Superacid-catalyzed reactions of pyridinecarboxaldehydes

Article abstract of DOI:10.1016/j.tet.2006.04.022

A variety of pyridinecarboxaldehydes are shown to give condensation products in high yields (80-99%, 10 examples) by reacting with benzene and CF₃SO₃H (triflic acid). In the superacidic solution, pyridinecarboxaldehydes can react with deactivated arenes (o-dichlorobenzene and nitrobenzene) and with saturated hydrocarbons (methylcyclohexane and adamantane). Dicationic intermediates from pyridinecarboxaldehydes in superacid (FSO₃H-SbF₅) have been directly observed using low temperature ¹³C NMR spectroscopy. Diprotonated pyridinecarboxaldehydes have also been studies using ab initio computational methods.

Full text of DOI:10.1016/j.tet.2006.04.022

Tetrahedron 62 (2006) 5915–5921
Superacid-catalyzed reactions of pyridinecarboxaldehydes
a
a
b
Douglas A. Klumpp,a, Yiliang Zhang, Patrick J. Kindelin and Siufu Lau
*
aNorthern Illinois University, Department of Chemistry and Biochemistry, DeKalb, IL 60115, USA
bDepartment of Chemistry, California State Polytechnic University, Pomona, CA 91768, USA
Received 3 February 2006; revised 30 March 2006; accepted 6 April 2006
Available online 11 May 2006
Abstract—A variety of pyridinecarboxaldehydes are shown to give condensation products in high yields (80–99%, 10 examples) by react-
ing with benzene and CF3SO3H (triflic acid). In the superacidic solution, pyridinecarboxaldehydes can react with deactivated arenes
(o-dichlorobenzene and nitrobenzene) and with saturated hydrocarbons (methylcyclohexane and adamantane). Dicationic intermediates
from pyridinecarboxaldehydes in superacid (FSO3H–SbF5) have been directly observed using low temperature 13C NMR spectroscopy.
Diprotonated pyridinecarboxaldehydes have also been studies using ab initio computational methods.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper, we provide a full report of our studies involving
the superacid-catalyzed reactions of pyridinecarboxalde-
hydes (1a–c). The superacid-catalyzed condensation reac-
tions of pyridinecarboxaldehydes with arenes are described
and a general mechanism involving dicationic intermediates
is proposed. These dicationic intermediates are also shown to
be capable of reacting with saturated hydrocarbons. Direct
observation of the dicationic species using low temperature
NMR is also reported. The diprotonated species from 2-,
3-, and 4-pyridinecarboxaldehyde have also been studied
using ab initio computational methods and these results are
described. The results from these studies demonstrate that
reactive dications can be formed in high concentrations and
they exhibit electrophilic reactivities comparable to super-
electrophiles.
We recently described the superacid-catalyzed chemistry of
3-pyridinecarboxaldehyde (1b), its reactions with deacti-
vated arenes, and the involvement of dicationic electrophilic
intermediates (Scheme 1).1 Because of the similarities to the
superelectrophilic systems like diprotonated benzaldehyde
(3–4),2 we proposed that dication 2 is a good model system
for the superelectrophilic intermediates.3 Since our report,
many similar dicationic electrophilic systems have been
described.4 These reactive, dicationic electrophiles typically
have a relatively stable cationic center (such as a pyridinium,
ammonium, or phosphonium cation) adjacent to a cationic
electrophilic site. We and others have shown that these di-
cationic electrophiles can exhibit dramatically increased
electrophilic reactivities compared to analogous mono-
cationic electrophiles.
2. Results and discussion
H
N
N
N
CF3SO3H
ArH
Some time ago, the condensations of pyridinecarboxalde-
hydes (1a–c) with benzene in H2SO4 were described in the
patent literature.5 Our previous report described the conden-
sation of 3-pyridinecarboxaldehyde (1b) with benzene and
CF3SO3H, and this Brønsted superacid was found to be an
outstanding catalyst for the condensation.1 In order to fur-
ther demonstrate the utility of CF3SO3H in these types of
condensation reactions, a series of pyridinecarboxaldehydes
have been reacted with benzene in CF3SO3H (Table 1). The
isomeric pyridinecarboxaldehydes (1a–c), and a number of
substituted derivatives (6–12), give the condensation prod-
ucts in excellent yields. An N-methylated pyridiniumcarbox-
aldehyde also gives the condensation product (21) in high
yield (Scheme 2). Although the yields have not been opti-
mized, it has been determined that as little as 2.7 equiv
of CF3SO3H can be used to convert 1a to product 13a
H
H
H
Ar Ar
OH
O
2
1b
OH2
OH
H
H
H
H
3
4
Scheme 1.
* Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4802;
e-mail: dklumpp@niu.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.022

5916
D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
Me
N
Table 1. Products and yields for the reactions of pyridinecarboxaldehydes
(1a–c, 6–12) with C6H6 and CF3SO3H
N
1) Me3O BF4
Cl
Ph
2) CF3SO3H
C6H6
3) Aq. Workup
Starting material
Product
Yield
(%)
CHO
Ph
1b
21
N
N
Ph
Ph
Scheme 2.
CHO
With less nucleophilic arenes, the pyridinecarboxaldehydes
(1a–c) give hydroxy alkylation products from superacid
(Table 2). The isomeric pyridinecarboxaldehydes were re-
acted with the deactivated arenes, chlorobenzene, o-dichloro-
benzene, and nitrobenzene, in excess of CF3SO3H (100
equiv), and in all cases the condensation products were ob-
tained. Remarkably, the pyridinecarboxaldehydes even react
with nitrobenzene in a solution wherein the nitro group is
largely protonated (protonated nitrobenzene, pKa¼ꢀ11).9
Under similar conditions, benzaldehyde reacts with chloro-
benzene in superacid to give some condensation product,
but it does not react with either o-dichlorobenzene or nitro-
benzene. Besides weak nucleophilic arenes, 4-pyridine-
carboxaldehyde (1c) is also found to react with saturated
hydrocarbons in superacid. When 4-pyridinecarboxaldehyde
is dissolved in 6 equiv of CF3SO3H with 1.0 equiv of methyl-
cyclohexane under CO pressure (750 psi; 25 ꢁC), the func-
tionalized product (22) is formed, al beit in low isolated
yield (Scheme 3). Similarly, adamantane gives the ester prod-
uct (23) in reasonable yield, along with a smaller amount
of 1-adamantanecarboxylic acid. To verify that functionali-
zation of the hydrocarbon is due to the reactivity of the
carboxonium ion, methylcyclohexane was reacted with
6 equiv of CF3SO3H, CO (5 atm), and 4-pyridinemethanol.
Under these conditions, there is no product (22) formed.
1a, 2-isomer
1b, 3-isomer
1c, 4-isomer
13a, 2-isomer
13b, 3-isomer
13c, 4-isomer
88
99
93
N
N
N
N
80
OHC
OHC
CHO
Ph
Ph
14
6
Ph
Ph
Ph
Ph
N
CHO
N
Ph
Ph
82
92
7
15
N
N
Ph
Br
CHO
CHO
Br
Ph
16
8
Ph
Me
N
Me
N
Ph
90
99
89
91
9
17
N
OMe
In order to characterize the electrophilic species arising from
the pyridinecarboxaldehydes (1a–c), ab initio theoretical
calculations were done along with spectroscopic studies.
For the isomeric pyridinecarboxaldehydes (1a–c), 10 struc-
tures were located at potential energy minima on the energy
surfaces for the N,O-diprotonated species (Fig. 1; all mini-
mized structures possess C1 symmetry). Geometry optimiza-
tions were done using density function theory and the hybrid
functional B3LYP at the 6-311G** level.10,11,12 Vibrational
analyses were performed at the B3LYP/6-311G** level of
theory and all optimized structures (24–26) were found to
have zero imaginary frequencies. Zero-point-energy correc-
tions were made to the single point energies for structures
24–26. From 2-pyridinecarboxaldehyde (1a), four structures
are found at energy minima: the conformational isomers
of the syn stereoisomer (syn-24a and syn-24b) and anti
stereoisomer (anti-24a and anti-24b) of the diprotonated
N
OMe
CHO
Ph
Ph
10
18
MeO2C
MeO2C
Ph
N
CHO
N
Ph
19
11
N
NH2
N
NH2
Ph
CHO
Ph
12
20
(>80% yield), and with larger quantities of CF3SO3H
(15 equiv), the condensation reaction is complete within
5 min.6 The condensation of 1a–13a can be accomplished
with H2SO4,5 H3PO4,5 and also AlCl3,7 but these acids
give the hydroxy alkylation products (13a–c) in somewhat
low yields (accompanied by unreacted 1a). Recently, it
was discovered that products 13a–c are highly potent dopa-
mine transporter inhibitors and it was proposed that these
types of compounds may have therapeutic value in the treat-
ment of cocaine abuse.8 The triflic acid catalyzed reactions of
pyridinecarboxaldehydes with benzene are effective, general
route to these products.
O
1c, CF3SO3H
H
CO, 25°C
10%
O
CH3
N
H3C
22
1c, CF3SO3H
N
O
CO, 25°C
67%
O
23
Scheme 3. Superacidic-functionalization of hydrocarbons with 4-pyridine-
carboxaldehyde (1c).

D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
5917
Table 2. Products and yieldsa from the reactions of pyridinecarboxaldehydes (1a–c) with deactivated arenes and CF3SO3H
Aldehyde
Chlorobenzene productsb
Yield (%)
o-Dichlorobenzene productsc
Yield (%)
Nitrobenzene productsd
Yield (%)
12
N
N
C6H3Cl2
C6H3Cl2
N
C6H4NO2
C6H4NO2
C6H4Cl
C6H4Cl
1a
88
72
H
H
H
H
H
H
H
H
H
N
N
N
C6H3Cl2
C6H3Cl2
C6H4NO2
C6H4NO2
C6H4Cl
C6H4Cl
1b
85
94
87
83
10
53
C6H4Cl
C6H4Cl
C6H3Cl2
C6H3Cl2
C6H4NO2
C6H4NO2
1c
N
N
N
a
Yields are reported as the mixture of isomers; result for 1b is taken from Ref. 1.
Reaction done at 25 ꢁC.
b
c
d
Reaction done at 80 ꢁC.
Reaction done at 140 ꢁC.
aldehyde. The global energy minimum is found at the syn-
24b structure, while the syn-24a structure is the next most
stable structure, estimated to be 2.5 kcal/mol less stable
than syn-24b. Diprotonation of 3-pyridinecarboxaldehyde
(1b) also gives four structures at energy minima. The calcu-
lations find the global energy minimum at the syn-25a
relative energy
(kcal•mol-1
relative energy
(kcal•mol-1
structure
E + ZPE
(Hartrees)
structure
H
E + ZPE
(Hartrees)
)
)
2+
2+
2+
2+
2+
H
H
H
H
H
N
N
O
O
-362.095123
-362.099126
2.5
-362.109605
-362.109488
0.0
syn-25a
syn-24a
H
H
H
O
O
H
H
0.0
0.1
N
N
H
syn-24b
syn-25b
2+
2+
H
H
N
H
O
H
H
N
N
O
-362.083881
-362.080414
9.6
-362.098031
-362.095243
7.3
9.0
H
anti-25a
H
anti-24a
H
O
2+
H
H
O
11.7
N
H
H
anti-24b
anti-25b
relative energy
(kcal•mol-1
structure
E + ZPE
(Hartrees)
)
2+
2+
H
O
H
0.0
-362.105289
-362.093665
N
H
syn-26
H
O
7.3
H
N
H
anti-26
Figure 1. Calculated structures and energies for the diprotonated pyridinecarboxaldehydes (24–26) at the B3LYP/6-311G**//B3LYP/6-311G** level of theory.

5918
D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
structure, but the syn-25b structure is just 0.1 kcal/mol less
stable. In the case of 4-pyridinecarboxaldehyde, the syn-26
and anti-26 structures (both C1 point group) are found at
energy minima, and the syn-26 is more stable by 7.3 kcal/
mol. These computational results are in accord with earlier
studies related to protonated aldehydes. Experimental and
theoretical results have previously shown that the anti
stereoisomers of protonated aldehydes are less stable than
the syn stereoisomers.13 Interestingly, the monocationic car-
boxonium ions from benzaldehyde (27–28) are estimated to
be 2.2 kcal/mol apart in relative energies for the syn and anti
stereoisomers (Scheme 4).2a The dicationic carboxonium
ions 24–26 show increasing relative energy differences for
the syn and anti stereoisomers (7.3–11.7 kcal/mol).
and in SbF5–FSO3H, the chemical shift (203.6 ppm) is
similar to other observed protonated aldehydes. For example,
protonated benzaldehyde (27 and 28) gives carboxonium
resonances at 203.5 and 205.9 ppm (Scheme 4).2a In our
earlier communication, we described similar NMR experi-
ments with 3-pyridinecarboxaldehyde (1b).1 With increasing
acidity, this compound also shows a dramatic down field shift
of the carbonyl carbon. In the SbF5–FSO3H solution, how-
ever, two peaks are observed for the carbonyl carbon and sev-
eral of the ring carbons. These doubled signals were initially
thought to be from the syn and anti stereoisomers of the pro-
tonated aldehyde, because previous NMR studies of proton-
ated aliphatic and aromatic aldehydes have observed both
stereoisomers.13 We now propose that the two observed ions
are not the syn and anti stereoisomers, but rather the rota-
tional isomers syn-25a and syn-25b. The computational
studies indicated that these two rotational isomers are very
close in energy, while the syn and anti isomers are ener-
getically far apart. Evidently, a sizable energy barrier sepa-
rates the conformational isomers syn-25a and anti-25b,
because their inter-conversion is slow on the NMR time-scale
at ꢀ80 ꢁC.13d The NMR studies of 4-pyridinecarboxalde-
hyde (1c) also suggest the formation of the N,O-diprotonated
species in superacid. The carbonyl 13C resonance moves
down field from 184.5 ppm in CF3CO2H to 211.2 ppm in
SbF5–FSO3H solution. The 13C NMR spectrum from
SbF5–FSO3H solution clearly shows that a single species is
generated from 1c (Fig. 2). Computational results indicate
that the syn-26 structurewould be heavily favoredin an equil-
ibration of diprotonated structures. Upon solvation in super-
acid, aldehyde 1c is converted to the syn-26 species, and at
the highest levels of acidity (SbF5–FSO3H, Ho<ꢀ18) the
conversion appears to be complete. The series of pyridine-
carboxaldehydes (1a–c) give NMR spectra from superacid
that are in accord with the results from the ab initio studies.
For both 1a and 1c, calculations show that only one N,O-
diprotonated species is located at or near the global minima,
and the 13C NMR spectra show only one species in each of the
SbF5–FSO3H solutions. But calculations on the 1b system
show two species at or near the global minimum, and both
ions are observed in the 13C NMR.
H
H
H
O
O
H
27
205.9 ppm
28
203.5ppm
Scheme 4.
The isomeric pyridinecarboxaldehydes were also studied by
13C NMR in acidic solvents and the results are consistent
with the formation of N,O-diprotonated structures in super-
acid (Table 3). When 2-pyridinecarboxaldehyde (1a) is dis-
solved in solutions of increasing acidity, the carbonyl (or
carboxonium) carbon is progressively shifted down field
from 181.9 ppm in CF3CO2H (Ho ꢀ2.7) to 203.6 ppm in
SbF5–FSO3H (Ho<ꢀ18). The down field shifts indicate an
increasing degree of protonation of the carbonyl group,
Table 3. 13C NMR data from pyridinecarboxaldehydes 1a–c in acidic
solution
Aldehyde
Acid system (Ho)
CF3CO2H (ꢀ2.7)
13C NMR data, d, ppma
1a
181.9 (c), 148.4, 142.1, 140.0,
130.3, 128.4
CF3SO3H (ꢀ14.1)
FSO3H (ꢀ15.1)
184.6 (c), 148.9, 142.1, 138.8,
131.1, 129.6
191.8 (c), 150.3, 144.4, 138.5,
133.7, 133.2
203.6 (c), 150.6, 150.0, 145.3,
140.9, 133.0
Based on the results of the NMR studies and the superacid-
promoted reactions, a general mechanism is proposed that
invokes these dicationic intermediates (Scheme 5). For
example in the case of 1c, the pyridine nitrogen is initially
protonated to give the pyridinium cation (29) and subsequent
protonation at the carbonyl oxygen yields the dicationic
intermediate syn-26. Electrophilic attack of benzene then
leads to the condensation products via dicationic intermedi-
ates 30 and 31. In the case of 2-amino-3-pyridinecarbox-
aldehyde (12), the analogous tricationic electrophile (33)
is likely generated from the dication 32.14 Given the low
nucleophilicity of C6H6, it is highly unlikely that the conden-
sation reaction occurs via the dication 32, but must involve
further protolytic activation of the carbonyl group. When
4-pyridinecarboxaldehyde (1c) is reacted with carbon
monoxide and methylcyclohexane in CF3SO3H, the product
is formed by hydride transfer from the cycloalkane to the
dicationic carboxonium ion (Scheme 6). This proposed
mechanism is in accord with another recent study show-
ing the reduction of 3-pyridinecarboxaldehyde to 3-pyridil-
carbinol and 3-methylpyridine from the reactions with
SbF5–FSO3H (<ꢀ18)
1b
CF3CO2H
CF3SO3H
FSO3H
184.0 (c), 142.9, 140.2, 138.1,
129.2, 123.4
193.3 (c), 147.1, 144.9, 142.3,
131.3, 127.5
201.0 (c), 149.7, 148.5, 146.1,
130.5, 129.5
208.6 (c), 155.8, 149.8, 144.6,
129.0, 125.2
SbF5–FSO3H
207.1 (c), 151.4, 150.5, 148.6,
129.0, 125.2
1c
CF3CO2H
CF3SO3H
FSO3H
184.5 (c), 143.2, 138.3, 121.3
194.6 (c), 142.1, 126.1, 122.8
199.6 (c), 143.9, 142.6, 127.0
211.2 (c), 143.3, 138.8, 130.4
SbF5–FSO3H
(c) Indicates carbonyl (or carboxonium carbon) signal. Data for 1b are taken
from Ref. 1.
a
Experiments with CF3CO2H or CF3SO3H were done at 25 ꢁC; experi-
ments with FSO3H or SbF5–FSO3H were done at ꢀ70 ꢁC with SO2ClF
diluent.

D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
5919
H
N
H
O
H
syn-26
Figure 2. 13C NMR spectrum of the dicationic product (syn-26) from 4-pyridinecarboxaldehyde (1c) and FSO3H–SbF5–SO2ClF at ꢀ80 ꢁC (ꢂ denotes external
solvent, d6-acetone).
H
N
H
N
H
N
H
N
CF3SO3H
C6H6
13c
1c
H
O
H
O
H
Ph
OH2
Ph
H
H
H
-26
syn
29
30
31
OH
H
N
NH3
O
NH3
OH
OH2
CH3
OH2
H
H
H
H
N
H
N
O
H3C
H3C
N
H
32
33
34
35
36
37
Scheme 5. Proposed reaction mechanisms and intermediates in the electrophilic reactions of 4-pyridinecarboxaldehyde (1c) and related electrophiles.
O
C
H
N
H
N
H
N
O
CH3
CH3
22
H
CH3
O
H
H
OH
OH
Scheme 6.
cyclohexane and superacid or excess AlCl3.2c In this recent
study, the diprotonated species (25) is thought to be involved
in hydride abstraction from cyclohexane. Because carboxo-
nium ions are relatively weak electrophiles, there are few
examples of carboxonium ions reacting with alkanes or
cycloalkanes.15 Superelectrophilic species like 34 and 35
are known to react with alkanes or cycloalkanes, while di-
cationic species like 36 and 37 have been shown to abstract
hydride from cyclohexane–methylcyclopentane.16
repulsive interaction of the cationic pyridinium ring and the
carboxonium proton. These studies also show the importance
of stable cationic groups in the structure–activity relation-
ships of electrophilic systems. A high level of electrophilic
reactivity can be achieved by the activation of the carboxo-
nium group by the stable pyridinium cationic center.17
3. Experimental
3.1. General
In summary, a series of pyridinecarboxaldehydes are shown
to give condensation products in excellent yields by reactions
with arenes in the Brønsted superacid, CF3SO3H. The reac-
tions involve dicationic intermediates, which exhibit very
high electrophilic reactivities, attacking even o-dichloro-
benzene, nitrobenzene, and some saturated hydrocarbons.
Evidence for the involvement of dicationic intermediates
comes from the direct observation of diprotonated species
by low temperature 13C NMR spectroscopy. For the diproto-
nated pyridinecarboxaldehydes, theoretical calculations
show that the syn-carboxonium structures are strongly desta-
bilized relative to the anti-forms, presumably due to the
The pyridinecarboxaldehydes were purchased from com-
mercial suppliersand used as received. The trifluoromethane-
sulfonic acid (triflic acid) was purchased from the
manufacturer and it was distilled from an Ar atmosphere
prior to use. SbF5 and triple distilled FSO3H were purchased
from commercial suppliers and used as received.
3.1.1. Procedure for the preparation of condensation
products. The pyridinecarboxaldehyde (0.2 g, ca. 1 mmol)
is dissolved in 1.0 mL of benzene, and 3 mL of CF3SO3H

5920
D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
is added. After 6 h, the mixture is poured over ice, the
solution is neutralized with NaOH, and the products are
extracted into CHCl3. The organic extracts are then washed
with H2O, brine, and dried with MgSO4. Concentration in
vacuo provides the crude products, which are then purified
by recrystallization or column chromatography.
3.2.6. 4-(6-Benzhydryl-pyridin-2-yl)-benzoic acid methyl
1
ester (19). White solid, mp 81–85 ꢁC (CHCl3). H NMR
(500 MHz, CDCl3), d, ppm: 4.02 (s, 3H), 5.93 (s, 1H),
7.19–7.21 (m, 1H), 7.33–7.37 (m, 2H), 7.41–7.47 (m, 8H),
7.55–7.58 (m, 1H), 7.69–7.70 (m 2H), 8.18 (d, J¼7.7 Hz,
1H), 8.35 (d, J¼7.7 Hz, 1H), 8.84 (s, 1H). 13C NMR
(125 MHz, CDCl3), d, ppm: 52.3, 59.7, 118.2, 122.9,
126.7, 128.1, 128.5, 129.0, 129.6, 130.0, 130.7, 131.6,
137.4, 139.8, 143.3, 155.6, 162.9, 167.1. MS: 379 (M+),
378, 348, 302, 241, 165. HRMS: C26H21NO2, calcd
379.157229, found 379.157033.
3.1.2. Procedure for the reactions and functionalization
of hydrocarbons. In a 125 mL Parr autoclave (glass-lined
and flushed with dry Ar), 4-pyridinecarboxaldehyde
(1 mmol) and methylcyclohexane (1 mmol) dissolved in
5 mL CHCl3 and 3 mL CF3SO3H were added. The reactor
is sealed and pressurized with carbon monoxide to 750 psi.
After 12 h of stirring at 25 ꢁC, the reactor was depressurized
and its contents were poured into an ice-cold solution of
CH3OH and Na2CO3. Filtration and removal of the solvent
gave crude product (22), which was further purified by
column chromatography.
3.2.7. 2-Amino-3-benzhydryl-pyridine (20). White solid,
1
mp 133–135 ꢁC (CHCl3). H NMR (500 MHz, CDCl3), d,
ppm: 4.32 (s, 2H), 5.36 (s, 1H), 6.64 (dd, J¼5.0, 7.5 Hz),
6.92 (d, J¼7.1 Hz, 1H), 7.14 (d, J¼7.1 Hz, 4H), 7.14–7.36
(m, 6H), 8.03 (d, J¼4.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3), d, ppm: 52.2, 114.5, 123.4, 127.1, 128.8, 129.4,
137.6, 141.3, 146.2, 156.6. MS: 260 (M+), 259, 242,
181, 165. HRMS: C18H16N2, calcd 260.131349, found
260.131390.
3.2. Analytical data for new compounds
3.2.1. 4,40-Dibenzhydryl-[2,20]bipyridinyl (14). Brown
solid, mp 181–187 ꢁC (CHCl3). 1H NMR (500 MHz,
CDCl3), d, ppm: 5.67 (s, 2H), 7.05 (d, J¼3.9 Hz, 2H),
7.18–7.37 (m, J¼20 Hz), 8.33 (s, 2H), 8.59 (d, J¼4.7 Hz,
2H). 13C NMR (125 MHz, CDCl3), d, ppm: 56.6, 122.4,
124.6, 126.8, 128.6, 129.4, 142.2, 149.3, 153.9. HRMS:
C36H28N2, calcd 488.225249, found 488.223488.
3.2.8. 3-Benzhydryl-1-methyl pyridinium triflate (21).
White solid, mp 131–133 ꢁC (Hexane–ether). 1H NMR
(CDCl3, 500 MHz), d, ppm: 4.36 (s, 3H), 5.85 (s, 1H), 7.12–
7.15 (m, 4H), 7.25–7.29 (m, 2H), 7.31–7.36 (m, 4H), 7.87
(dd, J¼6.1, 8.1 Hz, 1H), 8.05 (d, J¼8.2 Hz, 1H), 8.53 (s,
1H), 8.81 (d, J¼6.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz),
d, ppm: 48.8, 53.4, 120.7 (q, JC–F¼320 Hz), 127.7, 129.2,
129.3, 140.0, 143.8, 145.0, 145.3, 146.0. Calcd: C, 58.67;
H, 4.43; N, 3.42; found: C, 58.63; H, 4.35; N, 3.40.
3.2.2. 2,6-Dibenzhydryl-pyridine (15). Yellow solid, mp
1
94–101 ꢁC (CHCl3). H NMR (500 MHz, CDCl3), d, ppm:
5.66 (s, 2H), 7.06 (d, J¼7.7 Hz, 2H), 7.28–7.35 (m, 20H),
7.57 (t, J¼7.7 Hz, 1H). 13C NMR (125 MHz, CDCl3), d,
ppm: 59.2, 121.4, 126.4, 128.3, 129.5, 136.9, 143.2, 162.4.
MS: 411 (M+), 410, 332, 244, 165. HRMS: C31H25N, calcd
411.198700, found 411.198941.
3.2.9. 1-Methyl-cyclohexanecarboxylic acid pyridin-4-yl-
methyl ester (22). Oil. 1H NMR (CDCl3, 500 MHz), d, ppm:
1.16 (s, 3H), 1.20–1.56 (m, 8H), 2.00–2.04 (m, 2H), 5.08 (s,
2H), 7.19–7.21 (m, 2H), 8.56 (s, 2H). 13C NMR (CDCl3,
125 MHz), d, ppm: 23.1, 25.6, 35.4, 43.2, 63.9, 121.8,
145.5, 149.8, 177.2. MS: 233 (M+), 178, 125, 97.
3.2.3. 3-Benzhydryl-5-bromo-pyridine (16). Oil. 1H NMR
(500 MHz, CDCl3), d, ppm: 5.60 (s, 1H), 7.16–7.18 (d,
J¼7.4 Hz, 2H), 7.28–7.41 (m, 6H), 7.63 (br s, 1H), 8.42
(d, J¼1.2 Hz, 1H), 8.62 (d, J¼1.8 Hz, 1H). 13C NMR
(125 MHz, CDCl3), d, ppm: 54.1, 120.8, 127.1, 128.8,
129.3, 139.2, 141.4, 142.0, 148.9, 149.1. MS: 325 (M+),
323, 244, 167. HRMS: C18H14BrN, calcd 323.030961, found
323.030937.
3.2.10. Adamantane-1-carboxylic acid pyridin-4-yl-
methyl ester (23). White solid, mp 55–56 ꢁC (hexane–
ether). 1H NMR (CDCl3, 500 MHz), d, ppm: 1.66–1.74
(m, 6H), 1.92 (s, 6H), 1.99–2.03 (m, 3H), 5.09 (s, 2H),
7.23 (d, J¼4.4 Hz, 2H), 8.57 (d, J¼3.5 Hz, 2H). 13C NMR
(CDCl3, 125 MHz), d, ppm: 27.9, 36.4, 38.8, 40.8,
63.7, 121.7, 146.1, 149.5, 176.9. MS: 271 (M+), 227, 163,
135, 93.
3.2.4. 2-Benzhydryl-6-methyl-pyridine (17). White solid,
mp 53–58 ꢁC (CHCl3). 1H NMR (500 MHz, CDCl3), d,
ppm: 2.63 (s, 1H), 5.91 (s, 1H), 6.97 (d, J¼7.7 Hz, 1H),
7.02 (d, J¼7.7 Hz, 1H), 7.27–7.38 (m, 10H), 7.48–7.51
(m, 1H). 13C NMR (125 MHz, CDCl3), d, ppm: 24.6, 59.5,
121.0, 121.3, 126.6, 128.5, 129.6, 136.9, 143.1, 158.0,
162.5. MS: 259 (M+), 258, 243, 181, 165. HRMS:
C19H17N, calcd 259.136100, found 259.136453.
Acknowledgements
The financial support of the NIH-NIGMS (GM071368-01
and SO6GM53933-0251), and Northern Illinois University
is greatly appreciated. Special thanks are also given to
Professor Elisheva Goldstein for guidance with the ab initio
calculations, and to the reviewers of this manuscript for their
comments.
3.2.5. 3-Benzhydryl-2-methoxy-pyridine (18). White
solid, mp 98–101 ꢁC (CHCl3). 1H NMR (500 MHz,
CDCl3), d, ppm: 3.94 (s, 3H), 5.85 (s, 1H), 6.86 (dd,
J¼7.3, 5.0 Hz, 1H), 7.10–7.38 (m, 11H), 8.13 (dd, J¼5.0,
1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3), d, ppm:
49.7, 53.6, 116.6, 126.4, 126.9, 128.3, 128.8, 129.3, 138.5,
142.8, 144.7, 161.6. MS: 275 (M+), 260, 242, 184, 167.
HRMS: C19H17NO, calcd 275.131014, found 275.130983.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.04.022.

D. A. Klumpp et al. / Tetrahedron 62 (2006) 5915–5921
5921
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala,
P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
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Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
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Gaussian 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
13. (a) Olah, G. A.; White, A. M.; O’Brien, D. H. Chem. Rev. 1970,
70, 561; (b) Olah, G. A.; O’Brien, D. H.; Calin, M. J. Am.
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14. When compound 12 is dissolved in solvents of increasing acid-
ity, the carbonyl carbon shows evidence of increasing proton-
ation. 13C carbonyl signal: CDCl3 (191.7 ppm), CF3CO2H
(Ho ꢀ2.7, 192.4 ppm), CF3SO3H (Ho ꢀ14.1, 197.9 ppm).
15. (a) Brouwer, D. M.; Kiffen, A. A. Recl. Trav. Chim. Pays-Bas
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References and notes
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6. Reactions done at 25 ꢁC.
7. Reaction conditions: 0.0028 mol 1a, 0.0084 mol AlCl3, and
10 mL C6H6, refluxed for 2 h. About 20% of the starting
material 1a was unreacted.
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12. Calculations done using Frisch, M. J.; Trucks, G. W.; Schlegel,
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