Cross-Coupling Reactions

Has grown into an extremely powerful and general strategy for forming C–C, and C–heteroatom bonds. Pd(0) is most commonly used, but Ni(0)-catalysis is known. The reactions all start with the oxidative addition of the low valent metal into an organic electrophile (e.g., organohalide), involve a transmetallation step with another organometallic reagent (the nucleophile), and a reductive elimination to regenerate the catalyst. The name of the reaction refers to the organometallic (or nucleophilic) partner.

Simplified mechanistic scheme for Pd (Ni is very similar): O

1 2 R1 C R2 R R R1 X capture of CO L Pd L happens rapidly L Pd L even at –20 ºC R.E. O.A. R.E.

L L O L O L CO 1 1 R1 Pd L R Pd X R C Pd X R1 C Pd L R2 L L R2

RAR transmet. transmet. RAR L R2 M M R2 O L R1 Pd R2 R1 C Pd R2 X M M X L L Cross-Coupling Reactions

2010 Nobel Prize in Chemistry awarded jointly to Richard F. Heck, Ei-ichi Hegishi, and Akira Suzuki "for palladium-catalyzed cross couplings in organic synthesis"

Negishi Suzuki Heck

Kumada Stille (d. 2007) (d. 1989)

Sonogashira General Considerations Oxidative Addition Originally restricted to aryl and alkenyl halide (Br and I) and sulfonates (OTf), or substrates without β- hydrogens. β-hydride elimination is fast above –20 ºC. New catalysts systems have allowed chloride substrates and those with β-hydrogens to be used. Stereochemistry conserved with alkenyl halides. Order of reactivity: I > OTf > Br >> Cl alkenyl–OTf >> aryl–OTf

Transmetallation & Reductive Elimination Most always the rate-limiting step. If the coupling does not work well, it is this step that is likely to blame. Exact mechanism is poorly understood. Both metals must benefit energetically from this step. Additives are often required to promote. Metals used: Li, Mg, Zn, Zr, B, Al, Sn, Si, Ge, Hg, Tl, Cu, In, Bi, Ga, Ti, Ag, Mn, Sb, Te, Ni Reductive elimination is faster than β-hydride elimination so sp2 and sp3 organometallics are compatible. Usually proceeds with retention of stereochemisty on both organic partners.

Catalysts Wide range of ligands have been used, but phosphines are generally required for the oxidative addition step. Both bidentate and monodentate ligands can be used. Influence can be profound. Experimentation is often required. Pd(0) is required for O.A., but these catalysts can be quite air sensitive. Fortunately, Pd(+2) is easily reduced to Pd(0) by CO, ROH, R3N, alkenes, phosphines, and main group organometallics. Pd(PPh3)4 ("tetrakis") is commonly used along with Pd2(dba)3/phosphine. General Considerations "Polarity" of components

The electronics of the aryl halide and organometallic partner are important as well.

The aryl halide can be considered to be an "electrophile", while the organometallic can be considered to be a "nucleophile".

Oxidative addition into electron-deficient aryl halides is faster than electron-rich.

If one component must be electron-rch, consider using that as the organometallic, or use very electron- rich ligands to make the catalyst more nucleophilic. Kumada Coupling

J. Am. Chem. Soc. 1972, 94, 4374.; Chem. Commun. 1972, 144.; Bull. Chem. Soc. Jpn. 1976, 49, 1958.

catalyst R1 X + R2 MgBr R1 R2

The first example of a metal-catalyzed cross-coupling. Too a large extent this has been supplanted by other coupling partners. But it is a very ecconomical alternative due to low costs associated with Grignard reagents.

1º alkyl, 2º alkyl, aryl, alkenyl, & allyl Grignard reagents can all be used. Aryl and alkenyl halides and triflates are all good reaction partners, but must be stable to Grignard reagent.

Pd catalysts can be used, but Ni is more common. Ni(acac)2 is an inexpensive catalyst that is commonly used.

Reactivity trend with phosphine ligands: Ni(dppp)Cl2 > Ni(dppe)Cl2 > Ni(PR3)2Cl2 ~ Ni(dppb)Cl2

Chlorinated substrates react readily. Other cross-couplings are quite difficult with chlorides. Kumada Coupling

OMe OMe MeO MeO Ni(acac)2 THF, rt, 4d N N O MgCl Me Me O Cl N O N

Org. Lett. 2010, 12, 4513. O 63% yield

O OEt P O OEt Me

OMe MeMgCl OMe Ni(acac)2

THF, 0 ºC 10 min OTES C5H11 OTES C5H11 MeO 90% MeO

J. Org. Chem. 2002, 67, 8771. Negishi Coupling Zn: Chem. Commun. 1977, 683.; J. Org. Chem. 1977, 42, 1821; J. Org. Chem. 1978, 43, 358. Al: J. Am. Chem. Soc. 1976, 98, 6729; Chem. Commun. 1976, 596. Zr: J. Am. Chem. Soc. 1977, 99, 3168.

catalyst R1 X + R2 Zn R2 or R2 ZnCl R1 R2

Grignard reagents were the first step, but suffer from obvious competitive reactivity problems. In order to address this issue the Negishi group began looking at other organometallic reagents that are less reavtive to common funtional groups. They found that Al, Zr, and Zn are all competent. Zn among the most efficient at undergoing transmetallation.

Easy to prepare from organolithium reagents generated from the slective deprotonation or lithium-halogen exchange. Organozinc reagents of sp, sp2, and sp3 can be used.

Zn t-BuLi (2 equiv) ZnCl2 R1 ZnCl R1 X R1 Li R1 ZnCl THF, –78 ºC X = I, Br, Cl

Little to no β-hydride elimination observed. Cross-couplings often occur at lower temperatures than other reactions. Highly tollerant of other functional groups.

Transmetallation is fast enough to compete with CO insertion. Negishi Coupling

SEMO Me

a. t-BuLi (2 equiv) OTBDPS I ZnCl THF, –78 ºC 2 I

b. ZnCl2 (1 equiv) Pd(PPh3)4, THF, 22 ºC OTBDPS THF, –78 ºC to rt Me OTHP Me OTHP 84% (3 steps)

Me

J. Am. Chem. Soc. 1998, 120, 11198. OSEM

Me OTHP

10 mol% Pd(OAc) N 2 N Ph ONf 20 mol% XPhos Ph N BrZn N THF, 50 ºC 75% yield –ONf = –OSO2CF2CF2CF2CF3 "nonaflate" same reactivity as OTf, but more stable toward hydrolysis i-Pr XPhos = PCy3 i-Pr

Tetrahedron Lett. 2011, 52, 311. i-Pr Zirconium Coupling

H H catalyst 1 1 R X + ZrCp2Cl R R2 R2

Alkenylzirconium species from hydrozirconation of terminal alkynes also transmetallate efficiently.

OH 1. DMSO 5 mol% Pd(PPh ) 3 4 OH (COCl)2 TBSO Ι TBSO pyrrolidine, 23 ºC 2. CBr4, PPh3 92% yield K2CO3 68% yield

TBSO TBSO ZrCp2Cl Br TBSO 5 mol% Pd(PPh ) Cl Br TBSO 3 2 2 Br 10 mol% DIBAL

Tetrahedron Lett. 1999, 40, 431. Zirconium Coupling Alkenylzirconium species from hydrozirconation of internal alkynes do not transmetallate to Pd, but can transmetallate to Zn and then to Pd.

Me a. Cp2Zr(H)Cl Me Me THF, 50 ºC Ph Ph ZnCl 2 Pd(PPh ) b. ZnCl2 (3 equiv) 3 4 OMe Me 2 min, rt OMe THF, rt, 20 min 81% OTBDPS OTBDPS Me Me I Me Ph Me HN O OMe HN O J. Org. Chem. 1999, 64, 3000. i-Pr NHBoc

i-Pr NHBoc

Alkylzirconium complexes do not "carbozirconate" alkynes, but Cp2ZrCl2 does catalyze the carboalumination of alkynes with high syn selectivity.

R AlMe3 R 5 mol% Pd(PPh3)4 Me O 10 mol% Cp2ZrCl2 THF

AlMe2 O CH2Cl2 Me R Cl Me O Org. Lett. 2001, 3, 3253. Me 80% yield O Suzuki-Miyaura Coupling J. Chem. Soc., Chem. Commun. 1979, 866.; Tetrahedron Lett. 1979, 3437.; (review) Chem. Commun. 2005, 4759. catalyst 1 2 2 1 2 R X + R B(OR)2 or R BR2 R R

The cross-coupling of organoboron reagents has matured into on of the more powerful methods for constructing C–C bonds and has largely supplanted the use of other organometallic reagents. Part of this is related to the low toxicity associated with boron and the relative ease of handling of many organoboron reagents. They can also be prepared by various methods. hydroboration of alkenes/alkynes (catalyzed or non-catalyzed)

H BR2 or 2 BR2 or BR2 R2 R R2 R2 lithiation of organohalides or alkynes followed by reaction with a boronic triester

a. BuLi or Br or 2 or B(OH)2 Ar Br R2 R Ar B(OH)2 R2 b. B(OMe)3 + or 2 c. H3O R B(OH)2

R OH OR R B R B R B All can be used for cross-coupling R OH OR trialkylborane boronic acid boronic ester (boronate) Suzuki-Miyaura Coupling

During the transmetallation event, the main group organometallic is thought to serve as a "nucleophilic" reagent. As prepared, organoboron reagents are not suitable to use because the boron is electrophilic and the alkyl groups do not have sufficient nucleophilicty.

For this reason the boron must first be activated as a "borate". This happens with anionic bases such as hydroxide or alkoxides. Fluoride is another useful way to activate the boron. The use of TlOH or TlOEt can be quite useful in accelerating reaction (formation of insoluble TlX salts; J. Am. Chem. Soc. 1987, 109, 4756)

Two mechanisms have ben proposed: R R2 B H + OH– R 1 1 O R 1 2 R L2PdX R L2PdOH R1L Pd R L2PdR – X– 2 B R2 R

H H R + OH– R1L PdX R 2 O R 1 2 R2 B O 1 R L PdR R L2Pd 2 R B – X– B R2 R R2 R

Alkyl boranes react with retention of configuration (J. Org. Chem. 1998, 63, 458; J. Org. Chem. 1998, 63, 461) Suzuki Coupling method of choice for making biaryl compounds, especially with directed metallation to install boron Br a. s-BuLi, TMEDA CO Me TMS THF TMS 2 + N N b. B(Oi-Pr)3 CONEt 2 c. pinacol, 60% (pin)B CONEt2 O O

TMS Pd(PPh3)4 O N K PO –B(pin) = 3 4 B DMF, 90% CONEt2 O MeO2C

O Org. Lett. 2003, 5, 1889. O

MeO S Br Et B 0.67 mol% Pd(PPh3)4 N 2 2 (7.1 kg, 6.1 mol) + MeO2S N TBAB, K2CO3 Toluene, H O, 84 ºC • MeSO3H (215 kg (134 kg 2 915 mol) 912 mol) (278.3 kg) then MeSO3H 92.5% Org. Proc. Res. Dev. 2003, 7, 385. Suzuki Coupling

OMe OH OTBS Et Et Ι B Ι Me Me a. t-BuLi Me Me Me Me

b. MeO-9-BBN PdCl (dppf), AsPh , H O O O 2 3 2 Cs2CO3, DMF, 67%

Oi-Pr Oi-Pr OH OTBS Et

Me Me Me Me Me

O J. Org. Chem. 2005, 70, 4762. Oi-Pr

PdCl (PPh ) ,PPh O O Me OTf 2 3 2 3 B2(pin)2, PhOK Me B

TBSO 79% TBSO

Org. Lett. 2006, 8, 7. Suzuki Coupling least hindered

CBr4, Zn PPh , Pyr Br O 3

Me Me CH2Cl2 Me Me Br O2N 98% O2N MeO Me Pd(PPh3)4 TlOEt O THF/H2O O 64% OMe Me O O O B Me O Me Me Br O O2N Me O

Me2Zn Pd(t-Bu)2 OMe THF, 89% O Me

Me Me Me O O2N O light sensitive Me

Org. Lett. 2005, 7, 2473. Suzuki Coupling O O BnO O N B N PdCl2(dppf) Boc O CH Cl Boc 2 2 + O K2CO3, DME O 80 ºC, 75% N NHCbz H N BnO H NHCbz CO2Me I Angew. Chem. Int. Ed. 2002, 41, 512. CO2Me

Potassium trifluoroborates: Utility developed by Gary Molander (UPenn). Stable and easily prepared from the boronic acid. Essentially "pre-activated" for transmetallation. (Org. Lett. 2002, 4, 1867–1870; J. Org. Chem. 2002, 67, 8416; J. Org. Chem. 2002, 67, 8424)

OBn BnO

OH O Pd(PPh3)4 Cs2CO3 OH O OMOM OMOM O THF/H2O, Δ O 20 h, 42%

Br BF3K J. Am. Chem. Soc. 2004, 126, 10313. Stille Coupling J. Organomet. Chem. 1976, 117, C55.; Chem. Lett. 1977, 301.; Chem. Lett. 1977, 1423.; J. Am. Chem. Soc. 1978, 100, 3636.; J. Am. Chem. Soc. 1979, 101, 4992.; Organometallics 1984, 3, 1108.; Angew. Chem. 1986, 98, 504.

catalyst 1 2 1 2 R X + R SnBu3 R R

Use of organotin compounds in transmetallation reactions has been extensively developed. Relatively easy is install the organotin moiety and are reasonably unreactive. Readily transmetallate to Pd(II), often without additives to promote. The problem lies in the toxicity of organotin reagents. The byproducts are often difficult to remove completely.

R1–X can be alkenyl, allyl, and aryl halides and triflates. Acid chlorides react to give ketones.

Ease of transfer from tin to Pd: alkynyl > alkenyl > aryl > allyl >> alkyl

Bu3Sn–R is most often used, but Me3Sn–R sometimes used in difficult cases.

Transmetallation may require high temperatures, but use of lower donicity ligands (AsPh3, P(2-furyl)3) can enhance rate of transfer.

Conservation of stereochemistry during transmetallation is not guaranteed. Two transition states have been suggested to account for this. Stille Coupling

OTBS ONf O Me H Pd(PPh3)4, CuCl Bu3Sn Me LiCl, DMSO, 60 ºC OH Me H OTBS Me2PhSi OH O

ONf = nonaflate O Me (–OSO2C4F9) Me H OH Me J. Am. Chem. Soc. 2000, 122, 9044. H

Me2PhSi OH O

Carbonylative coupling O TIPSO TIPSO MeN NMe Pd2(dba)3, AsPh3 CO (50 psi) + N O LiCl, NMP, 70 ºC Bu Sn I 3 80% R N 2 Ot-Bu Ot-Bu J. Am. Chem. Soc. 1993, 115, 9293. Stille Coupling MeO O

Bu3Sn SnBu3 1. Pd(MeCN)2Cl2 Me DMF, THF, DIPEA Me NH NH Me MeO 2. CAN, THF/H2) Me O TBSO O 3. HF (aq), CH3CN HO O I 54% (3 steps) TIPSO I OMe HO OMe J. Am. Chem. Soc. 1998, 120, 4123.

Stille-Kelly coupling: use of distannanes to couple two halides. (Me3Sn)2, (Bu3Sn)2, Me3Si–SnBu3 can all be used. Two catalytic cycles operating in the same reaction. (Tetrahedron Lett. 1990, 31, 161.)

(Bu Sn) N 3 2 N Pd(PPh3)2Cl2 Br O Bu4NBr, LiCO3 O O toluene, Δ Br 68% O O O Heterocycles 1993, 36, 2597. Stille Coupling O Bu Sn I 3 Pd(PPh3)4 1. Dess-Martin CuI + OH O O 2. LiI, AcOH, MeCN O DMF, no light 43% (2 steps) Me 60% O O Org. Lett. 2005, 7, 2413. O O

O O O Me O Me O O O O

Br

CO2Me H CO2Me CO2Me

N O SnBu3 N O R R Pd(PPh3)4 N R H toluene, Δ 68% O N Boc N N Boc OTBDPS Boc OTBDPS TBDPSO J. Am. Chem. Soc. 1999, 121, 866. Stille Coupling Me I

Pd(PPh3)4, Me6Sn2 Me O PhthN LiCl, dioxane, 96% OTf PhthN H

O Org. Lett. 2006, 8, 1669.

Me NHBoc Me NHBoc H H N Pd(PPh ) , Me Sn N TBDPSO 3 4 6 2 TBDPSO O PhH, DIPEA, 90% O

I J. Am. Chem. Soc. 2002, 124, 11368. SnMe3

Boc PdCl (PPh ) Boc N 2 3 2 N Me4Sn N N Br HMPA, 120 ºC Me O 79% O Bioorg. Med. Chem. Lett. 2010, 20, 6667. Hiyama Coupling Synlett 1991, 845.; Tetrahedron Lett. 1997, 38, 439.; Chem. Pharm. Bull. 2002, 50, 1531.; Acc. Chem. Res. 2008, 41, 1486.

Pd cat. 1 2 2 1 2 R X + R SiR3 or R SiOR3 R R F– or HO–

Silicon is an inexpensive and inoccuous main group "metal" and is easily installed through a number of different methods. However, transmetallation from silicon to palladium does not occur readily. This allows selective reactions to occur. SiMe3

SiMe3 I Pd2(dba)3, CuI + Ar AsPh3, DMF, 83% Ar SnBu3

This lack of reactivity can be overcome by activating the silicon. This can be done in a number of ways.

fluoride activation: KF Bu4NF F F Me (TBAF) CsF 1 1 R SiMe3 R Si this is activated Me to transfer R1 Me NMe2

pentacoordinate S Me3SiF2 Si–F = 541 kJ/mol silcate Me N NMe (135 kcal/mol) 2 2 (TASF) Hiyama Coupling

halide extraction silanol/Ag2O activation:

Ag2O I Ag Me Me 5 mol% Pd(PPh3)4 2 Si + Ar I Ar1 Ar2 Ar2 Pd O Ag Ar1 OH THF, 60 ºC, 36h 1 Ar Si activation of Si silanol (& silyl ether)/TBAF or TMSOK activation: TBAF (2 equiv) OH 5 mol% Pd2(dba)3 Si Ar I Ar Note: low temps, quick reaction, "ligandless" Pd R R rt, 10 min

SiMe2R O Me proposed inrermediate L Si O R for transmetallation Pd Me Ar L Hiyama Coupling siletane/TBAF activation: "Strain Release Lewis Acidiy"

TBAF (2 equiv) Me 5 mol% Pd2(dba)3 Si Ar I Ar rt, 10 min

siletane

from: Si Me Cl

90º 109º F "Normal" silanes Si Si F ring strain (79º vs 109º) 79º 79º is partially relieved upon F activation (79º vs 90º). siletane Si Si F Hiyama Coupling

Me Me TBAF (2 eq) O O O Si I a. t-BuLi 2.5 mol% [(allyl)PdCl]2 OH + b. (Me2SiO)3 rt, 10-20 min 68% MeO 74% MeO Org. Lett. 2000, 2, 3221. OH

Me I TBAF (2 eq) 2.5 mol% Pd (dba) + 2 3 O Me H Si 74% MeO i-Pr i-Pr Org. Lett. 2001, 3, 61. MeO

Me Ar1–I Ar2–I Me Si OH TMSOK (2 eq) TBAF (2 eq) Ar1 2.5 mol% Pd2(dba)3 2.5 mol% Pd2(dba)3

Me dioxane rt THF rt Si 2 Me 88-96% yield 72-90% yield Ar Bn J. Am. Chem. Soc. 2005, 127, 8004. Sonagashira Coupling Tetrahedron Lett. 1975, 4467.

cat. PdCl2(PPh3)2 cat. CuI R1 X + R2 H R1 R2 Et3N

Organocuprates are typically poor reagents for transmetallation and are most often unstable at temperatures usually required to achieve transmetallation.

However, by taking advantage of the facil formation of copper acetylides (CuI, R3N), cross-coupling between terminal acetylenes and aryl/alkenyl halides/triflates can be acheived.

In situ formation of Cu–acetylide means catalytic amounts of both Pd and Cu can be used.

Homocoupling of acetylene is a common side reaction. This can be overcome by using excess acetylene, or by slow addition of acetylene. Many can be carried out at ambient temperatures.

Usually a pretty reliable way to make a C–C bond. Sonagashira Coupling

OH 3 mol% Pd(PPh ) Cl OH 3 2 2 MeO MeO I 20 mol% CuI + H Et2NH, C6H6, rt, 20 h Me OMe quant. Me OMe J. Org. Chem. 2001, 66, 309.

3 mol% Pd(PPh3)2Cl2 OH TMS 5 mol% CuI OH + N Cl H Et3N, DMF, rt, 1 h N 98% J. Org. Chem. 2000, 65, 7110. TMS

O O TBSO H O TBSO I O 5 mol% Pd(PPh3)2Cl2 5 mol% CuI O + O OH DIPEA, DMF, rt 77% OH TES J. Am. Chem. Soc. 2001, 123, 2887. TES Sonagashira Coupling

H SiMe 3 SiMe3 then add: I 6 mol% PdCl2(PPh3)2 12 eq. DBU 10 mol% CuI 40 mol% H2O

6 eq. Et3N, C6H6, I Br Br

Org. Lett. 2002, 4, 3199. Br

Alkyl halides (Br or I) in Sonagashira couplings: Cl O N N ligand = R R 5 mol% ligand Me I O 2.5 mol% [(π-allyl)PdCl]2 R = 1-adamantyl + Me 7.5 mol% CuI, 1.4 eq. Cs2CO3 DMF/Et O (1:2), 40 ºC Cl Cl 2 70% yield

J. Am. Chem. Soc. 2003, 125, 13642. Tetrahedron Lett. 2006, 47, 2925. Pd-Catalyzed Aminations Synlett 1997, 329.; Curr. Org. Chem. 1997, 1, 287.; Angew. Chem. Int. Ed. 1998, 37, 2046.; Acc. Chem. Res. 1998, 31, 805.; Acc. Chem. Res. 1998, 31, 852.;

catalyst H 1 + 2 (1º or 2º amine, amide 1 2 R X R NH2 aniline, hetereocycle) R N R

The ubiguity of C–N bonds in pharmaceuticals and other industrially important molecules perpetuated work aimed at developing metal-catalyzed aminations of ary halides. This proved to be quite difficult.

Mechanistically, it was determined that two factors were responsible for these difficulties: reversible and inefficient ligation of the amine to the Pd, and slow reductive elimination.

A breakthrough came when it was found that bulkly and electron rich phosphine ligands (i.e., P(o-tol)3) did promote these reactions. Not only was the reductive elimination promoted by the enhanced electron donation of these ligands, but their large size meant that the catalytically active Pd(0) catalyst only had one ligand.

The Buchwald group was able to use this information to design new ligands that have proved extremely useful and general for C–N bond formation. These same ligands are also quite useful in other Pd-catalyzed reactions (e.g. Suzuki reactions)

Even aryl chlorides can be used. Buchwald Ligands

P(t-Bu)2 PCy P(t-Bu) 2 2 i-Pr i-Pr Me2N PCy2 i-Pr i-Pr PCy2 i-Pr DavePhos MeO OMe JohnPhos tBuXPhos i-Pr SPhos XPhos OMe

MeO PCy2 i-Pr i-Pr PCy2 i-PrO Oi-Pr Review on biaryl phosphane ligands in aminations: Angew. Chem. Int. Ed. 2008, 47, 6338–6361.

i-Pr A "user's guide" to Pd-catalyzed amination: Chemical Science 2011, 2, 27–50. BrettPhos RuPhos primary alkyl amines secondary alkyl amines primary anilines secondary anilines Buchwald-Hartwig Coupling Too many examples are present. Br TBDPSO N3 Pd (dba) , BINAP Br 2 3 NaOt-Bu, toluene + N OTBDPS 80 ºC, 66% I N H J. Org. Chem. 1999, 64, 4224. N3

N N

NH Pd2(dba)3, dppf 2 Me NaOt-Bu, toluene Me + 80 ºC, 57% Me Me TfO PhHN Bioorg. Med. Chem. Lett. 2000, 10, 183.

MeO2C MeO2C H Pd(OAc) , BINAP N O 2 N O Cs2CO3, toluene OMe OMe 100 ºC, 50% N H N Br 2 Ph Ph Tetrahedron Lett. 2000, 41, 355. Buchwald-Hartwig Coupling From aryl chlorides

H H N N Me Me N H Hex N N N N CO2H N OH N AcHN OH Me

From aryl mesylates (Ar–OSO2Me) Me H N H MeO N H EtO2C N N MeO F Me CF3 OMe

CO2Et OMe H H H N N N

Ph Ac F CO2Et from Chemical Science 2011, 2, 27–50. Buchwald-Hartwig Coupling With aliphatic amines Boc N N N Boc N MeO N N

F3C

With amides, carbamates, ureas, sulfonamides. MeO2C O t-Bu O O N N

O N MeO N Ph H H

CF3 MeO2C O t-Bu O O O O Me N S N Ph Hex O N H Bu MeO N OMe

O from Chemical Science 2011, 2, 27–50. Buchwald-Hartwig Coupling With heterocyclic NH Me N Me N N N N N N N

Et N Et N N F NC F Me

Formation of "Ar–NH2" with ammonia equivalents Ar NH N TMS TMS TMS TMS N N Ph Ph Ph Ph Li Ar benzophenone imine + H3O + H3O or TBAF

O NH2 NH2 NH NH2 NH2 O 2 N N Et2NOC MeO from Chemical Science 2011, 2, 27–50. "Fu Ligands"

Acc. Chem. Res. 2008, 41, 1555.

Recal that the identity of the halide has a big impact on the success of oxidative addition. Order of reactivity: I > OTf > Br >> Cl

The reactivity of the halides is related to Ph–X bond strength (kcal/mol): Cl (95), Br (80), I (65)

The use of bulky and strongly electron donating ligands (i.e. P(t-Bu)3, P(t-Bu)2Me, PCy3) has allowed cross-coupling of aryl chlorides.

It is thought that these ligands speed up the rate of oxidative addition. Aryl chlorides usualy still require heating, but bromides and iodide can undergo reaction at rt.

Me 0.5–1.5% Pd2(dba)3 Me 1-4.5% P(t-Bu)3 MeO Cl + (HO)2B 3 equiv KF MeO THF or dioxane rt to 90 ºC 88%

Me Me 0.5% Pd2(dba)3 MeMe 1.2% P(t-Bu)3 Br + (HO)2B 3 equiv KF THF,rt Me Me 96% "Fu Ligands"

Acc. Chem. Res. 2008, 41, 1555.

Pd/P(t-Bu)3 is inneficient with aryl triflates Cl TfO TfO Cl 3% Pd(OAc)2 1.5% Pd2(dba)3 6% PCy3 3% P(t-Bu)3 Me + Me KF, THF, rt Me KF, THF, rt

87% 95% (HO)2B

These ligands hae been extended to all manner of cross-couping reactions with similar results.

They can also be used in so-called alkyl-alkyl suzuki couplings. This concept (but with different ligands) has been extented to include nickel catalysis.

O 4% Pd(OAc)2 O 8% PCy3 9-BBN + NC Br MeO MeO 4 CN 10 4 1.2 K3PO4 • H2O 10 THF, rt J. Am. Chem. Soc. 2001, 123, 10099. "Fu Ligands"

Acc. Chem. Res. 2008, 41, 1555. What is special about these ligands?

First, they are very electron rich (inductive) so they are able to increase the rate of oxidative addition. Second, they are very bulky (cone angles > 170º). This not only limits the number of ligands that can fit on the metal (at most two, sometimes only one), but also enforces a trans relationship.

Ph Br Ph Et2O + L Pd L L Pd L 0 ºC 94% Br (L = P(t-Bu)2Me) (X-ray) trans relationship prevents BHE from occuring at temps below 50 ºC J. Am. Chem. Soc. 2002, 124, 13662.

Ph KOt-Bu o-Tol Ph L Pd L o-Tol B(OH)2 t-amyl alcohol Br (1.1 equiv) rt, 94%

But how the transmetallation/reductive elimination occurs without BHE occuring is still unclear. Nozaki-Hiyama-Kishi (NHK) Coupling J. Am. Chem. Soc. 1977, 99, 3179.; Tetrahedron Lett. 1983, 24, 5281.; J. Am. Chem. Soc. 1986, 108, 6048.

CrCl 2 OH cat. NiCl2 R1 X + R2 CHO R1 C R2 DMF or DMSO H R1 = alkenyl, alkynyl allyl (w/ transposition)

Initial report focused on "Grignard-type" addition of allyl or alkenyl halides into aldehydes mediated by CrCl2. The reaction was selective toward aldehydes and tollerated ketones, esters, amides and nitriles. Extended to triflates and aryl halides.

The reaction was irrepreducible and was quite dependent on the source of CrCl2 that was used. This was traced to trace amounts of Ni that were present in the original source of CrCl2. By adding catalytic amounts of NiCl2 (3 mol% or less) reproducible results could be obtained. If too much Ni is prsent, then homocouling of halide is observed.

Mechanism is still unclear. Diastereoselectivity is frequently poor. NHK Couplings

Me Me H H CrCl2 (8.7 equiv) NiCl2 (1 mol%) OH O OTf O CHO DMF/THF, rt H 88% H

J. Am. Chem. Soc. 2004, 126, 1642. dr 2:1

OTBS O O I S + O N CrCl2/NiCl2 N Me CHO Me DMF, rt Me Bn 93%

OTBS OTBS Aux 1. SOCl2, –78 ºC Me 87% Me S OH S O

N Me 2. LiEt3BH N Me 88% HO Me Me Me dr 1:1 Org. Lett. 2001, 3, 2221.