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Copper-promoted dehydrosulfurative C–N cross-coupling of 3,4-dihydropyrimidin-1H-2-thione with amine accompanied by concomitant aromatization to generate 2-aryl(alkyl)aminopyrimidine derivatives is described.

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...

Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate...

A reaction method is described for the one-step synthesis of 2-alkynylpyrimidines from 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative Sonogashira cross-coupling with concomitant o...

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.

A copper-mediated oxidative dehydrosulfurative carbon–oxygen cross-coupling reaction with boric ester and six-membered cyclic thiourea for single-step production of densely substituted 2-alkoxypyrimidines incorporated in a privileged scaffold is described. This is the first demonstration of boric ester acting as an alkoxy donor in a metal-catalyzed coupling reaction to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives with rapid diversification and expands the utility of boric ester and the scope of Liebeskind–Srogl-type reactions.

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.

A method for the synthesis of 2-aryl(alkyl)aminopyrimidines from readily available 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative C–N cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system is described. This reaction protocol provides unprecedented diversity of fully substituted 2-aryl(alkyl)aminopyrimidines in a single step from a wide range of DHPMs and amine 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.

An isolable activated ester, diethyl thiophosphoryl [(Z)-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (9a, DAMA) was prepared in high purity, which was at least stable for 7 d at and 6 months at . Its reaction with 7-ACA (4) in the presence of tributylamine in i-PrOH provided cefotaxime (1) of high purity in good yield. Preparation of DAMA and its reaction with 7-ACA (4) to 1 was performed in one-pot manner, respectively with minimal unit operations of stirring and filtration.

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.

As a new strategy for the optimization of a chiral catalyst, the catalytic activity of the host-guest complexes of chiral bisphosphine bearing imidazolidinone was investigated in Rh-catalyzed asymmetric hydrogenation of enamide. Marginal enhancement in enantioselectivity was observed and the nature of interaction between host-guest was experimentally elucidated.

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).

Highly efficient syntheses of cylindol A (1) and the proposed structure of cylindol B (2) have been accomplished using common synthetic transformations from symmetrical starting materials 7 and 11, respectively. The latter synthesis revealed that the proposed structure of the natural cylindol B was assigned incorrectly. Isomers of 2 such as 15 and 16 were synthesized as a possible candidate of the natural cylindol B. However, their spectral data also did not match that of the natural cylindol B. Therefore, the structure of the natural cylindol B is yet to be resolved.

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.

Described is a scalable synthetic route towards LB30057 (1) which is based upon a chiron approach using methyl tyrosinate hydrochloride as a starting material. In situ protection of methyl tyrosinate to its N,O-bis-trimethylsilyl derivative and subsequent N-selective introduction of naphthalenesulfonyl group provided methyl N-2-naphthalenesulfonyltyrosinate (9). After the phenol group of 9 was triflated to 10, nickel-catalyzed cyanation provided 11 in good yield. The acid chloride 11a was generated via hydrolysis of the ester group followed by the treatment with SOCl2, and then coupled with cyclopentylmethylamine to give the amide 15. Imidate formation followed by amidrazone generation and final salt formation with maleic acid afforded 1.

Ubiquinone, as its name represents, exists ubiquitously in human body, particularly in the heart. It mediates the electron transfer process in mitochondria and also exerts strong antioxidant effect in its reduced form. In clinical trial, it showed beneficial effect on heart-related diseases such as myocardial infarction, angina, and other related symptoms to cause decreased mortality compared to the placebo group. These interesting biological effects have induced various synthetic efforts towards Coenzyme Q10 (CoQ10). Among them, two approaches seem practical for a large scale production in terms of the supply of the starting material, solanesol and their synthetic efficiency: for the construction of its complete carbon framework, Koo’s synthesis used the coupling of the sulfone 2 with solanesyl bromide (3) and Lipsultz group employed nickel catalyzed cross coupling reaction of 4 with vinyl aluminum reagent 5 as the key steps, respectively (Figure 1). Earlier in our synthetic study towards CoQ10, we investigated the reproducibility of the Koo’s synthetic procedure toward 2 obtained from the Friedel-Crafts reaction of (E)-4chloro-2-methyl-1-phenylsulfonyl-2-butene (7) with tetramethoxytoluene 6. Surprisingly, the reaction itself was pretty complicated with the formation of many side products in much lowered E:Z selectivity of ca. 3:1 to 7:1 than reported. Use of zinc chloride and bromide resulted in 3.3:1 and 7.4:1 E:Z ratio, respectively (Table 1, entries 1-2) with yields usually less than 20%. Best ratio of 7.6:1 was obtained by the use of boron trifluoride etherate, however with low conversion of ca. 20%. Aluminum chloride also showed marginal conversion of 21% with 3.4:1 E:Z selectivity. Details of the HPLC profiles of these reaction mixtures were provided in Figure 2. Other Lewis acid such as MgBr2, AlEt3, TiCl4, FeCl3 led to complete decomposition of starting materials and no sign of the formation of the desired product was observed by HPLC analysis. To improve the yield and stereoselectivity of the reaction, we turned our attention to the use of montmollironite K-10 (MK-10), in which the reaction partners might be confined in the layered space, thus rendering the stereoselectivity increased. First we tested commercial MK-10 for the reaction of 6 with 7. Happily, first attempt led to much cleaner reaction profile with significantly improved E:Z selectivity (Table 2, entry 1). However, the reaction did not complete in prolonged reaction time – the maximum conversion was accomplished in 18 h (74%). We speculated that the low conversion might be caused by residual water in clay (6.9% for commercial MK-10). In this respect, we tested a series of

A novel synthetic route was devised for 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)2O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney cobalt by suppressing the...

Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) to 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic protons for CMBP was found to drastically elevate both the reaction rate and selectivity to 4-aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) over Pd catalyst with a complete suppression of the major side reaction to 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solvent was found to increase the hydrogenation rate greatly compared to other solvents with a negligible decrease of selectivity. The leaching of Pd by acid and consequent accumulation of Pd ion in the reaction mixture was negligible in CMBP hydrogenation. The novel process of chemoselective CMBP hydrogenation in acidic media over Pd catalyst was thus much simpler yet m...

An efficient synthesis of the HIV-1 protease inhibitor LB71350 (1) is described. High diastereoselective epoxidation of the cis-allylic carbamate fragment of (5S)-[N-(benzyloxycarbonyl)-amino]-N-[2-methyl-(1R)-[(phenyl)carbonyl]-propyl]-6-phenylhex-(Z)-enamide (16) and one-pot preparation of N-[(1-methylethoxy)carbonyl]-3-(methylsulfonyl)-l-valine (4) are the key features of the synthesis.

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 radical derived from bromoacetal 12 undergoes intramolecular addition to give predominantly the cyclic acetal 13 in which the C12 methyl substituent is endo.

Efficient synthesis of clitocine has been accomplished via unprecedented 1,3-N (endo) to N (exo) migration as a key transformation. Incorporation of p-chlorobenzoyl (PCB) group as a protecting group led to the easy solidification of the intermediate of 7, thus making the isolation very facile and to the minimization of the epimerization of the anomeric center at the final deprotection stage.

An efficient synthesis of 2,6-dichloro-5-fluoronicotinoyl acetate (1) has been accomplished in a single step using the Blaise reaction of ethyl bromoacetate with 3-cyano-2,6-dichloro-5-fluoropyridine (4). Use of methanesulfonic acid as an in situ activator of zinc removed the induction period of the Blaise reaction to render it safe and viable for a large-scale operation.

Epoxidation of δ-amino-β,δ-unsaturated ester with trifluoroperacetic acid afforded its epoxide in a highly diastereo- H selective manner. Subsequent stereodivergent epoxide opening reactions provided synthetic routes towards both the threo and erythro hydroxyethylene peptide isostere.

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.

Coupling of nitriles (I) and (VII) with Reformatsky reagents, generated from bromides (II) and (V), followed by treatment with NaN(Tms)2 allows an efficient access to exo-cyclic enaminoesters.

1-Substituted-5-hydroxymethylimidazoles were prepared through green desulfurization of their 2-mercapto derivatives by the treatment of 30% hydrogen peroxide in the presence of a catalytic amount of transition metal catalysts.