Conversion of γ-substituted bicyclo[2.2.1] (Z)-vinylsulfones to the corresponding (E)-allylsulfones

Article abstract of DOI:10.1016/j.tetlet.2006.01.099

The preparation of bicyclo[2.2.1] (E)-allylsulfones starting from the corresponding (Z)-vinylsulfones is described. Starting from 2,3- bis(phenylsulfonyl)norbornadiene 1, the Michael addition of organometallic reagents followed by the base catalyzed isome

Full text of DOI:10.1016/j.tetlet.2006.01.099

Tetrahedron Letters 47 (2006) 2253–2256
Conversion of c-substituted bicyclo[2.2.1] (Z)-vinylsulfones
to the corresponding (E)-allylsulfones
Sergio Cossu,a,* Paola Peluso,b Flavio Morettoa and Mauro Marchettib
a
`
Dipartimento di Chimica, Universita Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
bIstituto di Chimica Biomolecolare ICB CNR, sezione di Sassari, Trav. La Crucca 3, Reg. Baldinca, I-07040 Li Punti, Sassari, Italy
Received 27 December 2005; revised 13 January 2006; accepted 17 January 2006
Available online 8 February 2006
Abstract—The preparation of bicyclo[2.2.1] (E)-allylsulfones starting from the corresponding (Z)-vinylsulfones is described. Starting
from 2,3-bis(phenylsulfonyl)norbornadiene 1, the Michael addition of organometallic reagents followed by the base catalyzed iso-
merization affords (E)-allylsulfones in high yields. The procedure allows to obtain vinylidenic norbornenes which are characteristic
nuclei of valuable biologically active compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
The synthesis of alkenes is a relevant field in organic
chemistry. The double bond is one of the most versatile
OH
functional groups in organic synthesis, founding
(Z)-(-)-β-santalol
widespread application in a series of synthetic transfor-
mations such as epoxidation, dihydroxylation, hydro-
formylation, metathesis, cross-coupling, conjugated
CHO
additions, polymerization and so forth. The growing
interest towards synthons or building blocks containing
®
DUPICAL
this functionality has prompted the development of a
(-)-β-santalene
(lily-of-the-valley odorant)
variety of alkenylation methods;1 among these, one of
the most used engages the Wittig reaction of carbonyl
OH
compounds or related reactions.2 However, both the ste-
ric demand as well as the structural rigidity of reactants
can make the condensation-type reactions inefficient.
Bridged polycyclic compounds are particularly sensitive
(E)-(-)-β-santalol
Figure 1.
to these effects, nevertheless, a number of valuable
biologically active compounds are characterized by a
bridged polycyclic skeleton bearing alkenyl substituents
pure or racemic form, no industrial viable process has
at the exocyclic position, such as the odour and fra-
yet been found. Therefore the perfumers have to mainly
grance compounds related to santalol and DupicalÒ
rely on cheaper synthetic substitutes.
(Fig. 1). The main constituents of natural sandalwood
oil have been synthesized starting from enantiopure 3-
Therefore, in connection with our interest on new syn-
methyl-2-norbornanones transforming the carbonyl
thetic strategies useful to achieve intermediates of
function to a vinylidenic group by means of Wittig-type
odours and fragrances related to santalol, we have
reactions.3 Despite all the synthetic attempts devoted to
developed an efficient and inexpensive way to prepare
the preparation of santalols in either enantiomerically
c-substituted bicyclo[2.2.1]allylarylsulfones containing
an exocyclic double bond linked to the bridged skeleton
at position 3 (Scheme 1).
Keywords: Polycyclic alkenes; Vinylsulfones; Allylsulfones; Alkene
isomerization; Grignard reagents.
*
We have previously reported on the reactivity of 2,3-
bis(phenylsulfonyl)norbornadiene 1 towards Grignard
Corresponding author. Tel.: +39 0 41 2348647; fax: + 39 0 41
2348517; e-mail: cossu@unive.it
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.099

2254
S. Cossu et al. / Tetrahedron Letters 47 (2006) 2253–2256
R
CH2R
SO2Ph
3
SO2Ph
SO2Ph
RCH2M
-PhSO2M
1 or 2 steps
SO2Ph
SO2Ph
1
SO2Ph
2
SO2Ph
M
CH2R
1
3
Scheme 1.
SO2Ph
R'Li
R
-R'H
H
1. RMgX (1 eq.)
THF, -10 oC
2. H
SO2Ph
R
SO2Ph
Li
R
H
R
H
SO2Ph
4
H
SO2Ph
1
2
Li
SO2Ph
SO2Ph
ii
i
Scheme 2.
Scheme 3.
reagents (Scheme 2).4 The reaction products are 3-aryl-
and 3-alkyl-2-phenylsulfonylnorbornadienes 2.
RMgX as the alkylating reagent, and of n-BuLi as base
was pursued. According to our procedures,4 a series of
3-alkyl-2-phenylsulfonyl norbornadienes, possessing dif-
ferent steric requirements has been prepared by reaction
between 1 and a suitable Grignard reagent (RMgX).
Compounds 3a–g (Table 1) have been treated with an
equivalent amount of n-BuLi at ꢀ20 °C. After 24 h at
room temperature the reaction cleanly furnishes the cor-
responding 3-alkenyl 4a–g derivatives. In all the cases,
flash chromatography of the crude reaction mixtures
(eluant: n-hexane/Et2O in a 7/3 ratio) gave chemically
pure compounds in very high yields (Table 1).
This Michael-type conjugated addition occurs through
an addition–elimination mechanism analogously to
what we have observed in the case of nucleophiles
centred on heteroatoms (O, S and N).5 Having a conve-
nient access to vinylsulfones of structure 3 containing
two active hydrogen atoms in the exocyclic c-position,
we have envisaged, based on the known chemistry of
arylsulfonyl stabilized carbanions,6,7 converting vinyl-
sulfones 3 to the corresponding allylsulfones 4 by a
base-induced c-deprotonation process. The strategy is
based on the formation of a stabilized allylic anion
species i (Scheme 3) a to the phenylsulfonyl group
(mesomer ii). The transformation is totally regioselec-
tive, converting c-substituted (Z)-vinylsulfones to the
corresponding allylsulfones of (E) stereochemistry. The
transformation, occurring through a reaction pathway
sterically controlled by the PhSO2-group, exclusively
furnishes endo oriented phenylsulfonyl isomers. This
chemistry constitutes a straightforward tool for endo-
cyclic to exocyclic isomerization of a C@C double bond
of substituted norbornadienic systems.
It is noted that, starting from 1, the synthetic process
could be realized in a single step by using two equiva-
lents of organolithium reagent (n-BuLi or MeLi) (Table
1, runs 2 and 5). Alternatively, under similar reaction
conditions, the use of Grignard reagents as base gave
poorer results, furnishing complex reaction mixtures.
Previously, Otera et al. observed the isomerization of
acyclic vinylsulfones to the corresponding allylsulfones
as a side reaction during the synthesis of acetylenes
from vinylsulfones.6 Successively, Inomata et al. have
reported the conversion of linear (E)- and (Z)-vinylsulf-
ones to the corresponding allylsulfones under mild basic
Both the nucleophilic and basic Grignard and organo-
lithium reagents have been carefully evaluated. An opti-
mized two-step route involving the sequential use of
Table 1. Alkylation-base induced isomerization of compound 1
R
1st
2nd
n-BuLi
(1eq.)
CHRR'
RR'CHMgX
(1 eq.)
R'
1
4
3
SO2Ph
SO2Ph
n-BuLi o MeLi (2 eq.)
#
R
R0
Reagent
Yield (%) first step
Yield (%) second step
endo/exo Ratio
1
2
3
4
5
6
7
H
H
Me
Me
n-Pr
Ph
H
H
H
Me
H
MeMgBr
MeLi
EtMgBr
i-PrMgCl
n-BuLi
82 (3a)
—
85 (3b)
60 (3c)
—
98 (4a)
98 (4a)
95 (4b)
Traces (4c)
92 (4d)
89 (4e)
65 (4f)
75/25
75/25
100/0
100/0
100/0
100/0
100/0
H
H
BnMgCl
AllylMgCl
72 (3e)
91 (3f)
Allyl
O
O
MgBr
O
O
8
H
78 (3g)
10 (4g)
100/0

S. Cossu et al. / Tetrahedron Letters 47 (2006) 2253–2256
2255
conditions (DBU).7 Moreover, they have found that
(E)-vinylsulfones preferentially afford (Z)-allylsulfones
as kinetically-controlled products, while (Z)-vinylsulf-
ones give (E)-allylsulfones exclusively. These results
were rationalized invoking the concept of conforma-
tional acidity (as a sort of kinetic acidity) related to a
‘syn-effect’ (as shown in Scheme 4), which was explained
in terms of 6p-electron homoaromaticity, r-orbital
interactions, dipole–dipole interactions and chelation.
modification introduced at the exocyclic position c to
the phenylsulfonyl group, by the substitution of one of
the hydrogen atoms with an alkyl group, inhibits the
deprotonation processes because of the difficulties to
arrange the phenylsulfonyl group and the internal
substituent of the alkyl moiety in a suitable position.
This effect was also observed in the case of the isopropyl
derivative 3c (Table 1, run 4) (Fig. 3) and the dioxolanic
derivative 3g (Table 1, run 8) making it difficult to
achieve tetrasubstituted olefin by this route.
In the case of polycyclic derivatives 3 only the (E)-iso-
mer can be obtained because of the hindered rotation
around the RC–C@C single bond (Fig. 2) due to steric
reasons.
As recently described by Knochel and co-workers,8 in
the case of 2-phenyl-3-alkylbicyclo[2.2.1]hept-2,5-dienes
the phenyl substituent can exert a stereoelectronic effect
similar to those aforementioned for the PhSO2-group.
In fact, the stabilization of the negative charge exerted
by the phenylsulfonyl group at the position a (Scheme
3, mesomer ii) requires a suitable interaction between
three pure p orbitals arranged in an almost parallel sit-
uation. Under these circumstances the substituents at
the c exocyclic position lie orthogonal to the pure p
orbital, therefore obliging one of the substituents to
occupy a position subjected to steric interactions with
the phenylsulfonyl group. As expected, even the slight
The structures of compounds 4a–g have been assigned
by NMR spectroscopy (NOESY, HMQC and HMBC).
In this regard, the case of 3f is representative (Fig. 4).
The presence of a vicinal coupling between H2 and H1
is helpful to recognize the exo configuration of H2.
Moreover the NOESY map shows a number of diagnos-
tic interactions: among these, particularly significant are
those between H2 and the vinylic exocyclic proton Hd,
as well as between Ha and H4 as the proposed structure
requires.9
H
Ts
In conclusion, it is possible to consider the vinylsulfone
functionality as a masked carbonyl function. Taking
into account this assumption and having interest in the
preparation of optically active alkenyl substituted
bis(phenylsulfonyl) norbornadienes, we have explored
the possibility to access this class of compounds through
an enantioselective addition of Et2Zn catalyzed by enan-
tiopure aminoalcohols. Therefore, in a preliminary
experiment, a THF sample of 1 was treated with Et2Zn
in the presence of optically pure (ꢀ)-ephedrine under the
classical conditions adopted for the aminoalcohol catal-
yzed Et2Zn addition to carbonyl compounds. We have
observed after 24 h that the reaction affords the optically
active 3-ethyl-2-phenylsulfonylnorbornadiene [20% ee
(HPLC): Chiralpak OT(+) (Daicel), MeOH 100%,
5 °C].
base
R1X
Y
H
R2
H
Ts
H
-H
+H
R1X
Y
R2
H
Y
Ts
H
H
Ts
H
-H
R1X
R1X
+H
Y
R2
R2
"syn
effect"
H
Ts
H
Ts
H
-H
H
R2Y
+H
R2Y
X
R1
H
X
"syn
X
R1
R1
Ts
H
effect"
R2Y
+H
-H
H
base
H3C
CH3
H
Ts
R2Y
X
Met
R1
SO2Ph
Scheme 4.
Figure 3.
H
H
NOESY
13C (HMBC, HMQC)
R
H
H
R
Hb
Hd
H7s
Ha
H4
H7a
H5
118.15
SO2Ph
SO2Ph
133.13
47.14
49.60
133.61
134.13
Hc
125.84
136.89
3f
H2
69.67
44.79
H6
(E)-alkene
(formed)
( )-alkene
(not formed)
Z
H1
SO2Ph
SO2Ph
Figure 2.
Figure 4.

2256
S. Cossu et al. / Tetrahedron Letters 47 (2006) 2253–2256
(b) Varela, J. A.; Pena, D.; Goldfuss, B.; Polborn, K.;
˜
Acknowledgements
Knochel, P. Org. Lett. 2001, 3, 2395–2398.
1
9. Compound endo-4a: H NMR (400 MHz, CDCl3): d 1.44
`
This work has been supported by Universita Ca’ Foscari
di Venezia (Fondi ex 60%). Thanks are due to Regione
Veneto (FSE Grant).
(db, 1H, J = 8.8 Hz, H7syn), 1.64 (dt, 1H, J = 8.8, 2.0 Hz,
H7anti), 3.04 (sb, 1H, H4), 3.29 (sb, 1H, H1), 4.20 (q, 1H,
J = 2.4 Hz, H2exo), 5.25 (d, 1H, J = 2.0 Hz, @CHH), 5.32
(d, 1H, J = 1.6 Hz, @CHH), 6.05 (dd, 1H, J = 5.6, 2.8 Hz,
H5), 6.13 (dd, 1H, J = 5.6, 3.2 Hz, H6), 7.52–7.67, 7.87–7.94
(series of m, 5H, Ar); 13C NMR (100 MHz, CDCl3, 1C
atom omitted): d 45.45, 49.81, 52.29, 69.00, 110.01, 128.71,
128.95, 133.07, 133.54, 135.08, 143.15. Compound exo-4a:
1H NMR (400 MHz, CDCl3): d 1.50 (dq, 1H, J = 9.2,
1.6 Hz, H7syn), 2.01–2.05 (m, 1H, H7anti), 3.17 (sb, 1H, H1),
3.28 (sb, 1H, H4), 3.49 (q, 1H, J = 2.0, H2endo), 5.11 (d, 1H,
J = 1.6 Hz, @CHH), 5.26 (dt, 1H, J = 2.0, 0.8 Hz, @CHH),
6.09 (dd, 1H, J = 5.6, 3.2 Hz, H6), 6.28 (dd, 1H, J = 5.6,
3.2 Hz, H5), 7.52–7.69, 7.87–7.97 (series of m, 5H, Ar); 13C
NMR (100 MHz, CDCl3): d 45.75, 46.29, 50.66, 67.46,
111.13, 128.69, 128.89, 129.12, 133.61, 135.57, 139.93,
142.82. Compound 4e: 1H NMR (400 MHz, CDCl3): d
1.42 (d, 1H, J = 8.7 Hz, H7syn), 1.66 (d, 1H, J = 8.7 Hz,
H7anti), 3.12 (sb, 1H, H1), 3.80 (sb, 1H, H4), 4.37 (t, 1H,
J = 3.0 Hz, H2exo), 6.08 (dd, 1H, J = 5.3, 2.6 Hz, H6), 6.18
(dd, 1H, J = 5.3, 2.9 Hz, H5), 6.97 (s, 1H, @CHPh), 7.24–
7.98 (m, 5H, Ar); 13C NMR (100 MHz, CDCl3): d 44.66,
48.01, 50.18, 69.92, 125.74, 127.06, 128.23, 128.34, 128.86,
128.98, 133.60, 134.05, 134.17, 136.62, 137.32, 139.32.
Compound 4f: 1H NMR (400 MHz, CDCl3): d 1.41 (d,
1H, J = 8.4 Hz, H7syn), 1.66 (dt, 1H, J = 8.6, 2.0 Hz,
H7anti), 3.03 (sb, 1H, H1), 3.73 (sb, 1H, H4), 4.25 (sb, 1H,
H6exo), 5.13 (dd, 1H, J = 10.4, 2.4 Hz, Hb), 5.25 (dd, 1H,
J = 16.8, 2.4 Hz, Hc), 6.01 (dd, 1H, J = 5.2, 2.4 Hz, H6),
6.05 (dd, 1H, J = 5.2, 3.2 Hz, H5), 6.49 (d, 1H, J = 10.4 Hz,
Hd), 6.54 (dt, 1H, J = 16.8, 10.8 Hz, Ha), 7.50–7.75, 7.79–
8.01 (series of m, 5H, Ar); 13C NMR (100 MHz, CDCl3): d
44.91, 47.14, 49.60, 69.67, 118.15, 125.84, 128.77, 128.93,
133.13, 133.59, 133.61, 134.13, 136.89, 139.42.
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