An Efficient Ugi-Azide Four-Component Approach for the Preparation of Novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] Indoles

Article abstract of DOI:10.1002/jhet.3499

The synthesis of novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] indole derivatives starting from the initially prepared 1-(2-bromoethyl)-3-chloro-1H-indole-2-carbaldehyde is described. A variety of likely biologically relevant pyrazino[1,2-a] indole-based 1,5-disubstituted tetrazoles was obtained in moderate to high yields via an Ugi-azide reaction. These reactions presumably proceed by the imine formation, intramolecular cyclization to iminium ion, and nucleophilic addition tandem reactions, respectively.

Full text of DOI:10.1002/jhet.3499

Month 2019 An Efficient Ugi-Azide Four-Component Approach for the Preparation of
Novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]
Indoles
*
Saleh Salahi, Mehdi Ghandi,
and Alireza Abbasi
School of Chemistry, College of Science, University of Tehran, P.O. Box 14155 6455, Tehran, Iran
*E-mail: ghandi@khayam.ut.ac.ir
Received August 27, 2018
DOI 10.1002/jhet.3499
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] indole deriva-
tives starting from the initially prepared 1-(2-bromoethyl)-3-chloro-1H-indole-2-carbaldehyde is described.
A variety of likely biologically relevant pyrazino[1,2-a] indole-based 1,5-disubstituted tetrazoles was
obtained in moderate to high yields via an Ugi-azide reaction. These reactions presumably proceed by the
imine formation, intramolecular cyclization to iminium ion, and nucleophilic addition tandem reactions,
respectively.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
antagonists [12] has been reported for 1,5-DS-1H-T rings
(Fig. 1) [13]. Recall that replacement of cis-amide in
somatostatin peptide with 1,5-DS-1H-Ts can be used for
the synthesis of more biologically active cyclic
hexapeptide analogues [14].
Expansion and diversification of drug candidate libraries
increasingly need new one-pot multicomponent reactions
(MCRs) in order to fuse the privileged structures with
bioactive scaffolds. Results obtained in this regard
provide an opportunity to the synthesis of “drug-like”
complex compounds, and also, the simplicity, high
efficiency, and atom economy are some advantages of
MCRs in general and their isocyanide-based subclass
(IMCRs) in particular. Combining three or more starting
materials in a vessel in order to obtain the desired
molecules via an expedient method is the unique feature
of this category of reactions [1–4].
The classical Ugi reaction is perhaps the most known
IMCR, which is widely used in the synthesis of peptides.
On the other hand, the Ugi-azide reaction as the most
popular subclass of Ugi reaction is traditionally the easiest
approach to the synthesis of 1,5-disubstituted-1H-tetrazole
In 1988, Evans published an article, in which the term
“privileged structures” was mentioned [15]. The so-called
privileged structure is a molecular scaffold, which
provides potent and selective ligands to a variety of
biological targets via modification of functional groups.
These prominent molecules usually exhibit drug-like
properties [16,17]. This in turn leads to more compound
libraries and leads. Among which, indole is the central
active scaffold due to its wide range of known
pharmacological and biochemical properties. Furthermore,
the presence of indole ring in the structure of a large
number of natural and synthetic bioactive molecules
makes this scaffold an interesting candidate for the design
of new drugs (Fig. 2) [18–20].
(1,5-DS-1H-T) [5,6].
A
variety of pharmacological
On the other hand, the piperazine nucleus is one of the
most important building blocks in today’s drug
discovery. Interestingly, the broad range of bioactivities
found for piperazines in the regulation of a wide variety
of biological processes has led to them being included in
properties including anti-inflammatory [7], antimalarial
activity [8], and anticancer activity [9], agonist of the
GHS receptor [10], anandamide transport blocker
LY218324010 [11], and cannabinoid CB1 receptor
© 2019 Wiley Periodicals, Inc.

S. Salahi, M. Ghandi, and A. Abbasi
Vol 000
Figure 1. Examples of drugs and bioactive molecules containing a 1,5-disubstituted-1H-tetrazole scaffold.
Figure 2. Examples of drugs and natural products containing an indole privileged scaffold [20].
the privileged structure category. Some piperazine
derivatives have pharmacological and therapeutic
properties including ligands for melanocortin-4 receptors
[21], farnesyltransferase and geranylgeranyl transferase-I
inhibitory activity [22], and D2/D4 receptor antagonists
[23].
we disclose our new synthetic method to novel 1-(1H-
tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]
indoles derivatives (Fig. 3).
RESULTS AND DISCUSSION
On the basis of the documented biological properties
such as an inhibition of protein kinase C [24], 5-HT2A, 5-
HT2C agonist [25,26], and antibacterial and antifungal
activities [27] of heterocyclic compounds containing the
1,2,3,4-tetrahydropyrazino[1,2-a] indole scaffolds, we
became interested in the synthesis of novel fused
heterocycles encompassing fused bioactive indole as well
as piperazine moieties.
In continuation of our previous approaches to the
synthesis of pyrazino[1,2-a] benzimidazoles [28],
indoloketopiperazines [29], 2,6-diketopiperazines [30], N,
N0-disubstituted piperazines [31], 1-(1H-tetrazol-5-yl)-
1,2,3,4-tetrahydropyrrolo[1,2-a] pyrazine derivatives [32],
tetazoles [33], and bis-tetrazolopiperazines [34], herein,
Initially, 3-chloro-1H-indole-2-carbaldehyde
2 was
prepared using the previously reported procedures
(Scheme 1) [35]. In the next step, N-alkylation of 2 with
1,2-dibromoethane or 1,2 dichloroethane as indicated in
Scheme 1 afforded 1-(2-bromoethyl)-3-chloro-1H-indole-
2-carbaldehyde 3a and 3-chloro-1-(2-chloroethyl)-1H-
indole-2-carbaldehyde 3b in 77% and 93% yields,
respectively [36].
To optimize reaction conditions, condensation of
bifunctional starting material 3a with benzylamine, tert-
butyl isocyanide, and trimethylsilyl azide (TMSN3) was
selected as a model to investigate the one-pot four-
component Ugi-azide reaction in methanol at room
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An Efficient Ugi-Azide Four-Component Approach for the Preparation of Novel
1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] Indoles
Figure 3. 1-(1H-Tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] indole containing indole and piperazine privileged structures. [Color figure
can be viewed at wileyonlinelibrary.com]
Scheme 1. Synthesis of compounds 3a and 3b.
temperature (RT) (Scheme 2). Product 5a was obtained in
Scheme 2. Synthesis of 5a via four-component Ugi-azide reaction.
31% yield within 12 h (entry 1, Table 1). Whereas
increasing the reaction time or temperature partially
improved the yields (entries 2–3, Table 1), utilization of
sodium azide instead of TMSN3 significantly enhanced
the yield of 5a to 44% (entry 4, Table 1). The higher
nucleophilicity of NaN3 in comparison with that of
TMSN3 seems to be responsible for the formation of 5a
in higher yield. Surprisingly, 5a was obtained in 70%
Table 1
yield when 3a initially was stirred with benzylamine in
methanol for 1 h at RT, followed by addition of
Optimization of reaction conditions.a
isocyanide and sodium azide (entry 5, Table 1). Such
Time
(h)
Temperature
(°C)
Yield
(%)b
Ugi-azide method has been reported by others and us
previously [32,37,38] since reaction presumably
proceeds via the formation of iminium ion 4 (Scheme 3).
On the other hand, 5a was obtained in 28% yield when
1-(2-chloroethyl)-3-chloro-1H-indole-2-carbaldehyde 3b
was used in the Ugi-azide reaction (entry 6, Table 1).
Compared with 1-(2-bromoroethyl)-3-chloro-1H-indole-2-
carbaldehyde 3a, which affords 5a and NaBr in higher
yields, utilization of 1-(2-chlorooethyl)-3-chloro-1H-
indole-2-carbaldehyde 3a furnishes 5a and NaCl more
slowly because Clꢀ is a rather weaker leaving group than
that of Brꢀ.
Entry
Aldehyde
1
2
3a
3a
3a
3a
3a
3b
12
24
12
12
12
12
RT
RT
40
RT
RT
RT
31
33
30
44
70
28
3
4c
5d
6
RT, room temperature.
aReaction conditions: All reactions were carried out using 1-(2-
bromoethyl) 3-chloro-1H-indole-2-carbaldehyde 3a (0.50 mmol),
benzylamine (0.50 mmol), tert-butyl isocyanide (0.55 mmol), TMSN3
(0.55 mmol), and MeOH (3 mL).
bIsolated yields.
cNaN3 was used instead of TMSN3.
dUsing a two-step procedure: initial stirring a mixing of 3a with
benzylamine in MeOH for 1 h, followed by addition of isocyanide and
TMSN3 or NaN3.
This new method was then applied to a reaction of 3a
with a variety of commercially available primary amines,
isocyanides, and sodium azide. The novel 1-(1H-tetrazol-
Scheme 3. Transformation of 3a to 5a through intermediate 4.
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5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino [1,2-a] indole
derivatives 5a–j were obtained in moderate to high yields
(Scheme 4 and Table 2). As indicated in Table 2,
whereas the Ugi-azide reactions with stronger benzylic
amines afforded the corresponding products in significant
yields (5a–e, Table 2), those with weaker aromatic
amines resulted in the desired products in rather lower
yields (5f–j, Table 2).
Scheme 4. Synthesis of novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-
tetrahy-dropyrazino[1,2-a] indole derivatives 5a–j.
Scheme 5. Synthesis of novel 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-
tetrahy-dropyrazino[1,2-a] indole derivatives 5k–o.
Table 2
Synthesis of 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] indoles 5a–j.a
aReaction conditions: All reactions were carried out using a two-step procedure as depicted in Scheme 3 with 1-(2-bromoethyl)-3-chloro-1H-indole-2-
carbaldehyde 3a (0.5 mmol), amine or amine source (0.5 mmol), isocyanide (0.55 mmol), NaN3 (0.55 mmol), and MeOH (3 mL) at RT for 12 h.
bStructure of 5a was confirmed by single-crystal X-ray diffraction analysis.
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An Efficient Ugi-Azide Four-Component Approach for the Preparation of Novel
1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] Indoles
Table 3
Synthesis of 1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] indoles 5k–o.a
aReaction conditions: All reactions were carried out using a two-step procedure as depicted in Scheme 3 with 1-(2-bromoethyl)-3-chloro-1H-indole-2-
carbaldehyde 3a (0.5 mmol), amine source (0.5 mmol), isocyanide (0.55 mmol), NaN3 (0.55 mmol), and MeOH (3 mL) at RT for 24 h.
bStructure of 5m was confirmed by single-crystal X-ray diffraction analysis.
Products 5k–o were then obtained in high yields when
this new method was applied to a reaction of 3a,
through
reactions (Scheme 6).
intramolecular
1,3-dipolar
cycloaddition
benzhydrazide
and
p-toluenesulfonyl
hydrazide,
isocyanides, and sodium azide. It was found that these
reactions proceed to completion within 24 h at RT
(Scheme 5 and Table 3).
CONCLUSION
All compounds were characterized by elemental
In summary, we have developed a practical and
convenient method for the synthesis of novel 1-(1H-
tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]
indoles via an Ugi-azide four-component approach in
moderate to high yields. These reactions presumably
proceed via the in situ generated iminium ion followed by
reaction with isocyanide and sodium azide. Simplicity,
greater efficiency, readily available chemicals, and prompt
isolation of the products with a generation of molecular
complexity are some advantages of this protocol. The
obtained novel privileged compounds broaden the
scaffolds that are prepared through the Ugi-azide
reactions, and many of them may represent interesting
pharmacophores. Study of the biological properties of the
1
analysis, MS, IR, and H and 13C NMR spectroscopy.
Unambiguous evidence for the proposed structures of 5a
[39] and 5m [40] was finally obtained by single-crystal
X-ray diffraction analysis, and the ORTEP diagrams are
shown in Figure 4.
The proposed mechanism for the Ugi-azide reaction is
illustrated in Scheme 6. The in situ generated iminium
ion 4 as the key intermediate from the condensation of
3a and amine undergoes nucleophilic reaction with
isocyanide to furnish nitrilium ion I (Scheme 6).
Subsequent addition of sodium azide to the nitrilium ion
I gives the azidoazomethine intermediate II. Finally, it
is transformed to the desired products 5a–j perhaps
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S. Salahi, M. Ghandi, and A. Abbasi
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Figure 4. ORTEP diagrams of compounds 5a and 5m [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.].
Scheme 6. Suggested mechanism for the formation of 5a–j.
prepared pyrazino[1,2-a] indole-based 1,5-disubstituted
tetrazoles is currently under investigation in our laboratory.
ATR–FTIR detection. 1H and 13C NMR spectra were
recorded on a Bruker DRX-300-ADVANCE spectrometer
(Bruker Corp.) at 300 MHz or Varian Unity INOVA
500 MHz using CDCl3 or DMSO-d6 as the solvent.
Chemical shifts (δ in ppm) are referenced to the solvent
CDCl3 (δ = 7.26 ppm for 1H and 77.0 ppm for 13C NMR).
Multiplicity abbreviations used for the chemical shifts are
as follows: s = singlet, d = doublet, t = triplet, q = quartet,
and m = multiplet. Mass spectra were recorded on an HP
(Agilent Technologies, Santa Clara, CA, USA) 5937 Mass
Selective Detector. Elemental analyses were performed
using a CHN-Rapid Heraeus elemental analyzer (Heraeus
Deutschland GmbH & Co. KG, Hanau, Germany).
EXPERIMENTAL
General information. The chemicals and reagents used
in this work were purchased from Merck Chemical
Company (Merck, Kenilworth, NJ) and used without
further purification. Melting points were obtained with an
electrothermal model 9100 apparatus and are uncorrected.
IR spectra were recorded using
a Bruker Alpha
spectrometer (Bruker Corp., Billerica, MA), with diamond
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Month 2019
An Efficient Ugi-Azide Four-Component Approach for the Preparation of Novel
1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] Indoles
Preparation method for the synthesis of compound 3a.
KOH (5.9 g, 100 mmol) was added in one portion to a
stirred solution of 3-chloro-1H-indole-2-carbaldehyde (2)
(1.8 g, 10 mmol) in dimethyl sulfoxide (DMSO) (10 mL)
at RT. After 1 h, Br (CH2)2Br (20 mL) was slowly added
at 0°C and the resulting solution stirred overnight at RT.
The reaction was quenched by addition of H2O (10 mL),
and the organic product was extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed
with brine (20 mL) and dried with Na2SO4. After
evaporation of the solvent under reduced pressure, the
crude product was purified by flash column
chromatography [SiO2, cyclohexane–EtOAc (9:1)] to
N, 5.79; O, 6.61. Found: C, 54.60; H, 3.71; Cl, 29.32;
N, 5.82; O, 6.60%.
General procedure for the synthesis of compounds 5a–o.
1-(2-Bromoethyl)-3-chloro-1H-indole-2-carbaldehyde 3a
(143 mg, 0.5 mmol) and primary amine (0.5 mmol) in
methanol (3 mL) were stirred for
1 h at RT.
Consequently, sodium azide (36 mg, 0.55 mmol) and
isocyanide (0.55 mmol) were added, and the reaction
mixture stirred for 23 h. After completion of the reaction
as indicated by thin-layer chromatography, the crude
product was collected by filtration and recrystallized from
acetonitrile to afford the desired solid products 5a–o.
2-Benzyl-1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-
give a yellow solid [36].
1,2,3,4-tetrahydropyrazino[1,2-a] indole (5a).
White solid
1-(2-Bromoethyl)-3-chloro-1H-indole-2-carbaldehyde
(3a). Yellow solid (2.2 g, 77%); mp 62–64°C; IR (KBr)
(149 mg, 71%); mp 121–123°C; IR (KBr) νmax: 3043,
2992, 2885, 2827, 1492, 1220, 1174, 1016, 813, 737,
698 cmꢀ1 1H NMR (300 MHz, DMSO): δ 1.78 (s,
;
ν
max: 3300, 2845, 2738, 1660, 1611, 1511, 1456, 1356,
890, 856, 742 cmꢀ1 1H NMR (300 MHz, CDCl3): δ
;
9H), 2.86 (dd, J1 = 14.0, J2 = 3.0 Hz, 1H), 3.25 (dt,
J1 = 15.0, J2 = 5.0 Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H),
4.06 (d, J = 13.0 Hz, 2H), 4.25 (dt, J1 = 12.1,
J2 = 4.7 Hz, 1H), 5.97 (s, 1H), 7.21 (t, J = 7.4 Hz,
1H), 7.30 (t, J = 7.9 Hz, 2H), 7.33–7.40 (m, 4H), 7.50
(d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 29.3, 37.4, 43.7, 51.1, 55.3,
62.2, 100.4, 110.3, 116.9, 120.7, 122.3, 124.2, 127.0,
127.6, 128.5, 129.0, 134.7, 137.1, 152.8 ppm; m/z (EI,
70 eV) 422 (15, M+), 420 (37, M+), 364 (15), 295 (74),
203 (44), 91 (100), 57 (22%); Anal. Calcd for
C23H25ClN6: C, 65.63; H, 5.99; Cl, 8.42; N, 19.97.
Found: C, 65.64; H, 5.96; Cl, 8.45; N, 19.99%.
3.64 (t, J = 6.7 Hz, 2H), 4.81 (t, J = 6.7 Hz, 2H), 7.21–
7.27 (m, 1H), 7.41–7.50 (m, 2H), 7.71 (d, J = 8.2 Hz,
1H), 10.12 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 30.2,
46.2, 110.8, 120.6, 120.7, 122.0, 124.3, 128.4, 128.6,
138.4, 180.8 ppm; m/z (EI, 70 eV) 287 (33, M+), 285
(26, M+), 206 (100), 192 (52), 178 (15), 164 (15), 150
(22), 123 (44), 114 (22), 89 (15%); Anal. Calcd for
C11H9BrClNO: C, 46.11; H, 3.17; Br, 27.88; Cl, 12.37;
N, 4.89; O, 5.58. Found: C, 46.13; H, 3.16; Br, 27.84;
Cl, 12.39; N, 4.91; O, 5.60%.
Preparation method for the synthesis of compound 3b.
1,2-Dichloroethane (10 mL), Bu4NI (1.02 g, 2.8 mmol),
and 50% aq NaOH (5 mL) were added to a solution of 3-
chloro-1H-indole-2-carbaldehyde (2) (0.500 g, 2.8 mmol)
in CH2Cl2 (2 mL), and the mixture was vigorously stirred
overnight. H2O (2 mL) was added, and the organic
product was extracted with CH2Cl2 (3 × 20 mL) and
washed with 1 M HCl (2 × 20 mL), saturated aqueous
NaHCO3 (2 × 20 mL), and brine (2 × 20 mL) and dried
with Na2SO4. After evaporation of the solvent under
reduced pressure, the crude product was purified by
column chromatography [SiO2, cyclohexane–EtOAc
(9:1)] to give a white solid [36].
2-Benzyl-10-chloro-1-(1-cyclohexyl-1H-tetrazol-5-yl)-
1,2,3,4-tetrahydropyrazino[1,2-a] indole (5b).
White solid
(165 mg, 74%); mp 116–118°C; IR (KBr) νmax: 3064,
3031, 2936, 2855, 1668, 1449, 1362, 1232, 1009, 739,
696 cmꢀ1 1H NMR (300 MHz, DMSO): δ 0.90–1.40
;
(m, 3H), 1.50–2.10 (m, 6H), 2.90–3.02 (m, 1H), 3.20–
3.35 (m, 1H), 3.78 (q, J = 13 Hz, 2H), 4.10–4.32 (m,
3H), 5.84 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.26–7.41 (m,
6H), 7.48 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 24.3, 24.5, 24.6, 32.0,
32.8, 43.1, 49.9, 55.8, 57.1, 100.5, 110.2, 117.0, 120.8,
122.5, 124.3, 126.1, 127.6, 128.6, 128.9, 134.6, 137.2,
152.1 ppm; m/z (EI, 70 eV) 448 (7, M+), 446 (22, M+),
315 (7), 295 (52), 203 (37), 91 (100), 55 (15%); Anal.
Calcd for C25H27ClN6: C, 67.18; H, 6.09; Cl, 7.93; N,
18.80. Found: C, 67.16; H, 6.10; Cl, 7.96; N, 18.84%.
3-Chloro-1-(2-chloroethyl)-1H-indole-2-carbaldehyde
(3b).
White solid (0.53 g, 93%); mp 76–78°C; IR
(KBr) νmax: 3060, 3025, 2960, 2726, 1660, 1612, 1510,
1345, 858, 745, 660 cmꢀ1
;
1H NMR (300 MHz,
J = 6.0 Hz, 2H), 4.86 (t,
DMSO): 3.92 (t,
δ
J = 6.0 Hz, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.50 (t,
J = 7.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.75 (d,
J = 8.6 Hz, 1H), 10.06 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 43.8, 45.6, 112.0, 118.0, 119.6, 122.0, 123.4,
128.2, 128.4, 138.1, 180.8 ppm; m/z (EI, 70 eV) 243
(37, M+), 241 (59, M+), 221 (44), 206 (88), 192 (100),
177 (30), 164 (30), 123 (88), 114 (22), 77 (37%); Anal.
Calcd for C11H9Cl2NO: C, 54.57; H, 3.75; Cl, 29.29;
10-Chloro-1-(1-cyclohexyl-1H-tetrazol-5-yl)-2-(4-
methylbenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a] indole (5c).
White solid (161 mg, 70%); mp 131–133°C; IR (KBr)
ν
max: 3056, 2935, 2854, 1612, 1475, 1363, 1312, 1179,
1
1099, 806, 747 cmꢀ1; H NMR (300 MHz, DMSO): δ
0.90–1.40 (m, 3H), 1.50–2.10 (m, 7H), 2.29 (s, 3H),
2.90–3.02 (m, 1H), 3.10–3.21 (m, 1H), 3.73 (q,
J = 13 Hz, 2H), 4.12–4.30 (m, 3H), 5.78 (s, 1H), 7.00–
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7.27 (m 5H), 7.29 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 7.8 Hz,
1H), 7.57 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 20.7, 24.3, 24.4, 24.5, 31.9, 32.8, 38.3, 43.1, 49.6, 55.5,
57.0, 100.5, 110.2, 116.9, 120.8, 122.5, 124.3, 126.1,
129.0, 129.2, 134.1, 134.6, 136.9, 152.2 ppm; m/z (EI,
70 eV) 462 (7, M+), 460 (22, M+), 308 (52), 205 (22),
203 (44), 146 (15), 105 (100%); Anal. Calcd for
C26H29ClN6: C, 67.74; H, 6.34; Cl, 7.69; N, 18.23.
J = 12.0 Hz, 1H), 4.21 (d, J = 9.0 Hz, 1H), 6.57 (s, 1H),
6.97 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.17–
7.32 (m, 4H), 7.51 (dd, J1 = 11.9, J2 = 7.5 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 29.0, 37.6, 43.4, 48.0, 62.5,
100.5, 110.3, 117.1, 119.1, 120.9, 122.3, 122.5, 124.0,
126.6, 129.8, 134.8, 147.0, 152.3 ppm; m/z (EI, 70 eV)
408 (7, M+), 406 (15, M+), 350 (15), 281 (100), 245
(15), 205 (15), 192 (15), 123 (7), 104 (15), 77 (30%);
Anal. Calcd for C22H23ClN6: C, 64.94; H, 5.70; Cl,
8.71; N, 20.65. Found: C, 64.93; H, 5.70; Cl, 8.73; N,
Found: C, 67.70; H, 6.36; Cl, 7.72; N, 18.20%.
2-Benzyl-10-chloro-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-
tetrazol-5-yl)-1,2,3,4-tetrahydropyrazino[1,2-a] indole (5d).
20.66%.
White solid (184 mg, 77%); mp 110–112°C; IR (KBr)
1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-2-(p-tolyl)-
1,2,3,4-tetrahydropyrazino[1,2-a] indole (5g).
(111 mg, 53%); mp 174°C decompose; IR (KBr) νmax
White solid
ν
max: 2952, 1666, 1608, 1359, 1223, 1113, 920, 740,
701 cmꢀ1; H NMR (500 MHz, DMSO): δ 0.80 (s, 9H),
1.77 (s, 3H), 1.88 (s, 3H), 1.98 (d, J = 15.1 Hz, 1H),
2.19 (d, J = 15.1 Hz, 1H), 2.96 (dd, J1 = 14.2,
J2 = 4.0 Hz, 1H), 3.17–3.26 (m, 1H), 3.88 (d,
J = 13.1 Hz, 1H), 4.00 (d, J = 13.1 Hz, 1H), 4.11 (dd,
J1 = 12.2, J2 = 4.7 Hz, 1H), 4.25 (Sextet, J = 4.9 Hz,
1H), 5.93 (s, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.29–7.34 (m,
2H), 7.35–7.43 (m, 4H), 7.52 (d, J = 7.8 Hz, 1H), 7.59
(d, J = 8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
29.8, 29.9, 30.8, 31.7, 35.7, 51.2, 53.2, 55.7, 66.4, 101.0,
110.8, 117.4, 121.2, 122.8, 124.7, 127.5, 128.2, 129.0,
129.9, 135.4, 137.2, 153.4 ppm; m/z (EI, 70 eV) 478 (2,
M+), 476 (7, M+), 364 (15), 295 (52), 203 (37), 168 (15),
91 (100%); Anal. Calcd for C27H33ClN6: C, 67.98; H,
6.97; Cl, 7.43; N, 17.62. Found: C, 68.01; H, 6.98; Cl,
1
:
3060, 2981, 2884, 1725, 1666, 1513, 1454, 1414, 1172,
1
808, 740 cmꢀ1; H NMR (300 MHz, DMSO): δ 1.68 (s,
9H), 2.18 (s, 3H), 3.36–3.67 (m, 2H), 3.89–4.05 (m, 1H),
4.10–4.23 (m, 1H), 6.48 (s, 1H), 6.98 (d, J = 8.3 Hz,
2H), 7.09 (d, J = 8.3 Hz, 2H), 7.17–7.27 (m, 2H), 7.46–
7.53 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 20.1, 29.0,
38.7, 43.7, 48.2, 62.5, 100.5, 110.3, 117.1, 119.3, 120.9,
122.5, 124.1, 126.7, 130.2, 131.4, 134.8, 144.7,
152.4 ppm; m/z (EI, 70 eV) 422 (7, M+), 420 (15, M+),
364 (15), 297 (37), 295 (100), 259 (15), 188 (22), 154
(15), 118 (15), 91 (37%); Anal. Calcd for C23H25ClN6:
C, 65.63; H, 5.99; Cl, 8.42; N, 19.97. Found: C, 65.62;
H, 6.01; Cl, 8.45; N, 19.96%.
1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-2-(4-
chlorophenyl)-1,2,3,4-tetrahydropyrazino[1,2-a] indole (5h).
7.45; N, 17.66%.
White solid (123 mg, 56%); mp 175°C decompose; IR
10-Chloro-2-(4-methylbenzyl)-1-(1-(2,4,4-trimethylpentan-2-
yl)-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrazino [1,2-a] indole
(5e). White solid (179 mg, 73%); mp 115–117°C; IR
(KBr) νmax: 3057, 2963, 2930, 1721, 1593, 1493, 1358,
1211, 1106, 823, 741 cmꢀ1 1H NMR (300 MHz,
;
(KBr) νmax: 2952, 1511, 1457, 1361, 1271, 1221, 1172,
DMSO): δ 1.69 (s, 9H), 3.34–3.73 (m, 2H), 4.06 (d,
J = 12.5 Hz, 1H), 4.19–4.23 (m, 1H), 6.54 (s, 1H), 7.08–
7.28 (m, 4H), 7.33 (d, J = 8.7 Hz, 2H), 7.50 (t,
J = 8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 29.0,
37.6, 43.5, 48.0, 62.5, 100.7, 110.3, 117.1, 120.1, 122.5,
124.0, 126.1, 126.2, 129.5, 134.8, 146.0, 152.2 ppm; m/z
(EI, 70 eV) 442 (7, M+), 440 (10, M+), 317 (59), 315
(100), 279 (7), 188 (22), 154 (15), 140 (15), 111 (22), 57
(44%); Anal. Calcd for C22H22Cl2N6: C, 59.87; H, 5.02;
Cl, 16.06; N, 19.04. Found: C, 59.90; H, 5.00; Cl, 16.07;
1
1116, 978, 831, 745 cmꢀ1; H NMR (500 MHz, DMSO):
δ 0.81 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 1.97 (d,
J = 15.1 Hz, 1H), 2.19 (d, J = 15.1 Hz, 1H), 2.31 (s,
3H), 2.98 (d, J = 10.9 Hz, 1H), 3.20–3.26 (m, 1H), 3.83
(d, J = 12.9 Hz, 1H), 3.91 (d, J = 12.9 Hz, 1H), 4.09 (dd,
J1 = 12.2, J2 = 5.1 Hz, 1H), 4.24 (Sextet, J = 5.0 Hz,
1H), 5.89 (s, 1H), 7.18–7.26 (m, 5H), 7.31 (t, J = 7.3 Hz,
1H), 7.52 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 21.2, 29.7, 29.9, 30.8,
31.7, 35.7, 51.1, 53.1, 55.5, 66.4, 101.0, 110.8, 117.4,
121.2, 122.7, 124.7, 127.5, 129.5, 129.9, 134.1, 135.4,
137.5, 153.4 ppm; m/z (EI, 70 eV) 492 (3, M+), 490
(7, M+), 378 (15), 308 (52), 245 (7), 203 (44), 105
(100%); Anal. Calcd for C28H35ClN6: C, 68.48; H, 7.18;
Cl, 7.22; N, 17.11. Found: C, 68.45; H, 7.20; Cl, 7.25;
N, 19.03%.
10-Chloro-1-(1-cyclohexyl-1H-tetrazol-5-yl)-2-phenyl-
1,2,3,4-tetrahydropyrazino[1,2-a] indole (5i).
White solid
(119 mg, 55%); mp 183°C decompose; IR (KBr) νmax
:
3053, 2934, 2860, 1594, 1489, 1446, 1226, 1088, 961,
1
741, 700 cmꢀ1; H NMR (500 MHz, DMSO): δ 0.80–
2.15 (m, 10H), 3.75–3.90 (m, 2H), 4.8 (Sextet,
J = 5.0 Hz, 1H), 4.42–4.55 (m, 2H), 6.92–7.02 (m, 2H),
7.21 (t, J = 7.5 Hz, 1H), 7.25–7.35 (m, 5H), 7.50 (d,
J = 7.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 24.9, 25.2, 33.0, 33.2, 41.2, 42.5,
49.2, 57.7, 100.1, 110.8, 117.5, 120.5, 121.3, 122.9,
123.0, 124.8, 127.9, 129.8, 134.8, 148.4, 152.1 ppm; m/z
N, 17.14%.
1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-2-phenyl-
1,2,3,4-tetrahydropyrazino[1,2-a] indole (5f).
White solid
(116 mg, 57%); mp 181°C decompose; IR (KBr) νmax
3055, 2992, 2885, 2952, 2879, 1596, 1452, 1356, 1116,
737, 702 cmꢀ1 1H NMR (300 MHz, DMSO): δ 1.68
(s, 9H), 3.70 (quint, J = 12.0 Hz, 2H), 4.06 (d,
:
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient Ugi-Azide Four-Component Approach for the Preparation of Novel
1-(1H-tetrazol-5-yl)-10-chloro-1,2,3,4-tetrahydropyrazino[1,2-a] Indoles
(EI, 70 eV) 434 (7, M+), 432 (30, M+), 281 (100), 245 (15),
188 (15), 154 (7), 104 (15), 77 (30%); Anal. Calcd for
C24H25ClN6: C, 66.58; H, 5.82; Cl, 8.19; N, 19.41.
Found: C, 66.60; H, 5.82; Cl, 8.17; N, 19.44%.
10-Chloro-1-(1-cyclohexyl-1H-tetrazol-5-yl)-2-(4-
43.6, 53.9, 63.8, 99.5, 110.4, 117.0, 120.9, 122.6, 124.3,
127.7, 128.0, 129.9, 134.1, 135.6, 143.9, 150.9 ppm; m/z
(EI, 70 eV) 501 (1, M+), 499 (3, M+), 315 (7), 260 (30),
192 (37), 190 (100), 154 (22), 139 (30), 91 (44), 57
(44%); Anal. Calcd for C23H26ClN7O2S: C, 55.25; H,
5.24; Cl, 7.09; N, 19.61; O, 6.40; S, 6.41. Found: C,
55.22; H, 5.25; Cl, 7.11; N, 19.59; O, 6.43; S, 6.40%.
N-(10-Chloro-1-(1-cyclohexyl-1H-tetrazol-5-yl)-3,4-
dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-
methoxyphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]
(5j).
indole
White solid (111 mg, 48%); mp 177°C
decompose; IR (KBr) νmax: 2923, 2853, 1609, 1507,
1447, 1222, 1029, 836, 740, 634 cmꢀ1 1H NMR
;
(500 MHz, DMSO): δ 0.79 (d, J = 11.0 Hz, 1H), 1.08 (q,
J = 12.7 Hz, 1H), 1.17 (q, J = 12.7 Hz, 1H), 1.43 (q,
J = 12.6 Hz, 1H), 1.53 (q, J = 12.8 Hz, 1H), 1.62 (d,
J = 11.1 Hz, 2H), 1.760 (t, J = 11.8 Hz, 1H), 1.82 (d,
J = 15.1 Hz, 1H), 2.07 (t, J = 8.7 Hz, 1H), 3.60 (d,
J = 11.9 Hz, 1H), 3.69 (s, 3H), 3.85 (t, J = 9.8 Hz, 1H),
4.11 (Sextet, J = 3.7 Hz, 1H), 4.35 (t, J = 11.1 Hz, 1H),
4.49 (d, J = 11.3 Hz, 1H), 6.76 (s, 1H), 6.87 (d,
J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.21 (t,
J = 7.4 Hz, 1H) 7.30 (t, J = 7.4 Hz, 1H), 7.49 (d,
J = 7.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 24.9, 25.1 25.2, 32.7, 33.3, 41.7,
43.8, 50.3, 55.8, 57.6, 99.8, 110.7, 114.9, 117.4, 121.3,
122.9, 123.2, 124.8, 128.3, 134.7, 142.0, 151.8,
156.1 ppm; m/z (EI, 70 eV) 464 (7, M+), 462 (22, M+),
313 (37), 311 (100), 275 (7), 190 (15), 154 (15), 123
(22), 83 (7%); Anal. Calcd for C25H27ClN6O: C, 64.86;
H, 5.88; Cl, 7.66; N, 18.15; O, 3.46. Found: C, 64.87; H,
methylbenzenesulfonamide (5m).
White solid (197 mg,
75%); mp 151–153°C; IR (KBr) νmax: 3315, 3100, 2943,
2859, 1450, 1339, 1165, 1092, 1020, 831, 750 cmꢀ1; H
1
NMR (300 MHz, DMSO): δ 0.90–1.40 (m, 3H), 1.50–
2.20 (m, 7H), 2.40 (s, 3H), 3.00–3.40 (m, 2H), 3.95 (s,
1H), 4.19 (s, 1H), 4.80 (s, 1H), 5.98 (s, 1H), 7.18 (t,
J = 7.7 Hz, 1H), 7.27 (t, J = 7.1 Hz, 1H), 7.40–7.55 (m,
4H), 7.74 (d, J = 8.0 Hz, 2H), 9.42 (s, 1H, NH); 13C
NMR (75 MHz, CDCl3) δ 21.1, 24.5, 24.8, 24.9, 32.4,
33.0, 46.7, 48.6, 57.5, 100.1, 110.3, 117.0, 120.9, 122.7,
124.3, 126.6, 127.5, 129.8, 134.2, 135.5, 143.9,
150.5 ppm; m/z (EI, 70 eV) 527 (1, M+), 525 (3, M+),
341 (15), 260 (22), 192 (37), 190 (100), 154 (37), 91
(37), 55 (44%); Anal. Calcd for C25H28ClN7O2S: C,
57.08; H, 5.37; Cl, 6.74; N, 18.64; O, 6.08; S, 6.09.
Found: C, 57.10; H, 5.38; Cl, 6.72; N, 18.66; O, 6.05; S,
6.11%.
N-(10-Chloro-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-
5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)
(5n). White solid (209 mg, 83%); mp 125–127°C; IR
benzamide
5.91; Cl, 7.65; N, 18.18; O, 3.49%.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-3,4-
dihydropyrazino[1,2-a]indol-2(1H)-yl) benzamide (5k).
(KBr) νmax: 3377, 3186, 2943, 2957, 1661, 1538, 1411,
1358, 1278, 1097, 1023, 916, 746, 706 cmꢀ1; H NMR
1
White solid (182 mg, 81%); mp 140–142°C; IR (KBr)
(300 MHz, DMSO): δ 0.82 (s, 9H), 1.88 (s, 6H), 2.06
(bs, 1H), 2.24 (bs, 1H), 3.54 (bs, 2H), 4.30 (bs, 2H), 6.26
(s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.1 Hz, 1H),
7.40–7.58 (m, 5H), 7.75 (d, J = 6.0 Hz, 2H), 10.25 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 29.0, 29.1, 30.5,
31.3, 35.6, 48.6, 53.4, 66.7, 100.0, 110.3, 116.8, 120.8,
122.3, 124.4, 126.9, 127.7, 128.1, 131.4, 133.4, 151.9,
165.1 ppm; m/z (EI, 70 eV) 505 (2, M+), 449 (2), 384
(9), 324 (5), 301 (9), 272 (18), 244 (27), 209 (9), 188
(18), 121 (54), 105 (100), 57 (100%); Anal. Calcd for
C27H32ClN7O: C, 64.08; H, 6.37; Cl, 7.01; N, 19.38; O,
3.16. Found: C, 64.12; H, 6.40; Cl, 6.59; N, 19.37; O,
ν
max: 3375, 3188, 2980, 1662, 1537, 1455, 1279, 1024,
917, 748, 702 cmꢀ1 1H NMR (300 MHz, DMSO): δ
;
1.71 (s, 9H), 3.60 (bs, 2H), 4.31 (bs, 2H), 6.29 (s, 1H),
7.20 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.1 Hz, 1H), 7.40–
7.54 (m, 4H), 7.59 (d, J = 8.1 Hz, 1H), 7.69 (bs, 2H),
10.21 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 29.5, 38.7,
43.6, 48.6, 62.5, 100.5, 110.4, 117.1, 119.3, 120.8,
124.5, 127.2, 127.5, 128.2, 131.5, 133.3, 144.7, 152.4,
164.8 ppm; m/z (EI, 70 eV) 449 (3, M+), 346 (4), 330
(15), 328 (44), 272 (15), 244 (22), 218 (52), 203 (22),
190 (22), 105 (100), 77 (52), 57 (22%); Anal. Calcd for
C23H24ClN7O: C, 61.40; H, 5.38; Cl, 7.88; N, 21.79; O,
3.56. Found: C, 61.41; H, 5.41; Cl, 7.85; N, 21.77; O,
3.13%.
N-(10-Chloro-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-
5-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-
3.57%.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-10-chloro-3,4-
dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-
methylbenzenesulfonamide (5o).
White solid (197 mg,
71%); mp 157–159°C; IR (KBr) νmax: 3117, 2952, 2871,
methylbenzenesulfonamide (5l).
White solid (182 mg,
73%); mp 148–150°C; IR (KBr) νmax: 3056, 2992, 2884,
2786, 1598, 1452, 1370, 1344, 1232, 1163, 752 cmꢀ1
1596, 1452, 1370, 1239, 1164, 1094, 812, 743,
1
671 cmꢀ1; H NMR (300 MHz, DMSO): δ 0.88 (s, 9H),
;
1H NMR (300 MHz, DMSO): δ 1.91 (s, 9H), 2.40 (s,
4H), 3.59 (s, 1H), 3.85 (s, 1H), 4.26 (s, 1H), 6.33 (s,
1H), 7.17 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.1 Hz, 1H),
7.42–7.50 (m, 4H), 7.35 (d, J = 8.0 Hz, 2H), 9.33 (s, 1H,
NH); 13C NMR (75 MHz, CDCl3) δ 21.1, 30.2, 37.4,
2.00 (s, 3H), 2.07 (s, 3H), 2.20–2.34 (m, 2H), 2.35–2.55
(m, 4H), 3.55 (bs, 1H), 3.85 (bs, 1H), 4.25 (d,
J = 8.9 Hz, 1H), 6.29 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H),
7.28 (t, J = 7.8 Hz, 1H), 7.35–7.60 (m, 4H), 7.75 (d,
J = 8.1 Hz, 2H), 9.31 (s, 1H); 13C NMR (75 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Salahi, M. Ghandi, and A. Abbasi
Vol 000
[22] Dinsmore, C. J.; Zartman, C. B.; Bergman, J. M.; Abrams, M.
T.; Buser, C. A.; Culberson, J. C.; Davide, J. P.; Ellis-Hutchings, M.;
Fernandes, C.; Graham, S. L.; Hartman, G. D.; Huber, H. E.; Lobell, R.
B.; Mosser, S. D.; Robinson, R. G.; Williams, T. M. Bioorg Med Chem
Lett 2004, 14, 639.
[23] Zhao, H.; Thurkauf, A.; He, X.; Hodgetts, K.; Zhang, X.;
Rachwal, S.; Kover, R. X.; Hutchison, A.; Peterson, J.; Kieltyka, A.;
Brodbeck, R.; Primus, R.; Wasley, J. W. F. Bioorg Med Chem Lett
2002, 12, 3105.
[24] Bit, R. A.; Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.;
Keech, E.; Kumar, H.; Lawton, G.; Maw, A.; Nixon, J. S.; Vesey, D. R.;
Wadsworth, J.; Wilkinson, S. E. J Med Chem 1993, 36, 21.
[25] Bös, M.; Jenck, F.; Martin, J. R.; Moreau, J. L.; Mutel, V.;
Sleight, A. J.; Widmer, U. Eur J Med Chem 1997, 32, 253.
[26] Chang-Fong, J.; Addo, J.; Dukat, M.; Smith, C.; Mitchell, N.
A.; Herrick-Davis, K.; Teitler, M.; Glennon, R. A. B. Bioorg Med Chem
Lett 2002, 12, 155.
CDCl3) δ 21.1, 28.8, 29.1, 30.6, 31.4, 35.7, 44.4, 54.4,
67.5, 99.7, 110.4, 117.0, 120.9, 122.7, 124.2, 127.6,
129.8, 134.5, 135.7, 143.9, 150.0 ppm; m/z (EI, 70 eV)
555 (1, M+), 371 (9), 259 (18), 190 (45), 156 (18), 139
(14), 113 (27), 97 (41), 57 (100%); Anal. Calcd for
C27H34ClN7O2S: C, 58.31; H, 6.16; Cl, 6.37; N, 17.63;
O, 5.75; S, 5.76. Found: C, 58.30; H, 6.18; Cl, 6.36; N,
17.61; O, 5.72; S, 5.77%.
Acknowledgment. We acknowledge the University of Tehran for
financial support of this research.
[27] Tiwari, R. K.; Verma, A. K.; Chhillar, A. K.; Singh, D.; Singh,
J.; Kasi Sankar, V.; Yadav, V.; Sharma, G. L.; Chandra, R. Bioorg Med
Chem 2006, 14, 2747.
REFERENCES AND NOTES
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[3] Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53.
[4] Domling, A.; Ugi, I. Angew Chem Int Edit Engl 2000, 39, 3168.
[5] Barreto, A. F. S.; Dos Santos, V. A.; Andrade, C. K. Z.
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TMSN3-Ugi Reaction; University of Groningen, 2016.
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[39] Copies of these, data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or, from the Cambridge Crys-
tallographic Data Centre, 12Union Road, Cambridge, CB2 1EZ, UK; fax:
þ44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk). The CCDC depo-
sition number for compound 5a is 1851772. Formula: C23H25Cl1N6. Unit
cell parameters: a 15.367(3) b 23.336(5) c 13.461(3) Pccn.
[40] Copies of these, data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or, from the Cambridge Crys-
tallographic Data Centre, 12Union Road, Cambridge, CB2 1EZ, UK; fax:
þ44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk). The CCDC depo-
sition number for compound 5m is 1851773. Formula: C25H28ClN7O2S.
Unit cell parameters: a 16.551(3) b 9.1966(18) c 20.251(8) P21/c.
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SUPPORTING INFORMATION
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet