Tetrazoles via Multicomponent Reactions

Abstract

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1 H- or 2 H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

Scheme 1. Tautomerism of Tetrazole Derivatives

Figure 1

(A) Number of publications containing the keyword “tetrazole(s)” in the title of the articles plotted against the publication date as analyzed by Scopus (December 2018, 2707 articles). (B) Documents by country/territory of most publications contain the keyword “tetrazole(s)” in the title of the articles as analyzed by Scopus (December 2018, 2707 articles). (C) Documents by subject area as analyzed by Scopus.

Figure 2

(A) Tetrazolic acids (5-substituted 1H-tetrazole or 2H-tetrazole) are bioisosteres of carboxylic acids. (B) The interactions of the 5-substituted 1H-tetrazoles with any N–H in CSD (655 different plotted compounds, left). The majority of these interactions exist around the two sp² 3- and 4-nitrogens of the tetrazole ring as shown also by the contour surface (right). (C) The interactions of the 5-substituted 1H-tetrazoles with any O–H in CSD (696 different plotted compounds, left). The majority of these interactions is distributed among the sp² nitrogens of the tetrazole ring and the N–H, respectively, as shown also by the contour surface (right). (D) The interactions of the 5-substituted 1H-tetrazoles with aromatic or sp² N in CSD (1315 different plotted compounds), which demonstrate the acidic character of the N–H of the tetrazole. (E) Likewise, the interactions of the 5-substituted 1H-tetrazoles with terminal oxygen (carbonyl, amides, esters, acids, etc.) in CSD (159 different plotted compounds) depict the hydrogen bond formation of N–H···O=C. (F) π–π Interactions of the 5-substituted 1H-tetrazoles with phenyl rings (different poses in left and right picture) in T-shaped edge-to-face and parallel-displaced stacking arrangement in CSD (50 different plotted compounds).

Figure 3

(A) The interactions of the 1,5-disubstituted 1H-tetrazoles with any N–H in CSD (2567 different plotted compounds, left). The majority of these interactions exists again around the two sp² 3- and 4-nitrogens of the tetrazole ring as shown also by the contour surface (right). (B) The interactions of the 1,5-disubstituted 1H-tetrazoles with any O–H in CSD (2180 different plotted compounds, left). The majority of these interactions is distributed among the sp² nitrogens of the tetrazole ring and the N–H, respectively, as shown also by the contour surface (right). (C) π–π Interactions of the 1,5-disubstituted 1H-tetrazoles with phenyl rings, mostly in parallel-displaced stacking arrangement (left) as shown also by the contour surface (right) in CSD (946 different plotted compounds).

Figure 4

Geometrical features of cis and trans amides. (A) A histogram of the torsion angle analysis. (B) A close-up histogram of the torsion angle analysis.

Figure 5

(A) Geometrical features of 1,5-disubstituted tetrazoles as cis-amides surrogates. (B) Plot of the torsion angle of 1,5-disubstituted tetrazoles. (C) Corresponding cone angle correlation (left) and the polar histogram (right) revealing the favorable synperiplanar conformation. (D) A comparison of the torsion angle (picture in bottom in zoom pose) between the cis-amides (blue) and 1,5-disubstituted tetrazoles (red), showing a more constrained conformation for the latter.

Figure 6

(A) Geometrical features of 2-substituted and 2,5-disubstituted tetrazoles. (B) Scatterplot of the distance R¹–N (DIST1, blue color) with the angle R¹–N-N (ANG1, blue color) of the 2,5-disubstituted tetrazoles with average values of 1.47 Å and 123.1°, respectively. (C) Scatterplot of the distance R²–N (DIST2, red color) with the angle R²–N-N (ANG2, red color) of the 2,5-disubstituted tetrazoles with average values of 1.46 Å and 123.9°, respectively.

Figure 7

Classification of the selected PDB cocrystal structures of tetrazole derivatives into the categories of 5-monosubstituted tetrazoles (green), 1-substituted tetrazoles (blue), 1,5-disubstituted tetrazoles (yellow), 2-substituted tetrazoles (magenta), 2,5-disubstituted tetrazoles (cyan), and tetrazolium salt (orange).

Figure 8

Examples of characteristic receptor–tetrazole binding modes found in the PDB. (A) Sterol 14α-demethylase (CYP51) from Trypanosoma cruzi in complex with the 1-monosubstituted-tetrazole derivative VT-1161 (1) (PDB 5AJR) exhibiting the metal ligand character of tetrazoles. (B) CTX-M-9 class A β-lactamase complexed with 1H-tetrazole 2 (PDB 3G34), exhibiting a hydrogen contact to water and one hydrogen contact to Gln side chain amide.

Figure 9

Comparison of the hydrogen bonding pattern of tetrazolyl and carboxyl. Example of a tetrazolyl (3) forming four hydrogen bonds (PDB 4DE1). Ser and Ser form each a hydrogen bond to the tetrazole −N2 and −N5 via their side chain −OH at 2.8 and 2.7 Å, respectively. N-3 is in a 2.7 Å contact to the side chain −OH of Thr. 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 bonding contacts.

Figure 10

Tetrazole compound 4 as a ligand for the metallo-β-lactamase (PDB 1A8T). The central Zn²⁺ is tetrahedrally coordinated by the ligands tetrazole-N1, the His side chain N3, Asp carboxyl-O, and Cys side chain-S. The tetrazoloyl not only forms a bond to Zn²⁺ but forms several hydrogen bonds to the receptor, including Asn backbone NH (3.3 Å), His side chain NH (2.8 Å), and Lys side chain NH₂ (3.8 Å). Moreover, the His imidazole moiety is on top of the tetrazolyl moiety, forming an electrostatic interaction with an interplane angle of ∼30°.

Figure 11

Kelch domain interaction of Keap1 with tetrazole 5 (PDB 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 boxed figure shows the Arg sandwich from a different orientation.

Figure 12

Kelch domain interaction of Keap1 with compound 6 (PDB 4L7B). Same as its bioisostere tetrazole 5, 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 Arg³⁸⁰ and the carboxylic ligand, which is caused by the special orientation of carboxylic group.

Figure 13

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 2GL7). Tcf peptide is shown in pink and green, and the hot spot Asp16-Glu17 is highlighted as pink sticks. β-Catenin is shown as surface representation, and interacting amino acids are shown as gray sticks. (B) Bioisosteric replacement step. (C) Close-up analysis of the aligned 7 and Asp16-Glu17 of Tcf with the β-catenin receptor. The indazole-1-ol forms H-bond and charge–charge interactions with β-catenin Lys508. The tetrazole ring was used to replace the carboxyl group of Asp16 and mimics the charge–charge and H-bond interactions with Lys435 and Asn430 of β-catenin. The deprotonated tetrazole ring with two more Lewis bases can form two additional H-bonds with the side chains of His470 and Ser473. These two H-bonds do not exist in the β-catenin/Tcf complex.

Scheme 2. Different Synthetic Routes to Tetrazoles Using Non-Multicomponent Reactions

Scheme 3. Intramolecular Cycloaddition of Azidonitriles: (a) Heterocyclic Nitrile, (b) Aliphatic Nitrile, (c) Aromatic Nitrile

Scheme 4. Synthesis of 5-Substituted 1H-Tetrazoles 17 via N-Substituted Cyanoacetamides

Scheme 5. Synthesis of 1-Substituted Tetrazoles by Click Reaction of Azides and Isocyanides

Scheme 6. Synthesis of 1-Substituted 1H-Tetrazoles 23 via N-Substituted Cyanoacetamides

Scheme 7. Synthesis of 1,5-Diaryl-Substituted Tetrazoles 25 via Amides 24

Figure 14

Classification of the MCR-based synthesis of tetrazole derivatives according to the number of cycles.

Scheme 8. Tetrazole MCRs Overview

Figure 15

Scope and limitations of the UT reaction.

Figure 16

SAR of the UT-4CR and typical reaction products (26–38) which are cited in the current review underlining the scope of the reaction.^,,,,,,,,,,,,

Scheme 9. Stereoselective Synthesis of Tetrazole Derivatives 40 and 41 via a Diasteroselective UT-4CR with Secondary Cyclic Amines

Scheme 10. UT-4CR vs GBB-3CR of the 2-Aminopyridine

Scheme 11. Isocyanide-less Ugi 4-CR Tetrazole Variation (UT-4CR)

Scheme 12. Example of an Application of the Isocyanide-less UT-4CR to Synthesize the Photocleavable Tetrazole Derivative 47

Scheme 13. UT-4CR to Diaziridine Tetrazole Derivative 48

Scheme 14. Hydroxylamines as Amine Equivalents in UT-4CR

Scheme 15. A Synthetic Pathway to N-Unsubstituted Primary α-Aminotetrazoles 52 Using an Ugi-4CR Employing Tritylamine As an Ammonia Surrogate

Figure 17

Crystal structures of tetrazole derivatives 50d,e. They are dominated not only by π-stacking and hydrophobic interactions between the trityl group, the alkyl group, and the phenylethyl groups but also the tetrazole ring makes short intermolecular contacts (CCDC 903083 and 903084).

Scheme 16. A Synthetic Pathway to α,α-Disubstituted α-Aminotetrazoles 53 and 54 Using an UT-4CR Employing Ammonium Chloride as an Ammonia Surrogate and the Post-Modification Towards Tetrazoles 55

Figure 18

Structures of tetrazoles as seen in the solid-state by X-ray structure analysis. (A) Compound 53a (CCDC 1441248) forms a hydrogen bridge of 2.4 Å length between the amine NH and the N4 of an adjacent molecule; moreover, the benzyl side chains undergo parallel and T-shaped π–π interactions. (B) Compound 53b (CCDC 1441249) forms a hydrogen bridge of 2.3 Å length between the amine NH and the N3 of an adjacent molecule. (C) Compound 55a (CCDC 1484778) forms a hydrogen bridge of 2.2 Å length between the amine NH and the N3 of an adjacent molecule.

Scheme 17. Diastereoselective Synthesis of α-Hydrazine Tetrazoles 56 via a Facile UT-4CR

Figure 19

Crystal structures of α-hydrazine tetrazole 56a and 56d. (A) Hydrophobic interactions between the C of phenyl group and N(2), N(3) of tetrazole, hydrophilic interactions between N(3) of tetrazole, and the N close to C=O (CCDC 950021). (B) Hydrophobic interactions between the C of oxo component cyclohexyl groups, and hydrophilic interactions between N(3), N(4) of tetrazole, and N close to C=O (CCDC 950022).

Scheme 18. Typical Two-Step Procedure Synthesis of N-Deprotected Tetrazole Derivatives 58

Figure 20

Crystal structures of the highly substituted 5-(Boc-hydrazinylmethyl)-1-methyl-1H-tetrazoles 57. (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 benzylethyl and N(4) of tetrazole (57d, CCDC 1438137). (B) Three hydrophobic interactions between carbon atom of methyl of isopropyl and oxygen (C=O) of Boc group, carbon atom of methylene of benzyl and oxygen 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 hydrozine close to Boc group (57e, CCDC 1438135). (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) (57f, CCDC 1438136).

Scheme 19. UT-4CR of BetMIC and Subsequent Acid Hydrolysis Yielding α-Aminomethyl Tetrazoles 60

Scheme 20. Synthesis of α-Aminoalkyltetrazoles 63

Scheme 21. Synthesis of α-Aminoalkyltetrazoles 66

Scheme 22. Synthesis of the UT-4CR Adducts and Their Corresponding Deprotected 5-Substituted 1H-Tetrazoles 69

Scheme 23. Synthesis of 1,5-Disubstituted Tetrazoles 70 through Tetrazole Imine Intermediates and Their Subsequent Oxidation

Scheme 24. Plausible Mechanism of the Synthesized Triazoles through the Tetrazole Formation

Scheme 25. Synthesis of a Series of Tetrazoles 73 Containing the 2,2-Bis(trimethylsilyl)ethenyl Group

Scheme 26. Synthesis of Ferrocenyl Substituted Amino Tetrazoles 74

Scheme 27. Synthesis of Substituted Benzyl Tetrazoles As Histamine H3 Receptor Antagonists 75

Scheme 28. Synthesis of Tetrazole/Naphthoquinone-Based Organoselenium Derivatives 78

Scheme 29. Representative Scheme for the Preparation of 1,5-Disubstituted Tetrazoles 80 Containing a Fragment of the Anticancer Drug Imatinib

Scheme 30. Synthesis of the Potent 1,5-Disubstituted Tetrazoles 81 and 82 as p53-MDM2 Inhibitors

Figure 21

Crystal structure of the 1,5-disubstituted tetrazole 82e (CCDC 1449789). The ring planes of substituents at positions 1 and 5 are almost coplanar, being constrained by tetrazole geometry and are oriented vertically to the plane of the tetrazole ring.

Scheme 31. Synthesis of Aminomethyltetrazoles 83 and 84

Figure 22

Two of the most potent compounds as positive allosteric modulators of EAATs.

Scheme 32. Antiviral Tetrazole Desoxyribose Derivatives 88

Scheme 33. Synthesis of the Thiadiazolo Tetrazole Derivatives 90

Figure 23

Crystal structure of N-((1-cyclohexyl-1H-tetrazol-5-yl)(5-methyl-1H-1,2,3-triazol-4-yl)methyl)-4-nitroaniline (90d). It shows that 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) are identified (CCDC 859295).

Scheme 34. Synthesis of New Nitroimidazole and Nitroimidazooxazine Derivatives 92

Scheme 35. Synthesis of 4-Aminoquinoline-Tetrazole Derivatives 94

Scheme 36. Representative Scheme for the Preparation of 1H-Tetrazol-5-yl-(aryl)methyl Piperazinyl-6-fluoro-quinolones 96

Scheme 37. Synthesis of a Variety of Tetrazole Substituted Tetrahydroisoquinolines 97

Figure 24

X-ray crystal structure of tetrahydroisoquinoline 97d (CCDC 1012826). Two intermolecular hydrophobic interactions between the two cyclohexyl groups are observed

Scheme 38. Synthesis of Tetrahydro-β-carbolines 98 Bearing a Tetrazole Moiety through an UT-4CR-5C

Scheme 39. Synthesis of Bis-1,5-disubstituted-1H-tetrazoles 99

Scheme 40. Synthesis of the Acylhydrazines with 1,5-Disubstituted Tetrazoles 97 via a Two Consecutive Hydrazine UT-4CR

Scheme 41. Synthesis of the MRI Agent Gd-TEMDO 106 Involving a Key UT-MCR

Figure 25

Left: Crystal structure of Gd-TEMDO 106. Middle and right: LVO mouse model showing the MRI properties of Gd-TEMDO. MRI obtained from isoflurane-anaesthetized mice (middle) taken 30 min after IP administration of Gd-TEMDO (0.6 mmol/kg). Middle: the heart fully visible. Right: heart with reduced brightness; the damaged tissue remains visible due to absorbed Gd-TEMDO following the red line. Reproduced with permission from ref (208). Copyright 2016 John Wiley and Sons.

Scheme 42. Synthesis of 5-(1′-Aminoalkyl)tetrazoles 109 on Solid Phase

Scheme 43. Repetitive Ugi Reaction on the Polystyrene AM RAM

Scheme 44. Synthesis of 5-Substituted Tetrazoles 116 on the Universal Rink-Isocyanide Resin

Scheme 45. On-Resin UT Reactions for the N-Terminal Derivatization of Peptide with Lipids and Steroids

Scheme 46. Synthesis of 1,5-Substituted Tetrazole Hydantoins and Thiohydantoins 120 and Imidazotetrazolodiazepinones 121

Figure 26

Crystal structure of a 4-bromophenyltetrazolohydantoin 120d 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).

Scheme 47. Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines 124 and 1H-Tetrazolyl-1H-1,4-diazepine-2,3-dicarbonitriles 125

Figure 27

Crystal structure of the benzodiazepin-2-one 124f (CCDC 900744). The symmetrical hydrogen bonding interaction between O and N was measured 3.0 Å

Figure 28

Crystal structure of compound 125d (CCDC 814967). A network of intramolecular hydrogen bonds of N–H can be observed among the NH and CN groups and the tetrazole moieties varying from 3.1 to 3.3 Å

Scheme 48. General Strategy for the Synthesis of the Tetrazole-isoindolines 127

Scheme 49. Compound Degradation after D₂O Shake during NMR Experiment and ORTEP Diagram Drawn of the Crystal Structure of (E)-3-(tert-Butylimino)-2-(4-methoxybenzyl)isoindolin-1-one (128) Determined at 293 K (CCDC 959960) (The Interaction between O of Lactam and Methyl of tert-Butyl Was Measured as 3.5 Å

Scheme 50. Synthesis of 2-Tetrazolylmethyl-2,3,4,9-tetrahydro-1H-β-carbolines 130

Scheme 51. Synthesis of the 3-Tetrazolyl-azepino[4,5-b]indol-4-ones 128 via a One-Pot (UT-4CR/N-Acylation/S_N2)/Xanthate Free-Radical Mediated Cyclization

Figure 29

X-ray crystal structure of azepinoindolones 133e (CCDC 948622). An intermolecular hydrogen bond of 2.3 Å is observed between the azepinoindole N–H and the nitrogen of the tetrazole moiety.

Scheme 52. UT Reaction of o-Aminoacetophenone, Aldehydes, Isocyanides, and TMSN₃, Followed by an Oxidation/Intramolecular Oxidative Amidation toward the Tetrazole Derivatives 135

Scheme 53. Dual α-Ketotetrazoles and α,β-Diketotetrazoles 137 Based on the MCR-Oxidative Deamination Approach

Figure 30

X-ray crystal structure and polar contacts of the tetrazole chalcone 137d (CCDC 1531964) and the α,β-diketotetrazole 137g (CCDC 1554390).

Scheme 54. Applications of Tetrazole Chalcones and α,β-Diketotetrazoles to Produce Diverse Tetrazole Chemotypes as the Derivatives 138, 139, and 140

Scheme 55. General Procedure for the Synthesis of 5-Aroyl-1-aryltetrazol Analogues 142

Scheme 56. General Synthesis for Tetrazolic Analogues of Chalcones 142

Scheme 57. General Synthesis for Tetrazolyl Imidazo[1,5-a]pyridines 144

Scheme 58. One-Pot Tetrazolyl Indazole 145 Formation

Scheme 59. Synthesis of the Ugi Adduct 146 and the Morpholines Derivatives 147

Figure 31

Crystal structures of the morpholine derivatives 138f (CCDC 1507665) and 138a (CCDC 1507068). An intermolecular hydrogen bond of the morpholine N–H to the N of the tetrazole can be identified at 2.2 and 2.4 Å, respectively.

Scheme 60. Further Derivatization of the Morpholine and Piperazine Scaffolds via Acylation, Thiourea Formation, and Reductive Amination, Respectively

Scheme 61. Synthesis of the Ugi Adduct 151 along with the Piperazine and Tetrahydroquinoxalines Derivatives 152

Scheme 62. General Strategy to Lactam-Tetrazoles

Scheme 63. Synthesis of Tetrazolyl-Isoindolinones via UT-4CR/Intramolecular Amidation

Scheme 64. General Synthetic Route to Access Bis-pyrrolidinone Tetrazole 155

Scheme 65. Synthesis of Bis-quinoxalinone Tetrazoles 158

Figure 32

Crystal structure of 3-(1-benzyl-1H-tetrazol-5-yl)-6,7-dimethylquinoxalin-2(1H)-one (158d) exhibiting an antiparallel π stacking alignment of two adjacent quinoxaline moieties, featuring in addition a low energy antiparallel dipole dipole alignment (CCDC 932013)

Scheme 66. Synthesis of Tetrazolobenzodiazepin-2-ones 156

Scheme 67. Diversity of Bis-heterocyclic Lactam-Tetrazoles

Figure 33

Examples of bis-heterocyclic tetrazolo scaffolds.

Scheme 68. Selective Tetrazole Formation over the Intramolecular Ugi Product

Figure 34

Crystal structure of a benzo[1,4]oxazepinone derivative 167c (CCDC 936637). It is noteworthy that there is an intramolecular hydrogen bond (3.0 Å) between N4 and O9 and a short contact (3.3 Å) between N3 and C10

Scheme 69. Synthesis of Tetrazole-Substituted Spirocyclic γ-Lactams 171 by One-Pot UT-Cyclization

Figure 35

Crystal structure of tetrazole-substituted spirocyclic γ-lactams 171e,f (CCDC 918594 and 918596). It is noteworthythat it is the antiparallel alignment of the phenyl units of two adjacent molecules with short contacts (3.6 Å, 3.7 Å, 4.1 Å) between C (sp³) and C (sp²). Similarly, there is also the semiantiparallel alignment of the phenyl units and lactam ring of two adjacent molecules with short contacts (3.1 Å, 3.2 Å) between O (C=O) and C (sp²).

Scheme 70. Devised Synthetic Pathway to Tetrazolo N-Unsubstituted γ- and δ-Lactams 173

Figure 36

(A) Crystal structure of a tetrazole fused γ-lactam 173a (CCDC 961190). It is worth mentioning that there is a pair wise hydrogen bonding with a neighbor lactam in short contacts (2.9 Å) between N6, O1 and N6′, O1′. (B) Alignment of several PDB structures (3D23, 3EWJ, 3QZR, 3RHK, 3TNT, 3UR9, 3DPM, 1H0V, 3JUC, and 3Q3Y) showing the polar interactions for 10 γ-lactam containing ligands.

Scheme 71. (A) Acidic Hydrolysis of Erythromycin Yields Desosamine Which Is Subsequently Transforms into 1-Isocyanodesosamine; (B) Synthesis of Disubstituted α-Aminomethyl Tetrazoles 174 Based on Desosamine with UT-4CR

Scheme 72. (A) Leuckart–Wallach Approach to Sugar Isocyanides; (B) Synthesis of 1,5-Disubstituted Tetrazoles 175 Using Glycosyl Isocyanide and Arabinosyl Isocyanide

Scheme 73. Synthesis of Tetrazole-Based Spirostan Saponin Analogues 176

Scheme 74. Synthesis of Calixarene Dihydrazide 178 via UT-4CR

Figure 37

Crystal structure of calixarene dihydrazide 178d (CCDC 1025095). Four hydrophobic interactions of two molecules were observed as O (C=O) and methyl, N(2), and methyl 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.

Scheme 75. UT-3CR with Trifluoroalkyl Cyclic Imines and Synthesis of N-Unsubstituted Tetrazoles 180

Scheme 76. Synthesis of Tetrahydroisoquinoline Tetrazoles 182

Scheme 77. Passerini Reaction Towards Tetrazole Derivatives 185

Scheme 78. Catalytic Enantioselective Synthesis of 5-(1-Hydroxyalkyl)tetrazole 186 by Three-Component Passerini Reaction (P-3CR)

Scheme 79. Synthesis of Alkoxylated 1H-Tetrazole Derivatives 187

Figure 38

Crystal structure of (E)-1-(tert-butyl)-5-(1-(cyclopentyloxy)-3-phenylallyl)-1H-tetrazole 187d (CCDC 862990).

Scheme 80. P-3CR under the “In Water” Or “In NaOTs” Conditions

Scheme 81. A Green P-3CR under Sonication Conditions

Scheme 82. Post-Modification on the Corresponding Hydroxyl Tetrazole 190 Towards the Fused Tetrazole 191

Scheme 83. Synthesis of Tetrazoles 192 and 193 from Carbonyl Compounds, Amines, and TMSN₃

Scheme 84. Synthesis of 1,5-Fused Tetrazoles 194 from Carboxylic Acid Derivatives, Amines, and TMSN₃

Scheme 85. Two-Step Synthesis of Cilostazol (192) by the MCR Methodology

Scheme 86. Synthesis of the Amino Acid Tetrazoles 197

Scheme 87. Synthesis of 3-Tetrazolyl Oxindoles 198 by a Facile Intermolecular [2 + 3] Cycloaddition

Figure 39

Solid-state structure of 3-hydroxy-3-(1H-tetrazol-5-yl) indolin-2-one 198a. The oxindole-NH acts as a hydrogen bond donor toward N1 of the tetrazole (CCDC 857953).

Figure 40

Solid-state structure of 3-(phenylamino)-3-(1H-tetrazol-5-yl)indolin-2-one 199. The oxindole-NH acts as a hydrogen bond donor toward N1 of the tetrazole (CCDC 857954).

Scheme 88. Synthesis of the 1,5-Disubstituted Tetrazoles 200 and 201

Figure 41

Crystal structure of (3R)-di-tert-butyl-2-(1-(tert-butyl)-1H-tetrazol-5-yl)-3-((triphenylsilyl)oxy)succinate 200d. It shows two short intermolecular interactions, O (C=O) and C (CH₃ in tert-butyl group) (CCDC 817391).

Scheme 89. 3-CR of N-Halo Succinimide, Sodium Azide, and Phenylisocyanide

Scheme 90. Synthesis of 1,5-Disubstituted 1H-Tetrazole Derivatives

Scheme 91. Synthesis of 7,8-Dihydrotetrazolo[1,5-a]pyrazines 207

Scheme 92. UT-4CR and Post-Condensation to Form the Tetrazolopiperazines 209

Scheme 93. Ammonia Promoted One-Pot Tetrazolopiperidinone 210 Synthesis by UT-4CR

Figure 42

Crystal structure of the tetrazolopiperidinone 210f. A hydrogen bond exhibits between the piperidinone-NH and the N-5 of a tetrazole moiety of an adjacent molecule.

Scheme 94. Synthesis of Tetrazolopiperazines 211

Scheme 95. Designed Synthetic Pathway to Tetrazolo Piperazine Derivatives 213

Figure 43

Crystal structures of 208d with the cyclohexyl moiety forming a short T-shaped interaction with the adjacent phenyl group (CCDC 1017121).

Scheme 96. Two-Step Synthesis of N-Unsubstituted ω-Carboxyl α-Aminotetrazoles 216

Figure 44

Crystal structures of 214d (CCDC 986844) (top) and 216e (CCDC 986845) (bottom). The tetrazole-fused ketopiperazine undergo three hydrogen-bonds.

Scheme 97. Employment of Hydrazine in UT-4CR and Its Post-Cyclization

Figure 45

Crystal structures of 219b (CCDC 1507441) and 221b (CCDC 1507440). (A) Two intermolecular hydrogen bonds of 2.0 Å are observed between the NH and the carbonyl moiety. (B) Hydrogen bond of 2.5 Å is observed between NH₂ and the N4 of the tetrazole.

Scheme 98. Synthesis of the Azepine-Tetrazoles 222

Scheme 99. Synthesis of Tetrazole-Fused Diazepinones 224

Scheme 100. UT-4CR/U-4CR/P-3CR Derived Macrocycle Synthesis Strategies

Figure 46

Four X-ray structures of the macrocycles 229 of different size involving different MCR assembly routes and different substituents (CCDC 1408649, 1408650, 1408653, 1408654). The most occupied interactions are included in the interactions between N of tetrazole and C of cycles, O and C of cycles, and C and C of cycles. The intramolecular bindings are mostly between O and N.

Figure 47

Two secondary amides form intermolecular hydrogen bonds to a neighbor macrocycle, whereas the cis-amide bioisosteric tetrazole moiety is not involved with hydrogen bonding. Looking into the different modules of compound 230b (CCDC 1442896), one can define the two amide groups, the tetrazole, and the lactone group as rigid elements which are separated by flexible sp³ center-based C1, C3, and C5 chain elements. These linker fragments ultimately will determine the flexibility of the overall macrocyclic conformations in aqueous and lipophilic environments, which will be a determinant of the passive diffusion through cell membranes

Scheme 101. α-Isocyano-ω-amine 231 Synthesis and UT-4CR Derived Macrocycle 232 Synthesis Pathway

Figure 48

Crystal structures of the MCR-derived 14-membered 232d (CCDC 1548701) and 12-membered 232b (CCDC 1548704) macrocycles in solid state featuring intermolecular hydrogen bonding contacts of 2.3 and 2.0 Å, respectively.

Scheme 102. Diversity of Ring Fused Tetrazole Scaffolds from the Common Precursor Building Block Isocyanoacetaldehyde Dimethylacetal

Scheme 103. Designed Synthetic Pathway to the Polyfused Tetrazolo Scaffolds 233

Scheme 104. Synthesis of Tetracyclic Piperazinotetrazoles 234

Figure 49

Crystal structures of 233d and 234d (CCDC 1017123 and 1017122 and some characteristic short contacts of 2.4 and 2.6 Å, respectively).

Scheme 105. Synthesized Fused 4,5-Dihydrotetrazolo[1,5-a]quinoxalines 237

Scheme 106. Synthesis of the Bis-tetrazolo Quinolones 238

Scheme 107. Fused Tetrazolodiazepines 240 Synthesized by UT

Figure 50

(A) Crystal structure of 240d (CCDC 780553). Two hydrogen bonds of 1.9 Å are shown between the amides of the diazepineone moieties. (B) Structures of the two JQ-1 stereoisomers.

Figure 51

The ANCHOR.QUERY virtual screening platform. (A) General sequence of steps to interrogate 2 billion MCR derived conformers. (B) Screen shot of ANCHOR.QUERY to search for inhibitors of the protein protein interaction NEMO/IKK-β. (C) View of the protein protein interaction NEMO/IKK-β with NEMO as yellow surface and IKK-β as pink α-helix (PDB 3BRV). (D) Close-up view of the hot spot formed by Trp741, Trp739, and Phe734 and the aligned to hit tetrazole in red sticks. Remarkably, the close alignment with the query amino acids and the hydrogen bonding cluster of the tetrazole with the Arg101. (E) 2D structure of the top hit 241. Reproduced with permission from ref (384). Copyright 2017 John Wiley and Sons.