Stereoselective oxymercuration of cyclopropylcarbinols with anchimeric assistance by aromatic groups

Article abstract of DOI:10.1016/S0040-4039(02)00069-2

Cyclopropylcarbinols bearing an adjacent stereocenter substituted by a phenyl group undergo anchimerically assisted mercurations, leading after reductive demercuration to oxygenated heterocycles or acyclic alcohols depending on the relative configurations

Full text of DOI:10.1016/S0040-4039(02)00069-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1801–1805
Stereoselective oxymercuration of cyclopropylcarbinols with
anchimeric assistance by aromatic groups
Janine Cossy,* Nicolas Blanchard and Christophe Meyer
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 26 November 2001; revised 7 January 2002; accepted 8 January 2002
Abstract—Cyclopropylcarbinols bearing an adjacent stereocenter substituted by a phenyl group undergo anchimerically assisted
mercurations, leading after reductive demercuration to oxygenated heterocycles or acyclic alcohols depending on the relative
configurations. © 2002 Elsevier Science Ltd. All rights reserved.
OR2
Organomercurials are frequently encountered interme-
diates in organic synthesis.1 The usual role of mercury
R = CH2OPiv
OH
R1O
is to introduce another associated nucleophilic reagent
and in most cases, after having served its purpose,
mercury is removed by reduction.1,2 This strategy is
exemplified by the oxymercuration of carbonꢀcarbon
double bonds1 and by cyclopropane ring cleavage.3 The
stereocontrolled synthesis of cyclopropanes followed by
inter- or intramolecular ring-opening is an attractive
strategy for the preparation of acyclic and heterocyclic
compounds bearing contiguous stereogenic centers.4,5
We have recently shown that stereotriads B could be
generated by oxymercuration–reduction of cyclopropyl-
carbinols of type A bearing an appropriately protected
hydroxymethyl group at C-4 (R=CH2OPiv).6 Here, we
would like to report that the mercuration–demercura-
tion of cyclopropylcarbinols of type A with a phenyl
group at C-4 (R=Ph) follows a different pathway and
leads to cyclic products of type C and/or linear prod-
ucts of type D and E, due to anchimeric assistance by
the aromatic substituent (Scheme 1).
a,b
B
H
H
1
R1 = H or Piv
R2 = Piv or H
OH
R
3
2
4
A
Ph
a,b
R = Ph
O
C
OH
Ph
Ph
OH
D
E
Scheme 1. Oxymercuration of cyclopropylcarbinols of type A.
Reagents and conditions: (a) Hg(OCOCF3)2, CH2Cl2; (b)
reductive demercuration.
Sm-promoted cyclopropanations to give the diastereo-
meric cyclopropylcarbinols 1 and 2 (Scheme 2).10,11
For this study, four cyclopropylcarbinols 1–4 were pre-
pared. Cyclopropylcarbinols 1 and 2 were synthesized
from 2-phenylpropanal 5. The latter aldehyde was first
transformed to the dibromoolefin 6 (85%).7 After treat-
ment of the dibromoolefin 6 with 2 equiv. of n-BuLi in
THF at −100°C,8 the resulting acetylide was quenched
with paraformaldehyde and the propargylic alcohol 7
(95%) was isolated. Reduction of the triple bond with a
zinc–copper couple afforded the corresponding (Z)-
allylic alcohol 8 (79%),9 which was subjected to Zn- or
Cyclopropylcarbinols 3 and 4 were synthesized in four
steps from 3-phenylprop-1-yne 9. Upon treatment of 9
with 2 equiv. of n-BuLi in THF at −20°C, the resulting
dianion12 was regioselectively alkylated with 3-bromo-
1-benzyloxypropane. Subsequent addition of para-
formaldehyde led to the propargylic alcohol 10 (85%).
Since the (Z)-allylic alcohol 13 could not be obtained
by reduction of 10 with the zinc–copper couple in
refluxing isopropanol,9 a two-step procedure was used.
The syn-hydrostannation of propargylic alcohol 10
13
with n-Bu3SnH catalyzed by Pd(PPh3)4 afforded two
* Corresponding author. Tel.: +33.1.40.79.46.63; fax: +33.1.40.79.
46.60; e-mail: janine.cossy@espci.fr
regioisomeric vinylstannanes 11 and 12 in a ratio of
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00069-2

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J. Cossy et al. / Tetrahedron Letters 43 (2002) 1801–1805
Table 1. Mercuration–demercuration of cyclopropyl-
H
H
Ph
OH
carbinols 1–4
a
b
Br
Ph
Ph
O
85%
95%
1) Hg(OCOCF3)2
Br
CH2Cl2, rt, then NaCl
6
7
5
Products (yield)
Substrates
2) LiAlH4, THF
c
79%
OH
(58%)4a
OH
d or e
OH
n-Bu
n-Bu
OH
OH
Ph
Ph
14
15
8
1
Ph
reagents
yield
1/2 ratio
OH
Ph
(11%)
Ph
Et2Zn/ICH2Cl
Sm/ICH2Cl
88%
74%
80/20
30/70
OH
Ph
2
O
16
OH
1
Ph
Scheme 2. Preparation of cyclopropylcarbinols 1 and 2.
Reagents and conditions: (a) PPh3, CBr4, CH2Cl2; (b) n-BuLi,
THF, −100°C, (CH2O)n, −78°C to rt; (c) Zn, Br(CH2)2Br,
CuBr, LiBr, THF/i-PrOH; (d) Et2Zn, ICH2Cl, DCE, −23°C;
(e) Sm(Hg), ICH2Cl, −50 to −20°C, THF.
OH
(21%)
(13%)
18
17
Ph
OH
OH
Ph
(65%)
2
O
19
95:5 in 90% overall yield. The allylic alcohol 13 was
obtained by transmetallation of 11 and 12 with n-BuLi
in THF followed by hydrolysis. Cyclopropanation of 13
according to the previously reported methods afforded
cyclopropylcarbinols 3 and 4 (Scheme 3).11
O
Ph
OR
OBn
Ph
R = Bn 25
3
(9%)
R = H 26 (41%)
Cyclopropylcarbinols 1–4 were then treated with 2
equiv. of mercuric trifluoroacetate followed by an
aqueous work-up with a saturated aqueous solution of
NaCl. The resulting intermediate organomercuric chlo-
rides were then subjected to reductive demercuration
with LiAlH4 in THF (Table 1).
Ph
Ph
OH
OBn
BnO
O
29,30
(78%)
d.r. = 70/30
4
The formation of diol 15 has been previously reported
in the case of cyclopropylcarbinol 14.4a The high
R2
R1
regioselectivity usually observed in the oxymercuration
of substituted cyclopropylcarbinols has been explained
by electrophilic ring-opening by Hg2+ of the most elec-
tron-rich bond of the three-membered ring, in consider-
ation of the inductive effect of the neighboring
electron-withdrawing hydroxymethyl moiety.4a,5c
OH
Ph
Ph
OH
a
b
Ph
85%
90%
OBn
OBn
9
10
R1 = H, R2 = SnBu3
R1 =SnBu3, R2 = H
11
12
11/12 = 95/5
When subjected to the mercuration–demercuration, the
anti,cis-cyclopropylcarbinol 1 was converted to a mix-
ture of products, from which three major components
were isolated by flash chromatography: the trisubsti-
tuted tetrahydrofuran 16 (11%),14 the known homoal-
lylic alcohols 1715 (13%) and 1816 (21%). By contrast,
the syn,cis-cyclopropylcarbinol 2 was exclusively con-
verted to the trisubstituted tetrahydrofuran 19 (65%),
obtained as a single diastereomer.14
c
77%
Ph
OH
Ph
OH
d or e
OBn
3
4
OBn
13
Ph
OH
OBn
reagents
yield
3/4 ratio
Et2Zn/ICH2Cl
Sm/ICH2Cl
85/15
40/60
92%
87%
In the case of cyclopropylcarbinols 1 and 2, the forma-
tion of tetrahydrofurans 16 and 19 as well as the acyclic
homoallylic alcohols 17 and 18 is explained by the
anchimeric assistance by the phenyl group adjacent to
the cyclopropane ring. We note that electrophilic ring
opening of the cyclopropane by Hg2+ with concomitant
participation of the phenyl group can only occur in a
conformation in which overlap of the aromatic p-sys-
Scheme 3. Preparation of cyclopropylcarbinols 3 and 4.
Reagents and conditions: (a) n-BuLi (2 equiv.), THF, −20°C,
then Br(CH2)3OBn, −20 to −10°C, (CH2O)n, −10°C to rt; (b)
Bu3SnH, cat. Pd(PPh3)4, THF, rt; (c) n-BuLi, THF, −78 to
−60°C, then aq. NH4Cl; (d) Et2Zn, ICH2Cl, DCE, −23°C; (e)
Sm(Hg), ICH2Cl, −50 to −20°C, THF.

J. Cossy et al. / Tetrahedron Letters 43 (2002) 1801–1805
1803
tem and the developing empty p-orbital at C-3 is
possible.17
are formed at this stage. Therefore the formation of
homoallylic alcohols 17 and 18 cannot be rationalized
by a simple cyclopropylcarbinyl cationic ring-opening
of cyclopropylcarbinol 1.
Thus for the anti,cis-cyclopropylcarbinol 1, the phenyl
group can assist in the cleavage of the most electron-
rich bond of the cyclopropane (bond a) in conformer F
leading to an intermediate phenonium ion17 G. How-
ever conformer F is destabilized by a severe 1,3-interac-
tion similar to A1,3 strain.18 Therefore, the phenyl group
can also assist in the cleavage of bond b in conformer H
leading to the phenonium ion I. The nucleophilic attack
of the hydroxy group onto the intermediate phenonium
ions G and I can lead to three organomercuric chlorides
20–22, after treatment with NaCl. The reductive demer-
curation of 20 leads to the trisubstituted tetra-
hydrofuran 16 but, as reductive demercuration is a
radical process, it can also initiate a b-fragmentation19
for organomercurials 21 and 22 and generate the
known homoallylic alcohols 1715 and 1816 (Scheme 4).
The fact that these two homoallylic alcohols essentially
derive from the reduction of the organomercuric com-
pounds 21 and 22 with LiAlH4 is also supported by
examination of the 1H NMR spectrum of the crude
reaction mixture (compounds 20–22) after mercuration
of 1, showing that only traces of olefinic compounds
By contrast, in the case of the syn,cis-cyclopropyl-
carbinol 2, the phenyl group can assist in the cleavage
of the most electron-rich bond of the cyclopropane
(bond a) in conformer J, which does not suffer from
1,3-strain compared to F. After nucleophilic attack of
the hydroxy group on the resulting intermediate pheno-
nium K, the organomercuric chloride 23 is obtained
exclusively. Reductive demercuration leads to the
trisubstituted tetrahydrofuran 19 (65%). The structure
of the intermediate organomercuric compound 23 was
further confirmed by its conversion to alcohol 24 (70%)
upon radical oxidation induced by O2/NaBH4 in DMF
(Scheme 5).20
With the aim of studying the competition between
anchimeric assistance by a phenyl group and assistance
by an appropriately located heteroatom, the mercura-
tion of cyclopropylcarbinols 3 and 4 was investigated.
When the anti,cis-diastereomer 3 was treated with mer-
curic trifluoroacetate followed by reductive demercura-
tion with LiAlH4, two products were formed: the
benzyl ether 25 and the alcohol 26 which were isolated
in 9 and 41% yield, respectively. The formation of these
products can be explained by a rapid intramolecular
oxymercuration promoted by the benzyl ether in con-
formation L, involving the most electron-rich bond
(bond a) of the cyclopropane, which leads to an inter-
mediate oxonium ion M. The latter can react with the
trifluoroacetate anion to give alcohol 28 or by nucle-
ophilic attack of the hydroxy group to give benzyl ether
27. Reductive demercuration then affords tetra-
hydropyrans 25 and 26. In this case, anchimeric assis-
tance by the phenyl group that would have involved
Scheme 5. Mercuration–demercuration of cyclopropyl-
carbinol 2.
Scheme 4. Mercuration–demercuration of cyclopropyl-
carbinol 1.

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J. Cossy et al. / Tetrahedron Letters 43 (2002) 1801–1805
cleavage of the less reactive bond of the cyclopropane
(bond b) is not observed (Scheme 6).
By contrast, mercuration–reductive demercuration of
the syn,cis-cyclopropylcarbinol 4 afforded a 70/30
diastereomeric mixture of two tetrahydrofurans 29 and
30 (78%). The formation of these compounds is
explained by anchimeric assistance by the phenyl group
with cleavage of the most electron-rich bond of the
cyclopropane (bond a) in conformer N, leading to an
intermediate phenonium ion O. Intramolecular nucle-
ophilic attack by the hydroxy group leads to the
organomercuric compound 31, which upon reductive
demercuration affords tetrahydrofuran 29. However, an
epimeric tetrahydrofuran 30 was also formed during
this reaction. Its formation can be attributed to the
assistance by the benzyl ether moiety in the ring-open-
ing of phenonium ion O leading to an intermediate
oxonium ion P, which is then attacked by the hydroxy
group to give the organomercuric compound 32.
Reductive demercuration affords the epimeric tetra-
hydrofuran 30. Worthy of note is the fact that
anchimeric assistance by the aromatic group in this
reaction overrides intramolecular oxymercuration pro-
moted by the benzyl ether (Scheme 7).
Scheme 7. Mercuration–demercuration of cyclopropyl-
carbinol 4.
We have shown that cyclopropylcarbinols of type A
bearing a phenyl group at C-4 undergo anchimerically
assisted mercuration reactions which can lead in some
cases to the formation of oxygenated heterocycles in
good yields. This study highlights the dramatic influ-
ence of the relative configuration of the stereocenter
substituted by the phenyl group on the course of the
mercuration reaction.
Acknowledgements
N.B. thanks the Ministe`re de la Recherche et de l’En-
seignement Supe´rieur for a grant.
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Scheme 6. Mercuration–demercuration of cyclopropyl-
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