A novel synthesis of imidazoles via the cycloaddition of nitrile ylides to their imidoyl chloride precursors

Article abstract of DOI:10.1039/b104130b

The synthesis of imidazoles via the cycloaddition of nitrile ylides to their imidoyl chloride precursors was presented. The nitrile ylides were prepared by the 1,3-dehydrochlorination of imidoyl chlorides. It was shown that the HOMO of the 'bent' nitrile ylide is heavily localized on the methane terminus and is compatible with protonation at this carbon in substituted nitrile ylides and with the regioisomers obtained in biomolecular nitrile ylide cycloadditions. The observed regiochemistry of the cycloaddition was rationalized by energy calculations on the frontier molecular orbitals of the reactants using semi-empirical methods.

Full text of DOI:10.1039/b104130b

View Article Online / Journal Homepage / Table of Contents for this issue
A novel synthesis of imidazoles via the cycloaddition of nitrile
ylides to their imidoyl chloride precursors
Paul W. Groundwater,*a Ian Garnett,a Andrew J. Morton,b Toqir Sharif,b Simon J. Coles,c
Michael B. Hursthouse,c Miklos Nyerges,d Rosaleen J. Anderson,a David Bendell,a
Alexander McKillop†a and Weimin Zhanga
1
a Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Sciences,
University of Sunderland, Sunderland, UK SR1 3SD
b Department of Chemistry, Cardiff University, P.O. Box 912, Cardiff, UK CF1 3TB
c EPSRC X-Ray Crystallography Service, Department of Chemistry,
University of Southampton, Highfield, Southampton, UK SO17 1BJ
d Research Group of the Hungarian Academy of Sciences,
Department of Organic Chemical Technology, Technical University of Budapest,
H-1521 Budapest, P.O.B. 91, Hungary
Received (in Cambridge, UK) 4th May 2001, Accepted 11th September 2001
First published as an Advance Article on the web 5th October 2001
Generation of nitrile ylides, 4 and 22, via the base-catalysed 1,3-dehydrochlorination of imidoyl chlorides, 3 and 21,
gives the imidazoles, 13, 23 and 24. These imidazoles are formed by the cycloaddition of the nitrile ylides, 4 and 22,
to their precursor imidoyl chlorides, 3 and 21, and the observed regiochemistry of this cycloaddition has been
rationalised by energy calculations on the frontier molecular orbitals of these reactants using semi-empirical
(MOPAC PM3) methods.
The 1,7-electrocyclisation of α,β:γ,δ-unsaturated 1,3-dipoles is
a useful route to seven-membered heterocycles.1 Using this
methodology, benzazepines 2 have been obtained as the sole
products of the 1,7-electrocyclisation of diene-conjugated
nitrile ylides 1, followed by a [1,5]-H shift (Scheme 1).2,3
Scheme 2
these nitrile ylide intermediates 4 are the formal products of a
cycloaddition of the nitrile ylides to their imidoyl chloride
precursors 3.4
Scheme 1
Results and discussion
The aim of this present work was to investigate the effect
on the periselectivity of such nitrile ylide cyclisations of the
inversion of the dipole moiety in such diene-conjugated nitrile
ylides. The corresponding nitrile ylides 4 could, theoretically,
also undergo a 1,7-electrocyclisation to a benzazepine 6 but
only via a cumulene intermediate 5 (Scheme 2). We wish to
report here that this inversion of the dipole group precludes the
1,7-electrocyclisation and the only products obtained from
The nitrile ylides were prepared by the well established 1,3-
dehydrochlorination of imidoyl chlorides,5 which are them-
selves readily prepared from the corresponding amides. The
synthesis of N-benzyl-3,3-diphenylpropenamide 10a was
achieved via ethyl 3-hydroxy-3,3-diphenylpropanoate 8, which
is readily available from the Reformatsky reaction of benzo-
phenone 7 and ethyl bromoacetate6 (Scheme 3). Condensation
of the hydroxyester 8 with benzylamine gave the hydroxyamide
9, which was dehydrated to the requisite amide 10a using a
mixture of acetic and concentrated sulfuric acids.
† Visiting Professor. Current address: Rhodia ChiRex, Dudley,
Cramlington, Northumberland, UK NE23 7QG.
DOI: 10.1039/b104130b
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787
This journal is © The Royal Society of Chemistry 2001
2781

View Article Online
Scheme 3 Reagents and conditions: i, BrCH2CO2Et, Zn, PhCH3, Et2O, reflux, 4 h, 90% or [(CH3)2CH]2NLi, EtOAc, rt, 4 h, 95%; ii, PhCH2NH2,
NH4Cl, reflux, 16 h, 32% or PhCH2NH2, Et2O, reflux, 16 h, 76%; iii, conc. H2SO4, AcOH, rt, 1 h, 77%; iv, (EtO)2P(O)CH2CO2Et, NaH, THF, reflux,
12 h, 92%; v, KOH, EtOH, rt, 15 h, 94%; vi, 4-ClC6H4CH2NH2, Et3N, DIPCDI, HOBt, rt, 20 h, 91%.
Attempts to prepare the N-(4-chlorobenzyl) analogue 10b
via this route proved unsuccessful and this derivative was
eventually synthesized from 3,3-diphenylpropenoic acid 12 by
standard amide bond formation using diisopropylcarbodiimide
(DIPCDI) and 1-hydroxybenzotriazole. The acid 12 was pre-
pared by hydrolysis of the corresponding ethyl ester 11, which
was readily obtained from the Wittig–Horner reaction of benzo-
phenone 7 and ethyl diethoxyphosphorylacetate (Scheme 3).7
The chlorination of the amides 10a,b with phosphorus penta-
chloride gave the imidoyl chlorides 3a,b, which were treated
with potassium tert-butoxide, at 0 ЊC in the dark, to give orange
solids. Spectroscopic analysis of these solids indicated that they
did not correspond to the products of a 1,7-electrocyclisation
but appeared to be dimers of the nitrile ylides 4a,b (Scheme 4).
Scheme 5
dimerisation (Scheme 5). The spectroscopic data for the
products obtained from the reaction of these nitrile ylides 4a,b
did not correspond to that expected for a pyrazine and the
products were eventually identified as imidazoles 13. The struc-
ture of the imidazole 13a was confirmed by NOE experiments;
irradiation of the benzylic singlet at δ 4.58 resulted in enhance-
ment of the alkene singlets at δ 6.52 (4.0%) and δ 6.57 (15.2%)—
indicating the close proximity of the benzylic CH2 to both
alkene protons.
An imidazole 16 could result from the cycloaddition of a
nitrile ylide 4 to its precursor imidoyl chloride 3, followed by
dehydrochlorination, but the regioisomer obtained 13 is not
that which is predicted by FMO theory. With all dipolarophiles,
except the very electron rich, nitrile ylide cycloadditions are
dipole HOMO controlled according to Sustmann’s classifi-
cation.9 That is, the interaction of the dipole HOMO with the
dipolarophile LUMO is the dominant frontier orbital inter-
action. Caramella and Houk10 have optimised the geometry of
the parent nitrile ylide, formonitrile methylide‡ 17, by ab initio
LCAO-MO-SCF calculations, and shown that this nitrile ylide
prefers a ‘bent’ allenic geometry to a linear propargylic geom-
etry by 46.4 kJ molϪ1. Caramella and Houk10 also showed that
the HOMO of this ‘bent’ nitrile ylide, is heavily localised on the
methine (C-1) terminus and this is compatible with protonation
at this carbon in simple substituted nitrile ylides and with the
regioisomers obtained in bimolecular nitrile ylide cyclo-
additions.11 The interaction of the 3-phenylcinnamonitrile
arylmethyl ylide HOMO with the imidoyl chloride LUMO
would thus be expected to produce the imidazole regioisomer
16.
Scheme 4
N-Benzyl-2-phenylbenzamide 20 was prepared from 2-
phenylbenzoic acid 19, itself easily prepared by the oxidation of
Dimerisation of nitrile ylides 14, in the absence of dipolaro-
philes, is a well known reaction and results in the formation
of pyrazines 15,8 via either a head-to-head or head-to-tail
‡ The IUPAC name for formonitrile methylide is (methylideneazonium-
diyl)methanide.
2782
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787

View Article Online
Fig. 1 Crystal structure of imidazole 23.
and 24 is the non-equivalence of the methylene protons of
the benzylic group, which, in both cases, appear as pairs
of doublets, with a coupling constant of 16.5 Hz.
A number of other examples of nitrile ylides giving the
‘wrong’ regioisomer in [3 ϩ 2] cycloadditions have been
reported. For example, photolysis of azirine 25 in the presence
of benzoyl chloride and triethylamine gave mostly oxazole 26
together with a small amount of the expected product 27
(Scheme 7).13 It has been proposed that those processes that lead
Scheme 7
to the formation of the ‘wrong’ regioisomer involve the trap-
ping of a deprotonated imidoyl chloride, e.g. 28, rather than a
nitrile ylide cycloaddition reaction. To test this proposal for
these systems, we have attempted to investigate the cycloaddi-
tion of a conjugated nitrile ylide with a hetero-dienophile. Our
initial attempts at trapping the nitrile ylides, 4 or 22, were
unsuccessful, but a related nitrile ylide 31 (generated by the
same 1,3-dehydrochlorination route from the amide 29 via the
imidoyl chloride 30) underwent a cycloaddition with benzalde-
hyde to give the oxazole 32 as the sole product (Scheme 8). Once
again, this is the opposite regioisomer to that predicted by
FMO theory. The opposite regioisomer 34 has previously been
obtained by trapping the nitrile ylide, generated by photolysis
of the azirine 33, with benzaldehyde (Scheme 9).14 In order
to account for this discrepancy, we have performed energy
calculations on the frontier molecular orbitals of the dipoles
and dipolarophiles using semi-empirical (MOPAC PM3)15
methods with Insight II (Release 2000)/MOPAC software
Scheme 6 Reagents and conditions: i, K2Cr2O7, H2SO4, rt, 4 days, 52%;
ii, 2-chloro-1-methylpyridinium iodide, PhCH2NH2, Bu3N, DCM, rt,
16 h, 77%; iii, PCl5, Et2O, reflux; iv, KOBut, THF, 0 ЊC.
2-phenylbenzaldehyde 18 (Scheme 6). 2-Phenylbenzaldehyde
was prepared by the method of Cullen and Sharp.12
Generation of N-benzyl-2-phenylbenzonitrile ylide 22, by
chlorination of the corresponding amide 20, followed by 1,3-
dehydrochlorination of the imidoyl chloride 21, gave a mixture
of the products 23 and 24 (Scheme 6). In this case, the ratio of
isomers obtained was approximately 1 : 1 (actually 51 : 39), with
the structure of the major isomer confirmed—by a single crys-
tal X-ray structure (Fig. 1)—as the ‘expected’ product 23 of the
cycloaddition, whilst the minor product 24 was the regioisomer
which is not that which is predicted by FMO theory. An inter-
1
esting feature of the H NMR spectra of both regioisomers 23
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787
2783

View Article Online
Table 1 Energies and frontier orbital coefficients for nitrile ylides 4,
22, and 31
Table 2 Energies and frontier orbital coefficients for dipolarophiles
PhCHO, 3 and 21
Dipole
31
4
22
Dipolarophile
PhCHO
3
21
HOMO/eV
Ϫ7.55
Ϫ0.46
ϩ0.05
ϩ0.61
Ϫ7.49
ϩ0.38
Ϫ0.03
Ϫ0.50
Ϫ7.51
ϩ0.46
Ϫ0.05
Ϫ0.60
HOMO/eV
C
X
Ϫ10.05
Ϫ0.01
Ϫ0.15
Ϫ9.19
Ϫ0.05
ϩ0.06
Ϫ9.52
Ϫ0.03
ϩ0.14
C1
N2
C3
LUMO/eV
C
X
Ϫ0.48
Ϫ0.36
ϩ0.33
Ϫ0.44
Ϫ0.14
ϩ0.03
Ϫ0.11
Ϫ0.14
0.00
LUMO/eV
Ϫ0.45
ϩ0.22
Ϫ0.40
ϩ0.24
Ϫ0.84
Ϫ0.19
ϩ0.36
Ϫ0.15
Ϫ0.50
ϩ0.19
Ϫ0.37
ϩ0.23
C1
N2
C3
is the regioisomer 34 which was previously obtained by trap-
ping the nitrile ylide, generated by photolysis of the azirine 33,
with benzaldehyde. In this case, the photochemical generation
of the nitrile ylide may lead to an excited state and the observed
regioisomer may be explained by the overlap of this new,
excited state, HOMO with the benzaldehyde LUMO.
In conclusion, we have discovered a new cycloaddition of
nitrile ylides, to their imidoyl chloride precursors to give
imidazoles, the regiochemistry of which can be predicted by
MOPAC PM3 calculations. These semi-empirical calculations
predict a linear dipole, with the HOMO localised on the
methylene carbon atom. Although calculations at higher levels
predict ‘bent’ allenic geometries for simpler nitrilium betaines,
these semi-empirical results are useful for the prediction of the
regiochemistry of the cycloaddition of these more complex and
highly conjugated dipoles.
Scheme 8 Reagents and conditions: i, PCl5, Et2O, reflux, 16 h;
ii, KOBut, THF, rt, 16 h; iii, PhCHO, THF, 38%.
Experimental
Mps were determined on a Gallenkamp apparatus and are
uncorrected. Elemental analyses were performed on a Perkin-
Elmer 240C or Carlo Erba 1106 Elemental Analyser. IR spectra
were recorded on a Perkin-Elmer 1600 series FTIR or Unicam
research series FTIR spectrophotometer using sodium chloride
plates. 1H NMR spectra were acquired on a JEOL GSX 270 FT
NMR at 270 MHz, Bruker WM360 spectrometer at 360 MHz,
or Bruker AVANCE 300 at 300 MHz. Coupling constants are
given in Hz and all chemical shifts are relative to an internal
standard of tetramethylsilane. 13C NMR spectra were obtained
on the JEOL GFX 270 FT NMR (68 MHz) spectrometer,
Bruker WM360 (90 MHz), and Bruker AVANCE 300 (75
MHz). Low resolution electron impact mass spectra were
obtained on a Trio 2000 VG or Fisons Platform II. High reso-
lution spectra were obtained on a VG ZAB-E spectrometer
(EPSRC Mass Spectrometry Service Centre, Swansea) or
Bruker APEX II FT mass spectrometer. Thin layer chrom-
atography was performed on Merck silica gel 60F254. All
solvents were purified according to standard procedures.
Diethyl ether and tetrahydrofuran were freshly distilled over
sodium wire with a trace of benzophenone. Toluene was dis-
tilled from, and stored over, sodium wire. Fisons silica gel 60
(35–70 micron) was used for wet flash chromatography. The
samples were applied in liquid form or were pre-adsorbed onto
silica 60 (35–70 micron) from dichloromethane solutions.
2-Phenylbenzaldehyde 18 was prepared by the method of
Cullen and Sharp.12 N-Benzylbenzamide 29 was prepared by
the method of Erdik and Daskapan.17 Ethyl 3,3-diphenylprop-
2-enoate 11 was prepared by the method of Wang and Shi7 and
3,3-diphenylprop-2-enoic acid 12 by the method of Collomb,
Cantegrel, and Deshayas.18
Scheme 9
(MSI/Biosymm, CA, U.S.A) on a Silicon Graphics Indigo II
workstation.
These semi-empirical calculations predict a linear geometry
for the simplest nitrile ylide, formonitrile methylide 17, in con-
trast to previous work by Caramella and Houk.10 It has previ-
ously been shown that the optimised geometry and the MO
energies and coefficients of the nitrilium betaines are dependent
upon the theoretical method used, with the ‘bent’ allenic struc-
ture being the only stable minimum at higher levels of theory.16
The incorporation of substituents with extended conjugation at
both termini of the nitrile ylide system would, however, be
expected to result in the linearisation of the dipole through an
increase in the delocalisation, and this is, in fact, substantiated
by the MOPAC PM3 calculations. Optimisation of the geom-
etry of all three dipoles, 4, 22, and 31, results in linear nitrile
ylides, and the calculated energies and coefficients of the
orbitals on the methine (C1) and methylene (C3) carbon atoms
for both the HOMO and LUMO are given in Table 1. The
HOMO and LUMO energies and coefficients for the precursor
imidoyl chlorides, 3 and 21, and for benzaldehyde, are given in
Table 2. As expected, the dipole HOMO–dipolarophile LUMO
is the dominant interaction. Close inspection of the HOMO for
each of these dipoles shows that, in each case, the coefficient on
the methylene (C3) carbon is greater than that on the methine
(C1). The methylene carbon atom would therefore be expected
to react with the carbon atom of the double bond (C᎐O or
᎐
Crystal data for 1-benzyl-4,5-bis(biphenyl-2-yl)-2-phenyl-
imidazole 23
C᎐N) of the dipolarophile, which has the larger coefficient in
᎐
the LUMO. In the case of 2-phenylbenzonitrile benzyl ylide 22
the ratio of isomers obtained was approx. 1 : 1 and this may
be due to steric factors due to the presence of the sterically
demanding biphenyl group. These results are, therefore, in
agreement with the experimental findings and the one anomaly
C40H30N2, M = 538.66. Monoclinic, a = 10.257(2), b = 28.375(5),
c = 10.590(2) Å, β = 112.21(3)Њ, V = 2853.5(9) Å3, T = 150 K,
colourless crystal (0.30 × 0.25 × 0.25 mm), space group P2(1)/n,
Z = 4, µ = 0.073 mmϪ1, 8026 reflections measured, 3913
2784
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787

View Article Online
independent reflections, Rint = 0.0627, wR2 and R1 = 0.1374 and
0.0626 (I > 2σ(I )) and 0.1863 and 0.1598 (all data). The struc-
ture was solved via direct methods (SHELXS-97)19 and refined
145.9 (2 × quat.), 171.9 (quat., C᎐O); m/z 331 (Mϩ, 17%), 314
᎐
(100), 254 (25), and 183 (25).
2
on Fo by full-matrix least-squares (SHELXL-97).20 Non-
Method 2. The hydroxyester 8 (5 g, 0.0185 mol) was dissolved
in dry ether (50 cm3) and cooled to 5 ЊC. Benzylamine (2.0 g,
0.018 mol) was then added dropwise to the cold solution and
the reaction mixture was allowed to warm to room temperature.
The solution was then refluxed for 16 h, cooled, and quenched
with ice–water (50 cm3). The organic phase was washed with
2 M aq. hydrochloric acid (50 cm3), 2 M aq. sodium hydroxide
(50 cm3), then water (50 cm3) before drying (MgSO4). Evapor-
ation under reduced pressure, followed by chromatography on
silica, eluting with petroleum ether 40–60 ЊC–ethyl acetate
(100 : 0 to 80 : 20) gave the hydroxyamide 9 (4.43 g, 76%), mp
165 ЊC. The spectroscopic data were identical to those obtained
for the previous sample.
hydrogen atoms were refined as anisotropic; hydrogens were in
idealised positions with Uisos tied to the Ueqs of the parent
atom. Full parameters of data collection and structure refine-
ment have been deposited with the Cambridge Crystallographic
Data Centre. CCDC reference number 163765. See http://
www.rsc.org/suppdata/p1/b1/b104130b/ for crystallographic
files in .cif or other electronic format.
Ethyl 3-hydroxy-3,3-diphenylpropanoate 8
Method 1. In a flame-dried 3-necked flask, ethyl bromo-
acetate (51.8 g, 34.4 cm3, 0.31 mol) and benzophenone 7 (27 g,
0.15 mmol) in dry toluene (40 cm3) and dry ether (110 cm3) were
added to activated powdered zinc (20 g) under N2. A few crys-
tals of iodine were added and the mixture heated, using a heat
gun, to initiate the reaction. After mechanically stirring over-
night, the mixture was allowed to warm in an ultra-sound bath,
followed by refluxing for 4 h. On cooling to room temperature,
the reaction mixture was poured into cold H2SO4 (100 cm3, 10%
w/v). The organic phase was separated and washed with cold
H2SO4 (2 × 50 cm3, 5% w/v). The organic layer was dried
(MgSO4) and evaporated under reduced pressure to give ethyl 3-
hydroxy-3,3-diphenylpropanoate 8 as a pale orange solid, which
was recrystallised from petroleum ether 60–80 ЊC (36.4 g, 90%),
mp 77–81 ЊC (lit.6 mp 87 ЊC) (Found: C, 75.3; H, 6.9. C17H18O3
requires C, 75.5; H, 6.7%); νmax (liquid film)/cmϪ1 3508 (OH),
N-Benzyl-3,3-diphenylprop-2-enamide 10a
N-Benzyl-3-hydroxy-3,3-diphenylpropanamide 9 (2 g, 6.04
mmol) was added to a cooled solution of concentrated sulfuric
acid (4 cm3) and glacial acetic acid (16 cm3). The mixture
was stirred for 1 h, under N2. The reaction was quenched with
water (100 cm3), followed by the addition of ethyl acetate
(100 cm3). The organic phase was separated, washed with
NaHCO3 (20 cm3, 10% w/v), water (3 × 100 cm3), dried
(MgSO4) and the solvent evaporated under reduced pressure to
give N-benzyl-3,3-diphenylprop-2-enamide 10a as a pale yellow
solid. Recrystallisation from ethanol gave an off-white solid
(1.46 g, 77%), mp 185–187 ЊC (Found: C, 84.3; H, 6.3; N, 4.3.
C22H19NO requires C, 84.3; H, 6.1; N, 4.4%); νmax (liquid film)/
cmϪ1 3303 (NH), 1633 (C᎐O), 1602 (C᎐C); δ (360 MHz,
1698 (C᎐O); δ (360 MHz, CDCl3) 1.20 (3H, t, J 6.9 Hz,
᎐
H
CH3), 3.30 (2H, s, CH2), 4.12 (2H, q, J 6.9 Hz, CH2), 4.80 (1H,
s, OH), 7.1–7.4 (10H, m, Ar-H); δC (90MHz, CDCl3) 13.9
(CH3), 45.9 (CH2), 60.9 (CH2), 125.7 (4 × CH), 127.3 (4 × CH),
᎐
᎐
H
CDCl ) 4.3 (2H, s, CH ), 5.5 (1H, s, NH), 6.4 (1H, s, C᎐CH),
᎐
3
2
6.94–6.96 (2H, m, Ar-H), 7.21–7.39 (13H, m, Ar-H); δC (90
MHz, CDCl3) 43.6 (CH2), 122.4 (CH), 127.3 (CH), 127.7 (CH),
127.9 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH),
128.9 (CH), 129.3 (CH), 137.6 (quat.), 138.4 (quat.), 140.6
128.2 (2 × CH), 145.9 (2 × quat.), 172.7 (quat., C᎐O); m/z 270
᎐
(Mϩ, 68%), and 183 (100).
Method 2. n-Butyllithium (50 cm3, 1.6 M solution in hexanes,
0.08 mol) was added dropwise to diisopropylamine (8.09 g,
11.2 cm3, 0.08 mol) at Ϫ78 ЊC and the mixture was stirred at
Ϫ78 ЊC for 30 minutes. Ethyl acetate (50 cm3, 0.51 mol) was
added and after a further 30 minutes at Ϫ78 ЊC, a solution of
benzophenone 7 (14.0 g, 0.077 mol) in dry ethyl acetate (50 cm3)
was added dropwise. The mixture was allowed to warm to room
temperature over 4 hours, then quenched with water (100 cm3)
and extracted with ethyl acetate (2 × 100 cm3). The combined,
dried organic phases were evaporated to give the ester 8 (19.8 g,
95%), which had identical analytical and spectroscopic data to
that prepared previously.
(quat.), 149.6 (quat.) 166.5 (quat., C᎐O); m/z 313 (Mϩ, 100%),
᎐
207 (94), and 179 (98).
N-( p-Chlorobenzyl)-3,3-diphenylprop-2-enamide 10b
To an ice-cooled solution of 3,3-diphenylpropenoic acid
(12.0 mmol), 4-chlorobenzylamine (1.70 g, 12.0 mmol), tri-
ethylamine (2.0 cm3) and 1-hydroxybenzotriazole (2.0 g) in
dichloromethane (70 cm3) was added diisopropylcarbodiimide
(1.90 cm3, 12.0 mmol), dropwise. with stirring. After 0.5 hours,
the ice bath was removed, and stirring was continued for 20 h at
room temperature. The solution was washed with 2 M aq. HCl
solution (20 cm3), 2 M aq. NaOH solution (20 cm3), water
(20 cm3) and brine (20 cm3), dried over MgSO4, and evaporated
to dryness. The residue was purified by column chromato-
graphy on silica eluting with hexane–diethyl ether (1 : 1) to give
N-(p-chlorobenzyl)-3,3-diphenylprop-2-enamide 10b as a white
solid. Recrystallisation from hexane–ether gave a white solid
(3.81 g, 92%), mp 153–155 ЊC (Found: C, 75.9; H, 5.4; N, 4.0.
C22H18NOCl requires C, 76.0; H, 5.2; N, 4.0%); νmax (liquid
film)/cmϪ1 3268 (NH), 1637 (C᎐O), and 1599 (C᎐C); δ (270
N-Benzyl-3-hydroxy-3,3-diphenylpropanamide 9
Method 1. A mixture of ethyl 3-hydroxy-3,3-diphenyl-
propanoate 8 (10 g, 0.037 mol), benzylamine (14.7 g, 15 cm3,
0.14 mol) and powdered ammonium chloride (1 g) was refluxed
overnight, under N2. After cooling, water (10 cm3) and ether
(30 cm3) were added. The aqueous phase was separated and
extracted with ether (2 × 50 cm3). The combined organic layers
were dried (MgSO4), and the solvent evaporated under
reduced pressure to give a pale brown oil. After refrigeration
for 36 h, the precipitated solid was filtered to give N-benzyl-
3-hydroxy-3,3-diphenylpropanamide 9 as off-white crystals.
Recrystallisation from ethanol, followed by washing with cold
petroleum 40–60 ЊC gave white crystals (3.95 g, 32%), mp
163–165 ЊC (Found: C, 79.4; H, 6.5; N, 4.1. C22H21NO2
requires C, 79.8; H, 6.3; N, 4.2%); νmax (liquid film)/cmϪ1 3313
᎐
᎐
H
MHz, CDCl3) 4.22 (2H, d, J 5.6 Hz, CH2), 5.60 (1H, br s, NH),
6.41 (1H, s, C᎐CH), 6.85 (2H, d, J 8.6 Hz, Ar-H), 7.15–7.35
᎐
(12H, m, Ar-H); δC (68 MHz, CDCl3) 42.7 (CH2), 122.2 (CH),
127.9 (2 × CH), 128.4 (2 × CH), 128.45 (CH), 128.5 (2 × CH),
128.7 (2 × CH), 129.0 (3 × CH), 129.2 (2 × CH), 133.0 (quat.),
136.3 (quat.), 138.4 (quat.), 140.5 (quat.), 149.75 (quat.), 166.5
(quat.); m/z 349 (Mϩ, 16%), 347 (Mϩ, 48), 208 (38), 207 (100),
and 178 (45).
(NH), 1639 (C᎐O), 1599 (C᎐C); δ (360 MHz, CDCl3) 3.10
᎐
᎐
H
(2H, s, CH2), 4.3 (2H, s, CH2), 6.1 (1H, s, OH), 6.3 (1H, s,
NH), 6.81–6.89 (2H, m, Ar-H), 7.2–7.45 (13H, m, Ar-H);
δC (90 MHz, CDCl3) 43.0 (CH2), 46.4 (CH2), 125.9 (CH), 126.7
(CH), 127.1 (CH), 128.3 (CH), 128.6 (CH), 137.5 (quat.),
Generation and reaction of 3,3-diphenylpropenylidyneammonio-
(phenyl)methanide 4a
N-Benzyl-3,3-diphenylprop-2-enamide 10a (0.5 g, 1.59 mmol)
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787
2785

View Article Online
was dissolved in dry ether (20 cm3). Phosphorus pentachloride
(0.5 g, 2.43 mmol) was added and the mixture refluxed over-
night, with stirring, under N2. After cooling, the solvent was
removed under reduced pressure, followed by removal of the
phosphorus oxychloride under high vacuum for 4 h. The result-
ing orange gum was dissolved in dry THF (20 cm3) and the
reaction mixture protected from the light and cooled to 0–5 ЊC
in ice–water. Potassium tert-butoxide (0.9 g, 8.02 mmol) was
then added in one portion and the solution was allowed to
warm to room temperature, with stirring, overnight. The mix-
ture was poured into aq. NH4Cl solution (20 cm3, 10% w/v) and
extracted with ethyl acetate (3 × 10 cm3). The combined organic
layers were dried (MgSO4) and the solvent evaporated under
reduced pressure to give a yellow oil (0.59 g, 63%), which was
purified by column chromatography on silica, eluting with
petroleum ether 40–60 ЊC–ethyl acetate (100 : 0 to 70 : 30), to
give 1-benzyl-2,5-bis(2Ј,2Ј-diphenylethenyl)-4-phenylimidazole
13a as a yellow solid (0.42 g, 89%), mp 162–164 ЊC (Found: C,
89.3; H, 5.8; N, 4.5. C44H34N2 requires C, 89.5; H, 5.8; N, 4.7%);
basified by the careful addition of 30% aq. sodium hydroxide
solution and extracted with ether (50 cm3). The aqueous phase
was acidified to pH 1 by the addition of conc. sulfuric acid and
extracted with dichloromethane (2 × 50 cm3). The combined
dichloromethane extracts were dried (MgSO4) and evaporated
under reduced pressure to give 2-phenylbenzoic acid 19 as a
white solid (2.04 g, 52%), mp 112–114 ЊC (lit.21 mp 112–114 ЊC )
(Found: MHϩ, 199.0755. Calc. for C13H11O2: MH, 199.075);
νmax (KBr)/cmϪ1 3015 (OH), 1685 (C᎐O); δ (270 MHz, CDCl )
᎐
H
3
7.28–7.38 (7H, m), 7.48–7.54 (1H, m), 7.90–7.94 (1H, m), 11.92
(1H, br s, OH); δC (75 MHz, CDCl3) 127.1 (CH), 127.3 (CH),
128.0 (2 × CH), 128.4 (2 × CH), 129.3 (quat.), 130.7 (CH),
131.2 (CH), 132.1 (CH), 141.0 (quat.), 143.4 (quat.), 174.05
(quat.).
N-Benzyl-2-phenylbenzamide 20
2-Phenylbenzoic acid (0.606 g, 3.03 mmol), 2-chloro-1-methyl-
pyridinium iodide (0.852 g, 3.33 mmol), tributylamine (2.89
cm3, 2.25 g, 12.12 mmol) and benzylamine (0.328 g, 3.06
mmol) were dissolved in dichloromethane (12 cm3). After
stirring for 16 hours, the reaction mixture was washed with
water (10 cm3), 1 M aq. hydrochloric acid (10 cm3), then
water (10 cm3), and dried (MgSO4). Evaporation of the
solvent under reduced pressure, followed by column chrom-
atography on silica, eluting with petroleum ether 40–60 ЊC–
ethyl acetate (80 : 20) gave N-benzyl-2-phenylbenzamide 20 as
a white solid (0.665 g, 77%), mp 97–99 ЊC (Found: C, 83.7; H,
6.0; N, 4.9. C20H17NO requires C, 83.6; H, 5.9; N, 4.9%)
(Found: MHϩ, 288.138. Calc. for C20H18NO: MH, 288.138);
νmax (KBr)/cmϪ1 3251 (NH), 1654 (C᎐O); δ (270 MHz,
δH (360 MHz, CDCl ) 4.57 (2H, s, CH ), 6.50 (1H, s, C᎐CH),
᎐
3
2
6.56 (1H, s, C᎐CH), 6.88–7.52 (30H, m, Ar-H); δ (90 MHz,
᎐
C
CDCl3) 47.3 (CH2), 115.1 (CH), 116.6 (CH), 126.3 (CH), 126.4
(CH), 127.4 (CH), 127.6 (CH), 128.1 (CH), 128.2 (CH), 128.3
(CH), 128.9 (CH), 129.9 (CH), 130.1 (CH), 130.3 (CH), 135.9
(CH), 126.4 (quat.), 135.1 (quat.), 137.3 (quat.), 139.4 (quat.),
139.6 (quat.), 139.8 (quat.), 142.3 (quat.), 142.4 (quat.), 144.8
(quat.), 147.5 (quat.), 148.1 (quat.); m/z 590 (Mϩ, 100%), 499
(23), and 422 (6).
Generation and reaction of 3,3-diphenylpropenylidyneammonio-
( p-chlorobenzyl)methanide 4b
᎐
H
CDCl3) 4.27 (2H, d, J 5.2 Hz, CH2Ph), 5.71 (1H, br s, NH),
6.82–6.85 (2H, m), 7.12–7.17 (3H, m), 7.30–7.45 (8H, m),
7.63 (1H, d, J 6.6 Hz); δC (75 MHz, CDCl3) 43.9 (CH2),
127.1 (CH), 127.4 (CH), 127.5 (CH), 127.55 (2 × CH), 128.3
(2 × CH), 128.5 (2 × CH), 128.6 (3 × CH), 129.9 (CH),
130.05 (CH), 135.5 (quat.), 137.35 (quat.), 139.35 (quat.),
140.0 (quat.), 169.3 (quat.).
N-(p-Chlorobenzyl)-3,3-diphenylprop-2-enamide 10b (0.52 g,
1.5 mmol) was dissolved in dry ether (20 cm3), phosphorus
pentachloride (0.63 g, 3.0 mmol) was added and the mixture
refluxed overnight, with stirring, under nitrogen. After cooling,
the solvent was removed under reduced pressure, followed by
high vacuum for 4 h. The resulting gum was dissolved in dry
THF (20 cm3), protected from light, cooled to 0–5 ЊC in an ice–
water bath, and potassium tert-butoxide (1.12 g, 10 mmol) was
added in one portion. The solution was allowed to warm to
room temperature, with stirring, overnight. The mixture was
poured into sat. aq. ammonium chloride solution (20 cm3) and
extracted with ether (2 × 20 cm3). The combined organic layers
were dried over magnesium sulfate and the solvent evaporated
under reduced pressure. The residue was purified by column
chromatography on silica eluting with hexane–ether (70 : 30) to
give a white solid, which was recrystallised from hexane–ether
to give 1-(4-chlorobenzyl)-2,5-bis(2,2-diphenylethenyl)-4-(4Ј-
chlorophenyl)imidazole 13b as white needles (0.72 g, 73%), mp
183–185 ЊC (Found: C, 79.7; H, 4.4; N, 3.8. C44H32N2Cl2
requires C, 80.1; H, 4.9; N, 4.2%) (Found: MHϩ, 659.202. Calc.
for C44H3335Cl2N2: MH, 659.2015); νmax (liquid film)/cmϪ1 1600
Generation and reaction of biphenyl-2-ylmethylidyneammonio-
(phenyl)methanide 22
To a solution of N-benzyl-2-phenylbenzamide 20 (0.341 g,
1.19 mmol) in dry ether (10 cm3) was added phosphorus
pentachloride (0.372 g, 1.8 mmol) and the reaction mixture was
refluxed for 16 hours. After cooling, the solvent was removed
under high-vacuum. The yellow oily residue was dissolved in
dry tetrahydrofuran (10 cm3), cooled to 0 ЊC and protected from
light. Potassium tert-butoxide (0.667 g, 5.95 mmol) was added
in one portion and the reaction was allowed to warm to room
temperature overnight. The resulting red solution was poured
into saturated aq. ammonium chloride (20 cm3) and extracted
with ethyl acetate (3 × 25 cm3). The organic layer was dried
(MgSO4) and evaporated under reduced pressure to give an
orange oil which was purified, by column chromatography on
silica eluting with petroleum ether 40–60 ЊC–ethyl acetate
(100 : 0 to 90 : 10) to give two fractions. The lower fraction
was identified as 1-benzyl-4,5-bis(biphenyl-2-yl)-2-phenylimid-
azole 23 (0.163 g, 51%) mp 174–176 ЊC (Found: C, 89.4; H, 5.6;
N, 5.1. C40H30N2 requires C, 89.2; H, 5.6; N, 5.2%) (Found:
Mϩ, 538.239. Calc. for C40H30N2: M, 538.241); νmax (KBr)/
cmϪ1 1600 (C᎐C/C᎐N); δ (270 MHz, CDCl3) 4.63 (1H, d,
(C᎐C); δ (270 MHz, CDCl3) 4.59 (2H, s, CH2), 6.46 (1H, s,
᎐
H
C᎐CH), 6.52 (1H, s, C᎐CH), 6.80 (2H, m, Ar-H), 6.89 (2H, d,
᎐
᎐
Ar-H), 7.10–7.42 (24H, m, Ar-H); δC (68 MHz, CDCl3) 46.6
(CH2), 114.5 (CH), 115.6 (CH), 125.6 (CH), 127.55 (2 × CH),
127.61 (2 × CH), 127.8 (2 × CH), 128.05 (3 × CH), 128.1
(4 × CH), 128.2 (2 × CH), 128.2 (2 × CH), 128.3 (2 × CH),
128.4 (2 × CH), 128.4 (CH), 128.9 (2 × CH), 129.7 (2 × CH),
130.1 (CH), 132.0 (quat.), 133.25 (quat.), 133.35 (quat.), 135.55
(quat.), 138.6 (quat.), 139.1 (quat.), 139.2 (quat.), 141.95 (quat.),
142.2 (quat.), 144.8 (quat.), 148.2 (quat.), and 148.51 (quat.).
᎐
᎐
H
J 16.5, CHaH), 4.87 (1H, d, J 16.5, CHbH), 6.11 (1H, d, J 7.9),
6.55 (4H, m), 6.73–7.36 (23H, m); δC (75 MHz, CDCl3) 48.3
(CH2), 126.3 (CH), 126.6 (2 × CH), 127.0 (CH), 127.2 (CH),
127.4 (CH), 127.5 (CH), 127.6 (CH), 127.9 (quat.), 128.0
(CH), 128.2 (2 × CH), 128.6 (CH), 128.7 (3 × CH), 128.75
(3 × CH), 128.8 (CH), 128.9 (2 × CH), 129.3 (2 × CH), 129.9
(CH), 129.95 (CH), 130.2 (CH), 131.1 (quat.), 131.65 (CH),
132.1 (CH), 133.4 (quat.), 137.5 (quat.), 139.5 (quat.), 140.8
(quat.), 141.3 (quat.), 142.3 (quat.), 142.35 (quat.), 147.8 (quat.).
2-Phenylbenzoic acid 19
2-Phenylbenzaldehyde (3.6 g, 19.8 mmol) was suspended in a
solution of acidified sodium dichromate [prepared from sodium
dichromate (0.43 g, 35 mmol) dissolved in water (60 cm3) and
conc. sulfuric acid (8 cm3)] and the reaction mixture was stirred
at room temperature for 4 days. The reaction mixture was then
2786
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787

View Article Online
The higher running fraction was identified as 1-benzyl-2,5-
bis(biphenyl-2-yl)-4-phenylimidazole 24, which was obtained
as a yellow oil (0.125 g, 39%) (Found: Mϩ, 538.241. Calc.
129.2 (2 × CH), 132.8 (CH), 140.9 (quat.), 142.4 (2 × quat.),
164.4 (quat.).
for C40H30N2: M, 538.241); νmax (KBr)/cmϪ1 1603 (C᎐C/
References
᎐
C᎐N); δ (270 MHz, CDCl3) 4.30 (1H, d, J 16.5 Hz, CHaH),
᎐
H
1 P. W. Groundwater and M. Nyerges, Adv. Heterocycl. Chem., 1999,
73, 97.
2 P. W. Groundwater, C. Struthers-Semple and J. T. Sharp, J. Chem.
Soc., Chem. Commun., 1987, 1367.
4.65 (1H, d, J 16.5 Hz, CHbH), 6.50 (2H, m), 6.95–7.60
(26H, m).
3 P. W. Groundwater and J. T. Sharp, Tetrahedron, 1992, 48, 7951.
4 P. W. Groundwater, A. J. Morton and R. Salter, J. Chem. Soc.,
Chem. Commun., 1993, 1789.
Generation and trapping of benzylidyneammonio(phenyl)-
methanide 31
5 R. Huisgen, H. Stangl, H. J. Sturm and H. Wagenhofer, Angew.
Chem., Int. Ed. Engl., 1962, 1, 50.
6 H. Rupe and E. Busolt, Chem. Ber., 1907, 40, 4538.
7 Z.-X. Wang and Y. Shi, J. Org. Chem., 1998, 63, 3099.
8 A. Orahovats, H. Heimgartner, H. Schmid and W. Heinzelman,
Helv. Chim. Acta, 1975, 58, 2662.
9 R. Sustmann, Tetrahedron Lett., 1971, 2717; R. Sustmann,
Tetrahedron Lett., 1971, 2721.
10 P. Caramella and K. N. Houk, J. Am. Chem. Soc., 1976, 98, 6397.
11 A. Padwa and J. Smolanoff, J. Chem. Soc., Chem. Commun., 1973,
342.
12 K. E. Cullen and J. T. Sharp, J. Chem. Soc., Perkin Trans. 1, 1993,
2961.
13 U. Schmid, P. Gilgen, H. Heimgartner, H. J. Hansen and H. Schmid,
Helv. Chim. Acta, 1974, 57, 1393.
14 A. Padwa, D. Dean and J. Smolanoff, Tetrahedron Lett., 1972, 4087.
15 J. J. P. Stewart, J. Comput.-Aided Mol. Design, 1990, 4, 1.
16 M. W. Wong and C. Wentrup, J. Am. Chem. Soc., 1993, 115, 7743.
17 E. Erdik and T. Daskapan, J. Chem. Soc., Perkin Trans. 1, 1999,
3139.
N-Benzylbenzamide 29 (0.50 g, 2.37 mmol) was dissolved in dry
THF (25 cm3) and phosphorus pentachloride (0.49 g, 2.37
mmol) was added. The mixture was refluxed overnight under
N2 and, after cooling, the solvent was removed under reduced
pressure at high vacuum. The residual orange gum was dis-
solved in dry THF (20 cm3) and benzaldehyde (0.50 g, 4.72
mmol) was added. The reaction mixture was cooled to 0 ЊC and
potassium tert-butoxide (0.53 g, 4.74 mmol) was added in one
portion. The solution was stirred and allowed to warm to room
temperature overnight. The reation mixture was quenched with
saturated aqueous ammonium chloride solution (20 cm3) and
extracted with ethyl acetate (3 × 20 cm3). The combined organic
layers were dried and evaporated under reduced pressure to
give a brown oil, which was purified by flash chromatography
on silica, eluting with petroleum ether 40–60 ЊC–diethyl ether
(90 : 10) to give 2,4,5-triphenyl-4,5-dihydrooxazole 32 as white
crystals, mp 93–95 ЊC (0.27 g, 38%) (lit.22 mp 86–87.5 ЊC)
(Found: C, 84.4; H, 5.8; N, 4.7. C21H17NO requires C, 84.3; H,
5.7; N, 4.7%) (Found: MHϩ, 300.138. Calc. for C21H17NO: MH,
300.138); νmax (liquid film)/cmϪ1 1648 (C᎐N), 1601 (C᎐C), 1580
18 D. Collomb, B. Cantegrel and C. Deshayas, Tetrahedron, 1996, 52,
10455.
19 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
20 G. M. Sheldrick, SHELXL-97: Program for Crystal Structure
Refinement, University of Göttingen, Germany.
21 A. I. Meyers, R. Gabel and E. D. Mihelich, J. Org. Chem., 1978, 43,
1372.
᎐
᎐
(C᎐C); δ (270 MHz, CDCl3) 5.22 (1H, d, J 7.2), 5.41 (1H, d,
᎐
H
J 7.2), 7.23–7.50 (13H, m), 8.15 (2H, d, J 6.8); δC (68 MHz,
CDCl3) 79.4 (CH), 89.4 (CH), 126.1 (3 × CH), 127.15 (2 × CH),
128.15 (CH), 128.0 (2 × CH), 128.7 (2 × CH), 128.8 (2 × CH),
22 T. Matsuura and Y. Ito, Bull. Chem. Soc. Jpn., 1975, 48, 3669.
J. Chem. Soc., Perkin Trans. 1, 2001, 2781–2787
2787