Hexafluoroisopropanol as the Acid Component in the Passerini Reaction: One-Pot Access to β-Amino Alcohols

Abstract

A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations.

Visible‐Light‐Induced Passerini Multicomponent Polymerization

“…Recently, there has been interest in using “non‐traditional” partners in multicomponent Passerini and Ugi reactions, partners including, as the acid component thioacetic acids and hexafluoro isopropanol, and as carbonyl components ketenes, and TiCl 4 ‐mediated thiocarbenium species . These non‐traditional components have advantages in that they lead to unique functional moieties beyond the typical amide and ester linkages in a single step that would otherwise require multiple (indirect) steps to access.…”

The 100 facets of the Passerini reaction

“…In 2018, Ruijter 66 reported the Passerini reaction with hexafluoroisopropanol as an acid surrogate: in this case, the intermediate imidate 97, unable to induce the Mumm rearrangement and to proceed to an alkylated Passerini adduct, was sufficiently stable and could be reduced under mild conditions to β-aminoalcohol 98 ( Scheme 29 ).…”

“…Applying the synthesis of β-amino alcohols trough the modified Passerini reaction discussed on chapter 3 ( Scheme 29 ), Ruijter reported the preparation of propranolol 217 and rivaroxaban 223 ( Scheme 58 ). 66 Starting from (1-naphthyloxy)acetaldehyde 215 and isopropylisocyanide 216, propranolol can be obtained in one step with excellent yield. The preparation of Rivaroxaban started from the commercially available aniline 218, which was efficiently transformed into the isocyanide 219 in 2 steps.…”

Automated and accelerated synthesis of indole derivatives on a nano-scale

“…15 Isocyanide-based multicomponent reactions (IMCRs) is a highly relevant reaction classes and span a relevant chemical space in drug discovery as it enables easy discovery and/or access to multiple commercial and experimental drugs, e.g. anti-pain carfentanil and xylocaine, 16,17 antiseizure lacosamide, 18 anti-depressant olanzepine, 19 blood coagulation rivaroxaban and clopidogrel, 20,21 HCV drug telaprevir, 22 birth-controlling epelsiban, 23 or cancer-starvation ivosidenib, 24 just to mention a few. In particular IMCR is robust, scalable, safe, green and fulfils the important requirement for syntheses to tolerate nitrogen heteroatoms and (unprotected) polar functional groups common in drug molecules.…”