New photochemical cross coupling reactions to prepare esters from aldehydes and alcohols

Faculdade de Farmácia da Universidade de Lisboa

New photochemical cross coupling reactions to

prepare esters from aldehydes and alcohols

Inês Alexandra Monteiro Raposo

Mestrado Integrado em Ciências Farmacêuticas

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Faculdade de Farmácia da Universidade de Lisboa

New photochemical cross coupling reactions to

prepare esters from aldehydes and alcohols

Inês Alexandra Monteiro Raposo

Trabalho de campo de Mestrado Integrado em Ciências Farmacêuticas apresentada à Universidade de Lisboa através da Faculdade de Farmácia

Orientador: Doutora Ana Paula Francisco

Co-orientador: Prof. ssa Lidia De Luca, PhD

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This work was carried out in the Department of Chemistry and Pharmacy of the University of Sassari under the supervision of Professor Lidia De Luca.

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Resumo

Os ésteres são compostos com características importantes para diversos setores, incluindo o farmacêutico. A sua presença pode ser encontrada em produtos como anti-inflamatórios, analgésicos ou antibióticos. Têm também sido testados como pró-fármacos antivirais e pró-fármacos contra a tuberculose, tendo demonstrado resultados promissores.

A síntese de ésteres tem sido, por isso, motivo de diversos estudos, no sentido de encontrar um método eficiente, económico, versátil e que faça uso de compostos ecologicamente vantajosos.

Os métodos mais clássicos fazem uso de álcoois e ácidos carboxílicos, ou dos seus derivados, promovendo uma substituição nucleofílica entre estes compostos na presença de um catalisador. Estas metodologias apresentam algumas desvantagens, tal como o uso de reagentes tóxicos (por exemplo, N,N′-diciclohexilcarbodiimida ou 1-hidroxibenzotriazol), a formação de produtos secundários que dificultam a purificação do produto ou o excesso de álcool.

Uma alternativa que tem estado a ganhar cada vez mais destaque é a esterificação oxidativa de aldeídos, havendo diversos estudos realizados nesta área.

Muitas destas alternativas utilizam metais de transição como catalisadores. Embora este tipo de catalisadores apresente como vantagens uma maior eficiência a nível da sua recuperação e reutilização, levando a uma menor contaminação do produto, eles têm custos elevados, o que constitui um obstáculo na passagem da escala laboratorial para uma mais elevada.

Outra característica comum a muitos destes estudos é a formação de um hemiacetal intermédio. Este composto é formado pela adição de um álcool a um aldeído, reação essa que até pode dispensar a utilização de um catalisador. No entanto, este composto intermédio também apresenta alguns obstáculos, visto ser um composto quaternário com impedimentos estéreos e instabilidade.

A esterificação de aldeídos pode também ser feita por processos eletrocatalíticos, eletrolisando uma solução com o aldeído, diversos mediadores e álcool como solvente. Os ésteres são então produzidos pela reação entre o aldeído e o

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álcool. Esta alternativa, embora demonstre bons resultados, apenas funciona para aldeídos aromáticos e necessita que o álcool esteja presente em excesso.

Uma outra alternativa para este tipo de síntese é a esterificação catalisada por carbenos N-heterocíclicos. Esta abordagem pode ou não envolver também uma catálise com metais de transição. Neste caso obtêm-se bons rendimentos a partir de vários álcoois e aldeídos, tanto aromáticos como alifáticos. No entanto, também se verifica a necessidade de um excesso de álcool e uma limitação aos aldeídos com um grupo funcional no carbono α.

Neste trabalho é proposta uma síntese de ésteres a partir de aldeídos e álcoois, num processo composto por dois passos sequenciais. O primeiro passo é uma oxidação do aldeído pelo ácido tricloroisocianúrico em diclorometano. Este passo é realizado sob radiação solar, que vai ativar a reação entre os compostos e favorecer a produção do cloreto de acilo. Para o segundo passo são adicionados o álcool, trietilamina e uma quantidade catalítica de 4-dimetilaminopiridina. Dá-se então uma substituição nucleofílica entre o álcool e o cloreto de acilo, dando origem ao éster desejado. Por fim, o produto é purificado por cromatografia de coluna e caracterizado espetroscopicamente.

Os compostos escolhidos apresentam diversas vantagens. Tanto os aldeídos como os álcoois são bastante comuns, estando presentes em qualquer laboratório e sendo obtidos a preços acessíveis. Por seu lado, o ácido tricloroisocianúrico também se apresenta como um composto economicamente acessível e ecologicamente vantajoso. É, inclusivamente, um produto utilizado como desinfetante de piscinas ou mesmo para lavagem de loiça a nível hospitalar e de restauração. A utilização da radiação solar, assim como o facto de não serem utilizados reagentes em excesso, apresentam-se também como pontos bastante atrativos, tanto económica como ecologicamente.

Procedeu-se, então, a uma otimização das condições da reação, de modo a estabelecer o tempo de reação do primeiro passo, assim como a quantidade de diclorometano a ser utilizado.

Depois da otimização, foram testados vários tipos de aldeídos e álcoois, tanto aromáticos como alifáticos. A nível dos aldeídos aromáticos, em geral, foram obtidos ésteres com bons rendimentos. Apresentaram-se como exceções o anisaldeído e o 4-hidroxibenzaldeído, que no primeiro passo levaram à produção de vários compostos secundários, sendo impossível obter o éster final. Relativamente aos aldeídos alifáticos

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não foram obtidos os ésteres correspondentes com nenhum dos compostos testados. Quanto aos álcoois testados, tanto os aromáticos como os alifáticos deram origem aos ésteres desejados, sem nenhuma dificuldade associada a qualquer dos diferentes tipos de álcoois testados.

Este método apresenta-se como bastante seletivo, uma vez que não se registou a formação de produtos secundários para além dos ésteres. É, portanto, um método muito atrativo, tanto em termos económicos como ecológicos.

Palavras-chave: Ácido Triclorocianúrico, Álcoois, Aldeídos, Ésteres, Luz solar,

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Abstract

Esters have many important characteristics, which make them useful in many fields, including the pharmaceutical one. They can be found in macrolide antibiotics, flavouring agents, fragrances, anti-inflammatory agents and analgesics.

For this reason, many investigations have been made, in order to find effective, economic and green methods for the synthesis of esters.

In this work a metal-free one-pot oxidative esterification of aldehydes is presented, in a two steps procedure. In the first step, trichloroisocyanuric acid in dichloromethane was used as an oxidant and chlorinating reagent, converting the aldehyde into an acyl chloride. This step was performed under a solar simulator so the radiation could act as an activator of the whole process. In the second step, the acyl chloride generated in situ was treated with an alcohol, in the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine, forming the desired ester.

The chosen reagents have several advantages. Both aldehydes and alcohols are readily available and have affordable prices. Trichloroisocyanuric acid is a green reagent, commonly used as a swimming pool disinfectant or even for dishwashing in hospitals and restaurants. All reagents are used in an optimal stoichiometric ratio, leading to a more economical and ecologically attractive method. Besides the reagents chosen, using sunlight as an activator is a cheap and ecological way to improve the reaction conditions without bringing any disadvantages to the procedure.

After an optimization of the reaction conditions regarding the time of the first step and the quantity of solvent used, an array of aldehydes and alcohols was used, both aromatic and aliphatic. Regarding the aromatic aldehydes, in general, the ester products were obtained in good yields. With the aliphatic aldehydes tested it wasn’t possible to achieve the desired products. The array of alcohols used didn’t show any obstacle. All the alcohols tested, such as benzylic alcohols, phenol, allylic, primary and secondary aliphatic alcohols have demonstrated to be good substrates for the synthesis of esters.

This method appears to be very selective, without any side-products detected, being an attractive, economical and green alternative for the synthesis of esters.

Key-words: Alcohols, Aldehydes, Esters, Oxidative Synthesis, Solar Light,

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Contents

1.1.1. Characteristics and importance ... 1

1.1.2. Conventional synthesis – Fischer esterification ... 1

1.1.3. Alternative synthetic processes ... 2

1.2 Previous work ... 4

1.3 Objective... 6

2. Methodology ... 7

2.1 Equipment... 7

2.2 Reagents and solutions ... 7

2.3 Experimental procedure... 8

2.3.1. Optimization of the time of reaction and solvent quantity ... 8

2.3.2. General procedure ... 10

2.3.3. Exception ... 10

3. Results ... 11

3.1 Optimization of the time of reaction and solvent quantity ... 11

3.1.1. Product characterization ... 11

3.2 Synthesis of esters ... 12

3.2.1. Product characterization: benzyl 4-(trifluoromethyl) benzoate (7a) ... 14

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3.2.3. Product characterization: methyl 2,4-dichlorobenzoate (7c) ... 15

3.2.4. Product characterization: 4-chlorobenzyl 2,4-dichlorobenzoate (7f) ... 15

3.2.5. Product characterization: cyclohexyl 2,4-dichlorobenzoate (7g) ... 16

3.2.6. Product characterization: 2-methylbenzyl 2,4-dichlorobenzoate (7h) ... 16

3.2.7. Product characterization: pentan-3-yl 2,4-dichlorobenzoate (7i) ... 17

3.2.8. Product characterization: 4-chloro-2-methylphenyl 4-cyanobenzoate (7i) ... 17

3.2.9. Product characterization: allyl 4-cyanobenzoate (7k) ... 18

3.2.10. Product characterization: sec-butyl 4-cyanobenzoate (7l) ... 18

3.2.11. Product characterization: 2-(thiophen-2-yl) ethyl 4-nitrobenzoate (7m) ... 19

3.2.12. Product characterization: methyl [1,1'-biphenyl]-4-carboxylate (7n) ... 19

3.2.13. Product characterization: ethyl 4-chlorobenzoate (7r) ... 20

4. Discussion of results ... 21

4.1 Reaction analysis ... 21

4.2 Optimization of the reaction conditions ... 22

4.3 Reaction scope ... 22 5. Conclusions ... 25 6. References ... 26 Appendix 1 – NMR spectra ... 29 Product 10a 1H NMR ... 29 Product 10b 1H NMR ... 30 Product 10b 13C NMR... 30 Product 10c 1H NMR ... 31

XIII Product 10c 13C NMR ... 31 Product 7a 1_{H NMR ... 32} Product 7a 13C NMR ... 32 Product 7b 1_{H NMR ... 33} Product 7b 13C NMR... 33 Product 7c 1H NMR ... 34 Product 7c 13C NMR ... 34 Product 7f 1H NMR ... 35 Product 7f 13C NMR ... 35 Product 7g 1H NMR ... 36 Product 7g 13C NMR... 36 Product 7h 1H NMR ... 37 Product 7h 13C NMR... 37 Product 7i 1H NMR... 38 Product 7i 13C NMR ... 38 Product 7j 1H NMR... 39 Product 7j 13C NMR ... 39 Product 7k 1H NMR ... 40 Product 7k 13C NMR... 40 Product 7l 1_{H NMR... 41} Product 7l 13C NMR ... 41 Product 7m 1_{H NMR... 42} Product 7m 13C NMR ... 42 Product 7n 1_{H NMR ... 43} Product 7n 13C NMR... 43 Product 7r 1H NMR ... 44 Product 7r 13C NMR ... 44

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Index of figures

Figure 1.1 Mechanism of Fischer esterification. ... 1

Figure 1.2 Hemiacetal formation ... 3

Figure 1.3 First step of the esterification method. ... 5

Figure 1.4 Second step of the esterification method ... 5

Figure 1.5 General formula of the esterification method studied ... 6

Figure 3.1 Benzyl 4-nitrobenzoate ... 11

Figure 3.2 Benzyl 4-(trifluoromethyl)benzoate ... 14

Figure 3.3 Tert-butyl 4-cyanobenzoate ... 14

Figure 3.4 Methyl 2,4-dichlorobenzoate ... 15

Figure 3.5 4-chlorobenzyl 2,4-dichlorobenzoate ... 15

Figure 3.6 Cyclohexyl 2,4-dichlorobenzoate ... 16

Figure 3.7 2-methylbenzyl 2,4-dichlorobenzoate ... 16

Figure 3.8 Pentan-3-yl 2,4-dichlorobenzoate ... 17

Figure 3.9 4-chloro-2-methylphenyl 4-cyanobenzoate ... 17

Figure 3.10 Allyl 4-cyanobenzoate ... 18

Figure 3.11 Sec-butyl 4-cyanobenzoate ... 18

Figure 3.12 2-(thiophen-2-yl) ethyl 4-nitrobenzoate ... 19

Figure 3.13 Methyl [1,1'-biphenyl]-4-carboxylate ... 19

Figure 3.14 Ethyl 4-chlorobenzoate ... 20

Figure 4.1 Proposed mechanism ... 21

Figure 4.2 Ester products. ... 23

Figure 4.3 A resonance structure for 4-anisaldehyde and 4-hydroxybenzaldehyde showing decreased double ... 24

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Index of tables

Table 3-1 Parameters analysed for optimization of reaction conditions ... 11 Table 3-2 Esterification of aldehydes ... 12

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Abbreviations

CAM - cerium ammonium molybdate 2,4-DNP - 2,4-dinitrophenylhydrazine DCC - N,N′-dicyclohexylcarbodiimide DCM - dichloromethane DIB - (diacetoxyiodo)benzene DMAP - 4-dimethylaminopyridine Et3N - triethylamine

EtOAc – ethyl Acetate

HOBt - 1-hydroxybenzotriazole NHC - N-heterocyclic carbene TBHP - tert-butyl hydroperoxide TCCA - trichloroisocyanuric acid TLC - thin-layer chromatography TMS - tetramethylsilane

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1. Introduction

1.1 Esters

1.1.1. Characteristics and importance

Esters have many important characteristics, like their fragrances and their biological activities, which make them useful in diverse fields (1). As a functional group, they can be found in many natural products, polymers, synthetic intermediates and pharmaceuticals (2), such as amino acid esters, macrolide antibiotics, flavouring agents, fragrances (3), tryptase inhibitors (4), anti-inflammatory agents or analgesics (5). They were also tested as anti-tuberculosis drugs, against multidrug-resistant strains of

mycobacterium (6) and as antiviral prodrugs (7), showing promising results.

1.1.2. Conventional synthesis – Fischer esterification

The omnipresence and usefulness of esters in both laboratory and industry led to the development of continuously more efficient methods for their synthesis (8,9). One of the conventional processes is the Fischer esterification, with a nucleophilic acyl substitution reaction between alcohols and carboxylic acids, with dehydrating agents as catalysts (1).

In the presence of an acid catalyst, the protonation of the carbonyl oxygen occurs, leading to the nucleophilic attack of the carbonyl carbon by the alcohol and creating a tetrahedral intermediate. After this point, the protonation of either hydroxy oxygen will result in the elimination of water and formation of the ester (Figure 1.1) (10).

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In order to shift the equilibrium toward the ester product, two strategies can be employed: an excess of one of the starting materials, for example by using the alcohol as a solvent, or the removal of the water produced (10).

An alternative to this process starts with the activation of the carboxylic acid, followed by the nucleophilic substitution reaction between the alcohol and the carboxylic acid derivative, that can be an acid halide or an acid anhydride (1,11). These derivatives are much more reactive than the carboxylic acids, therefore, the reaction with the alcohol is faster and there is no need of acid catalysts. Pyridine is usually added to react with the hydrogen halide produced (12). This procedure is applicable, for example, to macrolide synthesis (3).

However, the esterification of carboxylic acids presents some limitations. For instance, the coupling reagents used, like N,N′-dicyclohexylcarbodiimide (DCC) or 1-hydroxybenzotriazole (HOBt), are toxic. Besides their toxicity, they lead to the formation of by-products that may hinder a proper isolation of the final product (13). Another inconvenient is the need of large excess of alcohol, used as a solvent, in order to shift the equilibrium of the reaction toward the ester product. This leads to a non-optimal stoichiometric ratio of this reagent and to an increased expenditure of resources and energy (3,10). On the other hand, sometimes, strong acids are used as catalysts, as well as toxic reagents, such as thionyl chloride (SOCl2) or phosphorus tribromide (PBr3), to

activate the carboxylic acids (10). To overcome these limitations, alternative processes have been investigated.

1.1.3. Alternative synthetic processes

An attractive approach that has been receiving increasing attention is the oxidative esterification of aldehydes. Using aldehydes as starting materials, besides their readily availability, has the advantage of avoiding the formation of carboxylic acid intermediates (14). There are many different approaches to this kind of esterification.

Several methods use transition metal catalysts. The use of these heterogeneous catalysts, which have a more efficient recovery and recyclability, leads to less contamination of the product (11). There is a wide range of transition metals that have

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been used as catalysts in the form of complexes, such as gold (15), titanium (16), iron (17), copper (18,19) and palladium (13,20). On the other hand, most of these catalysts have higher costs, which represents an obstacle to large-scale use (11).

Some methods of esterification of aldehydes include the oxidation of intermediate hemiacetals. Hemiacetals are synthesized by the addition of alcohols to aldehydes (Figure 1.2) (10). Due to the good electrophilic properties of aldehydes and nucleophilic properties of alcohols, the reaction between them, and consequent formation of the hemiacetal, may not require a catalyst. However, in the presence of factors that may interfere with those good properties of the aldehyde and/or alcohol, a catalyst may be essential (15). That catalyst can be either a transition metal complex (18,21), a molecular halogen such as potassium iodide (KI) (22) or a Lewis acid like tris(pentafluorophenyl)borane [B(C6F5)3] (23), among others.

After the formation of the intermediate, the reaction proceeds with its oxidation. For this intend many oxidizing agents have been used, such as hydrogen peroxide (H2O2)

(1,21), tert-butyl hydroperoxide (TBHP) (18,19,22), (diacetoxyiodo)benzene (DIB) (24) or oxone (25).

Although all these different methodologies and their different catalysts and reagents, they have some common inconveniences which may represent a barrier to a broader method: the steric drawback associated to the hemiacetal intermediate (11) as well as its instability (26).

A metal-free approach for the esterification of aldehydes includes electrocatalytic processes (14). In these processes a platinum anode is used, along with mediators such as potassium iodide, potassium bromide, sodium cyanide or sodium methoxy. In general, the procedure goes by the electrolization of a solution with the aldehyde and the mediators, with the alcohol as solvent. The ester is synthesised through the reaction

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between the aldehyde and the alcohol (27–29). These methods show good results with aromatic aldehydes. An array of methyl benzoates is produced, with the alcohol being methanol (27,29,30).

This approach doesn’t need strong oxidizing agents and these mild reaction conditions allow to selectively oxidize aldehydes with sensitive functional groups (28). However, this method only applies to aromatic aldehydes and it requires an excess of alcohol (27,29,30).

Another interesting alternative procedure is the N-heterocyclic carbene (NHC) catalysed esterification of aldehydes. This process goes by an internal redox reaction and

in situ activation of α-functionalized aldehydes (31). Studies on both NHC

transition-metal catalysed (32) and transition-metal-free NHC catalysed esterifications (31) are reported. A wide range of esters derived from either aliphatic alcohols or phenols as well as both aromatic and aliphatic aldehydes can be produced in good yields (31,32). However, the alcohols are used in large excess, only the α-functionalized aldehydes can be used and, in the case of NHC transition-metal catalysed, the disadvantages of the transition metals, like the high costs associated, are present as well.

1.2 Previous work

De Luca et al. (26) have already presented a new method with the aim of overcoming all these barriers and achieving a general method, able to use either aliphatic or aromatic aldehydes as starting materials, as well as a wide array of alcohols. In the first step of this procedure, trichloroisocyanuric acid (TCCA) in dichloromethane (DCM) was used as an oxidant and chlorinating reagent, turning the aldehyde into an acyl chloride at room temperature. This reaction was monitored by thin-layer chromatography (TLC) and the acyl chloride was quantitatively formed after 5 days. In the second step, the acyl chloride generated in situ was treated with an alcohol, in the presence of a base at 0ºC, and the reaction proceeded for 1h at room temperature, forming the desired ester. After optimizing the conditions of both reactions, using benzaldehyde as the starting aldehyde and benzyl alcohol, they were able to achieve 90% yield of the ester product. These optimized conditions included 1.1 mmol of both the aldehyde and TCCA in the first step

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(Figure 1.3), 1 mmol of alcohol and 2 mmol of triethylamine (Et3N) as base with a

catalytic amount of 4-dimethylaminopyridine (DMAP) (10% mol) in the second step (Figure 1.4).

After optimizing all the conditions, the scope of the reaction was investigated. The array of alcohols tested gave the ester products in high yields, without any significant side product. Then, many kinds of aldehydes were used: aldehydes with electron-donating or electron-withdrawing groups, aliphatic and linear aldehydes and even very hindered aliphatic aldehydes. Good yields were achieved with all of these different aldehydes, without any significant side product as well.

These positive results, revealed this method itself like a general and selective method with an optimal stoichiometric molar ratio of reactants. The advantages of such method are several: the use of mild reaction conditions and green reagents, such as TCCA, which is commonly used as a swimming pool disinfectant or even for dishwashing in hospitals and restaurants (33), the bypassing of the hemiacetal formation and the avoidance of large excess of reagents. Nonetheless, there is a big inconvenience about the procedure: the five days duration of the first step.

Figure 1.3 First step of the esterification method.

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1.3 Objective

In order to overcome the long duration of the first step of the reaction, an improvement to that procedure is presented here. Solar light was tested as an activator to reduce the duration of the first step. In this way, the green aspect of the method is preserved as well as its cost-effectiveness, if the same positive results of the previous studies are obtained. The scope of the reaction was also investigated by testing different aldehydes and alcohols. Therefore, the aim of this work is to achieve a general and selective method for the synthesis of esters, using readily available starting materials (aldehydes and alcohols) as well as green reagents (TCCA and sunlight as the activator) and making it more feasible by reducing its reaction time (Figure 1.5).

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2. Methodology

2.1 Equipment

• Abet tech sun 2000 solar simulator (100 mW/cm2 _{simulated AM 1.5G irradiance);}

• Merck Kieselgel 60 F254 TLC plates;

• UV lamp Vilber Lourmat VL-208.G, 254 nm, 8 W;

• Bruker Avance III 400 spectrometer - chemical shifts are reported in parts per million (ppm,d) relative to internal tetramethylsilane standard (TMS, d 0.00). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet; dd, doublet of doublets; br, broad;

• Rotary evaporator BUCHI; • Leitz Laborlux S;

• Magnetic stirrer IKA Big Squid Ocean; • Kern analytical balance.

2.2 Reagents and solutions

• Silica gel with pore size 60 Å, 32-63nm particle size for the flash chromatography; • 2,4-dinitrophenylhydrazine (2,4-DNP) solution for TLC staining: 2,4-DNP aldrich, 97%), sulfuric acid aldrich, 99.999%) and ethanol (sigma-aldrich, 95%);

• Cerium ammonium molybdate (CAM) solution for TLC staining: ammonium molybdate (sigma-aldrich, 99.98%), ceric ammonium sulfate (sigma-aldrich) and sulfuric acid (sigma-aldrich, 99.999%);

• CDCl3 (sigma-aldrich, 99.96 atom % D; ≥99%) as the solvent for 1H NMR

and 13C NMR spectra;

• Tetramethylsilane (TMS) (sigma-aldrich, ≥ 99.5%) as the internal standard for 1_H

NMR and 13C NMR spectra; • TCCA (sigma-aldrich, ≥ 95%);

8 • Et3N (sigma-aldrich, ≥ 99.5%);

• DMAP (sigma-aldrich, ≥ 99%); • DCM (sigma-aldrich, ≥ 98%);

• Hexane (sigma-aldrich, solvent grade);

• Ethyl acetate (EtOAc) (sigma-aldrich, solvent grade);

• Aldehydes: butyraldehyde aldrich, ≥ 96%), 2-chlorobenzaldehyde (sigma-aldrich, 99%), 3-chlorobenzaldehyde (sigma-aldrich, 97%), 4-chlorobenzaldehyde (sigma-aldrich, 97%), 4-cyanobenzaldehyde (sigma-aldrich, ≥ 98%), 2,4-dichlorobenzaldehyde (sigma-aldrich, 99%), 4-hydroxybenzaldehyde aldrich, ≥ 95%), 4-methoxybenzaldehyde (sigma-aldrich, 98%), 4-nitrobenzaldehyde (sigma-(sigma-aldrich, 98%), 4-phenylbenzaldehyde (sigma-aldrich, 99%), 4-(trifluoromethyl)benzaldehyde (sigma-aldrich, 98%), trimethylacetaldehyde (sigma-aldrich, 96%);

• Alcohols: allyl alcohol (sigma-aldrich, ≥ 99%), benzyl alcohol (sigma-aldrich, 99.8%), 2-butanol aldrich, 99.5%), 4-chloro-3-methylphenol (sigma-aldrich, 99%), 4-chlorobenzyl alcohol (sigma-(sigma-aldrich, 99%), cyclohexanol aldrich, 99%), ethanol aldrich, ≥ 99.8%), 2-ethylphenol (sigma-aldrich, 99%), 4-fluorobenzyl alcohol (sigma-(sigma-aldrich, 97%), methyl alcohol (sigma-aldrich, 99.8%), 2-methylbenzyl alcohol (sigma-aldrich, 98%), 2-naphthol (sigma-aldrich, 99%), 3-pentanol (sigma-aldrich, 98%), propargyl alcohol (sigma-aldrich, 99%), tert-butanol (sigma-aldrich, ≥ 99.5%), 2-thiopheneethanol (sigma-aldrich, 98%).

2.3 Experimental procedure

2.3.1. Optimization of the time of reaction and solvent quantity

TCCA (256 mg; 1.1 mmol) was added to the 4-nitrobenzaldehyde (166 mg; 1.1 mmol) in 3.25 ml of DCM, at room temperature. The resulting suspension was capped, sealed with parafilm and stirred under the solar simulator. The reaction was monitored by TLC (Hexane:EtOAc, 4.2:0.8) until the 4-nitrobenzoyl chloride was quantitatively formed (1.5 hours). Then, the reaction mixture was put into an ice bath. The benzyl

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alcohol (108 mg; 1 mmol) was added, followed by the addition of DMAP (12 mg; 0.1 mmol) at once and Et3N (202 mg; 2 mmol) at a dropwise rate. 2 ml of DCM were added

as solvent. After the addition, the reaction was stirred at room temperature for 2 hours, monitored by TLC (Hexane:EtOAc, 4.2:0.8) until the ester product was quantitatively formed. Then, the solvent was removed under vacuum and the residue was purified by flash chromatography (Hexane:EtOAc, 4.2:0.8). This procedure was applied to the synthesis of product 10 (Table 3-1, entry 1).

In order to find the optimal quantity of solvent for the first step, a second reaction was performed. TCCA (256 mg; 1.1 mmol) was added to the 4-nitrobenzaldehyde (166 mg; 1.1 mmol) in 1 ml of DCM, at room temperature. The resulting suspension was capped, sealed with parafilm and stirred under the solar simulator. The reaction was monitored by TLC (Hexane:EtOAc, 4.2:0.8) until the 4-nitrobenzoyl chloride was quantitatively formed (1.5 hours). Then, the reaction mixture was put into an ice bath. The benzyl alcohol (108 mg; 1 mmol) was added, followed by the addition of DMAP (12 mg; 0.1 mmol) at once and Et3N (202 mg; 2 mmol) at a dropwise rate. 2 ml of DCM were

added as solvent. After the addition, the reaction was stirred at room temperature for 2 hours, monitored by TLC (Hexane:EtOAc, 4.2:0.8), until the ester product was quantitatively formed. Then, the solvent was removed under vacuum and the residue was purified by flash chromatography (Hexane:EtOAc, 4.2:0.8). This procedure was applied to the synthesis of product 10 (Table 3-1, entry 2).

Finally, with the aim of testing the results of a longer first step, a third reaction was carried out. TCCA (256 mg; 1.1 mmol) was added to the 4-nitrobenzaldehyde (166 mg; 1.1 mmol) in 1 ml of DCM, at room temperature. The resulting suspension was capped, sealed with parafilm and stirred under the solar simulator. The reaction was monitored by TLC (Hexane:EtOAc, 4.2:0.8) and had the duration of 2 hours. Then, the reaction mixture was put into an ice bath. The benzyl alcohol (108 mg; 1 mmol) was added, followed by the addition of DMAP (12 mg; 0.1 mmol) at once and Et3N (202 mg;

2 mmol) at a dropwise rate. 2 ml of DCM were added as solvent. After the addition, the reaction was stirred at room temperature for 2 hours, monitored by TLC (Hexane:EtOAc, 4.2:0.8) until the ester product was quantitatively formed. Then, the solvent was removed under vacuum and the residue was purified by flash chromatography (Hexane:EtOAc, 4.2:0.8). This procedure was applied to the synthesis of product 10 (Table 3-1, entry 3).

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2.3.2. General procedure

After the optimization of all conditions, a general method was applied.

TCCA (256 mg; 1.1 mmol) was added to the aldehyde (1.1 mmol) in 1 ml of DCM. When the aldehyde was a liquid, DCM was not used. The reaction was then capped, sealed with parafilm and stirred under the solar simulator for 1.5 hours, after which, the progress of the reaction was checked by TLC. When this step was successful, the addition for the second step was performed, with the reaction mixture into an ice bath. The first reagent added was the alcohol (1 mmol), followed by the addiction of DMAP (12 mg; 0.1 mmol) at once and Et3N (202 mg; 2 mmol) at a dropwise rate. 2 ml of DCM

were added as solvent. The reaction was stirred at room temperature until the disappearance of the alcohol or until the ester product was quantitatively formed, being monitored by TLC. Then, the solvent was removed under vacuum and the residue was purified by flash chromatography. This procedure was applied to the synthesis of products

7a-p and 7r.

2.3.3.Exception

TCCA (256 mg; 1.1 mmol) was added to the aldehyde (1.1 mmol) in 1 ml of DCM. The reaction was then capped, sealed with parafilm and stirred under the solar simulator for 1.5 hours. After this time, the addition for the second step was performed, with the reaction mixture into an ice bath. The first reagent added was the alcohol (1 mmol), followed by the addiction of DMAP (12 mg; 0.1 mmol) at once and Et3N (202

mg; 2 mmol) at a dropwise rate. 2 ml of DCM were added as solvent. After the addition, the reaction was stirred at room temperature until the ester product was quantitatively formed, being monitored by TLC. After the time of reaction, the solvent was removed under vacuum and the residue was purified by flash chromatography. This procedure was applied to the synthesis of product 7q.

11

3. Results

3.1 Optimization of the time of reaction and solvent quantity

Table 3-1 Parameters analysed for optimization of reaction conditions

Entry Time of the first step (h) CH2Cl2 (ml) η (after isolation)

1 1.5 3.25 77% 2 1.5 1 85% 3 2 1 80%

3.1.1.Product characterization

• Appearance: Yellow solid

1_{H NMR (400 MHz, CDCl}

3): δ 8.27 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 8.9 Hz, 2H), 7.50 –

7.34 (m, 5H), 5.41 (s, 2H).

13_{C-NMR (100 MHz, CDCl3): δ 164.57, 150.64, 135.56, 135.35, 130.87, 128.80, 128.70,}

128.48, 123.59, 67.69.

12

3.2 Synthesis of esters

Table 3-2 Esterification of aldehydes

Entry R1 R2 Solvent η (after isolation)

7a ---- 80% 7b CH2Cl2 60% 7c CH3 CH2Cl2 98% 7d ---- ---- No reaction 7e ---- CH2Cl2 No reaction 7f CH2Cl2 93% 7g CH2Cl2 80%

13 7h CH2Cl2 96% 7i CH2Cl2 77% 7j CH2Cl2 94% 7k CH2Cl2 107% 7l CH2Cl2 71% 7m CH2Cl2 47% 7n CH3 CH2Cl2 80% 7o ---- No reaction 7p ---- No reaction 7q ---- No reaction 7r CH3CH2 CH2Cl2 71%

14

3.2.1.Product characterization: benzyl 4-(trifluoromethyl) benzoate (7a)

• Rf: 0.303 (4.8:0.2; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl} 3): δ 8.19 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.50 – 7.34 (m, 5H), 5.40 (s, 2H). 13_{C-NMR (100 MHz, CDCl} 3): δ 165.36, 135.72, 134.68 (d, JC-F = 32.7 Hz), 133.51 (d, JC-F = 1.0 Hz), 130.25, 128.83, 128.63, 128.45, 125.56 (q, JC-F = 3.7 Hz), 123.76 (d, JC-F = 272.7 Hz), 67.39.

3.2.2. Product characterization: tert-butyl 4-cyanobenzoate (7b)

• Rf: 0.390 (4.5:0.5; Hexane:EtOAc) • Melting point: 67-75ºC

• Appearance: White solid

1_{H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 1.60}

(s, 9H).

13_{C-NMR (100 MHz, CDCl3): δ 164.13, 136.00, 132.19, 130.07, 118.29, 116.00, 82.52,}

28.23.

Figure 3.2 Benzyl 4-(trifluoromethyl)benzoate

15

3.2.3.Product characterization: methyl 2,4-dichlorobenzoate (7c)

• Rf: 0.300 (4.7:0.3; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl}

3): δ 7.79 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.29

(dd, J = 8.4, 2.0 Hz, 1H), 3.92 (s, 3H).

13_{C-NMR (100 MHz, CDCl3): δ 165.32, 138.46, 135.07, 132.63, 131.14, 128.37, 127.11,}

52.66

3.2.4.Product characterization: 4-chlorobenzyl 2,4-dichlorobenzoate (7f)

• Rf: 0.276 (4.7:0.3; Hexane:EtOAc) • Melting point: 69-70 ºC

• Appearance: White solid

1_{H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.39}

(d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 5.32 (s, 2H)

13_{C-NMR (100 MHz, CDCl3): δ 164.57, 138.72, 135.22, 134.55, 133.99, 132.75, 131.24,}

129.94, 128.99, 128.08, 127.18, 66.74.

Figure 3.4 Methyl 2,4-dichlorobenzoate

16

3.2.5.Product characterization: cyclohexyl 2,4-dichlorobenzoate (7g)

• Rf: 0.440 (4.7:0.3; Hexane:EtOAc) • Appearance: Colourless oil

1_{H NMR (400 MHz, CDCl} 3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 5.09 – 5.00 (m, 1H), 2.01 – 1.90 (m, 2H), 1.84 – 1.73 (m, 2H), 1.66 – 1.51 (m, 3H), 1.50 – 1.30 (m, 3H). 13_{C-NMR (100 MHz, CDCl3): δ 164.54, 138.05, 134.79, 132.50, 131.01, 129.41, 127.07,} 74.49, 31.62, 25.51, 23.73.

3.2.6.Product characterization: 2-methylbenzyl 2,4-dichlorobenzoate

(7h)

• Rf: 0.400 (4.7:0.3; Hexane:EtOAc) • Appearance: Colourless oil

1_{H NMR (400 MHz, CDCl} 3): δ 7.87 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.37 – 7.26 (m, 4H), 5.44 (s, 2H), 2.47 (s, 3H). 13_{C-NMR (100 MHz, CDCl} 3): δ 164.71, 138.56, 137.28, 135.21, 133.47, 132.74, 131.22, 130.60, 129.72, 128.95, 128.35, 127.15, 126.26, 66.01, 19.15.

Figure 3.6 Cyclohexyl 2,4-dichlorobenzoate

17

3.2.7.Product characterization: pentan-3-yl 2,4-dichlorobenzoate (7i)

• Rf: 0.410 (4.7:0.3; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl} 3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 5.04 (m, 1H), 1.76 – 1.67 (m, 4H), 0.97 (t, J = 7.5 Hz, 6H). 13_{C-NMR (100 MHz, CDCl} 3): δ 164.86, 137.96, 134.71, 132.29, 130.96, 129.36, 127.01, 78.72, 26.48, 9.74.

3.2.8. Product characterization: chloro-2-methylphenyl

4-cyanobenzoate (7j)

• Rf: 0.424 (4.2:0.8; Hexane:EtOAc) • Melting point: 116-121 ºC

• Appearance: White solid

1_{H NMR (400 MHz, CDCl} 3): δ 8.29 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 7.01 (dd, J = 8.6, 2.7 Hz, 1H), 2.41 (s, 3H). 13_{C-NMR (100 MHz, CDCl} 3): δ 163.62, 148.94, 137.89, 133.29, 132.57, 132.10, 130.78, 130.11, 123.92, 120.25, 117.92, 117.31, 20.40.

Figure 3.8 Pentan-3-yl 2,4-dichlorobenzoate

Figure 3.9

18

3.2.9.Product characterization: allyl 4-cyanobenzoate (7k)

• Rf: 0.270 (4.5:0.5; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl} 3): δ 8.15 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 6.10 – 5.96 (m, 1H), 5.41 (dd, J = 17.2, 1.1 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 4.85 (d, J = 5.8 Hz, 2H). 13_{C-NMR (100 MHz, CDCl3): δ 164.70, 134.09, 132.34, 131.70, 130.25, 119.14, 118.05,} 116.57, 66.41.

3.2.10. Product characterization: sec-butyl 4-cyanobenzoate (7l)

• Rf: 0.230 (4.7:0.3; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 5.14 –} 5.04 (m, 1H), 1.80 – 1.58 (m, 2H), 1.33 (d, J = 6.3 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). 13_{C-NMR (100 MHz, CDCl3): δ 164.59, 134.78, 132.21, 130.07, 118.10, 116.21, 74.06,} 28.89, 19.50, 9.73. Figure 3.10 Allyl 4-cyanobenzoate Figure 3.11 Sec-butyl 4-cyanobenzoate

19

3.2.11. Product characterization: 2-(thiophen-2-yl) ethyl 4-nitrobenzoate

(7m)

• Rf: 0.470 (4.2:0.8; Hexane:EtOAc) • Appearance: Yellow oil

1_{H NMR (400 MHz, CDCl} 3): δ 8.30 (d, J = 8.9 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 7.19 (dd, J = 5.1, 1.1 Hz, 1H), 6.97 (dd, J = 5.0, 3.5 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1H), 4.59 (t, J = 6.5 Hz, 2H), 3.33 (t, J = 6.5 Hz, 2H). 13_{C-NMR (100 MHz, CDCl} 3): δ 164.67, 150.80, 139.65, 135.64, 130.93, 127.15, 125.90, 124.45, 123.73, 66.18, 29.47.

3.2.12.Product characterization: methyl [1,1'-biphenyl]-4-carboxylate

(7n)

• Rf: 0.314 (4.5:0.5; Hexane:EtOAc) • Melting point: 100-106ºC

• Appearance: White solid

1_{H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.63}

(d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 3.95 (s, 3H).

13_{C-NMR (100 MHz, CDCl}

3): δ 167.06, 145.70, 140.07, 130.19, 129.01, 128.22, 127.35,

127.11, 52.18.

Figure 3.12 2-(thiophen-2-yl) ethyl

4-nitrobenzoate

Figure 3.13 Methyl

20

3.2.13.Product characterization: ethyl 4-chlorobenzoate (7r)

• Rf: 0.49 (4.8:0.2; Hexane:EtOAc) • Appearance: Colourless oil

1_{H NMR (400 MHz, CDCl}

3): δ 7.95 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 4.35

(q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

13_{C-NMR (100 MHz, CDCl}

3): δ 165.78, 139.30, 131.01, 129.05, 128.72, 61.26, 14.36. Figure 3.14 Ethyl 4-chlorobenzoate

21

4. Discussion of results

4.1 Reaction analysis

Each reaction consisted in two steps. In the first step, the aldehyde underwent a chlorination by TCCA, probably by a radical pathway (26,34) in which the solar light acted as an activator. After this step, the alcohol was added to the previously formed acyl chloride and a nucleophilic substitution reaction took place between them, in the presence of Et3N and a catalytic amount of DMAP. In the end of this second step the ester was

formed.

Based on previous studies, a mechanism for these reactions is proposed here (Figure 4.1). The solar radiation initiates a radical pathway in which the aldehyde provides an acyl radical (35,36). This radical pathway continues with the chlorination of the acyl radical by TCCA, producing an acyl chloride (26) and the dichloroisocyanuric acid (DCCA) (37). In the second step, DMAP acts as a catalyst, reacting with the acyl donor, the acyl chloride, and forming an acylpyridinium cation (38,39). The alcohol added is deprotonated by Et3N and performs a nucleophilic attack to the carbonyl carbon

(38,39). In this way the DMAP catalyst is regenerated and the desired ester product is obtained.

22

4.2 Optimization of the reaction conditions

This work started with the optimization of the reaction conditions, using 4-nitrobenzaldehyde and benzyl alcohol as starting materials. The conditions applied to the synthesis of product 10 (Table 3-1, entry 1) were based in the previous studies done by De Luca et al. (26), using 3.25 ml of DCM as solvent and extending the first step of the reaction for 1.5 hours. A yield of 77% of the desired ester product was achieved with these conditions.

In 10 (Table 3-1, entry 2) a different quantity of solvent was tested. Instead of the 3.25 ml of DCM used in 10 (Table 3-1, entry 1), only 1 ml was used. All the other conditions were mantained. A better result was achieved, with a yield of 85%, against the 77% yield of 10 (Table 3-1, entry 1). These results led to the reduction of the solvent volume used in the following reactions.

Finally, in 10 (Table 3-1, entry 3), the effect of an extended first step was tested, maintaining all the other conditions used in 10 (Table 3-1, entry 2). This step had the duration of 2 hours, instead of the 1.5 hours of both 10 (Table 3-1, entry 1) and 10 (Table

3-1, entry 2). A yield of 80% was achieved, lower than the yield of 10 (Table 3-1, entry

2) (85%), which led to the conclusion that there weren’t any advantages in extending the time of the first step.

Based on these observations, the conditions of 10 (Table 3-1, entry 2) were chosen as the optimal conditions of the general procedure used in this work.

As an exception, in 7q, although the aldehyde was liquid, DCM had to be added as solvent. This modification in the general procedure was due to an instantaneous reaction with the release of white smoke once the starting reagents were added without any solvent.

4.3 Reaction scope

After the reaction conditions were optimized, the scope of this process was investigated. In general, there weren’t any side products in any of the reactions and good to high yields were obtained.

23

Different kinds of aldehydes, including both aliphatic and aromatic aldehydes, were tested, in order to investigate the influence of their different characteristics in the outcome of the reactions. Regarding the aromatic aldehydes, all the halogenated aldehydes as well as the ones bearing NO2, CN and phenyl substituents in the aromatic

ring originated the desired esters in good to high yields (Figure 4.2).

7k had a yield of 107%, which can be explained by the presence of some solvents

used in the flash chromatography, due to an incomplete solvent removal. In the 1H NMR spectrum the presence of hexane is visible.

7m was the only exception regarding the good yields, achieving a yield of only

47%. This can be, in part, due to some loss of product during a second flash chromatography, which was needed after verifying that the first one hadn’t been enough to purify the ester product.

Aliphatic aldehydes, used in 7o, 7p and 7q, didn’t form the desired ester products. It is known that aliphatic aldehydes don’t survive under strong oxidative conditions (26). Although they can undergo a successful oxidation with TCCA alone (26), it is possible that the presence of the solar radiation, accelerating this process, may have jeopardized the oxidation of the aliphatic aldehydes.

In the cases of 4-anisaldehyde and 4-hydroxybenzaldehyde, the chlorination step with TCCA wasn’t successful, ending up with too many side-products. This can be due to the characteristics given to the aromatic ring by these electron-donating substituents. The presence of either OCH3 and OH groups in the aromatic ring in the para position can

lead to a decrease of the double bond character of the carbonyl group (40) (Figure 4.3).

24

This would benefit electrophilic chlorination products, already reported in some studies (41).

Regarding the alcohols, there wasn’t any particular difficulty detected with any of the alcohols used. Aromatic alcohols such as benzylic alcohols (10 (Table 3-1, entry 2), 7a,

7f, 7h and 7m) and phenol (7j), furnished the desired ester products successfully. All the

other alcohols, either allylic (7k), primary (7c, 7n and 7r), secondary (7g, 7i and 7l) or terciary (7b) aliphatic alcohols, were also good substrates for the synthesis of esters.

Figure 4.3 A resonance structure for 4-anisaldehyde and 4-hydroxybenzaldehyde showing decreased

25

5. Conclusions

This work presented a metal-free synthesis of esters using aldehydes and alcohols as starting materials and using mild reaction conditions. This one-pot procedure consisted in two steps: the chlorination of the aldehyde by TCCA, with solar radiation as an activator, and the nucleophilic substitution of the resulting acyl chloride by the alcohol, in the presence of Et3N and catalytic amounts of DMAP.

Using TCCA as the chlorinating agent and the solar radiation as an activator, the method can be considered as a green alternative to other esterifications studied. Considering the cheapness and ready availability of any of the reagents, this method arises as a very interesting alternative to transition-metal catalysed esterifications, making it more appealing for a large-scale use.

The reaction proceeds without the formation of the hemiacetal intermediate, with its characteristic steric drawback and instability, common to many approaches used for the esterification of aldehydes. Another advantage is the use of an optimal stoichiometric ratio of the starting materials, which contributes to the economic efficiency of the process, since it avoids large excess of reagents, unlike electrocatalytic processes and NHC catalysed esterification of aldehydes.

This procedure was successfully applied with a large array of aromatic aldehydes and both aromatic and aliphatic alcohols and appears to be very selective, without any side-products detected.

26

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29

Appendix 1 – NMR spectra

30

Product 10b

_{H NMR}

31

Product 10c

_{H NMR}

32

Product 7a

_{H NMR}

33

Product 7b

_{H NMR}

34

Product 7c

_{H NMR}

35

Product 7f

_{H NMR}

36

Product 7g

_{H NMR}

37

Product 7h

_{H NMR}

38

Product 7i

_{H NMR}

39

Product 7j

_{H NMR}

40

Product 7k

_{H NMR}

41

Product 7l

_{H NMR}

42

Product 7m

_{H NMR}

43

Product 7n

_{H NMR}

44

Product 7r

_{H NMR}