Synthesis of functionalized coumarins and quinolinones by NHC-catalyzed annulation of modified enals with heterocyclic C-H acids

Article abstract of DOI:10.1021/jo500693h

N-Heterocyclic carbene (NHC) catalyzed lactonization and lactamization of 2-bromoenals with heterocyclic C-H acids proceeding via the α,β- unsaturated acyl azolium intermediates is reported. The reaction furnished coumarin- or quinolinone-fused lactone/la

Full text of DOI:10.1021/jo500693h

Note
pubs.acs.org/joc
Synthesis of Functionalized Coumarins and Quinolinones by NHC-
Catalyzed Annulation of Modified Enals with Heterocyclic C−H Acids
Santhivardhana Reddy Yetra, Tony Roy, Anup Bhunia, Digvijay Porwal, and Akkattu T. Biju*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India
S
* Supporting Information
ABSTRACT: N-Heterocyclic carbene (NHC) catalyzed
lactonization and lactamization of 2-bromoenals with hetero-
cyclic C−H acids proceeding via the α,β-unsaturated acyl
azolium intermediates is reported. The reaction furnished
coumarin- or quinolinone-fused lactone/lactam derivatives. In
addition, results of the enantioselective version of this reaction
using chiral NHC are presented.
he coumarin core is one of the characteristic structural
motifs present in a variety of biologically active natural
or acyl fluorides,7 enals under oxidative conditions,8 ynals,9 and
2-haloenals.10 The nucleophilic coupling partners usually
employed are alcohols, masked enolates, β-diketones, β-
ketoesters, enamines, enolizable aldehydes, etc. Interestingly,
however, the synthetic utility of heterocyclic C−H acids as
nucleophile in α,β-unsaturated acyl azolium chemistry has
received only scant attention.8d,9b In 2010, Bode and co-
workers reported the enantioselective NHC-catalyzed reaction
of ynals with Kojic acids, which proceeds via the Claisen
rearrangement (Scheme 1, eq 1).9b However, the dihydropyr-
anone products are rather unstable, and the stable ester product
was obtained by the ring-opening of the dihydropyranones.
Moreover, this reaction is limited only to Kojic acids as the
heterocyclic C−H acid component.11 Herein, we report the
NHC-catalyzed reaction of 2-bromoenals with various hetero-
cyclic C−H acids, and the reaction resulting in the practical
T
products and numerous pharmaceuticals.1 Specifically, 4-
hydroxycoumarin and their derivatives are valuable starting
materials for the synthesis of natural products and drug
molecules.2 For instance, enantioselective organocatalytic
conjugate addition of 4-hydroxycoumarin to α,β-unsaturated
ketones is a straightforward method to access warfarin, which is
a widely used anticoagulant (Figure 1).3 Moreover, tioclomarol,
Figure 1. Selected drugs and natural product containing coumarin
core.
Scheme 1. NHC-Catalyzed Reaction of α,β-Unsaturated
Aldehydes with Heterocyclic C−H Acids
a 4-hydroxycoumarin-derived second-generation drug, is
employed as a rodenticide that is effective for the control of
rodents.4 Additionally, coumestan constitutes the essential core
of a variety of natural compounds incorporating the coumarin
moiety.5 The possibility of wide range of biological properties
make coumarins an interesting synthetic target. As a
consequence, developing straightforward and flexible synthetic
methods toward functionalized coumarins has attracted much
attention from organic chemists.
Umpolung of aldehydes catalyzed by N-heterocyclic carbene
(NHC) organocatalysis leading to the generation of nucleo-
philic acyl anion intermediates and homoenolate equivalents
constitute an unconventional protocol for the construction of
carbon−carbon and carbon−heteroatom bonds.6 An important
mode of action of NHCs that recently received immense
attention is the generation of α,β-unsaturated acyl azoliums.
NHC-catalyzed generation of α,β-unsaturated acyl azolium
intermediates can be achieved from α,β-unsaturated enol esters
Received: March 25, 2014
Published: April 9, 2014
© 2014 American Chemical Society
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Note
synthesis of coumarin/quinolinone fused dihydropyranones
and dihydropyridinones (Scheme 1, eq 2).
ring of 2 resulted in the smooth conversion to the product in
good yield (3f). Additionally, 2-bromoenals with disubstitution
on β-aryl ring furnished the desired product in moderate to
good yields (3g, 3h).16 Furthermore, this novel annulation
reaction is not limited to 4-hydroxycoumarin. Gratifyingly, 4-
hydroxy-6-methyl-2-pyrone and 2-hydroxynaphthoquinone17
were employed as the C−H acid component leading to the
formation of the desired products (3i−k) in moderate to good
yields, further expanding the scope of this annulation reaction.
Next, we focused our attention on various 4-(arylamino)-2H-
chromen-2-one with a view to synthesize fused dihydropyr-
idinones. As expected, the reaction of 4-(phenylamino)-
chromenone 1l with the parent bromoenal 2a furnished the
chromenone-fused dihydropyridinones 3l in 60%. The reaction
worked well with differently substituted 2-bromoenals furnish-
ing the desired products in moderate to good yields (3m−o).
In addition, electron releasing as well as electron-withdrawing
group at the 4-(arylamino) moiety were well tolerated affording
the fused dihydropyridinones in good yields (3p−q), thus
considerably expanding the scope of this reaction.
Our present study commenced with the treatment of 4-
hydroxycoumarin 1a and α-bromo cinnamaldehyde 2a with 10
mol % of imidazolium salt 4 and 1.1 equiv of the Cs2CO3. As
anticipated, the reaction afforded the functionalized pyrano[3,2-
c]chromene-2,5-dione derivative 3a in 29% yield.12 With this
initial result, standard optimization studies were performed,13
which revealed that the reaction carried out using a mixture of
toluene and THF (4:1)14 and an excess of Cs2CO3 (1.5 equiv)
resulted in the formation of 3a in 71% (Scheme 2).15
Scheme 2. NHC-Catalyzed Reaction of 4-Hydroxycoumarin
with 2-Bromocinnamaldehyde
After examining the scope of the reaction with various
coumarin-derived C−H acids, we then focused our attention on
another class of heterocyclic C−H acids, namely 4-hydroxy-1-
methylquinolin-2 (1H)-one 6, with a view to construct
quinolinone-fused dihydropyranones (Table 2). At the outset,
After optimizing the reaction conditions, we then studied the
substrate scope of this interesting NHC-catalyzed annulation
reaction (Table 1). In the beginning, we evaluated various 2-
bromoenals. Various electron-donating or -withdrawing groups
at the 4-position of the β-aryl ring of 2 were well tolerated,
leading to coumarin-fused dihydropyranones in good yields
(3b−e). Moreover, substitution at the 2-position of the β-aryl
Table 2. Substrate Scope of the NHC-Catalyzed Annulation
a
of Quinolinone-Derived C−H Acids with 2-Bromoenals
Table 1. Substrate Scope of the NHC-Catalyzed Annulation
a
of Heterocyclic C−H Acids with 2-Bromoenals
a
General reaction conditions: 6 (0.50 mmol), 2 (0.50 mmol), 4 (10
mol %), Cs2CO3 (1.5 equiv), toluene: THF (4:1, 10 mL), 20 °C, and
12 h. Yields of isolated products are provided.
treatment of 2-bromoenal 2a with 6 in the presence of carbene
generated from 4 using Cs2CO3 as base at 20 °C afforded the
2H-pyrano[3,2-c]quinoline-2,5(3H)-dione 7a in 92% yield.
Notably, this reaction worked at a lower temperature compared
to the reaction of 2 with coumarin derivatives. Interestingly, the
reaction worked well with a variety of electron-releasing and
-withdrawing groups at various positions of the β-aryl ring of 2.
In all cases, the quinolinone-fused dihydropyranone derivatives
were isolated in moderate to good yields (7b−h).18
Further insightful experiments have shed light on the
mechanism of this new transformation. Competition experi-
ments carried out using 4-hydroxycoumarin and differently
substituted 2-bromoenals showed that the rate of the reaction
increases in the order 2b (4-OMe) < 2a (4-H) < 2e (4-CF3),
with 2e reacting approximately 4 times faster than 2b under
optimized conditions (Scheme 3).13 This finding suggests that
the presence of electron-withdrawing group at the β-aryl group
of 2 makes the α,β-unsaturated acyl azolium more electrophilic
a
General reaction conditions: 1 (0.50 mmol), 2 (0.50 mmol), 4 (10
mol %), Cs2CO3 (1.5 equiv), toluene/THF (4:1, 10 mL), 30 °C and
12 h. Yields of isolated products are given. Reaction run using 15 mol
% of 4.
b
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Note
a
from the corresponding α,β-unsaturated aldehydes following the
literature procedure.22 The imidazolium salt 4 and triazolium salt 8
were synthesized following the literature procedure.19a,23 1H and 13C
NMR spectra were recorded in CDCl3 as solvent. Chemical shifts (δ)
are given in ppm. The residual solvent signals were used as references
and the chemical shifts converted to the TMS scale (CDCl3: δH =
7.26 ppm, δC = 77.16 ppm). HRMS measurements were carried out
using ESI method and ion-trap mass analyzer.
Scheme 3. Competition Experiment
General Procedure for the Synthesis of Functionalized
Coumarins. To a flame-dried screw-capped test tube equipped with a
magnetic stir bar was taken imidazolium salt 4 (17.5 mg, 0.05 mmol),
Cs2CO3 (244 mg, 1.5 equiv), 2-bromoenal 2 (0.50 mmol), and
coumarin derivative 1 (0.50 mmol). Then the screw-capped tube was
evacuated and backfilled with argon. To this mixture was added
toluene/THF (4:1, 10.0 mL) under argon atmosphere, and mixture
was stirred at 30 °C for 12 h. When the reaction was complete, the
solvent was evaporated and the crude residue was purified by flash
column chromatography on silica gel to afford the corresponding
functionalized coumarins (3).
a
1
The yields were determined by H NMR analysis of crude products
using CH2Br2 as the internal standard.
and facilitates efficient nucleophilic addition of 1a. This also
indicates the probable role of electronic nature of 2-bromoenals
in the rate-determining step.
In addition, we have carried out experiments on the
asymmetric version of this NHC-catalyzed annulation between
2-bromoenals and heterocyclic C−H acids. Treatment of 4-
hydroxy coumarin 1a and 2-bromoenal 2a in the presence
chiral triazolium salt 819 and 1.2 equiv of Na2CO3 resulted in
the formation of (R)-pyrano[3,2-c]chromene-2,5-dione deriva-
tive 3a′ in 75% yield and a promising 93:7 er (Table 3).20
4-Phenyl-3,4-dihydropyrano[3,2-c]chromene-2,5-dione (3a):20a
white solid (104.0 mg, 71%); Rf (petroleum ether/EtOAc = 70/30)
1
0.60; H NMR (400 MHz, CDCl3) δ 7.91 (dd, J1 = 1.7 Hz, J2 = 8.2
Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.39−7.24 (m, 7H), 4.53 (d, J = 7.3
Hz, 1H) 3.24−3.11 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 164.4,
160.9, 157.4, 153.3, 139.5, 133.1, 129.4, 128.2, 126.8, 124.8, 122.9,
117.0, 113.7, 106.5, 36.1, 36.0; HRMS calcd [M + Na]+ for
C18H12O4Na 315.0628, found 315.0624; FTIR (cm−1) 3065, 3028,
2924, 1793, 1722, 1645, 1609, 1578, 1456, 1328, 1108, 906, 757, 699,
637.
4-(4-Methoxyphenyl)-3,4-dihydro-2H,5H-pyrano[3,2-c]-
chromene-2,5-dione (3b):24 white solid (124.0 mg, 77%); Rf
(petroleum ether/EtOAc = 70/30) 0.46; 1H NMR (400 MHz,
CDCl3) δ 7.91(dd, J1 = 8.3 Hz, J2 = 8.3 Hz, 1H), 7.61 (t, J = 7.5 Hz,
1H), 7.39−7.35 (m, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz,
2H), 4.48 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.21−3.09 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 164.6, 160.9, 159.4, 157.1, 153.3, 133.09,
131.5, 127.9, 124.77, 122.9, 117.0, 114.7, 113.7, 106.8, 55.4, 36.3, 35.3;
HRMS calcd [M + Na]+ for C19H14O5Na 345.0731, found 345.0729;
FTIR (cm−1) 2925, 2853, 1792, 1721, 1644, 1609, 1379, 1251, 1105,
1034, 983, 760, 637.
Table 3. Enantioselective Synthesis of Functionalized
Coumarins
a
Methyl 4-(2,5-dioxo-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-4-
yl)benzoate (3c): white solid (135.0 mg, 77%); Rf (petroleum ether/
EtOAc = 70/30) 0.27; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4
Hz, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.40−7.37
(m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.58 (d, J = 7.5 Hz, 1H), 3.88 (s,
3H, CH3), 3.24 (dd, J1 = 7.8 Hz, J2 = 16.3 Hz, 1H), 3.14 (d, J = 16.2
Hz,1H). 13C NMR (100 MHz, CDCl3) δ 166.6, 163.9, 160.8, 157.7,
153.4, 144.45, 133.3, 130.7, 130.1, 126.9, 124.9, 123.0, 117.1, 113.5,
105.7, 52.3, 36.0, 35.8; HRMS calcd [M + Na]+ for C20H14O6Na
373.0683, found 373.0679; FTIR (cm−1) 3869, 3823, 3728, 3232,
3181, 2854, 2379, 1638, 1524, 1287, 1058, 988.
a
General reaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), 8 (8
mol %), Na2CO3 (1.2 equiv), toluene (1.0 mL), 30 °C, and 12 h.
4-(4-Fluorophenyl)-3,4-dihydropyrano[3,2-c]chromene-2,5-dione
Interestingly, electron-donating or -withdrawing groups at the
4-position of the β-aromatic ring of 2 were well tolerated,
leading to fused-dihydropyranones in good yields and with
moderate er values (3b′, 3d′). Moreover, substitution at 2-
position of β-aryl was also well tolerated (3f′).
(3d): white solid (133.0 mg, 86%); Rf (petroleum ether/EtOAc = 70/
1
30) 0.56; H NMR (400 MHz, CDCl3) δ 8.59 (dd, J1 = 1.9 Hz, J2 =
10.2 Hz, 1H), 8.24−8.19 (m, 1H), 7.94−7.88 (m, 2H), 7.74−7.70 (m,
2H), 7.47−7.41 (m, 2H), 4.35 (dd, J1 = 2.0 Hz, J2 = 9.5 Hz, 1H), 2.74
(dd, J1 = 9.5 Hz, J2 = 20.0 Hz, 1H), 2.61 (dd, J1 = 2.0 Hz, J2 = 20.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ 185.9, 185.23 (d, J = 310.2),
181.7, 177.4, 172.3, 149.7 (d, J = 4.26), 147.2, 141.3 (d, J = 9.8), 136.8,
134.4, 127.0, 126.2, 126.00, 122.6, 113.6, 26.0, 24.9; HRMS calcd [M +
Na]+ for C18H11FO4Na 333.0534, found 333.0527; FTIR (cm−1)
3065, 3028, 2924, 1793, 1722, 1645, 1609, 1578, 1456, 1328, 1108,
906, 757, 699, 637.
In conclusion, we have developed the NHC-organocatalyzed
reaction of 2-bromoenals with heterocyclic C−H acids leading
to the formation of coumarin/quinolinone-fused dihydropyr-
anone/dihydropyridinone derivatives. The reaction proceeds
via the generation of α,β-unsaturated acylazolium intermedi-
ates.21 Moreover, the results on the enantioselective version of
this reaction are also presented.
4-(4-(Trifluoromethyl)phenyl)-3,4-dihydropyrano[3,2-c]-
chromene-2,5-dione (3e): white solid (135.2 mg, 75%); Rf (petroleum
ether/EtOAc = 70/30) 0.44; 1H NMR (400 MHz, CDCl3) δ 7.94 (dd,
J1= 1.5 Hz, J2 = 8.2 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.59 (d, J = 8.1
Hz, 2H), 7.42−7.38 (m, 4H), 4.60 (d, J = 7.3 Hz, 1H), 3.29 (dd, J1=
EXPERIMENTAL SECTION
General Information. Unless otherwise specified, all reactions
were carried out under an atmosphere of argon in flame-dried reaction
vessels with Teflon screw caps. The 2-bromoenals were synthesized
■
7.8 Hz, J2 = 16.3 Hz, 1H), 3.17 (dd, J1= 1.5 Hz, J2 = 16.2 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 163.9, 160.8, 157.8, 153.4, 143.5, 133.5,
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Note
127.33, 126.5 (q, J = 3.7 Hz), 125.0, 123.0, 117.2, 113.5, 105.6, 35.9,
35.8; HRMS calcd [M + Na]+ for C19H11O4F3Na 383.0502, found
383.0498; FTIR (cm−1) 3179, 2863, 1617, 1326, 1164, 1118, 1069,
979.
1H), 3.28−3.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.9,
161.2, 153.8, 147.9, 139.3, 139.1, 131.4, 129.4, 129.2, 128.2, 127.7,
126.9, 126.1, 123.6, 117.7, 114.76, 114.4, 38.7, 35.5; HRMS calcd [M +
Na]+ for C24H17O3NNa 390.1101, found 390.1104; FTIR (cm−1)
1699, 1609, 1563, 1490, 1451, 1376, 1283, 1187, 1135, 1071, 1000,
756,687.
4-(4-Methoxyphenyl)-1-phenyl-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (3m): white solid (131.0 mg, 66%); Rf
(petroleum ether/EtOAc = 70/30) 0.41; 1H NMR (400 MHz,
CDCl3) δ 7.41−7.28 (m, 9H), 6.89−6.81 (m, 4H), 4.62 (dd, J1 = 1.9
Hz, J2 = 6.4 Hz, 1H), 3.76 (s, 3H, CH3), 3.28−3.16 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 170.0, 161.2, 159.0, 153.7, 147.6, 139.1,
131.3, 129.4, 128.2, 128.0, 126.0, 123.5, 117.6, 114.8, 114.8, 114.5,
55.3, 38.8, 34.8; HRMS calcd [M + Na]+ for C25H19O4NNa 420.1206,
found 420.1205; FTIR (cm−1) 1704, 1611, 1564, 1511, 1454, 1420,
1375, 1334, 1298, 1248, 1185, 1137, 1071, 1036, 1004, 954, 833, 755,
719, 689, 653.
4-(2-Methoxyphenyl)-3,4-dihydro-2H,5H-pyrano[3,2-c]-
chromene-2,5-dione (3f): white solid (110.0 mg, 68%); Rf (petroleum
ether/EtOAc = 70/30) 0.56; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J
= 7.8 Hz, 1H), 7.60 (t, J = 8.6 Hz, 1H), 7.39−7.31 (m, 3H), 7.28−7.24
(m, 1H), 6.93 (t, J = 7.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 4.52 (d, J =
8.5 Hz, 1H), 3.74 (s, 3H), 3.20−3.03 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 164.2, 161.0, 157.1, 156.8, 153.1, 132.6, 129.3, 127.3, 124.5,
122.9, 120.9, 116.8, 113.9, 110.8, 104.0, 54.3, 34.5, 34.2; HRMS calcd
[M + Na]+ for C19H14O5Na 345.0733, found 345.0726; FTIR (cm−1)
3070, 3014, 2926, 2841, 1792, 1722, 1645, 1609, 1490, 1456, 1378,
1248, 1108, 992, 906, 810, 758, 638.
4-(5-Bromo-2-methoxyphenyl)-3,4-dihydropyrano[3,2-c]-
chromene-2,5-dione (3g):20a white solid (112.0 mg, 56%); Rf
(petroleum ether/EtOAc = 70/30) 0.54; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 7.3, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.39−7.32 (m,
4H), 4.44 (d, J = 8.6 Hz, 1H), 3.71 (s, 3H), 3.16 (dd, J1 = 9.1 Hz, J2 =
17.0 Hz, 1H), 3.02 (d, J = 17.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 163.9, 160.9, 157.3, 156.3, 153.3, 133.0, 132.9, 132.1, 129.5,
124.7, 123.0, 117.0, 113.8, 113.2, 112.6, 103.4, 54.8, 34.2, 34.0. HRMS
calcd [M + Na]+ for C19H13O5BrNa 422.9839, found 422.9836; FTIR
(cm−1) 3014, 2926, 2842, 1793, 1721, 1645, 1490, 1512, 1490, 1456,
1378, 1327, 1250, 1108, 1031, 992, 759, 699.
4-(3-Bromo-4-methoxyphenyl)-3,4-dihydro-2H,5H-pyrano[3,2-c]-
chromene-2,5-dione (3h); white solid (150.1 mg, 75%); Rf
(petroleum ether/EtOAc = 70/30) 0.40; 1H NMR (400 MHz,
CDCl3) δ 7.92 (d, J1 = 8.1 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.43−
7.37 (m, 3H), 7.15 (dd, J1 = 2.2 Hz, J2 = 8.5 Hz, 1H) 6.83 (d, J = 8.5
Hz, 1H), 4.46 (d, J = 7.4 Hz, 1H), 3.85 (s, 3H), 3.22−3.08 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 164.1, 160.8, 157.5, 155.8, 153.4,
133.2, 132.9, 131.8, 126.8, 123.0, 117.1, 112.5, 106.1, 56.4, 36.3, 35.0;
HRMS calcd [M + Na]+ for C19H13O5BrNa 422.9839, found
422.9838; FTIR (cm−1) 3570, 3016, 2855, 1686, 1588, 1492, 1380,
1260, 1179, 1105, 1052, 983, 759.
7-Methyl-4-phenyl-3,4-dihydropyrano[4,3-b]pyran-2,5-dione
(3i): white solid (69.2 mg, 54%); Rf (petroleum ether/EtOAc = 70/30)
0.30; 1H NMR (400 MHz, CDCl3)) δ 7.32−7.29 (m, 2H), 7.26−7.23
(m, 1H), 7.19(d, J = 7.2 Hz, 2H), 5.99 (s, 1H), 4.35 (dd, J1 = 2.2 Hz, J2
= 6.9 Hz 1H), 3.10−3.01 (m, 2H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 163.6, 162.6, 161.8, 139.8, 129.3, 128.0, 126.7, 103.4,
98.9, 36.1, 35.3, 20.2; HRMS calcd [M + Na]+ for C15H12O4Na
279.0628, found 279.0624; FTIR (cm−1) 2924, 1794, 1719, 1648,
1597, 1512, 1492, 1217, 1104, 1033, 953, 667.
4-(4-Methoxyphenyl)-7-methyl-3,4-dihydro-2H,5H-pyrano[4,3-
b]pyran-2,5-dione (3j): white solid (110.3 mg, 77%); Rf (petroleum
ether/EtOAc = 70/30) 0.50; 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J
= 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.98 (s, 1H), 4.29 (d, J = 6.9
Hz, 1H) 3.74 (s, 3H), 3.07−2.97 (m, 2H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.0, 163.4, 162.6, 161.6, 159.2, 131.8, 127.7,
114.6, 103.7, 98.9, 55.3, 36.3, 34.5, 20.2. HRMS calcd [M + Na]+ for
C16H14O5Na 309.0733, found 309.0732; FTIR (cm−1) 3736, 3554,
3399, 2972, 2382, 2162, 1791, 1690, 1652, 1593, 1250, 1185, 1056,
1002, 832.
1-Phenyl-4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-
chromeno[4,3-b]pyridine-2,5(1H)-dione (3n): white solid (133.0 mg,
1
61%); Rf (petroleum ether/EtOAc = 70/30) 0.51; H NMR (500
MHz, CDCl3) δ 7.56−7.50 (m, 5H), 7.40−7.26 (m, 6H), 6.87 (t, J =
7.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.70 (d, J = 6.3 Hz, 1H), 3.30
(dd, J1 = 7.1 Hz, J2 = 15.6 Hz, 1H), 3.18 (d, J1 = 15.8 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 169.4, 161.0, 153.8, 148.3, 143.4, 138.8,
131.6, 130.3−129.7 (m), 129.5, 128.4, 127.4, 126.1, 125.1, 123.7,
122.9, 117.7, 114.5, 113.3, 38.4, 35.4; HRMS calcd [M + Na]+ for
C25H16O3NF3Na 458.0974, found 458.0974; FTIR (cm−1) 1702, 1658,
1612, 1532, 1490, 1441, 1373, 1322, 1248, 1116, 1066, 1008, 946, 843,
750, 711, 685.
4-(2-Methoxyphenyl)-1-phenyl-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (3o): white solid (110.2 mg, 55%); Rf
(petroleum ether/EtOAc = 70/30) 0.60; 1H NMR (400 MHz,
CDCl3) δ 7.42−7.33 (m, 6H), 7.23−7.14 (m, 3H), 6.89−6.78 (m,
4H), 4.88 (d, J = 7.1 Hz, 1H), 3.24−3.12 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 169.8, 160.9, 157.3, 153.9, 149.1, 139.2, 131.2, 129.3,
129.1, 128.1, 127.2, 126.3, 126.2, 123.4, 120.6, 117.7, 114.8, 112.7,
111.1, 55.4, 37.7, 31.8; HRMS calcd [M + Na]+ for C25H19O4NNa
420.1206, found 420.1210; FTIR (cm−1) 1707, 1610, 1566, 1459,
1370, 1278, 1247, 1127, 995, 725.
1-(4-Methoxyphenyl)-4-phenyl-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (3p): white solid (139.0 mg, 70%); Rf
(petroleum ether/EtOAc = 70/30) 0.37; 1H NMR (400 MHz,
CDCl3) δ 7.05−6.83 (m, 9H), 6.53−6.52 (m, 4H), 4.26 (dd, J1 = 2.2
Hz, J2 = 6.4 Hz, 1H), 3.44 (s, 3H, CH3), 2.90−2.79 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 170.2, 161.3, 159.1, 153.8, 147.9, 139.3,
136.4, 131.6, 131.3, 129.1, 127.6, 126.9, 126.2, 123.6, 117.6, 114.8,
114.7, 113.9, 55.6, 38.6, 35.4; HRMS calcd [M + Na]+ for
C25H19O4NNa: 420.1206, found: 420.1206; FTIR (cm−1) 1699,
1659, 1611, 1534, 1489, 1442, 1372, 1296, 1248, 1181, 1133, 1070,
1032, 1001, 946, 881, 830, 750, 688, 652.
1-(3,5-Bis(trifluoromethyl)phenyl)-4-phenyl-3,4-dihydro-2H-
chromeno[4,3-b]pyridine-2,5(1H)-dione (3q): white solid (202.3 mg,
1
80%); Rf (petroleum ether/EtOAc = 70/30): 0.48; H NMR (400
MHz, CDCl3) δ 7.85 (s, 1H), 7.47−7.40 (m, 3H), 7.32−7.24 (m, 6H),
6.94 (t, J = 8.3 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.74 (dd, J1 = 3.7 Hz,
J2 = 7.7 Hz, 1H), 3.28 (t, J = 3.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 169.9, 160.7, 153.9, 146.6, 140.4, 138.6, 132.0, 129.4, 128.1,
126.7, 125.1, 124.1, 118.3, 116.7, 113.9, 38.5, 35.3; HRMS calcd [M +
Na]+ for C26H15O3NF6Na: 526.0848, found: 526.0851; FTIR (cm−1)
1707, 1609, 1566, 1459, 1370, 1328, 1278, 1247, 1176, 1124, 993, 892,
845, 799.
General Procedure for the Synthesis of Functionalized
Quinolinones. To a flame-dried screw-capped test tube equipped
with a magnetic stir bar was taken imidazolium salt 4 (17.5 mg, 0.05
mmol), Cs2CO3 (244 mg, 1.5 equiv), 2-bromoenal 2 (0.50 mmol), and
4-hydroxy-1-methylquinolin-2(1H)-one 6 (0.5 mmol). Then the
screw-capped tube was evacuated and backfilled with argon. To this
mixture was added toluene/THF (4:1, 10.0 mL) under argon
atmosphere, and mixture was stirred at 20 °C (water bath) for 12 h.
When the reaction was complete, the solvent was evaporated and the
4-Phenyl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-trione (3k):
white solid (110.0 mg, 72%); Rf (petroleum ether/EtOAc = 70/30)
1
0.61; H NMR (400 MHz, CDCl3) δ 8.19−8.17 (m, 1H), 8.08−8.06
(m, 1H), 7.77−7.75 (m, 2H), 7.34−7.31 (m, 2H), 7.27−7.25 (m, 3H),
4.67−4.65 (m, 1H), 3.15−3.08 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 182.6, 177.4, 164.1, 151.5, 138.9, 134.7, 134.3, 131.5, 131.0,
129.6, 128.3, 127.0, 126.9, 126.8, 125.8, 35.4, 34.3; HRMS calcd [M +
Na]+ for C19H12O4Na 327.0628, found 327.0623; FTIR (cm−1) 3068,
3027, 2924, 2853, 1791, 1722, 1645, 1608, 1378, 1108, 991, 834, 758,
638, 607.
1,4-Diphenyl-3,4-dihydro-2H-chromeno[4,3-b]pyridine-2,5(1H)-
dione (3l): white solid (110.3 mg, 60%); Rf (petroleum ether/EtOAc =
1
70/30) 0.50; H NMR (400 MHz, CDCl3) δ 7.38−7.23 (m, 12H),
6.86 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.65 (d, J = 5.9 Hz,
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The Journal of Organic Chemistry
Note
crude residue was purified by flash column chromatography on silica
gel to afford the corresponding functionalized quinolinones (7).
6-Methyl-4-phenyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-
2,5(6H)-dione (7a): white solid (140.0 mg, 92%); Rf (petroleum
ether/EtOAc = 70/30) 0.30; 1H NMR (400 MHz, CDCl3) δ 8.14 (dd,
J1 = 1.5 Hz, J2 = 8.0 Hz, 1H), 7.75−7.66 (m, 1H), 7.43 (t, J = 8.5 Hz,
2H), 7.35−7.26 (m, 5H), 4.73 (dd, J1 = 3.7 Hz, J2 = 5.6 Hz, 1 H), 3.76
(s, 3H), 3.19−3.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 188.0,
182.3, 173.2, 156.2, 155.1, 145.5, 142.3, 140.4, 139.4, 134.0, 123.1,
120.1, 26.3, 26.0, 18.1; HRMS calcd [M + Na]+ for C19H15O3NNa
328.0944, found 328.0938; FTIR (cm−1) 3026, 2924, 2852, 1793,
1719, 1646, 1609, 1491, 1378, 1327, 1107, 905.99, 827.76, 758.07,
666.56
4-(4-Methoxyphenyl)-6-methyl-4,6-dihydro-2H-pyrano[3,2-c]-
quinoline-2,5(3H)-dione (7b): white solid (150.0 mg, 89%); Rf
(petroleum ether/EtOAc = 70/30) 0.30; 1H NMR (400 MHz,
CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.40 (d, J
= 8.9 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 8.9 Hz, 2H), 6.81
(d, J = 8.9 Hz, 2H), 4.65 (dd, J1 = 2.6 Hz, J2 = 6.4 Hz,1H), 3.74 (s,
3H), 3.71 (s, 3H), 3.12−3.10 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 166.0, 161.3, 159.1, 153.6, 139.5, 132.5, 131.8, 128.0, 123.2, 122.6,
114.6, 114.4, 113.9, 111.9, 55.4, 36.6, 35.5, 29.9; HRMS calcd [M +
Na]+ for C20H17O4NNa 358.1050, found 358.1046; FTIR (cm−1)
3858, 3722, 3310, 2935, 2826, 2308, 1790, 1457, 1024.
4-(2-Methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]-
quinoline-2,5(6H)-dione (7g): white solid (155.0 mg, 92%); Rf
(petroleum ether/EtOAc = 70/30) 0.28; 1H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.37 (d, J
= 8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.21
(t, J = 7.2 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H),
4.72 (d, J = 8.2 Hz, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.08−3.02 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 165.8, 157.2, 153.8, 139.4,
131.5, 130.1, 129.0, 128.2, 123.1,122.4, 120.8, 114.2, 114.1, 110.8, 54.6,
34.6, 34.1, 29.8; HRMS calcd [M + Na]+ for C20H17O4NNa 358.1050,
found 358.1047; FTIR (cm−1) 1782, 1648, 1597, 1495, 1463, 1382,
1282, 1025, 940, 756, 712, 681.
4-(3-Bromo-4-methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyrano-
[3,2-c]quinoline-2,5(6H)-dione (7h): white solid (180.0 mg, 87%); Rf
(petroleum ether/EtOAc = 70/30) 0.32; 1H NMR (400 MHz,
CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.42−7.40
(m, 2H), 7.34 (t, J = 8.3 Hz, 1H), 7.15 (dd, J1 = 2.5 Hz, J2 = 8.8 Hz,
1H), 6.80 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H),
3.71 (s, 3H), 3.12−3.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
165.5, 161.2, 155.5, 154.1, 139.6, 133.9, 132.0, 131.9, 126.9, 123.2,
122.7, 114.4,113.8, 112.4, 112.4, 111.0, 56.4, 36.5,35.2, 29.9; HRMS
calcd [M + Na]+ for C20H16O4NBrNa 436.0155, found 436.0155.
FTIR (cm−1) 1786, 1652, 1600, 1575, 1497, 1464, 1413, 1383, 1282,
1146, 1053, 974.
General Procedure for the Enantioselective Synthesis of
Functionalized Coumarins. To a flame-dried screw-capped test
tube equipped with a magnetic stir bar were taken triazolium salt 8
(7.4 mg, 0.02 mmol) and 2-bromoenal 2 (0.25 mmol), followed by 4-
hydroxy-2H-chromen-2-one 1a (0.25 mmol). Then the screw-capped
tube was evacuated and backfilled with argon. To this mixture was
added toluene (2.0 mL) under argon atmosphere, and the mixture was
allowed to stir at 30 °C. To this stirring solution was added the
Na2CO3 (1.2 equiv). Then the reaction mixture was stirred at 30 °C
for 12 h. When the reaction was complete, the solvent was evaporated
and the crude residue was purified by flash column chromatography on
silica gel to afford the corresponding functionalized coumarins 3′.
(R)-4-Phenyl-3,4-dihydropyrano[3,2-c]chromene-2,5-dione
(3a′):20 white solid (55.1 mg, 75%); 93:7 er; [α]D25 = −159.30 (c 0.1,
CHCl3); HPLC (Chiralcel OJ-H, 70:30 petroleum ether/EtOH, 1.0
mL/min) major 27.0 min, minor 35.4 min.
4-(4-Chlorophenyl)-6-methyl-4,6-dihydro-2H-pyrano[3,2-c]-
quinoline-2,5(3H)-dione (7c): white solid (63.0 mg, 37%); Rf
(petroleum ether/EtOAc = 70/30) 0.30; 1H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.44 (d, J
= 8.3, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.31−7.22 (m, 4H), 4.69(d, J= 6.8
Hz, 1H), 3.74 (s, 3H), 3.20−3.09 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 165.5, 161.2, 154.1, 139.6, 138.9, 132.0, 128.4, 122.8, 114.5,
113.8, 111.0, 36.2, 35.7, 29.9; HRMS calcd [M + Na]+ for
C19H14O3NClNa 362.0554, found 362.0552; FTIR (cm−1) 3856,
3727, 2865, 2382, 2307, 1636, 1544, 1498, 1461, 1369, 1315, 1168,
1057, 757.
4-(4-Fluorophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]-
quinoline-2,5(6H)-dione (7d): white solid (153.3 mg, 95%); Rf
(petroleum ether/EtOAc = 70/30) 0.28; 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.42 (d, J
= 8.2 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.28−7.23 (m, 2H) 6.98 (t, J =
8.5 Hz, 2H), 4.68 (d, J = 6.1 Hz, 1H), 3.72 (s, 3H), 3.15−3.07 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.4, 161.2, 161.0,
153.9, 139.5, 136.2, 131.9, 128.6, 128.5, 123.1, 122.7, 116.2, 115.9,
114.4, 113.8, 111.3, 36.4, 35.5, 29.9; HRMS calcd [M + Na]+ for
C19H14O3NFNa 346.0850, found 346.0850; FTIR (cm−1) 1788, 1653,
1601, 1508, 1465, 1417, 1385, 1316, 1280, 1226, 1149, 1113, 1042,
973.
6-Methyl-4-(4-(trifluoromethyl)phenyl)-4,6-dihydro-2H-pyrano-
[3,2-c]quinoline-2,5(3H)-dione (7e): white solid (103.0 mg, 55%); Rf
(petroleum ether/EtOAc = 70/30) 0.37; 1H NMR (500 MHz,
CDCl3) δ 8.09 (d, J = 7.8 Hz,1H), 7.68 (t, J = 7.6 Hz, 1H), 7.55 (d, J =
8.1 Hz, 2H), 7.43−7.34 (m, 4H), 4.74 (d, J = 7.4 Hz, 1H) 3.72 (s, 3H,
CH3), 3.19 (dd, J1 = 7.8 Hz, J2 = 16.2 Hz, 1H), 3.10 (d, J = 16.1
Hz,1H); 13C NMR (125 MHz, CDCl3) δ 165.3, 161.2, 154.3, 144,5,
139.6, 132.2, 130.5−129.7 (m), 127.5, 126.3−126.2 (m), 123.2, 123.0,
122.8, 114.5, 113.7, 110.6, 36.11, 36.0, 29.9; HRMS calcd [M + Na]+
for C20H14O3NF3Na 396.0818, found 396.0814; FTIR (cm−1) 3736,
3393, 3180, 2852, 1651, 1325, 1116, 993.
(R)-4-(4-Methoxyphenyl)-3,4-dihydro-2H,5H-pyrano[3,2-c]-
chromene-2,5-dione (3b′): white solid (65.0 mg, 81%); 92:8 er;
25
[α]D = −165.30 (c 0.1, CHCl3); HPLC (Chiralcel OJ-H, 70:30
petroleum ether/EtOH, 0.7 mL/min) major 30.7 min, minor 46.0
min.
(R)-4-(4-Fluorophenyl)-3,4-dihydropyrano[3,2-c]chromene-2,5-
25
dione (3d′): white solid (55.0 mg, 71%); 87:13 er; [α]D = −170.20
(c 0.1, CHCl3); HPLC (Chiralcel OJ-H, 70:30 petroleum ether/EtOH,
1.0 mL/min) major 22.6 min, minor 30.10 min.
(R)-4-(2-Methoxyphenyl)-3,4-dihydro-2H,5H-pyrano[3,2-c]-
chromene-2,5-dione (3f′): white solid (75.0 mg, 93%); 89:11 er;
25
[α]D = −173.5 (c 0.1, CHCl3); HPLC (Chiralcel OJ-H, 95:05 n-
hexane/EtOH, 1.0 mL/min) minor 61.6 min, major 67.0 min.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all products, details on
competition experiments, and HPLC data of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4-(3-Bromophenyl)-6-methyl-4,6-dihydro-2H-pyrano[3,2-c]-
quinoline-2,5(3H)-dione (7f): white solid (163.0 mg, 85%); Rf
(petroleum ether/EtOAc = 70/30) 0.42; 1H NMR (500 MHz,
CDCl3) δ 8.08 (d, J = 8.0 Hz,1H), 7.68−7.65 (m, 1H), 7.42−7.33 (m,
4H), 7.18−7.13 (m, 2H), 4.64 (d, J = 7.3 Hz, 1H), 3.71 (s, 3H, CH3),
AUTHOR INFORMATION
3.15 (dd, J1 = 7.4 Hz, J2 = 16.3 Hz, 1H), 3.08 (d, J = 16.2 Hz, 1H); 13
C
■
NMR (125 MHz, CDCl3) δ 165.3, 161.1, 154.3, 142.7, 139.7, 132.1,
131.0, 130.8, 130.1, 125.5, 121.3, 123.3, 122.7, 114.5, 113.7, 110.6,
36.3, 35.9, 29.9; HRMS calcd [M + Na]+ for C19H14O3NBrNa
406.0049, found 406.0052; FTIR (cm−1) 1786, 1651, 1600, 1498,
1463, 1413, 1383, 1313, 1282, 1249, 1146, 1022, 974, 817, 689.
Corresponding Author
*E-mail: at.biju@ncl.res.in.
Notes
The authors declare no competing financial interest.
4249
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The Journal of Organic Chemistry
Note
M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080. (j) De Sarkar, S.; Studer, A.
Angew. Chem., Int. Ed. 2010, 49, 9266.
ACKNOWLEDGMENTS
■
This work was supported by CSIR-New Delhi (as part of XII
Five Year plan programme under ORIGIN-CSC0108) and
CSIR-OSDD (HCP0001). S.R.Y. and A.B. thank CSIR-New
Delhi for the award of Research Fellowship, and D.P. thanks
DST for the award of the KVPY fellowship. We thank Dr. P. R.
Rajamohanan (CSIR-NCL) for NMR spectra and Ms. B.
Santhakumari (CSIR-NCL) for the HRMS data.
(9) (a) Zhu, Z.-Q.; Zheng, X.-L.; Jiang, N.-F.; Wan, X.; Xiao, J.-C.
Chem. Commun. 2011, 47, 8670. (b) Kaeobamrung, J.;
Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010,
132, 8810. (c) Zhu, Z.-Q.; Xiao, J.-C. Adv. Synth. Catal. 2010, 352,
2455. (d) Zeitler, K. Org. Lett. 2006, 8, 637.
(10) For reports on NHC-catalyzed generation of α,β-unsaturated
acyl azoliums from 2-haloenals, see: (a) Yetra, S. R.; Kaicharla, T.;
Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 5202.
(b) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-P.
Org. Lett. 2013, 15, 4750. (c) Yetra, S. R.; Bhunia, A.; Patra, A.; Mane,
M. V.; Vanka, K.; Biju, A. T. Adv. Synth. Catal. 2013, 355, 1089.
(d) Yao, C.; Jiao, W.; Xiao, Z.; Liu, R.; Li, T.; Yu, C. Tetrahedron 2013,
69, 1133. (e) Wang, X.-B.; Zou, X.-L.; Du, G.-F.; Liu, Z.-Y.; Dai, B.
Tetrahedron 2012, 68, 6498. (f) Zhang, B.; Feng, P.; Cui, Y.; Jiao, N.
Chem. Commun. 2012, 48, 7280. (g) Yao, C.; Wang, D.; Lu, J.; Li, T.;
Jiao, W.; Yu, C. Chem.Eur. J. 2012, 18, 1914. (h) Sun, F.-G.; Sun, L.-
H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134.
(11) Notably, attempted reactions of α,β-unsaturated acyl azolium
generated from ynals with heterocyclic C−H acids such as 4-
hydroxycoumarin were not successful. For details, see ref 8d.
(12) For selected reports on NHC-catalyzed methods for synthesis of
functionalized coumarins, see: (a) Bhunia, A.; Patra, A.; Puranik, V.;
Biju, A. T. Org. Lett. 2013, 15, 1756. (b) Sinu, C. R.; Padmaja, D. V.
M; Ranjini, U. P.; Seetha Lakshmi, K. C.; Suresh, E.; Nair, V. Org. Lett.
2013, 15, 68. (c) Ding, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949.
(d) Nair, V.; Sinu, C. R.; Rejithamol, R.; Seethalakshmi, K. C.; Suresh,
E. Org. Biomol. Chem. 2011, 9, 5511. (e) Phillips, E. M.; Wadamoto,
M.; Roth, H. S.; Andrew, W. O.; Scheidt, K. A. Org. Lett. 2009, 11, 105.
(13) See the Supporting Information for details.
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4664. (b) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013,
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(d) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2012, 51, 11686. (e) Grossmann, A.; Enders, D. Angew.
Chem., Int. Ed. 2012, 51, 314. (f) Vora, H. U.; Wheeler, P.; Rovis, T.
Adv. Synth. Catal. 2012, 354, 1617. (g) Douglas, J.; Churchill, G.;
Smith, A. D. Synthesis 2012, 44, 2295. (h) Knappke, C. E. I.; Imami,
A.; Jacobi von Wangelin, A. ChemCatChem 2012, 4, 937. (i) Biju, A.
T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (j) Nair, V.;
Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Vellalath, S.
Chem. Soc. Rev. 2011, 40, 5336. (k) Chiang, P.-C.; Bode, J. W. In N-
Heterocyclic Carbenes; The Royal Society of Chemistry: London, 2011;
p 399. (l) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37,
2691. (m) Enders, D.; Niemeier, O.; Henseler, H. Chem. Rev. 2007,
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(7) (a) Candish, L.; Forsyth, C. M.; Lupton, D. W. Angew. Chem., Int.
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Chem. Soc. 2011, 133, 4694. (e) Ryan, S. J.; Candish, L.; Lupton, D. W.
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H. Tetrahedron Lett. 2005, 46, 6265. (g) Movassaghi, M.; Schmidt, M.
A. Org. Lett. 2005, 7, 2453. (h) Nyce, G. W.; Lamboy, J. A.; Connor, E.
F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587. (i) Grasa,
G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4, 3583.
1a.
(15) Additional experiments were carried out to generate α,β-
unsaturated acyl azolium from ynal and enal (under oxidative
conditions). The reaction of ynal with 1a furnished 3a in 10%, and
the reaction of enal with 1a in the presence of oxidant 5 afforded 3a in
5%. These results indicate that the generation of α,β-unsaturated acyl
azolium from 2-bromoenal gave better results in the reaction with 1a.
(16) It may be noted that β-alkyl-substituted bromoenals did not
show any reactivity with 4-hydroxycoumarin under the optimized
conditions.
(17) 2-Hydroxynaphthoquinone was also reported to be not
participating in the reaction of α,β-unsaturated acyl azolium generated
from ynals. For details, see ref 8d.
(18) Our initial efforts on NHC-catalyzed reaction of 4-(arylamino)-
1-methylquinolin-2 (1H)-one with 2-bromoenals to synthesize
quinolinone-fused dihydropyridinones, however, failed.
(19) (a) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362. See
also: (b) Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192.
(20) For the enantioselective synthesis of similar functionalized
coumarins, see: (a) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S.
Org. Lett. 2005, 7, 979. (b) Ray, S. K.; Singh, P. K.; Molleti, N.; Singh,
V. K. J. Org. Chem. 2012, 77, 8802.
(21) The detailed mechanism of the addition of nucleophiles to α,β-
unsaturated acylazoliums has been studied by Studer et al. and Bode et
al. Whereas Studer et al. proposed the conjugate addition mechanism
supported by the theoretical and kinetic studies, Bode et al. explained
the initial 1,2-addition followed by [3,3]-sigmatropic rearrangement.
Interestingly, the mode of addition depends on the nature of the
nucleophile and the structure of the α,β-unsaturated acylazolium ion.
(8) (a) Samanta, R. C.; De Sarkar, S.; Frøhlich, R.; Grimme, S.;
Studer, A. Chem. Sci. 2013, 4, 2177. (b) Samanta, R. C.; Maji, B.; De
Sarkar, S.; Bergander, K.; Frohlich, R.; Muck-Lichtenfeld, C.; Mayr, H.;
̈
̈
Studer, A. Angew. Chem., Int., Ed. 2012, 51, 5234. (c) Kravina, A. G.;
Mahatthananchai, J.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9433.
(d) Mahatthananchai, J.; Kaeobamrung, J.; Bode, J. W. ACS Catal.
2012, 2, 494. (e) Lyngvi, E.; Bode, J. W.; Schoenebeck, F. Chem. Sci.
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Chem., Int. Ed. 2011, 50, 1673. (g) Wanner, B.; Mahatthananchai, J.;
Bode, J. W. Org. Lett. 2011, 13, 5378. (h) Biswas, A.; De Sarkar, S.;
Frohlich, R.; Studer, A. Org. Lett. 2011, 13, 4966. (i) Rong, Z.-Q.; Jia,
̈
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The Journal of Organic Chemistry
Note
Based on the [3,3] sigmatropic rearrangement mechanism suggested
by Bode et al. for the addition of kojic acid derivatives to α,β-
unsaturated acylazoliums (ref 9b), it is reasonable to believe that the
same mechanism can be invoked in the addition of heterocyclic C-H
acids to α,β-unsaturated acylazoliums.
(22) (a) Allen, C. F. H.; Edens, C. O., Jr. Org. Synth. 1945, 25, 92.
(b) Li, W.; Li, J.; Wan, Z.-K.; Wu, J.; Massefski, W. Org. Lett. 2007, 9,
4607.
(23) (a) Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55,
14523. (b) Cooke, J.; Lightbody, O. C. J. Chem. Educ. 2009, 86, 610.
(24) Yavari, I.; Sabbaghan, M.; Hossaini, Z. Synlett 2008, 8, 1153.
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