The Nakamura Reaction

ENOLATE ADDITIONS TO ALKYNES: THE NAKAMURA REACTION O

O

O

R1

Cat. In +3 R3

R2

R4

R5

O

R3 R2 H

R1 R4

R5

BRAD GILBERT DENMARK GROUP MEETING

1

APRIL 29, 2014

EIICHI NAKAMURA University of Tokyo: Chairman, Dept. of Chemistry Born 1951 in Tokyo B.S. (T. Mukaiyama), Ph.D. (I. Kuwajima) at Tokyo Inst. of Tech. Post Doc. at Columbia (G. Stork) JACS associate editor

http://www.chem.s.u-tokyo.ac.jp/users/common/NakamuraLabE.html

2

>400 publications

OUTLINE • 

Introduction:

• 

•  Vinylation of active methylenes •  The Conia-Ene reaction •  Zinc enolate additions to alkynes The Nakamura Reaction:

• 

•  Representative example •  Mechanism and transition state model •  Scope of the intermolecular reaction •  Limitations of the methodology Applications of the Nakamura reaction: Group Problem—enantioselective applications Enantioselective applications Cycloisomerization—Indium catalyzed Conia-ene reaction Use of metals other than In(III) Modular synthesis Total synthesis

3

•  •  •  •  •  • 

INTRODUCTION: VINYLATION OF ACTIVE METHYLENES O

O

O

R1

R3

+

R2

R5

M cat.

O

R4

R3

1

R1 R 2 R4

R5 O

O

O

R1

R3

+

Br

Ar

CuI/L-Proline

R1

O R3

2

Ar O R

O Y

Lewis acid cat. / ∆

OO R

Y

3

1: (Indium) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264. (Rhenium) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett., 2005, 7, 4823.; (Iridium) Onodera, G.; Kato, M.; Kawano, R.; Kometani, Y.; Takeuchi, R. Org. Lett., 2009, 11, 5038. 2: Qian, W.; Pei, L. Synlett, 2006, 11, 1719. 3: (Rhenium) Kuninobu, Y.; Kawata, A.; Takai, K.; Org. Lett., 2005, 7, 4823. (Nickel/Ytterbium) Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang, D. Org. Lett., 2005, 7, 2185. (Palladium/Ytterbium)[enantioselective] Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc., 2005, 127, 17168.

4

"Conia-ene reaction"

INTRODUCTION: THE CONIA-ENE REACTION CH3 Ph

∆ / Lewis Acid

CH3 Ph

O

O CH3 Ph O H

•  Pericyclic [1,5] •  Thermal reaction infrequently utilized •  Some enantioselective applications (Toste) Ar

O (R/OR)

(DTBM-SEGPHOS)Pd(OTf) 2 10 mol% Yb(OTf)3 20 mol% AcOH, 10 eq. Et 2O, r.t., 3 - 36 hr.

Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc., 2005, 127, 17168-17169.

OO Ar

(R/OR)

70 - 85% yield 74 - 93% ee

5

O

ZINC ENOLATE ADDITIONS TO ALKYNES: DISCOVERY OF THE NAKAMURA REACTION Ar

O

Ar-NH2

R1

Ar

H 3O+

R1

E

N

R1 R2

E+

O

H 3C

CH3

O

OEt

Inspired by previous discovery of zinc enamide additions to unactivated alkenes

Ar

ZnBu

N

R1 R2 OH

Zn(acac)2 30 mol%

+

Zn(OTf)2 20 mol% Et 3N 20 mol%

+

CH3

72%

Ph O H 3C

100 ºC, 40 hr.

CH3

O

H 3C

120 ºC, 36 hr.

O

H 3C

ZnBu

R2

R2 O

N

R1

2) ZnCl2 3) BuLi

R2

E

Ar

1) LDA

R1

R2

O

N

1.2 equiv.

O OEt

H 3C Ph

51%

Nakamura, M.; Hatakeyama, T.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 11820. Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

6

“We felt it necessary to find metal countercations more powerful than zinc…”

CATALYST SCREENING O

H 3C

OEt

M(OTf)n 5 mol%

+

O H 3C

100 ºC, 3 hr.

CH3

O OEt

H 3C Ph

1.2 equiv.

Metal triflate 5 mol%

Yield (3 hrs.)

Catalyst 5 mol%

Additive 15 mol%

Yield (12 hrs.)

Hg(OTf)2

3%

InCl3

--

0%

Al(OTf)3

0%

InCl3

AgOTf

80%

Ga(OTf)3

14%

--

AgOTf

6%

In(OTf)3

100%

In(OTf)3

--

100%

In[N(Tf)2]3 *6 hrs.

--

100%*

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

7

O

OUTLINE • 

Introduction:

• 

•  Vinylation of active methylenes •  The Conia-Ene reaction •  Zinc enolate additions to alkynes The Nakamura Reaction:

• 

•  Representative example •  Mechanism and transition state model •  Scope of the intermolecular reaction •  Limitations of the methodology Applications of the Nakamura reaction Group Problem—enantioselective applications Enantioselective applications Cycloisomerization—Indium catalyzed Conia-ene reaction Use of metals other than In(III) Modular synthesis Total synthesis

8

•  •  •  •  •  • 

THE NAKAMURA REACTION: A REPRESENTATIVE EXAMPLE O O

H 3C

OEt CH3

In(OTf) 3 0.05 mol%

+

neat, 140 ºC, 3 hr.

H 3C

OEt H 3C

90%

1.2 equiv.

• 

90-93% yield

• 

Forms a large variety of quaternary centers in excellent yield

• 

“Perfect” selectivity for the 1,1-disubstituted alkene

• 

The alkyne serves a purpose in trapping triflic acid released during catalyst activation, necessitating a slight excess

Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E. Org. Synth. 2009, 86, 325.

9

O

O

THE NAKAMURA REACTION: MECHANISM H TfO In TfO O

Ph O

OEt CH3

1.2 equiv. OTf OTf In O O

TfO OTf In O O

TfO

H 3C

CH3

OEt

H 3C

O H 3C H 3C

OEt

H 3C H

Ph

CH3

TfO

CO 2Et In(OTf) 2 H

H

H 3O+

O H 3C

O CH3

O

O OEt

H 3C Ph

proto-demetalation

O

H 3C

OEt H 3C H

98%

17%

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

10

20 mol% In(OTf)3, ambient temperature, 16 hours.

MECHANISM: COMPUTATIONAL STUDIES OF THE T.S. Noteworthy features: •  Advanced formation of the CIn bond over the C-C bond •  Plane of symmetry containing the indium, methylene and alkyne.

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

11

Basis sets: B3LYP/6-31G* and LANL2DZ for In

MECHANISM: DEUTERIUM LABELING STUDIES D

O OEt

+

In(OTf) 3 20 mol% C6D 6 0.2 M 50 ºC, 40 hr. 36% conv.

H

O

10% D H 3C

O

O

+

OEt (H:D)

H 3C

O OEt (H:D) 20% D

Ph

43% D

(H:D)

50% D

O

H

D

O OEt

+

In(OTf) 3 1 eq. Et 3N 1.1 eq. benzene, 0.1 M reflux, 20 hr.

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

O

CO 2Et

Ph

(H:D)

23% D

(H:D) 83% D

80% yield

12

O

THE NAKAMURA REACTION: ASSESSMENT OF SCOPE O

O

O

R1

R3 Y

R2

O

O

In(OTf) 3 0.05 - 20 mol% neat or toluene 60 - 140 ºC, 1 - 60 hrs. additives: nBuLi, Et 3N, DBU O

O

OEt R = n-hexyl 77% R

Ph

• 

O

97% (cat. equiv. Et 3N and nBuLi)

Y R2 R3

O O

R = Ph 90% (with Et 3N)

R

O

O

X

OEt

R = n-hexyl 88% R = Ph 94%

R

O O O

93%

Ph

Ph

99% (cat. equiv. Et 3N and nBuLi)

Acid sensitive substrates saw improved yield with the addition of catalytic base

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

13

O

R1

OEt R = n-hexyl 84%

R = Ph 93% (with Et 3N)

Cl

X

O

THE NAKAMURA REACTION: ASSESSMENT OF SCOPE O

O

O

O

OEt

O

OEt

Y = O 79% Y = S 99% (with DBU)

Y

O

Ph

I

OEt

92% (In(NTf 2) 3)

R

C8H17

O

O

O

O

OEt

O

98% 92% 96% 97% N.R.

O

OEt

94%

R = p-OMe p-CF 3 o-Br p-CO 2Me p-NMe 2

OEt

98% (In(NTf 2) 3)

90% PhtN

C6H13 O

O OEt 80%

(with Et 3N) OBn

O

O OEt

94% only E isomer

SiPhMe2

O OEt 1 atm acetylene

94% (with DBU)

• 

Tolerates alkenes, benzyl and allyl ethers, phthalimides, esters, silanes, furans/thiophenes, and halides.

• 

Acid sensitive substrates saw improved yield with the addition of catalytic base

• 

Difficult substrates generally gave better yields with the triflimide (and at lower temperatures)

Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264.

14

O

LIMITATIONS OF THE METHODOLOGY •  Indium triflate catalysis is applicable to a broad range of dicarbonyls and alkynes, however: •  Conditions are highly variable (solvent, time, temperature, additives) •  High temperatures are generally necessary •  (Cheaper) indium salts other than the triflate and the triflimide are unreactive •  Conversely: Catalyst loadings can be as low as 0.05 mol% Ligandless Perfect selectivity for terminal alkynes Highly general formation of 1,1-disubstituted alkenes

15

•  •  •  • 

OUTLINE • 

Introduction:

• 

•  Vinylation of active methylenes •  The Conia-Ene reaction •  Zinc enolate additions to alkynes The Nakamura Reaction:

• 

•  Representative example •  Mechanism and transition state model •  Scope of the intermolecular reaction •  Limitations of the methodology Applications of the Nakamura reaction: Group Problem—enantioselective applications Enantioselective applications Cycloisomerization—Indium catalyzed Conia-ene reaction Use of metals other than In(III) Modular synthesis Total synthesis

16

•  •  •  •  •  • 

GROUP PROBLEM: ENANTIOSELECTIVE REACTION

CO 2Et OH

s-Bu

OMe

In(OTf) 3 10 mol% nBuLi 10 mol% 120 ºC, 4 hr. MeO

AcOH/H2O THF

17

NH 2

ENANTIOSELECTIVE ADDITIONS: FORMING A CHIRAL QUATERNARY CENTER R 4

R 3O OMe O R1

OMe

H

O

s-Bu

NH 2

OR3 R2

O

R2

N

R1

H s-Bu

In

O Me

s-Bu

NH

O

R1

OR3 R2

In(OTf) 3 10 mol% BuLi 10 mol% 120 ºC, 8 - 24 hr. R4

OMe H s-Bu

N R1

O

H 2O/AcOH

O OR3

THF

R2 R4

O

R1

OR3 R2 R4

Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492.

18

•  nBuLi was an additive for all enantioselective reactions

STEREOSELECTIVE AT HIGH TEMPERATURES

Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492.

B

“Such a temperature effect suggests that the selectivity is controlled by an entropy factor.”

ENANTIOSELECTIVE SCOPE Conditions:

O

O

H 3C Bn Ph O

18 hr OEt 85% 98:2 e.r.

1)  In(OTf)3 10 mol%, BuLi 10 mol%, 120 ºC, 8 – 24 hr. 2)  H2O/HOAc, THF O

O O

O

8 hr 84% 96:4 e.r.

CO 2Et

33 hr 84% 93:7 e.r.

CO 2Bn

34 hr 79% 82:18 e.r.

Ph O

H 3C

18 hr OEt 82% 97:3 e.r.

O

CO 2Et

12 hr 88% 94:6 e.r.

CO 2Et

12 hr 78% 97:3 e.r.

O

Ph

CO 2Et Ph

8 hr 92% 99:1 e.r.

O

O H 3C

O OEt

Bn

48 hr 72% 64:36 e.r.

C6H13

Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492.

19

O

THE CONIA-ENE REACTION

∆ / Lewis Acid

O

CH3 Ph O

CH3 Ph O H

20

CH3 Ph

THE CONIA-ENE REACTION Nakamura proposes metal-dependent modes of Conia-ene substrate activation. In his model, only Indium activates both the alkyne and the enolate. H O

O

O

“Enol” activation M = Sn, Ti O

H

O

M

Alkyne activation M = Pd, Au O

M M

Ene-yne activation M = Ni, Co, Re O

M

O

O

Two metals M, M’ = (Ag, Cu); (K, Cu); (Pd, Yb)*

M'

Double Activation by one metal M = In

*Toste – Pd(SEGPHOS)

Itoh, Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161.

21

O

M

FORMATION OF MEDIUM-SIZED RINGS R1 OC

Conditions A: In(OTf) 3 0.01 mol% neat, 60 ºC

CO 2R 2

n

MeOC CO 2Et

X

Conditions B: In(NTf 2) 3 1 mol% toluene, 40 - 150 ºC

R1 OC CO 2R 2 X

n

MeOC CO 2Me

PhOC CO 2Et I

MeOC CO 2Me Ph

B 91% MeOC CO 2Me

B 98% O

E

H

B 93% 96:4 d.r.

B 91%

E = CO 2Me

B 84%

Consistent with the syn-carbometalation and internal selectivity of the intermolecular variant. Larger rings undergo double bond isomerization. Itoh, Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161.

22

A 99%

FORMATION OF MEDIUM-SIZED RINGS O

O CO 2Me

HO

CO 2Me

Conditions B

CO 2Et

O

O

+

CO 2Me

OH CO 2Me

CO 2Me

+

OH

CO 2Me

N Ts

75% 23:77 exo:endo

61% 85:15 exo:endo

Consistent with the syn-carbometalation and internal selectivity of the intermolecular variant. Larger rings undergo double bond isomerization. Itoh, Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161.

23

74%

SHORTENING THE TETHER O R1

R2

CO 2Et

In(OTf) 3 1 mol% r.t., 4 hr. or In(NTf 2) 3 5 mol% 60 ºC, 24 hr.

+ R 3-NH2

R1 O

CO 2Et CO 2Et

H 3C

N

CH3

R2 R3

R1 N

H 3C CO 2Et

82% yield

N CH3

EtO 2C

R2

•  Yields >80%, typically around 95%

Tsuji, H.; Yamagata, K. –I.; Ueda, Y.; Nakamura, E. Synlett. 2011, 7, 1015.

24

•  Tolerates R1, R2 = aryl, aliphatic, silyl

USE OF CATIONS OTHER THAN In(III): Au-Ga “SYNERGISTIC CATALYSIS” •  Reaction proceeds at room temperature •  Similar catalyst loadings (0.01-3 mol% Au, 5-10 mol% Ga) •  Requires both Au and Ga to proceed O

R1

R3 R2

+

O

time, temperature

Fc

R4

4.0 equiv.

OH

CO 2Et 5% Au; 15% Ga

O

H 3C

CH3

O

2.5% Au; 5% Ga 24 hr., r.t. 81%

H 3C

86% Ph

O

O O CH3

Cy

3.3% Au; 10% Ga

CO 2Et 18 hr, 45 ºC

CO 2Me OH

24 hr., r.t. 52%

2.5% Au; 5% Ga 24 hr., r.t. 40%

Wang, Y. X.; Ye, X.; Akhmedov, N. G.; Petersen, J. L.; Shi*, X. Org. Lett. 2014, 16, 306.

O

CH3 Ph

3.3% Au; 10% Ga 24 hr., r.t. 92%

25

O

XPhosAu(TA)OTf (X mol%) Ga(OTf)3 (Y mol%) DCM

WHY THE SWITCH TO AN INTERNAL ALKENE? O

O

H 3C

CH3

+

XPhosAu(TA)OTf (2.5 mol%) Ga(OTf)3 (5 mol%)

CO 2Me

OH H 3C

O CH3

DCM, 24 hr, r.t. CO 2Me

O H 3C

O CH3

+

CF3

OH

XPhosAu(TA)OTf (2.5 mol%) Ga(OTf)3 (5 mol%)

H 3C

O CH3

DCM, 24 hr, r.t. F 3C

•  The article gives no mention of the unusual switch in selectivity •  Possibly due to delocalization of the alkyne into the ester

26

•  Could also be due to coordination by the ester to the Ga center

MODULAR SYNTHESIS: COUPLING TO IODIOALKENES O H 3C

O OEt

H 3C Ph

I

PdCl 2(PPh 3) 2 5 mol% CuI 5 mol% Et 3N 1.5 eq.

O

O

H 3C

THF, r.t., 4 hr. phenylacetylene, 1.2 eq.

OEt

99%

H 3C Ph Ph

O

In(NTf 2) 3 5 mol% toluene, 70 ºC, 4 hr.

O

H 3C

OEt CH3

Ph

I 1.5 eq.

Pd(PPh 3) 4 2 mol% K 3PO 4 3.0 eq. dioxane, 120 ºC, 36 hr.

O

O

H 3C

Phenylboronic acid 2.0 eq.

OEt H 3C Ph

91%

Ph

Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E. Org. Lett., 2008, 10, 1219.

27

•  E:Z selectivity 100:0 (Z isomer not detected) •  In(NTf2)3 does not interfere with Suzuki coupling conditions— one pot reactions work well •  Applies to the majority of dicarbonyl substrates previously mentioned, giving >80% yield in most cases

ADDITIONS TO ACETAMIDOMALONATE EtO 2C

+

NHAc

CO 2Et

In(OTf) 3 10 mol%

R

N-methylmorpholine 20 mol% 120 ºC, 16 hr. CO 2Et NHAc

EtO 2C

85%

NHAc

EtO 2C

NHAc

CO 2Et

R = p-Cl 59% p-MeO 67% 3,4-MeO 88%

NHAc

EtO 2C

CO 2Et NHAc

1) H 2, Pd/C 2) HCl, H 2O

Angell, P.; Blazecka, P.; Lovdahl, M.; Zhang, J. J. Org. Chem. 2007, 72, 6606.

73% E:Z 10:1

CO 2Et

R

R

57%

C 4H 9

CO 2Et

EtO 2C

R

CO 2Et

Ph

EtO 2C

NHAc

EtO 2C

NH 2.HCl HO 2C CH3 R

28

CO 2Et

NATURAL PRODUCT SYNTHESIS: THREE STEPS TO MUSCONE

O CO 2Me

O

In(NTf 2) 3 2 mol%

CO 2Me CH3

0.01 M in toluene 150 ºC, 18 hr.

27%

O

2) NaCl, DMF/H 2O, 150 ºC, 36 hr.

CH3

(±)-muscone 58%

Itoh, Y.; Tsuji, H.; Yamagata, K. –I.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161

29

1) H 2, Pd/C, EtOH, r.t., 3.5 hr

HETEROATOM-TETHERED MALONIC ESTERS X R

O H 3C n-Bu

CO 2Me CO 2Me

In(OTf) 3 5 - 15 mol% DBU 5 - 15 mol%

Y

Bn N

CO 2Me 83%

Bn N

CO 2Me CO 2Me

CO 2Me

R

CO 2Me

PMB

CO 2Me CO 2Me

toluene, reflux

PMB N CO 2Me

X

O

N

93%

41% H 3C CH 3

CO 2Me CO 2Me

71%

O

CO 2Me CO 2Me

74%

• 

Expands the scope of the intramolecular reaction

• 

Improves utility towards more complex natural product synthesis

(a) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244. (b) Hatakeyama, S. Pure Appl. Chem. 2009, 81, 217.

30

Y

NATURAL PRODUCT SYNTHESIS: EARLY-STAGE CYCLIZATION IN (–)-CINATRIN C1 MeO 2C OH

CO 2Me

CO 2Me

N2

BnO OBn

O

CH 2Cl 2 then 30% H 2O2 80%, d.r. 5:1

BnO

HO

toluene, reflux 96%

OBn

OBn O

CO 2Me

BnO

Rh 2(OAc) 4 0.5 mol% benzene, reflux 69%

OsO 4 10 mol% NMO, PhB(OH) 2

In(OTf) 3 5.5 mol% DBU 5.0 mol%

CO 2Me O O

O HO

O

CO 2H

HO CO 2H

OBn O BnO

CO 2Me CO 2Me

(−)-Cinatrin C1 24 steps 2% overall yield

Urabe, F.; Nagashima, S.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. J. Org. Chem. 2013, 78, 3847.

31

•  Chosen as a cyclization method to selectively form exo-methylidenes and avoid alkene rearrangement into conjugation.

NATURAL PRODUCT SYNTHESIS: (–)-SALINOSPORAMIDE A O

PMB AcO

N

2) toluene, 1 hr.

AcO

MeO 2C

93% ee

PMB PMB N CO 2Me

O

CO 2Me

O

H N

OAc

75% 72:28 isomeric mixture

NH

PhSeBr AgBF4

O

BnO

PMB N CO 2Me CO 2Me

BnOH

O

SePh

96%, 90% ee 1) AIBN, Bu 3SnH 2) NaBH 4

O

O

H N

3) DMP

O BnO H

CO 2Me

O

H

OH HO

OH

PMB N CO 2Me CHO

BnO

CO 2Me

PMB N CO 2Me CO 2Me

CO 2Me

H O

CO 2Me

O

CO 2Me

CHO

• 

O

In(OTf) 3 5 mol% toluene, 110 ºC

Salinosporamide A OH 21 steps

H N

O

OH Cl

O

The cyclization precursor underwent a spontaneous thermal conia-ene reaction, resulting in epimerization. In(OTf)3 converted the rest of the material to the cyclized product with the expected retention of configuration.

Takahashi, K.; Midori, M,.; Kawano, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem. Int. Ed. 2008, 47, 6244.

32

HO

1) (COCl) 2, DMF CH 2Cl 2, 0 ºC

FUTURE APPLICATIONS: LEWIS BASE CATALYSIS? OTf O TfO In O LB

CH3 CH3

OEt CH3 CH3

LB

O

R 3O

H TfO LB In O TfO O

CH3 OEt CH3

N

R1

Ph O

O

R2

In s-Bu

N

Y P R N N R

Ph CH3

O

OEt CH3

O

N R

In OTf TfO

• 

At present the reaction requires high temperatures in order to proceed to completion and in good yield

• 

Lewis base coordination could activate the indium enolate and increase reactivity

• 

Highly organized transition state could allow for asymmetric induction with a chiral Lewis base • 

O Me

Has already proven successful with a “tethered” lewis basic chiral auxiliary

33

LB

OTf O In O OTf

OEt

H TfO TfO In

R4

IMPORTANT RESOURCES Seminal papers: Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 13002. Endo, K.; Hatakayema, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264. OrgSyn: Fujimoto, T.; Endo, K.; Nakamura, M.; Nakamura, E. Org. Synth. 2009, 86, 325. Enantioselective: Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492. Reviews: Dénès, F.; Pérez-Luna, A.; Chemla, F. Addition of Metal Enolate Derivatives to Unactivated Carbon-Carbon Multiple Bonds. Chem. Rev. 2010, 110, 2366.

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Dagorne, S.; Bellemin-Laponnaz, S. Group 13 Metal-Mediated Organic Reactions. The Group 13 Metals Aluminium, Gallium, Indium and Thallium: Chemical Patterns and Peculiarities. 2011, 654.