Triphenyl verdazyl radicals' reactivity with alkyne carboxylates as a synthetic route to 1-(phenyldiazenyl)isoquinoline-3,4-dicarboxylates

Article abstract of DOI:10.1016/j.tetlet.2012.05.135

A series of 1-(phenyldiazenyl)isoquinoline-3,4-dicarboxylates are synthesized by a unique reaction of triphenyl verdazyl radical with di-substituted electron deficient alkyne carboxylates. This transformation allows for the quick synthesis of this class of compounds in just three steps starting from a hydrazone. A radical mechanism that is consistent for the substitution patterns observed in the series of compounds made is proposed. The final product is obtained by a subsequent retro-Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.135

Tetrahedron Letters 53 (2012) 4026–4029
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Tetrahedron Letters
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Triphenyl verdazyl radicals’ reactivity with alkyne carboxylates as a
synthetic route to 1-(phenyldiazenyl)isoquinoline-3,4-dicarboxylates
⇑
Matthew Bancerz , Ernest Prack, Michael K. Georges
Department of Chemical and Physical Sciences, University of Toronto at Mississauga, 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-(phenyldiazenyl)isoquinoline-3,4-dicarboxylates are synthesized by a unique reaction of tri-
phenyl verdazyl radical with di-substituted electron deficient alkyne carboxylates. This transformation
allows for the quick synthesis of this class of compounds in just three steps starting from a hydrazone.
A radical mechanism that is consistent for the substitution patterns observed in the series of compounds
made is proposed. The final product is obtained by a subsequent retro-Diels–Alder reaction.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Received 4 May 2012
Revised 25 May 2012
Accepted 29 May 2012
Available online 7 June 2012
Keywords:
Verdazyl
Isoquinoline
Rearrangement
Azo
Gomberg synthesized the first detectable radical molecule,
namely, the triphenylmethyl radical, in 1900 marking the begin-
ning of organic radical chemistry.1 In organic synthesis, their
advantages as reagents having high functional group tolerance,
as well as the ability to react under very mild conditions, have of-
ten been overshadowed by their propensity to undergo side reac-
tions due to their reactive nature. Hence, they have had limited
acceptance by synthetic organic chemists as substrates toward
making small molecules. One of their niche uses is in cyclization
reactions, where they are applied quite successfully in the forma-
tion of a wide variety of ring systems.2
Stable organic radicals, although having found uses in many
other fields of chemistry, have been viewed as little more than nov-
elty compounds by the synthetic organic chemist. One family of sta-
ble organic radicals, verdazyl radicals, has found applications in the
study of molecular magnets,3 in ESR as spin labels,4 as polymeriza-
tion inhibitors,5 and as mediators in living radical polymerizations.6
Only recently has our group demonstrated their usefulness in
generating heterocyclic small molecules via a slow disproportion-
ation reaction between two 1,5-dimethyl-6-oxoverdazyl radicals
leading to azomethine imine intermediates capable of undergoing
1,3-dipolar cycloadditions with a variety of dipolarophiles.7
Departing from this 1,3-dipolar cycloaddition chemistry, we re-
port herein the synthesis of a variety of 1-(phenyldiazenyl)isoquin-
olines starting with a series of 1,3,5-triphenyl verdazyl radicals.
Isoquinolines are a common feature of many alkaloids.8 They also
appear as structural motifs in many drugs including quinapril, an
antihypertensive,9 papaverin, a vasodilator,10 and dimethisoquin,
an anesthetic.11 Although common syntheses for isoquinolines
are well known, as for example the Pomeranz–Fritsch and Bisch-
ler–Napieralski reactions, more recent developments include work
by Stoltz,12 Ma,13 and Lang.14 In contrast to these methods, the ap-
proach presented here leads directly to 3,4-substituted 1-phen-
yldiazenyl isoquinolines from verdazyl radicals and disubstituted
alkyne carboxylates.
In 1972, Neugebauer et al.15 reported a thermal disproportion-
ation reaction of the 1,3,5-triphenyl verdazyl radical to form the
corresponding leucoverdazyl and a 1,2,4-triazole. This suggested
to us that the triphenyl verdazyl radical could have an intermedi-
ate, analogous to the azomethine imines we observed with the ox-
overdazyl radical,7 leading to an intramolecular rearrangement to
form the triazole product reported. Attempts to trap this hypothe-
sized 1,3-dipole with the common dipolarophiles methyl acrylate
and styrene were unsuccessful. Only Neugebauer’s reported leu-
coverdazyl and 1,2,4-triazole were isolated along with a number
of unidentifiable by-products. We then tried a very electron poor
alkyne, dimethyl acetylene dicarboxylate (DMAD), as a dipolaro-
phile. After 24 h of heating 1,3,5-triphenyl verdazyl radical with
DMAD at 60 °C, a bright red compound was isolated in 62% yield,
later identified as compound 5 (Table 1) via single crystal X-ray
crystallography. This resulting dimethyl-1-(phenyldiazenyl)iso-
quinoline-3,4-dicarboxylate (5) structure surprised us since we
surmised that if 1,3,5-triphenyl verdazyl disproportionated, it
would form a dipole across the N-2 and C-6 positions which would
react with a dipolarophile as illustrated in Scheme 1.
⇑
Corresponding author.
E-mail address: matthew.bancerz@utoronto.ca (M. Bancerz).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.135

M. Bancerz et al. / Tetrahedron Letters 53 (2012) 4026–4029
4027
Table 1
Reactants and isoquinoline products
Entry
Verdazyl
Alkyne
Product(s)
Yield(%)
MeO2C
N
N
N
N
N
N
CO2Me
MeO2C
MeO2C
N
1
62
5
EtO2C
N
N
N
N
N
N
Ph
EtO2C
Ph
N
2
28
11
tBuO2C
N
N
N
N
N
N
t
CO2 Bu
tBuO2C
tBuO2C
N
3
63
10
MeO2C
N
N
N
N
N
N
CO2Me
MeO2C
MeO2C
N
4
49
Cl
Cl
6
MeO2C
N
N
N
N
N
N
N
N
CO2Me
MeO2C
MeO2C
N
MeO2C
MeO2C
N
5
6
7
28+26
Cl
Cl
Cl
8
9
MeO2C
N
N
N
N
N
N
CO2Me
MeO2C
MeO2C
N
58
Cl
Cl
7
MeO2C
N
N
N
N
N
N
CO2Me
MeO2C
MeO2C
N
57
O
O
12
To elucidate the mechanism of the observed transformation, a
series of chlorine substituted verdazyl radical derivatives were
made to ascertain where all the atoms were coming from in the fi-
nal isoquinoline. Entry 4 in Table 1 shows the chlorine from the
ortho-chloro derivative of the verdazyl radical ending up in the 5
position on the isoquinoline. The para-chlorine group ends up in
the 8 position (entry 6). Predictably the meta derivative should give
2 regioisomers and that is what is observed, with the regioisomers

4028
M. Bancerz et al. / Tetrahedron Letters 53 (2012) 4026–4029
N
N
N
NH
N
N
N
N
H
H
N
N
N
N
MeO2C
CO2Me
N
N
N
N
X
N
CO2Me
CO2Me
N
N
N
Scheme 1. Anticipated but not observed reaction mechanism and product for reaction of 1,3,5-triphenyl verdazyl radical with DMAD.
forming in approximately a 1:1 ratio. These experiments allowed
us to postulate the mechanism shown in Scheme 2.
a benzene ring as a driving force to give a dihydrotetrazinoisoquin-
oline fused ring system (c). This fused ring system then undergoes
a retro-Diels–Alder reaction to yield the final product. During the
course of the reaction an equivalent of verdazyl radical is reduced
to leucoverdazyl which one would expect to limit the theoretical
yield to 50%. However, when leucoverdazyl is isolated and left ex-
posed to air, it is observed to start oxidizing back to the verdazyl
radical within minutes, as evidenced by TLC and a color change
to green, the distinct color of this verdazyl radical. This rapid
According to this mechanism the verdazyl radical directly at-
tacks the low lying LUMO of the doubly EWG substituted alkyne
to form a vinyl radical (a). This unstable vinyl radical reacts with
the adjacent phenyl ring intramolecularly to form the delocalized
radical shown in the second step as intermediate (b). Another
equivalent of verdazyl radical then abstracts a hydrogen atom (a
feature of verdazyl chemistry we have previously seen7) reforming
N
N
N
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
a
V
b
N
N
N
N
N
N
N
CO2Me
CO2Me
N
CO2Me
CO2Me
Retro Diels-Alder
5
c
= 1,3,5-triphenylverdazyl radical
V
Scheme 2. Postulated mechanism for the formation of isoquinoline products derived from a triphenyl verdazyl radical.

M. Bancerz et al. / Tetrahedron Letters 53 (2012) 4026–4029
4029
oxidation of leucoverdazyl to verdazyl radical by atmospheric oxy-
Acknowledgments
gen is also reported by Neugebauer.16 Hence, throughout the reac-
tion, it is probably the case that the leucoverdazyl is recycled back
to the verdazyl radical.
Support was provided by the National Science and Engineering
Research Council of Canada. M.B. gratefully acknowledges a Uni-
versity of Toronto (UT) fellowship and a Helen Sawyer Hogg Grad-
uate Admission UT Fellowship. X-ray analysis was performed by
Alan Lough at the University of Toronto.
A series of isoquinolines were synthesized with yields ranging
from 28–63% as shown in Table 1. The low yield of entry 2 is not
surprising given that the alkyne used would have the highest en-
ergy LUMO and, therefore, be least accessible to radical attack.
Product 11 (entry 2) was isolated as a single regioisomer and its
structure confirmed by X-ray crystallography. The remaining
examples used alkynes substituted with two ester groups leading
to more satisfying yields of 49–63%. Entry 5, because of two possi-
ble orientations of the 3-(3-chlorophenyl) group can be preceding
the second step in Scheme 2, leading to two products in a near 1:1
ratio with a total yield of 54%.
We envisaged extending this chemistry to verdazyl radicals
with aromatic heterocycles at the 3 position. This would lead to
other ring systems such as naphthyridines in the case of pyridyl
derivatives and fused thienopyridines and furanopyridines in the
cases of thiophene and furan derivatives, respectively. All three
pyridyl derivatives, 2, 3, and 4-pyridyl, were prepared using litera-
ture procedures,17 however, upon addition of DMAD they reacted
very rapidly, resulting in a plethora of products. The reactions were
repeated at 0 °C under dilute conditions with only one equivalent
of DMAD, however, there still remained the difficulty of isolating
the reaction products clean enough for unambiguous characteriza-
tion. The thiophene and furan substituted verdazyl radicals, unre-
ported in the literature, proved elusive to synthesize with known
methods.
In conclusion, we have demonstrated a unique reactivity of
1,3,5-triphenyl verdazyl radicals and to our knowledge the first
application to small molecule synthesis with this class of verdazyl
radical. Their reaction with electron poor disubstituted alkyne car-
boxylates generate in one step a series of unique 1-(phenyldiaze-
nyl)isoquinoline-3,4-dicarboxylates in yields generally greater
than 50% under relatively mild conditions. These verdazyl radicals
themselves can be made in two steps starting from a hydrazone
thus providing a quick and easy access to this class of isoquino-
lines. A radical based mechanism for the formation of these
compounds, consistent with all the substitution patterns observed
in the products and involving as its last step a retro-Diels–Alder
reaction, is proposed.
Supplementary data
Supplementary data (experimental details, analytical data and
NMR spectra for compounds 1–12 as well as ORTEP’s for com-
pounds 5, 7 and 11) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
135. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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