Low-valent Titanium Reagent Research Articles

Synthesis of Succinonitrile Derivatives by Homocoupling from Cyanohydrin Derivatives with a Low-Valent Titanium Reagent.

A method is described for synthesizing succinonitrile derivatives bearing alkyl or aryl substituents from cyanohydrin derivatives using low-valent titanium. The active species in this reaction is proposed to be a resonance hybrid of the TiIV nitrile enolate and TiIII alkyl radical.

Recent advances of carbonyl olefination via McMurry coupling reaction.

McMurry coupling reaction utilizes the low-valent titanium reagents and carbonyl compounds to produce olefins. The wide synthetic application of McMurry reagents in intermolecular and intramolecular coupling reactions, tandem coupling reactions, and keto ester coupling reactions of carbonyl compounds for the last five years have been reviewed. The resulting coupling reaction produces natural and non-natural products, including strained olefins and unusual molecules as a candidate for nanomaterials, pharmaceuticals, electronic materials, and so forth. The advantages, scope, and limitations along with the improvement of the McMurry coupling reaction, including the addition of high functional group compatibility, McMurry reagents substitution, and several other treatments, have also been discussed.

Dual-mode coupling copolymerization of aryl dialdehyde and alkynylaldehyde monomers via Concurrent McMurry olefination and alkyne [2+2+2] cycloaddition trimerization reactions mediated by a low-valent titanium reagent

The application of a low-valent titanium reagent recently developed in our group, Ti(O-i-Pr)4/Me3SiCl/Mg, to the McMurry coupling polymerization of aryl dialdehyde monomers and [2 + 2 + 2] cycloaddition polymerization of aromatic diyne monomers is described. Furthermore, on the basis of these reactions, a low-valent titanium-mediated dual-mode coupling copolymerization of aryl dialdehyde and alkynylaldehyde monomers via concurrent McMurry olefination and alkyne cyclotrimerization reactions is proposed.

Total Synthesis of 1-Hydroxytaxinine.

1-Hydroxytaxinine (1) is a cytotoxic taxane diterpenoid. Its central eight-membered B-ring possesses four oxygen-functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six-membered A- and C-rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical-based strategy for assembling 1 from A- and C-ring fragments. The A-ring bearing an α-alkoxyacyl telluride moiety underwent intermolecular coupling with the C-ring fragment by a Et3 B/O2 -promoted decarbonylative radical formation. After construction of the C8-quaternary stereocenter, a pinacol coupling reaction using a low-valent titanium reagent formed the B-ring with stereoselective installation of the C1,C2-diol. Subsequent manipulations at the A- and C-rings furnished 1 in 26 total steps.

Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-reductant.

A nickel-catalyzed cross-electrophile coupling reaction between benzyl alcohols and aryl halides has been developed using a homolytic C-O bond cleavage protocol that has recently been established. The treatment of a benzyl alcohol and aryl halide with a nickel catalyst and low-valent titanium reagent generated from TiCl4(lutidine) (lutidine = 2,6-lutidine) and manganese powder afforded the cross-coupled product in high yield. A mechanistic study indicated the intermediacy of the benzyl radicals that originate from the benzyl alcohols.

Alkyne [2 + 2 + 2] Cyclotrimerization Catalyzed by a Low-Valent Titanium Reagent Derived from CpTiX3 (X = Cl, O-i-Pr), Me3SiCl, and Mg or Zn

Inter-, partially intra-, and intramolecular [2 + 2 + 2] cycloadditions of alkynes were catalyzed by a low-valent titanium species generated in situ from the reduction of CpTi(O-i-Pr)3, CpTiCl3, or Cp*TiCl3 with Mg or Zn powder in the presence of Me3SiCl. The role of Me3SiCl as an additive in the reaction mechanism is discussed.

Low-Valent Titanium-Mediated Radical Conjugate Addition Using Benzyl Alcohols as Benzyl Radical Sources.

A concise method to directly generate benzyl radicals from benzyl alcohol derivatives has been developed. The simple and inexpensive combination of TiCl4(collidine) (collidine = 2,4,6-collidine) and manganese powder afforded a low-valent titanium reagent, which facilitated homolytic cleavage of benzylic C-OH bonds. The application to radical conjugate addition reactions demonstrated the broad scope of this method. The reaction of various benzyl alcohol derivatives with electron-deficient alkenes furnished the corresponding radical adducts.

Efficient and Diastereoselective Synthesis of bis-Quinazolinedione Derivatives via Low-Valent Titanium Reagent

Efficient and Diastereoselective Synthesis of bis-Quinazolinedione Derivatives via Low-Valent Titanium Reagent

Synthetic Reactions Using Low-valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) in the Presence of Me3SiCl and Mg.

In the presence of Me3SiCl, Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low-valent titanium (LVT) species that mediates several synthetic reactions. The LVT-catalyzed C-O bond-cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O-allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N-S or O-S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra- and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT-mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino-pinacol coupling of imines is mediated by the LVT to provide 1,2-diamines.

ChemInform Abstract: A Facile One‐Step Synthesis of 2‐Arylindazoles via Reductive Cyclization of N‐(2‐Nitroarylidene)amines.

A mild and efficient synthesis of 2-arylindazole derivatives via the reductive cyclization of nitro-aryl substrates mediated by a low-valent titanium reagent (TiCl4/Sm/Et3N) has been developed. The attractive features of the current method include an N–N bond formation and the selective reduction of the C = N bond and nitro group, both of which were easily achieved in one-pot by controlling the pH of the reaction mixture.

Selective reduction of carbonyl groups in the presence of low-valent titanium reagents

The chemoselective reduction of several structurally diverse compounds containing carbonyl groups was achieved in the presence of low-valent titanium reagents. This novel synthetic method provides easy access to highly selective reduction of carbonyl groups, and possesses several advantages including one-step procedure, convenient manipulation, good to excellent yields, and short reaction times.

ChemInform Abstract: An Efficient and Convenient Synthesis of Heterocycle‐Fused Indazoles via the N—N Bond Forming Reaction of Nitroarenes Induced by Low‐Valent Titanium Reagent.

AbstractReductive cyclization of nitroaryl substrates using a low valent titanium reagent allows the synthesis of the title compounds (II) and (IV).

ChemInform Abstract: Synthetic Transformation of Homopropargylic Selenides to Conjugated Diene‐Substituted Alcohols and Amines Using Diisopropoxy(η2‐alkyne)titanium Intermediates.

Abstract The reaction of homopropargylic selenides with the low-valent titanium reagent, derived from Ti(O- i -Pr) 4 and 2 equiv of i -PrMgCl, proceeded via titanium–alkyne complexes, followed by the reaction with electrophiles, such as aldehydes and imines to afford allylic alcohols and amines having a phenylseleno group in moderate to high yields with excellent regioselectivity (up to >99:1). Especially, the reaction of the silyl-substituted alkynes with imines provided the desired products in almost complete regioselectivity. The resulting products were subjected to oxidation with H 2 O 2 to lead conjugated diene-substituted alcohols and amines via selenoxide elimination in high yields. In addition, the isomer ratio of products was nearly completely maintained under the oxidative deselenation conditions.

An efficient and convenient synthesis of heterocycle-fused indazoles via the N–N bond forming reaction of nitroarenes induced by low-valent titanium reagent

A mild and efficient one-pot protocol for the preparation of 8,13-dihydro-7H-indolo[2′,3′:3,4]pyrido[1,2-b]indazole and 5,6-dihydroindazolo[3,2-a]isoquinoline via the reductive cyclization of nitro-aryl substrates mediated by a low-valent titanium reagent has been developed. The attractive features of the current method include an N–N bond formation and the selective reduction of the CN bond and nitro group, both of which were easily achieved in one-pot by controlling the pH of the reaction mixture.

Reduction of hydrazines to amines with low-valent titanium reagent

The N,N bond cleavage in hydrazines to amines via low-valent titanium reagent prepared in situ by treatment of TiCl4 with Mg powder in THF or CH2Cl2-Et2O is described. The reaction proceeds smoothly under mild conditions to afford amines in good to excellent yields with diverse functional group tolerance such as chloride, methoxyl, benzyloxyl, ester, acyl, as well as C,C double bonds and benzyl-nitrogen bonds.

Synthetic transformation of homopropargylic selenides to conjugated diene-substituted alcohols and amines using diisopropoxy(η2-alkyne)titanium intermediates

The reaction of homopropargylic selenides with the low-valent titanium reagent, derived from Ti(O-i-Pr)4 and 2 equiv of i-PrMgCl, proceeded via titanium–alkyne complexes, followed by the reaction with electrophiles, such as aldehydes and imines to afford allylic alcohols and amines having a phenylseleno group in moderate to high yields with excellent regioselectivity (up to >99:1). Especially, the reaction of the silyl-substituted alkynes with imines provided the desired products in almost complete regioselectivity. The resulting products were subjected to oxidation with H2O2 to lead conjugated diene-substituted alcohols and amines via selenoxide elimination in high yields. In addition, the isomer ratio of products was nearly completely maintained under the oxidative deselenation conditions.

ChemInform Abstract: A Stereoselective Synthesis of Symmetrical and Unsymmetrical Bibenzo[e][1,3]oxazine‐2,2′‐dione Derivatives Induced by Low‐Valent Titanium Reagent.

Abstract A series of symmetrical and unsymmetrical bibenzo[e][1,3]oxazine-2,2′-dione derivatives were synthesized by the reaction of various o-hydroxy Schiff bases and triphosgene induced by low-valent titanium reagent (TiCl4/Sm). A variety of substrates can participate in the process with good yields. The present method provides a useful preparation of 3,3′,4,4′-tetrahydro-4,4′-bibenzo[e][1,3]oxazine-2,2′-dione derivatives, which cannot be prepared otherwise. The mechanistic course of the reaction suggests the involvement of reduction, coupling, and cyclization by one-pot.

ChemInform Abstract: An Efficient Synthesis of 2H‐Indazoles via Reductive Cyclization of 2‐Nitrobenzylamines Induced by Low‐Valent Titanium Reagent.

Abstract An efficient and improved synthesis of 2H-indazoles via reductive cyclization of 2-nitrobenzylamines induced by low-valent titanium reagent (TiCl4/Zn) is described. In this reaction triethylamine (TEA) was used to control the pH value. This method has the advantages of easily accessible starting materials, convenient manipulation, higher yield, shorter reaction time, and wider substrate scope.

McMurry Coupling of Aldehydes and Ketones for the Formation of Heterocyles Via Olefination

The low-valent titanium (LVT) reagents have gained widespread acceptance in organic synthesis since their first use in 1973. McMurry coupling reaction uses the LVT (low-valent titanium) reagents. This article is an attempt to review the broad synthetic utilizations of this reagent in inter and intramolecular coupling of carbonyl groups in olefination, resulting in the formation of heterocyclic compounds. Keywords: McMurry Coupling, Low-valent Titanium (LVT), Porphyrins, Cyclophanes, Giant Macrocycles, Five-membered Heterocycles, Seven-membered Heterocycles, Natural Products, olefination, heterocyclic.

A stereoselective synthesis of symmetrical and unsymmetrical bibenzo[e][1,3]oxazine-2,2′-dione derivatives induced by low-valent titanium reagent

A series of symmetrical and unsymmetrical bibenzo[e][1,3]oxazine-2,2′-dione derivatives were synthesized by the reaction of various o-hydroxy Schiff bases and triphosgene induced by low-valent titanium reagent (TiCl4/Sm). A variety of substrates can participate in the process with good yields. The present method provides a useful preparation of 3,3′,4,4′-tetrahydro-4,4′-bibenzo[e][1,3]oxazine-2,2′-dione derivatives, which cannot be prepared otherwise. The mechanistic course of the reaction suggests the involvement of reduction, coupling, and cyclization by one-pot.