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Microwave-assisted Synthesis ofHighly Substituted Aromatics
User Group Meeting
Fitzwilliam College, Cambridge
27 October 2005
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Department of ChemistryImperial College London
Microwave-assisted Synthesis ofHighly Substituted Aromatics
� Synthesis of homoallylic sulfones from allylic tosylacetates using a new variant of the Ireland–Claisen rearrangement reaction
� Mono and tandem rearrangements of allylic tosylmalonates
� Method development: synthesis of pyridines and phenols from 1,5-dicarbonyl compounds
� Applications to alkaloid total synthesis
� Use of microwave irradiation for sterically demanding substrates
Decarboxylative Claisen rearrangement (dCr) reaction: origins of the methoda hetero-Diels–Alder approach to (–)-alstonerine
NMe
O
MeN
O
NTs
O
MeN
O
NTs
O
MeN
OTBDMS
NTs
MeN
O
TsN
MeN
(-)-alstonerine
+
+
O O
Tetrahedron Lett. 2005, 46, 4687
dCr Reaction: origins of the methodNovel alk-2-en-1,5-dicarbonyl synthetic equivalents for phenol and pyridine synthesis
OSO2Ph
Li
O
Ts
NH3
N
R R
R R
O OR R
R
R
RR
R R
RR
Ts
base
R R
R
R
HO RR
The pent-2-en-1,5-dial equivalentphenol synthesis… using Pd(0) chemistry
CO2R
OCO2MeMeO2CO
Ts
R2
Pd(0)
+ +
R6
Ts
R2
Ts
R2
CO2R
R4R4
R2 OH
1. decarboxylate NaCl, DMSO, H2O µµµµw, 240 °C, 10 min
2. alkylate 1. O3
2. base
R6
R6 R6
1. O3
Ts
O OR2
CO2R
R6
2. base
CO2R
R2 OH
R6
The pent-2-en-1,5-dial equivalentphenol synthesis using Pd(0) chemistry
Ts
O OR2
CO2R
R6
base
CO2R
R2 OH
R6
base: 8 equiv NaHCO3, MeOH, rt, 30 min: yields < 50%
R2 = Me, R6 = H
base: 2.1 equiv NaHCO3, MeOH, µµµµW, 100 °C, 30 min: yields > 80%
The pent-2-en-1,5-dial equivalentpyridine synthesis using Pd(0) chemistry
Tetrahedron Lett. 2005, 46, 2559
Ts
R6
R2
Ts
R6
R2
CO2R R4R4
NR2 R6
1. decarboxylate
2. alkylate
1. O3
2. NH3, MeOH
problem: how do we access 3-/5- substituted pyridinesusing this methodology?
best ammonolysis conditions are now:
NH4HCO3 (8 equiv)MeOHµµµµw, 100 °C, 10 min
Extending the pyridine synthesissolving the substitution problem
R6
R2
Ts
R3
N
R3
R2 R6
R6
R2
Ts
R3
-CO2
O
OH
FGA
R6
Ts
O
R2
O
R3
R6HO
O
Br
R2
R3HO
Ts
+ +
+
dCr reaction: background
Davidson, A. H.; Eggleton, N.; Wallace, I. H. J. Chem. Soc., Chem. Commun. 1991, 378
O
OSO2Ph
O
MeHO
OSO2Ph
OSiMe3
MeH
OH
SO2Ph
CO2H
OH
SO2Ph
LDA, Me3SiCl warm to r.t.;
H3O+ work-up
NaHCO3, H2O
heat
The dCr reactiona new variant of the Claisen rearrangement
Ts
O
O
Ph
Me Ts
Ph
Me
TMSN
OTMS
(0.1 - 1 equiv)
KOAc (0.1 equiv)
PhMe, reflux, 16 hOR
microwave, 150 ºC, 5 min
"BSA"
R
RTs
Claisen-mediated[3,3]
R
RTs
Pd(0)-mediated
R
OR3Sn
R
HO
R
HO
Still-Wittig[2,3]
RLi
Decarboxylative Claisen rearrangementscope
OTs
OTs
OTs
OTs
OTs
OBnO
BnO
Ts
Ph OTs
O
Ph
Ts
Ph OTs
O
Ph
Ts
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
O
Ts
OTs
OTs
OTBS OTBS
OTs
OTs
BocNBn BocNBn
PhO
TsO
Ph
Ts
Decarboxylative Claisen rearrangementproposed catalytic cycle
Angew. Chem. Int. Ed. 2005, 44, 618; Organocatalysis Symposium-in-Print, Tetrahedron 2005, 61, in press
TMSN
OTMS
TMSN
O
TsO
R
O
+ TMSOAc
KOAc+
TsO
R
OTMS
TsO
R
OTMS
TMSNH
O
Ts
R
CO2
+ KOAc
K
[3,3]
'BSA'BSA only
or
BSA, Et3N
TsOH
R
O
Decarboxylative Claisen rearrangementscope and versatility
S
O
OTs
S
Ts
X
O
OTs
X
Ts
X = NTs, O, (S)comparable yields forconventional thermal andmicrowave conditions
BSA (1.0), KOAc (0.1)
heat
BSA (1.0), KOAc (0.1)
heat
thiophene-derived substrates: lower yields under microwave conditions
S
O
OTs
S
Ts
Me Me
NTs
NTs
R = H, Me
O
O
Ts
R = H, Me
Ts
BSA (1.0), KOAc (0.1)
heat
Decarboxylative Claisen rearrangementaccelerated reactions of tosylmalonates
Org. Lett. 2005, 7, 463
MeO O R1
O O
Ts
OMe
O
Ts
R1
TBDMSOTf (2.1 equiv), DBU (2.1 equiv)CH2Cl2room temperature, 15 min(R1 = Ph)83%
BSA (1 equiv), KOAc (0.1 equiv)CH2Cl2room temperature, 4 h(R1 = Ph)81%
MeO O R1
O O
t-BuOK
TsFDMSO
Decarboxylative Claisen rearrangementaccelerated reactions of tosylmalonates: an alternative mechanism
MeO O R1
O O
Ts
OMe
O
Ts
R1
TBDMSOTf (2.1 equiv), DBU(2.1 equiv)CH2Cl2room temperature, 15 min(R1 = Ph)83%
MeO O R1
TBDMSO O
Ts
MeO O R1
O OTBDMS
Ts
MeO O
O O
R1
[3,3]
R3Si
Ts
MeO
OSiR3
R1
Ts retro-
ene
work-
up
CO2
Decarboxylative Claisen rearrangementreactions of doubly allylic tosylmalonates
R1 O O R2
O O
Ts
O R2
O
Ts
R1
BSA (1 equiv), KOAc (0.1 equiv)room temperature
electron-rich R rearrange first
R2
Ts
R1
microwave
150 °C,5-10 min
Decarboxylative Claisen rearrangementhighly selective mono-rearrangement reactions of tosylmalonates
O O
O O
Ts
O Ph
O
Ts
4-MeOC6H4
4-MeOC6H4 Ph
O O
O O
Ts
O C6H44-NO2
O
Ts
Ph
Ph C6H44-NO2
O O
O O
Ts
O Ph
O
TsPh
O O
O O
Ts
O
O
Ts
Ph
Ph
BSA (1 equiv)
KOAc (0.1 equiv)CH2Cl2
r.t.
Decarboxylative Claisen rearrangementtandem rearrangement reactions of tosylmalonates: effect of substitution
O O
O O
Ts
Ph
Ts
Ph
BSA (3), KOAc (0.1)
170 °C, 4 min86%4 g scale
O O
O O
Ts
Ph
Ts
Ph
BSA (8), KOAc (0.1)
200 °C, 4 x 3 min77%
O O
O O
Ts
Ph
Ts
Ph
BSA (8), KOAc (0.1)
240 °C, 2 x 3 min70%
O O
O O
Ts
Ts
BSA (3), KOAc (0.1)
240 °C, 4 min81%
I-Pr
Decarboxylative Claisen rearrangementtandem rearrangement reactions of tosylmalonates: effect of substitution
O O
O O
Ts NBn2 NMe
O
O
Ts NBn2 NMe
TBDMSOTf (2.1), DBU (2.1), CH2Cl2µµµµw, 60 °C, 30 min
83%
Ts NBn2 NMe
NBn2 NMe
N
BSA (15), KOAc (0.1) no solventµµµµw, 10 x 1' pulses at 200 °C, 1 min cooling between each
19%
O3
NH3
Extending the pyridine synthesisapplying the new reaction to target synthesis
N
HOcananodine
Wu, Y.-C. et al.J. Nat. Prod. 2001, 64, 616.
Extending the pyridine synthesisretrosynthetic analysis of cananodine
N
HO
CO2Me
Ts
CO2Me
O
OTs
CO2Me
HO
N
O
OO
i-Pr(R)-citronellene
Total synthesis of cananodinealternative retrosynthetic analysis of the key acyloxazolidinone
N
O
OO
i-PrN
O
OO
i-PrN
O
OO
i-Pr
N
O
OO
i-PrBr
XC
O
H
XC
O
H
Nakai, T. et al. Tetrahedron Lett. 1996, 37, 8895, 8899.
N
O
OO
i-PrN
O
OO
i-PrBr
LHMDS, DMPU, -78 ºC
add
57%
N
O
OO
i-Pr
naphthalene
220 ºC, 5 h
83%
N
O
OO
i-Pr
L-Selectride
-78 ºC
60%
Total synthesis of cananodinealternative retrosynthetic analysis of the key acyloxazolidinone
ON
OO
i-Pr
6 steps
30-40%HO
PO Br1. NaHMDS,
2. HCl, MeOH3. Grubbs II
60-70% P = TBDPSN
O
OO
i-Pr
CO2Me
O
OTs
1. MeOH, K2CO3
2. esterify (DCC)
80-90%
Total synthesis of cananodineassembly of key dCr reaction substrate
Total synthesis of cananodinefailed dCr reaction…
CO2Me
O
OTs
CO2Me
HO
Ts
+BSA, KOAc
xylene, reflux
HO
OTs
Total synthesis of cananodinecompletion of the synthesis
CO2Me
Ts
CO2Me
O
OTs
BSA, KOAc
microwave, 150 ºC15 min
72%
H
assignedconfiguration
two diastereomers
N
HO
1. O3, Ph3P; NH3, EtOH2. MeMgBr
69%
AcknowledgementsDr Damien Bourgeois
Dr Fabienne Grellepois
Gavin Henry
Simon Lewis
David Mountford
Federica Paina
Stephen Johns
Alan Stewart
Dr Andrew White (X-ray)
GlaxoSmithKlineDr Paul King, Dr Juliet Simpson
PfizerDr Mark Lansdell
Rhône–Poulenc Rorer/Aventis Pharma/Aventis CropScienceDr Paul Cox, Sue Cramp
SyngentaDr Steve Smith
EPSRC
European Commission
