2007/09/08 Literature seminer

Tomoyuki Mashiko (M1 part)

Ate Complexes for Catalytic C-C Bond Forming Reaction
1/13

Organometallics
Lewis acid

Lewis base

B

R-Li
+

Al

Ate complex

R-MgX

etc

etc

R-Na
etc

Zn
Cu

R
R B- RR• Central metal is anionic.
The reaction proceeds as anioniccharacter is lost.

Generalization of Reaction Pathways for Ate Complexes
1) Non-Oxidative Charge Cancellation (Ligand Transfer)RM- (n)
R
R

R

R
M (n)
R-

<representative example>
LiAlH4, NaBH4...

M = B, Al, Zn etc

2) Oxidative Charge Cancellation (Non-Ligand Transfer)<representative example>RM- (n)
R
R

E+

R
(n+2)
M E
R
R

Gilman reagent
M = Cu
LiCuR2, R2Cu(CN)Li2...

OⅡ+ [LiCuR2]+

Ⅰ+

LiCuR2

O-

O-

Ⅰ

O
O

Li

+

RⅠ
CuR

Ⅲ

CuR2

RCu

R

0

Today's contents
1. Grignard Reaction for the Synthesis of 3°-Alcohol with Ate Complex
1-0 Introduction about Grignard Reaction of Ketone
1-1 Grignard Reaction of Ketone with Mg Ate Complex/ Zn Ate Complex (Prof. Ishihara and Dr. Hatano's work)

O
R1

RMgX+ 2RLi or RMgCl+ ZnCl2 (cat)

R2

OH
R
R2
R1

1-2 History About Zn Ate Complex
1-3 Perspective of Catalytic Synthesis of 3°-alcohol with Grignard Reaction

2. Cross Coupling Reaction of Alkyl Halide Catalyzed by Ate Complex
2-0 Introduction about the Relation between Cross Coupling and Ate Complex
2-1 Cross Coupling with Ni or Pd Ate Complex (Prof. Kambe and Dr. Terao's work)
NiCl2 (cat)Alkyl-R
Alkyl-X+
R-mNi Ⅱ
2-2 Cross Coupling with Cu Ate Complex (Prof. Kambe and Dr. Terao's work)
Appindix Other Representative Cross Coupling Catalyzed by Ate Complex

Li+

2/13

1 Grignard Reaction for the Synthesis of 3°-Alcohol with Ate Complex
1-0 Introduction about Grignard Reaction of Ketone

OH
R
R1
R2

O
+ RMgX

R1

R2~Reaction Mechanism~
1) Concerted reaction mechanism

O
RMgX +R1(MgX2)

R2

X

R
Mg

R2

X
Mg

RMgX

O
R1

X

R
Mg

R

RMgX
+

R

1

R

2

R2
R1

1

A

O

RMgX +XMgOOR2) Electron-transfer mechanism

R

R2

X

R
Mg

R

R2
O
1

R

R

RMgX

2

R

Grignard reagent
Basicity > Nucleophilicity

R2

OMgX R
R2
1

1

O HO R1

1

R1

RMgX

H
R2

HO H

MgX
O

1

R

R2

R1

R1
RMgX

4

HO R1

OMgX
R2
1

R2

<Classical solution>

R1

R1

RMgX-CeCl3 (1.3 equiv.)

R2

THF, 0 °C

OH
R
R1
R2

1)

O
R

1

Knochel et.al. Angew. Chem. Int. Ed. 2006, 45, 497-500
LnCl3• 6H2O

2LiCl
MS 4A

Table 1-1

LnCl3• 2LiCl(Ln = La, Ce, Nd)

CeCl3

2)

RMgX

R2

OH
5 (pinacol)

Iwamoto et.al. Tetrahedron Lett. 1985, 26, 4763, J. Am. Chem. Soc. 1989, 111, 4392-4398

OR2

R2 3 (aldol product)

R'

1

R2
R1

O
1

O
R1

1

B

<Byproduct>• Several byproducts are obtained.

XMgO

XMgO
R

<Problem>

R

R2+ CeCl3
RCeCl2R

2

weaker basicity• Although the preparation is rather difficult, THFsoluble lanthanide halides can be prepared. (0.3-0.5 M
solution in THF)
Superior promoters. (Table 1)(1.0 equiv.)• Hindered and enolizable ketones are1

successfully transformed into 3°-alcoholusing Knochel modification method.

2• Next, catalytic activation would bedesired.

3

Other approach fornucleophilicity > basicity

Ate complex!

1-1 Grignard Reaction of Ketone with Mg Ate Complex/ Zn Ate Complex (Prof. Ishihara and Dr. Hatano's work)

3/13

Org. Lett. 2005, 573-576
Scheme 1-1

Table 1-2
O
+ nBuMXPh
1 equiv.

THF,-78 °C, 5 h

Bu
+

O HO

Ph Ph

Ph
62%
50%
48%

7%
9%
27%

0%
8%
20%

99%
Bu3MgLi LiCl (7)82%Bu3MgLi (8)nBu3MgLi + Bpy (8 Bpy) 96%

0%
0%
0%

0%
0%
0%

BuLi
BuMgClnBu2Mgnn

Mg atecomplex

HO H
+

Ph

n

usual
alkylating
reagentnHOn<Preparation of Mg ate complex>
1) R2Mg + RLi

R3MgLi82) RMgX + 2RLi

R3MgLi + LiX

3) R2Mg + RLi

R3MgLi-+R3Mg Li2X
R3Mg- +Li·Bpy

Bpy

7
8 Bpy

R2

Reactivity;7>8> 8 Bpy

Bpy
Li
R
O
Mg
R
1R
R

R2

1·8

1·7

Bpy and LiX salt would increase the acidity of Li+. (Figure 1-1)

XLi
Li
R
O
Mg
R
R
R1

Figure 1-1♦ Hetero Mg ate complexes (R1R22MgLi, R1 ≠ R2) are also applicable.
R2 ; Dummy ligand. Me is best.
Scheme 1-2

O
R2

R1

i

Pr

t

Ph

92%(36%)

HO R
THF, -78 °C, 2 h

R1

R2

Pr

HO

n

Pr

HO

n

Ph

Ph

Ph

Ph

Ph

1.2 equiv.

HO Et

HO Et
Ph

+ RMe2MgLi • LiCl

Bu

89%(0%)HO Et

HO

α-NaphPh

94%(35%)i

87%(48%)>99%(15%)Bu

92%(0%)

Yields in the parenthesis ; RMgClin stead of Mg ate complex.

♦ Summary

O
R2
R

R
Mg

1R

R
Mg

R

XLi
Li
R
O
Mg
R
R
R1

R2

A
J. Am. Chem. Soc. 2006, 126, 9998-9999
O
1

R

HN
R1

R

ZnCl2 (10 mol%)R

2

RMgCl 1.3 equiv.)

H

THF, 0 °C or rt ,2-24h(up to 100 mmol)• Li+; More Lewis acidic. → The carbonyl moiety of ketone
become more electrophlic.

1·8

HO R
2

• Mg-; anionic → R's nucleophilicity increses.

1

R

2

R

HO NHR2
R1

H

Scheme 1-2 Highly efficient alkylation to ketones/andimines
with Grignard reagents catalyzed by ZnCl2

Table 1-3
HO

n

Bu

HO

Ph

Ph

Ph

74%(11%)
i

HO

i

HO

Et

Ph

Naph

85%(31%)

76%(35%)95%(56%)

Pr

i

Pr

i

HO

Pr HO

Pr

i

HO

i

• Zn(OTf)2 as strong Lewis acid was not effective.

Pr

This unique catalytic system should be based on R3ZnMgCl.

80%(20%)

Ph

i

OH

91%(40%)

Pr

PhHN

H

Ph

82%(28%)Figure 1-2 Proposed catalytic cycle and transition-state assembly

Et

Pr

S

PhHN

4/13

<mechanistic insight>

60%(43%)s

Bu PhHN

H

88%(44%)Ph

81%(29%)PhHN
H

86%(51%)

i

Pr

Ph

H

77%(33%)

Yields in the parenthesis ; RMgCl without ZnCl2 were used.

♦ They said asymmetric alkylation catalyzed by Zn ate complexes might be possible.
1-2 History About Zn Ate Complex
M. Isobe, T. Goto et. al. Chem. Lett. 1977, 679-682• First example trialkylzincate was used in organic chemistry.
O
O

K. Ohshima et. al. Chem. Ber. 1986, 119, 1581-1593'Heteroleptic ate complex'
OO1) LiRMe2Zn

LiR3Zn• Me is especially effective
as dummy ligand.

2) HClR
M. Uchiyama et. al. J. Am. Chem. Soc. 1997, 119, 11425
J. Am. Chem. Soc. 1997, 119, 12372

薬学雑誌, 2002, 122(1), 29-46<Heteroleptic ate complex for reduction of carbonyl moiety>R<Proof that Zn ate complex was reactive spiecies.>
two possibilities ; HMe2Zn- +Metal (Path A)
Lewis Acid + Metal hydride(Path B)
Scheme 1-3

Table 1-4

• If Zn hydride ate complex is active spicies, anti-diol 22 should
be obtained selectively.
Table 1-5
• Usually, LiH or NaH was used as base.
Basicity > Nucleophilicity
HMe2Zn-+Metal; Basicity < Nucleophilicity•Actually, anti-diol 22
was generated
mainly. (entry 1,2)

<Possible mechanism><Substrate generallity>

Scheme 1-4

5/13

LiH; 3 equiv.
Me2Zn; 30 mol%

• Enolizable
aldehydes weresuccessfully
reducted. (entry
2,3)
Carboxylic
acids werereducted toaldehyde.(enrty
9,10)• Considering this mechanism, Me2Zn should be catalytic.
<Trials with catalytic amount of Me2Zn>• Actually, Me2Zn works with catalytic amount.(5-10 mol%)
M. Uchiyama et. al. J. Am. Chem. Soc. 2004, 126, 10897-10903
1) DFT calculations about the structure of LiZnMe3
2) Ligand transfer selectivity of heteroleptic zincate Me2Zn(X)Li

1) DFT calculations about the structure of LiZnMe3• The gas phase calculations indicated MeLi and Me2Zn react to form a
trigonal planer complex with 24.2 kcal/mol exothermically.

Figure 1-3 The comparison between Me2Zn and Me3ZnLi

6/13(A) Energy diagram of the reaction
between Me2Zn and HCHO.
• Association complex CPi forms without muchenergy gain (3.6 kcal/mol) and with little change ofthe geometry.

Me2Zn +HCHO

• C-C formation occurs with activation energy of 19.9
kcal/mol. (← C-Zn > O-Zn)• The overall gain to form CPii is rather small (29.1
kcal/mol).
• This result is consistent with the experimental factthat R2Zn are inert in the carbonyl addition in a
nonpolar medium.
(B) Energy diagram of the reaction between
Me3ZnLi and HCHO.
• First, Me3ZnLi and HCHO form a Lewis
acid/Lewis base complex CPi-1.(15.9 kcal/mol)

Me3ZnLi +HCHO(Li coordination for carbonyl moiety)• Methyl groups bound to the lithium can migrate tocarbonyl carbon with a small activation energy.(8.0
kcal/mol from CPi-1)• The stabilization energy of the adduct,
Me2Zn(OCH2CH3)Li,CPii-1 is very large.(-53.1
kcal/mol)Figure 1-4 Charge change in 1,2-addition of Me3ZnLi to HCHO• The transfer of the Me group from Me3ZnLi to the carbonyl carbon
takes place as a single event.
negative charge
O of C=O
Me groupmonotonically increase
monotonically decrease toward zero.

• The charge of Zn remain especially constant.
→ The absence of any oxidation/reduction process in this reaction.
↔ different from the addition of Me2CuLi to an α,β- unstaturated
carbonyl compound.(Cu(I) → Cu(III))2) Ligand transfer selectivity of heteroleptic zincate Me2Zn(X)Li<Two possible structures of heteroleptic zincate>
X= H<Ligand-transfer selectivity for Me2Zn(X)Li>X; H= NR2 > SiR3 > alkyl
activation energy of
CPi to TS1 (kcal/mol)
H
NR2
SiR3
Me

Figure 1-5 Asymmetric and symmetric structures of Me2ZnHLi• Zn-H frequency between 2a and 2b must be different.
• Experimental data suggest 2a would be real structure of Me2ZnHLi .
→ Reaction pathway should be similar to that of Me3ZnLi.

3.1
2.7
6.1
8.0

7/13

1-3 Perspective of Catalytic Synthesis of 3°-alcohol with Grignard Reaction♦ Asymmetric version.
• Ligand transfer activity of alkyl group is very low.
• Ligand should be designed not to dessociate the chiral ligand.

∗→ Multidentate ligand is one of the possibility.

X
Me
O
Mg
R
R1
Zn
R2

• It might be possible to make chiral modification of counter cation(Mg2+, Li+).
cf. R3Mg-+Li·Bpy system

2. Cross Coupling Reaction of Alkyl Halide Catalyzed by Ate Complex
2-0 Introduction about the Relation between Cross Coupling and Ate Complex
About cross-coupling reaction → see. Dr. Maki's literature seminer 2006/03/18<Cross coupling reaction>
R-X

+

R'-m

R-R'

<Two reaction pathway>
Path B

Path AM

M

Cu (I)

R-R'

R'-m

R-R'

R-X

[M-R]-m+R M
highly anionic!!

R'
Cu (III)

Cu

(I)

M R
R M

R-X

R'-m

Figure 2-1 Cross-coupling via ate complex
J. K. Kochi, Synthesis, 1971, 303
Alkyl-X + R'MgX

X

R'

Alkyl -R'
Li2CuCl4R'MgX; high reactivity→ low functional group tolerancy.
• Ni or Pd ate complex (Prof. Kambe and Dr. Terao's work)→ 2-1
NiCl2 (cat)Alkyl-R
Alkyl-X + R-m

Figure 2-2 Cross-coupling via oxidative addition
J. K. Kochi et. al. J. Am. Chem. Soc. 1971, 93, 1487
R-X + R'MgX
FeCl2 or FeCl3
R = Alkenyl<Representative cross coupling>· Kumada-Tamao· Negishi· Stille· Suzuki-Miyaura· Hiyama· Sonogashira

R-R'

MgX
ZnX
Sn
B
Si
R≡C-CuApplication for R = alkyl<Problem>• Cu ate complex (Prof. Kambe and Dr. Terao's work)→ 2-2• One-electron donating Co, Fe system. → Appendix• Oxidative addition is slow.
• Resulted alkyl complex is highly reactive.
→ β- hydride elimination > transmetallation<Solution>• Pd + bulky phosphine ligand(PCy3, PtBu2Me),NHC ligand.

2-1 Cross Coupling with Ni or Pd Ate Complex
Adv. Synth. Catal. 2004, 346, 905-908
Scheme 2-1 Three component reaction of Alkyl
halides, butadiene, and Ar-M

8/13

<Some control experiments>
Scheme 2-2 The relative reactivities of alkyl halides(8 mol%)1.0 eq.

X = Cl, Br, I

1.0 eq. 1.0 eq. 1.0 eq. 1.5 eq.

M = Mg or Zn

Table 2-1
• the reactivity of R; 1°<2°<3°→ Alkyl groups are transferred
as radical or cationic species.

• Unsubstituted 1,3-butadiene failed to afford the corresponding product.
• 2°,3°-alkyl-Cl was reactive although 1°-alkyl-Cl didn't give the desired product.
• C=CMgBr, PhB(OH)2 and PhC=CSn(nBu)3 were ineffective.

Scheme 2-3 Reverse combination of the reagent
from Table 1 Run 2

Scheme 2-5 A plausible reaction pathway
nickelate complex
(0)

16 e-

(I)

(0)

• Cumene was the major product via an intermediate 5.
→ The present three component reaction may notproceed through 5.

16 e-

14 e15 e-

Scheme 2-4 control experiment 3

run 1
run 2

run 1
run 2

• In run 1, the major product was
Ph-Ph (reductive coupling).
Alkyl-Br was recovered completely.
• In run 2, three component coupling productwas afforded in 41% yield.
→ Excess PhMgBr promoted the C-Br bond cleavage.

(II)

18 e-

• The nickelate complex 7 would act as an active electrontransfer reagent.
→ The generation of an alkyl radical and arylnickel(I) complex 8.

9/13

J. Am. Chem. Soc. 2002, 124, 4222-4223
Table 2-3 Substrate generality

Scheme 2-6 Ni-catalyzed cross-couplingwith 1,3-butadiene

Table 2-2
n

C10H21Br + nBuMgClcat. (3 mol%)n

C14H30additive
1.3 equiv. (1.0 equiv.)• entry 1; Optimized results• entry 2; Br on Ar ring remained intact.
• entry 8; X=Cl is OK.
<control experiment>
1) NiBr2 + nOct-MgCl
2 equiv.
• When Ni complex bearing phosphine ligands,
such as NiCl2(PPh3)2, NiCl2(dppp), were used,
the yield was 45% and 22%, respectively.
• Unsubstituted 1,3-butadiene shows the highest
activity.(entry 6-10)

25 °C, 15 min

NiBr2 + nOct-MgCl

45%

43%

0%

n

Oct-Ni-Br• The present coupling reaction does not involve oxidative
addition of alkyl halides to Ni(0).
n-DecylBr + Ni(COD)2

1,3-butadiene
THF, 0 °C

n-DecylBr• Oxidative addition didn't occur.

Ni(0)

NiCl2

1-octene + octane + hexadecanen

BuMgCl2)
A radical pathway would
be ruled out.
Ni (II)

R-R'

R'-MgX

11

Ni(0) reacts with 2 equiv. of 1,3-butadiene to afford bis-π-allyl Ni
complex. (oxidative cycloaddition)

(II)

-

R Ni
R'
R'

13
R-X

Ni

→ Less reactive to R-X but readily reacts with R'-MgX to form 12.

(II)

+

MgBr

12

Figure 2-3 A plausible reaction pathway

The complexation for 12 might enhance nucleophilicity of Ni
toward R-X.
The central metal (Ni) in this catalyst system is always ...
d8, 16e-, plane structure.

♦ The difference between the condition of 3-component reaction and this cross coupling+ the presence/absence of phosphine ligand.
+ whether butadiene is substituted or not.
Scheme 2-6
Bidentate dppf ligand is bound strongly on Ni.
→ the supression of the formation of bis-allylnickel complex 11.
When substituents were introduced on butadiene skeleton,
formation of 11 became thermodynamically less favorable.

10/13

Angew. Chem. Int. Ed. 2004, 43, 6180-6182
Table 2-5 Functional group tolerancy
R'MgX; high reactivity→ low functional group tolerancy.

R'2Zn
n

C10H21-Br + Et2Zn
2 equiv.

cat. (3 mol%)dodecane

THF/NMP= 2/1,
25 °C, 48 h

Table 2-4

This catalyst system tolerates unsaturated heteroatom
functional groups, such as nitriles, ketones, amides,
esters.(enrty 1-4)
Table 2-6 Effects of additives(300)

Alkyl-F was reacted in this reaction system.
Tetraene 2b as additives; the yield was improved
dramatically.(entry 5)
In the case of 1,3- butadieneNi(0) center will react with more than 2 equiv. of 1,3butadiene .
The addition of MgBr2 increased the dodecane althoughside reactions could not be suppressed.(entry 2)
When tetraene 2a was used in stead of 1,3-butadiene,
this cross-coupling proceeded completely.(entry 16-19)
entry 18; the optimized condition.
Et2Zn 1.3 equiv.,9 mol% of 2a.

Chem. Commun. 2007, 825-827<the use of η3-allylnickel and η3-allylpalladium complexes
as catalyst>
Scheme 2-7

1) To prove the intermediary of bis(η3-allyl)nickel complexes.
2) Whether the ethylene tether between two ligand is essential or not.

→ Complexes composed of C12-butadieneoligomer units might be genarated.
Figure 2-4
Selective andefficient formation of 3
from Ni(0) and 2 would
facilitate the generationof 4.
→ accelerate thenucleophlic addition
that leads to 5.

Table 2-7

Table 2-8

1.3 equiv.

11/13

entry 3; 1-decene was obtained as a sole product.
entry 4
→ These results ruled out a radical pathway.
Pd or Ni complexes without η3-allyl ligands
were ineffective.(entry 1,2,5,6,9,10,13,14)
Mono(η3-allyl)metal complexes afforded a
successful result when MeMgBr was employed
but not in the case of nBuMgCl. (entry 3,7,11,15)

entry 5; Br on Ar ring was intact.

Scheme 2-9 a plausible reaction pathway

Scheme 2-8 control experiment

1 equiv.

Nearly equal amounts of octane andbis(η3-allyl)Pd complexes.
Possible products, 1-pentane or 1nonane by reductive elimination of an
allyl group were not formed.
→ Reductive elimination proceeds
preferentially with alkyl group than allyl(NMR yield) group.

2-2 Cu-catalyzed cross-coupling reaction

Table 2-10

J. Am. Chem. Soc. 2003, 125, 5646-5647
Scheme 2-10

Table 2-9
In entry 4,5 ; at -20 °C, the reaction proceeded slowly without significant
loss of catalytic activity in the absence of 1,3-butadiene.
→ 1,3-butadiene plays impotant roles in stabilizing an active species.

Scheme 2-10

the reactivity of R-X;
Cl< F< Br(the reason is not clear yet.)
R-Cl was almost
unreactive in this catalyst
system.

Angew. Chem. Int. Ed. 2007, 46, 2086-2089<Examination of the effect of 1-phenylpropyne>

Scheme 2-11

12/13

Figure 2-4 Time course of Cucatalyzed cross-coupling
reaction using different
amounts of 1-phenylpropyne
in THF under reflux.

R-Clwide availability
low cost

As the amount of additive wasincreased, the reaction rate at
early stage decreased.
When only 2 mol% of theadditive was employed, thecatalyst rapidly lost its activity
and reaction stopped.

Table 2-11

Scheme 2-12 competitive experiments

Scheme 2-14

the reactivity of R-X; Cl< F< Br
Scheme 2-13 site-selective sequential
cross-coupling

These results would ruleout a radical mechanism.

Scheme 2-15 the stereochemistry

The present reaction for primary-alkyl chlorides proceeds principallyby an SN2 mechanism.
Scheme 2-16 A plausible pathway
(I)
16 e-

1-phenylpropyne would stabilize the alkyl-copper complex to form thealkyne-alkyl-copper complex 11.
Increasing alkynes shifts the equilibium toward the formation of thecomplexes 13 or 14, which might be the resting states of the catalyst.

13/13

Appendix Other Representative Cross Coupling Catalyzed by Ate Complex
K. Ohshima et. al. J.Am. Chem. Soc. 2001, 123, 5374-5375<Cobalt-Catalyzed Tamdem Radical Cyclization and
Cross-Coupling Reaction>

Scheme 2-16 A draft mechanism

Table 2-12 Co-catalyzed phenylative radical cyclization

17e-

17e-

16e-

15e-

An active spicies would be the 17-electron-ate complex 17.
A single electron transfer from 17 to a substrate to yield an anion
radical of the substrate and Co(I) complex 18.
They also investigated the allylation, alkynylation with Co ate complex.
A. Furstner et. al. Angew. Chem. Int. Ed. 2004, 43, 3955-3957<Cross-Coupling catalyzed by Fe complex>
(-II)
R1
XMg
[Li(tmeda)]2[Fe(C2H4)4] 19
+
R3
X
R2
THF, -20 °C, 10 min

R1
R2

R3

X= Br, IOO+ PhMgBrI

19 (10 mol%)O

O

THF, -20 °C
85%

Ph

A consise mechanistic
interpretation is not yet possible.
2-iodoacetal derivative undergoes
ring-closure prior to cross-couplingseems to indicate a radical
intermediates.
→ This reaction pathway might be like
scheme 2-16.