Platinum(II) complex-catalyzed enantioselective aldol reaction with ketene silyl acetals in DMF at room temperature

[{(R)-binap}Pt(μ-OH)]₂2X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5 mol % loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry.     

Readily available (S)-proline-derived organocatalysts for the Lewis acid-mediated Lewis base-catalyzed stereoselective aldol reactions of activated thioesters

A set of enantiomerically pure Lewis bases containing different diphenyl phosphinyl oxide groups were easily synthesized in a straightforward procedure by reaction of readily available proline-based scaffolds and phosphinoyl chlorides. The newly synthesized derivatives were employed (0.1 mol equiv) as organocatalysts in the Lewis acid-mediated Lewis base-promoted direct stereoselective aldol reactions of activated thioesters with aromatic aldehydes, carried out in the presence of tetrachlorosilane and a tertiary amine. β-Hydroxy thioesters were obtained in moderate to high yields, with very high syn diastereoselectivities (dr up to >98:2), and fair enantioselectivities (ee up to 51%). Theoretical studies were performed in order to elucidate the origin of the stereoselection.     

Studies on the role of Lewis basicity of the aldehydes utilized in the enantioselective Mukaiyama aldol reaction promoted by chiral 1,3,2-oxazaborolidin-5-ones

N-Tosyl-2-1,3,2-oxazaborolidin-5-one 1 was used to probe the role of the Lewis basicity of aldehydes utilized in Mukaiyama aldol reactions promoted by oxazaborolidin-5-ones. Eight aldehydes were each allowed to undergo a Mukaiyama aldol reaction with ketene silyl acetal derived from methyl isobutanoate. Lewis basicity of the aldehydes was determined computationally. The best results were obtained with isobutyl aldehyde and 3,4,5-trimethoxy benzaldehyde (91% and 85% ee). The best fit of ee as a function of Lewis basicity gave a correlation of R²=0.79 [when two ortho-substituted aldehydes were excluded] suggesting that Lewis basicity of O_CHO can play a role in reactions of aldehydes promoted by 1.     

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

Enantioselective cyanosilylation of aldehydes catalyzed by a novel N,N′-dioxide-Ti(OPr)4 bifunctional catalyst

A novel bifunctional asymmetric catalyst containing N-oxide and titanium(IV) was developed and applied to the asymmetric cyanosilylation of aldehydes. Optically active trimethylsilyl cyanohydrin ethers were obtained up to 99% yield and 80% ee in the presence of 5 mol % catalyst loading at −78 °C. Based on the experimental results, the catalytic cycle was proposed as a pathway in which Lewis acid and Lewis base activated aldehyde and trimethylsilylcyanide (TMSCN), respectively.     

Acylation of N-p-toluenesulfonylpyrrole under Friedel-Crafts conditions: evidence for organoaluminum intermediates

The Friedel-Crafts acylation of N-p-toluenesulfonylpyrrole under Friedel-Crafts conditions has been reinvestigated. Evidence is presented in support of the hypothesis that when AlCl₃ is used as the Lewis acid, acylation proceeds via reaction of an organoaluminum intermediate with the acyl halide. This leads to the production of the 3-acyl derivative as the major product. With weaker Lewis acids (EtAlCl₂, Et₂AlCl) or less than 1 equiv of AlCl₃ the relative amount of 2-acyl product is increased. A mechanistic rationalization is presented to explain these data.     

Organo-catalyzed highly diastereo- and enantio-selective direct aldol reactions in water

The asymmetric direct aldol reactions of a wide scope of aromatic aldehydes, with unmodified ketones in the presence of 1 mol % of organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and trans-4-hydroxy-l-proline, were performed in water, affording aldol products in high yields with excellent diastereoselectivities of up to >99:1 and enantioselectivities of up to 98%.     

gem-Difluoropropargylation of aldehydes using cat. In/Zn in aqueous media

Zn (0.9 equiv) in combination with catalytic amounts of In (0.1 equiv) and I₂ (0.1 equiv) was found to effect the reaction of several difluoropropargyl bromide derivatives with aldehydes to produce gem-difluorohomopropargyl alcohols in aqueous media under conditions suitable for large scale applications.     

Synthesis of a biphenyl-based axially chiral amino acid as a highly efficient catalyst for the direct asymmetric aldol reaction

A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the use of only 0.1 mol % of (S)-2 was sufficient to complete the reaction between acetone and 4-nitrobenzaldehyde, giving the corresponding aldol adduct in good yield with an excellent enantioselectivity.     

Direct catalytic asymmetric aldol reaction of thioamides: a concise asymmetric synthesis of (R)-fluoxetine

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH₃CN)₄]PF₆/Li(OC₆H₄-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.     

Reductive amination of aldehydes and ketones to their corresponding amines with N-methylpyrrolidine zinc borohydride

A simple and convenient procedure for reductive amination of aldehydes and ketones using N-methylpyrrolidine zinc borohydride (ZBHNMP) as a reducing agent is described. The reactions are carried out with 1 equiv of amine and 1 equiv of aldehyde or ketone using 1 equiv of ZBHNMP in methanol under neutral conditions at room temperature.     

Titanium enolates of thiazolidinethione chiral auxiliaries: versatile tools for asymmetric aldol additions

[formula: see text] Asymmetric aldol additions using chlorotitanium enolates of thiazolidinethione propionates proceed with high diastereoselectivity for the "Evans" or "non-Evans" syn product depending on the nature and amount of the base used. With (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.     

Selective synthesis of multiply substituted 7-norbornenone derivatives or Diels-Alder cycloadducts from 1,2,3,4-tetrasubstituted 1,3-butadienes and maleic anhydride with or without Lewis acids

Reactions of 1,2,3,4-tetrasubstituted 1,3-butadienes with maleic anhydride and other dienophiles were investigated with or without addition of Lewis acid. When the silylated 1,3-butadienes, such as 1,4-bis(trimethylsilyl)-1,3-butadienes or 1-trimethylsilyl-1,3-butadienes, were treated with maleic anhydride in the presence of 2 equiv of AlCl₃, multi-substituted 7-norbornenones of well-defined exo,exo-disubstituted patterns were produced by an unprecedented and synthetically useful tandem process. Although some tetrasubstituted 1,3-butadienes could react directly with maleic anhydride under relative harsh conditions to afford Diels-Alder cycloadducts, the reactions, in the presence of 1 equiv of AlCl₃, afforded the corresponding cycloadducts in higher yields under mild conditions. These results showed that the size and substitution pattern of substituents on the butadienyl skeleton played a very important role in the reactivity of butadienes as a partner for the Diels-Alder reaction and Lewis acid could promote and/or realize the process of a Diels-Alder reaction.     

Enantioselective construction of quaternary asymmetric carbon centers using an aldol reaction of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate

An aldol reaction of 2,2-disubstituted trimethoxysilyl enol ethers with aldehydes catalyzed by a dilithium salt of (R)-3,3′-dichlorobinaphthol afforded the corresponding aldol adducts with quaternary carbon centers in high anti-selectivities (syn:anti = ∼1:50) and enantioselectivities (∼90% ee).     

Four- and five-coordinate magnesium compounds containing ketiminate ligands. Synthesis and characterization of L2Mg, L2Mg(LH), and L2Mg(Py), where L = MeC(O)CHC(NAr)Me

Magnesium complexes containing ketiminate ligands were synthesized and characterized. MgBu₂ reacted readily in toluene with two equiv. of [MeC(O)CHC(NHAr)Me], where Ar = 2,6-diisopropylphenyl, to generate [MeC(O)CHC(NAr)Me]₂Mg (1) in 43% yield. The four-coordinate magnesium compound 1 is very moisture sensitive and acts as a Lewis acid, accepting one equiv. of Lewis base to form five-coordinate magnesium compounds. Compound [MeC(O)CHC(NAr)Me]₂Mg[MeC(O)CHC(NHAr)Me] (2) was obtained in 57% yield from the reaction in toluene of MgBu₂ with three equiv. of [MeC(O)CHC(NHAr)Me]. Treatment of 1 with one equiv. of free ketimine ligands [MeC(O)CHC(NHAr)Me] also led to the formation of 2. The bulky η¹-ketimine of 2 can be replaced with a less bulky Lewis base such as pyridine. Treatment of 1 with excess pyridine in toluene at ambient temperature led to the formation of compound [MeC(O)CHC(NAr)Me]₂Mg[NC₅H₅] (3) as colorless crystalline solids in 51% yield. Compounds 1, 2, and 3 were characterized by NMR and X-ray crystallography. Compounds 2 and 3 showed no activity toward the polymerization of ε-caprolactone at 25 °C after 3 h. However, when the temperature was increased to 70 °C, compounds 2 and 3 efficiently catalyzed polymerization of ε-caprolactone to generate high molecular weight poly-ε-caprolactones. The polydispersity index (PDI) of these poly-ε-caprolactones is in the range 1.57-3.18.     

Highly enantioselective hetero-Diels-Alder reaction between trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene and aldehydes catalyzed by (R)-BINOL-Ti(IV) complex

An efficient enantioselective approach to 2,5-disubstituted dihydropyrones was developed. Some easily accessible inexpensive diol ligand metal complexes were employed, and [(R)-BINOL]₂-Ti(OiPr)₄ complex was found to be the most effective catalyst (up to 99% yield and 99% ee in the presence of 5 mol% catalyst) for the hetero-Diels-Alder reaction between trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene (1) and aldehydes. The potential and generality of this catalyst were evaluated by a variety of aldehydes including aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes. Based on the isolated intermediate from the reaction of benzaldehyde being confirmed by ¹H, ¹³C NMR and HRMS data, the mechanism was proposed as a Mukaiyama aldol pathway.     

Synthesis of α-aminonitriles under mild catalytic,metal-free conditions

α-Aminonitriles have been synthesized by a Strecker synthesis from aldehydes and ketones under mild catalytic, metal-free conditions. Aromatic aldehydes (1 equiv) were reacted with aromatic and 1° or 2° aliphatic amines (1 equiv) in EtOH containing 3 mol % of NH₄Cl to give high yields of α-aminonitriles. An alternative to adding NH₄Cl as a catalyst involved the use of excess TMSCN (1 equiv) and to promote the process. The reaction was also successful under microwave conditions using excess TMSCN with no solvent. Ketones similarly reacted with aromatic amines and excess TMSCN under conventional and microwave heating, but 30 mol % of added NH₄Cl was required for optimum conversion.     

Facile and clean synthesis of α-alkenoyl ketene-(S,S)-acetals via the aldol condensation reactions in water

The aldol condensation reactions of α,α-diacetyl ketene-(S,S)-acetals, 1a and 1b, with aromatic aldehydes 2 in the presence of NaOH in water have been investigated. At room temperature, the base-mediated condensations proceed smoothly to afford the corresponding mono-condensed products, α-alkenoyl ketene-(S,S)-acetals 3, in high yields. At reflux temperature, the reactions produce high yields of symmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 4 when 2 equiv of aldehyde are employed. Moreover, compounds 3 can condense with a different aldehyde to give unsymmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 5.     

Stereoselective titanium-mediated syn-aldol reaction from a lactate-derived chiral ethyl ketone

Stereoselectivity of the titanium-mediated aldol process based on (S)-2-benzyloxy-3-pentanone, 1, is dramatically modified by the presence of a Lewis acid. Among the Lewis acids surveyed, TiCl₄ has given access to the corresponding 2,4-anti-4,5-syn aldol adducts with the highest diastereomeric ratios. The excellent stereocontrol exerted by the aforementioned ketone has been demonstrated in double asymmetric reactions involving chiral α-methyl-β-OTBDPS aldehydes.     

The first example of atropisomeric amide-derived P,O-ligands used for an asymmetric Heck reaction

Atropisomeric N,N-diisopropyl 2-diphenylphosphino- and 2-di(tert-butyl)phosphino-1-naphthamides were used, for the first time, as bidentate P,O-ligands for intermolecular asymmetric Heck reactions of 2,3-dihydrofuran with aryl triflates. The reactions were carried out in the presence of 4 mol% Pd(OAc)₂, 8 mol% of the axially chiral ligand, and 3 equiv. of (i-Pr)₂NEt in THF at 60 °C for 3 days. Optically active 2-aryl-2,5-dihydrofurans were obtained as the major products along with the rearranged 2-aryl-2,3-dihydrofurans. Enantioselectivity up to 55.2% ee was obtained for the major product.