Synthesis of 2-tetrazolylmethyl-tetrahydro-1H--carboline methane-linked bis- heterocycles via one pot Ugi-azide / Pictet-Spengler process

A series of seven new 2-tetrazolylmethyl-tetrahydro-1H--carboline methane-linked bisheterocycles including their fluorine-containing analogs were synthesized in good to excellent yields (74-97%) via one pot Ugi-azide / Pictet-Spengler strategy under mild thermal conditions. One intermediate (Ugi-azide product) was isolated and fully characterized in order to confirm the reaction pathway. The products herein described may find application in medicinal chemistry because they are formed by two heterocyclic frameworks (1,5disubstituted-1H-tetrazole and tetrahydro--carboline), which are present in a variety of bioactive compounds and drugs. In the same context, it has been reported that fluorine atoms placed suitably into structures of bioactive compounds enhances often very interesting features like bioavailability, lipophilicity and metabolic resistance.


Introduction
Bis-heterocycles are a special class of synthetic or naturally occurring products formed by two heterocyclic moieties in spaced, linked, fused, merged or bound manner, 1 which are of high interest for synthetic chemists because they have proven to be useful in various fields like agrochemistry, optics, material-polymer science, and mainly in medicinal chemistry. 2In this context, we herein show the synthesis of seven new methane-linked bis-heterocycles formed by 1,5-disubstituted-tetrazole (1,5-DS-T) and tetrahydro-1H--carboline (THC) moieties, including some fluorine-containing analogs.
It is well documented that addition of fluorine atoms into structure of bioactive molecules often enhance very important features like bioavailability, lipophilicity and metabolic resistance. 3With respect to the two involved heterocyclic systems (1,5-DS-T and THC), the first one are bioisosters of cis-amide bond in peptides by adopting their bioactive conformations. 4 For this reason, 1,5-DS-T are present in numerous bioactive products and drugs like the Latamoxeb (3 rd generation cephalosporin antibiotic). 5Moreover, 1,5-DS-T's have shown other interesting applications, for example, as prime ligands and chelating agents. 6On the other hand, THC are the core of many natural and synthetic products exhibiting a broad spectrum of biological activity, mainly in central nervous system (CNS) related disseases. 75-DS-T's are synthesized commonly via click reactions between organic azides and nitriles prepared stepwise. 8However, the Ugi-azide reaction has become in the current method due to the inherent highlighting features of Multicomponent reactions (MCR) and one pot processes. 9There are only three reports describing the synthesis of methane-linked bisheterocycles containing the 1,5-DS-T moiety via One pot Ugi-azide based methods. 10oreover, THC are synthesized usually via Pictet-Spengler cyclization from tryptamine derivatives. 11It is noteworthy that methane-linked bis-heterocycles containing 1,5-DS-T and THC have not been synthesized by others via MRC, one pot or multistep methods.

Results and discussion
Thus, as a part of our ongoing program to develop Ugi-azide based methods to synthesize new methane-linked bis-heterocycles containing the 1,5-DS-T moiety, 12 we herein show our most recent results for the synthesis of 2-tetrazolylmethyl-tetrahydro-1H--carbolines, which must be understood as a smart improvement and extension of our original work 'synthesis of 2,3,4,9-tetrahydro--carboline-1,5-1H-tetrazoles by a one pot Ugi-azide / Pictet-Spengler process' published in Synthesis a couple of years back. 13As it will be discussed, various aspects were improved with respect to our previous methodology.For example, overall yields were increased, reaction conditions were milder, and substrate scope was enlarged because all products herein described are new, including some novel fluorine-containing analogs.We started the synthesis of bis-heterocycles 1a-g taking the fluorine-containing 2tetrazolylmethyl-tetrahydro-1H--carboline 1a as model to optimize the Ugi-azide/PS process using the conditions previously reported by us as starting point (i-MeOH [1.0 M], rt, 6 h; ii-MeOH/PhMe 1/1 v/v [1.0 M], MW {90 °C, 60 W}, 5 h). 13Thus, tryptamine (2) was combined sequentially with 2-fluorobenzaldehyde (3), tert-butyl isocyanide (4) and azidotrimethylsilane (5) in MeOH [1.0 M] as solvent under room temperature conditions to afford the new Ugi-azide product 6a in 90% yield after 5 h (Table 1).As seen, the Ugi-azide reaction finished one hour less with respect to our previous results. 13Then, after various unsuccessful attempts to synthesize the fluorine-containing bis-heterocycle 1a, we decided to use formaldehyde instead paraformaldehyde to avoid harsh conditions needed for its depolymerization MW (5 hours).Compound 6a reacted with formaldehyde (7) via Pictet-Spengler cyclization under conventional heating conditions (65 °C) for 5 hours and the novel product 1a was isolated in 94% (Table 1).Then, having in hand new optimal conditions for the Ugi-azide/Pictet-Spengler process, we synthesized the full series 1a-g, but in one pot manner to make more sustainable our MCR-cascade methodology.As seen, good to excellent yields were obtained (74-97%).Besides, good substrate scope was found because benzaldehydes containing one, two, or three fluorine atoms were used.In the same context, benzaldehyde without fluorine atom was used.Moreover, the stereoelectronic nature of isocyanide moiety was explored by using alkyl and aryl isocyanides (tert-butyl and 2,6dimethylphenyl).As seen, the product 1g could not be synthesized may be due to steric hindrance.To test the hypothesis, we calculated its minimal energy conformation by DFT approach using the robust TPSSh/6-311g(d) level of theory, finding a high steric hindrance between its three bulky moieties (THC, 2,3,4-FPh, and 2,6-MePh), (Fig. 1).

Conclusions
This work is a contribution to the synthesis of methane-linked bis-heterocycles via Ugi-azide based one pot MCR methodologies as well as to the synthesis of bis-heterocycles via MCR/cyclization. 14An Ugi-azide product was isolated and fully characterized to confirm the reaction pathway.The Pictet-Spengler reaction worked well using formaldehyde instead para-formaldehyde becoming milder the reaction conditions.A final bis-heterocycle could not be synthesized due to a high steric strain coming from its three bulky moieties.The products herein described may find application in medicinal chemistry because they have two heterocyclic cores (1,5-DS-T and THC) present in numerous bioactive products and drugs, even contain one or more fluorine atoms, which can be reflected by improving some interesting features like metabolic resistance, lipophilicity, and bioavailability.

Experimental
General Information, software, instrumentation and chemicals 1 H and 13 C NMR spectra were acquired on Bruker Advance III spectrometer (500 MHz).The solvent for NMR samples were d 6 -DMSO and CDCl3.Chemical shifts are reported in parts per million (δ/ppm).Internal reference for NMR spectra is TMS at 0.00 ppm.Coupling constants are reported in Hertz (J/Hz).Multiplicities of signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m).NMR spectra were analyzed using the MestreNova software (version 6.0.2-5475).IR spectra were recorded on a Perkin Elmer 100 spectrometer by the ATR method using neat compounds.
The wavelengths are reported in reciprocal centimeters (max/cm -1 ).FT-IR spectra were analyzed using the Report Builder software (Rev.2.01).HRMS spectra were acquired on a MaXis-Impact ESI(+)-QqTOF Bruker mass spectrometer.HRMS spectra were analyzed using the data Analysis (Bruker, version 4.1).The reaction progress was monitored by TLC and the spots were visualized under UV light (254 or 365 nm).Flash column chromatography was performed using silica gel (230-400 mesh) and mixtures of hexanes with diethyl ether or Hexanes with AcOEt as mobile phase.Melting points were determined on a Fisher-Johns apparatus and were uncorrected.Commercially available reagents were purchased in Sigma-Aldrich and were used without further purification.Structure names and drawings were done using the ChemBioDraw Ultra software (version 13.0.0.3015).