Nucleophilic alkynylation of N-bis(trimethylsilyl)methyl aldimines

N-Bis(trimethylsilyl)methyl aldimines undergo nucleophilic addition reaction with premixed lithium alkynides/BF₃·OEt₂ to give moderate to good yields of N-bis(trimethylsilyl)methyl propargyl amines.     

Diastereoselective formation of 2-fluoro-2-trifluoromethyl-3,4-alkadienamides from propargyl alcohols and hexafluoropropene-diethylamine adduct (PPDA)

Treatment of propargyl alcohols (1) with hexafluoropropene-diethylamine adduct (PPDA) affords N,N-diethyl-2-fluoro-2-trifluoromethyl-3,4-alkadienamides (2) that are produced by the Claisen rearrangement of intermediary 2-alkynyl 1-(N,N-diethylamino)-2,3,3,3-tetrafluoro-1-propenyl ethers. Starting from propargyl alcohols bearing a triple bond at the terminal position, the corresponding products (2) were formed with a high stereoselectivity.     

Enantioselective synthesis of phomallenic acid C, an inhibitor of FAS II pathway

Enantioselective synthesis of phomallenic acid C, an inhibitor of bacterial FAS II pathway, was successful. Allenyldiyne structure was constructed by a direct anti-S_N2′ coupling of propargyl mesylate with diynylindium in the presence of palladium catalyst. Enantiomeric purity was determined by Ohrui-Akasaka method to be 83%ee.     

Enantioselective synthesis of phomallenic acid C by In- and Pd-mediated anti-SN2′ coupling

Enantioselective synthesis of phomallenic acid C, an inhibitor of bacterial FAS II pathway, was succeeded. Allenyldiyne structure was constructed by a direct anti-S_N2′ coupling of propargyl mesylate with diynylindium in the presence of palladium catalyst. Enantiomeric purity was determined by Ohrui-Akasaka method to be 96% ee.     

Synthesis of the C6–C18 bis-tetrahydrofuran fragment of the proposed structure of iriomoteolide-2a via stepwise double SN2 cyclization reactions

The C6–C18 bis-tetrahydrofuran (bis-THF) fragment of the proposed structure of iriomoteolide-2a has been synthesized via stepwise double intramolecular S_N2-type etherifications. The C11 and C16 stereogenic centers could be secured in the forms of propargyl alcohols by asymmetric transfer hydrogenation of the corresponding propargyl ketones. The C9–C12 THF ring was first constructed via a tandem asymmetric dihydroxylation (AD)–S_N2 sequence while the C13–C16 THF ring was later installed via an intramolecular S_N2 reaction of a chiral propargyl mesylate. During the latter THF ring formation, epimerization at the propargylic carbon was not observed. Since the initially proposed (9R,11S,12R) configuration of iriomoteolide-2a has recently been revised to (9S,11R,12S), the established synthesis of the C6–C18 bis-THF fragment could be easily amended by using the opposite enantiomers of the chiral ligands for AD and asymmetric transfer hydrogenation.     

Cyclopenta[g]quinazolinone-based inhibitors of thymidylate synthase targeting α-folate receptor overexpressing tumours: synthetic approaches to 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid

An advanced intermediate for the synthesis of cyclopenta[g]quinazolinone-based antifolates such as (6RS)-CB300945 was prepared by a convergent methodology. The oxo-functionality required for the formation of the C-6-N-10 bond in 4 was introduced in the initial steps of the synthesis, then the tricyclic ring was constructed and finally the propargyl group was introduced using the (propargyl)Co₂(CO)₆⁺ complex without the need to protect the N-3-H or 2-hydroxymethyl functionalities.     

Synthesis of N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters

Using K₂CO₃ as a base and CH₃CN as solvent, different kinds of N-[5-alkoxy-2(5H)-furanonyl] amino acids were reacted with propargyl bromide via substitution reaction at 40?°C to give 16 N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters with the yields of 44?C85% (mostly over 74%). The structures of all newly synthesized compounds were elucidated and confirmed by FTIR, UV, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The rapid, efficient, and brief synthesis of the series propargyl esters with multiple bioactive units, will afford not only a basis for the activity test of potential drug molecules, but also an important synthetic strategy for 2(5H)-furanone derivatives with polyfunctional groups.     

Three component tandem reactions involving protected 2-amino indoles, disubstituted propargyl alcohols, and I2/ICl: iodo-reactant controlled synthesis of dihydro-α-carbolines and α-carbolines via iodo-cyclization/iodo-cycloelimination

Two simple, highly efficient three component tandem reactions for the synthesis of diversified N^aN^b di-carbamate-4,9-dihydro-3-iodo-α-carbolines and N^a-carbamate-3-iodo-α-carbolines have been described. The strategy involves one-pot condensation of bis-carbamate protected 2-amino indoles with disubstituted propargyl alcohols and I₂/ICl. The salient feature of the reaction involves iodocyclo-elimination of N^b-linked carbamate under mild condition in the final step.     

β-Mannosylation of N-acetyl glucosamine by propargyl mediated intramolecular aglycon delivery (IAD): synthesis of the N-glycan core pentasaccharide

An efficient and completely stereocontrolled synthesis of the N-glycan Manβ(1-4)GlcNAc disaccharide is achieved by propargyl mediated intramolecular aglycon delivery (IAD). Isomerisation of the 2-O-progargyl group of a manno thioglycoside to an allene is followed by iodonium ion mediated mixed acetal formation with the 4-OH of a protected GlcNAc derivative, and subsequent intramolecular glycosylation with complete control of anomeric stereochemistry. Access to this key disaccharide intermediate allows completion of the total synthesis of the core N-glycan pentasaccharide.     

Comparison of carbene and imidazole bonding to a copper(I) center

The bonding of (1,4,7-trithiacyclononane)copper(I) to N-methylimidazole and to N,N′-dimethylimidazol-2-ylidene (IMe) as its pseudo-tautomer has been compared by crystallography, spectroscopy, and electrochemical analyses. In the solid state, a shorter Cu-L bond is observed for L = carbene than for L = imidazole, which indicates that electronic effects override potential steric hindrance in this pair of complexes. The oxidation potential difference reveals that the imidazole is a substantially stronger donor than the carbene ligand, and it allowed for estimating the Lever electronic parameter for the carbene ligand, E_IMe = +0.30 V.     

Ultrasound-assisted addition of alcohols to N-acyliminium ions mediated by In(OTf)3 and synthesis of 1,2,3-triazoles

An easy and mild approach using ultrasound-assisted reaction addition of alcohols to N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the synthesis of ether pyrrolidinones; next, the products were converted to 1,2,3-triazoles using click chemistry reaction conditions. The products in both reactions were afforded in moderate to good yields.     

Synthesis of modified Weinreb amides: N-tert-butoxy-N-methylamides as effective acylating agents

An efficient preparation of N-methyl-O-tert-butylhydroxylamine hydrochloride has been settled, which allowed the synthesis of modified Weinreb amides. Nucleophilic addition of organolithium and Grignard reagents on these N-tert-butoxy-N-methylamides afforded efficiently the corresponding ketones and reduction with DIBAL furnished the corresponding aldehydes in good yields up to 97%.     

Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10α-tetrahydrooxazolo[3,2-b]isoquinolin-5-ones and their 2,3,10,10α-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed upon aryl radical reaction at the ketene-N,X(X=O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from both Bu₃SnH and (Me₃Si)₃SiH was investigated. The N,S-heterocyclic fused ring products may have potential medical value.     

Pd2dba3/P(i-BuNCH2CH2)3N: a highly efficient catalyst for the one-pot synthesis of trans-4-N,N-diarylaminostilbenes and N,N-diarylaminostyrenes

A Pd₂dba₃/P(i-BuNCH₂CH₂)₃N catalyzed one-pot synthesis of unsymmetrically substituted trans-4-N,N-diarylaminostilbenes and both symmetrically and unsymmetrically substituted N,N-diarylaminostyrene derivatives is reported. The procedure involves two or more palladium catalyzed sequential coupling reactions (an amination and an inter-molecular Heck reaction) in one-pot using the same catalyst system with two different aryl halides, including aryl chlorides and hetero aryl halides as the coupling partners.     

Base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates to 4-alkylidene-2-oxazolidinones

The base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates is studied in detail. The effect of various bases and solvents on the efficacy of this cyclization reaction is analyzed and a new base-solvent system (LiOH in DMF) for effective cyclization of these carbamates is reported. A number of differentially substituted O-propargyl carbamates were cyclized to the corresponding 2-oxazolidinones under these conditions. The reaction conditions reported here are mild and no side reactions were observed in any of the substrates studied. A propargyl carbonate group was unaffected during the course of the cyclization of the O-propargyl carbamate group. The propargyl carbamates were prepared from the corresponding alkyl or aryl amines and the corresponding propargyl chloroformate, resulting in oxazolidinones diversely substituted at the nitrogen atom. N-Aryl-O-propargyl carbamates cyclized readily to the corresponding oxazolidinones with LiOH in DMF, whereas N-alkyl-O-propargyl carbamates reacted slowly under the same conditions. O-Propargyl carbamates substituted at the 1-position tend to cyclize faster whereas those substituted at 3-position cyclize considerably slower than the unsubstituted carbamates.     

Catalytic photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine and carbon dioxide

Photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine (TMB) in MeCN under bubbling of CO₂ proceeded with high catalytic efficiency, giving 3,3-diphenylacrylic acid (DPA) and 3-hydroxy-3,3-diphenylpropionic acid (20). The turnover number (TON=(DPA+20)/TMB) reached 17. Similarly, 1-phenyl-1-cyclohexene yielded cis-2-acetamido-2-phenylcyclohexanecarboxylic acid with TON 5.9. As compared with related N,N-dimethylaniline derivatives, TMB is more resistant to photodecomposition, has the much larger absorbance in the S₀→S₁ transition, and has the lower quenching efficiency by CO₂. Probably these factors are partly responsible for the high TON observed for TMB.     

Synthesis and characterization of a tetraruthenium butterfly cluster containing a quadruply-bridging ligand derived from an N,N′-dipyrid-2-ylurea

The tetraruthenium cluster complex [Ru₄(μ₄-κ⁴-dmpu)(CO)₁₀], H₂dmpu = N,N′-bis(6-methylpyrid-2-yl)urea, has been prepared by treating [Ru₃(CO)₁₂] with H₂dmpu in toluene at reflux temperature. An X-ray diffraction study has determined that this cluster has a butterfly metallic skeleton hold up by a doubly-deprotonated N,N′-bis(6-methylpyrid-2-yl)urea ligand (dmpu). This ligand has the pyridine N atoms attached to the wing-tip Ru atoms and the amido N atoms spanning Ru-Ru wing-edges, in such a way that the cluster has C₂ symmetry. The donor atoms of doubly-deprotonated N,N′-dipyrid-2-ylureas seem to be appropriately arranged to hold butterfly tetranuclear clusters.     

Synthesis and properties of <Emphasis Type="Italic">N</Emphasis>-(alkenylidene)trifluoromethanesulfonamides

N-Alkenylidenetrifluoromethanesulfonamides TfN=CH–CR=C(Me)R′ (R, R′ = H, Me) have been synthesized by reaction of N-sulfinyltrifluoromethanesulfonamide TfNSO with (E)-but-2-enal, (E)-2-methylbut- 2-enal, and 3-methylbut-2-enal. Despite greater stability of N-alkenylidenetrifluoromethanesulfonamides relative to their propargyl isomers TfNHCH₂C≡CR, no rearrangement of the latter into the former occurs due to the presence of an acidic NH proton, which hampers formation of carbon-centered anion.     

N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

A simple and efficient biphasic method for the preparation of 4-nitrophenyl N-methyl- and N-alkylcarbamates

Treatment of 4-nitrophenyl chloroformate with alkylammonium hydrochloride salts and solid anhydrous Na₂CO₃ in either CH₂Cl₂ or CH₃CN gave 4-nitrophenyl N-methylcarbamate and other N-alkylcarbamate analogues in excellent yields. Of particular interest is the observation that 4-nitrophenyl N-methylcarbamate, a safer alternative to the highly toxic methyl isocyanate, is obtained in quantitative yield (?95% pure as determined by ¹H NMR) after simple filtration and solvent evaporation.