In India, the Murraya Koenigii is the best source for the isolation of the carbazole alkaloids such as murrayanine which is commonly called kadi patta leaf and used day to day life in kitchen . The alkaloids display wide-ranging range of pharmaceutical activity such as antitumor, anti-inflammatory, anti-histaminic, antioxidant, light emitting properties . Because of extensive use of distinctive skeleton, physicochemical properties and pharmaceutical activities as mentioned above, the introduction of novel, simple and efficient route to prepare the carbazole moiety has considerable attention in the scientist community. The numerous synthetic methods are present for the preparation of murrayanine (1), mukonine carbazole alkaloids [5-6].
The diverse synthetic reports available in the literature include Fischer indolization  the iron metal catalyzed oxidative coupling with cyclization of arylamine tricarbonyl(cyclohexadiene) complexes [8-9], oxidative cyclization in the palladium(II)-catalyzed , the thermal cyclization of 1-phenyl benzotriazole  cyclization of biarylnitrenes to carbazole  and some others methods. Recently, Banwell et al. described a new procedure for the preparation of Mukonine carbazole alkaloids with 66% yield via a Pd-Catalyzed oxidative C-C bond formation followed by reductive coupling reaction .Knoke et al. (1993) described the iron-promoted carbon-carbon, carbon-nitrogen bond formation followed by synthesis of koenoline, mukoeic acid, murrayafoliae A, murrayanine. murrayaquinone A, and mukonine natural product . Subha etal. described the novel cross coupling reaction followed by reductive cyclization in the presence of triphenylphosphine that gives a range of carbazole alkaloids, including mukonine, murrayafoline A, mukoeic acid, clauszoline K, koenoline, murrayanine,glycoborine, mukoline, glycozolicine, mukolidine, and glycozoline alkaloids . The natural product mukoline and mukolidine were produced by the reaction of aromatic amine with the exposure of palladium (II) acetate and copper (II) acetate in the pivalic acid .
As a researcher, always interested to report a novel methodology for the construction of bioactive heterocyclic compound [17-23]. In this paper, we have described a new method for the total synthesis of murrayanine (1), mukonine via construction of desire scaffold via Buchwald coupling followed by Pd(OAc)2 mediated oxidative coupling reaction to obtain desire molecule.
Material and methods
The experiment was performed in a dry glass apparatus and the required raw chemicals were bought from the national and international suppliers such as Spectrochem, Aldrich, Merck, Fisher and used directly. The dry reaction was carried out in the Argon gas atmosphere. The progress of reaction was checked on TLC. The synthesized compound purification was performed using column chromatography with Silica gel (60-120 Mesh) from Aura. The solvent was dried over A4 molecular sieves prior to use and the THF was dried over Na metal. The tetramethylsilane (TMS) used as internal standard at ambient temperature for the running of the 1H NMR, 13C NMR spectra over a Bruker 400, 500 MHz NMR machine. The FT-IR spectra were recorded over a Bruker- Perkin-Elmer model 683 B or 1605 spectrophotometer and absorptions were expressed in cm-1. All Buchi 501 apparatus was used for the recording of melting points and Boiling Points of pure compounds and are uncorrected.
Synthesis of methyl 4-bromo-3-methoxybenzoate (5)
To a solution of 4-bromo-3-methoxybenzoic acid, 6 (1,00 g, 1 eq) in methanol (15 ml) H2SO4 (20 µL, 0.15 eq) was added. The reaction mixture was blended to reflux for 5 h. After completion of the reaction, the solvent was removed under reduced pressure and the crude mass was mixed in DCM NaHCO3 and cold water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the pure product 5 methyl 4-bromo-3-methoxybenzoate; white crystalline product, mp 54-56 °C.
Methyl 3-methoxy-4-(phenylamino)benzoate (3)
In a dry seal tube with magnetic stir bar, Pd2(dba)3, methyl 4-bromo-3-methoxybenzoate2 (g, mmol), aniline ( g, mmol) was added, followed by xantphos (g, mmol) Cs2CO3 (g, mmol) in a dry 1,4-dioxane, the seal tube was then evacuated/backfilled with argon 3x with stirring. The seal tube was stirred vigorously at 110 °C for 48h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with 5 ml ethyl acetate and filter over sintered glass funnel, the organic solution concentrate under vacuum and purified using column chromatography to afford white crystal with 58% yield.
1HNMR (300MHz, CDCl3); δ: 3.88(s, 3H), 3.96 (s, 3H), 6.54 (br, 1H), 7.06 (t, J= 7.4 Hz, 1H), 7.19-7.26 (m, 3H), 7.34 (t, J= 8 Hz, 2H), .7.52 (d, J= 1.5 Hz, 1H), 7.59 (dd, J= 1.4 Hz & 8.1 Hz, 1H)
13CNMR (75 MHz, CDCl3), δ: 51.7, 55.7, 59.8, 110.5, 110.6, 119.9, 120.8, 123.0, 123.5, 129.4, 132.2, 140.6, 146.5, 167.1.
Synthesis of methyl 1-methoxy-9H-carbazole-3-carboxylate; Mukonine (2)
In a dry seal tube with magnetic stir bar was added Pd(OAc)2 and methyl 3-methoxy-4(phenylamino)benzoate 3in a 1,4-dioxane the seal tube was fluxed with argon 3x with stirring. The seal tube was blended vigorously at 100 °C for 16h. The progress of reaction was checked using TLC and after completion of reaction the mixture mix with 10 mL Ethyl acetate.
After completion of reaction (monitored by TLC), the reaction mixture was diluted with 10 mL ethyl acetate and filter over sintered glass funnel, the organic solution concentrate under vacuum and purified using column chromatography with ( ethyl acetate: hexane) to afford white solid.
Mukonine (5a): Yield (70%), mp 194-198 °C (lit. 4 mp 196 °C); 1H NMR (300 MHz, CDCl3): δ: 10.37 (s, D2O exchange, 1H), 8.34 (s, 1H), 8.06 (d, J=6.2 and washed with the saturated solution of
Hz, 1H), 7.61 (s, 1H), 7.51 (t, J = 9.1 Hz, J = 8.9 Hz, 1H), 7.40 (t, J = 8.8 Hz, J = 5.8 Hz, 1H), 7.09 (t, J = 6.2 Hz, 1H), 3.88 (s, 6H); 13CNMR (75 MHz, DMSO-d6): 167 δ 167.89, 146.01, 139.91 132.61, 126.02, 123.71, 123.83, 122.11, 120.22, 120.54, 116.21, 111.45, 107.23, 55.52, 55.01; The calculated HRMS for the molecular formula C15H13NO3 [M+ H]+, 256.0968 and observed 256.0970.
Synthesis of 1-methoxy-9H-carbazole-3-carbaldehyde; Murrayanine (1)
A solution of compound methyl 1-methoxy-9H-carbazole-3-carboxylate 0.500 mg in a 17 mL dry THF at -78 °C under the argon atmosphere di-isobutyl-aluminum hydride in THF was added drop wise and keep the vessel temperature below -65 °C. After completion of reaction, the reaction was quenched with 10 mL of 10% HCl, and extracted into 2 x 10 mL portions of ethyl acetate. The organic layer was also washed by using 10% HCl, solution and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentration under reduced pressure gave desired 1-methoxy-9H-carbazole-3-carbaldehyde. Murrayanine (1):Colourless crystals, Yield (78%), mp 164-168 °C ; 1H NMR (400 MHz, DMSO) δ: 11.68 (s, 1H), 8.78 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.03 (dd, J = 8.3, 5.5 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H).
Result and Dissection
The retrosynthesis analysis of murrayanine (1), mukonine (2), is shown in Figure-1. Our retrosynthetic analysis for the synthesis of the target molecule 1 murrayanine (1) and mukonine (2) carbazoles are expected to be obtained via Buchwald–Hartwig coupling followed by Pd catalyzed C-C coupling reaction (Scheme 2). The key precursor 5 has been required for the construction of murrayanine and mukonine carbazole alkaloids.
We have described a new and concise synthesis method of Murrayanine (1) and Mukonine (2), by using the novel approach that involves a Pd-catalyzed Buchwald coupling followed by oxidative coupling cyclization of the phenyl and aryl rings using stoichiometric amount of Pd(OAc)2.
The authors are thankful to Department of Chemistry Dr. D.Y. Patil A. C. S. College, Pimpri, Pune, 411018, India, Savitribai Phule Pune University for providing laboratory facilities for this research. The author RDK is thankful to BOD, Savitribai Phule Pune University, Pune for ASPIRE Research Grant (18TCR000044).
All authors contributed toward data analysis, drafting and revising the paper and agreed to be responsible for all the aspects of this work.
We have no conflicts of interest to disclose.