Solvent-dependent conformational switching of the aromatic N-methyl amides depending upon the acceptor properties of solvents

Okamoto, Iwao; Nabeta, Mayumi; Yamamoto, Misaki; Mikami, Maiko; Takeya, Tetsuya; Tamura, Osamu

doi:10.1016/j.tetlet.2006.08.012

Cited by 18 publications

(11 citation statements)

References 28 publications

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“…2) adopted by the corresponding Nmethyl-NAH derivative LASSBio-1004 (9b) shifted it to a shorter wavelength (291 nm) and its absorbance was diminished (log 3 ¼ 3.78) due to a difference in the electronic transition in aromatic moieties between the series caused by conformational variations. These results are in agreement with previous conformational studies of secondary and tertiary aromatic amides [20,22].…”

Section: Resultssupporting

confidence: 93%

Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

Kümmerle

Raimundo

Leal

et al. 2009

European Journal of Medicinal Chemistry

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Section: Resultssupporting

confidence: 93%

Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

Kümmerle

Raimundo

Leal

et al. 2009

European Journal of Medicinal Chemistry

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“…13−15 Okamoto et al synthesized 3°N-pyridyl amides and demonstrated that the conformational preference can switch upon the addition of acid 16,17 or in solvents capable of hydrogen bonding. 18 Many of the papers discussing the conformation of amides focus solely on acetamide and N-methylacetamide, and those preferences have been well established. 2,3,19,20 There have been significantly fewer studies of more complex systems.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to 2° amides, for which the trans conformation is nearly universally favored over the cis conformation (as shown in Figures and ), N -alkyl- N -aryl 3° amides demonstrate the opposite conformational preference. Both experimental and computational results from dozens of independent researchers, together studying hundreds examples of N -alkyl- N -aryl 3° amides have clearly identified that the cis conformation is generally favored over the trans conformation by between 0.5 and 5 kcal/mol. − Multiple studies have even taken advantage of this conformational preference, using 3° amides as cis backbones for chelating ligands and macromolecular architecture, , for preorganization to facilitate synthesis of lactams, , or for restricting rotation. − Okamoto et al synthesized 3° N -pyridyl amides and demonstrated that the conformational preference can switch upon the addition of acid , or in solvents capable of hydrogen bonding …”

Section: Introductionmentioning

confidence: 99%

Why Do N-Alkylated Anilides Bend Over? The Factors Dictating the Divergent Conformational Preferences of 2° and 3° N-Aryl Amides

Pros

Bloomfield

2019

J. Phys. Chem. A

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The conformational preferences of 28 sterically and electronically diverse N-aryl amides were determined using density functional theory (DFT), using the B3LYP functional and 6-31G(d) basis set. For each compound, both the cis and trans conformers were optimized, and the difference in ground state energy calculated. For six of the compounds, the potential energy surface was determined as a function of rotation about the N-aryl bond (by 5° increments) for both cis and trans conformers. A natural bond orbital (NBO) deletion strategy was also employed to determine the extent of the contribution of conjugation to the energies of each of the conformers. By comparing these computational results with previously reported experimental data, an explanation for the divergent conformational preferences of 2° N-aryl amides and 3° N-alkyl-N-aryl amides was formulated. This explanation accounts for the observed relationships of both steric and electronic factors determining the geometry of the optimum conformation, and the magnitude of the energetic difference between cis and trans conformers: except under the most extreme scenarios, 2° amides maintain a trans conformation, and the N-bound arene lies in the same plane as the amide unless it has ortho substituents; for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are connected in a small ring, trans conformations are also favored, for most cases other than formamides, and the arene and amide remain in conjugation; and for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are not connected in a small ring, allylic strain between the two N-bound substituents forces the aryl substituent to rotate out of the plane of the amide, and the trans conformation is destabilized with respect to the cis conformation due to repulsion between the π system of the arene and the lone pairs on the oxygen atom of the carbonyl. The cis conformation is increasingly more stable than the trans conformation as electron density is increased on the arene because the more electron-rich arenes adopt a more orthogonal arrangement, increasing the interaction with the carbonyl oxygen, while simultaneously increasing the magnitude of the repulsion due to the increased electron density in the π system. The trans conformation is favored for 2° amides even when the arene is orthogonal to the amide, in nearly all cases, because the C–N–C bond angle can expend at the expense of the C–N–H bond angles, while this is not favorable for 3° amides.

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“…The N–C(O), CO, and N–Ar bond lengths are 1.378, 1.225, and 1.407 Å. Compared with the corresponding N -Me- N -2-pyridyl (τ = 15.0°, χ N = 8.4°, χ C = 4.0°; N–C(O) = 1.366 Å; CO = 1.226 Å, N–Ar = 1.428 Å) and N -Me- N -Ph benzamide (τ = 9.1°, χ N = 6.6°, χ C = 2.1°; N–C(O) = 1.355 Å; CO = 1.232 Å, N–Ar = 1.437 Å), these values indicate a gradual increase in n N →π Ar conjugation.…”

mentioning

confidence: 94%

“…We observed the desired cross-coupling product in our proof-of-concept reaction using Pd(OAc) 2 /PCy 3 catalyst system and H 3 BO 3 as the promoter (entry 1). The acid can protonate N -heterocycle, resulting in a cis–trans isomer switch and selective metal-insertion along the isomerization pathway . From an early stage we identified the use of acid as essential for the formation of the desired product using Pd/phosphine catalysis (entries 1–10).…”

mentioning

confidence: 99%

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

et al. 2017

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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 n → π 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.

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Solvent-dependent conformational switching of the aromatic N-methyl amides depending upon the acceptor properties of solvents

Cited by 18 publications

References 28 publications

Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

Why Do N-Alkylated Anilides Bend Over? The Factors Dictating the Divergent Conformational Preferences of 2° and 3° N-Aryl Amides

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

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