Study of the formation and thermal decomposition of an azo-bridged tricyclic ring system

Article abstract of DOI:10.1002/ejoc.200600058

1-Amino-2-methyl-1,3-pentadienes were treated with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to give diazatricyclo[2.2.2.0]octenes and dimethyl 4-methylpyridazine-3,6-dicarboxylate, the product distribution being largely dependent on the nature of the amino substituent. Under similar conditions the analogous 1-morpholino-1,3-butadiene afforded dimethyl pyridazine-3,6-dicarboxylate as the major product. The tricyclic products underwent selective thermal decomposition to give dimethyl 4-methylpyridazine-3, 6-dicarboxylate in excellent yield. The proposed mechanism of the formation as well as of the decomposition was supported by quantum chemical calculations and experimental evidence. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600058

FULL PAPER
DOI: 10.1002/ejoc.200600058
Study of the Formation and Thermal Decomposition of an Azo-Bridged
Tricyclic Ring System
[a]
[a][‡]
[b]
[a]
Zoltán Novák, Zoltán Vincze,
Zsuzsanna Czégény, Gábor Magyarfalvi,
[c]
[a]
David M. Smith, and András Kotschy*
Dedicated to Prof. Douglas Lloyd on the occasion of his 85th birthday
Keywords: Cycloadditions / Nitrogen heterocycles / Retro reactions / Molecular modelling
1-Amino-2-methyl-1,3-pentadienes were treated with di-
decomposition to give dimethyl 4-methylpyridazine-3,6-di-
methyl 1,2,4,5-tetrazine-3,6-dicarboxylate to give diazatricy- carboxylate in excellent yield. The proposed mechanism of
clo[2.2.2.0]octenes and dimethyl 4-methylpyridazine-3,6-di-
carboxylate, the product distribution being largely depend-
ent on the nature of the amino substituent. Under similar
conditions the analogous 1-morpholino-1,3-butadiene af-
forded dimethyl pyridazine-3,6-dicarboxylate as the major
product. The tricyclic products underwent selective thermal
the formation as well as of the decomposition was supported
by quantum chemical calculations and experimental evi-
dence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
vinyl)pyridazines
3
in moderate to good yields
The analogous 2-methyl-dienamines (1, RЈЈ
CH ), on the other hand, reacted with two equivalents of
[
7,8]
(Scheme 1).
1,2,4,5-Tetrazines have received considerable attention in
=
3
[1]
fields as diverse as natural product synthesis, plant protec-
tetrazine 2, through the probable formation of intermediate
, and the pyridazine derivatives 5 and 6 were formed in
tion or the synthesis of liquid crystals.[3] The inherent re-
activity of the six-membered ring system also makes tetra-
zines useful reagents for the preparation of other heterocy-
[2]
4
[9]
equimolar amounts. Intriguingly, when a 1-amino-2-
methyl-1,3-pentadiene (1, RЈ = RЈЈ = CH ) was treated with
the tetrazine diester 2 the azo-bridged tricycle 7 was ob-
tained in good yield and with excellent diastereoselectiv-
ity. The structure of the product, which was confirmed by
X-ray analysis, suggests that the reaction proceeds via a
domino “inverse electron-demand” Diels–Alder reaction.
The first reaction takes place at the sterically less hindered
disubstituted double bond
3
cles such as pyridazines[ and pyrroles. Probably the most
characteristic transformation of tetrazines is their participa-
tion in “inverse electron-demand” Diels–Alder reactions
with electron-rich olefins,[ where minor steric differences
may lead to a dramatic change in the regioselectivity of the
cycloaddition. 4-Amino-1-hetaryl-1,3-butadienes (1, RЈ =
azolyl or azinyl, RЈЈ = H), for example, were found to react
with dimethyl tetrazine-3,6-dicarboxylate (2) selectively at
the double bond next to the amine moiety to give (hetaryl-
4]
[5]
[10]
6]
[11]
[12]
as before, giving 4, and this
then undergoes another intramolecular “inverse electron-
demand” Diels–Alder reaction, or alternatively reacts with
another molecule of 2, as previously reported for 1-amino-
[
8]
[
[
a] Institute of Chemistry, Eötvös Loránd University,
Pázmány P. s. 1/A, 1117 Budapest, Hungary
Fax: +36-1-209-0602
4-hetaryl-2-methyl-1,3-butadienes.
E-mail: kotschy@chem.elte.hu
b] Chemical Research Center, Institute of Materials and Environ- Results and Discussion
mental Chemistry, Hungarian Academy of Sciences,
P. O. Box 17, 1525 Budapest, Hungary
The unique structure of the ring system 7, and its poten-
Fax: +36-1-325-7892
tial use as a precursor in the synthesis of cage com-
E-mail: czegeny@chemres.hu
[
13]
[
c] School of Chemistry, University of St Andrews,
The Purdie Building, St Andrews, Fife KY16 9ST, Scotland,
United Kingdom
pounds, prompted us to study the scope and limitations
of the reaction leading to its formation. A series of amino-
substituted 2-methyl-1,3-pentadienes (8a–d) was prepared
in moderate to good yield from 2-methyl-2-pentenal and
the appropriate secondary amine in the presence of a min-
Fax: +44-1334-463808
E-mail: dms@st-andrews.ac.uk
‡] Present address: Department of Chemistry, Faculty of Veteri-
nary Sciences, Szent István University, István u. 2., 1078 Buda-
pest, Hungary
[
[
14]
eral clay using microwave irradiation.
The dienamines
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Formation and Thermolysis of an Azo-Bridged Tricyclic Ring System
FULL PAPER
Scheme 1. Alternative reactions of dienamines with the tetrazine diester 2.
8
a–d were added to the tetrazine diester 2 in acetonitrile at Table 1. Product distribution (%) of the reaction of dienamines 6a–
d with the tetrazine diester 2 (determined by NMR spectroscopy).
room temperature and a fast reaction took place, evidenced
by the evolution of nitrogen gas. Analysis of the reaction
mixtures revealed the concomitant formation of two major
new products in different ratios, which were identified as
the expected tricycles 7a–d along with the pyridazine deriv-
ative 9 (Scheme 2). The ratios of the components (7:9) were
determined by a high-resolution NMR spectroscopic inves-
tigation of the crude reaction mixtures (Table 1). The high-
est proportion of the tricycles 7a–d in the reaction mixture
Slow addition Inverse addition
7
9
7
9
a
b
c
Ͼ95
75
50
Ͻ5
25
50
85
75
55
40
Ͼ5
25
45
60
Ͻ95
d
15
was obtained by the slow addition of a dilute solution of 2 TLC and NMR spectroscopic analysis of the crude reaction
in acetonitrile to a solution of the appropriate dienamine mixture revealed the formation of a major product 11 and
6a–d. Fast or reverse addition, on the other hand, led to an a side product 12, the latter being converted into 11 when
increase in the proportion of 9 (Table 1). It appears that chromatographic separation was attempted (Scheme 2).
the higher the delocalisation ability of the lone pair on the Again, slow addition of the tetrazine 2 to morpholinobuta-
[
15]
nitrogen atom, the higher the proportion of product 9 in diene 10 leads to a purer product. When two equivalents of
the mixture. tetrazine 2 were added to 10 the isolated amount of 11 was
The tricyclic products 7a and 7b were isolated from crys- in excess of 10, indicating the presence of the 12Ǟ11 trans-
tallisation, while the lower proportion of 7c and 7d in the formation in solution. We were unable to find any evidence
[
16,17]
corresponding reaction mixtures made it impossible to ob- of the formation of a tricyclic product.
tain them in the pure form. Attempts to separate the prod- Attention was now turned to the directed decomposition
ucts using column chromatography were also in vain, as the of these molecules. Irradiation of 7a in different solvents
tricycles 7c,d partly decomposed under the applied condi- led to the formation of mixtures that we were unable to
tions to give 9 and other byproducts. When 1-morpholino- separate and characterise. However, thermal decomposition
1,3-butadiene (10) was treated with the tetrazine diester 2, experiments were more successful, not only in the prepara-
Scheme 2. The reactions of 1-aminobutadiene derivatives with the tetrazine diester 2.
Eur. J. Org. Chem. 2006, 3358–3363
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3359

Z. Novák, Z. Vincze, Z. Czégény, G. Magyarfalvi, D. M. Smith, A. Kotschy
FULL PAPER
tive sense, but in that they also provided an insight into the
The analogous tautomeric equilibria of 21 and 22 give
so far unanswered details of the formation of 9. Heating 7a rise to 23 and 24, respectively, followed by an elimination
or 7b in vacuo above its melting (decomposition) point step that leads to the formation of the pyridazine diester
[
18]
leads to the formation of 9 in quantitative yield
Scheme 3). By trapping the volatile side products we were 25 from 24). Compounds 25a and 25b are expected to af-
also able to detect the formation of the appropriate amine ford the N-methylated amines 15a,b and propyne (26) spon-
13a,b). Refluxing 7a or 7b for a prolonged time in toluene taneously by elimination, while the enamines 16a,b might
derivatives and the enamines (9 and 16 from 23; or 11 and
(
(
or xylene gave the same results. Removal of the volatiles undergo elimination to furnish the amine 13a,b and pro-
gave only the pyridazine diester 9, and the presence of the pyne (26), or in the presence of water 16a,b might hydrolyse
appropriate amine (13a,b) can also be detected in the gas to the amine 13a,b and propanal (14). The higher pro-
phase by GC analysis. In order to achieve significant de- portion of 9 and 13a,b in the product (compared to 11 and
composition the temperature had to be above 100 °C, both 15a,b) is in good accordance with the higher migratory apti-
in solution and in vacuo.
tude of the hydrogen compared with the methyl group.
Examination of the thermal decomposition equation
The key to the course of the decomposition is the direc-
brought our attention to the fact that there is another frag- tion of the opening step. In the tricycle there are two similar
ment of the molecule that has not been accounted for. For- six-membered rings that could break up in a retro “inverse
mation of the pyridazine diester 9 and the amine 13 also electron-demand” Diels–Alder reaction to generate either
implies the possible evolution of propyne. Samples of the 17a,b or 18a,b. The X-ray structure of 7a shows[
10]
a
tricycles 7a,b were heated at 200, 250 and 300 °C, and the strained structure with certain carbon–carbon bonds
volatile components that formed were injected into a GC- stretched beyond 158 pm. A comparison of the bond length
MS apparatus using an argon stream. Analysis of the chro- data for the carbon–carbon bonds (Scheme 4) that might
matograms unambiguously proved the presence of the ap- break up in the first step (158.9 pm for C1–C2 and
propriate secondary amine 13a,b and a C fragment, al- 158.8 pm for C3–C4 versus 151.8 pm for C4–C5 and
3
though not in the form of propyne but propanal (14). Di- 158.1 pm for C6–C1) suggests that the formation of 18a,b
methyl 4-methylpyridazine-3,6-dicarboxylate (9) was also is energetically favoured over 17a,b. Further support of this
identified in the pyrolysate along with varying minor hypothesis comes from quantum chemical studies. The op-
amounts (up to 6%) of other products, such as dimethyl timised structures for 7a–d, 17a–d and 18a–d as well as the
pyridazine-3,6-dicarboxylate (11), and the N-methyl (15a,b) appropriate 7–17 and 7–18 transition state geometries were
and N-propenyl (16a,b) derivatives[ of the appropriate calculated on the DFT/6-31G level and their energies were
amine (Scheme 3). The formation of propanal was rational- refined in single point calculations using the 6-31G(d) set
ised by hydrolysis of the enamines 16a,b under the analysis and the CPCM solvent model with settings corresponding
19]
[
20]
Increasing the pyrolysis temperature appar- to acetonitrile.[21] The results are summarised in Figure 1
conditions.
ently always leads to an increase in the proportion of side and Table 2.
products. We assume that the initial step of the thermal According to the calculations the formation of interme-
decomposition of is retro-Diels–Alder reaction diates 18a–d from 7a–d is preferred both kinetically and
Scheme 4) that leads either to 17 or 18. Formation of the thermodynamically. The differences in the calculated ener-
7
a
(
pyrolysis products stems from 18, which is in a tautomeric gies of the 17–18 pairs, as well as the 7–17 and 7–18 transi-
equilibrium with 19. This compound may be represented by tion states is significant, favouring the latter compounds
two mesomeric forms, the neutral form A and the zwitter- and reaction paths in all cases. The activation barrier of
ionic form B. In this latter form the rotation of the side the preferred (and observed) 7–18 transformation shows a
chain around the single bond gives rise to 20, which is cap- marked dependence on the electron-donating nature of the
able of undergoing a [1,5] sigmatropic rearrangement to amine, illustrated by the significant 18 kJ/mol difference be-
give either 21 (route a – hydrogen shift) or 22 (route b – tween the morpholine and pyrrolidine analogues. This find-
[
10]
methyl shift).
ing supports an earlier mechanism suggestion of a zwit-
Scheme 3. The thermal decomposition of 7a,b.
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Formation and Thermolysis of an Azo-Bridged Tricyclic Ring System
FULL PAPER
Scheme 4. The proposed decomposition pathway of 7a,b in the pyrolysis experiments.
Figure 1. The calculated geometries of 7a, 17a, 18a, and the TS(7a–17a) and TS(7a–18a) transition states and the zwitterionic representa-
tion of TS(7a–18a). The hydrogen atoms are omitted for clarity.
Eur. J. Org. Chem. 2006, 3358–3363
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Z. Novák, Z. Vincze, Z. Czégény, G. Magyarfalvi, D. M. Smith, A. Kotschy
FULL PAPER
Table 2. Calculated relative heats of formation (kJ/mol) of com-
pounds 7a–d, 17a–d, 18a–d and transition states along the 7–17
and 7–18 path.
Reaction of Dienamines 6a–d and 10 with Dimethyl 1,2,4,5-Tetraz-
ine-3,6-dicarboxylate (2)
General Procedure: The solution of 2 (0.198 g, 1 mmol) in acetoni-
trile (20 mL) was added dropwise from a glass capillary (ca. 3–4
hours) to the stirred solution of the dienamine (1 mmol) in acetoni-
trile (20 mL). The resulting solution was stirred for another hour
and the solvent was evaporated under reduced pressure. The resi-
due was recrystallised from ethyl acetate or chromatographed over
silica gel using hexane/ethyl acetate mixtures as the eluent.
1
7
TS(7–17)
7
TS(7–18)
18
a
b
c
48.27
49.03
49.52
38.84
141.39
142.57
144.04
135.78
0
0
0
0
83.58
80.50
75.80
65.56
9.30
11.12
10.21
7.39
d
Tricycle 7a:[11] 1H NMR (300 MHz, CDCl
): δ = 4.02 (s, 6 H), 3.58
3
terion-like transition state (Figure 1) with an iminium sub- (s, 1 H), 3.53–3.44 (m, 8 H), 2.63 (q, J = 6.9 Hz, 1 H), 2.58 (s, 1
structure. The lower activation barrier for the retro reaction H), 2.25 (s, 3 H), 1.33 (s, 3 H), 0.41 (d, J = 6.9 Hz, 3 H) ppm.
in the presence of the more electron-donating amines might
Tricycle 7b:[11] 1H NMR (300 MHz, CDCl
): δ = 3.97 (s, 3 H), 3.95
3
also account for the increased amount of 9 in the reaction
of the dienamines 6c,d with 2. Not only is the intermediate
of type 18 formed more easily from the tricycle 7 in these
processes, its rearrangement to 9 or 11 is further facilitated
by the increased electron-donating ability of the amine moi-
ety through the stabilisation of the zwitterionic transition
states.
(
s, 3 H), 3.54 (s, 1 H), 2.58 (q, J = 6.9 Hz, 1 H), 2.51 (s, 1 H), 2.32–
2.18 (m, 8 H), 2.15 (s, 3 H), 1.25 (s, 3 H), 0.37 (d, J = 6.9 Hz, 3
H) ppm.
1
Tricycle 7c: H NMR (300 MHz, CDCl
(
(
3
, crude product): δ = 3.95
s, 6 H), 3.52 (s, 1 H), 2.60–2.36 (m, 6 H), 2.10 (s, 3 H), 1.52–1.20
m, 9 H), 0.35 (d, J = 6.9 Hz, 3 H) ppm.
1
Tricycle 7d: H NMR (300 MHz, CDCl
3
, crude product): δ = 3.94
(
(
s, 6 H), 3.50 (s, 1 H), 2.67–2.30 (m, 6 H), 2.10 (s, 3 H), 1.62–1.40
m, 7 H), 0.35 (d, J = 6.9 Hz, 3 H) ppm.
Conclusions
Dimethyl 5-Methylpyridazine-3,6-dicarboxylate (8):[25] 1H NMR
300 MHz, CDCl ): δ = 8.10 (s, 1 H), 4.08 (s, 3 H), 4.06 (s, 3 H),
In general, the reaction of electron-rich conjugated dien-
(
3
amines (6a–d, 10) with tetrazines takes place at the sterically 2.63 (s, 3 H) ppm.
less hindered double bond of the diene chain. The fate of
Dimethyl Pyridazine-3,6-dicarboxylate (10):[26] 1H NMR
300 MHz, CDCl ): δ = 8.15 (s, 2 H), 4.07 (s, 6 H) ppm.
the initially-formed intermediate is largely influenced by the
nature of the amine substituent. In certain cases we have
been able to identify and/or isolate a product (7a–d) con-
taining a strained azo-bridged tricyclic system that in some
cases undergoes a selective retro “inverse electron-demand”
(
3
Pyrolysis of the Tricyclic Compounds 7a,b
In Solution: The tricyclic compound 7a or 7b (0,2 mmol) was
heated in dry xylene (5 mL) at reflux for 6 h. The solvent was re-
Diels–Alder reaction on heating, leading through a cascade moved under reduced pressure to give dimethyl 4-methylpyrid-
of tautomeric and sigmatropic shifts to the pyridazine de- azine-3,6-dicarboxylate (9) in quantitative yield. The presence of
rivative 9. This explanation for the selectivity that is experi- the appropriate amine (13a or 13b) in the gas phase could be de-
tected by GC.
enced is also supported by GC-MS identification of the
minor products and quantum chemical modelling of the
key reaction step.
In Solid State: The tricyclic compound 7a or 7b (0,2 mmol) was
placed at the bottom of a glass tube and half of the tube was in-
serted horizontally into a Kugelrohr oven, while the other half was
–
1
cooled by dry ice. After evacuation of the tube (10 mbar) the oven
was heated gradually (ca. 15 °C/min) to 150 °C. At around 120 °C
the colour of the starting material turned yellow, a white solid
started to condense in the heated part of the tube and a colourless
liquid condensed at the parts cooled by dry ice. The heating and
evacuation were stopped and the tube was cut into three pieces
following the visible borders. The fractions were analysed by NMR
spectroscopy. The colourless liquid consisted mostly of the appro-
priate amine 13a,b, the white solid was identified as dimethyl 4-
methylpyridazine-3,6-dicarboxylate (9), while the yellow solid
showed signals belonging to compound 9 along with a minor com-
ponent that was not identified.
Experimental Section
General Remarks: H NMR and 13C NMR spectra were recorded
with a Bruker AX 300 spectrometer at 300 and 75 MHz, respec-
tively; chemical shifts (δ) are reported in ppm units by reference to
1
4
Me Si and coupling constants (J) are reported in Hz. All Py-GC/
MS measurements were carried out with a CDS Pyroprobe 2000
equipped with a platinum coil and quartz sample tube. The pyro-
lyser was coupled to a Hewlett–Packard 5985B GC/MS instrument.
A sample (about 250 µg) was pyrolysed at 200–300 °C for 20 s. He-
lium carrier gas at a flow rate of 20 mL/min purged the pyrolysis
chamber, which was kept at 120 °C. The separation of pyrolysis
products was performed with a BP-10 fused-silica capillary column
(
25 m long, 0.2 mm I.D., 0.25 µm of 86% dimethyl/14% cyanopro- Acknowledgments
pylphenyl silicone phase, Chrompack), temperature programmed at
0 °C/min heating rate from 50 to 270 °C. The GC/MS interface
1
The authors are grateful to Dr. Sándor Bátori for the photolysis
studies and Prof. Hamish McNab for the flash vacuum pyrolysis
experiments and fruitful discussions. The financial support of The
Royal Society, London (A.K.) and the Hungarian Scientific Re-
search Fund (OTKA F047125) are also gratefully acknowledged.
was kept at 300 °C. The quadrupole mass spectrometer was oper-
ated in the EI mode at 70 eV. TLC was carried out on silica plates
using UV detection and iodine as a developing agent. The prepara-
[
22]
[10,23]
[24]
tion of 2, 6a–d
and 10 was reported earlier.
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Formation and Thermolysis of an Azo-Bridged Tricyclic Ring System
FULL PAPER
[
17] We also tried to extend the process to other tetrazine deriva-
tives such as 3,6-di(2Ј-pyridyl)tetrazine and 3,6-bis(trifluoro-
methyl)tetrazine, but the reactions led to complex mixtures
without any apparent evidence of the formation of the appro-
priate tricycles.
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9
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[
19] The presence of 16a was unambiguously proved by a compari-
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allylmorpholine. Signals arising from 16a were also detected in
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3
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9
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[
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7
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[
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[
[
[
[
[
[
[
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new substituent onto an electron-rich double bond usually
2
3
leads to a significant (10 –10 fold) decrease in reactivity
towards tetrazines: T. Hierstetter, B. Tischler, J. Sauer, Tetrahe-
dron Lett. 1992, 33, 8019–8022.
[
[
[
[
[
22] D. L. Boger, R. S. Coleman, J. S. Panek, F. X. Huber, J. Sauer,
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[
[
[
[
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3
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6
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cording to our experience the products that they reported arise
from oxidation during chromatographic purification, rather
than from the suggested oxidative cleavage of the intermediate
bis-adduct.
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Received: January 23, 2006
Published Online: May 30, 2006
Eur. J. Org. Chem. 2006, 3358–3363
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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