Reduction of Secondary Carboxamides to Imines

This article reports in detail on the discovery that zirconium(IV) salts of secondary amides and lactams are transformed by Cp(2)ZrHCl to N-substituted imines in one step. The method represents the first controlled reduction of amides and lactams to the corresponding imines, a transformation that is otherwise very difficult to achieve because imines are reduced more rapidly than carboxamides by most metal hydride reagents. No products of reductive cleavage of the carboxamides are observed. Efforts to replace 2 mol equiv of Cp(2)ZrHCl with simpler, less costly alternatives led to the finding that a diisobutylaluminum enolate can be substituted for the initial zirconium enolate. Such aluminum amides are smoothly reduced to the corresponding imine using Cp(2)ZrHCl in good yield. Moreover, aluminum amides are also reduced to imines using either low-valent titanium species or triethylsilane. In these alternative procedures, use of Cp(2)ZrHCl is eliminated altogether in the title transformation.     

General One‐Pot Reductive gem‐Bis‐Alkylation of Tertiary Lactams/Amides: Rapid Construction of 1‐Azaspirocycles and Formal Total Synthesis of (±)‐Cephalotaxine

Amides are a class of highly stable and readily available compounds. The amide functional group constitutes a class of powerful directing/activating and protecting group for C? C bond formation. Tertiary tert‐alkylamine, including 1‐azaspirocycle is a key structural feature found in many bioactive natural products and pharmaceuticals. The transformation of amides into tert‐alkylamines generally requires several steps. In this paper, we report the full details of the first general method for the direct transformation of tertiary lactams/amides into tert‐alkylamines. The method is based on in situ activation of amide with triflic anhydride/2,6‐di‐tert‐butyl‐4‐methylpyridine (DTBMP), followed by successive addition of two organometallic reagents of the same or different kinds to form two C? C bonds. Both alkyl and functionalized organometallic reagents and enolates can be used as the nucleophiles. The method displayed excellent 1,2‐ and good 1,3‐asymmetric induction. Construction of 1‐azaspirocycles from lactams required only two steps or even one‐step by direct spiroannelation of lactams. The power of the method was demonstrated by a concise formal total synthesis of racemic cephalotaxine.     

Cobalt-Catalyzed α-Arylation of Substituted α-Bromo α-Fluoro β-Lactams with Diaryl Zinc Reagents: Generalization to Functionalized Bromo Derivatives

A cobalt-catalyzed cross-coupling of α-bromo α-fluoro β-lactams with diarylzinc or diallylzinc reagents is herein disclosed. The protocol proved to be general, chemoselective and operationally simple allowing the C4 functionalization of β-lactams. The substrate scope was expanded to α-bromo lactams and amides, α-bromo lactones and esters as well as N - and O-containing heterocycles.     

First organophosphorus radical-mediated cyclisations to afford medium-sized rings: eight-membered lactones and seven- and eight-membered lactams

The phosphorus based radical precursors N-ethylpiperidine hypophosphite (EPHP) and diethylphosphine oxide (DEPO) are efficient reagents for carrying out the formation of seven- and eight-membered rings. Esters and amides were successfully converted into the corresponding eight-membered lactones and seven- and eight-membered lactams in good to excellent yields.     

Transition-Metal-Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α-Branched Amine Synthesis

A new method for the synthesis of α-branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional-group compatibility, operates under transition-metal-free reaction conditions, and is suitable for various synthetic applications on both sub-millimole and on multigram scales.     

Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

A new method for the synthesis of α‐branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional‐group compatibility, operates under transition‐metal‐free reaction conditions, and is suitable for various synthetic applications on both sub‐millimole and on multigram scales.     

Synthesis of beta,gamma-unsaturated lactams via a magnesium iodide promoted ring expansion of secondary methylenecyclopropyl amides

A novel and efficient route to exo-beta,gamma-unsaturated lactams from substituted and non-substituted secondary methylenecyclopropyl amides is reported. Subsequent modification of the resulting exo-beta,gamma-unsaturated lactams provides access to several pharmaceutically relevant scaffolds. [reaction: see text].     

The resonance energy of amides,the structure of aziridinone,and its relationship to other strained lactams

The resonance energy of amides (lactams) is calculated both with and without inclusion of the inversion barrier of model amines. Inclusion of the barrier yields a larger resonance energy for amides than for esters, whereas the reverse is true if the barrier is not included. This is consistent with intuitive views related to electronegativity. The high inversion barrier in aziridine and a lower intrinsic resonance stabilization in aziridinone explain nonplanar geometry at nitrogen in alpha-lactams. A surprisingly good correlation is seen when one plots the difference in carbonyl frequencies of strained lactams (amides) and ketones versus the enthalpy differences between two olefin analogues to the corresponding lactam (amide) resonance contributors. This correlation implies the need to invoke resonance arguments to understand strained lactams. The deviation of aziridinone from the correlation is explicable in terms of its nonplanar structure and its deviation from planarity.Dedicated to Professor Paul von R. Schleyer on the occasion of his 60th birthday.     

Azido-Schmidt reaction for the formation of amides, imides and lactams from ketones in the presence of FeCl3

Ketones undergo smooth rearrangement with TMSN₃ in the presence of FeCl₃ under extremely mild conditions to provide the corresponding amides, imides and lactams in good yields with high selectivity. This method is very useful for the preparation of a wide range of amides, imides and lactams from ketones. The use of FeCl₃ makes this method simple, convenient and cost-effective.     

Several convenient methods for the synthesis of 2-amido substituted furans

Several new methods for the synthesis of differently substituted 2-amidofurans are described. The thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl isocyanate was trapped with various organometallic reagents. A second method consists of a C-N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams. The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and 3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide alpha-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived from the reaction of the hydroxy pyrrolidinone with Tf(2)O undergoes a facile ring opening as a consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group leads to an imino dihydrofuran that reacts further with another equivalent of Tf(2)O to give the observed product.     

Cu(Ⅱ)-catalyzed aerobic oxidative amidation of azoarenes with amides

A method for Cu(Ⅱ)-catalyzed dehydrogenative amidation of azoarene using air as the terminal oxidant was developed. Various amides, such as arylamides, alkylamides, lactams, and imides, are all effective amidation reagents and provide the desired products in moderate to excellent yields. Notably, good yields can also be obtained on a gram-scale with this amidation reaction.In this protocol of azoarene amidation, the catalyst(Cu(OAc)_2) and oxidant(air) are inexpensive and readily available, and the process is highly efficient and atom economical.     

The amide-phenol ratios and structures in amide-picric acid complexes

Picric acid forms solid, isolable complexes with amides, with the amide-phenol ratio in these complexes being 1:1 for N,N-dialkylsubstituted amides and lactams and 2:1 for N-monoalkylsubstituted amides. With acetamide a 3:1 complex was also obtained, but this was unstable and changed over the 2:1 complex. It is suggested that these complexes result primarily from H-bonding interactions, and that in solution charge-transfer and proton-transfer structures also contribute.     

Regioselective Beckmann rearrangements of furanoside and pyranoside-derived oximes

The Beckmann rearrangement is a useful reaction employed to provide access to amides from oxime substrates. Applied to cyclic structures, the Beckmann rearrangement leads to ring expansion and allows access to cyclic lactams. Our investigations focused upon the synthesis of glycoside-derived lactams from oxime precursors. In probing a range of conditions, we observed that 2,4,6-trichloro[1,3,5]triazine (TCT) was an effective and mild promoter of the rearrangement affording pyrano- and heptanoside lactam products with excellent regioselectivities.     

A one-pot synthesis of tertiary amines from amines,lactams and urethanes

A one-pot synthesis of unsymmetrical tertiary amines from amides, lactams and urethanes has been developed. The reaction is general for all cases examined with the exception of N-aryl containing examples, which are not accessible by this method.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Solventless lactam synthesis by intramolecular cyclizations of alpha-iminoester derivatives under microwave irradiation

We have previously reported a new synthesis of amides from esters and amines under microwave irradiation, offering much higher yields than those achieved with conventional heating [1]. We have now extended these studies to the ring closure of neat iminoesters I2, I3 and I4-I6 to give five- and six-membered ring lactams L5, L6 and larger lactams L7-L9 (where I means imine and L means lactam), respectively, under both classical heating conditions and microwave irradiation.     

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.     

An efficient approach to the stereocontrolled synthesis of enamides

[reaction: see text] A fast, flexible, and efficient approach for the stereocontrolled synthesis of enamides has been developed starting from lactams and amides through the use of imides. This new approach provides access to enamide systems not easily or currently accessible through other approaches.     

Mercury-catalyzed rearrangement of ketoximes into amides and lactams in acetonitrile

An acetonitrile solution of mercury(II) chloride has been found to catalyze efficiently the conversion of a diverse range of ketoximes into their corresponding amides/lactams.     

Regression and principal component analyses of internal coordinates for the carboxamide and carboxylate groups. Diversity of amide bonding in primary carboxamides,oligopeptides, and lactams

A new model of electronic structure of the carboxamide and carboxylate bonds is proposed to account for the diversity of the patterns of structural variation displayed by such bonds in the crystal structures. The geometries of the amide and carboxylate ester fragments retrieved from the Cambridge Crystallographic Data Centre database were examined by means of the regression and principal component analyses. Correlations of the C=O and C-O/C-N bond distances and correlations of the bond distances with the out-of-plane distortions are consistent with the predictions of Pauling's resonance model only in the more extensively substituted esters, secondary amides, and common ring lactams. Surprisingly, in the unsubstituted methyl esters and primary amides, correlations between the bond distances are positive (e.g., both C-N and C=O increase or decrease). Furthermore, for the majority of the less substituted amides and lactams, an increase in pyramidalization at the nitrogen is associated with the shortening of the C-N bond instead of the expected lengthening. Consequently, factor analyses of ther(C=O),r(C-N), ¦ _N¦coordinates for the 42 subclasses of amides and lactams reveal three patterns of coupling of structural parameters, these patterns appear to be related to the major types of the amide substitution. A hypothesis explaining this diversity is based on the assumption that structural variation observed in each of the narrowly defined subclasses of amides maps out initial stages of rehybridization accompanying internal rotation, that is, the amide bonds in the crystal structures deform along the rehybridization/rotation path. It is proposed that the positions of the minimum and the saddle point along this path depend on the alkyl substitution of the bond and the size of the embedding ring.