Van Leusen pyrrole synthesis

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. 

The versatile van Leusen pyrrole synthesis (Section 4.2.3.3.4) is also useful for the preparation of fused pyrrole derivatives, for example, 165, which is obtained in good yield upon treatment of the lactam 164 with >-toluenesulfo-nylmethyl isocyanide (TosMIG) in the presence of DBU (Scheme 98) <2003BML1939>. This method has also been used in the construction of isoindole derivatives <1997H(45)1989, CHEC-III(3.03.9)327>. 

The second alternative synthesis of stannylpyrroles involves the versatile van Leusen pyrrole ring synthesis, illustrated below for the synthesis of 85 [69,70]. Several examples were prepared in these studies, although at present the scope of this reaction is limited to pyrroles having an electron-withdrawing group at the 3-position. The structure of a BOC derivative of 85 (Ri = Ph, R2 = Bz) was established by X-ray crystallography [69]. 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

In tMs approach, conjugate addition of the anion from an isocyano-acetate to an a,p-unsaturated nitrocompound with evenmal loss of nitrous acid, produces 5-unsubstituted pyrrole-2-esters. The example below shows a mechanistic sequence that can be seen to parallel that in the van Leusen synthesis. The most useful route to the a,P-unsaturated nitro-compound involves the base-catalysed condensation of an aldehyde with a nitroalkane giving an a-hydroxy-nitroalkane it can alternatively be generated in situ, in the presence of the isonitrile, using diazabicycloundecane (DBU) as base on the 0-acetate of the a-hydroxy-nitroalkane (for an example see 16.16.2.1). The process works even when the unsaturated nitro unit is a component of a polycyclic aromatic compound. ... 

In 1972 van Leusen described a simple synthesis of 4-phenylpyrroles bearing a cyano-, a keto- or an ester-group in the 3-position of the pyrrole ring, using TosMIC (5) as a key reagent (Scheme 15.2.1) [12]. 

Disubstituted pyrroles are important building blocks for porphyrin synthesis (cf p. 553). With two equal 3,4-substituents, they can be straightforwardly obtained by the Piloty-Robinson synthesis [118] ofhigher flexibility are isocyanide-based methods like the Barton-Zard synthesis [119] and the Van Leusen synthesis [120]. 

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