Studies on aluminium mediated asymmetric Friedel-Crafts hydroxyalkylation reactions of pyridinecarbaldehydes

Article abstract of DOI:10.1039/b009669p

The reaction of pyridinecarbaldehydes with aromatic C-H bonds mediated by chiral and achiral aluminium complexes has been investigated both experimentally and theoretically. It was found that pyridine-2-carbaldehyde activated by (R)-BINOL-AlCl reacts with e.g. N,N-dimethylaniline in a Friedel-Crafts hydroxyalkylation reaction to give the resulting alcohol in moderate yield and enantiomeric excess, whereas the pyridine-3- and -4-carbaldehydes give a diarylated product. The mechanism of the reaction has been investigated using theoretical calculations. The calculations show that the uncatalyzed reaction proceeds via a concerted, one-step mechanism, having a four-membered transition state with an energy barrier of 81 kcal mol^-1. However, for the Lewis acid-mediated reaction using AlCl₃ as the Lewis acid, the reaction proceeds through a zwitterionic intermediate in which the transition-state energy is significantly reduced. For the reaction of pyridine-2-carbaldehyde, the aluminium Lewis acid can coordinate in both a mono- and bidentate fashion to the substrate. Furthermore, two Friedel-Crafts intermediates have been found depending on the orientation of the incoming aromatic compound. Several transition states have been calculated for the formation of the Friedel-Crafts intermediates starting from the two different coordination modes of pyridine-2-carbaldehyde to AlCl₃. The lowest energy for the reaction has been calculated to be 5.6 kcal mol^-1 for pyridine-2-carbaldehyde activated by AlCl₃ in a monodentate fashion. The mechanistic aspects of these observations will be discussed.

Full text of DOI:10.1039/b009669p

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Studies on aluminium mediated asymmetric Friedel–Crafts
hydroxyalkylation reactions of pyridinecarbaldehydes
Aase Sejr Gothelf, Tore Hansen and Karl Anker Jørgensen*
1
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark. Fax: 45-86-19-61-99; E-mail: kaj@kemi.aau.dk
Received (in Cambridge, UK) 1st December 2000, Accepted 27th February 2001
First published as an Advance Article on the web 20th March 2001
The reaction of pyridinecarbaldehydes with aromatic C–H bonds mediated by chiral and achiral aluminium
complexes has been investigated both experimentally and theoretically. It was found that pyridine-2-carbaldehyde
activated by (R)-BINOL–AlCl reacts with e.g. N,N-dimethylaniline in a Friedel–Crafts hydroxyalkylation reaction
to give the resulting alcohol in moderate yield and enantiomeric excess, whereas the pyridine-3- and -4-carbaldehydes
give a diarylated product. The mechanism of the reaction has been investigated using theoretical calculations.
The calculations show that the uncatalyzed reaction proceeds via a concerted, one-step mechanism, having a four-
membered transition state with an energy barrier of 81 kcal molϪ1. However, for the Lewis acid-mediated reaction
using AlCl3 as the Lewis acid, the reaction proceeds through a zwitterionic intermediate in which the transition-state
energy is significantly reduced. For the reaction of pyridine-2-carbaldehyde, the aluminium Lewis acid can coordinate
in both a mono- and bidentate fashion to the substrate. Furthermore, two Friedel–Crafts intermediates have been
found depending on the orientation of the incoming aromatic compound. Several transition states have been
calculated for the formation of the Friedel–Crafts intermediates starting from the two different coordination modes
of pyridine-2-carbaldehyde to AlCl3. The lowest energy for the reaction has been calculated to be 5.6 kcal molϪ1 for
pyridine-2-carbaldehyde activated by AlCl3 in a monodentate fashion. The mechanistic aspects of these observations
will be discussed.
insight into the mechanism for the aluminium-mediated
Friedel–Crafts reaction of aromatic aldehydes with aromatic
compounds.
Introduction
The Friedel–Crafts reaction is
a well-known and well-
established reaction and among the most fundamental C–C
bond forming reactions known.1 Traditionally, the Friedel–
Crafts alkylation and acylation reactions involve alkyl halides
or acyl halides, respectively, that are activated by a Lewis acid
to perform an electrophilic substitution on the aromatic C–H
bond.1 Compared to the numerous reports on Friedel–Crafts
alkylation and acylation of alkyl and acyl halides, alkylation
reactions using aldehydes or ketones as the substrates have not
been as well developed [eqn. (1)].2
Results and discussion
The reaction of pyridine-2-carbaldehyde 1a with N,N-dimethyl-
aniline 2a mediated by aluminium complexes containing chiral
ligands leads to the formation of alcohol 3a [eqn. (2)]. In this
reaction a new stereogenic center is produced and in order to
(1)
(2)
Both Brønsted and Lewis acids can mediate the hydroxy-
alkylation reaction through an activation of the carbonyl
moiety. In both cases, the resulting electron deficiency at the
carbonyl carbon makes it susceptible to a nucleophilic attack
from the aromatic compound.
In spite of the high importance of the Friedel–Crafts
reaction only very limited attention has been paid to the
application in catalytic asymmetric synthesis of optically active
Friedel–Crafts products. Recently, the first examples of
catalytic enantioselective addition reactions of aromatic and
heteroaromatic C–H bonds to activated carbonyl compounds,2
α-dicarbonyl compounds3 and imines4 have been presented.
This paper presents the first investigation of an enantioselective
hydroxyalkylation reaction of pyridine-2-carbaldehyde with
N,N-dimethylaniline mediated by chiral aluminium catalysts.
The reaction will also be studied for other aromatic com-
pounds reacting with various types of pyridinecarbaldehydes.
Furthermore, the reaction has also been investigated from a
theoretical point of view in an attempt to obtain detailed
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J. Chem. Soc., Perkin Trans. 1, 2001, 854–860
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009669p

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Table 1 Friedel–Crafts reaction of pyridine-2-carbaldehyde 1a with N,N-dimethylaniline 2a catalyzed by the chiral BINOL ligands (R)-4a and
(S)-4b–e in combination with AlClMe2 as the Lewis acid under different reaction conditions
Reaction
temp./ЊC
Reaction
time/h
Yielda
(%)
Eeb
(%)
Entry
Ligand
Solvent
1
2
3
4
5
6
7
8
9
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
—
CH2Cl2
CH2Cl2
Et2O
CH3NO2
CH3CN
C6H6
20
0
19
27
18
19
18
18
19
18
18
18
18
2 days
63
36c
44
93
53
25
93
14
50
26
52
0
43
35
9
20
20
20
20
20
20
20
20
20
20
5d
14
50
15d
13
29
36
16d
—
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12e
a Isolated yield. b Ee measured by HPLC using a Daicel Chiralcel OD column. c Conversion measured by 1H NMR spectroscopy. d Opposite
enantiomer. e No catalyst present.
investigate the possibility of controlling the enantioselectivity
of this reaction a series of optically active aluminium com-
plexes formed by reaction of Me2AlCl with the optically active
BINOL (BINOL = 1,1Ј-binaphthyl-2,2Ј-diol) ligands (R)-4a
and (S)-4b–e were investigated. The chiral Lewis acids are
prepared by dissolving the BINOL ligand in the appropriate
solvent used for the reaction followed by the addition of a
commercially available heptane solution of AlMe2Cl which
gives the chiral Lewis acid as a white solid. After stirring for 1 h
at room temperature the chiral Lewis acid is ready for use.
Addition of the reagents gives upon stirring for a period of time
a homogeneous and slightly orange-coloured reaction mixture.
The reaction of pyridine-2-carbaldehyde 1a with N,N-
dimethylaniline 2a proceeds smoothly giving the resulting
alcohol ((4-dimethylaminophenyl)pyridin-2-ylmethanol) 3a in
63% yield. The reaction proceeds with the formation of an
optically active product and the study of the Friedel–Crafts
reaction in various solvents mediated by different chiral
BINOL–aluminium complexes gives the results presented in
Table 1. The most successful conditions found are to perform
the reaction at room temperature in CH2Cl2 as the solvent,
which gives 3a in 63% yield and with 43% ee. This is, according
to our knowledge, the first example of a simple aromatic alde-
hyde reacting with an aromatic C–H bond to give an optically
active Friedel–Crafts product in the presence of a chiral Lewis
acid. The highest ee of 3a is obtained in benzene as the solvent,
however, the yield was low (entry 6). The highest yield of 3a is
produced in CH3NO2 and THF where 93% isolated yield of 3a
is obtained, but in these solvents low ee’s are found (entry 4 and
7). As the product alcohol 3a binds to and deactivates the chiral
Lewis acid due to the strong Al–O bond, a stoichiometric
amount of the Lewis acid is required in order to obtain reason-
able conversion in the reaction. Fortunately, it was found that
the chiral BINOL ligand is easily recovered after the reaction by
column chromatography and can be recovered in 80–90% yield.
The Friedel–Crafts reaction of 1a with 2a has also been studied
for (S)-4b–e in combination with AlClMe2 as the Lewis acid.
The chiral BINOL ligands studied have proven to greatly
increase the enantioselectivity of other BINOL–aluminium-
mediated reactions,5 however, the results in entries 8–11 show
that only moderate yield and enantioselectivity of 3a were
obtained.
the presence of the various chiral aluminium complexes,
although in both cases the final product was the diarylated
species, 3b and 3c, respectively, in moderate yield [eqns. (3)
and (4)]. As is observed in an early example of this type
(3)
(4)
of reaction—the Bayer reaction—the alcohol-intermediate
formed is even more reactive than the starting material and
thus reacts with yet another molecule of aromatic compound
resulting in the diarylated product with loss of water.6
A compound such as benzaldehyde, in which the carbonyl
is less activated compared to e.g. pyridine-2-carbaldehyde 1a,
does not react under the present reaction conditions with e.g.
2a in the presence of a chiral aluminium complex. This implies
that the electron-withdrawing effect from the pyridine ring
lowers the energy barrier of the reaction.
Theoretical investigations
Pyridine-2-carbaldehyde 1a also reacts with other aromatic
compounds than N,N-dimethylaniline; reaction of 4-methoxy-
phenol 2b and 1,3-dimethoxybenzene 2c in CH2Cl2 proceeds
also in the presence of (R)-4a-AlCl to give the correspond-
ing Friedel–Crafts products in 54% and 49% isolated yield;
however, less than 15% ee of the products was obtained.
Furthermore, it was found that the 3- and the 4-isomer of the
pyridinecarbaldehyde, 1b and 1c, respectively, react with 2a in
In the following we will investigtate the Friedel–Crafts reaction
of especially pyridine-2-carbaldehyde 1a with N,N-dimethyl-
aniline 2a in the absence and in the presence of a Lewis acid,
from a theoretical point of view using ab initio calculations7 in
an attempt to obtain insight into the reaction mechanism and
the role of the Lewis acid for the reaction. According to the best
of our knowledge, there has only been a very limited number of
J. Chem. Soc., Perkin Trans. 1, 2001, 854–860
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Table 2 Structural and electronic changes of the carbonyl function-
ality of 1a–c, in the absence of a Lewis acid, and when coordinated
a
to AlCl3
1ab
1b
1c
No Lewis acid
C–O/Å
1.22
Ϫ10.02
1.76
0.34
Ϫ0.52
1.22
Ϫ10.14
1.67
0.35
Ϫ0.52
1.21
Ϫ10.08
1.44
0.34
Ϫ0.50
HOMO/eV
LUMO/eV
q(C)c
q(O)c
With AlCl3
C–O/Å
1.24
Ϫ11.57
Ϫ0.76
0.53
1.25
Ϫ11.70
Ϫ0.85
0.51
1.24
Ϫ11.33
Ϫ1.05
0.51
HOMO/eV
LUMO/eV
q(C)c
Fig.
1
Calculated transition-state structure for the uncatalyzed
Friedel–Crafts reaction of pyridine-2-carbaldehyde 1a with N,N-
q(O)c
Ϫ0.82
Ϫ0.83
Ϫ0.80
dimethylaniline 2a.
a Calculations performed using RHF/6-31G. b Values presented for
AlCl3 coordinated to 1a are calculated from the lowest energy structure,
complex I in Fig. 2. c Charge on the atoms in the carbonyl group
obtained from a Mulliken population analysis.
theoretical investigations of the role of Lewis acids for the
reaction of aromatic C–H bonds with carbonyl compounds.8
We will start with an investigation of the uncatalyzed
Friedel–Crafts reaction of 1a with 2a in order to understand
this reaction before moving to the AlCl3-mediated reaction. The
transition state for the reaction of 1a with 2a has been localised
and characterised and is presented in Fig. 1. All attempts to
locate a zwitterionic intermediate for the uncatalyzed reaction
failed. However, a four-membered transition state for the reac-
tion in which the formation of the C–C bond and the hydrogen
atom (proton) transfer take place simultaneously has been
calculated as the transition state for the uncatalyzed Friedel–
Crafts reaction. The transition-state energy has been calculated
to be 81.0 kcal molϪ1 which is a very high energy barrier and is
consistent with the fact that we see no reaction of 1a and 2a in
the absence of a catalyst (Table 1, entry 12). It appears from the
transition-state structure for the uncatalyzed Friedel–Crafts
reaction in Fig. 1 that the C–C bond being formed is calculated
to be 1.56 Å indicating a very late transition state for the
reaction, and that the aromatic C–H bond has increased
from 1.07 Å in N,N-dimethylaniline to 1.24 Å in the transition
state. The O–H bond going to be formed is calculated to be
1.58 Å. The transition state also shows that the hydrogen atom
(proton) is lined up for transfer to the oxygen atom of the
carbonyl bond, which now has increased from 1.22 Å in 2a to
1.42 Å in the transition state as the H–C–C–O dihedral angle is
calculated as Ϫ22.6Њ. The carbonyl bond becomes more polar-
ised in the transition state as the charges on the carbon and
oxygen atoms change from 0.34 (C) and Ϫ0.52 (O) (see Table 2)
in 1a to 0.18 (C) and Ϫ0.81 (O), respectively, in the transition
state.
For the Friedel–Crafts reaction between 1a and 2a we have
used AlCl3 as the Lewis acid in the calculations to resemble
the experimental results as much as possible.9 There are four
possible coordination modes of AlCl3 to 1a, depending on the
orientation of the carbonyl functionality relative to the nitro-
gen atom in the pyridine moiety. In Fig. 2, the two lowest
energy structures are shown. Complex I has a total energy of
Ϫ1979.814 Eh and is a monodentate coordination of 1a to
AlCl3, while in complex II, pyridinecarbaldehyde 1a coordin-
ates in a bidentate fashion to AlCl3 using the nitrogen lone-pair
electrons of the pyridine ring for the coordination. The energy
of complex II is calculated to be 6.4 kcal molϪ1 higher in energy
than complex I. The difference in coordination of AlCl3 to 1a is
also reflected in the O–Al bond distances in the complexes; in
complex I (monodentate coordination), a bond length of 1.85
Å has been calculated, while in complex II (bidentate coordin-
ation) the O–Al bond is 0.14 Å longer.
Fig. 2 The two lowest coordination modes of pyridine-2-carbaldehyde
1a to AlCl3. Complex I: monodentate coordination; complex II:
bidentate coordination.
the absence of AlCl3, and coordinated to AlCl3. It appears from
Table 2 that by coordination of AlCl3 to the carbonyl group of
1a there are three significant changes of the carbonyl function-
ality: (i) the C–O bond length increases (ii) the energy of the
LUMO (π*C᎐O) is lowered from 1.76 eV to Ϫ0.76 eV and (iii) the
charges on the carbon and oxygen atoms in the carbonyl group
are changed from 0.34 (C) and Ϫ0.52 (O), to 0.53 (C) and
Ϫ0.82 (O), respectively. For 1a coordinated to AlCl3 in a biden-
tate fashion, complex II, the C–O bond length increases simi-
larly to complex I, while the polarisation of the carbon atom is
The coordination of AlCl3 to 1a leads to an activation of the
carbonyl group of 1a for a nucleophilic attack by e.g. the
aromatic compound. In Table 2 are shown the electronic and
structural changes calculated for the carbonyl group for 1a–c in
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slightly lower compared to complex I (longer O–Al bond length
in complex II, compared to complex I). However, the LUMO
(π*C᎐O) for complex II is significantly lower (Ϫ1.05 eV) com-
pare᎐d to complex I. This low LUMO energy of complex II
might indicate that complex II can be more reactive than com-
plex I. The changes found for 1a coordinated to AlCl3 are also
observed for both 1b and 1c when activated by AlCl3, however,
for 1b and 1c coordinated to AlCl3 an increased reactivity, com-
pared to 1a, might be expected due to the low LUMO energy.
This is consistent with the experimental observations that 1b
and 1c react with N,N-dimethylaniline 2a in the presence of the
AlCl3 catalyst to give the diarylated product.
The transition-state structures for the reaction of the differ-
ent complexes for 1a coordinated to AlCl3 with N,N-dimethyl-
aniline 2a have been calculated. In the following the two lowest
energy reaction paths, starting from complex I and II shown
in Fig. 2, respectively, will be considered. For the Lewis-acid
mediated process, the Friedel–Crafts reaction proceeds as a
two-step reaction, with formation of the C–C bond as the first
step, followed by the deprotonation as the second step. We will
in the following concentrate only on the first step, the Lewis-
acid mediated C–C bond formation.
A calculated transition-state structure for the reaction start-
ing from complex I is shown in Fig. 3a and is formation of the
C–C bond. The transition-state energy for the reaction has been
calculated to be 10.6 kcal molϪ1 which is significantly lower
compared to the uncatalyzed reaction (81 kcal molϪ1). The C–C
bond in the transition state is calculated to be 2.05 Å, which is
0.49 Å longer than in the absence of a Lewis acid. It should be
noted that the aromatic C–H bond is virtually unchanged in the
transition state, while the O–Al bond length has been reduced
to 1.76 Å compared to 1.85 Å in complex I. A comparison of
the transition-state structures for the uncatalyzed and the
AlCl3-mediated reaction reveals that for the Lewis-acid
mediated reaction a much more loose transition state (an early
transition state) is calculated. Some structural data for the
latter transition state are shown in Fig. 3a.
In contrast to the uncatalyzed reaction, the AlCl3-mediated
reaction proceeds via a zwitterionic intermediate of type A
(Fig. 3a) in which the H–C–C–O dihedral angle is approx-
imately Ϫ60Њ. The total energy for this intermediate is calcu-
lated to be 2.0 kcal molϪ1 lower in energy than the total energy
of the reactants (total energy Ϫ2343.457 Eh). It is notable that
the major changes, when going from the transition state for the
Friedel–Crafts reaction presented in Fig. 3a to intermediate A
(Fig. 3b), are the formation of the C–C bond and the change
in hybridisation of the reacting carbon atoms from sp2 to sp3,
while only minor structural changes are found for the remain-
ing part of the molecules. Due to the early transition state of
this reaction the electronic changes in the system are only
minor, with the exception of the carbonyl bond. The carbonyl
bond in the transition state is more polarised in the AlCl3-
mediated reaction, compared with the reaction in the absence
of a Lewis acid. The charges on the carbon and oxygen atoms
in the transition state, and in the intermediate of type A starting
from complex I, are calculated to be 0.45 (C) and Ϫ0.99 (O),
and 0.31 (C) and Ϫ1.07 (O), respectively.
We have also calculated the transition-state structure for the
reaction leading to intermediate of type A (H–C–C–O dihedral
angle ~ Ϫ60Њ) starting from complex II in which AlCl3 is
coordinated in a bidentate fashion to 1a. For this reaction the
transition-state energy has been calculated to be 15.3 kcal molϪ1
(the total energy of the reactants is 6.4 kcal molϪ1 higher in
energy than the reaction starting from complex I). The total
energy of this Friedel–Crafts intermediate (type A) is calculated
to be 6.5 kcal molϪ1 higher in energy than the total energy of
complex I and N,N-dimethylaniline. These results show that for
the formation of intermediate type A (Fig. 3b), a monodentate
coordination of AlCl3 to 1a leads to the most favourable reac-
tion path. Furthermore, the total energy of intermediate type
Fig. 3 a: The calculated transition-state structure for the formation of
a Friedel–Crafts intermediate by reaction of pyridine-2-carbaldehyde
1a with N,N-dimethylaniline 2a starting from complex I. b: The
Friedel–Crafts intermediate of type A starting from complex I.
A, in which AlCl3 is coordinated in a bidentate fashion to
pyridine-2-carbaldehyde 1a, is 8.5 kcal molϪ1 higher in energy
compared to the same intermediate starting from complex I.
A schematic representation of the transition-state energies and
energies of the intermediates is outlined in Fig. 4.
Both complex I and complex II can by reaction with
N,N-dimethylaniline 2a also give another intermediate in which
the H–C–C–O dihedral angle is ~Ϫ180Њ, shown as an inter-
mediate of type B in Fig. 5b, here represented with a bidentate
coordination of AlCl3. The transition-state structure for the
formation of this intermediate has also been calculated from
both complex I and complex II and in Fig. 5a is shown the
structure of the transition state for the formation intermediate
of type B formed from complex II. The most distinct difference
between the transition-state structure shown in Fig. 3a leading
to the intermediate of type A and the transition-state structure
giving the intermediate of type B outlined in Fig. 5a is the
orientation of the incoming C–H bond relative to the Lewis
acid-activated carbonyl bond of pyridine-2-carbaldehyde 1a.
For the transition-state structure outlined in Fig. 3a the H–C–
C–O dihedral angle has been calculated to be Ϫ60.4Њ while for
the transition state in Fig. 5a the same dihedral angle is
Ϫ179.5Њ. In the former transition-state structure the hydrogen
J. Chem. Soc., Perkin Trans. 1, 2001, 854–860
857

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Fig. 4 A schematic presentation of the reaction paths for the form-
ation of intermediates of type A and type B from complex I (blue
curves) and complex II (green curves). Zero-point energy is Ϫ2343.457
Eh. All values are given relative to the zero-point energy.
atom (proton) is in the same direction as the oxygen of the
carbonyl functionality, while in the latter case an opposite
direction of the hydrogen atom (proton) is found. The
transition-state energy for the formation of the intermediate of
type B, in which the nitrogen atom of 1a also coordinates to the
aluminium atom of the Lewis acid, has been calculated to be
only 1.6 kcal molϪ1, relative to complex II and N,N-dimethyl-
aniline. Although this energy is lower than the transition-state
energy calculated for the formation of intermediate A, it has to
be taken into account that complex II is 6.4 kcal molϪ1 higher in
energy than complex I. A comparison of the structure of the
two calculated transition states in Fig. 3a and Fig. 5a shows
that they are very similar for the most important bond lengths
and angles, with the exception of the H–C–C–O dihedral angle.
The total energy of intermediate type B formed by reaction of
complex II with N,N-dimethylaniline is calculated to be 13.9
kcal molϪ1 lower in energy compared to the starting situation,
which is Ϫ7.5 kcal molϪ1 relative to the zero-point energy for
the reaction profile in Fig. 4.
The lowest energy transition-state structure for the formation
of intermediate of type B is obtained from complex I reacting
with N,N-dimethylaniline 2a. This transition-state energy has
been calculated to be 5.6 kcal molϪ1 and some structural data
are shown in Fig. 6. It appears from the data that this stucture is
also similar to the structure leading to an intermediate of type
B from complex II. The total energy of the intermediate formed
by this reaction path is calculated to be the lowest energy inter-
mediate for the AlCl3-catalyzed Friedel–Crafts reaction of 1a
with 2a and is found at Ϫ9.5 kcal molϪ1 relative to the zero-
point energy for the reaction profile in Fig. 4.
Fig. 5 a: The calculated transition-state structure for the formation of
a Friedel–Crafts intermediate by reaction of pyridine-2-carbaldehyde
1a with N,N-dimethylaniline 2a starting from complex II. b: The
Friedel–Crafts intermediate of type B starting from complex II.
kcal molϪ1 relative to the zwitterionic intermediate) in the
intramolecular proton transfer in intermediate A (Fig. 3b).
The calculations show that the most favorable Friedel–Crafts
reaction of pyridine-2-carbaldehyde 1a with N,N-dimethyl-
aniline 2a catalyzed by AlCl3 proceeds from a monodentate
coordination of AlCl3 to 1a (complex I) via a transition state in
which the H–C–C–O dihedral angle is Ϫ179.4Њ, i.e. the incom-
ing aromatic compound approaches the activated carbonyl
bond with the C–H bond to be broken in an anti-fashion
relative to the carbonyl bond. However, it should also be noted
that the formation of intermediate of type B, in which 1a has a
bidentate coordination to AlCl3 (complex II), leads to an inter-
mediate of nearly the same total energy as above. The transition
state for this reaction is slightly lower than the one starting from
complex I, while the energy of the reactants is higher.
The calculations for the formation of the Friedel–Crafts
intermediate for the AlCl3-catalyzed reaction of pyridine-2-
carbaldehyde 1a with N,N-dimethylaniline 2a show that the
most energetically favourable reaction is the one in which 1a
coordinates in a monodentate fashion to AlCl3 to give an
intermediate of type B. We have considered the formation of
the new C–C bond as being the important step in the com-
parison of the mechanistic possibilities. The second step is the
deprotonation or transfer of a proton, which can be mediated
by any base present in the reactions mixture, thus having a low
barrier despite the high energy barrier (calculated to be 35.5
It has been reported by Bigi et al. that the reaction of
pyridine-2-carbaldehyde 1a with 4-methoxyphenol 2b catalyzed
by AlCl3 proceeded smoothly at room temperature in CH2Cl2.9
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reasons). Instead in these cases we only obtain the diarylated
product. The calculations show that the most probable
aluminim-mediated reaction proceeds by a zwitterionic inter-
mediate via a transition state in which the H–C–C–O dihedral
angle is ~Ϫ180Њ, i.e. the incoming aromatic compound
approaches the activated carbonyl bond with the C–H bond to
be broken in an anti fashion.
Experimental and theoretical
General methods
All reactions were carried out using anhydrous solvent and
flame-dried glasware using standard Schlenk techniques under
N2. Commercially available compounds were used without
further purification. Solvents were dried according to standard
procedures. Purification of the products, when necessary, was
carried out by flash chromatography (FC) using Merck silica
gel 60 (230–400 mesh). TLC was performed using Merck silica
gel 60 F254 plates and visualized with blue stain. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
1H NMR and 13C NMR spectra were recorded at 400 and 100
MHz respectivly, using CDCl3 as the solvent, and are reported
in ppm downfield from CDCl3 (δ = 7.25) for 1H NMR and
relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR.
The enantiomeric excess (ee) of the products were determined
by HPLC.
Fig. 6 The lowest transition-state structure for the formation of a
Friedel–Crafts intermediate of type B by reaction of pyridine-2-
carbaldehyde 1a with N,N-dimethylaniline 2a starting from complex I.
They observed higher reactivity for 1a compared to the corre-
sponding 3- and 4-isomers, 1b and 1c, respectively, of pyridine-
carbaldehyde, and proposed that this could indicate a possible
coordination of the metal by the pyridine nitrogen atom,
because they at the same time observed no reactivity of benz-
aldehyde under similar conditions. Focusing on the hydroxy
product (in this product the proton has been transferred from
the aromatic C–H bond to the oxygen atom of the activated
carbonyl bond) in the reaction of the pyridine-2-carbaldehyde
General procedure
The appropriate BINOL ligand (0.2 mmol) was placed in the
reaction flask and was subjected to vacuum for 1 h. The flask
was then refilled with N2 and solvent (2.5 ml) was then added.
A commercially available heptane solution of AlMe2Cl (0.2
mmol) was added by microsyringe resulting in gas evolution
(CH4) and white precipitate. The reaction mixture was stirred at
room temperature for 1 h. If needed the reaction mixture was
cooled to the appropriate temperature and the pyridinecarb-
aldehyde (1.05 equiv.) and aromatic compound (1.0 equiv.) were
added resulting in a brownish color. The reaction was left stir-
ring giving a clear orange solution. The mixture was poured on
to 10 mL of NH4Cl (aq. sat.) and additional solvent was added.
The phases were separated and the aq. phase was extracted with
CH2Cl2 (10 ml) and EtOAc (10 ml). The combined organic
phases were dried over Na2SO4 and the solvent was removed.
The product was purified by column chromatography on
silica. (Rf(product): 0.25 in 5% MeOH–CH2Cl2) The BINOL
ligand and excess starting material were eluted using ether–
petroleum ether (30%) after which the product was collected
using 5% MeOH in CH2Cl2.
we can observe a stabilisation by chelation of 17.7 kcal molϪ1
.
The fact that bidentate coordination is not possible for the
3- and the 4-isomers and the fact that only the 2-isomer
gives the hydroxy product while the 3- and 4-isomers react fur-
ther to give a diarylated product, 3a and 3b, respectively, leads
us to believe that (i) chelation could be important for reaction
to stop at the alcohol stage, thereby making it possible upon
aqueous workup to isolate the hydroxy product 3a, and/or (ii)
that the increased reactivity for 1b and 1c is due to the lower
LUMO energy of these compounds compared to 1a.
Summary
We have found that it is possible to mediate an enantio-
selective Friedel–Crafts reaction of pyridine-2-carb-
aldehyde with N,N-dimethylaniline by the application of chiral
Lewis acids. The reactions proceed with moderate to good
yields depending on the reaction conditions, and moderate
enantioselectivity could be obtained by applying an optic-
ally active ligand ((R)-BINOL) to the catalyst system. The
3- and 4-isomers of the pyridinecarbaldehyde also react with
(4-Dimethylaminophenyl)pyridin-2-ylmethanol 3a. 1H NMR
δ 8.54 (d, J = 5.0 Hz, 1H), 7.59 (dt, J = 7.7 Hz, J = 1.7 Hz,
1H), 7.20 (d, J = 8.7 Hz, 2H), 7.12–7.22 (m, 2H), 6.68 (d, J = 8.7
Hz, 2H), 5.67 (d, J = 3.6 Hz, 1H), 5.06 (d, J = 3.6 Hz, 1H), 2.91
(s, 6H). 13C NMR δ 177.5, 150.3, 147.6, 136.6, 131.1, 128.1,
122.1, 121.3, 112.5, 74.7, 40.6. HPLC (Daicel Chiralcel OD,
hexane–i-PrOH = 90 : 10, flow rate = 0.5 ml minϪ1) tr = 33.9
min (major), tr = 41.1 min (minor). HRMS for C14H16N2O
(Naϩ): calcd 251.1160, found 251.1161.
The reactions of 4-methoxyphenol 2b and 1,3-dimethoxy-
benzene 2c with N,N-dimethylaniline in CH2Cl2 in the presence
of (R)-4a-AlCl were performed according to the general
procedure. The data for for the products are available from the
literature.9
N,N-dimethylaniline under similar conditions giving
a
diarylated product, while benzaldehyde showed no reactivity.
The investigation of a mono- vs. bidentate coordination of the
aluminium catalyst both experimentally and computationally
leads us to believe that the bidentate coordination is not
necessary for the reaction of 1a and 2a to proceed. The compu-
tational results point to monodentate coordination making
the lowest energy reaction path. Thus, we believe that it is the
electron-withdrawing effect of the pyridine ring that enhances
the reactivity of the pyridinecarbaldehydes as compared to e.g.
benzaldehyde. This is consistent with the fact that we also
observe reactions of 1b and 1c with 2a in the presence of an
aluminium catalyst. However, a bidentate coordination might
be important for the reaction to stop at the stage of the hydroxy
product. We see a stabilisation of the product by the bidentate
coordination; moreover we observe no hydroxy product in the
reactions of 1b or 1c (in which the coordination of the Lewis
acid to the nitrogen atom is not possible for geometrical
The reactions of pyridine-3- and -4-carbaldehyde, 1b and
1c, respectively, with N,N-dimethylaniline were performed
according to the general procedure. Compound 3b: 43% con-
1
version after 24 h. H NMR δ 8.25 (s, 2H), 7.41 (m, 1H), 7.19
(m, 1H), 6.94 (d, J = 9.2 Hz), 6.66 (d, J = 9.2 Hz), 5.33 (s, 1H),
1
2.93 (s, 12H). Compound 3c: 50% conversion after 24h. H
J. Chem. Soc., Perkin Trans. 1, 2001, 854–860
859

View Article Online
2 (a) F. Bigi, G. Casnati, G. Satori, C. Dalprato and R. Bortolini,
NMR δ 8.46 (d, J = 6.0 Hz, 2H), 7.05 (d, J = 6.0 Hz, 2H), 6.95
(d, J = 8.8 Hz), 6.66 (d, J = 8.8 Hz), 5.31 (s, 1H), 2.92 (s, 12H).
LRMS: calcd for C22H25N3 331.2 (M)ϩ, found (M ϩ H)ϩ 332.4.
Tetrahedron: Asymmetry, 1990, 1, 861; (b) F. Bigi, G. Bocelli,
R. Maggi and G. Sartori, J. Org. Chem., 1999, 64, 5004; (c) A. Ishii,
J. Kojima and K. Mikami, J. Org. Chem., 2000, 65, 1597; (d) A. Ishii
and K. Mikami, J. Fluorine Chem., 1999, 97, 51; (e) A. Ishii,
J. Kokoma and K. Mikami, Org. Lett., 1999, 1, 2013.
3 (a) G. Erker and A. A. H. van der Zeijden, Angew. Chem., Int. Ed.
Engl., 1990, 29, 512; (b) N. Gathergood, W. Zhuang and K. A.
Jørgensen, J. Am. Chem. Soc., 2000, 122, 12517; (c) N. Gathergood,
W. Zhuang, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 2001,
66, 1009.
Theoretical methods
Calculations were performed using Jaguar version 4.07 and
using Restricted Hartree–Fock (RHF) using a 6-31G basis set
for all calculations. The Hessians were calculated at all
stationary points to ensure that minima were characterised by
all positive normal modes and the transition states were
characterised by one negative normal mode corresponding to
the motion of the proper atoms. Energies reported were
obtained from single point energy calculations. Atomic
charges were obtained from Mulliken population analysis
which was performed on structures previously optimized on
the RHF/6-31G level.
4 (a) M. Johannsen, Chem. Commun., 1999, 2233; (b) S. Saaby,
X. Fang, N. Gathergood and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2000, 39, 4114.
5 See e.g.: (a) K. Maruoka and H. Yamamoto, in Catalytic Asymmetric
Synthesis, ed. I. Ojima, VCH Publishers, New York, 1993, p. 413;
(b) K. B. Simonsen, P. Bayón, R. G. Hazell, K. V. Gothelf and
K. A. Jørgensen, J. Am. Chem. Soc., 1999, 121, 3845; (c) K. B.
Simonsen, K. A. Jørgensen, Q.-S. Hu and L. Pu, Chem. Commun.,
1999, 811; (d) W.-S. Huang, Q.-S. Hu and L. Pu, J. Org. Chem., 1999,
64, 7940; (e) K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 1994,
116, 1561; ( f ) K. B. Simonsen, N. Svenstrup, M. Roberson and
K. A. Jørgensen, Chem. Eur. J., 2000, 6, 123; (g) L. Pu, Chem. Eur. J.,
1999, 5, 2227.
Acknowledgement
This paper is dedicated to the late Professor Göran Magnusson.
We are indebted to The Danish National Research Foundation
for financial support.
6 A. Bayer, Ber. Dtsch. Chem. Ges., 1872, 5, 1094.
7 Jaguar 4.0, Schroedinger, Inc. Portland, OR, 1991–2000.
8 (a) P. Tarakeswar, J. Y. Lee and K. S. Kim, J. Chem. Phys. A, 1998,
102, 2253; (b) P. Tarakeswar and K. S. Kim, J. Chem. Phys. A, 1999,
103, 9116. These papers describe the interaction of C6H6 with BF3
and AlCl3 in relation to a reaction with CO in zeolite catalysis.
9 For an investigation of the reaction of pyridine-2-carbaldehyde, as
well as the 3- and 4-isomer, with phenolic compounds, catalyzed by
AlX3 see G. Sartori, R. Maggi, F. Bigi, A. Arienti, C. Porta and
G. Predieri, Tetrahedron, 1994, 50, 10587.
References
1 J. E. Hofmann and A. Schriesheim, in Friedel–Crafts and Related
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860
J. Chem. Soc., Perkin Trans. 1, 2001, 854–860