A practical synthesis of 5-aroyl-1-aryltetrazoles using an Ugi-like 4-component reaction followed by a biomimetic transamination

Article abstract of DOI:10.1055/s-0030-1258273

Multicomponent reactions (MCRs), followed by subsequent transformations, are fascinating tools for the rapid and effective synthesis of molecular scaffolds with potential pharmacological relevance. We became interested in the preparation of novel 5-aroyl-1-aryltetrazoles as (1) they still represent challenging structures not easily accessible through the methods described in literature, and (2) the -ketotetrazolic framework may be considered as a potential bioisostere of the enonic linker of chalcones. In the present work, a novel, simple, effective and general synthesis for this class of compounds is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258273

PAPER
4107
A Practical Synthesis of 5-Aroyl-1-aryltetrazoles Using an Ugi-Like
4-Component Reaction Followed by a Biomimetic Transamination
S
ynthesis of 5-Aroyl-1
a
-aryltetrazo
r
les iateresa Giustiniano,a Tracey Pirali,b Alberto Massarotti,b Beatrice Biletta,b Ettore Novellino,a Pietro Campiglia,c
Giovanni Sorba,b Gian Cesare Tron*b
a
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli ‘Federico II’, Via D. Montesano 49, 80131 Napoli, Italy
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale
‘A. Avogadro’, Via Bovio 6, 28100 Novara, Italy
b
Fax +39(0321)375821; E-mail: tron@pharm.unipmn.it
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
c
Received 15 June 2010; revised 6 September 2010
as a replacement of chalcones,13 in order to generate meta-
bolically stable chalcone-like analogues with antitubulin-
ic activity (Scheme 1).14
Abstract: Multicomponent reactions (MCRs), followed by subse-
quent transformations, are fascinating tools for the rapid and effec-
tive synthesis of molecular scaffolds with potential
pharmacological relevance. We became interested in the prepara-
tion of novel 5-aroyl-1-aryltetrazoles as (1) they still represent chal-
lenging structures not easily accessible through the methods
described in literature, and (2) the a-ketotetrazolic framework may
be considered as a potential bioisostere of the enonic linker of chal-
cones. In the present work, a novel, simple, effective and general
synthesis for this class of compounds is described.
Key words: 5-aroyl-1-aryltetrazoles, multicomponent reactions,
isocyanides, Ugi reaction, chalcones
Multicomponent reactions (MCRs) are one-pot processes
that combine at least three substrates to deliver a single
complex product, incorporating essentially all of the at-
oms of the starting materials.1 Usually, MCRs are flexi-
ble, convergent, and atom-efficient processes with a high
exploratory power.2 This sort of ‘ideal synthesis’3 is expe-
riencing a growing interest, also due to the possibility of
incrementing the complexity and diversity of the molecu-
lar scaffolds by employing substrates able to undergo sec-
ondary transformations.4 In this way, large libraries of
complex substances, not easily accessible through con-
ventional two-component multistep synthesis, can be
quickly accessed speeding up the drug discovery process.
Scheme 1 Superimposition between a potent antitubulinic chalcone
and 5-aroyl-1-aryltetrazoles
Surprisingly, SciFinder® and CrossFire® surveys revealed
that only four 5-aroyl-1-aryltetrazoles have been reported
to date. This paucity has to be ascribed to the poor
chemoselective and low yield synthetic routes developed
so far. Indeed, only two synthetic strategies have been re-
ported (Scheme 2).
In the first strategy, nitrones react with hydrazoic acid fol-
lowed by an intramolecular [1,3] cycloaddition,15 while
the second synthetic strategy consists in the reaction be-
tween isocyanides and acyl chlorides to give a-ketoimi-
doyl chlorides, which undergo nucleophilic substitution
with an excess of hydrazoic acid, followed by an intramo-
lecular [1,3] cycloaddition.16 Very recently, the Sharpless
group has devised a synthesis of 5-acyltetrazoles from
azides and acyl cyanides, but the reaction was incompati-
ble with aryl azides in order to generate 5-aroyl-1-aryltet-
razoles.17
Post-transformation reactions are countless, starting from
classic textbooks organic reactions such as Pictet–Spengler
cyclization,5 intramolecular Diels–Alder reaction,6
Mitsunobu reaction and acyl migration,7 Knovenagel con-
densation,8 amide reduction,9 metathesis reaction10 – just
to cite few of them – to sequential multi-component trans-
formations such as Ugi–Ugi11 and Ugi–Petasis.12
Herein, we describe a novel and operationally simple
strategy for the synthesis of elusive 5-aroyl-1-aryltetra-
zoles by means of an Ugi-like four component reaction (4-
CR), followed by a hydrogenolysis/transamination post-
transformation. Our interest in 5-aroyl-1-aryltetrazoles
arose from the possibility of using this molecular scaffold
In a first attempt, the possibility to synthesize this scaffold
was envisaged through a Passerini 3-CR using trimethyl-
silyl azide in the place of the acidic component, followed
by an oxidation step (Scheme 3).
SYNTHESIS 2010, No. 23, pp 4107–4118
x
x.
x
x
.
2
0
1
0
Advanced online publication: 28.09.2010
DOI: 10.1055/s-0030-1258273; Art ID: T13310SS
© Georg Thieme Verlag Stuttgart · New York
It is interesting to note that, in a comprehensive review on
the Passerini reaction, there are no examples of tetrazole

4108
M. Giustiniano et al.
PAPER
a)
O
N
O
N
N
N
N
O
N3
HN3
N
O
b)
O
HN3 excess
N
Cl
Scheme 2 Reported syntheses for the generation of 5-aroyl-1-aryltetrazoles
aluminum trichloride did not suppress the formation of the
by-product 6.21 This strategy was therefore abandoned, as
it suffered from low yields, formation of by-products, and
difficult purification – features incompatible with the gen-
eration of a library during the drug discovery process.
NC
CHO
O
HO
N
N
N
N
N
N
N
N
+
R
R
R
R
Me
Me Si N3
Me
R
R
OMe
MeO
Scheme 3 First retrosynthetic analysis
OH
MeO
OMe
scaffolds generated by aromatic aldehydes and aromatic
isocyanides.18 When 3,4,5-trimethoxyphenyl isocyanide
(1), p-anisaldehyde (2), and trimethylsilyl azide (3) were
reacted in dichloromethane at room temperature, only the
3,4,5-trimethoxyphenyl-1H-tetrazole (4) was isolated in
90% yield (Scheme 4).19
N
N
N
N
5
CH2Cl2, AlCl3
+
1 + 2 +
3
r.t.
30%
OH
H
MeO
N
Different Lewis acids as catalysts (zinc triflate, lithium
bromide, indium trichloride, zinc chloride, aluminum
trichloride, cerium trichloride, ytterbium triflate, boron
trifluoride, and dysprosium acetate) were screened in or-
der to activate the aldehyde component. The test reactions
revealed that aluminum trichloride20 was the only catalyst
O
MeO
OMe
OMe
6
Scheme 5 MCR between an aromatic isocyanide, an aromatic alde-
able to promote the multicomponent process, affording, hyde, and trimethylsilyl azide catalyzed by aluminum trichloride
after column chromatography, in 30% yield an insepara-
ble mixture of the desired tetrazole compound 5 and the a-
hydroxy amide product 6 in a 1:1 ratio (Scheme 5). The
latter derives from water addition to the intermediate nitri-
lium ion. Attempts to avoid the formation of 6, using an-
hydrous sodium sulfate, 4 Å molecular sieves, or ultra dry
Another retrosynthetic analysis was consequently de-
vised, always using a MCR as key step for the introduc-
tion of all the functionalities in one single operation. In
practice, the carbonyl group of 5-aroyl-1-aryltetrazoles
could be created through a transamination reaction. The
N
N
NC
CHO
N
Me
N
CH2Cl2
r.t.
94%
Me Si N3
Me
+
+
MeO
OMe
OMe
OMe
MeO
OMe
1
OMe
3
2
4
Scheme 4 Formation of 3,4,5-trimethoxyphenyl-1H-tetrazole (4)
Synthesis 2010, No. 23, 4107–4118 © Thieme Stuttgart · New York

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Synthesis of 5-Aroyl-1-aryltetrazoles
4109
amine intermediate would derive from an Ugi-like 4CR filtration in 59% yield. Compound 10 was then hydro-
using benzylamine, aryl isocyanide, aryl aldehyde, and genolyzed to cleave the benzyl group, using 10% palladi-
trimethylsilyl azide22 followed by a hydrogenolytic cleav- um on charcoal as catalyst in methanol at 60 °C providing,
age of the N-benzyl group (Scheme 6).
after filtration over a Celite pad and evaporation of the
solvent, the amino derivative 11 in 91% yield. Finally, 11
was subjected to the transamination reaction. After an ex-
tensive screening, we identified the Rapoport procedure23
as the transamination reaction able to give the best yields,
allowing us to isolate, after acidic workup and column
chromatography, the 5-aroyl-1-aryltetrazoles derivative
12 in 50% yield (Scheme 7).
O
N
H2N
N
N
N
N
N
NH
N
N
R
N
N
R
N
N
R
R
R
The Rapoport transamination reaction represents a simple
and mild biomimetic conversion of amines to carbonyls in
the presence of 4-formyl-1-methylpyridinium benzene-
sulfonate as pyridoxal phosphate (vitamin B6) surrogate.
The amine and the formyl derivative were stirred in
CH2Cl2–DMF (3:1) for 8 hours at room temperature. Tri-
ethylamine was then added and deprotonation occurred
under mild conditions forming an azaenolate. After about
30 minutes, the resonance-stabilized anion was protonat-
ed and hydrolyzed with an aqueous solution of oxalic acid
to give the 4-(aminomethy)-1-methylpyridinium salt and
the desired carbonyl compound (Scheme 8).
B
R
NC
CHO
Me
R
R
+
NH2
Me Si N3
Me
To demonstrate the scope and generality of this new syn-
thetic strategy seven aldehydes 2, 9, 13–17 and seven iso-
cyanides 1, 8, 18–22 with different electron-withdrawing
and electron-donating substituents were employed
(Figure 1).
Scheme 6 Second retrosynthetic analysis
Initial experiments were carried out using benzylamine
(7), trimethylsilyl azide (3), 4-methoxyphenyl isocyanide
(8), and 3,4,5-trimethoxybenzaldehyde (9) as test sub-
strates. The four compounds reacted in methanol at room
temperature affording after 20 hours the desired adduct
10, which precipitated and could be collected by simple
Ugi-like 4-CR reaction was performed mixing the alde-
hyde, isocyanide, benzylamine, and trimethylsilyl azide
in methanol (2 M) by stirring at room temperature for
three days. All MCR products 10, 23–35 were isolated in
high yields (59–86%) (Figure 2).
CHO
MeO
NH2
N
MeO
MeO
N
MeO
OMe
N
7
OMe
N
MeOH, r.t.
59%
+
9
NC
NH
Me
N3 Si Me
Me
OMe
10
OMe
3
8
H2, 10% Pd/C
MeOH, 60 °C
91%
MeO
MeO
1) 4-formyl-1-methylpyridinium
benzenesulfonate
CH2Cl2–DMF (3:1), 8 h
N
N
MeO
MeO
N
N
N
MeO
MeO
N
N
2) Et3N, 30 min
3) aq oxalic acid soln, 6 h
50%
N
O
NH2
11
OMe
12
OMe
Scheme 7 General procedure for the synthesis of 5-aroyl-1-aroyltetrazoles
Synthesis 2010, No. 23, 4107–4118 © Thieme Stuttgart · New York

4110
M. Giustiniano et al.
PAPER
R2
H
O
N
NH2
R2
N
R2
N
R2
R1
R1
– H+
R1
Y
R1
N
Y
N
Y
N
N
Y
Me
Me
Me
Me
Y = C6H5SO3
H
NH2
N
R2
O
H2O
R1
Y
R1
R2
N
Y
N
Me
Me
Scheme 8 The Rapoport biomimetic transamination
Aldehydes
amines 11, 36–48 were isolated by simple filtration in ex-
cellent yields (60–95%) (Figure 3).
OMe
OH
MeO
MeO
MeO
MeO
Finally, the amine derivatives were subjected to the bio-
mimetic transformation giving the desired 5-aroyl-1-
aryltetrazoles 12, 49–61 in moderate to good yields (38–
61%) (Figure 4).
CHO
CHO
CHO
2
9
13
OMe
In conclusion, we have reported a novel, efficient and ver-
satile synthesis of 5-aroyl-1-aryltetrazoles, a class of mol-
ecules not easily synthesizable with the methods reported
in literature. The use of a MCR followed by two post-
transformation modifications allows the construction of
this molecular scaffold in only three synthetic steps and
the robustness of this methodology permits its use for the
synthesis of libraries in the drug discovery programs. The
biological evaluation of the synthesized products is under-
way and it will be reported in due course.
Cl
CHO
CHO
14
15
O
N
CHO
16
17
CHO
Isocyanides
MeO
OMe
MeO
CN
Commercially available reagents and solvents were used without
further purification and were purchased from Fluka-Aldrich or Lan-
caster. Melting points were determined in open glass capillary with
a Stuart scientific SMP3 apparatus and are uncorrected. All the
compounds were checked by IR (FT-IR Thermo-Nicolet Avatar),
1H and 13C APT (Jeol ECP 300 MHz), and mass spectrometry
(Thermo Finningan LCQ-deca XP-plus) equipped with an ESI
source and an ion trap detector. Chemical shifts are reported in ppm.
Column chromatography was performed on silica gel (Merck
Kieselgel 70–230 mesh ASTM) using the indicated eluents. TLC
was carried out on 5 × 20 cm plates with a layer thickness of 0.25
mm (Merck silica gel 60 F254). When necessary they were devel-
oped with KMnO4. Elemental analyses of all the 5-aroyl-1-aryltet-
razoles (C, H, N) were within 0.4% of the calculated values,
unless otherwise noted. Isocyanides 1, 8, 18–22 are described in lit-
erature. We synthesized them in two steps starting from the aromat-
ic anilines, forming the formamide and dehydrating it with POCl3.
Petroleum ether (PE) used refers to the fraction boiling in the range
40–60 °C.
O
O
NC
MeO
NC
O
1
8
18
NC
NC
19
20
OH
O
MeO
N
NC
NC
21
22
Figure 1 Structures of aldehyde and isocyanide building blocks
CAUTION! Trimethylsilyl azide (TMSN3) can release hydrazoic
acid. Hydrazoic acid causes eye irritation, cough, headache, fall in
blood pressure, weakness, palpitation, ataxia, and collapse. Certain
tetrazoles are known to be explosive. In this lab, no problems have
been encountered, but great caution should be exercised when heat-
ing compounds of this type. All experiments should be handled in
an efficient fume hood behind a protection shield.
When the product was solid, it was isolated by just filter-
ing the precipitate under vacuum, while, in the case of oily
products, they were purified by chromatographic column
using petroleum ether–EtOAc as eluent. Hydrogenolysis
was carried out for 24 hours and the resulting primary
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Synthesis of 5-Aroyl-1-aryltetrazoles
4111
OMe
MeO
MeO
MeO
OMe
NHBn
O
NHBn
N
NHBn
N
OMe
OMe
OMe
N
N
N
N
N
N
N
N
N
N
10 (59%)
23 (70%)
OMe
24 (74%)
OMe
MeO
MeO
MeO
MeO
O
NHBn
O
HO
O
NHBn
NHBn
MeO
O
O
N
N
N
N
N
N
N
N
N
N
N
N
25 (78%)
26 (86%)
27 (53%)
O
Cl
Cl
N
O
NHBn
N
NHBn
NHBn
O
N
N
N
N
N
N
N
N
N
N
N
28 (87%)
29 (65%)
30 (71%)
OMe
Cl
OMe
NHBn
O
NHBn
N
N
NHBn
N
OMe
N
N
N
N
N
N
OMe
N
N
N
N
31 (63%)
32 (69%)
OMe
33 (82%)
OMe
MeO
MeO
MeO
MeO
NHBn
NHBn
N
OMe
N
N
N
OMe
N
N
OH
N
N
34 (75%)
35 (81%)
Figure 2 MCR products
5-Aroyl-1-aryltetrazoles; General Procedure
CH2Cl2 (50 mL). After extraction with CH2Cl2 (3 × 20 mL), the
combined organic phases were washed with brine (1 × 25 mL),
dried (Na2SO4), filtered, and evaporated under reduced pressure.
The carbonyl compound was purified by column chromatography
using PE–EtOAc as eluent.
Aromatic isocyanide (20 mmol), aromatic aldehyde (20 mmol), N-
benzylamine (20 mmol), and trimethylsilyl azide (20 mmol) were
dissolved in anhyd MeOH (40 mL, 2 M) under N2 atmosphere. The
resulting solution was stirred at r.t. for 3 days. The solid formed was
collected by filtration and washed with cold MeOH (10 mL). For
oily products, the reaction mixture was evaporated and purified by
column chromatography using PE–EtOAc as eluents. The obtained
tetrazole intermediate was then stirred in MeOH (40 mL) under a H2
atmosphere in the presence of 10% Pd/C by heating at 60 °C for 24
h. The crude reaction mixture was filtered through a Celite pad and
evaporated to give the free amine pure enough for the following
step. The amine was dissolved in CH2Cl2–DMF (3:1, 20 mL) and 4-
formyl-1-methylpyridinium benzenesulfonate (1.2 equiv) was add-
ed. The reaction mixture was stirred at r.t. for 8 h, then treated with
Et3N (1.0 equiv) and stirred for 15–20 min. The reaction was finally
quenched with cold sat. aq oxalic acid (25 mL) and stirred over-
night. The mixture was then partitioned between H2O (25 mL) and
N-Benzyl-1-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]-1-(3,4,5-
trimethoxyphenyl)methanamine (10)
The crude material was filtered under vacuum and washed with cold
MeOH to give a white solid (59%); mp 112–116 °C.
IR (KBr): 3290, 2943, 1591, 1323, 1256, 1131, 834 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24–7.23 (m, 5 H), 7.01 (d,
J = 8.2 Hz, 2 H), 6.87 (d, J = 8.2 Hz, 2 H), 6.35 (s, 2 H), 4.88 (s, 1
H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 8 H).
13C NMR (75 MHz, CDCl3): d = 161.5, 160.4, 156.3, 155.5, 152.8,
137.9, 137.2, 127.8, 127.7, 126.7, 126.4, 125.3, 124.1, 113.9, 103.9,
60.1, 55.5, 55.41, 55.0, 50.5.
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4112
M. Giustiniano et al.
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OMe
MeO
MeO
OMe
NH2
N
NH2
N
NH2
O
MeO
OMe
OMe
OMe
N
N
N
N
N
N
N
N
N
N
11 (91%)
36 (72%)
OMe
37 (95%)
OMe
MeO
HO
MeO
MeO
MeO
O
NH2
N
O
O
NH2
N
NH2
N
MeO
O
O
N
N
N
N
N
N
N
N
N
38 (93%)
39 (70%)
40 (68%)
O
Cl
Cl
N
O
NH2
NH2
NH2
O
N
N
N
N
N
N
N
N
N
N
N
N
41 (77%)
42 (77%)
43 (92%)
OMe
Cl
OMe
NH2
NH2
N
NH2
N
O
OMe
N
N
N
N
N
N
OMe
N
N
N
N
N
44 (71%)
45 (60%)
46 (92%)
OMe
OMe
MeO
MeO
MeO
MeO
NH2
N
NH2
N
OMe
OH
N
OMe
N
N
N
N
N
47 (66%)
48 (92%)
Figure 3 Hydrogenolysis products
MS (ESI): m/z = 462 (M + H)+.
MS (ESI): m/z = 462 (M + H)+.
N-Benzyl-1-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]-1-(3,4,5-
trimethoxyphenyl)methanamine (23)
The crude material was purified by column chromatography using
N-Benzyl-1-(biphenyl-4-yl)-1-[1-(4-phenoxyphenyl)-1H-tetra-
zol-5-yl]methanamine (24)
The crude material was purified by column chromatography using
PE–EtOAc (6:4) as eluent to give a yellowish oil (70%).
PE–EtOAc (8:2) as eluent to give a brown oil (74%).
IR (KBr): 3288, 2326, 1275, 1128, 749, 764 cm–1.
IR (KBr): 3291, 2360, 2341, 1521, 1237, 733, 788, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.12–7.04 (m, 5 H), 7.01 (d,
J = 8.2 Hz, 2 H), 6.70 (d, J = 8.2 Hz, 2 H), 6.23 (s, 2 H), 4.93 (s, 1
H), 3.75 (s, 3 H), 3.764 (s, 3 H), 3.55 (s, 8 H).
13C NMR (75 MHz, CDCl3): d = 159.1, 155.8, 153.0, 138.8, 138.5,
128.6, 127.9, 127.7, 126.7, 113.7, 102.6, 60.4, 55.7, 54.9, 54.7,
50.5.
1H NMR (300 MHz, CDCl3): d = 7.59–6.97 (m, 23 H), 5.12 (s, 1 H),
3.80 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 159.5, 156.4, 155.8, 141.5, 140.3,
138.9, 137.0, 130.3, 129.0, 128.6, 128.5, 128.4, 127.7, 127.2, 124.8,
120.0, 118.7, 55.6, 51.2.
MS (ESI): m/z = 510 (M + H)+.
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PAPER
Synthesis of 5-Aroyl-1-aryltetrazoles
4113
OMe
MeO
MeO
MeO
OMe
O
O
N
O
N
O
OMe
OMe
OMe
N
N
N
N
N
N
N
N
N
N
12 (50%)
49 (50%)
50 (44%)
OMe
OMe
MeO
MeO
MeO
MeO
O
O
N
O
HO
O
O
N
O
N
MeO
O
O
N
N
N
N
N
N
N
N
N
51 (63%)
52 (50%)
53 (46%)
O
Cl
Cl
N
O
O
O
O
N
O
N
N
N
N
N
N
N
N
N
N
N
54 (40%)
55 (38%)
56 (61%)
OMe
Cl
OMe
O
O
O
N
O
N
OMe
N
N
N
N
N
OMe
N N
N
N
N
N
57 (41%)
58 (39%)
59 (46%)
OMe
OMe
MeO
MeO
O
O
MeO
MeO
OMe
OH
N
N
N
N
N
OMe
N
N
N
60 (46%)
61 (38%)
Figure 4 Synthesized 5-aroyl-1-aryltetrazoles
1-[1-(Benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl]-N-benzyl-1-
(3,4,5-trimethoxyphenyl)methanamine (25)
The crude material was filtered under vacuum and washed with cold
MeOH to give a pale yellow solid (78%); mp 123–126 °C.
IR (KBr): 3278, 2925, 1502, 1323, 1131, 894, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25–7.23 (m, 5 H), 6.78 (d,
J = 8.2 Hz, 1 H), 6.61–6.56 (m, 2 H), 6.41 (s, 2 H), 6.05 (s, 2 H),
4.89 (s, 1 H), 3.79 (s, 3 H), 3.75 (s, 6 H), 3.72 (s, 2 H).
IR (KBr): 3420, 1617, 1509, 1242, 1132, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–6.92 (m, 16 H), 6.38 (s, 2 H),
4.92 (s, 1 H), 3.76 (s, 2 H), 3.71 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 156.4, 155.6, 153.6, 138.9,
138.1, 133.4, 130.3, 128.6, 128.5, 127.9, 127.5, 127.4, 124.9, 120.0,
118.4, 104.9, 60.9, 56.3, 56.2, 51.2.
MS (ESI): m/z = 524 (M + H)+.
13C NMR (75 MHz, CDCl3): d = 156.3, 153.6, 149.5, 148.4, 138.7,
138.1, 133.4, 128.6, 128.5, 127.5, 127.0, 119.8, 108.4, 106.9, 104.9,
102.5, 60.9, 56.4, 56.3, 51.3.
5-{[(1-(Benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl](benzylami-
no)methyl}-2-methoxyphenol (27)
The crude material was purified by column chromatography using
PE–EtOAc (6:4) as eluent to give a colorless oil (53%).
MS (ESI): m/z = 476 (M + H)+.
IR (KBr): 3290, 2361, 1505, 1246, 1270, 1033, 743, 730, 699 cm–1.
N-Benzyl-1-[1-(4-phenoxyphenyl)-1H-tetrazol-5-yl]-1-(3,4,5-
trimethoxyphenyl)methanamine (26)
The crude material was filtered under vacuum and washed with cold
1H NMR (300 MHz, CDCl3): d = 7.22–7.16 (m, 5 H), 6.79 (d,
J = 2.1 Hz, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 6.64 (dd, J = 8.3, 2.1 Hz,
1 H), 6.54 (m, 1 H), 6.51 (d, J = 2.3 Hz, 1 H), 5.99 (s, 2 H), 4.86 (s,
1 H), 3.78 (s, 3 H), 3.67 (s, 2 H).
MeOH to give a pale yellow solid (86%); mp 126–130 °C.
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IR (KBr): 3286, 1597, 1453, 1101, 1008, 761, 733, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57–7.16 (m, 18 H), 5.11 (s, 1 H),
3.76 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 157.0, 142.1, 141.0, 139.6, 137.7,
134.2, 131.4, 130.5, 129.7, 129.3, 129.2, 129.1, 128.6, 128.4, 128.4,
128.1, 127.8, 126.1, 56.3, 51.9.
13C NMR (75 MHz, CDCl3): d = 156.6, 149.6, 148.6, 147.2, 146.4,
138.9, 131.0, 128.6, 128.6, 127.5, 127.0, 119.7, 119.6, 114.5, 111.2,
108.5, 106.8, 102.6, 60.6, 56.2, 55.5, 51.2.
MS (ESI): m/z = 432 (M + H)+.
1-[1-(Benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl]-N-benzyl-1-
(4-chlorophenyl)methanamine (28)
The crude material was purified by column chromatography using
MS (ESI): m/z = 418 (M + H)+.
PE–EtOAc (8:2) as eluent to give a colorless oil (87%).
IR (KBr): 3283, 1505, 1244, 1035, 811, 732, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.20–7.12 (m, 9 H), 6.68 (m, 1 H),
6.54–6.48 (m, 3 H), 5.96 (s, 2 H), 4.93 (s, 1 H), 3.62 (s, 2 H).
N-Benzyl-1-(4-chlorophenyl)-1-[1-(4-morpholinophenyl)-1H-
tetrazol-5-yl]methanamine (33)
The crude material was purified by column chromatography using
PE–EtOAc (6:4) as eluent to give a yellow oil (82%).
13C NMR (75 MHz, CDCl3): d = 156.2, 149.6, 148.7, 138.8, 136.7,
134.5, 129.5, 129.2, 128.9, 128.5, 127.5, 126.9, 119.7, 108.5, 106.7,
102.7, 60.5, 55.2, 51.2.
IR (KBr): 3290, 1521, 1450, 1236, 1120, 926, 823, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24–7.12 (m, 9 H), 6.92 (d,
J = 8.8 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H), 4.94 (s, 1 H), 3.75 (m, 4
H), 3.62 (s, 2 H), 3.13 (m, 4 H).
MS (ESI): m/z = 420 (M + H)+.
13C NMR (75 MHz, CDCl3): d = 156.8, 153.2, 139.5, 137.6, 134.9,
130.1, 129.7, 129.3, 129.1, 128.1, 127.1, 124.8, 115.8, 67.3, 55.9,
51.8, 48.9.
N-Benzyl-1-(4-chlorophenyl)-1-(1-phenyl-1H-tetrazol-5-
yl)methanamine (29)
The crude material was purified by column chromatography using
PE–EtOAc (9:1) as eluent to give a colorless oil (65%).
MS (ESI): m/z = 461 (M + H)+.
IR (KBr): 3295, 1492, 1091, 1015, 702, 762, 736, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.34 (m, 3 H), 7.23–7.09 (m,
11 H), 4.99 (s, 1 H), 3.67 (s, 2 H).
5-{(Benzylamino)[1-(3,4,5-trimethoxyphenyl)-1H-tetrazol-5-
yl]methyl}-2methoxyphenol (34)
The crude material was filtered under vacuum and washed with cold
MeOH to give a yellow solid (75%); mp 130–134 °C.
IR (KBr): 3284, 2835, 1509, 1465, 1232, 1133, 999 cm–1.
13C NMR (75 MHz, CDCl3): d = 156.5, 139.2, 137.1, 134.9, 133.9,
131.3, 130.3, 129.9, 129.6, 129.5, 129.1, 128.9, 128.4, 127.9, 125.9,
55.7, 51.6.
1H NMR (300 MHz, CDCl3): d = 7.25–7.12 (m, 5 H), 6.77 (s, 1 H),
6.68 (d, J = 8.3 Hz, 1 H), 6.59 (dd, J = 8.3, 2.2 Hz, 1 H), 6.29 (s, 2
H), 4.89 (s, 1 H), 3.85 (s, 3 H), 3.77 (s, 3 H), 3.66 (s, 6 H), 3.36 (s,
2 H).
13C NMR (75 MHz, CDCl3): d = 156.8, 154.1, 147.7, 146.9, 139.9,
139.3, 131.4, 129.2, 129.1, 128.9, 127.9, 120.1, 115.1, 111.6, 103.7,
61.6, 56.9, 56.6, 56.2, 51.6, 51.0.
MS (ESI): m/z = 389 (M + H)+.
N-Benzyl-1-(4-morpholinophenyl)-1-(1-phenyl-1H-tetrazol-5-
yl)methanamine (30)
The crude material was filtered under vacuum and washed with cold
MeOH to give an off-white solid (71%); mp 89–93 °C.
IR (KBr): 3238, 2812, 1513, 1263, 1112, 921, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.29 (m, 3 H), 7.17–7.05 (m,
8 H), 6.73 (d, J = 8.1 Hz, 2 H), 4.89 (s, 1 H), 3.69 (br s, 4 H), 3.62
(s, 2 H), 3.01 (br s, 4 H).
MS (ESI): m/z = 478 (M + H)+.
N-Benzyl-1-(3-methoxyphenyl)-1-[1-(3,4,5-trimethoxyphenyl)-
1H-tetrazol-5-yl]methanamine (35)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a colorless oil (81%).
IR (KBr): 3286, 1508, 1232, 1131, 1126, 735, 698 cm–1.
13C NMR (75 MHz, CDCl3): d = 157.2, 151.9, 139.7, 134.2, 131.2,
130.4, 129.4, 129.1, 129.1, 127.9, 126.0, 116.2, 67.4, 55.9, 51.7,
49.5.
MS (ESI): m/z = 450 (M + Na)+.
1H NMR (300 MHz, CDCl3): d = 7.07–7.01 (m, 5 H), 6.66–6.60 (m,
3 H), 6.22 (s, 2 H), 4.93 (s, 1 H), 3.68 (s, 3 H), 3.59 (s, 2 H), 3.55 (s,
3 H), 3.49 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 161.2, 157.1, 154.5, 139.8, 138.9,
135.4, 134.4, 131.3, 129.5, 129.3, 128.3, 118.6, 117.6, 112.2, 105.8,
78.7, 78.3, 77.8, 61.7, 61.3, 57.4, 57.1, 56.6, 52.2.
N-Benzyl-1-[2-(3-methoxyphenyl)-2H-tetrazol-5-yl]-1-(3,4,5-
trimethoxyphenyl)methanamine (31)
The crude material was purified by column chromatography using
PE–EtOAc (6:4) as eluent to give a yellow oil (63%).
IR (KBr): 3288, 1592, 1460, 1235, 1124, 729, 688 cm–1.
MS (ESI): m/z = 475 (M + H)+.
1H NMR (300 MHz, CDCl3): d = 7.06 (m, 6 H), 6.63 (br t, 3 H), 6.22
(s, 2 H), 4.93 (s, 1 H), 3.68 (s, 3 H), 3.59 (s, 2 H), 3.54 (s, 3 H), 3.49
(s, 6 H).
[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanamine (11)
Yellow-brown solid (91%); mp 123–125 °C.
IR (KBr): 3372, 3290, 2359, 1517, 1257, 1122, 834, 764 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.01 (d, J = 8.3 Hz, 2 H), 6.84
(d, J = 8.3 Hz, 2 H), 6.26 (s, 2 H), 5.14 (s, 1 H), 3.75 (s, 3 H), 3.68
(s, 3 H), 3.62 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 161.3, 157.1, 154.5, 139.8, 138.9,
135.4, 134.4, 131.4, 129.5, 129.3, 128.3, 118.6, 117.6, 112.2, 105.8,
61.7, 57.4, 57.1, 56.6, 52.2.
MS (ESI): m/z = 462 (M + H)+.
N-Benzyl-1-(biphenyl-4-yl)-1-(2-phenyl-2H-tetrazol-5-yl)meth-
anamine (32)
The crude material was purified by column chromatography using
PE–EtOAc (8:2) as eluent to give a colorless oil (69%).
13C NMR (75 MHz, CD3OD): d = 160.4, 156.9, 152.8, 137.1, 134.8,
126.4, 126.1, 125.2, 113.9, 103.2, 60.0, 55.8, 55.3, 50.6.
MS (ESI): m/z = 372 (M + H)+.
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Synthesis of 5-Aroyl-1-aryltetrazoles
4115
(4-Methoxyphenyl)[1-(3,4,5-trimethoxyphenyl)-1H-tetrazol-5-
yl]methanamine (36)
White solid (72%); mp 132–135 °C.
1-[1-(Benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl](4-chlorophe-
nyl)methanamine (41)
Off-white solid (77%); mp 238–241 °C.
IR (KBr): 3335, 3276, 2999, 1601, 1242, 1128, 1002, 848 cm–1.
IR (KBr): 3350, 3255, 2851, 1491, 1225, 1107, 893, 697 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.12 (d, J = 8.2 Hz, 2 H), 6.81
(d, J = 8.2 Hz, 2 H), 6.35 (s, 2 H), 5.24 (s, 1 H), 3.86 (s, 3 H), 3.76
(s, 3 H), 3.68 (s, 6 H).
1H NMR (300 MHz, CD3OD): d = 7.41–7.38 (m, 2 H), 7.22–7.26
(m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.72–6.67 (m, 2 H), 6.05 (s, 2
H), 6.01 (s, 1 H).
13C NMR (75 MHz, CD3OD): d = 159.1, 153.1, 138.9, 128.3, 127.9,
113.9, 102.7, 60.5, 55.8, 54.9, 50.4.
13C NMR (75 MHz, CD3OD): d = 152.9, 150.2, 148.9, 131.8, 130.6,
129.5, 128.6, 126.2, 119.8, 108.3, 106.3, 102.9, 50.0.
MS (ESI): m/z = 394.2 (M + Na)+.
MS (ESI): m/z = 330 (M + H)+.
Biphenyl-4-yl[1-(4-phenoxyphenyl)-1H-tetrazol-5-yl]methan-
amine (37)
(4-Chlorophenyl)(1-phenyl-1H-tetrazol-5-yl)methanamine (42)
Off-white solid (77%); mp 229–232 °C.
White solid (95%); mp 234–236 °C.
IR (KBr): 3420, 3330, 2852, 1588, 1240, 1166, 1008, 758 cm–1.
IR (KBr): 3300, 3278, 2853, 1560, 1458, 1258, 1075, 759, 530
cm–1.
1H NMR (300 MHz, CD3OD): d = 7.64–7.56 (m, 3 H), 7.47–7.14
1H NMR (300 MHz, CD3OD): d = 7.59–7.19 (m, 9 H), 5.98 (s, 1 H).
13C NMR (75 MHz, CD3OD): d = 153.9, 136.4, 133.5, 133.3, 131.5,
130.7, 130.4, 130.3, 129.9, 128.8, 125.8, 50.1.
(m, 8 H), 6.99–6.94 (m, 3 H), 6.12 (s, 1 H).
13C NMR (75 MHz, CD3OD): d = 159.9, 155.8, 152.8, 143.4, 139.4,
130.4, 129.9, 129.1, 128.8, 127.9, 127.7, 127.2, 126.7, 124.4, 119.4,
118.5, 49.8, 48.5.
MS (ESI): m/z = 286 (M + H)+.
MS (ESI): m/z = 420 (M + H)+.
(4-Morpholinophenyl)(2-phenyl-2H-tetrazol-5-yl)methan-
amine (43)
Yellowish oil (92%).
IR (KBr): 3367, 3296, 2360, 1515, 1231, 1118, 925, 749 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.54–7.46 (m, 3 H), 7.27 (d,
J = 8.1 Hz, 2 H), 7.02 (d, J = 8.1 Hz, 2 H), 6.81 (d, J = 8.3 Hz, 2 H),
5.46 (s, 1 H), 3.73 (br s, 4 H), 3.05 (br s, 4 H).
13C NMR (75 MHz, CD3OD): d = 157.7, 152.4, 134.1, 131.4, 130.4,
129.0, 126.1, 125.9, 116.4, 67.2, 50.8, 49.3.
[1-(Benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl](3,4,5-trimeth-
oxyphenyl)methanamine (38)
White solid (93%); mp 95–98 °C.
IR (KBr): 3323, 3280, 2901, 1425, 1463, 1252, 1119, 1002, 860
cm–1.
1H NMR (300 MHz, CD3OD): d = 6.90 (d, J = 8.2 Hz, 1 H), 6.78
(dd, J = 8.2, 2.1 Hz, 1 H), 6.70 (s, 1 H), 6.46 (s, 2 H), 6.06 (s, 2 H),
5.41 (s, 1 H), 3.71 (s, 6 H), 3.68 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 157.6, 153.5, 149.7, 148.5, 138.1,
134.3, 126.9, 120.2, 108.2, 106.8, 104.9, 102.8, 59.9, 55.5, 51.0.
MS (ESI): m/z = 337 (M + H)+.
(3-Methoxyphenyl)[1-(3,4,5-trimethoxyphenyl)-1H-tetrazol-5-
yl]methanamine (44)
MS (ESI): m/z = 386 (M + H)+.
Dark yellow oil (71%).
[1-(4-Phenoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanamine (39)
White solid (70%); mp 75–79 °C.
IR (KBr): 3376, 3289, 1601, 1463, 1125, 996, 774, 696 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.21 (br t, 1 H), 6.86–6.74 (m, 3
H), 6.55 (s, 2 H), 5.64 (s, 1 H), 3.77 (s, 3 H), 3.70 (s, 9 H).
13C NMR (75 MHz, CD3OD): d = 160.8, 157.1, 154.3, 140.2, 139.4,
130.8, 129.3, 120.3, 115.0, 114.2, 113.2, 104.4, 60.7, 56.4, 55.3,
51.4.
IR (KBr): 3370, 3280, 2838, 1512, 1462, 1244, 1125, 1009, 839
cm–1.
1H NMR (300 MHz, CD3OD): d = 7.42–6.98 (m, 9 H), 6.47 (s, 2 H),
5.64 (s, 1 H), 3.69 (s, 6 H), 3.67 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 171.7, 159.7, 156.5, 155.8, 153.6,
138.3, 130.1, 127.9, 127.7, 124.6, 119.7, 118.4, 105.1, 60.3, 59.9,
55.5.
MS (ESI): m/z = 372 (M + H)+.
Biphenyl-4-yl(2-phenyl-2H-tetrazol-5-yl)methanamine (45)
The reaction mixture was filtered through a Celite pad, evaporated
under vacuum, and purified by column chromatography using PE–
EtOAc (3:7) and then EtOAc as eluents to give a yellow amorphous
solid (60%).
IR (KBr): 3410, 3300, 1617, 1116, 760, 692 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.44–7.10 (m, 14 H), 5.36 (s, 1
H).
13C NMR (75 MHz, CD3OD): d = 158.9, 141.7, 140.8, 139.6, 134.2,
131.3, 130.4, 129.4, 128.1, 127.9, 127.7, 127.4, 126.3, 51.2.
MS (ESI): m/z = 328 (M + H)+.
MS (ESI): m/z = 434 (M + H)+.
5-{Amino[1-(benzo[d][1,3]dioxol-5-yl)-1H-tetrazol-5-yl]meth-
yl}-2-methoxyphenol (40)
Dark yellow amorphous solid (68%).
IR (KBr): 3368, 3300, 2602, 1852, 1508, 1256, 1028, 931, 890
cm–1.
1H NMR (300 MHz, CD3OD): d = 6.89–6.83 (m, 2 H), 6.73–6.59
(m, 4 H), 6.06 (s, 2 H), 5.56 (s, 1 H), 3.80 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 155.7, 150.0, 148.9, 148.8, 147.1,
128.0, 126.6, 119.9, 119.5, 114.6, 111.9, 108.3, 106.5, 102.9, 55.4,
50.2.
(4-Chlorophenyl)[2-(4-morpholinophenyl)-2H-tetrazol-5-
yl]methanamine (46)
Off-white solid (92%); mp 231–234 °C.
MS (ESI): m/z = 342 (M + H)+.
IR (KBr): 3371, 3290, 2859, 2630, 1523, 1451, 1237, 1126, 926,
697 cm–1.
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PAPER
1H NMR (300 MHz, CD3OD): d = 7.42–7.34 (m, 2 H), 7.22 (d,
J = 8.3 Hz, 2 H), 7.09–7.01 (m, 5 H), 5.98 (s, 1 H), 3.84 (br s, 4 H),
3.24 (br s, 4 H).
13C NMR (75 MHz, CD3OD): d = 153.6, 152.4, 132.5, 131.3, 130.3,
129.3, 127.2, 125.6, 117.1, 66.9, 50.8, 50.0.
Biphenyl-4-yl[2-(4-phenoxyphenyl)-2H-tetrazol-5-yl]methan-
one (50)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give an amorphous orange solid
(44%).
IR (KBr): 2860, 1630, 1452, 1121, 1049, 734, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.33 (d, J = 8.3 Hz, 2 H), 7.76 (d,
J = 8.3 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 2 H), 7.51–7.37 (m, 5 H), 7.19
(br t, 1 H), 7.08 (d, J = 8.2 Hz, 2 H).
MS (ESI): m/z = 371 (M + H)+.
5-{5-[Amino(3,4,5-trimethoxyphenyl)methyl]-2H-tetrazol-2-
yl}-2-methoxyphenol (47)
Yellow solid (66%); mp 138–140 °C.
13C NMR (75 MHz, CDCl3): d = 181.0, 159.8, 155.7, 150.1, 148.3,
139.4, 133.6, 131.7, 130.3, 129.2, 128.9, 128.6, 127.7, 127.5,
126.78, 124.8, 120.2, 118.5.
IR (KBr): 3400, 3300, 2839, 1507, 1464, 1126, 1017, 904, 867
cm–1.
1H NMR (300 MHz, CD3OD): d = 7.00 (d, J = 8.1 Hz, 1 H), 6.70
(dd, J = 8.1, 2.2 Hz, 1 H), 6.60 (s, 1 H), 6.49 (s, 2 H), 5.89 (s, 1 H),
3.90 (s, 3 H), 3.72 (s, 9 H).
13C NMR (75 MHz, CD3OD): d = 154.6, 153.9, 150.7, 148.1, 140.0,
128.1, 126.3, 117.9, 113.3, 112.3, 106.6, 60.8, 56.3, 51.2.
MS (ESI): m/z = 419 (M + H)+.
Anal. Calcd for C26H18N4O2 (418.1): C, 74.63; H, 4.34; N, 13.39.
Found: C, 74.80; H, 4.50; N, 13.40.
[2-(Benzo[d][1,3]dioxol-5-yl)-2H-tetrazol-5-yl](3,4,5-trimeth-
oxyphenyl)methanone (51)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a yellowish solid (63%); mp 109–
112 °C.
MS (ESI): m/z = 386.1 (M – H)–.
[1-(3-Methoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanamine (48)
Brownish solid (92%); mp 227–230 °C.
IR (KBr): 2894, 1620, 1504, 1474, 1336, 1124, 995, 860 cm–1.
IR (KBr): 3370, 3296, 2623, 1599, 1129, 1035, 988, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (s, 2 H), 6.93–6.88 (m, 3 H),
6.07 (s, 2 H), 3.95 (s, 3 H), 3.89 (s, 6 H).
1H NMR (300 MHz, CD3OD): d = 7.43 (br t, 1 H), 7.12 (dd, J = 8.1,
2.2 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.77 (s, 1 H), 6.54 (s, 2 H),
6.03 (s, 1 H), 3.75 (s, 3 H), 3.71 (s, 6 H), 3.69 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 179.8, 153.3, 150.1, 149.6, 148.4,
145.0, 129.6, 127.8, 119.3, 108.5, 108.4, 106.4, 102.6, 61.2, 56.4.
13C NMR (75 MHz, CD3OD): d = 161.6, 154.8, 153.7, 140.2, 134.8,
MS (ESI): m/z = 385 (M + H)+.
131.6, 127.9, 118.6, 117.8, 112.2, 106.9, 60.8, 56.5, 56.1, 51.1.
Anal. Calcd for C18H16N4O6 (384.1): C, 56.25; H, 4.20; N, 14.58.
Found: C, 55.90; H, 4.00; N, 14.70.
MS (ESI): m/z = 372 (M + H)+.
[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanone (12)
The crude material was purified by column chromatography, using
PE–EtOAc (7:3) as eluent to give a yellowish solid (50%); mp 156–
159 °C.
[2-(4-Phenoxyphenyl)-2H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanone (52)
The crude material was purified by column chromatography using
PE–EtOAc (8:2) as eluent to give a yellowish solid (50%); mp 183–
185 °C.
IR (KBr): 2945, 1655, 1472, 1339, 1133, 833, 775 cm–1.
IR (KBr): 2831, 1630, 1507, 1414, 1383, 1244, 1127, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (s, 2 H), 7.40 (d, J = 8.6 Hz,
2 H), 7.01 (d, J = 8.6 Hz, 2 H), 3.97 (s, 3 H), 3.90 (s, 6 H), 3.86 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 179.4, 160.7, 152.8, 149.6, 144.5,
129.1, 126.5, 126.0, 114.2, 108.0, 60.7, 55.9, 55.2.
1H NMR (300 MHz, CDCl3): d = 7.59 (s, 2 H), 7.44–7.39 (m, 4 H),
7.18 (br t, 1 H), 7.10–7.05 (m, 4 H), 3.97 (s, 3 H), 3.90 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 180.0, 159.9, 155.7, 153.4, 150.2,
145.2, 130.4, 129.7, 128.7, 126.8, 124.9, 120.3, 118.5, 108.7, 61.3,
56.6.
MS (ESI): m/z = 371 (M + H)+.
MS (ESI): m/z = 433.06 (M + H)+.
Anal. Calcd for C18H18N4O5 (370.1): C, 58.37; H, 4.90; N, 15.13.
Found: C, 58.30; H, 5.10; N, 15.30.
Anal. Calcd for C23H20N4O5 (432.1): C, 63.88; H, 4.66; N, 12.96.
Found: C, 64.05; H, 4.80; N, 12.90.
[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanone (49)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a yellowish solid (50%); mp 134–
135 °C.
[2-(Benzo[d][1,3]dioxol-5-yl)-2H-tetrazol-5-yl](3-hydroxy-4-
methoxyphenyl)methanone (53)
The crude material was purified by column chromatography using
EtOAc as eluent to give a light yellow solid (46%); mp 220–223 °C.
IR (KBr): 1645, 1505, 1282, 1126, 1036, 778 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.68 (d, J = 8.2 Hz, 1 H), 7.54
(s, 1 H), 7.27 (s, 1 H), 7.12–7.06 (m, 3 H), 6.16 (s, 2 H), 3.88 (s, 3
H).
13C NMR (75 MHz, DMSO-d6): d = 180.5, 155.2, 150.9, 149.7,
148.5, 147.5, 128.3, 128.1, 126.1, 120.3, 116.4, 112,3, 109.0, 107.4,
103.2, 56.7.
IR (KBr): 2930, 1600, 1512, 1280, 1173, 1026, 926, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (s, 2 H), 7.40 (d, J = 8.2 Hz,
2 H), 7.01 (d, J = 8.2 Hz, 2 H), 3.97 (s, 3 H), 3.90 (s, 6 H), 3.86 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 179.7, 165.3, 153.2, 149.9, 139.2,
133.0, 129.1, 127.5, 114.1, 102.3, 60.6, 56.0, 55.4.
MS (ESI): m/z = 392 (M + Na)+.
MS (ESI): m/z = 339.0 (M – H)–.
Anal. Calcd for C18H18N4O5 (370.1): C, 58.37; H, 4.90; N, 15.13.
Found: C, 58.60; H, 5.15; N, 15.00.
Anal. Calcd for C16H12N4O5 (340.1): C, 56.47; H, 3.55; N, 16.46.
Found: C, 56.60; H, 3.70; N, 16.70.
Synthesis 2010, No. 23, 4107–4118 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Aroyl-1-aryltetrazoles
4117
[2-(Benzo[d][1,3]dioxol-5-yl)-2H-tetrazol-5-yl](4-chloro-3-
methylphenyl)methanone (54)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a yellow solid (40%); mp 117–
121 °C.
IR (KBr): 2920, 1635, 1471, 1383, 1035, 922, 616 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.22 (m, 2 H), 7.71 (br t, 1 H),
7.58–7.52 (m, 2 H), 6.95–6.89 (m, 2 H), 6.09 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 181.7, 149.8, 148.6, 135.7, 135.0,
132.5, 131.1, 129.3, 127.3, 119.6, 108.6, 102.7.
MS (ESI): m/z = 329 (M + H)+.
Biphenyl-4-yl(2-phenyl-2H-tetrazol-5-yl)methanone (58)
The crude material was purified by column chromatography using
PE–EtOAc (9:1) as eluent to give a white solid (39%); mp 129–
132 °C.
IR (KBr): 1668, 1600, 1481, 1306, 924 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.32 (d, J = 8.2 Hz, 2 H), 8.76 (d,
J = 8.2 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 2 H), 7.56–7.43 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 181.7, 150.8, 148.9, 140.0, 134.2,
132.3, 131.7, 131.5, 130.4, 129.9, 129.6, 128.4, 128.2, 125.7.
MS (ESI): m/z = 327 (M + H)+.
Anal. Calcd for C20H14N4O (326.1): C, 73.61; H, 4.32; N, 17.17.
Found: C, 73.80; H, 4.56; N, 17.43.
Anal. Calcd for C15H9ClN4O3 (328.0): C, 54.81; H, 2.76; N, 17.04.
Found: C, 55.00; H, 2.90; N, 16.90.
(4-Chlorophenyl)[2-(4-morpholinophenyl)-2H-tetrazol-5-
yl]methanone (59)
The crude material was purified by column chromatography using
PE–EtOAc (6:4) as eluent to give a yellow solid (46%); mp 124–
128 °C.
(4-Chlorophenyl)(2-phenyl-2H-tetrazol-5-yl)methanone (55)
4-Formyl-1-methylpyridinium benzenesulfonate (2.2 equiv) was
used. The crude material was purified by column chromatography
using PE–EtOAc (9:1) as eluent to give a white solid (38%);
mp 85–87 °C.
IR (KBr): 1675, 1503, 1303, 918, 767 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25–8.22 (m, 2 H), 7.70 (br t, 1
H), 7.57–7.46 (m, 6 H).
IR (KBr): 1640, 1520, 1447, 1303, 1113, 927, 819 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.4 Hz, 2 H), 7.54 (d,
J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.93 (d, J = 8.4 Hz, 2
H), 3.84 (br t, 4 H), 3.23 (br t, 4 H).
13C NMR (75 MHz, CDCl3): d = 182.2, 150.6, 136.2, 135.4, 134.8,
133.7, 133.0, 131.6, 131.4, 130.3, 130.1, 129.7, 125.8, 125.6.
13C NMR (75 MHz, CDCl3): d = 182.6, 153.3, 150.7, 136.2, 135.7,
131.7, 129.8, 126.89, 126.8, 126.0 115.8, 67.5, 49.0.
MS (ESI): m/z = 285 (M + H)+.
MS (ESI): m/z = 370 (M + H)+.
Anal. Calcd for C14H9ClN4O (284.0): C, 59.06; H, 3.19; N, 19.68.
Found: C, 59.30; H, 3.40; N, 19.30.
Anal. Calcd for C18H16ClN5O2 (369.1): C, 58.46; H, 4.36; N, 18.94.
Found: C, 57.92; H, 4.24; N, 19.10.
(4-Morpholinophenyl)(2-phenyl-2H-tetrazol-5-yl)methanone
(56)
[2-(3-Hydroxy-4-methoxyphenyl)-2H-tetrazol-5-yl](3,4,5-tri-
methoxyphenyl)methanone (60)
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a yellow solid (61%); mp 164–
167 °C.
The crude material was purified by column chromatography using
PE–EtOAc (7:3) as eluent to give a yellow solid (46%); mp 166–
169 °C.
IR (KBr): 1610, 1395, 1250, 1191, 929 cm–1.
IR (KBr): 1643, 1514, 1255, 1124, 1021, 865 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09 (d, J = 8.2 Hz, 2 H), 7.51–
7.46 (m, 5 H), 6.86 (d, J = 8.2 Hz, 2 H), 3.82 (br t, 4 H), 3.39 (br t,
4 H).
1H NMR (300 MHz, CDCl3): d = 7.55 (s, 2 H), 7.01 (d, J = 2.1 Hz,
1 H), 7.97 (d, J = 2.1 Hz, 1 H), 6.94 (s, 1 H), 3.97 (s, 3 H), 3.94 (s,
3 H), 3.89 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 179.6, 156.3, 151.3, 135.1, 134.2,
131.2, 130.3, 125.7, 125.5, 113.6, 67.2, 47.6.
13C NMR (75 MHz, CDCl3): d = 181.0, 154.2, 151.0, 149.4, 147.4,
145.9, 130.6, 128.3, 117.8, 112.7, 111.6, 109.4, 62.1, 57.4, 57.2.
MS (ESI): m/z = 336.2 (M + H)+.
MS (ESI): m/z = 385 (M – H)–.
Anal. Calcd for C18H17N5O2 (335.1): C, 64.47; H, 5.11; N, 20.88.
Found: C, 64.45; H, 5.30; N, 20.80.
Anal. Calcd for C18H18N4O6 (386.1): C, 55.96; H, 4.70; N, 14.50:
Found: C, 56.22; H, 4.83; N, 14.30.
(3-Methoxyphenyl)[2-(3,4,5-trimethoxyphenyl)-2H-tetrazol-5-
yl]methanone (57)
4-Formyl-1-methylpyridinium benzenesulfonate (2.2 equiv) was
used. The crude material was purified by column chromatography
using PE–EtOAc (7:3) as eluent to give a yellow solid (41%);
mp 94–99 °C.
[1-(3-Methoxyphenyl)-1H-tetrazol-5-yl](3,4,5-trimethoxyphe-
nyl)methanone (61)
4-Formyl-1-methylpyridinium benzenesulfonate (2.2 equiv) was
used. The crude material was purified by column chromatography
using PE–EtOAc (6:4) as eluent to give a yellowish amorphous sol-
id (38%).
IR (KBr): 1632, 1506, 1339, 1277, 1127, 942 cm–1.
IR (KBr): 1610, 1578, 1237, 1134, 842, 684 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.76 (m, 1 H), 7.66 (br t,
J = 8.2 Hz, 1 H), 7.42 (br t, J = 8.1 Hz, 1 H), 7.25–7.05 (m, 1 H),
6.71 (s, 2 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.81 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 182.7, 161.1, 154.6, 151.1, 137.0,
131.2, 130.4, 125.0, 123.6, 123.5, 115.0, 103.8, 62.0, 57.5, 56.6.
1H NMR (300 MHz, CDCl3): d = 7.55 (s, 2 H), 7.40 (br t, 1 H), 7.08–
6.97 (m, 3 H), 3.97 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 180.9, 161.3, 154.3, 154.2, 151.1,
131.4, 130.5, 118.0, 117.9, 117.5, 109.4, 62.2, 57.5, 57.4, 56.7.
MS (ESI): m/z = 371 (M + H)+.
MS (ESI): m/z = 371 (M + H)+.
Anal. Calcd for C18H18N4O5 (370.1): C, 58.37; H, 4.90; N, 15.13.
Found: C, 58.62; H, 4.95; N, 15.30.
Anal. Calcd for C18H18N4O5 (370.1): C, 58.37; H, 4.90; N, 15.13.
Found: C, 58.45; H, 5.10; N, 15.13.
Synthesis 2010, No. 23, 4107–4118 © Thieme Stuttgart · New York

4118
M. Giustiniano et al.
PAPER
(11) Rivera, D. G.; Wessjohann, L. J. Am. Chem. Soc. 2009, 131,
3721.
(12) Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L.
Tetrahedron Lett. 2002, 44, 603.
Acknowledgment
Financial support from Università degli Studi del Piemonte Orien-
tale and M.I.U.R. PRIN 2008 Italy is gratefully acknowledged.
(13) In order to quantify the similarity between the chalcone and
the proposed structures, a flexible superimposition was
performed with Vega ZZ: Pedretti, A.; Villa, L.; Vistoli, G.
J. Mol. Graph. Model 2002, 21, 47; the RMSD values of
tetrazole was 1.164 Å.
(14) Ducky, S. Anti-Cancer Agents Med. Chem. 2009, 3, 336.
(15) Moderhack, D. J. Heterocycl. Chem. 1977, 14, 757.
(16) Zefirov, N. S.; Chapovskaya, N. K.; Tranch, S. S. Zh. Org.
Khim. 1972, 8, 629.
(17) Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2113.
(18) Banfi, L.; Riva, R. Org. React. 2005, 65, 1.
(19) Olivieri-Mandala, E.; Alagna, B. Gazz. Chim. Ital. 1910, 40,
441.
(20) (a) Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229. (b) Nixey,
T.; Hulme, C. Tetrahedron Lett. 2002, 43, 6833.
(21) Recently Zhu and co-workers demonstrated that the
formation of the a-hydroxy amide derivatives depends on
catalyst and cannot be suppressed: Yue, T.; Wang, M. X.;
Wang, D. X.; Zhu, J. Angew. Chem. Int. Ed. 2008, 47, 9454.
(22) (a) For the Ugi-like 4CR using HN3, see: Ugi, I. Angew.
Chem., Int. Ed. Engl. 1962, 1, 8; Angew. Chem. 1962, 74, 9.
(b) For the Ugi-like 4CR using TMSN3, see: Nixey, T.;
Kelly, M.; Hulme, C. Tetrahedron Lett. 2000, 41, 8729.
(23) Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1982, 104,
4446.
References
(1) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005, and references cited therein.
(2) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 29, 123.
(3) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
(4) (a) Marcaccini, S.; Torroba, T. In Multicomponent
Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH:
Weinheim, 2005, 33–69. (b) Akritopulou-Zanze, I.; Djuric,
S. W. Heterocycles 2007, 73, 125. (c) Hulme, C.; Nixey, T.
Curr. Opin. Drug Discovery Dev. 2003, 6, 921.
(5) Wang, W.; Herdtweck, E.; Dömling, A. Chem. Commun.
2010, 46, 770.
(6) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851.
(7) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23; and
references cited therein.
(8) Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T.
Heterocycles 1999, 50, 463.
(9) Pirali, T.; Callipari, G.; Ercolano, E.; Genazzani, A. A.;
Giovenzana, G. B.; Tron, G. C. Org. Lett. 2008, 10, 4199.
(10) (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.;
Picard, A.; Herdtweck, E.; Dömling, A. Org. Lett. 2003, 5,
1047. (b) Oikawa, M.; Naito, S.; Sasaki, M. Heterocycles
2007, 73, 377.
Synthesis 2010, No. 23, 4107–4118 © Thieme Stuttgart · New York