Ionic Liqids in Organic Synthesis: The Pummerer Reaction

Pummerer‐type reaction was carried out with α‐acyl sulfides and phenyliodine(III) bis(trifluoroacetate) (PIFA) instead of α‐acyl sulfoxides in the room temperature ionic liquid 1‐n‐butyl‐3‐methylimidazolium hexafluorophosphate [bmim][PF₆] under mild conditions to give the ene adducts 3 in good yields.     

Addition of titanium ester enolates to aldimines containing a chiral α-methylbenzylamine moiety: synthesis of chiral syn-β-amino esters

Addition of titanium ester enolates to N-arylidene derivatives containing a (R)-α-methylbenzylamine moiety afforded (2S,3S,αR)-β-amino esters in 73–93% yields with 86:14 to 96:4 diastereomeric ratios.     

Highly Enantioselective Conjugate Additions of Phosphites to α,β‐Unsaturated N‐Acylpyrroles and Imines: A Practical Approach to Enantiomerically Enriched Amino Phosphonates

The first highly enantioselective phosphonylation of α,β‐unsaturated N‐acylpyrroles has been developed. Excellent yields (91–99 %) and enantioselectivities (up to >99 % enantiomeric excess (ee)) were observed for a broad spectrum of both phosphites and N‐acylpyrroles under mild conditions. In particular, when diethyl phosphite was employed to test the scope of the N‐acylpyrroles, almost optically pure products (98 to >99 % ee) were obtained for 20 examples of N‐acylpyrroles. Moreover, optically pure α‐substituted β‐ or γ‐amino phosphonates can be obtained by several simple transformations of the pyrrolyl phosphonates. The versatility of the N‐acylpyrrole moiety makes the phosphorus adducts powerful chiral building blocks that enable the synthesis of various phosphonate‐containing compounds. Finally, the present strategy can also be applied to the asymmetric hydrophosphonylation of N‐acylimines with high enantioselectivities (93 to >99 % ee).     

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N‐Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N‐carbamoyl imines has been developed. Both α‐imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N‐tert‐butoxycarbonyl (Boc) or N‐carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N‐carbamate‐protected imines are generated in situ from stable and easily handled α‐amido sulfones.     

Synthesis of 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles by the reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles with sodium iodide

The reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles 1 with sodium iodide in N,N‐dimethyl‐formamide gave the corresponding 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N‐acyl‐1‐cyanocyclopropanecarboxamides 4 . The same compounds 2 were also obtained by treatment of 4 with sodium iodide. The starting compounds 1 were synthesized by the reaction of 2‐amino‐4,5‐dihydro‐3‐furan‐carbonitrile with acyl chlorides in pyridine.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Convenient and useful synthesis of N‐carboxyanhydride monomers through selective cyclization of urethane derivatives of α‐amino acids

A new convenient synthesis of N‐carboxyanhydrides (NCAs) of α‐amino acids was achieved by selective cyclization of urethane derivatives of α‐amino acids. The urethanes were readily synthesized via N‐carbamoylation of α‐amino acids by bis(4‐nitrophenyl)carbonate quantitatively. These urethanes having 4‐nitrophenoxy moiety were tolerant to air and moisture to allow their facile purification and storage. When the obtained urethanes were heated in 2‐butanone at 60 °C, they underwent the selective cyclization via intramolecular nucleophilic attack of the carboxyl moiety to the urethane moiety with releasing 4‐nitrophenol, leading to the successful formation of the corresponding NCAs. Addition of carboxylic acids remarkably stabilized the formed NCAs during the reaction, allowing their isolation in high yields. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3839–3844, 2009     

Combination of Tetrabutylammonium Iodide (TBAI) with tert‐Butyl Hydroperoxide (TBHP): An Efficient Transition‐Metal‐Free System to Construct Various Chemical Bonds

In this account, we describe our recent progress on transition‐metal‐free‐catalyzed cross‐coupling reactions using tetrabutylammonium iodide (TBAI) as the catalyst and tert‐butyl hydroperoxide (TBHP) as the oxidant. A rich variety of important organic compounds including α‐acyloxy ethers, tert‐butyl peresters, allylic esters, amides, α‐amino nitriles, fully substituted pyrazoles, N‐sulfonyl formamidines, α‐amino acid esters, cyanomethyl esters, N‐nitrosamines, and 3‐acyloxy‐2,3‐dihydrobenzofurans have been successfully achieved in high chemoselectivity. Mechanistic studies suggested that TBAI could decompose TBHP to ^tBuO^. and ^tBuOO^. or be oxdized to (hypo)iodite by TBHP.     

Stereoselective Organocatalyzed Synthesis of α‐Fluorinated β‐Amino Thioesters and Their Application in Peptide Synthesis

α‐Fluorinated β‐amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of α‐fluorinated monothiomalonates (F‐MTMs) to N‐Cbz‐ and N‐Boc‐protected imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling‐reagent‐free peptide synthesis in solution and on solid phase. The α‐fluoro‐β‐(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.     

Highly Enantioselective Synthesis of α‐Stereogenic Esters through Catalytic Asymmetric Michael Addition of 4‐Oxo‐4‐arylbutenoates

Highly enantioselective Michael addition of 1,3‐dicarbonyl compounds and nitromethane to 4‐oxo‐4‐arylbutenoates catalyzed by N,N′‐dioxide–Sc(OTf)₃ complexes has been developed. Using 0.5–2 mol % catalyst loading, various α‐stereogenic esters were obtained regioselectively with excellent yields (up to 97 %) and enantioselectivities (up to >99 % ee). Moreover, the reaction performed well under nearly solvent‐free conditions. The products with functional groups are ready for further transformation, which showed the potential value of the catalytic approach. According to the experimental results and previous reports, a plausible working model has been proposed to explain the origin of the activation and the asymmetric induction.     

Ene Reaction with Pummerer‐type Reaction Intermediate of α‐(Methylthio)‐N‐methoxy‐N‐methyl Acetamide: A New Synthesis of N‐methoxy‐N‐methyl‐(E,E)‐2,4‐dienamides

Pummerer‐type reaction intermediate 2 of α‐(methylthio)‐N‐methoxy‐N‐methyl acetamide (1) has been found to react with 1‐alkenes to afford ene adducts 3 . N‐Methoxy‐N‐methyl‐(E,E)‐2,4‐dienamides were synthesized from the adducts 3b‐f .     

Conjugate addition of lithium ester enolates to 1-chlorovinyl p-tolyl sulfoxides: a novel synthesis of functionalized esters and lactones having a tertiary or a quaternary carbon at the β-position

Addition of the lithium ester enolates to 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from chloromethyl p-tolyl sulfoxide and ketones or aldehydes, gave esters having a tertiary or a quaternary carbon at the 3-position, and chlorine and sulfinyl groups at the 4-position in high to quantitative yields. The adducts were converted to various esters having methyl, formyl, and hydroxycarbonyl groups at the 3-position. A novel method for the synthesis of γ-lactones, including spiro-type γ-lactones and α-methylene γ-lactones, was realized from the adducts in good overall yields. The scope and limitations of this method and the mechanism of the reactions are also discussed.     

Synthesis of α,β‐Unsaturated Ketones and Esters Using Polymer‐supported Selenium Bromide

Treatment of the polymer‐supported α‐phenylseleno ketones and esters prepared from polymer‐supported selenium bromide with ketone and ester enolates with hydrogen peroxide afford α,β‐unsaturated ketones and esters in good yields and high purities.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

Rapid and Catalyst‐Free α‐Halogenation of Ketones using N‐Halosuccinamides in DMSO

α‐Halogenation of various carbonyl compounds such as β‐keto‐esters, cyclic ketones, and lactams with N‐halosuccinamides (NBS, NCS, NIS) in the presence of DMSO proceeded very smoothly to give the corresponding α‐monohalogenated products in good to excellent yields with high selectivity under catalyst‐free conditions.     

A 4‐Hydroxypyrrolidine‐Catalyzed Mannich Reaction of Aldehydes: Control of anti‐Selectivity by Hydrogen Bonding Assisted by Brønsted Acids

An anti‐selective Mannich reaction of aldehydes with N‐sulfonyl imines has been developed by using a 4‐hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the α‐substituent of the pyrrolidine, the 4‐hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde‐derived imines, which have rarely been employed in previously reported enamine‐based anti‐Mannich reactions. Additionally, both N‐tosyl and N‐nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N‐deprotection the corresponding β‐amino acids and β‐amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine‐based reactions.     

Synthesis of tetronic acid derivatives from novel active esters of α‐hydroxyacids

Active esters, produced by condensation of O‐acetyl protected α‐hydroxyacids with N‐hydroxysuccin‐imide, react with anions of active methylene compounds to afford β,β‐tricarbonyl derivatives which upon deprotection undergo cyclization to 3‐alkoxycarbonyl and 3‐acyl tetronic acids. Incorporation of (S)‐2‐ace‐toxyphenylacetic acid in this reaction sequence enables the synthesis of optically active 5‐phenyltetronic acid derivatives.     

N‐Heterocyclic Carbene Catalyzed Enantioselective α‐Fluorination of Aliphatic Aldehydes and α‐Chloro Aldehydes: Synthesis of α‐Fluoro Esters,Amides, and Thioesters

The asymmetric fluorination of azolium enolates that are generated from readily available simple aliphatic aldehydes or α‐chloro aldehydes and N‐heterocyclic carbenes (NHCs) is described. The process significantly expands the synthetic utility of NHC‐catalyzed fluorination and provides facile access to a wide range of α‐fluoro esters, amides, and thioesters with excellent enantioselectivity. Pyrazole was identified as an excellent acyl transfer reagent for catalytic amide formation.