Asymmetric synthesis of diverse α,α-diarylmethylamines via aryl Grignard additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines

A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethylamines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in high yields and high diastereoselectivities. Higher stereoselectivity was obtained for most of the examples studied when the reactions are performed at ambient temperature as compared to cryogenic conditions. N-2,4,6-Triisopropylbenzenesulfinamide was shown to be the optimal chiral auxiliary as it provided higher diastereoselectivities when compared to the more commonly employed tert-butanesulfinamide or p-toluenesulfinamide in the synthesis of diarylmethylamine synthons. A rationale for the improved selectivity derived from the triisopropylbenzyl auxiliary is presented.     

Regio- and diastereoselective conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds derived from Oppolzer's sultam

Asymmetric conjugate addition of Grignard reagents to aryl substituted α,β-unsaturated carbonyl compounds (1) has been achieved with great regioselectivity (>20:1) and good to excellent diastereoselectivity (de up to 98%). The nucleophilicity and stereospecific blockade of the Grignard reagents play a key role in controlling the regioselectivities and diastereoselectivities of the conjugate addition reaction.     

Highly enantioselective Cu(I)-Tol-BINAP-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-unsaturated esters

The copper-catalyzed conjugate addition (CA) of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the most versatile synthetic methods for the construction of C-C bonds. Interestingly, the application of Grignard reagents, which are among the most widely used of organometallic compounds, in asymmetric conjugate addition (CA) reactions has received less attention. Therefore, our group and others have been exploring better catalytic systems to effect the asymmetric 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters. It is only in the past decade that significant breakthroughs have been made in this field. In our studies, we found that CuI-Tol-BINAP could catalyze the asymmetric conjugate addition (CA) reactions of Grignard reagents, including the addition of MeMgBr to α,β-unsaturated esters to afford the β-methylated esters in good yields with excellent regio- and enantioselectivities. Both enantiomers of the products could be obtained by either using the enantiomers of the chiral Tol-BINAP or by using the geometrical isomer of the starting material. This method is also suitable for other Michael acceptors. In this article, we describe the development of the asymmetric Cu(I)-Tol-BINAP catalyzed 1,4-conjugate addition of Grignard reagents to α,β-unsaturated esters and applications of this chemistry. This method provides a convenient method to synthesize β-alkyl esters with high enantioselectivity or diastereoselectivity using CuI and the inexpensive chiral ligand, Tol-BINAP.     

Synthesis of chiral sulfinyl-substituted 1-indolyl enones and asymmetric conjugate addition by an arylcopper reagent

The asymmetric conjugate addition of arylcopper reagents to chiral 1-[2-(p-tolylsulfinyl)]indolyl and 1-[3-(p-tolylsulfinyl)]indolyl enones was examined. With the 2-sulfinyl-indolyl derivatives, the reaction of the arylcopper reagent gave high diastereoselectivities (81-88% de's) to afford the adducts in excellent yields, although the similar addition reaction of the 3-sulfinyl derivatives afforded poor diastereoselectivities.     

Catalytic asymmetric conjugate addition of Grignard reagents to coumarins--synthesis of versatile chiral building blocks

A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible.     

Copper-catalyzed asymmetric conjugate addition with Grignard reagents and SimplePhos ligands

Herein we report the copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic and acyclic enones, with SimplePhos as chiral ligands. A variety of Grignard reagents can be added to a range of cyclic and acyclic enones, with moderate to good enantioselectivities (ee’s up to 86%).     

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones. Construction of all-carbon quaternary chiral centers

The copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted cyclic enones affords enantioenriched all-carbon quaternary centers with up to 96% ee. The chiral ligand is a diaminocarbene, directly generated in situ. The combination of Grignard reagent and diaminocarbene is unprecedented in conjugate addition, and the additon of the phenyl group, on such enones, cannot be done by other conjugate addition methods.     

Addition of indolyl and pyrrolyl grignard reagents to 1-acylpyridinium salts

Certain indolyl and pyrrolyl Grignard reagents add to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine to give the corresponding 1-acyl-2-heteroaryl-2,3-dihydro-4-pyridones in good to high yield. When the 1-acyl group contained a chiral auxiliary, (+/-)-trans-2-(alpha-cumyl)cyclohexyloxy, addition of the indolyl Grignards resulted in a separable mixture of diastereomeric 2,3-dihydro-4-pyridones.     

Conjugate addition of grignard reagents to N-(α,β-unsaturated)acylpyrazoles. Diastereoselective β-alkylation using 3-phenyl-l-menthopyrazole

The conjugate additions of N-(α,β-unsaturated)acylpyrazoles were carried out by the treatment with Grignard reagents in the presence of cuprous halides. The reaction of 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3a-h occurred in higher chemical yields and with asymmetric inductions on β-position, where the addition of magnesium bromide as a Lewis acid influenced to the yields and the diastereoselectivities. In the case of α-methylated 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3i-n , the excellent asymmetric induction on the α-position was also observed through the diastereofacial protonation.     

Asymmetric addition reactions of Grignard reagents to chiral 2-trifluoromethyl tert-butyl (Ellman) sulfinimine-ethanol adducts

The addition of Grignard reagents to chiral trifluoromethyl tert-butyl sulfinimine-ethanol adducts affords protected trifluoromethylamines in high yields with good to excellent diastereoselectivities. The stereochemical outcome of the addition is opposite to that expected via a chelation controlled transition state.     

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.     

手性助剂控制的不对称Michael加成立体选择性研究

手性助剂控制的不对称反应是不对称合成的主要方法之一.采用不同空间位阻Evans手性助剂对呋喃基丙烯酸进行立体选择性控制,通过不同空间位阻的格氏试剂对Michael受体1进行不对称1,4-Michael加成反应研究,合成了一系列新的Michael加成产物2a～2h.研究结果表明手性助剂及格氏试剂的空间位阻是影响反应立体选择性的主要因素.当手性助剂及格氏试剂的取代基为芳基时,产物的de值都大于95%,而取代基为烷基、苄基及脂环基时,产物的de值则低于70%.     

(S,S)-(+)-pseudoephedrine alpha-iminoglyoxylamide as a chiral glycine cation equivalent: a modular and flexible approach to enantioenriched alpha-amino ketones

We have studied the ability of an alpha-imino glyoxylamide derived from (S, S)-(+)-pseudoephedrine as a valuable chiral electrophile for the preparation of alpha-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile afforded the expected alpha-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into enantioenriched alpha-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl group with organolithium reagents.     

Grignard试剂与α-肉桂酰基环二硫缩烯酮的区域选择性加成反 应

乙基、丙基、丁基、苯基和苄基卤化镁等Grignard试剂与具有三个亲电中心的α-肉桂酰基环二硫缩烯酮类化合物2反应,加成反应发生在2中与芳基相邻的碳原子上,生成共轭加成产物3,反应具区域选择性。     

Regioselective arylation of 3-bromopyridine

The addition of aryl Grignard reagents to the 1-phenoxycarbonyl salt of 3-bromopyridine affords 2-aryl-5-bromo-1-phenoxycarbonyl-1,2-dihydropyridines and 4-aryl-3-bromo-1-phenoxycarbonyl-1,4-dihydropyridines. The crude dihydropyridines were aromatized with o-chloranil in refluxing toluene to give 4- and 6-aryl-3-bromopyridines. The regioselectivity of this two-step process, 6- vs. 4-substitution, was examined and found to be dependent upon the structure of the Grignard reagent. Unhindered aryl Grignard reagents, e.g., phenyl and 2-naphthyl, gave mainly 6-aryl-3-bromopyridines (49-52%) along with 9% of the 4-substituted isomer and less than 4% of the 2-aryl-3-bromopyridine. Hindered aryl Grignard reagents, e.g., o-tolyl and 1-naphthyl, are less regioselective. When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4-addition results. The crude 4-aryl-3-bromo-1,4-dihydropyridines were aromatized with p-chloranil to provide 4-aryl-3-bromopyridines in good yield and high isomeric purity. The sequential use of the cuprous iodide-catalyzed Grignard reaction and the “normal” Grignard reaction provided a regiospeci-fic synthesis of 3-bromo-6-(p-methoxyphenyl)-4-phenylpyridine from 3-bromopyridine.     

Copper catalyzed asymmetric synthesis of chiral allylic esters

The complex derived from Taniaphos ligand 4 and CuBr*Me2S catalyzes the asymmetric addition of Grignard reagents to 3-bromopropenyl esters 1 to provide allylic esters 2 in high yields and high chemio-, regio-, and enantioselectivities. The work demonstrates that allylic asymmetric alkylation (AAA) can be done on substrates bearing a heteroatom at the gamma-position. The method is a practical route to chiral, nonracemic allylic alcohols. The use of functionalized substrates 1 or Grignard reagents leads to more complex products 2, which can be further manipulated as demonstrated in conversion to (S)-5-ethyl-2(5H)-furanone 6 and (S)-benzoic acid-cyclopent-2-enyl ester 7.     

C(2) symmetric chiral NHC ligand for asymmetric quaternary carbon constructing copper-catalyzed conjugate addition of grignard reagents to 3-substituted cyclohexenones

The asymmetric construction of quaternary carbon centers by conjugate addition of Grignard reagents to 3-methyl- and 3-ethylcyclohexenones was realized in a maximum enantioselectivity of 80% by using a C 2 symmetric chiral N-heterocyclic carbene (NHC)-copper catalyst, generated from (4 S,5 S)-1,3-bis(2-methoxyphenyl)-4,5-diphenyl-4,5-dihydro-1 H-imidazol-3-ium tetrafluoroborate and copper(II) triflate. The stereostructures of the NHC-Au complexes were analyzed by X-ray crystallography, which rationalized the good stereocontrolling ability of N-aryl NHCs.     

Highly diastereoselective conjugate additions of monoorganocopper reagents to chiral imides

Stereoselective conjugate additions to chiral N-enoyl amides employing various monoorganocuprate reagents, Li[RCuI], are described. The presence of TMSI in the addition of Li[RCuI] in THF provided the highest stereoselectivities. Reversed major diastereomeric ratios were obtained employing Li[RCuI] in ether or conventional copper-promoted Grignard reagents. The results presented support the favored anti-s-cis conformation of the substrates using Li[RCuI]/TMSI in THF, while the copper-promoted Grignard reagents or the Li[RCuI] reagents in ether favor the opposite syn-s-cis conformation. Influence of lithium ions on the stereoselective conjugate addition of the monoorganocuprate reagent, Li[BuCuI], has been investigated and two different mechanistic pathways are presented. The results show that iodotrimethylsilane (TMSI) is crucial for the asymmetric conjugate addition of the copper reagent, but only in THF or when 12-crown-4 is used. The reaction is thought not to involve any halosilane in any critical steps in the organocopper mechanisms conducted in ether. The (CuI)₄(SMe₂)₃ complex precursor plays an instrumental role for the conjugate addition using monoorganocopper reagents.     

Addition of grignard reagents to aryl acid chlorides: an efficient synthesis of aryl ketones

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.     

Enantioselective one-pot conjugate addition of grignard reagents to cyclic enones followed by amidomethylation

Enantioselective conjugate addition of Grignard reagents to enones, catalyzed by Cu-Taniaphos or Josiphos complex, affords chiral enolates. Ensuing one-pot Mannich reaction with TiCl(4)-generated imine leads to aminocarbonyl compounds with benzyloxycarbonyl-protected nitrogen. Both diastereomers of these compounds are isolated in moderate yields but high enantiomeric purities (up to er 97.5:2.5).