A mild exchange reaction of xanthates with bromine

Article abstract of DOI:10.1055/s-2002-25343

Secondary S-alkyl-O-ethyl (or O-neopentyl) xanthates can be converted into the corresponding bromides by heating with ethyl 2-bromo-2-methylpropionate and cumyl peroxide in refluxing chlorobenzene; this transformation can be coupled to a xanthate transfer radical addition to an olefin.

Full text of DOI:10.1055/s-2002-25343

LETTER
811
A Mild Exchange Reaction of Xanthates with Bromine
A
F
Mild Excha
r
nge Reac
a
tion of
X
an
n
thates
w
ith B
c
romine is Barbier, François Pautrat, Béatrice Quiclet-Sire, Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Fax +33(1)69333851; E-mail: zard@poly.polytechnique.fr.
Received 14 March 2002
with the starting xanthate, this is a degenerate process that
does not compete with the desired bromine atom abstrac-
tion from ethyl 2-bromo-2-methylpropionate leading to
bromides 5a–f and isobutyryl radicals 6. In contrast to the
initial methyl radicals, the isobutyryl radicals 6 are too
stabilised to propagate the chain and presumably decay by
the usual radical-radical interactions (dimerisation and
disproportionation). Stoichiometric amounts of peroxide
are therefore required to ensure complete transformation
of the substrate.
Abstract: Secondary S-alkyl-O-ethyl (or O-neopentyl) xanthates
can be converted into the corresponding bromides by heating with
ethyl 2-bromo-2-methylpropionate and cumyl peroxide in refluxing
chlorobenzene; this transformation can be coupled to a xanthate
transfer radical addition to an olefin.
Key words: bromine atom transfer, xanthates, radical reactions,
lactones
We have, over the past few years, shown that xanthates 1
and related dithiocarbonate derivatives undergo an effi-
cient group transfer radical addition to a variety of olefins
1
2
(Scheme 1). The adducts, 3, are also xanthates and lend
themselves to a number of subsequent radical and non-
radical transformations. The xanthate group may thus be
2
used in another C-C bond forming radical sequence or re-
ductively removed using tri-n-butyltinhydride, Raney
nickel, nickel boride, or by the action of lauroyl peroxide
3
in isopropanol. Alternatively, the xanthate group can be
ionically cleaved to the corresponding thiol with alkali or
4
a primary or secondary amine. Alkylation of the resulting
thiol with 1,4-dibromobutane converts it to the sulfonium
bromide 4, which acts as a reasonably effective leaving
5
group. In the present Letter, we describe the direct trans-
formation of a secondary xanthate into the corresponding
Scheme 2
bromide 5, thus accessing an equally powerful nucleofuge
Indeed, gradual addition of cumyl peroxide (1.5 equiv) to
a refluxing solution of xanthate 3a–f (1.0 equiv) and ethyl
(
Scheme 1)
2
-bromo-2-methylpropionate (ethyl bromoisobutyrate)
(
5.0 equiv) in chlorobenzene resulted in the effective for-
6
mation of bromides 5a–f (30–85%). A fraction of the me-
thyl radicals is consumed by direct reaction with the
bromoisobutyrate; hence the need for over-stoichiometric
amounts of cumyl peroxide and an excess of the bromine
atom transfer agent. A number of examples is collected in
the Figure. Except for xanthate 3c, which gave only a poor
yield of the corresponding bromide, the desired conver-
sion occurred efficiently. The use of O-neopentyl xan-
thates in some cases was dictated by the need to facilitate
chromatographic separation of the bromide from the other
products of the reaction. We examined other peroxides
such as tert-butylperoxide and lauroyl peroxide as media-
tors for the reaction but these turned out to be generally in-
ferior to cumyl peroxide. Essentially all the precursors
were made by the xanthate transfer radical addition to ole-
fins containing various functional groups. Of special in-
terest are lactones 3e,f and 5e,f because they represent
sub-structures of many natural products.7
Scheme 1
Our concept is outlined in Scheme 2. Thermal decompo-
sition of cumyl peroxide generates highly reactive methyl
radicals which rapidly interact with the thiocarbonyl
group of the xanthate leading, by an addition-fragmenta-
tion sequence, to the formation of radicals R . Although
these radicals can exchange a xanthate group by reacting
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1
©
437-2096,E;2002,0,05,0811,0813,ftx,en;D05602ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

8
12
F. Barbier et al.
LETTER
Scheme 3 Conditions: cumyl peroxide 1.5 equiv. ethyl bromoiso-
butyrate 3 equiv. olefin 3 equiv. chlorobenzene (0.1 M). Reflux 6–8 h.
Scheme 4
One further interesting point concerns the choice of bro-
moisobutyrate as the bromine transfer agent. Our initial
experiments were in fact carried out with bromotrichlom-
ethane, a more commonly used bromine atom source.8
The results were disappointing: complex mixtures were
invariably obtained. We ascribed these initial failures to
the relatively high reactivity of the electrophilic trichlor-
omethyl radical generated upon bromine atom abstraction
from the bromotrichloromethane. Such radicals are
known to abstract hydrogen atoms leading to the uncon-
trolled formation of unwanted side products. Cristol and
Figure
We found in some cases that the intermolecular radical
addition to the olefin and the xanthate exchange with bro-
mine could be done in one pot, as illustrated by two exam-
ples pictured in Scheme 3. The yield in the second
example refers to the material obtained after one recrystal-
lisation of the concentrated reaction mixture. The actual
yield is obviously higher.
9
Seapy, who attempted to photochemically replace the C-
Not surprisingly, when the bromine atom was introduced
close to a nucleophilic site, a subsequent ionic cyclisation
was observed, as shown by the modestly efficient trans-
formations in Scheme 4. The formation of lactam 5i and
cyclic carbamate 5j could not be avoided due to the prox-
imity of the nucleophile in both cases. Such reactions are
nevertheless synthetically useful since the C-S bond of the
xanthate can be replaced by a C-N bond and a C-O bond
respectively.
O bond in xanhates using BrCCl , also obtained poor re-
sults.
3
In conclusion, we have described a simple, yet efficient
and flexible method for replacing a xanthate group with a
bromine atom under neutral conditions. A number of
functional groups commonly encountered in organic syn-
thesis are tolerated. This new functional group inter-
change process, in combination with the powerful C-C
bond forming ability of the xanthate transfer radical addi-
tion, opens access to structures not easily available other-
wise.
Synlett 2002, No. 5, 811–813 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Mild Exchange Reaction of Xanthates with Bromine
813
–
1
Acknowledgement
26.6 (CMe
), 15.0 (CH ). IR (CCl , cm ) 2962, 2250, 1777,
3 2 4
+
1
723, 1392, 1227, 1064. MS (CI): [MH] = 391,
We wish to thank Aventis Pharma for generous financial support
and Dr. Eric Bacqué for many friendly discussions.
+
[MNH ] = 408.
4
(
6) 0.20 g (0.5 mmol) of xanthate 3b and 0.49 g (2.5 mmol) of
ethyl 2-bromo-2-methylpropionate dissolved in 7 mL of
chlorobenzene were refluxed for a few minutes under
nitrogen before addition of 68 mg of commercially available
cumyl peroxide. While maintaining the reflux under
References
(
1) (a) Zard, S. Z. Angew. Chem. Int., Ed. Engl. 1997, 36, 672;
and references cited. (b) Quiclet-Sire, B.; Zard, S. Z.
Phosphorus, Sulfur Silicon Relat. Elem. 1999, 153.
nitrogen, the same amount of peroxide was added every 2 h
until complete disappearence of the starting xanthate. The
solvent was removed under reduced pressure and the residue
was purified by chromatography on silica gel (PE/EtOAc 9/
(
c) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon
Relat. Elem. 1999, 137; and references cited.
1
–7/3) to give after recrystallisation from ethanol 105 mg of
(
2) (a) Kim, S.; Song, H.-J.; Choi, T.-L.; Yoon, J.-Y. Angew.
Chem. Int. Ed. 2001, 40(13), 2524. (b) Ollivier, C.; Renaud,
P. J. Am. Chem. Soc. 2000, 122(27), 6496. (c) Ollivier, C.;
Renaud, P. J. Am. Chem. Soc. 2001, 123(20), 4717.
1
white crystals (mp 120 °C) 5b (70%). H NMR (CDCl , 400
3
MHz, ppm): = 7.90–7.85 (2 H, m), 7.78–7.40 (2 H, m),
.38 (1 H, m) 4.14 (1 H, dd, J = 7–14 Hz), 3.99 (1 H, dd, J =
–14 Hz), 2.72 (1 H, ddd, J = 4.5–8–17 Hz), 2.59 (1 H, td,
–17 Hz), 2.28 (1 H, m), 2.09 (1 H, m). C NMR (CDCl3,
00 MHz, ppm): = 167.9 (C=O), 134.5 (CHAr), 131.6
CqAr), 123.8 (CHAr), 118.4 (CN), 49.0 (CHBr), 43.8
4
7
8
1
(
(
(
d) Bertrand, F.; Le Guyader, F.; Liguori, L.; Ouvry, G.;
1
3
Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci.
Paris, Chimie 4 2001, 547. (e) Quiclet-Sire, B.; Seguin, S.;
Zard, S. Z. Angew. Chem. Int. Ed. 1998, 37(20), 2864.
–
1
CH ), 31.8 (CH ), 15.9 (CH ). IR (CCl , cm ): 2250, 1776,
(
f) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem.
2 2 2 4
+
1
724, 1392. MS (CI): [MNH ] = 324 and 326.
7) (a) Murakami, N.; Saka, M.; Shimada, H.; Matsuda, H.;
Int. Ed. 1999, 38 (13/14), 1943.
4
(
(
3) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett.
Yamahara, J.; Yoshikawa, M. Chem. Pharm. Bull. 1996,
4(6), 1279. (b) Jakupovic, J.; Castro, V.; Bohlmann, F.
Phytochemistry 1987, 26(2), 451. (c) Herz, W.; Sosa, V. E.
Phytochemistry 1986, 25(6), 1481. (d) Nagashima, F.;
Takaoka, S.; Asakawa, Y.; Huneck, S. Chem. Pharm. Bull.
994, 42(6), 1370. (e) Götz, M.; Bögri, A.; Gray, A. H.;
Strunz, G. M. Tetrahedron 1968, 24, 2631. (f) Tan, R. X.;
Jia, Z. J.; Zhao, Y.; Feng, S. L. Phytochemistry 1992, 31(9),
1996, 37, 5877.
4
(
(
4) Castro, E. A. Chem. Rev. 1999, 99, 3505.
5) (a) Boivin, J.; Pothier, J.; Ramos, L.; Zard, S. Z. Tetrahedron
Lett. 1999, 40, 9239. (b) Typical Procedure: 1 g
(
4.9 mmol) of xanthate 1a and 1.8 g (9.8 mmol) of olefin 2b
1
dissolved in 6 mL of 1,2-dichloroethane were refluxed for a
few minutes under nitrogen before addition of 98 mg
(
0.24 mmol) of commercially available lauroyl peroxide.
3
135. (g) Marco, J. A.; Sanz-Cervera, J. F.; Pareja, J. M.;
Sancenon, F.; Valles-Xirau, J. Phytochemistry 1994, 37(2),
77.
(8) (a) Barton, D. H. R.; Csuhai, E.; Doller, D. Tetrahedron
992, 48(42), 9195. (b) Moder, T. I.; Jensen, F. R. J. Am.
The reflux is maintained for another 2 h. The solvent was
then removed under reduced pressure and the residue was
purified by chromatography on silica gel (PE/EtOAc 9/1–7/
4
1
3) to give 1.8 g of a white solid (mp 107 °C) 3b (92%). H
1
NMR (CDCl , 200 MHz, ppm): = 7.92–7.83 (2 H, m),
3
Chem. Soc. 1975, 97(8), 2281. (c) Benedetti, M.; Forti, L.;
Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R. Tetrahedron 1997,
53(41), 14031. (d) See also: Yorimitsu, H.; Shinokubo, H.;
Matsubara, S.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Org.
Chem 2001, 66(23), 7776.
7
.80–7.70 (2 H, m), 4.30 (2 H, s), 4.29 (1 H, m), 4.03 (1 H,
dd, J = 7–14 Hz), 3.97 (1 H, dd, J = 7–14 Hz), 2.74–2.48
1
3
(
2H, m), 2.28–1.96 (2 H, m), 1.00 (9 H, s). C NMR (CDCl ,
3
50 MHz, ppm): = 212.0 (C=S), 168.0 (C=O), 134.4
(
(
CHAr), 131.9 (CqAr), 123.7 (CHAr), 118.7 (CN), 84.0
CH O), 48.8 (CHS), 40.4 (CH ), 32.0 (CMe ), 28.3 (CH ),
(
9) Cristol, S. J.; Seapy, D. G. J. Org. Chem. 1982, 47(1), 132.
2
2
3
2
Synlett 2002, No. 5, 811–813 ISSN 0936-5214 © Thieme Stuttgart · New York