Benzamide → HCID 89928165, compound

HRID 879981Notes

Reaction equation

HRID 879981 reaction equation
[C:1]([NH2:9])(=O)[C:2]1C=CC=CC=1.[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(C(F)(F)F)=O.[CH:50]([NH2:53])(C)C.[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:11])[CH3:12].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[C:50](=[C:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:53][NH:9][C:1]#[CH:2])([CH3:55])[CH3:56]

Participants

9

Reactant 5

HCID 2331BenzamideHCID 6363IsopropylamineHCID 6422Trifluoroacetic acidHCID 89928165HCID 89928165, compoundHCID 89945982HCID 89945982, compound

Product 3

HCID 89928165HCID 89928165, compoundHCID 89945982HCID 89945982, compoundHCID 131732635HCID 131732635, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

With these cyclization conditions in hand, N-acyl amino imidazolin-2-one amide 14 was synthesized to study the conformation of this model system in the solid state and in solution, using X-ray crystallography and NMR spectroscopy, respectively (Scheme 2). Benzhydrylidene aza-glycinyl-D-phenylalanine isopropyl amide 9 was prepared from benzhydrylidene aza-glycinyl-D-phenylalanine tert-butyl ester 7 by tertbutyl ester cleavage in a 1:1 v/v mixture of TFA: DCM, followed by coupling to iso-propylamine using a mixed anhydride approach.xx Employment of amide 9 in the alkylation and cyclization steps minimized racemization, likely due to preferential amide nitrogen deprotonation inhibiting removal of the α-hydrogen. Indeed, in comparison to the alkylation of aza-glycinyl-D-phenylalanine tert-butyl ester 7, the chemoselective alkylation of semicarbazone 9 gave aza-propargyl glycinamide 10 in 71% yield with no detectable racemization (see above). Subsequent NaH-promoted 5-exo-dig cyclization gave imidazolin-2-one 11, possessing an exocyclic double bond, in a 57% yield. However, olefin migration occurred upon hydrazone removal, using hydroxylamine hydrochloride in pyridine 11 to afford N-amino imidazalone 12, which without further purification was treated with 4-methoxybenzoyl chloride to provide N-acyl dipeptide amide 14 in 56% yield.

Workup

  1. customremoval of the α-hydrogen

Sources & evidence

ORD record
ord-daf2c7fe3ed048f8bbeaa899a8223c84
Source dataset
uspto-grants-2015_03
Patent number
US08993515B2

Reaction notes

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