Baran Group Meeting Ketenes Hai Dao 25/01/2014 [2+2] Cycloaddition Part 3. Reaction of Ketenes...

Hai Dao25/01/2014Baran Group Meeting Ketenes

A brief history1828: Synthesis of urea = the starting point of modern organic chemistry.1901: Wedekind's proposal for the formation of ketene equivalent (confirmed by Staudinger 1911)1902: Wolff rearrangement, Wolff, L. Liebigs Ann. Chem. 1902, 325, 129. Wolff adopt a ketene structure in 1912.1905: First synthesis and characterization of a ketene: in an efford to synthesize radical 2, Staudinger has synthesized diphenylketene 3, Staudinger, H. et al., Chem. Ber. 1905, 1735.1907-8: synthesis and dicussion about structure of the parent ketene, Wilsmore, J. Am. Chem. Soc. 1907, 1938; Wilsmore and Stewart Chem. Ber. 1908, 1025; Staudinger and Klever Chem. Ber. 1908, 1516.

Structure and Physical properties

Part 1. Introduction

R1

ON2

R2

CC

OR1

R2ROH

CHCO

R1

R2

ROhν

or ΔWolff rearrangement (1902)

Cl

OPh

PhCl

CC

OPh

Ph

wanted to make

Cl

OPh

Ph

21 3 (isolated)

Cl

OPh

PhH nPr3N C

CO Ph

Ph

nPr3NHCl+

Wedekind's proposal (1901)

Staudinger's discovery (1905)

O

OO

hot Pt wire CH2CO

CHC

HOvs.

Br

OBr

Zn

Wilsmore's synthesis and proposal (1907-8) Staudinger's synthesis and proposal (1908)

Latest books: ketene (Tidwell, 1995), ketene II (Tidwell, 2006), Science of Synthesis, Vol. 23 (2006); Latest review: new direactions in ketene chemistry: the land of opportunity (Tidwell et al., Eur. J. Org. Chem. 2012, 1081). Search for ketenes, Google gave 406,000 (vs. allenes: 950,000 ) Jan 23,2014.

Frontier orbitals

LUMO

HOMO

Resonance structure

C C O

C C O

C C O

Nu

E

Dipole moment

CH

HO

(2.27 D)

CH

HC O

(1.45 D)

Spectroscopy data

13C NMR: δCα =203-178 ppm; δCβ = 48-33 ppm.

IR: distinctive absorptions near 2200-2100 cm-1 (vs. alkene: 1680 cm-1, alkynes: 2200 cm-1; allenes: 1950-1960 cm-1, carbonyl 1760-1665 cm-1).

C C OCαCβ

(IR is frequently used to detect the formation of reactive ketene species)

Zn

αβ

Saturday, January 25, 14

Part 2. Synthesis of KetenesDue to its highly reactivity, many ketenes are synthesized in situ as intermediates which then react with other reagents to generate products

2.1 Ketenes from Carboxylic Acids and Their DerivativesFrom Acyl halides and Activated Acids (Wedekind's Method)

Cl(H2C)3

Cl

O Et3N

cyclohexane CCl(H2C)3

O

refluxNCbz

H

HCl(H2C)3

ONCbz

75%

From α-Halo Carboxylic Derivatives (Staudinger's Method)

Cl3CCl

O Zn, DME

Et2Oultrasound

ClC

ClO

PhC CEtOEt

Ph ClCl88%

From Acid Anhydrides

MeO

O

2

OO

H

Et

MeO

C OMe

O

O

Me

Mequinidine

DCM, −78 oC

500 oC

99% ee

From EstersE1cB mechanism (crowed esters...) or similar pathway

Me3Si

Me3Si

OtBu

O LDA

−78 oC Me3Si

Me3Si

OtBu

OLi

Me3SiC

Me3SiO

25 oC

60%

2.2 Ketenes from Diazo Ketones (Wolff's Rearrangement)

PhO

N24nanocluster (Ag)n

dioxane60 oC, H2O

PhC

4

O

Ph 4CO2H

80-91%2-98

other metal catalysts: Ag, Cu, Rh

Ph2C

Ph2C

O

N2

hνPh2C

Ph2C

C OMeOH

Ph2C

Ph2C

CO2Me

Ueda, K.; Toda, F. et al. Chem. Lett. 1975, 1421.

Cevasco, G.; Thea, S. et al. J. Org. Chem. 1999, 5422.

Rizzo, C. J. et al. Synth. Commun. 1995, 2781.

Calter, M. A. et al. Org. Lett. 2001, 1499.

Rethke, M. W. et al. J. Org. Chem. 1977, 2038.

Sudrik, S. G. et al. Org. Lett. 2003, 2355.

From Acids

CO2HOHC4 N

MeClI

+ iPr2NEt, MeCN

rtOHC

3C

O

9-O-acetylquinine

O

H

H

O

51%, 86% ee

Mukaiyama's reagent

proposed

O

O

N2

H

H

xylene

refluxO

CH

H

OMe

O

Me

O

H

H

70%

Miller, R.D., et al. J. Org. Chem. 1991, 1453

Me



2.3 Ketenes from Metal Carbene Complexes

OMe

Cr(CO)5

hνOMe

CO

Cr(CO)3 OMe

THF 78%

MeO Cr(CO)5 CO

OMe

Cr(CO)3 OOMe

63%

[2+2]

[2+2]

2.4 Other Methods

45 oC

From Cyclobutanones and CyclobutenonesO

N2

CO2Et OEtO2C EtO2CC O

EtO2CCO2H

Rh cat

H2O

75%

O

O

EtO

EtO

OEtO

EtO

ArLi

OH O

C

OEtOOH

EtOO

O

O

O

EtO

EtO

1, Δ

2, FeCl3 84%

From Cyclohexadienones and Other Cycloalkenones

OPhMe

CO

Ph

Me

PhCH=NBn OPh

Me

BnNPh

Barton-Quinkert reaction

From Dioxinones

O

O

O

OH Δ

O

CO

OH O

O

O

68%

Hegedus, L. S. et al. J. Am. Chem. Soc. 1996, 7873.

Cai, W. -L. et al. J. Chem. Soc. Perkin 1 1996, 2337.

Moore, H. W. et al. Org. Synth 1990, 220.

Quinkert, G. et al. Helv. Chim. Acta 1997, 1683.

Boeckmann, R. K. et al. J. Am. Chem. Soc. 1989, 8286.

OH

Me

CO2H

HO

hυ, MeOHOH

HOMeO2C

20%

Buscemi, S. et al. Photochem. Photobiol., A, 2003, 145.

mechanism

O

O

O

comercial available

From Cycloalkanones and Enones through Photolysis

tBu

O

tBu

OH

tBu

CO

tBu

CO2Mehν

96%Norrish Type I

Agosta, W. C.; Wolff, S. et al. J. Am. Chem. Soc. 1976, 4182.

Me

N2

O

Ph

NPh

Ph+

Pd2(dba)3

CO, PhMe60 oC

O

CMe

Ph

O

PdLnO

CMe

Ph

O

N

Ph

Ph

93%

Wang, J. et al. J. Am. Chem. Soc. 2011, 4330.

squaric acid derivative

MeOH

(30% decarboxylation)

H H


O


Part 3. Reaction of Ketenes3.1 [2+2] Cycloaddition

Reaction Mechanism: Concerted [π2s+π2a] vs. Two-step Reaction Involving a Dipolar Intermediate

R'C

HO +

H

R

R

H

H

R

R

HR'C

HO

O

R R

R'

Features and Supported Evidences- stereospecific to thermodynamically less stable cyclobutanones- Z olefins are more reactive than E olefine

R'C

HO

+

H

R

R

H

O

R R

R'

Features and Supported Evidences- initial orthogonal approach of the ketene to alkene from the least hindereddirection following by rotation at C2 lead to the same stereochemisty outcome as in concerted mechanism- high level calculation by Houk showed that the forming bond length of the carbonyl carbone is 1.78 Å; the other is 2.43 Å- solvent effects observed (it could be a ground state effect only)- evidence from studies of intramolecular [2+2]

H

R

R

HR'C

HO

less hindered bond rotation

H

R

R

HR'C

HO

C ONC

tBu O

CNtBu

H

H

C ONC

tBu O

CNtBu

H

H

+

+

O

HC O

stereochemisty = a net [π2s+π2s]

[2+2] Cycloaddition with Electrorich Olefins: Stepwise Mechanism

C OCl

Cl+

ORBn

OClCl

RO Bn

NH

O

RO Bn69%

dr = 94:6

C OCl

Ph O Ph

Cl

O

O

Ph

Cl

O

OO

OPhCl +

[2+2] Cycloaddition with Alkynes

C OCl

Cl O

ClCl

R'

R

R R'

OR'

R

OR'

R O

R' C

R

O CO

CR

R'

O

H2SO4

Zn, AcOH

vinylketene bisketene

Montaigne, R. et al. Angew. Chem., Int. Ed. 1968, 221.

Retigeranic acid synthesis: Corey, E. J. et al. J. Am. Chem. Soc. 1985, 4339.

Danheiser, R. L. et al. Tetraherdon Lett. 1987, 3299; Ammann, A. A. et al. Helv. Chim. Acta 1987, 321.

Reynolds, P. W. et al. J. Am. Chem. Soc. 1984, 4566.

Kanazawa, A. t al. J. Org. Chem. 1998, 4660.

H

relative reactivity:Cl2C C O > Ph2C C O > Me2C C O > H2C C O



Dutta, B. C. et al., Chem. Res. (S) 1999, 36.

[2+2] Cycloaddition with Imines: Staudinger Ketene-Imine Cycloaddition

uncatalyzed mechanism: stepwise formation of zwitterion followed by contotatory ring closure to give cis-product

C OR

+NR1

R2

COR

NR1

R2 N

O

R2

R

R1

C OBnON

Me Bn

O

O

+ N

O

Bn

BnO

MeO

O

80%β-aminoacids

cis-adduct

C OBnN

CO2BnN

R

NMe

Me

COBnN

NR

NR'2

CO2Bn

con.N

N

OBnN

R

CO2Bn

58-74%

trans-adduct

COBnN

N

R

NR'2

CO2Bn

more stable

chiral organic base or NHC catalysis

C OPh

EtN

Boc

C6H4Clo

NHC, Cs2CO3

THF, rt71%

+ N

O

Boc

Et

C6H4Clo

Ph

cis:trans = 91:999%ee

NNPh

N

OTBSPh

Ph

BF4

Cs2CO3

NNPh

N

OTBSPh

PhNHC

NNPh

N

TBSO

PhPh O

PhEt

ketene

imine

OTBS

Cl

ONTsCO2Bn

BQ, In(OTf)3

Et3NPhMe, -78 oC

N

O

TsBnO2Ccis:trans = 99:1

99%ee

OTBS

Me

59%

N

NCO2Ph

BQ

3.2 Other Cycloadditions

NN

S N ArAr

RC O

R = Ar, ClNN

SAr N

O

Ar

R

75-95%

Arrieta, A. et al. J. Org. Chem. 1998, 5869.

Palomo, C. et al. Chem. Commun. 1996, 1269.

Diez, E. et al. Org. Lett. 2004, 2749.

Zhang, Y. -R. et al. Org. Lett. 2008, 277.

Townsend, C. A. et al. Org. Lett. 2009, 3609.

solvents substrates

or catalystselectrophilic nucleophilic

Formal [4+2] Cycloaddition: with electro-deficient dienes

E+

general reaction mode (apart from concerted [π2s+π2a] ):

intra- or intermolecularreactions

C OR

RC

O

R

R

X

planar

conrot.

X-



acylketenes often work as good dienes in [4+2] reaction:

BuO

CO

MeO

+O

O

BnO Me

95 %

Cycloaddition with Carbonyl Groups

ketenes undergo [2+2] cycloaddition with electrophilic carbonyl group:

C O+

CCl3CH=O

quinidine

PhMe, −50 oC O

O

Cl3C89%, 98% ee

O

CCl3H

N

RO

Amine base catalyzed reactions

Lewis acid catalyzed reactionsOC

TMS

OBn O+

MgBr2, DCM −43 oC O

Mg O

BrBr

H

MeBn KFMeCN

O C TMS

O

Me

BnO

O

syn:anti = 2:9894%

3.3 Other ReactionsNucleophilic Addition and/or Rearrangement

NBn

NBn

O

CCl2 BnN

O

ClCl96%

OC

ClCl

+

OH

NH2

OC

R2R1

+OH

NH

CR1R2

OH N

OCHR1R2

52-83%

CO

EtPhEtO2C Ph

O+

Cs2CO3, THFO oC to rt

NNPh

N

OTBSPh

Ph

BF4O

O

PhEtO2C

EtPh

Zhang, Y. -R. et al. Chem. Eur. J. 2008, 8473.

Coleman, R. S. et al. J. Org. Chem. 1993, 385.

Wynberg, H. et al. J. Org. Chem. 1985, 1977.

Vemribo, R. et al. Tetrahedron Lett. 1995, 4159.

Olagbemiro, R. O. et al. Recl. Trav. Chim. Pays-Bas 1995, 337.

Edstrom, E. D. et al. J. Am. Chem. Soc. 1991, 6690.

OC

MeAr

NBoc

O

NPh

O

THF, − 78 oC NO

NBoc

O

O

ArMe N

NBoc

O

CO2ArMe

NNBoc

OCO2ArMe

NH4Cl

NH

O

MeAr

91%, 90% ee

Smith, A. D. et al. Org. Lett. 2009, 3858.

79%, 91% eedr = 24:1

electron richolefin


[3+2] Cycloaddition

C OPh

H Ph

ON

N+N N

OPh

O

PhH

HN N

OHPh

O

Ph

from dioxinone


Wittig Reaction

N NPPh3

PhPh

C OPh

N NC

PhPh

CHPh

C OPh

N NH

PhPh

PhO71%

ketenimine

Ketenes in Polymer ChemistryNew approach for polimer modification: polymer crosslinking through ketene dimerization

O

OO

O

NaBARFPd(II)

DCM O

OO

O

Δ

− acetone− CO2

C O

n

O

OIR: 2103 cm−1

used for printing submicrometer-scale patterns for microcontact printing

nn

n

Buono, G. et al. Tetrahedron Lett. 1990, 4859.

Molina, P. et al. Tetrahedron Lett. 1991, 4041.

Aida, T. et al. J. Am. Chem. Soc. 2011, 2840.

Moore's Cyclization

OPh

MeO OMe

Ph

OC

Ph

Ph

MeOOMe

PhMe110 oC

O

PhOMe

MeO

Ph

O

OMeMeO

Ph

Ph

O

OCH2

MeO

Ph

Ph

O

MeO

Ph

PhO

71%

Moore, H. W. et al. J. Org. Chem. 1992, 3765.

Ph

dimerization

CO

RO

OR

R

+OR

RO

cat.

ratio of the mixture depends on:R, cat.Clemens, R. J. et al. Chem. Rev. 1986, 241.

Organometallic Compounds

C O + AgOAc C OAg

AgH

H

Py, rt

HCl

Br2, CCl4, rtC O

Br

Br

Silver ketenideX-ray structure

Blues, E. T. J. Chem. Soc. Perkin Trans. 2, 1993, 1631

O

O

PPh3

C O O

O

C CH2

LnMO

R2

R1

LnM

O

R1R2

η2 (C−O) η2 (C−C)modes of ketene coordination

with transition metals

M(CO)xLy

unreactive

decarbonylation

To develop the transition metal catalyzed-reaction with ketenes, it is crucial to find the right ligands to stablize the ketene-metal complexes

Meldrum's acid derivatives

+ by products



Part 4. Ketenes in Synthesis

O O

O O

O

O

HtBu

HHO

HMe

HO HOHO

Ginkgolide Synthesis

ginkgolide B

O

O OtBu

HH

O

O

tBuH

H

O

tBu

OMe

HO2C

O

tBu

OMe

CO

1. (COCl)2

2. nBu3N

Corey et al. J. Am. Chem. Soc. 1998, 649.

(CO2Me)2C

Me Me

CO

EtPh

+Ni(COD)2 (5 mol%)

DPPB (5 mol%)

C6H6, 60 oC, 24 h86%

(MeO2C)2C

MeO

MePh

Et

Louie, J. et al. J. Am. Chem. Soc. 2011, 7719.

O

HOHO

MeOHhυ

CO

HOHO

CO2Me

HOHO

enantiomer

O

Me

N3O

H H

BocNMeO

MeH

OBnH

NH

NMe

HOBn

HH

NH

NH

H

20

(+)-20R-dihydrocleavamine

(+)-20R-dihydrocleavamine

Ogasawara, K. et al. Tetrahedron Lett. 2001, 7311.

single isomer

N N

O

O

O

O

Sx

SyOH

OHH

H

H

H

epicoccin

proposalN N

O

O

O

OOH

OHH

H

H

H

NH2

CO2

O

OH

H

H

H

H

NBoc

CO2tBu

H

H

O

O

NBoc

CO2tBu

H

H

O

cis-adduct

NBoc

CO2tBuCl

O+

Et3Ncyclohexane

reflux75%

Epicoccins

Brase, S et al. Chem. Eur. J. 2010, 11624.

CO



Part 5. Important References1. Ketenes; Thomas T. Tidwell , John Wiley and Sons, 1995.2. Ketenes II; Thomas T. Tidwell , John Wiley and Sons, 2006.3. Science of Synthesis, Vol. 23 (2006)4. New Directions in Ketene Chemistry: The Land of Opportunity, Tidwell, T. T. et al. Eur. J. Org. Chem. 2012, 1081.

NH

N

MeO2C

OMeEt

H

HH

hirsutine

NH

N

MeO2C

EtH

HH

NH

NCbz EtH

HH O

O

OPMB

NH

NCbz

H

OO

O

O

Et

OPMB

hetero-DA

then -Me2CO,-CO2,

Macrocidin Synthesis

O

RN OHO

O

OO

CO2Me

RN OO

O O

CO2Me

RHN

O

R = p-azidobenzyl

O

OO

PhMereflux

CO2Me

HRN OCO

86%

macrocidin A

Hoye, T. R. et al. J. Org. Chem. 2010, 7052.

(+)-FR900482 Synthesis

NO NH

OCONH2OH

OHC

OHOBn

OMOMNCO2tBu

OTBSOH OBn

OMOMN

OBnOTBS

80-110 oC88-94%

Danheiser, R. L. et al. J. Org. Chem. 2011, 1852.

CO

OMOMN

BnO

OTBS

CO2tBu

+

O

OMOM

PhMe

CO2tBu

Hirsutine Synthesis

Tietze, L. F. et al. Angew. Chem. Int. Ed. 1999, 38, 2045.

Cook. S. P. et al. J. Am. Chem. Soc. 2012, 13577.

OO

MeH

Me

HMe

H

OO

O

OMe

Me

H

MeO

Me

OTIPS

>95%Me

Me

O

+OMeTIPSO

Me Et2AlCl

DCM −78 oC to rt

silyl ketene acetal = ketene equivalence

(+)-Artemisinin Synthesis



Baran Group Meeting Ketenes Hai Dao 25/01/2014 [2+2] Cycloaddition Part 3. Reaction of Ketenes...

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