From C–O to C–C through Nickel Coupling

MeO2C CO2Me

>99% yield

Ph O Homocoupling R = S O OMOM OMe 80% yield Suzuki- Kumada 95% yield O Miyaura O

R = RO R = S NEt2 NEt2 R' O

O O R = R = P (OEt) Suzuki- Kumada 2 Miyaura n-octyl

Kumada R = Me 92% yield NOMe i86% yield Ph

N H Nathan Bennett 95% yield Group Meeting May 7, 2011

Title Page Ni Chemistry Timeline Initial Studies

1966 Saito and Yamamoto Et2Ni(bpy)

1960 1970 1980 1990 2000

Saito, T. and Yamamoto, A.

N N Et Et2AlOEt vacuum + Ni(acac)2 + Ni + Et O 110 °C N 2 N Et –20 ! –10 °C

Et2Ni(bpy)

J. Am. Chem. Soc. 1966, 88, 5198.

Timeline1 Saito Ni Chemistry Timeline Initial Studies

1966 1971 Saito and Yamamoto Semmelhack Et2Ni(bpy) Ni(COD)2

1960 1970 1980 1990 2000

Semmelhack, M. F.

Ni(COD)2 Br DMF 52 °C 82% yield

Ullmann Coupling Comparison

Cu Bronze Br cymene 180 °C 60% yield Ni: Semmelhack, M. F. J. Am. Chem. Soc. 1971, 93, 5908. Ullmann Coupling: Fanta, P. E. Chem. Res. 1964, 64, 613.

Timeline1 Semmelhack Ni Chemistry Timeline Initial Studies

1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1990 2000

Semmelhack, M. F.

OMe n yield (%)

MeO I 2 81 Ni(PPh3)4 3 83 n n DMF, 55 °C 4 76 MeO I 5 85 6 38 OMe

J. Am. Chem. Soc. 1975, 97, 3873. J. Am. Chem. Soc. 1981, 103, 646.

Timeline1Semmelhack Ni Chemistry Timeline Initial Studies

1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1990 2000 1975 Kende NiCl2(PPh3)2 + Zn

Kende, A. S.

0 Zn , PPh3 0 II 0 ! Tolman Research: Ni (PPh3)3 active catalyst Ni Cl2(PPh3)2 Ni (PPh3)3 DMF in situ ! Kende formed in situ

Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 53. Kende, A. S. Tetrahedron Lett. 1975, 3375.

Timeline1 Kende Ni Chemistry Timeline Initial Studies

1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1990 2000 1975 1977 Kende Kumada NiCl2(PPh3)2 + Zn Catalytic Ni

Kumada, M.

NiCl2(PPh3)2 (2.5 mol%) PPh3 (5 mol%) Br Zn (1 equiv) DMF, 50 °C 89% yield

Tetrahedron Lett. 1977, 47, 4089.

Timeline1 Kumada Why Phenol/Enol Derived Electrophiles?

Availability

! 50,000 commercial phenol and aryl polyol

! Enol electrophile from trapping enolates Reactivity

! Directed Ortho Metalation (DoM)

Possible with: i. sec-BuLi, TMEDA E THF, –93 °C Sulfamates O NEt2 O NEt2 S S Ethers + Esters O O ii. E , –93 " 23 °C O O Carbamates E = CHO, CONEt2, CH(OH)Ph, SMe, SiMe3, Cl, Br, I, SnBu3, boronate esters

! p-Direction

F F F Ph I2, AgOTf O NEt2 O NEt2 S S O O CH2Cl2, 65 °C O O I flurbiprofen 64% yield O OH

Garg, N. K. and Percec, V. Chem. Rev. 2011, ASAP, DOI: 10.1021/cr100259t. DoM Review: Snieckus, V. Chem. Rev. 1990, 90, 879. p-Direction Example: Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748.

Why Phenol/Enol E+? Ni Chemistry Timeline Sulfonate Highlights

1966 1971 1975 Saito and Yamamoto Semmelhack Semmelhack Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni

Yamishito, J.

NiCl2 (8 mol%) PPh3 (60 mol%) Zn (1.5 equiv) MeO OTf MeO OMe NaI (60 mol%) DMF, 60 °C 82% yield ultrasounds

Chem. Lett. 1986, 407.

Timeline2 Yamishito Ni Chemistry Timeline Sulfonate Highlights

1995 1966 1971 1975 Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni

Percec, V.

NiCl2(PPh3)2 (10 mol%) O Zn (1.7 equiv) O O OMs MeO Et4NI (1.5 equiv) MeO OMe THF, reflux >99% GC yield

J. Org. Chem. 1995, 60, 176.

Timeline2 Percec1 Ni Chemistry Timeline Sulfonate Highlights

1995 1995 1966 1971 1975 Percec Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Suzuki-Miyaura Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1986 1990 2000 1975 1977 Yamishito Kende Kumada Homocoupling NiCl2(PPh3)2 + Zn Catalytic Ni

Percec, V.

PhB(OH)2 NiCl2(dppf) (10 mol%) O Zn (1.7 equiv) O OMs Ph MeO K3PO4 (3 equiv) MeO dioxane, 95 °C 67% yield

J. Org. Chem. 1995, 60, 1060.

Timeline2 Percec2 Ni Chemistry Timeline Sulfonate Highlights

1995 1995 1966 1971 1975 Percec Percec Saito and Yamamoto Semmelhack Semmelhack Homocoupling Suzuki-Miyaura Et2Ni(bpy) Ni(COD)2 Ni(PPh3)4

1960 1970 1980 1986 1990 2000 Yamishito 1975 1977 1995 Homocoupling Kende Kumada Percec NiCl2(PPh3)2 + Zn Catalytic Ni Negishi

Percec, V.

MeO ZnCl

NiCl2(PPh3)2 (10 mol%) Zn (1 equiv) OMs OMe THF, 23 °C 31% GC yield

J. Org. Chem. 1995, 60, 6895.

Timeline2 Percec3 Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Sulfamate Ni Cross Coupling Directed Ortho Metalation (DoM)

Snieckus, V.

(HO)2B

i. sec-BuLi, TMEDA I Pd(PPh3)4 (5 mol%) THF, –93 °C Na2CO3 (aq.) O NEt2 O NEt2 S S O O ii. I2, –93 ! 23 °C O O DME, 80 °C, 16 h 78% yield 92% yield

BrMg OMe

OMe N N Mes Mes (2.5 equiv) NiClCpIMes (3 mol%) Cl Ni

O NEt2 S Et2O, reflux, 16 h NiClCpIMes O O 64% yield

Org. Lett. 2005, 7, 2519.

Sulfamate1 K1 Snieckus1 Sulfamate Ni Cross Coupling Kumada Coupling Du Bois, J. C-H Insertion

O O 1. Rh2(OAc)4 (2 mol%) O O S PhI(OAc)2 S i-BuMgCl (2 equiv) O NH O NBn i-Bu NHBn 2 MgO, CH2Cl2 NiCl2(dppp) (5 mol%)

2. BnBr, K2CO3, DMF benzene, 55 °C 78% yield 95% yield

Aziridine Formation

O O O O S Rh2(OAc)4 (2 mol%) S N O NH2 PhI(OAc)2, MgO O 1. H2O, then TBSCl

CH2Cl2 ii. MeI, K2CO3, DMF 83% yield 92% yield

O Me O S N i. PhMgCl (2 equiv) Boc O NiCl2(dppp) (5 mol%) Ph N OTBS benzene, 55 °C

ii. (Boc) O 2 OH 88% yield

Org. Lett. 2005, 7, 4685.

Sulfamate3 K3 Du Bois Sulfamate Ni Cross Coupling Suzuki-Miyaura Coupling Garg, N. K. R2

(HO) B R2 O O 2 S (2.5 equiv) O NMe2 NiCl2(PCy3)2 (5 mol%) K3PO4 (4.5 equiv) R1 R1 toluene, 110 °C, 24 h 17 examples R2 = -H, -OMe 63–95% yield

Ph Ph t-BuO Ph OMe O

CF3 OMe 81% 80% 85%a 63%

Ph N Ph OMe O 95% 75% 75%

a 10 mol% NiCl2(PCy3)2, 4 equiv ArB(OH)2, 7.2 equiv K3PO4, toluene, 130 °C J. Am. Chem. Soc. 2009, 131, 17748.

Sulfamate SM1 Garg Sulfamate Ni Cross Coupling Total Synthesis of Flurbiprofen

Garg, N. K.

Cl OMe

Me2NO2SO Me NO SO NaOH, MeOH; Me NO SO O 2 2 2 2 F AgOTf, 0 °C I2, AgOTf NiBr2(bpy) (HO)2B F

then, MS 3Å, THF CH2Cl2, 65 °C Mn, TFA Selectfluor! DMF, 50 °C 64% yield I 70% yield 70% yield

Me2NO2SO Ph Ph F F F PhB(OH)2 NiCl2(PCy3)2 H2SO4

K3PO4 p-dioxane, H2O OMe toluene, 130 °C OMe OH 84% yield O O 2 steps O flurbiprofen 5 steps, 26% yield

J. Am. Chem. Soc. 2009, 131, 17748.

Sulfamate SM2 Garg Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates

Kumada, M. TMS MgCl R TMS OP(O)(OEt) (1.7–3 equiv) 2 R Ni(acac)2 –OR– NiBr2

(3–5 mol%) n n n = 1, 2, 8 Et2O, 23 °C, 15 h 9 examples R = H, Ph 47–92% yield

TMS Ph TMS TMS TMS

5 Ph 81%a 48%b 92%b 47%a

a b Ni(acac)2. NiBr2

Kumada, M. Synthesis 1981, 1001. Nicolaou, K. C. Chem. Commun. 1998, 1757. Claesson, M. Tetrahedron Lett. 1983, 24, 5137. Backvall, J.-E. J. Org. Chem. 1999, 64, 1745.

Phosphonate1a K1 Kumada Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates

Kumada, M. Claesson, A. TMS MgCl R TMS (1.7–3 equiv) 2 OP(O)(OEt)2 R MgX (2.7 equiv) R 2 OP(O)(OEt)2 NiCl2(dppp) (2.5 mol%) R Ni(acac)2 –OR– NiBr2 R1 R1 (3–5 mol%) Et2O, 23 °C n n Et O, 23 °C, 15 h n = 1, 2, 8 2 9 examples R1 = H, Ph R2 = Ph, Bn, n-octyl, Me 4 examples R = H, Ph 47–92% yield 55–78% yield

TMS Ph TMS Ph Bn n-octyl Me TMS TMS Ph 5 Ph 81%a 48%b 92%b 47%a 67% 55% 78% 69%a

a b a Ni(acac)2. NiBr2 NiCl2(dppe).

Kumada, M. Synthesis 1981, 1001. Nicolaou, K. C. Chem. Commun. 1998, 1757. Claesson, M. Tetrahedron Lett. 1983, 24, 5137. Backvall, J.-E. J. Org. Chem. 1999, 64, 1745.

Phosphonate1b K1 Claesson Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates

Kumada, M. Claesson, A. TMS MgCl R TMS (1.7–3 equiv) 2 OP(O)(OEt)2 R MgX (2.7 equiv) R 2 OP(O)(OEt)2 NiCl2(dppp) (2.5 mol%) R Ni(acac)2 –OR– NiBr2 R1 R1 (3–5 mol%) Et2O, 23 °C n n Et O, 23 °C, 15 h n = 1, 2, 8 2 9 examples R1 = H, Ph R2 = Ph, Bn, n-octyl, Me 4 examples R = H, Ph 47–92% yield 55–78% yield

TMS Ph TMS Ph Bn n-octyl Me TMS TMS Ph 5 Ph 81%a 48%b 92%b 47%a 67% 55% 78% 69%a

a b a Ni(acac)2. NiBr2 NiCl2(dppe).

Nicolaou, K. C. TMS MgCl (3 equiv) Ni(acac) (5 mol%) 2 TMS OP(O)(OPh)2 N Et2O, 25 °C, 1 h N Boc 88% yield Boc

Kumada, M. Synthesis 1981, 1001. Nicolaou, K. C. Chem. Commun. 1998, 1757. Claesson, M. Tetrahedron Lett. 1983, 24, 5137. Backvall, J.-E. J. Org. Chem. 1999, 64, 1745.

Phosphonate1c K1 Nicolaou Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Aryl Phosphonates

Kumada, M.

OP(O)(OEt)2 RMgX (3 equiv) R Ni(acac)2 (5 mol%) R = CH2TMS 77% Ph 91% Et2O, 23 °C

OP(O)(OEt)2 PhMgBr (3 equiv) R Ni(acac)2 (5 mol%) R = 1-Ph 77% 2-Ph 75% Et2O, 23 °C

Tetrahedron Lett. 1981, 22, 4449.

Phosphonate3 K3 Kumada Phosphonate and Phosphoramide Cross Coupling Hydroxyphosphine Promoted Kumada Coupling

Nakamura, E.

PhMgBr (1.5 equiv) Ni(acac)2 (1 mol%) PO ligand (1 mol%) MeO OP(O)(OEt)2 MeO Ph OH PPh Et2O, 0 °C 2 PO Ligand 100% yield

J. Am. Chem. Soc. 2009, 131, 9590.

Phosphonate4a K4 Nakamura Phosphonate and Phosphoramide Cross Coupling Hydroxyphosphine Promoted Kumada Coupling

Nakamura, E.

PhMgBr (1.5 equiv) Ni(acac)2 (1 mol%) PO ligand (1 mol%) MeO OP(O)(OEt)2 MeO Ph OH PPh Et2O, 0 °C 2 PO Ligand 100% yield Ni / PO complex Coordination Reductive Elimination

P Ph O YMg Ni P Ni OMe O O OMe O P MgY EtO OEt

Transmetallation

BrMgOP(O)(OEt)2 P O P Ni OMe Ni Oxidative YMg O PhMgBr OMe Addition O MgY P O EtO OEt OP(O)(OEt)2

J. Am. Chem. Soc. 2009, 131, 9590.

Phosphonate4b K4 Nakamura P O Phosphonate and Phosphoramide Cross Coupling YMg Ni Hydroxyphosphine Promoted Kumada Coupling O O P (OEt)2

Nakamura, E.

R2MgX (1.5 equiv) 2 (EtO)2(O)PO R Ni(acac)2 (1–5 mol%) PO ligand (1–5 mol%) 1 1 R R OH PPh2 Et2O, 0 °C PO Ligand R2 = Ph, Ar 8 examples 53–100% yield

OMe Ph Ph

Me 100% 91% 96%

Me Me 54% 53%

J. Am. Chem. Soc. 2009, 131, 9590.

Phosphonate4c K4 Nakamura Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Total Synthesis

Yamada, Y. HO

O OP(O)(OEt)2 i. LDA MeMgI 7 steps Ni(acac) O THF, –78 °C O 2 O THF, 0 °C O ii. (EtO)2POCl O O –78 ! –20 °C CO Me CO2Me CO2Me 73% yield 2 98% yield fuscol

Lu, W. O O

O OP(O)(OEt)2 MgBr cryptotanshinone 7 steps NiCl2(dppp) (5 mol%) AlCl3

Et2O, 23 °C CH2Cl2, 0 °C O O OMe 45% yield OMe 95% yield OMe

O Yamada, Y. Tetrahedron Lett. 1992, 33, 81. tanshinone IIA Lu, W. Tetrahedron Lett. 2003, 44, 2073. 8 steps

Phosphonate5 Total Syn Phosphonate and Phosphoramide Cross Coupling Suzuki-Miyaura Coupling: Vinyl Phosphonates Yang, Z.

Ar B(OH)2 NiCl2(dppf) (3 mol%) n-BuLi (20 mol%) O dppf (3 mol%) R R = Ph 71% OP(OPh) p-F 75% 2 p-OMe 82% K3PO4 (2 equiv) toluene, 90 °C o-OMe 77%

Yang, Z. Tetrahedron Lett. 1999, 40, 3321. Yamada, Y. Chem. Commun. 2006, 4137. Yamada, Y. J. Org. Chem. 2007, 72, 6465.

Phosphonate6a SM1 Yang Phosphonate and Phosphoramide Cross Coupling Suzuki-Miyaura Coupling: Vinyl Phosphonates Yang, Z.

Ar B(OH)2 NiCl2(dppf) (3 mol%) n-BuLi (20 mol%) O dppf (3 mol%) R R = Ph 71% OP(OPh) p-F 75% 2 p-OMe 82% K3PO4 (2 equiv) toluene, 90 °C o-OMe 77% Yamada, Y.

B(OH)2 Ni(COD) (4 mol%) O 2 Cy3PHBF4 (8 mol%) OP(OPh)2 + K PO (3 equiv) 3 4 NC NC THF, 65 °C 96% yield

Ni(COD) (4 mol%) O 2 Cy3PHBF4 (8 mol%) OP(OPh)2 + Ph B(OH)2 Ph K3PO4 (3 equiv) BocN THF, 65 °C BocN 92% yield

Ni(COD)2 (4 mol%) O Cy3PHBF4 (8 mol%) + Ph B(OH)2 OP(OPh)2 Ph K3PO4 (3 equiv) THF, 65 °C 72% yield Yang, Z. Tetrahedron Lett. 1999, 40, 3321. Yamada, Y. Chem. Commun. 2006, 4137. Yamada, Y. J. Org. Chem. 2007, 72, 6465.

Phosphonate6b SM2 Yamada Phosphonate and Phosphoramide Cross Coupling Suzuki-Miyaura Coupling: Aryl Phosphoramides

Han, F.-S. O B(OH)2 NiCl2 (10 mol%) 1 O 1 2 R O dppp (8 mol%) R R O P N + R2 K2CO3 (4 equiv) O N dioxane, 100 °C 20 examples O 46–92% yield BOP

Chem. Eur. J. 2010, 16, 4991.

Phosphoramide8a SM3 Han Phosphonate and Phosphoramide Cross Coupling Suzuki-Miyaura Coupling: Aryl Phosphoramides

Han, F.-S. O B(OH)2 NiCl2 (10 mol%) 1 O 1 2 R O dppp (8 mol%) R R O P N + R2 K2CO3 (4 equiv) O N dioxane, 100 °C 20 examples O 46–92% yield BOP

B(OH)2 NiCl2 (10 mol%) dppp (8 mol%) R OBOP + R OMe K2CO3 (4 equiv) dioxane, 100 °C R = Me (75% yield) OMe F (92% yield)

B(OH)2 NiCl2 (10 mol%) OBOP dppp (8 mol%) OMe + K2CO3 (4 equiv) dioxane, 100 °C OMe 96% yield Chem. Eur. J. 2010, 16, 4991.

Phosphoramide8b SM3 Han Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Ether Cross Coupling Kumada Coupling

Wenkert, E.

OMe RMgBr (2 equiv) R NiCl2(PPh3)2 (10 mol%)

benzene, reflux R = Ph or Me 18 examples 16–93% yield

Ph Me Ph

Ph t-Bu t-Bu 75% 59% 20% 77%

Cyclic Ethers Ph

PhMgBr (2 equiv) Ph PhMgBr (2 equiv) O OH NiCl2(PPh3)2 (10 mol%) NiCl2(PPh3)2 (10 mol%)

O benzene, reflux HO benzene, reflux 64% 61%

J. Am. Chem. Soc. 1979, 101, 2246.

Ether1 K1 Wenkert Ether Cross Coupling Kumada Coupling: Aryl and Benzyl Ether Screen

Dankwardt, J. W. p-TolMgBr (3 equiv) NiCl2(PCy3)2 (5 mol%) OR p-Tol PCy3 (10 mol%)

(EtO)2CH2 or t-AmOMe 60–100 °C

R GC yield R GC yield

-Me 94% -MOM 92%

-(CH2)2OMe 77% -TMS 70%

-(CH2)2NMe2 99%

Aryl Ethers: Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. Aryl Ethers: Shi, Z.-J. Chem. Commun. 2008, 1437. Benzyl Ethers: Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 3268.

Ether2a K2 Ether Screen Ether Cross Coupling Kumada Coupling: Aryl and Benzyl Ether Screen

Dankwardt, J. W. Shi, Z.-J. p-TolMgBr (3 equiv) NiCl2(PCy3)2 (5 mol%) MeMgBr (1.2 equiv) OR p-Tol OR Me PCy3 (10 mol%) NiCl2(PCy3)2 (5 mol%)

(EtO)2CH2 or t-AmOMe toluene, 80 °C, 20 min 60–100 °C

R GC yield R GC yield R yield R yield

-Me 94% -MOM 92% -Me 92% -t-Bu 88% -Et 92% -MOM 69% -(CH2)2OMe 77% -TMS 70% -n-Bu 96% -TMS 95% -(CH2)2NMe2 99% -i-Bu 91% -Ph 95%

Aryl Ethers: Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. Aryl Ethers: Shi, Z.-J. Chem. Commun. 2008, 1437. Benzyl Ethers: Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 3268.

Ether2b K2 Ether Cross Coupling Kumada Coupling: Aryl and Benzyl Ether Screen

Dankwardt, J. W. Shi, Z.-J. p-TolMgBr (3 equiv) NiCl2(PCy3)2 (5 mol%) MeMgBr (1.2 equiv) OR p-Tol OR Me PCy3 (10 mol%) NiCl2(PCy3)2 (5 mol%)

(EtO)2CH2 or t-AmOMe toluene, 80 °C, 20 min 60–100 °C

R GC yield R GC yield R yield R yield

-Me 94% -MOM 92% -Me 92% -t-Bu 88% -Et 92% -MOM 69% -(CH2)2OMe 77% -TMS 70% -n-Bu 96% -TMS 95% -(CH2)2NMe2 99% -i-Bu 91% -Ph 95%

Shi, Z.-J.

OR MeMgBr (1.5 equiv) Me NiCl2(dppf) (2 mol%) dppf (2 mol%)

toluene, 23 °C

R yield R yield -Me 80% -Ph 75% -Et 73% -TMS 76% -t-Bu 79% -Ac 18%a a GC yield

Aryl Ethers: Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. Aryl Ethers: Shi, Z.-J. Chem. Commun. 2008, 1437. Benzyl Ethers: Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 3268.

Ether2c K2 Ether Cross Coupling Suzuki-Miyaura Chatani, N.

Aryl Ether Screen O Ph B O (1.2 equiv) Ni(COD)2 (10 mol%) OR PCy3 (20 mol%) Ph

CsF (4.5 equiv) toluene, sealed tube R yield R yield -Me 93% -i-Pr 16% -Et 74% -Ac 10%

Aromatic Ethers: Angew. Chem., Int. Ed. 2008, 47, 4866. Vinyl Ethers: Org. Lett. 2009, 11, 4890.

Ether6a SM Chatani Ether Cross Coupling Suzuki-Miyaura Chatani, N.

O Ar B O Aryl Ether Screen (1.5 equiv) Ni(COD) (10 mol%) O 2 OMe PCy (40 mol%) Ar Ph B 3 O (1.2 equiv) CsF (4.5 equiv) toluene, sealed tube Ni(COD)2 (10 mol%) 10 examples OR Ph PCy3 (20 mol%) 36–94% yield

CsF (4.5 equiv) O toluene, sealed tube CF3 CO2Me R yield R yield -Me 93% -i-Pr 16% (RO)2B (RO)2B (RO)2B 94% 83% 78%a -Et 74% -Ac 10%

F F

(RO)2B (RO)2B (RO)2B (RO)2B 89% 74% 65% 65%

TMS NMe2 OMe

(RO)2B (RO)2B (RO)2B 92% 79% 68% a 20 mol% Ni(COD)2, 80 mol% PCy3.

Aromatic Ethers: Angew. Chem., Int. Ed. 2008, 47, 4866. Vinyl Ethers: Org. Lett. 2009, 11, 4890.

Ether6b SM Chatani Ether Cross Coupling Suzuki-Miyaura Chatani, N.

O Ar B O Aryl Ether Screen (1.5 equiv) Ni(COD) (10 mol%) O 2 OMe PCy (40 mol%) Ar Ph B 3 O (1.2 equiv) CsF (4.5 equiv) toluene, sealed tube Ni(COD)2 (10 mol%) 10 examples OR Ph PCy3 (20 mol%) 36–94% yield

CsF (4.5 equiv) O toluene, sealed tube CF3 CO2Me R yield R yield -Me 93% -i-Pr 16% (RO)2B (RO)2B (RO)2B 94% 83% 78%a -Et 74% -Ac 10%

F F

(RO)2B (RO) B (RO) B (RO) B Vinyl Ethers 2 2 2 89% 74% 65% 65% conditions p-Tol + Ph OMe Ph p-Tol TMS NMe OMe Ph 2 2 h 66 / 34 24 h 5 / 95 (RO)2B (RO)2B (RO)2B 92% 79% 68% a 20 mol% Ni(COD)2, 80 mol% PCy3.

Aromatic Ethers: Angew. Chem., Int. Ed. 2008, 47, 4866. Vinyl Ethers: Org. Lett. 2009, 11, 4890.

Ether6c SM Chatani Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Garg, N. K. B(OH) 2 OMe

OPiv NiCl2(PCy3)2 (10 mol%) + K3PO4 (9 equiv) toluene, 110 °C, 24 h OMe 5 equiv 65% yield

Electronics R = p-OMe 95% OPiv B(OH) R 2 p-CF3 77% NiCl2(PCy3)2 (5 mol%) + Sterics R K3PO4 (4.5 equiv) toluene, 80 °C R = p-Me 91% m-Me 99% 2.5 equiv o-Me 58%

OH OPiv OMe PivCl, K3PO4 then, ArB(OH)2

toluene, 80 °C NiCl2(PCy3)2 (5 mol%) 86% yield J. Am. Chem. Soc. 2008, 130, 14422.

Ester1 SM1 Garg Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Shi, Z.-J. Ph B NiCl2(PCy3)2 (10 mol%) O Ph O O K3PO4 (2 equiv) + B B O Ph O Ph H2O (0.88 equiv) dioxane, 110 °C, 12 h 1.2 equiv 73% GC yield

J. Am. Chem. Soc. 2008, 130, 14468.

Ester2 SM2 Shi1 Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Shi, Z.-J. Ph B NiCl2(PCy3)2 (10 mol%) R = Me 73% O R Ph O O K3PO4 (2 equiv) Et 60% + B B i-Pr 51% O Ph O Ph H2O (0.88 equiv) t-Bu 51% dioxane, 110 °C, 12 h Ph 69% 1.2 equiv

J. Am. Chem. Soc. 2008, 130, 14468.

Ester2 SM2 Shi2 Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Shi, Z.-J. Ph B NiCl2(PCy3)2 (10 mol%) R = Me 73% O R Ph O O K3PO4 (2 equiv) Et 60% + B B i-Pr 51% O Ph O Ph H2O (0.88 equiv) t-Bu 51% dioxane, 110 °C, 12 h Ph 69% 1.2 equiv

p-tol B NiCl2(PCy3)2 (10 mol%) OPiv p-tol O O PCy3 (20 mol%) + B B p-tol O p-tol K3PO4 (2 equiv) MeO2C MeO2C H2O (0.88 equiv) 1.3 equiv dioxane, 110 °C, 12 h 75% yield

p-tol B NiCl2(PCy3)2 (10 mol%) OPiv p-tol O O PCy3 (20 mol%) + B B p-tol O p-tol K3PO4 (2 equiv) MeO MeO H2O (0.88 equiv) 1.3 equiv dioxane, 110 °C, 12 h 48% yield J. Am. Chem. Soc. 2008, 130, 14468.

Ester2 SM2 Shi3 Ester Cross Coupling Suzuki-Miyaura Coupling: Vinyl Esters

Garg, N. K. OMe

MeO B(OH)2

OPiv (2.5 equiv) NiCl2(PCy3)2 (5 mol%)

K3PO4 (4.5 equiv) toluene, 80 °C, 24 h

79% yield

Shi, Z.-J. NiCl2(PCy3)2 (4 mol%) phenylboroxine (1 equiv) K3PO4 (4 equiv)

Ph OAc H2O (1 equiv) Ph Ph toluene/dioxane, 110 °C 92% yield

OAc NiCl2(PCy3)2 (10 mol%) Ph phenylboroxine (2 equiv) K PO (8 equiv) H 3 4 H

H2O (2 equiv) H H toluene/dioxane, 110 °C H H HO HO 43% yield Garg, N. J. Am. Chem. Soc. 2008, 130, 14422. Shi, Z.-J. Chem. Eur. J. 2010, 16, 5844.

Ester3 SM3 Garg + Shi Ester Cross Coupling Negishi Coupling

Shi, Z.-J.

PhZnCl (3 equiv) NiCl2(PCy3)2 (5 mol%)

Ph OAc THF/DMA, 60 °C Ph Ph 86% yield

R ZnCl

(3 equiv) R OPiv NiCl2(PCy3)2 (5 mol%)

THF/DMA, 70 °C R = p-Me 80% o-Me 81%

PhZnCl (3 equiv) RO OPiv RO Ph NiCl2(PCy3)2 (5 mol%)

THF/DMA, 70 °C R = Me 70% MOM 77%

Angew. Chem., Int. Ed. 2008, 47, 10124. Chem. Eur. J. 2010, 16, 5844.

Ester4 N Shi Overview Sulfamates O

O S NEt2 O Phosphonates and Phosphoramides O O P P O (OEt)2 O (NR2)2 Ethers

O Me Esters O O

O O

Carbamates and Carbonates O O

O NEt2 O Ot-Bu

Contents Carbamate and Carbonate Cross Coupling Kumada Coupling: Vinyl Carbamate

Kocienski, P.

OH MeMgBr OH n-BuMgBr OH Ni(acac)2 (10 mol%) NiCl2(dppe) (10 mol%)

benzene, reflux benzene, reflux Me OCONi-Pr2 n-Bu

Kocienski, P. Sylett 1989, 52. Betzer, J.-F. Tetrahedron Lett. 2003, 44, 7553. Carbamate1a Kumada1 Kocienski Carbamate and Carbonate Cross Coupling Kumada Coupling: Vinyl Carbamate

Kocienski, P.

OH MeMgBr OH n-BuMgBr OH Ni(acac)2 (10 mol%) NiCl2(dppe) (10 mol%)

benzene, reflux benzene, reflux Me OCONi-Pr2 n-Bu

Betzer, J.-F.

OTBS OTBS

MgBr + OTBS Ni catalyst (5–10 mol%) A B solvent OTBS OTBS OCONi-Pr2 +

2 C D

Ni catalyst solvent yield A B C D

Ni(acac)2 Et2O 57% 100 0 0 0

Ni(acac)2 toluene 63% 89 5 0 6

NiCl2(dppp) toluene 56% 89 7 4 0

Kocienski, P. Sylett 1989, 52. Betzer, J.-F. Tetrahedron Lett. 2003, 44, 7553.

Carbamate1b Kumada1 Betzer Carbamate and Carbonate Cross Coupling Kumada Coupling: Aryl Carbamate

Snieckus, V.

OCONEt2 PhMgCl Ph Ni(acac)2 (5 mol%)

Et2O, 23 °C OMOM OMOM 80% yield

TMS MgCl

Ni(acac)2 (5 mol%) OCONEt2 TMS Et2O, 23 °C

81% yield

TMS TMS MgCl TMS Ni(acac)2 (5 mol%) OCONEt2 TMS Et2O, 23 °C N N 72% yield J. Org. Chem. 1992, 57, 4067.

Carbamate2 Kumada2 Snieckus P O Carbamate and Carbonate Cross Coupling YMg Ni Hydroxyphosphine Promoted Kumada Coupling O O C NEt2

Nakamura, E.

R2MgX (1.5 equiv) 2 Et2NOCO R Ni(acac)2 (1–5 mol%) PO ligand (1–5 mol%) 1 1 R R OH PPh2 Et2O, 0 °C PO Ligand R2 = Ph, Ar 13 examples 8–98% yielda

OMe Ph Ph

Me 85% (100%) 94% (91%) 98% (96%)

Me Me 62% (54%) 8% (53%)

a Phosphonate comparison in parentheses.

J. Am. Chem. Soc. 2009, 131, 9590.

Carbamate3 Kumada3 Nakamura Carbamate and Carbonate Cross Coupling Suzuki-Miyaura Coupling: Aryl Carbamates and Carbonates

Garg, N. K.

PhB(OH)2 (4 equiv) NiCl2(PCy3)2 (10 mol%) MeO OCONEt2 MeO K3PO4 (7.2 equiv) toluene, 130 °C, 24 h 41% yield

OMe ArB(OH)2 (4 equiv) OCONEt 2 NiCl2(PCy3)2 (10 mol%)

K3PO4 (7.2 equiv) toluene, 130 °C, 24 h 47% yield

OMe ArB(OH)2 (4 equiv) OCO t-Bu 2 NiCl2(PCy3)2 (10 mol%)

K3PO4 (7.2 equiv) toluene, 130 °C, 24 h 85% yield

J. Am. Chem. Soc. 2009, 131, 17748.

Carbamate4 SM1 Garg Carbamate and Carbonate Cross Coupling Suzuki-Miyaura Coupling: Aryl Carbamates

Snieckus, V.

OCONEt Ph 2 Ph NiCl2(PCy3)2 (5 mol%) B PCy3HBF4 (10 mol%) + O O O O K PO (5 equiv) B B 3 4 O Ph O Ph o-xylene, 150 °C O 2.5 equiv 31% yield 10:1 with boronic acid

Ar NiCl2(PCy3)2 (5 mol%) PCy HBF (10 mol%) OCONEt2 B 3 4 OMe + O O K3PO4 (5 equiv) F B B F Ar O Ar o-xylene, 150 °C 69% yield

Ph NiCl2(PCy3)2 (5 mol%) PCy HBF (10 mol%) N OCONEt B 3 4 N Ph 2 + O O K PO (5 equiv) B B 3 4 Ph O Ph o-xylene, 150 °C 85% yield

J. Am. Chem. Soc. 2009, 131, 17750.

Carbamate5 SM2 Snieckus Carbamate and Carbonate Cross Coupling Suzuki-Miyaura Coupling: Vinyl Carbamates

Shi, Z.-J.

Ph NiCl2(PCy3)2 (5 mol%) B PCy3 (10 mol%) O OCONMe O Ph 2 O O K3PO4 (5 equiv) + B B Ph O Ph H2O (1 equiv) 1.2 equiv o-xylene, 150 °C 80% yield

Ph NiCl2(PCy3)2 (5 mol%) PCy3 (10 mol%) OCONMe2 B Ph O O K3PO4 (5 equiv) + B B Ph O Ph H2O (1 equiv) 1.2 equiv o-xylene, 150 °C !-Ph 93% "-Ph 92%

Org. Lett. 2010, 12, 884.

Carbamate6 SM3 Shi Summary

MeO2C CO2Me

>99% yield

Ph O Homocoupling R = S O OMOM OMe 80% yield Suzuki- Kumada 95% yield O Miyaura O

R = RO R = S NEt2 NEt2 R' O

O O R = R = P (OEt) Suzuki- Kumada 2 Miyaura n-octyl

Kumada R = Me 92% yield NOMe i86% yield Ph

N H 95% yield

Summary

Cut1 History of Nickel Coupling First Ni Homocoupling Semmelhack, M. F.

0 R Ni (COD)2 R R II X + Ni X2 + DMF X = Cl, Br, I 25–60 °C 14–93% yield

O Reactivity Cl Br I EtO2C Br Br ! I > Br > Cl ! EWG > EDG 50 °C, 29 h 52 °C, 25 h 40 °C, 21 h 40–60 °C, 19 h 45 °C, 36 h ! o-substitution not well 14% 82% 71% 81% 93% tolerated O NC ! -NO2, -OH, -CO2H Br NC Br Br I Br not tolerated H • Reduction products 35 °C, 20 h 36 °C, 11 h 33 °C, 26 h 40 °C, 20 h 34 °C, 131 h with protic substrates 79% 81% 79% 63% 41% (GC yield) OMe Limitations S MeO Br H N Br ! Stiochiometric Ni 2 Br O Br ! Substrate issues O ! Ni decomposition @ 40 °C, 23 h 33–45 °C, 90 h 42 °C, 22 h 40–60 °C, 34 h high temp 83% 54% 30% (GC yield) 67% ! DMF only solvent Ullmann Coupling Comparison Proposed Mechanism Ar–X Ar–X Cu Bronze Ar L Ar X 0 II IV II Br Ni (COD)2 Ni Ni Ar–Ar + Ni X cymene 2 180 °C COD L X COD Ar X 60% yield L = COD or solvent Ni: Semmelhack, M. F. J. Am. Chem. Soc. 1971, 93, 5908. Ullmann Coupling: Fanta, P. E. Chem. Res. 1964, 64, 613.

H2 First Homocoupling History of Nickel Coupling Transition to Other Ni Sources

Semmelhack, M. F. OMe ! Stiochiometric Ni n yield (%) 0 ! Ni (PPh3)3 necessary 0 MeO I 2 81 ! Ni (COD)2 alone or with PPh3 or 0 PEt resulted in no coupling Ni (PPh3)3 3 83 3 n n DMF, 55 °C 4 76 MeO I 5 85 6 38 OMe Synthesis of Dimethyl Ether Alnusone

0 epoxide opening/ Ni (PPh3)3 dehydration coupling I MeO O MeO MeO + MeO O MeO O MeO H O MeO S S I

Kende, A. S. 0 Zn , PPh3 0 II 0 ! Tolman Research: Ni (PPh3)3 active catalyst Ni Cl2(PPh3)2 Ni (PPh3)3 DMF in situ ! Kende formed in situ

Semmelhack, M. F. J. Am. Chem. Soc. 1975, 97, 3873. Semmelhack, M. F. J. Am. Chem. Soc. 1981, 103, 6460. Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 53. Tolman, C. A. J. Am. Chem. Soc. 1972, 94, 2669. Kende, A. S. Tetrahedron Lett. 1975, 3375.

H3 Other Ni Sources History of Nickel Coupling NiII Catalyst and Reducing Metal Analysis Colon, I. Ni Catalyst Screen Reductant Screen

Ni catalyst (5 mol%) II Zn (1.55 equiv) Ni Cl2(5 mol%) PPh3 (0.38 equiv) reducing metal Cl + Cl + DMAc, 80 °C DMAc, 65–80 °C H H

GC yield (%) GC yield (%) Ni catalyst time (h) biphenyl benzene metal E0 (V) time (h) biphenyl benzene

NiCl2 2 99 1 Fe –0.44 24 0 0

NiBr2 2 99 1 Zn –0.76 2 99 1

NiI2 • 6H2O 2 58 42 Mn –1.18 24 >99 0

Ni(OOCMe)2 • 4H2O 17 66 34 Al –1.66 5 22 76

Ni(acac)2 • 2H2O 17 82 18 Mg –2.37 2 96 4

Ni(NO3)2 • 6H2O 24 0 0 Na –2.71 24 6 6 NiO 24 0 0 Ca –2.87 6 22 77

NiF2 24 0 0 ! Zn essential for reactivity • Ni(PPh ) + ArCl " stalls Strem: NiCl2 = $34 / 50 g 3 4 • Add Zn " completion NiBr2 = $78 / 50 g

J. Org. Chem. 1986, 51, 2627.

H5 Catalyst and Metals History of Nickel Coupling Homocoupling of Aryl Chlorides

NiCl2(5 mol%) Zn (1.55 equiv) R PPh3 (0.38 equiv) R R R Cl + H DMAc, 80 °C 25–100% GC yield reduction Reactivity O O ! Aryl Cl best substrates Cl Cl NC Cl Cl ! Aryl I and Br produce more H reduction and are slower 94% 100% 98% 99% 1% reduction ! EWG > EDG ! -NO2, -CO2H not tolerated

Cl AcO Cl MeO Cl HO Cl

90% 90%a 96%a 25% 3% reduction 5% reductiona 3% reduction 62% reduction

S H2N Cl Cl Cl N 31% 26% reduction 98% 70%b 31% biphenyl

a 5 mol% bpy added. b Isolated yield.

Colon, I. J. Org. Chem. 1986, 51, 2627.

H6 Aryl Cl Homocoupling History of Nickel Coupling Impact of Other Additives

First Cross Coupling ii. i. NiCl, Zn Cl Cl NiXL2 bpy, PPh3 O DMAc MeO MeO

Phosphines Halide Ions – – – – ! PAr3 best ! I > Br >> Cl > F ! P(alkyl)3 slower and lower yields ! Accelerates reaction substatially: ! dppe ineffective ! Ph from PPh3 transferred for Cl with NaI e– rich substitutents completely homocoupled in 2 min! ! Two Suggested Explinations for Results • Pentacoordinate anionic complex L Ph3P Ni PPh2 Ph3P Ni PPh2 L X– Ar 0 – Ar Ni Ar Ni X Ar–Ar + Ni + X o-insertion ruled out due PAr use Ar 3 L • Accelerated Ni Reduction ! Bridges Zn and Nickel ! Increase dielectric properties of solvent

Colon, I. J. Org. Chem. 1986, 51, 2627. Phosphine Pentacoordinate Intermediate: Favero, G. J. Organomet. Chem. 1978, 149, 395.

H7 Additives History of Nickel Coupling

Et4NI: A More Soluble Halogen Source

Iyoda, M.

Benzyl Halide Couplings

NiBr2(PPh3)2 (5 mol%) Zn (1.5 equiv) Et4NI (1 equiv)

Cl THF, 23 °C, 1.5 h 95% yield Aryl Halide Couplings

NiBr2(PPh3)2 (10 mol%) Zn (1.5 equiv) Et4NI (10 mol%) Br THF, 50 °C, 1.5 h 99% yield Conditions Screened ! Ni Sources: NiCl2(PPh3)2, NiBr2(PPh3)2, NiI2(PPh3)2 ! Solvents: THF, DMF, CH3CN, Acetone ! Loadings of Et4NI: 10 mol% p- & m-substituted; 1 equiv for o-substituted ! Excess PPh3 not neccesary Benzyl Coupling: Iyoda, M. Chem. Lett. 1985, 51, 2627. Aryl Coupling: Iyoda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80.

H8 Et4NI History of Nickel Coupling Aryl Halide Homocoupling

NiBr2(PPh3)2 (10 mol%) Zn (1.5 equiv) R Et4NI (10 mol%) R R X THF, 50 °C X = Cl, Br 57–99% yield Notes O O O O ! I >> Br > Cl Br Cl Br Cl Aryl I do not H H ! require Et4NI 20 h, 71% 20 h, 73% 20 h, 75% 20 h, 70% ! o-substituted require high Ni loadings Br Cl MeO2C Br MeO2C Cl

MeO2C MeO2C 4 h, 90% 20 h, 85% 20 h, 85% 20 h, 81%

Br Br Cl MeO Br MeO Cl

1.5 h, 99% 4 h, 89% 5 h, 81% 4 h, 72% 20 h, 67%

MeO Br Br Br Br

CO2Me OMe 10 h, 57% 24 h, 90%a 46 h, 81%b 5 h, 83%a

a b 20 mol% NiBr2(PPh3)2, 1 equiv Et4NI. 50 mol% NiBr2(PPh3)2. Iyoda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80.

H9 Aryl Homocoupling History of Nickel Coupling Heteroaromatic Homocoupling Pyridines Quinolines

R R NiBr2(PPh3)2 (30 mol%) NiBr2(PPh3)2 (30 mol%) Zn (1.5 equiv) Zn (5 equiv) N N Et4NI (1 equiv) R X Et4NI (1 equiv) –OR– N Cl THF, 50 °C N N THF, 50 °C 2 R R 84% yield

N N 53–90% yield NiBr2(PPh3)2 (30 mol%) Br Zn (1.5 equiv) Et NI (1 equiv) CO2Me 4

N THF, 50 °C N Br Br Cl 2 N N N 61% yield 72% 73%a 53% N MeO2C NiBr2(PPh3)2 (30 mol%) Cl Cl Zn (1.5 equiv) Et NI (1 equiv) Br N 4 MeO N THF, 50 °C b 69% 90% N 77% yield N a b 3 equiv Et4NI. 30 mol% Et4NI. Isoquinolines

NiBr2(PPh3)2 (30 mol%) NiBr2(PPh3)2 (30 mol%) N Zn (1.5 equiv) Br N Zn (1.5 equiv) Et4NI (1 equiv) Et4NI (1 equiv)

N THF, 50 °C N THF, 50 °C 37% yield 60% yield N Cl

Iyoda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80.

H10 Heteroaromatic History of Nickel Coupling Proposed Mechanisms Tsou, T. T. and Kochi, J. K. oxidative L L L oxidative addition L L addition X NiII Ar Ar NiIII X Performed in PhMe, THF, hexanes with Ni0(PEt ) ArX L X ArX 3 4 L 0 I Ni L3 L Ni X L

L L L ZnX Ar–Ar 2 L NiII X Ar NiIII Ar Zn X X L reductive elimination J. Am. Chem. Soc. 1979, 101, 6319. J. Am. Chem. Soc. 1979, 101, 7547. Rieke, R. D. L oxidative L 2 X NiII Ar addition Ni ArX L metathesis

ZnX2

0 Zn 2 Ni L3

Ar–Ar L L reductive II II elimination Ar Ni Ar + X Ni X L L J. Am. Chem. Soc. 1977, 99, 4089. J. Org. Chem. 1983, 48, 840.

M1&2 History of Nickel Coupling Proposed Mechanisms Bontempelli, G.

II Ni Cl2L2 Zn, L

ZnX2

0.5 ZnX Ni0L Ar–X 2 3 oxidative addition

0.5 Zn L oxidative Ar–X addition L

L L L L II II L Ni X Ar NiIII X X Ni Ar Zn, L L X L

ZnX 0.5 Zn, L Ar–Ar 2

reductive L L L 0.5 ZnX elimination L I 2 Ar NiIII Ar L Ni Ar X L L Ar–X oxidative addition

J. Chem. Soc., Dalton Trans. 1981, 1074.

M3

Cut 2 Sulfamate Ni Cross Coupling Kumada Coupling Snieckus, V.

Directed o-Metalation (DoM) OSO2NEt2 ArMgBr (1.2–2.0 equiv) Ar N N NiClCpIMes (1–2.5 mol%) Mes Mes OSO2NEt2 Cl Ni R R Et2O, 0–40 °C, 10 min–30 h E Ar = Ph, C6H4(3-OMe), 13 examples NiClCpIMes E = CHO, CONEt2, CH(OH)Ph, 2-Mes, p-Tol 47–86% yield SMe, SiMe3, Cl, Br, I, SnBu3, boronate esters OMe OMe Ph Ph ! Sulfamate is orthogonal functionality to Suzuki-Miyaura coupling with halides TMS

Ni Catalyst Screen OMe NHCOMe ! Ni(acac)2, NiCl2, NiCl2/P(t-Bu)3, 40 °C, 12 h 40 °C, 30 h 40 °C, 19 h 23 °C, 1 h NiCl2/dppf, NiClCpPPh3, NiClCpIMes 76% 64% 47% 50% ! Cp Complexes provided best yields ! NHC bulky ligands likely accelerate Ph p-Tol p-Tol reductive elimination 2-Mes ! NiClCpIMes air stable N N Solvent Screen 0 °C, 10 min 40 °C, 18 h 23 °C, 18 h 23 °C, 8 h ! PhMe, Et2O, THF 84% 69% 71% 82%

Org. Lett. 2005, 7, 2519.

Sulfamates1 K1 Snieckus Sulfamate Ni Cross Coupling Kumada Coupling Du Bois, J.

O O C-H Insertion to Form Sulfamate S 2 1 R MgX (2 equiv) 2 1 O O O O O NR R NHR Ni(dppp)Cl2 (5 mol%) S S n n O NH Rh (OAc) O NH 2 2 4 benzene, 55 °C

PhI(OAc)2 MgO, CH Cl 11 examples 2 2 72–95% yield

! NH " NR to allow Kumada coupling TMS ! NH under Kumada conditions results N(Me)COCF3 Me NHn-Pr i-Bu NHBn acyl moiety cleavage

Ni Catalyst Screen 80%a 75% 95% ! Ni(dppe)Cl2, Ni(PPh3)Cl2, Ni(acac)2, Ni(dppf)Cl2, Ni(dppp)Cl2, Ni(COD)+dppp ! Ni(dppp)Cl2 optimal n-Bu NHPMB Ph NHBn Ph NMeBoc ! Other NiII phosphine left starting material

OMe OH Solvent Screen ! benzene, CF3C6H5, Et2O, THF, DME, dioxane 94% 84% 88% ! THF, DME, dioxane inhibit reaction a 10 mol % Ni(dppp)Cl2.

Org. Lett. 2005, 7, 4685.

Sulfamates2 K2 Du Bois Sulfamate Ni Cross Coupling Suzuki-Miyaura Coupling Garg, N. K.

O O 2 Functionalization of Aryl Sulfamates (HO)2B R S Directed o-Metalation (DoM) 2 ! O NMe2 (2.5 equiv) R ! p-directed electrophilic aromatic NiCl2(PCy3)2 (5 mol%) substitution K3PO4 (4.5 equiv) R1 R1 toluene, 110 °C, 24 h 17 examples Total Synthesis of Flurbiprofen 2 R = -H, -OMe 63–95% yield Me2NO2SO Me2NO2SO 2 steps (HO)2B F Ph Ph t-BuO Ph OMe O I Ph CF3 OMe F 81% 80% 85%a 63% 3 steps

Ph OH N Ph OMe O O flurbiprofen 95% 75% 75% 5 steps, 26% yield a 10 mol% NiCl2(PCy3)2, 4 equiv ArB(OH)2, 7.2 equiv K3PO4, toluene, 130 °C

J. Am. Chem. Soc. 2009, 131, 17748.

Sulfamates3 SM Garg

Phosphate Cross Coupling Kumada Coupling: Vinyl Phosphates

Kumada, M. Claesson, A. TMS MgCl R TMS 2 OP(O)(OEt)2 R MgX (2.7 equiv) R 2 (1.7–3 equiv) OP(O)(OEt)2 Ni catalyst (2.5 mol%) R

1 1 Ni catalyst (3–5 mol%) R Et O, 23 °C R n n 2 Et2O, 23 °C, 15 h n = 1, 2, 8 9 examples R1 = H, Ph R2 = Ph, Bn, n-octyl, Me 4 examples R = H, Ph 47–92% yield 55–78% yield

TMS Ph TMS Ph Bn n-octyl Me TMS TMS Ph 5 Ph 81% 48% 92% 47% 67% 55% 78% 69%

Notes Notes Ni Catalysts: NiCl (dppe), NiCl (dppp) ! Ni Catalysts: Ni(acac)2, NiBr2 ! 2 2 ! NiII + Phophines also work (no examples) ! 2° Grignards inoperable: CyMgBr and 1-methylbutylMgBr

Nicolaou, K. C. TMS MgCl (3 equiv) Ni catalyst (5 mol%) TMS OP(O)(OPh)2 N Et2O, 25 °C, 1 h N Boc 88% yield Boc

Kumada, M. Synthesis 1981, 1001. Claesson, M. Tetrahedron Lett. 1983, 24, 5137. Nicolaou, K. C. Chem. Commun. 1998, 1757. Phosphonate1 K1 Kumada, Claesson, Nicolaou Phosphate Cross Coupling Kumada Coupling: Vinyl Phosphates Bäckvall, J.-E. 2 3 OP(O)(OR )2 R Notes R3MgX (1.5 equiv) ! Ni Catalyst: NiCl2(dppe) and NiCl2(dppp) NiCl2(L2) (1 mol%) ! 2° Grignard reagents possible for cyclic R1 R1 vinyl phosphates with longer coupling times Et O, 0 °C ! No product from 2-octylMgBr n 2 n R2 = Et or Ph R3 = Me, n-Bu, sec-Bu, 12 examples n = 1,2 n-octyl, Ph, Ar 40–92% yield Acyclic Diene ! Yield similar to Claesson report n-Bu n-octyl Ph Ph ! 2° Grignard reagents inoperable

E/Z Selectivity Study R2 = Ph 86% 85%a 68% 92% Et 81% OP(O)(OPh)2 Ph Ph 2 Ph (E)- (Z)-reactant conditions –OR– –OR– OTBS OTBS

OP(O)(OPh)2 (Z)- OTBS 3 3 Ph product 58% 40% 89% 2 Me sec-Bu

(E)-reactant Ph Ph Ph Ph ! Both reactant isomers favor (E)-product b ! (E)-reactant " (Z)-product (5:95 = E:Z) 63% 45% ! (Z)-reactant " (E)-product (57:43 = E:Z) a GC yield. b THF, 40 °C. J. Am. Chem. Soc. 1979, 101, 2246.

Phosphonate2 K2 Backvall Phosphate Cross Coupling Kumada Coupling: Aryl Phosphates

2 3 Kumada, M. (EtO)2(O)PO R MgX (3 equiv) R Ni Catalyst (5 mol%) Catalyst Screen R1 R1 Et2O ! Ni Catalyst: Ni(acac)2, NiCl2(PPh3)2, 2 and NiCl2(dppp) R = CH2TMS, p-tol, 12 examples ! Inoperable Catalysts: Pd(PPh3)4, PdCl2, CoCl3, n-Bu, Bn, Ph 52–98% yield Fe(acac)3, CuBr p-tol TMS TMS

Aluminum Reagents Ph (EtO)2(O)PO Al reagent R 77%a 91%a 56% Ni catalyst TMS TMS solvent TMS MeO Al reagent solvent yield 54% 52% Ph Bn Et Al Et O 95% 3 2 Ph Al(i-Bu)2 THF n-Bu 99% 77%a 80% 75%

a GC yield.

Tetrahedron Lett. 1981, 22, 4449.

Phosphonate3 K3 Kumada Phosphate Cross Coupling Kumada Coupling: Aryl Phosphates

Nakamura, E.

Notes R2MgX (1.5 equiv) (EtO)2(O)PO (EtO)2(O)PO ! Ligand provides cooperative effect Ni(acac)2 (1–5 mol%) ! 12 ligands screened PO ligand (1–5 mol%) 1 1 ! Effective for aryl F, Cl, Br, I, OTf, R R OH PPh2 OCONEt 2 Et2O, 0 °C PO Ligand R2 = Ph, Ar 8 examples 53–100% yield Push-Pull Mechanism OMe P P O O YMg Ni Ni YMg O O O P P O EtO OEt EtO Me Me OEt 100% 54% Oxidative Trans- Addition P Ni -metallation O Ph MgY Ph OP(O)(OEt)2

R Reductive Me Elimination P Ni R 53% 91% 96% O MgY a GC yield. b THF, 40 °C.

J. Am. Chem. Soc. 2009, 131, 9590.

Phosphonate4 K4 Nakamura

Aryl and Vinyl Ether Cross Coupling Kumada Coupling Wenkert, E. OR1 R2MgBr (2 equiv) R2 NiCl2(PPh3)2 (10 mol%)

Grignard Effects benzene, reflux ! PhMgBr effective with vinyl and aryl ethers R2 = Ph or Me ! MeMgBr is unreactive with aryl ethers 18 examples 16–93% yield

Ph Ph Me Cyclic Ethers Ph PhMgBr (2 equiv) Ph NiCl2(PPh3)2 (10 mol%) t-Bu t-Bu O benzene, reflux HO 64% 71% 75% 59% 59% Ph Ph

PhMgBr (2 equiv) Ph Ph Ph O OH NiCl2(PPh3)2 (10 mol%) 16% 20% 24% Ph benzene, reflux Ph Ph 61% Ph 70% 77% 45%

J. Am. Chem. Soc. 1979, 101, 2246.

Ethers1 K1 Wenkert Aryl and Vinyl Ether Cross Coupling Kumada Coupling: sp2–sp2 C–C Formation Dankwardt, J. W. 3 OR1 R MgBr (2 equiv) R3 Ni Catalyst Screen NiCl (PR4 ) (5 mol%) II 2 3 2 Numerous Ni catalysts investigated 4 ! PR 3 (0–10 mol%) 2 2 ! Ni(acac)2/2 PCy3 and Ni(acac)2/2 PPhCy2 are best R R solvent R3 = Ph, m-Tol, 39 examples Ligand Screen p-Tol, Mes 51–99% GC yield ! PMe , PEt , Pi-Bu , Pi-Pr , PCy , PPhCy , PPh Cy, PPh 3 3 3 3 3 2 2 3 Ph F3C p-Tol Mes Ph ! PCy3 and PPhCy2 are best ! Intermediate cone angle and good "-donating Ph 93% 61% 75% 95% Solvent Screen OH OH ! DME, THF, toluene, i-Pr2O, (EtO)2CH2, t-AmOMe, n-Bu2O ! Non-polar ethers or toluene preferred Ph ! MgBr(OMe) (catalyst poison) crashes out p-Tol NH2 in non-polar solvents Ph Ph 62% 61% 82%

Aryl Ether Screen p-TolMgBr (3 equiv) Ph N Ph NiCl2(PCy3)2 (5 mol%) OR p-Tol N PCy3 (10 mol%) N N (EtO)2CH2 or t-AmOMe H Ph Ph 60–100 °C 95% 74%a 58% GC yield GC yield R R a Isolated yield. -Me 94% -MOM 92% Reaction Scope Notes ! Amenable to functionalized benzene, napthalene, imidazole, -(CH ) OMe 77% -TMS 70% 2 2 pyridines, and indoles

-(CH2)2NMe2 99% ! Tolerant of free alcohols and amines ! Limited to aryl Grignard reagents Angew. Chem., Int. Ed. 2004, 43, 2428.

Ethers2 K2 Dankwardt Aryl and Vinyl Ether Cross Coupling Kumada Coupling: sp3–sp2 C–C Formation Shi, Z.-J. Catalyst Screen ! Fe, Co, Ni, Pd catalysts investigated OMe Me MeMgBr (1.5 equiv) ! NiCl (PCy ) and Ni(acac) /2 PCy are best 2 3 2 2 3 NiCl2(PCy3)2 (5 mol%) R1 R1 Ligand Screen toluene, 80–110 °C ! PCy3, PPh3, dppe, dppf 9 examples 62–98% yield ! PCy3 best Me Solvent Screen Me Me ! Dioxane, THF, toluene, Et2O ! Toluene and Et2O are best solvents Ph Aryl Ether Screen 92% 93% 94% MeMgBr (1.2 equiv) OR NiCl2(PCy3)2 (5 mol%) Me Me Me Me Me

toluene, 80 °C, 20 min Ph 62%a 71%a 74%a 94%b R yield R yield a b -Me 92% -t-Bu 88% GC yield. t-butyl phenyl ether 92% 69% -Et -MOM Reaction Scope Notes -n-Bu 96% -TMS 95% ! More favorable for napthalene and biphenyl -i-Bu 91% -Ph 95% ! Only MeMgBr explored

Differentiation Studies OMe OMe Methylates Both Positions 90% X monomethylated MeO X = -Br, -OMe, -On-Bu, -Oi-Pr, -Ot-Bu, -OPh Chem. Commun. 2008, 1437.

Ethers3 K3 Shi Aryl and Vinyl Ether Cross Coupling Kumada Coupling: sp3–sp3 C–C Formation Shi, Z.-J. Catalyst Screen 3 ! Fe, Ni, Pd catalysts investigated OMe R MgBr (1.2 equiv) R3 NiCl (PCy ) (5 mol%) ! NiCl2(dppf)/dppf and Ni(acac)2/dppf are best 2 3 2 R2 dppf (2 mol%) R2 1 1 Ligand Screen R R toluene, 23 °C ! PCy , PPh , dppe, dppf, dppb, dppp, dppe 3 3 3 17 examples ! PCy best R = Me, Et, n-Bu, 3 i-Pr, Ph 20–99% yield

Solvent Screen Me Me Me Et ! THF, toluene, Et2O Et Ph ! Toluene and Et2O are best solvents Ether Screen OR MeMgBr (1.5 equiv) Me 46% 45% 85% 96% NiCl2(dppf) (2 mol%) dppf (2 mol%) Me n-Bu i-Pr Ph toluene, 23 °C

R yield R yield -Me 80% -Ph 75% 51% 20% 22% 75% -Et 73% -TMS 76% Ph Ph -t-Bu 79% -Ac 18%a Me Me Me Me a GC yield Ph 99% 91% 86% >99%a Differentiation Studies Me X = -F 92% OMe -OMe 89% X -Me 95% MeO -OH 70% ! Methylate Sequentially: sp3–sp2 then sp2–sp2 a GC yield. ! Methylate Simulatenously: Use dppf + PCy3 J. Am. Chem. Soc. 2008, 130, 3268.

Ethers4 K4 Shi Aryl and Vinyl Ether Cross Coupling Suzuki-Miyaura Chatani, N. Organoboron Screen O ! PhB(OH)2, PhBF3K, NaBPh4 Ar B O (1.5 equiv) Ni(COD) (10 mol%) Aryl Ether Screen OMe 2 Ar PCy3 (40 mol%) O Ph B CsF (4.5 equiv) O (1.2 equiv) toluene, sealed tube 10 examples Ni(COD)2 (10 mol%) 36–94% yield OR PCy3 (20 mol%) Ph O CsF (4.5 equiv) CF CO Me toluene, sealed tube 3 2 R yield R yield (RO)2B (RO)2B (RO)2B a -Me 93% -i-Pr 16% 94% 83% 78% -Et 74% -Ac 10% F F

(RO)2B Electrophile Screen (RO)2B (RO)2B (RO)2B ! Napthalene and phenanthrene good electrophilic 89% 74% 65% 65% substrates (57–93%) ! Only EWG functionalized benzene couple (14–55%) TMS NMe2 OMe ! Olefins couple with poor E/Z selectivity p-Tol conditions (RO) B (RO) B (RO) B + 2 2 2 Ph OMe Ph p-Tol 92% 79% 68% Ph a 2 h 66 / 34 20 mol% Ni(COD)2, 80 mol% PCy3. 24 h 5 / 95 Aromatic Ethers: Angew. Chem., Int. Ed. 2008, 47, 4866. Vinyl Ethers: Org. Lett. 2009, 11, 4890.

Ethers5 SM1 Chatani

Cut 3 Price Comparison By Functional Group By Price O O R = CF3 $310 / mol Cl S R p-tol $70 / mol $7 / mol Cl O Me $20 / mol O $10 / mol O Cl

Cl S NEt2 $180 / mol I Me $20 / mol O O Cl S $20 / mol O O

P $130 / mol e

Cl (OEt) c O 2 i r $40 / mol P

Cl NEt2 g O I Me $20 / mol n i

s Cl S p-tol $70 / mol a

e O O r

R = t-Bu $10 / mol c O n

Me $7 / mol I Cl R P $130 / mol Cl (OEt)2 O O $40 / mol Cl S NEt2 $180 / mol Cl NEt2 O O O $220 / mol O O t-BuO O Ot-Bu $220 / mol O t-BuO O Ot-Bu Cl S CF3 $310 / mol Approximate Cost from Sigma-Aldrich O see also Garg, N. J. Am. Chem. Soc. 2008, 130, 14422.

Price Comparison

Sulfamate Ni Cross Coupling Kumada Ni Catalyst Screen

Snieckus, V.

p-tolMgBr (4 equiv) OSO2NEt2 catalyst (20 mol%) OSO2NEt2

solvent, temp, 24 h PPh3 Cl Ni entry catalyst solvent temp (°C) GC yield (%) NiClCpIMes 1 Ni(acac)2 PhMe 120 29

2 NiCl2 PhMe 120 72 N N 3 NiCl2 / P(t-Bu)3 PhMe 120 63 Mes Mes

4 NiCl2 / dppf PhMe 120 74 Cl Ni

5 NiClCpPPh3 PhMe 120 91 6 NiClCpIMes PhMe 40 85 NiClCpIMes

7 NiClCpIMes Et2O 40 >99

Org. Lett. 2005, 7, 2519.

Sulfamate2a K2 Snieckus2 Sulfamate Ni Cross Coupling Kumada Ni Catalyst Screen

Snieckus, V.

p-tolMgBr (4 equiv) OSO2NEt2 catalyst (20 mol%) OSO2NEt2

solvent, temp, 24 h PPh3 Cl Ni entry catalyst solvent temp (°C) GC yield (%) NiClCpIMes 1 Ni(acac)2 PhMe 120 29

2 NiCl2 PhMe 120 72 N N 3 NiCl2 / P(t-Bu)3 PhMe 120 63 Mes Mes

4 NiCl2 / dppf PhMe 120 74 Cl Ni

5 NiClCpPPh3 PhMe 120 91 6 NiClCpIMes PhMe 40 85 NiClCpIMes

7 NiClCpIMes Et2O 40 >99

Org. Lett. 2005, 7, 2519.

Sulfamate2b K2 Snieckus2

Phosphonate and Phosphoramide Cross Coupling Kumada Coupling: Vinyl Phosphonates

Bäckvall, J.-E.

OP(O)(OPh)2 RMgX (1.5 equiv) R NiCl2(dppe) (1 mol%)

Et2O, 0 °C R = n-Bu 85% Ph 68%

OP(O)(OPh)2 PhMgX (1.5 equiv) Ph NiCl2(dppe) (1 mol%)

Et2O, 0 °C 92% yield

n-BuMgX (1.5 equiv) OP(O)(OPh)2 n-Bu n-Bu NiCl2(dppe) (1 mol%) Ph Ph + Ph Et 2 2 2 Et2O, 23 °C Et Et (E) 62% yield (Z) (E) 95 : 5 J. Org. Chem. 1999, 64, 1745.

Phosphonate2 K2 Backvall

Ether Cross Coupling Kumada Coupling: sp2–sp2 C–C Formation

Dankwardt, J. W.

3 OR1 R MgBr (2 equiv) R3 Ni catalyst (5 mol%) ! NiCl2(PCy3)2, NiCl2(PPhCy2)2, –OR– 4 PR 3 (0–10 mol%) NiCl2(PPh2Cy)2 R2 R2 solvent ! Toluene, i-Pr2O, (EtO)2CH2, t-AmOMe, n-Bu2O R3 = Ph, m-Tol, 39 examples p-Tol, Mes 51–99% GC yield

PhMgBr (3 equiv) NiCl2(PCy3)2 (5 mol%) OEt Mes PCy3 (10 mol%)

t-AmOMe, 23 °C 75% yield

PhMgBr (3 equiv) MeO Ph NiCl2(PPhCy2)2 (5 mol%)

N t-AmOMe/Et2O, 23 °C N H H 95% yield

Angew. Chem., Int. Ed. 2004, 43, 2428.

Ether3 Kumada3 Dankwardt Ether Cross Coupling Kumada Coupling: sp3–sp2 C–C Formation

Shi, Z.-J.

OMe Me MeMgBr (1.5 equiv) NiCl2(PCy3)2 (5 mol%) R R toluene, 80–110 °C 9 examples 62–98% yield

MeMgBr (1.5 equiv) OMe NiCl2(PCy3)2 (5 mol%) Me

toluene, 80 °C 93% yield

OMe Me MeMgBr (1.5 equiv) NiCl2(PCy3)2 (5 mol%) R R toluene, 110 °C R = o-Me 71% p-Me 74%

Chem. Commun. 2008, 1437.

Ether4 Kumada4 Shi Ether Cross Coupling Kumada Coupling: sp3–sp3 C–C Formation

Shi, Z.-J.

3 OMe R MgBr (1.5 equiv) R3 NiCl2(dppf) (2 mol%) R2 dppf (2 mol%) R2 R1 R1 toluene, 23 °C R3 = Me, Et, n-Bu, 17 examples i-Pr, Ph 20–99% yield

MeMgBr (1.5 equiv) OMe NiCl2(dppf) (2 mol%) Me dppf (2 mol%) R = H 80% Me 46% R R toluene, 23 °C Et 45% Ph 85%

MeMgBr (1.5 equiv) NiCl2(dppf) (2 mol%) OMe dppf (2 mol%) Me

toluene, 23 °C >99% yield

J. Am. Chem. Soc. 2008, 130, 3268.

Ether5 Kumada5 Shi

Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Garg, N. K.

B(OH) 2 OMe

OPiv NiCl2(PCy3)2 (5 mol%) + K3PO4 (7.2 equiv) toluene, 110 °C, 24 h OMe 4 equiv 92% yield

B(OH) 2 OMe

OPiv NiCl2(PCy3)2 (10 mol%)

+ K3PO4 (9 equiv) toluene, 110 °C, 24 h OMe 5 equiv 65% yield

J. Am. Chem. Soc. 2008, 130, 14422.

Ester1 SM1 Garg1 Ester Cross Coupling Suzuki-Miyaura Coupling: Aryl Esters

Garg, N. K.

Electronics R = OMe 95%

OPiv B(OH)2 R CF3 77% NiCl2(PCy3)2 (5 mol%) + Sterics R K3PO4 (4.5 equiv) R = p-Me 91% toluene m-Me 99% 2.5 equiv o-Me 58%

OMe

OH OPiv PivCl, K3PO4 then, ArB(OH)2

toluene, 80 °C NiCl2(PCy3)2 (5 mol%) 86% yield J. Am. Chem. Soc. 2008, 130, 14422.

Ester1 SM1 Garg2