- March 2013 (4)
- February 2013 (6)
- January 2013 (9)
- December 2012 (13)
- November 2012 (20)
- October 2012 (25)
- September 2012 (23)
- August 2012 (3)
- July 2012 (12)
- June 2012 (6)
- March 2012 (15)
- February 2012 (12)
- January 2012 (14)
- December 2011 (5)
- November 2011 (12)
- October 2011 (14)
- September 2011 (20)
- August 2011 (14)
- JRC 2-1 (2)
The title compound was synthesised according to the procedure of Carrol with no modifications.
1) 5‐Amino‐2H‐pyran‐3(6H)‐one, 1, a Convenient Intermediate in the Synthesis of Pyran Containing 1,4‐Dihydropyridines DOI:10.1081/SCC-120027702
PT-1-11A (16.6 mg 48.8 umol), was suspended in MeOH (10 ml) and saturated aqueous ammonia (10 ml) and stirred for 30 minutes, whereupon TLC indicated completion. The reaction was concentrated in vacuo to give a solid which was purified the same way as Amidation of PT-1-9A (PT-1-10) then dried in vacuo to give a white solid PT-1-12-C1 (7 mg, 21 umol, 43%, Rf 0.55 (ethyl acetate)).
Analysis: NMR consistent with Amidation of PT-1-9A (PT-1-10), sans N-methyl group and introduction of an N-H at 5.1 ppm, plus traces of ethyl acetate. Mass spec consistent (ESI-Nom).
Following the procedure of Amination of PT-1-4 (PT-1-9), crude product Resynthesis of MD 6-3 (PT-1-4) (120 mg, 62% purity, 0.2 mmol) was suspended in 1ml of dry dichloromethane and to this was added dry dimethylformamide (1 equivalent, 14 mg, 15 ul, ca. 1 drop) followed by dropwise oxalyl chloride (8 equivalents, 203 mg, 137 uL). The reaction mixture was stirred at room temperature under an atmosphere of dry nitrogen overnight, whereupon TLC indicated generation of the acid chloride. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml), then dried over MgSO4 and concentrated in vacuo to give a brown oil (ca. 130 mg). This oil was suspended in dry pyridine (10 ml) and to this was added glycine methyl ester hydrochloride (5 eq, 1 mmol, 126 mg). The reaction mixture was stirred at room temperature for three hours, whereupon TLC indicated consumption of the acid chloride (Rf = 0.6, 1:1 ethyl acetate:heptane, PT-1-11-A1 TLC, left-hand spot) with concommitant appearance of a new product (Rf = 0.3, 1:1 ethyl acetate:heptane, PT-1-11-A1 TLC, right-hand spot). The solvents were removed in vacuo and the residue purified by DCVC (gradient, ethyl acetate/heptane, 25, 33, 41, 50, 66, 83, 100%) to givea tan oil (16.6 mg, 48 umol, 24%)
Risk Assessment as in Amination of PT-1-4 (PT-1-9)
1H and 13C were consistent with desired product plus some solvent residual peaks. By analogy to the N-methyl analogue previously prepared Resynthesis of MD 6-3 (PT-1-4), the CH3 peak at 2.9 ppm is no longer present.
Additional Observations: crude samples decomposed in NMR tubes at room temperature with indirect sunlight over the course of 72 hours. Reduced yield due to the second step not going to completion; TLC indicated absence of SM but may have been present as the activated ester pyridinium complex.
The product from the previous step Amination of PT-1-4 (PT-1-9) (42.1 mg 118 umol), was suspended in MeOH (10 ml) and saturated aqueous ammonia (10 ml) and stirred for 1 hour, whereupon TLC (PT-1-10-A1) indicated completion (ca. 90% pure by NMR, PT-1-10-B1). The reaction was concentrated in vacuo and purified by dry column vacuum chromatogrphy (gradient: 50-100% ethyl acetate, background heptane, 6 fractions, then ethyl acetate, 6 fractions) to give the desired product as a white foam (28.1 mg, 82 umol, 69%).
Mass spectroscopy: ESI-NOM found 362.0 [M+Na]+, 700.6 [2M + Na]+. ESI-ACC pending.
NMR Spectroscopy: Consistent with expected product.
Crude product Resynthesis of MD 6-3 (PT-1-4) (120 mg, 62% purity, 0.2 mmol) was suspended in 1ml of dry dichloromethane and to this was added dry dimethylformamide (1 equivalent, 14 mg, 15 ul, ca. 1 drop) followed by dropwise oxalyl chloride (8 equivalents, 203 mg, 137 uL) . The reaction mixture was stirred at room temperature under an atmosphere of dry nitrogen. Thin layer chromatography (t = 5 minutes, PT-1-9-A1) indicated the formation of a new, non-polar spot (Rf = 0.31, 1:3 EtOAc:Heptane) which did not coincide with starting material, oxalyl chloride, or pyridine. The new spot could be transformed into a more polar compound (Rf = 0.1, 1:3 EtOAc:Heptane) by the action of aqueous ammonia, suggesting a sulfonanic acid/sulfonamide conversion. This material displayed a mass spectrum consistent with a primary sulfonamide (m/z = 269, [M+H]+, 252 [M-NH2]+). Significant polar material remained (Rf = 0, 1:19 MeOH:CHCl3), so the reaction was left to stir overnight at room temperature. TLC indicated no further progress , and a portion quenched with 10% NaOH slowly reverted to starting material (Rf = 0.1, 1:19 MeOH:CHCl3).
A portion of the reaction mixture was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated . NMR (PT-1-9-A2) indicated the presence of a mono-substituted compound with intact pyrrole signals and split methyl peaks. The remaining reaction mixture was worked up in the same way to give a brown oil (100.4 mg, >99% recovery) , which was dissolved in dry pyridine (10 ml) and mixed with ClH•H-Sar-OMe (1 mmol, 5 eq, 125.55 mg). The reaction mixture was stirred overnight at room temperature. A sample taken was consistent with conversion to the desired product (m/z = 355, NMR consistent) . The solvent was removed in vacuo, and the residue dissolved in dichloromethane and washed with saturated aqueous sodium carbonate, then dried over magnesium sulfate and evaporated directly onto silica and purified by dry column vacuum chromatography  (1:3 ethyl acetate:heptane, TLC PT-1-9-C1) to give a cloudy white oil (PT-1-9-C1, 49.5 mg, 140 umol, 70% over 2 steps).
Proton NMR (PT-1-9-C1) indicates all signals present and accounted for, with correct integrals (4:1:2:3:3:3:3). Comparison to the doubly-substituted pyrrole Attempted synthesis of sulfonamide PT-1-3 indicates several differences that indicate mono-substitution only.
13C shows Carbon-Fluorine coupling, but by comparison with Scale-up (20 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-5) the following changes can be discerned: Pyrrole methyl peaks no longer symmetrical (12.64, 11.75). Additional peaks due to incorporation of Sarcosine: 169.46 (q, sp2), 52.13 (sp3, CH2/OMe) 51.05 (sp3, OMe/CH2), 36.79 (sp3, NMe). The possibility of 19F-13C decoupled spectroscopy is being investigated to clear this up.
Mass spectroscopy: ESI-MS nominal m/z = 377 [M+Na]+ (isotope peaks consistent
 the oxalyl chloride generated copious bubbles without elevating the temperature, probably indicating a rapid reaction with generation of CO rather than the solvent boiling.
 By eye, the TLC indicates only small changes (an extra faint spot) happened overnight, suggesting again the reaction was done in 5 minutes, but can mostly tolerate longer reaction times
 Most of the expected mass balance (100 ul of RM) survived the workup, in contrast to previous experiments - this would be unlikely if sulfonic acids were the predominant species.
 sample displayed a distinctive musty acid-chloride-like odour; this could be due to traces of (COCl)2.
 Dry Column Vacuum Chromatography used custom glassware, and procedures as described in the Curly Arrow blog, and references therein.