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6th July 2010 @ 11:12
Attempts to cleave the protection group of the dimethoxy acetal under acidic conditions – formation of the aldehyde or cyclisation products as an intermediate of the Pictet-Spengler cyclisation?

See also: Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)

Reaction Scheme correction


Table1


Hazard and Risk Assessment:
Reaction Class: 2
Hazards: X Irritant, C Corrosive
Risk rating: U = Unlikely

Start time: 3:30 PM 05/07/2010
End time: 7:30 PM 05/07/2010

The hydrochloride MW7 (50.0 mg, 165 µmol) was dissolved in various acids or acidic solutions as shown in Table1. The mixtures were stirred for 4 h at room temperature, quenched with water, basified with 2 N aq. NaOH to pH 12 and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated.

TLC (EA:MeOH:Et3N, 10:1:0.1; stain: Ceric ammonium molybdate)
TLC1


MW42-1:
Starting material reisolated: 38 mg (143 µmol, 87%)
Data: 1H NMR MW42-1

MW42-2:
Hemiaminal 15 mg (68.2 µmol, 41%), complete conversion of the starting material
Data: 1H NMR MW42-2
Data: 13C NMR MW42-2
hemiaminal


MW42-3:
Starting material reisolated: 42 mg (158 µmol, 96%)
Data: 1H NMR MW42-3

MW42-4:
Mixture of compounds, partial conversion to praziquanamine: 28 mg
Data: 1H NMR MW42-4

MW42-5:
Praziquanamine 19 mg (94.1 µmol, 57%), complete conversion of the starting material
Data: 1H NMR MW42-5
Data: 13C NMR MW42-5
praziquanamine


First results:
- The cleavage of the acetal needs strong acidic conditions. With 1 N HCl or a 50% aq. solution of TFA (at room temperature) only staring material could be reisolated.
- Concentrated hydrochloric acid cleaves the acetal and the formed aldehyde cyclizes to the hemiacetal
- conc. methanesulfonic acid forms the Pictete-Spengeler product praziquanamine, less concentrated acid needs longer reaction time / higher reaction temperatures (products?)


Continuation:

Table2


Start time: 2:10 PM 09/07/2010
End time (Trial MW42-2A, -7): 4:15 PM 09/07/2010
End time (Trial MW42-4A, -4B,- 6): 12:20 PM 10/07/2010

MW42-6:
2 N HCl, 22 h at r.t.
Starting material reisolated: 38 mg (143 µmol, 79%)

MW42-7:
6 N HCl, 2 h at r.t.
Starting material reisolated: 40 mg (150 µmol, 91%)

MW42-2A:
conc. HCl, 2 h at room temperature
hemiaminal 19 mg (86.2 µmol, 52%); clean conversion, only traces of impurities

MW42-4A:
10% MeSO3H in wet CHCl3, 22 h at room temperature
PZQamine 23 mg (114 µmol, 69%), small impurities, no starting material visible
1H NMR: 1. spectrum with remaining ethyl acetate, 2. spectrum: broad signals

MW42-4B:
10% MeSO3H in CHCl3, 22 h at 60°C
PZQamine (?) 27 mg, complete conversion of the starting material
NMR: very broad signals -> side products?

Summary:
- fast (tested) cleavage of the dimethoxy acetal function only with conc. HCl solution at room temperature, even 6 N HCl obtains only starting material after 2 h at r.t.

- 10% MeSO3H solution in CHCl3 (~ 1.7 N) leads to a selective cleavage of the acetal and a subsequent Pictet-Spengler cyclisation to praziquanamine after 22 h at r.t., higher concentrations or higher temperatures reduce the conversion time. Wet chloroform (in general: wet organic solvents?) doesn’t influence the formation of praziquanamine – no hemiaminal was observed!
Attached Files
Reaction Scheme
Table1
Reaction Scheme correction
1H NMR MW42-1
1H NMR MW42-1 JCAMP-DX
1H NMR MW42-2
1H NMR MW42-2 JCAMP-DX.dx
1H NMR MW42-3
1H NMR MW42-4
1H NMR MW42-5
1H NMR MW42-5 JCAMP-DX
13C NMR MW42-5
13C NMR MW42-5 JCAMP-DX
13C NMR MW42-2
13C NMR MW42-2 JCAMP-DX
TLC1
hemiaminal
praziquanamine
Table2