Synthesis of N-Biheteroarenes via Acceptorless Dehydrogenative

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Synthesis of N-Biheteroarenes via Acceptorless Dehydrogenative Coupling of Benzocyclic Amines with Indole Derivatives Xiuwen Chen, Yibiao Li, Lu Chen, Zhongzhi Zhu, Bin Li, Yubing Huang, and Min Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00200 • Publication Date (Web): 21 Feb 2019 Downloaded from http://pubs.acs.org on February 21, 2019

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The Journal of Organic Chemistry

Synthesis of N-Biheteroarenes via Acceptorless Dehydrogenative Coupling of Benzocyclic Amines with Indole Derivatives Xiuwen Chen,†,§ Yibiao Li,†,§ Lu Chen,† Zhongzhi Zhu,† Bin Li,† Yubing Huang † and Min Zhang*,†,‡ † School

‡

of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.

School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China.

E-mail: [email protected] OMe X

R2 N R1

+

R

3

N H

Cat b (1 mol %) TFE, N2, 50 oC

X

R2

R3 N

Cl Ir

N

N R1 Cat b

mild reaction conditions no need for oxidant

broad substrate scope high chemoselectiviy and atom efficiecny

ABSTRACT: Here, via a strategy of in situ capture of partially dehydrogenated cyclic amine motifs, we present an acceptorless dehydrogenative coupling (ADC) of benzocyclic amines with indole derivatives, which enables to access various quinoline-indole linked N-biheteroarenes in an efficient manner. The catalytic transformation is characteristic of operational simplicity, readily available catalyst system, good substrate and functional compatibility, mild conditions, high atom-efficiency, and no need for oxidant and halogenated coupling agents. INTRODUCTION N-Biheteroarenes constitute the core structures of numerous functional products, including bioactive molecules, pharmaceuticals, chemical sensors, ligands, and functional materials.1 Quinoline and indole extensively exist in a wide array of natural and synthetic products that exhibit interesting biological and therapeutic activities.

2

Therefore, the construction of quinoline-indole linked

heterobiarenes would be of important significance, as it offers the potential to result in structurally

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diverse products with original bioactivities, physical and chemical properties, and paves the way for the discovery of novel functional molecules. In general, quinoline-indole linked biheteroarenes could be synthesized by transition metal-catalyzed cross-coupling of organometallic reagents with heteroaryl halides or pseudohalides (e.g., Suzuki-Miyaura reaction).3 In recent years, several interesting approaches have been developed to access such compounds. The early examples, via palladium-catalyzed oxidative C–H indolylation of heteroarene N-oxides at position-2, were contributed by the groups of You and Li.4 A further reduction of the resulting N-oxides would afford the desired biaryl products. In the same year, Bergman and the co-workers reported a HCl-promoted addition of indoles to quinoline, where excess quinoline serves as both the coupling partner and a hydrogen acceptor.5 Later, the Pal group demonstrated an AlCl3-mediated cross-coupling of indoles with 2-chloroquinoline-3-carbonitriles, and the obtained products were proven to be a class PDE4 inhibitors.6 Despite the significant utility of these transformations, some key issues remains to be addressed, such as the need for pre-installation of specific coupling agents and directing groups, the generation of stoichiometric amount of inorganic wastes, the use of corrosive protonic and Lewis acids, the consumption of excess coupling components, and limited substrate and functional compatibility. Hence, the development of new approaches, enabling step and atom-economic construction of N-biheteroaryl systems, still remains a highly demanding goal.


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Scheme 1. Envisaged synthetic protocol [Ir]

+ N 2a H

N 1a H

+ N 3aa' H

[Ir]

NH

3aa

N

NH

1a-2

N

2a [Ir]

- [Ir], - H2 1a'

N H

st

[IrH]

1 DH

1a-1

N

2nd DH

In recent years, acceptorless dehydrogenative coupling (ADC) has emerged as an attractive tool for the elaboration of various functional molecules.7 Advantageously, the related transformations generate the desired products with liberation of hydrogen gas as the sole by-product, and there is no need for additional oxidants or hydrogen acceptors. In this regard, significant progress has been made. For instance, the groups of Milstein,8 Kempe,9 Li,10 Bruneau,11 Xiao and Wang,12 Kirchner,13 and others14 have reported a series of interesting examples. Attracted by the striking features of ADC strategy, and enlightened by our recent work on direct functionalization of N-heterocycles,15 we were motivated to develop a new synthesis of 2-indole-functionalized quinolines via a strategy of in-situ capture of partially dehydrogenated cyclic amine motif. As illustrated in Scheme 1 employing the coupling of tetrahydroquinoline (THQ) 1a and indole 2a as a prototypical example, the first dehydrogenation (DH) of 1a under iridium catalysis leads to generate imine 1a-1, which then is able to trap the nucleophilic site-3 of indole 2a, and delivers product 3aa via further dehydroaromatization of the coupling adduct 3aa’. However, it is important to note that direct dehydrogenation of 1a-1 to the non-coupling quinoline 1a-2 is a thermodynamically favourable process.16 To achieve selective synthesis of compound 3aa, there should be a compatible catalyst



Page 4 of 23

system to ensure that the trapping rate of 1a-1 by indole 2a is much faster than the dehydroaromatization process (from 1a-1 to 1a-2). RESULTS AND DISCUSSION To test the above idea, we chose the synthesis of product 3aa from 1a and 2a as a model reaction to determine an efficient catalyst system. First, the reaction in t-AmOH and trifluoroethanol (TFE) was performed at 50 oC for 16 h by testing 2 conventional iridium catalysts, but they showed no activity (Table 1, entries 1-4). Upon a literature investigation, the combination of Cat b with TFE solvent (pK a 12.5) is able to facilitate the dehydrogenation of amines to form imino intermediates.12a,12d Thus, we tested three C^N ligated iridium complexes. All of them in TFE were able to afford the desired product 3aa along with a certain amount of quinoline 1a-2, and Cat b showed the best catalytic performance (entries 5-7). However, the blank experiments showed that, in the absence of iridacyclic complexes or TFE solvent failed to give any product (entries 8-9), showing that both of which are critical to constitute an efficient reaction system. Decrease or increase of reaction temperature led to diminished product yield (entry 10). Thus, the best conditions are as described in entry 6 of Table 1.

Table 1. Screening of optimal reaction conditionsa 1a

Cat. solvent, N2,

2a

+

3aa Cl

Ir N

R1

+

N NH

1a-2

N

Cat a: R1 = H, R2 = H Cat b: R1 = OMe, R2 = H Cat c: R1 = OMe, R2 = OMe

R2

Entry

Cat. (1 mol %)

Solvent

3aa (yield %)b

1

[Cp*IrCl2]2

t-AmOH

－


1a-2 6

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aUnless

2 3 4 5

[Ir(COD)Cl]2 [Cp*IrCl2]2 [Ir(COD)Cl]2 Cat a

t-AmOH TFE TFE TFE

－－－ 58

4 －－ 6

6

Cat b

TFE

80

15

7

Cat c

TFE

44

32

8 9 10

－ Cat b Cat b

TFE t-AmOH TFE

－－ (40, 62)

－－ (15, 23)c

otherwise stated, the reaction was performed with 1a (0.5 mmol), 2a (0.6 mmol), cat. (1 mol %) in TFE

(1.5 mL) at 50 oC for 16 h under N2 protection. bIsolated yield. cYields are with respect to the temperatures at 40 oC and 60 oC, respectively.

With the availability of the preferred reaction conditions, we then explored the substrate scope. As illustrated in Scheme 2, the reactions of indole 2a in combination with a variety of 1,2,3,4-tetrahydroquinolines (THQs) were tested. All the reactions proceeded smoothly and furnished the desired products (3aa-3la) in moderate to good yields upon isolation. Moreover, a variety of substituents on the aryl ring of THQs 1, regardless of electron-donating and withdrawing ones (–Me, –OMe, –F, –Cl, –Br, –CO2Me, –NO2), were well tolerated. These substituents affected the product yields to some extent. Especially, THQs bearing an electron-donating group (3ba-3fa) afforded the corresponding products in relatively higher yields than those of THQs with an electron-withdrawing group (3ga-3ka). This phenomenon is attributable to the electron-rich THQs can result in slow dehydrogenation rate, thus favoring the capture of imine intermediates (Scheme 1). It

is

important

to

note

that,

under

oxidant-free

dehydrogenative

conditions,

both

hydrodehalogenation of the carbon-halide bonds (3ga-3ia) and reduction of the reducible group (i.e. –NO2) were not observed, indicating that the reaction undergoes in a chemoselective manner. In



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addition to tetrahydroquinolines, other benzocyclic amine such as tetrahydroquinoxaline (1l) was also amenable to the transformation, affording the desired cross-coupling product 3la in good yield. Scheme 2. Variation of benzocyclic amines a X

X

Cat b (1 mol %)

R1 +

N H1

2a

N 3aa, 76%

N H

TFE, N2, 50 oC

N

3, isolated yield

N NH

N

NH

3ca, 70%

NH

O

N 3ea, 70%

NH

NH

N

3ba, 71% O

3da, 58%

R1

N 3fa, 60%

NH

NH

Br

F

Cl N 3ga, 51%

N 3ha, 53%

NH

NH

NO2

O

N 3ia, 44%

NH

N

O N 3ja, 42%

N

N NH

3ka, 31%

NH

3la, 63%

NH

aStandard

conditions: 1a (0.5 mmol), 2a (0.6 mmol), cat. (1 mol %) in TFE (1.5 mL) at 50 oC for 16 h under N2 protection. Subsequently, we turned our attention to the variation of both coupling partners (Scheme 3). Thus, a range of benzocyclic amines in combination with various indoles (2b-2m) were examined. All the reactions underwent efficient dehydrogenative cross-coupling and generated the desired products in moderate to good yields (3ab-3am, 3lb, 3lf). Noteworthy, indoles 2 having an electron-donating group (3ab, 3ae, 4af) gave higher yields than those of reactants 2 with an electron-withdrawing substituent (3ah-3ak), presumably because the electron-donating groups enhance the nucleophilicity of the corresponding indoles, thus favoring the cross-coupling step (Scheme 1). Moreover, indoles with a substituent at position-2 and 4 disfavor the product formation


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(3ac, 3ag, 3al and 3am), presumably because of the influence of steric effect. Interestingly, 1H-pyrrolo[2,3-b]pyridine 2n, an indole analogue, also underwent smooth acceptorless dehydrogenative coupling, generating the desired product 3an in reasonable yield. Similar to the results described in Scheme 2, various functional groups such as –F, –Cl, –Br, –CO2Me, –Me, – OMe, and –OCH2Ph on both coupling partners are well tolerated, and the retention of these functionalities offers the potential for molecular complexity via further chemical transformations. It is important to know that, due to the existence of quinolyl N-atom and indolyl C-H unit at position 2, the obtained products can serve as highly conjugated C^N ligands for the preparation of cyclometallated metal complexes exhibiting potential strong luminescence property17. Scheme 3. Variation of both coupling partners X

X

R

+ N H

1

N 3ab, 65%

R2

Cat b (1 mol %)

2

2

N R1

3, isolated yield

N 3ac, 42%

NH

N

TFE, N2, 50 oC

N R1

N 3ad, 33%

NH

Ph

O

N O

O N 3ae, 66%

N 3af, 71%

NH

N 3ag, 53%

NH

NH Br

F Cl N 3ah, 51%

N 3ai, 41%

NH

N 3aj, 53%

NH

NH

CO2CH3 N 3ak, 32%

NH

N

N 3al, 40%

NH

NH

N 3lf, 60%

N 3am, 51%

NH

O

N

N 3lb, 50%

OCH3

N NH


3an, 33%

N NH


Page 8 of 23

To gain mechanistic insight into the reaction, we performed several control experiments. As show in Scheme 4, the reaction of quinoline 1a-2 with indole 2a was unable to yield product 3aa (eq 1), showing that 1a-2 is not a reaction intermediate. Then, the reaction of dihydroquinolines (the mixture of imine 1a-1 and its tautomer enamine)18 with indole 2a produced product 3aa in 75% yield along with the coupling adduct 3aa’ in 5% yield (eq 2). Further, under the standard conditions, compound 3aa’ could be further transformed into product 3aa with high yield (eq 3). These two experiments show that both dihydroquinolines and the coupling adduct 3aa’ are the key reaction intermediates. All these results are in well consistent with the reaction pathway proposed in Scheme 1. Although the effect of TFE has not been elucidated at the current stage, according to the reported literatures,12a,19 it is believed that the TFE plays a key role in assisting the liberation of H2 gas from [IrH] species (Scheme 1, species 1a’) and regeneration of the catalyst. Scheme 4. Control experiments

1a-2

N

+

standard conditions

N H 2a

standard + 2a conditions 3aa, 75% +

+ N

1a-1

3aa'

N H

N H

N 3aa, 0%

1a-1'

standard conditions

N H 3aa', 5%

3aa, 82%

(eq 1) NH

(eq 2) NH (eq 3)

NH

CONCLUSIONS In conclusion, through a strategy of in situ capture of partially dehydrogenated cyclic amine motifs, we have developed an iridium-catalyzed acceptorless dehydrogenative cross-coupling of benzocylic amines with indole derivatives, which enables to assemble a variety of quinoline-indole


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linked biheteroaryl products in moderate to good isolated yields. The catalytic transformation proceeds with mild conditions, operational simplicity, no need for external oxidants, good functional and substrate compability, easily available catalyst system, and high atom-efficiency, which offers an environmentally benign way for straightforward access to N- biheteroaryl systems, and demonstrates the potential for further development of oxidant-free cross-coupling reactions that lead to the discovery of bioactive molecules and functional materials. EXPERIMENTAL SECTION General Information. All experiments were carried out under the standard conditions. Flash column chromatography was performed over silica gel (200−300 mesh). 1H NMR and 13C {1H} NMR spectra were recorded on a Bruker-AV (400 and 100 MHz, respectively) instrument internally referenced to TMS, chloroform and DMSO signals. MS analyses were performed on an Agilent 5975 GC−MS instrument (EI). High resolution mass spectra (HRMS) were recorded using electrospray ionization (ESI) and time-of-flight (TOF) mass analysis. Melting points were uncorrected. The new compounds were characterized by 1H NMR, 13C {1H} NMR, MS and HRMS. General procedure for the preparation of cyclometalated complexes cat a-c. Ketone (5.0 mmol) and amine (5.50 mmol) were dissolved in toluene (80 mL). NaHCO3 (420 mg, 5 mmol) and 4Å MS (1.2 g) were then added. The mixture was stirred under reflux for 24 h, then cooled to room temperature and filtered through celite. The solvent was removed under vacuum and the resulting crude mixture was recrystallized using DCM/hexane to give the corresponding imine. [Cp*IrCl2]2 (200.0 mg, 0.25 mmol), imine ligand (0.55 mmol), NaOAc (205.9 mg, 2.5 mmol) were placed in a carousel reaction tube. DCM (10 mL) was introduced and the resulting mixture was stirred for 24 h at room temperature. The reaction mixture was then filtered through celite and dried over Na2SO4. The solvent was evaporated under vacuum and the resulting solid was washed with hexane/diethyl ether (2:1) mixture. All the cyclometalated complexes cat a-c are were consistent with the literature.


known, and their NMR spectra


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Typical procedure for the synthesis of product 3. Under N2 atmosphere, tetrahydroquinoline 1 (0.3 mmol), indole 2 (0.45 mmol), cat b (1 mol %) and TFE (1.5 mL) were introduced into a Schlenk tube (25 mL), successively. Then, the Schlenk tube was closed and the resulting mixture was stirred at 50 °C for 16 h. After cooling down to room temperature, the reaction mixture was concentrated by removing the solvent under vacuum, and the residue was purified by preparative TLC on silica, eluting with petroleum ether (60-90 °C): ethyl acetate (4:1) to give product 3. Synthesis of 2-(1H-indol-3-yl)quinoline (3aa): Under N2 atmosphere, tetrahydroquinoline 1a (399 mg, 3 mmol), indole 2a (526.5 mg, 4.5 mmol), cat b (17.6 mg, 1 mol %) and TFE (10 mL) were introduced into a Schlenk tube (50 mL), successively. Then, the Schlenk tube was closed and the resulting mixture was stirred at 50 °C for 16 h. Puriﬁcation of the residue by column chromatography (4:1 petroleum ether:ethyl acetate) gave 3aa as a yellow solid (497.8 mg, 68% yield). Known compound

15c;

m.p: 189.1-190.5 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR

(400 MHz, CDCl3) δ 8.78 (s, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.82 – 7.66 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.24 – 7.14 (m, 2H). 13C {1H} NMR (101 MHz, CDCl3) δ 155.1, 148.3, 137.0, 136.2, 129.5, 128.9, 127.5, 126.4, 125.8, 125.6, 125.4, 122.9, 122.0, 121.3, 119.6, 117.5, 111.4. HRMS (ESI) m/z: [M+H]+ Calcd for C17H13N2 245.1073; Found 245.1066. 2-(1H-indol-3-yl)-6-methylquinoline (3ba). Yellow solid (50.0 mg, 71% yield); m.p: 138.6-139.9 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.98 – 8.89 (m, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.56 – 7.48 (m, 2H), 7.24 (dd, J = 4.9, 2.0 Hz, 2H), 2.46 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.3, 146.8, 137.7, 135.5, 134.6, 131.8, 128.7, 127.9, 127.0, 126.2, 126.1, 123.1, 122.5, 120.7, 119.7, 116.1, 112.2, 21.5. HRMS (ESI) m/z: [M+H]+ Calcd for C18H15N2 259.1230; found: m/z 259.1227. 2-(1H-indol-3-yl)-7-methylquinoline (3ca). Gray solid (54.3 mg, 70% yield); m.p: 133.2-135.1 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 5/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.96 (dd, J = 5.7, 2.9 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 5.8, 2.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.26 (dd, J =


Page 11 of 23 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


5.8, 2.8 Hz, 2H), 2.54 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.1, 148.5, 139.5, 137.8, 135.8, 128.1, 128.0, 127.8, 127.4, 126.2, 124.3, 123.2, 122.6, 120.8, 118.8, 116.2, 112.3, 21.9. 2-(1H-indol-3-yl)-8-methylquinoline (3da). Yellow oil (44.9 mg, 58% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 9.11 – 8.86 (m, 1H), 8.39 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.53 (dd, J = 7.6, 3.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 5.3, 1.8 Hz, 2H), 2.89 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.0, 147.2, 137.8, 136.4, 136.0, 129.9, 128.2, 126.1, 125.0, 123.0, 122.6, 120.9, 119.3, 116.5, 112.3, 18.8. HRMS (ESI) Calcd. for: 259.1230 [M+H]+; found: m/z 259.1229. 2-(1H-indol-3-yl)-5-methoxyquinoline (3ea). Reddish brown solid (57.5 mg, 70% yield); m.p: 184.3-186.2 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.88 – 8.83 (m, 1H), 8.41 (d, J = 8.9 Hz, 1H), 8.32 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.62 (t, J = 4.6 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.24 – 7.17 (m, 1H), 6.97 – 6.91 (m, 1H), 3.99 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.3, 155.2, 149.2, 137.7, 130.1, 129.9, 128.2, 126.1, 123.0, 122.6, 121.2, 120.8, 118.7, 117.8, 115.9, 112.2, 104.2, 56.2. HRMS (ESI) m/z: [M+H]+ Calcd for C18H15N2O 275.1179; found: m/z 275.1179. HRMS (ESI) Calcd. for: 275.1179 [M+H]+; found: m/z 275.1179. 2-(1H-indol-3-yl)-6-methoxyquinoline (3fa). Brown solid (49.3 mg, 60% yield); m.p: 224.7-226.1 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.99 – 8.79 (m, 1H), 8.28 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.55 – 7.46 (m, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.31 (s, 1H), 7.27 – 7.16 (m, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.8, 153.8, 144.1, 137.7, 135.1, 130.4, 127.4, 127.2, 126.0, 123.0, 122.5, 121.7, 120.6, 119.9, 116.1, 112.2, 106.5, 55.9. HRMS (ESI) Calcd. for: 275.1179 [M+H]+; found: m/z 275.1175. 6-fluoro-2-(1H-indol-3-yl)quinoline

(3ga).

Yellow

solid

(40.1

mg,

51%

yield);

m.p:

157.2-159.1 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.11 (t, J = 9.3 Hz, 2H), 7.71 – 7.52 (m, 3H), 7.28 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 159.4 (d, J = 243.1 Hz), 155.7, 145.5, 137.8, 135.6 (d, J = 4.8 Hz), 131.4 (d, J = 9.0 Hz), 128.3, 126.8 (d, J = 10.0 Hz), 126.1, 123.1,



Page 12 of 23

122.7, 120.9, 120.5, 119.4 (d, J = 25.3 Hz), 115.9, 112.3, 111.3 (d, J = 21.6 Hz). 19F NMR (376 MHz, DMSO-d6) δ -116.0. HRMS (ESI) Calcd. for: 263.0979 [M+H]+; found: m/z 263.0977. 6-chloro-2-(1H-indol-3-yl)quinoline

(3ha).

Brown

solid

(44.2

mg,

53%

yield);

m.p:

148.1-149.3 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.93 – 8.85 (m, 1H), 8.39 (d, J = 2.9 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.9, 2.4 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.28 – 7.21 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.6, 146.8, 137.8, 135.4, 130.9, 130.2, 129.4, 128.7, 127.1, 126.8, 126.0, 123.1, 122.7, 121.0, 120.7, 115.8, 112.3. HRMS (ESI) Calcd. for: 279.0684 [M+H]+; found: m/z 279.0682. 5-bromo-2-(1H-indol-3-yl)quinoline (3ia). Reddish brown solid (42.5 mg, 44% yield); m.p: 166.1-168.2 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.97 – 8.87 (m, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.54 (dd, J = 6.1, 3.1 Hz, 1H), 7.28 – 7.24 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.9, 149.3, 137.8, 134.6, 130.5, 129.1, 129.1, 129.0, 126.1, 125.2, 123.1, 122.8, 121.5, 121.2, 121.1, 115.4, 112.4. HRMS (ESI) Calcd. for: 323.0178 [M+H]+; found: m/z 323.0180. Methyl 2-(1H-indol-3-yl)quinoline-6-carboxylate (3ja). Yellow solid (38.1 mg, 42% yield); m.p.:217.2-218.6 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.12 (m, 3H), 7.52 (s, 1H), 7.25 (s, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 166.6, 158.3, 150.5, 137.8, 137.3, 130.9, 129.5, 129.2, 129.0, 126.1, 125.9, 125.5, 123.2, 122.8, 121.2, 120.5, 115.8, 112.4, 52.6. HRMS (ESI) Calcd. for: 303.1128 [M+H]+; found: m/z 303.1129. 2-(1H-indol-3-yl)-5-nitroquinoline (3ka). Yellow solid (26.9 mg, 31% yield); m.p.:223-224 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.93 – 8.84 (m, 1H), 8.69 (d, J = 9.2 Hz, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 9.3 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.51 (dd, J = 6.2, 2.9 Hz, 1H), 7.29 – 7.22 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 157.2, 148.6, 145.9, 137.8, 135.7, 131.0,


Page 13 of 23 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


129.7, 128.6, 125.9, 123.0, 123.0, 122.9, 122.6, 121.3, 118.4, 115.1, 112.4. HRMS (ESI) Calcd. for: 290.0924 [M+H]+; found: m/z 290.0922. 2-(1H-indol-3-yl)quinoxaline (3la). Pale yellow solid (46.4 mg, 63% yield); m.p.:207-208 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.53 (d, J = 2.0 Hz, 1H), 8.89 – 8.82 (m, 1H), 8.64 (d, J = 1.3 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.58 – 7.53 (m, 1H), 7.31 – 7.25 (m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 151.4, 145.0, 142.4, 139.9, 137.7, 130.4, 129.4, 129.2, 128.9, 128.2, 126.1, 123.2, 122.9, 121.4, 113.5, 112.5. HRMS (ESI) Calcd. for: 246.1026 [M+H]+; found: m/z 246.1024. 2-(6-methyl-1H-indol-3-yl)quinoline (3ab). Yellow oil (50.2 mg, 65% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.68 (m, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.16 – 7.09 (m, 2H), 2.46 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.3, 148.5, 137.5, 135.9, 132.6, 129.4, 129.0, 127.5, 126.4, 125.2, 124.9, 123.6, 123.0, 121.6, 119.6, 117.5, 111.4, 21.7. HRMS (ESI) Calcd. for: 259.1230 [M+H]+; found: m/z 259.1233. 2-(2-methyl-1H-indol-3-yl)quinoline (3ac). Yellow oil (32.5 mg, 42% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.18 (t, J = 9.3 Hz, 2H), 8.09 – 8.00 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.32 (dd, J = 6.2, 2.9 Hz, 1H), 7.23 – 7.13 (m, 2H), 2.71 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.1, 148.5, 136.2, 136.2, 135.6, 129.56, 128.7, 127.7, 127.6, 126.3, 125.6, 122.4, 121.7, 120.5, 119.2, 113.4, 110.9, 13.0. HRMS (ESI) Calcd. for: 259.1230 [M+H]+; found: m/z 259.1229. 2-(1-methyl-1H-indol-3-yl)quinoline

(3ad).

Yellow

solid

(25.5

mg,

33%

yield);

m.p.:152.4-153.7 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 7.4 Hz, 1H), 8.33 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.34 – 7.21 (m, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ



Page 14 of 23

155.7, 148.3, 138.2, 136.2, 132.2, 129.9, 128.9, 128.1, 126.5, 126.3, 125.4, 123.2, 122.7, 121.1, 119.5, 115.0, 110.6, 33.4. HRMS (ESI) Calcd. for: 259.1230 [M+H]+; found: m/z 259.1234. 2-(6-methoxy-1H-indol-3-yl)quinoline

(3ae).

Yellow

solid

(54.2

mg,

66%

yield);

m.p.:182.4-183.8 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.75 (d, J = 8.7 Hz, 1H), 8.21 (t, J = 5.3 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.7, 2.2 Hz, 1H), 3.82 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 156.5, 156.1, 148.3, 138.5, 136.0, 129.8, 128.8, 128.1, 127.1, 126.3, 125.3, 123.8, 120.3, 119.6, 116.1, 110.9, 95.1, 55.6. HRMS (ESI) Calcd. for: 275.1179 [M+H]+; found: m/z 275.1177. 2-(5-methoxy-1H-indol-3-yl)quinoline

(3af).

Brownish

oil

(58.4

mg,

71%

yield);

m.p.:185.8-187.1 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 15.7 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.69 – 7.55 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H), 7.11 (dd, J = 8.2, 6.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 3.94 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.5, 155.3, 148.3, 136.1, 132.2, 129.5, 128.8, 127.6, 126.4, 126.4, 126.3, 125.3, 119.4, 116.9, 113.0, 112.2, 104.1, 55.9. HRMS (ESI) Calcd. for: 275.1179 [M+H]+; found: m/z 275.1178. 2-(4-(benzyloxy)-1H-indol-3-yl)quinoline (3ag). Gray oil (55.3 mg, 53% yield); Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz, 2H), 7.82 – 7.75 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 11.2, 4.1 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.26 – 7.14 (m, 6H), 7.11 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.14 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.8, 153.3, 147.5, 138.8, 136.9, 134.9, 129.2, 128.4, 128.2, 127.7, 127.7, 127.5, 126.7, 126.0, 125.4, 124.9, 123.1, 117.9, 115.9, 105.8, 102.4, 70.5. HRMS (ESI) Calcd. for: 351.1492 [M+H]+; found: m/z 351.1494. 2-(5-fluoro-1H-indol-3-yl)quinoline (3ah). Gray solid (40.1 mg, 51% yield); m.p.:164.7-165.9 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.71 (dd, J = 10.6, 2.5 Hz, 1H), 8.50 (d, J = 23.1 Hz, 1H), 8.25 (t, J = 12.1 Hz, 1H), 8.09 (t, J = 9.4 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 – 7.44 (m, 2H), 7.13 (td, J = 9.1, 2.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 158.4 (d, J = 232.0 Hz), 155.8, 148.2, 136.2, 134.4,


Page 15 of 23 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


130.0, 129.9, 128.9, 128.1, 126.5 (d, J = 11.1 Hz), 126.3, 125.5, 119.5, 116.1 (d, J = 4.7 Hz), 113.3 (d, J = 9.8 Hz), 110.8 (d, J = 26.2 Hz), 107.8 (d, J = 24.5 Hz).

19F

NMR (376 MHz, DMSO-d6) δ

-122.98. HRMS (ESI) Calcd. for: 263.0979 [M+H]+; found: m/z 263.0976. 2-(6-chloro-1H-indol-3-yl)quinoline (3ai). Reddish brown solid (34.2 mg, 41% yield); m.p.:204.4-205.9 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.91 (d, J = 8.6 Hz, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.24 (dd, J = 8.6, 1.9 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.6, 148.2, 138.2, 136.3, 129.9, 129.2, 128.9, 128.1, 127.3, 126.4, 125.6, 124.9, 124.5, 121.1, 119.6, 116.2, 111.9. HRMS (ESI) Calcd. for: 279.0684 [M+H]+; found: m/z 279.0682. 2-(5-bromo-1H-indol-3-yl)quinoline

(3aj).

Yellow

solid

(51.2

mg,

53%

yield);

m.p.:200.3-202.2 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.17 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.04 (dd, J = 17.4, 8.5 Hz, 2H), 7.83 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 11.2, 4.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.39 (dd, J = 8.6, 1.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.5, 148.2, 136.5, 136.3, 129.9, 129.4, 128.9, 128.1, 127.9, 126.4, 125.6, 125.3, 125.2, 119.5, 115.7, 114.3, 113.8. HRMS (ESI) m/z: [M+H]+ Calcd for C17H12BrN2 323.0178; found: m/z 323.0179. Methyl 3-(quinolin-2-yl)-1H-indole-5-carboxylate (3ak). Yellow solid (29.0 mg, 32% yield); m.p.:201.5-202.8 °C; Rf = 0.2 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.88 (d, J = 7.9 Hz, 1H), 8.61 (d, J = 2.7 Hz, 1H), 8.37 (s, 1H), 8.18 – 8.04 (m, 3H), 7.95 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.5, 154.9, 147.2, 137.1, 132.1, 130.4, 129.4, 128.3, 128.1, 126.4, 125.9, 123.8, 122.5, 121.6, 119.8, 115.6, 114.3, 52.4. HRMS (ESI) Calcd. for: 303.1128 [M+H]+; found: m/z 303.1130. 2-(2,5-dimethyl-1H-indol-3-yl)quinoline (3al). Brownish oil (32.7 mg, 40% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.21 (dd, J = 8.4, 4.5 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.52 (t, J



Page 16 of 23

= 7.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 2.64 (s, 3H), 2.51 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 148.4, 135.9, 133.7, 129.8, 129.4, 128.9, 127.7, 127.5, 126.2, 125.4, 123.2, 122.3, 119.1, 113.3, 110.3, 21.7, 13.4. HRMS (ESI) Calcd. for: 273.1386 [M+H]+; found: m/z 273.1389. 2-(5-methoxy-2-methyl-1H-indol-3-yl)quinoline (3am). Brownish oil (44.0 mg, 51% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.15 (dd, J = 8.4, 4.1 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 14.3, 8.2 Hz, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.7, 2.3 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H).

13C{1H}

NMR (101 MHz, CDCl3) δ 155.9, 154.9, 148.5, 136.6, 136.1, 130.6, 129.5, 128.8,

128.1, 127.6, 126.2, 125.5, 122.0, 113.5, 111.3, 111.3, 102.1, 55.9, 13.4. HRMS (ESI) Calcd. for: 289.1335 [M+H]+; found: m/z 289.1338. 2-(6-methyl-1H-indol-3-yl)quinoxaline

(3lb).

Brownish

solid

(38.9

mg,

50%

yield);

m.p.:177.5-179.1 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.70 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.26 – 7.15 (m, 2H), 2.53 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 150.4, 143.9, 142.7, 140.3, 137.4, 133.5, 129.9, 129.0, 129.0, 128.1, 125.2, 123.6, 123.5, 122.0, 115.0, 111.4, 21.8. HRMS (ESI) Calcd. for: 260.1182 [M+H]+; found: m/z 260.1187. 2-(5-methoxy-1H-indol-3-yl)quinoxaline

(3lf).

Yellow

solid

(49.5

mg,

60%

yield);

m.p.:188.1-189.5 °C; Rf = 0.4 (petroleum ether/ethyl acetate = 5/1, v/v); 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.87 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 8.3, 1.0 Hz, 1H), 8.04 (dd, J = 8.2, 1.0 Hz, 1H), 7.92 (d, J = 2.9 Hz, 1H), 7.76 – 7.69 (m, 1H), 7.66 – 7.56 (m, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H), 3.97 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.7, 150.5, 143.7, 142.6, 140.2, 131.9, 130.0, 129.0, 128.9, 128.1, 126.4, 126.3, 114.6, 113.8, 112.2, 104.2, 55.9. HRMS (ESI) Calcd. for: 276.1131 [M+H]+; found: m/z 276.1136. 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinoline (3an). Brownish solid (24.3 mg, 33% yield); m.p: 120.1-122.0 °C; Rf = 0.3 (petroleum ether/ethyl acetate = 4/1, v/v); 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.19 (dd, J = 7.9, 1.4 Hz, 1H), 8.52 (s, 1H), 8.36 (dd, J = 4.6, 1.4 Hz, 1H), 8.30 (d, J =


Page 17 of 23 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


8.7 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.79 – 7.69 (m, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.29 (dd, J = 7.9, 4.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.4, 150.0, 148.2, 144.0, 136.4, 131.3, 129.9, 128.9, 128.4, 128.2, 126.5, 125.7, 119.3, 118.6, 117.3, 114.8. HRMS (ESI) Calcd. for: 246.1026 [M+H]+; found: m/z 246.1021. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.XXX. 1H

and 13NMR spectra for the products (PDF)

AUTHOR INFORMATION Corresponding Author [email protected] Author Contributions § X.C.

and Y.L. contributed equally to this work.

Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We thank the foundation of the Department of Education of Guangdong Province (2016KTSCX144,

2017KZDXM085),

Foundation

for

Young

Talents

(Construction

of

N-Biheteroarenes by hydrogen transfer strategy and its antitumor activity), the Science and Technology Program of Guangzhou (201607010306) for financial support. REFERENCES (1) (a) Tan, G. Y.; You, Q. L.; You, J. S. Iridium-catalyzed oxidative heteroarylation of arenes and alkenes: overcoming the restriction to specific substrates. ACS Catal. 2018, 8, 8709–8714; (b) She, Z. J.; Wang, Y.; Wang, D. P.; Zhao, Y. S.; Wang, T. B.; Zheng, X. S.; Yu, Z. X.; Gao, G.; You, J. S. Two-fold C−H/C−H cross-coupling using RhCl3·3H2O as the catalyst: direct fusion of



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Synthesis of N-Biheteroarenes via Acceptorless Dehydrogenative

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