Synthesis of Aromatic nitriles using CuSCN under Pd-catalyzed conditions

A very recent report by Cheng and co-workers about cyanation of aryl halides and borons using CuSCN interested me.

 

Nitrile group is very important in organic synthesis because it is a very good handle for the easy functional group conversion intro tetrazoles and other carboxylic deri. Like aldehydes, amines, amandine and most importantly amides. Also, nitrile group is present as a key feature in various pharmaceutically important molecules and drugs like letrazole, Febuxostat, Bicalutamide, Fedrozole to name the few.

There are various methods for intodcuign nitrile group on an aromatic ring. This might be done by conversion of amides or protected amindes, from aldehydes via hydroxylamine imines etc. The most sought-after approach is by coupling of various alkali cyanides like CuCN, NaCN, Zn(CN)2 and KCN with aryl halides under transition metal catalyzed conditions. Bellar and co-workers reviewed the work carried out from 2000 until 2010. The major drawback of these approaches is the toxic and hazardous nature of the cyanides.

In recent times, reaction conditions were developed using various other non-hazardous and less-toxic cyanating reagents like K4[Fe(CN)6] (My Blog), K3[Fe(CN)6], BnSCN, acetonitrile, cyanohydrines (though required cyanide reagents to prepare these reagents).

An overview of an article by Cheng and cor-workders is presented here. The authors chose p-iodoanisole for the reaction condition optimization for the cyanation method using CuSCN. After certain number of experimentations they found –

• PdCl2(dppe) as a best catalyst
• Formic acid as an acid: “Acid was believed to be essential as in the abs. of acid the reaction is very sluggish“. Howver, in the abs. of an acid, prolonged reaction time gave good conversion.
• Sodium acetate as an additive: Use of other carboxylates reduced the yield to ~50%.
• DMSO/Water (8:1) as solvent combination: Reduced DMSO content decreased the yield and use of other solvent like DMF also reduced the yield whereas “no reaction” when toluene used.

The optimized conditions applied for the functional group tolerance study and found that free phenolic OH, Free amines, methoxy, benzyloxy, acetamido were very well tolerated to give good yield of the nitrile deri. The effect of EWG and ERG on aryl iodides were also studied and found that iodides with EWG has slightly lower yield compared to iododies having ERGs. Also, ortho-substitution and multi-substitutions had no effect on yield of the product. However, the alkyl iodides failed to provide the cyanated product.

The reaction was carried out on 10 mmol scale using p-iodoanisole and the product was isolated in 73% yield after elongated time suggests the practicality of the reaction.

Aryl bromides and borons gave moderate yield of the product. In aryl borons, boronic acids and boronic esters were tested.

The substances carrying other XCN (X = O or S, like KOCN or KSCN ) were tested for the possible sourcing of “CN”. However, the missing “Cu” did not give any conversion product. When CuI added, the product was isolated in moderate yields. The organic thiocyantes like methylthicyante and 1-methyl-4-thiocyantobenzene gave moderate yield whereas isothiocyantes failed to provide the product.

Benzamides like benzenethioamides and benzmide were tested under the condtion and found that thiobenzamide gave moderate yield whereas benzamide failed.

The authors provided a plausible mechanism involving Oxidation (reduction of Pd(II) to Pd(0) by additive), Carbopalladation and isomerization. However, the mechanism does not cover the role of Cu. They suggested a possible role of Cu.

Overall, a very interesting and important article in the area of transition-metal catalyzed cyanation reaction without using hazardous cyanides. Considering the importance of cyanation in organic synthesis, I am expecting that sooner, another better and milder reaction conditions would be reported.

The only drawback of the reported reaction conditions is the usage of larger amount of iodoarenes (1.25 equi.) as compared to CuSCN. This would definitely affect the scale-up approach considering the cost involved in the preparation of aryliodides. However, this could be compensated with the less-hazardous reagent and reduced cost incurred for the decomposition and treatment of waste generated by hazardous reagents.

Interestingly, Chang and co-workers used a combination of DMF/NH3 as a “CN source” for the direct cyanation of indole. (Tempting to right the Next blog ).

A Novel Diazaspirocyclic System - 1,5-Diazaspiro[2.3]hexanes

Kimpe and co-workers from Ghent University, Belgium and Kaunas University of Technology, Lithuania reported an unknown and intersting spirocyclic diamine compound 1,5-diazaspiro[2.3]hexanes (Fig. 1). Their approach to the synthesis of the target spiro-compound began with ethyl 2-(bromomethyl)-1-tosylaziridine-2-carboxylate (marked in red in scheme 1). This key intermediate was prepared from the hydroxy deri. 2 in overall 79% yield following the reaction sequence as depicted in scheme 1 as against the reported 17% yield from corresponding bromo compound 3.

First the hydroxy deri. was treated under Mitsunobu condition with BocNHTs to deliver the product in 91% yield. The Boc-group is derprotected and the tosyl deri. thus obtained was brominated to give the dibromo compoundd that was cyclized by treating with pot. Carbonate in acetonitrile to give the key intermediate. 

After condition optimziation, the key intermediate was further reduced using LAH at -78 °C to deliver the corresponding aldehyde which was treated with various amines to give respective imines. This imines when reduced with sodium borohydride, an unexpcted rearraged product was isolated in 80-90 yield and the same were cyclized after treatment with potasium carbonate to give the protected targeted spirocyclic diamine derivatives. The aurthors tried deprotection of strained spirocyclic compound and succeeded in the isolation of the free amine compound without ring-opening. The free amine was fully characterized and the analytical data supported the structure. However, the authors failed to get the analytically pure amino-compd via column purification or the oxalate salt formation.

Overall, a very good synthesis has been reported for the preparation of highly strained spirocylic diamine compounds with excellent yields at each stage. 

This report will deinitely boost the confidence of synthetic organic chemists to prepare and synthesise various strained diamino derivatives.

New Quinoxalines Synthesis

Quinoxalines are class of compounds important as core for various biological activities. The general methodology involves coupling or condensation of o-phenylenediamines with diketones. 

Recently, Baohua Chen and co-workers reported interesting synthesis of Cu-catalyzed quinoxalines synthesis from nitroolefins and o-phenylenediamines.

In the optimization study, catalysts including CuBr2, Cu(OAc)2, CuO were screened under various conditions of solvents and temperature and (E)-(2-nitroprop-1-en-1-yl)benzene

and o-phenylenediamine were chosen as model substrates.  The best results were obtained using 10 mol% of CuBr2 as catalyst in ethanol as a solvent at 110 °C, to give the 90% yield of desired quinoxaline deri. after column purification. Later, the optimized condition was extended for the substrate suitability reactions to give the yield of desired products in moderate to good yields depending on the EWG and EDG on diamine part or nitroolefin part.

The group has proposed a mechanism were the nitro-group plays a key role in the reaction.

Overall, a new, different and good process for the synthesis of quinoxaline deri. considering the availability and easier acess to nitroolefins by one step synthesis and o-phenylenediamines.

Novel Preparation of Benzimidazole using amidine hydrochlorides

There are various methods available for the synthesis of diversely substituted benzimidazoles. The one of the method is condesnsation of o-phenylenediamines with aldehydes or acids or amides under oxidative conditions and metal-catalyzed reactions.  Another known route is the coupling of o-haloanilines with aldehydes under Cu-catalyzed conditions.

There is interesting report by Peng and co-workers about the Cu-catalyzed synthesis of library of benzimidazole compounds in water.  They used (o-haloaryl)benzamidine derivatives as a key RM, Cu2O (5 mol%) as catalyst, DMEDA (10 mol%) as ligand and K2CO3 (2.0 equiv.) as a base.

I came across a very recent an another interesting report by Qu Y. et al. for the preparation of benzimidazole derivatives where amidine hydrochlorides or aryl amidines were coupled with o-haloanilines under Cu-catalyzed conditions. DMEDA was used a lignd and Cesium carbonate as a base.  Also, combinations of various ligands and base were screened to get the best combination for the highest yield when aryl amidines were used as a coupling partner. The only draw-back of the reaction could be the higher temperature (140-145 °C) and the best part of this methodology is the higher yield (upto 90%).

Practical one-pot conversion of aryl bromides into aromatic nitriles without Cyanide reagent

Most of the aromatic cyanation reactions involved use of Hazardous Cyanide reagents - Sodium Cyanide, Potassium Cyanide, Zinc cyanide etc under the Pd-catalyzed conditions. I came across an recent article by Ishii Genki et al for the conversion of aromatic bromides into aromatic nitriles without previous metal catalysts. The

In their findings, firstly they treated aromatic bromide (reactive ones) with Mg-turning and subsequently with DMF.  The complex/reactive intermediate thus obtained was treated with aq. NH3 and molecular iodine to deliver the corresponding aromatic nitriles in very good yields. Howver, for the weakly reactive bromides, they used isopropylmagnesium chloride·lithium chhloride complex to complete the conversion.

The same methodolgy has been extended for the conversion of β-bromostyrenes into aromatic cinnamonitriles.