One-pot double functionalisation of π-deficient heterocyclic lithium reagents

Abstract

Herein, we report an efficient method for the double functionalisation of lithiated halogenopyridines, -pyrazines or -furopyridines through a convenient one-pot electrophilic trapping/nucleophilic substitution sequence.

Recent Advances in Retained and Dehydrogenative Dual Functionalization Chemistry

“…Double functionalization of various π‐deficient azaheterocycles ( 74 ) with disulfides ( 75 ) or amides ( 76 ) via electrophilic trapping of lithio intermediate and subsequent nucleophilic substitution to furnish bis(alkylthio)‐ and bis(arylthiol)‐heterocycles ( 77 ) and amino‐carbonyl heterocycles ( 78 ), respectively was achieved by Fort and co‐workers (Scheme 23). [31] …”

“…Addition of a thiocarbonyl group in 29 provides sulfonium ylide intermediates (29-B), and the subsequent proton transfer of 29-B generates N,S-acetals (29-C). The N,S-acetals are converted into desired products (31) through an intramolecular N-cyclization by the elimination of alcohols.…”

“…Double functionalization of various π-deficient azaheterocycles (74) with disulfides (75) or amides (76) via electrophilic trapping of lithio intermediate and subsequent nucleophilic substitution to furnish bis(alkylthio)-and bis(arylthiol)-heterocycles (77) and amino-carbonyl heterocycles (78), respectively was achieved by Fort and co-workers (Scheme 23). [31] Kumar and co-workers demonstrated a synthesis of 3amino-benzamides (81, X=CONHR 3 ) from 4-substituted p-quinols (79) by sequential CÀ N and CÀ C cross coupling reactions with amines and isocyanides (Scheme 24, left) and a synthesis of 3-amino-arylphosphonates (81, X=PO(OR 4 ) 2 ) from 4-substituted p-quinol methyl ethers (80) by sequential CÀ N and CÀ P cross coupling reactions with amines and trialkylphosphites (Scheme 24, right). [32] This 1,3-double functionalization firstly forms either iminium cation intermediates (79-A) or isomerized diene epoxides (79-B) through the activation of p-quinols (79) with amines.…”

Lithiated Aza‐Heterocycles in Modern Synthesis

“…With the goal to control regioselectivities during the metallation processes, the direct functionalization of such a substrate remains always an interesting challenge and allows envisioning the introduction of a large range of functionalities on heterocycle rings. Comoy and colleagues [102b,104,105] have recently investigated the regioselective lithiation of furo[3,2-b] or [2,3-c]pyridine isomers and reported new detailed procedures to achieve successive functionalizations of these heterocycles. In these studies, the choice of the lithiated basic system was proven to be crucial in controlling the regioselectivity (Figure 15.9).…”

“…Moreover, Fort and colleagues [105] have developed a new efficient double functionalization of various π-deficient heterocycles (pyrazine, pyridine, and furopyridine) through a one-pot cascade process combining electrophilic trapping of a lithio intermediate and subsequent nucleophilic substitution. As depicted in Scheme 15.25 with the example of halogeno-pyrazines or -pyridines, the proposed mechanism involved a lithioheterocycle which was trapped in the presence of the E-Nu reagent.…”