Allylic Amine Products Research Articles

Fe-Catalyzed C-H Alkenylation of Dialkyl Anilines with Disulfonylethenes.

The oxidative alkenylation reaction of α-aminoalkyl C(sp3)-H bonds has been investigated with (E)-1,2-bis(sulfonyl)ethenes. The catalytic process of iron-polypyridyl complexes drives the single-electron oxidation of dialkyl anilines, resulting in the formation of α-aminoalkyl radical species. Subsequent cascades of radical addition and elimination reactions ensue, ultimately leading to the generation of sulfonylated allylic amine products. The utility of these products extends further, enabling the synthesis of multisubstituted heterocycles like pyrroles, pyrazines, and triazoles.

Mechanistic Investigation of Zirconium-Catalyzed Hydroaminoalkylation of Alkynes: Substrate and Ligand Effects

The mechanism of zirconium-catalyzed hydroaminoalkylation of diphenylacetylene, and the origin of the contrasting reactivity with N-benzylaniline or N-(trimethylsilyl)benzylamine substrates, have been investigated. Isolated intermediates have revealed that the nature of the C–H activation and C–C bond-forming steps in alkyne hydroaminoalkylation are analogous to those of the alkene variant, regardless of the amine substrate. In the zirconium-catalyzed hydroaminoalkylation of alkynes, the open coordination sphere at the zirconium center, supported by the bis(ureate) ligand, enables the coordination of neutral protic donors. This is essential for promoting catalytic turnover in these reactions. Under catalytic conditions, dimethylamine acts as a proton source for releasing the allylic amine products while minimizing the formation of side products. Additionally, we identified the formation of a homoleptic tetra(ureate) zirconium complex as the main catalyst decomposition pathway in catalytic alkyne hydroaminoalkylation. The formation of similar homoleptic structures is further favored when employing smaller bis(urea) proligands, thus explaining the poor performance of some ligands in catalysis. However, further increasing the bis(urea) proligand size to minimize such catalyst decomposition favors isomerization side-products resulting in reduced yields of the desired product. This study provides ligand design principles that guide the development of coordinatively flexible catalysts to achieve catalytic turnover in systems that rely upon protonolysis steps, as in hydroaminoalkylation.

Titanium‐Catalyzed Intermolecular Hydroaminoalkylation of Allenes and Methylenecyclopropanes

AbstractIntermolecular hydroaminoalkylation reactions of 1,1‐ and 1,3‐disubstituted allenes as well as methylenecyclopropanes with secondary amines can be achieved in the presence of a 2,6‐bis(phenylamino)pyridinato titanium catalyst at 140 °C within 2–8 h. Corresponding reactions of allenes with N‐benzylanilines deliver branched allylamine products in very good yields (up to 83 %) and with branched‐linear‐ratios between 75 : 25 and 95 : 5. In contrast, bicyclic methylenecyclopropanes undergo hydroaminoalkylation with N‐benzylanilines or N‐alkylbenzylamines to give linear products in good to excellent yields (up to 98 %) with perfect regio‐ and diastereoselectivity. The corresponding 1,2,3‐trisubstituted (2‐aminoethyl)cyclopropane products exhibit a structurally interesting cis‐orientation of all three cyclopropane hydrogen atoms.

Pd(0)-Catalyzed Intramolecular Reductive Heck Reaction of Vinyl Iodide and Oxime Ether: Enantioselective Synthesis of Cyclic Allylic N-Alkoxy Amine.

Whereas the intramolecular reductive Heck reaction of aryl/vinyl halide and alkene has been well documented, the oxime analogue remains extremely elusive. Herein we report the Pd(0)-catalyzed intramolecular reductive Heck reaction of vinyl iodide and oxime ether with the use of formic acid as the reductant. It is found that the TsOH additive plays a crucial role in the reaction efficiency, and the (S)-SEGPhos ligand enables cyclic allylic N-alkoxy amine products with high enantioselectivity.

Electrochemical Synthesis of Allylic Amines from Terminal Alkenes and Secondary Amines

Allylic amines are valuable synthetic targets en route to diverse biologically active amine products. Current allylic C-H amination strategies remain limited with respect to the viable N-substituents. Herein, we disclose a new electrochemical process to prepare aliphatic allylic amines by coupling two abundant starting materials: secondary amines and unactivated alkenes. This oxidative transformation proceeds via electrochemical generation of an electrophilic adduct between thianthrene and the alkene substrates. Treatment of these adducts with aliphatic amine nucleophiles and base provides allylic amine products in high yield. This synthetic strategy is also amenable to functionalization of feedstock gaseous alkenes at 1 atm. In the case of 1-butene, high Z-selective crotylation is observed. This strategy, however, is not limited to the synthesis of simple building blocks; complex biologically active molecules are suitable as both alkene and amine coupling partners. Preliminary mechanistic studies implicate vinylthianthrenium salts as key reactive intermediates.

Hydrogen bonding and non-covalent interaction assisted nickel(0) catalysed reversible alkenyl functional group swapping: a computational study

An extensive DFT study is carried out to explore the mechanistic pathways involved in nickel(0) catalysed functional group swapping, where the less substituted N-tosyl allylamine transforms into a more substituted N-tosyl allylamine product.

Pd-Catalyzed Stereodivergent Allylic Amination of α-Tertiary Allylic Alcohols towards α,β-Unsaturated γ-Amino Acids.

Tertiary allylic alcohols were conveniently converted into either (Z)- or (E)-configured α,β-unsaturated γ-amino acids by treatment with secondary amines under Pd catalysis at ambient conditions. The key to control the stereochemical course of these formal allylic aminations was the presence of a suitable diphosphine ligand, with dppp [1,3-bis(diphenylphosphino)propane, L12] providing high yields and selectivities for the (Z) isomers, whereas the bis[(2-diphenylphosphino)phenyl]ether (DPEPhos) derivative L1' allowed for selective formation of the corresponding (E) isomeric products. This ligand-controlled, stereodivergent protocol thus shows promise for the stereoselective preparation of allylic amine products from a common substrate precursor.

Asymmetric Allylic Amination of Morita–Baylis–Hillman Adducts with Simple Aromatic Amines by Nucleophilic Amine Catalysis

Asymmetric allylic amination of Morita–Baylis–Hillman (MBH) adducts with simple aromatic amines is successfully realized by nucleophilic amine catalysis. A range of substituted α-methylene-β-arylamino esters is accessed in moderate to high yields (up to 88%) and with excellent enantioselectivities (up to 97% ee). Inorganic fluorides are found to be able to improve the enantioselectivity of the allylic amination reaction. A pyrrole-2-carboxylate and a cyclic imide are also compatible with this catalytic system. A chiral 2,3-dihydroquinolin-4-one derivative is easily obtained from the allylic amination product.

Iridium-Catalyzed Isomerization of N-Sulfonyl Aziridines to Allyl Amines.

The Crabtree's reagent catalyzes the isomerization of N-sulfonyl 2,2-disubstituted aziridines to allyl amines. The selectivity of allyl amine vs imine is very high (up to 99/1). The unprecedented isomerization takes place in mild conditions without activation of the catalyst by hydrogen. The mechanism has been studied computationally by DFT calculations; instead of the usual hydrogenation of COD, the catalytic species is formed by a loss of the pyridine ligand. Approaching of aziridine to this unsaturated species leads to a carbocation intermediate through a low energy barrier. A metal-mediated tautomerization involving sequentially γ-H elimination and N-H reductive elimination affords selectively the allyl amine. The readiness of the CγH bond to participate in the H elimination step accounts for the selectivity toward the allyl amine product.

Ni(II)-catalyzed asymmetric alkenylations of ketimines

Chiral allylic amines are not only present in many bioactive compounds, but can also be readily transformed to other chiral amines. Therefore, the asymmetric synthesis of chiral allylic amines is highly desired. Herein, we report two types of Ni(II)-catalyzed asymmetric alkenylation of cyclic ketimines for the preparation of chiral allylic amines. When ketimines bear alkyl or alkoxycarbonyl groups, the alkenylation gives five- and six-membered cyclic α-tertiary allylic amine products with excellent yields and enantioselectivities under mild reaction conditions. A variety of ketimines can be used and the method tolerates some variation in alkenylboronic acid scope. Furthermore, with alkenyl five-membered ketimine substrates, an alkenylation/rearrangement reaction occurs, providing seven-membered chiral sulfamide products bearing a conjugated diene skeleton with excellent yields and enantioselectivities. Mechanistic studies reveal that the ring expansion step is a stereospecific site-selective process, which can be catalyzed by acid (Lewis acid or Brønsted acid).

Stereoselective and Versatile Preparation of Tri- and Tetrasubstituted Allylic Amine Scaffolds under Mild Conditions.

Significant progress has been observed in recent years in the synthesis of allylic amines, which are important building blocks in synthetic chemistry. Most of these processes are effective toward the preparation of allylic amines, with limited potential to introduce three or four different substituents on the olefinic unit in a stereocontrolled fashion. Therefore, the discovery of a mild and operationally simple protocol allowing such challenging stereoselective synthesis of multisubstituted allylic amines remains an inspiring target. Herein, we report the first general and practical methodology for the stereoselective synthesis of tri- and tetrasubstituted allylic amines based on Pd-catalyzed conversion of allyl surrogates readily obtained from cyclic vinyl carbonates. These rare conversions are characterized by excellent stereoselectivity, operational simplicity, mild reaction conditions, and wide scope in reaction partners. DFT studies were performed to rationalize the stereocontrol in these allylic amine formation reactions, and evidence is provided that the formation of a six-membered palladacyclic intermediate leads toward the formation of (Z)-configured allylic amine products.

DFT Rationalization of the Diverse Outcomes of the Iodine(III)-Mediated Oxidative Amination of Alkenes.

A computational study of the mechanism for the iodine(III)-mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO2 Me)2 )2 and three different representative substrates: styrene, α-methylstyrene, and (E)-methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO2 Me)2 )(+) unit on the double bond, and formation of an intermediate with a single C-I bond and a planar sp(2) carbocationic center. The major path, leading to 1,2-diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behavior is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C-H position in the common intermediate. The regioselectivity of this amination depends on the availability of the resonant structures of an alternate carbocationic intermediate. Only in cases where a high electronic delocalization is possible, as in (E)-methylstilbene, does the allylic amination occur without migration of the double bond.

Facile Generation and Isolation of π-Allyl Complexes from Aliphatic Alkenes and an Electron-Deficient Rh(III) Complex: Key Intermediates of Allylic C–H Functionalization

It has been established that a strongly electrophilic η5-cyclopentadienylrhodium complex, [CpERhCl2]2, is capable of reacting with aliphatic alkenes in the presence of a silver salt and cesium acetate at room temperature to give the corresponding π-allyl complexes in high yields. The use of an alkenyltosylamide as the alkene also afforded the corresponding π-allyl complex. Treatment of the thus obtained π-allyl complex with a silver(I) salt and copper(II) acetate afforded the allylic amination product, which proves the intermediacy of this π-allyl complex in the rhodium(III)-catalyzed intramolecular oxidative allylic amination.

Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates.

Azidoformates are interesting potential nitrene precursors, but their direct photochemical activation can result in competitive formation of aziridination and allylic amination products. Herein, we show that visible-light-activated transition-metal complexes can be triplet sensitizers that selectively produce aziridines through the spin-selective photogeneration of triplet nitrenes from azidoformates. This approach enables the aziridination of a wide range of alkenes and the formal oxyamination of enol ethers using the alkene as the limiting reagent. Preparative-scale aziridinations can be easily achieved under continuous-flow conditions.

Spin‐Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible‐Light Photosensitization of Azidoformates

AbstractAzidoformates are interesting potential nitrene precursors, but their direct photochemical activation can result in competitive formation of aziridination and allylic amination products. Herein, we show that visible‐light‐activated transition‐metal complexes can be triplet sensitizers that selectively produce aziridines through the spin‐selective photogeneration of triplet nitrenes from azidoformates. This approach enables the aziridination of a wide range of alkenes and the formal oxyamination of enol ethers using the alkene as the limiting reagent. Preparative‐scale aziridinations can be easily achieved under continuous‐flow conditions.

Palladium‐Catalyzed Regioselective and Stereoselective Oxidative Heck Arylation of Allylamines with Arylboronic Acids

AbstractA general and convenient palladium‐catalyzed oxidative Heck arylation of both N‐protected and N,N‐diprotected allylic amines with arylboronic acids under mild conditions has been developed. The catalyst system, consisting of Pd(OAc)2 (palladium acetate), AgOAc (silver acetate) and KHF2 (potassium hydrogen fluoride), could efficiently catalyze the coupling reaction in acetone without the aid of any ligand, leading exclusively to the γ‐arylated allylic amine products in good to excellent yields. This method is highlighted with excellent regio‐ and stereocontrol and remarkable functional group tolerance. The carbamate moiety in allylic amine substrates is of crucial importance to the catalytic performance, and the chelation between the carbonyl O (oxygen) and Pd (palladium) atoms is believed to be responsible for the high regioselectivity and stereoselectivity observed.

Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines

The palladium complex [(3IPtBu)Pd(allyl)]OTf previously displayed excellent catalytic activity for the hydroamination of 1,1-dimethylallene with anilines, selectively producing the branched substituted allylamine product (kinetic product) in high conversion. In the current report, the scope of this hydroamination reaction has been expanded to include both alkyl amines and anilines in combination with an array of seven alkyl and aryl allenes. For the majority of amines investigated, the hydroamination of 1,1-dimethylallene, cyclohexylallene, benzylallene, and select aryl allenes with alkyl amines gave the branched substituted allylamine product in nearly quantitative conversion at ambient temperature in less than 1 hour. In contrast, anilines displayed a more limited reaction scope and yielded the linear hydroamination product (thermodynamic product) with all allenes other than 1,1-dimethylallene. Both branched and linear products could be formed selectively in the hydroamination of p-fluorophenylallene with alkyl amines through careful control of [(3IPtBu)Pd(allyl)]OTf catalyst loading and reaction duration. Overall, the branched allylamines produced are useful synthetic intermediates due to their available unsaturated vinyl group, while the linear allylamine products are chemically similar to a class of known pharmaceuticals.

A Stable Route to Selectivity

Chemistry In general, the purpose of catalysis is to speed up reactions that otherwise proceed too slowly. Asymmetric catalysis is something of a special case though: When the catalyst's role is to bias a reaction toward one particular product isomer, problems arise if the background reaction is too fast on its own. This circumstance limited a prospectively promising route to chiral allylic amines. Specifically, decades-old chemistry established that adducts of terminal olefins and imido-sulfur compounds quickly rearrange to form carbon-nitrogen bonds. Bao and Tambar realized that stabilization of such adducts could slow down the bond-forming event sufficiently for a catalyst to dictate stereoselectivity. Benzenesulfonyl sulfurdiimide proved the optimal reagent, affording an adduct so slow to rearrange that it persisted for days below 0°C. The authors could then introduce a palladium catalyst coordinated by a chiral ligand to coax the adducts toward allylic amine products with enantioselectivities exceeding 90%. The reaction tolerated electrophilic substituents on the olefin framework, such as aldehydes, nitriles, and halides. J. Am. Chem. Soc. 134 , 10.1021/ja307851b (2012).

ChemInform Abstract: Cinchona Alkaloid Catalyzed Regio‐ and Enantioselective Allylic Amination of Morita—Baylis—Hillman Carbonates with Isatins.

AbstractThe allylic amination products are obtained with good yields and enantioselectivities using (DHQD)2‐PHAL as a catalyst.

Cinchona Alkaloid Catalyzed Regio‐ and Enantioselective Allylic Amination of Morita–Baylis–Hillman Carbonates with Isatins

AbstractAn efficient enantioselective allylic amination of Morita–Baylis–Hillman (MBH) carbonates derived from methyl acrylate and aromatic aldehydes with isatins has been realized in the presence of commercially available cinchona alkaloids. The allylic amination products were obtained in moderate‐to‐good yields (46–74 %) with moderate‐to‐good enantioselectivities (up to 89 % ee) under mild conditions. The synthetic utility of the amination products has been well demonstrated by the facile synthesis of methyl (3R,4R)‐10‐oxo‐4‐phenyl‐2,3,4,10‐tetrahydropyrimido[1,2‐a]indole‐3‐carboxylate.