HOMOGENEOUS HYDROGENATION OF ELECTRON-DEFICIENT ALKENES BY USING
IRIDIUM-COMPLEXES
Dissertation
zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften
an der Universität Konstanz
vorgelegt von
Volodymyr Semeniuchenko
Konstanz 2009
Konstanzer Online-Publikations-System (KOPS) URN: http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-80951
URL: http://kops.ub.uni-konstanz.de/volltexte/2009/8095/
Tag der mündlichen Prüfung: 19.05.2009 Erstgutachter: Prof. Dr. Ulrich Groth Zweitgutachter: Prof. Dr. Helmut Fischer Prüfungsvorsitzender: Prof. Dr. Thomas Exner
For my wonderful family
partnership between the University of Konstanz and the National Taras Shevchenko University Kiev.
Special thanks to:
Prof. Dr. Ulrich Groth for giving me the opportunity to work in his group, for discussions concerning my work and for his entire support;
Prof. Dr. Volodymyr Khilya for the interesting topic, for discussions concerning my work and for his entire support;
Prof. Dr. Thomas Exner for quantum-chemical computations, theirs interpretation and discussions;
Prof. Dr. Helmut Fischer, for writing the second evaluation;
Michael Burgert, Victor Iaroshenko, Dr. Thomas Huhn, Anton Kotljarov, Dr. Markus Ringwald, Dr. Olga Tšubrik, Dr. Christian Kesenheimer, Aleksei Bredihhin, Kateryna Gura, Angelika Früh, Steffen Lang and all the members of workgroup Groth for interesting discussions and useful comments regarding the topic of the work and to Milena Quentin for all the help she gave me;
Anke Friemel, Ulrich Haunz, Prof. Dr. Heiko Möller and Andreas Berkefeld for measurements and discussions of NMR-spectra;
Michael Burgert, Rheinhold Weber, Dmitry Galetsky and Sascha Keller for measurements and discussions of mass-spectra;
Thomas Haas for a possibility to perform column chormatography at low temperature;
Qiong Tong and Yan Wang for Chinese translations, Stelmakh Svetlana and Christian Kesenheimer for Japanese translations;
All my friends in Konstanz with whom I had a wonderful time here;
Last but not least I wish to thank and to express my deep gratitude to my family and my parents for supporting and encouraging me during this time.
The research would not have been possible without the scholarships on part of the Herbert- Quandt Stiftung der Altana AG (now Nycomed) and the Deutsche Akademische Austauschdienst (DAAD). The scholarships are kindly acknowledged.
PUBLICATIONS
Volodymyr Semeniuchenko, Volodymyr Khilya, Ulrich Groth. Nucleophilic Homogeneous Hydrogenation by Iridium Complexes, Synlett, 2009, 2, 271-275
CONFERENCE PRESENTATIONS
Volodymyr Semeniuchenko, Volodymyr Khilya, Ulrich Groth. Nucleophilic homogeneous hydrogenation by Ir-complexes, 10th Frühjarssymposium, 27th-29th March 2008, Rostock (Germany).
Volodymyr Semeniuchenko, Volodymyr Khilya, Ulrich Groth. Nucleophilic homogeneous hydrogenation by Ir-complexes, International Synposium on Homogeneous Catalysis ISHC- XVI, 6th-11th July 2008, Florence (Italy).
Volodymyr Semeniuchenko, Volodymyr Khilya, Ulrich Groth. High-efficient Synthesis of (Phosphanodihydrooxazole) (1,5-cyclooctadiene) Iridium Complexes, 11th Frühjarssymposium, 11th-14th March 2009, Essen (Germany).
TABLE OF CONTENTS
1 INTRODUCTION ... 1
1.1 Synthesis of chroman-4-ons by reduction of chromones ... 1
1.1.1 Hydrogenation of chromones ... 4
1.1.1.1 With palladium on charcoal ... 4
1.1.1.2 With palladium on the other support or elemental palladium... 11
1.1.1.3 With platinum... 13
1.1.1.4 With Raney-Nickel... 16
1.1.2 Transfer hydrogenation of chromones on palladium ... 18
1.1.3 Reduction of chromones with complex hydrides... 22
1.1.4 Reduction of chromones with diisobutylaluminium hydride... 28
1.1.5 Reduction of flavonols with sodium dithionite ... 29
1.1.6 Other methods for the reduction of chromones... 30
1.1.7 Conclusion... 36
1.2 Synthesis of chroman-2-ons by reduction of coumarins... 36
1.2.1 Hydrogenation of coumarins... 39
1.2.1.1 With palladium on charcoal ... 39
1.2.1.2 With palladium on the other support or elemental palladium... 47
1.2.1.3 With platinum... 50
1.2.1.4 With nickel ... 52
1.2.2 Transfer hydrogenation of coumarins ... 53
1.2.3 Reduction of coumarins with metals... 56
1.2.4 Reduction of coumarins with complex hydrides... 60
1.2.5 Homogeneous hydrogenation of coumarins... 64
1.2.6 Electrochemical reduction... 67
1.2.7 Other methods for the reduction of coumarins... 68
1.2.8 Conclusion... 71
1.3 Biologically active compounds: racemates versus pure enantiomers. ... 72
1.4 Homogeneous catalytic hydrogenation of alkenes... 75
1.4.1 Homogeneous hydrogenation of alkenes: rhodium catalysis... 76
1.4.2 Homogeneous hydrogenation of alkenes: iridium catalysis... 79
1.4.3 Homogeneous hydrogenation of alkenes: ruthenium and osmium catalysis ... 81
1.4.4 Homogeneous hydrogenation of alkenes: metallocenes ... 84
1.4.5 Homogeneous hydrogenation of alkenes: other metals... 85
1.5 Enantioselective homogeneous catalytic hydrogenation... 86
2 OBJECTIVES... 92
3 RESULTS AND DISCUSSION... 93
3.1 Attempts to hydrogenate model flavonoids ... 93
3.2 Attempts to prepare a heterogenized catalyst... 100
3.3 Nucleophilic hydrogenation of 7-methoxyisoflavone... 110
3.4 Nucleophilic hydrogenation: catalyst screening ... 114
3.5 Nucleophilic hydrogenation of various substrates ... 129
3.6 Proposed mechanism of nucleophilic hydrogenation... 135
3.7 Hydrogenation of 7-methoxy-3-(pyridin-2-yl)chromone... 146
4 SUMMARY... 152
5 ZUSAMMENFASSUNG ... 159
6 OUTLOOK ... 166
7 EXPERIMENTAL SECTION ... 169
7.1 Attempts to hydrogenate model flavonoids ... 170
7.2 Attempts to prepare a heterogenized catalyst... 182
7.3 Nucleophilic hydrogenation of 7-methoxyisoflavone... 186
7.4 Nucleophilic hydrogenation: catalyst screening ... 188
7.5 Nucleophilic hydrogenation of various substrates ... 228
7.6 Proposed mechanism of nucleophilic hydrogenation... 234
7.7 Hydrogenation of 7-methoxy-3-(pyridin-2-yl)chromone... 275
8 REFERENCES ... 283
ABBREVIATIONS
Ac Acetyl (actinium is not mentioned in the dissertation) ATR Attenuated Total Reflectance
B3LYP Becke 3-Parameter (Exchange), Lee, Yang and Parr (correlation;
density functional theory)
BARF Tetrakis(3,5-bis(trifluoromethyl)phenyl) borate 9-BBN 9-Borabicyclo[3.3.1]nonane
BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2- diazaphosphorin
BINAP 2,2`-Bis(diphenylphosphino)-1,1`-binaphtyl borsm Based on recovery of starting material
BTED Bis[t-butylthio]ethane-diborane
iBu iso-Butyl
nBu n-Butyl
sBu sec-Butyl
tBu tert-Butyl
C^N Chelating ligand, having coordinations sites at carbon (carbene) and on nitogen atoms
C^P Chelating ligand, having coordinations sites at carbon (carbene) and on phosphorus atoms
CD Circular Dichroism
COD 1,5-Cyclooctadiene COE Cyclooctene
COSY COrrelation SpectroscopY COX Cyclooxygenase
CP Cross-Polarization
CPTOSS Cross-Polarization TOtal Side-band Suppresion CTH Catalytic Transfer Hydrogenation
Cy Cyclohexyl
de Diastereomeric excess
DFT Density Functional Theory
DIPEA Diisopropylethylamine, Hünig’s base DMF Dimethylformamide DMSO Dimethylsulfoxide
DPPB 1.4-Bis(diphenylphosphinyl)butane DPPP 1.4-Bis(diphenylphosphinyl)propane
ee Enantiomeric excess
ESI ElectroSpray Ionisation
ESP Electro-Static Potential Et Ethyl
EWG Electron Withdrawing Group FT-ICR Fourier Transfrom - Ion-Cyclotrone Resonance GC/MS Gas-Chromatogphy with Mass Selective detector
GLC Gas-Liquid Chromatography
GLYMO Glycidoxypropyltrimethoxysilane (trimethoxy(3-(oxiran-2- ylmethoxy)propyl)silane)
HMBC Heteronuclear Multiple Bond Correlation HMDS Hexamethyldisilazane
HOMO Highest Occupied Molecular Orbital HRMS High-Resolved Mass-Spectrometry
HSQC Heteronuclear Single Quantum Coherence HTC High Throughput Computation
HTE High Throughput Experimentation HTS High Throughput Screening
IL Interleukin
IMe 1,3-dimethylimidazol-2-ene IR Infrared
LAH Lithium tetrahydridoaluminate, LiAlH4 LHMDS Lithium hyxamethyldisilazide LOX Lypooxygenase
LSR Lantanoid Shift Reagent
LUMO Lowest Unoccupied Molecular Orbital MAS Magic Angle Spinning
Me Methyl
MeO Methoxy MOM Methoxymethyl
MS Mass-Spectrometry MW Microwave
N/A Not available
Na2EDTA Dinatrium salt of ethylendiamine tetraacetic acid
NADH Nicotinamide Adenine Dinucleotide carrying two electrons and bonded with H+
NADPH Nicotinamide adenine dinucleotide phosphate carrying two electrons and bonded with H+
NBD Nor-bornadiene NBO Natural Bond Orbital
NHC N-Hetecocyclic Carbene
NMR Nuclear Magnetic Resonance
NOESY Nuclear Overhauser Effect SpectroscopY NPA Natural Population Analysis
P^N Chelating ligand, having coordinations sites at phosphorus and on nitogen atoms
P^P Chelating ligand, having coordination sites at both phosphorus atoms
PCC Pyridinium chlorochromate
PM3 Parameterized Model number 3 (semi-empirical method, based on Neglect of Differential Diatomic Overlap)
Ph Phenyl
Phox Phosphinooxazoline
iPr iso-Propyl
Py Pyridine Rf Retention factor
ROESY Rotational nuclear Overhauser Effect SpectroscopY
r.t. Room temperature
Tf Triflyl
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin-Layer Chromatography
TMEDA Tetramethylethylenediamine TMS Trimethylsilyl
TOF Time Of Flight
o-Tol ortho-Tolyl, 2-methylphenyl Ts Tosyl, p-methylbenzosulphonyl US Ultrasound
WCA Weakly Coordinating Anion 2,6-Xyl 2,6-Xylyl, 2,6-dimethylphenyl
1 INTRODUCTION
1.1 Synthesis of chroman-4-ons by reduction of chromones
The flavonoids are widely spread in plants and are known as biologically active compounds (the most recent rewievs and books1). Chromones 1 (4H-chromen-4-ones, 1- benzopyran-4-ones) and coumarins (2H-chromen-2-ones, 1-benzopyran-2-ones) with their derivatives belong to the class of flavonoids. Natural chromones 1 are represented in most cases by flavones 2 (2-arylbenzopyran-4-ones) and isoflavones 3 (3-arylbenzopyran-4-ones).
The numeration in such systems is given in scheme 1. Natural flavonoids are mono- or polyhydroxylated, methoxylated or glycosylated in annelated and/or side aryl-ring.
Scheme 1
If you want to reduce the chromone 1, it is possible to obtain several compounds (see scheme 2): chromanones 4, chromanols 5, chromenes 6, chromans 7. The preparation of chromenols 8 is also reported2. The chromanones could be opened by alkali or spontaneously to alkenes 9, the latter could be reduced to arylpropanones 10. The conversion 4Æ9 is especially easy for flavanones 11, since a stabilized chalcone 12 is formed. Of course, chalcone 12 is notably more stable than 14, but a similar transformation 13Æ14 is reported to exist3-5. The ketones 9 and 10 could be further reduced to alcohols and alkanes.
O
O
O
O O
OH
[H]
[H]
O
[H]
O O
OH [H]
OH
O
[H] OH
O
1 6
5
6
9 10
[H] [H]
7 O
O
- H2O
[H]
4 8
O
O 11
Ar OH
O 12
Ar
O
O 13
OH
O 14 Ar
Ar OH
OH
[H] OH
OH [H] [H]
OH [H]
[H]
Scheme 2
Chroman-4-ones have a wide spectrum of biological activity, hence the synthesis of such compounds has both a theoretical and practical significance. Many isoflavanones and related compounds show estrogenic activity, hence are active against human breast cancer6. Sophorol 15 is a phytoalexine, active against fungi7. Orientanol F 16 can suppress methicillin- resistant Staphylococcus aureus8. Sophoraisoflavanone A 17 inhibits cyclooxygenase-1 (COX-1), echinoisosophoranone 18 and kenusanone A 19 inhibit 5-lipoxygenase (5-LOX)9. G. Bojase et al.10 report about antimicrobial isoflavanones. Natural homoisoflavanones are phytoalexins11. The silybin 20 has a hepatoprotective12 and anti-cancer (skin13 and prostate14) activity, which is associated with its antioxidative properties15. It is also proven to be effective in the treatment of type II diabetes16. The flavonol, derived from silybin (2,3-dehydroxilybin) also has an antioxidative activity17. Rotenon 21 is poisonous for fishes, while compound 22 is
not18. The chromone and the chromanone ring can serve as a steroid-isosteric group which is proven in articles19, 20.
O HO
OHO O
O
Sophorol,15
O
OHO OH
O
Orientanol F,16
O
OH HO
O OH
OMe
Sophoraisoflavanone A,17
O
O OH
MeO OMe
OH Echinoisosophoranone,18
O HO
OH O OH
O O
OH
OH OMe
Silybin,20
O O O
MeO O
OMe
21- poisonous to fishes
O O O
MeO O
OMe
22- not poisonous [O]
O HO
OH O
OH
OH Kenusanone A,19
Scheme 3
There are several methods for chromones’ reduction. These methods, their benefits and disadvantages are described in this review. The search was carried out with SciFinder Scholar 2007 by the American Chemical Society. Only the reduction of chromones is reviewed, e.g.
the addition of organometallics to chromone can give 2-substituted chromanone, but it is not a reduction, hence is not reviewed.
One rewiev is available where the reduction of isoflavones is described5. It refers only to the reduction by DIBAL, Selectride and NaHTe, but the authors give information about their own experience in this field. Another review21 dedicated to biflavonoids includes the reactions of reduction relevant to biflavonoids synthesis.
Some books have information about chromones reduction22, 23. It is noted therin that commonly there is no sense to reduce the chromone in order to obtain the chromanone since chromanones are readily accessible from the other precursors. The reduction of chromone makes sense if this chromone is cheap and readily accessible or if there is no other way to obtain a purposeful chromanone. On the other hand, the flavanones and isoflavanones have one or several chiral centers and enantioselective reduction which is studied quite well24, 25,
could be a method of chiral chromanones’ preparation. The examples of enantioselective reduction of chromones are reviewed in the corresponding sections.
1.1.1 Hydrogenation of chromones 1.1.1.1 With palladium on charcoal
This method is the most common one for the chromones. It gives various yields and goes with various chemical selectivity. If the other is not stated, 10% Pd/C was used. Table 2 represents the information about chromones’ hydrogenation on Pd/C that gives chromanones.
In 1973 Szabo et al. published the articles26 about the selective hydrogenation of the isoflavone. They assert that its hydrogenation goes almost quantitative in dioxane to give the corresponding chromanone, while hydrogenation in ethanol gives the isoflavonol (3- phenylchroman-4-ol, mixture of diastereomers). If the hydrogenation of 3-phenylchromone in ethanol is interrupted after 1 equivalent of hydrogen is consumed, the mixture of isoflavanone and isoflavanol with the educt is obtained. The selectivity of chromanone’s formation was dependent on the supplier of Pd/C. The authors also designed a method of selective chromanone synthesis by reduction of chromone in aqueous ethanol. The selectivity was pH- dependent.
Chinese researcher27 have optimized the hydrogenation of 5,7-dihydroxyflavon. They have used ethanol as a solvent, Pd/C as a catalyst, and the hydrogenation was performed under pressure of 3 bar of hydrogen. They have varied the amount of the catalyst, the temperature and reaction time. The amount of the substrate was fixed to 5 g in each experiment. The results are shown in table 1. In case of too low catalyst amount, too little reaction time or low temperature, the whole educt failed to convert to the 5,7- dihydroxyisoflavanone, otherwise an overreduction and formation of flavonol took place.
Another interesting fact is that the three-component mixture of solvents was used for the products’ separation by silica gel chromatography: MeOH/EtOAc/petrol ether 2/10/100. A little later the same authors28 have slightly improved the method and had the yield of 5,7- dihydroxyflavanone 84.44% (0.2 cat./substrate ratio, 60º C, 2 h, EtOH).
Table 1. Optimization of hydrogenation of 5,7-dihydroxyflavon27
Fixed parameter Varied parameter Yield of 5,7-
dihydroxyflavanon, % Catalyst amount: 0.5 g 50.45
Temperature = 53º C, time = 2
h, p(H2) = 3 bar Catalyst amount: 1.0 g 83.26
Catalyst amount: 1.5 g 71.87 Catalyst amount: 2.0 g 66.63 Catalyst amount: 2.5 g 60.51 Catalyst amount: 3.0 g 46.12 Temperature: 25º C 23.45 Temperature: 32º C 38.34 Temperature: 39º C 43.87 Temperature: 46º C 66.63 Temperature: 53º C 83.26 Catalyst amount = 1.0 g, time
= 2 h, p(H2) = 3 bar
Temperature: 60º C 52.62
Time: 1 h 31.45
Time: 2 h 83.26
Time: 3 h 73.51
Time: 4 h 60.62
Time: 5 h 51.65
Time: 6 h 43.87
Catalyst amount = 1.0 g, temperature = 53º C, p(H2) = 3 bar
Time: 7 h 33.21
Farkas et al.29 have successfully hydrogenated 23, 24 and prunitrin pentaacetate 25 in AcOH by allowing to absorb only one equivalent of hydrogen by reaction mixture. The same strategy was applied in further publications of this group: 26, 2730; 28, 2931 were reduced.
Scheme 4
A successful application of “titration with hydrogen” is illustrated in patent32, where isoflavones were hydrogenated either to isoflavan-4-ones or to isoflavans, by allowing to absorb 1 or 3 equivalents of hydrogen. The same technique was applied in order to reduce 30 into 3133.
Scheme 5
In order to hydrogenate very insoluble 5,7-dihydroxy-2`,4`-dimethoxyisoflavone K. G.
Neill34 has acetylated it, then hydrogenated (in AcOH, 43%) and desacetylated.
F. Visser and G. Lane35 tried to synthesize 3,9-dihydroxypterocarpan 32 through the hydrogenation of 2`,4`,7-tribenzyloxyisoflavone 33. They have studied the selectivity of such a hydrogenation. The mixture of a fully deprotected isoflavone and isoflavanone was obtained by hydrogenation in acetone with aqueous HCl. Compound 34 was separated by preparative TLC. Partially deprotected isoflavones and 35 were proven to exist in the reacting mixture after the hydrogenation in acetone with low catalyst/substrate ratio (160 g/mol). However, 35 was not isolated due to coeluting with the other compounds. On the other hand, 7,2`-
dibenzyloxy-4`,5`-methylenedioxyisoflavone was selectively debenzylated over Pd/C in EtOAc (67% yield of 7,2`-dihydroxy-4`,5`-methylenedioxyisoflavone)36. In patent37 the debenzylation of chromones under 1 bar of hydrogen on 5% or 10% Pd/C in MeOH, EtOH or EtOAc is described, while actually chromone was reduced with Raney-Nickel.
Scheme 6
M. D. Woodward38 made a debenzylation of 7,2′,4′-tribenzyloxyisoflavone by hydrogenation over 5% Pd/C under 3 bar of hydrogen. 7,2′,4′-trihydroxyisoflavone was not hydrogenated in such conditions. In order to obtain 7,2′,4′-trihydroxyisoflavanon he had to acetylate it and reduce the 7,2′,4′-triacetoxyisoflavone. It is interesting that hydrogenation of 7-(benzyloxy)-2-(4-(furan-3-yl)-3-methoxyphenyl)-3,5-dimethoxychromone at 40º C under 1 bar of hydrogen over 10% Pd/C in EtOH/EtOAc 1/1 yielded 7-hydroxy-3,5-dimethoxy-2-(3- methoxy-4-(tetrahydrofuran-3-yl)phenyl)chromone, i.e. furane-ring was reduced, but chromone was not affected39.
In order to design the new inhibitors of interleukin-5 the derivatives of sophoricoside were studied40. Actually, the hydrogenation of partially acetylated sophoricoside 36 and of 37 is described. The latter compound could be debenzylated in MeOH over Pd/C under 1.3 bar of hydrogen, while under 2 bar it is reduced to chromanone. The other O-benzylated chromones were also deprotected by such a method, but not reduced to chromanones. Parmar et al.41 also describe the hydrogenation of chromones with simultaneous debenzylation.
Scheme 7
Patent42 describes the hydrogenation of chromone-2-carboxylic acid and chiral resolution of the esters of this acid using the lipase.
C. Schmiz and F. Eiden43 have reduced 38 to trichromanone 39 or to trichroman 40 by this method. The yield of chromanone was not very good (41%), that of chromane was better (89%). J. H. Kwak et al.44 report about similar hydrogenation of ethyl 7-hydroxychromon-2- carboxylate in EtOH/AcOH 25/1 over Pd/C directly to the corresponding chromane.
O O
O O
O O
O O
O O
O O
O O
O 38
39, 41% 40, 89%
H2
Pd/C AcOH r.t.
H2 Pd/C AcOH 60°
Scheme 8
Y. Vasquez-Martinez et al.45 report about the hydrogenation of isoflavones 41 and 42.
Hydrogenation in ethanol over 10% Pd/C gave isoflavanones 43-44, while the use of 0.1%
AcOH in EtOH as a solvent leads to the formation of chromans 45-46.
Scheme 9
Table 2. Summary table of chromones’ hydrogenation on palladium on charcoal. If otherwise is not stated, 10% Pd/C was used. If otherwise not stated, the product is the corresponding 4-chromanone.
Substrate p(H2),
bar solvent yield, % time additional information ref.
2-R-chromon-7-yl sulfamate
(R=phenyl, cyclohexyl, 1-adamanthyl) 1 EtOAc 61, 20,
49, resp. 3 h unselective hydrogenation, chromanols are isolated
19
isoflavone N/A dioxane, ethanol
with Britton- Robinson buffer
100, 90,
resp. N/A cannot be hydrogenated in benzene
26
5,7-dihydroxyflavon 3 EtOH 83.26 2 h 53º C, optimization 27
study 5,7-dihydroxyflavon 3 EtOH 84.44 2 h 60º C, 0.2
cat./substrate ratio, optimisation study
28
23, 24, 25 N/A AcOH 40, 80,
80, resp. N/A 29
26, 27 N/A AcOH 39, 38,
resp.
N/A 30
2`,5,7-triacetyloxy-4`-
methoxyisoflavone N/A AcOH N/A N/A crude product was further deacetylated.
Overall yield (2 stage) – 45%
30
26, 27 N/A AcOH N/A N/A synthetical procedure
– from article30
31
7-n-hexadecyloxyisoflavone, 7- ethoxy-5-methylisoflavone, 7-(1- cyclohex-2-enyloxyl)isoflavone
N/A Acetone 82 N/A patent, reaction given as an example
32
5,7-diacetoxy-2`,4`-
dimethoxyisoflavone N/A AcOH 43 N/A concentration of Pd on C is unknown
34
36, 37 2 Methanol 94.5,
68.7, resp.
15, 2 h resp.
37 – hydrogenated with debenzylation
40
7-benzyloxy-8-methoxychromone N/A EtOAc/MeOH
1/1 78 32 h with debenzylation 41 2-carboxychormone 2 Ac2O/AcOH 41-69 N/A 60º C, patent,
reaction is given as an example
42
38 N/A AcOH 41 16 h 43
7,2′,4′-triacetoxyisoflavone N/A EtOAc 39 16 h 5% Pd/C used 38
41, 42 1 EtOH 52, 48m
resp. 6 h 45
5-hydroxy-7-methoxy-6,8- dimethylchromone, 5-acetoxy-7- methoxy-6,8-dimethylchromone
N/A MeOH, EtOH 50, 46
resp N/A 5% Pd/C used 46 7,4`-diacetoxyisoflavone N/A EtOAc 80 72 h 5% Pd/C used,
patent, reaction given as an example
47
prunetin diacetate (5,4`-diacetoxy-7-
methoxyisoflavone) 3.3 AcOH 63 8 h 48
4`-benzyloxy-2`,5-dimethoxy-7- methoxymethoxyisoflavone
N/A EtOH 86 N/A with debenzylation 49 7-methoxychromone 53, 7-hydroxy-2-
methylchromone N/A AcOH 100 3 h,
9 h Synthetic procedure published in50
51
5,7-dihydroxychromone N/A DMF 77 N/A DMF was prehydrogenated
52
8-methoxy-2,5-dimethylchromone N/A MeOH 14 N/A 53 5,7-dihydroxy-6-methoxychromone,
5,7-dimethoxy-3-(4-methoxybenzyl)- chromone
N/A acetone, EtOAc,
resp. N/A N/A no synthetic procedure available 7-benzyloxy-5-hydroxy-8-
methoxychromone, 7-benzyloxy-5- methoxychromone
N/A EtOAc/MeOH, DMF/MeOH, resp.
N/A N/A with debenzylation, no synthetic
procedure available
54
3-(3,4-dimethoxybenzyl)-7-methoxy-
4-chromone 1.72 EtOAc 98 4 h 55
2'-methoxy-7-pivaloyloxyisoflavone, 7,4'-dipivaloyloxyisoflavone, 4'- methoxy-7-pivaloyloxyisoflavone
2 acetone 60, 70,
85, resp. 9 h 5% Pd/C 56 3-benzylchromone, 3-(3,4-
dimethoxybenzyl)-5,7- 1 THF 73, 79
resp. N/A hydrogenation until 1.2 equvalents of
57
dimethoxychromone hydrogen are consumed
2-butylchromone-6-carboxylic acid
methyl ester 4 N/A N/A 7 h 5% Pd/C, patent, reaction is given as an example
58
6,7-dihydroxy-3-(4- methoxyphenol)chromone
1 EtOH N/A N/A with NEt3, patent, reaction is given as an example
59
5,7-dihydroxy-3-(4-
hydroxybenzyl)chromone 1 MeOH N/A N/A with overreduction to chroman
60
2-hydroxymethylchromone 1 MeOH 42 N/A 5% Pd/C used, hydrogenation until
computed amount of hydrogen is
consumed
61
5,7-dihydroxy-2,3-dimethylchromone N/A N/A N/A N/A no information about this reaction is provided
62
7-benzyloxychromone N/A EtOAc 46 4 h with debenzylation, with overreduction
63
2-carboxychromone, 6-bromo-2-
carboxychromone 1 EtOH 40, 55
resp. N/A hydrogenation until computed amount of hydrogen is
consumed
64
5,6,7,4`-tetramethoxyisoflavone
(dimethylmuningin) N/A EtOH 77 35
min concentration of Pd on C is unknown
65
5,7-dimethoxy-3-(4-
methoxybenzyl)chromone N/A N/A 98 N/A no synthetic procedure available
66
5,7-dibenzoyloxychromone N/A EtOAc 100 N/A 67
5,7,4′-trimethoxyisoflavone N/A MeOH 80 N/A Pd/C prepared from 0.5 g of charcoal and 20 ml of 1% solution of PdCl2
68
9-methoxy-7-(2-methoxyphenyl)-8H-
[1,3]dioxolo[4,5-g]chromen-8-one N/A EtOH 85 42
min 5% Pd/C used 69 5,5',7,7'-tetramethoxy-2,2'-diphenyl-
4H,4'H-3,3'-bichromene-4,4'-dione N/A AcOH N/A 4 h or
12 h 80º C, products are 5,5',7,7'-
tetramethoxy-2,2'- diphenyl-2H,4'H-3,3'- bichromene-4,4'(3H)- dione and 5,5',7,7'- tetramethoxy-2,2'- diphenyl-3,3'- bichroman-4,4'- dione, procedure very unselective, in the other solvents no hydrogenation observed
70
5,5',7,7'-tetramethoxy-2,2'-diphenyl- 2H,4'H-3,3'-bichromene-4,4'(3H)- dione
N/A AcOH N/A N/A Product is 5,5',7,7'- tetramethoxy-2,2'- diphenyl-3,3'- bichroman-4,4'-dione
70
In summary, the hydrogenation of chromones over Pd/C is a good method of chroman- 4-ones synthesis, a good starting point if a new chromone should be reduced. Although an overreduction to chromanol (in acid even to chroman because of acid-induced elimination,
hence chromene appearance) is possible, almost always a “titration with hydrogen” is possible, i.e. quenching of reaction after 1 equivalent of hydrogen is absorbed. On the other hand, a solvent screening should be performed in order to achieve the desired “hydrogen titration”, otherwise a simultaneous hydrogenation of chromone and chroman-4-one is possible. A problem with this method is a strong dependence of the hydrogenation possibility on substrate and on hydrogen pressure. And, of course, the hydrogenation of chromone is impossible without debenzylation and without hydrogenation of side alkene-groups, though the opposite is possible.
1.1.1.2 With palladium on the other support or elemental palladium
O. Dann and G. Volz have published several articles about the hydrogenation of chromones over Pd(OH)2/BaSO4. The method described in article71 presumes the two-stage procedure: at first the chromone is reduced to chromanol, then the latter is oxidized by PCC.
In article72 this two-stage procedure is not mentioned, but no method at all is described there.
They have tested several methods of dehydrorotenons’ hydrogenation in order to obtain the purposeful rotenons18. The best procedure was the hydrogenation of 47 to the corresponding chromanol 48 over PdO or over Pd(OH)2/BaSO4 under 250 bar of H2, then oxidation by Jones reagent. But they have found that hydrogenation over Pd(OH)2/BaSO4 under low H2 pressure gives directly 49, unfortunately contaminated with 48 and with 50. LAH have reduced 47 to the chromanol without affecting the side isopropenyl-group (see section 1.1.3).
O O O
MeO O
OMe 47
O O O
MeO O
OMe 49 +
O O O
MeO OH
OMe
O O O
MeO O
OMe 50
+ H2 Pd(OH)2/ BaSO4
48
Scheme 10
Later the same authors report about hydrogenation of khellin 90 (see section 1.1.3) on Pd(OH)2/BaSO473. The product is the corresponding chromanol, which was oxidized to the chroman-4-one.
E. Müller and W. Wiesemann74 inform about 2-methylchromone hydrogenation over Pd/CaCO3 in benzene. The 2-methylchroman-4-one was characterized through its p- nitrophenylhydrazone. They have also tested the hydrogenation of methylchromonelithium (product of reaction of 2-methylchromone with buthyllithium, the formula is not assigned).
T.A. Geissman and A. Armen75 have hydrogenated 2-methylchromone in benzene over Pd/CaCO3 with a yield of 56% in 22 hours (purified through formation of hydrazide with Girard reagent T.).
V. Szabo and E. Antal26 report about the use of Pd/BaSO4 and Pd/Al2O3, although the selectivity in hydrogenation was achieved only by using of Pd/C.
Patent76 describes the hydrogenation of 6-epoxyethyl-3-(1H-tetrazol-5-yl)-chromone to 6-hydroxyethyl-3-(1H-tetrazol-5-yl)-chromone with palladium black or 5% Pt on activated carbon at r.t. or 100ºC. The chromone ring was not reduced.
Patent77 describes the hydrogenation of two isoflavones 51 and 52 in EtOAc over 10%
Pd/Al2O3. The rate of hydrogenation of 51 was too low, and overall 105 weight-% of the catalyst was added in 64 h in order to achieve a full conversion of 51. On the other hand, 52 was hydrogenated in 4 h using 45 weight-% of the catalyst.
Scheme 11
Japanese researchers78 have tested several metal catalysts in hydrogenation of 2-methyl- and 3-methylchromone in ethanol. Pd black was not effective for chroman-2-ones synthesis (yields 12 and 11%, resp.), the main products were chromanols and chromans. The article is not synthetical, and the products (after 50% conversion of the starting chromone) were only analyzed by GLC.
In summary, elemental palladium or palladium on the support, other than activated carbon, are not very well studied concerning the chromones’ reduction. Such catalysts are usually not as active as Pd/C, and a high load of catalyst or a high pressure of hydrogen should be used. On the other hand, this can and does result in overreduction.
1.1.1.3 With platinum
Platinum is used for heterogeneous hydrogenation much more rarely than palladium.
Hence there are less examples of chromones’ hydrogenation, catalyzed by platinum. In this reaction platinum could be involved as platinum black, Adams catalyst (PtO2) or platinum on charcoal. Table 3 presents the information about chromones’ hydrogenation on platinum that gives chromanone.
P. Pfeiffer and J. Grimmer79 report about a reduction of 3-methoxychromone, 7- methoxychromone 53 and 54 on platinum black in AcOH. However, 55 could not be hydrogenated under such conditions.
O
O
O
O
O
O O
O H2, Pt black
AcOH
H2, Pt black AcOH O
O O
O O O
H2, Pt black 53 AcOH
54
55
60%
50%
Scheme 12
R. B. Bradbury and D. E. White80 have studied the hydrogenation of derivatives of genistein 56 and formononetin 57 over PtO2. Some isoflavones were hydrogenated with bad yields, while 5,7,4`-trimethoxyisoflavone was hydrogenated within 5 min with a yield of 70%. An attempt was made to hydrogenate genistein, but it resulted in an inseparable mixture of compounds.
Scheme 13
Methylated formononetin (7,4′-dimethoxyisoflavone) was proven to be not reducible by Na/Hg and by hydrogen in EtOH on PtO281. However, it was hydrogenated in AcOH on PtO2.
Hydrogenation over PtO2 often goes with overreduction. M. Suzuki et al.82,83 report about a phenyl-ring reduction (with double-bond and carbonyl groups) of flavones. Flavan and flavone were hydrogenated by S. Mitsui84 in AcOH over PtO2 under 1 bar of hydrogen to dodecahydroflavan. On the other hand, Albert Mondon et al.85 have reduced Chromon A 58 on PtO2 (Adams), and chromanone 59 is only the side-compound, while the yield of 60 is 73%.
O
Dodecahydroflavan
O O O
Flavone,2
Flavan
H2, PtO2
O O
O
O
O O
O
O
Chromon-A,58
60, 74%
O O
O
O
59, 9%
O OH
O
O
11%
+
+ H2, PtO2 MeOH
O
Dodecahydroflavan H2, PtO2
Scheme 14
K.S. Rehder and J. Kepler62 could not hydrogenate 61 to 62 over PtO2, only 63 was obtained. Unfortunately, they do not provide an information about the solvent for the former hydrogenation.
O O
OH O
O O
OH O
O O
OH O
H2, PtO2 MeOH H2
PtO2
62 61 63
Scheme 15
Patent86 describes the hydrogenation of isoflavone 64 and 65 to give the corresponding isoflavanone 66 and 67. The methylated compounds were first demethylated and then without purification or after column chromatography hydrogenated over PtO2.
Scheme 16
Table 3. Summary table of chromones’ hydrogenation on platinum. If otherwise not stated, the product is the corresponding 4-chromanone.
Substrate p(H2),
bar
solvent yield,
%
time additional information ref.
3-methylchromone N/A EtOH 66 27.2
h Pt black used. With overreduction, only 50%
conversion of educt, not synthetical article, reaction mixture was analyzed by GLC
78
7-methoxychromone 53 , 54 N/A AcOH 60, 50,
resp. N/A Pt black used 79 7-acetoxy-4`-methoxy-2-methyl-, 7,4`-
diacetoxy-2-methyl-, 2-methyl-7,4`- dimethoxy-, 7,4`-dimethoxy-, 5,7,4`- trimethoxyisoflavone
1 AcOH 27, 33, 27, 70 0.5 h,
night, 5 min
PtO2 used 80
7,4′-dimethoxyisoflavone N/A AcOH 70 12
min PtO2 used 81 Chromon-A 58 N/A MeOH 9 N/A PtO2 used, chromanon is
side-compound of hydrogenation
85
64 1.6 AcMe 31 3 h 86 2,5-dihydroxy-3-(7-hydroxychromone-3-
yl)benzonitrile (derivative of 65) 1.6 AcMe 19 1.5 h
first demethylated, then hydrogenated, yield of 66 or 67 over two steps, PtO2
used, patent, reactions are given as examples
86
luteolin (5,7,3`,4`-tetrahydroxyflavone) 2-2.5 EtOH 31 5 h PtO2 used, the crude product was acetylated, and tetraacetate isolated
87
7,8-dimethoxychromone N/A AcOH 100 N/A Pt black used 88 6-methoxy-2-methylchromone 3.44 EtOH/
HCl 6 N/A PtO2 used 89
3-dimethylaminomethyl-7- methoxychromone hydrochloride
3.44 EtOH 1.5 N/A PtO2 used 90 7-acetyloxychromone N/A AcOH 74 N/A Pt black used 91 N,N-diethyl-chromone-2-carboxamide N/A EtOH 58 N/A PtO2 used 92 7-carboxymethyl-5-chloro-3-
phenylchromone N/A MeOH 40 N/A PtO2 used, patent, reaction is given as an example
93
6-fluoro-N-((S)-1-phenylethyl)-chromone-2-
carboxamide 7 EtOH 84 N/A Pt/C with MeSO3H was used, de 60%, patent, reaction is given as an example
94
6-fluorochromone-2-carboxylic acid 7 EtOH 89 N/A Pt/C was used, patent, reaction is given as an example
95
N-(1-phenylethyl)-chromone-2-carboxamide 5.5 AcOH 77 N/A Pt/C used, 50 º, patent, reaction is given as an example
96
isoflavone, 7-hydroxy-, 7-methoxy-, 6- hydroxy-, 6-methoxy-, 7-hydroxy-4′- methoxy-, 7-acetoxy-3′,4′-methylenedioxy-, 7-methoxy-3′,4′-methylenedioxy-, 5,7- dimethoxyisoflavone
1 AcOH 50, 60, 20, 60, 30, 40, 60, 20, 75, resp.
7-55
min PtO2 used, isoflavanone was isolated through formation of semicarbazone with further hydrolisis
97
7,2`,4`-trimethoxyisoflavone 1 AcOH 35 56
min PtO2 used 98
In summary, the hydrogenation of chromones over Platinum-derived catalysts is very solvent-dependent. The best conditions are the use of acetic acid as a solvent, and “titration with hydrogen”, until one equivalent is absorbed. In alcoholic solvents this hydrogenation often fails to complete, sometimes also fails to start. The latter peculiarity could allow the side-chains hydrogenation of the appropriate substrates.
1.1.1.4 With Raney-Nickel
Table 4 presents the information about chromones’ hydrogenation on Raney-Nickel that gives chromanones. Here, hydrogenation means that hydrogen as a gas was involved in the reaction, although a reduction is also possible in case of Raney-Nickel (reaction without gaseous hydrogen or some other sources of hydrogen, other that NiRa).
7-Hydroxychromone and 6-ethyl-7-hydroxychromone were hydrogenated on Raney- Nickel with high yields (79 and 88%, resp.)99. 7-hydroxychromanone obtained was further hydrogenated on Raney-Nickel to give 7-hydroxychroman.
The hydrogenation of chromones on Raney-Nickel is not used often because the result of such a reduction is not well predictable. S. Mitsui et al. 84 report about the reduction of flavone and flavan to 2-(3-phenylpropyl)phenol with 95% yield (in presence of traces of NaOH). V. Ramanathan and K. Venkataraman100 made reductive detosylation of 5-hydroxy- 7-tosyloxyflavone and 5-hydroxy-3-methoxy-7-tosyloxyflavone by hydrogen on Raney- Nickel (without chromone-ring reduction). J.E. Gowan et al.101 also made reductive detosylation of 5-tosyloxyflavone, but have isolated only a mixture of α- and β-4- hydroxyflavans. C. I. Jarowski et al.102 report that the hydrogenation of ethyl 5- hydroxychromon-2-carboxylate on Raney-Nickel needed more than the required amount of hydrogen, although the starting compound was recovered alone with chromanone. M.
Tsukayama et al.103, 104 report about the reduction of triple bond (without hydrogenation of chromone ring) of 8-(3-methyl-3-hydroxybutynyl)-5,7,4'-tribenzyloxyisoflavone with hydrogen over Raney-Nickel.
Table 4. Summary table of chromones’ hydrogenation on Raney-Nickel. If otherwise not stated, the product is the corresponding 4-chromanone.
Substrate p(H2),
bar solvent yield,
% time additional information ref.
2-methylchromone, 3-methylchromone N/A EtOH 94, 90, resp.
0.1 h With overreduction, only 50%
conversion of educt, not synthetical article, reaction mixture was analyzed by GLC
78
6-ethyl-7-hydroxychromone N/A EtOH 88 3,5 h 45º 99
7-hydroxychromone N/A EtOH/
MeOH 79 3 h 99, 105
5-hydroxychromon-2-carboxylic acid ethyl
ester 2 EtOH 44 10
min 80º, part of starting compound recovered
102
2'-benzyloxy-6-(3-hydroxy-3- methylbutynyl)-7-methoxy-4',5'- methylenedioxyisoflavone
N/A MeOH 77 N/A 20ºC, with hydrogenation of triple C≡C bond
104
ethyl 7-(5-(4-acetyl-3-hydroxy-2- propylphenoxy)pentyloxy)-4-oxo-8- propylchromone-2-carboxylate, 2- carboethoxy-7-[5-(2-n-
propylphenoxy)pentoxy]-8-n- propylchromone
1.13 EtOH, THF/
EtOH 51, 89 resp.
7 h, 30 min
patent, reactions are given as examples
106
2-ethylchromone 100-
200 EtOH 30 16
min 120-130ºC 107
1.1.2 Transfer hydrogenation of chromones on palladium
This type of hydrogenation does not involve hydrogen in form of a gas, but uses the other reducing compounds. The reaction is an abstraction of hydrogen from the reducer onto catalyst with subsequent hydrogenation of the oxidizer (substrate). There is an interesting review108 dedicated to such a method of hydrogenation. Among the reducing reagents isopropanol, dioxane, cyclohexene, formic acid, ammonium formate, triethylamine and complexes of formic acid with triethylamine are the best known ones.
Table 5 presents the information about chromones’ catalytic transfer hydrogenation (CTH) that gives chromanones-4. If not stated otherwise, 10% Pd/C was used as a catalyst.
J. Massicot et al.109 have found that chrysin 68 and acacetin 69 could be hydrogenated by tetraline, catalyzed by Pd black, to give the corresponding isoflavanones. The CTH of the structurally similar 70 and 72 yielded the corresponding dihydrochalcones. In their further publication110 the regularities of product formation were found. The flavones 72-75 were reduced to the corresponding flavanones, while the compounds 76-80 – gave the dihydrochalcones. Compound 81 was reduced to the mixture of flavanone and dihydrochalcone.
O OH
HO O
Chrysin,68
PD black
tetraline OH O
HO O
O OH
HO O
Acacetin,69
OMe
O OH
HO O
Isosakuranetin OMe
PD black tetraline
O OH
HO O
OMe OMe
O OH
HO OH OMe
OMe
PD black tetraline
O
HO O
OMe
O
HO OH OMe
PD black tetraline 70
Pratol,71
O O Ph
81 MeO
MeO
PD black
tetraline O
O Ph MeO
MeO
O OH MeO
MeO Ph
O
O Ph
R R2 R1
R3
72R1= OH
73R1= OH, R3= OMe 74R2= OMe
75R4= OMe
O
O Ph
R R2 R1
R3
76R2= OH
77R=OMe, R2= OH 78R = R2= OMe 79R1= OH, R2= OMe 80R4= OH
+ 25%
41%
35%
Scheme 17
3-Imidazolylchromone was reduced by natrium hypophosphite over 10% Pd/C111 with yield of 53%.
The authors of the article112 have investigated CTH of isoflavone. They report that cyclohexene and isopropanol are ineffective in this reaction. The use of such systems as sodium formate – fomic acid, ammonium formate and triethylamine – formic acid was studied. Although isoflavone could be reduced by all three systems, the highest yield was 62%.
K. Wähälä and T.A. Hase113 report that the yields are not very high because of flavan-4- ol formation. The latter is not too stable and undergoes further transformations. In the series of flavones’ reductions they have synthesized flavanones with yields of 52-60% and also have isolated flavan-4-ols with yields of 13-21%.
Korean researcher114 have reduced the isoflavone using ammonium formate and Pd/C in EtOH within 2 h with a yield of 94%. The prolongued reaction time (12 h) leads to isoflavonol formation115. The same authors report that CTH of flavone in MeOH by ammonium formate over Pd/C during a day is very unselective and gives eight compounds116.
In order to establish a structure of biologically active flavonoid from Aloe barbadensis R. Hong et al.117 have reduced compound 82. They have found out that 82 was sparingly reactive under the standard catalytic hydrogenation. If it had been stored in a refrigerator, it could be hydrogenated by CTH. Hydrogenation of 82 stored at room temperature did not occur.
Scheme 18
S. K. Sabui et al.118 have prepared a series of 9 lipophilic chromones (without OH- groups) in order to perform hydrogenation in CTH-conditions. They report about very high yields (93-95%), and only one compound (2,3,7-trimethylchromone) was hydrogenated with a 70% yield and 15%-recovery of the starting compound. In case of 7-methylflavone no chromanone is obtained, but 1-(2-hydroxy-4-methylphenyl)-3-phenylpropan-1-one is synthesized. In the other article119 they inform about CTH of ethyl 7-methyl-6- methoxychromone-2-carboxylate to the corresponding chromanone with a 75% yield, while hydrogenation on Pd/C leads to chromanol which was oxidized to chromanone with Jones’
reagent (70% yield).
H.G. Krishnamurty et al.120 report about debenzylation of phenyl-benzyloxy ethers using CTH. The 7-benzyloxyisoflavone was deprotected and hydrogenated to 7- hydroxyisoflavanone, while 5-hydroxy-7-benzyloxyflavone was only deprotected. Similar transformation of 2`,4`-dibenzyloxy-7-methoxyisoflavone (hydrogenation with debenzylation) is reported by American scientists121.
The similar CTH of side-chain of 2-stirylchormones is known. The chromone ring was not affected, only the 2-stiryl substituent122.
An interesting reaction was found in patent123. 7,4`-diacetoxyisoflavone 83 was converted to rac-equol 84 in AcOH by ammonium formate, using Pd(OH)2/C. In this reaction, ammonium formate played a role as a reducing reagent and also performed deacetylation since acetamide was detected. The similar 7,4`-bis(methoxymethoxy)isoflavone 85 was hydrogenated to the corresponding isoflavanone 86 by ammonium formate on Pd/C124.
O O
OAc
AcO O
OH HO
Pd(OH)2/C NH4OCHO
O O
OMOM MOMO
O O
OMOM MOMO
Pd/C NH4OCHO
83 84
85 86 82.2%
83.2%
Scheme 19
Table 5. Summary table of chromones’ catalytic thransfer hydrogenation. If otherwise not stated, the product is the corresponding 4-chromanone, and a catalyst - 10% Pd/C.
Substrate reducing reagent solvent yield,
% time additional information ref.
7-benzyloxychromone NaCOOH MeOH/
AcOH
61 5 h reflux, with debenzylation 63
68, 69 tetraline tetraline 25,
N/A, resp.
N/A 210º C, Pd black used, not reacted chrysin partially recovered
109
72, 73, 74, 75, 81 tetraline tetraline 20, 16, 24, 4, 41, resp.
N/A 210º C, Pd black used, not reacted substrate partially recovered, 81 yilded
dihydrochalcone with yield of 35%
110
3-(imidazol-1-yl)chromone NaH2PO2 aqueous
EtOH 53 16 h reflux 111
HCOOH MeOH 40-62 3 h reflux 112
NH4OCHO MeOH 52-60 3-4 h reflux 112 7-hydroxy-, 7-methoxy-, 5,7-
dihydroxy-, 5,7,2`,4`- tetramethoxy-, 5,7,2`,5`-
tetramethoxyisoflavone NEt3- HCOOH
no solvent 50-54 3 h 100º 112 7-hydroxy-, 7,41-dihydroxy-, 7- NH4OCHO MeOH 52-60 2 h reflux, isoflavanols isolated 113
