Rhodium-­Catalyzed  Borylation  of  Aryl  2-­Pyridyl  Ethers  through  Cleavage  of  the  Carbon–Oxygen  Bond:  Borylative  Removal  of  the  Directing  Group  J.  Am.  Chem.  Soc.,  Ar%cle  ASAP  DOI:  10.1021/ja511622e    James  Johnson,  Wipf  Group  Current  Literature  

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Transition  Metal  Catalyzed  C-­‐H  bond  transformations  

Chem.  Soc.  Rev.,  2011,  40,  5068–5083  

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HR

[MLn]XR

YR2

R

Y = Sn, Cu, Ni, Zn, etc

R2

Traditional cross-coupling

[MLn]

YR2

R

R2[MLn]

HR2

Direct cross-coupling Dehydrogenative cross-coupling

[Ox]

HDG

R

C-H activation

HR

HH

Y = Br, I, M

HR

Substrate  dependent  

Angew.  Chem.  Int.  Ed.  2012,  51,  10236  –  10254  

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Common  directing  groups  

HDG

[M]DG

FGDG

(Het)Ar (Het)Ar (Het)Ar

N N

NN N

O

NR

HN R

ON

ROMe CO2H OHn

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Adv  Synth  Catal.  2011,  8,  353  

Directing  groups  in  C-­‐H  activation  

Angew.  Chem.  Int.  Ed.  2011,  50,  2450  –  2494  

NR

R

H

NR

R

ArAr-X removal of DG?

R

ArH

NSOO

NH

CO2Me

NH

CO2Me

B NHN N

HSiEt3RuH2(CO)(PPh3)3

1)

2) HCl aq., RT, 2h

R

B(OH)2

R

SiEt3

Pd(CH3CN)2Cl2

1)

2) Zn, NH4Cl THF RT

CO2H

R

Pd(OAc)2AgOAc/AcOH

ArI

RAr

H1)

2) CuO, 1,10-phenNMP, 160 °C 24h

OH

R

RhCl(PPh3)PR2OAr or PR2Cl

ArX

OH

R

Ar

toluene, reflux

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2-­‐pyridylsilyl  directing  group  

Pd(OAc)2PhI(OR)2AgOAcDCE

100 °C, 8 h22 examples

SiR N

DCE 70 °C, 1 h

24 examples

SiR N

X iPriPr

iPriPr

SiR N

iPriPr

SiR N

NX iPriPr

Pd(OAc)2PhI(OR)2

NXS

SiR N

iPriPr

OR

OR2) Pd(OAc)2, PhI(OR)2

AgOAc, DCE, 80°C, 20 h

1) Pd(OAc)2, PhI(OR)2NXS, DCE, 50°C, 12 hSi

R N

NiPriPr

21 examples

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Angew.  Chem.,  Int.  Ed.  2011,  50,  2450  Chem.  Soc.  Rev.  2014,  43,  6906.  SynleQ  2013,  24,  145.  

Removal  of  2-­‐pyridylsilyl  group  

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Chem.  Soc.  Rev.  2014,  43,  6906  

2-­‐Aminopyridine  directing  groups  

NN

Pd(OAc)2AgNO3, BQ

tBuOH60°C, 24 h

ArBF3K

NN

Ar

24 examples

1) MeOTf, CH2Cl2rt, 24 h

2) NaOH, MeOHreflux, 12 h

HN Ar

ArNO2

OMe

80%

75%

70%

HNN

Pd(OAc)2Ag2O, BQ

THF80°C, 24 h

ArB(OH)2

HNN

Ar

15 examplesR R

1) Pd/C, H2, HCliPrOH, rt, 16 h

2) NH2NH2 AcOHiPrOH, 120°C, 2.5h

78% (2 steps)

H2N

N

O

N

Cu(OAc)2PivOHxylenes

150°C, 24 h

HetAr

35 examples

N

O

N

HetAr

NH

O

O

N1) MeOTf, CH2Cl2rt, 24 h

2) KOtBu, EtOHEt2O rt.

60%

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J.  Am.  Chem.  Soc.  2010,  132,  8270  Angew.  Chem.,  Int.  Ed.  2010,  49,  8729.  Angew.  Chem.,  Int.  Ed.  2013,  52,  10800.  

2-­‐Pyridyloxy  directing  group  

OPd(OAc)2PhI(OAc)2

Ac2O/AcOH100 °C, 12 h

R

20 examples

N

N OR N

NOAc

OPd(OAc)2

Cu(OTf)2, Ag2O

toluene, 120 °C, 24 h

R

20 examples

N

N OR N

NAr

ArB(OH)2

O1) BBr3, DiPEA

CH2Cl2, 0 °C, 12h

2) Et3N, rt,12hR

20 examples

N

OR NH B

O OHO OH

O MesCO2H, K2CO3

toluene, 120 °C, 20 h

R

23 examples

N

OR N

Ar[RuCl2(p-cymene)]2

F F

ArX

OPd(OAc)2, Ag2CO3

BQ (1 eq), DMSO (4eq)

CH2Cl2, 130°C48h

R

20 examples

N

OR N

ArArBF3K

heated in bomb

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9  JACS.  2000,  122,  12882  JACS.  2001,  123,  10935  JACS.  2012,  134,  12924  OL.  2014,  16,  2748.  J.  Organometallics  2013,  32,  272  

Deprotection  of  2-­‐Pyridyloxy    O

R NBO O

1) Cu(OAc)2, O2, 4Å MSCH2Cl2, 40°C, 15h, 60%

2) MeOTf, PhMe, 100°C, 2h3) Na/MeOH, reflux 30 min 70%

PhNH2

OH

NHPh

1) Pd(PPh3)4, PhMeNa2CO3, reflux 12h 90%

2) MeOTf, PhMe, 100°C, 2h3) Na/MeOH, reflux 30 min92%

OH

ON OMe

R1) MeOTf, PhMe100 °C OH OMe

R

2) Na/MeOH,reflux, 30 min

R = H, 81%R = F, 90%

ON NO2 1) MeOTf, PhMe100 °C 2 h OH NO2

2) Na/MeOH,reflux, 15 min

79%

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JOC.  2009,  74,  7203.  J.  Organometallics  2010,  29,  4058.  OL.  2012,  14,  1154.    

C-­‐O  bond  cleavage  

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Early  work  CN

Si2Me6[RhCl(cod)]2 5 mol%

ethylcyclohexane130 °C, 15 h

RSiMe3

R

38 examples

CN

ethylcyclohexane130 °C, 15 h

R R

13 examples

SiEt3

SiEt3Si2Me6

[RhCl(cod)]2 5 mol%

CNSi2Me6

[RhCl(cod)]2 5 mol%

ethylcyclohexane130 °C, 15 h

R

10 examples

XR2 R

XR2

Me3Si

CN

ethylcyclohexane160 °C, 15 h

RH

R

17 examples

HSi(i-Pr)3[RhCl(cod)]2 10 mol%P(O-i-Pr)3 (20 mol%)

CNXantPhos 20 mol%

[RhCl(cod)]2 5 mol%

DABCO 1 eq.toluene 100 °C, 15 h

RB

R

60 examples

OB

OB

O

O

O

O

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12  JACS.  2006,  128,  8152.  JACS.  2008,  130,  15982.  JACS.  2009,  131,  3174  Bull.  Korean  Chem.  Soc.  2010,  31,  582.  JACS.  2012,  134,  115  

Title  paper  

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Optimization  of  conditions  

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Optimization  of  conditions  

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Sequential  functionalization  

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C-­‐OPy  cleavage  

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CN

(SiMe3)2, PCy3[RhCl(cod)]2 5 mol%

ethylcyclohexane130 °C, 15 h

RSiMe3

R

O

N

O

NtBu

(SiMe3)2[RhCl(cod)]2 5 mol%

(SiMe3)2, IMes[RhCl(cod)]2 5 mol%

toluene, 100°C, 15h

toluene, 130°C, 15h

NR

NR

PhB(OH)2, PCy3[RhCl(cod)]2 5 mol%O

N

O

NtBu

PhB(OH)2, IMes[RhCl(cod)]2 5 mol%

toluene, 100°C, 15h

toluene, 130°C, 15h

NR

NR

B2(pin)2, PCy3[RhCl(cod)]2 5 mol%O

N

O

NtBu

B2(pin)2, IMes[RhCl(cod)]2 5 mol%

toluene, 100°C, 15h

toluene, 130°C, 15h

OH

OH

tBu

92%

90%

ON

B2(pin)2, IMes[RhCl(cod)]2 5 mol%

toluene, 130°C, 15h90%

NR

Deuterium  Exchange  

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O

NtBu

B2(pin)2, IMes[RhCl(cod)]2 5 mol%

toluene-d8, 130°C, 15h

O

NtBu

B(pin)

tBu

23% D3% D

73%

O

NtBu

B(pin)

tBu

17% D3% D

B2(pin)2, IMes[RhCl(cod)]2 5 mol%

toluene-d8, 130°C, 6h

21% 65%

2% D28% D 90% D

86% D

87% D78% D

O

NtBu

O

NtBu

IMes[RhCl(cod)]2 5 mol%

toluene-d8, 130°C, 15h

87%

10% D19% D 78% D

72% D

74% D78% D

Conclusions  •  Developed  Rh-­‐catalyzed  boryla%on  reac%on  for  Ar-­‐2-­‐pyridyl  ethers.  

•  A    new  applica%on  in  directed  C-­‐H  ac%va%on  that  can  be  used  as  a  handle  for  further  manipula%on.  

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OPivR

B2(nep)2,P(4-MeOPh)3[RhCl(cod)]2

toluene130°C, 15 h

BR O

O