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

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Chapter 2

Review: tetrazoles via multicomponent reaction

routes

Ting Zhao, Alexander Dömling, In preparation.

Chapter 2

Page | 10

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

DB00177

Cefotiam

DB00229

A broad spectrum of activity against both gram-

Cefmenoxime

DB00267

Cefmetazole

DB00274

An antibiotic with a broad spectrum of activity against

Review: tetrazoles via multicomponent reaction routes

Page | 11

Angiotensin-receptor blocker

positive and gram-negative microorganisms

A third-generation cephalosporin

antibiotic

both gram-positive and gram-negative microorganisms

Olmesartan

DB00275

Antihypertensive agent, which

belongs to the class of medications

called angiotensin II receptor

Cefpiramide

DB00430

A third-generation cephalosporin antibiotic

Losatan

DB00678

An angiotensin-receptor blocker

(ARB) that may be used alone or with

other agents to treat hypertension

Candesartan

DB00796

An angiotensin-receptor blocker (ARB) that may be

used alone or with other agents to treat hypertension

Alfentanil

DB00802

A short-acting opioid anesthetic and analgesic of

fentanyl

Pemirolast

DB00885

A mast cell stabilizer that acts as antiallergic agent

Ceforanide

DB00923

A second-generation parenteral

cephalosporin antibiotic

Irbesartan

DB1029

An angiotensin receptor blocker (ARB) used mainly

for the treatment of hypertension

Cilostazol

DB01166

A medication used in the alleviation of

the symptom of intermittent

claudication in individuals with

peripheral vascular disease

Cefamandole

DB01326

A broad-spectrum cephalosporin antibiotic

Cefazolin

DB01327

A broad-spectrum antibiotic

Forasartan

DB01342

A specific angiotensin II antagonist, is used alone or with other antihypertensive agents to treat hypertension

Cefonicid

DB01328

Cefoperazone

DB01329

Cefotetan

DB01330

Tasosartan

DB01349

Chapter 2

Page | 12

A second-generation

cephalosporin administered

intravenously or intramuscularly

Semisynthetic broad-spectrum cephalosporin with a tetrazolyl moiety

A semisynthetic cephamycin antibiotic

that is administered intravenously or intramuscularly

A long-acting angiotensin II (AngII) receptor blocker

Pranlukast

DB01411

A cysteinyl leukotriene receptor-1

antagonist to antagonize or

reduce bronchospasm

caused

2-(2f-Benzothiazolyl)-5-Styryl-3-(4f-

Phthalhydrazidyl)Tetrazolium Chloride

DB01897

(5r,6s,7s,8s)-5-Hydroxymethyl-

6,7,8-Trihydroxy-Tetrazolo[1,5-a]Piperidine

DB02294

Nojirimycine Tetrazole

DB02471

Mercaptocarboxylate Inhibitor

DB02706

1-(5-Chloroindol-3-Yl)-3-Hydroxy-3-(2h-Tetrazol-

5-Yl)-Propenone

DB03118

N,N-Bis(4-Chlorobenzyl)-1h-

1,2,3,4-Tetraazol-5-Amine

DB04037

7-((Carboxy(4-Hydroxyphenyl)Acetyl)Amino)-7-Methoxy-(3-((1-Methyl-

1h-Tetrazol-5-Yl)Thio)Methyl)-8-Oxo-5-

Oxa-1-Azabicyclo[4.2.0]Oct-2-Ene-2-Carboxylic Acid

DB04342

3-(4-Phenylamino-Phenylamino)-2-

(1h-Tetrazol-5-Yl)-Acrylonitrile

DB04430

Latamoxef

DB04570

Broad- spectrum beta-lactam antibiotic

N-(1,4-Dihydro-5H-tetrazol-5-ylidene)-9-oxo-9H-xanthene-2-

sulfonamide

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 | 13

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

Chapter 2

Page | 14

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

Bacteroides Fragilis Metallo-β-Lactamase

1QS49

the HIV-1 Integrase Catalytic Domain

1SL311

P1 Aryl Heterocycle-Based Thrombin

1V4062

Human Hematopoietic Prostaglandin D Synthase

1M5B41

the Glur2 Ligand Binding Core (S1S2J)

1PZO43

TEM-1 β-Lactamase

1PZP43

TEM-1 β-Lactamase

1JZ675 3VD749

E. Coli (lacZ) β-Galactosidase

1JTQ54 1DD655 1QJX73 1QJU73


Page | 15

Human and Escherichia Coli

Thymidylate Synthases

the IMP-1 Metallo β-Lactamase from

Pseudomonas Aeruginosa

Human Rhinovirus 16 Human Rhinovirus 16

1JZ675 3VD749

Escherichia Coli (Lacz) β-

Galactosidase

1E6Q76 1NOI77 1NOJ77 1NOK77 1V0858 2J7B57

β-Glycosidase

1WVP61

Chemically modified myoglobin

2I1R72

HCV NS5B Polymerase

2C9042

Thrombin

2C4W46

Helicobacter Pylori Type II Dehydroquinase

2CVD51

Human Hematopoietic

Prostaglandin D Synthase

2P2A56

the GluR2 ligand binding core (S1S2J)

2NT739

Thiophene PTP1B

3KYR[a]

BACE-1

3UOL6

Aurora A

3G3412

CTX-M-9 Class A β-Lactamase

3ZM619

the Essential Peptidoglycan

Biosynthesis Enzyme Murf

3KEJ20

Human Matrix Metalloproteinase-13

3KEC20


3O2X[a]


3G3212


3G3512


3G2Y12

CTX-M-9

class A β-lactamase

3GR247

AmpC β-lactamase

3G2Z12

CTX-M-9 class A β-lactamase

Chapter 2

Page | 16

3O2M27

JNK1-α1 Isoform

3FMH[a]

p38 Map Kinase

3FMK[a]

p38 Map Kinase

3G7678

XIAP-BIR3

3R8A50

the Nuclear Hormone Receptor PPAR-

gamma

3SOR63

Factor XIa

3SOS63

Factor XIa

3W9H65 3W9J65

Bacterial Multidrug Exporters

3NY466

BlaC-K73A

3N8S66

BlaC-E166A

3N2Y68

Tyrosyl-tRNA Synthetase

4DE17


4DDS7


4DE07


4DE27


4DDY7


4DE37


4UA722 4UAA22


4E3M8

AmpC β-Lactamase

4E3L8

AmpC β-Lactamase

4E3N8

AmpC β-Lactamase

4E3K8

AmpC β-Lactamase

4E3J8

AmpC β-Lactamase

4KAC[a] 4KAJ[a] 4KYV[a]

Haloalkane Dehalogenase HaloTag7

4L3414

Tankyrase 2

4M4Q17

Influenza 2009 H1N1 Endonuclease

4W9S23

Influenza 2009 H1N1 Endonuclease

4M5U16

Influenza 2009 pH1N1 Endonuclease

4HEE10

PPARgamma

4XT226

the High Affinity Heterodimer of HIF2 α

4BXK13 4BO924


Page | 17

and ARNT C-Terminal PAS Domains

the Angiotensin-1 Converting Enzyme

N-Domain

3-Oxoacyl-(Acyl-Carrier-Protein) Reductase (FabG)

from Pseudomonas aeruginosa

4BO7[b]

3-Oxoacyl-(Acyl-Carrier-Protein)

Reductase (FabG) from Pseudomonas

Aeruginosa

4X6N25

Factor XIa

4Y8Z28

Factor XIa

4Y8Y28

Factor XIa

4X6O25

Factor XIa

4Y8X28

Factor XIa

4CRB38 5E2P34

Factor XIa

4X6P25

Factor XIa

4KOS30

GNAT Superfamily Acetyltransferase

PA4794

4AJ233

Rat LDHA

4XOZ79 4XRJ79

ERK2

4UAI21

CXCL12 Chemokine

4P3H18

Kaposi's Sarcoma-associated

Herpesvirus (KSHV) Protease

4XZ031

ZAP-70-tSH2

4ZYC32

p53-MDM2

4ANU45

PI3Kgamma

4FSR[a]

the CHK1

4L7C15

Keap1 Kelch Domain

4N8R52

RXRa LBD

4N5G52

RXRa LBD

4K8A53

Focal Adhesion Kinase

4ZUD64

Human Angiotensin Receptor

4CRC38

F1

4MF367

Human GRIK1

Chapter 2

Page | 18

4ITE69

the Human Vitamin D Receptor Ligand Binding Domain

4ITF69

the Human Vitamin D Receptor Ligand Binding

Domain

4YAY74

Human Angiotensin Receptor

4YD029

Influenza Polymerase Basic Protein 2 (PB2)

5ALT40

Epoxide Hydrolase

5AOK48

the p53 Cancer Mutant Y220C

5A6N70

Human Death Associated Protein

Kinase 3

5E2O34

Factor XIa

O

N NN

HN

Cl

Cl

5EGM35

Factor XIa

5AJR71

Sterol 14-α Demethylase (CYP51) from

Trypanosoma Cruzi

5EEG[a]

Carminomycin-4-O-Methyltransferase

DnrK

5EH736

Human carbonic anhydrase II

5FHO37

the GluA2 ligand-binding domain

(S1S2J)

5FHN37

the GluA2 ligand-binding domain (S1S2J)

5FHM37

the GluA2 ligand-binding domain

(S1S2J)

5FLP36

Carbonic anhydrase 2

5FLO36


5FNG36


5FNI36


5FNH36


[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 | 19

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°.

Chapter 2

Page | 20

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.


Page | 21

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

Compound Log D[a] Polar surface area [Å2][b]

Efflux ratio[c]

Unbound brain-to-plasma (Bu/Pu)[d]

Cu

[µM][e]

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

4 (carboxylic acid) 1.36 95 20 <0.01

0.4[f]

<0.01

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

2GL7).81 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

Chapter 2

Page | 22

design. The D16 and E17 of human Tcf were chosen as a critical binding element and converted

into small molecules mimicking this key element (Figure 2.5).82 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.


Page | 23

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.

Chapter 2

Page | 24

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).


Page | 25

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

Chapter 2

Page | 26

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 | 27

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.

Chapter 2

Page | 28

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 | 29

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

Chapter 2

Page | 30

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 | 31

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

Chapter 2

Page | 32

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 | 33

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

Chapter 2

Page | 34

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 | 35

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

Chapter 2

Page | 36

TMSN3

NC

MeOH

r.t., 12 - 24 h45 - 60%

NH

N NN

NR

SNN

CHO

NNS R

NH2

+

NH

N NN

N

SNN

23a, 47%

NH

N NN

N

SNN

23b, 50%

Cl

NH

N NN

N

SNN

23c, 48%

F

23

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 | 37

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.

R1CHO

TMSN3 R2NC

EtOH

MW, 100 oC, 30 minNH

R1

N NN

N

R246 - 87%

TFA in CH2Cl2

r.t., 1 minquantitative yields

TFA H2N

R1

N NN

N

R2

NH N N

NN

24a, 83%

NH N N

NN

24b, 73%

N NN

N

24c, 75%

TFA H2N

N NN

N

25a, 99%

TFA H2N

N NN

N

25b, 99%

TFA H2N

N NN

N

25c, 99%

+

NH2

NH

24 25

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).

Chapter 2

Page | 38

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 | 39

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,

TMSN3 and isocyanides (Scheme 2.23).131 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

Chapter 2

Page | 40

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.

R1 NH

O

NH2R2

O

R3NC

TMSN3

MeOH

r.t. 24h54 - 65%

R1

HN O

NH

N NN

N

R3

R2+

HN O

NH

N NN

N

HN O

NH

N NN

N

S

28b, 63%, dr 78:22

SHN

NH

N NN

N

28c, 67%, dr 80:20

O

O

28

28a , 60%, dr 68:32

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 | 41

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.

Chapter 2

Page | 42

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 | 43

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.

Chapter 2

Page | 44

R1CHO

Boc

HN

NH2

TMSN3 R2NC

34 - 88% NH

R1

N NN

NHN

Boc

R2

NH

N NN

NHN

Boc

33awithout ZnCl2 70%

with ZnCl2 69%

NH

N NN

NHN

Boc

33bwithout ZnCl2 -with ZnCl2 40%

NH

N NN

NHN

Boc

Cl

Cl

33cwithout ZnCl2 -with ZnCl2 37%

+

10% ZnCl2MeOH, r.t.18 - 24h

33

NH

R1

N NN

NHN

Boc

R2

34

2 M HCl in MeOH24 - 48h

65 - 99%

N

Cl

NH

N NN

H2N

34a, 80%

NH

N NN

NH2N

34b, 99%

NH

N NN

NH2N

Cl

Cl

34c, 85%

N

Cl

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 | 45

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

Chapter 2

Page | 46

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 | 47

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).

Chapter 2

Page | 48

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

H+R1N

C NR2 N

R2

R1N

NH

NR2

R2

NN

N R1N

N

HN

NR2

R2

NN

NH

N

R1

N NN

N

R2

R1

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 | 49

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-

Chapter 2

Page | 50

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).

CH2O

HN

HN

NH

NH

TMSN3 NCCN

+MeOH, 12h

r.t., > 99%

N

N

N

N

NNN

N

CN

N

NN

N

NC

N NN

N

NC

N

NN

N

CN

NaOHACN/H2O

r.t., 86%

N

N

N

N

NHNN

N

HNN

NN

HN NN

N

NH

NN

NGdCl3

70 oC, 7d

H2O

pH 6.7~ 40%

N

N

N

N

NHNN

N

HNN

NN

HN NN

N

NH

NN

N

Gd3+

44

45

46 47

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


Page | 51

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

Boltjes et al.146 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-

Chapter 2

Page | 52

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 | 53

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

Chapter 2

Page | 54

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 | 55

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.

Chapter 2

Page | 56

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 | 57

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).

CHO1. MeOH (3 M)

r.t., 12h

2. P(OEt)3 (5 eq.)DMF (2M)

140 oC, 10h

TMSN3

NO2

61

+24 - 65%

R1NH2

R2NC

N NN

N

R2

NNR1

61a, 65%

N NN

N

NN

OMe

61b, 24%

N NN

N

OMe

NN

61c, 49%

N NN

N

OMe

NNCl

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

Chapter 2

Page | 58

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 | 59

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.

Chapter 2

Page | 60

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).

EtOOC

O

R1 NH2

NO2

TMSN3 R2NC

MW, 10 min

o-xylene70 - 90%

R2+

O O

O

orR1

R2 N

HN

OR3

NCand TMSN3

MeOH, p-TsOHr.t. 1 h

65 - 70%

NO2

NH2R1

EtOOC

O

TMSN3 R2NC

+

1. MeOH, r.t. 48 h

2. SnCl2 2H2Oreflux, 12 h63 - 70%

NaH, THF

85 oC, 5 h40 -46%

NH

N NN

N

R3

COOEtNH2

R1

route 1

route 2

R1

R2 NH

HN

O

NN

NN

R2

NH

HN

O

NN

NN

64aroute 1 65%route 2 45%

NH

HN

O

NN

NN

64broute 1 70%

NH

HN

O

NN

NN

64croute 2 40%

64

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 | 61

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.

Chapter 2

Page | 62

Br

CHO

R1 R2NH2

NaN3 R3NC

+MeOH, r.t.

72 - 99% N NN

N

R3

N

R2

R1

N NN

N

N

65a, 96%

N NN

N

N

65b, 79%

F

N NN

N

N

65c, 76%

OMe

OMe

OMe

65

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 | 63

EtOOCCHO

R1NH2

TMSN3 R2NC

+DCE, MW, 120 oC, 1 h 1. TFA, r.t., 12 hN

H

COOEt

N NN

N

R2

R1

2. R3NCX

EtOH, r.t., 2 - 36 h, 49 - 79%

or EtOH, MW, 120 - 180 oC

25 - 99%

N NN

N

R2

NN

O

OR1

R3

NH

N NN

N

Cl

66a, 54%

N NN

N

NN

O

O

Cl

Br

4-Br-PhNCO67a, 77%

NH

N NN

N

66b, 43%

N NN

N

NN

O

O

PhNCO67b, 64%

NH

COOEt

N NN

N

66c, 60%

N NN

N

NHN

O

S

TMSNCS67c, 25%

66 67

O O O O

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

Chapter 2

Page | 64

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.

CHO

R1

X

R2NH2

TMSN3

NC+

MeOH, r.t. 7 h

79 - 95% NH

N NN

NR2

XR1

R3NC

Pd(OAc)2, Cs2CO3

DMF, 90 oC, 1 h

65 - 75% N NN

HNN

R2

NR3

R1

NH

N NN

N

Br

MeO

68a, 95%

N NN

HN

69a, 70%

N

MeO

N

NH

N NN

N

Br

68b, 88%

N NN

HN

69b, 75%

NN

N NN

N

Br

68c, 80%

N NN

HN

69c, 68%

NN

NH

MeO

F

F

68 69

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 | 65

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;

Chapter 2

Page | 66

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 | 67

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

Chapter 2

Page | 68

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 | 69

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

OHOH OO

O NH

NH2

OHN

H2N

R1 R2

O

TMSN3 R3NC

MeOH, r.t.

24 h58 - 80% OHOH OO

O NH

NHOHN

HNR2

R1

NN N

NR3

R2

R1

N

N NN R3

OHOH OO

O NH

NHOHN

HN

N NN

N NN

N N

OHOH OO

O NH

NHOHN

HN

N NN

N NN

N N

77a, 80% 77b, 70%

OHOH OO

O NH

NHOHN

HN

N NN

N NN

N N

77c, 58%

+

77

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

Chapter 2

Page | 70

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 | 71

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.

Chapter 2

Page | 72

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 | 73

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).

RCHO

2 NaN3 NCH2O-NaOTs

air, r.t.R

OH

N NN

N

OH

N NN

N

84a45% 4 M NaN3

95% 3.8 M NaOTs 10 equiv. NaN3

OH

N NN

N

84b>90% 3.8 M NaOTs 10 equiv. NaN3

+ +

84

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

Chapter 2

Page | 74

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 | 75

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).

NCN

I

O O H2O, HCCl3

Me4NBr

87, 90%

+ NaN3 +

I

N NN

N

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

X

X

CHO

COOMe R1NH2

R2NC

MeOH, 2 days

TMSN3

73 - 78%+

NaOEt, EtOH heat 84 - 92%

MeO

or spontaneous11 - 79%

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

NH

X

X

COOMe

R1

N NN

N

R2

N NN

N

R2

NR1

O

X

X

N NN

NNO

N NN

N

S

NO

OON N

NNN

O

Cl

MeO

88 89

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

Chapter 2

Page | 76

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 | 77

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

Chapter 2

Page | 78

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 | 79

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.

Chapter 2

Page | 80

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 | 81

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).

Chapter 2

Page | 82

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).

MeOOC CHOn

TMSN3 RNC

MeOH, 100oC

MW, 30 min

1. TFA/CH2Cl21 min, r.t.

2. NaH, THFr.t., 4 h

HN

On

N NN

N

R

NH

N NN

N

COOMe

102a, 50%

NH

N NN

N

102b, 68%

COOMe

N NN

NNH

O

103a, 89%

N NN

N

103b, 99%

NH

O

+ NH

TrtNH2

N NN

N

R

Trt

COOMe

n

NH

N NN

N

COOMe

102c, 40%

N NN

NNH

O

103c, 95%

102 103

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 | 83

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

Chapter 2

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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).

R1

O

R2R3

NH2

TMSN3 R4NC

1) MeOH, MW, 100oC, 15 min

56 - 96%

2) TFA, CH2Cl2, r.t.67 - 90%

NH

R1

N NN

N

R4

R3R2 KO

O

NCn

Et3N, HOBt, DCCMeCN, 48 h40 - 75%

NH

R1

N NN

N

R4

R2O

CN

n

1.5 eq. KOH

EtOHNH

R1

N NN

N

R4

R2O

CN

n

R5

O

R6R7

NH2

MeOH (0.01 M), r.t.17 - 34%

MCR 1

MCR 2N

NH

N

N

O R1R2R3

O

n

OR4R3

R2

NN

N

n

HN

N

N

HN

O

O

NN

NO

107a, 30%

N

NH

NH

N

O

O

N NN

Cl

O

107b, 27%

N

NH

NNH

O

O

N NN

O

107c, 36%

104 105

106 107

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

macrocyclisation yields after purification.


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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

Chapter 2

Page | 86

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.

MeOOC

R3

NCTMSN3

R1 R2

O

N

N NN

HN

NR5

R4

R6

O

R3

1. MeOH, r.t., 24h2. 10%TFA/CH2Cl23. PS-DIEA, DMF/dioane

1:1, reflux+

111

BocHN

N N

HN

O

N NN

111a, 84%

N N

NO

N NN

111b, 48%

NHN

O N N

HN

O

N NN

111c, 80%

NN

N

CHO

R6

4. PS-NCO, PSTs-NHNH2

THF/CH3CHCl2, 1/145 - 100%

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 | 87

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

Chapter 2

Page | 88

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).

NN

OO

Cl

S

NN

114 JQ1

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

R H

O

+ R2

NR3 or PR4

R

OH

R2

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 | 89

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-

Chapter 2

Page | 90

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 | 91

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

Chapter 2

Page | 92

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-


Page | 93

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).

Chapter 2

Page | 94

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).

MeO

OMe

NC

NH2

TMSN3

MeOH, r.t., 18h

68 - 98%

HN

N NN

N

MeO OMe

+ 32 - 95%

CH3SO3H,r.t., 18h

121g, 68%

122c, 58%

(hetero)aroyl

R1

O

R2 R1R2

(hetero)aroyl

N

N

NN

N

R1

(hetero)aroyl

HN

N NN

N

MeO OMe

MeO

MeO

NN

NN

N

OMeMeO

122a, 77%

121h, 86%

HN

N NN

N

MeO OMe

HN

MeO

OMe

OMe

N

N

NN

N

122b, 32%

OMe

MeO OMe

NH

121i, 88%

HN

N NN

N

MeO OMe

HN

N

N

NN

N

NH

Polyfused Tetrazolo Piperazine Scaffolds

121c 122

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


Page | 95

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.

Chapter 2

Page | 96

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.

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