Highly Regioselective Nitration Reactions Provide a Versatile Method of Functionalizing Benzocycloheptapyridine Tricyclic Ring Systems:  Application toward Preparation of Nanomolar Inhibitors of Farnesyl Protein Transferase

Abstract

A comprehensive study of nitration reaction of azatricyclic systems has been carried out. Whereas classical nitrations using KNO(3)-H(2)SO(4) at low temperatures gave nitrated products mainly at the 9-position, use of tetrabutylammonium nitrate-trifluoroacetic anhydride (TBAN-TFAA) resulted in exclusive nitration of the 3-position in the case carbamates 1, and 4-6 and the tricyclic ketone 7. These 3-nitro tricyclic derivatives have been valuable intermediates for the preparation of the very potent farnesyl protein transferase inhibitors such as the tricyclic pyridyl acetamide 32 and other new analogues.

(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent

“…Compounds prepared for this study are shown in Tables and , and their synthetic routes are illustrated in Schemes −7. Chemistry for the preparation of 3-bromo carbamate 3 utilizing the versatile chemistry that effects regioselective nitration of the benzocycloheptapyridine system at the 3-position of the pyridine has been previously described . Preparation of compounds described in this paper has been greatly facilitated by our finding that electrophilic nitration of the benzocycloheptapyridine ring system using classic nitration conditions occurs mainly at the 9-position of the tricyclic ring system .…”

Regioselective 3-Nitration of Flavones: A New Synthesis of 3-Nitro- and 3-Aminoflavones

“…that proposed by other authors, 27,32 involving the reaction of ammonium nitrate with TFAA to form nitronium trifluoroacetate which decomposes to trifluoroacetyl and nitro free radicals; the latter reacts with the substrate to give the nitro derivatives obtained (Scheme 2).…”

“…To determine whether the nitration reaction proceeds through a nitronium ion (NO 2 + ) or a free-radical mechanism, the nitration of 4¢-methoxyflavone (1c) was performed in the presence of a free-radical scavenger (TEMPO). 27,32 Analysis after 24 hours showed that no appreciable amount of 4¢-methoxy-3-nitroflavone (4c, 4%) had been obtained and no side products were formed. These results imply that the reaction occurs through a free radical pathway.…”

Green Synthetic Approach for High-Performance Energetic Nitramino Azoles

“…This green protocol features mild conditions, short reaction time, simple operation, and good yields. 25,26 The synthetic route to the new energetic salts 1−10 is shown in Scheme 1. 3,5-Diamino-4-nitropyrazole (I) was prepared according to the literature.…”

“…In comparison with mixed acid, potassium nitrate is more economical as it has a longer shelf life and is less hazardous than nitric acid. This green protocol features mild conditions, short reaction time, simple operation, and good yields. , …”