Hai Dao
25/01/2014
Ketenes
Baran Group Meeting
Part 1. Introduction
Ph
A brief history
Cl
Ph
H
nPr
3N
Ph
C
O
C
Ph
+
nPr
3NHCl
1828: Synthesis of urea = the starting point of modern organic chemistry.
O
Wedekind's proposal (1901)
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.
R2
Wolff adopt a ketene structure in 1912.
R2
hν
R2
ROH
1
1905: First synthesis and characterization of a ketene: in an efford to synthesize radical 2,
R
C
CH
RO
N2
Staudinger has synthesized diphenylketene 3, Staudinger, H. et al., Chem. Ber. 1905, 1735.
C
R1
C
R1
or Δ
O
1907-8: synthesis and dicussion about structure of the parent ketene, Wilsmore,
O
O
J. Am. Chem. Soc. 1907, 1938; Wilsmore and Stewart Chem. Ber. 1908, 1025; Staudinger and
Wolff rearrangement (1902)
Klever Chem. Ber. 1908, 1516.
Ph
Ph
Ph
Zn
Cl
hot Pt wire
O
Zn
Cl
Cl
Br
CH2
CH
C
Ph
Ph
Br
C
C
vs.
C
Ph
O
HO
O
O
O
O
O
1
O
2
wanted to make
Staudinger's discovery (1905)
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.
Wilsmore's synthesis and proposal (1907-8)
Staudinger's synthesis and proposal (1908)
3 (isolated)
Structure and Physical properties
Frontier orbitals
Nu
Resonance structure
C
C
β
α
Spectroscopy data
Dipole moment
O
H
C
O
Cβ
Cα
C
C
O
H
LUMO
C
C
O
(2.27 D)
IR: distinctive absorptions near 2200-2100 cm-1
(vs. alkene: 1680 cm-1, alkynes: 2200 cm-1; allenes: 19501960 cm-1, carbonyl 1760-1665 cm-1).
(IR is frequently used to detect the formation of reactive
ketene species)
H
C
HOMO
E
Saturday, January 25, 14
C
C
O
C
O
H
(1.45 D)
13 C
NMR: δCα =203-178 ppm; δCβ = 48-33 ppm.
Hai Dao
25/01/2014
Ketenes
Baran Group Meeting
Part 2. Synthesis of Ketenes
Due 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 Derivatives
From Esters
From Acyl halides and Activated Acids (Wedekind's Method)
E1cB mechanism (crowed esters...) or similar pathway
Et 3N
O
Cl(H2C) 3
NCbz
H
O
Cl(H2C) 3
C O
Cl cyclohexane
75%
Me 3Si
O
Me 3Si
OtBu −78 oC
Cl 3C
HMe
O
Ph
Cl
Cl
N2
H
H Me
xylene
CEt
88%
Cl
OtBu
C O
60%
Me 3Si
O
Et
C O
Et 2O
ultrasound
Cl
PhC
Me 3Si
Me 3Si
2.2 Ketenes from Diazo Ketones (Wolff's Rearrangement)
From α-Halo Carboxylic Derivatives (Staudinger's Method)
Cl
OLi
Rethke, M. W. et al. J. Org. Chem. 1977, 2038.
Cevasco, G.; Thea, S. et al. J. Org. Chem. 1999, 5422.
Zn, DME
25 oC
Me 3Si
N
Cl(H2C) 3 H Cbz
reflux
O
LDA
O
C O
Me
H
70%
reflux
O
H
H
O
O
Rizzo, C. J. et al. Synth. Commun. 1995, 2781.
From Acid Anhydrides
Miller, R.D., et al. J. Org. Chem. 1991, 1453
Et
O
Me
quinidine
O
500 oC
H
O
C O
O
Me
O
2
Me
O
Me
Ph 2C
O
O
hν
DCM, −78 oC
Me
99% ee
Ph 2C
Calter, M. A. et al. Org. Lett. 2001, 1499.
N2
Ph 2C
MeOH
Ph 2C
CO2Me
C O
Ph 2C
Ph 2C
From Acids
Ueda, K.; Toda, F. et al. Chem. Lett. 1975, 1421.
OHC
iPr
CO2H +
4
N
I Me
2NEt,
Cl
Mukaiyama's reagent
rt
MeCN
OHC
3
C
Ph
proposed
9-O-acetylquinine
H
O
N2
4
O
dioxane
60 oC, H 2O
O
51%, 86% ee
H
Saturday, January 25, 14
nanocluster (Ag)n
O
other metal catalysts: Ag, Cu, Rh
Ph
4
C
O
80-91%
Ph
4
CO2H
2-98
Sudrik, S. G. et al. Org. Lett. 2003, 2355.
From Cycloalkanones and Enones through Photolysis
2.3 Ketenes from Metal Carbene Complexes
OMe
Cr(CO)5
OMe
Cr(CO) 3
[2+2]
C
hν
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25/01/2014
Ketenes
Baran Group Meeting
O
THF
OMe
O
hν
tBu
O
78%
O
H
C
tBu
O
tBu
CO2Me
MeOH
tBu
96%
Norrish Type I
MeO
C
Cr(CO)5
O
Agosta, W. C.; Wolff, S. et al. J. Am. Chem. Soc. 1976, 4182.
[2+2]
OMe
Cr(CO) 3
45 oC
O
63%
CO2H
H
OH
OMe
Hegedus, L. S. et al. J. Am. Chem. Soc. 1996, 7873.
N2
Ph
Me
O
+
Ph
N
Ph
HO
20%
Me
Pd 2(dba) 3
Me
C
PdL n
CO, PhMe
60 oC
Ph
O
Me
C
93% Ph
O
N
(30% decarboxylation) MeO 2C
Ph
From Cyclohexadienones and Other Cycloalkenones
O
Ph
C
Ph
O
CO2Et
O
EtO 2C
Barton-Quinkert reaction
EtO 2C
H 2O
C O
Rh cat
75%
From Dioxinones
O
O
EtO
squaric acid
derivative
Saturday, January 25, 14
O
1, Δ EtO
C
OH
O
EtO
O
EtO
Me
Quinkert, G. et al. Helv. Chim. Acta 1997, 1683.
84%
O
EtO
O
Moore, H. W. et al. Org. Synth 1990, 220.
O
O
O
OH
O
O
2, FeCl 3
OH O
Ph
Me
CO2H
Cai, W. -L. et al. J. Chem. Soc. Perkin 1 1996, 2337.
O ArLi EtO
O
Ph
O
EtO 2C
Bn
N
PhCH=NBn
Me
From Cyclobutanones and Cyclobutenones
EtO
HO
Buscemi, S. et al. Photochem. Photobiol., A, 2003, 145.
Ph
2.4 Other Methods
EtO
OH
O
O
Wang, J. et al. J. Am. Chem. Soc. 2011, 4330.
N2
H
mechanism
hυ, MeOH
O
Δ
O
C
OH
O
O
68%
O
O
comercial available
Boeckmann, R. K. et al. J. Am. Chem. Soc. 1989, 8286.
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Ketenes
Baran Group Meeting
Part 3. Reaction of Ketenes
3.1 [2+2] Cycloaddition
Reaction Mechanism: Concerted [ π2s+π2a] vs. Two-step Reaction Involving a Dipolar Intermediate
H
H
C O
R'
R
H
+
H
R'
R
H
R'
R
O
C O
H
R'
R
R
R
Features and Supported Evidences
- stereospecific to thermodynamically less stable cyclobutanones
- Z olefins are more reactive than E olefine
H
tBu
+
O
C O
CN
NC
+
tBu
H
H
tBu
H
H
+
H
R'
R
H
H H
R
R
O
C O
C O
H
R'
R
R' H
R
R
R
less hindered bond rotation
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]
C O
H
H
CN
H
H
C O
O
C O
NC
R
O
tBu
Montaigne, R. et al. Angew. Chem., Int. Ed. 1968, 221.
relative reactivity:
stereochemisty = a net [π2s+ π2s ]
Cl2C C O > Ph 2C C O > Me 2C C O > H 2C C O
Retigeranic acid synthesis: Corey, E. J. et al. J. Am. Chem. Soc. 1985, 4339.
[2+2] Cycloaddition with Alkynes
R
Cl
R'
R'
[2+2] Cycloaddition with Electrorich Olefins: Stepwise Mechanism
O
H 2SO 4
R'
O
Ph
C O
Cl
R
Cl
Cl
R
O
C O
O
C
O
R'
O
R'
C
Cl
Cl
O
Cl
R
vinylketene
Saturday, January 25, 14
R
R
C
O
bisketene
Danheiser, R. L. et al. Tetraherdon Lett. 1987, 3299;
Ammann, A. A. et al. Helv. Chim. Acta 1987, 321.
C O
Cl
Ph
Cl
Ph
Zn, AcOH
R'
O
O
Bn
+
OR
O
O
+
O
Ph
Cl
O
Reynolds, P. W. et al. J. Am. Chem. Soc. 1984, 4566.
O
Cl
O
Cl
NH
69%
dr = 94:6 RO
Bn
RO
Bn
Kanazawa, A. t al. J. Org. Chem. 1998, 4660.
Hai Dao
25/01/2014
Ketenes
Baran Group Meeting
[2+2] Cycloaddition with Imines: Staudinger Ketene-Imine Cycloaddition chiral organic base or NHC catalysis
uncatalyzed mechanism: stepwise formation of zwitterion followed by
contotatory ring closure to give cis-product
Ph
C O +
C6H 4Clo
Et
+
N
O
R
R
R1
C
N R2
C O
R2
conrot.
R
THF, rt
Cs2CO 3
N
R2
NPh
N
cis-adduct
N
N
BF 4
N
+
O
BnO
BnO
C O
Ph
Ph
OTBS
80%
O
β-amino
acids
O
CO2Bn
OTBS O
O
NPh ketene
Cl
NPh
N
O
Ph
TBSO Ph
Et
Zhang, Y. -R. et al. Org. Lett. 2008, 277.
OTBS
NTs
O
Me
N
N
Et 3N
PhMe, -78 oC
59%
BnO 2C
N
Ts
CO2Ph
cis:trans = 99:1
99%ee
BQ
Townsend, C. A. et al. Org. Lett. 2009, 3609.
Me
N
BnN
N
BQ, In(OTf) 3
Palomo, C. et al. Chem. Commun. 1996, 1269.
CO2Bn
cis:trans = 91:9
99%ee
OTBS
O
N
Me Bn
Boc
Ph
NHC
Bn
N
imine
Ph
Ph
Arrieta, A. et al. J. Org. Chem. 1998, 5869.
Me
O
C6H 4Clo
71%
N
planar
Boc NHC, Cs CO
2
3
O
R1
R1
N
Et
Ph
N
R
C O
Me
CO2Bn
O
BnN
C
N NR' 2
CO2Bn
O
BnN
C
N NR' 2
R
R
more stable
CO2Bn
BnN
O
N
R
N
general reaction mode (apart from concerted [ π2s+π2a] ):
solvents
R
X
substrates
C O
C
or
catalysts
R
R
O
X
nucleophilic
electrophilic
R
intra- or intermolecular
reactions
3.2 Other Cycloadditions
Formal [4+2] Cycloaddition: with electro-deficient dienes
con.
58-74%
trans-adduct
Diez, E. et al. Org. Lett. 2004, 2749.
R
R
N N
Ar
Saturday, January 25, 14
E+
S
C O
N
Ar
R = Ar, Cl
75-95%
O
N N
Ar
S
N
Ar
Dutta, B. C. et al., Chem. Res. (S) 1999, 36.
N
C
Ph
Ph
Ph
O
+
Et
EtO 2C
Ph
[3+2] Cycloaddition
NPh
N
O
O
BF 4
Et
Ph
OTBS
O
EtO 2C
Cs2CO 3, THF
O oC to rt
Ph
C O
Ph
79%, 91% ee
dr = 24:1
acylketenes often work as good dienes in [4+2] reaction:
+
BuO
O
electron rich
olefin
H
O
BnO
from dioxinone
O
N
N
Ph
H
N N
OH
Ph
Ph
HN N
O
O
Nucleophilic Addition and/or Rearrangement
O
OH
NH 2
Me
OH
CR1R 2
C
+
Me
O
Ph
95 %
C
+
O
Ph
3.3 Other Reactions
Zhang, Y. -R. et al. Chem. Eur. J. 2008, 8473.
O
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25/01/2014
Ketenes
Baran Group Meeting
R1
Coleman, R. S. et al. J. Org. Chem. 1993, 385.
CHR1R 2
N
OH 52-83%
N
H
R2
O
Olagbemiro, R. O. et al. Recl. Trav. Chim. Pays-Bas 1995, 337.
Cycloaddition with Carbonyl Groups
ketenes undergo [2+2] cycloaddition with electrophilic carbonyl group:
O
Amine base catalyzed reactions
C O
+
CCl 3CH=O
N
O
quinidine
O
H
N
PhMe, −50 oC
CCl 3
O
89%, 98% ee
O
+
OBn O
Br
Mg
Br
O
O
TMS
H
Me
KF
MeCN
O
BnO
syn:anti = 2:98
94%
O
96%
O
Cl
Cl
O
Me
O
O
N
Boc
Ar
Me
N
Me
Ar
CO2
O
N
Boc
Me
Ar
O
O
Me
N
Vemribo, R. et al. Tetrahedron Lett. 1995, 4159.
Saturday, January 25, 14
O
THF, − 78 oC
Ar
Bn
Ph
O
N
C
O
MgBr 2, DCM
−43 oC
Bn
Cl
Bn
N
CCl2
Edstrom, E. D. et al. J. Am. Chem. Soc. 1991, 6690.
Lewis acid catalyzed reactions
TMS
Cl
N
O
Wynberg, H. et al. J. Org. Chem. 1985, 1977.
O C
Bn
C
Cl 3C
R
C
+
CO2
NBoc
N
N
Boc
Ar
Me
NH 4Cl
O
91%, 90% ee
N
H
Smith, A. D. et al. Org. Lett. 2009, 3858.
Wittig Reaction
Ketenes in Polymer Chemistry
New approach for polimer modification: polymer crosslinking through
ketene dimerization
NaBARF
O
O
Pd(II)
Δ
O
O
O
O
C O
O
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25/01/2014
Ketenes
Baran Group Meeting
O
C CH2
PPh 3
Buono, G. et al. Tetrahedron Lett. 1990, 4859.
Ph
Ph
Ph
N
N
C O
PPh 3
Ph
N
Ph
C O
N
71%
C
ketenimine
Ph
Ph
Ph
O
N
O
O
n
Meldrum's acid derivatives
NH
O
O
CHPh
Ph
Ph
Molina, P. et al. Tetrahedron Lett. 1991, 4041.
C O
n IR: 2103 cm−1
Moore's Cyclization
Ph
Ph
Ph
PhMe
110 oC
O
Ph
C
− acetone
− CO2
O
DCM
O
n
used for printing submicrometer-scale patterns for microcontact printing
O
O
n
Aida, T. et al. J. Am. Chem. Soc. 2011, 2840.
Ph
Organometallic Compounds
MeO
MeO
OMe
MeO
OMe
OMe
Ph
Py, rt
H
C O + AgOAc
O
Ph
MeO
71%
HCl
O
dimerization
Ph
O
Ph
MeO
MeO
R
O
C
O
R
O
+
O
R
R
ratio of the mixture depends on:R, cat.
Clemens, R. J. et al. Chem. Rev. 1986, 241.
Saturday, January 25, 14
Ag
C O
Br
Blues, E. T. J. Chem. Soc. Perkin Trans. 2, 1993, 1631
Ph
OMe
L M
Moore, H. W. et al. J. Org. Chem. 1992, 3765. n
cat.
R
Ph
OCH2
Br
Silver ketenide
X-ray structure
O
Ph
Br 2, CCl4, rt
C O
H
O
Ag
O
R1
R2
O
η2 (C−O)
decarbonylation
L nM
R1 R 2
η2 (C−C)
M(CO) xL y
unreactive
+ by products
modes of ketene coordination
with transition metals
To develop the transition metal catalyzed-reaction with ketenes, it is crucial to
find the right ligands to stablize the ketene-metal complexes
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Ketenes
Baran Group Meeting
Epicoccins
O
(CO 2Me) 2
C
Me
Ni(COD) 2 (5 mol%)
DPPB (5 mol%)
O
+
C
Me
oC,
C6H 6, 60
24 h
86%
Et
Ph
Me
O
Sx
O
Me
H
N
(MeO 2C)2C
Et
O
H
OH
Ph
Sy
O
H
single isomer
epicoccin
O
Louie, J. et al. J. Am. Chem. Soc. 2011, 7719.
O
CO2tBu
O
O
H
O
C
O
+
O
O
HO
O
H
H
tBu
O
O H
HO
HO
tBu
O H
N
Boc
HO
HO
CO2tBu
reflux
75%
CO2Me
O
enantiomer
OMe
O
N3
MeO
Me
Boc
N
N
O
O
tBu
C
tBu
O
1. (COCl) 2
2.
nBu
Me
H
3N
HO 2C
H
H
tBu
H
OBn H
N
N
H
N H
H
OBn
H
20
H
Corey et al. J. Am. Chem. Soc. 1998, 649.
H
Me
O
Saturday, January 25, 14
Et 3N
cyclohexane
HO
HO
O
O
O
hυ
MeOH
C
OMe
H
N
H Boc
CO2tBu
(+)-20R-dihydrocleavamine
ginkgolide B
H
H
Brase, S et al. Chem. Eur. J. 2010, 11624.
O
O
Me
O
cis-adduct
Cl
HO
HO H
N
O
N
H Boc
OH
O H
H
O
N
H H2
Ginkgolide Synthesis
OH
H
H
H
OH
N
proposal
H
O
CO2
Part 4. Ketenes in Synthesis
H O
OH
N
H
H
(+)-20R-dihydrocleavamine
Ogasawara, K. et al. Tetrahedron Lett. 2001, 7311.
Hirsutine Synthesis
(+)-FR900482 Synthesis
H
N
OH
Et
N H
H
H
MeO 2C
OHC
H
N
O
NH
OMOM
MeO 2C
hirsutine
O
OPMB
NCbz H Et
OPMB hetero-DA
N H
H
H
O
O
NCbz
Et
OMOM
O
OH
H
O
O
O
RN
RHN
O
CO2Me
CO2Me
O
O
O
O
O
O
HO
H
O
R = p-azidobenzyl
C
HRN
Me
MeO
O
H
Me
OTIPS
Me
Me
Me
Et 2AlCl
O
>95%
DCM
−78 oC to rt
silyl ketene acetal = ketene equivalence
OMe
Cook. S. P. et al. J. Am. Chem. Soc. 2012, 13577.
O
CO2Me
Hoye, T. R. et al. J. Org. Chem. 2010, 7052.
Saturday, January 25, 14
O
TIPSO
O
Me
Me
+
O
macrocidin A
Me
O
O
PhMe
reflux
86%
CO2tBu
(+)-Artemisinin Synthesis
Macrocidin Synthesis
O
CO2tBu
Danheiser, R. L. et al. J. Org. Chem. 2011, 1852.
Me
O
N
OMOM
O
O
N
PhMe
80-110 oC
88-94%
BnO
O
N H
H
then -Me2CO,
-CO2,
C
O
N
OMOM
CO2tBu
OTBS
+
Tietze, L. F. et al. Angew. Chem. Int. Ed. 1999, 38, 2045.
RN
OBn
OTBS
OBn
OTBS
OH
OBn
OCONH2
OH
H
N
Et
OMe
N H
H
Hai Dao
25/01/2014
Ketenes
Baran Group Meeting
Part 5. Important References
1. 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.