the acylnitroso hetero-Diels-Alder reaction to give a 79%
yield of the desired N-tosyl cycloadduct 11. Encouragingly,
treatment of cycloadduct 11 with palladium(0) provided the
targeted benzodiazepine 12. While the yield was quite modest
(20%), the concept of lowering the pKa of the nucleophile
to induce benzodiazepine formation had been demonstrated.
To increase the yield of benzodiazepine formation, the pKa
was lowered further by incorporating a nitro group onto the
sulfonamide. Once again, starting from anthranilic acid (4),
the 3-nitrobenzenesulfonamide 13 was produced in 64% yield
(Scheme 4, B). Coupling of acid 13 with O-tert-butyldim-
ethylsilyl hydroxylamine,19 followed by removal of the silyl
protecting group, provided hydroxamic acid 15. Oxidation
of the hydroxamic acid in the presence of cyclopentadiene
gave the desired cycloadduct 16 in 81% yield from acid 13.
Treatment of cycloadduct 16 with palladium(0) provided
benzodiazepine 17 in 38% yield. Thus, by lowering the pKa
of the sulfonamide through the inclusion of a nitro group,
the yield of benzodiazepine formation nearly doubled.
Continuing the trend of lowering the sulfonamide pKa, 2,4-
dinitrobenzenesulfonamide cycloadduct 21 was targeted.
Initially, an attempt was made to construct cycloadduct 21
from anthranilic acid (4). Treatment of anthranilic acid (4)
with 2,4-dinitrobenzenesulfonyl chloride and sodium carbon-
ate did not give the desired sulfonamide, however. Instead,
2,4-dinitroaniline 20 was obtained, presumably through the
intramolecular Meisenheimer complex 19 (Scheme 5).20
Scheme 6a
a Reagents: (i) 2,4-dinitrobenzenesulfonyl chloride, pyridine,
CH2Cl2, 56%; (ii) Pd(PPh3)4, THF, ∆, 56%.
exposed to palladium(0), a gratifying 56% yield of the
desired benzodiazepine 22 was obtained. The structure of
22 was confirmed by analysis of the X-ray crystal structure
(see Supporting Information). The increased yield of ben-
zodiazepine 22 demonstrated a clear trend between the pKa
of the nucleophilic sulfonamide and the yield of benzo-
diazepine formation.
In conclusion, the biologically important 1,4-benzodiaz-
epine template was shown to be accessible from acylnitroso
hetero-Diels-Alder cycloadducts in a single synthetic trans-
formation. Furthermore, a trend was observed between the
pKa21 of the cycloadduct sulfonamide and the yield of
benzodiazepine formation. As the pKa of the sulfonamide
decreased, the yield of the reaction increased. An intriguing
feature of the benzodiazepines formed from the cycloadduct
rearrangement is the presence of a hydroxamic acid in the
benzodiazepine ring system. This presents the possibility of
metal binding and so makes these benzodiazepines interesting
potential substrates for and inhibitors of metalloenzymes such
as the zinc containing ras farnesyltransferase.9 Biological
testing against ras farnesyltransferase, as well as broad screen
testing of the hydroxamic acid containing benzodiazepines,
is currently under consideration.
Scheme 5a
Acknowledgment. We gratefully acknowledge the NIH
for partial financial support of this research, the University
of Notre Dame for support in the form of a J. Peter Grace
fellowship, the Lizzadro Magnetic Resonance Research
Center at Notre Dame for NMR facilities, Dr. W. Boggess
and N. Sevova for mass spectrometry facilities, Dr. A. Beatty
for X-ray crystal determination, and Maureen Metcalf for
assistance with the manuscript.
a Reagents: (i) 2,4-dinitrobenzenesulfonyl chloride, Na2CO3,
H2O, ∆; (ii) HCl.
Attempts to modify the reaction conditions to provide the
desired 2,4-dinitrobenzenesulfonamide were unsuccessful, so
an alternative synthetic approach was taken.
The reactivity of the 2,4-dinitrobenzenesulfonamide sug-
gested a late stage introduction of this group would be
prudent. Therefore, cycloadduct 21 was obtained through the
treatment of cycloadduct 1 with 2,4-dinitrobenzenesulfonyl
chloride and pyridine (Scheme 6). When cycloadduct 21 was
Supporting Information Available: Experimental pro-
cedures and characterization data for products 1, 5, 8, 9, 11-
13, 16, 17, 21, and 22. This material is available free of
OL017036W
(19) West, R.; Boudjouk, P. J. Am. Chem. Soc. 1973, 95, 3987.
(20) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(21) Dauphin, G.; Kergomard, A. Bull. Soc. Chim. Fr. 1961, 3, 486.
Org. Lett., Vol. 4, No. 1, 2002
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