Diversity of Trityl isocyanide as a Novel Reagent in Multicomponent Reactions

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Diversity of Trityl Isocyanide as a Novel

Reagent in Multicomponent Reactions

written by:

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3 | P a g e Research institute:

Vrije Universiteit Amsterdam

Research group:

Synthetic & Bio-Organic Chemistry

Examiners:

Prof. Dr. Romano Orru en Dr. Eelco

Supervisor: Razvan Cioc

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SUMMARY

In Multi Component Reactions (MCRs), 3 or more substrates are combined in a one-pot synthesis to form a product which essentially contains most of the atoms from the reactants. Characteristic are their simplicity, (atom)-efficiency, and compatibility with the important concepts of green chemistry. For these reasons they offer advantageous procedures towards more complex functionalized molecules in a straightforward manner. They are especially well appreciated in the pharmaceutical industry for their compatibility with diversity orientated synthesis strategies (DOS), yielding huge libraries of various target compounds. However, the fact is that most MCRs are dominated by the extraordinary reactivity of isocyanides. Many isocyanides are hazardous and volatile compounds, legendary for their foul odor. Therefore, it still remains desirable to improve on the safety aspect of applications regarding isocyanides. Here, we present the development of a convenient procedure that employs trityl isocyanide (Tr-NC) as a safe, easy to handle and convertible isocyanide. The application of trityl isocyanide in landmark MCRs demonstrates the incredible versatility of this reagent, which enables safe and reproducible general procedures towards various interesting MCR products. Furthermore, straightforward follow-up chemistry allows the further exploration of chemical space in a diversity-oriented synthesis approach.

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SAMENVATTING

In Multi Component Reacties (MCRs) worden 3 of meer beginstoffen gecombineerd tot één eindproduct. Meestal bestaat het product dat wordt gevormd merendeels uit de atomen van de reagentia. Kenmerkend aan MCRs zijn daarom hun efficiëntie, simpliciteit, en tevens de associatie met milieu-vriendelijke (groene) reactie condities. Zodoende verschaffen MCRs verfijnde procedures om op een elegante manier meer complexe moleculen te maken. Met name in farmaceutische industrie worden MCRs enorm gewaardeerd vanwege hun combinatorische mogelijkheden: Op diversiteit georiënteerde strategieën (DOS) kunnen namelijk een enorm aantal verschillende moleculen generen, welke vervolgens worden onderzocht op hun fysiologische eigenschappen. De meeste MCRs worden echter gedomineerd door de bijzondere reactiviteit van hun isocyanide component. Het nadeel is dat de gebruikelijke isocyanides vluchtige en schadelijke stoffen zijn, berucht vanwege hun onaangename geur. Vanuit het gedachtegoed van de groene chemie is het daarom de moeite waard om te onderzoeken of er procedures ontwikkeld kunnen worden die de veiligheidsaspecten bij het gebruik van isocyanides kunnen verbeteren. In dit onderzoek presenteren wij daarom de applicatie van een nieuw isocyanide reagens, namelijk trityl isocyanide. Dit is een veilige, makkelijk te hanteren vaste stof, die gebruikt kan worden in de meest significante MCRs. Een grote diversiteit aan verschillende multicomponent producten is gesynthetiseerd door de reactie condities slechts minimaal aan te passen. Dit demonstreert de veelzijdigheid van het nieuwe isocyanide reagens, dat zodoende middels een veilige, universele en reproduceerbare methode de synthese van verscheidene interessante multicomponent producten mogelijk maakt.

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LIST OF ABBRIVIATIONS

DOS Diversity oriented synthesis

DCM Dichloromethane

EDG Electron donating functional group

Et Ethyl

Et al. Et alli (and others)

EWG Electron withdrawing functional group

GBB-3CR Gröebke Blackburn Bienyamé 3 component reaction

HOMO Highest occupied molecular orbital

HRMS High resolution mass spectroscopy

HTS High throughput screening

IR Infrared spectroscopy

LUMO Lowest unoccupied molecular orbital

MCR Multicomponent reaction

Me Methyl

NMR Nuclear magnetic resonance

P-3CR Passerini 3 component reaction

ppm Parts per million

PTSA Para toluene sulfonic acid

RT Room temperature

S-3CR Strecker 3 component reaction

TFA trifluoroacetic acid

TLC Thin layer chromatography

Tr-NC trityl (triphenylmethyl) isocyanide

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INTRODUCTION

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1.1) Green Chemistry

In the public opinion the environmental impact of hazardous and wasteful chemical processes has given the chemical industry a bad reputation. This is partly justified by some disastrous incidents, and the fact industry traditionally draws heavily upon (increasingly scarce) natural resources. Indeed, many chemical processes were designed at

In the early 1990’s, Anastas and Zimmerman (2) of the US Environmental Protection Agency (EPA) recognized the importance of safer and more eco-friendly processes within the chemical industry. And so, they were the first to formulate the principles of green chemistry, which shortly summarized focus on:

 Waste prevention and atom-efficiency

 Shorter and safer syntheses which are energy efficient

 Using innocuous solvents and auxiliaries instead of hazardous or toxic chemicals

 Preferably renewable raw materials, and catalytic rather than stoichiometric reagents

 The design of products and analytical methodologies for degradation and pollution prevention.

times when environmental issues were of little importance. However, in the past two decades the immediate threat to our health and the environment has become clearly evident. This has also caused increased public awareness that in order to prevent further pollution and climate change, serious efforts towards a sustainable future are now absolutely necessary. Here, the term of sustainability can be defined as ’’to meet the needs of the current generation, without sacrificing the ability to meet the needs of future generations’’ (1). Obviously, a sustainable future should be regarded as one of our most important goals. There are various means towards reaching it, and green chemistry is an important one.

Briefly simplified, the concept of green chemistry is to design safe and efficient chemical processes that prevent waste and avoid hazards in the first place rather than treating them (3). Ideally, these will become the standard in both the academic and industrial domains. Several factors have contributed to this change in paradigm, of which societal pressure, government policy and of course pure economic benefit have been the most important factors. However, as companies adopt the concept of green chemistry, they apply cleaner and more efficient synthetic technologies. And in the end, the reward is a winning business strategy: saving costs on waste treatment improves their economic

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11 | P a g e performance, and marks their

commitment to the environment. Scientists and engineers have never been unfamiliar with these arguments, although being primarily concerned with improving the yields of reactions. But this takes not into account the amount of solvent needed, energy required, kg’s of waste produced, and so on. In this perspective, a much better way to quantify the environmental impact of chemical processes is to assess their atom-efficiency and ‘E-factor’. Here, the atom-efficiency is the percentage of atoms originating from the starting materials ending up in the final product, and the

E-factor is the ratio between the

amount of waste (kg) divided by the amount of product (kg) (and here, waste means anything else but the product).

Chemical processes are there in all sorts and scales, with E-factors greatly varying. A most general rule applies here:

the more complex the final product, the greater its environmental impact. Indeed, most bulk processes such as petrochemicals manufacture are being run quite efficiently (generally E-factors around 0.2 – 5). Therefore, it might not come as a surprise that increasingly complex molecular structures such as specialty chemicals and pharma-ceuticals perform quite poor in terms of their E-factor (some cases 25 - >100) (4). They are commonly subject to multistep synthetic routes, which require a lot of skill, effort, and resources. The environmental burden on heavily functionalized and complex molecules is huge, and this methodology can become a costly and cumbersome process. Especially in the pharmaceutical industry there is much room for improvement. And so, the ’green’ and efficient synthesis of valuable molecules remains among the most interesting challenges for organic chemists within industry today.

1.2) Multicomponent reactions

There are many ways to strive for green chemistry, of which improving on chemical reactions is only one. A different approach to traditional linear synthetic procedures is offered by multicomponent reactions (MCRs), which are widely associated with green chemistry (5). In MCRs 3 or more substrates are combined in a one-pot synthesis to form the desired product in a single step. The reactants usually do not combine all at once in a concerted fashion. Instead, most MCRs are described rather as a sequence of elementary steps leading to the final product, in which the newly formed

chemical bonds connect all of the substrates (6). Their general concept is illustrated in scheme 1, which shows how most MCRs are inherently more ’green’ in terms of (atom)-efficiency, as most of the atoms in the substrates are retained in the final product. In general, they offer the advantage of building more complex functionalized molecules by means of straightforward and simple procedures. Since MCRs are practically single-step conversions, their simplicity also eliminates the preparative complexity of multistep synthesis, which usually requires additional isolation and purification.

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12 | P a g e Scheme 1. Classic linear synthesis versus MCRs: in MCRs all reagents are combined in a

one-pot synthesis to afford final the product in a single operation.

Besides offering such efficient chemistry, MCRs are renowned for their performance under green conditions as well. For their obvious advantages, MCRs have gained considerable attention within the scientific community, and over the last few decades the field has been vastly growing. Well known MCRs have reached high levels of sophistication, and under intense development they have been constantly further improved (7,8). Stimulated by the ever-increasing demand for greener production methods, MCRs have become

particularly interesting in the field of medicinal chemistry and modern drug development (9). Characterized by their modular fashion, large substrate scope, and ease of use, they are perfectly amenable to automated High Throughput Screening (HTS) methods. This

makes MCRs a powerful

methodology by the basic principle of combinatorial chemistry: synthetic strategies that quickly lead to large numbers of different compounds, which are then screened to identify the useful (bioactive) ones.

Scheme 2. MCRs in the total synthesis of popular medicine: A. Emmacyin was discovered as

a drug against MRSA by employing the B-3CR. B. An efficient strategy towards the drug Telepravir employs both the Ugi and Passerini 3CR.

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13 P a g e | Indeed, MCRs have proven especially

useful to generate libraries of target molecules of various structural diversity and complexity (10). This is nicely exemplified by Spring et al, who employed the Biginelli 3CR (B-3CR) to generate a diversity oriented library, and discovered a novel drug against Methicilline Resistente Staphylococcus Aureus (MRSA) (11). This illustrates how MCRs are ideally suited to study the structure-activity relationship by constructing

natural products. An interesting example is the synthesis of the drug Telepravir by Orru et al. (12), who devised an efficient strategy that combines a biocatalytic desym-metrization with both the Ugi and Passerini 3CRs as the key steps to construct a complex molecule in a very efficient way. Despite their synthetic possibilities, it seems peculiar enough that MCRs have been applied relatively rarely on an industrial scale thus far.

Scheme 3. A. The classical Strecker synthesis of the aminoacid Alanine. B. The Mannich

reaction as an example of a textbook MCR by many not immediately recognized as such.

large collections of target molecules. Therefore, they are especially advantageous in Diversity Oriented

Syntheses (DOS), utilizing their

diversity, efficiency, and ability to rapidly access huge chemical space. In such a manner, MCRs offer tremendous opportunities to generate scaffold libraries in a time and cost effective way.

However, MCRs are by no means limited to any particular field of research. Regarding the principles of green synthesis, MCRs are applicable in a much broader sense, and there are many interesting examples where MCRs have been applied in the total synthesis of medicines and

Ivar Ugi recognized their tremendous potential already as early as in the 1960’s, but there are several possible explanations for the fact they have been laying around on the shelf for decades; Not all chemists are completely familiar with MCRs, and for many, it probably remains challenging to envision the multicomponent product retro-synthetically. In other words, many (medicinal) chemists experience some difficulties recognizing the product of a MCR within the complex molecular structure of natural

products and potential

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14 | P a g e Therefore, MCRs not yet fully

appreciated as an integrated part of our common synthetic knowledge (13). Perhaps surprisingly, the most famous MCRs are actually very old, and their history dates back more than 150 years! Many are even named textbook-reactions, such as the Mannich reaction (M-3CR) (14), in which formaldehyde, ammonia,

and a carbonyl compound with an α-acidic proton react to form β-amino carbonyls. The mechanism is not complicated at all; acid catalyzed iminium formation is followed by addition of the enol (or any carbonyl compound with an acidic proton). In the following paragraphs, the most important MCRs will be presented in more extensive detail.

1.2.1) An historic overview: The Strecker reaction

Generally accepted as the first ever MCR is the Strecker 3 component reaction (S-3CR) published in 1850 (15). Here, acetaldehyde, ammonia, and hydrogen cyanide were combined to give the α-aminoacid alanine after hydrolysis of the cyanide group. Typically, substrates for the Strecker reaction are primary and secondary amines, aldehydes and ketones.

form an imine, also known as a Shiff base. Imines can be seen as the nitrogen-analogues of carbonyls, and just like carbonyls, upon protonation the C=N double bond becomes more electrophilic. The cyanide can now react as a nucleophile, affording the α-aminonitrile.

Scheme 4. The proposed mechanism of the Strecker reaction: cyanide attacks the iminium

ion to afford α-aminonitriles.

According to the mechanism proposed (16), the oxo compounds are condensed with the amine in the presence of a cyanide source. The first step is the formation of the hemiaminal, which condenses to

As shown in scheme 4, these products have proven to be very versatile intermediates, and are considered important pharma- ceutical building blocks (17).

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15 | P a g e Most apparently, α-aminonitriles are

the precursors in the synthesis of α-aminoacids. However, α-amino-nitriles possess various modes of reactivity, and in such a way, the S-3CR can afford a large variety of different products, generated in a rapid, step and atom-economical fashion. Besides the obvious reactivity arising from the electrophilicity of the nitrile carbon

2, nucleophilic addition reactions

are also possible upon loss of cyanide in certain conditions. In this manner, α-aminonitriles can behave like masked iminium ions 3, yielding α-substituted amines.

In contrary to the electrophilic character of the iminium carbon atom, this species can perform a wide range of nucleophilic reactions, as the negative charge is partially stabilized by the nitrile. The most obvious example of this reactivity is the von Miller-Plöchl synthesis (18) (1898); where diarylated α-aminonitrile performs a 1,4 addition on α,-unsaturated carbonyl, yielding pyrroles. This reaction clearly demonstrates how α-aminonitriles can be used for the construction of heterocycles, a class of compounds fundamentally important to the biochemistry of life.

Scheme 5. Formation of various heterocycles by MCRs: A. The Hantschz synthesis of dihydropyridines. B. The B-3CR gives access to dihydropyrimidones. C. The

Bucherer-Bergs 4CR affords the hydantoin product.

However, in a basic medium, α-aminonitriles are also capable of losing the α-proton, which results in the reversed polarity of a α-amino carbanion 4.

As a matter of fact, many MCRs are employed to afford heterocycles. The first of these was the Hantzsch synthesis of dihydropyridines (19), discovered in 1881.

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16 P a g e | Here, an aldehyde and 2 equivalents

of β-ketoester are condensed in the presence of ammonia. The well-known Biginelli reaction (B-3CR) (20), developed in 1891, is related to the Hantzsch synthesis: reacting an aldehyde, urea, and β-ketoester dihydropyrimidones are obtained. This scaffold is still widely used in drugs serving as calcium channel blockers and antihypertensive agents (21). Both of these procedures are based on simple enolate/aldol type chemistry, but rather like the Strecker reaction, the first step is the condensation between the aldehyde and urea.

Another striking example is the Bucherer-Bergs (BB-4CR) reaction, found by the Theodor Bucherer in 1929 (22). The reaction is really just an extension of the S-3CR with carbon dioxide, and considered as the first ever 4-component reaction. The reaction involves ketones, potassium cyanide and ammonium carbonate, and affords the hydantoin scaffold, a valuable target associated with extensive biological activity (for instance, hydantoin derivatives are used as antiepileptic drugs (23).

1.2.2) The Passerini reaction: the first MCR with isocyanides

Another MCR that made a significant impact was established by Mario Passerini in 1921 (24), in Florence, Italy, and is described as the formation of α-acyloxo-carboxamides 5 from carboxylic acids, an oxo-compound, and isocyanides in a single step. The Passerini reaction is considered as the first MCR with isocyanides, and the product belongs to a class of compounds frequently occurring in many natural products.

The mechanism of Passerini reaction, outlined in scheme 7, is very interesting and has been the subject of much discussion. In view MCRs being described as essentially cascades of elementary steps, the ionic mechanism seems quite obvious. Here, the acid component plays an important role: as the first step is protonation of the aldehyde, which is followed by nucleophilic attack of the isocyanide and the

Scheme 6. Historically the Passerini reaction is the first MCR with isocyanides. The reaction is another example of

excellent atom economy, as all the atoms in each of the three components are incorporated in the final product.

subsequent addition of the carboxylate. In the past this part of the mechanism has been subject of much debate: But since the reaction performs better in aprotic solvents,

R1 O O H N O R3 R4 O O R3 H + PASSERINI_PRODUCT R2 + R1 O R2 C N R4 5

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17 | P a g e the more plausible suggestion is that

the starting materials react in concerted fashion. Although this is much in contrary with the more classical view on MCRs, in the case of the Passerini reaction this hypothesis complies very well with kinetic investigations (25). Initially, there is the formation of a hydrogen bonded adduct between the oxo-compound and the carboxylic acid, followed by the formation of an intermediate which also incorporates the isocyanide.

The P-3CR has an incredibly large substrate scope. There are however some limitations: regarding the oxo-compounds, sterically hindered ketones are obviously exceptional, but less electrophilic aldehydes can also prove rather unreactive. Particularly interesting are however the bifunctional components, which can yield cyclic variations of the P-3CR as well. These types of starting materials can afford a rich variety of different scaffolds, and some of these products are depicted in scheme 8.

Scheme 7. The mechanism of the Passerini reaction has been extensively debated upon: suggested is a concerted instead of an ionic mechanism.

This intermediate then generates the final product via an intramolecular rearrangement called the Mumm rearrangement. Each step is believed to be irreversible, which favorably drives the process towards the final product side.

For example, α-chloroketones are prone to ring closure after formation of the P-3CR product, yielding α-epoxyamides 6 (26). The same happens when the oxo-compound also has a carboxyl function. Here, the product is a lactone ring 7, and the size of the ring will depend on the distance between the two functional groups (27).

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18 | P a g e An early example of varying the acid

component dates back to 1931 (28), using hydrazoic acid to form tetrazoles 9. And a more recent intermolecular version of the P3CR was described by Kobayashi et al (29), employing 1-(2-isocyano-phenyl)-pyrrole as a bifunctional isocyanide component: The pyrrole CH in 2-position also carries a formally acidic function performing the ring closure, yielding pyrrolo-[1,2]quinoxalines 8.

One such an example is the synthesis of the alkaloid Hydrastine, which is used as a haemostatic drug. J. R. Falk

et al. achieved the synthesis of the

important intermediate depicted in scheme 10 by means of an intramolecular P-3CR reaction (30). Another interesting publication is the synthesis of the natural product Azinomycin. The Passerini product is easily recognizable within the complex molecular structure, which contains several functionalities

Scheme 8. The intramolecular P-3CR with bifunctional components yields various

(heterocyclic) products.

The versatility of the P-3CR makes it especially useful in a combinatorial approach, as the screening of highly diverse libraries has even become the preferred method of exploring chemical space. In this manner, the P-3CR reaction has played an important role in the discovery of novel drugs containing the α-acyloxocarboxamides moiety. The P-3CR has also made some valuable contributions in the total synthesis of several pharma-ceuticals. Literature reports numerous applications that demonstrate the efficient simplicity of MCRs over traditional synthesis.

suggesting potent anti-tumor activity (31, 32).

Nowadays the Passerini reaction is still being actively explored. Much progress in asymmetric catalysis has even provided some advantageous enantioselective procedures (33). However, since its invention in the early 1920’s, the discovery of new MCRs has slumbered for decades. It was not until the isocyanide reagents became more available that the field was boosted enormously by the introduction of Ugi reaction, which marked the start of a new era in multicomponent chemistry.

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19 P a g e | Scheme 9. The Passerini product is easily recognizable in the important intermediate

towards (+/-) Hydrastine, and the possible anti-tumor agent Azinomycin A,B.

1.2.3) Trademark versatility: the Ugi 4 component reaction

The Ugi reaction, found by Ivar Ugi in 1959 (34), is undoubtedly the most famous and most versatile of all isocyanide based multi-component reactions (IMCRs). In the classical Ugi reaction an aldehyde or ketone, amine, carboxylic acid, and isocyanide react to form a α-acyl aminoamides 10.

the amine can now attack the carbonyl group of the acid component, leading to the stable Ugi amide product. Normally, chemical reactions are confined by a certain substrate scope. But for the Ugi reaction there seem to be almost no limitations; and only few inputs do not.react.

Scheme 10. The Ugi 4 component reaction. Again, the first step is the formation of the electrophilic iminium ion that adds to the carbon atom of the isocyanide. The nucleophilic carb-oxylate anion can now add to form the α-adduct, an intermediate that can be seen as the nitrogen analogue of an acid anhydride. Just like in the Passerini reaction, the final step is the intramolecular Mumm rearrangement (35): The nitrogen lone pair originating from

Normally, chemical reactions are confined by a certain substrate scope. But for the Ugi reaction there seem to be almost no limitations; and only few inputs don’t react. It was soon recognized the U-4CR is variable like no other, as the Ugi product has at least four diversity points. Especially by varying the acid or the amine component, not only products carrying many different substituents, but also a rich variety

Me OMe O O O H N O N H O R N HO AcO O O O N H O O MeO MeO

(+/-) Hydrastine Azinomycin A,B

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20 P a g e | Scheme 11. The proposed mechanism for the Ugi reaction.

of different scaffolds, like tetrazoles

18 or hydantoins 14, can be

generated (36). Moreover, the U-4CR can actually be seen as a union of the 3CR and P-3CR (U-4CR = S-3CR  P-3CR), and it virtually covers the complete substrate scope of both reactions, including educts like disubstituted amines, acids, carbon dioxide, water 13, thiosulfate, hydroxylamine 11, hydrazines 12, azides, (thio)isocyanates, and many other related compounds.

Most of these variations on the U-4CR have yielded interesting medicinal building blocks and pharmaceutically relevant mole-cules. For instance, the renowned  -lactam antibiotics 16 are an early yet very important application, starting from -aminoacids as the bifunctional component (37a,b). Another post cyclization strategy employs anthranilic acids to afford the much desired benzodiazepines

15, better known as the prescribed

Scheme 12. The Ugi reaction is highly versatile: generating a huge variety of different

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21 P a g e | pshyco-active tranquilizer Diazepam

(Valium) (38). There are even variations on the U-4CR that carry their own name, such as the Ugi-Smiles reaction 17, where the acid is replaced by p-nitrophenols, and the Smiles rearrangement is irreversible step (39).

toxic Tubulysin analogues (41). To provide for the 1,4 piperazine moiety in Crixivan (42), an HIV protease inhibitor supplied by Merck, a special adaptation of the U-4CR is required. Yet another example is provided by Matsuda et

al., who synthesized the potent

antibacterial natural product

Scheme 13. Examples of applications of the U-4CR in the total synthesis of various

interesting compounds.

In view of its versatility, the Ugi reaction offers expansive synthetic possibilities. Moreover, the potential for preparing unnatural and unusual aminoacids and polypeptides was therefore recognized almost immediately; as reacting pre-condensed Schiff bases with unprotected amino acids and isocyanides in principle leads to the one-step protecting group-free (oligo)-peptide synthesis (40). Likewise, the Ugi reaction has seen numerous applications in the total synthesis of important pharma-ceuticals and natural products as well. For example, Wessjohan et al. employed the U-4CR in the synthesis of highly cyto-

Muraymycin, using the U-4CR as the key-step to construct this complex molecule (43).

Even though the Ugi reaction is still being actively explored today, its chemistry was actually only moderately used until the mid 90’s. Especially in the last few decades, the field has experienced a wave of renewed interest, initiated by Dömling and Ugi himself, introducing the MCRs of seven and more components. They carried out a one-pot synthesis, combining the U-4CR and the Asinger reaction (A-3CR). Here, the Asinger product functions as the imine in the Ugi reaction, yielding the thiazolidine 19

Scheme 14. Some complex products derived from the one-pot synthesis of 7 -or even 8

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22 P a g e | product in a reasonable yield (44).

Subsequently, a number of MCRs with seven or even more components were established by the unions of the U-4CR and other reactions. These types of procedures are called tandem, cascade, or

domino reactions. The group of Orru

et al, even achieved a 8CR, composed of two novel 3CRs and the U-4CR (45), affording a highly complex product 20 in a one-pot synthesis. The difficulty with this technique is that as the number of components increase, so do the number of

competing side reactions. Nevertheless, there are some highly advantageous procedures in terms of their selectivity for the desired product, resulting in good yields and little byproducts. These methodo-logies are an intriguing way to access molecular complexity and diversity at the same time. Therefore, they are illustrative of how the field of multicomponent chemistry has reached such a high degree of sophistication, and of how most MCRs have been well extended and refined along the way.

1.2.4) Modern day MCRs: The Gröebke Blackburn Bienyamé reaction

After the introduction of the Ugi reaction only few novel MCR have been discovered. Nonetheless there are some notable examples; such as R. Bossio and his research group (46a,b), who published many new syntheses of unusual molecules by new types of isocyanide based MCRs. However, among the most valuable contributions ever since is the Gröebke Blackburn Bienyamé reaction (GBB-3CR) (47a,b,c).

relevant fused N-bridgehead

heterocyclic compounds 20. These types of scaffolds are known to exhibit a wide range of biological activities and are considered valuable targets, found in several bioactive compounds and drug like molecules (48). Just like in the Ugi reaction, the GBB-3CR is considered to proceed via non-concerted mechanism. But in this case, the intramolecular cyclization

Scheme 15. An aldehyde, isocyanide and 2-aminopyridines can produce the

therapeutically interesting N-fused bicyclic imidazole scaffold.

The reaction was described by the three independent research groups in 1998, and involves readily available aldehydes, isocyanides and heterocyclic amidine building blocks in the synthesis of therapeutically

generates a new ring system rather than the open-chain peptide-like Ugi product. The first step is the in situ formation of an iminium species, followed by an interesting formal [4+1] cycloaddition of the

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23 P a g e | Scheme 16. The proposed mechanism of the Gröebke Blackburn Bienyamé (GBB-3CR)

reaction.

isocyanide. Finally, rearomatization by a subsequent [1,3] H-shift yields the imidazo(1,2-α) annulated heterocycle as the final product. The GBB-3CR has been well appreciated, with the scope of this reaction being the subject many studies (49): Similar to other MCRs described in this text, the reaction is accelerated by a wide range of catalysts, and can be performed under microwave irradiation, and/or even solvent free conditions. In line with the above the synthesis of even more complex scaffolds can be achieved via various post modification reactions. These include cyclizations, nucleophilic substitutions, and further MCRs as well. In this manner, the GBB reaction has contributed to diverse applications in combinatorial and medicinal chemistry.

Moreover, the Ugi, Passerini, other MCRs have generated many products that are of great use in drug discovery. MCRs have increased in popularity, and generating libraries of target compounds is now an established

methodology within the

pharmaceutical industry to screen new drug candidates. There are still many interesting developments ongoing, which proves that this field of research is far from exhausted, and remains a promising part of chemistry for years to come. In the last few decades much progress has already been made, and some excellent reviews have summarized the most remarkable synthetic achievements (50a,b,c). However, since the chemistry of MCRs is so versatile, there are still enough possibilities expected for much new chemistry to be…discovered.

1.3) The chemistry of isocyanides

It was Lieke who first discovered Isocyanides in 1859, and made a derivative for the first time from allyl iodide and silver cyanide (51). At the time, isocyanides were not recognized at such and believed to be nitriles. Only much later, in 1950,

Rothe discovered the first naturally occurring isocyanide in the

Penicillium notatum Westling (52).

This was later used as the antibiotic Xanthocillin. Ever since, many more interesting compounds containing the isocyanide functionality have

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24 | P a g e been isolated from the cells

predominately marine species (53a,b).

Isocyanides are an extraordinary functional group, and their unique reactivity is of tremendous importance in multicomponent chemistry. Compared to nitriles, they are connected to an alkyl fragment via the nitrogen instead of the carbon atom.

unusual ability to react as both nucleophile and electrophile at the isocyanide carbon atom. The key difference in reactivity between these two isomeric functional groups is demonstrated by their molecular orbitals. On both, a nucleophile will attack the carbon atom because it has the largest coefficient in the LUMO (* orbital).As for nitriles, the electrophile interacts with nitrogen atom, because the more

Scheme 17. A. The resonance structures of isocyanides functional group. B. Isocyanides

are known for their versatile reactivity.

Isocyanides are best described by their two resonance structures shown in Scheme 17; a complete review by Ugi (54) summarized the experimental evidence in support of the polarized triple bond structure. But much like carbenes, they are a stable functional group of formally divalent carbon, as where the triple bond of the dipolar zwitterion accounts for their linear structure. Both resonance forms contribute to the structure and account for their carbene-like reactivity. But where nitriles and other functional groups react with nucleophiles and electrophiles at different centers, isocyanides possess the

element has a higher density coefficient in the HOMO (CN 

orbital), much like carbonyls. However, isocyanides behave differently, as the HOMO is a lone pair in an sp-hybridized ( orbital), which is unusually high in energy as it is only developed on the more electropositive terminal carbon atom. And so, both nucleophile and electrophile will attack the same terminal carbon. It is also possible to alkylate isocyanides by threating isocyanides with a base. Easy radical formation is another trademark, useful for various cyclization strategies. However, their most valuable synthetic property is to react with both nucleo -and

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25 | P a g e electrophiles at the same terminal

carbon atom. The isocyanide will usually do so in a sequential fashion; It can first react with an electrophile, after which the isocyanide carbon becomes much more electrophilic. It can then undergo addition from a

nucleophile, and in this way an  -adduct is generated. This rare ability is by far their most important synthetic property, which is applied very conveniently in most MCRs based on isocyanide reagents.

1.4) Tr-NC as a novel isocyanide reagent

The advantageous synthetic possibilities of isocyanides are widely associated with MCRs. Moreover, the most famous MCRs are in fact dominated by isocyanide-based reactions. Considering their reactivity, the isocyanide based MCRs are quite similar from a mechanistic point of view: in all of the above, the isocyanide attacks an electrophilic species leading to a nitrilium ion, which is followed by addition of a nucleophile if present.

In the U-4CR, the carboxylate anion adds to the α-adduct, whereas in the Gröebke reaction the lone pair on the pyridine nitrogen atom functions as the nucleophile. All of these reactions share the nitrilium ion as a common intermediate, from which multiple pathways towards various products are possible, as shown in scheme 18. However, in the classical Strecker reaction the cyanide source is HCN, and the reaction requires an additional feature if it is to be

carried out with an isocyanide.

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26 | P a g e Now, the substituent of the

isocyanide would have to dissociate from the intermediate to generate the α-aminonitrile. For this purpose, the R (-alkyl) group should favorably form a stable tertiary carbocation, which then recombines with the solvent. We envisioned the triphenylmethyl (or trityl) group should be perfectly suitable, and therefore, we set out to explore the reactivity of triphenylmethyl isocyanide (trityl isocyanide: Tr-NC) as novel isocyanide reagent in the Strecker 3CR, and other landmark MCRs as well.

Conveniently, Tr-NC is a stable, odorless, and easy to handle white solid, which greatly enhances the safety aspect of these procedures. This is much in contrast with experiments employing the classical

cyanating agents, or conventional isocyanides. Moreover, their reputation alone has probably also suffered the employment of MCRs by assuming their poor availability, stability, toxicity, and not to mention their unpleasant odor. From a green perspective these are obviously serious drawbacks, and since the implementation of safe and environmentally friendly organic reactions has become of such an importance, the development of methods that avoid the use of toxic reagents or transition metal-based catalysts remains an important strategy within this ﬁeld. This implies it is still desirable to search for a safe and practical isocyanide reagent, and develop efﬁcient methods for their employment in MCRs.

1.5) Aim and outline

Apart from theoretical studies considering the isonitrile–nitrile isomerization, the trityl group is known as a protecting group in peptide chemistry (55a,b). The utility of Tr-NC has also been explored in an effort to prepare nitriles from lithium aldimines (made by adding alkyllithium reagents to isocyanides) via an isocyanide metal exchange reaction (56a,b). But to the best of our knowledge, the synthetic possibilities of Tr-NC as a reagent in MCRs are yet to be explored. And so, Tr-NC could be considered a novel reagent, at least in MCRs. Therefore, the signiﬁcant features of this research are the use of this new reagent as a safe alternative to replace the traditionally toxic and volatile cyanating agents, and the simplicity of the synthetic procedures, which also avoid use of

metal catalysts or other hazardous chemicals. Aiming at an efficient general protocol, we employed Tr-NC to generate large variety of different MCR products in simple and straightforward manner. Since the triphenylmethyl group is not expected to be of special interest in any particular MCR product, we also explored the ability of Tr-NC to function as a convertible isocyanide. As further derivatization is offered by simple follow up reactions, the synthesis of secondary products implies an even greater versatility. However, our first requirement is to develop a scalable synthesis of Tr-NC from commercially available starting material, which is described in the first part of the results chapter. With the new reagent in hand some optimization studies were performed, in order to obtain

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27 P a g e | Scheme 19. The versatile trityl isocyanide (Tr-NC) can yield a large variety of different

MCR products.

reaction conditions suitable for employing Tr-NC in various MCRs. At this stage, we also planned to investigate the mechanism of the very old, yet highly efficient Strecker reaction with Tr-NC. Next, the P-3CR, U-4CR, GBB-3CR, and various deprotections were carried out to

generate a diverse library of various scaffolds. In this way, the aim of this project is to demonstrate how a library of various MCR products can be afforded by making only slight adjustments to a safe and straightforward general procedure employing Tr-NC.

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28 | P a g e

RESULTS

_

2.1) Isocyanide synthesis

During this project the versatile reactivity of Tr-NC is explored in various MCRs. Generating a library of many different products means that a scalable synthesis of the starting material is very important, as significant amounts of Tr-NC are required. Isocyanides were already made early on by Lieke in 1859, who produced them by reacting allyl iodides with silver cyanide. However, due to the poor substrate scope of this reaction only few isocyanides were prepared.

of isocyanides was only moderately explored for centuries to come. A new approach provided by Ugi in 1959 eventually rendered the isocyanides more readily available via the dehydradation of formamides by inorganic dehydrants such as (di/tri) phosgene or surrogates and a tertiary amine as base (58). Nowadays, this remains the preferred methodology to obtain isocyanides, even though many more preparations have been described ever…since.

Scheme 20. There are various ways to synthesize isocyanides. The dehydration of

formamides is usually the method of choice.

Hoffmann and Gautier then further developed the classical isocyanide synthesis, as Gautier first discovered the isomeric nature between nitriles and isocyanides, and Hoffmann developed the carbylamine method: reacting primary amines with potash and chloroform to form isocyanides (57a,b). However, this reaction remained complicated and low yielding, although much better procedures are available today. The problem however partly lies in the fact that the isocyanides are not easily separated from the accompanying nitriles. This, and their foul smell meant the chemistry

The synthetic route towards Tr-NC is depicted in scheme 21; a two-step sequence of formylation – dehydration was carried out starting from triphenylmethanol 1 (R=H), which is commercially available. The formylation was achieved by dissolving triphenylmethanol and formamide in acetic acid and acetic anhydride. A catalytic amount of sulfuric acid is required for the reaction to proceed, and the N-trityl formamide product 2 is then obtained in almost quantative yield of 96% on a gram scale. Because the trityl group is lost in the case of the S-3CR, we also carried out the

R X + AgCN R N C + AgX

R NH2 + CHCl3 + KOH R N C + +

R NHCHO + PHOCl2 + NEt3 R N C + PHO2 + Cl

H2O NHEt3 KCl 3 3 3 Lieke 1859 Hofmann 1870 Ugi 1959

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29 P a g e | Scheme 21. The dehydration of the formamide affords a scalable synthesis of trityl

isocyanide.

formylation reaction starting from Tr-OMe to evaluate the recycling possibility. The yield is lower (61%) but does indicate that it is possible to partly regenerate the trityl isocyanide.

For the dehydration step several reagents were tested, but the use of POCl3 and triethylamine proved

most convenient in terms of yield and execution of the work-up procedure.

The trityl isocyanide 3 is easily isolated as an off-white to pale yellow solid in a 88% yield on a gram scale, which can be considered as an important result regarding further experiments.

The synthesis of isocyanides has to carried out at low temperatures and under dry conditions. This is done to prevent the intermediate formed from reverting back to the formamide.

Scheme 22. The dehydration of formamides is carried out at low temperatures in order to

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30 P a g e | An appropriate base is also required,

in order to neutralize the HCl released during the reaction. The presence of any acid could otherwise catalyze both the polymerization and isomerization of the isocyanide, as depicted in scheme 22. The ability of isocyanides to isomerize was reported as early as 1873, and is well known to be catalyzed by Ag+

ions (59). This rearrangement has been the subject of several theoretical studies as well, and speciﬁcally the tritylisocyanide to tritylcyanide transformation has been examined in more detail (60). These experiments indicate that the rate of the isomerization is significantly faster compared to aliphatic isocyanides. Even though this process is normally very slow at room temperature in typical organic solvents, more recent studies have

shown that the isomerization process proceeds much faster in polar solvents such as acetonitrile. Very striking is the observation that no detectable isomerization of Tr-NC was observed in nonpolar solvents such as cyclohexane. However, the polarity of the solvent, and particularly the presence of salts or acidic catalysts have a significant influence on accelerating the rate of the iso-nitrile isomerization. The isomerization of Tr-NC is likely more favored by the formation of the stable yet reactive carbocation, which can be trapped by either the solvent, cyanide, or another isocyanide. This intermediate then dissociates once more to give trityl cyanide and yet another cation, so it is important to realize that the presence of acid even catalyzes the reaction…(61).

2.2) The Strecker reaction

With a solid and scalable isocyanide synthesis in hand, we were eager to explore the reactivity of Tr-NC in the S-3CR. However, in the classical Strecker reaction HCN is used, whereas this procedure would employ an isocyanide as the cyanide source. Nowadays the S-3CR has become a proven methodology for the preparation of α-aminonitriles, but highly toxic cyanides such as TMSCN are still commonly used. And although more recent research efforts have further advanced the Strecker reaction into a more clean and efficient synthetic protocol, the usual cyanating agents like TMSCN, HCN, NaCN, KCN, CuCN, and Zn(CN)2,

are toxic and hazardous chemicals, unsafe to use on a practical scale. There are however still many encouraging results living up to the demand for greener synthetic

technologies, as the Strecker reaction performs well in bio-degradable and eco-friendly solvents, in H2O, and even solvent

free conditions. The reaction is also favorably aided by transition metal catalysts (62, 63), and the use of several heterogeneous acid catalysts have also been explored: they are easily separated from the reaction mixture, and under microwave conditions the reaction times were seriously reduced (64). There are even some advantageous methods to obtain the Strecker product enantioselectively, as described by Barbero et al (65), using their chiral derivative of o-benzene disulfon-imide as asymmetric acid catalysts. On the other hand there are only few reports that avoid the use of a highly toxic cyanide source at all;

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31 | P a g e potassium hexacyanoferrate appears

to be the safest reagent that can be used in a Strecker reaction (66), but it is important to note that this reagent is in fact prepared from HCN, so it does not eliminate the issue of cyanide toxicity completely. If however, the novel trityl isocyanide reagent proves to be stable under the employed reaction conditions, this procedure could

truly enable cyanide-free methodology to perform Strecker reactions. The reason is that the triphenyl group can dissociate from the isocyanide, but possibly does so only after the formation of the nitrilium ion, releasing the relatively stable tertiary carbocation and the Strecker product, without the formation of any cyanide during the course of the reaction.

2.2.1) Optimization of the reaction conditions In the Strecker reaction with trityl

isocyanide, the product is formed according to a sequence of elementary chemical reactions like in most other MCRs. The performance of this reaction is therefore clearly dependent on realizing advantageous reaction conditions, and the solvent, temperature, concentration, type of starting materials and possible catalysts are thus important considerations.

more susceptible to nucleophilic attack of the isocyanide. After the formation of the nitrilium ion, the trityl group can dissociate from the intermediate to release the  -minontrile and recombine with the solvent. The acid additive is of significant importance, and from our preliminary results we immediately discovered the acid is in fact indispensable. As expected, there is competition with the U-4CR when

acetic acid is used.

Scheme 23. The mechanism of the S-3CR with trityl isocyanide. The trityl group is cleaved

and combines with the solvent.

Like in the classical S-3CR the first step is the formation of an imine, which is (essentially) an equilibrium. Then, an acidic additive is used to protonate the imine, making it much Interestingly, if much stronger acids are used the Strecker product is

favored, but the formation of the U-3CR is also observed. The formation of the U-3CR product is explained by the presence of water arising from the condensation reaction, which can compete for the nitrilium ion, as depicted in scheme 23.

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32 | P a g e However, the point is to design an

MCR that proceeds mainly towards the envisioned product and yields as little side products as possible.

room temperature. Although imines are known to be easily hydrolyzed, N-benzylideneaniline is among the few conveniently isolated as a brown solid, and is used to perform the optimization reactions summarized in table 1. From the first experiments it became immediately

No. Cat. Solvent Additive Imine Strecker “Ugi 3CR” TrOR Others 0a _none _DCM/EtOH

1:1 none 100% trace 0% trace - 1a _{AcOH 1 equiv} _DCM/EtOH

1:1 none 60% 20% 0% 20% U-4CR20%

2a _HClO₄ _MeOH _none _0% _90% _7% _106% _no

3a _PhO)₂_P(O)OH _MeOH _none _0% _83% _5% _85% _little

4a _MeSO₃_H _MeOH _none _0% _84% _5% _100% _~10%

5a _PTSA _MeOH _none _0% _90% _5% _110% _little

6a _PTSA _EtOH _none _0% _88% _2% _110% _little

7a _PTSA _DCM/EtOH

1:1 none 0% 91% 5% 100% little

8 PTSA EtOH none 6% 60% 18% 40% A lot

9 PTSA DCM/EtOH

1:1 Na2SO4 6% 65% 15% 50% A lot 10 PTSA DCM/EtOH

1:1 3Å MS 2% 90% 0% 95% little

Standard conditions employ benzaldehyde (20 µL, 0.2 mmol), aniline (18 µL, 0.2 mmol) and trityl isocyanide (65 mg, 0.22 mmol) and are stirred at RT for 4 hrs according to general procedure 3.2.1. Yields based on crude 1_{H-NMR with mesitylene external standard. a = reactions were}

performed with N-benzylideneaniline as the starting material.

Table 1. Optimization of the reaction conditions for the S-3CR with Tr-NC. Therefore we set out to perform

some optimization experiments, in order to establish conditions favoring the Strecker product. In these experiments the model system is the reaction between aniline, benzaldehyde, and a slight excess of Tr-NC. The reactants are simply dissolved in a [0.5 M] solution containing 10 mol% of acidic additive, and stirred for 4 hrs at

evident that without any additive the reaction is very slow, and the imine barely reacts. The use of strong proton donors gave much better results (entry 2-4), with the TrOEt formation nicely corresponding to the yield of S-3CR product. The reaction is usually very fast and complete within 2 hrs. Perchloric acid (HClO4) and

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33 | P a g e among the most advantageous

candidates (entry 2 and 5). However, PTSA is an easy to handle solid and the formation of the Ugi –and other byproducts are minimized. The solvent is seemingly not very crucial, and a 1:1 mixture of DCM:EtOH offered improved solubility of the isocyanide at room temperature. Most important is the pre-formation of the imine (entry 6 vs. 8), which is indeed easily hydrolyzed; the starting materials are repeatedly encountered in the crude of the reaction mixture, and there are also a lot more side products. As a counter-measure several drying

agents were attempted. The removal of water should drive the equilibrium, and possibly diminish the formation of the U-3CR product corresponding to water addition to the nitrilium ion. 3Å molecular sieves offered the best solution; and a good yield is achieved for this model system. There is only little formation of any side products, and there are almost no starting materials left. However, as imine formation proved to be quite troublesome, it is noteworthy that a separate procedure for the more basic alkylamines still needs to be explored.

2.2.2) S-3CR reaction scope

According to the procedure described above, the benchmark S-3CR product was eventually isolated in a 85% yield. So, all of the S-3CR products are made by pre-forming the imine, and stirring the solution with 3Å molecular sieves for 20 hrs. Then, a stock solution of the acid catalyst is added, prior to the isocyanide. The reaction mixtures are stirred for 1-24 hrs and quenched with NEt3 upon

completion, following the conversion of the isocyanide by TLC. The pure products are usually isolated as colored solids, and are fully characterized by 1_H-NMR, _IR

measurements, and HRMS. Except for the combination of the conjugated heteroatomic

nicotin-aldehyde 4j with

2-methylthioaniline, most of the aldehyde inputs display good reactivity. In combination with aniline, bulky aliphatic aldehydes like 4b and cyclohexanone 4c are also tolerated. Some combinations with non-basic amines like 6-chloro-

2-aminopyride 4i, and 3-iodoaniline

4k generate the Strecker product as

well. On the other hand, the reactivity of the aromatic aldehydes is however clearly altered by their substituents. The inductive effect of strongly electron withdrawing groups, such as p-CF3 group in 4e,

obviously makes the aldehyde more electrophilic, although the effect is not very pronounced. In the case of electron donating substituents reactivity seems to depend on their position on the ring. The meta position of both methoxy groups in 3,5 dimetoxybenzaldehyde gives a good yield of 4h. However, the yields

of p-chloro 4d and

p-methoxybenzaldehyde 4g are seriously hampered. But, since these inputs were expected to display at least similar reactivity we might have to consider the influence of the aniline component in this particular case. 1_{H-NMR also indicates that}

these products are not very stable, seen the detection of the imine over time.

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34 P a g e | Scheme 24. Products of the S-3CR with Tr-NC.

As depicted in scheme 25, we suggest that the formation of the imine might be stimulated by the participation of EDGs in ortho –or

para position of the aromatic

aldehyde. This could assist the cyanide as a leaving group, but remains a suggestion yet to be further clarified.

In the case of 2-nitrobenzaldehyde

4f the isolated product is clearly

lacking the characteristic NMR signal of the -proton, and the resonance of the NH IR stretching frequency of the Strecker product. Instead, an interesting post-cyclization yields the N-oxide product, which is known in literature (67).

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35 P a g e | We suggest that the nitro group is in

close enough proximity to abstract the -proton. This intermediate is then stabilized by conjugation of the lone pare on the amine nitrogen, so eventually water can be released from the nitro group. The imine must then attack the N-oxide in the subsequent cyclization step.

In general, both aliphatic and aromatic aldehydes are accepted. Whereas for the amines, only aromatic ones are applied successfully. The aliphatic amines are much more basic, and therefore prone to complexation with strong acids, rendering them non-nucleophilic.

Scheme 26. Mechanistic suggestion for the formation of indazole-oxide product 3f. Aromaticity is now restored, and the

final indazole-oxide product 4f is in afforded in a 90% yield.

Apart from a few interesting exceptions, we have developed a convenient procedure employing Tr-NC for the synthesis of S-3CR products in good yields.

For this reason, it remains unsure whether the scope of this procedure can be expanded with aliphatic amines as well. As such, the procedure outlined in these experiments might require some adjustments in order to evaluate the reactivity of aliphatic amines with Tr-NC.

2.2.3) Mechanistic aspects

The Strecker reaction with the novel trityl isocyanide reagents has proven to be a straightforward and efficient way to synthesize a-aminonitriles. However, the possible mechanism of the reaction remains an interesting point of discussion; considering the influence of catalytic acid on the isomerization of isocyanides, the course of the S-3CR could follow two possible pathways: If the isocyanide dissociates first,

hydrogen cyanide (HCN) is generated in situ, and cyanide could actually perform the addition to the iminium ion. If however Tr-NC is stable under the reaction conditions employed, the reaction follows an Ugi-type mechanism; this means there is no cyanide present at any stage of the reaction, and Tr-NC affords a cyanide free cyanation procedure, as depicted in scheme 28. N N CN O NC HN N O O H NO2 CN N H N CN N O O H H N CN N O OH2 N CN N O S-3CR N NC N H O OH N N CN O 3f

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36 P a g e | Scheme 28. The presumably stable Tr-NC possibly enables a cyanide free cyanation

method in the S-3CR.

Encouraging results indicating the latter came from several control experiments; even though the stability of Tr-NC was evaluated in the presence of much weaker proton donors, careful analysis of NMR data revealed only trace amounts of TrOEt. Even at elevated temperatures no trityl cyanide was

detected. In addition, the formation of the U-3CR product must mean the nitrilium ion is generated. This implies that the generation of the trityl cation is only realized after the isocyanide addition, and that during the reaction there is most likely no cyanide present.

2.3) The Ugi reaction

The classic version of the U-4CR is normally described as the reaction between an amine, an oxo compound, a carboxylic acid and an isocyanide to give an  -acylaminoamide. Like other MCRs, the classical view on the U-4CR is that the reaction is essentially a cascade of elementary steps, which are all equilibria. Only more recently, extensive computational efforts pointed out the opposite; all steps are probably irreversible,

favorably driving the reaction towards the final product side, in line with the eventual intramolecular Mumm rearrange-ment. As two thermodynamically stable amide bonds are formed within the course of this interesting reaction, the driving force is the formal oxidation of the isocyanide CII

atom to the amide CIII_atom.

Therefore, the U-4CR is usually exothermic and proceeds quite fast at room temperature.

2.3.1) U-4CR reaction scope

More than 40 years of exploration have led to the experience that the Ugi reaction is usually carried out in solution, considering alcohols such as methanol or ethanol as solvents.

However, aprotic polar solvents like DMF, chloroform, or DCM also seem to work particularly well in some circumstances. The effects of the solvent and concentration of the

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37 | P a g e reactants on the reactivity of

different isocyanides has been monitored in many experiments. Moreover, the performance of the U-4CR based on different reaction conditions has been examined extensively. Experience suggests that the inductive and mesomeric effects of the reactants are the most important factor, whereas sterics have a less pronounced influence on the performance of the reaction.

solubility of Tr-NC in polar solvents we eventually chose to carry out the U-4CR in DCM, using a similar procedure as for the S-3CR.

In this particular case, pre-condensation of the amine and the oxo compound usually has a positive effect on the yields for another reason; without precondensation the Passerini reaction could otherwise be a competitive side reaction.

Standard conditions: thiophenecarboxaldehyde (18.7 µL, 0.2 mmol), p-toluidine (21.4 mg, 0.2 mmol), acetic acid (34.7 µL, 0.6 mmol) and trityl isocyanide (65 mg, 0.22 mmol) according to general procedure 3.2.2. Yields based on crude 1_{H-NMR with mesitylene external standard.}

Table 2. Optimization of reaction conditions for the U-4CR with Tr-NC. Moreover, the Ugi reaction proceeds

much better if the reactants are present in high concentrations up to 2 M. This seems to be much more important than the properties of the solvent [68]. Furthermore, the addition of Lewis acids can also be advantageous, which is under-standable considering the mechanism of the U-4CR discussed in the introduction.

Based on what is already known, some test reactions were carried out to verify if these conditions apply for the U-4CR reaction with Tr-NC as well. Indeed, higher concentrations are clearly beneficial, as seen in table 2. However, to combat the limited

Therefore, the procedure for the Ugi reaction involves adding 3 Å molecular sieves as well, and the carboxylic acid is added prior to the adding Tr-NC. An important note is to properly seal the reaction medium to prevent the volatile solvent form evaporating. Except for

5b, the Ugi products were isolated as

white solids, easily characterized by their distinctive 1_{H-NMR signal}

corresponding to the -proton. The U-4CR products are obtained in reasonable to moderate yields. Therefore it seems that Tr-NC might be less nucleophilic than other isocyanides (such as tBu-NC) often reported. However, the yields of 5a and 5e are quite comparable. No. Solvent Conc.[M] Prod.

imine Aldehyde Tr-OMe

1 MeOH 0.5 M 30% 40% 7% 8%

2 MeOH:EtOAc 7:1 0.5 M 33% 51% 10% 6%

Diversity of Trityl isocyanide as a Novel Reagent in Multicomponent Reactions