Novel concerted fragmentation upon alcoholysis of a urazole

Article abstract of DOI:10.1021/ol040051r

(Chemical Equation Presented) Instead of yielding the expected hydrazine, alcoholysis of the above heterocycle results in fragmentation via a highly unusual pathway.

Full text of DOI:10.1021/ol040051r

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3837-3839
Novel Concerted Fragmentation upon
Alcoholysis of a Urazole
Yanjun Wei* and David M. Lemal*
Department of Chemistry, Dartmouth College, HanoVer, New Hampshire 03755
daVid.m.lemal@dartmouth.edu
Received August 16, 2004
ABSTRACT
Instead of yielding the expected hydrazine, alcoholysis of the above heterocycle results in fragmentation via a highly unusual pathway.
Askani showed that alkaline cleavage of 1, the Diels-Alder
adduct of 1,3-cyclohexadiene (3) with azoester, gives 2,3-
diazabicyclo[2.2.2]oct-5-ene (2), as anticipated.1
Scheme 1
Hydrolysis (or alcoholysis) of Diels-Alder adducts of
triazolinediones generally requires vigorous conditions,2 but
we have found that the adduct 43 of diene 3 with 4-phenyl-
1,2,4-triazolinedione is quite easily cleaved by methoxide.
Surprisingly, the products are 3, nitrogen, carbon monoxide,
and methyl N-phenylcarbamate (5). Formation of carbon
scission of the heterocyclic ring was detected. Adduct 6 was
monoxide was confirmed both by its infrared absorption at
slowly transformed into methoxide-d3 adduct 7, which in turn
2171 and 2117 cm-1 4 and by its reaction with PdCl2/CuCl2
added a second equivalent of methoxide-d3 to give 8.8
to give a black precipitate.5,6
Formation of the unsymmetrical 7 was revealed by the
development of two new 1H NMR signals at δ 4.22 and 4.06
(2) See, for example: Altundas, A.; Akbulut, N.; Balci, M. HelV. Chim.
Acta 1998, 81, 828. Adam, W.; Hill, K. J. Am. Chem. Soc. 1985, 107, 3686.
(3) Gillis, B. T.; Hagarty, J. D. J. Org. Chem. 1967, 32, 330.
(4) Williams, G. D.; Whittle, R. R.; Geoffrey, G. L.; Rheingold, A. L.
J. Am. Chem. Soc. 1987, 109, 3936.
(5) Oranskaya, O. M.; Shmulyakovskii, Y. E.; Semenskaya, I. V.
Neftepererab. Neftekhim. 1976, 6, 47.
(6) Eguchi, H.; Hamada, H.; Nishitani, S. Japanese Patent 76-152731
19761217, 1978.
For comparison, hydrogenated adduct 67 was subjected
to methanolysis under identical conditions (Scheme 1). No
(7) Snyder, J. P.; Bandurco, V. T.; Darack, F.; Olsen, H. J. Am. Chem.
Soc. 1974, 96, 5158.
(1) Askani, R. Chem. Ber. 1965, 98, 2551.
10.1021/ol040051r CCC: $27.50
© 2004 American Chemical Society
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for the bridgehead hydrogens, which slowly diminished at
the expense of one newer signal at δ 4.14 as C2-symmetric
dianion 8 appeared. The configuration of 8 is tentatively
assigned as trans simply on electrostatic grounds. That ring
opening had not occurred was clear from the fact that
acidification caused immediate disappearance of the bridge-
head peak for 8 and more slowly the pair of peaks for 7,
returning the starting material. The negative charges in
adducts 7 and 8 must enjoy considerable stabilization by the
geminal heteroatoms, through both inductive electron with-
drawal and negative hyperconjugation. Thus, generation of
7 and 8 is driven by the fact that they are weaker bases than
methoxide, and after acidification that driving force is gone.9
Cleavage of 6 to diazabicyclo[2.2.2]octane 9 occurred only
after long heating at higher temperatures.
B3LYP/6-31G* structure of the hydrate 11 of urazole 4
(Figure 1).11 The crystal structure of urazole 6 reveals a
similar degree of pyramidalization.12
The unsaturated adduct 4 disappears with pseudo-first-
order rate constant k ) 2 × 10-3 s-1 at 50 °C in 3:1 CD3-
OD/CD3SOCD3, 2 M in KOH.10 It reacts about 10 times
faster than 6 under these conditions. A pair of bridgehead
signals at δ 4.94 and 4.89 corresponding to CD3O- adduct
1
10 are detectable in the H NMR spectrum during the
reaction. In contrast to the behavior of 7, 10 fragments readily
via what we believe to be the fully concerted process depicted
in Scheme 2.
Figure 1.
Normal hydrolysis or alcoholysis of a urazole ring,
producing a hydrazine, leaves the carbonyl carbons in the
+IV oxidation state. In this case, oxidation occurs at nitrogen
with the result that a carbonyl carbon is reduced to the +II
oxidation state. The fact that alcoholysis of 4 is far easier
than that of its saturated counterpart 6 indicates that the
concerted fragmentation enjoys significant driving force.
Barton et al. recovered ergosterol (13) from its adducts
with triazolinediones (12) upon treatment with KOH in
Scheme 2
This transformation actually comprises two linked con-
certed events, fragmentation of the heterocyclic ring and
retro-Diels-Alder reaction. They are made energetically
feasible by the simultaneous formation of both π bonds of
the very stable molecular nitrogen. Whereas the newly
forming carbonyl bond is poorly aligned to stabilize the
negative charge developing on nitrogen, the phenyl ring may
play that role. Alternatively, covalent bonding to a hydrogen-
bonded deuteron may occur as the charge develops at
nitrogen. Formation of the mutually perpendicular N-N π
bonds is facilitated by the fact that the nitrogen atoms are
already pyramidalized in the ground state, as shown in the
ethanol.13 They suggested that the reaction proceeds with
formation of a diimide, as shown in Scheme 3. This pathway
(11) Gaussian 98, Revision A.5; Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratman, R. E.; Burant, J. C.; Dapprich, S.; Millam,
J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian,
Inc.; Pittsburgh, PA, 1998.
(8) For examples of stable “hemiketals” and hydrates formed from
structurally related carbonyl groups, see: Addink, R.; Berends, W.
Tetrahedron 1981, 37, 833. Yakushijin, K.; Suzuki, R.; Kawaguchi, N.;
Tsuboi, Y.; Furukawa, H. Chem. Pharm. Bull. 1986, 34, 2049. Goerlitzer,
K.; Buss, D. Arch. Pharm. 1985, 318, 97. Capuano, L.; Lazik, W.; Zander,
R. Chem. Ber. 1974, 107, 3237. Tanaka, F. S.; Hoffer, B. L.; Wien, R. G.
J. Agric. Food Chem. 1988, 36, 180. Barr, D. A.; Grigg, R.; Gunaratne, H.
Q. N.; Kemp, J.; McMeekin, P.; Sridharan, V. Tetrahedron 1988, 44, 557.
(9) Consistent with this finding are calculations of the free energy of
addition of water across, and of hydroxide ion to, the carbonyl group of a
simple amide. In this case, both processes are thermodynamically unfavor-
able, but hydroxide addition to give the “hemiketal” anion is considerably
less so. Guthrie, J. P. J. Am. Chem. Soc. 1974, 96, 3608.
(12) van der Ende, C.; Offereins, B.; Romers, C. Acta Crystallogr. 1974,
B30, 1947.
(13) Barton, D. H. R.; Lusinchi, X.; Ramirez, J. S. Bull. Soc. Chim. Fr.
1985, 849. Barton, D. H. R.; Shioiri, T.; Widdowson, D. A. J. Chem. Soc.
C 1971, 1968.
(10) The p-nitro analogue of 4 reacts somewhat faster. In the same
medium but at 30 °C, its pseudo-first-order rate constant k is 1 × 10-3 s-1
.
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Org. Lett., Vol. 6, No. 21, 2004

the two linked nitrogens two bonds are broken and two new
ones are formed.16 Not all reactions in which concerted
processes are coupled necessarily fit the definition of
coarctate reactions, however. A case in point would be an
acetylene-tetrazine reaction in which Diels-Alder addition
is concerted with nitrogen loss to give a pyridazine, a retro-
Diels-Alder reaction (Scheme 5). According to a detailed
Scheme 3
Scheme 5
lacks the driving force of forming molecular nitrogen, and
it is not clear why the bonds to the ergosterol moiety should
be broken. We have compared the thermodynamics of
Barton’s mechanism and ours for the alcoholysis of 4 with
calculations at the B3LYP/6-31G* level of theory.14 Because
1,3-cyclohexadiene (3) is common to both, it sufficed to
compare the other fragments from the two pathways, as
shown in Scheme 4. The great difference in both enthalpy
theoretical analysis of one such transformation, it is “con-
ceivable that reaction . . . actually involves the addition of
acetylene and elimination of nitrogen occurring in a one-
step, yet asynchronous, process.”17
Finally, the question remains why the azoester adduct (1)
of 1,3-cyclohexadiene gives the hydrazine 2 upon treatment
with alcoholic base instead of fragmentation products. A
likely reason is that in the favored conformations of 1 the
bicyclic system is twisted, and the free energy barrier for
“bridge flipping” is 16.4 ( 0.3 kcal/mol.18 Thus, considerable
energy would be required to bring the methoxycarbonyl
groups into proper alignment for the concerted process
depicted in Scheme 2.
Scheme 4
and entropy, corresponding to ∆G° ) -68.4 kcal/mol at 25
°C, provides strong support for the interpretation offered in
Scheme 2.
Acknowledgment. The authors are grateful to the Na-
tional Science Foundation for support of this work.
Regarding just the retro-Diels-Alder component of the
coupled concerted process, fragmentation of 2,3-diazabicyclo-
[2.2.2]octa-2,5-diene (14) occurs quickly at -78 °C.15 From
B3LYP/6-31G* calculations, ∆H° ) -39.5 kcal/mol and
∆S° ) 42.4 cal/mol K for this process, corresponding to ∆G°
) -52.2 kcal/mol at 25 °C.
Supporting Information Available: Experimental de-
tails, including characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL040051R
(14) The calculations take account of zeropoint energy differences and
thermal corrections to 289.15 K.
(15) Rieber, N.; Alberts, J.; Lipsky, J. A.; Lemal, D. M. J. Am. Chem.
Soc. 1969, 91, 5668.
(16) Herges, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 255.
(17) Cioslowski, J.; Sauer, J.; Hetzenegger, J.; Karcher, T.; Hierstetter,
T. J. Am. Chem. Soc. 1993, 115, 1353. See also: Sauer, J.; Heldmann, D.
K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.; Schuster, J. Eur. J. Org. Chem.
1998, 2885.
The transformation shown in Scheme 2 belongs to the class
of concerted reactions termed coarctate, because at each of
(18) Anderson, J. E.; Lehn, J. M. Tetrahedron 1968, 24, 123.
Org. Lett., Vol. 6, No. 21, 2004
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