Oxazolinethiones and oxazolidinethiones for the first copper-catalyzed desulfurative cross-coupling reaction and first sonogashira applications

Article abstract of DOI:10.1021/ol703003e

Cyclic thionocarbamates, namely chiral oxazolidinetiones (OZT) and aromatic ozazolinethiones (OXT), were involved, for the first time, in Sonogashira cross-coupling. A cooperative effect of two different copper (I) species-Cul and CuTC-accounts for this new copper-catalyzed desulfurative carbon-carbon cross-coupling reaction. This cooperative reactivity could also be extended to other copper (I) catalysts.

Full text of DOI:10.1021/ol703003e

ORGANIC
LETTERS
2008
Vol. 10, No. 5
853-856
Oxazolinethiones and
Oxazolidinethiones for the First
Copper-Catalyzed Desulfurative
Cross-Coupling Reaction and First
Sonogashira Applications
Sandrina Silva,‡,† Balla Sylla,‡ Franck Suzenet,‡ Arnaud Tatiboue
1
t,*,‡
Amelia P. Rauter,† and Patrick Rollin‡
Institut de Chimie Organique et Analytique, UniVersite´ d’Orle´ans, CNRS-UMR 6005,
BP 6759, F-45067 Orle´ans Cedex. France, and Centro de Qu´ımica e Bioqu´ımica /
Departamento de Qu´ımica e Bioqu´ımica, Faculdade de Cieˆncias da UniVersidade de
Lisboa, Campo Grande, Edif´ıcio C8, 5 Piso, 1749-016 Lisboa, Portugal
arnaud.tatibouet@uniV-orleans.fr
Received December 13, 2007
ABSTRACT
Cyclic thionocarbamates, namely chiral oxazolidinethiones (OZT) and aromatic oxazolinethiones (OXT), were involved, for the first time, in
Sonogashira cross-coupling. A cooperative effect of two different copper (I) species CuI and CuTC accounts for this new copper-catalyzed
desulfurative carbon carbon cross-coupling reaction. This cooperative reactivity could also be extended to other copper (I) catalysts.
s
s
−
Despite the tremendous methodological variety of transition
metal-catalyzed cross-coupling protocols known today,1 there
is still room for alternative methods that would overcome
the stability problems of sensitive electrophiles and signifi-
cantly extend the versatility of the processes. In recent years,
heteroaromatic thioethers have been introduced as a new
class of electrophiles for their greater stability.2 The alkyl-
sulfanyl method developed by Liebeskind and Srogl, mostly
onto heteroaromatic templates,3 can be regarded as a reliable
(2) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260-
11261. (b)Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554-3557.
(c) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind, L.
S. J. Am. Chem. Soc. 2007, 129, 1132-1140. (d) Leconte, N.; Keromnes-
Wuillaume, A.; Suzenet, F.; Guillaumet, G. Synlett 2007, 204-210. (e)
Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979-981. (f) Kusturin, C.
L.; Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983-985. (g)
Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91-93. (h)
Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.;
Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349-4352. (i) Alphonse,
F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett.
2003, 5, 803-805. (j) Oumouch, S.; Bourotte, M.; Schmitt, M.; Bourgui-
gnon, J.-J. Synthesis 2005, 25-27.
‡ Universite´ d’Orle´ans, CNRS.
† Universidade de Lisboa.
(1) For reviews, see : (a) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: New York, 1985. (b) Tsuji, J. Palladium
Reagents and Catalysts: InnoVations in Organic Synthesis; Wiley &
Sons: New York, 1995. (c) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25,
508-524. (d) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(f) Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674-
7684. (g) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A.; Diederich, F.; Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vols.1
and 2.
(3) (a) Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Synlett 2002, 447-450. (b) Aguilar-Aguilar, A.; Liebeskind,
L. S.; Pena-Cabrera, E. J. Org. Chem. 2007, 72, 8539-8542.
10.1021/ol703003e CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

alternative tool in heteroaromatic C-C bond formations. The
recent publication by Kappe of a modified desulfurative
cross-coupling method, using direct reaction on thioamides
under microwave assistance,4 prompted us to disclose our
own results.
with previous works on Suzuki reactions.2j,4 The different
conditions explored are displayed in Table 1. Using the sole
Table 1. Sonogashira Cross-Coupling Optimization
The development of hybrid structures, involving small
heterocyclic units connected on carbohydrate frames for the
elaboration of nucleoside analogues and other biologically
active molecules, is one of our main pipelines of research.5
Targeting this goal, we have developed various methods to
generate a large range of 1,3-oxazolidine-2-thiones (OZTs)
and 1,3-oxazoline-2-thiones (OXTs) linked to carbohydrate
skeletons.6 Making use of the chemoselective S-alkylation,
we have explored cyclocondensations and, for the first time,
the Stille and Suzuki Pd cross-coupling reactions with
alkylsulfanylated chiral heterocycles were accomplished.7
With a view to shorten the process, Suzuki cross-coupling
conditions on cyclic thionoamides, using microwave activa-
tion, have been tested successfully.4 The Sonogashira
coupling was the next protocol to be investigated because
of its impressive impact on modern organic chemistry.8
Extending the Sonogashira coupling to OXTs and OZTs
would open new attractive synthetic routes to alkynylox-
azoles and alkynyloxazolinessuseful synthons in total
synthesis and medicinal chemistry.9
When considering the Pd(0) coupling reactions with alkyl
heteroarylsulfides or with thioamides, the major drawback
in the processes is the relative amount of copper additives:
Cu(I)-thiophene-2-carboxylate (CuTC), Cu(I)-3-methylsali-
cylate (CuMeSal), or CuBr‚Me2S are always needed in more
than one equivalent. Designing a new coupling process
involving only catalytic amounts of copper cofactors would
bring a major improvement in paving the way to extended
uses of thiofunctionalized reaction partners for cross-coupling
reactions. In the present letter, we report our first results on
this new copper-catalyzed desulfurative protocol.
Et3N DMF
entry (mL) (mL) Pd(Ph3P)4 CuI CuTC
time yieldsa
(h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5
5
5
5
5
5
5
5
-
5
5
5
5
5
5
5
2
2
2
2
2
2
2
2
2
-
2
2
2
2
2
2
0.1
0.1
0.1
0.1
0.05
0.05
0.05
0.05
0.05
0.05
0.5
-
-
2.2
1
1
-
-
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.1b
0.5
0.5
2.2
1.1
1.1
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1c
0.1d
1
1
1
1
1
1
1
63
85
83
85
79
73a
-
1
1
33
-
-
0.05
0.05
0.05
0.05
0.05
0.25
0.25
0.25
0.25
0.25
77
56
33
53
75
a 1.5 equiv of phenylacetylene. b Cu2S was used instead of CuI.
c CuBr‚Me2S was used instead of CuTC. d CuMeSal was used instead of
CuTC.
standard Sonogashira copper additive (CuI) in catalytic
amount was ineffective (entry 1). Likewise (entry 2) replac-
ing CuI by CuTC (effective copper additive for Suzuki
coupling) did not result in a C-C coupling reaction. The
implication of copper (I) in the reaction mechanism was taken
into consideration on two distinct steps: (i) the transmetal-
lation of copper iodide with the alkyne and (ii) the copper-
assisted activation of the thiolactim-type intermediate. Con-
sequently, we postulated that a conjunction of both copper
(I) species in the medium would allow CuI and CuTC to
react independently of one another, and this approach proved
fruitful (Table 1).
Our starting point for this investigation was to examine
the coupling abilities of phenylacetylene with the D-xylo-
furano-derived OXT 1, easily accessible from D-glucose.6a
Our selected Sonogashira conditions required a Pd(0) source
and CuI and Et3N in DMF in order to obtain an homogeneous
medium; microwave heating was then applied, in accordance
By mixing CuI and CuTC (entry 3), the 2-phenylethyny-
loxazole 2a was obtained with a reasonable 63% yield. A
search was then engaged for reducing the amount of copper
additive. Decreasing the amount of CuTC to 1.1 equiv (entry
4) resulted in a dramatic improvement to 85% yield, and
further reduction of the Pd(0) catalyst to 0.05 equiv (entry
5) did not lower the yield. Further, using CuTC in 0.5 equiv
(entry 6) did not induce significative modification of the
yield, whereas lowering CuTC down to 0.1 equiv (entry 7)
only caused minor reduction of the yield to 79%.
Some additional modifications of the conditions were
investigated: (i) Reducing phenylacetylene to 1.5 equiv
(entry 8) still afforded the product 2 in fair yield. (ii)
Removing one solvent resulted in no reaction without Et3N
(entry 9), or to a low 33% yield in neat Et3N (entry 10). In
this last case, the poor solubility of OXT 1 was involved.
(4) (a) Prokopcova, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440-
4448. (b) Prokopcova, H.; Kappe, C. O. AdV. Synth. Catal. 2007, 349, 448-
452.
(5) (a) Yang, J.; Dowden, J.; Tatiboue¨t, A.; Hatanaka, Y.; Holman. G.
D. Biochem. J. 2002, 367, 533-539. (b) Girniene, J.; Tatiboue¨t, Sackus,
A. A.; Yang, J.; Holman, G. D.; Rollin, P. Carbohydr. Res. 2003, 338,
711-719.
(6) (a) Girniene, J.; Apremont, G.; Tatiboue¨t, A.; Sackus, A.; Rollin, P.
Tetrahedron 2004, 60, 2609-2619. (b) Tatiboue¨t, A.; Lawrence, S.; Rollin,
P.; Holman, G. D. Synlett 2004, 1945-1948. (c) Leconte, N.; Silva, S.;
Tatiboue¨t, A.; Rauter, A. P.; Rollin, P. Synlett 2006, 301-305.
(7) Leconte, N.; Pellegatti, L.; Tatiboue¨t, A.; Suzenet, F.; Rollin, P.;
Guillaumet G. Synthesis 2007, 857-864.
(8) Chinchilla, R.; Najera, N. Chem. ReV. 2007, 107, 874-922.
(9) (a) Su, Q.; Dakin, L.A.; Panek, J. S. J. Org. Chem. 2007, 72, 2-24.
(b) Wang, Y.; Janjic, J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161-
1169. (c) Cook, G. R. Manivannan, E.; Underdhal, T.; Lukacova, V.; Zhang,
Y.; Balaz, S. Bioorg. Med. Chem. Lett. 2004, 14, 4935-4939. (d) Paterson,
I.; Tudge, M. Tetrahedron 2003, 59, 6833-6849. (e) Talley, J. J.;
Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C.
M.; Masferrer, J. L.; Norman, B. H.; Rogier, D. J.; Zweifel, B. S.; Seibert,
K. Med. Res. ReV. 1999, 19, 199-208.
854
Org. Lett., Vol. 10, No. 5, 2008

Figure 1. Proposed mechanism for the catalytic process.
(iii) No reaction occurred after removing Pd(Ph3P)4 (entry
11). (iv) Reducing the reaction time to 15 min (entry 12)
did not appreciably hamper the cross-coupling process (77%
yield); the latter conditions were therefore adopted as a
standard, using various OXTs and OZTs. (v) Bringing the
catalytic quantity of CuI down to 10 mol % (entry 13) still
kept the catalytic process efficient albeit resulting in a much
lower yield.
induces an important yield variation, especially with the
fluoro derivative 2c, which undergoes coupling with a
moderate yield and produces a significant amount of the
Table 2. Variation of Alkynes
This coupling reaction stands as a new alternative approach
to the alkynyloxazole synthesis developed by Panek.10 The
most surprising aspect of this original copper-catalyzed
desulfurative Sonogashira cross-coupling is the catalytic
amounts of both palladium and CuTC used in the coupling
process. From the first experiments performed, both copper
(I) species were needed for the chemical coupling, which
might mean that both copper complexes are implicated in
the catalytic process (Figure 1). Based on the reaction scheme
proposed by Kappe,4 the copper (I) sulfide formed in situ
might play a central role in the catalytic cycle. Indeed, by
replacing CuI by Cu2S (entry 14), the catalytic reaction still
proceeds, albeit with a poor 33% yield. Our proposed
mechanism (Figure 1) highlights the important role of the
alkynylcopper in the regeneration of CuTC and in the
formation of CuSH which could then be a source of Cu(I)
(cycle B) able to regenerate the alkynylcopper species. Under
the same conditions, CuBr‚Me2S (entry 15) as well as
CuMeSal (entry 16) could be used instead of CuTC, but a
clear preference for the Suzuki Cu(I) additives had to be
admitted.
One of our main streams of research is the structural-
modulation potential of OXTs and OZTs connected to
carbohydrate templates to mimick C-linked nucleosides. We
have thus applied the selected conditions with different
alkynes to react on OXT 1 (Table 2). A careful analysis of
the reaction has shown the additional formation of the
oxazole 3 in moderate proportions. The coupling reaction
occurred with various alkynes in fair to good yields.
Aromatic substitution on phenylacetylene (entries 2 and 3)
Standard protocol : alkyne (3 equiv), CuI (0.5 equiv), CuTC (0.1 equiv),
DMF (2 mL), Et3N (5 mL), MW 15 min.
reduced compound 3; the reactivity of alkyne 3c is clearly
perturbed by the electron-withdrawing effect of fluorine.
Heptyne proved as reactive as phenylacetylene (entry 4)
with a good 78% yield of 2d; however, slightly reduced
efficiency was observed in the formation of 2e and 2f with
enhanced production of oxazole (entries 5 and 6).11 Finally,
the process was also tested on a complex carbohydrate-
derived alkyne, 1-O-propargyl-2,3;4,5-di-O-isopropylidene-
â-D-fructopyranose (entry 7), with which a reasonable 58%
coupling yield could be obtained. In all cases, the oxazole
formation (7-24% yield) was indicative of a competing
reaction during the transmetallation process.
The scope of the reaction was then explored in two
different directions (Table 3); one consisted in changing the
carbohydrate platform bearing the OXT heterocycle (entries
(11) The interesting triethylsilylacetylene gave a good yield of the
coupling product, while the trimethylsilyl analogue showed important
instability during the process and no coupling product could be detected.
(10) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485-
2488.
Org. Lett., Vol. 10, No. 5, 2008
855

fructopyrano frame (15) was then selected because of the
known stereoinductive ability of this carbohydrate template;
an excellent 88% yield of alkyne 16 was obtained.12 We then
moved to pentose derivatives 17, 19, and 21, in which the
OZT is anchored on the anomeric position. A good coupling
efficiency was observed with the O-silyl-protected D-xylo
OZT 17, with an 82% yield of the resulting alkynyl oxazoline
18. A drop of reactivity was noted in the case of unprotected
OZTs 19 and 21, with D-xylo- and D-ribo-oxazolines 20 and
22 being produced in 57% and 61% yield, respectively.
Nevertheless, the above experiments clearly indicate that
unprotected hydroxyls are compatible with our coupling
process; such complex alkynyl derivatives could therefore
be produced in only two steps from the corresponding
pentoses.5b The last example (entry 10) involved a non-
carbohydrate norephedrine-derived molecule 23,13 which was
shown to behave similarly by delivering a 62% yield of the
substituted 1,3-oxazoline 24. An overall analysis of the
various experiments performed demonstrates the versatility
of our cross-coupling protocol, in which diverse sensitive
carbohydrate derivatives, either O-protected with benzyl/silyl
ethers or acetal groups, or even unprotected ones, can be
used under microwave heating conditions at 100 °C.
In summary, this exploration of a novel Sonogashira cross-
coupling has given us the opportunity not only to disclose
the first alkynyl C-C bond formation using thionocarbamates
but moreover to disclose the possibility to use copper(I) in
catalytic amount and to suggest, consequently, a mechanism
(Figure 1) in which CuSH might play the central role. Further
exploration of this mechanism to extend the catalytic copper-
(I) potential will be disclosed in due time.
Table 3. Substrate and Heterocycle Modulation
a Not detected.
Acknowledgment. We thank the ANR for funding, the
PESSOA program, the Universite´ d’Orle´ans, the Univer-
sidade de Lisboa for financial support, and the FCT for a
fellowship (S.S.).
1-4), and the other focused on the parent OZTs connected
with miscellaneous templates (entries 5-10). An overview
of the reactions demonstrated the ability of the method for
C-C bond formation on either aromatic OXTs or chiral
OZTs. Coupling phenylacetylene with the R-D-xylo deriva-
tives 1 and 4 and R-D-ribo derivatives 7 and 10 unvaryingly
afforded good yields (73-85%) of hybrid alkynes 2a, 5, 8,
and 11, respectively. In all the above cases, the reductive
process gave small (5-8%) yields of oxazoles 3, 6, 9, and
12, whereas no competing reduction could be detected in
the case of OZT derivatives.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all new products; typical
procedure for the palladium-catalyzed Sonogashira reaction.
This material is available free of charge via the Internet at
http://pubs.ac.org.
OL703003E
(12) (a) Girniene, J.; Tardy, S.; Tatiboue¨t, A.; Sackus, A.; Rollin, P.
Tetrahedron Lett. 2004, 45, 6443-6446. (b) Garcia Fernandez, J. M.; Ortiz
Mellet, C.; Fuentes, J. J. Org. Chem. 1993, 58, 5192-5199. (c) Desroses,
M.; Che´ry, F.; Tatiboue¨t, A.; De Lucchi, O.; Rollin P. Tetrahedron:
Asymmetry 2002, 13, 2535-2539.
(13) Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60,
6604-6607.
The first carbohydrate-linked OZT 13 to be tested was
closely related to OXT 4, and the phenylacetylene cross-
coupling proved as efficient as on the aromatic OXT. A
spiro-OZT connected to a 1,2;4,5-di-O-isopropylidene-D-
856
Org. Lett., Vol. 10, No. 5, 2008