Efficient one-pot synthesis of N-substituted 2-aminochromones, their benzo-fused derivatives, and diaminobenzodipyrandiones of two new structural classes

Article abstract of DOI:10.1055/S-0029-1218623

N-Substituted 2-aminochromones and their benzo-fused derivatives were obtained in high yields by a new one-pot synthesis, starting from the appropriate acetamides, salicylic acid or its benzo-fused derivatives, and phosphoryl chloride. By the same reaction, from suitable dihydroxybenzenedicarboxylic acids, some compounds of two new structural classes, 2,7-diaminobenzo[1,2-b:4,5-b']dipyran-4,9-diones and 2,8-diamino-4H,6H-benzo[1,2-b:5,4-b']dipyran-4,6-diones, were synthesized. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218623

PAPER
849
Efficient One-Pot Synthesis of N-Substituted 2-Aminochromones, Their
Benzo-Fused Derivatives, and Diaminobenzodipyrandiones of Two New
Structural Classes
O
ne-Pot Synthesis
i
of
N
-S
o
ubstituted 2-
r
A
minoch
g
romones io Roma,* Daniela Piras, Mario Di Braccio, Giancarlo Grossi
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy
Fax +39(010)3538358; E-mail: roma@unige.it
Received 20 October 2009; revised 27 October 2009
sists of four steps, in the last of which 2-(ethylsulfi-
nyl)chromone is treated with a primary or secondary
amine to give the corresponding variously N-substituted
2-aminochromones or, in some cases, with other suitable
Abstract: N-Substituted 2-aminochromones and their benzo-fused
derivatives were obtained in high yields by a new one-pot synthesis,
starting from the appropriate acetamides, salicylic acid or its benzo-
fused derivatives, and phosphoryl chloride. By the same reaction,
from suitable dihydroxybenzenedicarboxylic acids, some com- nucleophilic reagents to give other 2-substituted
pounds of two new structural classes, 2,7-diaminobenzo[1,2-b:4,5-
b¢]dipyran-4,9-diones and 2,8-diamino-4H,6H-benzo[1,2-b:5,4-
b¢]dipyran-4,6-diones, were synthesized.
chromones.
Herein, we describe a new synthesis of N-substituted 2-
aminochromones 3 and their benzo-fused derivatives 4–6,
Key words: amines, chromones, heterocycles, one-pot synthesis,
and how the same reaction proved to be satisfactorily ef-
pyrans
fective for the synthesis of some examples of N-substitut-
ed 2,7-diaminobenzo[1,2-b:4,5-b¢]dipyran-4,9-diones 12
and 2,8-diamino-4H,6H-benzo[1,2-b:5,4-b¢]dipyran-4,6-
N-Substituted 2-aminochromones (2-amino-4H-1-ben-
diones 13, new classes of tricyclic 2-aminochromone de-
zopyran-4-ones) and their benzo-fused derivatives show,
rivatives. All the above compounds were directly obtained
depending on their structure, some very interesting phar-
in often good yields.
macological properties, such as the inhibition of human
platelet aggregation,1 antiproliferative activity,2 the inhi-
bition of some kinases,3 and psychotropic activity.4a
Compounds 3–6 were synthesized by a one-pot method
(Scheme 1): first, a 1,2-dichloroethane solution of the ap-
propriate N-substituted acetamide 1 (large excess) and a
suitable amount of phosphoryl chloride is stirred at room
temperature; then salicylic (2a) or benzo-fused salicylic
acid (2b–d) is added to this solution, and the resulting
mixture in 1,2-dichloroethane is heated at reflux, while
stirring (95 °C, 24 h). The final reaction mixture is then
stirred with an aqueous sodium acetate solution at 90 °C
for one hour.
We have a long-standing interest in new synthetic routes
to N-substituted 2-aminochromones and their benzo-
fused derivatives, for both chemical and pharmacological
reasons. We initially reported the one-pot synthesis of an-
gular and linear benzo-fused N-substituted 2-amino-
chromones through the cyclocondensation of suitable
naphthols with appropriately N-substituted ethyl mal-
onamates in the presence of phosphoryl chloride.4 Some
of the compounds obtained clearly showed effects on the
central nervous system.4a Subsequently, we applied the
same reaction to phenol for the preparation of N-substitut-
ed 2-aminochromones,5a,b some of which exhibited inter-
esting in vitro human platelet antiaggregating properties.1a
The same procedure was used for the synthesis of benzo-
dipyran derivatives 12 and 13, except that a different sto-
ichiometric ratio of the N-substituted acetamide 1 to the
dihydroxybenzenedicarboxylic acid 11a or 11b needs to
be used (Scheme 2). The N-substituted acetamides 1 were
used in high excess compared with salicylic acid (2a), to
facilitate their cyclocondensation with salicyloyl chloride
by hindering the cyclocondensation of two chloride mol-
ecules. This strategy was also applied to the reactions of
hydroxynaphthoic acids 2b–d (Scheme 1) and the reac-
tions of dihydroxybenzenedicarboxylic acids 11a,b
(Scheme 2), but because of the more complex structures
of 11a,b, the desired compounds 12 and 13 were obtained
in lower yields, except for 12b,c, which were obtained in
higher yields. On the whole, the yields of the above new
compounds, afforded by this one-pot synthesis, also ap-
pear to be satisfactory.
The following syntheses of N-substituted 2-amino-
chromones appear to be the most interesting among the
approaches reported in the literature:5 Morris et al.5e de-
scribed a method consisting of two steps, namely the reac-
tion of a suitable acetamide lithium enolate with methyl
salicylate to give the appropriately N-substituted 2-salicyl-
oylacetamide (55–86% yield), whose cyclodehydration,
by treatment with triflic anhydride, affords substituted 2-
(dimethylamino)chromones or 2-morpholinochromones
(yield of second step 56–78%). On the other hand, the
synthetic route reported by Bantick and Suschitzky5c con-
A possible reaction mechanism is proposed in Scheme 3,
with the synthesis of compounds 3 used as example. The
determining activation of acetamide 1 is achieved by ad-
SYNTHESIS 2010, No. 5, pp 0849–0857
Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1218623; Art ID: Z22309SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

850
G. Roma et al.
PAPER
dition of phosphoryl chloride to give the Vilsmeier-type tion mixture is stirred at 90 °C with an aqueous sodium
reagent 1A, whose chloride is then nucleophilically dis- acetate solution.
placed by the hydroxy substituent of salicyloyl chloride.
By the two-step cyclocondensation of 2A, the desired 2-
In some cases, in addition to the desired compounds 3–6,
12, and 13, 4-chlorocoumarin 7 and its linear benzo-fused
aminochromone 3 is finally obtained via the tautomeric
derivative 9 (Scheme 1), as well as 4-chlorocoumarin
4H-1-benzopyran-4-one derivative intermediate. On the
benzodipyran derivatives 14a,b (Scheme 2) were also ob-
other hand, the corresponding tautomer, a 4-hydroxy-2H-
tained, in smaller yields. Also, most likely due to their suf-
1-benzopyran derivative, by reaction with phosphoryl
ficiently high boiling points, morpholine and piperidine,
chloride gives the 4-chloro derivative 7A, which is then
derived from the hydrolysis of the corresponding 7A
hydrolyzed to the 4-chlorocoumarin 7 when the final reac-
R1
OH
O
N
N
O
O
R2
+
COOH
3a
68%
7
9%
O
O
Cl
2a
POCl3
R1
R2
ii
3b 84% 3d 69%
3c 70% 3e 66%
iii
POCl3
O
O
i
R1
R2
O
C
R1
O
N
O
N
Me
N
R2
+
R1
R2
1a–f
O
3f
8a
13%
POCl3
i
44%
COOH
OH
OH
COOH
R1
R2
N
R1
R2
POCl3
N
O
2c
2b
O
ii
ii
O
O
iii
iii
POCl3
POCl3
5a
4a 70%
4b 71%
i
53%
O
O
C
R1
R2
R1
R2
Me
C
N
Me
N
1b
1b,c
R1
R2
N
Compounds
OH
COOH
1a, 3a, 6a
NMe2
NEt2
NPr2
POCl3
2d
R1
R2
1b, 3b, 4a, 5a, 6b
1c, 3c, 4b
ii
O
O
N
O
O
+
iii
NMePh
N
1d, 3d
POCl3
9
Cl
6a 62%
i
3.5–20%
1e, 3e, 6c
6b 75%
6c 68%
O
C
R1
R2
Me
N
N
N
O
1f, 3f, 8a
1a,b,e
1g, 6d, 10a
OH
COOH
POCl3
2d
R1
R2
ii
O
O
N
O
N
O
O
O
+
+
iii
POCl3
R1
R2
9
6d
10a
Cl
i
20%
50%
11.5%
O
C
R1
R2
Me
N
1g
Scheme 1 Synthesis of the N-substituted 2-aminochromones 3a–f and benzo-fused 2-aminochromones 4a,b, 5a, and 6a–d. Reagents and con-
ditions: (i) DCE, r.t., 50 min; (ii) DCE, r.t., 20 min; (iii) 1. DCE, 95 °C, 24 h; 2. aq NaOAc, 90 °C, 1 h.
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Substituted 2-Aminochromones
851
(Scheme 3) or its appropriate benzo-fused derivative, features in the IR and 1H NMR spectral data of the above
gave 4-aminocoumarin 8a and benzo-fused 4-aminocou- N-substituted 2-aminochromones 3 and their benzo-fused
marin 10a, by reaction with the corresponding 4-chloro derivatives 4 and 6 result from their b-enaminonic group:
derivatives 7 and 9 (Scheme 1), respectively.
the IR spectra (KBr) show a carbonyl stretching absorp-
tion band at characteristic low frequencies (1595–1630
cm–1), and an often strong absorption band due to the dou-
ble bond of this group (1553–1567 cm–1), whereas the 1H
NMR spectra (CDCl3) exhibit the unusual chemical shift
of the H3 singlet (d = 5.25–5.61), and the characteristic
H5 signal, shifted downfield due to the deshielding effect
of 4-C=O (3c,d, d = 8.12, 8.08; 4b, d = 8.15; 6a–d, d =
The structures assigned to the novel compounds 3, 4, and
6 reported here are supported by the results of elemental
analyses and IR, 1H and 13C NMR spectroscopic data. In
this connection, the IR and 1H NMR spectroscopic data of
compounds 3c,d, 4b, and 6a–d, described here, are in ac-
cordance with those of compounds 3, 4, and 6, previously
described by us.4d,e,5a,b In particular, the distinguishing
HOOC
OH
HO
COOH
11a
POCl3
O
R1
ii
O
O
N
R2
R1
R2
iii
N
O
POCl3
i
12a 32%
12b 65%
12c 73%
O
C
R1
2
Me
N
R2
1a–c
HOOC
OH
HO
COOH
11a
POCl3
O
O
O
O
R1
R2
ii
O
O
O
O
N
R1
R2
R1
iii
+
N
N
R2
POCl3
Cl
i
12d 33%
12e 33%
14a 9%
14b 11%
O
C
R1
2
Me
N
R2
1d,e
HO
OH
HOOC
COOH
11b
POCl3
R1
R2
R1
N
ii
N
O
O
O
O
R2
iii
POCl3
13a 32%
13b 37%
i
O
C
R1
2
Me
N
R2
1b,c
R1
N
Compounds
R2
NMe2
1a, 12a
NEt2
NPr2
1b, 12b, 13a
1c, 12c, 13b
NMePh
N
1d, 12d, 14a
1e, 12e, 14b
Scheme 2 Synthesis of the N-substituted 2,7-diaminobenzo[1,2-b:4,5-b¢]dipyran-4,9-diones 12a–e, and 2,8-diamino-4H,6H-benzo[1,2-
b:5,4-b¢]dipyran-4,6-diones 13a,b. Reagents and conditions: (i) DCE, r.t., 50 min; (ii) DCE, r.t., 20 min; (iii) 1. DCE, 95 °C, 24 h; 2. aq NaOAc,
90 °C, 1 h.
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

852
G. Roma et al.
PAPER
1
8.63–8.65). It is interesting that the H NMR H10 signal Thus, in the case of compounds 13a,b, the IR absorption
of compounds 5 shows a notably downfield chemical shift band frequencies of C=O (1638, 1629 cm–1) and C=CH
(d = ~10.30) due to the particular position of the 1-C=O (1558, 1556 cm–1) (b-enaminonic group) are clearly dis-
group in their angular structures and the consequent very tinguishable from each other and are similar to the corre-
high deshielding effect on H10.4a
sponding frequencies of the N-substituted 2-
aminochromones 3c,d (C=O: 1630, 1614 cm–1; C=CH:
1559, 1553 cm–1). On the other hand, in the IR spectra of
12a–e, the C=O band appears at a lower frequency, result-
ing in the fusing of this band and those of the aromatic and
g-pyrone double bonds into only one broad band (12a,e:
1605, 1595 cm–1); also, the C=O band of 12b–d (1614–
1619 cm–1) is not plainly separate from the fused C=CH
broad bands appearing at a lower frequency (1563–1578
cm–1).
Concerning the benzodipyran derivatives 12a–e and
13a,b, synthesized by us as first examples of two novel
structural classes, the structures assigned to these com-
pounds are confirmed by both the elemental analysis re-
1
sults and the IR, H and 13C NMR spectral data. The IR
and NMR spectra of these compounds are also strongly
characterized by the presence of the b-enaminonic groups,
as is also the case of the above 2-aminochromone deriva-
tives 3, 4, and 6. Obviously, the structural differences be-
tween the isomeric tricyclic linear systems of compounds As regards the 1H NMR spectral data of the above benzo-
12 and 13 result in some differences between their spec- dipyran derivatives 12 and 13, the singlets correlated to
tral data.
the g-pyrone C=CH protons show similar chemical shifts
X–
=
–OPOCl2
O
P
–
N
Cl
X–
R1
+
R2
O
O
C
O
C
Cl
R1
R2
P
R1
R2
Me
C
N
+
Me
N
Me
Cl
X–
Cl
Cl
Cl
Cl
1A
1
H
Cl
R1
R2
–
N
+
O
C
Me
Cl
OH
OH
O
POCl3
O
Cl
COOH
2a
– HCl
X–
R1
R1
R2
–
N
+
N
O
O
R2
C
– H+X–
C
Cl
H
Cl
C
H
H
C
H
H
O
O
2A
Cl–
Cl–
R1
R1
R2
+
+
N
N
O
O
R2
H
H
OH
O
POCl3
– HCl
N
R1
R2
Cl–
+
N
O
R1
O
R2
O
3
Cl
7A
R1
R2
H2O
R1
R2
O
O
O
N
O
–
HN
– HCl, HN
– HCl
R1
R2
Cl
8
7
Scheme 3 Proposed reaction mechanism for the one-pot synthesis of N-substituted 2-aminochromones 3
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Substituted 2-Aminochromones
853
terephthalic acids were commercially available; 4,6-dihydroxy-
isophthalic acid was prepared according to a literature procedure.6
for compounds 12a–e (d = 5.30–5.57) and 13a,b (d = 5.39,
5.35). However, in the case of compounds 12a–e, the
downfield-shifted signals of the aromatic protons H5 and
H10, subjected to the same carbonyl deshielding effect,
obviously appear as only one singlet (d = 7.95–8.06),
whereas in the spectra of compounds 13a,b, the H5 singlet
is shifted further downfield (d = 8.86, 8.91), due to the
combined deshielding effects on H5 of both 4-C=O and 6-
C=O.
N-Substituted 2-Amino-4H-1-benzopyran-4-ones 3a–f,
2-Amino-4H-naphtho[1,2-b]pyran-4-ones 4a,b, 3-Amino-1H-
naphtho[2,1-b]pyran-1-one (5a), and 2-Amino-4H-naphtho[2,3-
b]pyran-4-ones 6a–d; General Procedure
POCl3 (16.10 g, 105 mmol) was added dropwise to an ice-bath-
cooled stirring soln of the appropriate N-substituted acetamide 1 (80
mmol) in DCE (80 mL), and then the resulting mixture was stirred
at r.t. for 50 min. Subsequently, a soln of salicylic acid (2a; 2.76 g,
20 mmol) or the appropriate hydroxynaphthoic acid 2b–d (3.76 g,
20 mmol) in DCE (40 mL) was added, and the resulting reaction
mixture was stirred at r.t. for 20 min, after which it was heated at re-
flux (95 °C), with stirring, for 24 h. After cooling of the reaction
mixture, aq NaOAc·3H2O (150 mL, 92.53 g, 0.68 mol) was careful-
ly added under stirring, and the thus obtained mixture was vigorous-
ly stirred at 90 °C for 1 h. After cooling of the mixture, the organic
layer was collected and the aqueous phase was exhaustively extract-
ed with CH2Cl2. The combined organic phases were washed with 1
N aq NaOH, followed by H2O, dried (Na2SO4), and finally evapo-
rated to dryness under reduced pressure; this gave a thick oil (or a
pasty solid), which was dissolved in a small amount of CH2Cl2, and
then chromatographed (silica gel column); this gave the desired
compounds reported below.
Analogously, the structures of isomeric tricyclic com-
pounds 12 and 13 can be confirmed by their 13C NMR
spectra. For instance, the C5 and C10 13C NMR signals of
the 12c tricyclic system are superimposed, to give a sin-
glet as a result of their structural identity, whereas the C5
and C10 signals of the isomer 13b appear as two separate
singlets due to their clearly different structural environ-
ments. On the whole, the 13C NMR spectra of 12c and 13b
contain nine and ten peaks, respectively.
In conclusion, the herein described reaction of N-substi-
tuted acetamides 1 with salicylic acid (2a) or benzo-fused
salicylic acids 2b–d in the presence of phosphoryl chlo-
ride is a new easy and useful one-pot synthesis, giving, in
good or high yields, N-substituted 2-aminochromones 3
or angular and linear benzo-fused 2-aminochromones 4–6
(Scheme 1). A plausible mechanism of the reaction has
been proposed (Scheme 3). In addition, by substituting in
the same reaction the salicylic acid with 2,5-dihydroxy-
terephthalic or 4,6-dihydroxyisophthalic acid (11a or
11b), we obtained some compounds of two new interest-
ing structural classes, the N-substituted 2,7-diaminoben-
zo[1,2-b:4,5-b¢]dipyran-4,9-diones 12a–e and 2,8-di-
amino-4H,6H-benzo[1,2-b:5,4-b¢]dipyran-4,6-diones 13a,b
(Scheme 2). The significant connections between the
2-(Dimethylamino)-4H-1-benzopyran-4-one (3a) and 4-Chloro-
2H-1-benzopyran-2-one (7)
The thick oil obtained from the reaction of salicylic acid (2a; 2.76
g) and N,N-dimethylacetamide (1a; 6.97 g) was chromatographed
(silica gel, CH2Cl2); the eluate afforded, after removal of the sol-
vent, 4-chlorocoumarin 7.
Yield: 0.33 g (9%); whitish solid (cyclohexane); mp 94.5–95.5 °C
(Lit.7 93.5–94.5 °C).
Chromatography was continued [EtOAc (to remove impurities),
then THF]; this gave, after removal of the solvent and treatment of
the residue with a little i-Pr2O, pure compound 3a.
Yield: 2.57 g (68%); white crystals (EtOAc); mp 125–126 °C (Lit.5b
125–126 °C).
1
structures and the characteristic IR, H and 13C NMR
spectral data of these new compounds have been pointed
out. On the basis of the various pharmacological activities
shown by 2-aminochromone derivatives, it seems possi-
ble that appropriately substituted novel benzodipyran de-
rivatives 12 and 13 may prove to be interesting
pharmacological agents.
2-(Diethylamino)-4H-1-benzopyran-4-one (3b)
The thick oil obtained from the reaction of 2a (2.76 g) and N,N-di-
ethylacetamide (1b; 9.21 g) was chromatographed [silica gel,
CH2Cl2 (to remove some impurities), then EtOAc]; this gave, after
removal of the solvent, a solid residue which was taken up in a little
i-Pr2O to give pure 3b.
Yield: 3.65 g (84%); white crystals (EtOAc–i-Pr2O); mp 97–
97.5 °C (Lit.5b 96–97 °C).
Melting points were determined on a Fisher-Johns (Electrothermal
when above 300 °C) apparatus and are uncorrected. IR spectra were
recorded on a Perkin-Elmer Spectrum One spectrophotometer (IR
2-(Dipropylamino)-4H-1-benzopyran-4-one (3c)
The thick oil obtained from the reaction of 2a (2.76 g) and N,N-
dipropylacetamide (1c; 11.46 g) was worked up exactly as for com-
pound 3b; this gave pure 3c.
bands: br = broad, s = strong, w = weak, s = shoulder). 1H and 13
C
NMR spectra were recorded on a Varian Gemini 200 (200 MHz)
spectrometer, and TMS was used as an internal reference (d = 0
ppm). Analyses of all new compounds were performed by the Lab-
oratorio di Microanalisi, Dipartimento di Scienze Farmaceutiche,
Università di Genova. TLC was carried out on Merck silica gel 60
F254 precoated plastic sheets (layer thickness 0.2 mm). Column
chromatography was performed on Carlo Erba silica gel (0.05–0.20
mm). N,N-Dimethylacetamide, N,N-diethylacetamide, and 4-
acetylmorpholine were commercially available; N,N-dipropylacet-
amide, 1-acetylpyrrolidine, 1-acetylpiperidine, and N-methylacet-
anilide were prepared through the reaction (r.t., 1 h) of AcCl with
the suitable amine in CH2Cl2 in the presence of anhyd pyridine and
were purified by distillation under reduced pressure or by crystalli-
zation (N-methylacetanilide). Salicylic, 1-hydroxy-2-naphthoic, 2-
hydroxy-1-naphthoic, 3-hydroxy-2-naphthoic, and 2,5-dihydroxy-
Yield: 3.43 g (70%); white crystals; mp 87–88 °C (PE).
IR (KBr): 1630 (s, C=O), 1559 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.95 [t, J = 7.4 Hz, 6 H,
N(CH2CH2CH3)2], 1.68 [m, 4 H, N(CH2CH2CH3)2], 3.35 [t, J = 7.4
Hz, 4 H, N(CH2CH2CH3)2], 5.54 (s, 1 H, H-3), 7.20–7.35 (m, 2 H,
H-6,8), 7.51 (m, 1 H, H-7), 8.12 (near d, J = 7.8 Hz, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 11.2, 21.0, 50.7, 85.9, 116.1,
123.0, 124.5, 125.5, 131.7, 153.6, 162.3, 176.4.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.23; H, 7.78; N, 5.67.
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

854
G. Roma et al.
PAPER
2-[Methyl(phenyl)amino]-4H-1-benzopyran-4-one (3d)
The thick oil obtained from the reaction of 2a (2.76 g) and N-meth-
ylacetanilide (1d; 11.94 g) was chromatographed [silica gel,
CH2Cl2–Et2O, 1:2 (to remove unchanged 1d), then Et2O–EtOAc];
this gave, after removal of solvents, a pasty solid residue, which was
crystallized (cyclohexane) to give pure 3d.
Hz, 4 H, N(CH2CH2CH3)2], 5.61 (s, 1 H, H-3), 7.61 (m, 2 H, H-8,9),
7.71 (d, J = 8.7 Hz, 1 H, H-6), 7.89 (m, 1 H, H-7), 8.15 (d, J = 8.7
Hz, 1 H, H-5), 8.21 (m, 1 H, H-10).
13C NMR (50 MHz, CDCl3): d = 11.3, 21.0, 51.2, 86.8, 118.3,
121.07, 121.13, 123.2, 124.5, 126.9, 128.2, 128.3, 135.4, 150.3,
162.1, 176.2.
Yield: 3.47 g (69%); whitish crystals; mp 109.5–110.5 °C (cyclo-
hexane).
IR (KBr): 1614 (s, C=O), 1553 (s, g-pyrone C=CH) cm–1.
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.08; H, 7.48; N, 4.69.
3-(Diethylamino)-1H-naphtho[2,1-b]pyran-1-one (5a)
The thick oil obtained from the reaction of 2-hydroxy-1-naphthoic
acid (2c; 3.76 g) and the acetamide 1b (9.21 g) was chromato-
graphed [silica gel, Et2O (to remove some impurities), then EtOAc];
this gave a nearly solid residue which was treated with a little Et2O
to afford pure 5a.
1H NMR (200 MHz, CDCl3): d = 3.40 (s, 3 H, NCH3), 5.33 (s, 1 H,
H-3), 7.13–7.54 (m, 8 H, H-6,7,8 + C6H5), 8.08 (near d, J = 7.8 Hz,
1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 38.3, 88.2, 116.4, 122.9, 124.6,
125.3, 126.5, 127.5, 129.8, 132.0, 142.5, 153.6, 162.7, 176.5.
Yield: 2.81 g (53%); white crystals; mp 142–143 °C (Lit.4b 142–
143 °C) (EtOH).
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C,
76.28; H, 5.43; N, 5.64.
2-(Pyrrolidin-1-yl)-4H-1-benzopyran-4-one (3e)
2-(Dimethylamino)-4H-naphtho[2,3-b]pyran-4-one (6a) and
4-Chloro-2H-naphtho[2,3-b]pyran-2-one (9)
The thick oil obtained from the reaction of 3-hydroxy-2-naphthoic
acid (2d; 3.76 g) and acetamide 1a (6.97 g) was chromatographed
(silica gel, CH2Cl2); this gave, after removal of solvent, pure com-
pound 9.
The nearly solid residue obtained from the reaction of 2a (2.76 g)
and N-acetylpyrrolidine (1e; 9.05 g) was chromatographed [silica
gel, CH2Cl2 (to remove some impurities), then EtOAc–THF, 4:1];
this gave, after removal of solvents, a solid residue which was taken
up in a little i-Pr2O and filtered to give compound 3e.
Yield: 2.84 g (66%); white crystals (EtOAc–i-Pr2O, 4:1); mp
Yield: 0.94 g (20%); whitish crystals (toluene); mp 195.5–196.5 °C
(Lit.9 198–198.5 °C).
152.5–153.5 °C (Lit.8 148–150 °C).
Chromatography was continued [EtOAc (to remove some impuri-
ties), then acetone]; this gave, after evaporation, a solid residue
which was taken up in a little EtOAc and filtered; this gave pure 6a.
2-Morpholino-4H-1-benzopyran-4-one (3f) and 4-Morpholino-
2H-1-benzopyran-2-one (8a)
The thick oil obtained from the reaction of 2a (2.76 g) and N-acetyl-
morpholine (1f; 10.33 g) was chromatographed (silica gel, Et2O);
this gave, after removal of solvent, a pasty solid, which was then
crystallized from i-Pr2O–EtOAc (4:1) to give compound 8a.
Yield: 2.98 g (62%); whitish crystals; mp 185–186 °C (EtOAc).
IR (KBr): 1615 (s, br, C=O), 1561 (g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.07 [s, 6 H, N(CH3)2], 5.36 (s, 1
H, H-3), 7.43 (m, 2 H, H-7,8), 7.63 (s, 1 H, H-10), 7.76 and 7.93 (2
near d, J = 7.8 Hz, 1 H + 1 H, H-6,9), 8.64 (s, 1 H, H-5).
Yield: 0.59 g (13%); white crystals; mp 141.5–142.5 °C (Lit.7 139–
141 °C).
The chromatography was continued [EtOAc (to remove some im-
purities), then EtOAc–THF, 1:1]; this gave, after evaporation of the
eluate, a solid residue which was crystallized (EtOAc) to give pure
3f.
Yield: 2.04 g (44%); white crystals; mp 160–161.5 °C (Lit.5e 160–
160.5 °C).
13C NMR (50 MHz, CDCl3): d = 37.5, 85.2, 112.3, 122.1, 125.5,
126.1, 127.0, 127.9, 129.4, 130.3, 134.9, 150.6, 163.4, 176.6.
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C,
75.28; H, 5.36; N, 5.56.
2-(Diethylamino)-4H-naphtho[2,3-b]pyran-4-one (6b) and
Chloro Derivative 9
The thick oil obtained from the reaction of 2d (3.76 g) and the acet-
amide 1b (9.21 g) was chromatographed (silica gel, Et2O); from the
first fractions of this eluate pure compound 9 was obtained.
2-(Diethylamino)-4H-naphtho[1,2-b]pyran-4-one (4a)
The thick oil obtained from the reaction of 1-hydroxy-2-naphthoic
acid (2b; 3.76 g) and the acetamide 1b (9.21 g) was chromato-
graphed [silica gel, Et2O, then EtOAc (to remove some impurities),
then EtOAc–acetone, 1:1]; this gave, after removal of solvents, an
oily residue, which was crystallized (EtOAc–cyclohexane) to give
pure 4a.
Yield: 0.16 g (3.5%).
Chromatography was continued (EtOAc); this gave, after removal
of the solvent, a solid residue which was taken up in a little i-Pr2O
and filtered to give pure 6b.
Yield: 3.75 g (70%); white crystals; mp 107–108.5 °C (Lit.4d 106–
107 °C).
Yield: 4.00 g (75%); white crystals; mp 154.5–155.5 °C (toluene–
cyclohexane).
2-(Dipropylamino)-4H-naphtho[1,2-b]pyran-4-one (4b)
The thick oil obtained from the reaction of 2b (3.76 g) and the acet-
amide 1c (11.46 g) was chromatographed [silica gel, CH2Cl2 (to re-
move some impurities), then EtOAc–EtOH, 9:1]; this gave, after
removal of solvents, a pasty oil which was treated with a small
amount of i-Pr2O–EtOAc (2:1) to give pure compound 4b.
IR (KBr): 1602 (s, br, C=O), 1556 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.24 [t, J = 7.2 Hz, 6 H,
N(CH2CH3)2], 3.45 [q, J = 7.2 Hz, 4 H, N(CH2CH3)2], 5.41 (s, 1 H,
H-3), 7.43 (m, 2 H, H-7,8), 7.64 (s, 1 H, H-10), 7.77 and 7.94 (2 near
d, J = 7.8 Hz, 1 H + 1 H, H-6,9), 8.65 (s, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 13.2, 43.4, 85.0, 112.2, 121.9,
Yield: 4.19 g (71%); whitish crystals; mp 163–164 °C (EtOAc).
IR (KBr): 1614 (s, br, C=O), 1558 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 [t, J = 7.4 Hz, 6 H,
N(CH2CH2CH3)2], 1.78 [m, 4 H, N(CH2CH2CH3)2], 3.46 [t, J = 7.4
125.5, 126.1, 126.9, 128.0, 129.4, 130.4, 134.9, 150.6, 162.5, 176.2.
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.57; H, 6.57; N, 5.29.
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Substituted 2-Aminochromones
855
2-(Pyrrolidin-1-yl)-4H-naphtho[2,3-b]pyran-4-one (6c) and
Chloro Derivative 9
The thick oil obtained from the reaction of 2d (3.76 g) and N-
acetylpyrrolidine (1e; 9.05 g) was chromatographed (silica gel,
CH2Cl2–Et2O, 1:1); after removal of solvents, the pure chloro deriv-
ative 9 was obtained.
mmol) in DCE (100 mL), and then the mixture was stirred at r.t. for
50 min. 2,5-Dihydroxyterephthalic acid 11a (for the synthesis of
compounds 12) (1.98 g, 10 mmol) or 4,6-dihydroxyisophthalic acid
11b (for the synthesis of compounds 13) (1.98 g, 10 mmol) and
DCE (40 mL) were added to the mixture, which was then stirred at
r.t. for 20 min, and subsequently heated at reflux (95 °C) for 24 h,
with stirring. After cooling of the mixture, aq NaOAc·3H2O (150
mL, 92.53 g, 0.68 mol) was carefully added to the stirring mixture;
then vigorous stirring continued at 90 °C for 1 h. After cooling of
the mixture, the organic layer was collected and the aqueous phase
was exhaustively extracted with CH2Cl2. The combined organic
phases were washed with 1 N aq NaOH, followed by H2O, dried
(Na2SO4), and finally evaporated to dryness under reduced pres-
sure; this generally gave a pasty solid from which the desired com-
pounds were obtained after direct column chromatography (silica
gel) or by treatment of the above pasty solid with an appropriate sol-
vent to isolate the most insoluble compound, the concentrated fil-
trate of which was then subjected to column chromatography.
Yield: 0.93 g (20%).
Chromatography was continued [EtOAc (to remove impurities),
then EtOAc–acetone, 1:1]; this gave, after removal of solvents, pure
6c.
Yield: 3.62 g (68%); whitish crystals; mp 205–206 °C (EtOAc).
IR (KBr): 1602 (s, br, C=O), 1563 sh (g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.98 (m, 4 H, pyrrolidine b-CH2),
3.46 (m, 4 H, pyrrolidine a-CH2), 5.25 (s, 1 H, H-3), 7.43 (m, 2 H,
H-7,8), 7.61 (s, 1 H, H-10), 7.75 and 7.93 (2 near d, J = 7.8 Hz, 1 H
+ 1 H, H-6,9), 8.65 (s, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 25.1, 46.7, 85.4, 112.2, 122.6,
2,7-Bis(dimethylamino)benzo[1,2-b:4,5-b¢]dipyran-4,9-dione
(12a)
125.4, 126.1, 127.0, 127.8, 129.3, 130.3, 134.8, 150.8, 161.5, 176.0.
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
77.20; H, 5.77; N, 5.10.
After the final reaction mixture of 2,5-dihydroxyterephthalic acid
11a (1.98 g) with N,N-dimethylacetamide 1a (6.97 g) had been hy-
drolyzed with aq NaOAc·3H2O, the mixture was cooled, and the in-
soluble solid from both phases was recovered by filtration, washed,
and dried. This gave the first amount (0.68 g) of nearly pure 12a.
The filtered mixture was then treated as described above in the gen-
eral method. The finally obtained pasty residue was chromato-
graphed [silica gel, EtOAc (to remove all the impurities), then
MeOH]; this afforded an additional amount of 12a (0.28 g).
2-(Piperidin-1-yl)-4H-naphtho[2,3-b]pyran-4-one (6d), 4-(Pipe-
ridin-1-yl)-2H-naphtho[2,3-b]pyran-2-one (10a), and Chloro
Derivative 9
The thick oil obtained from the reaction of 2d (3.76 g) and N-
acetylpiperidine (1g; 10.17 g) was chromatographed (silica gel,
CH2Cl2); from the first fractions of this eluate the pure chloro deriv-
ative 9 was obtained.
Total yield: 0.96 g (32%); yellowish crystals; mp >350 °C (EtOH).
IR (KBr): 1605 (s, br, C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.08 [s, 12 H, 2 N(CH3)2], 5.40 (s,
2 H, H-3,8), 8.03 (s, 2 H, H-5,10).
13C NMR (50 MHz, CDCl3): d = 37.6, 86.0, 112.9, 126.0, 149.9,
163.5, 175.2.
Yield: 0.93 g (20%).
The subsequent fractions of this eluate, after removal of solvent, af-
forded compound 10a.
Yield: 0.64 g (11.5%); whitish crystals; mp 195–196 °C (EtOH).
IR (KBr): 1716 (s, C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.80 (m, 6 H, piperidine b + g-
CH2), 3.23 (m, 4 H, piperidine a-CH2), 5.70 (s, 1 H, H-3), 7.43 (m,
2 H, H-7,8), 7.65 (s, 1 H, H-10), 7.75 and 7.84 (2 near d, J = 8.2 Hz,
1 H + 1 H, H-6,9), 8.03 (s, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 24.3, 25.7, 52.5, 97.8, 113.2, 116.7,
125.3, 125.4, 127.1, 128.0, 128.6, 129.3, 134.4, 150.6, 161.6, 162.8.
Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C,
64.30; H, 5.37; N, 9.39.
2,7-Bis(diethylamino)benzo[1,2-b:4,5-b¢]dipyran-4,9-dione
(12b)
The pasty solid finally resulting from the reaction of 11a (1.98 g)
with N,N-diethylacetamide (1b; 9.21 g) was directly crystallized
from CH2Cl2 to give a first amount (0.62 g) of pure 12b. The filtrate
was chromatographed [silica gel, CH2Cl2, then EtOAc (to remove
all the impurities), then THF]; this afforded the remaining amount
of 12b (1.70 g).
Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.21; H, 6.21; N, 5.08.
Chromatography was continued [CH2Cl2–EtOAc, 2:1 (to remove
some impurities), then EtOAc]; this gave, after removal of solvent,
pure 6d.
Total yield: 2.32 g (65%); white crystals; mp 284–285.5 °C (EtOH).
IR (KBr): 1619 (C=O), 1578 (s, br, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.22 [t, J = 7.2 Hz, 12 H, 2
N(CH2CH3)2], 3.41 [q, J = 7.2 Hz, 8 H, 2 N(CH2CH3)2], 5.41 (s, 2
H, H-3,8), 8.02 (s, 2 H, H-5,10).
Yield: 2.80 g (50%); white crystals; mp 229–230.5 °C (EtOAc).
IR (KBr): 1595 (s, br, C=O), 1567 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.66 (m, 6 H, piperidine b + g-
CH2), 3.52 (m, 4 H, piperidine a-CH2), 5.49 (s, 1 H, H-3), 7.44 (m,
2 H, H-7,8), 7.64 (s, 1 H, H-10), 7.77 and 7.94 (2 near d, J = 8.2 Hz,
1 H + 1 H, H-6,9), 8.63 (s, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 13.0, 43.5, 85.6, 112.6, 125.9,
149.9, 162.4, 175.0.
13C NMR (50 MHz, CDCl3): d = 24.1, 25.3, 46.0, 85.6, 112.2, 122.2,
125.4, 126.0, 126.9, 127.9, 129.4, 130.3, 134.9, 150.6, 162.5, 177.1.
Anal. Calcd for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86. Found: C,
67.51; H, 6.93; N, 7.82.
Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.42; H, 6.33; N, 5.16.
2,7-Bis(dipropylamino)benzo[1,2-b:4,5-b¢]dipyran-4,9-dione
(12c)
N-Substituted 2,7-Diaminobenzo[1,2-b:4,5-b¢]dipyran-4,9-di-
ones 12a–e and 2,8-Diamino-4H,6H-benzo[1,2-b:5,4-b¢]dipyr-
an-4,6-diones 13a,b; General Procedure
The pasty residue resulting from the reaction of 11a (1.98 g) with
N,N-dipropylacetamide (1c; 11.46 g) was chromatographed [silica
gel, CH2Cl2, then EtOAc (to remove all the impurities), then
POCl3 (16.10 g, 105 mmol) was added dropwise to a stirring, ice-
bath-cooled soln of the appropriate N-substituted acetamide 1 (80
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

856
G. Roma et al.
PAPER
CH2Cl2–THF, 1:1]; after removal of the solvents from the collected
fractions, pure 12c was obtained.
Anal. Calcd for C16H12ClNO4: C, 60.48; H, 3.81; N, 4.41. Found: C,
60.61; H, 4.03; N, 4.67.
Yield: 3.00 g (73%); white crystals; mp 255.5–257 °C (EtOH).
Chromatography was continued (THF) to give a small amount (0.04
g) of pure 12e.
IR (KBr): 1619 (C=O), 1576 (s, br, g-pyrone C=CH) cm–1.
Total yield: 1.15 g (33%); yellowish crystals; mp >350 °C (EtOH).
IR (KBr): 1595 (s, br, C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.08 (m, 8 H, 2 pyrrolidine b-
CH2), 3.55 (m, 8 H, 2 pyrrolidine a-CH2), 5.49 (s, 2 H, H-3,8), 8.00
(near s, 2 H, H-5,10).
1H NMR (200 MHz, CDCl3): d = 0.96 [t, J = 7.4 Hz, 12 H, 2
N(CH2CH2CH3)2], 1.70 [m, 8 H, 2 N(CH2CH2CH3)2], 3.68 [t,
J = 7.4 Hz, 8 H, 2 N(CH2CH2CH3)2], 5.57 (s, 2 H, H-3,8), 8.06 (s, 2
H, H-5,10).
13C NMR (50 MHz, CDCl3): d = 11.3, 21.1, 51.1, 85.9, 112.7, 126.0,
149.9, 162.9, 175.1.
13C NMR (50 MHz, CDCl3): d = 25.0, 46.7, 86.0, 112.7, 126.0,
149.8, 161.4, 174.5.
Anal. Calcd for C24H32N2O4: C, 69.88; H, 7.82; N, 6.79. Found: C,
69.75; H, 7.86; N, 6.76.
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C,
68.18; H, 5.60; N, 8.21.
2,7-Bis[methyl(phenyl)amino]benzo[1,2-b:4,5-b¢] dipyran-4,9-
dione (12d) and 4-Chloro-7-[methyl(phenyl)amino]benzo[1,2-
b:4,5-b¢]dipyran-2,9-dione (14a)
The pasty residue resulting from the reaction of 11a (1.98 g) with
N-methylacetanilide (1d; 11.94 g) was dissolved in a little CH2Cl2
and chromatographed [silica gel, Et2O (to recover unreacted 1d),
then EtOAc]; this gave, after removal of solvent, pure 14a.
2,8-Bis(diethylamino)-4H,6H-benzo[1,2-b:5,4-b¢]dipyran-4,6-
dione (13a)
The pasty solid derived from the reaction of 4,6-dihydroxyisoph-
thalic acid (11b; 1.98 g) with N,N-diethylacetamide (1b; 9.21 g)
was taken up in Et2O–EtOAc (2:1); after standing, the resulting sus-
pension was stirred and then filtered to give crude 13a, which was
crystallized from EtOH–EtOAc (1:1) to give a first amount (0.88 g)
of pure 13a. The combined mother liquors of crude and crystallized
13a were evaporated to dryness in vacuo to give a thick oil, which
was chromatographed [silica gel, CH2Cl2–THF, 1:1 (to remove im-
purities), then CH2Cl2–MeOH, 9:1]; this gave, after removal of sol-
vents, an additional amount of pure 13a (0.26 g).
Yield: 0.32 g (9%); pale yellow solid; mp 260–261.5 °C (EtOH).
IR (KBr): 1732 (s, a-pyrone C=O), 1617 (s, g-pyrone C=O), 1538
(s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.40 (s, 3 H, NCH3), 5.47 (s, 1 H,
H-8), 6.66 (s, 1 H, H-3), 7.20–7.50 (m, 5 H, C6H5), 7.70 (s, 1 H, H-
5), 7.98 (s, 1 H, H-10).
13C NMR (50 MHz, CDCl3): d = 38.8, 88.4, 113.4, 117.7, 120.8,
126.6, 128.3, 130.2, 142.0, 147.8, 149.1, 149.4, 158.2, 163.2, 174.1.
Total yield: 1.14 g (32%); whitish crystals; mp 260–262 °C (EtOH–
EtOAc, 1:1).
IR (KBr): 1638 (s, C=O), 1558 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 [t, J = 7.2 Hz, 12 H, 2
N(CH2CH3)2], 3.44 [q, J = 7.2 Hz, 8 H, 2 N(CH2CH3)2], 5.39 (s, 2
H, H-3,7), 7.18 (s, 1 H, H-10), 8.86 (s, 1 H, H-5).
Anal. Calcd for C19H12ClNO4: C, 64.51; H, 3.42; N, 3.96. Found: C,
64.42; H, 3.55; N, 3.99.
Chromatography was continued (THF); the eluate collected, after
removal of solvent, gave pure 12d.
13C NMR (50 MHz, CDCl3): d = 13.1, 43.4, 85.4, 103.5, 120.1,
124.2, 155.3, 161.9, 175.0.
Yield: 1.39 g (33%); whitish crystals; mp 306.5–308 °C (dec)
(EtOH).
IR (KBr): 1614 (C=O), 1563 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.41 (s, 6 H, 2 NCH3), 5.30 (s, 2
H, H-3,8), 7.12–7.48 (m, 10 H, 2 C6H5), 7.95 (s, 2 H, H-5,10).
Anal. Calcd for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86. Found: C,
67.33; H, 7.01; N, 7.91.
2,8-Bis(dipropylamino)-4H,6H-benzo[1,2-b:5,4-b¢]dipyran-4,6-
dione (13b)
13C NMR (50 MHz, CDCl3): d = 38.6, 87.9, 113.1, 126.2, 126.8,
128.1, 130.1, 142.3, 149.9, 163.4, 175.3.
The pasty residue derived from the reaction of 11b (1.98 g) with
N,N-dipropylacetamide (1c; 11.46 g) was dissolved in a small
amount of CH2Cl2–CHCl3 (1:1) and chromatographed [silica gel,
CH2Cl2, then CH2Cl2–EtOAc, 1:1 (to remove all the impurities),
then THF, then CHCl3–MeOH, 1:1]; this gave, after removal of sol-
vents, pure 13b.
Anal. Calcd for C26H20N2O4: C, 73.57; H, 4.75; N, 6.60. Found: C,
73.44; H, 4.73; N, 6.64.
2,7-Di(pyrrolidin-1-yl)benzo[1,2-b:4,5-b¢]dipyran-4,9-dione
(12e) and 4-Chloro-7-(pyrrolidin-1-yl)benzo[1,2-b:4,5-b¢]dipyr-
an-2,9-dione (14b)
The pasty solid obtained from the reaction of 11a (1.98 g) with N-
acetylpyrrolidine (1e; 9.05 g) was taken up in acetone and the result-
ing suspension was stirred and then filtered to give a major amount
(1.11 g) of nearly pure 12e. The filtrate was evaporated to dryness
and the resulting thick oil was chromatographed [silica gel, CH2Cl2
(to remove some impurities), then EtOAc]; this gave pure 14b.
Yield: 1.51 g (37%); white crystals; mp 225–226 °C (EtOH–
EtOAc, 1:1).
IR (KBr): 1629 (s, C=O), 1556 (s, g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.98 [t, J = 7.4 Hz, 12 H, 2
N(CH2CH2CH3)2], 1.71 [m, 8 H, 2 N(CH2CH2CH3)2], 3.35 [t,
J = 7.4 Hz, 8 H, 2 N(CH2CH2CH3)2], 5.35 (s, 2 H, H-3,7), 7.12 (s, 1
H, H-10), 8.91 (s, 1 H, H-5).
13C NMR (50 MHz, CDCl3): d = 11.1, 20.9, 50.7, 85.4, 103.1,
Yield: 0.36 g (11%); yellow solid; mp 272–274.5 °C (EtOH).
120.3, 124.2, 155.2, 162.1, 175.2.
IR (KBr): 1731 (s, a-pyrone C=O), 1619 (s, g-pyrone C=O), 1544
(g-pyrone C=CH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.10 (m, 4 H, pyrrolidine b-CH2),
3.58 (m, 4 H, pyrrolidine a-CH2), 5.52 (s, 1 H, H-8), 6.70 (s, 1 H,
H-3), 7.74 (s, 1 H, H-5), 8.00 (s, 1 H, H-10).
13C NMR (50 MHz, CDCl3): d = 25.1, 47.0, 86.5, 113.0, 113.4,
117.4, 120.4, 127.2, 148.0, 148.9, 149.5, 158.4, 161.2, 173.4.
Anal. Calcd for C24H32N2O4: C, 69.88; H, 7.82; N, 6.79. Found: C,
69.96; H, 7.94; N, 6.87.
Acknowledgment
The authors wish to thank O. Gagliardo for elemental analyses, F.
Tuberoni for IR spectra, and Dr. R. Raggio and Dr. M. Anzaldi for
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Substituted 2-Aminochromones
857
NMR spectra. Grateful appreciation is expressed by the authors to
Prof. F. Lucchesini for his skilful assistance in the structural inter-
pretation of 13C NMR spectra. The financial support from the Uni-
versity of Genoa is gratefully acknowledged.
Martin, N.; Richardson, C.; Rigoreau, L.; Stockley, M.;
Smith, G. C. M. J. Med. Chem. 2005, 48, 569.
(4) (a) Ermili, A.; Roma, G.; Mazzei, M.; Balbi, A.; Cuttica, A.;
Passerini, N. Farmaco, Ed. Sci. 1974, 29, 225. (b) Ermili,
A.; Roma, G. Gazz. Chim. Ital. 1971, 101, 269. (c) Ermili,
A.; Roma, G.; Balbi, A. Gazz. Chim. Ital. 1971, 101, 651.
(d) Ermili, A.; Balbi, A.; Roma, G.; Ambrosini, A.;
Passerini, N. Farmaco, Ed. Sci. 1976, 31, 627. (e) Roma,
G.; Vigevani, E.; Mazzei, M.; Ermili, A.; Ambrosini, A.;
Passerini, N. Farmaco, Ed. Sci. 1978, 33, 822.
(5) (a) Ermili, A.; Mazzei, M.; Roma, G.; Cacciatore, C.
Farmaco, Ed. Sci. 1977, 32, 375. (b) Ermili, A.; Balbi, A.;
Di Braccio, M.; Roma, G. Farmaco, Ed. Sci. 1977, 32, 713.
(c) Bantick, J. R.; Suschitzky, J. L. J. Heterocycl. Chem.
1981, 18, 679. (d) Morris, J.; Wishka, D. G.; Fang, Y.
J. Org. Chem. 1992, 57, 6502. (e) Morris, J.; Wishka, D. G.;
Fang, Y. Synth. Commun. 1994, 24, 849. (f) Morris, J.;
Luke, G. P.; Wishka, D. G. J. Org. Chem. 1996, 61, 3218.
(6) Gore, T. S.; Inamdar, P. K.; Nagarkar, P. M. Indian J. Chem.
1974, 12, 946.
References
(1) (a) Mazzei, M.; Balbi, A.; Roma, G.; Di Braccio, M.;
Leoncini, G.; Buzzi, E.; Maresca, M. Eur. J. Med. Chem.
1988, 23, 237. (b) Morris, J.; Wishka, D. G.; Lin, A. H.;
Humphrey, W. R.; Wiltse, A. L.; Gammill, R. B.; Judge, T.
M.; Bisaha, S. N.; Olds, N. L.; Jacob, C. S.; Bergh, C. L.;
Cudahy, M. M.; Williams, D. J.; Nishizawa, E. E.; Thomas,
E. W.; Gorman, R. R.; Benjamin, C. W.; Shebuski, R. J.
J. Med. Chem. 1993, 36, 2026. (c) Benjamin, C. W.; Lin, A.
H.; Morris, J.; Wishka, D. G.; Gorman, R. R. J. Pharmacol.
Exp. Ther. 1993, 265, 457. (d) Roma, G.; Cinone, N.;
Di Braccio, M.; Grossi, G.; Leoncini, G.; Signorello, M. G.;
Carotti, A. Bioorg. Med. Chem. 2000, 8, 751.
(2) (a) Bonin, P. D.; Singh, J. P.; Gammill, R. B.; Erickson, L.
A. J. Vasc. Res. 1993, 30, 108. (b) Morris, J.; Shebuski, R.
J. Curr. Pharm. Des. 1995, 1, 469. (c) Roma, G.;
(7) Oh, C.; Yi, I.; Park, K. P. J. Heterocycl. Chem. 1994, 31,
841.
(8) Kaye, P. T.; Ramaite, I. D. I. J. Chem. Res., Synop. 1997,
414.
(9) Roma, G.; Di Braccio, M.; Carrieri, A.; Grossi, G.; Leoncini,
G.; Signorello, M. G.; Carotti, A. Bioorg. Med. Chem. 2003,
11, 123.
Di Braccio, M.; Grossi, G.; Marzano, C.; Simonato, M.;
Bordin, F. Farmaco 1998, 53, 494. (d) Di Braccio, M.;
Grossi, G.; Roma, G.; Marzano, C.; Baccichetti, F.;
Simonato, M.; Bordin, F. Farmaco 2003, 58, 1083.
(3) (a) Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F.
J. Biol. Chem. 1994, 269, 5241. (b) Abbott, B. M.;
Thompson, P. E. Bioorg. Med. Chem. Lett. 2004, 14, 2847.
(c) Leahy, J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, J.
R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg.
Med. Chem. Lett. 2004, 14, 6083. (d) Griffin, R. J.; Fontana,
G.; Golding, B. T.; Guiard, S.; Hardcastle, J. R.; Leahy, J. J.;
Synthesis 2010, No. 5, 849–857 © Thieme Stuttgart · New York