Effect of high pressure on Biginelli reactions. Steric hindrance and mechanistic considerations

The effect of high pressure is examined in 3-CC Biginelli reactions. This effect is small when moderately hindered aldehydes or ureas are involved. However, particularly in the case of bulky aldehydes, the sensitivity of the reaction to pressure increases with increasing steric congestion in line with earlier studies described in the reference list. The results also provide insights into the mechanism. Such a result highlights the synthetic utility of high pressure activation for the preparation of hindered Biginelli products.     

Steric hindrance effects in the use of heterocyclic azodyestuffs as spectrophotometric reagents

The heterocyclic azo dyestuffs 4-(n-methyl-2 -pyridylazo)-resorcinol (where n = 3', 4', 5', 6') have been prepared, and their possible use as spectrophotometric reagents investigated. The dyestuffs are shown to function analogously to the parent ligand 4-(2'-pyridylazo) resorcinol (PAR) in giving red complexes with the ions Co(2+), Ni(2+), Cu(2+), Zn(2+) and UO(2)(2+). Steric effects resulting from the position of the methyl group in the heterocyclic ring are shown to occur in relation both to the spectra of the dyestuffs themselves and to the sensitivity of their reactions with the metal ions.     

Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous catalysis: mechanistic aspects

The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was studied over supported rhodium and ruthenium catalysts at room temperature and a pressure of 5 MPa. The reaction was diastereoselective with the predominant formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric excess (de) of up to 96%. The most stable conformation was determined by means of a combination of modelling calculations, NMR spectroscopy and X-ray structural determination. In this conformation, the carbonyl group of the pyroglutamate auxiliary shields one face of the aromatic ring. The observed selectivity may thus be explained by a preferential adsorption at the unshielded face which avoids steric repulsion by the C=O group to result in a cis hydrogenation. The addition of an amine, the nature of the support (alumina or active carbon) or of the metal (Rh or Ru) were shown to give additional stabilisation of the adsorption at the unshielded face to increase the diastereoisomeric excess.     

New synthetic technology for the synthesis of hindered alpha-diazoketones via acyl mesylates

[formula: see text] A mild and reliable one-pot protocol for the elaboration of sterically demanding carboxylic acids into alpha-diazoketones via acyl mesylates has been developed. Aside from delineating the reaction parameters which render this strategy quite general for hindered carboxylic acids, we have directly proven the existence of the fleeting acyl mesylate group as the reactive species in these reactions and shed light onto the differing mechanisms which are operative in the activation of hindered and simple carboxylic acids with methanesulfonyl chloride.     

Steric hindrance to the solvation of melamines and consequences for non-covalent synthesis

Steric hindrance to solvation disfavors structures like 1 synanti in which the melamine exposes to the solvent faces, such as tBu-H, for whom binding to the ring nitrogen is hindered but not blocked; steric hindrance to solvation lowers the barriers to rotation in solvents which bind the triazine nitrogens, therefore these solvents display the fastest rates for assembling/disassembling processes.     

Application of organolithium and related reagents in synthesis. Part 25: Novel specific synthesis of the 4-arylisochroman-3-acetic acids via conversion of benzoic acids

The transformation of the benzanilides 1 into 4-arylisochroman-3-acetic acids 8 applying the following sequence of reactions is described. At first, the 3-arylphthalides 3 were obtained via metallation [n-BuLi] of benzanilides 1 and subsequent treatment of the generated bis-lithiated anilides 2 with aromatic aldehydes. Next, the 3-arylphthalides 3 were reduced [LiBH₄] to phthalanes 5 and then, via reductive metallation [Li/C₁₀H₈] and reaction of the generated bis-lithiated species 6 with dimethylformamide, 3-hydroxy-4-arylisochromans 7 were produced. In the final step the isochromans 7 were treated with 1-methoxy-1-trimethylsilyloxyethene in the presence of titanium tetrachloride and furnished 4-arylisochromans-3-acetic acid methyl esters 8 as trans stereoisomers (Ψ-e/e).     

Application of organolithium and related reagents in synthesis,Part X. Metallation-electrophilic substitution sequence of secondary chlorobenzamides

Summary The lithiation (Bu ⁿLi/THF) of 2-chloro- (1), 3-chloro- (2) and 4-chlorobenzanilides (3) and the subsequent reactions of the corresponding bis-lithiated anilides4–6 with electrophiles (MeI, CH₂=CH-CH₂Br,Me ₃SiCl,MeCHO,o-MeOC₆H₄CHO,p-MeOC₆H₄CHO,Me ₂NCHO andp-MeOC₆H₄CONMe ₂) towards the synthesis of theortho substituted chlorobenzoesic acids derivatives12–14 have been described. The effect of the chlorine substituent upon the generation and stability of the bis-lithiated chloro-anilides4–6 has been studied. It has been found that the bis-lithiated chloro-anilide5 derived fromm-chloro-benzanilide (2) at a temperature above –30°C converts into the corresponding benzyne9. The anilide moiety (masking group) of the formedortho-substituted chlorobenzanilides appeared to be effectively removable on acid-driven hydrolysis.

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Anwendungen von Organolithium und verwandten Reagenzien in organischen Synthesen, 10. Mitt. Metallierung und nachfolgende elektrophile Substitution sekundärer Chlorbenzamide

Zusammenfassung Die Lithiierung (Bu ⁿLi/THF) der 2-Chlor-(1), 3-Chlor- (2) and 4-Chlorbenzanilide (3) und nachfolgende Reaktion der entsprechenden doppellithiierten Anilide4–6 mit elektrophilen Reagenzien (MeI, CH₂=CH-CH₂Br,Me ₃SiCl,MeCHO,o-MeOC₆H₄CHO,p-MeOC₆H₄CHO,Me ₂NCHO undp-MeOC₆H₄CONMe ₂) zur Synthese vonortho-substituierten Benzoesäurederivaten12–14 wird beschrieben. Der Einfluß des Chlorsubstituierten auf die Bildung und Stabilität der doppellithiierten Chloranilide4–6 wurde untersucht. Es wurde festgestellt, daß das doppellithiierte, vomm-Chlorbenzanilid erhaltene Chloranilid5 bei Temperaturen über –30°C das entsprechende Arin9 bildet. Der Anilidrest (eine maskierende Gruppe) der gebildetenortho-substituierten Chloranilide kann durch saure Hydrolyse abgespalten werden.

     

Steric effects in synthesis—steric limits to the alkylation of nitriles and carboxylic acids

The steric limits to the alkylation of aliphatic nitriles and carboxylic acids have been investigated in some detail. For the experimental conditions considered (ionization by i-Pr₂NLi in THF followed by alkylation with RI/THF/HMPA) the most hindered nitriles R-CN and carboxylic acids R-CO₂H have the same secondary alkyi group RtBuPⁱCH-, but different tertiary. i.e. Rt-BuPrⁱEtC- or i-Pr₃C- for RCN and REt₂MeC for RCO₂H. A comparison of the relative merits of alkylation of esters, carboxylic acids, and nitriles is considered.     

On the α-lithiation-rearrangement of N-toluensulfonyl aziridines: mechanistic and synthetic aspects

A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and without added ligands such as (−)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In most cases, p-toluenesulfonamide (TsNH₂) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These reactions are believed to involve α-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to allylic or bicyclic sulfonamides via C-H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and subsequent elimination of TsNH₂. In the (−)-sparteine reactions, the products were generated with 38-66% ee and the sense of asymmetric induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.     

A facile synthesis of α-chloroboronic esters via the base induced reaction of α,α-dichloromethyl methyl ether with hindered borinic esters

Treatment of hindered borinic esters, R₂ BOR′; with an equimolar quantity of α,α-dichloromethyl methyl ether and lithium triethylcarboxide yields the α-chloroboronic esters, R₂ CHClB(OCH₃)OR′, in excellent yields. In cases where the steric requirements of R are not sufficient, the steric requirements of R′ can be increased to achieve the synthesis.     

Advances in the synthesis of aromatic and heteroaromatic carboxylic acids and their esters

Modern approaches to the synthesis of aromatic and heteroaromatic carboxylic acids and their esters based on the latest advances in organic chemistry are compiled and systematized in this review.     

Application of organolithium and related reagents in synthesis,Part XII. Synthesis of phenyl- and pyridylpyridopyridazinones and their derivatives

Summary The preparation of the pyridazinones10a,10b,11a,11b, and12a,12b from the ketoamides7,8, and9 and hydrazine hydrate is described. It was found that from ketoamides8b and9b in addition to the expected pyridopyridazinones11b and12b also aminopyridopyridazines14 and15 were formed and that ketoamide7b gave exclusively aminopyridopyridazine13. The pyridopyridazinones10b,11b, and12b were alkylated with alkyl iodides.

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Anwendungen von Organolithium und verwandten Reagenzien in organischen Synthesen, Teil XII. Synthese von Phenyl- und Pyridylpyridopyridazinonen und ihren Derivaten

Zusammenfassung Die Darstellung der Pyridazinone10a,10b,11a,11b und12a,12b aus Ketoamiden7,8 und9 und Hydrazinhydrat wird beschrieben. Es wurde festgestellt, daß aus Ketoamiden8b und9b außer den erwarteten Pyridopyridazinonen11b und12b auch Aminopyridopyridazine14 und15 enstanden und daß das Ketoamid7b ausschließlich ins Aminopyridopyridazin13 überführt wurde. Die Pyridopyridazinone10b,11b und12b wurden mit Alkyljodiden alkyliert.

     

Steric hindrance in the synthesis and properties of the dimer of 1-(2,4,6-Tri-tert-butylphenyl)phosphole 1-oxide

Steric hindrance was observed during the oxidation of 2,4,6-tri-tert-butylphenylphosphole to the P oxide and in the dimerization of this latter species to the corresponding phosphanorbornene derivative. Single-crystal X-ray analysis of the dimer revealed considerable steric crowding around the P atoms. Deoxygenation of the dimer of the phosphole oxide by Cl₃SiH–C₆H₅N could only be accomplished under forcing conditions at 110°C. © 1997 John Wiley & Sons, Inc. Heteroatom Chem 8 : 527–531, 1997     

The reaction of β-enaminoesters with organolithium reagents: a convenient method for the regioselective synthesis of enaminoketones

A simple and practical method for the regioselective preparation of β-enaminoketones is described. The method relies on the reaction of β-enaminoesters with organolithium reagents, and allows the preparation of a range of unusual β-enaminoketones.     

Regio- and stereoselective double alkylation of β-enamino esters with organolithium reagents followed by one-pot reduction: convenient method for the synthesis of tertiary γ-amino alcohols

An easy, high yielding and stereoselective procedure for the preparation of tertiary γ-amino alcohols starting from β-enamino esters is presented. In this procedure, the double alkylation of β-enamino esters with organolithium reagents is followed by one-pot reduction with sodium borohydride in methanol/acetic acid. A hypothesis of mechanism is given, explaining the observed diastereoselectivity through molecular modeling. The configuration of the products was determined by ¹H NMR spectroscopy coupled with conformational analysis.     

Selenoesters in organic synthesis. 1. Conversion of mixed carboxylic acid esters to selenoesters

Conclusions The rules governing the reaction of mixed carboxylic acid esters with dimethylaluminum methyl selenide have been investigated; it was found that the nature of the solvent and the structure of the precursor ester both exert significant effects on the selectivity of selenoester formation.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1650–1654, July, 1985.     

Counterion effects on geometric control in the Peterson reaction of bistrimethylsilyl esters: synthetic scope and mechanistic implications

An interesting and useful level of geometric control can be read in the reaction of enolates derived from bistrimethylsilyl acetates and aldehydes leading to a-trimethylsilyl esters and derived compounds depending upon the cation employed. Mechanistic experiments are described which suggest that chelation may play a role in the origin of the observed selectivities.