The synthesis of a verdazyl radical-derived biphenylophane

Article abstract of DOI:10.1016/j.tetlet.2012.06.141

Biphenylophanes with two stacked biphenyl units are synthetically challenging and consequently are rare. Herein, we report on the synthesis of a [3.3](3,4′,3,4′)biphenylophane, formed from bifunctional verdazyl radicals. Its formation is surmised to originate from two intermediate verdazyl radical-derived azomethine imines and their subsequent tandem inter-intramolecular 1,3-dipolar cycloaddition reaction with each other.

Full text of DOI:10.1016/j.tetlet.2012.06.141

Tetrahedron Letters 53 (2012) 4877–4879
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of a verdazyl radical-derived biphenylophane
⇑
Jeremy D. Dang , Gordon K. Hamer, 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:
Biphenylophanes with two stacked biphenyl units are synthetically challenging and consequently are
rare. Herein, we report on the synthesis of a [3.3](3,40,3,40)biphenylophane, formed from bifunctional ver-
dazyl radicals. Its formation is surmised to originate from two intermediate verdazyl radical-derived azo-
methine imines and their subsequent tandem inter-intramolecular 1,3-dipolar cycloaddition reaction
with each other.
Received 14 June 2012
Accepted 29 June 2012
Available online 6 July 2012
Keywords:
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Verdazyl radical
Biphenylophane
1,3-Dipolar cycloaddition
Azomethine imine
Verdazyl radicals have been shown to be useful as spin probes,1
polymerization inhibitors,2–4 substrates for molecular magnets,5–7
and mediators for living-radical polymerizations.8 They have also
been demonstrated to be excellent substrates for organic synthesis
and have provided a variety of distinctive nitrogen-containing het-
erocyclic compounds as a result of a disproportionation reaction
that produces azomethine imine intermediates that can subse-
quently undergo 1,3-dipolar cycloaddition (1,3-DC) reactions with
various dipolarophiles.9 The emergence of verdazyl radicals as
starting materials for organic synthesis marks a cornerstone in
their history, opening up a whole new area of research for them.
In a continuing effort to explore the chemistry of verdazyl radicals
as novel organic substrates, our laboratory initiated a study to
scope out the different types of verdazyl-derived molecular scaf-
folds that could be constructed from them.
Bridged aromatic compounds, known as phanes, have attracted
considerable interest in the last few decades due to their synthetic
challenges, conformational behaviors, structural properties, and
their role as molecular receptors in host–guest binding chemis-
try.10–14 Phanes that incorporate a single bridged biphenyl unit in
their molecular structure are called biphenylophanes and only a
small number of these structures have been synthesized.15–17 Even
rarer are biphenylophanes with two bridging biphenyl moieties
used as an entry into their synthesis and in the process augment
the collection of [12]-, [13]-, and [21]-paracyclophanes we recently
reported.19 Within this present investigation, we describe two syn-
thetic routes to 1,5-dimethyl-3-(40vinylbiphenyl-3-yl)-6-oxoverda-
zyl radical 4, and its subsequent conversion into [3.3](3,40,3,40)
biphenylophane 5.
The blueprint for the synthesis of 5 required the intermediacy of
the 6-oxoverdazyl radical 4. Verdazyl radical 4 was specifically de-
signed to incorporate a styrene dipolarophile functionality as part
of its structure in order to grant the molecule the bifunctional role
of a 1,3-dipole, via an intermediate azomethine imine, and a dipol-
arophile, via the styrene functionality.
Verdazyl radical 4 was initially synthesized in a three-step pro-
cess that started with a Suzuki coupling reaction of 3-bromobenz-
aldehyde with 4-vinylphenylboronic acid in the presence of
tetrakis(triphenylphosphine)palladium(0) and potassium carbon-
ate at 110 °C that afforded 40-vinylbiphenyl-3-carbaldehyde (1)
in 85 % yield (Scheme 1). A condensation reaction of 1 with N,N0-
dimethylcarbonohydrazide (2) at 85 °C gave 1,5-dimethyl-3-(40-
vinylbiphenyl-3-yl)-1,2,4,5-tetrazinan-6-one (3) in 45 % yield.
Tetrazinanone 3 was treated with NaIO4 in a biphasic system to
afford verdazyl radical 4 in 85 % crude yield. The purification of
4, using standard silica gel column chromatography, gave a low
yield of the product. We suspect some decomposition of the
verdazyl radical occurred on the column, which is not unusual
for verdazyl radicals in general. Numerous attempts at crystalliz-
ing 4 from the crude reaction mixture failed. It was decided based
on these results to use 4 as recovered from the oxidation reaction.
Biphenylophane 5 was obtained in 14% yield by heating ver-
dazyl radical 4 in THF at 55 °C for 5 days under an atmosphere of
oxygen gas. The yield was determined with respect to the crude
verdazyl radical mixture and is in line with the yields reported
arranged in a p-stacked orientation—face-to-face, edge-to-face, or
slip-stacked. One of the few examples is 1,8-bis[(4-(tributylstan-
nyl)phenyl]naphthalene, obtained from 1,8-[1,8-naphthalenediylbis
(40,4-biphenyldiyl)]naphthalene via a copper-catalyzed coupling
reaction reported by Iyoda et al.18 This scarcity of biphenyl-stacked
biphenylophanes prompted us to see if verdazyl radicals could be
⇑
Corresponding author. Tel.: +1 905 828 5528.
E-mail address: jdpenny.dang@mail.utoronto.ca (J.D. Dang).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.141

4878
J. D. Dang et al. / Tetrahedron Letters 53 (2012) 4877–4879
B(OH)2
(1.5 equiv),
O
O
O
O
H
Pd(PPh3)4 (0.05 equiv),
K2CO3 (2.5 equiv),
N
N
N
NH
N
NH
(2, 1.1 equiv),
H
NH2 NH2
DMF, 110oC, 16 hrs
Toluene, 85oC
45 %
Br
85 %
3
1
NaIO4 (2.5 equiv),
EtOAc / H2O
(Biphasic)
O
85 %
(Crude)
N
N
N
N
O
N
N
O
O
N
N
N
N
N
H
N
N
N
N
O2,
THF, 55oC
5 days
+
+
N
N
H
N
N
N
N
N
O
5
6
7
5 %
4
14 %
10 %
O
Scheme 1. Synthetic route to biphenylophane 5.
by other groups for the synthesis of their biphenyl-stacked biphe-
nylophanes.20–22 1H and 13C NMR spectra were consistent with the
structure of 5 and were further confirmed via a single crystal X-ray
diffraction analysis (See Supplementary data, CCDC deposition
number: 880927).
The synthetic route outlined above for 3 involved the use of two
hazardous chemicals, triphosgene, and methyl hydrazine. A safer,
and more reproducible, alternative route to 3 involved the reaction
of carbohydrazide with 1 to form the bishydrazone 8 in 82% yield
(Scheme 2).23 A sodium hydride-induced dimethylation reaction of
8 gave 9 in 85% yield. A subsequent ring closure in the presence of
p-toluenesulfonic acid and carbohydrazide produced tetrazina-
none 3 in 53% yield.
In a previous paper, we reported on the synthesis of pyrazolotet-
razinanone heterocyclic compounds from their respective verdazyl
radicals and proposed that their formation occurred via the inter-
mediacy of an azomethine imine, which subsequently underwent
a 1,3-DC reaction with various dipolarophiles.5 In the present inves-
tigation, where the styrene dipolarophile functionality is appended
to the verdazyl radical structure, we surmise that the mechanism
for the transformation of 4 to 5 proceeds by a tandem inter-intra-
molecular double 1,3-DC process (Scheme 3). Two molecules of ver-
dazyl radicals 4 react with each other in a disproportionation-type
hydrogen abstraction reaction to form the leucoverdazyl 4a and the
azomethine imine 4b, a 1,3-dipole. To improve the yield of 5, the
reaction is carried out under an atmosphere of oxygen to oxidize
4a back to 4. The azomethine imine 4b reacts in an intermolecular
1,3-DC reaction with a molecule of 4 via the styrene functionality to
give the verdazyl cycloadduct 4c. A second disproportionation reac-
tion converts 4c into the azomethine imine cycloadduct 4d, which
cyclizes through an intramolecular 1,3-DC reaction to afford biphe-
nylophane 5. An alternative mechanism, where two intermolecular
1,3-DC reactions take place simultaneously between two azome-
thine imines 4b, is unlikely. The formation of 4b is suggested to
be the rate-determining step and once it is formed in situ, it reacts
immediately with a nearby dipolarophile, in this case the styryl unit
on another verdazyl radical. Due to their high reactivity it is highly
improbable that two azomethine imines would remain around long
enough that they would approach each other at the same time, with
the right orientation, and undergo two intermolecular 1,3-DC reac-
tions simultaneously to form 5.
The yield of 5 is reduced, in part, due to the formation of two
semicarbazone compounds, 6 and 7, formed in 10 % and 5 % yields,
respectively. These semicarbazone structures, with a nitrogen
atom missing from the tetrazinanone backbone, were unexpected.
To determine if this is a general reaction of verdazyl radicals, a
solution of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical (10) in
DCM was allowed to stir at room temperature for 7 days (Scheme
4). From the reaction mixture, 11 was isolated in 11 % yield. This
signifies that verdazyl radicals do decompose over time to form
semicarbazones, a finding previously unreported.
O
O
O
H
HN
N
NH
N
HN
NH2 NH2
NH
(0.45 eq),
MeOH, Reflux
82 %
8
1
O
O
O
NaH (3 eq),
THF (anh.), Reflux
S
O
(2.2 eq) 85 %
O
The versatility of verdazyl radicals as organic substrates in
heterocyclic syntheses was examined by employing one of these
stable radicals in the synthesis of a biphenyl-stacked biphenylo-
phane, rare compounds found in the family of phanes. Within this
Letter, we have described the synthetic approach to both the [3.3]
(3,40,3,40)biphenylophane (5) and its precursor, 1,5-dimethyl-3-(40-
vinylbiphenyl-3-yl)-6-oxoverdazyl radical (4). The four-step syn-
thesis to forming 5 was initiated with the Suzuki coupling reaction
between 4-vinylphenylboronic acid and 3-bromobenzaldehyde to
give 40-vinylbiphenyl-3-carbaldehyde (1), which was subsequently
O
(1.5 eq),
HN
NH
N
N
N
N
NH2 NH2
3
p-TsOH (2.2 eq),
MeOH
53 %
9
Scheme 2. Alternative synthetic route to tetrazinanone 3.

J. D. Dang et al. / Tetrahedron Letters 53 (2012) 4877–4879
4879
O
O2
N
N
N
N
O
H
CH2
O
H
CH2
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
N
N
N
N
4b
H
Abstraction
Concerted
Intermolecular
1,3-DC
+
+
N
N
N
N
4
4a
4b
5
4
O
Intermolecular
4
1,3-DC
Intramolecular
1,3-DC
O
O
N
N
N
N
N
N
N
N
H Abstraction
N
N
N
N
O
N
N
4d
4c
N
N
O
Scheme 3. Proposed mechanism for the transformation of verdazyl radical 4 to biphenylophane 5.
References and notes
O
O
DCM
rt, 7 d
N
N
N
N
N
N
N
H
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Acknowledgments
The authors wish to acknowledge funding for this research from
the Natural Sciences and Engineering Research Council (NSERC) of
Canada.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.141.