Article pubs.acs.org/OPRD
A Method for Heteroaromatic Nitration Demonstrating Remarkable Thermal Stability Gregory L. Beutner,†,* Lopa Desai,†,* Dayne Fanfair,† Paul Lobben,† Eric Anderson,† Simon W. Leung,‡ and Martin D. Eastgate† †
Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States Chemical Development Operations, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States
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S Supporting Information *
ABSTRACT: Herein we report a novel heterogeneous pyrrole nitration that can be run on a large scale in batch mode. Activation of sodium nitrate by SO3−pyridine in acetonitrile leads to the formation of an insoluble nitronium sulfate intermediate that effects a high-yielding reaction. These conditions allow for a safer and practical nitration reaction with unique thermal stability that appears to be a function of the low solubility of the proposed nitronium ion carrier. Mechanistic insights gained from reaction kinetics as well as 1H and 15N NMR studies are presented to support this analysis.
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the use of flow reactors.10 When a nitration is performed in a flow system, the active nitrating agent need only be generated in small amounts under conditions of rapid heat transfer. This strategy has proven successful in a variety of settings, as evidenced by the large number of publications in this area.11 Despite these successes, the use of flow reactors is not a universal solution since it typically requires that both the starting material and product be fully soluble in the reaction medium under the desired conditions and that reaction rate be high relative to the accessible flow rate through the reactor. Alternative general strategies to accomplish nitrations in a safe manner are still required. As part of an ongoing program, we became interested in finding a practical solution to the noncontinuous nitration of electron-rich ethyl 4-bromopyrrole-2-carboxylate (1) (Scheme 1). A review of the literature revealed that acetyl nitrate systems
INTRODUCTION The nitration of aromatic compounds is a classical strategy for the synthesis of aromatic amines.1 This textbook functionalization, one of the oldest in the lexicon of organic chemistry, has been applied to countless aromatic systems. However, from the perspective of a chemist interested in drug discovery, the nitration of heterocycles is of greater interest.2 The nitrations of electron-rich heteroaromatics (e.g., furans, thiophenes, pyrroles, and their fused analogues) present particular challenges due to the inherent instability of these compounds under the strongly acidic and oxidizing conditions of classical nitrations (HNO3 and H2SO4).3,4 For example, in the case of pyrroles a variety of methods have been developed to circumvent these problems (Figure 1).5 Several nitronium ion carriers, such as acetyl
Scheme 1. Nitration of pyrrole 1
Figure 1. Methods for pyrrole nitration.
have most commonly been employed for the nitration of 1, likely because of the less-acidic conditions obtained by these reactions.6 However, acetyl nitrate undergoes facile thermal decomposition and degrades exothermically, a major concern for the application of these reactions in any setting. We hypothesized that some of this thermal behavior is due to the acetate methyl group undergoing nitration or oxidation, precipitating decomposition. Thus, the initial aim was to investigate new modes of activation for nitric acid (or its salts),
nitrate6 and those developed by Olah (e.g., NO2BF4) allow access to nitropyrroles under milder conditions.7 However, the yields are generally low (
