Acid catalyzed cyclization reaction of 3-hydrazono-1,1,1-trifluoro-2-alkanones to 6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines

Article abstract of DOI:10.3987/COM-05-10482

Mechanisms for the acid catalyzed cyclization reaction of 3-dialkylhydrazono-1,1,1-trifluoro-2-alkanones (1) to 6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines (2) are discussed. The results indicate 1,5-sigmatropic shift of hydrogen atom from N-methy

Full text of DOI:10.3987/COM-05-10482

HETEROCYCLES, Vol. 65, No. 9, 2005
2139
HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2139 - 2150
Received, 17th June, 2005, Accepted, 20th July, 2005, Published online, 22nd July, 2005
ACID CATALYZED CYCLIZATION REACTION OF 3-HYDRAZONO-1,1,1-
TRIFLUORO-2-ALKANONES TO 6-TRIFLUOROMETHYL-3,6-DIHYDRO-
2H-[1,3,4]OXADIAZINES
Yasuhiro Kamitori* and Tomoko Sekiyama
Department of Chemical Science and Engineering, Faculty of Engineering,
Kobe University, Kobe 657-8501, Japan, e-mail: kamitori@cx.kobe-u.ac.jp
Abstract
-
Mechanisms for the acid catalyzed cyclization reaction of 3-
dialkylhydrazono-1,1,1-trifluoro-2-alkanones (1) to 6-trifluoromethyl-3,6-dihydro-2H-
[1,3,4]oxadiazines (2) are discussed. The results indicate 1,5-sigmatropic shift of
hydrogen atom from N-methyl group to carbonyl carbon center on protonated 1 to be a key
step for this cyclization reaction.
INTRODUCTION
In the previous papers,1,2 we reported a novel cyclization reaction of 3-dimethylhydrazono-
1,1,1-trifluoro-2-alkanones (1)3 affording 6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxadiazines (2) under
very mild conditions. This cyclization reaction proceeds in the presence of acid catalyst, such as
acetic acid, trifluoroacetic acid (TFA), and silica gel. During the reaction, one of the N-methyl carbon
atoms of hydrazone (1) that seems not to be so reactive in general, is easily incorporated into
oxadiazine ring system of the products. These findings prompted us to study about the mechanism of
this interesting cyclization reaction.
AcOH,
TFA,
or SiO2
CH3
CH3
CH3
CH3
CH3
COCF3
R
TFAA
N
N
O
2
NN
NN
R
CF3
R
1
RESULTS AND DISCUSSION
Taking it in consideration that this cyclization reaction requires acid catalysis, we tried to estimate
protonated structures of hydrazone (1) as an initial intermediate. On the basis of the 6-31G* level

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HETEROCYCLES, Vol. 65, No. 9, 2005
density functional calculations (RB3LYP/6-31G*//RB3LYP/6-31G*), the estimations were carried out
about 3-dimethylhydrazono-1,1,1-trifluoro-2-propanone (3) as a model compound for 1. In the
presence of acid, reversible protonation should be possible at carbonyl oxygen, Schiff base nitrogen,
dimethylamino nitrogen, and azomethine carbon atoms of hydrazone (3). In each case, the
geometrically optimized structure (4a - d) as well as its energy were computed, and the results are
summarized in Scheme 1 together with those for hydrazone (3). Among these mono cations, 4a
derived from 3 by protonation at carbonyl oxygen atom was predicted to be most stable. The values in
parentheses computed by RMP2/6-31G*//RMP2/6-31G* are also compatible with these predictions.
These results suggest that considerable amounts of hydrazones (1) are converted to cations (4, Scheme
2) in the presence of acid catalyst. Dications (5) may be also possible in the presence of strong acid
such as TFA.
CH3
N
CH3
N
CH3
N
1.127
1.324
1.433
CH3
N
H
CH3
N
CH3
N
1.013
F
F
F
F
1.417
1.143
C
C
O
F
F
C
O
F
H O
4a
F
1.703
1.188
4b
F
3
E = -679.284775 a.u.
(-677.425872 a.u.)
CH3
E = -679.295862 a.u.
(-677.430435 a.u.)
E = -678.944107 a.u.
(-677.087304 a.u.)
CH3
CH3
N
R
H
N
O
O
CH3
N
H
F
CH3
CH3
F
N
F
F
F
N
C
N
C
C
H
C
C
F
F
H
O
F
F
4c
4d
H
5
E = -679.282337 a.u.
(-677.429024 a.u.)
E = -679.277564 a.u.
(-677.421028 a.u.)
E = -679.451041 a.u. (R= H)
(-677.584129 a.u.)
Scheme 1
On the basis of RMP2/6-31G*, Mulliken bond populations4 were calculated about hydrazone (3) and
cation (4a). These are also indicated in Scheme 1. These data reveal exceeding multiple bonding
characters on N-N and C-C bonds of cation (4a) in comparison with those of 3, i.e. considerable
contribution of the canonical form B in Scheme 2. Similar situation should be true for hydrazones (1),
and this suggests more enhanced azoolefinic character of 4 by protonation at carbonyl oxygen atom of 1.
On the basis of RB3LYP/6-31G*, estimated rotational barriers around central C-N bond are 19.4 Kcal/mol

HETEROCYCLES, Vol. 65, No. 9, 2005
2141
and 11.9 Kcal/mol for cations (4a) and (4, R= Ph), respectively. Such azoolefinic character should be
correlated with notable reactivity of 1 leading to several heterocyclic ring-formations. For instance, we
reported TFA mediated hetero-Diels-Alder reaction of protonated hydrazone (6) affording pyridazine (7)
in the previous report.5 These findings suggest the cation (4) to be the most reasonable precursor for
the present cyclization reaction accessible oxadiazine (2).
CH3
N
CH3
N
CH3 OH
R
CH3
N
CH3
N
R
CH3
N
CF3
N
CF3
CF3
R
HO
HO
4'
A
B
4
R
CF3
COCF3
N
N
H2NN
CF3
R
R
7
6
Scheme 2
Ionic as well as concerted processes are possible as a mechanism of the present cyclization reaction
from cation (4) to oxadiazine (2). As for the mechanisms including only ionic processes, we can
propose two possible pathways (Path A and Path B) illustrated in Scheme 3. Path A contains
deprotonation process on N-methyl group of 4 affording betaines (8 and 8’) as intermediates. Betaine
(8) should be in equilibrium with 8’. The RB3LYP/6-31G* level calculations suggest that intermediate (8,
R= H) in Path A is 28.1 Kcal/mol less stable than hydrazone (3, R= H). Betaine (8’, R= H) is estimated
to be 7.2 Kcal/mol less stable than 8 (R= H). Subsequent protonation at C4 of 8’ affords cation (9) and
intramolecular nucleophilic attack of hydroxyl oxygen atom toward terminal azomethine carbon atom on 9
followed by deprotonation should afford 2.
On the other hand, Path B includes the formation of dication (5) and subsequent deprotonation process
on N-methyl group of 5 affording cationic intermediates (10 and 10’). Cyclization mediated by nucleophilic
attack of hydroxyl oxygen atom toward terminal azomethine carbon atom on 10’ and subsequent
deprotonation afford oxadiazine (11),6 i.e. a tautomer of 2.
Also, protonation at Schiff base nitrogen atom of 8’ in Path A can give intermediate (10’), and
consequently, oxadiazine (2) via 11.

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HETEROCYCLES, Vol. 65, No. 9, 2005
Path A
4'
4
- H
- H
-
CH2
-
CH2 OH
CH2 OH
CH3
N
R
-
1
CH3
N
CH3
N
CF3
CF3
N
8
4
CF3
N
N
8'
2
3
R
R
HO
H
H
H
O
CH2
OH
- H
CF3
CH3
N
2
CH3
N
N
C
CF3
N
N
R
R
9
H
Path B
4
CH2
CH2
N
CH3
CH3
N
H
R
R
- H
H
N
H
5
CF3
CF3
HO
O
HO
10
CH2
OH
R
- H
CF3
CH3
N
H
2
CH3
N
CF3
N
N
R
H
11
10'
Scheme 3
As a mechanism including concerted process as a key step, the reaction path shown in Scheme 4 is
possible. There, 1,5-sigmatropic shift of N-methyl hydrogen atom to C4 on 4’ affords intermediate (9)
directly. The cyclization of 9 as is seen in Scheme 3 leads to oxadiazine (2).
If the cyclization reaction proceeds via 1,5-sigmatropic shift, a methine hydrogen atom bound to C6 of
oxadiazines (2) is derived from N-methyl hydrogen atoms of hydrazones (1). In contrast, if the
cyclization occurs according to ionic mechanism shown in Scheme 3, the proton from acid catalyst must
be incorporated into oxadiazine (2) as the methine hydrogen atom. In order to clarify whether this

HETEROCYCLES, Vol. 65, No. 9, 2005
2143
methine hydrogen atom is derived from acid or not, we examined the cyclization reaction of hydrazone (1,
R= p-Tol) in trifluoroacetic acid-d.
The reaction was monitored by 1H NMR spectrometer.
H
H
CH3 OH
C
H
OH
4
1
4
CH3
N
CF3
CH3
N
C
R
CF3
N
N
2
3
R
4'
C
- H
2
9
Scheme 4
During the reaction, no signal assignable as the methine proton at C6 of 2 (R= p-Tol) appeared in the
spectra, and the methine hydrogen atom of obtained oxadiazine after workup was completely replaced
with a deuterium atom. Pseudo-first-order rate constant for this cyclization reaction was roughly
1
estimated as 1.9 x 10-4 s-1 by H NMR spectral measurement. These facts seem to suggest that this
cyclization reaction proceeds according to ionic manner (Path A or Path B). However, we found that
H-D exchange reaction also occurs at C6 of oxadiazines (2) in trifluoroacetic acid-d. To elucidate a
possibility of such H-D exchange reaction on 2, we examined monitoring experiments about oxadiazine
(2, R= p-Tol) in trifluoroacetic acid-d by means of 1H NMR spectroscopy. The signal intensity of methine
proton of 2 (R= p-Tol) decreased smoothly in trifluoroacetic acid-d. The pseudo-first-order rate constant
for this exchange reaction was calculated as ca. 2.0 x 10-3 s-1. This rate of H-D exchange reaction is
over 10 times higher than that of cyclization reaction from hydrazone (1, R= p-Tol) to oxadiazine (2, R=
p-Tol) described above. Such H-D exchange on 2 is thought to occur along with enamine-imine
tautomerization as is shown in Scheme 5.
From above results, it seems to be difficult to decide whether the cyclization reaction proceeds according
to ionic manner or concerted one. However it is necessary to take in account that H-D exchange
occurred neither on N-methyl nor methylene groups of deuteriooxadiazine (2’, R= p-Tol). Both Path A
and Path B in Scheme 3 contain a deprotonation process from N-methyl groups of the starting cations (4
or 4’), or dication (5). In addition, these processes need to proceed in the presence of strong acid, i.e.
trifluoroacetic acid. There should be rapid equilibrium between cations (4, 4’) and betains (8, 8’) in the

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HETEROCYCLES, Vol. 65, No. 9, 2005
case of Path A, and that between dication (5) and cation (10) in the case of Path B. These equilibriums
in the presence of trifluoroacetic acid-d should mediate rapid H-D exchange reaction at N-methyl
CH3
CF3CO2D
N
N
O
1 (R= p-Tol)
D
-4
_
~
k 1.9 x 10
CF3
R
2' (R= p-Tol)
CF3CO2D
2 (R= p-Tol)
2' (R= p-Tol)
-3
_
~
kH-D 2.0 x 10
- D+
D+
CH3
D+
CH3
CH3
D
-H+
N
O
N
N
O
N
N
O
H
D
+
+
N
CF3
D
D
CF3
CF3
p-Tol
p-Tol
p-Tol
Scheme 5
groups of the cations (4, 4’) and dication 5, and, consequently, result in complete duteration of N-methyl
1
and methylene groups of the product (2’). However H NMR spectra of the obtained product after the
monitoring experiment reveal no duteration on the N-methyl as well as methylene groups of 2’ (R= p-Tol).
These results are not compatible with ionic pathways (Path A and Path B) in Scheme 3. From these
facts, we can exclude the ionic pathways (Path A and Path B) as a mechanism for the present cyclization
reaction from hydrazones (1) to oxadiazines (2). Although it is still indefinite at this stage that the
cyclization reaction of 1 catalyzed by silica gel or acetic acid also proceeds along with the same reaction
path as that promoted by trifluoroacetic acid, the pathway including 1,5-sigmatropic shift shown in
Scheme 4 is thought to be most reasonable as a mechanism for the reaction from hydrazones (1) to
oxadiazines (2).
On the basis of RB3LYP/6-31G*, the transition state structure for the present 1,5-sigmatropic shift
process in Scheme 4 (R= H) was estimated as C illustrated in Figure 1. Except for H atom, five atoms
N1, N2, C3, C4, and C5 lie almost on the same plane in the six-membered ring transition state structure.
Dihedral angles ∠N2,C3,C4,H and ∠N2,N1,C5,H were calculated as 25.5° and –34.4°, respectively.
The distance between C4 and H was predicted to be almost equal to that between C5 and H.

HETEROCYCLES, Vol. 65, No. 9, 2005
2145
Computed energy of this transition state structure was -679.219960 a.u., and activation energy (∆E) from
4’ (R= H) to C was calculated as 38.1 Kcal/mol. Estimated rotational barrier between cations 4a and 4’
(R=H) was 19.4 Kcal/mol.
These values can be correlated with required energy for the process from
cation (4a) to intermediate (9, R= H). We also carried out the estimation of energies using RHF/6-31G*
and RMP2/6-31G* level calculations. The results are summarized in Table 1.
H
1.471Å
1.300Å
1.352Å
N1
F
C
H
N2
H
C3
F
C
1.359Å
H
C4
H
C5
F
1.391Å
1.386Å
H
O
H
C
Figure 1
The energy values more than 35 Kcal/mol seem to be too large in the case of the TFA mediating reaction
of hydrazone (1) affording oxadiazines (2), because the conversion from 1 to 2 proceeds smoothly at
room temperature. We also carried out calculations about 4 (R= Ph, Table 1). Computed activation
energies are 5 – 10 Kcal/mol lower than those for 4a. However, even in these cases, the energy values
are a little large for the reaction proceeding at room temperature.
Table 1
4
Calculation
Rotational Barrier
∆E from 4 to
from 4 to 4’ (Kcal/mol)
Transition State (Kcal/mol)
R= H
RB3LYP/6-31G*
RHF/6-31G*
19.4
13.4
15.7
38.1
53.2
35.7
(4a)
RMP2/6-31G*
R= Ph
RB3LYP/6-31G*
RHF/6-31G*
11.9
5.0
28.6
47.6
26.6
RMP2/6-31G*
9.2

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HETEROCYCLES, Vol. 65, No. 9, 2005
CH3 OH
H+
CH3
N
4
4'
CF3
N
H
R
5'
H
C H
H
H
CH2
OH
- 2H+
OH
CH3
N
N
C
CH3
N
C
R
2
CF3
CF3
N
D
H
R
H
12
Scheme 6
Taking these results in account, we focused on the possibility of second protonation on cation (4’) in the
presence of strong acid such as TFA. We calculated activation energy for 1,5-sigmatropic hydrogen
shift on dication (5’, R=Ph) affording 12 (R= Ph). Required energy from 5’ (R= Ph) to transition state D
(R= Ph) was estimated as 13.7 Kcal/mol (RHF/6-31G*) and 18.1 Kcal/mol (RB3LYP/6-31G*). These
values are consistent with the fact that the reaction from hydrazones (1) to oxadiazines (2) proceeds
even at room temperature in the presence of TFA. Thus TFA catalyzed reaction should proceed mainly
along with the second protonation assisted mechanism via 5’ as is illustrated in Scheme 6. On the other
hand, acetic acid catalyzed reaction of hydrazones (1) requires heating, and prolonged reaction time is
necessary for conversion of 1 to oxadiazines (2) under the catalysis of silica gel.3 In the presence of
such relatively week acid catalysts, the reaction is thought to proceed mainly along with the reaction path
via mono cations (4’, Scheme 4).
H
H
CH3 OH
C
H
OH
CH3
X
C
CH3
X
CZ3
CZ3
∆E
Y
Y
Ph
Ph
Entry
X
C
C
N+
N+
Y
Z
H
F
H
F
∆E (Kcal/mol)
40.9
1
2
3
4
CH
CH
37.1
N
N
30.9
28.6
Scheme 7

HETEROCYCLES, Vol. 65, No. 9, 2005
2147
It is known that rates of thermal pericyclic reactions are affected by properties as well as positions of
substituents on a substrate, and these substituent effects vary with a type of pericyclic reaction itself.7 In
Scheme 7, estimated activation energies (RB3LYP/6-31G*) about 1,5-sigmatropic hydrogen shift for
related compounds of cation (4’, R= Ph) are listed. Entry 1 is corresponding to the parent system for the
present 1,5-sigmatropic shift (Entry 4). When one methyl group of 5-methyl-2,4-hexadien-2-ol is
replaced with trifluoromethyl group (Entry 2), ∆E decreases in the rage of 3 – 4 Kcal/mol. On the other
hand, a replacement of two carbon atoms of 5-methyl-3-phenyl-2,4-hexadien-2-ol with nitrogen atoms
(Entry 3) reduces ∆E in the range of ca.10 Kcal/mol. In the case of 4’ (R= Ph, Entry 4), these two
factors reduce activation energy additively, and the lowest ∆E is resulted among these four systems in
Scheme 7.
Relatively small difference (∆∆E<3 Kcal/mol) between the cases of Entry 3 and 4 suggests that the
cyclization reaction accessible the corresponding oxadiazines may be possible for hydrazones bearing
no trifluoromethyl group if the reaction is carried out under appropriate conditions. However our all
attempts to obtain oxadiazine (15) from hydrazone (13) resulted in failure. Intermediate (19) resulted by
1,5-sigmatropic hydrogen shift on 18 (Entry 3) is calculated as 6.9 Kcal/mol less stable than 18, whereas
intermediate (9, R= Ph, Entry 4) is estimated as 5.9 Kcal/mol more stable than 4’ (R= Ph).8 This should
be one of the reasons why the conversion of 13 to the corresponding oxadiazine (15) was unsuccessful
contrary to the case of hydrazones (1). We also examined the cyclization reaction about hydrazones
(14) under several conditions. Similarly, all of these attempts were unsuccessful except for only the
following case. When 14 was treated with hot diluted acetic acid, oxadiazine (17),9 the tautomer of 16,
was obtained, though the yield was no more than 5%.
R
R
H
COR'
Ph
R
N
N
O
N
N
O
N N
CH3
R'
R'
Ph
15
16
Ph
R
R'
CH3 CH3
13
14
tert-Bu Ph
17
CH3 OH
CH2
H
OH
CH3
N
CH3
N
C
CH3
CH3
N
N
Ph
Ph
18
19

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HETEROCYCLES, Vol. 65, No. 9, 2005
CONCLUSION
In conclusion, we can present the most reasonable mechanism for the cyclization reaction from
3-dimethydrazono-1,1,1-trifluoro-2-alkanones (1) to 6-trifluoromethyl-3,6-dihydro-2H-[1,3,4]oxa- diazines
(2). Molecular orbital calculations and H-D exchange experiments suggest a concerted 1,5-sigmatropic
shift of N-methyl hydrogen to carbonyl carbon on protonated or diprotonated hydrazones to be a key step
in the overall reaction processes.
An extension of this cyclization reaction to general
α-hydrazonoketone systems is under investigation.
COMPUTATIONAL METHODS
All calculations employed in this paper were accomplished using the computer programs packages
SPARTAN and PC SPARTAN 02.10 All calculations for geometrical optimizations were performed with
the 6-31G* basis set at B3LYP11 and MP212 level. The starting geometries employed for all
optimizations were resulted from molecular mechanics using SYBYL13 force field and subsequent
semi-empirical PM314 optimizations. The calculations for energy of intermediates as well as transition
states were also taken with ab initio calculations using the 6-31G* basis set at HF and MP2 level together
with density functional B3LYP.
EXPERIMENTAL
13
1H and C NMR spectra were recorded at 60 MHz on a JEOL PMX60SI and at 59.5 MHz on a Bruker
AC250, respectively.
Monitoring Experiments for the Cyclization of 3-Dimethylhydrazono-3-(p-tolyl)-1,1,1-trifluoro-2-
propanone (1, R= p-Tol) and the H-D Exchange Reaction of 3-Methyl-5-(p-tolyl)-6-trifluoromethyl-
3,6-dihydro-2H-[1,3,4]oxadiazine (2, R= p-Tol)
To 1 (R= p-Tol) or 2 (R= p-Tol, 77.5 mg, 0.300 mmol) in φ5 NMR glass tube was added trifluoroacetic
1
acid-d (0.45 mL, 5.84 mmol). The well-mixed solution was immediately monitored at 35°C using H
NMR spectroscopy. The rate for the cyclization reaction of 1 (R= p-Tol) was measured by monitoring
the appearance of methylene protons of 2’ (R= p-Tol), and that for H-D exchange reaction of 2 (R= p-Tol)
was done by following the disappearance of methine proton of 2 (R= p-Tol). The rates were measured
in duplicate.
Preparation of 2-t-Butylmethylhydrazono-1,2-diphenylethanone (14)
To a mixture of diphenylethanedione (4.205 g, 20 mmol) and tert-BuNHNH2·HCl (3.735 g, 30 mmol)
dissolved in MeOH (200 mL) was added NaOAc (2.461 g, 30 mmol), and the mixture was stirred for 4

HETEROCYCLES, Vol. 65, No. 9, 2005
2149
days at ambient temperature. The reaction mixture was poured into saturated aq. Na2CO3 (100 mL)
and the organic layer was extracted with CH2Cl2 (2 x 100 mL). The extract was dried over Na2SO4 and
the solvent was removed in vacuo. The residue was dissolved in DMF (48.9 mL), then KOH (1.614 g,
24.5 mmol) was added, and the mixture was stirred for 30 min at 40°C. After cooling to ambient
temperature, MeI (10.2 mL, 163 mmol) was added and the mixture was stirred for 24 h. The mixture
was poured into 1N HCl (100 mL) and the organic layer was extracted with CH2Cl2 (2 x 100 mL). The
extract was washed with 1N aq. NaHCO3 (100 mL) and dried over Na2SO4. Removal of the solvent
followed by fractionation of the residual materials by silica gel column chromatography (benzene) gave
3.438 g (58%) of 14.15 Without further purification this was used in the following experiment.
Cyclization Reaction of 2-tert-Butylmethylhydrazono-1,2-diphenylethanone (14)
To 14 (320 mg, 1.1 mmol) dissolved in AcOH (2.2 mL, 38.1 mmol) was added water (0.75 mL, 41.7
mmol). After stirring for 20 h at 70°C, the mixture was poured into 0.5N aq. Na2CO3 (100 mL) and the
organic layer was extracted with CH2Cl2 (2 x 50 mL). The extract was dried over Na2SO4 and the
solvent was evaporated. Fractionation of the residual materials by preparative TLC (benzene) afforded
14 mg (5%, Rf= 0.1) of 3-tert-butyl-5,6-diphenyl- 3,4-dihydro-2H-[1,3,4]oxadiazine (17) as pale yellow
crystals, mp 97-99°C (cyclohexane): 13C NMR (CDCl3) δ 27.8 (CH3), 59.1 (CCH3), 59.3 (CH2, 1JCH= 149.6
Hz), 126.9, 127.1, 127.9, 128.0, 129.3, 129.4, 136.2, 137.0 (C6H5), 140.8 (NC=), 158.4 (OC=); 1H NMR
(CDCl3) δ 1.40 (s, 9H, tert-Bu), 4.33 (s, 2H, CH2), 6.91-7.49 (m, 11H, C6H5 and NH); IR (KBr) ν 2980 (m),
1600 (m), 1570 (m), 1440 (m), 1370 (m), 1205 (s), 1150 (s), 1040 (m), 960 (m) cm-1.
REFERENCES AND NOTES
1. Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and T. Yokoyama, Synthesis, 1988, 208.
2. Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, K. Kawasaki, and Y. Kawamura, Synthesis, 1990, 493.
3. Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and T. Yokoyama, J. Org. Chem., 1988, 53,
129; Y. Kamitori, M. Hojo, R. Masuda, T. Yoshida, S. Ohara, K. Yamada, and T. Yokoyama, J. Org.
Chem., 1988, 53, 519.
4. R. S. Mulliken, J. Chem. Phys., 1955, 23, 1833, 1841, 2338, 2343.
5. Y. Kamitori, M. Hojo, and T. Yoshioka, Heterocycles, 1998, 48, 2221.
6. On the basis of our calculations (RMP2/6-31G*), oxadiazine tautomer (9) is estimated as 15.0
Kcal/mol less stable than 2 (R= H). Such tautomer like 9 could not be detected in any experiment
we examined so far using hydrazones (1).
7. B. K. Carpenter, Tetrahedron, 1978, 34, 1877, and references cited therein.

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HETEROCYCLES, Vol. 65, No. 9, 2005
8. The difference of ∆H between the reaction from 18 to 19 and that from 4’ to 9 is thought to be mainly
owing to the instability of 4’ compared to 18. Electron-withdrawing CF3 group is directly attached to
the cation conjugate system on 4’, whereas CH3 hyperconjugation should stabilize cation (18)
effectively. The following proton exchange reaction is 8.1 Kcal/mol exothermic (RB3LYP/6-31G*//
RB3LYP/6-31G*).
CH3
CH3
Ph
Ph
CH3 N
CH3 N
4' (R= Ph)
+
+
18
N
N
COCH3
COCF3
Such substituent effects should be insignificant for intermediates 9 and 13.
9. Larger resonance energy expected in oxadiazine (17) in comparison with 16 should be the main
reason why 16 could not be isolated at all. Semi-empirical PM3 calculations suggest that 17 is
about 0.8 Kcal/mol more stable than 16.
10. Wavefunction, Inc.
11. A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
12. W. J. Hehre, L. Radom, P. v. R. Schleyer, and J. A. Pople, ‘Ab Initio Molecular Orbital Theory,’ Wiley,
Inc., New York, 1986.
13. M. Clark, R. D. CramerⅢ, and N. van Opdensch, J. Computational Chem., 1989, 10, 982.
14. J. J. P. Stewart, J. Computer Aided Molecular Design, 1992, 6, 69.
1
15. H NMR (CDCl3) δ 1.13 (s, 9H, tert-Bu), 2.45 (s, 3H, NCH3), 6.97-7.87 (m, 10H, C6H5).