Highly regioselective decarboxylative Claisen rearrangement reactions of diallyl 2-sulfonylmalonates

Article abstract of DOI:10.1016/j.tetlet.2007.08.130

The decarboxylative Claisen rearrangement of a range of substituted diallyl 2-sulfonylmalonates is described. The substrates are made by C-carboxylation of the corresponding allyl sulfonylacetates with allyl para-nitrophenyl carbonates. The reactions display a high degree of regioselectivity, with allylic substituents possessing electron-rich substituents at the allyl three-position rearranging preferentially.

Full text of DOI:10.1016/j.tetlet.2007.08.130

Tetrahedron Letters 48 (2007) 7861–7864
Highly regioselective decarboxylative Claisen
rearrangement reactions of diallyl 2-sulfonylmalonates
Donald Craig,a,* Mark I. Lansdellb and Simon E. Lewisa
aDepartment of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
bDiscovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 2 July 2007; revised 23 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—The decarboxylative Claisen rearrangement of a range of substituted diallyl 2-sulfonylmalonates is described. The
substrates are made by C-carboxylation of the corresponding allyl sulfonylacetates with allyl para-nitrophenyl carbonates. The
reactions display a high degree of regioselectivity, with allylic substituents possessing electron-rich substituents at the allyl three-
position rearranging preferentially.
Ó 2007 Elsevier Ltd. All rights reserved.
The Claisen rearrangement continues to be the focus of
considerable research effort.1 Since its introduction in
1972,2 the Ireland silyl ketene acetal variant in particular
has been widely used in complex target-oriented synthe-
sis.3 This modified process benefits from the ease of
preparation of the ketene acetal substrates and the rela-
tively mild conditions for the sigmatropic rearrange-
ment. In addition, it enables overall C-allylation of
carboxylic acids using allylic alcohols as the surrogate
electrophiles, with regiospecific allylic double-bond
transposition. We recently reported4,5 a novel variant
of the Ireland–Claisen rearrangement reaction in which
a-tosyl silyl keteneacetals formed in situ from allylic
tosylacetates 1 in the presence of sub-stoichiometric
amounts of N,O-bis(trimethylsilyl)acetamide (BSA)
and potassium acetate undergo thermally induced
[3,3]-sigmatropic rearrangement followed by acetate-
induced desilylation–decarboxylation to provide homo-
allylic sulfones 2 in a single step.6,7 We subsequently8
showed that introduction of an additional electron-with-
drawing a-substituent enables malonyl substrates 3 to
undergo decarboxylative Claisen rearrangement (dCr)
to provide a-carboxyhomoallyl sulfones 4 at ambient
temperature (Scheme 1).
O
BSA (0.1 or 1 equiv.)
KOAc (0.1 equiv.)
Ts
R
Ts
R
O
PhMe, 110 °C
1
2
or microwave irradiation
OSiMe3
O
OSiMe3
O
[3,3]
Ts
R
Ts
R
BSA (1 equiv.)
KOAc (0.1 equiv.)
O
O
O
O
R
Ts
MeO
MeO
Ts
R
CH2Cl2, 25 °C
3
4
Scheme 1.
These diallyl esters are in principle able to undergo
two dCr reaction cycles within the same molecule. We
anticipated that substrates such as 5 would be converted
into monorearrangement products 6 when subjected to
the mild reaction conditions shown to be effective for
substrates 3 (Scheme 2). Further reaction of 6 was not
expected, since although sulfonylesters 6 are themselves
substrates for a second dCr reaction cycle, they lack the
additional electron-withdrawing a-substituent necessary
for reaction at ambient temperature. Intramolecular
competition experiments have been reported previ-
ously9–13 for the Claisen and related rearrangements.
We became interested in the properties of unsymmetri-
cal 2-tolylsulfonylmalonyl dCr substrates such as 5.
Keywords: Carboxylation; Claisen rearrangement; Microwave-assisted
synthesis; Regioselectivity; Substituent effects.
*
Corresponding author. E-mail: d.craig@imperial.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.130

7862
D. Craig et al. / Tetrahedron Letters 48 (2007) 7861–7864
O
R1
6
O
R2
O
O
Ts
and/or
R1
O
O
R2
O
Ts
5
R1
O
R2
Ts
Scheme 2.
O
R1
O
Ts
O
O
1
NaH (2 equiv.)
DMF, 25 ˚C
R1
O
O
R2
+
Ts
O2N
5
O
O
O
R2
7
Scheme 3.
However, the substrates utilised possessed a single ester
grouping, which was derived from a doubly allylic sec-
ondary alcohol. Additionally, competition in the
decarboxylative variant has not been studied to date.
During the synthesis of 5g, c-lactone 8 was formed as
a by-product in 35% yield (entry 8), presumably by
intramolecular 5-exo-trig addition of the 2-sulfonylm-
alonyl enolate to the 4-nitrostyryl group.15
O2N
Previously,8 2-tolylsulfonylmalonate dCr substrates 3
were synthesised by sulfonylation of the corresponding
malonates with tosyl fluoride under basic conditions at
high concentration. In the present study, we adopted
an alternative synthetic approach based on C-carboxyl-
ation. Esters 1 were generated14 by straightforward acyl-
ation of allylic alcohols using commercially available
tosylacetic acid (DIC, CH2Cl2, 0 °C!25 °C; 65–94%
yields). Carbonates 7 were prepared14 by the reaction
of allylic alcohols with 4-nitrophenyl chloroformate
(Et3N, CH2Cl2, 0 °C!25 °C; 76–91% yields). Reaction
of the sodium salts of 1 with 7 provided diallyl 2-sulfon-
ylmalonates 5 in moderate yields (Scheme 3, Table 1).
O
O
Ph
8
Ts
O
O
With a variety of dCr substrates 5 in hand, their rear-
rangement behaviour was studied. Substrate 5b under-
went smooth dCr reaction at 25 °C in 2 h, furnishing a
1:1 diastereomeric mixture of rearrangement product
6b as a single regioisomer in high yield (Scheme 4).
That the products were those of methoxycinnamyl side-
chain rearrangement was confirmed by X-ray crystallo-
graphic analysis16 of one of the diastereomers 6b
(Fig. 1). Encouraged by this complete regioselectivity,
we explored the rearrangement reactions of substrates
5a and 5c–h (Scheme 5). The results of all the dCr reac-
tions of 5 are collected in Table 2.
Table 1. Synthesis of diallyl 2-sulfonylmalonates 5
Entry R1
R2
Product Yield (%)
1
2
3
4
5
6
7
8
9
4-MeOC6H4
4-MeOC6H4
E-MeCH@CH C6H5
E-MeCH@CH 5a
16
39
30
46
56
2
28
23
17
C6H5
5b
5c
5d
5e
5f
Et
C6H5
C6H5
Me3SiC„C
C6H5
C6H5
H
H
C6H5
Several features of these results merit comment. Firstly,
the complete regioselectivity observed for substrate 5b
was seen for many of the other substrates also. It seems
unlikely that the remote vinylic substituents on the
Me3SiC„C
4-O2NC6H4
Me3SiC„C
5f
5g
5h
O
O
O
BSA (1 equiv.)
KOAc (0.1. equiv.)
O
Ph
O
O
Ph
Ts
sole product
6b
CH2Cl2, 25 ˚C
2 h
Ts
5b
MeO
MeO
Scheme 4.

D. Craig et al. / Tetrahedron Letters 48 (2007) 7861–7864
7863
reaction temperatures and longer reaction times, and
yields of 6 were lower. In the most extreme instance,
substrate 5h was found to be inert to conventional ther-
mal conditions, and use of microwave irradiation was
necessary to induce rearrangement, giving 6h in modest
yield.18
It seems likely that dCr reaction selectivity is influenced
by steric as well as electronic factors. For example, the
unexpected skipped diene product 5c, in which conjuga-
tive stabilisation has been lost, may arise from the less
sterically congested of the two possible regioisomeric
transition states. The electronic effect is demonstrated
unambiguously by substrates 5b and 5g, in which differ-
ing aryl para-substituents are distant from the reactive
array and therefore will not sterically influence the regio-
selectivity. For substrates 5f and 5h we ascribe the low
reactivity of the trimethylsilylethynyl-substituted allyl
moiety to the electron-withdrawing nature of silicon.
Figure 1. The molecular structure of one of the diastereomers 6b.
Precedent does exist for rate enhancement in the Ire-
land–Claisen rearrangement with an electron-donating
substituent on the terminal alkene carbon atom of the
allylic moiety. Curran has shown19 that the presence
of an oxygen atom in this position leads to an increase
in the rate of one or more orders of magnitude. This
effect (which has been studied computationally20) is
rationalised as a ‘vinylogous anomeric’ (p!r*) stabili-
sation19d,21 of the transition state, in that weakening of
the allylic C–O bond facilitates its cleavage upon going
to an early transition state,22,23 in which bond-breaking
may be significantly more advanced than bond-mak-
ing.24 The observations that an oxygen substituent at
the allylic position leads to a similar rate acceleration,19e
and that solvent effects19e,23c and H-bonding additives19f
are significant provide further support for the idea of a
dipolar transition state. Such an argument could equally
allylic moieties have an influence upon the regiochem-
istry of silyl ketene acetal formation. Facile interconver-
sion of the regioisomers may take place in a bimolecular
fashion, via acetate-mediated desilylation–resilylation or
intramolecularly, by a [1,5]-silatropic shift.17 Following
this analysis we interpret the selectivity in terms of the
inherent reactivity of the competing allylic groups. The
only substrates for which total regioselectivity was not
observed were 5d and 5g (entries 4 and 7). In these
instances the phenyl-substituted side-chain was more
reactive.
Overall, a preference for the reaction of electron-rich
side-chains was observed. As indicated in Table 2, sub-
strates with less electron-rich side chains required higher
O
O
O
BSA (1 or 2 equiv.)
KOAc (0.1 equiv.)
R1
O
R2
R1
O
O
R2
Ts
6a-h
Ts
5a-h
Scheme 5.
Table 2. Decarboxylative rearrangement reactions of diallyl 2-sulfonylmalonates 5a–h
Entrya
Substrate
Product
R1
R2
T (°C)
t (h)
Yield (%)
1
2
3
4b,c
5b,c
6
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
4-MeOC6H4
4-MeOC6H4
E-MeCH@CH
Ph
Ph
Ph
Ph
H
E-MeCH@CH
Ph
Ph
Et
0
25
25
55
110
25
2
2
16
4
16
16
16
95
81
79
84d
66
82
29e
26
H
Me3SiC„C
4-O2NC6H4
Me3SiC„C
7
8f
5g
5h
6g
6h
25
130
0.08
a Reactions were carried out in CH2Cl2 using 1.0 equiv of BSA unless otherwise stated.
b Toluene was used as a solvent.
c 2.0 equiv of BSA was used.
d The product was formed as a 3:1 mixture of regioisomers 6d (R1 = Ph, R2 = Et) and 6d (R1 = Et, R2 = Ph).
e The product was formed as a 3:1 mixture of regioisomers 6g (R1 = Ph, R2 = 4-O2NC6H4) and 6g (R1 = 4-O2NC6H4, R2 = Ph).
f Reaction was carried out under microwave irradiation conditions.

7864
D. Craig et al. / Tetrahedron Letters 48 (2007) 7861–7864
11. Mulzer, J.; Bock, H.; Eck, W.; Buschmann, J.; Luger, P.
Angew. Chem., Int. Ed. 1991, 30, 414–416.
12. Broadhurst, M. J.; Brown, S. J.; Percy, J. M.; Prime, M. E.
J. Chem. Soc., Perkin Trans. 1 2000, 3217–3226.
be applied to our substrates 5a,b, albeit with the conju-
gated oxygen further removed from the reacting array.
In summary, electronic selectivity of the decarboxylative
Claisen rearrangement in bifunctional substrates has
been demonstrated. We have recently completed a quan-
titative kinetic study of these effects.25 Current investiga-
tions in our laboratory are directed towards effecting the
double rearrangement of diallyl 2-sulfonylmalonates 5
and employing the resultant 1,6-dienes in the synthesis
of carbocyclic and heterocyclic natural and unnatural
products. The results of these investigations will be re-
ported in due course.
13. (a) Zhang, X.; McIntosh, M. C. Tetrahedron Lett. 1998,
39, 7043–7046; (b) Hong, S.; Lindsay, H. A.; Yaramasu,
T.; Zhang, X.; McIntosh, M. C. J. Org. Chem. 2002, 67,
2042–2055; (c) Hutchison, J. M.; Hong, S.; McIntosh, M.
C. J. Org. Chem. 2004, 69, 4185–4191; (d) McFarland, C.;
Hutchison, J.; McIntosh, M. C. Org. Lett. 2005, 7, 3641–
3644.
14. See Supplementary data for full experimental details.
15. The structure of 8 was assigned by X-ray crystallographic
analysis, for which we thank Dr. A. J. P. White (Imperial
College). Details are provided in the Supplementary data.
16. The structure was solved for the more crystalline
diastereoisomer of 6b, which was crystallised selectively
from the mixture. In general, mono-dCr reactions of
substrates 5 gave products 6 in diastereoisomeric ratios
between 1:1 and approximately 2:1. We thank Dr. A. J. P.
White (Imperial College) for the analysis.Crystal data for
6b: C28H28O5S, M = 476.56, monoclinic, Pn (no. 7),
Acknowledgements
We thank EPSRC and Pfizer Global Research and
Development (Industrial Training Grant to S.E.L.) for
support.
˚
a = 8.1024(11), b = 6.0389(19), c = 25.8931(15) A, b =
3
ꢀ3
,
˚
91.852(13)°, V = 1266.3(4) A , Z = 2, Dc = 1.250 g cm
l(Cu-Ka) = 1.426 mmꢀ1, T = 293 K, colourless prisms,
Bruker P4 diffractometer; 2035 independent measured
reflections, F2 refinement, R1 = 0.055, wR2 = 0.128, 1277
independent observed absorption-corrected reflections
[jFoj > 4r(jFoj), 2hmax = 120°], 297 parameters. The abso-
lute structure of 1 was determined by a combination of R-
factor tests [Rþ1 ¼ 0:0545; Rꢀ1 ¼ 0:0569] and by use of the
Flack parameter [x+ = +0.13(9), xꢀ = +0.87(9)]. CCDC
658206.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.08.130.
References and notes
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