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A Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the ready availability of diverse DHPMs and aryl alcohols, the reaction method offers facile access to biologically and pharmacologically valuable 2-aryloxypyrimidine derivatives with rapid diversification.

A highly convergent, gram-scale synthesis of vitamin D3 analogue tacalcitol 1 is disclosed, starting from L-valine and Inhoffen–Lythgoe diol. Key features of the synthesis include modified Julia ol...

Synthesis of the C1–C13 fragment of eribulin mesylate has been accomplished. It features a highly stereoselective construction of a trans-dihydropyran framework using three key reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.

A reaction method is described for selective reductive cleavage of 2-(phenylthio)pyrimidines using Pd(OAc)2 and Et3SiH to produce 2-(H)pyrimidines. The reaction proceeds efficiently with a wide range of 2-(phenylthio)pyrimidines. Considering the ready availability of 2-(arylthio)pyrimidines derived from oxidative C S cross coupling of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs), this method unambiguously provides a shortcut to the preparation of 2-(H)pyrimidines with unprecedented diversity.

Decarboxylative C C cross-couplings of 2-aminopyrimidine-5-carboxylic acids under a Pd/Ag-based catalytic system opens a new platform for the introduction of diverse C5 substituents. The reaction methods proceeded efficiently with a wide range of the acids and the coupling partners of aryl iodides, alkenes, bromoalkynes, and azoles. Considering ready availability of 2-aminopyrimidine-5-carboxylic acid from the oxidative dehydrosulfurative C N cross-coupling of the 3,4-dihydropyrimidin-1H-2-thiones, this reaction method unambiguously pave a shortcut to densely substituted 2-aminopyrimidine derivatives with unprecedented diversity.

This report describes a cascade reaction method for the synthesis of 2-arylpyrimidine derivatives via dehydrosulfurative carbon-carbon cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system. It provides rapid and general access to a diverse range of 2-arylpyrimidines in a single step from a wide range of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) and arylboronic acids.

Described is a copper-catalyzed cascade reaction method for the conversion of 3,4-dihydropyrimidine-2(1 H )-thiones to arylthiopyrimidines, likely proceeded via C–S cross-coupling and oxidative dehydrogenation under aerobic conditions. The reaction method proceeded efficiently with a wide range of the dihydropyrimidinethione substrates and aryl iodides as coupling partners.

Copper-mediated Michael addition of ethyl bromodi­fluoroacetate to Michael acceptors is accompanied by the formation of a substantial amount of byproducts. Elucidation of their structure hinted the cause of their formation, from which we discovered a highly improved and robust protocol by treatment with protic additives such as H2O and AcOH. This modification led to significant increase of yield with concomitant decreased use of reagent.

Tandem transformations of nitriles into various N-heterocycles have been accomplished through the reaction of electrophiles with Blaise reaction intermediates formed in situ. The reaction of the Blaise reaction intermediates with propiolates gives 2-pyridones through consecutive C- and N-nucleophilic reactions. The tandem reactions of the Blaise reaction intermediate with 1,3-enynes proceed through C-nucleophilic addition followed by an electrocyclization–aromatization cascade to give pyridines. Exocyclic enamino esters can be prepared by transformations of ω-chloroalkyl nitriles through chemoselective intramolecular alkylation of the Blaise reaction intermediate. Palladium-catalyzed intramolecular arylations or copper-catalyzed intermolecular cross-coupling reactions of the Blaise reaction intermediate give a range of indole derivatives. Combinations of tandem alkylations and palladium-catalyzed couplings of the Blaise reaction intermediates of ω-chloroalkyl nitriles give N-fused indoles.

The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with ω-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles.

A novel tandem one-pot method for the synthesis of α-aminomethylene-γ-butyrolactone derivatives has been developed through the regioselective epoxide opening reactions with the Blaise reaction intermediates, generated by the reaction of a Reformatsky reagent with nitriles. Formation of a modified Blaise reaction intermediate by the addition of a stoichiometric amount of n-BuLi followed by slow addition of epoxide is required for the good yield of γ-butyrolactones.

We have devised a new route toward 2-unsubstituted pyrimidine derivatives from the Biginelli product, dihydropyrimidin-2(1H)-thiones in two steps: Oxidation of dihydropyrimidin-2(1H)-thiones using oxone on wet alumina or hydrogen peroxide in the presence of catalytic amount of vanadyl sulfate provided 1,4-di-hydropyrimidine, which was further oxidized to 2-unsubstituted pyrimidines by the treatment of KMnO 4 . Oxidation of dihydropyrimidin-2(1H)-ones by KMnO 4 formed 2-hydroxypyrimidine in excellent yield, whereas attempted direct desulfurative aromatization of dihydropyrimidin-2(1H)-thiones by KMnO 4 resulted in the formation of 2-hydroxypyrimidines, the same products obtained in the oxidation of dihydropyrimidin-2(1H)-one.

(4S)-N-Boc-4-fluoro-l-proline methyl ester (4) was prepared from the following sequence of reactions: esterification of trans-4-hydroxy-l-proline (2), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7. Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9. Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17. Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis- and trans-17 at this stage. After the deprotection of the N,O-methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis- and trans-mixture of LC15-0133 (1) in the course of tartrate salt formation provided cis-LC15-0133 (1a) tartrate salt in 83% yield (>98% de).

The Blaise reaction intermediate, generated in situ from Reformatsky reagent and nitrile, reacted with propiolates in a chemo- and regioselective manner to afford 2-pyridone derivatives in good to excellent yields.

Efficient synthesis of TERT-butyl [(3 R,5 S)-6-hydroxy-methyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate ( 1) has been accomplished. Unprecedented hydration of 3 in the presence of lithium chloride provided 4A, B, the primary hydroxyl group of which reacted with pivaloyl- and 1-naphthoyl chloride, respectively, in pyridine to give 7A or 7D in improved selectivity. Diastereoselective reduction of 7A and protection-deprotection sequence provided 1.

Ethyl 4-substituted-1H-pyrrole-3-carboxylates were prepared in a one-pot manner starting from aromatic or aliphatic aldehydes via a Horner−Wadsworth−Emmons reaction and subsequent reaction with tosylmethylisocyanide (TosMIC) in the presence of sodium tert-amylate in toluene. Judicious selection of base and solvent led to the use of a single solvent, i.e., toluene, for reactions as well as for crystallization to render the one-pot process more practical and greener than the stepwise version.

Reaction of aryl nitriles with potassium ethyl malonate in the presence of zinc chloride and a catalytic amount of Hünig's base provided beta-amino acrylates in moderate to good yield. Compared to the classical Blaise reaction, this reaction is safer (endothermic), devoid of lacrimatory reagent, and is possible with 0.5-1.0 equiv of zinc chloride.

An efficient synthesis of 2,6-dichloro-5-fluoronicotinoylacetate (1) has been accomplished in a single step using the unprecedented decarboxylative Blaise reaction of 3-cyano-2,6-dichloro-5-fluoropyridine (4) with potassium ethyl malonate in the presence of zinc chloride.

The in situ generated Blaise reaction intermediate, a zinc bromide complex of beta-enaminoester, reacts with various unactivated terminal alkynes and an internal alkyne under mild conditions to afford alpha-vinylated beta-enaminoesters in good to excellent yields.

Careful examination of nucleophilicity, basicity, and leaving group ability led us to discover the nucleophilic fluorination of triflates by weakly basic tetrabutylammonium bifluoride, which provides excellent yields with minimal formation of elimination-derived side products. Primary hydroxyl groups as well as secondary hydroxyl groups in acyclic chains or in five-membered rings are excellent substrates, whereas benzylic and aldol-type secondary hydroxyl groups give poor yields as a result of the instability of their triflates.