Acyl-metal Intermediates Research Articles

Evaluation of Cyclic Amides as Activating Groups in N-C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions.

The development of efficient methods for facilitating N-C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N-C(O) bond cross-coupling. Evaluation of N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and six-membered rings using Pd(II)-NHC and Pd-phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki-Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O-C(O) and S-C(O) cross-coupling under the same reaction conditions. Most notably, the study reveals N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling. The X-ray structure of the model N-acyl-δ-valerolactam is characterized by an additive Winkler-Dunitz distortion parameter Σ(τ+χN) of 54.0°, placing this amide in a medium distortion range of twisted amides. Computational studies provide insight into the structural and energetic parameters of the amide bond, including amidic resonance, N/O-protonation aptitude, and the rotational barrier around the N-C(O) axis. This class of N-acyl-lactams will be a valuable addition to the growing portfolio of amide electrophiles for cross-coupling reactions by acyl-metal intermediates.

N-Acylphthalimides: Efficient Acyl Coupling Reagents in Suzuki–Miyaura Cross-Coupling by N–C Cleavage Catalyzed by Pd–PEPPSI Precatalysts

We report a general, highly selective method for Suzuki–Miyaura cross-coupling of N-acylphthalimides via N–C(O) acyl cleavage catalyzed by Pd–PEPPSI-type precatalysts. Of broad synthetic interest, the method introduces N-acylphthalimides as new, bench-stable, highly reactive, twist-controlled, amide-based precursors to acyl-metal intermediates. The reaction delivers functionalized biaryl ketones by acylative Suzuki–Miyaura cross-coupling with readily available boronic acids. Studies demonstrate that cheap, easily prepared, and broadly applicable Pd–PEPPSI-type precatalysts supported by a sterically demanding IPr (1,3-Bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) ancillary ligand provide high yields in this reaction. Preliminary selectivity studies and the effect of Pd–N-heterocyclic carbenes (NHC) complexes with allyl-type throw-away ligands are described. We expect that N-acylphthalimides will find significant use as amide-based acyl coupling reagents and cross-coupling precursors to acyl-metal intermediates.

Pd-Catalyzed Suzuki-Miyaura Cross-Coupling of Pentafluorophenyl Esters.

Although the palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl esters has received significant attention, there is a lack of methods that utilize cheap and readily accessible Pd-phosphane catalysts, and can be routinely carried out with high cross-coupling selectivity. Herein, we report the first general method for the cross-coupling of pentafluorophenyl esters (pentafluorophenyl = pfp) by selective C–O acyl cleavage. The reaction proceeds efficiently using Pd(0)/phosphane catalyst systems. The unique characteristics of pentafluorophenyl esters are reflected in the fully selective cross-coupling vs. phenolic esters. Of broad synthetic interest, this report establishes pentafluorophenyl esters as new, highly reactive, bench-stable, economical, ester-based, electrophilic acylative reagents via acyl-metal intermediates. Mechanistic studies strongly support a unified reactivity scale of acyl electrophiles by C(O)–X (X = N, O) activation. The reactivity of pfp esters can be correlated with barriers to isomerization around the C(acyl)–O bond.

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.

Transition-Metal-Free Esterification of Amides via Selective N-C Cleavage under Mild Conditions.

A general, transition-metal-free, and operationally simple method for esterification of amides by a highly selective cleavage of N-C(O) bonds under exceedingly mild conditions is reported. The reaction is characterized by broad substrate scope and excellent functional group tolerance. The potential of this mild esterification is highlighted by late-stage diversification of natural products and pharmaceuticals. Conceptually, the metal-free acyl functionalization of amides represents a significant step forward as a practical alternative to ligand exchange in acylmetal intermediates.

N-Methylamino Pyrimidyl Amides (MAPA): Highly Reactive, Electronically-Activated Amides in Catalytic N-C(O) Cleavage.

Despite recent progress in catalytic cross-coupling technologies, the direct activation of N-alkyl-N-aryl amides has been a challenging transformation. Here, we report the first Suzuki cross-coupling of N-methylamino pyrimidyl amides (MAPA) enabled by the controlled nN → πAr conjugation and the resulting remodeling of the partial double bond character of the amide bond. The new mode of amide activation is suitable for generating acyl-metal intermediates from unactivated primary and secondary amides.

Nickel-Catalyzed Negishi Cross-Coupling of N-Acylsuccinimides: Stable, Amide-Based, Twist-Controlled Acyl-Transfer Reagents via N–C Activation

This paper reports a room temperature, nickel-catalyzed Negishi cross-coupling of N-acylsuccinimides with arylzinc reagents via selective N–C bond cleavage enabled by amide bond twist. The reaction proceeds using a commercially available, air-stable Ni(II) precatalyst in the absence of additives under exceedingly mild conditions. Of broad interest, this report introduces N-acylsuccinimides as stable, crystalline, electrophilic, cost-effective, benign, amide-based acyl transfer reagents via acyl metal intermediates. The reaction selectivity is governed by half-twist of the amide bond in N-acylsuccinimides, thus opening the door for applications in metal-catalyzed manifolds via redox­-neutral reaction pathways tuneable by amide bond distortion.

General Method for the Suzuki–Miyaura Cross-Coupling of Amides Using Commercially Available, Air- and Moisture-Stable Palladium/NHC (NHC =N-Heterocyclic Carbene) Complexes

The direct Suzuki–Miyaura cross-coupling of amides catalyzed by Pd-NHC complexes is reported. Using a single protocol, commercially available, air- and moisture-stable (NHC)Pd(R-allyl)Cl complexes can effect Suzuki–Miyaura cross-coupling of a wide range of amides with arylboronic acids in very good yields. The studies described herein represent the use of versatile Pd-NHC complexes as catalysts for transition-metal-catalyzed cross-coupling of amides by N–C bond activation. The Pd-NHC catalysts provide a significant improvement over all current Pd-PR3 systems employed for the amide N–C bond activation. Mechanistic studies provide strong support for the development of a unified reactivity scale of the amide bond for the generation of acyl-metal intermediates.

Chemoselective acyl C–O bond activation in esters for Suzuki–Miyaura coupling

The use of palladium–NHC (bulky) catalyst enables selective acylative coupling in esters via blocking the potential C(aryl)–O oxidative addition and decarbonylation processes. Mechanistic studies elucidate the role of bulky carbene catalysts in promoting C(acyl)–O activation, and as a result, the acyl metal intermediates undergo coupling without the loss of carbonyl group.

N-Acylsaccharins: Stable Electrophilic Amide-Based Acyl Transfer Reagents in Pd-Catalyzed Suzuki-Miyaura Coupling via N-C Cleavage.

The development of efficient catalytic methods for N-C bond cleavage in amides remains an important synthetic challenge. The first Pd-catalyzed Suzuki-Miyaura cross-coupling of N-acylsaccharins with boronic acids by selective N-C bond activation is reported. The reaction enables preparation of a variety of functionalized diaryl and alkyl-aryl ketones with broad functional group tolerance and in good to excellent yields. Of general interest, N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-metal intermediates. Mechanistic studies strongly support the amide N-C(O) bond twist as the enabling feature of N-acylsaccharins in the N-C bond cleavage.

Sterically Controlled Pd-Catalyzed Chemoselective Ketone Synthesis via N-C Cleavage in Twisted Amides.

Highly chemoselective, palladium(0)-catalyzed, direct cross-coupling between boronic acids and geometrically activated amides is reported. The reaction proceeds via selective activation of the N-C(O) bond, shows excellent functional group tolerance, and delivers the versatile ketone products in high yields. The observed reactivity is consistent with a decrease of nN → π*C═O conjugation resulting from destabilization of the amide ground state. Notably, the method provides direct access to acyl-metal intermediates from sterically distorted, bench-stable amide precursors under mild catalytic conditions.

Novel ring-opened reaction of μ-(1–3-η:4–7-η-cycloheptatrienyl)-tricarbonylirontricarbonylmanganese with aryllithium reagents

The reactions of µ-(1–3-η:4–7-cycloheptatrienyl)tricarbonylirontricarbonylmanganese [Mn(CO)3Fe(CO)3- (C7H7)] 1, with aryllithium reagents, ArLi (Ar = Ph, o-, m-, p-MeC6H4), in ether at low temperature, followed by alkylation of the acylmetalate intermediates with Et3OBF4 in aqueous solution at 0 °C affords four novel ring-opened polyene complexes [Mn(CO)3Fe(CO)3{C8H7(OEt)Ar}] (Ar = Ph 2, o-MeC6H4 3, m-MeC6H4 4, p-MeC6H4 5), of which the structure of 2 has been established by a single-crystal X-ray diffraction study.

Reactions of m- and p-Divinylbenzene−Diiron Hexacarbonyl with Aryllithium Reagents. Crystal Structures of [(CO)3Fe(m-C10H10)(CO)2FeC(OC2H5)C6H4CH3-o] and [(CO)3Fe(p-C10H10)(CO)2FeC(OC2H5)C6H4CF3-p

The reactions of m-divinylbenzene−diiron hexacarbonyl (1) with aryllithium reagents, ArLi (Ar = C6H5, o-, m-, p-CH3C6H4, p-CH3OC6H4, p-CF3C6H4, m-ClC6H4), in ether at low temperature gave acylmetalate intermediates followed by alkylation with Et3OBF4 in aqueous solution at 0 °C to afford the isomerized divinylbenzene-coordinated alkoxycarbene complexes [(CO)3Fe(m-C10H10)(CO)2FeC(OC2H5)Ar] (3, Ar = C6H5; 4, Ar = o-CH3C6H4; 5, Ar = m-CH3C6H4; 6, Ar = p-CH3C6H4; 7, Ar = p-CH3OC6H4; 8, Ar = p-CF3C6H4; 9, Ar = m-ClC6H4) with two types of structures. The p-divinylbenzene-diiron hexacarbonyl (2) also reacted with the aryllithium reagents under the same conditions to give the corresponding isomerized alkoxycarbene complexes [(CO)3Fe(p-C10H10)(CO)2FeC(OC2H5)Ar] (10, Ar = C6H5; 11, Ar = o-CH3C6H4; 12, Ar = m-CH3C6H4; 13, Ar = p-CH3C6H4; 14, Ar = p-CH3OC6H4; 15, Ar = p-CF3C6H4; 16, Ar = m-ClC6H4). The structures of complexes 4 and 15 have been determined by single-crystal X-ray diffraction studies.

Unexpected reactions of (cyclooctatetraene) diiron hexacarbonyl with aryllithium reagents: Crystal structures of [(CO) 3Fe(1–4-η:5–7-ηC 8H 9)(CO) 2Fe (COC 6H 5)] and [(CO) 3Fe(1–4-η:5–8-η-C 8 H 8)(CO) 2FeC(OC 2H 5)C 6H 5

The reaction of (cyclooctatetraene)diiron hexacarbonyl ( 1) with aryllithium reagents ArLi (Ar = C 6H 5, o-, m-, p-CH 3C 6H 4, p-CH 3OC 6H 4 in ether at low temperature afforded acylmetalate intermediates. Subsequent alkylation with Et 3OBF 4 in aqueous solution at 0°C gave the (8,8-dihydro-1-4-η:5-7-η-cyclooctatrienyl) tricarbonylirondicarbonyl(arylformacyl)iron complexes [(CO) 3Fe(1–4-η:5–7-η-C 8H 9) (CO) 2Fe(COAr)] ( 2a-e) ( 2a, Ar = C 6H 5; 2b, Ar = o-CH 3C 6H 4; 2c, Ar = m-CH 3C 6H 4; 2d, Ar = p-CH 3C 6H 4; 2e, Ar = p-CH 3OC 6H 4) and (1–4-η:5–8-η-cyclooctatetraene)tricarbonylirondicarbonyl [ethoxy(aryl)carbene]iron complexes [(CO) 3Fe(1–4-η:5–8-η-C 8H 8) (CO) 2FeC(OC 2H 5)Ar] ( 3a-e) ( 3a, Ar = C 6H 5; 3b, Ar = o-CH 3C 6H 4; 3c, Ar = m-CH 3C 6H 4; 3d, Ar = p-CH 3C 6H 4; 3e, Ar = p-CH 3OC 6H 4). The structures of 2a and 3a have been established by X-ray diffraction studies, which indicate that the Fe(CO) 3 unit and the (CO) 2Fe(COC 6H 5 moiety in 2a and the (CO) 2FeC(OC 2H 5)C 6H 5 moiety in 3a are on opposite sides of the cyclooctatetraene ring.

The role of nickel in acetyl-CoA synthesis by the bifunctional enzyme CO dehydrogenase/acetyl-CoA synthase: enzymology and model chemistry

CO dehydrogenase/acetyl-CoA synthase (CODH/ACS) is one of the four known nickel enzymes. It is a bifunctional protein that catalyzes the oxidation of CO to CO2 at a nickel iron-sulfur cluster (Cluster C) and a remarkable condensation reaction between a methyl group (donated from a methylated corrinoid iron-sulfur protein), carbon monoxide, and coenzyme A to form acetyl-CoA at a separate nickel iron-sulfur cluster (Cluster A). This review focuses on the current understanding of the structure and function of Cluster A and on related model chemistry. It describes studies that uncovered the first example of a biological organometallic reaction sequence. The mechanism of acetyl-CoA synthesis includes enzymebound methylnickel, iron-carbonyl, and acylmetal intermediates. Discovery of the methylnickel species constituted the first example of an alkylnickel species in biology and unveiled a new biological role for nickel.

Studies on olefin-co-ordinating transition-metal carbene complexes. Part 14. An unusual reaction of tricarbonyl(η4-cyclopenta-1,3-diene)iron: a new approach to acyldicarbonyl(η-cyclopentadienyl)iron complexes, and the X-ray crystal structure of [Fe(COC6H4CF3-p)(η-C5H5)(CO)2

Reaction of tricarbonyl(η4-cyclopenta-1,3-diene)iron (1) with aryl-lithium reagents, LiR (R = Ph, C6H4Me-o or -p, C6H4OMe-p, or C6H4CF3-p), in diethyl ether at low temperature, followed by the reaction of the acylmetalate intermediates formed with Et3OBF4 in CH2Cl2 at –60 °C or in aqueous solution at 0 °C, afforded yellow crystalline compounds formulated as [Fe(COR)(η-C5H5)(CO)2](2)–(6) based on elemental analyses, i.r., 1H n.m.r., and mass spectra. Complex (6) has been studied by X-ray diffraction: triclinic, space group P with the unit-cell constants a= 7.670(7), b= 9.008(4), c= 10.662(1)Å, α= 103.70(2), β= 96.496(8), γ= 100.03(2)°, Z= 2, R= 0.039, and R′= 0.045 for 2 834 reflections with I > 3σ(I).