Closed alintheopen closed 9 years ago
mattodd
commented
11 years ago The students have finished the class and Stefan is just going through some of the spectra before making it all public. Lots of compounds appear to have been made, which is exciting.
sdebbert
commented
11 years ago Okay, sorry for the delay! I've got the following:
So: where can I send these samples for testing?
Now that we've worked out some kinks in our process here, I hope to have the next batch ready early in the summer. I'm planning on varying both aromatic rings in the next iteration, so any guidance as to what would be helpful would be appreciated. I'm looking forward to having the chance to digest all the work I see here on GitHub, and will try to tune my efforts accordingly.
Experimental details:
R = m-OCH3 (SP/JJ) 1-(3-methylphenyl)-2,5-dimethylpyrrole: m-Anisidine (5 mmol, 0.57mL) was added to 2,5-hexanedione (4.5 mmol, 0.53mL) and heated to 130ºC overnight. The reaction was combined with ether (10 mL) and citric acid (10 mL) in a separatory funnel, and the organic layer was washed with water (10 mL) followed by sodium chloride (10 mL). The organic layer was then dried over magnesium sulfate (MgSO4) and filtered. Evaporation of the solvent was followed by the addition of methanol (1 mL) and purification by flash chromatography (silica gel, hexanes-ethyl acetate, 8:1) to give the title compound as a yellow oil (350 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 7.338 (t, 1H), 6.943 (dd, 1H), 6.807 (dd, 1H), 6.753 (d, 1H), 5.891 (s, 2H), 3.804 (s, 3H), 2.045 (s, 6H).
1-(3-methylphenyl)-2,5-dimethylpyrrole-3-carboxaldehyde: Phosphoryl chloride (0.192 mL) was added to dimethylformamide (1 mL), stirring on ice and under a nitrogen atmosphere for 25 minutes. Dimethylformamide (1 mL) was added to the crude compound 1; this was added dropwise to the stirring reaction on ice. Using TLC (hexanes-ethyl acetate, 3:1) to monitor, upon completion the reaction was poured over ice. The pH was adjusted to 11 using NaOH (10%), followed by an aqueous workup where the reaction was first combined with NaOH. Ethyl acetate was added to the aqueous layer, and the two organic layers were combined; water was added, and the organic layer was then combined with a saturated brine solution. This was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure to give compound 2 as a colorless oil (117 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 9.868 (s, 1H), 7.418 (t, 1H), 7.02 (m, 1H), 6.79 (m, 1H), 6.731 (ds, J = 2 Hz, 1H), 6.375 (s, 1H), 3.847 (s, 3H), 2.299 (s, 3H), 2.008 (s, 3H); IR υmax 2921.16, 2837.17, 1734.73, 1654.77 cm-1.
Final Product: (Z)-2-((3-phenyl)imino)thiazolidin-4-one (96 mg) was dissolved in ethanol (2 mL) and piperdine (0.078 mL) was added. This was combined with the aldehyde above (115 mg) and heated to 60ºC. The reaction was monitored using TLC (hexanes-ethyl acetate, 3:1) and after 4.5 hours, the product precipitated out. This was filtered and washed with ethanol to give compound 3 as a tan powder (68 mg, m.p. 251-255°C, 33%). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.40 (m, 3H), 7.8 (m, 3H), 6.99 (m, 1H), 6.75 (m, 1H), 6.69 (t, 1H), 3.83 (s, 3H), 2.16 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.362, 138.665, 135.444, 131.565, 130.179, 129.420, 125.022, 121.808, 120.151, 115.505, 114.321, 113.740, 105.230, 55.519, 12.668, 11.050; IR υmax 2961.47, 2793.77, 1683.33, 1622.90 cm-1.
R = p-CH3 (SG/GS)
1-(4-methylphenyl)-2,5-dimethylpyrrole: p-Toluidine (0.562 g, 5.245 mmol) was combined with 2,5-hexanedione (0.530 mL, 4.518 mmol) and heated to 130º C overnight. The solution was allowed to cool and was then dissolved in ether (20 mL). Citric acid (20 mL, 10%) was added to the reaction. The bottom layer was extracted with ether (20 mL) and organic layers were combined. Organic layer was washed with H2O (15 mL) and the bottom aqueous layer was removed. Saturated NaCl (15 mL) was added to the solution and the bottom aqueous layer was separated. The organic layer was dried (MgSO4) and filtered. Filtered product was concentrated under reduced pressure. A stream of air was applied to the product, and the product was scraped until a solid formed. Recrystallization (ethanol) and vacuum filtration afforded a light brown solid (0.3243 g, 39%): Melting point 44.5º C - 45.5º C; FTIR 3033.95, 2987.29, 2919.29, 1913.44, 1625.31, 1582.40; 1H NMR (400 MHz, CDCl3) δ 7.247 (d, J= 8 Hz, 2H), 7.086 (d, J= 8 Hz, 2H), 5,884 (s, 2H), 2.415 (s, 3H), 2.019 (s, 6H).
1-(4-methylphenyl)-2,5-dimethylpyrrole-3-carboxaldehyde: Dimethylformamide (1 mL, 12.97 mmol) was put under a nitrogen atmosphere. Phosphoryl chloride (0.118 mL, 1.27 mmol) was added, and the reaction was put in an ice bath and stirred for 25 minutes; the solution turned bright red during stirring. Product pyrrole (0.2 g, 1.08 mmol) was dissolved in DMF (1 mL, 12.97 mmol) and added dropwise to the reaction over five minutes. The reaction was warmed to room temperature. TLC was performed to monitor the reaction by taking a drop of reaction product and adding 3:1 hexanes, NaOH (0.5 mL, 26.63 mmol), and ether (0.5 mL, 4.81 mmol), and then performing TLC on the top extracted layer. Product was poured over ice (20 mL), and NaOH (10%) was added to adjust the pH to 6 and then to 11. The product was stirred for 45 minutes while pH was continuously monitored. The development of crystals was observed. The product was filtered and dried for 10 minutes. Product crystals were dissolved in MeCN (3 mL), swirled, and heated until dissolved. Recrystallization and vacuum filtration yielded a dark brown crystalline solid (0.129 g, 56): Melting point 109.2º C - 111.0º C; FTIR 3333.79, 2920.23, 2738.18, 1648.91, 1532.12, 1514.79; 1H NMR (400 MHz, CDCl3) δ 9.868 (s, 1H), 7.297 (m, 2H), 7.075 (m, 2H), 6.3725 (d, 1H), 2.443 (s, 3H), 2.270 (s, 3H), 1.979 (s, 3H).
Final Product: (Z)-2-((3-phenyl)imino)thiazolidin-4-one (0.1021 g, 0.49 mmol) was dissolved in EtOH (2 ml), and piperidine (0.08 mL, 0.809 mmol) followed by product pyrrole (0.1039 g, 0.488 mmol) were added to the dissolved solution. Solution was incubated for 90 minutes (60º C); crystallization was observed. Product underwent vacuum filtration and was washed with EtOH (4 mL). Final product was a tan crystalline powder (0.0514 g, 27%): Decomposition temperature: 240.3º C; FTIR 3041.29, 2943.76, 2917.61, 2738.94, 1701.25, 1636.69, 1585.99. 1H NMR (400 MHz, CDCl3) δ 7.733, (s, 1H), 7.414 (t, J= 7.8 Hz, 2H), 7.20 (m, 5-6H), 7.041 (d, J= 8 Hz, 2H), 6.114 (s, 1H), 2.429 (s, 3H), 2.130 (s, 3H), 1.973 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 138.720, 135.653, 134.941, 131.696, 130.086, 129.420, 127.631, 126.090, 124.975, 121.777, 115.397, 105.114, 21.185, 12.707, 11.065.
R = p-OCH3 (JG/CS)
1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole: p-Anisidine (.614g, 5.0mmol) was combined with 2,5-hexanedione and heated overnight (130°C). Product was dissolved in 2 tube volumes of ether and 2 tube volumes of 10% citric acid. After separation of layers, the organic layer was washed with H2O (10 mL) and NaCL in solution (10 mL). The solution was dried with MgSO4. Filtrate was concentrated under reduced pressure. The resulting solid was dissolved in a minimal (<5 mL) amount of hot ethanol. The solution was allowed to cool and water was added dropwise until the solution became cloudy (4 drops). Solution transferred into ice-cold beaker for further crystallization. Vacuum filtration was used to filter the solution and separate out the product (0.258 g). Melting point of substance was 59.7-59.8 oC. FTIR: 3012, 3004, 2958 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.77-7.75 (m, 2H), 6.0 (s, 2H), 4.1 (s, 3H), 2.1 (s, 6H).
1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde: An ice bath was created in which POCl3 (0.144mL, 1.54mmol) and DMF (1.0mL) were added and stirred (25 min). DMF (1.0mL) was added to the above pyrrole (258mg, 1.28mmol). The two solutions were combined dropwise (5 min). Allowed reaction to warm to room temp until reaction was complete (monitored via TLC). Poured reacted material over ice. Added NaOH (approx. 6mL) dropwise (monitored pH with pH paper). The reaction was filtered under vacuum. The solid was allowed to dry overnight and then massed (172mg, 66.6%). Melting Point: 140.1°C to 141.7°C. IR: 3100, 2933, 1650.89, 1513.56 cm-1; 1H-NMR (400MHz, CDCl3) δ 9.867 (s, 1H), 7.26 (s, 1H), 7.10 (d, J= 6.8Hz, 2H), 7.01 (d, J=6.8Hz, 2H), 6.367 (s, 1H), 3.879 (s, 3H), 2.269 (s, 3H), 1.979 (s, 3 H).
Thiazolidinone Pyrrole: (Z)-2-((3-phenyl)imino)thiazolidin-4-one (0.1297 g, 0.675 mmol) was dissolved in ethanol (0.6 mL). Piperidine (0.1 mL, 1.0125 mmol) was added to this solution. The aldehyde synthesized above (0.1548g, 0.675 mmol) was combined with this solution. The solution heated at 60 °C overnight until completion (monitored by TLC). The resulting solid was filtered under vacuum. The resulting brown crystals were the final product (0.1560 g, 59.6%). The melting point was 279.0-279.5 °C. FTIR: 3401, 3093, 3054, 2943, 1628, 1590 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.41, (t, 2H) 7.22 (m, 3H) 7.07 (d, 2H), 6.98 (d, 2H), 6.11 (s, 1H), 3.86 (s, 3H), 2.13 (s, 3H), 1.97 (s, 3H).
R = p-I (KV/AH)
1-(4-iodophenyl)-2,5-dimethyl-1H-pyrrole (IDP): 4-iodoaniline (2.19 g, 10 mmol), 2,5-hexanedione (1.4 mL, 12 mmol) and sulfamic acid (50 mg, 0.5 mmol, 5 mol%) combined in capped tube. Solution crystallized completely within ~1 hr. Solid recrystallized from hot ethanol to give 1.72 g (55%) peach-colored needles.
1-(4-iodophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (IDPCA): DMF (1.0 mL) and phosphoryl chloride (0.118 mL, 1.27 mmol, 1.9 equiv.) were stirred for 25 minutes in an ice bath under a nitrogen atmosphere. The reaction was removed from the ice bath and IDP (203 mg, 0.684 mmol, 1.0 equiv.) dissolved in DMF (1.0 mL) was added. Continuing to stir, the reaction was complete by TLC after 45 minutes. The reaction was poured over ice (10 mL), stirred, and 10% NaOH was added dropwise until a pH of 11 was achieved. Subsequent suction filtration yielded IDPCA as a sticky beige solid (>100% due to residual solvent). m.p.=135.6°C-138.2°C; FTIR (neat) 3387, 1641 cm-1; 1H-NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 1.2 Hz, 1H), 2.28 (s, 3H), 1.99 (s, 3H).
Knoevenagel condensation of 1-(4-iodophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (IDPCA): (Z)-2-((3-phenyl)imino)thiazolidin-4-one (70 mg, 0.347 mmol, 1.00 equiv.) was dissolved in ethanol (5.0 mL). Piperidine (0.051 mL, 0.521 mmol, 1.50 equiv.) and IDPCA (113 mg, 0.347 mmol, 1.0 equiv.) were added to the mixture, and the solution was monitored by TLC and refluxed at 60°C overnight. The reaction was let cool to r.t., washed with ethanol (1.0 mL), and filtered to give thiazolidinone pyrrole as a yellow powder (106 mg, 0.21 mmol, 61%): m.p.=309 °C (dec.); FTIR (neat) 3057, 2947, 2776, 1699, 1640 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.70 (s, 1H), 7.41 (t, 2H), 7.21 (t, 1H), 7.15 (br s, 2H), 6.93 (d, 2H), 6.12 (s, 1H), 2.14 (s, 3H), 1.98 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 138.78, 137.31, 135.04, 129.78, 129.44, 125.05, 121.74, 105.66, 12.71, 11.09.
R = p-SO2NH2 (SA/MB)
4-(2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide: Sulfanilamide (1.72 g, 10 mmol), 2,5-hexanedione (1.4 mL, 12 mmol) and sulfamic acid (50 mg, 0.5 mmol, 5 mol%) combined in capped tube and heated to 130 °C overnight. Solid recrystallized from hot ethanol to give a beige powder. 1H NMR (400 MHz, CDCl3): 8.04 (d, 2H), 7.37 (d, 2H), 5.93 (s, 2H), 5.25 (br s, 2H), 2.05 (s, 6H).
4-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide: Cold DMF (0.8mL) was stirred in an ice bath under nitrogen atmosphere. Phosphoryl chloride (0.19mL, 1.54mmol, 1.2 equiv.) was added dropwise and reaction was stirred for 25 minutes. A solution of 4-(2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide (0.32g, 1.28 mmol, 1.0 equiv) and DMF (0.8mL) was added dropwise over five minutes, then brought to rt until complete (30 min; monitored with TLC). Poured over ice (16mL) and stirred until melted. Reaction pH was 1. Reaction was neutralized with NaOH (3.4mL, 10%NaOH) until it held a pH of 6. Reaction was filtered using vacuum filtration, and was rinsed with cold clean water; yielded a sandy-brown powder (0.191g). Recrystallization in acetonitrile gave similar brown solid (0.105g, 33%). Melting point: 202.6-206.7°C; IR: peaks not labeled, however, spectra showed benzene ring, carbonyl peak, the presence of single and double carbon-carbon bonds, and amine; 1H NMR (400 MHz, CDCl3): 9.89 (s, 1H), 8.07 (d, 2H), 7.32 (d, 2H), 6.41 (s, 1H), 3.19 (s, 2H), 3.10 (s, 2H), 2.3 (m, 3H), 2.01 (m, 3H).
Knoevenagel Condensation: (Z)-2-((3-phenyl)imino)thiazolidin-4-one (0.078 g, 0.375 mmol) was dissolved in ethanol (7 mL) at rt. Piperidine (0.06 mL, 0.5625 mmol) and 2,5-dimethyl-N-phenyl(4-sulfamine)-pyrrole-3-carbaldehyde (0.10 g, .0375 mmol) were added. Solution refluxed overnight at 60°C and cooled to rt. Vacuum filtration (ethanol) afforded brown solid crystals (0.0696 g, 67%). MP: Decomposed at 250.4°C. IR: 3401, 3094, 3054, 2943, 2744, 1628, 1590, 1537, 1497 cm-1. 1H NMR (400 MHz, CDCl3) δ 9.884 (s, 1H), 8.198-8.016 (m, 2H), 7.284-7.141 (m, 8H), 3.193-3.085 (d, 2H).
R = p-CΞN (PD/BH)
4-(2,5-Dimethyl-1H-pyrrol-yl)benzonitrile: 4-aminobenzonitrile (1.36 g, 10 mmol), 2,5-hexanedione (1.4 mL, 12 mmol) and sulfamic acid (50 mg, 0.5 mmol, 5 mol%) combined in capped tube and heated to 130 °C overnight. Solid recrystallized from hot ethanol to give a tan powder (1.403 g, 63%).
4-(3-Formyl-2,5-dimethyl-1H-pyrrol-1-yl)benzonitrile (FPBC): DMF (0.40 mL) was stirred with phosphoryl chloride (0.14 mL, 1.5 mmol,) at 0 °C under a nitrogen atmosphere. 4-(2,5-Dimethyl-1H-pyrrol-yl)benzonitrile (PBC) (196 mg, 1.0 mmol,) in DMF (0.40 mL) was added dropwise over 5 min. Once the reaction reached completion (20 min, monitored by TLC), the solution was poured over ice (4 mL) and the pH brought to 8 (approx. 10% NaOH). Once fully reacted (30 min) the reaction was filtered and the resulting grey crystal purified with MeCN and filtered affording FPBC (90 mg, 40%) as a brown crystal: FTIR (neat) 3094, 3060, 2956, 2923, 2837, 2755, 2229, 1651, 1603 cm-1; 1HNMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.86 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), 6.42 (s, 1H), 2.29 (s, 3H), 2.01 (s, 3H). mp 162.4-163.9.
Nitrile Thiazolidinone Pyrrole (NTP): Dissolved FPBC (72 mg, 0.32 mmol) and (Z)-2-((3-phenyl)imino)thiazolidin-4-one (61 mg, 0.32 mmol) in EtOH (4.8 mL). Piperidine (0.048 mL, 0.48 mmol) was added and the solution heated to 60 °C. Upon reaction completion (90 min) the solution was cooled to room temperature and filtered and the solid precipitate washed with EtOH yielding NTP (57 mg, 49%) as a yellow solid: FTIR (neat) 3066, 2978, 2792, 2232, 1700, 1641, 1600 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H), 7.69 (s, 1H), 7.42 (m, 2H), 7.32 (m, 2H), 7.15 (m, 3H), 6.16 (s, 1H), 2.15 (s, 3H), 2.00 (s, 3H) (two sets of spinning sidebands around CHCl3/7.26 peak observed); 13C NMR (399 MHz, CDCl3) δ 165.3, 163.3, 141.6, 134.4, 133.3, 131.0, 129.4, 128.9, 126.6, 125.1, 121.9 117.7, 116.5, 112.8, 106.4, 110.5, 12.8, 11.2. mp 315 (dec.)
Thiazolidinone used in the above syntheses: (Z)-2-((3-hydroxyphenyl)imino)thiazolidin-4-one: A suspension of N-phenylthiourea (4.56 g, 30 mmol) and sodium acetate (3.20 g, 39 mmol) in 95% ethanol (12 mL) was refluxed until dissolution, whereupon ethyl bromoacetate (4.3 mL, 39 mmol) in 95% ethanol (5 mL) was added dropwise over 10 min. The solution was held at reflux for 4 h, then poured on ice and filtered. The precipitate was then recrystallized from 95% ethanol to yield a dull pink powder; yield not measured.
sdebbert
commented
11 years ago Hey, what's the best way to upload PDFs here? Otherwise, I'm happy to send them by email to interested users.
mattodd
commented
11 years ago This is really great, @sdebbert - just handling a conference session today/tomorrow, but will reply ASAP. There are a few simple things you and your students can do to disseminate this, and I'll walk you through it - likely on Friday. Just sensational that you have compounds for screening and that you've assembled all the data.
mattodd
commented
11 years ago OK @sdebbert sorry for the delay. The first thing to do is to get the data onto the lab notebook. The relevant lab notebook is here:
http://malaria.ourexperiment.org/near_neighbours
Alice has written a very nice how-to of how to make an entry and post chemical data. We've had this stress-tested by people new to the lab notebook, so it should be clear:
General: http://malaria.ourexperiment.org/uri/3dc Chemistry-specific: http://malaria.ourexperiment.org/uri/3dd
The very best way forward here would be to have the individual students responsible for each experiment post the data relevant to that experiment. There's only a login based on an existing account (e.g. Google) so it's easy. That way the author is responsible for the writing. Obviously if your class has moved on then this will be hard?
Yes, to publish this stuff we'll need to secure all the primary data as well as the write-up. As you can see from the instructions and previous entries, it's easy to append files like NMR files (raw and processed) to lab book entries.
But come back to us here if any of this is difficult or unclear.
Testing: I will ask.
mattodd
commented
11 years ago @sdebbert Would you be able to ship compounds overseas for testing? MMV have various centres they support, and this might be simplest. Also, are you considering a new round of synthesis with a new class? If so, we should plan. Lastly, we're likely to have our next online project meeting some time next week. Would be great if you could join us. Details coming.
sdebbert
commented
11 years ago Yes and yes! I've got a research student prepping materials for the new class' batch right now. I'm still working on getting the data in the right spot in GitHub - I'll serve as "author" for the last batch, but I'll plan to have students do it themselves next spring. Looking forward to the meeting - I'm a night owl anyway, so the time difference won't deter me.
Sent from my iPhone
On Oct 1, 2013, at 8:03 AM, "Mat Todd" notifications@github.com<mailto:notifications@github.com> wrote:
@sdebberthttps://github.com/sdebbert Would you be able to ship compounds overseas for testing? MMV have various centres they support, and this might be simplest. Also, are you considering a new round of synthesis with a new class? If so, we should plan. Lastly, we're likely to have our next online project meeting some time next week. Would be great if you could join us. Details coming.
— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/38#issuecomment-25446691.
mattodd
commented
11 years ago @sdebbert So the above comment I made contains the location of the lab notebook where the data should go, as well as the how-to's for making posts that should be clear. It's very simple. Typically we make one post per reaction, uploading the raw data to each, as you can see from other examples. Part of the enjoyment of the electronic lab notebook is that you can attach all the data associated with a given experiment, i.e. both raw and processed data.
So in your case we're looking at a fair number of posts, since you've done a fair number of reactions! However, the most pressing issue is to upload the data for the final compounds - the ones that we're due to ship for evaluation. We always check the NMR data at least before sending, to double check the purity - it's an important quality control step that is easy in an open project. The lab that will evaluate your compounds is ready and waiting, so if you're able to upload the details of the final compounds, that'd be great. The text write-up you have pasted (above) is useful, ultimately, for a publication, but we need the NMR data and anything else you have for each compound in the lab notebook. We'd then assign an OSM number, and ship for testing against the parasite.
mattodd
commented
11 years ago @sdebbert has placed the data in the ELN - check out:
the NMR's look fine to me, meaning the compounds are ready to send for testing, for which a lab in the US is ready. Could someone with more experience than me with these molecules do a swift sanity check on these 6 compounds, please? Calling @murrayfold @incoherentboy as well as @alintheopen
mattodd
commented
9 years ago All available data included in draft Series 1 paper about to be submitted, so closing.
A group of 49 undergraduate students have been working on the synthesis of near-neighbour analogs. There is currently no data online but we hope to receive this soon.