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17th January 2013 @ 18:13

Reaction Scheme

Solid PT 1-1 (567 mg, 3mmol) was dissolved in dry dichloromethane (3 mL). The reaction was split into three equal parts A, B, and C. To each portion was added 1, 2, and 4 equivalents of chlorosulfonic acid respectively (1eq = 1mmol, 116.5 mg, 66.5 uL). The reactions were stirred at RT under nitrogen for 16h. Sarcosine methyl ester hydrochloride (1.88g, 15 mmol) was suspended in dichloromethane and washed with 10% NaOH solution. After drying over MgSO4, most of the dichloromethane was carefully evaporated and the residue taken up in pyridine (6 ml). The solution was split into three equal parts and added dropwise  to reactions A, B, and C with cooling in an ice-bath (5 eq. per reaction). The reactions were then stirred at room temperature for 4 hours, whereupon TLC indicated the formation of a new spot and consumption of starting material in C only (with highly polar species also present in every case). The reactions were then worked up as follows:

The reaction mixture was diluted with EtOAc (40 mL) and washed with 50mL each of saturated aqueous sodium carbonate, 2M HCl and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield a solid.

A: 51.0mg, Starting material (by 1H NMR)

B: 53.4mg, Starting material (by 1H NMR)

C: 86.5mg brown-red oil.

 

68.3mg of the crude product C was purified by dissolving in ethyl acetate and passing through a plug of silica with 88% recovery to give a pale green oil D, subjected to further analysis. NMR indicated double substitution. MS-ESI+ [M+Na]+ = 542

 

NMR:

PT-1-3D.pdf
PT-1-3D 13C.pdf

 

 

 

 

MS:

PT-1-3C mass spec.jpg
Linked Entries
Attached Files
PT-1-3 scheme.png
Sarcosine Freebase.pdf
Sarcosine HCl.pdf
PT-1-3C.pdf
PT-1-3A.pdf
PT-1-3B.pdf
PT-1-3D NMR.zip
PT-1-3D.pdf
PT-1-3 scheme new.png
PT-1-3C mass spec.jpg
PT-1-3D 13C.pdf
Comments
Re: Synthesis of sulfonamide PT-1-3 by Patrick Thomson
17th January 2013 @ 19:03
The reactions warmed to the boiling point of DCM during the addition... I don't think it was as dry as the bottle claims.
Re: Synthesis of sulfonamide PT-1-3 by Patrick Thomson
18th January 2013 @ 13:32
The amine addition was significantly exothermic as it also destroyed the excess equivalents of ClSO3H - more foaming was observed in B and most in C, in line with expectations.
Re: Synthesis of sulfonamide PT-1-3 by Patrick Thomson
18th January 2013 @ 19:11
During the preparation of the freebased sarcosine methyl ester, I established that it was volatile enough to be removed on a rotary evaporator, hence there shouldn't be any left in the final samples.
Re: Synthesis of sulfonamide PT-1-3 by Patrick Thomson
18th January 2013 @ 19:16
From my skim over Chlorosulfonic Acid: A Versatile Reagent it seems that chlorosulfonation "most probably" goes via a sulfonation, then subsequent chloronation with another equivalent of ClSO3H - so it'd take at least 1.1 equivalents before something other than the sulfonic acid was generated.
Re: Attempted synthesis of sulfonamide PT-1-3 by Andrey
26th January 2013 @ 21:33
Dear Patrick! It's not surprising that your DCM solution was boiling upon the addition of chlorosulfonic acid. The reaction is exothermic + evolution of HCl. Try to do it in an ice-water bath with addition of 1.2 eq of chlorosulfonic acid
Re: Attempted synthesis of sulfonamide PT-1-3 by Patrick Thomson
31st January 2013 @ 10:47
Andrey, thanks! Unfortunately I needed to use an excess of chlorosulfonic acid - but I'll admit I got lazy with the ice.
Re: Attempted synthesis of sulfonamide PT-1-3 by Patrick Thomson
31st January 2013 @ 10:48
Freebasing the H-Sar-OMe was necessary on purely pragmatic grounds - it wasn't soluble at the required concentrations. This can be omitted in more dilute reactions.