quinolines from Alkynes and Anilines - ACS Publications

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Transition Metal Free Approach for the Synthesis of 4-Aryl-quinolines from Alkynes and Anilines Mandalaparthi Phanindrudu, Sandip Balasaheb Wakade, Dipak Kumar Tiwari, Pravin R. Likhar, and Dharmendra Kumar Tiwari J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01204 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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The Journal of Organic Chemistry

Transition Metal Free Approach for the Synthesis of 4-Arylquinolines from Alkynes and Anilines Mandalaparthi Phanindrudu,†,‡ Sandip Balasaheb Wakade,†,‡ Dipak Kumar Tiwari,†,‡ Pravin R. Likhar,‡, §, and Dharmendra Kumar Tiwari*,†,‡ †

Division of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. § Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. ‡ Academy of Scientific & Innovative Research (AcSIR), New Delhi, 110001, India. ABSTRACT: An efficient and transition metal-free approach for the synthesis of 4-arylquinolines from readily available anilines and alkynes in the presence of K2S2O8 and DMSO has been developed. A variety of alkynes and anilines having diverse range of substitution patterns can undergo the one pot cascade process successfully. Effectively, this method uses DMSO as one carbon source, thus providing a highly atom economical and environmentally benign approach for the synthesis of 4-arylquinolines.

INTRODUCTION Quinoline is one of the most prevalent nitrogen-containing motifs frequently found in various natural products and FDAapproved pharmaceuticals (Fig.-1, A-E).1 In particular, 4arylquinoline scaffolds are an integral part of various medicinally important compounds displaying a wide range of biological activities such as anti-thyroid cancer, antifungal, analgesic, antimalarial, antibacterial, anti-inflammatory, antiasthmatic, antiproliferative activity, ALK5 and PI3K inhibitory properties (Fig -1, B-E).1-2 This key heterocyclic core exhibits common pharmacophoric and chelating properties, as a result of which it has found broad applications in both, drug designing, as well as material sciences.3 H N O

O Br

H N O

F

O HO A N TMC-207; BQ

O N

B N anti-thyroid cancer N

HN N

N

O HN N

N

N C Antiproliferative activity

O

S

N D PI3K inhibitor

N E ALK5 inhibitor

Figure 1. Biologically active molecules containing substituted quinolines.

Owing to the immense pharmacological activity, the synthesis of quinoline and its derivatives has seen extensive research over the years. 4 Amongst all the reported protocols, the

R1 Metal

R1

R2

+ H2N

R2

O S

N

• Transition metal free • DMSO as one carbon source • One C-N and two C-C bond formation • Broad substrate scope

(a) Previous work: Transition metal catalyzed

Ar

+

H2N

Ar

Cp*[Co(CO)I 2] AgNTf2, K2S2O8 DMSO

(b) This work:Transition metal free: Alkynes and Anilines

Ar

K2S2O8

+ H2N

DMSO Transition metal free;

N Ar

N

In-situ generation of Imine from anilne and DMSO

DMSO as one carbon source and solvent

Broad substrate scope

Scheme 1. Strategies for the synthesis of 4-arylquinolines from alkynes and amines.

transition metal catalyzed C-H functionalization is considered to be one of the most attractive, reliable, and atom economical method for the synthesis of 4-substituted quinolines.5 In this regard very recently Yi and co-workers have developed a Co(III)-catalyzed C−H activation strategy for the one-pot tandem synthesis of 4- arylquinolines from aryl methyl ketones and aryl amines using paraformaldehyde as the carbonyl surrogate.6a In yet another report, Singh and co-workers developed an elegant iron catalyzed synthesis of 4-arylquinolines from aryl methyl ketones and anilines via K2S2O8 promoted oxidative annulation.6b Very recently, Yi and co-workers disclosed the Co(III)-catalyzed and DMSO-involved C-H activation/cyclization of amines and alkynes to prepare 4arylquinolines.7 In this transformation, authors reported that the two different additives such as AgNTf2 and K2S2O8 are essential to facilitate this reaction (Scheme-1a). Although all these transition metal catalyzed approaches allow a convenient access to 4-arylquinolines, the use of expensive and toxic transition metal catalysts and additives are major drawbacks asso-

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ciated with them. Therefore, developing more efficient, ecofriendly and transition metal free synthesis of 4-arylquinolines from readily available starting materials is highly desirable and presents an urgent need. As a part of our continuing research interest in pharmaceutically important heterocyclic frameworks,8 we recently developed two new protocols i.e. transition metal catalyzed as well as transition metal-free synthesis of 3-keto-quinolines from readily available starting materials.9 In continuation of the same research programme, herein we present an atomeconomical and transition metal free synthesis of 4arylquinolines from readily available aryl amines and alkynes in the presence of K2S2O8 and DMSO. RESULT AND DISCUSSION At the outset of this investigation, we explored the cascade reaction of phenyl acetylene (1a) and p-toluidine (2a) using DMSO as the solvent and the details are summarized in Table-1. Our initial efforts by reacting phenyl acetylene (1a, 1.0 mmol) and p-toluidine (1.2 mmol) in the presence of K2S2O8 (2.5 equiv) in DMSO (3.0 mL) at room temperature under nitrogen condition was unsuccessful (Table-1, entry 1). Gratifyingly, a 15% yield of aimed product 3aa was obtained Table 1. Optimization of reaction conditionsa

Ph H2N

Additives

+

Ph

Entry

1

2a Additive

when the mixture was heated at 60 °C for 12 h under a nitrogen atmosphere (entry-2). At this stage, the structure of 3aa was well characterized using different spectroscopic techniques and the spectral data of 3aa was exactly matching with previously reported compounds. To our delight, a higher yield (79%) of the desired 3aa was obtained when reaction mixture was heated at 120 °C (entry-3). However, further raising the reaction temperature (140 °C), furnished slightly lower yield of desired 3aa (entry-4). Increasing or decreasing the amount of oxidant significantly reduced the yield of desired 3aa (entries 5-6). In order to improve the yields of the desired 3aa, various oxidants such as (NH4)2S2O8, KHSO4, TBHP, and TEMPO were screened. Unfortunately, no better results were obtained (entries 7-10). Thereafter, several solvents such as DMF, DMA, and NMP were investigated as one carbon source,10 of which no better result was obtained (entries 1113). In further efforts to optimize the yield of desired 3aa, reactions were conducted under air and oxygen atmosphere, however under both the conditions inferior yields of desired 3aa was obtained (entries 14-15). After having the optimized reaction conditions (Table-1, entry 3) in hand, the substrate scope of the reaction with respect to various alkynes and anilines was evaluated. As shown in Table- 2, a wide range of alkynes (1a-1r) and anilines (2b-2g) effectively participated in this one-pot tandem reaction and furnished the desired products in moderate to good yields. Table 2. Substrate scope with different alkynes

temperature

1a

N

Solvents

C5H11

3aa b

Solvent

Yields

(2.5 equiv.)

Temp/[°C ]

K2S2O8

rt

DMSO

n.o.

N

N

3aa; 79%

2

K2S2O8

60

DMSO

15%

3

K2S2O8

120

DMSO

79%

4

K2S2O8

140

DMSO

61%

5

K2S2O8

120

DMSO

41%

6

K2S2O8

120

DMSO

25%

7

(NH4)2S2O8

120

DMSO

17%

8

KHSO4

120

DMSO

trace

c

N

N

9

TBHP

120

DMSO

trace

10

TEMPO

120

DMSO

trace

11

K2S2O8

120

DMF

12%

12

K2S2O8

120

DMA

trace

13

K2S2O8

120

NMP

trace

14

K2S2O8

120

DMSO

40%

15

K2S2O8

120

DMSO

37%

N

3la; 74%

Br

N

N

3ia; 73%

3ja; 68%

CN F3C

N

N

3ea; 72%

Cl

3ha; 66%

NO2

N

3da; 72%

F

3ga; 69%

I

N

3ca; 77%

OMe

3fa; 71%

d

N

3ba; 81%

3ka; 75%

a

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N

N 3ma; 70%

N

3na; 67%

3oa; 68%

S N

N 3pa; 71%

Different anilines

N

N

3qa; 62%

3ra; 61%

N

N 3sa; 0%

3bb; 77%

e

O Cl

f

Reaction was performed using 1a (1.0 mmol), 2a (1.2 mmol), DMSO (2.0 mL) and additive (2.5 mmol) under nitrogen atmosphere for 12 h. b isolated yield; c when 3.5 equiv. of K2S2O8 was used; d when 1.5 equiv. of K2S2O8 was used; e under air; f under O2; n.o = not observed

N 3bc; 72%

N 3bd; 72% OMe

N 3be; 70%

N 3bf; 74%

N 3bg; 69% OMe

Reaction conditions: Aryl alkynes (1a-1r; 1.0 mmol), anilines (2a-2g; 1.2 mmol), DMSO (3.0 mL) and K2S2O8 (2.5 mmol) under N2 at 120 °C for 12 h.

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The Journal of Organic Chemistry Generally, the reaction proceeded smoothly under the standard conditions with various terminal alkynes bearing both electron donating (1b-1g) and electron withdrawing (1h-1n) groups at a different position of aryl ring and readily furnished the corresponding 4-arylquinolines (3aa-3na) in good to moderate yields. Aryl alkynes with various substituent’s on the aromatic ring such as alkyl (1b-1f), tert-butyl (1e), methoxy (1g), fluoro (1h), chloro (1i), bromo (1j) and iodo (1k) were tested under the standard conditions and the corresponding products were obtained in good yields. Substrates with strong electron-withdrawing groups such as nitro (-NO2; 1l), cyano (CN; 1m) and CF3 (1n) were also tolerated, leading to the desired products in good yields. Furthermore, the polycyclic aromatic alkynes smoothly underwent this one pot tandem reaction to furnish desired products (3oa & 3pa) in good yields. Furthermore, the heteroaryl alkynes such as 2ethynylthiophene (1q) and 2-ethynylpyridine (1r) were also found to be compatible under present condition and furnished the desired products (3qa & 3ra) in very good yields. Aliphatic alkyne (1-hexyne, 1sa) was also employed in this reaction under the standard condition, unfortunately, no desired product was detected. The substrate scope of the present methodology was further extended to various substituted anilines (2b2g). Anilines bearing both electron donating (2b-2d) group as well as electron withdrawing group (2e) worked well in this cascade reaction and afforded the aimed products (3bb-3bd and 3be) in good yields. Polycyclic anilines (2f & 2g) also effectively reacted with alkyne (1b) to furnish the desired products in moderate to good yields. The synthetic potential of quinolines thus obtained is illustrated in Scheme 2. The quinolines (3ca & 3ia) were treated with m-CPBA in chloroform at room temperature under air to give to quinoline N-Oxides (4 & 7) in 90 and 88% yields respectively. The intermediate 4 was then subjected to amidation reaction with N-morpholine in the presence of catalytic Cu(OAc)2 and Ag2CO3 (2.0 equiv) to give to medicinally valuable 4-aryl-2-morpholinoquinoline (6)11 in 88% yield. On the other hand, the intermediate 7 was then treated with sodium sulfinate (8) in the presence of I2/TBHP to furnish 4-aryl-2tosylquinoline (9) in very good yield via one-pot deoxygenation and direct sulfonylation.12 Scheme 2. Synthetic utility Et

Et

m-CPBA

N

CHCl3, 12 h

3ca

Cl

+ N

O

4, 90% O

5

Scheme-3. Mechanistic Insights Ph

N

without

(1)

K2S2 O8

N

2a

3aa; 0%

Ph Ph

+ H2N

O S

+

1a

Ph

standard condition

(2)

N

2a

3aa; 38%

Ph Ph

O + S Ph Ph

+ H2N 1a

standard condition

(3)

N

3aa; 0%

2a

Ph O

+

Ph

O S

+

H2N

F

standard condition

(4)

N 3aa;31%

2a

Ph

+ H2N

Ph

+ D3C

O S

CD3

standard condition

(5)

D

100% D

2a

1a

N 3aa-d 2 62%

side product. On the other hand, no product (3aa) formation was observed when the reaction was performed in diphenyl sulfoxide solvent. These experiments suggest that DMSO serves as a carbon source in this reaction. In order to check another possible route for the formation of 3aa, the acetophenone (5) was treated with aniline (2a) under standard reaction conditions, furnishes the desired 3aa in 31% yield. It indicates that reaction may also go through arylmethyl ketones generated in situ from aryl alkynes in the presence of oxidant. To shed more light on the reaction mechanism, a deuteriumlabeling experiment was conducted by treating 1a with 2a in DMSO-d6 under standard reaction conditions, which furnished the desired 3aa-d2 in 62% yield. 1H NMR analysis revealed 100% deuteration at the C-2 position of 3aa. Based on the above preliminary experimental results and the previous literature reports the formation of 4-aryl quinolines may be explained by two pathways (Scheme 4). The reaction process may begin with the generation of the sulfenium ion

K 2 S 2O8 KHSO5

N

6, 88% O

Cl

+

1a

O S

Cu(OAc) 2 (10 mol%) Ag2 CO3 (2 equiv) benzene, 120 °C, 24 h

+ H2N

Ph

O S

Scheme 4. Proposed reaction pathways

Et

H N

that led to the formation of 3aa in 38% yield along with thiophenol as

O

Cl

S A

2a

S

N H

N B

C

………………………………………………………………

SO2Na m-CPBA

N 3ia

CHCl3, 12 h

I2, (1.1 equiv) aq. TBHP (3.3 equiv)

+ N 7, 89% O

N

DMF, rt

8

Ts

9, 82%

In order to further understand the reaction mechanism, we carried out a series of control experiments (Scheme 3). When the reaction was performed without K2S2O8, no product formation was observed which indicates that oxidant is essential for this reaction. In order to verify the carbon source, we carried out the reaction in the methyl phenyl sulfoxide solvent



O

R

O8 K 2S 2

N

R F 2a

c R N -

N

O

O

R F'

Path-II

FR

Path-I

N

GH

R

DH R [1,3]-H shift

H N OH

a) [1,3]-H shift b) -H2O c) [O]

N [O] R

E

3aa R

(A) from DMSO in the presence of K2S2O8.7 The sulfenium ion (A) reacts with aniline to form intermediate B, which undergoes to demethylthiolation9c to form the iminium intermediate C. In pathway I, the iminium intermediate C reacts with alkyne (2a) in Diels-Alder fashion to give intermediate D, which undergoes to 1,3-hydrogen shift to form E, which upon auto-oxidation leads to the formation of the desired 3aa.13 In another pathway, alkyne (2a) may be getting oxidized to form acetophenone (F), which subsequently enolizes to give intermediate F’. This intermediate F’ then undergoes to nucleophilic attack on iminium intermediate C, followed by cyclization, leading to the formation of intermediate G. This intermediate G then rearranges to final product 3aa through 1,3 hydrogen shift, followed by dehydration and auto-oxidation steps.6b CONCLUSION In conclusion, an atom-economical and transition metal free, three component reactions cascade have been developed for the synthesis of 4-arylquinolines from the readily available alkynes, anilines and DMSO in the presence of K2S2O8. The reaction worked well with various substituted alkynes and anilines. As a result, a number of 4-substituted quinolines were synthesized, reflecting the generality of this method. The synthetic utility of current methodology was further extended to the synthesis of medicinally important 4-aryl-2morpholinoquinoline and 4-aryl-2-tosylquinoline. EXPERIMENTAL SECTION General Information. All reagents were purchased from Sigma Aldrich, Alfa Aesar and TCI were used without further purification. All experiments were carried out under nitrogen atmosphere. All the solvents used for the reaction were distilled before use. The product purification by column chromatography was accomplished using silica gel 100 - 200 mesh. Analytical TLC was performed with Merck silica gel 60 F254 plates, and the products were visualized by UV detection. 1H and 13C NMR spectra were recorded with 300, 400 and 500 MHz NMR instruments with tertramethylsilane (TMS) as an internal standard. High-resolution mass spectra (ESI-HRMS) were recorded on ESI-QTOP mass spectrometer. Chemical shifts (δ =) are reported in ppm using TMS as an internal standard, and spin -spin coupling constants (J) are given in Hz. Multiplicities in the 1H NMR spectra are described as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs =

Page 4 of 8

broad singlet; coupling constants are reported in Hz. Low (MS) and high (HRMS) resolution mass spectra were recorded on a Waters 2695 and Thermo Scientific Exactive spectrometer respectively and mass/charge (m/z) ratios are reported as values in atomic mass units. Representative Procedure for the synthesis of 4phenylquinolines (3aa):6b To a solution of alkyne 1a (0.11 mL, 1.0 mmol) and toluidine 2a (0.13 mL, 1.2 mmol) in DMSO (3.0 mL) was added K2S2O8 (0.68 gm, 2.5 mmol) at room temperature under nitrogen atmosphere. The temperature of oil bath was increased up to 120 °C.; and mixture was stirred at same temperature for another 12 h. After completion of reaction (confirmed by TLC), the reaction mixture was then allowed to attain room temperature and diluted with ethyl acetate (60 mL). The organic layer was washed with water (20 mL), sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was further dried over anhydrous sodium sulphate and solvent was evaporated under reduced pressure to get crude product which was purified by column chromatography using a mixture of ethyl acetate/petroleum ether (15%) on silica gel to provide the desired product 3aa as a white solid (173 mg, 79%). mp 120 - 123 °C.; 1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.58 7.47 (m, 6H), 7.29 (d, J = 4.4 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.8, 147.9, 146.9, 138.08, 136.6, 131.6, 129.4, 129.2, 128.5, 128.2, 126.7, 124.5, 121.3, 77.3, 77.0, 76.7, 21.8. 6-methyl-4-(p-tolyl)quinoline (3ba).6b Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ba as a yellow semi solid (189 mg, 81%). 1H NMR (400 MHz, Chloroform-d) δ 8.85 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J = 8.6, 1.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 4.4 Hz, 1H), 2.47 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.7, 148.1, 146.9, 138.3, 136.5, 135.2, 131.6, 129.4, 129.3, 129.2, 126.8, 124.6, 121.3, 21.8, 21.3; HRMS (ESI) m/z: [M + H]+ calcd for C17H16N 234.1277; Found 234.1284. 4-(4-ethylphenyl)-6-methylquinoline (3ca). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 86/14) to afford 3ca as a yellow liquid (190 mg, 77%). 1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 7.56 (dd, J = 8.6, 1.5 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 4.4 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.47 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, Chloroform-d) δ 148.5, 146.6, 144.6, 136.6, 135.3, 131.7, 129.4, 128.9, 128.1, 126.8, 124.6, 121.4, 28.6, 21.8, 15.4; HRMS (ESI) m/z: [M + H]+ calcd for C18H18N 248.1424; Found 248.1433. 6-methyl-4-(4-pentylphenyl)quinoline (3da). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 86/14) to afford 3da as a white semi solid (208 mg, 72%). 1H NMR (500 MHz, Chloroform-d) δ = 8.86 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.56 (dd, J = 8.6, 1.9 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 4.4 Hz, 1H), 2.72 (t, J = 7.9 Hz, 2H), 2.48 (s, 3H), 1.75 - 1.65 (m, 2H), 1.43 - 1.39 (m, 4H), 0.94 (t, , J = 7.0 Hz, 3H); 13C NMR (125 MHz, Chloroform-d) δ = 13C NMR (101 MHz, Chloroform-d) δ 148.8, 148.1, 147.0, 143.3, 136.5,


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The Journal of Organic Chemistry 135.4, 131.6, 129.4, 129.2, 128.6, 126.8, 124.7, 121.4, 114.0, 35.8, 31.6, 29.7, 22.6, 21.8, 14.1; HRMS (ESI) m/z: [M + H]+ calcd for C21H24N 290.1891; Found 290.19033. 4-(4-(tert-butyl)phenyl)-6-methylquinoline (3ea). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ea as a yellow liquid (198 mg, 72%). 1H NMR (400 MHz, Chloroform-d) δ 8.86 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.57 - 7.54 (m, 3H), 7.47 - 7.43 (m, 2H), 7.29 (d, J = 4.4 Hz, 1H), 2.49 (s, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, Chloroform-d) δ 151.4, 148.9, 147.9, 147.1, 136.4, 135.2, 131.6, 129.9, 129.4, 129.2, 126.8, 125.5, 124.7, 121.4, 34.7, 31.4, 21.8; HRMS (ESI) m/z: [M + H]+ calcd for C20H22N 276.1736; Found 276.1747. 4-(3,4-dimethylphenyl)-6-methylquinoline (3fa). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 88/12) to afford 3fa as a white solid (175 mg, 71%). mp = 266 - 268 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.34 - 7.27 (m, 2H), 2.56 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, Chloroform-d) δ 155.9, 142.5, 139.8, 139.6, 139.1, 137.7, 135.3, 133.5, 130.5, 130.3, 127.3, 127.0, 125.4, 123.8, 121.2, 22.0, 19.9, 19.7; HRMS (ESI) m/z: [M + H]+ calcd for C18H18N 248.1422; Found 248.1434. 4-(4-methoxyphenyl)-6-methylquinoline (3ga).6b Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 87/13) to afford 3ga as a yellow semi solid (171 mg, 69%). 1H NMR (400 MHz, Chloroform-d) δ 8.85 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.56 (dd, J = 8.6, 1.9 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.27 (t, J = 3.2 Hz, 1H), 7.10 -7.04 (m, 2H), 3.91 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 159.8, 149.0, 147.7, 147.2, 136.5, 131.6, 130.8, 130.5, 129.4, 127.0, 124.7, 121.4, 114.1, 55.4, 21.9. 4-(4-fluorophenyl)-6-methylquinoline (3ha).6b Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ha as a yellow solid (156 mg, 66%). mp = 90 - 92 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.58 (dd, J = 8.6, 1.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.28 (d, J = 4.4 Hz, 1H), 7.27 - 7.20 (m, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 162.9 (d, J = 248.1 Hz), 148.7, 147.0 (d, J = 9.2 Hz), 136.9, 134.0, 131.8, 131.2 (d, J = 8.1 Hz), 129.4, 126.7, 124.3, 121.4, 115.8, 115.6, 21.8. 4-(4-chlorophenyl)-6-methylquinoline (3ia)6b Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ia as a yellow solid (184 mg, 73%). mp = 121 - 123 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.54 - 7.50 (m, 2H), 7.46 - 7.42 (m, 2H), 7.27 - 7.26 (m, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 149.1, 147.3, 146.5, 136.9, 136.7, 134.6, 131.8, 130.8, 129.7, 128.9, 126.5, 124.2, 121.3, 21.9. 4-(4-bromophenyl)-6-methylquinoline (3ja).6b Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 84/16) to afford 3ja as a yellow solid (202 mg, 68%). mp = 123 - 126 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.88 (d, J = 4.2 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.71 - 7.66

(m, 2H), 7.59 (d, J = 8.9 Hz, 2H), 7.38 - 7.35 (m, 2H), 7.29 (d, J = 4.4 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.3, 147.3, 146.4, 137.2, 136.8, 132.1, 131.8, 131.0, 128.9, 126.4, 124.2, 122.9, 121.2, 21.8. 4-(4-iodophenyl)-6-methylquinoline (3ka). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ka as a white solid (258 mg, 75%). mp = 140 - 146 °C. 1H NMR (500 MHz, Chloroform-d) δ = 8.90 (s, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.69 - 7.63 (m, 2H), 7.38 (d, J = 4.4 Hz, 1H), 7.31 - 7.25 (m, 2H), 2.51 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 149.1, 146.9, 144.7, 138.0, 137.9, 136.9, 133.0, 131.2, 127.7, 126.5, 124.4, 121.1, 95.1, 21.9; HRMS (ESI) m/z: [M + H]+ calcd for C16H13NI 346.0087; Found 346.0077. 6-methyl-4-(4-nitrophenyl)quinoline (3la). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 83/17) to afford 3la as a yellow solid (194 mg, 74%). mp = 218 - 221 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.93 (d, J = 4.4 Hz, 1H), 8.46 - 8.39 (m, 2H), 8.15 (d, J = 8.6 Hz, 1H), 7.71 - 7.67 (m, 2H), 7.63 (dd, J = 8.6, 1.8 Hz, 1H), 7.51 (s, 1H), 7.33 (d, J = 4.4 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.5, 147.9, 146.7, 145.7, 144.7, 137.7, 132.3, 130.5, 129.4, 126.0, 123.9, 123.7, 121.2, 21.9; HRMS (ESI) m/z: [M + H]+ calcd for C16H13N2O2 265.0972; Found 265.0972. 4-(6-methylquinolin-4-yl)benzonitrile (3ma). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3ma as a white solid (170 mg, 70%). mp = 163 - 165 °C. 1H NMR (400 MHz, Chloroform-d) δ = 8.91 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.65 - 7.59 (m, 3H), 7.51 (s, 1H), 7.29 (d, J = 4.4 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.6, 146.8, 145.9, 142.8, 137.5, 132.4, 132.2, 130.2, 129.5, 125.9, 123.7, 121.1, 118.4, 112.4, 21.8; HRMS (ESI) m/z: [M + H]+ calcd for C17H13N2 245.1065; Found 245.1073. 6-methyl-4-(3-(trifluoromethyl)phenyl)quinoline (3na). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3na as a white solid (192 mg, 67%). mp = 69 - 71 °C. 1H NMR (400 MHz, Chloroformd) δ 8.90 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 5.2, 0.7 Hz, 2H), 7.72 - 7.64 (m, 2H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 (s, 1H), 7.29 (d, J = 4.4 Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 148.9, 147.2, 146.0, 139.0, 137.1, 132.8, 131.8, 131.2 (q, J = 32.5 Hz), 129.7, 129.0, 126.2 (q, J = 3.5 Hz), 125.3, 125.1 (q, J = 3.4 Hz), 123.9, 123.5 (q, J = 272.5 Hz), 121.4, 21.8; HRMS (ESI) m/z: [M + H]+ calcd for C17H13NF3 288.0995; Found 288.0982. 6-methyl-4-(phenanthren-9-yl)quinoline (3oa). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 86/14) to afford 3oa as a yellow semi solid (216 mg, 68%). 1H NMR (500 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.81 (d, J = 8.3 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.75 (s, 1H), 7.73 - 7.64 (m, 3H), 7.59 (s, 1H), 7.47 - 7.43 (m, 1H), 7.34 (d, J = 8.6 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 149.9, 146.7, 144.0, 138.1, 133.7, 133.4, 131.0, 130.6, 130.5, 130.4, 128.9, 128.3, 127.6, 127.3, 127.1, 127.1, 126.6, 125.3, 123.1, 122.7, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for C24H18N 320.1423; Found 320.1434.



6-methyl-4-(pyren-1-yl)quinoline (3pa). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 86/14) to afford 3pa as a yellow solid (243 mg, 71%). mp = 182 - 185 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.05 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.24 - 8.17 (m, 3H), 8.07 (t, J = 7.6 Hz, 1H), 7.97 (t, J = 7.7 Hz, 2H), 7.70 (d, J = 9.7 Hz, 2H), 7.56 (d, J = 9.1 Hz, 1H), 7.28 (s, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 151.4, 145.6, 143.1, 138.6, 133.9, 131.8, 131.5, 131.3, 130.7, 129.1, 128.6, 128.5, 127.2, 126.5, 125.9, 125.7, 125.5, 124.7, 124.6, 124.5, 124.3, 123.1, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for C24H18N 344.1426; Found 344.1434. 7-methyl-4-(thiophen-3-yl)quinoline (3qa). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3qa as a yellow semi solid (140 mg, 62%). 1H NMR (500 MHz, Chloroform-d) δ 9.27 (d, J = 4.5 Hz, 1H), 8.57 (d, J = 3.5 Hz, 1H), 8.10 – 8.06 (m, 1H), 7.80 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 0.5 Hz, 3H), 7.24 – 7.19 (m, 1H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.3, 148.7, 148.0, 143.3, 137.8, 137.1, 135.0, 134.9, 134.1, 130.7, 129.0, 128.3, 127.8, 126.7, 21.6; HRMS (ESI) m/z: [M + H]+ calcd for C14H12NS 226.0685; Found 226.0697. 7-methyl-4-(pyridin-2-yl)quinoline (3ra). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 84/16) to afford 3ra as a yellow sticky solid (132 mg, 61%). 1 H NMR (400 MHz, Chloroform-d) δ 9.47 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 4.7 Hz, 1H), 8.67 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.93 – 7.79 (m, 2H), 7.68 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.33 – 7.29 (m, 1H), 2.56 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 155.0, 150.1, 148.3, 146.8, 137.0, 136.9, 133.2, 132.3, 131.8, 128.8, 127.9, 127.2, 122.7, 120.8, 21.6; HRMS (ESI) m/z: [M + H]+ calcd for C15H13N2 221.1073; Found 221.1079. 8-methyl-4-(p-tolyl)quinoline (3bb). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3bb as a yellow semi solid (180 mg, 77%). 1H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 4.4 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.40 - 737 (m, 3H), 7.34 - 7.32 (m, 3H), 2.88 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 149.2, 148.4, 147.3, 138.3, 137.0, 135.4, 129.7, 129.5, 129.2, 126.9, 126.2, 124.0, 121.1, 21.3, 18.7; HRMS (ESI) m/z: [M + H]+ calcd for C17H16N 234.1277; Found 234.1274. 5,7-dimethyl-4-(p-tolyl)quinoline (3bc). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3bc as a brown solid (177 mg, 72%). mp = 104 - 106 °C. 1H NMR (400 MHz, Chloroform-d) δ = 8.70 (d, J = 4.3 Hz, 1H), 7.76 (s, 1H), 7.18 - 7.09 (m, 4H), 7.05 - 7.03 (m, 2H), 2.42 (s, 3H), 2.36 (s, 3H), 1.92 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 149.7, 149.2, 148.2, 139.4, 139.1, 137.5, 135.3, 132.2, 128.5, 127.3, 124.5, 122.8, 77.3, 77.0, 76.7, 24.3, 21.4, 21.2; HRMS (ESI) m/z: [M + H]+ calcd for C18H18N 248.1423; Found 248.1431. 8-methoxy-4-(p-tolyl)quinoline (3bd). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 82/18) to afford 3bd as a white solid (179 mg, 72%). mp = 77 - 79 °C. 1H NMR (500 MHz, Chloroform-d) δ = 8.78 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.38 (dd, J = 9.2, 2.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.28 -

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7.23 (m , 2H), 3.79 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 157.8, 147.5, 147.2, 144.4, 138.3, 135.3, 130.9, 129.4, 129.2, 127.8, 121.9, 121.6, 103.7, 77.3, 77.0, 76.7, 55.4, 21.3; HRMS (ESI) m/z: [M + H]+ calcd for C17H16NO 250.1215; Found 250.1226. 6-chloro-4-(p-tolyl)quinoline (3be). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 85/15) to afford 3be as a yellow solid (177 mg, 70%). mp = 157 - 160 °C.; 1H NMR (400 MHz, Chloroform-d) δ = 9.28 (s, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.9, 2.6 Hz, 3H), 7.35 (d, J = 8.0 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 194.1, 150.5, 147.7, 144.3, 137.4, 134.1, 133.4, 132.5, 131.1, 130.3, 129.5, 129.4, 127.5, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for C16H13NCl 254.0731; Found 254.0732. 4-(p-tolyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (3bf). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 78/22) to afford 3bf as a brown solid (192 mg, 74%). mp = 70 - 72 °C.; 1H NMR (400 MHz, Chloroformd) δ 8.80 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.21 - 7.17 (m, 3H), 2.98 (t, J = 7.5 Hz, 2H), 2.46 (s, 3H), 2.39 (t, J = 7.4 Hz, 2H), 1.95 - 1.86 (m, 2H); 13C NMR (100 MHz, Chloroform-d) δ 148.5, 148.2, 147.7, 143.5, 139.7, 138.2, 137.7, 129.2, 128.9, 128.5, 128.4, 126.8, 124.8, 122.7, 35.2, 33.2, 25.6, 21.3; HRMS (ESI) m/z: [M + H]+ calcd for C19H18N 260.1424; Found 260.1434. 5-methoxy-1-(p-tolyl)benzofuro[2,3-f]quinoline (3bg). Purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 75/25) to afford 3bg as a yellow solid (233 mg, 69%). mp = 120 - 122 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.99 (d, J = 4.4 Hz, 1H), 8.00 -7.92 (m, 1H), 7.59 (s, 1H), 7.48 -7.44 (m, 3H), 7.39 - 7.30 (m, 5H), 4.25 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 155.9, 152.4, 148.1, 146.0, 145.1, 140.7, 138.1, 136.7, 129.3, 128.4, 126.3, 124.3, 124.0, 122.7, 119.9, 116.4, 111.9, 99.4, 56.5, 21.4; HRMS (ESI) m/z: [M + H]+ calcd for C23H18O2N 340.1325; Found 340.1332. Preparation of 4-(4-chlorophenyl)-6-methylquinoline 1oxide (7):11a A solution of quinoline (3ia, 2.0 mmol) in CHCl3 (20 mL) was stirred at 0 °C for 15 min. Then m-CPBA (3chloroperbenzoic acid, 3.0 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated aqueous NaHCO3 solution (30 mL), the aqueous layer was extracted with CHCl3 (40 mL × 3). Then it was dried by Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 column chromatography (eluent: 1:9; MeOH:EtOAc) to afford desired product N-oxide (7) in 90% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.77 – 8.72 (m, 1H), 8.52 (d, J = 6.2 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.55 - 7.51 (m, 2H), 7.44 – 7.40 (m, 2H), 7.19 (d, J = 6.2 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 140.1, 139.3, 137.0, 135.6, 134.8, 134.3, 132.6, 130.8, 129.1, 128.7, 125.1, 121.4, 120.0, 21.70; HRMS (ESI) m/z: [M + H]+ calcd for C16H13ClNO 270.0680; Found 270.0673. 4-(4-ethylphenyl)-6-methyl-2-morpholinoquinoline 1-oxide (6):11a To a mixture of quinoline N-oxide (4, 0.1 mmol), Nmorpholine 5 (0.3 mmol, 3.0 equiv) in benzene (1.0 mL) was


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The Journal of Organic Chemistry added Cu(OAc)2 (0.01 mmol, 5.0 mol%), Ag2CO3 (0.2 mmol, 2.0 equiv) at room temperature. The reaction mixture was then allowed to stir at 120 °C for 24 h under air atmosphere. The reaction was cooled down to room temperature and the mixture was passed through a short pad of celite, washing with a mixture of AcOEt/MeOH in a 1:1 ratio repeatedly. The organic layer was concentrated under reduced pressure to give a crude oil, which was purified by column chromatography (eluent: 40:60; MeOH:EtOAc) on silica gel to afford the desired products 6 in 92% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.63 (d, J = 9.6 Hz, 1H), 7.59 – 7.56 (m, 2H), 7.43 – 7.35 (m, 4H), 6.93 (s, 1H), 4.02 – 3.95 (m, 4H), 3.65 – 3.59 (m, 4H), 2.78 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.34 (t, J = 7.6 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 149.3, 144.9, 140.7, 139.8, 136.1, 134.9, 132.8, 129.5, 128.3, 125.5, 124.5, 118.9, 113.6, 66.7, 48.1, 28.7, 21.4, 15.5; HRMS (ESI) m/z: [M + H]+ calcd for C22H25N2O2 349.1911; Found 349.1911. Preparation of 4-(4-chlorophenyl)-6-methyl-2tosylquinoline (9):12 To a mixture of Quinoline N-oxide 7 (2.00 mmol, 1.0 equiv.), sodium sulfinate salt 2 (5.00 mmol, 2.50 equiv.), in DMF (8.0 mL) was added I2 (2.20 mmol, 2.20 equiv.), and TBHP in water (6.0 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. Upon completion, saturated Na2S2O3 (10 mL) and H2O (10 mL) were added and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated NaCl, dried with anhydrous Na2SO4 and concentrated under reduced pressure the residue was purified by column chromatography using a mixture of petroleum ether/ethyl acetate (75/25) on silica gel to give 2-sulfonylquinoine 9, in 88% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 6.9 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 2.48 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 157.1, 149.2, 146.7, 144.7, 139.9, 136.2, 135.5, 135.3, 133.1, 130.8, 130.6, 129.7, 129.1, 127.1, 124.2, 117.7, 22.0, 21.6; HRMS (ESI) m/z: [M + H]+ calcd for C23H19ClNO2S 408.0820; Found 408.0811. 6-methyl-4-phenylquinoline-2-d-(3aa-d2). 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.58 – 7.49 (m, 6H), 7.31 (s, 1H); 2.47 (s, 3H).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Characterization of new compounds (1H and 13C NMR spectra) (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected] & [email protected] Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT The Department of Science and Technology (DST), India is acknowledged for the award of DST-INSPIRE Faculty award to D.K.T. The Science and Engineering Research Board (SERB), New Delhi India, is thanked for the financial support. M.P. is thankful to the University Grants Commission (UGC) India for his fellowship. S.B.W is thankful to Council of Scientific and Industrial Research (CSIR), India for fellowship. M.P., S.B.W. and D. K. T. gratefully acknowledge the Academy of Scientific and Innovative Research (AcSIR) for PhD registration. The authors are grateful to the Director, CSIR-IICT, for providing the necessary infrastructure.

REFERENCES (1) (a) Saga, Y.; Motoki, R.; Makino, S.; Shimizu,Y.; Kanai, M.; Shibasaki, M. Catalytic Asymmetric Synthesis of R207910. J. Am. Chem. Soc. 2006, 132, 7905 – 7907. (b) Lemmon, M. A.; Schlessinger, J. Cell Signaling by Receptor‐Tyrosine Kinases. Cell, 2010, 141, 1117 – 1134. (c) Klock, C.; Herrera, Z.; Albertelli, M.; Khosla, C. Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042 – 9064. (d) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic Chemistry II Eds.; Pergamon Press: Oxford, UK, 1996, 05, 245 – 1260. (e) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.; Bawa, S. A Review on Anticancer Potential of Bioactive Heterocycle Quinoline. Eur. J. Med. Chem. 2015, 97, 871- 910. (f) Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai, H. Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics. J. Med. Chem. 2006, 49, 1506 – 1508. (g) Barluenga, J.; Rodriguez, F.; Fananas, F. J. Recent Advances in the Synthesis of Indole and Quinoline Derivatives through Cascade Reactions Chem. Asian J. 2009, 4, 1036 - 1048. (h) Michael, J. P. Quinoline, Quinazoline and Acridone Alkaloids. Nat. Prod. Rep. 2008, 25, 166 - 187. (2) (a) Venkatesan, H.; Hocutt, F. M.; Jones, T. K.; Rabinowitz, M. H. A One-Step Synthesis of 2,4-Unsubstituted Quinoline-3-carboxylic Acid Esters from o-Nitrobenzaldehydes. J. Org. Chem. 2010, 75, 3488 - 3499. (b) Solomon, V. R.; Lee, H. Quinoline as a Privileged Scaffold in Cancer Drug Discovery. Curr. Med. Chem. 2011, 18, 1488 – 1508. (c) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Quinolines and Structurally Related Heterocycles as Antimalarials. Eur. J. Med. Chem. 2010, 45, 3245 – 3265. (d) Michael, J. P. Quinoline, Quinazoline and Acridone Alkaloids. Nat. Prod. Rep., 2007, 24, 223 – 246. (e) Klingenstein, R.; Melnyk, P.; Leliveld, S. R.; Ryckebusch, A. Korth, C. Similar Structure-Activity Relationships of Quinoline Derivatives for Antiprion and Antimalarial Effects. J. Med. Chem. 2006, 49, 5300 – 5308. (f) Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A. Ramesh, C.; Harakishore, K.; Gangadasu, B.; Murthy, U. S. N.; Rao, V. J. Synthesis of Multisubstituted Quinolines from Baylis–Hillman Adducts Obtained from Substituted 2Chloronicotinaldehydes and their Antimicrobial Activity Bioorg. Med. Chem., 2006, 14, 4600 – 4609. (g) Suresh, K.; Sandhya, B.; Himanshu, G. Biological Activities of Quinoline Derivatives. MiniRev. Med. Chem. 2009, 9, 1648 – 1654. (3) (a) Musiol, R. An Overview of Quinoline as a Privileged Scaffold in Cancer Drug Discovery. Expert Opin. Drug Discov. 2017, 12, 583 – 597. (b) Lee, J. C.; Tseng, C. K.; Lin, C. K.; Tseng, C. H. Discovery of Novel Diarylpyrazolylquinoline Derivatives as Potent Anti-



dengue Virus Agents. Eur. J. Med. Chem. 2017, 141, 282 – 292. (c) Rouffet, M.; de Oliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.; McCammon, J. A.; Cohen, S. M. From Sensors to Silencers: Quinoline and Benzimidazole Sulfonamides as Inhibitors for Zinc Proteases. J. Am. Chem. Soc. 2010, 132, 8232 – 8233. (d) Bhalla, V.; Vij, V.; Kumar, M.; Sharma, P. R.; Kaur, T. Recognition of Adenosine Monophosphate and H2PO4– using Zinc Ensemble of New Hexaphenylbenzene Derivative: Potential Bioprobe and Multichannel Keypad System. Org. Lett. 2012, 14, 1012 - 2015. (4) (a) Saunthwal, R. K.; Patel, M.; Verma, A. K. Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines. Org. Lett. 2016, 18, 2200 – 2203. (b) Wang, H.; Xu, Q.; Shen, S.; Yu, S. Synthesis of Quinolines through Three-Component Cascade Annulation of Aryl Diazonium Salts, Nitriles, and Alkynes. J. Org. Chem. 2017, 82, 770 – 775. (c) Rehan, M.; Hazra, G.; Ghorai, P. Synthesis of Polysubstituted Quinolines via Transition-Metal-Free Oxidative Cycloisomerization of oCinnamylanilines. Org. Lett., 2015, 17, 1668 – 1671. (d) Gao, Q.; Liu, S.; Wu, X.; Wu, A. Povarov-Type Reaction Using Methyl as New Input: Direct Synthesis of Substituted Quinolines by I2-Mediated Formal [3 + 2 + 1] Cycloaddition. Org. Lett. 2014, 16, 4582 - 4585. (e) Kong, L.; Zhou, Y.; Huang, H.; Yang, Y.; Liu, Y.; Li, Y. CopperCatalyzed Synthesis of Substituted Quinolines via C–N Coupling/Condensation from ortho-Acylanilines and Alkenyl Iodides. J. Org. Chem. 2015, 80, 1275 – 1278. (f) Li, H.; Wang, C.; Huang, H.; Xu, X.; Li, Y. Silver-catalyzed cascade reaction of o-aminoaryl compounds with alkynes: an aniline mediated synthesis of 2-substituted quinolines. Tetrahedron Lett. 2011, 52, 1108 – 111. (g) Ahmed, W.; Z. Sheng, Yu, X.; Yamamotoa, Y.; Bao, M. Brønsted acid-catalyzed metal- and solvent-free quinoline synthesis from N-alkyl anilines and alkynes or alkenes. Green Chem. 2018, 20, 261–265. (5) (a) Xia, X.; Zhang, L.; Song, X.; Liu, X.; Liang, CopperCatalyzed Oxidative Cyclization of Enynes for the Synthesis of 4Carbonyl-quinolines with O2. Y. Org. Lett. 2012, 14, 2480 – 2483. (b) Wang, Y.; Chen, C.; Peng, J.; Li, M. Copper(II)‐Catalyzed Three‐Component Cascade Annulation of Diaryliodoniums, Nitriles, and Alkynes: A Regioselective Synthesis of Multiply Substituted Quinolines. Angew. Chem., Int. Ed. 2013, 52, 5323 – 5327. (c) Ji, X.; Huang, H.; Li, Y.; Chen, H.; Jiang, H. Palladium‐Catalyzed Sequential Formation of C-C Bonds: Efficient Assembly of 2‐Substituted and 2,3‐Disubstituted Quinolines. Angew. Chem. Int. Ed. 2012, 51, 7292 – 7296. (d) Cho, C. S.; Kim, B. T.; Kim, T. J.; Shim, S. C. Ruthenium-Catalysed Oxidative Cyclisation of 2-Aminobenzyl Alcohol with Ketones: Modified Friedlaender Quinoline Synthesis. Chem. Commun. 2001, 2576 - 2576. (6) (a) Xu, X.; Yang, Y.; Chen, X.; Zhang, Z.; Yi, W. The One-Pot Synthesis of Quinolines via Co(III)-catalyzed C–H Activation/Carbonylation/Cyclization of anilines. Org. Biomol. Chem. 2017, 15, 9061 – 9065. (b) Jadhav, S. D.; Singh, A. Oxidative Annulations Involving DMSO and Formamide: K2S2O8 Mediated Syntheses of Quinolines and Pyrimidines. Org. Lett. 2017, 19, 5673 – 5676; (c) Bharate, J. B.; Wani, A.; Sharma, S.; Reja, S. I.; Kumar, M.; Vishwakarma, R. A.; Kumar, A.; Bharate, S. B. Synthesis, and the antioxidant, neuroprotective and P-glycoprotein induction activity of 4arylquinoline-2-carboxylates. Org. Biomol. Chem. 2014, 12, 6267 – 6277. (7) Xu, X.; Yang, Y.; Chen, Zhang, X.; Yi, W. Direct Synthesis of Quinolines via Co(III)-Catalyzed and DMSO-Involved C–H Activation/Cyclization of Anilines with Alkynes. Org. Lett. 2018, 20, 566 569. (8) (a) Tiwari, D. K.; Pogula, J.; Sridhar, B.; Tiwari, D. K.; Likhar, P. R. Nano-Copper Catalysed Highly Regioselective Synthesis of 2,4Disubstituted Pyrroles from Terminal Alkynes and Isocyanides. Chem. Commun., 2015, 51, 13646 – 13649. (b) Phanindrudu, M.; Tiwari, D. K.; Sridhar, B.; Likhar, P. R.; Tiwari, D. K. Magnetically Separable Nano-Copper Catalyzed Unprecedented Stereoselective Synthesis of E-vinyl Sulfones from Tosylmethyl Isocyanide and Alkynes: TosMIC as a Source of the Sulfonyl Group. Org. Chem. Front.

Page 8 of 8

2016, 03, 795 – 798. (c) Tiwari, D. K.; Phanindrudu, M.; Aravilli, V. K.; Sridhar, B.; Likhar, P. R.; Tiwari, D. K. Magnetically Recoverable Cu0/Fe3O4 Catalyzed Highly Regioselective Synthesis of 2,3,4- Trisubstituted Pyrroles from Unactivated Terminal Alkynes and Isocyanides. Chem. Commun., 2016, 52, 4675 – 4678. (d) Phanindrudu, M.; Tiwari, D. K.; Aravilli, V. K.; Bhadwaj, K.C.; Sabapathi, G.; Likhar, P. R.; Tiwari, D. K. Magnetically Recoverable Cu0/Fe3O4-Catalysed One-Pot Tandem Synthesis of Sulfur-Containing Triazoles from Alkynes and Azide: DMSO Acts as an Alkylating Agent. Eur. J. Org. Chem. 2016, 4629 - 4634. (e) Tiwari, D. K.; Maurya, R. A.; Nanubolu, J. B. Visible-Light/Photoredox-Mediated sp3 C-H Functionalization and Coupling of Secondary Amines with Vinyl Azides in Flow Microreactors. Chem. Eur. J. 2016, 22, 526. (9) (a) Tiwari D. K.; Phanindrudu M.; Wakade S. B.; Nanubolu J. B.; Tiwari D. K. α,β-Functionalization of Saturated Ketones with Anthranils via Cu-Catalyzed Sequential Dehydrogenation/azaMichael addition/Annulations Cascade Reactions in One-Pot, Chem. Commun., 2017, 53, 5302 – 5305. (b) Wakade, S. B.; Tiwari, D. K.; Ganesh, P. S. K. P.; Phanindrudu, M.; Likhar, P. R.; Tiwari, D. K. Transition-Metal-Free Quinoline Synthesis from Acetophenones and Anthranils via Sequential One-Carbon Homologation/Conjugate Addition/Annulation Cascade. Org. Lett. 2017, 19, 4948 – 4951. (c) Liu, Y. F.; Zhan, X.; Ji, P. Y.; Xu, J. W.; Liu, Q.; Luo, W. P.; Chen, T. Q.; Guo, C. C. Transition metal-free C(sp3)–H bond coupling among three methyl groups. Chem. Commun. 2017, 53, 5346 - 5349. (10) (a) Kim, J.; Choi, J.; Shin, K.; Chang, S. Copper-Mediated Sequential Cyanation of Aryl C–B and Arene C–H Bonds Using Ammonium Iodide and DMF. J. Am. Chem. Soc. 2012, 134, 2528 – 2531. (b) Yan, Y.; Yuan, Y.; Jiao, N. Cu-Mediated C–H Cyanation of Arenes Using N,N-Dimethylformamide (DMF) as the “CN” Source. Org. Chem. Front. 2014, 1, 1176 – 1179. (c) Xu, X.; Zhang, M.; Jiang, H.; Zheng, J.; Li, Y. A Novel Straightforward Synthesis of 2,4Disubstituted-1,3,5-triazines via Aerobic Copper-Catalyzed Cyclization of Amidines with DMF. Org. Lett. 2014, 16, 3540 – 3543. (11) (a) Li, G.; Jia, C.; Sun, K. Copper-Catalyzed Intermolecular Dehydrogenative Amidation/Amination of Quinoline N-Oxides with Lactams/Cyclamines. Org. Lett. 2013, 15, 5198 – 5201. (b) Joshi, P. V.; Sayed, A. A.; Kumar, A. R.; Puranik V. G.; Zinjarde, S. S. 4Phenyl Quinoline Derivatives as Potential Serotonin Receptor Ligands with Antiproliferative Activity Eur. J. Med. Chem. 2017, 136, 246 – 258. (c) Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Synthesis and Antiulcer Activity of the Metabolites of 2-(4-Ethyl-1-piperazinyl)-4-phenylquinoline Dimaleate (AS-2646), a Novel Gastric Antisecretory and Antiulcer Agent. Chem. Pharma. Bull, 1989, 37, 190 - 192. (12) Sumunnee, L.; Buathongjan, C.; Pimpasri, C.; Yotphan, S. Iodine/TBHP‐Promoted One‐Pot Deoxygenation and Direct 2‐Sulfonylation of Quinoline N‐Oxides with Sodium Sulfinates: Facile and Regioselective Synthesis of 2‐Sulfonylquinolines. Eur. J. Org. Chem. 2017, 1025 - 1032. (13) Kulkarni, A.; Torok, B. Microwave-Assisted Multicomponent Domino cyclization Aromatization: an Efficient Approach for the Synthesis of Substituted Quinolines. Green Chem. 2010, 12, 875 878.


quinolines from Alkynes and Anilines - ACS Publications

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