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Home > Combination of Sonogashira coupling and 5-endo-dig cyclization for the synthesis of 2,6-disubstituted- 5-azaindoles
Combination of Sonogashira coupling and 5-endo-dig cyclization for the synthesis of 2,6-disubstituted- 5-azaindoles
Michael N. Balfoura, Julio Zukerman-Schpectorb, Maria Jos´e D´avila Rodriguezb,
Joel Savi Reisa, Carlos Henrique A. Estevesa, and H´elio A. Stefania
aFaculdade de Ci^encias Farmac^euticas, Departamento de Farm´acia, Universidade de S~ao Paulo, S~ao Paulo, SP, Brazil; bLaborat´orio de Cristalografia, Estereodin^amica e Modelagem Molecular, Departamento de Qu´ımica, Universidade Federal de S~ao Carlos, S~ao Carlos, SP, Brazil
Introduction
4-, 5-, 6-, and 7-Azaindoles, more technically named 1H-pyrrolo [3,2-b] or [3,2-c] or [2,3-c] or [2,3-b] pyridines, respectively, have been frequently explored in drug discovery, as they demonstrate broad-spectrum of biological activity and clinical applications. Some exam-ples are as benzodiazepine receptor ligands (compound 1),[1] dopamine D4 receptor ligands (compounds 2–5),[2] and antineoplasic agents (compounds 6–8).[3] In the infectious diseases field, studies have described the inhibitory potential of azaindoles against models of Giardia duodenalis (compounds 9–11)[4] as well as Trypanosoma brucei rhode- siense, Trypanosoma cruzi, Leishmania donovani (axenic amastigotes), and Plasmodium falciparum (compounds 12–16) (Figure 1).[5] More specifically, there have been several reports of nitrogen-containing heterocyclic compounds displaying anti-leishmanial activ- ity,[6] especially in the case of 1H-pyrrolo[3,2-c]pyridines (5-azaindoles).
Among the synthetic strategies available to obtain these heterocycles, we can highlight 5-endo-dig, aza-cyclization, eletrophilic, nucleophilic and metal-catalyzed cyclizations.[7] Recently, we reported the synthesis and the trypanocidal activity of a library of 4-substituted-5-azaindoles derivatives.[8] Herein, we describe our efforts towards the synthesis of a library of 2,6-di-substituted-5-azaindoles with the goal of extending the series of compounds to be biologically evaluated against different classes of parasites. More spe- cifically, we have achieved the synthesis of three different bromo-substituted and several 2-substituted-6-(alkynyl)-5-azaindole derivatives relying on a coordinated sequence of Sonogashira couplings and 5-endo-dig annulation.
Results and discussion
Our initial efforts were focused on the synthesis of biological relevant 2-substituted-6- alkynyl-5-azaindoles, following the disconnections as shown in Scheme 1.
In order to test this strategy, amino-pyridine 19 was prepared from 4-amino-2-bro- mopyridine 17, which was iodinated in 43% yield with ICl,[10] followed by N-mesyla- tion with MsCl in two steps (71%, combined yield) (Scheme 2).
With compound 19 in hand, we turned our attentions to the tandem Sonogashira coupling/5-endo-dig cyclization/Sonogashira coupling proposed in Scheme 1. Gratifyingly, when compound 19 and 1-hexyne were subjected to standard coupling conditions, 5-azaindole 20 was cleanly obtained in 74% yield (Scheme 3).
Next, we explored the substrate scope for this transformation using different alkynes. The results are summarized in Table 1.
The tandem sequence tolerated well substituents bearing aliphatic chains (20, 23 and 24), aliphatic chains containing remote aromatic groups (26 and 28) and unpro- tected alcohols (21, 22, 25 and 27), affording a series of 5-azaindoles in moderate to high yields. It was found, however, that the reaction generally failed with some terminal alkynes directly connected to aromatic rings, leading to decomposition of the starting material 19.We speculate that the distinct electronic characteristics of some aryl alkynes could be affecting their reactivity. Negative results were also obtained with tertiary amines and esters.
In order to expand the scope of the products obtained, we next examined the feasibil- ity of a Sonogashira/5-endo-dig sequence. This shorter version would leave a bromine atom as a useful handle for further functionalization (important feature for the con- struction of libraries). We reasoned that the more pronounced reactivity of aryl iodides over bromides towards oxidative addition[11] would furnish the Sonogashira coupling preferentially at position 5 in substrate 19. A rapid intramolecular 5-endo-dig should then furnish 6-bromo-5-azaindoles. Indeed, using 1.05 equivalents of the alkyne, it was possible to obtain two examples of these products, demonstrating the concept. Interestingly, 3-butynol delivered the brominated azaindole in good yield even with three equivalents added, suggesting a low reactivity of this substrate (Table 2).
In order to show the usefulness of 6-bromo-5-azaindoles, compound 31 was subjected to Suzuki-Miyaura coupling conditions, furnishing products 34 and 35 (Table 3). Finally, the structure of compound 31 was unambiguously determined by single-crys- tal X-ray analysis and is shown in Figure 2. In the crystal above, the molecules are linked in isolated centrosymmetric dimers through a Br … p interaction, as shown in Figure 3. The 5-azaindole ring and the phenyl ring make a dihedral angle of 58.80(5)o, whereas the methoxy moiety is almost coplanar with the ring and the C10–C11–O1–C14 torsion angle being of —4.4(3)o.
Conclusions
We have demonstrated the synthesis of a small library of 2-substituted-6-alkynyl-5- azaindoles via a tandem Sonogashira coupling/5-endo-dig/Sonogashira coupling sequence. Exploring the selectivity of the coupling reaction, 6-bromo-5-azaindoles were also obtained allowing the construction of libraries of compounds using coupling chem- istry. This methodology tolerated alkynes containing alcohols, aromatic substituents and aliphatic chains. Biological tests on Trypanosoma spp and other parasites will be reported in due course.
Experimental
General procedure for the synthesis of 2,6-disubstituted-5-azaindoles A 25 mL single necked round bottom flask equipped with a reflux condenser, under nitrogen atmosphere, was charged with N-(2-bromo-5-iodopyridin-4-yl)methanesulfona- mide 19 (1 equiv.), CuI (0.05 equiv.). In a separate 25 mL single necked round bottom flask, Et3N (5 equiv) and DMF (0.25 mol.L—1, conc. 19), were degassed with three freeze-pump-thaw cycles. Et3N and DMF, followed by terminal alkyne (3.0 equiv), were then added to the reaction. Pd(PPh3)2Cl2 (0.05 equiv) was then added and the reaction mixture was stirred, at 60 ○C, for 4 h. The crude mixture was diluted with EtOAc, trans- ferred to a separating funnel and was added sat. NH4Cl(aq). The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and volatiles were evaporated. The residue was purified by flash column chromatography over silica using n-hexane/ethyl acetate (99:1 to 0:100) mix- tures as eluent to give the di-substituted compounds.
General procedure for the synthesis of 6-bromo-2-substituted-5-azaindoles
A 25 mL single necked round bottom flask equipped with reflux condenser, under nitro- gen atmosphere, was charged with 19 (1.0 equiv), CuI (0.02 equiv), 1-alkyne (1.05 equiv), and Pd(PPh3)2Cl2 (0.02 equiv). In a separate 25 mL single necked round bottom flask, Et3N (5.0 equiv) and DMF (0.25 mol.L—1, conc. 19), were degassed with three freeze-pump-thaw cycles. Et3N and DMF were then added and the reaction mixture was stirred at 60 ○C for 5 h. The crude mixture was diluted with EtOAc, transferred to a sep- arating funnel and was added sat. NH4Cl(aq). The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and volatiles were evaporated. The residue was purified by flash column chromatography over silica using n-hexane/ethyl acetate (99:1 to 60:40) mixtures as eluent to give 2-substituted-6-bromo-5-azaindoles (31–33).
General procedure for the synthesis of compounds 34 and 35 via Suzuki-Miyaura cross coupling
A 25 mL two necked round bottom flask was charged with 31 (1.0 equiv), Na2CO3 (3.0 equiv), and R-BF3K (1.5 equiv). In a separate 50 mL single necked round bottom flask, toluene and tert-butanol (3:1, v/v), were degassed with three freeze-pump-thaw cycles. The mixture toluene/tert-butanol and then Pd(PPh3)4 (0.1 equiv) were added to the reaction. The reaction mixture was stirred, at 110 ○C, for 17 h. The crude mixture was diluted with EtOAc, transferred to a separating funnel and was added sat. NH4Cl(aq). The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and volatiles were evaporated. The residue was purified by flash column chromatography over silica using n-hexane/ethyl acetate (99:1 to 0:100) mixtures as eluent to 2,6-disubstituted-5-azaindoles 34 and 35.
Acknowledgments
We thank Professor Regina H. A. Santos from IQSC-USP for the X-ray data collection.
Funding
The authors are grateful for the financial support provided by the S~ao Paulo Research Foundation (Fundac¸~ao de Amparo a Pesquisa do Estado de S~ao Paulo – FAPESP, Grant 2017/ 24821-4, fellowships 2014/19221-0 to M. N. B., 2017/26673-2 to C.H.A.E. and 2016/02392-1 to J.S.R.), the National Council for Scientific and Technological Development (CNPq-306119/2014-5 to H. A. S. and 303207/2017-5 to J. Z. S.) and Coordination for the Improvement of Higher Education Personnel (CAPES for a scholarship to M. J. D. R.).
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