Radical cation salt-promoted catalytic aerobic sp3 C-H oxidation: Construction of quinoline-fused lactones and lactams

Article abstract of DOI:10.1021/jo502184k

A direct construction of quinoline-fused lactones and lactams was achieved by sp³ C-H bond oxidation of N-aryl glycine esters and amides under catalytic radical cation salt-induced conditions. These polycyclic products are formed in a single step from readily accessible starting materials, and this method provides a new synthetic approach to this class of heterocycles.

Full text of DOI:10.1021/jo502184k

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Note
Radical Cation Salt Promoted Catalytic Aerobic sp3 C-H Oxidation:
Construction of Quinoline Fused Lactones and Lactams
Yaxin Wang, Fangfang Peng, Jing Liu, Congde Huo, Xicun Wang, and Xiaodong Jia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502184k • Publication Date (Web): 03 Dec 2014
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Radical Cation Salt Promoted Catalytic Aerobic sp3 C−H Oxidation:
Construction of Quinoline Fused Lactones and Lactams
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Yaxin Wang, Fangfang Peng, Jing Liu, Congde Huo, Xicun Wang and Xiaodong Jia *
Key Laboratory of EcoꢀEnvironmentꢀRelated Polymer Materials, Ministry of Education, China.
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, China
Eꢀmail: jiaxd1975@163.com
Table of Contents Graphic
Abstract: A direct construction of quinoline fused lactones and lactams was achieved by sp3 C−H
bond oxidation of Nꢀaryl glycine esters and amides under catalytic radical cation salt induced
conditions. These polycyclic products are formed in a single step from readily accessible starting
materials, and this method provides a new synthetic approach to this class of heterocycles.
Heterocycle fused lactones and lactams represent interesting classes of natural and synthetic
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compounds which display a wide range of biological properties. Therefore, the development of
streamlined protocols which allow access these valuable molecules from relatively simple starting
materials is a worthwhile endeavor. For example, derivatives of furo[3,4ꢀb]quinolinꢀ3(1H)ꢀone
have been used to synthesize quinolineꢀ2ꢀcarboxamides A, which represent promising new
radioligands for the molecular imaging of the 18kDa translocator protein (TSPO).[1] Furthermore,
the group of Nicolaou has employed a lactone fused analog towards their synthesis of enediyne
antibiotic, uncialamycin. (Figure 1, eq. 1).[2] Quinoline fused 2ꢀpyranꢀ1ꢀone system B can be
perceived as a class of analogs of the dihydroisocoumarin glucosides C, which have been
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extracted from the fungus Cephalosporium sp. AL031, and exhibited antibacterial and fungicidal
[3]
properties. (Figure 1, eq. 2)
Additionally, quinoline fused lactams are key intermediates to
luotonin A, a cytotoxic alkaloid isolated from the Chinese medicinal plant Peganum nigellastrum,
which is active against murine leukaemia cell line Pꢀ388 with an IC50 value of 1.8 mg·mL−1.
(Figure 1, eq. 3) [4]
Figure 1. Heterocycles Fused Lactone and Lactam
Quinolineꢀfused variants are important members of these classes of heterocycles, and several
research groups have established protocols which to construct these scaffolds. Nevertheless, the
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development of new catalytic approaches still remains an active field of research, and efforts are
validated by the multitude of possible synthetic and biological applications. A stepwise approach
toward these heterocycles is usually employed where quinoline formation occurs prior to a final
lactonꢀ or lactamization (Figure 2, eq. 1). [1f, 3b, 4b] For example, van de Weghe reported an elegant
approach involving a tandem intermolecular Povarov cyclization/lactonization or lactamization. [2c]
However, this method requires a tedious synthetic route to obtain the desired starting materials
which suffers from low yields. We hypothesized that both the heteroaromatic ring and either the
lactone or lactam ring could be constructed via intramolecular process involving the C−H
oxidation/functionalization of readily accessible linear starting materials using the catalytic radical
chemistry developed in our laboratory[5] (Figure 2, eq. 2). This would represent a highly efficient
approach which could inspire new synthetic disconnections in the synthesis of heterocycles.
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Recently, we reported a catalytic radical cation initiated C−H functionalization of glycine
[5]
derivatives with styrenes to build quinoline skeletons.
This method represented a novel
approach to CDCs (cross dehydrogenative couplings), avoiding using excess quantities of the
oxidants (such as DDQ, TEMPO oxoammonium, and peroxides).[6] Preliminary results obtained
during testing the intramolecular variant, suggested that our hypothesis concerning a one step
construction of quinoline fused lactones and lactams was indeed feasible. Herein, report a novel
method for the direct formation of heterocycles fused lactones and lactams by catalytic aerobic
oxidation of glycine derivatives 1.
Figure 2. Synthetic Disconnections in the Synthesis of Quinoline Fused Lactones and
Lactams
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[5a]
We found that previously reported optimal conditions
employing 20 mol % of TBPA+•
o
(tris(4ꢀbromophenyl)aminium hexachloroantimonate), O2 (1 atm) and at 60 C led to efficient
formation of the desired quinoline fused lactone 2. With these conditions in hand we applied them
to a diverse array of Nꢀaryl glycine cinnamyl ester derivatives, and the results are compiled in
Table 1.
Table 1. Intramolecular Cyclization of NꢀAryl Glycine Cinnamyl Estersa
Entry
R
time (h)
72
product
2a
yield (%) b
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2
3
4
5
6
7
8
pꢀBr
pꢀCl
pꢀF
92
72
97
2b
72
72
2c
H
36
49
2d
pꢀMe
pꢀMeO
pꢀOH
oꢀMe
12
91 c
85 c
83 c
20
2e
12
2f
24
2g
36
2h
a) Reaction conditions: 1 (0.5 mmol), TBPA+. (20 mol %), O2 (1 atm), 60 oC. b) Isolated yield.
c)
The reaction was carried out in the presence of 10 mol % TBPA+..
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This study revealed that substituted Nꢀaryl glycine cinnamyl esters containing both
electronꢀwithdrawing and ꢀdonating groups were transformed to the desired products in moderate
to excellent yields. However, electronꢀwithdrawing groups were found to cause a decrease in
reaction rate (entries 1ꢀ3), presumably the electronꢀwithdrawing groups increasing the difficulty of
oxidation. In the absence of a substituent on the paraꢀposition of aniline a diminution of yields
results was obtained (entries 4 and 8). This is in accordance with our previously reported
intermolecular variant. [5]. One reason for the yield attenuation observed is that coupling can occur
at the paraꢀposition of aniline during oxidation.[7] A free phenol group was also tolerated, leading
to the desired product in 83% yield, thus implying that these mild oxidation condition are
amenable to the synthesis of more complicated compounds without tedious requiring
protectionꢀdeprotection of fragile functional groups (entry 7). The reaction conditions were also
tested using Nꢀaryl glycine allyl esters, however no desired product was isolated, suggesting that
radical or carbocation intermediate stability is crucial for the success of this reaction (Scheme 1).
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Scheme 1. Reaction of Glycine Allyl Esters
To determine the generality of this protocol, we turned our attention toward the construction of
quinoline fused lactams using the optimized conditions (Table 2). All tested Nꢀaryl glycine
cinnamyl amides exhibited good reactivity, affording the quinoline fused lactams in good to
excellent yields. Bulky amide Nꢀprotecting groups, including tꢀbutyl and iꢀpropyl gave better
results than the corresponding nꢀbutyl analogs (entries 1 vs. 2 and 3). This might be due to the fact
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that large Nꢀgroups provide a larger population of the reactive rotamer (Scheme 2). When the
group is large, the cinnamyl group is closer to the desired reactive radical, which is in favor of
intramolecular annulation. The substituent effect on cinnamyl group was also compared, and the
result shows that electronꢀdonating group increased the annulation yields (entries 4 and 5).
Otherwise, electronꢀwithdrawing group (4ꢀBr) reduced the yields to 66% and 70% repectively
(entries 6ꢀ7), which supported the existence of electronꢀdeficient intermediate. One reviewer
presented a reasonable reason for the substituent effect in Table 2, and we agree with him. The
results in Table 1 shows that increasing electron donation on the Nꢀaryl group of the glycine esters
accelerates the reaction, presumably due to the rate limiting step is sp3 CꢀH bond oxidation, not
the cyclization. However, when a powerful electronꢀdonating group is connected on aniline, the
oxidation process is no longer rate limiting, and increased electron donation on the cinnamyl
group renders alkene more nucleophilic, accelerating closure to the electron deficient radical A
(Scheme 4). All this results supported that an electron transfer may indeed be the pathway to
radical intermediate A.The reaction of N,Nꢀdicinnamyl amide also occurred smoothly leaving one
Nꢀcinnamyl group unchanged (entry 9). This implies that the C−H bond adjacent to the aniline
nitrogen is more active than the C−H bond adjacent to amide group, due to higher resonance
stabilization. Even the benzyl C−H bond adjacent to amide nitrogen does not disturb the oxidation
process, showing good selectivity under the oxidation conditions (entry 8).
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Scheme 2. Rotamerization of Glycine Amide
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Table 2. Intramolecular Cyclization of Glycine Amide a
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R1
Ar
R2
N
TBPA+. (10 mol %)
O2, 60oC, CH3CN
R1
Ar
N
N R2
H
O
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N
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O
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entry R1
R2
Ar
time
product yield
(%) b
(h)
20
12
19
20
1
2
pꢀOMe nꢀBu
pꢀOMe tꢀBu
pꢀOMe iꢀPr
pꢀOMe Ph
pꢀOMe Ph
pꢀOMe Ph
Ph
Ph
Ph
Ph
72
93
83
70
94
66
70
70
64
62
4a
4b
4c
4d
4e
4f
3
4
5
pꢀMeOC6H4 12
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pꢀBrC6H4
24
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16
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pꢀOMe 2,4ꢀdimethylphenyl pꢀBrC6H4
4g
4h
4i
8
pꢀOMe CH2Ph
Ph
Ph
Ph
9
pꢀOMe cinnamyl
10
Br
tꢀBu
4j
a) Reaction conditions: 3 (0.5 mmol), TBPA+. (10 mol %), O2 (1 atm), 60 oC b) Isolated yield
Having succeeded in constructing quinoline fused fiveꢀmembered lactones and lactams, we
wanted to explore the possibility of formation of sixꢀmember lactones (Table 3). The results show
that the desired 3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone skeleton can also be built efficiently.
The substituent on aniline does not affect the efficiency of the reaction, providing the polycyclic
products in high yields.
Table 3. Construction of Sixꢀmembered Lactones a
entry
R
time (h)
72
product
6a
yield (%) b
97
75 d
92 c
83 c
1
2
3
4
5
pꢀBr
pꢀCl
72
6b
pꢀOCH3
pꢀOH
oꢀ OCH3
72
6c
24
6d
36
49 c
6e
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a)
Table Footnote. Reaction conditions: 3 (0.5 mmol), TBPA+. (20 mol %), O2 (1 atm), 60 oC.b)
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7
c)
d)
Isolated yield. The reaction was carried out in the presence of 10 mol % TBPA+.. Under
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refluxing.
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To probe the reaction mechanism, some control experiments were conducted (Scheme 3). In the
presence of radical inhibitor TEMPO (1 equivalent), the reaction was inhibited and only 13% of
the desired product was isolated after 48 hours (eq. 1), which suggested that radical intermediates
might be involved. Other oxidants, such as Cu(II) and Fe(III), were used to initiate this reaction,
but no reaction occurred, implying that TBPA+. is crucial to induce the oxidation of the sp3 CꢀH
bond in glycine derivatives (eq. 2). A rate study was conducted to confirm the electronic effects on
glycine esters. The standard reaction conditions were applied to the mixture of 1b and 1f (eq. 3).
The ratio of the desired products is 1:5 (2b:2f), showing that electronꢀdonating groups accelerated
the oxidation of the sp3 CꢀH bond. These results also supported the involvement of
electronꢀdeficient intermediate.
Scheme 3. Control Experiments
Based on the results of our group and others, [5,7] a plausible mechanism was proposed (Scheme 4).
The sp3 C−H bond adjacent to anilino group was oxidized by TBPA+• in the presence of O2,
yielding a radical intermediate A, which can be further oxidized to the corresponding glycine
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imine (Scheme 2, path a). Then a radical cation salt induced Povarov reaction can occur [8] to
provide the quinoline derivatives. However, another pathway might also be operative (Scheme 2,
path b). The radical intermediate A adds to the double bond directly, followed by radical addition
to the phenyl group. After further oxidation and aromatization, the quinolino lactones or lactams
are afforded. At this stage, two different pathways cannot be fully ruled out.
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Scheme 4. Proposed Mechanism of Radical Cation Prompted Intramolecular Annulation
In conclusion, we have demonstrated an efficient synthesis of quinoline fused lactones and
lactams using a radical cation salt prompted sp3 C−H aerobic oxidation. The catalytic aerobic
oxidation of glycine esters and amides was screened for a broad range of substrates. This approach
provides one step access to these biologically and synthetically relevant core structures from
simple starting materials. The mild reaction conditions, good functional group tolerance and the
high efficiency will allow for further application in the synthesis of complicated natural products.
Experimental Section
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Typical Procedure for TBPA+. Induced Reaction of Nꢀaryl glycine cinnamyl esters
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A solution of 1 (0.5 mmol) in CH3CN (5 ml) was mixed fully and then flushed with O2 (keep
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o
flushing until the reaction completed), followed by addition of TBPA+. (20 mol %) under 60 C.
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After completion monitored by TLC (by UV visualization), the reaction was quenched by addition
of saturated Na2CO3 in MeOH (10 ml) solution. The mixture was poured into a separator funnel
with the addition of excess DCM (10 ml), and then the crude organic solution was extracted three
times with water to remove inorganic salts. The organic phase was then dried over anhydrous
magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The products
were separated by silica gel column chromatography eluted with petroleum ether/acetone (v/v
10:1) to afford the products.
7ꢀBromoꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2a)
Compound 2a was isolated in 92% yield (156 mg, colorless crystal); mp 168ꢀ171 °C; Rf value: 0.20
1
(vPE : vacetone = 8:1); H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H),
7.91 (dd, J = 9.1, 2.1 Hz, 1H), 7.73 – 7.58 (m, 3H), 7.50 – 7.41 (m, 2H), 5.40 (s, 2H); 13C NMR (101
MHz, CDCl3) δ 168.2, 149.2, 144.6, 143.1, 134.3, 133.1, 132.8, 129.9, 129.5, 128.9, 128.7, 127.9,
125.5, 124.2, 67.7; EIꢀMS m/z (relative intensity, %): 341 (99.3%), 339 (100%), 312 (12.6%), 310
(11.9%), 284 (64.7%), 282 (68.0%), 232 (11.3%), 216 (19.2%), 203 (39.3%), 176 (16.4%); IR (KBr,
neat, cmꢀ1) ν 3057, 2965, 2915, 2851, 1779, 1574, 1482, 1439, 1378, 1262, 1134, 1049, 1006;
HRMS (ESI): Calc’d for C17H10BrNO2 + H+, 339.9973; found, 339.9976.
7ꢀChloroꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2b)
Compound 2b was isolated in 97% yield (143 mg, colorless crystal); mp 154ꢀ158 °C; Rf value: 0.20
1
(vPE : vacetone = 8:1); H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H),
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7.77 (dd, J = 9.1, 2.3 Hz, 1H), 7.68 – 7.58 (m, 3H), 7.45 (dd, J = 7.8, 1.6 Hz, 2H), 5.40 (s, 2H); 13C
NMR (101 MHz, CDCl3) δ 168.1, 148.7, 144.3, 143.0, 135.6, 133.1, 132.7, 132.5, 131.5, 129.7, 129.4,
128.7, 128.3, 124.4, 67.7; EIꢀMS m/z (relative intensity, %): 297 (12.8%), 295 (45.8%), 268 (5.0%),
266 (12.9%), 240 (20.1%), 238 (52.1%), 203 (11.3%), 85 (64.6%), 71 (74.3%), 57 (100%); IR (KBr,
neat, cmꢀ1) ν 3051, 2920, 2848, 1774, 1676, 1486, 1447, 1368, 1342, 1270, 1132, 1054, 1008;
HRMS (ESI): Calc’d for C17H10ClNO2 + H+, 296.0478; found, 296.0488.
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7ꢀFluoroꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2c)
Compound 2c was isolated in 97% yield (100 mg, colorless crystal); mp 150ꢀ152 °C; Rf value: 0.20
(vPE : vacetone = 8:1); 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 9.2, 5.6 Hz, 1H), 7.76 – 7.56 (m, 4H),
7.56 – 7.39 (m, 3H), 5.41 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 168.3, 162.3 (d, J = 253.1 Hz), 147.7,
143.9 (d, J = 2.9 Hz), 143.3 (d, J = 6.4 Hz), 134.0 (d, J = 9.6 Hz), 133.0 (d, J = 9.4 Hz), 129.7, 129.5,
129.1, 129.0, 128.6, 121.4 (d, J = 26.5 Hz), 109.1 (d, J = 23.7 Hz), 67.6; EIꢀMS m/z (relative
intensity, %): 279 (79.7%), 250 (29.6%), 234 (12.2%), 222 (100%); IR (KBr, neat, cmꢀ1) ν 2919,
2854, 1769, 1705, 1634, 1578, 1507, 1458, 1225, 1126, 1048, 1013; HRMS (ESI): Calc’d for
C17H10FNO2 + H+, 280.0774; found, 280.0786.
9ꢀPhenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2d)
1
Compound 2d was isolated in 49% yield (64 mg, colorless oil); Rf value: 0.20 (vPE : vacetone = 8:1); H
NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.86 (ddd, J = 8.4, 6.8,
1.4 Hz, 1H), 7.70 – 7.56 (m, 4H), 7.46 (dd, J = 7.8, 1.6 Hz, 2H), 5.40 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 168.6, 150.6, 144.2, 143.9, 133.5, 132.2, 131.3, 130.6, 129.5, 129.3, 129.3, 128.8, 127.8,
125.7, 67.7; EIꢀMS m/z (relative intensity, %): 261 (100%), 241 (19.9%), 232 (24.5%), 216 (17.3%),
204 (91.7%), 121 (46.6%); IR (KBr, neat, cmꢀ1) ν 2953, 2926, 2847, 1775, 1578, 1458, 1112, 1056;
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HRMS (ESI): Calc’d for C17H11NO2 + H+, 262.0868; found, 262.0876.
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7ꢀMethylꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2e)
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Compound 2e was isolated in 91% yield (125 mg, colorless crystal); mp 142ꢀ143 °C; Rf value: 0.20
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(vPE : vacetone = 8:1); 1H NMR (400 MHz, CDCl3): δ 8.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.67 (d, J = 8.7
Hz, 1H), 7.65 – 7.54 (m, 4H), 7.49 – 7.41 (m, 2H), 5.35 (s, 2H), 2.51 (s, 3H); 13C NMR (100.6
MHz, CDCl3): δ 168.8, 149.3, 143.3, 142.9, 140.0, 133.7, 133.1, 132.5, 131.0, 129.4, 129.3, 128.8,
127.9, 124.3, 67.8, 22.1; IR (KBr, neat, cmꢀ1) ν 3051, 2920, 2848, 1781, 1578, 1505, 1447, 1375,
1132, 1048, 1021; HRMS (ESI): Calc’d for C18H13NO2 + H+, 276.1025; found, 276.1026.
7ꢀMethoxyꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2f)
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Compound 2f was isolated in 85% yield (124 mg, colorless oil); Rf value: 0.20 (vPE : vacetone = 8:1); H
NMR (400 MHz, CDCl3): δ 8.33 (d, J = 9.3 Hz, 1H), 7.68 – 7.54 (m, 3H), 7.54 – 7.42 (m, 3H), 7.10 (d,
J = 2.7 Hz, 1H), 5.35 (s, 2H), 3.81 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 169.0, 160.1, 147.0,
141.9, 141.7, 133.9, 133.1, 132.9, 129.5, 129.4 (two 13C), 128.6, 123.9, 102.9, 67.7, 55.6; IR (KBr,
neat, cmꢀ1) ν 3058, 2927, 2854, 1774, 1617, 1505, 1460, 1420, 1368, 1290, 1224, 1126, 1047, 1021
HRMS (ESI): Calc’d for C18H13NO3+ H+, 292.0974; found, 292.0980.
;
7ꢀHydroxyꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2g)
Compound 2g was isolated in 83% yield (115 mg, colorless crystal); mp 218.0−220.0 °C; Rf value:
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0.20 (vPE : vacetone = 3:1); H NMR (400 MHz, d6ꢀacetone) δ 8.17 (d, J = 9.2 Hz, 1H), 7.70 – 7.52 (m,
6H), 7.17 (d, J = 2.6 Hz, 1H), 5.43 (s, 1H); 13C NMR (101 MHz, d6ꢀacetone) 13C NMR (101 MHz,
CD3OD) δ 169.4, 159.2, 146.8, 142.5, 141.7, 135.0, 134.5, 133.5, 130.5, 123.0, 129.9, 129.8, 124.2,
107.0, 68.3; EIꢀMS m/z (relative intensity, %): 277 (100%), 248 (17.0%), 220 (88.6%); IR (KBr, neat,
cmꢀ1) ν 3445, 3051, 2914, 2848, 1761, 1610, 1518, 1460, 1387, 1244, 1126, 1047, 1014; HRMS (ESI):
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Calc’d for C17H11NO3 + H+, 278.0817; found, 278.0828.
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5ꢀMethylꢀ9ꢀphenylfuro[3,4ꢀb]quinolinꢀ3(1H)ꢀone (2h)
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Compound 2h was isolated in 20% yield (28 mg, colorless oil); Rf value: 0.20 (vPE : vacetone = 8:1); H
NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 6.7 Hz, 1H), 7.55 – 7.41 (m, 4H), 7.39
– 7.33 (m, 2H), 5.27 (s, 2H), 2.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 149.8, 143.8, 142.9,
139.5, 133.9, 132.1, 130.5, 129.3, 129.1, 129.0, 128.8, 127.8, 123.6, 67.61, 18.6; EIꢀMS m/z (relative
intensity, %): 275 (100%), 241 (49.0%), 229 (63.0%), 202 (24.3%), 166 (36.4%), 120 (87.6%); IR
(KBr, neat, cmꢀ1) ν 2967, 2911, 2855, 1769, 1486, 1260, 1076, 1013; HRMS (ESI): Calc’d for
C18H13NO2 + H+, 276.1025; found, 276.1030.
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2ꢀButylꢀ7ꢀmethoxyꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4a)
Compound 4a was isolated in 72% yield (125 mg, colorless crystal); mp 180−183 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.3 Hz, 1H), 7.66 – 7.52 (m, 3H), 7.48
(d, J = 6.8 Hz, 2H), 7.40 (dd, J = 9.3, 2.0 Hz, 1H), 7.01 (s, 1H), 4.32 (s, 2H), 3.76 (s, 3H), 3.68 (t, J =
7.5 Hz, 2H), 1.64 (dt, J = 15.2, 7.6 Hz, 2H), 1.44 – 1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 166.4, 158.8, 148.8, 145.6, 141.5, 134.7, 132.3, 129.1, 128.9, 128.8, 128.6, 122.2,
103.4, 55.4, 47.1, 42.8, 30.1, 20.0, 13.7; EIꢀMS m/z (relative intensity, %): 346 (100%), 294 (43.2%),
265 (25.5%), 250 (42.9%), 214 (13.3%); IR (KBr, neat, cmꢀ1) ν 3051, 2959, 2927, 2861, 1702, 1617,
1578, 1512, 1460, 1414, 1264, 1224, 1119, 1028; HRMS (ESI): Calc’d for C22H22N2O2 + H+,
347.1760; found, 347.1761.
2ꢀ(tertꢀButyl)ꢀ7ꢀmethoxyꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4b)
Compound 4b was isolated in 93% yield (161 mg, colorless crystal); mp 172ꢀ176 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.3 Hz, 1H), 7.57 – 7.43 (m, 3H), 7.40 –
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7.34 (m, 2H), 7.32 (dd, J = 9.3, 2.6 Hz, 1H), 6.93 (t, J = 6.7 Hz, 1H), 4.29 (s, 2H), 3.67 (s, 3H), 1.49 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 166.7, 158.7, 149.8, 145.7, 141.3, 134.7, 132.3, 129.1, 128.8,
128.8, 128.7, 128.4, 122.1, 103.3, 55.3, 55.0, 45.4, 27.8; EIꢀMS m/z (relative intensity, %): 346
(26.1%), 331 (22.8%), 290 (21.6%), 173 (88.5%), 171 (100%), 151 (51.1%),108 (62.8%); IR (KBr,
neat, cmꢀ1) ν 3051, 2979, 2920, 1695, 1584, 1493, 1447, 1395, 1264, 1224; HRMS (ESI): Calc’d
for C22H22N2O2 + H+, 347.1760; found, 347.1768.
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2ꢀIsopropylꢀ7ꢀmethoxyꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4c)
Compound 4c was isolated in 83% yield (138 mg, colorless crystal); mp 177ꢀ179 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.3 Hz, 1H), 7.66 – 7.53 (m, 3H), 7.47
(d, J = 6.8 Hz, 2H), 7.42 (dd, J = 9.3, 2.5 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 4.85 (m, 1H), 4.27 (s, 2H),
3.77 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 165.8, 158.8, 149.1, 145.6, 141.6,
134.7, 132.3, 129.1, 128.8, 128.8, 128.7, 128.6, 122.2, 103.3, 55.3, 43.0, 42.1, 20.4; EIꢀMS m/z
(relative intensity, %): 332 (100%), 317 (65.1%), 303 (16.8%), 290 (23.0%), 261 (13.8%), 246 (48.5%);
IR (KBr, neat, cmꢀ1) ν 3051, 2973, 2927, 1696, 1624, 1505, 1460, 1414, 1230, 1119, 1028;
HRMS (ESI): Calc’d for C21H20N2O2 + H+, 333.1603; found, 333.1611.
7ꢀMethoxyꢀ2,9ꢀdiphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4d)
Compound 4d was isolated in 70% yield (128 mg, colorless crystal); mp 232−233 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.3 Hz, 1H), 7.87 (dd, J = 8.7, 1.0 Hz,
2H), 7.69 – 7.55 (m, 3H), 7.51 (dd, J = 8.0, 1.4 Hz, 2H), 7.41 (ddd, J = 15.3, 9.0, 1.9 Hz, 3H), 7.20 –
7.11 (m, 1H), 7.03 (d, J = 2.7 Hz, 1H), 4.77 (s, 2H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.5,
159.2, 148.4, 146.1, 141.7, 139.3, 134.6, 132.5, 129.3, 129.2, 129.1, 129.1, 128.8, 128.1, 125.0, 122.7,
119.5, 103.4, 55.5, 48.1; EIꢀMS m/z (relative intensity, %): 366 (100%), 337 (24.8%), 293 (7.9%), 247
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(11.1%), 204 (9.7%), 71 (38.8%), 57 (53.8%); IR (KBr, neat, cmꢀ1) ν 3058, 2927, 2842, 1702, 1610,
1505, 1460, 1382, 1296, 1244, 1171, 1028; HRMS (ESI): Calc’d for C24H18N2O2 + H+, 367.1447;
found, 367.1460.
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7ꢀMethoxyꢀ9ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3ꢀone (4e)
Compound 4e was isolated in 94% yield (186 mg, colorless crystal); Rf value: 0.20 (vPE : vacetone = 4:1);
mp 227−230 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 7.7 Hz, 2H), 7.46
– 7.37 (m, 5H), 7.23 – 7.06 (m, 4H), 4.79 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.5, 160.1, 159.0, 148.3, 145.9, 141.6, 139.2, 132.3, 130.2, 129.4, 129.0, 128.2, 126.5,
124.9, 122.5, 119.3, 114.7, 103.4, 55.4 (two 13C), 48.1; EIꢀMS m/z (relative intensity, %): 396 (8.7%),
353 (20.7%), 266 (18.9%), 201 (26.3%), 158 (59.3%), 147 (100%), 121 (30.5%); IR (KBr, neat, cmꢀ1)
ν 3058, 2926, 2847, 1705, 1613, 1507, 1450, 1394, 1295, 1239, 1176, 1133, 1027; HRMS (ESI):
Calc’d for C25H20N2O3 + H+, 397.1552; found, 397.1561.
9ꢀ(4ꢀBromophenyl)ꢀ7ꢀmethoxyꢀ2ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3ꢀone (4f)
Compound 4f was isolated in 66% yield (147mg, colorless crystal); mp 225ꢀ229 °C; Rf value: 0.20
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(vPE : vacetone = 4:1); H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 2H),
7.79 (d, J = 6.9 Hz, 2H), 7.49 – 7.32 (m, 5H), 7.22 – 7.11 (m, 1H), 6.96 (s, 1H), 4.72 (s, 2H), 3.79 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 165.1, 159.3, 148.2, 145.9, 140.4, 139.1, 133.4, 132.6, 132.4,
130.6, 129.1, 128.8, 128.0, 125.0, 123.5, 122.8, 119.3, 103.0, 55.5, 47.9; EIꢀMS m/z (relative
intensity, %): 446 (26.5%), 444 (27.0%), 417 (6.2%), 415 (6.8%), 365 (2.0%), 289 (2.5%), 203 (3.5%),
183 (6.9%), 161 (2.7%), 149 (3.7%), 147 (3.3%), 77 (7.7%), 44 (100%); IR (KBr, neat, cmꢀ1) ν 3058,
2918, 2853, 2224, 1708, 1622, 1589, 1496, 1470, 1391, 1305, 1232, 1173, 1139, 1067, 1028;
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HRMS (ESI): Calc’d for C24H17BrN2O2 + H+, 445.0552; found, 445.0541.
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9ꢀ(4ꢀBromophenyl)ꢀ2ꢀ(2,4ꢀdimethylphenyl)ꢀ7ꢀmethoxyꢀ1,2ꢀdihydroꢀ3Hꢀpyrrolo[3,4ꢀb]quinoli
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nꢀ3ꢀone (4g)
Compound 4f was isolated in 70% yield (166mg, colorless crystal); mp 231ꢀ233 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 6.2 Hz, 2H),
7.48 (d, J = 8.0 Hz, 1H), 7.38ꢀ7.37 (m, 2H), 7.12 (s, 2H), 7.10 – 6.99 (m, 2H), 4.63 (s, 2H), 3.82 (s,
3H), 2.33 (s, 3H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.5, 159.4, 148.1, 145.9, 140.5, 138.4,
135.7, 134.1, 133.5, 132.7, 132.5, 132.0, 130.5, 129.3, 128.6, 127.5, 126.7, 123.4, 122.9, 103.1, 55.6,
50.5, 21.0, 18.2; EIꢀMS m/z (relative intensity, %): 474 (5.9%), 472 (6.3%), 268 (13.6%), 184 (3.7%),
169 (2.2%), 167 (2.0%), 139 (3.5%), 77 (4.6%), 71 (10.8%), 44 (100%); IR (KBr, neat, cmꢀ1) ν 2919,
2853, 1708, 1622, 1589, 1510, 1457, 1411, 1239, 1028; HRMS (ESI): Calc’d for C26H21BrN2O2 +
H+, 473.0865; found, 473.0874.
2ꢀBenzylꢀ7ꢀmethoxyꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4h)
Compound 4h was isolated in 70% yield (133 mg, colorless crystal); mp 212−214 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.3 Hz, 1H), 7.60 – 7.46 (m, 3H), 7.40
(m, 3H), 7.27 (m, 5H), 6.97 (s, 1H), 4.86 (s, 2H), 4.20 (s, 2H), 3.75 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 166.5, 158.9, 148.3, 145.6, 141.7, 136.4, 134.5, 132.3, 129.0, 128.9, 128.8, 128.8, 128.7,
128.2, 127.7, 122.3, 103.4, 55.4, 47.0, 46.7; EIꢀMS m/z (relative intensity, %): 380 (33.9%), 330
(29.4%), 315 (17.3%), 246 (17.7%), 161 (20.1%), 71 (70.5%), 57 (100%); IR (KBr, neat, cmꢀ1)
ν 3052, 2926, 1705, 1620, 1577, 1507, 1457, 1408, 1218, 1028; HRMS (ESI): Calc’d for
C25H20N2O2 + H+, 381.1603; found, 381.1609.
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2ꢀCinnamylꢀ7ꢀmethoxyꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4i)
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Compound 4i was isolated in 64% yield (130 mg, colorless crystal); mp 242−246 °C; Rf value: 0.20
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(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.3 Hz, 1H), 7.63 – 7.49 (m, 3H), 7.49
– 7.38 (m, 3H), 7.38 – 7.16 (m, 5H), 7.00 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.23 (dt, J =
15.6, 6.6 Hz, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.33 (s, 2H), 3.76 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
166.3, 158.9, 148.4, 145.6, 141.7, 136.0, 134.6, 133.8, 132.3, 129.1, 129.0, 128.9, 128.8, 128.7, 128.5,
127.9, 126.4, 123.6, 122.3, 103.4, 55.3, 46.8, 45.2; EIꢀMS m/z (relative intensity, %): 406 (100%), 345
(24.0%), 291 (60.2%), 247 (56.4%), 219 (13.6%), 204 (36.0%), 168 (38.4%); IR (KBr, neat, cmꢀ1)
ν 2960, 2919, 2847, 1698, 1613, 1500, 1408, 1288, 1218 1028; HRMS (ESI): Calc’d for
C27H22N2O2 + H+, 407.1760; found, 407.1771.
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7ꢀBromoꢀ2ꢀ(tertꢀbutyl)ꢀ9ꢀphenylꢀ1Hꢀpyrrolo[3,4ꢀb]quinolinꢀ3(2H)ꢀone (4j)
Compound 4j was isolated in 62% yield (122 mg, colorless crystal); mp 239−242 °C; Rf value: 0.20
(vPE : vacetone = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.0 Hz, 1H), 7.78 – 7.66 (m, 2H), 7.66
– 7.55 (m, 3H), 7.43 (d, J = 6.6 Hz, 2H), 4.43 (s, 2H), 1.59 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
166.2, 152.3, 148.0, 142.3, 133.7, 133.7, 132.4, 130.6, 129.2, 128.8, 128.7, 128.1, 124.3, 121.3, 55.3,
45.4, 27.7; EIꢀMS m/z (relative intensity, %): 396 (0.1%), 394 (0.1%), 326 (80.0%), 279 (9.0%), 234
(16.7%), 232 (16.4%), 167 (38.1%), 149 (100%); IR (KBr, neat, cmꢀ1) ν 3056, 2966, 2918, 2849,
1697, 1596, 1490, 1442, 1389, 1262, 1082, 1024; HRMS (ESI): Calc’d for C21H19BrN2O + H+,
395.0759; found, 395.0759.
7ꢀBromoꢀ5ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone (6a)
Compound 6a was isolated in 97% yield (172 mg, colorless crystal); mp 162ꢀ166 °C; Rf value: 0.20
(vPE : vacetone = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H),
7.70 (s, 1H), 7.65 – 7.53 (m, 3H), 7.36 – 7.25 (m, 2H), 4.55 (t, J = 5.8 Hz, 2H), 3.04 (t, J = 5.7 Hz, 2H);
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13C NMR (101 MHz, CDCl3) δ 162.8, 146.4, 146.0, 143.4, 134.1, 133.7, 132.8, 130.0, 129.6, 129.2,
129.1, 128.0, 124.1, 66.9, 26.6; EIꢀMS m/z (relative intensity, %): 355 (99.1%), 353 (100%), 297
(34.1%), 295 (35.2%), 230 (23.5%), 216 (48.2%); IR (KBr, neat, cmꢀ1) ν 3058, 2953, 2920, 1741,
1486, 1290, 1178; HRMS (ESI): Calc’d for C18H12BrNO2 + H+, 354.0130; found, 354.0140.
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7ꢀChloroꢀ5ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone (6b)
Compound 6b was isolated in 75% yield (116 mg, colorless crystal); mp 170ꢀ171 °C; Rf value: 0.20
(vPE : vacetone = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H),
7.57 – 7.46 (m, 3H), 7.44 (s, 1H), 7.23 (d, J = 7.5 Hz, 2H), 4.47 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.7 Hz,
2H); 13C NMR (101 MHz, CDCl3) δ 162.8, 146.1, 146.1, 143.2, 135.5, 134.1, 132.7, 131.0, 130.0,
129.2, 129.1, 129.1, 124.6, 66.8, 26.5; EIꢀMS m/z (relative intensity, %): 311 (33.0%), 309 (100%),
266 (4.0%), 264 (12.4%), 253 (25.2%), 251 (82.4%), 230 (25.4%), 216 (50.5%); IR (KBr, neat, cmꢀ1)
ν 3058, 2920, 2848, 1738, 1486, 1283, 1178, 1087, 1021; HRMS (ESI): Calc’d for C18H12ClNO2
+ H+, 310.0635; found, 310.0641.
7ꢀMethoxyꢀ5ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone (6c)
Compound 6c was isolated in 92% yield (140 mg, colorless oil); Rf value: 0.20 (vPE : vacetone = 5:1);
1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.3 Hz, 1H), 7.57 (dq, J = 14.1, 6.9 Hz, 3H), 7.41 (dd, J =
9.2, 2.2 Hz, 1H), 7.31 (d, J = 7.0 Hz, 2H), 6.75 (d, J = 2.0 Hz, 1H), 4.53 (t, J = 5.7 Hz, 2H), 3.74 (s,
3H), 3.00 (t, J = 5.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 163.4, 160.0, 144.9, 144.3, 140.5, 135.2,
132.9, 130.2, 129.5, 129.1, 129.0, 128.7, 123.0, 103.3, 66.9, 55.4, 26.6; EIꢀMS m/z (relative
intensity, %): 305 (100%), 247 (40.9%), 232 (34.9%), 204 (26.3%); IR (KBr, neat, cmꢀ1) ν 3051,
2920, 2848, 1741, 1617, 1493, 1460, 1414, 1296, 1224, 1172, 1087, 1028; HRMS (ESI): Calc’d
for C19H15NO3 + H+, 306.1130; found, 306.1141.
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7ꢀHydroxyꢀ5ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone (6d)
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Compound 6d was isolated in 83% yield (121 mg, colorless crystal); mp 210ꢀ212 °C; Rf value: 0.20
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(vPE : vacetone = 2:1); 1H NMR (400 MHz, d6ꢀacetone) δ 8.12 (d, J = 9.1 Hz, 1H), 7.70 – 7.54 (m, 3H),
7.48 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 7.7 Hz, 2H), 6.81 (s, 1H), 4.55 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 5.7
Hz, 2H); 13C NMR (101 MHz, d6ꢀacetone) δ 166.1, 161.6, 147.5, 146.8, 144.1, 139.1, 136.0, 133.8,
133.6, 132.9, 132.4, 132.0, 126.1, 110.0, 70.2, 30.0; EIꢀMS m/z (relative intensity, %): 291 (92.7%),
246 (14.3%), 233 (100%), 204 (16.3%); IR (KBr, neat, cmꢀ1) ν 3451, 3058, 2920, 2848, 1729, 1617,
1467, 1244, 1184, 1021; HRMS (ESI): Calc’d for C18H13NO3 + H+, 292.0974; found, 292.0978.
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9ꢀMethoxyꢀ5ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀpyrano[3,4ꢀb]quinolinꢀ1ꢀone (6e)
Compound 6e was isolated in 49% yield (75 mg, colorless oil); Rf value: 0.20 (vPE : vacetone = 5:1); 1H
NMR (400 MHz, CDCl3) δ 7.62 – 7.44 (m, 3H), 7.35 – 7.18 (m, 3H), 7.10 – 7.06 (m, 2H), 4.52 (t, J =
5.8 Hz, 1H), 4.11 (s, 1H), 3.01 (t, J = 5.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 162.7, 156.5, 146.5,
141.7, 140.3, 135.2, 129. 8, 129.7, 129.2, 128.9, 128.7, 117.4, 107.6, 66.8, 56.1, 26.7; EIꢀMS m/z
(relative intensity, %): 304 (100%), 276 (18.8%), 258 (52.0%), 230 (33.3%); IR (KBr, neat, cmꢀ1)
ν 3182, 2914, 2848, 1735, 1624, 1512, 1211, 1159, 1021; HRMS (ESI): Calc’d for C19H15NO3 +
H+, 306.1130; found, 306.1144.
Acknowledgments
We thank Natural Science Foundation of China (NSFC, No. 21002079 and 21362030) for
supporting our research.
1
Supporting Information. Copies of all H NMR and 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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