Methanesulfonic Acid → 7-Bromo-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline

HRID 576093Notes

Reaction equation

HRID 576093 reaction equation
CS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[CH2:10][N:11]([CH3:22])[CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)O.[OH-].[NH4+]>ClCCCl>[Br:6][C:7]1[CH:8]=[C:9]2[C:23]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH2:12][N:11]([CH3:22])[CH2:10]2)=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 6395Methanesulfonic AcidHCID 14923Ammonium HydroxideHCID 667881872-((3-Bromobenzyl)(methyl)amino)-1-p-tolylethanol

Product 1

HCID 667885467-Bromo-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinolineYield 40%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
40 °C

Procedure

Methane sulfonic acid (30 mL, 480 mmol) was added dropwise via addition funnel to a mixture of the product from Step B (4.58 g, 8.57 mmol) in 1,2-dichloroethane (80 mL) at 40° C. After the addition was completed, the reaction mixture was heated at 40° C. for an additional hour. The cooled reaction mixture was poured over ice and made basic to pH 9 with concentrated ammonium hydroxide. The reaction mixture was extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (120 g silica; 90:10 hexane/ethyl acetate) provided 7-bromo-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline (1.05 g, 40%). This product was resolved by chrial HPLC (Chiralpak AD, 95:5 heptane/isopropanol with 0.1% diethylamine). The (+)enantiomer (430 mg, 41%) was obtained as a clear oil: [α]25d+11.9° (0.2, methanol); 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 4.03-3.98 (m, 1H), 3.70 (d, J=15.0 Hz, 1H), 3.56 (d, J=15.0 Hz, 1H), 3.01-2.98 (m, 1H), 2.53-2.49 (m, 1H), 2.40 (s, 3H), 2.32 (s, 3H).

Workup

  1. additionAfter the addition
  2. customThe cooled reaction mixture
  3. additionwas poured over ice
  4. extractionThe reaction mixture was extracted with ethyl acetate (4×)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification by column chromatography (120 g silica; 90:10 hexane/ethyl acetate)

Sources & evidence

ORD record
ord-ab7e8524c1f44631924f3b2a2cd93487
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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