1,4-Dilithio-1,3-dienes: reaction and synthetic applications

The development of organometallic reagents remains one of the most important frontiers in synthetic chemistry. Commonly used organometallic reagents (such as RLi and RMgBr) are typically monometallic compounds, although they aggregate in many cases. When two carbon-metal bonds are in the same molecule in close proximity, however, these two carbon-metal moieties may exhibit novel reactivity. In this Account, we outline our work on new reactions and synthetic applications of the organo-dilithio reagents 1,4-dilithio-1,3-butadienes. The 1,4-dilithio-1,3-butadienes can be accessed readily in high efficiency with a wide variety of substitution patterns on the butadienyl skeleton. The configuration has been predicted and demonstrated to favor a double dilithium bridging structure in both solution and solid states. The two Li atoms are bridged by a butadiene moiety and are in close proximity. By taking advantage of this unique configuration, we have developed useful and interesting synthetic methodologies. Three types of reactions of 1,4-dilithio-1,3-butadienes, termed dilithio reagents here, have been developed and are discussed. An intramolecular reaction is introduced in the first section. The reaction is a result of the intracooperative effect among the two C-Li moieties, the butadienyl bridge, and the substituents. A useful transformation from silylated 1,4-dilithio-1,3-butadienes to α-lithio siloles is described. Second, we discuss an intermolecular reaction that results from the intercooperative effect of the two C-Li moieties toward substrates. As an example of the formation of functionalized cyclic dianions from the linear dianions of the dilithio reagents and organic substrates, we describe the isolation and structural characterization of a novel type of cyclic dianion; that is, fully substituted oxy-cyclopentadienyl dilithium formed via the reaction of dilithio reagents with CO. We also describe diverse reactions of dilithio reagents with nitriles to form substituted pyridines, tricyclic 1-bipyrrolines, and siloles, demonstrating the remarkable effect of substituents on the butadienyl skeleton. Third, we discuss transmetalation of dilithio reagents to generate other organo-dimetallic compounds. This section focuses on organo-dicopper compounds and their reactivity toward the synthesis of strained ring systems, such as semibullvalenes and twisted four-membered rings, with the metal-mediated C-C bond-forming approach. In addition to these three representative reactions, other useful applications are also briefly introduced. The dimetallic 1,4-dilithio-1,3-butadienes and their transmetalated derivatives provide unique synthetic organometallic reagents that are very different from monometallic reagents, both in terms of reactivity and synthetic application. These organo-dimetallic reagents provide access to interesting and useful compounds that are not available by other means. Moreover, given the possibilities afforded, the study of organo-dimetallic and organo-polymetallic compounds should yield further synthetic applications in the near future.     

Alkenyl Copper Derivatives 251: Synthesis of E or Z Enol Ethers by Carbocupration of Alkoxy-Allenes

Alkoxy-allenes react smoothly with organocopper and cuprate derivatives to afford almost pure E or Z substituted enol ethers according to the reaction conditions. Lithium diorganocuprate reagents in diethyl ether show the greatest E selectivity, while lithium organocopper reagents in THF are completely Z selective. The obtained alkenyl copper or cuprate derivatives may react further with various electrophiles leading to polysubstituted enol ethers of known configuration.     

Stereoselective synthesis of substituted arylsulfonylated 1,3-butadienes and 2-propenoates by sulfonylation of acetylenic ester

Protonation of the reactive intermediates produced in the reaction between sodium arylsulfinates and two equiv. of dialkyl acetylenedicarboxylates in DMF, by H₂O lead to substituted (1E,3E)-1-(arylsulfonyl)-1,3-butadiene-1,2,3,4-tetracarboxylates in moderate yields. A regioselective method for the synthesis of alkyl (E)-3-(arylsulfonyl)-2-propenoates is described. These reactions provide a useful synthetic route to highly functionalized 1,3-butadienes and 2-propenoates.     

Regioselective Cobalt‐Catalysed Hydrovinylation for the Synthesis of Non‐Conjugated Enones and 1,4‐Diketones

The highly regioselective cobalt‐catalysed 1,4‐hydrovinylation of terminal alkenes with 2‐trimethylsilyloxy‐1,3‐butadiene generates in a stereospecific fashion unsaturated E‐configured silyl enol ether intermediates that are suitable for diastereoselective Mukaiyama‐aldol reactions with bulky aliphatic aldehydes. The acidic hydrolysis of the enol ethers to γ,δ‐unsaturated ketones followed by ozonolysis can be used for the synthesis of various 1,4‐diketones and polycarbonyl derivatives. The 1,4‐diketones and polycarbonyl derivatives were successfully tested for the synthesis of some mono‐ and bis‐pyrrole derivatives. The γ,δ‐unsaturated ketones are useful building blocks (e.g., in natural product synthesis) and can be generated in a one‐pot procedure.     

Untersuchungen zur elektrochemischen reduktion vinyloger carbonsäurechloride

Electrochemical reduction of vinylogous carbonic acid chlorides of the type ArCOCHCHCl (aryl 2-chlorovinyl ketones) has been studied using dc-polarography, cyclic voltammetry and coulometry at controlled potential. Preparative scale electrolyses yielded mainly 1,4-diaroyl-1,3-butadienes and 1,4-diaroyl-2-butenes, which thereby are accessible in a new way.     

β-Enaminoesters as building blocks in heterocyclic synthesis. A novel synthesis of fused azines by using blaise reaction as a key step

Ethyl bromoacetate 4 reacts with nitriles in the presence of activated zinc dust to afford the β-enaminoesters 7 and 19 . Compounds 7 and 19 show high reactivity towards a variety of reagents to give polyfunctional heterocyclic compounds. For example, the enaminoesters 7 and 19 react with benzaldehyde to give the 1,4 dihydropyridine derivatives 9 and 20 respectively. Isothiocyanates 24 (R = Ph, OEt) added to 19 to furnish pyrimidine-thiones 26 and 27 respectively. Structures and conceivable mechanisms are discussed     

Fused Polycyclic Hydrocarbons Through Superacid-Induced Cyclialkylation of Aromatics

Benzene and substituted derivatives (toluene, ortho-xylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, anisole), when applied in large excess, react with 1,4 diols (pentan-1,4-diol, hexan-2,5-diol, and 2,5-dimethylhexan-2,5-diol) or an oxolane (2,2,5,5-tetramethyltetrahydrofuran) in the presence of the Brønsted superacid trifluoromethanesulfonic acid (triflic acid, TFSA) to afford substituted tetralins in excellent yields with high selectivity. Reacting benzene with a small excess of alkylating agents yields octahydroanthracenes. The transformation of naphthalene with oxolane leads to a partially saturated octamethyloctahydrotetracene under similar conditions. Product formation is interpreted by intermolecular Friedel-Crafts alkylation followed by cyclialkylative ring closure.     

Synthesen mit 1,3-Dithietanen. XIV. Ringumwandlungen von substituierten Dihydropyrazolo[5, 1-b]thiazolcarbonsäureestern

Syntheses with 1,3-Dithietanes. XIV. Ring Transformations of Substituted Dihydropyrazolo [5,1-b]thiazolecarboxylates Dihydropyrazolo[5,1-b]thiazolecarboxylates 2 react with aliphatic amines to give dihydrothiazolo[2,3-g][1,2,4]triazepinecarboxylates 4 . Compounds 2c , d and o-phenylenediamine, o-amino-phenols or o-amino-thiophenol afford substituted ethyl benzimidazol-, benzoxazol- or benzothiazol-2-yl-acetates 6 . Hydrazine hydrate and compounds 2 yield derivatives of ethyl pyrazolidin-4-yliden-4-thiazoline-5-carboxylates 8 .     

Asymmetric Synthesis of Functionalized Tetrahydronaphthalenes via an Organocatalytic Nitroalkane‐Michael/Henry Domino Reaction

An organocatalytic nitroalkane‐Michael/Henry reaction sequence to functionalized 1,2,3,4‐tetrahydronaphthalen‐1‐ols is described. Starting from 2‐(nitromethyl)benzaldehyde and nitroalkenes a bifunctional quinine‐based squaramide organocatalyst is used to afford the title compounds in moderate to very good yields (25–84%), high diastereomeric ratios (dr>95:5) after crystallization and good to excellent enantioselectivities of 63–99% ee. Starting from γ‐nitro aldehydes and ketones secondary and tertiary cyclohexanols bearing four stereogenic centers can also be prepared with this Michael/Henry domino reaction.     

The Growing Synthetic Utility of Weinreb′s Amide

The preparation and the synthetic utility of the N‐methoxy‐N‐methyl amides, also called as Weinreb amides, for the preparation of aldehydes and ketones has been discussed. Also the various reagents based on Weinreb′s amide has been compiled.     

Einige ungewöhnliche Umsetzungen des Dinatrium-2-oxo-1,3-dithiol-4,5-dithiolats mit Biselektrophilen

Some Unusual Reactions of Disodium 2-Oxo-1,3-dithiole-4,5-dithiolates with Biselectrophiles Reaction of disodium 2-oxo-1,3-dithiole-4,5-dithiolate (3) with dichloro-maleic anhydride (4) , Mucobromic acid (7) and its pseudoester 9 leads to the formation of the 1,3-dithiolo[4,5-b]-1,4-dithiins 6, 8 and 10. 3 condenses with cis-3,5-dibromo-cyclopentene (15) to yield the tricyclic compounds 16 and 17. 3 is silylated by trimethylsilyltriflate (19) to give the unstable bis(trimethylsilyl)-thioether 20 which reacts with aldehydes and ketones to furnish the 1,3-dithiolo[4,5-d]-1,3-dithiole-2-ones 22a–c .     

Functional monomers and polymers, 163. Inclusion polymerization of cyclic diene monomers in deoxycholic acid canals

Inclusion polymerization of cyclic diene monomers, such as cyclopentadiene, 1,3-cyclohexadiene, 1,3-cycloheptadiene, 1,5-cyclooctadiene, and 2,5-norbornadiene, was studied, using deoxycholic acid (DCA) as the canal component. The formation of monomer-DCA adducts was observed, however, the polymerization occurred only in the case of cyclopentadiene, 1,3-cyclohexadiene, or 1,3-cycloheptadiene. The polymers obtained consisted preferably of 1,4-units and almost 100% of 1,4-units in the case of 1,3-cyclohexadiene. ESR measurements revealed that inclusion polymerization of cyclopentadiene or 1,3-cyclohexadiene in DCA canals proceeds by a free radical mechanism.     

Substituent effect on “Ring-Chain” tautomerism of 1,2,3,4-Tetrahydro-s-tetrazines

Methylhydrazones ( III ) of aromatic aldehydes and ketones react with nitrile imines ( II ) to give 1,2,3,4-tetrahydro-s-tetrazines IV ( 1-9 ) which exhibits “ring-chain” tautomerism in solution. The extent of this tautomerism is dependent both on steric and electronic effects of substituent groups at C-3 and C-6 ring carbons.     

Vilsmeier–Haack–Arnold formylations of aliphatic substrates with N-chloromethylene-N,N-dimethylammonium salts

The classical electrophilic substitution of activated aromatics with the Vilsmeier–Haack reagent N-chloromethylen-N,N-dimethylammonium chloride (Schemes 1 and 2) has been more recently extended to a great variety of aliphatic substrates, mainly due to the work of Arnold. In this review, a collection of representative examples for these henceforth called Vilsmeier–Haack–Arnold (VHA) formylation reaction of aliphatics is given: the reaction of polymethine cyanines, merocyanines, and other vinylogous iminium salts with the VHA reagent gives, after hydrolysis of the primary substitution products, trialdehydes such as triformylmethane (Scheme 3); VHA reaction with ene-diamines and diene-diamines yields N,N-dialkylaminomalonaldehydes and tetraaldehydes such as 1,1,2,2-tetraformylethane, respectively (Schemes 4 and 5); aldehyde acetals, enol ethers, and carboxylic acids deliver with VHA reagents 2-substituted malonaldehydes (Scheme 6), and α-amino acids give derivatives of the unstable aminomalonaldehyde (Scheme 7); alkenes and polyenes react with VHA reagents to give α,β-unsaturated or higher vinylogous aldehydes (Schemes 8 and 9), and alkenes with donor substituents yield alkylidene-malonaldehydes (Scheme 10); enolizable methyl and methylene ketones produce with VHA reagents 3-chlorovinylaldehydes (Scheme 11). Eventually, the VHA reagent can be used for the intermediate preparation of nucleophilic amino-chlorocarbenes (Scheme 12).     

Ketene N,S-acetals in heterocyclic synthesis: Part 1: Synthesis of N-phenyl-2-ylidene and 2,5-diylidene-4-thiazolidinone derivatives

Ketene N,S-acetal potassium salts (2a–g), prepared via reaction of active methylenes (1a–g) with phenyl isothiocyanate in the presence of potassium hydroxide, were allowed to react with ethyl chloroacetate or chloroacetamide to afford the corresponding 2-ylidene-4-thiazolidinones (3a–g) in good yields. Compounds (3a–g) reacted with a variety of aromatic aldehydes to afford the corresponding 5-arylidene-2-ylidene-4-thiazolidinone derivatives (10a–e). Reaction of compound (3a) with triethylorthoformate afforded 5-ethoxymethylene-2-ylidene-4-thiazolidinone derivative (7), which was allowed to react with ammonia or phenyl hydrazine to give the corresponding enamino or hydrazino derivatives (8a) or (8b), respectively.     

Enantioselective Silylcyanation of Aldehydes and Ketones by a Titanium Catalyst Prepared from a Partially Hydrolyzed Titanium Alkoxide and a Schiff Base Ligand

In the presence of small amount (0.2–1.0 mol%) of a titanium complex catalyst prepared from a partially hydrolyzed titanium alkoxide and an optically active tridentate Schiff base ligand, the enantioselective silylcyanation of aldehydes and ketones proceeded in a short reaction time at room temperature to afford the corresponding optically active cyanohydrin derivatives in excellent chemical yield with high enantiomeric excess (86–97% ee). The results indicate that partially hydrolyzed titanium alkoxides are a promising titanium source for the preparation of efficient catalysts for asymmetric synthesis.     

Research Note Interferences due to Ozone-Scavenging Reagents in the GC-ECD Determination of Aldehydes and Ketones as the (2, 3, 4, 5, 6, -Pentafluorobenzyl) oximes

In order to study ozonation byproduct (OBP) formation as a function of time, it is necessary to quench ozone and thereby fix the concentrations of the byproducts. Reagents chosen for this purpose must not react with the OBPs or otherwise adversely impact the analysis. Six potential ozone-scavenging reagents were tested for possible interference in the GC-ECD determination of aldehydes and ketones after derivatization with O-(2,3,4,5,6-pentafluorobenzyl)oxylamine (PFBOA). All six—sodium nitrite, sodium cyanide, sodium methanoate (formate), indigo-5,5′-disulfonate disodium (Indigo Carmine), indigo-5,5′,7-trisulfonate tripotassium, and tin(II) chloride—were found to interfere in the analysis.     

Enantioselective Vanadium‐Catalyzed Oxidation of 1,3‐Dithianes from Aldehydes and Ketones using β‐Amino Alcohol Derived Schiff Base Ligands

The asymmetric vanadium‐catalyzed oxidation of 1,3‐dithianes from aldehydes and ketones by β‐amino alcohol‐derived Schiff base ligands with two stereogenic centers was investigated. Using aqueous hydrogen peroxide as the oxidant and the Schiff base 3b as a chiral ligand, a variety of 1,3‐dithianes derived from aldehydes were easily converted into the corresponding mono‐sulfoxides in good yields (81–88%) with excellent enantioselectivities (up to 99% ee). Additionally, 99% ee was obtained for the enantioselective vanadium‐catalyzed oxidation of the 1,3‐dithianes derived from ketones. We found a slight kinetic resolution when using a higher ratio of hydrogen peroxide during the oxidation of the aldehyde‐derived 1,3‐dithianes but not in the ketone‐derived 1,3‐dithianes.     

Wet 2,4,6-trichloro[1,3,5]triazine (TCT) an efficient catalyst for synthesis of -bis(substituted-benzylidene) cycloalkanones under solvent-free conditions

An array of aromatic aldehydes undergo crossed aldol condensation with ketones in the presence of catalytic amounts of wet-TCT under solvent-free conditions to afford the corresponding α,α^′-bis(substituted-benzylidene) cycloalkanones in excellent yields. Contrary to the existing methods, which use classical Lewis acids a new catalyst (TCT) is employed. This method is also general with respect to all types of aromatic aldehydes and is an eco friendly procedure.     

Microwave-assisted reactions of α-diazoketones with hetaryl and ferrocenyl thioketones*

Differently substituted hetaryl thioketones react with less reactive diazoketones under microwave (MW) irradiation in toluene solution. After only 2?min, the reactions were complete and, depending on the type of the used diazoketone, α,β-unsaturated ketones, acyl substituted thiiranes or 1,3-oxathioles were obtained as final products. In the case of azibenzil and di(thiophen-2-yl) thioketone, a new type of 1,5-dipolar electrocyclization of the intermediate thiocarbonyl ylide involving a thiophene ring led to a fused sulfur heterocycle. In contrast to hetaryl thioketones, the ferrocenyl analogues decompose under MW irradiation. Alternatively, they react with diazopropanone and 2-diazo-1-phenylethanone in boiling THF in the presence of LiClO₄ to give α,β-unsaturated ketones as sole products. In these cases, the reactions require long reaction times.