Synthesis of heterocyclic-fused imidazoles by pyrolysis of n-heterocyclic isoxazol-5(2h)-ones

Article abstract of DOI:10.1071/CH14119

The synthesis of heterocyclic-fused imidazoles was achieved by flash vacuum pyrolysis (FVP) of N-heterocyclic isoxazol-5(2H)-ones via an iminocarbene intermediate. Unlike iminocarbenes generated from triazoles, no structural rearrangements were observed d

Full text of DOI:10.1071/CH14119

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH14119
Synthesis of Heterocyclic-fused Imidazoles
by Pyrolysis of N-Heterocyclic Isoxazol-5(2H)-ones
A
A
A
Steven-Alan G. Abel, Mathew O. Eglinton, James K. Howard,
A
B
A C
,
Dylan J. Hunt, Rolf H. Prager, and Jason A. Smith
A
School of Physical Sciences-Chemistry, University of Tasmania,
Hobart, Tas. 7001, Australia
B
School of Chemical and Physical Sciences, Flinders University,
Adelaide, SA 5001, Australia
C
Corresponding author. Email: Jason.Smith@utas.edu.au
The synthesis of heterocyclic-fused imidazoles was achieved by flash vacuum pyrolysis (FVP) of N-heterocyclic isoxazol-
5(2H)-ones via an iminocarbene intermediate. Unlike iminocarbenes generated from triazoles, no structural rearrange-
ments were observed during the current synthesis method. We also demonstrated that less volatile isoxazol-5(2H)-one
derivatives yield the corresponding imidazoles by condensed phase pyrolysis.
Manuscript received: 6 March 2014.
Manuscript accepted: 28 March 2014.
Published online: 19 May 2014.
Introduction
of chlorinated heterocycles with the corresponding
N-unsubstituted isoxazol-5(2H)-one. The 3-ethoxycarbonyl-
4-methylisoxazol-5(2H)-one derivatives featured the same
substitution pattern as that reported by Rees that underwent
rearrangement.[17] With the precursors in hand, FVP of the
compounds was investigated. FVP was performed by subli-
mation of the starting material under vacuum into a furnace set
at 5408C (Table 1). The products were condensed upon exit
from the pyrolysis tube and were isolated simply by washing
the tube with solvent (Fig. 2). The quinoline derivative gave the
imidazole 7 in 65 % isolated yield via a proposed iminocarbene
intermediate that underwent attack by the nucleophilic nitro-
gen of the heterocyclic compound. The 5-nitropyridine deriv-
ative and bulky 2-phenylquinazoline gave the corresponding
imidazoles 9 and 11 in good-to-moderate yields. For compar-
ison, the isoquinoline derivative gave the imidazole 13 in low
yields, as reported previously,[16] presumably because of lack
of volatility of the starting material, whereas the pyrimidine
gave the imidazole 15 in excellent 90 % yield.[18] In all cases,
only a single isomer of the imidazole was observed indicating
that rearrangement of the iminocarbene, electronically similar
to those observed by Rees for N-phenyl and N-napthyl,[17] did
not occur. The structural assignments were supported by
analysis of the spectral data of imidazole 13, reported previ-
ously,[14] and X-ray crystallography data of the pyrimidine
derivative.[18] Interestingly, solutions of the pyrimidine
derivative are fluorescent.
Heterocyclic compounds are key features in synthetic chemistry
owing to their vast array of applications such as in pharma-
ceuticals, material science, and diagnostics to mention a few.
Heterocyclic-fused imidazoles are no exception and their
biological activity includes antibiotics,[1] antifungal,[2] anti-
tumour,[3] anti-inflammatory,[4] and analgesic properties[5]
among others. There are numerous drugs based on such scaf-
folds, including zolimidine,[6] zolpidem,[7] and alpidem[8]
(Fig. 1). This molecular scaffold also displays photo-physical
properties,[9,10] and these established and potential applications
have generated much interest in the synthesis of this scaffold.
Methods for synthesis have involved cyclisation of amino
pyridines[11] as a key starting point, and photo-cyclisation of
1-strylimidazoles.[12] Recent examples include oxidative cycli-
sation of pyridine.[13] Previously, we reported photochemical
and thermal reactions of heterocyclic isoxazol-5-ones[14–16] for
the synthesis of this scaffold. However, Rees reported that
N-napthyl and N-phenyl iminocarbenes generated from triazoles
with electron withdrawing groups attached to the imino group
can rearrange and give mixtures of products.[17] The rearrange-
ment of iminocarbenes had only been observed for one reaction
system in our group[15] (Scheme 1, 1: R1 ¼ CH3, R2 ¼ CO2Et)
and we endeavoured to investigate if this rearrangement
would occur in the reaction involving isomeric isoxazol-5-ones
(Scheme 1, 1: R1 ¼ CO2Et, R2 ¼ CH3). Herein, we report the
synthesis of heterocyclic-fused imidazoles and investigate the
rearrangement of the intermediate iminocarbenes, which contain
aryl and ester groups attached to the imidazole ring, by flash
vacuum pyrolysis (FVP) and condensed phase pyrolysis.
The pyrolysis of N-heterocyclic-3,4-diphenylisoxazol-
5-ones was also investigated (Table 2). The synthesis of the
starting isoxazol-5(2H)-ones was achieved by reaction between
the chlorinated heterocycles and 3,4-diphenylisoxazol-5-one.
However, harsher conditions were required compared with
those employed in reactions involving the 3-ethyoxycarbonyl-
4-methyl derivatives.
Results and Discussion
The synthesis of N-heterocyclic 3-ethoxycarbonyl-4-methyl-
isoxazol-5(2H)-ones was performed by the substitution
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

B
S.-A. G. Abel et al.
The FVP of the pyrimidine derivative occurred smoothly to
derivatives was not as effective because the starting materials
were not volatile and the solid melted in the sublimation flask.
However, on analysis of the residue, it was observed that
decarboxylation and formation of the corresponding imidazoles
19 and 21 had occurred in the condensed phase. As a test, the
quinazoline derivative 20 (0.5 g) was heated at 2008C and gave
the corresponding imidazole in 95 % yield. Typically, melting of
the starting isoxazol-5-ones in the sublimation flask had led to
decomposition. Therefore, there is potential for subjecting less
volatile substrates to condensed phase pyrolysis rather than
FVP, which would overcome one of the limitations of FVP.
To examine this hypothesis, the isoxazol-5-ones 14 and 20 were
heated in nitrobenzene in a microwave reaction tube at 2008C.
The products were isolated by chromatography and the corre-
sponding imidazoles 15 and 21 were obtained in 53 % and 70 %
yields, respectively. This showed that pyrolysis could be effec-
tively performed in readily available microwave equipment
rather than the custom equipment as required for FVP. More-
over, Wentrup et al. have demonstrated the use of microwave
reactors as an effective means for conducting pyrolysis chemis-
try to synthesise reactive intermediates.[19] However, it would
be desirable to use a solvent other than nitrobenzene or the
heavier hydrocarbons, such as biphenyl or diphenyl ether, that
are traditionally used for condensed phase pyrolysis. To this
effect, we investigated the heating of isoxazol-5-one 20 in
different solvents in a sealed tube in a microwave reactor.
Heating 20 in acetone and 1,2-dimethoxyethane presented
difficulties in reaching the set temperature 2008C, thus resulting
in unreacted starting material. The use of acetonitrile afforded
heating to 2008C and resulted in the consumption of the
isoxazolone, however, produced multiple products. In contrast,
heating in nitromethane for 1 h allowed complete consumption
of the starting material, with the imidazole 21 observed as the
only product. The use of nitromethane over nitrobenzene is more
give the fused imidazole 17 in 95 % yield. The structure was
assigned based on the 13C NMR and IR spectra that showed a
loss of the carbonyl signal, and mass spectrometry data that
showed a clear loss of CO2 and this was consistent with results
reported therein.[11] The FVP of the quinoline and quinazoline
Fig. 1. Examples of drugs based on the imidazo[1,2-a]pyridine scaffold.
Ϫ
2
3
1
5
4
Scheme 1. Photolysis and pyrolysis of N-heterocyclic isoxazol-5(2H)-
ones.
Table 1. FVP Pyrolysis of N-heterocyclic-3-ethoxycarbonyl-4-methylisoxazol-5(2H)-ones
Heterocycle Isoxazol-5-one Imidazole Yield [%]
FVP reaction conditionsA
5408C, 1308C, 0.01, 1 h
2-Chloroquinoline
6
7
65
2-Chloro-5-nitropyridine
4-Chloro-2-phenylquinazoline
2-Chloroisoquinoline
2-Chloropyrimidine
8
10
12
14
5408C, 1008C, 0.01, 3 h
5408C, 1308C, 0.01, 12 h
5408C, 1308C, 0.05, 1 h
5408C, 1208C, 0.05, 2 h
9
11
13
15
80
50
20[16]
90[18]
AFVP reaction conditions are given as: pyrolysis furnace temperature, sublimation oven temperature, vacuum
[mm Hg], and sublimation time.
7
9
11
13
15
17
19
21
Fig. 2. Fused imidazoles from pyrolysis of N-heterocyclic isoxazol-5(2H)-ones.

Synthesis of Heterocyclic-fused Imidazoles
C
practical because the solvent can be readily removed by evapo-
ration and this may offer a practical alternative to the FVP of less
volatile isoxazol-5(2H)-ones.
62.27 (t), 109.37 (s), 113.14 (d), 126.16 (s), 126.38 (d), 126.41
(s), 127.50 (d), 127.86 (d), 130.39 (d), 139.06 (d), 145.34 (s),
149.19 (s), 150.39 (s), 159.44 (s), 169.36 (s). m/z 298 (11 %,
Mþ), 254 (4), 145 (100), 128 (29), 117 (50), 90 (26). Anal. Calc.
for C16H14N2O4: C 64.42, H 4.73, N 9.39. Found: C 64.26,
H 4.74, N 9.35 %.
Conclusion
We demonstrated that the iminocarbenes derived from
3-ethoxycarbonyl-4-methylisoxazol-5(2H)-ones do not undergo
rearrangement unlike those generated from triazoles, and that
FVP and condensed phase pyrolysis are effective methods for
preparing heterocyclic-fused imidazoles. Additionally, we dem-
onstrated that conducting condensed phase pyrolysis in sealed
tubes in microwave reactors is a practical alternative to FVP.
Ethyl 4-Methyl-2-(5-nitropyridin-2-yl)-5-oxo-2,
5-dihydroisoxazole-3-carboxylate (8)
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate[20]
(500 mg, 2.9 mmol) and 2-chloro-5-nitropyridine (453 mg,
2.9 mmol) were heated neat in an oil bath at 1408C for 30 min.
The product was purified by radial chromatography, eluting
with dichloromethane/light petroleum (60 : 40) to give the title
compound 8 as a straw-coloured oil which solidified on standing
(70 % yield), mp 83–858C. nmax (Nujol)/cmꢁ1 1772, 1741, 1605,
1579, 1470, 1416, 1350, 1237, 1012, 767. dH (CDCl3, 300 MHz)
1.40 (3H, t, J 7), 2.08 (3H, s), 4.49 (2H, q, J 7), 7.48 (1H, d, J 9),
8.59 (1H, dd, J0 9, J00 2.5), 9.09 (1H, d, J 2.5). dC (CDCl3,
75 MHz) 7.28 (q), 13.92 (q), 63.08 (t), 109.19 (s), 112.04 (d),
134.44 (d), 141.29 (s), 144.14 (d), 147.58 (s), 153.70 (s), 158.94
(s), 167.98 (s). m/z 293 (100 %, Mþ), 249 (10), 204 (48), 175
(41), 123 (50), 83 (14), 77 (96), 67 (40). Found: C 49.05, H 3.84,
N 14.36 %; Mþ 293.0631. C12H11N3O6 requires C 49.15, H
3.78, N 14.33 %; Mþ 293.0647.
Experimental
Methods and Materials
1H and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively on a Varian Gemini spectrometer or at 400 and
100 MHz, respectively on a Bruker spectrometer. Spectra were
run in CDCl3 unless otherwise stated. Chemical shifts are
measured in ppm and referenced internally to residual CHCl3 for
1H NMR (d 7.26 ppm) and the central peak of CDCl3 for 13C
NMR (d 77.04 ppm). Infrared spectra were recorded on a
Perkin–Elmer 1600 FT-infrared spectrophotometer using fused
sodium chloride cells. Solids were prepared as Nujol mulls and
liquids as films. Mass spectra and high-resolution mass spectra
(HRMS) were recorded on a Kratos MS25RF spectrometer.
Microanalyses were performed at the Australian Microanaly-
tical Service (Melbourne) and the Chemical & Micro Analytical
Services Pty Ltd (Essendon North). Melting points were deter-
mined on a Reichert hot stage microscope and were uncorrected.
Solvents and reagents were obtained from Aldrich, AJAX, and
BDH chemicals, and used either as supplied or purified using
standard laboratory methods if required. FVP studies were
carried out by slowly subliming the substrate through a silica
tube (400 mm ꢀ 25 mm) packed with silica chips, and heated to
the desired temperature under reduced pressure. Condensed
phase pyrolysis was carried out in a CEM Discover microwave
reactor in a sealed tube.
Ethyl 4-Methyl-5-oxo-2-(2-phenylquinazolin-4-yl)-2,
5-dihydroisoxazole-3-carboxylate (10)
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate[20]
(500 mg, 2.9 mmol) and 4-chloro-2-phenylquinazoline (704 mg,
2.9 mmol) were refluxed in dichloromethane (10 mL) for 2 h.
The solution was cooled, filtered, and the solvent removed to
give a white solid that was recrystallised from ethanol to give
the title compound 10 as colourless plates (85 % yield), mp
140–1438C. nmax (Nujol)/cmꢁ1 1751, 1739, 1457, 1376, 1233.
dH (CDCl3, 300 MHz) 1.13 (3H, t, J 7), 2.25 (3H, s), 4.31 (2H, q,
J 7), 7.47–8.46 (9H, m). dC (CDCl3, 75 MHz) 7.85 (q), 13.80 (q),
62.48 (t), 113.01 (s), 116.14 (s), 125.27 (d), 127.89 (d), 128.25
(d), 128.52 (d), 128.69 (d), 131.06 (d), 134.61 (d), 136.49 (s),
149.99 (s), 153.10 (s), 157.36 (s), 158.78 (s), 159.19 (s), 163.84
(s), 169.50 (s). m/z 331 (3 %, Mþ–CO2), 222 (100), 205 (9), 119
(95), 111 (10), 104 (15), 90 (16), 77 (14). Found: C 67.24, H
4.57, N 11.22. C21H17N3O4 requires C 67.19, H 4.57, N 11.20 %.
Synthesis
Ethyl 4-Methyl-5-oxo-2-(quinolin-2-yl)-2,
5-dihydroisoxazole-3-carboxylate (6)
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate[20]
(1.1 g, 5.84 mmol) and 2-chloroquinoline (0.96 g, 5.84 mmol)
were refluxed in ethanol (40 mL) for 16 h. The solvent was
removed to give a gum-like product that was recrystallised from
t-butyl methyl ether/light petroleum to give the title compound 6
as a powdery solid (90 % yield), mp 97–998C. nmax (Nujol)/cmꢁ1
1754, 1640, 1595, 1237, 1124, 1069, 1029, 830, 758, 738. dH
(CDCl3, 300 MHz) 1.29 (3H, t, J 7), 2.14 (3H, s), 4.46 (2H, q,
J 7), 7.46–8.20 (6H, m). dC (CDCl3, 75 MHz) 7.25 (q), 13.80 (q),
Ethyl 2-(Isoquinolin-1-yl)-4-methyl-5-oxo-2,
5-dihydroisoxazole-3-carboxylate (12)
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate[20]
(960 mg, 5.6 mmol) and 1-chloroquinoline (1 g, 5.6 mmol) was
refluxed in dichloroethane (20 mL) for 7 h. The solvent was
removed and the product passed through a plug of silica with
dichloromethane to give a cream solid that was recrystallised
Table 2. FVP Pyrolysis of N-heterocyclic-3,4-diphenylisoxazol-5(2H)-ones
Isoxazol-5-one Imidazole
FVP reaction conditionsA
16 5408C, 1658C, 0.05, 2 h 17
Heterocycle
Yield [%]
2-Chloropyrimidine
65
10 (80)B
0 (95)B
2-Chloroquinoline
18
20
5408C, 1608C, 0.01, 1 h
5408C, 100–2008C, 0.05, 1 h
19
21
4-Chloro-2-phenylquinazoline
AFVP reaction conditions are given as: pyrolysis furnace temperature, sublimation oven temperature, vacuum
[mm Hg], and sublimation time.
BYield obtained from condensed phase pyrolysis in the sublimation flask.

D
S.-A. G. Abel et al.
from t-butyl methyl ether to give the title compound 12 as fine
colourless needles (90 % yield), mp 125–1278C. nmax (Nujol)/
cmꢁ1 1252, 1240, 1076, 846, 757, 738. dH (CDCl3, 300 MHz)
1.11 (3H, t, J 7), 2.26 (3H, s), 4.26 (2H, q, J 7), 7.63 (1H, d, J 5.6),
7.71 (2H, dt, J0 10, J00 1), 7.84 (1H, dd, J0 8, J00 1), 8.19 (1H, d, J
5.6), 8.53 (1H, dd, J0 8, J00 1). dC (CDCl3, 75 MHz) 8.10 (q),
13.61 (q), 61.95 (t), 113.35 (s), 122.20 (d), 123.56 (s), 125.19
(d), 126.55 (d), 128.39 (d), 131.15 (d), 137.94 (s), 140.10 (d),
151.47 (s), 151.63 (s), 159.03 (s), 170.89 (s). m/z 298 (43 %,
Mþ), 254 (27), 209 (16), 180 (37), 128 (100), 44 (36). Anal.
Calc. for C16H14N2O4: C 64.42, H 4.73, N 9.39. Found: C 64.51,
H 4.79, N 9.39 %.
149 (100), 112 (14), 70 (21), 57 (33). Anal. Calc. for
C11H11N3O4: C 53.11, H 4.46, N 16.89. Found: C 53.01, H
4.45, N 16.86 %.
Pyrolysis of Ethyl 4-Methyl-5-oxo-2-
(2-phenylquinazolin-4-yl)-2,
5-dihydroisoxazole-3-carboxylate (10)
The isoxazol-5(2H)-one 10 (200 mg, 0.53 mmol) was pyr-
olysed under FVP conditions (5408C, 1308C, 0.05 mm Hg, 12 h).
The pyrolysis was slow and the sample melted in the sublima-
tion flask with very little material passing through the furnace
in the last 6 h of he process. The pyrolysate was washed from
the furnace tube with dichloromethane and recrystallised
from benzene/light petroleum to give ethyl 3-methyl-5-pheny-
limidazol[1,2-c]quinazoline-2-carboxylate (11) as cream
needles (60 % yield), mp 178–1808C. nmax (Nujol)/cmꢁ1 1715,
1668, 1601, 1278, 1220, 1172, 767. dH (CDCl3, 300 MHz) 1.45
(3H, t, J 7), 2.22 (3H, s), 4.46 (2H, q, J 7), 7.53– 7.71 (7H, m),
7.92 (1H, d, J 8), 8.68 (1H, d, J 8). dC (CDCl3, 75 MHz) 13.23
(q), 14.37 (q), 61.12 (t), 118.56 (s), 123.18 (d), 128.04 (d),
128.53 (d), 128.66 (d), 130.50 (s), 130.58 (d), 132.69 (d), 134.46
(s), 140.29 (s), 143.38 (s), 147.27 (s), 163.81 (s). m/z 331 (7 %,
Mþ), 222 (85), 205 (9), 119 (100), 111 (15), 104 (14), 90 (19), 77
(29). Anal. Calc. for C20H17N3O2: C 72.39, H 4.99, N 12.45.
Found: C 72.49, H 5.17, N 12.68 %.
Ethyl 4-Methyl-5-oxo-(pyrimidin-2-yl)-2,
5-dihydroisoxazole-3-carboxylate (14)
Ethyl 4-methyl-5-oxo-2,5-dihydroisoxazole-3-carboxylate[20]
(500 mg, 2.9 mol) and 2-chloropyrimidine (340 mg, 2.9 mmol)
were refluxed in dichloroethane (20 mL) for 16 h. The solvent
was removed and the product passed through a plug of silica
eluting with dichloromethane. The resulting solid was recrys-
tallised from t-butyl methyl ether to give the title compound 14
as yellow needles (80 % yield), mp 62–648C. nmax (Nujol)/cmꢁ1
1763, 1740, 1571, 1406, 1237. dH (CDCl3, 300 MHz) 1.34 (3H,
t, J 7), 4.23 (2H, q, J 7), 7.15 (1H, t, J 5), 8.64 (2H, d, J 5).
dC (CDCl3, 75 MHz) 7.38 (q), 13.84 (q), 62.65 (t), 109.56 (s),
118.30 (d), 148.02 (d), 156.79 (s), 158.47 (s), 159.32 (s), 168.82
(s). m/z 249 (100 %, Mþ), 204 (12), 188 (11), 176 (15), 160 (34),
133 (22), 79 (91), 67 (19), 53 (91). Found: C 53.01, H 4.45,
N 16.86. C11H11N3O4 requires C 52.82, H 4.47, N 16.87 %.
Pyrolysis of Ethyl 2-(Isoquinolin-1-yl)-4-methyl-
5-oxo-2,5-dihydroisoxazole-3-carboxylate (12)
The isoxazolone 12 (100 mg, 0.33 mmol) was pyrolysed
under FVP conditions (5408C, 1308C, 0.05 mm Hg, 60 min).
Only a small amount of the isoxazolone had sublimed when
pyrolysis was stopped as the sample melted and appeared to
decompose. The product was washed from the pyrolysis tube,
and eluted through a short plug of silica (dichloromethane) to
give a solid that was identified as ethyl 3-methylimidazol[2,1-a]
isoquinoline-2-carboxylate (13) (20 % yield), mp 143–1468C.
The spectral data was consistent with that reported pre-
viously.[14] nmax (Nujol)/cmꢁ1 1713, 1456, 1398, 1311, 1283,
1218, 1153, 1069, 786, 697. dH (CDCl3, 300 MHz) 1.48 (3H, t, J
7), 2.48 (3H, s), 4.50 (2H, q, J 7), 7.15 (1H, d, J 7.4), 7.58–7.75
(4H, m), 8.78 (1H, d, J 7.2). dC (CDCl3, 75 MHz) 9.58 (q), 14.54
(q), 61.09 (t), 114.98 (d), 116.03 (s), 120.12 (d), 121.62 (s),
124.48 (d), 127.04 (d), 128.73 (d), 129.24 (d), 129.66 (s), 132.7
(s), 141.82 (s), 163.80 (s). m/z 254 (42 %, Mþ), 210 (26), 180
(89), 144 (33), 128 (100). m/z 254.1060. HRMS Anal. Calc. for
C15H14N2O2 254.1055.
Pyrolysis of Ethyl 4-Methyl-5-oxo-2-(quinoline-2-yl)-2,
5-dihydroisoxazole-3-carboxylate (6)
The isoxazol-5(2H)-one 6 (250 mg, 0.84 mmol) was pyro-
lysed under FVP conditions (5408C, 1308C, 0.05 mm Hg,
60 min), and the product was washed from the pyrolysis tube
with dichloromethane. The product was purified by radial
chromatography eluting with dichloromethane/light petroleum
(70 : 30) to give ethyl 1-methylimidazo[1,2-a]quinolone-2-
carboxylate (7) as a cream solid (65 % yield), mp 127–1298C.
nmax (Nujol)/cmꢁ1 1697, 1543, 1222, 1079, 745. dH (CDCl3,
300 MHz) 1.47 (3H, t, J 7), 3.29 (3H, s), 4.48 (2H, q, J 7), 7.42–
8.59 (4H, m), 7.75 (1H, dd, J0 7.8, J00 1.6), 8.39 (1H, d, J 8.5). dC
(CDCl3, 75 MHz) 14.47 (q), 14.55 (q), 60.76 (t), 116.23 (d),
117.98 (d), 124.98 (s), 125.19 (d), 127.59 (d), 128.26 (d), 129.30
(d), 131.56 (s), 131.84 (s), 134.87 (s), 143.22 (s), 164.27 (s). m/z
254 (51 %, Mþ), 209 (20), 180 (85), 128 (100), 101 (19). m/z
254.1068. HRMS Anal. Calc. for C15H14N2O2 254.1055.
Pyrolysis of Ethyl 4-Methyl-5-oxo-(pyrimidin-2-yl)-2,
Pyrolysis of Ethyl 4-Methyl-2-(5-nitropyridin-2-yl)-
5-dihydroisoxazole-3-carboxylate (14)
5-oxo-2,5-dihydroisoxazole-3-carboxylate (8)
The isoxazolone 14 (200 mg, 0.8 mmol) was pyrolysed under
FVP conditions (5408C, 1208C, 0.05 mm Hg, 2 h). A solid was
collected from the pyrolysis tube and recrystallised from ethanol
to give colourless needles of ethyl 3-methylimidazo[1,2-a]
pyrimidine-2-carboxylate (15) (90 % yield), mp 195–1968C.
nmax (Nujol)/cmꢁ1 1702, 1503, 1196, 1086, 786, 768. dH
(CDCl3, 300 MHz) 1.28 (3H, t, J 7), 2.65 (3H, s), 4.29 (2H, q,
J 7), 6.90 (1H, dd, J0 7, J00 4), 8.34 (1H, dd, J0 7, J00 2), 8.46 (1H,
dd, J0 4, J00 2). dC (CDCl3, 75 MHz) 8.69 (q), 14.06 (q), 60.64 (t),
109.30 (d), 124.67 (s), 131.58 (s), 132.76 (s), 146.31 (s), 154.22
(d), 163.53 (s). m/z 205 (11 %, Mþ), 158 (4), 133 (100), 132 (77),
78 (14). Anal. Calc. for C10H11N3O2: C 58.64, H 5.31, N 20.40.
Found: C 58.54, H 5.40, N 20.48 %.
The isoxazolone 8 (250 mg, 0.85 mmol) was subjected to
FVP conditions (5408C, 1008C, 0.05 mm Hg, 3 h). The product
was washed from the pyrolysis tube with dichloromethane and
passed through a short plug of silica to give a yellow solid that
was recrystallised from ethanol to give ethyl 3-methyl-6-nitroi-
midazo[1,2-a]pyridine-2-carboxylate (9) as yellow plates (80 %
yield), mp 209–2118C. nmax (Nujol)/cmꢁ1 1711, 1537, 1500,
1248. dH (CDCl3, 300 MHz) 1.47 (3H, t, J 7), 2.92 (3H, s), 4.49
(2H, q, J 7), 7.75 (1H, d, J 10), 8.02 (1H, dd, J0 10, J00 2.2), 9.10
(1H, d, J 2.2). dC (CDCl3, 75 MHz) 9.39 (q), 14.38 (q), 61.40 (t),
118.81 (d), 119.31 (d), 123.95 (d), 128.90 (s), 135.55 (s), 138.02
(s), 143.50 (s), 163.12 (s). m/z 249 (5 %, Mþ), 203 (7), 167 (35),

Synthesis of Heterocyclic-fused Imidazoles
E
Condensed Phase Pyrolysis
Pyrrolysis of 3,4-Diphenyl-2-(pyrimidin-2-yl)
isoxazol-5(2H)-one (16)
The isoxazolone 14 (60 mg, 0.24 mmol) was irradiated in a CEM
Discover microwave in a sealed tube at 2008C in nitrobenzene
(3 mL) for 1 h. After this time, the solution was transferred to
a short plug of silica gel and eluted with dichloromethane
to remove the nitrobenzene before eluting with methanol/
ethyl acetate (20 : 80) to give 3-ethyl methylimidazol[1,2-a]
pyrimidine-2-carboxylate (15) in 53 % yield.
The isoxazolone 16 (50 mg, 0.16 mmol) was pyrolysed under
FVP conditions (5408C, 1658C, 0.05 mm Hg, 2 h). The product
condensed on the exit tube and was washed off with dichlor-
omethane and passed through a plug of silica eluting with ether
to give a gum-like product that was identified as 2,3-dipheny-
limidazo[1,2-a]pyrimidine (17) (95 % yield). nmax (Nujol)/cmꢁ1
1698, 1504, 762, 700. dH (CDCl3, 300 MHz) 6.89 (1H, dd, J0 6.8,
J00 4.1), 7.28–7.79 (10H, m), 8.27 (1H, dd, J0 6.8, J00 2), 8.61 (1H,
dd, J0 6.8, J00 2). dC (CDCl3, 75 MHz) 109.09 (d), 119.45 (s),
128.23 (d), 128.35 (d), 129.51 (d), 129.80 (d), 130.58 (d), 130.88
(d), 132.80 (s), 142.95 (s), 147.50 (s). m/z 210 (4 %), 182 (5), 122
(12), 105 (100), 77 (49).
3,4-Diphenyl-2-(pyrimidin-2-yl)
isoxazol-5(2H)-one (16)
3,4-Diphenylisoxazol-5(2H)-one[21] (200 mg, 0.84 mmol)
and 2-chloropyrimidine (100 mg, 0.87 mmol) were heated neat
at 1408C for 10 min. The resultant oil was subjected to silica
chromatography, eluting with diethyl ether/hexanes (80 : 20) to
give a yellow solid that was recrystallised from ethanol to give
the title compound 16 as fine yellow needles (65 % yield), mp
176–1798C (dec.). nmax (Nujol)/cmꢁ1 1737, 1562, 1401. dH
(CDCl3, 300 MHz) 7.07 (1H, t, J 4.6), 7.21–7.43 (10H, m),
8.52 (2H, d, J 4.6). dC (CDCl3, 75 MHz) 106.96 (s), 118.56 (d),
127.60 (s), 127.71 (d), 128.34 (d), 128.42 (s), 128.61 (d), 128.73
(d), 129.01 (d), 130.37 (d), 156.88 (s), 158.48 (d), 167.62 (s). m/z
315 (32 %, Mþ), 271 (68), 219 (100), 186 (19), 122 (59). m/z
(HRMS) 315.1005; Mþ requires 315.1007.
Pyrolysis of 3,4-Diphenyl-2-(quinolin-2-yl)
isoxazol-5(2H)-one (18)
The isoxazolone 18 (100 mg, 0.27 mmol) was pyrolysed
under FVP conditions (5908C, 1608C, 0.05 mm Hg, 1 h). After
1 h, the sample had melted in the sublimation flask and pyrolysis
was stopped. The pyrolysate and residue were combined and
passed through a plug of silica with dichloromethane to give 2,3-
diphenylimidazo[1,2-a]quinoline (19), which was recrystallised
from ethanol to give cream needles (80 % yield), mp 166–
1678C. (lit. 164–1658C[22]). nmax (Nujol)/cmꢁ1 1602, 1538,
1137, 803, 776, 749, 714, 700. dH (CDCl3, 300 MHz) 7.14–
7.60 (14H, m), 7.67 (1H, d, J 9.3), 7.74 (1H, dd, J0 6.3, J00 1.2). dC
(CDCl3, 75 MHz) 116.59 (d), 117.17 (d), 124.27 (d), 124.37 (s),
124.61 (s), 126.82 (d), 127.09 (d), 127.79 (d), 128.11 (d), 129.16
(d), 129.41 (d), 129.55 (d), 131.65 (d), 132.85 (s), 134.10 (s),
134.18 (s), 143.72 (s). 210 (4 %), 122 (11), 105 (100), 77 (43).
Anal. Calc. for C23H16N2: C 86.22, H 5.03, N 8.74. Found: C
86.13, H 5.05, N 8.81 %.
3,4-Diphenyl-2-(quinolin-2-yl)
isoxazol-5(2H)-one (18)
3,4-Diphenylisoxazol-5(2H)-one[21] (500 mg, 2.1 mmol) and
2-chloroquinoline (350 mg, 2.1 mmol) in nitrobenzene (1 mL)
were heated in an oil bath at 1408C for 20 min. Light petroleum
(10 mL) was added and the resultant solid collected and recrys-
tallised from ethanol to give the title compound 18 as
yellow needles (70 % yield), mp 152–1548C. nmax (Nujol)/
cmꢁ1 1749, 1426, 1363, 954, 777, 751, 703. dH (CDCl3,
300 MHz) 7.74–7.60 (14H, m), 7.67 (1H, dd, J0 8.1, J00 1.8),
8.17 (1H, d, J 8.4). dC (CDCl3, 75 MHz) 105.59 (s), 114.48 (d),
126.49 (s), 126.67 (d), 127.37 (d), 127.44 (d), 128.29 (d), 128.44
(d), 128.55 (d), 128.60 (d), 129.15 (d), 130.21 (d), 130.28 (d),
138.84 (d), 145.84 (s), 149.66 (s), 157.78 (s). m/z 364 (6 %, Mþ),
320 (100), 245 (3), 150 (17), 128 (10), 44 (21). Found: C 79.18,
H 4.47, N 7.69 %; Mþ 364.1213. Anal. Calc. for C24H16N2O2:
C 79.10, H 4.43, N 7.69 %; Mþ 364.1213.
Pyrolysis of 3,4-Diphenyl-2-(3-phenylquinazolin-1-yl)
isoxazol-5(2H)-one (20)
The isoxazolone 20 (450 mg, 1.04 mmol) was pyrolysed
under FVP conditions (5408C, 100–2008C, 0.05 mm Hg, 1 h).
The material did not sublime and the isoxazolone melted with
apparent loss of CO2 in the sublimation flask when the tempera-
ture was raised to 2008C. The product was passed through a short
plug of silica (dichloromethane) and recrystallised from ethanol/
chloroform to give fine yellow needles of 2,3,5-triphenylimi-
dazo[1,2-c]quinazoline (21) (95 % yield), mp 216–2188C. nmax
(Nujol)/cmꢁ1 1595, 1478, 1462, 1375, 1328, 1271, 941, 711. dH
(CDCl3, 300 MHz) 6.95–7.24 (13H, m), 7.52 (2H, m), 7.72 (2H,
m), 8.00 (1H, dd, J0 7.5, J00 1.8), 8.82 (1H, d, J 7.5). dC (CDCl3,
75 MHz) 118.54 (s), 122.94 (d), 123.25 (s), 127.48 (d), 127.70
(d), 127.95 (d), 128.10 (d), 128.62 (d), 128.65 (d), 129.23 (d),
130.06 (d), 130.39 (s), 131.19 (d), 133.74 (s), 140.53 (s), 142.52
(s), 144.28 (s), 147.50 (s). m/z 397 (100 %, Mþ), 293 (7), 199
(16), 165 (16), 147 (17), 84 (16), 49 (12). Found: C 84.63,
H 4.74, N 10.50 %; Mþ 397.1593. C28H19N3 requires C 84.61,
H 4.82, N 10.57 %; Mþ 397.1579.
3,4-Diphenyl-2-(3-phenylquinazolin-1-yl)
isoxazol-5(2H)-one (20)
3,4-Diphenylisoxazol-5(2H)-one[21] (500 mg, 2.1 mmol) and
4-chloro-2-phenylquinazoline (640 mg, 2.1 mmol) in dichloro-
ethane (40 mL) were refluxed for 3 h. The solvent was removed
and the product recrystallised from ethanol/chloroform to give
fine yellow needles (80 % yield), mp 223–2248C. nmax (Nujol)/
cmꢁ1 1754, 1547, 1485, 1377, 1351, 968, 703. dH (CDCl3,
300 MHz) 7.24–7.56 (13H, m), 7.74 (1H, td, J0 7, J00 1.2), 7.80
(2H, m), 7.96 (1H, td, J0 7, J00 1.2), 8.11 (1H, dt, J0 8, J00 1.1), 8.66
(1H, dt, J0 8, J00 1.1). dC (CDCl3, 75 MHz) 108.70 (s), 117.67 (s),
125.51 (d), 128.02 (d), 128.17 (d), 128.23 (d), 128.31 (d), 128.44
(d), 128.58 (d), 128.89 (d), 128.97 (d), 129.09 (d), 129.66 (s),
130.59 (d), 130.82 (d), 134.63 (d), 153.38 (s), 157.14 (s), 159.24
(s), 159.54 (s), 168.57 (s). m/z 441 (3 %, Mþ), 397 (100), 320 (4),
293 (8), 205 (10), 165 (14), 77 (9), 44 (26). m/z 441.1462. HRMS
Anal. Calc. for C29H19N3O2 441.1477.
Condensed Phase Pyrolysis
The isoxazolone 20 (39 mg, 0.10 mmol) was irradiated in a CEM
Discover microwave in a sealed tube at 2008C in nitrobenzene
(3 mL) for 1 h. After this time, the solution was transferred to a
short plug of silica gel and eluted with dichloromethane to
remove the nitrobenzene before eluting with methanol/ethyl

F
S.-A. G. Abel et al.
acetate (20 : 80) to give the imidazole 21, in 70 % yield. Alter-
natively, the isoxazolone 20 (23 mg, 0.05 mmol) was irradiated
in a CEM Discover microwave in a sealed tube at 2008C in
nitromethane (3 mL) for 1 h. The solvent was evaporated and the
residue passed though a plug of silica (ethyl acetate/hexanes,
1 : 3) to give the imidazole 21 in 72 % yield.
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Acknowledgements
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The authors thank Flinders University and the University of Tasmania for
financial support. The Prager research group and its former members are also
appreciative of the support of the late Professor Roger Brown.
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