Thionation using fluorous Lawesson's reagent

Article abstract of DOI:10.1021/ol060208a

Thionation of amides, 1,4-diketones, N-(2-oxoalkyl)amides, N,N-acylhydrazines, and acyl-protected uridines with the use of a fluorous analogue of the Lawesson's reagent leads to thioamides, thiophenes, 1,3-thiazoles, 1,3,4-thiadiazoles, and acyl-protected 4-thiouridines. The isolation of the final products in high yields is achieved in most cases by a simple filtration (fluorous solid-phase extraction).

Full text of DOI:10.1021/ol060208a

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1625-1628
Thionation Using Fluorous Lawesson’s
Reagent
Zolta´n Kaleta,†,‡ Brian T. Makowski,† Tibor Soo´s,*,‡ and Roman Dembinski*,†
Department of Chemistry, Oakland UniVersity, 2200 North Squirrel Road,
Rochester, Michigan 48309-4477, and Institute of Biomolecular Chemistry,
Chemical Research Center of Hungarian Academy of Science, P.O. Box 17,
1525 Budapest, Hungary
dembinsk@oakland.edu
Received January 24, 2006
ABSTRACT
Thionation of amides, 1,4-diketones, N-(2-oxoalkyl)amides, N,N′-acylhydrazines, and acyl-protected uridines with the use of a fluorous analogue
of the Lawesson’s reagent leads to thioamides, thiophenes, 1,3-thiazoles, 1,3,4-thiadiazoles, and acyl-protected 4-thiouridines. The isolation of
the final products in high yields is achieved in most cases by a simple filtration (fluorous solid-phase extraction).
Fluorous chemistry, which targets resource- and time-
consuming separation, exploits the different phase affinities
of organic and fluorous molecules.1,2 Fluorous allure is
introduced into molecules by means of various fluorous
ponytails which are attached onto different reaction compo-
nents: reactants, catalysts, or reagents. The last two options
provide tools that can usually be applied for broad synthetic
transformations.
Many applications of the fluorous synthetic approach have
been developed over the past few years. Several well-known
organic reactions have been adapted for various fluorous
protocols. These include, among others, the Swern3 and
Baeyer-Villiger4 oxidations, Friedel-Crafts acylation,5 and
the Mitsunobu reaction.6 In this paper, we report the synthesis
and reactions of a fluorous analogue of the Lawesson’s
reagent (LR).7
2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-
disulfide (LR) is an efficient thionation reagent.7 Its broad
applications range from the conversion of carbonyl com-
pounds into their thiocarbonyl analogues, through to the
synthesis of sulfur and non-sulfur containing heterocycles,8
and the solid-phase synthesis of oligodeoxyribonucleoside
(4) Hao, X.; Yamazaki, O.; Yoshida, A.; Nishikido, J. Tetrahedron Lett.
2003, 44, 4977-4980.
(5) (a) Hao, X.; Yoshida, A.; Nishikido, J. Tetrahedron Lett. 2005, 46,
2697-2700. (b) Barrett, A. G. M.; Braddock, D. C.; Catterick, D.;
Chadwick, D.; Henschke, J. P.; McKinnell, R. M. Synlett 2000, 847-849.
(6) (a) Ba´lint, A.-M.; Bodor, A.; Go¨mo¨ry, AÄ .; Ve´key, K.; Szabo´, D.;
Ra´bai, J. J. Fluorine Chem. 2005, 126, 1524-1530. (b) Szabo´, D.; Bonto,
A.-M.; Ko¨vesdi, I.; Go¨mo¨ry, AÄ .; Ra´bai, J. J. Fluorine Chem. 2005, 126,
639-650. (c) Dandapani, S.; Curran, D. P. J. Org. Chem. 2004, 69, 8751-
8757. (d) Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10, 3130-
3138. (e) Dembinski, R. Eur. J. Org. Chem. 2004, 2763-2772.
(7) Perregaard, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I.; Lawesson,
S.-O. Bull. Soc. Chim. Belg. 1977, 86, 679-691.
† Oakland University.
‡ Chemical Research Center.
(1) (a) Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
Horva´th, I. T., Eds.; Wiley-VCH: Weinheim, 2004; pp 1-595. (b) Ubeda,
M. A.; Dembinski, R. J. Chem. Educ. 2006, 83, 84-92.
(2) Representative specialized recent reviews: (a) Curran, D. P. Ald-
richim. Acta 2006, 39, 3-9. (b) Zhang, W. Chem. ReV. 2004, 104, 2531-
2556. (c) Zhang, W. ArkiVoc 2004, i, 101-109.
(3) Crich, D.; Neelamkavil, S. J. Am. Chem. Soc. 2001, 123, 7449-
7450.
10.1021/ol060208a CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/18/2006

Scheme 1. Synthesis of Fluorous Lawesson’s Reagents f6-LR
and f8-LR
Scheme 2. Synthesis of Fluorous Anisole 1-f6
option, the ponytails were trimmed from Rf8 to F(CF2)6 (Rf6),
which lowered the molecular formula of f-LR by C4F8.
Concurrently, to target a higher preparation efficiency of the
fluorous component, the perfluoroalkyl moiety was intro-
duced during the last stage of the synthesis of the fluorous
anisole (1-f6). Radical addition of perfluorohexyl iodide,
F(CF2)6I, to the double bond of but-3-en-1-yl phenyl ether
(2)16 gave an iodide that was subsequently reduced without
isolation to tridecafluorodecyl phenyl ether (1-f6), in reactions
analogous to a known procedure (Scheme 2).17 Reaction of
the fluorous ether 1-f6 (6 equiv) with P2S5 (1 equiv),
following a similar procedure as for f8-LR (170 °C, 3 h,
Scheme 1), gave f6-LR in 39% yield. Both f-LRs precipitated
from the reaction mixture at room temperature and were
isolated by simple filtration. This offered an opportunity to
recover the remaining fluorous anisole 1-f6, which could be
reused for further synthesis of f6-LR (similarly anisole 1-f8
was reused for the synthesis of f8-LR). Both f6-LR and f8-
LR reagents are less odiferous than regular LR, but
unfortunately are still not odorless. The IR fragments
matched the pattern of the original LR. Spectral characteriza-
tion by 1H, 13C, and 31P NMR confirmed the structure. Mass
spectra for both f6-LR and f8-LR exhibited intense half-
molecular ions (100% and 90% for [M/2]+) and their accurate
high-resolution peaks. Both f-LR reagents were used as
prepared for further transformations.
phosphorothioates.9 A variety of experimental protocols have
been developed for the use of LR.8 Since chromatographic
isolation of the desired product from the spent LR limits the
utility of the reagent, we turned our attention to fluorous
chemistry as a possible solution to the ever-present LR
separation problems. The synthesis and application of
fluorous Lawesson’s reagent (f-LR) for various thionation
reactions, followed by a fluorous workup protocol based on
solid-phase extraction, are presented below.
The most straightforward approach to append fluorous
affinity to the LR would include extension of the methyl
group of the phosphorus ligand with a fluorous ponytail
F(CF2)m(CH2)n. Such a route involves minimal modification
of the original reagent. This strategy also provides an
opportunity for fine-tuning the electronic properties of the
anisole derivative by manipulating the length of the meth-
ylene spacers (n). The C6H4OCH2 unit does not completely
insulate the reactive center from the electron-withdrawing
effect of the fluorines;10 thus, to avoid low reactivity of an
insufficiently electron-rich fluorous anisole toward phos-
phorus, we embedded four methylene spacers (n ) 4). Efforts
toward the synthesis of fluorous LR with ponytails containing
fewer methylene groups, such as F(CF2)8(CH2)3, directly
attached to the aromatic ring, were unsuccessful.11 Consider-
ing the above, a fluorous anisole was developed from
inexpensive phenol. Etherification of phenol with fluoroalkyl
bromide F(CF2)8(CH2)4Br12 or iodide F(CF2)8(CH2)4I13 gave
heptadecafluorododecyl phenyl ether (1-f8) with yields
comparable to those reported for similar reactions.14 Treat-
ment of the fluorous anisole 1-f8 with phosphorus pentasul-
fide in o-dichlorobenzene at 170 °C gave, after 4 h, a fluorous
Lawesson’s reagent (f8-LR) in 51% yield (Scheme 1).
The perfluoroalkyl group F(CF2)8 (abbreviated Rf8) was
applied initially. However, it is now known that a lower
fluorous content may be sufficient for fluorous solid-phase
separation (the light fluorous approach).2a,15 To explore this
Scheme 3. Synthesis of Thioamides (Top) and Sulfur
Heterocycles (Bottom)
A comparison of the reactivity and separation of each
fluorous Lawesson’s reagent was investigated by thionation
of the carbonyl of a simple amide (Scheme 3).18 Conversion
of benzamide (3a) to thiobenzamide (4a) with the use of
f8-LR and f6-LR was accomplished in THF at 55 °C within
(8) (a) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929-
1958. (b) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061-5087.
(9) Ju, J.; McKenna, C. E. Bioorg. Med. Chem. Lett. 2002, 12, 1643-
1645.
(10) (a) Bhattacharyya, P.; Croxtall, B.; Fawcett, J.; Fawcett, J.;
Gudmunsen, D.; Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Russell,
D. R.; Stuart, A. M.; Wood, D. R. W. J. Fluorine Chem. 2000, 101, 247-
255. (b) Relevant work with bipy: Bennett, B. L.; Robins, K. A.; Tennant,
R.; Elwell, K.; Ferri, F.; Bashta, I.; Aguinaldo, G. J. Fluorine Chem. 2006,
127, 140-145.
(11) For a concurrent approach to fluorous Lawesson’s reagent based
upon implementation of the fluorous ponytail ortho to the methoxy group
by the Wittig reaction of cinnamaldehyde derivative with Rf8CH2CH2PPh3+I-,
see: Kaleta, Z.; Ta´rka´nyi, G.; Go¨mo¨ry, AÄ .; Ka´lma´n, F.; Nagy, T.; Soo´s, T.
Org. Lett. 2006, 8, 1093-1095.
(12) Wilson, R. W.; Cayetano, V.; Yurchenko, M. Tetrahedron 2002,
58, 4041-4047.
1626
Org. Lett., Vol. 8, No. 8, 2006

Table 1. Thionation with the Use of Fluorous Lawesson’s Reagentsa
a For a representative procedure, see ref 26. b Reactions were carried out on a ca. 0.1-0.5 mmol scale with 1.0-2.0 equiv of f6-LR in THF at 55 °C
unless referenced otherwise. c Reaction using f8-LR. d After recrystallization. e Microwave, solvent-free. f Dioxane, 100 °C. g After silica gel column
chromatography.
4 h in 94% and 92% yields, respectively (Table 1, entry 1)
and revealed that the f8-LR offered no distinct advantage
over f6-LR. Thus, all of the remaining experiments were
carried out with the use of f6-LR. Analogously (THF, 55
°C, 6 h), acetanilide (3b) was converted into thioacetanilide
(4b, Table 1, entry 2). The reaction was carried out with an
equimolar ratio of 3b and f6-LR, on a 0.2 mmol scale. After
the addition of alumina, the solvent was removed and the
resulting solid was placed on a fluorous reversed-phase silica
gel. Elution with acetonitrile gave 4b in 97% yield.
The reactivity of f6-LR was further examined for the
synthesis of a variety of five-membered ring heterocycles
(Scheme 3). Since thiophenes represent an important class
(13) Alvey, L. J.; Meier, R.; Soo´s, T.; Bernatis, P.; Gladysz, J. A. Eur.
J. Inorg. Chem. 2000, 1975-1983.
(14) (a) Johansson, G.; Percec, V.; Ungar, G.; Smith, K. Chem. Mater.
1997, 9, 164-175. (b) Markowicz, M. W.; Dembinski, R. Org. Lett. 2002,
4, 3785-3787.
(15) Curran, D. P.; Light Fluorous Chemistry - A Users’s Guide. In
Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horva´th,
I. T., Eds.; Wiley-VCH: Weinheim, 2004; pp 128-155.
(16) Westwell, A. D.; Williams, J. M. J. Tetrahedron 1997, 53, 13063-
13078.
(17) Johansson, G.; Percec, V.; Ungar, G.; Zhou, J. P. Macromolecules
1996, 29, 646-660.
(18) Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Bull. Soc. Chim.
Belg. 1978, 87, 229-238.
(19) (a) Liu, W.-D.; Chi, C.-C.; Pai, I.-F.; Wu, A.-T.; Chung, W.-S. J.
Org. Chem. 2002, 67, 9267-9275. (b) See also: Kiryanov, A. A.; Sampson,
P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925-7929.
Org. Lett., Vol. 8, No. 8, 2006
1627

of compounds, commercially available symmetrical and
unsymmetrical 1,4-diketones (5a,b) were converted into 2,5-
substituted thiophenes (6a,b).19 These reactions were carried
out in a manner analogous to that above (THF, 55 °C, 6 h).
Isolation by solid-phase extraction afforded 6a/b in 88/92%
yield. Synthesis of two representative 1,3-thiazoles20 was also
attempted. First, N-(1-methyl-2-oxohexyl)benzamide (7a)
was treated with f6-LR (entry 5). The formation of two
organic products was observed. These products were sepa-
rated from the spent LR by fluorous solid-phase extractive
workup. Both thiazole (8a) and an analogous oxazole
(tentatively confirmed by GC/MS) were detected in an 81:
for the reaction of 11b with f6-LR, a higher temperature but
shorter reaction time (dioxane, 100 °C, 4 h) was applied.
The yield of isolated nucleoside 12b was lower (56%), and
formation of other products prompted an additional purifica-
tion by silica gel column chromatography. Complex thion-
ation reactions of related 2′-deoxy-5,6-dihydropyrimidines
with the use of nonfluorous LR are well-documented.25
The purity of all sulfur-containing products was confirmed
by 1H and 13C NMR. After solid-phase extraction, no fluorous
1
LR or its byproducts were observed by H NMR in any of
the isolated material.
In summary, the fluorous approach offers new avenues
for solutions to the separation problems encountered with
Lawesson’s reagent by simplifying the isolation protocol,
including elimination of column chromatography, and thus
improving yields. We have demonstrated that f-LR can be
applied for the high-yield synthesis of a variety of thio
compounds, including heterocycles. We have applied a user-
friendly workup based upon solid-phase extraction without
the need for fluorous solvents. Our approach can supply
thioamides, thiophenes, thiazoles, thiadiazoles, and 4-thiou-
ridines for automated combinatorial chemistry protocols. The
selected examples include important synthetic and materials
chemistry intermediates and biologically active structural
motifs.
1
19 ratio, as determined by H NMR. Crystallization gave
8a in 48% yield. Thus, alternative reaction conditions were
sought. A microwave protocol has been successfully applied
in LR chemistry.21 Therefore, f6-LR and N-[2-(4-methox-
yphenyl)-2-oxoethyl]-4-methylbenzamide (7b) were com-
bined and the solvent-free mixture was irradiated in a
conventional microwave at atmospheric pressure (entry 6).
A too short or too long irradiation time led to incomplete
conversion or decomposition; the optimal reaction time was
found to be 3 min. Fluorous workup gave a 2,5-diaryl-
substituted 1,3-thiazole (8b) which contained a small amount
of impurity (but not oxazole), as observed by TLC. Recrys-
tallization gave 8b in 82% yield.
The applications of f6-LR were further extended; starting
from N′-acylbenzohydrazides (9a,b), two 1,3,4-thiadiazoles
(10a,b)22 were synthesized by the solution-phase protocol
in 94% and 93% yield (entries 7 and 8). Finally, entries 9
and 10 illustrate that two acyl-protected representative
pyrimidine nucleosides, uridine and 2′-deoxy-5-iodouridine23
(11a and 11b), can be converted into their 4-thiouridine
derivatives (12a,b).24 Although acetylated thiouridine 12a
was isolated in 94% yield (THF, 55 °C, 17 h), 5-iodouridine
(11b) reacted sluggishly under the same conditions. Thus,
Acknowledgment. We thank the Oakland University,
Research Excellence Program in Biotechnology, and in part
NIH Grant No. CA111329 for support of this research, Prof.
B. Borhan for helpful discussions, and Dr. P. Wilkinson for
NMR advice. We acknowledge SiliCycle for the donation
of Fluorochrom and SiliaBond Fluorochrom cartridges.
Supporting Information Available: Synthetic proce-
dures, analytical and spectral characterization data, and
spectra for compounds 1, f-LR, 4, 6, 8, 10, and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Synthesis using LR/ionic liquid: Yadav. J. S.; Reddy, B. V. S.;
Eeshwaraiah, B.; Gupta, M. K. Tetrahedron Lett. 2004, 45, 5873-5876.
(21) (a) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697-700. (b)
Olsson, R.; Hansen, H. C.; Anderson, C.-M. Tetrahedron Lett. 2000, 41,
7947-7950. (c) Rico-Go´mez, R.; Na´jera, F.; Lo´pez-Romero, J. M.; Can˜ada-
Rudner, P. Heterocycles 2000, 2275-2278.
(22) (a) Rasmussen, P. B.; Pedersen, U.; Thomsen, I.; Yde, B.; Lawesson,
S.-O. Bull. Soc. Chim. Fr. 1985, 62-65. (b) Gierczyk, B.; Zalas, M. Org.
Process Res. DeV. 2005, 37, 213-222.
(23) (a) Chang, P. K.; Welch, A. D. J. Med. Chem. 1963, 6, 428-430.
(b) Esho, N.; Desaulniers, J.-P.; Davies, B.; Chui, H. M.-P. Rao, M. S.;
Chow, C. S.; Szafert, S.; Dembinski, R. Bioorg. Med. Chem. 2005, 13,
1231-1238.
(24) Wenska, G.; Taras-Gos´lin´ska, K.; Skalski, B.; Hug, G. L.; Car-
michael, I.; Marciniak, B. J. Org. Chem. 2005, 70, 982-988.
OL060208A
(25) (a) Peyrane, F.; Clivio, P. Org. Biomol. Chem. 2005, 3, 1685-
1689. (b) Peyrane, F.; Fourrey, J.-L.; Clivio, P. Chem. Commun. 2003, 736-
737.
(26) 2-Methyl-5-phenylthiophene (6a).19 A Schlenk tube was charged
under N2 with 5a (0.0352 g, 0.200 mmol), f6-LR (0.225 g, 0.200 mmol),
and THF (4 mL), and placed into a 55 °C oil bath. After 4 h, when the
reaction was completed as determined by TLC, alumina (2 g) was added
and the solvent was evaporated. The resulting solid was placed on a short
column packed with fluorous reverse phase silica (2 g). The column was
eluted with acetonitrile (20 mL) to give 6a as a white solid (0.0307 g, 0.176
mmol, 88%).
1628
Org. Lett., Vol. 8, No. 8, 2006