Synthesis of di- and cis-triaryl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles and their ring-opening reactions

Article abstract of DOI:10.1016/S0040-4020(01)00184-3

The Δ³-imidazoline 3-oxides 1 undergo diastereoselective cycloaddition with dimethyl acetylenedicarboxylate 2 to give 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 3. Thermally and base induced ring-opening reactions of compounds 3 were demonstra

Full text of DOI:10.1016/S0040-4020(01)00184-3

TETRAHEDRON
Pergamon
Tetrahedron 57 A2001) 3413±3417
Synthesis of di- and
cis-triaryl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles and their
ring-opening reactions
a,p
Necdet CosËkun, Fatma Tirli Tat and Ozden Ozel GuÈven
a
b
È
È
a
Ï
Department of Chemistry, Uludag University, 16059 Bursa, Turkey
bDepartment of Chemistry, Zonguldak Karaelmas University, 67100 Zonguldak, Turkey
Received 6 July 2000; revised 19 January 2001; accepted 8 February 2001
AbstractÐThe D3-imidazoline 3-oxides 1 undergo diastereoselective cycloaddition with dimethyl acetylenedicarboxylate 2 to give
3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 3. Thermally and base induced ring-opening reactions of compounds 3 were demonstrated.
cis-6-Phenyl substituted adducts 3d,e undergo ring opening with secondary but not with tertiary amines. The same adducts undergo regio-
and diastereoselective Michael addition with sodium methoxide to give 2-methoxy-3a,5,6-triphenyl-hexahydro-imidazo[1,5-b]isoxazole-
2,3-dicarboxylic acid dimethyl esters 6. q 2001 Elsevier Science Ltd. All rights reserved.
The inter- and intramolecular 1,3-dipolar cycloadditions of
nitrones with different dipolarophiles provide valuable
routes leading to many heterocyclic compounds. The
cycloaddition of nitrones with a variety of alkynes is used
in the synthesis of isoxazolines.1±3 The intramolecular 1,3-
dipolar cycloaddition of acetylenic nitrones leading to
bicyclic nitrogen heterocycles has been investigated.4
Intermolecular 1,3-dipolar cycloadditions of acyclic5±8 and
cyclic nitrones9±12 with DMAD have been reported.
Dihydroazet-1-oxide,9 dihydro-b-carboline N-oxide,10 and
3,4-dihydro-2H-pyrrole 1-oxide derivatives11,12 are the few
known heterocyclic nitrones which have been used in 1,3-
dipolar cycloaddition reactions with DMAD. The synthesis
of the ®rst examples of the 4H-imidazo[4,5-c]isoxazole ring
system was recently reported.13
dicarboxylate in benzene at re¯ux gave the corresponding
imidazoisoxazolines in almost quantitative yields
3
AScheme 1, Table 1). Nitrones 1d,e reacted with dimethyl
acetylenedicarboxylate with high diastereoselectivity. A
tentative cis con®gurational assignment11,12 for compounds
1
3d,e was made on the basis of H NMR spectroscopic data
and NOESY experiments. We have observed the same dia-
stereoselectivity in the reaction of imidazoline oxides 1 with
aryl isocyanates and styrene.15±17
Thermal treatment of compounds 3a±e in the condensed
phase under vacuum led to the formation of the imidazoles.
This was in contrast with the behaviour of the adducts
formed from imidazoline 3-oxides and isocyanates or
styrene where thermal treatment led to retro 1,3-dipolar
cycloaddition.
Recently, we have reported our preliminary results on the
reaction of imidazoline 3-oxides 1 with DMAD.14 We report
herein, in detail, the diastereoselective synthesis of a new
class of 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles by
cycloaddition of D3-imidazoline 3-oxides with dimethyl
acetylenedicarboxylate as well as their thermal and base
induced ring-opening reactions. The cis adducts 3d,e were
shown to undergo concerted double cis elimination with
secondary but not with tertiary amines. Bases such as
methoxide ion add regio- and diastereoselectively to the
carbon±carbon double bond instead of the expected ring
opening.
In the case of cis-3a,6-diaryltetrahydroimidazo[1,5-
b][1,2,4]oxadiazol-2A1H)-ones, we have found that second-
ary amines open the ring producing imidazole, while
tertiary amines led to retro 1,3-dipolar cycloaddition giving
the starting cyclic nitrone.18 The adducts obtained from the
same imidazoline oxides and styrene did not undergo
reaction with secondary and tertiary amines. This reaction
would have been useful in distinguishing the diastereomers
obtained from the reaction of imidazoline 3-oxides and
isocyanates; the cis con®guration was assigned tentatively
on the basis of NOE experiments and the second diastereo-
mer was not available by cycloaddition reaction. The
adducts 3 were subjected to the same amine test and showed
surprisingly similar behaviour to the imidazooxadiazolones
AScheme 2). Compounds 3a±e were converted to imidazoles
4a±e and dimethyl oxaloacetate 5 in re¯uxing acetonitrile in
The reaction of the nitrones 1a±e with dimethyl acetylene-
Keywords: Michael addition; cycloaddition; isoxazole.
Corresponding author. E-mail: coskun@uludag.edu.tr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020A01)00 184-3

3414
N. CosËkun et al. / Tetrahedron 57 +2001) 3413±3417
Scheme 1.
Table 1. 3a,4,5,6-Tetrahydroimidazo[1,5-b]isoxazoles
Entry
R
R1
Yield of 3
A%)
Yield of 4 A%)
Mp of 3 A8C)
Thermal
Piperidine
Triethylamine
a
b
c
d
e
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
H
H
H
Ph
Ph
98
99
97
97
95
85
72
91
68
67
8085
73
85
65
70
134.8
70116
80135.5
No reaction
No reaction
129
104±105.3
Scheme 2.
the presence of an excess of piperidine. Compounds 3d,e
were converted to the corresponding imidazoles in the
presence of piperidine but remain unchanged in the presence
of triethylamine under the same reaction conditions. The
easy ring opening of adducts 3 led us to suspect an abnorm-
ality in their formation. Such an abnormal adduct would be
formed if imidazoline 3-oxides react via their rearranged
oxaziridinoimidazole17 form to give dimethyl 5,6,7,7a-tetra-
hydroimidazo[5,1-b][1,3]oxazole-2,3-dicarboxylates. The
On the basis of reported chemical shifts for appropriately
substituted isoxazolidine ring hydrogenes,19,20 we assigned
the singlet near 4.25 ppm to the proton at C-3. The C-2
proton of the alternative regioisomer is expected to absorb
at d 5.00±5.20 ppm.19,20 The presence of characteristic frag-
ments in the mass spectra of the diastereomeric mixtures
was evidence for the C-2 methoxy regioisomer.21
The stereochemistry of the isoxazolidine ring of compounds
6 was deduced from NOESY experiments made for 6d AFig.
2). The 1H NMR spectra of 6d,e have shown that adducts 6
1
IR and H NMR spectra were consistent with both struc-
tures; therefore, we needed to elucidate this structure by an
X-ray diffraction method. The adduct is proved unequivo-
cally to be the cis isomer by X-ray crystallographic analysis.
A 3D perspective view of the crystal structure of 3e is
shown in Fig. 1. Thus the con®guration of adducts 3d,e
has to be cis for the double cis elimination with secondary
amines.
The mechanism proposed for the ring opening of adducts
3d,e by bases requires the base to have a proton which is
probably involved in the transition state, as shown in
Scheme 2. Synchronous abstraction of the cis protons at
C-4 and C-6, and protonation of the isoxazolidine oxygen
and C-3 is possible only in the case of secondary amines.
The reaction of cis adducts 3d,e with methoxide in re¯uxing
methanol gave the corresponding Michael addition
products 6d,e AScheme 3). This would serve as further
evidence for the concerted type of cis elimination as
depicted in Scheme 2.
Figure 1. 3D perspective view of the crystal structure of 3e.

N. CosËkun et al. / Tetrahedron 57 +2001) 3413±3417
3415
Figure 2. Selected NOESY correlations for 6d.
1.2. Tetrahydroimidazo[1,5-b]isoxazolines '3): general
procedure
To a solution of imidazoline 3-oxide 1 A3 mmol) in benzene
A20mL) dimethyl acetylenedicarboxylate A12 mmol,
1.704 g) was added. The mixture was re¯uxed for 1 h.
The solvent and the excess of DMAD were removed
under vacuum. The product was recrystallised from ether±
petroleum ether A2:1).
Scheme 3.
are a mixture of diastereomers due to the difference at the
con®gurations of C-2. The ratio of the diastereomers I and II
is approximately 2:1. The major diastereomers of both 6d
and e were isolated by preparative TLC. 3D modelling
studies show that only in the case of diastereomer II, the
proton at C-6 is close enough to the C-2 linked methoxy
protons to give cross peaks in the NOESY spectrum. This
was the case; cross peaks are observed only for the 6-H and
2-methoxy group of the minor diastereomer II. For both
diastereomers, the protons at C-3 gave cross peaks with
the o-protons of the phenyl at C-3a. The proton at C-3
also gives cross peaks with C-2 methoxy protons which in
turn give cross peaks with the methyl protons of the C-2
methoxycarbonyl. This allowed us a tentative cis-2,3-
dimethoxycarbonyl assignment for the major and trans
assignment for the minor diastereomer.22
1.2.1. Dimethyl 3a-phenyl-5-'4-methylphenyl)-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate
'3a). The compound was obtained according to the general
procedure. Yield 98%. The melting point of the colourless
crystals after recrystallisation from ether±petroleum ether is
1
134.88C. IR AKBr) nCvO 1750, 1716; nCvC 1665 cm21; H
NMR CDCl3 d 2.27 A3H, s), 3.42 A1H, d, Jˆ11 Hz), 3.64
A3H, s), 3.87 A3H, s), 4.19 A1H, d, Jˆ11 Hz), 4.65 A1H, d,
Jˆ11 Hz), 5.05 A1H, d, Jˆ11 Hz), 6.71 A2H, d, Jˆ8 Hz),
7.08 A2H, d, Jˆ8 Hz), 7.28±7.39 A3H, m), 7.60A2H, d,
Jˆ8 Hz); 13C NMR CDCl3 d 20.84; 52.23; 53.60; 57.65;
76.54; 83.06; 111.48; 115.74; 127.34; 128.47; 128.77;
129.60; 130.27; 141.21; 144.24; 152.20; 159.42; 162.87.
MS m/z 394 AM1). Anal. calcd for C22H22N2O5 A394.42):
C, 66.99; H, 5.62; N, 7.10. Found: C, 67.12; H, 5.69; N,
6.84.
1.2.2. Dimethyl 3a-phenyl-5-'4-methoxyphenyl)-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate
'3b). Yield 99%. The melting point of the colourless crys-
tals after recrystallisation from ether±petroleum ether is
1. Experimental
1.1. General
1
1168C. IR AKBr) nCvO 1750, 1716; nCvC 1665 cm21; H
Melting points were taken on an Electrothermal Digital
melting point apparatus. Infrared spectra were recorded on
a Mattson 1000 FTIR. Proton magnetic resonance spectra
were recorded on a Bruker Dpx 400 MHz spectrometer. All
spectra were taken in deuteriochloroform. Mass spectra
were routinely recorded at 70eV by electron impact on a
Fisons VG Platform II instrument. The X-ray data for 3e
were collected on an Enraf-Nonius CAD-4 automatic
diffractometer with graphite-monochromated CuKa radia-
NMR CDCl3 d 3.40A1H, d, Jˆ11 Hz), 3.64 A3H, s), 3.77
A3H, s), 3.88 A3H, s), 4.12 A1H, d, Jˆ11 Hz), 4.62 A1H, d,
Jˆ11 Hz), 5.09 A1H, d, Jˆ11 Hz), 6.72 A2H, d, Jˆ8 Hz),
6.85 A2H, d, Jˆ8 Hz), 7.28±7.39 A3H, m), 7.60A2H, d,
Jˆ8 Hz). MS m/z 410AM 1). Anal. calcd for C22H22N2O6
A410.42): C, 64.38; H, 5.40; N, 6.82. Found: C, 64.37; H,
5.47; N, 6.66.
1.2.3. Dimethyl 3a-phenyl-5-'4-chlorophenyl)-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate
'3c). Yield 97%. The melting point of the colourless crystals
after recrystallisation from ether±petroleum ether is
Ê
tion Alˆ1.5418 A copper tube) at ambient temperature. The
structure was solved by the direct method ASHELXS-97)
and was re®ned by a full-matrix least-square technique.
Visualisation was effected with UV light. Freshly prepared
imidazoline 3-oxides were used after recrystallisation from
either ethanol or acetone.
1
135.58C. IR AKBr) nCvO 1750, 1716; nCvC 1665 cm21; H
NMR CDCl3 d 3.44 A1H, d, Jˆ11 Hz), 3.65 A3H, s), 3.87
A3H, s), 4.22 A1H, d, Jˆ11 Hz), 4.65 A1H, d, Jˆ11 Hz), 5.03

3416
N. CosËkun et al. / Tetrahedron 57 +2001) 3413±3417
A1H, d, Jˆ11 Hz), 6.70A2H, d, Jˆ8 Hz), 7.22±7.40A5H, m),
7.60A2H, d, Jˆ8 Hz). MS m/z 413.9 AM1). Anal. calcd for
C21H19N2O5Cl A414.84): C, 60.80; H, 4.62; N, 6.75. Found:
C, 60.68; H, 4.55; N, 6.64.
2.3. Tertiary amine induced ring opening: general
procedure for imidazoles 4a±c
To a solution of compound 3 A1 mmol) in acetonitrile
A5 mL), triethylamine A3 mL) was added and the reaction
mixture was re¯uxed for 30min. The solvent was evapo-
rated and the residue extracted with warm hexane
A4£5 mL). The combined extracts were ®ltered and concen-
trated. The formed crystals were collected by ®ltration. The
compounds were identical in all respects with authentic
samples.
1.2.4. Dimethyl 3a,6-diphenyl-5-'4-methylphenyl)-3a,4,
5,6-tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate
'3d). Yield 97%. The melting point of the colourless crys-
tals after recrystallisation from ether±petroleum ether is
1
1298C. IR AKBr) nCvO 1750, 1716; nCvC 1665 cm21; H
NMR CDCl3 d 2.23 A3H, s), 3.62 A3H, s), 3.81 A3H, s),
4.13 A1H, d, Jˆ11 Hz), 4.76 A1H, d, Jˆ11 Hz), 5.97 A1H,
s), 6.64 A2H, d, Jˆ8 Hz), 7.01 A2H, d, Jˆ8 Hz), 7.21±7.39
A8H, m), 7.57 A2H, d, Jˆ8 Hz); 13C NMR CDCl3 d 20.79;
52.39; 53.65; 57.72; 81.03; 87.93; 112.27; 115.04; 126.99;
127.94; 128.25; 128.55; 128.72; 128.81; 128.92; 130.17;
137.77; 141.44; 143.97; 151.52; 159.48; 163. 01. MS m/z
310AM 12MeO2CCCCO2Me±H2O). Anal. calcd for
C28H26N2O5 A470.52): C, 71.48; H, 5.57; N, 5.95. Found:
C, 72.35; H, 5.47; N, 5.97.
2.4. Reaction of cis adducts 3d,e with sodium methoxide
2.4.1. cis- and trans-2-Methoxy-5-'4-methylphenyl)-3a,6-
diphenyl-hexahydro-imidazo[1,5-b]isoxazole-2,3-dicar-
boxylic acid dimethyl ester 6d. To a solution of sodium
methoxide Ain situ from 0.046 g, 2 mmol sodium) in metha-
nol A10mL) adduct 3d A1 mmol) was added and the reaction
mixture re¯uxed for 2 h, then left to cool. The white crystals
formed after addition of water A6 mL) were ®ltered and
dried in a vacuum oven. Yield 52%. Mp 98±1008C. IR
1.2.5. Dimethyl 3a,6-diphenyl-5-'4-methoxyphenyl)-3a,
4,5,6-tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxyl-
ate '3e). Yield 95%. The melting point of the colourless
crystals after recrystallisation from ether±petroleum
ether is 104±105.38C. IR AKBr) nCvO 1750, 1716;
1
AKBr) nCvO 1750cm 21; H NMR CDCl3 d 2.22 A3H, s),
3.29 and 3.62 A3H, two s, C-2 MeO), 3.64 and 3.67 A3H,
two s, ester MeO), 3.77 and 3.84 A3H, two s, ester MeO),
3.93 and 4.21 A1H, two s, C-3 H), 4.48 and 4.67 A2H, two AB
systems), 5.73 and 6.02 A1H, two s, C-6 H), 6.46 and 6.50
A2H, two d), 7.00±7.05 A9H, m), 7.11 A1H, m), 7.36 and 7.38
A2H, d, C-3a Ph ortho H). MS m/z 502 AM1). Anal. calcd for
C29H30N2O6 A502.57): C, 69.31; H, 6.02; N, 5.57. Found: C,
69.43; H, 6.34; N, 5.61.
nCvC 1665 cm21
;
1H NMR CDCl3 d 3.68 A3H, s),
3.70A3H, s), 3.82 A3H, s), 4.16 A1H, d, Jˆ11 Hz),
4.62 A1H, d, Jˆ11 Hz), 5.82 A1H, s), 6.70A2H, d,
Jˆ8 Hz), 6.77 A2H, d, Jˆ8 Hz), 7.29±7.40A8H, m),
7.59 A2H, d, Jˆ8 Hz). MS m/z 326 AM12MeO2CCC-
CO2Me±H2O). Anal. calcd for C28H26N2O6 A486.52):
C, 69.13; H, 5.39; N, 5.76. Found: C, 69.20; H, 5.30;
N, 5.78.
2.4.2. cis-2-Methoxy-5-'4-methylphenyl)-3a,6-diphenyl-
hexahydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
dimethyl ester 6d. H NMR CDCl3 d 2.15 A3H, s), 3.62
1
A3H, s, C-2 MeO), 3.57 and 3.70A6H, two s, ester
MeO), 3.86 A1H, s, C-3 H), 4.43 A2H, AB system,
JABˆ9.89 Hz), 5.66 A1H, s, C-6 H), 6.42 A2H, d,
Jˆ8.23 Hz), 6.91±6.95 A10H, m), 7.30 A2H, d, Jˆ7.29 Hz,
C-3a Ph ortho H).
2. Ring-opening reactions of compounds 3
2.1. Thermally induced ring opening: general procedure
Compound 3 A0.1 mmol) was placed in a glass sample
vial, heated in a vacuum oven at 1.3£1023 mmHg and
left to cool at room temperature. The obtained 4 was
extracted with warm hexane A3£2 mL). The extract was
concentrated and cooled. The formed crystals were
collected by ®ltration. The identity of the obtained
imidazoles was determined comparing their melting
points as well as their IR spectra with those of the
authentic samples.
2.4.3. 2-Methoxy-5-'4-methoxyphenyl)-3a,6-diphenyl-
hexahydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
dimethyl ester 6e. Yield 52%. Mp 80±828C. IR AKBr)
1
nCvO 1750cm 21; H NMR CDCl3 d 3.31 and 3.62 A3H,
two s, C-2 MeO), 3.65 and 3.68 A3H, two s, ester MeO),
3.72 A3H, s), 3.78 and 3.87 A3H, two s, ester MeO), 3.93 and
4.21 A1H, two s, C-3 H), 4.46 and 4.54 A2H, two AB
systems), 5.70and 5.94 A1H, two s, C-6 H), 6.54 and 6.82
A2H, two d), 6.98±7.05 A9H, m), 7.12 A1H, m), 7.37 and 7.45
A2H, d, C-3a Ph ortho H). MS m/z 518 AM1). Anal. calcd for
C29H30N2O7 A518.57): C, 67.17; H, 5.83; N, 5.40. Found: C,
67.40; H, 6.00; N, 5.40.
2.2. Secondary amine induced ring opening: general
procedure for imidazoles 4a±e
To a solution of compound 3 A0.33 mmol) in acetonitrile
A5 mL), piperidine A1 mL) was added and the reaction
mixture was re¯uxed for 30min. The solvent was evapo-
rated and the residue extracted with warm hexane
A3£5 mL). The combined extracts were ®ltered and concen-
trated. The formed crystals were collected by ®ltration. The
compounds were identical in all respects with authentic
samples.
2.4.4. cis-2-Methoxy-5-'4-methoxyphenyl)-3a,6-diphenyl-
hexahydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
dimethyl ester 6e. H NMR CDCl3 d 3.55 A3H, s, C-2
MeO), 3.58 and 3.65 A6H, two s, ester MeO), 3.71 A3H, s),
3.86 A1H, s, C-3 H), 4.40A2H, AB system, JABˆ9.74 Hz),
5.63 A1H, s, C-6 H), 6.43 and 6.70A4H, two d, Jˆ8.89 Hz),
6.91±6.98 A8H, m), 7.12 A1H, m), 7.31A2H, d, Jˆ7.06 Hz,
C-3a Ph ortho H).
1

N. CosËkun et al. / Tetrahedron 57 +2001) 3413±3417
3417
È
È
È
14. CosËkun, N.; Tat, F. T.; GuÈven, O. O.; UlkuÈ, D.; Arõcõ, C.
Tetrahedron Lett. 2000, 41, 5407±5409.
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
149019. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [Fax: 144-A0)1223-336033 or email:
15. CosËkun, N. Tetrahedron Lett. 1997, 38, 2299±2302.
16. CosËkun, N. Tetrahedron 1997, 53, 13873±13882.
17. CosËkun, N.; Ay, M. Heterocycles 1998, 48, 537±544.
18. CosËkun, N. Tr. J. Chem., in press.
19. Padwa, A.; Fisera, L.; Koehler, F. K.; Rodriguez, A.; Wong,
G. S. K. J. Org. Chem. 1984, 49, 276±281.
deposit@CCDC.cam.ac.uk].
20. March, P.; Figueredo, M.; Font, J.; Milan, S.; Alvarez-Larena,
A.; Piniella, J. F.; Molins, E. Tetrahedron 1997, 53, 2979±
2988.
Acknowledgements
È
Dr DincËer UlkuÈ and Dr Cengiz Arici from, Department of
Engineering Physics, Hacettepe University are gratefully
acknowledged for the X-ray analysis of compound 3e.
21. The presence of ions at m/z 384 and m/z 400 in the mass
spectra of the diastereomeric mixtures, resulted from the prob-
able fragmentation of adducts 6d,e as shown in the scheme
below and the absence of ions at m/z 415 and 431 correspond-
ing to the alternative 3-methoxy regioisomers may serve as
additional evidence for C-2 methoxy regioisomers. Ion m/z
118 is present in both mass spectra but especially intensive
in the case of 6d.
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NOESY experiment for the pure cis-6d while the con®gura-
tions of the trans-6d,e are on the basis of NOESY for the
diastereomeric mixture of 6d.