Iodine catalyzed one-pot multicomponent synthesis of a library of compounds containing tetrazolo[1,5-a]pyrimidine core

Article abstract of DOI:10.1021/cc9000983

Versatile and novel reactions of 5-aminotetrazole with structurally diverse aryl aldehydes and building blocks with active methylene catalyzed by iodine were investigated in a multicomponent one-pot protocol. A series of 5,7-diaryl-4,7-dihydrotetrazolo[1,

Full text of DOI:10.1021/cc9000983

J. Comb. Chem. 2010, 12, 35–40
35
Iodine Catalyzed One-Pot Multicomponent Synthesis of a Library of
Compounds Containing Tetrazolo[1,5-a]pyrimidine Core
Li-Yan Zeng and Chun Cai*
Chemical Engineering College, Nanjing UniVersity of Science & Technology, Nanjing 210094, China
ReceiVed July 9, 2009
Versatile and novel reactions of 5-aminotetrazole with structurally diverse aryl aldehydes and building blocks
with active methylene catalyzed by iodine were investigated in a multicomponent one-pot protocol. A series
of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a]pyrimidines C and 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]py-
rimidine-6-carboxylates D were obtained in moderate to good yields. Further exploration rapidly afforded
various E in good to excellent yields; in addition, compound F was also obtained under the same condition.
1
The structures of products were characterized by LC-MS, H NMR, 13C NMR, and elemental analysis.
Introduction
to generate multiple molecular scaffolds from the same
starting materials or intermediates because of their intrinsic
convergence, complexity-generating power, as well as op-
erational simplicity, resource and energy effectivity from the
viewpoint of atom-economy and sustainable technology.
Moreover, MCRs have constituted an increasingly valuable
approach to large libraries of structurally related drug-like
compounds.6 Meanwhile, molecule iodine, as a cheap, less-
toxic and readily available mild Lewis acid, has been applied
to catalyze various organic transformations.7 Keeping in view
of above points and following our continuous interest in
iodine-catalyzed MCRs,8 we initially performed an one-pot
procedure based on the three-component reactions of 5-AT,
pyruvic acid, and aromatic aldehydes, with the aim of
examing the activity of iodine. Fortunately, this methodology
provided effective access to a series of dihydrotetrazolopy-
rimidine carboxylic acids (Scheme 2).9 Then, we envisioned
that the scope and generality of the construction of the
tetrazolopyrimidines might likewise be extended by replacing
the pyruvic acid with active methylenes such as 1,3-
cyclohexanedione, ethyl acetoacetate, malononitrile and so
on. To our delight, further research suggested that the iodine
catalyzed multicomponent cyclocondensations of 5-AT with
the precursors of R,ꢀ-unsaturated unit, aldehydes and me-
thylene active compounds proceeded excellently. In this
Organic compounds containing pyrimidine as a core unit
are known to exhibit various biological and pharmaceutical
activities,1 the synthesis of these complex heterocyclic
scaffolds is assigned as one of the most fertile areas for both
organic and medicinal chemistry. Over the past decades,
many procedures have been reported for the preparation of
4-aryl or 4,6-diaryl pyrimidinones;2 however, after a detailed
literature survey, we found that there were only limited
publications devoted to the synthesis of azolopyrimidines,
especially tetrazolopyrimidines,3-5 wherein the 5-aminotet-
razole (5-AT) with both endocyclic nitrogen and exocyclic
amino group participated in the formation of the fused
heterocyclic molecular as 1,3-binucleophile synthons instead
of urea. To date, the most widespread pathway to these
structures involved the initial synthesis of the R,ꢀ-unsaturated
carbonyl skeletons,3,4 such as chalcones, Mannich bases, or
arylidenepyruvic acids in rather poor yields, followed by
further cyclocondensation with 5-AT (Scheme 1). However,
some flaws, namely, tedious workup procedures, poor yields,
or time- and resource-wasting procedures, have occurred
along with these multistage routines. Although the three-
component reactions of 5-AT with methylene active com-
pounds and aldehydes5 have been developed and thus
improved the efficiency for the synthesis of tetrazolopyri-
midines, the high-temperature, long reaction time, or low
yields, as well as the stoichiometric amounts of corrosive
protonic acid, used in these protocols would limit the
practical use in a large scale considering the demand of
“Green Chemistry”.
Scheme 1. Previous Methods for Synthesis of
Tetrazolopyrimidines
Intrigued by these facts, we surmised whether a conve-
nient, effective, and eco-friendly process could be developed
leading to a library of tetrazolopyrimidines, which might
result in an entirely new complementary biological activity.
Among the strategies used to construct the small molecule,
Multicomponent reactions (MCRs) are ideal synthetic tools
* To whom correspondence should be addressed. Phone: +86-25-
84315514. Fax: +86-25-84315030. E-mail: c.cai@mail.njust.edu.cn.
10.1021/cc9000983  2010 American Chemical Society
Published on Web 12/01/2009

36 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Zeng and Cai
Scheme 2. Iodine Catalyzed One-Pot Synthesis of the Dihydrotetrazolopyrimidine Carboxylic Acids
Scheme 3. Preparation of the 5,7-Diphenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine C1 in Two Ways
Table 1. Conditions Optimization of Iodine Catalyzed One-Pot
Synthesis of 5,7-Diphenyl-4,7-dihydrotetrazolo[1,5-a]-
pyrimidinea
paper, we would like to describe an efficient and mild
procedure in detail that provides rapid assembly of fused
tetrazolopyrimidines and tolerates a wide range of starting
building blocks.
Results and Discussion
Preparation of 5,7-Diaryl-4,7-dihydrotetrazolo[1,5-a]-
pyrimidines C. On the basis of our previous work,9 as a
pilot experiment, a mixture of 5-AT, chalcone, and iodine
(ratio 1:1:0.2) in refluxing AcOEt was stirred (Scheme 3),
the reaction was terminated after 3 h monitored by TLC,
the purified product C1 was yielded in 44% after work up.
Then, we replaced the chalcone with its synthetic precursors,
aldehyde and ketone, and as expected, the same product C1
was obtained in 39% yield after treatment of benzaldehyde,
acetophenone, and 5-AT under the same conditions (Scheme
3). The structure of product C1 was unambiguously con-
firmed by LC-MS and 1H NMR, wherein the signals
recognized as arising from the pivotal elements of dihydro-
pyrimidine ring were obviously exhibited, such as the sharp
doublet signal for the 5-CH (δ ) 6.61, 6.62), the appearance
of which as a chiral center lead to coupling of 6-CH proton
signals into doublet observed at 5.31 and 5.32 ppm, the sharp
singlet at 10.6 ppm for the NH without proton-exchange;
and also the signals of aromatic atoms were shown at
7.37-7.67 ppm.
To our knowledge, 5,7-diphenyl-4,7-dihydrotetrazolo[1,5-a]-
pyrimidine C1 has been previously prepared only by multistep
synthesis.3,4b Since we considered it to be a promising
alternative procedure for the 5,7-diaryl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidines, we were prompted to optimize the
conditions and investigate the scope of the reaction.
As shown in Table 1, the reaction without iodine provided
little product (Table 1, entry 2), and the catalyst concentration
was also allowed to reduce to 10 mol %. Further screening
of solvents indicated that alcohols displayed as relatively
better medium while others suppressed the formation of
desired product. Disappointedly, the product was formed in
rather small amounts in the course of our attempts to improve
the yield by adding Et3N or K2CO3 as base and KI as
additive.
entry
I2 (mol %)
solvent
t (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
0
25
15
10
5
10
10
10
10
10
10
10
10
10
10
10
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
MeCN
H2O
8
24
8
8
8
8
6
4
6
39
16c
40
39
47
33
48
29
30
15
32
48
41
31
57
51
46
12
0.15d
EtOH
MeOH
DCE
i-PrOH
n-PrOH
n-BuOH
6
6
6
6
6
6
a Reaction conditions: 5-AT (5 mmol), benzaldehyde (5 mmol),
acetophenone (5 mmol), refluxing temperature. b Isolated yields. c Yield
based on the analysis of LC-MS. d The reaction mixture was solidified
in 10 min.
dihydrotetrazolo[1,5-a]pyrimidines C starting from several
representatives of the aldehydes and ketones. The results
were collected in Table 2. Most of the substrates selected,
including para-substituted benzaldehydes and meta-substi-
tuted acetophenone, participated in the reaction smoothly,
and the desired products were obtained in moderate yields.
Compared to electron-withdrawing group, the reaction time
was slightly prolonged in the case of 4-methoxybenzalde-
hyde, while 4-hydroxybenzaldehyde gave lower yield, which
might be caused by the particularity of hydroxyl. Unfortu-
nately, the ortho-substituted benzaldehydes failed to provide
the expected products based on the analysis of LC-MS, taking
2-chlorobenzaldehyde for example (Table 2, entry 2). The
reason for this is not yet clear. Additionally, careful literature
search indicated that there was no report describing the
synthesis of any 5-(ortho-substituted)aryl-7-aryl-4,7-dihy-
drotetrazolo[1,5-a]pyrimidine before.3,4b
The optimized conditions outlined above (Table 1, entry
15) were initially employed to generate 5,7-diaryl-4,7-

Tetrazolo[1,5-a]pyrimidine Core
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 37
Table 2. Iodine Catalyzed Three-Component One-Pot Synthesis of 5,7-Diaryl-4,7-dihydrotetrazolo[1,5-a]pyrimidines Ca
entry
A
R2
t(h)
product
yield (%)b
1
2
3
4
5
6
C6H5CHO
H
H
H
H
3-Cl
H
6
5
6
7
5
C1
C2
57
54
0c
56
61
33
4-ClC6H4CHO
2-ClC6H4CHO
4-MeOC6H4CHO
C6H5CHO
C3
C4
C5
4-OHC6H4CHO
10
a Reaction conditions: 5-AT (5 mmol), A (5 mmol), B1 (5 mmol), iodine (0.5 mmol), refluxing temperature. b Isolated yields. c No desired product
was detected.
Scheme 4. Screening of the Building Blocks to Synthesize Tetrazolopyrimidines
Screening of Building Blocks. With these results in hand,
we were encouraged to further explore the potentiality of
this protocol with other building blocks. Initially, typical
building blocks (Scheme 4) with methylene active structure
were anticipated to play the role of acetophenone B1 in the
reaction while benzaldehyde was chosen as representative
A. Systematic work for screening of the activated building
block B was subsequently carried out under the modified
conditions. It can be inferred from Scheme 4 that the ketones
(cyclohexanone and acetone) and the methylene active
nitriles were not suitable synthons, while ethyl acetoacetate
B2 and dimedone B3 behaved excellently. In addition, the
2,2-dimethyl-1,3-dioxane-4,6-dione and acetylacetone struc-
turally, which are similar to dimedone and ethyl acetoacetate,
respectively, did not afford the desired products. The catalytic
activity of iodine was therefore settled down to furnish ethyl
5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxylate D1 and 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahy-
drotetrazlo[1,5-a]quinazolin-8(4H)-one E1. A careful survey
of the literature revealed that only sporadic publications
reported the synthesis of tetrazoloquinazolines,3f and this is
a unique methodology that may be adopted to form functional
tetrazolopyrimidine and tetrazoloquinazoline scaffolds for
their potential contribution to drug development as privileged
strtuctures. Accordingly, we were attracted to apply this
strategy in further investigation of the generality and
limitation.
Preparation of Compounds D, E, and F. Fortunately,
most of our attempts to complement the library compounds
ethyl 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-
6-carboxylates D and 6,6-dimethyl-9-aryl-5,6,7,9-tetrahy-
drotetrazlo[1,5-a]quinazolin-8(4H)-ones E starting from build-
ing blocks B2 and B3, respectively, 5-AT, and various A
were successful. In the case of B2, all of the desired products
obtained with moderate to good yields in 10 mol % I2/i-
PrOH system within 3-6 h were structurally established with
the appearance of new signals at δ 1.00-1.05 ppm and δ
2.46-2.5 ppm assigned as ethyl, at δ 3.94-3.99 ppm
assigned as 5-methyl and also with the disappearance of
the signals for the 6-CH at δ 5.3 ppm compared to the
1
compounds C in terms of the H NMR spectra. The ad-
ditional mass spectra and 13C NMR measured for the samples
did not contradict the product structures proposed. The results
listed in Table 3 (entries 1-7) indicated that the presence
of substituents at the para- and ortho-positions on the
benzaldhyde had no obvious effect on the yields of the

38 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Zeng and Cai
Table 3. Iodine-Catalyzed Three-Component One-Pot Synthesis of D and Ea
a Reaction conditions: 5-AT (5 mmol), A (5 mmol), B (5 mmol), iodine (0.5 mmol), i-PrOH (10 mL), refluxing temperature. b Isolated yields.
c Proceeded without iodine. d Yield based on the LC-MS. e The reaction terminated in several minutes and the same product E10 was provided with
1
high yields in this iodine-catalyzed system based on the analysis of LC-MS and H NMR.

Tetrazolo[1,5-a]pyrimidine Core
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 39
Scheme 5. Reaction Process for the Synthesis of E4
reaction, whereas the reaction time was slightly prolonged
in the case of ortho- substituted ones ascribed to the steric
effect. The electron-donating group 4-MeO afforded lower
yield (39%) than electron-withdrawing substrates.
Scheme 6. Synthesis of 5′,6′,7′,8′-Tetrahydro-4′H-
spiro[cyclohexane-1,9′-tetrazolo[5,1-b]quinazoline]
On the other hand, building block B3 was likewise coupled
with 5-AT and substituted benzaldehydes in the formation
of structure E1-E9 with good to excellent yields up to 92%
within rather short reaction time. However, when the ketones
such as cyclohexanone, acetone, and acetophenone were
considered, the intermidiate E10 was the only product with
the molecular ion peaks displayed at the same m/z values
207 by mass spectra analysis, while the 1H NMR assisted to
confirm the structure, any attempt to force the further
cyclization of E10 with 4-nitrobenzaldehyde was failed. The
reactions were neat, and the products were isolated by simple
filtration with higher purity characterized by means of LC-
MS, further recrystallization would afford the analytic
sample. The structures of the products were deduced from
their 1H NMR, LC-MS, and 13C NMR. The mass spectra of
these samples displayed molecular ion peaks at the appropri-
ate m/z values, while the 1H NMR spectra consisted of signals
for the protons of hexatomic ring, the aromatic nuclei, the
substituent, and the NH group, and did not contain the 6-CH
signal. Also, the 13C NMR spectra showed good agreement
with the structure. The results were summarized in Table 3
(entries 8-16). Similarly, the sterically hindered substrates
proceeded in rather longer time taking entries 9 and 14 for
examples, and the electron-donating substituted benzalde-
hydes gave somewhat lower yields than electron-withdrawing
ones. In addition, we noticed that the substituent -NO2
presented whether on p- or o-benzaldhyde lead to a relatively
lower yield. We analyzed the crude product from p-NO2 one
via LC-MS and found the desired product took up 70%,
while an unknown compound whose molecular ion peak
appeared at 414 m/z yielded in 30%. Nevertheless, a different
situation was encountered during the reaction of B3, 5-AT,
and 4-nitrobenzaldehyde. With the temperature increased,
the reaction mixture turned into homophase. Normally, the
product would precipitate gradually after refluxing them
several minutes. In this case, however, a large amount of
solid emerged suddenly after the starting materials were
refluxed 5 min, and continued stirring resulted in homophase
once again, and which was maintained about 12 min as far
as the solid was generated gradually. Thereupon, we isolated
the first emerged solid, and discovered that the intermediate
E10 was formed before the final product in high yield.
Subsequently, we reacted the intermediate E10 with 4-ni-
trobenzaldehyde under the same conditions with aimed to
validate the reaction pathway, the contemplated product E4
was obtained smoothly. The reaction routine in this case was
proposed as Scheme 5.
The significant results above manifested this strategy as a
powerful tool for the rapid introduction and expansion of
venerable tetrazolopyrimindines and tetrazoloquinazolines.
However, we were always failed to apply it to the aliphatic
ketones. Notably, there has been only one compound 5′,6′,
7′,8′-tetrahydro-4′H-spiro[cyclohexane-1,9′-tetrazolo[5,1-b]-
quinazoline] F described in literature starting from aliphatic
ketone,3f to the best of our knowledge, which was obtained
by condensation of 5-AT with cyclohexanone. Our meth-
odology (Scheme 6), via treating 5-AT and cyclohexanone
(2 equiv) under the previous modified conditions, resulted
in the the target product F readily separating out from the
homophase of the reaction mixture with the yield of 43%.
However, when we employed the cyclopentanone as building
block, the anticipated product was not afforded.
Conclusion
In conclusion, we have devised a versatile, convenient and
cost-effective multicomponent approach to construct the
structurally diverse tetrazolopyrimidines and tetrazoloquinazo-
lines. The operational simplicity, availability of starting
materials make it a rather favored alternative procedure than
traditional multistep methods to prepare 5,7-diaryl-4,7-
dihydrotetrazolo[1,5-a]pyrimidines C. Under the same condi-
tions, building blocks with methylene active structure were
screened, and B2 and B3 were found effective to perform
the procedure. In this way, 5-methyl-7-aryl-4,7-dihydrotet-
razolo[1,5-a]pyrimidine-6-carboxylates D and 6,6-dimethyl-
9-aryl-5,6,7,9-tetrahydrotetrazlo[1,5-a]quinazolin-8(4H)-
ones E were rapidly synthesized for the first time in good to
excellent yields and structurally confirmed by means of LC-
1
MS, H NMR, 13C NMR, and elemental analysis, and the
reaction route for the synthesis of E4 was observed according
to the experiment results. In addition, compound F was also
prepared in the same way. The facility, generality, and
ecologically benign nature of this methodology made itself
a competent lead candidate to furnish compounds containing
tetrazolopyrimidine core as potential privileged medicinal
scaffolds.
Supporting Information Available. Experimental meth-
ods, general procedures, spectral assignments, and copies of

40 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Zeng and Cai
1H NMR and 13C NMR spectra for all previous unreported
products. This information is available free of charge via
the Internet at http://pubs.acs.org/.
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CC9000983