Efficient Synthesis of Indole Derivatives Containing the Tetrazole Moeity Utilizing an Ugi-Azide Post-Transformation Strategy

Article abstract of DOI:10.1055/s-0037-1610502

An efficient strategy has been developed for the synthesis of indole derivatives containing the tetrazole moiety using a AuCl ₃ -catalyzed cyclization reaction. The precursors of the cycloadduct were easily prepared by an Ugi-azide 4-CR in methanol at room temperature. The merit of this protocol lies in its operational simplicity, readily available starting materials, high yields of product, and good functional group tolerance.

Full text of DOI:10.1055/s-0037-1610502

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
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en
A. Nikbakht et al.
Letter
Synlett
Efficient Synthesis of Indole Derivatives Containing the Tetrazole
Moeity Utilizing an Ugi-Azide Post-Transformation Strategy
Ali Nikbakhta
Ph
Saeed Balalaie*a,b
Fatemeh Baghestania
Frank Romingerc
0
0
0
0
0-
0
0
2
5-
7
6
4
0-
4
4
2
Ph
Ph
AuCl3
(5 mol%)
N
O
NH
MeOH
+
N
N
+ R3
R1
R2
–
N
N
Me3Si N3
+
NH2
+
R1
R2
R2
N
R1
r.t.
24 h
toluene,
100 °C, 12 h
N
N
a Peptide Chemistry Research Center, K. N. Toosi University of
Technology, P. O. Box 15875-4416, Tehran, Iran
balalaie@kntu.ac.ir
N
N
R3
R3
b Medical Biology Research Center, Kermanshah University of
Medical Sciences, Kermanshah, Iran
c Organisch-Chemisches Institut der Universitaet Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Dedicated to Prof. Bernhard Breit on the occasion of his birthday
Received: 04.04.2018
Accepted after revision: 29.06.2018
Published online: 26.07.2018
bioisosteres of carboxylic acids and are often used as a re-
placement for carboxylic acid groups. The tetrazole skeleton
is a constituent of a range of drugs including losartan and
valsartan that demonstrate antihypertensive activities (Fig-
ure 1).19 It has been reported that the attachment of an in-
dole moiety to the tetrazole nucleus enhances its antimi-
crobial activity. These hybrid compounds also have peroxi-
some proliferator-activated receptor (PPAR) activity and
can be used for lowering triglycerides and blood sugar (Fig-
ure 1).20
DOI: 10.1055/s-0037-1610502; Art ID: st-2018-d0207-l
Abstract An efficient strategy has been developed for the synthesis of
indole derivatives containing the tetrazole moiety using a AuCl3-cata-
lyzed cyclization reaction. The precursors of the cycloadduct were easi-
ly prepared by an Ugi-azide 4-CR in methanol at room temperature.
The merit of this protocol lies in its operational simplicity, readily avail-
able starting materials, high yields of product, and good functional
group tolerance.
Key words Ugi-azide post-transformation strategy, metal catalyzed
alkyne cyclization, heterocyclization, indole, tetrazole
OH
O
OH
N
HN
N
N
HN
N
N
N
N
N
Cl
N
Indoles have attracted a great deal of interest due to
their presence in natural products and pharmaceutical
compounds with extensive biological properties such as an-
ticancer, antibacterial, antifungal, and antimicrobial activi-
ty.1 The presence of the indole scaffold in many natural
sources such as serotonin, tryptophan, and plant growth
hormones underlines the importance of these compounds.1
Moreover, synthetic indole derivatives possess the potential
to be integrated in technical applications, such as ion sen-
sors, organic-light emitting diodes (OLEDs) or organic field-
effect transistors (OFETs).2
O
losartan
valsartan
N
N
R
N
N
N
There are several different strategies for the synthesis of
indoles.3–6 Among these synthetic approaches, the hetero-
cyclization of 2-alkynylanilines to 2-substituted indoles re-
mains the most commonly employed strategy.7 Different
A
Figure 1 Structure of some bioactive compounds containing tetrazole
and indole moieties
transition metals have exploited in order to carry out this
13
cyclization including Cu,8,9 Pd,10–12 Ag,
catalysts.
Au,14–16 and In17
Several methods for the synthesis of tetrazoles have
been reported in the literature.21 Synthesis of tetrazoles
through the classical Ugi-azide four-component reaction
(UA-4CR) has a wide scope with regard to the starting
materials.22
On the other hand, tetrazole derivatives have attracted
considerable attention due to their distinct structural fea-
tures and their notable biological activities.18 Tetrazoles are
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
A. Nikbakht et al.
Letter
Synlett
Ph
N
Ph
Ph
N
O
AuCl3 (5 mol%)
MeOH
+
N
NH
R3
N
–
R3
+
R1
R2
Me3Si N3
+
+
N
N
r.t., 24 h
R1
R2
R2
R1
3a–g
toluene
100 °C, 12 h
NH2
N
N
N
N
1
2
4a,b
R3
5a–i
6a–i
Scheme 1 Synthesis of 2-aryl-indoles containing tetrazole moieties through Ugi-azide reaction followed by AuCl3-catalyzed cyclization
The combination of the Ugi-azide four-component reac-
tion with post-transformational reactions has become a
useful tool for generating complex and diverse molecular li-
braries with novel properties.23 In a continuation of our
previous research work on the design of post-transforma-
um dioxide, and palladium acetate but the reaction did not
proceed. However, performing the reaction using InCl3
(10%) or AuCl3 (5%) resulted in the desired product 6a in
66% and 85% yields, respectively (Table 1, entries 2 and 3).
The use of 3% AuCl3 decreased the yield to 78% (Table 1, en-
try 1). Spectroscopic analysis of 6a confirmed the forma-
tion of the indole moiety. The absence of the acetylenic car-
bons at δ = 85.0 and 95.0 ppm in the 13C NMR spectrum
confirmed the cyclization and the C-3 in the indole ring was
observed at δ = 108.0 ppm.
With the optimized reaction conditions established, we
explored the scope of our methodology using various car-
bonyl substrates and isocyanides. The reaction conditions
were found to be compatible with a range of aromatic alde-
hydes and ketones (Scheme 2).
In addition to the spectroscopic analyses, X-ray crystal-
lographic analysis of 6d confirmed the formation of the de-
sired product (Figure 2).26 The orientation of the tetrazole
ring with the indole ring is interesting, the torsion angle is
54° and the 2-aryl group in position 2 is not coplanar with
the indole motif.
To confirm the importance of this strategy, palladium
acetate-catalyzed cyclization of O-(phenylethynyl)-N-ethoxy-
carbonylanilide for the synthesis of 2-phenylindole was at-
24
tion reactions, we report herein an efficient approach to
2-aryl-indoles containing a tetrazole moiety through AuCl3-
catalyzed cyclization. The precursors of the cycloadduct
were easily prepared through Ugi-azide reaction of 2-(phe-
nylacetylenyl)aniline, trimethylsilylazide, isocyanides, and
carbonyl compounds (Scheme 1).
The 2-(phenylethynyl)aniline (1) was efficiently pre-
pared by the reported procedure.25 Next, the four-compo-
nent reaction of 2-(phenylethynyl)aniline (1), trimethylsilyl
azide (2), cyclohexanone (3a), and cyclohexyl isocyanide
(4a) was selected as the model reaction for the screening of
suitable reaction conditions. The reaction was carried out
in methanol at ambient temperature and product 5a was
formed in 75% yield (Table 1). The structure of the Ugi-azide
product was confirmed using spectroscopic analysis.
Next, the heterocyclization reaction of 5a was investi-
gated using different Lewis acid catalysts to access the in-
dole skeleton 6a. Different attempts were made at the het-
erocyclization using copper(I) iodide, silver nitrate, zirconi-
Table 1 Optimization of the Reaction Conditions for the Synthesis of 6a
Ph
Ph
O
Ph
N
MeOH
r.t., 24 h
Lewis acid
NH
Cy
N
+
N
–
N
N
+
N3
Cy
+
Me3Si
+
N
toluene
100 °C, 12 h
NH2
N
N
N
Cy
N
1
2
3a
4a
5a (75%)
6a
Entry
Lewis acid
Yield (%)
1
2
4
5
6
7
8
AuCl3(3%)
AuCl3(5%)
InCl3 (10%)
ZrO2
78
85
66
–
AgNO3
–
CuI
–
Pd(OAc)2
–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
A. Nikbakht et al.
Letter
Synlett
Ph
N
Ph
Ph
N
O
AuCl3 (5 mol%)
MeOH
+
N
NH
R3
N
–
R3
+
R1
R2
Me3Si N3
+
+
N
N
r.t., 24 h
R1
R2
R2
R1
3a–g
toluene
100 °C, 12 h
NH2
N
N
N
N
1
2
4a,b
R3
5a–i
6a–i
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Et
Et
t-Bu
6b, 82%
6c, 85%
6e, 89%
6a, 86%
6d, 87%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Cl
Cl
6f, 90%
6g, 92%
6h, 88%
6i, 69%
Scheme 2 Scope of the optimized protocol for the synthesis of 2-aryl-indoles containing a tetrazole moiety
O
Ph
EtONa
EtOH
MeOH
r.t.
Ph
no reaction
reflux
N
H
Cy-NC
TMSN3
NHCOOEt
59%
Scheme 3
A mechanistic rationale for the cyclization reaction is
outlined in Scheme 4. The Lewis acidic Au(III) coordinates
to the alkynyl moiety of 5a–i, and the resulting electron-de-
ficient triple bond in I undergoes intramolecular nucleop-
hilic attack by the poorly basic nitrogen atom of the free
amine moiety leading to the intermediate II via a 5-endo-
dig cyclization in preference to a 4-exo-dig mode of cycliza-
tion, the latter being disfavored according to Baldwin’s
rules. Finally, protiodemetallation during the workup af-
fords cyclized 6a–i (Scheme 4).
Figure 2 ORTEP structure of 6d
In conclusion, we have developed an efficient method
for the synthesis of functionalized 2-phenyl indoles con-
taining the tetrazole skeleton. The reaction proceeds
through AuCl3 catalyzed cyclization of Ugi-azide products
containing an alkyne moiety. Good to high yields and sim-
plicity of the reaction are features of the procedure.
tempted. However, the subsequent Ugi-azide reaction of
the 2-phenylindole with cyclohexanone, cyclohexylisocya-
nide, and trimethylsilyl azide did not take place and the
starting materials remained (Scheme 3). This result con-
firms the importance of the reaction sequence disclosed
herein.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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R1
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N
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R3
R1
R2
[Au]
N
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6a–i
R3
5a–i
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N
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Scheme 4 Proposed mechanistic pathway for the gold-catalyzed
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https://doi.org/10.1055/s-0037-1610502.
S
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(26) HRMS data were collected using an Apex-QC-FT- ICR instru-
ment with ESI.
(300 MHz, CDCl3): δ = 0.84 (s, 9 H, t-Bu), 1.16–1.34 (m, 4 H, HCy-
clohexyl), 1.42–1.68 (m, 5 H, HCyclohexyl), 1.73–1.93 (m, 8 H, HCyclo-
hexyl), 2.87–2.91 (m, 2 H, HCyclohexyl), 4.72 (m, 1 H, CHN), 5.07 (s, 1
H, NH), 6.08 (d, 1 H, J = 8.1 Hz, H-Ar), 6.63 (t, 1 H, J = 7.5 Hz, H-
Ar), 6.86–6.92 (dt, 1 H, J = 7.2, 1.5 Hz, H-Ar), 7.3(dd, 1 H, J = 8.1,
1.2 Hz, H-Ar), 7.34–7.43(m, 3 H, H-Ar), 7.53–7.56 (m, 2 H, H-Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 23.7, 24.8, 25.6, 27.5, 32.4,
33.5, 39.0, 47.6, 54.4, 59.2, 85.6, 95.7, 108.8, 111.8, 118.0, 123.0,
128.6, 128.7, 129.9, 131.3, 132.1, 145.4, 153.3 ppm.
1-[4-(tert-Butyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl)
hexyl]-2-phenyl-1H-indole (6d)
cyclo-
Colorless solid; yield 417.6 mg (87%); Rf = 0.38 (PE/EtOAc, 3:1);
mp 178–181 °C. IR (KBr): ν = 1453, 1611, 2940 cm–1 1H NMR
(300 MHz, CDCl3): δ = 0.78 (s, 9 H, t-Bu), 0.88–1.56 (m, 17 H,
HCyclohexyl), 2.10–2.30 (m, 2 H, HCyclohexyl), 3.10–3.15 (m, 1 H, HCy-
.
clohexyl), 6.47 (s, 1 H, H-3 indole), 6.82 (t, 1 H, J = 8.4 Hz, H-Ar),
6.89(dt, 1 H, J = 7.2, 1.2 Hz, H-Ar), 7.01 (t, 1 H, J = 7.2, H-Ar),
7.46–7.59(m, 6 H, H-Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.1, 23.9, 24.7, 25.3, 25.4, 26.9, 27.4, 31.2, 32.3, 32.8, 38.1,
38.6, 46.9, 47.0, 58.1, 62.5, 108.1, 112.4, 120.5, 121.3, 122.6,
124.0, 126.0, 128.3, 128.4, 137.1, 137.5, 140.9, 156.4 ppm.
HRMS (ESI): m/z calcd for C31H40N5 [M + H]+: 482.3272; found:
482.3288; C31H39N5Na [M + Na]+: 504.3097; found: 504.3106.
Colorless crystal (polyhedron), dimensions 0.130 × 0.120 ×
0.050 mm3, crystal system triclinic, space group P, Z = 2, a =
10.4530(5) Å,
b = 12.9781(6) Å, c = 13.3411(6) Å, α =
108.2879(14)°, β = 112.3234(14)°, γ = 100.5989(14)°, V =
1491.99(12) Å3, ρ = 1.189 g cm–3, T = 200(2) K, θmax= 22.980°,
raduiation Mo Kα, λ = 0.71073 Å, 0.5° ω scans with CCD area
detector, covering the asymmetric unit in reciprocal space with
a mean redundancy of 3.1 and a completeness of 98.3% to a
resoltion of 0.91 Å, 12857 reflections measured, 4082 unique
(R(int) = 0.0380), 2672 observed (I > 2σ(I)), intensities were cor-
rected for Lorentz and polarization effects, an empirical scaling
and absorption correction was applied using SADABS based on
General Procedure for the Synthesis of Compounds 5a–i
2-(Phenylethynyl)aniline in MeOH (5 ml) and cyclohexanone (1
mmol) were stirred at room temperature for 2 h, then the requi-
site isocyanide (1 mmol) and trimethylsilyl azide were added.
The mixture was stirred for 24 h until the reaction was com-
pleted. Then, the desired product was either filtered off as a
white solid filtered for 5a–e (ketone derivatives) or purified
using column chromatography on silica gel (n-hexane/EtOAc,
9:1) for 5f–i (aldehyde derivatives). The yields were in the range
of 75–92%.
General Procedure for the Synthesis of Compounds 6a–i
The products 5a–i (1mmol) and AuCl3 (5 mol%, 15 mg) were
added to a reaction flask containing toluene (10 mL). After 12 h
the toluene was evaporated under reduced pressure. The crude
products were purified by silica gel chromatography (n-hex-
ane/EtOAc, 7:1) to obtain the indole derivatives.
the Laue symmetry of the reciprocal space, μ = 0.09 mm–1, Tmin
=
0.93, Tmax = 0.96, structure refined against F2 with a full-matrix
least-squares algorithm using the SHELXL-2014/7 (Sheldrick,
2014) software, 393 parameters refined, hydrogen atoms were
treated using appropriate riding models, goodness of fit 1.05 for
observed reflections, final residual values R1(F) = 0.052, wR(F2) =
0.125 for observed reflections, residual electron density –0.21
to 0.14 eÅ–3. 27CCDC 1551544 contains the supplementary
crystallographic data for this paper. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/getstructures.
N-[4-(tert-Butyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl)
cyclo-
hexyl]-2-(phenylethynyl) aniline (5d)
Colorless solid; yield 440 mg, (80%); Rf = 0.45 (PE/EtOAc 3:1);
mp 142–146 °C. IR (KBr): ν = 1586, 2197, 3377 cm–1 1H NMR
.
(27) Sheldrick, G. M. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E