Copper-Catalyzed Cyclization for Access to 6H-Chromeno[4,3-b

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES

Article

Copper-Catalyzed Cyclization for Access to 6H-Chromeno[4,3b]quinolin-6-ones Employing DMF as Carbon Source Yiyi Weng, Hao Zhou, Chen Sun, Yuanyuan Xie, and Weike Su J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01515 • Publication Date (Web): 08 Aug 2017 Downloaded from http://pubs.acs.org on August 9, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Copper-Catalyzed Cyclization for Access to 6H-Chromeno[4,3-b]quinolin-6-ones Employing DMF as Carbon Source Yiyi Weng, Hao Zhou, Chen Sun, Yuanyuan Xie* and Weike Su* Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China E-mail: [email protected], [email protected]

ABSTRACT: The first example of the copper-catalyzed cyclization of 4-(phenylamino)-2H-chromen-2-ones employing N-methyl moiety of DMF as the source of methine (CH) group has been developed, providing an efficient synthetic pathway to access novel functionalized 6H-chromeno[4,3-b]quinolin-6-ones in moderate to good yields.

INTRODUCTION: The quinoline scaffold is prevalent in a variety of bioactive and natural compounds.1,2 The quinolines possess useful pharmacological and biological activities including antimicrobial,3 antimalaria,4 antidepressant,5 6

and anticancer activities. Chromeno-quinoline derivatives with a 2H-chromen-2-one ring and a 2H-chromene ring fused to quinoline ring exhibit remarkable properties, such as anticancer activities

7,8

and fluorescent pH

sensors and estrogen receptor β-selective ligands functions.9,10 The reported routes for preparation of 6H-chromeno[4,3-b]quinolin-6-ones usually empolyed Vilsmeier reagent or formyl group of benzaldehydes as the main source to generate the methine (CH) group in quinoline ring. In 1987, Tabakovic and co-workers11 reported the traditional strategies for preparation of 6H-chromeno[4,3-b]quinolin-6-ones from 4-arylaminocoumarins using Vilsmeier reagent (POCl3/DMF) as the formylation reagents. However, the toxicity and the environmental impact of POCl3 limited the application of this

process.

Then,

Wu

and

co-workers12

developed

a

1

ACS Paragon Plus Environment

method

for

preparation

of


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

6H-chromeno[4,3-b]quinolin-6-ones

employing

Page 2 of 18

4-chloro-2-oxo-2H-chromene-3-carbaldehyde 13

isocyanides as substrates, but this method suffered from narrow substrate scope. In 2014, Yao

and

aryl

developed a

protocol of Fe/AcOH mediated one pot synthesis of 6H-chromeno[4,3-b]quinolin-6-ones, which required excessive Fe/AcOH (5 equiv.) as reductive reagents. Recently, Sashidhara group reported that molecular iodine could be successfully used to catalyze an one-pot tandem annulation of 4-hydroxycoumarin, aromatic 7

aldehydes and aromatic amines under MW irradiation, affording 6H-chromeno[4,3-b]quinolin-6-ones. Hence, it is highly desirable to develop novel, efficient, and environment-friendly methylation reagents for the construction of 6H-chromeno[4,3-b]quinolin-6-ones with a cheap and robust catalytic system. As one of the most inexpensive and abundant industrial raw material and solvent, N,N-dimethylformamide (DMF) is considered to be a multipurpose, versatile synthon in organic transformations, such as the formylation,14 amination,15 cyanation16 and methylation17 reactions in terms of cost-efficiency and step economy. To the best of our knowledge, employing N-methyl moiety of DMF as a source of one carbon synthon has not been reported until 2014. In 2014, Xue and Xiao18 fristly reported Rh-catalyzed direct methylation of ketones. Then Lei19 developed Cu-catalyzed direct oxidative C(sp3)-H methylenation of 20

2

arylketones in the same year. In 2015, Das presented Pd/Ag catalyzed carbonylation of C(sp )-H bonds using atmospheric O2 (Scheme 1a). However, employing the methyl group of DMF as the source of methine group (CH) in cyclization reaction has not been reported until elegant works reported by Zhao21a and Liu21b (Scheme 1b)。These two methods disclosed novel synthesis of symmetrical 2,3,5,6-tetrasubstituted pyridines using DMF as methine group source, respectively. However, construction of unsymmetrical heterocyclic compounds cannot be accomplished by these two strategies. Herein, we wish to report a simple and highly efficient protocol for construction of 6H-chromeno[4,3-b]quinolin-6-one employing DMF as methine group source via aerobic copper-catalyzed cyclization of 4-arylaminocoumarins (Scheme 1c). To our knowledge, the application of DMF as methine group source in transition-metal-catalyzed cyclization for the synthesis of quinoline skeleton has not been demonstrated thus far.

2


Page 3 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. Employing N-methyl group of DMF as carbon source

RESULT AND DISCUSSION To validate our hypothesis, we initiated our studies with 4-((4-bromophenyl)amino)-2H-chromen-2-one (1a) as the model substrate. Positive result was obtained using Cu(OAc)2H2O as catalyst, TBPB as oxidant, and KOAc as base in DMF, providing the desired 9-bromo-6H-chromeno[4,3-b]quinolin-6-one (2a) in 16% yield. None of O2, Na2S2O8, and TBHP as oxidants afforded better yields of 2a (Table 1, entries 2-4). We envisioned changing addition sequence might increase the reaction yield considering the potential complexation of copper catalysts with the arylamines. To our delight, the yield of 2a was increased from 16% to 28% as expected (entry 5, for details, see the typical procedure for the preparation of 2a). A significant

3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 18

improvement was achieved by adding NaHSO3 to the reaction mixture and the yield was dramatically increased up to 80 % (entry 6). Notably, the reaction could also proceed smoothly by using CuCl as the catalyst instead of Cu(OAc)2H2O, albeit with decreased yield (72%, entry 8). Either decreasing the loading of TBPB or Cu(OAc)2H2O afforded the lower yields (entries 9-11). There was no desired product detected in the absence of Cu(OAc)2H2O, which approved it was essential for this transformation. Conducting the reaction in absense of KOAc also made the yield decline (60%, entries 12). Table 1. Optimization of Reaction Conditionsa,b

entry

Catalyst

Oxidant

Additive

Yield (%)

1

Cu(OAc)2H2O

TBPB

-

16

2

Cu(OAc)2H2O

O2

-

0

3

Cu(OAc)2H2O

TBHP

-

trace

4

Cu(OAc)2H2O

Na2S2O8

-

16

c

Cu(OAc)2H2O

TBPB

-

28

6

c

Cu(OAc)2H2O

TBPB

NaHSO3

80

7c,d

Cu(OAc)2H2O

TBPB

NaHSO3

78

c

CuCl

TBPB

NaHSO3

72

Cu(OAc)2H2O

TBPB

NaHSO3

48

-

TBPB

NaHSO3

0

c,f

Cu(OAc)2H2O

TBPB

NaHSO3

58

c,g

Cu(OAc)2H2O

TBPB

NaHSO3

60

5

8

c,e

9

10c 11 12

b

a

Conditions: 0.2 mmol of 1a in the presence of [Cu] (15 mol %), oxidant (3.0 equiv), KOAc (1.0 equiv), and o

b

NaHSO3 (1.2 equiv) in 3.5mL DMF under 150 C conditions for 24 h, O2 ballon. Isolated yield based on 1a. c

1a, catalyst, oxidant, base, and additive with novel addition sequence (For details, see the typical procedure d

e

f

g

for the preparation of 2a). NaHSO3 (2.0 equiv). Cu(OAc)2H2O (10 mol %). TBPB (2.0 equiv). without KOAc. TBHP = tert-butyl hydroperoxide. TBPB = tert-butyl perbenzoate.

4


Page 5 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


With the optimal conditions identified, the scope and generality of the reaction were investigated, and the results are summarized in Table 2. Both substrates with electron-donating (2c-2f, 2j, 2k, 2l) and electron-withdrawing (2h and 2i) groups on the aniline ring proceeded smoothly and afforded the desired products in moderate to good yields. It was note of that the substitution position of aryl moieties had little effect on this reaction. Ortho- and para-substituted aniline ring afforded 2c and 2d in similar yields. Moreover, a slight decrease in yield was observed by switching Br to Cl (2g) or F (2h). Pleasingly, naphthyl and tetrahydronaphthalene moieties were also tolerated, leading to the corresponding products (2m and 2n) in 63% and 56% yields, respectively. Next, the screening of substitution effect on the coumarin moiety of 4-(phenylamino)-2H-chromen-2-ones was conducted. It was observed that in all cases tested, the corresponding products (2o, 2p, 2q) were isolated in 70%-75% yields. Finally, substrates with substituents on both the aniline ring and chromen-2-one ring underwent reactions smoothly to yield the targeted products in moderate yields (2r, 2s, and 2t). Table 2. Cu-Catalyzed Cyclization of 4-(phenylamino)-2H-chromen-2-ones with DMF

5


a


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

a

Conditions: 1 (0.2 mmol), Cu(OAc)2H2O (15 mol %), TBPB (3.0 equiv), NaHSO3 (1.2 equiv), KOAc (1.0 o

equiv), DMF (3.5 mL), 150 C, 24 h, O2 ballon with novel addition sequence. Isolated yields based on 1.

a

Table 3. Control Experiments and the Reaction Mechanism Studies

a

conditions: 1a (0.2 mmol), Cu(OAc)2H2O (15 mol %), TBPB (3.0 equiv), NaHSO3 (1.2 equiv), KOAc (1.0 o

equiv.), analogues of DMF (3.5 mL), 150 C, 24 h, O2 ballon with novel addition sequence (SI). Isolated yields based on 1b. In order to gain insight into the mechanism of the reaction, we designed a set of parallel experiments to confirm whether the carbon source is from N-methyl or formyl moiety of DMF. To clarify this, different amides were employed to test this notable transformation (Table 3). As expected, N,N-dimethylacetamide and N,N-dimethylaniline gave rise to the desired product with relatively low yields (53% and 46%), while no conversion was observed using N,N-diethylformamide. All these factors indicated that the CH group of the cyclization product should be from the methyl group on DMF. Based on the above experiments and previous literatures,22 a possible mechanism for the synthesis of 6H-chromeno[4,3-b]quinolin-6-ones from 1 is proposed (Scheme 2). Initially, the nucleophilic addition of 1 to the iminium intermediate A which is presumably generated from DMF in the presence of Cu(OAc)2H2O/TBPB proceeds through a radical pathway. Secondly, reaction of substrate 1 and intermediated A afford intermediate B. After releasing of one molecule of MeNHCHO, the resulting intermediate D is attacked by NaHSO3, followed by an intramolecular cyclization to generate a dihydropyridine intermediate F (Scheme 2, path a).

21a

On the other hand, intermediate D

experiencing the sequential 6π electro-cyclization could also convert into F (Scheme 2, path b).21b Finally, aromatization of F under oxidative conditions affords the desired product 2. Obviously, nucleophilic substitution by the NaHSO3 then intramolecular cyclization step (path a) could occur prior to 6π electro-cyclization step (path b) in this reaction (see Table 1, entries 5 and 6).

6


Page 6 of 18

Page 7 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 2. Plausible Reaction Mechanism

CONCLUSION In summary, an efficient approach for the synthesis of 6H-chromeno[4,3-b]quinolin-6-ones by Cu-catalyzed oxidative cyclization has been developed using DMF as methine group source, giving corresponding derivatives in moderate to good yields (56-81%). The mechanism investigation imply that the carbon added is from the methyl group of DMF. With the cheap metal catalyst, economic reagent DMF, easy availability of the substrates, and excellent functional group tolerability, we envision this protocol could complete the current methods employing DMF as a source of one carbon synthon. This protocol is also recognized as a cheap and green route for synthesis of chromeno-quinoline derivatives.

EXPERIMENTAL SECTION General information: All commercial materials were used as received unless otherwise noted. Commercially available chemicals were obtained from Energy Chemical, TCI, Alfa Aesar, J&K. 1H NMR spectra

7



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 18

were recorded at 400 MHz, 500 MHz, and 600 MHz using TMS as internal standard,

13

C NMR spectra were

recorded at 100 MHz, 125 MHz, and 150 MHz using TMS as internal standard. The multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), multiplet (m), triplet (t) and broad resonances (br). Mass spectroscopy data of the products were collected on an HRMS-TOF instrument. General

Procedure

for

the

Preparation

of

Starting

Materials

1.

A

mixture

of

4-hydroxy-2H-chromen-2-ones (1 mmol), anilines (3 mmol, 3 equiv) (without solvent) in a 10mL flask was heated at 180oC for 2-4 hours. After being cooled to room temperature, the reaction mixture was washed with methanol (5 mL) at 60oC for 0.5 hour, then filtered to give the pure products 1. 4-((4-Bromophenyl)amino)-2H-chromen-2-one (1a): Yellow solid, yield: 239mg, 76%, m.p. 299.6-300.2 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.22 (dd, J = 8.0, 1.0 Hz, 1H), 7.68-7.64 (m, 3H), 7.44-7.34 (m,

4H), 5.38 (s, 1H).

13

C NMR (150 MHz, DMSO-d6) δ 161.8, 153.8, 152.4, 138.2, 132.9, 132.8, 127.3, 124.1, +

123.3, 118.3, 117.5, 114.9, 85.6. MS (ESI): m/z = 316.4 [M + H] . HRMS-ESI: calcd for C15H10BrNNaO2 [M+ Na]+: 337.9787; Found: 337.9794. 4-(Phenylamino)-2H-chromen-2-one (1b): Yellow solid, yield: 216 mg, 91%, m.p. 267.5-268.3 oC (lit.11 1

267-268 °C). H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.65-7.63 (m, 1H), 7.50-7.46 (m, 2H), 7.41-7.36 (m, 4H), 7.29 (t, J = 7.6 Hz, 1H), 5.30 (s, 1H).

13

C NMR (100 MHz, DMSO-d6) δ

161.1, 153.1, 152.1, 137.9, 132.0, 129.2, 125.7, 124.8, 123.3, 122.6, 116.8, 114.3, 84.2. MS (ESI): m/z = 238.4 [M + H]+. HRMS-ESI: calcd for C15H11NNaO2 [M+ Na]+: 260.0682; Found: 260.0688. 4-(p-Tolylamino)-2H-chromen-2-one (1c): Yellow solid, yield: 206mg, 82%, m.p. 273.4-274.0 °C (lit.

11

279-280 °C). 1H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.41-7.37 (m, 2H), 7.31-7.26 (m, 4H), 5.23 (s, 1H), 2.35 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.2, 136.0, 135.9, 132.8, 130.5, 125.7, 124.0, 123.2, 117.5, 115.0, 84.4, 21.1. MS (ESI): m/z = 252.3 [M + +

+

H] . HRMS-ESI: calcd for C16H13NNaO2 [M+ Na] : 274.0838; Found: 274.0848. 4-((4-Ethylphenyl)amino)-2H-chromen-2-one (1d): Yellow solid, yield: 188mg, 71%, m.p. 235.1-235.5 oC. 1

H NMR (600 MHz, DMSO-d6) 9.28 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.68-7.65 (m, 1H), 7.42-7.37 (m, 2H), 13

7.34-7.28 (m, 4H), 5.25 (s, 1H), 2.67 (q, J = 7.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.1, 142.2, 136.2, 132.8, 129.3, 125.7, 124.0, 123.2, 117.5, 115.0, 84.5, 28.2, 16.0. MS (ESI): m/z = 266.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO2 [M+ Na]+: 288.0995; Found: 288.0997. 4-((4-Methoxyphenyl)amino)-2H-chromen-2-one

(1e):

Yellow

solid,

yield:

179mg,

67%,

m.p.

240.0-240.3 °C (lit.11 245-246 °C). 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.25-8.23 (m, 1H), 7.68-7.64

8


Page 9 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(m, 1H), 7.41-7.37 (m, 2H), 7.31-7.29 (m, 2H), 7.10-7.05 (m, 2H), 5.11 (s, 1H), 3.81 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.6, 157.6, 153.4, 153.3, 132.4, 130.6, 127.2, 123.6, 122.7, 117.1, 114.8, 114.5, 83.6, 55.4. MS +

+

(ESI): m/z = 268.2 [M + H] . HRMS-ESI: calcd for C16H13NNaO3 [M+ Na] : 290.0788; Found: 290.0791. 4-((4-Ethoxyphenyl)amino)-2H-chromen-2-one (1f): Yellow solid, yield: 208mg, 74%, m.p. 230.1-230.5 °C 11

(lit.

1

218-220 °C). H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.23-8.22 (m, 1H), 7.66-7.63 (m, 1H),

7.40-7.35 (m, 2H), 7.28-7.25 (m, 2H), 7.04-7.01 (m, 2H), 5.09 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.5, 156.8, 153.4, 153.2, 132.3, 130.5, 127.2, 123.6, 122.7, 117.0, 115.2, 114.5, 83.5, 63.3, 14.7. MS (ESI): m/z = 282.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO3 [M+ Na]+: 304.0944; Found: 304.0941. 4-((4-Chlorophenyl)amino)-2H-chromen-2-one (1g): Yellow solid, yield: 222mg, 82%, m.p. 301.2-302.2 °C (lit.11 306 °C). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 13

7.53 (d, J = 8.8 Hz, 2H), 7.41-7.36 (m, 4H), 5.34 (s, 1H). C NMR (100 MHz, DMSO-d6) δ 160.7, 152.9, 151.7, +

137.0, 131.8, 129.4, 128.9, 126.0, 123.1, 122.3, 116.5, 114.1, 85.0. MS (ESI): m/z = 272.3 [M + H] . HRMS-ESI: calcd for C15H10ClNNaO2 [M+ Na]+: 294.0292; Found: 294.0301. 4-((4-Fluorophenyl)amino)-2H-chromen-2-one (1h): Yellow solid, yield: 168mg, 66%, m.p. 275.3-276.3 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.23-8.22 (m, 1H), 7.68-7.65 (m, 1H), 7.44-7.37 (m, 4H),

7.35-7.31 (m, 2H), 5.20 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 161.9, 160.4 (JC-F = 243.2 Hz), 153.8, 153.3, 134.9 (JC-F = 2.7 Hz), 132.9, 128.0 (JC-F = 8.6 Hz), 124.1, 123.2, 117.5, 116.8 (JC-F = 22.6 Hz), 114.9, 84.7. MS +

+

(ESI): m/z = 256.2 [M + H] . HRMS-ESI: calcd for C15H10FNNaO2 [M+ Na] : 278.0588; Found: 278.0595. Ethyl

4-((2-oxo-2H-chromen-4-yl)amino)benzoate

(1i):

White

solid,

yield:

226mg,

73%,

m.p.

238.8-239.2°C. 1H NMR (600 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.25-8.24 (m, 1H), 8.05 (d, J = 6.0 Hz, 2H), 7.70-7.67 (m, 1H), 7.55 (d, J = 12.0 Hz, 2H), 7.44-7.41 (m, 2H), 5.68 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 6.0 Hz, 3H).

13

C NMR (150 MHz, DMSO-d6) δ 165.7, 161.8, 153.9, 151.6, 143.8, 133.0, 131.1, 126.3, 124.2,

123.5, 123.5, 117.5, 115.1, 87.5, 61.1, 14.7. MS (ESI): m/z = 310.2 [M + H]+. HRMS-ESI: calcd for +

C18H15NNaO4 [M+ Na] : 332.0893; Found: 332.0896. o

4-(o-Tolylamino)-2H-chromen-2-one (1j): Yellow solid, yield: 211mg, 84%, m.p. 221.8-222.5 C (lit.

11

214-216 °C). 1H NMR (600 MHz, DMSO-d6) 9.25 (s, 1H), 8.28-8.26 (m, 1H), 7.69-7.66 (m, 1H), 7.43-7.29 (m, 2H), 4.61 (s, 1H), 2.21 (s, 3H).

13

C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.7, 136.7, 135.8, 132.8, +

131.7, 128.5, 128.2, 127.7, 124.1, 123.2, 117.6, 114.7, 84.0, 17.7. MS (ESI): m/z = 252.2 [M + H] . HRMS-ESI: calcd for C16H13NNaO2 [M+ Na]+: 274.0838; Found: 274.0833.

9



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

4-((2-Methoxyphenyl)amino)-2H-chromen-2-one 11

(1k):

Yellow

Page 10 of 18

solid,

yield:

163mg,

61%,

m.p.

1

224.4-225.1 °C (lit. 223-225°C). H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.25(d, J = 7.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.39-7.29 (m, 4H), 7.21 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.71 (s, 1H), 3.79 (s, 3H). 13

C NMR (100 MHz, DMSO-d6) δ 161.2, 154.3, 153.0, 152.9, 132.0, 128.5, 128.2, 125.6, 123.4, 122.6, 120.8, +

+

116.8, 114.3, 112.5, 83.9, 55.6. MS (ESI): m/z = 268.2 [M + H] . HRMS-ESI: calcd for C16H13NNaO3 [M+ Na] : 290.0788; Found: 290.0797. 4-((2,4-Dimethylphenyl)amino)-2H-chromen-2-one (1l): Yellow solid, yield: 196mg, 74%, m.p. 246.3-247.8 o

C. 1H NMR (600 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.27-8.26 (m, 1H), 7.68-7.65 (m, 1H), 7.42-7.37 (m, 2H), 7.23

(s, 1H), 7.17-7.14 (m, 2H), 4.60 (s, 1H), 2.34 (s, 3H), 2.16 (s, 3H).

13

C NMR (150 MHz, DMSO-d6) δ 161.9,

153.9, 153.9, 137.5, 135.5, 134.0, 132.8, 132.2, 128.3, 128.2, 124.1, 123.2, 117.5, 114.8, 83.8, 21.1, 17.6. MS (ESI): m/z = 266.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO2 [M+ Na]+: 288.0995; Found: 288.0990. 4-(Naphthalen-1-ylamino)-2H-chromen-2-one (1m): Yellow solid, yield: 181mg, 63%, m.p. 259.1-260.0 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.45-8.43 (m, 1H), 8.08 (d, J = 10.0 Hz, 1H), 8.04 (s, J = 10.0 Hz,

1H), 7.88 (d, J = 10.0 Hz, 1H), 7.73-7.69 (m, 1H), 7.68-7.65 (m, 1H), 7.63-7.56 (m, 3H), 7.49-7.46 (m, 1H), 7.43-7.41 (m, 1H), 4.57 (s, 1H).

13

C NMR (125 MHz, DMSO-d6) δ 161.8, 154.7, 153.9, 134.7, 134.4, 132.9,

129.9, 129.0, 128.4, 127.4, 127.2, 126.6, 126.0, 124.2, 123.4, 123.3, 117.6, 114.8, 85.1. MS (ESI): m/z = 288.2 [M + H]+. HRMS-ESI: calcd for C19H13NNaO2 [M+ Na]+: 310.0838; Found: 310.0849. 4-((5,6,7,8-Tetrahydronaphthalen-1-yl)amino)-2H-chromen-2-one (1n): Yellow solid, yield: 236mg, 81%, 1

m.p. 211.8-212.3 °C. H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.27-8.25 (m, 1H), 7.67-7.64 (m, 1H), 7.42-7.37 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.63 (s, 1H), 2.79 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 5.5 Hz, 2H), 1.71-1.70 (m, 4H).

13

C NMR (125 MHz, DMSO-d6) δ 161.4, 153.4,

153.3, 138.8, 135.9, 134.4, 132.3, 128.6, 126.3, 125.3, 123.6, 122.6, 117.1, 114.3, 83.2, 29.0, 24.0, 22.3, 22.2. +

+

MS (ESI): m/z = 292.3 [M + H] . HRMS-ESI: calcd for C19H17NNaO2 [M+ Na] : 314.1151; Found: 314.1160. 6-Methyl-4-(phenylamino)-2H-chromen-2-one (1o): Yellow solid, yield: 198mg, 79%, m.p.306.2-307.8 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.08 (s, 1H), 7.51-7.47 (m, 3H), 7.39 (d, J = 7.5 Hz, 2H),

7.31-7.27 (m, 2H), 5.31 (s, 1H), 2.42 (s, 3H).

13

C NMR (125 MHz, DMSO-d6) δ 161.7, 152.4, 151.5, 138.3,

133.1, 132.9, 129.5, 125.9, 124.9, 122.5, 116.8, 114.2, 84.4, 20.5. MS (ESI): m/z = 252.3 [M + H]+. HRMS-ESI: +

calcd for C16H13NNaO2 [M+ Na] : 274.0838; Found: 274.0847. 6-Methoxy-4-(phenylamino)-2H-chromen-2-one

(1p):

Yellow

solid,

yield:

190mg,

71%,

m.p.

265.2-266.9 °C (lit.23 269-270 °C). 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H),

10


Page 11 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.52-7.49 (m, 2H), 7.39-7.37 (m, 2H), 7.33-7.30 (m, 2H), 7.27-7.24 (m, 1H), 5.30 (s, 1H), 3.87 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.7, 155.3, 152.4, 147.7, 138.2, 129.6, 126.1, 125.2, 119.9, 118.2, 114.8, 105.6, +

+

84.6, 56.0. MS (ESI): m/z = 268.2 [M + H] . HRMS-ESI: calcd for C16H13NNaO3 [M+ Na] : 290.0788; Found: 290.0799. 6-Chloro-4-(phenylamino)-2H-chromen-2-one (1q): Yellow solid, yield: 217mg, 80%, m.p. 300.1-300.7 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.72(dd, J = 9.0, 2.5 Hz, 1H), 7.52-7.49

(m, 2H), 7.44 (d, J = 9.0 Hz, 1H), 7.39-7.37 (m, 2H), 7.32-7.29 (m, 1H), 5.36 (s, 1H).

13

C NMR (125 MHz,

DMSO-d6) δ 161.0, 152.1, 151.5, 138.0, 132.1, 129.6, 127.9, 126.1, 124.9, 122.5, 119.1, 116.0, 84.9. MS (ESI): +

+

m/z = 272.2 [M + H] . HRMS-ESI: calcd for C15H11NClO2 [M + H] : 272.0473; Found: 272.0485. 6-Methyl-4-(p-tolylamino)-2H-chromen-2-one (1r): Yellow solid, yield: 186mg, 70%, m.p. 285.9-287.5 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.07 (s, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.30-7.24 (m, 5H),

5.22 (s, 1H), 2.42 (s, 3H), 2.35 (s, 3H).

13

C NMR (125 MHz, DMSO-d6) δ 161.7, 152.6, 151.5, 135.6, 135.3, +

133.1, 132.8, 130.0, 125.1, 122.5, 116.8, 114.1, 84.0, 20.6, 20.5. MS (ESI): m/z = 266.3 [M + H] . HRMS-ESI: calcd for C17H15NNaO2 [M + Na]+ : 288.0995; Found: 288.0995. 4-((4-Chlorophenyl)amino)-6-methyl-2H-chromen-2-one (1s): Yellow solid, yield: 211mg, 74%, m.p. 1

280.7-281.4 °C. H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.04 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 9.6 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 5.36 (s, 1H), 2.42 (s, 3H).

13

C NMR (150 MHz,

DMSO-d6) δ 162.0, 152.4, 151.9, 137.9, 133.6, 133.3, 130.0, 129.9, 126.8, 123.0, 117.3, 114.6, 85.6, 21.0. MS +

+

(ESI): m/z = 286.3 [M + H] . HRMS-ESI: calcd for C16H12ClNNaO2 [M + Na] : 308.0449; Found: 308.0454. 6-Chloro-4-(p-tolylamino)-2H-chromen-2-one (1t): Yellow solid, yield: 200mg, 70%, m.p. 300.7-301.1 °C. 1

H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.70 (dd, J = 9.0, 2.5 Hz, 1H), 7.41 (d, J 13

= 8.5 Hz, 1H), 7.31-7.24 (m, 4H), 5.27 (s, 1H), 2.35 (s, 3H). C NMR (125 MHz, DMSO-d6) δ 161.0, 152.1, 151.7, 135.5, 135.3, 132.0, 130.1, 127.9, 125.0, 122.4, 119.0, 116.0, 84.5, 20.6. MS (ESI): m/z = 286.3 [M + H]+. HRMS-ESI: calcd for C16H12ClNNaO2 [M + Na]+ : 308.0449; Found: 308.0454. Typical procedure for the Preparation of 9-bromo-6H-chromeno[4,3-b]quinolin-6-one (2a): A mixture of Cu(OAc)2H2O (15 mol %, 0.03 mmol, 7mg), TBPB (3 equiv, 0.6 mmol, 116 mg), KOAc (1 equiv, 0.2 mmol, 20 mg) and DMF (3.5 mL) in a 10 mL flask was heated at 150 oC under oxygen atmosphere for 12 hours. Then 4-((4-bromophenyl)amino)-2H-chromen-2-one 1a (0.2 mmol, 63 mg) and NaHSO3 (1.2 equiv, 0.24 mmol, 25 o

mg) was added to the flask and heated at 150 C under oxygen atmosphere for 24 h. The reaction mixture was cooled to room temperature, and then the solvent was removed under vacuum. The crude product was purified

11



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 18

by column chromatography on silica gel (pure CH2Cl2) to yield 2a (52 mg, 80%) as yellow solid. Isolated yield: o

1

52mg, 80%, m.p. 230.0-231.0 C. H NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.97-7.95 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.45-7.38 (m, 2H).

13

C NMR

(125 MHz, CDCl3) δ 160.9, 152.7, 149.9, 149.5, 140.0, 136.8, 132.7, 131.1, 131.1, 128.2, 125.3, 125.1, 121.5, +

+

119.3, 117.5, 116.4. MS (ESI): m/z = 326.1 [M + H] . HRMS-ESI: calcd for C16H8BrNNaO2 [M + Na] : 347.9631; Found: 347.9616. 6H-Chromeno[4,3-b]quinolin-6-one (2b): Yellow solid. Isolated yield: 36mg, 73%, m.p. 221.9-223.1 oC (lit.11 227-228 °C). 1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H), 8.79 (dd, J = 8.0, 1.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.94-7.91 (m, 1H), 7.66-7.63 (m, 1H), 7.61-7.58 (m, 1H), 7.45-7.42 (m, 1H), 7.40 (dd, J = 8.5, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 161.4, 152.7, 151.1, 149.6, 141.1, 133.4, 132.4, 129.6, 129.5, 127.4,127.4, 125.3, 125.0, 119.6, 118.4, 115.8. MS (ESI): m/z = 248.3 [M + H]+. [M + H]+. HRMS-ESI: +

calcd for C16H9NNaO2 [M + Na] : 270.0525; Found: 270.0524. 9-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2c): Yellow solid. Isolated yield: 42mg, 81%, m.p. 234.3-235.1 oC (lit.11 201-203 °C). 1H NMR (500 MHz, CDCl3) δ 9.15 (s, 1H), 8.84 (dd, J = 8.0, 1.5 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.78-7.76 (m, 2H), 7.62-7.59 (m, 1H), 7.47-7.43 (m, 1H), 7.42 (dd, J = 8.0, 1.0 Hz, 1H), 13

2.61 (s, 3H). C NMR (125 MHz, CDCl3) δ 161.4, 152.6, 149.6, 148.8, 140.4, 137.8, 136.1, 132.3, 129.0, 128.0, 127.4, 125.3, 125.0, 119.6, 117.4, 115.8, 21.7. MS (ESI): m/z = 262.4 [M + H]+. HRMS-ESI: calcd for C17H12NO2 +

[M + H] : 262.0863; Found: 262.0850. 9-Ethyl-6H-chromeno[4,3-b]quinolin-6-one (2d): Yellow solid. Isolated yield: 41mg, 75%, m.p. 152.8-154.5 o

C. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.71 (dd, J = 8.0, 1.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.75-7.70

(m, 2H), 7.56-7.52 (m, 1H), 7.40-7.36 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 2.89 (q, J = 3.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ 160.6, 151.9, 149.2, 148.2, 143.2, 139.8, 134.4, 131.6, 128.8, 127.0, +

126.1, 124.7, 124.4, 119.3, 117.0, 115.4, 29.2, 15.6. MS (ESI): m/z = 276.3 [M + H] . HRMS-ESI: calcd for C18H13NNaO2 [M + Na]+ : 298.0838; found: 298.0845. 9-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2e): Yellow solid. Isolated yield: 36mg, 66%, m.p. o

11

1

233.5-235.0 C (lit. 236-237 °C). H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (dd, J = 7.5, 1.0 Hz, 1H), 8.16 (d, J = 9.5 Hz, 1H), 7.59-7.55 (m, 2H), 7.44-7.38 (m, 2H), 7.22 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.6, 158.5, 152.4, 147.6, 147.5, 139.0, 131.8, 131.0, 128.6, 127.2, 124.9, 124.9, 119.8, 117.3, +

+

115.9, 105.6, 55.8. MS (ESI): m/z = 278.2 [M + H] . HRMS-ESI: calcd for C17H12NO3 [M + H] : 278.0812; found: 278.0809.

12


Page 13 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


9-Ethoxy-6H-chromeno[4,3-b]quinolin-6-one (2f): Yellow solid. Isolated yield: 43mg, 74%, m.p. o

11

1

228.0-228.7 C (lit. 229-230 °C). H NMR (600 MHz, CDCl3) δ 9.08 (s, 1H), 8.79 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 7.59-7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 4.22 (q, J = 6.6 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H).

13

C NMR (150 MHz, CDCl3) δ 161.5, 157.8, 152.3, 147.3, 147.3,

139.1, 131.9, 130.8, 128.6, 127.5, 125.0, 124.9, 119.6, 117.3, 115.9, 106.2, 64.2, 14.7. MS (ESI): m/z = 292.2 [M + H]+. HRMS-ESI: calcd for C18H14NO3 [M + H]+: 292.0968; Found: 292.0959. 9-Chloro-6H-chromeno[4,3-b]quinolin-6-one (2g): Yellow solid. Isolated yield: 41mg, 73%, m.p. o

11

1

245.7-246.4 C (lit. 246-247 °C). H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 8.76 (d, J = 7.5 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.40 (dd, J = 8.5, 1.0 Hz, 1H).

13

C NMR (125 MHz, CDCl3) δ 161.0, 152.7, 149.9, 149.5, 140.0, 134.3, +

133.4, 132.7, 131.2, 127.7, 127.7, 125.3, 125.1, 119.4, 117.5, 116.5. MS (ESI): m/z = 282.3 [M + H] . +

HRMS-ESI: calcd for C16H8ClNNaO2 [M + Na] : 304.0136; Found: 304.0146. 9-Fluoro-6H-chromeno[4,3-b]quinolin-6-ones (2h): Yellow solid. Isolated yield: 32mg, 60%, m.p. o

1

242.3-243.0 C. H NMR (600 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (dd, J = 7.8, 1.2 Hz, 1H), 8.30-8.27 (m, 1H), 13

7.73-7.70 (m, 1H), 7.65-7.60 (m, 2H), 7.46-7.44 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H). C NMR (150 MHz, CDCl3) δ 161.1, 160.8 (JC-F = 251.9 Hz), 152.6, 149.1, 148.2, 140.4, 140.4, 132.5, 132.1 (JC-F = 9.0 Hz), 127.8 (JC-F = 10.4 Hz), 125.1 (JC-F = 8.1 Hz), 124.1 (JC-F = 26.3 Hz), 119.3, 117.5, 116.4, 112.0 (JC-F = 21.9 Hz). MS (ESI): +

+

m/z = 266.2 [M + H] . HRMS-ESI: calcd for C16H9FNO2 [M + H] : 266.0612; Found: 266.0611. Ethyl 6-oxo-6H-chromeno[4,3-b]quinoline-9-carboxylate (2i): White solid. Isolated yield: 45mg, 71%, m.p. 263.4-263.9 oC. 1H NMR (600 MHz, CDCl3) δ 9.36 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 1.2 Hz, 1H), 8.52-8.50 (m, 1H), 8.33 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 13

8.4 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl3) δ 165.5, 160.8, 153.0, 152.5, 151.4, 142.8, 133.2, 132.8, 132.3, 129.7, 129.3, 126.5, 125.7, 125.2, 119.2, 117.6, 116.5, 61.8, 14.4. MS +

+

(ESI): m/z = 320.2 [M + H] . HRMS-ESI: calcd for C19H13NaNO4 [M + Na] : 342.0737; Found: 342.0735. 11-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2j): Yellow solid. Isolated yield: 38mg, 73%, m.p. 209.6-211.7 oC(lit.11 201-203 °C). 1H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.80 (dd, J = 7.5, 1.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.60-7.57 (m, 1H), 7.53 (dd, J = 8.0, 7.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.39 (dd, J = 7.5, 1.0 Hz, 1H), 2.92 (s, 3H).

13

C NMR (125 MHz, CDCl3) δ 161.6, 152.7, 150.1, 148.4, 141.1,

137.8, 133.2, 132.1, 127.5, 127.4, 127.2, 125.2, 124.9, 120.1, 117.4, 115.4, 17.9. MS (ESI): m/z = 262.4 [M +

13



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 18

H]+. HRMS-ESI: calcd for C17H12NO2 [M + H]+: 262.0863; Found: 262.0870. 11-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2k): Yellow solid. Isolated yield: 44mg, 80%, m.p. o

11

1

219.2-220.2 C (lit. 236-237 °C). H NMR (500 MHz, CDCl3) δ 9.11 (s, 1H), 8.79 (dd, J = 7.5, 1.5 Hz, 1H), 7.60-7.55 (m, 1H), 7.54-7.50 (m, 2H), 7.43-7.39 (m, 1H), 7.37 (dd, J = 8.5, 0.5 Hz, 1H), 7.20 (dd, J = 6.5, 2.0 Hz, 1H), 4.13 (s, 3H).

13

C NMR (125 MHz, CDCl3) δ 161.2, 155.2, 152.5, 148.4, 143.0, 140.7, 132.2, 128.3, 127.6, +

125.5, 124.8, 120.9, 119.6, 117.2, 116.0, 111.1, 56.3. MS (ESI): m/z = 278.2 [M + H] . HRMS-ESI: calcd for C17H12NO3 [M + H]+: 278.0812; Found: 278.0825. 9,11-Dimethyl-6H-chromeno[4,3-b]quinolin-6-one (2l): Yellow solid. Isolated yield: 38mg, 70%, m.p. o

1

219.8-220.5 C. H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 8.81 (dd, J = 7.5, 1.5 Hz, 1H), 7.59-7.56 (m, 3H), 7.45-7.42 (m, 1H), 7.40 (dd, J = 8.0, 1.0 Hz, 1H), 2.90 (s, 3H), 2.55 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.7, 152.6, 148.9, 147.6, 140.1, 137.3, 137.3, 135.8, 131.8, 127.5, 125.8, 125.1, 124.8, 120.2, 117.3, 115.4, 21.7, +

+

17.8. MS (ESI): m/z = 276.1 [M + H] . HRMS-ESI: calcd for C18H14NO2 [M + H] : 276.1019; Found: 276.1029. 6H-Benzo[h]chromeno[4,3-b]quinolin-6-one (2m): Yellow solid. Isolated yield: 38mg, 63%, m.p. 290.4-292.1oC. 1H NMR (600 MHz, CDCl3) δ 9.54-9.52 (m, 1H), 9.14 (s, 1H), 8.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.96 (dd, J = 6.0, 2.4 Hz, 1H), 7.88-7.86 (m, 1H), 7.83-7.80 (m, 3H), 7.64-7.61 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H).

13

C NMR (150 MHz, CDCl3) δ 161.6, 152.8, 150.5, 148.9, 139.3, 135.2, 132.2, 130.9,

130.2, 129.0, 128.2, 127.6, 126.0, 125.8, 125.5, 125.2, 125.0, 120.0, 117.4, 115.8. MS (ESI): m/z = 298.1 [M + H]+. HRMS-ESI: calcd for C20H12NO2 [M + H]+: 298.0863; Found: 298.0876. 10,11,12,13-Tetrahydro-6H-benzo[h]chromeno[4,3-b]quinolin-6-one (2n): White solid. Isolated yield: 34mg, 56%, m.p. 272.5-273.2 oC. 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.42-7.39 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 3.43 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.01-1.92 (m, 4H).

13

C NMR (125 MHz, CDCl3) δ 161.7, 152.6, 149.9,

148.2, 142.9, 140.4, 135.3, 131.9, 130.00, 126.00, 125.7, 125.2, 124.8, 120.2, 117.3, 114.5, 30.7, 24.7, 22.7. MS (ESI): m/z = 302.5 [M + H]+. HRMS-ESI: calcd for C20H15NNaO2 [M + Na]+: 324.0995; Found: 324.1006. 2-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2o): Yellow solid. Isolated yield: 36mg, 70%, m.p. o

1

225.0-226.3 C, H NMR (500 MHz, CDCl3) δ 9.20 (s, 1H), 8.55 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.02(dd, J = 8.0, 1.0 Hz, 1H), 7.94-7.91 (m, 1H), 7.66-7.62 (m, 1H), 7.40 (dd, J = 8.5, 1.5 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 2.52 (s, 3H).

13

C NMR (125 MHz, CDCl3) δ161.4, 151.0, 150.8, 149.7, 141.1, 134.7, 133.3, +

130.9,129.4, 129.4, 127.3, 127.2, 124.9, 119.1, 117.1, 115.8, 21.0. MS (ESI): m/z = 262.4 [M + H] . HRMS-ESI: calcd for C17H12NO2 [M + H]+: 262.0863; Found: 262.0861.

14


Page 15 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2p): Yellow solid. Isolated yield: 39mg, 70%, m.p. o

1

230.7-231.3 C. H NMR (600 MHz, CDCl3) δ 9.22 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 9.0, 2.4 Hz, 1H), 4.00 (s, 3H).

13

C NMR (150 MHz, CDCl3) δ 161.4, 156.7, 150.8, 149.5, 147.1, 141.3, 133.5, +

129.4 (d, J = 6.0 Hz), 127.5, 127.3, 120.7, 119.9, 118.6, 115.7, 106.8, 56.1. MS (ESI): m/z = 278.4 [M + H] . +

HRMS-ESI: calcd for C17H12NO3 [M + H] : 278.0812; Found: 278.0823. 2-Chloro-6H-chromeno[4,3-b]quinolin-6-one (2q): White solid. Isolated yield: 42mg, 74%, m.p. 268.7-269.1 oC (lit.24273 °C). 1H NMR (600 MHz, CDCl3) δ 9.26 (s, 1H), 8.79-8.78 (m, 1H), 8.29-8.27 (m, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.99-7.96 (m, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 160.9, 151.1, 151.0, 148.5, 141.3, 133.7, 132.3, 130.7, 129.6, 129.5, 127.9, 127.5, 124.9, 120.9, 118.9, 115.6. MS (ESI): m/z = 282.2 [M + H]+. HRMS-ESI: calcd for C16H9ClNO2 [M +

+ H] : 282.0316; Found: 282.0325. 2,9-Dimethyl-6H-chromeno[4,3-b]quinolin-6-one (2r): Yellow solid. Isolated yield: 40mg, 72%, m.p. 210.0-211.9 oC. 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.54 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.74-7.73 (m, 2H), 7.38 (dd, J = 8.5, 1.5 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 2.58 (s, 3H), 2.51 (s, 3H).

13

C NMR (125 MHz,

CDCl3) δ 161.6, 150.6, 149.7, 148.9, 140.1, 137.5, 135.8, 134.6, 133.0, 129.1, 127.9, 127.3, 124.8, 119.3, 117.1, 115.7, 21.6, 21.0. MS (ESI): m/z = 276.3 [M + H]+. HRMS-ESI: calcd for C18H14NO2 [M + H]+: 276.1019; Found: 276.1009. 9-Chloro-2-methyl-6H-chromeno[4,3-b]quinolin-6-one (2s): White solid. Isolated yield: 44mg, 75%, m.p. 246.5-248.5 oC (lit.12 252-253 °C). 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.0, 2.5 Hz, 1H), 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.28 (d, J = 13

2.2 Hz, 1H), 2.52 (s, 3H). C NMR (125 MHz, DMSO) δ 161.0, 150.8, 149.9, 149.3, 140.0, 134.9, 134.2, 133.6, +

133.2,131.0,127.7,127.6, 124.9, 118.8, 117.2, 116.5, 21.0. MS (ESI): m/z = 296.4 [M + H] . HRMS-ESI: calcd for C17H11ClNO2 [M + H]+: 296.0473; Found: 296.0477. 2-Chloro-9-methyl-6H-chromeno[4,3-b]quinolin-6-one (2t): White solid. Isolated yield: 44mg, 75%, m.p. o

24

1

274.8-276.2 C (lit. 280 °C). H NMR (600 MHz, CDCl3) δ 9.15 (s, 1H), 8.77 (d, J = 3.0 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 6.6 Hz, 2H), 7.54 (dd, J = 8.4, 2.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 2.62 (s, 3H).

13

C

NMR (150 MHz, CDCl3) δ 161.0, 150.9, 149.7, 147.7, 140.4, 138.2, 136.3, 132.0, 130.6, 129.2, 128.0, 127.6, +

+

124.8, 121.0, 118.9, 115.5, 21.7. MS (ESI): m/z = 296.4 [M + H] . HRMS-ESI: calcd for C17H11ClNO2 [M + H] : 296.0473; Found: 296.0479.

15



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ASSOCIATED CONTENT

Supporting Information Copies of 1H and 13C NMR spectra of all starting materials and products. This material is available free of charge via the Internet at http:// pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21506190, 21576239, 21506191) and Natural Science Foundation of Zhejiang Province (No. LQ16B060005) for financial support. REFERENCES (1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166-187. (2) Eicher,T.; Hauptmann, S. The Chemistry of Heterocycles, seconded. Wiley- VCH, Weinheim, 2003, 316-336. (3) Kharb, R.; Kaur, H. Int. Res. J. Pharm. 2013, 4, 63-69. (4) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem. 2010, 45, 3245-3264. (5) Bureau, Y.; Handa, M.; Zhu, Y.; Laliberte, F.; Moore, C. S.; Liu, S.; Huang, A.; MacDonald, D.; Xu, D. G.; Robertson, G. S. Neuropharmacology 2006, 51, 974-985. (6) (a) Kerrigan, J. E.; Pilch, D. S. Biochemistry 2001, 40, 9792-9798. (b) Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 1585-1604. (c) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488-1508. (7) Sashidhara, K. V.; Palnati, G. R.; Singh, L. R; Upadhyay, A.; Avula, S. R.; Kumar, A.; Kant, R. Green Chem. 2015, 17, 3766-3770.

16


Page 16 of 18

Page 17 of 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(8) (a) Muruganatham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2004, 27, 1683-1687. (b) Mulakayala, N.; Rambabu, D.; Raja, M. R.; Chaitanya, M.; Kumar, C. K.; Kalle, A. M.; Krishna, G. R.; Reddy, C. M.; Rao, M. V. Bioorg. Med. Chem. 2012, 20, 759-768. (c) Goswami, L.; Gogoi, S.; Gogoi, J.; Boruah, R. K.; Boruah, R. C.; Gogoi, P. ACS Comb. Sci. 2016, 18, 253-261. (9) Huang, W.; Lin, W.; Guan, X. Tetrahedron Lett. 2014, 55, 116-119． (10) (a)Vu, A. T.; Campbell, A. N.; Harris, H. N.; Unwalla, R. J.; Manas, E. S.; Mewshaw, R. E. Bioorg. Med. Chem. Lett. 2007, 17, 4053-4056. (b) Zhi, L.; Tegley, C. M.; Pio, B. ; Edwards, J. P.; Motamedi, M.; Jone, T. K.; Marschke, K. B.; Male, D. E.; Risek, B.; Schrader, W. T. J. Med. Chem. 2003, 46, 4104-4112. (11) Tabakovic, K.; Tabakovic, I.; Ajdini, N.; Leci, O. Synthesis 1987, (3), 308-310. (12) Wu, J.; Wang, X. Org. Biomol. Chem. 2006, 4, 1348-1351. (13) Rajawinslin, R. R.;Gawande, S. D.; Kavala, Y.; Huang, Y.-H.; Kuo, C.-W.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. RSC Adv. 2014, 4, 37806-37811. (14) (a) Johansson, M. J.; Andersson, K. H. O.; Kann, N. J. Org. Chem. 2008, 73, 4458-4463. (b) Suchy, M.; Elmehriki, A. A. H.; Hudson R. H. E. Org. Lett. 2011, 13, 3952-3955. (c) Liu, L.; Zhang, N.; Du, F.; Zhao, K. Org. Lett. 2014, 16, 436-439. (15) (a) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2011, 47, 3652-3654. (b) Chen, W.-X.; Shao, L.-X. J. Org. Chem. 2012, 77, 9236-9239. (c) Huang, X.; Wang, J.; Ni, Z.; Wang, S.; Pan, Y. Chem. Commun. 2014, 50, 4582-4584. (16) (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272-10274. (b) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374-12377. (c) Kim, J.; Kim, H.; Chang, S. Org. Lett. 2012, 14, 3924-3927. (17) Borah, A.; Goswami, L.; Neog, K.; Gogoi, P. J. Org. Chem. 2015, 80, 4722-4728. (18) Li, Y.; Xue, D.; Lu, W.; Wang, C.; Liu, Z.-T.; Xiao, J. Org. Lett. 2014, 16, 66-69. (19) Liu, J.; Yi, H.; Zhang, X.; Liu, C.; Liu, R.;Zhang, G.; Lei, A. Chem. Commun. 2014, 50, 7636-7638. (20) Rao, D. N.; Rasheed, S.; Das, P. Org. Lett. 2016, 18, 3142-3145. (21) (a) Zhao, M.-N.; Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2014, 16, 3082-3085. (b) Liu, W.; Tan, H.; Chen, C.; Pan, Y. Adv. Synth. Catal. 2017, 359, 1-6. (22) (a) Pu, F.; Li, Y.; Song, Y.; Xiao, J.; Liu, Z.; Wang, C.; Liu, Z.; Chen, J.; Lu, J. Adv. Synth. Catal. 2016, 358, 539-542. (b) Mondal, S.; Samanta, S.; Santra, S.; Bagdi, A. K.; Hajra, A. Adv. Synth. Catal. 2016, 358, 3633-3641.

17



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(23) Di, Braccio, M.; Grossi, G.; Roma, G.; Marzano, C.; Baccichetti, F.; Simonato, M.; Bordin, F. Farmaco. 2003, 58, 1083-1097. (24) Heber, D. Arch. Pharm. 1987, 320, 595-599.

18


Page 18 of 18

Copper-Catalyzed Cyclization for Access to 6H-Chromeno[4,3-b

Recommend Documents