663; B. Quiclet-Sire and S. Z. Zard,
Pure Appl. Chem., 2011, 83, 519; B. Quiclet-Sire and S. Z. Zard, Chimia, 2012, 66, 404.
2. J. Boivin, C. Tailhan, and S. Z. Zard, J. Am. Chem. Soc., 1991, 113, 5874.
3. J. Boivin, E. B. Henriet, C. Tailhan, and S. Z. Zard, Tetrahedron Lett., 1993, 34, 2763; J. Boivin, E.
B. Henriet, and S. Z. Zard, J. Am. Chem. Soc., 1994, 116, 9739; J. Boivin, E. B. Henriet, and S. Z.
Zard, Tetrahedron Lett., 1995, 36, 5171; M. Tromeur-Fauré and S. Z. Zard, Tetrahedron Lett., 1998,
39, 7301; M. Tromeur-Fauré and S. Z. Zard, Tetrahedron Lett., 1999, 40, 1305.
4. J. Boivin, C. Tailhan, and S. Z. Zard, Tetrahedron Lett., 1992, 33, 7853.
5. C. Coulle, M. Cariou, M. Bainville, A. Gorgues, P. Hudhomme, J. Orduna, and J. Garin,
Tetrahedron Lett., 1997, 38, 81.
6. E. H. Krenske, E. W. Perry, S. V. Jerome, T. J. Maimone, P. S. Baran, and K. N. Houk, Org. Lett.,
2012, 14, 3016.
7. For reviews on the Diels-Alder reaction, see: K. Takao, R. Munakata, and K. Tadano, Chem. Rev.,
2005, 105, 4779; K. C. Nicolaou, S. A. Snyder, T. Montagnon, and G. Vassilikogiannakis, Angew.
Chem. Int. Ed., 2002, 41, 1668.
8. For alternative methods towards similar substituted chromenes, see: K. A. Korthals and W. D. Wulff,
J. Am. Chem. Soc., 2008, 130, 2898.
9. M. Curini, G. Cravotto, F. Epifano, and G. Giannone, Curr. Med. Chem., 2006, 13, 199.
10. For recent examples of chromene containing biologically interesting structures, see: F. Borges, F.
Roleira, N. Milhazes, L. Santana, and E. Uriarte, Curr. Med. Chem., 2005, 12, 887; G. A. Kraus and
I. Kim, J. Org. Chem., 2003, 68, 4517; J. G. Tangmouo, A. L. Meli, J. Komguem, V. Kuete, F. N.
Ngounou, D. Lontsi, V. P. Beng, M. I. Choudhary, and B. L. Sondengam, Tetrahedron Lett., 2006,
47, 3067; F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, S. Carradori, A. Granese, D.
Rivanera, D. Lilli, M. M. Scaltrito, and M. I. Brenciaglia, Eur. J. Med. Chem., 2006, 41, 208.
11. N. Crivillers, N. S. Oxtoby, M. Mas-Torrent, J. Veciana, and C. Rovira, Synthesis, 2007, 1621.
12. J.-Y. Cho, S. Barlow, S. R. Marder, J. Fu, L. A. Padilha, E. W. van Stryland, D. J. Hagan, and M.
Bishop, Optics Lett., 2007, 32, 671; M. R. Bryce, J. Mater. Chem., 1995, 5, 1481.
13. K. L. Marshall and S. D. Jacobs, Mol. Cryst. Liq. Cryst., 1988, 159, 181; K. L. Marshall, G. Painter,
K. Lotito, A. G. Noto, and P. Chang, Lab. Laser Energ. Rev., 2006, 106, 112; K. L. Marshall, B.
Schudel, and I. A. Lippa, Proc. Soc. Photo. Inst. Eng., 2003, 5213, 201; R. N. Lyubovskaya, Russ.
Chem. Rev., 1983, 52, 736.

HETEROCYCLES, Vol. 86, No. 2, 2012
971
14. C. Kisker, H. Schindelin, D. Baas, J. Retey, R. U. Meckenstock, and P. M. H. Kroneck, FEMS
Microbio. Rev., 1999, 22, 503.
15. U. T. Mueller-Westhoff, A. Nazzal, R. J. Cox, and A. M. Giroud, Mol. Cryst. Liq. Cryst. Lett., 1980,
56, 249; K. Ohta, H. Takagi, I. Muroki, K. Yamamoto, T. Matsuzaki, T. Inabe, and Y. Maruyama,
Mol. Cryst. Liq. Cryst., 1987, 147, 15.