Patrick Robichaux Tang Group University of Wisconsin-Madison Department of Chemistry Literature...

1

Patrick RobichauxTang Group

University of Wisconsin-MadisonDepartment of Chemistry

Literature Seminar04/28/2011

A Recent Inquiryinto the Preparation and Practical Application of

Benzyne

2

OverviewHistory Preparation

Regioselectivity Application

?

R

3



?

R

4

Evidence for Benzyne

Cl NEt2

NEt2

no isomerization in NH3 (l)

LiNEt2

NH3 (l), -38 oC

Reaction is fast even at such low temperatures

Br

LiNEt2

NH3 (l), -38 oC

Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290.

5

Neutral Benzyne Intermediate?

Cl= 14C

NH2

NH2KNH2

NH3

1 : 1

Evidence of neutralintermediate

Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290.

6

Singlet or Triplet?O

O

O

O

h

or h

or h

I

HgI

I

Hg

IPhPh

Ph Ph

O

Ph

Ph

Ph

Ph

gasphase

•hν = diradical?•Benzyne actually singlet• singlet-triplet splitting of 37.5 kcal/mol•lifetime at least 20 ms

Wittig, G.; Ebel, H. F. Angew. Chem. 1960, 72, 564.Wentrup, C. Aust. J. Chem. 2010, 63, 979.

7



?

R

8

Traditional Formation of Benzyne

H

X

X1

X2

X

OTf

Strong base: RLi, RMgX, etc.

X=halogen

Fluoride ion: Bu4NF, KF, CsF, etc.

SiMe3

OTf

SiMe3

I(Ph)OTf

Thermolysis

CO2-

N2+

CO2-

IPh

Oxidation: Pb(OAc)4, etc.

NN

NNH2

Kitamura, T. Aust. J. Chem. 2010, 63, 987.Wentrup, C. Aust. J. Chem. 2010, 63, 979.Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.

9

Synthesis of Silyltriflate

HO

i-PrN=C=O

Et3N, CH2Cl2 O ii. TMEDA, n-BuLi

-78 oC

i. TMEDA, TBSOTf

Et2O, 0 to 23 oC

NH

O

N

TBS

LiO

O

NN

TMSCl

acidic workupON

H

OTMS

DBU, Et2NH

CH3CN, 40 oCHO

TMSPhNTf2

23 oC

TMS

TfO66% yieldfrom phenol

OMe

MeO OH

NBS

CH2Cl2-78 oC

OMe

MeO OH

HMDS, THF, 70 oC

n-BuLi, then Tf2O

THF, -100 oC

Br

OMe

MeO OTf

TMS

67%63%

42% overall yield

Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74, 8842-8843.

Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224-1227.

Wu, Q.-c.; Li, B.-s.; Shi, C.-q.; Chen, Y.-x. Hecheng Huaxue 2007, 111.Himeshima, Y.; Sonada, T.; Kobayashi, H. Chem. Lett. 1983, 1211.Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002. 1454.

10

Activation DominoOH

SiMe3

NfF, Cs2CO3, 15-c-6

MeCN

ONf

Si

F

Cycloadditions

Nucleophilic additions

TM catalyzed Reactions

SO O

F F

F F

F FF

FF

Nf=

TBDMSO

OH

TMS

OTBDMSO

O86%

conditions

CsF (1.0 equiv.)

18-c-6 (0.60 equiv.)

MeCN (0.10 M)

50 oC, 2.5 h

OHO

86%

Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S. Org. Lett. 2011, 13, 1730.

•Silyl protecting group tolerant

11

OH

OPdX2, L

HXPd

O

O

L L CO2

PdL2 PdL2

New Method: C-H activation

•highly solvent and concentration dependent•Optimized conditions: Pd(OAc)2 (10 mol %)

Cu(OAc)2 (0.75 equiv.) 1,10-phenanthroline (10 mol %) K2HPO4 (2 equiv.) , TBAB (1 equiv.)

sulfonane, 4 Å MS

Cant, A. A.; Roberts, L.; Greaney, M. F. Chemical Communications 2010, 46, 8671-8673.

CHEAP!

<47% yield+ side products

12



?

R

13

Regioselectivity: StericsMe

>

Me

ArLiArLi

84%

16%

R

>>

R

ArLiArLi

100%

0% R = TMS, Ph,

MeO

MeOTMS

>>

TMS

ArLiArLi

100%

0%

Me Me

Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.

14

Regioselectivity: Sterics vs. Electronics

OMe

>>

OMe

ArLiArLi

addition favoured bysteric hinderance ofmethoxy group

100% 0%

OMe OMe2-biaryllithium intermediate stablized by methoxy group in ortho position

Ar

Li

Li

Ar


15

Regioselectivity: Electronics

OMe

>>

OMe

ArLiArLiaddition disfavoured by

steric hinderance ofmethyl group

100% 0%

OMe OMe2-biaryllithium intermediate stablized by methoxy group in ortho position

Ar

Li

Li

Ar

Me Me

MeMe


16

Distortion/Interaction Model

Cheong, P. H. Y.; Paton, R. S.; Bronner, S. M.; Im, G. Y. J.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267.Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.

127o127o

110o

122o122o

110o

internal bond angle NH2

119o

121o121o

110o

113o136o

H2N

NH

=

54

NR

125o

129o5

6NR

127o

129o6

7NR

135o

116o

17

Reactivity of Indolyne Systems

NH2

54

NR

5

6 NR

6

7NR

5

4

NR

54

NR

NHPhPhHN

R = MeH

Boc

12.56.48.3

:::

111

5

6NR

5

6 NR

+

+PhHN

PhHN

R = MeH

Boc

3.02.91.5

:::

111

91%93%84%

73%91%83%

6

7NR

67 N

R

+PhHN

PhHN

R = MeH

Boc

only13.8only

:::

-1-

91%79%66%

Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.

18



?

R

19

Nucleophilic Additions

20

Acyl-Alkylation of Arynes

TMS

OTf OMe

OO CsF (2.5 equiv.)

MeCN (0.2 M)

80 oC, 45-60 minCO2Me

O

OMe

OO

CO2Me

O O

O

OMe

H+

90%

Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.

21

Acyl-Alkylation of Arynes

O

O

OTf

TMS

OMe

OMe

EtO2C

O

O

O

OMe

OMe

EtO2C

+Cs-O

O

O

OMe

OMeEtO2C

+Cs-O

CsF (2.5 equiv.)

MeCN (0.2 M)

80 oC

O

O

OMe

OMe

EtO2C

O 57%

O

O

OMe

OMe

N Me

(+)-Amurensinine

Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752.

22

Indolines and Isoquinolines

O

NH

CO2Me

N

Boc

CO2Me

N

CO2Me

O

NCO2Me

Boc

Indolines

N

CO2Me

isoquinolines

BocHN CO2Me

87%

61%

Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558.

23

Indolyne: Regioselectivity Reversal

Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832.

NH

TMS

TfO

Br

NH

HN

OMe

OOH

O

CsF, CH3CN, 0 oC to rt NHBr

N

HN

OMeO

OH

O

62%

N

HN

O

NH

OH

indolactam V

NHBr

130o

124o

24Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chemistry-a European Journal 2002, 8, 2034.

E+ E Yield (%)

H2O H 75

Bu3SnCl SnBu3 67

PhCHO PhC(H)OH 69

Me2CO Me2COH 73

ClCO2Et CO2Et 73

PhCH-NPh PhCHNHPh 59

BrCH2CH2Br Br 61

Indole Synthesis

F

N BrMe

1. 3.3 equiv. t-BuLi, -78 to 20 oC

2. E+, -78 to 20 oC

3. H2O

F

N LiMe

F

N LiMe

N LiMe

Li

N

Li

MeNMe

Li

N

Me

E

25

Biaryl Synthesis

Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.

n-BuLi

Br

Cl

i-PrO Oi-PrBr

Oi-Pri-PrO

PCy2

Oi-Pri-PrO

n-BuLi

Cy2PCl

i-PrO Oi-Pr

Li Br

Cl

Li

Cl

i-PrO Oi-Pr

Li

Li

Oi-Pri-PrO

Br

Cl

Br

Oi-Pri-PrO

Negishi Coupling ligand

26

Cycloadditions

27

OTf

TMS

CsF (4.0 equiv.)

1,4-dioxane

N

Ts

[2+2]

110 oC

N

Ts

ring-opening: amide in an outward rotation

NTs

NTs18 h

95% yield

NTs

H

H

Enamide Cascade

Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666.

28

OH

Cl

Cl

NaH

DMF

(-)-mentholR O

OR*

R*O =O

F

F

F

F

F

BuLi, heptane

0 oC to rt, 12 h

F

F

F

F

R O OR**

F

F

F

F

OR* *R O(R,R) (S,S)

*

Chiral Ligands = L*

[4+2] Cycloaddition on Arene System

O

PhB(OH)2

[RhCl(L*)]2

(3 mol % Rh)

KOH (50 mol %)

1,4-dioxane/H2O

(10/1), 30 oC, 1 h

O

Ph

[RhCl(R,R)]2 97%, 99% ee (R)[RhCl(S,S)]2 94%, 99% ee (S)

Nishimura, T.; Nagaosa, M.; Hayashi, T. Chem.Lett.2008, 37, 860.

29

Metal Free Click Chemistry

SiO

Si SiO

Si PhI(OAc)2, TfOH

CH2Cl2, 0 oC to rt

SiO

Si

Si(OH)Me2

I(Ph)OTfi-Pr2NH, rt

CsF SiO

Si

N3Si

OSi N

NN

SiO

Si NN

N SiO

Si NN

N SiO

Si NN

N

SiO

Si NN

N

OMe Me Cl

NO2

56% 63% 80%

87%67%

Lin, Y.; Chen, Y.; Ma, X.; Xu, D.; Cao, W.; Chen, J. Tetrahedron 2011, 67, 856.

30Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784.

N

Ph HPh N

H

Ph

Ph

HN

NN

Ph

Ph

Ph

Ph H

Ph

Ph

Ph

Indole Synthesis

31

Transition Metal Reactions

32

3-Component Benzyne Coupling

O

O OO

OO

O

O

OMe

OMe

M

H

OOSiPh2t-Bu

O

OMe

OMe

OH

OH

OMe

OMe

O

SharplessEpoxidation

Three-ComponentBenzyne Coupling

OxidativeLactonization

RCM

O

O OO

O

Clavilactone B

Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.

33

3-Component Benzyne Coupling

O

O OO

O

Clavilactone B

Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.

OMe

OMe

F 1) n-BuLi, THF, -78oC

2)

-78 to 25 oC

MgCl

MeO

OMe

MgCl

OH

OSiPh2t-Bu

OMe

OMe

O

H

OOSiPh2t-Bu

O

-78 to -35 oC

65% total yield 2:1 d.r.

34

Catalytic Carbonylation

cat [(p-C3H5)PdCl]2

dppe, CsFCO, OAc

CH3CN

1 atm, 80 oC, 4 h

TMS

OTf

O

80%

Pd(OAc)Ln Pd(OAc)LnCO

Pd(OAc)Ln

O

OPd(OAc)Ln

PdLn + HOAc

Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2001, 123, 12686.

35

Pd-catalyzed

Heck:

Suzuki:

Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2005, 7, 2921.Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9, 5589.

I OTf

TMS

CO2t-BuCO2t-Bu

CsF (6 equiv.)Pd(OAc)2 (5 mol %)P(o-tol)3 (10 mol %)

MeCN, 45 oC, 4 h

63%

Br

Br

OTf

TMS

Cl

(HO)2B

Ph

CsF, MeCN, rt, 8 h

Pd(dba)2 / dppb

Ph88%

36

Conclusions

=

M-R

M

RComplex Skeleton

Image from google images

37

Acknowledgments

• Professor Weiping Tang• Tang and Hsung group• Kat Myhre• Practice Talk Attendees:

– Jenny B. Werness– Dongxu Shu – Wei Zhang– Renhe Liu– Xiaoxun Li – Dr. Xingzhong Shu– Suyu Huang– Andrew G. Lohse– Kyle Dekorver

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