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14th March 2011 @ 06:22
Bronsted acid-catalyzed Pictet-Spengler cyclization of 'Ugi-intermediates' of PZQ (derivatives) using rac-1,1’-Binaphthalene-2,2’-disulfonic acid as a strong Bronsted-acidic catalyst.

Reaction Scheme


See also:
  • Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)
  • Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7 (MW42-1 to MW42-7)
  • Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis
  • [3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)
  • Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41)
    and following experiments:
  • Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)
  • Continuation: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-9 to MW56-12)

    Hazard and Risk Assessment:
  • HRAF MW56.pdf


    Start time: 6:30 pm 14/03/2011
    End time: 9:30 am 16/03/2011

    MW56-1:
    A solution of MW29-4 (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) and 1,1’-Binaphthalene-2,2’-disulfonic acid (2.1 mg, 5.0 µmol, 10 mol%, M.W. 414.5 g/mol) in toluene (1 mL) was stirred for 16 h at 70°C.
    Product, see: PZQ

    LCMS (ESI +): m/z (%) = 345 [hemiacetal] (100), 399 [M+Na] (30), 775 [2M+Na] (30). -> starting material (see MW56-3)
    Data: LCMS MW56-1 after 16h.pdf

    - heated for a furter 24 h (reaction time 30 h)
    LCMS (column: C18 waters sunfire, gradient A: water, B acetonitrile + 0.1% formic acid; 0 to 100% B over 15 min, flow 0.2 mL/min)
    Data: LCMS MW56-1 (30h).pdf -> starting material, small amount of PZQ

    MW56-2:
    A solution of MW51-1 (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) and 1,1’-Binaphthalene-2,2’-disulfonic acid (2.1 mg, 5.0 µmol, 10 mol%, M.W. 414.5 g/mol) in toluene (1 mL) was stirred for 16 h at 70°C.
    Product, see: MW53-4
    LCMS (ESI +): m/z = 339 [hemiacetal] (100), 393 [M+Na] (30), 763 [2M+Na] (30). Data: LCMS MW56-2 after 16h.pdf
    - heated for a furter 24 h
    LCMS: starting material, small amount of product
    Data: LCMS MW56-2 (30h).pdf

    MW56-3:
    A solution of MW40-1 (21.8 mg, 50.0 µmol, M.W. 436.5 g/mol) and 1,1’-Binaphthalene-2,2’-disulfonic acid (2.1 mg, 5.0 µmol, 10 mol%, M.W. 414.5 g/mol) in toluene (1 mL) was stirred for 16 h at 70°C.
    LCMS (ESI +): m/z = 405 [hemiacetal] (100), 459 [M+Na] (30). Data: LCMS MW56-3 after 16h.pdf
    - heated for a furter 24 h
    Data: LCMS MW56-3 (30h).pdfData: LCMS MW40-1 starting material for MW56-3.pdf

    MW56-4:
    A solution of MW52-1 (21.5 mg, 50.0 µmol, M.W. 430.5 g/mol) and 1,1’-Binaphthalene-2,2’-disulfonic acid (2.1 mg, 5.0 µmol, 10 mol%, M.W. 414.5 g/mol) in toluene (1 mL) was stirred for 16 h at 70°C.
    Product, see: MW54-3
    LCMS (ESI +): m/z = 399 [hemiacetal] (100), 453 [M+Na] (30). Data: LCMS MW56-4 after 16h.pdf
    - heated for a furter 24 h
    Data: LCMS MW56-4 (30h).pdf

    - Catalyst is sparingly soluble in toluene at rt -> temperature raised to 70°C after 30 min.

    After 16 h:
    - TLC (ethyl acetate, 100%; stain:ceric ammonium molybdate) showed no difference between starting material and product (no reaction?)
    TLC MW56-1 to MW56-4.JPG

    - 10 µL of each sample were withdrawn, purified by a small column (silica gel, ethyl acetate, 100%), evaporated and dissolved in acetonitrile (c= 0.05 mg/mL), filtered by a syringe filter and evaluated by LC/MS.
    LCMS showed mass of the hemiaminals but also the starting material [M+Na] and the dimere of it and only one LC peak in the PDA spectrum
    -> hemiaminal or fragmentation of the starting material ??
    hemiaminal.png


    After 30 h:
    TLC MW56-1 to MW56-8.JPG


    LCMS of reaction and starting material (fragmentation?)

    See also: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)

    Results:
    -> non-selective reaction for MW56-5 and MW56-6 (unactivated compound) - increasing the catalyst concentration
    -> almost selective Pictet-Spengler reaction of both dimethoxy-substituted Ugi-intermediates
    Linked Posts
    Attached Files
    Reaction Scheme
    HRAF MW56.pdf
    TLC MW56-1 to MW56-4.JPG
    LCMS MW56-1 after 16h.pdf
    LCMS MW56-2 after 16h.pdf
    LCMS MW56-3 after 16h.pdf
    LCMS MW56-4 after 16h.pdf
    TLC MW56-1 to MW56-8.JPG
    hemiaminal.png
    LCMS MW56-1 (30h).pdf
    LCMS MW56-2 (30h).pdf
    LCMS MW56-3 (30h).pdf
    LCMS MW40-1 starting material for MW56-3.pdf
    LCMS MW56-4 (30h).pdf
    Comments
    Re: Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4) by Matthew Todd
    15th March 2011 @ 10:14
    That's odd. No reaction at all? I'd expect the acetal to go, even if the cyclization does not. Your follow-up reaction with MeSO3H is the right thing to do, yes.
    ;