Thermal reaction of 5-aryl-6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines accessing 5-trifluoromethylimidazols

Article abstract of DOI:10.3987/com-07-s(w)12

Thermal reaction of 5-aryl-6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines (2) readily obtainable from 3-aryl-3-dimethylhydrazono-1,1,1-trifluoro-2-propanones (1) afforded 4-aryl-l-methyl-5-trifluoromethyl-imidazoles (3) in moderate to good yields. Mechanism for this thermal transformation reaction is also discussed.

Full text of DOI:10.3987/com-07-s(w)12

HETEROCYCLES, Vol. 74, 2007
351
HETEROCYCLES, Vol. 74, 2007, pp. 351 – 356. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2007, Accepted, 30th August, 2007, Publisehd online, 4th September, 2007. COM-07-S(W)12
THERMAL REACTION OF 5-ARYL-6-TRIFLUOROMETHYL-3,6-DIHYDRO-
2H-[1,3,4]OXADIAZINES ACCESSING 5-TRIFLUOROMETHYLIMIDAZOLS
Yasuhiro Kamitori,* Tomoko Sekiyama, and Etsuji Okada
Department of Chemical Science and Engineering, Graduate School of
Engineering, Kobe University, Kobe 657-8501, Japan,
e-mail: kamitori@kobe-u.ac.jp
Abstract – Thermal reaction of 5-aryl-6-trifluoromethyl-3,6-dihydro-2H-
[1,3,4]oxadiazines (2) readily obtainable from 3-aryl-3-dimethylhydrazono-
1,1,1-trifluoro-2-propanones (1) afforded 4-aryl-1-methyl-5-trifluoromethyl-
imidazoles (3) in moderate to good yields. Mechanism for this thermal
transformation reaction is also discussed.
INTRODUCTION
Fluorine-containing heterocycles are very attractive targets for synthetic organic chemists because of
their potentially high physiological activities.1-4 Previously we reported an acid catalyzed novel
cyclization reaction of 3-aryl-3-dimethydrazono-1,1,1-trifluoro-2-propanones (1) affording 5-aryl-6-
trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines (2).5,6
hydrazones (1) in refluxing tetrachloromethane gave oxadiazines (2) together with small amounts of
4-aryl-1-methyl-5-trifluoromethylimidazoles (3).7
In contrast, imidazoles (3) were obtained
On the other hand, thermal reaction of
predominantly together with 5-aryl-1-methyl-4-trifluoromethylimidazoles (4) as minor products, when
hydrazones (1) were heated in refluxing toluene.8 Above results seem to suggest a possibility of
reaction pathway from 1 to imidazoles (3 and 4) via oxadiazines (2). As a part of investigation about
mechanisms for the reaction from hydrazones (1) to 3 and 4, we elucidated in detail the thermal
transformation of oxadiazines (2) to imidazoles (3 and 4).
RESULTS AND DISCUSSION
Thermal reaction was carried out for oxadizines (2a - e)5,6 and are summarized in Table 1. In refluxing
This Paper is dedicated to Professor Dr. Ekkhard Winterfeldt on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 74, 2007
Me
Ar
CF3
Ar
N
Me
Me
N
COCF3
Ar
N
N
O
N N
1
N
N
CF3
CF3
Me
Me
4
Ar
2
3
1 - 4
a
e
c
b
d
Ar
Ph
p-MeC6H4 p-MeOC6H4 p-ClC6H4 p-O2NC6H4
tetrachloromethane, oxadiazine (2b) was remained intact and no imidazole was obtained even after 4
days (Entry 2). However, 83% of 2b was converted to 5-trifluoromethylimidazole (3b) and no
4-trifluoromethylimidazole (4b) was detected in the reaction mixture when 2b was heated for 2 days in
refluxing toluene (Entry 3). To complete the reaction, prolonged reaction time (4 days) was required,
and 3b was obtained as a sole product (Entry 4).8 No isomerization of 3b to 4b was observed even
after 4 days in refluxing toluene. In contrast, hydrazone (1b) was completely converted to 3b (major
product) and 4b (minor product) within 2 days in refluxing toluene.8 Apparently, conversion of 2b to 3b
proceeds more slowly than that of 1b to 3b or 4b. These results indicate that oxadiazines (2) are not
intermediates of the reaction from hydrazones (1) to imidazoles (3 and 4).
The selective transformation of oxadiazines (2a and 2c) to the corresponding 5-trifluoro-
methylimidazoles (3a and 3c) was also successful under the same conditions with 2b (Entries 1 and 5).
Oxadiazines bearing electron-withdrawing substituents on the benzene ring, 2d and 2e, were less
reactive than 2a - c. The reaction of p-chlorophenyl derivative (2d) in refluxing toluene proceeded more
slowly and gave the mixture of two regioisomers (3d and 4d) together with 11% recovery of 2d (Entry 6).
In the case of p-nitrophenyl derivative (2e), no reaction occurred with the whole recovery of 2e (Entry 8).8
The reaction of 2e at 110 °C and at 125 °C without solvent afforded the mixture of 3e and 4e in the ratio
of ca. 3 : 2 together with recovery of 2e (Entries 9 and 10). Apparently, these results show that
electron-withdrawing group at the p-position of aryl substituent hinders the present ring transformation
reaction. Moreover, the reaction of oxadiazines having electron-withdrawing group on aryl substituent
gave 4-trifluoromethylimidazoles (4) together with 5-trifluoromethylimidazoles (3).9,10
The use of p-xylene as a solvent having higher boiling point was found to be especially effective for 2d
and 2e. The reactions of 2d and 2e for 4 - 6 days in refluxing p-xylene took place selectively to provide
the single regioisomers (3d and 3e) without any formation of the other ones (4d and 4e) (Entries 7 and
11).

HETEROCYCLES, Vol. 74, 2007
353
Table 1. Thermal reaction of oxadiazines (2) affording 5-trifluoromethylimidazoles (3). a
Entry
1
Substrate
2a
Solvent
toluene
CCl4
Time (d)
Product
Conversionb (%) Yieldc (%)
4
4
2
4
4
4
4
4
3a
-
100
0e
95d
-
2
2b
3
2b
toluene
toluene
toluene
toluene
p-xylene
toluene
-
3b
3b
3c
83
100
100
89
65
86d
92d
82f
91
-
4
2b
5
2c
6
2d
3d, 4d (88 : 12)b
7
2d
3d
100
8
2e
-
0e
9
2e
1 (110°C)g
3e, 4e (61 : 39)b
3e, 4e (59 : 41)b
3e
66
71
59f
66f
57
10
11
2e
-
1 (125°C)g
2e
p-xylene
6
100
1
a The reaction was carried out under reflux conditions. b Calculated by H NMR spectroscopy.
c
f
Isolated yield. d Ref. 8. e Substrate was recovered.
Combined yield of isomers (3 and 4). g The
reaction was carried out in sealed tube without solvent at the indicated temperatures.
As for the reaction mechanism from oxadiazines (2) to 5-trifluoromethylimindazoles (3), the pathway
containing reverse reaction process from 2 to hydrazones (1) followed by recyclization of 1 to 3 is unlikely,
because thermal reaction of 1 to 3 does not proceed selectively and 4-trifluoromethyimidazoles (4) are
always obtained as minor products.
Taking it into account that the ring construction reaction of oxadiazines (2) to imidazoles (3) is induced
thermally and required no catalyst, and cleavage of both N-N and C-O bonds on 2 is included in the
reaction, we proposed the most reasonable pathway illustrated in Scheme 1. Retro Diels-Alder reaction
of tautomeric isomers (2’) of 2 affords 3-imino-1,1,1-trifluoro-2-propanones (5) and N-methyformimine (6).
The subsequent cycloaddition of 5 with 6 gives betaines (7). Prototropy on 7 followed by dehydration
affords 5-trifluoromethylimidazoles (3).
In order to confirm above mechanism, we computed, on the basis of the 6-31G* level density functional
calculations (RB3LYP/6-31G*// RB3LYP/6-31G*), the optimized structures as well as the energies of 2
and intermediates (2’, 5 and 6), in addition to the transition state structures (A and B) and the correspond-
ing activation energies. The estimated transition state structures (A and B) were illustrated in Figure 1.
Tautomer 2a’ (Ar= Ph) is 3.0 Kcal/mol less stable than oxadiazine (2a).
Activation energy (ΔEA) of

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HETEROCYCLES, Vol. 74, 2007
≠
Me
N
Me
Me
N
N
O
ΔE
ΔEA
6
O
O
2
HN
N
CF3
ΔER
CF3
H
CF3
N
Ar
2'
H
Ar
A
Ar
5
ΔEB
≠
Me
Me
Me
N
N
N
- H2O
δ
3
OH
CF3
O
N
O
N
δ+
H
N
H
CF3
CF3
Ar
8
Ar
Ar
B
7
Scheme 1
retro Diels-Alder reaction from 2a’ (Ar= Ph) to ketoimine (5; Ar= Ph) and formimine (6) was calculated as
35.9 Kcal/mol. The second activation energy (ΔEB) of cycloaddition reaction from 5 (Ar= Ph) and 6
affording betaines (7; Ar= Ph) was estimated as 6.9 Kcal/mol. This value is much smaller than that of
first activation energy (ΔEA). In addition, activation energy (ΔER) of reverse reaction (Diels-Alder
reaction) from 5 (Ar= Ph) and 6 to 2a’ (Ar= Ph) is calculated as 28.7 Kcal/mol, which is much larger than
the value of ΔEB but ca. 7 Kcal/mol smaller than that of ΔEA. These results indicate that, under the
reaction conditions, there is an equilibrium state between 2’ and intermediates (5 and 6) and once 5 and
6 are produced by retro Diels-Alder reaction of 2’, they are quickly consumed to yield betaines (7).
Retro Diels-Alder reaction of 2’ would be a key step of overall reaction processes from oxadiazines (2) to
imidazoles (3). The energy value (35.9 Kcal/mol) of ΔEA for 2a’ (Ar= Ph) is compatible with the reaction
conditions from 2a to 3a (Table 1).
We also calculated ΔE, ΔEA, and ΔEB for the ring transformation of oxadiazine (2e) bearing nitro group on
the benzene ring to the corresponding imidazole (3e), which required higher temperature to complete the
reaction. Unexpectedly, estimated activation energies, ΔEA (34.9 Kcal/mol) and ΔEB (6.0 Kcal/mol)
are slightly lower than the corresponding ΔEA (35.9 Kcal/mol) and ΔEB (6.9 Kcal/mol), respectively, on
the reaction of 2a to 3a. On the other hand, tautomer (2e’; Ar= p-O2NC6H4) is ca. 7 Kcal/mol less stable
than oxadiazine (2e), whereas 2a’ (Ar= Ph) is only 3 Kcal/mol less stable than 2a. Instability of 2e’ (Ar=
p-O2NC6H4) relative to 2a’ (Ar= Ph) is unfavorable for the reaction of 2e to 3e. In addition, ΔER (25.1

HETEROCYCLES, Vol. 74, 2007
355
Kcal/mol) in the case of 2e being 3.6 Kcal/mol lower than ΔER (28.7 Kcal/mol) in the case of 2a means
that the reverse reaction of 5 with 6 to 2’ proceeds more rapidly in the case of 2e than in the case of 2a.
Relatively rapid reverse reaction (Diels-Alder reaction of 5 with 6) is unprofitable for conversion of
oxadiazine (2e) to imidazole (3e).
1.306Å
F
C
C
N
1.688Å
2.086Å
F
1.772Å
O
C
1.589Å
C
C
O
F
N
N
C
1.268Å
1.369Å
C
F
C
C
C
F
1.315Å
N
F
1.419Å
2.037Å
1.280Å
A
B
Figure 1
CONCLUSION
Thermal reaction of oxadiazines (2) in refluxing toluene or p-xylene gave 5-trifluoromethylimidazoles (3)
selectively. Molecular orbital calculations suggest that key steps of the reaction processes from 2 to 3
would be retro Diels-Alder reaction of tautomers (2’) and subsequent cycloaddition of resulted ketoimines
(5) and formimine (6). The tandem transformations hydrazones (1) → 2 → 3 would be superior
method to prepare 5-trifluoromethylimidazoles (3) selectively.
4-trifluoromethylimidazoles (4) from hydrazones (1) was reported previously,11 so we established
selective synthetic methods suitable for each 5-trifluoromethylimidazoles (3) and
Selective synthesis of
4-trifluoromethylimidazoles (4) starting from common hydrazones (1) readily obtainable from various
arylaldehydes.7
COMPUTATIONAL METHODS
All calculations employed in this paper were accomplished using the computer programs packages PC
SPARTAN 02.12 All calculations for geometrical optimizations were performed with the 6-31G* basis set
at B3LYP13 levels. The starting geometries employed for all optimizations were resulted from
semi-empirical PM314 optimizations. The calculations for energy of intermediates as well as transition

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HETEROCYCLES, Vol. 74, 2007
states were also taken with density functional calculations using the 6-31G* basis set at B3LYP levels.
EXPERIMENTAL
Thermal reaction of 5-aryl-6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines (2a - e) with the use of
1
solvents was carried out according to literature manner.8 The products were analyzed by H NMR
spectroscopy.
Conversion and product ratio were calculated from signal intensities of the
corresponding NMe protons of 2, 3, and 4.5,6,8
Thermal reaction of 5-(p-nitrophenyl)-6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazine (2e)
without solvent
In a nitrogen replaced Φ6 mm glass sealed tube, 2e (0.18 mmol, 50.8 mg) was heated for 24 h at 110 °C
or 125 °C (oil bath temperature). Crude materials were analyzed by 1H NMR spectroscopy. Yields and
ratios (2e : 3e : 4e) are as follows - 47.4 mg, 17 : 20 : 13 (110 °C); 44.8 mg, 29 : 42 : 29 (125 °C).
1
Identification of 3a - e and 4d - e were pursued by comparing H NMR spectra of them with those of
authentic samples.7,8
REFERENCES AND NOTES
1. Review: R. Filler, “Organofluorine Chemicals and their Industrial Applications”, ed. By R. E. Banks,
Ellis Horwood, London, 1979, p. 123.
2. V. N. Pathak and V. Grover, Pharmazie, 1979, 34, 568 (Chem. Abstr., 1980, 92, 181060n).
3. H. V. Secor and J. F. DeBardeleben, J. Med. Chem., 1971, 14, 997.
4. H. Kimoto and L. A. Cohen, J. Org. Chem., 1980, 45, 3831.
5. Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and T. Yokoyama, Synthesis, 1988, 208.
6. Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, K. Kawasaki, and Y. Kawamura, Synthesis, 1990, 493.
7. Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and T. Yokoyama, J. Org. Chem., 1988, 53,
129.
8. Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, K. Kawasaki, Y. Kawamura, and M. Tanaka, J.
Heterocycl. Chem., 1990, 27, 487.
9. When 4-trifluoromethyimidazole (4e) was heated for 6 d in refluxing p-xylene (the conditions for Entry
11), no isomerization to 5-trifluoromethylimidazole (3e) occurred with the whole recovery of 4e.
10. Although the reaction mechanism from 2e (or 2d) to 4e (or 4d) is still unknown, the reverse reaction
from oxadiazines (2) to hydrazones (1) followed by recyclization of 1 to 4 (and 3)8 would be one of
possible pathways from 2e (or 2d) to 4e (or 4d).
11. Y. Kamitori, M. Hojo, R. Masuda, Y. Kawamura, and X. Fang, Heterocycles, 1990, 31, 2103.
12. Wavefunction, Inc.
13. A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
14. J. J. P. Stewart, J. Comput.-Aided Mol. Des., 1992, 6, 69.