Efficient Synthesis of Highly Functionalized Indazoles and 2,3-Dihydro-1,2-benzisoxazoles by Reaction of Stable Fischer Dienyl Carbenes and Isocyanides

Abstract

A range of stable chromium and tungsten Fischer dienyl carbenes have been prepared by [3+2] cycloaddition of alkenylethynyl carbene complexes with nitrones or diazoalkanes. Treatment of these systems with isocyanides gives entry to highly functionalized 2,3-dihydro-1,2-benzisoxazoles and indazoles in a completely regioselective fashion, under mild conditions, and with high yields. This methodology can be also applied to the preparation of analogous naphthoisoxazoles starting from arylethynyl Fischer complexes. Reductive cleavage of the isoxazole moiety in the prepared heterocycles also enables the efficient synthesis of highly substituted p-aminophenols.

New heterocyclization reactions with Fischer carbene complexes

“…Thereby, the initial 1-metalla-1,3,5-hexatrienes resulting from the [3+2] cycloaddition of enynylcarbenes 9 with diazoalkanes or nitrones, participate in a benzannulation reaction with isocyanides, affording indazoles 10 or 2,3-dihydro-1,2-benzisoxazoles 12 respectively (Scheme 4). 5 Both reactions proceed under mild conditions, in high yields and with complete regioselectivity. We have observed a higher reactivity of the alkynyl carbenes in comparison to the acetylenic ester analogues in this process.…”

“…(CO) 5 M Ph In our laboratory, these novel chiral alkynyl(alkoxy)carbenes have been applied in the synthesis of 1,4-dihydropyridines through a [4+2] cycloaddition, as it is shown in Scheme 8. …”

“…A nucleophilic attack of the unsubstituted nitrogen of azadiene at the carbenic carbon could be the first step of the reaction, leading to the formation of zwitterion VI, stabilized in a chairlike conformation. Secondly, a [1,2]-Cr(CO) 5 shift would induce the diastereoselective cyclization to give intermediate VII, which after elimination of the metallic fragment and metal coordination to the nitrogen would form VIII. Finally, the decomplexation of the metallic fragment and tautomerization in the presence of silica gel would lead to azepines 30.…”

“…THF, -78 to -55 ºC 3. 6N HCl (CO) 5 Cr R A feasible mechanism to account the formation of these five-and six-memebered ring products is depicted in Scheme 20. The first two steps would be common for both products, consisting on an initial 1,2-addition of the lithium enolate to the carbenic carbon of complexes 67 generating intermediate XIV, followed by addition of allylmagnesium bromide to the carbonyl group leading to XV.…”

“…Thus, the reaction of alkynylcarbene complexes 17 with different fulvenes in the same conditions as above, but under CO pressure (20 bar) furnished the [4+3] cycloadducts 70 in moderate to high yields, allowing the quantitative recovery of W(CO) 6 . The formation of these bicyclo[3.2.1]octadien-2-ones 70 can be explained by a 1,2-addition of fulvene to the carbenic carbon of the Fischer carbene to generate intermediate XXI, and a regioselective cyclization promoted by 1,2-[W(CO) 5 ] shift.…”