A new mechanistic proposal for the origin of α-homoallylic alcohols in indium-mediated allylation reactions in water

Article abstract of DOI:10.1016/S0040-4039(01)01884-6

A new mechanism is proposed for the α-regioselective indium-mediated allylation reaction in water. Based on the results and observations obtained from an NMR study, a cross-over experiment and the complete inversion of the stereochemistry of 22β γ-adduct

Full text of DOI:10.1016/S0040-4039(01)01884-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8705–8708
A new mechanistic proposal for the origin of a-homoallylic
alcohols in indium-mediated allylation reactions in water
Teck-Peng Loh,* Kui-Thong Tan and Qi-Ying Hu
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 28 August 2001; revised 21 September 2001; accepted 5 October 2001
Abstract—A new mechanism is proposed for the a-regioselective indium-mediated allylation reaction in water. Based on the
results and observations obtained from an NMR study, a cross-over experiment and the complete inversion of the stereochemistry
of 22b g-adduct homoallylic sterols to the 22a a-adduct homoallylic sterols, it is suggested that the initially formed g-adduct
undergoes a bond cleavage to generate the parent aldehyde in situ followed by a concerted rearrangement, perhaps a retro-ene
reaction followed by a 2-oxonia [3,3]-sigmatropic rearrangement to furnish the a-adduct. © 2001 Elsevier Science Ltd. All rights
reserved.
In the previous paper, we have successfully demon-
strated that the indium-mediated allylation reaction of
aldehydes proceeds smoothly with crotyl and cinnamyl
bromides in water (10 M) to give almost exclusively the
a-homoallylic alcohol adducts in moderate to good
yields (Scheme 1). As far as we know, this is in fact the
first general procedure by which linear homoallylic
alcohols can be obtained with high a-regioselectivity in
an aqueous media.1 The high a-regioselectivity of this
abnormal Barbier-type, indium-mediated, allylation has
prompted us to investigate the mechanism further.
Three mechanisms have been proposed to account for
the high a-selectivities observed for the known systems.
They can generally be grouped into three categories: (i)
The external activator or Lewis acid is involved in the
formation of a 6-membered transition state to afford
the a-adduct directly as shown in Scheme 2. (ii) Direct
attack of the allylic metal on the a-position via a
four-membered transition state (Scheme 3).8 (iii)
Transmetallation of the allylic metal species with the
external activator or Lewis acid to generate a new
allylic species which undergoes g-attack to afford the
a-adduct (Scheme 4).
To the best of our knowledge, the development of a
general procedure for highly a-regioselective metal-
mediated allylation reactions in water has never been
reported. Nevertheless, there are a few metal-mediated
allylation methods that have been reported to achieve
high a-regioselectivities in an organic solvent. Reported
examples include the addition of a stoichiometric
amount of AlCl3 to a Grignard reaction2 and the
reaction of crotyl tributylstannanes with aldehydes in
the presence of a Lewis acid.3 Furthermore, highly
a-selective allylation can also be achieved by the reac-
tion with aldehydes of allylic barium,4 and allylic
cerium5 reagents and Me3SiCl/NaI/H2O.6 There are
also a few special cases where the indium-mediated
allylation reaction produces a-adducts.7 However, these
isolated cases provide insufficient data and further
investigation is called for.
In our initial study of this a-regioselective indium-medi-
ated allylation, low regioselectivities were obtained if
stirring of the reaction mixture was not prolonged. The
best selectivity was obtained, when the reaction was
OH
OH
R1
Br
O
R1
+
R
R
In, water (10 M)
H
R1
γ-adduct
R
α-adduct
≥ 96 : 4 (α : γ)
Scheme 1.
M
X
X
X
X
X
RCHO
α-adduct
M
M1
R
M1 X
X
O
H
* Corresponding author. Tel.: +65-874-1781; fax: +65-779-1691;
e-mail: chmlohtp@nus.edu.sg
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01884-6

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T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 8705–8708
alcohol which slowly converted to the thermodynamic
O
a-homoallylic alcohol (24 h).9 After 2 h, the g-homoal-
lylic alcohol adduct was obtained as the sole product
with no sign of any a-isomer. By the fourth hour, the
O Metal
R''
OH
R''
R'
R''
+
R
R'
R'
R
Metal
1
R
a-adduct started to appear, as can be seen in the H
NMR spectrum, the peaks around l 5.5 and 3.3 ppm
being assigned as the internal double bond and the
a-hydroxyl protons of the a-adduct. If the reaction was
stirred further, after 24 h, all the g-adducts were rear-
ranged to the thermodynamically more stable a-adduct
with complete consumption of the aldehyde, as indi-
cated by the disappearance of the peaks at l 5.8, 5.1
and 3.1 ppm.
Scheme 3.
OH
OH
MeLn
RCHO
MX
MeLn–1
– MXL
R
RCHO
MeLn–1
R
Furthermore, a cross-over experiment was conducted
(Scheme 5). After the reaction, column chromatogra-
phy provided the cross-over products 1 and 2 in 10 and
11% yields, respectively. This proved that the rear-
rangement of this g-adduct to its isomeric a-adduct
may involve the cleavage of the g-adduct to the alde-
hyde substituent and an allyl fragment.
Scheme 4.
stirred for up to 72 h for cyclohexane carboxaldehyde
with crotyl bromide.
In order to understand the origin of these linear
homoallylic alcohol adducts, the progress of the reac-
tion of cyclohexane carboxaldehyde with crotyl bro-
mide was monitored by 1H NMR after work-up at
various intervals. The spectra were taken at 2, 4 and 24
h, respectively (Fig. 1).
With the establishment of the reaction conditions for
obtaining the a-adduct, the application to the construc-
tion of a steroidal side chain was effected. Especially
noteworthy is that the indium-mediated allylation of
the steroidal aldehyde
3 with cinnamyl bromide
afforded the 22b g-homoallylic alcohols which rear-
range to the 22a a-products with complete inversion of
stereochemistry. (The relative stereochemistry was
It was observed that the reaction proceeded very
rapidly to afford the kinetically favored g-homoallylic
Figure 1. NMR xtudy of indium-mediated allylation.
OH
OH
O
Ph
Br
Ph
H
In, 10 Molar water
OH
1 (10%)
OH
OH
Ph
Ph
Ph
Ph
2 (11%)
Scheme 5. Cross-over experiment.

T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 8705–8708
8707
Scheme 6. Inversion of the steroid stereochemistry.
OH
concerted rearrangement, perhaps by a retro-ene12 fol-
lowed by a 2-oxonia [3,3]-sigmatropic rearrangement.13
R2
Br
O
R1
R1
R2
In
H
This indicates the possibility of the concurrent involve-
ment of both mechanisms for the generation of thermo-
dynamic a-adducts in various allylation reactions. It
should be noted that the indium complexes (InmXn)14,15
generated after the CꢀC bond formation function as
Lewis acids to catalyze this conversion.
OH
InmBrn
OH
R2
R2
R1
R1
O
R2
R1
H
In conclusion, a general and new method for obtaining
a-adducts in indium-mediated allylation has been devel-
oped. Detailed mechanistic studies have led to a new
mechanistic proposal for the origin of this exceptionally
high a-selectivity. Mechanistic understanding of the
process leads to predictable stereochemistry for the
a-adduct and the possible design of a-selectivity in
other allyl transfer reactions.16
R1
R1
O
O
OH
R1
R1
R1
OH
R2
O
R2
R1
+ OH–
– OH–
O
Furthermore, this study showed that the origin of the a
homoallylic alcohols from many of the reported metal-
mediated allylation reactions with or without activators
warrants further studies to clarify their mechanisms.
R1
R1
R2
R2
Scheme 7. Proposed mechanism for rearrangement.
Acknowledgements
determined by single crystal X-ray diffraction analy-
sis,10,11 Scheme 6.) In other words, the allyl fragment
reattaches to the steroid in an anti-Cram manner,
which excludes the possibility of allyl anion re-addition
to the aldehyde.
We thank the National University of Singapore for
generous financial support. We also thank Dr. Jagadese
J. Vittal and Ms. Tan Geok Kheng for determining the
crystal structures of 3a and 3b.
Based on the results and observations presented above,
a new mechanism (Scheme 7) was proposed for this
indium-mediated allylation reaction in water (10 M).
As opposed to the allyl anion transfer mechanism2,3 or
steric effect7c,8 previously proposed to account for the
formation of the a homoallylic alcohol adduct, our
study suggested that the initially formed g-adduct
underwent a bond cleavage to generate the parent
aldehyde in situ and subsequently proceeded via a
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8708
T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 8705–8708
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,
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,
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