Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15

Some im

portant events in the history of Ni:M

edieval times: A red ore was discovered and was nam

ed kupfernickel1751: Baron Axel Fredric Cronstedt tried to extract copper from

kupfernickel ore and instead obtained a white m

etal that he named nickel.

1824: Nickel can be obtained readily (byproduct of cobalt blue production)1889: Nickel is used in the production of steel1890: Ni(CO

)4 was synthesized by Ludwig Mond (M

ond Process); process is still used to obtain high purity (> 99.99%

) nickel1897: Sabatier discovers that trace nickel catalyzes the hydrogenation of ethylene1940: Reppe discovers Ni can cyclopolym

erize acetylene, yielding cyclooctatetraene1966: W

ilke invents Ni(cod)21968: Shell higher olefin process is discoverd.1972: Kum

ada publishes Ni-catalyzed cross-coupling of grignard reagents with aryl/vinyl halides1986: NiCl2 is found to be an efficient co-catalyst for the NHK couplingFun Facts about Nickel:1. Philippines, Indonesia, Russia, Canada and Australia produce m

ost nickel.2. Nickel is extrem

ely cheap (< $0.01/g vs $18.93/g for Pd, $22.51/g for Rh as of 3/21/16).3. M

ajority of nickel is used in alloys (stainless steel).4. U.S. nickel is 25%

nickel (the rest is copper).

Ni-catalyzed Cross-Coupling

R1

XNiCl2 (dppe) (0.7 m

ol%)

R2M

gXR

2 = alkyl, aryl R1

R2

XorTam

ao, Sumitani, and Kum

adaJ. Am

. Chem

. Soc., 1972, 94, 4374.

Humble beginnings:

80 - 98%

Corriu and Masse,

J. Chem

. Soc. Chem

. Com

mun. 1972, 144a.

RX

Ni(acac)2 (0.5 - 1 m

ol%)

ArMgX

R = aryl,alkenyl

RAr

50 - 75%

Early mechanistic analysis:

Morrell and Kochi, J. Am

. Chem

. Soc. 1975, 97, 7262.Tsou and Kochi, J. Am

. Chem

. Soc. 1979, 101, 6319 - 6332Kochi, Pure Appl. C

hem. 1980, 52, 571..

Ni Me

Et3 PPEt3

80 °C, O2 , or ArBr

Me

Oxidative addition of aryl halides:

Reductive elimination from

Ni(II):

Ni 0L4

Ni 0L3 + L

Ni 0L3 + ArX

[NIL

3 ArX- ]

[NIL

3 ArX- ]

ArNIIXL

2 + L

NIL

3 + X- + Ar

slow

Yield of Ni I:X = I, 91%X = Br, 7%X = Cl, 0%

Ni(PEt3 )4 + ArXpurple

ArNIIXL

2 + XNIL

3yellow-brown

Ar =M

eO2 C

X

L2 Ni II(Ar)M

e + ArXslow

[L2 Ni III(Ar)CH

3 +ArX -]fast

L2 Ni III(Ar)CH

3 +[L

2 Ni I] + + ArCH3

[L2 Ni I] + + ArX -

fastL

2 Ni IIArX

Proposed catalytic cycle: Ni(I)/Ni(II)/Ni(III)Recent study proposing a strict 2e

- Ni(I)/Ni(III) catalytic cycle for coupling of aryl halides/alkylzinc reagents:Cardenas and coworkers, C

hem. Eur. J.

2009, 15, 12681.

The focus of this group meeting is on use of Ni in the past decade. This includes Ni catalyzed

cross-coupling as well as some other uses of nickel in organic synthesis. In the interest of

time, not all topics can be included.

28NiNickel 58.6934

[Ar]3d84s

2

Nickel Facts:d 10 first-row transition m

etalelectropositiveSm

aller than PdCom

mon oxidation states in catalysis: 0, 1, 2, 3, 4

Facile oxidative additionEasy β-m

igratory insertionSlow β-hydride elim

inationReductive elim

ination from Ni(II) can be difficult; often requires Ni(III)

or Ni(IV)Radical m

echanistic pathways are accessible

solvent

Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15

Cross-coupling with alkyl electrophiles: O

lefins as ligandsCoupling of 1

° alkyl iodides with dialkylzinc reagents:

Knochel and coworkers, Angew. Chem. Int. Ed. Engl. 1995, 34, 2723.

In

R2 Zn (2 equiv)

Ni(acac)2 (7 mol%

)

THF/NMP (2:1)

-35 °C, 0.5 - 18 hr

Rn

Olefin prom

otes reductive elim

inationby coordination to Ni:see Yam

amoto and coworkers,

J. Am. Chem

. Soc. 1971, 93, 3350.

NiR64 - 90%

Similar reactions are prom

oted by exogenous olefin additives:F

3 C

1°alkyl iodides with

dialkylzinc reagents:Knochel and coworkers, Angew. Chem

. Int. Ed. 1998, 37, 2387.

FAlkylzinc halides with

1° alkyl halides:

Knochel and coworkers, J. O

rg. Chem. 2002, 67, 79.

F3 C

Aryllzinc halides with 1

° alkyl halides:Knochel and coworkers,

J. Am. Chem

. Soc. 1998, 120, 11186.

1°alkyl brom

ides and tosylates with alkyl G

rignard reagents: Kam

be and coworkers,

J. Am. Chem

. Soc. 2002, 124, 4222.

Angew. Chem. Int. Ed.

2016, 55, 1.

An important breakthrough: coupling of 2° alkyl halides w

ith alkylzinc reagentsZhou and Fu, J. Am

. Chem. Soc. 2003, 125, 14726.

X

R = alkylX = Br, I

R'ZnBr (1.6 equiv)

Ni(cod)2 (4 mol%

)

s-Bu-PyBOX (8 m

ol%)

DMA, rt, 0.5 - 18 hr

R' = alkyl

R RR

'

62 - 91%

R RN

O

NN

O

s-Bus-Bu

- ligand is essential to success of the reaction; tridentate PyBOX ligand helps to suppress

deleterious β-hydride elimination

s-Bu-PyBOX

Arylation with organosilicon reagents: J. Am. Chem

. Soc. 2004, 126, 7788.Arylation with m

onoorganotin reagents: J. Am. Chem

. Soc. 2005, 127, 510.

R

R

Arylation of 2° electrophiles:Zhou and Fu, J. Am

. Chem. Soc., 2004, 126, 1340.

R'

ArB(OH)2 (1.6 equiv)

Ni(cod)2 (4 mol%

)

bathophenanthroline (8 mol%

)KO

t-Bu (1.6 equiv)s-BuO

H, 60 °C, 5 hrR' = alkyl

X

R = alkylX = Br, I

R R

44 - 91%N

N

PhPhbathophenanthroline

Proposed catalytic cycle: Ni(0)/Ni(II)

Proposed mechanism

with butadiene as a ligand: Ni(II)/Ni(IV)

Ni 0

R1M

gX

Ni II

Ni IIR

1

Ni IV

R1

R2

R1

R2

Br+ RM

gXNiCl2 (1 m

ol%)

(10 mol %

)R

Ring opening experiment:

R2X

Mechanistic discussion:

1. Ni(cod)2 does not react with octyl bromide in the presence of butadiene.

2. Oxidative addition does not occur through radical pathway (likely S

N 2).3. β-hydride elim

ination is suppressed due to coordinative saturation at Ni.

Arylation of 3° electrophiles:Zultanski and Fu, J. Am

. Chem. Soc., 2013, 135, 624.

R

R

R'

(2.5 equiv)NiBr2 •diglym

e (10 mol%

)

di-t-Bubipy (11 mol%

)LiO

t-Bu (2.4 equiv)i-BuO

H (2.4 equiv)PhH, 40 °C

X

X = Br, ClR R

54 - 88%N

N

tiBut-Bu

di-t-Bubipy

R

(9-BBN)Ar

R

Cross-coupling with alkyl electrophiles: Pyridine/Im

ine ligands

Coupling of 2° propargyl halides with 2° alkylzinc reagents:

Smith and Fu, Angew. Chem

. Int. Ed. 2008, 47, 9334.

NN

N

NN

NNN

X

R = TIPS, t-Bu

R'ZnBr (1.6 equiv)

NiCl2 •glyme (10 m

ol%)

terpyridine (10 mol%

)DM

A, rt, 0.5 - 18 hrR' = 2° alkyl

alkyl

50 - 89%

R

R1

alkyl

R

For alkylzinc reagents more hindered than

cyclohexyl or isopropyl, using 2,6-bis(N-pyrazolyl)pyridine

in THF was superior to terpyridine/DMA.

terpyridine

2,6-bis(N-pyrazolyl)pyridine

Revisiting N

ickelJacob T. Edw

ardsB

aran Group M

eeting3/26/15

Mechanistic insight:

First catalytic enantioselective cross-coupling of 2° alkyl electrophiles:Fischer and Fu, J. Am

. Chem

. Soc. 2005, 127, 4594.

NPh

BnO

Br R

R'ZnBr (1.3 equiv)

NiCl2 •glyme (10 m

ol%)

(R)-i-Pr-PyBO

X (13 mol%

)DM

I/THF (7:1) 0 °C, 12 hrR' = alkyl

racemic

R = alkyl

NO

NN

O

i-Pri-Pr

(R)-i-Pr-PyBO

X

NPh

BnO

R' R

51 - 90%77 - 95%

ee

R1

R2

R3

alkyl

J. Am. C

hem. Soc.

2008, 130, 2756.

Some other enantioselective transform

ations:

R1O

OR

2

ArJ. Am

. Chem

. Soc. 2008, 130, 3302.

R

alkyl Ar

J. Am. C

hem. Soc.

2008, 130, 12645.

ArR

1O

Ar 1Angew. C

hem., Int. Ed.

2009, 48, 154.

ArR

1O

F Ar 1

J. Am. C

hem. Soc.

2014, 136, 5520.

O

NN

O

R1

R1

R2

R2BO

X

NN

O

RQ

uinox

Ni IINN

Me Me

Me

MeMe

Me

terpyridineN

NN

Ni IM

e

vs.N

NN

Ni IIM

e

Ni(I)-alkyl com

plexes with pyridine/im

ine ligands are Ni(II)-ligand anion com

plexes.Vicic and coworkers, J. Am

. Chem

. Soc. 2004, 126, 8100.Vicic and coworkers, C

hem. C

omm

un. 2005, 4211.Vicic and coworkers, J. Am

. Chem

. Soc. 2006, 128, 13175 (extensive list of ligands).

- 1/2 ethane

square planarµ

eff = 1.64 µBE

° = - 1.32 V (vs Ag/Ag + in THF)

Evidence of radical intermediates:

Cardenas and coworkers,Angew. C

hem. Int. Ed. 2007, 46, 8790.

O

Ni IX

General N

i(I)/Ni(III) m

echanism:

R1Ni I

R2X

R1Ni IIX

+R2

Ni IIIX

R2

R1

R1

R2

RZnBrNi(py)4 Cl2 (10 m

ol%)

(S)-s-Bu-PyBOX

(10 mol%

)THF

R = alkyl

OO

H HR

(57:43)Sam

e ratio with otherdiastereom

er.

MR

1

F3 C

alkyl

Ar

J. Am. C

hem. Soc.

2015, 137, 9523.

LNi IBr

RR

Ni IIIArL

Ni IIBr2

[LNi IIAr]Br

ZnAr2

R

Br

BrZnAr

R

Ar

Not all N

i(I)/Ni(III) catalytic cycles are the sam

e:Schley and Fu, J. Am

. Chem

. Soc., 2014, 136, 16588.

Key findings:

1.i-PrPyBoxNi IPh is a Ni(II)-complex with ligand-centered anionic charge.

2. Higher catalyst concentration reduces 5-exo-trig cyclization products (bimetallic oxidative

addtion).3. Reaction is essentially EPR silent (indicates Ni is predom

inantly found as Ni(II), not Ni(I) or Ni(III).4. Reaction of stoichom

etric i-PrPyBoxNi IIPh with propargyl bromide results in sim

ilar yield/ee to catalytic process; i-PrPyBoxNi IPh gives worse yield/ee (L

n Ni IPh may not be part of cycle).

5. Addition of substoichiometric TEM

PO to i-PrPyBoxNi IIPh and propargyl brom

ide results in an induction period; introducing i-PrPyBoxNi IBr initiates reaction. 6. i-PrPyBoxNi IBr reacts rapidly with propargyl brom

ide (transmetallation likely doesn't happen

at Ni I).Proposed m

echanism:

(tpy)Ni +M

eI -

octane 8%

(tpy)NiM

eoctane 90%

C7 H

15 I

C7 H

15 ZnBr

Also see Fu and coworkers, J. Am

. Chem

. Soc. 2005, 127, 510.

(tpy)NiI

`RX

R'ZnBr

RR' 76%

(5 mol%

)

O

I

NN

NNi IBr

Radical is centered on Ni:see Vicic and coworkers,

Inorg. Chem

. 2011, 50, 8630.

TMS

n-Bu

Br

Ph2 Zn (1.6 equiv)

glyme, -20 °C, 17h

Ph2 Zn (1.6 equiv)

NiBr2 •glyme (3 m

ol%)

TMS

n-Bu

Ph77%

, 82% ee

Br

Revisiting N

ickelJacob T. Edw

ardsB

aran Group M

eeting3/26/15

Cross-coupling w

ith alkyl electrophiles: Diam

ine and amino alcohol ligandsR

R

R'

ArB(OH)2 (1.2 equiv)

NiI2 (6 mol%

)

trans-2-aminocyclohexanol

(6 mol%

)NaHM

DS(2.0 equiv)i-PrO

H, 60 °CrX = Br, I

XR

1 = alkyl, HR

2 = alkylR

2

R1

66 - 97%

ArB(OH)2 (1.2 equiv)

NiCl2 •glyme (6 m

ol%)

prolinol (12 mol%

)KHM

DS (2.0 equiv)i-PrO

H, 60 °C, 5 hrX = Cl

R2

R1

R'46 - 87%

NH2

OH

NH

OH

Ph

First report:G

onzales-Bobes and Fu, J. Am. Chem

. Soc. 2006, 128, 5360.

R1

Br

(9-BBN)R

2

(1.5 equiv)Ni(cod)2 (10 m

ol%)

(R)-(R

)-diamine(12 m

ol%)

KOt-Bu (1.2 equiv)

i-BuOH (2.0 equiv)

i-PrOH, 5 °C or rt

PhR

1

R2

First asymm

etric cross-coupling of unactivated alkyl electrophiles:Saito and Fu, J. Am

. Chem. Soc. 2008, 130, 6694.

68 - 86%66 - 90%

ee

NHMe

MeHN

CF3

F3 C

(R)-(R

)-diamine

OO

BrPhB(O

H)2as above5-exo-trig

OO

PhHH

> 20:1 endo:exo

Mechanistic experim

ent:

Cross-coupling w

ith alkyl electrophiles: Pincer ligands

NNi

Cl

NMe

2

NMe

2

Nickamine

Coupling of alkyl grignards w

ith alkyl electrophiles:Vechorkin and Hu, Angew. Chem

. Int. Ed. 2009, 48 , 2937 –2940.

R1X + R

2MgCl

Nickamine (3 m

ol%)

DMA, - 35 °C

R1, R

2 = alkyl

R1

R2

Low temperature allows functional group

tolerance (-CN, -CO2 R, ketones, etc).

Mechanistic Features:

Hu and coworkers, J. Am. Chem

. Soc. 2013, 135, 12004.Hu and coworkers, O

rganometallics 2014, 33, 5708.

1. Radical intermediates are found in oxidative addition (rearrangem

ent of cyclopropyl electrophiles/5-exo-trig cyclizations observed).2. O

xidative addition is bimetallic.

3. Key intermediate for electrophile activation: [(N

2 N)Ni-alkyl2 ](alkyl2 -MgCl).

3. Oxidation states are not entirely clear due to redox-activity of ligand (sim

ilar pincer ligands have been shown to have radical cation character, see J. Am

. Chem. Soc. 2008, 130, 3676).

For coupling with aryl Grignard reagents:

Hu and coworkers, J. Am. Chem

. Soc. 2009, 131, 9756.

NNi IIIR

1

NMe

2

NMe

2 R2

NNi II

R1

NMe

2

NMe

2 R2

NNi

Cl

NNMe

2

New

and improved Pincer ligand N

i. cat:Hu and coworkers, ACS Catal. 2016, 6, 258.

Ligand enables reaction of acylic 2° halides with alkyl G

rignard reagents as well as reaction of 1°and 2° alkyl

halides with aryl-and alkyl-(9-BBN) reagents.

For more discussion on catalyst developm

ent:J. Am

. Chem. Soc., 2011, 133, 7084-7095.

vs.

Cross-coupling w

ith aryl electrophiles/alkyl organometallics:

Aryl halides w

ith 1° and 2° alkylzinc reagents:X

R1

NiCl2 (2 - 5 mol%

)terpyridine (2 - 5 m

ol%)

LiBF4

(0 - 1.0 equiv)THF, 40 - 80 °C

ZnIR

3

R2

R1

R3R

2

61 - 92%

NiCl2 (py)4 (3 mol%

)bpy (3 m

ol%)

R2

ZnBr

THF, 23 °C52 - 89%

Aryl halides/triflates w

ith 3° Grignard reagents:

Biscoe and coworkers, J. Am. Chem

. Soc. 2011, 133, 8478.

XR

1NiCl2 •(H

2 O)1.5 (10 m

ol%)

NHC (10 mol%

)THF, -10 °C

MgCl

R3

R2

R1

R3R

2

37 - 86%

R4

N+

N

Cl -

Biscoe and coworkers, O

rg. Lett., 2011, 13, 1218.

R2

R1Cardenas and coworkers, Chem

. Eur. J.2009, 15

, 12681.

Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15

Fluoromethylation:

Zhang and coworkers, Angew. Chem

. Int. Ed. 2015, 54, 9079.

Fluoromethylation reactions:

RB(O

H)2 NiCl2 •glyme (5 m

ol%)

phen (5 mol%

)DM

AP (10 mol%

)K

2 CO3 (2.0 equiv)

DME/dioxane, 70 °C

42 - 90%R'=CH

2 F

RR

'

CH2 FBr (1.0 equiv)

(1.5 equiv)

Difluoromethylation:

Xu and Vicic, J. Am. Chem

. Soc. 2016, 138, 2536

RX

(dppf)Ni(cod) (15 mol%

)

DMSO

, 25 °C, 24h10 - 91%

X = Br, I, OTf

R'=CF2 H

Zn(CF2 H)2 (DM

PU)2(1.2 equiv)

Trifluoromethylation:

Vicic and coworkers, Organom

etallics 2008, 27, 3933.Sanford and coworkers, J. Am

. Chem. Soc. 2015, 137, 8034.

NiPP

i-Pri-Pr

i-Pri-PrPhCF

3

ZnBr2 or H2 O

CF3

19 - 22%Ni II

N NB

NN

NN

CF3

CF3

HNBu

4 +Ph

2 IBF4 or

PhN2 BF

4(1.1 equiv)

42 - 77%

Carbon-heteroatom bond form

ing reactions:

C-N bond formation:

Wolfe and Buchwald, J. Am

. Chem. Soc. 1997, 119, 6054.

RCl

HNR'2 (1.2 - 3.0 equiv)Ni(cod)2 or NiCl2 /M

eMgBr (2 - 5 m

ol%)

DPPF or phen (4 - 10 mol%

)

PhMe or pyridine, 100 °C

RNR'2

50 - 91%

C-O bond form

ation:M

ann and Hartwig, J. O

rg. Chem. 1997, 62, 5413.

NaOR' (1.2 - 3.0 equiv)

Ni(cod)2 (15 mol%

)DPPF (30 m

ol%)

PhMe, 95 °C

R' = Me, t-Bu, TBS

RO

R'

58 - 76%

RCl

C-O electrophiles (not just -O

Ts and -OTf):

For seminal studies for oxidative addition into unactivated ethers (−O

Me), see: W

enkert and coworkers, J. Am

. Chem. Soc. 1979, 101, 2246. Dankwardt, Angew. Chem

. Int. Ed. 2004, 43, 2428.

Also see: Garg and coworkers, O

rg. Lett. 2012, 14, 4182.For the arylation of am

monia using Ni-catalysis: Stradiotto and coworkers,

Angew. Chem. Int. Ed. 2015, 54, 3773.

OPiv

R

ArB(OH)2

(2.5 - 4.0 equiv)NiCl2 (PCy

3 )2 (5 mol%

)

K3 PO

4 (4.5 equiv)PhM

e, 80 °C, 24h

ArR

73 - 99%

For carbamates, carbonates,

sulfamates: G

arg and coworkers, J. Am

. Chem. Soc. 2009, 131

17748.

Pivalates:G

arg and coworkers, J. Am. Chem

. Soc. 2008, 130, 14422.

Other transform

ations:C-O

bond reduction: Martin and coworkers, J. Am

. Chem. Soc. 2010, 132, 17352.

Heck-type reactions: Watson and coworkers, O

rg. Lett. 2012, 14, 1203.Am

ination: Garg and coworkers, O

rg. Lett. 2012, 14, 4182.

Stereospecific cross-coupling of benzylic ethers: Jarvo and coworkers, J. Am

. Chem. Soc. 2011, 133, 389.

Ar

OM

eR

MeM

gI (2.0 equiv)Ni(cod)2 (5 m

ol%)

rac-BINAP (10 mol%

)PhM

e, rt, 24 hR = Et, Ar'

enantioenrichedAr

MeR

69 - 96%

Ligand controls inversion or retention:Jarvo and coworkers, J. Am

. Chem. Soc.

2013, 135, 3303.

Ar 1Ar 2

OO

N

Ar 3B(OR)2 (2.0 equiv)

Ni(cod)2 (10 mol%

)Ligand (11 - 20 m

ol%)

t-BuOK (2.0 equiv)

n-BuOH (3.0 equiv)

THF:PhMe (1:1), rt, 24 h

Ar 1Ar

Ar 3

Ar 1Ar 2

Ar 3

L = PCy3

L = SIMes

+

Decarbonylative cross-coupling:Rovis and coworkers, J. Am

. Chem. Soc. 2003, 125, 10498.

O OOR

n

Ni(cod)2 (1.5 equiv)neocuproine (1.0 equiv)

dppb (0.5 equiv)

Ph2 Zn (2.0 equiv)

F(1.0 equiv)THF, 66 °C

CO2 H

Ph

50 - 85%n

Ph2 P

PPh2

dppb

NN

Me

Me

neocuproine

C-S bond formation:

Zhang and Vicic, J. Am. Chem

. Soc. 2012, 134, 183.X

R

Me

4 NSCF3 (1.2 equiv)

Ni(cod)2 (15 mol%

)4,4'-dim

ethoxy-bpy (30 m

ol%)

THF, rt, 22h

NN

MeO

OM

e

4,4'-dimethoxy-bpy

SCF3

R

Also see Schoenebeck and coworkers, J. Am. Chem

. Soc. 2015, 137, 4164.For a review on Ni-catalyzed aryl sulfide form

ation:Eichm

an and Stambuli, M

olecules, 2011, 16, 590.

C-B bond formation from

aryl fluorides:M

artin and coworkers, J. Am. Chem

. Soc. 2015, 137, 12470.

FR

B2 nep

2Ni(cod)2 (5 m

ol%)

PCy3 (20 m

ol%)

NaOPh (3.0 equiv)

THF, 110 °C

BnepR

Also see Zhang and coworkers, Angew. Chem

. Int. Ed. 2014, 53, 9909.

46 - 81%

37 - 92%

Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15

N

nBu

TsH

bpyNi(Et)2or (bipy)Ni(cod)

Hn-Bu

H

TsD

NiN

C-N electrophiles:

HDN N

O2

>92% inversion

>95% inversion

N

n-Bu

TsH

HD(bpy)Ni 0

Ni IIN N

HD

NTs

n-Bu

H

Oxidative addition: S

N 2-like nucleophilic ring-opening

Hn-Bu

H

TsD

NiN

N N

Initial studies for oxidative addition and reductive elimination to break and

form C-N bonds:

Hillhouse and coworkers: J. Am. C

hem. Soc. 2002, 124, 2890.

Reductive elimination proceeds through inversion through either hom

olysis or heterolysis of the Ni-N bond. Concerted and Ni-C hom

olysis mechanism

s are not considered because they should give retention or scram

bling of stereochemistry, respectively.

Extension to cross-coupling:

ArNTs

NiCl2 •glyme (5 m

ol%)

RZnBr (3.0 equiv)dioxane/DM

A, 23 °C,2-34 h

48 - 90%

MeO

2 CCO

2 Me

(10 mol%

)Ar

NHTsR

R1

NTsNiCl2 (5 m

ol%)

Me

4 Phen (6.25 mol%

)

R2ZnBr (3.0 equiv)DCE/THF (2:3), 26 °C, 28 - 24 h

66 - 97%>20:1 regioselectivity

R1

R2

NHTs

Jamison and coworkers, J. Am

. Chem

. Soc. 2014, 136, 11145.

Me

4 Phen

NN

Me M

eM

eMe

For extension to alkyl aziridines:J. Am

. Chem

. Soc. 2013, 135, 13605.

Doyle and coworkers, J. Am. C

hem. Soc. 2012, 134, 9541.

- also works with with alkylzinc prepared from direct zinc insertion in DM

A (79 - 93% yield),

but requires LiCl (3 equiv)l; postulated that LiCl and the alkyzinc halide form an ate com

plex of the type RZnX

2 Li.

PhNTs

standard conditions

99% ee

For generation of quaternary centers:J. Am

. Chem

. Soc. 2015, 137, 5638.

PhNHTs

n-Bu

11% ee,

inversion

PhNTs

99% ee

90% conv.

+

Me

4 phenNi 0

NiLn

R1

TsND

NTs

D R1

NZnBr

TsR1

NiLn R

2

D

NZnBr

TsR1

R2

D

Proposed mechanism

(Jamison):

R2ZnBr

ArN

OM

e

Ph

ROH (1.2 equiv)

Ni(cod)2 (10 mol%

)SIPr (10 m

ol%)

PhMe 80° C

49 - 91%Ar

OR

O

Amide-bond activation:

Garg and coworkers, N

ature, 2015, 524, 79.

NN

i-Pri-Pr

i-Pr

i-PrSIPr

N

nBu

TsH

HD

For subsequent coupling of amides with boronic acids:

Garg and coworkers, N

at. Chem

. 2016, 8, 75.For the generation of am

ides via acyl C-O bond activation:

Garg and coworkers, Angew. C

hem. Int. Ed. 2016, 55, 2810.

R1 = alkyl

Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15

R

O

Cl(1.2 equiv) +

Me

ClNiCl2 •glym

e (10 mol%

)(R,R

)-diphenyl-BOX (22 m

ol%)

Mn

0 (3.0 equiv)DM

BA (0.75 equiv)DM

A/THF (30% v/v)

3Å MS, 20 °C, 24 h

R

O

Me Ph

38 - 79%72 - 93%

ee

N+

NR

RCl-

R = iPr, tBuNHC

BrM

e

MeR

1R

2Br

(1.0 - 2.0 equiv)

+

(1.0 - 2.0 equiv)

Ni(acac)2 (10 mol%

)NHC (0 to 30 m

ol%)

pyr or DMAP (30 - 100 m

ol%)

MgCl2 (1.0 - 1.5 equiv)Zn (2.0 equiv), DM

AR

2

MeR

1M

e

Aryl- 3° alkyl coupling:G

ong and coworkers, J. Am. Chem

. Soc., 2015, 137, 11562.

Enantioselective cross-electrophile coupling:Reism

an and coworkers, J. Am. Chem

. Soc. 2013, 135, 7442

Biaryl multim

etallic coupling:W

eix and coworkers, Nature, 2015, 524, 454.

Cross-electrophile coupling:

R1

NiI2 •xH2 O

(10.7 mol %

)4,4'-di-t-Bubpy (5 m

ol%)

o-(PH2 P)2 C

6 H4 (5 m

ol%)

pyridine (10 mol%

)M

n (2.0 equiv)DM

PU, 60 - 80°C38 - 88%

X

R2

X(1.0 equiv)

R2 = 1

°, 2° alkyl

(1.0 equiv)R

1R

2PPh

2

PPh2

o-(Ph2 P)2 C

6 H4

X = Br, I

+

Follow up full article:

Weix and coworkers,

J. Am. Chem

. Soc. 2012, 134, 6146.O

ptimized conditions:

NiI2 •xH2 O

(5 - 10 mol %

)phen or 4,4'-dim

ethoxy-bpy (5 - 10 mol%

)pyridine (Zn (2.0 equiv)

Proposed mechanism

:Biswas and W

eix, J. Am. Chem

. Soc., 2013, 135, 16192.

Ni 0N N

Ni IIN N

XAr

Ni IIIN N

XAr

CH2 R

Ni IN N

X

Ni IIN N

X

Mn

MnI2

ArX

CH2 R

XCH2 R

XCH2 R

Ni IIIN N

XAr

X

ArX

ArX

low [radical]

high [radical]

ArR

NiBr2 (diglyme) (5 m

ol%)

bpy (5 mol%

)PdCl2 (5 m

ol%)

dppp (5 mol%

)Zn (2.0 equiv)(KF 1.0 equiv)

DMF, 40 °C

R1

Br

1.0 equiv R2

OTf

1.0 equiv

+R

1

R2

53 - 94%

PPh2

Ph2 P

dppp

Ni 0

Ni IIArBrNi IIO

TfBr

Ar 1Br

ZnZnBrO

Tf

PdIIAr

BrPdIIAr 2

Ar 1

Pd0Ar 1

Ar 2

Ar 2OTf

Generalized m

echanism:

Keys to success:1. Ligand choice for Pd (see Farm

er, Ligands in Transition Metal Catalysis,

Baran Lab Group M

eeting, 2016 and Hayashi and coworkers, Tet. Lett., 1997, 38, 7087)2. KF can reduce dim

eric byproducts in Ni catalysis as well as favor C-X over C-OTf ox. add. for

Pd catalysis.3. ArPdO

Tf does not readily react with itself; transient Ni(I)Ar complexes readily react with Pd,

however.

NN

phenN

NR = tBu, 4,4'-di-t-Bubpy

R = OM

e, 4,4'-dimethoxy-bpy

RR

Initial report: Weix and coworkers, J. Am

. Chem. Soc., 2010, 132, 920.

+RCH

2

For alkyl-alkyl cross-electrophile coupling:G

ong and coworkers, Org. Lett. 2014, 16, 4984

N

OO

N Me

Me

PhPh

Revisiting N

ickel: Cross-coupling and M

oreJacob T. Edw

ardsB

aran Group M

eeting3/26/15

C-H

Activation w

ith Nickel:

First example of C

-H activation w

ith nickel:Kleim

an and Dubeck: J. Am. Chem

. Soc. 1963, 85, 1544.

Ni

NN

Ni

NN

135 °Cneat

First example of a transform

ation of an ortho C-H

bond using chelation assistance:Chatani and coworkers, J. Am

. Chem. Soc. 2011, 133, 14952.

NH

OHN

R2

R1(3.0 equiv)

Ni(cod) (5 mol%

)PPh

3 (20 mol%

)

PhMe, 160

°C, 6 hr

N

O

N

R1

R2

Extended to arylation of aliphatic C-H

bonds:Aihara and Chatani, J. Am

. Chem. Soc. 2014, 136, 898.

O

NHN

Ni(OTf)2 (10 m

ol%)

MesCO

2 H (20 mol%

)

DMF, 140

°C, 24 hr

ArI (2.0 equiv)

R = alkyl, aryl

RR

H

O

NHN

RR

Ar

R1

O

NHN

R2

R2 = aryl, J. O

rg. Chem., 2014, 79, 11922.

R2 = alkyl, J. Am

. Chem. Soc. 2013, 135, 5308.

O

NHN

R1 R

1R2

R2 = alkyl, G

e and coworkers, J. Am

. Chem. Soc. 2014, 136, 1789.

NiX2

O

N

N

RR

HNiX

O

NNi N

RR

O

NNi N

RR

ArI

O

N

N

RR

Ar NiX

O

NHN

RR

Ar

HXArH

NiAr

IO

N

N

RR

HNiAr

HXA

O

NHN

RR

H

AA

HX

Possible catalytic cycle (J. Am. Chem

. Soc. 2014, 136, 898):ArI

Ni(0)

HXArH

What type of catalysis is this? N

i(0)/Ni(II)? N

i(I)/Ni(III)? N

i(II)/Ni(IV)?

1. TEMPO

did not inhibit the reaction.2. Catalysis works with both Ni(0) and Ni(II) precatalysts.3. No biaryl product is form

ed when Ni(0) is used.4. Substantial reduced aryl halide (i.e. ArH) is produced with Ni(0).

For related transformations (not all-inclusive):

C-H

alkylation of heterocyclic C-H

bonds:Hu and coworkers, Angew. Chem

. Int. Ed. 2010, 49, 3061.

RX (1.2 equiv)CuI (5 m

ol%)

LiOt-Bu (1.4 equiv)

dioxane, 140 °C, 16hX = Cl, Br, IR = 1

° alkyl

O NR

HetH

Het = oxazole, benzoxazole, thiazole,

benzothiazole, thiophene Nickamine (5 m

ol%)

ArI

Also seeAckerm

ann and coworkers, Adv. Synth. Catal. 2011, 353,

3325.

44 - 86%

Revisiting N

ickelJacob T. Edw

ardsB

aran Group M

eeting3/26/15

Heck R

eactions:

Branched-selective H

eck reaction:Jam

ison and coworkers, Angew. Chem. Int. Ed. 2014, 53, 1858.

R

ArXNi(cod)2 (10 m

ol%)

ligand (12 mol%

)TESO

Tf (2.0 equiv)DABCO

(3 - 5 equiv)PhM

e or THF, 60 °CX = Cl, O

Ms, O

Ts, OSO

2 NMe

2R = alkyl

R

Ar

54 - 97%>37:1 branched/linear

P+ H

P+

H2BF

4 -

Jamison and coworkers, J. Am

. Chem. Soc. 2011,133, 19020.

ClR

1

R2

(5.0 equiv)Ni(cod)2 (5 - 10 m

ol%)

CyPPh2 (10 - 20 m

ol%)

TESOTf (1.75 equiv)

Et3 N (6.0 equiv)neat, rt

R2 = H, alkyl

R1

R2

NiR

2P

proposed cationic intermediate

NiPCyPh2

PCyPh2

o-TolCl

For an air-stable precatalyst, seeJ. Am

. Chem. Soc. 2013, 135, 1585.

Ligand-controlled site selectivity:M

ontgomery and coworkers, J. Am

. Chem. Soc. 2010, 132, 6304.

O

Hn-hex

Me c-hexenyl

Ni(cod)2 (10 mol%

)L (10 m

ol%)

i-Pr3 SiH, KOt-Bu

c-hexenylM

en-hex

OTIPS

+

Me

c-hexenyln-hex

OTIPS

A, 97:3, 99%

B 9:91, 77%

NN

ArAr

LA R = p-Tol

Reductive coupling:

see Reductive Coupling (Young), Baran Lab Group M

eeting

H

OR

1

R2

R4

R3

Ni(cod)2 (10 mol%

)IPr•HCl (10 m

ol%)

KOt-Bu, M

eOH

THF, 50 °CM

eO

O

R1

R4

HR

2R3

X

OR

NiBr2 •3H2 O

(10 mol%

)PhM

e2 P (40 m

ol%)

i-PrOH, 60 °C

X

HOH

R

Use of m

ild reducing agents:M

ontgomery and coworkers, J. Am

. Chem. Soc. 2008, 130, 469.

NN

ArAr

R = 2,6-i-PrPh

Beaver and Jamison, O

rg. Lett. 2011, 13, 4140.

55 - 82%, 88:12 to >95:5 E/Z

Polymerization:

SI

Bri-PrM

gCl

THF, 0 °C

SClM

gBr

Ni(dppp)Cl2rt

S

C6 H

13C

6 H13

C6 H

13

nM

n = 3300 - 17200M

W /MJ = 1.10 - 1.26

H-T > 99%

Yokazowa and coworkers, J. Am. Chem

. Soc. 2005, 127, 17542.O

saka and McCullough, Acc. Chem

. Res. 2008, 41, 1202.

Proposed mechanism

:S

ClMg

BrNi(dppp)Cl2

rtC

6 H13

SL

n NiBr

C6 H

13

SClM

gBr

C6 H

13S

Ln

NiBr

C6 H

13

SBrC

6 H13

SBr

S

C6 H

13C

6 H13

NiLn

SClM

gBr

C6 H

13S

C6 H

13

Hn-1

SBr

C6 H

13

Ni(0)/Ni(II) catalysis.Transm

etallation is rate-limiting with dppp ligand.

Reductive elimination is rate-lim

iting with dppe ligand: see Lanni and McNeil,

J. Am. Chem

. Soc. 2009, 131, 16573.

68 - 99%

45 - 76%

NN

ArAr

LB R = 2,6-i-PrPh

PhPh

Revisiting NickelJacob T. Edw

ardsBaran G

roup Meeting

3/26/15O

ther transformations:

Addition to carbonyl groups (NHK coupling):Kishi and coworkers, J. Am

. Chem. Soc. 1986, 108, 5644.

CHO+

InBu

NiCl2TM

U(4.0 equiv)

[Cr *]

85% ee O

HnBu

Me

N

O

NtBu

CrS

OO

2-naphthyl

Enantioselective variant:Kishi and coworkers, O

rg. Lett., 2002, 4, 4431.

O

OO

BnOO

BnO

Bn

CHO

Me

Me

+

OTBDPS

OBn O

Bn

NiCl2 (0.6 mol%

)CrCl2 (6.0 equiv)

DMSO

, rt71%

, 1.3:1 dr

OH

O

OBn

BnO

BnO

OO

Me

Me

OTBDPS

OBn O

BnI

Ring construction (cycloadditions):7-m

embered rings:

Ni and Montgom

ery, J. Am. Chem

. Soc. 2004, 126, 11162Ni and M

ontgomery, J. Am

. Chem. Soc. 2006, 128, 2609.

MeO

2 C

MeO

2 C

NiCl2 (PPh3 )2 (20 m

ol%)

Zn (40 mol%

)H

2 O (20 m

ol%)

THF, 60 °C

NiBr2 •glyme (20 m

ol%)

Zn (40 mol%

)H

2 O (20 m

ol%)

THF, 60 °C

MeO

2 CM

eO2 C

MeO

2 C

MeO

2 C

CO2 M

e

CO2 M

e81%

(1:20)

97% (6.9:1)

8-mem

bered rings:W

ender and coworkers, J. Am. Chem

. Soc. 2007, 129, 13402.W

ender and coworkers, Angew. Chem. Int. Ed. 2009, 48, 2687.

Addition to CO2 (carboxylation):

Martin and coworkers, J. Am

. Chem. Soc. 2014, 136, 11212.

Reductions:

OXO

Bz

OM

eO

OPh

NaBD4 ,

NiCl2EtO

H94%X = I

ODO

Bz

OM

eO

OPh

Russell and Liu, Tet. Lett. 1989, 30, 5729.

RX

R = alkylX = Br, O

Ts

NiBr2 •glyme (10 m

ol%)

ligand 1 or 2 (22 - 26 m

ol%)

Mn (2.2 - 2.4 equiv)

CO2 (1 atm

)DM

F, 50 °C

RCO

2 HN

NR'

R'R' = M

e, Et

RZnX

[Ni(PCy3 )2 ]2 N2 (5 m

ol%)

CO2 (1 atm

)PhM

e, 0 °CR = aryl, alkyl

RCO

2 H

Yeung and Dong, J. Am. Chem

. Soc. 2008, 130, 7826.

NN

NiNi

Cy3 P

Cy3 PPCy

3

PCy3

Ni as a mild lew

is acid:Kyler and W

att, J. Am. Chem

. Soc. 1983, 105, 619.

THPO

Me

Me

Me

R

Me

Me

OH

NiCl2tBuO

H/H2 O

60 °C, 70%R = H, SM

eTHPO

Me

Me

R

Me

Me

OH

Me

Me

O

Me

TMSCHN

2(2.0 equiv)

Ni(cod)2 (10 mol%

)THF, 60 °C

69% (> 95:5 dr)

PhMe,

110 °CO

HMe

Me

TMS

75% (> 95:5 dr)

O

H

Me

TMS

Also see Oshim

a and coworkers, Org. Lett. 2008, 10, 2681.

Me

CO2 M

e

CO2 M

e

For catalytic process: Kishi and coworkers, Kishi and coworkers, Org. Lett., 2002, 4, 4435.

Revisiting N

ickel: Cross-coupling and M

oreJacob T. Edw

ardsB

aran Group M

eeting3/26/15

Applications in synthesis:

see Nickel in Synthesis (Guerrerro), Baran Lab G

roup Meeting

Some topics not covered (extensively or at all) for the sake of tim

e:1. Nickel and photochem

istry2. Ni-catalyzed cycloadditions3. Ni-catalyzed conjugate additions4. Reductive coupling5. O

lefin, alkyne, and diene functionalization6. Hom

o-reductive coupling of organic halides

Useful review

s/book chapters:Jam

ison and coworkers, Nature, 2014, 509, 299.M

ontgomery, O

rganometallics in Synthesis: Fourth M

anual (edited by Lipshutz).Jahn, Top. Curr. Chem

. 2012, 320, 323.Ananikov, ACS Cat. 2015 5, 1964.Hu, Chem

. Sci. 2011, 2, 1867.

Some key players in N

i chemistry:

isodomoic acids G

and HM

ontgomery and coworkers, J. Am

. Chem. Soc. 2009, 131, 17714.

O HNO

THPO

O

NO

O NO

O

Me

Me

Me

muscoride A

:Itam

i and coworkers, J. Am. Chem

. Soc. 2012, 134, 13573.

N OM

e

MeO

2 C

O N

Me O

PhON

Boc

Ni(cod)2 (20 mol%

)dcype (40 m

ol%)

K3 PO

4 (2.0 equiv)dioxane, 165 °C, 39%

+

O N

Me

NBoc

O

N

Me

MeO

2 C

O N

Me

NBoc

O

N

Me

OO

Me

Me

O N

Me

NO

N

Me

OO

Oi-Pr

NHM

e

Me

Me

Me

1. LiOH

2.Me

Me

OH

muscoride A

72%(2 steps)

Cp2 ClZr

Me O

TIPS

(3 steps from

D-serine methyl ester)

Ni(cod)2 (10 mol%

)ZnCl2 (20 m

ol%),

THF, 0 °C74%

N

OO

ONO O

Me Me

Me

OTIPS

Me

2 steps

NHHO

2 C

Me

CO2 H

Me

HO2 C

isodomoic acid G

(4 steps)

ONO

ON

OOM

eM

e

3 steps

3 stepsON

O

ON

OO

Me M

e

OTIPS

Me

I

OTIPS

Me

[Pd], CuI, i-Pr2 NH

83%

N

OO

ONO O

Me Me M

e

Me

Ni(cod)2 (10 m

ol%)

Me

2 ZnTHF, 0 °C

77%O

TIPS

NHHO

2 C

HO2 C

Me

Me

CO2 H

isodomoic acid H

2 steps

Asym

metric sp

2−sp3

Jacob T. Edwards

Baran G

roup Meeting

3/26/15

ElectrophileN

ucleophile[N

i]Ligand(s)

Reagents/

Additives/

Conditions

Ref.

Notes

R1O

Oalkyl

Br

RSi(OM

e)3R = aryl, alkenyl

MeHN

NHMe

PhPh

NiCl2 •glyme

(10 mol%

)

(12 mol%

)

TBAT (2.0 equiv)dioxane, rt

First catalytic asymm

etricarylation of α-halo carbonyl

compounds

Fu and coworkers,J. Am

. Chem

. Soc. 2008, 130, 3303.

RX

alkylArZnEt

X = Cl, BrR = alkyl, TM

S

NiCl2 •glyme

(3.0 mol%

)N

N

OO

N

H

HH

H

(3.9 mol%

)

glyme, -20 °C

Smith and Fu,

J. Am. C

hem. Soc. 2008, 130, 12645.

Arylzinc halidesresulted in inferior yields/ee.

Ar

O

Br R1

Ar'ZnINiCl2 •glym

e (5 m

ol%)

NN

OO

N

OM

e

PhPh

MeO

(6.5 mol%

)

glyme/THF, -30 °C

Fu and coworkers,Angew. C

hem. Int. Edu. 2009, 48, 154.

R

O

Br R1

ArMgBr

NiCl2 •glyme

(7 mol%

)O

NN

OM

eM

e

PhPh

(9 mol%

)

glyme, -30 °C

Lou and Fu,J. Am

. Chem

. Soc. 2010, 132, 1264.

R

O

Br R1

Cp2 ClZr

R2

NiCl2 •glyme

(3 mol%

)O

NN

OM

eM

e

PhPh

PhPh

(3.6 mol%

)

glyme/THF, 10 °C

Lou and Fu,J. Am

. Chem

. Soc. 2010, 132, 5010.

N

O

Cl RAr

(9-BBN)NiBr2 •diglym

e (8 m

ol%)

MeHN

NHMe

F3 C

CF3

KOt-Bu (1.3 equiv)

i-BuOH (1.5 equiv)

PhMe, -5 °C

Lundin and Fu,J. Am

. Chem

. Soc. 2010, 132, 11027

(10 mol%

)

Asym

metric sp

2−sp3

Jacob T. Edwards

Baran G

roup Meeting

3/26/15

ElectrophileN

ucleophile[N

i]Ligand(s)

Reagents/

Additives/

Conditions

Ref.

Notes

NN

OO

N

H

HH

H

(3.9 mol%

)

Ralkyl

OCO

2 Ar 1Ar 2ZnI

NiCl2 •(PCy)3 (13 m

ol%)

glyme/THF (1:1)10 °C

Fu and coworkers,J. Am

. Chem

. Soc. 2012, 134, 2966.Propargylic chlorides

and bromides also work

NCR

1

BrR

2 ZnR = aryl, alkenyl

NiCl2 •glyme

(10 mol%

)O

NN

O

i-Pri-Pr

(13 mol%

)

THF-60 to -78 °C

5-exo-trig cyclizationdoes not occur

Fu and coworkers,J. Am

. Chem

. Soc. 2012, 134, 9102.

ArR

OM

sArZnI

NiBr2 •diglyme

(9 mol%

)ON

N OPh

Ph

MeO

OM

e

(13 mol%

)

LiI (4.0 equiv)CH

2 Cl2 /THF-40 °C

Gram

scaleZoloft synthesis.

Fu and coworkers,J. Am

. Chem

. Soc. 2013, 135, 16288.

R2 NH S

R1

OOBr

ArZnINiCl2 •glym

e (10 m

ol%)

O

NN

O

PhPh

Me

Me

THF, -20 °CM

ech. suggestsnon-cage radical interm

ediatesFu and coworkers,

J. Am. C

hem. Soc. 2014, 136, 12161.

Ar

O

X

alkylF

Ar'ZnClNiCl2 •glym

e (15 m

ol%)

O

NN

O

PhPh

PhPh

(16 mol%

)THF/diglym

e, -25 °CLiang and Fu,

J. Am. C

hem. Soc. 2014, 136, 5520.

X = Cl, Br

Ph2 Zn results in lower yield

O

NN

O

PhPh

Me

Me

(13 mol%

)

F3 C

alkyl

XArZnCl

NiCl2 •glyme

(6 mol%

)(7.8 m

ol%)

THF/diglyme, -20 °C

Liang and Fu,J. Am

. Chem

. Soc. 2015, 137, 9523.

O

NHN

O

Ar'Ar'

CN

2.2 mol%

Ar' = 4-t-BuPh

NiCl2 •glyme

(2 mol%

)R

BocHNCO

2 HArBr

[Ir[dF(CF3 )ppy]2 (dtbbpy)]PF

6 (2 mol%

)Cs2 CO

3 , blue LEDglym

e/PhMe, rt

Macm

illan, Fu, and coworkers,J. Am

. Chem

. Soc. 2016, 138, 1832.

Asym

metric sp

3−sp3

Jacob T. Edwards

Baran G

roup Meeting

3/26/15

ElectrophileN

ucleophile[N

i]Ligand(s)

Reagents/

Additives/

Conditions

Ref.

Notes

NPh

BnO

Br RR'ZnBr

R = 1° alkyl

NiCl2 •glyme

(10 mol%

)N

O

NN

O

i-Pri-Pr

(13 mol%

)

DMI/THF, 0 °C, 12 hr

Fischer and Fu, J. Am

. Chem

. Soc. 2005, 127, 4594.

R = alkyl

For R = Me,

%ee drops

(Et is much better)

X

RX = Cl, Br

R'ZnBrR = 1

° alkylNiBr2 •diglym

e (10 m

ol%)

NO

NN

O

i-Pri-Pr

(13 mol%

)

DMA, 0 °C

Arp and Fu, J. Am

. Chem

. Soc. 2005, 127, 10482.

R1

R3

Cl

R2

R'ZnBrR = 1

° alkylNiCl2 •glym

e (5 m

ol%)

NO

NN

O

BnBn

NaCl (4.0 equiv)DM

A/DMF (1:1), - 10 °C

(5.5 mol%

)

Son and Fu, J. Am

. Chem

. Soc. 2008, 130, 2756.NaCl increases rate(does not affect ee)

Aralkyl

BrR

(9-BBN)Ni(cod)2

(10 mol%

)

F3 C

CF3

MeHN

NHMe

(12 mol%

)

KOt-Bu (1.2 equiv)

i-BuOH (2.0 equiv)

i-Pr2 O, 5 °C or rt

Saito and Fu, J. Am

. Chem

. Soc. 2008, 130, 6695.

OR

XPhBnN

OR'

(9-BBN)M

eHNNHM

e

(12 mol%

)

NiBr2 •diglyme

(10 mol%

)KO

t-Bu (1.4 equiv)n-HexO

H (1.8 equiv)i-Pr2 O

, rtO

wston and Fu, J. Am

. Chem

. Soc. 2010, 132, 11908.

Asym

metric sp

3−sp3

Jacob T. Edwards

Baran G

roup Meeting

3/26/15

ElectrophileN

ucleophile[N

i]Ligand(s)

Reagents/

Additives/

Conditions

Ref.

Notes

Mechanistic

study suggeststransm

etallation is rate-lim

iting

Fu and coworkers,J. Am

. Chem

. Soc. 2011, 133, 8154.N

R1

Cl

Ar

RR

2(9-BBN)

Ar'Ar'

MeHN

NHMe

(12 mol%

)Ar' = 1-naphthyl

NiBr2 •diglyme

(10 mol%

)KO

t-Bu (1.2 equiv)n-HexO

H (2.0 equiv)i-Pr2 O

, rt

Y

OR

XR

'(9-BBN)

NiBr2 •diglyme

(10 mol%

)

PhPh

MeHN

NHMe

(12 mol%

)

KOt-Bu (1.4 equiv)

n-HexOH (1.8 equiv)

Et2 O/hexanes (1:1), rt

Irreversibleoxidative addition

X = Br, ClR = alkyl

Zultanski and Fu,J. Am

. Chem

. Soc. 2011, 133, 8154.

R1

R3

XR' = sulfone,

sulfonamide, carbm

ate

R'

(9-BBN)NiBr2 •diglym

e (10 m

ol%)

ArAr

MeHN

NHMe

(12 mol%

)Ar = Ph, 3-(F

3 C)C6 H

4

KOt-Bu (1.4 equiv)

n-HexOH (1.8 equiv) ori-BuO

Hi-Pr2 O

, rt

Oxygen atom

slikely bind to Ni to direct

Fu and coworkers,J. Am

. Chem

. Soc. 2012, 134, 5794.

ArR

XR'

ZnIR' = 2° alkyl

R2 = 1

° alkyl

R' = 1° alkyl

R' = 1° alkyl

NiBr2 •glyme

(10 mol%

)N

O

NN

O

i-Pri-Pr

(13 mol%

)

CsI (1.2 equiv)CH

2 Cl2 /dioxane-30 °C

Acyclic nuc.results in significantbranched product.

Fu and coworkers,J. Am

. Chem

. Soc. 2012, 134, 17003.

RX

R = 1° and 2° alkylX = Br, I

NBocZnI

NiCl2 •glyme

(15 mol%

)

Ar'Ar'

MeHN

NHMe

(17 mol%

)Ar' = 1-naphthyl

Fu and coworkers,J. Am

. Chem

. Soc. 2013, 135, 10946.First exam

ple of racemic

nuc. in enantioconvergentreaction

THF, rt

(9-BBN)Y

RX

R = 1° and 2° alkylX = Br

NiBr2 •glyme

(10 mol%

)

PhPh

MeHN

NHMe

(12 mol%

)

KOt-Bu (1.7 equiv)

i-BuOH (2.7 equiv)

i-Pr2 O/THF

-5 to 25 °C

Cong and Fu,J. Am

. Chem

. Soc. 2014, 136, 3788.