Synthesis of Aliphatic Hydroxyaryl Ketones or (Hetero)aryl Hydroxyaryl Ketones by Acylation of Organometallic Reagents

Abstract

Diverse hydroxyarenecarboxylic acids afford stable N-(hydroxyaroyl)benzotriazoles that react with heteroaryl, alkyl, and aryl Grignard or lithium reagents to give the corresponding hydroxyaryl ketones in 51-94% yields.Hydroxyaryl ketones 1 are precursors for the synthesis of biologically active chalcones, 2 flavones, 2b,3 isoflavones, 4 and xanthones. 5 Aryl o-hydroxyaryl ketones exhibit protein kinase B inhibitor, 6 cyclin-dependent kinase inhibitor, 7 and cysteine protease modulator activities. 8 Aryl hydroxyaryl ketone moieties occur in natural products such as cotoin, 9 balanol, 10 and daunorubicin. 11 Many aryl hydroxyaryl ketones including dioxybenzone, 12 mexenone, 13 oxybenzone, 14 benzophenone-6, 15 and benzoresorcinol 16 are used as ultraviolet screens.The conventional Friedel-Crafts acylation of phenols and naphthols with acid chlorides in the presence of Lewis acid catalysts 5,17 and Fries-type rearrangement of suitable aryl esters, 18 which are both frequently used for the preparation of hydroxyaryl ketones, are often unselective in that ortho-and para-acylation of phenols and naphthols result leading to mixture of products. Moreover, acid chlorides are sensitive to moisture and hence they are difficult to handle. 19 Alternative, less frequently used, syntheses of hydroxyaryl ketones include (i) palladiumcatalyzed coupling of o-hydroxyaryl aldehydes with hypervalent iodonium salts 20 and (ii) intramolecular acyl radical [1,6]-ipso-substitution reactions. 21 N-Acylbenzotriazoles are easily prepared activated derivatives of carboxylic acids. 22 Applications of N-acylbenzotriazoles include: (i) N-acylation of amines, 23 amides, 23,24 and sulfonamides, 25 (ii) O-acylation of aldehydes, 26 steroids, 27 hydroxyterpenes and alcohols, 28 (iii) many C-acylations of, for example, pyrroles and indoles, 29 ketones and heteroaromatics, 30 alkyl sulfones, 31 alkyl cyanides, 32 alkyl azines, 33 a-nitroalkanes, 34 furan and thiophene; 35 syntheses of (iv) peptides, 36 (v) oxazolines, 37 (vi) esters, 38 (vii) benzodioxin-4-ones, 39 (viii) ketones, 40 (ix) benzodiazepin-2-ones, 41 (x) thiol esters, 42 (xi) alcohols, 43 (xii) acyl azides and hydrazides, 44 (xiii) heteroaromatics, 45 and (xiv) heterocycles. 46

2, 2′‐Dihydroxybenzophenones and Derivatives. Efficient Synthesis and Structure Endoscopy by DFT and NMR. Credentials as Potent Antiinflammatory Agents.

“…Alternatively, a versatile protocol (Scheme ) takes advantage of either an amide acylation or an anionic ortho ‐Fries rearrangement and an amide reduction to an aldehyde as the key reactions. Thus, amide 22 , directly acylated with Grignard component 23 (route a) or reduced by in situ prepared Schwartz reagent (Cp 2 ZrCl 2 /LiAl(OBu‐t) 3 ) (route b) to the aldehyde 14 , ultimately led to 1–4. 22 was conveniently obtained by lithiation of the carbamate 21 followed either by an anionic ortho ‐Fries rearrangement (route b, (iii)) or its in situ further treatment (route b, (iv)) to 14 .…”

“…0.03 Å to 0.09 Å. Comparing the H bonding of 1–6 with that in 2‐hydroxy‐benzophenones or tricyclic planar anthralin (Table of the SI), one can see the effects of bifurcation on conformation flexibility. Thus, an elongation ( ca .…”

“…Most of the biologically active benzophenones are sterically crowded substrates having substituents at ortho positions to the ketone moiety . Among them, natural hydroxybenzophenones, biologically active metabolites present in plants and especially in Guttiferae family or polyhydroxybenzophenones have displayed significant free radical scavenging activity. Substituted ortho hydroxybenzophenones, are ubiquitous in naturally occurring and synthetic compounds with important biological activities .…”

“…Their structure and the inherent intramolecular H bonding have been the subject of extensive theoretical investigations . The ortho ‐hydroxy diaryl ketone entity in many biologically active compounds and natural products makes it a privileged structure in medicinal chemistry and a synthesis target . Well‐known and important members are the combretastatins and phenstatins .…”

Synthesis of Acyl Pyrroles via Palladium-Catalyzed Carbonylative Amination of Aryl and Alkenyl Iodides

“…The addition of organometallic reagents to N -methoxy- N -methylamides, commonly known as Weinreb amides, − is a standard method for the synthesis of ketones from carboxylic acid derivates. Morpholine amides − and acyl triazoles have also proven to be effective acylating agents in the synthesis of ketones, but their use is much less frequent. In general, these amides are prepared by condensation of carboxylic acid derivatives with the corresponding amine.…”