Organic Pedagogical Electronic Network

Pyridine C–H Functionalization

The Sarpong LabUniversity of California, Berkeley

2014

N Transition Metal

HH

H NR

R X

Ubiquity and Importance of Substituted Pyridine Derivatives

N

N

NHN

Me

HN

O

NN

Me

Gleevec (Novartis)Antitumoral agent

NMe

N

Cl

MeO2S

Arcoxia (Merck)Treatment of Arthritis

NCl

S

HO2CMe OH

Me

Singulair (Merck)Treatment of Asthma

NMe

Me

OH

Cananodine

N

O

OH2N

MeO

N CO2H

MeH2NOH

OMeOMe

Streptonigrin

NN

S

CO2Me

SN

N

S

N

SHN

ONH

O

N

S

HN O

N

SMe N

H

O

H2N

O

Amythiamicin D

OMe

O

AcOO

N

Me

Me

O

OMe OH

AcOAcO OAc

OAc

OAc

Euonymine

Pharmaceutical Agents:

Bioactive Natural Products:

Approaches to Functionalize Pyridines

Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

1 - Nucleophilic Addition to Activated PyridinesNucleophilic substitution with halopyridines (SNAr)

Organometallic addition / oxidation

N X

X = F, Cl, Br

R M

NR

XM+ N R

- M-X

- Preactivation (often halogenation) required

N

R M

N R

- Oxidation step required- 2- and 4-substitution only- Functional group compatibility issues(use of Grignards or organolithiums)

L.A. NH

R NH

R

[ O ]

N

R

Approaches to Functionalize Pyridines

Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

2 - Metallation of pyridines / Addition of electrophiles

Approaches to Functionalize Pyridines

Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

3 - Transition-Metal Mediated (or Catalyzed) Functionalization of Pyridines

Cross-Coupling of Pseudonucleophilic Pyridines

N [M]

[M] = B(OR)2, SnR3, ZnX

Transition Metal Cat.

R X

N R

- Preactivation required- Stability/price issues of metallopyridines

Direct C-H Functionalization

N Transition Metal Cat.

HH

H NR

R X

- No stoichiometric wastes (M-X)- Increased Functional group compatibility- No oxidation step required

Grand Challenge: Control of the Regioselectivity – Direct C(2)-H Functionalization

Using stoichiometric amounts of early transition metals 1

1 – Regioselectivity relying on proximity of the metal (Pyridine Nitrogen as Directing group)

1. (a) Durfee, L. D.; Rothwell, I. P. Chem. Rev. 1988, 88, 1059. (b) Sadimenko, A. P. Adv. Heterocycl. Chem. 2005, 88, 111. (c) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.

2. (a) Fagnou, K. et al J. Am. Chem. Soc. 2009, 131, 3291. (b) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org. Chem. 2010, 75, 8180. (c) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683. (d) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Grand Challenge: Control of the Regioselectivity – Direct C(2)-H Functionalization

Pd-catalyzed Direct CH Arylation of Pyridine N-Oxides 2

2 – Regioselectivity relying on Bond Dissociation Energies

1. (a) Durfee, L. D.; Rothwell, I. P. Chem. Rev. 1988, 88, 1059. (b) Sadimenko, A. P. Adv. Heterocycl. Chem. 2005, 88, 111. (c) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.

2. (a) Fagnou, K. et al J. Am. Chem. Soc. 2009, 131, 3291. (b) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org. Chem. 2010, 75, 8180. (c) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683. (d) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

NO

H

HH

Calculated Free Energy of Activation

34.1 kcal/mol

36.3 kcal/mol

35.9 kcal/mol

Grand Challenge: Control of the Regioselectivity – Direct C(3)-H Functionalization

1. (a) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (b) Yu, J.-Q. et al., J. Am. Chem. Soc. 2011, 133, 19090.

2. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.

1 – Regioselectivity relying on p-basicity of pyridines (C-3 is the most p-basic position) 1

- Ligand driven isomerization(electron rich and hindered)

- C3 is most electron rich, Pd is thus closer to C3 in the p-donor form (directs CMD)

Grand Challenge: Control of the Regioselectivity – Direct C(3)-H Functionalization

1. (a) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (b) Yu, J.-Q. et al., J. Am. Chem. Soc. 2011, 133, 19090.

2. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.

2 – Regioselectivity relying on Bond Dissociation Energies (with EWG as ‘Directing’ groups) 2

Grand Challenge: Control of the Regioselectivity – Direct C(4)-H Functionalization

1 – Regioselectivity relying on Bond Dissociation Energies (with EWG as ‘Directing’ groups) 1

1. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.2. (a) Wei, Y.; Kan, J.; Wang, M.; Su, W.; Hong, M. Org. Lett. 2009, 11, 3346. (b) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377.3. Murphy, R. A.; Sarpong, R. Org. Lett. 2012, 14, 632.

Grand Challenge: Control of the Regioselectivity – Direct C(4)-H Functionalization2 – Regioselectivity relying on substrate bias

1. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.2. (a) Wei, Y.; Kan, J.; Wang, M.; Su, W.; Hong, M. Org. Lett. 2009, 11, 3346. (b) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377.3. Murphy, R. A.; Sarpong, R. Org. Lett. 2012, 14, 632.

N

(3 equiv) (1.5 equiv)

+

Ag2CO3 (2 equiv)ArCO2K (0.5 equiv)PivOH (0.6 equiv)

Pd(OAc)2 (5 mol%)

DMA, 120 °C, 10 h

HF

N

PhFF

F F

B(OH)2F

F F

71%

All other positions blocked 2

OTf

O

O H

NMeO

OMePd(OAc)2 (10 mol%)DavePhos (30 mol%)

K2CO3

DMF, 100 °C, 20 hO

O H

NMeOOMe

62% (2 steps)

Intramolecular example 3

Regioselective C(4)-H Functionalization of pyridine without substrate bias is still a challenge…

Problems

1. García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.2. Mousseau, J. J.; Bull, J. A.; Ladd, C. L.; Fortier, A.; Sustac Roman, D.; Charette, A. B. J. Org. Chem. 2011, 76, 8243.

3. Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964.4. Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127, 3648.

Please provide a reasonable mechanism that accounts for the observed regioselectivity, and explain what type(s) of approach was used to control this regioselectivity

Pd(OAc)2 (5 mol%)DavePHOS (10 mol%)

K2CO3 (3 equiv)

DMF, 100 °C

N

Me

Br

N

Me

93%

N

Me+

2.1 : 1

(a)

NCO2Et

(16 equiv) (1 equiv)

+

Ag2CO3 (0.5 equiv)Pd(OAc)2 (10 mol%)

phenanthroline (13 mol%)

DMF, 140 °C, 12 h N

CO2Et

73%

(c)

NNBz

AgOBz (3 equiv)PdBr2 (5 mol%)PAr3 (15 mol%)

Dioxane, 125 °C, 16 h

N

(2 equiv)

+

(1 equiv)

IN

Ar = 4-MeO-C6H4-

Br

Br

70%

NNBz

Br

(b)

N

(1 equiv)

+

Ru3(CO)12 (2 mol%)PPh3 (4 mol%)

Cs2CO3 (1.2 equiv)

t-BuOH, 150 °C, 18 h

I

(1 equiv)

N

36%

(d)

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Contributed by:

The Sarpong Lab

University of California, Berkeley, 2014