Benzotriazol-1-ylmethanol: An excellent bidentate ligand for the copper/palladium-catalyzed C-N and C-C coupling reaction

An efficient benzotriazole based N,O bidentate ligands for the Cu-catalyzed N-arylation of π-excessive nitrogen heterocycles is described. This ligand accomplishes C-N coupling of N-heterocycles and C-C coupling of boronic acids with a variety of hindered, functionalized aryl/heteroaryl halides under mild reaction conditions in good to excellent yields. Using his ligand C-N and C-C (Suzuki) couplings with bromoarenes could be conducted with less catalyst loading. A wide array of deactivated and hindered aryl halides react cleanly to afford the functionalized biaryl derivatives in high yields.


Introduction
The classical copper-mediated Ullmann reaction has strengthened the research community with the functionalities such as diaryl ethers, diaryl amines and diaryl thio-ethers, owing to their importance as structural motif in a wide range of molecules.However, the harsh reaction conditions and moderate yields give rise to increased demand for new methods to facilitate the synthesis of such compounds. 1,2Among such compounds, N-aryl heterocycles are an important class of compounds because of their significant pharmacological, biological and chemical activities. 3Accordingly, during the last decade, significant advances have been reported in the development of cross-coupling methodology. 2Traditionally, these moieties have been prepared with nucleophilic aromatic substitution or by Ullman type coupling. 1,4However, for N-aryl heterocycles, other methodologies need additional steps to convert aryl halides into the corresponding reagents such as aryllead triacetate, 5a-c arylboronic acids, 5d-f aryl stannanes, 5g-j triphenylbismuths, 5h diaryliodonium salts, 5k aryl siloxanes, 5l and which are limited by the high costs and poor availability of the substrate.Also, in addition, the synthesis of some of these reagents may involve the use of highly toxic materials and unstable reagents.3c Although, there are lot of development in palladium-catalyzed C-N bond forming reactions 6 but the copper catalyzed N-arylations of N-heterocycles with aryl halides promoted by ligands attracted much attention due to its economy and efficiency. 2,6So far, many efficient ligands have been used with copper such as (S)-pyrrolidinylmethylimidazoles, 7 diazabutadiene, 8 2-aminopyrimidine-4, 6diol, 9 1,10-phenanthroline derivatives, 10 diamines, 11 aminoarenethiol, 12 amino acid derivatives, 13 8-hydroxyquinoline, 14 pyrrolidine-2-phosphate, 15 oxime-phosphine oxides, 16 phosphoramidite, 17 N-hydroxymaleimide, 18a acylhydrazone 18b and L-histidine, 19 while various phosphine ligands have been explored in the case of palladium-catalyzed reactions.2f The Pd-catalyzed C-C coupling reaction (Suzuki-Miyuara) also represents one of the most synthetically valuable methods for the synthesis of biaryl derivatives. 20These catalytic systems using different derivatives of indole, benzimidazole, pyrrole and imidazole have been reported.However, very few examples of coupling of aryl halides with different nitrogen heterocycles have been disclosed.The majority of aryl halides investigated to date, already limited in examples, were aryl iodides.All of these methods are useful in their own right, though each suffers a lack of generality.With these requirements in mind, we considered that steric hindrance and strong electron-donation property of the benzotriazole derivatives could create practical catalyst system for the coupling reactions.The benzotriazole moiety has been much explored by the Katritzky group 21 as a synthetic auxiliary in a number of transformations due to its interesting properties.

Figure 1.
Coupling reactions using benzotriazole as a ligand.
Our group has also been utilizing benzotriazole as a catalyst for various transformations. 22Thus, as a part of our ongoing research, we noticed that this air and moisture stable molecule have excellent coordination capability which could be favourable for stabilizing catalytic species and assisting the catalytic cycle (Figure 1).
Using benzotriazole (L1) as ligand, C-N, C-S and C-C coupling with different derivatives of indole, benzimidazole, pyrrole and imidazole and substituted aryl halides have been reported.22a-c Recently, we reported the use of benzotriazole (L1) and benzotriazol-1-yl-methanol (L3) (BtCH2OH) as a ligand in the tandem synthesis of indolo-and pyrrolo-[2,1-a]isoquinolines by the addition of N-heterocycles onto ortho-haloarylalkynes, followed by intramolecular arylation.
In continuation of our ongoing work using benzotriazole as a ligand, herein we are reporting benzotriazol-1-yl-methanol (L3) as a robust and inexpensive ligand for the copper-catalyzed C-N coupling and palladium-catalyzed C-C (Suzuki) coupling reactions.

Results and Discussion
In our initial communication, with utilizing benzotriazole as ligands for copper-catalysis, a number of N-heterocycles were reported to undergo coupling with aryl halide in DMSO as a solvent.In a subsequent, more detailed exploration of the coupling of aryl halides with indoles became apparent that derivatives of benzotriazole were superior to the parent ligand (Figure 2).To search for most optimal catalysts system for the N-arylation, we initiated our investigation with 1.0 mmol indole (1a) and 1.2 equiv of p-bromotoluene (2a) using 5.0 mol % of CuI, 10 mol % of ligand L1 and 2.0 equiv of K-O-tBu in 2.0 mL of DMSO at 25 °C for 12 h, the coupling product 3a was observed in poor yield (Table 1, entry 1).With increasing temperature upto 80 °C, product 3a was obtained in 32% yield (Table 1, entry 2).On further increasing the temperature upto 120 °C, coupling product 3a was obtained in 40% (after 12 h) and 48% yields (after 18 h) respectively (Table 1, entry 3-4).Increasing the catalyst loading from 5 to 10 mol % affprded the coupling product 3a in 58% yield (Table 1, entry 5). a All the reactions were performed using 1.0 mmol of indole 1a, 1.2 equiv of 2a, 2.0 equiv of KO-tBu, catalyst and ligand (L) in 2.0 mL of solvent under nitrogen atmosphere unless otherwise noted.b Isolated yields.c using 2.0 equiv of NaOEt.d Using 2.0 equiv of K3PO4.e Using 2.0 equiv of NaOH.
When the same reaction was continued for a longer time, no significant effect on the yield of the product was observed (Table 1, entry 6).In order to increase the yields and make reaction conditions mild, we investigated some designed N,N-and N,O-bidentate ligands having more donating sites with bulkiness which could create practical catalyst system for the coupling reactions.The use of N,N-bidentate ligand L2 made no considerable improvement on the yield of the coupling product (Table 1, entries 7-8).The use of 10 mol % of the ligand L2 could afford the coupling product in 74% yield (Table 1, entry 9).After obtaining the slight improvement in the yield of the coupling product with N, N-bidentate ligand, we next employed the N, Obidentate ligand L3 , and it was found that ligand L3 afforded the desired coupling product in 90% at 120 °C after 18 h (Table 1, entry 10).When the same reaction was carried out with 5 mol % ligand-catalyst system, thedesired product was obtained in 62% yield (Table 1, entry 11).
Other strong bases like NaOEt, K3PO4, and NaOH, gave inferior results under the same conditions (Table 1, entries 12-14).Amongst different solvents, polar solvents like DMSO, DMF and DMA were found suitable for the reaction and afforded the coupling product in high yield in comparison to the non polar solvents like dioxane and toluene (Table 1, entries 15-18).
Other copper sources like CuCl, CuBr afforded the desired product in comparable yield (Table1, entries 19-20) while Cu2O and Cu(OAc)2 were found to be less effective (Table1, entries 21-22).The commercially available ligand L3 can be readily prepared in a straightforward fashion from the inexpensive starting material benzotriazole and formaldehyde, in a single step with excellent yield, in multigram-scale.
After optimizing the reaction condition for N-arylation, we extend the methodology to more challenging substrate combinations (Table 2).We were delighted to find that the N-arylation of indole and substituted indoles such as 3-methyl and 2-methyl indole with a variety of aryl bromides containing electron-rich o-and p-substituents proceeded smoothly to give the corresponding products in good to excellent yields (Table 2, entries 1-14).When aryl halide bearing electron-withdrawing substituents were reacted with indoles, coupling-products were obtained in comparative yields (Table 2, entries 4, 9-10).Having attained results on the coupling of indoles, we further extended the scope of the reaction on other π-electron-rich nitrogen heterocycles with functionalized aryl bromides.The coupling proceeded smoothly with imidazole, substituted imidazoles and pyrroles and afforded the corresponding N-arylated products in 72-90% yields (Table 2, entries 15-25).In case of carbazoles, significant yields of the products were obtained with substituted aryl halides (Table 2, entries 26-29).We were pleased to find that our catalytic system could tolerate a variety of functional groups such as nitrile and nitro functionality (Table 2, entries 4, 9-10, 20).Besides these arylhalides, Nheterocycles were also coupled with heteroaryl halide 2c efficiently (Table 2, entries 3, 7, 15, 21).The results indicated that the developed protocol worked well with a wide range of Nheterocycles (Table 2).Gratifyingly, the hindered substrate also underwent N-arylation smoothly in good yields.A plausible catalytic cycle for the formation of N-aryl heterocycles based on the previously reported mechanism is shown in Scheme 1. 2,4 Presumably, CuI and ligand L3 (BtCH2OH) generates the copper (I) complex A, which upon oxidative addition with aryl halides results in the formation of intermediate B. Copper complex C is formed by the attack of nucleophile (Nheterocycle) in the presence of base.Reductive elimination of C affords N-arylated product 3 and regenerates copper complex A. Study of the accuracy of this mechanism is in progress.

Conclusions
In summary, we have described benzotriazol-1-yl-methanol (L3) as an efficient N, O-bidentate ligand for the C-N and Suzuki coupling reaction.The ligand efficiently catalyzed the coupling of π-excessive nitrogen heterocycles with variety of aryl halides under copper-catalysis.Efficasy of the ligand was sucessfully extended for the palladium-catalyzed Suzuki coupling reaction.The C-C coupling of variety of boronic acids with various aryl halides has been accomplished under mild reaction conditions using low catalyst loading.The designed catalyst for the C-N and C-C coupling reaction tolerates variety of functional groups and afforded the coupling products in good to excellent yield.Mild reaction conditions, low cost of the catalyst and high yield of the coupling products, increasing the overall utility of this process.The catalytic system is expected to find application in general, and in the synthesis of various biologically important heterocyclic compounds.

Experimental Section
General.All reagents used were AR grade.Melting points were determined using a Buchi B-540 melting point apparatus. 1H (300 MHz), and 13 C NMR (75 MHz) spectra were recorded on a Bruker 300 NMR spectrometer and 1 H (400 MHz), and 13 C NMR (100 MHz) was recorded on Jeol 400 NMR spectrometer in CDCl3 (with TMS for 1 H and chloroform-d for 13 C as internal references) unless otherwise stated.Column chromatography was performed on silica gel (100-200 mesh).The reactions were monitored by thin-layer chromatography (TLC) using aluminum sheets with silica gel 60 F254 (Merck).High resolution mass spectra were recorded on a double focusing magnetic sector mass spectrometer.
General procedure for the synthesis of BtCH2Bt, L2.The CuI (1.0 mol %) was added to a 50 mL round bottom flask containing the BtCH2Cl (1.00 mmol), benzotriazole (1.0 mmol) and potassium tert-butoxide (1.6 equiv) in 5 mL of DMSO.The flask was sealed with a cap containing a PTFE septum.The mixture was then heated at 110 ˚C for 1 h.The reaction mixture was washed with ethyl acetate and water.The organic layer was then washed with brine and dried over Na2SO4.The solvent was removed in vacuo, and the crude residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent.General procedure for the synthesis of N-aryl heterocycles (3a-3ac).The CuI (10 mol %) and ligand L3 (10 mol %), was added to a 5ml round bottom flask containing the aryl halide 2 (1.0 mmol), N-heterocycles 1 (1.0 mmol) and potassium tert-butoxide (2.0 equiv.) in 1.5 ml of DMSO.The flask was sealed with a cap containing a PTFE septum.The mixture was then heated at 120 °C until the aryl halides were consumed, as determined by TLC.The reaction mixture was washed with ethyl acetate and water.The organic layer was then washed with brine and dried over Na2SO4.The solvent was removed in vacuo, and the crude residue was purified by column chromatography on silica gel using hexanes or a mixture of hexane and ethylacetate as eluent.Narylheterocycles were isolated in the yields reported in Table 2

Table 1 .
Optimization of the reaction condition for the N-arylation a

Table 2 .
Coupling of aryl and heteroaryl bromides with N-heterocycles using CuI and ligand L3 a

Table 3 .
Suzuki reaction with different boronic acids a