Synthesis of 5-Amino-1,10b-dihydro-2 H-chromeno[3,4-c ]pyridine-2,4(3 H)-diones from coumarins and cyanoacetamides under basic conditions

Article abstract of DOI:10.1055/s-0029-1217128

The reaction of various coumarins with cyanoacetamide derivatives under basic conditions (sodium ethoxide, piperidine or 2,2,6,6-tetramethylpiperidine), proceeds via an interesting process which involves skeletal rearrangement of the coumarin, a Michael addition and two cyclizations to afford 5-amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-diones. The same reaction in the presence of N,N￠-ethane-1,2-diylbis(2-cyanoacetamide) gives the corresponding mono and bis 5-amino-1,10b-dihydro-2H-chromeno[3,4-c] pyridine-2,4(3H)-diones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217128

PAPER
239
Synthesis of 5-Amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-
diones from Coumarins and Cyanoacetamides under Basic Conditions
5
-Amino-1,10b-dih
r
ydro-2
H
n
-chromeno[
e
3,4-
c
]pyrid
l
ine-2,4
i
(3
H
)-di
o
ones Rosati,*a Massimo Curini,*a Maria Carla Marcotullio,*a Gildas Oball-Mond,a Caroline Pelucchini,*a
Antonio Procopio*b
a
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia (PG), Italy
Dipartimento Farmaco-Biologico, Università degli Studi della Magna Græcia Complesso Ninì Barbieri, 88021 Roccelletta di Borgia
b
(CZ), Italy
Fax +39(075)5855116; E-mail: ornros@unipg.it
Received 28 May 2009; revised 23 September 2009
O
R1
R2
Abstract: The reaction of various coumarins with cyanoacetamide
derivatives under basic conditions (sodium ethoxide, piperidine or
2,2,6,6-tetramethylpiperidine), proceeds via an interesting process
which involves skeletal rearrangement of the coumarin, a Michael
addition and two cyclizations to afford 5-amino-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-diones. The same reaction in the
presence of N,N¢-ethane-1,2-diylbis(2-cyanoacetamide) gives the
corresponding mono and bis 5-amino-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-diones.
CN
O
EtO
R3
Br
OEt
NH2
R
O
NH2
O
1
2 (HA14-1)
Figure 1 Examples of 2-amino-4H-chromene derivatives
During a recent study in the coumarin field,7 we devel-
oped a one-pot method to prepare 2-amino-4H-chromenes
by means of the reaction of coumarins with cyanoacetate
derivatives in the presence of nucleophilic bases such as
alkoxides or piperidine. This process involved both a cou-
marin skeletal rearrangement and a Michael addition via a
coumaric acid intermediate to afford a substituted 4H-
chromene or a 2-chromanone derivative (Scheme 1).8
Key words: coumarins, Michael addition, heterocycles, cycliza-
tions, chromenes
The 2-aminochromene skeleton is an important heterocy-
clic system found in many structures that possess biolog-
ical activity and which have various applications.1 The
significance of this class of compounds justifies efforts to
develop simple routes for their synthesis. Several methods
have been reported for the preparation of these com-
pounds using one-pot procedures.1,2 For example, a fre-
quently exploited method to synthesize 2-amino-4H-
chromenes such as 1 (Figure 1) requires the use of a sali-
cylaldehyde derivative and an excess of a cyanoacetyl es-
ter under basic heterogeneous catalysis.3–6
Our interest in this class of compounds derived from the
biological consideration that several 4H-chromene deriv-
atives, for example, HA14-1 (2, Figure 1), bind to the Bcl-
2 protein and induce apoptosis in tumor cells.9 The Bcl-2
protein is a promising target in the fight against cancer,
and could be useful in avoiding drug resistance, one of the
NC
COR2
NCCH2COR2
COR1
R1ONa/R1OH
or
COR1
piperidine
OH
OH
O
O
5a R1 = R2 = OEt
4a R1 = OEt
4b R1 = OMe
4c R1 = C5H10
3a
5b R1 = R2 = OMe
5c R1 = C5H10N, R2 = OEt
5d R1 = R2 = C5H10
N
N
COR1
COR1
COR2
CN
+
O
NH2
O
O
7a R1 = OEt
6a R1 = R2 = OEt
7b R1 = OMe
6b R1 = R2 = OMe
7c R1 = C5H10
N
6c R1 = C5H10N, R2 = OEt
Scheme 1 Synthesis of 2-amino-4H-chromene and 2-chromanone derivatives
SYNTHESIS 2010, No. 2, pp 0239–0248
x
x
.
x
x
.2
0
0
9
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217128; Art ID: T10909SS
© Georg Thieme Verlag Stuttgart · New York

240
O. Rosati et al.
PAPER
major problems in this field.10 At the molecular level, drug Many of the cyanoacetamide derivatives used in this re-
resistance can be acquired through over-expression of search (Figure 2) were easily prepared from methyl cy-
anti-apoptotic Bcl-2 proteins which protect cancer cells anoacetate and an appropriate amino derivative using a
from apoptosis induced by cancer therapy.11 The potential reported procedure.13
to inhibit anti-apoptotic Bcl-2 proteins is a promising ap-
O
proach to overcoming drug resistance in cancer treatment,
O
as has been demonstrated by research in this field.12
H
NC
NC
N
H
N
H
In our efforts to synthesize new functionalized 4H-
chromenes starting from coumarins, we investigated the
reaction using cyanoacetamide derivatives under the same
conditions as those reported in Scheme 1. In line with our
previous results,8 the use of cyanoacetamides should yield
substituted chromene derivatives 9 (Scheme 2). However,
when the reaction of coumarin (3a) with 2-cyanoacet-
amide (8a, R = H) was carried out using sodium ethoxide
in ethanol, a compound with spectroscopic characteristics
different from those expected for chromene 9a, was ob-
tained.
The 1H NMR spectrum of the product in DMSO-d6 did not
show the presence of an ethoxy group, however, signals
due to aromatic protons and three distinct doublet of dou-
blets at 2.46, 3.11 and 4.02 ppm were evident. The occur-
rence of the three doublet of doublets along with the
8a
8b
O
O
NC
NC
N
CO2Me
N
Ph
Ph
H
8c
H
8d
H
N
O
O
OTBDMS
NC
NC
Ph
N
H
N
H
8f
8e
O
O
O
NC
NC
NC
Ph
N
H
N
N
H
H
8g
8h
8i
associated coupling constants could be explained by the Figure 2 Structures of cyanoacetamides 8a–i
presence of two methylene and one methine protons on a
rigid cyclic system, such as that found in 5-amino-1,10b-
The preparation of cyanoacetamide 8e required initial se-
lective protection of the hydroxy group of 2-aminoethanol
using tert-butyldimethylsilyl chloride and imidazole.14
dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-dione 10a
(R = H) (Scheme 2). The formation of 10a occurs via cy-
clization between the amide group and the carboxy ester
side chain of the intermediate 9a, leading to an additional
heterocyclic ring on the 4H-chromene skeleton.
Treatment of cyanoacetamides 8b–f with sodium ethox-
ide in ethanol, followed by addition of coumarin (3a) at 60
°C, afforded the corresponding 5-amino-1,10b-dihydro-
2H-chromeno[3,4-c]pyridine-2,4(3H)-diones 10b–f. Un-
der these reaction conditions, the use of cyanoacetamide
8g afforded a mixture of the two amino-chromene deriva-
tives 9g and 10g, while cyanoacetamides 8h and 8i gave
only 2-amino-4H-chromenes 9h and 9i, respectively
(Table 1).
O
O
R
EtO
O
N
NHR
NH2
O
8a–i
3a
EtONa, EtOH
60 °C
O
O
NH2
9g–i
10a–g
The increase in steric hindrance at the carbon atom adja-
cent to the nitrogen of the amide group in cyanoacet-
amides 8g–i may impede or completely prevent
cyclization of 2-amino-4H-chromene intermediates 9g–i.
Scheme 2 Synthesis of 5-amino-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-diones using sodium ethoxide as base
Furthermore, the 13C NMR spectrum was consistent with
the structure of compound 10a, showing the presence of
twelve carbon atoms, among which a quaternary carbon
was observed at 72.8 ppm being typical of an olefinic car-
bon at position 3 of a 2-aminochromene.8 5-Amino-1,10b-
dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-dione 10a
represents a new heterocyclic skeleton possessing a 2-
aminochromene core.
Only small amounts of the starting coumarin (4–7%)
could be recovered after work-up. The poor-to-moderate
yields of the products was due to the formation of by-
products. These by-products were characterized by very
low retention factors (Rf) on thin layer chromatography,
and always appeared below the spot due to the major ad-
duct. It was difficult to resolve the mixture of these by-
products, and we can only hypothesize on their structures
as being mixtures of ring-opened coumarin intermediates
similar to those reported in our previous work.8
The possibility to access complex heterocycles using one-
pot processes is very important in organic chemistry.
Therefore we decided to carry out a more detailed inves-
tigation of the synthesis of 5-amino-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-diones under basic
conditions starting from coumarin (3a) and various cy-
anoacetamide derivatives.
To extend the applicability of this process we also consid-
ered the possibility of using functionalized coumarins
such as 6-methylcoumarin (3b), 7-methoxycoumarin (3c)
and 6-nitrocoumarin (3d). Since coumarins 3b and 3c
demonstrated an unusual lack of reactivity under basic
Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York

PAPER
5-Amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-diones
241
Table 1 Reaction of Coumarin (3a) with Cyanoacetamides 8a–ia
amides was restricted to the less sterically hindered deriv-
atives 8a–d as shown in Table 2.
Entry
Cyanoacetamide Time (h) Yield (%)b
Yield (%)b
of 9
of 10
O
R2
1
2
3
4
5
6
7
8
9
8a
16
20
18
20
20
23
20
20
20
–
52
48
26
33
33
20
10
–
N
NC CONHR2
8a–d
piperidine
(or 2,2,6,6-TMP)
EtOH, 60 °C
8b15
8cc
–
O
O
O
R1
–
O
NH2
R1
3a R1 = H
10a–d R1 = H
8d16
8e
–
3b R1 = 6-Me
11a–d R1 = 9-Me
12a–d R1 = 8-OMe
13a–d R1 = 9-NO2
3c R1 = 7-OMe
3d R1 = 6-NO2
–
8f17
8g18
8h13
8i13
–
Scheme 3 Synthesis of various 5-amino-1,10b-dihydro-2H-chro-
meno[3,4-c]pyridine-2,4(3H)-diones using piperidine or 2,2,6,6-te-
tramethylpiperidine as base
19
21
37
In the case of coumarin (3a), a comparison is possible to
establish the efficiency of the basic media used for the re-
action. When the reaction of 3a was carried out in the
presence of piperidine or 2,2,6,6-tetramethylpiperidine
(2,2,6,6-TMP), the reaction yields were superior to those
obtained using sodium ethoxide. The use of 6-nitrocou-
marin (3d) afforded the expected chromenes 13a,b,d, al-
beit in lower yields compared to the products of
coumarins 3a–c and, at the same time, an increase in the
amount of by-products was observed.
–
a Reagents and conditions: 3a (1 equiv), cyanoacetamide (2 equiv),
EtONa (1.2 equiv), EtOH, 60 °C.
b Yield of isolated product.
c MeONa and MeOH were used to avoid transesterification.
conditions mediated by alkoxides, as reported in our pre-
vious work,8 we limited the use of these coumarin deriva-
tives to reactions promoted by piperidine or 2,2,6,6-
tetramethylpiperidine (Scheme 3). The use of cyanoacet-
Table 2 Reactions of Coumarins 3a–d with Cyanoacetamides 8a–da
Entry
Coumarin
Cyanoacetamide
Adduct
Piperidine
2,2,6,6-TMP
Time (h)
Time (h)
24
Yield (%)b
Yield (%)b
1
2
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
8a
8b
8c
8d
8a
8b
8c
8d
8a
8b
8c
8d
8a
8b
8c
8d
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
65
48
18
65
47
23
17
66
48
30
12
49
45
11
–
22
20
22
24
22
21
21
22
24
24
24
6
70
52
41
72
83
55
38
75
82
58
26
77
68
21
–
24
3
24
4
24
5
24
6
24
7
20
8
24
9
24
10
11
12
13
14
15
16
24
24
22
24
18
22
21
3
23
23
5
13
24
a Reagents and conditions: coumarin (1 equiv), cyanoacetamide (1.2 equiv), piperidine or 2,2,6,6-TMP (2 equiv), EtOH, 60 °C.
b Yield of isolated product.
Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York

242
O. Rosati et al.
PAPER
This procedure was also extended to the use of the cy- and 14 were solved ab initio from laboratory X-ray pow-
anoacetamide isostere, 1H-benzimidazol-2-ylacetonitrile der diffraction data (XRPD) (Figure 3).19
(8j),15 which on reaction with coumarin (3a) gave
Another interesting application of this process involved
chromene 14 in 33% yield (Scheme 4), but only in the
the reaction with N,N¢-ethane-1,2-diylbis(2-cyanoacet-
presence of sodium ethoxide as base. It is assumed that pi-
amide) (8k),20 which enabled the synthesis of mono and
bis 5-amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-
2,4(3H)-dione derivatives 15–17 (Scheme 5).
peridine and 2,2,6,6-tetramethylpiperidine were not suffi-
ciently basic to remove the acidic proton from the
activated methylene group of 8j. Despite the low yield,
this reaction could prove to be very important for obtain-
ing unusually complex polycyclic systems in a one-pot
process starting from simple commercially available com-
pounds.
With the aim of preparing bis-derivatives 15b–17b, the
above reaction was carried out on coumarins 3a–c using
0.4 equivalents of N,N¢-ethane-1,2-diylbis(2-cyanoacet-
amide) (8k) in the presence of one equivalent of piperidine
or 2,2,6,6-tetramethylpiperidine as base, in ethanol at 80
°C. The reaction was characterized by the formation of a
O
white solid which precipitated from the reaction mixture.
N
H
After the appropriate amount of time, the reaction mixture
was cooled and then filtered to afford a white solid. When
coumarin (3a) or 6-methylcoumarin (3b) was used, the re-
sulting white solid product was identified as the bis 5-ami-
no-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-
dione derivative 15b or 16b, respectively.21 Under the
same reaction conditions, 7-methoxycoumarin (3c) gave a
mixture of mono and bis derivatives 17a and 17b. The
best results were obtained consistently using 2,2,6,6-tet-
ramethylpiperidine as base. Our efforts to increase the re-
action yield using one equivalent of 8k always afforded a
mixture of mono and bis 5-amino-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-diones (Table 3).
NC
N
N
3a
EtONa/EtOH
60 °C
N
O
NH2
14 33%
8j
Scheme 4 Synthesis of aminochromene 14
The structures of compounds 10a and 14 were confirmed
by crystallographic analysis. Although several attempts to
obtain crystals of suitable dimensions for single crystal X-
ray analysis proved unsuccessful, the structures of 10a
Figure 3 ORTEP structures and atom labelling schemes for 10a and 14. For reasons of clarity the hydrogen atoms are not labelled. Thermal
ellipsoids are set at 50% probability.
H2N
O
O
H
N
O
O
R
O
H
N
N
CN
NC
N
N
N
H
CN
O
O
+
O
O
O
8k
O
O
base, EtOH, 80 °C
R
O
NH2
O
NH2
R
R
15b R = H
16b R = 9-Me
17b R = 8-OMe
3a R = H
15a R = H
16a R = 9-Me
17a R = 8-OMe
3b R = 6-Me
3c R = 7-OMe
Scheme 5 Synthesis of mono and bis 5-amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-diones 15–17
Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York

PAPER
5-Amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-diones
243
Table 3 Reactions of Coumarins 3a–c with 8ka
Coumarin
Products
Piperidine
Time (h)
2,2,6,6-TMP
Yield (a/b) (%)b
– (23)/38 (17)
– (24)/39 (19)
11 (19)/13 (9)
Time (h)
22 (22)
24 (24)
24 (22)
Yield (a/b) (%)b
– (37)/56 (23)
– (35)/57 (21)
18 (31)/22 (11)
3a
3b
3c
15a/15b
16a/16b
17a/17b
22 (12)
22 (15)
24 (16)
a Reagents and conditions: coumarin (1 equiv), 8k (0.4 equiv), base (1 equiv), EtOH, 80 °C. The values in parentheses refer to reactions using
1.2 equiv of 8k.
b Yield of isolated product.
at 60 °C for the appropriate amount of time (see Table 2). In several
cases, the product precipitated from the reaction as a white powder
and was isolated by filtration. In cases were the product did not pre-
cipitate, the mixture was concd to half volume then poured onto
H2O and acidified with 1 N HCl until pH 3–4. The product was ex-
tracted with CH2Cl2 or EtOAc and the combined organic layer was
dried over Na2SO4 and then concd under vacuum. The crude residue
was purified by column chromatography or by crystallization.
In addition to the novelty of these results, the advantage of
this method is the possibility of developing the procedure
to access complex carbocyclic products via a one-pot re-
action. Despite the poor-to-moderate yields, compounds
15b, 16b and 17b may represent interesting scaffolds for
new DNA-bisintercalating models.22 Compounds 15a,
16a and 17a can also be considered as interesting starting
materials for the potential synthesis of non-symmetrical
DNA-intercalating models. The presence of a cyanoacet-
amido moiety in these compounds could be exploited in
order to perform several multicomponent or Biginelli-
type reactions to generate a modified secondary heterocy-
clic system.
Coumarins 15a–17a and 15b–17b; General Procedure
To a soln of 8k (0.4 mmol or 1 mmol) in EtOH (2 mL) at r.t. under
N2, piperidine or 2,2,6,6-tetramethylpiperidine (1 mmol or 1.2
mmol) was added. After stirring for 15 min, a soln of coumarin
3a–c (1 mmol) in EtOH (2 mL) was added and reaction stirred at 80
°C for the appropriate amount of time (see Table 3). During the re-
action a white solid precipitated from the soln. The reaction mixture
was cooled to r.t. and the white solid product was isolated by filtra-
tion. The bis 5-amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-
2,4(3H)-diones 15b–17b always had higher Rf values (TLC) com-
pared to the mono derivatives 15a–17a. The products were separat-
ed by flash column chromatography on silica gel (CH2Cl2–MeOH,
19:1).
All chemicals were purchased from commercial sources as highest
purity grades and were used without any further purification. Col-
umn chromatography was performed with Merck silica gel 60 (70–
230 mesh, ASTM), using mixtures of CH2Cl2–EtOAc or CH2Cl2–
MeOH as eluent. Melting points were recorded using an Electro-
thermal 9100 apparatus and are uncorrected. FT-IR spectra were
obtained using a Jasco model 410 spectrometer with ATR sampling.
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 us-
ing Bruker Avance DRX 200 [200.1 (1H) and 50 MHz (13C), respec-
tively] or Bruker Avance DPX 400 [400.13 (1H) and 100.62 MHz
(13C), respectively] spectrometers. Chemical shifts (d) are reported
in ppm relative to TMS; J values are given in Hz. GC–MS analyses
were obtained using an HP-6890 gas chromatograph (dimethyl sili-
cone column, 12.5 m) equipped with an HP-5973 mass-selective de-
tector at an ionizing voltage of 70 eV. Elemental analyses were
recorded using a Carlo Erba 1106 elemental analyzer.
Methyl [(Cyanoacetyl)amino]acetate (8c)
White solid; yield: 53%; mp 73–75 °C.
1H NMR (200 MHz, DMSO-d6): d = 3.68 (s, 3 H, OCH3), 3.75 (s, 2
H, NCCH2) 3.93 (d, J = 5.8 Hz, 2 H, NHCH2), 8.73 (br t, J = 5.8 Hz,
1 H, NHCH2).
13C NMR (50 MHz, DMSO-d6): d = 25.4, 41.3, 52.2, 116.3, 163.2,
170.2.
GC–MS: m/z = 156 [M+], 124, 97, 84, 68.
Anal. Calcd for C6H8N2O3: C, 46.15; H, 5.16; N, 17.94. Found: C,
45.97; H, 5.26; N, 17.78.
Coumarins 9g–i, 10a–g and 14 Using Sodium Ethoxide as Base;
General Procedure
To a soln of NaOEt (1.2 mmol) in EtOH (2 mL) at r.t. under N2, a
soln of cyanoacetamide derivative (2 mmol) in EtOH (1 mL) was
added. After stirring for 20 min, a soln of coumarin (3a) (1 mmol)
in EtOH (2 mL) was added and the reaction was stirred at 60 °C for
the appropriate amount of time (see Table 1). The reaction mixture
was concd to half volume then poured onto H2O and extracted with
CH2Cl2 or EtOAc. The organic layer was dried over Na2SO4, concd
under vacuum and the crude residue was purified by column chro-
matography or by crystallization to afford chromenes 9g–i, 10a–g
and 14.
N-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-2-cyanoacetamide
(8e)
Yellow oil; yield: 61%.
1H NMR (400 MHz, CDCl3): d = 0.08 [s, 6 H, (CH3)2Si], 0.91 [s, 9
H, C(CH3)3], 3.39 (s, 2 H, NCCH2), 3.43 (t, J = 5.2 Hz, 2 H, NCH2),
3.71 (t, J = 5.2 Hz, 2 H, OCH2), 6.63 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = –5.1, 18.5, 26.11, 26.14, 42.6,
61.5, 114.9, 161.2.
GC–MS: m/z = 242 [M+], 227, 185, 144, 100.
Anal. Calcd for C11H22N2O2Si: C, 54.51; H, 9.15; N, 11.56. Found:
C, 54.64; H, 9.29; N, 11.41.
Coumarins 10a–d, 11a–d, 12a–d and 13a,b,d Using Piperidine
or 2,2,6,6-Tetramethylpiperidine as Base; General Procedure
To a soln of cyanoacetamide derivative (1.2 mmol) in EtOH (2 mL)
at r.t. under N2, piperidine or 2,2,6,6-tetramethylpiperidine (2
mmol) was added. After stirring for 15 min, a soln of coumarin 3a–
d (1 mmol) in EtOH (2 mL) was added and the reaction was stirred
Ethyl {2-Amino-3-[(isopropylamino)carbonyl]-4H-chromen-4-
yl}acetate (9g)
White solid; mp 178–180 °C.
Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York

244
O. Rosati et al.
PAPER
IR (KBr): 3307, 1675, 1632 cm–1.
Anal. Calcd for C12H10N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C,
62.68; H, 4.36; N, 12.04.
1H NMR (400 MHz, DMSO-d6): d = 0.88 (d, J = 6.5 Hz, 3 H, CH3),
0.92 (d, J = 6.5 Hz, 3 H, CH3), 1.23 (t, J = 7.1 Hz, 3 H, CH3), 2.07
(dd, J = 13.3, 9.4 Hz, 1 H, HaCHbCO), 2.30 (dd, J = 13.3, 4.1 Hz, 1
H, HaCHbCO), 3.71–3.82 (m, 1 H, CHMe2), 4.06–4.22 (m, 3 H,
OCH2, H-4), 6.99 (d, J = 7.9 Hz, 1 H, H-8), 7.05 (t, J = 7.6 Hz, 1 H,
H-6), 7.16–7.26 (m, 2 H, H-5, H-7), 7.34 (d, J = 7.6 Hz, 1 H,
NHCO), 7.52 (br s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): d = 15.3, 22.9, 23.1, 31.6, 40.6,
46.1, 59.3, 76.1, 116.2, 124.6, 126.9, 128.2, 129.4, 150.2, 162.6,
168.8, 169.6.
5-Amino-3-propyl-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (10b)
White solid; mp 140–141 °C.
IR (neat): 3393, 3284, 1699, 1651, 1608 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.91 (t, J = 7.1 Hz, 3 H,
CH3CH2CH2N), 1.48–1.73 (m, 2 H, CH3CH2CH2N), 2.59 (dd,
J = 15.6, 14.1 Hz, 1 H, HaCHbCO), 3.21 (dd, J = 15.6, 4.4 Hz, 1 H,
HaCHbCO), 3.64–3.95 (m, 2 H, CH3CH2CH2N), 4.01 (dd, J = 14.1,
4.4 Hz, 1 H, H-10b), 6.96 (d, J = 7.9 Hz, 1 H, H-7), 7.09–7.19 (m,
3 H, H-8, H-9, H-10).
GC–MS: m/z = 318 [M+], 272, 229, 215, 186, 172.
Anal. Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C,
64.06; H, 6.91; N, 8.75.
13C NMR (50 MHz, CDCl3): d = 11.4, 21.7, 26.8, 39.6, 41.1, 74.6,
116.3, 122.6, 125.0, 126.6, 128.5, 148.7, 159.9, 168.1, 170.9.
Ethyl (2-Amino-3-{[(1-phenylethyl)amino]carbonyl}-4H-
chromen-4-yl)acetate (9h)
White solid; 3:2 mixture of diastereoisomers.
IR (KBr): 3306, 1674, 1633 cm–1.
GC–MS: m/z = 272 [M+], 256, 244, 229, 186, 172, 159, 145.
Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.25; H, 5.98; N, 10.26.
Methyl {5-Amino-2,4-dioxo-1,10b-dihydro-2H-chromeno[3,4-
c]pyridin-3(4H)-yl}acetate (10c)
White solid; mp 177–178 °C.
IR (neat): 3382, 1738, 1703, 1660, 1614 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.75 (dd, J = 15.8, 14.0 Hz, 1 H,
HaCHbCO), 3.33 (dd, J = 15.8, 4.4 Hz, 1 H, HaCHbCO), 3.79 (s, 3
H, OCH3), 4.15 (dd, J = 14.0, 4.4 Hz, 1 H, H-10b), 4.56 (d, J = 16.8
Hz, 1 H, NHaCHbCO), 4.73 (d, J = 16.8 Hz, 1 H, NHaCHbCO), 7.03
(d, J = 8.1 Hz, 1 H, H-7), 7.15–7.36 (m, 3 H, H-8, H-9, H-10).
13C NMR (50 MHz, DMSO-d6): d = 26.3, 38.7, 40.7, 52.4, 72.6,
116.3, 123.3, 125.2, 127.7, 128.9, 148.8, 161.0, 166.7, 169.4, 170.8.
1H NMR (400 MHz, CDCl3): d = 1.24–1.49 (m, 6 H, 2 × CH3),
2.22–2.36 (m, 1 H, HCHCO), 2.56–2.65 (m, 1 H, HCHCO), 4.17–
4.31 (m, 2 H, OCH2), 4.31–4.41 (m, 1 H, H-4), 5.02–5.15 (m, 1 H,
CHNH), 5.39–5.53 (m, 1 H, NH), 6.29 (br s, 2 H, NH2), 6.95 (d,
J = 8 Hz, 1 H, ArH), 7.05–7.44 (m, 8 H, ArH).
13C NMR (100 MHz, CDCl3): d = 14.9, 21.6/21.7, 32.1/32.2, 46.7/
46.8, 48.8, 59.9, 77.4/77.5, 116.0/116.1, 124.7/124.8, 125.7/125.8,
126.5/126.6 (2C), 127.5/127.6, 127.8/127.9, 128.8/128.9 (2C),
129.0/129.1, 143.2/143.3, 149.9, 161.6/161.7, 169.3/169.4, 171.1/
171.2.
Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C,
69.55; H, 6.31; N, 7.28.
GC–MS: m/z = 302 [M+], 271, 241, 201, 186, 172, 159.
Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C,
59.57; H, 4.62; N, 9.33.
Ethyl [2-Amino-3-(anilinocarbonyl)-4H-chromen-4-yl]acetate
(9i)
White solid; mp 168–169 °C.
IR (KBr): 3311, 1677, 1649 cm–1.
5-Amino-3-benzyl-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (10d)
White solid; mp 216–217 °C.
IR (neat): 3304, 1708, 1653, 1601 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.67 (dd, J = 15.6, 14.0 Hz, 1
H, HaCHbCO), 3.31 (dd, J = 15.6, 4.3 Hz, 1 H, HaCHbCO), 4.08
(dd, J = 14.0, 4.3 Hz, 1 H, H-10b), 4.88 (d, J = 14.8 Hz, 1 H, HaCH-
bPh), 4.98 (d, J = 14.8 Hz, 1 H, HaCHbPh), 7.04 (d, J = 8.1 Hz, 1 H,
H-7), 7.15–7.37 (m, 7 H, ArH), 7.44 (d, J = 7.5 Hz, 1 H, ArH), 8.16
(br s, 2 H, NH2).
1H NMR (200 MHz, CDCl3): d = 1.29 (t, J = 7.0 Hz, 3 H, CH3),
2.45 (dd, J = 13.6, 7.8 Hz, 1 H, HCH), 2.69 (dd, J = 13.6, 4.6 Hz, 2
H, HCH), 4.18 (q, J = 7.0 Hz, 2 H, OCH2), 4.40 (dd, J = 7.8, 4.6 Hz,
1 H, H-4), 6.30 (br s, 2 H, NH2), 6.91–7.42 (m, 9 H, ArH).
13C NMR (50 MHz, CDCl3): d = 14.9, 31.4, 47.0, 59.1, 75.4, 116.0,
119.5 (2C), 123.4, 124.6, 126.8, 128.1, 128.8, 129.0 (2C), 139.5,
150.0, 162.4, 168.5, 169.5.
GC–MS: m/z = 352 [M+], 307, 279, 215, 186, 172, 159, 145, 118.
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C,
68.02; H, 5.83; N, 7.91.
13C NMR (100 MHz, DMSO-d6): d = 26.7, 39.5, 42.4, 73.4, 116.5,
123.8, 125.5, 127.4, 127.9 (2C), 128.0, 128.9 (2C), 129.1, 139.1,
149.2, 161.2, 167.6, 171.3.
5-Amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-2,4(3H)-
dione (10a)
White solid; mp 220–221 °C.
IR (KBr): 3385, 1670, 1605 cm–1.
GC–MS: m/z = 320 [M+], 292, 261, 229, 201, 186, 172.
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.31; H, 4.97; N, 8.78.
1H NMR (400 MHz, DMSO-d6): d = 2.46 (dd, J = 15.6, 13.8 Hz, 1
H, HaCHbCO), 3.11 (dd, J = 15.6, 4.5 Hz, 1 H, HaCHbCO), 4.02
(dd, J = 13.8, 4.5 Hz, 1 H, H-10b), 7.03 (dd, J = 7.9, 1.3 Hz, 1 H,
H-7), 7.16 (td, J = 8.9, 7.9, 0.7 Hz, 1 H, H-9), 7.29 (td, J = 8.9, 7.9,
1.3 Hz, 1 H, H-8), 7.41 (br d, J = 7.5 Hz, 1 H, H-10), 8.03 (br s, 2
H, NH2), 10.20 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 27.8, 39.0, 72.8, 116.5, 124.1,
125.4, 128.0, 129.0, 149.2, 160.8, 168.7, 172.2.
GC–MS: m/z = 230 [M+], 186, 159, 145, 131, 118.
5-Amino-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1,10b-dihy-
dro-2H-chromeno[3,4-c]pyridine-2,4(3H)-dione (10e)
White solid; mp 130–131 °C.
IR (neat): 3269, 1701, 1654 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.07 [s, 6 H, (CH3)2Si], 0.89 [s, 9
H, C(CH3)3], 2.62 (dd, J = 15.5, 14.1 Hz, 1 H, HaCHbCO), 3.25 (dd,
J = 15.5, 4.4 Hz, 1 H, HaCHbCO), 3.74–3.80 (m, 2 H, CH2O), 3.90–
3.98 (m, 1 H, HaCHbN), 4.03 (dd, J = 14.1, 4.4 Hz, 1 H, H-10b),
4.11–4.18 (m, 1 H, HaCHbN), 7.01 (dd, J = 8.1, 1.2 Hz, 1 H, H-7),
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7.17 (ddd, J = 7.5, 7.1, 1.2 Hz, 1 H, H-9), 7.22 (br d, J = 6.9 Hz, 1
H, H-8), 7.26 (ddd, J = 7.1, 1.8, 0.9 Hz, 1 H, H-10).
13C NMR (100 MHz, CDCl3): d = –5.1, 18.5, 26.1, 27.0, 39.8, 41.4,
60.6, 74.7, 116.6, 122.9, 125.3, 126.8, 128.8, 149.1, 160.3, 168.2,
171.2.
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H,
CH3CH2CH2N), 1.56–1.73 (m, 2 H, CH3CH2CH2N), 2.34 (s, 3 H,
CH3), 2.61 (dd, J = 14.7, 14.3 Hz, 1 H, HaCHbCO), 3.23 (dd,
J = 15.5, 4.3 Hz, 1 H, HaCHbCO), 3.71–3.80 (m, 1 H, N-
HaCHbCH2CH3), 3.84–3.91 (m, 1 H, N-HaCHbCH2CH3), 3.99 (dd,
J = 14.1, 4.3 Hz, 1 H, H-10b), 6.88 (d, J = 8.2 Hz, 1 H, H-7), 7.01
(s, 1 H, H-10), 7.05 (d, J = 8.2 Hz, 1 H, H-8).
GC–MS: m/z = 388 [M+], 331, 289, 246, 214, 172.
13C NMR (100 MHz, CDCl3): d = 11.7, 21.2, 22.0, 27.1, 39.9, 41.4,
74.9, 116.2, 122.5, 127.2, 129.3, 134.8, 146.9, 160.3, 168.5, 171.3.
Anal. Calcd for C20H28N2O4Si: C, 61.83; H, 7.26; N, 7.21. Found:
C, 61.68; H, 7.19; N, 7.32.
GC–MS: m/z = 286 [M+], 269, 257, 229, 186, 172, 159, 145.
5-Amino-3-anilino-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (10f)
White solid; mp 238–239 °C.
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.15; H, 6.42; N, 9.71.
IR (neat): 3304, 1708, 1660, 1601 cm–1.
Methyl {5-Amino-9-methyl-2,4-dioxo-1,10b-dihydro-2H-
chromeno[3,4-c]pyridin-3(4H)-yl}acetate (11c)
White solid; mp 180–181 °C.
IR (neat): 3307, 1737, 1705, 1652 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.37 (s, 3 H, CH3), 2.72 (dd,
J = 15.8, 14.0 Hz, 1 H, HaCHbCO), 3.31 (dd, J = 15.8, 4.4 Hz, 1 H,
HaCHbCO), 3.79 (s, 3 H, OCH3), 4.10 (dd, J = 14.0, 4.4 Hz, 1 H, H-
10b), 4.56 (d, J = 16.7 Hz, 1 H, N-HaCHb), 4.72 (d, J = 16.7 Hz, 1
H, N-HaCHb), 6.91 (d, J = 8.2 Hz, 1 H, H-7), 7.03 (s, 1 H, H-10),
7.08 (d, J = 8.2 Hz, 1 H, H-8).
1H NMR (400 MHz, CDCl3): d = 2.83 (dd, J = 15.9, 13.9 Hz, 1 H,
HaCHbCO), 3.43 (dd, J = 15.9, 4.3 Hz, 1 H, HaCHbCO), 4.24 (dd,
J = 13.9, 4.3 Hz, 1 H, H-10b), 6.64 (br s, 1 H, NH), 6.86 (d, J = 8.6
Hz, 2 H, ArH), 6.96 (t, J = 7.6 Hz, 1 H, ArH), 7.04 (d, J = 7.8 Hz, 1
H, ArH), 7.18–7.27 (m, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 26.3, 39.7, 73.2, 112.7 (2C), 116.3,
119.2, 123.3, 125.3, 127.9, 129.0, 129.1 (2C), 148.5, 148.8, 160.7,
166.5, 169.9.
GC–MS: m/z = 321 [M+], 279, 230, 190, 172, 145.
13C NMR (50 MHz, CDCl3): d = 20.8, 26.5, 39.0, 40.5, 52.2, 73.5,
116.0, 121.8, 126.8, 129.0, 134.6, 146.5, 160.4, 167.1, 169.2, 170.7.
Anal. Calcd for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C,
67.26; H, 4.81; N, 13.01.
GC–MS: m/z = 316 [M+], 285, 255, 200, 173, 159.
5-Amino-3-isopropyl-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (10g)
White solid; mp 162–163 °C.
Anal. Calcd for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C,
60.79; H, 5.12; N, 8.81.
IR (neat): 3368, 1692, 1636, 1615 cm–1.
5-Amino-3-benzyl-9-methyl-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione (11d)
White solid; mp 225–226 °C.
IR (neat): 3291, 1705, 1653, 1602 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.66 (dd,
J = 15.5, 14.1 Hz, 1 H, HaCHbCO), 3.28 (dd, J = 15.5, 4.3 Hz, 1 H,
HaCHbCO), 4.03 (dd, J = 14.1, 4.3 Hz, 1 H, H-10b), 5.04 (d,
J = 14.3 Hz, 1 H, N-HaCHb), 5.13 (d, J = 14.3 Hz, 1 H, N-HaCHb),
6.89 (d, J = 8.3 Hz, 1 H, H-7), 7.01 (s, 1 H, H-10), 7.08 (d, J = 8.3
Hz, 1 H, H-8), 7.21–7.38 (m, 3 H, ArH), 7.38–7.45 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 21.2, 27.0, 39.9, 42.9, 74.7, 116.3,
122.4, 127.2, 127.3, 128.4 (2C), 128.6 (2C), 129.3, 134.9, 138.4,
146.9, 160.5, 168.2, 171.2.
1H NMR (400 MHz, CDCl3): d = 1.44 (d, J = 6.9 Hz, 3 H, CH3),
1.48 (d, J = 6.9 Hz, 3 H, CH3), 2.62 (dd, J = 15.7, 14.1 Hz, 1 H,
HaCHbCO), 3.18 (dd, J = 15.7, 4.2 Hz, 1 H, HaCHbCO), 4.02 (dd,
J = 14.1, 4.2 Hz, 1 H, H-10b), 4.97 (sept, J = 6.9 Hz, 1 H, NCH),
6.99 (d, J = 8.1 Hz, 1 H, H-7), 7.18–7.27 (m, 3 H, H-8, H-9, H-10).
13C NMR (50 MHz, CDCl3): d = 19.7, 20.9, 27.3, 41.1, 44.9, 75.8,
116.5, 122.9, 125.2, 126.9, 128.7, 149.0, 160.0, 169.0, 171.5.
GC–MS: m/z = 272 [M+], 229, 186, 172, 159, 145.
Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.08; H, 5.85; N, 10.34.
5-Amino-9-methyl-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (11a)
White solid; mp 271–272 °C.
GC–MS: m/z = 334 [M+], 318, 291, 243, 215, 186, 132.
Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C,
71.93; H, 5.37; N, 8.42.
IR (neat): 3411, 1712, 1678, 1652 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.28 (s, 3 H, CH3), 2.44 (dd,
J = 15.5, 13.7 Hz, 1 H, HaCHbCO), 3.08 (dd, J = 15.5, 4.4 Hz, 1 H,
HaCHbCO), 3.98 (dd, J = 13.7, 4.4 Hz, 1 H, H-10b), 6.91 (d, J = 8.3
Hz, 1 H, H-7), 7.08 (br d, J = 8.2 Hz, 1 H, H-8), 7.21 (s, 1 H, H-10),
8.05 (br s, 2 H, NH2), 10.23 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 35.8, 42.5, 53.7, 87.4, 130.9,
138.4, 142.8, 144.1, 149.2, 161.8, 175.6, 183.4, 186.9.
5-Amino-8-methoxy-1,10b-dihydro-2H-chromeno[3,4-c]pyri-
dine-2,4(3H)-dione (12a)
White solid; mp 275–276 °C.
IR (neat): 3410, 3211, 1698, 1669, 1607 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.39 (dd, J = 15.1, 13.8 Hz, 1
H, HaCHbCO), 3.06 (dd, J = 15.1, 4.2 Hz, 1 H, HaCHbCO), 3.76 (s,
3 H, OCH3), 3.92 (dd, J = 13.8, 4.2 Hz, 1 H, H-10b), 6.56 (d,
J = 2.1 Hz, 1 H, H-7), 6.76 (dd, J = 8.6, 2.1 Hz, 1 H, H-9), 7.31 (d,
J = 8.6 Hz, 1 H, H-10), 8.08 (br s, 2 H, NH2), 10.19 (br s, 1 H, NH).
GC–MS: m/z = 244 [M+], 227, 214, 200, 186, 173, 159, 146.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C,
63.83; H, 5.01; N, 11.45.
13C NMR (100 MHz, DMSO-d6,): d = 27.3, 39.2, 56.2, 73.0, 101.8,
5-Amino-9-methyl-3-propyl-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione (11b)
White solid; mp 159–160 °C.
111.6, 115.9, 128.7, 149.8, 159.8, 160.7, 168.7, 172.3.
GC–MS: m/z = 260 [M+], 242, 216, 200, 189, 174, 148.
Anal. Calcd for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found: C,
60.13; H, 4.58; N, 10.70.
IR (neat): 3388, 2964, 1693, 1652, 1616 cm–1.
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5-Amino-8-methoxy-3-propyl-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-dione (12b)
White solid; mp 140–141 °C.
IR (neat): 3389, 2960, 1700, 1651, 1627 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 27.9, 38.6, 72.1, 118.0, 124.1,
124.9, 125.8, 144.7, 153.8, 159.8, 168.5, 171.7.
Anal. Calcd for C12H9N3O5: C, 52.37; H, 3.30; N, 15.27. Found: C,
52.48; H, 3.38; N, 15.22.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.4 Hz, 3 H, CH3CH2),
1.54–1.70 (m, 2 H, CH3CH2CH2), 2.57 (dd, J = 15.1, 14.1 Hz, 1 H,
HaCHbCO), 3.19 (dd, J = 15.3, 4.3 Hz, 1 H, HaCHbCO), 3.81 (s, 3
H, OCH3), 3.72–3.94 (m, 2 H, NCH2CH2), 3.94 (dd, J = 14.0, 4.3
Hz, 1 H, H-10b), 6.53 (d, J = 2.5 Hz, 1 H, H-7), 6.73 (dd, J = 8.6,
2.5 Hz, 1 H, H-9), 7.10 (d, J = 8.6 Hz, 1 H, H-10).
13C NMR (100 MHz, CDCl3): d = 11.7, 21.9, 26.6, 40.1, 41.4, 55.8,
75.2, 101.9, 111.4, 114.7, 127.5, 149.7, 159.9, 160.1, 168.5, 171.3.
GC–MS: m/z = 302 [M+], 287, 274, 259, 245, 202, 189, 174, 161,
148.
5-Amino-9-nitro-3-propyl-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione (13b)
Yellow solid; mp 224–225 °C.
IR (neat): 3378, 1698, 1652 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H, CH3CH2),
1.54–1.67 (m, 2 H, CH3CH2CH2), 2.70 (dd, J = 15.0, 14.0 Hz, 1 H,
HaCHbCO), 3.34 (dd, J = 15.0, 4.0 Hz, 1 H, HaCHbCO), 3.73–3.82
(m, 1 H, N-HCHCH2), 3.85–3.94 (m, 1 H, N-HCHCH2), 4.12 (dd,
J = 14.0, 4.0 Hz, 1 H, H-10b), 7.16 (d, J = 9 Hz, 1 H, H-7), 8.15–
8.21 (m, 2 H, H-8, H-10).
Anal. Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.45; H, 5.94; N, 9.30.
13C NMR (100 MHz, CDCl3): d = 11.8, 22.0, 27.3, 39.6, 41.7, 74.3,
117.7, 123.2, 124.6, 124.8, 145.0, 153.5, 159.2, 168.1, 170.1.
Methyl {5-Amino-8-methoxy-2,4-dioxo-1,10b-dihydro-2H-
chromeno[3,4-c]pyridin-3(4H)-yl}acetate (12c)
White solid; mp 184–185 °C.
Anal. Calcd for C15H15N3O5: C, 56.78; H, 4.76; N, 13.24. Found: C,
57.71; H, 4.83; N, 13.17.
5-Amino-3-benzyl-9-nitro-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione (13d)
Dark-orange solid; mp 286–288 °C.
IR (neat): 3273, 1733, 1704, 1652 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.74 (dd, J = 15.3, 14.0 Hz, 1 H,
HaCHbCO), 3.37 (dd, J = 15.5, 4.4 Hz, 1 H, HaCHbCO), 4.14 (dd,
J = 14.0, 4.4 Hz, 1 H, H-10b), 5.04 (d, J = 14.3 Hz, 1 H, HaCHbPh),
5.11 (d, J = 14.3 Hz, 1 H, HaCHbPh), 7.15 (d, J = 8.5 Hz, 1 H, H-
7), 7.26–7.43 (m, 5 H, ArH), 8.15–8.21 (m, 2 H, H-8, H-10).
13C NMR (100 MHz, CDCl3): d = 27.5, 39.6, 43.2, 74.1, 117.8,
123.3, 124.4, 124.8, 127.7, 128.6 (2C), 128.8 (2C), 138.1, 145.0,
153.5, 159.4, 167.8, 170.3.
IR (neat): 3406, 2957, 1756, 1701, 1657 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.66 (dd, J = 15.6, 14.0 Hz, 1 H,
HaCHbCO), 3.25 (dd, J = 15.6, 4.3 Hz, 1 H, HaCHbCO), 3.77 (s, 3
H, OCH3), 3.82 (s, 3 H, OCH3), 4.04 (dd, J = 14.0, 4.3 Hz, 1 H, H-
10b), 4.54 (d, J = 16.7 Hz, 1 H, N-HaCHb), 4.69 (d, J = 16.7 Hz, 1
H, N-HaCHb), 6.55 (d, J = 2.5 Hz, 1 H, H-7), 6.74 (dd, J = 8.6, 2.5
Hz, 1 H, H-9), 7.11 (d, J = 8.6 Hz, 1 H, H-10).
13C NMR (100 MHz, CDCl3): d = 26.4, 39.6, 40.9, 52.6, 55.8, 74.6,
102.0, 111.6, 114.6, 127.5, 149.6, 159.9, 160.6, 167.6, 169.5, 171.1.
GC–MS: m/z = 332 [M+], 301, 271, 242, 215, 189, 174.
Anal. Calcd for C16H16N2O6: C, 57.83; H, 4.85; N, 8.43. Found: C,
57.95; H, 4.93; N, 8.33.
Anal. Calcd for C19H15N3O5: C, 62.46; H, 4.14; N, 11.50. Found: C,
62.53; H, 4.07; N, 11.56.
5-Amino-3-benzyl-8-methoxy-1,10b-dihydro-2H-
chromeno[3,4-c]pyridine-2,4(3H)-dione (12d)
White solid; mp 160–161 °C.
IR (neat): 3299, 1705, 1657, 1628 cm–1.
13-Amino-4b,5-dihydro-6H-chromeno[3¢,4¢:3,4]pyrido[1,2-
a]benzimidazol-6-one (14)
White solid; mp 222–224 °C.
1H NMR (400 MHz, CDCl3): d = 2.63 (dd, J = 15.4, 14.1 Hz, 1 H,
HaCHbCO), 3.25 (dd, J = 15.5, 4.3 Hz, 1 H, HaCHbCO), 3.81 (s, 3
H, OCH3), 3.99 (dd, J = 14.1, 4.3 Hz, 1 H, H-10b), 5.04 (d, J = 14.3
Hz, 1 H, N-HaCHb), 5.12 (d, J = 14.3 Hz, 1 H, N-HaCHb), 6.54 (d,
J = 2.6 Hz, 1 H, H-7), 6.74 (dd, J = 8.6, 2.6 Hz, 1 H, H-9), 7.11 (d,
J = 8.6 Hz, 1 H, H-10), 7.21–7.35 (m, 3 H, ArH), 7.37–7.44 (m, 2
H, PhH).
13C NMR (100 MHz, CDCl3): d = 26.6, 40.1, 42.9, 55.8, 75.1,
102.0, 111.5, 114.8, 127.4, 127.5, 128.4 (2C), 128.7 (2C), 138.4,
149.6, 159.9, 160.3, 168.2, 171.3.
IR (neat): 3388, 1716, 1647 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.89 (dd, J = 16.1, 13.9 Hz, 1 H,
HaCHbCO), 3.43 (dd, J = 16.1, 4.6 Hz, 1 H, HaCHbCO), 4.35 (dd,
J = 13.9, 4.6 Hz, 1 H, H-4b), 6.65 (br s, 2 H, NH2), 7.07 (d, J = 8.2
Hz, 1 H, ArH), 7.18–7.38 (m, 5 H, ArH), 7.57 (d, J = 7.8 Hz, 1 H,
ArH), 8.22 (d, J = 7.8 Hz, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6): d = 28.7, 39.6, 69.2, 114.9, 116.8,
117.8, 123.0, 123.3, 125.3, 125.6, 127.9, 129.1, 131.3, 144.7, 149.8,
155.1, 156.2, 168.6.
GC–MS: m/z = 303 [M+], 247, 207, 189, 165, 136.
GC–MS: m/z = 350 [M+], 334, 307, 259, 216, 189, 175.
Anal. Calcd for C18H13N3O2: C, 71.28; H, 4.32; N, 13.85. Found: C,
71.23; H, 4.25; N, 13.97.
Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.52; H, 5.11; N, 7.92.
N-{2-(5-Amino-2,4-dioxo-1,10b-dihydro-2H-chromeno[3,4-
c]pyridin-3(4H)-yl)ethyl]-2-cyanoacetamide (15a)
White solid; mp 285 °C (dec.).
IR (neat): 3405, 2257, 1694, 1644 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.58 (t, J = 14.4 Hz, 1 H, H-
1a), 3.19–3.29 (m, 3 H, CH2NH, H-1b), 3.54 (s, 2 H, CH2CN), 3.69–
3.79 (m, 1 H, N-HaCHb-), 3.83–3.94 (m, 1 H, N-HaCHb-), 4.00 (dd,
J = 13.9, 4.1 Hz, 1 H, H-10b), 7.04 (d, J = 8.1 Hz, 1 H, H-7), 7.20
(t, J = 7.5 Hz, 1 H, H-9), 7.30 (t, J = 7.6 Hz, 1 H, H-8), 7.43 (d,
5-Amino-9-nitro-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-
2,4(3H)-dione (13a)
Pale-yellow solid; mp >320 °C (dec.).
IR (neat): 3306, 1735, 1682, 1604 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.56 (dd, J = 15.4, 13.7 Hz, 1
H, HaCHbCO), 3.25 (dd, J = 15.7, 4.7 Hz, 1 H, HaCHbCO), 4.13
(dd, J = 13.7, 4.7 Hz, 1 H, H-10b), 7.27 (d, J = 9.0 Hz, 1 H, H-7),
8.13 (br s, 2 H, NH2), 8.16 (dd, J = 9.0, 2.6 Hz, 1 H, H-8), 8.29 (d,
J = 2.6 Hz, 1 H, H-10), 10.31 (s, 1 H, NH).
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247
J = 7.6 Hz, 1 H, H-10), 8.16 (br s, 2 H, NH2), 8.30 (br t, J = 5.8 Hz,
IR (neat) 3410, 3299, 2259, 1658 cm–1.
1 H, NHCO).
1H NMR (400 MHz, DMSO-d6): d = 2.44–2.58 (m, 1 H, H-1a),
3.12–3.28 (m, 3 H, CH2NH, H-1b), 3.53 (s, 2 H, CH2CN), 3.70–3.79
(m, 4 H, OCH3, N-HaCHb-), 3.84–3.95 (m, 2 H, H-10b, N-HaCHb-),
6.56 (d, J = 2.1 Hz, 1 H, H-7), 6.77 (dd, J = 8.5, 2.1 Hz, 1 H, H-9),
7.33 (d, J = 8.5 Hz, 1 H, H-10), 8.10 (br s, 2 H, NH2), 8.27 (br t,
J = 5.3 Hz, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 26.0, 26.2, 38.2, 38.6, 39.7,
56.2, 73.9, 101.8, 111.7, 115.6, 116.8, 128.6, 149.8, 159.9, 160.9,
163.0, 167.9, 171.5.
13C NMR (100 MHz, DMSO-d6): d = 26.0, 26.7, 38.2, 38.6, 39.4,
73.6, 116.5, 116.8, 123.8, 125.5, 127.9, 129.1, 149.1, 161.0, 163.1,
167.8, 171.4.
GC–MS: m/z = 340 [M+], 255, 229, 215, 186, 159, 146, 118, 89.
Anal. Calcd for C17H16N4O4: C, 60.00; H, 4.74; N, 16.46. Found: C,
60.13; H, 4.85; N, 16.37.
1¢,2¢-Bis{5-amino-1,10b-dihydro-2H-chromeno[3,4-c]pyridine-
2,4(3H)-dione}ethane (15b)
White solid; mp 298–299 °C.
Anal. Calcd for C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C,
58.26; H, 4.78; N, 14.97.
IR (neat): 3409, 3293, 1661 cm–1.
1¢,2¢-Bis{5-amino-8-methoxy-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione}ethane (17b)
White solid; mp 290–293 °C.
IR (neat) 3408, 3300, 1653 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.38 (dd, J = 14.2, 15.1 Hz, 2
H, H-1a, H-1a′), 3.14–3.22 (m, 2 H, H-1b, H-1b′), 3.73–3.82 (m, 8 H,
2 × OCH3, H-10b, H-10b′), 3.85–3.92 (m, 2 H, CH2N), 3.96–4.04 (m,
2 H, CH2N), 6.54 (dd, J = 1.4, 2.5 Hz, 2 H, H-7, H-7′), 6.75 (dd, J =
2.6, 8.5 Hz, 2 H, H-9, H-9′), 7.33 (d, J = 8.5 Hz, 2 H, H-10, H-10′),
8.03 (br s, 4 H, 2 × NH2).
13C NMR (100 MHz, DMSO-d6): d = 26.2, 37.7, 39.6, 56.2, 73.8–
73.9, 101.8, 111.7, 115.7, 128.6, 149.8, 159.8, 160.8–160.9, 168.0,
171.4–171.5.
1H NMR (400 MHz, DMSO-d6): d = 2.45 (t, J = 14.7 Hz, 2 H, H-1a,
H-1a¢), 3.23 (dd, J = 16.0, 4.1 Hz, 2 H, H-1b, H-1b¢), 3.82–3.99 (m,
4 H, H-10b, H-10b¢, CH2N), 3.99–4.11 (m, 2 H, CH2N), 7.01 (d,
J = 8.1 Hz, 2 H, H-7, H-7¢), 7.16 (t, J = 7.5 Hz, 2 H, H-9, H-9¢), 7.29
(t, J = 7.4 Hz, 2 H, H-8, H-8¢), 7.43 (d, J = 7.6 Hz, 2 H, H-10, H-
10¢), 8.09 (br s, 4 H, 2 × NH2).
13C NMR (100 MHz, DMSO-d6): d = 26.7, 37.7, 39.3–39.4, 73.5–
73.6, 116.5, 123.9, 125.4, 127.9, 129.1, 149.2, 160.9–161.0, 167.9–
168.0, 171.3–171.4.
Anal. Calcd for C26H22N4O6: C, 64.19; H, 4.56; N, 11.52. Found: C,
64.31; H, 4.61; N, 11.43.
N-{2-(5-Amino-9-methyl-2,4-dioxo-1,10b-dihydro-2H-
chromeno[3,4-c]pyridin-3(4H)-yl)ethyl}-2-cyanoacetamide
(16a)
Anal. Calcd for C28H26N4O8: C, 61.53; H, 4.80; N, 10.25. Found: C,
61.38; H, 4.91; N, 10.42.
White solid; mp 230 °C (dec.).
IR (neat): 3408, 3281, 2259, 1647 cm–1.
Acknowledgment
1H NMR (400 MHz, DMSO-d6): d = 2.28 (s, 3 H, CH3), 2.55 (dd,
J = 15.3, 14.0 Hz, 1 H, H-1a), 3.18–3.28 (m, 3 H, CH2NH, H-1b),
3.53 (s, 2 H, CH2CN), 3.69–3.78 (m, 1 H, HaCHbN), 3.83–3.92 (m,
1 H, HaCHbN), 3.95 (dd, J = 14.0, 4.0 Hz, 1 H, H-10b), 6.92 (d,
J = 8.4 Hz, 1 H, H-7), 7.09 (d, J = 8.4 Hz, 1 H, H-8), 7.23 (s, 1 H,
H-10), 8.13 (br s, 2 H, NH2), 8.28 (t, J = 5.6 Hz, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 21.1, 26.0, 26.7, 38.2, 38.6,
39.5, 73.5, 116.2, 116.8, 123.4, 128.1, 129.5, 134.6, 147.0, 161.1,
163.1, 167.9, 171.4.
The authors thank Ferdinando Costantino for X-ray measurements
and Mary Kerrigan (MA, Cantab) for valuable linguistic sugges-
tions.
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1¢,2¢-Bis{5-amino-9-methyl-1,10b-dihydro-2H-chromeno[3,4-
c]pyridine-2,4(3H)-dione}ethane (16b)
White solid; mp 274 °C (dec.).
IR (neat): 3456, 3321, 1704, 1652 cm–1.
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(t, J = 14.7 Hz, 2 H, H-1a, H-1a¢), 3.19 (dd, J = 15.5, 3.8 Hz, 2 H, H-
1b, H-1b¢), 3.80–3.97 (m, 4 H, H-10b, H-10b¢, CH2N), 3.97–4.08 (m,
2 H, CH2N), 6.90 (dd, J = 8.1, 1.2 Hz, 2 H, H-7, H-7¢), 7.08 (d,
J = 8.3 Hz, 2 H, H-8, H-8¢), 7.23 (s, 2 H, H-10, H-10¢), 8.02 (br s, 4
H, 2 × NH2).
13C NMR (100 MHz, DMSO-d6): d = 21.1, 26.7, 37.7, 39.4–39.5,
73.5–73.6, 116.2, 123.4, 128.1, 129.5, 134.5, 147.1, 161.0–161.1,
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N-{2-(5-Amino-8-methoxy-2,4-dioxo-1,10b-dihydro-2H-
chromeno[3,4-c]pyridin-3(4H)-yl)ethyl}-2-cyanoacetamide
(17a)
White solid; mp 239–240 °C.
Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York

248
O. Rosati et al.
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Synthesis 2010, No. 2, 239–248 © Thieme Stuttgart · New York