CrossâCoupling Reaction of

DOI: 10.1002/ajoc.201600411

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Cross-Coupling Reaction

Nickel-Catalyzed C(Aryl)@O Bond Activation/Cross-Coupling Reaction of Carbazoles with Methyl Grignard: Synthesis of Ellipticine Sk. Rasheed,[a, b] Desaboini Nageswar Rao,[a, b] and Parthasarathi Das*[a, b] Abstract: A nickel-catalyzed cross-coupling reaction between methoxy-substituted carbazoles and MeMgBr has been developed. This protocol for the cleavage of the

Introduction Transition-metal-catalyzed cross-coupling reactions between organic halides and organometallics for the formation of C@C bonds have emerged as powerful tools in organic synthesis.[1] In recent years, the use of nontoxic and readily available C@O electrophiles has been shown to be a viable and powerful alternative to aryl halides in cross-coupling reactions.[2] Among the many phenol derivatives that could be potentially used as electrophiles in these types of reactions, methoxy arenes stand out as the most attractive in terms of their availability and atom economy. The C(aryl)@O bond of an aryl ether, however, is one of the most inert among C(aryl)@O bonds of phenol derivatives and, therefore, poses a daunting challenge for organic chemists. In recent years nickel catalysts have played a huge role in the activation of C@O-based electrophiles.[3] From the time of Wenkert’s initial report of the nickel-catalyzed Kumada-type cross-coupling reactions of methoxy arenes with ArMgX,[4] which involved the activation of an inert C(aryl)@OMe bond, the scope of nickel-catalyzed cross-couplings of methoxy arenes has expanded to a wide range of nucleophiles, including organoboron,[5] organozinc,[6] organolithium,[7] hydride,[8] and amine compounds.[9] However, efforts to develop methods for the alkylation and alkynylation of aryl ethers by using Csp3 and Csp-based nucleophiles have met limited success. In a significant development, the Dankwardt and Shi groups independently demonstrated that the arylation/alkylation of me[a] S. Rasheed, D. N. Rao, P. Das Medicinal Chemistry Division CSIR-Indian Institute of Integrative Medicine Canal Road, Jammu-180001 (India) E-mail: [email protected] [b] S. Rasheed, D. N. Rao, P. Das Academy of Scientific and Innovative Research (AcSIR) New Delhi-110025 (India) Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ajoc.201600411. Asian J. Org. Chem. 2016, 5, 1499 – 1507

C(aryl)@OMe was used to efficiently assemble various methyl-substituted carbazoles and successfully applied to the total synthesis of the antitumor agent ellipticine.

thoxy arenes is possible by using a Ni0/PCy3 (Cy = cyclohexyl) catalyst and (aryl/alkyl)MgBr.[10] An elegant approach by Chatani’s group found that Ni0/ICy (ICY = 1,3-dicyclohexylimidazol-2ylidene) and Ni0/1,2-bis(dicyclohexylphosphino)ethane (dcype) systems can be used to promote a Kumada-type alkylative cross-coupling of methoxy arenes with a range of (alkyl/alkenyl)MgX reagents.[11] Although significant progress has been made, in particular with nickel catalysts, the diversity of compatible coupling partners still remains limited with naturally occurring heteroarene systems. Carbazole is a ubiquitous structural motif, and compounds that contain this moiety have attracted considerable attention in biological and material sciences because of their broad range of medicinal and material properties.[12] Because of the importance of these privileged molecular entities, a large number of synthetic routes have been developed for their synthesis.[13] Much effort has been made to synthesize highly oxygenated carbazoles (Figure 1),[14] but late-stage functional modifications to oxygenated carbazoles by C@OMe bond activation are rare.[11b, c] Herein, we have developed a method for the C@O bond activation of methoxy carbazoles by employing a Ni-catalyzed cross-coupling reaction with MeMgBr (Scheme 1). The direct methylation of unprotected N-H carbazoles through C@OMe bond activation is rare despite the potential pharmaceutical importance of the transformation. Our developed optimized protocol is robust and has been successfully applied to the synthesis of various methyl-substituted carbazoles and further extended to the total synthesis of the anticancer compound ellipticine.

Results and Discussion Our initial studies focused on finding an efficient catalytic system for C@O bond activation and the methylation of methoxy-substituted carbazoles. We began our experiment with 3-methoxy-substituted carbazole 1 a, methylmegnesium bromide, and Ni(PCy3)2Cl2 in toluene at 80 8C under N2, but only 25 % of the desired product was observed (Table 1, entry 1). 1499

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Figure 1. Oxygenated and methylated naturally occurring carbazoles.

Scheme 1. Ni-catalyzed C(aryl)@OMe bond activation of oxygenated carbazoles.

Table 1. Optimization reaction conditions for nickel-catalyzed C(aryl)@O bond activation of carbazoles.[a]

Entry

Catalyst

Ligand

Solvent

Yield[b] [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17[d] 18[e]

Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(dppf)Cl2 Ni(COD)2[c] Ni(PPh3)2Cl2 NiI2 Ni(C5H5)2 Ni(OAc)2 PdCl2 CoBr2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2 Ni(PCy3)2Cl2

– dppf[c] XPhos[c] PPh3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3

toluene toluene toluene DMF[c] toluene toluene toluene toluene toluene toluene toluene toluene toluene THF 1,4-dioxane diethyl ether toluene toluene

25 52 32 75 95 54 n.r. 72 n.r. n.r. n.r. n.r. n.r. 60 58 70 n.r. 75

[c]

[a] Reagents and conditions: 3-methoxycarbazole (0.25 mmol), MeMgBr (0.50 mmol), Ni(PCy3)2Cl2 (5 mol %), PCy3 (10 mol %), toluene (3 mL), 80 8C, 12 h, under N2. [b] Isolated yields are reported. [c] dppf = 1,1’-bis(diphenyphosphino)ferrocene, XPhos = 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, DMF = N,N-dimethylformamide, COD = 1,5-cyclooctadiene, n.r. = no reaction.[d] Reaction was carried out at room temperature. [e] Reaction was performed with MeMgI (0.5 mmol). Asian J. Org. Chem. 2016, 5, 1499 – 1507

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Next, we carried out the reaction in the presence of various ligands (Table 1, entries 2–5) in toluene, which showed that PCy3 was the best choice, as the desired product 2 a was isolated in an excellent 95 % yield (Table 1, entry 5). Next, we performed the reaction in the presence of different nickel catalysts, but others failed to give a better yield (Table 1, entries 6– 11). When we performed the reaction with different metal catalysts, such as palladium or cobalt, the reaction did not proceed (Table 1, entries 12 and 13). Next, we investigated the effect of changing the solvent, but the desired products were isolated in lower yields when the reactions were conducted in tetrahydrofuran (THF), 1,4-dioxane, and diethyl ether (Table 1, entries 14–16). At room temperature, no product formation was observed (Table 1, entry 17). Finally we performed the reaction with MeMgI (0.5 mmol) and isolated the methylated carbazole in 75 % yield (Table 1, entry 18). Thus, the combination of Ni(PCy3)2Cl2 (5 mol %)/PCy3 (10 mol %) in toluene under N2 remained our standard conditions for the C(aryl)@OMe bond activation/cross-coupling reaction of carbazoles with MeMgBr (Table 1, entry 5). As depicted in Table 2, the Ni/PCy3 system catalyzed the Kumada-type cross-coupling reactions of a wide variety of methoxy-substituted carbazoles. Initial studies reveal that carbazoles 1 a–1 c, which are substituted with a methoxy group at different positions, underwent smooth cross-coupling reactions to afford the desired methyl-substituted carbazoles 2 a–2 c in excellent yields (91–95 %, Table 2, entries 1–3). We then examined the methylation of various dimethoxysubstituted carbazoles 1 d–1 h. We noticed that these crosscoupling reactions were not selective, as dimethylated carbazoles 2 d–2 h were isolated in excellent yields (85-97 %) when 1500


Full Paper Table 2. Methylation of different alkoxy-substituted carbazoles.[a]

Entry

Substrate

Product

Entry

1

11

2

12

3

13

4

14

5

15

6

16

7

17

8

18

9

19

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Substrate

Product


Full Paper Table 2. (Continued)

Entry

Substrate

Product

Entry

10

Substrate

Product

20

[a] Reagents and conditions: carbazole (0.25 mmol), MeMgBr (0.50 mmol), Ni(PCy3)2Cl2 (5 mol %), PCy3 (10 mol %), toluene (3 mL), 80 8C, 12 h, under N2. [b] MeMgBr (0.75 mmol) was employed.

an excess amount (0.75 mmol) of MeMgBr was used (Table 2, entries 4–8). To further compare the reactivity of the methoxy relative to other alkoxy groups [i.e., OPh (1 i), OnPr (1 j), and OnBu (1 k)], we performed the cross-coupling reaction under the same conditions (Table 2, entries 9–11). In the presence of 0.50 mmol of MeMgBr and dimethylated product 2 d (35 %), monomethylation also took place (2 i: 25 %; 2 j: 20 %; 2 k: 22 %). However, the presence of an excess amount of MeMgBr (0.75 mmol) resulted in the methylation of the different dialkoxy carbazoles, and dimethylated product 2 d was isolated (87-90 %) exclusively. These results indicate that the different alkoxy groups in the same carbazole system cannot be differentiated under these reaction conditions. Next, we investigated the reactivity of the methoxy group in halogenated derivatives [i.e., F (1 l), Cl (1 m), Br (1 n)]. The fluoro derivative produced dimethylated product 2 d in 45 % yield in the presence of MeMgBr (0.50 mmol), whereas the C@ Cl bond did not react under the optimized conditions, and monoalkylated product 2 m was isolated in good yield (55 %, Table 2, entries 12 and 13). The highly reactive C@Br bond was not tolerated under the reaction conditions, and dimethylated carbazole 2 d was isolated in 30 % yield when 0.50 mmol of MeMgBr was used (Table 2, entry 14). When we used 0.75 mmol of MeMgBr, the fluoro (i.e., 1 l) and bromo (i.e., 1 n) groups were replaced along with the OMe group to furnish dimethylated carbazole (2 d) in excellent yields (91 and 88 % yield, respectively, Table 2, entries 12 and 14). The power and utility of this alkylation method was further demonstrated by its application to naturally occurring pyranocarbazoles 1 o and 1 p), and the corresponding methylated carbazoles 2 o and 2 p

were isolated in good yields (70 and 68 % yield, respectively, Table 2, entries 15 and 16). We further examined 3-tert-butyl-6methoxycarbazole (1 q) and 6-nitro-3-methoxycarbazole (1 r), which afforded the desired methyl-substituted carbazoles 2 q and 2 r in excellent yields (88 and 75 % yield, respectively, Table 2, entries 17 and 18). The two naturally occurring carbazoles clausenine (1 s) and glycozolidine (1 t), which contain dimethoxy groups, were then examined, and the cross-coupled products 2 s and 2 t were isolated in excellent yields (85 and 89 % yield, respectively, Table 2, entries 19 and 20). Next, we performed a competition experiment with a mixture of 1-, 2-, and 3-methoxy-substituted carbazoles (0.30 mmol) and MeMgBr (0.60 mmol) under the standard reaction conditions and found the reactivity of the derivatives to be in the following order: 3-methoxy > 2-methoxy > 1-methoxy (Scheme 2). The natural product ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) has gained interest because of its potential antitumor activity.[15] Indeed, both ellipticine and its derivatives have drawn tremendous attention from synthetic chemists, and many methods for the synthesis of ellipticine and its derivatives have been reported.[16] In most cases, these compounds were directly derivatized from ellipticine, which left a limited scope to the structure–activity relationship (SAR) studies. In this context, the development of methods for the synthesis of ellipticine from readily available starting materials is valuable. In our approach, we used commercially available 2,5-dimethoxybenzaldehyde (3) as the starting material and introduced the methyl group through a Ni-catalyzed Kumada-type coupling reactions at a late stage of the synthesis.

Scheme 2. Competition experiment between 1-, 2-, and 3-methoxy-substituted carbazoles. Asian J. Org. Chem. 2016, 5, 1499 – 1507

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Scheme 3. Total synthesis of ellipticine.[a] [a] Reagents and conditions: (i) (a) CuSO4·6H2O, Ac2O, RT, 24 h; (b) HNO3 (1.4 equiv), 0 8C- -RT, 1 h; (c) 1 n HCl, RT, 2 h, 80 %; (ii) aminoacetaldehyde diethyl acetal, benzene, reflux, 6 h; (iii) NaBH4/MeOH, 0 8C to RT, 4 h, 85 %; (iv) TsCl/Py, ACN, RT, 6 h, 90 % (Ts = para-toluenesulfonyl, Py = pyridine, ACN = acetonitrile); (v) 1,4-dioxane, 1 n HCl, reflux, 4 h, 60 %; (vi) Pd/C (10 mol %), N2H4·H2O (2.0 equiv), MeOH, 50 8C, 4 h, 80 %; (vii) Cu(OAc)2 (20 mol %), Et3N (3.0 equiv), dichloromethane (DCM), RT, 24 h, 70 %; (viii) Pd(OAc)2 ( 10 mol %), Cu(OAc)2 (2.0 equiv), AcOH, 120 8C, 24 h, 70 %; (ix) Ni(PCy3)2Cl2 (5 mol %), PCy3 (10 mol %), MeMgBr (0.75 mmol), toluene, 80 8C, 12 h, 85 %.

We began the synthesis with the nitration reaction (CuSO4·6H2O/HNO3) of 2,5-dimethoxybenzaldehyde (3) to afford nitration product 4 in 80 % yield (Scheme 3). The condensation reaction of 4 with aminoacetaldehyde diethyl acetal in dry benzene gave imine product 5. The subsequent reduction of 5 with sodium borohydride in methanol at 0 8C to room temperature for 4 h afforded amine 6 in 85 % yield. The protection of amine 6 with a tosyl group gave protected compound 7, which underwent cyclization in an acidic medium to furnish isoquinoline 8 in 54 % yield (two steps). In the next step, the reduction of the nitro group was achieved by using Pd/C in methanol, and amine 9 was isolated in 80 % yield. This product was then subjected to a Cu-catalyzed Chan–Lam-type coupling with phenylboronic acid to afford N-arylated product 10.[17] Subsequently, the preparation of carbazole 11 was achieved in 70 % yield by using a Pd-catalyzed cross-dehydrogenative (CDC) coupling reaction. Finally, we applied our optimized Ni-catalyzed protocol to replace the methoxy with a methyl group to afford ellipticine in 85 % yield.

Conclusions In summary, an efficient and simple Ni-catalyzed C(aryl)@OMe bond cleavage and subsequent C(aryl)@Me bond formation by treating carbazoles with MeMgBr has been developed. This protocol was successfully applied to the synthesis of the natural product ellipticine from readily available starting materials. Specifically, this protocol demonstrates that the lipophilicity of bioactive carbazoles can be easily modified by replacing a methoxy with a methyl group, which is important in the regulation of drug properties such as bioavailability and metabolic stability.

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Experimental Section General Methods: Analytical thin layer chromatography was performed on precoated silica gel plates (60 F254, Merck). The developed TLC plates were visualized by exposing them to UV light or iodine vapors or by immersing the plate in a ninhydrin solution and then heating with a hot plate. The 1H and 13C NMR spectroscopic data were recorded with Bruker 500 and 400 MHz instruments. HRMS measurement were recorded with a LC–MS-QTOF (Q = quadrupole) Module No. G6540A [ultra high definition (UHD)] instrument. Melting points were measured in open capillary tubes and are uncorrected. Unless otherwise indicated, chemicals and solvents were purchased from commercial suppliers. General Procedure for the Methylation of Alkoxy Carbazole and Its Derivatives: To an oven-dried round-bottom flask were added 3-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (5 mol %), PCy3 (10 mol %), and anhydrous toluene (3 mL) under nitrogen. Methylmagnesium bromide (3 m in ether, 0.50 mmol) was then added at room temperature, and the resulting mixture was stirred at 80 8C under nitrogen until there was complete conversion of the starting material (monitored by TLC analysis). The reaction mixture was then diluted with water (20 mL), and the resulting solution was extracted with ethyl acetate (3 V 20 mL). The combined organic layers were dried with Na2SO4 and filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (petroleum ether/ethyl acetate) to obtain the desired product. 3-Methyl-9H-carbazole (2 a):[18] By following the general procedure, a mixture of 3-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.75 mg, 5 mol %), PCy3 (7.1 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.168 mL, 0.50 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 a (43.6 mg, 95 % yield) as a white solid. M.p. 206–209 8C; 1H NMR (400 MHz, CDCl3): d = 8.04 (d, J = 7.8 Hz, 1 H), 7.94 (s, 1 H), 7.87 (s, 1 H), 7.40 (m, 2 H), 7.32 (d, J = 8.2 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.22 (m, 1 H), 2.53 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.8, 137.7, 128.7, 127.1, 125.6, 123.5, 123.2, 120.2, 119.2, 110.5, 110.2, 21.4 ppm; HRMS (ESI): m/z: calcd for C13H12N: 182.0964 [M+ +H] + ; found: 182.0971.

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Full Paper 2-Methyl-9H-carbazole (2 b):[18] By following the general procedure, a mixture of 3-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.75 mg, 5 mol %), PCy3 (7.1 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.168 mL, 0.50 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 b (42.7 mg, 93 % yield) as a white solid. M.p. 262–264 8C; 1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.87 (s, 1 H), 7.37 (d, J = 7.9 Hz, 2 H), 7.22 (m, 1 H), 7.18 (s, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 2.51 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.9, 139.4, 136.0, 125.2, 123.4, 121.0, 120.9, 119.9, 119.9, 119.3, 110.7, 110.4, 22.0 ppm; HRMS (ESI): m/z: calcd for C13H12N: 182.0964 [M+ +H] + ; found: 182.0962. 1-Methyl-9H-carbazole (2 c):[18] By following the general procedure, a mixture of 3-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.75 mg, 5 mol %), PCy3 (7.1 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.168 mL, 0.50 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 c (41.8 mg, 91 % yield) as a white solid. M.p. 122–123 8C; 1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 7.8 Hz, 1 H), 7.98 (s, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.42 (m, 1 H), 7.23 (m, 2 H), 7.16 (t, J = 7.5 Hz, 1 H), 2.57 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.3, 138.8, 126.4, 125.6, 123.8, 120.5, 119.7, 119.5, 119.4, 117.9, 114.1, 110.7, 16.9 ppm; HRMS (ESI): m/z: calcd for C13H12N: 182.0964 [M+ +H] + ; found: 182.0968. 3,6-Dimethyl-9H-carbazole (2 d):[18] By following the general procedure, a mixture of 3,6-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.251 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 d (47.4 mg, 97 % yield) as a white solid. M.p. 215–217 8C; 1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 7.6 Hz, 1 H), 7.27 (d, J = 7.9 Hz, 1 H), 7.20 (dd, J = 8.2, 1.2 Hz, 1 H), 2.51 ppm (s, 6 H); 13C NMR (125 MHz, CDCl3): d = 137.5, 127.9, 126.5, 122.9, 119.6, 109.7, 20.9 ppm; HRMS (ESI): m/z: calcd for C14H14N: 196.1121 [M+ +H] + ; found: 196.1120. 2,6-Dimethyl-9H-carbazole (2 e):[18] By following the general procedure, a mixture of 3,6-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.251 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 e (45.0 mg, 92 % yield) as a white solid. M.p. 223–225 8C; 1H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 7.9 Hz, 1 H), 7.82 (s, 2 H), 7.27 (m, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.03 (d, J = 7.9 Hz, 1 H), 2.51 ppm (s, 6 H); 13C NMR (125 MHz, CDCl3): d = 140.3, 137.6, 135.8, 128.6, 126.6, 123.5, 120.9, 120.7, 120.0, 119.9, 110.7, 110.1, 22.1, 21.4 ppm; HRMS (ESI): m/z: calcd for C14H14N: 196.1121 [M+ +H] + ; found: 196.1120. 1,6-Dimethyl-9H-carbazole (2 f):[18] By following the general procedure, a mixture of 3,6-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.251 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 f (43.5 mg, 89 % yield) as a white solid. M.p. 172–174 8C; 1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.7 Hz, 1 H), 7.45 (m, 1 H), 7.40 (m, 1 H), 7.22 (dd, J = 7.9, 3.8 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 2.77 (s, Asian J. Org. Chem. 2016, 5, 1499 – 1507

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3 H), 2.56 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.4, 138.8, 126.4, 125.6, 123.8, 122.8, 120.4, 119.7, 119.5, 119.4, 117.9, 110.6, 18.6, 16.9 ppm; HRMS (ESI): m/z: calcd for C14H14N: 196.1121 [M+ +H] + ; found: 196.1127. 2,7-Dimethyl-9H-carbazole (2 g):[19] By following the general procedure, a mixture of 3,6-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.251 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 g (41.6 mg, 85 % yield) as a white solid. M.p. 224–226 8C; 1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 7.9 Hz, 2 H), 7.81 (s, 2 H), 7.75 (s, 1 H), 7.02 (d, J = 7.7 Hz, 2 H), 2.51 ppm (s, 6 H); 13C NMR (125 MHz, CDCl3): d = 138.0, 128.4, 127.0, 123.4, 120.1, 110.2, 21.4 ppm; HRMS (ESI): m/z: calcd for C14H14N: 196.1121 [M+ +H] + ; found: 196.1125. 1,4-Dimethyl-9H-carbazole (2 h):[20] By following the general procedure, a mixture of 3,6-methoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.251 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 h (42.9 mg, 88 % yield) as a white solid. M.p. 102–105 8C; 1H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 7.9 Hz, 1 H), 7.99 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H), 7.24 (t, J = 7.3 Hz, 1 H), 7.13 (d, J = 7.3 Hz, 1 H), 6.94 (d, J = 7.3 Hz, 1 H), 2.85 (s, 3 H), 2.53 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.4, 138.7, 130.9, 126.2, 125.0, 124.5, 122.6, 121.4, 120.9, 119.4, 117.0, 110.5, 20.6, 16.6 ppm; HRMS (ESI): m/z: calcd for C14H14N: 196.1121 [M+ +H] + ; found: 196.1121. 3-Methyl-6-phenoxy-9H-carbazole (2 i): By following the general procedure, a mixture of 3-methoxy-6-phenoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.5 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.124 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.6:0.4) to provide 2 i (17.0 mg, 25 % yield) as a white solid. M.p. 208–210 8C; 1H NMR (400 MHz, [D6]DMSO): d = 10.58 (s, 1 H), 7.67 (s, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 1 H), 7.01 (dd, J = 8.6, 2.1 Hz, 1 H), 6.95 (t, J = 7.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 2 H), 2.41 ppm (s, 3 H); 13C NMR (100 MHz, [D6]DMSO): d = 153.4, 143.9, 141.9, 134.3, 132.3, 132.1, 128.1, 127.5, 126.8, 124.8, 123.3, 121.9, 116.5, 115.6, 115.8, 26.1 ppm; HRMS (ESI): m/z: calcd for C19H16NO: 274.1227 [M+ +H] + ; found: 274.1213. 3-Methyl-6-propoxy-9H-carbazole (2 j): By following the general procedure, a mixture of 3-methoxy-6-propoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.125 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.7:0.3) to provide 2 j (11.9 mg, 20 % yield) as a white solid. M.p. 144–146 8C; 1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.22 (dd, J = 8.5, 3.9 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 1 H), 4.10 (t, J = 8.4 Hz, 2 H), 2.20 (s, 3 H), 1.75 (m, 2 H), 0.97 ppm (t, J = 8.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3): d = 153.1, 139.3, 130.9, 128.8, 127.1, 124.0, 123.5, 120.1, 115.4, 114.0, 111.3, 110.4, 70.5, 33.8, 22.7, 14.1 ppm; HRMS (ESI): m/z: calcd for C16H18NO: 240.1383 [M+ +H] + ; found: 240.1390. 6-Butoxy-3-methyl-9H-carbazole (2 k): By following the general procedure, a mixture of 3-methoxy-6-butoxy-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.7 mg, 5 mol %), PCy3 (7.1 mg, 10 mol %),

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Full Paper anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.126 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.7:0.3) to provide 2 k (14.0 mg, 22 % yield) as a white solid. M.p. 136–138 8C; 1H NMR (400 MHz, CDCl3): d = 7.83 (s, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.30 (m, 2 H), 7.22 (d, J = 8.1 Hz, 1 H), 7.05 (m, 1 H), 4.08 (t, J = 7.6 Hz, 2 H), 2.53 (s, 3 H), 1.83 (m, 2 H), 1.56 (m, 2 H), 1.03 ppm (t, J = 8.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3): d = 153.1, 138.5, 134.8, 128.2, 127.0, 123.6, 123.5, 120.1, 115.5, 114.0, 111.1, 110.4, 68.3, 31.6, 29.7, 19.3, 13.4 ppm; HRMS (ESI): m/z: calcd for C17H20NO: 254.1540 [M+ +H] + ; found: 254.1537. 3-Chloro-6-methyl-9H-carbazole (2 m): By following the general procedure, a mixture of 3-chloro-6-methoxy-9H-carbazole (50 mg, 1.0 equiv), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.125 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.8:0.2) to provide 2 m (29.6 mg, 55 % yield) as a white solid. M.p. 209–211 8C; 1H NMR (400 MHz, CDCl3): d = 7.98 (s, 1 H), 7.95 (s, 1 H), 7.81 (s, 1 H), 7.31 (m, 3 H), 7.26 (d, J = 7.4 Hz, 1 H), 2.52 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 138.2, 138.0, 129.2, 127.9, 125.7, 124.7, 124.4, 122.7, 120.3, 119.9, 111.5, 110.4, 21.4 ppm; HRMS (ESI): m/z: calcd for C13H11ClN: 216.0575 [M+ +H] + ; found: 216.0570. 3-Bromo-6-methyl-9H-carbazole (2 n): By following the general procedure, a mixture of 3-bromo-6-methoxy-9H-carbazole (0.50 mmol), NiCl2(PCy3)2 (17.4 mg, 5 mol %), PCy3 (14.2 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.252 mL, 1.0 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.8:0.2) to provide 2 n (25.5 mg, 20 % yield) as a white solid. M.p. 178–180 8C; 1H NMR (400 MHz, CDCl3): d = 8.15 (s, 1 H), 7.99 (s, 1 H), 7.81 (s, 1 H), 7.47 (dd, J = 8.6, 3.7 Hz, 1 H), 7.31 (m, 1 H), 7.26 (d, J = 8.0 Hz, 2 H), 2.52 ppm (s, 3 H); 13 C NMR (125 MHz, CDCl3): d = 138.3, 138.0, 129.2, 128.3, 128.0, 125.0, 123.0, 122.5, 120.4, 112.0, 110.5, 21.4 ppm; HRMS (ESI): m/z: calcd for C13H11BrN: 260.0070 [M+ +H] + ; found: 259.9902. 3,3,9-Trimethyl-3,7-dihydropyrano[2,3-c]carbazole (2 o):[14g] By following the general procedure, a mixture of 9-methoxy-3,3-dimethyl-3,7-dihydropyrano[2,3-c]carbazole (0.25 mmol), NiCl2(PCy3)2 (8.5 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.124 mL, 0.50 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.5:0.5) to provide 2 o (45.4 mg, 70 % yield) as a light brown semisolid. 1H NMR (400 MHz, CDCl3): d = 8.00 (d, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.24 (s, 1 H), 7.15 (dd, J = 8.3, 3.7 Hz, 2 H), 6.99 (t, J = 8.6 Hz, 1 H), 6.89 (m, 1 H), 5.82 (d, J = 7.8 Hz, 1 H), 2.51 (s, 3 H), 1.50 ppm (s, 6 H); 13C NMR (125 MHz, CDCl3): d = 145.5, 140.0, 134.5, 133.7, 130.2, 120.9, 119.8, 119.7, 119.1, 117.8, 114.3, 113.8, 109.7, 109.2, 74.1, 26.2, 20.9 ppm; HRMS (ESI): m/z: calcd for C18H18NO: 264.1383 [M+ +H] + ; found: 264.1389. 3,3,5,8-Tetramethyl-3,11-dihydropyrano[3,2-a]carbazole (2 p): By following the general procedure, a mixture of 8-methoxy-3,3,5-trimethyl-3,11-dihydropyrano[3,2-a]carbazole (0.25 mmol), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (7.0 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.124 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.5:0.5) to provide 2 p (46.8 mg, 68 % yield) as a white solid. M.p. 188–190 8C; 1H NMR (400 MHz, CDCl3): d = 7.71 (s, 1 H), 7.62 (s, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 6.94 (dd, J = 8.7, 3.3 Hz, 1 H), 6.59 (d, J = 8.7 Hz, 1 H), 5.68 (d, J = 7.9 Hz, 1 H), 2.50 Asian J. Org. Chem. 2016, 5, 1499 – 1507

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(s, 3 H), 2.32 (s, 3 H), 1.48 ppm (s, 6 H); 13C NMR (125 MHz, CDCl3): d = 153.9, 149.8, 135.7, 134.4, 129.3, 124.4, 121.1, 118.3, 117.3, 116.8, 113.1, 111.1, 104.5, 102.6, 75.9, 27.6, 18.5, 16.2 ppm; HRMS (ESI): m/z: calcd for C19H20NO: 278.1540 [M+ +H] + ; found: 278.1546. 3-(tert-Butyl)-6-methyl-9H-carbazole (2 q): By following the general procedure, a mixture of 3-(tert-butyl)-6-methoxy-9H-carbazole (50 mg, 1.0 equiv), NiCl2(PCy3)2 (8.6 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.125 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.8:0.2) to provide 2 q (51.9 mg, 88 % yield) as a white solid. M.p. 210–212 8C; 1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 8.7 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.23 (d, J = 7.7 Hz, 1 H), 6.87 (dd, J = 8.8, 3.2 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 2.34 (s, 3 H), 1.50 ppm (s, 9 H); 13C NMR (125 MHz, CDCl3): d = 143.5, 142.7, 138.9, 127.2, 124.5, 123.4, 123.1, 122.7, 121.2, 116.7, 110.3, 110.0, 34.7, 31.9, 17.0 ppm; HRMS (ESI): m/z: calcd for C17H20N: 238.1590 [M+ +H] + ; found: 238.1589. 3-Methyl-6-nitro-9H-carbazole (2 r): By following the general procedure, a mixture of 3-methoxy-6-nitro-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.5 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.124 mL, 0.5 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (nhexane/EtOAc = 9.5:0.5) to provide 2 r (42.0 mg, 75 % yield) as a white solid. M.p. 190–192 8C; 1H NMR (400 MHz, CDCl3): d = 8.34 (m, 2 H), 7.87 (d, J = 0.6 Hz, 1 H), 7.63 (dd, J = 8.4, 3.5 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.32 (dd, J = 8.3, 1.1 Hz, 1 H), 2.54 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 146.5, 143.1, 133.4, 132.6, 132.5, 129.3, 127.1, 126.3, 125.0, 116.1, 115.6, 104.7, 25.7 ppm; HRMS (ESI): m/z: calcd for C13H11N2O2 : 227.0815 [M+ +H] + ; found: 227.0825. 1,3,6-Trimethyl-9H-carbazole (2 s):[18] By following the general procedure, a mixture of 1,6-dimethoxy-3-methyl-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.5 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.250 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.8:0.2) to provide 2 s (44.1 mg, 85 % yield) as a white solid. M.p. 122–124 8C; 1H NMR (400 MHz, [D6]DMSO): d = 7.89 (s, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.17 (s, 1 H), 2.51 ppm (s, 9 H); 13C NMR (125 MHz, [D6]DMSO): d = 139.3, 137.8, 128.1, 127.5, 126.8, 124.0, 123.3, 120.3, 119.3, 117.6, 110.5, 21.1, 16.2 ppm; HRMS (ESI): m/z: calcd for C15H16N: 210.1277 [M+ +H] + ; found: 210.1280. 2,3,6-Trimethyl-9H-carbazole (2 t):[21] By following the general procedure, a mixture of 2,6-dimethoxy-3-methyl-9H-carbazole (0.25 mmol), NiCl2(PCy3)2 (8.5 mg, 5 mol %), PCy3 (6.9 mg, 10 mol %), anhydrous toluene (3 mL), and methylmagnesium bromide (3 m in ether, 0.250 mL, 0.75 mmol) was stirred at 80 8C for 12 h under nitrogen. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.8:0.2) to provide 2 t (49.5 mg, 89 % yield) as a white solid. M.p. 210–212 8C; 1H NMR (400 MHz, CDCl3): d = 7.99 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.35 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.25 (s, 1 H), 7.08 (m, 1 H), 2.39 (s, 3 H), 2.33 (s, 3 H), 2.31 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 139.3, 138.9, 135.1, 127.5, 126.9, 126.4, 123.5, 121.0, 120.6, 119.8, 115.9, 110.3, 29.3, 22.7, 19.4 ppm; HRMS (ESI): m/z: calcd for C15H16N: 210.1277 [M+ +H] + ; found: 210.1287. Procedure for Competition Experiment between 1 a, 1 b, and 1 c: In an oven-dried round bottom flask, a mixture of 1a, 1b, and 1c (0.3 mmol) was dissolved in dry toluene under nitrogen, and NiCl2(PCy3)2 (5 mol %), PCy3 (10 mol %), and then the methylmagne-

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Full Paper sium bromide (3 m in ether, 0.60 mmol) were added at room temperature. The reaction mixture was stirred at 80 8C for 12 h under nitrogen and then diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 V 20 mL), and the combined the organic layers were dried with Na2SO4 and then filtered. The filtrate was concentrated under vacuum, and the crude product was purified by flash chromatography on a silica gel column (petroleum ether/ethyl acetate). The solvent of the product fractions was evaporated under vacuum. NMR yields were determined by 1H NMR using TMS as the internal standard. The ratio of the products was determined by 1H NMR spectral results. 2,5-Dimethoxy-4-nitrobenzaldehyde (4):[22] A mixture of 3 (1.0 equiv) and CuSO4·7H2O (0.1 equiv) in acetic anhydride (70 mL) was stirred at room temperature for 24 h. After the mixture was cooled to 10–15 8C, 70 % nitric acid (25 mL) was added dropwise. The solution was stirred for 1 h, and then 1 n HC1 (250 mL) was added. The mixture was stirred for 2 h and then extracted with ether (3 V 50 mL). The combined ethereal layers were dried with Na2SO4 and evaporated. The crude product was purified by flash chromatography (n-hexane/EtOAc = 9.8:0.2) to provide 4 (80 % yield) as a yellow solid. M.p. 169–171 8C; 1H NMR (400 MHz, CDCl3): d = 10.48 (s, 1 H), 7.55 (s, 1 H), 7.45 (s, 1 H), 3.97 ppm (s, 6 H); 13 C NMR (125 MHz, CDCl3): d = 188.1, 168.2, 154.9, 146.6, 127.6, 112.9, 109.3, 57.0, 56.5 ppm; HRMS (ESI): m/z : calcd for C9H10NO5 : 212.0554 [M+ +H] + ; found: 212.0560. N-(2,5-Dimethoxy-4-nitrobenzyl)-2,2-diethoxyethanamine (6): To an oven-dried round-bottom flask equipped with a magnetic stir bar and condenser were added 2,5-dimethoxy-4-nitrobenzaldehyde (4, 1.0 equiv), aminoacetaldehyde diethyl acetal (1.1 equiv), and anhydrous benzene (20 mL) under nitrogen. The yellow solution was stirred and heated at reflux for 6 h. Upon completion of the reaction (monitored by TLC analysis), the solvent was removed under reduced pressure, and the residue was evaporated to dryness to yield 5 as a brown oil. This brown oil was dissolved in methanol, and the solution was treated with NaBH4 (4 equiv) portionwise. The reaction mixture was stirred at room temperature for 4 h, and the solvent was then evaporated under reduced pressure. The crude product was purified by flash chromatography (chloroform/ methanol = 9.7:0.3) to provide 6 (85 % yield). 1H NMR (400 MHz, CDCl3): d = 7.42 (s, 1 H), 7.16 (s, 1 H), 4.65 (t, J = 8.5 Hz, 1 H), 3.94 (s, 3 H), 3.87 (s, 2 H), 3.85 (s, 3 H), 3.70 (m, 2 H), 3.54 (m, 2 H), 2.75 (d, J = 7.5 Hz, 2 H), 1.25 ppm (t, J = 8.5 Hz, 6 H); 13C NMR (100 MHz, CDCl3): d = 150.5, 147.7, 139.2, 128.8, 115.4, 107.4, 101.5, 62.6, 57.1, 56.0, 51.0, 48.1, 15.3 ppm; HRMS (ESI): m/z: calcd for C15H25N2O6 : 329.1707 [M+ +H] + ; found: 329.1719. N-(2,2-Diethoxyethyl)-N-(2,5-dimethoxy-4-nitrobenzyl)-4-methylbenzenesulfonamide (7): In a oven-dried round bottom flask, compound 6 was dissolved in dry pyridine (4.0 equiv), and a solution of 2-nitrobenzenesulfonyl chloride (1.5 equiv) in dry CH3CN (10 mL) was added as the mixture was stirred. The resulting mixture was stirred at room temperature for 6 h, and the solvent was removed under reduced pressure upon completion of the reaction. The resulting residue was diluted with water and extracted with CH2Cl2. The organic layer was dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.8:0.2) to afford the desired product 7 (90 % yield) as yellow oil. 1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.27 (s, 1 H), 7.16 (s, 1 H), 4.58 (t, J = 7.3 Hz, 1 H), 4.54 (s, 2 H), 3.87 (s, 3 H), 3.75 (s, 3 H), 3.65 (m, 2 H), 3.42 (m, 2 H), 3.33 (d, J = 7.4 Hz, 2 H), 2.42 (s, 3 H), 1.12 ppm (t, J = 7.0 Hz, 6 H); 13C NMR (125 MHz, CDCl3): d = 149.9, 147.6, 143.6, 137.6, 136.9, 133.1, 129.7, 127.1, 115.1, 107.1, 101.9, 63.1, 57.0, 55.9, 51.5, 48.3, 21.5, Asian J. Org. Chem. 2016, 5, 1499 – 1507

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15.2 ppm; HRMS (ESI): m/z: calcd for C22H31N2O8S: 483.1796 [M+ +H] + ; found: 483.1801. 5,8-Dimethoxy-6-nitroisoquinoline (8): To a round-bottom flask equipped with a magnetic stir bar and condenser were added 7 (1.0 equiv) and dioxane/6 m HCl (4:1, 10 mL). This slurry was stirred and heated to reflux in an oil bath for 3 h. Upon completion of the reaction (monitored by TLC analysis), the mixture was adjusted to pH 8 by the addition of a 1 n NaOH solution. The resulting mixture was extracted with CH2Cl2 (3 V 50 mL), and the combined extracts were dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.7:0.3) to afford the desired product 8 (60 % yield) as a yellow semisolid. 1H NMR (400 MHz, CDCl3): d = 9.75 (s, 1 H), 8.86 (d, J = 8.3 Hz, 1 H), 8.19 (d, J = 8.6 Hz, 1 H), 7.88 (s, 1 H), 4.06 (s, 3 H), 3.69 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 150.1, 145.3, 143.3, 141.1, 129.5, 128.1, 124.5, 117.0, 110.0, 58.7, 56.4 ppm; HRMS (ESI): m/z: calcd for C11H11N2O4 : 235.0714 [M+ +H] + ; found: 235.0720. 5,8-Dimethoxyisoquinolin-6-amine (9): To a mixture of compound 8 and Pd/C (10 mol %) in methanol (15 mL) was slowly added hydrazine hydride (2.0 equiv), and the resulting mixture was stirred at 50 8C for 4 h. Upon completion of the reaction (monitored by TLC analysis), the mixture was diluted with water (20 mL), and the resulting mixture was extracted with dichloromethane (3 V 20 mL). The combined organic layers were dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.6:0.4) to afford the desired product 9 (80 % yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): d = 9.77 (s, 1 H), 8.59 (d, J = 8.3 Hz, 1 H), 8.11 (d, J = 8.6 Hz, 1 H), 6.24 (s, 1 H), 4.08 (s, 3 H), 3.80 ppm (s, 3 H); 13 C NMR (125 MHz, CDCl3): d = 150.1, 147.0, 143.0, 140.1, 129.3, 126.7, 123.5, 115.1, 109.2, 60.1, 55.7 ppm; HRMS (ESI): m/z: calcd for C11H13N2O2 : 205.0972 [M+ +H] + ; found: 205.0968. 5,8-Dimethoxy-N-phenylisoquinolin-6-amine (10): To a solution of compound 9 in dichloromethane (5 mL) were added phenylboronic acid (1.2 equiv), Cu(OAc)2 (0.1 equiv), and triethylamine (3.0 equiv), and the resulting mixture was vigorously stirred at room temperature for 24 h in the open air. The reaction mixture was diluted with dichloromethane (60 mL) and then filtered through Whatman filter paper. The filtrate was washed with water, and the organic layer was dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.7:0.3) to afford the desired product 10 (70 % yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): d = 9.68 (s, 1 H), 8.46 (d, J = 7.9 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.38 (m, 3 H), 7.20 (t, J = 8.0 Hz, 2 H), 6.30 (s, 1 H), 6.19 (s, 1 H), 3.98 (s, 3 H), 3.68 ppm (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 149.8, 145.7, 142.6, 140.1, 130.4, 127.3, 127.1, 123.3, 123.0, 122.8, 120.9, 113.9, 110.5, 59.4, 56.0 ppm; HRMS (ESI): m/z: calcd for C17H17N2O2 : 281.1285 [M+ +H] + ; found: 281.1272. 5,11-Dimethoxy-6H-pyrido[4,3-b]carbazole (11): A mixture of compound 10, palladium acetate (0.1 equiv), and copper acetate (2.0 equiv) in acetic acid was stirred at 120 8C for 24 h. Upon completion of the reaction (monitored by TLC analysis), the mixture was diluted with dichloromethane (60 mL) and then filtered through Whatman filter paper. The filtrate was washed with water, and the organic layer was dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.5:0.5) to afford the desired product 11 (70 % yield) as a yellow semisolid. 1 H NMR (400 MHz, [D6]DMSO): d = 11.04 (s, 1 H), 9.67 (s, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.35 (d, J = 8.6 Hz, 1 H), 7.91 (m, 1 H), 7.52 (m, 2 H), 7.25 (m, 1 H), 4.06 (s, 3 H), 3.64 ppm (s, 3 H); 13C NMR

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Full Paper (125 MHz, [D6]DMSO): d = 149.3, 143.1, 141.5, 139.2, 133.1, 129.2, 127.8, 124.3, 124.2, 123.5, 119.8, 116.9, 111.3, 108.8, 58.3, 56.4 ppm; HRMS (ESI): m/z: calcd for C17H15N2O2 : 279.1128 [M+ +H] + ; found: 279.1130. Elipticine (12):[16] In an oven-dried round bottom flask, compound 11 (0.25 mmol), NiCl2(PCy3)2 (5 mol %), PCy3 (10 mol %), and anhydrous toluene (5 mL) were added under nitrogen, and then methylmagnesium bromide (3 m in ether, 0.75 mmol) was added at room temperature. The reaction mixture was stirred at 80 8C under nitrogen until there was complete conversion of the starting material (monitored by TLC analysis). The reaction mixture was diluted with water (20 mL) and then extracted with dichloromethane (3 V 20 mL). The combined organic layers were dried with Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column (chloroform/methanol = 9.5:0.5) to afford the desired product 12 (85 % yield). M.p. 309–311 8C; 1H NMR (400 MHz, [D6]DMSO): d = 11.38 (s, 1 H), 9.70 (s, 1 H), 8.40 (d, J = 7.9 Hz, 2 H), 7.93 (d, J = 6.9 Hz, 1 H), 7.55 (m, 2 H), 7.27 (m, 1 H), 3.27 (s, 3 H), 2.80 ppm (s, 3 H); 13C NMR (100 MHz, [D6]DMSO): d = 150.1, 143.2, 143.1, 141.0, 140.9, 132.9, 128.5, 127.5, 124.2, 123.8, 123.6, 119.6, 116.3, 111.1, 108.5, 14.8, 12.4 ppm; HRMS (ESI): m/z: calcd for C17H15N2 : 247.1230 [M+ +H] + ; found: 247.1225.

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Manuscript received: September 8, 2016 Final Article published: November 7, 2016

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CrossâCoupling Reaction of

CrossâCoupling Reaction of

CrossâCoupling Reaction of

CrossâCoupling Reaction of