C−H Cyanation of 6‐Ring N‐Containing Heteroaromatics

Abstract Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.

The nitrile group is an important chemical motif commonly found in molecules throughout chemistry,b iology,a nd medicine. In chemistry, it is av ersatile intermediate that can act as precursor to an umber of functional groups, such as amides, amines,a nd carboxylic acids, and to five-ands ix-membered heterocycles through cycloaddition or condensation reactions. [1] In medicine, the polarity,d irectionality,a nd low molecular weight of the nitrile moiety make it as ubstituent of choicei nS AR studies, both as ad iverse isostere capable of precise hydrogen bonding, and as ab eneficial modifier of physicochemical properties. [2] As ar esult of these properties, it is found attached to N-containingh eterocycles in ah ost of important pharmaceuticals including the tyrosine kinasei nhibitor bosutinib (1), xanthine oxidase inhibitor topiroxostat (2), and MIV-150 (3), an on-nucleoside reverse transcriptasei nhibitor (Scheme 1a). Owing to their synthetic relevance and prevalence in biologically active heterocyclic compounds, there is demand forn ew and effective methods to install this important functional group. To this end, recent efforts have largely focused on thed iscoveryo fm etal-catalyzedc ouplingp rocedures, [3] as well as the invention of direct CÀHa ctivation protocols. [4] Despitet he many advances in the field, we recognized that the development of ac omplementary and direct CÀHc yanation protocol that was general to many classes of N-containingh eterocycles would likely find application in library generation and target synthesis, and herein, we report our findings.
Our plan was to exploit the nucleophilicity of the N-atom contained within various 6-ring heterocycles as ag enerala ctivation mode to introducet he nitrile moiety.F ollowing initial nucleophilic addition to as uitable electrophilic species( such as triflic anhydride), the heteroaromatic ring would be activated towards subsequent nucleophilic attack of cyanideand concomitantb ase mediated elimination of trifluoromethanesulfinate anion could generatet he cyanated heteroaromatic ring (Scheme 1b). [5] Thea ctivation of N-containing heteroaromatic speciesb yr eaction of various electrophiles at nitrogen has previously been deployed to effect ar ange of transformations, and examples of carbon-, phosphorus-, and sulfur-based activating groups have been reported. [6] We hoped to build on this approach to develop am ild and convenient one-pot cyanation protocol that would be both general to many 6-ring Ncontaining heterocyclesa nd useful for late-stage functionalization of drug-like molecules.
2-Phenylpyridine (4)w as chosen as am odel substrate to enable us to study reactivity andp roduct isomeric ratio distribution in the plannedt hree-stage, one-pot cyanation protocol. An initial survey of variables, such as electrophilica ctivator,c yanide source,and base was performed. Inspired by the work of Corey,t riflic anhydride (Tf 2 O) was found to be uniquely effective as an activator, [7] whereas trimethylsilyl cyanide was identified as the most convenient and effective cyanides ource for productiveC ÀCb ond formation. Following full consumption of the activatedp yridiniums pecies, addition of N-methylmorpholine (NMM) ensuredc onversion to the final, heteroaromatic product. By using this combination of reagents, nitrile 5 was produced as am ixture of isomers in moderate yield, but importantly in the absence of any non-aromatized intermediates ( Table 1, entry 1). The timing and temperature of the different steps in the procedure were found to be importantf or reaction yield:d elayinga ddition of base (entry 2) significantly improvedp roduction of 5,w ith furtheri mprovement afforded by warmingt he first step of the reactionf rom À78 8Ct or oom temperature (entry 3). Switching to higher boiling solvents allowed us to assess the effect of temperature in the rearomatization step (entries 4, 5a nd 6), and CHCl 3 at 60 8Cw as identified as optimal, with high yield retained upon scale up (entry 7). It is noteworthy that the ratio of 5/5' remained essentially constantt hroughout our studies despite temperature and solvent variation,w ith as light preference for cyanation in the 4-position over the 6-position (5/5'; % 60:40). Products of cyanation at the 2-, 3-, or 5-position of 4 were not observed.
With an optimized general procedure in hand, the substrate scope of the cyanation was investigated (Scheme 2). Pyridines are extremelyw idespread motifs in bioactive compounds, both in nature andi nt he clinic, and as such methods for their functionalization are highly sought after.W ew ere delighted to see that this practical, one-pot protocol was effective across a diverser ange of heteroaromatic ring systems, giving aromatic cyanated products in up to 96 %y ield (Scheme 2a). Substrates possessing aromatic (5, 6)a nd electron-withdrawing (8-13) substituents gave excellenty ields, with no competitive addition to the ester group in 11 observed.H alide (14, 15)a nd alkyl (7,(16)(17)(18)(19)s ubstituentsw ere also well-tolerated in various positions. The alkyl substituents demonstrate compatibility with electron-donatingg roups, whereas the halopyridines are particularly noteworthy for their potential for further downstream orthogonal transformations. Of the pyridines surveyed, substitution was generally favored att he 4-position, with minor,s eparableq uantities of other isomersp roduced in some cases. The isolation of these additional compounds could be valuablea sf urther analogues for inclusioni nS AR studies. Quinolinesa nd isoquinolines represent an important class of ring system in medicinal chemistry and accordingly were attractive substrates to investigate. [8] Pleasingly,c yanated quinolines 20-22 were produced in excellent yields (Scheme 2b), with substitution att he 2-position predominating (a reversal of the selectivity observed forp yridines). Isoquinolines were also highly effectives ubstrates yielding fully rearomatized 1-substitutedn itriles 23 and 24 as single isomers. Diazines (pyridazine, pyrimidine, and pyrazine) represent ad iversec lass of heterocycle where the presence of the second nitrogen atom in the sixmembered ring provides electronically distinct examples;i ti s thus not unsurprising that no single reported cyanation procedure is applicable to members of each class. However,o ur protocol provedt ob es uccessful across ad iverse range, with cyanated pyridazine (25-27, 34), pyrimidine (28-30, 35), and pyrazine (31-33)e xamples produced in moderate to excellent yields (Scheme 2c). Bidentateligandsare ubiquitous in organometallicc hemistry,a nd new methods to modify and tune them are in constant demand. We observed straightforward cyanation of 36-38,w ith only traces of di-cyanated products observed for 36,a llowing facile synthesis of useful unsymmetrical cyanated ligands.
To furtherd emonstrate the general applicabilityo fo ur methodology,w eexamined more complex heterocyclic structures, which are commonly found in commercial pharmaceuticals and agrochemicals (Scheme 2e). [8] As eries of cyanated heterocycles were produced (39-51), with excellent yields obtained in the presence of halides( 40, 42, 44, 46, 47), and non- strates, ac oncept that is becoming increasingly popular (Scheme 3). [9,10] By using the standard protocol, we were able to cyanate abiraterone acetate (52,atreatment for prostate cancer) in excellent yield with three different analogues produced. Protected erlotinib (53,at reatment for lung and pancreatic cancer) gave ag ood yield of as ingle isomer,w hereas mirtazapine (54,a na ntidepressant) gave am oderate yield of the 4-CN derivative in the presenceo fe lectron-donating groups on the pyridine moiety.Q uininew as included on the World Health Organization's List of Essential Medicines for its important antimalarial properties;f ollowing O-methylation,i t was cyanated in good yield to provide 55 as as ingle regioisomer.A sw ell as further extendingt he scope, the latter two examplesd emonstrate the tolerance of the method to basic amine functionality,a lthoughw eh ypothesize that competitive and reversiblec oordination of these groups to the activator gave low conversion in the case of 54.
We performed DFT (M06-2X/def2-SVP) calculations to understand the site-selectivity of cyanation in terms of each heterocycle's electronic structure. [11] We found that the condensed Fukui index, f + (r), is ag ood quantitative predictor for the position(s) of attack and the level of selectivity observed. [12] Al arge value of f + (r)f or ag iven carbon atom is associated with a large change in chemical potential when electron density is added-it indicates greater susceptibility towards nucleophilic attack. Functionalization at the most electrophilic position(s) of the N-triflyl cation is consistent with irreversible, selectivity-determining nucleophilic attack by cyanide. For 29 of the substrates studied experimentally,t he largest Fukui index predicts the major site of cyanation 23 times;i nt he other six cases, cyanation occurs at the second most electrophilicp osition. This is attributable to the absence of steric effects in this electronic model (see Figures S2 andS 3i nt he Supporting Information). Differences in atomicF ukui indicesm atch the experimental regioselectivity values well (particularly for pyridines and quinolines/isoquinolines; Figure 1).
We also computed 13 CNMR chemical shifts of the activated pyridines.T he most deshielded nucleus matches the site of nucleophilic addition observed in the major (or single) regioiso-mer formed ( Figure S4 in the Supporting Information). This is consistentw ith the results obtained by using condensed Fukui indices and supports the mechanistic interpretation above. Chemical shifts of other heterocycles do not match well with the observed sites of addition (unlike the Fukui index), presumably due to magnetic effects unrelated to chemical reactivity. Therefore, we focus on the use of Fukui indices, whichc an be employed by end-users of this methodology to predict site-selectivityi nl ate-stage heterocycle cyanation. These calculations consider the substrate only and do not requirem ore laborious transition state modelling.
In conclusion, we have developedadirect and general onepot protocol that enables CÀHc yanation of aw ide range of 6ring N-containingh eterocycles. The procedure is easy to perform andi ss uitable forl ate stage functionalization of drug derivatives and advanced intermediates. Work to furthere xpand the generalityo ft his CÀHf unctionalization approachi so ngoing, and the resultswill be reported in due course.

Experimental Section
Triflic anhydride (1.2 equiv) was added dropwise to a0 .1 m solution of the substrate (1.0 equiv) in anhydrous CHCl 3 in av ial capped with as eptum at room temperature under an atmosphere of argon or nitrogen. The resulting solution was stirred for 1h,t hen trimethylsilyl cyanide (5.0 equiv) was added. The septum was exchanged for as crew cap, and the mixture was stirred at 60 8Cf or 3h.T he reaction vessel was removed from the heating source, and N-methylmorpholine (1.3 equiv) was added quickly before the vial was resealed. The mixture was then stirred at 60 8Cf or af urther 17 hb efore cooling to room temperature and quenching with saturated NaHCO 3 solution. The phases were separated, and the organic phase was extracted twice with CH 2 Cl 2 .The combined organic phase was dried (MgSO 4 )a nd concentrated in vacuo. The crude residue was purified by silica flash column chromatography. of Oxford, for generous financial support of this work. We are also grateful to Heyao Shi for assistance with characterization.