We describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.
An efficient and practical copper‐catalyzed domino synthesis of benzo[4,5]imidazo[1,2‐a]pyrimidin‐4(10H)‐ones has been developed. The protocol uses N‐(2‐halophenyl)‐3‐alkylpropiolamides and cyanamide as the starting materials, inexpensive copper(I) iodide and pipecolinic acid as the catalyst and ligand, and the corresponding products were obtained in moderate to good yields.
A general and efficient method for the synthesis of oxazolidin‐2‐ones and imidazolidin‐2‐ones directly from 1,3‐diols and 3‐amino alcohols has been developed using the same reagent combination of iodobenzene dichloride (PhICl2) and sodium azide (NaN3).
An unexpected palladium‐catalyzed carbonylative synthesis of 2,3‐disubstituted chromones has been developed. Starting from 2‐bromofluorobenzenes and ketones, the corresponding chromones were produced in good yields. By control experiments, this transformation was found to proceed through a sequential carbonylation/Claisen–Hasse rearrangement/intramolecular nucleophilic aromatic substitution approach (SNAr). More specifically, the reaction sequence started with a palladium‐catalyzed carbonylation of the ketone with o‐bromofluorobenzene to give the vinyl benzoates, which subsequently transformed into 1,3‐diketones via a Claisen–Hasse rearrangement. The final products were produced after an intramolecular SNAr reaction of the in situ formed 1,3‐diketone.
A three‐fold cross‐linked polymer‐bound phosphine (POL‐Ph3P) with high phosphorus content has been prepared. The phosphorus‐containing polymer forms a monodentate‐P‐ligated palladium complex, which shows excellent activity in Suzuki–Miyaura cross‐coupling reactions of aryl chlorides. Importantly, the catalyst Pd/POL‐Ph3P is highly stable and can be reused for at least 10 times without losing reactivity.
A unique one‐pot synthesis of cyclic cis‐1,2‐amino alcohols from trans‐1,2‐azido alcohol precursors was developed. The key step is highlighted by the stereoselective reduction of the cyclic α‐alkoxy imines, which could be prepared from the corresponding azides by ruthenium catalysis under photolytic conditions. Remarkably, this unprecedented reaction pathway offers a stereodivergent access to structurally diverse cyclic 1,2‐amino alcohols.
We have developed a novel strategy for the direct substitution of benzyl alcohols with anthranilic acids using water‐soluble copper catalysts through a radical pathway in water, which offers efficient and environmentally friendly N‐, S‐, and C‐benzylations under neutral conditions. Radical scavengers strongly inhibited the benzylation. Radical clock experiments using α‐cyclopropylbenzyl alcohol were conducted to observe the rapid isomerization of the cyclopropylmethyl radical to the allylmethyl radical. Hammett plots could be fitted to a two‐parameter Hammett relationship containing both radical and polar contributions [log (kX/kH)=−1.24 σ.–0.38 σ, R2=0.99]. The relative parameter ρ./ρ of 3.3 suggested that these reactions involved a strong radical character with minor polar influence at the transition state.
A wide range of imidazo[1,2‐a]pyridines are accessible from cheap and readily available 2‐aminopyridines and 1,3‐dicarbonyl compounds using a unique CBrCl3/2‐aminopyridine system for bromination at the α‐carbon. 2‐Aminopyridine is not only the substrate but also acts as a bromination shuttle, transferring the bromine atom from CBrCl3 to the α‐carbon of the 1,3‐dicarbonyl. The reaction mechanism involves a series of reversible steps, including an addition reaction with cyclic transition state, to form a bromo‐hemiaminal intermediate. Isolated yields of up to 97% were obtained under mild conditions and at short reaction times in this transition metal‐free, one‐pot synthesis.
A mild and convenient oxidative transformation of secondary alcohols to 1,5‐disubstituted tetrazoles is uncovered by employing trimethylsilyl azide (TMSN3) as a nitrogen source in the presence of a catalytic amount of copper(II) perchlorate hexahydrate [Cu(ClO4)2.6 H2O] (5 mol%) and 2,3‐dichloro‐5,6‐dicyano‐para‐benzoquinone (DDQ) (1.2 equiv.) as an oxidant. This reaction is performed under ambient conditions and proceeds through C C bond cleavage.
The iron(III) chloride‐multicatalyzed dioxygenation of enamides with TEMPO in the presence of alcohols has been developed. This multicomponent domino process affords efficient new strategies for the synthesis of α‐oxy‐N‐acylhemiaminals or α‐oxyimides in good to excellent yields under mild conditions.
The combination of benzyl bromide, sodium hydroxide and 15‐crown‐5 in tetrahydrofuran is shown to be an efficient method for installing benzyl groups at both the 4‐ and 6‐positions regioselectively directly from peracetylated N‐trichloroacetyl‐protected glucosamine and galactosamine. Application of this benzylation strategy proved to significantly shorten the synthetic route to hyaluronic acid tetra‐ and hexamers.
A highly stereoselective three‐component Povarov reaction, catalyzed by (R)‐ and (S)‐BINOL hydrogen phosphate, was achieved for the first time with aminopyrroles and aminopyrazoles as 2‐azadiene precursors. A variety of aldehydes, enecarbamates, amino‐substituted azines participated in the reaction to afford the tetrahydropyrrolopyridines and tetrahydropyrazolopyridines in good yields with excellent diatereo‐ and enantioselectivities. A stereochemical model is proposed to account for the observed absolute stereochemistry.
The reaction of N‐[2.2]paracyclophanyl‐substituted amides or amines with phenyliodine diacetate (PIDA) and protic nucleophiles affords mixed para‐substituted [2.2]paracyclophane derivatives in moderate to good yields. As protic nucleophiles carboxylic acids and alcohols as well as pyridine hydrobromide can be used. 4‐Hydroxy[2.2]paracyclophane reacts in an analogous manner.
The ring‐opening of N‐tert‐butanesulfinylethynylaziridines with lithium tris(dimethylphenylsilyl)zincate is reported. The reaction is demonstrated to be both stereoselective and stereospecific and to proceed through an anti‐SN2′ process. Further deprotection of the nitrogen atom under mild conditions allows access to 4‐amino‐1‐(dimethylphenylsilyl)allenes with high yields and levels of stereoselectivity.
This paper describes the synthesis of quinazolinones via a tandem reaction using the laccase‐mediator system under mild conditions. The procedure involved the laccase‐catalyzed oxidation of alcohols to the corresponding aldehydes, followed by cyclocondensation with isatoic anhydride and a number of amines to afford 2,3‐dihydroquinazolin‐4(1H)‐ones, which were further oxidized to quinazolinones in useful yields. The use of an enzyme as the catalyst, O2 as an environmentally friendly oxidant, and a citrate buffer as the green solvent represents a novel and efficient approach for the one‐pot synthesis of quinazolinones.
An (R/S)‐titanium(IV) BINOLate‐catalyzed highly enantioselective intramolecular Heck/aza‐Diels–Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)‐BINOL α‐phosphoryloxy carbamate ( αPPC2 ) in one pot. Chiral cooperativity between (R/S)‐αPPC2 and (R/S)‐titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples).
Dehydrogenative coupling of primary alcohols with secondary amines to form tertiary amides and dihydrogen (H2) is efficiently catalyzed by bipyridyl‐based ruthenium pincer complexes (0.2–1 mol%) under neutral conditions (in case of the dearomatized complexes), or with added catalytic amount of base. The reaction is sensitive to steric hindrance; in the case of amidation of bulky secondary amines a less sterically hindered complex is more efficient. Selective acylation of primary amines in the presence of secondary amines was also demonstrated.
An efficient three‐component reaction involving carbon monoxide with a range of aryl bromides and N‐substituted acetoacetamides is reported for the synthesis of β‐keto amides. This transformation is promoted by Pd‐catalysis followed by an acid‐mediated deacetylation upon work‐up, enabling a large number of β‐keto amides to be isolated. Finally, d2‐13C‐dyclonine could be synthesized in three steps utilizing the developed catalytic system as the key step.
Novel copper‐catalyzed three‐component reactions of phenylacetonitrile, sulfur and DMF (dimethyformamide) for the selective preparation of N,N‐dimethylthiobenzamide and N,N‐dimethyl‐2‐phenylethanethioamides in yields of up to 96% are described.
An interesting group of multifunctional phosphines (Ar‐BINMOL‐Phos; Ar‐BINMOL=1,1′‐binaphthalene‐2‐α‐arylmethanol‐2′‐ol) with multi‐stereogenic centers of axial and sp3‐central chirality has been prepared successfully from a single chiral source through a concise synthetic route, in which the neighbouring lithium‐promoted [1,2]‐Wittig rearrangement proceeding with excellent diastereoselectivity and enantioselectivity is the key process in this approach. Also, in the catalytic alkynylation of aromatic aldehydes with terminal alkynes, the combination of these Ar‐BINMOL‐Phos ligands with dimethylzinc was found to be an effective catalyst system to afford predominantly the S‐configured propargylic alcohols, whereas the additional use of calcium hydride and n‐butyllithium along with the same Ar‐BINMOL‐Phos ligands gave the R‐configured products in high yields and excellent enantioselectivities (up to >99% ee).
