Embed Size (px)
Citation preview
1
Microwaves for the Synthesis of Heterocycles
July 29-31 2008, Edinburgh
Doris Dallinger
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)and Institute of Chemistry, University of GrazHeinrichstrasse 28, A-8010 Graz, [email protected]
Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250; Chem. Soc. Rev. 2008, 37, 1127 Kappe, C. O.; Stadler, A. “Microwaves in Organic and Medicinal Chemistry” Wiley-VCH, 2005Van der Eycken, E.; Kappe, C. O. (Eds.) “Microwave-Assisted Synthesis of Heterocycles”, Springer, 2006
Applications
• Transition Metal Catalyzed C-X Bond Formation• Other Metal-Mediated Processes• Metathesis, CH-Bond Activation• Cycloaddition Reactions• Rearrangements• Enantioselective Reactions• Organocatalysis, Biocatalysis• Radical Reactions• Oxidations, Reductions• Heterocycle Synthesis• Total Synthesis
• Solid- /Fluorous Phase Synthesis• Immobilized Reagents,Scavengers and Catalysts• Solid Phase Peptide Synthesis
Microwave Heating in Modern Organic Synthesis
2
Outline
• Quinolinones
• Bisquinolones
• Desulfitative C-C cross-couplings
Heterocycle Synthesis
SiC Passive Heating Elements
• Heating aids
• Modulation of MW power (MW effects)
N OR1
R2
OR3
R4
R5
R6
R7 N O
H
CO2EtOMe
Cl
F3C
N OH
CH2OHOMe
Cl
F3C
• active in in vivo animal model of male ED
Bristol-Myers Squibb (BMS) Compounds
Hewawasam,P. et al. J. Med. Chem. 2003, 46, 2819
Hewawasam,P. et al. (BMS), Int. Pat. WO 00/34244 (2000)
4-Aryl-2-quinolinones as Maxi-K+ Channel Openers for the Treatment of Erectile Dysfunction
3
Suzuki
HeckN OH
CO2Et
OMe
Cl
F3C
Transition Metal-Catalyzed Chemistry
• highly diverse• flexible• amenable to high-speed MAOS• commercially available building blocks
A Modular Strategy
Glasnov, T. N. et al. J. Org. Chem. 2005, 70, 3864
Multistep Synthesis of 4-Aryl-2-quinolinones –“First Choice”, not “Last Resort”
NH2
F3C
NH
F3CO O
NH
CF3CH2(COCl)2 DCM
(lit.)
95 %
N OH
F3COH
P4O10 in MeSO3H (Eaton's Reagent)
MW, 120 °C, 20 min
65 %
7 steps total, 32% overall yield, no chromatography!
NH2
F3C
NH
F3CO O
NH
CF3CH2(COCl)2 DCM
(lit.)
95 %
N OH
F3COH
P4O10 in MeSO3H (Eaton's Reagent)
MW, 120 °C, 20 min
65 %
N OH
F3CCl1. POCl3, dioxane
MW, 120 °C, 20 min
2. MeSO3H, EtOH MW, 120 °C, 25 min
72 %
N OH
OMe
Cl
F3C Br NBS, MeCN
MW, 100 °C, 1 h
97 %
N OH
CO2EtOMe
Cl
F3C
ethyl acrylate Pd(PPh3)4 Et3N, DMF
MW, 150 °C, 45 min
90 %N OH
OMe
Cl
F3C
1.2 equiv ArB(OH) 20.5 mol% Pd(OAc) 2, PPh3 Et3N, DME/H2O (3:1)
MW, 150 °C, 30 min
91 %
Glasnov, T. N. et al. J. Org. Chem. 2005, 70, 3864
4
N OMe
NBS, MeCN
MW N OMe
Br
N OMe
Br
+
A B
Temperature Time Ratio A : B
0 °C (DMF) 17 h 92 : 825 °C ∆ 4.5 h 83 : 1750 °C ∆ 3 h 55 : 45100°C MW (MeCN) 0.3h 5 : 95
Temperature Dependence Thermodynamic Stability
B ∆ kcal/mol
AM1 -4.86PM3 -3.82B3LYP(3-21G*) -1.25B3LYP(6-31G*) -3.01
Glasnov, T. N. et al. J. Org. Chem. 2005, 70, 3864
Where Microwaves Don ´t Work:Bromination of Quinolin-2-ones
Importance of Symmetrical Biaryl Units
• Part of natural products including alkaloids, coumarins, polyketides, terpenes
• Chiral ligands and reagents, chiral phases for chromatography, chiral liquid crystals
• Pharmaceuticals, agrochemicals
Williams. L. P.; Giralt, E. Chem. Soc. Rev., 2001, 30, 145
NH
OH
Me
OMeOH
OHOMe
Me
HN
OHMe
Me
Me OH
MeHO
michellamine Banti-HIV
PPh2
PPh2
BINAP
O O
O
OOOO
O
O O
paracyclophanes
OHHO
4,4'-biphenollaxative
N N MeMe
2 Cl
paraquatherbicide
5
Symmetrical 4,4 ´-Bis-quinoline-2(1 H)-ones
• Aza-analogues of biscoumarin natural products
• Fluorescent properties (push-pull carbostyrils)
• Aza-BINAP analogues
Pharkphoom, P. et al. Planta. Med. 1998, 64, 774
Lei, J.-G. et al. Chin. J. Chem. 2002, 20, 1263
N O
R1R2R3
R4
NO
R1 R2
R3
R4
O O
OMe
HO
MeO
OO OH
OMe
OMe
N
N O
O
R3
R4
R4
R3
R1
R1
PPh2
PPh2
R1 = Me, Ph; R2 = H, alkylR3 = R4 = H, OMe
4,4'-biisofraxidin "aza-BINAP"
N OR1R2
R3
R4
NOR1 R2
R3
R4
N OR1R2
R3
R4Cl
OB
OBO
O[B(Pin)] 2
[Pd(0)], dppf, [B(Pin)] 2, base, solvent
[Ni(0)], PPh 3, solvent
cf. Pd(0) + Ni(0): Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265
Pd(0): Nising, F. N. et al. J. Org. Chem. 2004, 69, 6830
Ni(0): Tiecco, M. et al. Synthesis 1984, 736
Janiak, C. et al. Synthesis 1999, 959
Symmetrical Bisquinolones
via Pd(0) catalyzed one-pot borylation/Suzuki cross-coupling or
Ni(0) mediated homocoupling
6
One-Pot Borylation/Suzuki Cross-Coupling Reaction
Model Reaction
N OMe
OH
N OMe
ClPOCl3, dioxane
82 %
MW, 120 °C, 25 min
OB
OB
O
O
N O
B
Me
OO
MW, temp, time
[Pd], ligand, base, solvent
Best conditions
[Pd]: 10 mol% PdCl2(dppf)ligand: 7 mol% dppfbase: KOH (4.5 equiv)solvent: n-BuCltemp/time: 130 °C, 30 min
NMe
O
Cl
N O
N O
Me
Me
N
H
MeO
97% conv 3% conv
Hashim, J. et al. J. Org. Chem. 2006, 71, 1707
Reaction Monitoring
• 97% conversion to
product based on
HPLC peak area (%)
NMe
O
Cl
N O
NMe
O
Me
97% conv85% yield
10 mol% PdCl 2(dppf), 7 mol% dppf, 0.7 eq [B(Pin)] 2 4.5 eq KOH, n-BuCl, MW, 130°C, 30 min N
MeO
H
1 2
Optimized Conditions
HPLC of Crude Rxn Mixture (215 nm)
2
1
7
Ni(0)-Mediated Homocoupling Reaction
NMe
O
Cl
NMe
O
NMe
O
NiCl 2, Zn, PPh3, solventiodide additive
MW, temp, time N
Me
O
H
Model Reaction
Best conditions
[Ni]: NiCl2 (1.3 equiv)Zn: 1.3 equivligand: PPh3 (4.0 equiv)iodide additive: KI (1.8 equiv)solvent: DMFtemp/time: 205 °C, 25 min
90% 4%
General High-Speed Protocols for Symmetrical Biaryl Syntheses
(Het)Ar-X
Method A:PdCl2(dppf), dppf, [B(Pin)]2, KOH, n-BuClMW, 130 °C, 35 min
Method B:NiCl2, Zn, PPh3, KI, DMFMW, 205 °C, 25 min
(Het)Ar-Ar(Het)
X = Cl, Br10 examples
(39-98% yield)
N O
NMe
O
MeO
MeO
Me
N
Ph
O
N OPh
Pd (83%)Ni (39%)
Pd (83%)Ni (70%)
O O
O O
SS
Pd (91%)Ni (65%)
Pd (89%)Ni (65%)
Pd (67%)Ni (98%)
N
N
Pd (91%)Ni (94%)
Examples:
Hashim, J. et al. J. Org. Chem. 2006, 71, 1707
8
General High-Speed Protocols for Symmetrical Biaryl Syntheses
(Het)Ar-X
Method A:PdCl2(dppf), dppf, [B(Pin)]2, KOH, n-BuClMW, 130 °C, 35 min
Method B:NiCl2, Zn, PPh3, KI, DMFMW, 205 °C, 25 min
(Het)Ar-Ar(Het)
X = Cl, Br10 examples
(39-98% yield)
Disadvantages:
Hashim, J. et al. J. Org. Chem. 2006, 71, 1707
Borylation/Suzuki:
• expensive [B(Pin)]2
• 10 mol% of costly PdCl2(dppf)
Homocoupling:
• stoichiometric amount of Ni(II)
• 4 equiv PPh3 → work-up tedious
• Preparation of bisquinolones in < 50 mg
• Scale-up troublesome
Ni(0)-Catalyzed Homocoupling Reaction
N
R1
O
ClNiCl2(PPh3)2, DPEphos , Zn, KI
dioxane
MW, 130 °C, 30 min
R2
R3
R4
N
R1
O
R2
R3
R4
NR1
OR2
R3
R4
6 examples(71-92%)
O
PPh2 PPh2
R1, R2 = Me, (CH2)3R3, R4 = H, OMe
Ni(0)-mediated
[Ni]: NiCl2 (1.3 equiv)Zn: 1.3 equivligand: PPh3 (4.0 equiv)iodide additive: KI (1.8 equiv)solvent: DMFtemp/time: 205 °C, 25 min
Ni(0)-catalyzed
[Ni]: NiCl2(PPh3)2 (0.25 equiv)Zn: 1.3 equivligand: DPEphos (0.25 equiv)iodide additive: KI (1.8 equiv)solvent: dioxanetemp/time: 130 °C, 30 min
• less metal required
• purification simplified
• equal yields
• scale-up possible (g scale)
Hashim, J.; Kappe, C. O. Adv. Synth. Catal. 2007, 349, 2353
9
Arshad, N. et al. J. Org. Chem. 2008, 73, 4755
Aza-BINAP Ligand Synthesis
N
Cl
MeO
NMe
O
NMe
O
N
Me
O
NMe
O
XBr
NiCl 2(PPh3)2DPEphos, Zn, KI
dioxane
MW, 130 °C, 30 min
NBS, DMF
[Pd] = Herrmann's palladacycle
X = Br: 82%X = H: 62%
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeOMeO
MeO
rt, 35-50 min
NMe
O
NMe
O
H
PPh2
Ph2PH, [Pd]KOAc, DMF
MW, 160 °C, 10 min
X = H MeO
MeO
MeO
MeO
75%
NMe
O
NMe
O
PPh2
PPh2
Ph2PH, [Pd]KOAc, DMF
MW, 160 °C, 10 min
X = BrMeO
MeO
MeO
MeO
73%
High-Speed, High-Throughput DHPM Decoration
Polymer-Supported Reagents and Scavengers, Solid-Phase Extraction, Fluorous Reagents and Scavengers
Me N
NH
O
MeO
O
F
Me NH
NMeO
O
F
Cl
S
Me N
Ni-PrO
O
NO2
O
O Cl
Me N
NEtO
O
OMe
COOMe
Me NH
NHEtO
O
O
NH
O
Me NH
NHNH
O
S
Cl
Me N
NHO
O
OMe
NH
NH
O
Me O
F
F
Br
NH
NHO
O
O
S
NNN
Et
CF3
17 examplesSL 2002, 1901
44 examplesOL 2003, 1205MD 2003, 229
17 examplesT 2006, 4261
27 examplesJCC 2004, 884
6 examplesOL 2004, 771
10 examplesJCC 2005, 574
19 examplesJCC 2005, 574
10 examplesT 2006, 4261
30 examplesJCC 2007, 415
Me NH
NH
Z
X
RX
O
10
N
NEtS
O
Me O
H
H
86%
N
NEtS
O
Me O
H
S
Me
62%
N
NEtS
O
Me O
H
H
OMeOMe
76%
N
NEtS
O
Me O
H
H
CF3
66%
Br
Examples
Synthesis of C5 Thiol Esters
OHN
H
R1
OTMSCl, MeCN
MW, 120°C, 10 min N
NEtS
O
Me
R2
O
HR1
R2
+
Me O
(53-90%)6 examples
O
EtS NH2
Synthesis of 5-Aroyl-DHPMs Step 1: The Biginelli Reaction
cf. Kadis, V. et al. Khim. Geterotsikl. Soedin. 1985, 117Prokopcová, H. et al. Synlett 2007, 43Pisani, L. et al. J. Comb. Chem. 2007, 9, 415
Liebeskind-Srogl Ketone Synthesis
• base free
• orthogonal to Suzuki reaction
• catalytic in Pd(0)
• stoichiometric amounts of Cu(I) carboxylate
• other Cu(I) salts not effective
Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979
Proposed Mechanism
PdLL
SR1OC
O
2-thienylOCu
BOH
R3
HO
PdLL
R3R1OC
-(OH)2BTC
-CuSR2
R2
Carbon-Carbon Coupling of Thiol Esters
CuTC =S COOCu
B(OH)2
[Pd], ligand,Cu(I) cofactor (CuTC)
THF, 50 °C, 18 h
O
S R1R2O
R3 R1
13 examples(52-93%)
R3
Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260
OOMe O O
ClCF3
OO2N
88% 81% 57% 63%
N
N
Examples:
11
N
NEtS
O R1
O
H
R2
Me
B(OH)2
N
NR3
O R1
O
H
R2
Me
10 mol% Pd(OAc) 220 mol% PPh 3
3 equiv CuTC, dioxane
MW, 130 °C, 1 h+ R3
Synthesis of 5-Aroyl-DHPMs Step 2: Thiol Ester-Boronic Acid Coupling
Scale Up
2 mmol
Pisani, L. et al. J. Comb. Chem. 2007, 9, 415
• automated vessel transfer
• liquid handler
• reaction optimization
• sealed vessels (0.2-5 mL)
• up to 120 reactions
• 250 °C, 20 bar
Emrys Liberator
0.3 mmol
Automated Sequential Library Synthesis
6 thiol esters 5 boronic acids 30 examples(57-88%)
• 48 vessels• filling volume 6-25 mL• 200 °C, 20 bar• screw-cap with cone-shaped seal• metal safety disk (30 bar)• p/T-sensor for reference vessel
HTP Rotor48 (Synthos 3000) Reaction Homogeneity
0
10
20
30
40
50
60
70
80
90
100
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46
Vessel Number
Con
vers
ion
[%]
• good homogeneity between individual vessels• good translation from single-mode rxns
Parallel Processing (Multimode Cavity)
O OH O OEtOH/1 M H2SO4 = 2:1
MW, 140 °C, 20 min
Pisani, L. et al. J. Comb. Chem. 2007, 9, 415
12
Pisani, L. et al. J. Comb. Chem. 2007, 9, 415Kremsner, J. et al. J. Comb. Chem. 2007, 9, 285
Parallel Library Synthesis
N
NEtS
O R1
O
H
R2
Me
B(OH)2
N
NR3
O R1
O
H
R2
Me
10 mol% Pd(OAc) 220 mol% PPh 3
3 equiv CuTC, dioxane
MW, 130 °C, 1 h+
16 examples(63-86%)
5 thiol esters 5 boronic acids
R3
• 16 compounds synthesized in rotor• total irradiation time: 1 h• minimal yield deviation between
single-mode and multimode run (typically 3-4%)
48 vessel rotor200 °C, 20 bar6-25 mL
• 16 compounds synthesized in rotor• total irradiation time: 1 h• minimal yield deviation between
single-mode and multimode run (typically 3-4%)
48 well plate200 °C, 20 bar0.05-0.3 mL
Comparison of Yields:Sequential vs Parallel Synthesis
N
N
O
MeH
O
H
S: 86%P: 80%
N
N
O
MeH
O
HCl
S: 64%P: 62%
Br
N
N
O
MeH
O
H
F
S: 66%P: 63%
CF3
N
N
O
MeH
O
HCl
S: 74%P: 71%
MeOOMe
N
N
O
MeMe
O
H
S: 68%P: 66%
N
N
O
MeMe
O
H
S: 82%P: 86%
S
N
N
O
MeH
O
H
S: 63%P: 64%
MeOOMe
N
N
O
Me
H
O
H
S: 66%P: 69%
Br
F
Me
S
Me
Examples of 5-Aroyl Dihydropyrimidines
13
Gartner, M. et al. ChemBioChem 2005, 6, 1173Garcia-Saes, I. et al. J. Biol. Chem. 2007, 282, 9740Review : Sarli, V.; Giannis, A. ChemMedChem 2006, 1, 293
Mitotic Kinesin Eg5 Inhibitors X-Ray of Human Eg5 / (R)-mon-97Complex
NH
NH
S
O
Me
MeNH
NHEtO
Me S
O
N
NHPh
Me S
O
(S)-MonastrolIC50 14.000 nM
DimethylenastronIC50 200 nM
(R)-mon-97IC50 110 nM
NN
F
F
O Me
OH
(S)-Pyr azole (Merck)IC50 26 nM
OH OH
OH
Me
Application
F
ClCHO
OMe
MeO2CNH2
H2N S
NH
NH
Me
MeO2C
S
F
ClYb(OTf) 3, MeCN
MW, 120 °C, 20 min+
87 %
ArB(OH) 2Pd(PPh3)4, CuTC
THF
MW, 100 °C, 25-60 minNH
N
Me
MeO2C
F
Cl
Ar
NH
NMeO2C
Me
F
Cl
N
F
FBay 41-4109
14-81%
Ar = Ph, 4-ClPh, 3-MePh, 2,6-F 2Ph, 2-thiopheneScience 2003, 299, 893
Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771
Synthesis of 2-Aryldihydropyrimidines (Bay 41-4109 Analogs)
Nonnucleosidic Inhibitors of Hepatitis B Virus Replication
14
Summary Heterocycle Synthesis
• Development of a novel general route to pharmacologically important 4-aryl-2-quinolones
• Six Step, all microwave multistep synthesis• Diversity introduced at a late stage of the synthesis via transition metal-
catalyzed protocols
• Synthesis of symmetrical (hetero)biaryls via MW-assisted Pd(0)-catalyzed borylation/Suzuki coupling or Ni(0)-mediated homocoupling
• Development of a Ni(0)-catalyzed homocoupling protocol for the synthesis of symmetrical bisquinolones
• Synthesis of novel types of aza-BINAP analogues derived from the 4,4’-bisquinolone framework
• Diversity generation on the DHPM scaffold via a 2-step Biginelli-C-C coupling rxn• Generation of a small library of 30 5-aroyl-DHPMs via an automated sequential
or parallel protocol• Time reduction by applying parallel processing techniques (16 h vs 1 h for 16
cmpds)
Silicon Carbide as Novel Passive Heating Elements for Organic Synthesis
15
Low Microwave Absorbing Solvents
Problems:
• Microwave heating relies on polar solvents � dipolar polarization mechanism
• Reaction mixtures involving non-polar solvents often do not absorb microwave energy
• Microwave synthesis in low-absorbing or microwave transparent solvents is often
not feasible
20
40
60
80
100
120
0 50 100 150 200 250 300
Tem
pera
ture
[°C
]
Time [s]
4 mL Solvent, Quartz Vessel, 150 W Single-mode MW Irradiation
CCl4
dioxane
hexane
toluene
xylene
Heating Aids for Low Absorbing Solvents:Standard Methods
20
60
100
140
180
220
0 100 200 300 400 500 600
0.300 M
0.150 M
0.070 M
0.035 M
0.000 M
20
60
100
140
180
0 100 200 300
100% EtOH
15% EtOH
10% EtOH
5% EtOH
2% EtOH
1% EtOH
pure CCl4
20
60
100
140
180
220
0 100 200 300 400
0.06 M
0.015 M
0.0075 M
0.00375 M
0.0 M
NaCl Concentration:
N
N
Me
Me
PF6
DCE Doped with Ionic Liquid
CCl4 Doped with EtOH Water Doped with NaCl
• Invasive• Inadvertently modify the polarity of the
solvent• May be incompatible with the chemistry• Technical difficulties in case of biphasic
mixtures (ionic liquids)
Disadvantages:
Nüchter, M. et al. Chem. Eng. Technol. 2003, 26, 1207Leadbeater, N. E.; Torenius, H. M.; Tye, H. Comb. Chem. High Throughp. Screen. 2004, 7, 511Habermann, J.; Ponzi, S.; Ley, S. V. Mini-Rev. Org. Chem. 2005, 2, 125
16
General Properties of SiC
Properties of Silicon Carbide (Ed.: Harris, G. L.), Institute of Electrical Engineers, 1995Silicon Carbide: Recent Major Advances (Eds.: Choyke, W. J. et al.), Springer, Berlin, 2004Advances in Silicon Carbide Processing and Applications (Eds.: Saddow, S. E.; Agarwal, A.), Artech House, 2004
• mp > 2700 °C; density 3.10 g/cm3
• specific heat capacity 650 J/kgK• very low thermal expansion coefficient• excellent thermal shock resistance• high thermal conductivity• excellent corrosion resistance• strong microwave absorber
262 °C after 1 min at 600 W
Silicon Carbide as Novel Passive Heating Elements for Organic Synthesis
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651
• sintered (2000 °C) SiC cylinders10 x 18 mm, 4.35 g10 x 10 mm, 1.94 g
• corrosion resistant till 1500 °C• compatible with all existing MW equipment
(including magnetic stirring)
Sintered Silicon Carbide Passive Heating Elements
17
4 mL CCl4, Constant 150 W, Single Mode
Heating Profiles for Low Absorbing Solvents using SiC Heating Elements
20
60
100
140
180
220
0 20 40 60 80 100 120
Tem
pera
ture
[°C
]
Time [s]
CCl4
SiC
Solvent tan δδδδ bp [ °C] T [°C]without SiC
T [°C]with SiC
Time [s]
CCl4 n.d. 76 40 172 81
dioxane n.d. 101 41 206 114
hexane 0.020 69 42 158 77
toluene 0.040 111 54 231 145
THF 0.047 66 93 151 77
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651
CCl4
CCl4 + SiC
Claisen Rearrangement
O OHtoluene, SiC heating element
MW, 250 °C, 105 min
>99% conversion95% purity
cf. with ionic liquid (45 min at 220 °C): Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, 1482
Heating Profiles (Set Temperature 250 °C)
20
60
100
140
180
220
260
0 100 200 300 400 500 600
toluene (quartz)
20
60
100
140
180
220
260
0 100 200 300 400 500 600
rxn mixture (Pyrex)
toluene (quartz)
run terminated< 1% conv
20
60
100
140
180
220
260
0 100 200 300 400 500 600
rxn mixture with SiC cylinder
rxn mixture (Pyrex)
toluene (quartz)
run terminated< 1% conv
Time [s]
Tem
pera
ture
[°C
]
Applications in Microwave Chemistry
18
Diels-Alder Cycloaddition
Applications in Microwave Chemistry
Me
Me
CN Me
Me
CNtoluene, SiC heating element
MW, 240 °C, 20 min97%
HN NHCO2Me
N NMeO2C
CO2Metoluene, SiC heating element
MW, 200 °C, 10 min98%
BrN NHNN
toluene, NaHCO 3SiC heating element
MW, 250 °C, 30 min
88%
EtO2C
NMe
Ph
S
NH2
EtO2C
NH
Me
Ph
NH
S
toluene, SiC heating element
MW, 220 °C, 30 min 68%
Michael Addition
N-Alkylation
Dimroth Rearrangement
0
50
100
150
200
250
300
350
0 50 100 150 200
0
50
100
150
200
250
300
350
Pyrex Vessel
0
50
100
150
200
250
300
350
0 50 100 150 200
0
50
100
150
200
250
300
350
0
50
100
150
200
250
300
350
0 50 100 150 200
0
50
100
150
200
250
300
350
Pyrex + SiC
Quartz Vessel
2 mL MeCN, 120 °C Set Temperature (CEM) tan δ (MeCN): 620 x 10-4
tan δ (Pyrex): 10 x 10-4
tan δ (Quartz): 0.6 x 10-4
Tem
pera
ture
[°C
]
Time [s]
Pow
er [W
]
200 WQuartz
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651
140 WPyrex
45 WSiC
P
T
Influence of Passive Heating Elements on Microwave Power
19
Thermal Effects (Kinetics)
accelerations of chemical transformations that can not be achieved or duplicated by conventional heating, but essentially are thermal effects
accelerations of chemical transformations that can not be rationalized by thermal or specific microwave effects
accelerations of chemical transformations that are a consequence of the high reaction temperatures that can be attained under microwave conditions (Arrhenius equation)
Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250
Microwave Effects - Definitions
Specific Microwave Effects
Non-thermal (Athermal) Microwave Effects
Microwaves in Organic Synthesis, Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2006
Early TS���� Small ∆∆∆∆G���� Weak MW-Effect
Late TS���� Large ∆∆∆∆G���� Strong MW-Effect
• Position of TS‘s along the reaction coordinate (Hammond postulate):late TS’s have increased polarity and are favored by MW
• Arrhenius law (k = A exp(-∆G≠/RT):increase in pre-exponential factor Adecrease in activation energy ∆G ≠ (entropy term)
definition: rate acceleration effects that can not be rationalized by thermal or specific microwave effects
• Decrease in activation energy ∆G ≠ (for polar mechanisms):relative stabilization of more polar TS electrostatic molecule-electric field interactions GS
TS∆∆∆∆G∆∆∆∆‡
∆∆∆∆GMW‡
Nonthermal Microwave Effects(direct wave-material interactions/orientation effe cts)
20
J. Org. Chem. 2008, 73, 36
0
30
60
90
120
150
180
210
240
0 1 2 3 4 5 6 7 8 9Time [min]
Tem
pera
ture
[°C
]
0
100
200
300
400
Pow
er [W
]
with SiC (T)without SiC (T)
with SiC(P)
without SiC (P)
Ph
NH
Me
EtO
O
OEt
O
Me
Ph
NMe
EtO
O
OEt
O
Me
MnO2, DCMMW, 150 °C, 8 min
without SiC: 118 Wwith SiC: 52 W
with + without SiC: 100 %
Entry SiC Temp ( °C) Time (min) Conv (%) Power (W)
1 ─ 120 3 86 97
2 Cyl 120 3 86 48
3 ─ 100 5 65 65
4 Cyl 100 5 64 39
Case Study 1: Oxidation of Dihydropyridines
Razzaq, T. et al. J. Org. Chem. 2008, 73, ASAP
21
20
30
40
50
60
70
0 50 100 150 200
Time [s]
Tem
pera
ture
[°C
]
without MnO2
withMnO2
100 mg MnO2 in 4 mL CCl4150 W, Quartz
20
40
60
80
100
120
0 20 40 60 80 100
Time [s]
Tem
pera
ture
[°C
]
withoutMnO2
withMnO2
100 mg MnO2 in 4 mL Rxn Mixture(DCM), 150 W, Pyrex
Selective Heating of Heterogeneous Reagent
O
O
O
O
O
Otoluene (SiC)
MW, 100-200 °C, 5-10 min+
a Isolated yield
Entry SiC Temp ( °C) Time (min) Conv (%) Power (W)
1 ─ 200 5 (94)a 113
2 Cyl 200 5 (90)a 60
3 ─ 100 10 63 42
4 Cyl 100 10 67 17
5 ─ 100 5 58 41
6 Cyl 100 5 57 21
Case Study 2: Diels-Alder Reaction
22
Me
Me Me
O
OH
Me
Me Me
O
OEt
EtBr, K 2CO3acetone (SiC)
MW, 80 °C, 5 min
56% (60 W)53% (39 W, SiC)
O
OHI
NC
OH
O
NC
+
Pd/C, Et 3NMeCN (SiC)
MW, 150 °C, 5 min
64% (113 W)66% (56 W, SiC)
NH
NH
PhEtOOC
Me S NH
N
PhEtOOC
Me Ph
Pd(PPh3)4, CuTCdioxane (SiC)
MW, 120 °C, 20 min+ PhB(OH)2
83% (108 W)86% (33 W, SiC)
Esterification
Heck Reaction
Liebeskind-Srogl
Claisen Rearrangement
O OH
chlorobenzene (SiC)
MW, 250 °C, 25 min54% (190 W)67% (62 W, SiC)
Case Studies 3-6 (Selected Data Points)
Summary SiC Heating Elements
• Non-invasive heating aids for microwave synthesis
• Allow the use of non-polar, low-absorbing solvents
• PHEs are easily removed mechanically
• Compatible with any solvent or reagent
• Compatible with single- and multimode instruments
• Valuable tool in cases where other options to increase the microwave absorbance of the reaction medium (e.g. ionic liquids) are not feasible
• Use of strongly absorbing SiC heating elements uses less power at the same temperature
• For our chemistry examples the amount of microwave power used was irrelevant, only temperature proved important
23
C. Oliver Kappe
Acknowledgements
Heterocycle Synthesis
Toma GlasnovJamshed Hashim
Nuzhat ArshadHana ProkopcováLeonardo Pisani
SiC Heating Elements
Jenny KremsnerTahseen Razzaq
