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17th March 2011 @ 07:14
Acid-catalyzed Pictet-Spengler using methanesulfonic acid in various concentrations

Continuation of Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8)

reaction scheme MW56-9 to MW56-14


reaction scheme MW56-9 to MW56-14


See also:
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)

Hazard and Risk Assessment:
HRAF MW56.pdf


Start time: 6:30 pm 17/03/2011
End time: 9:30 am 18/03/2011

MW56-9:
A solution of MW29-4 (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) and methanesulfonic acid (4.8 mg, 50.0 µmol, 3.25µL, 1 eq., M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 15 h at 70°C.
Data: LCMS MW56-9 (16h).pdf: unspecific signals, no starting material or product
[M.W.(PZQ) = 312 g/mol]

MW56-10:
MW29-4 (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) was dissoved in a solution of toluene (0.9 mL) and methanesulfonic acid (0.1 mL) and was stirred for 15 h at 70°C.
Data: LCMS MW56-10 (16h).pdf: PZQ (RT = 13.3 min) + unknown side product (RT = 12.9 min, m/z = 339)

MW56-11:
MW29-4 (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) was dissoved in a solution of chloroform (0.9 mL) and methanesulfonic acid (0.1 mL) and was stirred for 15 h at 65°C.
Data: LCMS MW56-11 (16h).pdf: unknown main product (RT = 12.9 min, m/z = 339), see MW56-10, PZQ (RT = 13.3 min)

MW56-12:
A solution of MW51-1 (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) and methanesulfonic acid (4.8 mg, 50.0 µmol, 3.25µL, 1 eq., M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 15 h at 70°C.
Data: LCMS MW56-12 (16h).pdf: N-benzyl-PZQ (RT = 12.4 min), no side products visible
[M.W.(N-benzyl-PZQ) = 306 g/mol]


MW56-13:
MW51-1 (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) was dissoved in a solution of toluene (0.9 mL) and methanesulfonic acid (0.1 mL) and was stirred for 15 h at 70°C.
Data: LCMS MW56-13 (16h).pdf: N-benzyl-PZQ (RT = 12.4 min), no side products

MW56-14:
MW51-1 (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) was dissoved in a solution of chloroform (0.9 mL) and methanesulfonic acid (0.1 mL) and was stirred for 15 h at 65°C.
Data: LCMS MW56-14 (16h).pdf: N-benzyl-PZQ (RT = 12.3 min), no side products


Work-up:
- neutralized with sat. Na2CO3 solution, extracted with ethyl acetate, dried over Na2SO4.
- sample preparation for LCMS: 30 µL solution (c=3.3 mg/mL in ethyl acetate) was filtered through a micro column (silica gel, ethyl acetate, 100%) and evaporated. The residue (about 10 µg) was dissolved in 2.5 mL acetonitrile (c ~ 40 µg/mL).

TLC1: before work-up (ethyl acetate, 100%, stain: potassium permanganate)
TLC2: after work-up (ethyl acetate, 100%, stain: potassium permanganate)
TLC1 MW56-9 to 14.jpg
TLC2 MW56-9 to 14.JPG


* LCMS Method: HPLC: Waters sunfire C18; gradient A water, B acetonitrile + 0.1 % formic acid, 0 to 100%B over 15 min, flow 0.2 ml/min flow rate.

Results:
MW56-9 to MW56-11 (Ugi-intermediate):
Different results for different conditions; no product in MW56-9 (mistake in the procedure ??), different product/ (unknown) side product ratio for toluene and chloroform, respectively

MW56-12 to MW56-14 (N-benzoyl-intermediate):
Clean Pictet-Spengler cyclization to N-benzoyl-PQZ in all cases, no side products obtained.
Linked Posts
Attached Files
15th March 2011 @ 05:28
Acid-catalyzed Pictet-Spengler using 10 mol% methanesulfonic acid in order to compare the results of Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)

Reaction Scheme


Hazard and Risk Assessment:
HRAF MW56.pdf


See also: Continuation: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-9 to MW56-14)

Start time: 5:40 pm 15/03/2011
End time: 9:30 pm 16/03/2011

MW56-5:
A solution of MW29-4 (18.8 mg, 50.0 µmol, M.W. 376.5 g/mol) and methanesulfonic acid (0.48 mg, 5.0 µmol, 10 mol%, M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 17 h at 70°C.
- orange solution

LCMS: unselective reaction, no specific product / starting material signals.
Data: LCMS MW56-5 (16h).pdf

MW56-6:
A solution of MW51-1 (18.5 mg, 50.0 µmol, M.W. 370.4 g/mol) and methanesulfonic acid (0.48 mg, 5.0 µmol, 10 mol%, M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 17 h at 70°C.
Product, see: MW53-4
- yellow solution

LCMS: unselective reaction, no specific product / starting material signals.
Data: LCMS MW56-6 (16h).pdf

MW56-7:
A solution of MW40-1 (21.8 mg, 50.0 µmol, M.W. 436.5 g/mol) and methanesulfonic acid (0.48 mg, 5.0 µmol, 10 mol%, M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 17 h at 70°C.
- brown solution

LCMS: no more starting material, two peaks with the mass of the prodcut m/z = 373 [M+H]+ (RT = 10.23, 11.15).
Data: LCMS MW56-7 (16h).pdf

MW56-8:
A solution of MW52-1 (21.5 mg, 50.0 µmol, M.W. 430.5 g/mol) and methanesulfonic acid (0.48 mg, 5.0 µmol, 10 mol%, M.W. 96.1 g/mol) in toluene (1 mL) was stirred for 17 h at 70°C.
- orange solution
Product, see: MW54-3

LCMS: no more starting material, two peaks with the mass of the prodcut m/z = 367 [M+H]+ (RT = 9.551, 10.37).
Data: LCMS MW56-8 (16h).pdf

TLC (ethyl acetate, stain: ceric ammonium molybdate):
TLC MW56-1 to MW56-8.JPG


* LCMS Method: HPLC: Waters sunfire C18; gradient A water, B acetonitrile + 0.1 % formic acid, 0 to 100%B over 15 min, flow 0.2 ml/min flow rate.

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
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