Origin of the regio- and stereoselectivity in palladium-catalyzed electrophilic substitution via bis(allyl)palladium complexes

Article abstract of DOI:10.1002/chem.200305002

Palladium-catalyzed allylic substitution of aryl allyl chlorides with aromatic and heteroaromatic aldehydes was performed in the presence of hexamethylditin. This procedure involves palladium-catalyzed formation of transient allylstannanes followed by gen

Full text of DOI:10.1002/chem.200305002

FULL PAPER
Origin of the Regio- and Stereoselectivity in Palladium-Catalyzed
Electrophilic Substitution via Bis(allyl)palladium Complexes
Olov A. Wallner and K a¬ lm a¬ n J. Szab o¬ *[a]
Abstract: Palladium-catalyzed allylic
substitution of aryl allyl chlorides with
aromatic and heteroaromatic aldehydes
was performed in the presence of hex-
amethylditin. This procedure involves
palladium-catalyzed formation of tran-
sient allylstannanes followed by gener-
ation of a bis(allyl)palladium intermedi-
ate, which subsequently reacts with the
aldehyde electrophile. The catalytic sub-
stitution reaction proceeds with high
regio- and stereoselectivity. The stereo-
selectivity is affected by the steric and
electronic properties of the allylic sub-
stituents. Various functionalities includ-
ing NO , COCH , Br, and F groups are
conditions. Density functional calcula-
tions at the B3PW91/DZ ‡ P level of
theory were applied to study the steric
and electronic effects controlling the
regio- and stereoselectivity of the elec-
trophilic addition. The development of
the selectivity was studied by modeling
the various bis(allyl)palladium species
occurring in the palladium-catalyzed
substitution of cinnamyl chloride with
benzaldehyde. It was found that the
electrophilic attack proceeds via a six-
membered cyclic transition state, which
has a pronounced chair conformation.
The regioselectivity of the reaction is
controlled by the location of the phenyl
1
group on the h -allyl moiety of the
complex. The stereoselectivity of the
addition process is determined by the
relative configuration of the phenyl
substituents across the developing car-
bon ± carbon bond. The lowest energy
path corresponds to the formation of the
branched allylic isomer with the phenyl
groups in anti configuration, which is in
excellent agreement with the experi-
mental findings.
Keywords: allyl ligands
functional calculations
¥
density
electro-
¥
philes ¥ palladium ¥ regioselectivity
stereoselectivity
2
3
¥
tolerated under the applied catalytic
ed[10, 11] another method for palladium-catalyzed allylic sub-
stitution which involves formation of transient allylstannane
reagents generated from allyl chloride or acetate precursors
(Scheme 2) in the presence of hexamethylditin. In this
reaction the allylstannane intermediate is not reactive enough
for direct addition to the electrophile, but it undergoes
transmetalation with the monoallylpalladium complex avail-
Introduction
Employment of palladium catalysis to generate reactive
allylmetal intermediates from allyl chlorides and acetates
offers a powerful approach for stereo- and regioselective
transformation of electrophilic substrates. There are two
basically different methods to perform these reactions. The
first one involves palladium-catalyzed formation of allylmetal
[1]
able in the reaction mixture to generate a bis(allyl)palladium
12, 13]
species that are reactive enough to couple directly with the
complex.[
Subsequently, the bis(allyl)palladium inter-
electrophiles (Scheme 1).[
2±9]
Recently, we have publish-
mediate reacts
[13±1ꢀ]
with various electrophiles such as alde-
hydes, imines, and activated alkenes.
We have found that the palladium-catalyzed electrophilic
substitution reaction (Scheme 2) proceeds with an excellent
regioselectivity to yield the branched allylic product. Inter-
estingly, this regiochemistry is in sharp contrast with the
3
regioselectivity of the nucleophilic attack on (h -allyl)palla-
Scheme 1. Palladium-catalyzed formation of reactive allylmetal inter-
mediates followed by direct addition to electrophiles.
dium complexes, which usually takes place at the less
substituted allylic terminus.[
19±23]
The stereoselectivity of the
[
a] Prof. Dr. K. J. Szab o¬ , M. Sc. O. A. Wallner
Stockholm University, Arrhenius Laboratory
Department of Organic Chemistry
reaction is dependent on the actual allyl precursor and
electrophile combination. A very high level of stereoselectiv-
ity was observed, particularly, when bulky substituents are
present in the substrates.
1
06 91 Stockholm (Sweden)
E-mail: kalman@organ.su.se
Considering the low reactivity of the transient allylstan-
nanes and the well-known functional group tolerance of
Supporting information for this article is available on the WWW under
http://www.chemeuj.org or from the author.
Chem. Eur. J. 2003, 9, 4025 ± 4030
DOI: 10.1002/chem.200305002
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4025

K. J. Szab o¬ and O. A. Wallner
FULL PAPER
deactivates the catalyst before
a full conversion of the sub-
strates. Slow addition helps to
keep the catalyst in solution,
thus improving the yield of the
reaction.
The regioselectivity of the
reaction is excellent, as the
substitution takes place exclu-
sively at the more substituted
Scheme 2. Palladium-catalyzed formation of transient allylstannane followed by addition to electrophiles via a
bis(allyl)palladium intermediate.
palladium catalysis,[24] this transformation offers a flexible
synthetic route for allylic substitution by electrophilic re-
agents. However, the nature of the electronic and steric effects
determining the regio- and stereoselectivity in this novel
transformation have remained unexplored. In this study we
present our results on the possibilities to further extend the
synthetic scope of the palladium-catalyzed regio- and stereo-
selective electrophilic substitution of allyl chlorides. In
particular, we have investigated the influence of various aryl
substituents on the stereochemical outcome of the reaction.
Furthermore, we performed DFT calculations to understand
the nature of the steric and electronic interactions governing
the selectivity of the catalytic reactions.
Table 1. Palladium-catalyzed allylic substitution of 1a ± d in the presence
of hexamethylditin.
Entry[a]
Substrates
Product
Ar
Yield[c] d.r.[d]
R[b]
1
2
3
4
5
6
7
ꢀ
9
1a
2a
2b
2b
2b
2c
2d
2e
2 f
2a
2g
2 h
2i
H
Me
F
C H
4-NO
4-NO
6
5
3a
3b ꢀ5
3c 7ꢀ
3d 90
ꢀ0
14:1
7:1
10:1
5:1
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
2
2
2
2
2
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
4
4
4
4
4
OMe 4-NO
OMe 3-NO
OMe 2-NO
OMe 4-CH
OMe 4-BrC
OMe
OMe 4-MeC
OMe 2-furyl
OMe 4-pyridyl
3e
3 f
3g
94
91
93
7:1
11:1
10:1
14:1
19:1
1ꢀ:1
5:1
3 6 4
COC H
6
H
4
3 h ꢀ0
C
6
H
5
3i
3j
60
57
1
1
1
0
1
2
6 4
H
3k 67
3l 71
7:1
3
[
a] All reactions were conducted using 5 mol% [{(h -allyl)PdCl}
2
] catalyst
Results and Discussion
with slow addition of (SnMe3)2 in THF at 408C. [b] See Scheme 3 for
abbreviation. [c] Yield of isolated product. [d] Diastereomer ratio (anti/
syn).[9]
3
Experimental studies: Employment of 5 mol% [{(h -allyl)-
PdCl} ] catalyst (Scheme 3) facilitated the reaction of various
2
allyl chlorides (1a ± d) with different aldehydes (2a ± i) in
the presence of a stoichiometric amount of hexamethyl-
ditin (Table 1). The catalytic reactions proceed under mild
allylic terminus. As we reported before,[10, 11] this selectivity
feature is typical for the palladium-catalyzed electrophilic
substitution reactions. The synthetic scope of the reaction is
broad due to a high level of functional group tolerance. The
nitro-benzaldehyde derivatives (2b ± d) resist both the Can-
nizzaro reaction and reduction of the nitro functionality,
which may take place under basic conditions and on using
[25]
low-valent metals (e.g. SnCl , Scheme 1).
2
The carbonyl functionality of 2e also remains intact under
the applied reaction conditions (Table 1, entry 7). This
indicates that the reaction is highly chemoselective, since
the aldehyde functionality can be manipulated in the presence
of a keto group. The aromatic bromo functionality (2 f,
Table 1, entry ꢀ) is also tolerated. Oxidative addition of
palladium to the CÀBr bond was not observed. Heteroar-
omatic aldehydes, such as furyl (2h) and pyridyl (2i)
derivatives, can also be employed under the standard reaction
conditions.
Scheme 3. Experimentally studied palladium-catalyzed electrophilic sub-
stitution reactions.
The diastereomeric ratio of the reaction varies from 5:1
(
Table 1, entries 4 and 11) to 19:1 (Table 1, entry 9), and the
major diastereomer is always the anti form. Activated
aldehydes usually react with lower stereoselectivity (Table 1,
entries 2 ± ꢀ) than benzaldehyde itself (Table 1, entries 1 and
neutral conditions giving the corresponding homoallyl alcohol
products (3a ± l) in good to excellent yield. It was found that in
many cases the addition rate of hexamethylditin has a great
influence on the yield of the reaction. A rapid addition often
leads to precipitation of amorphous palladium black, which
9
). The sterically bulky ortho-nitro derivative (2d) reacts with
higher selectivity than the para- (2b) and meta-nitro (2c)
analogues (c.f. Table 1, entries 4 ± 6). The diastereoselectivity
4026
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Chem. Eur. J. 2003, 9, 4025 ± 4030

Regio- und Stereoselectivity in Pd-Catalyzed Electrophilic Substitution
4025±4030
also depends on the substituent effects in the allylic substrates.
The methoxy derivative (1d) generates a more reactive
nucleophile than the fluoro derivative (1c). Comparison of
entries 3 and 4 in Table 1 reveals that the more reactive allylic
substrate reacts with a lower selectivity. Thus the stereo-
selectivity of the reaction appears to be inversely propor-
tional to the reactivity of the allylic substrate and the
electrophile.
Computational methods: All geometries were fully optimized
by employing a Becke-type[ three-parameter density func-
tional model B3PW91 (Figure 1). This so-called hybrid func-
tional includes the exact (Hartree ± Fock) exchange, the
gradient corrected exchange functional of Becke,[ and the
more recent correlation functional of Perdew and Wang.[
All calculations have been carried out using a double-
27]
27]
2ꢀ]
[
29±31]
z(DZ) ‡ P basis constructed from the LANL2DZ basis
by adding one set of d-polarization functions to the heavy
atoms (exponents: C 0.63, O 1.154) and one set of diffuse
d-functions on palladium (exponent: 0.062ꢀ). Harmonic
frequencies have been calculated at the level of optimization
for all structures to characterize the calculated stationary
points and to determine the zero-point energies (ZPE). Fully
optimized transition-state structures 9b, 9d, 10b, 10d, 11b,
and 12b have been characterized by a single imaginary
frequency, while the rest of the optimized structures possess
only real frequencies. All calculations have been carried out
by employing the Gaussian 9ꢀ program package.[
Mechanistic aspects: The catalytic electrophilic substitution
reaction proceeds via two coupled catalytic cycles (Scheme 4).
3
The two cycles are linked by (h -allyl)palladium complex 4,
which is generated by oxidative addition of 1 to palladium(0).
The reaction of hexamethylditin results in the transient
allylstannane (5).[ It is well documented
26]
[12, 13]
that allylstan-
3
nanes readily undergo transmetalation with (h -allyl)palladi-
um complexes to give bis(allyl)palladium complexes. Accord-
ingly, bis(allyl)palladium complex 6 can be formed from 4 and
32]
Structure and stability of the
3
3
h ,h -coordinated
complexes:
3
3
Four different h ,h -coordinated
bis(allyl)palladium complexes
are expected to form, when one
phenyl substituent is attached to
each allyl moiety. In complexes
8
a, b (Figure 1) the allyl moiet-
ies are in a trans orientation,
while in 8c, d the allyl groups are
cis-oriented. Similarly to the un-
substituted analogue,[ the en-
ergy difference between the dif-
ferent forms is small, however
the trans complex is somewhat
more stable than the cis form.
Interestingly, in the most stable
isomer (8a) the phenyl substitu-
ents are located on the adjacent
allylic termini.
16]
Scheme 4. Catalytic cycle of the palladium-catalyzed electrophilic substitution process.
Structure and stability of the
1
3
1
3
5
under the catalytic conditions. Subsequently, complex 6
h ,h -coordinated complexes: It is well established that h ,h -
3
3
reacts with electrophiles to provide the final product 7.
The electrophilic attack on the bis(allyl)palladium inter-
mediate 6 by the electrophiles 2 is probably the most
important step of the catalytic reaction, since this step
determines the regio- and stereochemical outcome of the
catalytic transformation. Understanding the nature of the
steric and electronic effects governing this process is partic-
ularly important, since the mechanistic aspects of the devel-
opment of regio- and stereoselectivity in palladium-catalyzed
electrophilic substitution has not been studied before. There-
fore, we have performed theoretical studies on the selectivity
determining step of the above described reaction. As a model
reaction, we have chosen the electrophilic substitution of
cinnamyl chloride (1a) with benzaldehyde (2a), which gives
homoallyl alcohol 3a with high regio- and stereoselectivity
bis(allyl)palladium complexes easily form from the h ,h -
[
16, 33]
analogues by coordination of an external ligand.
The
catalytic reactions were conducted in the absence of strongly
coordinating ligands (such as phosphines), under so-called
™ligand-free∫ conditions. However, the DFT calculations
indicate that the electrophilic substrate (2a) has a fairly good
coordination ability to palladium (9a, 10a, 11a, and 12a).
1
3
Formation of the h ,h -complexes by coordination of benzal-
dehyde to 8a is an endothermic process. The stability of these
species is highly dependent on the location of the phenyl
group on the allyl moieties. In the most stable form (9a) the
1
phenyl substituent is attached to the g-carbon atom of the h -
3
moiety and the h -phenyl group is attached to the allylic
1
terminus trans to the h -allyl group. The corresponding
complex, in which the phenyl group is attached to the a-
1
(
Table 1, entry 1).
carbon atom of the h -allyl (11a) is considerably (by
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K. J. Szab o¬ and O. A. Wallner
FULL PAPER
À1
Figure 1. Calculated structure and stability of the bis(allyl)palladium species. The energy values are given in kcalmol and the bond lengths are given in ä.
The ZPVcorrected energies are given in italics.
4028
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Chem. Eur. J. 2003, 9, 4025 ± 4030

Regio- und Stereoselectivity in Pd-Catalyzed Electrophilic Substitution
4025±4030
À1
4
.1 kcalmol ) less stable. Clearly, substitution of the meta-
mutually syn. Formation of syn complexes 9e and 10e
proceeds through TS structures 9d and 10d, respectively.
The activation barrier (Figure 2) to the formation of these syn
1
3
lated carbon atom (C ) strongly destabilizes the h ,h com-
a
plexes.[
10, 11, 16±1ꢀ]
When both phenyl groups are on the same
À1
side of the complex (10a and 12a), the steric interactions lead
products is considerably higher (by 4.0 ± 4.3 kcalmol ) than
to a low stability.
the activation barrier (9b and 10b) for formation of anti
products (9c and 10c). This result is in good agreement with
the experimental results (Table 1) that the major product of
the palladium-catalyzed electrophilic substitution is the
branched allylic product with anti stereochemistry.
Regioselectivity of the electrophilic attack: The electrophilic
substitution reactions takes place through six-membered
cyclic transition states, in which the distance between the
forming carbon ± cabon bond varies between 2.0ꢀ and 2.26 ä.
Inspection of the reoriented TS geometries (Figure 3)
reveals the underlying substituent effects governing the
stereochemistry of the reaction. The six-membered TS has a
pronounced chair conformation as indicated by the red bars.
In 9b leading to the anti product 9c the phenyl groups are in
trans-diequatorial positions across the newly forming car-
bon ± carbon bond, while in TS structure 9d (which provides
the syn product 9e) the phenyl group of benzaldehyde is axial
À1
The lowest energy path (11.6 kcalmol ) involves 9b (Fig-
ure 2), which bears the phenyl substituent at the g-position of
1
the h -allyl moiety. This reaction path leads to slightly
À1
endothermic (3.5 kcalmol ) formation of the branched allylic
product 9c. Formation of the unbranched product 11c
proceeds through
a
much higher activation barrier
À1
3
(
15.9 kcalmol ). When the phenyl substituent of the h -
1
1
ligand and the phenyl substituent of the h -moiety are located
on the same side of the complex, the reaction profiles (10a !
and the h -allylic phenyl group is equatorial. Accordingly, in
9d the axial phenyl group is involved in a destabilizing steric
3
1
0b ! 10c and 12a ! 12b ! 12c ) are similar to the above,
interaction with the h -allyl moiety of the complex, which
however the activation energies are much higher.
explains its low stability. Interestingly, the activation barrier
for the reverse process (9c ! 9b ! 9a) is lower for the anti
À1
Stereoselectivity of the electrophilic attack: Formation of the
branched allylic product may proceed by formation of four
different complexes. The above discussed processes lead to 9c
and 10c, in which the phenyl groups are in anti configuration.
However, by changing the relative orientation of the h -
moiety and the benzaldehyde molecule, two other products
product 9c (ꢀ.1 kcalmol ) than that for the corresponding
(9e ! 9d ! 9a) process for the syn product 9e
À1
(10.0 kcalmol ). This suggests that the decomposition of
the syn product (9e) is somewhat more difficult than the
decomposition of the anti product (9c), which explains the
fact that a small amount of syn isomer (anti/syn ratio is 14:1,
Table 1) is also formed under catalytic conditions.
There are many highly stereo-
1
can be obtained (9e and 10e) in which the phenyl groups are
selective transformations pro-
ceeding through six-membered
cyclic transition states. However,
an important new feature in the
process described above is that
the sterically demanding substi-
3
tuted h -allyl moiety controls the
stereoselection of the reaction.
Employment of this new way of
stereoinduction can be useful in
development of novel highly
stereoselective catalytic trans-
formations.
Conclusions
In this study we have shown that
palladium catalysis can be ap-
plied for electrophilic allylic sub-
stitution of aromatic allyl chlor-
ides in the presence of hexame-
thylditin. This reaction proceeds
with high regio- and stereoselec-
tivity for various aldehyde elec-
trophiles. Many functionalities
involving
aromatic
NO2,
CH CO, Br, and F substituents
are tolerated; and the reaction
Figure 2. Reaction profiles for the electrophilic attack resulting different regio- and stereoisomers. The energies
3
À1
are given in kcalmol
.
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K. J. Szab o¬ and O. A. Wallner
FULL PAPER
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[
2
[
[
1
h -moiety of the bis(allyl)palladium intermediate; and the
6
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3
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was stirred for additional 12 h at 408C. After evaporation of the solvent the
crude product was purified by silica gel chromatography. Further exper-
imental details and characterization of 3b ± l are given in the Supporting
Information.
Acknowledgement
This work was supported by the Swedish Natural Science Research Council
(
NFR). The calculations were done at the IBM SP2 parallel computer
facility of the Parallelldatorcentrum (PDC) at the Royal Institute of
Technology, Sweden. The authors thank the PDC for a generous allotment
of computer time.
[
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Received: March 2ꢀ, 2003 [F5002]
4030
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4025 ± 4030