An unusual carbon-carbon bond scission reaction with molecular oxygen under mild conditions; formation of piperidines from 1-azabicyclo[2.2.2]octanes

Article abstract of DOI:10.1039/a701223c

Molecular oxygen reacts with 2-(1-phenylethyl)- and 2-benzhydryl-3-alkylimino-1-azabicyclo[2.2.2]-octanes 1-7 in neutral solution at room temperature to form 1-acylpiperidine-4-carboxylic acid N-alkylamides 8-14. During the transformation two new carbonyl bonds are formed and a carbon-carbon bond is cleaved. The transformation is quite general provided the 2-substituent of the imine is of sufficient steric bulk, such as the 2-(1-phenylethyl) or 2-benzhydryl groups. No reaction is observed in the absence of a 2-substituent, as in the case of imine 15.

Full text of DOI:10.1039/a701223c

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An unusual carbon–carbon bond scission reaction with molecular
oxygen under mild conditions; formation of piperidines from
1-azabicyclo[2.2.2]octanes
Timothy Norris,* Dinos Santafianos and Jon Bordner
Pfizer Central Research Laboratories, Groton, Connecticut 06340, USA
Molecular oxygen reacts with 2-(1-phenylethyl)- and 2-benzhydryl-3-alkylimino-1-azabicyclo[2.2.2]-
octanes 1–7 in neutral solution at room temperature to form 1-acylpiperidine-4-carboxylic acid N-alkyl-
amides 8–14. During the transformation two new carbonyl bonds are formed and a carbon–carbon bond
is cleaved. The transformation is quite general provided the 2-substituent of the imine is of sufficient
steric bulk, such as the 2-(1-phenylethyl) or 2-benzhydryl groups. No reaction is observed in the absence
of a 2-substituent, as in the case of imine 15.
NHAc
Introduction
O
Cu(I) catalyst
O2, heat
We have observed that 2-(1-phenylethyl)- and 2-benzhydryl-3-
alkylimino-1-azabicyclo[2.2.2]octanes 1–7 react with molecular
oxygen when in neutral solution at room temperature to
form 1,4-disubstituted piperidines 8–14 (Scheme 1). Oxygen is
NHAc
N
H
NHCHO
R3
R1
R1
O
N
R3
R2
H
N
O
R2
O
O
Cu(I) catalyst
O2, heat
N
atmospheric O2,
25 °C ~48 h
N
+
N
O
H
N
solvent
H
R4
H
O
R4
1–7
8–14
O
imine
piperidine
R1
R2
R3
R4
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
H
OMe
Me
Ph
Ph
Ph
Ph
Me
Ph
Ph
OMe
OMe
H
H
H
Pri
H
Me
H
H
O
1O2
O
O
N
N
light
H
H
O
O
O
Scheme 1
readily soluble in organic solvents but does not typically react
with unsaturated organic substrates at room temperature. This
is in sharp contrast to singlet oxygen where, in its excited state,
molecular oxygen causes limited and specific oxidation of a
wide variety of organic substrates.1
R
H
R
O2, 25 °C
solvent
O
There are a few examples reported where singlet oxygen has
been shown to add across the double bond of enamines in five
and six membered rings in complex polycyclic systems to form
the corresponding carbonyl compounds with carbon–carbon
bond scission. Typically, light,2 light and Rose Bengal on SiO2,3
or light and Rose Bengal4 have been used for generation of
singlet oxygen in these reactions. The simplest examples
reported are the conversion of indol-3-ylacetic acid5 or 2-(N-
methylindol-3-yl)ethanol6 to the corresponding aniline deriv-
atives, using light and Rose Bengal in phosphate buffer as
sensitizer. One example7 is known where the ene bond of the
enamine is exo to the ring system.
N
R
+
O
not observed
R
R
R
N
H
NH2
NH
CONH2
O
H
Ph
O2
N
Ph
N
Ph
Ph
N
There are rare examples8,9 where ground state triplet oxygen
reacts directly with an enamine, but in these cases a copper
catalyst is required (Scheme 2).
Ph
Ph
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 1997
3679

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Table 1 Yield, reaction conditions and melting points for piperidines
8–14
Table 2 Yield and melting points for imines 1–7
Compound
Yield (%)
90
Mp/ЊC
Compounda Yield (%) Reaction conditions
Mp/ЊC
1
158–159
8
9
10
11
12
13
14
95
22b
77
53
91
78
65
CH2Cl2–hexane 2:1, 16 h, 25 ЊC 133–138
(lit.,16 162–165)
yellow oil
153–156
76–79
hexane, 16 h, 25 ЊC
EtOAc, 24 h, 25 ЊC
EtOAc, 60 h, 25 ЊC
142–144
oil
123–125
2
95a
97
3 (ref. 17)
4
5
6
7
55
EtOAc–hexane 1:2, 72 h, 25 ЊC oil
EtOAc, 24 h, 25 ЊC oil
EtOAc–hexane 2:1, 24 h, 25 ЊC oil
100a
76
oil
116–117
80–84
55
a Satisfactory elemental analysis obtained for these compounds. b High
mother liquor loss of 9, HPLC analysis of reaction mixture indicated
all of 2 had been consumed.
a Product reacted directly under oxygenation conditions.
48 h at room temperature and details are noted in Table 1. TLC
and HPLC reaction monitoring indicates that all the starting
material is consumed during reaction with oxygen and the main
reaction product is the piperidine. Isolated yields observed so
far range from 22–95%. The low yield of 22% observed for 9
is a result of mother liquor loss on crystallization, HPLC and
TLC monitoring indicating that this reaction also went to
completion.
The evidence for the piperidine structure, using 8 as an
example, is supported by the characteristic 1H NMR (300 MHz;
CDCl3) spectral resonances at δ 5.95 (1H, t, J 5.4 Hz) due to the
amide NH proton and δ 4.36 (2H, d, J 5.7 Hz) due to the
methylene protons of the benzyl group. The nine characteristic
proton resonances of the 4-substituted piperidine ring are
observed as follows: δ 1.33 (1H, qd, J 4.0 and 11.8 Hz), 1.53–
1.67 (2H, m), 1.81 (1H, br d, J 11.4 Hz), 2.22 (1H, tt), 2.66 (1H,
td, J 2.8 and 12.8 Hz), 2.92 (1H, td, J 2.8 and 12.8 Hz), 3.93
(1H, dm, J 13.8 Hz) and 4.62 (1H, dm, J 13.5 Hz). In the case of
8 and 9 the piperidine structure assignment is confirmed by a
single crystal X-ray determination.
The starting materials, imines 1–7, are prepared from the
appropriate 2-substituted 1-azabicyclo[2.2.2]octan-3-one and
benzylamine by heating at reflux in toluene in the presence of
camphorsulfonic acid catalyst (Table 2). NMR spectral data
indicates the imines 1–7 exist as syn:anti mixtures. An NMR
study12 has been reported on related compound 15, which has
no 2-substituent. We suspect that elongation along the
C(2)᎐C(3) bond of the imines 1–7 may occur, caused by a com-
bination of the introduction of an sp2 carbon into the 1-
azabicyclo[2.2.2]octane ring system and that of a 2-benzhydryl
or 2-(1-phenylethyl) group. Both factors appear to be necessary
for the reaction to proceed, see below. A weak σ carbon bond in
the C(2)᎐C(3) position may be the cause of the unusual reactiv-
ity with molecular oxygen described below.
Examples where oxygen reacts directly with an imine causing
scission between the α and β carbon atom, as depicted in
Scheme 2, are not generally known. If, however, tautomerism
between the imine and corresponding enamine occurs in solu-
tion, the result of the reaction we observed with 2-benzhydryl-
3-alkylimino-1-azabicyclo[2.2.2]octanes 1–7 and molecular
oxygen does bear a superficial resemblance, in terms of out-
come, to the reaction of triplet oxygen and an enamine in the
presence of a copper catalyst mentioned above, or with singlet
oxygen and an enamine10 (Scheme 2). The reaction we dis-
covered is distinctly different, because the oxidation we have
observed occurs at room temperature without the aid of a
catalyst or singlet oxygen generator, unlike the literature
examples noted above. The reactants are also different in the
singlet oxygen and copper catalysed examples, as they are
predominantly enamine systems.
In our reaction the starting substrate is predominantly in the
imine form. We have found no direct evidence for the enamine
tautomer in NMR spectra collected for the imines 1–7, and the
tendency to tautomerize from the imine into the enamine is
disfavored by the molecular architecture of the azabicyclo-
[2.2.2]octane ring system (Scheme 3). The enamine–imine
R1
R3
R2
R1
R3
N
N
R2
NH
N
R4
R4
The imines 1–7 can be dissolved in any suitable neutral sol-
vent such as ethyl acetate or mixtures of ethyl acetate and
hexane, tetrahydrofuran, or mixtures of dichloromethane and
hexane. The reaction does not occur to any appreciable extent
in the solid phase. The imines 1–7, when isolated as solids, are
stable in dry air for several months and do not undergo signifi-
cant reaction with molecular oxygen in air when stirred as a
solid or crystal slurry in a solvent in which they are insoluble.
In order to demonstrate that the oxidation reaction is caused
by atmospheric oxygen, the reaction was investigated under dif-
ferent conditions using imine 1 as a representative example. The
conversion of imine 1 into piperidine 8 proceeded smoothly in
99.9% anhydrous tetrahydrofuran in the presence of air at room
temperature in 16 h. When the experiment was repeated under
the same conditions in an argon purged system, no detectable
reaction was observed after 5 days.
When imines 3, 5 and 7 were dissolved in dichloromethane no
reaction was observed after stirring in air for 48 h at room
temperature, even though the imines were completely in solu-
tion; however, addition of some hexane allowed the reaction to
proceed. On the other hand, imine 2 is converted into piperidine
9 in dichloromethane alone. We have no simple explanation for
this observation, since oxygen is readily soluble in dichloro-
1–7
1–7
enamine tautomer
imine tautomer
Scheme 3
tautomer equilibrium is not necessarily an important factor in
the reaction that we report. A long neglected observation by
Bird11 shows that 3-amino-1,2-diphenylindole undergoes very
rapid autoxidation by atmospheric oxygen in diethyl ether solu-
tion to yield 2-(N-benzoyl-N-phenylamino)benzamide (Scheme
2). We believe the autoxidation studied by Bird is closely
related to the reaction we have observed in the 2-imino-1-
azabicyclo[2.2.2]octanes 1–7. However, in the 3-aminoindole
system enamine–imine tautomerism probably occurs readily
compared to the 3-iminoazabicyclo[2.2.2]octane system.
Observations and discussion
The oxidation of 2-(1-phenylethyl)- and 2-benzhydryl-3-alkyl-
imino-1-azabicyclo[2.2.2]octanes 1–7 with molecular oxygen is
observed in neutral solution at room temperature to form 1,4-
disubstituted piperidines 8–14. The ring opening reaction is
demonstrated by the conversions of 1–7 into 8–14 shown in
Scheme 1. Typically the reaction proceeds to completion over
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J. Chem. Soc., Perkin Trans. 1, 1997

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H
N
Ph
O
atmospheric O2,
70 °C toluene
Ph
N
N
N
H
H
O
16
15
observed when a solution in toluene was stirred in air at
25 ЊC overnight and then for 7 h at 70 ЊC, similar to conditions
in which 1–7 were converted into 8–14, respectively. When 15
was dissolved in toluene and held at reflux (110 ЊC) for 16 h
with an air bleed through the reaction solution, still no conver-
sion to the corresponding piperidine 16 was observed. Except
for some slight coloration of the reaction solution the starting
material 15 was recovered unchanged. This result appears to
show that a bulky substituent at the 2-position of 1-azabicyclo-
[2.2.2]octane is required for the scission of the C(2)᎐C(3)
carbon bond to occur. When the 2-substituent is hydrogen, as in
the case of imine 15, no reaction is observed. This may indicate
that the steric bulk of the 2-substituent contributes to the
elongation of the C(2)᎐C(3) bond in imines 1–7, and hence
results in the unusual reactivity towards molecular oxygen. The
following experiment supports this hypothesis.
The rates at which imines 1 and 5 were converted into piper-
idines 8 and 12, respectively, were monitored by HPLC. In
this experiment, 1 and 5 were stirred in air in a solution of
dichloromethane and hexane (1:1) at room temperature and
the growth of the peaks corresponding to 8 and 12 were moni-
tored. The rate of reaction from 5 to piperidine 12 is much
slower than for 1 to 8 under similar conditions (see Fig. 2). This
observation is thought to be mainly an effect of the steric vol-
ume of the 2-substituent. It can be seen by comparing imines 1
and 5 that imine 1 has a benzhydryl group in the 2-position,
while 5 has a 1-phenylethyl group, which has a lower steric
volume; consequently, the 1-phenylethyl group exerts less of a
contribution to the elongation of the C(2)᎐C(3) bond than does
the benzhydryl group. This is consistent with the reduced rate
of reaction observed for 5 with molecular oxygen relative to
imine 1 under the same reaction conditions.
Fig. 1 Rate of formation of piperidine 8 in light, dark and the
presence of BHT
methane and should be available for reaction with the dissolved
imine as in the case of imine 2.
The reaction was investigated under different conditions
using imine 1 as a representative example. Using dichloro-
methane–hexane (1:1) as a common reaction solvent, we
compared the reaction with atmospheric oxygen at room
temperature (~25 ЊC). The reaction proceeded both in normal
laboratory light and in a reactor sealed from light with alu-
minium foil. The reaction progress was monitored using HPLC.
The rate of reaction in the dark was significantly slower than
the reaction carried out in normal laboratory light. When the
reaction was repeated in light with the presence of a molar
equivalent to 2,6-di-tert-butyl-4-methylphenol (BHT) to inhibit
any radical processes that may be occurring, the reaction rate
was intermediate between the light and dark reaction, see Fig.
1. These observations may implicate involvement of a radical
process or an excited electronic state of 1–7 in the oxidation
into 8–14 by molecular oxygen (see Scheme 4).
Ar
Ar
N
OH
N
O2
N
O
N
Ph
Ph
Ph
Ph
homolysis
Ar
N
•OH
The effects of the substituents on the N-benzyl ring are
generally not as pronounced compared with the 2-substituent
effect. Thus piperidines 8, 9, 10 and 13 for example are formed
from their corresponding imines 1, 2, 3 and 6 after about the
same period of reaction (16–24 h) at room temperature and
HPLC indicates that the reaction liquors contain very little
residual starting material after this period of time.
•
Ar
N
N
•
O
•OH
N
Ph
Ph
Ph
O
Ph
The reaction of an enamine with singlet oxygen formed in
the presence of UV light and a sensitizer is thought to pro-
ceed via either a 1,2-dioxetane intermediate13 or possibly a
four centered transition state, both of which give rise to the
observed products, similar to the piperidine products 8–14, by
formation of two carbonyl bonds at the expense of breaking
the C(2)᎐C(3) bond. However, this is only a superficial simi-
larity with our reaction, which is more closely related to the
rapid autoxidation of 3-aminoindoles studied by Bird,11 where
evidence is presented indicating that the first step of the
autoxidation process is probably formation of a hydroperoxide
at the 2-position of the indole ring. In our substrates 1–7 the
required equilibrium in solution with the enamine tautomer
of 1 is not energetically favored; this is different from the 3-
aminoindole system, where tautomerism is more labile, but
this does not appear to be an important factor in the
autoxidation process. There is some provisional evidence that
the C(2)᎐C(3) bond found in imines 1–7 may be abnormally
long for a σ carbon single bond, which may explain why a bulky
substituent is required at the 2-position of imines 1–7 in
order for the reaction to proceed. Certainly, the lack of reac-
Ar
Ar
HN
O
N
OH
N
N
Ph
Ph
O
O
Ph
Ph
Scheme 4
The imine 15 was investigated to see if it would react with
oxygen to yield piperidine 16 or a derived product. Imine 15 was
prepared12 by coupling 3-quinuclidone and benzylamine under
Dean–Stark conditions for water removal in the presence of
camphorsulfonic acid. In the case of imine 15, no reaction was
J. Chem. Soc., Perkin Trans. 1, 1997
3681

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resultant slurry was stirred at room temperature for 1 h. The
product was collected by filtration, washed with hexane (10
cm3), and dried under vacuum to give 4 as a white solid (1.49 g,
55%). Yield and melting points are noted in Table 2. Analytical
data collected for new compounds and unreported analytical
data for known compounds are reported below. Compound 15
was consistent with previously reported data.12
Formation of piperidines 8–14
A typical procedure is noted for 8.
N-Benzyl-1-(diphenylacetyl)piperidine-4-carboxamide 8.
A
solution of imine 1 (5.0 g, 13.14 mmol) in hexane (50 cm3) and
dichloromethane (100 cm3) was stirred in air for 48 h at 25 ЊC.
The reaction mixture was concentrated by evaporation, dis-
solved in dichloromethane (150 cm3) and ethyl acetate (20 cm3),
filtered and concentrated to give a white solid which was
washed with ethyl acetate, and dried under vacuum to give 8
(5.18 g, 95%). Yields, reaction details of other examples and
melting points are noted in Table 2.
Fig. 2 Effect of 2-substituent on rate of piperidine formation
tion of the unsubstituted imine 15 and the decrease in reac-
tion rate observed from imine 1 (2-benzhydryl) relative to
imine 5 [2-(1-phenylethyl)] (Fig. 2) is consistent with this
hypothesis.
We have no direct evidence for the nature of the intermediate
or transition state formed during the course of our reaction, but
we believe that it may be similar to 3-aminoindole autoxidation.
A possible mechanistic pathway is noted in Scheme 4, which is
consistent with the parallels that exist between our oxidation
and the 3-aminoindole autoxidation. The first process step is
formation of a hydroperoxide at the 2-position, followed by
homolysis to form radicals which lead to the piperidine product
as shown. The involvement of radicals is consistent with the
reaction rate data noted in Fig. 1, observed for conversion of
imine 1 into piperidine 8.
The following spectral and analytical data was collected for
imines 1–7 and piperidines 8–14.
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-
benzylamine 1
δH(300 MHz; CDCl3) 1.70–1.76 (2H, m), 1.80–1.86 (2H, m),
2.39–2.79 (2H, m), 3.04–3.09 (3H, m), 4.28 (1H, d, J 8.1), 4.48
(1H, d, J 17.8), 4.61 (1H, d, J 15.9), 4.71 (1H, d, J 8.1), 7.02
(2H, d, J 7.2), 7.12–7.48 (13H, m); δC(CDCl3; 75.5 MHz) 25.7,
26.3, 27.9, 41.9, 49.7, 52.0, 54.3, 69.0, 125.8, 126.2, 126.3, 127.0,
128.1, 128.3, 129.0, 129.1, 140.6, 143.4, 144.6, 177.7; νmax(KBr)/
cmϪ1 1667 (s); m/z 380 (Mϩ) [HRMS (FABϩ) found 381.2304.
C27H28N2 Calc. for (M ϩ H)ϩ 381.2324].
Conclusions
Imines of the class 1–7 undergo an unusual oxidation reaction
with molecular oxygen at the C(2)᎐C(3) carbon bond, resulting
in the formation of piperidines 8–14. The reaction sequence is
most likely initiated by formation of a hydroperoxide at pos-
ition 2 of the azabicyclo[2.2.2]octane ring system, which paral-
lels observations reported11 for 3-aminoindoles. It is postulated
that the C(2)᎐C(3) bond in imines 1–7 is elongated, which facili-
tates reaction to the observed products. The reaction itself is of
synthetic value, giving direct access to 4-substituted piperidines
in good yields under very mild conditions, although other
methods using piperidine based starting materials would more
normally be used to gain access to compounds such as 8–14.
The real interest of this reaction is that it provides a novel and
unexpected synthetic pathway that may be applied to other sys-
tems. The mechanism of the reaction is not strongly established
and merits further investigation.
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-5-
isopropyl-2-methoxybenzylamine 2
δH(300 MHz; CDCl3) 1.27 (3H, d, J 6.8), 1.28 (3H, d, J 6.9),
1.66–1.72 (2H, m), 1.80–1.85 (2H, m), 2.45–2.50 (2H, m), 2.89
(1H, septet, J 6.9), 3.03–3.13 (2H, m), 3.17 (1H, pentet, J 3.1),
3.83 (3H, s), 4.26 (1H, d, J 6.9), 4.57 (2H, ABq, J 16.0, 30.0),
4.87 (1H, d, J 6.8), 7.02–7.48 (13H, m); δC(CDCl3; 75.5 MHz)
21.5, 24.3, 24.4, 26.0, 26.1, 27.9, 28.9, 29.3, 30.4, 33.3, 69.2,
109.7, 124.5, 125.9, 126.1, 126.5, 127.3, 127.4, 128.1 (2), 128.2,
128.3, 128.4, 128.5, 128.6, 129.0, 129.1, 129.2, 140.9, 143.4,
144.7, 146.5, 155.0, 177.9; νmax(KBr)/cmϪ1 1663 (s); m/z 453
(M ϩ H)ϩ [HRMS (FABϩ) found 453.2911. C31H36N2O Calc.
for (M ϩ H)ϩ 453.2906].
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-2-
methoxybenzylamine 3
Experimental
Benzylamines and 1-azabicyclo[2.2.2]octan-3-one starting
materials were obtained from commercial sources.
δH(300 MHz; CDCl3) 1.71–1.87 (4H, m), 2.43–2.70 (2H, m),
3.07 (2H, t, J 7.5), 3.15 (1H, t, J 3.0), 4.30 (1H, d, J 7.9), 4.48
(1H, d, J 16.5), 4.59 (1H, d, J 16.5), 4.72 (1H, d, J 8.1), 6.75–
6.89 (3H, m), 7.15–7.48 (11H, m); δC(CDCl3; 75.5 MHz) 25.7,
26.4, 27.9, 41.9, 48.7, 49.8, 50.6, 52.0, 55.2, 69.0, 109.5, 120.4,
125.8, 126.1, 127.1, 128.1, 128.3, 128.7, 128.8, 128.9, 129.0,
177.7; νmax(KBr)/cmϪ1 1667 (s); m/z 410 (M)ϩ [HRMS (FABϩ)
found 411.2435. C28H30N2O Calc. for (M ϩ H)ϩ 411.2429].
Formation of imines 1–7 and 15
Imines were prepared from either 2-(diphenylmethyl)-1-aza-
bicyclo[2.2.2]octan-3-one,14
2-(1-phenylethyl)-1-azabicyclo-
[2.2.2]octan-3-one or 1-azabicyclo[2.2.2]octan-3-one, plus the
corresponding benzylamine using camphorsulfonic acid as a
catalyst. A typical procedure is noted for 4.
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-3-
methylbenzylamine 4
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-3-
methylbenzylamine 4
δH(300 MHz; CDCl3) 1.69–1.89 (5H, m), 2.31 (1.5H, s), 2.33
(1.5H, s), 2.42–2.75 (2H, m), 3.01–3.06 (2H, m), 4.36 (1H, d, J
8.0), 4.48 (2H, ABq, J 15.9, 33.3), 7.01–7.42 (14H, m);
δC(CDCl3; 75.5 MHz) 21.4, 21.5, 25.7, 26.2, 27.9, 28.7, 41.7,
41.9, 42.9, 43.5, 45.5, 49.7, 50.5, 51.9, 54.4, 54.9, 69.0, 124.6,
124.8, 125.9, 126.1, 127.0, 127.1, 128.0, 128.1, 128.2 (2), 128.4,
128.5, 128.7, 128.9, 129.0 (2), 137.7, 138.1, 140.4, 143.3, 144.6,
173.6, 177.6; νmax(KBr)/cmϪ1 1660 (s); m/z 394 (Mϩ) [HRMS
(FABϩ) found 395.2459. C28H30N2 Calc. for (M ϩ H)ϩ
395.2480].
A mixture of the ketone (2.0 g, 6.86 mmol), 3-methylbenzyl-
amine (1.0 g, 8.84 mmol) and camphorsulfonic acid (3 mg) was
added to toluene (7.2 cm3) and heated at reflux under Dean–
Stark conditions for 16 h to remove water. The solvent was
removed by evaporation to give a mobile oil, which was treated
with a small quantity of hexane to give a clear solution which
solidified on standing to give a white solid. The total volume
was made up to 30 cm3 by addition of further hexanes, and the
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N-[2-(1-Phenylethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]benzyl-
amine 5
28.5, 28.7, 39.3, 41.7, 42.9, 45.5, 54.9, 55.4, 110.4, 120.7, 126.2,
127.0, 127.1, 128.5, 128.6, 129.0 (2C), 129.7, 139.5 (2C), 157.5,
170.1, 173.5; νmax(CHCl3)/cmϪ1 3448 (s), 1639 (s); m/z 443
(M ϩ H)ϩ (Found: C, 76.06; H, 6.74; N, 5.99. C28H30N2O3
requires C, 75.99; H, 6.83; N, 6.33%).
δH(300 MHz; CDCl3) 1.41–1.58 (3H, m), 1.65–1.99 (5H, m),
2.62–3.01 (3H, m), 3.08–3.30 (3H, m), 3.55 (1H, t, J 10.4), 4.39
(0.8H, ABq, J 16.4, 44.5), 4.68 (1.2H, ABq, J 15.2, 35.2), 7.15–
7.39 (10H, m); δC(CDCl3; 75.5 MHz) 21.5, 22.2, 24.2, 24.6, 26.9,
27.4, 27.9, 41.3, 41.5, 41.6, 42.2, 49.6, 49.7, 53.9, 54.7, 71.3,
125.7, 126.0, 126.1, 126.6, 127.1, 127.2, 127.4, 127.5, 127.7,
128.0, 128.1, 128.2, 128.5, 140.6, 146.2, 177.5, 179.6 [HRMS
(FABϩ) found 319.2162. C22H26N2 Calc. for (M ϩ H)ϩ
319.2174].
N-(3-methylbenzyl)-1-(diphenylacetyl)piperidine-4-carboxamide
11
δH(300 MHz; CDCl3) 1.25–1.38 (1H, m), 1.62–1.68 (2H, m),
1.85 (1H, br d, J 12.0), 2.21–2.29 (1H, m), 2.33 (3H, s), 2.70
(1H, br t, J 11.3), 2.95 (1H, br t, J 11.7), 3.96 (1H, dm, J 13.2),
4.35 (2H, d, J 5.6), 4.66 (1H, dm, J 13.0), 5.19 (1H, m), 5.69
(1H, br s), 7.00–7.31 (14H, m); δC(CDCl3; 75.5 MHz) 21.4, 28.5,
28.6, 41.7, 42.8, 43.4, 45.5, 54.9, 124.7, 127.0, 127.1, 128.3,
128.5, 128.5, 128.6, 128.9, 129.0, 138.2, 138.4, 139.4, 139.5,
170.1, 173.7; νmax(CHCl3)/cmϪ1 3322 (s), 1644 (s), 1628 (s); m/z
426 (M)ϩ (Found: C, 79.10; H, 7.70; N, 6.61. C28H30N2O2
requires C, 78.84; H, 7.09; N, 6.57%).
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-4-
methoxybenzylamine 6
δH(300 MHz; CDCl3) 1.66–1.69 (2H, m), 1.75–1.84 (2H, m),
2.42–2.63 (2H, m), 3.00–3.04 (3H, m), 3.79 (3H, s), 4.22 (1H, d,
J 8.0), 4.43 (2H, ABq, J 16.0, 36.1), 4.65 (1H, d, J 8.1), 6.76
(2H, d, J 8.7), 6.88 (2H, d, J 8.2), 7.08–7.41 (10H, m); δC(CDCl3;
75.5 MHz) 25.7, 26.3, 27.8, 41.9, 49.7, 51.9, 53.6, 55.3, 69.0,
113.5, 125.8, 126.1, 128.1, 128.2, 128.4, 128.6, 128.7, 128.8,
129.0 (2), 132.8, 143.3, 144.6, 177.4; νmax(KBr)/cmϪ1 1669 (s);
m/z 410 (M)ϩ [HRMS (FABϩ) found 411.2458. C28H30N2O
Calc. for (M ϩ H)ϩ 411.2429].
N-Benzyl-1-(2-phenylpropanoyl)piperidine-4-carboxamide 12
NMR spectra of two diastereomers in 1:1 ratio: δH(300 MHz;
CDCl3) 0.78 (0.5H, qd, J 3.6, 12.6), 1.38–1.50 (3.5H, m), 1.62–
1.65 (1H, m), 1.72–1.77 (1H, m), 1.86–1.97 (1H, m), 2.17–2.25
(1H, m), 2.50–2.71 (2H, m), 2.82–2.97 (1H, m), 3.81–3.86 (2H,
m), 4.31 (1H, d, J 5.6), 4.38 (1H, d, J 5.6), 4.51 (0.5H, br d, J
12.9), 4.64 (0.5H, br d, J 13.3), 5.99 (0.5H, br s), 6.21 (0.5H, br
s), 7.14–7.28 (10H, m); δC(CDCl3, 75.5 MHz) 20.8, 21.6, 28.2,
28.4, 28.6, 28.8, 40.5, 41.1, 41.4, 41.6, 42.8, 43.0, 43.4, 44.9,
45.0, 49.3, 126.7, 126.9, 127.1, 127.5, 127.6, 127.9, 128.3, 128.4,
128.7, 128.9, 129.0, 138.2, 142.0, 141.9, 173.7; νmax(CHCl3)/
cmϪ1 3444 (s), 3331 (br), 1664 (s), 1633 (s); m/z 351 (M ϩ H)ϩ
(Found: C, 75.25; H, 7.67; N, 7.72. C22H26N2O2 requires C,
75.44; H, 7.48; N. 8.00%).
N-[2-(Diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-ylidene]-4-
methylbenzylamine 7
δH(300 MHz; CDCl3) 1.66–1.83 (5H, m), 2.32 (3H, s), 2.42–2.66
(2H, m), 3.01–3.06 (2H, m), 4.23 (0.6H, d, J 7.8), 4.36 (0.4H, d,
J 5.6), 4.48 (2H, ABq, J 15.6, 34.7), 4.69 (1H, d, J 7.8), 6.84–6.89
(1.4H, m), 7.04–7.44 (12.6H, m); δC(CDCl3; 75.5 MHz) 21.1,
25.8, 26.2, 27.8, 41.9, 43.0, 49.8, 50.5, 51.8, 54.0, 54.9, 69.0,
125.8, 126.1, 127.4, 127.5, 127.8, 128.1, 128.2, 128.5, 128.7,
128.8, 128.9, 129.0, 129.4, 135.7, 137.5, 143.3, 144.6, 177.5;
νmax(KBr)/cmϪ1 1668 (s); m/z 394 (M)ϩ [HRMS (FABϩ) found
395.2462. C28H30N2 Calc. for (M ϩ H)ϩ 395.2480].
N-(4-Methoxybenzyl)-1-(diphenylacetyl)piperidine-4-carbox-
amide 13
N-Benzyl-1-(diphenylacetyl)piperidine-4-carboxamide 8
δH(300 MHz; CDCl3) 1.33 (1H, qd, J 4.0, 11.8), 1.53–1.67 (2H,
m), 1.81 (1H, br d, J 11.4), 2.22 (1H, tt, J 3.9, 11.2), 2.66 (1H, td,
J 2.8, 12.8), 2.92 (1H, td, J 2.8, 12.8), 3.93 (1H, dm, J 13.8), 4.36
(2H, d, J 5.7), 4.62 (1H, dm, J 13.5), 5.19 (1H, s), 5.95 (1H, br t,
J 5.4), 7.17–7.35 (15H, m); δC(CDCl3; 75.5 MHz) 28.5, 28.6,
41.7,42.8,43.5,45.5,54.9,126.9,127.0,127.6,127.7,128.5,128.6,
128.7, 128.9, 129.0, 138.2, 139.4, 139.5, 170.1, 173.7; νmax(KBr)/
cmϪ1 3246 (s), 1642 (s), 1633 (s); m/z 413 (M ϩ H)ϩ (Found: C,
78.36; H, 6.64; N, 6.94. C27H28N2O2 requires C, 78.61; H, 6.84;
N, 6.79%).
δH(300 MHz; CDCl3) 1.34 (1H, m), 1.55–1.68 (2H, m), 1.82
(1H, br d, J 11.3), 2.18–2.26 (1H, m), 2.67 (2H, tm, J 11.4), 3.78
(3H, s), 3.94 (1H, dm, J 13.8), 4.31 (2H, d, J 5.5), 4.64 (1H, dm,
J 13.0), 5.19 (1H, s), 5.74 (1H, br t), 6.84 (2H, d, J 8.6), 7.13–
7.32 (12H, m); δC(CDCl3; 75.5 MHz) 28.6, 28.7, 41.7, 42.9, 43.0,
45.5, 54.9, 55.3, 114.1, 126.9, 127.1, 128.5, 128.6, 129.0, 129.1,
130.5, 139.4, 139.5, 159.2, 170.1, 173.6; νmax(KBr)/cmϪ1 3443
(s), 1639 (br); m/z 443 (M ϩ H)ϩ (Found: C, 75.60; H, 6.68; N,
6.05. C28H30N2O3 requires C, 75.99; H, 6.83; N, 6.33%).
N-(4-Methylbenzyl)-1-(diphenylacetyl)piperidine-4-carboxamide
14
N-(5-Isopropyl-2-methoxybenzyl)-1-(diphenylacetyl)piperidine-
4-carboxamide 9
δH(300 MHz; CDCl3) 1.26–1.38 (1H, m), 1.52–1.66 (2H, m),
1.79 (1H, br d, J 13.2), 2.20 (1H, tt, J 3.8, 11.2), 2.33 (3H, s),
2.64 (1H, tm, J 14.0), 2.90 (1H, tm, J 14.1), 3.93 (1H, br d, J
13.6), 4.31 (2H, d, J 5.6), 4.60 (1H, br d, J 13.4), 5.19 (1H, s),
6.02 (1H, br t, J 5.3), 7.00–7.39 (14H, m); δC(CDCl3; 75.5 MHz)
21.1, 28.5, 28.6, 41.7, 42.8, 43.2, 45.5, 54.9, 127.0, 127.1, 127.7,
128.5, 128.6, 128.9, 129.0, 129.4, 135.2, 137.2, 139.4, 139.5,
170.1, 173.7; νmax(KBr)/cmϪ1 3313 (br), 1643 (br); m/z 427
(M ϩ H)ϩ (Found: C, 78.52; H, 7.18; N, 6.44. C28H30N2O2
requires C, 78.84; H, 7.09; N, 6.57%).
δH(300 MHz; CDCl3) 1.21 (1H, d, J 6.9), 1.33 (1H, qd, J 4.0,
12.5), 1.54–1.66 (2H, m), 1.82 (1H, br d, J 13.2), 2.21 (1H, tt, J
3.8, 11.2), 2.69 (1H, tm, J 13.7), 2.84 (1H, septet, J 6.9), 2.93
(1H, tm, J 14.3), 3.81 (3H, s), 3.94 (1H, br d, J 13.7), 4.39 (2H, d,
J 5.7), 4.64 (1H, br d, J 13.5), 5.20 (1H, s), 6.04 (1H, br t, J 5.5),
6.81 (1H, d, J 8.3), 7.08 (1H, d, J 2.2), 7.12 (1H, dd, J 2.3, 8.3),
7.16–7.33 (10H, m); δC(CDCl3; 75.5 MHz) 24.2, 28.5, 28.7, 33.3,
39.7, 41.7, 43.0, 45.5, 54.9, 55.5, 110.3, 125.8, 126.5, 126.9,
127.0, 128.1, 128.5, 128.6, 128.9, 129.0, 139.4, 139.5, 141.2,
155.7, 170.1, 173.3; νmax(KBr)/cmϪ1 3359 (s), 1654 (s), 1640 (s);
m/z 484 (Mϩ) (Found: C, 76.80; H, 7.40; N, 5.87. C31H36N2O3
requires C, 76.83; H, 7.49; N, 5.78%).
2-(1-Phenylethyl)-1-azabicyclo[2.2.2]octan-3-one
A 3  solution of methylmagnesium chloride in tetrahydro-
furan (100 cm3, 0.3 ), under nitrogen, was cooled in an ice–
water bath and treated with copper() bromide–dimethyl sulfide
complex (1.25 g, 6.08 mmol). The mixture was stirred for
5 min and treated slowly with a solution of 2-benzylidene-1-
azabicyclo[2.2.2]octan-3-one15 (53.3 g, 0.25 ) in tetrahydro-
furan (480 cm3). The resultant solution was stirred at 0 ЊC for
15 min. A solution of ammonium chloride (40.1 g, 0.75 ) in
water (260 cm3) was added slowly. The resultant mixture was
stirred at room temp. for 1 h. The organic layer was removed,
N-(2-Methoxybenzyl)-1-(diphenylacetyl)piperidine-4-carbox-
amide 10
δH(300 MHz; CDCl3) 1.33 (1H, m), 1.64–1.52 (2H, m), 1.80
(1H, br d, J 13.5), 2.20 (1H, m), 2.67 (1H, tm, J 14.1), 2.92 (1H,
tm, J 14.0), 3.82 (3H, s), 3.92 (1H, dm, J 13.3), 4.39 (2H, d, J
5.7), 4.62 (1H, dm, J 13.3), 5.19 (1H, s), 6.07 (1H, br s), 6.91
(1H, dd, J 0.8, 7.5), 7.18–7.32 (12H, m); δC(CDCl3; 75.5 MHz)
J. Chem. Soc., Perkin Trans. 1, 1997
3683

View Article Online
filtered through a short pad of Celite and concentrated by
evaporation to give a yellow oil, which was treated with propan-
2-ol (200 cm3) and concentrated by evaporation to give a clear
yellow oil which solidified on standing overnight. The solid was
washed with propan-2-ol (30 cm3), collected by filtration,
washed with propan-2-ol (50 cm3) and dried in vacuo at 55 ЊC
for 12 h to afford the product (31.62 g, 55%) as a white solid
(mp 114–116 ЊC). δH(300 MHz; CDCl3) 1.45 (3H, d, J 6.9),
1.88–2.01 (4H, m), 2.44 (1H, quintet, J 3.0), 2.53–2.64 (1H, m),
2.74–2.85 (1H, m), 2.88–3.04 (2H, m), 3.13 (1H, dq, J 6.8, 9.7),
3.28 (1H, d, J 9.7), 7.16–7.37 (5H, m); δC(CDCl3; 75.5 MHz)
21.6, 25.1, 27.1, 40.0, 41.1, 41.2, 49.3, 74.2, 126.4, 127.2, 127.8,
128.4, 145.2, 221.3; νmax(KBr)/cmϪ1 1721 (s); m/z 230 (M ϩ H)ϩ
(Found: C, 78.80; H, 8.37; N, 6.01. C15H19NO requires C,
78.56; H, 8.35; N, 6.11%).
able via the RSC Web pages (http://chemistry.rsc.org/rsc/
p1pifa.htm). Any request to the CCDC for this material should
quote the full literature citation and the reference number 207/
161.
Acknowledgements
X-Ray single crystal structural data for compounds 8 and 9
were generated by Dr Jon Bordner and Ms Debra DeCosta in
the Pfizer Central Research X-Ray Crystallography Laboratory.
We thank Dr T. C. Crawford, Dr R. W. Dugger, Dr F. J. Urban
and Professor S. V. Ley for useful discussions and helpful com-
ments on this work.
References
1 Singlet Oxygen: Reaction with Organic Compounds and Polymers, ed.
B. Ranby and J. F. Rabek, Wiley, New York, 1978; Singlet Molecular
Oxygen, ed. A. P. Schaap, Wiley, New York, 1976.
2 K. Orito and M. Itoh, J. Chem. Soc., Chem. Commun., 1978, 812.
3 J. F. Pinella, J. Estape, P. Lupon, L. Merino, M. Puig, J.-J. Bonet,
J. L. Brainso and G. Germain, Bull. Chem. Soc. Jpn., 1987, 60, 3011.
4 I. Saito, Y. Takahashi, M. Imuta, S. Matsugo, H. Kaguchi and
T. T. Matsuura, Heterocycles, 1976, 5, 53.
5 I. Saito, M. Imuta, S. Matsugo, H. Yamamoto and T. Matsuura,
Synthesis, 1976, 255.
6 I. Saito, M. Imuta, S. Matsugo, H. Yamamoto and T. Matsuura,
J. Am. Chem. Soc., 1975, 97, 7191.
7 M. E. Kuehne and J. B. Pitner, J. Org. Chem., 1989, 54, 4553.
8 V. van Rheenen, J. Chem. Soc., Chem. Commun., 1969, 314.
9 J. Tsuji, H. Kezuka, H. Takayanagi and K. Yamamoto, Bull. Chem.
Soc. Jpn., 1981, 54, 2369.
10 A. P. Schaap and K. A. Zaklika, The 1,2-Cycloaddition Reactions
of Singlet Oxygen, in Singlet Oxygen, ed. H. H. Wasserman and
R. W. Murray, Acadenic Press, New York, 1979, ch. 6, pp. 224–225;
C. S. Foote, A. A. Dzakpasu and J. W.-P. Lin, Tetrahedron Lett.,
1975, 1247.
Crystal data collected for compounds 8 and 9
Compound 8. C27H28N2O2, M = 412.5, orthorhombic, a =
17.717(3), b = 81.77(1), c = 6.269(1) Å, V = 9082(3) Å3, space
group Fdd2 (no. 43), Z = 16, Dx = 1.207 g cmϪ3, colorless plates,
crystal dimensions 0.08 × 0.44 × 0.50 mm, µ(Cu-Kα) = 5.99
cmϪ1
.
Compound 9. C31H36N2O3, M = 484.6, triclinic, a = 9.193(1),
b = 9.441(1), c = 16.654(1) Å, α = 83.81(1), β = 80.47(1), γ =
3
¯
67.69(1)Њ, V = 1317.2(2) Å , space group P1 (no. 2), Z = 2,
Dx = 1.222
g , colorless needles, crystal dimensions
cmϪ3
0.03 × 0.06 × 0.16 mm, µ(Cu-Kα) = 6.18 cmϪ1
.
Data collection and processing
Siemens R3m/v diffractometer, ω/2θ mode with ω scan
width = 1.2Њ plus Kα-separation, ω scan speed 4 deg per min,
graphite monochromated Cu-Kα (λ = 1.541 78 Å) radiation;
for C27H28N2O2 (8), 1032 reflections measured with 798
(I > 3.0σ), for C31H36N2O3 (9), 2711 reflections measured with
1631 (I > 3.0σ).
11 C. W. Bird, J. Chem. Soc., 1965, 3490.
12 T. Ya. Filipenko, K. F. Turchin, Yu. N. Sheinker, V. A. Bondarenko,
E. E. Mikhlina and L. N. Yakhontov, Khim. Geterotsikl Soedin.,
(Engl. Transl.), 1978, 14, 1003.
Structure analysis and refinement
Trial structures were obtained using direct methods. These trial
structures were refined in a full-matrix least-squares fashion
ultimately using anisotropic temperature factors for the non-
hydrogen atoms. All crystallographic calculations were facili-
tated by the Siemens SHELXTL PLUS computer programs.
The hydrogen positions were calculated wherever possible.
Methyl hydrogens were located by difference Fourier techniques
and then idealized by calculation. The hydrogen atoms were
added to the structure factor calculations but were not refined.
The final data fit criteria were as follows: for C27H28N2O2 (8),
final difference map, ϩ0.39 to Ϫ0.45 e ÅϪ3, R = 9.37%, GOF =
1.22; for C31H36N2O3 (9), final difference map, ϩ0.20 to Ϫ0.20 e
13 P. D. Bartlett and M. E. Landis, The 1,2-Dioxetanes, in Singlet
Oxygen, ed. H. H. Wasserman and R. W. Murray, Academic Press,
New York, 1979, ch. 7, pp. 243–248.
14 E. J. Warawa, N. J. Mueller and R. Jules, J. Med. Chem., 1974, 17,
497.
15 E. J. Warawa and J. R. Campbell, J. Org. Chem., 1974, 39, 3511.
16 E. J. Warawa, N. J. Mueller and J. S. Fleming, J. Med. Chem., 1975,
18, 587.
17 J. A. Lowe, S. E. Drozda, R. M. Snider, K. P. Longo, S. H. Zorn,
J. Morrone, E. R. Jackson, S. McLean, D. K. Bryce, J. Bordner,
A. Nagahisa, Y. Kanai, O. Suga and M. Tsuchiya, J. Med. Chem.,
1992, 35, 2591.
Å
Ϫ3, R = 5.72%, GOF = 1.02.
Full crystallographic details, excluding structure factor
tables, have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). For details of the deposition scheme, see
‘Instructions for Authors’, J. Chem. Soc., Perkin Trans. 1, avail-
Paper 7/01223C
Received 21st February 1997
Accepted 22nd August 1997
3684
J. Chem. Soc., Perkin Trans. 1, 1997