qin yuan - chemistry

Recent Developments in Organometallic Diyne Cyclization

Reactions

Qin YuanMichigan State University

November, 23 20053:00 PM

R'

R"

SiR3

R'

R"

OH

R'

R"

O

SilylativeCyclization

Hydrative Cyclization

R'

R"

+R'

R"

Metathesis Cyclization/Addition

Others

Outline

C-C Bond Formation in Organic Chemistry

New Catalysis: Transition metal catalyzed C-C coupling reactions

C-C bond formation is the backbone of synthetic organic chemistry

Advantages:

1. Substrates are readily prepared by simple, high-yield reactions.

2. Substrates are stable toward many reaction conditions required

to assemble other portions of a complex organic molecule.

Metathesis vs Cyclization

R1

R2

R1

R2

R1

R2

+R1

R2

Diyne:Diene:

Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255

Fürstner, A. et. al. J. Am. Chem. Soc. 1999, 121, 11108Grubbs, R. H.; Hoppin, C. R. J. Am. Chem. Soc. 1979, 101, 1499

Metathesis:

Cyclization:

Chavan, S. P.; Ethiraj, K. S. Tetrahedron Lett. 1995, 36, 2281

R1

R2

+

R2

R2

R1

R2

R1 R1

Outline

R'

R"

R'

R"

+R'

R" SiR3

R'

R"

OH

R'

R"

O



Hydrative Cyclization Others

Availability of silanes

Reactivity of silylated carbocycles

Both C-C and C-Si bonds can be formed

Ni-Catalyzed Silylative CyclizationTerminal Diynes

H

H+ H-SiX3

1 mol% Ni(acac)2, DIBAL-H

benzene, 50oC, 6h HSiX3

H

H

Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478

Tamao, K.; Ito, Y.; Kobayashi, K. Synlett 1992, 539

SiMe2(O-i-Pr) toluene, refluxNPh

O

ONPh

14 h, 95%O

OH

H

(i-PrO)Me2Si

+

Entry Silane Yield (%)

1 H-Si(OEt)3 70

2 H-SiMe(OEt)2 68

3 H-SiMe2(O-i-Pr) 67

4 H-SiMeEt2 55

5 H-SiMe2(NEt2) 52

Z/E = 94:6

Reactivity Toward Electrophiles

SiMe2(O-i-Pr) toluene, refluxNPh

O

ONPh

14 h, 95%O

OH

H

(i-PrO)Me2Si

+

O YR H H

SiMe2PhRZRE

N YR H H

SiMe2PhRZRE

CO2R'RZ

RE YSiR3

R HO

LAR H

OMe+

R HO

LA

RO

R HN

LAR'O2C +

N O+

O YR

SiR3RZRE

YCOR

RERZ

R3SiNO Y

XRE

R YOH

RE RZ

R YOMe

RE RZR Y

NHCO2R'

RE RZ

[3+2][3+2]

RZ=H

+

+

Dihydrofurans

Tetrahydrofurans

Homoallylic Alcohols

CyclopentanesRZ=H

Homoallylic Amines

Pyrrolidines

Isoxazolines: X=HIsoxazoles: X=SiR3

HomoallylicEthers

Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293

Fleming Oxidation:

H2O2, KF, KHCO3NPh

O

OH

H

HO

DMF, r t, 10h, 57%

SiMe2(O-i-Pr) toluene, reflux, 14h

NPh

NPh95%

H

H

(i-PrO)Me2Si O

O

O

O

Reactivity Toward Oxidants

Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun., 1984, 29

Fleming, I.; Sanderson, P.E.J. Tetrahedron Lett. 1987, 28, 4229

Ph PhCO2Me CO2MePhMe2Si OH

1) HBF4, OEt22) m-CPBA, NEt3

SiMe2Ph SiMe2BF4 ArCO3HBase

H+BF4 Ar O O

(OMe)2Si

O_

OHHydrolysis

Tamao-Kumada Oxidation:

Ni-Catalyzed Silylative Cyclization

Terminal Diynes:

Internal Diynes:

H

H+

OO

H

HH-SiMe2(O-i-Pr)


benzene, 50oC, 6h, 73% HSiMe2(O-i-Pr)

H

H

Z : E ≥ 95 : 5

OO

H

H

CH3

CH3

+ H-Si(OEt)3 HSi(OEt)3

CH3

CH31 mol% Ni(acac)2, DIBAL-H

PPh3, toluene, 100oC, 12h22%



Ni-Catalyzed Silylative Cyclization

HSiMe2(O-i-Pr)

H

n-BuH

n-Bu+ H-SiMe2(O-i-Pr) 1 mol% Ni(acac)2, DIBAL-H

benzene, 50oC, 24h36%

HSiMe2(O-i-Pr)

n-Bu

H



R = n-BuSiX3 = SiMe2(O-i-Pr)

Not ObservedH

R HSiX3

R

H

+ H-SiX3

Ni (0)

H

RNi SiX3

H NiSiX3

R

H

H

Ni

HSiX3

RH

1

2

3

Ni vs Pt

1,7-diynes Silylated (Z)-1,2-dialkylidenecyclohexanes

1,6-diynes ?

Ni:

Pt:HSiX3

R

H

Pt-Catalyzed Silylative Cyclization of 1,6-Diynes

5 mol% 1a/B(C6F5)3HSiEt3, toluene110oC, 74%

MeO2CMeO2C

Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385

1a

N

NPt

Me

Me

Catalyst Scope

SiEt3MeO2CMeO2C

MeO2CMeO2C+

SiEt3

Z E18 : 1

SiEt3MeO2CMeO2C

CH3

MeO2CMeO2C

MeO2CMeO2CZ

I2/H2O77%

TFA63%

Substituted 1,3-dienes are formed

2.5 mol% (dba)3Pd2 CHCl3MeO2CMeO2C

HOAc, PPh3, PMHS

0oC r t

.MeO2CMeO2C

MeO2CMeO2C

OAc

+

52% 27%

3 mol% Rh(COD)2OTfBIPHEP, DCE, H2 (1 atm)

25oC, 68%MeO2CMeO2C

Ph

CH3

MeO2CMeO2C

Ph

CH3

Pd: Mild conditions, Mixed productsRh: Only S-cis-productPt: Mild conditions, forms both S-cis- and S-trans-product

Two steps

Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255Jang, H. Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875

SiEt3MeO2CMeO2C

CH3

MeO2CMeO2C

MeO2CMeO2CZ

I2/H2O77%

TFA63%

Synthetic Applications

SiEt3MeO2CMeO2C

O

O

+toluene, 110oC

12h, 89%

O

O

H

HEt3Si

MeO2CMeO2C

NC CN

NC CNSiEt3MeO2CMeO2C +

toluene, 110oC

12h, 85%MeO2CMeO2C

Et3Si

CNCN

CN

CN

Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207

NN

NPh

O

O

SiEt3MeO2CMeO2C +

toluene, 25oC

0.5h, 73% NNMeO2C

MeO2C

Et3Si

NPh

O

O

Pt-Catalyzed Silylative Cyclization of 1,6-Diynes

1b

N

NPt

Me

Cl

MeO2CMeO2C

SiEt3

SiEt3MeO2CMeO2C

SiO273%

Al2O383%

E:Z ≥ 30:1

Z:E = ~6:1


Catalyst Scope

MeO2CMeO2C

5 mol% 1b/

HSiEt3, 110oC

MeO2CMeO2C

SiEt3

Z:E = ~6:1

CF3

CF3

NaB 4


MeO2CMeO2C

SiEt3MeO2CMeO2C

+ HSiEt3

N

NMe

Me

Ar

Ar

B(C6F5)3, 1:1

PtMe

Me1c

N

NMe

Me

Ph

Ph

PtMe

Me

Pt-Catalyzed Silylative Cyclization of 1,6-DiynesCatalyst Scope

The rate appeared to decrease slightly with both the increasing electron densityand steric bulk of the ligand.

Entry Ar Temp

(oC)

Time

(min)

Yield

(%)

Z:E

1 Ar = C6H5 110 10 95 ≥30:1

2 Ar = C6H5 70 85 98 ≥30:1

3 Ar = 4-C6H4OMe 70 300 91 20:1

4 Ar = 4-C6H4Me 70 88 97 26:1

5 Ar = 4-C6H4CF3 70 43 88 ≥30:1

Entry Silane Time (min) Yield (%) Z:E

1 HSiEt3 10 82 26:1

2 HSiMe2t-Bu 20 73 21:1

3 HSiMe2Bn 15 74 ≥30:1

4 HSi(n-Bu)3 30 69 20:1

5 HSi(i-Pr)3 100 70 23:1


Pt-Catalyzed Silylative Cyclization of 1,6-DiynesSubstrate Scope

MeO2CMeO2C

SiR3MeO2CMeO2C

1c/B(C6F5)3, (1:1)

Silane, toluene110oC

1c

N

NMe

Me

Ph

Ph

PtMe

Me

The rate of the silylative cyclization decreased with increased steric bulk of silanes.

28:17710HSiEt34

21:13660HSiBu33

≥30:18010HSiEt32

29:17415HSiEt31

Z:EYield(%)

ProductTime(min)

SilaneDiyneEntry

MeO2CMeO2S

MeO2CMeO2S

SiEt3


MeO2CMe2N(O)C

MeO2CMe2N(O)C

SiEt3

O OSiBu3

EtO2CEtO2C

EtO2C

EtO2CSiEt3EtO2C

EtO2CEtO2C

EtO2C

Substrate ScopeSiR31c/B(C6F5)3, (1:1)

( )n

( )nn=1,2

HSiR31c

N

NMe

Me

Ph

Ph

PtMe

Me

A number of functional groups in the substrates are tolerated

Regioselectivity

1c

N

NMe

Me

Ph

Ph

PtMe

Me

MeO2CMeO2C

MeH

1c/B(C6F5)3

HSiEt3, 80% SiEt3MeO2CMeO2C

MeH

MeO2CMeO2C

MeH

SiEt3+

1 : 1.2

MeO2CMeO2C

MeMe

1c/B(C6F5)3


MeMe

MeO2CMeO2C

MeMe

SiEt3+

1 : 2.3

Silyl group is predominantly transferred to the more e- rich alkyne

Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778

MeO2CMeO2C

1c/B(C6F5)3


CO2MeCO2Me

single isomer

Rationale for Pt-Catalyzed Silylative Cyclization

PtSiR3N

N

EE

CH4

PtSiR3

NN

E

E

HR3SiE

E

PtNN

R3SiEE

EE

PtNR3Si

E

E

E

E

R3Si EE

HSiR3

III

IV

V

VI

N

Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385

PtMe

Me

N

N

B(C6F5)3Pt

MeN

NPt Me

SiR3

NN

EE

H

HSiR3Me

IIIE

E

E = CO2Me

Summary for Silylative Cyclization of Diynes

H

H+ H-SiX3 H

SiX3

H

HNi

Ni

Pt

(Z)

(Z)

Good Regio- & Stereo-selectivity

Good Regio- & Stereo-selectivity

SiX3

( )n

( )n

n=1,2Pt

+ HSiX3

Limitations: 1,7-diynes only, no reaction for 1,6-diynes

1,6-diynes & 1,7-diynes

Outline

R'

R"

R'

R"

+R'

R" SiR3

R'

R"

OH

R'

R"

O



Hydrative Cyclization Others

Ru-Catalyzed Hydrative Cyclization of Diynes

Ru

MeCNNCMeMeCN

PF6-

2

+

RR'

O

( )n

A new method:


?Aldol Condensation

Disadvantages: 1) Difficult and lengthy synthesis ?

2) Frequent protecting ?

3) More enolate ?

R'

R( )n

Method B

R

R'

O

( )nMethod A

O


X X

O5 mol% 210 vol% H2O/acetone2h, 60oC

O10 mol% 210 vol% H2O/acetone4h, 60oC, 60%

OO

O7 mol% 210 vol% H2O/acetone2h, 60oC, 58%

Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516

Entry Substrate Yield (%) 1 X = C(CO2Me) 2 91

2 X = TsN 99

3 X = O 92

4 X = CH2CH2 70

Ru

MeCNNCMeMeCN

PF6-

2

+

Both 5- and 6- membered rings with a range of functionality can be formed

Hydrative Cyclization of DiynesVS

Intramolecular Aldol CondensationO

OO

OOAldol Condensation

O O+

78.7% 4.5%

O

+

OAldol Condensation

Nearly an equimolar mixture of products.Not a good synthetic method.

Hydrative Cyclization of Diynes:

Intramolecular AldolCondensation:

Danishefsky, S.; Zimmer, A. J. Org. Chem. 1976, 41, 4059

Ru

MeCNNCMeMeCN

PF6-

2

+

5 mol% 210 vol% H2O/acetone2h, 60oC, 70%

Mechanistic Rationale

Ru

MeCNNCMeMeCN

PF6-

2

+X

R

XR'

R"( )

n

2 X( )n

R

R"R'X

O

OMeTsNTsNR

R

5 mol% 2, 2 h10% MeOH/DCM90%R= Me, t-Bu


X Ru

XR"R'

Ln( )n

R +

CpRu+

H+

H2O

X Ru

XR"R'

Ln( )n

R +

X Ru Ln( )n

R OH

X( )n

RuOH

R"R'X

R

LnCp

Cp Cp

CpR"R'X

H+

I II

III

IV

TsNOTsN 5 mol% 2, acetone

2 hr, r t, 74%

OH

X = H, alkylR, R’, R” = H, alkyl

Os-Cyclopentatriene

OsNH2

H2N NH2

H2N

H2O

H H

Os

NH2

NH2

H2N

H2NH3CC CCH3acetone

5 67

8

I II

2+ 2+

NH2C(CH3)3Os H

H3C CH3H3C H

H

H2NNH2

H2N

H2N

2+

III

Taube, H.; Pu, L.; Hasegawa, T.; Parkin, S. J. Am. Chem. Soc. 1992, 114, 7609

Os-C(5): 1.940 Os-Vinylidene

Os-C(8): 1.931 Os-Vinylidene

C(6)-C(7): 1.357 C=C

C(5)-C(6): 1.461 C-C

C(7)-C(8): 1.448 C-C

II

Ru-Cyclopentatriene

Ru

MeCNSbPh3MeCN

+

RuSbPh3

+

CH3

CH H

H

CH3

CH3

A B

RuSbPh3

CH3H

H

H13 8

+

C

Bond Length: C(8)-C(13) 1.33

Kirchner, K.; Becker, E.; Rüba, E.; Mereiter, K.; Schmid, R. Organometallics, 2001, 20, 3851

C=C

Monitoring this reaction by 1H and 13C revealed the appearance of an intermediate consistent with B

C

Regioselectivity Studies

Ru

MeCNNCMeMeCN

PF6-

2

+

O O OO

O

5 mol% 2, 2 hr, 60oC

92% overall

2.8 : 1

+10% H2O/acetone


9710 mol% 230min

3

905 mol% 224 h

2

9710 mol% 22-8 h

1

Yield(%)

ProductConditionsSubstrateEntry

TsNTMS TsN

O

TsN( )

2TsN

O

TsNTsN

O

Complete chemoselectivity was achieved if the steric differences were made more significant.

(+)-Cylindricine C

N

OH

OHCylindricine C

NHR'

O

OR

2, H2O R"

NHR'

ORA1: R" =A2: R" = Me

NHBoc

OTBDPS

5 mol% 2

60oC, 2h, 90%10% H2O/acetone

Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599

NHBoc

OTBDPS

O

N

OH

OHCylindricine C

Ru

MeCNNCMeMeCN

PF6-

2

+

An efficient route to substituted 3-sulfolenes

SO

O

SO2

SEt

Et

O

O

10 mol% 2

60oC, 6h, 97% PrEtS

O

O

2 eq. H2O/acetoneO

Ru

MeCNNCMeMeCN

PF6-

2

+

Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097

Synthetic Application

Pr

EtS

O

O

O Microwave, 160oCPhMe, 90min

74% Pr

Et

O

SO

OS

O

O

O

SO

O

OOMeO

H

H

HMeO

O O

2, H2O/acetone

50%

methyl acrylate5% Grubbs II, PhH51% (63% brsm)

Microwave, 160oCPhMe

85%

Intramolecular Diels-Aldol Reaction:


Ru

MeCNNCMeMeCN

PF6-

2

+

Substrate Scope


SR1

R2

O

O

10 mol% 2

60oC R2

R1SO

O

2 vol% H2O/acetoneO

+R1

R2SO

O

ORu

MeCNNCMeMeCN

PF6-

2

+

18

636h4

8218h3

8120h2

7622h1

Yield(%)

ProductTime (h)SubstrateEntry

SO

O SO

O

O

SPh

O

O SO

O

O

Ph

S

O

O

OS

O

OO

O

S

O

O

O ( )2

SO

OO O

( )3

SO

OO

O

( )3

Unsymmetric dipropargylic sulfone substrates displayed very good chemoselectivity

Ru-Catalyzed Diyne Hydrative Cyclization

S

O

O

OS

O

OO

O

10 mol% 2

60oC2 vol% H2O/acetone

RuS OCp

O

ORuS O

Cp

O

O

+

RuS OCp

O

O

OH

RuSO

O

SO

O

[CpRu]+

H2OH+

CpLn

O

OH

ORu Ln

O

H+

Cp

+

I II

III IV

V

Ru

MeCNNCMeMeCN

PF6-

2

+


Substrate Scope


SR1

R2

O

O

10 mol% 2

60oC R2

R1SO

O

2 vol% H2O/acetoneO

+R1

R2SO

O

ORu

MeCNNCMeMeCN

PF6-

2

+

18

636h4

8218h3

8120h2

7622h1

Yield(%)

ProductTime (h)SubstrateEntry

SO

O SO

O

O

SPh

O

O SO

O

O

Ph

S

O

O

OS

O

OO

O

S

O

O

O ( )2

SO

OO O

( )3

SO

OO

O

( )3

Ru-Catalyzed Diyne Hydrative Cyclization

S

O

O

OS

O

O

O

10 mol% 2

60oC2 vol% H2O/acetone

O( )

3( )

2

RuS OCp

O

ORuS O

Cp

O

O

+

RuS OCp

O

O

OH

RuSO

O

SO

O

[CpRu]+

H2OH+

CpLn

O

OH

ORu Ln

O

H+

Cp

+

I II

III IV

V

( )2 ( )

( )( )

( )2

2

2

2

Ru

MeCNNCMeMeCN

PF6-

2

+


+ SO

O

O

O( )

363% 18%

A seven-membered Ru-cycle was formed which allowed H2O to add to the less hindered side to give the minor product.

Ru-Catalyzed Diynol Cycloisomerization

Ru

MeCNNCMeMeCN

PF6-

2

+

RX( )n

R2R1

O

Advantages:

Diynols are synthetically very simple and robust!

Ru-Catalyzed Diynol Cycloisomerization

RX( )n

R2R1

O

R3

Syntheses of Diynol Substrates

baseR1 R2

O OHR1

R2

OHR2

R1

R3MeO2CMeO2C

1) NaH, DMF2) NaH, DMF

R3

Br

X

( )

( )n

n

n

n( )( )MeO2C

MeO2C


Generally:

HOO

OOHO

DCC, DMAPDCM, 83%

Specifically:

Ru-Catalyzed Cycloisomerization of Tertiary Diynols

HO

O

HO

5 mol% 210 vol% acetone/THF1 eq. H2O, -20oC r t77%

2

Ru

MeCNNCMeMeCN

PF6-

2

+



OH

MeO2CMeO2C

HO

MeO2CMeO2C

1 mol% 2acetone, 1eq. H2O r t, 98%

Scott, W. J.; Kling, J.K.; Hettrick, C. M. J. Org. Chem. 1991, 56, 1489

Other synthetic routes to α,β,γ,δ-unsaturated ketones or aldehydes

EtO2CEtO2CEtO2C

EtO2C

+H Ph

O 5 mol% Ni(COD)210 mol% SIPr, toluener t, 78%

OPhEtO2C

EtO2CEtO2C

EtO2C

H

MeO2CMeO2C

+H Ph

O 5 mol% Ni(COD)2

10 mol% SIPr, toluener t, 91%

MeO2CMeO2C

PhO

Lousie, J.; Tekevac, T. N. Org. Lett. 2005, 7, 4037

Ni:

Chemoselectivity is not good.

OH

MeO2CMeO2C

HO

MeO2CMeO2C


Application of α,β,γ,δ-unsaturated ketones or aldehydes

Annulation:

Scott, W. J.; Hettrick, C. M. J. Am. Chem. Soc 1991, 113, 4903

O O

Bu Bu

Pd(PFu3)2Cl2toluene, 110oC, 83%

1) LDA

2) TMSCl

OTMS

Bu

Mechanism for Tertiary Diynols

Ru

MeCNNCMeMeCN

PF6-

2

+

OH

MeO2CMeO2C

HO

MeO2CMeO2C


XR

OHR'

R"( )

n

X Ru

OHR"R'

Cp

X Ru

R"R'

CpX Ru

R"R'

Cp

X Ru

R"R'

Cp

RX( )n

R'R"

O

( )

n

nn

n( )

( )

( )

R

RR OH

+

2++

+

H

CpRu +

H+

H2O

H+ H2O

RO

I

IIIII

IV



H2O Elimination

H2O Addition

Ru-Catalyzed Cycloisomerization of Tertiary 1,6-Diynols

XOH

X

O1 eq. H2O, r t

8954

9933

9022

9811

Yield(%)

ProductCatalyst 2(mol%)

SubstrateEntry

OHMeO2CMeO2C


HO

MeO2CMeO2C

OOH

O

O

TsNOH

HTsN

O

OH

O

Ru

MeCNNCMeMeCN

PF6-

2

+

Both terminal and internal alkynes were well tolerated

Rationale for Formation of Cyclopentadiene

RuCp

Ln

OH

+AcO Ru

CpLn

OH

2+

RuCp

Ln

OH

+ O

H+OAc

OAc

OH

O10 mol% 2, 1 eq. H2O

r t, 1h, 63%

OH

AcOO

10 mol% 2, 1 eq. H2O

r t, 1h, 40%


Ru

MeCNNCMeMeCN

PF6-

2

+

Propargyl acetate was eliminated as well. Functionalized Cyclopentadienes

Ru-Catalyzed Cycloisomerization of Tertiary 1,7-Diynols

OH

OMeO2CMeO2C MeO2C

MeO2C7 mol% 2, 1 eq. H2Oacetone, r t, 91%

OH( )3

OHH

O10 mol% 2

60oC, 90%

10 vol% H2O/acetone1 eq. Malonic acid


1,8-Diynols: Very low yield

OHMeO2CMeO2C

Ru

MeCNNCMeMeCN

PF6-

2

+

Ru-Catalyzed Cycloisomerization of Secondary Diynols

3

2

1

Entry

6010

705

702

Yield(%)

ProductCatalyst 2(mol%)

Substrate

OHMeO2CMeO2C

HO

MeO2CMeO2C


OHPh

MeO2CMeO2C

H

Ph

OMeO2CMeO2C

OHH

O

X OH

R

HX

R

O2, 1 eq. H2Or t, 1hRu

MeCNNCMeMeCN

PF6-

2

+

Secondary diynols cyclized to form the expected products as a single Z isomers

Mechanism for Secondary Diynol Cycloisomerization

XR

OHR'

R"( )

n

X Ru

OHR"R'

Cp

X Ru

R"R'

CpX Ru

R"R'

Cp

X Ru

R"R'

Cp

RX( )n

R'"R

O

( )

n

nn

n( )

( )

( )

R

RR OH

+

2++

+

H

CpRu +

H+

H2O

H+ H2O

RO

I

IIIII

IV

X OH

R'

HX

R'

O2

Ru

MeCNNCMeMeCN

PF6-

2

+


R=HR”=H

H2O Elimination

H2O Addition

Ru-Catalyzed Cycloisomerization of Primary Diynols

OH

MeO2CMeO2C

HO

MeO2CMeO2C

10 mol% 210 vol% H2O/acetone60oC, 45%

OH

MeO2CMeO2C

HO

MeO2CMeO2C

10 mol% 2acetone, 1eq. H2Or t, very low conversion

Ru

MeCNNCMeMeCN

PF6-

2

+


Primary Diynol

Tertiary DiynolOH

MeO2CMeO2C

HO

MeO2CMeO2C



Ru

MeCNNCMeMeCN

PF6-

2

+

OH

MeO2CMeO2C

HO

MeO2CMeO2C



OH

MeO2CMeO2C


O

MeO2CMeO2C

MeO2CMeO2C

1.5 : 1

OHO

+

Expected Product Hydrative product

Expected product : Hydrative product sensitive to reaction conditions and substrates

Carbons are pictured in the same spatial orientation

The two products didn’t interconvert: Submission of either isolated product to the

reaction conditions didn’t result in formation of the other product

Different mechanisms


Ru

MeCNNCMeMeCN

PF6-

2

+


OH

MeO2CMeO2C


O

MeO2CMeO2C

MeO2CMeO2C

1.5 : 1

OHO

+


OH

MeO2CMeO2C

O

MeO2CMeO2C

MeO2CMeO2C

1 : 2

OHO

+

MeO2CMeO2C OH


O

1 : 3.3

OHO

+MeO2CMeO2C

MeO2CMeO2C

Mechanistic Rationale for Cycloisomerizationof Primary Diynols

H+H2O

Cycle A

Ru( )n Cp

+

OH

Ru( )n Cp

+

OH

Ru( )n Cp

OHOH

( )n RuCp

OHH

O

( )nRuCp

OHO

( )nOH

O

H+

2 1

3

4 5

6

RuCp

+

H+H2O

Cycle B

Ru( )n Cp

+

OH

Ru( )n Cp

+

OH

Ru( )n Cp

OH

OH

( )n Ru

OH

Cp

H

O

( )n Ru

OHCp

O

( )n

OH+

H2O

1 2

7

89

10

Ru

MeCNNCMeMeCN

PF6-

2

+


O

MeO2CMeO2C

MeO2CMeO2C

OHO

+


OH

MeO2CMeO2C

H2O Elimination

H2O Addition

Mechanism for Tertiary Diynols

Ru

MeCNNCMeMeCN

PF6-

2

+

OH

MeO2CMeO2C

HO

MeO2CMeO2C


XR

OHR'

R"( )

n

X Ru

OHR"R'

Cp

X Ru

R"R'

CpX Ru

R"R'

Cp

X Ru

R"R'

Cp

RX( )n

R'R"

O

( )

n

nn

n( )

( )

( )

R

RR OH

+

2++

+

H

CpRu +

H+

H2O

H+ H2O

RO

I

IIIII

IV



H2O Elimination

H2O Addition

H2O Elimination vs Addition

XR

OHR'

R"( )n

X Ru

OHR"R'

CpX Ru

R"R'

Cp

RX( )n

R'"R

O

( )nn( )

R +

H

CpRu +

H+H2O

H+H2O

X Ru

OHR"R'

Cp( )n

R +

X Ru

OHR"R'

Cp( )n

R OH

X Ru

R"R'

Cpn( ) H

OH

RO

RO

A B

CD

E

+

OH

MeO2CMeO2C

HO

MeO2CMeO2C

10 mol% 210 vol% H2O/acetone0.02M, 60oC, 45%

OH

MeO2CMeO2C

HO

MeO2CMeO2C



Ru

MeCNNCMeMeCN

PF6-

2

+

H2O Elimination

H2O Addition

Synthesis of α–Kainic Acid

Ru

MeCNNCMeMeCN

PF6-

2

+

Ru-CatalyzedCycloisomerization RN

ROOR

TsNBnOHBnO

O

OTBS


10 mol% 2, 2% H2O/acetone40oC, 1 eq. malonic acid, 3h80% yield, 96% ee

TsN

O

BnO

HN

OTsN

HO2C CO2H(+)-α-Kainic acid RO

TsN

HO2C CO2H(+)-α-Kainic acid

14 steps, 20.5% yield

Other Syntheses toward Kainic Acid

H2N Ph NPh

PhO

MeO

t-BuLi, HMPA, THF

-40oC, 60hsatd NH4Cl soln

NMeO

O

H

H

PhPh

Limits: Starting material is expensive commercially $95/g

17 steps, 7.1% yield

A racemic products

Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317

(+)Kainic Acid_

Conclusions

H

H+ H-SiX3


benzene, 50oC, 6h HSiX3

H

H

Ni-catalyzed silylative cyclization of 1,7-diynes gives (Z)-silylated-

1,2-dialkylidenecyclohexanes in good yield.

MeO2CMeO2C

SiEt3MeO2CMeO2C

+ HSiEt3

N

NMe

Me

Ph

PhB(C6F5)3

PtMe

Me

Z:E ≥ 30:1

Pt-catalyzed silylative cyclization of 1,6-diynes gives (Z)-silylated-1,2-dialkylidenecyclopentanes in good yield.

Conclusions

OH

MeO2CMeO2C

HO

MeO2CMeO2C

1 mol% [CpRu(CH3CN)3]PF6

acetone, 1eq. H2O r t, 98%

Diynols cycloisomerize to form a range of 5- and 6-membered rings

as well as α,β,γ,δ-unsaturated aldehydes and ketones.

An efficient synthesis of substituted-3-sulfolenes has been developed.

Control of regiochemistry is a problem.

SEt

Et

O

O PrEtS

O

O

O10 mol% [CpRu(CH3CN)3]PF6

acetone, 2eq. H2O60oC, 6h, 97%

AcknowledgementsDr Baker

Dr Wulff

Dr Borhan

Group members:

Ying, Xuwei, Erin, Feng, Ping, Bao, Jon, Sampa, Leslie, DJ

Friends:

Yu, Zhenjie, Yana, Feng, Tao, Jun

qin yuan - chemistry

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