Phosphine-catalyzed construction of sulfur heterocycles

Article abstract of DOI:10.1021/ol701563e

A simple and efficient method for constructing sulfur heterocycles was developed using a phosphine-catalyzed tandem umpolung addition and intramolecular cyclization of bifunctional sulfur pronucleophiles on arylpropiolates. The reaction offers a promising

Full text of DOI:10.1021/ol701563e

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3925-3927
Phosphine-Catalyzed Construction of
Sulfur Heterocycles
Sandra Gabillet, Delphine Lecercle´, Olivier Loreau, Michael Carboni,
Sophie De´zard, Jean-Marie Gomis, and Fre´de´ric Taran*
CEA, iBiTecS, SerVice de Chimie Bioorganique et de Marquage,
Gif sur YVette F-91191, France
frederic.taran@cea.fr
Received July 3, 2007
ABSTRACT
A simple and efficient method for constructing sulfur heterocycles was developed using a phosphine-catalyzed tandem umpolung addition
and intramolecular cyclization of bifunctional sulfur pronucleophiles on arylpropiolates. The reaction offers a promising route to synthetically
useful as well as biologically active heterocycles under neutral conditions.
Sulfur heterocycles continue to receive widespread attention
due to their potential biological activity and pharmaceutical
significance.1 Despite the wealth of traditional methods, there
is an ongoing search for new, more efficient approaches to
form sulfur heterocycles. Among the new synthetic strategies,
a series of organocatalyzed reactions induced by phosphines
have emerged over the past decade as a powerful approach
to construct oxygen or nitrogen heterocycles. Reactions
employing electron-deficient multiple bond substrates, in
particular, have proven to be very efficient for the straight-
forward construction of numerous heterocycles.2 In these
reactions, the phosphine catalyst proceeds through the forma-
tion of zwiterionic phosphonium intermediate which is able
to react either with electrophiles3 or pronucleophiles4 to gen-
erate umpolung adducts that undergo subsequent cyclization.
In this context, we recently described a phosphine-cata-
lyzed tandem reaction for dioxygenated heterocycles con-
struction.5 The reaction uses diols or catechols that undergo
R-O-addition and transesterification on arylpropiolates, both
steps being catalyzed by n-Bu3P. This finding stimulated us
to explore the reaction with other bifunctional pronucleo-
philes. One of the crucial points for the success of such
approach is chemoselectivity of the first step of the process
(e.g., the R-addition step) for only one of the two nucleo-
philes. For this purpose, we were interested on using
bifunctional sulfur nucleophiles to develop a new and simple
procedure for sulfur heterocycles preparation (Scheme 1).
The strong nucleophilic character of the thiol function should
facilitate a chemoselective n-Bu3P-catalyzed R-S-addition of
the bifunctional nucleophile on the alkyne. The resulting
umpolung adduct should then undergo cyclization due to the
(3) (a) Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org.
Lett. 2005, 7, 1387-1390. (b) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031-
5041. (c) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005,
7, 2977-2980. (d) Zhu, X.-F.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716-4717. (e) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8,
5417-5419.
(1) (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. ComprehensiVe
Medicinal Chemistry; Pergamon Press: Oxford 1990; Vol. 2, Chapter 7.1.
(b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004,
104, 2239-2258.
(2) For reviews on phosphine-catalyzed reactions employing electron-
deficient alkynes or allenes, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535-544. (b) Methot, J. L.; Roush, W. R. AdV. Synth. Catal.
2004, 346, 1035-1050. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005,
77, 1985-1990. (d) Valentine, D. H.; Hillhouse, J. H. Synthesis 2003, 3,
317-334.
(4) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9260-9266. (b) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W.
J. Org. Chem. 2002, 67, 4595-4598. (c) Kuroda, H.; Tomita, I.; Endo, T.
Org. Lett. 2003, 5, 129-131. (d) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677-
4679. (e) Yavari, I.; Souri, S.; Sirouspour, M.; Djahaniani, H. Synthesis
2006, 19, 3243-3249.
(5) Gabillet, S.; Lecercle´, D.; Loreau, O.; De´zard, S.; Gomis, J.-M.; Taran,
F. Synthesis 2007, 4, 515-522.
10.1021/ol701563e CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/06/2007

Table 1. Preparation of Sulfur Heterocyclesa
Scheme 1. Proposed Route to Sulfur-Containing Heterocycles 1
close proximity of the second nucleophile with respect to
the ester group (path A, Scheme 1) resulting in the formation
of sulfur heterocycle 1.
To test the feasibility of this approach, aryl propiolates
were reacted with a series of bifunctional sulfur-oxygen or
sulfur-nitrogen pronucleophiles in the presence of n-Bu3P.
To our delight, the reaction appeared to be applicable for
a variety of substrates affording a straighforward route to 5-
or 6-membered sulfur-containing rings (Table 1). Mercapto
alcohols, amines, or even amides all participated well to give
the corresponding arylidene heterocyles 1a-f as pure Z
isomers in moderate to good yields.6
The reaction was also found to proceed successfully when
thioureas are used as bifunctional S,N-pronucleophiles lead-
ing to 2-iminothiazolidin-4-ones derivatives 1g-j. The later
heterocycles are well-known to display several important
biological activities.7 All of these products were obtained in
a very simple manner: just mixing the thioureas in the
presence of alkynoate and n-Bu3P afforded the desired
heterocycles which are easily recovered by flash chroma-
tography.
a Reactions conducted under argon; the concentration of the substrates
was 0.5 M. b Isolated yields. c In these reactions, 10% of PTSA were added
after 2 h at 25 °C and the mixture was heated at 110 °C for 1 h to help the
cyclization step.
The structures of compounds 1a-j were assigned by
comparison to published NMR data8 and further proven by
the X-ray crystallography of a representative product 1e.
Finally, we have undertaken the preparation of arylidene
rhodanine derivatives. The rhodanine (2-thioxo-4-thiazoli-
dinone) heterocyle is an interesting core for the development
of biologically active molecules. Arylidene rhodanine-based
molecules, in particular, are known to possess multiple
biological activities through the inhibition of numerous
targets such as HCV NS3 protease,9 â-lactamase,10 PMT1
It is noteworthy that, in all of these reactions, no Michael-
type adduct nor other heterocylic regioisomers were ob-
served. Besides the desired heterocycles, non cyclized R-S-
adducts 2 (Scheme 1) were the only side products that were
detected. The abundance of this byproduct seems to be
related to the nature of the aryl group. For certain alkyne
substrates it was necessary to help the cyclization by adding
catalytic amount of PTSA to get reasonable yields of the
desired heterocycle (entries 3 and 4, Table 1).
(6) The reaction conducted with aromatic amino thiols produced the
desired cyclic products with only poor yields (∼15%).
(8) (a) Erol, S.; Dogan, I. J. Org. Chem. 2007, 72, 2494-2500. (b)
Kasmi-Mir, S.; Djafri, A.; Paquin, L.; Hamelin, J.; Rahmouni, M. Molecules
2006, 11, 597-602. (c) Rudorf, W.-D.; Schwarz, R. Heterocycles 1986,
24, 3459-3465.
(7) (a) Ottana`, R.; Maccari, R.; Barreca, M. L.; Bruno, G.; Rotondo, A.;
Rossi, A.; Chiricosta, G.; Di Paola, R.; Sautebin, L.; Cuzzocrea, S.; Vigorita,
M. G. Bioorg. Med. Chem. 2005, 13, 4243-4252. (b) Holla, B. S.; Rao, B.
S.; Sarojini, B. K.; Akberali, P. M. Eur. J. Med. Chem. 2004, 39, 777-
783. (c) Mavrova, A. T.; Anichina, K. K.; Vuchev, D. I.; Tsenov, J. A.;
Kondeva, M. S.; Micheva, M. K. Bioorg. Med. Chem. 2005, 13, 5550-
5559. (d) Takasu, K.; Pudhom, K.; Kaiser, M.; Brun, R.; Ihara, M. J. Med.
Chem. 2006, 49, 4795-4798.
(9) Sing, W. T.; Lee, C. L.; Yeo, S. L.; Lim, S. P.; Sim, M. M. Bioorg.
Med. Chem. Lett. 2001, 11, 91-94.
(10) Grant, E. B.; Guiadeen, D.; Baum, E. Z.; Foleno, B. D.; Jin, H.;
Montenegro, D. A.; Nelson, E. A.; Bush, K.; Hlasta, D. J. Bioorg. Med.
Chem. Lett. 2000, 10, 2179-2182.
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Org. Lett., Vol. 9, No. 20, 2007

followed by a Knoevenagel condensation with aldehydes.13
We were convinced that such compounds would be easily
obtained in a one-pot process through the reaction of
dithiocarbamates (prepared in situ from amines and CS2) and
arylpropiolates in the presence of Bu3P. As hoped, this
reaction was found to proceed successfully at room temper-
ature with a variety of substrates (Scheme 2).
Scheme 2. Phosphine Catalyzed Reaction of Dithiocarbamates
with Aryl Propiolates Leading to Rhodanine Derivativesa
Although the procedure showed some limitations (dithio-
carbamates prepared from hindered or aromatic amines did
not afford the desired cyclized product; only the R-S-adduct
was observed), it presents many advantages over previous
ones. Besides the fact that the reaction is trivial to run, an
added bonus is the easy of product recovery. In many cases
the rhodanine products precipitate in i-PrOH and are obtained
in good yields as pure Z-isomer14 after simple filtration and
washing. This reaction is therefore well adapted to the
preparation of libraries of these biologically actives com-
pounds.
In conclusion, we have developed a simple and practical
method for the preparation of arylidene sulfur-containing
heterocyles via n-Bu3P-catalyzed tandem R-S-addition and
intramolecular cyclization. This strategy offers a straight-
forward way for constructing various heterocycles that are
found in many biologically active products. The reaction
should be successfully extended to the preparation of others
interesting heterocyles.
Acknowledgment. We thank E. Zekri and D. Buisson
(CEA) for experimental assistance with MS and LC/MS
measurements. We also warmly thank Dr. A. Chiaroni from
the CNRS (ICSN, Gif sur Yvette, France) for the resolution
of the RX structure.
Supporting Information Available: Experimental pro-
cedures for synthesis and full characterization for compounds;
1HNMR and 13CNMR spectra of products 1a-l and 3a-s.
RX structure of product 1e. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Isolated yields.
OL701563E
manosyl transferase,11 and PRL-3 and JSP-1 phosphatases.12
Classical methods for their preparation need several steps
and generally involve the preparation of the rhodanine moiety
(13) (a) Brown, F. C. Chem. ReV. 1961, 61, 463-521. (b) Singh, S. P.;
Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. ReV. 1981, 81, 175-203.
(c) Lee, C. L.; Sim, M. M. Terahedron Lett. 2000, 41, 5729-5732. (d)
Lohray, B. B.; Bhushan, V.; Rao, P. B.; Madhavan, G. R.; Murali, N.; Rao,
K. N.; Reddy, K. A.; Rajesh, B. M.; Reddy, P. G.; Chakrabarti, R.;
Rajagopalan, R. Bioorg. Med. Chem. Lett. 1997, 7, 785-788. (e) Rudorf,
W.-D.; Schwarz, R. Heterocycles 1986, 24, 3459-3463. (f) Khodair, A. I.;
Nielsen, J. Heterocycles 2002, 57, 1017-1032.
(14) The geometry of the double bond was assigned by comparison to
published NMR data: (a) Hanefeld, W.; Schlitzer, M.; Schu¨tz, H.; Wocadlo,
S.; Massa, W. Liebigs Ann. Chem. 1992, 337-344. (b) Fresneau, P.; Cussac,
M.; Morand, J.-M.; Szymonski, B.; Tranqui, D.; Leclerc, G. J. Med. Chem.
1998, 41, 4706-4715.
(11) Orchard, M. G.; Neuss, J. C.; Galley, C. M. S.; Carr, A.; Porter, D.
W.; Smith, P.; Scopes, D. I. C.; Haydon, D.; Vousden, K.; Stubberfield, C.
R.; Young, K.; Page, M. Bioorg. Med. Chem. Lett. 2004, 14, 3975-3978.
(12) (a) Ahn, J. H.; Kim, S. J.; Park, W. S.; Cho, S. Y.; Ha, J. D.; Kim,
S. S.; Kang, S. K.; Jeong, D. G.; Jung, S.-K.; Lee, S.-H.; Kim, H. M.;
Park, S. K.; Lee, K. H.; Lee, C. W.; Ryu, S. E.; Choi, J.-K. Bioorg. Med.
Chem. Lett. 2006, 16, 2996-2999. (b) Cutshall, N. S.; O’Day, C.; Prezhdo,
M. Bioorg. Med. Chem. Lett. 2005, 15, 3374-3379.
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