21 c n bond forming reactions

Myers Chem 115 C!N Bond-Forming Reactions: Reductive Amination Reviews: Reducing Agents Abel-Magid, A F.; Mehrman, S J Org Proc Res Devel 2006, 10, 971–1031 Abdel-Magid, A F.; Carson, K G.; Harris, B D.; Maryanoff, C A.; Shah, R D J Org Chem 1996, • Common reducing agents: NaCNBH3, Na(OAc)3BH, H2/catalyst 61, 3849-3862 Bhattacharyya, S Tetrahedron Lett 1994, 35, 2401–2404 Hutchins, R O.; Hutchins, M K., Reduction of CdN to CHNH by Metal Hydrides In Comprehensive Organic Synthesis; Trost, B N., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol Overview: • Iminium ions are reduced selectively in the presence of their carbonyl precursors Reagents such as sodium cyanoborohydride and sodium triacetoxyborohydride react selectively with iminium ions and are frequently used for reductive aminations Reduction with Sodium Cyanoborohydride: • The reductive amination of aldehydes and ketones is an important method for the synthesis of primary, secondary, and tertiary amines • Reductive amination is a powerful and reliable strategy for the formation of C–N bonds, and can avoid the problem of overalkylation that often accompanies direct alkylation of amines with alkyl halides • Borch and co-workers showed that sodium cyanoborohydride and lithium cyanoborohydride are acid-stable reagents capable of rapidly reducing carbonyl compounds to alcohols at pH 3–4, presumably via a protonated carbonyl cation • Reductive amination involves a one- or two-step procedure in which an amine and a carbonyl compound condense to afford an imine or iminium ion that is reduced in situ or subsequently to form an amine product R3 O R1 + R2 NaBH3CN CH3OH O Mechanism: R3 N H R4 R1 N HO R4 Ph CH3 pH 3, 23 °C, h 93% OH Ph CH3 (±) Borch, R F.; Bernstein, M D.; Durst, H D J Am Chem Soc 1971, 93, 2897–2904 H+ (cat.) R2 R3 R4 hydride R2 source N R1 R3 R1 N H R4 R2 • At pH 7, reduction of carbonyl compounds with lithium cyanoborohydride is very slow, even at reflux in methanol R1, R2, R3, R4 = H, alkyl, aryl !H2O R4 = H R3 R1 hydride, N R2 proton source Ph • relative rates of reductive amination: LiBH3CN CH3OH O CH3 pH 7, reflux, 72 h 36% OH Ph CH3 (±) H N H2NR > > n n = 1, HNR2 > H2NAr Borch, R F.; Durst, H D J Am Chem Soc 1969, 91, 3996–3997 Jonathan William Medley, Fan Liu C!N Bond-Forming Reactions: Reductive Amination Myers Chem 115 • With care to maintain a pH of 6–7, a mixture of a ketone or aldehyde reactant, an amine, and sodium cyanohydride provides products of reductive amination selectively, without competitive reduction of the carbonyl substrate Reduction with Sodium Triacetoxyborohydride: • Though the conditions of the Borch reduction are mild, sodium cyanoborohydride is highly toxic, as are its byproducts • This protocol is generally high yielding, highly functional group tolerant, and proceeds without release of cyanide salts The substrate scope includes aromatic and aliphatic aldehydes, ketones, and primary and secondary amines Ammonia can be employed successfully if used in large excess as its acetate salt O R1 + R2 R3 N H R4 carbonyl compound amine O O NaBH3CN CH3OH pH 6–8,a R3 R1 23 °C N H • Sodium triacetoxyborohydride has been found to be a highly selective reducing agent for reductive amination; acetic acid is frequently employed as a proton donor R4 O R2 R1 isolated yield (%) product + R3 N H R2 carbonyl compound H3C CH3NH2 H3C CH3 H EtO cycloheptanone OH H2NOH N 66 yield (%) 96 N NH2 H N II EtO 88 OEt NH4OAc (10 equiv) IIb cycloheptylamine CH3 N CH3 96 I O 80c NHPh NHPh O H3C PhNH2 H 78 H OHC CH3 CH3 N NH2 O OH HO O product Ph PhNH2 H3C R2 90 Ph N H R4 N OEt CH3 O R1 N N H NHCH3 Ph Method II 79 O O R3 Ph N O N H NaHB(OAc)3 methoda amine O N R4 O NH3 HO OH O O II 95 N N N(i-Pr)2 H (±) Borch, R F.; Bernstein, M D.; Durst, H D J Am Chem Soc 1971, 93, 2897–2904 COOEt O 51 aThe pH was maintained by addition of HCl and/or KOH as needed using bromocresol green as an indicator COOEt H N (i-Pr)2NH II 88 aMethod I: ClCH2CH2Cl, AcOH (1!2 equiv), NaBH(OAc)3 (1.3!1.6 equiv) Method II: ClCH2CH2Cl, NaBH(OAc)3 (1.3!1.6 equiv) bEt3N (1.5!2.0 equiv) added cyield of HCl salt Jonathan William Medley Myers Chem 115 C!N Bond-Forming Reactions: Reductive Amination Reaction with Weakly Nucleophilic Amines: O R1 + R3 R2 carbonyl compound N H R4 Reduction with Sodium Borohydride: NaHB(OAc)3 R3 Method R1 methoda amine • Reductive amination of carbonyl compounds with primary amines can be complicated by overalkylation In these cases, formation and isolation of the imine followed by reduction can prove to be a superior alternative R4 N R2 H • It was found that the use of methanol as solvent allows for rapid (< 3h) and nearly quantitative imine formation from aldehydes without the need for dehydrating reagents product yield (%) O Br O Br III H N 89b R1 + R3 NH2 CH3OH !H2O R2 R3 NaBH4 N R1 R2 10!15 R3 R1 N H R4 R2 H2N aldehyde Cl O Cl Cl H IV amine O Cl H3CO N yield (%)a product H N H PhNH2 Cl 95 Ph 84 H2N O H O N IV H2N Cl Cl H H NO2 95 Ph H PhNH2 N H H t-BuNH2 N H Ph 90 S IV N H 89 Bn O 60 N N t-Bu 83 H O Ph H S H2N N H O NO2 O H2N H2N Ts H IVc N Ts 80 Bn H Ph BnNH2 Ph NHBn 85 O aMethod III: ClCH2CH2Cl, AcOH (1 equiv), NaBH(OAc)3 (1.4 equiv) Method IV: ClCH2CH2Cl, AcOH (2!5 equiv), carbonyl compound (1.5!2 equiv), NaBH(OAc)3 (2.0!2.8 equiv) byield of HCl salt cEt3N (2.0 equiv) added aproducts isolated as HCl salts Abdel-Magid, A F.; Carson, K G.; Harris, B D.; Maryanoff, C A.; Shah, R D J Org Chem 1996, 61, 3849!3862 Jonathan William Medley C!N Bond-Forming Reactions: Reductive Amination Myers Chem 115 Examples in Synthesis O CH3 OTBS AcO CH3 H3C Na(AcO)3BH, Sn(OTf)2 + CHO N H H O H3C Å MS, ClCH2CH2Cl, °C HO H O CH3O 66% O CH3 HO O CH3 O OCH2 OCH3 Et O O N(CH3)2 O CH3 NaBH3CN O OH OH CH3 OH CH3 CH3OH, NH tylosin AcO 79% OTBS CH3 N H3C CH3 N Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S Tetrahedron Lett 2000, 41, 6435-6439 H3C HO CH3O O O NaBH3CN H N H CH3 CH2O O O H O Ph Ph O Ph Ph H N H3C CH3 CH3 O OCH2 OCH3 Et HO O CH3 O O N(CH3)2 O CH3 O O OH OH CH3 OH CH3 Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S J Antibiot 1983, 36, 1713-1721 84% Jacobsen, E J.; Levin, J.; Overman, L E J Am Chem Soc 1988, 110, 4329-4336 H CO2Bn H CO2Bn OHC • Formic acid can also be used as a hydride donor: H3C HO H3C H3C H N OH H3C O CH3 OH CH3 HO O CH3 O H3C HO H3C N(CH3)2 O OCH3 CH3 OH CH3 CH3 H3C CH2O, HCO2H N OH H3C O CH3 H OH CH3 HO O O O CHCl3, 65 ºC 71% OTHP + H3C O O N CO2t-Bu CH3 O NaBH3CN H CO2Bn N CO2t-Bu N CH3OH H CO2Bn H CO2Bn OTHP 59% H2, Pd/C, EtOH, H2O, HCl TFA CO2Bn NH•TFA N(CH3)2 O CH3 OCH3 CH3 OH CH3 H CO2H H CO2H H CO2H N H N OH 2'-deoxymugineic acid Ohfune, Y.; Tomita, M.; Nomoto, K J Am Chem Soc 1981, 103, 2409-2410 Dokic, S.; Kobrehel, G.; Lopotar, N.; Kamenar, B.; Nagl, A.; Mrvos, D J Chem Res (S) 1988, 152 Mark G Charest, Fan Liu Myers Chem 115 C!N Bond-Forming Reactions: Reductive Amination • A regioselective reductive amination using sodium triacetoxyborohydride was employed in the construction of the pyrrolidine ring of (!)-communesin A: H3C CH3 O N H3C H3C O O H3C CH3 O HN N H3C H3C O OH NH4OAc NaHB(OAc)3 CH3OH, >92% NH • In a complex transformation, a tryptamine derivative and an enantioenriched dialdehyde were combined to give a cyclic bis-hemiaminal interemediate; electrophilic activation with trifluoroacetic anhydride initiated a Mannich/Sakurai cascade Subsequent iminium reduction with sodium cyanoborohydride afforded a pentacyclic diamine en route to (!)-aspidophytine OH NH N CH3 NH2 N CH3 H3CO O CH3 N N OCH3 CH3 N CH3CN OHC steps H3C OHC H3CO R TMS R = CH2COOi-Pr HO N OCH3 CH3 R TMS TFAA (2 equiv) !TFA Ac N CF3COO NH N CF3COO R TMS N !CF3COOTMS N CH3 H3CO (!)-communesin A N OCH3 CH3 H3CO N OCH3 CH3 R TMS Zuo, Z.; Ma, D Angew Chem., Int Ed 2011, 50,12008!12011 • Regio- and stereoselective indolenine reduction and reductive methylation of two secondary amines was achieved using Borch conditions en route to (+)-haplophytine O N N H N O N CO2CH3 TFA HCHO, NaBH3CN AcOH MsO H3CO CH2Cl2, CH3OH " 23 °C 55% N O CH3 OCH3 O N CH3 N O N N H OCH3 CH3 H3CO O N O N O HO N H O CH3 OCH3 CH3 R NaBH3CN (5 equiv) 66% N H OCH3 CH3 CO2CH3 O MsO CH3 N O N CF3COO R N O N H O CH3 OCH3 CH3 1N NaOH, CH3OH, 60 °C K3Fe(CN)6, NaHCO3, t-BuOH, H2O, 70% (2 steps) N steps H3CO N H OCH3 CH3 R N H OCH3 CH3 H3CO (!)-aspidophytine (+)-haplophytine Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H Angew Chem., Int Ed 2009, 48, 7600!7603 He, F.; Bo, Y.; Altom, J.; Corey, E J J Am Chem Soc 1999, 121, 6771!6772 Jonathan William Medley Myers Chem 115 C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Reviews: Solvent Choices: • Most general: toluene, THF, DME, dioxane, and tertiary alcohols • Water is compatible but rates of reaction are often slower • DMF, NMP, MeCN, acetone, etc., should be avoided as single solvents, but they can be great cosolvents, especially for substrates containining potentially chelating functional groups that otherwise might inhibit catalysis Surry, D S.; Buchwald, S L Chem Sci 2011, 2, 27–50 Klinkenberg, J L.; Hartwig, J F Angew Chem Int Ed 2011, 50, 86–95 Industrial Review of C-N and C-O Coupling: Schlummer, B.; Scholz, U Adv Synth Catal 2004, 346, 1599–1626 Activation • The Buchwald-Hartwig reaction is the coupling of an amine with an aryl halide mediated by a palladium catalyst R R' NH + X Ar PdLn R' Base, Solvent R • In order for the catalytic cycle to begin, palladium must be in the Pd(0) oxidation state One of the most common Pd(0) sources is Pd2dba3 • Pd(II) sources can be used and are more stable, but they require reduction to Pd(0) One of most common activation methods is via reduction of Pd(OAc)2 with PR3, water, and heat N Ar Pd(II)(OAc)2 + 2PR3 Mechanism: (R3P)Pd(0)(OAc) + AcOPR3 Pd(0)PR3 H2O O=PR3 + 2HOAc Activation LnPd(0) or LnPd(II) R Reductive Elimination N Ar R' Oxidative Addition Ar X Ozawa, F.; Kubo, A.; Hayashi, T Chem Lett 1992, 11, 2177–2180 Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M Organometallics 1995, 14, 1818–1826 Fors, B P.; Krattiger, P.; Strieter, E.; Buchwald, S L Org Lett 2008, 10, 3505–3508 LnPd(0) • Precatalyst systems allow for lower reaction temperatures LnPd(II)(Ar)[N(R)R'] LnPd(II)(Ar)(X) Coordination R Base-HX Deprotonation Base H R' R N N H NaOtBu R' Pd Cl NH2 dioxane, 23 ºC L–Pd(0) (active catalyst) + L N H LnPd(II)(Ar)(X) Biscoe, M R.; Fors, B P.; Buchwald, S L J Am Chem Soc 2008, 130, 6686-6687 The Base (bolded bases are the most commonly used): • For fast reactions: strong bases such as NaOt-Bu, KOH (uncrushed pellets) • For substrates bearing sensitive functional groups: weaker bases such as K3PO4, Cs2CO3, K2CO3 with t-BuOH or t-amyl alcohol • For substrates bearing acidic functional groups, use of LiHMDS as base affords lithiates that can prevent catalyst inhibition K3PO4 Pd Cl NH2 THF, 23 ºC L–Pd(0) (active catalyst) + N H L Kinzel, T.; Zhang, Y.; Buchwald, S L J Am Chem Soc 2010, 132, 14073–14075 Harris, M C.; Huang, X.; Buchwald, S L Org Lett 2002, 4, 2885–2888 Rob Singer, David Bernhardson Myers Chem 115 C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Oxidative Addition Coordination • Electron-rich and sterically hindered aryl halides undergo slower oxidative addition Reactivity order: I > Br > OTf > Cl > OTs • Electron-rich amines are superior substrates due to their enhanced nucleophilicities Deprotonation • Binding to Pd increases the acidity of the amine, which facilitates deprotonation I R H2N R Cl R= H2N 90% Cl Pd2(dba)3, Xantphos NaOt-Bu, toluene 80 ºC Br Reductive Elimination NH H2N Br 96% Br • Electron deficient amines undergo slower reductive elimination • Bulky ligands help to accelerate reductive elimination through steric repulsion Ph Ph P Ph Pd Fe N R1 P R2 Ph Ph Amine R1 Ph N R2 Temp 1.5 h pKa (HNR2) Temp (ºC) Yield (%) N(tolyl)2 25 85 90 NHPh 30 25 80 NHi-Bu 41 64 Larsen, S B.; Bang-Andersen, B.; Johansen, T N.; Jorgensen, M Tetrahedron, 2008, 64, 2938–2950 Hartwig, J F Inorg Chem 2007, 46, 1936–1947 Examples of Ligands Boc N Ph2P PPh2 Buchwald OCH3 O Boc N N H Br N Pd2(dba)3, Xantphos N Cl NaOt-Bu, toluene 100 ºC, 96% H3C CH3 N PCy2 Oi-Pr i-PrO Cl addition Boc N N H Fe OCH3 H3CO i-Pr NaOt-Bu, toluene 100 ºC, 95% N Br Ji, J.; Li, T.; Bunnelle, W H Org Lett 2003, 5, 4611–4614 Maes, B U W.; Loones, K T J.; Jonckers, T H M.; Lemiere, G L F.; Dommisse, R A.; Haemers, A Synlett, 2002, 1995–1998 Josiphos CyPFtBu Ph Pd Q-phos O P(t-Bu)2 i-Pr i-Pr NH Cl L Pre-Ru: L = RuPhos Pre-Brett: L = BrettPhos i-Pr N N Ph P(Ad)2 JackiePhos P(t-Bu)2 Ph Singer N i-Pr N Fe Ph Stradiotto 3,5-CF3C6H4 P 3,5-CF3C6H4 i-Pr Br Br Ph Ph BrettPhos (for 1º amines) RuPhos (for 2º amines) readily, and tend to form bridged palladium dimers • Halides in the 2- and 4-positions of 6-membered hetercycles are predisposed towards oxidative N P(t-Bu)2 PCy2 i-Pr • Iodides are less frequently used because they tend to be more expensive, dehalogenate more Pd2(dba)3, Xantphos CH3 PCy2 i-Pr Xantphos • OTf and OTs may undergo competing hydrolysis Boc N H3CO i-Pr Hartwig Mor-DalPhos Ph N N P(t-Bu)2 Ph Bippyphos tBuXPhos Rob Singer, David Bernhardson Myers Chem 115 C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Nitrogen nucleophiles Secondary Amines vs Primary Amines • Listed, in decreasing order, by approximate ease of coupling: anilines, secondary amines, primary amines, amides, sulfamides, five-membered heterocycles (i.e pyrazole, imidazole, etc.), and ammonia • Ligand choice is important A catalyst that is too hindered inhibits reactions with secondary amines, while primary amines require a hindered ligand, to avoid double arylation Anilines OR OR N N Br N N O N H O Ar CH3 ArNH2, K3PO4, DME, 80oC N H Pd2(dba)3, BINAP CH3 N N N N O O N H O O N N H CH3 Br CH3 61-81% OTBS OTBS OTBS OTBS R = CH2Ph or 4-CN-PhCH2CH2 Meier, C.; Sonja, G Sylett 2002, 802–804 • A selective C–N coupling reaction was used in the synthesis of the core of variolins, a group of marine natural products with potent cytotoxic activities against murine leukemia cells: H2N Cl Br N Cl Br N Cl N Pd(OAc)2 (5 mol%) JohnPhos (10 mol%) NaOt-Bu (1.4eq) THF, 70 ºC, 83% N PdL (1 mol%) NaOt-Bu, dioxane 100 ºC H3CO H3CO CH3 n = or H N PdL (1 mol%) NaOt-Bu, dioxane H CO 100 ºC n CH3 n = or PdL Pre-Ru - 30% (GC), n = Pre-Brett - 99% (GC), n = Pd(dba)2/Qphos - 85% (isolated), n = PdL Pre-Ru - 99% (GC) Pre-Brett - 17% (GC) Pd(dba)2/Qphos - 96% (isolated) Fors, B.; Buchwald, S L J Am Chem Soc., 2010, 132, 15914–15917 Kataoka, N.; Shelby, Q.; Stambuli, J P.; Hartwig, J F J Org Chem 2002, 67, 5553–5566 (1.2 eq) N H2N N HN N • The combination of Pd(OAc)2 and CyPFt-Bu is highly effective for monoarylation of primary amines While it can be used to effect arylation of secondary amines, the rate is slower and higher catalyst loading is required: N O O P(t-Bu)2 N Johnphos N 69% (isolated) • The selectivity in this case is attributed to the directing effects of the neighboring nitrogen atoms N H Pd(OAc)2 (1 mol%) CyPFt-Bu (1 mol%) NaOt-Bu, DME, 90 ºC Cl N n-C8H17 NH2 Pd(OAc)2 (0.005 mol%) CyPFt-Bu (0.005 mol%) NaOtBu, DME, 90 ºC n-C8H17 N H N 100% (GC) 92% (isolated) A Baeza, C Burgos, J Alvarez-Builla, J J Vaquero, Tetrahedron Lett 2007, 48, 2597 Shen, Q.; Ogata, T.; Hartwig, J F J Am Chem Soc 2008, 130, 6586–6596 Rob Singer, David Bernhardson Myers Amides as Substrates Challenging Substrate for Coupling CH3 • Aminopyridines frequently function as chelating ligands with palladium This effect can be mitigated by the use of LiHMDS and hindered, reactive ligands O Cl HN H2N O N H N H N Br PdL (2 mol%) LiHMDS, 65 ºC NH2 N Chem 115 C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction N PdL (4 mol%) LiHMDS, 65 ºC NH2 PdL Pre-Ru - 79% (isolated) Pre-Brett -