Kinetics of H· Transfer from CpCr(CO)3H to Various Enamides: Application to Construction of Pyrrolidines.

The rate constants kH (kD) have been determined at 27 °C for H· (D·) transfer from CpCr(CO)3H(D) to the C=C bonds of various enamides. This process leads to the formation of α-amino radicals. Vinyl enamides with N-alkyl and N-phenyl substituents have proven to be good H· acceptors, with rate constants close to those of styrene and methyl methacrylate. A methyl substituent on the incipient radical site decreases kH by a factor of 4; a methyl substituent on the carbon that will receive the H· decreases kH by a factor of 380. The measured kH values indicate that these α-amino radicals can be used for the cyclization of enamides to pyrrolidines. A vanadium hydride, HV(CO)4(dppe), has proven more effective at the cyclization of enamides than Cr or Co hydrides-presumably because the weakness of the V-H bond leads to faster H· transfer. The use of the vanadium hydride is operationally simple, employs mild reaction conditions, and has a broad substrate scope. Calculations have confirmed that H· transfer is the slowest step in these cyclization reactions.

[(NHC)PdCl2(Aniline)] Complexes: Easily Synthesized, Highly Active Pd(II)-NHC Precatalysts for Cross-Coupling Reactions.

We report the synthesis, characterization, and reactivity of [(NHC)PdCl2(aniline)] complexes. These well-defined, air- and moisture-stable catalysts are highly active in the Suzuki-Miyaura cross-coupling of amides by N-C(O) activation as well as in the Suzuki-Miyaura cross-coupling of esters, aryl chlorides, and Buchwald-Hartwig amination. Most crucially, this study introduces broadly available anilines as stabilizing ligands for well-defined Pd(II)-NHC catalysts. The availability of various aniline scaffolds, including structural and electronic diversity, has a significant potential in fine-tuning of challenging cross-couplings by Pd-NHCs. The parent catalyst in this class, [Pd(IPr)(AN)Cl2], has been commercialized in collaboration with Millipore Sigma, offering broad access for reaction screening and optimization.

Generation of α-Boryl Radicals by H. Transfer and their Use in Cycloisomerizations.

Carbon-centered radicals can be stabilized by delocalization of their spin density into the vacant p orbital of a boron substituent. α-Vinyl boronates, in particular pinacol (Bpin) derivatives, are excellent hydrogen atom acceptors. Under H2 , in the presence of a cobaloxime catalyst, they generate α-boryl radicals; these species can undergo 5-exo radical cyclizations if appropriate double bond acceptors are present, leading to densely functionalized heterocycles with tertiary substituents on Bpin. The reaction shows good functional group tolerance with wide scope, and the resulting boronate products can be converted into other useful functionalities.

A Survey of Smallholder Farms Regarding Demographics, Health Care, and Management Factors of Donkeys in Northeastern China.

Essential information on the population dynamics and the health and welfare of Chinese donkeys is scarce. The objectives of this study were to describe the demographic characteristics, management and health care of a sample of donkeys under smallholder farm conditions of northeastern China. A cross-sectional survey of 731 randomly selected donkey owners on smallholder farms (1,658 donkeys) in 40 villages of northeastern China was conducted. Data on the composition and management of the donkeys and their routine health care were analyzed. The surveyed donkey population consisted of mostly (83.8%) jenny/filly donkeys with a mean age of 6.2 ± 5.0 years. Most (91.2%) of the farms kept 1-4 donkeys. The majority of donkeys were used for breeding and labor. Most (93.8%) of the farms did not have bedding, and their mean stable size was 17.7 ± 10.1 m2. All of the animals were turned out for at least part of the year. The mean size of the turnout areas on the farms was 17.8 m2. The condition of 12.5% of the donkeys was evaluated as "poor" with a body condition score of 1 on a scale of 5. More than one third (37.9%) of the donkeys had never been dewormed. Also, none of them were ever vaccinated or received dental care from a veterinarian. Their hoofs were trimmed once (45.9%) or twice (27.6%) a year. Forty percent of the donkeys were reported to suffer from at least one medical problem in the preceding year. The most common medical problems were colic, respiratory disorders and skin conditions. Owners seemed to underestimate some of the most prevalent diseases in donkeys, suggesting that their knowledge of the management of donkeys, including routine healthcare practices should be improved to ensure the health and welfare of donkeys in northeastern China.

Catalytic Cycloisomerization onto a Carbonyl Oxygen.

We have found that terminal N-vinylindoles bearing cycloalkanone substituents are excellent hydrogen atom acceptors, generating α-aminyl radicals with a variety of catalysts (Co(II)/H2 or Co(III)Cl precatalysts with silane reductants). These radicals can be converted to internal vinylindoles but eventually add to the oxygen of the cycloalkanone substituents. These cyclizations eventually furnish a densely functionalized dihydrofuran (a net cycloisomerization). The internal vinylindoles are slowly converted to the dihydrofurans, but the final cycloisomerization/isomerization ratio is affected by the size of the cycloalkanone ring (seven- and eight-membered rings give the highest ratio). These results demonstrate how HAT can isomerize substrates in nonintuitive ways, here leading to the first HAT-promoted formation of a C-O bond.

A Cross-Sectional Survey of Foaling-Related Parameters of Jennies (Equus asinus) Under Smallholder Farm Conditions in Northeast China.

It is important to assess the reproductive efficiency and improve the reproductive management to promote the donkey population development. The overall foaling-related parameters of jennies under smallholder farm conditions in China were hardly under investigation. A cross-sectional survey of randomly selected 694 smallholder farms was conducted in 40 villages in the north, east, and south areas of Western Liaoning Province and Eastern Inner Mongolia Autonomous Region between March and July, 2017. Foaling-related parameters were assessed such as the mean age at first foaling, foaling rate and foaling interval during 2014-2017. Only two-thirds of the adult jennies foaled during the 3-year survey period and delivered a foal every 1.9 years. The mean age at first foaling was 45.3 months. The lowest incidence of foaling rate was in coincidence with the peak of foaling. The overall mean values for the foaling rate and foaling interval were 75% and 500.5 days, respectively. Significant changes of foaling rates before the age of 15 years and foaling intervals in the first 8 parities were not observed. The results indicate that the jennies could maintain relatively fine foaling-related parameters under smallholder farm conditions in northeast of China. However, the foaling rates hardly remained high during the whole breeding season represented a major loss to the donkey breeding.

Decarbonylative Borylation of Amides by Palladium Catalysis.

The development of transition-metal-catalyzed borylation reactions is of significant importance for the fields of organic synthesis and medicinal chemistry because of the versatility of organoboron functional groups. Herein, we report the direct decarbonylative borylation of amides by highly selective carbon-nitrogen bond cleavage by palladium catalysis. The approach capitalizes on the ground-state destabilization of the amide bond in N-acyl glutarimides to achieve Pd-catalyzed insertion into the amide N-C bond and decarbonylation (deamidation). Mechanistic studies and the utility of this methodology in orthogonal sequential cross-couplings of robust, bench-stable amides are reported.

17O NMR and 15N NMR chemical shifts of sterically-hindered amides: ground-state destabilization in amide electrophilicity.

The structure and spectroscopic properties of the amide bond are a topic of fundamental interest in chemistry and biology. Herein, we report 17O NMR and 15N NMR spectroscopic data for four series of sterically-hindered acyclic amides. Despite the utility of 17O NMR and 15N NMR spectroscopy, these methods are severely underutilized in the experimental determination of electronic properties of the amide bond. The data demonstrate that a combined use of 17O NMR and 15N NMR serves as a powerful tool in assessing electronic effects of the amide bond substitution as a measure of electrophilicity of the amide bond. Notably, we demonstrate that steric destabilization of the amide bond results in electronically-activated amides that are comparable in terms of electrophilicity to acyl fluorides and carboxylic acid anhydrides.

Triflamides: Highly Reactive, Electronically Activated N-Sulfonyl Amides in Catalytic N-C(O) Amide Cross-Coupling.

The direct, highly chemoselective Suzuki-Miyaura cross-coupling of trifluoromethanesulfonamides (triflamides) by selective N-C(O) amide bond cleavage is reported. This operationally simple, mild, and user-friendly method accomplishes the direct synthesis of ketones from amides by a catalytic manifold as a powerful alternative to Weinreb amides. Mechanistic studies support rotational inversion and electronic activation, favoring selective insertion under mild conditions. Our data strongly suggest that triflamides should be routinely considered as precursors in amide bond cross-coupling.

The Most Twisted Acyclic Amides: Structures and Reactivity.

The synthesis, crystal structures, and reactivity of the most twisted acyclic amides described to date are reported. Substitution at the nitrogen atom in simple benzamides with Ts and acyl or carbamate groups provides a unique way to achieve almost perpendicular twist in N-acyclic amides (τ = 77°, N = Ac; τ = 87°, N = Boc). The overlap between the Nlp and CO π* orbital is disrupted due to geometrical constraints around the N-substituents. The perpendicular acyclic twisted amides represent a transition state mimic of cis-trans peptide isomerization thus far only accessible by excessively twisted bridged lactams.

Well-Defined Palladium(II)-NHC Precatalysts for Cross-Coupling Reactions of Amides and Esters by Selective N-C/O-C Cleavage.

Transition-metal-catalyzed cross-coupling reactions represent a most powerful tool for the rapid construction of C-C and C-X bonds available to synthetic chemists. Recently, tremendous progress has been made in the burgeoning area of cross-coupling reactions of amides and esters enabled by regio- and chemoselective acyl C-X (X = N, O) cleavage using well-defined Pd(II)-NHC complexes. The use of N-heterocyclic carbenes as ligands in palladium-catalyzed cross-couplings permits reactions of amides and esters that were previously impossible using palladium or could be achieved only under harsh conditions. These reactions provide an attractive method to synthetic chemists to manipulate the traditionally inert amide and ester bonds with the broad cross-coupling generality inherent to palladium catalysis. Research in the area of cross-coupling of stable acyl electrophiles can be broadly categorized by the type of electrophile undergoing the cross-coupling. Recent studies have shown that cross-coupling of amides by transition-metal catalysis represents one of the most straightforward and wide-ranging ways of manipulating the classically inert amide bonds into generic acyl-metal intermediates that can be systematically exploited in cross-coupling reactions as a new paradigm in organic synthesis. The key to achieving high chemoselectivity of the process is control of amidic resonance (nN to πC═O* conjugation, rotation of ca. 15-20 kcal/mol in planar amides), enabling oxidative addition of the N-C amide bond to a metal in a rational and predictable manner. This mode of catalysis has been extended to C(acyl)-O cross-coupling reactions of aryl esters, where selective C-O bond cleavage is accomplished through a rational match of aryl ester electrophiles and nucleophilic metal catalysts. These two types of transition-metal-catalyzed cross-coupling reactions represent an attractive concept in synthetic chemistry because of the ubiquity of esters and amides as precursors in organic synthesis. Furthermore, the high stability of amides and esters provides unprecedented opportunities for orthogonal cross-coupling strategies in the presence of other electrophiles. In this Account, we highlight advances that have taken place in the past few years in the field of cross-coupling of amides and esters, focusing on both (1) the stereoelectronic properties of well-defined Pd(II)-NHC complexes that have been critical to realize this challenging cross-coupling manifold and (2) the role of the isomerization barrier of the acyl electrophiles undergoing the cross-coupling. In a broader sense, the chemistry described here provides a practical approach to functionalize common amide and ester functional groups in organic synthesis and establishes straightforward access to acyl-metal intermediates that enable nonconventional cross-coupling strategies.

Reversible Twisting of Primary Amides via Ground State N-C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides.

Since the seminal studies by Pauling in 1930s, planarity has become the defining characteristic of the amide bond. Planarity of amides has central implications for the reactivity and chemical properties of amides of relevance to a range of chemical disciplines. While the vast majority of amides are planar, nonplanarity has a profound effect on the properties of the amide bond, with the most common method to restrict the amide bond relying on the incorporation of the amide function into a rigid cyclic ring system. In a major departure from this concept, here, we report the first class of acyclic twisted amides that can be prepared, reversibly, from common primary amides in a single, operationally trivial step. Di-tert-butoxycarbonylation of the amide nitrogen atom yields twisted amides in which the amide bond exhibits nearly perpendicular twist. Full structural characterization of a range of electronically diverse compounds from this new class of twisted amides is reported. Through reactivity studies we demonstrate unusual properties of the amide bond, wherein selective cleavage of the amide bond can be achieved by a judicious choice of the reaction conditions. Through computational studies we evaluate structural and energetic details pertaining to the amide bond deformation. The ability to selectively twist common primary amides, in a reversible manner, has important implications for the design and application of the amide bond nonplanarity in structural chemistry, biochemistry and organic synthesis.

Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide.

Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N-heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI2, Kagan's reagent) has been widely used to forge challenging C-C bonds through reductive coupling reactions. Historically, the use of SmI2 in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI2 for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E1/2 of up to -2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI2. In particular, radical cross-coupling reactions exploiting SmI2-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI2-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI2. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI2 are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan's reagent.

Suzuki-Miyaura cross-coupling of amides and esters at room temperature: correlation with barriers to rotation around C-N and C-O bonds.

The Suzuki-Miyaura cross-coupling has been widely recognized as one of the most important methods for the construction of C-C bonds. However, in contrast to traditional aryl halide or pseudohalide electrophiles, coupling reactions with unactivated C-N and C-O electrophiles have proven significantly more challenging. Here we report the first general palladium-catalyzed Suzuki-Miyaura cross-coupling of both common amides and aryl esters through the selective cleavage of the C-N and C-O bonds under exceedingly mild conditions. Notably, for the first time we demonstrate selective C(acyl)-N and C(acyl)-O cleavage/cross-coupling under the same reaction conditions. The reaction uses a commercially available, bench-stable and operationally-convenient (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst. Furthermore, we demonstrate that the reactivity of generic amides and aryl esters can be correlated with barriers to isomerization around the C(acyl)-X (X = N, O) bond, thus providing a blueprint for the development of a broad range of novel coupling reactions of ester and amide electrophiles by the selective activation of C-O and C-N bonds.

Pd-PEPPSI: a general Pd-NHC precatalyst for Buchwald-Hartwig cross-coupling of esters and amides (transamidation) under the same reaction conditions.

Amides are of fundamental interest in many fields of chemistry involving organic synthesis, chemical biology and biochemistry. Here, we report the first catalytic Buchwald-Hartwig coupling of both common esters and amides by highly selective C(acyl)-X (X = O, N) cleavage to rapidly access aryl amide functionality via a cross-coupling strategy. Reactions are promoted by versatile, easily prepared, well-defined Pd-PEPPSI type precatalysts, and proceed in good to excellent yields and with excellent chemoselectivity for the acyl bond cleavage. The method is user friendly because it employs commercially-available, moisture- and air-stable precatalysts. Notably, for the first time we demonstrate selective C(acyl)-N and C(acyl)-O cleavage/Buchwald-Hartwig amination under the same reaction conditions, which allows for streamlining amide synthesis by avoiding restriction to a particular acyl metal precursor. Of broad interest, this study opens the door to using a family of well-defined Pd(ii)-NHC precatalysts bearing pyridine "throw-away" ligands for the selective C(acyl)-amination of bench-stable carboxylic acid derivatives.

Decarbonylative Cyanation of Amides by Palladium Catalysis.

Transition-metal-catalyzed cyanation of aryl halides is a process of significant importance in the preparation pharmaceuticals, organic materials and agrochemicals. Here, we demonstrate a palladium-catalyzed decarbonylative cyanation of amides by highly selective carbon-nitrogen bond cleavage for the synthesis of a wide range of aryl nitriles. The utility of this technology is demonstrated by the synthesis of isotopically labeled aryl nitriles and orthogonal cross-coupling reactions of bench-stable amides to establish cross-coupling synthons with opposite polarity.

Mechanistic Study of SmI2/H2O and SmI2/Amine/H2O-Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals.

Samarium(II) iodide-water and samarium(II) iodide-water-amine complexes have been recognized as valuable reagents for the selective generation of aminoketyl radicals from amides and derivatives. The resulting aminoketyl radicals can undergo reduction or reductive cyclization pathways, providing a powerful method for (i) direct synthesis of alcohols from amides by the challenging N-C bond scission and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic investigation into samarium(II) iodide-water and samarium(II) iodide-water-amine-mediated generation of benzylic aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly more dependent on the electronic effects of α-substitution than the corresponding aminoketyl radicals generated by single-electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is observed. These observations will have implications for the design of reductive processes involving Sm(II)-mediated reduction of amides and reductive umpolung cyclizations via aminoketyl radicals as a key step.

Metal-Free Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions.

Nonplanar, electronically destabilized amides have emerged as powerful intermediates in organic synthesis. We report a highly selective method for transamidation of common secondary amides under mild, metal-free conditions that relies on transient N-selective functionalization to weaken amidic resonance. The combination of rational modification of the amide bond with nucleophilic addition mechanism, and the thermodynamic collapse of the resultant tetrahedral intermediate constitutes a two-step procedure to accomplish a challenging transamidation of secondary amides under mild conditions.

Nickel-Catalyzed Diaryl Ketone Synthesis by N-C Cleavage: Direct Negishi Cross-Coupling of Primary Amides by Site-Selective N,N-Di-Boc Activation.

A general Negishi acylation of primary amides enabled by a combination of site-selective N,N-di-Boc activation and nickel catalysis is reported for the first time. The reaction is promoted by a bench-stable, inexpensive Ni catalyst. The reaction shows excellent functional group compatibility, affording functionalized diaryl ketones by selective N-C cleavage. Most notably, this protocol represents the first amide cross-coupling by direct metal insertion of simple and readily available primary amides. The overall strategy by N,N-di-Boc activation/metal insertion is suitable for a broad range of coupling protocols via acylmetals. Mechanistic experiments suggest high reactivity of N,N-di-Boc activated 1° amides in direct amide C-N cross-couplings.