1,3-Dipolar cycloaddition reactions initiated with the 1,5-dimethyl-3- phenyl-6-oxoverdazyl radical

Article abstract of DOI:10.1002/ejoc.200800687

The 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical reacts at room temperature in the presence of styrene to give a dihydrotetrazinone heterocyclic structure. We surmise that the reaction occurs by a 1,3-dipolar cycloaddition via the intermediacy of an azomet

Full text of DOI:10.1002/ejoc.200800687

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800687
1,3-Dipolar Cycloaddition Reactions Initiated with the
1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical
Angela Yang,[a] Takahito Kasahara,[a] Eric K. Y. Chen,[a] Gordon K. Hamer,[a] and
Michael K. Georges*[a]
Keywords: Verdazyl radicals / 1,3-Dipolar cycloaddition / Azomethine imine / Dihydrotetrazinone
The 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical reacts at
room temperature in the presence of styrene to give a dihy-
rylate, methacrylate, fumarate and maleate dipolarophiles
react regioselectively and stereospecifically to provide a
drotetrazinone heterocyclic structure. We surmise that the re- series of dihydrotetrazinone heterocyclic structures. These
action occurs by a 1,3-dipolar cycloaddition via the interme-
diacy of an azomethine imine. While initial reactions under
nitrogen gave relatively poor yields (40%) of the cycload-
dition product, improved yields (up to 84%) were realized
when the reaction mixtures were saturated with oxygen. Ac-
initial results demonstrate the feasibility of using verdazyl
radicals as substrates for organic synthesis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Herein, we report the successful use of the 1,5-dimethyl-
3-phenyl-6-oxoverdazyl radical (1) as a precursor to a struc-
turally unique azomethine imine, which, in the presence of
dipolarophiles, undergoes [3+2] cycloaddition reactions to
give dihydrotetrazinone heterocyclic structures. Cycload-
dition reactions in general constitute one of the most
powerful methods for the synthesis of heterocyclic struc-
tures often found in therapeutic drugs, natural products and
advanced materials.[6]
The use of azomethine imines in 1,3-dipolar cycload-
dition (1,3-DC) reactions was highlighted in a seminal pa-
per by Huisgen.[7] Synthetic approaches to azomethine im-
ines include the condensation of pyrazolidinone derivatives
with aldehydes[8] or hydrazides with aldehydes,[9] as well as
deprotonation of alkylated N-nitrosoamines,[10] thermal[11]
and acid-catalyzed[12] isomerization of hydrazones and 1,4-
silatropic shifts in α-silylnitrosoamines.[13] Recent develop-
ments in the chemistry of azomethine imines include an
asymmetric variant of the reaction,[14] a formal [3+3][15] and
[4+3][16] cycloaddition, and a kinetic resolution of enantio-
mers using a chiral catalyst.[17]
Introduction
While radical molecules are typically transient species, ni-
troxide and verdazyl radicals are unusual in that they are
stable and in many cases can be isolated and stored for long
periods without any appreciable decomposition.[1] Histori-
cally, these stable radicals have been employed as spin
probes[2] or as polymerization inhibitors.[1,3] Recently, they
have been successfully used to moderate living-radical poly-
merizations.[4] Verdazyl radicals, in association with various
transition metals, are also showing promise as molecular
magnets.[5] To date, however, there are no examples of these
stable radicals having been used as substrates for organic
synthesis, presumably because of their perceived low reac-
tivity. In fact, it is their inability to initiate the radical poly-
merization of styrene and acrylate monomers that have en-
abled them to be so successful in mediating living-radical
polymerizations. But certain members of these families have
been shown to undergo various transformations under spe-
cific conditions. While the chemistry of these transforma-
tions is reasonably well known for nitroxides,[1b] the chemis-
try of verdazyl radicals is largely unexplored. We were in-
trigued by this latter omission and became interested in see-
ing if these molecules could find use as substrates for or-
ganic synthesis.
Results and Discussion
In an ongoing program to synthesize compounds con-
taining a benzylic C–N or C–O σ bond that could mediate
living-radical polymerization,[4] we added compound 1 to
styrene and benzoyl peroxide (BPO) under N2 anticipating
the formation of 2 [Equation (1)]. However, only a small
amount of compound 2 resulted with compound 3 being
the major product, although admittedly in modest yield.
[a] Department of Chemical and Physical Sciences, University of
Toronto at Mississauga,
3359 Mississauga Road, Mississauga, Ontario, Canada, L5L
1C6
E-mail: michael.georges@utoronto.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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A. Yang, T. Kasahara, E. K. Y. Chen, G. K. Hamer, M. K. Georges
SHORT COMMUNICATION
Scheme 1. Proposed reaction mechanism.
We surmised that compound 3 formed by a cycloaddition Table 1. Optimization of reaction conditions for the 1,3-dipolar cy-
cloaddition of 1 with styrene.
reaction via an azomethine imine (6) (Scheme 1), which in
turn, resulted from a disproportionation reaction between
two molecules of compound 1 to give leucoverdazyl 5 and
compound 6. Exploratory density functional theory calcu-
lations [B3LYP/6-31G(d)] support the hydrogen atom ab-
straction mechanism leading to the stable intermediates 5
and 6.[18] Intermediate 6 subsequently undergoes a 1,3-DC
reaction with styrene to give compound 3.[19] The re-
gioisomer 4 was not observed.
Entry
Conditions
Time [h]
% Yield of 3
1
2
3
4
5
6
N2
N2
air
24
96
24
24
48
72
26
46
52
63
66
70
[a]
O2[a]
O2[a]
O2
[a] Compressed gas.
The proposed mechanism suggests that BPO is not part
of the reaction sequence and this was verified by repeating
the aforementioned reaction in the absence of BPO. After
24 h, a 26% yield of 1 was obtained (Table 1, Entry 1), sim-
ilar to the yield in the presence of BPO [Equation (1)]. In-
creasing the reaction time to 96 h gave an improved yield
but still less than 50% (Entry 2). Assuming the proposed
reaction mechanism is correct this result should not be too
surprising since half the verdazyl radical is consumed to
form leucoverdazyl 5, a product that is stable in an inert
atmosphere but readily oxidized in air back to the verdazyl
radical.[20] The presence of 5 was confirmed indirectly by
isolating its benzylated derivative formed, after the cycload-
dition reaction was allowed to proceed for 24 h, by adding
sodium hydride and benzyl chloride to the reaction mix-
ture.[20] In an attempt to recycle 5 in situ and improve the
reaction yields, reactions were performed in air. While a
clear improvement in the yield of compound 3 of a 24-h
cycloaddition reaction was evident (Table 1, Entry 3), a bet-
ter result was obtained when the reaction was performed in
under O2 (Entry 4). Extending the reaction time beyond
24 h offered only marginal improvements (Entries 5, 6). Re-
actions performed in dichloromethane, acetone, and
DMSO showed the reaction rate to be relatively insensitive
to solvent polarity with isolated yields of compound 3 of
The reaction was subsequently extended to other olefinic
substrates (Table 2). Various acrylates reacted smoothly
(Entries 1–3) regardless of the steric bulk of the alkoxy moi-
ety (Entry 2) or the presence of a substituent on the α-
carbon (Entry 3). Reactions with diethyl fumarate and ma-
leate proceeded stereospecifically to give only one dia-
stereoisomer each (Entries 5,6), while N-methylmaleimide
afforded a tricyclic product (Entry 7). Reactions with iso-
prene gave 14 and 14Ј (Entries 8,9), with the disubstituted
double bond reacting slightly faster than the monosubsti-
tuted one. Lower yields were generally observed with acry-
lonitrile in comparison to styrene, methyl acrylate and
methyl methacrylate. (Entry 4). Reactions with unactivated
(1-hexene and cyclohexene) or electron-rich (vinyl ethyl
ether and N-vinylmorpholine) dipolarophiles provided very
low or no yield of cyclic products.
As a consequence of forming the azomethine imine from
45%, 51% and 53%, respectively. The lower yield in these 1, the structure of 6 differs from previously reported cyclic
reactions relative to the reaction in neat styrene (Table 1, and acyclic azomethine imines containing a hyrazide back-
Entry 4) can probably be attributed to a dilution effect.
bone. In the ylide resonance forms of the azomethine imines
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Eur. J. Org. Chem. 2008, 4571–4574

Verdazyl for 1,3-Dipolar Cycloaddition Reaction
Table 2. Summarized results from the 1,3-dipolar cycloaddition re- bone. In the ylide resonance forms of the azomethine imines
action with various dipolarphiles.[a]
derived from hydrazides 16 or pyrazolidinones 17, the alkyl
substituent is bonded to the β-nitrogen. In contrast, the
alkyl group in 6 is situated on the α-nitrogen. The charges
on the nitrogen atoms in the ylide structures are therefore
transposed (cf. 6 with 16 and 17), resulting in the cyclic
products derived from 6 having a different substitution
pattern compared to those from 16 or 17. The use of 1 as
a starting material also enables the incorporation of a novel
dihydrotetrazinone moiety into these heterocyclic struc-
tures.
In summary, we have demonstrated the use of a verdazyl
radical as a precursor for 1,3-DC reactions with various
dipolarophiles under mild conditions. The regioselective
and stereospecific nature of the cyclization reactions, the
various substrate reactivities and the insensitivity to solvent
polarity all support the 1,3-DC mechanism. This work pro-
vides access to unique bicyclic and tricyclic heterocyclic
compounds with structural motifs unattainable by other
1,3-DC reactions. These initial findings lay the foundation
for future work in this area. In that regard, an area that is
presently been investigated is an interesting and unexpected
rearrangement of some of these cyclic structures into a ge-
neral structure that has been shown to have anti-inflamma-
tory activity.
Experimental Section
Supporting Information (see also the footnote on the first page of
this article): Experimental data for cycloadducts and NMR spectra.
Acknowledgments
The authors gratefully acknowledge funding from the National Sci-
ence and Engineering Research Council of Canada and University
of Toronto (fellowships for T. K. and E. K.Y.C.).
[a] Reaction conditions: 1 (1.8 mmol) was dissolved in 10 equiv. of
substrate, the solution was purged with O2 for 10 min and the reac-
tion allowed to proceed for 24 h. [b] Isolated yield. [c] Dissolved in
5 mL of dry THF. [d] Reaction performed over 60 h. [e] Ratio of
14/14Ј.
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Eur. J. Org. Chem. 2008, 4571–4574
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Received: July 10, 2008
Published Online: August 12, 2008
4574
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Eur. J. Org. Chem. 2008, 4571–4574