Enol-Ugi Reaction of Hydroxycoumarins: Straightforward Synthesis of Amino Acid Derived Coumarin Enamines

Article abstract of DOI:10.1055/s-0034-1380436

Hydroxycoumarins containing electron-withdrawing groups have been successfully used as acidic components in Ugi-type multicomponent condensations with imines and isocyanides. The reaction takes place smoothly at room temperature, with no need of catalysis

Full text of DOI:10.1055/s-0034-1380436

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2431–2438
2431
special topic
A. G. Neo et al.
Special Topic
Synthesis
Enol-Ugi Reaction of Hydroxycoumarins: Straightforward Synthesis
of Amino Acid Derived Coumarin Enamines
R1
Ana G. Neo*
H
N
R2
OH
R3
N
Teresa G. Castellano
Carlos F. Marcos*
E
R3
O
i-PrOH
or
R2
N
E
R1
N
O
or
E
O
CH2Cl2
O
R1
r.t.
O
O
Laboratory of Bioorganic Chemistry & Membrane Biophysics,
School of Veterinary Sciences, University of Extremadura,
10071 Cáceres, Spain
cfernan@unex.es
aneo@unex.es
N
+
R2
H
16 examples, 27–95% yield
E
R3NC
OH
O
or
O
O
E
R2
N
O
O
R3
N
H
E = CO2Et, NO2
R1
R1 = Ph, 2-furyl, 4-MeC6H4, 4-FC6H4
R2 = Ph, Bn, 3,4-(OCH2O)Bn
O
O
R3 = Cy, t-Bu, 2,6-Me2C6H3, CH2CO2t-Bu
6 examples, 59–78% yield
Received: 21.04.2015
Accepted after revision: 24.05.2015
Published online: 25.06.2015
bonyl compounds, amines, and isocyanides10 has been ex-
tensively used for the synthesis of complex biologically ac-
tive compounds.11 We have recently demonstrated that
enols 3 can react in one-pot with carbonyl compounds 1,
amines 2, and isocyanides 4, considerably widening the di-
versity attainable by IMCR.12 Mechanistically, the reaction
is similar to the Ugi condensation with carboxylic acids, but
in this case the driving force is a Michael–retro-Michael re-
arrangement of the primary adduct, leading to a stable
enamine 10 (Scheme 1). Accordingly, a structural determi-
nant of the reaction is the presence of at least one α,β-un-
saturated electron-withdrawing group in the enol, which
facilitates this rearrangement. Enols derived from 3- and 4-
hydroxycoumarins meeting this constraint are readily
available starting materials for enol-Ugi reactions. Here we
report the use of this new strategy for the straightforward
synthesis of amino acid derived coumarin enamines.
DOI: 10.1055/s-0034-1380436; Art ID: ss-2015-c0258-st
Abstract Hydroxycoumarins containing electron-withdrawing groups
have been successfully used as acidic components in Ugi-type multi-
component condensations with imines and isocyanides. The reaction
takes place smoothly at room temperature, with no need of catalysis,
affording 3- and 4-coumarin enamines in a highly convergent manner.
Key to this transformation is the conjugate addition-β-elimination rear-
rangement on the primary adduct, irreversibly leading to the final prod-
uct.
Key words multicomponent reaction, heterocycles, Michael addition,
natural products, combinatorial chemistry
Coumarins constitute a large family of plant metabolites
possessing important biological activities. Remarkably, 3-
and 4-aminocoumarins are in the structural core of many
pharmaceuticals. For example, 4-aminocoumarins have
shown potent antimicrobial,1 antiproliferative,2 cytotoxic,3
antiplatelet,4 and anthrax inhibitory5 activities. They have
also been used as synthetic precursors of polycyclic 3,4-
fused coumarins.6 Natural 3-aminocoumarin antibiotics,
such as novobiocin and coumermycin, are known DNA gy-
rase inhibitors7 that have raised new attention due to their
antitumor activity related to selective inhibition of heat
shock protein 90.8 Also, the 3-aminocoumarin alkaloids
lamellarins have shown to selectively inhibit HIV-1 inte-
grase. In spite of the interest of aminocoumarins, synthetic
approaches to these compounds are scarce, and most of
them are multi-step processes having limited applications
in library synthesis.
O
R5
R4
OH
R3
N
R6
R2
R1
H
R1
H
R2
N
N
• •
C
R2
N+
1
+
4
3
+
R1
H
R2 NH2
R1
N
R6
2
5
6
7
R5
O–
R3
R4
R6
R1
R5
R6
HN
O
N
N
R6
–
O
R2
O
R5
R4
R4
R3
N
R5
R4
• •
N
R2
Multicomponent reactions of isocyanides (IMCR) pro-
vide a highly convergent strategy for the synthesis of di-
verse molecular libraries through one-step processes with
extraordinary atom and bond economy.9 Prototypically, the
Ugi four-component condensation of carboxylic acids, car-
R1
R1
R3
N
R2
H
R3
10
Scheme 1 Mechanism of the enol-Ugi reaction
primary adduct 8
9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438

2432
A. G. Neo et al.
Special Topic
Synthesis
To begin our study, 4-hydroxycoumarin was used,
which is a stable enol containing a conjugated lactone
prone to enable the required Michael–retro-Michael final
step of the enol-Ugi reaction. Thus, equimolar amounts of
4-hydroxycoumarin (3a), cyclohexyl isocyanide (4a), and
(E)-N-1-diphenylmethanimine (5a) were mixed in metha-
nol under different reaction conditions, but unfortunately
no product was formed in any of the cases. We hypothe-
sized that an extra withdrawing group would provide a
more reactive Michael acceptor that could react in the ex-
pected manner. Accordingly, ethyl 4-hydroxy-2-oxo-2H-
chromene-3-carboxylate (3b), readily available from acetyl-
salicylic acid,13 was used in the reaction. Thus, an equimo-
lar mixture of this enol 3b with imine 5a, and cyclohexyl
isocyanide (4a) was stirred in methanol at 25–30 °C for
three days, giving a precipitate that was characterized as
the enamine 10a (Scheme 2). The structure of 10a was fur-
ther confirmed by monocrystal X-ray diffraction (Figure 1).
Encouraged by this result, different conditions and cata-
lysts were examined in order to optimize the reaction. As
NO REACTION
E = H
Ph
Ph
+
N
OH
O
5a
E
Ph
HN
NC
Ph
N
O
O
E = CO2Et
CO2Et
3a, E = H
3b, E = CO2Et
4a
O
O
10a
Scheme 2 Enol-Ugi reaction of 4-hydroxycoumarins
some enol remained unreacted at the end of the reaction,
we decided to increase the molar ratio of imine and isocya-
nide. However, this did not seem to improve the reaction
(Table 1, entry 2). Also, increasing the temperature did not
reduce the reaction time and complex reaction mixtures or
decomposed starting materials were obtained (entries 3
and 4). The use of different Lewis acid catalyst also did not
improve the reaction. The use of different solvents were
then explored. Best results were obtained both in isopropyl
alcohol (entry 11) and water (entry 13), but in this latter
Table 1 Optimization of Enol-Ugi Reaction of Ethyl 4-Hydroxy-2-oxo-2H-chromene-3-carboxylate (3b)
Ph
N
HN
OH
Ph
NC
CO2Et
O
+
+
Ph
N
Ph
CO2Et
O
O
O
O
3b
5a
4a
10a
Entry
3b/4a/5a Ratio
Solvent
Temp (°C)
Time (h)
Catalyst
Yield (%) of 10a
1
2
1:1:1
1:2:2
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
25–30
25–30
70 (MW) + 25
75
72
72
–
52
49
29
NRa
40
51
30
34
32
30
63
CMb
60
40
30
–
3
5 min + 72 h
–
4
72
72
–
5
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
Sc(OTf)3
6
120
96
Y(OTf)3
7
Mg(ClO4)2
8
96
ZnCl2
9
148
96
Cu(OTf)2
10
11
12
13
14
15
CF3CH2OH
i-PrOH
–
–
–
–
–
–
96
toluene
H2O
72
72
H2O + SDSc
CH2Cl2
72
48
a NR: No reaction.
b CM: Complex mixture.
c SDS: Sodium dodecyl sulfate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438

2433
A. G. Neo et al.
Special Topic
Synthesis
In order to study the effect of the electron-withdrawing
group on the enol, 4-hydroxy-3-nitrocoumarin (3c) was
prepared by nitration of 4-hydroxycoumarin.15 An addi-
tional interest of this enol is the possibility of reducing the
nitro group after the condensation to obtain amino-derived
adducts. Thus, the reaction of enol 3c with equimolar
amounts of imine 5a and cyclohexyl isocyanide (4a) in iso-
propyl alcohol at room temperature for 24 hours gave the
desired enamine adduct 11a in a 56% yield; however, the
reaction was much less clean than the corresponding reac-
tion with enol 3b. After some optimization, the reaction
was successfully performed in dichloromethane at room
temperature to cleanly afford 11a in a 95% yield, in less than
two hours.
Figure 1 X-ray crystal structure of 10a14
Thus, the reaction of 4-hydroxy-3-nitrocoumarin (3c)
with different combinations of isocyanides 4 and imines 5
under similar conditions readily afforded the expected cou-
marin enamines 11 in moderate to good yields (Table 3).
solvent, the formation of insoluble aggregates reduces the
reproducibility of the reaction and the purity of the prod-
uct. Conversely, when the reaction is performed in isopro-
pyl alcohol the product precipitates from the reaction me-
dium allowing to readily isolate it in high purity. Thus, opti-
mal reaction conditions are the use of equimolar amounts
of the three starting reagents in isopropyl alcohol at room
temperature (entry 11).
To explore the scope of this reaction, different imines 5
and isocyanides 4 were treated with ethyl 4-hydroxy-2-
oxo-2H-chromene-3-carboxylate (3b) under the optimized
conditions (Table 2). In all the cases, the expected enamine
10 precipitates from the reaction medium, and is obtained
in moderate yields.
Table 3 Enol-Ugi Reactions of 4-Hydroxy-3-nitrocoumarin
OH
NO2
O
R3
NH
R2
O
O
N
CH2Cl2
20 °C
R1
NO2
3c
R2
+
R3NC
O
N
R1
O
5
4
11
Entry R1
R2
Bn
R3
c-C6H11
Product (Yield, %)
Table 2 3-Component Synthesis of 4-Aminoacylcoumarins 10
1
2
3
4
5
6
7
8
Ph
11a (95)
11b (63)
11c (63)
11d (42)
11e (66)
11f (48)
11g (65)
11h (44)
OH
Ph
Ph
Ph
Ph
Bn
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
CO2Et
O
R3
NH
c-C6H11
t-Bu
R2
O
O
N
2,6-Me2C6H3
c-C6H11
c-C6H11
t-Bu
i-PrOH
R1
CO2Et
3b
4-FC6H4
25 °C
R2
+
R3NC
4-MeC6H4
4-MeC6H4
O
N
R1
O
5
4
10
Analogously, the isomeric enol 3d, obtained by nitration
Entry R1
R2
Bn
R3
Product (yield, %)
of 3-hydroxycoumarin, reacted with a variety of isocya-
nides 4 and imines 5, affording the corresponding enamine
adducts 12 in good yields (Table 4).
1
2
3
4
5
6
7
8
Ph
c-C6H11
t-Bu
10a (63)
10b (60)
10c (43)
10d (42)
10e (65)
10f (27)
10g (62)
10h (47)
Ph
Ph
Ph
Ph
Bn
Bn
Bn
In conclusion, coumarin enamines 10, 11, or 12 contain-
ing α-amino amide substituents at position 3 or 4 can be
readily obtained by the new enol-Ugi condensation of
imines, isocyanides, and hydroxycoumarins containing
electron-withdrawing groups at positions 4 and 3, respec-
tively. The reaction mechanism is similar to that of the clas-
sical Ugi condensation, except that in this case the final step
leads to the product through a conjugate addition-β-elimi-
2,6-Me2C6H3
CH2CO2t-Bu
c-C6H11
3,4-(OCH2O)Bn
2-furyl
Ph
Bn
Ph
Ph
c-C6H11
c-C6H11
Ph
2,6-Me2C6H3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438

2434
A. G. Neo et al.
Special Topic
Synthesis
Table 4 Enol-Ugi Reactions of 3-Hydroxy-4-nitrocoumarin
13C NMR (100 MHz, CDCl3): δ = 168.89 (C), 166.38 (C), 159.58 (C),
159.30 (C), 152.91 (C), 135.90 (C), 135.27 (C), 132.72 (CH), 129.40
(CH), 128.69 (CH), 128.60 (CH), 128.51 (CH), 128.20 (CH), 127.70
(CH), 123.60 (CH), 119.33 (C), 116.84 (CH), 71.76 (CH), 62.64 (CH2),
57.77 (CH2), 48.36 (CH), 32.75 (CH2), 32.38 (CH2), 25.40 (CH2), 24.85
(CH2), 24.79 (CH2), 14.11 (CH3).
NO2
OH
NO2 R2
O
O
O
N
R3
MS (CI): m/z (%) = 539 (M+•, <5), 234 (27), 218 (90), 188 (62), 93 (56).
CH2Cl2
20 °C
3d
N
H
HRMS (CI): m/z calcd for C33H36N2O5: 539.2546; found: 539.2544.
R1
R2
+
O
O
R3NC
N
Ethyl 4-{Benzyl[2-(tert-butylamino)-2-oxo-1-phenylethyl]ami-
no}-2-oxo-2H-chromene-3-carboxylate (10b)
R1
12
5
4
Yield: 154 mg (60%); yellow solid; mp 195–197 °C.
Entry
R1
R2
R3
12 (% Yield)
IR (KBr): 3325, 3057, 2971, 1723, 1670, 1597, 1537, 1452, 1406, 1346,
1233, 1049, 762, 698 cm–1
.
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Bn
c-C6H11
c-C6H11
c-C6H11
t-Bu
12a (78)
12b (59)
12c (78)
12d (64)
12e (73)
12f (67)
1H NMR (500 MHz, CDCl3): δ = 7.45–7.37 (m, 4 H), 7.26–7.14 (m, 7 H),
7.08–7.01 (m, 3 H), 6.89 (br s, 1 H), 5.05 (s, 1 H), 4.52–4.35 (m, 2 H),
4.46 (d, J = 14.2 Hz, 1 H), 4.28 (d, J = 14.4 Hz, 1 H), 1.41 (t, J = 7.1 Hz, 3
H), 1.23 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 168.94 (C), 166.05 (C), 159.48 (C),
159.31 (C), 152.86 (C), 135.88 (C), 135.38 (C), 132.63 (CH), 129.35
(CH), 128.73 (CH), 128.52 (CH), 128.48 (CH), 128.14 (CH), 127.72
(CH), 123.59 (CH), 119.41 (C), 116.78 (CH), 72.64 (CH), 62.50 (CH2),
57.69 (CH2), 51.47 (C), 28.41 (CH3), 14.07 (CH3).
3,4-(OCH2O)Bn
Ph
Ph
Ph
Ph
2,6-Me2C6H3
4-MeC6H4
c-C6H11
nation rearrangement on the primary adduct. These trans-
formations of coumarin derivatives demonstrate the utility
of enol-Ugi reactions to efficient introduce complex func-
tionality on electron-deficient heterocyclic enols.
MS (CI): m/z (%) = 513 (M+• + 1, <5), 278 (14), 192 (58), 188 (41), 136
(100).
HRMS (CI): m/z calcd for C31H33N2O5: 513.2389; found: 513.2389.
Ethyl 4-(Benzyl{2-[(2,6-dimethylphenyl)amino]-2-oxo-1-phenyl-
ethyl}amino)-2-oxo-2H-chromene-3-carboxylate (10c)
Melting points are uncorrected. IR spectra were recorded as KBr pel-
lets. 1H and 13C NMR spectra were recorded on a 400 or 500 MHz
spectrometer. The assignments of signals in 13C NMR were made us-
ing DEPT. Mass spectra (MS) and high-resolution mass spectra
(HRMS) were recorded using chemical ionization (CI) with CH4, or
ESI-TOF. Liquid reagents were measured using positive-displacement
micropipettes with disposable tips and pistons.
Yield: 121 mg (43%); yellow solid; mp 118–120 °C.
IR (KBr): 3433, 3030, 1691, 1604, 1555, 1494, 1454, 1242, 1031, 760,
699 cm–1
.
1H NMR (500 MHz, CDCl3, 320 K): δ = 8.49 (br s, 1 H), 7.61 (d, J = 7.2
Hz, 2 H), 7.44–7.32 (m, 2 H), 7.30–7.14 (m, 7 H), 7.12–7.06 (m, 2 H),
7.04–6.88 (m, 4 H) 5.45 (s, 1 H), 4.60 (d, J = 14.2 Hz, 1 H), 4.45 (m, 3
H), 1.89 (br s, 6 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3, 278 K): δ = 166.34 (C), 159.61 (C), 159.26
(C), 152.98 (C), 135.43 (C), 134.89 (C), 133.41 (C), 132.83 (CH), 129.57
(CH), 128.87 (CH), 128.72 (CH), 128.54 (CH), 128.33 (CH), 128.31
(CH), 127.69 (CH), 127.24 (CH), 123.70 (CH), 119.57 (C), 117.84 (C),
116.81 (CH), 72.20 (CH), 62.75 (CH2), 58.21 (CH2), 18.30 (CH3),14.12
(CH3).
Enol-Ugi Adducts 10; General Procedure
To a solution of imine 5 (0.5 mmol) in i-PrOH (1 mL) were added suc-
cessively isocyanide 4 (0.5 mmol) and enol 3b (0.5 mmol). The reac-
tion mixture was stirred at 25–30 °C for 48–96 h, and then cooled to 0
°C. The resulting precipitate was filtered and washed with hexanes (4
mL), yielding analytically pure product 10. Then, 10% aq HCl (4 mL)
and H2O (20 mL) were added to the filtrate, and the resulting mixture
was extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was purified by
column chromatography (SiO2, gradient from 100% hexanes to hex-
anes–EtOAc, 7:3), giving a solid that was combined with the previous-
ly isolated precipitate (Table 2).
MS (CI): m/z (%) = 561 (M+• + 1, 62), 560 (58), 188 (43), 278 (31), 240
(100).
HRMS (CI): m/z calcd for C35H33N2O5: 561.2389; found: 561.2394.
Ethyl 4-[Benzyl(2-{[2-(tert-butoxy)-2-oxoethyl]amino}-2-oxo-1-
phenylethyl)amino]-2-oxo-2H-chromene-3-carboxylate (10d)
Ethyl 4-{Benzyl[2-(cyclohexylamino)-2-oxo-1-phenylethyl]ami-
no}-2-oxo-2H-chromene-3-carboxylate (10a)
Yield: 120 mg (42%); white solid; mp 137–139 °C.
IR (KBr): 3445, 1725, 1678, 1599, 1557, 1450, 1391, 1368, 1342, 1292,
1246, 1158, 1053, 757 cm–1
.
Yield: 170 mg (63%); white solid; mp 127–130 °C.
1H NMR (500 MHz, CDCl3): δ = 7.50–7.11 (m, 14 H), 7.00 (t, J = 7.4 Hz,
1 H), 5.23 (s, 1 H), 4.69 (d, J = 14.6 Hz, 1 H), 4.42 (q, J = 7.3 Hz, 2 H),
4.37 (d, J = 14.7 Hz, 1 H), 4.10 (dd, J = 17.8, 6.3 Hz, 1 H), 3.76 (dd, J =
17.9, 3.9 Hz, 1 H), 1.45 (s, 9 H), 1.39 (t, J = 7.0 Hz, 3 H).
IR (KBr): 3304, 3061, 2926, 2853, 1717, 1667, 1595, 1541, 1449, 1346,
1237, 1049, 752, 698 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45–7.36 (m, 3 H), 7.35–7.30 (m, 1 H),
7.25–7.11 (m, 8 H), 7.06–6.99 (m, 3 H), 5.17 (s, 1 H), 4.54–4.41 (m, 2
H), 4.44 (d, J = 14.9 Hz, 1 H), 4.29 (d, J = 14.5 Hz, 1 H), 3.65–3.59 (m, 1
H), 1.75–1.05 (m, 10 H), 1.43 (t, J = 7.1 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438

2435
A. G. Neo et al.
Special Topic
Synthesis
13C NMR (126 MHz, CDCl3): δ = 170.77 (C), 168.89 (C), 166.39 (C),
159.66 (C), 158.97 (C), 153.15 (C), 135.59 (C), 135.39 (C), 132.68 (CH),
129.63 (CH), 129.08 (CH), 128.91 (CH), 128.81 (CH), 128.64 (CH),
128.27 (CH), 127.73 (CH), 123.70 (CH), 119.53 (C), 117.41 (C), 116.96
(CH), 82.27 (C), 71.56 (CH), 62.82 (CH2), 57.60 (CH2), 42.16 (CH2),
28.22 (CH3), 14.20 (CH3).
13C NMR (126 MHz, CDCl3): δ = 175.78 (C), 172.08 (C), 157.86 (C),
154.70 (C), 147.21 (C), 135.62 (CH), 128.69 (CH), 128.59 (CH), 128.20
(CH), 125.34 (CH), 124.39 (CH), 123.14 (CH), 119.68 (CH), 117.10
(CH), 115.00 (C), 114.02 (CH), 93.39 (C), 64.63 (CH), 62.93 (CH2), 60.09
(CH), 33.31 (CH2), 32.67 (CH2), 26.00 (CH2), 25.14 (CH2), 24.97 (CH2),
14.41 (CH3).
MS (CI): m/z (%) = 571 (M+• + 1, 6), 515 (24), 324 (26), 86 (100).
MS (ESI-FIA-TOF): m/z (%) = 547 (M+• + Na, 40), 435 (24), 384 (28) 182
(100).
HRMS (CI): m/z calcd for C33H35N2O7: 571.2443; found: 571.2444.
HRMS (ESI-FIA-TOF): m/z calcd for C32H32N2O5Na: 547.2203; found:
547.2201.
Ethyl 4-{(Benzo[d][1,3]dioxol-5-ylmethyl)[2-(cyclohexylamino)-2-
oxo-1-phenylethyl]amino}-2-oxo-2H-chromene-3-carboxylate
(10e)
Ethyl 4-({2-[(2,6-Dimethylphenyl)amino]-2-oxo-1-phenyleth-
yl}(phenyl)amino)-2-oxo-2H-chromene-3-carboxylate (10h)
Yield: 189 mg (65%); white solid; mp 128–130 °C.
Yield: 128 mg (47%); white solid; mp 127–129 °C.
IR (KBr): 3435, 2932, 1664, 1607, 1530, 1490, 1448, 1397, 1249, 1037,
812, 755 cm–1
.
IR (KBr): 3433, 1720, 1605, 1566, 1499, 1382, 1240, 1046, 761, 699
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.49–7.40 (m, 4 H), 7.37–7.16 (m, 4 H),
7.15–7.03 (t, J = 7.6 Hz, 2 H), 6.64 (d, J = 7.9 Hz, 1 H), 6.57 (s, 1 H), 6.50
(d, J = 7.2 Hz, 1 H), 5.92 (s, 2 H), 5.20 (s, 1 H), 4.56–4.41 (m, 2 H), 4.37
(d, J = 14.4 Hz, 1 H), 4.21 (d, J = 14.4 Hz, 1 H), 3.70–3.58 (m, 1 H), 1.77–
1.08 (m, 13 H).
1H NMR (500 MHz, CDCl3): δ = 8.97 (br s, 1 H), 7.60 (d, J = 7.5 Hz, 2 H),
7.47 (dt, J = 8.7, 1.5 Hz, 1 H), 7.34–7.27 (m, 2 H), 7.21–7.05 (m, 9 H),
7.01 (d, J = 7.4 Hz, 3 H), 5.79 (s, 1 H), 4.36–4.19 (m, 2 H), 1.93 (s, 6 H),
1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.15 (C), 166.50 (C), 159.64 (C),
159.47 (C), 153.11 (C), 147.88 (C), 147.67 (C), 136.06 (C), 132.97 (CH),
129.33 (C), 128.88 (CH), 128.81 (CH), 127.82 (CH), 123.89 (CH),
123.21 (CH), 119.51 (C), 117.11 (CH), 109.83 (CH), 108.33 (CH),
101.30 (CH2), 71.96 (CH), 62.84 (CH2), 57.67 (CH2), 48.58 (CH), 32.97
(CH2), 32.58 (CH2), 25.56 (CH2), 25.05 (CH2), 24.99 (CH2), 14.28 (CH3).
13C NMR (126 MHz, CDCl3): δ = 168.66 (C), 164.80 (C), 158.22 (C),
153.51 (C), 145.72 (C), 135.31 (C), 133.24 (CH), 133.20 (C), 132.64 (C),
130.53 (CH), 129.66 (CH), 129.25 (CH), 128.30 (CH), 128.11 (CH),
127.25 (CH), 127.13 (CH), 124.47 (CH), 121.76 (CH), 119.09 (C),
116.84 (CH), 116.00 (CH), 62.79 (CH2), 18.22 (CH3), 13.88 (CH3).
MS (CI): m/z (%) = 547 (M+• + 1, <5), 500 (12), 398 (21), 309 (64), 238
(100).
MS (CI): m/z (%) = 583 (M+• + 1, <5), 189 (13), 134 (100).
HRMS (CI): m/z calcd for C34H35N2O7: 583.2443; found: 583.2444.
HRMS (CI): m/z calcd for C34H31N2O5: 547.2233; found: 547.2236.
Ethyl 4-{Benzyl[2-(cyclohexylamino)-1-(furan-2-yl)-2-oxoeth-
Enol-Ugi Adducts 11 and 12; General Procedure
yl]amino}-2-oxo-2H-chromene-3-carboxylate (10f)
To a solution of imine 5 (0.5 mmol) in CH2Cl2 (1 mL) were added iso-
cyanide 4 (0.5 mmol) and enol 3c/d (0.5 mmol) successively. The re-
action mixture was stirred at 20 °C for 2–3 h, and then concentrated.
The residue was purified by column chromatography (SiO2, gradient
from 100% hexanes to hexanes–EtOAc, 7:3) to give the enamine 11 or
12 as an analytically pure solid (Tables 3 and 4).
Yield: 71 mg (27%); white solid; mp 183 °C (dec.).
IR (KBr): 3333, 2933, 1730, 1677, 1602, 1560, 1451, 1397, 1341, 1241,
1112, 1052, 761 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.5
Hz, 1 H), 7.31–7.05 (m, 9 H), 6.42 (s, 1 H), 6.28 (s, 1 H), 5.45 (s, 1 H),
4.51–4.33 (m, 4 H), 3.73 (br s, 1 H), 1.86–1.59 (m, 5 H), 1.38 (t, J = 7.0
Hz, 3 H), 1.33–1.16 (m, 5 H).
13C NMR (126 MHz, CDCl3): δ = 166.67 (C), 166.12 (C), 159.60 (C),
157.92 (C), 153.44 (C), 148.84 (C), 143.20 (CH), 136.42 (C), 132.89
(CH), 128.66 (CH), 128.60 (CH), 128.04 (CH), 127.29 (CH), 124.21
(CH), 118.62 (C), 117.40 (CH), 111.87 (CH), 111.00 (CH), 65.31 (CH),
62.75 (CH2), 55.29 (CH2), 49.10 (CH), 32.90 (CH2), 32.83 (CH2), 25.62
(CH2), 25.10 (CH2), 14.17 (CH3).
2-[Benzyl(3-nitro-2-oxo-2H-chromen-4-yl)amino]-N-cyclohexyl-
2-phenylacetamide (11a)
Yield: 243 mg (95%); yellow solid; mp 110–112 °C.
IR (KBr): 3385, 2930, 2854, 1728, 1680, 1601, 1550, 1453, 1404, 1350,
1117, 1056, 761, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.07 (dd, J = 8.2, 1.3 Hz, 1 H), 7.57 (dt,
J = 6.7, 1.6 Hz, 1 H), 7.39–7.31 (m, 6H ), 7.27 (dd, J = 8.3, 1.0 Hz, 1 H),
7.23–7.15 (m, 5 H), 6.00 (d, J = 8.1 Hz, 1 H), 5.24 (s, 1 H), 4.69 (d, J =
14.9 Hz, 1 H), 4.20 (d, J = 15.0 Hz, 1 H), 3.78–3.67 (m, 1 H), 1.89–1.54
(m, 5 H), 1.36–0.97 (m, 5 H).
13C NMR (126 MHz, CDCl3): δ = 168.00 (C), 154.98 (C), 153.17 (C),
152.28 (C), 135.18 (C), 134.75 (C), 133.79 (CH), 129.28 (CH), 129.02
(CH), 129.00 (CH), 128.98 (CH), 128.42 (CH), 128.27 (CH), 128.25 (C),
124.84 (CH), 118.20 (C), 117.48 (CH), 71.12 (CH), 55.85 (CH2), 48.86
(CH), 32.55 (CH2), 32.48 (CH2), 26.92 (CH2), 25.32 (CH2), 24.74 (CH2),
24.66 (CH2).
MS (CI): m/z (%) = 529 (M+• + 1, <5), 402 (14), 358 (6), 266 (12), 234
(8), 206 (100).
HRMS (CI): m/z calcd for C31H33N2O6: 529.2339; found: 529.2338.
Ethyl 4-{[2-(Cyclohexylamino)-2-oxo-1-phenylethyl](phenyl)ami-
no}-2-oxo-2H-chromene-3-carboxylate (10g)
Yield: 163 mg (62%); white solid; mp 101–103 °C.
IR (KBr): 3431, 2931, 1702, 1649, 1602, 1521, 1497, 1461, 1414, 1384,
1229, 1041, 755, 696 cm–1
.
MS (ESI-FIA-TOF): m/z (%) = 534 (M+• + Na, 100), 512 (M+• + 1, 50), 340
(67).
1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J = 7.9 Hz, 1 H), 7.67 (dd, J =
11.4, 4.2 Hz, 1 H), 7.34–7.22 (m, 8 H), 6.85 (s, 2 H), 6.69 (d, J = 7.8 Hz, 2
H), 6.03 (br s, 1 H), 4.98 (s, 1 H), 4.04–3.98 (m, 2 H), 3.74 (br s, 1 H),
2.22–1.00 (m, 10 H), 1.46 (t, J = 7.1 Hz, 3 H).
HRMS (ESI-FIA-TOF): m/z calcd for C30H30N3O5: 512.2180; found:
512.2178.
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Synthesis
2-[Benzyl(3-nitro-2-oxo-2H-chromen-4-yl)amino]-N-(tert-butyl)-
N-(2,6-Dimethylphenyl)-2-[(3-nitro-2-oxo-2H-chromen-4-
yl)(phenyl)amino]-2-phenylacetamide (11e)
2-phenylacetamide (11b)12
Yield: 153 mg (63%); yellow solid; mp 84–89 °C.
Yield: 171 mg (66%); red solid; mp 156–158 °C.
IR (KBr): 3379, 2968, 1685, 1601, 1548, 1455, 1364, 1364, 1222, 760,
IR (KBr): 3383, 1742, 1715, 1604, 1536, 1499, 1381, 1278, 1043, 769
699 cm–1
.
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.02 (dd, J = 8.2, 1.3 Hz, 1 H), 7.58 (dt,
J = 8.5, 1.5 Hz, 1 H), 7.39–7.27 (m, 7 H), 7.24–7.19 (m, 3 H), 7.18–7.14
(m, 2 H), 5.84 (s, 1 H), 5.12 (s, 1 H), 4.68 (d, J = 14.9 Hz, 1 H), 4.21 (d, J =
14.9 Hz, 1 H), 1.26 (s, 9 H).
1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 7.5 Hz, 1 H), 7.80 (s, 1 H),
7.58 (dt, J = 8.7, 1.6 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 2 H), 7.33–7.23 (m, 5
H), 7.20–7.17 (m, 4 H), 7.11–7.05 (m, 2 H), 7.01 (d, J = 7.5 Hz, 2 H),
5.87 (s, 1 H), 1.95 (s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 168.02 (C), 154.96 (C), 153.36 (C),
152.25 (C), 135.12 (C), 134.86 (C), 133.77 (CH), 131.86 (C), 129.22
(CH), 129.03 (CH), 128.97 (CH), 128.47 (CH), 128.35 (CH), 128.28
(CH), 124.76 (CH), 118.29 (C), 117.47 (CH), 71.56 (CH), 56.16 (CH2),
51.93 (C), 28.36 (CH3).
13C NMR (126 MHz, CDCl3): δ = 167.53 (C), 153.96 (C), 152.59 (C),
150.56 (C), 144.73 (C), 135.07 (C), 134.37 (CH), 132.80 (C), 131.96 (C),
130.18 (CH), 129.78 (CH), 129.74 (CH), 129.01 (CH), 128.61 (CH),
128.42 (CH), 127.48 (CH), 125.33 (CH), 123.44 (CH), 118.46 (CH),
118.36 (C), 117.11 (CH), 70.26 (CH), 18.31 (CH3).
MS (CI): m/z (%) = 486 (M+• + 1, 40), 385 (56), 328 (57), 297 (58), 263
MS (ESI-FIA-TOF): m/z (%) = 542 (M+• + Na, 60), 520 (M+• + 1, 65), 238
(63), 105 (100).
(100).
HRMS (CI): m/z calcd for C28H28N3O5: 486.2029; found: 486.2015.
HRMS (ESI-FIA-TOF): m/z calcd for C31H25N3O5: 520.1867; found:
529.1877.
N-Cyclohexyl-2-[(3-nitro-2-oxo-2H-chromen-4-yl)(phenyl)ami-
no]-2-phenylacetamide (11c)
N-Cyclohexyl-2-(4-fluorophenyl)-2-[(3-nitro-2-oxo-2H-chromen-
4-yl)(phenyl)amino]acetamide (11f)
Yield: 157 mg (63%); red solid; mp 174–176 °C.
Yield: 124 mg (48%); red solid; mp 166–167 °C.
IR (KBr): 3445, 2929, 2856, 1746, 1655, 1607, 1557, 1496, 1453, 1384,
760, 703 cm–1
.
IR (KBr): 3427, 3300, 2933, 2856, 1744, 1655, 1607, 1530, 1509, 1385,
1231, 759 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.2
Hz, 1 H), 7.34–7.17 (m, 7 H), 7.16–7.11 (m, 2 H), 7.07–6.99 (m, 3 H),
6.46 (d, J = 7.6 Hz, 1 H), 5.61 (s, 1 H), 3.86–3.75 (m, 1 H), 1.93–0.92 (m,
10 H).
13C NMR (126 MHz, CDCl3): δ = 167.77 (C), 153.95 (C), 152.69 (C),
150.30 (C), 144.59 (C), 137.77 (C), 134.15 (CH), 132.57 (C), 129.82
(CH), 129.54 (CH), 129.41 (CH), 128.76 (CH), 128.54 (CH), 125.19
(CH), 123.22 (CH), 118.45 (CH), 117.98 (C), 117.24 (CH), 70.02 (CH),
48.63 (CH), 32.55 (CH2), 32.27 (CH2), 25.32 (CH2), 24.57 (CH2), 24.47
(CH2).
1H NMR (500 MHz, CDCl3): δ = 7.67 (dd, J = 8.1, 1.3 Hz, 1 H), 7.59 (dt,
J = 8.7, 1.5 Hz, 1 H), 7.33–7.20 (m, 6 H), 7.08–7.05 (m, 1 H), 7.03–7.01
(m, 2 H), 6.85 (t, J = 8.6 Hz, 2 H), 6.34 (d, J = 8.1 Hz, 1 H), 5.55 (s, 1 H),
3.86–3.76 (m, 1 H), 1.92–0.96 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 167.57 (C), 163.99 (C), 162.00 (C),
153.78 (C), 152.72 (C), 149.97 (C), 144.39 (C), 137.87 (C), 134.29 (CH),
131.81 (CH), 131.74 (CH), 129.63 (CH), 128.48 (CH), 128.43 (C),
128.41 (C), 125.29 (CH), 123.44 (CH), 118.45 (CH), 117.81 (C), 117.46
(CH), 115.75 (CH), 115.58 (CH), 69.23 (CH), 48.69 (CH), 32.57 (CH2),
32.28 (CH2), 25.28 (CH2), 24.55 (CH2), 24.44 (CH2).
MS (ESI-FIA-TOF): m/z (%) = 520 (M+• + Na, 100), 498 (M+• + 1, 20), 188
(46).
MS (ESI-FIA-TOF): m/z (%) = 538 (M+• + Na, 100), 516 (M+• + 1, 25), 206
(54).
HRMS (ESI-FIA-TOF): m/z calcd for C29H28N3O5: 498.2023; found:
498.2019.
HRMS (ESI-FIA-TOF): m/z calcd for C29H27FN3O5: 516.1929; found:
516.1926.
N-(tert-Butyl)-2-[(3-nitro-2-oxo-2H-chromen-4-yl)(phenyl)ami-
no]-2-phenylacetamide (11d)
N-Cyclohexyl-2-[(3-nitro-2-oxo-2H-chromen-4-yl)(phenyl)ami-
no]-2-(p-tolyl)acetamide (11g)
Yield: 99 mg (42%); red solid; mp 151–153 °C.
Yield: 166 mg (65%); red solid; mp 157–160 °C.
IR (KBr): 3391, 2966, 2925, 1746, 1671, 1603, 1493, 1461, 1370, 1057,
758, 699 cm–1
.
IR (KBr): 3450, 3307, 2933, 2856, 1476, 1656, 1607, 1629, 1384, 1277,
1120, 1051, 759 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.67 (dd, J = 8.1, 1.1 Hz, 1 H), 7.59–7.54
(m, 1 H), 7.31–7.18 (m, 7 H), 7.14 (t, J = 7.3 Hz, 2 H), 7.07 (d, J = 7.4 Hz,
1 H), 7.03 (d, J = 7.9 Hz, 2 H), 6.37 (s, 1 H), 5.49 (s, 1 H), 1.32 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 167.84 (C), 153.89 (C), 152.66 (C),
150.22 (C), 144.71 (C), 137.95 (C), 134.18 (CH), 132.69 (C), 129.78
(CH), 129.55 (CH), 129.42 (CH), 128.71 (CH), 128.55 (CH), 125.20
(CH), 123.14 (CH), 118.13 (CH), 117.92 (C), 117.23 (CH), 70.61 (CH),
51.90 (C), 28.25 (CH3).
1H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 7.2
Hz, 1 H), 7.30–7.21 (m, 5 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.03 (t, J = 7.4 Hz,
2 H), 6.94 (d, J = 7.9 Hz, 2 H), 6.40 (d, J = 8.2 Hz, 1 H), 5.56 (s, 1 H),
3.87–3.74 (m, 1 H), 2.23 (s, 3 H), 1.95–0.92 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 167.96 (C), 153.98 (C), 152.69 (C),
150.38 (C), 144.70 (C), 139.41 (C), 137.85 (C), 134.11 (CH), 129.70
(CH), 129.53 (CH), 129.41 (C), 129.25 (CH), 128.75 (CH), 125.18 (CH),
123.10 (CH), 118.29 (CH), 118.04 (C), 117.25 (CH), 69.83 (CH), 48.57
(CH), 32.57 (CH2), 32.28 (CH2), 25.33 (CH2), 24.58 (CH2), 24.47 (CH2),
21.09 (CH3).
MS (ESI-FIA-TOF): m/z (%) = 494 (M+• + Na, 100), 472 (M+• + 1, 20), 162
(24).
HRMS (ESI-FIA-TOF): m/z calcd for C27H26N3O5: 472.1867; found:
472.1863.
MS (ESI-FIA-TOF): m/z (%) = 534 (M+• + Na, 100), 488 (20), 304 (40),
202 (30).
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Synthesis
HRMS (ESI-FIA-TOF): m/z calcd for C30H29N3O5Na: 534.1999; found:
HRMS (ESI-FIA-TOF): m/z calcd for C31H29N3O7Na: 578.1898; found:
534.2000.
578.1904.
N-(tert-Butyl)-2-[(3-nitro-2-oxo-2H-chromen-4-yl)(phenyl)ami-
no]-2-(p-tolyl)acetamide (11h)
N-Cyclohexyl-2-[(4-nitro-2-oxo-2H-chromen-3-yl)(phenyl)ami-
no]-2-phenylacetamide (12c)
Yield: 107 mg (44%); red solid; mp 181–183 °C.
Yield: 194 mg (78%); red solid; mp 104–106 °C.
IR (KBr): 3385, 2967, 2926, 1747, 1674, 1606, 1534, 1497, 1367, 1278,
IR (KBr): 3410, 2930, 2853, 1740, 1661, 1605, 1545, 1497, 1453, 1383,
1228, 1054, 761, 600 cm–1
.
754 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.66 (dd, J = 8.1, 1.3 Hz, 1 H), 7.57 (dt,
J = 8.7, 1.5 Hz, 1 H), 7.31–7.22 (m, 4 H), 7.10 (d, J = 8.1 Hz, 2 H), 7.06
(d, J = 7.4 Hz, 1 H), 7.04–7.00 (m, 2 H), 6.94 (d, J = 7.8 Hz, 2 H), 6.34 (s,
1 H), 5.44 (s, 1 H), 2.23 (s, 3 H), 1.31 (s, 9 H).
1H NMR (500 MHz, CDCl3): δ = 7.63 (ddd, J = 8.7, 7.5, 1.4 Hz, 1 H), 7.47
(d, J = 6.8 Hz, 2 H), 7.43–7.39 (d, J = 7.7 Hz, 1 H), 7.38–7.34 (m, 2 H),
7.31–7.19 (m, 6 H), 7.02 (t, J = 7.4 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 2 H),
5.57 (s, 1 H), 3.90–3.80 (m, 1 H), 2.10–0.89 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 167.99 (C), 153.93 (C), 152.67 (C),
150.31 (C), 144.83 (C), 139.39 (C), 138.02 (C), 134.12 (CH), 129.66
(CH), 129.58 (C), 129.52 (CH), 129.26 (CH), 128.71 (CH), 125.18 (CH),
123.01 (CH), 118.00 (CH), 117.23 (CH), 70.43 (CH), 51.81 (C), 28.26
(CH3), 21.09 (CH3).
13C NMR (101 MHz, CDCl3): δ = 168.55 (C), 160.36 (C), 156.09 (C),
152.26 (C), 145.06 (C), 133.68 (CH), 133.04 (C), 130.33 (CH), 129.41
(CH), 129.34 (CH), 128.60 (CH), 125.76 (CH), 123.51 (CH), 123.06 (C),
122.34 (CH), 117.36 (CH), 116.54 (CH), 111.38 (C), 69.49 (CH), 47.87
(CH), 32.58 (CH2), 32.19 (CH2), 25.42 (CH2), 24.40 (CH2), 24.17 (CH2).
MS (ESI-FIA-TOF): m/z (%) = 508 (M+• + Na, 100), 462 (20), 304 (80),
MS (CI): m/z (%) = 498 (M+• + 1, 20), 342 (60), 254 (100).
284 (70), 220 (50), 192 (45), 176 (55).
HRMS (CI): m/z calcd for C29H8N3O5: 498.2029; found: 498.2029.
HRMS (ESI-FIA-TOF): m/z calcd for C28H27N3O5Na: 508.1843, found:
508.1850.
N-(tert-Butyl)-2-[(4-nitro-2-oxo-2H-chromen-3-yl)(phenyl)ami-
no]-2-phenylacetamide (12d)
2-[Benzyl(4-nitro-2-oxo-2H-chromen-3-yl)amino]-N-cyclohexyl-
2-phenylacetamide (12a)
Yield: 151 mg (64%); red solid; mp 167–169 °C.
IR (KBr): 3328, 2976, 1728, 1673, 1604, 1544, 1503, 1454, 1277, 1166,
Yield: 200 mg (78%); orange solid; mp 87–89 °C.
1056, 759, 701 cm–1
.
IR (KBr): 3383, 2930, 2853, 1740, 1660, 1607, 1544, 1453, 1107, 750,
1H NMR (400 MHz, CDCl3): δ = 7.84–6.69 (m, 15 H), 5.41 (s, 1 H), 1.29
(s, 9 H).
699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.45 (m, 3 H), 7.46–7.18 (m, 8 H),
7.14 (dd, J = 6.4, 2.8 Hz, 2 H), 7.06 (d, J = 7.8 Hz, 1 H), 6.88 (br s, 1 H),
5.13 (s, 1 H), 4.17 (d, J = 12.8 Hz, 1 H), 4.14 (d, J = 12.8 Hz, 1 H), 3.87–
3.74 (m, 1 H), 2.11–1.17 (m, 10 H).
13C NMR (101 MHz, CDCl3): δ = 169.44 (C), 159.25 (C), 152.00 (C),
135.39 (C), 132.88 (CH), 129.98 (CH), 129.84 (CH), 129.04 (CH),
128.89 (CH), 128.70 (CH), 128.54 (CH), 125.55 (CH), 123.31 (CH),
117.26 (CH), 111.76 (C), 72.55 (CH), 57.92 (CH2), 48.26 (CH), 33.13
(CH2), 33.03 (CH2), 25.68 (CH2), 24.91 (CH2), 24.85 (CH2), 21.26 (CH2).
13C NMR (101 MHz, CDCl3): δ = 168.84 (C), 160.37 (C), 156.36 (C),
152.49 (C), 145.40 (C), 133.88 (CH), 133.46 (C), 130.50 (CH), 129.60
(CH), 129.50 (CH), 128.80 (CH), 125.95 (CH), 123.71 (CH), 123.20 (C),
122.50 (CH), 117.56 (CH), 116.67 (CH), 111.53 (C), 70.41 (CH), 51.51
(C), 28.49 (CH3).
MS (CI): m/z (%) = 472 (M+• + 1, 7), 371 (20), 162 (100).
HRMS (CI): m/z calcd for C27H26N3O5: 472.1877; found: 472.1872.
N-(2,6-Dimethylphenyl)-2-[(4-nitro-2-oxo-2H-chromen-3-
yl)(phenyl)amino]-2-phenylacetamide (12e)
MS (CI): m/z (%) = 512 (M+• + 1, <5), 340 (21), 174 (61), 104 (100).
HRMS (CI): m/z calcd for C30H30N3O5: 512.2183; found: 512.2185.
Yield: 190 mg (73%); red solid; mp 98–100 °C.
IR (KBr): 3287, 3062, 1720, 1674, 1598, 1548, 1499, 1455, 1282, 1239,
2-[(Benzo[d][1,3]dioxol-5-ylmethyl)(4-nitro-2-oxo-2H-chromen-
3-yl)amino]-N-cyclohexyl-2-phenylacetamide (12b)
1164, 1125, 754 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.92 (s, 1 H), 7.72–7.69 (m, 2 H), 7.68–
7.66 (m, 1 H), 7.39–7.24 (m, 7 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.10–7.03
(m, 4 H), 6.01 (d, J = 7.5 Hz, 1 H), 5.85 (s, 1 H), 1.95 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 167.94 (C), 160.98 (C), 155.66 (C),
152.20 (C), 145.26 (C), 135.12 (C), 133.75 (CH), 133.32 (C), 132.82 (C),
130.62 (CH), 129.74 (CH), 129.59 (CH), 128.66 (CH), 128.36 (CH),
127.07 (CH), 125.86 (CH), 123.61 (CH), 123.07 (CH), 117.66 (CH),
117.40 (CH), 111.53 (C), 70.27 (CH), 18.41 (CH3).
Yield: 164 mg (59%); orange solid; mp 88–90 °C.
IR (KBr): 3385, 2928, 2852, 1739, 1661, 1608, 1544, 1503, 1490, 1447,
1250, 1101, 1038, 929, 756 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.56–7.52 (m, 1 H), 7.50–7.48 (m, 2 H),
7.30–7.19 (m, 4 H), 7.10 (dd, J = 8.3, 1.4 Hz, 1 H), 6.82 (br s, 1 H), 6.67
(d, J = 7.9 Hz, 1 H), 6.64 (d, J = 1.6 Hz, 1 H), 6.57 (dd, J = 7.9, 1.6 Hz, 1
H), 5.94 (dd, J = 7.4, 1.4 Hz, 2 H), 5.09 (s, 1 H), 4.26 (d, J = 12.9 Hz, 1 H),
4.09 (d, J = 12.9 Hz, 1 H), 3.84–3.75 (m, 1 H), 1.98–1.20 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 169.20 (C), 159.04 (C), 151.87 (C),
147.86 (C), 147.64 (C), 139.0 (C), 135.17 (C), 132.69 (CH), 129.60 (CH),
129.01 (C), 128.83 (CH), 128.52 (CH), 125.66 (C), 125.36 (CH), 123.44
(CH), 123.13 (CH), 117.10 (CH), 111.65 (C), 109.93 (CH), 108.28 (CH),
101.11 (CH2), 72.22 (CH), 57.51 (CH2), 48.06 (CH), 32.95 (CH2), 32.83
(CH2), 25.48 (CH2), 24.72 (CH2), 24.65 (CH2).
MS (CI): m/z (%) = 520 (M+• + 1, 6), 473 (22), 339 (14), 238 (48), 105
(100).
HRMS (CI): m/z calcd for C36H27N3O5: 520.1868; found: 520.1872.
N-Cyclohexyl-2-[(4-nitro-2-oxo-2H-chromen-3-yl)(phenyl)ami-
no]-2-(p-tolyl)acetamide (12f)
Yield: 171 mg (67%); red solid; mp 84–85 °C.
MS (ESI-FIA-TOF): m/z (%) = 578 (M+• + Na, 100), 384 (80), 262 (70),
135 (70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438

2438
A. G. Neo et al.
Special Topic
Synthesis
IR (KBr): 3336, 2929, 1730, 1672, 1606, 1546, 1501, 1454, 1283, 1246,
1163, 1144, 760 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.63 (dt, J = 8.6, 1.5 Hz, 1 H), 7.43–7.32
(m, 5 H), 7.30–7.24 (m, 2 H), 7.03 (dd, J = 6.3, 4.3 Hz, 2 H), 7.00 (d, J =
7.4 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 2 H), 5.52 (s, 1 H), 3.87–3.79 (m, 1 H),
2.21 (s, 3 H), 1.97–0.90 (m, 10 H).
(4) Roma, G.; Braccio, M. D.; Carrieri, A.; Grossi, G.; Leoncini, G.;
Grazia Signorello, M.; Carotti, A. Bioorg. Med. Chem. 2003, 11,
123.
(5) Zhu, P. J.; Hobson, J. P.; Southall, N.; Qiu, C.; Thomas, C. J.; Lu, J.;
Inglese, J.; Zheng, W.; Leppla, S. H.; Bugge, T. H.; Austin, C. P.;
Liu, S. Bioorg. Med. Chem. 2009, 17, 5139.
.
(6) (a) Peng, S.; Wang, L.; Huang, J.; Sun, S.; Guo, H.; Wang, J. Adv.
Synth. Catal. 2013, 355, 2550. (b) Lin, C.-H.; Yang, D.-Y. Org. Lett.
2013, 15, 2802. (c) Iaroshenko, V. O.; Erben, F.; Mkrtchyan, S.;
Hakobyan, A.; Vilches-Herrera, M.; Dudkin, S.; Bunescu, A.;
Villinger, A.; Sosnovskikh, V. Y.; Langer, P. Tetrahedron 2011, 67,
7946. (d) Liao, Y.-X.; Kuo, P.-Y.; Yang, D.-Y. Tetrahedron Lett.
2003, 44, 1599. (e) Trkovnik, M.; Kalaj, V.; Kitan, D. Org. Prep.
Proced. Int. 1987, 19, 450.
13C NMR (126 MHz, CDCl3): δ = 168.77 (C), 160.38 (C), 156.08 (C),
152.32 (C), 145.17 (C), 140.38 (C), 139.18 (C), 133.59 (CH), 130.22
(CH), 129.98 (C), 129.30 (CH), 125.72 (CH), 123.55 (CH), 123.21 (C),
122.26 (CH), 117.37 (CH), 116.55 (CH), 69.30 (CH), 47.83 (CH), 32.57
(CH2), 32.20 (CH2), 25.44 (CH2), 24.39 (CH2), 24.16 (CH2), 21.10 (CH3).
MS (CI): m/z (%) = 472 (M+• + 1, 7), 371 (20), 162 (100).
HRMS (CI): m/z calcd for C27H26N3O5: 472.1877; found: 472.1872.
(7) Gellert, M.; O’Dea, M. H.; Itoh, T.; Tomizawa, J. Proc. Natl. Acad.
Sci. U.S.A. 1976, 73, 4474.
(8) (a) Radanyi, C.; Le, B. G.; Messaoudi, S.; Bouclier, C.; Peyrat, J.-F.;
Brion, J.-D.; Marsaud, V.; Renoir, J.-M.; Alami, M. Bioorg. Med.
Chem. Lett. 2008, 18, 2495. (b) Burlison, J. A.; Neckers, L.; Smith,
A. B.; Maxwell, A.; Blagg, B. S. J. J. Am. Chem. Soc. 2006, 128,
15529. (c) Marcu, M. G.; Schulte, T. W.; Neckers, L. J. Natl. Cancer
Inst. 2000, 92, 242.
(9) Cioc, R.; Ruijter, E.; Orru, R. Green Chem. 2014.
(10) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem.
1959, 71, 386.
Acknowledgment
We thank the financial support from Junta de Extremadura and FEDER.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380436.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(11) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(12) Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org.
Lett. 2012, 14, 6218.
References
(13) Stefanou, V.; Matiadis, D.; Melagraki, G.; Afantitis, A.;
Athanasellis, G.; Igglessi-Markopoulou, O.; McKee, V.;
Markopoulos, J. Molecules 2011, 16, 384.
(14) For a detailed description of the crystal structure, see the Sup-
porting Information.
(1) Dekic, B. R.; Radulovic, N. S.; Dekic, V. S.; Vukicevic, R. D.; Palic,
R. M. Molecules 2010, 15, 2246.
(2) Di Braccio, M.; Grossi, G.; Roma, G.; Marzano, C.; Baccichetti, F.;
Simonato, M.; Bordin, F. Farmaco 2003, 58, 1083.
(3) Dong, Y.; Nakagawa-Goto, K.; Lai, C.-Y.; Morris-Natschke, S. L.;
Bastow, K. F.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2010, 20, 4085.
(15) Savel’ev, V. L.; Artamonova, O. S.; Troitskaya, V. S.; Vinokurov, V.
G.; Zagorevskii, V. A. Chem. Heterocycl. Compd. 1973, 9, 816.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 26, 2431–2438