Lithiation of meso-octamethylcalix[4]pyrrole: a general route to C-Rim monosubstituted calix[4]pyrroles

Lithiation and subsequent addition of an electrophile to meso-octamethylcalix[4]pyrrole provides a straightforward synthetic route to new, C-rim monosubstituted calix[4]pyrroles. A variety of electrophiles were used, resulting in calix[4]pyrroles with appended functional groups including carboxyl, ester, iodo, and formyl. This method was optimized to give maximum yields of the monosubstituted derivatives with lowest possible contamination by di- and trisubstituted congeners. Solid-state studies, performed for a number of these derivatives, showed unexpected supramolecular interactions involving both solvents and the monosubstituted calix[4]pyrrole derivatives themselves.     

Synthesis of mono- and disubstituted porphyrins: A- and 5,10-A2-type systems

General syntheses have been developed for meso-substituted porphyrins with one or two substituents in the 5,10-positions and no beta substituents. 5-Substituted porphyrins with only one meso substituent are easily prepared by an acid-catalyzed condensation of dipyrromethane, pyrrole-2-carbaldehyde, and an appropriate aldehyde using a "[2+1+1]" approach. Similarly, 5,10-disubstituted porphyrins are accessible by simple condensation of unsubstituted tripyrrane with pyrrole and various aldehydes using a "[3+1]" approach. The yields for these reactions are low to moderate and additional formation of either di- or monosubstituted porphyrins due to scrambling of the intermediates is observed. However, the reactions can be performed quite easily and the desired target compounds are easily removed due to large differences in solubility. A complementary and more selective synthesis involves the use of organolithium reagents for S(N)Ar reactions. Reaction of in situ generated porphyrin (porphine) with 1.1-8 equivalents of RLi gave the monosubstituted porphyrins, while reaction with 3-6 equivalents of RLi gave the 5,10-disubstituted porphyrins in yields ranging from 43 to 90 %. These hitherto almost inaccessible compounds complete the series of different homologues of A-, 5,15-A(2)-, 5,10-A(2)-, A(3)-, and A(4)-type porphyrins and allow an investigation of the gradual influence of type, number, and regiochemical arrangement of substituents on the properties of meso-substituted porphyrins. They also present important starting materials for the synthesis of ABCD porphyrins and are potential synthons for supramolecular materials requiring specific substituent orientations.     

A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl–Aryl Cross‐Coupling of Aryl Halides and Olefins

We report an efficient means of sp²–sp³ cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron‐deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air‐stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium‐labeling studies indicate that deuterium scrambling does not take place in this sp²‐sp³ cross coupling, implying that β‐hydride elimination is not a significant process in this transformation.     

Palladium β-diketonate complex catalyzed synthesis of monosubstituted arylferrocenes

Palladium β-diketonate complexes are reported as efficient catalysts for the selective synthesis of monosubstituted arylferrocenes by a cross-coupling reaction of bis(ferrocenyl)mercury with aryl halides. The present protocol was applicable to aryl halides providing good to excellent yields of the desired products.     

Mild persubstitution of di- and tetrabrominated arenes with arylthiolate nucleophiles

A mild selective protocol was used to prepare tetrakis(2-chlorophenylthio)anthracene from tetrabromoanthracene and sodium 2-chlorobenzenethiolate avoiding the thiolate self-attack. The uncatalyzed nucleophilic substitution of a series of mono-, di-, and tetrabrominated arenes by arylthiolate ions was attempted in mild conditions to investigate the scope of the substitution reaction regarding the size of the aromatic system as well as the number of bromine atoms. Successful reactions afforded only the persubstituted products in good purity and yield after a simple workup and chemoselectivity of Br versus Cl substituents was achieved for the tetrabromide.     

Dehydrogenative coupling reactions between hydrosilanes and monosubstituted alkynes catalyzed by solid bases

Dehydrogenative coupling reactions between phenylsilane and monosubstituted alkyne afford mono-, di- and trialkynylphenylsilane in the presence of magnesium or calcium oxide.     

Enantio‐ and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis

A protocol for the highly enantioselective synthesis of 9‐substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol‐based N‐triflyphosphoramide was found to promote the in situ generation of ortho‐quinone methides and their subsequent reaction with 1,3‐cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio‐ and diastereoselective Brønsted acid catalyzed desymmetrization of 5‐monosubstituted 1,3‐dicarbonyl substrates with ortho‐quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.     

A hydrazine- and phosgene-free synthesis of tetrazinanones, precursors to 1,5-dialkyl-6-oxoverdazyl radicals

A complementary approach to published synthetic methods for tetrazinanones, precursors to verdazyl radicals, is described herein. This approach uses carbohydrazide, a commercially available reagent, as a common starting material. Unlike previous methods described in the literature, this synthetic scheme does not rely on phosgene, phosgene substitutes, or the limited pool of commercially available monosubstituted hydrazines for its execution. A large variety of alkyl substitution patterns at the N-1 and N-5 positions of verdazyl radicals are possible, including both symmetrically and unsymmetrically substituted products. An initial condensation reaction of carbohydrazide with a specific aldehyde introduces the desired C-3 substituent in the final verdazyl radical product and protects the NH(2) groups during the subsequent N-1 and N-5 alkylation reactions. A succeeding methanolysis and concomitant ring-closing reaction gives the tetrazinanone. A number of known oxidation methods can then be employed to form the final verdazyl radical product.     

氯化亚锡催化“一锅法”合成N1-取代的3,4-二氢嘧啶-2(1H)-酮

以芳香醛、乙酰乙酸乙酯(甲酯)、单取代脲为原料,氯化亚锡为催化剂,在无溶剂、80℃条件下,通过三组分"一锅法"合成了一系列N1-取代的3,4-二氢嘧啶-2(1H)-酮衍生物。考察了催化剂用量和反应温度对产品收率的影响。通过IR、~1H NMR、~(13)C NMR和元素分析对目标产物结构进行确证,提出了可能的催化作用机理。本文的合成方法具有催化剂活性高、廉价易得和反应时间短、条件温和、产率高、绿色环保等优点。     

Rapid Synthesis of Block and Cyclic Copolymers via Click Chemistry in the Presence of Copper Nanoparticles

A new method for the rapid and efficient coupling of homopolymers to yield di- and triblock copolymers as well as cyclic polymers using the 3 + 2 π Huisgen copper catalyzed cyclo-addition reaction has been developed. This facile method utilizes commercially available Cu nanoparticles that are tolerant to O(2), easily removable and recyclable.     

A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl–Aryl Cross-Coupling of Aryl Halides and Olefins

We report an efficient means of sp²–sp³ cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron-deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air-stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium-labeling studies indicate that deuterium scrambling does not take place in this sp²-sp³ cross coupling, implying that β-hydride elimination is not a significant process in this transformation.     

Reversed-phase high-performance thin-layer chromatography of mono-, di- and trisubstituted bile acid methyl esters

A comparative study is reported on separation of series of mono-, di-, and trisubstituted methyl 5β-cholanates, which differ only in the position and stereochemistry of hydroxyl or keto groups at position and stereochemistry of hydroxyl or keto groups at positions C-3, C-7, and/or C-12, by reversed-phase [with chemically-bonded (C-18) silica gel] and normal-phase (silica gel) high-performance thin-layer chromatography (HPTLC). Methnol (or acetonitrile)/water systems were employed as mobile phase. Reversed-phase HPTLC found to be particulary effective for separation of the stereoisomers of di- and trisubstituted compounds whereas the less polar monosubstituted isomers are well resolved in normal-phase HPTLC.     

Pd-catalyzed synthesis of α-aryl ketones through couplings of α-arylacetyl chlorides with triarylbismuths as multi-coupling nucleophiles

The cross-coupling reaction of α-arylacetyl chlorides with triarylbismuths was studied under Pd-catalyzed conditions. The reaction was found to be facile under the established protocol and furnished high yields of α-aryl ketones in short reaction times. This work also demonstrated a facile synthesis of various regio-isomeric mono-, di- and tri-substituted α-aryl ketones in high yields. Triarylbismuths were employed as sub-stoichiometric multi-coupling organometallic nucleophiles in this coupling protocol.     

Temperature dependence of the reactivity of monosubstituted thiophenols by applying the hydrogen-isotope exchange reaction in a liquid-solid system

In order to reveal the reactivity of monosubstituted thiophenols, the hydrogen-isotope exchange reaction between T-labeled poly(vinyl alcohol) and each monosubstituted thiophenol (unlabeled) was studied in a liquid-solid system. Using both the data obtained and theA-McKay plot method, the reaction was analyzed, and the rate constant (k) for the monosubstituted thiophenol has been obtained. Consequently, it has been found that (1) the higher the temperature is, the larger is the reactivity of monosubstituted thiophenols, (2) the temperature dependence of the effect of the substituent (in a monosubstituted thiophenol) on the reactivity of the monosubstituted thiophenol is weak, (3) the reactivity of monosubstituted thiophenols follows the Hammett rule, (4) the reactivity of monosubstituted thiophenols can be enhanced with one of the electron-attractive substituents.     

Synthesis of 3‐Ω‐amino‐2‐thiohydantoins

In the reaction of ethyl isothiocyanatoacetate with diamines, followed by cyclization of the intermediate product, 3‐monosubstituted thiohydantoins have been obtained. It was found that the reaction course depends on the purity of the isothiocyanate used and also, in the case of dialkylaminoamines, the self‐cyclization occurs. Besides the dialkylamino derivatives of 3‐monosubstituted 2‐thiohydantoins also new monoalkylamino, amino and heterocyclic derivatives were synthesized. The aryldiazonium derivative of 3‐monosubstituted 2‐thiohydantoin yielded both respective phenol derivative after hydrolysis and the product of coupling with 2‐naphthol.     

Efficient difluoromethylation of isoflavonoids and flavonoid under mild conditions

A simple and efficient protocol for difluoromethylation of isoflavones, flavonoids, and coumarins has been developed. The protocol uses readily available, non-ozone-depleting and easy handling BrCF₂PO(OEt)₂ as difluorocarbene precursor. The reaction underwent the formation of difluorocarbene under mild reaction conditions with relatively weak base therefore demonstrates high selectivity. Application of the reaction led to difluoromethylated biologically relevant molecules.     

Enantioselective and stereodivergent hydromonofluoroalkylation of conjugated and remote dienes

Because of the widespread applications of optically active alkyl fluorides in medicinal and agro chemicals, enantioselective and even stereodivergent construction of alkyl fluorides remains highly desirable but underdeveloped. Transition-metal-catalyzed asymmetric hydrofluoroalkylation of readily available dienes represents a novel route to achieve this goal, yet receives scarce study. Here we report an intriguing palladium-catalyzed enantioselective hydromonofluoroalkylation reaction of conjugated dienes. Both monosubstituted and internal dienes proceed well with the transformation and furnish alkyl fluorides in generally >80% yield and >90% ee. A stereodivergent hydromonofluoroalkylation protocol via Pd/Cu co-catalysis is also established for the access to all four stereoisomers of corresponding moieties bearing a fully-substituted F-stereogenic center and vicinal tertiary carbon center. In addition, asymmetric migratory hydromonofluoroalkylation of skipped dienes is developed to realize the direct allylic CH fluoroalkylation. A compound library of enantioenriched cyclic fluorides is thus built to highlight the transformation potential of present methodology.     

Acidity of di- and triprotected hydrazine derivatives in dimethyl sulfoxide and aspects of their alkylation

The pK(a) values in DMSO for 22 di- and triprotected hydrazine NH acids and two monosubstituted hydrazines have been determined using potentiometric titration. The results of density functional theory calculations at the B3LYP/6-311+G level of gas-phase acidities of a representative selection of mono-, di-, and trisubstituted hydrazines are compared with both the relevant published and novel experimental titration data. In the course of this work, a rough estimation of the pK(a) value of hydrazine in DMSO (ca. 38.0) has been deduced. For typical triprotected compounds of this kind containing moderately electron-withdrawing carbamate and imidodicarbonate or arenesulfonylcarbamate functions the pK(a) values fall in the range 15.1-17.3, whereas for N,N'-diprotected hydrazines with a carbamate and an aromatic sulfonyl group the corresponding values are 12.7-14.5. Several of these triprotected derivatives have recently been applied preparatively in stepwise synthesis of substituted hydrazines using alkyl halides as electrophiles in the presence of a phase transfer catalyst, and a few of them, with varying success, have been examined in model experiments with benzyl alcohol, triphenylphosphine, and diethyl azodicarboxylate in the Mitsunobu reaction. The dependence of the reactivity on the intrinsic acidity of the hydrazines in this reaction is highlighted. Furthermore, the regioselective alkylation of an N,N'-diprotected hydrazine can be rationalized on the basis of the presented data.     

Stereoselective synthesis of D-α-glucopyranosides,di-and tri-saccharides via 6-O-acetyl-glucopyranosyl bromides

Acetyl bromide cleaved 2,3,4-tri-O-benzyl-l,6-anhydro-B-D-glucopyranose (la) or 2,3,4-tri-O-benzyl-1,6-anhydro-B-Z)-galactopyranose (1a') to give the corresponding a-D-pyranosyl bromides (2). Reaction of 2 with ROH/diisopropylethylamine gave the corresponding a-glucopyra-nosides, di- and tri-saccharides with good yield. It was available to use 13C NMR to monitor the glycosidation reaction.     

Synthesis of new molecules containing head,spacer, and label moieties

We describe the synthesis and characterization of novel molecules containing head with precise shape, spacer, and label moieties. The protocol is based on a Pd(0)-catalyzed cross-coupling reaction between ethynylphenyl/bromide to obtain a rigid head followed by the attachment of a flexible spacer possessing two reactive functional groups on the termini. The final step consists of forming a covalent bond between spacer and label. In addition, monosubstituted soluble labels were synthesized in good yields.