Palladium(0)-Catalyzed Directed syn-1,2-Carboboration and -Silylation

Literature Report IV

Engle, K. M. et al. Angew. Chem. Int. Ed. 2019, 58, 17068.

Reporter Checker

Date

: Yi-Xuan Ding : Zhou-Hao Zhu : 2019-11-18

CV of Prof. Keary M. Engle

Education and Employment: 2003–2007 B.S., University of Michigan

2008–2013 Ph.D., Chemistry, The Scripps Research Institute

2008–2013 D.Phil., Biochemistry, University of Oxford

2013–2015 Postdoc., California Institute of Technology

2015–Now Assistant Professor, The Scripps Research Institute

Research Interests: To advance the efficiency, effectiveness, and sustainability of organic small

molecules synthesis.

2

Contents

1

2

Introduction

3

syn-1,2-Carboboration and -Silylation Summary

3

Introduction

4

1,2-carboboration of alkenes

Cu-catalyzed

Ni-catalyzed

Pd-catalyzed

Coopera-tive

catalysis

Introduction

pinB Bpin+

R1 X SIMesCuCl

R4 R1

R4

(pin)BR2 R3

Cu(OAc)2 PCy3

R1

R3

pinB

R2

R1 = alkyl, benzyl, cinnamyl; R2, R3 = alkyl, aryl, H; R4 = boryl, phenyl, silyl

LCuOR

pinB Bpin(pin)BOR

LCu Bpin R R'

CuL

R'

pinB

R

CuL

R'

pinB

R

KOt-BuOt-Bu

K

LCuOt-Bu

R" X

R"

R'

pinB

R

pinB Bpin

(pin)BOt-Bu

A

Cu-catalyzed

Takaki, K. et al. Org. Lett. 2013, 15, 952.

5

Introduction

Ar + B2pin2[Cu]

Ar

[Cu]Bpin

Y

OP(OEt)2

O

Ar Bpin

Y

Ar = alkyl, heteroarylY = H, Me, Ph, Br 66-96% ee

L*

[Cu] + L*

L*Cu BpinpinBOMe

B2pin2

Ar

Ar

L*Cu

Bpin

LG

Cu∗

Ar

pinB

*L

LG

∗

Ar

pinB

L*Cu LG

B2pin2LiOMe

A

B

C

Yun, J. et al. Org. Lett. 2017, 19, 6144.

6

Introduction Ni-catalyzed

Ar1 R1Ar1 R1

Bpin

Ar2Ni

Ar2BrB2pin2KOEtDMA

Ni

Ar2BrB2pin2KOMetoluene Ar2 = 3,5-(Me)2C6H3

Ar1 R1

Ar2

Bpin

5 mol% NiCl2(DME)B2pin2 (2.0 equiv)PhBr (1.5 equiv)

NaOt-Bu, THF/DMA

R

pinBRPh

pinBR[Ni]via:

Brown, M. K. et al. Angew. Chem. Int. Ed. 2019, 58, 10956.

Brown, M. K. et al. J. Am. Chem. Soc. 2019, 141, 9391.

7

Introduction

NiCl2(DME)B2pin2KOR

2 KCl2 ROBpin

2 KCl2 ROBpin [Ni(II)]

[Ni(I)] XX = Cl, Br

pinBOEtLiX

LiOEtB2pin2

[Ni(I)] Bpin

Me

Ar1

[Ni(I)]

Bpin

Me

Ar1

[Ni(III)]

BpinAr2

Br

Comproportionation

Ar2Br

Ar1

Me

Bpin

Ar2

[Ni(0)]

[Ni(II)]Ar2

Br

Ar2Br

Me

Ar1

[Ni(II)]

Ar2

Br

Ar1

Me

Ar1

MepinBOMe

KBr

KOMeB2pin2

Me

Ar1

[Ni(II)]

Ar2

Bpin

Ar1

Me

Ar2

Bpin

DMAToluene

A

B

C

D

Brown, M. K. et al. Angew. Chem. Int. Ed. 2019, 58, 10956.

8

Introduction Pd-catalyzed

N2BF4

Ar1

Ar2

+Pd(0)

Ar1

Ar2PdLn B2pin2

Ar1

Ar2Bpin

R1NH

O

R2 N

+ H [C] + B2pin2

5-10 mol% Pd(OAc)21-2 equiv KF

10-20 mol% BQHFIP, O2 (1 atm), 60 oC(AQ)

[C]

O

R2R1

Bpin

AQ

Song, Q. et al. Org. Lett. 2016, 18, 5460.

Engle, K. M. et al. J. Am. Chem. Soc. 2018, 140, 3223.

9

Introduction

LnPd(0) N2BF4Ar2

PdLnAr2

Ar1

Ar1

Ar2PdLn

Ar1

Ar2PdLn

B2pin2

Ar1

Ar2Bpin

oxidativeaddition

insertionπ-allylformation

Ar1

Ar2

Ar1LnPd H

Ar1

PdLn B2pin2

LnPd(0)

Ar1

Bpin

AC

B

D

E F G

Song, Q. et al. Org. Lett. 2016, 18, 5460.

10

Introduction

PdIIXm

NH

O

N

N

O

NPdII

X

Pd(OAC)2

Nu H KX

HX

N

OK

NPdII

XNu

pinB Bpinbase

X BpinN

OK

NPdII

B(pin)Nu

Pd0Lm

HX

OBpin

AQNu

[O]

catalystreoxidation

ligandexchange

nucleo-palladation

trans-metalation

reductiveelimination

Engle, K. M. et al. J. Am. Chem. Soc. 2018, 140, 3223.

11

Introduction

GR

G Bpin

R

Ar2

cat. Pd/CuAr2 X B2pin2+ +

NaOMeG = Ar1 or CO2MeR = H or Me

Pd Cycle Cu CycleLPd0

Bpin

LPdII Ar1

Ar2

XLPdII

Ar2

Ar1

CuL'

Bpin

L'Cu X L'Cu OR

L'Cu BpinAr2 X

Ar1

Bpin

Ar2

M OR M X

pinB Bpin

pinB OR

Ar1

A

B

C

D

cooperative catalysis (Pd/Cu)

Nakao, Y. et al. J. Am. Chem. Soc. 2014, 136, 7567.

12

Introduction cooperative catalysis (Ni/Cu)

Ar1 RAr1 R

Bpin

Ar2Ni

Ar2 X B2pin2+ +Cu

X = Cl or OTs

Ni Cycle Cu CycleLNi0

ClLNiII

Ar2

Ar1

CuLR

LCu Cl LCu Ot-Bu

LCu BpinAr2 Cl

Ar1

Bpin

Ar2

LiOt-Bu

pinB Bpin

pinB Ot-Bu

Ar1

R

Ar1

Bpin

LNi

R

Ar2

LiCl

R

BpinA

B

C

D

Nakao, Y. et al. Org. Lett. 2016, 18, 3956.

13

Background and project synopsis

RNH

O

N(AQ)

B2pin2+ +cat. PdII

KF, HFIP, O2

RO

n

[C]

Bpin

AQ

n = 1 or 2 (indole)

n [C]-H

previous work: anti-carboboration via Wacker-type nucleopalladation (PdII/Pd0 cycle)

this work: syn-carboboration/silylation via Heck-type migratory insertion (Pd0/PdII cycle)

RNH

O

N(AQ)

[M]-Bpin+ +cat. Pd0/L R

O

n

[C]

[M]

AQ[C]-OTfn

n = 1 or 2

[C] = Aryl, Alkenyl, [M] = Bpin, SiMe2Ph

14

Optimization of 1,2-arylboration reaction

RNH

O

N(AQ)

OTf

B2pin2+ +

Pd2dba3 (10 mol%)Ligand (20 mol%)

base (2 equiv)100 oC

RO

n

Ph

Bpin

AQ

R = H, 1aR = Et, 1c 2a 3a 4a or 4c

Entry[a] Substrate Solvent Base Ligand Yield [%][b]

1 1a DMPU K2CO3 Cy-JohnPhos 61

2 1a DMPU KF Cy-JohnPhos 70

3 1a DMPU K2HPO4 Cy-JohnPhos 89

4 1a DMPU i-Pr2NEt Cy-JohnPhos 90

5 1a t-AmylOH KF Cy-JohnPhos 95

6 1a DMSO KF Cy-JohnPhos 15

7 1a toluene KF Cy-JohnPhos 89

8[c] 1a t-AmylOH i-Pr2NEt Cy-JohnPhos (98)

15

Optimization of 1,2-arylboration reaction

Entry[a] Substrate Solvent Base Ligand Yield [%][b]

9[c] 1c t-AmylOH i-Pr2NEt PPh3 trace

10[c] 1c t-AmylOH i-Pr2NEt CyPPh2 12

11[c] 1c t-AmylOH i-Pr2NEt RuPhos >99

12[c] 1c t-AmylOH i-Pr2NEt XPhos 98

[a] Reaction conditions: 1a or 1c (0.1 mmol), 2a (1.5 equiv), 3a (2 equiv), Pd2dba3 (10 mol%), Ligand (20 mol%), base (2 equiv), 4Å MS (15-30 mg), 100 ºC, N2, 16-20 h. [b] Yields were determined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as internal standard. Values in parentheses represent isolated yields. [c] Pd2dba3 (3 mol%), Ligand (6 mol%), 90 ºC.

16

RNH

O

N(AQ)

OTf

B2pin2+ +

Pd2dba3 (10 mol%)Ligand (20 mol%)

base (2 equiv)100 oC

RO

n

Ph

Bpin

AQ

R = H, 1aR = Et, 1c 2a 3a 4a or 4c

Alkene scope of 1,2-arylboration

RNH

O

Nn = 1 or 2n

(AQ)

OTf

B2pin2+ +

Pd2dba3 (3 mol%)L (6 mol%)

i-Pr2NEt (2 equiv)90 oC, t-AmylOH, 4 Å MS

(then [O])

RO

n

Ph

Bpin

AQPCy2

L

1a-q 2a 3a 4a-q

MeO

Ph

Bpin

AQPhOBpin

AQ

O

Ph

Bpin

AQMePh

OBpin

AQ

Me

O

Ph

Bpin

AQPhthN

O

Ph

Bpin

AQTsHN 4Ph

O

Ph

Bpin

AQ

BocHN

PhBpin

O

AQ

PhO

AQ

MepinB PhOBpin

AQMe Me

PhO

AQ

MepinB

Me Me

4a, 98% (±)-4b, 99% (±)-4c, 99%(from E-alkene)

(±)-4d, 97%(from Z-alkene)

(±)-4e, 87%(from E-alkene)

(±)-4f, 98%(from E-alkene)

4g, 96%(from E-alkene)

(±)-4h, 92%dr = 16:1

[b]

4i, 99% 4j, 92%[c] 4k, 61%[c]

17

Alkene scope of 1,2-arylboration

RNH

O

Nn = 1 or 2n

(AQ)

OTf

B2pin2+ +

Pd2dba3 (3 mol%)L (6 mol%)

i-Pr2NEt (2 equiv)90 oC, t-AmylOH, 4 Å MS

(then [O])

RO

n

Ph

Bpin

AQPCy2

L

1a-q 2a 3a 4a-q

O

AQPh

Bpin

Me O

AQPh

Bpin

Me

O

AQPh

Bpin NPhth

HN

Ph

OH O

N

(PA)

AQ

O

OH

Ph

(±)-4m, 85%(from Z-alkene)

4n, 99%dr = 1.2:1

4o, 99%dr = 2:1

4p, 70%[c,d] 4q, 54%[d]

[a] Reaction conditions: 1a-q (0.05 mmol or 0.1 mmol), 2a (1.5 equiv), 3a (2 equiv), Pd2dba3 (3 mol%), L (6mol%), i-Pr2NEt (2 equiv), 4 Å MS (15-30 mg), N2, 38-44 h. Percentages refer to isolated yields. Unlessotherwise noted, diastereomeric ratio (dr) was found to be > 30:1 in all cases. [b] 2a (3 equiv), 3a (3 equiv),Pd2dba3 (5 mol%), L (10 mol%), i-Pr2NEt (3 equiv). [c] 2a (2 equiv), 3a (3 equiv), Pd2dba3 (4.5 mol%), L (9mol%), i-Pr2NEt (3 equiv). [d] The final product was oxidized to the corresponding alcohol with NaBO3•4H2O (5 equiv) for ease of isolation.

O

AQPh

Bpin

4l, 98%

18

Electrophile scope

R1

O

n = 1 or 2n R2OTf B2pin2+ +

Pd2dba3 (3 mol%)L (6 mol%)

i-Pr2NEt (2 equiv)

90 oC, t-AmylOH, 4 Å MS(then [O])

R2

O

n

R1

Bpin

AQ

1a, 1c, 1l 2b-i 3a 4r-z

AQ

R2 = Aryl or Alkenyl

OBpin

AQ

Me

(±)-4r, 98%(from E-alkene)

OBpin

AQ

Me

(±)-4s, 99%(from E-alkene)

MeO OOH

AQ

Me

(±)-4t, 83%(from E-alkene)

F3C

OBpin

AQ

Me

(±)-4u, 98%(from E-alkene)

[X-ray]

O2N

OBpin

AQ

4v, 70%

NOBpin

AQ

N OOH

AQ

4x, 61%[c]

BocNOBpin

AQ

Me

(±)-4y, 86%(from E-alkene)

[b,c]

4w, 62%

[a] Unless otherwise specified, reaction conditions were as in Table 1. dr values were found to be >30:1 in all cases. [b] 2d (2 equiv), 3a (3 equiv). [c] The final product was oxidized to the corresponding alcohol with NaBO3•4H2O (5 equiv) for ease of isolation.

19

Dearomative aryl/alkenylboration

ROTf B2pin2+ +

Pd2dba3 (5 mol%)L (10 mol%)

i-Pr2NEt (3 equiv)

100 oC, t-AmylOH, 4 Å MS

1t-v 2a-c, 2i 3a 5a-f

X

AQ

O

X H

R

pinB

AQO

NMe

H

Ph

pinB

AQO

NAc

H

Ph

pinB

AQO

O H

Ph

pinB

AQO

O H

pinB

AQOOMe

O H

pinB

AQO

O H

pinB

AQO

[b](±)-5a, 63% (±)-5b, 66% (±)-5c, 86%

(±)-5d, 73%[c] (±)-5e, 87% (±)-5f, 72%

[a] Reaction conditions: 1t-v (0.05 mmol or 0.1 mmol), 2a-c, or 2i (3 equiv), 3a (3 equiv), Pd2dba3 (5 mol%), L (10 mol%), i-Pr2NEt (3 equiv), 4 Å MS (20-30 mg), N2, 38-44 h. Percentages refer to isolated yields. The diastereomeric ratio (dr) wasfound to be > 30:1 in all cases. [b] Reaction time of 96 h. [c] 1v (0.1 mmol), 2c (2 equiv), Pd2dba3 (4.5 mol%), L (9 mol%).

20

Scope of alkene aryl/alkenylsilylation

R1

O

R2OTf+ +

Pd2dba3 (5 mol%)L (10 mol%)

i-Pr2NEt (2 equiv)100 oC, DMF, 4 Å MS R1

O

R2

Si

AQ

1a, 1c, 1z 2a-d, 2g, 2i 3b 6a-i

AQ

R2 = Aryl or Alkenyl

Si BpinPh

MeMe

PhMeMe

O

Ph

Si

AQ

PhMeMe

PhOSi

AQ

PhMeMe

MePh

OSi

AQ

PhMeMe

n-Pr

OSi

AQ

PhMe

MeMeO

OSi

AQ

PhMeMe

Me

OMe

OSi

AQ

PhMe

MeOSi

AQ

PhMe

Me

F3C

OSi

AQ

PhMe

N

Me

6a, 79% (±)-6b, 71%(from E-alkene)

(±)-6c, 71%(from Z-alkene)

6d, 81%

(±)-6e, 72%(from E-alkene)

6f, 87% 6g, 68% 6h, 47%

[a] Reaction conditions: 1a, 1c, 1z (0.1 mmol), 2a-d, 2g, 2i (1.5 equiv), 3b (3 equiv), Pd2dba3 (5 mol%), L (10 mol%), i-Pr2NEt (2 equiv), 4 Å MS (20-30 mg), N2, 38-44 h. Percentages refer to isolated yields.

21

Diversification of arylborylated products

n = 1 or 2

1) Boc2O, DMAP, 60 oC, MeCN

2) pyrrolidine, tolueneR

O

n

Bpin

AQ

8a-c4c, 4j, 4l

R

O

n

Bpin

N

OBpin

N

PhMe

OBpin

NPh

O

N

Bpin

PhMe Me

(±)-8a, 93% 8b, 79%

8c

Ph

OBpin

AQ

(±)-4c (0.1 mmol)

Me100 oC, MeOH

Ni(tmhd)2

Ph

OBpin

OMe

(±)-9, 78%

Me

A

B

C

SelectfluorTHF

cat. AgNO3MgBr

2) I2/NaOMe

1)

8c, 84%

O

N

F

Ph

11, 37%

O

NPh

10, 87%

22

Summary

RNH

O

N(AQ)

B2pin2+ +cat. Pd0/L

i-Pr2NEt, t-AmylOH

RO

n

[C]

Bpin

AQ[C]-OTfn

n = 1 or 2[C] = Aryl, Alkenyl 54-99% yield

23

RNH

O

N(AQ)

PhMe2Si-Bpin+ +cat. Pd0/L R

O

[C]

PhMe2Si

AQ

[C] = Aryl

[C]-OTf

47-87% yield

Carboboration

Carbosilylation

24

The first paragraph

写作思路

阐述金属催化的 碳硼化反应的重要性

总结前人的工作 (催化体系、底物范围等)

The first paragraph

Metal-catalyzed 1,2-carboboration of alkenes is a powerful means of

simultaneously forming a C(sp3)-C and a C(sp3)-B bond in a single step

with multiple levels of selectivity control. Indeed, successful examples of

catalytic 1,2-carboboration have been developed with copper, palladium,

nickel, and dual catalyst systems. Of the various coupling

partners that can be engaged in 1,2-carboboration, organohalides and

pseudohalides are particularly important, given the structural diversity and

widespread availability of these electrophiles. In this area, classical

limitations have included the scope of compatible alkenes and associated

issues with regiocontrol; indeed, the vast majority of successful examples

involve activated alkenes, such as styrenes or norbornenes.

25

The first paragraph

Previously, Xiao and Fu developed a Cu-catalyzed regiodivergent 1,2-

alkylboration of non-conjugated terminal alkenes containing a proximal

heteroatom. Recently, Brown has developed an elegant series of nickel-

catalyzed 1,2-arylboration methods capable of functionalizing mono-, di-

and tri-substituted nonconjugated alkenes without formation of

competitive chain-walking products. These reactions are believed to

proceed via a NiI-Bpin intermediate, which generally delivers the Bpin

group to the less substituted carbon atom. With trisubstituted alkenes, the

reactions are highly regioselective, whereas with non-symmetric 1,2-

disubstituted alkenes and terminal alkenes, regiomeric ratios (r.r.) are

variable and controlled by a combination of steric and electronic factors.

26

27

The last paragraph

总结工作(完成烯烃的碳硼化和碳硅化)

底物范围广

反应可放大量

产物实用性强

可以合成手性产物

The last paragraph In conclusion, we have developed highly regio- and diastereoselective

carboboration and carbosilylation reactions of alkenyl carbonyl

compounds using a substrate directivity strategy. Compatible substrates

include alkenes with various substitution patterns and benzo-fused

heteroaromatics that react through five- and six-membered palladacycle

intermediates. These methods allow direct access to carbonyl products

containing boron and silicon groups at the β and γ positions. Furthermore,

an array of aryl and alkenyl triflates are suitable carbon electrophiles. The

reactions are scalable and operationally simple. Diversification of

arylborylated products was also demonstrated, showcasing the synthetic

versatility of the products. Finally, examples of diastereoselective 1,2-

arylboration using a chiral directing group were shown.

28

Representative examples

These methods allow direct access to carbonyl products containing

boron and silicon groups at the β and γ positions.

Furthermore, an array of aryl and alkenyl triflates are suitable carbon

electrophiles.

Previously, Xiao and Fu developed a Cu-catalyzed regiodivergent 1,2-

alkylboration of non-conjugated terminal alkenes containing a proximal

heteroatom.

Recently, Brown has developed an elegant series of nickel-catalyzed

1,2-arylboration methods capable of ……

Though useful in its own right, this method is limited in terms of the

carbogenic groups that can be introduced (indole-type nucleophiles) and

the alkene scope (terminal and 1,2-disubstituted alkenes).

29