MSc Chemistry
Molecular Sciences
Master Thesis
A Synthetic approach to Yaequinolone B utilizing
Pd/S,O-ligand catalyzed C-H olefination
by
Youri van Valen
11094176
October 2019
48 ECTS
February 2019-September 2019
Supervisor/Examiner:
Examiner:
dr. M.A. (Tati) Fernández Ibáñez
dr. E. (Eelco) Ruijter
Daily supervisor:
N. (Nick) Westerveld, BSc.
i
Abstract
The Fernández-Inbáñez group developed a Pd(II)-catalyzed C-H olefination for the para-selective olefination of indolines and tetrahydroquinolines. Utilizing their S,O-ligand a wide range of indoline and tetrahydroquinoline substrates were olefinated under mild conditions.
Yaequinolones are a family of compounds which show insecticidal properties. These compounds all show the tetrahydroquinoline motif. Yaequinolones B through F have an olefin on the C-6. The C-H olefination method developed by the Fernández-Inbáñez could unlock a synthetic route to all these compounds.
In this work a method is proposed for the synthesis of yaequinolone B, utilizing C-H olefination as a final step in the synthesis. The C-H olefination will be tested on various model substrates to test the reactivity and selectivity.
ii
Abbreviations list
Cat. Catalyst DCE 1,2-Dichloroethane DCM Dichloromethane DMF Dimethyl formamide EA Ethyl acetate eq Equivalent IS Internal standard MeOH MethanolNMR Nuclear magnetic resonance
o.n. Overnight PG Protective group rt Room temperature (≈23 °C) SM Starting material TBPB tert-Butyl peroxybenzoate THQ Tetrahydroquinoline TIPS Triisopropylsilyl
iii
Table of contents
Abstract ... i
Abbreviations list ...ii
1 Overview of thesis work ... 1
1.1 Introduction ... 1
1.2 Objectives ... 2
2 Background ... 3
2.1 Known total syntheses of yaequinolones ... 3
3 Results and Discussion... 5
3.1 Retrosynthetic analysis of Yaequinolone B ... 5
3.2 Synthetic approach ... 5
3.2.1 Test substrates ... 8
3.3.Substrate synthesis ... 8
3.3.1 Synthesis of 5-hydroxyquinolin-2(1H)-one (13) ... 8
3.4 Protection of functional groups ... 9
3.4.1 Synthesis of 1-methylquinolin-2(1H)-one (11A) ... 9 3.4.2 Synthesis of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12A) ... 9 3.4.3 Synthesis of 5-methoxy-1-methyl-1,2-dihydroquinoline (13A) ... 10 3.5 Dihydroxylation ... 10 3.5.1 Synthesis of 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (14) ... 10 3.5.2 Synthesis of 3,4-dihydroxy-5-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (15) ... 11 3.6 C-H Olefination ... 13 3.6.1 Olefination of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (16) ... 13 3.6.2 Olefination of 5-methoxy-1-methyl-1,2-dihydroquinoline (17) ... 14 3.6.3 Olefination of 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (18)... 15 4 Conclusions ... 17 5 Outlook ... 17 6 Experimental Section ... 19 6.1 General information ... 19 6.2 Experimentals ... 19 6.2.1 5-acetyl-6-methylpyridin-2(1H)-one (21) ... 19 6.2.2 5-acetyl-6-(2-(dimethylamino)vinyl)pyridin-2(1H)-one (23) ... 19 6.2.3 5-hydroxyquinolin-2(1H)-one (13)... 20 6.2.4 1-methylquinolin-2(1H)-one (11A) ... 20 6.2.5 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12A) ... 20
iv 6.2.6 5-methoxy-1-methyl-1,2-dihydroquinoline (13A) ... 21 6.2.7 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (14) ... 21 6.2.8 3,4-dihydroxy-5-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (15) ... 22 6.2.9 ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate (16) ... 22 6.2.10 ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acrylate (17) ... 23 6.2.11 ethyl (E)-3-(3,4-dihydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate (18) 23 7 References ... 24 8 Acknowledgements ... 25
1
1 Overview of thesis work
1.1 Introduction
Chemical transformation of C-H bonds has been an interesting topic of research in the recent years.1,2,3 C-H activation has the potential to uncover new opportunities for the synthesis of biologically
relevant molecules.4 Successful C-H activation and functionalisation can save numerous steps during
the development of total syntheses. By limiting the amount of synthetic steps the atom economy of synthetic pathways can be improved. Utilizing C-H activation can help limit the use of toxic and harmful chemicals used in traditional organic transformation.
The inert character of the C-H bonds was the first challenge to overcome in the development of C-H activation methods.5,6 By utilizing transition metals, complexes can be formed that activate C-H
bonds. Transition metal complexes, especially palladium complexes,2,3,6 have already shown to be
successful in activating C-H bonds. The transition metal reacts with the C-H bond forming a more reactive C-M bond. The newly formed C-M bond can subsequently react with a variety of functional groups to form C-C or C-X bonds.
The second challenge of C-H activation is selectivity. Various methods can be applied to achieve the desired selectivity: Intrinsic control, intramolecular control, directing groups and ligands. There are drawbacks associated with most of these control modes. Intrinsic control utilises the most reactive C-H bond in the molecule, and therefor lacks the ability to precisely tune selectivity. Intramolecular control relies on leaving groups in the molecule to direct the structure of the complex, this mode of control is used for intramolecular couplings. Directing groups coordinate the molecule to the metal complex to bring the desired C-H bond in close proximity to the metal centre. While the use of directing groups allows for cross-coupling reactions these directing groups are generally unwanted in the final product.7 Ligand controlled selectivity has been a topic of research for C-H activation for a couple of
years and shows promising results.6
The Fernández-Inbáñez group developed a method utilizing a Pd-catalyst combined with their S,O-ligand, 2-i-propyl-2-(phenylthio) acetic acid, for the C-H olefination of nondirected arenes.8 The
same catalytic system was used successfully for the para-selective olefination of aniline derivatives9,
indolines, and tetrahydroquinolines(THQ).10 The general reaction equation is shown in Scheme 1. The
indoline and THQ motifs are especially interesting for the application of the C-H olefination method as these commonly occur in biologically active compounds.11
Scheme 1: Pd/S,O-ligand promoted C-H olefination of indoles and THQs.10 n= 1, indole; n=2, THQ
2 Omura et al.(2006)12 isolated a family of compound named Yaequinolones, shown in Scheme
2, which all share a THQ core. These compounds were isolated from a strain of Penicillium and have shown to exhibit insecticidal properties.12 In 2018 Hanessian et al. 13 corrected the stereochemistry
reported by Omura et al. (2006)12 in their total syntheses of yaequinolone J1 and J2. The structures of
this family of compounds are shown in Scheme 2. Yaequinolones B through F are of particular interest as these contain an alkene attached to the C-6 position of the THQ core. These yaequinolones could be promising targets for successful application of the C-H olefination method developed by the Fernández-Inbáñez group.
1.2 Objectives
The goal of this research is to perform the total synthesis of yaequinolone B using C-H olefination as the last step of the synthesis. This will allow the synthesis of all yaequinolones B through F by changing the olefin.
The reach the goal, a retrosynthetic analysis of yaequinolone B will be performed. The reactivity towards C-H olefination will be tested on model substrates. These model substrates will be derived from the THQ core of yaequinolone B.
3
2 Background
2.1 Known total syntheses of yaequinolones
Total syntheses have been reported for yaequinolones A2, J1, and J2.13, 14, (±)-Yaequinolone A2
was the first yaequinolone to be synthesised.14 Hanessian et al. (2018)13 reported the enantioselective
synthesis of yaequinolones J1 and J2.
The THQ core in yaequinolones J1 and J2 combined with the alkene attached to the C6 carbon of the THQ core is similar to the desired product. A summary of the total synthesis is shown in Scheme 3 and Scheme 4. The total synthesis can be divided into 2 parts. Scheme 3 shows the first part of the total synthesis. The products of this sequence, compounds (IVa) and (IVb), are key intermediates in the total synthesis of (-) - yaequinolone J1 and (+)-yaequinolone J2. Starting from compound (I) in 8 steps compound (II) was formed. This compound already contains one of the three stereocentres present in yaequinolones J1 and J2, labelled with 3”. The most interesting step is the Evan’s asymmetric aldol reaction between (II) and (VI) resulting in compound (III) as this reaction forms the stereocenter at 4. Only one syn-adol diol was formed with the desired S configuration at the C-3 methoxy.13
Reduction of (III) resulted in equal amounts of the diastereomers (IVa) and (IVb) which were separated by column chromatography.
The second part of the synthesis starts with compound (IVa) for (-)-yaequinolone J1 and (IVb) for (+)-yaequinolone J2. The reaction steps are identical for each product, so only the synthesis of (-)-yaequinolone J1 starting from compound (IVa) is shown. Following the steps shows in Scheme 4, the primary alcohol in compound (IVa) is protected and the secondary benzylic alcohol is oxidized to its ketone. A Grignard reaction is performed to install the p-methoxyphenyl moiety and generate the desired 4S stereocentre in compound (V). From (V) (-) - yaequinolone J1 is obtained after deprotection of the primary alcohol, an oxidative cyclisation to form the lactam, and finally cleavage of the N-Boc group to obtain the desired product.
4
5
3 Results and Discussion
3.1 Retrosynthetic analysis of Yaequinolone B
Yaequinolone B is the simplest of the yaequinolone family which could be synthesised using the C-H activation method developed by the Fernández-Inbáñez group.10 A retrosynthetic analysis is
shown in Scheme 5.
Starting from 3-aminophenol A1 synthesised using a C-H olefination/cyclisation cascade reaction.15 Dihydroxylation of A1 will result in A2. The final step is the C-H olefination on the C6 position
of A2 resulting in yaequinolone B after the remaining protective groups (PG) have been cleaved.
3.2 Synthetic approach
Using the retrosynthetic analysis a synthetic approach towards yaequinolone B can be hypothesised. Scheme 6 shows the first part, the creation of the THQ core with the p-methoxyphenyl group at position 4, and the installation of the required protective groups (PG) at the phenolic alcohol and amide. Starting from compound 1 a MOM-ether PG is installed at the phenolic alcohol yielding compound 2.16 This alcohol is part of our end product, therefor the PG is installed to stop any
interference with the following reactions. A one pot C-H activation/Cyclisation reaction between compound 2 and 3 yields compound 4,15 forming the THQ core. The amide in compound 4 is protected
using a triisopropylsilyl (TIPS) PG to yield compound 5.17,18 The N-PG is a necessity for the following
dihydroxylation19 and C-H olefination reactions. Scheme 5: Retrosynthetic analysis of Yaequinolone B
6 In Scheme 7 the second part of the synthetic plan is shown. Dihydroxylation of compound 5 yields compound 6.19 Next step is the methylation of the hydroxyl group at position 3.
Methylation of compound 6 to yield compound 7. Steric hindrance of the p-methoxyphenyl at position 4 makes the hydroxyl at position 3 more favourable for attack. C-H olefination on compound 7 will yield compound 8.10 From compound 8 the tips group is removed to yield compound 9.20 A cleavage of
the MOM ether will yield the desired product yaequinolone B.21 Scheme 6: Synthetic approach part 1
7
8
3.2.1 Test substrates
The C-H olefination reaction has not been performed on quinonilones prior to this research, and very few articles report on dihydroxylation reactions performed on quinolinones. To obtain a proof of principle both reactions will be tested on less complex quinolinone substrates. The substrates that have been synthesised and tested are shown in Scheme 8. For the C-H olefination reaction the method developed by the Fernández-Inbáñez group will be used.10 The dihydroxylation reactions will be
performed according the method reported by Plietker and Niggeman in 2005.19 Compounds 11 and 12
are commercially available, 13 will be synthesised. Compounds 14 and 15 are products of the successful dihydroxylation of 11 and 13, respectively.
3.3.Substrate synthesis
3.3.1 Synthesis of 5-hydroxyquinolin-2(1H)-one (13)
The synthesis of compound 13 was reported by Singh in 199122 in an extension to a paper
published in 199023. The synthetic steps are shown in Scheme 9. Starting with compounds 19 and 20
compound 21 was synthesised with 30% yield. Refluxing compound 21 in the presence of compound 22 (Bredereck’s reagent) gave compound 23 in 91% yield. Stirring compound 23 in concentrated hydrochloric acid for 24h gave compound 13 with 52% yield. Compound 13 was successfully synthesised with an overall yield of 14%.
Scheme 8: Substrates to be tested on a: dihydroxylation and b: C-H olefination. R=H or PG
9
3.4 Protection of functional groups
Each of the substrates to be tested contain an amide group, and substrates 12 and 13 also contain an phenolic alcohol group. For the C-H olefination method a protecting group on the amide has shown to be beneficial to the reactivity in most of the THQs that have already been tested by the Fernández-Inbáñez group.10 Likewise in the dihydroxylation reaction using the method developed by
Plietker and Niggeman (2005)19 a protective group is present on substrates containing an amide group.
The protective group used by the Fernández-Inbáñez group was a methyl group, and thus the same protective group will be used during this research. The method used was reported by Verhaeghe et al. (2018).24
3.4.1 Synthesis of 1-methylquinolin-2(1H)-one (11
A)
Using a base and methyl iodide the amide is methylated. The reaction conditions are shown in Scheme 10. Compound 11A was synthesised with 64% yield, however, only partial conversion of the
starting material was observed. The remaining 36% was left untouched, suggesting that a stronger base might be necessary to achieve full conversion.
3.4.2 Synthesis of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12
A)
The desired product 12A was successfully synthesized using the conditions shown in Scheme
11 with a 16% yield. The partially converted product 12B amounted for the remainder of the yield. Due
to the low conversion towards to desired product a follow up reaction was performed on compound 12B using sodium hydride as a base. The reaction conditions are shown in Scheme 12. These conditions
produced the desired product 12A with full conversion and 76% yield.
Scheme 10: Synthesis of 1-methylquinolin-2(1H)-one (11)
Scheme 11: Synthesis of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12A)
Scheme 12: Synthesis of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12A) using NaH
10
3.4.3 Synthesis of 5-methoxy-1-methyl-1,2-dihydroquinoline (13
A)
Using the same method as the synthesis of compound 11, compound 13A was synthesised.
NMR shows formation of the desired product 13A, however, partially converted product 13B was also
present in the crude mixture. NMR analysis of the crude mixture shows around 10% of compound 13B,
giving a respectable 90% conversion. Efforts to separate the compounds were unsuccessful. In order to obtain compound 13A a follow up reaction was performed on the crude product. The same
conditions were used as the follow up reaction performed during the synthesis of 12A. This did yield
compound 13A.
Following this result the reaction was run using compound 13 with the conditions shown in Scheme 14. gave the desired product with 62% yield. No starting material was left and only trace amounts of compound 13B were observed.
3.5 Dihydroxylation
In order to obtain the syn addition a stereo specific dihydroxylation method was chosen. While the use of OsO4 is very common for dihydroxylation reactions it is a toxic chemical and non-toxic
alternatives are preferable wherever possible. The method developed by Plietker and Niggeman (2005)19 produces racemic syn-diols and reported high yields (>80%) on amides and on coumarin. The
dihydroxylation is performed using a catalytic system consisting of RuCl3, CeCl3, and NaIO4, thereby
avoiding the use of toxic OsO4.
3.5.1 Synthesis of 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (14)
While the yields reported for all the substrates tested by Plietker and Niggeman (2005)19
showed great promisve, initial results for the dihydroxylation of compound 11A painted a different
picture. Table 1 gives an overview of the different reactions and reaction conditions.
Scheme 13: Synthesis of 5-methoxy-1-methyl-1,2-dihydroquinoline(13A)
Scheme 14: Synthesis of 5-methoxy-1-methyl-1,2-dihydroquinoline(13A)
using sodium hydride
Scheme 15: Synthesis of 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (14), based on Table 1, entry 4.
11 Entry 1 was performed using compound 11 and resulted in no yield. The lack of protecting group on the amide was suspected to be the cause of this. The reaction was performed with compound 11A (see entry 2) and resulted in a 10% yield. Entry 2 did not reach full conversion, 1H-NMR analysis of
the crude mixture shows a ratio of 2:3 of starting material to product. The resulting yield was lower than expected from the conversion. This could indicate that losses were made during the workup or over oxidation of the product takes place.
Entry Scale (mmol) Cat (mol %) RuCl3 (mmol) CeCl3•7 H2O (mmol) NaIO4 (mmol) T (°C) t (min) Yield (%) 1a 4 0.5 0.02 0.4 6 0 -> rt 20 0 2b 2 0.5 0.01 0.2 3 0 -> rt 60 10 3b 4 0.5 0.02 0.4 6 0 60 26 4b 5.89 1 0.06 1.2 17.67 0 90 35
Table 1: Results and conditions for the synthesis of compound 14 reactions a: Reaction performed using compound 11. b: Reaction performed using compound 11A
For entries 3 and 4 the temperature was kept stable at 0 °C in order to minimize any over oxidation. TLC analysis on the crude mixture of entry 3 showed full conversion of the starting material, however, NMR analysis of the collected fractions after column chromatography revealed that starting material was still present. 30% of the starting material was recovered, determined by 1H-NMR using
CH2Br2 as an internal standard. 1H-NMR analysis of the product revealed some unidentified compound
still present. Further purification was attempted, however, these efforts did not achieve any results. TLC analysis of the product showed a single spot over a range of eluents. The GC-MS chromatogram showed two peaks, confirming the presence of impurities. 13C-NMR analysis showed the expected 9
peaks. However, both of the hydroxyl carbon peaks show slightly down shifted peaks with similar intensity.
Entry 4 was performed nearing the end of the research period. In an attempt to achieve full conversion of the starting material the catalyst concentration was doubled and the reaction time was increased. The reaction was performed on a larger scale than previous experiments in order to obtain enough product for multiple C-H olefination reactions regardless of the yield. 1H-NMR analysis of the
crude mixture did not show any starting material, so full conversion was achieved. After purification using column chromatography 35% yield was obtained. 1H-NMR analysis of the product showed similar
impurities as identified in entry 3.
3.5.2 Synthesis of 3,4-dihydroxy-5-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (15)
For the synthesis of compound 15 the conditions reported in Table 1 entry 4 were used as a starting point. Due to time constraints only two experiments were run in an effort obtain the desired product. The conditions and results are shown in Table 2.
Scheme 16: Synthesis of 3,4-dihydroxy-5-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (15)
12 Initial 1H-NMR analysis of the crude mixture obtained in entry 1 indicated that the desired
product had been formed. However, the starting material was only partially converted. Comparing the integrals of the starting material peaks with the product peaks showed that 15 mol% of starting material was left, along with various other impurities. The starting materials has poor solubility in DCM, so attempts were made to precipitate the starting materials by dissolving the crude in a minimal amount of DCM. A precipitate formed, which was collected and dried; however, the collected precipitate was not the starting materials. 1H-NMR analysis of the precipitate showed peaks of
unidentified impurities. The DCM solution was concentrated to dryness under reduced pressure and
1H-NMR analysis of the resulting solids confirmed the presence of the desired product and starting
materials. Entry Scale (mmol) Cat (mol %) RuCl3 (mmol) CeCl3•7 H2O (mmol) NaIO4 (mmol) T (°C) t (min) Yield (%)a 1 2 1 0.01 0.4 6 0 90 13b (SM: 2%) 2 4 2c 0.08c 1.6c 24c 0 240 45d (SM: 11%)d
Table 2: Results and conditions for the synthesis of compound 15. a: Yields determined by NMR using CH2Br2 as internal standard. b: Yield determined after multiple purification attempts. c: Catalyst added in 2 portions, each 50% of total. Second portion added after 150 min. d: Yield determined prior to purification attempts.
Following these observations efforts were made to separate the compound using column chromatography. Various eluents and mixtures were tested using TLC. A solvent system using DCM, Ethyl acetate (EA), and methanol(3:1:1 vol%) was chosen. The TLC plate showed three peaks with a good separation. Upon analysing the collected fractions by TLC, using the same solvent system, more peaks started to show up then the three identified in the crude mixture. The fractions containing the product all showed 3 distinct peaks on TLC with a narrow separation. 1H-NMR analysis confirmed that
the product fractions still contained the starting material in an identical ratio as the crude mixture, along with unidentified impurities. The yield was determined using CH2Br2 as an internal standard on
the collected fractions.
The experiment was repeated using the conditions shown in entry 2 of Table 2. Notable differences are the increase in time and the addition of a second portion of catalyst. The reaction was followed on TLC to check if the starting material was converted. After 150 minutes starting material was still present, the increase in reaction time did not seem to increase the conversion. A second portion of catalyst complex was prepared and added to the reaction mixture. Continuously following the reaction on TLC and not seeing the starting materials spot disappear the reaction was stopped after a total run time of 250 min.
The crude mixture was analysed using 1H-NMR, confirming the presence of 25 mol% starting
materials compared to product. The yield was determined by 1H-NMR analysis using CH
2Br2 as internal
standard prior to purification. Purification was attempted via column chromatography using DCM, EA, and methanol (3:1:5 vol%). In contrast to entry 1 no new peaks showed up after the column. However, the fractions containing the product were mixtures of already identified peaks. A few select fraction contained little to no secondary peaks. These were collected and concentrated under reduced pressure. 1H-NMR analysis showed that 2 mol% of starting material compared to product was still
present in the collected fractions, along with various other impurities. MS analysis was performed on the same sample and the presence of the desired product was confirmed.
The decrease in ratio starting material to product observed in entry 2 shows that separation of the product and starting material is possible. A better solvent system needs to be found to achieve the separation or several columns need to be run in order to separate each spot individually. Due to time constraints this could not be done during this research.
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3.6 C-H Olefination
The C-H Olefinations were performed using the method developed by the Fernández-Inbáñez group.10 All reactions were performed at multiple temperatures and with different solvents. All
experiments were run with and without the S,O-Ligand to test the influence of the ligand in the C-H olefination reaction. NMR analysis was used to determine yields using dibromomethane as an internal standard(IS), whenever possible the products would be isolated.
3.6.1 Olefination of 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (16)
The results and conditions of the experiments are shown in Table 3. All experiments were performed with a concentration of 0,2 mmol/mL. No significant evidence of C-H olefination at any other positions then C-6 was found in the isolated product.
Entry Solvent Scale
(mmol) t(h) T(°C) S,O-Ligand Yield (%) SM (%) 1 1,4-Dioxane 0.1 18 50 Yes 8 ND 2 DCE 0.1 18 50 Yes 38 (22) ND 3 1,4-Dioxane 0.1 18 50 No No Yield ND 4 1,4-Dioxane 0.1 18 80 Yes 20 80 5 DCE 0.1 18 80 Yes 50 50 6 1,4-Dioxane 0.1 18 80 No 20 80 7 DCE 0.1 18 80 Yes 20 80 8 DCE 0.1 18 80 Yes 50 40 9 DCE 0.1 18 100 Yes 40 50
Table 3: Results of synthesis of compound 17. Yield are determined on NMR. Yields in parenthesis are isolated yields.
The initial results showed great reactivity towards C-H olefination for compound 12A. Entries 1
through 3 showed that performing the C-H olefination in DCE with ligand gives good yield. The addition of the ligand has significant effect as no yield was obtained when the ligand was not present.
Starting material was present in the reaction mixture of entries 1 through 3. The amount of starting material left could not be determined, the integrals of the starting materials peaks compared to the IS were greater than the integrals of the starting material should be. A cause of this could be that the IS was not added properly during sample preparation. Not adding enough IS could explain the bigger integrals for the starting material. This also makes the NMR yields obtained not accurate, and explains the isolated yield in entry 2 being significantly smaller.
Entries 4 through 8 show that an increase in temperature results in an increased yield and conversion. Using DCE as a solvent at 80 °C gives 50% yield and 50% of the starting material left, as determined via NMR. The yield was confirmed by performing the experiment multiple times in entry 7 and 9. Entry 7 is an outlier, as the yield only reached 20%. In entry 8 the yield was identical to the one reached in entry 5.
Scheme 17: Synthesis of ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate. (17) Conditions based on Table 3, entry 8
14 The experiment performed for entry 9 at 100 °C reaches a lower yield as the experiments performed at 80 °C. In all entries the amount of starting material left is equal to the initial amount minus the yield. This experiment was the first experiment in which the amount of starting material left was less than amount of starting material converted to product. This could indicate that the starting material or the product degrades during the reaction. There is a caveat to this conclusion. When looking at the starting material left in entry 9 a loss of material is observed as well. This loss of material was not observed in the other experiments run at identical temperatures. The loss of material observed in entry 8 is identical to the loss of material in entry 9. The discrepancy in the amount of starting material and product observed compared to the initial amount of materials could be explained by inaccuracies in the analysis.
3.6.2 Olefination of 5-methoxy-1-methyl-1,2-dihydroquinoline (17)
The results and conditions of the experiments are shown in Table 4. All experiments were performed with a concentration of 0,2 mmol/mL.
Entry Solvent Scale
(mmol) t(h) T(°C) S,O-Ligand Yield (%) SM (%) 1 1,4-Dioxane 0.1 18 50 Yes 0 69 2 DCE 0.1 18 50 Yes 0 86 3 1,4-Dioxane 0.1 18 50 No 0 75 4 1,4-Dioxane 0.1 18 80 Yes 0 ND 5 DCE 0.1 18 80 Yes 28 80 6 1,4-Dioxane 0.1 18 80 No 10 90 7 DCE 0.25 24h 100 Yes 18 58%
Table 4: Results and conditions of the synthesis of compound 16. Yields are determined on NMR.
Entries 1 through 3 did not result in any of the desired product. Evidence of starting material left in the reaction mixture was found during NMR analysis. The partial conversion of starting material suggests that an elevated temperature can aid in reactivity and yield the desired product.
Entries 4 through 6 were run at an elevated temperature, and the results shows formation of the desired product. The yields are low, 28% being the highest yield acquired for this product. The amount of starting material in entry 4 could not be determined due to the IS not being properly added. When comparing the integral of the IS to the integrals if the product the product integrals were larger than expected. Efforts were made to isolate the compound from the reaction mixture of entry 5. Various solvents and mixtures were examined in order to separate the different compounds on TLC. The compounds were separated using column chromatography, however, the starting material and the product eluted simultaneously. The amount recovered after the column was too starting material all to attempt any further purification.
Scheme 18: Synthesis of ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acrylate (16)
15 Entry 7 was performed at 100 °C, the highest temperature this experiment has been performed at. The left over starting materials in entries 4 through 6 suggested that the temperature could go even higher in order to improve reactivity. However, the results show a different picture. The yield, 18%, was considerably lower compared to the yield obtained in entry 5. The amount of starting materials left was the lowest amount of all entries, indicating more conversion has taken place. Efforts were made to isolate the product. Likewise as the efforts made with entry 5 this proved to be difficult. The product and the starting materials eluted simultaneously. Due to the research period coming to an end no further attempts to purify the product have been made.
The yields reached in the synthesis of compound 17 with the results from the synthesis of compound 16 are significantly lower. When comparing the structures of compounds 12A and 13a the
only difference is the double bond at C-2/C-3. The extra double bond creates a conjugated system, therefore lowering the overall electron density in the aromatic ring. The decreased electron density of compound 13A can be the cause of the decreased reactivity towards C-H activation.
3.6.3 Olefination of 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (18)
The results and conditions of the experiments are shown in Table 5. All experiments were performed with a concentration of 0,2 mmol/mL.
C-H olefination of compound 14a gives different results than expected from the previous experiment. Entries 1 through 3 show no formation of the product at all. The initial amount of starting material was present in all samples, indicating no reaction had taken place.
When looking through entries 4 through 8 a new pattern is observed. The entries in which no ligand has been used show higher yields for the C-H olefination compared to the entries with a ligand. After the first observation of this during the experiments of entries 4, 5, and 8. The result for entry 8 was suspected to be the result of an error during the sample preparation. The experiment was repeated in order to rule out this error. However, the results observed in entries 6, 7, and 9 show similar yields for the entries with and without the ligand.
Entry Solvent Scale
(mmol) t(h) T(°C) S,O-Ligand Yield (%) SM (%) 1 1,4-Dioxane 0.1 18 50 Yes 0 100 2 DCE 0.1 18 50 Yes 0 100 3 1,4-Dioxane 0.1 18 50 No 0 100 4 1,4-Dioxane 0.1 18 80 Yes 7 72 5 DCE 0.1 18 80 Yes 14 81 6 1,4-Dioxane 0.1 18 80 Yes 15 72 7 DCE 0.1 18 80 Yes 12 59 8 1,4-Dioxane 0.1 18 80 No 22 61 9 1,4-Dioxane 0.1 18 80 No 27 58
Table 5: Results of the synthesis of ethyl (E)-3-(3,4-dihydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate (18). Yields are determined by NMR analysis.
Scheme 19: Synthesis of ethyl (E)-3-(3,4-dihydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate. (18) Conditions based on Table 5, entry 9.
16 The results show that the addition of the S,O-ligand hampers the reactivity towards C-H olefination for compound 14. Comparing compound 14 to compound 16 the addition of the hydroxyl groups is the likely cause. However, whether this is due to electronic or steric reasons is unclear. Solvent effects could also play a role, and cannot be ruled out based on the performed experiments.
Efforts were made to isolate the product using column chromatography. However, no pure sample of the product could be obtained. The product and the starting materials eluted from the column simultaneously. Due to research period coming to an end no further attempts have been made to purify the product. Only characteristic peaks could be identified in the 1H-NMR spectrum, however
17
4 Conclusions
A synthetic route towards Yaequinolone B has not been realised during this research period. The experiments conducted did give insight in the potential of the proposed route. The method chosen to perform the dihydroxylation reaction does not achieve good results on the tested substrates. In order to synthesize the target molecule additional steric build must be added onto the substrate. The effects of this are currently unknown, on account of this not being tested, however one can speculate that additional steric build does not bode well for the reactivity. The chosen method for dihydroxylation is not a suitable method for the proposed substrate.
All of the substrates showed to be successfully olefinated via C-H activation. The addition of functional groups has significant effects on the reactivity towards the C-H olefination reaction. The most notable example is the synthesis of compound 18. The addition of hydroxyl groups at 3 and C-4 causes the S,O-ligand to be ineffective. The hydroxyl groups change the electronic and/or the steric properties of the substrate which makes the S,O-ligand less effective. Another possibility could be that the hydroxyl groups act as coordination sites and competes with the coordination of the ligand.
It seems unlikely that the route proposed in section [3.1] will produce the desired compound with any reasonable yield. The dihydroxylation reaction performs poorly on the tested substrate, and having hydroxyl groups on C-3 and C-4 reduces the reactivity towards C-H olefination using ligand developed by the Fernández-Inbáñez group.
5 Outlook
For further research into a synthetic route to yaequinolone B a different approach is recommended. The dihydroxylation method tested during this research gives low yields, which will greatly reduce the overall yield of the reaction. If the synthetic approach proposed in section [3.1] is followed it is recommended to use a different method for the dihydroxylation.
The research has shown that the C-H olefination reaction is sensitive to which types of functional groups are present on the substrate. Whether the effects are due to steric or electronic properties is not known at this time. Substrates with a p-methoxyphenyl at C-4 have not been tested, and should be the starting point for further research.
The final recommendation is to use a different synthetic approach. The synthetic approach given during this research has a few flaws. The first flaw is that the produced product will be a racemic mixture, which will cut the overall yield in half. The second flaw is the methylation of the C-3 hydroxyl group. A selective method was not found, and relying on steric hindrance is no guarantee to the desired result. The dihydroxylation reaction is another difficult step in the process. No literature has been found on dihydroxylations being performed on the quinolinone core.
In section [2.1] the total synthesis of yaequinolone J1 and J2 are discussed. The synthesis developed by Hanessian et al. (2018)13 can be used as a starting point for a synthetic approach towards
yaequinolone B. The retro synthetic analysis is shown in Scheme 20. From B1 an Evans asymmetric aldol addition to B2, followed by a Grignard reaction to form B3, fixing the stereocenters on positions
3 and 4 respectively. From there the lactam is made via oxidation to form B4. C-H olefination on B4
will result in yaequinolone B. The phenolic alcohol should be protected until after the C-H olefination has been performed to not cause any interference with the necessary reactions.
18 Using this synthetic approach the correct stereo chemistry will be obtained, no dihydroxylation reaction has to be performed, and the C-3 methoxy is selectively obtained.
19
6 Experimental Section
6.1 General information
Chemical reagents and solvents were bought from chemical suppliers and used without further purification. The S,O-ligand was synthesised and supplied by a colleague. 1H NMR and 13C NMR spectra
were obtained on a Bruker DRX 400 Mhz spectrometer using Chloroform-d as a solvent, unless otherwise specified. Chemical shift values are reported in ppm relative to the solvent used. Infrared spectra were recorded on a Bruker IFS 28 FT-spectrometer and wavelengths are reported in cm-1. The
mass spectra were measured on an AccuTOF GC-MS 4g, JMS-T100GCV mass spectrometers with FD ionization methods.
6.2 Experimentals
6.2.1 5-acetyl-6-methylpyridin-2(1H)-one (21)
4-aminopent-3-en-2-one (10.00 g, 100.87 mmol) was dissolved in DMF (45mL) and placed in a round-bottom flask fitted with a reflux cooler. Methyl propiolate (9.87 mL, 110.96 mmol) was added over the course of 15 min. The reaction mixture was left to stir at room temperature for 3.5h, after which is was heated to reflux and left for 24h. The solvent was partially removed under reduced pressure and the resulting mixture was cooled in an ice bath. The product precipitated from the solution and was acquired through filtration. The solids were washed with cold ethanol to remove impurities. Yield: 43% (6.56 g, 43.39 mmol), beige powder. 1H NMR(400 MHz) 12.45 (1H, broad), 7.92
(1H, d), 6.48 (1H, d), 2.74 (3H, s), 2.52 (3H, s) mp 194-196 °C23
6.2.2 5-acetyl-6-(2-(dimethylamino)vinyl)pyridin-2(1H)-one (23)
Compound 21 (2.00 g, 13.36 mmol) and Bredereck’s Reagent (3.06 mL, 14.80 mmol) were dissolved in 1,4-dioxane (14 mL) and placed in a round-bottom flask fitted with a reflux cooler. The reaction mixture was stirred and brought to reflux for 2.5h. During the reaction yellow solids started to form. The solids were acquired through filtration and air dried. Yield: 92% (2.44g, 12.32 mmol), yellow powder. 1H NMR(400 MHz) 11.71 (1H, broad), 8.02 (1H, d), 7.80 (1H, d), 6.68 (1H, d), 5.97 (1H,
20
6.2.3 5-hydroxyquinolin-2(1H)-one (13)
Compound 23 (2.00 g, 9.69 mmol) was added to a cooled concentrated HCl solution (10 mL) and left to stir at rt for 24h. The HCl solution was removed under reduced pressure and the resulting residue was treated with a slight excess of 10% potassium carbonate solution. The resulting solution is acidified using AcOH and the product precipitates. The precipitate is acquired via filtration and the resulting solid is washed with MeOH. Yield: 52% (1.56 g, 5.08 mmol) 1H NMR(400 MHz, DMSO-d) 11.60
(1H, broad), 10.41 (1H, broad), 8.02 (1H, d), 7.26 (1H, t), 6.74 (1H, d), 6.61 (1H, d), 6.36 (1H, d). mp 336-341 °C22
6.2.4 1-methylquinolin-2(1H)-one (11
A)
2-Quinolinone(11) (2 g, 13.8 mmol) is dissolved in DMF (60 ml) and K2CO3 (3 g, 21.6 mmol) is
added. The reaction mixture is heated to 80 °C and methyliodide (1.72 g, 27.6 mmol) is added dropwise. The solution is stirred for 48h. The reaction mixture is poured in water (50 mL) and the product is extracted using DCM (3x 100 mL). The organic layer is washed with water and dried using MgSO4. The volatiles were removed under reduced pressure and the crude product was purified using
column chromatography (DCM:EA 3:1). Yield: 64% (1.29 g, 8.9 mmol). 1H NMR(400 MHz) 7.62 (1H, d),
7.53 (1H, t), 7.52 (1H, d), 7.32 (1H, d), 7.20 (1H, t), 6.67 (1H, d), 3.68 (1H, s) mp 76 °C24
6.2.5 5-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline (12
A)
5-hydroxy-3,4-dihydroquinolin-2(1H)-one(12) (2.67 mmol, 435 mg) is dissolved in DMF (12 ml) and K2CO3 (2.22 g,16 mmol) is added. The reaction mixture placed in a nitrogen atmosphere and heated
to 80 °C. Methyliodide (1 mL, 16 mmol) is added. The solution is stirred for 48h. The reaction mixture is poured in water (20 mL) and the product is extracted using DCM (3x30 mL). The organic layer is washed with water and dried using MgSO4. Volatiles were removed under reduced pressure and the
crude product was purified with column chromatography (DCM:ACN 9:1).12A: white crystals, yield 26%
(62 mg, 0.35 mmol) 1H NMR(400 MHz) 7.73 (1H, t), 6.67 (2H, d), 3.87 (3H, s), 3.37 (3H, s), 2.92 (2H, t),
2.62 (2H, t) mp 63.5 - 65.5 °C. 12B: white crystals, Yield: 30% (133, 0.81 mmol) 1H NMR(400 MHz) 8.39
21 In a round bottom flask with a nitrogen atmosphere compound 12B (133 mg, 0.81 mmol) and
a 60% dispersion of NaH (48.8 mg, 1.22 mmol) were dissolved in DMF (10 mL). Methyl iodide (2 mL, 32 mmol) was added. The reaction mixture was stirred overnight at rt. The reaction was quenched by adding water (20 mL). The product was extracted using DCM (3x 60 mL). The volatiles were evaporated under reduced pressure. The crude product was purified using column chromatography (DCM:ACN 9:1) to yield white solids. Yield: 76% (110 mg, 0.62 mmol) 1H NMR(400 MHz) 7.73 (1H, t), 6.67 (2H, d),
3.87 (3H, s), 3.37 (3H, s), 2.92 (2H, t), 2.62 (2H, t) mp 63.5 - 65.5 °C25
6.2.6 5-methoxy-1-methyl-1,2-dihydroquinoline (13
A)
In a round bottom flask with a nitrogen atmosphere compound 13 (500 mg, 3.10 mmol) and a 60% dispersion of NaH (372 mg, 9.30 mmol) were dissolved in DMF (20 mL). Methyl iodide (0.78 mL, 12.40 mmol) was added. The reaction mixture was stirred for 48h at room temperature. The reaction was quenched by adding water (20 mL). The product was extracted using DCM (3x 100 mL). The volatiles were evaporated under reduced pressure. The crude product was purified using column chromatography (DCM:ACN 9:1) to yield brown solids. Yield: 62% (341 mg, 1.94 mmol) 1H NMR (400
MHz) 8.06 (1H, d), 7.43 (1H, t), 6.89 (1H, d), 6.64 (1H, d), 6.59 (1H, d), 3.91 (3H, s), 3.65 (3H, s) mp: 129-130 °C26
6.2.7 3,4-dihydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (14)
NaIO4 (3.78 g, 17.67 mmol) was dissolved in a solution of CeCl3 ᛫7 H2O in water (447.1 mg, 1.2 mmol, 6
mL) and placed in a round bottom flask. The mixture was gently heated using a heat gun until a bright yellow suspension was formed. Ethyl acetate (16.5 mL) and acetonitrile (19.8 mL) were added to the suspension and stirred for approx. 10 min at 0 °C. To this mixture a solution of RuCl3 in water(0.06
mmol, 0.6 mL) was added. The mixture was stirred for an additional 10 minutes. To the resulting solution compound 11A (937 mg, 5.89 mmol) in ethyl acetate (3.3 mL) was added and stirred for 90
minutes. Na2SO4 (2.95 g) and ethyl acetate (19.8 mL) were added to the reaction mixture. The resulting
solids were filtered off and the filter cake was washed with ethyl acetate. The filtrate was washed with a saturated Na2SO3 solution (2x 20 mL) and dried over Na2SO4. Volatiles were evaporated under
reduced pressure. The crude product was purified by column chromatography (DCM:EA 3:1 with 1 vol% MeOH) yielding a white solid. Yield: 37% (400mg, 2.07 mmol) 1H NMR(400 MHz, DMSO-d) 7.40
22 169.9, 139.2, 130.5, 124.0, 123.7, 70.4, 68.7, 30.3, 1.04 mp: 123-125 °C IR Wavelenghts: 3451 cm-1,
3324 cm-1,3044 cm-1,1666 cm-1,1114 cm-1. FD-MS calcd for C
11H11NO3 193.07 found 193.07
6.2.8 3,4-dihydroxy-5-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one (15)
NaIO4 (2.56 g, 12 mmol) was dissolved in a solution of CeCl3 ᛫7 H2O in water (298.1 mg, 0.8 mmol, 3.6
mL) and placed in a round bottom flask. The mixture was gently heated using a heat gun until a bright yellow suspension was formed. Ethyl acetate (9 mL) and acetonitrile (12 mL) were added to the suspension and stirred for approx. 10 min at 0 °C. To this mixture a solution of RuCl3 in water(8.3 mg,
0.04 mmol, 0.4 mL) was added. The mixture was stirred for an additional 10 minutes. To the resulting solution compound 13A (756.84 mg, 4 mmol) in ethyl acetate (3 mL) was added and stirred for 150
minutes. Another portion of the catalyst complex was created according to the previously described process and added to the reaction mixture. The reaction mixture was stirred for an additional 90 minutes. Na2SO4 (2 g) and ethyl acetate (12 mL) were added to the reaction mixture. The resulting
solids were filtered off and the filter cake was washed with ethyl acetate. The filtrate was washed with a saturated Na2SO3 solution (2x 20 mL) and dried over Na2SO4. Volatiles were evaporated under
reduced pressure. Yield: 45% (Determined by NMR. IS: CH2Br2) 1H NMR(400 MHz) 7.37 (1H, t), 6.75
(1H, d), 6.70 (1H, d), 5.32 (1H, d), 4.28 (1H, d), 3.92 (3H, s), 3.43 (3H, s) FD-MS calcd for C12H13NO4
223.08 found 223.08
6.2.9 ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate (16)
Pd(OAc)2 (2.24, 0.01 mmol) and compound 12A (19.3 mg, 0.1 mmol) are placed in a pressure
tube. The S,O-ligand (2.08 mg, 0.01 mmol) is dissolved in 1,2-dichloroethane (0.5 mL) and added to the pressure tube. Ethyl acrylate (16 µL, 0.11 mL) followed by tert-butyl peroxybenzoate (19.2 µL, 0.1 mmol) are added to the solution. The tube was placed in an oil bath pre-heated to 80 °C and left stirring for 18h. The reaction mixture was filtered over celite. Volatiles were evaporated from the resulting solution under reduced pressure. The crude product was purified by column
chromatography (DCM:EA 95:5). Orange oily substance, yield: 51%(Determined by NMR. IS: CH2Br2). 1H NMR(400 MHz) 7.92 (1H, d), 7.50 (1H, d), 6.83 (1H, d), 6.48 (1H, d), 4.29 (2H, q), 3.77 (3H, s), 3.38 (3H, s), 2.95 (2H, t), 2.65 (2H, t), 1.37 (3H, t) 13C NMR (CDCl 3) 170, 170, 167, 156, 143, 138, 127, 122, 119, 118, 111, 61, 60, 31, 29, 18, 14. IR Wavelenghts: 2923 cm-1, 2852 cm-1, 1675 cm-1, 1628 cm-1, 1596 cm-1, 1265 cm-1, 1167 cm-1. FD-MS calcd for C 16H19NO4 289.13 found 223.13
23
6.2.10 ethyl (E)-3-(5-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acrylate (17)
Pd(OAc)2 (2.24, 0.01 mmol) and compound 13A (18.9 mg, 0.1 mmol) are placed in a pressure
tube. The S,O-ligand (2.08 mg, 0.01 mmol) is dissolved in 1,2-dichloroethane (0.5 mL) and added to the pressure tube. Ethyl acrylate (16 µL, 0.11 mL) followed by tert-butyl peroxybenzoate (19.2 µL, 0.1 mmol) are added to the solution. The tube was placed in an oil bath pre-heated to 80 °C and left stirring for 18h. The reaction mixture was filtered over celite. Volatiles were evaporated from the resulting solution under reduced pressure. Yield: 28% (Determined by NMR. IS: CH2Br2) 1H NMR (400
MHz) 8.04 (1H, d), 7.99 (1H, d), 7.77 (1H, d), 6.77 (1H, d), 6.74 (1H, d), 6.52 (1H, d), 4.31 (2H, q), 3.92 (3H, s), 3.74 (3H, s), 1.38 (1H, t). FD-MS calcd for C16H17NO4 287.32 found 287.11
6.2.11 ethyl (E)-3-(3,4-dihydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acrylate (18)
Pd(OAc)2 (2.24, 0.01 mmol) and compound 13A (18.9 mg, 0.1 mmol) are placed in a pressure
tube and dissolved in 1,4-dioxane (0.5 mL). Ethyl acrylate (16 µL, 0.11 mL) followed by tert-butyl peroxybenzoate (19.2 µL, 0.1 mmol) are added to the solution. The tube was placed in an oil bath pre-heated to 80 °C and left stirring for 18h. The reaction mixture was filtered over celite. Volatiles were evaporated from the resulting solution under reduced pressure. Yield: 27% (Determined by NMR. IS: CH2Br2) 1H NMR (400 MHz) 6.43 (2H, d), 4.86 (1H, d), 4.37(1H, d), 4.29 (2H, q), 3.44 (3H, s),
24
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25
8 Acknowledgements
This research was carried out at the Synthetic Organic Chemistry (SOC) group of the University of Amsterdam from February 2019 up and including September 2019. It was a great opportunity to gain experience in chemical synthesis and the application of new and innovative methods in total synthesis.
I would like to whole heartedly thank dr. M.A. Fernández-Ibáñez for giving me this chance to work on this project and the supervision throughout the process. I would like to thank dr E. Ruijter for making time to be my second examiner. My thanks go out to Nick Westerveld, BSc, for being my daily supervisor and his help throughout the research period, and PhD candidate Wen-Liang Jia for his insights. Furthermore I would like to express my gratitude the rest of the members of the Fernández-Ibáñez and SOC groups for their help and the great time I had during my internship. Amsterdam
Youri van Valen 11-10-19
