Regioselective palladium-catalyzed allylic alkylations

Article abstract of DOI:10.1016/j.tetlet.2004.09.190

Palladium-catalyzed allylic alkylations on asymmetrical allylic carbonates using a variety of chiral ligands gave good to excellent ee's and poor to excellent regioselectivity depending on the nucleophile used.

Full text of DOI:10.1016/j.tetlet.2004.09.190

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 353–355
Regioselective palladium-catalyzed allylic alkylations
Ying Dong,a Paul Teesdale-Spittleb and John O. Hoberga,c,
*
aSchool of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
bSchool of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
cDepartment of Chemistry, University of Wyoming, Laramie, WY 82071, USA
Received 29 June 2004; accepted 23 September 2004
Abstract—Palladium-catalyzed allylic alkylations on asymmetrical allylic carbonates using a variety of chiral ligands gave good to
excellent eeꢀs and poor to excellent regioselectivity depending on the nucleophile used.
Ó 2004 Published by Elsevier Ltd.
The search for chiral ligands for asymmetric allylic
alkylation (AAA) reactions with Pd catalysts have led
to numerous designs and types.1–9 Although the major-
ity of these studies have used allylic substrates such as
1a, Eq. 1 that lead to symmetric p-allyls,10,11 several
studies have addressed the question of regioselectivity
in asymmetric systems similar to 1b.12–18
in terms of regiochemistry, we present herein its use in
the AAA thus providing further information on the
scope of this reaction.
Formation of 4 involves a straightforward synthesis
involving the known diol 5, Scheme 2. Thus, modified
reduction of the aldol product20 of cinnamaldehyde
and ethyl acetate gives 5 in an overall 86% yield. Stan-
dard protection of the primary alcohol followed by reac-
tion with ethyl chloroformate gives the desired
carbonate 4 in an excellent overall yield. This synthesis
can be performed on the large scale providing gram
quantities of 4.
ð1Þ
Recently, we required acid 2 that we envisioned could
arise from a palladium catalyzed dealloxycarbonyl-
ation19 of 3, which would be assembled in a stereoselec-
tive manner using an AAA reaction and 4, Scheme 1.
Given that the use of 4 in the AAA reaction is novel
Treatment of 4 under AAA conditions could potentially
result in the formation of either 6 or 7, presumably with
6 in abundance, Eq. 2. Prior to the formation of 4, we
OH
c, d
a, b
CHO
4
O
O
Ph
Ph
OH
5
CO2H
OTBDPS
O
O
Scheme 2. Reagents: (a) EtOAc, LDA then PhCH@CHCHO, 94%; (b)
NABH4, I2, 91%; (c) TBDPSCl, imidazole, 95%; (d) ClCO2Et, Py,
87%.
Ph
Ph
Ph
OTBDPS
OTBDPS
2
3
AAA
OCO2Et
4
Scheme 1.
*
Corresponding author. Tel.: +307 766 2795; fax: +307 766 2807;
e-mail: hoberg@uwyo.edu
ð2Þ
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.09.190

354
Y. Dong et al. / Tetrahedron Letters 46 (2005) 353–355
Table 1. AAA reactions with chiral ligandsa
Entry
Nucleophile
Chiral ligandb
Base
Reaction condition
Yield (%)
Ratio 6:7
eec (%)
d
d
d
d
d
d
1
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
4-Methoxyphenol
4-Methoxyphenol
4-Methoxyphenol
4-Methoxyphenol
Phenol
s-Binap
s-Binap
NaH
THF, reflux 3h
THF, reflux 2h
THF, reflux, 4h
CH2Cl2, reflux, 2h
THF, reflux, 3h
THF, reflux, 1h
THF, reflux, 12h
THF, reflux 12h
THF, reflux 12h
THF, reflux 24h
THF, reflux 12h
THF, reflux 48h
THF, reflux 12h
THF, reflux 24h
THF, reflux 12h
THF, reflux 12h
88
93
90
69
91
81
88
87
89
92
94
90
94
88
50
52
1.5:1
2.2:1
2
Cs2CO3
BSA
NaH
3
s-Binap
s-Binap
0.8:1
0.8:1
4
5
s-p-Tolbinap
s,s-Trost
s-Binap
Cs2CO3
Cs2CO3
Cs2CO3
NaH
1.6:1
4.8:1
6
7
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>1:99
88
89
87
94
92
93
94
98
92
98
8
s-Binap
9
s-p-Tolbinap
s,s-Trost
s-Binap
Cs2CO3
nBu4NCl
Cs2CO3
nBu4NCl
Cs2CO3
nBu4NCl
Cs2CO3
Cs2CO3
10
11
12
13
14
15
16
Phenol
s,s-Trost
s-Binap
4-tert-Butylphenol
4-tert-Butylphenol
4-Methoxyaniline
Aniline
s,s-Trost
s-Binap
s-Binap
a 3mol% Pd2dba3ÆCHCl3 used in all reactions.
b 8mol%.
c Determined by chiral GC on crude samples.
d Not determined due to overlapping peaks in the GC.
felt that control of the regiochemistry would be gov-
erned by retention of conjugation to the alkene/aromatic
ring and that the large TBDPS group was remote en-
ough to produce limited steric interactions. As diallyl
malonate is not commercially available,21 we initially
tested dimethyl malonate to determine the feasibility
of the concept. Using a loading of 3 and 8mol% palla-
dium and BINAP ligand, respectively, we observed a
disappointing ratio of 1.5:1, entry 1 Table 1.22–24 Con-
versely, the olefin geometry remained as the E isomer
in all cases as expected.16 The use of caerium carbonate
as a base, entry 2, improved this ratio only slightly while
bis(trimethylsilyl)acetamide (BSA) reversed the level of
selectivity, entry 3. One attempt was made at changing
the solvent (entry 4), which resulted in reduced yields.
With an indication of conditions in hand, we next
screened alternative ligands. Toluene binap proved to
be no better then binap, however Trostꢀs ligand
(1S,2S-(ꢀ)-1,2,-diaminocyclohexane-N,N0-bis(20-diph-
enylphosphinobenzoyl)), did show moderate improve-
ment with only slightly diminished yields, entries 5
and 6.
poor yields, however we were surprised to see a complete
reversal of selectivity with aniline as the nucleophile.
The regioselectivity of metal catalyzed allylic alkylation
is comprised of both steric and electronic effects, with
steric effects usually dominating in palladium catalyzed
reactions.25 Furthermore, Cook et al. have shown that
hydrogen bonding also plays a role in regioselectivity
in specific substrates.26 Two possible explanations for
the change in selectivity in these reactions are the slight
change in the size of the incoming nucleophile, or more
probable, the change in the hardness/softness of the
nucleophile. Given that palladium p-allyls are relatively
soft, the change from a softer malonate carbanion to a
hard phenoxide could result in the observed selectivity.
Similar observations have been observed in nucleophilic
attack on iron complexes.27 However, surprisingly a
remarkable change in the selectivity is observed when
using aniline, a presumed hard nucleophile. Thus, in
employing asymmetrical allylic carbonates, the use of
the appropriate nucleophile can lead to excellent regio-
and enantioselectivity. However, in view of the modest
to poor selectivity of the malonate products 6/7 and
the inability to separate these, we our pursuing alterna-
tive routes to the synthesis of 2.
O
NH PPh2
Trost ligand
NH PPh2
O
Acknowledgements
Financial support was provided by the New Zealand
Cancer Society and the Public Good Science Fund.
We then turned to alternative nucleophiles that had
literature precedence for more selective attack. As seen
in entries 7–14, excellent regioselectivity is observed for
these nucleophiles with concurrent high eeꢀs and yields.
Noticeable is that the Trost ligand in entries 10 and 14
does give improved eeꢀs. Finally, we also tested two
amine nucleophiles that both gave excellent eeꢀs but
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.09.190. Spectral data and experimental conditions
available.

Y. Dong et al. / Tetrahedron Letters 46 (2005) 353–355
355
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