C–N bond formation via Cu-catalyzed cross-coupling with boronic acids leading to methyl carbazole-3-carboxylate: synthesis of carbazole alkaloids

Abstract

Copper promoted N-arylation of methyl 4-amino-3-iodobenzoate with boronic acids followed by Pd-catalyzed intramolecular C–H arylation provides an efficient route to methyl carbazole-3-carboxylate derivatives. This methodology was implemented in the synthesis of naturally occurring carbazole alkaloids clausine C, clausine H, clausine L, clausenalene, glycozoline, glycozolidine, glycozolidal and sansoakamine.

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Introduction

Carbazoles have attracted considerable attention both in biological and material sciences as ubiquitous structural motif due to their medicinal,¹ photophysical² and optoelectronic application.³ Naturally occurring carbazomycin and ellipticine are well known for their antibacterial and anticancer properties respectively.⁴ Carbazole containing carveidilol and carazolol are used for the treatment of hypertension, ischemic heart disease and congestive heart failure.⁵ Carbazoles having –CO₂Me group at 3-position represent a wide class of naturally occurring alkaloids (Fig. 1). Methyl carbazole-3-carboxylate (2a) and methyl 6-methoxycarbazole-3-carboxylate (2c) have been isolated from the roots of Clausena lansium.⁶

Fig. 1 Naturally occurring methyl carbazole-3-carboxylate alkaloids.

Wu et al. reported the isolation of clausine C (2b),^7a clausine H (2k),^7b clausine M^7c from the root bark of Clausena excavata. Clausine L (2j) and mukonidine both isolated by Wu and co-workers form the Chinese medicinal plant Clausena excavata.⁸ Recently, 2,6-dioxygenated sansoakamine (6) was isolated from the stem of Clausena excavata.⁹ In 2012 Laphookhieo et al. reported the isolation and biological activity of methyl carbazole-3-carboxylate (clausine C, clausine H, clausine L and mukonidine) and during the evaluation of antibacterial properties, mukonidine showed weak activity against MRSA (MIC 64 μg mL⁻¹) and moderate activity against Gram-negative pathogen S. typhimurium with an MIC value of 32 μg mL⁻¹.¹⁰ Further the anti-plasmodial activity (IC₅₀ 5.5–8.2 μg mL⁻¹) of clausine H has been reported.¹¹ For structure–activity relationships (SAR) study, the diversity in carbazole synthesis, especially the regiospecific installation of substituent's onto each of the nine positions of the carbazole skeleton, is challenging from synthetic point. Thus, the development of a mild, efficient and regio-controlled diversified method for the preparation of carbazole remains of high interest.

Transition metal-catalyzed N-arylation has been extensively studied over the past decade.¹² The discovery of Pd- or Cu-catalyzed amination reactions pioneered by Buchwald and Hartwig is a hallmark reaction in this field.^13,14 Despite these significant progresses in improvements of the reaction conditions, limitation exists in terms of functional group tolerability and high cost of palladium. In 1998 independent publications by Chan,¹⁵ Evans¹⁶ and Lam¹⁷ revolutionized the copper mediated heteroatom arylation reaction for the formation of N-aryl and O-aryl bonds using boronic acids. Later discovery by Collman¹⁸ has demonstrated that this reaction can be rendered catalytic for the arylation of imidazoles when [Cu(OH)·TMEDA]₂Cl₂ is used as a copper source. In the course of time the Chan–Lam type coupling became a useful synthetic tool due to the mild reaction conditions employed e.g. room temperature, weak base, ambient atmosphere (open-flask chemistry).^19–21

Many different approaches for construction of carbazoles have been studied.^22,23 Among them the approaches involving transition metal-catalyzed intramolecular C–C bond formation in diarylamines via C–H activation provide an excellent access to these important class of natural product.²² While the direct synthesis of carbazoles by cascade Buchwald–Hartwig N-arylation followed by C–H arylation using o-haloanilines has been reported.²⁴ The main drawback of these reactions are use of expensive ligand, strong base and high reaction temperature. It is well precedented that oxidative insertion into a C–X bond is most facile for aryl iodides, so use of aryl iodides as coupling partner can give easy access to the desired arylated product.²⁵

Keeping this in mind, we decided to use o-iodoanilines as substrate for cross-coupling reaction. Thus to find a mild reaction conditions for carbazole synthesis here we wish to report our study on Cu-catalyzed N-arylation of methyl 4-amino-3-iodobenzoate²⁶ with boronic acid at room temperature under air followed by Pd-catalyzed intramolecular cyclization (Scheme 1). This protocol is general and culminated in the synthesis of several naturally occurring carbazoles including first total synthesis of sansoakamine.

Scheme 1 Synthesis of methyl carbazole-3-carboxylate.

Results and discussion

For N-arylation of methyl 4-amino-3-iodobenzoate, we first use the protocol as reported by Chan¹¹ and Evans¹⁶ for O-arylation of o-iodophenol. Our initial experiment starts with N-arylation of methyl 4-amino-3-iodobenzoate with phenylboronic acid by using Cu(OAc)₂ (1 equiv.) and Et₃N (2 equiv.) in DCM under air and room temperature. But this reaction ended with poor conversion (only 40%) of the starting material even after 48 h. Screening of different solvents, copper salts and base frustrated us with poor yield (see ESI† for details of optimization protocol). Interestingly, the reaction also have only 40% conversion under catalytic (10 mol%) use of Cu(OAc)₂. Careful observation on the progress of this reaction, revealed that the reaction proceed smoothly with 30 to 40% conversion in the first 5–6 h and then catalytic activity diminished over the next 20 h. J. C. Antilla and S. L. Buchwald²⁷ have previously reported similar observations and they modified the conditions by using 2,6-lutidine as a base, myristic acid as an additive and toluene the preferred solvent. To our delight, when we subjected methyl 4-amino-3-iodobenzoate to the N-arylation conditions with phenylboronic acid by using catalytic Cu(OAc)₂ (10 mol%), 2,6-lutidine in toluene under air the reaction proceed smoothly with 70% isolated yield (1a). In this reaction condition we used n-decanoic acid (20 mol%) as an additive. The use of molecular oxygen did not have any further improvement with the isolated yield. By using this optimized condition a series of N-arylated methyl 4-amino-3-iodobenzoate have been synthesized (Table 1). Methoxy substituted phenylboronic acids became our first choice as coupling partner so that naturally occurring carbazoles can be synthesized in subsequent cyclization process (Table 2). We were pleased to find that methoxy substitution of phenylboronic acids both at m- and p-position gave satisfactory coupling products (1b and 1c). The versatility of this reaction protocol has been demonstrated by further using different boronic acids as coupling partner (Table 1). Three more p-substituted boronic acids have been used to synthesize the corresponding N-arylated product (1d–f) in good yield. Phenylboronic acids containing electron withdrawing group (EWG) also resulted (1g–h) in satisfactory yield (65–66%) under this cross-coupling conditions. Bicyclic benzo[d][1,3]dioxol-5-ylboronic acid also gave clean coupled product with 72% isolated yield (1i). To find the generality and substrate scope of this methodology we further explore the N-arylation of 2-methoxy derivative of methyl 4-amino-3-iodobenzoate with different boronic acids. Phenyl boronic acid works satisfactorily to yield 1j in 70%. Both m- and p-substituted methoxyboronic acid gave the cross coupled product (1k–l) in 72% and 70% yield respectively.

Table 1 Cu-catalyzed coupling of methyl 4-amino-3-iodobenzoate with boronic acids^a

a Methyl 4-amino-3-iodobenzoate (1 equiv.), boronic acids (1.5 equiv.), Cu(OAc)2 (10 mol%), n-decanoic acid (20 mol%), 2,6-lutidine (2 equiv.), toluene (5 mL), rt, air, 24 h.

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Table 2 Pd-catalyzed C–H arylation of methyl 3-iodo-4-(phenylamino)benzoate^a

a Methyl-3-iodo-4-(phenylamino)benzoate (1 equiv.), Pd(OAc)2 (10 mol%), K2CO3 (2 equiv.), DMSO (5 mL), sealed tube, 130 °C.

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After successful completion of the synthesis of diverse N-arylated product (1a–l), these 2-iodo diarylamine derivatives were used for intramolecular cyclization to obtain different carbazole alkaloids. To achieve the intramolecular C–H arylation of N-phenyl-2-iodoaniline derivatives, we first performed the reaction with methyl 3-iodo-4-(phenylamino)benzoate by using Pd(OAc)₂ (10 mol%) as catalyst, K₂CO₃ as base and DMSO as solvent in sealed tube at 130 °C.²⁸ To our expectation the reaction proceeded smoothly with complete conversion of starting material in 3 h to give methyl carbazole-3-carboxylate (2a)²⁹ with 92% isolated yield (Table 2). This Pd-catalyzed reaction is very clean and works well without NH-protection. By following same reaction conditions naturally occurring carbazoles clausine C^30a,b,e (2b), clausine L^30c,d (2j), clausine H^30a,f (2k) have been synthesized successfully. Clausine C can be converted to 7-hydroxy derivative, clausine M as reported by Knölker.^30b Clausine H (2i) can be considered as crucial precursor for several 2,7-dioxygenated carbazoles particularly for clausine K and clausine O.^30a Chloro and fluoro derivatives of N-arylated methyl 4-amino-3-iodobenzoate smoothly cyclized under this catalytic condition to give halogenated carbazoles (2g–h). Another naturally occurring carbazole methyl 6-methoxycarbazole-3-carboxylate (2c)³¹ synthesized in this process can be used as precursor for glycozoline (Scheme 2). 2,6-Dioxygenated carbazole (2l) and methylenedioxy carbazole (2i) synthesized by this route can be used as precursor for the synthesis of different carbazole alkaloids (Schemes 2 & 3).

Scheme 2 Synthesis of glycozoline (3), glycozolidine (4), clausenaline (5): (a) LiAlH₄ (2 equiv.), THF, 65 °C, 1 h.

Scheme 3 Synthesis of sansoakamine (6), glycozolidal (7): (a) BBr₃ (2 equiv.), CH₂Cl₂, −78 °C to −20 °C, 24 h, 76%; (b) DIBAL-H (1 equiv.), toluene, −78 °C, 1 h, 86%.

Two more new 6-oxygenated carbazoles 2d (85%) and 2e (80%) have also been synthesized by using this intramolecular C–H arylation process. Methyl 6-propyl-9H-carbazole-3-carboxylate (2f) has been synthesized under this Pd-catalyzed cyclization condition and the structure has been confirmed by X-ray crystal structure analysis (Fig. 2).³²

Fig. 2 Molecular structure of methyl 6-propyl-9H-carbazole-3-carbaxylate (2f) in crystal.

Methyl group at C-3 position remains one of the common structural features for many carbazole alkaloids. Thus to synthesize more naturally occurring carbazoles we pay our attention to the functional transformation of the 3-CO₂Me group. We first consider methyl 6-methoxycarbazole-3-carboxylate (2c) and it is obvious that carbazole 2c can serve as precursor for glycozoline (3).³³ Thus reduction of –CO₂Me group of 2c with LiAlH₄ gave glycozoline (3) in 75% yield (Scheme 2).³⁴ By following the same reduction condition we successfully synthesized glycozolidine (4)³⁵ from carbazole 2l in 65% yield and methylenedioxy carbazole clausenalene (5)³⁶ form 2i in 72% yield. Synthesized glycozoline, glycozolidine and clausenalene have been fully characterized by spectroscopic data which are in good agreement with those reported for natural product.

With the readily available 2,6-dioxygenated carbazole 2l in hand we envisaged direct access to sansoakamine and glycozolidal. BBr₃ mediated cleavage of both the methyl ether groups of 2l afforded sansoakamine (6) in 76% yield (Scheme 3). The spectroscopic data of the synthesized carbazole was in good agreement with the reported data.⁹ To the best of our knowledge this is the first report of total synthesis of sansoakamine. The methyl ester group of 2l was reduced directly into aldehyde group (Scheme 3) by DIBAL-H³⁷ to produce another natural alkaloid glycozolidal (7), which was structurally confirmed by its spectroscopic data.^35b

Conclusion

The Cu-catalyzed N-arylation and subsequent Pd-catalyzed intramolecular C–H arylation protocol has been successfully utilized in synthesizing various methyl carbazole-3-carboxylate derivatives. This two-step reaction sequence resulted in the direct synthesis of clausine C, clausine L and clausine H. This exercise also resulted in first total synthesis of 2,6-dioxygenated carbazole sansoakamine in four steps with 40% overall yield. Considering the availability of starting material and mild reaction conditions the procedure involved, we have demonstrated that this can be general methodology for synthesis of this family of compounds. Further studies including biological activity of these derivatives are presently being carried out in our laboratory.

Experimental

General information

Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel plates (60 F254; MERCK). TLC plates were visualized by exposing UV light or by iodine vapours or immersion in ninhydrin followed by heating on hot plate. ¹H and ¹³C NMR spectra were recorded with BRUKER 500 and 400 MHz NMR instruments. All the NMR spectra were processed in MestReNova. Mass spectra were recorded with VARIAN GC-MS instrument. HRMS spectra were recorded with LCMS-QTOF Module no. G6540 A (UHD) instrument. IR spectra were recorded on Jasco FT/IR-5300 spectrophotometer. 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 N-arylation of amine with boronic acids (1a–l)

Methyl 3-iodo-4-(phenylamino)benzoate (1a). To a solution of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol) in toluene (5 mL) was added phenylboronic acid (66 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) and was stirred vigorously for 24 h at room temperature in open air. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered through Whatman filter paper. The organic layer was washed with water (2 × 10 mL) and dried over Na₂SO₄. Then filtered and the solvent was removed under reduce pressure. The crude reaction mixture was purified by column chromatography on silica gel by using ethyl acetate–hexanes (2 : 8) as eluent to give 1a (92 mg, 70%). Colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 7.82 (dd, J = 8.6, 1.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 8.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.32 (br s, 1H), 3.87 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.0, 148.1, 140.8, 138.4, 131.5, 129.5, 123.1, 121.1, 120.4, 114.5, 96.6, 51.8; MS (ESI): m/z = 354 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₂INO₂ [M + H]⁺: 353.9986; found: 353.9988.

The following compounds 1b–l were prepared according to this procedure.

Methyl 3-iodo-4-(3-methoxyphenylamino)benzoate (1b). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 3-methoxyphenylboronic acid (82 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1b (102 mg, 74%); eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 7.83 (dd, J = 8.6, 1.9 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J = 8.4, 1H) 6.30 (br s, 1H), 3.85 (s, 3H), 3.79 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.0, 157.5, 153.1, 148.8, 136.1, 131.5, 129.8, 129.7, 123.1, 120.1, 118.4, 113.8, 96.4, 55.0, 51.7; MS (ESI): m/z = 384 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₄INO₃ [M + H]⁺: 384.0091; found: 384.0100.

Methyl 3-iodo-4-(4-methoxyphenylamino)benzoate (1c). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 4-methoxyphenylboronic acid (82 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1c (91 mg, 70%), eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.78 (dd, J = 8.7, 1.4 Hz, 1H), 7.15 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.8, 1.3 Hz, 2H), 6.75 (dd, J = 8.7, 1.3 Hz, 1H), 6.22 (br s, 1H), 3.86 (s, 3H), 3.84 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.1, 156.5, 149.8, 138.4, 133.4, 131.5, 124.4, 119.9, 114.8, 113.2, 96.1, 55.5, 51.6; MS (ESI): m/z = 384 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₄INO₃ [M + H]⁺: 384.0091; found: 384.0100.

Methyl 3-iodo-4-(4-phenoxyphenylamino)benzoate (1d). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 4-phenoxyphenylboronic acid (115.5 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0. 072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1d (105 mg, 65%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (500 MHz, CDCl₃) δ 8.42 (s, 1H), 7.82 (dd, J = 8.9, 1.9 Hz, 1H), 7.35 (m, 2H), 7.18 (dd, J = 8.6, 1.9 Hz, 2H), 7.12 (m, 1H), 7.03 (m, 3H), 7.00 (dd, J = 7.1, 2.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.26 (br s, 1H), 3.86 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.0, 160.7, 147.8, 142.2, 138.2, 135.2, 131.4, 130.2, 121.3, 115.0, 112.5, 108.3, 106.0, 89.2, 51.7; MS (ESI): m/z = 446 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₁NO₄ [M + H]⁺: 446.0248; found: 446.0249.

Methyl 4-(4-butoxyphenylamino)-3-iodobenzoate (1e). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 4-butoxyphenylboronic acid (105 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1e (106 mg, 70%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (500 MHz, CDCl₃) δ 8.39 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.13 (dd, J = 6.5, 2.1 Hz, 2H), 6.92 (dd, J = 8.4, 2.2 Hz, 2H), 6.74 (d, J = 8.6 Hz, 1H), 6.20 (br s, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 1.77 (dd, J = 14.3, 6.6 Hz, 2H), 1.51 (dd, J = 14.8, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.1, 156.2, 149.9, 138.4, 133.2, 131.5, 124.4, 119.9, 115.4, 113.2, 96.3, 68.1, 51.6, 29.2, 19.2, 13.7; MS (ESI): m/z = 426 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₈H₂₀INO₃ [M + H]⁺: 426.0561; found: 426.0554.

Methyl 3-iodo-4-(4-propylphenylamino)benzoate (1f). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 4-n-propylphenylboronic acid (88 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1f (90 mg, 68%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H), 7.80 (dd, J = 8.7, 1.3 Hz, 1H), 7.22 (dd, J = 8.7, 2.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 8.5 Hz, 1H), 6.28 (br s, 1H), 3.86 (s, 3H), 2.59 (t, J = 7.6 Hz, 2H), 1.65 (m, 2H), 0.95 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.1, 147.7, 137.3, 137.0, 132.3, 130.5, 128.4, 120.1, 119.5, 113.0, 97.6, 50.7, 36.4, 23.6, 12.8; MS (ESI): m/z = 396 [M + H]⁺; HRMS (ESI): calcd for C₁₇H₁₈INO₂ [M + H]⁺: 396.0455; found: 396.0446.

Methyl 4-(3-chlorophenylamino)-3-iodobenzoate (1g). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 3-chlorophenylboronic acid (84 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1g (92 mg, 66%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (500 MHz, CDCl₃) δ 8.44 (s, 1H), 7.86 (m, 1H), 7.28 (t, J = 1.3 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H), 7.08 (dd, J = 6.9, 5.1 Hz, 2H), 6.29 (br s, 1H), 3.88 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 165.5, 147.2, 141.6, 141.3, 135.2, 131.0, 130.6, 124.2, 123.0, 121.6, 119.7, 113.0, 86.2, 52.0; MS (ESI): m/z = 388 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₁IClNO₂ [M + H]⁺: 387.9596; found: 387.9587.

Methyl 4-(4-fluorophenylamino)-3-iodobenzoate (1h). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), 4-fluorophenylboronic acid (76 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1g (88 mg, 65%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.80 (m, 1H), 7.19 (m, 2H), 7.08 (m, 2H), 6.84 (dd, J = 8.7, 2.1 Hz, 1H), 6.24 (br s, 1H), 3.86 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 148.7, 141.2, 135.9, 130.9, 128.8, 125.5, 121.9, 116.5, 111.6, 84.7, 51.9; MS (ESI): m/z = 372 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₁IFNO₂ [M + H]⁺: 371.9891; found: 371.9886.

Methyl-4-(benzo[d][1,3]dioxol-5-ylamino)-3-iodobenzoate (1i). The reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (89 mg, 0.54 mmol), Cu(OAc)₂ (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) gave 1i (105 mg, 72%). Eluent: ethyl acetate–hexanes (3 : 7); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 7.79 (dd, J = 8.6, 1.7 Hz, 1H), 6.81 (dd, J = 8.4, 7.2 Hz, 2H), 6.73 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 8.2, 1.8 Hz, 1H), 6.18 (br s, 1H), 6.00 (s, 2H), 3.86 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 179.9, 167.1, 149.4, 148.3, 144.3, 134.7, 131.5, 120.2, 115.7, 113.5, 108.6, 104.6, 101.3, 96.7, 51.7; MS (ESI): m/z = 398 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₂INO₄ [M + H]⁺: 397.9884; found: 397.9883.

Methyl 5-iodo-2-methoxy-4-(phenylamino)benzoate (1j). The reaction of methyl 4-amino-5-iodo-2-methoxybenzoate (100 mg, 0.32 mmol), phenylboronic acid (58.5 mg, 0.48 mmol), Cu(OAc)₂ (5.8 mg, 0.032 mmol), n-decanoic acid (11 mg, 0.064 mmol), 2,6-lutidine (68.5 mg, 0.64 mmol) in toluene (5 mL) gave 1j (97 mg, 70%). Eluent: ethyl acetate–hexanes (1 : 9); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.94 (dd, J = 8.3, 2.1 Hz, 2H), 6.76 (t, J = 7.8 Hz, 1H), 6.25 (br, 1H), 3.86 (s, 3H), 3.84 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 167.8, 162.2, 157.0, 140.8, 137.9, 129.5, 123.8, 120.4, 114.5, 110.6, 96.1, 56.3, 51.8; MS (ESI): m/z = 384 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₄INO₃ [M + H]⁺: 384.0091; found: 384.0100.

Methyl 5-iodo-2-methoxy-4-(3-methoxyphenylamino)benzoate (1k). The reaction of methyl 4-amino-5-iodo-2-methoxybenzoate (100 mg, 0.32 mmol), 3-methoxyphenylboronic acid (74 mg, 0.48 mmol), Cu(OAc)₂ (5.8 mg, 0.032 mmol), n-decanoic acid (11 mg, 0.064 mmol) and 2,6-lutidine (68.5 mg, 0.64 mmol) in toluene (5 mL) gave 1k (105 mg, 72%). Eluent: ethyl acetate–hexanes (3 : 7); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.28 (dd, J = 8.6, 2.3 Hz, 2H), 6.82 (d, J = 7.9 Hz, 1H), 6.77 (t, J = 2.1 Hz, 1H), 6.72 (d, J = 2 Hz, 2H), 6.24 (br s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 164.8, 161.4, 160.8, 148.6, 142.9, 141.3, 130.4, 114.3, 112.2, 110.1, 107.7, 97.2, 56.0, 55.3, 51.7; MS (ESI): m/z = 414 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₆H₁₆INO₄ [M + H]⁺: 414.0197; found: 414.0222.

Methyl 5-iodo-2-methoxy-4-(4-methoxyphenylamino)benzoate (1l). The reaction of methyl 4-amino-5-iodo-2-methoxybenzoate (500 mg, 1.62 mmol), 4-methoxyphenylboronic acid (371 mg, 2.44 mmol), Cu(OAc)₂ (30 mg, 0.16 mmol), n-decanoic acid (56 mg, 0.32 mmol) and 2,6-lutidine (348 mg, 3.24 mmol) in toluene (20 mL) gave 1l (450 mg, 70%). Eluent: ethyl acetate–hexanes (1 : 9); colourless gel; ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.35 (s, 1H), 6.14 (br s, 1H), 3.84 (s, 6H), 3.69 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 164.8, 161.7, 157.4, 150.4, 142.8, 132.6, 130.9, 126.0, 116.0, 114.9, 95.8, 55.8, 55.5, 51.6; MS (ESI): m/z = 414 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₆H₁₆INO₄ [M + H]⁺: 414.0197; found: 414.0222.

General procedure for preparation of carbazoles (2a–l)

Methyl 9H-carbazole-3-carboxylate (2a). An oven-dried sealed tube was charged with, methyl 3-iodo-4-(phenylamino)benzoate 1a (80 mg, 0.220 mmol), K₂CO₃ (62.6 mg, 0.453 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol), DMSO (5 mL) and magnetic stir bar under argon atmosphere. The tube was sealed with Teflon cap and the reaction mixture was stirred at 130 °C for 3 h. The progress of the reaction was monitored by TLC and after completion the mixture was allowed to cool down to room temperature. The reaction mixture was diluted with H₂O (3 mL) and was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dried over Na₂SO₄ and was evaporated under vacuum. The crude product was purified by column chromatography (ethyl acetate–hexanes; 2 : 3) to afford the corresponding carbazole 2a as white solid (47 mg, 92%). mp. 174–176 °C (ref. 6: 168–170 °C); IR (NaCl) ν (cm⁻¹) 3344, 2947, 1692, 1591, 1522, 1497, 1448, 1434, 1327, 1312, 1250, 1172, 1110; ¹H NMR (400 MHz, acetone-d₆) δ 10.77 (br s, 1H), 8.82 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.09 (dd, J = 8.6, 1.6 Hz, 1H), 7.58 (dd, J = 8.3, 3.5 Hz, 2H), 7.46 (m, 1H), 7.28 (m, 1H), 3.92 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.9, 142.3, 139.9, 127.4, 126.5, 123.3, 123.1, 122.9, 121.4, 120.6, 120.3, 110.9, 110.1, 51.9; MS (ESI): m/z = 226 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₁NO₂ [M + H]⁺: 226.0863; found: 226.0859.

The following carbazoles 2b–l were prepared by following this procedure.

Clausine C (2b). The reaction of methyl 3-iodo-4-(3-methoxyphenylamino)benzoate 1b (100 mg, 0.26 mmol), Pd(OAc)₂ (5.8 mg, 0.025 mmol), and K₂CO₃ (72.1 mg, 0.521 mmol) in DMSO (5 mL) at 130 °C for 4 h afforded 2b as yellow solid (58 mg, 88%): eluent: ethyl acetate–hexanes (2 : 3); mp 194–195 °C (ref. 30b: 195 °C); IR (NaCl) ν (cm⁻¹) 3271, 2921, 2850, 1698, 1605, 1440, 1403, 1328, 1291, 1265, 1193, 1160, 1135, 1098; ¹H NMR (500 MHz, CDCl₃) δ 8.70 (s, 1H), 8.18 (br s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 8.1, 2.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.92 (dd, J = 8.4, 2.1 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.4, 160.6, 143.5, 142.7, 126.7, 124.2, 122.2, 122.0, 121.7, 117.4, 111.2, 109.8, 95.7, 55.2, 51.8; MS (ESI): m/z = 256 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₃NO₃ [M + H]⁺: 256.0968; found: 256.0973.

Methyl 6-methoxy-9H-carbazole-3-carboxylate (2c). The reaction of methyl 3-iodo-4-(4-methoxyphenylamino)benzoate 1c (90 mg, 0.23 mmol), Pd(OAc)₂ (5.2 mg, 0.023 mmol) and K₂CO₃ (64.9 mg, 0.47 mmol), in DMSO (5 mL) at 130 °C for 4 h afforded 2c as white solid (50 mg, 86%). Eluent: ethyl acetate–hexanes (2 : 3); mp 148–150 °C (ref. 6: 147–149 °C); IR (NaCl) ν (cm⁻¹) 3281, 2921, 2851, 1699, 1631, 1606, 1441, 1401, 1384, 1329, 1292, 1191, 1161, 1099, 1033; ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.18 (br s, 1H), 8.06 (dd, J = 8.5, 1.9 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.89 (dd, J = 8.6, 2.1 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.9, 154.5, 143.0, 134.7, 127.2, 123.8, 123.1, 122.9, 120.9, 115.9, 111.6, 110.2, 103.2, 55.9, 51.9; MS (ESI): m/z = 256 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₅H₁₃NO₃ [M + H]⁺: 256.0968; found: 256.0973.

Methyl 6-phenoxy-9H-carbazole-3-carboxylate (2d). The reaction of methyl 3-iodo-4-(4-phenoxyphenylamino)benzoate 1d (100 mg, 0.22 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol) and K₂CO₃ (62.1 mg, 0.45 mmol) in DMSO (5 mL) at 130 °C for 6 h afforded 2d as white solid (60 mg, 85%). Eluent: ethyl acetate–hexanes (2 : 3); mp 182–183 °C; IR (NaCl) ν (cm⁻¹) 3340, 2919, 2850, 1687, 1633, 1608, 1588, 1489, 1460, 1437, 1308, 1282, 1257, 1219, 1168, 1119, 1095; ¹H NMR (400 MHz, CDCl₃): δ 8.71 (s, 1H), 8.30 (br s, 1H), 8.13 (dd, J = 8.6, 1.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.34 (m, 2H), 7.22 (dd, J = 8.7, 2.3 Hz, 1H), 7.09 (dd, J = 10.6, 4.2 Hz, 1H), 7.02 (dd, J = 8.7, 1.0 Hz, 2H), 3.95 (s, 3H); ¹³C NMR (125 MHz, CD₃OD): δ 168.2, 159.2, 150.28, 143.85, 137.3, 129.3, 126.9, 123.57, 122.42, 122.0, 120.1, 119.1, 117.2, 111.1, 110.7, 110.2, 50.9; MS (ESI): m/z = 316 [M − H]⁺; HRMS (ESI): m/z calcd for C₂₀H₁₄NO₃ [M − H]⁺: 316.0979; found: 316.0967.

Methyl 6-butoxy-9H-carbazole-3-carboxylate (2e). The reaction of methyl 4-(4-butoxyphenylamino)-3-iodobenzoate 1e (100 mg, 0.23 mmol), Pd(OAc)₂ (5.3 mg, 0.023 mmol), K₂CO₃ (65 mg, 0.470 mmol) in DMSO (5 mL) at 130 °C for 5 h afforded 2e as white solid (56 mg, 80%); eluent: ethyl acetate–hexanes (2 : 3); mp 123–125 °C; IR (NaCl) ν (cm⁻¹) 3320, 2955, 2918, 2870, 1692, 1630, 1604, 1497, 1467, 1433, 1384, 1290,1273, 1196, 1175, 1117, 1097; ¹H NMR (400 MHz, acetone-d₆) δ 10.58 (br s, 1H), 8.82 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.92 (s, 3H), 1.83 (m, 2H), 1.57 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 167.9, 153.9, 142.9, 134.6, 127.1, 123.7, 123.0, 122.8, 120.7, 116.5, 111.5, 110.2, 104.2, 68.6, 51.8, 31.4, 19.2, 13.8; MS (ESI): m/z = 320 [M + Na]⁺; HRMS (ESI): m/z calcd for C₁₈H₁₉NO₃ [M + H]⁺: 298.1438; found: 298.1431.

Methyl 6-propyl-9H-carbazole-3-carboxylate (2f). The reaction of methyl 3-iodo-4-(4-propylphenylamino)benzoate 1f (80 mg, 0.20 mmol), Pd(OAc)₂ (4.5 mg, 0.020 mmol) and K₂CO₃ (55.9 mg, 0.404 mmol) in DMSO (5 mL) at 130 °C for 5 h afforded 2f as white solid (47 mg, 88%); eluent: ethyl acetate–hexanes (2 : 3); mp 144–146 °C; IR (NaCl) ν (cm⁻¹) 3298, 2959, 2922, 2852, 1697, 1632, 1607, 1466, 1430, 1384, 1320, 1281, 1261, 1193, 1161, 1131, 1093, 861, 803, 759, 632 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.29 (br s, 1H), 8.10 (dd, J = 7.8, 1.9 Hz, 1H), 7.92 (s, 1H), 7.37 (dd, J = 8.9, 1.9 Hz, 2H), 7.26 (dd, J = 8.6, 2.9 Hz, 1H), 3.97 (s, 3H), 2.76 (t, J = 7.9 Hz, 2H), 1.73 (dd, J = 15.0, 7.5 Hz, 2H), 0.98 (dd, J = 7.7, 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.0, 142.6, 138.3, 134.7, 127.3, 127.1, 123.3, 123.0, 122.7, 120.9, 119.9, 110.5, 110.0, 51.9, 38.0, 25.1, 13.7; MS (ESI): m/z = 290 [M + Na]⁺; HRMS (ESI): m/z calcd for C₁₇H₁₇NO₂ [M + H]⁺: 268.1332; found: 268.1333.

Methyl 7-chloro-9H-carbazole-3-carboxylate (2g). The reaction of methyl 4-(3-chlorophenylamino)-3-iodobenzoate 1g (80 mg, 0.20 mmol), Pd(OAc)₂ (4.6 mg, 0.020 mmol) and K₂CO₃ (57 mg, 0.412 mmol) in DMSO (5 mL) at 130 °C for 5 h afforded 2g as white solid (40 mg, 75%). Eluent: ethyl acetate–hexanes (2 : 3); mp 224–226 °C; IR (NaCl) ν (cm⁻¹) 3441, 2922, 2852, 1701, 1627, 1436, 1335, 1264, 1133, 1016, 912, 820; ¹H NMR (400 MHz, acetone-d₆) δ 10.89 (br s, 1H), 8.81 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 8.6, 1.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.27 (dd, J = 8.4, 1.9 Hz, 1H), 3.92 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.4, 142.7, 141.4, 128.4, 123.4, 123.4, 123.1, 123.0, 123.0, 122.7, 122.4, 118.2, 118.2, 111.0, 110.6, 110.5, 52.1; MS (ESI): m/z = 260 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₀ClNO₂ [M + H]⁺: 260.0473; found: 260.0474.

Methyl 6-fluoro-9H-carbazole-3-carboxylate (2h). The reaction of methyl 4-(4-fluorophenylamino)-3-iodobenzoate 1h (80 mg, 0.21 mmol), Pd(OAc)₂ (4.8 mg, 0.021 mmol) and K₂CO₃ (59.5 mg, 0.43 mmol) in DMSO (5 mL) at 130 °C for 5 h afforded 2h as white solid (39 mg, 75%). Eluent: ethyl acetate–hexanes (2 : 3); mp 196–199 °C; IR (NaCl) ν (cm⁻¹) 3436, 2925, 2853, 1634, 1466, 1431, 1315, 1286, 1261, 1159, 1016, 768; ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.32 (br s, 1H), 8.15 (dd, J = 8.6, 1.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 8.7, 4.1 Hz, 1H), 7.20 (m, 1H), 3.98 (s, 3H). ¹³C NMR (125 MHz, acetone-d₆) δ 167.9, 159.4, 157.6, 144.5, 137.8, 128.2, 123.8, 121.8, 115.0, 114.7, 113.0, 111.7, 106.9, 52.0; MS (ESI): m/z = 244 [M + H]⁺; HRMS (ESI): m/z calcd for C₁₄H₁₀FNO₂ [M + H]⁺: 244.0769; found: 244.0773.

Methyl 5H-[1,3]dioxolo[4,5-b]carbazole-8-carboxylate (2i). The reaction of methyl 4-(benzo[d][1,3]dioxol-5-ylamino)-3-iodobenzoate 1i (80 mg, 0.21 mmol), Pd(OAc)₂ (4.8 mg, 0.021 mmol) and K₂CO₃ (69.6 mg, 0.503 mmol) in DMSO (5 mL) at 130 °C for 6 h afforded 2i as light yellow solid (60 mg, 87%); eluent: ethyl acetate–hexanes (2 : 3); mp 220–222 °C; IR (NaCl) ν (cm⁻¹) 3341, 2923, 2853, 1708, 1601, 1521, 1501, 1485, 1433, 1280, 1233, 1173, 1107, 1037; ¹H NMR (400 MHz, acetone-d₆) δ 10.62 (br s, 1H), 8.68 (s, 1H), 7.96 (dd, J = 8.5, 1.6 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.06 (s, 1H), 6.05 (s, 2H), 3.90 (s, 3H). ¹³C NMR (125 MHz, acetone-d₆) δ 168.0, 148.8, 143.8, 137.0, 129.0, 126.1, 124.0, 122.3, 121.5, 117.1, 111.2, 102.0, 100.3, 93.3, 51.9; MS (ESI): m/z = 270 [M + H]⁺; HRMS (ESI): calcd for C₁₅H₁₁NO₄ [M + H]⁺: 270.0761; found: 270.0755.

Clausine L (2j). The reaction of methyl 5-iodo-2-methoxy-4-(phenylamino)benzoate 1j (80 mg, 0.21 mmol), Pd(OAc)₂ (4.8 mg, 0.021 mmol) and K₂CO₃ (57.7 mg, 0.417 mmol) in DMSO (5 mL) at 130 °C for 4 h afforded 2j as colourless solid (45 mg, 87%). Eluent: ethyl acetate–hexanes (3 : 7); mp 171–172 °C (ref. 30c: 172–173 °C); IR (NaCl) ν (cm⁻¹) 3325, 2923, 1704, 1635, 1618, 1588, 1492, 1469, 1433, 1384, 1346, 1296, 1246, 1199, 1156, 1116, 1081, 1027; ¹H NMR δ (400 MHz, CDCl₃) 8.60 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 8.7, 2.7 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 167.9, 160.23, 144.81, 143.0, 127.2, 125.3, 123.8, 120.9, 119.9, 117.3, 113.7, 111.6, 94.4, 55.9, 51.9; MS (ESI): m/z = 256 [M + H]⁺; HRMS (ESI): calcd for C₁₅H₁₃NO₃ [M + H]⁺: 256.0968; found: 256.0973.

Clausine H (2k). The reaction of methyl 5-iodo-2-methoxy-4-(3-methoxyphenylamino)benzoate 1k (80 mg, 0.20 mmol), Pd(OAc)₂ (4.4 mg, 0.019 mmol) and K₂CO₃ (53.5 mg, 0.387 mmol) in DMSO (5 mL) at 130 °C for 5 h afforded 2k as white crystals (44 mg, 80%). Eluent: ethyl acetate–hexanes (3 : 7); mp 192–193 °C (ref. 30a: 191–192 °C); IR (NaCl) ν (cm⁻¹) 3350, 2922, 2850, 1692, 1591, 1522, 1492, 1458, 1434, 1337, 1311, 1277, 1192, 1174, 1156, 1109, 1045 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.21 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.86 (dd, J = 8.5, 2.1 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.89 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 167.6, 160.0, 158.8, 143.4, 141.2, 123.8, 120.5, 118.0, 116.8, 114.9, 108.5, 96.8, 95.6, 56.3, 55.6, 51.8; MS (ESI): m/z = 286 [M + H]⁺; HRMS (ESI) calcd for C₁₆H₁₅NO₄ [M + H]⁺: 286.1072; found: 286.1081.

Methyl 2,6-dimethoxy-9H-carbazole-3-carboxylate (2l). The reaction of methyl 5-iodo-2-methoxy-4-(4-methoxyphenylamino) benzoate 1l (450 mg, 1.08 mmol), Pd(OAc)₂ (24.4 mg, 0.109 mmol) and K₂CO₃ (301.1 mg, 2.178 mmol) in DMSO (20 mL) at 130 °C for 5 h afforded 2l as white crystals (240 mg, 78%). Eluent: ethyl acetate–hexanes (3 : 7); mp 165–167 °C; IR (NaCl) ν (cm⁻¹) 3327, 2999, 2948, 2834, 1704, 1635, 1618, 1492, 1470, 1346, 1296, 1246, 1199, 1157, 1081; ¹H NMR (400 MHz, acetone-d₆) δ 10.33 (br s, 1H), 8.54 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.99 (dd, J = 8.7, 2.5 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H); ¹³C NMR (125 MHz, acetone-d₆) δ 167.4, 159.7, 155.4, 145.1, 135.9, 125.2, 117.0, 114.9, 113.2, 112.4, 112.3, 103.5, 94.7, 56.3, 56.1, 51.7; MS (ESI): m/z = 286 [M + H]⁺; HRMS (ESI): calcd for C₁₆H₁₅NO₄ [M + H]⁺: 286.1072; found: 286.1081.

Glycozoline (3). A solution of methyl 6-methoxy-9H-carbazole-3-carboxylate 2c (40 mg, 0.16 mmol) in THF (3 mL) was added drop wise to a suspension of LiAlH₄ (12.1 mg, 0. 32 mmol) in dry THF (4 mL) at 0 °C. The suspension was then allowed to warm to 65 °C and was stirred until the reaction was completed. The reaction mixture was quenched by methanol and ice cold water followed by the methanol was removed under reduced pressure in a rotary evaporator. The reaction mixture was diluted with ethyl acetate and washed with water (3 × 10 mL). The organic layer was dried over MgSO₄ and evaporated under reduced pressure. The residue was then purified by column chromatography on silica gel by using ethyl acetate–hexanes (3 : 7) to give glycozoline (3) in 75% yield (25 mg). Light yellow solid; mp180–182 °C (ref. 33b: 179–180 °C); IR (NaCl) ν (cm⁻¹) 3404, 2922, 2851, 1742, 1585, 1495, 1461, 1437, 1331, 1295, 1254, 1209, 1172, 1143, 1032; ¹H NMR (400 MHz, CDCl₃) δ 8.21 (br s, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7 (d, J = 7.8 Hz, 1H), 7.08 (dd, J = 8.5, 1.2 Hz, 1H), 3.97 (s, 3H), 2.54 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 150.6, 133.3, 128.4, 127.2, 124.21, 123.5, 120.1, 119.5, 113.4, 112.6, 110.3, 99.7, 55.5, 23.6; LC-MS (ESI): m/z = 212 [M + H]⁺; HRMS (ESI): calcd for C₁₄H₁₃NO [M + H]⁺: 212.1070; found: 212.1083.

Glycozolidine (4). Following the same reaction procedure as reported for glycozoline (3) reaction of carbazole 2l (50 mg, 0.17 mmol) with LiAlH₄ (13.3 mg, 0.35 mmol) in THF (5 mL) afforded glycozolidine 4 (21 mg, 65%). Eluent: ethyl acetate–hexanes (3 : 7); light yellow solid; mp164–166 °C (ref. 35a: 158–161 °C); IR (NaCl) ν (cm⁻¹) 3404, 2922, 2851, 1742, 1585, 1461, 1437, 1384, 1331, 1295, 1254, 1209, 1172, 1032; ¹H NMR (400 MHz, acetone-d₆) δ 9.94 (br, 1H), 7.78 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J = 8.7, 2.6 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.5, 153.1, 141.3, 134.4, 123.4, 121.0, 118.6, 116.9, 112.5, 110.1, 102.3, 92.3, 56.0, 55.3, 14.1; MS (ESI): m/z = 242 [M + H]⁺; HRMS (ESI): calcd for C₁₅H₁₅NO₂ [M + H]⁺: 242.1176; found: 242.1171.

Clausenalene (5). Following the same reaction procedure as reported for glycozoline (3) reaction of carbazole 2i (50 mg, 0.18 mmol) with LiAlH₄ (14.1 mg, 0.37 mmol) in THF (4 mL) afforded clausenalene 5 (31 mg, 72%). Eluent: ethyl acetate–hexanes (3 : 7); white solid; mp 224–227 °C (ref. 36a: 224–225 °C); IR (NaCl) ν (cm⁻¹) 3386, 2918, 2850, 1687, 1585, 1484, 1458, 1378, 1318, 1297, 1269, 1217, 1189, 1151, 1036; ¹H NMR (400 MHz, acetone-d₆) δ 10.04 (br s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 8.3, 1.2 Hz, 1H), 6.97 (s, 1H), 5.99 (s, 2H), 2.45 (s, 3H); ¹³C NMR (125 MHz, acetone-d₆) δ 148.0, 142.9, 139.2, 136.7, 128.3, 126.1, 124.5, 119.8, 116.8, 111.3, 101.7, 99.8, 92.9, 21.5; LC-MS (ESI): m/z = 226 [M + H]⁺; HRMS (ESI): calcd for C₁₄H₁₁NO₂ [M + H]⁺: 226.0863; found: 226.0859.

Sansoakamine (6). Boron tribromide (1 M solution in CH₂Cl₂, 0.34 mL, 0.34 mmol) was added at −78 °C to a solution of 2l (50 mg, 0.17 mmol) in CH₂Cl₂ (5 mL) under nitrogen atmosphere and the mixture was stirred at that temperature for 2 h. The reaction mixture was warmed to −20 °C and was stirred for another 20 h. The progress of the reaction was monitored by TLC and after completion the reaction mixture was quenched with saturated aqueous solution of NaHCO₃ at 0 °C and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography by using ethyl acetate–hexanes (2 : 8) to give sansoakamine (6) in 76% (34 mg) yield. Light brown solid; mp 243–246 °C (ref. 9: 243.8–245.6 °C); IR (NaCl) ν (cm⁻¹) 3338, 2923, 2853, 1660, 1597, 1436, 1383, 1265, 1162, 1089, 1042; ¹H NMR (400 MHz, acetone-d₆) δ 10.31 (br s, 1H), 8.53 (s, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.93 (dd, J = 8.6, 2.3 Hz, 1H), 6.86 (s, 1H), 3.99 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.6, 160.6, 152.2, 147.9, 135.2, 125.5, 122.1, 114.3, 112.6, 109.8, 107.8, 104.4, 95.2, 51.8; MS (ESI): m/z = 258 [M + H]⁺; HRMS (ESI) calcd for C₁₄H₁₁NO₄ [M + H]⁺: 258.0761; found: 258.0762.

Glycozolidal (7). To a solution of 2l (50 mg, 0.17 mmol) in dry toluene (5 mL) was added a solution of DIBAL-H (1.0 M in THF, 0.17 mL, 0.17 mmol) at −78 °C under nitrogen atmosphere. The mixture was stirred at −78 °C for 1 h. The progress of the reaction was monitored by TLC. The resulting mixture was quenched with methanol (5 mL) followed by ice cold water (5 mL). The methanol was removed under reduced pressure and the reaction mixture was diluted with ethyl acetate. The organic layer was separated dried over Na₂SO₄ and was concentrated under vacuum. The crude reaction mixture was purified by column chromatography on silica gel by using by using ethyl acetate–hexanes (2 : 8) to afford glycozolidal (7) in 86% (37.8 mg) yield. Yellow solid; mp190–193 °C (ref. 35b: 188–193 °C); IR (NaCl) ν (cm⁻¹) 3400, 2923, 2852, 1606, 1487, 1469, 1433, 1384, 1295, 1274, 1202, 1112; ¹H NMR (400 MHz, acetone-d₆) δ 10.49 (br s, 1H), 10.45 (s, 1H), 8.50 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.7, 2.1 Hz, 1H), 7.12 (s, 1H), 4.02 (s, 3H), 3.91 (s, 3H); ¹³C NMR (125 MHz, acetone-d₆) δ 189.7, 159.7, 155.4, 145.1, 135.9, 125.2, 121.1, 118.7, 117.0, 114.9, 112.3, 103.5, 94.7, 56.3, 56.1; MS (ESI): m/z = 256 [M + H]⁺; HRMS (ESI): calcd for C₁₅H₁₃NO₃ [M + H]⁺: 256.0968; found: 256.0972.

Acknowledgements

Sk. R and K. R. thank CSIR for research fellowship. N. R. likes to thank UGC for research fellowship. CSIR, New Delhi (BSC 0108) is acknowledged for the financial support.

References

1. (a) D. P. Chakraborty, The Alkaloids, ed. A. Bossi, Academic Press, New York, 1993, vol. 44, p. 257; (b) H.-J. Knölker, Advances in Nitrogen Heterocycles, ed. C. J. Moody, JAI, Greenwich, 1995, vol. 1, p. 173; (c) H.-J. Knölker and K. R. Reddy, in The Alkaloids, ed. G. A. Cordell, Academic Press, Amsterdam, 2008, vol. 65, p. 1; (d) K. K. Gruner and H.-J. Knölker, in Heterocycles in Natural Product Synthesis, ed. K. C.Majumdar and S. K. Chattopadhyay, Wiley-VCH, Weinheim, Germany, 2011, p. 341; (e) I. Bauer and H.-J. Knölker, Top. Curr. Chem., 2012, 309, 203.
2. (a) Y. Ooyama, S. Inoue, T. Nagano, K. Kushimoto, J. Ohshita, I. Imae, K. Komaguchi and Y. Harima, Angew. Chem., Int. Ed., 2011, 50, 7429; (b) S.-I. Kato, S. Shimizu, H. Taguchi, A. Kobayashi, S. Tobita and Y. Nakamura, J. Org. Chem., 2012, 77, 3222.
3. (a) V. Vaitkeviciene, A. Kruzinauskiene, S. Grigalevicius, J. V. Grazulevicius, R. Rutkaite and V. Jankauskas, Synth. Met., 2008, 158, 383; (b) H.-Y. Wang, F. Liu, L.-H. Xie, C. Tang, B. Peng, W. Huang and W. Wei, J. Phys. Chem. C, 2011, 115, 6961; (c) W. Yang, Z. Zhang, C. Han, Z. Zhang, H. Xu, P. Yan, Y. Zhao and S. Liu, Chem. Commun., 2013, 49, 2822.
4. (a) J. Verdome, S. Letand, F. Martin, F. Svinarchuk, P. Dubreuil, C. Auclair and M. L. Bret, J. Med. Chem., 2005, 48, 1493; (b) C. M. Miller and F. O. McCarthy, RSC Adv., 2012, 2, 8883; (c) F. M. Deane, E. C. Osullivan, A. R. Maguine, J. Gilbert, J. A. Sakoff, A. McCluskey and F. O. McCarthy, Org. Biomol. Chem., 2013, 11, 1334.
5. (a) E. A. Dubois, J. C. van den Bos, T. Doornbos, P. A. P. M. van Doremalen, G. A. Somsen, J. A. J. M. Vekemans, A. G. M. Janssen, H. D. Batink, G. J. Boer, M. Pfaffendorf, E. A. van Royen and P. A. Van Zwieten, J. Med. Chem., 1996, 29, 3256; (b) S. Chakraborty, D. Shukla, B. Mishra and S. Singh, Expert Opin. Drug Metab. Toxicol., 2010, 6, 237.
6. W.-S. Li, J. D. McChesney and F. S. El-Feraly, Phytochemistry, 1991, 30, 343.
7. (a) T.-S. Wu, S.-C. Huang and P.-L. Wu, Phytochemistry, 1996, 43, 1427; (b) T.-S. Wu, S.-C. Huang, P.-L. Wu and C.-M. Teng, Phytochemistry, 1996, 43, 133; (c) T.-S. Wu, S.-C. Huang, P.-L. Wu and C.-S. Kuoh, Phytochemistry, 1999, 52, 523.
8. (a) T.-S. Wu, S.-C. Huang, J.-S. Lai, C.-M. Teng, F.-N. Ko and C.-S. Kuoh, Phytochemistry, 1993, 32, 449; (b) C. Ito, S. Katsuno, H. Ohata, M. Omura and I. Furukawa, Chem. Pharm. Bull., 1997, 45, 48.
9. T. Sripisut and S. Lphookhieo, J. Asian Nat. Prod. Res., 2010, 12, 614.
10. W. Maneerat, T. Ritthiwigrom, S. Cheenpracha, T. Promgool, K. Yossathera, S. Deachathai, W. Phakhodee and S. Laphookhieo, J. Nat. Prod., 2012, 75, 741.
11. C. Yenjai, S. Sripontan, P. Sriprajun, P. Kittakoop, A. Jintasirikul, M. Tanticharoen and Y. Thebtaranonth, Planta Med., 2000, 66, 277.
12. For selected reviews, see: (a) J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046; (b) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400; (c) D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (d) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954; (e) C. Fisher and B. Koenig, Beilstein J. Org. Chem., 2011, 7, 59; (f) T. Liu and H. Fu, Synthesis, 2012, 44, 2805.
13. Selected palladium catalyzed N-arylation reaction, see: (a) J. Yin, M. Zhao, M. A. Huffman and J. M. Macnamura, Org. Lett., 2002, 4, 3481; (b) M. D. Charles, P. Schultz and S. L. Buchwald, Org. Lett., 2005, 7, 3965; (c) S. Ueda, M. Su and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 8944; (d) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura and S. L. Buchwald, Chem. Sci., 2011, 2, 57; (e) S. Ueda, M. Su and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 700.
14. Selected copper catalyzed N-arylation reaction, see: (a) J. C. Antilla, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 11684; (b) B. M. Choudhary, C. Sridhar, M. L. Kantam, G. T. Venkanna and B. Sreedhar, J. Am. Chem. Soc., 2005, 127, 9948; (c) L. Zhu, P. Guo, G. Li, J. Lan, R. Xie and J. You, J. Org. Chem., 2007, 72, 8535; (d) L. Liang, Z. Li and X. Zhou, Org. Lett., 2009, 11, 3294; (e) Y. Zhang, X. Yang, Q. Yao and D. Ma, Org. Lett., 2012, 14, 3056.
15. D. M. T. Chan, K. L. Monaco, R. P. Wang and M. P. Winters, Tetrahedron Lett., 1998, 39, 2933.
16. D. A. Evans, J. L. Katz and T. R. West, Tetrahedron Lett., 1998, 39, 2937.
17. P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941.
18. (a) J. P. Collman and M. Zhong, Org. Lett., 2000, 2, 1233; (b) J. P. Collman, M. Zhong, C. Zhang and S. Costanzo, J. Org. Chem., 2001, 66, 7892.
19. D. M. T. Chan and P. Y. S. Lam, in Boronic Acids: Preparation and Application in Organic Synthesis and Medicine, ed. D. G. Hall, Wiley-VCH, 2006, p. 205.
20. For Chan–Lam type coupling review, see: (a) J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 829; (b) K. S. Rao and T. S. Wu, Tetrahedron, 2012, 68, 7735.
21. For recent Chan–Lam type coupling of N-arylation, see: (a) C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li and A. Li, Angew. Chem., Int. Ed., 2008, 47, 6414; (b) K. Sreeramamurthy, E. Ashok, V. Mahendar, G. Santoshkumar and P. Das, Synlett, 2010, 721; (c) N. Matsuda, K. Hirano, T. Satoh and M. Miura, Angew. Chem., 2012, 51, 3702; (d) R. Adepu, K. Shivakumar, S. Sandra, D. Ramababu, G. Ramakrishna, C. Mallareddy, A. Kandale, P. Mishra and M. Pal, Bioorg. Med. Chem., 2012, 20, 5127; (e) D. S. Raghuvanshi, A. K. Gupta and K. N. Singh, Org. Lett., 2012, 14, 4326; (f) J. Li, S. Benard, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 5980; (g) T. Chen, Q. Huang, Y. Luo, Y. Hu and W. Lu, Tetrahedron Lett., 2013, 54, 1401; (h) D. N. Rao, S. Rasheed, S. Aravinda, R. A. Vishwakarma and P. Das, RSC Adv., 2013, 3, 11472.
22. For recent carbazole review, see: (a) A. W. Schmidt, K. R. Reddy and H.-J. Knölker, Chem. Rev., 2012, 112, 3193; (b) J. Roy, A. K. Jana and D. Mal, Tetrahedron, 2012, 68, 6099.
23. For rececnt carbazole synthesis, see: (a) S.-W. Youn, J. H. Bihn and B. S. Kim, Org. Lett., 2011, 13, 3738; (b) S. H. Cho, J. Yoon and S. Chang, J. Am. Chem. Soc., 2011, 133, 5996; (c) W. Yang, J. Zhou, B. Wang and H. Ren, Chem.–Eur. J., 2011, 17, 13665; (d) A. P. Antonchick, R. Samanta, K. Kulikov and J. Lategahn, Angew. Chem., Int. Ed., 2011, 50, 8605; (e) W. Kong, C. Fu and S. Ma, Org. Biomol. Chem., 2012, 10, 2164; (f) Y. Qiu, D. Ma, C. Fu and S. Ma, Org. Biomol. Chem., 2013, 11, 1666; (g) S. Chakarborty, I. Chatterjee, L. Tebben and A. Studer, Angew. Chem., Int. Ed., 2013, 52, 2968.
24. Carbazole synthesis from o-haloaniline, see: (a) L.-C. Campeau, P. Thansandote and K. Fagnou, Org. Lett., 2005, 7, 1857; (b) R. B. Bedford and M. Betham, J. Org. Chem., 2006, 71, 9403; (c) L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581; (d) N. Della Ca, G. Sassi and M. Catellani, Adv. Synth. Catal., 2008, 350, 2179; (e) M. E. Buden, V. A. Vaillard, S. E. Martin and R. A. Rossi, J. Org. Chem., 2009, 74, 4490.
25. G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644.
26. For synthesis of o-iodoaniline derivatives, see the ESI†.
27. J. C. Antilla and S. L. Buchwald, Org. Lett., 2001, 3, 2077.
28. D. Alberico, M. E. Scotts and M. Lautens, Chem. Rev., 2007, 107, 174.
29. For synthesis of methyl carbazole-3-carboxylate, see: (a) T. G. Back, A. Pandyra and J. E. Wulff, J. Org. Chem., 2003, 68, 3299; (b) Z. Liu and R. C. Larock, Org. Lett., 2004, 6, 3739; (c) C. Y. Liu and P. Knochel, Org. Lett., 2005, 7, 2543; (d) L. Ackermann and A. Allthammen, Angew. Chem., Int. Ed., 2007, 46, 1627.
30. For synthesis of clausine alkaloids, see: (a) O. Kataeva, M. P. Krahl and H.-J. Knölker, Org. Biomol. Chem., 2005, 5, 3099; (b) M. P. Krahl, A. Jager, T. Krause and H.-J. Knölker, Org. Biomol. Chem., 2006, 4, 3215; (c) R. Forke, A. Jager and H.-J. Knölker, Org. Biomol. Chem., 2008, 6, 2481; (d) T. Watanabe, S. Oishi, N. Fuji and H. Ohno, J. Org. Chem., 2009, 74, 4720; (e) W. Kong, C. Fu and S. Ma, Chem.–Eur. J., 2011, 17, 13134; (f) M. P. Krahl, O. Kataeva, A. W. Schmidt and H.-J. Knölker, Eur. J. Org. Chem., 2013, 59.
31. For synthesis of methyl 6-methoxycarbazole-3-carboxylate, see: R. Forke, M. P. Krahl, T. Krause, T. G. Schlechtingen and H.-J. Knölker, Synlett, 2007, 268.
32. Crystal data of 2f: C₁₇H₁₇N₁O₂, M = 267.32, monoclinic, space group: P21/n, a = 12.8565(7), b = 13.8210(7), c = 8.0271(4) Å, b = 98.229(5)°, V = 1411.63(13) ų, Z = 4, D_c = 1.258 g cm⁻³, μ = 0.082 mm⁻¹, T = 293(2) K, λ = 0.71073 Å, θ range: 3.9–27.0°, 1 1900 reflections measured, 3031 independent (R_int = 0.0305), 249 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F²; final R indices for 1989 observed reflections [I > 2σ(I)]: R₁ = 0.0520, wR₂ = 0.1298; maximal/minimum residual electron density: 0.158/−0.213 Å⁻³. See ESI†.
33. For synthesis of glycozoline, see: (a) M. Iwao, H. Takehara, S. Furukawa and M. Watanabe, Heterocycles, 1993, 36, 1483; (b) D. Kajiyama, K. Inoue, Y. Ishikawa and S. Nishiyama, Tetrahedron, 2010, 66, 9779.
34. C. Borger and H.-J. Knölker, Tetrahedron, 2012, 68, 6727.
35. For synthesis of glycozolidine and glycozolidal, see: (a) M. Schmidt and H.-J. Knölker, Synlett, 2009, 2421; (b) V. Sridharan, M. A. Martin and J. C. Menendez, Eur. J. Org. Chem., 2009, 4614.
36. For synthesis of clausenalene, see: (a) P. Bhattacharayya, G. K. Biswas, A. K. Barua, C. Saha, I. B. Roy and B. K. Chowdhury, Phytochemistry, 1993, 33, 248; (b) T. L. Scott, X. Yu, S. P. Gorugantula, G. Carrero-Martinez and B. C. G. Soderberg, Tetrahedron, 2006, 62, 10835.
37. M. Fuchsenberger, R. Forke and H.-J. Knölker, Synlett, 2011, 2056.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details and spectroscopic data for all compounds. CCDC 909569. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra44903c

‡ IIIM communication no. 1565.

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