Synthesis of Novel Hybrid 4 H -Pyran-lipoic and 4 H -Pyran-azetidine Derivatives

Article abstract of DOI:10.1055/s-0036-1591730

In this study, a molecular hybridization strategy was used to design and synthesize two novel series of hybrid compounds: 4 H -pyran-lipoic and 4 H -pyran-azetidine, employing ammonium hydroxide and involving the participation of aldehydes, malononitrile, and compounds derived from β-ketoesters to obtain the products with good yields.

Full text of DOI:10.1055/s-0036-1591730

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
F. Hernández-Borja et al.
Paper
Synthesis
Synthesis of Novel Hybrid 4H-Pyran-lipoic and 4H-Pyran-azetidine
Derivatives
Fernando Hernández-Borjaa
Leticia Contrerasa
Julio Lópeza
Yolanda Alcarazb
David Cruza
Samuel Estrada-Sotoc
Francisco Delgadod
Miguel A. Vázquez*a
a Departamento de Química, Universidad de Guanajuato,
Noria Alta s/n, Guanajuato, Gto. CP. 36050, México
mvazquez@ugto.mx
b Departamento de Farmacia, Universidad de Guanajuato,
Noria Alta s/n, Guanajuato, Gto., CP. 36050, México
c Facultad de Farmacia, Universidad Autónoma del Estado de
Morelos, Av. Universidad 1001, Col. Camilpa, Cuernavaca,
Morelos, CP. 62209, México
d Departamento de Química Orgánica, Escuela Nacional de
Ciencias Biológicas, Instituto Politécnico Nacional, Prol
Carpio y Plan de Ayala s/n, Cuidad de México, CP. 11340, México
Received: 03.08.2017
Accepted after revision: 27.10.2017
Published online: 23.11.2017
the azetidine core, for instance, propranolol-azetidine de-
rivatives (5),11 fluoroquinolones-azetidine (6),12 and 1,4-di-
hydropyridine-azetidine (azelnidipine) (7);13 some of these
compounds are in the preclinical phase while another priv-
ileged group is already used for the treatment of some dis-
eases (Figure 1).
DOI: 10.1055/s-0036-1591730; Art ID: ss-2017-m0506-op
Abstract In this study, a molecular hybridization strategy was used to
design and synthesize two novel series of hybrid compounds: 4H-pyran-
lipoic and 4H-pyran-azetidine, employing ammonium hydroxide and in-
volving the participation of aldehydes, malononitrile, and compounds
derived from β-ketoesters to obtain the products with good yields.
On the other hand, various studies have shown that the
4H-pyran core exhibits a wide range of biological activities
such as antibacterial,14 antiproliferative,15 antipyretic,16 and
anti-inflammatory activity.17 Our research group has con-
ducted previous studies regarding this core, showing that
this skeleton has vasorelaxant activity.18,19 Furthermore, it
was demonstrated that if an electron-withdrawing group
was incorporated into the structure, the biological activity
can be increased. Their physiological mechanism was also
determined and found to proceed through inhibitors of cal-
cium channels.20 Likewise, some studies revealed that if an
ester group was modified in a base structure, the biological
activity could be affected.21,22 In contrast, the increase of
the chain size of different esters drastically changed the sta-
bility of the compound in the presence of enzymes.23
According to this background, the syntheses of two new
series of hybrid compounds were performed in the present
work; the first one includes a fragment of lipoic acid at-
tached to a 4H-pyran core and the second corresponds to
4H-pyran-azetidine derivatives. By applying this modifica-
tion and varying the ester size, it was expected that a clear
correlation would be found between structure and biologi-
cal activity of the molecules. Addressing the approaches to
obtain them, the multi-component reaction (MCR) strategy
is considered a convenient option24 because it provides
both high selectivity and atomic economy of the products.
Key words molecular hybridization, multicomponent reaction, 4H-
pyran-lipoic, 4H-pyran-azetidine core
One of the current trends in organic and medicinal
chemistry fields is the design, synthesis, and development
of novel potential drugs. Such compounds should present
better pharmacological properties for the treatment of ill-
nesses and also exhibit low toxicity. One of the strategies
employed to generate these types of compounds has been
the use of molecular hybridization (MH), which is based ei-
ther on the combination of different pharmacophoric frag-
ments already studied or on the combination of various
substances with previously known biological activity; this
union generates a new hybrid compound which can have a
better activity than its predecessor.1
Several methodologies have been reported on the appli-
cations of MH to generate new hybrid compounds,2–6 some
of which concern the synthesis of hybrid compounds using
lipoic acid, for example, tacrine-lipoic (1),7 polyphenols-li-
poic (2),8 ibuprofen-lipoic (3),9 and Trolox-lipoic (4).10 In
these reports, the compounds exhibited improved biologi-
cal activity compared with those of the starting com-
pounds. There are also reports on hybrid compounds using
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
F. Hernández-Borja et al.
Paper
Synthesis
O
H
O
O
AcO
N
S
O
4
2
S
2 NH
N
4
O
S
H
S
AcO
2
3
Neuroprotective activity
Butyrylcholinesterase inhibitors
Ibuprofen
analogues
Caffeic acid
analogues
OH
HN
3 NH
4
H
N
Trolox
analogues
O
S
Tacrine
analogues
S
O
4
S
OH
S
S
S
O
Cl
N
4
1
Cardioprotective activity
Alzheimer’s disease
Propranolol
analogues
HN
Nifedipine
analogues
NO2
O
Ciprofloxacin
analogues
O
O
O
N
OH
N
O
N
O
N
NH2
O
N
O
F
H
F
5
OH
7
Relaxant activity
Cardiovascular disease
N
HO
N
H2N
F
6
Antibiotic activity
Figure 1 Examples of hybrid compounds
These features have motivated an interest to extend its ap-
plication not only for pyran scaffolds but also other classes
of cores.25–27
To obtain the target compounds 12 and 13, the synthet-
ic route used is depicted in Scheme 1. Compounds 8 and 9
were accomplished by using published methodologies.
Based on the above considerations, alcohol 8 was obtained
by reduction of lipoic acid using lithium aluminum hydride
(LAH) and tetrahydrofuran as solvent; after that, disulfide
bond formation was carried out using copper chloride in an
ethanol/water mixture. The yields of compound 8 were
similar to those already reported.28
Formation of alcohol 9 was carried out through reaction
between diphenylmethanamine and epichlorohydrin as the
first step, the mixture was stirred with isopropanol at room
temperature to generate the epoxide opening product;
upon completion of this reaction (TLC), the solvent was
evaporated and an acetonitrile/methanol mixture was add-
ed in combination with triethylamine as base, then heated
to reflux until 9 was obtained in equal yields as reported.29
OH
O
Ar
O
4
CN
O
O
O
O
S
S
b
8
S
RO
S
NH2
O
O
10
11
12
a
O
O
b
O
Ar
N
RO
Ph
Ph
CN
O
N
OH
O
NH2
9
13
Scheme 1 Reagents and conditions. (a) I2 (30 mol%), PhMe, reflux, 12 h; (b) ArCHO, malononitrile, NH4OH (10 mol%), MeCN, r.t., 2 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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F. Hernández-Borja et al.
Paper
Synthesis
To obtain compounds 10 and 11, a transesterification
reaction was used, in which ethyl acetoacetate was reacted
with the corresponding alcohol (8/9) using molecular io-
dine as catalyst and toluene as solvent.30 The mixture was
heated at reflux and, after 12 hours, the corresponding 1,3-
dicarbonyl compound was formed in 80 and 75% yield, re-
spectively. Before continuing, both were characterized by
NMR spectroscopic analysis and other techniques, showing
distinctive signals for each one.
Our research group previously reported the synthesis of
4H-pyrans using infrared irradiation.24 Based on this, we
wanted to obtain the desired compounds by a MCR in
which an aldehyde, malononitrile, and a 1,3-dicarbonyl sys-
tem reacted using ammonium hydroxide as base, which
had already been determined as the best base to promote
this kind of reaction. In the present study, several solvents
were tested to optimize the conditions. When ethanol was
employed, the transesterification product was formed as
the main component of the mixture; on the other hand, di-
chloromethane prevented this problem but the yield re-
mained low (15%). Acetonitrile proved to be the best option,
allowing an efficient transformation toward the target
product (90%) after 2 hours of stirring at room temperature.
When the MCR approach was used, it was shown that
by changing the nature of the aldehydes, the yields were
similar. However, a slight increase in yield was observed
with electron-releasing groups in the aromatic moiety. The
presence of halogens in the aldehyde caused yields to di-
minish. In contrast, reaction with heteroaromatic aldehydes
resulted in good yields (Table 1).
All compounds obtained were characterized by using a
range of analytical techniques. The 1H NMR spectra exhibit-
ed two singlets between δ = 4.5 and 5.0 ppm that corre-
spond to the hydrogen of the 4-position and the hydrogen
atoms of the amine group; all compounds also exhibited
characteristic signals according to their identity. A single-
crystal determination for compound 13g allowed us to con-
firm its molecular construction (Figure 2). The X-ray struc-
ture showed that the compound was co-crystallized with
an acetonitrile molecule and showed disorder in a portion
of the molecule. On the other hand, the structure also indi-
cated that the 4H-pyran core presents almost a coplanarity
in the system with a deviation of 6.92°. A short hydrogen
bond (2.142 Å) was also observed between the amine group
of one molecule and the nitrile group of another. Finally,
the torsion angle of the aryl group at the 4-position among
the carbons C(1), C(6), C(10), and C(25) was 84.81°.
Figure 2 Structure of 13g with thermal ellipsoids at the 30% probabil-
ity level (CCDC 1514593).
Table 1 Preparation of 4H-Pyran Hybrid Compounds
O
Ar
Ph
CN
O
Ar
O
O
Ph
N
To our knowledge, these 4H-pyran hybrids 12a–l and
13a–j have not been reported; for our research, the chain
on ester group is important for biological studies. In fact,
the in vivo studies on 4H-pyran derivatives with an ethyl
ester moiety showed that vasorelaxant activity is decreased
or even lost, probably when the chain in the ester group is
too short.23 We envisioned that if the size in the ester chain
were lengthened the stability could be increased. All these
findings will soon be reported.
In conclusion, a novel series of 4H-pyran-lipoic 12a–l
and 4H-pyran-azetidine 13a–j hybrid compounds were
synthesized using a MCR strategy under mild conditions,
and good yields were observed for products with potential
biological activity. With respect to the scope of the reac-
tion, the methodology has enormous potential in synthesis
and could be extended to obtain other types of hybrid mol-
ecules.
CN
S
S
O
O
NH2
NH2
12
13
Product Ar
Yield (%) Product Ar
Yield (%)
12a
12b
12c
12d
12e
12f
12g
12h
12i
C6H5
90
87
88
85
83
81
86
85
83
85
86
91
13a
13b
13c
13d
13e
13f
13g
13h
13i
C6H5
85
90
92
87
89
86
79
92
80
86
4-O2NC6H4
3-O2NC6H4
2-ON2C6H4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
C5H4N
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
C5H4N
C4H3S
C4H3S
12j
4-FC6H4
13j
4-MeOC6H4
12k
12l
3-ClC6H4
C4H3O
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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F. Hernández-Borja et al.
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Synthesis
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-phe-
nyl-4H-pyran-3-carboxylate (12a)
All chemicals, reagents, and solvents were of commercially high puri-
ty grade purchased from Sigma–Aldrich. Melting points were ob-
tained in open glass capillaries with an Electrothemal digital 90100
melting point apparatus and are uncorrected. Analytical thin-layer
chromatography (TLC) was carried out using Merck silica gel 60F254
plates and visualized using UV light and iodine vapor as visualizing
reagent. Column chromatography was performed with silica gel
(230–400 mesh) Machery–Nagel Co. using hexane/EtOAc. 1H NMR
and 13C NMR spectra were recorded in CDCl3 with tetramethylsilane
(TMS) as internal standard with Bruker UltraShield (500 MHz) and
Bruker Ascend (400 MHz) instruments. Chemical shift values are giv-
en in ppm (δ) relative to TMS as internal reference and coupling con-
stants (J) in hertz. The splitting pattern abbreviations are assigned as
s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m
(multiplet) or bs (broad singlet). High-resolution mass spectra were
recorded with a spectrometer Bruker ESI-QTOFMS maXis impact and
the samples were analyzed in combination with methyl stearate as an
internal standard.
Yield: 90%; white solid; mp 135–136 °C.
1H NMR (500 MHz, CDCl3): δ = 7.31–7.28 (m, 2 H), 7.23–7.28 (m, 3 H),
4.48 (s, 2 H), 4.43 (s, 1 H), 4.04–3.98 (m, 1 H), 3.96–3.90 (m, 1 H),
3.55–3.48 (m, 1 H), 3.21–3.09 (m, 2 H), 2.48–2.39 (m, 1 H), 2.38 (s,
3 H), 1.92–1.87 (m, 1 H), 1.63–1.54 (m, 2 H), 1.49–1.41 (m, 2 H), 1.39–
1.25 (m, 2 H), 1.17–1.06 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.9, 157.4, 157.2, 143.8, 128.7,
127.3, 127.2, 118.9, 107.7, 64.5, 62.5, 56.5, 40.3, 38.7, 38.5, 34.7, 28.9,
28.3, 25.6, 18.5.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H27N2O3S2Na]+: 453.1277;
found: 453.1277.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-(4-ni-
trophenyl)-4H-pyran-3-carboxylate (12b)
Yield: 87%; yellow solid; mp 131–132 °C.
1H NMR (500 MHz, CDCl3): δ = 8.15 (t, J = 29.8 Hz, 2 H), 7.38 (d,
J = 8.1 Hz, 2 H), 4.57 (m, 3 H), 4.15–3.86 (m, 2 H), 3.54 (m, 1 H), 3.18–
3.11 (m, 2 H), 2.44 (s, 4 H), 1.89 (s, 1 H), 1.58 (s, 2 H), 1.52–1.42 (m,
2 H), 1.43–1.24 (m, 2 H), 1.12 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.3, 158.3, 157.6, 151.1, 147.1,
128.3, 124.1, 118.2, 106.7, 64.9, 61.1, 56.4, 40.3, 38.8, 38.5, 34.7, 28.8,
28.3, 25.7, 18.7.
1,3-Dicarbonyl Compounds 10, 11; General Procedure
To a solution of compound 8/9 (1 mmol) in toluene (15 mL) was add-
ed ethyl acetoacetate (1.1 mmol) and iodine (0.3 mmol), and the reac-
tion mixture was heated at reflux using a Dean–Stark apparatus for
12 h until the reaction was complete (progress monitored by TLC).
The resulting mixture was extracted with dichloromethane. The or-
ganic layer was washed with a saturated solution of sodium thiosul-
fate, dried over anhydrous sodium sulfate, and concentrated. The resi-
due was purified by silica gel column chromatography (hexane/EtOAc,
8:2) to afford 10/11.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26N3O5S2Na]+: 498.1128;
found: 498.1136.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-(3-ni-
trophenyl)-4H-pyran-3-carboxylate (12c)
5-(1,2-Dithiolan-3-yl)pentyl 3-oxobutanoate (10)
Yield: 88%; yellow solid; mp 95–96 °C.
Yield: 80%; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.12 (d, J = 7.9 Hz, 1 H), 8.05 (s, 1 H),
7.58 (d, J = 7.2 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 4.58 (s, 3 H), 4.00 (m,
2 H), 3.52 (s, 1 H), 3.22–3.03 (m, 2 H), 2.45 (s, 3 H), 1.90 (dd, J = 12.2,
6.2 Hz, 1 H), 1.58 (d, J = 9.6 Hz, 3 H), 1.48 (d, J = 6.4 Hz, 2 H), 1.45–1.23
(m, 3 H), 1.23–1.06 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 164.3, 157.2, 156.6, 147.6, 145.1,
132.9, 128.6, 121.4, 117.2, 105.8, 63.9, 60.4, 55.5, 39.3, 37.8, 37.5,
33.7, 27.8, 27.3, 24.7, 17.7.
1H NMR (500 MHz, CDCl3): δ = 4.14 (t, J = 6.7 Hz, 2 H), 3.60–3.54 (m,
1 H), 3.45 (s, 2 H), 3.24–3.05 (m, 2 H), 2.50–2.44 (m, 1 H), 2.27 (s, 3 H),
1.96–1.88 (m, 1 H), 1.76–1.59 (m, 4 H), 1.55–1.33 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 200.7, 167.3, 65.5, 56.7, 50.3, 40.5,
38.7, 35.0, 30.4, 29.1, 28.5, 25.9.
HRMS (ESI+): m/z [M + H]+ calcd for [C12H21O3S2]+: 277.0927; found:
277.0934.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26N3O5S2Na]+: 498.1128;
found: 498.1133.
1-Benzhydrylazetidin-3-yl 3-oxobutanoate (11)
Yield: 75%; yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.40 (m, 4 H), 7.38 (m, 4 H), 7.17 (m,
2 H), 5.13 (q, J = 10.0 Hz, 1 H), 4.37 (s, 1 H), 3.60 (d, J = 15.0 Hz, 2 H),
3.45 (s, 2 H), 3.04 (d, J = 15.0 Hz, 2 H), 2.26 (s,3 H).
13C NMR (125 MHz, CDCl3): δ = 200.3, 166.6, 141.3, 128.6, 127.2, 78.3,
64.9, 60.0, 49.9, 30.3.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-(2-ni-
trophenyl)-4H-pyran-3-carboxylate (12d)
Yield: 85%; yellow solid; mp 101–102 °C.
1H NMR (500 MHz, CDCl3): δ = 8.11 (d, J = 8.1 Hz, 1 H), 8.05 (d,
J = 1.6 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 4.69 (s,
2 H), 4.57 (s, 1 H), 4.05–3.94 (m, 2 H), 3.56–3.49 (m, 1 H), 3.24–3.08
(m, 2 H), 2.51–2.40 (m, 4 H), 1.90 (ddq, J = 14.0, 6.9, 1.6 Hz, 1 H),
1.64–1.53 (m, 2 H), 1.53–1.44 (m, 2 H), 1.42–1.27 (m, 2 H), 1.23–1.08
(m, 2 H).
HRMS (ESI+): m/z [M + H]+ calcd for [C20H22NO3]+: 324.1594; found:
324.1595.
4H-Pyran-lipoic Hybrids (12a–l); General Procedure
13C NMR (125 MHz, CDCl3): δ = 165.3, 158.2, 157.8, 148.6, 146.2,
133.9, 129.6, 122.4, 118.3, 106.8, 64.9, 61.1, 56.5, 40.3, 38.8, 38.5,
34.7, 30.9, 28.8, 28.3, 25.7, 18.7.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26N3O5S2Na]+: 498.1128;
found: 498.1140.
The appropriate aldehyde (1.0 mmol), malononitrile (1.0 mmol), β-
ketoester compound (10; 1.0 mmol) and ammonium hydroxide (0.1
mmol) in acetonitrile (5.0 mmol) was stirred for 2 h. Upon comple-
tion of the reaction (monitored by TLC), a solid product was formed.
The formed product was filtered and washed well with warm hexane
to afford the pure products in excellent yields (80–91%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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F. Hernández-Borja et al.
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Synthesis
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-4-(4-chlorophenyl)-5-cya-
no-2-methyl-4H-pyran-3-carboxylate (12e)
1H NMR (500 MHz, CDCl3): δ = 7.16 (d, J = 4.9 Hz, 1 H), 6.97–6.83 (m,
2 H), 4.79 (s, 1 H), 4.60 (s, 2 H), 4.13–4.04 (m, 2 H), 3.56–3.52 (m, 1 H),
3.20–3.11 (m, 2 H), 2.48–2.44 (m, 1 H), 2.35 (s, 3 H), 1.92–1.88 (m,
2 H), 1.71–1.52 (m, 4 H), 1.44–1.36 (m, 2 H), 1.31–1.16 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.8, 158.1, 157.4, 148.4, 127.1,
124.6, 124.5, 118.8, 108.2, 64.9, 62.3, 56.6, 40.4, 38.6, 34.9, 33.9, 29.0,
28.5, 25.8, 18.6.
Yield: 83%; white solid; mp 137–138 °C.
1H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.4 Hz, 1 H), 7.13 (d,
J = 8.4 Hz, 1 H), 4.53 (s, 2 H), 4.41 (s, 1 H), 4.12–3.89 (m, 2 H), 3.53 (m,
1 H), 3.25–3.06 (m, 2 H), 2.46 (m, 1 H), 2.39 (s, 3 H), 1.91 (d,
J = 12.8 Hz, 1 H), 1.72–1.54 (m, 2 H), 1.54–1.40 (m, 2 H), 1.40–1.25 (m,
2 H), 1.10 (m, 2 H).
HRMS (ESI+): m/z [M + Na]+ calcd for [C20H25N2O3S3Na]+: 459.0841;
13C NMR (125 MHz, CDCl3): δ = 165.8, 157.6, 157.5, 142.6, 133.1,
129.0, 128.9, 118.7, 107.5, 64.8, 62.2, 56.7, 40.4, 38.4, 34.9, 29.0, 28.5,
25.8, 18.5.
found: 459.0861.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-4-(4-fluorophe-
nyl)-2-methyl-4H-pyran-3-carboxylate (12j)
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26ClN2O3S2Na]+: 487.0887;
Yield: 85%; white solid; mp 116–117 °C.
found: 487.0905.
1H NMR (500 MHz, CDCl3): δ = 7.24–7.09 (m, 2 H), 6.99 (t, J = 8.6 Hz,
2 H), 4.48 (s, 2 H), 4.43 (s, 1 H), 4.06–3.99 (m, 1 H), 3.99–3.91 (m, 1 H),
3.52 (m, 1 H), 3.15 (m, 2 H), 2.46 (m, 1 H), 2.39 (s, 3 H), 1.93–187 (m,
1 H), 1.66–1.54 (m, 2 H), 1.52–1.43 (m, 2 H), 1.43–1.27 (m, 2 H), 1.18–
1.08 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.9, 163.1, 161.1, 157.4 (d,
J = 24.9 Hz), 139.9, 129.0 (d, J = 8.1 Hz), 118.8, 115.5 (d, J = 21.5 Hz),
107.8, 64.8, 62.5, 56.6, 40.4, 38.6, 38.3, 34.9, 29.0, 28.5, 25.8, 18.6.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-4-(4-bromophe-
nyl)-2-methyl-4H-pyran-3-carboxylate (12f)
Yield: 81%; yellow solid; mp 114–115 °C.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.9 Hz, 2 H), 7.09 (d,
J = 7.9 Hz, 2 H), 4.83 (s, 2 H), 4.40 (s, 1 H), 4.09–3.90 (m, 2 H), 3.54 (d,
J = 6.4 Hz, 1 H), 3.25–3.08 (m, 2 H), 2.54–2.36 (m, 6 H), 1.60 (s, 2 H),
1.54–1.43 (m, 2 H), 1.42–1.23 (m, 2 H), 1.19–1.03 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.8, 157.9, 143.1, 131.7, 129.1,
120.9, 118.7, 107.1, 64.6, 61.4, 56.5, 40.2, 38.4, 34.7, 28.9, 28.3, 25.6,
18.5.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26FN2O3S2Na]+: 471.1183;
found: 471.1198.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-4-(3-chlorophenyl)-5-cya-
no-2-methyl-4H-pyran-3-carboxylate (12k)
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26BrN2O3S2Na]+: 531.0382;
found: 531.0405.
Yield: 86%; yellow solid; mp 137–138 °C.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-4-(2,4-dichloro-
phenyl)-2-methyl-4H-pyran-3-carboxylate (12g)
1H NMR (500 MHz, CDCl3): δ = 7.25–7.19 (m, 2 H), 7.15 (s, 1 H), 7.12–
7.08 (m, 1 H), 4.58 (s, 2 H), 4.41 (s, 1 H), 4.09–4.01 (m, 1 H), 3.98–3.91
(m, 1 H), 3.56–3.48 (m, 1 H), 3.23–3.08 (m, 2 H), 2.47–2.44 (m, 1 H),
2.40 (s, 3 H), 1.92–1.90 (m, 1 H), 1.64–1.55 (m, 2 H), 1.48–1.46 (m,
2 H), 1.41–1.27 (m, 2 H), 1.19–1.07 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.7, 157.8, 157.7, 146.1, 134.6,
130.1, 127.7, 127.6, 125.9, 118.7, 107.3, 64.8, 62.0, 56.6, 40.4, 38.8,
38.6, 34.8, 29.0, 28.4, 25.8, 18.7.
Yield: 86%; yellow solid; mp 123–124 °C.
1H NMR (500 MHz, CDCl3): δ = 7.37 (s, 1 H), 7.21 (d, J = 7.8 Hz, 1 H),
7.10 (d, J = 8.2 Hz, 1 H), 5.01 (s, 1 H), 4.55 (s, 2 H), 4.09–3.84 (m, 2 H),
3.53 (d, J = 6.4 Hz, 1 H), 3.25–3.08 (m, 2 H), 2.42 (s, 3 H), 1.91 (s, 2 H),
1.59 (d, J = 5.6 Hz, 2 H), 1.51–1.23 (m, 4 H), 1.10–1.06 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.4, 158.6, 157.6, 140.1, 133.7,
133.3, 130.5, 129.6, 127.8, 118.3, 106.4, 64.8, 60.8, 56.5, 40.3, 38.5,
35.0, 34.8, 28.9, 28.3, 25.7, 18.5.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26ClN2O3S2Na]+: 487.0887;
found: 487.0905.
HRMS (ESI+): m/z [M + Na]+ calcd for [C22H26Cl2N2O3S2Na]+: 521.0498;
found: 521.0526.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-4-(furan-2-yl)-2-
methyl-4H-pyran-3-carboxylate (12l)
Yield: 91%; orange solid; mp 126–127 °C.
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-(pyri-
din-4-yl)-4H-pyran-3-carboxylate (12h)
1H NMR (500 MHz, CDCl3): δ = 7.30 (s, 1 H), 6.28 (dd, J = 3.0, 1.8 Hz,
1 H), 6.08 (d, J = 2.9 Hz, 1 H), 4.61 (s, 3 H), 4.16–4.09 (m, 1 H), 4.08–
4.00 (m, 1 H), 3.59–3.51 (m, 1 H), 3.23–3.08 (m, 2 H), 2.49–2.44 (m,
1 H), 2.36 (s, 3 H), 1.94–1.87 (m, 1 H), 1.71–1.61 (m, 2 H), 1.61–1.53
(m, 2 H), 1.46–1.37 (m, 2 H), 1.33–1.21 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.7, 158.6, 158.1, 155.4, 141.9,
118.7, 110.4, 105.8, 105.6, 64.7, 59.3, 56.5, 40.2, 38.5, 34.8, 32.4, 28.9,
28.4, 25.7, 18.5.
Yield: 85%; red solid; mp 144–145 °C.
1H NMR (500 MHz, CDCl3): δ = 8.53 (d, J = 5.8 Hz, 2 H), 7.15 (d,
J = 5.8 Hz, 2 H), 4.75 (s, 2 H), 4.43 (s, 1 H), 4.05–3.89 (m, 2 H), 3.53–
3.51 (m, 1 H), 3.25–3.05 (m, 2 H), 2.52–2.35 (m, 4 H), 1.96–1.86 (m,
1 H), 1.70–1.55 (m, 2 H), 1.52–1.43 (m, 2 H), 1.38–1.22 (m, 2 H), 1.19–
1.04 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.4, 158.6, 158.6, 157.9, 152.6,
150.1, 122.4, 118.4, 106.3, 64.8, 60.6, 56.5, 40.3, 38.5, 38.3, 34.7, 30.9,
28.8, 28.2, 25.6, 18.6.
HRMS (ESI+): m/z [M + Na]+ calcd for [C20H24N2O4S2Na]+: 443.1070;
found: 443.1089.
HRMS (ESI+): m/z [M + H]+ calcd for [C21H26N3O3S2]+: 432.1410;
found: 432.1435.
4H-Pyran-azetidine Hybrids (13a–j); General Procedure
A mixture of the appropriate aldehyde (1.0 mmol), malononitrile (1.0
mmol), β-ketoester compound (11; 1.0 mmol) and ammonium hy-
droxide (0.1 mmol) in acetonitrile (5.0 mmol) was stirred for 1 h.
Upon completion of the reaction (monitored by TLC), the solid prod-
5-(1,2-Dithiolan-3-yl)pentyl 6-Amino-5-cyano-2-methyl-4-(thio-
phen-2-yl)-4H-pyran-3-carboxylate (12i)
Yield: 83%; yellow solid; mp 124–125 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
F. Hernández-Borja et al.
Paper
Synthesis
uct was formed. The formed product was filtered and washed well
with warm hexane to afford the pure product in excellent yields (79–
92%).
1-Benzhydrylazetidin-3-yl 6-Amino-4-(4-chlorophenyl)-5-cyano-
2-methyl-4H-pyran-3-carboxylate (13e)
Yield: 89%; white solid; mp 87–89 °C.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.17 (m, 14 H), 4.91 (q, J = 6.0 Hz,
1 H), 4.53 (s, 2 H), 4.44 (s, 1 H), 4.11 (s, 1 H), 3.51 (t, J = 7.5 Hz, 1 H),
3.43 (t, J = 7.5 Hz, 1 H), 2.85–2.82 (m, 1 H), 2.46–2.43 (m, 1 H), 2.36 (s,
3 H).
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-phenyl-
4H-pyran-3-carboxylate (13a)
Yield: 85%; yellow solid; mp 81–83 °C.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.15 (m, 15 H), 4.92 (q, J = 6.0 Hz,
1 H), 4.48 (s, 2 H), 4.45 (s, 1 H), 4.14 (s, 1 H), 3.51 (t, J = 7.5 Hz, 1 H),
3.41 (t, J = 7.5 Hz, 1 H), 2.88–2.85 (m, 1 H), 2.48–2.46 (m, 1 H), 2.35 (s,
1 H).
13C NMR (125 MHz, CDCl3): δ = 165.3, 157.8, 157.3, 144.0, 141.9,
141.8, 130.1, 128.9, 128.6, 128.5, 127.8, 127.5, 118.8, 107.3, 78.3, 64.1,
62.7, 60.1, 59.6, 39.0, 18.5.
13C NMR (125 MHz, CDCl3): δ = 165.0, 142.7, 141.8, 141.8, 133.3,
129.2, 129.1, 128.7, 128.6, 127.5, 127.4, 127.4, 118.6, 106.9, 78.4, 64.3,
62.0, 60.2, 59.6, 38.5, 18.5.
HRMS (ESI+): m/z [M + H]+ calcd for [C30H27ClN3O3]+: 512.1735; found:
512.1730.
1-Benzhydrylazetidin-3-yl 6-Amino-4-(4-bromophenyl)-5-cyano-
2-methyl-4H-pyran-3-carboxylate (13f)
HRMS (ESI+): m/z [M + H]+ calcd for [C30H28N3O3]+: 478.2125; found:
478.2127.
Yield: 86%; white solid; mp 97–98 °C.
1H NMR (500 MHz, CDCl3): δ = 7.50 (d, J = 8.4 Hz, 2 H), 7.37–7.15 (m,
10 H), 7.11 (d, J = 8.4 Hz, 2 H), 4.92 (q, J = 6.0 Hz, 1 H), 4.54 (s, 2 H),
4.42 (s, 1 H), 4.11 (s, 1 H), 3.51 (t, J = 7.5 Hz, 1 H), 3.43 (t, J = 7.5 Hz,
1 H), 2.84–2.82 (m, 1 H), 2.46–2.43 (m, 1 H), 2.35 (s, 1 H).
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-(4-nitro-
phenyl)-4H-pyran-3-carboxylate (13b)
Yield: 90%; yellow solid; mp 170–173 °C.
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.5 Hz, 2 H), 7.41 (d, J =
8.5 Hz, 2 H), 7.33–7.16 (m, 10 H), 4.93 (q, J = 5.5 Hz, 1 H), 4.64 (s, 2 H),
4.60 (s, 1 H), 4.14 (s, 1 H), 3.51 (t, J = 7.5 Hz, 1 H), 3.41 (t, J = 7.5 Hz,
1 H), 2.88–2.85 (m, 1 H), 2.53–2.51 (m, 1 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.6, 158.9, 157.6, 151.1, 147.2,
141.6, 141.5, 128.6, 127.4, 127.3, 127.3, 127.2, 124.1, 118.2, 106.1,
78.3, 64.5, 60.8, 59.9, 59.6, 38.8, 18.6.
13C NMR (125 MHz, CDCl3): δ = 165.0, 158.3, 157.3, 143.2, 141.8,
141.7, 132.0, 129.5, 128.7, 128.6, 127.5, 127.4, 127.4, 121.4, 118.6,
106.7, 78.4, 64.3, 61.9, 60.2, 59.5, 38.5, 18.5.
HRMS (ESI+): m/z [M + H]+ calcd for [C30H27BrN3O3]+: 556.1230; found:
556.1237.
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-4-(2,4-dichlorophe-
nyl)-2-methyl-4H-pyran-3-carboxylate (13g)
HRMS (ESI+): m/z [M + H]+ calcd for [C30H27N4O5]+: 523.1976; found:
523.1974.
Yield: 79%; white solid; mp 114–115 °C.
1H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 2.0 Hz, 1 H), 7.37–7.10 (m,
13 H), 5.05 (s, 1 H), 4.98–4.87 (m, 1 H), 4.51 (d, J = 4.2 Hz, 2 H), 4.12 (s,
1 H), 3.51 (t, J = 7.5 Hz, 1 H), 3.42–3.36 (m, 1 H), 2.93 (dd, J = 8.5,
5.5 Hz, 1 H), 2.38 (s, 3 H), 2.31 (dd, J = 8.6, 5.4 Hz, 1 H).
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-(3-nitro-
phenyl)-4H-pyran-3-carboxylate (13c)
Yield: 92%; yellow solid; mp 88–89 °C.
1H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1 H),
7.59 (d, J = 8.0 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.35–7.14 (m, 10 H),
4.96 (q, J = 6.0 Hz, 1 H), 4.78 (s, 2 H), 4.57 (s, 1 H), 4.17 (s, 1 H), 3.51 (t,
J = 7.5 Hz, 1 H), 3.42 (t, J = 7.5 Hz, 1 H), 2.91–2.89 (m, 1 H), 2.55–2.53
(m, 1 H), 2.37 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.7, 158.8, 157.9, 148.6, 146.3,
141.7, 141.6, 134.1, 129.8, 128.6, 127.4, 127.4, 122.7, 122.6, 118.4,
106.4, 78.3, 64.3, 60.7, 60.1, 59.7, 38.9, 18.7.
13C NMR (125 MHz, CDCl3): δ = 164.7, 159.1, 157.6, 157.5, 141.9,
141.8, 140.3, 134.0, 133.7, 130.8, 129.7, 128.7, 128.6, 128.0, 127.5,
127.4, 127.3, 118.2, 106.0, 78.6, 64.2, 60.8, 60.3, 59.3, 35.1, 18.4.
HRMS (ESI+): m/z [M + H]+ calcd for [C30H26Cl2N3O3]+: 546.1346;
found: 546.1248.
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-(pyri-
din-4-yl)-4H-pyran-3-carboxylate (13h)g
HRMS (ESI+): m/z [M + H]+ calcd for [C30H27N4O5]+: 523.1976; found:
523.1975.
Yield: 92%; yellow solid; mp 97–99 °C.
1H NMR (500 MHz, CDCl3): δ = 8.58 (d, J = 8.0 Hz, 2 H), 7.35–7.16 (m,
14 H), 4.93 (q, J = 6.0 Hz, 1 H), 4.84 (s, 2 H), 4.44 (s, 1 H), 4.15 (s, 1 H),
3.51 (t, J = 7.5 Hz, 1 H), 3.43 (t, J = 7.5 Hz, 1 H), 2.85–2.83 (m, 1 H),
2.57–2.53 (m, 1 H), 2.38 (s, 1 H).
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-(2-nitro-
phenyl)-4H-pyran-3-carboxylate (13d)
Yield: 87%; yellow solid; mp 90–91 °C.
13C NMR (125 MHz, CDCl3): δ = 164.7, 159.2, 157.9, 152.7, 150.3,
147.7, 147.6, 128.7, 128.6, 127.4, 127.4, 122.7, 118.4, 105.8, 78.3, 64.5,
60.5, 60.0, 59.7, 38.5, 18.7.
HRMS (ESI+): m/z [M + H]+ calcd for [C30H28N3O3]+: 479.2078; found:
479.2077.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 1 H), 7.57 (t, J =
8.0 Hz, 1 H), 7.40–7.15 (m, 12 H), 5.29 (s, 1 H), 4.90 (q, J = 6.0 Hz, 1 H),
4.67 (s, 2 H), 4.25 (s, 1 H), 3.44 (t, J = 7.5 Hz, 1 H), 3.35 (t, J = 7.5 Hz,
1 H), 2.82 (t, J = 7.5 Hz, 1 H), 2.37–2.33 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 164.4, 158.9, 157.9, 149.0, 141.7,
139.1, 133.5, 130.6, 128.5, 128.4, 128.1, 127.5, 127.4, 127.2, 127.2,
124.4, 118.0, 106.6, 77.9, 63.9, 61.1, 59.8, 59.3, 33.1, 18.4.
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-2-methyl-4-(thio-
phen-2-yl)-4H-pyran-3-carboxylate (13i)
HRMS (ESI+): m/z [M + H]+ calcd for [C30H27N4O5]+: 523.1976; found:
523.1977.
Yield: 80%; orange solid; mp 65–67 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
F. Hernández-Borja et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.38–7.16 (m, 11 H), 6.97–6.95 (m,
2 H), 5.04 (q, J = 6.0 Hz, 1 H), 4.82 (s, 1 H), 4.57 (s, 2 H), 4.27 (s, 1 H),
3.56 (t, J = 7.5 Hz, 1 H), 3.51 (t, J = 7.5 Hz, 1 H), 3.00–2.97 (m, 1 H),
2.78–2.75 (m, 1 H), 2.33 (s, 1 H).
(8) Koufaki, M.; Detsi, A.; Theodorou, E.; Kiziridi, C.;
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M. A. Med. Chem. Res. 2017, 26, 1325.
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Hsu, M. C.; Lee, E. C.; Peterson, M. J.; Plata, D. J.; Raje, P. S.;
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E.; Gein, V. L. Pharm. Chem. J. 2016, 50, 519.
13C NMR (125 MHz, CDCl3): δ = 165.1, 157.9, 148.3, 141.9, 128.6,
127.5, 127.4, 127.1, 124.8, 124.7, 118.7, 107.6, 78.3, 64.4, 60.1, 59.8,
33.8, 18.6.
HRMS (ESI+): m/z [M + H]+ calcd for [C28H26N3O3S]+: 489.1689; found:
489.1690.
1-Benzhydrylazetidin-3-yl 6-Amino-5-cyano-4-(4-methoxyphe-
nyl)-2-methyl-4H-pyran-3-carboxylate (13j)
Yield: 86%; yellow solid; mp 95–96 °C.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.17 (m, 10 H), 7.15 (d, J = 8.5 Hz,
2 H), 6.90 (d, J = 8.5 Hz, 2 H), 4.93 (q, J = 5.5 Hz, 1 H), 4.46 (s, 2 H), 4.41
(s, 1 H), 4.15 (s, 1 H), 3.81 (s, 3 H), 3.52 (t, J = 7.3 Hz, 1 H), 3.42 (t, J =
7.3 Hz, 1 H), 2.88–2.86 (m, 1 H), 2.48–2.46 (m, 1 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.4, 158.9, 157.4, 157.1, 141.9,
136.3, 128.9, 128.6, 127.5, 127.4, 127.4, 127.3, 119.0, 114.2, 107.5,
78.3, 64.1, 62.7, 60.1, 59.6, 55.4, 38.1, 18.4.
HRMS (ESI+): m/z [M + H]+ calcd for [C31H30N3O4]+: 508.2231; found:
508.2232.
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Med. Chem. 2013, 70, 669.
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Hernández-Borja, F.; Villalobos-Molina, R.; Bazán-Perkins, B.;
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Funding Information
The authors thank the Consejo Nacional de Ciencia y Tecnología
(CONACYT research grants: FHB scholarship 482137 and JL posdoc-
toral grant CB-2014/241803) for financial support. Dirección de
Apoyo a la Investigación y al Posgrado (DAIP, research grant 811/2016,
MAV) and National Laboratory UG-CONACYT (research project
260373) are acknowledged for the analytical characterization provid-
ed.
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Supporting Information
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Bioorg. Med. Chem. 2004, 12, 3581.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591730.
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