22 c o bond forming reactions

Myers Williamson Ether Synthesis Relative Reactivities: Background • Relative reactivities of electrophiles, with respect to the alkyl substituent: • The synthesis of ethyl ether from sodium ethoxide and ethyl iodide was first reported by Alexander W Williamson in 1851: H3C OH O Na+ Me, allylic, benzylic > 1º alkyl > 2º alkyl > branched 2º alkyl >> neopentyl, 3º alkyl • Relative reactivities of electrophiles, with respect to the leaving group: EtI Na H3C Chem 115 C–O Bond-Forming Reactions: SN2 Reactions (yield not provided) H3C O CH3 OTf > OTs > OMs I > Br > Cl • Trimethyloxonium tetrafluoroborate (Meerwein's salt) is a powerful alkylating agent: Williamson, W Liebigs Ann Chem 1851, 77, 37!49 Williamson, W J Chem Soc 1852, 106, 229–239 H3C • Since its original discovery, the Williamson ether synthesis method has become widely used in both academic and industrial settings CH3 O CH3 BF4 Intramolecular Williamson Ether Synthesis: Overview • Relative rates of ring formation: R OH base R O R' X R OR' Ring size: 3~5>6>4>7>8 Fast • R = 1º, 2º, and 3º alkyl allyl, benzyl, aryl, heteroaryl • X = I, Br, Cl, OSO2R Slow • R' = 1º, and 2º alkyl, allyl, benzyl • Base = alkali metals/NH3(l), metal hydrides • Proximity effect: in the following intramolecular etherification reaction, successive addition of methyl groups on the substrate places the electrophile and nucleophile in closer proximity LHMDS, LDA, NaOH, KOH, K2CO3, Cs2CO3 • Solvents: alcohol (alkoxide), DMF, DMSO and HMPA O Mechanism OMs CH3 H3C O OMs OMs H3C CH3 • The reaction proceeds through an SN2 pathway Limitations O relative rate of ether formation 3.5 x 103 CH3 H3C O OMs H3C CH3 8.6 x 105 • For hindered substrates, base-catalyzed elimination of the alkylating agent can be problematic • For phenoxides, C–alkylation can compete with O–alkylation Kirby, A J Adv Phys Org Chem 1980, 17, 183–179 Anslyn, E V.; Dougherty, D A Modern Physical Organic Chemistry; University Science Books: Sausalito, CA, 2006; pg 497 Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu Myers Chem 115 C–O Bond-Forming Reactions: SN2 Reactions Examples OCH3 OH OCH3 O K2CO3 Br + acetone 60 ºC, 98% NO2 EtO H3C CH3 NO2 t-BuOK, THF ! ºC CH3 O MsO N OH S (180 g) N CF3 ! 18 ºC Garcia, A L L.; Carpes, M J S.; de Oca, A C B M.; dos Santos, M A G.; Santana, C C.; Correia, C R D J Org Chem 2005, 70, 1050–1053 (232 g) CH3 O • For hindered substrates, KH often performs better than NaH EtO H3C CH3 • KH is highly flammable and is supplied commercially as a 30% w/w slurry in mineral oil In the examples below, the authors used a 50% by weight homogenate of KH in paraffin, which is observed to be air stable and operationally more convenient: O N 75% S (246.5 g) H3C CH3 OH CF3 H3C CH3 KH, BnBr OBn THF, 23 ºC, 99% H3C CH3 N Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R K.; Shen, L.; Youells, S.; Zhang, Y Org Process Res Dev 2007, 11, 1010–1014 • In the following example, etherification proceeds via an epoxide intermediate Addition of ZnBr2 was found to promote epoxide opening: H3C CH3 KH, BnBr O O CH3 THF, 23 ºC, 91% O O OH CH3 OBn OH HO HO TsO H • Alkyl chlorides can be converted in situ to the more reactive alkyl iodide: F N H3CO OH CO2H K2CO3, BnCl, KI acetone, 60 ºC, 79% H3CO THF, 65 ºC H N O F O CO2H O OBn F Huang, H.; Nelson, C G.; Taber, D F Tetrahedron Lett 2010, 51, 3545–3546 OBn NaH, THF, ºC ZnBr2 F OBn Wu, G G Org Process Res Dev 2000, 4, 298–300 Bourke, D G.; Collins, D J Tetrahedron 1997, 53, 3863–3878 Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu Myers OH OCH3 OCH3 CH3 NC • Synthesis of a 5-HT2C receptor agonist : OCH3 NaH, CH3I CH3 O Chem 115 C–O Bond-Forming Reactions: SN2 Reactions steps CH3 O DMF, ºC, 87% OCH3 CH3 NC HO CH3 OCH3 (20 g) O O S OEt K2CO3, EtO butanone, 110 ºC CH3 EtO NO2 H2, Pd/C MeOH, 23 ºC 94% (2 steps) steps CH3 NH2•HCl EtO NH2 N (18.6 g) OCH3 OCH3 Peters, R.; Waldmeier, P.; Joncour, A Org Proc Res Dev 2005, 9, 508!512 CH3 H3C CH3O OH O H N CH3 • Synthesis of maxacalcitol (Oxarol"), an antihyperparathyroidism and antipsoriatic vitamin D3 analogue: OH H OCH3 O H3C O H3C Pederin H3C TBSO CH3 Wan, S.; Wu, F.; Rech, J C.; Green, M E.; Balachandran, R.; Horne, W S.; Day, B W.; Floreancig, P E J Am Chem Soc 2011, 133, 16668!16679 OH H3C NaH, THF, 23 ºC TBSO • Synthesis of didemniserinolipid B: H Br (17.2 kg) OH H OH O H3C N CH3 Boc + MsO O 15 O NaH, DMSO 86% H O O H3C Ph CH3 CH3 H3C TBSO CH3 TBSO L-selectride O 15 THF, 70 ºC, 99% H O N CH3 CH3 H O CH3 THF, 70 ºC OH H O O Boc Ph H3C H3C O OH steps steps OH O O S NaO O O NH2 O H3C TBSO CH3 O OH H3C CH3 TBSO (19.6 kg) O 15 H3C H3C CH3 H HO OH Maxacalcitol EtO2C didemniserinolipid B Marvin, C C.; Voight, E A.; Burke, S D Org Lett 2007, 9, 5357!5359 Shimizu, H.; Shimizu, K.; Kubodera, N.; Mikami, T.; Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.; Shimizu, M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.; Kobayashi, M.; Kigawa, M.; Kato, M.; Kozono, T.; Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M Org Proc Res Dev 2005, 9, 278!287 Angela Puchlopek-Dermenci, Alpay Dermenci, Fan Liu Myers Chem 115 C–O Bond-Forming Reactions: Diazoalkane Reagents • Other acidic functional groups, such as phenols, can also be methylated Introduction • Diazo compounds are uniquely reactive 1,3-dipoles O H OH H N N H HO O O CH3 N N H OH HO O CH3 CH2N2, CH2Cl2 20 ºC, 60% OH O • Diazo compounds are toxic and potentially explosive They covalently modify nucleobases and thus are mutagens Consequently, care must be taken when handling these compounds OH H3CO O OH Blade, R J.; Hodge, P J Chem Soc Chem Commun 1979, 85–86 • Alcohols are not sufficiently acidic to protonate diazomethane and require a catalyst to react Common catalysts include BF3•OEt2, HBF4, SnCl2 and silica gel: Fulton, J R.; Aggarwal, V K.; de Vicente, J Eur J Org Chem 2005, 1479–1492 Esterification and Etherification Using Diazomethane O BzO BzO OBz OH CH2N2, BF3•OEt2 O BzO CH2Cl2, ºC, 74% BzO OBz OCH3 Sammakia, T Diazomethane in Encyclopedia of Reagents for Organic Synthesis Chavis, C.; Dumont, F.; Wightman, R H.; Ziegler, J C.; Imbach, J L J Org Chem 1982, 47, 202!206 • Diazomethane is one of the most effective reagents for the preparation of methyl esters from carboxylic acids The carboxylic acid protonates the diazomethane reagent to generate a diazonium-carboxylate ion pair, which collapses to form the methyl ester Preparation of Diazomethane • Diazomethane is prepared by the decomposition of a variety of N-methyl-N-nitrosoamines and is obtained most often as a solution in ethyl ether • Products can typically be isolated by simple evaporation of the volatile ethereal solvent (ethereal solutions of diazomethane are obtained by distillation using special fire-polished glassware, to prevent explosion) Diazomethane itself is highly volatile (bp = –23 ºC) O OBn OBn OBn HO OBn OBn O CH2N2, Et2O 23 ºC, 70% • The example below utilizes N–methyl-N-nitroso-p-toluenesulfonamide (Diazald") OBn OBn OBn H3CO OBn OBn H3C O O N S N O CH3 KOH EtO O H2C N N OH Et2O, H2O, 65 ºC Schmidt, R R.; Frick, W Tetrahedron 1988, 44, 7163–7169 Hudlicky, M J Org Chem 1980, 45, 5377–5378 de Boer, T J.; Backer, H J.; Org Synth 1963, 4, 250–253 Fan Liu Myers Chem 115 C–O Bond-Forming Reactions: Diazoalkane Reagents • Reaction set-up: • The reaction proceeds through in situ generation of the active methylating agent, diazomethane O Dropping funnel containing (Diazald") distillation apparatus R OH + O TMS N N R TMS + O N N Receiving flask containing a solution of CH2N2 in Et2O, cooled to –15 ºC special joints, NOT ground-glass O OH EtO KOH, H2O, Et2O heated to 65 ºC CH3OH O O R R OCH3 + OH N2 H2C N N + TMSOCH3 • Kits can be purchased which include non-ground glassware to decrease the likelihood of diazomethane explosion • Leftover diazomethane should be quenched with dilute acetic or oxalic acid Kühnel, E.; Laffan, D D P.; Lloyd-Jones, G C.; Martinez del Campo, T.; Shepperson, I R.; Slaughter, J L Angew Chem Int Ed 2007, 46, 7075–7078 • If a pipette is to be used to transfer diazomethane, it must be fire polished first • Diazomethane is one of the most dangerous diazo compounds because of its volatility and propensity to detonate All operations should be conducted behind a blast shield and care must be taken when handling this compound • Enols can also be methylated: Hudlicky, M J Org Chem 1980, 45, 5377–5378 de Boer, T J.; Backer, H J.; Org Synth 1963, 4, 250–253 O H3CO Trimethylsilyldiazomethane H3C O O O Shioiri, T.; Aoyama, T Trimethylsilyldiazomethane in Encyclopedia of Reagents for Organic Synthesis H N OH O N H CH3 TMSCHN2 toluene, MeOH 25 ºC, 90% O H3C • Because of the high volatility and toxicity of diazomethane, the safer, less volatile reagent, trimethylsilyldiazomethane is often used, solutions of which are commercially available O CH3 O TBSO CH3 O TMSCHN2 OH C6H6, MeOH # 25 ºC, >69% TBSO H3CO OCH3 H3C O O O H N OCH3 O N H CH3 O H3C Evans, M A.; Morken, J P Org Lett 2005, 7, 3371–3373 Coleman, R S.; Tierney, M T.; Cortright, S B.; Carper, D J J Org Chem 2007, 72, 7726!7735 Fan Liu Myers Chem 115 C–O Bond-Forming Reactions: Diazoalkane Reagents Esterification and Etherification Using Phenyldiazomethane Sammakia, T Phenyldiazomethane in Encyclopedia of Reagents for Organic Synthesis OH OBn H3C N O HO H3C OH H O O O PhCHN2, Et2O OCH3 CH3 H N O HO H3C 20 ºC, >85% OBn H O O O O Goulet, M T.; Boger, J Tetrahedron Lett 1990, 31, 4845–4848 PhCHN2, HBF4 (cat) H PhCHN2, HBF4 (cat) SO2Ph SO2Ph Bachi, M D.; Korshin, E E.; Hoos, R.; Szpilman, A M.; Ploypradith, P.; Xie, S.; Shapiro, T A.; Posner, G H J Med Chem 2003, 46, 2516–2533 • Neat phenyldiazomethane is commonly prepared by vacuum pyrolysis of the sodium salt of benzaldehyde tosylhydrazone: OBn CH2Cl2, –40 ºC, 81% N O O H3C CH2Cl2, –30 ºC, 86% Preparation of Phenyldiazomethane • HBF4 can be used as an acid catalyst for the benzylation of alcohols and amines using phenyldiazomethane Amines react more slowly under these conditions: OH H3C OCH3 CH3 H O PhCHN2, TfOH (30 mol%) O O H3C N Ph N Bn Ts N NaOCH3 H H N CH3OH, 23 ºC Ph Ts N Na H evaporate and dry 90 ! 220 ºC vacuum 76–80 ºC N2 Ph H Creary, X Org Synth 1990, 7, 438–443 CH2Cl2, ! 23 ºC, 60% • Alternatively, phenyldiazomethane can be prepared by dehydrogenation of benzaldehyde hydrazone using Swern-like conditions: NH2+BF4– OH PhCHN2, HBF4 (cat) CH2Cl2, –40 ºC basic work-up, 68% Liotta, L J.; Ganem, B Tetrahedron Lett 1989, 30, 4759–4762 NH2+BF4– OBn N Ph NH2 H (COCl)2, DMSO Et3N, THF, –78 ºC filtration of Et3N•HCl N2 H Ph (solution in THF) Javed, M I.; Brewer, M Org Lett 2007, 9, 1789–1792 Wommack, A J.; Moebius, D.; Travis, A.; Kingsbury, J S Org Lett 2009, 11, 3202–3205 Fan Liu Myers Chem 115 C–O Bond-Forming Reactions: Diazoalkane Reagents • More complex esterification reagents can be generated by in situ oxidation of their corresponding N-tert-butyldimethylsilylhydrazones with (difluoroiodo)benzene: • Diazoalkanes can also be generated in situ from the corresponding tosyl hydrazone at high temperature: NO2 H O H N N H TBS TBS O H O OBz H O I Ph N HO F , OBz O H O O O 110 ºC, O CH3 CH3 Ts N H CH3 OBz HO Ph CH3 µwave, 155 ºC H3C Ph O K2CO3, PhF + 72% H3CO HO N OBz N2 NO2 H3CO N2 H O 84% K2CO3, dioxane H H3CO 2-chloropyridine CH2Cl2, –78 " 23 ºC NO2 Ts N CH3 H O NO2 O F H O Sc(OTf)3 (0.01 mol%) " 23 ºC, >95% TBS N N H H3C 74% Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C Angew Chem Int Ed 2010, 122, 5113–5116 Rhodium-Mediated Etherification Reactions TBS N N H H3CO H3CO H NO2 Reviews: F Ph I + HO H3C OH O CO2H Valdes, C.; Barluenga, J Angew Chem Int Ed 2011, 50, 7486–7500 Fulton, J R.; Aggarwal, V K.; de Vicente, J Eur J Org Chem 2005, 1479–1492 F O 2-chloropyridine CH2Cl2, –78 " 23 ºC • Diazo compounds bearing an electron-withdrawing group are considered much safer than diazomethane because of resonance stabilization by the electron-withdrawing group In addition, stabilized diazo compounds tend to much less volatile 82% • Treatment of simple !-diazoketones in aqueous acids provides the corresponding alcohols O HO H3C OH OO O OCH3 O2N Furrow, M E.; Myers, A G J Am Chem Soc 2004, 126, 12222–12223 Furrow, M E.; Myers, A G J Am Chem Soc 2004, 126, 5436–5445 OCH3 O N2 MeS F aq HCl, acetone 40 ºC, 62% O MeS OH F Pirrung, M C.; Rowley, E G.; Holmes, C P J Org Chem 1993, 58, 5683–5689 Fan Liu Myers • Ethyl diazoacetate can be deprotonated with LDA at low temperature The resulting anion can be trapped with electrophiles O H Chem 115 C–O Bond-Forming Reactions: Diazoalkane Reagents O LDA, THF, –90 ºC Li OEt N2 H3C O H3C OEt –75 ºC, THF N2 Reviews: Heydt, H Sci Synth 2004, 27, 843–937 OH O O Synthesis of Diazo Compounds N2 51% • In addition to the methods described above for the generation of reactive diazo reagents, diazo compounds can be prepared by the following methods: CO2Et • Regitz Diazo Transfer Reaction • Rhodium catalysts readily transform "-diazoesters into stabilized carbenoids, which readily etherify alcohols: • Reaction of an enolate with sulfonyl azide affords diazo compounds: OH O H3C N2 Rh2OAc4 (1 mol%) C6H6, 80 ºC, 80% CO2Et O H3C O CO2Et O H3CO O O O S N3 + CH3 K2CO3, MeCN O 23 ºC, 96% H3CO OH N2 O Rh2OAc4 (1 mol%) CO2Et C6H6, 80 ºC, 77% O O C6H13 CO2Et Koskinen, A M P.; Munoz, L J Chem Soc Chem Commun 1990, 652–653 • Formation of medium-sized rings is entropically unfavorable and competitive C–H insertion by the rhodium carbenoid is observed: OEt O Rh2OAc4 (5 mol%) C6H6, 80 ºC, 77% O O O OH N2 OH + H3C CH3 (120 equiv) Rh2OAc4 (1 mol%) CH2Cl2, 23 ºC, 92% O O O NaHMDS, –78 ºC N Ph N2 PNBSA, 85–87% Bn 69% O Bn • The above reaction is highly sensitive to the enolate counterion, the quenching reagent, and the sulfonyl azide structure: using triisopropylsulfonyl azide (trisyl azide) instead led to selective azide transfer • Intermolecular trapping is also possible: CO2Et N Ph CO2Et Moody, C J.; Taylor, R J J Chem Soc Perkin Trans 1989, 721–731 O O CO2Et + 12% Ph • p-nitrobenzenesulfonyl azide (PNBSA) was found to be an effective diazo transfer agent for carboximide enolates: O N2 OH CH3 N2 H3C C6H13 O Ph CO2Et O CH3 CH3 Cox, G G.; Miller, D J.; Moody, C J.; Sie, E.-R H B.; Kulagowski, J J Tetrahedron 1994, 50, 3195! 3212 O O Ph N Bn O O O KHMDS, –78 ºC Trisyl-N3 AcOH, 25 ºC N Ph N3 91% O Bn Evans, D A.; Britton, T C.; Ellman, J A.; Dorow, R L J Am Chem Soc 1990, 112, 4011–4030 Fan Liu Myers C–O Bond-Forming Reactions: Diazoalkane Reagents Chem 115 • When only one electron-withdrawing group is present on the substrate, a second electronwithdrawing group is usually introduced to activate the parent compound towards diazo transfer The second electron-withdrawing group is removed at the end of the reaction: O O F3C CH3 O OCH2CF3 O F3C O MsN3, Et3N CF3 LiHMDS, THF, –78 ºC S O N2 H2O, CH3CN 25 ºC, 92% S O S O OCH2CF3 LiHMDS, THF, –78 ºC MsN3, Et3N N2 H2O, CH3CN 25 ºC, 81% Danheiser, R L.; Miller, R F.; Brisbois, R G.; Park, S Z J Org Chem 1990, 55, 1959–1964 • Reaction of acyl chlorides or anhydrides with diazomethane yields diazo compounds: H3C H HO2C H3C CH3 H CH3 CH3 CH3 H (COCl)2, C6H6 CH2N2, 23 ºC >78% N2 O H CH3 CH3 Smith, A B.; Dorsey, B D.; Visnick, M.; Maeda, T.; Malamas, M S J Am Chem Soc 1980, 108, 3110–3112 • Diazotization of primary amines also affords diazo compounds: OEt H2N •HCl O NaNO2, NaOAc H2SO4 (cat), H2O OEt N2 O ºC, >70% Wuzr, R P.; Charett, A B Org Lett 2002, 4, 4531–4533 Fan Liu Myers Metal-Catalyzed C!O Bond-Forming Reactions: Buchwald!Hartwig Coupling Chem 115 Reviews: Initial Reports: Hartwig, J F Organotransition Metal Chemistry, 1st Edition; University Science Books: USA, • Buchwald and co-workers reported an intramolecular C-O coupling procedure following a mechanism similar to that of Pd-catalyzed amination Bidentate phosphine ligands afford high conversions to product 2009 Condition A: Frlan, R.; Kikelj, D Synthesis, 2006, 14, 2271!2285 Schlummer, B.; Scholz, U Adv Synth Cat 2004, 346, 1599!1626 Reaction Highlights X • The main challenge in the Pd-catalyzed C-O bond forming reactions is to prevent "-H elimination of the alcohol substrate Many factors, including Pd source, ligand, base, solvent, and temperature can influence the efficiency of the reaction CH3 CH3 OH Pd(OAc)2 (5 mol%) Tol-BINAP (6 mol%) K2CO3 (1.2 equiv) toluene, 100 °C X: Br or I CH3 CH3 O 60% 89% I: Br: Condition B: • Much of the improvement in this field has come from the development of ligands, which permits couplings of substrates with varying steric and electronic parameters OH CH3 CH3 • The development of ligands has also improved the reactivity of unactivated aryl halides Pd(OAc)2 (3 mol%) dppf (3.6 mol%) NaOt-Bu (1.2 equiv) O toluene, 80 °C Br CH3 CH3 69% General Mechanism Condition C: O Ar Pd(OAc)2 (5 mol%) dppf (10 mol%) NaOt-Bu (2.0 equiv) OH R1 R2 LnPd Ar!X toluene, 90 °C Br R2 R1 Ln Pd H Ar elimination Ln Pd Ar X R2 O H Pd Ar Ln R1 HO LnPd O + + R1 R2 ArH Base•HX Base Ln Pd Ar X R2 Palucki, M.; Wolfe, J P.; Buchwald, S L J Am Chem Soc 1996, 118, 10333!10334 • Electron-deficient aryl bromides were found to be more reactive than electron-neutral and electron-rich aryl bromides R1 HO H Condition A (24!36 h) gives product cleanly while Condition B gives product with a faster reaction rate (1!6 h) Condition C works well for secondary alcohols R1 "-H O 66% reductive elimination O H R2 O + Br Pd(dba)2 (10 mol%) dppf (12 mol%) O NaOt-Bu (1.2 equiv) 100 °C, toluene Ot-Bu 69% Mann, G.; Hartwig, J F J Am Chem Soc 1996, 118, 13109!13110 Alpay Dermenci 10 Myers Chem 115 Metal-Catalyzed C"O Bond-Forming Reactions: Buchwald"Hartwig Coupling • The methodology was extended to intermolecular cross-coupling with primary and secondary alcohols Pd2(dba)3 (1.5 mol%) Tol-BINAP (3.6 mol%) X + R1 R2OH • Ligands and Their Applications • A series of ligands developed by Buchwald and co-workers improved reactivities of a combination of substrates, including unactivated aryl halides and triflates OR2 P(t-Bu)2 P(t-Bu)2 toluene, ! R1 (1.2 equiv) Ligand A Aryl halide Alcohol Br Product O OH H3C NC CH3 CH3 CH3 NC Temp (°C) Yield (%)a 50 80 (76) Ligand B X Pd(OAc)2 (2.0 mol%) Ligand (3 mol%) K3PO4 (2.0 mol%) HO + (1.2 equiv) CH3 CH3 i-Pr NC 70 O i-Pr OH 77 (73) Aryl halide Phenol Br NC HO H3C Br 100 Ligand OH Product CH3 O A OTf CH3 96 (95)a H3C HO i-Pr O B i-Pr 84 t-Bu O 70 65 (