Reactivity of functionalized N, S-ketene acetal: Regioselective construction of tetrahydrobenzo[b]pyran and chromeno[2,3-b] quinoline derivatives

Article abstract of DOI:10.1021/jo101902z

Regioselective synthesis of functionalized tetrahydrobenzo[b]pyrans has been developed by multicomponent reactions (MCRs) and tandem [3 + 3] annulations of β-benzoylthioacetanilides or β-(2-haloaroyl)thioacetanilides as valuable sources with aromatic alde

Full text of DOI:10.1021/jo101902z

pubs.acs.org/joc
Reactivity of Functionalized N,S-Ketene Acetal: Regioselective
Construction of Tetrahydrobenzo[b]pyran and Chromeno[2,3-b]quinoline
Derivatives
Ming Li,* Yan-Li Hou, Li-Rong Wen,* and Fu-Meng Gong
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering,
Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao 266042, P. R. China
liming928@qust.edu.cn; wenlirong@qust.edu.cn
Received September 27, 2010
Regioselective synthesis of functionalized tetrahydrobenzo[b]pyrans has been developed by multi-
component reactions (MCRs) and tandem [3 þ 3] annulations of β-benzoylthioacetanilides or
β-(2-haloaroyl)thioacetanilides as valuable sources with aromatic aldehydes and 5,5-dimethyl-1,3-
cyclohexanedione catalyzed by triethylamine. This MCR followed by a postcondensation cyclization
via an intramolecular SNAr in the presence of K2CO3 led to an unprecedented novel chromeno-
[2,3-b]quinoline framework containing an important chromene moiety in good yields. The reactions
were very mild, convenient, and o-selective to form new fused tetracyclic target molecules.
Introduction
The exploration of privileged structures in drug discovery
is a rapidly emerging theme in medicinal chemistry.4 The
chromene structural framework and heterofused analogues,
as important privileged heterocyclic scaffolds,5 appear in a
plethora of natural products and in a variety of known
inhibitors for a broad range of receptors.6
A major challenge of modern drug discovery is the design
of highly efficient chemical reaction sequences that provide
maximum structural complexity and diversity with a mini-
mum number of synthetic steps to assemble compounds with
interesting properties.1 Recently multicomponent reactions
(MCRs) have emerged as a highly valuable tool in modern
organic synthesis and modern drug discovery. The atom
economy and convergent character,2 the simplicity of a
one-pot procedure, the possible structural variations, the
accessible complexity of the molecules, and the very large
number of accessible compounds are among the described
advantages of a MCR.3
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Published on Web 11/18/2010
DOI: 10.1021/jo101902z
r
2010 American Chemical Society

Li et al.
JOCArticle
FIGURE 1. Selected examples of tetrahydrobenzo[b]pyrans and chromene-based heterocycles with biological and medicinal acitivities.
FIGURE 2. Reactivity profile of β-(2-haloaroyl)thioacetanilides 2.
Among the different types of chromene systems (Figure 1),
tetrahydrobenzo[b]pyrans (I) are of considerable interest
because of their wide range of biological properties,7 such
as spasmolytic, diuretic, anticoagulant, anticancer, and anti-
ancaphylactia activities.8 They can also be used as cognitive
enhancers not only for the treatment of schizophrenia and
myoclonus but also for the treatment of neurodegenerative
disease, including Alzheimer’s disease, amyotrophic lateral
sclerosis, Huntington’s disease, Parkinson’s disease, AIDS-
associated dementia, and Down’s syndrome.9 Similar com-
pounds (II), as the first class of compounds, have shown fully
selective inhibition of the human excitatory amino acid
transporter subtype 1 (EAAT 1).10 Based on the chromene-
based heterocycles framework, a typical example of an
approved drug is amlexanox (III), which is a commonly
prescribed antiallergic and typical antiulcer agent,11
and many other compounds such as compound IV, V,
and VI exemplify the wide therapeutic spectrum and active
interest.12
In the course of studies on the chemistry of functionalized
N,S-ketene acetal,13 β-(2-haloaroyl)thioacetanilides 2 being
novel building blocks with four active reaction sites show
structural features of highly polarized push-pull interaction
CdC double bond and Cl atom as leaving group (Figure 2).
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electron-donating amino groups and electron-withdrawing
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acetanilides 1 would subject it to an intramolecular nucleophilic
aryl substitution reaction (SNAr). The SNAr may occur by either
(i) theo-chloro of the aryl group by attack of the mercapto group
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SCHEME 1
leading to thiochromone ring A14 or (ii) the o-chloro of the aryl
group by attack of the NH group to form quinoline ring B with
chemo- and regioselectivity in this context.
toward the design and development of new domino and
multicomponent procedures involves the use of building
block 2 that contains a number of chemically distinct func-
tionalities, which could be selectively reacted to generate
diversity with aldehydes 3 and 5,5-dimethyl-1,3-cyclohexa-
nedione 4. Three directions of the reaction are outlined in
Scheme 1.
In direction 1, the intermediate B undergoes the intra-
molecular N-cyclization and SNAr of the mercapto group to
give 7, which follows the route of our recent studies.15 In
direction 2, the intermediate B undergoes the intramolecular
S-cyclization and SNAr of the amino group to give 8. In
direction 3, the intermediate B undergoes the intramolecular
O-cyclization to give 5 and SNAr of the amino group to give
6. During our investigation, we did not trace 7 or 8, and only
5 and 6 were obtained exclusively. Surprisingly, the reactions
described show high regioselectivity.
In continuation of our research interests regarding the
development of the synthetic utility of β-aroylthioacetani-
lides as valuable sources,14,15 we wish to report herein a
simple and convenient protocol for chemo- and regioselec-
tive synthesis of tetrahydrobenzo[b]pyrans 5 via a one-pot
three-component tandem [3 þ 3] annulation of β-(aroyl)-
thioacetanilides with aromatic aldehydes and 5,5-dimethyl-
1,3- cyclohexanedione. This novel MCR followed by a post-
condensation cyclization via an intramolecular SNAr in the
presence of K2CO3 leads to unprecedented new fused chromeno-
[2,3-b]quinoline derivatives 6. To the best of our knowledge,
there have not been reports about the application of β-(aroyl)-
thioacetanilides in the synthesis for chromene scaffold.
Results and Discussion
In the initial experiment, the transformation of β-(2,4-
dichlorobenzoyl)thioacetanilide 2a with 3a and 4 proceeded
smoothly with Et3N (1 equiv) in refluxing ethanol (15 mL),
and at the end of the reaction (about 20 h later, monitored
by TLC), the product was collected by filtration and recrys-
tallized from ethanol, affording the nicely crystalline 5a
in good yield (68%, Table 1, entry 3). A variety of condi-
tion parameters were also investigated, and the results are
collected in Table 1. There was no reaction with Et3N (1 equiv)
Reactions of β-(Aroyl)thioacetanilides with Aromatic Alde-
hydes and 5,5-Dimethyl-1,3-cyclohexanedione. Our approach
(14) (a) Wen, L.-R.; Sun, J.-H.; Li, M.; Sun, E.-T.; Zhang, S.-S. J. Org.
Chem. 2008, 73, 1852–1863. (b) Wen, L.-R.; Ji, C.; Li, M.; Xie, H.-Y.
Tetrahedron 2009, 65, 1287–1293.
(15) (a) Wen, L.-R.; Ji, C.; Li, Y.-F.; Li, M. J. Comb. Chem. 2009, 11, 799–
805. (b) Li, M.; Zuo, Z.-Q.; Wen, L.-R.; Wang, S.-W. J. Comb. Chem. 2008,
10, 436–441.
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TABLE 1. Reaction of 2a with 3a and 4 under Different Conditions
substrates, β-(2,4-dichlorobenzoyl)thioacetanilide 2a and 4
were used as model substrates to react with 3a-f (Table 2,
entries 1-6). The reactions showed remarkable flexibility,
as the desired products were formed in moderate yields
(53-68%) with various aromatic aldehydes selected to have
either electron-withdrawing or electron-donating substi-
tutes. Different substituents on thioamides 2 (Table 2,
entries 7-11) did not show obvious differences in reactivity
for the formation of 5.
The versatility of the above MCR was further demonstrated
by reaction of 2-benzoylthioacetanilides 1 with various aro-
matic aldehydes 3a-k and 4 (Table 2, entries 12-22). Under
the same experimental conditions, tetrahydrobenzo[b]pyrans
5l-v were formed in better yields.
Although the yields are not high, these results certainly
indicate the importance of our strategy for providing the
tetrahydrobenzo[b]pyrans. Notably, it is found that the
above reactions proceed in a highly regioselective manner.
In this operationally simple three-component domino pro-
cess, at least seven reactive distinct chemical sites participate
in the chemical transformation that lead to the concomitant
creation of three chemical bonds (two C-C bonds and one
C-O bond).
SNAr Reactions of Tetrahydrobenzo[b]pyrans 5 Leading to
Tetracyclic Chromeno[2,3-b]quinoline Derivatives 6. On the
basis of the results as described above and in continuation
of our ongoing research toward the discovery of new reac-
tions for the synthesis of heterocycles containing chro-
mene-based frameworks, we designed a novel protocol
by introducing an o-halo group into the aryl ring of
2-benzoylthioacetanilides for the preparation of tetracyclic
chromeno[2,3-b]quinolines 6 from 5 through the intramolecular
SNAr (Scheme 2).
Conductinga postcondensation reactioncan generate more
complicated molecules.3d During the course of our research
toward the synthesis of novel chromeno[2,3-b]quinoline deri-
vatives 6, a varietyof conditions were investigated by using 5a.
The results of the cyclization step from 5a to 6a in DMF under
different conditions are summarized in the Table 3. In a
preliminary experiment, first this reaction was tested in the
presence of K2CO3 at different reaction times and tempera-
tures (Table 3, entries 1-5). It was observed that 6a could be
obtained in 88% yield in the presence of K2CO3 (1.0 equiv) for
120 min at 100 °C (Table 3, entry 3). Next, this reaction was
examined in the presence of K2CO3/AgNO3 in different molar
ratio, and 6a could also be obtained in moderate yields but
lower than that with K2CO3 as catalyst (Table 3, entries
6-10). Unfortunately, AgNO3 (1.0 equiv) was utterly ineffec-
tive for this reaction (Table 3, entry 11). KOH gave only
catalyst
(equiv)
temp
(°C)
time
(h)a
yield
(%)b
entry
solvent
1
2
3
4
5
6
7
8
Et3N (1.0)
c
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
DMF
DMF
rt
78
78
78
78
78
78
78
78
78
100
100
100
20
20
20
20
20
20
20
20
20
20
20
20
20
d
d
Et3N (1.0)
piperidine (1.0)
pyridine (1.0)
morpholine (1.0)
KOH (1.0)
K2CO3 (1.0)
Na2CO3 (1.0)
CsCO3 (1.0)
K2CO3 (1.0)
NaH (1.0)
K2CO3 (1.0)/
AgNO3 (1.0)
KOH (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (0.5)
Et3N (2.0)
68
34
30
31
26
6
9
4
10
11
12
13
13
8e
8
10
14
15
16
17
18
19
DMF
DMF
CH3CN
CH3OH
EtOH
EtOH
100
100
81
64
78
20
20
20
20
20
20
30
12
27
34
53
44
78
aConventional heating. bIsolated yield. cNo base. dNo reaction.
in EtOH at room temperature (Table 1, entry 1) or in refluxing
EtOH without Et3N (Table 1, entry 2). In the presence of
piperidine, pyridine, morpholine, KOH, K2CO3, Na2CO3,
Cs2CO3, K2CO3/AgNO3, NaH in EtOH or DMF, the reac-
tions became sluggish (Table 1, entries 4-14). Different sol-
vents were also tested in the presence of Et3N as catalyst, for
example, DMF, CH3CN, and CH3OH, but unfortunately they
resulted in low yields (Table 1, entries 15-17). The yields of 5a
were not further improved with increased or decreased amount
of the catalyst (Table 1, entries 18 and 19). Thus, it is clear from
the experiments that the best condition for 5a could be entry 3,
employing Et3N (1.0 equiv) as base and EtOH as solvent under
refluxing conditions.
The tandem process described above represents a simple
and efficient methodology for constructing tetrahydroben-
zo[b]pyrans. To test the generality of this new reaction, the
reactions of four β-o-chloroaroylthioamides 2a-d, different
aldehydes 3 and 4 were examined under the optimized
conditions (Table 2). Initially, to test the scope of aldehyde
SCHEME 2. Retrosynthetic Analysis for Chromeno[2,3-b]quinolines 6
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TABLE 2. Synthesis of Tetrahydrobenzo[b]pyrans 5a-v
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TABLE 2. Continued
aIsolated yield.
moderate yield (Table 3, entry 12). Thus, it was clear from the
experiments that the best condition for this reaction is K2CO3
as a catalyst in DMF at 100 °C.
Michael addition with [A] to generate the intermediate [B],
which could probably undergo three directions of O-, N-, or
S-cyclization (Scheme 1). 5,5-Dimethyl-1,3-cyclohexanedione
with a very low pKa value (pKa=5.32)18 is highly acidic, indicat-
ing that proton transfer from the keto [B] to enol [C] under-
going a rapid keto-enol tautomerization would be easier. Then
[C] is followed by the intramolecular regiospecific O-cyclization
to give the intermediate [D], rather than the pathway of
N-cyclization or S-cyclization. The [D] eliminates one mole-
cule of H2S to afford tetrahydrobenzo[b]pyrans 5. Finally an
intramolecular SNAr of the o-halo of aryl group by attack of
NH group in the presence of K2CO3 leads to new and highly
functionalized chromeno[2,3-b]quinoline derivatives 6.
Then the broad tolerance for various R1 and R substitu-
ents to SNAr reaction was investigated (Table 4). The results
showed that tetrahydrobenzo[b]pyrans 5 with either aryl
groups bearing electron-donating or electron-withdrawing
groups could afford the corresponding thiochromeno[2,3-
b]quinolines 6 in good to excellent yields. It is noteworthy
that the reaction is easy to perform, and all of the isolated
products only need recrystallization rather than column
chromatography. This ease of purification makes this meth-
odology facile, practical, and rapid to execute.
The structural determination of all products 5a-v and
6a-l was achieved by 1H NMR, 13C NMR, IR, and HRMS
and unequivocally established by the X-ray single crystal
diffraction analysis of compounds 5u16 and 6g.17
A plausible reaction scenario for the domino cycloconden-
sation is outlined in Scheme 3. First, compounds 3 proceed
through Knoevenagel condensation with 4 under Et3N as
catalyst to give the intermediate [A]; 2 are mediated by Et3N
and deprotonate to form the anions of β-(haloaroyl)thioace-
tanilides, which trigger tandem [3þ3] annulation involving
Conclusion
In conclusion, we have developed a convenient and regioselec-
tive synthesis of functionalized tetrahydrobenzo[b]pyran and
chromeno[2,3-b]quinoline frameworks containing a chromene
moiety, thus demonstrating the applications of β-(2-haloaroyl)
thioacetanilides. In this experimentally simple process, at least
10 different active sites are involved: two C-C bonds, two C-N
bonds, and two new rings are constructed with all reactants effi-
ciently utilized. The advantages of these methods, which include
high regioselectivity, high bond-forming efficiency, and the
(16) For X-ray diffraction data for 5u, see: Wen, L.-R.; Sun, J.-H.; Ji, C.;
Xie, H.-Y. Acta Crystallogr. 2008, E64, o407.
(17) X-ray diffraction data for 6g has been deposited in the Cambridge
Crystallographic Data Center with supplementary publication number
705397. Its CIF file is also available in the Supporting Information.
ꢀ
ꢀ ꢀ
(18) Stankevich, E. I.; Grinshtein, E. E.; Dubur, G. Ya. Chem. Heterocycl.
Compd. 1975, 11, 196–198.
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SCHEME 3. Plausible Reaction Scenario of 5 and 6
TABLE 3. Conversion 5a to 6a under Different Conditions
Experimental Section
General Procedure for the Synthesis of 5 (5a). An equimolar
mixture of β-(2,4-dichlorophenyl)thioacetanilide 2a (0.324 g,
1 mmol), 4-chlorobenzaldehyde 3a (0.140 g, 1 mmol), and
5,5-dimethyl-1,3-cyclohexanedione 4 (0.140 g, 1 mmol) was
refluxed for 20 h in EtOH (15 mL) containing Et3N (0.10 g,
1 mmol). After completion of the reaction as indicated by
TLC (petroleum-EtOAc, 8:2, v/v), the mixture was cooled to
room temperature, and the solid product was filtered, washed
with water, subsequently dried, and recrystallized from EtOH
to give the pure product 5a.
4-(4-Chlorophenyl)-3-(2,4-dichlorobenzoyl)-7,7-dimethyl-2-(phe-
nylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5a). Yellow pow-
der; mp 186-188 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.82 (s,
3H), 1.05 (s, 3H), 2.08 (d, J = 16.0 Hz, 1H), 2.28 (d, J = 16.0 Hz,
1H), 2.50 (d, J = 18.0 Hz, 1H), 2.71 (d, J = 18.0 Hz, 1H), 4.36 (s,
1H), 6.71-7.66 (m, 12H), 12.78 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 26.7, 29.1, 32.4, 34.9, 50.4, 90.9, 116.3, 123.0, 125.7, 127.8,
128.3, 129.5, 129.9, 131.3, 134.7, 136.5, 138.4, 138.8, 144.1, 158.1,
161.7, 190.5, 196.0; IR (KBr, cm-1) 1688, 1670, 1626, 1593, 1564,
1363, 1309, 828, 748; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H25Cl3NO3 552.0900, found 552.0912.
4-(Benzo[d][1,3]dioxol-5-yl)-3-(2,4-dichlorobenzoyl)-7,7-dime-
thyl-2-(phenylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5b).
Yellow powder; mp 180-182 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.86 (s, 3H), 1.05 (s, 3H), 2.09 (d, J = 16.0 Hz, 1H), 2.28 (d, J =
16.0 Hz, 1H), 2.54 (d, J = 17.4 Hz, 1H), 2.68 (d, J = 17.4 Hz, 1H),
4.28 (s, 1H), 5.91 (bs, 1H), 5.93 (bs, 1H), 6.13-7.66 (m, 11H), 12.75
(s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 29.1, 32.4, 34.9,
41.4, 50.4, 91.4, 101.2, 108.1, 108.4, 116.6, 121.3, 122.9, 125.6, 127.7,
129.4, 129.9, 134.5, 136.6, 138.5, 139.2, 146.0, 147.2, 158.0, 161.4,
190.6, 196.1; IR (KBr, cm-1) 1670, 1627, 1594, 1561, 1363, 1309,
1204, 820, 750; HRMS (ESI-TOF, [M þ H]þ) calcd for C31H26Cl2-
NO5 562.1188, found 562.1178.
temp
(°C)
time
(min)
yield
(%)a
entry
catalyst (equiv)
solvent
1
2
3
4
5
6
b
DMF
DMF
DMF
DMF
DMF
DMF
78
25
100
100
100
100
160
160
120
160
120
90
c
c
88
69
86
50
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (0.5)
K2CO3 (1.2)
K2CO3 (1.0)/
AgNO3 (1.0)
K2CO3 (1.0)/
AgNO3 (0.25)
K2CO3 (0.5)/
AgNO3 (1.0)
K2CO3 (0.5)/
AgNO3 (0.5)
K2CO3 (0.5)/
AgNO3 (0.25)
AgNO3 (1.0)
KOH (1.0)
7
DMF
DMF
DMF
DMF
100
100
100
100
80
90
80
80
66
55
71
77
8
9
10
11
12
DMF
DMF
100
100
120
120
c
76
aIsolated yield. bNo base. cNo reaction.
ready availability of a wide range of substrates from cheap
starting materials, make this new strategy highly attractive. The
simplicity of the sequence, mild reaction conditions, lack of need
for transition metals, and economy of the sequence indicate that
this process could be capable of broad application for highly
functionalized tetracyclic systems. Further investigations to
expand the scope of β-(2-haloaroyl)thioacetanilides as versatile
building blocks by the combined use of domino and MCRs are
in progress and will be reported elsewhere in due course.
4-(4-Bromophenyl)-3-(2,4-dichlorobenzoyl)-7,7-dimethyl-2-(phe-
nylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5c). Yellow powder;
mp 232-235 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.80 (s, 3H),
1.03 (s, 3H), 2.05 (d, J = 16.5 Hz, 1H), 2.27 (d, J = 16.5 Hz, 1H),
2.51 (d, J = 20.0 Hz, 1H), 2.69 (d, J = 20.0 Hz, 1H), 4.31 (s, 1H),
6.61-7.67 (m, 12H), 12.77 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ 26.7, 29.1, 32.4, 34.9, 50.3, 90.9, 116.3, 119.8, 123.0,
125.8, 127.8, 129.5, 129.9, 130.3, 131.0, 131.2, 134.7, 136.5, 138.4,
8528 J. Org. Chem. Vol. 75, No. 24, 2010

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TABLE 4. Synthesis of Chromeno[2,3-b]quinolines 6a-l
aIsolated yield. b6h, 6i, and 6j are the same. c6k is the same as 6l.
144.5, 158.1, 161.8, 190.5, 196.1; IR (KBr, cm-1) 1680, 1669, 1626,
1591, 1563, 1363, 1311, 1206, 829, 747; HRMS (ESI-TOF, [Mþ
H]þ) calcd for C30H25BrCl2NO3 596.0395, found 596.0382.
3-(2,4-Dichlorobenzoyl)-7,7-dimethyl-2-(phenylamino)-4-p-tolyl-
7,8-dihydro-4H-chromen-5(6H)-one (5d). Yellow powder; mp 203-
205 °C; 1H NMR (DMSO-d6, 500 MHz) δ0.81 (s, 3H), 1.04 (s, 3H),
2.05 (d, J = 16.0 Hz, 1H), 2.18 (s, 3H), 2.28 (d, J = 16.0 Hz, 1H),
2.52 (d, J = 18.0 Hz, 1H), 2.70 (d, J = 18.0 Hz, 1H), 4.30 (s, 1H),
6.54-7.66 (m, 12H), 12.74 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 21.1, 26.6, 29.2, 32.4, 34.8, 50.4, 91.6, 117.0, 122.9, 125.7,
127.8, 127.9, 129.0, 129.5, 129.9, 134.6, 135.8, 136.6, 138.6, 142.3,
158.1, 161.5, 190.6, 196.1; IR (KBr, cm-1) 1688, 1671, 1627, 1590,
1560, 1370, 1321, 827, 761; HRMS (ESI-TOF, [M þ H]þ) calcd for
C31H28Cl2NO3 532.1446, found 532.1437.
3-(2,4-Dichlorobenzoyl)-7,7-dimethyl-4-phenyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5e). Pale yellow powder; mp
188-189 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.81 (s, 3H), 1.04
(s, 3H), 2.06 (d, J = 16.0 Hz, 1H), 2.28 (d, J = 16.0 Hz, 1H), 2.52
(d, J = 17.5 Hz, 1H), 2.70 (d, J = 17.5 Hz, 1H), 4.35 (s, 1H), 6.67-
7.80 (m, 13H), 12.76 (s, 1H); 13C NMR (DMSO-d6, 125 MHz)
δ 26.6, 29.1, 32.4, 35.2, 50.4, 91.5, 116.8, 122.9, 125.6, 126.8, 127.7,
128.0, 128.4, 129.4, 129.9, 134.5, 136.6, 138.5, 145.2, 158.1, 161.5,
190.6, 196.0; IR (KBr, cm-1) 1687, 1674, 1627, 1595, 1562, 1360,
745, 699; HRMS (ESI-TOF, [M þ H]þ) calcd for C30H26Cl2NO3
518.1290, found 518.1295.
3-(2,4-Dichlorobenzoyl)-4-(4-methoxyphenyl)-7,7-dimethyl-
2-(phenylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5f). Yellow
1
powder; mp 192-194 °C; H NMR (CDCl3, 500 MHz) δ 0.93
J. Org. Chem. Vol. 75, No. 24, 2010 8529

Li et al.
JOCArticle
(s, 3H), 1.12 (s, 3H), 2.17 (d, J=16.0 Hz, 1H), 2.26 (d, J=16.0 Hz,
1H), 2.48 (d, J = 17.5 Hz, 1H), 2.55 (d, J = 17.5 Hz, 1H), 3.73 (s,
3H), 4.39 (s, 1H), 6.36-7.43 (m, 12H), 13.07 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 27.2, 29.3, 32.3, 35.10, 40.4, 50.8, 55.2, 91.5,
113.4, 117.9, 125.2, 126.8, 129.2, 129.6, 130.1, 130.8, 134.9, 136.7,
137.5, 138.2, 158.1, 158.2, 159.9, 191.5, 195.9; IR (KBr, cm-1) 1684,
1668, 1626, 1591, 1559, 1368, 1256, 827, 775, 757, 690; HRMS (ESI-
TOF, [M þ H]þ) calcdforC31H28Cl2NO4 548.1395, found 548.1385.
4-(4-Chlorophenyl)-3-(2,5-dichlorobenzoyl)-7,7-dimethyl-2-(phe-
nylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5g). Pale yellow
powder; mp 169-171 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.81
(s, 3H), 1.03(s, 3H), 2.05(d, J =16.5Hz, 1H), 2.27(d, J= 16.5 Hz,
1H), 2.51 (d, J = 18.0 Hz, 1H), 2.68 (d, J = 18.0 Hz, 1H), 4.31 (s,
1H), 6.68-7.50 (m, 12H), 12.76 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 26.7, 29.1, 32.4, 35.0, 41.2, 50.4, 90.8, 116.1, 123.1, 125.8,
128.3, 129.9, 130.1, 130.7, 131.4, 131.7, 132.3, 136.5, 141.1, 144.2,
158.2, 161.6, 189.9, 196.1; IR (KBr, cm-1) 1685, 1668, 1622, 1594,
1564, 1364, 1205, 822, 757, 691; HRMS (ESI-TOF, [M þ H]þ) calcd
for C30H25Cl3NO3 552.0900, found 552.0885.
2.18 (d, J = 16.1 Hz, 1H), 2.26 (d, J = 16.1 Hz, 1H), 2.47 (d, J =
18.0 Hz, 1H), 2.54 (d, J= 18.0 Hz, 1H), 4.81 (s, 1H), 6.71-7.39(m,
14H), 13.17 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 29.2,
32.5, 34.9, 41.7, 50.5, 91.2, 100.0, 116.5, 122.4, 125.1, 127.0, 128.5,
128.7, 129.6, 129.8, 130.2, 131.2, 137.4, 138.0, 140.9, 144.8, 157.6,
162.4, 194.6, 196.3; IR (KBr, cm-1) 1687, 1667, 1624, 1593, 1561,
1362, 1318, 841, 753, 706; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H27ClNO3 484.1679, found 484.1682.
4-(Benzo[d][1,3]dioxol-5-yl)-3-benzoyl-7,7-dimethyl-2-(phenyl-
amino)-7,8-dihydro-4H-chromen-5(6H)-one (5m). Pale yellow
powder; mp 210-212 °C; 1H NMR (CDCl3, 500 MHz) δ 0.94 (s,
3H), 1.11 (s, 3H), 2.18 (d, J = 16.0 Hz, 1H), 2.25 (d, J = 16.0 Hz,
1H), 2.47 (d, J = 17.5 Hz, 1H), 2.51 (d, J = 17.5 Hz, 1H), 4.75 (s,
1H), 5.84 (d, J = 1 Hz, 1H), 5.85 (d, J = 1 Hz, 1H), 6.22-7.40 (m,
13H), 13.13 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.9, 29.2,
32.5, 34.8, 41.5, 50.6, 91.7, 101.3, 108.0, 108.3, 117.0, 120.7, 122.3,
125.0, 127.0, 128.6, 129.8, 130.2, 137.4, 139.8, 141.0, 145.9, 147.4,
157.5, 162.2, 194.6, 196.4; IR (KBr, cm-1) 1685, 1669, 1625, 1596,
1560, 1361, 1248, 753, 700; HRMS (ESI-TOF, [M þ H]þ) calcd for
C31H28NO5 494.1967, found 494.1965.
4-(4-Chlorophenyl)-3-(2-fluorobenzoyl)-7,7-dimethyl-2-(phenyl-
amino)-7,8-dihydro-4H-chromen-5(6H)-one (5h). Yellow powder;
3-Benzoyl-4-(4-bromophenyl)-7,7-dimethyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5n). Pale yellow powder;
1
mp 232-234 °C; H NMR (CDCl3, 500 MHz) δ 0.93 (s, 3H),
1
mp 248-250 °C; H NMR (CDCl3, 500 MHz) δ 0.96 (s, 3H),
1.13 (s, 3H), 2.16 (d, J=16.0 Hz, 1H), 2.26 (d, J=16.0 Hz, 1H),
2.47 (d, J = 17.5 Hz, 1H), 2.55 (d, J = 17.5 Hz, 1H), 4.60 (s, 1H),
6.69-7.44 (m, 13H), 13.13 (s, 1H); 13C NMR (CDCl3, 125 MHz)
δ 27.1, 29.3, 32.3, 34.7, 40.4, 50.7, 91.2, 115.8, 116.0, 117.2, 122.6,
124.2, 125.2, 128.0, 128.6, 128.7, 129.2, 129.3, 130.8, 130.9, 131.9,
1.14 (s, 3H), 2.18 (d, J = 16.0 Hz, 1H), 2.28 (d, J = 16.0 Hz, 1H),
2.49 (d, J = 17.5 Hz, 1H), 2.56 (d, J = 17.5 Hz, 1H), 4.82 (s, 1H),
6.67-7.43 (m, 14H), 13.17 (s, 1H); 13C NMR (CDCl3, 125 MHz)
δ 27.2, 29.3, 32.4, 34.9, 40.5, 50.8, 90.0, 117.4, 120.1, 122.5, 125.0,
126.3, 128.3, 129.3, 129.5, 129.6, 131.1, 137.0, 140.7, 144.3, 158.0,
160.9, 195.5, 195.9; IR (KBr, cm-1) 1688, 1669, 1626, 1592, 1560,
1362, 1318, 1050, 839, 753, 706; HRMS (ESI-TOF, [M þ H]þ)
calcd for C30H27BrNO3 528.1174, found 528.1179.
136.6, 143.6, 157.0, 157.8, 158.9, 160.4, 190.7, 195.8; IR (KBr, cm-1
)
1688, 1668, 1626, 1593, 1563, 1362, 769, 754; HRMS (ESI-TOF,
[M þ H]þ) calcd for C30H26ClFNO3 502.1585, found 502.1581.
4-(Benzo[d][1,3]dioxol-5-yl)-3-(2-fluorobenzoyl)-7,7-dimethyl-
2-(phenylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5i). Yel-
low powder; mp 189-191 °C; 1H NMR (DMSO-d6, 500 MHz) δ
0.84 (s, 3H), 1.03 (s, 3H), 2.06 (d, J = 16.5 Hz, 1H), 2.26 (d, J =
16.0 Hz, 1H), 2.48 (d, J = 15.0 Hz, 1H), 2.67 (d, J = 15.0 Hz, 1H),
4.38 (s, 1H), 5.88 (bs, 1H), 5.91 (d, J = 1 Hz, 1H), 6.06-7.46 (m,
12H), 12.68 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 29.2,
32.4, 34.7, 50.4, 92.1, 101.2, 108.1, 108.2, 116.7, 120.9, 122.9, 124.9,
125.5, 128.8, 129.0, 129.8, 131.7, 131.8, 136.7, 139.5, 145.9, 147.2,
157.6, 159.1, 161.7, 189.9, 196.2; IR (KBr, cm-1) 1684, 1671, 1615,
1598, 1558, 1490, 1366, 1307, 758; HRMS (ESI-TOF, [M þ H]þ)
calcd for C31H27FNO5 512.1873, found 512.1888.
3-(2-Bromobenzoyl)-4-(4-chlorophenyl)-7,7-dimethyl-2-(phenyl-
amino)-7,8-dihydro-4H-chromen-5(6H)-one (5j). Yellow powder;
mp 197-200 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.79 (s, 3H),
1.02 (s, 3H), 2.03 (d, J = 16.0 Hz, 1H), 2.27 (d, J = 16.5 Hz, 1H),
2.50 (d, J = 18.0 Hz, 1H), 2.70 (d, J = 18.0 Hz, 1H), 4.35 (s, 1H),
6.59-7.59 (m, 13H), 12.81 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 26.8, 29.4, 32.7, 35.3, 50.6, 90.8, 114.9, 116.6, 123.1, 125.9,
128.3, 128.5, 129.0, 130.2, 131.4, 131.5, 133.2, 136.8, 141.6, 144.4,
158.3, 162.1, 188.1, 192.86, 196.53; IR (KBr, cm-1) 1669, 1627,
1596, 1565, 1364, 1306, 752, 690; HRMS (ESI-TOF, [MþH]þ)
calcd for C30H26BrClNO3 562.0785, found 562.0796.
3-Benzoyl-7,7-dimethyl-2-(phenylamino)-4-p-tolyl-7,8-dihydro-
4H-chromen-5(6H)-one (5o). Yellow powder; mp 197-199 °C;
1H NMR (DMSO-d6, 500 MHz) δ 0.81 (s, 3H), 1.03 (s, 3H), 2.03
(d, J = 17.5 Hz, 1H), 2.13 (s, 3H), 2.25 (d, J = 17.5 Hz, 1H), 2.47
(d, J = 17.5 Hz, 1H), 2.67 (d, J = 17.5 Hz, 1H), 4.66 (s, 1H),
6.56-7.42 (m, 14H), 12.41 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 21.0, 26.7, 29.2, 32.4, 34.6, 41.2, 50.5, 91.7, 117.1, 122.2,
124.9, 127.0, 127.4, 128.5, 129.1, 129.8, 130.1, 135.6, 137.3, 140.9,
142.8, 157.6, 162.2, 194.5, 196.2; IR (KBr, cm-1) 1688, 1671,
1625, 1596, 1560, 1361, 1305, 1211, 897, 755, 703; HRMS (ESI-
TOF, [M þ H]þ) calcd for C31H30NO3 464.2226, found 464.2236.
3-Benzoyl-7,7-dimethyl-4-phenyl-2-(phenylamino)-7,8-dihydro-
4H-chromen-5(6H)-one (5p). Pale yellow powder; mp 166-168 °C;
1H NMR (CDCl3, 500 MHz) δ 0.95 (s, 3H), 1.14 (s, 3H), 2.19 (d,
J = 16.5 Hz, 1H), 2.28 (d, J = 16.5 Hz, 1H), 2.50 (d, J = 17.5 Hz,
1H), 2.56 (d, J = 17.5 Hz, 1H), 4.86 (s, 1H), 6.82-7.44 (m, 15H),
13.21 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 29.3, 32.5,
35.2, 50.6, 91.7, 117.0, 122.3, 125.0, 126.7, 127.1, 127.6, 128.6, 128.6,
129.8, 130.2, 137.4, 141.0, 145.8, 157.7, 162.36, 194.6, 196.2; IR
(KBr, cm-1) 1686, 1668, 1625, 1594, 1561, 1362, 755, 695; HRMS
(ESI-TOF, [M þ H]þ) calcd for C30H28NO3 450.2069, found
450.2074.
4-(Benzo[d][1,3]dioxol-5-yl)-3-(2-bromobenzoyl)-7,7-dimethyl-
2-(phenylamino)-7,8-dihydro-4H-chromen-5(6H)-one (5k). Yel-
low powder; mp 176-179 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.84 (s, 3H), 1.04 (s, 3H), 2.07 (d, J = 16.0 Hz, 1H), 2.27 (d, J =
16.0 Hz, 1H), 2.53 (d, J = 17.5 Hz, 1H), 2.68 (d, J = 17.5 Hz, 1H),
4.28 (s, 1H), 5.89 (bs, 1H), 5.91 (d, J = 1 Hz, 1H), 6.10-7.62 (m,
12H), 12.79 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.7, 29.0,
32.4, 35.0, 50.3, 91.1, 101.1, 108.0, 108.5, 116.8, 121.2, 122.7, 125.4,
127.8, 128.6, 129.8, 130.8, 132.8, 136.6, 139.3, 141.5, 145.8, 147.1,
157.8, 161.4, 192.6, 196.0; IR (KBr, cm-1) 1682, 1672, 1627, 1597,
1561, 1361, 1297, 1248, 751; HRMS (ESI-TOF, [M þ H]þ) calcd
for C31H27BrNO5 572.1073, found 572.1091.
3-Benzoyl-4-(4-methoxyphenyl)-7,7-dimethyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5q). Pale yellow powder; mp
172-174 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.81 (s, 3H), 1.03
(s, 3H), 2.06 (d, J = 16.0 Hz, 1H), 2.24 (d, J = 16.0 Hz, 1H), 2.48
(d, J = 17.5 Hz, 1H), 2.67 (d, J = 17.5 Hz, 1H), 3.60 (s, 3H), 4.64
(s, 1H), 6.59-7.42 (m, 14H), 12.41 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ 26.7, 29.2, 32.4, 34.2, 50.5, 55.3, 91.8, 113.8, 117.2,
122.2, 124.9, 127.0, 128.5, 128.6, 129.8, 130.1, 137.3, 137.8, 140.9,
157.5, 157.9, 162.0, 194.6, 196.2; IR (KBr, cm-1) 1688, 1670,
1624, 1596, 1559, 1361, 1241, 834, 753, 702; HRMS (ESI-TOF,
[M þ H]þ) calcd for C31H30NO4 480.2175, found 480.2164.
3-Benzoyl-7,7-dimethyl-4-(4-nitrophenyl)-2-(phenylamino)-7,8-
dihydro-4H-chromen-5(6H)-one (5r). Pale yellow powder; mp
3-Benzoyl-4-(4-chlorophenyl)-7,7-dimethyl-2-(phenylamino)-7,8-
dihydro-4H-chromen-5(6H)-one (5l). Pale yellow powder; mp 254-
255 °C; 1H NMR (CDCl3, 600 MHz) δ 0.93 (s, 3H), 1.13 (s, 3H),
1
262-264 °C; H NMR (CDCl3, 600 MHz) δ 0.92 (s, 3H), 1.14
(s, 3H), 2.17 (d, J = 16.5 Hz, 1H), 2.28 (d, J=16.5 Hz, 1H), 2.50
8530 J. Org. Chem. Vol. 75, No. 24, 2010

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(d, J =16.8 Hz, 1H), 2.58 (d, J =16.8 Hz, 1H), 4.97 (s, 1H),
6.91-7.93 (m, 14H), 13.21 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 26.9, 29.2, 32.5, 35.8, 50.4, 90.7, 100.0, 115.7, 122.4,
123.8, 125.1, 127.0, 128.7, 129.2, 129.8, 130.3, 137.3, 140.8, 146.3,
153.3, 157.5, 162.9, 194.5, 196.3; IR (KBr, cm-1) 1685, 1665,
1625, 1594, 1560, 1518, 1362, 1346, 752, 702; HRMS (ESI-TOF,
[M þ H]þ) calcd for C30H27N2O5 495.1920, found 495.1905.
3-Benzoyl-4-(2-chlorophenyl)-7,7-dimethyl-2-(phenylamino)-7,8-
dihydro-4H-chromen-5(6H)-one (5s). Pale yellow powder; mp
168-170 °C; 1H NMR (DMSO-d6, 500 MHz) δ0.90 (s, 3H), 1.08 (s,
3H), 2.06 (d, J = 16.0 Hz, 1H), 2.29 (d, J = 16.0 Hz, 1H), 2.71 (d,
J = 17.5 Hz, 1H), 5.06 (s, 1H), 6.52-7.45 (m, 14H), 12.44 (s,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 29.2, 32.3, 35.2, 50.6,
90.1, 100.0, 114.6, 114.8, 122.3, 124.9, 126.6, 126.9, 128.35, 128.7,
129.8, 132.5, 132.6, 137.4, 141.0, 141.2, 157.3, 161.8, 194.6, 196.1; IR
(KBr, cm-1) 1683, 1660, 1619, 1595, 1553, 1362, 751, 701; HRMS
(ESI-TOF, [M þ H]þ) calcd for C30H27ClNO3 484.1679, found
484.1670.
3-Benzoyl-4-(2,4-dichlorophenyl)-7,7-dimethyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5t). Pale yellow powder; mp
218-220 °C; H NMR (CDCl3, 500 MHz) δ 1.00 (s, 3H), 1.13
(s, 3H), 2.15 (d, J = 16.5 Hz, 1H), 2.23 (d, J = 16.5 Hz, 1H), 2.47
(d, J = 17.5 Hz, 1H), 2.53 (d, J = 17.5 Hz, 1H), 5.05 (s, 1H), 6.29-
7.42 (m, 13H), 13.22 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 27.4,
29.2, 32.1, 35.6, 40.4, 50.7, 88.2, 114.0, 122.8, 125.0, 126.0, 126.1,
128.5, 129.2, 129.3, 129.9, 132.6, 133.8, 134.0, 136.9, 138.7, 141.0,
158.0, 161.4, 195.2, 196.2; IR (KBr, cm-1) 1688, 1669, 1623, 1594,
1562, 1361, 837, 753, 702; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H26Cl2NO3 518.1290, found 518.1297.
3-Benzoyl-4-(2,5-dichlorophenyl)-7,7-dimethyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5u). Yellow powder; mp 194-
196 °C; 1H NMR (DMSO-d6, 500 MHz) δ0.91 (s, 3H), 1.07 (s, 3H),
2.08 (d, J = 16.1 Hz, 1H), 2.28 (d, J = 16.1 Hz, 1H), 2.70 (d, J =
17.6 Hz, 1H), 4.92 (s, 1H), 6.22-7.47 (m, 13H), 12.66 (s, 1H); 13C
NMR (DMSO-d6, 125 MHz) δ 26.7, 29.2, 32.2, 36.3, 50.5, 88.6,
100.0, 112.8, 122.5, 125.2, 126.6, 128.3, 128.8, 129.9, 130.0, 131.0,
131.6, 132.0, 132.7, 137.1, 140.9, 142.3, 157.5, 162.7, 194.5, 196.3;
IR (KBr, cm-1) 1679, 1663, 1620, 1596, 1562, 1367, 1204, 753, 700;
HRMS (ESI-TOF, [M þ H]þ) calcd for C30H26Cl2NO3 518.1290,
found 518.1279.
3-Benzoyl-4-(2,6-dichlorophenyl)-7,7-dimethyl-2-(phenylamino)-
7,8-dihydro-4H-chromen-5(6H)-one (5v). Pale yellow powder; mp
186-188 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.94 (s, 3H), 1.08
(s, 3H), 2.04 (d, J = 16.0 Hz, 1H), 2.29 (d, J = 16.0 Hz, 1H), 2.43
(d, J = 17.7 Hz, 1H), 2.68 (d, J = 17.7 Hz, 1H), 5.51 (s, 1H), 7.06-
7.37 (m, 13H), 11.45 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ
26.3, 28.8, 31.6, 32.9, 50.3, 89.9, 99.5, 111.6, 120.7, 123.6, 127.0,
128.1, 128.4, 129.2, 129.9, 137.2, 137.8, 140.3, 155.9, 162.9, 194.5,
195.7; IR (KBr, cm-1) 1671, 1624, 1597, 1558, 1361, 1210, 764,
747, 699; HRMS (ESI-TOF, [M þ H]þ) calcd for C30H26Cl2NO3
518.1290, found 518.1279.
General Procedure for Synthesis of Chromeno[2,3-b]quinolines
6 (6a). A mixture of corresponding 5a (1.158 g, 1.0 mmol) and
K2CO3 (0.138 g, 1 mmol) was heated to 100 °C in DMF (15 mL).
After completion of the reaction as indicated by TLC (about 40
min, petroleum-EtOAc, 8:2 v/v), the mixture was cooled to
room temperature and was added to an amount of ice-water to
precipitate the product, which was then collected by filtration
and washed with cool water to afford pure 6a.
8-Chloro-12-(4-chlorophenyl)-3,3-dimethyl-6-phenyl-3,4,6,12-
tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6a). Yel-
low powder; mp 280-282 °C; H NMR (DMSO-d6, 500 MHz)
1544, 1361, 830, 711; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H24Cl2NO3 516.1133, found 516.1147.
12-(Benzo[d][1,3]dioxol-5-yl)-8-chloro-3,3-dimethyl-6-phenyl-
3,4,6,12-tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione
(6b). Yellow powder; mp 289-292 °C; 1H NMR (DMSO-d6, 500
MHz) δ 0.87 (s, 3H), 0.98(s, 3H), 2.11-2.36(m, 4H), 4.95(s, 1H),
5.91 (bs, 1H), 5.93 (bs, 1H), 6.64-8.13 (m, 11H); 13C NMR
(DMSO-d6, 125 MHz) δ 26.9, 29.0, 32.3, 32.6, 50.5, 101.2, 102.8,
108.2, 109.4, 115.5, 116.8, 121.7, 123.2, 124.2, 128.1, 129.6, 130.0,
130.7, 130.8, 130.9, 135.5, 137.4, 138.4, 140.9, 146.1, 147.3, 151.8,
163.0, 174.8, 196.4; IR (KBr, cm-1) 1680, 1660, 1616, 1590, 1543,
1370, 1358, 1312, 1209, 794, 698; HRMS (ESI-TOF, [M þ H]þ)
calcd for C31H25ClNO5 526.1421, found 526.1423.
12-(4-Bromophenyl)-8-chloro-3,3-dimethyl-6-phenyl-3,4,6,12-
tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6c). Yel-
low powder; mp 288-290 °C; 1H NMR (DMSO-d6, 500 MHz) δ
0.86 (s, 3H), 0.98 (s, 3H), 2.10 (d, J = 16.0 Hz, 1H), 2.20 (d, J =
17.0 Hz, 1H), 2.27 (d, J = 16.0 Hz, 1H), 2.32 (d, J = 17.0 Hz, 1H),
4.97 (s, 1H), 6.64-8.11 (m, 12H); 13C NMR (DMSO-d6, 125 MHz)
δ 26.8, 29.0, 32.3, 32.8, 50.4, 102.2, 114.9, 116.8, 119.8, 123.2, 124.3,
128.0, 129.6, 129.9, 130.7, 130.8, 130.89, 131.0, 131.2, 135.4, 137.4,
140.9, 143.8, 151.8, 163.2, 174.8, 196.4; IR (KBr, cm-1) 1668, 1617,
1590, 1544, 1361, 1207, 722, 704; HRMS (ESI-TOF, [M þ H]þ)
calcd for C30H24BrClNO3 560.0628, found 560.0638.
1
8-Chloro-3,3-dimethyl-6-phenyl-12-(p-tolyl)-3,4,6,12-tetrahydro-
1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6d). Yellow powder;
mp 249-252 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.83 (s, 3H),
0.96 (s, 3H), 2.08 (d, J = 16.0 Hz, 1H), 2.18 (d, J = 17.5 Hz, 1H),
2.20 (s, 3H), 2.25 (d, J = 16.0 Hz, 1H), 2.30 (d, J = 17.5 Hz, 1H),
4.96(s, 1H), 6.62-8.10 (m, 12H); 13C NMR (DMSO-d6, 125MHz)
δ 21.1, 26.8, 29.1, 32.3, 32.5, 50.5, 103.0, 115.6, 116.7, 123.2, 124.2,
128.1, 128.6, 129.0, 129.6, 129.9, 130.7, 130.8, 130.9, 135.5, 135.8,
137.4, 140.9, 141.5, 151.7, 163.0, 174.8, 196.3; IR (KBr, cm-1
)
1666, 1614, 1591, 1534, 1366, 1203, 721, 700; HRMS (ESI-TOF,
[M þ H]þ) calcd for C31H27ClNO3 496.1679, found 496.1681.
8-Chloro-3,3-dimethyl-6,12-diphenyl-3,4,6,12-tetrahydro-1H-
chromeno[2,3-b]quinoline-1,11(2H)-dione (6e). Yellow powder;
mp 292-294 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.85 (s, 3H),
0.98 (s, 3H), 2.10 (d, J = 16.0 Hz, 1H), 2.22 (d, J = 17.5 Hz, 1H),
2.28 (d, J = 16.0 Hz, 1H), 2.32 (d, J = 17.5 Hz, 1H), 5.03 (s, 1H),
6.65-8.12 (m, 13H); 13C NMR (DMSO-d6, 125 MHz) δ26.7, 29.0,
32.3, 32.9, 50.4, 102.8, 115.5, 116.7, 123.2, 124.2, 126.7, 128.0,
128.4, 128.6, 129.5, 129.9, 130.6, 130.8, 130.9, 135.4, 137.3, 140.8,
144.3, 151.8, 163.1, 174.8, 196.3; IR (KBr, cm-1) 1669, 1618, 1591,
1541, 1366, 1202, 701; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H25ClNO3 482.1523, found 482.1531.
8-Chloro-12-(4-methoxyphenyl)-3,3-dimethyl-6-phenyl-3,4,6,12-
tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6f). Yel-
low powder; mp 263-264 °C; 1H NMR (DMSO-d6, 500 MHz) δ
0.86 (s, 3H), 0.98 (s, 3H), 2.09 (d, J= 16.0 Hz, 1H), 2.20 (d, J=17.5
Hz, 1H), 2.26 (d, J = 16.0 Hz, 1H), 2.31 (d, J = 17.5 Hz, 1H), 3.67
(s,3H),4.97(s,1H),6.64-8.12 (m, 13H); 13C NMR (DMSO-d6, 125
MHz) δ 26.8, 29.1, 32.0, 32.3, 50.5, 55.5, 103.1, 115.7, 116.7, 123.2,
124.2, 128.0, 129.6, 129.9, 130.7, 130.8, 130.9, 135.5, 136.6, 137.3,
140.87, 151.7, 162.9, 174.8, 196.4; IR (KBr, cm-1) 1670, 1662, 1613,
1591, 1544, 1364, 1312, 1254, 1209, 825, 720, 698; HRMS (ESI-TOF,
[M þ H]þ) calcd for C31H27ClNO4 512.1629, found 512.1618.
9-Chloro-12-(4-chlorophenyl)-3,3-dimethyl-6-phenyl-3,4,6,12-
tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6g). Pale
yellow powder; mp 293-295 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.86 (s, 3H), 0.98 (s, 3H), 2.12-2.30 (m, 4H), 5.00 (s, 1H),
6.76-8.03 (m, 12H); 13C NMR (DMSO-d6, 125 MHz) δ26.8, 29.0,
32.3, 32.8, 50.4, 102.2, 115.0, 120.2, 124.6, 125.6, 128.3, 128.8,
129.6, 129.9, 130.6, 130.6, 130.8, 131.3, 132.8, 135.6, 138.8, 143.4,
151.7, 163.2, 174.3, 196.4; IR (KBr, cm-1) 1664, 1618, 1590, 1549,
1363, 1206, 830, 767, 698; HRMS (ESI-TOF, [M þ H]þ) calcd for
C30H24Cl2NO3 516.1133, found 516.1152.
1
δ 0.85 (s, 3H), 0.98 (s, 3H), 2.10 (d, J = 16.0 Hz, 1H), 2.20 (d, J =
17.5 Hz, 1H), 2.27 (d, J = 16.0 Hz, 1H), 2.32 (d, J = 17.5 Hz, 1H),
4.99 (s, 1H), 6.64-8.11 (m, 12H); 13C NMR (DMSO-d6, 125 MHz)
δ 26.8, 29.0, 32.3, 32.7, 50.4, 102.3, 115.0, 116.8, 123.2, 124.4, 128.0,
128.3, 129.6, 130.0, 130.6, 130.8, 130.9, 131.3, 135.4, 137.5, 140.9,
143.4, 151.8, 163.2, 174.8, 196.4; IR (KBr, cm-1) 1668, 1619, 1591,
J. Org. Chem. Vol. 75, No. 24, 2010 8531

Li et al.
JOCArticle
12-(4-Chlorophenyl)-3,3-dimethyl-6-phenyl-3,4,6,12-tetrahydro-
1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6h, 6i, and 6j). Pale
yellow powder; mp 266-268 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.86 (s, 3H), 0.98 (s, 3H), 2.10 (d, J = 16.0 Hz, 1H), 2.20 (d, J =
17.5 Hz, 1H), 2.27 (d, J = 16.0 Hz, 1H), 2.34 (d, J = 17.5Hz, 1H),
5.02 (s, 1H), 6.73-8.11 (m, 13H); 13C NMR (DMSO-d6, 125
MHz) δ 26.8, 29.1, 32.3, 32.7, 50.4, 101.7, 115.1, 117.6, 124.0,
124.4, 125.7, 128.3, 129.6, 130.0, 130.4, 130.6, 130.7, 131.2, 132.9,
6.67-8.22 (m, 12H); 13C NMR (DMSO-d6, 125 MHz) δ 26.8, 32.3,
32.5, 50.4, 101.2, 102.3, 108.2, 109.3, 115.5, 117.6, 121.5, 124.0, 124.4,
125.7, 129.5, 130.0, 130.3, 130.6, 130.7, 132.8, 135.8, 140.0, 146.0,
147.2, 151.4, 163.1, 175.5, 196.6; IR (KBr, cm-1) 1665, 1616, 1591,
1553, 1371, 1232, 1207, 761, 699; HRMS (ESI-TOF, [MþH]þ) calcd
for C31H26NO5 492.1811, found 492.1808.
Acknowledgment. This work was financially supported by
the National Natural Science Foundation of China (nos.
20872074 and 21072110), the Natural Science Foundation of
Shandong Province (No. Z2008B03 and ZR2010BM007).
135.9, 140.1, 143.6, 151.4, 163.3, 175.4, 196.4; IR (KBr, cm-1
)
1668, 1616, 1591, 1555, 1366, 1209, 757, 703; HRMS (ESI-TOF,
[M þ H]þ) calcd for C30H25ClNO3 482.1523, found 482.1542.
12-(Benzo[d][1,3]dioxol-5-yl)-3,3-dimethyl-6-phenyl-3,4,6,12-
tetrahydro-1H-chromeno[2,3-b]quinoline-1,11(2H)-dione (6k and 6l).
Yellow powder; mp 252-254 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.81 (s, 3H), 0.92 (s, 3H), 2.05 (d, J = 16.0 Hz, 1H), 2.13 (d, J =
18.0 Hz, 1H), 2.21 (d, J = 16.0 Hz, 1H), 2.25 (d, J = 18.0 Hz, 1H),
4.91 (s, 1H), 5.97 (d, J = 1 Hz, 1H), 5.98 (d, J = 1 Hz, 1H),
Supporting Information Available: Copies of 1H NMR, 13
C
NMR and HRMS spectra of all new compounds, and X-ray
data for compound 6g in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
8532 J. Org. Chem. Vol. 75, No. 24, 2010