Configuration of the amide bond in N-acylindolines and N-acyltetrahydroquinolines

Nagarajan, K.; Nair, M. D.; Pillai, Prasanth A.

doi:10.1016/s0040-4020(01)82566-7

Cited by 73 publications

(19 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The geometry-optimized structures of 1a ( Figure 2) show that the N-CH 3 of Z 1 but not of E 1 is in the diamagnetic region of the isoquinolinyl ring current field and that this ring current likely causes the reversal of the N-CH 3 peaks. 36,38 Both 1 H and 13 C peak intensity invariably favored assignment of E as the major rotamer of 1a in solution. This does not fully agree with our calculations, which indicate that Z 1 and E 1 are isoenergetic.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Lee

Siméon

Briard

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Eighteen kilodalton translocator protein (TSPO) is an important target for drug discovery and for clinical molecular imaging of brain and peripheral inflammatory processes. PK 11195 [1a; 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinoline carboxamide] is the major prototypical high-affinity ligand for TSPO. Elucidation of the solution structure of 1a is of interest for understanding small-molecule ligand interactions with the lipophilic binding site of TSPO. Dynamic 1 H/ 13 C NMR spectroscopy of 1a revealed four quite stable but interconverting rotamers, due to amide bond and 2-chlorophenyl group rotation. These rotamers have been neglected in previous descriptions of the structure of 1a and of the binding of 1a to TSPO. Here, we used quantum chemistry at the level of B3LYP/ 6-311+G(2d,p) to calculate 13 C and 1 H chemical shifts for the rotamers of 1a and for the very weak TSPO ligand, N-desmethyl-PK 11195 (1b). These data, plus experimental NMR data, were then used to characterize the structures of rotamers of 1a and 1b in organic solution. Energy barriers for both the amide bond and 2′-chlorophenyl group rotation of 1a were determined from dynamic 1 H NMR to be similar (ca.17 to 18 kcal/mol), and they compared well with those calculated at the level of B3LYP/6-31G*. Furthermore, the computed barrier for Z to E rotation is considerably lower in 1a (18.7 kcal/mol) than in 1b (25.4 kcal/mol). NMR (NOE) unequivocally demonstrated that the E rotamer of 1a is the more stable in solution by about 0.4 kcal/mol. These detailed structural findings will aid future TSPO ligand design and support the notion that TSPO prefers to bind ligands as amide E-rotamers.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 98%

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Lee

Siméon

Briard

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…and from d i~o l e moment \ 1 , studies for solutions of several anilides in benzene and in dioxan (34). In both studies angles of approximately 38" between the planes containing the amide group and the aromatic ring were p r o p o~e d .~ For N-acetyl indoline, where coplanarity is ensured by the carbons of the indoline ring rather than a hydrogen bond, the acylation shift ofH-7is 106 Hz (35). 2Carter (4), employing a different rationale, has model for the anisotropy of the carbonyl group is theorized that this difference should be about 0.3 p.p.m., possible with slight extension of the deshielding cone.…”

Section: Discussionmentioning

confidence: 99%

Proton magnetic resonance spectra of some aromatic amines and derived amides

Brown¹,

Radom²,

Sternhell³

et al. 1968

Can. J. Chem.

View full text Add to dashboard Cite

The chemical shifts of ring protons in substituted anilines, N-methylanilines, some heterocyclic amines, and their derived acetamides and 4'-bromobenzamides are reported. The magnitude of the downfield shift accompanying acylation is related to the preferred configuration of the amide.Canadian Journal of Chemistry, 46, 2577Chemistry, 46, (1968 IntroductionIn connection with another project (1) we have commented on the relation between the downfield shifts of ring protons accompanying acetylation of anilines and the substitution pattern in the aromatic ring. The present work represents a systematic extension of these observations and rationalization of the principal effects observed.

show abstract

“…quinolin-2(4H)one: [31] SmI 2 (4.5 mL of a 0.1 m solution in THF, 0.45 mmol, 2.5 equiv) was added to a solution of 1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfanyl)-5,6-dihydro-1H-pyrroloA C H T U N G T R E N N U N G [3,2,1-ij]quinolin-2(4H)-one (2) (118 mg, 0.18 mmol, 1 equiv) in THF (5 mL) and the reaction was allowed to stir at room temperature for 24 h. NaHCO 3 (10 mL) was added to the reaction and the aqueous layer was extracted with EtOAc (2 10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo.…”

Section: -mentioning

confidence: 99%

A Fluorous, Pummerer Cyclative‐Capture Strategy for the Synthesis of N‐Heterocycles

McAllister

McCormick

James

et al. 2007

Chemistry A European J

View full text Add to dashboard Cite

A fluorous, cyclative-capture strategy based on a new Pummerer cyclization process allows rapid access to tagged, heterocyclic frameworks. Convenient modification of the fluorous, heterocyclic scaffolds by using a variety of approaches including Pd-catalyzed cross-couplings is possible. Traceless, reductive cleavage of the fluorous-phase tag or oxidative cleavage and further elaboration, completes a strategy for the high-throughput, fluorous-phase synthesis of a diverse range of N-heterocycles.

show abstract

Configuration of the amide bond in N-acylindolines and N-acyltetrahydroquinolines

Cited by 73 publications

References 11 publications

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Proton magnetic resonance spectra of some aromatic amines and derived amides

A Fluorous, Pummerer Cyclative‐Capture Strategy for the Synthesis of N‐Heterocycles

Contact Info

Product

Resources

About

Configuration of the amide bond in N-acylindolines and N-acyltetrahydroquinolines

Cited by 73 publications

References 11 publications

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

Proton magnetic resonance spectra of some aromatic amines and derived amides

A Fluorous, Pummerer Cyclative‐Capture Strategy for the Synthesis of N‐Heterocycles

Contact Info

Product

Resources

About

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with ¹H/¹³C NMR Spectroscopy and Quantum Chemistry