Potassium-Exchanged Zirconium Hydrogen Phosphate [α-Zr(KPO4)2]-Catalyzed Synthesis of 2-Amino-4 H -pyran Derivatives under Solvent-Free Conditions

Article abstract of DOI:10.1055/s-0035-1560411

A high-yielding, one-pot, three-component synthesis of functionalized 2-amino-4H-pyrans from β-dicarbonyl compounds, activated cyanomethylene compounds, and aldehydes, mediated by potassium-exchanged zirconium hydrogen phosphate [α-Zr(KPO₄)₂], is reported. The protocol shows excellent versatility, as it can be applied to aromatic, aliphatic, or α,β-unsaturated aldehydes under solvent-free conditions.

Full text of DOI:10.1055/s-0035-1560411

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
O. Rosati et al.
Paper
Synthesis
Potassium-Exchanged Zirconium Hydrogen Phosphate [α-Zr(KPO4)2]-
Catalyzed Synthesis of 2-Amino-4H-pyran Derivatives under Solvent-
Free Conditions
Ornelio Rosati*a
Azzurra Pelosia
Andrea Temperinia
Vittorio Paceb
O
R3
O
O
NC
R2
R2
Zr(KPO4)2
+
R1
R1
60 °C, 2–24 h
R3CHO
O
NH2
R1 R1
Massimo Curinia
33–93% (22 examples)
1 = H, Me; R2 = CN, CO2Et; R3 = aromatic, aliphatic
R
a Dipartimento di Scienze Farmaceutiche, Università degli Studi di
Perugia, Via del Liceo 1, 06123 Perugia, Italy
ornelio.rosati@unipg.it
b Department of Pharmaceutical Chemistry, University of Vienna,
Althanstrasse 14, 1090 Vienna, Austria
Received: 16.12.2015
Accepted after revision: 20.01.2016
Published online: 25.02.2016
The presence of an amino or nitrile group on the 4H-
pyran core2 broadens the range of applications of these het-
erocycles; such compounds have been used as pigments,3
agrochemicals,4 or versatile synthetic scaffolds.5 The impor-
tance of these compounds is further demonstrated by the
numerous recent efforts made to synthesize them.6 A closer
examination of the preparative methods available indicates
that the three-component coupling of an aldehyde, a β-di-
carbonyl derivative, and an activated methylene donor is
the method of choice for obtaining the 4H-pyran nucleus.
Kaupp and co-workers reported a catalyst-free synthesis of
2-amino-4H-pyran derivatives from Michael adducts at
high temperatures (97–130 °C).7 Evidently, this procedure
requires Michael adducts that need to be synthesized in ad-
vance, and the harsh conditions for the reaction are not
amenable to the safe use of volatile aldehydes.
In this respect, the use of heterogeneous processes is
particularly desirable because of the simplicity of the syn-
thetic operations that are required.8 Although the use of
catalyst can be avoided by performing the reactions in gly-
cerol,9 the difficulties associated with the extraction of the
products from the water-miscible phase cannot be neglect-
ed, and these lessen the synthetic appeal of the overall
transformation.
DOI: 10.1055/s-0035-1560411; Art ID: ss-2015-z0719-op
Abstract A high-yielding, one-pot, three-component synthesis of
functionalized 2-amino-4H-pyrans from β-dicarbonyl compounds, acti-
vated cyanomethylene compounds, and aldehydes, mediated by potas-
sium-exchanged zirconium hydrogen phosphate [α-Zr(KPO4)2], is re-
ported. The protocol shows excellent versatility, as it can be applied to
aromatic, aliphatic, or α,β-unsaturated aldehydes under solvent-free
conditions.
Key words pyrans, amines, heterogeneous catalysis, solvent-free syn-
thesis, multicomponent reactions, cyclizations
The pyran moiety is a well-known motif in synthetic,
medicinal, and natural-product chemistry,1 as illustrated by
the selected structures shown in Figure 1.
O
O
CO2Me
OH
O
OH
O
OH
O
O
H2N
HO
OH
OH
O
H
CO2Me
HO
O
D-glucosamine
warfarin
rubioncolin B
In recent years, there has been increasing interest in the
use of acidic or basic solids in liquid organic synthesis.10
Among the obvious advantages of their use in preparative
processes are their uniformly good yields, high regio- and
chemoselectivities, and short reaction times, which are in
accord with Anastas and Eghbali’s philosophical principles
for green chemistry.11 In this context, our group has intro-
duced the use of layered potassium-exchanged zirconium
hydrogen phosphate [α-Zr(KPO4)2]12 as an excellent hetero-
geneous catalyst for C–C bond-forming processes through
Michael-type, Henry, or Knoevenagel chemistries.13 Inter-
OMe
O
O
N
O
O
CN
EtO
O
HO
O
O
Br
OEt
NH2
O
cordypyridone D
(R)-rugulactone
HA14-1
Figure 1 Examples of compounds containing a pyran moiety
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
O. Rosati et al.
Paper
Synthesis
estingly, we were able to employ this effective species for a
straightforward synthesis of 2-amino-4H-chromene deriv-
atives under solvent-free conditions.14
To evaluate the effects of various solvents, the reactions
of benzaldehyde (3a) or hexanal (3e) with cyclohexane-1,3-
dione (1b) and malononitrile (2a) were performed in etha-
nol or acetonitrile. As shown in Table 2, the reactions under
solvent-free conditions gave slightly higher yields, regard-
less of the electronic nature of the aldehyde.
As a consequence of these successful precedents, and as
part of our continuing interest in developing the synthesis
of derivatives with pyran as a core moiety,15 we wondered
whether α-Zr(KPO4)2 might be used as a heterogeneous cat-
alyst for the preparation of 2-amino-4H-pyrans from com-
binations of β-dicarbonyl compounds, cyano derivatives,
and aldehydes. Here, we report the results of our investiga-
tions (Scheme 1).
Table 2 Effects of Solvents on the Reaction of Benzaldehyde or Hex-
anal with Malononitrile and Cyclohexane-1,3-dione at 60 °C for 2 Hours
Yield (%)
Neat
EtOH
MeCN
O
R3
O
O
PhCHO (3a)
93
89
85
88
75
83
R2
Zr(KPO4)2
60 °C
R3CHO
CN
R2
+
+
Me(CH2)4CHO (3e)
R1
R1
O
NH2
R1 R1
To determine the scope of the reaction, two 1,3-dicar-
bonyl compounds [cyclohexane-1,3-dione (1b) and 5,5-di-
methylcyclohexane-1,3-dione (1a)] and two cyano deriva-
tives [malononitrile (2a) and ethyl cyanoacetate (2b)] were
condensed with various aromatic or aliphatic aldehydes
3a–h under the optimized conditions (Table 3).
R
R
1 = H, Me
2 = CN, CO2Et
R3 = aromatic,
aliphatic
Scheme 1 General scheme for the reaction of β-dicarbonyl com-
pounds, cyano derivatives, and aldehydes catalyzed by α-Zr(KPO4)2
One point merits attention: the reaction of ethyl cyano-
acetate (2b), benzaldehyde (3a), and 5,5-dimethylcyclohex-
ane-1,3-dione (1a) gave 2,2′-(phenylmethylene)bis(3-hy-
droxy-5,5-dimethylcyclohex-2-en-1-one) (10) as a byprod-
uct and, after 12 hours, the tetrahydrochromene 5a was
obtained in only 53% yield (Table 3, entry 9). A plausible ra-
tionale for this intriguing result arises from the fact that ad-
ducts 8 and 9 are formed at comparable, if not similar, rates,
suggesting that the competition between 5,5-dimethylcy-
clohexane-1,3-dione (3a) with ethyl cyanoacetate (2b) for
condensation with the Knoevenagel adduct 8 might occur
(Scheme 2). This behavior was not observed when malono-
nitrile (2a) was used instead of ethyl cyanoacetate (2b). The
greater reaction rate of malononitrile (2a) towards benzal-
dehyde (1a), compared with that of ethyl cyanoacetate (2b),
decreases the possibility of formation of the Knoevenagel
adduct 8 and, subsequently, the Michael adduct 10.
To explore the generality and feasibility of the α-
Zr(KPO4)2-catalyzed synthesis of 2-amino-4H-pyran deriva-
tives, we selected the condensation of benzaldehyde, cyclo-
hexane-1,3-dione, and malononitrile as a model reaction
under solvent-free conditions. To ensure mild conditions
during the process, the reaction mixtures were heated to
only 60 °C. As shown in Table 1, the use of 10 mol% of the
catalyst was optimal, affording the desired compound 6a in
an excellent 93% isolated yield (Table 1, entry 2). The bene-
ficial effect of the catalyst can be deduced from the control
reaction run in its absence (entry 4), which gave the target
product in a markedly decreased yield after a prolonged re-
action time (12 h).
Table 1 Optimization of the Catalyst Loading for the Reaction of Benz-
aldehyde, Malononitrile, and Cyclohexane-1,3-dione at 60 °C
O
O
Ph
O
O
Ph
O
Ph
CN
Zr(KPO4)2
+
NC CN
+
PhCHO
1a
neat, 60 °C
O
O
NH2
O
OHHO
Zr(KPO4)2
8
1b
2a
3a
6a
10
1a + 2b + 3a
2b
neat, 60 °C
+
O
Ph
Ph
Entry
Zr(KPO4)2 (mol%)
Time (h)
Yield (%)
CO2Et
NH2
CN
CO2Et
1a
1
2
3
4
20
10
5
2
2
82
93
78
47
O
9
5a
2
Scheme 2 Possible pathways for the reaction of 5,5-dimethylcyclohex-
ane-1,3-dione (1a), ethyl cyanoacetate (2b), and benzaldehyde (3a) in
the presence of α-Zr(KPO4)2
0
12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
O. Rosati et al.
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Synthesis
Table 3 Reactions of Aldehydes, Malononitrile or Ethyl Cyanoacetate, and Cyclohexane-1,3-dione or 5,5-Dimethylcyclohexane-1,3-dione at 60 °C in
the Presence of 10 mol% of α-Zr(KPO4)2
R3
O
O
O
R2
Zr(KPO4)2
NC
R2
R3CHO
+
+
neat, 60 °C
R1
R1
R1 R1
O
NH2
1a,b
2a,b
3a–h
4a–h
5a–d,g,h
6a–d,g,h
7a–d,g,h
Entry
Product
R2
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
4a
Ph
3-ClC6H4
4-O2NC6H4
4-MeO2CC6H4
4-Tol
3-HO-4-MeOC6H3
(CH2)4Me
(E)-CH=CHPh
2
2
2
2
2
2
2
2
93
90
91
71
92
90
89
42
4b
4c
4d
4e
4f
4g
4h
O
R2
CN
O
NH2
9
10
11
12
13
14
5a
5b
5c
5d
5g
5h
Ph
3-ClC6H4
4-O2NC6H4
4-MeO2CC6H4
(CH2)4Me
(E)-CH=CHPh
12 (20)a
53 (71)a
O
R2
20
24
20
5
62
82
87
50
–
CO2Et
NH2
O
12
15
16
17
18
19
20
6a
6b
6c
6d
6g
6h
Ph
3-ClC6H4
4-O2NC6H4
4-MeO2CC6H4
(CH2)4Me
(E)-CH=CHPh
4
2
3
2
1
4
92
86
93
88
89
33
O
O
R2
CN
O
NH2
21
22
23
24
25
26
7a
7b
7c
7d
7g
7h
Ph
3-ClC6H4
4-O2NC6H4
4-MeO2CC6H4
(CH2)4Me
(E)-CH=CHPh
18
20
24
22
24
12
69
80
87
84
51
–
R2
CO2Et
NH2
O
a Two-step one-pot reaction
It is noteworthy that Michael adduct 10 was obtained in
a quantitative yield after two hours when benzaldehyde
(3a) was treated with two equivalents of 5,5-dimethylcy-
clohexane-1,3-dione (1a) under the optimized reaction
conditions.
To avoid the formation of byproduct 10, a two-step one-
pot reaction was carried out by treating benzaldehyde (3a)
with ethyl cyanoacetate (2b), with subsequent addition of
5,5-dimethylcyclohexane-1,3-dione (1a) after 14 hours. By
using this modified procedure, it was possible to obtain
compound 5a in 71% yield after a total of 20 hours (Table 3,
entry 9).
As shown in Table 3, the reactions carried out with
malononitrile (2a) were faster and more efficient than
those involving ethyl cyanoacetate (2b). For example, hex-
anal (3e) reacted in higher yield with malononitrile (Table
3, entries 7 and 19) than with the ethyl cyanoacetate (en-
tries 13 and 25). In contrast, cinnamaldehyde (3h) gave a
moderate yield with malononitrile (1b) (entries 8 and 20)
but failed to give a product with ethyl cyanoacetate (2b) in
the presence of either 5,5-dimethylcyclohexane-1,3-dione
(1a) or cyclohexane-1,3-dione (1b) (entries 14 and 26). The
presence of electron-withdrawing or electron-donating
groups on aromatic aldehydes was well tolerated, and good
yields were obtained in both cases (entries 2–6).
To evaluate the efficiency and capability of our protocol,
we compared the reaction of 1a, 2a, and 3a to give tetrahy-
drochromene 4a with other reported methods and cata-
lysts. The results, reported in Table 4, demonstrate the ef-
fectiveness of our protocol. The use of α-Zr(KPO4)2 as a solid
catalyst under neat conditions gave results that were com-
parable or better than those of the other protocols. More-
over, in many of these protocols the reactions were limited
to the use of malononitrile and aromatic aldehydes, and the
use of aliphatic aldehydes or the less-reactive ethyl cyano-
acetate as an activated methylene compound were not con-
sidered.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
O. Rosati et al.
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Synthesis
Table 4 Comparison of Syntheses of Tetrahydro-4H-Chromene 4a by
points were determined on a Kofler Hot Stage apparatus, and are un-
Various Protocols
corrected. Elemental analyses were performed by a Fisons
EA1108CHN analyzer, and the results for C, H, and N were all within
0.4% of the theoretical values (≥95% purity). Physical data (mp, solid
state, etc.) for known compounds matched those already reported.
Full and unambiguous characterization by spectroscopic methods (1H
NMR, 13C NMR, FT-IR) is reported for all the synthesized compounds.
O
Ph
O
O
CN
Zr(KPO4)2
NC
CN
Ph CHO
+
+
neat, 60 °C
O
NH2
1a
2a
3a
4a
2-Amino-5-oxotetrahydro-4H-chromene Derivatives 4–7; General
Procedure
Entry Catalyst
mol% Reaction conditions
Yield
(%)
Zr(KPO4)2 (10 mol%) was added to a neat mixture of malononitrile or
ethyl cyanoacetate (1 mmol), the appropriate1,3-dicarbonyl com-
pound (1 mmol), and the appropriate aldehyde (1 mmol). The mix-
ture was heated to 60 °C, and the progress of the reaction was moni-
tored by TLC. After the appropriate time, the mixture was diluted
with CH2Cl2 and filtered under reduced pressure. To obtain the pure
ethoxycarbonyl derivatives 5a–d,g, and 7a–d,g, the solvent was evap-
orated under vacuum and the residue was purified by chromatogra-
phy on silica gel.
a
1
2
3
4
5
6
7
α-Zr(KPO4)2
10
1
neat, 60 °C, 2 h
93
93
86
95
97
93
96
a,16
CoFe2O4
ZnO6e
H2O–EtOH (1:3), 60 °C, 7 min
H2O–EtOH (1:1), r.t., 3.5 h
neat, MW, 70 °C, 10 min
H2O–EtOH (1:1), r.t., 5 min
glycerol, 80 °C, 1 h
10
20
5
NaBr8f
megluminea,8a
glycerola,9
–
electrogenerated base6f
–
MeCN, r.t., 4–5 h
The 3-carbonitrile derivatives 4a–h and 6a–d,g,h have very low solu-
bilities; consequently, the treatment with CH2Cl2 was useful for elimi-
nating unreacted material and byproducts. The solid residue was
treated with hot MeOH or acetone, and the solid catalyst was recov-
ered by filtration at reduced pressure. The filtrate was concentrated
under vacuum to obtain products 4a–h and 6a–d,g,h in high purity.
a The authors describe the possibility of reusing the catalyst.
Finally, we examined the recycling of the solid catalyst
by a simple washing–drying sequence. The activity of the
catalyst was substantially preserved after five consecutive
condensations of benzaldehyde (3a), malononitrile (2a),
and 5,5-dimethylcyclohexane-1,3-dione (1b), giving yields
of 91, 90, 91, 89, and 87%, respectively. This valuable char-
acteristic of the catalyst is an important advantage in terms
of the sustainability of the process, which would be wel-
come for the purposes of scaling up.
We have reported the use of layered potassium-
exchanged zirconium hydrogen phosphate [α-Zr(KPO4)2] as
a heterogeneous catalyst for high-yielding multicomponent
reactions that give 2-amino-4H-pyran derivatives under
solvent-free conditions. This process tolerates various func-
tionalities, which gives it a remarkably wide scope and is
particularly attractive from the perspective of sustainabili-
ty. The thermal and chemical stability of the catalyst and
the possibility of recovering it by simple filtration ensure
that the process is simple to perform and that it results in
the formation of negligible amounts of chemical wastes. To
optimize the use of less-reactive ethyl cyanoacetate, a two-
step one-pot multicomponent reaction was also investigat-
ed
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4a)
White solid; yield: 274 mg (93%); mp 227–228 °C (Lit.8a 225–226 °C).
FT-IR: 2200, 1679, 1661 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.35–7.05 (m, 5 H, PhH), 7.02 (br s,
2 H, NH2), 4.19 (s, 1 H, CH), 2.52 (br s, 2 H, CH2), 2.26 and 2.11 (AB
system, J = 16 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.96 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.4, 163.2, 159.3, 145.5, 129.1 (2
C), 127.9 (2 C), 127.3, 120.4, 113.5, 59.1, 50.7, 40.5, 36.3, 32.5, 29.1,
27.6.
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.61;
H, 6.03; N, 9.40.
2-Amino-4-(3-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carbonitrile (4b)
White solid; yield: 296 mg (90%); mp 234–236 °C (Lit.8a 235–236 °C).
FT-IR: 2190, 1682, 1656 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.33 (t, J = 8 Hz, 1 H, PhH), 7.27 (d,
J = 8.Hz, 1 H, PhH), 7.17 (s, 1 H, PhH), 7.13 (d, J = 8 Hz, 1 H, PhH), 7.10
(br s, 2 H, NH2), 4.22 (s, 1 H, CH), 2.53 (br s, 2 H, CH2), 2.26 and 2.13
(AB system, J = 16 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.96 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.4, 163.6, 159.3, 148.0, 133.6,
131.0, 127.8, 127.4, 126.7, 120.2, 112.8, 58.4, 50.7, 40.4, 36.1, 32.6,
29.0, 27.6.
All chemicals were purchased in the highest purity grade from major
chemical suppliers and were used without further purification. Col-
umn chromatography was performed on Merck silica gel 60 (70–230
mesh ASTM) with CH2Cl2–EtOAc or CH2Cl2–MeOH. 1H and 13C NMR
spectra were recorded in CDCl3 or DMSO-d6 with a Bruker Avance
DRX 200 spectrometer at frequencies of 200.1 and 50 MHz, respec-
tively, or with a Bruker Avance DPX 400 spectrometer at frequencies
of 400.13 and 100.62 MHz, respectively. IR spectra were recorded
with a Jasco model 410 spectrometer with a diffuse-reflectance sam-
pling cell; only significant absorption maxima are reported. Melting
Anal. Calcd for C18H17ClN2O2: C, 65.75; H, 5.21; N, 8.52. Found: C,
65.68; H, 5.17; N, 8.41.
2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carbonitrile (4c)
White solid; yield: 309 mg (91%); mp 184–185 °C (Lit.8a 185–186 °C).
FT-IR: 2192, 1713, 1687 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
O. Rosati et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 8.18 (d, J = 8.6 Hz, 2 H, PhH), 7.45
(d, J = 8.6 Hz, 2 H, PhH), 7.17 (br s, 2 H, NH2), 4.38 (s, 1 H, CH), 2.54 (br
s, 2 H, CH2), 2.26 and 2.12 (AB system, J = 16 Hz, 2 H, CH2), 1.04 (s, 3 H,
CH3), 0.96 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.4, 163.8, 159.3, 153.0, 147.0,
129.4 (2 C), 124.4 (2 C), 120.0, 112.5, 57.8, 50.6, 40.5, 36.4, 32.6, 29.0,
27.7.
FT-IR: 2189, 1682, 1652, 1604 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.53 (br s, 2 H, NH2), 3.44 (t, J = 6.0 Hz,
1 H, CH), 2.37 (br s, 2 H, CH2), 2.29 (br s, 2 H, CH2), 1.71–1.48 (m, 2 H,
CH2), 1.42–1.16 (m, 6 H, 3 × CH2), 1.12 (s, 3 H, CH3), 1.10 (s, 3 H, CH3),
0.86 (t, J = 6.3 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.9, 163.0, 159.1, 119.6, 114.3, 61.5,
51.1, 40.9, 34.9, 32.3, 32.0, 29.6, 29.4, 27.7, 24.8, 22.9, 14.3.
Anal. Calcd for C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C,
63.82; H, 4.94; N, 12.30.
Anal. Calcd for C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.72;
H, 8.29; N, 9.62.
Methyl 4-(2-Amino-3-cyano-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromen-4-yl)benzoate (4d)
White solid; yield: 250 mg (71%); mp 278–280 °C (Lit.17 280–282 °C).
2-Amino-7,7-dimethyl-5-oxo-4-[(E)-2-phenylvinyl]-5,6,7,8-tetra-
hydro-4H-chromene-3-carbonitrile (4h)
White solid; yield: 135 mg (42%); mp 187–189 °C (Lit.16 185–188 °C).
FT-IR: 2193, 1718, 1684, 1651, 1606 cm–1
.
FT-IR: 2184, 1687, 1652 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.90 (d, J = 8.1 Hz, 2 H, PhH), 7.31
(d, J = 8.1 Hz, 2 H, PhH), 7.08 (br s, 2 H, NH2), 4.27 (s, 1 H, CH), 3.83 (s,
3 H, OCH3), 2.48–2.61 (m, 2 H, CH2), 2.27 and 2.09 (AB system, J = 16
Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.4, 166.8, 163.6, 159.3, 150.8,
130.1 (2 C), 128.8, 128.4 (2 C), 120.2, 112.9, 58.2, 52.8, 50.6, 40.4, 36.4,
32.5, 29.1, 27.5.
1H NMR (400 MHz, DMSO-d6): δ = 7.38 (d, J = 7.3 Hz, 2 H, PhH), 7.30
(t, J = 7.3 Hz, 2 H, PhH), 7.22 (t, J = 7.3 Hz, 1 H, PhH), 7.05 (br s, 2 H,
NH2), 6.37 (d, J = 15.7 Hz, 1 H, CHCH=CHPh), 6.09 (dd, J = 7.4, 15.7 Hz,
1 H, CHCH=CHPh), 3.82 (d, J = 7.4 Hz, 1 H, CHCH=CH), 2.44 (br s, 2 H,
CH2), 2.29 and 2.21 (AB system, J = 16 Hz, 2 H, CH2), 1.03 (s, 3 H, CH3),
1.01 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 163.2, 160.0, 137.2, 131.9,
130.0, 129.3 (2 C), 128.2, 127.0 (2 C), 120.6, 112.6, 56.0, 50.8, 40.5,
33.5, 32.6, 29.0, 27.7.
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.27;
H, 5.81; N, 7.84.
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.85;
H, 6.21; N, 8.62.
2-Amino-7,7-dimethyl-5-oxo-4-(4-tolyl)-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4e)
White solid; yield: 284 mg (92%); mp 215–217 °C (Lit.8a 211–212 °C).
Ethyl 2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
FT-IR: 2192, 1675, 1639, 1602 cm–1
.
4H-chromene-3-carboxylate (5a)
White solid; yield: 242 mg (71%); mp 152–154 °C (Lit.16 150–152 °C).
1H NMR (400 MHz, DMSO-d6): δ = 7.09 (d, J = 8.0 Hz, 2 H, PhH), 7.02
(d, J = 8.0 Hz, 2 H, PhH), 6.97 (br s, 2 H, NH2), 4.13 (s, 1 H, CH), 2.51 (m,
2 H, CH2), 2.25 (s, 3 H, CH3), 2.25 and 2.09 (AB system, J = 16 Hz, 2 H,
CH2), 1.04 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.4, 163.0, 159.2, 142.6, 136.4,
129.6 (2 C), 127.8 (2 C), 120.5, 113.6, 52.2, 50.7, 40.4, 35.9, 32.5, 29.2,
27.5, 21.3.
FT-IR: 1667, 1661, 1612 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.57 (br s, 2 H, NH2), 7.37–7.06 (m,
5 H, PhH), 4.50 (s, 1 H, CH), 3.95 (q, J = 7 Hz, 2 H, OCH2), 2.57 and 2.46
(AB system, J = 18 Hz, 2 H, CH2), 2.27 and 2.05 (AB system, J = 16 Hz, 2
H, CH2), 1.09 (t, J = 7 Hz, 3 H, CH3), 1.03 (s, 3 H, CH3), 0.89 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.2, 168.4, 162.5, 159.5, 146.7,
128.1 (2 C), 128.0 (2 C), 126.2, 115.9, 78.2, 59.1, 50.3, 39.9, 33.6, 32.3,
29.0, 26.8, 14.6.
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.87;
H, 6.78; N, 9.19.
Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.23;
H, 6.86; N, 4.21.
2-Amino-4-(3-hydroxy-4-methoxyphenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4f)
White solid; yield: 306 mg (90%); mp 238–240 °C (Lit.18 237–239 °C).
Ethyl 2-Amino-4-(3-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
FT-IR: 2191, 1674, 1600 cm–1
.
tetrahydro-4H-chromene-3-carboxylate (5b)
White solid; yield: 233 mg (62%); mp 129–131 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.87 (s, 1 H, OH), 6.92 (br s, 2 H,
NH2), 6.79 (d, J = 8.2 Hz, 1 H, PhH), 6.55 (d, J = 2.0 Hz, 1 H, PhH), 6.51
(dd, J = 8.2, 2.0 Hz, 1 H, PhH), 4.01 (s, 1 H, CH), 3.70 (s, 3 H, OCH3), 2.51
and 2.44 (AB system, J = 16.6 Hz, 2 H, CH2), 2.24 and 2.08 (AB system,
J = 16.2 Hz, 2 H, CH2), 1.02 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.0, 162.4, 158.8, 146.7, 146.6,
137.8, 120.2, 118.1, 114.9, 113.5, 112.4, 59.0, 56.0, 50.4, 40.1, 35.2,
32.1, 28.8, 27.2.
FT-IR: 1692, 1667, 1525 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.07 (m, 4 H, PhH), 6.23 (br s, 2 H,
NH2), 4.69 (s, 1 H, CH), 4.05 (q, J = 7 Hz, 2 H, OCH2), 2.46 (s, 2 H, CH2),
2.24 and 2.20 (AB system, J = 16 Hz, 2 H, CH2), 1.18 (t, J = 7 Hz, 3 H,
CH3), 1.11 (s, 3 H, CH3), 1.00 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.6, 169.2, 161.9, 158.6, 148.2,
133.9, 129.3, 128.7, 126.9, 126.5, 116.4, 80.4, 60.1, 50.9, 40.9, 34.1,
32.5, 29.3, 27.7, 14.5.
Anal. Calcd for C19H20N2O2: C, 67.05; H, 5.92; N, 8.23. Found: C, 66.89;
H, 5.78; N, 8.32.
Anal. Calcd for C20H22ClNO4: C, 63.91; H, 5.90; N, 3.73. Found: C,
63.76; H, 5.98; N, 3.81.
2-Amino-7,7-dimethyl-5-oxo-4-pentyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4g)
Pale-yellow solid; yield: 257 mg (89%); mp 149–151 °C (Lit.19 150–
Ethyl 2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tet-
rahydro-4H-chromene-3-carboxylate (5c)
153 °C).
Yellow solid; yield: 317 mg (82%); mp 179–181 °C (Lit.8a 180–181 °C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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O. Rosati et al.
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Synthesis
FT-IR: 1695, 1652, 1520 cm–1
.
FT-IR: 2196, 1687, 1644 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.11 (d, J = 8.4 Hz, 2 H, PhH), 7.69
(br s, 2 H, NH2), 7.42 (d, J = 8.4 Hz, 2 H, PhH), 4.62 (s, 1 H, CH), 3.94 (q,
J = 7.1 Hz, 2 H, OCH2), 2.54 (d, J = 19 Hz, 1 H, HCH), 2.44 (d, J = 19 Hz, 1
H, HCH), 2.28 and 2.06 (AB system, J = 16 Hz, 2 H, CH2), 1.07 (t, J = 7.1
Hz, 3 H, CH3), 1.04 (s, 3 H, CH3), 0.88 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 196.5, 168.4, 163.4, 159.9, 154.9,
146.4, 129.9 (2 C), 123.8 (2 C), 115.1, 77.3, 59.7, 50.6, 40.3, 34.6, 32.6,
29.3, 27.3, 14.9.
1H NMR (400 MHz, DMSO-d6): δ = 7.33 (t, J = 7.5 Hz, 1 H, PhH), 7.26
(d, J = 7.5 Hz, 1 H, PhH), 7.19 (s, 1 H, PhH), 7.14 (d, J = 7 Hz, 1 H, PhH),
7.10 (br s, 2 H, NH2), 4.22 (s, 1 H, CH), 2.73–2.55 (m, 2 H, CH2), 2.41–
2.23 (m, 2 H, CH2), 1.83–2.02 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 165.6, 159.3, 148.0, 133.6,
131.0, 127.8, 127.3, 126.7, 120.3, 113.9, 58.3, 37.0, 36.0, 27.2, 20.5.
Anal. Calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C,
64.04; H, 4.31; N, 9.42.
Anal. Calcd for C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.31;
H, 5.63; N, 7.35.
2-Amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6c)
Yellowish crystals; yield: 290 mg (93%); mp 234–236 °C (Lit.6d 234–
236 °C).
Ethyl 2-Amino-4-[4-(methoxycarbonyl)phenyl]-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (5d)
White solid; yield: 348 mg (87%); mp 163–165 °C.
FT-IR: 2194, 1681, 1650 cm–1
.
FT-IR: 1719, 1689, 1657, 1608 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.17 (d, J = 8.6 Hz, 2 H, PhH), 7.47
(d, J = 8.6 Hz, 2 H, PhH), 7.18 (br s, 2 H, NH2), 4.37 (s, 1 H, CH), 2.72–
2.57 (m, 2 H, CH2), 2.39–2.20 (m, 2 H, CH2), 2.05–1.85 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 165.9, 159.3, 153.1, 147.0,
129.3 (2 C), 124.4 (2 C), 120.1, 113.5, 57.6, 36.9, 36.3, 27.3, 20.5.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8 Hz, 2 H, ArH), 7.35 (d, J = 8
Hz, 2 H, ArH), 6.27 (br s, 2 H, NH2), 4.75 (s, 1 H, CH), 4.02 (q, J = 7.1 Hz,
2 H, OCH2), 3.88 (s, 3 H, OCH3), 2.44 (s, 2 H, CH2), 2.25 and 2.14 (AB
system, J = 16 Hz, 2 H, CH2), 1.14 (t, J = 7.1 Hz, 3 H, CH3), 1.10 (s, 3 H,
CH3), 0.96 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.2, 168.8, 167.1, 161.6, 158.3,
151.1, 129.2 (2 C), 128.3 (2 C), 127.8, 116.0, 79.9, 59.7, 51.9, 50.5, 40.6,
34.0, 32.1, 29.1, 27.2, 14.1.
Anal. Calcd for C16H13N3O4: C, 61.73; H, 4.21; N, 13.50. Found: C,
61.60; H, 4.08; N, 13.59.
Methyl 4-(2-Amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-
chromen-4-yl)benzoate (6d)
Anal. Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.28;
H, 6.17; N, 3.71.
White solid; yield: 286 mg (88%); mp 234–235 °C.
FT-IR: 2192, 1725, 1681, 1646, 1606 cm–1
.
Ethyl 2-Amino-7,7-dimethyl-5-oxo-4-pentyl-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate (5g)
1H NMR (400 MHz, DMSO-d6): δ = 7.89 (d, J = 8 Hz, 2 H, PhH), 7.32 (d,
J = 8 Hz, 2 H, PhH), 7.10 (br s, 2 H, NH2), 4.27 (s, 1 H, CH), 3.83 (s, 3 H,
OCH3), 2.72–2.55 (m, 2 H, CH2), 2.41–2.20 (m, 2 H, CH2), 2.07–1.82 (m,
2 H, CH2).
Yellow oil; yield: 168 mg (50%).
FT-IR: 1688, 1667, 1615 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.15 (br s, 2 H, NH2), 4.26–4.09 (m, 2 H,
OCH2), 3.72 (t, J = 4.5 Hz, 1 H, CH), 2.34 (br s, 2 H, CH2), 2.26 (br s, 2 H,
CH2), 1.57–1.39 (m, 2 H, CH2), 1.26 (t, J = 7.1 Hz, 3 H, CH3), 1.37–0.96
(m, 6 H, 3 × CH2), 1.09 (s, 3 H, CH3), 1.05 (s, 3 H, CH3), 0.81 (t, J = 6.4
Hz, 3 H, CH3),
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 166.8, 165.6, 159.2, 150.9,
130.1 (2 C), 128.7, 128.4 (2 C), 120.2, 113.9, 58.2, 52.8, 37.0, 36.3, 27.2,
20.5.
Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.45;
H, 4.83; N, 8.77.
13C NMR (100 MHz, CDCl3): δ = 197.2, 169.5, 163.0, 159.4, 116.3, 78.9,
59.4, 50.8, 40.7, 34.9, 32.0, 31.9, 29.3, 27.2, 27.1, 24.3, 22.6, 14.4, 13.9.
2-Amino-5-oxo-4-pentyl-5,6,7,8-tetrahydro-4H-chromene-3-car-
bonitrile (6g)
Anal. Calcd for C19H29NO4: C, 68.03; H, 8.71; N, 4.18. Found: C, 68.21;
H, 8.93; N, 4.01.
White solid; yield: 232 mg (89%); mp 122–123 °C.
FT-IR: 2186, 1678, 1646, 1606 cm–1
.
2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-car-
1H NMR (400 MHz, CDCl3): δ = 4.52 (br s, 2 H, NH2), 3.43 (t, J = 4.6 Hz,
1 H, CH), 2.59–2.33 (m, 4 H, 2 × CH2), 2.16–1.94 (m, 2 H, CH2), 1.68–
1.41 (m, 2 H, CH2), 1.35–1.14 (m, 6 H, 3 × CH2), 0.87 (t, J = 6.4 Hz, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 196.7, 164.2, 158.7, 119.4, 115.1, 61.0,
36.9, 34.8, 31.6, 29.2, 26.9, 24.3, 22.5, 20.2, 14.0.
bonitrile (6a)
White solid; yield: 245 mg (92%); mp 235–236 °C (Lit.16 234–235 °C).
FT-IR: 2192, 1682, 1645 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.44–7.07 (m, 5 H, PhH), 7.00 (br s,
2 H, NH2), 4.20 (s, 1 H, CH), 2.72–2.54 (m, 2 H, CH2), 2.48–2.34 (m, 2 H,
CH2), 2.15–1.97 (m, 2 H, CH2).
.
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C,
69.05; H, 7.53; N, 10.87.
13C NMR (100 MHz, DMSO-d6): δ = 196.6, 165.2, 159.2, 145.5, 129.1 (2
C), 127.9 (2 C), 127.3, 120.5, 114.5, 59.0, 37.1, 36.2, 27.2, 20.5.
Anal. Calcd for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C,
72.33; H, 5.42; N, 10.38.
2-Amino-5-oxo-4-[(E)-2-phenylvinyl]-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6h)
Yellow solid; yield: 97 mg (33%); mp 193–195 °C (Lit.16 195–198 °C).
2-Amino-4-(3-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6b)
FT-IR: 2190, 1679, 1648, 1608 cm–1
.
White solid; yield: 259 mg (80%); mp 224–224 °C (Lit.20 223–224 °C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
O. Rosati et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.42–7.15 (m, 5 H, PhH), 6.52 (d, J = 16
Hz, 1 H, CHCH=CHPh), 6.12 (dd, J = 7.0, 16.0 Hz, 1 H, CHCH=CH), 4.68
(br s, 2 H, NH2), 4.11 (d, J = 7 Hz, 1 H, CH), 2.64–2.36 (m, 4 H, 2 × CH2),
2.17–1.98 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 196.5, 163.7, 158.6, 137.1, 131.2,
130.1, 128.7 (2 C), 127.8, 126.8 (2 C), 119.1, 114.7, 60.8, 37.1, 32.7,
27.3, 20.4.
FT-IR: 1687, 1663, 1610 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.2 Hz, 2 H ArH), 7.36 (d,
J = 8.2 Hz, 2 H ArH), 6.24 (br s, 2 H, NH2), 4.83 (s, 1 H, CH), 3.96–4.11
(m, 2 H, OCH2), 3.88 (s, 3 H, OCH3), 2.69–2.50 (m, 2 H, CH2), 2.43–2.28
(m, 2 H, CH2), 2.12–1.86 (m, 2 H, CH2), 1.13 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.7, 169.1, 167.4, 163.6, 158.6,
151.6, 129.5 (2 C), 128.7 (2 C), 128.2, 117.7, 80.2, 60.0, 52.2, 37.1, 34.4,
27.2, 20.5, 14.5.
Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C, 74.15;
H, 5.40; N, 9.67.
Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N, 3.77. Found: C, 64.88;
H, 5.83; N, 3.56.
Ethyl 2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-
3-carboxylate (7a)
Ethyl 2-Amino-5-oxo-4-pentyl-5,6,7,8-tetrahydro-4H-chromene-
White solid; yield: 216 mg (69%); mp 188–190 °C.
3-carboxylate (7g)
FT-IR: 1684, 1653, 1613 cm–1
.
Yellow oil; yield: 157 mg (51%).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.08 (m, 5 H, PhH), 6.20 (br s, 2 H,
NH2), 4.75 (s, 1 H, CH), 4.18–4.03 (m, 2 H, OCH2), 2.69–2.51 (m, 2 H,
CH2), 2.46–2.28 (m, 2 H, CH2), 2.13–1.91 (m, 2 H, CH2), 1.16 (t, J = 7.1
Hz, 3 H, CH3).
1H NMR (400 MHz, CDCl3): δ = 6.12 (br s, 2 H, NH2), 4.23–4.04 (m, 2 H,
OCH2), 3.68 (t, J = 4.5 Hz, 1 H, CH), 2.58–2.24 (m, 4 H, 2 × CH2), 2.10–
1.83 (m, 2 H, CH2), 1.21 (t, J = 7.1 Hz, 3 H, CH3), 1.47–0.92 (m, 8 H, 4 ×
CH2), 0.76 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.8, 169.4, 163.3, 158.6, 146.3,
128.5 (2 C), 128.1 (2 C), 126.3, 118.4, 81.1, 59.9, 37.2, 34.1, 27.2, 20.5,
14.5.
13C NMR (100 MHz, CDCl3): δ = 197.7, 169.7, 165.0, 159.7, 117.8, 79.1,
59.7, 37.2, 35.4, 32.2, 27.4, 27.2, 24.5, 22.9, 20.7, 14.7, 14.3.
Anal. Calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56. Found: C, 66.55;
H, 8.01; N, 4.37.
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 69.14;
H, 6.23; N, 4.34.
Ethyl 2-aAmino-4-(3-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carboxylate (7b)
Supporting Information
Supporting information for this article is available online at
Yellow solid; yield: 278 (80%); mp 181–183 °C.
http://dx.doi.org/10.1055/s-0035-1560411.
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FT-IR: 1685, 1654, 1614 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.14–7.08 (m, 4 H, PhH), 6.25 (br s, 2 H,
NH2), 4.71 (s, 1 H, CH), 4.05 (q, J = 7.1 Hz, 2 H, OCH2), 2.70–2.51 (m, 2
H, CH2), 2.46–2.30 (m, 2 H, CH2), 2.14–1.92 (m, 2 H, CH2), 1.16 (t,
J = 7.1 Hz, 3 H, CH3),
13C NMR (100 MHz, CDCl3): δ = 196.7, 169.2, 163.6, 158.6, 148.4,
133.8, 129.3, 128.7, 127.0, 126.5, 117.7, 80.4, 60.0, 37.1, 34.1, 27.2,
20.5, 14.5.
References
(1) (a) Wickel, S. M.; Citron, C. A.; Dickschat, J. S. Eur. J. Org. Chem.
2013, 2906. (b) Dong, Z.; Liu, X.; Feng, J.; Wang, M.; Lin, L.; Feng,
X. Eur. J. Org. Chem. 2011, 137. (c) Henrikson, J. C.; Ellis, T. K.;
King, J. B.; Cichewicz, R. H. J. Nat. Prod. 2011, 74, 1959. (d) Moafi,
L.; Ahadi, S.; Bazgir, A. Tetrahedron Lett. 2010, 51, 6270.
(e) Gibbons, S.; Denny, B. J.; Ali-Amine, S.; Mathew, K. T.;
Skelton, B. W.; White, A. H.; Gray, A. I. J. Nat. Prod. 2000, 63, 839.
(f) Uckun, F. M.; Chen, M.; Vassilev, A. O.; Huang, H.; Jan, S.-T.
Bioorg. Med. Chem. Lett. 2000, 10, 541. (g) González, R.; Martín,
N.; Seoane, C.; Marco, J. L.; Albert, A.; Cano, F. H. Tetrahedron
Lett. 1992, 33, 3809. (h) Hatakeyama, S.; Ochi, N.; Numata, H.;
Takano, S. J. Chem. Soc., Chem. Commun. 1988, 1202.
(2) (a) Litvinov, Y. M.; Shestopalov, A. M. Adv. Heterocycl. Chem.
2011, 103, 175. (b) Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.;
Kapur, S. Eur. J. Med. Chem. 2009, 44, 3805.
(3) The Chemistry of Heterocyclic of Compounds; Vol. 31;
Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1977.
(4) Hafez, E. A. A.; Elnagdi, M. H.; Elagamey, A. G. A.; El-Taweel, F. M.
A. A. Heterocycles 1987, 26, 903.
(5) Nakhi, A.; Rahman, M. S.; Archana, S.; Kishore, R.; Seerapu, G. P.
K.; Lalith, K. K.; Haldar, D.; Pal, M. Bioorg. Med. Chem. Lett. 2013,
23, 4195.
(6) (a) Dekamin, M. G.; Eslami, M.; Maleki, A. Tetrahedron 2013, 69,
1074. (b) Liu, J.; Li, J.; Zhang, L.; Song, L.; Zhang, M.; Cao, W.;
Zhu, S.; Deng, H.; Shao, M. Tetrahedron Lett. 2012, 53, 2469.
(c) Tian, J. J.; Guo, H. Y. Youji Huaxue 2011, 31, 2009. (d) Xu, J.-C.;
Li, W.-M.; Zheng, H.; Lai, Y.-F.; Zhang, P.-F. Tetrahedron 2011, 67,
9582. (e) Bhattacharyya, P.; Pradhan, K.; Paul, S.; Das, A. R. Tet-
Anal. Calcd for C18H18ClNO4: C, 62.16; H, 5.22; N, 4.03. Found: C,
62.05; H, 5.34; N, 4.17.
Ethyl 2-Amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carboxylate (7c)
White solid; yield: 312 mg (87%); mp 179–181 °C (Lit.6d 181–182 °C).
FT-IR: 1689, 1658, 1613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.7 Hz, 2 H, PhH), 7.46 (d,
J = 8.7 Hz, 2 H, PhH), 6.17 (br s, 2 H, NH2), 4.82 (s, 1 H, CH) 4.11–3.97
(m, 2 H, OCH2), 2.70–2.54 (m, 2 H, CH2), 2.42–2.30 (m, 2 H, CH2), 2.15–
1.92 (m, 2 H, CH2), 1.13 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.7, 168.9, 163.9, 158.7, 153.9,
146.6, 129.5 (2 C), 123.5 (2 C), 117.1, 79.6, 60.1, 37.0, 34.5, 27.3, 20.4,
14.5.
Anal. Calcd for C18H18N2O6: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.44;
H, 5.16; N, 7.74.
Ethyl 2-Amino-4-[4-(methoxycarbonyl)phenyl]-5-oxo-5,6,7,8-tet-
rahydro-4H-chromene-3-carboxylate (7d)
White solid; yield: 311 mg (84%); mp 167–169 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
O. Rosati et al.
Paper
Synthesis
rahedron Lett. 2012, 53, 4687. (f) Fotouhi, L.; Heravi, M. M.;
Fatehi, A.; Bakhtiari, K. Tetrahedron Lett. 2007, 48, 5379.
(g) Peng, Y.; Song, G. Catal. Commun. 2007, 8, 111.
(12) Costantino, U.; Marmottini, F.; Curini, M.; Rosati, O. Catal. Lett.
1993, 22, 333.
(13) Curini, M.; Rosati, O.; Costantino, U. Curr. Org. Chem. 2004, 8,
591.
(7) Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetrahedron 2003,
59, 3753.
(14) Curini, M.; Epifano, F.; Chimichi, S.; Montanari, F.; Nocchetti,
M.; Rosati, O. Tetrahedron Lett. 2005, 46, 3497.
(15) Temperini, A.; Barattucci, A.; Bonaccorsi, P. M.; Rosati, O.;
Minuti, L. J. Org. Chem. 2015, 80, 8102.
(16) Rajput, J. K.; Kaur, G. Catal. Sci. Technol. 2014, 4, 142.
(17) Suárez, M.; Salfrán, E.; Verdecia, Y.; Ochoa, E.; Alba, L.; Martín,
N.; Martínez, R.; Quinteiro, M.; Seoane, C.; Novoa, H.; Blaton, N.;
Peeters, O. M.; De Ranter, C. Tetrahedron 2002, 58, 953.
(18) Jin, T.-S.; Zhang, J.-S.; Xiao, J.-C.; Wang, A.-Q.; Li, T.-S. Synlett
2004, 866.
(8) (a) Guo, R. Y.; An, Z.-M.; Mo, L.-P.; Wang, R.-Z.; Liu, H.-X.; Wang,
S.-X.; Zhang, Z.-H. ACS Comb. Sci. 2013, 15, 557. (b) Maheshwar,
R. B.; Reddy, G. N.; Reddy, T. V.; Devi, B. L. A. P.; Prasad, R. B. N.;
Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2013, 54, 2466.
(c) Karmakar, B.; Nayak, A.; Banerji, J. Tetrahedron Lett. 2012, 53,
5004. (d) Sun, W.-B.; Zhang, P.; Fan, J.; Chen, S.-H.; Zhang, Z.-H.
Synth. Commun. 2010, 40, 587. (e) Surpur, M. P.; Kshirsagar, S.;
Samant, S. Tetrahedron Lett. 2009, 50, 719. (f) Devi, I.; Bhuyan, P.
T. Tetrahedron Lett. 2004, 45, 8625.
(9) Safaei, H. R.; Shekouhy, M.; Rahmanpur, S.; Shirinfeshan, A.
Green Chem. 2012, 14, 1696.
(19) Abdel-Latif, F. F.; Masahaly, M. M.; El-Gawish, E. H. J. Chem. Res.,
Synop. 1995, 5, 178.
(10) (a) Hattori, H. Chem. Rev. 1995, 95, 537. (b) Corma, A. Chem. Rev.
1995, 95, 559.
(20) Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R.
J. Org. Chem. 2012, 77, 878.
(11) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H