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Home , Amination, Amine, Hemiaminal, Reductive amination, Sodium cyanoborohydride

Myers C!N Bond-Forming Reactions: Reductive Chem 115

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. • Iminium are reduced selectively in the presence of their carbonyl precursors. Reagents Hutchins, R. O.; Hutchins, M. K., Reduction of CdN to CHNH by Metal Hydrides. In Comprehensive such as cyanoborohydride and sodium triacetoxyborohydride react selectively with iminium ions and are frequently used for reductive . Organic Synthesis; Trost, B. N., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8.

Overview: Reduction with : • The of and is an important method for the synthesis of primary, secondary, and tertiary . • Borch and co-workers showed that sodium cyanoborohydride and lithium cyanoborohydride are -stable reagents capable of rapidly reducing carbonyl compounds to at pH • Reductive amination is a powerful and reliable strategy for the formation of C–N bonds, and 3–4, presumably via a protonated carbonyl cation. can avoid the problem of overalkylation that often accompanies direct of amines with halides.

NaBH CN O 3 OH Mechanism: CH3OH

Ph CH3 Ph CH3 • Reductive amination involves a one- or two-step procedure in which an and a carbonyl pH 3, 23 °C, 1 h (±) compound condense to afford an or iminium that is reduced in situ or subsequently 93% to form an amine product.

Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. R3 4 3 4 R H+ (cat.) R3 R4 R R O R3 R4 N N hydride N + N • At pH 7, reduction of carbonyl compounds with lithium cyanoborohydride is very slow, even 2 1 2 2 R1 R R R 1 2 source R1 R at reflux in . H HO R R H R1, R2, R3, R4 = H, alkyl, !H2O R4 = H R3 N hydride, proton source R1 R2 LiBH CN O 3 OH CH3OH Ph CH Ph CH 3 pH 7, reflux, 72 h 3 • relative rates of reductive amination: 36% (±)

H N H2NR > > HNR2 > H2NAr n Borch, R. F.; Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. n = 1, 2 Jonathan William Medley, Fan Liu

1 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115

• With care to maintain a pH of 6–7, a mixture of a or reactant, an amine, and Reduction with Sodium Triacetoxyborohydride: sodium cyanohydride provides products of reductive amination selectively, without • Sodium triacetoxyborohydride has been found to be a highly selective reducing agent for competitive reduction of the carbonyl substrate. reductive amination; is frequently employed as a proton donor. • Though the conditions of the Borch reduction are mild, sodium cyanoborohydride is highly • This protocol is generally high yielding, highly tolerant, and proceeds without toxic, as are its byproducts. release of salts. The substrate scope includes aromatic and aliphatic aldehydes, ketones, and primary and secondary amines. can be employed successfully if used in large excess as its acetate salt. NaBH3CN R3 R4 O R R CH3OH N R R 3 4 O NaHB(OAc)3 3 4 + N R3 R4 N R R a + N 1 2 H pH 6–8, 23 °C R1 R2 H R1 R2 H Method R R 1 H 2

carbonyl compound amine product isolated yield (%) carbonyl compound amine methoda product yield (%)

O Ph Ph N O O O N II 96 N N 79 N N H H H O EtO N NH2 II 88 O NHCH OEt EtO 3 OEt H C H C 3 Ph CH3NH2 3 Ph 90 NH OAc CH3 CH3 cycloheptanone 4 b cycloheptylamine c (10 equiv) II 80

O H OH CH3 CH3 N N N H2NOH 66 PhNH2 I 96

O NHPh O NHPh H3C PhNH H3C 78 COOEt COOEt H 2 H OHC H CH3 CH3 N II N 95 N N

O NH2 O N(i-Pr)2 HO OH NH3 HO OH 51 H (i-Pr)2NH II 88 O O O O (±)

a The pH was maintained by addition of HCl and/or KOH as needed using bromocresol green as an a Method I: ClCH2CH2Cl, AcOH (1!2 equiv), NaBH(OAc)3 (1.3!1.6 equiv). Method II: ClCH2CH2Cl, indicator. b c NaBH(OAc)3 (1.3!1.6 equiv). Et3N (1.5!2.0 equiv) added. yield of HCl salt. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. Jonathan William Medley

2 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115

Reaction with Weakly Nucleophilic Amines: Reduction with :

• 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 NaHB(OAc) R3 R4 O R R 3 N to be a superior alternative. + 3 N 4 R1 R2 H Method R1 R H 2 • It was found that the use of methanol as allows for rapid (< 3h) and nearly quantitative imine formation from aldehydes without the need for dehydrating reagents.

carbonyl compound amine methoda product yield (%)

R3 R3 R4 Br O CH3OH N NaBH4 N + R3 NH2 O Br !H O 10 15 min H R1 R2 2 R1 R2 ! R1 R2 III N 89b H

H2N

aldehyde amine product yield (%)a

O Cl Cl Ph O H3CO N Cl Cl H PhNH2 84 H H IV N 95 Cl

H2N O

H N 89 H2N H Cl Cl O H N H IV 95 H2N NO O 2 Ph NO2 N H PhNH2 90 H

O S H S H N IV N 60 O 2 t-Bu Ph H N Bn N N H t-BuNH2 83 H O H c H2N Ts IV N Ts 80 Ph H Bn Ph H BnNH2 Ph NHBn 85 O

a a products isolated as HCl salts. Method III: ClCH2CH2Cl, AcOH (1 equiv), NaBH(OAc)3 (1.4 equiv). Method IV: ClCH2CH2Cl, b AcOH (2!5 equiv), carbonyl compound (1.5!2 equiv), NaBH(OAc)3 (2.0!2.8 equiv). yield of HCl Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. salt. cEt N (2.0 equiv) added. 3 1996, 61, 3849!3862. Jonathan William Medley

3 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115 Examples in Synthesis

O

CH3 OTBS O AcO CH3 Na(AcO)3BH, Sn(OTf)2 CH3 H C + H3C H N(CH3)2 NaBH CN 3 O O 3 CHO 4 Å MS, ClCH2CH2Cl, 0 °C CH HO N HO OCH2 3 O O OH H O O CH3 CH3OH, H OCH CH O 3 CH3 3 O OH 66% Et O OH NH O CH3

tylosin 79%

OTBS AcO CH3 H3C N O O H O CH3 N Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, CH3 41, 6435-6439. H3C N(CH3)2 O HO HO OCH2 CH3 O O O O CH3 OH OCH CH O 3 CH3 3 O OH Et O OH CH Ph Ph Ph Ph 3 O O NaBH3CN N H N H CH2O Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S. J. Antibiot. 1983, 36, 1713-1721. H CH3 CH3 H3C 84%

Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329-4336. H CO2Bn H CO2Bn CO2Bn H CO2Bn H CO2Bn OHC NaBH3CN H • can also be used as a hydride donor: N OTHP N N OTHP CH3OH CO2t-Bu CO2t-Bu

+ 59% H H C 3 1. H , Pd/C, EtOH, N N 2 CH3 CH3 CO2Bn H3C H3C H H2O, HCl HO OH HO OH 2. TFA H C H C NH•TFA 3 OH CH 3 OH CH 3 N(CH3)2 3 N(CH3)2 H C H C H3C 3 HO H3C 3 HO O O O CH3 O O O CH3 CH2O, HCO2H CO2H H CO2H H CO2H O O OCH O O OCH H 3 3 N N OH CH3 CHCl3, 65 ºC CH3 CH3 CH3 H O OH 71% O OH CH CH 3 3 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

4 Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115

• A regioselective reductive amination using sodium triacetoxyborohydride was employed in • In a complex transformation, a tryptamine derivative and an enantioenriched dialdehyde the construction of the ring of (!)-communesin A: were combined to give a cyclic bis- interemediate; electrophilic activation with trifluoroacetic anhydride initiated a Mannich/Sakurai cascade. Subsequent iminium reduction H3C CH 3 OH H3C CH3 with sodium cyanoborohydride afforded a pentacyclic diamine en route to (!)-aspidophytine. O O O HN H C N NH4OAc 3 H3C N H C O NaHB(OAc)3 3 H3C O OH NH CH3OH, >92% NH OHC N NH N N 2 CH3CN CH 3 CH3 OHC HO N H CO N R H3CO R 3 TMS 4 steps CH OCH CH3 OCH3 3 TMS 3

R = CH2COOi-Pr TFAA (2 equiv) H C Ac !TFA 3 CH 3 N O N

N CF3COO CF3COO NH R TMS N N !CF3COOTMS CH N R 3 H3CO TMS H CO N 3 OCH CH3 (!)-communesin A CH 3 OCH3 3 Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50,12008!12011. • Regio- and stereoselective indolenine reduction and reductive of two secondary amines was achieved using Borch conditions en route to (+)-haplophytine. N N H R CF3COO R N CO2CH3 NaBH3CN O N HCHO, NaBH CN TFA N O 3 AcOH (5 equiv) MsO N N H3CO H H3CO H 66% CH2Cl2, CH3OH CH CH OCH3 3 OCH3 3 O N 0 " 23 °C CH 55% 3 CH3 OCH3 N CO2CH3 O N N O MsO O N O N O CH3 O N H 6 steps R N CH O N O CH3 OCH3 3 N O HO N H N H 1. 1N NaOH, CH3OH, 60 °C. H3CO H3CO CH CH 2. K3Fe(CN)6, NaHCO3, OCH3 3 OCH3 3 O N H t-BuOH, H O, 70% (2 steps). 2 (!)-aspidophytine CH CH3 OCH3 3 (+)-haplophytine Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem., He, F.; Bo, Y.; Altom, J.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771!6772. Int. Ed. 2009, 48, 7600!7603. Jonathan William Medley

5 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Reviews: Solvent Choices: • Most general: toluene, THF, DME, dioxane, and tertiary alcohols Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50. • Water is compatible but rates of reaction are often slower. Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 86–95. • DMF, NMP, MeCN, acetone, etc., should be avoided as single , but they can be great co- solvents, especially for substrates containining potentially chelating functional groups that Industrial Review of C-N and C-O Coupling: otherwise might inhibit catalysis. Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626. Activation

• In order for the catalytic cycle to begin, palladium must be in the Pd(0) oxidation state. One of the • The Buchwald-Hartwig reaction is the coupling of an amine with an mediated by a most common Pd(0) sources is Pd2dba3. palladium catalyst.

• Pd(II) sources can be used and are more stable, but they require reduction to Pd(0). One of most

R' PdLn R' common activation methods is via reduction of Pd(OAc)2 with PR3, water, and heat. + NH X Ar N Ar R , Solvent R Pd(0)PR H2O 3 Pd(II)(OAc)2 + 2PR3 (R3P)Pd(0)(OAc) + AcOPR3 O=PR3 + 2HOAc Mechanism: Activation L Pd(0) or L Pd(II) n n Oxidative Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 11, 2177–2180 Addition R R' Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M. Organometallics 1995, 14, 1818–1826 N Ar X Reductive Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505–3508. Elimination Ar LnPd(0)

• Precatalyst systems allow for lower reaction temperatures.

LnPd(II)(Ar)[N(R)R'] LnPd(II)(Ar)(X) Coordination NaOtBu R R' L–Pd(0) + N NH2 Pd dioxane, 23 ºC (active catalyst) N H H H Cl L Base-HX R R' N Deprotonation Base 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) K PO 3 4 L–Pd(0) + • For substrates bearing sensitive functional groups: weaker bases such as K PO , Cs CO , 3 4 2 3 (active catalyst) NH2 THF, 23 ºC K2CO3 with t-BuOH or t-amyl Pd N • For substrates bearing acidic functional groups, use of LiHMDS as base affords lithiates that can Cl L H prevent catalyst inhibition.

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

6 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Oxidative Addition Coordination

• Electron-rich and sterically hindered aryl halides undergo slower oxidative addition. Reactivity • Electron-rich amines are superior substrates due to their enhanced nucleophilicities. order: I > Br > OTf > Cl > OTs. Deprotonation • Binding to Pd increases the acidity of the amine, which facilitates deprotonation. R Reductive Elimination I H2N R NH R = H N 2 90% • Electron deficient amines undergo slower reductive elimination. Cl Pd (dba) , Xantphos Cl 2 3 • Bulky help to accelerate reductive elimination through steric repulsion.

NaOt-Bu, toluene H N 2 Ph Br 80 ºC Br Ph Amine pKa (HNR2) Temp (ºC) Yield (%) 96% Br P Ph R Temp 1 N(tolyl)2 25 85 90 Fe Pd Ph N N R 1.5 h P 1 R2 NHPh 30 25 80 R2 Ph Ph NHi-Bu 41 0 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.

Boc Examples of Ligands N Ph P PPh 2 2 Buchwald OCH3 Hartwig O Boc Br N CH3 H3CO PCy2 N Pd2(dba)3, Xantphos P(t-Bu)2 PCy i-Pr i-Pr P(t-Bu)2 Ph Ph H C CH 2 Fe N NaOt-Bu, toluene N 3 3 i-PrO Oi-Pr PCy2 N Fe Ph Ph H 100 ºC, 96% Xantphos Cl Cl i-Pr Ph Josiphos Q-phos • OTf and OTs may undergo competing . RuPhos BrettPhos (for 2º amines) (for 1º amines) CyPFtBu • Iodides are less frequently used because they tend to be more expensive, dehalogenate more readily, and tend to form bridged palladium dimers. OCH3 Stradiotto Singer • Halides in the 2- and 4-positions of 6-membered hetercycles are predisposed towards oxidative 3,5-CF3C6H4 addition. H3CO P 3,5-CF C H 3 6 4 O i-Pr i-Pr Boc N N N Ph N Boc Br P(Ad) P(t-Bu)2 i-Pr 2 N Pd2(dba)3, Xantphos N N N P(t-Bu)2 Ph N Ph NaOt-Bu, toluene N JackiePhos i-Pr i-Pr N H 100 ºC, 95% Br Br NH Mor-DalPhos Bippyphos Pd i-Pr L Cl tBuXPhos Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611–4614. Pre-Ru: L = RuPhos Maes, B. U. W.; Loones, K. T. J.; Jonckers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.; Haemers, A. Pre-Brett: L = BrettPhos Synlett, 2002, 1995–1998. Rob Singer, David Bernhardson

7 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Nitrogen Secondary Amines vs. Primary Amines

• choice is important. A catalyst that is too hindered inhibits reactions with secondary Listed, in decreasing order, by approximate ease of coupling: , secondary amines, primary • amines, while primary amines require a hindered ligand, to avoid double arylation. amines, , , five-membered heterocycles (i.e. pyrazole, imidazole, etc.), and ammonia.

Anilines

OR OR N Ar N N O o N O O O Br ArNH2, K3PO4, DME, 80 C N CH CH Br N N N 3 H N N N 3 N H2N CH3 H H Pd2(dba)3, BINAP H N N CH O CH3 O CH3 H n = 2 or 4 n 3 61-81% PdL (1 mol%) H3CO PdL (1 mol%) OTBS OTBS OTBS OTBS H CO NaOt-Bu, dioxane NaOt-Bu, dioxane 3 H3CO 100 ºC 100 ºC n = 2 or 4 R = CH2Ph or 4-CN-PhCH2CH2 PdL PdL Pre-Ru - 99% (GC) Pre-Ru - 30% (GC), n = 7 Meier, C.; Sonja, G. Sylett 2002, 802–804. Pre-Brett - 17% (GC) Pre-Brett - 99% (GC), n = 7 • A selective C–N coupling reaction was used in the synthesis of the core of variolins, a group of marine Pd(dba)2/Qphos - 96% (isolated) Pd(dba)2/Qphos - 85% (isolated), n = 5 natural products with potent cytotoxic activities against murine leukemia cells:

H N 2 N Cl Br Cl Br Fors, B.; Buchwald, S. L. J. Am. Chem. Soc., 2010, 132, 15914–15917. (1.2 eq) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566. N N N Pd(OAc)2 (5 mol%) N N JohnPhos (10 mol%) N • The combination of Pd(OAc) and CyPFt-Bu is highly effective for monoarylation of primary Cl HN 2 NaOt-Bu (1.4eq) amines. While it can be used to effect arylation of secondary amines, the rate is slower and THF, 70 ºC, 83% higher catalyst loading is required: N

O O P(t-Bu)2 N Cl n-C8H17 H H n-C8H17 NH2 N N Johnphos Pd(OAc)2 (1 mol%) N Pd(OAc)2 (0.005 mol%) CyPFt-Bu (1 mol%) CyPFt-Bu (0.005 mol%) N N NaOt-Bu, DME, 90 ºC NaOtBu, DME, 90 ºC 69% (isolated) 100% (GC) • The selectivity in this case is attributed to the directing effects of the neighboring . 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

8 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Amides as Substrates Challenging Substrate for Coupling

• Aminopyridines frequently function as chelating ligands with palladium. This effect can be mitigated CH3 CH3 by the use of LiHMDS and hindered, reactive ligands. [Pd(allyl)Cl]2 (1 mol%) O Cl HN O JackiePhos (5 mol%) N O H2N Cs2CO3, 3Å MS O N H t-Bu toluene, 130 ºC, 81% t-Bu N H Br N PdL (2 mol%) PdL (4 mol%) N NH2 LiHMDS, 65 ºC N NH2 N NH2 LiHMDS, 65 ºC PdL PdL Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc., 2009, 131, 16720– Pre-Ru - 79% (isolated) Pre-Ru - 47% (GC) 16734. Pre-Brett - <10% (GC) Pre-Brett - 78% (isolated) • Application to the synthesis of an HIV-1 integrase inhibitor:

Perez, F.; Minatti, A. Org. Lett. 2011, 13, 1984–1987.

Selective Coupling of Primary over Secondary Amines H CO N N 3 OH N N N O 1. Pd(OAc) , Xantphos N 2 O N N NH NH NH Cs2CO3, dioxane, 65 ºC Ph NH 2 Br N Cl H N 2. TMSCl, NaI H 2 F N MeCN, 92% O F Pre-Brett (1 mol%) 1% Pre-Brett NH H N BrettPhos (1 mol%) 1% BrettPhos O HN Ph NaOt-Bu, dioxane NaOt-Bu, dioxane 80 ºC, 89% 80 ºC, 84%

Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc., 2008, 130, 13552– Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey, 13554. J. L.; Miller, W. H. Bioorg. Med. Chem. Lett., 2009, 19, 1807–1810.

Large-Scale Amination as Substrates Application to the synthesis of a CNS-Active aminotetralin: • • Application to the synthesis of a TRPV1 receptor antagonist: CH3 CH3 CH3 N N CH3 H Pd(OAc)2 (0.5 mol%) O CH3 N BINAP (2 mol%) O N Ph CH3 + Pd2(dba)3 (1 mol%) H HN NH2 N N N Ph NaOt-Bu, toluene N Bippyphos (2 mol%) HN N H N H Br 100 ºC CH3 K PO , DME "quantitative yield" N 3 4 F3C t-Bu Cl 80 ºC, 84% 125-kg scale CH3 F3C t-Bu

Federsel, H.-J.; Hedberg, M.; Qvarnström, F. R.; Tian, W. Org. Process Res. Dev. 2008, 12, 512–521. Federsel, H.-J.; Hedberg, M.; Qvarnström, F. R.; Sjögren, M. P. T.; Tian, W. Acc. Chem. Res. 2007, Yu, S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill, D. R. J. Org. Chem., 2009, 74, 9539–9542. 40, 1377–1384. Rob Singer, David Bernhardson

9 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Sulfamides as Substrates • Application to the synthesis of an intermediate en route to a tetracycline antibiotic:

• Application to the synthesis of a c-Met Kinase Inhibitor:

O CH3 O O H N N O 2 S Br t-BuO NH2 t-BuO NH Br O Pd (dba) (5 mol%) O (2.88 kg) CH3 2 3 CH3 CH3 O N Xantphos (15 mol%) N O N Cl Br Pd (dba) (6.6 mol%) CH3 O 2 3 O H Xantphos (15 mol%) Cl N N O Br CO2Ph Cs2CO3, dioxane Br CO2Ph t-BuO N CO2Ph S H OBn 80 ºC, 62% OBn OBn N O Cs2CO3, THF O 60 ºC, 69% N (3.4 kg) (9.6 kg) 4 : 1

Stewart, G. W.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.; Davies, A. J.; Edwards, J. S.; Gibson, A. W.; Hamilton, S. E.; Katz, J. D.; Keen, S. P.; Mullens, P. R.; Scott, J. P.; Wallance, D. J.; Clark, R. B.; He, M.; Fyfe, C.; Lofland, D.; O'Brien, W. J.; Plamondon, L.; Sutcliffe, J. A.; Xiao, X.-Y. J. Wise, C. S. Org. Process Res. Dev, 2010, 14, 849–858 Med. Chem., 2011, 54, 15-11-1528

Carbamates as Substrates N-Heterocyles as Substrates

H3C

Pd2(dba)3•CHCl3 (3 mol%) H N Br t-BuXPhos (9 mol%) N O H3C Cl N NH H2N O H Ot-Bu N N HCl N t-Bu Ot-Bu NaOt-Bu, toluene t-Bu N NH2 dioxane, 70% 23 ºC, 76% H N N

Pd2(dba)3 (0.5 mol%) Xantphos (1.5 mol%) Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger, K. R. J. Org. Chem., 2009, 74, 4634– Na2CO3, dioxane 4637. 70 ºC, 73%

H3C Pd2(dba)3 (1.5 mol%) H Br t-BuBrettPhos (3.6 mol%) N O N NH NaOCN N 2 N tBuOH*, 130 ºC, 73% N Ot-Bu N O O t-Bu t-Bu N

*Other alcohols can be used to make other

Shen, Z.; Hong, Y.; He, X.; Mo, W.; Hu, B.; Sun, N.; Hu, X. Org. Lett. 2010, 12, 552–555.

Perez, F.; Minatti, A. Org. Lett. 2013, 15, 1394–1397. Rob Singer, David Bernhardson

10 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115

Ammonia as a substrate • Application to the synthesis of E Amines:

1. NH2 [Pd(cinnamyl)Cl2]2 (1.5 mol%) Cl NH2 Mor-DalPhos (2.25 mol%) Pd(OAc)2, BINAP NaOt-Bu, toluene, 80 ºC N N NaOt-Bu, NH3, 1,4-dioxane 2. Pd/C, HCO NH 110 ºC, 79% 2 4 MeOH, 65 ºC 67% (2 steps)

CH3 CH F3C O 3 S H N O O 2 [Pd(cinnamyl)Cl2]2 (3.0 mol%) R H C O Mor-DalPhos (4.5 mol%) 3 CH R Cl NH2 3 1. H C O CH3 3 CH3 NaOt-Bu, NH , 1,4-dioxane CH3 t-Bu 3 t-Bu 110 ºC, 69% NH

Pd(OAc)2, BINAP, NaOt-Bu toluene, 80 ºC

Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed., 2010, 49, 4071– 2. HCl, H2O, THF 4074. 23 ºC, 79% (2 steps)

Ammonia Surrogates CH3 CH3 CH3 R = CH • Application to the synthesis of a JAK2 Inhibitor: 3

1. Mazzini, F.; Netscher, T.; Salvadori, P. Eur. J. Org. Chem. 2009, 2063–2068. OCH3 OCH3

NH H3CO O H3CO O CH3 CH3 Pd2(dba)3, Xantphos N N Ot-Bu Cs CO , dioxane, 90oC N Ot-Bu N 2 3 NH S S N N N N N N 2. HCl, water, THF, 2 min Pd2(dba)3 (0.25 mol%) N N NH2 Cl 23 ºC, 89% H2N Br BINAP (0.75 mol%) CH3 CH3 NaOCH3, toluene, 83–87 ºC; 37% HCl, 70–78 ºC; 5N NaOH, 55–65 ºC

PCT Int. Appl., 2011028864, 10 Mar 2011. 14-kg scale, 86%

Liu, Y.; Prashad, M.; Repic, O.; Blacklock, T. J. J. Heterocyclic Chem. 2003, 40, 713–716. Rob Singer, David Bernhardson

11 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115

Reviews: Typical Ligands: 1,2-diamines (most common), amino , 1,3-, 1,2-amino alcohols, 1,2-diols Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13–31. • Examples Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954–6971. Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. O H C O Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400–5449. 3 N N OH CH OH N N 3 A comparison between Pd- and Cu-catalyzed C–N Bond-Forming Processes: NH OH Beletskaya, I. P.; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808.

Overview O O O O CH3 H3C NH HN CH3 OEt N R' Cu salt R' CH3 O OH NH + X Ar N Ar R Base, Solvent R

O OH • The Ullman-type reaction involves coupling amines and other nitrogen nucleophiles with an aryl N N N O halide, catalyzed by salts. N H OH H3C NH HN CH3 N N O • Copper is highly effective for coupling aryl halides with amides, carbamates, azoles and ureas. These substrates tend to be problematic in Pd-catalyzed couplings. • 1,2-Diamines are among the most general supporting ligands in Cu-Catalyzed C-N Couplings: The • The mechanism may follow the same cycle as with Pd, but is more likely to involve coordination of amine nucleophiles often coordinate to copper to form a stable bis-amine complex which impedes the amine prior to oxidative addition (Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. catalysis. Diamine chelation suppresses this undesired pathway. Chem. Soc. 2005, 127, 4120–4121). Critical Features of Ligand Design:

Mechanism: or cyclohexane R = CH gives highest backbone is most 3 reaction rate; larger effective. R R' R R' groups impede rate. N N Coordination Ar LnCu(I)X R NH HN R Reductive H Elimination Further substitution to R = H leads to ligand arylation. give tertiary amine, such as TMEDA, leads to LnCu(III)X(Ar)[N(R)R'] LnCu(I)X[NH(R)R'] ineffective ligands.

Typical Cu salts: Base Oxidative Addition LnCu(I) CuI (most common), CuBr, CuOAc, Cu2O. Ar X N Base-HX Deprotonation Typical Solvents: R R' NMP, DMAC, DMSO, DMF, toluene, THF, DME, dioxane.

Typical Bases:

• an alternative mechanism involves oxidative addition prior to coordination. Most general: Cs2CO3. Commonly used: K2CO3, K3PO4. May be used: KOH, CsF, CsOAc. Rob Singer, David Bernhardson

12 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115

Preparation of benzimidazoles: • couple selectively over secondary amines:

Bn H3C NH HN CH3 O Et Et NH (10 mol%) Bn H3C NH HN CH3 Et HN R O R NH R N NH (20 mol%) AcOH N + CuI (5 mol%), K2CO3, O NH O + R' Br toluene, 110 ºC, 78% R' NH2 I CuI (5 mol%), Cs CO , N R' 68–93% N 2 3 H dioxane, 90 ºC

Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529– Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749–4751. 3533. Selective coupling of pyridazinone in the presence of a and a secondary : Application to the Synthesis of the Natural Product Geldanamycin O

I N Oi-Pr O N O Oi-Pr S S H3CO HN HN H3CO O O O H C NH HN CH O O H3C NH HN CH3 O 3 3 NC Br + NH (10 mol%) NC (2 equiv) N N N Oi-Pr H N O H N H3C 2 CuI (1 equiv) Oi-Pr CH3 CuI (4 mol%) H3C OBn K PO , DMF, o BnO H3CO 3 4 H3CO CH OCH CH K2CO3, 110 C, H 110 ºC H 3 3 3 N N toluene, 81% H3CO OMOM CH3 CH3 H C 3 CH3 CH3 O O OMOM

Schweinitz, A.; Dönnecke, D.; Ludwig, A.; Steinmetzer, P.; Schulze, A.; Kotthaus, J.; Wein, S.; 4 steps Clement, B.; Steinmetzer, T. Bioorg. Med. Chem. Lett. 2009, 19, 1960–1965.

Preparation of quinolones: O H CO 3 O H3C NH HN CH3 O O N R (20 mol%) R O H O CH3 O CH NaOH R H3C CH3 CuI (10 mol%) 3 + HO H3CO O Ph NH2 NH Br K2CO3, toluene, dioxane, 110 ºC N Ph H3CO O NH2 110 ºC 67–89% H O Ph CH3 CH3

Geldanamycin

Qin, H.-Li.; Panek, J. S. Org. Lett. 2008, 10, 2477–2479. Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2007, 72, 7968–7973. Rob Singer, David Bernhardson

13 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115 Couplings of Azoles Couplings of Primary Amines: • is one of few ligands that can facilitate Cu-catalyzed C–N coupling with anilines: Cu2O (5 mol%) I (20 mol%) OH H N NH + I Br N N Cs CO , MeCN Br CuI (20 mol%) N 2 3 N OCH3 50 ºC, 89% Br L-proline (40 mol%) OH I K CO , DMSO OCH3 H2N 2 3 OCH 90 ºC, 97% OCH Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607–5622. 3 3

Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173. CuBr (10 mol%) O O II (20 mol%) • Room-temperature C–N coupling can be achieved using ligand V: N NH + I N N OEt Cs2CO3, DMSO 60 ºC, 85% II

NH2 CuI (5 mol%) O O

Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867. V (20 mol%) H N CH3 + I Br Cs CO , DMF Br • Inexpensive amino acids can be used as ligands and demonstrate a broad substrate scope: 2 3 CH 23 ºC, 98% 3 O V H O I Bn CuI (10 mol%) N N N Bn N NH2 L-proline (20 mol%) N N Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743. N O N K2CO3, DMSO N O Bn 80 ºC, 77% Bn • Couplings of acyclic secondary amines was virtually unprecedented until the discovery of DMPAO as a supporting ligand: Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496–499. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173. O H C O Br CuI (10 mol%) 3 N Ph • Ligand III is effective for heterocycles and even activated aryl chlorides: H3C OH DMPAO (20 mol%) NH H3C N Ph K PO , DMSO CuI (10 mol%) H 3 4 90 ºC, 86% N III (20 mol%) N CH3 + Cl OCH3 OCH NaOCH , DMSO N 3 DMPAO N N 3 O N O H 110 ºC, 90% N OH III • This methodology can also be applied to primary amines and cyclic secondary amines, but not to Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943–8946. anilines. • Couplings catalyzed by Ligand IV proceed under mild conditions and with a low loading of the Zhang, Y.; Yang, X.; Tao, Q.; Ma, D. Org. Lett. 2012, 14, 3056–3059. copper catalyst: • DMPAO can also be applied to the synthesis of aryl carbamates: CuBr (1 mol%) H Br CuI (20 mol%) N On-Bu IV (2 mol%) N O NH + I N Cs CO , DMSO DMPAO (40 mol%) N 2 3 N + KOCN O 60 ºC, 84% OH O2N n-BuOH, 110 ºC, 80% O2N Cl Cl IV

Yang, X.; Zhang, Y.; Ma, D. Adv. Synth. Catal. 2012, 354, 2443–2446. Yang, K.; Qiu, Y. Q.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011, 76, 3151–3159. Rob Singer, David Bernhardson, Fan Liu

14 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115

Ligand-controlled N-Arylation versus O-arylation of amino alcohols Heterocycle formation via tandem coupling and hydroamidation

NH2 OH 1. H3C NH HN CH3 H N (20 mol%) 2 H3C NH HN CH3 CuI (5 mol%) CuI (5 mol%) H (20 mol%) Boc L2 (10 mol%) Br I L1 (20 mol%) n-Pr Boc N Br O N Boc n-Pr I NH Boc + Br NH NH H 2 n-Pr N n-Pr CsCO , PhCH CsCO , DMF 3 3 3 N 90 ºC, 86% 23 ºC, 97% CuI (5 mol%), Cs2CO3 CuI (5 mol%), Cs2CO3 HO THF, 80 ºC, 84% n-Pr THF, 80 ºC, 84% 20:1 >50:1 n-Pr 2. TFA, CH2Cl2, 23 ºC CH3 CH3 O O Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 7079–7082. CH3 H C 3 N CH3 Cu-catalyzed C–N couplings with boronic acids N H C 3 L2 L1 CH3 H [Cu(OH) TMEDA] Cl Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490–3491. H3C • 2 2 N (10 mol%) + N B(OH)2 N • Chemoselective N-Arylation of 1,2-amino alcohols: the substrate functions as the ligand. The CH2Cl2, 23 ºC choice of solvent dictates C–N versus C–O bond formation. O , 98% 2 N

OH Ph OH Ph CuI (2.5 mol%), K3PO4 H O Ph I H2N N O OH OH ethylene glycol, i-PrOH Et Cu(OAc)2 (1.1 equiv) Et + CH CH N NH N N 3 75 oC, 76% 3 + B(OH)2 air, Et N, CH Cl favors C-N coupling 3 2 2 4Å MS, 79% Ph Ph Ph I + H3CHN CuI (5 mol%) H3CHN OH OPh Cu(OAc)2 (10 mol%) CH Cs2CO3, n-butyronitrile CH 3 3 + 125 ºC, 74% O2, CH2Cl2, 23 ºC Aprotic solvent favors C-O coupling NH2 B(OH)2 4Å MS, 85% N H Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706.

• C–N coupling can be facilitated by ortho-chelating groups:

CO2CH3 Cu(OAc)2 (10 mol%) CO CH + 2 3 Ph Ph B(OH) O2, CH2Cl2, 23 ºC H2N 2 N O CuI (5 mol%) O 4Å MS, 90% H Cs2CO3, DMF, 23 ºC (no epimerization observed) OH OH + n-Hexylamine 96% yield Br N CH3 (0% yield in the absence of CuI) H Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422–6425. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400. Rob Singer, David Bernhardson

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