TCMDC_ArylPyrrole

PT-1-14C3 (24.0 mg, 90 umol) was suspended in methanol (2ml) and ammonia (4 ml, saturated aqueous) and stirred for 1 hour, then concentrated in vacuo to give the title compound as a tan solid (22.4 mg, 98%)

Analysis: NMR Consistent with desired product,ESI-Nom 273 (M+Na)+, 523 (2M+Na). HRMS consistent.

375 mg of 4-fluorophenyl azide (2 mmol) and 127 mg of methyl propynyloxyacetate (1 mmol) were dissolved in DCM:H2O (3ml:2ml) and stirred overnight with copper sulfate (12 mg) and sodium ascorbate (20 mg). The mixture was diluted with DCM and the organic layer washed with water, dried over magnesium sulfate and concentrated in vacuo to give 272 mg of yellow solid which was purified by dry column vacuum chromatography (40% ethyl acetate in heptane, followed by 100% ethyl acetate after 20 fractions) to give 4 products:

C1, 8.6 mg orange waxy solid. Inconsistent mass spec data.

C2, 42.3 mg (15%) white solid ESI-Nom 302 (M+Na)+, 581 (2M+Na) HRMS consistent

C3, desired product, white solid, 44.7 mg (17%) ESI-Nom 288 (M+Na+), 553 (2M+Na) HRMS consistent

C4, 18.6 mg (4%) white solid ESI-Nom 449 (M+Na+), 875 (2M+Na) HRMS consistent

Results and discussion.

C1, C3, and C4 seemingly correspond to the three possible products of the previous reaction and are present due to insufficient purification of PT-1-13 shown here:

 C2 has apparently been produced by trans-esterification with ethanol even though no ethanol was used at any point.

The Mass Spectroscopy evidence for C1 is extremely unreliable, but the NMR evidence fits extremely well with analagous chemical shifts for CH2 groups in similar environments in product C4 (triazole-CH2-ester) and methyl bromoacetate (Br-CH2-ester). DEPT is consistent but there isn't enough sample to identify all the quaternary carbons - requires further study if it's a compound of interest.

C1-C4 have all been sent for antimalarial screening.

The title compound was synthesised according to the procedure of Carrol[1] with no modifications. 

References:

 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).

ESI-Acc (Finnegan MAT-900 ESI-Positive HRMS): Expected 325.08909 (C14H16O3N3FS) Found 325.08881 (0.28 ppm)

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)

Analysis:

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.