MCR Synthesis of a Tetracyclic

Tetrazole Scaffold

Oleh :
Kelompok 3
Budiman Yasir N012171029
Risna N012171012
Rismayanti Fauziah N012171022
 ABSTRACT
Scaffold diversity is key in the ongoing exercise
of discovery of novel bioactive compounds using high
throughput screening (HTS). Based on the Ugi tetrazole
synthesis we have designed novel bi- and tri-cyclic
scaffolds featuring interesting pharmacophore properties.
The compounds of the scaffold (B) are synthesizable in
large diversity and numbers in two steps using
(hetero)phenylethylamines, HN3, oxo components and
iscyanoacetaldehyde (dimethylacetale). The chemistry is
amenable to parallel synthesis and is used to enhance
and fill the screening decks of the European Lead factory
(ELF). Here, we are reporting full experimental details,
scope and limitations of the reaction, cheminformatic
analysis and the 3D structures of selected compounds.

Author manuscript
Bioorg Med Chem. Author manuscript; available in PMC 2016 June 01.
 INTRODUCTION
historical compound collections, low diversity, discovery of hits novel unconventional
targets such as protein–protein interactions or intrinsically disordered proteins.

ELF is an Innovative Medicines Initiative (IMI) academic and industrial drug discovery
by creating a library of 500,000 compounds by the end of 2017

Molecular probes (small molecule or antibody) has been recently and impressively
demonstrated to be a key determinant of progress in basic biology and disease areas

MCR very well suited for the creation of large libraries of compounds for several
reasons. leads to target scaffolds in only one or few synthetic steps

Major importance minimize the time and effort to accomplish libraries of suitable size

Common functional groups with many derivatives commercially accessible

Discover novel bioactive compounds we describe here the design of a novel tetracyclic
tetrazole scaffold with full experimental detail
 Multicomponent reaction (MCR)
synthetic methodology in which three or more reactants come
together in a single reaction vessel to form a new product.
Final products contain almost all portions of substrates, generating
almost no by-products.
Extremely ideal and eco-friendly reaction system.
Target compounds can be obtained in one pot with much fewer step
UGI REACTION
 Tetracyclic tetrazole scaffold
Class of synthetic organic heterocyclic compound, consisting of a 5-member
ring of four nitrogen atoms and one carbon atom CH2N4.
Reaction of anhydrous hydrazoic acid and hydrogen cyanide under pressure.
Organic nitriles with sodium azide in the presence of iodine or silica-
supported sodium bisulfate as a heterogeneous catalyst enables an
advantageous synthesis of 5-substituted 1H-tetrazoles. 2-Aryl-2H-tetrazoles
are synthesized by a [3+2] cycloaddition reaction between an aryl diazonium
and trimethylsilyldiazomethane.

Tetracyclic compound tetrazole scaffold

 EXPERIMENTAL
Computational methods

Preparation of Ugi-adducts

Synthetic procedure A (Ugi reaction/Ugi-adduct)

Synthetic procedure B (Pictet-Spengler cyclization

Synthesis

Analytical data of Ugi-adducts and cyclization products

Compound 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a,
10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b,
19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, 24a, 24b, 25a, 25b, 26a, 26b, 27a,
27b, 28a, 28b, 29a, 29b, 30a, 30b, 31a, 31b, 32a, 32b, 33a, 33b, 34a, 34b, 35a, 35b,
36a, 36b, 37a, 37b, 38a, 38b, 39a, 39b, 40a, 40b , 41a, 41b, 42a, C

Analytical instrument
 Pictet–Spengler cyclization reaction
Chemical reaction which a β-arylethylamine such as tryptamine undergoes ring
Closure after condensation with an aldehyde or ketone.
Usually an acidic catalyst is employed and the reaction mixture heated
1911 by Amé Pictet and Theodor Spengler
Reaction of β-phenethylamine with the dimethyl acetal of formaldehyde and
hydrochloric acid forming a tetrahydroisoquinoline.
Formation of an iminium ion (2) electrofilic addition at the 3-position, in
nucleophilicity of indoles to give the spirocycle (3). migrating group,
deprotonation gives the product (5).
 Varians Pictet–Spengler cyclization
Pictet–Spengler tetrahydroisoquinoline synthesis

N-acyliminium ion Pictet–Spengler reaction

Asymmetric Pictet–Spengler reaction

Tryptophans: diastereocontrolled reaction

 Ugi reaction
Multi-component reaction in organic chemistry involving a ketone or aldehyde,
an amine, an isocyanide and a carboxylic acid to form a bis-amide.
Ivar Karl Ugi, who first reported this reaction in 1959.
Exothermic and usually complete within minutes of adding the isocyanide
High concentration (0.5M - 2.0M) of reactants give the highest yields.
Polar, aprotic solvents, like DMF, methanol and ethanol work. Recent research has
shown that the Ugi reaction is accelerated in water
 Varians Ugi reaction

Ugi–Diels–Alder reaction Ugi–Smiles reaction

Ugi–Buchwald–Hartwig reaction Ugi–Heck reaction

General procedure A: preparation of Ugi-adducts
Synthetic procedure A (Ugi reaction/Ugi-adduct)

1 M aldehyde in methanol
+1.0 equiv of amine
+1.0 equiv of azidotrimethylsilane
+1.0 equiv of isocyanoacetaldehyde dimethylacetal
mixture was stirred
room temperature for 18 h

solvent removed
Reduce pressure

residue purified
+FCCSG

Ugi-product ESI-MS 1H and 13C NMR 500 MHz

General procedure A: preparation of Ugi-adducts
Synthetic procedure B (Pictet-Spengler cyclization)

1 mmol Ugi-tetrazolee + 100 mmol methanesulfonic acid

Stirred
room temperature
18 h
reaction quenched
saturated sodium carbonate
extracted EtOAc (20 mL × 3)

solvent removed
Reduce pressure

residue purified
+FCCSG

cyclic product ESI-MS 1H and 13C NMR 500 MHz

 Computational methods
1000 randomly generated examples were made of the described scaffolds using previously described
methods.
200 compounds were randomly selected and physiochemical properties relating to drug likeness were
calculated via ChemAxon’s Calculator Plugins (Marvin 6.1.0, 2013, ChemAxon
http://www.chemaxon.com).
Scaffold key distances were calculated using previously described methods31 and plotted using
Cytoscape (Cytoscape v3.1.1, www.cytoscape.org).
Compound 3d generation of compounds was done using Moloc’s Mol3d software (Moloc
http://www.moloc.ch).
Principal moment of inertia was calculated using Schrodinger’s Maestro V 9.3 (Suite 2012: Maestro,
version 9.3, Schrödinger, LLC, New York, NY, 2012.).
 PRINCIPLE of SYNTHESIS

Ugi reaction, product Pictet-Spengler cyclization)

A B

85 compound synthesis
 Analytical data of Ugi-adducts and cyclization products
Compound 1a: 1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4 dimethoxyphenethyl)propan-1-amine (1a)
Compound 1b:8-ethyl-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazoleo[1′,5′:4,5]pyrazino [2,1-a]isoquinoline (1b)
Compound 2a: 1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxyphenethyl)-2-methylpropan-1-amine (2a)
Compound 2b:8-isopropyl-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazoleo[1′,5′:4,5]pyrazino[2,1-a]isoquinoline (2b)
Compound 3a: 1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxyphenethyl)-3-phenylpropan-1-amine (3a)
Compound 3b:2,3-dimethoxy-8-phenethyl-6,8,13,13a-tetrahydro-5H-tetrazoleo[1′,5′:4,5]pyrazino[2,1-a]isoquinoline (3b)
Compound 4a: 1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxyphenethyl)-2-phenylethanamine (4a)
Compound 4b:8-benzyl-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazoleo[1′,5′:4,5]pyrazino [2,1-a]isoquinoline (4b)
Compound 5a:N-((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(phenyl)methyl)-2-(3,4-dimethoxy phenyl)ethanamine (5a)
Compound 5b: 2,3-dimethoxy-8-phenyl-6,8,13,13a-tetrahydro-5H-tetrazolo[1′,5′:4,5]pyrazino [2,1-a]isoquinoline (5b)
Compound 6a:N-((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)-2-3,4-dimethoxyphenyl)ethanamine
Compound 6b:8-(4-chlorophenyl)-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazolo[1′,5′:4,5]pyrazino[2,1-a]isoquinoline
Compound 7a:N-((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-fluorophenyl)methyl)-2-(3,4-dimethoxyphenyl)ethanamine
Compound 7b:8-(4-fluorophenyl)-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazolo[1′,5′:4,5] pyrazino[2,1-a]isoquinoline
Compound 8a:N-([1,1′-biphenyl]-4-yl(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)-2-(3,4-
dimethoxyphenyl)ethanamine (8a)
Compound 8b:8-([1,1′-biphenyl]-4-yl)-2,3-dimethoxy-6,8,13,13a-tetrahydro-5H-tetrazolo[1′,5′:4,5]pyrazino[2,1-
a]isoquinoline (8b)
Compound 9a:2-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxyphenethyl)butan-2-amine (9a)
Compound 9b:8-ethyl-2,3-dimethoxy-8-methyl-6,8,13,13a-tetrahydro-5H-tetrazolo[1′,5′:4,5] pyrazino[2,1-a]isoquinoline
Compound 10a:1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxyphenethyl) cyclohexanamine (10a)
Compound 10b:2′,3′-dimethoxy-5′,6′,13′,13a′-tetrahy-drospiro[cyclohexane-1,8′-tetrazolo[1′,5′:4,5]pyrazino[2,1-a]-
isoquinoline] (10b)
Compound 11a:1-benzyl-4-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-(3,4-dimethoxy phenethyl)piperidin-4-amine
Compound 11b:1-benzyl-2′,3′-dimethoxy-5′,6′,13′,13a′-tetrahydrospiro[piperidine-4,8′-tetrazolo[1′,5′:4,5]pyrazino[2,1-
a]isoquinoline] (11b)
Compound 16a: N-(2-(1H-indol-3-yl)ethyl)-1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)propan-1-amine (16a)
Compound 16b: 4-ethyl-4,6,7,12,12b,13-hexahydro-tetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2] pyrido[3,4-b]indole (16b)
Compound 17a: N-(2-(1H-indol-3-yl)ethyl)-1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl) cyclohexanamine (17a)
Compound 17b:7′,12′,12b′,13′-tetrahydro-6′H-spiro[cyclohexane-1,4′-tetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole] (17b)
Compound 18a: N-(2-(1H-indol-3-yl)ethyl)-1-benzyl-4-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)piperidin-4-amine (18a)
Compound 18b:1-benzyl-7′,12′,12b′,13′-tetrahydro-6′H-spiro[piperidine-4,4′-tetrazolo
[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-b]indole] (18b)
Compound 19a: N-((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)-2-(1H-indol-3-yl)ethanamine (19a)
Compound 19b: 4-(4-chlorophenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino [1′,2′:1,2]pyrido[3,4-b]indole
Compound 20a:N-((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-nitrophenyl)methyl)-2-(1H-indol-3-yl)ethanamine (20a)
Compound 20b:4-(4-nitrophenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino [1′,2′:1,2]pyrido[3,4-b]indole
Compound 21a:N-((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(3,4,5-trimethoxyphenyl)methyl)-2-(1H-indol-3-
yl)ethanamine (21a)
Compound 21b:4-(3,4,5-trimethoxyphenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole (21b)
Compound 22a: N-(2-(1H-indol-3-yl)ethyl)-1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-3-(methylthio)propan-1-amine
Compound 26a: methyl2-((1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-2-methylpropyl)amino)-3-(1H-indol-3-
yl)propanoate (26a
Compound 26b: methyl 4-isopropyl-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino [1′,2′:1,2]pyrido[3,4-b]indole-
6-carboxylate (26b)
Compound 27a: methyl2-((1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-3-phenylpropyl)amino)-3-(1H-indol-3-
yl)propanoate (27a)
Compound 27b: methyl4-phenethyl-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-b]indole-
6-carboxylate (27b)
Compound 28a:methyl 2-((1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-3-(methylthio)propyl) amino)-3-(1H-indol-3-
yl)propanoate (28a)
Compound 29a:methyl 2-((2-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)butan-2-yl)amino)-3-(1H-indol-3-yl)propanoate
Compound 29b:methyl4-ethyl-4-methyl-4,6,7,12,12b,13hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole-6-carboxylate (29b)
Compound 30a: methyl 2-((1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)cyclohexyl)amino)-3-(1H-indol-3-yl)propanoate
Compound 30b:methyl7′,12′,12b′,13′-tetrahydro-6′H-spiro[cyclohexane-1,4′-
tetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-b]indole]-6′-carboxylate (30b)
Compound 31a:methyl2-((1-benzyl-4-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)piperidin-4-yl)amino)-3-(1H-indol-3-
yl)propanoate (31a)
Compound 31b:methyl1-benzyl-7′,12′,12b′,13′-tetrahydro-6′H-spiro[piperidine-4,4′-tetrazolo
[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-b]indole]-6′-carboxylate (31b)
Compound 32a: methyl 2-(((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(phenyl)methyl)amino)-3-(1H-indol-3-
yl)propanoate
Compound 32b:methyl 4-phenyl-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino [1′,2′:1,2]pyrido[3,4-b]indole-6-
carboxylate (32b)
Compound 33a:methyl2-(((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)amino)-3-(1H-indol-3-
yl)propanoate (33a)
Compound 33b:methyl4-(4-chlorophenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole-6-carboxylate (33b)
Compound 34a:methyl2-(((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-fluorophenyl)methyl)amino)-3-(1H-indol-3-
yl)propanoate (34a)
Compound 34b:methyl4-(4-fluorophenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole-6-carboxylate (34b)
Compound 35a:methyl2-(((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-nitrophenyl)methyl)amino)-3-(1H-indol-3-
yl)propanoate (35a)
Compound 35b:methyl4-(4-nitrophenyl)-4,6,7,12,12b,13-hexahydrotetrazolo[1″,5″:4′,5′]pyrazino[1′,2′:1,2]pyrido[3,4-
b]indole-6-carboxylate (35b)
Compound 36a:methyl2-(((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-nitrophenyl)methyl)amino)-3-(thiophen-2-
yl)propanoate (36a)
Compound 36b:methyl7-(4-nitrophenyl)-5,7,12,12a-tetrahydro-4H-tetrazoleo[1,5-a]thieno[3′,2′:3,4]pyrido[1,2-
d]pyrazine-5-carboxylate (36b)
Compound 37a: 1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)-N-phenethylcyclohexanamine (37a)
Compound 38a: N-((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)-2-phenylethanamine (38a)
Compound 39a: 4-(2-(((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)amino)ethyl)phenol (39a)
Compound 40a: N-((4-chlorophenyl)(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)methyl)-2-(2-methoxyphenyl)ethanamine
Compound 41a:Methyl2-((1-(1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)cyclohexyl)amino)-3-(4-
methoxyphenyl)propanoate (41a)
Compound 42a: N-((1-(2,2-dimethoxyethyl)-1H-tetrazole-5-yl)(4-nitrophenyl)methyl)-2-(4-methoxyphenyl)ethanamine
Compound C: 7-(4-Methoxyphenethyl)-8-(4-nitrophenyl)-7,8-dihydrotetrazolo[1,5-a]pyrazine (C)
 Analytical Instrument
Nuclear magnetic resonance spectra (NMR) Bruker Avance 500 spectrometer (1H NMR (500 MHz),
13C NMR (126 MHz)). 1H NMR δ values and coupling constants hertz (Hz). spin multiplicity: s =
singlet, d = doublet, t = triplet, dd = double doublet, m = multiplet, brs = broad singlet. Chemical
shifts for 13C NMR in ppm relative to the solvent peak. TLC Fluka precoated silica gel plates (0.20 mm
thick, particle size 25 μm). FC Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase Silica
Flash Columns (Silica Gel 60 Å, 230–400 mesh). ESI–MS were recorded on a Waters Investigator semi-
prep-15 SFC–MS instrument
RESULTS
Figure 1. Physicochemical properties and pharmacophore of the new scaffolds.
Figure 2. Compound 18b in the solid state. Key contacts and distances are highlighted.
Figure 3. Compound 27b in the solid state. Key contacts and distances are highlighted.
Figure 4. Compound 30b in the solid state. Key contacts and distances are highlighted.
Figure 5. Compound 5b in the solid state. Key contacts and distances are highlighted.
Figure 6. Principal moment of inertia of randomly generated compounds from
this class of compounds vs those compounds physically synthesized in this paper
(grouped by amine starting material).
Figure 7. Scaffold map of tetrazole containing compounds described via MCR.
plotted by scaffold key distances, and color coded by cLogP
 Optimization of the Pictet–Spengler cyclization stepa

aReaction conditions: 1a (0.3 mmol), acid (30.0 mmol), solvent (3.0 mL).
bThe reaction was performed under classical heating conditions.
cDetermined by SFC–MS analysis of crude reaction mixture.
dIsolated product.
aIsolated yield after silica gel column chromatography.
bDiastereomeric ratio determined by 1H and 13C spectra or SFC–MS.
cDetermined by SFC–MS analysis of crude reaction mixture.
dIsolated yield of compound C.
Scheme 4. Side reaction to C observed.
 CONCLUSION
In this study, we demonstrated that the MCR synthesis of a tetracyclic
tetrazole scaffold found of 85 compound synthesis have done and maximum yield
UGI reaction having product synthesis from compound 20 and 40 until 98%,
Pictet–Spengler cyclization reaction compound 20 until 95%, Side reaction to C
observed compound 61%, used methanesulfonic acid, methanol, 80 OC, and 18 h
optimation condition of reaction.
 ACKNOWLEDGMENTS

This work was supported by Innovative Medicine

Initiative European Lead Factory project (Grant
agreement no. 115489) and National Institute of
Health (1R01GM097082-01).