Cuprous Oxide Catalyzed Oxidative CC Bond Cleavage for CN Bond Formation: Synthesis of Cyclic Imides from Ketones and Amines

Selective oxidative cleavage of a C? C bond offers a straightforward method to functionalize organic skeletons. Reported herein is the oxidative C? C bond cleavage of ketone for C? N bond formation over a cuprous oxide catalyst with molecular oxygen as the oxidant. A wide range of ketones and amines are converted into cyclic imides with moderate to excellent yields. In‐depth studies show that both α‐C? H and β‐C? H bonds adjacent to the carbonyl groups are indispensable for the C? C bond cleavage. DFT calculations indicate the reaction is initiated with the oxidation of the α‐C? H bond. Amines lower the activation energy of the C? C bond cleavage, and thus promote the reaction. New insight into the C? C bond cleavage mechanism is presented.     

Photoredox‐Catalyzed Reductive Coupling of Aldehydes,Ketones, and Imines with Visible Light

Ketyl radical and amino radical anions, valuable reactive intermediates for C? C bond‐forming reactions, are accessible through a C?O/C?NR umpolung. However, their utilization in catalysis remains largely underdeveloped owing to the high reduction potential of carbonyl compounds and imines. In the context of photoredox catalysis, tertiary amines are commonly employed as sacrificial co‐reducing agents. Herein, an additional role of the amine is proposed, in which it is essential for the organocatalytic substrate activation. The combination of photoredox catalysis and carbonyl/imine activation enables the reductive coupling of aldehydes, ketones, and imines under mild reaction conditions.     

Factors Influencing the Regioselectivity of the Oxidation of Asymmetric Secondary Amines with Singlet Oxygen

Aerobic amine oxidation is an attractive and elegant process for the α functionalization of amines. However, there are still several mechanistic uncertainties, particularly the factors governing the regioselectivity of the oxidation of asymmetric secondary amines and the oxidation rates of mixed primary amines. Herein, it is reported that singlet‐oxygen‐mediated oxidation of 1° and 2° amines is sensitive to the strength of the α‐C?H bond and steric factors. Estimation of the relative bond dissociation energy by natural bond order analysis or by means of one‐bond C?H coupling constants allowed the regioselectivity of secondary amine oxidations to be explained and predicted. In addition, the findings were utilized to synthesize highly regioselective substrates and perform selective amine cross‐couplings to produce imines.     

A pitfall of using 2‐[(2E)‐3‐(4‐tert‐butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile as a matrix in MALDI TOF MS: chemical adduction of matrix to analyte amino groups

2‐[(2E)‐3‐(4‐tert‐Butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile (DCTB) has been considered as an excellent matrix for matrix‐assisted laser desorption/ionization (MALDI) of many types of synthetic compounds. However, it might provide troublesome results for compounds containing aliphatic primary or secondary amino groups. For these compounds, strong extra ion peaks with a mass difference of 184.1 Da were usually observed, which might falsely indicate the presence of some unknown impurities that were not detected by other matrices. On the basis of the possible mechanisms proposed, these extra ions are the products of nucleophilic reactions between analyte amino groups and DCTB molecules or radical cations. In these reactions, an amino group replaces the dicyanomethylene group of DCTB forming a matrix adduct via a ? C?N‐bond. An aliphatic primary amine could react easily with DCTB and the reaction could start once they are mixed in a MALDI solution. For an aliphatic secondary amine, on the other hand, the reaction most likely occurs in the gas phase. Protonation of amino groups by adding acid seems to be a useful way to stop DCTB adduction for compounds with one single amino group, but not for compounds with multiple amino groups. Unlike aliphatic primary or secondary amines, aliphatic tertiary amines and aromatic amines do not yield DCTB adducts. This is because tertiary amines do not have the required transferrable H‐(N) atom to form an extra ? C?N‐bond, while aromatic amines are not sufficiently nucleophilic to attack DCTB. In view of the possible matrix adduction, care should be taken in MALDI time‐of‐flight mass spectrometry (TOF MS) when DCTB is used as the matrix for compounds containing amino group(s). Copyright © 2010 John Wiley & Sons, Ltd.     

Visible‐Light‐Enabled Direct Decarboxylative N‐Alkylation

The development of efficient and selective C?N bond‐forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry owing to the key roles of amines in synthesis, drug discovery, and materials science. Herein, we present a dual catalytic system for the N‐alkylation of diverse aromatic carbocyclic and heterocyclic amines directly with carboxylic acids, by‐passing their preactivation as redox‐active esters. The reaction, which is enabled by visible‐light‐driven, acridine‐catalyzed decarboxylation, provides access to N‐alkylated secondary and tertiary anilines and N‐heterocycles. Additional examples, including double alkylation, the installation of metabolically robust deuterated methyl groups, and tandem ring formation, further demonstrate the potential of the direct decarboxylative alkylation (DDA) reaction.     

Rh‐Catalyzed C?C Cleavage of Benzyl/Allylic Alcohols to Produce Benzyl/Allylic Amines or other Alcohols by Nucleophilic Addition of Intermediate Rhodacycles to Aldehydes and Imines

We report three transformations: 1) direct transformation from biarylmethanols into biarylmethylamines; 2) direct transformation from one biarylmethanol into another biarylmethanol; 3) direct transformation from allylic alcohols into allylic amines. These transformations are based on pyridyl‐directed Rh‐catalyzed C? C bond cleavage of secondary alcohols and subsequent addition to C?X (X=N or O) double bonds. The reaction conditions are simple and no additive is required. The driving force of C? C bond cleavage is the formation of the stable rhodacycle intermediate. Other directing groups, such as the pyrazolyl group, can also be used although it is not as efficient as the pyridyl group. We carried out in‐depth investigations for transformation 1 and found that: 1) the substrate scope was broad and electron‐rich alcohols and electron‐deficient imines are more efficient; 2) as the leaving group, aldehyde had no significant impact on either the C? C bond cleavage or the whole transformation; 3) mechanistic studies (intermediate isolation, in situ NMR spectroscopic studies, competing reactions, isotopic labeling experiments) implied that: i) The C? C cleavage was very efficient under these conditions; ii) there is an equilibrium between the rhodacycle intermediate and the protonated byproduct phenylpyridine; iii) the addition step of the rhodacycle intermediate to imines was slower than the C? C cleavage and the equilibrium between the rhodacycle and phenylpyridine; iv) the whole transformation was a combination of two sequences of C? C cleavage/nucleophilic addition and C? C cleavage/protonation/C? H activation/nucleophilic addition, with the latter being perhaps the main pathway. We also demonstrated the first example of cleavage of an C(alkenyl)? C(benzyl) bond. These transformations showed the exchange (or substitution) of the alcohol group with either an amine or another alcohol group. Like the “group transplant”, this method offers a new concept that can be used to directly synthesize the desired products from other chemicals through reorganization of carbon skeletons.     

Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2‐Dioxides Catalyzed by Cinchona Alkaloid‐based Primary Amines

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2‐dioxides could be successfully carried out utilizing a combination of cinchona alkaloid‐derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89–97 % ee and with various aryl methyl ketones in 85–98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.     

Cuprous Oxide Catalyzed Oxidative C?C Bond Cleavage for C?N Bond Formation: Synthesis of Cyclic Imides from Ketones and Amines

Selective oxidative cleavage of a C C bond offers a straightforward method to functionalize organic skeletons. Reported herein is the oxidative C C bond cleavage of ketone for C N bond formation over a cuprous oxide catalyst with molecular oxygen as the oxidant. A wide range of ketones and amines are converted into cyclic imides with moderate to excellent yields. In‐depth studies show that both α‐C H and β‐C H bonds adjacent to the carbonyl groups are indispensable for the C C bond cleavage. DFT calculations indicate the reaction is initiated with the oxidation of the α‐C H bond. Amines lower the activation energy of the C C bond cleavage, and thus promote the reaction. New insight into the C C bond cleavage mechanism is presented.     

Large steric effect in the substitution reaction of amines with phosphoimidazolide-activated nucleosides

Aliphatic amines react with phosphoimidazolide-activated derivatives of guanosine and cytidine (ImpN) by replacing the imidazole group. The kinetics of reaction of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) with glycine ethyl ester, glycinamide, 2-methoxyethylamine, n-butylamine, morpholine, dimethylamine (Me2NH), ethylmethylamine (EtNHMe), diethylamine (Et2NH), pyrrolidine, and piperidine were determined in water at 37 degrees C. With primary amines, a plot of the logarithm of the rate constant for attack by the amine on the protonated substrate, log kSH(A), versus the pKa of the amine exhibits a good linear correlation with a Bronsted slope, beta nuc = 0.48. Most of the secondary amines tested react with slightly higher reactivity than primary amines of similar pKa. Interestingly, some secondary amines show substantially lower reactivity than might be expected: EtNHMe reacts about eight times, and Et2NH at least 100 times, more slowly than Me2NH although all three amines are of similar basicity. For comparison, the kinetics of reaction of guanosine 5'-phosphoimidazolide (ImpG) and cytidine 5'-phosphoimidazolide (ImpC) were determined with Me2NH, EtNHMe, and Et2NH, and similar results were obtained. These results establish that the increased steric hindrance observed with the successive addition of ethyl groups are not due to any special steric requirements imposed by the guanosine or the methyl on the 2-methylimidazole leaving group of 2-MeImpG. It is concluded that addition of ethyl and, perhaps, groups larger than ethyl dramatically increases the kinetic barrier for addition of aliphatic secondary amines to the P-N bond of ImpN. This study supports the observation that the primary amino groups on the natural polyamines are at least 2 orders of magnitude more reactive than the secondary amino groups in the reaction with ImpN.     

Chromium‐Catalyzed Alkylation of Amines by Alcohols

The alkylation of amines by alcohols is a broadly applicable, sustainable, and selective method for the synthesis of alkyl amines, which are important bulk and fine chemicals, pharmaceuticals, and agrochemicals. We show that Cr complexes can catalyze this C?N bond formation reaction. We synthesized and isolated 35 examples of alkylated amines, including 13 previously undisclosed products, and the use of amino alcohols as alkylating agents was demonstrated. The catalyst tolerates numerous functional groups, including hydrogenation‐sensitive examples. Compared to many other alcohol‐based amine alkylation methods, where a stoichiometric amount of base is required, our Cr‐based catalyst system gives yields higher than 90 % for various alkyl amines with a catalytic amount of base. Our study indicates that Cr complexes can catalyze borrowing hydrogen or hydrogen autotransfer reactions and could thus be an alternative to Fe, Co, and Mn, or noble metals in (de)hydrogenation catalysis.     

Chiral Primary‐Amine‐Catalyzed Conjugate Addition to α‐Substituted Vinyl Ketones/Aldehydes: Divergent Stereocontrol Modes on Enamine Protonation

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α‐chiral carbonyls. We describe herein chiral primary‐amine‐catalyzed conjugate additions of indoles to both α‐substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate‐limiting in iminium formation and they all involve a uniform H₂O/acid‐bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α‐branched acroleins, facial selections on H₂O‐bridged protonation determine the enantioselectivity, which is enhanced by an OH???π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the C? C bond‐formation step, which precedes a highly stereospecific enamine protonation.     

A general nickel-catalyzed hydroamination of 1,3-dienes by alkylamines: catalyst selection, scope, and mechanism

A simple colorimetric assay of various transition-metal catalysts showed that the combination of DPPF, Ni(COD)(2), and acid is a highly active catalyst system for the hydroamination of dienes by alkylamines to form allylic amines. The scope of the reaction is broad; various primary and secondary alkylamines react with 1,3-dienes in the presence of these catalysts. Detailed mechanistic studies revealed the individual steps involved in the catalytic process. These studies uncovered unexpected thermodynamics for the addition of amines to pi-allyl nickel complexes: instead of the thermodynamics favoring the reaction of a nickel allyl with an amine to form an allylic amine, the thermodynamics favored reaction of a nickel(0) complex with allylic amine in the presence of acid to form a Ni(II) allyl. The realization of these thermodynamics led us to the discovery that nickel and some palladium complexes in the presence or absence of acid catalyze the exchange of the amino groups of allylic amines with free amines. This exchange process was used to reveal the relative thermodynamic stabilities of various allylic amines. In addition, this exchange reaction leads to racemization of allylic amines. Therefore, the relative rate for C-N bond formation and cleavage influences the enantioselectivity of diene hydroaminations.     

Nickel(0)‐Catalyzed Hydroalkenylation of Imines with Styrene and Its Derivatives

A nickel(0)‐catalyzed hydroalkenylation of imines with styrene and its derivatives is described. A wide range of aromatic and aliphatic imines directly coupled with styrene and its derivatives, thus providing various synthetically useful allylic amines with up to 95 % yield. The reaction offers a new atom‐ and step‐economical approach to allylic amines by using alkenes instead of alkenyl‐metallic reagents. Experiments and DFT calculations showed that TsNH₂ promotes the proton transfer from the coordinated olefin to the imine, accompanied by a new C?C bond formation.     

Direct Acyl Substitution of Carboxylic Acids: A Chemoselective O‐ to N‐Acyl Migration in the Traceless Staudinger Ligation

A chlorophosphite‐modified, Staudinger‐like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32–97 % yield after a simple aqueous workup without the need for a pre‐activation step. The use of chlorophosphites as dual carboxylic acid–azide activating agents enables the formation of acyl C? N bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described.     

Preparation and characterization of novel hyperbranched poly(amido amine)s from Michael addition polymerizations of trifunctional amines with diacrylamides

Novel hyperbranched poly(amido amine)s containing tertiary amines in the backbones and acryl as terminal groups were synthesized via the Michael addition polymerizations of trifunctional amines with twofold molar diacrylamide. The hyperbranched structures of these poly(amido amine)s were verified by ¹³C NMR (INVGATE). The polymerization mechanisms were clarified by following the polymerization process with NMR method, and the results show that the reactivity of secondary amine formed in situ is much lower than that of the secondary amine in 1‐(2‐aminoethyl) piperazine (AEPZ) ring and the primary amine. The secondary amine formed in situ was almost kept out of the reaction before the primary and secondary amines in AEPZ were consumed, leading to the formation of the AB2 intermediate, and the further reaction of the AB2 yielded the hyperbranched polymers. The molecular weights and properties of poly(amindo amine)s obtained were characterized by GPC, DSC, and TGA, respectively. Based on the reaction of active acryl groups in the polymers obtained with glucosamine, hyperbranched polymers containing sugar were formed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5127–5137, 2005     

Efficient,Simple Preparation of 1,3‐Diamine Derivatives through Addition of Acrylamides with Secondary Amines

Abstract

Reaction of acrylamides with secondary amines results in the formation of β‐amino‐propionamide through the addition reaction of N–H bond of amines across the double bond of acrylamides in the good to excellent yield. The structure of 2‐methyl‐3‐(1‐piperidinyl)‐propionamide has been determined by X‐ray analysis.     

Direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by chiral amines

Chiral amines such as (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine and the C(2)-symmetric (2S,5S)-2,5-diphenylpyrrolidine can catalyze the direct enantioselective Michael addition of simple aldehydes to vinyl ketones. The conditions for this organocatalytic reaction have been optimized and it has been found that the chiral amines catalyze the formation of optically active substituted 5-keto aldehydes in good yields and enantioselectivities, using aldehydes and, e.g., methyl vinyl ketone as starting compounds. Taking into account that the chiral amine can activate the aldehyde and/or the enone, the mechanism for the reaction has been investigated. On the basis of intermediate synthesis, nonlinear effect, and theoretical investigations, the mechanism for the catalytic direct enantioselective Michael addition of aldehydes to vinyl ketones is discussed.     

Synthesis of functionalized amine oligomers by free‐radical telomerization of methyl methacrylate with a peculiar telogen: 2‐Aminoethanethiol hydrochloride

The Telomerization of methyl methacrylate with 2‐aminoethanethiol hydrochloride initiated by 2,2′‐azobisisobutyronitrile, was investigated in dimethylformamide (DMF). First, the peculiar behavior of 2‐aminoethanethiol was highlighted because it behaves as a peculiar transfer agent; this is because its transfer constant (C_T) is weak compared with that of other thiols. The presence of the amine function greatly disturbs the free radical telomerization reaction. Telomerization was performed in the presence of hydrochloric acid (HCl) to protect the amine group. The transfer constant was strongly influenced by the acid and water concentration. This work emphasized that the nature of the solvent plays an important role in the determination of the transfer constant. Thus, the value of C_T increased from 0.23 in DMF to 0.56 in the HCl/DMF mixture. The primary and secondary amines were recovered after the reaction. The functionality of the primary and secondary amines was measured by titration. The influence of the concentration of HCl on the resulting amine functionality was investigated. The acid presence prevents the formation of secondary amines, arising from Michael's reaction, on methyl methacrylate. Finally, these results were applied to the synthesis of amine‐functionalized telomers with molecular masses of 2000 to 15,000 g/mol. The amine function was correlated with the decrease of R₀ ([telogen]/[monomer]). © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5146–5160, 2004     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

Reductive Molybdenum‐Catalyzed Direct Amination of Boronic Acids with Nitro Compounds

The synthesis of aromatic amines is of utmost importance in a wide range of chemical contexts. We report a direct amination of boronic acids with nitro compounds to yield (hetero)aryl amines. The novel combination of a dioxomolybdenum(VI) catalyst and triphenylphosphine as inexpensive reductant has revealed to be decisive to achieve this new C?N coupling. Our methodology has proven to be scalable, air and moisture tolerant, highly chemoselective and engages both aliphatic and aromatic nitro compounds. Moreover, this general and step‐economical synthesis of aromatic secondary amines showcases orthogonality to other aromatic amine syntheses as it tolerates aryl halides and carbonyl compounds.