Multi-step reactions of N-monosubstituted (polyfluoroalkane)thioamides with alkyllithium reagents

Reactions of N-alkyl- or N-aryl(perfluoroalkyl)thiocarboxamides with alkyl lithium reagents are described. Trifluorothioacetamides are converted into the corresponding lithium salts. Compounds bearing a long polyfluorinated chain terminated by a CHF₂ group and compounds containing an N-alkyl substituent with a proton adjacent to nitrogen react further via a multi-step reaction sequence involving HF elimination and then vinylic fluorine substitution and/or S_N′ type fluorine substitution. These transformations led to unsaturated N-monosubstituted polyfluorinated thioamides.     

Diastereoselective Ti-mediated preparation of bicyclic aminocyclopropanes from N-alkenyl amides

Intramolecular Ti-mediated alkene-amide couplings of a range of N-alk-3-enyl amides fitted with a substituent at the homoallylic position are described. CF₃-substituted compounds are suitable substrates and bicyclic aminocyclopropanes bearing a CF₃ group can be prepared in this way. Good diastereoselectivities can be observed depending on the substitution pattern, and best results are obtained in diethyl ether rather than in THF.     

Reactions of N-sulfenyl-1,2-benzisothiazolin-3-ones with nucleophiles

Reactions of N-[2-(alkoxycarbonyl)benzenesulfenyl]-1,2-benzisothiazolin-3-ones (1) with various nucleophiles were examined. Anions of active methylene compounds attacked the sulfur atoms of the sulfenyl moieties of 1 to afford sulfide compounds, while thiols attacked the sulfur atoms of the benzisothiazolinone moieties of 1 to afford ring-opened products. Grignard reagents attacked both the above sulfur atoms to give ring-opened products along with sulfide compounds.     

Cyclopropane-annelated azaoligoheterocycles by Ti-mediated intramolecular reductive cyclopropanation of cyclic amino Acid amides

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.     

IBX/TEAB-mediated oxidative dimerization of thioamides: synthesis of 3,5-disubstituted 1,2,4-thiadiazoles

Thioamides undergo oxidative dimerization on treatment with hypervalent iodine(V)-containing reagents, particularly o-iodoxybenzoic acid (IBX), in the presence of tetraethylammonium bromide (TEAB) to generate 3,5-disubstituted 1,2,4-thiadiazoles in excellent yield.     

The unusual 1,4-chelation-controlled nucleophilic addition to aldehydes with high stereoselectivity. A systematic study of stereoselectivity in the addition reaction of carbon nucleophiles to cis-substituted cyclopropanecarbaldehydes

The addition reaction of carbon nucleophiles to cis-substituted cyclopropanecarbaldehydes was systematically investigated. Ab initio calculations of model cyclopropanecarbaldehydes suggested that the bisected s-cis and s-trans conformers are the only two minimum energy conformers, which are stabilized due to the π-donating stereoelectronic effect of the cyclopropane ring. The experimental results of a series of substrates, that is, cyclopropanecarbaldehydes 1-5 bearing a cis-(tert-butyldiphenylsilyloxy)methyl group, a cis-benzyloxymethyl group, a cis-(p-methoxybenzyloxy)methyl group, cis-N,N-diethylcarbamoyl and trans-phenyl groups, and cis-(tert-butyldiphenylsilyloxy)methyl and trans-phenyl groups, respectively, showed that highly anti-selective Grignard additions could be realized. It turned out that it occurred via an unusual 7-membered 1,4-chelation-controlled pathway. Highly stereoselective Grignard addition via the chelation-controlled pathway occurred even in the reaction of the usually non-chelating silyl ether-type substrate 5. The results have great importance because the 1,4-chelation-controlled stereoselective addition reactions can indeed be realized. Under non-chelation conditions, the syn-products were produced with moderate stereoselectivity, which are likely to be formed via the bisected s-cis conformation-like transition state stabilized by the characteristic orbital interaction. These reactions, especially the chelation-controlled reaction, should be useful because of their t stereoselectivity and stereochemical predictability.     

A facile and convenient synthesis of functionalized ortho-nitrophenylboronic acids

A variety of ortho-nitrophenylboronic acids bearing functional groups such as cyano, nitro, halo, α-bromomethyl, and ester were prepared in good yields via I-Mg exchange followed by quenching with trimethyl borate. All reagents employed in this procedure are commercially available and were used without further purification, and the procedure can be executed in about an hour.     

Titanium-mediated syntheses of cyclopropylamines

The transformations of N,N-dialkylcarboxamides and nitriles with 1,2-dicarbanionic organometallics in situ generated from organomagnesium (Grignard) as well as organozinc reagents in the presence of stoichiometric or substoichiometric (semi-catalytic) quantities of a titanium alkoxide derivative of type XTi(OR)₃ with X=OR, Cl, Me and OR=OiPr, OEt are described. The key step in the transformation of a monocarbanionic into a 1,2-dicarbanionic organotitanium species is a disproportionation of a dialkyltitanium intermediate to form an alkane and a titanium alkene complex which has the reactivity of a titanacyclopropane derivative. The latter are able to undergo insertion of the carbonyl group of an N,N-dialkylcarboxamide or a cyano group to furnish, after ring contraction and hydrolysis, dialkylcyclopropylamines or cyclopropylamines, respectively. The titanium alkene complexes can also undergo ligand exchange with alkenes to afford new titanacyclopropanes, which subsequently react as 1,2-dicarbanionic equivalents. In many cases, these titanium-mediated formations of a wide range of synthetically and/or pharmacologically important cyclopropylamines proceed in good to very good yields (from 20% to 98% for dialkylcyclopropylamines from N,N-dialkylcarboxamides and from 27% to 73% for primary cyclopropylamines from nitriles) and with high chemo- and stereoselectivity. These circumstances in conjunction with the simplicity of the experimental handling and inexpensiveness of the reagents favor these reactions for an ever increasing range of applications in organic synthesis.     

Enantioselective intramolecular crossed Rauhut-Currier reactions through cooperative nucleophilic activation and hydrogen-bonding catalysis: scope and mechanistic insight

A highly efficient and enantioselective intramolecular crossed Rauhut-Currier (RC) reaction of nitroolefins with tethered enonates has been developed through cooperative nucleophilic activation and a hydrogen-bonding catalytic strategy (≤98% ee and 98% yield). The reaction features simple experimental procedures and is completely chemoselective and atom-economic in character. The potential synthetic applications have been demonstrated by the conversion of the RC reaction products into biologically and pharmaceutically valuable compounds with highly diastereoselectivity. In addition, computational investigations were employed to support the proposed mechanism and to obtain a good understanding of the origin of the stereoselectivity in RC reactions.     

Enantioselective nucleophilic addition to N-(2-pyridylsulfonyl)imines by use of dynamically induced chirality

Enantioselective nucleophilic addition of Grignard reagents to N-(2-pyridylsulfonyl)imines in the presence of bis(oxazoline) afforded products with good enantioselectivity. Dynamically induced chirality on the sulfur by coordination of a chiral Lewis acid to a pyridyl nitrogen and one of the sulfonyl oxygens fixes the conformation of the complex and induces enantioselectivity. Since the 2-pyridylsulfonyl group can be easily removed after the addition reaction, it acts not only as a protecting group but also as an efficient stereocontroller.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

New fused dithiabicyclic compounds from the reaction of N,N-dialkyl perfluorothioamides with allylmagnesium halides

Allylmagnesium reagents react with N,N-dialkylperfluorothioamide to give, at low temperature, an adduct stable enough to be trapped. At room temperature, this adduct can evolve by elimination of either a sulfide salt, leading to an iminium intermediate, and then an N,N-dialkyl-α,α-bis(allyl)-α-perfluoroalkylamine. This process is favoured if an excess of allyl magnesium is used. Alternatively, the adduct eliminates an aminyl moiety giving allyl(perfluoroalkyl)thioketone which is converted in situ into an unprecedented fused bis(perfluoroalkyl) bis(dihydrothiopyrane). A sequence deprotonation of the thioketone - oxidation of the resulting dienethiolate - dimerization of the dienethiyl radical is proposed to rationalize the formation of this unexpected bicyclic compound.     

Stereoselective synthesis and functionalization of N-alkyl-β-lactams

Novel polyfunctionalized N-alkyl-β-lactams were prepared with high stereoselectivity in an efficient manner by a palladium-catalyzed [2+2] carbonylative cycloaddition of allyl bromide with heteroarylidene N-alkyl-amines The type of alkyl group linked to the nitrogen atom influences the reaction stereoselectivity. Moreover, the C-3 and the C-4 positions of the azetidinone ring can be further stereoselectively functionalized inserting various groups through the generation of a stable azetidinyl carbanion and then captured by various electrophiles.     

Stereoselective synthesis of N-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides

The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of γ-(N-arylamino) alkenes, these transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl bromide substrates.     

Total synthesis of (±) maculalactone A, maculalactone B and maculalactone C and the determination of the absolute configuration of natural (+) maculalactone A by asymmetric synthesis

Maculalactones A, B and C from the marine cyanobacterium Kyrtuthrix maculans are amongst the only compounds based on the tribenzylbutyrolactone skeleton known in nature and (+) maculalactone A from the natural source possesses significant biological activity against various marine herbivores and marine settlers. We now report a concise synthesis of racemic maculalactone A in five steps from inexpensive starting materials. Maculalactones B and C were synthesized by a minor modification to this procedure, and the synthetic design also permitted an asymmetric synthesis of maculalactone A to be achieved in around 85% ee. The (+) and (−) enantiomers of maculalactone A were assigned, respectively, to the S and R configurations on the basis of the chiral selectivity expected for catecholborane reduction of an unsymmetrical ketone in the presence of Corey's oxazoborolidine catalyst. Surprisingly, it appeared that natural (+) maculalactone A was biosynthesized in K. maculans in a partially racemic form, comprising ca. 90-95% of the (S) enantiomer and 5-10% of its (R) enantiomer. Coincidentally therefore, the percentage enantiomeric excess of the product obtained from asymmetric synthesis almost exactly matched that found in nature.     

From Oblivion into the Limelight: Iron (Domino) Catalysis

Sleeping beauty? Is the scientific community about to kiss awake iron catalysis, a topic that has been dormant for decades? A recent study on a user‐friendly direct cross‐coupling reaction of alkyl and aryl halides constitutes an important step toward this end through the integration of two different iron‐catalyzed elementary steps into a practical one‐pot procedure.

     

Novel intramolecular cyclization of N-alkynyl heterocycles containing proximate nucleophiles

Intramolecular cyclization of 2-acyl-1-propargyl-1H-indoles in the presence of ammonia provides an easy entry to pyrazino[1,2-a]indole nucleus.