employing transition metal catalysts.6 We envisaged that
ortho-metallated phenyl isocyanides which, to our knowl-
edge, are not known7 could also be versatile precursors for
certain types of heterocycles.
and hypoglycemic agents.10,14 They are also potent antibac-
terial, antifungal, antiviral, antimycobacterial, and antima-
larial agents.10 Therefore, not surprisingly, they have been
included in the list of molecules with “privileged structure”15
for combinatorial chemistry, capable of binding to multiple
receptors with high affinity.16 Many of the numerous reported
syntheses of these heterocycles start from anthranilic acid
or its derivatives, but none of them use the advantages of
isocyanide chemistry.17,18
In particular, 3H-quinazolin-4-ones, some derivatives of
which occur as natural products8,9 (Figure 2), might be
To investigate the possibility of generating ortho-metal-
lated phenyl isocyanide, two possible precursors for
halogen-metal exchange reactions, ortho-bromo- and ortho-
iodophenyl isocyanides 1 and 2a, were synthesized. The iodo
derivative 2a turned out to undergo fast (<10 min) trans-
metallation reactions, when it was treated with n-BuLi,
t-BuLi (-100 °C), or i-PrMgCl·LiCl19 (-78 °C) in THF.
The target ortho-lithiophenyl isocyanide could also be
obtained from the bromo derivative 1, synthesized from
inexpensive 2-bromoaniline. The best and most reproducible
results, in this case, were achieved with n-BuLi in THF at
-78 °C. Different electrophiles were tested in their reaction
with ortho-lithiophenyl isocyanide generated in situ in this
way (Table 1). The respective 2-substituted phenyl isocya-
Figure 2.
Some naturally occurring 3H-quinazolin-4-ones.8,9
accessible by reactions of such ortho-metallated phenyl
isocyanides with isocyanates. This would be extremely
useful, as 3H-quinazolin-4-ones have been reported to
possess a vast range of biological activities, including
analgesic, anti-Parkinsonian, CNS depressant, and CNS
stimulating as well as tranquilizing, antidepressant, and
anticonvulsant effects. Some of these compounds also act
as psychotropic, hypnotic, cardiotonic, and antihistamine
agents10,11 and possess cardiovascular activity as well as
antiinflammatory activity.10,12 Quinazolinones also inhibit
monoamine oxidase, aldose reductase, tumor necrosis factor
R, thymidylate synthase, pyruvic acid oxidation, as well as
acetylcholine-esterase activity and are antitumor, antiulcer,
antiplatelet aggregation (glycoprotein IIb/IIIa inhibitors),13
Table 1. Synthesis of 2-Substituted Phenyl Isocyanides
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(7) R-Addition of organolithium reagents to phenyl isocyanide followed
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(13) (a) Liverton, N. J.; Armstrong, D. J.; Claremon, D. A.; Remy, D. C.;
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for 2-formylphenyl isocyanide 2d (55%). The standard
reagent for the electrophilic installation of a formyl group,
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