ZrCl4-catalyzed X-C/C-C bond formation for the geometric selective synthesis of (E)-β-iodo aza Morita-Baylis-Hillman (MBH) adducts

A geometric selective synthesis of (E)-β-iodo and β-alkyl vinyl ketones (MBH amino adducts) has been developed through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate intermediates via the α,β-unsaturated addition of TMS-I to 3-butyn-2-one followed by a carbonyl addition onto N-aryl imines in the presence of ZrCl₄ catalyst. The resulting β-iodo allylic amines can be readily converted into β-alkyl Morita-Baylis-Hillman adducts by performing Suzuki and Kumada cross-couplings.     

Reversal Diastereoselectivity Between the Organomagnesium and Organolithium Reagents on Chiral N-Tert-Butylsulfinylaldimines for the Preparation of Chiral Amines

The asymmetric synthesis of both the enantiomer of chiral amines from the single chiral source of N-tert-butylsulfinylaldimines (3) by simply changing the organometallic reagents through diastereoselective addition. An efficient enantioselective synthesis of chiral amines including (S)-3-methyl-1-(2-piperidin-1-yl-phenyl)butyl amine (6a), a key intermediate to prepare antidiabetic drug repaglinide (1), is reported.     

A direct functionalization of tertiary alkyl bromides with O-, N-, and C-nucleophiles

Silver oxide used in stoichiometric amounts promoted the direct functionalization of tert-alkyl bromides and provided the desired adducts in 39-96% isolated yield. Reaction of tert-bromides with carboxylic acids yielded esters, with alcohols and phenols yielded alkyl and aryl ethers, with amines and anilines yielded selectively mono-alkylated amines and anilines, and with a C-nucleophile yielded an all-carbon quaternary hydrocarbon. The method was applied to a sequential alkylation of a primary amine with two different alkyl bromides yielding selectively a tertiary amine with three different substituents in one-pot.     

Conversion of tertiary alcohols to tert-alkyl azides by way of quinone-mediated oxidation-reduction condensation using alkyl diphenylphosphinites

A novel method for the preparation of alkyl azides from alcohols by way of oxidation-reduction condensation is described. In this reaction, the sterically-hindered tert-alkyl phosphinites that are prepared from the corresponding alcohols are converted into tert-alkyl azides with almost complete inversion of their stereochemistry: the obtained alkyl azides are then successfully reduced to afford the corresponding amines on treatment with LiAlH₄, thus, a versatile method for the preparation of chiral amines from the corresponding chiral alcohols is established.     

Facile N-tert-butoxycarbonylation of amines using La(NO3)3·6H2O as a mild and efficient catalyst under solvent-free conditions

Facile N-tert-butoxycarbonylation of amines is described by the treatment of various primary, secondary, benzylic and aryl amines with di-tert-butyl dicarbonate in the presence of catalytic amounts of La(NO₃)₃·6H₂O under solvent-free conditions at room temperature to afford N-tert-butylcarbamates in excellent yields.     

Stereoselective and diversity-oriented synthesis of trisubstituted allylic alcohols and amines

Stereoselective and diversity-oriented synthesis of trisubstituted olefins was achieved by using ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing group for allylic substitution. The starting point of this methodology was a set of α-methylene aldehydes derived from Baylis-Hillman adducts. Subsequent addition of different organometallic reagents led to a variety of allylic alcohol substrates. After introduction of the reagent-directing o-DPPB group, copper-mediated allylic substitution with a wide range of Grignard reagents enabled the stereoselective construction of a large number of E-configured trisubstituted allylic alcohols and amines in excellent yields and stereoselectivities. Remarkable is the synthetic flexibility, which allows a wide range of permutations starting from an aldehyde followed by successive introduction of the substituents R(2) and R(3) from organometallic Grignard based reagents. Thus, starting from only a few precursors, a diversity-oriented synthesis of stereodefined trisubstituted allylic alcohols and amines becomes possible.     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.     

From terminal alkynes directly to branched amines

The one-pot synthesis of several branched secondary aliphatic amines is described. Hydroamination of terminal alkynes with aliphatic primary amines in the presence of Cp₂Ti(η²-Me₃SiCCSiMe₃) gives the corresponding aldimines as intermediates. Reaction of these in situ produced aldimines with organolithium reagents (n-BuLi, PhLi) provides the α-branched amines in an easy way in upto 78% overall yield.     

Application of NO2/supercritical CO2 system for safe and selective nitration of adamantanes and tertiary alkyl bromides

A concise safe approach for selective nitration and nitroxylation of tert-alkanes, in particular adamantane, and tert-alkyl bromides utilizing NO₂ in supercritical CO₂ medium has been established. Major reaction products were tert-alkyl nitro compounds and tert-alkyl nitrates depending on the reaction conditions.     

Enhancing the solubility for hypervalent ortho-sulfonyl iodine compounds

The synthesis and characterization of new hypervalent iodine reagents ArINTs (2a), ArIO (3a), and ArIO₂ (4a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are described. These reagents are compared to previously reported analogous set of reagents Ar=2-tert-butylsulfonylphenyl and found to have significantly enhanced solubility and similar chemical reactivity. The X-ray crystal structures of 4a and of ArI (1a) (Ar=2-tert-butylsulfonyl-5-tert-butylphenyl) are discussed and compared. These reagents find use in atom and group transfer reactions.     

Solvent-assisted thiocarboxylation of amines and alcohols with carbon monoxide and sulfur under mild conditions

DMSO or DMF as a solvent strongly accelerated the thiocarboxylation of amines and alcohols with carbon monoxide and sulfur. Under mild conditions (1 atm, 20 °C), this thiocarboxylation of amines assisted by DMSO with carbon monoxide and sulfur has been developed into a practical and convenient synthetic method for S-alkyl thiocarbamates in good to excellent yields, including EPTC, thiobencarb, orbencarb, and molinate (herbicides). DMF also showed the similar solvent effect. NMP slightly decreased the effect for the thiocarboxylation of amines, and the yield of S-alkyl thiocarbamate was lowered in DMAc. Surprisingly, no formation of S-alkyl thiocarbamate was observed at the use of the other solvents, such as THF, hexane, toluene, AcOEt, MeCN, MeOH, and H₂O. The present solvent-assisted thiocarboxylation with carbon monoxide and sulfur could be also applied to a new synthesis of S-alkyl O-alkyl carbonothioates from alcohols under mild conditions (1 atm, 20 °C) in DMF using DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).     

Synthesis of [μ-methyllenebis(η5-3-tert-butyl-2-methylinden-1-yl)dichlorozirconium(IV)]

An efficient synthetic approach to 3-alkyl(aryl)-2-bromoindenes was developed. The reaction of 2-bromo-3-tert-butylindene with MeMgl catalyzed by Ni(dppp)Cl₂ afforded 3-tert-butyl-2-methylindene from which bis(3-tert-butyl-2-methylinden-1-yl)methane and the correspondingansa-zirconocene were synthesized.     

Native amine-directed site-selective C(sp3)-H arylation of primary aliphatic amines with aryl iodides

Direct C(sp³)-H functionalization of N-unprotected aliphatic amines represents one of the most efficient and straightforward strategies for amine synthesis. Despite some recent progress in this field, the NH₂-directed γ-C(sp³)-H arylation of primary aliphatic amines except α-amino esters remained an unmet challenge. In this report, we established a simple and efficient method for site-selective C(sp³)-H arylation of primary aliphatic amines by aryl iodides. In the presence of only 5 mol% Pd(OAc)₂, a wide range of aliphatic amines including O-benzyl and O-silyl amino alcohols were arylated at γ- or δ-positions by aryl iodides containing a broad scope of functional groups. The synthetic application of this method had also been demonstrated by large-scale synthesis, the synthesis of a fingolimod analogue, and the conjugation with natural d-menthol and fluorescent 1,8-naphthalimide.     

Poly(difluorophosphazene): A New Intermediate for the Synthesis of Poly(organophosphazenes)

Although many poly(organophosphazenes) have been synthesized, new preparative pathways are needed, especially for polymers that contain alkyl side groups. A new development involves the use of poly(difluorophosphazene), (NPC1₂) instead of poly-(dichlorophosphazene), (NPC1²)_n, as a substrate for reactions with organometallic reagents. This approach has allowed the preparation of a new class of poly(organophosphazenes) that possess substituent groups linked to the skeleton through direct phosphorus-carbon bonds. The synthesis of uncrosslinked poly-(difluorophosphazene) and its reactions with alkoxides and amines are also reviewed.     

Ruthenium-catalysed asymmetric transfer hydrogenation of N-(tert-butanesulfinyl)imines

The ruthenium complex prepared from [RuCl₂(p-cymene)]₂ and (1S,2R)-1-amino-2-indanol is a very efficient catalyst for the asymmetric transfer hydrogenation of (R)-N-(tert-butanesulfinyl)ketimines in isopropanol. By carefully removing all possible moisture from the reaction medium, chiral primary amines with very high optical purities (up to >99% ee) can be easily prepared in excellent yields by the diastereoselective reduction of the imines followed by removal of the sulfinyl group under mild acidic conditions. Reaction times of 1-4 h were needed to complete the reduction reactions when they were performed at 40 °C.     

Chemoselective synthesis of 6-amino(alkoxy)-1,4,5,6-tetrahydropyridines from cyclic β-alkoxyvinyl α-ketoester

The synthetic versatility of ethyl 2-(2-ethoxy-3,4-dihydro-2H-pyran-5-yl)-2-oxoacetate for the synthesis of ethyl 2-oxo-2-(1-alkyl/aryl-6-(amino/ethoxy)-1,4,5,6-tetrahydropyridin-3-yl)acetates, from the reaction with primary amines, is presented. The methodology proposed herein is highly chemoselective, and twenty products were obtained in moderate to good yields (up to 87%).     

Solid-phase synthesis of isoindolinones and naturally-occurring benzobutyrolactones (phthalides) using a cyclative-cleavage approach

Starting from Merrifield resin, 2-formylbenzoic acids were immobilized on solid supports. Reactions between immobilized 2-formylbenzoic acids and different organometallic reagents (Grignard reagents, zinc reagents, allyl silanes via Sakurai type reactions) furnished secondary alcohols which cyclized depending on the metal counter ion and reaction conditions, forming benzoannelated lactones. Asymmetric synthesis was possible on the resin using chiral [2.2]paracyclophane ligands. While the reaction of immobilized ortho-carboxy benzaldehydes with primary amines at elevated temperatures yielded 3-hydroxyisoindolinones, a reaction at ambient temperature allowed imine formation, which underwent 1,2-addition-cleavage reaction with various nucleophiles, yielding isoindolinones with three points of diversity.     

Generation of oxodiazonium ions 4. Nitramine O-alkyl derivatives in the synthesis of benzotetrazine-1,3-dioxides

A new method for the synthesis of benzotetrazine-1,3-dioxides was developed from the 2-(tert-butyl-NNO-azoxy)-N-nitroaniline O-alkyl derivatives upon the action of strong acids (H₂SO₄, MeSO₃H, CF₃CO₂H) or BF₃·Et₂O. A mechanism suggested for these reactions includes transformation of the N=N(O)OR group (R = Me, Prⁱ) to the oxodiazonium ion (N=N=O)⁺, which intramolecularly reacts with the neighboring tert-butyl-NNO-azoxy group, furnishing the tetrazine-1,3-dioxide ring.     

Facile S-alkyl thiocarbamate synthesis by a novel DBU-assisted carbonylation of amines with carbon monoxide and sulfur

A novel DBU-assisted carbonylation of amines with carbon monoxide and sulfur has been developed for the synthesis of S-alkyl thiocarbamates. In the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), S-alkyl thiocarbamates are synthesized in excellent yields from amines, carbon monoxide, sulfur, and alkyl halides under mild conditions (1 atm, 20°C). In the absence of DBU, however, no formation of S-alkyl thiocarbamate is observed. The present DBU-assisted carbonylation can also be applied to new synthetic methods for benthiocarb and orthobencarb (herbicides) and carbamoyl chlorides.     

A concise synthesis of (R)- and (S)-α-alkyl isoserines from d- and l-malic acids

A simple and diastereoselective method for the synthesis of (R)- and (S)-α-alkyl isoserines has been developed in four steps starting from commercially available d- and l-malic acid, respectively. This approach features stereocontrolled alkylation of 2-(2-tert-butyl-5-oxo-1,3-dioxolan-4-yl)acetic acid and proceeds through a methylcarbamate via a Curtius rearrangement.