Efficient and Practical Method for Synthesizing N-Heterocyclic Compounds Using Intramolecular Nucleophilic Acyl Substitution Reactions Mediated by Ti(O-i-Pr)₄/2i-PrMgX Reagent. Synthesis of Quinolones, Pyrroles, Indoles, and Optically Active N-Heterocycles Including Allopumiliotoxin Alkaloid 267A

Abstract

Treatment of N-(2- or 3-alkynyl)amino esters with a low-valent titanium reagent diisopropoxy(η2-propene)titanium (1), generated in situ by the reaction of Ti(O-i-Pr)4 and 2i-PrMgCl, resulted in an intramolecular nucleophilic acyl substitution (INAS) reaction to afford α-alkylidene-pyrrolidinones or -piperidinones. Thus, treatment of N-propargyl-anthranilates 5, -indole-2-carboxylates 10, or -pyrrole-2-carboxylates 13 with 1 gave 4-quinolones 7, [1,2-a]indoles, or [1,2-a]pyrroles, respectively. Similarly, N-alkynylated α- or β-amino esters 14 or 15 with 1 afforded N-heterocycles 18 or 19. In the reaction of N-(2- or 3-alkenyl)amino esters with 1, the resulting INAS product underwent intramolecular carbonyl addition (ICA) reaction to afford the N-heterocyclic compounds having a cyclopropanol moiety in good to excellent yields. Thus, the treatment of N-alkenyl-anthranilate 4a, -indole-2-carboxylates 8 and 9, or -pyrrole-2-carboxylates 11 and 12 with 1 gave the corresponding quinoline derivative 6a, [1,2-a]indoles, or [1,2-a]pyrroles, respectively. The optically active N-heterocyclic compounds 20 and 21 were obtained from N-alkenylated α- or β-amino esters 16 or 17. A highly efficient total synthesis of allopumiliotoxin alkaloid 267A has also been accomplished. Thus, the N-propargyl-2[(1-hydroxy-1-methoxycarbonyl)ethyl]pyrrolidine 24 (from l-proline in six steps) reacted with 1 to afford the corresponding indolidinone 25 in 67% yield, which has previously been converted to allopumiliotoxin 267A.

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

“…Recently, this type of early transition metal-mediated process has appeared as a key step in the total synthesis of allopumiliotoxin 267A (Scheme 32B). 87 …”

The Divalent Titanium Complex Ti(O-i-Pr)4/2i-PrMgX as an Efficient and Practical Reagent for Fine Chemical Synthesis

“…The syntheses of N-heterocycles including optically active compounds starting from readily available starting materials exemplified in Table 8 strongly indicate the utility of the reaction. [62] Thus, the treatment of readily available N-allyl-or -propargyl-anthranilates, -indole-2-carboxylates, -pyrrole-2-carboxylates, and -a-amino esters with Ti(O-i-Pr) 4 /2 i-PrMgX reagent gave the corresponding pyrrolidines and piperidines. The synthetic utility of the reaction was further demonstrated by an efficient synthesis of azasugars [63] and allopumiliotoxin 267A, [62] which is one component of the toxic skin secretion of certain neotropical frogs and displays significant cardiotoxic activity.…”

“…[62] Thus, the treatment of readily available N-allyl-or -propargyl-anthranilates, -indole-2-carboxylates, -pyrrole-2-carboxylates, and -a-amino esters with Ti(O-i-Pr) 4 /2 i-PrMgX reagent gave the corresponding pyrrolidines and piperidines. The synthetic utility of the reaction was further demonstrated by an efficient synthesis of azasugars [63] and allopumiliotoxin 267A, [62] which is one component of the toxic skin secretion of certain neotropical frogs and displays significant cardiotoxic activity. Using the Ti(II)-mediated INAS reaction as a key step, optically active 5-[(t-butyl)dimethylsilyl]oxy-2-cyclohexenone was prepared efficiently from readily available 4-chloro-3-hydroxybutanoate or epichlorohydrin as shown in Equation 26.…”

Cyclopropane‐Annelated Azaoligoheterocycles by Ti‐Mediated Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides

“…[7,9,10] We envisaged the possibili-ty of employing our amide variant [11,12] of the Kulinkovich reaction [12,13] to prepare cyclopropane-annelated pyrrolizidine and indolizidine skeletons from N-alkylpyrrole and Nalkylindole carboxamides, just as Sato et al converted pyrrole-and indole-2-carboxylic acid methyl esters to tri-and tetracyclic cyclopropanols. [14] As we have previously demonstrated, a variety of 1-amino-3-azabicyclo[3.1.0]hexane derivatives can be obtained by this Ti-mediated intramolecular reductive cyclopropanation of appropriate N,N-dialkylcarboxamides, which are readily available from natural amino acids or bromoacetyl bromide by simple transformations. [15,16] Here we report the intramolecular aminocyclopropanation of the N-allyl group in N,N-dialkylamides of type 3 leading to tricyclic and tetracyclic systems of type 4 as cyclopropane-annelated analogues of natural skeletons such as in 1 and 2 (Scheme 1).…”