Steric effects on the regioselectivity in two-step Diels-Alder reactions of 1,2,4,5-tetrazines with 2-cyclopropylidene-4,5-dihydro-1,3-dimethyl- imidazolidine

Article abstract of DOI:10.1016/S0040-4020(00)00346-X

The regioselectivity of the two-step Diels-Alder reaction of unsymmetrically substituted tetrazines 4 with 2-cyclopropylidene- imidazolidine 6 is investigated. The first reversible step of the cycloaddition affording zwitterions 7 and 8 is controlled by s

Full text of DOI:10.1016/S0040-4020(00)00346-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4213±4218
Steric Effects on the Regioselectivity in Two-Step Diels±Alder
Reactions of 1,2,4,5-Tetrazines with
2-Cyclopropylidene-4,5-dihydro-1,3-dimethyl-imidazolidine
*
Klaus-Peter Hartmann and Manfred Heuschmann
È È
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13, Haus F, D-81377 Munich, Germany
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 9 April 2000; accepted 19 April 2000
AbstractÐThe regioselectivity of the two-step Diels±Alder reaction of unsymmetrically substituted tetrazines 4 with 2-cyclopropylidene-
imidazolidine 6 is investigated. The ®rst reversible step of the cycloaddition affording zwitterions 7 and 8 is controlled by steric effects,
which are explained using a simple model. The overall regioselectivity, however, is determined in the second step of the cycloaddition or at
an even later stage. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Activation of the hydrazides 1 with phosphorus penta-
chloride in re¯uxing tetrachloromethane afforded the
hydrazidedioyl dichloride 2b or the 1,3,4-oxadiazole 3c.
Both reacted smoothly with hydrazine hydrate to yield
dihydrotetrazines 5, which were oxidized by nitrous gases
to the tetrazines 4 (Scheme 1).
3,6-Diphenyl-1,2,4,5-tetrazine (4a) reacts rapidly at
room temperature with 2-cyclopropylidene-1,3-dimethyl-
imidazolidine (6) to give a dispiro adduct 11a which is
formed via [412]-cycloaddition and consecutive elimina-
tion of nitrogen in accordance with a generally accepted
mechanism.1,2 The high reactivity of the dienophile3 in
inverse electron demand Diels±Alder reactions4 allows the
addition to be performed at low temperatures and thus a
zwitterion 7a can be isolated as an intermediate. This
seems to be an ideal system to investigate steric and elec-
tronic effects and to separate their implication on both steps
of the [412]-cycloaddition. We report here on steric effects
in¯uencing the regioselectivity of two-step Diels±Alder
reactions with unsymmetrically substituted 1,2,4,5-tetra-
zines.
On addition of 2-cyclopropylidene-imidazolidine 6 to the
tolyl-tetrazine 4b below 2108C in tetrahydrofuran the violet
Results
We selected diaryl substituted 1,2,4,5-tetrazines as dieno-
philes to get similar electronic in¯uences and to avoid alkyl
groups at the tetrazines, because the high basicity of 65 is
suf®cient to deprotonate methyl groups in triazines and
opens the route to competing reaction paths.6 Thus the
2-methylphenyl- and the 2,4,6-trimethylphenyl-tetrazines
4b and 4c were prepared from diacylhydrazides 1 according
Â
to a procedure developed by Stolle.
7
Keywords: Diels±Alder reactions; ketene acetals; regiochemistry; zwitter-
ions.
* Corresponding author. Tel.: 149-89-2180-7735; fax: 149-89-2180-
7640; e-mail: mhh@cup.uni-muenchen.de
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00346-X

4214
K.-P. Hartmann, M. Heuschmann / Tetrahedron 56 (2000) 4213±4218
red color vanished after 1 h and an orange±yellow precipi-
tate was formed. At 2788C this reaction was complete after
6 h. The precipitate was isolated below 2208C, dissolved in
[D2]dichloromethane and characterized as a mixture of
zwitterions 7b and 8b (33:67). As 7b and 8b were far better
soluble than the parent 7a (ˆ8a)1 it was possible for the ®rst
time to get NMR data of such zwitterions. The structure
assignment of the 2,3-dihydrotetrazinide8 and 4,5-dihydro-
imidazolium moiety1,5 is quite straightforward by compari-
son with literature data. However, the distinction between
the two regioisomers was not quite trivial. A combination of
carbon atoms to be identi®ed together with their connectivi-
ties and thus the structures of 7b and 8b were unambigu-
ously assigned. Interestingly, the apparently more congested
zwitterion 7b shows separate signals for both the N-methyl
and N-methylene groups. This might be caused by restricted
rotation of the two single bonds connecting the imidazole
and tetrazine rings.
When the solution of the zwitterions 7b and 8b (33:67) was
allowed to warm slowly, gas evolution was monitored
around 08C. NMR spectra at intermediate times showed
that the signals of 7b decreased faster than those of 8b.
After reaching room temperature, both isomers had dis-
appeared. But in the resulting mixture only dispiro adduct
11b (56%) could be identi®ed besides 44% of tetrazine 4b.
If the zwitterions 7b and 8b (33:67) were warmed up in
tetrahydrofuran, nearly quantitative formation of 11b was
determined spectroscopically. Likewise, if the reaction of
tetrazine 4b with 2-cyclopropylidene-imidazolidine 6 was
performed at room temperature in tetrahydrofuran, nitrogen
evolution ceased after a few minutes and 84% of isomer 11b
could be isolated after recrystallization. The structure
assignment again was based on intensive NMR studies
such as above. In this case, however, the reliability of this
method was proven by X-ray analysis9 of 11b (Scheme 2).
1
high resolution H, 13C, HETCOR and COLOCS NMR
spectra ®nally allowed the signals of all hydrogen and
When 2-cyclopropylidene-imidazolidine 6 was added to the
mesityl-tetrazine 4c at temperatures below 2108C, again a
yellow solid was formed. Isolation and NMR spectroscopic
identi®cation in [D2]dichloromethane showed that only one
regioisomeric zwitterion 8c had been formed. Warming of
this zwitterion to room temperature did not lead to a gas
evolution, no traces of dispiro compounds 11c or 12c could
be identi®ed. After prolonged heating the zwitterion decom-
posed to the starting mesityl-tetrazine 4c and reaction
products of 2-cyclopropylidene-imidazolidine 6 with the
solvent. The same behavior was observed in tetrahydrofuran
and benzene.
Figure 1.
Scheme 2.
Figure 2.

K.-P. Hartmann, M. Heuschmann / Tetrahedron 56 (2000) 4213±4218
4215
Discussion
Indeed the predicted ratios of 1:2 or 0:2 are exactly repro-
duced by the 7b:8b (33:67) and 7c:8c ratios (0:100), respec-
tively. It is not necessary to consider the small electronic
effect of the methyl group, because even strong donor-
substituents such as dimethylamino or methoxy and/or
acceptor-substituents in para- or para±para0-position of
the phenyl rings in 4 did not in¯uence the regioselectivity
of zwitterions or cycloaddition products markedly.11
In principle four directions of attack at the 3- and 6-position
of tetrazines 4 are possible (Fig. 1). In the diphenyl deriva-
tive 4a the four additions should occur with the same prob-
ability leading to a 50:50 distribution of C-3 and C-6 attack
which cannot be proven experimentally, as 7a and 8a are
identical as well as 11a and 12a. A simple model may
explain the selectivities found for the unsymmetrically
substituted tetrazines 4b and 4c. The neighboring rings of
the tetrazines 4 are probably not coplanar but rather perpen-
dicular on the time average. This is corroborated by AM1
calculations.10 The experimental results comply with the
assumption, that a methyl group in 2- or 6-position of the
aryl ring will completely prevent nucleophilic attack at the
adjacent carbon from the same side of the tetrazine ring.
On heating, the minor tolyl zwitterion 7b is converted to the
dispiro adduct 11b. However, the yield of 11b was clearly
higher in all cases than the maximum of 33% that could be
expected from direct ring closure of 7b and although the
major regioisomeric zwitterion 8b also disappeared from
the reaction mixture, the expected regioisomeric dispiro
adduct 12b was not observed. Thus, 7b and 8b must both
Table 1. AM1 calculated relative energies (kcal mol21) for the intermediates and transition states of the cycloaddition reactions of 4 with 6
11
TS5
9
TS3
7
TS1
416
TS2
8
TS4
10
TS6
12
a
b
c
240.2
240.6
238.7
44.7
46.7
55.5
23.0
25.6
31.8
27.2
35.4
39.9
17.6
21.1
27.4
28.7
34.8
43.6
0
0
0
28.7
33.2
39.8
17.6
18.6
19.4
27.2
35.3
46.7
23.0
29.0
38.6
44.7
51.2
65.8
240.2
237.7
236.0
Figure 3. Structures of transition states and intermediates for the cycloaddition of 4a and 6 with selected distances in pm, as calculated by AM1.

4216
K.-P. Hartmann, M. Heuschmann / Tetrahedron 56 (2000) 4213±4218
be precursors for 11b. The only reasonable explanation
demands that the zwitterion 8b splits up to the starting
materials 4b and 6, which recombine to give a mixture of
7b and 8b again. While 8b is caught in a dead end equi-
librium, 7b is gradually converted to 11b as the only
product. The reason for this behavior again must clearly
be a steric effect. To achieve ring closure, the imidazolium
ring and the aryl or phenyl ring must be nearly coplanar.
This is easily achieved with the phenyl ring in 7b, while the
methyl group in 8b disfavors this conformation (Fig. 2).
MAT 90. Semiempirical AM1 calculations were carried out
by using the amsol12 program package. Transition states
were localized using the POWELL algorithm.12
N-Benzoyl-N0-(2,4,6-trimethylbenzoyl)hydrazide (1c).
2,4,6-Trimethylbenzoyl chloride (5.88 g 32.2 mmol) was
added dropwise to a solution of benzoyl hydrazide
(4.39 g, 32.2 mmol) in 20.1 g pyridine. The mixture was
stirred overnight and poured on 150 mL ice water. The
precipitate was collected, washed with water and recrystal-
lized from methanol/ethanol to yield 4.55 g (50%) colorless
needles with mp 2058C. 1H NMR (CD3OD, 400 MHz): 2.23
(s, 4-Me); 2.40 (2/6-Me); 7.27 (3/5-H, Ar); 7.46 (3/5-H,
4-H, Ph); 7.89 (2/6-H, Ph). 13C NMR (CD3OD, 100 MHz):
19.4 (2/6-Me); 21.2 (4-Me); 128.7 (C-3/5, Ph); 129.1 (C-3/
5, Ar); 129.6 (C-2/6, Ph); 133.2 (C-4, Ph); 133.7 (C-1, Ar);
133.9 (C-1, Ph); 136.3 (C-2/6, Ar); 140.3 (C-4, Ar); 169.2
(CvO, Ph); 172.5 (CvO , Ar). MS (2208C) m/zˆ282 M1,
2%). Anal. Calcd for C17H18N2O2 (282.3): C, 72.32; H, 6.43;
N, 9.92. Found: C, 72.07; H, 6.35; N, 10.09.
The reactivity of 8c is consistent with this picture. The
mesityl ring prevents the ring closure to 12c. 8c Also splits
up to the educts 4c and 6 in equilibrium. In this case,
however, nucleophilic attack to give the regioisomeric
zwitterion 7c and ring closure to 11c is no feasible alterna-
tive and thus the highly reactive 2-cyclopropylidene-1,3-
dimethyl-imidazolidine 6 slowly decomposes, e.g. by
reaction with the solvent and the mesityl tetrazine 4c
accumulates.
But an alternative explanation for the regioselectivities of
the overall reaction might be envisaged. The highest transi-
tion states on the way to the ®nal products 11 or 12 do not
necessarily have to be the ring closures. These could be
reversible, low energy steps while the real obstacles are
the [412]-cycloreversions with loss of nitrogen. There is
no way to address this problem experimentally. Semi-
empirical calculations (AM110) seem to support this second
hypothesis (Table 1, Fig. 3). But these calculations are not
very reliable, as they ®nd the relative energies of the
zwitterions too high by at least 20 kcal mol21, suggesting
that they should not be isolable in these reactions at all. This
weakness, which is probably due to the fact that the gas
phase is much less favorable for zwitterions than a
condensed phase, cannot be overcome by using solvent
models.12 But as it is probable that mainly the zwitterions
and the surrounding transition states will be lowered in
energy by solvation, the cycloreversion might really have
the highest transition state in the whole reaction sequence.
At any rate, the relative heights of the calculated barriers are
compatible with the experimental selectivities for zwitter-
ions (TS1 vs. TS2) and ®nal products (TS3b vs. TS4b or
TS5b vs. TS6b).
N-[1-Chloro-1-(2-methylphenyl)methylene]-N0-(1-chloro-
1-phenylmethylene)-hydrazine (2b) 1b.13 (20.0 g,
78.7 mmol) and PCl5 (87.6 g, 420 mmol) in 130 mL CCl4
were heated to re¯ux until the gas evolution had stopped
(2 h). The mixture was poured on ice water and extracted
with ether (4£50 mL). The combined organic phases were
washed with water, until it had pH 7, dried over MgSO4 and
evaporated. The resulting yellow oil (22.0 g, 96%) was used
1
without further puri®cation for the next step. H NMR
(CDCl3, 80 MHz): 2.61 (s, Me); 7.0±7.5 (m, 3/5-H, 4-H,
Ph; 3/5-H, 4-H, Ar); 7.67 (6-H, Ar); 8.00 (2/6-H, Ph). 13C
NMR (CDCl3, 20.2 MHz): 21.4 (Me); 125.8 (C-5, Ar);
128.3 (C-2/6, Ph); 128.3 (C-3/5, Ph); 129.9 (C-3, Ar);
130.5 (C-6, Ar); 131.2 (C-4, Ar); 131.7 (C-4, Ph); 133.5
(C-1, Ph); 134.2 (C-1, Ar); 137.5 (C-2, Ar); 143.2 (CCl);
143.5 (CCl). UV (CCl4): lmaxˆ272 (log eˆ3.511). MS: m/z
294 (M1, 4%).
2-Phenyl-5-(2,4,6-trimethylphenyl) 1,3,4-oxadiazole (3c)
1c. (12.5 g, 44.4 mmol) and PCl5 (52.1 g, 250 mmol) in
70 mL CCl4 were heated to re¯ux until the gas evolution
had stopped (2 h). The mixture was poured on ice water and
extracted with ether (4£30 mL). The combined organic
phases were washed with water, until it had pH 7, dried
over MgSO4 and evaporated. The residue was recrystallized
from CH3CN to yield 6.44 g (55%) of a colorless solid with
Though we do not know what exactly the rate and product
determining step is, it is absolutely clear that the ®nal
product ratios are not controlled by the preferred site of
nucleophilic attack but rather in a later step. These results
might help to understand other Diels±Alder reactions of
ketene acetals with tetrazines and triazines,2 where inter-
mediates cannot be isolated, but may well be short-lived
intermediates.
1
mp 91±928C. H NMR (CDCl3, 400 MHz): 2.31 (s, 2/6-
Me); 2.34 (s, 4-Me); 6.97 (s, 3/5-H, Ar); 7.52 (3/5-H, 4-H,
Ph); 8.10 (2/6-H, Ph). 13C NMR (CDCl3, 100 MHz): 20.5
(2/6-Me); 21.3 (4-Me); 121.1 (C-1, Ar); 124.1 (C-1, Ph);
128.9 (C-2/6, Ph); 128.9 (C-3/5, Ph); 128.9 (C-3/5, Ar);
131.7 (C-4, Ph); 138.8 (C-2/6, Ar); 141.0 (C-4, Ar); 163.9
(C-2); 164.8 (C-5). MS: m/z 264 (M1, 100%). Anal. Calcd
for C17H16N2O (264.3): C, 77.23; H, 6.10; N, 10.61. Found:
C, 76.90; H, 6.10; N, 9.73.
Experimental
1,2-Dihydro-3-(2-methylphenyl)-6-phenyltetrazine (5b).
To a solution of dichloride 2b (21.5 g, 73.8 mmol) in
350 ml acetonitrile absolute hydrazine hydrate (3.70 g,
74.0 mmol) was added dropwise and the mixture was stirred
for 1 h at 40±508C. The yellow precipitate was collected by
®ltration, washed with acetonitrile (3£20 mL) and degassed
General
All cycloaddition reactions were performed in oven-dried
glassware with dry solvents under argon. NMR spectra:
Varian VXR 400S or Bruker WP 80. UV spectra: Perkin±
Elmer Lambda-3 and Zeiss PMQ II. MS spectra: Finnigan

K.-P. Hartmann, M. Heuschmann / Tetrahedron 56 (2000) 4213±4218
4217
water (20 mL). Drying in vacuo yielded 13.5 g (73%) of
analytically clean 5b as orange crystals with mp 204±
(C-2/6, Ar); 140.2 (C-4, Ar); 163.1 (C-3); 168.2 (C-6).
UV/VIS (CHCl3): lmaxˆ548 (log eˆ3.919), 2.76 (3.539).
Anal. Calcd for C17H16N4 (276.3): C, 73.89; H, 5.79; N,
20.08. Found: C, 73.56; H, 5.77; N, 20.27.
1
2058C. H NMR (CD3OD, 400 MHz): 2.48 (s, Me); 7.25
(5-H, Ar); 7.27 (3-H, Ar); 7.35 (4-H, Ar); 7.45 (3/5-H,
4-H, Ph); 7.68 (2/6-H, Ph); 7.69 (6-H, Ar). 13C NMR
(CD3OD, 100 MHz): 19.8 (Me); 126.1 (C-3/5, Ph); 126.2
(C-5, Ar); 128.9 (C-2/6, Ph); 128.9 (C-6, Ar); 130.1 (C-4,
Ar); 130.2 (C-1, Ar); 130.7 (C-1, Ph); 130.7 (C-3, Ar); 131.0
(C-4, Ph); 137.0 (C-2, Ar); 148.6 (C-6); 149.9 (C-3). UV
(CH3CN): lmaxˆ335 (log eˆ3.972). Anal. Calcd for
C15H14N4 (250.3): C, 71.98; H, 5.63; N, 22.38. Found: C,
72.05; H, 5.64; N, 22.18.
2,3-Dihydro-3,6-diphenyl-3-[1-(4,5-dihydro-1,3-dimethyl-
2-imidazolio)cyclopropyl]-1,2,4,5-tetrazinide (7a).1 To a
suspension of red tetrazine 4a (550 mg, 2.35 mmol) in
20 mL toluene at 2308C 2 (400 mg, 2.89 mmol) was
added dropwise. After 3 h at 2158C the color of the pre-
cipitate had changed to orange. The yellow solid was
collected in a cooled glass ®lter, washed with toluene and
dried for two days in vacuo at 2208C to yield 780 mg (86%)
7a.
1,2-Dihydro-3-phenyl-6-(2,4,6-trimethylphenyl)tetrazine
(5c). To a solution of oxadiazole 3c (6.41 g, 24.3 mmol) in
125 ml acetonitrile absolute hydrazine hydrate (1.22 g,
24.4 mmol) was added dropwise and the mixture was stirred
for 1 h at 40±508C. The yellow precipitate was collected by
®ltration, washed with acetonitrile (3£20 mL) and degassed
water (20 mL). Drying in vacuo yielded 4.33 g (64%) of
analytically clean 5c as orange crystals with mp 2208C.
1H NMR (CD3OD, 400 MHz): 2.30 (s, 4-Me); 2.32 (s,
2/6-Me); 6.90 (3/5-H, Ar); 7.44 (3/5-H, 4-H, Ph); 7.67
(2/6-H, Ph). 13C NMR (CD3OD, 100 MHz): 19.4 (2/6-
Me); 21.2 (4-Me); 126.1 (C-3/5, Ph); 128.5 (C-3/5, Ar);
128.9 (C-2/6, Ph); 129.1 (C-1, Ar); 130.4 (C-1, Ph); 130.6
(C-4, Ph); 137.4 (C-2/6, Ar);139.5 (C-4, Ar); 148.4 (C-3);
149.4 (C-6). UV (CH3CN): lmaxˆ340 (log eˆ3.715). Anal.
Calcd for C17H18N4 (278.4): C, 73.35; H, 6.52; N, 20.13.
Found: C, 73.10; H, 6.02; N, 20.06.
2,3-Dihydro-3-(2-methylphenyl)-6-phenyl-3-[1-(4,5-di-
hydro-1,3-dimethyl-2-imidazolio)cyclopropyl]-1,2,4,5-
tetrazinide (7b) and 2,3-dihydro-6-(2-methylphenyl)-3-
phenyl-3-[1-(4,5-dihydro-1,3-dimethyl-2-imidazolio)cyclo-
propyl]-1,2,4,5-tetrazinide (8b). To a solution of tetrazine
4b (693 mg, 2.79 mmol) in 30 mL THF at 2108C a
precooled solution of 6 (404 mg, 2.93 mmol) in 5 mL
THF was added slowly. After the color had changed to
orange, the yellow solid (1.02 g, 95%) was collected in a
cooled glass ®lter, washed with pentane and dried in vacuo
at 2208C. A solution of this solid in CD2Cl2 was prepared at
2508C and characterized by NMR spectroscopy as a
mixture of 7b and 8b (33:67). 1H NMR (CD2Cl2,
400 MHz, 2508C): 7b: 0.92 (mc, 2H, cPr); 1.32 (mc, 2H,
cPr); 2.44 (Me, Ar); 3.16 (s, N±Me); 3.26 (s, N±Me); 3.58
(mc, N±CH2); 3.74 (mc, N±CH2); 6.85 (5-H, Ar); 6.90 (3-H,
Ar); 6.99 (4-H, Ar); 6.99 (4-H, Ph); 7.14 (3/5-H, Ph); 7.43
(6-H, Ar); 7.53 (2/6-H, Ph). 8b: 0.92 (mc, 2H, cPr); 1.54 (mc,
2H, cPr); 1.75 (Me, Ar); 3.14 (s, 2N±Me); 3.61 (mc, 2N±
CH2); 6.94 (3-H, Ar); 6.94 (5-H, Ar); 7.04 (4-H, Ar); 7.09
(3/5-H, Ph); 7.13 (4-H, Ph); 7.35 (2/6-H, Ph); 7.88 (6-H,
Ar). 13C NMR (CD2Cl2, 100 MHz, 2508C): 7b: 10.1
(2CH2, cPr); 22.5 (cPr); 24.5 (Me, Ar); 35.4 (N±Me); 35.8
(N±Me); 49.60 (N±CH2); 49.7 (N±CH2); 87.0 (C-3, tetra-
zinide); 122.0 (C-2/6, Ph); 124.2 (C-3, Ar); 125.1 (C-4, Ph);
127.5 (C-4, Ar); 128.2 (C-3/5, Ph); 130.1 (C-6, Ar); 131.3
(C-3-Ar); 136.8 (C-1, Ar); 136.9 (C-1, Ph); 139.9 (C-2, Ar);
157.6 (C-6, tetrazinide); 168.4 (C-2, imidazolium). 8b: 10.4
(2CH2, cPr); 21.1 (Me, Ar); 23.4 (cPr); 35.3 (2N±Me);
49.61 (2N±CH2); 84.5 (C-3, tetrazinide); 124.8 (C-6, Ar);
125.40 (C-5, Ar); 127.1 (C-3/5, Ph); 125.43 (C-4, Ar); 128.1
(C-4, Ph); 129.0 (C-2/6, Ph); 130.9 (C-3, Ar); 134.3 (C-2,
Ar); 136.0 (C-1, Ar); 139.6 (C-1, Ph); 157.7 (C-6, tetra-
zinide); 168.8 (C-2, imidazolium).
3-(2-Methylphenyl)-6-phenyltetrazine (4b). A 6 N solu-
tion of NaNO2 in water (25 mL, 150 mmol) was added drop-
wise to 18 mL of conc. HCl (ca. 180 mmol). The resulting
nitrous gases were bubbled through a suspension of 5b
(3.90 g, 15.4 mmol) in 15 mL of CH2Cl2 cooled to 08C.
After 0.5 h the solvent was evaporated and the residue
recrystallized from methanol/ethanol to give 3.30 g (85%)
1
of 4b as violet±red needles with mp 93±948C. H NMR
(CDCl3, 400 MHz): 2.70 (s, Me); 7.38±7.46 (m, 4/5-H,
Ar), 7.50 (4-H, Ph); 7.58±7.67 (m, 3/5-H, Ph; 3-H, Ar);
8.17 (6-H, Ar); 8.67 (2/6-H, Ph). 13C NMR (CDCl3, 20.2
MHz): 21.6 (Me); 126.5 (C-5, Ar); 128.1 (C-3/5, Ph); 129.2
(C-2/6, Ph); 130.9 (C-3, Ar); 131.3 (C-1, Ph); 131.4 (C-6,
Ar); 131.6 (C-1, Ar); 132.0 (C-4, Ar); 132.6 (C-4, Ph); 138.7
(C-4, Ar); 162.7 (C-6); 166.9 (C-3). UV/VIS (CHCl3):
lmaxˆ545 (log eˆ3.073), 288 (3.683). Anal. Calcd for
C15H12N4 (248.3): C, 72.56; H, 4.87; N, 22.57. Found: C,
72.82; H, 4.93; N, 22.29.
3-Phenyl-6-(2,4,6-trimethylphenyl)tetrazine (4c). A 6 N
solution of NaNO2 in water (25 mL, 150 mmol) was
added dropwise to 18 mL of conc. HCl (ca. 180 mmol).
The resulting nitrous gases were bubbled through a suspen-
sion of 5c (4.33 g, 15.6 mmol) in 15 mL of CH2Cl2 cooled to
08C. After 20 min the solvent was evaporated and the resi-
due recrystallized from methanol/ethanol to give 3.35 g
2,3-Dihydro-3-phenyl-6-(2,4,6-trimethylphenyl)-3-[1-(4,5-
dihydro-1,3-dimethyl-2-imidazolio)cyclopropyl]-1,2,4,5-
tetrazinide (8c). To a solution of tetrazine 4c (304 mg,
1.10 mmol) in 10 mL THF at 2108C a precooled solution
of 6 (176 mg, 1.27 mmol) was added slowly. After the color
had changed to orange, the solvent was evaporated and the
remaining yellow solid (437 mg, 96%) dried in vacuo at
2208C. A solution of this solid in CD2Cl2 was prepared at
1
(78%) of 4c as violet±red needles with mp 98±998C. H
1
NMR (CDCl3, 400 MHz): 2.17 (2/6-Me); 2.38 (4-Me);
7.00 (3/5-H, Ar); 7.58 (3/5-H, 4-H, Ph); 8.63 (2/6-H, Ph).
13C NMR (CDCl3, 100 MHz): 20.2 (2/6-Me); 21.3 (4-Me);
128.2 (C-3/5, Ph); 129.0 (C-3/5, Ar); 129.3 (C-2/6, Ph);
130.0 (C-1, Ph); 131.8 (C-1 Ar); 132.8 (C-4, Ph); 137.2
2508C and characterized by NMR spectroscopy as 8c. H
NMR (CD2Cl2, 400 MHz, 2508C): 0.95 (mc, 2H, cPr); 1.74
(mc, 2H, cPr); 1.51 (2/6-Me, Ar); 2.20 (4-Me, Ar); 3.06 (s,
2N±Me); 3.70 (mc, N±CH2); 3.83 (mc, N±CH2); 6.71 (3/5-
H, Ar); 7.10±7.22 (3/4/5-H, Ph); 7.44 (2/6-H, Ph). 13C NMR

4218
K.-P. Hartmann, M. Heuschmann / Tetrahedron 56 (2000) 4213±4218
(CD2Cl2, 100 MHz, 2508C): 11.2 (2CH2, cPr); 20.1 (2/6-
Me, Ar); 21.1 (4-Me, Ar); 23.8 (cPr); 35.2 (2N-Me); 49.7
(2N-CH2); 81.0 (C-3, tetrazine); 127.6 (C-3/5, Ph); 128.5
(C-4, Ph); 128.1 (C-3/5, Ar); 128.9 (C-2/6, Ph); 133.6 (C-4,
Ar); 136.5 (C-1, Ar); 138.1 (C-2/6, Ar); 141.1 (C-1, Ph);
155.1 (C-6, tetrazinide); 168.5 (C-2, imidazolium).
Acknowledgements
We are indebted to Dr Kurt Polborn for the X-ray analysis9
of 11b. We thank the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie for ®nancial
support.
5,8-Dimethyl-9,12-diphenyl-5,8,10,11-tetraazadispiro-
[2.0.4.4]dodeca-9,11-diene (11a).1 To 4a (431 mg,
1.84 mmol) in 20 mL toluene 6 (307 mg, 2.22 mmol) was
added at room temperature. The rapid gas evolution (44 mL,
1.96 mmol) ceased after a few minutes, the red color of the
mixture had changed to yellow. The precipitate was
collected by ®ltration, washed with toluene and recrystal-
lized from ethanol/ethyl acetate to yield 515 mg (79%)
yellow crystals with mp 186±1878C. UV (CHCl3):
lmaxˆ245 (log eˆ4.113). MS: m/z 344 (M1, 100%).
Anal. Calcd for C22H24N4 (358.5): C, 76.71; H, 7.02; N,
16.27. Found: C, 75.95; H, 6.98; N, 16.30.
References
1. Hartmann, K.-P.; Heuschmann, M. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1267±1268.
2. Sauer, J. 1,2,4,5-Tetrazines. In: Comprehensive Heterocyclic
Chemistry II; Boulton, A. J., Ed.; Elsevier: Amsterdam, 1996;
Vol. 6; pp 901±955. Boger, D. L. Chem. Rev. 1986, 89, 781±
793; Tetrahedron 1983, 39, 2869±2939.
3. Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28,
6027±6030.
4. Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19,
779±814. Sustmann, R. Pure Appl. Chem. 1974, 40, 569±593.
5. Gruseck, U.; Heuschmann, M. Chem. Ber. 1987, 120, 2053±
2064.
5,8-Dimethyl-12-(2-methylphenyl)-9-phenyl-5,8,10,11-
tetraazadispiro[2.0.4.4]dodeca-9,11-diene (11b). To a
deep red solution of 4b (816 mg, 3.29 mmol) in 3 mL
THF, 6 (473 mg, 3.42 mmol) was added at room tempera-
ture. The rapid gas evolution (71 mL, 3.17 mmol) ceased
after a few minutes, the red color had changed to yellow.
The solvent was evaporated and the residue recrystallized
from ethyl acetate to yield 991 mg (84%) yellow crystals
6. Ernd, M. Ph.D Thesis, Ludwig-Maximilians-University,
Munich, 1998.
Â
7. Stolle, R. J. Prakt. Chem. 1906, 73, 277±300.
8. Counotte-Potman, A.; van der Plas, H. C.; van Veldhuizen, B.
J. Org. Chem. 1981, 46, 3805±3810.
9. Crystallographic data, including atomic coordinates, bond
lengths and angles have been deposited at the Cambridge Crystal-
lographic Data Centre.
1
with mp 172±1738C. H NMR (CD2Cl2, 400 MHz): 1.25
(mc, 4H, cPr); 2.00 (s, N±Me); 2.36 (s, Me, Ar); 2.60 (s,
N±Me); 3.00 (mc, 2N±CH2); 7.25 (5-H, Ar); 7.27 (3-H, Ar);
7.30 (6-H, Ar); 7.33 (4-H, Ar); 7.39 (3/5-H, Ph); 7.42 (4-H,
Ph); 7.88 (2/6-H, Ph). 13C NMR (CD2Cl2, 100 MHz): 10.8
(C-1/2); 19.8 (Me, Ar); 22.5 (C-3); 36.5 (2N±Me); 52.5
(C-6/7); 75.8 (C-4); 125.2 (C-5, Ar); 127.9 (C-3/5, Ph);
128.7 (C-6, Ar); 129.1 (C-4, Ph); 129.7 (C-2/6, Ph); 130.0
(C-4, Ar); 130.9 (C-3, Ar); 134.8 (C-1, Ar); 136.8 (C-2, Ar);
140.8 (C-1, Ph); 160.9 (C-9); 169.2 (C-12). UV (CH3CN):
lmaxˆ295 (log eˆ5.256). Anal. Calcd for C23H26N4
(358.5): C, 77.06; H, 7.20; N, 15.63. Found: C, 77.07; H,
7.31; N, 15.77.
10. Dewar, M. J. S.; Zoebisch, E. G.; Hearly, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902.
11. Hartmann, K.-P. Ph.D Thesis, Ludwig-Maximilians-
University, Munich, 1995.
12. Cramer, C. J.; Hawkins, G. D.; Lynch, G. C.; Giesen, D. J.;
Rossi, I.; Storer, J. W.; Truhlar, D. G.; Liotard, D. A. amsol
version 5.0, Quantum Chemistry Program Exchange Program
606, based in part on ampac version 2.1 by Liotard, D. A.;
Healy, E. F.; Ruiz, J. M.; Dewar, M. J. S.
13. Harris, R. L. N.; Huppatz, J. L. Aust. J. Chem. 1977, 30,
2225±2240.