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
(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