Ruthenium-catalyzed ortho alkenylation of aromatic nitriles with activated alkenes via C–H bond activation †

The ruthenium-catalyzed ortho alkenylation of substituted aromatic and heteroaromatic nitriles with activated alkenes providing ortho alkenylated aromatic and heteroaromatic nitriles in a highly regio-and stereoselective manner is described.

Selective transformation of the C-H bond of organic moieties into C-C and C-heteroatom bond catalyzed by transition metal complexes via C-H bond activation is one of the most versatile and well-acknowledged methods in organic synthesis. 1This transformation has gained tremendous attention in chemical and pharmaceutical industries, because it provides step-and atom-economical routes to synthesize useful organic molecules from the readily available starting materials. 2Particularly, a transition metal-catalyzed oxidative cross-coupling of heteroatom substituted aromatics with alkenes has proven to be a highly efficient route to synthesize disubstituted alkenes without having any prefunctionalized starting materials in a highly regio-and stereoselective manner. 3The selectivity of the C-H bond of organic moieties can be controlled by using suitable directing groups.In most cases, the lone pair of electrons of nitrogen or oxygen atom of the directing groups coordinate with the metal complex through s-coordination and activate the C-H bond of organic moieties selectively (Fig. 1, eqn (1)). 4,5The search for new variants to activate the C-H bond of aromatics is very important to expand the synthetic scope of the alkenylation reaction.Very recently, Cheng's group disclosed an alkene assisted alkenylation of aromatics with activated alkenes in the presence of a palladium catalyst via an unusual carbon-carbon p-bond coordination (Fig. 1, eqn (2)). 6itrile is a versatile functional group which can be efficiently used for various organic transformations. 7In addition, nitrile group containing organic molecules are used as pharmaceuticals, pesticides and dyes. 8The strong electron withdrawing nature and better hydrogen bond accepting properties of the nitrile group allow it to be used widely in designing drug molecules.0][11] It is known that the lone pair of electrons of the nitrogen atom of the nitrile group of benzonitrile coordinate with the metal complex through s-coordination, and this process leads to the formation of a linear metal complex. 9Also, a less likely, CRN p-bond of benzonitrile coordinates with the metal, yielding the p-coordinated metal complexes. 10Recently, by employing the s-coordination of the nitrile moiety, the meta C-H bond of aromatics could be activated efficiently for the alkenylation reaction (Fig. 2, eqn ( 1)). 11To date, there is no report on the CRN p-bond assisted alkenylation at the ortho position of aromatic nitriles with alkenes due to the difficulty in coordination of the p-bond of CRN with metals.
Our ongoing interest in the finding of a new C-H bond transformation reaction prompted us to explore the possibility of CRN p-bond assisted ortho alkenylation of substituted aromatic  nitriles with alkenes.Herein, we wish to report for the first time nitrile as a p-bond coordinating group for the ortho alkenylation of aromatic and heteroaromatic nitriles with activated alkenes in the presence of a ruthenium catalyst (Fig. 2, eqn ( 2)).The alkenylation reaction was compatible with functional group substituted aromatic nitriles.Later, the ortho alkenylated aromatic nitrile was converted into a chiral phthalide in the presence of AD-mix-b.By employing nitrile as a directing group, arylation was performed at the alkene C-H bond of the ortho alkenylated aromatic nitriles with aromatic iodides in the presence of a Pd catalyst.
Initially, the ruthenium-catalyzed alkenylation reaction was examined using benzonitrile (1a) and n-butyl acrylate (2a) (Scheme 1).It is expected that the nitrogen atom of 1a prefers to coordinate with the metal via the lone pair electrons rather than p-coordination.However, for successful ortho C-H bond activation, p-coordination of nitrile is crucial.Meanwhile, a metal acetate base is needed for the deprotonation of the C-H bond of weak coordinating group substituted aromatics.Thus, a combination of the ruthenium catalyst and metal acetate having a Lewis acidic nature was selected.The main idea behind the selection of the Lewis acidic metal acetate is that the lone pair of nitrogen of the nitrile moiety would coordinate with the Lewis acid prior to the ruthenium catalyst reaction and block the corresponding site.Therefore, a possibility is created for the p-bond coordination of the nitrile moiety with the ruthenium catalyst and initiates the C-H bond activation.With this idea, a combination of [{RuCl 2 ( p-cymene)} 2 ] (5 mol%), AgSbF 6 (20 mol%) and Cu(OAc) 2 ÁH 2 O (2.0 equiv.) was used for the reaction.As a nitrile is a weak coordinating group, AgSbF 6 was used to generate a cationic ruthenium species for the C-H bond reaction.However, in the reaction, hydration takes place at the nitrile group and only benzamide (3a) was observed.If the same reaction is run for a long time, a cyclic isoindolin-1-one derivative was observed. 12ater, the reaction was examined using various Lewis acids such as Co(OAc) 2 , Mn(OAc) 2 , Ag 2 O, AgOAc, Ag 2 CO 3 , Ag(CF 3 CO 2 ) and Fe(OAc) 2 (2.0 equiv.).Very interestingly, in AgOAc, the ortho C-H bond activation takes place selectively and further reaction with n-butyl acrylate (2a) provides the ortho alkenylated benzonitrile 4aa in 75% isolated yield.In the reaction, benzamide 3a was observed only in a very minor 3% yield.In other silver salts such as Ag 2 O, Ag 2 CO 3 and Ag(CF 3 CO 2 ), the product 4aa was observed in 45%, 49% and 61% yields.Benzamide 3a was observed in 25%, 19% and 14% yields, respectively.But, in Co(OAc) 2 and Mn(OAc) 2 , benzamide 3a was observed in more than 45% and 51% yields and product 4aa was observed in 15% and 19% yields, respectively.Meanwhile, the acidic solvent AcOH is crucial for the reaction.Other solvents such as 1,2-dichloroethane, THF, 1,4-dioxane, DMF, toluene and CF 3 COOH were not suitable for the reaction.However, in iso-PrOH, the product 4aa was observed only in 10% yield without benzamide 3a formation.
The alkenylation reaction was also examined with disubstituted benzonitriles (1m-o).2,3-Dimethoxy (1m) and 3,4-dimethoxy (1n) benzonitriles reacted with 2a or 2b, affording ortho alkenylated benzonitriles 4ma and 4nb in moderate 38% and 29% yields, respectively (entries 11 and 12).In the substrate 1n, the C-H bond activation takes place at the less hindered ortho C6-H bond.In contrast, a sterically hindered ortho C-H bond of piperonylonitrile (1o) reacted with 2a or 2g providing products 4oa and 4og in 52% and 48% yields, respectively (entries 13 and 14).The present result clearly reveals that a strong electron donating OMe group as the substituent on the benzonitrile decreases the yield of the product, and SMe, halogens and electron withdrawing substituents on the benzonitrile moderately increases the yield.In unsubstituted benzonitrile and 2-naphthonitrile substrates, good yields were observed.
A substituted ortho alkenyl aromatic nitrile is a versatile synthetic intermediate which can be used for synthesizing various useful organic molecules. 7,8ortho Alkenyl benzonitrile 4ab underwent an intramolecular cyclization in the presence of AD-mix-b, yielding a chiral phthalide 6 in 93% yield in 99 ee% (Scheme 4). 13y using AD-mix-a, the reverse chiral phthalide derivative can be prepared in a highly enantioselective manner. 13Further,  A possible reaction mechanism is proposed to account for the present alkenylation reaction in Scheme 5.It is strongly believed that first the lone electron pair of the nitrogen atom of benzonitrile 1 coordinates with the Lewis acid AgOAc, providing a linear benzonitrile silver complex 9.A similar observation is strongly supported by DFT calculations. 14 To support the hypothesis that ortho C-H bond cleavage of 9 is a reversible and rate determining process, the reaction of 1b was carried out in the presence of CD 3 COOD under similar reaction conditions.In this reaction, the product D-1b was observed in 40% yield, in which 40% of deuterium incorporation was observed at both C-1 as well as C-3 carbons of 1b.
In conclusion, we have demonstrated a ruthenium-catalyzed CRN p-bond assisted ortho alkenylation of substituted aromatic and heteroaromatic nitriles with activated alkenes providing ortho alkenylated aromatic and heteroaromatic nitriles in good to moderate yields in a highly regio-and stereoselective manner.
We thank the CSIR (02(0179)/14/EMR-II), India, for the support of this research.M.C.R. thanks the CSIR for a fellowship.
as a directing group, arylation was performed at the alkene C-H bond of 4ab and 4aa with 4-iodo nitrobenzene (7) in the presence of Pd(OAc) 2 and Ag 2 O in CF 3 COOH at 110 1C for 12 h, giving trisubstituted alkenes 8a and 8b in 82% and 87% yields in a 10 : 1 Z : E ratio.
Subsequently, AgSbF 6 likely removes the Cl À ligand from the [{RuCl 2 ( p-cymene)} 2 ] complex, providing a cationic ruthenium species 10.Coordination of the CRN p-bond of 9 into the ruthenium species10 followed by ortho-metalation provides intermediate 11.Coordinative insertion of activated alkene 2 into the Ru-carbon bond of intermediate 11 affords intermediate 12. Subsequent b-hydride elimination of intermediate 12 in the presence of AgOAc gives product 4 and regenerates the active ruthenium species 10.