New radical homoallylation reactions

Article abstract of DOI:10.1055/s-2003-41011

Xanthate addition to 3-aryl-4-methanesulfonylbutene and structurally related derivatives triggers a cascade involving aryl migration and elimination of a sulfonyl radical, the result being an overall homoallylation of the initial radical. Other slow migra

Full text of DOI:10.1055/s-2003-41011

LETTER
1627
New Radical Homoallylation Reactions
New
Radical
H
om
i
oallyla
l
R
e
l
actionses Ouvry, 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 16 June 2003
A carbon centered radical R, generated from xanthate 1,
adds to an olefin 2 containing a 1,2 migrating group (MG)
to give adduct radical 3, which can then undergo a revers-
ible 1,2 translocation into isomer 4. The equilibrium be-
tween species 3 and 4 is drained towards the desired
product by the subsequent b-elimination of a methane-
sulfonyl radical. Extrusion of sulfur dioxide produces the
highly reactive methyl radical, which propagates chain by
reacting with the initial xanthate. There are several 1,2-
migrating groups described in the literature. We first fo-
cused on aryls and their known neophyl rearrangement.8
Abstract: Xanthate addition to 3-aryl-4-methanesulfonylbutene
and structurally related derivatives triggers a cascade involving aryl
migration and elimination of a sulfonyl radical, the result being an
overall homoallylation of the initial radical. Other slow migrating
groups such as an ester can replace the aryl group.
Key words: radical homoallylation, xanthates, alkylsulfones, neo-
phyl rearrangement, Surzur–Tanner rearrangement
There is a recent trend to devise radical transformations
that do not involve organotin and other heavy metal inter-
mediates or reagents.1 In this respect, b-elimination and a-
scission of alkylsulfonyl radicals have found some inter-
esting applications2 such as tin-free allylations,3 vinyla-
tions,4 azidations5 and acylations.6 In the present Letter,
we describe a new homoallylation process, which com-
bines the ability of the xanthate transfer reaction for ac-
complishing intermolecular radical additions to
unactivated olefins7 with a 1,2-migration of a suitable
group and b-elimination of a sulfonyl radical. The overall
result is a homoallylation of the initial radical entity, as
depicted in the general manifold in Scheme 1.
The neophyl rearrangement (Scheme 2) is a relatively
slow process,9 with a rate constant of the order of 102s–1,
and therefore at the lower limit of synthetically useful val-
ues.10 It is not surprising that such rearrangements have
only scarcely been applied in synthesis.11 Indeed, crucial
to the success of our enterprise is the fact that the reaction
of radical 3 with xanthate 1, although fast, is reversible
and degenerate and therefore not in competition with the
desired but sluggish neophilic rearrangement leading to
radical 4 and ultimately to olefin 5.
S
Me
S
R
1
S
S
S
OEt
Me
Me
R
S
OEt
OEt
– SO2
Scheme 2
MG
MG
R
R
2
MeO2S
5
SO2Me
The various olefins 2a–e required for our study are readily
accessible. Compound 2a was obtained by an Ireland–
Claisen-type rearrangement of cinnamyl sulfinate (6), by
analogy with an earlier example in the literature.12 The
other substrates 2b–e18 were obtained by conjugate addi-
tion of vinylcuprate to the corresponding a,b-unsaturated
sulfones, available from the precursor aldehydes by the
classical Knoevenagel condensation, as shown in
Scheme 3.
1,2 radical
migration
MG
R
MG
R
4
3
SO2Me
SO2Me
R
S
S
1
OEt
MG
R
With a convenient and flexible route to the olefins in
hand, we set out to test our homoallylation scheme with
various xanthates. We were pleased to find that refluxing
a 1,2-dichloroethane solution of xanthates 1a–e and 1.5
equivalents of olefins 2a–d (2.0 equiv for olefin 1a) in the
presence of a small amount of lauroyl peroxide as initiator
resulted in a smooth transformation leading to the expect-
ed homoallylated products 5a–g.18 The results of these ex-
periments are assembled in Table 1.
MG : migrating group
SO2Me
Scheme 1
Synlett 2003, No. 11, Print: 02 09 2003. Web: 11 08 2003.
Art Id.1437-2096,E;2003,0,11,1627,1630,ftx,en;D14103ST.pdf.
DOI: 10.1055/s-2003-41011
© Georg Thieme Verlag Stuttgart · New York

1628
G. Ouvry, S. Z. Zard
LETTER
Table 1 Radical Addition/Aryl Shift/Sulfonyl Elimination (X = -SCSOEt)
Olefin 1
Xanthate 2
Product 3 (yield)
O
O
X
MeO
MeO
2a
1a
5a (57%)
CF3
O
MeO
CO2Et
CF3
2b
2b
1a
5b (60%)
O
O
O
N
O
O
X
O
N
CO2Et
1b
5c (63%)
Cl
Cl
O
O
O
N
C(O)Me
2c
2c
1b
5d (54%)
Cl
Cl
O
PhthN
O
PhthN
X
C(O)Me
S
1c
5e (64%)
O
O
X
F
C(O)Me
C(O)Me
F
2d
2d
1d
5f (33%)
S
O
O
X
1e
5g (37%)
The yield in most cases is quite acceptable, taking into ac- Under the same conditions, the radical cascade in the case
count the complexity of the sequence. Various aryl groups of olefin 2e was not satisfactory. However, by operating
can be implicated, even though in the case of the in the higher boiling chlorobenzene and by using tert-bu-
thiophene derivatives 5f,g, the yield is only modest. The tyl peroxide as initiator, it was possible to obtain, starting
1,2-migration of such electron-rich heteroaromatics is with xanthates 1b and 1f, the corresponding ring expand-
particularly slow.13 A high E-selectivity was observed for ed lactones 5h and 5i but in only 33% and 22% yield re-
disubstituted olefinic products (5b–g). The formation of a spectively (Scheme 4). The causes for the relatively poor
quaternary centre in example 5g is worthy of note since it outcome in this case are still not clear. Although a prece-
implies the addition of a tertiary radical with a nucleo- dent exists for such a ring enlargement,15 the of the present
philic character to a non activated olefinic bond.14
sequence offers the possibility of introducing a variety of
Synlett 2003, No. 11, 1627–1630 © Thieme Stuttgart · New York

LETTER
New Radical Homoallylation Reactions
1629
O
1) TMSOTf, Et3N
CH2Cl2, –78 °C
lauroyl peroxide,
OAc
OAc
N2
O
O
1a
+
2) Toluene, reflux
SO2Et
CH2ClCH2Cl
reflux
MeO
SO2Me
SO2Me
2a (34%)
6
5j (20%)
2f
E
ECH2SO2Me,
ArCHO
O
O
SO2Me
CF3
CH2=CHMgBr, CuI
THF, –78 °C
Ar
piperidine / AcOH
toluene, reflux
OAc
OAc
E
MeO
MeO
SO2Et
EtO2S
SO2Me
Ar
2b–e
OEt
Scheme 5
MeO2S
2b
O
Cl
Cl
S
allylated product 5j, but in a disappointingly low yield of
20% (Scheme 5). The sequence is thus feasible but still
requires considerable optimisation.
SO2Me
O
MeO2S
MeO2S
2c
O
In summary, the xanthate–sulfone system appears to be
extremely flexible, allowing exploitation of an otherwise
not very useful rearrangement. On one hand, the long life
of the intermediate radicals generated by means of the de-
generative xanthate transfer give the sluggish neophilic
rearrangement enough time to take place and, on the oth-
er, the elimination of a sulfonyl radical provides the driv-
ing force necessary to overcome its inherent reversibility
and pushes the equilibrium in the right direction. The ex-
perimental procedure is straightforward.17 In most cases,
the unoptimised yield is quite satisfactory and many func-
tional groups are tolerated. For the less efficient examples,
at least the feasibility has been demonstrated and further
work will hopefully allow us a better understanding of the
subtle interplay of the various parameters involved.
O
O
2d
2e
Scheme 3
R
tBuO-OtBu, N2
5h (33%)
5i (22%)
+ 2e
R
SC(S)OEt
Chlorobenzene
reflux
1b,f
O
O
R
R
SO2Me
SO2Me
O
O
O
O
References
O
O
O
1b, 5h R =
1f, 5i R =
O
N
(1) For reviews, see: (a) Baguley, P. A.; Walton, J. C. Angew.
Chem. Int. Ed. 1998, 37, 3072. (b) Studer, A. Synthesis
2003, 835.
Scheme 4
(2) Bertrand, F.; Leguyader, F.; Liguori, L.; Ouvry, G.; Quiclet-
Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci. 2001, 4, 547.
(3) (a) Xiang, J.; Evarts, J.; Rivkin, A.; Curran, D. P.; Fuchs, P.
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Chem. Soc. 1997, 119, 4123. (c) Gong, J.; Fuchs, P. L. J.
Am. Chem. Soc. 1996, 118, 4486. (d) Xiang, J.; Jiang, W.;
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38, 1943.
(5) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717.
(6) Kim, S.; Song, H.-J.; Choi, T.-L.; Yoon, J.-Y. Angew. Chem.
Int. Ed. 2001, 40, 2524.
(7) For reviews, see: (a) Zard, S. Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 672. (b) Quiclet-Sire, B.; Zard, S. Z.
Phosphorus, Sulfur Silicon Relat. Elem. 1999, 153, 137.
(c) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon
Relat. Elem. 1999, 154, 137. (d) Zard, S. Z. In Radicals in
Organic Synthesis, Vol. 1; Renaud, P.; Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001, 90.
substituents by simply altering the starting xanthate, with-
out the need to laboriously synthesize each substrate sep-
arately.
These preliminary studies on the neophyl rearrangement
demonstrated the validity of our conception and encour-
aged us to extend it to other slow migrating groups such
as esters. We thus investigated the possibility of incorpo-
rating a Surzur–Tanner16 rearrangement into our se-
quence. The 1,2-migration of ester groups has found some
applications in the carbohydrate and nucleoside field.17 In
our case, a linear, usefully functionalised structure would
be obtained.
Olefin 2f was prepared in a straightforward manner by
opening isoprenyl oxide with ethyl mercaptan, followed
by oxidation of the sulfide and acetylation of the tertiary
alcohol. Addition of lauroyl peroxide to a refluxing solu-
tion of xanthate 1a and 2 equivalents of olefin 2f in 1,2-
dichloroethane indeed furnished the expected homo-
Synlett 2003, No. 11, 1627–1630 © Thieme Stuttgart · New York

1630
G. Ouvry, S. Z. Zard
LETTER
(8) For a recent review on aryl transfers, see: Studer, A.;
Bossart, M. Tetrahedron 2001, 57, 9649.
1705, 1623, 1584, 1468, 1328, 1143, 1106 cm–1. MS (CI,
NH3): m/z [MNH4]+ = 311.
(9) (a) Newcomb, M. Tetrahedron 1993, 49, 1151.
(b) Newcomb, M. In Radicals in Organic Synthesis, Vol. 1;
Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001,
317.
(10) Curran, D. P. In Comprehensive Organic Synthesis, Vol. 4;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 715–777.
(11) (a) Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J.
Org. Chem. 1987, 52, 4072. (b) Parker, T. L.; Spero, D. M.;
Irman, K. Tetrahedron Lett. 1986, 27, 2833. (c) Ishibashi,
H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem.
2000, 65, 9022. (d) Ishibashi, H.; Ohata, K.; Niihara, M.;
Sato, T.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 2000, 547.
(12) Davidson, A. H.; Eggleton, N.; Wallace, I. H. J. Chem. Soc.,
Chem. Commun. 1991, 378.
(13) For another example, see: Ishibashi, H.; So, T. S.; Okochi,
K.; Sato, T.; Nakamura, N.; Nakatami, H.; Ikeda, M. J. Org.
Chem. 1991, 56, 95.
(14) Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard, S. Z. Synlett
2003, 382.
(15) Zheng, B. Z.; Dowd, P. Tetrahedron Lett. 1993, 34, 7709.
(16) (a) Surzur, J.-M.; Tessier, P. Bull. Soc. Chim. Fr. 1970,
3060. (b) Tanner, D. D.; Law, F. C. J. Am. Chem. Soc. 1969,
91, 7535. (c) Crich, D.; Beckwith, A. L. J.; Filzen, G. F.;
Longmore, L. W. J. Am. Chem. Soc. 1996, 118, 7422.
(d) For reviews on such rearrangements, see: Beckwith, A.
L. J.; Crich, D.; Duggan, P.; Yai, Q. Chem. Rev. 1997, 97,
3273. (e) See also: Crich, D. In Radicals in Organic
Synthesis, Vol. 2; Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001, 188.
To a solution of CuI (12 mmol) in THF (50 mL), was added
vinylmagnesium bromide (24 mL of a 1.0 M solution in
THF) at –78 °C under an inert atmosphere. The solution was
warmed to –40 °C for 10 min then cooled back to –78 °C. A
solution of the above vinylsulfone (2.93 g, 10.0 mmol) in
THF (20 mL) was added dropwise to the cuprate solution at
–78 °C under an inert atmosphere. The reaction was stirred
for 30 min then quenched with a sat. solution of NH4Cl (20
mL). The mixture was extracted with EtOAc (2 × 30 mL),
and the combined organic layers were washed with brine (20
mL), dried over MgSO4, concentrated in vacuo and purified
by flash chromatography on silica gel (EtOAc/petroleum
ether: 2/8) gave compound 1c (1.09 g; 34%; 5/1 mixture of
diastereoisomers.) as a pale brown solid which was used
without further purification. 1H NMR (400 MHz, CDCl3) d
= 7.41 (d, J = 1.9 Hz, 1 H), 7.24 (dd, J = 1.9, 8.6 Hz, 1 H),
7.16 (d, J = 8.6 Hz, 1 H), 6.03 (ddd, J = 8.3, 9.0, 18.6 Hz, 1
H), 5.29 (d, J = 18.6 Hz, 1 H), 5.23 (d, J = 9.0 Hz, 1 H),
4.72–4.51 (m, 2 H, CH-SO2), 3.02 (s, 1.5 H), 2.84 (s, 1.5 H),
2.34 (s, 1.5 H), 2.45 (s, 1.5 H) ppm. 13C NMR (100 MHz,
CDCl3) d = 200.8, 199.8, 148.0, 145.7, 137.4, 134.2, 133.7,
133.6, 130.6, 130.6, 130.3, 130.2, 129.7, 129.3, 120.5,
118.9, 77.2, 75.4, 45.5, 45.2, 39.7, 39.3, 33.7, 32.4 ppm. IR
(CCl4): 3505, 3087, 2930, 1721, 1586, 1472, 1356, 1325,
1121, 955 cm–1. MS (CI, NH3): m/z [MNH4]+ = 339.
Synthesis of Adduct 5d: To a solution of xanthate 1b (124
mg, 0.50 mmol) and olefin 1c (240 mg, 0.75 mmol) in
refluxing, degassed 1,2-dichloroethane (2 mL) was added
lauroyl peroxide (0.05 mmol) under an inert atmosphere.
Further portions of lauroyl peroxide were added every hour
until complete consumption of the starting xanthate (0.4
mmol in total; TLC monitoring). The reaction mixture was
cooled, concentrated in vacuo and purified by flash
chromatography on silica gel (EtOAc/petroleum ether: 5/5)
to give compound 5d (100 mg; 54%) as a white solid. 1H
NMR (400 MHz, CDCl3): d = 7.41 (d, J = 2 Hz, 1 H), 7.26
(dd, J = 2.0, 8.3 Hz, 1 H), 7.18 (d, J = 8.3 Hz, 1 H), 6.80 (dd,
J = 7.3, 16.0 Hz, 1 H), 6.1 (d, J = 16.0 Hz, 1 H), 4.41 (t,
J = 8.2 Hz, 2 H), 4.10 (ddd, J = 7.3, 7.3, 7.3 Hz, 1 H), 4.0 (t,
J = 8.2 Hz, 2 H), 2.95 (ddd, J = 6.7, 8.8, 17.3 Hz, 1 H), 2.87
(ddd, J = 6.0, 8.5, 17.3 Hz, 1 H), 2.25 (s, 3 H), 2.26 (m, 1 H),
2.12 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): d = 198.3,
172.4, 153.5, 147.3, 137.2, 134.9, 133.5, 131.3, 129.8,
129.3, 127.8, 62.2, 42.6, 42.3, 32.7, 29.1, 27.5. IR (CCl4):
2923, 1791, 1702, 1682, 1473, 1384, 1360, 1222, 1104, 1047
cm–1. MS (CI, NH3): m/z [MNH4]+ = 388, [MH]+ = 371.
Anal. Calcd for C17H17Cl2NO4 (%): C, 55.15; H, 4.63. Found
(%): C, 54.96; H, 4.71.
(17) (a) Giese, B.; Groningen, K. S. Org. Synth. 1990, 69, 66.
(b) Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118,
9190. (c) Gimisis, T.; Ialongo, G.; Chatgilialiglu, C.
Tetrahedron 1998, 54, 573.
(18) Typical Experimental Procedures: Synthesis of olefin 2c:
A solution of 2,4-dichlorobenzaldehyde (2.00 mL, 18.0
mmol) and methylsulfonylmethyl methylketone19 (2.44 g,
18.0 mmol) in toluene (12 mL) was refluxed in a Dean–Stark
apparatus. A few drops of piperidine and few drops of acetic
acid were added to the solution. Once complete (TLC), the
reaction was cooled to r.t., concentrated in vacuo and
purified by flash chromatography on silica gel (EtOAc/
petroleum ether: 15/85) to give 4-(2¢,4¢-dichlorophenyl)-3-
methylsulfonyl-but-3-en-2-one (76%, 12/1 mixture of
isomers, 4.00 g) as pale green solid, which was used directly
in the next step. 1H NMR (400 MHz, CDCl3, major isomer
only): d = 7.99 (s, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 7.30 (dd,
J = 2.0, 8.3 Hz, 1 H), 7.17 (d, J = 8.3 Hz, 1 H), 3.20 (s, 3 H),
2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major
isomer only): d = 199.6, 143.4, 137.9, 137.0, 135.4, 130.5,
130.3, 128.5, 127.7, 43.1, 31.6 ppm. IR (CCl4): 2927, 2360,
(19) Attanasi, O. A.; Filippone, P.; Santensanio, S.; Serra-
Zanetti, F. Synthesis 1987, 381.
Synlett 2003, No. 11, 1627–1630 © Thieme Stuttgart · New York