Meta tags:
description=6 posts published by milkshake during November 2006;

Headings (most frequently used words):

november, 2006, org, prep, daily, 28, 25, 17, 16, 15, 14, thianthrenyl, morpholinyl, pyranone, for, few, carbons, more, diazaindole, cyclization, sonogashira, on, diamino, bromopyrimidine, difluorobenzyl, piperidine, hydrochloride, the, end, is, nigh,

Text of the page (most frequently used words):
the (108), was (74), and (39), with (31), mixture (25), for (21), reaction (16), #november (15), silica (15), under (13), product (13), 2007 (12), added (12), were (11), this (10), 2006 (10), 2010 (10), residue (10), from (10), min (10), 2009 (9), stirred (9), september (8), milkshake (8), evaporated (8), dried (8), highvac (8), washed (8), org (7), daily (7), comments (7), october (7), march (7), june (7), july (7), 2008 (7), procedures (7), mmol (7), etoac (7), used (7), prep (6), august (6), december (6), 2011 (6), but (6), filed (6), bath (6), hours (6), ethyl (6), solid (6), cui (6), 128 (6), filtrates (6), dichloromethane (6), january (5), april (5), may (5), 2015 (5), solution (5), cooled (5), methanol (5), acetate (5), then (5), gradient (5), these (5), that (5), not (5), cdcl3 (5), vial (5), through (5), aldrich (5), pad (5), base (5), procedure (5), february (4), 2012 (4), 2013 (4), 2025 (4), will (4), end (4), pure (4), dissolved (4), water (4), filtered (4), precipitate (4), overnight (4), purified (4), column (4), diaminopyrimidine (4), conditions (4), thf (4), acetylene (4), 5mol (4), 400mhz (4), 127 (4), 6hz (4), log (3), have (3), wordpress (3), com (3), other (3), 2014 (3), chemistry (3), flask (3), all (3), bf3 (3), tfa (3), also (3), large (3), obtained (3), piperidine (3), oil (3), chloroform (3), 50ml (3), suspended (3), 10ml (3), slurry (3), over (3), complete (3), material (3), make (3), sonogashira (3), above (3), tms (3), yields (3), 60c (3), important (3), excess (3), 4hz (3), 13c (3), 100mhz (3), 5mg (3), anh (3), triethylamine (3), 135 (3), suzuki (3), anhydrous (3), carbonate (3), morpholinyl (3), pyranone (3), app (3), report (2), sign (2), subscribed (2), subscribe (2), account (2), rss (2), 2017 (2), 2018 (2), 2019 (2), uncategorized (2), mechanisms (2), destruction (2), links (2), about (2), updates (2), adding (2), here (2), few (2), much (2), acid (2), than (2), without (2), case (2), addition (2), etherate (2), easier (2), workup (2), tes (2), acetyl (2), difluorobenzyl (2), 80ml (2), 140c (2), tbme (2), 200ml (2), briefly (2), sonicated (2), white (2), 100ml (2), 20ml (2), salt (2), argon (2), 15ml (2), dropwise (2), hour (2), concentrated (2), small (2), diluted (2), ether (2), 300ml (2), combined (2), hexane (2), followed (2), straight (2), rate (2), failed (2), provide (2), conversion (2), starting (2), net3 (2), together (2), coordinating (2), properties (2), bromides (2), coupling (2), various (2), systems (2), pdcl2 (2), dppf (2), high (2), like (2), catalyst (2), usualy (2), very (2), can (2), weighing (2), since (2), 3hz (2), 162 (2), 157 (2), 139 (2), bromo (2), mol (2), 4ml (2), closed (2), capped (2), formation (2), plug (2), mix (2), using (2), voluminous (2), removed (2), 40g (2), 132 (2), barton (2), tried (2), works (2), cyanide (2), acetylenes (2), diazaindoles (2), cyclized (2), 0hz (2), 8hz (2), 114 (2), equipped (2), stopcock (2), crude (2), light (2), tan (2), cyclization (2), typical (2), heck (2), ready (2), resulted (2), acetaldehyde (2), dimedone (2), loading (2), when (2), patent (2), error (2), due (2), experiment (2), tetrakis (2), desired (2), dioxane (2), problem (2), dry (2), molecular (2), chloro (2), dmso (2), 129 (2), potassium (2), 130c (2), microwave (2), collapse, bar, manage, subscriptions, view, site, reader, content, privacy, already, now, join, 179, subscribers, blog, meta, xfn, valid, xhtml, create, archives, 2016, 2026, search, categories, questions, lit, highlights, lab, krest17, industry, life, chris, douglas, behold, idle, words, edible, serious, eats, stellen, fuer, chemiker, practical, fragments, chem, portal, open, med, chemist, pipeline, chemjobber, pages, resources, bug, older, posts, regular, friday, nov, keep, monthly, personal, page, continue, experimental, happen, infrequently, thank, you, your, visits, during, past, weeks, nigh, stronger, alone, reduction, stops, benzylic, alcohol, advantageous, scale, evaporate, conc, hcl, refluxed, quickly, hygroscopic, 212g, hplc, cesi, 212, difluorobenzoyl, 00g, astatech, triethylsilane, 125mmol, 20c, ice, boron, trifluoride, 119, 10c, volume, ambient, 150ml, saturated, nahco3, slowly, co2, evolution, extracted, twice, 2x200ml, extracts, brine, mgso4, 80g, 100, hydrochloride, analogous, iodides, had, faster, initial, curiously, possible, progress, inhibited, accumulation, pyrimidines, relatively, troublesome, substrate, class, comparison, frequently, far, superior, many, phenyacetylene, coupled, less, electron, rich, alkynes, phenylacetylene, applied, within, one, day, degassing, essential, last, quantities, difficult, weight, cut, tip, pasteur, pippet, overload, controlling, its, promotes, side, reactions, cubr, place, products, tendency, tail, therefore, elution, stating, close, ensure, 880, 331, 258, 387, 274, 598, 5hz, 437, 442, 575, 465, 188, 2hz, 950, 160, benzylamino, ethylaminopyrimidine, 276, previous, step, ch2cl2, 5ml, 19ml, 35mmol, hexyne, 155ml, 9mg, 7mol, flushed, placed, 20h, progres, monitored, observing, et3n, hbr, dcm, 45ml, 10g, 249mg, pale, yellow, dichloropyrimidine, 989g, 89mmol, vigorous, stirring, amine, 15min, formed, cooling, 240ml, oily, neat, benzylamine, dryness, 250ml, same, solidified, crystallized, 631g, crystalline, minor, regioisomer, remained, supernatants, 710, 333, 221, 852, 098, 542, 416, 174, 161, 158, 155, 533, diamino, bromopyrimidine, low, boiling, strong, serves, both, copper, ligand, keeps, things, soluble, deprotonates, aminopyrimidine, bases, dbu, even, slower, complication, binds, strongly, break, complex, trimethylsilyl, poisonous, has, handled, gloves, hood, succesfully, cyclize, number, excellent, substituent, groups, amines, phe, tolerated, only, protected, compounds, deprotected, smoothly, 330, 393, 298, 223, 025, 707, 677, 071, 635, 686, 453, 280, 973, compound, 6mmol, dimethylacetamide, 8ml, 25ml14, round, degassed, purge, 75mmol, fluka, 1ml, 25ml, precipitated, cucn, filtration, 35g, 77mg, diazaindole, wild, story, does, beta, eliminate, undergoes, protonolysis, instead, emerges, sequence, hunt, down, oxidize, another, molecule, credits, roesy, apparently, reductive, condensation, plus, fairly, pre, guess, equivalent, generated, promoted, oxidation, trying, diaminobromopyrimidines, catalyzed, arylation, cyclic, diketone, met, strangers, carbons, more, improvement, published, reading, experimentals, suspected, reported, there, ranging, suffered, some, kind, execution, perhaps, lack, care, experiments, set, run, parallel, done, aqueous, na2co3, dme, returned, next, into, contained, rapid, became, clear, actual, moisture, sensitivity, presence, k2co3, thieves, supressed, decomposition, making, posted, oct, equaly, well, 763, 601, 470, 357, 254, 532, 690, 383, 177, 134, 133, 131, before, preparation, granulated, powdered, spatula, beaker, glassware, drying, oven, pressure, stirbar, 216mg, 00mmol, thiantrene, boronic, 390mg, 5mmol, activated, sieves, powder, 5um, 16ml, sparged, gas, pph3, 90mg, sparging, continued, additional, heated, biotage, initiator, poured, onto, 20g, solids, first, discarded, methanolic, purification, meoh, provided, sticky, glass, benzene, freeze, 345mg, fluffy, amorphous, thianthrenyl,

Text of the page (random words):
november 2006 org prep daily org prep daily november 28 2006 2 1 thianthrenyl 6 n morpholinyl 4 pyranone filed under procedures milkshake 2 40 am before the preparation anhydrous potassium carbonate granulated aldrich was powdered with a spatula and dried in a beaker in glassware drying oven at 130c overnight in a microwave ready pressure vial equipped with a stirbar 2 chloro 6 n morpholinyl 4 pyranone 216mg 1 00mmol mixture with thiantrene 1 boronic acid 390mg 1 5mmol 90 pure aldrich dry potassium carbonate 1 4g and activated 4a molecular sieves 1 1g powder 5um aldrich was suspended in anhydrous dioxane 16ml and the slurry was sparged with ar gas for 10 min pd pph3 4 90mg 7 5mol was added and sparging was continued for additional 10 min the vial was then capped under ar and heated in a biotage initiator microwave at 130c for 2 hours the cooled reaction mixture was poured onto a pad of silica 20g and the solids on the silica pad were washed with ethyl acetate 100ml these first filtrates were discarded the silica pad was then washed with a 2 1 chloroform methanol mix 300ml the methanolic filtrates were evaporated purification of the crude product on a silica column 40 g in a methanol gradient in chloroform 0 to 5 meoh provided the pure product as a sticky glass this purified product was dissolved in benzene 10ml and the solution was freeze dried on highvac y 345mg 87 of a fluffy light tan amorphous solid 1h d6 dmso 400mhz 7 763 app d 7 6hz 1h 7 601 app t 7 3hz 3h 7 470 app t 7 8hz 1h 7 357 m 2h 6 254 d 1 6hz 1h 5 532 d 1 6hz 1h 3 690 br m 4h 3 383 br m 4h 13c d6 dmso 100mhz 177 77 162 93 157 95 135 38 135 04 134 59 133 58 132 65 131 26 129 36 129 10 128 82 128 78 128 43 128 24 114 00 89 41 65 24 2c 44 44 2c the procedure for making the 2 chloro 6 n morpholinyl 4 pyranone was posted on oct 3 the suzuki procedure works equaly well with 5mol of pd tetrakis the 7 5mol loading was due to weighing error the above procedure is an improvement over the patent procedure published y 4 th from reading the patent experimentals i suspected that all suzuki procedures reported there with yields ranging from 2 to 13 suffered from some kind of execution error perhaps due to a lack of care when experiments were set and run in parallel also experiment done under typical aqueous suzuki reaction conditions na2co3 pd tetrakis dme water returned no desired product at all next i tried adding water to the anhydrous dioxane experiment into a reaction mixture that contained the desired product and this resulted in a rapid destruction of the product under the reaction conditions so it became clear that the actual problem was the moisture sensitivity of the product in the presence of carbonate using a large excess of dry k2co3 together with 4a molecular thieves supressed this decomposition problem comments 6 november 25 2006 for a few carbons more filed under mechanisms milkshake 7 27 am i was trying to make diazaindoles from diaminobromopyrimidines by pd catalyzed arylation of a cyclic 1 3 diketone dimedone when i met these cyclized strangers apparently the cyclization product resulted from a reductive heck coupling with a condensation product of acetaldehyde plus dimedone i used a fairly high pd ii pre catalyst loading 10 mol so i guess the acetaldehyde equivalent was generated by the pd ii promoted oxidation of triethylamine in this wild story the addition product does not beta eliminate pd 0 as in typical heck reaction but undergoes a protonolysis instead pd ii re emerges from the sequence at the end ready to hunt down and oxidize another molecule of triethylamine credits dr ni for roesy comments 5 november 17 2006 diazaindole cyclization filed under procedures milkshake 4 46 pm the acetylene compound 92 5mg 0 3 mmol and cui 114 5mg 0 6mmol was suspended in anh dimethylacetamide 0 8ml in a 25ml14 20 round flask equipped with a straight stopcock the mixture was degassed by highvac ar purge barton base 0 15ml 0 75mmol fluka was added through the stopcock and the mixture was stirred at 135 140c oil bath under ar in a closed flask for 3 hours the mixture was cooled to rt methanol 1ml was added followed by tms cn 0 25ml the mixture was diluted with dichloromethane 10ml sonicated for 10 min and then stirred at rt for 1 hour the precipitated cucn was removed by filtration through a pad of silica the silica was washed with 50ml of a 10 1 mixture of dichloromethane with methanol the filtrates were evaporated and the residue was dried on highvac the crude product was purified on a column of silica 35g in etoac gradient in dichloromethane 10 to 30 of etoac in 45 min 20ml min y 77mg 83 of a light tan solid 1h cdcl3 400mhz 8 330 br s 1h 7 393 m 2h 7 298 m 2h 7 223 m 1h 6 025 s 1h 5 707 br s 1h 4 677 s 2h 4 071 q 7 0hz 2h 2 635 t 7 8hz 2h 1 686 m 2h 1 453 m 2h 1 280 t 7 0hz 3h 0 973 t 7 4hz 3h the above procedure was succesfully used to cyclize a large number of diaminopyrimidine acetylenes with excellent yields 82 to 96 y various substituent groups on amines and phe bu h on acetylene were tolerated only tms protected acetylene compounds failed to provide diazaindoles but the deprotected acetylenes r h cyclized smoothly barton base is a low boiling strong base it serves here both as a copper ligand and a base it keeps things soluble and it deprotonates the aminopyrimidine nh i have not tried other bases like dbu but the reaction works even without base the reaction was slower and formation of voluminous precipitate was a complication since the product binds strongly to cu cyanide excess was used in the workup to break the complex trimethylsilyl cyanide is very poisonous it has to be handled with gloves in the hood end of daily updates comments 8 november 16 2006 sonogashira on 2 4 diamino 5 bromopyrimidine filed under procedures milkshake 10 41 pm a solution of 5 bromo 2 4 dichloropyrimidine 4 989g 21 89mmol aldrich in anh thf 20 ml was cooled to 0c with vigorous stirring a solution of 2m ethyl amine in thf 24 ml 48 mmol aldrich was added dropwise over 15min a voluminous precipitate formed the cooling bath was removed and the mixture was stirred at rt for 45 min the reaction mixture was filtered through a 40g plug of silica and silica was washed with 5 1 mixture dichloromethane ethyl acetate 240ml the filtrates were evaporated and the residue was dried on highvac overnight the obtained oily residue was dissolved in neat benzylamine 14 4ml 132 mmol and the mixture was stirred under argon at 60c for 11 hours overnight the reaction mixture was concentrated on highvac to dryness the residue was dissolved in a mixture 4 1 dichloromethane ethyl acetate filtered through a pad of silica 40g and silica was washed with 250ml of the same mixture the filtrates were evaporated and dried on highvac the solidified residue was re crystallized from hexane y 5 631g 84 of a white crystalline solid the minor regioisomer remained in the supernatants 1h cdcl3 400mhz 7 710 br s 1h 7 333 7 221 m 5h 5 852 br s 1h 5 098 s 1h 4 542 d 6hz 2h 3 416 m 2h 1 174 t 7 4hz 3h 13c cdcl3 100mhz 161 05 158 16 155 66 139 65 128 44 127 533 127 01 45 72 35 78 14 74 5 bromo 2 benzylamino 4 ethylaminopyrimidine 276 5mg 0 90 mmol from the previous step was combined with 15 mg of pdcl2 dppf ch2cl2 2 mol and 2 5ml of anh thf in a 4ml vial triethylamine 0 19ml 1 35mmol and 1 hexyne 0 155ml 1 35 mmol was added and the mixture was stirred in a closed vial for 10 min solid cui 2 9mg 1 7mol was added the vial was briefly flushed with ar capped and placed on oil bath the mixture was stirred at 60c for 20h the progres of reaction was monitored by observing formation of et3n hbr precipitate the reaction mixture was filtered through a plug of silica 2g washed with 5 1 dcm etoac mix 45ml the filtrates were evaporated and the residue was purified on a column of silica 10g using a ethyl acetate gradient in dichloromethane 0 to 15 etoac y 249mg 90 of a pale yellow solid 1h cdcl3 400mhz 7 880 br s 1h 7 331 7 258 m 5h 5 387 br s 1h 5 274 br s 1h 4 598 d 5 5hz 2h 3 437 m 2h 2 442 t 7 3hz 2h 1 575 m 2h 1 465 m 2h 1 188 t 7 2hz 3h 0 950 t 7 4hz 3h 13c cdcl3 100mhz 162 14 160 64 157 73 139 72 128 45 127 52 127 01 96 50 73 77 45 45 35 39 31 03 22 06 19 44 14 85 13 63 coordinating properties of diaminopyrimidine make these bromides a relatively troublesome substrate class in the sonogashira coupling by comparison with various frequently used sonogashira systems the above conditions thf net3 pdcl2 dppf cui were far superior to many other systems for these diaminopyrimidine bromides phenyacetylene and tms acetylene also coupled with high yields 80 with less electron rich alkynes like phenylacetylene 5mol of the catalyst was usualy applied to make the reaction complete within one day at 60c degassing is not essential it is important that cui is added very last small quantities of cui can be difficult to weight a cut tip of pasteur pippet was used for weighing but it is important not to overload the reaction with cu salt cu is not rate controlling and its excess promotes side reactions cubr can be used in place of cui the products have tendency to tail on silica therefore the gradient elution was used since the stating material is usualy close to the product it is important to ensure a complete conversion of the starting material the analogous diaminopyrimidine iodides had faster initial rate but curiously failed to provide a complete conversion of the starting material under these reaction conditions it is possible that the reaction progress was in this case inhibited by accumulation of net3 hi together with coordinating properties of the pyrimidines comments 2 november 15 2006 4 2 4 difluorobenzyl piperidine hydrochloride filed under procedures milkshake 6 52 pm tfa 100ml was added to 1 acetyl 4 2 4 difluorobenzoyl piperidine 5 00g astatech 18 7 mmol slurry in triethylsilane 20ml 125mmol the mixture was stirred at rt for 30 min then cooled to 20c on salt ice bath under argon boron trifluoride etherate 15ml 119 mmol was added dropwise over 5 min and the mixture was stirred at 20 to 10c for 4 hours then at 10 to 5c for 1 hour the reaction mixture was concentrated to a small volume from ambient bath the residue was diluted with water 50ml and ether 150ml saturated nahco3 solution 300ml was slowly added co2 evolution and the mixture was stirred at rt overnight 16 hours the mixture was extracted twice with ether 2x200ml the extracts were washed with brine 200ml combined dried mgso4 and evaporated the residue was purified on a column of silica 80g in a etoac gradient in hexane 0 to 100 etoac followed by straight etoac the obtained pure 1 acetyl 4 2 4 difluorobenzyl piperidine was dissolved in conc hcl 80ml water 80ml was added and the mixture was refluxed on oil bath 140c for 5 hours the obtained solution was cooled and evaporated the residue was re evaporated from a 2 1 chloroform methanol mixture 50ml and dried on highvac the residue was suspended in ethyl acetate 10ml tbme 200ml was added the slurry was briefly sonicated 5 min filtered quickly hygroscopic the precipitate washed with tbme and dried on highvac y 4 212g 91 y of a white solid pure by hplc lc ms cesi 212 m 1 bf3 in tfa is much stronger acid than tfa alone without bf3 the reduction stops at benzylic alcohol in this case addition of bf3 etherate is also advantageous for easier workup on large scale tes f is much easier to evaporate than tes oh comments 3 november 14 2006 the end is nigh filed under uncategorized milkshake 5 33 pm the regular daily updates will end this friday nov 17 i will keep org prep monthly up as my personal chemistry page i will continue adding experimental procedures here but this will happen infrequently so thank you all for your visits during the past few weeks milkshake comments 4 older posts pages about milkshake about org prep daily bug report chemistry resources chemistry chemjobber in the pipeline med chemist open flask org chem portal practical fragments stellen fuer chemiker edible links serious eats links to behold idle words categories chris douglas industry life krest17 lab destruction lit highlights mechanisms procedures questions uncategorized search archives january 2026 december 2025 november 2025 october 2025 september 2025 april 2019 march 2019 december 2018 june 2018 september 2017 august 2017 march 2016 october 2015 august 2015 july 2015 june 2015 march 2015 november 2014 july 2014 may 2014 september 2013 july 2013 may 2013 april 2013 october 2012 september 2012 august 2012 january 2012 december 2011 november 2011 october 2011 july 2011 june 2011 april 2011 december 2010 november 2010 october 2010 september 2010 july 2010 june 2010 may 2010 march 2010 february 2010 january 2010 december 2009 november 2009 september 2009 august 2009 june 2009 may 2009 april 2009 march 2009 february 2009 november 2008 august 2008 july 2008 june 2008 march 2008 february 2008 january 2008 december 2007 november 2007 october 2007 september 2007 august 2007 july 2007 june 2007 may 2007 april 2007 march 2007 february 2007 january 2007 november 2006 october 2006 september 2006 meta create account log in rss comments rss valid xhtml xfn wordpress com blog at wordpress com subscribe subscribed org prep daily join 179 other subscribers sign me up already have a wordpress com account log in now privacy org prep daily subscribe subscribed sign up log in report this content view site in reader manage subscriptions collapse this bar