Facile transformation of benzocyclobutenones into 2,3-benzodiazepines via 4π-8π tandem electrocyclic reactions involving net insertion of diazomethylene compounds

Article abstract of DOI:10.1021/ja065277z

Efficient transformations of benzocyclobutenones into 2,3-benzodiazepines by a formal insertion of diazomethylene compounds are described. This sequential process includes nucleophilic addition of diazomethylene anion, oxy-anion accelerated o-quinodimethane formation by an electrocyclic ring-opening reaction, and 8π-electrocyclization in one-pot under remarkably mild conditions. Intermediary oxy-anion plays an important role for the efficient transformations. Copyright

Full text of DOI:10.1021/ja065277z

Published on Web 09/20/2006
Facile Transformation of Benzocyclobutenones into 2,3-Benzodiazepines via
4π-8π Tandem Electrocyclic Reactions Involving Net Insertion of
Diazomethylene Compounds
Yuji Matsuya, Noriko Ohsawa, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, UniVersity of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Received July 24, 2006; E-mail: nemotoh@pha.u-toyama.ac.jp
Scheme 1
Benzocyclobutenes have been a powerful tool for organic
synthesis and utilized for past decades, especially for construction
of polycarbocyclic and heterocyclic systems.1 Versatility of this
class of compounds is mainly attributed to facile formation of highly
reactive o-quinodimethane intermediates, which can participate in
tandem pericyclic reactions in an inter- or intramolecular fashion
such as electrocyclization and Diels-Alder reactions.1a,b Facility
of the thermally allowed conrotatory 4π-electrocyclic ring opening
of benzocyclobutenes has been known to highly depend on the
electronic nature of the substituent(s) on the cyclobutene ring; in
Scheme 2
general, electron-donating substituents facilitate the quinodimethane
formation with a strong outward torquoselectivity.2,3 Particularly,
the accelerating effect of an oxy-anion substituent is striking, which
enforces the ring fission at temperatures even below 0 °C despite
loss of the 6π aromatic stability of the benzene ring.4 It is expected,
reversely, that the second pericyclic reaction of the quinodimethane
thus formed can proceed more easily than that of the usual diene
Table 1. Transformation of Benzocyclobutenones into
compounds because of reconstruction of the stable 6π aromatic
system involved. Although these sequential processes have been
applied for various synthetic studies,1a it still remains to be
developed for new ring system construction.5 In this Communica-
tion, we wish to report a notably facile and mild transformation of
benzocyclobutenones to 2,3-benzodiazepines, which is a biologically
important heterocyclic core structure.6 This transformation is
accomplished through a nucleophilic addition of a diazomethylene
anion followed by a cascade electrocyclic reaction sequence
involving a formal and net diazomethylene insertion into the
cyclobutene ring.
Our strategic outline is illustrated in Scheme 1, representing
stepwise transformations with three running reactions. The initial
nucleophilic addition of diazomethylene anion to benzocyclo-
butenone 1 provides an alkoxide 2, which may easily undergo an
oxy-anion-accelerated electrocyclic ring-opening reaction at low
temperature to generate o-quinodimethane 3. Strong preference for
outward rotation of the oxide group can dictate the geometry of 3,
in which the diazo function lies at a favorable position for the next
electrocyclization. Formal 8π electrocyclization of 3 will be
promoted by the reconstruction of the stable benzene ring to furnish
the 2,3-benzodiazepine derivative 5 via its enolate form 4 (Scheme
1).
Initially, lithiated (trimethylsilyl)diazomethane was examined as
a nucleophile, and several substituted benzocyclobutenones (1a-
d) were subjected for the reaction (Scheme 2). (Trimethylsilyl)-
diazomethane was treated with n-BuLi in THF at -78 °C, and to
the resulting solution, the benzocyclobutenone (1) was added at
the same temperature. After that, a cooling bath was immediately
removed to allow the reaction to warm to ambient temperature for
1 h. Gratifyingly, in all cases (substrates 1a-d), clean conversion
was observed to result in the formation of 2,3-benzodiazepin-5-
ones (5a-d) in high isolated yields (Table 1, entries 1-4). Because
2,3-Benzodiazepines
entry
benzocyclobutenone
reagent
product
yield (%)a
1
2
3
4
5
6
7
8
1a (R1 ) R2 ) H)
5a
5b
5c
5d
6a
6b
6c
6d
70
79
72
82
67
79
78
69
1b (R1 ) H, R2 ) OMe)
R ) TMSb
1c (R1 ) OMe, R2 ) H)
1d (R1 ) R2 ) OMe)
1a
1b
1c
1d
R ) CO2Etc
a
Isolated yields. b The substrate was allowed to react with 3.6 equiv of
the reagent in THF at -78 °C and then immediately warmed to room
temperature for 1 h. c The substrate was allowed to react with 3.0 equiv of
the reagent in THF at -78 °C for 15 min and then warmed to room
temperature for 1 h.
precedent researches have suggested that the o-quinodimethane
formation under the influence of the oxide group can be achieved
at ca. -25 °C,4 we consider that the present reaction proceeded
through the tandem electrocyclic reactions depicted in Scheme 1.
Although there have been several reports on 1,2-diazepine syn-
thesis, including benzodiazepines, via an analogous 1,7-electro-
cyclization of diazo compounds,7 all of these require thermal
activation and often suffer from predominant pyrazole formation
via 1,5-cyclization.8 In our reaction system, on the other hand, high
reactivity and geometrical fixation of the quinodimethane inter-
mediate are reason for the efficient transformation under the
extraordinarily mild conditions, which have not been reported in
the similar diazepine synthesis, to the best of our knowledge.
We expected that a simple adduct 7 could be isolated when the
reaction of 1b was stopped at -78 °C. This compound was,
however, found to be so unstable in aqueous solvent at room
temperature that degradation took place with loss of nitrogen during
a workup process, to produce indanone derivatives (8 and 9) in
9
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10.1021/ja065277z CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
35% and 41% yields, respectively. This transformation is associated
with one-carbon homologation of ketones, which has been fre-
quently utilized in diazomethane chemistry as a carbenoid.9
In summary, we have described a remarkably facile and mild
transformation of benzocyclobutenones into 2,3-benzodiazepines
based on anion-accelerated successive electrocyclic reactions. This
reaction has the following advantages: (1) the oxy-anion formed
by the nucleophilic addition extremely facilitates the first electro-
cyclic ring-opening, (2) the exclusive outward torquoselectivity of
the oxide group dictates geometry of the o-quinodimethane as
required for the next electrocyclization, and (3) reconstruction of
the stable 6π aromatic system facilitates the second 8π electro-
cyclization, involving a diazo group, which usually requires thermal
activation. Further applications are in progress for the synthesis of
various derivatives using o-quinodimethane chemistry.
For comparison, the substrate 1b was conducted to the reaction
promoted by Lewis acid, which is a standard condition for such
homologation reactions,10 leading to the formation of the ring-
expanded product (8) and acetyl derivatives (10, a mixture of silyl-
containing and desilylated compounds) in a high total yield (Scheme
3).11 These acid-promoted reactions are in good contrast with the
anion-mediated diazepine-forming reaction, in which (trimethyl-
silyl)diazomethane acts as a C-N-N three-atom source.
CAUTION: Some of the diazo compounds may be explosive
and should be handled with great care.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (5a-d, 6a-d, and 11).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Scheme 3
References
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The other diazomethylene anion such as lithiated diazoacetate
was demonstrated to work well for the diazepine-forming reaction
as shown in Scheme 2 and Table 1 (entries 5-8). In every case,
efficient transformation was achieved to afford 2,3-benzodiazepin-
5-ones possessing a carboxylate functionality at the 4-positions.
These results imply that a wide variety of R-diazocarbonyl
compounds, which can generate a corresponding diazomethylene
anion, may be applicable for the synthesis of functionalized 2,3-
benzodiazepine derivatives. As shown in Scheme 4, when using
diazoacetate with 1b, a corresponding adduct alcohol 11 could be
isolated in a high yield by quenching the reaction at -78 °C. In
addition, this compound was confirmed to be a precursor of the
diazepine product, because the alkoxide regenerated by treatment
of 11 with LDA was cleanly converted to the diazepine 6b after
warm to room temperature.12 On the other hand, thermal reaction
of 11 in refluxing benzene resulted in a formation of a complicated
mixture including ring-expanded compounds with loss of nitrogen,
and the diazepine 6b could not be detected. Thus, the oxide anion
has a good effect on the benzodiazepine-forming reaction, keeping
low reaction temperature to circumvent the thermal decomposition
of the diazo group.
(3) In conjunction with this subject, we have recently reported that the
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Soc. 2006, 128, 412-413.
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(11) The latter products (10) were probably formed via epoxide formation,
acid-catalyzed isomerization to form aldehyde, and further one-carbon
homologation.
Scheme 4
(12) A retroreaction to release the diazomethylene anion is responsible for the
somewhat lower yield of 6b (69%) than that expected, which is supported
by the isolation of the ketone 1b (30% yield) from the reaction medium.
This implies that the initial nucleophilic addition step is in equilibrium,
and therefore, 3.0 equiv of lithiodiazoacetate was used to increase the
adduct form.
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