david mountford and prof. donald craig centre for chemical synthesis, department of chemistry,
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Stereoselective Claisen and Related Rearrangements: Fundamental Methodology and Synthetic Applications. David Mountford and Prof. Donald Craig Centre for Chemical Synthesis, Department of Chemistry, Imperial College London. SW7 2AZ Industrial Supervisor: Dr Paul King, GSK - PowerPoint PPT PresentationTRANSCRIPT
Stereoselective Claisen and Related Rearrangements: Fundamental Methodology and
Synthetic Applications
David Mountford and Prof. Donald CraigCentre for Chemical Synthesis,
Department of Chemistry,Imperial College London.
SW7 2AZ
Industrial Supervisor: Dr Paul King, GSK
13th September 2005
The Claisen Rearrangement
• The Claisen rearrangement is the [3,3] sigmatropic rearrangement of an allyl-vinyl ether.
• Many variants exist…
• IrelandClaisen Rearrangement.
O
R'
O
O
R'
OTMS
2.TMSCl
O
R'
OTMS
HO
R'
O
1. LDA 3. H3O+R R R R
O Oheat
O
OH
O
OR
O
NR2
Ireland ClaisenJohnson Claisen Eschenmoser Claisen
FelkinAnh Model in Pericyclic Reactions • The FelkinAnh model can be applied to a wide range of pericyclic
processes by the replacement of C=O by C=CH-EWG'.
• In the Claisen rearrangement.
O
OO
O
OMe
2.TMSClO
CO2HO
OMe O
CO2HO
OMe
Felkin anti-Felkin
+1. LDA
59% Yield
22 : 78
H
O
H
O XH
O
H
OXO
OO
OMeO
Li
O
OO
OMeO
Li
Felkin anti-Felkin
EWG
H R
OH
Nu
EWG
H R
HNu
EWG'
Belluš−Claisen Rearrangement(Aza-Claisen, Zwitterionic Claisen Rearrangement)
• in situ generation of a ketene. • Activation with a suitable Lewis acid. • Addition to a tertiary allyllic amine.
Cl
ORNR3
NR2R
R'
O
OR
NR2R
R'
OLA
OR
LA
NR2
OLA
R
R'
R'
NR2
(Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726).
Aim of Project
SN
O iPr2NEt
RCH2COCl
NO
SO
NO
SO
Lewis acid Major Diastereoisomer
Minor Diastereoisomer
N
H
H
SL
H
ROLA
O
H
N
OLA
H
H
RH
SL
OL
L
L
R
R
NR'2R
R*
O
NR'2
OLAR
R*R*
NR'2 iPr2NEt
RCH2COCl
Lewis acid
• 1,2-Asymmetric Induction.
Initial Studies
• Cyclic amines have a greater nucleophilicity compared to acyclic amines.
• Diagnostic morpholine protons in 1H NMR would aid analysis of diastereomeric mixtures.
• anti diastereomer formed exclusively.
NO
O
Ph
NO
MeCH2COClCH2Cl2
PhCH2COClCH2Cl2
NO
O
Me
79% Yield 58% Yield
TiCl4 iPr2NEtTiCl4 iPr2NEt
Synthesis of Chiral Allylic Amine Substrate
• Neighbouring group effects gave selective reduction to the aldehyde.
• The presence of BF3∙OEt2 prevented 1,4-reduction.
OMe
O
H
OEtO
PO O
CO2EtEtO
BocNBn BocNBn
BocNBn
NO
NaHTHF BocNBn
BocNBn
OH
CO2Et
BF3·OEt2DIBAL-HCH2Cl2 78ºC
90% Yield
86% Yield
87% Yield
70% Yield
DIBAL-H
Et2O 78ºC
PPh3, NBS
morpholineTHF, 70ºC
Chiral Allylic Amine Claisen Rearrangement
• Deprotected allylic alcohol generated by the hydrolysis of an intermediate vinyl aziridine.
NOBocNBn
PhCH2COClCH2Cl2 BocNBn
O
NOPh BocNBn
O
NOPh HNBn
O
NOPh
17% Yield4.5% Yield
TiCl4 iPr2NEt+
4.5% Yield
+
BocNBnN
O
HNBnOH
NBnO
t-Bu OTiCl4
NO
NBnOH2 N
Bn
BnNN
O
:OH2
(Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry 1998, 9, 3929).
Optimisation of Lewis Acid and Reaction Conditions
• AlCl3, BF3·OEt2, Sc(OTf)3, SnCl4 and ZnCl2 gave very low yields of rearranged product.
• What about a milder titanium Lewis acid?
N
O
N
OPh
O
PhCH2COClCH2Cl2
Lewis Acid iPr2NEt
TiCl4 + n Ti(OiPr)4 (n+1) TiCl4/(n+1)(OiPr)4n/(n+1)
TiCl4 + n AgOTf TiCl4-n(OTf)n + nAgCl
Optimisation of Titanium Lewis Acid
• Optimum conditions found were 0.1 equiv. TiCl(OTf)3, with a 0.17M solution of the acid chloride added dropwise over 5 hours.
N
OMe
ON
O
CH3CH2COClCH2Cl2
PhCH2COClCH2Cl2
N
OPh
O
84% Yield(cf. 79% with TiCl4)
96% Yield(cf. 58% with TiCl4)
TiCl(OTf)3iPr2NEt
TiCl(OTf)3iPr2NEt
Lewis Acid Yield of Product
TiCl4 79%
Ti(OiPr)4 No product isolated
TiCl(OiPr)3 No product isolated
TiCl2(OiPr)2 44%
TiCl3(OiPr) 61%
TiCl2(OTf)2 73%
TiCl(OTf)3 84%
“Ti(OTf)4” 68%
Application of Optimised Conditions to Chiral Substrate
NOBocNBn
PhCH2COClCH2Cl2 BocNBn
O
NOPh
TiCl(OTf)3iPr2NEt
• 0.1 equiv. TiCl(OTf)3 – Starting material.
• 1.2 equiv. TiCl(OTf)3 – 13% deprotected rearranged product.
• Lewis acid coordinating with Boc group.• Lowering the temperature reduced decomposition but inhibited
rearrangement.
• Solution: Use a less Lewis basic tosyl group…
Synthesis of New Chiral Allylic Amine Substrate
OMe
O
H
OEtO
PO O
CO2EtEtO
TsNBn TsNBn
TsNBn
NO
NaHTHF TsNBn
TsNBn
OH
CO2Et
BF3·OEt2DIBAL-HCH2Cl2 78ºC
88% Yield
71% Yield (Over 2 Steps)
76% Yield
DIBAL-H
Et2O 78ºC
PPh3, NBS
morpholineTHF, 70ºC
• 0.2, 1.5 and 2.5 equiv. TiCl(OTf)3 – Starting material.
• Steric hindrance may also be contributing to the lack of reactivity.• Due to lack of reactivity and the large quantities of AgOTf being
used a new method was required…
Belluš−Claisen Modification
N
O
PhCH2COClCH2Cl2
NO
OTMS
Ph
N
OPh
O
N O
OTMS
Ph
74% Yield(cf. 79% TiCl4)
(cf. 84% TiCl(OTf)3)
TMSOTfiPr2NEt
NR2
OLA
R
R' R'
NO
OTMS
R
R'
O
OTMS
R
Ireland ClaisenBelluš Claisen ?
N
OMe
ON
O
CH3CH2COClCH2Cl2
Cl2CHCOClCH2Cl2
N
O
OCl
Cl
83% Yield(cf. 58% TiCl4)
(cf. 96% TiCl(OTf)3)
57% Yield(cf. 44% TiCl4)
(cf. 64% TiCl(OTf)3)
TMSOTfiPr2NEt
TMSOTfiPr2NEt
Extension of Modification to Other Ketenes and Silylating Agents
N
O
PhCH2COClCH2Cl2
N
OPh
OR3SiOTfiPr2NEt
• Catalytic TMSOTf gave a lower yield of rearranged product (44%) and recovery of starting material (48%).
• This is due to the generation of TMSCl, which is less active than TMSOTf.
___________________ Me3SiOTf 74% tBuMe2SiOTf 30% iPr3SiOTf 0%
Silylating Agent Yield
Me3SiCl 0%
Catalytic Belluš−Claisen Modification
N
O
N
OPh
O
53% Yield(15% cat. TMSOTf)
iPr2NEtCH2Cl2
Tf2OPhCH2CO2H
TMSOTfN
OPh
O
52% Yield(12% cat. TMSOTf)
iPr2NEtCH2Cl2
DCCPhCH2CO2H
TMSOTf
• Carboxylic Acid Activation Approach.
• Pentafluorophenol Ester Approach.
N
O
N
OPh
O64% Yield
(13% cat. TMSOTf)
PhOPFP
O
F
FOH
F
FF
76% Yield
PhCH2CO2HDCC
DMAPCH2Cl2
PFP esterTMSOTf
iPr2NEtCH2Cl2
Wolff−Belluš−Claisen Rearrangement
• Wolff Rearrangement Approach.
• In the presence of a tertiary amine and silver salts, α-diazoketones
undergo the Wolff rearrangement.
R Cl
O CH2N2
RN2
OR
OWolff
N
O PhCO2AgNEt3
TMSOTf
PhCOCHN2CH2Cl2
N
OPh
O 43% Yield
Wolff−Belluš−Claisen Rearrangement
• Wolff Rearrangement Approach.
• In the presence of a tertiary amine and silver salts, α-diazoketones
undergo the Wolff rearrangement.
R Cl
O CH2N2
RN2
OR
OWolff
N
ORh2(octanoate)4
TMSOTf
PhCOCHN2CH2Cl2
PhN2
O
TMS
N
OPh
O52% Yield
(46% cat. TMSOTf)
Via (Steer, J. T. Ph.D. Thesis, University of London, 2002).
Extension of Modification to Other Substrates
Ph
OH
Ph
N
O
Ph NO
O
Ph
90% Yield
88% Yield
amination Claisen
OHN
O
N
Ph O
O
H76% Yield
76% Yield
amination Claisen
OH
O
N NPh
O
O
H73% Yield
77% Yield
amination Claisen
OH N
O
NPh
O
O89% Yield
79% Yield
amination Claisen
HNBn
O
NOPh
ON
BocNBn
16% YieldClaisen
Return to Chiral Nitrogen Substrates
• New protecting group strategy.
• Direct reduction using DIBAL-H or lithium aluminium hydride led only to decomposition.
O
NOPh
ON
CH3CH2COClCH2Cl2
MeNBnPhCH2COClCH2Cl2MeNBn MeNBn
O
NOMe
71% Yield
TMSOTfiPr2NEt
TMSOTfiPr2NEt
49% Yield
55 : 45 Mixture of Diastereomers
86 : 14 Mixture of Diastereomers
NO O
N
NaBH(OAc)3HCHO
BocNBn HNBnEtOAc CH2Cl2 MeNBn
NO
92% Yield 75% Yield
HCl
Synthesis of Chiral Oxygen Substrates
• Substrate synthesis.
• The analogous methyl ether failed to undergo rearrangement due to the ether oxygen sequestering the silylating agent.
OTBS
CO2Me
OH
H
OTBSOH
76% Yield(Over 2 steps)
78% Yield
62% Yield
OTBSN
O
PPh3, NBSmorpholineTHF, 70ºC
1) TBSCl imidazole CH2Cl2
2) BuLi ClCO2Me
THF, 78ºC
Red-Al®
Et2O, 30 ºC
OOMeN
Rearrangement of Chiral Oxygen Substrates
• Claisen rearrangement.
NOOTBS RCH2COCl
CH2Cl2
O
NOPhTBSO
O
NOMeTBSO
TMSOTf iPr2NEt
96% Yield(R = Ph)
66% Yield(R = Me)
Single Diastereomers
OOTMS
OR
X
**
(Mulzer, J.; Shanyoor, M. Tetrahedron Lett. 1993, 34, 6545).
Rearrangement of Chiral Carbon Substrates
NOPh
Me
RCH2COClCH2Cl2
MeO
NOPhPh
MeO
NOMePh
TMSOTf iPr2NEt
98% Yield(R = Ph)
72% Yield(R = Me)
Me
PhOH
83 : 17 Mixture of Diastereomers
Single Diastereomer
77% Yield(Over 2 steps)
95% Yield
84% Yield
PhOH
Me
Ph
MeOH
Ph
Me CO2Et
Ph
MeN
O
1) IBX, DMSO
EtOP
O O
CO2EtEtO
NaH, THF
CH2Cl2 78ºC PPh3, NBS
morpholineTHF, 70ºC
2)
DIBAL-H
• Will rearrangement proceed with good 1,2-asymmetric induction in the absence of a heteroatom in the chiral substituent?
Decarboxylative Claisen Rearrangement Reaction
R
OTs
O
R
Ts
PhMe110ºC
BSA KOAc
R
OTs
O
R
Ts
MeOTMS
NTMSKOAc
KTMSOAcMe
NTMS
OCO2
Me NTMS
O
KOAcH
R
OTs
OTMS
R
OTs
OTMS
+
+
+
• Reaction catalytic in both BSA and KOAc.
• Silylating agent essential, no reaction with only KOAc or NaH.
• If 1 equiv. BSA and no KOAc used then rearranged acid formed.
Application and Development of the Decarboxylative Claisen
O
OTs
Ts
OH
88% Yield
esterification DCRR Thermal: 83%Microwave: 89%Microwave, n/s: 83%
OO
Ts
Ts
OH
95% Yield
esterification DCRR Thermal: 89%Microwave: 67%Microwave, n/s: 80%
O
OTs Ts
OH
61% Yield
esterification DCRR Thermal: 86%Microwave, n/s: 74%
Ph
OTs
OTs
PhPh
OH
88% Yield
esterification DCRR Thermal: 88%Microwave, n/s: 72%
BnO OTs
O
BnO
Ts
BnO OH
96% Yield
esterification DCRR Thermal: 77%Microwave, n/s: 58%
Asymmetric Induction in the Decarboxylative Claisen
BocNBn
O
OTs
DCRR
BocNBn
Ts
BocNBn
Ts+ 74% Yield
50 : 50
TsNBn
O
OTs
DCRR
TsNBn
Ts
TsNBn
Ts+
55 : 45
78% Yield
O
OTs
OTBS
DCRR Ts
OTBS
Ts
OTBS
+
88 : 12
62% Yield
MeO
OTs
Ph
DCRR Me Ts
Ph
Me Ts
Ph
+
60 : 40
63% Yield
Heteroaromatic Claisen Rearrangements
OOH
OEt O
CHO
O
CHO
O CHO
21% Yield
2% Yield
Hg(OAc)2 NaOAc
100°C 18 h
• The Claisen rearrangement of heteroaromatic substrates.
OHS
CO2Et
MeC(OEt)3 Me(CH2)4CO2H
OS
CO2Et
OR'
CO2Et
O
OEt
S
SCO2Et
CO2Et
61% Yield185°C 18 h
(Thomas, A. F.; Ozainne, M. J. Chem. Soc. C 1970, 220).
(Raucher, S.; Lui, A. S.-T.; Macdonald J. E. J. Org. Chem. 1979, 44, 1885).
Heteroaromatic Decarboxylative Claisen
O
OTs
O
DCRR
S
OTs
O
DCRR
NTs
OTs
O
DCRR
O
Ts
S
Ts
NTs
Ts
Thermal: 63%Microwave: 75%
Thermal: 75%Microwave: 22%
Thermal, cat: 47%
Thermal: 67%Microwave: 77%
Thermal, cat: 48%Microwave n/s: 70%
• Ts group on nitrogen essential for synthesis and stability of ester.
S
OTs
O
S
Ts
58% YieldDCRR
Extension of Heteroaromatic Substrates
O
O
OTs
O
OO
OTsTs
OS
O
OTs
S H
O MeMgCl
THF S Me
OH Esterify
S
OTs
O
Me
92% Yield 95% Yield
• Secondary alcohol derived ester.
X
O
OTMSTs
X
OTs
OTMS
Where X=O or S
• However,
No rearrangement.
DCRRS
Ts
Me
Stoichiometric: 58%Catalytic: 43%
Mechanistic Details
X
OTs
O
X
X
OTs
OTMS
Ts O
OTMS
X
Ts
X
Ts
• Proposed Mechanism,
• What about indoles?
NH
CO2H
H2SO4
Ts
NTs
EtOH
DCRR
NTs
O
OTs
NH
CO2Et THF
NaH TsCl
Esterify
OHNTs
NTs
CO2Et
LiAlH4 THF
95% Yield 73% Yield
79% Yield
83% Yield
Indoles as Heteroaromatic Substrates
O
OTMSTs
NTs
O
NTs
TsOTMS
• Considering electron density…
H
O
NH
NaH TsCl
THF NTs
H
O
DCRR
NTs
Ts
THF
LiAlH4
O
O
NTs
Ts
NTs
OH
Esterify
Thermal: 28%Microwave: 16%
Thermal, cat: 61%Microwave, cat: 29%
79% Yield
95% Yield
92% Yield
• Try again
Mechanistic Studies
O
OTs
NTs
NTs
TsNTs Ts
OTMS
O
O
OTMSTs
NTs
• 1H NMR Studies.
Stoichiometric: 58%Catalytic: 60%
NTs
TsNTs
O
OTs
Me Me
DCRR
• Secondary alcohol derived ester.
Carboaromatic Claisen Rearrangements
O
O O
O HO
OMe
• Allyl phenyl ethers undergo Claisen rearrangement, benzyl vinyl ethers however, will not generally undergo rearrangement .
76% Yield
DMFOH
OMe
NMe2
CONMe2
Me+
160ºC
• An EschenmoserClaisen rearrangement.
(Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta. 1969, 52, 1030).
OMe
MeO
OTs
O
DCRR
OMe
TsMeO MeO
MeO
MeO OMe
OTs
O
+
47% Yield20% Yield
O
OTs
OTs
O
23% Yield
Me
OTs
O
NO2Me
NO2
O
OTs
MeNO2
17% YieldDCRR
DCRR
Carboaromatic Decarboxylative Claisen
• No evidence of Claisen rearrangement observed.
Alkylation of Carboaromatic Substrates
OMe
MeO
OTs
O
OMe
MeOTs
O
MeO
MeO
OTs
MeO OMe
OMe
MeO
OTs
O
OMe
MeO
OH
OMe
MeO
Ts
O
O
+
• Proposed mechanism.
• Attempts to facilitate both a radical-induced reaction and a Lewis acid-catalysed rearrangement led only to decomposition.
Conclusion
Belluš−Claisen Rearrangement
• Refined experimental procedure for Belluš−Claisen rearrangement.• Developed a novel, metal free variant of the Belluš−Claisen
rearrangement.• Applied new methodology to a range of ketenes and allylic amines,
substrates with exopericyclic substituents shows good selectivity.
Decarboxylative Claisen Rearrangement Reaction
• Decarboxylative Claisen rearrangement applied to a wide range of substrates, including heteroaromatics.
• Microwaves greatly increased reaction rate and removed need for solvent.
Thanks to…
• Prof. Donald Craig• Dr Paul King (GSK)• The Craig Group, especially Drs Damien Bourgeois, John Caldwell
and Tanya Wildman• Ian Campbell (Microwaves)• Dr Andrew White (Crystal Structures)• Dick Shepard, Peter Haycock and Sean Lynn (NMR)
• EPSRC• GSK (CASE Studentship)