Convergent access to ketones, vinyl esters and vinyl bromides by a tin-free radical addition-intramolecular hydrogen atom transfer

Article abstract of DOI:10.1039/b212841a

Xanthate-mediated intermolecular radical addition, hydrogen atom transfer and sulfonyl radical elimination have been efficiently combined in a new convergent synthesis of ketones and substituted olefins.

Full text of DOI:10.1039/b212841a

Convergent access to ketones, vinyl esters and vinyl bromides by a
tin-free radical addition-intramolecular hydrogen atom transfer†
Gilles Ouvry* and Samir Z. Zard
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France.
E-mail: zard@poly.polytechnique; Fax: +33(0)169333851; Tel: +33 (0)169334872
Received (in Cambridge, UK) 3rd January 2002, Accepted 12th February 2003
First published as an Advance Article on the web 21st February 2003
9
Xanthate-mediated intermolecular radical addition, hydro-
gen atom transfer and sulfonyl radical elimination have been
efficiently combined in a new convergent synthesis of
ketones and substituted olefins.
radical onto the aromatic ring, was formed. In contrast to the
observations of Phillips and Whitham, who found that only the
threo isomer underwent the sequence depicted in Scheme 1, we
encountered no such limitation. This reflects the importance of
the relative long life of intermediate radical 3 in allowing
hydrogen abstraction even from the less favourable erythro
epimer.
The xanthate-mediated intermolecular radical addition has
1
emerged as a powerful synthetic tool. This process allows the
efficient addition of a carbon-centered radical to an unactivated
olefin and thus the creation of a new carbon–carbon bond under
mild, essentially neutral conditions. Recently, this methodology
has been successfully combined with the b-elimination and a-
The same transformation was accomplished using various
combinations of olefins and xanthates, as illustrated by the
examples compiled in Table 1. In the reaction between xanthate
1a and olefin 2b, we isolated a significant amount of p-
methoxyacetophenone (34%) in addition to the desired ketone
7b. Clearly in this case, intermolecular abstraction of the labile
tertiary benzylic hydrogen competes with the addition of the
radical to the terminal olefin. Various useful functional groups
can be introduced through the xanthate portion; in the case of
7d, the ready creation of a quaternary centre is worthy of
note.
Placing a suitable substituent on the oxygen would prevent
the conversion into a ketone and would lead to the re-
gioselective formation of an enol derivative instead. We found
that although addition to the TBS-protected hydroxysulfone 2c
took place smoothly, the intermediate enol silyl ether did not
survive the experimental conditions and only ketone 7e was
isolated in 57% yield. In contrast, the corresponding acetate 2d
provided the more robust enol acetates 6a and 6b in moderate
yield.10
2
scission of alkylsulfonyl radicals resulting in interesting tin-
free allylation,3 vinylation,4 azidation5 and acylation6 reac-
tions.
It seemed interesting to see if the use of xanthates as the
radical precursors and the b-elimination of sulfonyl radicals
could be combined with an intramolecular 1,5-hydrogen atom
abstraction into a synthetically useful process. Internal hydro-
gen abstractions have found occasional applications in organic
synthesis, sometimes with spectacular results.7 We took
inspiration from a study by Phillips and Whitham, who found
that, under the action of benzoyl peroxide, d-unsaturaterd bA-
hydroxysulfones rearranged into e-ketosulfones in modest to
good yield, as outlined in Scheme 1.8
Our concept is displayed in Scheme 2. Peroxide mediated
addition of xanthate 1 to olefin 2 leads to another xanthate 4,
which can fragment back to intermediate radical 3 through a
reversible radical addition-fragmentation sequence. The possi-
bility of continuous regeneration of radical 3 should allow the
desired intramolecular abstraction leading to radical 5 to occur
eventually. Rapid b-elimination of a methylsulfonyl radical
then gives adduct 6 and, in cases where X represents a hydroxy
group, this is followed by tautomerisation into the correspond-
ing ketone 7. The methylsulfonyl radical collapses into a
molecule of sulfur dioxide and a methyl radical which is capable
of propagating the chain. The required olefins 2 are readily
obtained by alkylation and reduction of the corresponding
ketosulfones.
In a further extension, we applied the sequence to bromo-
sulfone 2e which resulted in the formation of vinyl bromides in
satisfactory yield. Hydrogen abstraction is more favoured than
intramolecular transfer of the bromine atom.11 It is worth
underlining the compatibility of bromides with the xanthate
Indeed, when a solution of xanthate 1a and olefin 2a in
,2-dichloroethane was heated to reflux under an inert atmos-
1
phere and treated with lauroyl peroxide, a smooth reaction
occurred to give the expected diketone in 81% yield (Table 1).‡
No tetralone, resulting from cyclization of the intermediate
Scheme 1 Whitham’s rearrangement.
†
Dedicated with respect to Professor Gordon Whitham.
Scheme 2 General reaction manifold.
7
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CHEM. COMMUN., 2003, 778–779
This journal is © The Royal Society of Chemistry 2003

Table 1 Synthesis of olefins 6 and ketones 7
Entry
Xanthate 1
Olefin 2
Product 6 or 7
Yield
81%
1
2
1a
53%a
3
4
2a
2b
73%
58%
5
57%
6
7
1a
1b
38% Z+E 65+35
43% Z+E 65+35
2d
8
1b
65% Z+E 25+75
a
4-Methoxyacetophenone was also isolated in 34% yield.
based system for radical generation and capture. Such bromides
would not survive stannane based radical chemistry. Vinyl
bromide are useful starting materials in a plethora of organome-
tallic reactions.
2854, 1719, 1682, 1601, 1257, 1170. Calc. for C16
H
22
O
3
(%): C,73.25, H,
8
.45. Found (%): C,73.29; H, 8.53.
1
For two recent applications see: L. Chabaud, Y. Landais and P. Renaud,
Org. Lett., 2002, 4, 4257; F. Gagosz and S. Z. Zard, Org. Lett., 2002, 4,
In summary, this preliminary study has shown the possibility
of performing an intermolecular addition to an unactivated
olefin followed by an intramolecular hydrogen abstraction
leading to the ultimate removal of the xanthate from the product
and the regioselective introduction of a remote ketone function
or a vinyl acetate or bromide. Many of the products obtained
would be tedious to prepare by more conventional routes.
Finally, no tin or other heavy metals are involved in the process,
which uses cheap, readily available starting materials and
reagents
4
1
345; For a general review see: S. Z. Zard, Angew. Chem., Int. Ed. Engl.,
997, 36, 672; S. Z. Zard, Xanthates and Related Derivatives as Radical
Precursors, , in Radicals in Organic Synthesis, Eds. P. Renaud and M.
P. Sibi, Wiley-VCH, Weinheim, 2001, 1, , 90.
2 F. Bertrand, F. Leguyader, L. Liguori, G. Ouvry, B. Quiclet-Sire, S.
Seguin and S. Z. Zard, C. R. Acad. Sci., 2001, 4, 547.
3
4
B. Quiclet-Sire, S. Seguin and S. Z. Zard, Angew. Chem., Int. Ed. Engl.,
998, 37, 2864.
1
F. Bertrand, B. Quiclet-Sire and S. Z. Zard, Angew. Chem., Int. Ed.
Engl., 1999, 38, 1943.
C. Ollivier and P. Renaud, J. Am. Chem., Soc., 2001, 123, 4717.
S. Kim, H.-J. Song, T.-L. Choi and J.-Y. Yoon, Angew. Chem., Int. Ed.
Engl., 2001, 40, 2524.
For recent reviews, see: J. Robertson, J. Pillai and R. K. Lush, Chem.
Soc. Rev., 2001, 30, 94; L. Feray, N. Kurnetsov and P. Renaud
Hydrogen Atom Abstraction, , in Radicals in Organic Synthesis, Eds. P.
Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001, 2, , 246;For
examples of cascades involving hydrogen abstraction and b-elimination
of a sulfonyl radical, see: P. C. Van Dort and P. L. Fuchs, J. Org. Chem.,
1997, 62, 7142; L. Boiteau, J. Boivin, B. Quiclet-Sire, J.-B. Saunier and
S. Z. Zard, Tetrahedron, 1998, 54, 2087.
5
6
Notes and references
7
‡
Typical procedure: to a solution of xanthate 1a (105 mg, 0.38 mmol, 1.0
equiv.) and olefin 2a(112 mg, 0.58 mmol, 1.5 equiv.) in refluxing degassed
1
0
0
,2-dichloroethane (2 mL) was added lauroyl peroxide (DLP) (15.1 mg,
.038 mmol, 0.1 equiv.) under N atmosphere. DLP (15.1 mg, 0.038 mmol,
.1 equiv.) was added every hour until complete consumption of the starting
2
material. 80% DLP was needed to complete the reaction. The reaction was
cooled to room temperature and concentrated in vacuo. Purification by flash
chromatography (ethyl acetate–petroleum ether: 2+8) gave diketone 7a (106
8 E. D. Phillips and G. H. Whitham, Tetrahedron Lett., 1993, 34, 2541.
9 A. Liard, B. Quiclet-Sire, R. N. Saicic and S. Z. Zard, Tetrahedron Lett.,
1997, 38, 1759.
10 For an example of a decreased rate of hydrogen abstraction in the case
of an acetate, see: A. Gross, L. Fensterbank, S. Bogen, R. Thouvenot and
M. Malacria, Tetrahedron, 1997, 53, 13797.
1
mg, 81%) as colourless crystals (mp 64–65; ethanol). H NMR (400 MHz;
CDCl
H), 2.91 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.72
tt, J = 7.3, 7.3 Hz, 2H), 1.59 (tt, J = 7.4, 7.4 Hz, 2H), 1.40–1.32 (m,
3
) d ppm: 7.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.87 (s,
3
(
4
13
H). C NMR (100 MHz; CDCl
3
) d ppm: 209.3, 198.8, 163.4, 130.3, 130.2,
2
1
1
13.7, 55.5, 43.5, 38.2, 29.9, 29.2, 29.0, 24.4, 23.7; IR (CCl
4
, cm ): 2932,
11 C. H. Schiesser and L. M. Wild, Tetrahedron, 1996, 52, 13265.
CHEM. COMMUN., 2003, 778–779
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