o-Xylyl bromide → (Z)-7-Chloro-5-(4-methoxyphenyl)-1-methyl-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one

HRID 885007Notes

Reaction equation

HRID 885007 reaction equation
C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH:15]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1

Participants

6

Reactant 4

HCID 6992o-Xylyl bromideHCID 308581814-BENZDIAZPIN-2-ONE,1ME5-(4MEOPH)7CLHCID 18522661Acetone cardiceHCID 23665647Potassium tert-butoxide

Product 1

HCID 59594404(Z)-7-Chloro-5-(4-methoxyphenyl)-1-methyl-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-oneYield 84.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred and cooled (dry ice/acetone bath) solution of (Z)-7-chloro-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.50 g, 1.59 mmol) in THF (8 mL) was slowly added 1 M KOtBu (2.4 mL, 2.4 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 2-methylbenzyl bromide (0.46 g, 2.5 mmol, 1.5 eq) in THF (2 mL). After stirring another ˜35 min at −78° C., the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 20-40% EtOAc/heptane gave 0.56 g (yield of 84%) of the title product [Note: when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature]. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.41 (s, 3H), 3.5-3.65 (m, 2H), 3.74 (dd, 1H), 3.84 (s, 3H), 6.89 (dt, 2 H), 7.05-7.15 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.5 (m, 3H).

Workup

  1. stirringThe resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min
  2. stirringAfter stirring another ˜35 min at −78° C.
  3. customthe reaction mixture was quenched with water
  4. additiondiluted with EtOAc
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated (rotovap

Sources & evidence

ORD record
ord-ceca491088ce4100918ef7243b6d155b
Source dataset
uspto-grants-2012_08
Patent number
US08242109B2

Reaction notes

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