Preparation of symmetrical C2-C2-linked bis-and tris-6-bromoindoles by Sonogashira couplings and 5-endo-dig cyclization induced by nBu 4 NF

Preparation of symmetrical C2-C2 linked bis-6-bromoindoles and one tris-6-bromoindole containing ether spacers is described. Double regioselective Sonogashira coupling at the C-I bond of benzyl (5-bromo-2-iodophenyl)carbamate with dialkynes allowed preparation of the corresponding bis-benzyl(2-alkynyl-5-bromo)carbamates.


Introduction
The indole nucleus is a privileged structure present in a myriad of bioactive compounds many of which have been translated in pharmaceutical leads.2][3] Scheme 1.It is noteworthy that structural modifications of these natural products had led to synthetic analogs with DNAquadruplex recognition, 4 antibacterial, 5,6 antilesihmanial, 7 antitumoral, [8][9][10][11] and angiogenesis inhibition 12 activity.Most of these compounds are linked through the indole C3 position, with only a few exceptions such as Gelliusines F which is a C2-C3 linked bis-indole.In view of the structural diversity of these compounds it is likely that the C2-C2 bis-indoles hold promise for

Scheme 2
With these coupling products in hand, their cyclization to produce indoles was investigated.0][31][32][33][34][35][36] In order to keep the procedure simple, the protocol using tetrabutylammonium fluoride (TBAF) 17,18 was chosen.Thus alkynes 4a-i were treated with TBAF (3 equiv for each carbamate group) in refluxing THF (Scheme 3).Reactions of aryldialkynes 4a-c were sluggish, starting material decomposition was observed but no evidence of formation of the desired products could be found by 1 H NMR analysis of the reaction crude complex mixtures.On the other hand, the alkyldialkynes 4d-i underwent smooth cyclization to afford the desired bisindoles 5d,e,g,i and the tris-indole 5f, the exception being ketone 4h which decomposed in the reaction conditions and did not give any of the expected indole 5h.(Scheme 3)

Scheme 3
Failure of aryldialkynes 4a-c to cyclize is likely due these to the presence of aryl rings with electron rich groups that make the alkyne group too electron-rich to undergo the base promoted cyclization.Compare for example the successful cyclization reaction of 4d vs. the failed reaction of 4a.Electron delocalization in 4a from the carbazole unit towards the alkyne carbon which should undergo nucleophilic attack from the carbamate anion renders the alkyne unreactive; on the contrary, in 4d no such electron delocalization is possible and the alkyne underwent cyclization (Scheme 4).Recent literature reports describe similar diarylalkyne substrates which have required gold catalysts using microwave 4 or ultrasound 37 techniques or indium tribromide 27 to accomplish the 5-endo-dig cyclization.

Conclusions
We have found an efficient protocol for the C-I regioselective consecutive Sonogashira coupling of benzyl (5-bromo-2-iodophenyl)carbamate 2 with aryldialkynes and alkyldialkynes to afford the corresponding bis-alkynes.The scope of the reaction indicates that only alkyldialkynes underwent TBAF induced 5-endo-dig cyclization to form bis-indoles while aryldialkynes failed to cyclize.Despite this limitation, the protocol shown here is simple, reaction conditions for both the Sonogashira coupling and cyclization are mild and the reaction sequence was efficient for the synthesis of symmetrical C2-C2 bis-6-bromoindoles and one tris-6-bromoindole.Such structures are building blocks for further development of new bioactive compounds.
Visualization of TLC plates was carried out with a UV lamp (254, 365 nm) and staining with cerium molybdate solution.IR spectra were obtained on a Perkin-Elmer FT-IR Spectrum GX spectrometer.High resolution mass spectra were obtained either on a JEOL GCmate spectrometer by electronic impact (IE+) at 70 eV or on a Maxis Impact ESI-QTOF MS, Bruker Daltonics with chemical ionization (CI).Melting points were determine on a Büchi® Melting Point B-540 apparatus and are uncorrected. 1H and 13 C NMR spectra were obtained in CDCl 3 or DMSO-d6 solutions on a Varian VNM System 400 MHz spectrometer using TMS (= 0.0 ppm) CDCl 3 ( = 77.16ppm) and DMSO-d6 (= 29.84 ppm) as internal references.

General procedure for cyclization of carbamates 4c-i with TBAF in THF for preparation of indoles 5d-g and 5i.
In a round-bottom flask, equipped with a condenser and a stirring bar, under a N 2 atmosphere was placed 0.3 mmol of the corresponding carbamate 4d-i in 5 mL of dry THF and 1.8 mL of a solution of 1M de TBAF (1.8 mmol, 6.0 equiv) in THF for all bis-carbamates 4d,e, 4g-i and 2.7 mL of 1M TBAF (2.7 mmol, 9.0 equiv) for tris-carbamate 4f (i.e.3.0 equivalents of TBAF for each carbamate group that undergoes cyclization).The solution was heated to reflux for 1h under N 2 and then cooled to room temperature, diluted with 200 mL of ethyl acetate and washed with water (3x60 mL) and brine (1x50mL).The organic phase was dried with anh.Na 2 SO 4 , absorbed in sílica gel and dried under vacuum.Column chromatography using gradients of hexanes:THF (95:5, 90:10, 80:20) gave the indoles 5d-i.