Synthesis of Δ1-1,2-diazetines via a Diels-Alder cycloaddition approach

Article abstract of DOI:10.1021/ol0164942

(figure presented) A novel method for the synthesis of Δ¹-1,2-diazetines is presented. Diels-Alder cycloaddition of dienophile 4 with five dienes afforded cycloadducts in good to excellent yields. Four of the obtained cycloadducts were converte

Full text of DOI:10.1021/ol0164942

ORGANIC
LETTERS
Synthesis of ∆1-1,2-Diazetines via a
Diels−Alder Cycloaddition Approach
2001
Vol. 3, No. 20
3185-3187
Gary W. Breton,* John H. Shugart, Christine A. Hughey, Suzanne M. Perala, and
Alisa D. Hicks
Department of Chemistry, Berry College, P.O. Box 495016,
Mount Berry, Georgia 30149
gbreton@berry.edu
Received July 25, 2001
ABSTRACT
A novel method for the synthesis of ∆1-1,2-diazetines is presented. Diels−Alder cycloaddition of dienophile 4 with five dienes afforded
cycloadducts in good to excellent yields. Four of the obtained cycloadducts were converted to the corresponding diazetines.
∆1-1,2-Diazetines (1, Figure 1) are a class of strained four-
membered ring azo compounds.1,2 Their properties remain
largely unexplored presumably as a result of the difficulty
of their synthesis. Even though the first member of this
family of compounds was described in 1962, fewer than a
dozen diazetines are currently known.3 Despite the propensity
for decomposition of diazetines to ultimately afford nitrogen
and the corresponding alkene (Figure 1, ∆H ≈ -50 kcal/
mol), diazetines are quite thermally robust (∆H‡ ≈ 35 kcal/
mol).1,4 This has prompted questions concerning the mech-
anism of decomposition of these compounds with advocacy
of concerted (both [2s + 2s] and [2s + 2a] retrocycloaddi-
tions being suggested) and nonconcerted (i.e., via diradical
intermediates) processes.1,5 Detailed studies on the decom-
position process have been hampered by the inaccessibility
of diazetine substrates.1a,6 We sought to develop a synthetic
method that would be more generally applicable than
traditional methods and allow for additional studies on this
fascinating class of organic compounds.
The Diels-Alder cycloaddition reaction is widely recog-
nized as a powerful synthetic method that is broadly
applicable for a given dienophile in its reactions toward diene
substrates.7 We sought to develop a suitable dienophile that
would act as a diazetine synthon as illustrated in Figure 2.
Figure 2. A route for the synthesis of 1,2-diazetines that utilizes
a diazetine synthon (2) in a Diels-Alder reaction.
A compound with a suitable structure, 3, was already known
(Figure 3),8 but its limited thermal stability toward electro-
cyclic ring opening (t1/2[20 °C] ) 7 h) suggested it would
be an ineffective dienophile since Diels-Alder reactions
Figure 1. Products from the decomposition of diazetines.
(1) (a) Engel, P. S. Chem. ReV. 1980, 80, 99-150. (b) Hogenkamp, D.
J.; Greene, F. D. J. Org. Chem. 1993, 58, 5393-5399.
10.1021/ol0164942 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

mixture of the more stable sulfoxides 8.10 The poor overall
yield of this two-step reaction (∼15%) can be traced to the
[2 + 2] reaction where formation of a polymer competes
with the cycloaddition.11 Attempts to increase the yield by
varying the reaction solvent, altering the sequence of reagent
mixing, and changing the reaction temperature have not yet
been successful. Furthermore, attempts to effect the direct
[2 + 2] cycloaddition of 6 with phenyl vinyl sulfoxide to
yield 8 directly either thermally (80 °C, CHCl3), via Lewis
acid catalysis (BF3‚Et2O, CH2Cl2), or photochemically met
with failure.
Figure 3. The result of thermal orbital-symmetry allowed conro-
tatory ring openings for compounds 3 and 4.
Solution-phase pyrolysis of sulfoxide 8 (C6H5Cl, 150 °C,
4 h) yielded the desired diazetine 4 in good yield (∼70%).
1
The H NMR spectrum of 4 displays two singlets (δ 3.1
often require elevated temperatures. We reasoned, on the
basis of the behavior of hydrocarbon analogues,9 that by
“tying back” the free ends of the carbamate groups of
compound 3 into a urazole ring (i.e., compound 4) that the
thermal stability of the dienophile would be enhanced. Ring
opening of 4 is expected to be hindered since a thermally
allowed conrotatory electrocyclic process would ultimately
lead to the hopelessly strained (1Z,3E)-heterocyle 5 (Figure
3).
[N-Me] and 6.71) consistent with the proposed structure.
Similarly, the three signals observed in the 13C NMR (δ
156.4, 130.9, and 26.8) were consistent with the symmetry
of the compound’s structure. The overall yield of 4 from 6
was only 8-10%, but the ability to synthesize 4 with only
a single rigorous purification step (see Supporting Informa-
tion) still makes it a feasible route. We are currently seeking
higher-yielding alternative routes, however. The ability of 4
to withstand the temperatures required for its synthesis (150
°C), as well as those required for subsequent Diels-Alder
reactions (see below), demonstrate that it is indeed resistant
to electrocyclic ring opening as predicted.
Synthesis of dienophile 4 was accomplished via the route
illustrated in Scheme 1. Reaction of N-methyltriazolinedione
Diels-Alder cycloadditions of 4 with various dienes took
place readily in benzene or chlorobenzene at temperatures
of 100-150 °C (Table 1). Cyclopentadiene afforded a
mixture of both endo and exo stereoisomers in a 15:1 ratio,
respectively. The exo isomer was readily identified by
Scheme 1
1
comparison of its H and 13C NMR spectrum with that of
authentic material formed via the [2 + 2 + 2] cycloaddition
of 6 with quadricyclane.12
In contrast, 1,3-cyclohexadiene afforded a single stereoi-
somer, which is assumed to have the endo stereochemistry
(Table 1). Reaction with anthracene afforded the expected
cycloadduct in very good yield. The acyclic diene 2,3-
dimethyl-1,3-butadiene afforded the expected cycloadduct
in 67% yield. Reaction with 2,4-hexadiene yielded a mixture
of two stereoisomers 14 and 15 in a 2.9:1 ratio, respectively.
These isomers were differentiated primarily on the basis of
their 1H NMR spectra. The vinyl protons of the minor isomer
were split into a doublet (J ) 7.2 Hz) by coupling with the
neighboring methine protons, which was more consistent
with the geometry of the lowest energy conformation of
isomer 15 (predicted J ) 5.4 Hz) than that of 14 (predicted
J ) 1.4 Hz).13 Furthermore, the vinyl protons of the major
6 with phenyl vinyl sulfide yielded a labile [2 + 2] adduct
7 that was oxidized (without isolation) to a diastereomeric
(2) Preliminary results on this work: Breton, G. W. Ph.D. Dissertation,
Massachusetts Institute of Technology, Cambridge, MA, 1991. We thank
Prof. F. D. Greene for encouragement in the investigation and publication
of these findings.
(3) See references within ref 1b for leading articles to all known
diazetines.
(4) (a) White, D. K.; Greene, F. D. J. Am. Chem. Soc. 1978, 100, 6760-
6761.
(10) The spectroscopic data for 7 is similar to that reported for the
corresponding DMAD adduct; see: Firl, J.; Sommer, S. Tetrahedron Lett.
1972, 4713-4716.
(11) Polymer formation is a common side reaction in the reactions of
triazolinediones with electron-rich alkenes; see: Hall, H. J.; Jones, M. L.
J. Org. Chem. 1983, 48, 822-826.
(5) Olsen, H. J. Am. Chem. Soc. 1982, 104, 6836-6838.
(6) Pincock, J. A.; Druet, L. M. Tetrahedron Lett. 1980, 21, 3251-3252.
(7) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part B;
Kluwer Academic: New York, 2001; pp 332-359.
(8) Nunn, E. E.; Warrener, R. N. J. Chem. Soc., Chem. Commun. 1972,
818-819.
(12) Adam, W.; De Lucchi, O. Tetrahedron Lett. 1981, 22, 929-932.
(13) The geometries of stereoisomers 14 and 15 were minimized utilizing
the MMFF94 force-field as implemented within PC Spartan Pro software
(Wavefunction, Inc.). Coupling constants were estimated from the dihedral
angles formed from the vinyl protons and the neighboring methine protons
as predicted by the minimized structures.
(9) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part A;
Kluwer Academic: New York, 2000; p 607.
3186
Org. Lett., Vol. 3, No. 20, 2001

Table 1. Cycloadduct Products Resulting from Reaction of
Dienophile 4 with Various Dienesa
Table 2. Diazetine Products Synthesized from Some of the
Diels-Alder Cycloadductsa
a Detailed procedures are available in Supporting Information. b Isolated
yields.
reactivities of these new diazetines will be presented in a
future publication.
In summary, the Diels-Alder cycloaddition approach for
the synthesis of novel diazetines appears to be general and
quite useful. We intend to utilize this new method for the
synthesis of a series of structurally related diazetines that
might ultimately yield new insights into the mechanism of
decomposition of these compounds.
a Detailed procedures are available in Supporting Information. b Isolated
yields.
Acknowledgment. We thank Ocean Optics, Inc. (Edu-
cational Grant Program Award OOI00-415) and Berry
College for financial support of this work. The FT-NMR
upgrade used in this work was made possible by NSF DUE
ILI-IP grant 9750684. The UV-vis spectrophotometer used
in this work was made possible by the 1998 Camille and
Henry Dreyfus Special Grant Program in the Chemical
Sciences.
isomer revealed themselves as a broadened singlet consistent
with the geometry of 14 according to the above analysis.
To demonstrate the utility of this novel synthetic route,
four of the cycloadducts were converted to the corresponding
diazetines via a standard hydrolysis/oxidation reaction se-
quence (Table 2).14 Thus, the urazole rings of the adducts
were hydrolyzed with KOH in refluxing 2-propanol to afford
the corresponding hydrazines, followed by in situ oxidation
with CuCl2. The expected diazetines were obtained in yields
typical of this process. The thermal and photochemical
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new compounds
1
and H NMR spectra for all of the new diazetines and 15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Adam, W.; De Lucchi, O.; Erden, I. J. Am. Chem. Soc. 1980, 102,
4806-4809.
OL0164942
Org. Lett., Vol. 3, No. 20, 2001
3187