Carbene-Catalyzed Construction of Carbazoles from Enals and 2

Publication Date (Web): October 23, 2018. Copyright © 2018 American Chemical Society. *E-mail: [email protected]. Cite this:J. Org. Chem. XXXX, X...
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Carbene-Catalyzed Construction of Carbazoles from Enals and 2‑Methyl-3-oxoacetate Indoles Dehai Liu,†,§ Yaru Gao,†,§ Jie Huang,† Zhenqian Fu,*,† and Wei Huang†,‡ †

J. Org. Chem. 2018.83:14210-14217. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/16/18. For personal use only.

Key Laboratory of Flexible Electronics & Institute of Advanced Materials, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, China ‡ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi’an 710072, China S Supporting Information *

ABSTRACT: Direct and rapid construction of carbazoles has been successfully developed via carbene-catalyzed oxidative formal [4 + 2] annulation of enals with 2-methyl-3-oxoacetate indoles. This metal-free reaction features a broad substrate scope, features good functional-group tolerance, proceeds under mild conditions, and can be easily scaled up.

C

synthesis of carbazoles has drawn continuous attention. A large number of elegant methods have been well developed,7 including classical named reactions (such as Borsche−Drechsel cyclization8 and Graebe−Ullmann reaction9), transition-metalcatalyzed cyclization,10 and π-extension of indoles.11 Among them, direct π-extension of easily available indoles has proven to be one of the most rapid and efficient methods. However, some of them suffer from harsh conditions, multistep synthesis, or the use of expensive transition-metal catalysts. Further development of a mild and facile method for the synthesis of carbazoles starting from easily available indoles still remains a considerable challenge and highly desirable. Carbene, as one of the most efficient privileged organocatalyts, has enabled the construction of a series of structurally diverse carbo- and heterocycles.12 Recently, the carbenecatalyzed synthesis of arenes from easily available acyclic raw materials has received considerable attention (Scheme 1). In 2014, the Chi group13 reported pioneering work on carbenecatalyzed oxidative formal [3 + 3] cycloaddtions of β-methyl enals (or esters) with enones, which allowed access to benzene units (Scheme 1a). Significantly, the same group14 subsequently developed a novel method for the construction of multisubstituted arenes and 3-ylidenephthalides on the basis of a carbene-catalyzed δ-LUMO activation of α,β−γ,δ-diunsaturated enals. In 2015, the Lupton group15 established a carbenecatalyzed intramolecular redox isomerization of trienyl esters to furnish tetrasubstituted benzaldehydes (Scheme 1b). Subsequently, the groups of Wang16 and Ye17a independently described an NHC-catalyzed oxidative formal [4 + 2] annulation of enals with α-cyano-β-methylenones for the rapid construction of benzene rings, respectively (Scheme 1c). The Ye group17b further developed a new approach for the synthesis of trisubstituted benzenes from α-bromo enals and α-

arbazoles are privileged structural motifs frequently present in a large number of bioactive molecules and natural products with a wide range of promising biological properties (Figure 1).1 Specifically, Carprofen, as a kind of

Figure 1. Examples of carbazole-containing useful compounds.

nonsteroidal anti-inflammatory pharmaceuticals, is applied in treatment of joint pain and postoperative pain.2 Carvedilol is used for treating mild to severe congestive heart failure (CHF) as well as high blood pressure.3 Staurosporine, originally isolated from the bacterium Streptomyces staurosporeus, exhibits antifungal, antihypertensive, and anticancer activities.4 Moreover, due to a wide band gap and outstanding luminescent efficiency, the carbazole as a core unit is wildly used for constructing organic optoelectronic materials.5 Especially, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), containing four carbazolyl units as an excellent thermally activated delayed fluorescence (TADF) material, demonstrated a very high external quantum efficiency (EQE) of 19% for a green organic light emitting diode (OLED).6 Therefore, the © 2018 American Chemical Society

Received: October 1, 2018 Published: October 23, 2018 14210

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

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The Journal of Organic Chemistry Scheme 1. Methods for the Construction of Arene Rings Promoted by Carbene

Table 1. Screening Reaction Conditions

entrya 1 2 3 4 5 6 7 8 9 10 11b 12

NHC precursor A (mol %) 20 20 20 20 20 20 20 20 20 10 10

base

solvent

yieldc (%)

DBU DBN DIPEA Cs2CO3 t-BuONa DBU DBU DBU DBU DBU DBU DBU

THF THF THF THF THF CH3CN DCM 1,4-dioxane toluene THF THF THF

81 74 nd 15 21 66 74 nd 51 77 86 nd

a

Standard conditions: NHC (20 mol %), 1a (0.15 mmol), 2a (1.0 equiv), base (2.0 equiv), oxidant (2.2 equiv), solvent (1.5 mL), 30 °C, 24 h. bUnder a nitrogen atmosphere. cYield of isolated product 3a after column chromatography. nd = not detected.

absence of NHC precursor A, no product 3a was found (entry 12). With acceptable optimized conditions in hand (Table 1, entry 11), we next evaluated the reaction scope for enal substrates by using methyl 2-(2-methyl-1-tosyl-1H-indol-3-yl)2-oxoacetate 2a as a model substrate (Table 2). Enals 1 bearing various substituents with diverse electronic and steric properties on the β-aryl were well tolerated, and all reactions proceeded smoothly to generate the corresponding carbazoles 3a−3h in good to excellent yields. Enals with heteroaromatic rings (such as 2-furyl or 2-thienyl) also worked well (3i and 3j). β-styryl enal also gave the product 3k in excellent yield. Notably, β-alkyl enal can realize this transformation as well and gave the desired product 3l, albeit with a lower yield. Delightingly, β-indolyl and carbazolyl enals were also suitable substrates for this transformation (3m and 3n). To further demonstrate the generality of this NHC-catalyzed formal [4 + 2] annulation, the scope of 2-methyl-3-oxoacetate indoles 2 was investigated by using cinnamaldehyde 1a as a model substrate (Table 3). For several substituents (such as F, Cl, Br, NO2, and Me) at the 4, 5, and 6 positions on the indole ring, all reactions worked efficiently and led to the formation of corresponding carbazoles 3o−v in acceptable to good yields. Replacement of methyl ester with Et, i-Pr, or Bn ester did not influence the efficiency of this transformation (3w−y). Delightingly, 2-methyl-3-oxoacetate benzo[b]thiophene 2l was a suitable sustrate to give dibenzo[b,d]thiophene 3z in 64% yield. Unfortunately, changing Ts to other protecting groups (such as Me and CO2Et) or the use of 2-Et and 2-Bn substituted substrates, none of desired product was found. The proposed pathway for the NHC-catalyzed rapid construction of carbazoles is illustrated in Scheme 2. The carbene attacks the enal to give a homoenolate intermediate

cyano-β-methylenones in the absence of an oxidant. One degree of unsaturation was provided through decyanation. Recently, the Fang group reported on the use of a carbenecatalyzed umpolung of β,γ-unsaturated diketones to produce 1,3,4-triaryl benzenes via an intermolecular cyclization followed by decarboxylation (Scheme 1d).18 Although aforementioned methods can elegantly and rapidly construct the arene ring, they often relied on enone and its derivatives as starting materials. In contrast, a method based on other kinds of easily available raw materials was undeveloped so far.19 As a part of our ongoing interest in the carbene catalysis,20 we herein present an efficient carbene-catalzyed oxidative formal [4 + 2] annulation of enals with 2-methyl-3-oxoacetate indoles for the construction of multisubstituted carbazoles in a single operation under mild conditions (Scheme 1e). This metal-free catalytic approach can avoid heavy metal resin, significantly increasing the feasibility of applications in pharmaceuticals and organic optoelectronic materials. We selected the reaction of cinnamaldehyde 1a and readily available methyl 2-(2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate 2a as the model reaction for optimizing conditions. The key results are summarized in Table 1. To our delight, the desired substituted carbazole 3a could be efficiently obtained in up to 81% yield when triazolium NHC precursor A was employed in the presence of DBU and oxidant B in THF at room temperature (entry 1). Then, base screening indicated that DBU was the best choice (entries 2−5). Next, several solvents were investigated, with THF proving to be the best choice (entries 6−9). Reducing catalyst loading into 10 mol % led to a decrease in the product yield considerably (entry 10). Gratifyingly, the product 3a was obtained in up to 86% yield when the reaction was performed with 10 mol % NHC precursor A under a nitrogen atmosphere (entry 11). In the 14211

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

Note

The Journal of Organic Chemistry Table 2. Scope of 1 and 2aa

Scheme 2. Proposed Mechanism

which undergoes oxidation to form α,β-unsaturated acyl triazolium intermediate I. Subsequently, intermediate II generated from the deprotonation of 2a undergoes Michael addition to intermediate I to give intermediate III. Intramolecular cyclization of intermediate III furnishes hydrocarbazole intermediate IV, which undergoes intramolecular lactonalization to generate intermediate V and release the free carbene. Intermediate V undergoes release of CO221 and further oxidative aromatization to finally give the carbazole 3a. To increase potential application of this mild and efficient method, a gram-scale reaction was performed (Scheme 3).

a

Reaction conditions as in Table 1, entry 11, 24 h; yields (after SiO2 chromatography purification) were based on 2a. b1 (3.0 equiv), NHC (20 mol %), and DBU (4.0 equiv) were used.

Table 3. Scope of 1a and 2a

Scheme 3

Pleasingly, with the use of 5 mmol of 2-(2-methyl-1-tosyl-1Hindol-3-yl)-2-oxoacetate 2a under standard conditions, the reaction proceeded efficiently and gave 1.8 g of the carbazole 3a (79% yield). The Ts group could be easily removed by using TBAF in THF at reflux, leading to the formation of the product 4 in 82% yield. In summary, we have successfully developed a direct and efficient carbene-catalyzed oxidative formal [4 + 2] annulation of enals with 2-methyl-3-oxoacetate indoles for the construction of substituted carbazoles. This metal-free reaction

a

Reaction conditions as in Table 1, entry 11, 24 h; yields (after SiO2 chromatography purification) were based on 2. b1a (3.0 equiv), NHC (20 mol %), and DBU (4.0 equiv) were used.

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DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

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The Journal of Organic Chemistry

Methyl 2-(4-Chloro-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2b). Yield 60% (243.5 mg), yellow solid; mp 95.4−96.1 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.30 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 3H), 3.96 (s, 3H), 2.79 (m, 3H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 182.7, 164.8, 146.8, 146.5, 136.3, 135.1, 131.5, 130.5, 126.8, 125.6, 125.0, 121.4, 115.3, 114.6, 53.1, 21.7, 14.1; HRMS(ESI) calcd for C19H17ClNO5S (M+H)+: 406.0510, Found: 406.0510. Methyl 2-(5-Fluoro-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2c). Yield 75% (292.0 mg), white solid; mp 109.6−111.1 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.22 (dd, J = 9.2, 4.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.10 (td, J = 8.8, 2.8 Hz, 1H), 3.97 (s, 3H), 2.81 (s, 3H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 182.7, 164.8, 161.7, 147.7, 146.3, 135.2, 132.1, 130.4, 126.7, 115.6, 115.5, 113.5, 113.3, 106.8, 106.6, 53.1, 21.7, 14.2; HRMS(ESI) calcd for C19H17FNO5S (M+H)+: 390.0806, Found: 390.0809. Methyl 2-(5-Chloro-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2d). Yield 65% (263.8 mg), white solid; mp 106.4−108.6 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.19 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 9.2, 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 3.97 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 182.6, 164.7, 147.4, 146.4, 135.1, 134.2, 131.0, 130.4, 127.7, 126.7, 125.8, 120.5, 115.4, 115.0, 53.1, 21.7, 14.1; HRMS(ESI) calcd for C19H17ClNO5S (M +H)+: 406.0510, Found: 406.0510. Methyl 2-(5-Bromo-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2e). Yield 55% (247.7 mg), white solid; mp 115.0−116.2 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.13 (d, J = 9.2 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 9.2, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 3.97 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 182.6, 164.7, 147.2, 146.4, 135.1, 134.6, 130.5, 128.5, 128.1, 126.7, 123.5, 118.7, 115.8, 114.9, 53.1, 21.7, 14.1; HRMS(ESI) calcd for C19H17BrNO5S (M +H)+: 450.0005, Found: 450.0004. Methyl 2-(2,5-Dimethyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2f). Yield 70% (269.8 mg), brown solid; mp 115.4−118.1 °C; 1H NMR (400 MHz, CDCl3) δ = 8.12 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 8.4, 1.6 Hz, 1H), 3.96 (s, 3H), 2.81 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.2, 165.1, 146.4, 146.0, 135.5, 134.8, 134.1, 130.3, 126.8, 126.7, 126.6, 120.4, 115.4, 114.1, 53.0, 21.7, 21.5, 14.1; HRMS(ESI) calcd for C20H20NO5S (M+H)+: 386.1057, Found: 386.1057. Methyl 2-(6-Chloro-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2g). Yield 67% (271.9 mg), yellow solid; mp 147.8−149.3 °C; 1H NMR (400 MHz, CDCl3) δ = 8.19 (dd, J = 7.2, 2.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.25−7.29 (m, 4H), 3.87 (s, 3H), 2.66 (m, 3H), 2.37 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.8, 162.1, 146.1, 143.3, 136.7, 135.4, 130.4, 126.7, 125.7, 125.5, 125.2, 124.8, 117.9, 113.2, 53.4, 21.7, 13.4; HRMS(ESI) calcd for C19H17ClNO5S (M+H)+: 406.0510, Found: 406.0510. Methyl 2-(6-Bromo-2-methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2h). Yield 62% (279.2 mg), white solid; mp 136.2−137.5 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.46 (d, J = 1.6 Hz, 1H), 7.76 (t, J = 8.8 Hz, 3H), 7.45 (dd, J = 8.8, 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 2.78 (s, 3H), 2.41 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 182.7, 164.7, 146.7, 146.5, 136.5, 135.1, 130.5, 128.3, 126.8, 125.3, 121.7, 119.3, 117.4, 115.3, 53.1, 21.7, 14.1; HRMS(ESI) calcd for C19H17BrNO5S (M+H)+: 450.0005, Found: 450.0005. Methyl 2-(2-Methyl-5-nitro-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2i). Yield 85% (353.9 mg), yellow solid; mp 170.5−172.2 °C; 1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 9.6 Hz, 1H), 8.27 (dd, J = 9.2, 2.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.01 (s, 3H), 2.85 (s, 3H), 2.42 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 182.1, 164.3, 149.1, 147.0, 145.2, 138.7, 134.8, 130.7, 126.9, 126.6, 120.6, 116.9, 115.7, 114.8, 53.3, 21.8, 14.3; HRMS(ESI) calcd for C19H17N2O7S (M+H)+: 417.0751, Found: 417.0752.

features a broad substrate scope, features good functionalgroup tolerance, proceeds under mild conditions, and can be easily scaled up. This facile approach may be applied to construct other types of arenes, and further investigations are undergoing in our laboratory.

■

EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker (400 MHz) spectrometer. Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ 0.00) or chloroform (δ = 7.26, singlet). 1H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), m (multiplets), etc. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker (400 MHz) (100 MHz) spectrometer. High resolution mass spectral analysis (HRMS) was performed on a Waters Q−TOF Premier Spectrometer. TLC was performed on a silica-gel-coated glass slide. All solvents were dried and distilled before being used. Commercially available solvents were freshly distilled before the reaction. Aldehydes 1b, 1d, 1e, 1h, 1i, 1k, 1m, and 1n were synthesized according to the literature.22 General Procedure for the Indoles 223 (2a as an Example). To a solution of 2-methyl-1H-indole (10.0 mmol, 1.31 g) in dry Et2O (50 mL) was added dropwise oxalyl chloride (30.0 mmol, 2.70 mL) at 0 °C. Then, the ice bath was removed and the reaction mixture was kept stirring for 2 h at room temperature. After cooling to 0 °C, MeOH (50.0 mmol, 2.0 mL) was added. The reaction mixture was filtered and washed with cold Et2O. To a solution of the resulting methyl 2-(2-methyl-1H-indol-3-yl)-2-oxoacetate (8.0 mmol, 1.74 g) in dry CH2Cl2 (0.1 M) was successively added Et3N (16.0 mmol, 2.3 mL) and 4-DMAP (0.8 mmol, 0.10 g). After stirring at room temperature for 15 min, TsCl (10.4 mmol, 2.0 g) was added, and the reaction mixture was stirred at room temperature until the substrate was consumed completely. It was then poured into 2% aq HCl (10 mL) and extracted with CH2Cl2 (2 × 20 mL). The organic layers were collected and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Further purification was carried out by flash column chromatography on silica gel with elution (30% v/v EtOAc in hexane), to afford the product 2a in 60% yield. General Procedure for the Carbazoles 3 (3a as an Example). To a dried 10 mL Schlenk tube equipped with a tiny magnetic stir bar under a N2 atmosphere were added 1a (0.15 mmol, 19.0 μL), 2a (0.10 mmol, 37.2 mg), NHC precatalyst (0.01 mmol, 3.20 mg), and oxidant (0.22 mmol, 90.0 mg). To this mixture was added dry THF (1.5 mL) and DBU (0.20 mmol, 30 μL) via a microsyringe; then, the reaction mixture was stirred at 30 °C until 1a disappeared (detected by TLC), and the residue was purified by silica gel column chromatography (50% v/v DCM in hexane) to afford 3a as a white solid in 85% yield. General Procedure for the Carbazoles 4. To a solution of 3a (0.20 mmol, 91.10 mg) in THF (1.0 mL) was added 1.0 mL of TBAF (1.0 M in THF). The mixture was stirred at refluxing temperature for 2 h. Then, the residue was purified by silica gel column chromatography (50% v/v DCM in hexane) to afford 4 as a white solid in 82% yield. Methyl 2-(2-Methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2a). Yield 80% (297.1 mg), white solid; mp 87.7−88.9 °C; 1H NMR (400 MHz, CDCl3) δ = 8.26 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.30−7.39 (m, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H), 2.84 (s, 3H), 2.36 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.1, 165.0, 146.5, 146.2, 135.9, 135.4, 130.4, 126.7, 126.4, 125.5, 124.9, 120.4, 115.5, 114.4, 53.0, 21.7, 14.1; HRMS(ESI) calcd for C19H18NO5S (M+H)+: 372.0900, Found: 372.0902. 14213

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

Note

The Journal of Organic Chemistry

114.8, 52.6, 52.3, 21.5; HRMS(ESI) calcd for C29H24NO6S (M+H)+: 514.1319, Found: 514.1320. Methyl 2-(4-Chlorophenyl)-9-tosyl-9H-carbazole-4-carboxylate (3e). Yield 72% (35.3 mg), white solid; mp 208.6−210.0 °C; 1H NMR (400 MHz, CDCl3) δ = 8.82 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.65− 7.69 (m, 4H), 7.55 (td, J = 7.2, 1.2 Hz, 1H), 7.47−7.50 (m, 2H), 7.36−7.40 (m, 1H), 7.09 (d, J = 8.0 Hz, 2H), 4.04 (s, 3H), 2.25 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.6, 145.3, 140.1, 139.5, 138.4, 138.3, 134.6, 134.2, 129.8, 129.2, 128.7, 128.4, 126.5, 126.1, 125.5, 125.1, 124.7, 124.6, 124.2, 116.8, 114.8, 52.6, 21.5; HRMS(ESI) calcd for C27H21ClNO4S (M+H)+: 490.0874, Found: 490.0874. Methyl 2-(4-Nitrophenyl)-9-tosyl-9H-carbazole-4-carboxylate (3f). Yield 54% (27.0 mg), white solid; mp 217.5−218.6 °C; 1H NMR (400 MHz, CDCl3) δ = 8.90 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.37 (dt, J = 8.8, 2.0 Hz, 2H), 8.16 (d, J = 1.6 Hz, 1H), 7.89 (dt, J = 8.8, 2.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.56−7.60 (m, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 4.06 (s, 3H), 2.27 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.4, 147.5, 146.3, 145.5, 140.1, 139.7, 139.3, 138.3, 136.9, 134.6, 129.9, 128.9, 128.2, 126.5, 126.4, 125.7, 125.3, 124.4, 124.3, 117.2, 114.8, 52.7, 21.6; HRMS(ESI) calcd for C27H21N2O6S (M+H)+: 501.1115, Found: 501.1117. Methyl 2-(2-Methoxyphenyl)-9-tosyl-9H-carbazole-4-carboxylate (3g). Yield 81% (39.3 mg), white solid; mp 129.4−131.2 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.91 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.54 (td, J = 7.2, 1.2 Hz, 1H), 7.46 (dd, J = 7.6, 2.0 Hz, 1H), 7.37−7.43 (m, 2H), 7.06−7.14 (m, 4H), 4.02 (s, 3H), 3.91 (m, 3H), 2.26 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.9, 156.6, 145.1, 139.5, 139.3, 137.0, 134.8, 131.1, 129.7, 129.4, 128.2, 126.6, 125.2, 125.2, 125.0, 125.0, 124.1, 121.1, 120.2, 114.9, 111.5, 55.8, 52.4, 21.5; HRMS(ESI) calcd for C28H24NO5S (M+H)+: 486.1370, Found: 486.1371. Methyl 2-(Naphthalen-2-yl)-9-tosyl-9H-carbazole-4-carboxylate (3h). Yield 84% (42.5 mg), white solid; mp 235.9−237.6 °C; 1H NMR (400 MHz, CDCl3) δ = 9.01 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 7.97−8.01 (m, 2H), 7.88−7.92 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.51−7.58 (m, 3H), 7.39−7.43 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.07 (s, 3H), 2.24 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.8, 145.3, 139.6, 137.2, 134.7, 133.7, 129.8, 128.8, 128.4, 128.3, 127.8, 126.6, 126.5, 126.4, 126.3, 126.1, 126.0, 125.5, 125.1, 124.8, 124.2, 117.3, 114.9, 52.6, 21.5; HRMS(ESI) calcd for C31H24NO4S (M+H)+: 506.1421, Found: 506.1426. Methyl 2-(Thiophen-2-yl)-9-tosyl-9H-carbazole-4-carboxylate (3i). Yield 86% (39.7 mg), white solid; mp 181.7−182.7 °C; 1H NMR (400 MHz, CDCl3) δ = 8.87 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.51−7.56 (m, 2H), 7.35−7.39 (m, 2H), 7.16 (dd, J = 5.2, 3.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.04 (s, 3H), 2.26 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.6, 145.3, 143.3, 140.0, 139.6, 134.6, 132.9, 129.8, 128.4, 128.3, 126.6, 126.1, 125.9, 124.9, 124.7, 124.4, 124.3, 124.2, 115.5, 114.8, 52.6, 21.5; HRMS(ESI) calcd for C25H20NO4S2 (M+H)+: 462.0828, Found: 462.0830. Methyl 2-(Furan-2-yl)-9-tosyl-9H-carbazole-4-carboxylate (3j). Yield 85% (37.9 mg), white solid; mp 129.5−130.1 °C; 1H NMR (400 MHz, CDCl3) δ = 8.91 (d, J = 1.2 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 1.2 Hz, 1H), 7.52 (td, J = 7.2, 1.2 Hz, 1H), 7.35−7.38 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 3.2 Hz, 1H), 6.56 (dd, J = 3.2, 2.0 Hz, 1H), 4.04 (s, 3H), 2.25 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 167.6, 152.9, 145.2, 142.9, 139.9, 139.5, 134.6, 129.8, 129.3, 128.2, 126.5, 126.0, 124.9, 124.8, 124.2, 124.1, 122.4, 114.8, 113.5, 112.1, 106.6, 52.6, 21.5; HRMS(ESI) calcd for C25H20NO5S (M+H)+: 446.1057, Found: 446.1055. Methyl (E)-2-Styryl-9-tosyl-9H-carbazole-4-carboxylate (3k). Yield 93% (44.8 mg), white solid; mp 145.7−146.1 °C; 1H NMR (400 MHz, CDCl3) δ = 8.77 (d, J = 1.6 Hz, 1H), 8.61 (dd, J = 8.0, 0.8

Ethyl 2-(2-Methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2j). Yield 90% (346.9 mg), brown oil; 1H NMR (400 MHz, CDCl3) δ = 8.28 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.30−7.39 (m, 2H), 7.24−7.26 (m, 2H), 4.41−4.47 (m, 2H), 2.88 (s, 3H), 2.33 (s, 3H), 1.36−1.41 (m, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.5, 164.8, 146.5, 146.2, 135.9, 135.3, 130.3, 126.7, 126.5, 125.5, 124.9, 120.5, 115.5, 114.4, 62.6, 21.6, 14.2, 14.0; HRMS(ESI) calcd for C20H20NO5S (M+H)+: 386.1057, Found: 386.1057. Isopropyl 2-(2-Methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2k). Yield 88% (351.5 mg), brown oil; 1H NMR (400 MHz, CDCl3) δ = 8.24 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.26−7.33 (m, 2H), 7.15 (d, J = 7.6 Hz, 2H), 5.20−5.27 (m, 1H), 2.86 (m, 3H), 2.22 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.8, 164.4, 146.3, 146.1, 135.9, 135.3, 130.3, 126.7, 126.5, 125.4, 124.9, 120.6, 115.5, 114.4, 70.8, 21.6, 21.5, 14.2; HRMS(ESI) calcd for C21H22NO5S (M+H)+: 400.1213, Found: 400.1215. Benzyl 2-(2-Methyl-1-tosyl-1H-indol-3-yl)-2-oxoacetate (2l). Yield 80% (358.0 mg), brown solid; mp 94.7−95.9 °C; 1H NMR (400 MHz, CDCl3) δ = 8.24 (d, J = 8.4 Hz, 1H), 7.71−7.76 (m, 3H), 7.42−7.45 (m, 2H), 7.38−7.41 (m, 3H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.21−7.27 (m, 3H), 5.40 (s, 2H), 2.76 (m, 3H), 2.37 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 183.2, 164.5, 146.7, 146.1, 135.9, 135.4, 134.2, 130.3, 129.2, 129.0, 128.8, 126.7, 126.4, 125.4, 124.9, 120.5, 115.5, 114.4, 68.1, 21.7, 14.1; HRMS(ESI) calcd for C25H22NO5S (M+H)+: 448.1213, Found: 448.1215. Methyl 2-Phenyl-9-tosyl-9H-carbazole-4-carboxylate (3a). Yield 86% (39.2 mg), white solid; mp 141.5−142.2 °C; 1H NMR (400 MHz, CDCl3) δ = 8.91 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H) 8.18 (d, J = 1.6 Hz, 1H), 7.78−7.80 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.54−7.60 (m, 3H), 7.44−7.48 (m, 1H), 7.40−7.43 (m, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.07 (s, 3H), 2.28 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.8, 145.3, 140.1, 139.9, 139.7, 139.5, 134.7, 129.8, 129.1, 128.3, 128.0, 127.5, 126.5, 125.9, 125.8, 125.0, 124.7, 124.2, 117.1, 114.9, 52.6, 21.6; HRMS(ESI) calcd for C27H21NO4SNa (M+Na)+: 478.1083, Found: 478.1081. Methyl 2-(p-Tolyl)-9-tosyl-9H-carbazole-4-carboxylate (3b). Yield 86% (40.4 mg), white solid; mp 210.5−212.7 °C; 1H NMR (400 MHz, CDCl3) δ = 8.87 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 4H), 7.54 (td, J = 7.2, 1.2 Hz, 1H), 7.37−7.41 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.04 (s, 3H), 2.45 (s, 3H), 2.25 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.9, 145.2, 142.4, 140.1, 139.6, 139.5, 138.0, 137.0, 134.7, 129.8, 128.2, 127.3, 126.5, 125.9, 125.6, 125.0, 124.8, 124.2, 124.1, 116.8, 114.9, 52.5, 21.5, 21.2; HRMS(ESI) calcd for C28H24NO4S (M+H)+: 470.1421, Found: 470.1422. Methyl 2-(4-Methoxyphenyl)-9-tosyl-9H-carbazole-4-carboxylate (3c). Yield 83% (40.3 mg), white solid; mp 219.6−220.4 °C; 1 H NMR (400 MHz, CDCl3) δ = 8.83 (d, J = 1.6 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 11.6, 8.8 Hz, 4H), 7.53 (td, J = 7.2, 1.2 Hz, 1H), 7.36−7.40 (m, 1H), 7.06 (t, J = 9.6 Hz, 4H), 4.04 (s, 3H), 3.88 (s, 3H), 2.24 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.9, 156.6, 145.1, 139.5, 139.3, 137.0, 134.8, 131.1, 129.7, 129.4, 128.2, 128.1, 126.6, 125.2, 125.0, 124.9, 124.0, 121.1, 120.2, 114.9, 111.5, 55.8, 52.4, 21.5; HRMS(ESI) calcd for C28H24NO5S (M+H)+: 486.1370, Found: 486.1373. Methyl 2-(4-(Methoxycarbonyl)phenyl)-9-tosyl-9H-carbazole-4carboxylate (3d). Yield 72% (37.0 mg), white solid; mp 209.4− 212.4 °C; 1H NMR (400 MHz, CDCl3) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.16−8.19 (m, 3H), 7.80 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.53−7.57 (m, 1H), 7.36−7.40 (m, 1H), 7.09 (d, J = 8.0 Hz, 2H), 4.05 (s, 3H), 3.97 (s, 3H), 2.25 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.6, 166.8, 145.4, 144.2, 140.0, 139.6, 138.3, 134.6, 130.4, 129.8, 129.6, 128.6, 127.4, 126.5, 126.1, 125.7, 125.2, 124.5, 124.2, 117.2, 14214

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

Note

The Journal of Organic Chemistry

7.76 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.56−7.43 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 2.27 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.4, 145.5, 140.5, 140.4, 139.7, 137.9, 134.4, 129.9, 129.8, 129.1, 128.3, 128.2, 127.5, 126.5, 126.2, 126.1, 126.0, 125.1, 123.5, 117.3, 115.8, 52.7, 21.6; HRMS(ESI) calcd for C27H21ClNO4S (M+H)+: 490.0874, Found: 490.0871. Methyl 6-Bromo-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3r). Yield 64% (34.2 mg), white solid; mp 164.3−164.6 °C; 1H NMR (400 MHz, CDCl3) δ = 8.86 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 10.4, 4.0 Hz, 1H), 8.38 (dd, J = 8.8, 4.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.75−7.77 (m, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.43−7.47 (m, 1H), 7.27 (td, J = 8.8, 2.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 4.04 (s, 3H), 2.27 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.4, 145.4, 140.9, 140.3, 139.7, 134.4, 129.8, 129.1, 128.2, 127.5, 126.5, 126.1, 126.0, 117.5, 116.0, 115.9, 115.8, 115.7, 111.6, 111.4, 104.6, 52.6, 21.5; HRMS(ESI) calcd for C27H21BrNO4S (M+H)+: 534.0369, Found: 534.0369. Methyl 6-Nitro-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3s). Yield 53% (26.5 mg), white solid; mp 230.0−230.7 °C; 1H NMR (400 MHz, CDCl3) δ = 9.73 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.43 (dd, J = 9.2, 2.4 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.75−7.77 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.54−7.57 (m, 2H), 7.45−7.50 (m, 1H), 7.16 (d, J = 8.4 Hz, 2H), 4.10 (s, 3H), 2.29 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.0, 146.2, 144.3, 142.6, 141.3, 141.0, 139.4, 134.3, 130.2, 129.2, 128.5, 127.5, 126.8, 126.6, 126.4, 125.0, 123.2, 121.9, 117.2, 114.7, 52.8, 21.6; HRMS(ESI) calcd for C27H21N2O6S (M+H)+: 501.1115, Found: 501.1115. Methyl 6-Methyl-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3t). Yield 53% (24.9 mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ = 8.86 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 2.50 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 167.8, 145.1, 140.3, 140.0, 139.5, 137.7, 134.7, 133.8, 129.7, 129.5, 129.1, 128.0, 127.5, 126.5, 125.9, 125.7, 124.9, 124.5, 117.2, 114.6, 52.5, 21.7, 21.5; HRMS(ESI) calcd for C28H24NO4S (M+H)+: 470.1421, Found: 470.1422. Methyl 7-Chloro-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3u). Yield 74% (36.3 mg), white solid; mp 169.0−169.3 °C; 1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J = 1.6 Hz, 1H), 8.38 (dd, J = 8.0, 0.8 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.42−7.47 (m, 2H), 7.37 (dd, J = 8.0, 0.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 2.30 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 170.1, 145.7, 140.8, 140.6, 139.9, 139.6, 134.5, 130.0, 129.4, 129.1, 128.9, 128.8, 128.3, 128.2, 127.5, 126.6, 125.9, 123.9, 123.0, 115.0, 113.4, 52.5, 21.6; HRMS(ESI) calcd for C27H21ClNO4S (M+H)+: 490.0874, Found: 490.0877. Methyl 7-Bromo-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3v). Yield 79% (42.2 mg), white solid; mp 194.3−195.6 °C; 1H NMR (400 MHz, CDCl3) δ = 8.85 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.74− 7.78 (m, 2H), 7.70 (dt, J = 8.4, 2.0 Hz, 2H), 7.54−7.58 (m, 2H), 7.51 (dd, J = 8.4, 1.6 Hz, 1H), 7.45−7.49 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 4.05 (s, 3H), 2.31 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.5, 145.6, 140.2, 140.1, 139.7, 134.4, 130.0, 129.1, 128.2, 127.5, 127.4, 126.6, 126.5, 126.2, 125.8, 123.8, 123.7, 122.2, 117.7, 117.1, 52.6, 21.6; HRMS(ESI) calcd for C27H21BrNO4S (M+H)+: 534.0369, Found: 534.0369. Ethyl 2-Phenyl-9-tosyl-9H-carbazole-4-carboxylate (3w). Yield 89% (41.8 mg), white solid; mp 112.5−113.6 °C; 1H NMR (400 MHz, CDCl3) δ = 8.93 (d, J = 1.6 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.56−7.61 (m, 3H), 7.49−7.41 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.57 (q, J = 6.8 Hz, 2H), 2.26 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.4, 145.3, 140.1, 139.7, 139.5, 134.7, 129.8, 129.1, 128.3, 128.1, 127.5, 126.5, 126.4, 125.7, 125.1, 124.8, 124.4, 124.1, 117.0, 114.9,

Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.68 (dt, J = 8.4, 2.0 Hz, 2H), 7.65−7.62 (m, 2H), 7.53−7.57 (m, 1H), 7.42− 7.46 (m, 2H), 7.37−7.41 (m, 1H), 7.35 (dt, J = 7.2, 1.2 Hz, 1H), 7.33 (d, J = 2.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.07 (s, 3H), 2.29 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.8, 145.2, 140.0, 139.5, 136.8, 136.1, 134.6, 130.3, 129.8, 128.9, 128.2, 128.1, 127.7, 126.8, 126.5, 125.9, 124.9, 124.8, 124.6, 124.2, 116.5, 114.9, 52.6, 21.6; HRMS(ESI) calcd for C29H24NO4S (M+H)+: 482.1421, Found: 482.1420. Methyl 2-Propyl-9-tosyl-9H-carbazole-4-carboxylate (3l). Yield 39% (16.4 mg), white solid; mp 145.4−146.9 °C; 1H NMR (400 MHz, CDCl3) δ = 8.58 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.48−7.52 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 4.00 (s, 3H), 2.81 (t, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.81−1.72 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 168.0, 145.1, 141.7, 139.7, 139.2, 134.6, 129.7, 127.8, 127.2, 126.5, 125.4, 125.1, 124.7, 124.0, 123.4, 118.9, 114.9, 52.4, 38.2, 24.8, 21.5, 13.7; HRMS(ESI) calcd for C24H24NO4S (M+H)+: 422.1421, Found: 422.1421. Methyl 2-(1-Methyl-1H-indol-2-yl)-9-tosyl-9H-carbazole-4-carboxylate (3m). Yield 92% (46.8 mg), white solid; mp 190.1−191.5 °C; 1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J = 1.6 Hz, 1H), 8.70 (dd, J = 8.4, 0.8 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.71−7.74 (m, 3H), 7.59−7.63 (m, 1H), 7.43−7.47 (m, 2H), 7.35 (td, J = 7.2, 1.2 Hz, 1H), 7.21−7.25 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 0.4 Hz, 1H), 4.08 (s, 3H), 3.90 (s, 3H), 2.31 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.6, 145.4, 140.3. 139.6, 139.4, 138.8, 134.7, 131.1, 129.8, 128.6, 127.9, 127.5, 126.5, 125.9, 125.1, 124.6, 124.5, 124.2, 122.3, 120.7, 120.2, 118.8, 114.8, 109.8, 102.9, 52.7, 31.6, 21.6; HRMS(ESI) calcd for C30H25N2O4S (M+H)+: 509.1530, Found: 509.1528. Methyl 9′-Methyl-9-tosyl-9H,9′H-[2,2′-bicarbazole]-4-carboxylate (3n). Yield 87% (48.6 mg), white soild; mp 130.3−131.6 °C; 1 H NMR (400 MHz, CDCl3) δ = 9.00 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.45−8.47 (m, 2H), 8.30 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.4, 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.54−7.59 (m, 3H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.10 (s, 3H), 3.93 (s, 3H), 2.28 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 168.0, 145.2, 141.5, 140.9, 140.8, 140.2, 139.5, 134.7, 130.9, 129.8, 128.0, 126.6, 126.1, 125.9, 125.8, 125.4, 124.9, 124.8, 124.1, 123.6, 123.5, 122.8, 120.6, 119.3, 119.2, 117.0, 114.9, 109.0, 108.7, 52.5, 29.3, 21.5; HRMS(ESI) calcd for C34H27N2O4S (M+H)+: 559.1686, Found: 559.1686. Methyl 5-Chloro-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3o). Yield 50% (24.5 mg), white solid; mp 183.3−183.9 °C; 1H NMR (400 MHz, CDCl3) δ = 8.83 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 4.03 (s, 3H), 2.28 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.5, 145.6, 140.2, 140.1, 140.0, 139.8, 134.5, 134.2, 130.0, 129.1, 128.2, 127.5, 126.6, 126.2, 126.1, 125.7, 124.6, 123.8, 123.3, 117.1, 114.9, 52.6, 21.6; HRMS(ESI) calcd for C27H21ClNO4S (M+H)+: 490.0874, Found: 490.0877. Methyl 6-Fluoro-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3p). Yield 84% (39.8 mg), white solid; mp 230.1−232.4 °C; 1H NMR (400 MHz, CDCl3) δ = 8.87 (d, J = 2.4 Hz, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.74− 7.76 (m, 2H), 7.62−7.65 (m, 3H), 7.52−7.56 (m, 2H), 7.43−7.47 (m, 1H), 7.10 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 2.27 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.3, 145.5, 140.4, 139.7, 138.3, 134.4, 131.0, 129.9, 129.1, 128.2, 128.1, 127.5, 126.5, 126.5, 126.3, 126.0, 123.4, 117.6, 117.2, 116.2, 52.7, 21.6; HRMS(ESI) calcd for C27H21FNO4S (M+H)+: 474.1170, Found: 474.1170. Methyl 6-Chloro-2-phenyl-9-tosyl-9H-carbazole-4-carboxylate (3q). Yield 82% (40.2 mg), white solid; mp 175.2−176.0 °C; 1H NMR (400 MHz, CDCl3) δ = 8.86 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.74− 14215

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

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The Journal of Organic Chemistry 61.7, 21.5, 14.4; HRMS(ESI) calcd for C28H24NO4S (M+H)+: 470.1421, Found: 470.1421. Isopropyl 2-Phenyl-9-tosyl-9H-carbazole-4-carboxylate (3x). Yield 82% (39.7 mg), white solid; mp 127.4−130.1 °C; 1H NMR (400 MHz, CDCl3) δ = 8.92 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.57−7.61 (m, 3H), 7.46−7.50 (m, 21), 7.43 (td, J = 7.6, 0.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.44−5.47 (m, 1H), 2.28 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.0, 145.3, 140.2, 140.0, 139.7, 139.5, 134.7, 129.8, 129.1, 128.2, 128.0, 127.6, 126.9, 126.5, 125.5, 125.1, 124.8, 124.3, 124.1, 116.9, 114.9, 69.3, 22.0, 21.6; HRMS(ESI) calcd for C29H26NO4S (M+H)+: 484.1577, Found: 484.1575. Benzyl 2-Phenyl-9-tosyl-9H-carbazole-4-carboxylate (3y). Yield 80% (42.5 mg), white solid; mp 134.2−136.0 °C; 1H NMR (400 MHz, CDCl3) δ = 8.91 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 8.0, 0.4 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.76−7.78 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.53−7.59 (m, 5H), 7.35−7.49 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 5.54 (s, 2H), 2.28 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 167.2, 145.3, 140.1, 140.0, 139.7, 139.5, 135.6, 134.6, 129.8, 129.1, 128.7, 128.5, 128.3, 128.0, 127.5, 126.5, 126.0, 125.7, 125.1, 124.7, 124.5, 124.1, 117.2, 114.8, 67.3, 21.6; HRMS(ESI) calcd for C33H26NO4S (M+H)+: 532.1577, Found: 532.1577. Methyl 3-Phenyldibenzo[b,d]thiophene-1-carboxylate (3z). Yield 64% (20.4 mg), white solid; mp 90.0−91.6 °C; 1H NMR (400 MHz, CDCl3) δ = 8.82 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.72−7.74 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.49−7.56 (m, 3H), 7.39−7.44 (m, 2H), 4.09 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 169.3, 141.7, 140.2, 139.5, 138.8, 133.7, 131.5, 129.0, 128.7, 128.0, 127.3, 127.1, 125.5, 125.3, 124.5, 123.9, 122.7, 52.8; HRMS(ESI) calcd for C20H15O2S (M+H)+: 319.0787, Found: 319.0785.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02532. 1 H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhenqian Fu: 0000-0002-3806-6684 Author Contributions §

D.L. and Y.G. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support by National Natural Science Foundation of China (21602105), Natural Science Foundation of Jiangsu Province (BK20171460), National Key R&D Program of China (2017YFA0204704), and National Key Basic Research Program of China (973) (2015CB932200).

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REFERENCES

(1) (a) Schmidt, A. W.; Reddy, K. R.; Knolker, H. J. Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193−3328. (b) Gluszynska, A. Biological potential of carbazole derivatives. Eur. J. Med. Chem. 2015, 94, 405− 426. (c) Caruso, A.; Iacopetta, D.; Puoci, F.; Cappello, A. R.; Saturnino, C.; Sinicropi, M. S. Carbazole Derivatives: A Promising Scenario for Breast Cancer Treatment. Mini-Rev. Med. Chem. 2016, 14216

DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217

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DOI: 10.1021/acs.joc.8b02532 J. Org. Chem. 2018, 83, 14210−14217