Double-chelation-assisted Rh-catalyzed intermolecular hydroacylation

[reaction: see text] Rh-Catalyzed intermolecular hydroacylation between salicylaldehydes and 1,5-hexadienes proceeded under remarkably mild reaction conditions to afford a mixture of iso- and normal-hydroacylated products in good yields. The experiments using deuterated salicylaldehyde-d revealed that "double chelation" of salicylaldehyde and 1,5-hexadiene to Rh-complex played vital roles in the catalytic cycle of intermolecular hydroacylation.     

N-Heterocyclic carbene (NHC)-catalyzed intermolecular hydroacylation of cyclopropenes

We report the first intermolecular NHC-catalyzed hydroacylation of electron-neutral olefins. Treatment of aromatic aldehydes with cyclopropenes under mild conditions affords valuable acylcyclopropanes in moderate to high yields with an excellent level of diastereocontrol. Preliminary mechanistic studies suggest that product formation occurs via a concerted syn hydroacylation pathway.     

Nitrile-promoted Rh-catalyzed intermolecular hydroacylation of olefins with salicylaldehyde

Rh-catalyzed intermolecular hydroacylation between salicylaldehyde and alkenylnitriles proceeded at room temperature to preferentially give normal-hydroacylated products. Addition of CH3CN and NaOAc accelerated the Rh-catalyzed hydroacylation of monoolefins to exclusively produce the normal-hydroacylated products under mild reaction conditions. Plausible mechanisms for the regioselections are also described.     

Catalytic hydroacylation as an approach to homoaldol products

A method has been developed for the intermolecular hydroacylation of homoallyl alcohols with salicylaldehydes to furnish homoaldol products in 50-98% yields. The method also applies to the hydroacylation of 2-hydroxystyrenes. This work highlights the use of hydroacylation as a unified approach to both aldol and homoaldol products.     

Iridium‐Catalyzed Coupling Reaction of Primary Alcohols with 2‐Alkynes Leading to Hydroacylation Products

A novel iridium‐catalyzed intermolecular coupling reaction of primary alcohols or aldehydes with 2‐alkynes was successfully achieved with high regioselectivity to give hydroacylation products such as α,β‐unsaturated ketones in good yields. The mechanistic investigation of the reaction strongly indicated that the coupling proceeds through the initial formation of homoallylic alcohols followed by dehydrogenation to β,γ‐unsatutated ketones and then isomerisation, which leads to the hydroacylation products.     

Rhodium-catalyzed intermolecular chelation controlled alkene and alkyne hydroacylation: synthetic scope of beta-S-substituted aldehyde substrates

The use of beta-S-substituted aldehydes in rhodium-catalyzed intermolecular hydroacylation reactions is reported. Aldehydes substituted with either sulfide or thioacetal groups undergo efficient hydroacylation with a variety of electron-poor alkenes, such as enoates, in Stetter-like processes and with both electron-poor and neutral alkynes. In general, the reactions with electron-poor alkenes demonstrate good selectivity for the linear regioisomer, and the reactions with alkynes provide enone products with excellent selectivity for the E-isomers. The scope of the process was shown to be broad, tolerating a variety of substitution patterns and functional groups on both reaction components. A novel CN-directing effect was shown to be responsible for reversing the regioselectivity in a number of alkyne hydroacylation reactions. Catalyst loadings as low as 0.1 mol % were achievable.     

Efficient synthesis of benzofuranones: N-heterocyclic carbene (NHC)/base-catalyzed hydroacylation-Stetter-rearrangement cascade

A N-heterocyclic carbene/base-catalyzed cascade reaction leading to the formation of functionalized benzofuranones is reported. The reaction proceeds via an intramolecular hydroacylation of unactivated alkynes followed by an intermolecular Stetter reaction and a base-catalyzed chromanone to benzofuranone rearrangement.     

Enantioselective desymmetrization of cyclopropenes by hydroacylation

We report an enantioselective desymmetrization of cyclopropenes by intermolecular Rh-catalyzed hydroacylation. Cyclopropylketones, bearing quaternary stereocenters, are produced with diastereocontrol (up to >20:1) and excellent enantiomeric excess (up to >99 ee).     

Azine-N-oxides as effective controlling groups for Rh-catalysed intermolecular alkyne hydroacylation

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry. We show that by using azine N-oxide substituted aldehydes, good reactivity can be achieved, and that they are highly effective substrates for the intermolecular hydroacylation of alkynes. Employing a Rh(i)-catalyst, we achieve a mild and scalable aldehyde C–H activation, that permits the coupling with unactivated terminal alkynes, in good yields and with high regioselectivities (up to >20 : 1 l:b). Both substrates can tolerate a broad variety of functional groups. The reaction can also be applied to diazine aldehydes that contain a free N-lone pair. We demonstrate conversion of the hydroacylation products to the corresponding azine, through a one-pot hydroacylation/deoxygenation sequence. A one-pot hydroacylation/cyclisation, using N-Boc propargylamine, additionally leads to the synthesis of a bidentate pyrrolyl ligand.

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry; using the N-oxide derivatives allows efficient reactions to be achieved.     

A General Approach to Intermolecular Olefin Hydroacylation through Light-Induced HAT Initiation: An Efficient Synthesis of Long-Chain Aliphatic Ketones and Functionalized Fatty Acids

Herein, an operationally simple, environmentally benign and effective method for intermolecular radical hydroacylation of unactivated substrates by employing photo-induced hydrogen atom transfer (HAT) initiation is described. The use of commercially available and inexpensive photoinitiators (Ph₂CO and NHPI) makes the process attractive. The olefin hydroacylation protocol applies to a wide array of substrates bearing numerous functional groups and many complex structural units. The reaction proves to be scalable (up to 5 g). Different functionalized fatty acids, petrochemicals and naturally occurring alkanes can be synthesized with this protocol. A radical chain mechanism is implicated in the process.     

α-Amidoaldehydes as Substrates in Rhodium-Catalyzed Intermolecular Alkyne Hydroacylation: The Synthesis of α-Amidoketones

We show that readily available α-amidoaldehydes are effective substrates for intermolecular Rh-catalyzed alkyne hydroacylation reactions. The catalyst [Rh(dppe)(C₆H₅F)][BAr^F₄] provides good reactivity, and allows a broad range of aldehydes and alkynes to be used as substrates, delivering α-amidoketone products. High yields and high levels of regioselectivity are achieved. The use of α-amidoaldehydes as substrates establishes that 1,4-dicarbonyl motifs can be used as controlling groups in Rh-catalyzed hydroacylation reactions.     

Direct intermolecular hydroacylation of N,N-dialkylacrylamides with aldehydes catalyzed by a cationic rhodium(I)/dppb complex

[structure: see text]. A cationic rhodium(I)/dppb complex catalyzed direct intermolecular hydroacylation of N,N-dialkylacrylamides with both aliphatic and aromatic aldehydes has been achieved through the stabilization of acylrhodium intermediates by alkene chelation to rhodium. This method represents a versatile new route to gamma-ketoamides in view of the high atom economy and commercial availability of substrates.     

Chelation-controlled intermolecular alkene and alkyne hydroacylation: the utility of beta-thioacetal aldehydes

[reaction: see text]. Beta-thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO4 as a catalyst and are proposed to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or reduced to alkanes in good yields.     

O-substituted alkyl aldehydes for rhodium-catalyzed intermolecular alkyne hydroacylation: the utility of methylthiomethyl ethers

Combining α-methylthiomethyl (MTM) ether substituted aldehydes and 1-alkynes in the presence of [Rh(dppe)]ClO(4) results in efficient intermolecular alkyne hydroacylation to deliver α-O-MTM-substituted enone products. The product MTM ethers can be converted to the free hydroxyl group either in situ, by the addition of water to the completed reaction, or in a separate operation, by the action of silver nitrate.     

The effects of amine and acid catalysts on efficient chelation-assisted hydroacylation of alkene with aliphatic aldehyde

Efficient intermolecular hydroacylation of 1-alkene with aliphatic aldehyde was achieved using a catalyst mixture of cyclohexylamine, p-trifluoromethylbenzoic acid, Wilkinson’s complex and 2-amino-3-picoline. The formation of unwanted aldol side-product was avoided through the conjugate addition of cyclohexylamine to the aldol intermediate that was initially generated, followed by the retro-Mannich-type fragmentation of the resulting β-aminoaldimine.     

Highly regioselective intermolecular hydroacylations of enamides with salicylaldehydes

Highly regioselective intermolecular hydroacylations of enamides under rhodium catalysis with monodentate phosphane ligands are reported for the first time. The presence of MeCN facilitates this novel C-C bond formation, and the electron-deficient phosphine P(p-F-Ph)(3) has proven most effective for the direct hydroacylation of 1-vinyl-2-pyrrolidinone. Accordingly, an atom-economic synthetic route to α-amido ketones from readily available substrates has been developed.     

Highly efficient copper-catalyzed hydroacylation reaction of aldehydes with azodicarboxylates

The hydroacylation reaction of aldehydes with azodicarboxylates catalyzed by copper(II) acetate monohydrate has been reported. The reaction of various aldehydes gave the corresponding hydroacylation products in 60-98% yields under mild conditions. The method is simple, economical, and has practical advantages for the construction of the carbon-nitrogen bonds.     

Diene hydroacylation from the alcohol or aldehyde oxidation level via ruthenium-catalyzed C-C bond-forming transfer hydrogenation: synthesis of beta,gamma-unsaturated ketones

Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a-g to deliver beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form beta,gamma-unsaturated ketones. In all cases, complete branch regioselectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product (homoallyl alcohol or beta,gamma-unsaturated ketone) are accessible.     

Double-chelation-assisted Rh-catalyzed intermolecular hydroacylation between salicylaldehydes and 1,4-penta- or 1,5-hexadienes

Intermolecular hydroacylation between salicylaldehydes 1, 26-40 and 1,4-penta- or 1,5-hexadienes 4-13 by Rh-catalyst proceeded under mild reaction conditions to give a mixture of iso- and normal-hydroacylated products 14-25, 41-55, and 57-60. In the hydroacylation reaction, chelation of both salicylaldehyde and diene to the Rh-complex plays a crucial role. The ratio of iso- and normal-hydroacylated products could be regulated by the addition of salicylic acid or amines. The effects of various Rh-complexes, solvents, and additives were examined, and the plausible mechanisms of the catalytic cycle were proposed on the basis of the deuterium-labeling salicylaldehyde experiments.     

Rhodium-catalyzed intramolecular hydroacylation of 5- and 6-alkynals: convenient synthesis of alpha-alkylidenecycloalkanones and cycloalkenones

A novel intramolecular hydroacylation of 5- and 6-alkynals leading to alpha-alkylidenecycloalkanones was accomplished by using cationic a rhodium(I)/BINAP complex. For all cyclizations described, a single (E)-olefin isomer was obtained. At elevated temperature, hydroacylation and double bond migration of 5- and 6-alkynals proceeded in a one-pot reaction to give cycloalkenones. An intramolecular hydroacylation of a 7-alkynal was unsuccessful. This method represents an attractive new route to highly functionalized alpha-alkylidenecycloalkanones and cycloalkenones.