Chiral N-Sulfinyl Imines Research Articles

TBADT-Mediated Photocatalytic Stereoselective Radical Alkylation of Chiral N-Sulfinyl Imines: Towards Efficient Synthesis of Diverse Chiral Amines.

Herein we describe a sustainable and efficient photocatalytic method for the stereoselective radical alkylation of chiral sulfinyl imines. By employing readily available non-prefunctionalized radical precursors and the cost-effective TBADT as a direct HAT photocatalyst, we successfully obtain diverse chiral amines with high yields and excellent diastereoselectivity under mild conditions. This method provides an efficient approach for accessing a diverse array of medicinally relevant compounds, including both natural and synthetic α-amino acids, aryl ethyl amines, and other structural motifs commonly found in approved pharmaceuticals and natural product.

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

One Step Selective Counterion Dependent Formation of Conjugated Chiral N-Sulfinylimines from Aldehydes.

We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach. Aldehyde vinylogation optimizations have revealed significant counterion effects and unexpected competing reaction challenges that needed to be addressed to achieve high yields.

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics.

The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.

Stereoselective Total Syntheses of Solifenacin and N-Acetyl-1-(4-chloro­phenyl)-6,7-dimethoxytetrahydroisoquinoline

A highly stereoselective synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinoline drugs such as solefinacin (muscarinic acetylcholine receptor antagonist) and N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxytetrahydroisoquinoline (AMPA receptor antagonist) has been accomplished using (R)-tert-butanesulfinamide as a chiral source. Chiral tetrahydroisoquinolines have been prepared through the aryl Grignard addition to chiral N-sulfinylimines followed by haloamide cyclization.

A One-Pot Asymmetric Synthesis of Homoallylic Amines via Indium-Mediated Allylation of Hydrazones

Homoallylic amines are an important structural element of natural products and valuable synthetic building blocks in organic syntheses. The nucleophilic addition of organometallic reagents to the C=N bond is a straightforward method for the synthesis of homoallylic amines. However, due to the low reactivity of imines toward nucleophiles, more reactive nucleophiles are required for the addition reaction. Thus, there are some drawbacks to such methods including aza-enolization and competitive formation of side products. Some organometallic reagents such as allylsilanes and allylboronates have been successfully employed for the formation of homoallylic amines. Employing allylindium reagents for the synthesis of homoallylic amines is attractive as indium reagents have low toxicity and low basicity and are stable to moisture and air. Recently, various methodologies for the enantioselective allylation of imines in the presence of chiral ligands have been developed. However, the synthesis of chiral ligands is frequently difficult and requires multi-step synthesis. Diastereoselective allylation of imines bearing a chiral auxiliary is a reliable and efficient method for the synthesis of optically pure homoallylic amines. Several chiral imines have been developed for indium-mediated allylations. Since Loh and co-workers’ report, chiral N-aliphatic imines, which are derived from amino acid derivatives such as (S)-valinol and (R)-phenylglycinol, have been used for diastereoselective allylations. Yus and co-workers developed a method for the synthesis of optically pure homoallylic amines via chiral Nsulfinyl imines. Chiral imines have also been widely employed. Among the chiral imine derivatives, chiral hydrazones are the choice of chiral auxiliary due to advantages that include ease of preparation, high reactivity, and high selectivity. Although (S)-1-amino-2-methoxymethylpyrrolidine and (S)-4-phenylmethyl-oxazolidin-2-one-derived hydrazones have been employed for indium-mediated diastereoselective allylations, these auxiliaries have some drawbacks such as the use of expensive and toxic reagents and multiple steps for their synthesis. Herein, we wish to report a one-pot stereoselective allylation of aldimines bearing an L-proline moiety to afford chiral homoallylic amine derivatives in a highly stereoselective manner. A one-pot asymmetric reaction that involves aldehydes, chiral hydrazides, and an allyindium species is attractive since the reaction is simple and easy to perform as well as being both eco-friendly and rapid. Benzaldehyde was chosen as a model substrate, and Zn(ClO4)2·6H2O was chosen as the catalyst since it is known to be an efficient promoter for the formation of hydrazones. We examined the one-pot allylation with benzaldehyde, a chiral L-proline-derived hydrazide, allyl bromide and indium in the presence of 1 mol % Zn(ClO4)2 in methanol at room temperature. The reaction proceeded smoothly and was complete in 2 h affording 87% of the allylated product with a 60:40 dr (Table 1, entry 1). The reaction rate was much faster than that of the reaction performed without a catalyst (15 h). This result suggests that Zn(ClO4)2·6H2O promotes the formation of hydrazone as well as assists in the allylation of the resulting hydrazone. The same reaction performed using allyl iodide instead of allyl bromide at room temperature gave an 85% chemical yield of the product with no stereoselectivity (entry 3). However, the reaction time was shortened. As the reaction temperature was lowered, the stereoselectivity increased. When performed at −20 C, the reaction was complete in 10 h with high diastereoselectivity (entry 5). Upon changing from methanol, a polar solvent, to nonpolar solvents such as toluene, dichloromethane, or chloroform, the reaction did not proceed at −20 C. With optimized reaction conditions in hand, we investigated the scope of the reaction with various aldehydes. The results are presented in Table 2. The reaction with aromatic aldehydes that were substituted with an electron-donating

Asymmetric Addition of Alkoxy Ethynyl Anion to Chiral N-Sulfinyl Imines

The addition of lithiated ynol ethers to chiral N-sulfinyl imines proceeds in high yield and diastereoselectivity. The selectivity is completely reversed by the addition of boron trifluoride. These alkoxypropargyl sulfinamides can be reduced to afford enol ethers, selectively oxidized to busyl derivatives, or the ynol ether can be hydrolyzed to afford β-amino esters.

Diastereoselective addition of lithium enolate of γ-substituted α-diazoacetoacetate to N-sulfinyl imines

Highly diastereoselective addition of lithium enolate of γ-substituted α-diazoacetoacetate to chiral N-sulfinyl imines has been developed. The addition products were further subjected to photo-induced Wolff rearrangement or Rh(II)-catalyzed intramolecular N-H insertion to afford chiral 4,5-disubstituted 2-oxo and 3-oxo pyrrolidines, respectively.

Stereoselective synthesis of 3-substituted tetrahydroisoquinolines from phthalan and chiral N-sulfinylimines

The reaction of the dianionic intermediate [resulting from the reductive opening of phthalan ( 1) with lithium] with chiral N- tert-butylsulfinyl aldimines 3 in the presence of ZnMe 2 gives, after hydrolysis, N- tert-butylsulfinyl amino alcohols 4 with high diastereoselectivity. Successive treatment of compounds 4 with hydrogen chloride in methanol, thionyl chloride in chloroform and sodium hydroxide yields 3-substituted tetrahydroisoquinolines 6.

Dimethylzinc-Initiated Radical Reactions

Developments in modern organic synthesis owe much to the field of radical chemistry. Mild reaction conditions, high selectivity, good functional group tolerance and high product yield are features that have made reactions involving radical species indispensable tools for synthetic chemists. In part, the discovery of new radical initiators has led to the efficiency that now characterizes most radical reactions. This Account describes our investigations of radical reactions initiated by dimethylzinc. In 2001, we unexpectedly observed this reaction while investigating the amidophosphane-copper-catalyzed asymmetric addition of dimethylzinc to N-sulfonyl imines with tetrahydrofuran (THF) as reaction solvent. However, instead of adding the desired methyl group to the N-sulfonyl imine, we produced the THF adduct in excellent yield. This result laid the foundation for our discovery of novel modes of reactivity. Further investigations of the unexpected addition reaction revealed that a trace amount of air was needed for reaction progress, indicating that radical intermediates were involved. Indeed, controlled injection of air into the reaction flask by a syringe pump through a sodium hydroxide tube afforded the products in good to excellent yield. In addition, the reaction proved to be chemoselective for a C=N bond over a C=O bond, as well as for 1,4-addition over 1,2-addition. We developed asymmetric variants of the radical addition reaction of ethers to imines using chiral N-sulfinyl imines to produce the adducts in reasonably high stereoselectivity (up to 11:1). A 93:7 diastereomeric ratio of the adduct was obtained when bis(8-phenylmenthyl) benzylidenemalonate was used in the radical addition of ethers to C=C bonds. Interestingly, in the presence of dimethylzinc and air, arylamines, alkoxyamines, and dialkylhydrazines react with THF to give amino alcohols, oximes, and hydrazones, respectively, in moderate to high yields. We performed a tin-free intermolecular addition of functionalized primary alkyl groups, generated from their corresponding iodides, to N-sulfonyl imines using dimethylzinc, air, boron trifluoride diethyl etherate, and a catalytic amount of copper(II) triflate. Direct C-H bond cleavage from cycloalkanes was also feasible in the presence of dimethylzinc, air, and boron trifluoride diethyl etherate to give the corresponding cycloalkyl radicals, which were suitable nucleophiles for N-sulfonyl imines. In all of the above reactions, dimethylzinc was a superior radical initiator than other conventional initiators such as dibenzoyl peroxide, diethylzinc, and triethylborane. We hope the coming decades will witness the report of other novel radical initiators that would complement the reactivity modes of existing ones.

Highly Diastereoselective Addition of the Lithium Enolate of α-Diazoacetoacetate to N-Sulfinyl Imines: Enantioselective Synthesis of 2-Oxo and 3-Oxo Pyrrolidines

The highly enantioselective synthesis of 2-oxo and 3-oxo pyrrolidines has been achieved by diastereoselective addition of the lithium enolate of alpha-diazoacetoacetate to chiral N-sulfinyl imines, followed by photoinduced Wolff rearrangement or Rh(II)-catalyzed intramolecular N-H insertion.

Stereoselective Synthesis of β-Substituted β-Amino Sulfones and Sulfonamides via Addition of Sulfonyl Anions to Chiral N-Sulfinyl Imines

[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.

A Lewis Acid Promoted Asymmetric Umpolung Reaction with Chiral N‐Sulfinyl Imines as the Electrophiles.

ChemInformVolume 36, Issue 35 Preparative Organic Chemistry A Lewis Acid Promoted Asymmetric Umpolung Reaction with Chiral N-Sulfinyl Imines as the Electrophiles. Xin Xu, Xin Xu Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorJun-ying Liu, Jun-ying Liu Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorDian-jun Chen, Dian-jun Chen Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorCody Timmons, Cody Timmons Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorGuigen Li, Guigen Li Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this author Xin Xu, Xin Xu Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorJun-ying Liu, Jun-ying Liu Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorDian-jun Chen, Dian-jun Chen Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorCody Timmons, Cody Timmons Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this authorGuigen Li, Guigen Li Dep. Chem. Biochem., Tex. Tech. Univ., Lubbock, TX 79409, USASearch for more papers by this author First published: 02 August 2005 https://doi.org/10.1002/chin.200535034Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume36, Issue35August 30, 2005 RelatedInformation

Synthesis of enantiopure pyrrolidine and piperidine derivatives via ring closing metathesis

The additions of lithiated allylsulfone carbanion to chiral N-sulfinylimines were found to proceed with good to excellent selectivity. The resulting intermediates 4a– d after transformation to dienylamides 7a– d and 16a– d, were converted to functionalized enantiopure piperidines and pyrrolines, respectively, via ring closing metathesis (RCM).

Asymmetric aziridination by reaction of chiral N-sulfinylimines with sulfur ylides: Stereoselectivity improvement by use of tert-butylsulfinyl group as chiral auxiliary

Chiral tert-butylsulfinyl group has been shown to be the chiral auxiliary of choice for the asymmetric aziridination of N-sulfinyliminas. Moreover, the sense of the asymmetric induction can be tuned in two ways: the chirality at the tert-butylsulfinyl Sulfur, or the nature of the methylene transfer reagent used. Thus, both aziridines 10( S s, S) and 10( R s, R), epimeric at C-2, were obtained in enantiomerically pure form by a single crystallisation (75% yield).