iridium-catalyzed borylationof primary c(sp )-h bonds

Iridium-Catalyzed Borylation of Primary C(sp3)-H Bonds

2020.12.11

Reporter：Yu Yibo

Supervisor：Prof. Ma Shengming

Background01

022.1 Borylation of activated substrates

2.2 Borylation of unactivated substrates

2.3 Borylation of methane

03Summary and outlook

CONTENT >>

2

Background01





CONTENT >>

3

Background

Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2.

Well developed:

Less developed:

C-H bonds are stronger and less electron rich

4

RR

H

R

R R

R R

R

H

HH

H

RR

FG

R

R R

R R

R

FG

FGH

FG

benzylic C-H

allylic C-H

secondary C-H

tertiary C-H

R H

HH C-H Functionalization

R FG

HH

primary C-H

Background

Brown, H. C. et al., Pure & Appl. Chem. 1987, 59, 879.Aggarwal, V. K. et al., Chem. Eur. J. 2011, 17, 13124.Sigman, M. S. et al., Chem. Rev. 2011, 111, 1417.Morken, J. P. et al., Synlett 2018, 29, 1749.

H2O2, NaOH

or NaBO3R OH Oxidation

MeONH 2,

t-BuO

K

R NH2

CsF

or TBAF, H2 O

R H Protodeboronation

Amination

[Pd]BaseR'X

R R'Suzuki-Miyaura coupling

[Pd]R'X

Base

operational simplicityenvironmentally benign nature

thermal stability of the transmetalation agents

Application of Alkylboron Reagents:

5

R +O

HBO

[RhCl(PPh3)] RBO

O

R +O

HBO

[IrCl(cod)]2/dppe

HBcat

OBO

HBpin

R + HBBr2•SMe2-78 oC

Et2OR

BBr2•SMe2

R''OHB(OR'')2R

R''OH = H2O, alcohol or diol

R

Background

Tranditional Synthesis of Alkylboron Reagents:

(1) From Grignard and Lithium Reagents

(2) via Hydroboration

Cons: Multistep synthetic sequencesFunctionalized precursor

Limited functional group compatibility

Sigman, M. S. et al., Chem. Rev. 2011, 111, 1417. 6

Background

Hartwig, J. F. et al., Science 1997, 277, 211.

Hartwig, J. F. et al., Angew. Chem., Int. Ed. 1999, 38, 3391.


7

Background

8

Bergman, R. G. et al., J. Am. Chem. Soc. 1982, 104, 352.

Graham, W. A. G. et al., J. Am. Chem. Soc. 1982, 104, 3723.Graham, W. A. G. et al., J. Am. Chem. Soc. 1983, 105, 7190.

Background01





CONTENT >>

9

Borylation of activated substrates--Benzylic C-H

Ir

BpinN

N SiMe2Bpin

H

Hartwig, J. F. et al., Chem. Sci. 2014, 5, 694.10

R

Bpin

Bpin

A

ArBr (1 eq.)Pd[P(t-Bu)3]2 (5.0 mol%)

NaOH (3 eq.)THF/H2O, 70 oC, 16 h

ArI (1 eq.)Pd[P(t-Bu)3]2 (5.0 mol%)

CsF (2 eq.)THF, 70 oC, 16 h

B

(1.5 eq.)

R

Bpin

Ar RAr

TMSCl (1.2 eq.)KI (1.2 eq.)

H2O (1.2 eq.)CH3CN, 25 oC

SiMe2HR

Bpin

Bpin

Hartwig, J. F. et al., Chem. Sci. 2014, 5, 694.11


Hartwig, J. F. et al., J. Am. Chem. Soc. 2015, 137, 8633.12


Hartwig, J. F. et al., J. Am. Chem. Soc. 2015, 137, 8633.

IrNN Bpin

Bpin

SiEt3

I

TS-I

II

TSb-II

TSa-II

III

TSb-III

IV

0.0

24.1

17.3

24.9

28.0

11.3

15.6

4.5

+ PhCH3

IrNN Bpin

Bpin

SiEt3

Ph

H

IrNN Bpin

Bpin

SiEt3

Ph

H

IrNN Bpin

Bpin

SiEt3

Ph

H IrNN Bpin

SiEt3

HOR Ir

NN H

SiEt3

Bpin

+ PhCH2Bpin

IrNN H

Bpin

SiEt3

Ph

Bpin

IrNN Bpin

Bpin

SiEt3

Ph

H

IrNN Bpin

Bpin

SiEt3

Ph

H

Gsolkcal/mol

M06, LANL2TZ, 6-31++G**

13


IrNN Bpin

Bpin

SiEt3

IrNN Bpin

Bpin

SiEt3

Ar

H

IrNN Bpin

Bpin

SiEt3

Ar

H

IrNN Bpin

SiEt3

H

Ar Bpin

ArCH3

Turnover-Limiting Step

Et3SiBpin

Et3SiHI

II

III

IV



Suginome, M. et al., J. Am. Chem. Soc. 2012, 134, 17416. 15

R1Si

CH3

R2Cl

(4 eq.)1.2 mmol

B2pin2 (1 eq.)[Ir(OMe)(COD)]2 (2.5 mol%)

Me4phen (5 mol%)

cyclohexane80 oC, 12 h

i-PrOHEt3N

cyclohexane N NMe

Me Me

Me

Me4phen

55 (93)%a, 78%b 58 (77)%a

H3CSi

H3C Oi-PrBpin H3C

Sii-PrO Oi-Pr

BpinSi

H3C Oi-PrBpinSi

H3C

CH3i-PrO

81%

OSi

H3C Oi-PrBpinSii-PrO

H3C

H3C67%

a 1H NMR yield before isolated in the parentheses. b 120mmol scale.

selected examples:

82%

n-BuSi

H3C Oi-PrBpin

R1SiR2

ClBpin

R1SiR2

Oi-PrBpin

Borylation of activated substrates--Silanes

Himo, F. et al., Chem. Sci. 2015, 6, 1735.

M06, LANL2TZ(f), 6-311+G(2d,2p)

X

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“α-silyl effect”α-carbanion stabilizing effect of silicon

Suginome, M. et al., Organometallics 2013, 32, 617017


Reactivity: Ar-H > Ar-CH3 > Si-CH3 > alkyl-CH3

18

Control experiments：



Hyland, S.N. et al., Tetrahedron Letters 2019, 60, 1096

R1

O

NMe

BpinBCl3, CH2Cl2, -78 oC

then MeOH, H2O R1

O

NMe

BOH

OH

R1 = Me 91%t-Bu 74%

N

NO

NH O

HN B

OH

OH

Me

Me

Ph

Bortezomib (Velcade )

O

NH O

HN B

OH

OH

Me

Me

lxazomib (Ninlaro )

Cl

Cl

OBOH

CO2H

HNO

S

RPX7009 (Vaborbactam )

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Borylation of activated substrates

Background01





CONTENT >>

21

Sawamura, M. et al., J. Am. Chem. Soc. 2013, 135, 2947 22

Borylation of unactivated substrates

NMe

+ B2pin2[Ir(COD)Cl]2 (5 mol%)

n-octane, refluxN Bpin(3.5 eq.)

BpinBpin

N Bpin

BpinBpin

OMe

95 (81)%a

N Bpin

BpinBpin

<1%

MeO

N Bpin

BpinBpin

77 (52)%a

N Bpin

BpinBpin

NO2

1%

N Bpin

BpinBpin

57 (44)%aN Bpin

BpinBpin

2%

selected examples:

a isolated yield in the parentheses.

Sato, Y. et al., Chem. Commun. 2013, 49, 560123


Sato, Y. et al., Chem. Commun. 2013, 49, 560124



β-selectivity

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RX CH3

n RX

n Bpin

X = NR, O

B2pin2 (1 eq.)Ir( 6-mes)(Bpin)3

Me4phenKHF2

RX

n BF3-K+

RX

n Ar

[Pd]ArXN N

Me

Me Me

Me

Me4phen(9 eq.)

NEt

Me Bpin

84%

NEt

Et Bpin

103%

GC yield

NEt

n-Pr Bpin

108%Et:n-Pr = 83:17

NEt

n-Bu Bpin

129%Et:n-Bu = 86:14

NMe

n-Pr

69%n-Pr:Me = 96:4

Bpin On-Pr Bpin

146%Et:n-Pr = 85:15

On-Bu Bpin

130%Et:n-Bu = 87:13

Ot-Bu Bpin

112%

selected examples:



β-selectivity



2. C-HꞏꞏꞏO interaction1. Weak Lewis acid-base interaction

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1. Repulsive steric interactions

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3. C-HꞏꞏꞏO interactions

2. Weak Lewis acid-base interactions

β-selectivity


Suginome, M. et al., Chem. Commun. 2014, 50, 6333 29


Schley, N. D. et al., J. Am. Chem. Soc. 2020, 142, 6488

IrNN

X

X

postulated3-binding mode

MXX

5-Cp*

R

B2pin2 (1 eq.)[Ir(OMe)(COD)]2 (5 mol%)

Ligand (10 mol%)

neat, 120 oCBpin

N NMe

Me Me

Me

Me4phen82%

N N

L14%

N N

L220%

N N

L37%

F

N N

L4180%

F

N N

L548%

F

N N

L622%

F F

30


Schley, N. D. et al., J. Am. Chem. Soc. 2020, 142, 6488 31


R H

B2pin2 (2-3 eq.)[Ir(OMe)(COD)]2 (2.5 mol%)

2-mphen (5 mol%)

cyclooctane, 100 oCO: open vial under N2

R BpinN

N

2-mphenMe

MeBpin

8

O: 79 (65)%a

mono:di = 6:1

Bpin8

BpinOH

Bpin

O: (49)%a

+R

Bpin6

OO

R = H O: 60 (47)%a

Me O: 81 (54)%a

Br Bpin

Bpin

O: 58 (36)%a

N Bpin4

O: 73 (63)%a

a isolated yield in the parentheses.

selected examples:

limitimg reagent

Hartwig, J. F. et al., Science 2020, 368, 736.32



O+ B2pin2

(0.47 M)

(MesH)Ir(Bpin)3 (5 mol%)Ligand (5 mol%)

neat, 100 oC O

Bpin

N NMeD

D

DD D

D

D

2-mphen-d7

NN CD3

2-mphen-d3

NN Me

2-mphen

33


Background01





CONTENT >>

34

Borylation of methane

Poor selectivityOverfunctionalization

Mindiola, D. J. et al., Science 2016, 351, 1424.Sanford, M. S. et al., Science 2016, 351, 1421.

Challenge！35


Mindiola, D. J. et al., Science 2016, 351, 1424.

+ B2pin2

2068 kPaCH4

[Ir(OMe)(COD)]2 (1.25 mol%)L3 (2.5 mol%)

cyclohexane, 120 oC, 16 h-MeOBpin

N NMe

Me Me

Me

L3

H3C Bpin CH2(Bpin)2 HBpin O(Bpin)21 2 3 4

+ + +

N NL1

N NBpin

L2

Bpin

2.0%1:2 = 3.9:1

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Mindiola, D. J. et al., Science 2016, 351, 1424.

IrXX

Ir1/2 +N

N+ 2 R2B BR2

-XBR2

-X = OMe, ClR2 = pinacolate

IrNN

BR2BR2

BR2

IrNN

BR2BR2

BR2

CH3H

IrNN

BR2BR2

BR2

H2C H

IrNN

BR2BR2

BR2

a

b

b-TS

HCH3

IrNN

HBR2

BR2

BR2

CH3

cc-iso

IrNN

HBR2

BR2

BR2H3C

c-iso-TS

IrNN

HBR2

BR2 dH3C BR2

R2B BR2

H BR2

=

N N

N

N

37

Background01





CONTENT >>

38

Summary and outlook

Summary

39

Activated substrates:

R H

HH

Unactivated substrates ：

R H

HH

Summary and outlook

Summary

40

Unactivated substrates ：

R H

HH

Methane：

H3C H

IrNN

BR2BR2

BR2

HCH3

IrNN

HBR2

BR2

BR2

CH3

c c-iso

P P MeMe

MeMe

dmpe

Mindiola, D. J.

Summary and outlook

Outlook

1. The utilization of HBpin

2. The utilization of phosphine ligands

3. The borylation of tertiary C-H bonds

4. Metal-free

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Thanks for your attention

42

iridium-catalyzed borylationof primary c(sp )-h bonds

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