Al(III) chloride catalyzed multi-component domino strategy: Synthesis of library of dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2017.09.052

Tetrazolo[1,5-a]pyrimidines are well recognized and valuable scaffolds in drug discovery. In the current manuscript, we demonstrated AlCl₃ catalyzed synthesis of series of dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazo

Full text of DOI:10.1016/j.tetlet.2017.09.052

Accepted Manuscript
Al(III) Chloride catalyzed Multi-Component Domino Strategy: Synthesis of
Library of Dihydrotetrazolo[1,5-a]pyrimidines and Tetrahydrotetrazolo[1,5-
a]quinazolinones
Parteek Kour, Varun P. Singh, Brijmohan Khajuria, Tajinder Singh, Anil Kumar
PII:
S0040-4039(17)31179-6
https://doi.org/10.1016/j.tetlet.2017.09.052
TETL 49322
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 July 2017
14 September 2017
18 September 2017
Please cite this article as: Kour, P., Singh, V.P., Khajuria, B., Singh, T., Kumar, A., Al(III) Chloride catalyzed Multi-
Component Domino Strategy: Synthesis of Library of Dihydrotetrazolo[1,5-a]pyrimidines and
Tetrahydrotetrazolo[1,5-a]quinazolinones, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.09.052
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Al(III) Chloride catalyzed Multi-Component Domino Strategy: Synthesis of Library of
Dihydrotetrazolo[1,5-a]pyrimidines and Tetrahydrotetrazolo[1,5-a]quinazolinones
Parteek Kour,a Varun P. Singh, Brijmohan Khajuria,c Tajinder Singhd and Anil Kumara*
aSynthetic Organic Chemistry Laboratory, Faculty of Sciences, Shri Mata Vaishno Devi University, Katra, J & K – 182 320, India.
bMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
cDepartment of Chemistry, University of Jammu, Jammu– 180006, J&K, India.
dDepartment of Chemistry, GDC Poonch, Poonch—185101, J&K.
*Corresponding author: E. Mail: anilsharmachemistry@gmail.com contact: +91 – 94191 66329; fax: +91–1991 28569.
Abstract: Tetrazolo[1,5-a]pyrimidines are well recognized and valuable scaffolds in drug
discovery. In the current manuscript, we demonstrated AlCl3 catalyzed synthesis of series of
dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones via a modified
Bignelli type multi-component reaction of 5-aminotetrazole, aldehyde and diverse active
methylene components such as acetophenone/alkylacetoacetates/dimedone. This provides an
efficient route to construct highly functionalized dihydrotetrazolo[1,5-a]pyrimidines and
tetrahydrotetrazolo[1,5-a]quinazolinones directly from readily available starting materials.
Keywords: Aluminium(III) chloride, multi-component reaction, domino reaction,
tetrazolopyrimidines and tetrazoloquinazolinones.
Introduction
A multi-component domino strategy represents a powerful tool in which three or more reactants
participate simultaneously resulting in the quick synthesis of diversified complex structures thus
obviating the need for isolation and purification of intermediates, resulting in reduction of waste
and reaction time, which also improves the overall yield.1
Over the past several years, these reactions have witnessed an extensive development in the field
of combinatorial and medicinal chemistry for the synthesis of compound libraries and bioactive
heterocycles from small set of readily accessible raw materials.2
Pyrimidines are among the privileged class of heterocyclic scaffolds known to exhibit broad
range of biological and pharmacological activities, such as antihypertensive,3 antiviral,4
antitumor.5 Minoxidil6 and Trimethoprim7 are well known hypertensive and antimalarial drugs
containing pyrimidine moiety. Likewise, tetrazoles are an important subunit of many natural and
synthetic compounds that exhibit biological activity.8 Further, tetrazoles fused with pyrimidines
are also known to display a broad range of biological properties, which includes antimicrobial,9
antidepressant,10 and antituberculosis activities.11
Previous methods for the synthesis of tetrazolopyrimidines, involve initial synthesis of
chalcones, Mannich bases or arylidenepyruvic acids followed by cyclocondensation with 5-
aminotetrazole in overall poor yield (Scheme 1, top).12 Further, these methods are associated
with several drawbacks such as multistep synthesis, tedious work-up procedure, long reaction
time, and the use of expensive and toxic acid catalysts that would limit the use of these protocols
in accordance with the principles of “Green Chemistry”.

However, Wang and co-workers have reported the synthesis of dihydrotetrazolo[1,5-
a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones via Hg2+-induced desulfurization
and cyclization of entirely different substrate, dihydropyridine-2-thiones with sodium azide
utilizing mercuric acetate (Scheme 1, middle).13 However, a very convenient strategy which
attracted our attention is the one pot three-component reaction of 5-aminotetrazole, aromatic
aldehyde and acetophenone/related active methylene building blocks to generate diverse
dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones (Scheme 1,
bottom). A variety of catalysts like boiling acetic acid,14 Iodine,15 [bmim+][BF-4],16 TBBDA,17
have been used to mediate this reaction. Recently, diisopropylammonium trifluoroacetate
mediated synthesis and antimicrobial and antioxidant activity of these scaffolds have also been
recognized.18 Even though, three-component reactions have been able to raise the overall yield,
however, most of these methods are plagued with the use of corrosive catalyst, low yield, and
limited substrate scope. Iodine15a mediated synthesis has been successful for the construction of
library of these heterocyclic core using a broad range of active methylene building blocks but the
was ver low especially when substituted acetophenone acts as an active methylene partner (0-
61%). In spite of the latest developments, it remains extremely challenging to develop a
sustainable route for the synthesis of diverse dihydrotetrazolo[1,5-a]pyrimidines and
tetrahydrotetrazolo[1,5-a]quinazolinones which could avoid tedious job of isolation/purification
of intermediates and final products. Therefore, we intended to develop an expedient, effective,
mild and sustainable synthetic route that could be compatible with wide range of substrates to
afford library
a]quinazolinones.
of
dihydrotetrazolo[1,5-a]pyrimidines
and
tetrahydrotetrazolo[1,5-
Scheme 1. Previous reports to access dihydrotetrazolo[1,5-a]pyrimidines.
Scheme 2. Present work: One-pot domino MCR’s approach.
Recently, AlCl3 has received considerable attention in the literature as a potent Lewis acid
catalyst in organic synthesis owing to its special attributes such as safe, economical, easy
handling, mild and of course its recyclability.19
In view of above stated valid points and following our persistent desire to develop new synthetic
routes,20 we herein report AlCl3 as mild and powerful Lewis acid catalyst for synthesis of diverse
dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones via three-
component domino strategy as outlined in Scheme 2.
Results and Discussion
At the outset, p-chlorobenzaldehyde (1a), 5-aminotetrazole (2) and acetophenone (3a) were
chosen as model substrates to investigate one-pot three-component approach to construct diverse
5,7-diaryl-4,7-dihydrotetrazolo[1,5-a]pyrimidines. As summarized in table 1 (Entries 1-7),

several catalysts (10 mol%) such as AlCl3, LiBr, FeCl3, nano-YO, nano-CuO, ZnCl2, ZrOCl2
were screened in acetonitrile under reflux conditions to determine the best catalytic system.
Surprisingly, AlCl3 gave (4a) in 75% yield after 5 h. Under similar reaction condition, LiBr,
FeCl3, nano-YO, nano-CuO, ZnCl2 and ZrOCl2 gave (4a) in 20%, 34%, 40%, 38%, 25% and
33% respectively after 5 h. Next, concentration of AlCl3 was optimized and at 15 and 20 mol%
loading yields increased (85% and 92%) and reaction time was decreased to 4 and 3 h
respectively (Entries 8 and 9). Importantly, when the reaction was investigated without any
catalyst no product formation was observed even after prolonged reaction time. Subsequently,
the evaluation of different solvents revealed that acetonitrile gave the best yield (92%) in
minimum (3 hrs). Contrary to acetonitrile, CHCl3 furnished the minimum yield (Table 1, entry-
1
10) among the tested solvents. The structure of the product, (4a) was confirmed by HNMR
analysis and comparison with reported data15a as summarized in Supporting Information.
Table 1 Optimization of reaction conditions for the synthesis of 4aa
Entry Catalyst (mol%)
Solvent Temperature Time (h) Yieldb (%)
1
2
AlCl3 (10)
LiBr (10)
FeCl3 (10)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
5
5
5
5
5
5
5
4
3
5
5
5
75
20
34
40
38
25
33
85
92
75
77
80
3
4
Nano-YO (10)
nano-CuO (10)
ZnCl2 (10)
ZrOCl2 (10)
AlCl3 (15)
AlCl3 (20)
AlCl3 (20)
AlCl3 (20)
AlCl3 (20)
5
6
7
8
9
10
11
12
CH2Cl2
DMSO
aReactions were carried out using 1a(1 mmol), 2 (1 mmol) and 3a(1 mmol) and solvent (3 mL).
bIsolated yields.
Next, to explore the scope of current protocol optimal conditions were applied to wide-range of
aromatic aldehyde and acetophenone. As summarized in Table 2 the aromatic aldehyde
containing electron withdrawing group such as 4-NO2, 4-Cl as well as electron releasing group
such as 4-OMe, 4-Me were well tolerated and underwent three-component domino reaction
smoothly to afford the anticipated product 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a]pyrimidines,
(4a–i) in high yields (Table 2, entries 1-9 ). On the other hand, replacement of acetophenone
with p-Br-acetophenone was also found to be compatible under the optimal reaction conditions.
All the reactions were completed in a duration of 3-5 h to afford the desired products.
Table 2 Synthesis of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a]pyrimidinesa
Entry Aldehyde Ketone
Productb
Time (h) Yieldc (%)

1
3
92
2
3
4
4
90
89
4
5
4
4
88
91
6
4
90
7
8
9
4
3
5
89
91
91
aReaction condtions: Aldehyde 1(1 mmol), 5- aminotetrazole 2(1 mmol), acetophenone/
4-Br-acetophenone 3(1 mmol), CH3CN (3 ml). 21(a)
bAll compounds gave C, H and N analysis within 0.4 % and satisfactory spectral
(1H NMR 13C NMR) data.
cYield of isolated and purified products.

With the exceptional results with AlCl3 in hand (Table 2), we tried to further expand the utility of
this methodology, other three-component reaction of benzaldehydes (1b, 1d and 1e) 5-
aminotetrazole (2) and ethylacetoacetate (5a) were reacted under optimized conditions and the
results obtained are summarised in table 3. Fortunately, the reaction worked cleanly to deliver
the corresponding products ethyl 5-methyl-7aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxylates, (6a-c) in excellent yields, however, the time required in this case was longer in
comparison to substituted acetophenone. Interestingly, in this case also the reaction was
compatible with both electron withdrawing and donating group on aromatic aldehyde furnishing
products in high yields. Likewise, methylacetoacetate also reacted efficiently to afford the
products, (6d-e) in very high yields (94-96%).
Table 3 Synthesis of alkyl 5-methyl-7aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylatesa
Entry
1
Aldehyde
Ketone
Productb
Time (h)
4
Yieldc (%)
94
2
3
6
5
91
92
4
5
5
5
96
94
aReaction condtions: Aryl aldehyde 1(1 mmol), 5-aminotetrazole 2(1 mmol), ethylacetoacetate/ methylacetoacetate
5(1 mmol), CH3CN (3 ml). 21(a)
bAll compounds gave C, H and N analysis within 0.4 % and satisfactory spectral (1H NMR 13C NMR) data.
cYield of Isolated and purified products.
A careful examination of literature reveals the limited records for the synthesis of
tetrahydrotetrazolo[1,5-a]quinazolinones, a potential scaffold in drug development are available.
Consequently, versatility of this three-component domino strategy was further explored with an
aim to construct highly functionalized 6,6-dimethyl-9-aryl-5,6,7,9-tetrahydrotetrazolo[,5-

a]quinazolin-8(4H)-ones. In this context, we turned our attention to investigate the three
component reaction of p-chlorobenzaldehyde, 5-aminotetrazole and dimedone as active
methylene partner under established optimal reactions conditions. Indeed, dimedone successfully
reacted in the presence of AlCl3 to deliver entirely different scaffold, tetrahydrotetrazolo[1,5-
a]quinazolinone, 8a in 95% yield (Table 4, entry 1). Afterwards, the reaction was extended to
differently substituted benzaldehydes. The maximum yield was obtained for (8a), 95% (Table 4,
entry 1) and minimum yield was obtained for (8d), 90% (Table 4, entry 4). The reaction was
further extended with fused heterocyclic aldehyde, tetrazoloquinolinecarbaldehyde, 1f.
Delightfully, the reaction gave a complex hybrid molecule incorporating two important
scaffolds, tetrazoloquinoline and tetrahydrotetrazolo[1,5-a]quinazolinone in excellent yield
(Table 4, entry 6).
Table 4 Synthesis of 6,6-dimethyl-9-aryl-5,6,7,9-tetrahydrotetrazolo[1,5-a]quinazolin-8(4H)-onesa
Entry Aldehyde Ketone Productb
1
Time (h) Yieldc (%)
3
95
2
3
4
4
92
91
4
5
4
90
5
3
94
94
CHO
6
N
N
N
N
1f

aReaction condtions: Aryl aldehyde 1(1 mmol), 5-aminotetrazole 2(1 mmol), dimedone
7(1 mmol), CH3CN (2 ml). 21(b)
bAll compounds gave C, H and N analysis within 0.4 % and satisfactory spectral
(1H NMR 13C NMR) data.
cYield of Isolated and purified products.
It is remarkable that the current method can be efficiently applied for the preparation of diverse
dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones using wide
range of easily available starting materials. Importantly, purification of all these products was
done without using column chromatography and recrystallization techniques except for
compound, 8f which was purified by column chromatography.21b After completion of reaction,
the mixture was cooled at room temperature, solid was filtered, followed by washing with cold
acetonitrile to deliver the pure product. Hence, the current method avoided the traditional
purification steps of recrystallization and column chromatography thus reducing unwanted waste
generated from silica and solvents during the course of column chromatography.
A plausible reaction mechanism for the formation of 4a in presence of AlCl3 is depicted in
scheme 3. In this typical tandem reaction p-chlorobenzalaldehyde, (1a) and acetophenone, (2a)
reacts to form benzylideneacetophenone, (9) a strong Michael acceptor. Subsequently, 5-
aminotetrazole readily attacks Michael acceptor to give an intermediate, 10 which undergoes
imine-enamine tautomerism to form intermediate, (11) which finally undergoes intramolecular
nucleophilic attack at the keto-carbonyl site followed by elimination of water to afford the
desired cyclic product (4a).
Scheme 3
Conclusion:
In conclusion, this study has expanded the applicability of AlCl3 as an effective catalyst for the
synthesis of diverse dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-
a]quinazolinones via one pot, convergent and expedient multi-component domino strategy
utilizing 5-aminotetrazole as key a component. The prominent features associated with this
novel protocol are the use of readily available starting materials, operationally convenient
conditions, mild reactions conditions, high yields. In addition, this method showed great
tolerance towards diverse substrates and the products were purified without using column
chromatography thus reducing the generation of waste in the form of silica and toxic solvents.

Further extension of this protocol with varied quinolinecarbaldehyde and quinolinecarbaldehyde
are underway and will be reported in due course of time.
Acknowledgement
We are thankful to SAIF Chandigarh for providing spectral data. P. K. thanks UGC, Govt. of
India for BSR fellowship.
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21. (a) General procedure for the synthesis of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-
a]pyrimidines (4a-i) and alkyl 5-methyl-7aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine
-6-carboxylates ( 6a-e)
To a mixture of substituted aldehydes (1mmol), 5-aminotetrazole (1 mmol) and
acetophenones /alkylacetoacetates (1 mmol) in CH3CN (3 mL), was added 20 mol%
AlCl3. The contents of reaction mixture were heated under reflux for appropriate time
(Table 2 and 3). After completion of the reaction as monitored by TLC, the reaction
mixture was cooled at room temperature and the solid was filtered followed by washing
with cold acetonitrile to afford the pure product.
(b) General procedure for the synthesis of 6,6-dimethyl-9-aryl-5,6,7,9-tetrahydrotetraz-
olo[1,5-b]quinazolin-8(4H)-ones (8a-f)
To a mixture of substituted aldehydes (1 mmol), 5-aminotetrazole (1 mmol) and
dimedone (1 mmol) in CH3CN (3 mL), was added 20 mol% AlCl3. The contents of
reaction mixture were heated under reflux for appropriate time (Table 4). After
completion of the reaction as monitored by TLC, the reaction mixture was cooled at room
temperature and the solid was filtered followed by washing with cold acetonitrile to
afford the pure product, however 8f is purified by column chromatography using ethyl
acetate/hexane (70:30).

ꢀ Highlights of the research work:
ꢁ Synthesis of dihydrotetrazolo[1,5-a]pyrimidines and related quinazolinones.
ꢁ One-pot, Multi-component domino strategy with good to excellent yield (88-96%).
ꢁ Great toleration towards broad substrates of the devised protocols.
ꢁ Developed methodology avoided column chromatography and recrystallization steps.

Graphical Abstract:
Al(III) Chloride catalyzed Multi-Component Domino Strategy: Synthesis of Library of
Dihydrotetrazolo[1,5-a]pyrimidines and Tetrahydrotetrazolo[1,5-a]quinazolinones