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Pictet-Spengler route to Praziquantel
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14th March 2011 @ 06:22
Bronsted acid-catalyzed Pictet-Spengler cyclization of 'Ugi-intermediates' of PZQ (derivatives) using [url=http://www.ourexperiment.org/racemic_pzq/587][i]rac[/i]-1,1’-Binaphthalene-2,2’-disulfonic acid[/url] as a strong Bronsted-acidic catalyst. [data=size:500x220]889[/data] See also: [*] [url=http://www.ourexperiment.org/racemic_pzq/262]Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/470]Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7 (MW42-1 to MW42-7)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/525]Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/464]Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41)[/url] and following experiments: [*] [url=http://www.ourexperiment.org/racemic_pzq/1765]Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)[/url] [*] [url=http://www.ourexperiment.org/racemic_pzq/1799]Continuation: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-9 to MW56-12)[/url] [b]Hazard and Risk Assessment:[/b] [data]891[/data] Start time: 6:30 pm 14/03/2011 End time: 9:30 am 16/03/2011 [b]MW56-1:[/b] A solution of [url=http://www.ourexperiment.org/racemic_pzq/241][b]MW29-4 [/b][/url] (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) and [url=http://www.ourexperiment.org/racemic_pzq/587]1,1’-Binaphthalene-2,2’-disulfonic acid[/url] (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: [url=http://www.ourexperiment.org/racres_pzq/1700][b]PZQ[/b][/url] LCMS (ESI +): m/z (%) = 345 [hemiacetal] (100), 399 [M+Na] (30), 775 [2M+Na] (30). -> starting material (see MW56-3) [data=text]897[/data] - 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=text]911[/data] -> starting material, small amount of PZQ [b]MW56-2:[/b] A solution of [url=http://www.ourexperiment.org/racemic_pzq/1555][b]MW51-1[/b][/url] (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) and [url=http://www.ourexperiment.org/racemic_pzq/587]1,1’-Binaphthalene-2,2’-disulfonic acid[/url] (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: [url=http://www.ourexperiment.org/racemic_pzq/1654][b]MW53-4[/b][/url] LCMS (ESI +): m/z = 339 [hemiacetal] (100), 393 [M+Na] (30), 763 [2M+Na] (30). [data=text]899[/data] - heated for a furter 24 h LCMS: starting material, small amount of product [data=text]913[/data] [b]MW56-3:[/b] A solution of [url=http://www.ourexperiment.org/racemic_pzq/386][b]MW40-1[/b][/url] (21.8 mg, 50.0 µmol, M.W. 436.5 g/mol) and [url=http://www.ourexperiment.org/racemic_pzq/587]1,1’-Binaphthalene-2,2’-disulfonic acid[/url] (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=text]901[/data] - heated for a furter 24 h [data=text]915[/data][data=text]917[/data] [b]MW56-4:[/b] A solution of [url=http://www.ourexperiment.org/racemic_pzq/1597][b]MW52-1[/b][/url] (21.5 mg, 50.0 µmol, M.W. 430.5 g/mol) and [url=http://www.ourexperiment.org/racemic_pzq/587]1,1’-Binaphthalene-2,2’-disulfonic acid[/url] (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: [url=http://www.ourexperiment.org/racemic_pzq//1658][b]MW54-3[/b][/url] LCMS (ESI +): m/z = 399 [hemiacetal] (100), 453 [M+Na] (30). [data=text]903[/data] - heated for a furter 24 h [data=text]919[/data] - 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?) [data]895[/data] - 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 ?? [data]907[/data] After 30 h: [data]905[/data] LCMS of reaction and starting material (fragmentation?) See also: [url=http://www.ourexperiment.org/racemic_pzq/1765]Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)[/url] [b]Results:[/b] -> 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
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.