Reissert activating agents

Range of Activating Agents in Reissert-Type Reactions. 132... 

Besides the classic Reissert process, a wide range of modifications have been described. Structural variations on each component have been extensively screened, and several approaches have been designed based on the interaction of azines, activating agents, and nucleophiles to yield substituted dihydroazines or related compounds. This chapter does not provide an exhaustive list of these many transformations rather, it offers a general overview of the field (Scheme 6). 

Different types of activating agents have been employed in Reissert-related reactions (Scheme 6). In many cases, it is mandatory to generate, or even isolate, the corresponding azinium salt intermediate, and sequentially proceed with the nucleophilic addition. Moreover, since the former step often takes place selectively and at a fast rate, the transformation can be performed in a multicomponent manner without any functional group interference. 

Scheme 6 Range of activating agents used in Reissert processes...

Acid chlorides 21 and chloroformates 23 are the most commonly used activating agents and the preferred reagents for evaluating the reactivity of other components in new Reissert-type processes. For example, in studies on the total synthesis of the indolopyridine alkaloids 42, acetyl chloride was used in the key step to prepare the common synthetic intermediate 41. In this case, an enamide moiety intramole-cularly attacks the in situ generated Ai-acylazinium salt, and the Reissert adduct is spontaneously oxidized and hydrolyzed to regain aromaticity in the last step (Scheme 7) [44, 45]. 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

The Ugi-Reissert reaction is quite general [188] it accepts a wide array of isocyanides, azines (excluding pyridine and derivatives lacking unsubstituted a-positions) and activating agents (chloroformates, acid chlorides, anhydrides. 

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