C-5 Alkylidation of hydantoins An overview of three different synthetic approaches

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C-5 Alkylidation of hydantoins

An overview of three different synthetic approaches

Jens D. Giskeødegård

Thesis submitted for the degree of Master in Chemistry

30 credits

Department of Chemistry

Faculty of mathematics and natural sciences UNIVERSITY OF OSLO

07.06.2021

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C-5 Alkylidation of hydantoins

An overview of three different synthetic approaches

Jens D. Giskeødegård

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C-5 Alkylidation of hydantoins Jens D. Giskeødegård

http://www.duo.uio.no/

Printed: Reprosentralen, Universitetet i Oslo

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Acknowledgments

If you told me at the start of my time here at UiO, that I would finish my education while writing a thesis on organic chemistry in the midst of a pandemic, I would probably not believe you. The work presented in this master thesis was carried out in the Department of chemistry at the University of Oslo under the supervision of Associate Professor Alexander Sandtorv.

I want to express my sincerest gratitude to my supervisor Alexander Sandtorv. Your positivity and professionalism is infecting! This is made obvious in the competent and pleasant group that study under your guidance. I am truly grateful for this opportunity you have given me which has taught me much in regards to science and teamwork.

Thank you, Dirk Pedersen and Frode Rise, for your vigilant work at maintaining and improving the NMR facilities. I also want to thank Frode Rise for teaching me everything I know about NMR, and presenting it as a subject on its own, not only as support for an organic chemist.

I would like to thank our group, Arild Xue Hagen, Kristian Sørnes, Linn Berntsen, Caroline Corneliussen, Thomas Solvi, Ingeborg Tangevold and in particular Magnhild Solum whom I shared my office with and always could discuss chemistry or news with.

I want to thank the student association Kjellern for becoming my home at Blindern and allowing me to get to know so many different people. My time as a student would never have been the same without you. Maybe the real master was the friends we made along the way.

Lastly I want to thank my family and friends home at Giske, as they have always supported and encouraged me along the way.

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Abstract

Three different synthetic approaches to the synthesis of 5-alkylidene-hydantoins is investigated. The E/Z configuration of the products is analyzed. A possible project within chemistry education is presented and discussed.

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Abbreviations

DCM dichloromethane EtOAc ethyl acetate EtOH ethanol MeOH methanol

TsCl 4-toluenesulfonyl chloride Ts toluenesulfonyl group Et3N trimethylamine MeCN acetonitrile

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Description and aim of the project

Scheme 1 shows the three methods used by the Sandtorv-group to synthesize 5-alkylidene- hydantoin.

Scheme 1: The three different methods used to synthesize 5-alkylidene-hydantoin The aim of this project is to broadly categorize aldehydes into groups like electron rich, electron deficient, acidic or aliphatic, based on their overall structure, and to then test which method that provides the highest yield and purity for the respective structure. The reaction is an aldol-condensation and will form a double bond that can either have a Z or E configuration.

The stereochemistry of these product will be investigated by using NMR-techniques.

An educational project based on the chemistry of this project is presented and discussed.

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1. Introduction

1.1 Chemical background

This section will provide an overview over the chemical properties of the hydantoin as this is central for the work presented.

1.1.1 Introduction to hydantoin

Imidazolidine-2,4-dione, colloquially referred to as hydantoin has its name from the first time the compound was discovered by Baeyer in 1861.⁴ In his study of uric acid, Baeyer reduced products of allantoin (2) resulting in hydantoin (1) being isolated. Obtaining its name from the reduction (hydrogenation) of allantoin.⁴ However in the following decades there has been presented several ways to synthesize this compound as will be discussed.^1,4,5

Figure 1.1: The structure of hydantoin and allantoin

Hydantoin have been extensively researched due to their versatile medicinal and industrial applications.¹ The hydantoin scaffold is part of a five membered multiheterocyclic ring-group within medicinal chemistry that has been in some controversy lately. The ring-groups has been characterized as both a privileged scaffold to be used in drug discovery, or as a “frequent hitter”. An assay-interfering compound that is useless in this discovery.⁵

Figure 1.2: The five membered multiheterocyclic rings related to hydantoin.

The controversy of whether hydantoin and other five membered multiheterocyclic ring-group are useful in medicinal discovery, has resulted in a comparative study from 2011 that

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2 discussed this issue.⁵ They found that characterizing these ring-groups as “frequent hitters”

are mostly based on anecdotal evidence and concludes that “We therefore think that rhodanines and related scaffolds should not be regarded as problematic or promiscuous binders per se. However, it is important to note that the intermolecular interaction profile of these scaffolds make them prone to bind to a large number of targets with weak or moderate affinity.”⁵.

In a study from 2019 on applications of hydantoin and thiohydantoin in medicinal chemistry they are still considered “a valuable, privileged scaffold in medicinal chemistry”.¹

The chemical interest of these five membered multiheterocyclic ring-group comes from the fact that they can perform many of the same reactions of the hydantoin but will exhibit different properties.

1.1.2 Chemical properties of hydantoin

Hydantoin is a five-membered heterocycle and is an oxidized form of imidazolidine with a cyclic urea core.¹ The fact that the structure of hydantoin is based on this active urea moiety is a strong indicator that the compound can have several different biological properties.⁶

Despite the small size of the molecule, hydantoin contains four derivatizable positions that can result in a plethora of different compounds with unique traits.¹

Figure 1.3: The hydantoin and its derivatization sites.¹

Research has shown that hydantoin with substituents on the R¹ or the R² site are less reactive and more stable than the unsubstituted version of the hydantoin.⁴ In moderately acidic conditions hydantoin will remain stable, but in basic conditions the compound will form ureido acid salts.⁴ Hydantoin acts as a weak acid of approximately the same strength as phenol, a property arising from the fact that the negative charge can be stabilized after the proton transfer by relocating to the two neighbouring carbonyl groups.⁴

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3 Certain mechanisms of different reactions with hydantoin have earlier been explained with the existence of different tautomeric forms of the hydantoin.⁴ This includes an existence of both amido-imidol and keto-enol tautomerism as shown in figure 1.5.⁴ This could be useful in discussing possible explanations in how the hydantoin reacts with other compounds.

Figure 1.5: The five different proposed tautomerism of the hydantoin. ^[4]

1.1.3 Synthesis of hydantoin

Since the reduction of allantoin in 1864 by Baeyer, several efficient and useful methods to synthesize hydantoin have been developed depending on the availability of the starting material and the desired form of hydantoin. Figure 1.6 shows a selection of efficient and widely used reactions today.^1,4,21,22 These methods can be used to synthesize hydantoin with different substitutes, and can be a valuable tool to produce different hydantoins to perform a C-5-alkylidation on.

Figure 1.6: A selection of methods for the synthesis of the hydantoin

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4 1.1.4 C-5 alkylidation of hydantoin

The aim of this project is very specific in the synthesis of different 5-alkylidene-hydantoins with three different approaches. While there are several ways to synthesize these compounds, the Sandtorv-group have identified three main reactions to be used in this research. This is due to the availability of products, the safety and the success of the reactions.

While the reactions have clear differences, the common denominator is that the main reactants always consist of a hydantoin and an aldehyde performing an aldol condensation to form the 5-alkylidene-hydantoin. The general mechanism for an aldol condensation of a hydantoin and an aldehyde is presented (Figure 1.7).

Figure 1.7: The aldol condensation mechanism with hydantoin and an aldehyde

Method A

Figure 1.8: Method A for C-5 alkylidation of hydantoin

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5 Method A is a safe and easy method utilizing only water and ethanol as solvents, and

ethanolamine as a base. The method is time demanding, and the literature reporting the

method have only used the reaction to synthesize a selection of 5-alkyldene-hydantoins with a phenyl-moiety as shown in figure 1.9.²

Figure 1.9: The different phenylmethylene synthesized from method A.²

Method B

Figure 1.10: Method B for C-5 alkylidation of hydantoin

The reaction utilize piperidine as both a solvent and base. The article providing the reaction presents it as a highly specialized method to synthesize compound 8.⁷

Figure 1.11: The specific product synthesized with method B.⁷

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6 It is reported in the literature that using this reaction with different five membered

multiheterocyclic ring-group as thiohydantoin or rhodanine, instead of hydantoin, the compounds turn into a mixture of insoluble products.⁷

Method C

Figure 1.12: Method C for C-5 alkylidation of hydantoin

Method C is an alternative to method B presented in the article by Chowdhry, et al.⁷ While method B resulted with the highest yield for the specific reaction in forming compound 8, method C were able to utilize different five membered multiheterocyclic ring-group to synthesize 5-alkylidene-hydantoinderivatives. The amino acid glycine is introduced to the reaction as an improvement, as the amphoteric nature of glycine in water may promote the condensation reaction.⁷

This method were reported to successfully synthesize the compounds at figure 1.13.⁷

Figure 1.13: The different compounds synthesized from method C.⁷

These products reveals that it is possible to synthesize several different types of 5-alkylidenes- hydantoins utilizing these methods. It is reasonable to assume that these methods has their own strengths and weaknesses in regards to this synthesis. The goal of this study is to identify these aspects of the different methods.

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1.2 Biological background

This section will provide a selection of different applications of the relevant alkylidene- hydantoin within medicinal and biological research. The relevant activities are picked based on economical and medicinal significance.

1.2.1 Anticancer activity

According to the estimates of the World Health Organization (WHO) in 2018, cancer is expected to rank as the leading cause of death and the single most important barrier to

increase life expectancy in every country of the world.¹³ For females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death with an incidence and mortality rate increasing annually.¹³Prostate cancer is the leading cause of men’s mortality and constitutes the second leading cause of cancer deaths for men in the United States.¹² Post-mortem analysis of deaths attributed to prostate cancer reveals that most subjects have evidence of metastatic disease.¹²There is therefore a need to develop therapeutic methods and strategies to control this spread of cancer-cells. New and effective drugs could be a central part in this endeavour.¹²

In 2010, an article on phenylmethylene hydantoins (PMH) as prostate cancer invasion and migration inhibitors was published. The article presents several new PMH derivatives with enhanced anti-migratory and anti-invasive activities. The hydantoin derivatives were found to have androgen receptor modulation, which can be used for treating prostate cancer and other androgen receptor-related diseases.¹² They found that the active methylene hydantoins contains lipophilic and bulky substituents especially at the para-position of the benzylidene moiety.¹² Figure 1.14 shows some of the most effective compounds for inhibition of metastasis and cancer-proliferation.¹²

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8 Figure 1.14: A selection of PMH derivatives were structure 14-17 shows strong metastatic

inhibition, and structure 18 that is synthesized in this project shows moderate metastatic inhibition.¹²

1.2.2 Pesticidal activity

Research on 5-alkylidene-hydantoin regarding pesticidal activity have been conducted with good results.⁶ It is a well-known fact that compounds with a hydantoin skeleton exhibits bactericidal as well as fungicidal activity.⁶ The most important hydantoin fungicide, Iprodione is commonly used. Iprodione functions as a contact fungicide inhibiting the germination of spores while also inhibiting the growth of fungus mycelium.⁶ Hydantoin pesticides are environmentally safe because they degrade in the soil to biologically inactive compounds.⁶ Of the different 5-alkylidene-hydantoin tested, the compounds 11-16 exhibits strong disease control with 95.1-100% efficiency against different types of parasites as bacteria and fungi.⁶

Figure 1.15: A selection of hydantoin derivatives showing high efficiency regarding disease control related to water-sprayed plants

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9 1.2.3 Anticonvulsant activity

Epilepsy is one of the most common neurological afflictions in the human population.⁸ In the United States alone it was estimated in 2015 that 1.2% of the population were suffering from active epilepsy of varying degree.¹⁰ The affliction is characterized by excessive temporary neuronal discharges resulting in uncontrolled convulsion.⁸

To combat this affliction, anticonvulsant medicine is introduced to cope with the symptoms a patient can exhibit.⁸ One of the most widely used drugs for controlling epileptic seizure is Phenytoin (5, 5 diphenylhydantoin), a compound containing the hydantoin scaffold.^8,9 While Phenytoin is still widely used, the usage has decreased since 2013 due to better alternatives as the drug contains a number of side effects.^{7, 11}Already in 1989, 5-benzylidene-hydantoin were proposed as an anticonvulsant. Since then several phenyl-substituted drugs containing

hydantoin have been discovered, and is shown to have a good anticonvulsant activity with structure 19 and 20 as strong candidates (Figure 1.16).^8,9

Figure 1.16: Shows a selection of different PMH derivatives that act as an anticonvulsant.

Structure 17 being the widely used Phenytoin. Compound 23 was an early lead and 26-27 are compounds with good anticonvulsant activity.^8,9

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2. Results and discussion 2.1 Introduction

By basing this project on the literature that presented these methods, further investigation on which type of chemical structure which would be best suited for the different methods was conducted.

Scheme 2.1: The three different methods used to synthesize 5-alkylidene-hydantoin The different aldehydes used in this project (Figure 2.1) was picked based on the desired chemical structure that was deemed relevant to investigate, as well as the price and availability of the compounds.

Figure 2.1: The different aldehydes tested with the methods

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11 For further discussion on the three methods, these aldehydes will be assigned to general categories that best suits the current discussion. One structure can exhibit several properties, as for example structure 39 that is an aromatic group that contains an EDG, which is a sensitive proton.

The formation of the double bond on the 5-alkylidene-hydantoin creates a stereoisomer that can either have an E or Z configuration (Figure 2.2). This occurrence will be investigated in regards to the different methods by using NMR-techniques.

Figure 2.2: 5-benzylidene-hydantoin as an example of the stereoisomer formed

Fig 2.3: 3D-model of (E)-5-benzylidene-hydantoin with relevant distances between protons

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12 Fig 2.4: 3D-model of (Z)-5-benzylidene-hydantoin with relevant distances between protons Considering the fact that distances near 2.5 Å should yield strong NOE-signals. We should expect a strong NOE-correlation between the N-3 and the vinyl proton if the molecule has an E-configuration (Figure 2.3). A Z-configuration would show no correlation between those two protons, but could possibly show correlation between the N-3 and the aromatic proton with a distance of approximately 3.6 Å (Figure 2.4).

2.2 Aromaticity and p-substitute

The project began surveying how the aromatic structure benzaldehyde 30 would react with the different methods, and whether a weak activating group would affect the yield and

stereochemistry.

Table 2.1: A summary of the different isolated yield and stereochemistry that the methods yielded from the aldehyde structures 30-31.

Aldehyde Product Method A Method B Method C

#30 51%

(Z)

34%

(Z)

64%

(Z)

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#31 49%

(Z)

7%

(Z)

36%

(Z)

aNo precipitation or product shown with TLC

bInsoluble inhomogeneous mixture as product

cPrecipitation but no product formed

The three methods tested were all compatible with this type of structure, however method A and C is preferred based on yield and purity (Table 2.1). The weak para-substituted

activating group affected method B and C by providing lower yield then the phenyl-structure.

Method A were seemingly unaffected and provided pure crystals for both the structures.

The stereochemistry was analysed with 2D-NOESY and both structures showed signals of a Z-configuration with the three methods. This was as expected due to electrostatic repulsion experienced by the oxygen at the C-4 position and the phenyl-ring⁷, but also disappointing.

One of the aspirations of this project was to investigate whether the reactions could yield different configurations with the different methods, and design a stereospecific synthesis based on this knowledge. The NOESY-spectre (Figure 2.5) demonstrates the different signals. Compound 23 synthesized with method C will be used to illustrate the elucidation process that was used to decide the configuration of the products 23 and 48.

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14 Figure 2.5: NOESY-spectre of 5-Benzylidene-hydantoin (23) synthesized with method C (400

MHz, DMSO)

The discussion onward is based on the proton signals arranged to their respective structure in the experimental section of this project. On the NOESY-spectre (Figure 2.5) it is observed that the H-1 signal only correlates with an aromatic proton (H-7), and the water peak. These correlations, while also not correlating with the vinyl proton indicates as earlier discussed a Z- configuration for the structure. The NOESY-spectre of the products synthesized from the different methods are provided in the appendix and corresponds well to this elucidation. This will also apply in further discussion unless something else is stated.

The ¹HNMR-spectre (Figure 2.6) of compound 23 from the different methods exhibit identical proton signals. It is however worth noting that method A provides the product with the highest degree of purity. This observation corresponds with the ¹HNMR-spectre (Figure 2.7) of compound 48 as well, but here it is observed a bigger difference in both purity and yield with different methods. Method C has a considerable amount of impurities compared with the yield of method A.

Figure 2.6: ¹HNMR-spectre of 23 with method A (blue), method B (red) and method C (green) (400 MHz, DMSO)

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15 Figure 2.7: ¹HNMR-spectre of 48 with method A (blue), method B (red) and method C

(green) (400 MHz, DMSO)

These observations laid the foundation for further research. The next step of this experiment was to test whether sensitive protons would affect the reaction.

2.3 Sensitive proton- and protection-groups

Considering the fact that the three methods investigated are all performing the general aldol condensation, where the mechanism is initiated by a deprotonation on the C-5 position.

Research on whether sensitive protons on the aldehyde-structure would interfere with the reactions was conducted.

Two highly acidic aldehydes (41 and 37) were selected as shown with Pka values (Figure 2.8).

Figure 2.8: The two acidic aldehydes tested, with their respective PKa-value

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16 While method B would consistently yield less product for the initial aromatic structures 23 and 48. Method B proved itself to have the highest yield for both the acidic compounds, while also being the only method to yield product 49 (Table 2.2).

Table 2.2: Shows the yield and the isomeric configuration of the compounds for the different methods.

#41 0%^a 34%

(Z)

0%^a

#37 0%^a 54%

(Z)

17%

(Z)

The general method A would not yield any of the two acidic structures. To explain why method A didn’t successfully synthesize product 49, it was theorised that ethanolamine, which is used as a base for method A, would deprotonate the carboxylic acid proton instead of the C-5 position on the hydantoin. An extra alteration for method A were therefore conducted by adding an equimolar amount of NaOH to the mixture, and allowing it to reflux for an additional hour. This was done in an effort to promote the deprotonation on the C-5 position of the hydantoin and kick-start the aldol condensation. After the reflux, the mixture was surveyed with TLC to discover any product but to no avail. This experiment yielded nothing and no further testing were conducted.

The E/Z configuration for the structures was elucidated in the same way as discussed earlier.

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17 Figure 2.9: NOESY of compound 50, method B (400 MHz, DMSO)

The NOESY-spectre (Figure 2.9) show no sign of correlation between the N-3 and the vinyl proton, but shows correlations between an aromatic proton (H-8) and the vinyl proton. This indicates a Z-configuration for the structure.

The ¹HNMR-spectre of compound 50 (Figure 2.10) synthesized from method B and C illustrates that both method contains different type of impurities. Method B yielded a higher amount of product, and is the preferred structure for both the acidic compounds.

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18 Figure 2.10 ¹HNMR-spectre of compound 50 with method B (blue) and method C (red)

Further research on sensitive protons would be conducted by using the three methods by utilizing compound 39 and 40.

In an attempt to isolate the sensitivity of the protons as the independent variable for these experiment, both the structures was applied a protecting group in the form of Ts creating compound 42 and 43.

Table 2.3: A summary of the different isolated yield and stereochemistry that the methods yielded

#40 0%^c 42%

(Z)

61%

(Z)

#39 22%

(Z)

0%^b 98%

(Z)

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#42 0%^a 0%^b 0%^a

#43 0%^a 0%^b 0%^a

Method C proved itself to be a much more efficient method than method A or B for synthesis of the products 51 and 18 when considering the yield (Table 2.3). This may stem from the amphoteric glycine propagating the condensation reaction strongly, while not being affected by the sensitive proton. Method A and B seems on the other hand to be affected by the sensitive protons in different manners. Method A would form a homogenous mixture but would show no sign of product after the reflux period, while method B would result in an insoluble mixture.

Figure 2.11 ¹HNMR-spectre of compound 18 made with method A (blue) and method C (red)

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20 The ¹HNMR-spectre (Figure 2.11) illustrates the purity of the products yielded from method A and C. Method B would yield an insoluble mixture of products that would characterize many of the products method B would make.

It is difficult to assess the reason for why method A is able to synthesize structure 18, but not structure 51. When considering the mechanism of an aldol reaction it is logical to assume that the issue arise at the initial deprotonation, and that the vanillin (40) interacts with the

ethanolamine in some way.

This the reason why both structure 39 and 40 was protected with Ts and was tested simultaneously to assess whether this sensitive proton was limiting the reaction.

Disappointingly, none of the protected aldehydes, structure 42 and 43, would seemingly react with the hydantoin to perform the C-5 alkylidation. Method A was tested with a few different alterations as it was clear from general procedure that utilizing ethanol as a solvent would not solve the aldehydes 42 and 43. Other solvents such as MeCN and 2-propanol was tested, as they would solve the aldehyde while still being miscible with water. 2-propanol being a polar protic solvent, just as ethanol, while MeCN would be a polar aprotic solvent (Scheme 2.2).

Scheme 2.2: The two different alterations for method A, where RCHO are compound 42 and 43 respectively.

This was seemingly to no avail, as the product turned into small amounts of a thick viscous inhomogeneous mixture. A sample of the inhomogeneous mixture formed in an attempt to produce compound 53 were analysed with ¹H-NMR to detect signals that could represent the desired structure (Figure 2.14).

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21 Figure 2.13: ¹HNMR-spectre of the crude product in an attempt to synthesize compound 53.

The arrow shows the possible vinyl proton.

The ¹H-NMR spectra showed a small singlet within a ppm-value range that could represent the vinyl proton formed after a C-5 alkylidation (Figure 2.13). This was in such small amounts in an already low yield, which for a protecting group prompted no further investigation.

Method C provided a very high yield for structure 39 and 40 and is seemingly the fastest, cheapest and highest yielding method in formation of these structures. While the sensitive proton seemingly did not hinder the reaction, these structure would mark the start of a new independent variable.

The hydroxyl-group, while sensitive, is also considered an activating EDG that affects the electron density of the structure.

2.4 Electron density

To investigate whether the electron density of the aldehydes affected the reaction, a selection of aldehydes with different electron densities was investigated. The aldehydes 33, 34, 35 and 39 are all electron rich structures while compound 32, 36 and 38 are electron deficient structures.

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22 2.4.1 Electron rich aldehydes

These experiments were designed to have two electron rich aromatic homocycles in the form of compound 33 and 39 containing different types of EDG, and two electron rich aromatic heterocycles in the form of compound 34 and 35.

#33 75 %

(Z)

72 % (Z)

98 % (Z)

#39 22 %

(Z)

0 %^b 98 %

(Z)

#34 9 %

(Z)

0 %^b 41 %

(Z)

#35 9 %

(Z)

0 %^b 49 %

(E/Z)

While method A provided a high yield for the homocyclic structures 54 and 18, it was not as effective for the heterocyclic structures 55 and 56. While this was equally as true for method C, this method also provided a significant larger yield for every single electron rich structure.

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23 Figure 2.14:¹HNMR-spectre of 54 with method A (blue), method B (red) and method C

(green) (400 MHz, DMSO)

The purity of 54 synthesized with different method varied in a smaller degree then for similar compounds like structure 48. For that structure method C would show considerable signs of impurities compared with the other methods. This already suggest that electron rich structures greatly promotes the desired reaction.

Curiously, structure 56 with method C yielded a racemic mixture. This was not apparent when synthesized with method A (Figure 2.15).

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24 Figure 2.15: ¹HNMR-spectre of 56 with method A (blue), method C (red) (400 MHz, DMSO) This was the only instance where a desired isomer can be synthesized based on the method used. The racemic mixture was not separated in this project, but this illustrates the theorized method to distinguish the E and Z configuration. As observed on the NOESY-spectre synthesized with method A (Figure 2.17) a correlation between the H-2 and the H-10 is shown, while not showing any correlation between H-6 and H-2.

The NOESY-spectre (Figure 2.18) of the racemic product synthesized with method C on the other hand also show this same arrangement for one of the isomers. This method also

provides an isomer which shows a correlation between H-6 and H-2, while not showing any correlation between H-10 and H-2. This proves that method A synthesises (Z)-5-(2-

pyrrolylmethylene)-hydantoin, while method C contains a racemic mixture.

Figure 2.16: The two possible stereoisomer of product 56

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25 Figure 2.17: NOESY-spectre of compound 56 synthesized with method A (400 MHz, DMSO)

Figure 2.18: NOESY-spectre of compound 56 synthesized with method C (400 MHz, DMSO) The other heterocyclic electron rich structure 55 had equal amount of yield comparable with compound 56, but it did not yield a racemic mixture, showing signal of a Z-configuration for both method used.

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26 2.4.2 Electron deficient aldehydes

These experiments were designed to have two electron deficient aromatic homocycles in the form of compound 32 and 36 containing different types of EWG.

#36 x %^d 0 %^b 0 %^a

#32 23 %

(Z)

0 %^b 0 %^c

dProduct formed but no isolated

For the two electron deficient homocyclic structures 36 and 32, only method A provides a small yield. This is in stark contrast to the electron rich homocyclic structures 54 and 18 as discussed earlier. Method C is seemingly more affected by this difference in electron density, as earlier it was shown that with electron rich structure it would yield near equimolar amounts of product, while with these electron deficient aldehydes it would not react at all. When synthesizing compound 57 with method A, a yellow powder precipitated and was analysed.

The yield of the inhomogeneous precipitate was low at only 8% and it was observed with the

1HNMR-spectre (Figure 2.19) of the compound that it was not pure.

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27 Figure 2.19: ¹HNMR-spectre of 57 synthesized with method A (400 MHz, DMSO) It was originally planned to perform a flash chromatography to purify the product, but due to time constraint and difficulties solving the powder, it was ultimately not conducted. In the light of the aim of this project it would neither be as relevant due to the fact that the yield would definitely be lower than ~4%. This would be a severely inefficient method to produce the structure.

The other structure, 58 involved a halogenic substituent which is less deactivating than the nitro-group on the previous structure. This would yield a decent amount of crystals only by using method A. Method C would precipitate a white powder that was analysed with NMR- techniques. The ¹HNMR-spectre (Figure 2.20) of compound 58 would reveal that none of the desired product was formed. This is easily observed by the complete lack of the vinylic proton signal on the ¹HNMR-spectre (Figure 2.20).

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28 Figure 2.20: ¹HNMR comparison between method A (red) and C (blue) of Compound 58

2.5 Aliphatic structures

To provide a larger chemical scope to the methods, three different aliphatic structures 44, 45 and 46 was tested and analysed. The literature that these methods were based on had

previously only used aromatic structures to synthesize the 5-alkylidene-hydantoins.

#44 28 %

(Z)

0 %^b 0 %^a

#46 0 %^a 0 %^b 0 %^a

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#45 0 %^a 0 %^b 0 %^a

Disappointingly, only structure 44 would react accordingly to form the desired product 60 by using method A.

While method B would form an insoluble inhomogeneous mixture for every structure tested, method A and C would not precipitate any product, and when the mixtures was tested with TLC it would show no sign of product. While this selection of structures is not a large enough of a sample size to make conclusions, it is worth noting that only the cyclic structure would condensate to form the desired 5-alkylidene-hydantoin. Structure 46 contains an aromatic phenyl-group that is not directly attached to the aldehyde, but does not react to form

compound 61. Structure 45, which contains no aromatic functional groups did not form any product 62. This indicates that the aldehyde group needs to be seated directly attached to an aromatic structure to perform the aldol-condensation, and that aliphatic structures will not perform the reaction with the methods used.

2.6 Metallocene and diazole

Two final curious aromatic structures were tested in the form of the metallocene ferrocenecarboxaldehyde 47, and the diazole structure 38.

#47 61 % 0 %^b 73 %

#38 42 %

(Z)

31 % (Z)

84 % (Z)

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30

Method A and B both provided amazingly a medium to high yield for the metallocenic structure (Table 2.7), while method B failed to yield a product. This compound is a new product not reported in the literature.

Compound 63 proved to be difficult to investigate with NMR techniques compared with the other structures. It would seemingly not dissolve properly with a large selection of deuterated solvents. DMSO-d6, CDCl3-d1, TFE-d3, TFA-d1, Benzene-d6 and D2O was the different solvents used to solve the compound. The solutions was also sifted through a cotton-filter in an attempt to remove large particles inhibiting the homogeneity of the solution. This was seemingly to no avail and the best ¹HNMR-spectre (Figure 2.21) obtained was a poorly shimmed spectre. No carbon peaks was detected on the ¹³CNMR-spectre, most likely due to poor concentration and shimming.

Figure 2.21: ¹HNMR-spectre of compound 63 (400 MHz, DMSO)

To further characterize the product it was analysed with IR, MS, HRMS and melting point.

The HRMS showed an exact mass that corresponded with the molecular formula

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31 C14H12FeN2O2, while the IR-spectre showed characteristics of 5-alkylidene-hydantoin and a ferrocene moiety.

The diazole-structure 59, was successfully synthesized with all of the three methods. The interest in the imidazole structure was to test whether a heterocycle with two other non-carbon atoms would react compared with the other heterocycles. Imidazole contains a sensitive proton and has an electron density comparable to benzene. The methods are seemingly not negatively affected by this structure.

This product would again illustrate a general rule of yield and purity when considering the three methods. Method A would deliver a moderate yield with high degree of purity, method B would deliver a low yield with a low degree of purity, and method C would deliver a high yield with moderate purity.

Figure 2.22: ¹HNMR comparison between method A (blue), method B (red) and method C (green) of Compound 59

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32

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33

2.7 Summary

This project started by presenting the chemical and biological properties of the hydantoin.

Further it was narrowed down to the investigation of an aldol condensation on the C-5 position of the hydantoin, presenting three different methods for this synthesis.

Different aldehyde-structures was categorised based on the desired property that warranted investigation. The majority of this work was to present the different yield and stereochemistry as detected with the different methods. Some areas demanded more time and effort such as the aldehydes containing sensitive protons. The protecting of the OH-groups and further testing with the protected group proved to be difficult and several experiments were conducted.

A detailed investigation on the stereochemistry that arises when forming a 5-alkylidene- hydantoin with these methods has been discussed.

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34

2.8 Application in education

2.8.1 Establishing relevancy

This project was made possible through the lecture-program at UiO. A program designed to give the candidate a deeper specialisation in a subject than what ordinary teaching programs provides.²⁴ With this context it is relevant to briefly discuss how this project could be used as an asset within education in chemistry.

Chemistry is a unique subject with an identity strongly tied to the laboratory experience.²⁵ This notion of identity is expressed by Chang, who discerns physicists from chemists by writing about chemists as makers, concluding that the inclusion of laboratory environment is an implicit part of a chemist’s identity.²⁵ Work within the laboratory can be regarded as both a form of active- and exploratory-learning which is shown to strengthen learning within

scientific subjects.^{25, 26, 27} Exploratory learning being defined by Knain and Kolstø as a process in three steps:

1. Formulation of a question – Relevant work is introduced by formulating questions 2. Collection of data – Students gather data and information to develop, verify and

choose possible answers

3. Building knowledge – Students continue working by gather, asses and develop knowledge in an exploratory process

Establishing these aspects as important within education in chemistry we can now discuss how the content of this project could be applied in the Norwegian school system.

In 2020 a new curriculum were developed and designed with the vision that students should be able to learn more and better.²⁹ This is to be achieved by focusing on more practical education, more in depth learning and focus on the interdisciplinary.^{28, 29} Teaching within a laboratory setting fits very well in this new vision if planned correctly.

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35 2.8.2 Proposal of a project and didactic analysis

Considering the information in chapter 2.8.1, this segment will provide a concrete project in chemistry that is anchored in the current pedagogical vision of “Fagfornyelsen, 2020”.

Method C which is a safe and quick reaction that could be used as an example to create a project that encompass much of the school chemistry. The experiment will be organised as exploratory learning where students must first deliver a pre-lab, which is designed to give an academic background to the students before conducting the experiment.

This reaction synthesize a product that can function as a model to describe E/Z configuration and reactions with a double bond.

Figure 1.15: Shows method C as a potential project for students

As the curriculum is a legally binding document for teachers, experiments based on this project could be directly tied to primarily three competence goals within chemistry (Kjemi 2):

-«Gjøre rede for reaksjonstypene addisjon, eliminasjon, substitusjon, hydrolyse og kondensasjon og bruke elektrostatiske krefter til å forklare noen av

reaksjonsmekanismer»

-«Gjennomføre synteser og gjøre rede for faktorer som påvirker utbytte og renhet i synteser»

-«Planlegge og gjennomføre forsøk, drøfte metode og tiltak for å redusere risiko og vurdere usikkerhet og feilkilder i egne og andres forsøk»²⁸

The learning conditions for this project are students with a beginner background in organic chemistry. The student must be able to know how to behave in a laboratory environment and handle the equipment. The setting of this project will primarily be based inside a school- laboratory with enough room to work as well. It is recommended that larger classes should be divided in two groups, where one group conducts the experiment, while the other has an

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36 alternative learning session. This project is designed to use two full chemistry session, and demands some preparation at home for the students. The reagents are relatively cheap.

The learning goal of this project is to give the student an in depth experience in how a chemist can approach a synthesis of a compound. The student will learn how to set up an experiment based on the scientific literature, and then perform it in a lab with a focus on safety. The student will learn which aspects are relevant to discuss in regard to a chemical product.

The content of this project is presented in a booklet that the student receives. The learning process is based on active exploratory learning with one degree of freedom where the student is presented the problem and method, while the results are up to the student to discover.

The evaluation of this project will be based on the both the practical and theoretical aspect of work within a laboratory. The theoretical will be evaluated based on the answers the student give in regard to the questions in the booklet, while the practical evaluation is primarily based on safety and practice inside a laboratory environment.

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37 2.8.3 The project

Synthesis of 5-benzylidenehydantoin

Purpose

In this project, we will synthesize 5-benzylidenehydantoin by using common and practical methods within organic chemistry. We will use general chemistry knowledge to assess the reaction practically and discuss the yield.

Background

In organic chemistry, brand new compounds are consistently synthesized and characterized.

Some of these compounds are researched for possible biological or medicinal effects.

A very common anti-seizure medication widely used today is phenytoin. Phenytoin is composed of a hydantoin with two phenyl groups substituted on the structure.

While Phenytoin is effective against epilepsy and seizures, it also comes with a string of side effects that include nausea, stomach pain, increased hair growth and other. There is therefore an interest for new compounds that has the same applicability, while not exhibiting the same side effects. 5-benzylidenehydantoin, while not on the market have several articles published on its anticonvulsant effect. This project will focus on the synthesis of this possibly new and exciting drug against epilepsy.

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38 Preparation

An article from 2004 on the synthesis of 5-benzylidene-hydantoin describes the procedure as follows:

“Benzaldehyde (0.494 g, 4.66 mmol, 1 eq.) was added dropwise to a flask containing hydantoin (0.466 g, 4.66 mmol, 1 eq.), glycine (0.350 g, 1 eq.), and sodium carbonate (0.247 g, 0.5 eq.) followed by distilled water (3 cm³). Upon stirring, vigorous effervescing was observed and the mixture was stirred at reflux for 1 h. The bright yellow precipitate was collected and washed with water and dried in vacuo to give a bright yellow powder which did not require further

purification.” ⁷

a) Use pubchem.ncbi.nlm.nih.gov and write down the hazard statement for the following compounds:

-Benzaldehyde :

-Hydantoin :

-Glycine :

-Na2CO3 :

Fill in the general risk assessment regarding work with chemicals in organic laboratories.

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39 Table 1. General risk assessment

What can go wrong What can we do to prevent it

What can we do to reduce the consequences if

something happens

b) Fill in this table with the relevant information of the different compounds needed to perform the experiment at a 5.0 mmol scale.

Table 2. The different reagents with their respective stoichiometry

Reagents n

(mmol) Mm (g/mol)

m (g)

ρ (g/mL)

V (mL)

Eq.

c) Use the text regarding the procedure above and write your own “recipe” for how you will step by step conduct the experiment at a 5.0 mmol scale.

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40 d) Create a drawing of the setup with all the equipment needed before adding the

reagents.

Experiment and discussion

e) Conduct the experiment carefully as planned on task c, isolate the yield and describe the product. Let it dry in a fume hood until next class session instead of in vacuo.

f) Calculate expected yield of the product

g) Calculate the percent yield of the product

h) Collect and compare your yield with different groups, and later compare it with the average yield of the class. What could cause this different yield among the groups?

i) Describe which type of organic reaction this was, what is characteristic of this type of reaction? Which role does Na2CO3 and glycine respectively play in this reaction?

j) Draw the two possible isomers of the product. Which one to you think is generally favoured?

k) It was mentioned that this and similar compound could be used as treatment against afflictions like epilepsy. Discuss the solubility of this compound and why it is possible that it affects the brain.

Further research

a) Which new functional group has been formed from the reaction? What type of reaction could react with this functional group? Optional: Draw the mechanism for this reaction.

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41

2.9 Conclusion and future prospects

The conclusions from this study is based on the yield, purity and configuration of the different aldehyde-structure that was tested with the three different methods.

Method A is a time-demanding reaction that yields the product in a high degree of purity but with consistently lower yield. It is seemingly a more general reaction that yields product for aromatic, electron rich, electron poor, cyclic aliphatic, metallocenes and diazoles. Electron poor aldehydes gave significantly lower yield, but method A was the only reaction to yield small amounts of products like 57. Method C consistently provided a higher yield when the product were formed, but is seemingly a more selective method. The method is especially selective when it comes to electron rich vs electron poor structures, where the method provided the highest yield for the electron rich structures while not reacting at all with the electron poor structures. This reaction also yielded a racemic mixture for some rare compounds like structure 55.

Method B is a volatile reaction that forms an insoluble mixture with most of the structures tested. Interestingly, it was the only method to successfully react with both the acidic structures to yield product with a high degree of purity. When the method didn’t form an insoluble inhomogeneous mixture it consistently yielded a lower yield and a lower degree of purity than the other methods. This was the only method to react with both acidic structures.

The stereochemistry for the compounds synthesized heavily favoured the Z-configuration.

A possible school project tied to the practical aspects of these experiments were provided, with a pedagogical foundation based on the school reform (LK20).

The methods in this project, alongside the overview of which structures that best fitted them could be a valuable tool for further synthesis of 5-alkylidene-hydantoin. The variety of structures that can be achieved with the three methods is promising, and further testing with other structures could be warranted. These products can react further in other areas of synthesis. For example N³-arylation on a selection of these 5-alkylidene-hydantoins to provide a large scope of new products.

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42

3. Experimental section

General

NMR-solvents were used as delivered from Sigma Aldrich and Cambridge Isotope Laboratories. Think layer chromatography was performed on 60 F254 silica coated aluminium plates from Merck.

1H- and ¹³C-NMR experiments were recorded in DMSO using Bruker AVII400 operating at 400 MHz (¹H), 101 MHz (¹³C). All spectra were recorded at 25 °C. Chemical shifts (δ) are given in parts per million (ppm) relative to the solvent used. Reference peaks: DMSO: 2.50 ppm (¹H) 39.52 ppm (¹³C). For some compounds ¹H and ¹³C shifts were assigned with the help of COSY and HSQC, while stereochemistry were assigned with NOESY. Spectra are included in the appendix.

Mass-spectra were obtained on a Bruker Daltonik GmbH MAXIS II ETD (ESI) and SCION- TQ (EI) spectrometer by Osamu Sekiguchi.

FTIR spectra were recorded in ATR (Bruker ATR A225/Q) on a Vertex 80 Bruker infrared spectrophotometer, equipped with a DTGS detector; 32 interferograms (recorded at 4 cm^-

1 resolution) were typically averaged for each spectrum.

All melting points are uncorrected and were measured by a Büchi B-545 melting point apparatus.

Concentration in vacuo was carried out in a Büchi R-100 rotary evoparation system bundled with a V-100 vacuum pump

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43 General method A:

Hydantoin (0.500 g, 5.0 mmol, 1.0 eq) was added to a 250 mL round bottom flask and dissolved with water (50.0 mL) while stirring at moderate heat. Ethanolamine (0.61 mL, 10.0 mmol, 2.0 eq) was added when the hydantoin was completely dissolved, and the reaction mixture was slowly heated to 70 °C while stirring. The respective aldehyde (x g, 5.0 mmol, 1.0 eq) was dissolved in EtOH (5.0 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 70 °C with reflux for 5 hours. After the stirring period, the solution was cooled to RT and allowed to precipitate over the night. No further purification was needed, and the precipitate was collected and dried in vacuo.²

General method B:

Hydantoin (0.550 g, 5.5 mmol, 1.1 eq) and the respective aldehyde (x g, 5.0 mmol, 1.0 eq) was added to a 50 mL round bottom flask before piperidine (1.0 mL, 10.1 mmol, 2.0 eq.) was added dropwise. The reaction mixture was slowly heated to 130 °C with stirring and

maintained at this temperature for 1 hour with reflux. The reaction mixture was cooled to 60

°C before water (20.0 mL) was added. Stirring was continued until the mixture reached room temperature and all solid material had dissolved. The product was precipitated by addition of concentrated hydrochloric acid (0.7 mL), filtered, washed with cold water (0.5 mL) and ethanol (0.5mL). The product was collected and dried in vacuo.⁷

General method C:

Hydantoin (0.500 g, 5.0 mmol, 1.0 eq), glycine (0.375 g, 5.0 mmol, 1.0 eq) and Na2CO3(s)

(0.265 g, 2.5 mmol, 0.5 eq) was added to a 50 mL round bottom flask. The respective aldehyde (x g, 5.0 mmol, 1.0 eq) was carefully added to the round bottom flask before distilled water (4.0 mL) was added. The reaction mixture was stirred with reflux at 80 °C for 1 hour. After the stirring period the precipitate was filtered and washed with cold water (1.0 mL). The product was collected and dried in vacuo.⁷

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44 5-Benzylidene-hydantoin [CAS: 3775-01-7]

Compound 23 was obtained using general method A. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a white, crystalline solid (0.494g, 53%).

1H-NMR (400 MHz, DMSO-d6): δ10.47-11.30 (br. s, 2H, H-1), 7.61-7.62 (m, 2H, H-8), 7.38-7.42 (m, 2H, H-7), 7.31-7.34 (m, 1H, H-9), 6.41 (s, 1H, H-5)

13C-NMR (101 MHz, DMSO-d6): δ165.56 (C-3), 155.70 (C-2), 132.96 (C-6), 129.36 (C-7), 128.76 (C-8), 128.36 (C-9), 127.96 (C-4), 108.25 (C-5)

HRMS (ESI) m/z [M + Na]: Calculated for C10H8N2NaO2 at 211.0478, found 211.0477 Melting point: 218-220 °C

FTIR (neat, Vmaxcm^-1): 3446, 3274, 1708, 1650, 1623 The spectroscopic data is in accordance with the literature.¹

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45 Figure 5.1: ¹H NMR spectrum of 5-Benzylidene-hydantoin (23) (400 MHz, DMSO)

Figure 5.2: ¹³C NMR spectrum of 5-Benzylidene-hydantoin (23) (101 MHz, DMSO)

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46 5-Vanillydene-hydantoin [CAS: 52036-16-5]

Compound 51 was obtained using general method C. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a brown powder (0.496g, 42%).

1H-NMR (400 MHz, DMSO-d6): δ10.37 (br. s, 2H, H-1), 7.71 (br. s, 1H, H-11), 7.05-7.11 (m, 2H, H-7), 6.78-6.80 (m, 1H, H-8), 6.35 (s, 1H, H-5), 3.83 (s, 3H, H-12)

13C-NMR (101 MHz, DMSO-d6): δ165.7 (C-3), 155.7 (C-2), 147.7(C-9), 147.6(C-10), 125.4 (C-6), 124.3 (C-4), 123.5 (C-7), 115.7 (C-8), 113.2 (C-5), 109.8 (C-7’), 55.8 (C-12)

FTIR (neat, Vmaxcm^-1): 3357, 3136, 3012, 2750, 1762, 1720, 1649

The spectroscopic data is in accordance with the literature but shows signs of impurities.^{15, 23}

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47 Figure 5.3: ¹H NMR spectrum of 5-Vanillydene-hydantoin (51) (400 MHz, DMSO)

Figure 5.4: ¹³C NMR spectrum of 5-Vanillydene-hydantoin (51) (101 MHz, DMSO)

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48 5-Ferrocylidene-hydantoin

Compound 63 was obtained using general method A. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a red powder (449 mg, 61 %).

MS (EI): m/z ((relative intensity (%)): 296 (30), 231 (45), 121 (70), 77 (47), 56 (100) HRMS (ESI) m/z [M]: Calculated for C14H12FeN2O2 at 296.0243, found 296.0242 Melting point: >300 °C

FTIR (neat, Vmaxcm^-1): 3508, 3444, 3255, 2997, 2756, 1703, 1650, This compound has not been reported in the literature.

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49 5-(2-pyrrolylmethylene)-hydantoin [CAS: 857767-91-0]

Compound 56 was obtained using general method A. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a yellow, crystalline solid (80.2mg, 9

%).

1H-NMR (400 MHz, DMSO-d6): δ12.06 (s, 1H, H-2), 11.20 (br. s, 1H, H-11), 10.10 (br. s, 1H, H-1), 7.05-7.03(m, 1H, H-10), δ6.50-6.48 (m, 1H, H-8), 6.29 (s, 1H, H-5), 6.17-6.15 (m, 1H, H-9).

13C-NMR (101 MHz, DMSO-d6): δ126.8 (C-4), 123.5 (C-3), 121.8 (C-5), 115.0 (C-7), 109.9 (C-6, C-9), 107.3 (C-8)

FTIR (neat, Vmaxcm^-1): 3506, 3444, 3253, 3006, 2759, 1703, 1650

This compounds has been reported in the literature but not characterized. The NMR- spectroscopic data shows sign of acetone.²³

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50 Figure 5.5: ¹H NMR spectrum of 5-(2-pyrrolylmethylene)-hydantoin (56) (400 MHz, DMSO)

Figure 5.6: ¹³C NMR spectrum of 5-(2-pyrrolylmethylene)-hydantoin (56) (101 MHz, DMSO)

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51 5-(4-hydroxybenzylidene)-hydantoin [CAS: 80171-33-1]

Compound 18 was obtained using general method A. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a yellow powder (222.1 mg, 22%).

1H-NMR (400 MHz, DMSO-d6): δ10.39 (br. s, 2H, H-1), 7.46 (m, 2H, H-7), 6.78 (m, 2H, H- 8), 6.34(s, 1H, H-5)

13C-NMR (101 MHz, DMSO-d6): δ166.13 (C-3), 158.48(C-9), 156.08(C-2), 131.73(C-7), 125.82(C-2), 124.32(C-6), 116.18(C-8), 109.75(C-5)

FTIR (neat, Vmaxcm^-1): 3334, 3292, 3159, 3010, 2723, 1745, 1701, 1645 The spectroscopic data is in accordance with the literature.⁸

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52 Figure 5.7: ¹H NMR spectrum of 5-(4-hydroxybenzylidene)-hydantoin (18) (400 MHz,

DMSO)

Figure 5.8: ¹³C NMR spectrum of 5-(4-hydroxybenzylidene)-hydantoin (18) (101 MHz, DMSO)

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53 4-[(2,5-dioxo-4-imidazolidinylidene)methyl]-benzoid acid [CAS: 140894-75-3]

Compound 49 was obtained using general method B. The compound was obtained after vacuum-filtrating the precipitate and dried in vacuo as a yellow powder (0.299g, 26%).

1H-NMR (400 MHz, DMSO-d6): δ13.03 (br. s, 1H, H-13), 11.35 (br. s, 1H, H-1), 10.71 (br.

s, 1H, H-3), 7.92 (m, 2H, H-10), 7.71 (m, 2H, H-9), 6.44 (s, 1H, H-6)

13C-NMR (101 MHz, DMSO-d6): δ166.9 (C-12), 165.4 (C-4), 155.7 (C-2), 137.3 (C-7), 129.9 (C-10), 129.6 (C-11), 129.5 (C-9), 129.3 (C-5), 106.7 (C-6)

HRMS (ESI) m/z [M+2Na]: Calculated for C11H8N2Na2O4 at 277.0196, found 277.0195 Melting point: >300°C

FTIR (neat, Vmaxcm^-1): 3287, 3227, 1796, 1738, 1670, 1607

This compounds has been reported in the literature but not characterized.

C-5 Alkylidation of hydantoins An overview of three different synthetic approaches

C-5 Alkylidation of hydantoins

An overview of three different synthetic approaches

Jens D. Giskeødegård

Thesis submitted for the degree of Master in Chemistry

30 credits

Department of Chemistry

Faculty of mathematics and natural sciences UNIVERSITY OF OSLO

C-5 Alkylidation of hydantoins

An overview of three different synthetic approaches

Jens D. Giskeødegård

Acknowledgments

Abstract

Abbreviations

Description and aim of the project

Table of Contents

1. Introduction

1.1 Chemical background

1.2 Biological background

2. Results and discussion 2.1 Introduction

2.2 Aromaticity and p-substitute

2.3 Sensitive proton- and protection-groups

2.4 Electron density

2.5 Aliphatic structures

2.6 Metallocene and diazole

2.7 Summary

2.8 Application in education

Synthesis of 5-benzylidenehydantoin

2.9 Conclusion and future prospects

3. Experimental section