RSC Advances

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Fig. 1 Naturally occurring methyl c

aAcademy of Scientic and Innovative ReseabMedicinal Chemistry Division, Indian Instit

Road, Jammu-180001, India. E-mail: partha

† Electronic supplementary information (spectroscopic data for all compounds. CCDdata in CIF or other electronic format see

‡ IIIM communication no. 1565.

Cite this: RSC Adv., 2014, 4, 4960

Received 5th September 2013Accepted 22nd October 2013

DOI: 10.1039/c3ra44903c

www.rsc.org/advances

4960 | RSC Adv., 2014, 4, 4960–4969

C–N bond formation via Cu-catalyzed cross-coupling with boronic acids leading to methylcarbazole-3-carboxylate: synthesis of carbazolealkaloids†‡

Sk. Rasheed,ab D. Nageswar Rao,ab K. Ranjith Reddy,ab S. Aravinda,b

Ram A. Vishwakarmab and Parthasarathi Das*ab

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.

Introduction

Carbazoles have attracted considerable attention both in bio-logical and material sciences as ubiquitous structural motif dueto their medicinal,1 photophysical2 and optoelectronic applica-tion.3 Naturally occurring carbazomycin and ellipticine are wellknown for their antibacterial and anticancer propertiesrespectively.4 Carbazole containing carveidilol and carazolol areused for the treatment of hypertension, ischemic heart diseaseand congestive heart failure.5 Carbazoles having –CO2Me groupat 3-position represent a wide class of naturally occurring

arbazole-3-carboxylate alkaloids.

rch (AcSIR), India

ute of Integrative Medicine (CSIR), Canal

@iiim.ac.in; Fax: +91-191-2569019

ESI) available: Experimental details andC 909569. For ESI and crystallographicDOI: 10.1039/c3ra44903c

alkaloids (Fig. 1). Methyl carbazole-3-carboxylate (2a) andmethyl 6-methoxycarbazole-3-carboxylate (2c) have been iso-lated from the roots of Clausena lansium.6

Wu et al. reported the isolation of clausine C (2b),7a clau-sine H (2k),7b clausine M7c from the root bark of Clausenaexcavata. Clausine L (2j) and mukonidine both isolated by Wuand co-workers form the Chinese medicinal plant Clausenaexcavata.8 Recently, 2,6-dioxygenated sansoakamine (6) wasisolated from the stem of Clausena excavata.9 In 2012Laphookhieo et al. reported the isolation and biologicalactivity of methyl carbazole-3-carboxylate (clausine C, clausineH, clausine L and mukonidine) and during the evaluation ofantibacterial properties, mukonidine showed weak activityagainst MRSA (MIC 64 mg mL�1) and moderate activity againstGram-negative pathogen S. typhimurium with an MIC valueof 32 mg mL�1.10 Further the anti-plasmodial activity (IC50

5.5–8.2 mg mL�1) of clausine H has been reported.11 Forstructure–activity relationships (SAR) study, the diversity incarbazole synthesis, especially the regiospecic installation ofsubstituent's onto each of the nine positions of the carbazoleskeleton, is challenging from synthetic point. Thus, thedevelopment of a mild, efficient and regio-controlled diversi-ed method for the preparation of carbazole remains of highinterest.

Transition metal-catalyzed N-arylation has been extensivelystudied over the past decade.12 The discovery of Pd- or Cu-catalyzed amination reactions pioneered by Buchwald andHartwig is a hallmark reaction in this eld.13,14 Despite thesesignicant progresses in improvements of the reaction condi-tions, limitation exists in terms of functional group tolerabilityand high cost of palladium. In 1998 independent publicationsby Chan,15 Evans16 and Lam17 revolutionized the coppermediated heteroatom arylation reaction for the formation of

This journal is © The Royal Society of Chemistry 2014

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N-aryl and O-aryl bonds using boronic acids. Later discovery byCollman18 has demonstrated that this reaction can berendered catalytic for the arylation of imidazoles when[Cu(OH)$TMEDA]2Cl2 is used as a copper source. In the courseof time the Chan–Lam type coupling became a useful synthetictool due to the mild reaction conditions employed e.g. roomtemperature, weak base, ambient atmosphere (open-askchemistry).19–21

Many different approaches for construction of carbazoleshave been studied.22,23 Among them the approaches involvingtransition metal-catalyzed intramolecular C–C bond forma-tion in diarylamines via C–H activation provide an excellentaccess to these important class of natural product.22 Whilethe direct synthesis of carbazoles by cascade Buchwald–Hartwig N-arylation followed by C–H arylation using o-hal-oanilines has been reported.24 The main drawback of thesereactions are use of expensive ligand, strong base and highreaction temperature. It is well precedented that oxidativeinsertion into a C–X bond is most facile for aryl iodides, souse of aryl iodides as coupling partner can give easy access tothe desired arylated product.25

Keeping this in mind, we decided to use o-iodoanilines assubstrate for cross-coupling reaction. Thus to nd a mild reac-tion conditions for carbazole synthesis here we wish to report ourstudy on Cu-catalyzed N-arylation of methyl 4-amino-3-iodo-benzoate26 with boronic acid at room temperature under air fol-lowed by Pd-catalyzed intramolecular cyclization (Scheme 1).This protocol is general and culminated in the synthesis ofseveral naturally occurring carbazoles including rst totalsynthesis of sansoakamine.

Table 1 Cu-catalyzed coupling of methyl 4-amino-3-iodobenzoatewith boronic acidsa

Results and discussion

For N-arylation of methyl 4-amino-3-iodobenzoate, we rstuse the protocol as reported by Chan11 and Evans16 for O-arylation of o-iodophenol. Our initial experiment starts withN-arylation of methyl 4-amino-3-iodobenzoate with phenyl-boronic acid by using Cu(OAc)2 (1 equiv.) and Et3N (2 equiv.)in DCM under air and room temperature. But this reactionended with poor conversion (only 40%) of the startingmaterial even aer 48 h. Screening of different solvents,copper salts and base frustrated us with poor yield (see ESI†for details of optimization protocol). Interestingly, the reac-tion also have only 40% conversion under catalytic (10 mol%)use of Cu(OAc)2. Careful observation on the progress of thisreaction, revealed that the reaction proceed smoothly with 30

Scheme 1 Synthesis of methyl carbazole-3-carboxylate.

This journal is © The Royal Society of Chemistry 2014

to 40% conversion in the rst 5–6 h and then catalytic activitydiminished over the next 20 h. J. C. Antilla and S. L. Buch-wald27 have previously reported similar observations and theymodied 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-iodo-benzoate to the N-arylation conditions with phenylboronicacid by using catalytic Cu(OAc)2 (10 mol%), 2,6-lutidine intoluene under air the reaction proceed smoothly with 70%isolated yield (1a). In this reaction condition we used n-dec-anoic acid (20 mol%) as an additive. The use of molecularoxygen did not have any further improvement with the iso-lated yield. By using this optimized condition a series ofN-arylated methyl 4-amino-3-iodobenzoate have been synthe-sized (Table 1). Methoxy substituted phenylboronic acidsbecame our rst choice as coupling partner so that naturallyoccurring carbazoles can be synthesized in subsequent cycli-zation process (Table 2). We were pleased to nd thatmethoxy substitution of phenylboronic acids both at m- andp-position gave satisfactory coupling products (1b and 1c).The versatility of this reaction protocol has been demon-strated by further using different boronic acids as couplingpartner (Table 1). Three more p-substituted boronic acidshave been used to synthesize the corresponding N-arylatedproduct (1d–f) in good yield. Phenylboronic acids containingelectron withdrawing group (EWG) also resulted (1g–h) insatisfactory yield (65–66%) under this cross-coupling condi-tions. Bicyclic benzo[d][1,3]dioxol-5-ylboronic acid also gaveclean coupled product with 72% isolated yield (1i). To ndthe generality and substrate scope of this methodology wefurther explore the N-arylation of 2-methoxy derivative ofmethyl 4-amino-3-iodobenzoate with different boronic acids.Phenyl boronic acid works satisfactorily to yield 1j in 70%.

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.

RSC Adv., 2014, 4, 4960–4969 | 4961

Table 2 Pd-catalyzed C–H arylation of methyl 3-iodo-4-(phenyl-amino)benzoatea

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

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%.

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Both m- and p-substituted methoxyboronic acid gave the crosscoupled product (1k–l) in 72% and 70% yield respectively.

Aer successful completion of the synthesis of diverse N-arylated product (1a–l), these 2-iodo diarylamine derivativeswere used for intramolecular cyclization to obtain differentcarbazole alkaloids. To achieve the intramolecular C–H aryla-tion of N-phenyl-2-iodoaniline derivatives, we rst performedthe reaction with methyl 3-iodo-4-(phenylamino)benzoate byusing Pd(OAc)2 (10 mol%) as catalyst, K2CO3 as base and DMSOas solvent in sealed tube at 130 �C.28 To our expectation thereaction proceeded smoothly with complete conversion ofstarting material in 3 h to give methyl carbazole-3-carboxylate(2a)29 with 92% isolated yield (Table 2). This Pd-catalyzed reac-tion is very clean and works well without NH-protection. Byfollowing same reaction conditions naturally occurring carba-zoles clausine C30a,b,e (2b), clausine L30c,d (2j), clausine H30a,f (2k)have been synthesized successfully. Clausine C can be con-verted to 7-hydroxy derivative, clausine M as reported byKnolker.30b Clausine H (2i) can be considered as crucialprecursor for several 2,7-dioxygenated carbazoles particularlyfor clausine K and clausine O.30a Chloro and uoro derivativesof N-arylated methyl 4-amino-3-iodobenzoate smoothly cyclizedunder this catalytic condition to give halogenated carbazoles(2g–h). Another naturally occurring carbazole methyl 6-methoxycarbazole-3-carboxylate (2c)31 synthesized in thisprocess 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 thesynthesis of different carbazole alkaloids (Schemes 2 & 3).

Two more new 6-oxygenated carbazoles 2d (85%) and 2e(80%) have also been synthesized by using this intramolecular

4962 | RSC Adv., 2014, 4, 4960–4969

C–H arylation process. Methyl 6-propyl-9H-carbazole-3-carbox-ylate (2f) has been synthesized under this Pd-catalyzed cycliza-tion condition and the structure has been conrmed by X-raycrystal structure analysis (Fig. 2).32

Methyl group at C-3 position remains one of the commonstructural features for many carbazole alkaloids. Thus tosynthesize more naturally occurring carbazoles we pay ourattention to the functional transformation of the 3-CO2Megroup. We rst consider methyl 6-methoxycarbazole-3-carbox-ylate (2c) and it is obvious that carbazole 2c can serve asprecursor for glycozoline (3).33 Thus reduction of –CO2Megroup of 2c with LiAlH4 gave glycozoline (3) in 75% yield(Scheme 2).34 By following the same reduction condition wesuccessfully synthesized glycozolidine (4)35 from carbazole 2lin 65% yield and methylenedioxy carbazole clausenalene (5)36

form 2i in 72% yield. Synthesized glycozoline, glycozolidineand clausenalene have been fully characterized by spectro-scopic data which are in good agreement with those reportedfor natural product.

With the readily available 2,6-dioxygenated carbazole 2l inhand we envisaged direct access to sansoakamine and glyco-zolidal. BBr3 mediated cleavage of both the methyl ether groupsof 2l afforded sansoakamine (6) in 76% yield (Scheme 3). Thespectroscopic data of the synthesized carbazole was in goodagreement with the reported data.9 To the best of our knowledgethis is the rst report of total synthesis of sansoakamine. Themethyl ester group of 2l was reduced directly into aldehydegroup (Scheme 3) by DIBAL-H37 to produce another naturalalkaloid glycozolidal (7), which was structurally conrmed by itsspectroscopic data.35b

This journal is © The Royal Society of Chemistry 2014

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

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Conclusion

The Cu-catalyzed N-arylation and subsequent Pd-catalyzedintramolecular C–H arylation protocol has been successfullyutilized in synthesizing various methyl carbazole-3-carboxylatederivatives. This two-step reaction sequence resulted in thedirect synthesis of clausine C, clausine L and clausine H. Thisexercise also resulted in rst total synthesis of 2,6-dioxygenatedcarbazole sansoakamine in four steps with 40% overall yield.Considering the availability of starting material and mildreaction conditions the procedure involved, we have demon-strated that this can be general methodology for synthesis ofthis family of compounds. Further studies including biologicalactivity of these derivatives are presently being carried out inour laboratory.

ExperimentalGeneral information

Analytical thin layer chromatography (TLC) was performed onpre-coated silica gel plates (60 F254; MERCK). TLC plates werevisualized by exposing UV light or by iodine vapours orimmersion in ninhydrin followed by heating on hot plate. 1Hand 13C NMR spectra were recorded with BRUKER 500 and 400MHz NMR instruments. All the NMR spectra were processed inMestReNova. Mass spectra were recorded with VARIAN GC-MSinstrument. HRMS spectra were recorded with LCMS-QTOFModule no. G6540 A (UHD) instrument. IR spectra were recor-ded on Jasco FT/IR-5300 spectrophotometer. Melting pointswere measured in open capillary tubes and are uncorrected.Unless otherwise indicated, chemicals and solvents werepurchased from commercial suppliers.

General procedure for N-arylation of amine with boronic acids(1a–l)

Methyl 3-iodo-4-(phenylamino)benzoate (1a). To a solutionof methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol) intoluene (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

This journal is © The Royal Society of Chemistry 2014

open air. The reaction mixture was diluted with ethyl acetate(10 mL) and ltered through Whatman lter paper. Theorganic layer was washed with water (2 � 10 mL) and driedover Na2SO4. Then ltered and the solvent was removedunder reduce pressure. The crude reaction mixture waspuried by column chromatography on silica gel by usingethyl acetate–hexanes (2 : 8) as eluent to give 1a (92 mg,70%). Colourless gel; 1H NMR (400 MHz, CDCl3) d 8.43 (s,1H), 7.82 (dd, J ¼ 8.6, 1.8 Hz, 1H), 7.38 (t, J ¼ 7.9 Hz, 2H),7.21 (d, J ¼ 8.4 Hz, 2H), 7.16 (t, J ¼ 8.1 Hz, 1H), 7.04 (d, J ¼8.7 Hz, 1H), 6.32 (br s, 1H), 3.87 (s, 3H); 13C NMR (125 MHz,CDCl3) d 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 ¼ 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 tothis procedure.

Methyl 3-iodo-4-(3-methoxyphenylamino)benzoate (1b). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 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) d 8.43 (s, 1H),7.83 (dd, J¼ 8.6, 1.9 Hz, 1H), 7.26 (d, J¼ 8.8 Hz, 1H), 7.10 (d, J¼8.5 Hz, 1H), 6.80 (d, J¼ 8.5 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J¼ 8.4,1H) 6.30 (br s, 1H), 3.85 (s, 3H), 3.79 (s, 3H); 13C NMR (125 MHz,CDCl3) d 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 ¼ 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). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 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) d 8.41 (s, 1H),7.78 (dd, J ¼ 8.7, 1.4 Hz, 1H), 7.15 (d, J ¼ 8.7 Hz, 2H), 6.94 (dd,J ¼ 8.8, 1.3 Hz, 2H), 6.75 (dd, J ¼ 8.7, 1.3 Hz, 1H), 6.22 (br s,1H), 3.86 (s, 3H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3) d167.1, 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 ¼ 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). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 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. 072mmol) 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) d 8.42 (s, 1H), 7.82(dd, J ¼ 8.9, 1.9 Hz, 1H), 7.35 (m, 2H), 7.18 (dd, J ¼ 8.6, 1.9 Hz,2H), 7.12 (m, 1H), 7.03 (m, 3H), 7.00 (dd, J ¼ 7.1, 2.1 Hz, 1H),6.90 (d, J ¼ 8.7 Hz, 1H), 6.26 (br s, 1H), 3.86 (s, 3H); 13C NMR(125 MHz, CDCl3) d 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

RSC Adv., 2014, 4, 4960–4969 | 4963

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(ESI): m/z ¼ 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, 0.36mmol), 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) intoluene (5 mL) gave 1e (106 mg, 70%). Eluent: ethyl acetate–hexanes (2 : 8); colourless gel; 1H NMR (500 MHz, CDCl3) d

8.39 (s, 1H), 7.76 (d, J ¼ 8.6 Hz, 1H), 7.13 (dd, J ¼ 6.5, 2.1Hz, 2H), 6.92 (dd, J ¼ 8.4, 2.2 Hz, 2H), 6.74 (d, J ¼ 8.6 Hz,1H), 6.20 (br s, 1H), 3.97 (t, J ¼ 6.4 Hz, 2H), 3.85 (s, 3H), 1.77(dd, J ¼ 14.3, 6.6 Hz, 2H), 1.51 (dd, J ¼ 14.8, 7.4 Hz, 2H),0.99 (t, J ¼ 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 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 ¼ 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). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 4-n-propylphenylboronic acid (88 mg, 0.54 mmol),Cu(OAc)2 (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072mmol) 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); col-ourless gel; 1H NMR (500 MHz, CDCl3) d 8.41 (s, 1H), 7.80 (dd,J¼ 8.7, 1.3 Hz, 1H), 7.22 (dd, J¼ 8.7, 2.1 Hz, 2H), 7.12 (d, J¼ 8.0Hz, 2H), 6.98 (t, J¼ 8.5 Hz, 1H), 6.28 (br s, 1H), 3.86 (s, 3H), 2.59(t, J ¼ 7.6 Hz, 2H), 1.65 (m, 2H), 0.95 (m, 3H); 13C NMR (125MHz, CDCl3) d 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 ¼396 [M + H]+; HRMS (ESI): calcd for C17H18INO2 [M + H]+:396.0455; found: 396.0446.

Methyl 4-(3-chlorophenylamino)-3-iodobenzoate (1g). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 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) d 8.44 (s,1H), 7.86 (m, 1H), 7.28 (t, J ¼ 1.3 Hz, 1H), 7.20 (d, J ¼ 1.7 Hz,1H), 7.11 (d, J ¼ 1.1 Hz, 1H), 7.08 (dd, J ¼ 6.9, 5.1 Hz, 2H),6.29 (br s, 1H), 3.88 (s, 3H). 13C NMR (125 MHz, CDCl3) d

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 ¼ 388 [M + H]+;HRMS (ESI): m/z calcd for C14H11IClNO2 [M + H]+: 387.9596;found: 387.9587.

Methyl 4-(4-uorophenylamino)-3-iodobenzoate (1h). Thereaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36mmol), 4-uorophenylboronic 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) d 8.42 (s, 1H),7.80 (m, 1H), 7.19 (m, 2H), 7.08 (m, 2H), 6.84 (dd, J ¼ 8.7, 2.1Hz, 1H), 6.24 (br s, 1H), 3.86 (s, 3H). 13C NMR (125 MHz,CDCl3) d 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 ¼ 372 [M + H]+; HRMS

4964 | RSC Adv., 2014, 4, 4960–4969

(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) d8.40 (s, 1H), 7.79 (dd, J ¼ 8.6, 1.7 Hz, 1H), 6.81 (dd, J ¼ 8.4,7.2 Hz, 2H), 6.73 (d, J ¼ 2.1 Hz, 1H), 6.68 (dd, J ¼ 8.2, 1.8 Hz,1H), 6.18 (br s, 1H), 6.00 (s, 2H), 3.86 (s, 3H); 13C NMR (125MHz, CDCl3) d 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 ¼ 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). Thereaction of methyl 4-amino-5-iodo-2-methoxybenzoate (100mg, 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 (5mL) gave 1j (97 mg, 70%). Eluent: ethyl acetate–hexanes(1 : 9); colourless gel; 1H NMR (400 MHz, CDCl3) d 8.41 (s,1H), 7.79 (dd, J ¼ 8.5, 2.1 Hz, 1H), 7.17 (d, J ¼ 8.4 Hz, 2H),6.94 (dd, J ¼ 8.3, 2.1 Hz, 2H), 6.76 (t, J ¼ 7.8 Hz, 1H), 6.25(br, 1H), 3.86 (s, 3H), 3.84 (s, 1H); 13C NMR (125 MHz,CDCl3) d 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 ¼ 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-methoxyphenylbor-onic 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) d 8.27 (s, 1H), 7.28 (dd, J ¼ 8.6, 2.3 Hz, 2H), 6.82 (d, J ¼7.9 Hz, 1H), 6.77 (t, J ¼ 2.1 Hz, 1H), 6.72 (d, J ¼ 2 Hz, 2H), 6.24(br s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H); 13C NMR (125MHz, CDCl3) d 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 ¼414 [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-methoxyphenylbor-onic 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) d 8.25 (s, 1H), 7.17 (d, J¼ 8.8 Hz, 2H), 6.94 (d, J¼ 8.7 Hz,2H), 6.35 (s, 1H), 6.14 (br s, 1H), 3.84 (s, 6H), 3.69 (s, 3H); 13CNMR (125MHz, CDCl3) d 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 ¼414 [M + H]+; HRMS (ESI): m/z calcd for C16H16INO4 [M + H]+:414.0197; found: 414.0222.

This journal is © The Royal Society of Chemistry 2014

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

Methyl 9H-carbazole-3-carboxylate (2a). An oven-driedsealed tube was charged with, methyl 3-iodo-4-(phenylamino)benzoate 1a (80 mg, 0.220 mmol), K2CO3 (62.6 mg, 0.453mmol), Pd(OAc)2 (5 mg, 0.022 mmol), DMSO (5 mL) andmagnetic stir bar under argon atmosphere. The tube wassealed with Teon cap and the reaction mixture was stirred at130 �C for 3 h. The progress of the reaction was monitored byTLC and aer completion the mixture was allowed to cooldown to room temperature. The reaction mixture was dilutedwith H2O (3 mL) and was extracted with ethyl acetate (3 � 10mL). The combined organic layer was dried over Na2SO4 andwas evaporated under vacuum. The crude product was puri-ed 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)n (cm�1) 3344, 2947, 1692, 1591, 1522, 1497, 1448, 1434, 1327,1312, 1250, 1172, 1110; 1H NMR (400 MHz, acetone-d6) d

10.77 (br s, 1H), 8.82 (s, 1H), 8.26 (d, J ¼ 7.8 Hz, 1H), 8.09(dd, J ¼ 8.6, 1.6 Hz, 1H), 7.58 (dd, J ¼ 8.3, 3.5 Hz, 2H), 7.46(m, 1H), 7.28 (m, 1H), 3.92 (s, 3H); 13C NMR (125 MHz,CDCl3) d 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 ¼ 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 followingthis procedure.

Clausine C (2b). The reaction of methyl 3-iodo-4-(3-methoxy-phenylamino)benzoate 1b (100 mg, 0.26 mmol), Pd(OAc)2 (5.8mg, 0.025 mmol), and K2CO3 (72.1 mg, 0.521 mmol) in DMSO (5mL) 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) n (cm�1) 3271, 2921, 2850, 1698, 1605, 1440,1403, 1328, 1291, 1265, 1193, 1160, 1135, 1098; 1H NMR (500MHz, CDCl3) d 8.70 (s, 1H), 8.18 (br s, 1H), 8.12 (d, J ¼ 8.6 Hz,1H), 8.06 (dd, J ¼ 8.1, 2.5 Hz, 1H), 7.56 (d, J ¼ 8.6 Hz, 1H), 7.11(d, J ¼ 2.5 Hz, 1H), 6.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 3.97 (s, 3H),3.92 (s, 3H); 13C NMR (125 MHz, CDCl3) d 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 ¼ 256 [M + H]+; HRMS (ESI): m/z calcdfor C15H13NO3 [M + H]+: 256.0968; found: 256.0973.

Methyl 6-methoxy-9H-carbazole-3-carboxylate (2c). Thereaction of methyl 3-iodo-4-(4-methoxyphenylamino)benzoate1c (90 mg, 0.23 mmol), Pd(OAc)2 (5.2 mg, 0.023 mmol) andK2CO3 (64.9 mg, 0.47 mmol), in DMSO (5 mL) at 130 �C for 4 hafforded 2c as white solid (50 mg, 86%). Eluent: ethyl acetate–hexanes (2 : 3); mp 148–150 �C (ref. 6: 147–149 �C); IR (NaCl) n(cm�1) 3281, 2921, 2851, 1699, 1631, 1606, 1441, 1401, 1384,1329, 1292, 1191, 1161, 1099, 1033; 1H NMR (400 MHz, CDCl3) d8.70 (s, 1H), 8.18 (br s, 1H), 8.06 (dd, J¼ 8.5, 1.9 Hz, 1H), 7.98 (d,J ¼ 8.5 Hz, 1H), 7.38 (d, J ¼ 8.5 Hz, 1H), 6.92 (d, J ¼ 7.9 Hz, 1H),6.89 (dd, J ¼ 8.6, 2.1 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H); 13C NMR(125 MHz, CDCl3) d 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 ¼ 256 [M + H]+; HRMS (ESI): m/z calcd for C15H13NO3

[M + H]+: 256.0968; found: 256.0973.

This journal is © The Royal Society of Chemistry 2014

Methyl 6-phenoxy-9H-carbazole-3-carboxylate (2d). Thereaction of methyl 3-iodo-4-(4-phenoxyphenylamino)benzoate1d (100 mg, 0.22 mmol), Pd(OAc)2 (5 mg, 0.022 mmol) andK2CO3 (62.1 mg, 0.45 mmol) in DMSO (5 mL) at 130 �C for 6 hafforded 2d as white solid (60 mg, 85%). Eluent: ethyl acetate–hexanes (2 : 3); mp 182–183 �C; IR (NaCl) n (cm�1) 3340, 2919,2850, 1687, 1633, 1608, 1588, 1489, 1460, 1437, 1308, 1282,1257, 1219, 1168, 1119, 1095; 1H NMR (400 MHz, CDCl3): d 8.71(s, 1H), 8.30 (br s, 1H), 8.13 (dd, J ¼ 8.6, 1.6 Hz, 1H), 7.76 (d, J ¼8.1 Hz, 1H), 7.44 (d, J ¼ 8.6 Hz, 2H), 7.34 (m, 2H), 7.22 (dd, J ¼8.7, 2.3 Hz, 1H), 7.09 (dd, J ¼ 10.6, 4.2 Hz, 1H), 7.02 (dd, J ¼ 8.7,1.0 Hz, 2H), 3.95 (s, 3H); 13C NMR (125 MHz, CD3OD): d 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/z¼ 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 reac-tion of methyl 4-(4-butoxyphenylamino)-3-iodobenzoate 1e (100mg, 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 aswhite solid (56 mg, 80%); eluent: ethyl acetate–hexanes (2 : 3);mp 123–125 �C; IR (NaCl) n (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) d 10.58 (br s, 1H), 8.82 (s,1H), 8.06 (d, J ¼ 8.6 Hz, 1H), 7.85 (d, J ¼ 2.1 Hz, 1H), 7.55 (d, J ¼8.6 Hz, 1H), 7.48 (d, J ¼ 8.8 Hz, 1H), 7.11 (dd, J ¼ 8.7, 2.3 Hz,1H), 4.16 (t, J ¼ 6.5 Hz, 2H), 3.92 (s, 3H), 1.83 (m, 2H), 1.57 (m,2H), 1.02 (t, J¼ 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): d 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 ¼320 [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 reac-tion of methyl 3-iodo-4-(4-propylphenylamino)benzoate 1f (80mg, 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 hafforded 2f as white solid (47 mg, 88%); eluent: ethyl acetate–hexanes (2 : 3); mp 144–146 �C; IR (NaCl) n (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) d 8.80 (s, 1H), 8.29 (br s, 1H), 8.10 (dd, J¼ 7.8,1.9 Hz, 1H), 7.92 (s, 1H), 7.37 (dd, J ¼ 8.9, 1.9 Hz, 2H), 7.26 (dd,J¼ 8.6, 2.9 Hz, 1H), 3.97 (s, 3H), 2.76 (t, J¼ 7.9 Hz, 2H), 1.73 (dd,J¼ 15.0, 7.5 Hz, 2H), 0.98 (dd, J¼ 7.7, 7.0 Hz, 3H); 13C NMR (125MHz, CDCl3) d 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/z¼ 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 reac-

tion of methyl 4-(3-chlorophenylamino)-3-iodobenzoate 1g (80mg, 0.20 mmol), Pd(OAc)2 (4.6 mg, 0.020 mmol) and K2CO3 (57mg, 0.412 mmol) in DMSO (5 mL) at 130 �C for 5 h afforded 2gas white solid (40 mg, 75%). Eluent: ethyl acetate–hexanes(2 : 3); mp 224–226 �C; IR (NaCl) n (cm�1) 3441, 2922, 2852,1701, 1627, 1436, 1335, 1264, 1133, 1016, 912, 820; 1H NMR (400MHz, acetone-d6) d 10.89 (br s, 1H), 8.81 (s, 1H), 8.26 (d, J ¼ 8.4

RSC Adv., 2014, 4, 4960–4969 | 4965

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Hz, 1H), 8.10 (dd, J ¼ 8.6, 1.6 Hz, 1H), 7.62 (d, J ¼ 8.1 Hz, 1H),7.60 (s, 1H), 7.27 (dd, J ¼ 8.4, 1.9 Hz, 1H), 3.92 (s, 3H); 13C NMR(125 MHz, CDCl3) d 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 ¼ 260 [M + H]+; HRMS (ESI): m/z calcdfor C14H10ClNO2 [M + H]+: 260.0473; found: 260.0474.

Methyl 6-uoro-9H-carbazole-3-carboxylate (2h). The reac-tion of methyl 4-(4-uorophenylamino)-3-iodobenzoate 1h (80mg, 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 afforded2h as white solid (39 mg, 75%). Eluent: ethyl acetate–hexanes(2 : 3); mp 196–199 �C; IR (NaCl) n (cm�1) 3436, 2925, 2853,1634, 1466, 1431, 1315, 1286, 1261, 1159, 1016, 768; 1H NMR(400 MHz, CDCl3) d 8.76 (s, 1H), 8.32 (br s, 1H), 8.15 (dd, J¼ 8.6,1.4 Hz, 1H), 7.77 (d, J¼ 8.6 Hz, 1H), 7.43 (d, J¼ 8.5 Hz, 1H), 7.38(dd, J¼ 8.7, 4.1 Hz, 1H), 7.20 (m, 1H), 3.98 (s, 3H). 13C NMR (125MHz, acetone-d6) d 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 ¼ 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, 0.021mmol) and K2CO3 (69.6 mg, 0.503 mmol) in DMSO (5 mL) at130 �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) n(cm�1) 3341, 2923, 2853, 1708, 1601, 1521, 1501, 1485, 1433,1280, 1233, 1173, 1107, 1037; 1H NMR (400 MHz, acetone-d6) d10.62 (br s, 1H), 8.68 (s, 1H), 7.96 (dd, J ¼ 8.5, 1.6 Hz, 1H), 7.69(s, 1H), 7.50 (d, J ¼ 8.7 Hz, 1H), 7.06 (s, 1H), 6.05 (s, 2H), 3.90 (s,3H). 13C NMR (125MHz, acetone-d6) d 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 ¼ 270 [M + H]+; HRMS (ESI): calcd forC15H11NO4 [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 (4.8mg, 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 (45mg, 87%). Eluent: ethyl acetate–hexanes (3 : 7); mp 171–172�C (ref. 30c: 172–173 �C); IR (NaCl) n (cm�1) 3325, 2923, 1704,1635, 1618, 1588, 1492, 1469, 1433, 1384, 1346, 1296, 1246,1199, 1156, 1116, 1081, 1027; 1H NMR d (400 MHz, CDCl3)8.60 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J ¼ 7.8 Hz, 1H), 7.39 (dd,J ¼ 8.7, 2.7 Hz, 2H), 7.26 (d, J ¼ 8.3 Hz, 1H), 6.93 (s, 1H),3.98 (s, 3H), 3.95 (s, 3H). 13C NMR (125 MHz, CDCl3) d 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 ¼ 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, 0.387mmol) in DMSO (5 mL) at 130 �C for 5 h afforded 2k as whitecrystals (44 mg, 80%). Eluent: ethyl acetate–hexanes (3 : 7); mp192–193 �C (ref. 30a: 191–192 �C); IR (NaCl) n (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) d

4966 | RSC Adv., 2014, 4, 4960–4969

8.48 (s, 1H), 8.21 (br s, 1H), 7.86 (d, J ¼ 8.5 Hz, 1H), 7.12 (s, 1H),6.90 (d, J ¼ 2.6 Hz, 1H), 6.86 (dd, J ¼ 8.5, 2.1 Hz, 1H), 3.96 (s,3H), 3.94 (s, 3H), 3.89 (s, 3H). 13C NMR (125 MHz, CDCl3) d167.6, 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/z¼ 286 [M +H]+; HRMS (ESI) calcd for C16H15NO4 [M + H]+: 286.1072; found:286.1081.

Methyl 2,6-dimethoxy-9H-carbazole-3-carboxylate (2l). Thereaction of methyl 5-iodo-2-methoxy-4-(4-methoxyphenylamino)benzoate 1l (450 mg, 1.08 mmol), Pd(OAc)2 (24.4 mg, 0.109mmol) and K2CO3 (301.1 mg, 2.178 mmol) in DMSO (20 mL) at130 �C for 5 h afforded 2l as white crystals (240 mg, 78%).Eluent: ethyl acetate–hexanes (3 : 7); mp 165–167 �C; IR (NaCl) n(cm�1) 3327, 2999, 2948, 2834, 1704, 1635, 1618, 1492, 1470,1346, 1296, 1246, 1199, 1157, 1081; 1H NMR (400 MHz, acetone-d6) d 10.33 (br s, 1H), 8.54 (s, 1H), 7.70 (d, J ¼ 7.9 Hz, 1H), 7.40(d, J ¼ 8.4 Hz, 1H), 7.12 (s, 1H), 6.99 (dd, J ¼ 8.7, 2.5 Hz, 1H),3.87 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H); 13C NMR (125 MHz,acetone-d6) d 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 ¼ 286 [M + H]+; HRMS (ESI): calcd for C16H15NO4 [M + H]+:286.1072; found: 286.1081.

Glycozoline (3). A solution of methyl 6-methoxy-9H-carba-zole-3-carboxylate 2c (40 mg, 0.16 mmol) in THF (3 mL) wasadded drop wise to a suspension of LiAlH4 (12.1 mg, 0. 32mmol) in dry THF (4 mL) at 0 �C. The suspension was thenallowed to warm to 65 �C and was stirred until the reaction wascompleted. The reaction mixture was quenched by methanoland ice cold water followed by the methanol was removed underreduced pressure in a rotary evaporator. The reaction mixturewas diluted with ethyl acetate and washed with water (3 � 10mL). The organic layer was dried over MgSO4 and evaporatedunder reduced pressure. The residue was then puried bycolumn chromatography on silica gel by using ethyl acetate–hexanes (3 : 7) to give glycozoline (3) in 75% yield (25 mg). Lightyellow solid; mp180–182 �C (ref. 33b: 179–180 �C); IR (NaCl) n(cm�1) 3404, 2922, 2851, 1742, 1585, 1495, 1461, 1437, 1331,1295, 1254, 1209, 1172, 1143, 1032; 1H NMR (400 MHz, CDCl3) d8.21 (br s, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.41 (d, J ¼ 8.5 Hz, 1H),7.35 (d, J¼ 8.1 Hz, 1H), 7 (d, J¼ 7.8 Hz, 1H), 7.08 (dd, J¼ 8.5, 1.2Hz, 1H), 3.97 (s, 3H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3) d150.6, 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 ¼ 212 [M + H]+;HRMS (ESI): calcd for C14H13NO [M + H]+: 212.1070; found:212.1083.

Glycozolidine (4). Following the same reaction procedure asreported for glycozoline (3) reaction of carbazole 2l (50 mg, 0.17mmol) with LiAlH4 (13.3 mg, 0.35 mmol) in THF (5mL) affordedglycozolidine 4 (21 mg, 65%). Eluent: ethyl acetate–hexanes(3 : 7); light yellow solid; mp164–166 �C (ref. 35a: 158–161 �C);IR (NaCl) n (cm�1) 3404, 2922, 2851, 1742, 1585, 1461, 1437,1384, 1331, 1295, 1254, 1209, 1172, 1032; 1H NMR (400 MHz,acetone-d6) d 9.94 (br, 1H), 7.78 (s, 1H), 7.53 (d, J ¼ 2.4 Hz, 1H),7.32 (d, J ¼ 8.7 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J ¼ 8.7, 2.6 Hz,1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz,CDCl3) d 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 ¼ 242

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[M + H]+; HRMS (ESI): calcd for C15H15NO2 [M + H]+: 242.1176;found: 242.1171.

Clausenalene (5). Following the same reaction procedure asreported for glycozoline (3) reaction of carbazole 2i (50 mg, 0.18mmol) with LiAlH4 (14.1 mg, 0.37 mmol) in THF (4mL) affordedclausenalene 5 (31 mg, 72%). Eluent: ethyl acetate–hexanes(3 : 7); white solid; mp 224–227 �C (ref. 36a: 224–225 �C); IR(NaCl) n (cm�1) 3386, 2918, 2850, 1687, 1585, 1484, 1458, 1378,1318, 1297, 1269, 1217, 1189, 1151, 1036; 1H NMR (400 MHz,acetone-d6) d 10.04 (br s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.31 (d,J¼ 8.2 Hz, 1H), 7.09 (dd, J¼ 8.3, 1.2 Hz, 1H), 6.97 (s, 1H), 5.99 (s,2H), 2.45 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 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 ¼ 226 [M + H]+; HRMS (ESI): calcdfor C14H11NO2 [M + H]+: 226.0863; found: 226.0859.

Sansoakamine (6). Boron tribromide (1 M solution inCH2Cl2, 0.34 mL, 0.34 mmol) was added at �78 �C to a solutionof 2l (50 mg, 0.17 mmol) in CH2Cl2 (5 mL) under nitrogenatmosphere and the mixture was stirred at that temperature for2 h. The reaction mixture was warmed to�20 �C and was stirredfor another 20 h. The progress of the reaction was monitored byTLC and aer completion the reaction mixture was quenchedwith saturated aqueous solution of NaHCO3 at 0 �C and dilutedwith ethyl acetate. The aqueous layer was extracted with ethylacetate (2 � 10 mL). The combined organic layer was dried overanhydrous Na2SO4 and was evaporated under reduced pressure.The crude product was puried by silica gel column chroma-tography by using ethyl acetate–hexanes (2 : 8) to give san-soakamine (6) in 76% (34 mg) yield. Light brown solid; mp 243–246 �C (ref. 9: 243.8–245.6 �C); IR (NaCl) n (cm�1) 3338, 2923,2853, 1660, 1597, 1436, 1383, 1265, 1162, 1089, 1042; 1H NMR(400 MHz, acetone-d6) d 10.31 (br s, 1H), 8.53 (s, 1H), 7.51 (d, J¼2.2 Hz, 1H), 7.29 (d, J ¼ 8.6 Hz, 1H), 6.93 (dd, J ¼ 8.6, 2.3 Hz,1H), 6.86 (s, 1H), 3.99 (s, 3H); 13C NMR (125 MHz, CDCl3) d171.6, 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 ¼ 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 drytoluene (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. Themixture was stirred at �78 �C for 1 h. The progress of thereaction was monitored by TLC. The resulting mixture wasquenched with methanol (5 mL) followed by ice cold water(5 mL). The methanol was removed under reduced pressure andthe reaction mixture was diluted with ethyl acetate. The organiclayer was separated dried over Na2SO4 and was concentratedunder vacuum. The crude reaction mixture was puried bycolumn chromatography on silica gel by using by using ethylacetate–hexanes (2 : 8) to afford glycozolidal (7) in 86% (37.8mg) yield. Yellow solid; mp190–193 �C (ref. 35b: 188–193 �C); IR(NaCl) n (cm�1) 3400, 2923, 2852, 1606, 1487, 1469, 1433, 1384,1295, 1274, 1202, 1112; 1H NMR (400 MHz, acetone-d6) d 10.49(br s, 1H), 10.45 (s, 1H), 8.50 (s, 1H), 8.03 (d, J¼ 2.2 Hz, 1H), 7.76(d, J ¼ 8.4 Hz, 1H), 7.39 (dd, J ¼ 8.7, 2.1 Hz, 1H), 7.12 (s, 1H),4.02 (s, 3H), 3.91 (s, 3H); 13C NMR (125 MHz, acetone-d6) d

189.7, 159.7, 155.4, 145.1, 135.9, 125.2, 121.1, 118.7, 117.0,

This journal is © The Royal Society of Chemistry 2014

114.9, 112.3, 103.5, 94.7, 56.3, 56.1; MS (ESI):m/z¼ 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 tothank UGC for research fellowship. CSIR, New Delhi (BSC 0108)is acknowledged for the nancial support.

References

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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.

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107, 174.29 For synthesis of methyl carbazole-3-carboxylate, see: (a)

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30 For synthesis of clausine alkaloids, see: (a) O. Kataeva,M. P. Krahl and H.-J. Knolker, Org. Biomol. Chem., 2005, 5,3099; (b) M. P. Krahl, A. Jager, T. Krause and H.-J. Knolker,Org. Biomol. Chem., 2006, 4, 3215; (c) R. Forke, A. Jager andH.-J. Knolker, 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. Knolker, 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. Schlechtingenand H.-J. Knolker, Synlett, 2007, 268.

32 Crystal data of 2f: C17H17N1O2,M¼ 267.32, monoclinic, spacegroup: P21/n, a ¼ 12.8565(7), b ¼ 13.8210(7), c ¼ 8.0271(4)A, b ¼ 98.229(5)�, V ¼ 1411.63(13) A3, Z ¼ 4, Dc ¼ 1.258 gcm�3, m ¼ 0.082 mm�1, T ¼ 293(2) K, l ¼ 0.71073 A,q range: 3.9–27.0�, 1 1900 reections measured, 3031

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independent (Rint ¼ 0.0305), 249 parameters. Thestructure was solved by direct methods and rened byfull-matrix least-squares on F 2; nal R indices for 1989observed reections [I > 2s(I)]: R1 ¼ 0.0520, wR2 ¼0.1298; maximal/minimum residual electron density:0.158/�0.213 A�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 andS. Nishiyama, Tetrahedron, 2010, 66, 9779.

34 C. Borger and H.-J. Knolker, Tetrahedron, 2012, 68, 6727.

This journal is © The Royal Society of Chemistry 2014

35 For synthesis of glycozolidine and glycozolidal, see: (a)M. Schmidt and H.-J. Knolker, 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 andB. K. Chowdhury, Phytochemistry, 1993, 33, 248; (b)T. L. Scott, X. Yu, S. P. Gorugantula, G. Carrero-Martinezand B. C. G. Soderberg, Tetrahedron, 2006, 62, 10835.

37 M. Fuchsenberger, R. Forke and H.-J. Knolker, Synlett, 2011,2056.

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