Elwin Janssen

Palladium-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by isocyanide insertion.

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.

The Efficient One‐Pot Reaction of up to Eight Components by the Union of Multicomponent Reactions

The development of synthetic methods has advanced enormously in the past decades. At present, chemists can design and prepare almost any type of molecule. The typical approach for the synthesis of (complex) molecules with predefined properties is, however, still characterized by rather inefficient step-by-step reaction sequences. The greatest challenge for synthetic chemists is therefore the improvement of overall efficiency by using atom-, step-, and energyeconomic procedures that proceed with high yield and selectivity. 2] This goal can be achieved by focusing on bond construction and functional-group compatibility in the development of new reaction types. Multicomponent reactions (MCRs) are important tools for the accomplishment of this goal as they inherently involve the formation of several bonds in one operation. As such, MCRs are convergent stepefficient procedures that can take place with remarkably high atom economy and E factors, by reducing the number of functional-group manipulations and thus avoiding the use of protecting groups. Synthetic efficiency can be further improved by combining more than one MCR. Central to this concept of the union of MCRs is the orthogonal reactivity of functional groups, which can be combined in one molecule to allow the union of different reactions if their reactivity is fully independent (orthogonal). Such strategies avoid the use of protective groups and increase efficiency in organic synthesis. The most straightforward approach to such combinations is the incorporation of a functional group in one of the inputs of the primary MCR that does not participate in the reaction, but does react as one of the components in a secondary MCR (Figure 1). In an ideal case, both reactions are combined in one pot to create a higher-order MCR. Although there are several reports of combinations of MCRs in the literature, the true one-pot combination (union of MCRs first introduced by the research group of Ugi) is generally not possible because: 1) the experimental procedure limits the scope in substrate inputs, 2) additional (de)protection steps are required, and 3) solvent incompatibilities mean that the solvent must be changed between subsequent reaction steps. Consequently, one-pot sequences of MCRs have remained limited to isolated examples by Ugi and co-workers, Portlock and co-workers, and our research group. We report herein a novel approach that combines two or more MCRs in one pot to achieve higher-order MCRs with unprecedented possibilities for complexity generation and diversification. Our strategy is based on two recently reported MCRs that display extraordinary functional-group and solvent compatibilities and lead to 2H-2-imidazolines and N(cyanomethyl)amides, respectively. In an initial approach, we focused on the introduction of a carboxylic acid function in the 2H-2-imidazoline produced by the primary MCR using an amino acid as one of the starting materials. Thus, reaction of isocyanide 1, acetone, and sodium glycinate (2) led to a clean conversion to form intermediate A (Scheme 1). After protonation of the intermediate carboxylate A (methanolic HCl, one equivalent), a one-pot combination with iPrCHO, n-propylamine, and tBuNC in an Ugi 4CR led to the isolation of 3a in 38% yield. The yield could be improved to 62% by using benzylamine instead of npropylamine, which is excellent when considering the number Figure 1. Combination (or union) of MCRs.

Synthesis of 4-Aminoquinazolines by Palladium-Catalyzed Intramolecular Imidoylation of N-(2-Bromoaryl)amidines

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type cyclization sequence

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds.

Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists.

The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pK(i) values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.

A Multicomponent Reaction Towards N-(Cyanomethyl)amides

Multicomponent reactions (MCRs)[1] have emerged as useful tools in diversity-oriented synthesis (DOS).[2] Although a number of substituents can be varied over a broad range, MCRs often access products of one specific scaffold, limiting the overall chemical diversity. To overcome this, MCRs have been combined with other types of reactions such as Diels–Alder reactions,[3] click chemistry,[4] and cyclization strategies[5] to generate structural diversity and a high degree of complexity in a minimal number of reaction steps. Our group contributed in this field by trapping 1-azadienes,[ 6] generated by the three-component reaction (3-CR) between phosphonates, nitriles and aldehydes,[7] with various reactants resulting in novel 4-CRs for a variety of heterocyclic scaffolds.[8]

Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that the reaction is compatible with a variety of functional groups. The products are obtained in high optical purity and in reasonable to good yield. We present a plausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator. To demonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences, including a phenserine analogue as a potential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5-HT6 serotonin receptor and the TRPV1 ion channel.

Multicomponent Synthesis of 3,6-Dihydro-2H-1,3-thiazine-2-thiones

Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in synthetic intermediates towards thioureas and amidines. We now report the multicomponent reaction (MCR) of in situ-generated 1-azadienes with carbon disulfide. With this reaction, a one-step protocol towards the potentially interesting 3,6-dihydro-2H-1,3-thiazine-2-thiones was established and a small library was synthesized.

One‐Pot Synthesis of N‐Substituted β‐Amino Alcohols from Aldehydes and Isocyanides

A practical two-stage one-pot synthesis of N-substituted β-amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon-carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α-halo ketones, β-halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.

Chemoselective addition of isocyanides to N-tert-butanesulfinimines.

The reaction of isocyanides with N-tert-butanesulfinimines shows remarkable chemoselectivity. β-Sulfinylamino isocyanides are formed exclusively with aromatic sulfinimines, while α-sulfeneimino acetamides result when using aliphatic derivatives. A mechanism is suggested for the latter transformation, together with an explanation for the observed selectivity. Finally, a scope study is presented for this remarkably chemoselective reaction.