1,2,4,5-Tetrazines as oxidant and reactant with DBU: An unexpected formation of a novel fused tetraheterocyclic azepine

Full text of DOI:10.1021/jo001363k

J . Org. Chem. 2000, 65, 9265-9267
9265
1
,2,4,5-Tetr a zin es a s Oxid a n t a n d Rea cta n t
w ith DBU: An Un exp ected F or m a tion of a
Novel F u sed Tetr a h eter ocyclic Azep in e
†
†
Robert E. Sammelson, Marilyn M. Olmstead,
Makhluf J . Haddadin,*,‡ and Mark J . Kurth*,†
†
Department of Chemistry, University of California,
‡
One Shields Avenue, Davis, California 95616-5295, and
Department of Chemistry, American University of Beirut,
Beirut, Lebanon
F igu r e 1. Adducts II-IV from reaction of π-deficient tetra-
zine I.
Sch em e 1.
mjkurth@ucdavis.edu, haddadin@aub.edu.lb
Received September 14, 2000
Im id a zop yr id a zin op yr im id in oa zep in es fr om
Rea ction of Tetr a zin es w ith DBU
In tr od u ction
The first 1,2,4,5-tetrazine derivative was prepared by
1
2
Pinner over 100 years ago. Tetrazines, which are highly
π-deficient systems, have been utilized as dienophiles in
3
inverse electron demand cycloadditions, including con-
densation reactions with enamines and enolates.4 In
particular, the condensation of 1,2,4,5-tetrazines (I,
Figure 1) with the enolates of aldehydes and ketones
5
have been reported in the synthesis of pyridazines II,
1
6
7
,2-diazocines, and heterocyclic molecular clefts. In all
these enolate reactions, the ketone or aldehyde contains
at least two protons on the same R-carbon, which allows
for the concomitant dehydration after condensation and
extrusion of nitrogen.
to refluxing MeOH) showed no reaction between 3,6-
diphenyl-1,2,4,5-tetrazine 1a (Scheme 1) and DBU. When
the reaction was carried out in triglyme at reflux (216
°C), the reaction did proceed, and the intense purple hue
of the tetrazine gradually disappeared. Isolation of the
reaction product, however, did not yield IV but rather
2a (Figure 2), which contains an unexpected 5,6,6,7-fused
heterocyclic ring system.
Resu lts a n d Discu ssion
The reaction of amidines with 1,2,4,5-tetrazines has
previously been reported to give 1,2,4-triazines III. In
8
this reaction, benzamidine was employed, which allows
for elimination of ammonia after initial cycloaddition. In
this study, we were curious if an N-substituted amidine,
such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), would
deliver IV which could not achieve aromatization by
elimination. In our search for unaromatized dihydrotri-
azine IV, attempts conducted at lower temperatures (rt
We have examined this interesting finding in an
attempt to determine its scope and limitations. Mecha-
nisic considerations and experimental observations (i.e.,
9
minimized side-products as judged by TLC) indicated
that a 5:1 stoichiometric ratio of tetrazine to DBU was
most effective. Next, the removal of the triglyme from
the reaction mixture was problematic and a more efficient
method of purification was sought. When the reaction
was conducted in refluxing m-xylene (bp 138-9 °C), it
was incomplete (presence of tetrazine by TLC) even after
2 days. The best solvent found for the reaction and
subsequent purification of product 2a was DMSO (bp 189
†
University of California.
American University of Beirut.
‡
(
1) Pinner, A. Ann. Chem. 1897, 297, 221-71.
(2) (a) Neunhoeffer, H. Tetrazines and Pentazines. In Comprehensive
Heterocyclic Chemistry; Boulton, A. J ., McKillop, A., Eds.; Pergamon
Press: New York, 1984; Vol. 3, pp 531-72. (b) Katritzky, A. R.;
Soloducho, J .; Belyakov, S. ARKIVOC 2000, 1, 46-51. (c) Lim, C. L.;
Pyo, S. H.; Kim, T. Y.; Yim, E. S.; Han, B. H. Bull. Korean Chem. Soc.
°
C). The reaction of other s-tetrazines [bis(4-methyl-
phenyl)tetrazine 1b and bis(4-methoxyphenyl)tetrazine
c] with DBU were also examined and found to yield the
1
995, 16, 374-7. (d) Sauer, J . In Comprehensive Heterocyclic Chemistry
II; Boulton, A. J ., Ed.; Pergamon: New York, 1996; Vol. 6, pp 901-95.
3) (a) Carboni, R. A.; Lindsey, R. V. J . Am. Chem. Soc. 1959, 81,
1
corresponding azepine heterocycles 2b and 2c. Isolated
yields of 2a -c ranged from 38 to 45%. The reactivity of
(
4
8
342-6. (b) Sauer, J .; Heinrichs, G. Tetrahedron Lett. 1966, 4979-
4. (c) Boger, D. L. Tetrahedron 1983, 39, 2869-939. (d) Boger, D. L.;
3
,6-di-(2-pyridyl)-1,2,4,5-tetrazine was much greater;
Schaum, R. P.; Garbaccio, R. M. J . Org. Chem. 1998, 63, 6329-37. (e)
Warrener, R. N.; Margetic, D.; Amarasekara, A. S.; Butler, D. N.;
Mahadevan, I. B.; Russell, R. A. Org. Lett. 1999, 1, 199-202. (f) Benson,
S. C.; Lee, L.; Yang, L.; Snyder, J . K. Tetrahedron 2000, 56, 1165-80.
employing toluene at reflux resulted in the starting
tetrazine being consumed within 1 h. Unfortunately, any
material that was formed decomposed quickly and could
not be isolated.
(
4) Boger, D. L. Chem. Rev. 1986, 86, 781-793.
(5) Haddadin, M. J .; Firsan, S. J .; Nader, B. S. J . Org. Chem. 1979,
4
4, 629-30.
6) Haddadin, M. J .; Agha, B. J .; Salka, M. S. Tetrahedron Lett.
984, 25, 2577-80.
7) Haddadin, M. J .; Wang, Y.; Frenkel, S.; Bott, S. G.; Yang, L.;
Products 2a -c, with their 4-aminoimidazole moiety,
(
10
appeared red to orange on silica gel, and their struc-
1
(
Braterman, P. S.; Carvallo, C.; Marchand, A. P.; Watson, W. H.;
(9) This is determined by analyzing the products which show 2 equiv
of tetrazine are used as reactant in condensing with the DBU core
and 3 equiv are consumed in oxidizing the DBU-containing intermedi-
ates.
Kashyap, R. P.; Krawiec, M.; Bourne, S. A. Heterocycles 1994, 37, 869-
8
2.
(
8) Figeys, H. P.; Mathy, A. Tetrahedron Lett. 1981, 22, 1393-6.
1
0.1021/jo001363k CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

9
266 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
F igu r e 4. Side-products from the reaction of 1 + DBU.
D undergoes subsequent oxidation to 2 with another
molecule of tetrazine acting as the oxidizing agent.
Attempts to isolate any of these or other intermediates
were unsuccessful. However, the reduced form of tetra-
zine, dihydrotetrazine 3, is formed in each of the adduct
oxidation steps and was isolated from the reaction
mixture (Figure 4). Furthermore, rearrangement of 3 to
the aminotriazole 4 was also observed.15 When the
reaction (utilizing 1a ) was carried out with triglyme as
solvent, the aroma of benzonitrile (5) was detected, and
a swab of the condensate in the reflux condenser showed
this substance to be identical to authentic benzonitrile
by reverse-phase HPLC. The possibility that the imida-
zole ring resulted from the participation of benzonitrile
F igu r e 2. X-ray crystal structure of 2a .
(formed by the decomposition of 1a ) was ruled out by
finding no reaction upon heating DBU with benzonitrile
in triglyme at reflux. In addition, diphenyltetrazine (1a )
was found to be stable in triglyme under these reaction
times (up to 3 h). These findings support the postulate
of a seven-membered triazepine ring (A) being formed,
which contracts with extrusion of the aryl nitrile to
deliver amino imidazole B (Figure 3).
F igu r e 3. Mechanistic rationale for 1 + DBU f 2.
Con clu sion
tures were established by spectroscopic data. In addition,
the structure of 2a was verified by X-ray crystallography
It is noteworthy that this novel reaction involves the
sequential addition of amidines, enamines, and dien-
amines (originally present or generated from DBU) to the
tetrazine moiety. It also demonstrates the oxidative
nature of 1,2,4,5-tetrazines. In addition, our finding
establishes the reductive effect of DBU in that the
oxidized DBU core is present in these tetraheterocyclic
azepine products. These 2,8,11-triaryl-3H,4H,5H,6H,7H-
imidazo[4,5,1-ef][1,3]-diazaperhydroino[1,2-f]pyridazino-
[4,5-d]azepines are a new class of the C N C N C N C N
(Figure 2).
Formation of 2 can be rationalized by a mechanism11
which involves intermediates shown in Figure 3. In this
process, DBU acts as both reactant and reducing agent
while the tetrazine acts as both reactant and oxidizing
agent. Nazer and Haddadin12 observed the reductive
effect of DBU on o- and p-nitrobenzaldehydes, which were
reduced to the corresponding aminobenzoic acids. Fur-
thermore, Sauer et al. recently described the use of
3
2
4
2
4
2
6
fused heterocyclic ring system.
1
,2,4,5-tetrazine as both reactant and oxidizing agent.13
While it is possible that triazepine ring contraction
Exp er im en ta l Section
with extrusion of benzonitrile could succeed tetrahydro-
azepine oxidation and cycloaddition, this is not likely
given the relative instability of triazepines at these
Gen er a l P r oced u r es. Melting points were determined using
an Electrothermal 9100 apparatus and are uncorrected. Infrared
spectra were taken on the solids with the use of a refractive
1
4
elevated reaction temperatures (189 °C). Intermediate
1
13
spectrophotometer. H and C NMR were measured in CDCl
unless otherwise noted) at 300 and 75 MHz, respcecitvely.
3
(
(
10) Solutions of these adducts turned from yellow to red on addition
of acetic acid or picric acid.
11) The proposed reaction mechanism is included in the Supporting
Information as Figure S1.
12) Unpublished results on the reaction of DBU with o-nitrobenz-
Elemental analysis was preformed by Midwest Microlabs,
Indianapolis, IN. Dimethyl sulfoxide purchased from Fischer
Scientific was distilled, with the first 20% being discarded, onto
molecular sieves. The dihydrotetrazines were prepared from
their corresponding nitriles and hydrazine monohydrate with
sulfur in EtOH.16 Oxidation to the tetrazines was accomplished
by adding sodium nitrate portionwise to a mixture of the
dihydrotetrazine in acetic acid.17
(
(
aldehyde (Professors Nazer, M. Z. and Haddadin, M. J .): o-Nitrobenz-
aldehyde (0.5 g) was dissolved in dry THF (5 mL), and DBU (0.6 mL)
was added. After one week at room temperature, the solvent was
removed, water (10 mL) was added, and the solution was made slightly
acidic with dilute HCl. This was extracted with ether, dried, and
concentrated to a volume of about 5 mL. An equal volume of pentane
was added, and slow evaporation deposited crystals that proved to be
anthranilic acid (unoptimized yield 50 mg) as determined by mixed
mp, IR, and NMR.
2
,8,11-Tr ip h en yl-3H,4H,5H,6H,7H-im id a zo[4,5,1-ef][1,3]-
d ia za p er h yd r oin o[1,2-f]p yr id a zin o[4,5-d ]a zep in e (2a ). To
(15) Bentiss, F.; Lagrenee, M.; Barbry, D. Tetrahedron Lett. 2000,
41, 1539-41.
(
13) Sauer, J .; Heldmann, D. K.; Hetzenegger, J .; Krauthan, J .;
Sichert, H.; Schuster, J . Eur. J . Org. Chem. 1998, 2885-96.
14) Sharp, J . T. Triazepines. In Comprehensive Heterocyclic Chem-
istry; Lwowski, W., Ed.; Pergamon Press: New York, 1984; Vol. 7, pp
36-41.
(16) Abdel-Rahman, M. O.; Kira, M. A.; Tolba, M. N. Tetrahedron
Lett. 1968, 35, 3871-2.
(
(17) Guither, W. D.; Coburn, M. D.; Castle, R. N. Heterocycles 1979,
12, 745-9.
6

Notes
.68 g (7.18 mmol) of diphenyltetrazine in 15 mL of dimethyl
sulfoxide was added 0.219 g (1.44 mmol) of DBU. This mixture
was then heated at reflux under nitrogen for 2 h. The solution
was cooled to room temperature, dichloromethane (20 mL) was
J . Org. Chem., Vol. 65, No. 26, 2000 9267
1
2,8,11-Tr is(4-m eth oxyp h en yl)-3H,4H,5H,6H,7H-im id a zo-
[4,5,1-ef][1,3]-d ia za p er h yd r oin o[1,2-f]p yr id a zin o[4,5-d ]-
a zep in e (2c). The procedure described for 2a was employed to
scale with the following differences: 1.08 g (3.66 mmol) of
diphenyltetrazine, 0.111 g (0.73 mmol) of DBU gave 0.155 g,
39%. Mp 266-9 °C dec; IR 2956, 2832, 1586, 1505, 1240, 1175,
added followed by H
and the organic layer was washed twice more with H
2
O (15 mL). The aqueous layer was removed,
O. The
2
-
1 1
white precipitate, if any, was filtered and washed with several
small amounts of dichloromethane. The concentrated organic
layer was submitted to flash chromatography on silica gel with
EtOAc followed by 9:1 EtOAc:MeOH and provided 2a as a yellow
solid (0.295 g, 45%). Mp 245-8 °C dec; IR 3056, 2935, 1570, 1531,
1029 cm ; H NMR δ 2.12 (quint, J ) 6 Hz, 2H), 3.07 (m, 2H),
3.35 (t, J ) 6 Hz, 2H), 3.69 (m, 2H), 3.80 (s, 3H), 2.87 (s, 3H),
3.90 (s, 3H), 4.04 (t, J ) 6 Hz, 2H), 6.83 (d, J ) 9 Hz, 2H), 6.96
(d, J ) 9 Hz, 2H), 7.02 (d, J ) 9 Hz, 2H), 7.19 (d, J ) 9 Hz, 2H),
1
3
7.50 (d, J ) 9 Hz, 2H), 7.62 (d, J ) 9 Hz, 2H); C NMR (CDCl
3
/
-
1 1
1
3
7
1
1
465 cm ; H NMR δ 2.13 (quint, J ) 6 Hz, 2H), 3.07 (m, 2H),
.39 (t, J ) 6 Hz, 2H), 3.72 (m, 2H), 4.08 (t, J ) 6 Hz, 2H), 7.16-
DMSO-d ) δ 22.2, 30.6, 42.6, 47.5, 55.09, 55.15, 55.23, 56.4,
112.1, 112.7, 113.5, 113.6, 114.3, 122.5, 128.9, 130.0, 130.7, 130.8,
132.6, 133.0, 140.1, 140.7, 156.2, 157.3, 158.9, 159.3, 159.5.
6
1
3
18
.65 (m, 15H); C NMR δ 22.4, 30.8, 42.9, 47.6, 56.2, 112.6,
27.2, 127.47, 127.52, 128.0, 128.26, 128.34, 129.5, 129.7, 130.0,
32.7, 133.3, 137.9, 140.3, 140.8, 141.1, 149.1, 157.3, 158.3. Anal.
Ack n ow led gm en t. We acknowledge Mr. J oshua
Halsey for the initial experiments that led to this work.
M.J .H. is grateful to the American University of Beirut
for a sabbatical leave at the University of California,
Davis. The authors are thankful to Professor Costas H.
Issidorides for many helpful discussions. We are grateful
to the National Science Foundation for financial support
of this research. The 300 and 400 MHz NMR spectrom-
eters used in this study were funded in part by a grant
from NSF (CHE-9808183).
Calcd for C30
H, 5.61; N, 14.99.
,8,11-Tr is(4-m et h ylp h en yl)-3H ,4H ,5H ,6H ,7H -im id a zo-
4,5,1-ef][1,3]-d ia za p er h yd r oin o[1,2-f]p yr id a zin o[4,5-d ]-
25 5
H N : C, 79.10; H, 5.53; N, 15.37. Found: C, 79.32;
2
[
a zep in e (2b). The procedure described for 2a was employed to
scale with the following differences: 1.02 g (3.89 mmol) of
diphenyltetrazine, 0.116 g (0.76 mmol) of DBU, and eluent for
flash chromatography was EtOAc and gave 0.143 g, 38%. Mp
2
95-8 °C dec; IR 3028, 2917, 1584, 1510, 1479, 1382 cm-1; H
1
NMR δ 2.11 (quint, J ) 6 Hz, 2H), 2.33 (s, 3H), 2.43 (s, 3H),
2
4
.47 (s, 3H), 3.03 (m, 2H), 3.32 (t, J ) 6 Hz, 2H), 3.67 (m, 2H),
.02 (t, J ) 6 Hz, 2H), 7.08 (s, 4H), 7.22 (d, J ) 8 Hz, 2H), 7.28
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of 2b and 2c, a complete reaction mechanism, and the crystal
structure data for 2a are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
d, J ) 8 Hz, 2H), 7.43 (d, J ) 8 Hz, 2H), 7.52 (d, J ) 8 Hz, 2H);
1
3
C NMR δ 21.2, 21.3, 21.4, 22.5, 30.7, 42.9, 47.7, 56.6, 112.6,
1
1
27.3, 127.5, 128.1, 128.9, 129.0, 129.5, 129.7, 132.6, 133.2, 135.1,
1
8
36.7, 137.9, 138.1, 140.3, 140.8, 157.2, 158.1.
(18) See Supporting Information.
J O001363K