Barton-Zard reaction

Base-induced reaction of nitroalkenes with alkyl a-isocyanoacetates to afford pyrroles. 

Barton, D. H. R. Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 1098. Samir Z. Zard, a Barton student, emigrated from Lebanon to the UK in 1975. He is a professor at CNRS and Ecole Polytechnique in France. 

Gribble, G. W. Barton—Zard Reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 70-78. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 16, Springer International Publishing Switzerland 2014 

Exanq)le 3, A Barton-Zard reaction on a ferrocene ring  

The Barton-Zard reaction refers to the base-induced reaction of nitroalkenes 1 with alkyl a-isocyanoacetates 2 to afford pyrroles 3. Solvents used are THF or alcohols (or mixtures) and the reaction often proceeds at room temperature. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates. An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

The use of stronger bases than, for example, DBU, such as proazaphosphatrane 13 or 

The Barton-Zard reaction found its application in the synthesis of LY2059346, a positive allosteric modulator of the a-amino-3-hydroxyl-L-aspartate (AMPA) receptor as a potential treatment of neurological and psychiatric disorders.  

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The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

DBU IS most widely employed as the base m the Barton-Zard reaction Stronger nonionic bases such as PrMeNCH-,CH-j,N and the phosphazene base Csiipplied by Flukai are more effective to induce pyrrole formadon in the reaction of nitroalkenes v/ith isocyano esters than DBU Sterically hindered nitroalkenes are converted into the corresponding pyrroles using these bases, as shovm in Eq 10 35, but DBU is not effective in this transformation... 

Heterocyclic aromatic nitro compounds are more reactive toward nucleophiles than carbo-cyclic aromatic nitro compounds Various heterocyclic aromatic nitro compounds are thus converted into the corresponding pyrroles by the Barton-Zard reaction fEq 10 37 ... 

The reaction pathways for the pyrrole formation are summarized in Scheme 10.3. The group that is eliminated at the final stage is a nitrite ion (Barton-Zard reaction) or a toluenesulfinate ion (Leusen reaction), depending on the reaction pattern. 

Aida and coworkers have used the Barton-Zard reaction in the synthesis of axially dissymmetric pyrroles as shown in Eq. 10.30.35... 

Polymer-supported reagents and other solid sequestering agents may be used to generate an array of 1,2,3,4-tetrasubstituted pyrrole derivatives using the Barton-Zard reaction as a key pyrrole formation reaction. Pure pyrroles are obtained without any chromatographic purification... 

Pyrroles prepared by the Barton-Zard reaction are very important as precursors of porphyrins and also of conducting polymers. The ester group at the 2-position is readily removed on heating with KOH in ethylene glycol at 170 °C to give a-free pyrroles, which are useful for preparing porphyrins (Eq. 10.42)47 or polypyrroles (Eq. 10.43).38a,4S... 

Scheme 43 The Barton-Zard reaction (general scheme)...

It is a common point of view that the Barton-Zard reaction is a favorable one for the pyrrole synthesis. It is based on interaction of conjugated nitroalkenes with isocyanoacetates in the presence of a base [6, 74-76] and, basically, involves three steps (Scheme 43) the Michael-type addition of isocyanide carbanion to the C=C double bond of nitroalkene, cyclization of the resulting anion to give pyrroline derivative, and elimination of the nitrite anion followed by aromatization. 

However, nitroaromatic compounds with a profound nitroalkenic character, as well as their dinitro derivatives, proved to undergo the Barton-Zard reaction much easier to give moderate-to-good yields of the target products. Indeed, 1,3-, 1,5-, and 2,7-dinitronaphthalenes gave the corresponding isoindoles in the presence of DBU in 25 5% yields [82, 83] (Scheme 45). When the phosphazene base 95 was used instead of DBU, it became possible to increase yields of isoindoles up to 31-78%. Besides, the formation of h A-annelation product 98 was observed in case of 1,3-dinitronaphthalene. 

However, the Barton-Zard reaction seems to be rather sensitive to the structure of starting nitroarenes, and depending on position of the nitro group, the reaction results in the formation of various heterocycles. 4-Nitrobenzothia- and selenadiazoles have been shown to react with ethyl isocyanoacetate/DBU to give the expected isoindoles in moderate yields [78, 81, 86], while isomeric 5-nitro derivatives afford pyrimidines fused with benzoazoles under the same reaction conditions [78] (Scheme 49). 

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