Synthesis of quinolinones with palladium-catalyzed oxidative annulation between acrylamides and arynes

Article abstract of DOI:10.1021/jo5027673

An unprecedented palladium-catalyzed oxidative annulation of acrylamides with benzyne precursors has been successfully developed. By using this mild "N-H activation/Heck reaction" method, a wide variety of quinolinones were conveniently prepared in one st

Full text of DOI:10.1021/jo5027673

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Note
Synthesis of Quinolinones with Palladium-Catalyzed
Oxidative Annulation between Acrylamides and Arynes
Weiguo Wang, Xianglong Peng, Xiaoyu Qin, Xiangyun Zhao, Chen Ma, Chen-Ho Tung, and Zhenghu Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5027673 • Publication Date (Web): 16 Feb 2015
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Synthesis of Quinolinones with PalladiumꢀCatalyzed
Oxidative Annulation between Acrylamides and Arynes
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†,§
†,
†
†
†
§
Weiguo Wang , Xianglong Peng , Xiaoyu, Qin , Xiangyun Zhao , Chen Ma,* Chen-
Ho Tung and Zhenghu Xu*†‡
†Key Lab of Colloid and Interface Chemistry of Ministry of Education,
School of Chemistry and Chemical Engineering, Shandong University, No.
27 South Shanda Road, Jinan, Shandong 250100, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR
China
xuzh@sdu.edu.cn, chenma@sdu.edu.cn
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Abstract: An unprecedented palladiumꢀcatalyzed oxidative annulation of acrylamides with
benzyne precursors has been successfully developed. By using this mild “NꢀH
activation/Heck reaction” method, a wide variety of quinolinones were conveniently prepared
in one step with high efficiency.
2ꢀQuinolinones represent an important class of heterocycles prevalent in a number of
natural alkaloids, biologically active compounds as well as pharmaceuticals.1 They have
been reported with various important bioactivities, such as antiviral, antibiotic, anticancer,
and antihypertensive activities (Scheme 1).2 For example, 3,4ꢀdiarylquinolinone
containing a pyridine moiety is a promising lead compound as potent and selective
p38αMAP kinase inhibitors (IC50 = 1.8 ꢁm).2c Importantly, quinolinones are also useful
building blocks in organic synthesis and this skeleton has also been utilized to design
fluorescent probes.3
The development of new synthetic methods toward this heterocycle has remained a
longꢀlasting interest in the past decade.4 Recently, various transitionꢀmetalꢀcatalyzed
crossꢀcoupling/cyclization cascade reactions have been developed.5 For example, in 2003,
the Larock group reported an elegant palladiumꢀcatalyzed threeꢀcomponent cyclization of
2ꢀiodoanilines, internal alkynes and CO.5b Most of these methods start from a
preactivated arylhalides, which need to be prepared in advance. Transitionꢀmetalꢀ
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catalyzed oxidative annulation from easily available starting materials with direct CꢀH
functionalization represents an attractive synthetic strategy for the synthesis of
quinolinone structure. However, this activation pathway is still very limited in the
literature.6
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Scheme 1. Natural products and bioactive pharmaceuticals containing quinolinones
Directing group assisted CꢀH functionalization reactions have been attracting
increasing attentions from the synthetic community in recent years. Electronꢀrich alkenes
such as enamides have been widely exploited in direct CꢀH functionalization reactions.7,8
In contrast, the electronꢀdeficient alkenes are more elusive because the rateꢀlimiting
electrophilic metallation step favors the electronꢀrich substrates. To date, only very
limited examples have been reported (Scheme 2).9 Loh and Glorius have reported the
direct trifluoromethylation and alkynylation of acrylamides with hypervalent iodonium
reagents in the presence of copper(I) or rhodium(III)ꢀcatalyst (eq 1, 2). Li and Rovis
demonstrated a rhodium(III)ꢀcatalyzed CꢀH/NꢀH activation of acrylamides, leading to the
pyridines skeletons in one step. Ackermann et al developed similar oxidative annulation
reactions between acrylamides and internal alkynes with ruthenium catalyst (eq 3).
Arynes10 are strained alkynes, and the oxidative annulation of acrylamides with arynes
would generate quinolinone structure in one step (eq 4). However the high reactivity of
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aryne intermediates ready to many side reactions, and also the difficulties in CꢀH
activation of electronꢀdeficient acrylamides, make this transformation very challenging.
We wish to report our recent efforts on the efficient synthesis of quinolinone derivatives
via a palladiumꢀcatalyzed oxidative annulation of electronꢀdeficient acrylamides with
benzyne precursors.11,12
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Scheme 2. C-H activation of electron-deficient alkenes
Trifluoromethylation via C-H Activation (1)
O
O
O
R1
R2
Ts
R1
R2
Ts
CuCl
N
N
O
Loh
H
H
I
CF3
H
CF3
Alkynylation via C-H Activation (2)
O
O
TIPS
Rh(III)
O
O
R1
R2
R
R1
R2
R
I
N
N
H
Loh, Glorius
H
H
TIPS
Oxidative Annulation with alkynes to Pyridones via C-H/N-H Activation (3)
O
O
R1
R2
R
R1
R2
R
Rh(III)
N
Rovis, Li
N
H
R3
R4
Ackermann
R3
or Ru(II)
H
R4
Oxidative Annulation with Arynes to Quinolinones via C-H/N-H Activation (4)
O
O
R1
R2
OMe
R1
R2
OMe TfO
TMS
Pd(II)
CsF
N
N
H
R3
(this work)
H
R3
To achieve the challenging transformation, we optimized the reaction conditions
employing acrylamide 1a and benzyne precursor 2a as model substrates (Table 1). After
a detailed study of different reactions parameters, the oxidative annulation of 1a with 2a
Table 1. Optimization of Reaction Conditions
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Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (0.4 mmol), CsF
(0.48 mmol), TBAB (0.2 mmol), 4Å molecular sieve (100 mg), solvent (1 mL), 24 h. TBAB = tetraꢀnꢀ
butylammoniumꢀbromide, TBAF = tetraꢀnꢀbutylammoniumꢀfluoride.
gave quinolinone 3a in 82% yield under the standard conditions: Pd(OAc)2 (5 mol%),
o
Cu(OAc)2 (2 equiv), and CsF (2.4 equiv) in dioxane and DMSO mixed solvent at 80 C
for 24 h (entry 1). The structure of 3a was unambiguously characterized by single crystal
Xꢀray analysis. The choice of palladium catalyst was crucial for the reaction. Replacing
Pd(OAc)2 with the mostly used Rh(III) or Ru(II) catalysts, no desired product was
observed and the starting 1a remained intact (entries 2, 3). Using other palladium catalyst
such as Pd(PPh3)4 could generate the product in a little lower 65% isolated yield (entry 4).
As to oxidants, K2S2O8 gave very low yield (entry 5) and AgOAc gave only 36% yield
(entry 6). Other solvents also resulted in decreased yield (entries 7, 8). TBAB is a very
important additive and its removal greatly decreased the yield (entries 9, 10). Adding
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extra triphenylphosphine ligand did not help the reaction (entry 11). Replacing of CsF by
TBAF lowered the yield (entry 12). TBAF is more soluble in organic solvents and thus
could generate benzyne intermediate instantly. These results indicate that the rate of
benzyne generation should synchronize with that of the rateꢀlimiting CꢀH activation. No
product was formed without palladium catalyst (entry 13).
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Table 2. Palladium-catalyzed annulation of various acrylamides with aryne
precursors for the synthesis of quinolinones.a
O
Pd(OAc) (5 mol%)
2
O
1
2
R
OMe
OTf
1
N
Cu(OAc) (2 equiv)
2
R
R
OMe
3
N
H
R
CsF (2.4 equiv)
TBAB (1 equiv)
R
TMS
2
H
3
3
1
2
R
DMSO / Dioxane = 1 /
9
o
80 C, 24h
Acrylamides scope:
MeO
OMe
F C
3
Me
O
O
O
O
Ph
OMe
OMe
OMe
N
N
N
N
3d, 72%
3c, 72%
3b, 81%
3a, 82%
Me
O
O
O
OMe
OMe
OMe
N
N
N
Me
3g, 70%
3e, 76%
3f, 81%
O
O
O
O
OMe
OMe
Bn
OMe
Me
OMe
N
N
N
N
3h, 55%
3j, 74%
3k, 55%
3i, 43%
b
O
N
O
Arynes scope
:
Ph
OMe
Ph
OMe
OTf
TMS
N
O
Me
OTf
O
Me
TMS
Me
O
2m
2l
3l (61%)
3m (40%)
O
Me
O
O
O
Ph
OMe
Ph
OMe Ph
OMe
N
OTf
TMS
F
F
OTf
TMS
N
N
Me
F
2o
Me
2n
3n (35%)
F
3o/3o' = 1:1 ( 42%)
Me
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (0.4 mmol), CsF
(0.48 mmol), TBAB (0.2 mmol), solvent (1 mL), 4Å molecular sieve (100 mg), 24 h, isolated yields.
bPd(OAc)2 (10 mol%), the solution of 2 in 1.5 mL solvent was added slowly with syringe pump in 15
h.
With the optimized conditions, the oxidative annulation of benzyne with a range of
acrylamides was tested (Table 2). Benzyne reacted with a variety of acrylamides bearing
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aromatic or alkyl substituents, leading to the formation of quinolinone 3 in good yields
(3aꢀ3k). Different aromatic substituents bearing electronꢀdonating group or electronꢀ
withdrawing group at the αꢀposition of the acrylamides does not affect the reaction, and
everyone afforded 3ꢀaryl quinolinones in very good yields (3aꢀ3g). Acrylamides with
alkyl group at the αꢀposition proceeded in moderate yields (3h, 3i). Cyclic substrates
could also react efficiently to furnish desired fused quinolinones in moderate to good
yields (3j, 3k). However, trying to extend this reaction to the more challenging cinnamide
and crotonyl amide was not successful.
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The reaction scope with regard of different arynes were also examined (Table 2). We
need to inject the aryne precursors solution slowly into the reaction system to obtain good
yields of the corresponding annulation products. For substituted arynes, bearing both
electronꢀdonating group and electronꢀwithdrawing group could all react with acrylamide
1a, generating the corresponding quinolinones in low to moderate yields of 35–61% (3lꢀ3n).
For unsymmetric aryne 2o, a 1/1 regioisomers mixture was obtained, which very
importantly, indicated the formation of aryne intermediate in the reaction.
The methoxy group on the nitrogen atom serves as a very important protecting
group.13 Notably, it could be easily removed by NaH to give free quinolinone 4 in 93%
yield.14 This product was further transformed into important 2ꢀcholoroquinoline 5 in 92%
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yield in the presence of POCl3 (eq 5).6c The oxidative annulation of Nꢀmethyl acrylamide
6 with 2a gave quinolinone 7 in 25% yield under the standard conditions (eq. 6).15 On the
other hand, very tiny product (<5%) was observed in the standard reaction of dimethyl
butꢀ2ꢀynedioate with 2a. No reaction occurred between diphenylacetylene and 2a,
showing the importance of strain releasing.
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Since this reaction occurs with CꢀH functionalization, an intermolecular KIE
experiment was conducted. A KIE value of 1.7 was observed (eq 6). This value is much
lower than that of other CꢀH functionalization reactions, indicating that maybe the CꢀH
cleavage is not involved in the rateꢀdeterming step.9,11,12
Scheme 3. Possible reaction pathways
On the basis of these experiments and literature precedents, two possible reaction
pathways were proposed in Scheme 3. Sequential NꢀH and CꢀH activation of acrylamide
1a to form the fiveꢀmembered palladacycle M2. Subsequent benzyne insertion and
reductive elimination would generate the product 3a and Pd(0), which was reoxidized to
Pd(II) by Cu(OAc)2 (Path A). On the other hand, the aminopalladation of intermediate M1
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to benzyne would form the palladium intermediate M4, which went through a Heck type
reaction: insertion to the electronꢀdeficient double bond and subsequent βꢀhydrogen
elimination would also produce the target product (pathway B). Even though pathway A
cannot be excluded, pathway B is more likely because of the following aspects: 1)
Electrophilic palladation of the electronꢀdeficient alkene is difficult to form the proposed
palladacycle M2. No similar metal complex was reported so far to our knowledge.
Actually, all our efforts trying to synthesize this palladacycle were not successful and
only palladium black was observed either under acid or basic condition. 2) In a recent
related work from Jeganmohan group the Nꢀarylated product was observed under many
conditions.11a These results indicated the fromation of M4 is very possible. The
intramolecular CꢀH activation to form a seven membered palladium intermediate from
M4 is not easy, but another 6ꢀendoꢀtrig addition/subsequent βꢀhydrogen elimination
sequence forms the final product 3a. Similar 6ꢀendoꢀtrig, but not 5ꢀexoꢀtrig pathway was
also observed in an early intramolecular Heck reaction from Dankwardt.16 For the cyclic
substrates, the direct synꢀinsertion and synꢀβꢀhydrogen elmination could not form the
target products 3j and 3k. The subsequent double bond migration is needed.16a
In summary, we have developed the first palladiumꢀcatalyzed strain releasing oxidative
annulation between acrylamides and arynes. Application of this protocol led to the
concise and flexible synthesis of quinolinones, which cannot easily be accessed by other
methods. This approach reprents a new direction for the transitionꢀmetal chemistry of
benzynes.
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Experimental Section:
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General Details. All NMR spectras were recorded on 400 MHz spectrometer. Highꢀ
resolution mass spectrometry (HRMS) were measured in positiveꢀion mode on a QꢀTOF
instrument with an ESI ion source. Routine monitoring of the reaction was performed by
TLC using precoated silica gel plates. All the reagents and solvents were used directly.
Acrylamides and deuterated substrates were prepared according to reported
procedures.9d,17
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Typical Procedure for the Synthesis of Substituted Quinolinone (3). A mixture of
Pd(OAc)2 (2.24 mg, 0.01 mmol, 5 mmol%) , Cu(OAc)2 (72.7 mg, 0.4 mmol), 1a (35.4
mg, 0.2 mmol) , CsF (73.0 mg, 0.48 mmol) ,TBAB (64.4 mg, 0.2 mmol) and 4Å molecular
sieve (100 mg) were dissolved in a mixed solvent of dioxane (0.9 mL) and DMSO (0.1
mL), 2a (119.2 mg, 2 equiv) was added to the reaction system. The resulting mixture was
stirred at 80℃ until the reaction was completed (monitored by TLC). The reaction
mixture was filtered and evaporated under reduced pressure and purified by column
chromatography (silica gel) with petroleum ether/ethyl acetate (10:1) to give the pure
product 3a (41.2 mg, 82%).
3-Phenyl-1H-quinolin-2-one (4). NaH (0.6 mmol, 60%) was added into a stirred
solution of 1ꢀmethoxyꢀ3ꢀphenylꢀ1Hꢀquinolinꢀ2ꢀone 3a (0.2 mmol) in DMF (1 mL) and
the resulting mixture was heated at 120 ℃for 0.5ꢀ1.0 h. After the reaction was completed,
the reaction mixture was allowed to cool down to room temperature, and washed with
H2O (16 mL), extracted with CH2Cl2 (10 mL x 3). The combined organic layer was dried
over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude
product was purified by column chromatography (silica gel) with petroleum ether/ethyl
1
acetate (2:1) to give the White solid 4 (41.1 mg, 93%)14: mp 227ꢀ228 ℃. H NMR (400
MHz, D6ꢀDMSO) δ 7.14ꢀ7.18 (m, 1H), 7.30ꢀ7.42 (m, 4H), 7.45ꢀ7.49 (m, 1H), 7.69ꢀ7.74
(m, 3H), 8.07(s, 1H), 11.92(s, 1H).
2-Chloro-3-phenyl-quinoline (5). Phosphorous oxychloride (POCl3) (0.24 mmol) was
added into a solution of 3ꢀphenylꢀ1Hꢀquinolinꢀ2ꢀone (4) (0.2 mmol) in CH3CN (3.0 mL).
The reaction mixture was heated to reflux at 90 °C for 10 h. After the reaction mixture
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was cooled to room temperature, ice water was poured and extracted with ethyl acetate.
The organic layer was separated, dried with Na2SO4, and concentrated under the reduced
pressure. The residue was purified on column chromatography (silica gel) with petroleum
1
ether/ethyl acetate (10:1) to give the yellow solid 5 (44.4 mg, 92%)6c: mp 54ꢀ55 ℃. H
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NMR (400 MHz, CDCl3) δ 7.45ꢀ7.54 (m, 6H), 7.56ꢀ7.60 (m, 1H), 7.73ꢀ7.77 (m, 1H),
7.82ꢀ7.84 (m, 1H), 8.06ꢀ8.10 (m, 1H).
1-Methyl-3-phenyl-1H-quinolin-2-one (7). A mixture of Pd(OAc)2 (2.24 mg, 0.01 mmol,
5 mmol%) , Cu(OAc)2 (72.7 mg, 0.4 mmol), Nꢀmethyl acrylamide (32.2 mg, 0.2 mmol) ,
CsF (73.0 mg, 0.48 mmol) ,TBAB (64.4 mg, 0.2 mmol) and 4Å molecular sieve (100 mg)
were dissolved in a mixed solvent of dioxane (0.9 mL) and DMSO (0.1 mL), 2a (119.2
mg, 2 equiv) was added to the reaction system. The resulting mixture was stirred at 80℃
until the reaction was completed (monitored by TLC). The reaction mixture was filtered
and evaporated under reduced pressure and purified by column chromatography (silica
gel) with petroleum ether/ethyl acetate (8:1) to give the liquid product 6 (11.8 mg, 25%).
1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 7.37ꢀ7.50 (m, 5H), 7.57ꢀ7.62 (m, 2H)，7.70ꢀ
7.72 (m, 2H ), 7.80 (s, 1H).
Intermolecular isotope effect of the palladium-catalyzed oxidative annulation
between 1a and [d]-1a with 2a. A mixture of Pd(OAc)2 (3.36 mg, 0.015 mmol, 5
mmol %), 1a (53.1 mg, 0.30 mmol), [D2]ꢀ1a (53.7 mg, 0.30 mmol), Cu(OAc)2 (108.9 mg,
0.6 mmol), CsF (54 mg, 0.36 mmol) and TBAB (96.7 mg, 0.3 mmol) were dissolved in a
mixed solvent of dioxane (0.9 mL) and DMSO (0.1 mL). 2a (89.4 mg, 0.30 mmol) was
added to the reaction system. The resulting mixture was stirred at 80⁰C for 1h. The
reaction mixture was filtered, evaporated under reduced pressure and purified by column
chromatography (silica gel) to give 3a/[d1]-3a (23.3 mg, 31% yield) as a white solid
1-Methoxy-3-phenyl-1H-quinolin-2-one (3a). White solid (41.2 mg, 82%)：mp 126ꢀ
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128 ℃. H NMR (400 MHz, CDCl3) δ 4.14 (s, 3H), 7.26ꢀ7.30 (m, 1H), 7.38ꢀ7.47 (m,
3H)，7.61ꢀ7.66 (m, 3H ), 7.74ꢀ7.76 (m, 2H), 7.81(s, 1H); 13C NMR (100 MHz, CDCl3) δ
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62.7, 111.6, 119.7, 122.9, 128.3, 128.4, 128.5, 128.9, 130.8, 133.5, 135.7, 135.8, 137.4,
157.3; IR (neat): v (cmꢀ1) 3038, 2933, 2862, 1721, 1650, 1596, 1263, 1172, 1061, 1036,
991, 848, 729, 674, 543; HRMS (ESI, m/z) calcd for C16H13NO2 (M+H): 252.1019,
found 252.1022. The CCDC number for the cystal of 3a is 1037415.
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1-Methoxy-3-(4-trifluoromethyl-phenyl)-1H-quinolin-2-one (3b). Yellow liquid (51.7
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mg, 81%). H NMR (400 MHz, CDCl3) δ 4.15 (s, 3H), 7.29ꢀ7.33 (m, 1H), 7.64ꢀ7.71 (m,
5H), 7.85ꢀ7.89 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 62.8, 111.8, 119.4, 123.2, 125.2
(q, JCꢀF = 3.7 Hz, C ), 128.7, 129.2, 130.1, 130.4, 131.4, 131.9, 136.6, 137.7, 139.4 (d, JCꢀ
F = 1.4 Hz, C), 156.9; IR (neat): v (cmꢀ1) 3041, 2933, 2857, 1725, 1660, 1587, 1268, 1150,
1055, 991, 852, 766, 703, 568, 548; HRMS (ESI, m/z) calcd for C17H12F3NO2 (M+H):
320.0893, found 320.0892.
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1-Methoxy-3-p-tolyl-1H-quinolin-2-one (3c). Yellow liquid (38.2 mg, 72%). H NMR
(400 MHz, CDCl3) δ 2.38 (s, 3H), 4.12 (s, 3H),7.23ꢀ7.27 (m, 3H), 7.57ꢀ7.65 (m, 5H),
7.77 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 62.7, 111.5, 119.7, 122.9, 128.3, 128.7,
129.0, 130.5, 132.9, 133.3, 135.2, 137.2, 138.3, 157.3; IR(neat): v (cmꢀ1) 3027, 2933,
2855, 1719, 1645, 1594, 1259, 1180, 1055, 960, 882, 819, 745, 657, 573, 515; HRMS
(ESI, m/z) calcd for C17H15NO2 (M+H): 266.1176, found 266.1177.
1-Methoxy-3-(4-methoxy-phenyl)-1H-quinolin-2-one (3d). Yellow liquid (38.6 mg,
72%). 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 4.13 (s, 3H), 6.96ꢀ6.98 (m, 2H), 7.24ꢀ
7.28 (m, 1H), 7.57ꢀ7.63 (m, 3H), 7.71ꢀ7.75 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 55.4,
62.7, 111.6, 113.8, 119.8, 122.9, 128.3, 130.1, 130.3, 130.4, 132.9, 134.7, 137.1, 157.4,
159.8; IR(neat): v (cmꢀ1) 3068, 2927, 2860, 1717, 1667, 1582, 1257, 1162, 1073, 1052,
981, 862, 743, 652, 510; HRMS (ESI, m/z) calcd for C17H15NO3 (M+H): 282.1125,
found 282.1112.
3-(4-tert-Butyl-phenyl)-1-methoxy-1H-quinolin-2-one (3e). Yellow liquid (46.7 mg,
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76%). HNMR (400 MHz, CDCl3) δ 1.34 (s, 9H), 4.12 (s, 3H), 7.24ꢀ7.25 (m, 1H), 7.45ꢀ
13
7.47 (m, 2H), 7.58ꢀ7.63 (m, 3H) 7.68ꢀ7.70 (m, 2H), 7.79 (s, 1H); C NMR (100 MHz,
CDCl3) δ 31.3, 34.6, 62.6, 111.5, 119.7, 122.8, 125.2, 128.3, 128.5, 130.5, 132.9, 133.3,
135.2, 137.3, 151.4, 157.3; IR(neat): v (cmꢀ1) 3466, 2959, 1708, 1651, 1604, 1274, 1206,
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1112, 1065, 960, 871, 839, 745, 647, 526; HRMS (ESI, m/z) calcd for C20H21NO2 (M+H):
308.1651, found 308.1649.
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81%). H NMR (400 MHz, CDCl3) δ 2.36 (s, 6H), 4.12 (s, 3H), 7.02 (s, 1H), 7.23ꢀ7.27
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(m, 1H), 7.35 (s, 2H), 7.58ꢀ7.62 (m, 3H), 7.76 (s, 1H); C NMR (100 MHz, CDCl3) δ
21.3, 62.7, 111.5, 119.7, 122.3, 122.8, 126.6, 128.3, 130.1, 130.6, 135.5, 135.7, 137.3,
137.7, 157.4; IR(neat): v (cmꢀ1) 3052, 2946, 2855, 1717, 1658, 1653, 1260, 1168, 1067,
1022, 972, 854, 736, 663, 526; HRMS (ESI, m/z) calcd for C18H17NO2 (M+H): 280.1338,
found 280.1338.
1-Methoxy-3-naphthalen-2-yl-1H-quinolin-2-one (3g). Yellow liquid (42.1 mg, 70%).
1H NMR (400 MHz, CDCl3) δ 4.15 (s, 3H), 7.24ꢀ7.29 (m, 1H), 7.47ꢀ7.49 (m, 2H), 7.60ꢀ
7.66 (m, 3H), 7.83ꢀ7.91 (m, 5H), 8.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 62.8, 111.6,
119.7, 123.0, 126.1, 126.4, 126.5, 127.5, 127.7, 128.2, 128.4, 128.5, 130.8, 133.1, 133.2,
133.2, 133.3, 136.1, 137.4, 157.4; IR(neat): v (cmꢀ1) 3052, 2922, 1724, 1645, 1595, 1268,
1189, 1118, 1063, 963, 892, 812, 737, 636, 511; HRMS (ESI, m/z) calcd for C20H15NO2
(M+H): 302.1176, found 302.1175
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1-Methoxy-3-methyl-1H-quinolin-2-one (3h). Yellow liquid (20.1 mg, 55%). H NMR
(400 MHz, CDCl3) δ 2.27 (s, 3H), 4.08 (s, 3H), 7.19ꢀ7.24 (m, 1H), 7.50ꢀ7.57 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 17.3, 62.7, 111.5, 119.7, 122.7, 127.5, 129.8, 131.3, 134.9,
136.9, 158.5; IR(neat): v (cmꢀ1) 3043, 2942, 2851, 1712, 1643, 1582, 1264, 1153, 1071,
991, 957, 840, 726, 691, 536; HRMS (ESI, m/z) calcd for C11H11NO2 (M+H): 190.0863,
found 190.0870.
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3-Benzyl-1-methoxy-1H-quinolin-2-one (3i). Yellow liquid (22.8 mg, 43%). H NMR
(400 MHz, CDCl3) δ 4.00 (s, 2H), 4.11 (s, 3H), 7.17ꢀ7.21 (m, 2H), 7.25ꢀ7.33 (m, 5H),
7.44ꢀ7.46 (m, 1H), 7.53ꢀ7.58 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 36.5, 62.8, 111.5,
119.6, 122.7, 126.5, 127.9, 128.6, 129.5, 130.1, 134.8, 134.8, 136.9, 138.7, 157.9;
IR(neat): v (cmꢀ1) 3052, 2927, 2871, 1715, 1662, 1593, 1257, 1168, 1082, 982, 953, 854,
734, 680, 527; HRMS (ESI, m/z) calcd for C17H15NO2 (M+H): 266.1176, found
266.1167.
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1-Methoxy-7,8,9,10-tetrahydro-5H-phenanthridin-6-one (3j). Yellow liquid (33.9 mg,
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74%). H NMR (400 MHz, CDCl3) δ 1.79ꢀ1.89 (m, 4H), 2.69 (t, J = 6.0 Hz, 2H), 2.85 (t,
J = 6.4 Hz, 2H), 4.08 (s, 3H), 7.23ꢀ7.27 (m, 1H), 7.51ꢀ7.55 (m, 1H), 7.59 (d, J = 8.3 Hz,
1H), 7.69 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 21.9, 24.3, 25.5, 62.7,
111.6, 120.4, 122.4, 123.5, 129.5, 129.8, 135.9, 141.4, 157.7; IR(neat): v (cmꢀ1) 3067,
2958, 2844, 1718, 1663, 1581, 1251, 1183, 1062, 1027, 982, 857, 745, 692, 558; HRMS
(ESI, m/z) calcd for C14H15NO2 (M+H): 230.1176, found 230.1184.
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1,2,3,5-tetrahydro-cyclopenta[c]quinolin-4-one (3k). Yellow liquid (23.6 mg, 55%). 1H
NMR (400 MHz, CDCl3) δ 2.60ꢀ2.71 (m, 2H), 3.44 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 7.6
Hz, 2H), 4.52 (s, 3H), 7.67ꢀ7.95 (m, 1H), 7.95ꢀ8.05(m, 3H); 13C NMR (100 MHz, CDCl3)
δ 22.8, 31.0, 32.0, 62.9, 112.1, 118.3, 122.5, 125.2, 129.9, 134.0, 137.4, 149.6, 156.6;
IR(neat): v (cmꢀ1) 3063, 2938, 2849, 1724, 1651, 1588, 1243, 1180, 1059, 1023, 976, 851,
735, 678, 547; HRMS (ESI, m/z) calcd for C13H13NO2 (M+H): 216.1019, found
216.1017.
1-Methoxy-6,7-dimethyl-3-phenyl-1H-quinolin-2-one (3l). Yellow liquid (34.1 mg,
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61%). H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.42 (s, 3H), 4.11 (s, 3H), 7.33ꢀ7.44
(m, 5H), 7.71ꢀ7.74 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 19.2, 20.7, 62.6, 112.1, 117.9,
128.1, 128.2, 128.5, 128.8, 131.8, 132.1, 135.4, 135.7, 136.2, 140.9, 157.2; IR(neat): v
(cmꢀ1) 3048, 2936, 2861, 1718, 1647, 1572, 1268, 1182, 1091, 973, 962, 861, 747, 663,
521; HRMS (ESI, m/z) calcd for C18H17NO2 (M+H): 280.1338, found 280.1339.
1-Methoxy-7-phenyl-5H-[1,3]dioxolo[4,5-g]quinolin-6-one (3m). Yellow liquid (23.6
mg, 40%). 1H NMR (400 MHz, CDCl3) δ 4.10 (s, 3H), 6.05 (s, 2H), 6.97 (s, 1H), 7.08 (s,
1H), 7.34ꢀ7.35 (m, 1H), 7.39ꢀ7.43 (m, 2H), 7.64 (s, 1H), 7.70ꢀ7.72 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 62.7, 92.7, 102.0, 105.9, 114.0, 128.0, 128.2, 128.7, 130.5, 134.7,
135.4, 136.0, 144.3, 151.3, 157.0; IR(neat): v (cmꢀ1) 3063, 2917, 2870, 1714, 1645, 1588,
1247, 1185, 1065, 996, 871, 829, 735, 657, 510; HRMS (ESI, m/z) calcd for C17H13NO4
(M+H): 296.0923, found 296.0914.
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6,7-Difluoro-1-methoxy-3-phenyl-1H-quinolin-2-one (3n). Yellow liquid (20.1 mg,
35%). 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 3H), 7.38ꢀ7.45 (m, 5H), 7.68ꢀ7.70 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 62.9, 100.9 (d, JCꢀF = 46.6 Hz, C), 115.6 (d, JCꢀF = 4.2 Hz,
C), 115.7, 115.8 (d, JCꢀF = 4.4 Hz, C), 128.4, 128.7, 128.8, 134.0, 134.3, 134.3, 135.2,
147.8, 156.9; IR(neat): v (cmꢀ1) 3047, 2922, 2849, 1729, 1656, 1578, 1274, 1143, 1059,
996, 845, 824, 745, 694, 526; HRMS (ESI, m/z) calcd for C16H11F2NO2 (M+H):
288.0836, found 288.0831.
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1-Methoxy-6-methyl-3-phenyl-1H-quinolin-2-one
and
1-Methoxy-7-methyl-3-
phenyl-1H-quinolin-2-one (3o/3o' = 1/1). Yellow liquid (22.3 mg, 42%). 1H NMR (400
MHz, CDCl3) δ 2.43 (s, 3H), 2.52 (s, 3H), 4.11 (s,3H), 4.12 (s, 3H), 7.07ꢀ7.09 (m, 1H),
7.35ꢀ7.45 (m, 9H), 7.50ꢀ7.52 (m, 2H), 7.72ꢀ7.75 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
20.8, 22.4, 62.7, 111.5, 111.5, 117.5, 119.7, 124.4, 128.1, 128.2, 128.2, 128.2, 128.3,
128.3, 128.8, 128.9, 132.1, 132.5, 133.3, 135.4, 135.6, 135.7, 136.0, 136.0, 137.4, 141.7,
157.1, 157.4; IR(neat): v (cmꢀ1) 3042, 2925, 2853, 1714, 1653, 1597, 1258, 1142, 1058,
958, 841, 808, 725, 686, 514; HRMS (ESI, m/z) calcd for C17H15NO2 (M+H): 266.1181,
found 266.1171.
Supporting Information
1
Full experiment detail, H and 13C NMR spectra and HRMS data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: xuzh@sdu.edu.cn.
*Eꢀmail: chenma@sdu.edu.cn.
Author Contributions
§These authors contributed equally to this work.
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Acknowledgements.
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We are grateful for financial support from the Natural Science Foundation of China
(Grant No.21102085, 21172131), the fundamental research and subject construction
funds of Shandong University (No. 2014JC008, 104.205.2.5)
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