Mg-promoted reductive coupling of aromatic carbonyl compounds with trimethylsilyl chloride and bis(chlorodimethylsilyl) compounds

Mg-promoted reductive coupling of aromatic carbonyl compounds (1) with chlorosilanes, such as trimethylsilyl chloride (TMSCl:2), 1,2-bis(chlorodimethylsilyl)ethane (3) and 1,5-dichlorohexamethyltrisiloxane (4), in N,N-dimethylformamide (DMF) at room temperature brought about selective and facile reductive formation of both of carbon-silicon and oxygen-silicon bonds to give the corresponding α-trimethylsilylalkyl trimethylsilyl ethers (5) and cyclic siloxanes (6), (7) in moderate to good yields, respectively. The present facile and selective coupling may be initiated through electron transfer from Mg metal to aromatic carbonyl compounds (1).     

Copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine

A copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine has been developed. Under the catalysis of CuBr₂ and in the presence of pyrrolidine, either tetrahydrofuran 2a or tetrahydropyran 2b can react smoothly with a series of methyl aryl ketones 1a–m to give desired coupling products 3aa–mb using TBHP as an oxidant. The advantages of the dehydrogenative cross-coupling reaction are adoption of unmodified ethers as substrates, good tolerance of many functional groups and use of cheap copper salt as a catalyst. A plausible radical mechanism through enamine attack is proposed.     

Ring-opening reactions of cyclic ethers with diiodo- and dibromodimethylsilane equivalents

Ring-opening halosilation of cyclic ethers with reagents of (Me₂N)₂SiMe₂/4MeI (1a) and (Me₂N)₂SiMe₂/4allylBr (1b) was studied. Tetrahydrofuran and cyclohexene oxide reacted with 1a and 1b to give ring-opened di(haloalkoxy)dimethylsilanes in good yield. With less strained tetrahydropyran, however, only reagent 1a gave the ring-opened product. Reactions of reagents 1a and 1b with propylene oxide also proceeded smoothly, although the regioselectivity was rather low. When similar reactions were carried out with (Me₂N)₂SiMe₂/2MeI (2a) and (Me₂N)₂SiMe₂/2allylBr (2b) in a ratio of cyclic ethers/2a or 2b = 1/1, the corresponding 1:1 adducts were obtained.     

Calix[4]quinones. Part 4: The ClO2 oxidation of calix[4]arene dialkyl ethers

Except for the special case of calix[4]arene diethyl ether 1, the chlorine dioxide oxidation of dialkyl ethers 2-5 yielded only the corresponding calix[4]diquinone dialkyl ethers 8-11. Chlorine dioxide oxidation of calix[4]arene diethyl ether 1 produced two isomeric products 6 and 7, which were stable enough to be isolated by column chromatography. However, a slow conformational interconversion between isomeric pair 6 and 7 was observed at room temperature, and the equilibrium was reached after 400 h at 18 °C with an amount of 5:3 in favor of syn-isomer.     

De-novo approach for a unique spiro skeleton-1,7-dioxa-2,6-dioxospiro[4.4]nonanes

2-Oxoglutaric acid (1) underwent facile indium mediated allylation with allyl bromide (2), and ethyl 4-bromocrotonate (3), cinnamyl bromide (4) and subsequent in situ dehydration to provide respective 5-oxotetrahydrofuran-2-carboxylic acids 5-7 (90-95%). The reaction of 1 with 3 and 4 proceeded with high regio and stereo selectivity to provide only γ-addition products with syn stereochemistry as ascertained from their cyclic products. Compounds 5-7 underwent diastereoselective iodocyclization to provide respective 1,7-dioxa-2,6-dioxospiro[4.4]nonanes 8-13. The relative stereochemistries have been ascertained by single crystal X-ray structures, NOE experiments and coupling constants in ¹H NMR spectra.     

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodifluoromethyl ketones 2 in good yields. The reaction of 1a with electrophilic reagent ICl yielded α-iodoenone 4. The substitution reaction of the cyclic enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate yields.     

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane with enol ethers of cyclic ketones

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane (1) with methyl and trimethylsilyl ethers of cyclopentanone and cyclohexanone enols (2a-d) in a MeCN/H₂O system were investigated. 2-(2,2,2-Trifluoroethylidene)cyclopentanone (4a) and 2-(2,2,2-trifluoroethylidene)-cyclohexanone (4b), respectively, were obtained as the main products and isolated in reasonable yields. The reaction with a 1:1 mixture of 5- and 3-methyl substituted 1-methoxycyclohexenes, 2e and 2f, revealed strong influence of steric hindrance on the reaction rate; a mixture of 2-(2,2,2-trifluoroethylidene)-5-methylcyclohexanone (6) and 2-(2,2,2-trifluoroethylidene)-3-methylcyclohexanone (7) in a 9:1 ratio was formed. Ketones 4a and 4b were reduced to the corresponding alcohols 8 and 9 and the reaction of 4b with hydrazine gave an indazole derivative 10.     

Preparation of glycoluril monomers for expanded cucurbit[n]uril synthesis

Glycoluril derivatives bearing free ureidyl groups (1) and bis(cyclic ethers) (2) are the fundamental building blocks for the synthesis of cucurbituril, its derivatives, and its congeners. The known derivatives of 1 and 2 fall into two main classes—those bearing alkyl or aryl functional groups on their convex face. In this paper we present a third class of glycolurils, namely those bearing substituents that are electron withdrawing in character. This class of compounds carries carboxylic acid derived functional groups on their convex face and are derived from diesters 1e and 2e. An improved synthesis of 1e and 2e is reported and their modification described. For example, 1e and 2e are converted into secondary amides (10-15) by heating in solutions of the neat primary amines. The secondary amides can be transformed into imides (19-22, 24, 25) by heating with PTSA in ClCH₂CH₂Cl. The isolation of these compounds in pure form in high yields is accomplished by simple and scalable washing or recrystallization procedures. We also present the X-ray crystallographic characterization of bis(cyclic ethers) 2e, 8, and 22. We anticipate that the ready availability of ester, carboxylate, acid, secondary amide, imide, and tertiary amide derivatives of 1 and 2 will expand the scope of the synthesis of cucurbituril derivatives by providing a new class of building blocks with electron withdrawing substituents.     

An efficient synthesis of 4,4′,5,5′-tetraiododibenzo-24-crown-8 and its highly conjugated derivatives

4,4′,5,5′-Tetraiododibenzo-24-crown-8 (9), a practical building block, was prepared under efficient and mild reaction conditions starting from the simple starting material, catechol (1). Highly conjugated 4,4′,5,5′-tetraethynyldibenzo-24-crown-8 (10a,b) were prepared via a Sonogashira coupling reaction from tetraiodocrown ether 9. These highly conjugated crown ethers form complexes in CD₂Cl₂ with dibenzylammonium hexafluorophosphate in a 1:1 ratio. Emission spectrum of pseudorotaxane 11 shows a dramatic shift from the non-complexed precursor.     

Di-, tri-, and tetra-arylterephthalic acids as novel clathrate host compounds

Novel terephthalic acid host compounds having aromatic substituent 1-4 have been prepared and their inclusion properties were investigated. These host compounds enclathrated several kinds of alcohols, ethers, ketones, amides, and sulfoxides. The X-ray structures of 1:1 2a/EtOH, 1:2 2b/DMF, 1:2 3/MeOH, and 1:1 4/EtOH complexes revealed complexation mode.     

Reaction behavior of cyclopropylmethyl cations derived 1-phenylselenocyclopropylmethanols with acids

The 1-phenylselenocyclopropylmethyl cations are generated by the reaction of the corresponding cyclopropylmethanols 1 with TsOH. The reaction in methanol proceeds to afford the homoallylic ethers 2, ring-enlargement products 3, 4, and ring opening products 5 depending upon the kind of substituent on the cyclopropane ring or the α-carbon. On the other hand, in the case of the absence of methanol as nucleophile, 4H-selenochromene derivative 7 is obtained exclusively. The oxidative elimination of the phenylselenyl group in the resulting phenylselenohomoallylic compounds 2 furnishes functionalized allene derivatives and alkyne derivatives.     

A synthetic route to 1,3-dihydroisobenzofuran natural products: the synthesis of methyl ethers of pestacin

A synthetic route to 1-(2,6-dihydroxyphenyl)phthalan natural products is described. It is typified by the synthesis of permethyl and monomethyl ethers (21 and 22) of pestacin (1), a 1,3-dihydroisobenzofuran natural product. The key step is hydrodeoxygenation of the corresponding isobenzofuranone 19 in 2 steps: reduction and intramolecular etherification. A route involving hydrodesulfurization of a thionophthalide to a phthalan (e.g., 8) is also reported.     

Cocrystals of U-shaped ureadicarboxylic acid with 2-aminopyrimidine and melamine: rhombus-shaped cyclic heterotetramer motifs

Single crystal X-ray structures of cocrystals, 1·2 and 1·3, derived from U-shaped ureadicarboxylic acid (1) with 2-aminopyrimidine (2) and melamine (3), respectively, were examined. Cocrystals were obtained as a 1:1 mixture of 1 and the corresponding base. Two molecules of 1 and two molecules of the base were combined together via intermolecular H-bonding creating a supramolecularly assembled cyclic heterotetramer motif of rhombus shape. In the case of cocrystal 1·3, the cyclic heterotetramers were connected via H-bonding by utilizing a remaining amino group of melamine resulting in the formation of a tape of cyclic heterotetramer.     

Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or ¹H NMR spectroscopy and X-ray diffraction.     

Intramolecular carbolithiation promoted by a DTBB-catalysed chlorine-lithium exchange

The reaction of 6-chlorohex-1-ene 1 with lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5% molar) in THF at −78°C gives the corresponding organolithium intermediate 2, which by reaction with different electrophiles affords, after hydrolysis with diluted hydrochloric acid, the expected products 3. The same reaction performed at −30°C gives cyclopentyl derivatives 5, probably by cyclisation of the open-chain intermediate 2 to give the cyclic organolithium compound 4. When the double bond in the starting material contains an alkyl substituent, for instance compounds 6 and 9, the corresponding cyclisation is inhibited, so the corresponding acyclic products 8 and 11 are respectively, obtained. However, when the substituent at the same positions is a phenyl group, like in starting materials 12 and 15, the cyclised products 14 and 17 were respectively, isolated. In the case of the secondary starting chlorinated material 18, the reaction can be directed to both, the acyclic products 20 or the cyclic ones 22, working at −78 or −30°C, respectively, as it happens in the case of the unsubstituted chlorinated material 1. For the tertiary chloro derivative 23, only the cyclic compound 27 could be isolated at −30°C due to the great instability of the corresponding tertiary organolithium intermediate 24, which undergoes a proton abstraction even at −78°C. From allyl 2-chlorophenyl ether 28 or N,N-diallyl-2-chloroaniline 32, only the corresponding cyclic compounds 31 and 33, respectively, are isolated either at −78 or at −30°C. In all cases a carbanionic cyclisation, better than a radical one, is postulated to occur as mechanistic pathway.     

Electrochemical synthesis of 1,3,4-thiadiazol-2-ylthio-substituted catechols in aqueous medium

Anodic oxidation of catechols 1a-e in the presence of 5-methyl-2-mercapto-1,3,4-thiadiazole 2 has been studied in acetate buffer solution by cyclic voltammetry and controlled-potential electrolysis techniques. The effects of various electrolytic conditions (amount of passed charge, anodic materials, pH of the electrolytic solution, applied potential, and concentration of substrates) on the yield have also been investigated. The results showed that the position of the initial substituent of the starting catechol derivatives dominated the formation of monothiadiazol-2-ylthio-substituted or/and dithiadiazol-2-ylthio-substituted products. For 4-substituted catechols 1a-b, monothiadiazol-2-ylthio-substituted products (3a-b) were exclusively produced in high to excellent yields. However, in the cases of catechol itself (1c) and 3-substituted catechols (1d-e), both monothiadiazol-2-yl-substituted (3c-e and 5d-e) and dithiadiazol-2-ylthio-substituted products (4c-e) were isolated. In addition, the nature of the initial substituent of the starting 3-substituted catechols (1d and 1e) affected the relative ratio of the two monothiadiazol-2-ylthio-substituted isomers (3d-e vs 5d-e).     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Platinum-catalyzed double silylations of alkynes with bis(dichlorosilyl)methanes

Bis(dichlorosilyl)methanes 1 undergo the two kind reactions of a double hydrosilylation and a dehydrogenative double silylation with alkynes 2 such as acetylene and activated phenyl-substituted acetylenes in the presence of Speier’s catalyst to give 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes 4 as cyclic products, respectively, depending upon the molecular structures of both bis(dichlorosilyl)methanes (1) and alkynes (2). Simple bis(dichlorosilyl)methane (1a) reacted with alkynes [R¹-CC-R²: R¹ = H, R² = H (2a), Ph (2b); R¹ = R² = Ph (2c)] at 80 °C to afford 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 as the double hydrosilylation products in fair to good yields (33-84%). Among these reactions, the reaction with 2c gave a trans-4,5-diphenyl-1,1,3,3-tetrachloro-1,3-disilacyclopentane 3ac in the highest yield (84%). When a variety of bis(dichlorosilyl)(silyl)methanes [(Me_nCl_3 − nSi)CH(SiHCl₂)₂: n = 0 (1b), 1 (1c), 2 (1d), 3 (1e)] were applied in the reaction with alkyne (2c) under the same reaction conditions. The double hydrosilylation products, 2-silyl-1,1,3,3-tetrachloro-1,3-disilacyclopentanes (3), were obtained in fair to excellent yields (38-98%). The yields of compound 3 deceased as follows: n = 1 > 2 > 3 > 0. The reaction of alkynes (2a-c) with 1c under the same conditions gave one of two type products of 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes (4): simple alkyne 2a and terminal 2b gave the latter products 4ca and 4cb in 91% and 57% yields, respectively, while internal alkyne 2c afforded the former cyclic products 3cc with trans form between two phenyl groups at the 3- and 4-carbon atoms in 98% yield, respectively. Among platinum compounds such as Speier’s catalyst, PtCl₂(PEt₃)₂, Pt(PPh₃)₂(C₂H₄), Pt(PPh₃)₄, Pt[ViMeSiO]₄, and Pt/C, Speier’s catalyst was the best catalyst for such silylation reactions.     

Studies towards the synthesis of the marine alkaloid chartelline C

2,6-Dibromoindole 5 underwent regioselective Sonogashira coupling at the 2 position with simple acetylenic partners. While, imidazole-acetylene 16 failed to couple to 5, cyclic carbonate 19 succeeded to give 20, which was further elaborated into indole-imidazole 23.     

The rearrangement of cyclopropyl chlorides to allyl chlorides : Stereospecificity in the recapture of the chloride ion

The cyclopropyl chlorides (1 and 2) rearrange on heating to give stereospecifically the allyl chlorides (3 and 4, respectively). In the presence of nucleophiles such as methoxide ion, the corresponding allyl ethers (5 and 6, respectively) are formed. Analysis of the stereochemistry of these products indicates that they are formed from the corresponding allyl chlorides (3 and 4), which are evidently the first-formed products of the reaction even in the presence of strong nucleophiles. The reaction of the allyl chlorides (3 and 4) with sodium phenylthioxide in aprotic non-polar solvents goes predominantly with retention of configuration, but in methanol is normal in giving predominantly inversion of configuration.