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Novel Applications of Tetrazoles Derived from the TMSN3-Ugi Reaction Zhao, Ting

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Download date: 01-10-2021 Chapter 2

Review: tetrazoles via multicomponent reaction routes

Ting Zhao, Alexander Dömling, In preparation. Chapter 2

2.1 Introduction

Tetrazoles are a class of doubly unsaturated five-membered ring aromatic heterocycles, containing one carbon and four nitrogen atoms (Scheme 2.1). They do not exist in nature. The first tetrazole derivative was obtained occasionally by the Swedish chemist J. A. Bladin in 1885.1 He proposed the name “tetrazole" for this new ring structure. Base on the number of the substitution, the systems can be classified into un-, mono- and disubstituted tetrazoles.

Scheme 2.1. Tautomerism of tetrazole derivatives.

Tetrazoles consist of the highest nitrogen contents among the stable heterocycles. They have wide applications in numerous fields, such as organic chemistry, coordination chemistry, the photographic industry, explosives, and in particular, medicinal chemistry. For example, tetrazole derivatives are investigated as potential explosives and also as rocket propellant formulations based on its high-energy properties.2 Meanwhile, the nitrogen atom-rich feature could be an environmentally benign component of gas generators with a high burn rate and relative stability.3

However, the most important and fruitful applications of tetrazoles are the utilization in medicinal chemistry. Apparently, the number of publications on new drugs and promising biologically active compounds containing the tetrazole moieties increases annually. To date, Drug Bank mentioned 43 FDA approved drugs that contain 1H- or 2H-tetrazole substituents; these compounds possess hypertensive, antimicrobial, antiviral, antiallergic, cytostatic, nootropic, and other biological activities (Table 2.1).

Table 2.1. FDA approved drugs containing tetrazole moiety

Valsartan Cefotiam Cefmenoxime Cefmetazole DB00177 DB00229 DB00267 DB00274 A broad spectrum of An antibiotic with a broad activity against both gram- spectrum of activity against

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Angiotensin- positive and gram-negative A third-generation both gram-positive and gram- receptor blocker microorganisms cephalosporin negative microorganisms antibiotic

Olmesartan Cefpiramide Losatan Candesartan DB00275 DB00430 DB00678 DB00796 Antihypertensive A third-generation An angiotensin- An angiotensin-receptor agent, which cephalosporin antibiotic receptor blocker blocker (ARB) that may be belongs to the class (ARB) that may be used alone or with other of medications used alone or with agents to treat hypertension called angiotensin II other agents to treat receptor hypertension

Alfentanil Pemirolast Ceforanide Irbesartan DB00802 DB00885 DB00923 DB1029 A short-acting A mast cell stabilizer that A second-generation An angiotensin receptor opioid anesthetic acts as antiallergic agent parenteral blocker (ARB) used mainly and analgesic of cephalosporin for the treatment of fentanyl antibiotic hypertension

Cilostazol Cefamandole Cefazolin Forasartan DB01166 DB01326 DB01327 DB01342 A medication used A broad-spectrum A broad-spectrum A specific angiotensin II in the alleviation of cephalosporin antibiotic antibiotic antagonist, is used alone or the symptom of with other antihypertensive intermittent agents to treat hypertension claudication in individuals with peripheral vascular disease

Cefonicid Cefoperazone Cefotetan Tasosartan DB01328 DB01329 DB01330 DB01349

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A second- Semisynthetic broad- A semisynthetic A long-acting angiotensin II generation spectrum cephalosporin cephamycin antibiotic (AngII) receptor blocker cephalosporin with a tetrazolyl moiety that is administered administered intravenously or intravenously or intramuscularly intramuscularly

Pranlukast 2-(2f-Benzothiazolyl)-5- (5r,6s,7s,8s)-5- Nojirimycine Tetrazole DB01411 Styryl-3-(4f- Hydroxymethyl- DB02471 Phthalhydrazidyl)Tetrazoliu 6,7,8-Trihydroxy- A cysteinyl m Chloride Tetrazolo[1,5- leukotriene a]Piperidine receptor-1 DB01897 antagonist to DB02294 antagonize or reduce bronchospasm caused

Mercaptocarboxylate 1-(5-Chloroindol-3-Yl)-3- N,N-Bis(4- 7-((Carboxy(4- Inhibitor Hydroxy-3-(2h-Tetrazol- Chlorobenzyl)-1h- Hydroxyphenyl)Acetyl)Amin DB02706 5-Yl)-Propenone 1,2,3,4-Tetraazol-5- o)-7-Methoxy-(3-((1-Methyl- DB03118 Amine 1h-Tetrazol-5- DB04037 Yl)Thio)Methyl)-8-Oxo-5- Oxa-1-Azabicyclo[4.2.0]Oct- 2-Ene-2-Carboxylic Acid DB04342

3-(4-Phenylamino- Latamoxef N-(1,4-Dihydro-5H- Phenylamino)-2- DB04570 tetrazol-5-ylidene)-9- (1h-Tetrazol-5-Yl)- oxo-9H-xanthene-2- Acrylonitrile Broad- spectrum beta- sulfonamide lactam antibiotic DB04430 DB04698

The successful insertion of tetrazoles used as components of materials for medicinal purposes is supported by the concept of bioisosterism which was initially defined by Friedman.4 Bioisosterism has been identified as one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. And it also is classified as either classical or nonclassical. Carboxylic acid functional group is an important constituent of a pharmacophore. However, faced to the obvious drawbacks, including metabolic

Page | 12 Review: tetrazoles via multicomponent reaction routes instability, toxicity and limited passive diffusion across biological membranes, medicinal chemists always investigate to employ carboxylic acid bioisosteres to avoid part of these disadvantages and meanwhile remain the desired attributes of the acid moiety. 1,5-Disubstituted tetrazoles are effective bioisosteres for cis-amide bonds in peptidomimetic, and 5-substituted tetrazoles are surrogates for carboxylic acids.

The introduction of the tetrazole ring into a molecule of an organic substrate quite often leads not only to an increase in the efficacy but also to an increase in the prolongation of drug action. These improvements are all based on the structural features of tetrazole ring. First of all, both carboxylic acids and tetrazoles exhibit a planar structure. However, tetrazoles show both aliphatic and aromatic properties and have the similar pKa values with the corresponding carboxylic acids (4.5 – 4.9 vs 4.2 – 4.4, respectively). The ability to delocalize the negative charge tetrazoles over five atoms resulting in a reduced per atom charge could help to penetrate through biological membranes and be favorable for a receptor–ligand interaction, or may complicate the contact, depending on the local charge density available at the interface. Secondly, same like their carboxylic acid counterparts, tetrazoles are ionized at physiological pH (≈7.4), but are almost 10 times more lipophilic than the corresponding carboxylates which could facilitate further a drug molecule to pass through cell membranes. Thirdly, the high- density of nitrogens in tetrazoles could provide more opportunities to form hydrogen bonds with receptor recognition sites which explain the sometimes enhanced binding affinity. Last but not least, tetrazoles are resistant to many biological metabolic degradation pathways which are conjugation reactions to form β-N-glucuronides, a metabolic fate that often befalls aliphatic carboxylic acids to form o-β-glucuronic acid conjugates.

Thus, effective and time-saving synthetic methods are important to build up libraries of tetrazoles for high-throughput screening and other low throughput pharmaceutical research.

Multicomponent reactions (MCRs) are chemical reactions where more than two compounds react to form a single product in a sequence with several descriptive features, such as atom economy, efficiency and convergence. Ugi and co-worker, firstly reported the use of HN3 replacing carboxylic acid in the Passerini and Ugi reactions to form tetrazole derivatives in 1960s. And since then, numerous advancements were published on the synthesis of tetrazoles via multicomponent reaction. In this review, we summarize the currently mostly used synthetic routes for the preparation of tetrazole derivatives through non-multicomponent reaction. Our focus, however is on the use of multicomponent reactions for the preparation of substituted

Page | 13 Chapter 2 tetrazole derivatives. We would like to reveal specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and estimated prospects for further research in this field. Moreover, we believe the structural understanding of this scaffold class and its 3D conformations is of uttermost importance for the process of understanding and predicting binding properties of compounds towards its receptor, e.g. in structure-based drug design and in a wider sense to predict properties of specific molecules. Therefore we will also discuss in addition to synthetic accessibility the 3D solid- state conformations of tetrazole derivatives as well as some tetrazoles cocrystallized in their protein receptors. Thus, this review covers the literatures in this area reported to date as exhaustive as possible.

2.1.1 Structural biology of tetrazoles

Up until 10th April 2016, there are 112 tetrazole cocrystal structures present in the protein data bank (Table 2.2). The PDB files can serve as excellent resources to study preferential binding poses and interactions of the tetrazole moiety towards the receptors.5-74 These can be used to understand the bioisosteric features towards the carboxylic acids and to elaborate similarities and differences and to develop guiding rules when the use tetrazole scaffolds is appropriate. Understanding typical binding poses of tetrazoles in receptor pockets can help in the structure-based design of novel inhibitors. Some selected examples are discussed as follows.

Table 2.2. Protein structures with cocrystallized tetrazole moieties

1A8T5 1QS49 1SL311 1V4062 Bacteroides Fragilis the HIV-1 Integrase P1 Aryl Heterocycle- Human Hematopoietic Metallo-β-Lactamase Catalytic Domain Based Thrombin Prostaglandin D Synthase

1M5B41 1PZO43 1PZP43 1JZ675 3VD749 the Glur2 Ligand TEM-1 β-Lactamase TEM-1 β-Lactamase E. Coli (lacZ) β-Galactosidase Binding Core (S1S2J)

1JTQ54 1DD655 1QJX73 1QJU73

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Human and the IMP-1 Metallo β- Human Rhinovirus 16 Human Rhinovirus 16 Escherichia Coli Lactamase from Thymidylate Pseudomonas Aeruginosa Synthases

1JZ675 3VD749 1E6Q76 1NOI77 1NOJ77 1WVP61 2I1R72 77 58 57 Escherichia Coli 1NOK 1V08 2J7B Chemically modified HCV NS5B Polymerase (Lacz) β- β-Glycosidase myoglobin Galactosidase

2C9042 2C4W46 2CVD51 2P2A56 Thrombin Helicobacter Pylori Type Human the GluR2 ligand binding core II Dehydroquinase Hematopoietic (S1S2J) Prostaglandin D Synthase

2NT739 3KYR[a] 3UOL6 3G3412 Thiophene PTP1B BACE-1 Aurora A CTX-M-9 Class A β- Lactamase

3ZM619 3KEJ20 3KEC20 3O2X[a] the Essential Human Matrix Human Matrix Human Matrix Peptidoglycan Metalloproteinase-13 Metalloproteinase-13 Metalloproteinase-13 Biosynthesis Enzyme Murf

3G3212 3G3512 3G2Y12 3G2Z12 CTX-M-9 Class A β- CTX-M-9 Class A β- CTX-M-9 CTX-M-9 class A β-lactamase Lactamase Lactamase class A β-lactamase 3GR247 AmpC β-lactamase

Page | 15 Chapter 2

3O2M27 3FMH[a] 3FMK[a] 3G7678 JNK1-α1 Isoform p38 Map Kinase p38 Map Kinase XIAP-BIR3

3R8A50 3SOR63 3SOS63 3W9H65 3W9J65 the Nuclear Hormone Factor XIa Factor XIa Bacterial Multidrug Exporters Receptor PPAR- gamma

3NY466 3N8S66 3N2Y68 4DE17 BlaC-K73A BlaC-E166A Tyrosyl-tRNA CTX-M-9 Class A β- Synthetase Lactamase

4DDS7 4DE07 4DE27 4DDY7 CTX-M-9 Class A β- CTX-M-9 Class A β- CTX-M-9 Class A β- CTX-M-9 Class A β- Lactamase Lactamase Lactamase Lactamase

4DE37 4UA722 4UAA22 4E3M8 4E3L8 CTX-M-9 Class A β- CTX-M-14 Class A β- AmpC β-Lactamase AmpC β-Lactamase Lactamase Lactamase

4E3N8 4E3K8 4E3J8 4KAC[a] 4KAJ[a] 4KYV[a] AmpC β-Lactamase AmpC β-Lactamase AmpC β-Lactamase Haloalkane Dehalogenase HaloTag7

4L3414 4M4Q17 4W9S23 4M5U16 Tankyrase 2 Influenza 2009 H1N1 Influenza 2009 H1N1 Influenza 2009 pH1N1 Endonuclease Endonuclease Endonuclease

4HEE10 4XT226 4BXK13 4BO924 PPARgamma the High Affinity Heterodimer of HIF2 α

Page | 16 Review: tetrazoles via multicomponent reaction routes

and ARNT C-Terminal the Angiotensin-1 3-Oxoacyl-(Acyl-Carrier- PAS Domains Converting Enzyme Protein) Reductase (FabG) N-Domain from Pseudomonas aeruginosa

4BO7[b] 4X6N25 4Y8Z28 4Y8Y28 3-Oxoacyl-(Acyl- Factor XIa Factor XIa Factor XIa Carrier-Protein) Reductase (FabG) from Pseudomonas Aeruginosa

4X6O25 4Y8X28 4CRB38 5E2P34 4X6P25 Factor XIa Factor XIa Factor XIa Factor XIa

4KOS30 4AJ233 4XOZ79 4XRJ79 4UAI21 GNAT Superfamily Rat LDHA ERK2 CXCL12 Chemokine Acetyltransferase PA4794

4P3H18 4XZ031 4ZYC32 4ANU45 Kaposi's Sarcoma- ZAP-70-tSH2 p53-MDM2 PI3Kgamma associated Herpesvirus (KSHV) Protease

4FSR[a] 4L7C15 4N8R52 4N5G52 the CHK1 Keap1 Kelch Domain RXRa LBD RXRa LBD

4K8A53 4ZUD64 4CRC38 4MF367 Focal Adhesion Human Angiotensin F1 Human GRIK1 Kinase Receptor

Page | 17 Chapter 2

4ITE69 4ITF69 4YAY74 4YD029 the Human Vitamin D the Human Vitamin D Human Angiotensin Influenza Polymerase Basic Receptor Ligand Receptor Ligand Binding Receptor Protein 2 (PB2) Binding Domain Domain

5ALT40 5AOK48 5A6N70 5E2O34 Epoxide Hydrolase the p53 Cancer Mutant Human Death Factor XIa Y220C Associated Protein Kinase 3

Cl H N Cl O N N N

5EGM35 5AJR71 5EEG[a] 5EH736 Factor XIa Sterol 14-α Demethylase Carminomycin-4-O- Human carbonic anhydrase II (CYP51) from Methyltransferase Trypanosoma Cruzi DnrK

5FHO37 5FHN37 5FHM37 5FLP36 the GluA2 ligand- the GluA2 ligand-binding the GluA2 ligand- Carbonic anhydrase 2 binding domain domain (S1S2J) binding domain (S1S2J) (S1S2J)

5FLO36 5FNG36 5FNI36 5FNH36 Carbonic anhydrase 2 Carbonic anhydrase 2 Carbonic anhydrase 2 Carbonic anhydrase 2

[a] The relevant literature is to be published; [b] No literature is mentioned.

2.1.2 Tetrazoles may participate in up to 4 hydrogen bonds with their four nitrogen σ-lone pairs

This is exemplified in Figure 2.1 of a β-lactamase inhibitor complex.80 There the central tetrazole moiety is embedded between two Ser, one Thr and one water molecule forming an extended hydrogen bonding network with distances between 2.7 and 2.8 Å. Remarkably the four receptor heavy atoms involved in the hydrogen bonds are almost coplanar with the tetrazole

Page | 18 Review: tetrazoles via multicomponent reaction routes plain underlining the involvement of the σ-lone pairs of the four nitrogen atoms. This structure also shows a key difference between the two isosteres: carboxylic acid and tetrazole, based on their lone pairs both which can form, in principle, four hydrogen bonds, however, with differential special orientation. The tetrazolyl forms four orthogonal hydrogen bonds in the plain of the 5-membered ring, whereas the carboxylate forms four hydrogen bonds along the O-lone pairs in the plain spanned by the three atoms O-C-O.

Figure 2.1. Comparison of the hydrogen bonding pattern of tetrazolyl and carboxyl. Left: an example of a tetrazolyl 1 forming 4 hydrogen bonds (PDB ID 4DE1).80 Ser 130 and Ser 237 from each a hydrogen bond to the tetrazole-N2 and -N5 via their side chain hydroxyl-OH at 3.8 and 3.7 Å, respectively. N-3 is in a 2.7 Å contact to the side chain hydroxyl-OH of Thr 235. The fourth N-4 forms a close hydrogen bonding contact of 2.8 Å to a water molecule, which itself is further involved into hydrogen contacts.

2.1.3 The tetrazole moiety is an efficient metal chelator similar to carboxylate

Figure 2.2. Biphenyl-substituted tetrazole 2 as a ligand for the Metallo-β-lactamase (PDB ID 1A8T).5 The central Zn2+ is tetrahedrally coordinated by the ligands tetrazole-N1, the His206 side chain, Asp86 carboxyl-O and Cys164 sidechain-S. The tetrazolyl forms not only a bond to Zn2+ but also several hydrogen bonds to the receptor, including Asn176 backbone NH (3.3 Å),

His145 side chain NH (2.8 Å) and Lys187 side chain NH2 (3.8 Å). Moreover, the His145 imidazole moiety is on the top of the tetrazolyl moiety to form an electrostatic interaction with an inter plane angle of ~30°.

Page | 19 Chapter 2

The X-ray crystal structure of the enzyme bound biphenyl-substituted tetrazole 2 shows that the tetrazole moiety interacts directly with one of the two zinc atoms in the active site, replacing a metal bound water molecule. The two N-N polar interactions and two C-N interactions are presented in the following graph (Figure 2.2).

2.1.4 The tetrazolyl unit is forming an Arg-sandwich

The protein-protein interaction of the Keap1 with Nef2 recently became a hot target in drug discovery for neuro-inflammatory diseases. A tetrazole molecule 3 was described binding to the Kelch protein (PDB ID 4L7C, Figure 2.3).15 Interestingly the bioisostere carboxylic acid compound 4 (PDB ID 4L7B) is also available together with structural biology information thus providing the opportunity for a direct comparative analysis.15 The alignment of the two structures is very good and only small differences in the two ligand and receptor side chain orientations can be observed (RMSD 0.142, Figure 2.4). Both acid units of 3 and 4 are sandwiched between R415 and R380. However, tetrazole 3 can bury a water molecule underneath the tetrazole moiety which makes several close contacts possible to the receptor which cannot be detected with the carboxylic acid 4. Therefore, the highly buried water molecule can be considered as part of the receptor. Moreover, the conformation of R415 is slightly different in compounds 3 and 4, placing R415 closer to the two carboxylic acid oxygens by a ~80o turn around the C2-C3-Arg415 bond. Taken together carboxylic acid 4 binds with an

IC50 of 2.4 μM slightly better than that of tetrazole 3, which is 7.4 μM.

Figure 2.3. Kelch domain interaction of Keap1 with tetrazole 3 (PDB ID 4L7C). A dense network of electrostatic and hydrogen bindings contributes to the tight small-molecule receptor interaction. It features an interesting sandwich charge-charge interaction driven motive between two positively charged arginines and the tetrazole moiety. The insert shows the Arg-sandwich from a different orientation.

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Figure 2.4. Kelch domain interaction of Keap1 with carboxylic compound 4 (PDB ID 4L7B). Same as its bioisostere tetrazole 3, a dense network of electrostatic and hydrogen bindings also contributes to the tight small-molecule receptor interaction. The difference is the weaker interaction between residue Arg 380 and the carboxylic ligand which is caused by the special orientation of carboxylic group. In addition, the in-vivo brain exposure was tested for both compounds, and several physicochemical and DMPK properties are summarized in Table 2.3. None of the two compounds showed sufficient brain penetration likely due to being substrates for efflux pumps phosphoglyco protein (PGP).

Table 2.3. Physicochemical and DMPK properties of compound 4 and its bioisostere 3

[a] Polar surface Efflux Unbound brain-to- Cu Compound Log D 2 [b] [c] [d] [e] area [Å ] ratio plasma (Bu/Pu) [µM]

3 (tetrazole) 0.69 107 NT[g] <0.01 <0.01

4 (carboxylic acid) 1.36 95 20 <0.01 <0.01 0.4[f] 0.18[f]

[a] Measured at pH 7.4; [b] Polar surface area (PSA); [c] Efflux ratio (ER)) in MDCKMDR1 cells (10 µm incubated up to 120 min); [d] Unbound brain-toplasma ratio measured in mice; [e]

Unbound brain concentration measured in mice at Cmax; [f] Measured in Mdr1a/1b/Bcrp knock- out mice; [g] Not tested.

Yu et al. designed inhibitors of the β-Catenin/T-Cell Factor protein-protein interaction by pursuing a bioisosteric replacement approach. The available crystal structures reveal a very large protein−protein contacting surface between β-catenin and Tcf4 of ≥2800Å2 (PDB ID 81 2GL7). Moreover biochemical analyses indicate that the dissociation constant (Kd) value of β-catenin/Tcf PPIs is in the 7-10 nM range. To disrupt such a large and tightly binding complex it requires an extraordinarily high ligand efficiency of the small molecule. Biochemical analysis of truncated and mutated Tcf peptides revealed several potential hot spots for small-molecule

Page | 21 Chapter 2 design. The D16 and E17 of human Tcf were chosen as a critical binding element and converted 82 into small molecules mimicking this key element (Figure 2.5). The tetrazole ring (pKa = 4.5 - 4.95) was used to replace the carboxyl group of D16 and mimic the charge−charge and H-bond interactions with K435 and N430 of β-catenin. The four lone pairs of the deprotonated tetrazole ring are evenly distributed on the five-membered ring and can form two additional H-bonds with the side chains of H470 and S473. These two H-bonds do not exist in the β-catenin/Tcf complex.

Tetrazole derivative 5 with a molecular weight of 230 Da and a ligand efficiency of 0.512 has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β- catenin/Tcf interactions. Replacement of the tetrazole moiety with other carboxyl bioisosteres such as 5-oxo-1, 2, 4-oxadiazole and 5-thioxo-1, 2, 4-oxadiazole (pKa = 6.1 - 6.7) decreased binding affinity dramatically. According to modelling studies, the tetrazole mimics D16 carboxylic acid and the indazole-1-ol moiety the carboxyl group of E17 (Figure 2.5).

a b c Figure 2.5. Bioisosteric replacement strategy for the design of β-catenin/Tcf protein-protein interaction. (a) Hot spot of β-catenin/Tcf interaction showing key electrostatic interactions (PBD ID 2GL7).81 Tcf peptide is shown in pink and green and the hot spot D16-E17 is highlighted as pink sticks. B-Catenin is shown as surface representation and interacting amino acids are shown as grey sticks; (b) bioisosteric replacement step; and (c) close-up analysis of the aligned 5 and D16-E17 of Tcf with the b-catenin receptor. The indazole-1-ol forms H-bond and charge−charge interactions with β-catenin K508. The tetrazole ring was used to replace the carboxyl group of D16 and mimic the charge−charge and H-bond interactions with K435 and N430 of β-catenin. The deprotonated tetrazole ring with two more Lewis bases can form two additional H-bonds with the side chains of H470 and S473. These two H-bonds do not exist in the β-catenin/Tcf complex.

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2.2 Tetrazoles through non-multicomponent reaction synthetic routes

To date, the multitude of synthetic methods of 1,5-disubstituted tetrazoles and 5-substituted tetrazoles has been reviewed several times, and thus they will be mentioned here only briefly.83- 86 The most common used synthesis of tetrazole derivatives is the 1,3-dipolar cycloaddition reaction between nitriles and azides (azide ion or hydrazoic acid) (Scheme 2.2a).87, 88 It was first mentioned for the preparation of 5-substituted tetrazoles is the formal [3+2] cycloaddition of an azide to a nitrile in 1901 by Hantzsch and Vagt, A (Scheme 2.2b).89 Electron withdrawing groups lowering the LUMO of the nitriles and thus enhance the interaction opportunities with the HOMO of the azide lead to a smooth reaction.90, 91 However, the requirement of the strong electron withdrawing groups in the nitrile substrate limits the scope of the reaction somehow. Thus, high reaction temperature and suitable catalysts can overcome this substrate limitation. Amongst the many methods, noteworthy Demko and Sharpless in 2002 reported the formal cycloaddition of an azide to a p-toluenesulfonyl cyanide (TsCN) with a nice substrate scope of aromatic and aliphatic azides under solvent-free conditions following simple isolation and essentially quantitative yield (Scheme 2.2c).92 Later, they continued to extend this methodology to produce acyltetrazoles with readily available acyl cyanides and aliphatic azides in high yield and with simple purification (Scheme 2.2c).93

Scheme 2.2. Different synthetic routes to tetrazoles using non-multicomponent reaction.

Page | 23 Chapter 2

While the 1,3-dipolar cycloaddition reaction between nitriles and azides (azide ion or hydrazoic acid) towards 1,5-disubstitued tetrazoles is well established, equivalently worthwhile to be mentioned is the [3+2] cycloaddition of isocyanides and azides to synthesize 1,5- disubstitued tetrazole derivatives, which was invented by Oliveri and Mandala in Italy at the beginning of 20th century.94 This reaction is less known, however, quite general and works both with aliphatic and aromatic substrates and has a broader scope than the corresponding nitrile cycloaddition (Scheme 2.3). Due to the recent in situ access to a much greater diversity of isocyanides from their formamides, this method is a worthwhile pathway allowing for the synthesis of many 5-N-monosusbtituted tetrazoles (Scheme 2.4).95

Scheme 2.3. Intramolecular cycloaddition of azidonitriles: (a) heterocyclic nitrile, (b) aliphatic nitrile, and (c) aromatic nitrile.

Scheme 2.4. Isocyanide-less Ugi 4-CR tetrazole variation (UT-4CR).

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2.3 Multicomponent reaction for the synthesis of tetrazoles

In the following, the MCR based tetrazole syntheses will be presented according to the number of cycles, e.g. monocyclic, bicyclic, and tricyclic, etc (Scheme 2.5).

Scheme 2.5. Tetrazole MCRs overview.

2.3.1 Monocyclic tetrazole derivatives

The most important approach using multicomponent reaction to synthesize aminomethyl tetrazoles by fare represents the Ugi-4CR. Ivar Ugi described it in his seminal publication from 1959 where he introduced the even today most important variations of his MCR.96 Some years later again Ivar Ugi introduced a Passerini MCR variation leading to α-hydroxymethyl tetrazoles.97 Although it is a reaction mechanistically related to the Passerini reaction described 30 years earlier, it was first described by Ivar Ugi. Some other less described MCR will be then discussed in the following. These include reactions involving, for example acetylenedicarboxylic acid esters and three component reaction of isocyanides, azide and another nucleophile leading to interesting 1,5-disubstituted building blocks.

2.3.1.1 Ugi 4-component reaction towards monocyclic tetrazoles (UT-4CR)

α-Aminomethyl tetrazoles are of general interest due to isosterism to α-amino acids. Bioisosteric replacement of a functional group prevails in medicinal chemistry to alter unfavorable ADME properties and/or to access free patent space. There are many presented examples: the replacement of carboxylic acid functional group with 5-substituted tetrazole in angiotensin-II receptor antagonists, VLA-4 antagonists, in hepatitis C NS3 protease inhibitors, histone deacylase inhibitors, negamycin derivatives, AMPA antagonists, 5-HT3 receptor antagonists, CRH antagonists, or NK1 receptor antagonists.

The classical Ugi tetrazole synthesis is of great scope regarding the starting materials, isocyanide, oxo component and amine. The reaction is often performed in the solvent methanol

Page | 25 Chapter 2 however 2,2,2-trifluoroethanol or biphasic water chloroform mixtures were also reported.98 The reaction is fast at room temperature; only some special adduct combinations require heating, for example the reaction of trityl amine in the UT-4CR.99, 100 The UT-4CR is considerably more exothermic than the classical Ugi four component condensation of isocyanides, oxo components, primary amines and carboxylic acids yielding α-aminoacylamides. Therefore, addition of the components should proceed under cooling when running the reaction on a larger scale. The order of addition of the component in the Ugi reaction does not matter in most cases, and yields are comparable. Often the components are added to the flask in the order oxo component, amine, isocyanide and azide source. While Ugi was using isolated hydrazoic acid in a benzene stock solution,101, 102 nowadays mostly, the safer substitute trimethylsilylazide

(TMSN3) is used, which forms in situ hydrazoic acid in methanolic solution. Sodium azide is the hydrazoic acid source of choice if ammonium salts of the 1° or 2° amines are used. Aromatic as well as aliphatic isocyanides work well. Functional groups in the isocyanide side chain are often well tolerated. e. g. amino acid derived isocyano esters work well. However, α- and β- amino acid derived isocyano methylester, can cyclize with the primary or secondary amine of the tetrazole side chain forming -lactams. This has been advantageously used to create tetrazoloketopiperazines and will be discussed below. Oxo components can be aldehydes, ketones and substituted variants thereof. Substituted benzaldehydes, heteroaromatic aldehydes, including formyl-ferrocene and substituted aliphatic aldehydes as well as glyoxales and formaldehyde work well; substituted cyclic and acyclic aliphatic ketones, mono arylketones work well. In the UT-4CR primary and secondary amines react well, which is different from the classical U-4CR where normally only primary amines can be reacted to.103-109 The amines can be aliphatic or aromatic and widely substituted. Even super bulky trityl amine can be reacted with aliphatic aldehydes, however, using microwave conditions due to the slow Schiff base formation.99, 100 Even ammonia, which causes often problems in other Ugi variations reacts reasonably well with ketones in the UT-4CR (Figure 2.6).

Interestingly, 2-aminopyridine also reacts in the UT-4CR as an amine component. This is worthwhile to note since 2-aminopyridine, in principle, could also undergo the GBB-3CR with isocyanides and aldehydes in a competing reaction.110-112 Apparently, however, the GBB-3CR is of slower kinetic than the UT-4CR (Scheme 2.6). Taken together the UT-4CR is very easy to perform,113, 114 have an amazingly great scope in all three classes of variable starting materials. Since its first description in 1959, many researchers have used the UT-4CR and some applications are highlighted in the following.

Page | 26 Review: tetrazoles via multicomponent reaction routes

Figure 2.6. Structure-activity relationship of the Ugi tetrazole 4CR and typical reaction products underlining the scope of the reaction.

Scheme 2.6. The comparison of Ugi reaction and GBB-3CR in which 2-aminopyridine reacts.

Page | 27 Chapter 2

In 1972, Zinner et al. started the early studies of UT-4CR using amine variations. In their approach, diaziridine reacted with formaldehyde, cyclohexylisocyanide, and HN3 to generate a diaziridine tetrazole derivative, however, in low yield. The subsequent acidic treatment broke the diaziridine ring to give a quantitative yield of the hydrazine 6, unexpectedly (Scheme 2.7).115

Scheme 2.7. The UT-4CR to diaziridine tetrazole derivative 6.

In 1974, Zinner et al. described a UT-4CR approach to 1,5-disubstituted tetrazoles using hydrozylamines as amine components. Reaction with formaldehyde in the presence of cyclohexylisocyanide, and hydrazoic acid (HN3) give the corresponding 1,5-disubstituted tetrazole methylene hydroxylamines. Sterically hindered cycloketone and different substituted benzylhydroxylamines could lead to the expected products at a mild reaction condition, though with lower yields (Scheme 2.8).116

Scheme 2.8. Hydrocylamines as amine equivalents in UT-4CR.

In 2005, Mayer et al. chose two new cleavable isocyanides 3-isocyano-3-phenyl- ethylpropionate and 2-isocyano succinic acid dimethyl ester to react with aldehydes, amines, TMS azide to give a library of tetrazole Ugi adducts 8 bearing three points of diversity in good yields. They can be cleaved in a following step with alkoxide base to afford 5-substituted 1H- tetrazoles 9. The two new cleavable isocyanide both were synthesized from β-amino acid obtained by an α-amino alkylation, followed by esterification in ethanol with thionyl chloride,

Page | 28 Review: tetrazoles via multicomponent reaction routes formylation in ethyl formate, and dehydration in a two-step procedure treated with phosphoryl chloride in the presence of triethylamine (Scheme 2.9).117

Scheme 2.9. Synthesis of α-aminoalkyltetrazoles.

In 2007, Marcaccini and Torroba described a detailed protocol for the UT-4CR including the general mechanism and the effects of the components, as well as the reaction conditions for the Ugi reaction. In addition, a detailed step-by-step workup protocol was established (Scheme 2.10).113

Scheme 2.10. Preparation of tetrazole 10 by a Ugi-4CR.

As one of the most devastating infectious disease in history, smallpox has killed numerous people on earth. It is caused by two virus variants, Variola major and Variola minor. After vaccination campaigns throughout the 19th and 20th centuries, the last naturally-occurring case of smallpox (Variola minor) was diagnosed on 26 October 1977. The WHO certified the eradication of smallpox in 1980. Since then smallpox could not be a bioterrorist and biowarfare threat to human beings any more. However, due to vaccination compliance issues, there is the

Page | 29 Chapter 2 danger that small pox can return. Therefore, drug designers do not stop their interests to study potent inhibitors against variola and related vaccinia and cowpox viruses. No drug treatment has been found for the latter disease. In an attempt to discover novel virostatica, Torrence et al. designed a series of previously undescribed hyper modified nucleosides 11 using the multicomponent Ugi reaction and also evaluated their activity against vaccinia virus, cowpox virus, and the parasite Leishmania donovani. They replaced carboxylic acid with TMS azide to possess two more novel tetrazole derivatives in good yield after the success of the desired N- acylamino acid amide. Unfortunately, these two synthetic products did not possess significant antiviral activity against either vaccinia virus or cowpox virus (Scheme 2.11).118

Scheme 2.11. Antiviral tetrazole desoxyribose derivatives.

Multiple applications of the UT-4CR in medicinal chemistry have been described. Histamine H3 receptor (H3R) is mainly expressed and located in the central nervous system and exists less in the peripheral nervous system. It acts as an auto receptor in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release.119 Attracted by the potential of the H3R as a drug target, Davenport et al. described a series of potent and subtype selective H3 receptor antagonists 12 containing a novel tetrazole core and diamine motif. A one-pot UT-4CR was utilized to rapidly develop the structure– activity relationships (SAR) of these compounds. According to the biological screening results, six-membered piperazine ring should be remained, and the receptor preferred a small sterically demanding alkyl groups. Shielding around nitrogen did not afford an improvement in metabolic stability. They continued to select 12c for further optimization by remaining the active amine and modifying the aromatic substituents to enhance potency. The best potency of substituted compounds was derived from meta-substituted position. Meanwhile, both electrons

Page | 30 Review: tetrazoles via multicomponent reaction routes withdrawing and donating groups suggest that the electron density on the aromatic ring does not significantly influence the binding. Besides, amide, sulfone and sulfonamide examples similarly gave significantly improved potencies.

Encouraged by these results, a range of analogues containing para substituted heterocycles was synthesized to take advantage of these findings. Compound 12e presented the longest half- life time (HLM t1/2 = 74 min) and demonstrated the tolerance of the receptor to an additional basic center. The introduction of fused heterocycles reduced potency and provided no improvement in stability (Scheme 2.12).103

Scheme 2.12. Synthesis of substituted benzyl tetrazoles as histamine H3 receptor antagonists.

Tron et al. discovered an attractive short synthetic approach to 5-aroyl-1-aryltetrazoles 14, a class of compounds hardly accessible by other means.120 The novel and operationally simple synthetic procedure to obtain elusive 5-aroyl-1-aryltetrazoles consists of UT-4CR, followed by a hydrogenolysis/transamination post-transformation (Scheme 2.13). Initially, they envisaged to synthesize this scaffold through Passerini 3-CR followed by an oxidation step (Scheme 2.14). However, due to aromatic functional groups of the aldehydes and isocyanides the P-3CRs did not easily afford the target compounds. In addition, simply mixing 3,4,5-trimethoxyphenyl isocyanide, p-anisaldehyde, and trimethylsilyl azide in dichloromethane at room temperature only afforded the 3,4,5-trimethoxyphenyl-1H-tetrazole 15 with a 90% yield (Scheme 2.15). Furthermore, the application of Lewis acids led to the products in low yield with the formation of unexpected side products 17 (Scheme 2.16). In the end, they discovered a synthetic strategy initiated by a UT-4CR followed by a hydrogenolytic N-deprotection; application of the

Page | 31 Chapter 2

Rapoport procedure gives 5-aroyl-1-aryltetrazole derivatives in good yield. The Rapoport transamination reaction is a simple and mild biomimetic conversion to transfer amines to carbonyls in the presence of 4-formyl-1-methylpyridinium benzene-sulfonate as a pyridoxal phosphate (vitamin B6) surrogate (Scheme 2.17). In this work, Tron et al. employed different aldehydes and isocyanides with various different electron-withdrawing and electron-donating substituents to demonstrate the functional group tolerance and generality of this new synthetic process. α-Keto (hetero) aromates are a significant compound class as they have been described as covalent serine protease inhibitors.121

Scheme 2.13. General procedure for the synthesis of 5-aroyl-1-aroyltetrazol.

Scheme 2.14. First retrosynthetic analysis.

Page | 32 Review: tetrazoles via multicomponent reaction routes

Scheme 2.15. Formation of 3,4,5-trimethoxyphenyl-1H-tetrazole 15.

Scheme 2.16. MCR among an aromatic isocyanide, an aromatic aldehyde, and trimethylsilyl azide catalyzed by aluminum trichloride.

Scheme 2.17. The Rapoport biomimetic transamination.

Chalcones exists widely in many important biological compounds with an aromatic ketone and an enone to form the central core. Chalcones and their derivatives have a wide range of biological activities such as anti-diabetic, anti-neoplastic, anti-hypertensive, anti-retroviral, anti-inflammatory, anti-parasital, anti-histaminic, anti-malarial, anti-oxidant, anti-fungal, anti- obesity, anti-platelet, anti-tubercular, immunosuppressant, anti-arrhythmic, hypnotic, anti-gout, anxiolytic, anti-spasmodic, anti-nociceptive, hypolipidemic, anti-filarial, anti-angiogenic, anti- protozoal, anti-bacterial, anti-steroidal, etc.122-124

The double bond in the chalcone scaffold is commonly thought to be an important structural linker, but not essential for the interaction with tubulin. In the chalcone scaffold, it is thought that the double bond is an important structural linker, but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. To circumvent this, Tron et al. in 2011, devised a novel multicomponent reaction/post transforamtion strategy.125 Firstly, they mixed four components Ugi-like reaction among TMS azide, the respective isocyanide, the respective aldehyde and the respective benzylamine in methanol at room temperature to give 1, 5-disubstituted tetrazole

Page | 33 Chapter 2 derivatives 18. Then these derivatives underwent a hydrogenolytic cleavage of the N-benzyl group to affording the amine derivatives 19, and these amines were converted in the 1-aryl-5- aroyl tetrazole 20 through a transamination reaction with moderate and good yields in these three synthetic steps. All compounds were investigated for their biological antiproliverative activity. For the tetrazole series, only 20a were both active in SH-SY5Y cells and the cell cycle analysis with a low potency. Meanwhile, their work also proved that the olefinic bridge on chalcones is not merely a structural linker (Scheme 2.18).

Scheme 2.18. General synthesis procedure for tetrazolic analogues of chalcones.

Mammalian brain function can be regarded as a fine-tuned balance of excitatory and inhibitory signals. An imbalanced interaction between excitators and inhibitors may underlie numerous neuropathological and psychiatric diseases of the central nervous system (CNS). γ- Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system.126, 127 It plays the principal role in reducing neuronal excitability throughout the nervous system. And perturbations in GABA neurotransmission play a key role in the pathophysiology of neurological disorders, i.e. epilepsy, Morbus Parkinson, Morbus Alzheimer, Huntington’s chorea, neuropathic pain, schizophrenia, and depression.

Considering all receptors, metabolic enzymes and transporters involved in GABAergic neurotransmission can be considered as valid targets, Wanner et al. employed a TMSN3- modified Ugi reaction as a key step to synthesize 1, 5-disubstituted 21 and 5-monosubstituted aminomethyltetrazole derivatives 22 derived from glycine (Scheme 2.19).104 And all products were evaluated regarding their inhibitory potency and subtype selectivity at the four murine GABA transporter subtypes mGAT1–mGAT4. The results showed that none of the 5-

Page | 34 Review: tetrazoles via multicomponent reaction routes monosubstituted tetrazoles have a potential inhibition of GABA uptake; however the 1,5- disubstituted tetrazole derivatives displayed a distinct activity, especially at the GABA transport proteins mGAT2–mGAT4. A reasonable potent and selective inhibitor of mGAT3 was found. Additionally, two more compounds were identified as potent inhibitors of mGAT2. This is especially relevant, as up to date only few potent and selective inhibitors of mGAT2 that do not affect mGAT1 are known.

Scheme 2.19. Synthesis of aminomethyltetrazoles.

In 2012, Fan et al. designed and synthesized N-((1-cyclohexyl-1H-tetrazol-5-yl)(5-methyl- 1,2,3-thiadiazol-4-yl) methyl)-4-nitrobenzenamine 24 via Ugi four-components condensation reaction (U-4CR), based on their previous work which has shown that some of the compounds they obtained have broad-spectrum of activities against several fungi tested and excellent antiviral activity (Scheme 2.20 and Figure 2.7).128

Page | 35 Chapter 2

N S N N N R S NH 2 R N CHO MeOH N + H N r.t., 12 - 24 h N N 45 - 60% TMSN3 NC 23

N S Cl N S F N S N N N

N N N N N N H N H N H N N N N N N N

23a, 47% 23b, 50% 23c, 48%

Scheme 2.20. Synthesis of N-((1-cyclohexyl-1H-tetrazol-5-yl)(5-methyl-1,2,3-thiadiazol-4- yl) methyl)-4-nitrobenzenamine.

Figure 2.7. The cystal structure of N-((1-cyclohexyl-1H-tetrazol-5-yl)(5-methyl-1H-1,2,3- triazol-4-yl)methyl)-4-nitroaniline. It showed the dihedral angles formed between the thiadiazole and tetrazole rings, the benzene and tetrazole rings and the thiadiazole and benzene rings are 62.59, 86.73 and 70.07°, respectively. Three intermolecular hydrogen bonds N(1)−H(2)···N(6), C(4)−H(4B)···O(2) and C(17)−H(17)···N(3) (CCDC: 859295).

In 2013, Dömling et al. introduced tritylamine as a convenient ammonia substitute in the Ugi tetrazole synthesis.99 They synthesized 15 trityl protected 1,5-disubstituted tetrazole derivatives 25 in satisfactory to good yields (Scheme 2.21 and Figure 2.8). The trityl deprotecting reaction went through a mild acidic condition with quantitative yields. Ammonia was found to lead to a mixture of multiple products caused by its high reactivity. The experimental results have revealed that a mixture of mono-, di-, and tri- Ugi products were detected when formaldehyde, ammonia reacts in Ugi reaction to form tetrazoles. Moreover, due to the too slow conversion of the Schiff base at room temperature, they switched to employing microwave irradiation to form the products. They also tested the scope and limitations of the reaction. Ketone and aromatic aldehydes could not give the target product under the present reaction condition. Presumably it

Page | 36 Review: tetrazoles via multicomponent reaction routes was caused by the high sterical hindrance of the two reactants and also no such Schiff base with tritylamine has been reported with a ketone via a condensation reaction before.

R1 R1 CHO NH2 R EtOH N TFA in CH2Cl2 1 N N N TFA H2N o H r.t., 1 min N MW, 100 C, 30 min N N + N quantitative yields N 46 - 87% R2 R2

NC TMSN3 R 2 24 25

N N N N N N H N H N H N N N N N N N

24a, 83% 24b, 73% 24c, 75%

N TFA H N N 2 N TFA H2N N N N N N N TFA H2N N N N

25a, 99% 25b, 99% 25c, 99%

Scheme 2.21. A synthetic pathway to N-unsubstituted primary α-aminotetrazoles 25 using a Ugi-4CR employing tritylamine as an Ammonia surrogate.

Figure 2.8. The crystal structures of N-unsubstituted primary α-aminotetrazole. It is dominated by π-π stacking and hydrophobic interactions between the trityl group, the alkyl group and the phenylethyl groups but also the tetrazole ring makes intermolecular contacts (CCDC 903083 and 903084).

Page | 37 Chapter 2

Figure 2.9. Three nitroimidazoles: metronidazole, tinidazole, and nimorazole.

Scheme 2.22. Synthesis of new nitroimidazole and nitroimidazooxazine derivatives.

Tuberculosis (TB) is amongst the major fatal infection in the world. There are more than 9 million new infected cases and nearly 2 million deaths reported annually. For the past dozens of years, many different classes of compounds were undergoing clinical development. Although nitroimidazoles (Figure 2.9) are highly effective against both the replicating and nonreplicating persistent forms of Mycobacterium tuberculosis (Mtb) which is the causative agent of tuberculosis, people still investigated to get more promising results by replacing the benzyl group with various (hetero)biaryl side-chains and amide groups. Herein, Chibale et al. aimed at identifying new quinoline-based compounds that have potential application in malaria and incorporated the tetrazole moiety and protonatable nitrogen(s) into the deoxyamodiaquine scaffold in their research.129 They designed and synthesized a new library of nitroimidazooxazine derivatives 26 in moderate to excellent yields and diastereoselectivity using the modified TMSN3−Ugi MCR (Scheme 2.22). Three of these compounds appeared to be rapidly metabolized in both human and rat liver microsomes and had high metabolic

Page | 38 Review: tetrazoles via multicomponent reaction routes clearance that was comparable to that of amodiaquine. All synthesized tetrazole derivatives were evaluated in vitro for their antiplasmodial (against the multidrug-resistant K1 strain) and antimycobacterial activity (against the drug-sensitive H37Rv Mtb strain). Two of these compounds exhibited potent activity against the K1 strain of P. falciparum, with IC50 values in the low micromolar range.

Scheme 2.23. Synthesis of 4-aminoquinoline-tetrazole derivatives.

Parasitic diseases are a global problem, affecting 30% of the world’s population. Among parasitic diseases, Malaria is one of the most devastating infectious disease claiming many lives. There were at least 216 million cases of acute malaria reported in 2010, and about 655,000 people died from malaria, 86% of which are children under 5 years of age.130 In 2013, Chauhan et al. synthesized a series of novel tetrazole derivatives 27 of 4-aminoquinoline via a UT-4CR of primary and secondary amines, aliphatic, aromatic and ferrocene containing aldehydes, 131 TMSN3 and isocyanides (Scheme 2.23). All the products were screened for their antimalarial activities against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of plasmodium falciparum as well as for cytotoxicity against VERO cell lines. Most of the synthesized compounds exhibited potent antimalarial activity as compared to chloroquine

Page | 39 Chapter 2 against K1-strain. Some of the compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii following both intraperitoneal (ip) and oral administration.

O O R1

NH2 O R N HN R2 1 H NH MeOH N R + r.t. 24h 2 N NC N N TMSN3 R3 54 - 65% R3 28

S

O HN O S O HN NH HN O NH N NH N N N N N N N N N N N

28a , 60%, dr 68:32 28b, 63%, dr 78:22 28c, 67%, dr 80:20

Scheme 2.24. Diastereoselective synthesis of α-hydrazine tetrazoles via a facile azide Ugi four-component reaction.

Figure 2.10. The crystal structures of α-hydrazine tetrazoles. Hydrophobic interactions between C of phenyl group and N(2), N(3) of tetrazole, hydrophilic interactions between N(3) of tetrazole and N close to C=O (CCDC 950021); Hydrophobic interactions between C of oxo componental cyclohexyl groups, and hydrophilic interactions between N(3), N(4) of tetrazole and N close to C=O (CCDC 950022).

The basic amino group is highly hydrophilic and is also a good hydrogen bond acceptor which is the major resource of high potency of the drug candidates. Ammonia and other amine-like components that have been reported sporadically in Ugi reactions; however, often affording mixed or poor yields, such as hydroxylamine, N-acylated hydrazine, N-sulfonated hydrazine and unprotected hydrazine. In 2013，Balalaie et al. reported a novel and efficient method for the diastereoselective synthesis of α-hydrazine tetrazoles 28 using cyclic ketones, TMS azide,

Page | 40 Review: tetrazoles via multicomponent reaction routes hydrazides, and corresponding isocyanide without any catalyst via an isocyanide-based multicomponent reaction is reported in mostly good yields (Scheme 2.24).132 When using 4- substituted cyclohenxanone two diastereomers were observed during the Ugi reaction up to de 4:1. Based on a solved X-ray structure the major diastereomer is –E (Figure 2.10).

Scheme 2.25. Synthesis of 1, 5-disubstituted tetrazole imine intermediates and the process of oxidation.

Tetrazoles are widely recognized for their pharmacological activities and for their high chemical and thermal stabilities.85, 133 And the decomposition of substituted tetrazoles normally occurs above 250oC. The fragmentation at lower temperatures mainly was only found during acylation of monosubstituted tetrazoles (Huisgen fragmentation). In 2013, El Kaïm et al. presented an unprecedented Lewis acid triggered fragmentation of tetrazoles 29 easily obtained through UT-4CR (Scheme 2.25).134 The Ugi tetrazole undergoes Cu catalyzed oxidative Schiff base formation, which then forms Zn-catalyzed under microwave conditions under extrusion of tert-butyl diazo the 1,5-disubstituted triazole 30 (Scheme 2.26). Noteworthy, this is the opposite regioselectivity obtained through classical click reaction. The high-potential application of diazo derivatives in transition-metal-triggered processes make the use of tetrazoles as efficient carbene precursors in palladium- or ruthenium-catalyzed processes very promising.

Page | 41 Chapter 2

Scheme 2.26. Proposed mechanism for 1,2,3-triazole formation.

Scheme 2.27. Synthesis of a series of new tetrazoles containing the 2, 2- bis(trimethylsilyl)ethenyl group.

Compared with the ordinary organic compounds, most organosilicon compounds consist of the similar properties, but are more hydrophobic, and stable. Due to C(sp2)–Si bonds in organosilicon compounds undergo numerous transformations, Safa et al. developed tetrazoles 31 bearing 2,2-bis(trimethylsilyl)ethenyl groups from the synthesized 4-[2,2-bis(trimethylsilyl) ethenyl] benzaldehyde in the presence of catalytic amounts of MgBr2·2Et2O as catalyst via a simple one-pot Ugi four-component condensation reaction (Scheme 2.27).135 Noteworthy, primary aromatic amines with electron-donating groups such as methoxy and methyl gave the tetrazole derivatives in slightly higher yield than amines with electron withdrawing groups such

Page | 42 Review: tetrazoles via multicomponent reaction routes as nitro, more bulky cyclohexylisocyanide instead of tert-butyl isocyanide required longer reaction times to afford the similar products.

Despite increasing numbers of novel and effective antibacterial agents, antibiotic resistance makes these medications less effective in both treating and preventing infections. The most prevalent approach to remove bacterial resistance is to modify the existing classes of antibacterial agents to provide new analogues. Chauhan et al. introduced a novel series of 7- piperazinylquinolones with tetrazole derivatives 32 and evaluated their antibacterial activity against various strains of Staphylococcus aureus (Scheme 2.28). All the compounds showed significant in vitro antibacterial activity against Gram-positive bacteria whereas only some displayed moderate activity in vivo.109

Scheme 2.28. Representative scheme for the preparation of 1H-tetrazol-5-yl-(aryl)methyl piperazinyl-6-fluoro-quinolones.

Recently, Dömling et al. synthesized a series of substituted 5-(hydrazinylmethyl)-1-methyl- 1H-tetrazoles 33 from the Ugi-tetrazole reaction using Boc hydrazine, aldehydes or ketones, isocyanide and TMS azide and subsequent deprotection via a two-step procedure (Scheme 2.29 and Figure 2.11).136 In order to further improve the transformation of Ugi reaction, Lewis acid

ZnCl2 was used as a catalyst to increase the activities of Schiff base during the cyclization step. Meanwhile, various aldehydes, ketones, isocyanides were used to test the scope and limitations of the reaction. The straightforward access to highly substituted hydrazine is of interest since hydrazines can act as Asp-protease inhibitor needles interacting through charge-charge interactions with the active side aspartate residues.

Page | 43 Chapter 2

10% ZnCl2 2 M HCl H MeOH, r.t. in MeOH CHO R R1 N H 1 24 - 48h H R1 Boc NH2 18 - 24h N N + N N Boc N Boc N N 34 - 88% H N 65 - 99% H NC N N N TMSN3 R N R 2 R2 2

33 34

Cl H H N N N N N Boc N Boc N N N H H H N N N N N N Boc N H N N N

Cl

Cl 33a 33b 33c

without ZnCl2 70% without ZnCl2 - without ZnCl2 - with ZnCl2 69% with ZnCl2 40% with ZnCl2 37%

Cl

N H2N N H2N N N N N H H N N N N H2N N N H N N N

Cl

Cl 34a, 80% 34b, 99% 34c, 85%

Scheme 2.29. Synthesis of N-Boc-protected intermediate and N-deprotected final product.

a b

c Figure 2.11. Crystal structures of highly substituted 5-(Boc-hydrazinylmethyl)-1-methyl- 1H-tetrazoles. (a) Three hydrophobic interactions between carbon atom of cyclohexanyl and oxygen atom of Boc group, carbon atom of cyclohexanyl and N(4) of tetrazole, and C(1) of

Page | 44 Review: tetrazoles via multicomponent reaction routes benzylethyl and N(4) of tetrazole (CCDC 1438137); (b) three hydrophobic interactions between carbon atom of methyl of isopropyl and O (C=O) of Boc group, carbon atom of methylene of benzyl and O of Boc group, and carbon atom of benzyl and N(3) of tetrazole; and one hydrophilic interaction between N (4) of tetrazole and N of hydrazine close to Boc group (CCDC 1438135); and (c) four hydrophobic interactions between C(α) of isocyanide and N(3) of tetrazole, carbon atom of methyl of isopropyl and N(3) of tetrazole, and O(C=O) of Boc group and methyl of isopropyl; and one hydrophilic interaction between N(4) of tetrazole and N of hydrazine close to C(α) (CCDC 1438136).

2.3.1.2 Ugi 3-component reaction (UT-3CR)

Dömling et al. investigated a versatile and commercially available isocyanide, 1- isocyanomethylbenzotriazoles (BetMIC) in the tetrazole variation of the U-4CR. Initially, they reacted 1-isocyanomethylbenzotriazoles with an enamine and TMS azide in methanol to form the expected tetrazole in good yields. Moreover, in the following cleavable step, they observed the almost quantitative and mild cleavage of the Ugi product to give the expected α- aminomethyl tetrazole. The isolation of the Ugi intermediate or in-situ reaction both worked in this case (Scheme 2.30).137

Scheme 2.30. UT-3CR of BetMIC and subsequent acid hydrolysis yielding α-aminomethyl tetrazole.

Recently, the chemistry of organofluorine compounds has attracted more and more interest due to their important properties in pharmaceutical applications and materials science.138 The medicinal chemist often employs bioisostere to replace the functional group of drugs to improve ADMET properties. The replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate might block metabolism without compromising biological activity and increasing half-life time. Nenajdenko et al. studied the application of trifluoroalkylated cyclic imines in azido-Ugi reactions.139 They started from different arrays of

Page | 45 Chapter 2 five-, six- and seven- membered trifluoroalkylated cyclic amines to form target tetrazole derivatives 36 of saturated nitrogen heterocycles bearing the trifluoroalkyl moieties. The scope and limitations of this approach are also discussed. In addition, the final 1H-tetrazoles could easily be obtained by catalytic hydrogenation in excellent yields (Scheme 2.31).

Scheme 2.31. TMSN3-modified Ugi reaction with trifluoroalkyl cyclic imines and synthesis of N-unsubstituted tetrazoles.

In 2013, Ukaji et al. firstly synthesized the novel 1,5-disubstituted tetrazoles containing tetrahydroisoquinoline skeletons based on the isocyanide based multicomponent reaction in good yields (Scheme 2.32).140 Both aliphatic and aromatic isocyanides are tolerated under this synthetic methodology. They started from the imine analogs, C, N-cyclic N’-acyl azomethine imines based on their property to activate the C=N bond and strongly coordinate to metals. Therefore, when a molecule (Z-X) containing of an electrophilic (Z) and a nucleophilic group (X) could force the intramolecular trapping of the nitrilium intermediate through an N’-acyl group (A) and undergo nucleophilic trapping by X (B) to achieve a multicomponent reaction (Scheme 2.33). They employed the combination of TMSCl and sodium azide, which are less expensive than TMSN3 and also effective in this reaction to afford the tetrazoles. Meanwhile, they also evaluated silyl halides containing other substituents. The results indicated that a large sterical hindrance could reasonably affect the efficient completion of the reaction. A non-fused C, N-cyclic azomethine imines was also examined. The result showed that the absence of the fused aromatic ring does not affect the cyclization occurred.

Page | 46 Review: tetrazoles via multicomponent reaction routes

Scheme 2.32. Synthesis of tetrahydroisoquinoline tetrazoles.

Scheme 2.33. Mechanistic hypothesis.

In 2012, Kazemizadeh et al. firstly disclosed a three-component reaction of isocyanides, carbodiimides, and TMS azide, leading to 1,5-disubstituted 1H-tetrazole derivatives 39 (Scheme 2.34).141 The reaction proceeded smoothly in methanol with a ratio of carbodiimides, isocyanides and TMS azide of 1/1/1 to give the targeted products without the need of any further purification. The mechanism is similar to the classical UT-4CR. Here, carbodiimide reacted similar to a Schiff base and was attacked by the nucleophilic addition of isocyanide. Then the protonation of the resulting adduct leads to the nitrilium intermediate, which subsequently is attacked by the azide anion to form the adduct followed by ring closure (Scheme 2.35).

Page | 47 Chapter 2

Scheme 2.34. Synthesis of 1, 5-disubstituted 1H-tetrazole derivatives.

R2 R R NH HN 2 N 1 R2 R2 C R2 N R2 R1 N N N N N R N N N N N 1 N R1 + N H H R1 N N N N N R2

Scheme 2.35. Proposed mechanism for the formation of 1,5-disubstituted 1H-tetrazoles.

2.3.1.3 Repetitive Ugi tetrazole 4-component reaction

Scheme 2.36. Synthesis of bis-1, 5-disubstituted-1H-tetrazoles.

Gámez-Montaño et al. developed a catalyst-free Ugi-azide repetitive process to quickly prepare a series of five novel bis-1,5-disubstituted-1H-tetrazoles (bis-1,5-DS-1H-T) 40 in excellent yields (Scheme 2.36).142 They simply mixed one equivalent of primary amine, two equivalents of aldehydes and isocyanide and TMS azide in MeOH at room temperature for several hours to afford firstly the mono Ugi product and then upon further microwave heating

Page | 48 Review: tetrazoles via multicomponent reaction routes the repetitive Ugi products in excellent yields. Many proteins in nature exist as symmetrical homodimers, e.g. the HIV-protease. Symmetrical dimeric MCR reaction products might be useful to interact with the interface of symmetrical protein homodimers to stabilize such complexes.143

Scheme 2.37. Two-step synthesis of N-unsubstituted ω-carboxyl α-aminotetrazoles.

In 2014, Dömling et al. also developed an effective procedure for the novel synthesis of highly substituted tetrazole-fused ketopiperazines 43 through Ugi tetrazole/deprotection and Ugi 4CR (Scheme 2.37 and Figure 2.12).100 First, they synthesized the N-unsubstituted α-

Page | 49 Chapter 2 aminotetrazoles by using an Ugi tetrazole reaction; second, the N-unsubstituted α- aminotetrazoles were then employed in a second intramolecular Ugi 4CR reaction to afford the desired products in moderate to good yields. The Ugi tetrazole synthesis was initially performed under Ugi azide conditions with tritylamine (TrtNH2) as the amine component, various aldehydes, and isocyanides derived from α-amino acids and azido trimethylsilane to produce desired tetrazoles. These scaffolds are related to the clinically exploited oxytocin reactor antagonists Epelsiban and Retosiban.144, 145

Figure 2.12. The crystal structures of N-substituted ω-carboxyl α-aminotetrazoles and tetrazole-fused ketopiperazine (CCDC 986844 and 986845).

CN H N N N N NH N N N N HN N CH2O N NC N MeOH, 12h N + H N r.t., > 99% CN 44 N N N N CN N N TMSN3 NC N N N NC 45

N NH N NH N N N N N N N N N N N N NaOH NH GdCl3 NH o ACN/H2O N 70 C, 7d N Gd3+ r.t., 86% N H2O N HN pH 6.7 HN N N N N ~ 40% N N N N N N N N HN N HN N 46 47

Scheme 2.38. Synthesis of the MRI agent Gd-TEMDO involving a key UT-MCR.

Page | 50 Review: tetrazoles via multicomponent reaction routes

a b c Figure 2.13. (a) Crystal structure of Gd-TEMDO; Middle and right: LVO mouse model showing the MRI properties of Gd-TEMDO. MRI obtained from isoflurane-anaesthetized mice; (b) taken 30 minutes after I.P. administration of Gd-TEMDO (0.6 mmol/kg); the heart is fully visible; and (c) heart with reduced brightness; the damaged tissue remains visible due to absorbed Gd-TEMDO following the red line.

Another example of a molecule with multiple tetrazole units was described recently by 146 Boltjes et al. Reaction of cyclen 44 with formaldehyde, TMS azide and β- cyanoethylisocyanide quantitatively yields 45 (Scheme 2.38). The β-cyanoethyl protecting groups was used due to its mild deprotection conditions: LiOH in water at room temperature. The deprotected TEMDO ligand 46 can then be metallated e.g. with any lanthanide metal and the crystal structure of the Gd, Ln and Eu complexes have been published. Moreover, the authors showed the use of the Gd-TEMDO complex 47 in magnetic resonance imaging (MRI) in a left ventricular occlusion (LVO) mouse model (Figure 2.13). The overall complex and magnet properties agreed well with the mostly used Gd-DOTA complex in the MRI field. Clearly, the TEMDO synthesis is short, experimentally simple and high yielding. Moreover, it can be anticipated that many more oligo amino tetrazoles can be synthesized accordingly with interesting material properties.

2.3.1.4 Ugi 4-component reaction on solid phase synthesis (UT-4CR on SPS)

Solid-phase synthesis (SPS) is a method in which a starting material is bound on solid support and reacts with the other reactants in solution. SPS is often performed in sequential syntheses to automate synthesis and intermediate purification, e.g. in oligo-DNA or peptide synthesis. Chemists explored the field of SPS for many years.147 The synthetic application of the solid phase in tetrazole synthesis using MCR started in 1997 when Mjalli et al. firstly produced a small library of 1,5-disubstuted tetrazole derivatives 48 encouraged by their success on solid phase to obtain small-ring lactams, α-(dialkylamino)amids, hydantoin 4-imides, 2-

Page | 51 Chapter 2

thiohydantoin 4-imides (Scheme 2.39). In their synthetic process, amines, aldehydes, NaN3 and isocyanides were simply stirred in a solvent mixture containing methanol and dichloromethane

(CH2Cl2)-water (1:1:0.3) containing pyridine hydrochloride for 4 days to afford the corresponding tetrazole-resin 49. The subsequent cleavable step was accomplished to agitate the Ugi products with 20% trifluroacetic acid (TFA) in CH2Cl2 after washing with methanol and CH2Cl2. Varied amines and aldehydes could lead to the target tetrazoles in this methodology. Probably caused by poor activity of ketones in this reaction, they did not afford the tetrazole under this condition. Only formamide could be detected after stirring for a long time.148

Scheme 2.39. Synthesis of 5-(1’-aminoalkyl)tetrazoles on solid phase.

Continually, in 2011, Ugi et al. also prepared a variety of hydantoinimide and tetrazole derivatives 51 by the combination of two distinguished Ugi reaction in solid and liquid phases separately (Scheme 2.40). Although many types of the combinations of U-4CRs and further reactions have been developed, this was the first time to employ two different types of U-4CRs with the primary amines supported by the polystyrene AM RAM or the TentaGel S Ram. In the first U-4CRs, Fmoc protected amino acid reacted as a carboxylic acid with aldehydes, isocyanides and solid supported primary amines to form the corresponding amides 50. Subsequently, after the cleavage of Fmoc group with 20% piperidine in DMF, the second U- 4CRs was carried out with TMS azide as an acid component and the removal of the resin with TFA treatment led to the final tetrazole derivatives 51 formation. Interestingly, the aromatic aldehydes could be tolerated in the second U-4CR to form tetrazoles with good yields compared with low yields of the hydantoinimides. Moreover, they also compared the two liquid phases combinational MCRs with that of the solid-liquid method. The results showed that the former one could have higher yields.149

Page | 52 Review: tetrazoles via multicomponent reaction routes

Scheme 2.40. Repetitive Ugi reaction on polystyrene AM RAM.

Then Chen et al. employed a Rink-isocyanide resin as a universal platform for classical Ugi reactions to prepare a small library of five 5-substituted 1H-tetrazoles 52. This is the first time that this class of scaffolds was synthesized using an MCR approach (Scheme 2.41).150

Scheme 2.41. Synthesis of 5-substituted tetrazoles on the universal rink-isonitrile resin.

Ferrocene is well known as a sandwich organometallic compound which is a type of organometallic chemical compound consisting of two cyclopentadienyl rings bound on opposite sides of a central metal atom. The rapid growth of organometallic chemistry is often attributed to the excitement arising from the discovery of ferrocene and its many analogues. Characterized by the ability to form metal-centered redox (Reduction-Oxidation) systems leading to oxidized or reduced forms with different properties, ferrocene derivatives exhibit a wide range of pharmacological activities such as displaying interesting cytotoxic, antitumor, anti-malarial, antifungal, and DNA-cleaving activities. Because both N-heterocycles and

Page | 53 Chapter 2 ferrocene moieties contain their distinguished features respectively, the combinations of these characters might increase their biological activity or create new medicinal properties. In 2012, Bazgir et al. synthesized a series of ferrocenyl dialkylamino tetrazoles and ferrocenyl arylamino tetrazoles 53 via an isocyanide-based four component reaction without any catalyst in CH2Cl2 at room temperature and a convenient isolation step (Scheme 2.42).151 This is the first example of an efficient synthesis of ferrocenyl-fused tetrazoles. To explore the scope and limitations of the reaction, both aliphatic secondary amines and aromatic primary amines were employed. Both of them could afford good yields for the final ferrocenyl tetrazoles.

Scheme 2.42. Synthesis of ferrocenyl substituted amino tetrazoles.

Scheme 2.43. On-resin Ugi reactions for the N-terminal derivatization of peptide with lipids, Steroids.

Page | 54 Review: tetrazoles via multicomponent reaction routes

Very recently, Rivera et al. reported an efficient and reproducible method implementing on- resin Ugi reactions with peptides, and its utilization in combination with peptide couplings for the solid phase synthesis of N-substituted and tetrazolo peptides 54 (Scheme 2.43).152

2.3.1.5 Ugi 4-component reaction (PT-4CR) following subsequent post condensation

Multi-component reactions combine two major principles in organic synthesis, convergence and atom economy. One synthetic step could bear three (or more) chemically distinct functions through covalent bonds. Before Ugi replaced carboxylic acid with NaN3 in Passerini reaction to form tetrazoles, Ugi reaction focused on the assembling of amides. However, hydrophilicity might always be a problem for enhancing the bioavailability of drug-like structures, and thus for many applications, more hydrophobic molecule libraries would be of greater value.

Scheme 2.44. Synthesis of bis-quinoxalinone tetrazoles.

The combinations of Ugi reaction with other types’ syntheses are widely recognized as an efficient tool to obtain more varieties in structure through a short reaction process, for example, Ugi/Pictet-Spengler Multicomponent Formation.

Page | 55 Chapter 2

The combinations of MCRs and post-transformation reactions are another tremendously useful tool to increment the complexity and diversity of the molecular scaffolds. There are many classical documented post-transformation reactions, for example, Pictet–Spengler cyclization, intramolecular Diels–Alder reaction, Mitsunobu reaction and acyl migration, Knovenagel condensation, amide reduction, metathesis reaction, Ugi–Ugi and Ugi–Petasis.93, 94, 153-168

The strategies entailing intramolecular variants of the Ugi and post condensation modifications of the Ugi product inspire the development of methodology that enables concise access to diverse pharmacologically relevant compounds. These Ugi variants indeed afforded enticing structures for further diversification. In 2012, Hulme et al utilized the Ugi-Azide MCR to generate unique 1,5-disubstituted tetrazole with ethyl glyoxalate and mono-N-Boc-protected- o-phenylenediamine derivatives 55. The subsequent acid treatment and intramolecular cyclization led to bis-3,4-dihydroquinoxalinone tetrazoles 56 in just two steps but moderate yields (Scheme 2.44). Continually, directly catalytic oxidation using a stable solid-phase radical catalyst (2, 2, 6, 6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) generated the final targeted bis-quinoxalinone tetrazoles 57 (Scheme 2.44).98 They also extended the research to synthesize 3-(1-butyl-1H-tetrazol-5-yl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-2(3H)-one 58 with N-Boc-2-aminobenzylamine. Unexpectedly, the similar acidic deprotecting procedure did not go further to afford the cyclized product and the additional aminolysis of the ester by either activating the ester or the amine failed. In the end, they performed the hydrolysis under basic conditions followed by an EDC-promoted intramolecular amide coupling to obtain 3-(1-butyl-1H-tetrazol-5-yl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-2(3H)-one 60 in 35% (Scheme 2.45 and Figure 2.14).

Scheme 2.45. Synthesis of 3-(1-butyl-1H-tetrazol-5-yl)-4,5-dihydro-1H- benzo[e][1,4]diazepin-2(3H)-one 60.

Page | 56 Review: tetrazoles via multicomponent reaction routes

Figure 2.14. The crystal structure of 3-(1-benzyl-1H-tetrazol-5-yl)-6,7-dimethylquinoxalin- 2(1H)-one exhibiting an antiparallel pi stacking alignment of two adjacent quinoxaline moieties, featuring in addition a low energy antiparallel dipole dipole alignment (CCDC 932013).

1. MeOH (3 M) CHO r.t., 12h NH2 R 2. P(OEt) (5 eq.) R1 1 3 N N NO2 DMF (2M) N 140 oC, 10h + N 24 - 65% N N NC R2 TMSN3 R2 61

N N N N N N Cl N N N N N N N N N N N N

OMe OMe OMe 61a, 65% 61b, 24% 61c, 49%

Scheme 2.46. One-pot tetrazolyl indazole formation.

Driven by the fast and convenient synthetic process of multicomponent reactions (MCRs), numerous novel scaffolds and synthetic methodologies are developed. Among the MCRs and post-condensation examples, most of them refer to the preparation of mono rings or fused structures via C-N and C-C bond formations.169 On the other hand, N-N bond formations were rarely disclosed up to date. El Kaïm et al. envisioned that a N–N bond formation as the Ugi postcondensation transformation could lead to unusual scaffolds (Scheme 2.46).170 They selected starting materials (primary amines and o-nitrobenzaldehyde) to react with TMS azide and various isocyanides to form indazole derivatives 61 in good yields via a highly efficient multicomponent condensation process involving a Ugi-Cadogan cascade. The UT-4CR

Page | 57 Chapter 2 reactions is followed by a Cadogan reductive cyclisation using triethyl phosphite as the reducing agent. A one-pot synthetic strategy was developed and compared with the two-step procedure. It was shown that there is no big difference between these two methods, if so, the one-pot sequence gave a slightly lower yield 61% compared with 62% from two-step. A variety of amines were tested the generality of this reaction. Even sterically hindered amines could lead to the expected products with a slight decreased yield. Aniline gave a sluggish yield probably caused by the lower nucleophilicity of the nitrogen atom. Indazoles are a highly underused but privileged scaffold in drug discovery.171

Figure 2.15. Examples of benzodiazepine-based drugs and tetrazole-based drugs.

Benzodiazepines are important drugs with a wide spectrum of biological and medicinal activities and marketed applications as anxiolytics, anticonvulsants, hypnotics, sedatives, skeletal muscle relaxants, amnestics, just to name a few.172 Besides these classical applications benzodiazepine scaffold is also of interest in numerous other areas, including antagonizing the protein-protein interaction p53-MDM2,173 GPIIbIIIa antagonists,174 and inhibitors of Farnesyltransferase,175 just to name a few. Multiple synthetic pathways are described to benzodiazepines and routes involving MCRs have been known and have been reviewed recently.98, 105, 176-186 Because of privileged scaffold character of tetrazoles and benzodiazepines (Figure 2.15), several researchers designed synthetic strategies to combine the two heterocycles.187 Tetrazoles, due to its good metabolic stability, have received significant attention in drug design field.188 Many examples are presented, like losartan, angiotensin II antagonist, pentylenetetrazole (PTZ), and tetrazole. In 2012, Shaabani et al. firstly disclosed two hitherto unknown IMCRs to afford 1H-tetrazolyl-1H-1,4-diazepine-2,3-dicarbonitriles 62

Page | 58 Review: tetrazoles via multicomponent reaction routes and 1H-tetrazolyl-benzo[b][1,4]diazepines 63 in high yields with regiochemical control via a condensation reaction (Schemes 2.47 and 2.48, and Figure 2.16).189 By varying the isocyanides and ketones component, they explored the scope of this method. The versatility of this multicomponent reaction with respect to 3-oxopentanedioic acid was also studied. Surprisingly, the Schiff base formation did not proceed in methanol in the presence of p-TsOH·H2O.

Scheme 2.47. Synthesis of 1H-tetrazolyl-1H-1,4-diazepine-2,3-dicarbonitriles

Scheme 2.48. Synthesis of 1H-tetrazolyl-benzo[b][1,4]diazepines.

Page | 59 Chapter 2

Figure 2.16. The crystal structure of 1H-tetrazolyl-1H-1,4-diazepine-2,3-dicarbo-nitriles 6a– g and 1H-tetrazolyl-benzo[b][1,4]diazepine (CCDC 814967).

O

OO

or H O R NH N NC 1 2 R1 R and TMSN3 EtOOC MW, 10 min 3 route 1 O o-xylene MeOH, p-TsOH R2 NO2 R + 70 - 90% 2 N r.t. 1 h NC H O TMSN3 R 65 - 70% 2 R1 N

NO NH COOEt R2 N 2 2 H N EtOOC 1. MeOH, r.t. 48 h N NaH, THF N N R2 N O R1 NH2 R1 N N route 2 H 85 oC, 5 h + 2. SnCl2 2H2O N 64 NC N reflux, 12 h R3 40 -46% TMSN3 R2 63 - 70%

H O H O H O N N N

N N N H N H N H N N N N N N N N N N

64a route 1 65% 64b 64c route 2 45% route 1 70% route 2 40%

Scheme 2.49. Synthesis of 1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines.

Shaabani et al. reported a new class of benzodiazepine-containing tetrazole scaffold, 1H- tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines 64, via a two-step condensation reaction of o-phenylenediamines or 2-nitroanilines, ethyl 3-oxobutanoate or 2,2,6-trimethyl-4H-1,3- dioxin-4-one, an isocyanide and trimethylsilyl azide (Scheme 2.49).190 The first reaction involves the cyclocondensation of o-phenylenediamine with a β-ketoester to yield benzodiazepineone Schiff base which reacts in a second step in an azido-Ugi reaction.

Monosubstituted (NO2 and CH3) phenylenediamines reacted highly regioselective as indicated by NMR and only the imine in p-position is formed. The regioselectivity is explained by the

Page | 60 Review: tetrazoles via multicomponent reaction routes electronic effect of the electron-withdrawing or electron-releasing groups. This is in contrast Bougrin’s report in 1994 of opposite regioselectivity. To confirm the regioselectivity, Shaabani unambiguously proved the p-regioselectivity by a crystal structure (Figure 2.17). o- Phenylendiamines are a limiting component in this otherwise interesting scaffold since only a few are commercially available. Therefore, Shabaani elaborated a second variation to this scaffold by first reacting 2-nitroanilines in the azido-Ugi reaction followed by reduction of the o-nitro group, and NaH promoted cyclisation. While the second synthetic access is much more versatile in the o-nitroaniline component, it also involves a longer synthetic route. The overall yields are higher for the first route and also leading to short reaction time.

Figure 2.17. The crystal structure of 4-(1-cyclohexyl-1H-tetrazol-5-yl)-4,7-dimethyl- 1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one (CCDC 900744). The hydrophilic interaction between O and N was measured as 3.0Å.

Sharada et al. developed a facile one-pot, four-component domino reaction between fixed 2- (2-bromoethyl)benzaldehyde, isocyanide, amine, and azide for the synthesis of tetrazolyl- tetrahydroisoquinoline derivatives without any use of catalyst or additive, under ambient conditions, with short reaction times and in good to excellent yields (Scheme 2.50 and Figure 2.18).191 Noteworthy, not even an external base is needed for the intramolecular tetrahydroisoquinoline ring closure. To test the generality of this methodology, various amines with electron donating and withdrawing aromatic groups as well as secondary and tertiary aliphatic isocyanides were employed and afforded good to excellent yields. However, nitro- substituted anilines failed to give the expected products due to amine deactivation through the strong electron withdrawing features. Only one aliphatic amine, cyclohexylamine, was tested and also failed to result in the final ring-closed compound 65. This result suggested that this protocol is only applicable for aromatic amines.

Page | 61 Chapter 2

R2 Br N NH R1 R 2 2 MeOH, r.t. N CHO + N 72 - 99% N NC N NaN R1 R3 3 R3 65 F OMe OMe N N N OMe N N N N N N N N N N N N

65a, 96% 65b, 79% 65c, 76%

Scheme 2.50. Synthesis of tetrazole substituted tetrahydroisoquinolines.

Figure 2.18. X-ray crystal structure of tetrahydroisoquinoline. Thermal ellipsoids are drawn at 30% probability level (CCDC 1012826). Two hydrophobic intereactions between two phenyl groups in two molecules.

The hydantoin (imidazoline-2,4-dione) scaffold is a reoccurring motif in many biologically relevant compounds with anti-convulsant, anti-muscarinic, anti-ulcer, anti-viral, and anti- diabetic activities and recent research compounds show strong BACE binding for potential anti- Alzheimers application.192-197 Hulme et al. described a novel methodology to elegantly obtaining new and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins 67 with three points of variation (Scheme 2.51 and Figure 2.19).198 Initial UT- 4CR using glyoxale ethylester as not variable oxo input, followed by the treatment of the Ugi intermediate with an excess of isocyanate or isothiocyanate to generate the final scaffold in moderate to good yields. Various amines, isocyanides and isocyanates or isothiocyanate were used to test the generality of this methodology. Due to the general availability of a large number of isocyanide, aldehydes, ketones and iso(thio)cyanates this reaction sequence is of high combinatorial value representing a large chemical space.

Page | 62 Review: tetrazoles via multicomponent reaction routes

O COOEt R1 CHO NH2 o N EtOOC R1 DCE, MW, 120 C, 1 h R1 N 1. TFA, r.t., 12 h R N N 3 N + H N NC N 2. R3NCX N TMSN R N O N 3 2 R2 EtOH, r.t., 2 - 36 h, 49 - 79% N R2 or EtOH, MW, 120 - 180 oC 66 25 - 99% 67

O O O O COOEt N N N N N N N H N H N H N N N N N N

Cl

66a, 54% 66b, 43% 66c, 60%

O O S N N NH N N Br N N N N N O N N N N O O N N N N Cl

4-Br-PhNCO PhNCO TMSNCS 67a, 77% 67b, 64% 67c, 25%

Scheme 2.51. Synthesis of 1,5-substituted tetrazole hydantoins and thiohydantoins.

Figure 2.19. The crystal structure of a 4-bromophenyltetrazolohydantoine featuring two short contacts (3.2 and 3.3 Å) between the p-Br and N2 and N3 of an adjacent tetrazole moiety exhibiting halogen bonding character (CCDC 922820).

Isoindoline is a heterocyclic organic compound with a bicyclic structure, consisting of a six- membered benzene ring fused to a five-membered nitrogen-containing ring. The compound's structure is similar to indoline except that the nitrogen atom is in the 2 position instead of the 1 position of the five-membered ring. No Isoindoline has been found in nature, but several related derivatives have. Due to their broad structural diversity and broad-spectrum biological activities, many biologically active compounds have been discovered, i.e. Endothelin-A Receptor Antagonists, inhibition of prolyl dipeptidase DPP8, PPARd agonists, histone deacetylase inhibitors, inhibitors of selective serotonin reuptake, diuretic, NMDA receptor antagonists, herbicidal, anti-inflammatory, and antileukemic agents. Yet, various synthetic

Page | 63 Chapter 2 procedures have been reported for the preparation of isoindoline core structural skeletons. Frequently encountered problems list for the use of expensive starting materials/catalysts or high catalyst loadings, suffer from a long reaction time, difficulty in workup, high temperature, and with fewer points of diversity. Meanwhile, palladium catalysis often acts for the formation of carbon–carbon and carbon–heteroatom bonds. Moreover, isocyanide insertion under palladium catalysis has attracted considerable attention to synthesize the biologically important heterocycles due to this is an efficient but relatively unexplored method.

R1 NC R1 CHO R3 NH2 R2 R1 X Pd(OAc) , Cs CO MeOH, r.t. 7 h 2 2 3 N H R N N X 2 DMF, 90 oC, 1 h N + 79 - 95% N N R3 N NC H R N N N 65 - 75% 2 N TMSN3

68 69

Br Br F Br N N N N N N N H N H N H N N N N MeO N N MeO

68a, 95% 68b, 88% 68c, 80%

N H H H N N N N N N N N N N N N F N N N N N MeO 69a, 70% 69b, 75% 69c, 68%

Scheme 2.52. General strategy for the synthesis of tetrazole-isoindoline.

Figure 2.20. ORTEP diagram drawn with 30% ellipsoid probability for non-H atoms of the asymmetric unit of the crystal structure of (E)-3-(tert-butylimino)-2-(4- methoxybenzyl)isoindolin-1-onedetermined at 293 K (CCDC 959960). The interaction between O of lactam and methyl of tert-butyl was measured as 3.5Å.

Page | 64 Review: tetrazoles via multicomponent reaction routes

Recently, Chauhan et al., firstly employed a two-step combination of efficient Ugi-azide reaction and palladium-catalyzed cyclization with isocyanide insertion for the synthesis of tetrazole isoindolone 69. They constructed a series of 1, 5-disubstituted-1H tetrazoles with good to excellent overall yields. And the reaction condition tolerated a wide range of functional groups (Scheme 2.52 and Figure 2.20).199

The intramolecular Mannich reaction of electron rich aromatic rings with oxo components and 1o or 2o amines, also called Pictet–Spengler reaction is an often used postmodfication in MCR.200-207

Scheme 2.53. Synthesis of 2-tetrazolylmethyl-2, 3, 4, 9-tetrahydro-1H-β-carbolines.

El Kaim et al. firstly prepared an array of tetrahydro-1H-β-carboline-tetrazoles 71 in excellent overall yields using Ugi-azide/Pictet Spengler (Scheme 2.53).142 Tryptamine was used as a fixed starting material in the Ugi-azide reaction and the subsequent Pictet-Spengler reaction was performed with formaldehyde to form a series of 2-Tetrazolylmethyl-2,3,4,9-tetrahydro- 1H-β-carbolines either under refluxing conditions in methanol/toluene or under microwave conditions in the same reaction solvent with generally good to excellent yields. A direct comparison of the two methods of Pictet Spengler ring closure reveals that the yields are similar;

Page | 65 Chapter 2 however, the microwave variation was generally slightly less yielding. β-Carbolines are heterocyclic systems isolated from natural sources and therefore tetrahydro-β-carbolines are often key intermediates in natural product syntheses. Due to their structural similarity with a number of neurotransmitters, they are also incorporated in numerous compounds with biological activity.

2.3.1.6 The TMS azide modified Ugi 4-component reaction to synthesize 1,5- disubstituted tetrazoles containing sugar moiety

Many natural products are glycosylated and their biological activity is crucially dependent on the glycosylation. Glycosylation is the reaction in which a carbohydrate is attached to a hydroxyl or other functional group of another molecule. In living organism, glycosylation mainly represents the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells (along with DNA, RNA, and proteins). Glycosylation is a form of co-translational and post-translational modification.

In 2006, Dömling et al. introduced a ubiquitously occurring desosamine into isocyanide based multicomponent reaction chemistry (Scheme 2.54). They prepared desosamine 72 in a big scale by acid hydrolysis from readily available erythromycin and subsequent aminolysis. Subsequently, two syntheses were accomplished by stirring 1 mmol each of TMS-azide, aldehyde, 2-amino desosamine and the corresponding isocyanide in methanol at room temperature for 24 h to give the products as a mixture of diastereomers in 37% and 25% yield respectively.208

Another successful application of sugar moieties in MCRs also presented by Dömling et al. in 2015 (Scheme 2.55).209 In their last research work, they synthesized 1-isocyanodesosamine and employed desosamine as the amino resource in IMCR. In the present case, they synthesized a series of glycosyl isocyanides, which has been known and sporadically used in IMCRs. Sugar moieties in drugs are used for different purposes, e.g. the glycosyl substituent will be recognized by the receptor and contribute directly to the biological activity, or it helps to improve transport properties through transporters and increase water solubility. Glycosyl-organic fragment chimeras are traditionally synthesized by sequential multi-step synthesis.

Page | 66 Review: tetrazoles via multicomponent reaction routes

Scheme 2.54. (1) Acid hydrolysis of erythromycin yields desosamine 72; (2) preparation of 1-aminodesoasamine from desosamine and ongoing synthesis of 1-isocyanodesosamine 73; and (3) synthesis of disubstituted α-aminomethyl tetrazoles 74 according to Ugi.

Scheme 2.55. Synthesis of 1,5-disubstituted tetrazoles using glycosyl isocynide and arabinosyl isocynide.

They utilized our recently introduced Leuckart–Wallach approach to synthesize a class of anomeric sugar isocyanides in good overall yields and two steps including (2R,3R,4S,5R,6R)- 2-(acetoxymethyl)-6-isocyanotetrahydro-2H-pyran-3,4,5-triyl triacetate and β-anomer. They

Page | 67 Chapter 2 also gave the general usage of these two isocyanides in IMCRs to produce 1,5-disubstituted and α-alkylamino tetrazole derivatives 75.

The conjugation of steroids to other biomolecules, like amino acids and proteins, is a common strategy employed both by nature and chemists to modulate the biological and chemical behavior of these molecules. Considering the growing importance of sugar/steroid hybrids in drug discovery and biological chemistry, Rivera et al., firstly employed multicomponent reactions for the conjugation of carbohydrates to steroidal derivatives 76 with the great level of molecular diversity and complexity that generates with low synthetic cost (Scheme 2.56). This protocol contributed to the construction of glycoconjugate libraries by utilizing the assembly of steroidal macrocycles.210

Scheme 2.56. Synthesis of tetrazole-based spirostan saponin analogs.

Calixarenes, are a type of macrocycles or cyclic oligomers produced by the condensation of p-substituted phenols with aldehydes. They have been widely used in various fields, i.e. the synthesis of multivalent/multifunctional ligands. They are the ideal candidates for studying noncovalent interactions occurred in many biological processes based on the easy accessibility and functionalization at their wide and narrow rims. Moreover, tetrazoles and their derivatives are important nitrogen heterocyclic compounds, which possess a broad range of biological

Page | 68 Review: tetrazoles via multicomponent reaction routes activities in both medicinal and pharmaceutical areas.211 Beside, owing to the four nitrogen atoms in the tetrazole ring, it is interesting to be act in coordination chemistry.212-215

Therefore, Zadmard et al. chose to synthesize more functionalized calixarenes 77 through multi-component reaction (Scheme 2.57 and Figure 2.21). Compared with parelled reaction strategy, multicomponent reaction could generate of diverse sets of complex molecules in short period. The presence of numerous nitrogen atoms makes a bidentate bonding mode likely for metal ion complexation. They firstly prepared the basic precursor calixarene dihydrazide with good yield using the previously reported synthetic procedure for the latter investigation.216

O

R R MeOH, r.t. 1 2 O OH OH O 24 h 58 - 80% O OH OH O NH HN + O O NH2 H2N NH HN O R O R1 NH HN 1 R R2 TMSN NC 2 3 R3 N N R3 N N R3 N N N N 77

OH OH O OHOH O O OH O O OH O

NH HN NH HN O NH HN O O O O O NH HN NH HN NH HN N N N N N N N N N N N N N N N N N N N N N N N N

77a, 80% 77b, 70% 77c, 58%

Scheme 2.57. Synthesis of calixarene dihydrazide via Ugi-azide reaction.

Figure 2.21. The crystal structure of calixarene dihydrazide (CCDC: 1025095). Four hydrophobic interactions of two molecules were observed as O (C=O) and methyl, N(2) and

Page | 69 Chapter 2 methelen of calixarene ring. Six hydrophilic interactions consist of four interactions between N(4) of tetrazole and N of hydrazine, two interactions between hydroxyls and O of calixarene ring.

2.3.1.7 Synthesis of tetrazole using Passerini 3-component reaction (PT-3CR)

Passerini reaction involved an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form an α-acyloxy amide. Isocyanide was firstly introduced into MCR in 1921 by Passerini.217, 218 And the first application of azides in the Passerini reaction to synthesize tetrazole was first reported by Ugi in 1961.219

Scheme 2.58. Passerini reaction to form tetrazoles.

Aspartyl proteases which catalyze amide bond hydrolysis could be found to play a key role in many biological processes, including the development of a variety of diseases and the important therapeutic targets. Several common amide isosteres and secondary alcohols could be utilized as the mimetic of the tetrahedral intermediate. Moreover, considering to enhance pharmacological properties of enzyme inhibitors, 1, 5-disubstituted tetrazoles were prepared and provided a strong evidence for the role of the cis amide conformation in receptor recognition. Hulme et al. reported the facile synthesis of analogous cis constrained norstatine mimetics 78 by simply mixing an N-Boc-amino aldehyde, an isocyanide and trimethylsilylazide in dichloromethane, followed by deprotection with TFA and N-capping with TFP esters to the

Page | 70 Review: tetrazoles via multicomponent reaction routes desired amides and sulfonamides 79 in good isolated yields. This reaction proved to tolerate a range of functionalities including a variety of isocyanides and N-Boc-α-amino aldehydes (Scheme 2.58).168

Scheme 2.59. Catalytic enantioselective synthesis of 5-(1-Hydroxyalkyl)tetrazole 80 by three-component Passerini Reaction (P-3CR).The Catalyst 81 was applied for the enantioselective synthesis of 1-(4-methoxyphenyl)-5-(1-hydroxyisobutyl)tetrazole by P-3CR.

Chiral 5-substituted tetrazoles have been recognized as efficient organocatalysts.220-224 Many methods have been developed for the synthesis of 1,5-disubstituted tetrazoles, including the 5- (1-hydroxyalkyl)tetrazoles. In 2008, Zhu et al. firstly reperted to synthesize enantioselective 5- (1-hydroxyalkyl)tetrazole 80 catalyzed by a [(salen)AlIIIMe] (salen=N,N’- bis(salicylidene)ethylenediamine dianion) through Passerini-type reaction of aldehydes, isocyanides and hydrazoic acid with good-to-excellent enantioselectivity (Schemes 2.59 and 2.60). Four different catalysts were optimized in several reaction conditions.225 With the optimized conditions and ctoichiometries for the reaction (isobutyraldehyde/1-isocyano-4- methoxybenzene/HN3/81 = 1.2/1/2.5/0.1), they also examined the generality of this catalytic enantioselective process by varying the structure of the aldehyde and isocyanide. They found that aliphatic aldehydes and those with a potentially coordinating pyridine ring could tolerate these reaction conditions even as the expense of markedly reduced yields, while aliphatic and aromatic isocyanides with electron-donating or electronic-withdrawing groups behaved effectively as reaction partners. However, in the case of the sterically encumbered 2,6- dimethylphenylisocyanide, yield and enantio-selectivity both diminished. When α- isocyanoester was used, a spontaneous hydrolysis/lactonization sequence proceeded well. Based on the facts that salen-Al complexes catalyze the nucleophilic addition of azide to α, β- unsaturated imides and to α, β-unsaturated ketones, they also performed a tandem Michael addition/enantioselective P-3CR using an α, β-unsaturated aldehyde as the carbonyl substrate.

Page | 71 Chapter 2

The results showed that 1-(4’-methoxyphenyl)-5-(1’-hydroxy-3-azidopropyl)tetrazole 82 could be obtained with a good yield and enantio-selectivity (Scheme 2.61).

Scheme 2.60. Proposed mechanism for the formation of tetrazole and amide byproduct.

Scheme 2.61. Tandem Michael addition/enantioselective P-3CR to functionalized tetrazoles.

Scheme 2.62. Synthesis of alkoxylated 1H-tetrazole products.

Generally, when a reaction component in the established MCRs is replaced by a substrate having different reactive functionalities, this synthetic methodology potentially could lead to a new class of compounds. In 2012, Yanai et al. developed a novel four component reaction of aldehydes, isocyanides, TMS azide, and free aliphatic alcohols without amines catalyzed by the chemically stable, soft, and mild Lewis acid indium(III) triflate [In(OTf)3] to give rise to

Page | 72 Review: tetrazoles via multicomponent reaction routes

α-alkoxyamides 83 in good yields (direct O-alkylative P3C reaction) (Scheme 2.62 and Figure 2.22). Aliphatic and aromatic aldehydes both tolerated this synthetic mythology.226

Figure 2.22. The crystal structure of (E)-1-(tert-butyl)-5-(1-(cyclopentyloxy)-3-phenylallyl)- 1H-tetrazole (CCDC 862990).

OH CHO H2O-NaOTs N 2 R ++NaN3 NC R N air, r.t. N N

84 OH OH N N N N N N N N

84a 84b 45% 4 M NaN3 >90% 3.8 M NaOTs 10 equiv. NaN3 95% 3.8 M NaOTs 10 equiv. NaN3

Scheme 2.63. Passerini reaction to form tetrazole under the “in Water” or “in NaOTs” conditions.

Although the reaction conditions in MCRs are more environmentally benign compared with the classical tetrazole synthetic methods, it is of great interest to employ water as the reaction solvent. To date, the beneficial effects of water on a variety of organic transformations have been widely recognized:227-229 the poor hydration often facilitates to obtain higher reactivity and/or selectivity when compared with reactions in organic media. Several features of water, such as high cohesion energy density, hydrogen bonding-stabilized transition state, enhanced hydrophobic effect in the ground vs. transition state, could explain the reaction acceleration in aqueous media.227, 228, 230-236 Meanwhile, there are only a few reports about the influence to the selectivity of organic reactions by adding salt. Herein, based on these theoretical cornerstones and rare previous works, Vigalok et al. demonstrated that simple sodium salts addition in Passerini reaction in aqueous media can completely reverse the product ratios. Furthermore, the use of the “salting-in” salt and a small excess of the nucleophile could lead to significantly

Page | 73 Chapter 2 higher yields of Passerini products 84 instead of more equivalence of the nucleophile participation (Scheme 2.63).237

2.3.1.8 Other monocyclic tetrazole MCRs

In 2011, Shaabani et al. reported an efficient and simple two-step strategy for the preparation of 1,5-disubstituted tetrazole derivatives containing siloxy 85 or sulfonamide groups 86 via an isocyanide-based MCR (IMCR) in fairly good yields (Scheme 2.64 and Figure 2.23). By simply mixing isocyanides, dialkylacetylenedicarboxylates, and triphenylsilanol the products are formed. First, a formal 1:1:1 addition reaction takes place selectively, yielding ketenimines containing a siloxy group in high yields. Next an intermolecular cycloaddition reaction of the siloxy ketenimines with TMS azide yields the corresponding 1,5-disubstituted tetrazoles.238

Scheme 2.64. Synthesis of 1, 5-disubstituted tetrazoles.

The reaction of N-halo succinimide, sodium azide, phenylisocanide in chloroform with a PTK yields 5-halo-1-phenyltetrazole 87 in a 3-component reaction.239-241 5-Halo-1-substituted tetrazoles might be interested building blocks, e.g. in Pd catalyzed C-C couplings (Scheme 2.65). For example the synthesis of tetrazolyl β-lactam systems was described using 5-halo-1-

Page | 74 Review: tetrazoles via multicomponent reaction routes benzyltetrazole as a coupling building block.242 Another tricyclic benzodiazepine scaffold is discussed in the chapter tricyclic tetrazoles.

Figure 2.23. The crystal structure of (3R)-di-tert-butyl 2-(1-(tert-butyl)-1H-tetrazol-5-yl)-2- methyl-3-((triphenylsilyl)oxy)succinate. It shows two short intermolecular interactions, O

(C=O) and C (CH3 in tert-butyl group) (CCDC 817391).

I N I NC N N O N O H2O, HCCl3 N +NaN3 + Me4NBr

87, 90%

Scheme 2.65. Synthesis of 5-halo-1-substituted tetrazoles and tetrazolyl β-lactam systems.

2.3.1.9 The tetrazole-lactam derivatives synthesized by Ugi reaction

CHO X X X NH2 X X COOMe R1 NaOEt, EtOH heat X MeOH, 2 days COOMe 84 - 92% + O NC 73 - 78% R1 N or spontaneous N N R N N TMSN3 2 H N 11 - 79% N R1 N N N R R2 2 88 89

MeO

MeO O N N O N N N N N O N N N N N N S O N N O Cl

89a, 70% 89b, 11% 89c, 71%

Scheme 2.66. Synthesis of tetrazolyl-isoindolinones via Ugi-CC/intramolecular amidation.

To obtain heterocyclic systems by means of post-condensation modifications of the Ugi reaction, Marcaccini et al. employed methyl o-formylbenzoates as bireactive carbonyl

Page | 75 Chapter 2 components and mixed it with amines, isocyanides, and trimethylsilyl azide to afford the expected tetrazolyl-isoindolinones 89 with good isolated yields via a tandem Ugi four- component condensation/intramolecular amidation (Scheme 2.66).243 In some cases the intermediate Ugi tetrazole intermediate cyclized spontaneously in other cases the cyclisation occurred only in ethanolic sodium ethanolate under refluxing conditions. Aliphatic amines generally cyclized spontaneously and also precipitated in a pure form fromthe mother liquor, whereas deactivated anilines needed forced conditions for cyclisation.

Hulme et al. established a similar postcondensation modification methodology which reacted keto-esters (methyl levulinate), primary amines, isocyanides, and TMSN3 in one-pot via the Ugi−Azide reaction followed by the lactam formation under acidic condition to afford a small library of novel peptidomimetic-like bispyrrolidinone tetrazoles 90 (Scheme 2.67).244 Noteworthy is this is the first example of a TFA mediated γ-lactam formation. Sterically hindered amines gave no or low yields, such as 2,6-dichlorobenzylamine, 4-morpholinoaniline, 1-benzylpiperidin-4-amine and cyclohexylamine. A virtual library of 400.00 compounds was enumerated and compared to the NIH molecular libraries small molecule repository (MLSMR) to show uniqueness of occupancy of chemical space by principal component analysis. A small library of 84 compounds was physically generated in 24-well plates. The yields ranged from 2 to 84%.

Scheme 2.67. General synthetic route to access bis-pyrrolidinone tetrazole.

In 2013, Hulme et al. expanded the Macros et al. procedure by an unprecedented significant scope expansion and combinatorial applications towards novel pharmacologically relevant complex bis-heterocyclic lactam-tetrazoles.245 Seven series of bis-heterocyclic lactam-

Page | 76 Review: tetrazoles via multicomponent reaction routes tetrazoles were synthesized: tetrazolyl-pyrrolidinones 91, indolinonetetrazoles 92, thiomorpholinone-tetrazoles 93, 4-sulfonyl-2-piperazinone-tetrazole derivatives 94, 4,5,6,7- tetrahydropyrazolo[1,5-a]-pyrazine-4-one tetrazole derivatives 95, [1,4]thiazepanone derivatives 96 and benzo[1,4]oxazepinone derivatives 97 (Figure 2.24 and Table 2.4).

Figure 2.24. Diversity of bis-heterocyclic lactam-tetrazoles.

Depending on the used oxo-carboxylic acid esters, quite different cyclisation conditions were applied. In the tetrazolyl-pyrrolidinones series 91 simply TFA in DCM was added after completion of the Ugi tetrazole reaction. Alternatively, the Ugi intermediate was isolated, purified and then subjected to methanolic KOH solution to afford the tetrazolyl-pyrrolidinones. The methodology was importantly shown to be compatible with 96-well plate based production. Yields reported for 8 isolated compounds varied between 40 and 78%.

Advantageously for library synthesis applications, the tetrazolyl-pyrrolidinone series 91 could be formed in-situ from the intermediate Ugi tetrazole upon addition of TFA without removing methanol from the first step. On contrary, upon removal of solvent, cyclization was drastically diminished and only trace amounts of cyclic products were obtained. Finally, the

Page | 77 Chapter 2 cyclized step was carried on basic condition followed the isolation of Ugi intermediates. Moreover, 8 more tetrazolyl-pyrrolidinones were obtained with this strategy.

Tetrazolyl-indolinones 2-acetylbenzoate 92 was found to be a poor substrate in the Ugi reaction, while methyl 2-formylbenzoate worked well in all 8 cases (36 - 66% yield). As described previously the cyclisation occurred spontaneously at room temperature.

In the 6-membered piperidinone-tetrazoles, cyclisation is accomplished by KOH mediated hydrolysis of the Ugi tetrazole methylester followed by EDC/DMAP cyclisation or thionylchloride medicated cyclisations. Interestingly, by using 5-oxo-hexanoic acid the Ugi tetrazole product 98 is formed exclusively and no trace of the alternatively possible Ugi lactam 99 is formed (Scheme 2.68).

Scheme 2.68. Selective tetrazole formation over the intramolecular Ugi product.

The intermediate and unisolated Ugi tetrazole can then be cyclized using DCC in situ. The author argued that the small and strongly nucleophilic azide ion leads to a kinetically favorable formation of the 4-component Ugi tetrazole product. Several examples underpin the generality of the reaction.

Then they found the integration of a sulfur atom into the 6-member ring to generate tetrazole- thiomorpholinone derivatives 93 might be another interesting scaffold. Under optimized conditions, the intermediate Ugi tetrazole was hydrolyzed and subsequently the intramolecular amidation using SOCl2 in DCM afforded 5 isolated products in yields ranging from 22 to 96% yield.

The 4-sulfonyl-2-piperazinone skeleton 94 can be incorporated into the Ugo tetrazole reaction sequence by choosing the appropriate starting material (Figure 2.24). The 4-sulfonyl-2- piperazinone motif represents an essential structural feature of human factor XIa and gene transcription inhibitors. 246, 247 A series of six 4-sulfonyl-2-piperazinones were generated with yields between 16 and 74% for the Ugi tetrazole reaction, and 58 – 93% for the hydrolysis and cyclisation step respectively.

Page | 78 Review: tetrazoles via multicomponent reaction routes

Table 2.4. Synthesis of bifunctional building blocks in the Ugi-azide condensation reaction

Oxo-component Ugi-azide product Yield (%) Condensation product Yield (%)

NA NA 40 - 78

NA NA 29 - 66

42 - 86 58 - 93

16 - 74 58 - 93

42 - 74 51 - 78

61 - 75 45 - 66

63 - 80 29 - 84

Intrigued by the potentially pharmaceutical applications of unprecedented bifunctional scaffolds, a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazine-4-one 95 were synthesized with moderate to good isolated yields through the combination of UT-4CR and subsequent basic hydrolysis and SOCl2-mediated ring closure step. Five compounds were isolated in yields between 42 - 74% and 51 - 78% for the UT-4CR and cyclisation, respectively.

Page | 79 Chapter 2

Also several 7-membered lactam motifs were also introduced. Four examples of azepinone- tetrazoles were synthesized in two steps comprising consecutive basic hydrolysis and in situ acyl chloride formation.

A small series of five [1,4]thiazepanones 96 was synthesized by UT-4CR, KOH hydrolysis and SOCl2 mediated cyclisation in yields between 61 - 75% and 45 - 66% for the UT-4CR and cyclisation, respectively.

Last but not least the benzo[1,4]oxazepinone motif 97 was incorporated into the UT-4CR by employing the appropriate benzaldehyde starting material. Six compounds were isolated with yields between 66 - 80% and 31 - 84% for the UT-4CR and cyclisation, respectively (Figure 2.25).

In summary, the reaction of suitable protected or unprotected orthogonal oxo-carboxylic acids yields a great diversity of bis-heterocyclic lactam-tetrazole scaffolds. Many contain fragments of importance in medicinal chemistry. Cleary many of these scaffolds can be synthesized in parallel to provide libraries of interesting compounds.

Figure 2.25. Crystal structure of a benzo[1,4]oxazepinone derivative (CCDC 936637). Noteworthy is the hydrogen bond (3.0 Å) and a short contact (3.3 Å) between N4, O9 and N3, C10.

In an analog fashion, Stolyarenko et al. used 1-ethoxycarbonyl-cycloalkane oxo compounds, isocyanides and primary amines in the UT-4CR to afford the interesting class of tetrazole- substituted spirocyclic -lactams 100. 248 No spontaneous cyclisation occurred under the UT- 4CR conditions (MeOH, r.t.), but it was accomplished under acidic conditions in DCE with 10% TFA under heating conditions for 10h. A library of 20 compounds was produced with yields between 52 and 72% (Scheme 2.69). Noteworthy the substrate scope of the reaction is quite broad, including aliphatic, aromatic and bulky isocyanides and heterocyclic, aliphatic and aromatic primary amines. Moreover, the straightforward introduction of a spiro tetrohydro-2H-

Page | 80 Review: tetrazoles via multicomponent reaction routes pyran is noteworthy, which otherwise is very difficult to access. Tetrohydro-2H-pyranes are used in medicinal chemistry to improve pharmacokinetic and CYP inhibition profile of lead compounds.249 Moreover, a spirocyclic connection adjacent to an amide carbonyl might protect from spontaneous or enzymatic cleavage. Spirocyclic fragments are present in many biologically active compounds. The -lactam moiety is also the common structural unit for a large nootropic class of drug, called racetams (e.g. Piracetam). Racetams are memory enhancer and are hypothesized to work through interaction with cholinergic and glutamate receptors in the central nervous system. Therefore, compounds containing such spirocyclic N-substituted g- lactams are of great interest.

Scheme 2.69. Synthesis of tetrazole-substituted spirocyclic γ-lactams by one-pot azido-Ugi reaction-cyclization.

They used 4 different -oxo esters 101 are prepared from the corresponding cyclic esters, by LDA induced allyl bromide addition, followed by sodium periodate oxidation with catalytic amounts of OsO4 (Scheme 2.70), in all cases in excellent yields >75% over two steps.

Scheme 2.70. The prepared route for γ-oxo esters 101.

The author also described the crystal structures of two compounds, which give some ideas on the 3D conformation and intermolecular contacts (Figure. 2.26).

Page | 81 Chapter 2

Figure 2.26. Crystal structure of a tetrazole-substituted spirocyclic -lactam (CCDC 918594 and 918596). Noteworthy is the anti-parallel alignment of the phenyl units of two adjacent molecules with short contacts (3.6Å, 3.7Å, 4.1Å) between C (SP3) and C (SP2). Similarly, there is also the semi-anti-parallel alignment of the phenyl units and lactam ring of two adjacent molecules with short contacts (3.1Å, 3.2Å) between O (C=O) and C (SP2).

COOMe NH2 MeOOC CHO Trt n 1. TFA/CH2Cl2 O n MeOH, 100oC Trt N 1 min, r.t. n + N N HN N MW, 30 min H 2. NaH, THF N NC N N TMSN3 R R r.t., 4 h N N R 102 103

COOMe COOMe COOMe

N N N N N N H N N N N H H N N N N N

102a, 50% 102b, 68% 102c, 40%

O N N O N O N N N H N H N N N H N N N N N

103a, 89% 103b, 99% 103c, 95%

Scheme 2.71. Devised synthetic pathway to tetrazolo N-unsubstituted γ- and δ-lactams 103.

The N-unsubstituted γ- and δ-lactam moiety is a fragment of broad medicinal chemistry importance, occurring for example in the anti-Parkinson drug oxotremorin, and in the anti- rhinoviral and -enteroviral rupintrivir. The substitution on the lactam nitrogen position clearly affects its hydrogen bonding profile in the receptor binging site. Dömling et al. posited their interests on designing and synthesizing a series of N-unsubstituted γ- and δ-lactams 103 which are conveniently difficult to access in a three step synthesis involving a UT-4CR followed by cyclisation with overall good yields.250 While ammonia is often troublesome in the Ugi reactions tritylamine was introduced as a convenient ammonia surrogate. However, due to the

Page | 82 Review: tetrazoles via multicomponent reaction routes bulkiness of the trityl group, only aliphatic aldehydes gave good yields between 40 and 80%. Ketones did not give the required Schiff base. With aromatic aldehydes, only in some cases a moderate yield was observed. The trityl amine tetrazole intermediate was deprotected in quantitative yields using TFA in DCM. Optimization of the final cyclisation conditions revealed that using sodium hydride is a suitable base to afford γ- and δ-lactams in most cases with reasonable to good yields (Scheme 2.71).

A typical interaction pattern of the γ- and δ-lactam sub structures was found by analyzing the PDB. A general strong tri-directional hydrogen bond donor-acceptor interaction between the receptor amino acids and the N-unsubstituted γ- and δ-lactam fragment reveals a useful molecular moiety to address corresponding receptor motives (Figure 2.27). The same motive is generally found in the X-ray structures of small tetrazolo-lactams leading to dimerization via the γ- and δ-lactam NH-CO group.

Figure 2.27. Crystal structure of a tetrazole fused γ-Lactams (CCDC 961190). Noteworthy is that there is a pair wise hydrogen bonding with a neighbor lactams with short contacts (2.9 Å) between N6, O1 and N6’ O1’.

2.3.2 Bicyclic tetrazole derivatives

2.3.2.1 The TMS azide modified Ugi 4-component reaction to synthesize 1,5- disubstituted tetrazoles in macrocycles

Macrocycles are commonly presented in natural products, and several macrocycles are marketed as drugs. Macrocycles are a fascinating and however, underrepresented class of compounds in medicinal chemistry. They do not behave according to drug-likeliness rules and nevertheless, can lead to oral bioavailability. Due to their large cycle size from 10 - 25 membered they show on the one hand side conformational restriction but on the other hand, are very flexible and can show multiple conformations. Due to their large surface area, macrocycles are assumed to be useful to target nontraditional protein-protein interaction targets, which often are large, flat and featureless. Protein-protein interaction targets in most cases currently are the

Page | 83 Chapter 2 domain of antibodies. Artificial macrocycles have therefore, recently experienced a renaissance as scaffolds in medicinal chemistry. Unfortunately, there are few short, diverse and general synthetic pathways towards this interesting class of compounds.

Figure 2.28. Four X-ray structures of macrocycles of different size involving different MCR assembly routes and different substituents. The most occupied interactions are included the interactions between N of tetrazole and C of cycles, O and C of cycles, C and C of cycles. The intramolecular bindings are mostly between O and N (CCDC 1408649, 1408650, 1408653 and 1408654).

O O o NH 1) MeOH, MW, 100 C, 15 min R NC O R 2 1 KO 1 R3 56 - 96% R2 R2 R1 R2 R3 N n CN N N N NC 2) TFA, CH2Cl2, r.t. H N Et3N, HOBt, DCC n H N TMSN3 R4 67 - 90% N N MeCN, 48 h N N R 4 40 - 75% R4 MCR 1 104 105 O R1 O R2 N NH R3 O R1 2 n 1.5 eq. KOH R2 R R R7 N O CN N 5 6 N N N EtOH n H N MeOH (0.01 M), r.t. N NH N N 17 - 34% n R4 R2 N MCR 2 R3 R4 O 106 107

O O H O O N Cl N O N NH NH N HN O

O N N N O N N N N N H O N N N N H N N 107a, 30% 107b, 27% 107c, 36%

Scheme 2.72. Ugi/U-4CR derived macrocycle synthesis pathway and some examples with macrocyclisation yields after purification.

Page | 84 Review: tetrazoles via multicomponent reaction routes

Multicomponent reactions for accessing macrocycles was firstly reported by Failli and Immer.251 Dömling et al. recently introduced α-isocyano-ω-carboxylic acids in macrocycle synthesis via Ugi reaction. They focused on the cyclisation using bifunctional α-isocyano-ω- carboxylic acids to leverage the most versatile building blocks primary amine and oxo component to incorporate into the macrocycle (Scheme 2.72 and Figure 2.28).252

2.3.2.2 The TMS azide modified Ugi 4-component reaction to synthesize 1,5-disubstituted bicyclic tetrazoles derivatives

In 1998, Bienaymé et al. rigidified the basic UT-4CR scaffold of α-alkylaminotetrazole to result in the 7,8-dihydrotetrazolo[1,5-a]pyrazine scaffold 108 (Scheme 2.73).253 In this procedure they mixed an oxo component, a primary amine, methyl-β-(N,N-methylamino)-α- isocyanoacrylate and trimethylsilyl azide a ratio of 1/1/1/1.4 at ambient temperature in molar methanolic solutions to give an intermediate UT-4CR adduct. Methyl-β-(N,N-methylamino)-α- isocyanoacrylate in honor of its inventor also called Schöllkopf’s isocyanide is a very useful isocyanide for a lot of different heterocycle syntheses.254 Subsequent treatment with diluted acid catalyzes the secondary amine attack and dimethylamine substitution under ring formation to form the final bicyclic product. Overall yields were fair to good. Interestingly, there were two intermediates, a diastereomeric mixture, which could survive chromatographic purification. However, after treating with diluted aqueous acids, both intermediate adducts apparently converted into their cyclized final products.

Scheme 2.73. Synthesis of 7,8-dihydrotetrazolo[1,5-a]pyrazines.

In 2000, Hulme et al. disclosed an efficient one-step protocol, involving a Ugi reaction followed by a post-condensation reaction to access 6,5-fused tetrazole system 110 with three potential diversity points (Scheme 2.74).255 α-Amino acid derived isocyano esters react in the

Page | 85 Chapter 2

UT-4CR and the secondary amine in the side chain spontaneously undergoes a lactamisation. A range of commercially available aldehydes and aliphatic or aromatic substituted primary amines were investigated. It was shown that more sterically hindered groups in the aldehydes or amines would largely decrease both yields.

Scheme 2.74. UT-4CR and post-condensation to form 6,5-fused fetrazole system.

O R6 1. MeOH, r.t., 24h H R6 N R R1 R2 BocHN CHO 2. 10%TFA/CH2Cl2 O 4 3. PS-DIEA, DMF/dioane N 1:1, reflux R5 R3 R N + 3 N 4. PS-NCO, PSTs-NHNH2 N TMSN3 MeOOC NC N THF/CH3CHCl2, 1/1 45 - 100% 111

O O O H H N N N

N N N N N N O N N N N N N N N N N N HN N N

111a, 84% 111b, 48% 111c, 80%

Scheme 2.75. Synthesis of the 7,5-fused azepine-tetrazoles.

In 2002, Hulme et al. extended their cyclic reaction research to synthesize fused azepine- tetrazole libraries (7,5-fused tetrazole system) 111 in high yields via the TMSN3 modified Ugi 4-component reaction UT-4CR (Scheme 2.75).256 Compared with their previous work leading to the 6,5-fused tetrazole system; they employed secondary amines together with Boc protected amino acid derived aldehydes components to enlarge the fused ring by one carbon to form azepine-tetrazoles. The first tetrazole formation was particularly well-suited for the solution phase reaction of methyl-isocyano acetate, N-Boc-aminoaldehydes, TMSN3 and secondary amines and generally proceeded with high yields. The subsequent Boc-deprotection was carried

Page | 86 Review: tetrazoles via multicomponent reaction routes out with 10% trifluoroacetic acid in dichloromethane to free the amine nucleophile for the next cycloamidation step. The lactamisation was promoted by proton scavenging with PS- diisopropylethylamine and reflux for 24h. Final compound purities were substantially improved by removal of the acyclic amine and excess aldehyde, via dissolution in THF:CH2 addition of polystyrol bound scavenger resins PS-NCO and PS-TsNHNH2, producing the desired 7,5-fused product.

Hiller et al. in 2004 employed a synthetic mythology whereby cyclisation to the 6,5-tetrazole system occurs in situ via a toluene sulfone group (Scheme 2.76).257 Noteworthy, the cyclization step could proceed at room temperature without acid addition or refluxing. Simply following a classical UT-4CR procedure mixing aldehydes, primary amines, trimethylsilylazide and 2- isocyanoethyltoluolsulfonate in a ratio of 1/1/1.5/1.5 to lead to the expected fused tetrazoles. The 2-isocyanoethyltoluolsulfonate building block employed in this versatile reaction can be synthesized in two steps from ethanolamine via selective N-formylation followed by O- tosylation and dehydration using tosylchloride. Gratifyingly the isocyanide is an odorless and bench stable white powder.

Scheme 2.76. Synthesis of tetrazolopiperazines.

With final products containing two points of potential diversity and a facile and rapid production protocol, access to thousands of diverse analogues with the aforementioned core structure is now feasible.

A crystal structure showing the 3D structure of 113 in the solid stage is shown in Figure 2.29. The overall 3D structure comprises a butterfly shape with the cyclohexyl and benzene rings presenting the wings. Clearly, the compound class of 1,4-benzodiazepines are amongst the most widely used drugs with potent tranquilizer, muscle relaxant, anticonvulsant, antiseizure and sedative-hypnotic activities.258 Recently heterocyclic-conjugated benzodiazepines emerged as

Page | 87 Chapter 2 an important class of epigenetic drugs.259, 260 For example, similar structures are potent inhibitors BET family of bromodomain proteins, e.g. JQ-1 114 (Figure 2.30).261

Figure 2.29. Crystal structure of fused tetrazolodiazepine 113 (CCDC 780553). Three molecules of the elementary cell are shown, two are interconnected by two short hydrogen bonds (2.8 Å, red dotted lines) between the amides of the diazepineone moieties. The phenyl groups of two neighbor molecules undergo a stacking interaction at a closes distance of 3.5 Å (blue dotted lines).

O O N N

N N S

Cl 114 JQ1

Figure 2.30. Structure of a cell-permeable small molecule JQ1 114.

OH O NR3 or PR4 R2 + R2 R H R

R2 = electron withdrawing group

Scheme 2.77. Baylis–Hillman reaction

The Baylis–Hillman reaction occurs between the α-position of an activated alkene and an aldehyde, or generally a carbon electrophile to form a new C-C bond with the help of a nucleophilic catalyst, such as tertiary amine and phosphine. It could offer multifunctional products which have been illustrated to be useful for the synthesis of an array of organic compounds. In 2010, Batra et al. firstly synthesized substituted allyl isonitriles from primary allyl amines using the Baylis–Hillman reaction (Schemes 2.77 and 2.78).262 They employed this E-isomeric isocyanide in an Ugi/hydrolyze/couple strategy to obtain tetrazole-fused diazepinones in good yields. After obtaining the expected compounds of Ugi reaction at room temperature, they also investigated a one-pot reaction combining Ugi and cyclization process

Page | 88 Review: tetrazoles via multicomponent reaction routes without isolating the intermediate. Two cases were reported successfully with an amine and aldehyde with an electron withdrawing group. Noteworthy, they also found that the use of aniline in the place of the primary amine did not work and the formation of tetrazoles was not observed.

Scheme 2.78. Synthesis of tetrazole-fused diazepinones.

2.3.3 Tricyclic tetrazole derivatives

Annulated polyheterocyclic structures are interesting to medicinal chemists due to their rigidity and often good blood-brain-penetration to target neurological diseases. Therefore, strategies for reducing the number of synthetic and purification steps to prepare suitably modified compounds are of special interest in medicinal/combinatorial chemistry. In 2006, Kalinski et al. described a Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution for the preparation of a library of polysubstituted fused 4,5-dihydrotetrazolo[1,5- a]quinoxalines 119 (Scheme 2.79).263 The first synthetic step corresponds to a classical UT-

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4CR, exploring 2-fluorophenylisocyanide as a new bifunctional starting material yielding tricyclic tetrazoles with two points of diversity.

Scheme 2.79. Synthesis of fused 4, 5-dihydrotetrazolo[1,5-a]quinoxalines.

2-Fluorophenylisocyanide as a new bifunctional starting material allows for a subsequent nucleophilic aromatic substitution (SNAr) in a second step and this ring formation. They found the best yield could be reached by mixing the four components amine/aldehyde/TMS azide/isocyanide in a ratio of 1/1/1.5/1.5 in the Ugi reaction. The intermediate UT-4CR product is subject to purification. The nucleophilic aromatic substitution-cyclisation conditions were optimized studying different bases and solvents yielding Cs2CO3 in DMF as best conditions. They also exploited a range of amines and aldehydes for this strategy. They found amines and carbonyls can be varied broadly, yielding tricyclic tetrazoles with two potential diversity points.

In 2010, Voskressensky et al. developed an effective procedure for the syntheses of substituted tetrazolo[1,5-a][1,4]benzodiazepines 120 via tetrazoles U-5C-4CR (Scheme 2.80).264 The tetrazolodiazepines were synthesized by simply mixing 1 mmol of a ketone with 1.2 mmol of sodium azide, 1.2 mmol of ammonium chloride, and 1 mmol of the corresponding anthranilic acid derived isocyanide in aqueous methanol. After 24 - 48h of vigorous stirring at room temperature, the target products precipitated from the reaction mixture. Symmetrical and unsymmetrical, cyclic and acyclic, sterically not hindered and very bulky (e.g. adamantly

Page | 90 Review: tetrazoles via multicomponent reaction routes ketone) ketones are good substrates. Interestingly all attempts to isolate the corresponding products from aldehydes failed. Heterocyclic thiophene e.g. substituted anthranilic acid derived isocyanides were used. Moreover, the reaction with methylamine hydrochloride instead of ammonium chloride aiming to yield the N-methyl substituted benzodiazepines stopped at the intermediate Ugi tetrazole stage, and no cyclisation was observed under the reaction conditions.

Scheme 2.80. Fused tetrazolodiazepines 120 synthesized by U-5C-4CR.

Scheme 2.81 Diversity of ring fused tetrazole scaffolds form the common precursor building block isocyanoacetaldehyde dimethylacetal.

In 2014, Dömling et al. discovered three new different heterocyclic scaffolds 122 - 124 easily accessible from isocyanoacetaldehyde dimethylacetal 121 by MCR (Scheme 2.81).111 The

Page | 91 Chapter 2 initial UT-4CR with isocyanoacetaldehyde dimethylacetal yields an intermediate which can undergo a range of condensation reactions, e.g. Pictet-Spengler. The cyclisations were carried out under acidic condition at room temperature.

Scheme 2.82. Synthesis of 7,8-dihydrotetrazolo[1,5-a]pyrazines.

The first scaffold of 7,8-dihydrotetrazolo[1,5-a]pyrazines 123 is formed from aliphatic or aromatic aldehyde and aliphatic amine components, which cannot undergo a subsequent Pictet- Spengler reaction (Scheme 2.82). The cyclisation simply runs in neat methansulfonic acid giving generally good to excellent yields of the 7,8-dihydrotetrazolo[1,5-a]pyrazines.

The 11H-benzo[d]tetrazolo[1,5-a]azepin-11-amine scaffold 124 can be accessed from activated electron rich benzaldehydes, primary or secondary amines and isocyanoacetaldehyde dimethylacetal (Scheme 2.83). The reaction sequence involves a UT-4CR followed by a condensation. Again, the cyclisation runs smoothly under MSA neat conditions in good to excellent yields.

When using electron rich substituted (hetero)phenylethyl amines polyfused piperazinotetrazoles can be accessed in great diversity (Scheme 2.84). The intermediate UT-

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4CR product 122 can undergo a Pictet-Spengler type condensation under MSA room temperature conditions, in decent to excellent yields. The reaction involves an acid induced dimethylacetal deprotection, followed by an imine formation and attack onto the nucleophilic (hetero)aromate. Phenylethyl amines and tryptamines lead to the alkaloid-type scaffolds of isoquinolines and Iboga, respectively. Libraries of >1.000 compounds per scaffold have been synthesized and are part of the screening collection of the European Lead Factory.

Scheme 2.83. Designed synthetic pathway to 11H-benzo[d]tetrazolo[1,5-a]azepin-11-amine Scaffold.

The 3D structures and other physicochemical properties, physicochemical properties of each scaffold were also extensively discussed. Unexpectedly, these scaffolds possess very different characteristics even though these scaffolds are all derived from the same first Ugi tetrazole multicomponent reaction in terms of their chemical space due to their connectivity, substitution pattern, and ring sizes (Figure 2.31).

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a

b c Figure 2.31. The crystal structures of (a) 7,8-dihydrotetrazolo[1,5-a]pyrazines 123; (b) 11H- benzo[d]tetrazolo[1,5-a]azepin-11-amine scaffold 124; and (c) polyfused tetrazolo piperazine scaffold 122 (CCDC 1017121, 1017122 and 1017123).

Polyfused Tetrazolo Piperazine Scaffolds

(hetero) aroyl O (hetero) R1 R2 R1 R2 CH3SO3H, aroyl NH2 N N r.t., 18h N MeOH, r.t., 18h (hetero) HN N N aroyl 32 - 95% N + N N N OMe 68 - 98% R TMSN NC 1 3 OMe MeO MeO

121c 122

OMe MeO OMe

MeO N N N HN HN N HN N HN N N N N HN N MeO N N OMe MeO OMe MeO MeO OMe 121g, 68% 121h, 86% 121i, 88% OMe MeO OMe

N N N N N N N N N N N N N N N MeO NH NH OMe 122a, 77% 122b, 32% 122c, 58%

Scheme 2.84. Designed synthetic pathway to polyfused tetrazolo piperazine scaffolds.

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Scheme 2.85. Synthesis of tetracyclic tetrazole scaffold.

In 2015, Dömling et al. designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties (Scheme 2.85).201 The compounds of the scaffold are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). They tested the synthesis of Ugi 4-CR adducts using different oxo components and various aryl ethyl amines to explore the scope of the methodology. The cyclized product was obtained in moderate to good yield (50 - 89%) in all cases. And aliphatic aldehydes gave moderate yields while aromatic aldehydes and cyclic ketones gave good yields. The benzylaldehyde containing chlorine at para position gave excellent yield (89%). However, by replacing chlorine to more electronegative fluorine atom in the para position of the phenyl ring of aldehyde, the yield of the cyclized product dropped dramatically. They also employed tryptamine as the amine component in the Ugi reaction. 3- (Methylmercapto) propionicaldehyde gave a lower yield of the Ugi-adduct; while cyclic ketones failed to give Ugi-adduct under the same conditions. For the cyclization step, the Pictet– Spengler reaction of the Ugi-adduct containing electron-rich aldehyde gave a lower yield, and electron-deficient p-nitrobenzaldehyde gave an excellent yield with only one major stereoisomer. They continued to extend their study to various other aryl ethyl amines.

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Surprisingly, all aryl ethyl amines gave reasonable to excellent yields of the Ugi-adducts. Only the Ugi-adduct of 3-(2-thienyl)-D,L-alanine gave the required cyclized product in good yield at 5:1 dr ratio, which was in the same as it is Ugi-adduct.

2.4 Conclusions

More than 120 tetrazole-based scaffolds have been presented in this review, which can be convergent and easily synthesized by using multicomponent reactions. Especially the Ugi variation UT-4CR of tetrazole synthesis is very fruitful in accessing many different drug-like scaffolds. Thus amongst all organic chemistry methods, clearly MCR sands out and provides the most versatile access to this class of heterocycle. Tetrazole derivatives will continue to be a prime class of heterocycles due to their isosteric character to carboxylic acid and cis-amide moieties and due to their metabolic stability and other physicochemical properties. Efficient synthetic access to a wide variety of derivatives is therefore, a key to leverage the potential of tetrazoles to generate lead compounds.

2.5 References

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