An efficient multicomponent transformation of alkyl isocyanides, dialkyl acetylenedicarboxylates, and 2,4-dihydroxybenzophenones or 2,4- dihydroxyacetophenones into 2-amino-4//-chromene derivatives

Article abstract of DOI:10.1007/s00706-009-0226-3

The addition of 2,4-dihydroxybenzophenones or 2,4-dihydroxyacetophenones to dialkyl acetylenedi-carboxylates under neutral conditions in the presence of alkyl isocyanides leads to 2-amino-4ff-chromene derivatives in high yields. Springer-Verlag 2009.

Full text of DOI:10.1007/s00706-009-0226-3

Monatsh Chem (2010) 141:213–218
DOI 10.1007/s00706-009-0226-3
ORIGINAL PAPER
An efficient multicomponent transformation of alkyl isocyanides,
dialkyl acetylenedicarboxylates, and 2,4-dihydroxybenzophenones
or 2,4-dihydroxyacetophenones into 2-amino-4H-chromene
derivatives
•
Robabeh Baharfar Seyed Mohammad Vahdat
•
•
Majid Ahmadian Mohammad Javad Taghizadeh
Received: 27 December 2008 / Accepted: 20 November 2009 / Published online: 8 January 2010
Ó Springer-Verlag 2009
Abstract The addition of 2,4-dihydroxybenzophenones
or 2,4-dihydroxyacetophenones to dialkyl acetylenedi-
carboxylates under neutral conditions in the presence of
alkyl isocyanides leads to 2-amino-4H-chromene deriva-
tives in high yields.
coworkers [18, 19] reported that 4H-chromene derivatives
bind to Bcl-2 protein and induce apoptosis in the tumor
cells. Many studies have been published on the synthesis of
the chromene ring system yet [20, 21]. 2-Amino-4H-
chromenes have been of interest because of their biological
activities, but few methods have been reported for their
synthesis [22].
Keywords Dialkyl acetylenedicarboxylates ꢀ
2,4-Dihydroxybenzophenone ꢀ Alkyl isocyanides ꢀ
2,4-Dihydroxyacetophenone ꢀ 2-Amino-4H-chromene ꢀ
Three component reaction
As part of our current studies [23–25] on the development
of new routes to heterocyclic systems, we have recently
reported the synthesis of a novel class of coumarin deriva-
tives [25] using the reaction of dihydroxybenzophenones or
dihydroxyacetophenones with dialkyl acetylenedicarboxy-
lates in the presence of triphenylphosphine as a nucleophile.
Now, we wish to report an efficient synthesis of a novel class
of 4H-chromenes using alkyl isocyanides as nucleophiles.
Thus, a three-component reaction of 2,4-dihydroxybenzo-
phenones or 2,4-dihydroxyacetophenones with dialkyl
acetylenedicarboxylates in the presence of alkyl isocyanides
proceeds spontaneously at room temperature in dichloro-
methane, and produces dialkyl 6-benzoyl(or acetyl)-2-(alkyl
amino)-5-hydroxy-4H-chromene-3,4-dicarboxylates 4 and
dialkyl 6-acetyl-2-(alkylamino)-7-hydroxy-4H-chromene-
3,4-dicarboxylates 5 in fairly good yields (Scheme 1;
Table 1).
Introduction
The development of multicomponent reactions (MCRs)
designed to produce elaborate biologically active com-
pounds has become an important area of research in
organic, combinatorial, and medicinal chemistry [1–4]. The
MCR strategy offers significant advantages over conven-
tional linear-type synthesis because of its flexible,
convergent, and atom-efficient nature [5, 6].
The chromene moiety is often an important structural
component in both biologically active and natural alka-
loids, flavonoids, tocopherols, and anthocyanins [7–12].
Moreover, in recent years functionally substituted chrom-
enes have played an ever increasing role in synthetic
approaches towards promising compounds in biomedicinal
chemistry [13–16]. Substituted 4H-chromenes are a new
class of anti-cancer compounds [17]. Recently, Huang and
Results and discussion
The structures of the products 4 and 5 were determined on
1
the basis of their elemental analyses, mass spectra, H and
1
13C NMR, and IR spectroscopic data. The H NMR spec-
R. Baharfar (&) ꢀ S. M. Vahdat ꢀ M. Ahmadian ꢀ
M. J. Taghizadeh
Department of Chemistry, Mazandaran University,
47415 Babolsar, Iran
e-mail: baharfar@umz.ac.ir
trum of 4a contained four singlets identified as acetyl
(d = 2.57 ppm), two methoxy (d = 3.69 and 3.85 ppm),
and methine (d = 4.95 ppm) protons. On addition of a
drop of D2O to a solution of compound 4a in CDCl3 the
123

214
R. Baharfar et al.
Scheme 1
O
R"
OH
CH2Cl2
r.t
R'O2C
CO2R'
R
N
C
+
+
1
2
OH
3
O
R"
O
R"
OH
OH
R'O2C
R'O2C
CO2R'
CO2R'
+
O
O
NHR
NHR
5
4
distinct resonance signals in agreement with the proposed
structure. The presence of oxo and amino groups at one
end of the double bond leads to polarization of the
olefinic system. The a-carbon atom of this polarized
system appears at d = 161.4 ppm, and the b-carbon at
d = 71.4 ppm. Similar chemical shifts have been
observed for the polarized carbon–carbon double bonds in
2-alkylamino-4H-benzo[h]chromene derivatives [26]. The
carbonyl groups of 4a appear at d = 169.6, 173.5, and
203.1 ppm for ester and keto groups, respectively.
A possible mechanism for the formation of products 4
and 5 is proposed in Scheme 2. On the basis of the well
established chemistry of isocyanides [4, 27, 28], it is rea-
sonable to assume that compounds 4 and 5 resulted from
nucleophilic addition of alkyl isocyanides to the acetylenic
esters and subsequent protonation of the 1:1 adduct by the
OH-acid. Then, the resulting positively charged ion 6 is
attacked by the anion of the OH-acid from the ortho
positions relative to the strong activating group forming
ketenimines 7 and 8. These addition products may tauto-
merize and then cyclize under the reaction conditions
employed to produce 4 and 5.
Table 1 Yields of compounds 4 and 5
4, 5
R
R0
R00
Yield (%)
4
5
a
b
c
d
e
f
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
t-Bu
Me
Et
Me
Me
Me
Ph
90
65
60
88
90
93
–
–
30
35
–
t-Bu
Me
Et
Ph
–
t-Bu
Me
Et
Ph
–
g
h
i
Me
Me
Me
Ph
85
75
70
–
t-Bu
10
15
87
88
95
t-Bu
t-Bu
Me
Et
j
t-Bu
k
l
t-Bu
Ph
–
t-Bu
t-Bu
Ph
–
NH signal (d = 8.66 ppm) disappeared. Also, a single peak
was observed at (d = 13.03 ppm) that was assigned to the
remaining hydroxy proton. This proton has been deshielded
because of intramolecular hydrogen bonding with the
neighboring carbonyl compounds.
In conclusion, we have found a three component syn-
thetic method for preparation of some 4H-chromenes. The
method has the advantage that not only is the reaction
performed under neutral conditions, but also the starting
materials and reagents can be mixed without any activation
or modification.
Interestingly, when 2,4-dihydroxybenzophenone was
used as OH-acid, only product 4 was formed regioselec-
tively. The regiochemistry of the cyclization was confirmed
by observation of an AX pattern corresponding to the
aromatic protons of 4d which were displayed at d = 6.59
1
and 7.54 ppm (3J = 8.9 Hz). H NMR spectroscopy was
also used to distinguish structures 4 from 5. For example,
1
the H NMR spectrum of 4b displayed an AX pattern for
Experimental
the aromatic protons, whereas that for compound 5b
exhibited two single lines at d = 6.64 and 7.62 ppm. The
proton decoupled 13C NMR spectrum of 4a contained 21
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were
123

An efficient multicomponent transformation
215
Scheme 2
CO2R'
R
N
C
C
C
R
N
R'O2C
CO2R'
C
+
R'O2C
OH
O
R"
O
OH
N
C
CO2R'
R
R"
HO
C
C
+
H
R'O2C
O
6
CO R'
OH
O
2
CO2R'
H
OH
O
R'O2C
R"
R'O2C
RHN
R"
C
O
N
O
4
R
7
OH
O
OH
O
R"
R"
O
O
C
H
R
N
5
RHN
CO2R'
CO2R'
CO2R'
CO2R'
8
performed using a Heraeus CHN–O-Rapid analyzer and the
results agreed favorably with calculated values. IR spectra
10 min alkyl isocyanide (2 mmol). The reaction mixture
was stirred for 24 h. The solvent was then removed under
reduced pressure and the residue was separated by column
chromatography (silica gel, Merck 230–400 mesh) using
n-hexane–ethyl acetate (70:30) as eluent.
1
were measured on a Shimadzu IR-460 spectrometer. H
and 13C NMR spectra were measured on a Bruker DRX-
500 Avance instrument with CDCl3 as solvent at 500.1 and
125.7 MHz, respectively. Mass spectra were recorded on a
Finnigan MAT 8430 mass spectrometer operating at an
electron energy of 70 eV. Alkyl isocyanides, dialkyl acet-
ylenedicarboxylate, and 2,4-dihydroxybenzophenones and
2,4-dihydroxyacetophenones were obtained from Fluka
(Buchs, Switzerland) and were used without further
purification.
Dimethyl 6-acetyl-2-(cyclohexylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4a, C21H25NO7)
Yellow powder, yield 90%; m.p. 98–100 °C; IR (KBr):
vꢀ ¼ 1;625 and 1,770 (C=O), 3,360–3,460 (OH) cm-1; MS:
1
m/z (%) = 403 (M?, 4), 344 (100), 277 (65), 230 (68); H
NMR (500.13 MHz, CDCl3): d = 1.25–2.02 (10 H, m, 5
CH2), 2.57 (3 H, s, CH3), 3.69 and 3.85 (6 H, 2s, 2 OMe),
3.85 (1 H, m, CHN), 4.95 (1 H, s, CH), 6.62 (1 H, d,
3J = 8.9 Hz, CH), 7.66 (1 H, d, 3J = 8.9 Hz, CH), 8.66 (1
H, d, 3J = 6.0 Hz, NH), 13.03 (1 H, s, OH) ppm; 13C NMR
(125.77 MHz, CDCl3): d = 24.4, 25.4, 26.4, 33.50, 33.8
(5 CH2), 25.5 (CH3), 35.4 (CH), 49.8 (CHN), 52.3, 53.4
(2 OCH3), 71.4 (C=C–N), 107.4, 130.8 (2 CH), 110.4,
General procedure
To a magnetically stirred solution of a 2,4-dihydroxyben-
zophenone or 2,4-dihydroxyacetophenone (2 mmol) and
dialkyl acetylenedicarboxylate (2 mmol) in 10 cm3
CH2Cl2 was added dropwise at room temperature over
123

216
R. Baharfar et al.
116.1, 155.1, 160.0 (4 C), 161.4 (C=C–N), 169.6, 173.5 (2
C=O, ester), 203.1 (C=O, ketone) ppm.
(C=C–N), 169.6, 173.6 (2 C=O, ester), 200.5 (C=O,
ketone) ppm.
Diethyl 6-acetyl-2-(cyclohexylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4b, C23H29NO7)
Diethyl 6-benzoyl-2-(cyclohexylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4e, C28H31NO7)
Yellow powder, yield 65%; m.p. 140–143 °C; IR (KBr):
vꢀ ¼ 1;625 and 1,770 (C=O), 3,300–3,450 (OH) cm-1; MS:
m/z (%) = 432 (M??1, 32), 358 (100), 276 (75), 230 (60);
1H NMR (500.13 MHz, CDCl3): d = 1.21 and 1.29 (6 H,
2 t, 3J = 7.1 Hz, 2 CH3), 1.37–2.02 (10 H, m, 5 CH2), 2.59
(3 H, s, CH3), 3.79 (1 H, m, CHN), 3.74–3.80 (1 H, m,
Yellow powder, yield 90%; m.p. 97–99 °C; IR (KBr): vꢀ ¼
3;282 (NH), 1,750 and 1,660 (C=O) cm-1; MS: m/z
(%) = 509.6 (M?, 2), 437.5 (100), 412.4 (58), 365.5 (76),
324.4 (20), 214 (23); 1H NMR (500.13 MHz, CDCl3):
3
d = 1.26 and 1.28 (6 H, 2 t, J = 7.1 Hz, 2 CH3), 1.29–
2.03 (10 H, m, 5 CH2), 3.74–3.80 (1 H, m, CHN), 3.95–
3
CHN), 3.92–4.05 (2 H, 2 dq, ABX3 System, J = 7.2 Hz,
2J = 10.7 Hz, OCHAHBCH3), 4.08–4.20 (2 H, 2 dq, ABX3
4.11 (2 H,
2
dq, ABX3 System, 3J = 7.2 Hz,
2J = 10.7 Hz, OCHAHBCH3), 4.14–4.30 (2 H, 2 dq,
ABX3 System, 3J = 7.2 Hz, 2J = 10.7 Hz, OCHAHBCH3),
3
2
System, J = 7.2 Hz, J = 10.7 Hz, OCHAHBCH3), 4.93
(1 H, s, CH), 6.60 (1 H, d, 3J = 8.8 Hz, CH), 7.67 (1 H, d,
3
4.95 (1 H, s, CH), 6.59 (1 H, d, J = 8.9 Hz, CH), 7.47–
3
3
3J = 8.8 Hz, CH), 8.68 (1 H, d, J = 6.4 Hz, NH), 13.05
7.66 (5 H, m, 5 CH), 7.60 (1 H, d, J = 8.9 Hz, CH), 8.74
(1 H, s, OH) ppm; 13C NMR (125.77 MHz, CDCl3):
d = 14.1, 14.5 (2 CH3), 24.4, 25.4, 26.4, 33.5, 33.8 (5
CH2), 25.4 (CH3), 35.6 (CH), 49.8 (CHN), 59.4, 60.9 (2
OCH2), 71.5 (C=C–N), 107.4, 130.7 (2 CH), 110.4, 116.0,
155.2, 159.8 (4 C), 161.5 (C=C–N), 169.3, 173.3 (2 C=O,
ester), 203.1 (C=O, ketone) ppm.
(1 H, br, NH), 12.91 (1 H, s, OH) ppm; 13C NMR
(125.77 MHz, CDCl3): d = 14.2, 14.6 (2 CH3), 24.5, 24.6,
25.6, 33.6, 33.9 (5 CH2), 36.5 (CH), 49.9 (CHN), 59.8, 60.2
(2 OCH2), 71.8 (C=C–N), 107.1, 128.4, 129.1, 131.9, 137.9
(5 CH), 110.3, 115.4, 133.7, 155.0, 161.0 (5 C), 162.4
(C=C–N), 169.3, 173.0 (2 C=O, ester), 200.5 (C=O,
ketone) ppm.
Di-tert-butyl 6-acetyl-2-(cyclohexylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4c, C27H37NO7)
Di-tert-butyl 6-benzoyl-2-(cyclohexylamino)-5-hydroxy-
4H-chromene-3,4-dicarboxylate (4f, C32H39NO7)
Yellow powder, yield 60%; m.p. 122–125 °C; IR (KBr):
vꢀ ¼ 1;656 and 1,735 (C=O), 3,370–3,450 (OH) cm-1; MS:
m/z (%) = 487 (M?, 1), 330 (100), 230 (65), 386 (65), 57
Yellow powder, yield 93%; m.p. 138–140 °C; IR (KBr):
vꢀ ¼ 3;259 (NH), 1,727 and 1,661 (C=O) cm-1; MS: m/z
(%) = 565.7 (M?, 28), 510 (16), 466 (68), 409 (100), 214
1
(81); H NMR (500.13 MHz, CDCl3): d = 1.24–1.77 (10
H, m, 5 CH2), 1.39 and 1.52 (18 H, 2s, 2 t-Bu), 2.58 (3 H, s,
1
(19); H NMR (500.13 MHz, CDCl3): d = 1.29–2.04 (10
H, m, 5 CH2), 1.44 and 1.55 (18 H, 2s, 2 t-Bu), 3.73–3.76
(1 H, m, CHN), 4.85 (1 H, s, CH), 6.56 (1 H, d,
3J = 8.9 Hz, CH), 7.48–7.66 (5 H, m, 5 CH), 7.61 (1 H, d,
CH3), 3.71 (1 H, m, CHN), 4.43 (1 H, s, CH), 6.57 (1 H, d,
3
3J = 8.8 Hz, CH), 7.62 (1 H, d, J = 8.8 Hz, CH), 8.57
3
(1 H, d, J = 6.4 Hz, NH), 13.02 (1 H, s, OH) ppm; 13C
3
3J = 8.9 Hz, CH), 8.59 (1 H, d, J = 6.5 Hz, NH), 12.90
NMR (125.77 MHz, CDCl3): d = 24.7, 25.5, 26.4, 33.7,
34.1 (5 CH2), 25.6 (CH3), 28.0, 28.6 (6 CH3), 37.1 (CH),
50.0 (CHN), 73.1 (C=C–N), 79.2, 80.4 (2 C), 107.3, 130.5
(2 CH), 111.1, 115.8, 155.4, 159.6 (4 C), 161.5 (C=C–N),
169.0, 172.7 (2 C=O, ester), 203.2 (C=O, ketone) ppm.
(1 H, s, OH) ppm; 13C NMR (125.77 MHz, CDCl3):
d = 24.7, 24.8, 25.6, 33.7, 34.1 (5 CH2), 28.1, 28.7
(6 CH3), 37.2 (CH), 50.1 (CHN), 73.2 (C=C–N), 79.2, 80.6
(2 OCMe3), 107.2, 128.4, 129.0, 131.8, 137.9 (5 CH),
111.4, 115.2, 133.5, 155.5, 159.7 (5 C), 162.5 (C=C–N),
169.1, 172.8 (2 C=O, ester), 200.5 (C=O, ketone) ppm.
Dimethyl 6-benzoyl-2-(cyclohexylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4d, C26H27NO7)
Diethyl 6-acetyl-2-(tert-butylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4h, C21H27NO7)
Yellow powder, yield 88%; m.p. 128–130 °C; IR (KBr):
vꢀ ¼ 3;261 (NH), 1,750 and 1,674 (C=O) cm-1; MS: m/z
(%) = 466 (M?, 3), 406 (100), 324 (18), 292 (16), 214
White powder, yield 10%; m.p. 127–129 °C; IR (KBr):
vꢀ ¼ 1;670 and 1,750 (C=O), 3,350–3,450 (OH) cm-1; MS:
m/z (%) = 405 (M?, 5), 346 (45), 276 (70), 230 (75), 57
1
(16); H NMR (500.13 MHz, CDCl3): d = 1.26–2.02 (10
1
H, m, 5 CH2), 3.68 and 3.76 (6 H, 2s, 2 CH3), 3.77–3.82 (1
H, m, CHN), 5.03 (1 H, s, CH), 6.59 (1 H, d, 3J = 8.9 Hz,
CH), 7.48–7.66 (5 H, m, 5 CH), 7.54 (1 H, d, 3J = 8.9 Hz,
(100); H NMR (500.13 MHz, CDCl3): d = 1.20 and 1.29
(6 H, 2 t, J = 7.1 Hz, 2 CH3), 1.45 (9 H, s, t-Bu), 2.58
3
(3 H, s, CH3), 3.97–4.13 (2 H, 2 dq, ABX3 System,
3J = 7.2 Hz, 2J = 10.7 Hz, OCHAHBCH3), 4.14–4.28
(2 H, 2 dq, ABX3 System, 3J = 7.2 Hz, 2J = 10.7 Hz,
OCHAHBCH3), 4.94 (1 H, s, CH), 6.61 (1 H, d,
3
CH), 8.68 (1 H, d, J = 6.5 Hz, NH), 12.93 (1 H, s, OH)
ppm; 13C NMR (125.77 MHz, CDCl3): d = 24.4, 24.5,
25.5, 33.5, 33.9 (5 CH2), 35.6 (CH), 49.9 (CHN), 51.0, 52.4
(2 OCH3), 71.5 (C=C–N), 107.2, 128.4, 129.0, 131.9, 137.8
(5 CH), 110.5, 115.5, 133.8, 155.2, 160.1 (5 C), 162.4
3
3J = 8.9 Hz, CH), 7.65 (1 H, d, J = 8.9 Hz, CH), 8.81
(1 H, s, NH), 13.05 (1 H, s, OH) ppm; 13C NMR
123

An efficient multicomponent transformation
217
(125.77 MHz, CDCl3): d = 14.1, 14.6 (2 CH3), 26.4
(CH3), 30.6 (3 CH3), 35.5 (CH), 52.6 (CMe3), 59.5, 60.9
(2 OCH2), 72.4 (C=C–N), 107.2, 130.9 (2 CH), 110.5,
116.1, 155.0, 161.3 (4 C), 161.5 (C=C–N), 169.3, 173.2
(2 C=O, ester), 203.2 (C=O, ketone) ppm.
Di-tert-butyl 6-benzoyl-2-(tert-butylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4l, C30H37NO7)
Yellow powder, yield 95%; m.p. 143–145 °C; IR (KBr):
vꢀ ¼ 3;262 (NH), 1,726, 1,663 (C=O) cm-1; MS: m/z
(%) = 539.7 (M?, 35), 422 (75), 366 (100), 310 (34), 292
1
(25), 214 (23); H NMR (500.13 MHz, CDCl3): d = 1.43,
Di-tert-butyl 6-acetyl-2-(tert-butylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4i, C25H35NO7)
1.46, 1.54 (27 H, 3s, 3 t-Bu), 4.86 (1 H, s, CH), 6.57 (1 H,
d, 3J = 8.9 Hz, CH), 7.47–7.66 (5 H, m, 5 CH), 7.61 (1 H,
d, 3J = 8.9 Hz, CH), 8.75 (1 H, s, NH), 12.88 (1 H, s, OH)
ppm; 13C NMR (125.77 MHz, CDCl3): d = 28.1, 28.6,
30.7 (9 CH3), 37.2 (CH), 52.4 (CMe3), 74.2 (C=C–N), 79.4,
80.6 (2 OCMe3), 107.0, 128.4, 129.0, 131.8, 137.9 (5 CH),
111.5, 115.3, 133.6, 155.3, 161.1 (5 C), 162.5 (C=C–N),
169.1, 172.6 (2 C=O, ester), 200.5 (C=O, ketone) ppm.
White powder, yield 15%; m.p. 163–166 °C; IR (KBr):
vꢀ ¼ 1;675; 1,719 (C=O), 3,400–3,450 (OH) cm-1; MS: m/z
(%) = 462 (M??1, 27), 360 (76), 304 (100), 248 (82), 57
(78); 1H NMR (500.13 MHz, CDCl3): d = 1.39, 1.45, 1.52
(27 H, 3s, 3 t-Bu), 2.57 (3 H, s, CH), 4.78 (1 H, s, CH),
6.59 (1 H, d, 3J = 8.9 Hz, CH), 7.64 (1 H, d, 3J = 8.9 Hz,
CH), 8.73 (1 H, s, NH), 13.02 (1 H, s, OH) ppm; 13C NMR
(125.77 MHz, CDCl3): d = 26.5 (CH3), 28.0, 28.6, 30.7
(9 CH3), 37.0 (CH), 52.3 (CMe3), 74.0 (C=C–N), 79.3,
80.5 (2 CMe3), 107.2, 130.7 (2 CH), 111.2, 116.0, 155.2,
161.0 (4 C), 161.6 (C=C–N), 169.1, 172.6 (2 C = O, ester),
203.2 (C = O, ketone) ppm.
Diethyl 6-acetyl-2-(cyclohexylamino)-7-hydroxy-4H-
chromene-3,4-dicarboxylate (5b, C23H29NO7)
White powder, yield 30%; m.p. 140–143 °C; IR (KBr):
vꢀ ¼ 1;625; 1,770 (C=O), 3,350–3,480 (OH) cm-1; MS: m/z
(%) = 432 (M??1, 35), 358 (100), 276 (72), 230 (55); 1H
NMR (500.13 MHz, CDCl3): d = 1.20, 1.28 (6 H, 2 t,
3J = 7.1 Hz, 2 CH3), 1.33–2.02 (10 H, m, 5 CH2), 2.58 (3
H, s, CH3), 3.79 (1 H, m, CHN), 3.97–4.12 (2 H, 2 dq,
ABX3 System, 3J = 7.2 Hz, 2J = 10.7 Hz, OCHAHBCH3),
4.14–4.27 (2 H, 2 dq, ABX3 System, 3J = 7.2 Hz,
2J = 10.7 Hz, OCHAHBCH3), 4.53 (1 H, s, CH), 6.64,
7.62 (2 H, 2s, 2 CH), 8.60 (1 H, d, 3J = 6.3 Hz, NH), 12.65
(1 H, s, OH) ppm; 13C NMR (125.77 MHz, CDCl3):
d = 14.0, 14.7 (2 CH3), 24.4, 25.4, 26.5, 33.7, 33.9
(5 CH2), 25.5 (CH3), 38.6 (CH), 49.7 (CHN), 59.3, 60.9
(2 OCH2), 72.8 (C=C–N), 104.8, 130.7 (2 CH), 110.5,
115.3, 155.2, 159.6 (4 C), 161.5 (C=C–N), 169.2, 174.3
(2 C=O, ester), 203.2 (C=O, ketone) ppm.
Dimethyl 6-benzoyl-2-(tert-butylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4j, C24H25NO7)
Yellow powder, yield 87%; m.p. 130–132 °C; IR (KBr):
vꢀ ¼ 3;261 (NH), 1,739, 1,671 (C=O) cm-1; MS: m/z
(%) = 455.5 (M?, 3), 397 (100), 339 (73), 277 (24), 214
1
(21); H NMR (500.13 MHz, CDCl3): d = 1.47 (9 H, s,
t-Bu), 3.68, 3.75 (6 H, 2s, 2 OCH3), 5.05 (1 H, s, CH), 6.61
(1 H, d, 3J = 8.9 Hz, CH), 7.48–7.66 (5 H, m, 5 CH), 7.55
(1 H, d, 3J = 8.9 Hz, CH), 8.82 (1 H, s, NH), 12.91 (1 H, s,
OH) ppm; 13C NMR (125.77 MHz, CDCl3): d = 30.6
(3 CH3), 35.4 (CH), 51.1, 52.4 (2 OCH3), 52.7 (CMe3),
72.4 (C=C–N), 107.0, 128.4, 129.0, 131.9, 137.8 (5 CH),
110.7, 115.6, 133.9, 155.0, 161.5 (5 C), 162.4 (C=C–N),
169.7, 173.4 (2 C=O, ester), 200.5 (C=O, ketone) ppm.
Di-tert-butyl 6-acetyl-2-(cyclohexylamino)-7-hydroxy-4H-
chromene-3,4-dicarboxylate (5c, C27H37NO7)
Diethyl 6-benzoyl-2-(tert-butylamino)-5-hydroxy-4H-
chromene-3,4-dicarboxylate (4k, C26H29NO7)
White powder, yield 35%; m.p. 102–104 °C; IR (KBr):
vꢀ ¼ 1;671; 1,750 (C=O), 3,300–3,450 (OH) cm-1; MS: m/z
(%) = 487 (M?, 1), 330 (100), 230 (79), 386 (90), 57 (33);
1H NMR (500.13 MHz, CDCl3): d = 1.25–2.03 (10 H, m,
5 CH2), 1.42, 1.49 (18 H, 2s, 2 t-Bu), 2.59 (3 H, s, CH3),
3.71 (1 H, m, CHN), 4.43 (1 H, s, CH), 6.58, 7.85 (2 H, 2s,
2 CH), 8.57 (1 H, br, NH), 12.32 (1 H, s, OH) ppm; 13C
NMR (125.77 MHz, CDCl3): d = 24.7, 25.5, 26.5, 33.7,
34.1 (5 CH2), 25.4 (CH3), 27.9, 28.5 (6 CH3), 41.7 (CH),
49.9 (CHN), 72.2 (C=C–N), 79.2, 80.6 (2 C), 104.7, 131.6
(2 CH), 111.9, 116.9, 154.7, 159.0 (4 C), 162.9 (C=C–N),
169.0, 172.5 (2 C=O, ester), 203.0 (C=O, ketone) ppm.
Yellow powder, yield 88%; m.p. 97–99 °C; IR (KBr): vꢀ ¼
3;271 (NH), 1,729, 1,669 (C=O) cm-1
; MS: m/z
(%) = 483.6 (M?, 2), 394 (100), 338 (80), 310 (6), 292
1
(30), 214 (29); H NMR (500.13 MHz, CDCl3): d = 1.24,
3
1.26 (6 H, 2 t, J = 7.1 Hz, 2 CH3), 1.47 (9 H, s, t-Bu),
3.98–4.11 (2 H, 2 dq, ABX3 System, 3J = 7.2 Hz,
2J = 10.7 Hz, OCHAHBCH3), 4.12–4.24 (2 H, 2 dq,
ABX3 System, 3J = 7.2 Hz, 2J = 10.7 Hz, OCHAHBCH3),
3
5.03 (1 H, s, CH), 6.60 (1 H, d, J = 8.9 Hz, CH), 7.48–
3
7.66 (5 H, m, 5 CH), 7.65 (1 H, d, J = 8.9 Hz, CH), 8.84
(1 H, s, NH), 12.93 (1 H, s, OH) ppm; 13C NMR
(125.77 MHz, CDCl3): d = 14.2, 14.6 (2 CH3), 30.6 (3
CH3), 35.6 (CH), 52.6 (CMe3), 59.5, 60.0 (2 OCH2), 72.5
(C=C–N), 107.0, 128.4, 129.0, 131.9, 137.8 (5 CH), 110.8,
115.5, 133.8, 155.1, 161.3 (5 C), 162.5 (C=C–N), 169.4,
173.3 (2 C=O, ester), 200.5 (C=O, ketone) ppm.
Dimethyl 6-acetyl-2-(tert-butylamino)-7-hydroxy-4H-
chromene-3,4-dicarboxylate (5g, C19H23NO7)
Yellow powder, yield 85%; m.p. 105–110 °C; IR (KBr):
vꢀ ¼ 1;690; 1,750 (C=O), 3,400–3,450 (OH) cm-1; MS: m/z
(%) = 377 (M?, 7), 318 (43), 262 (70), 230 (43), 57 (100);
123

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R. Baharfar et al.
1H NMR (500.13 MHz, CDCl3): d = 1.47 (9 H, s, t-Bu),
2.61 (3 H, s, CH3), 3.66, 3.70 (6 H, 2s, 2 OMe), 4.64 (1 H,
s, CH), 6.63, 7.81 (2 H, 2s, 2 CH), 8.80 (1 H, s, NH), 12.40
(1 H, s, OH) ppm; 13C NMR (125.77 MHz, CDCl3):
d = 26.0 (CH3), 30.0 (3 CH3), 39.7 (CH), 50.4, 51.9 (2
OCH3), 52.2 (CMe3), 71.1 (C=C–N), 104.2, 131.2 (2 CH),
110.8, 116.8, 153.8, 160.3 (4 C), 162.7 (C=C–N), 169.0,
173.1 (2 C=O, ester), 202.6 (C=O, ketone) ppm.
References
1. Orru RVA, Greef M (2003) Synthesis 10:1471
2. Balme G, Bossharth E, Monteiro N (2003) Eur J Org Chem 4101
¨
3. Brase S, Gil C, Knepper K (2002) Bioorg Med Chem 10:2415
¨
4. Domling A, Ugi I (2000) Angew Chem Int Ed 39:3168
5. Weber L (2002) Drug Discov Today 7:143
¨
6. Domling A (2002) Curr Opin Chem Biol 6:306
7. Harbone JB (1988) The flavonoids—advances in research.
Chapman & Hall, London
8. Iacobucci GA, Sweeny JG (1983) Tetrahedron 39:3005
9. Bohm BA, Choy JB, Lee AYM (1989) Phytochemistry 28:501
10. Gill M (1995) Aust J Chem 48:1
Diethyl 6-acetyl-2-(tert-butylamino)-7-hydroxy-4H-
chromene-3,4-dicarboxylate (5h, C21H27NO7)
Yellow powder, yield 75%; m.p. 148–151 °C; IR (KBr):
vꢀ ¼ 1;672; 1,734 (C=O), 3,350–3,400 (OH) cm-1; MS: m/z
(%) = 405 (M?, 2), 346 (40), 276 (65), 230 (75), 57 (100);
1H NMR (500.13 MHz, CDCl3): d = 1.22, 1.26 (6 H, 2 t,
3J = 7.1 Hz, 2 CH3), 1.46 (9 H, s, t-Bu), 2.60 (3 H, s,
11. Parmar VS, Jain SC, Bisht KS, Jain R, Taneja P, Jha A, Tyagi
OD, Prasad AK, Wengel J, Olsen CE, Boll PM (1997) Phyto-
chemistry 46:597
12. Polyakov VV (1999) Chem Nat Compd (Engl Transl) 1:21
13. Sun W, Cama LJ, Birzin ET, Warrier S, Locco L, Mosley R,
Hammond ML, Rohrer SP (2006) Bioorg Med Chem Lett
16:1468
14. Stachulski AV, Berry NG, Low ACL, Moores SL, Row E,
Warhurst DC, Adagu IS, Rossignol JF (2006) J Med Chem
49:1450
15. Garino C, Bihel F, Pietrancosta N, Laras Y, Quelever G, Woo I,
Klein P, Bain J, Boucher JL, Kraus JL (2005) Bioorg Med Chem
Lett 15:135
16. Leahy JJJ, Golding BT, Griffin RJ, Hardcastle IR, Richardson C,
Rigoreau L, Smith GCM (2004) Bioorg Med Chem Lett 14:6083
17. Aramini YN, Germann JM, Huang Z (2000) Tetrahedron Lett
41:6993
18. Skommer J, Wlodkowic D, Matto M, Eray M, Pelkonen J (2006)
Leuk Res 30:322
3
CH3), 3.98–4.10 (2 H, 2 dq, ABX3 System, J = 7.2 Hz,
2J = 10.7 Hz, OCHAHBCH3), 4.14–4.25 (2 H, 2 dq, ABX3
3
2
System, J = 7.2 Hz, J = 10.7 Hz, OCHAHBCH3), 4.62
(1 H, s, CH), 6.63, 7.84 (2 H, 2s, 2 CH), 8.81 (1 H, s, NH),
12.37 (1 H, s, OH) ppm; 13C NMR (125.77 MHz, CDCl3):
d = 14.2, 14.5 (2 CH3), 26.6 (CH3), 30.6 (3 CH3), 40.3
(CH), 52.6 (CMe3), 59.5, 61.1 (2 OCH2), 71.6 (C=C–N),
104.7, 131.8 (2 CH), 111.3, 117.2, 154.3, 160.7 (4 C),
163.2 (C=C–N), 169.2, 173.3 (2 C=O, ester), 203.2 (C=O,
ketone) ppm.
19. Wang JL, Liu D, Zhang Z, Shan S, Han X, Srinvasula SM, Croce
CM (2000) Proc Natl Acad Sci USA 97:7124
20. Hepworth JD, Gabbutt CD, Heron BM (1996). In: Katritzky AR,
Rees CW, Scriven EFV (eds) Comprehensive heterocyclic
chemistry, vol 5. Pergamon, Oxford, p 351
21. Yavari I, Ramazani A (1996) J Chem Res (S) 382
22. Bloxam J, Dell CP, Smith CW (1994) Heterocycles 38:399
23. Baharfar R, Ostadzadeh A, Abbasi A (2004) J Chem Res 37
24. Baharfar R, Hossein-nia R, Baghbanian SM (2008) Lett Org
Chem 5:128
25. Baharfar R, Vahdat SM, Hakimabadi FG (2009) Monatsh Chem
140:489
26. Yavari I, Anary-Abbasinejad M, Alizadeh A, Hossaini Z (2003)
Tetrahedron 59:1289
27. Ugi I (1982) Angew Chem Int Ed 21:810
28. Walborsky HM, Periasamy MP (1983). In: Patai S, Rappoport Z
(eds) The chemistry of functional groups. Wiley, New York, p
835
Di-tert-butyl 6-acetyl-2-(tert-butylamino)-7-hydroxy-4H-
chromene-3,4-dicarboxylate (5i, C25H35NO7)
Yellow powder, yield 80%; m.p. 156–159 °C; IR (KBr):
vꢀ ¼ 1;672; 1,730 (C=O), 3,350–3,450 (OH) cm-1; MS: m/z
(%) = 462 (M??1, 58), 360 (87), 304 (100), 248 (67), 57
(97); 1H NMR (500.13 MHz, CDCl3): d = 1.41, 1.46, 1.49
(27 H, 3s, 3 t-Bu), 2.61 (3 H, s, CH3), 4.43 (1 H, s, CH),
6.61, 7.84 (2 H, 2s, 2 CH), 8.78 (1 H, s, NH), 12.35 (1 H, s,
OH) ppm; 13C NMR (125.77 MHz, CDCl3): d = 26.5
(CH3), 28.0, 28.6, 30.7 (9 CH3), 41.7 (CH), 52.4 (CMe3),
73.0 (C=C–N), 79.3, 80.6 (2 CMe3), 104.6, 131.7 (2 CH),
112.0, 116.9, 154.5, 160.4 (4 C), 163.0 (C=C–N), 169.0,
172.5 (2 C=O, ester), 203.1 (C=O, ketone) ppm.
Acknowledgments We are grateful for financial support from
Mazandaran University of the Islamic Republic of Iran.
123