Copper-Catalyzed Cyanopropylation of Activated Alkenes

Abstract A practical copper-catalyzed alkylarylation of activated alkenes with azobisisobutyronitrile (AIBN) and beyond has been developed, in which incorporation of 3o nitrile moiety into an oxindole scaffold proceeded smoothly through cascade radical addition/C(sp2)-H cyclization. The use of readily available AIBN as radical source and inexpensive CuI as catalyst, as well as broad substrate scope and the simplicity of operation and handling, make this protocol a highly attractive approach to oxindoles bearing 3o nitrile moiety. GRAPHICAL ABSTRACT


INTRODUCTION
The efficient construction of multiple C-C bonds in a cascade process is a perennial topic of interest for organic chemists. [1] In this regards, inexpensive metalcatalyzed radical biscarbonation of alkenes to form a dual C-C bond simultaneously has attracted increasing attention, where various aryl=alkyl radical precursors, such as aryl diazonium salts, carbazates, diaryliodonium salts, CF 3 reagents, C-H reactants, etc., were successfully utilized to initiate the tandem addition=interception process. [2] Aliphatic azo compound (e.g., azobisisobutyronitrile [AIBN] and diethyl acetylenedicarboxylate [DEAD]), a type of widespread reagent in organic and polymer synthesis, decomposes softly to give radical species, which could be used for C-H functionalization [Fig. 1,Eq. (1)]. [3] Therefore, we envisage that the difunctionalization of alkenes with AIBN, by judicious design, makes it possible to give oxindoles with a tertiary-alkyl nitrile moiety via a tandem radical addition=C(sp 2 )-H cyclization process [Fig. 1,Eq. (2)]. Remarkably, AIBN in combination with Bu 3 SnH was commonly used as a initiator for radical addition of alkyl halide onto alkene, [4] whereas direct addition of electrophilic radical produced by AIBN onto the double bond of an electron-poor alkene (e.g., acrylamides) was usually slow and thus less commonly encountered. [4c] Moreover, despite of significant advances in alkene difunctionalization research (including Heck-type and free radical reactions), the direct construction of afunctionalized quaternary carbon center via simple alkene biscarbonation step remains rare and challenging. [5] It can be expected that this strategy would undoubtedly represent a highly interesting approach to oxindole scaffold with an a-cyano quaternary carbon center. Unfortunately, this alkylarylation of activated alkenes with AIBN, to our best knowledge, has not been reported.
It had been known that oxindoles are common structural motifs in pharmaceutical agents and natural products. [6] Given that cyano-containing molecules exhibit important functions in materials, synthetic intermediates, and pharmaceuticals, the incorporation of cyano-containing group into oxindole scaffold via C-H activation of acetonitrile has attracted increasing interests recently. [7] For example, Liu and coworkers [7a] reported a pioneering Pd-catalyzed oxidative alkylarylation of alkene with the aid of stoichiometric AgF in the early stage [Eq. (1)]. Just recently, You
and coworkers [7b] reported an elegant copper-catalyzed oxidative radical cyanomethylation of activated alkenes using a catalytic combination of CuCl and t BuOO t Bu [Eq. (2)]. Regardless of substantial achievements realized through the a-C sp3 -H activation of acetonitrile for this purpose, apparent limitation remains: (1) requirement of either the combination of expensive Pd=N-Ligand combination with stoichiometric AgF or an elevated temperature (≥120°C) [7c] and (2) in general inefficiency for the introduction of 3 o nitrile moiety via a-C(sp 3 )-H functionalization of 3 o alkyl nitrile (possibly due to steric hindrance or lower reactivity of a-C sp3 -H bond of 3 o nitriles). [7a] Remarkably, oxindoles bearing an a-cyano quaternary carbon center are important synthetic precursor for many pharmaceutically interesting scaffolds. [8] As a continuation of our interest in oxindole synthesis, [9] we herein want to demonstrate an alternative AIBN-mediated cyanopropylation reaction of N-arylacrylamides by copper catalysis, which allows for the preparation of rarereported oxindoles bearing 3 o nitrile moiety under rather mild conditions [Eq. (3)].

RESULTS AND DISCUSSION
Initially, the reaction between N-methyl-N-phenylacrylamide 1a and AIBN was employed as the model reaction to explore the optimal conditions to prepare oxindoles with 3 o alkyl nitrile moiety (Table 1, for more detail see the electrospray ionization [ESI]). Delightedly, we observed the formation of the desired cyclization product 3a in a 23% yield when the reaction was conducted in the absence of metal catalyst (Table 1, entry 1). Encouraged by this result, various inexpensive copper(I) and iron(II) salts were subsequently used as the catalyst to enhance the yield (entries 2-8). Among the metals examined, CuI turned out to be the most effective one, and afforded 3a in a yield of 78% when using di-tert-butyl peroxide (DTBP) as an oxidant (entry 4). In this process, adding an oxidant improved the reaction and using DTBP is optimal. Other oxidants, such as tert-butyl hydroperoxide (TBHP), K 2 S 2 O 8 , PhI (OAc) 2 , and PhI(OTF) 2 , resulted in unparalleled yields (entries 9-13). Sequential screening of solvents revealed CH 3 CN as the best choice (entries 14-16). The optimal temperature effect for the current reaction was 80°C (entries 17 and 18).
After the standard reaction conditions had been established, we set out to investigate the scope of N-arylacrylamides in the difunctionalization reaction using AIBN as a-cyano alkyl radical source (Scheme 1). Initial screening revealed that N-substituents of acrylamides had obvious effects on the reaction. For example, N-arylarylamides with a benzyl or ethyl group on the N-atom were found to be well compatible with the reaction conditions, whereas unprotected N-arylacrylamide (R 2 ¼ H) was less efficient in the cyclization (products 3b, 3c, and 3d). Next, we embarked upon investigating the substitution effect on the N-aryl moiety in the reaction. Gratifyingly, a wide array of substituents including Me, MeO, Cl, F, and CF 3 at the 4-, 3-, or 2-position of the aromatic ring displayed good reactivity, and the reactive order is poor electron-withdrawing and electron donating groups > strong electron-withdrawing groups (products 3e-o). Notably, the halo groups, such as Cl and F on the 3-or 4-position of the N-aryl moiety, were intact in the difunctionalization process, whereas bromo substituent at 2-position was very reactive and lead to many unidentified by-products. The reaction of meta-methyl substituted N-arylacrylamide afforded a mixture of two regioselective products 3j and 3j'.
Ortho-substituted N-arylacrylamides were also tolerated, but the yield decreased to some extent owing to the steric hindrance (products 3k and 3i). Remarkably, a polycyclic oxindole derivative was successfully synthesized by this protocol (product 3p), and the N-containing ligand (1,10-phenanthroline) was found useful to achieve good yield. Sequential investigations revealed that several groups (Ph and CH 2 OAc) at the 2-position of the acrylamide moiety were compatible with the optimal conditions to afford 3q and 3 s respectively, whereas hydroxymethyl (R 3 ¼ CH 2 OH) and mono-substituted olefins (R 3 ¼ H) were inefficient for the cyclization process (products 3r and 3 t).
b Yield of the isolated product. c 60°C. d 100°C.
good to excellent yield (products 3u-v). Notably, no reaction was observed when using the azo compounds bearing carboxylic group CO 2 H (3y).
To investigate the mechanism of the cascade addition=C(sp 2 )-H cyclization process, the inter-and intramolecular kinetic isotope control experiments were performed (Scheme 3). Small kinetic isotopic effects (the intramolecular K H =K D ¼ 1.3 and intermolecular K H =K D ¼ 1.0) were observed, which suggested that either the S E Ar mechanism or the free radical mechanism was involved in the reaction. [10] Notably, the free radical mechanism was supported by the control experiment: a stoichiometric amount of 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) (4 equiv.), a well-known radical inhibitor, was used in the reactions of 1a with AIBN, and the formation of the corresponding oxindoles was suppressed [Eq. (4)].

CONCLUSIONS
In summary, we have developed a practical copper-catalyzed oxidative cyanopropylation reaction of activated alkenes with AIBN, providing a rare access to oxindoles bearing 3 o nitrile moiety. In addition, the use of safe and readily available AIBN, inexpensive copper as the catalyst-and ligand-free catalytic system, as well as the simplicity of operation and handling make this protocol a highly attractive complement for the construction of pharmaceutically interesting cyano-containing oxindoles. The detail mechanism and application of the novel reaction to more complex targets are currently under investigation in our laboratory.

EXPERIMENTAL
All reactions were carried out under a nitrogen atmosphere in flame-dried glassware. Syringes used to transfer anhydrous solvents or reagents were purged with argon prior to use. NMR spectra were recorded on solutions in deuterated chloroform (CDCl 3 ) with residual chloroform (d 7.26 ppm for 1 H NMR and d 77.0 ppm for 13 C NMR). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad. Column chromatographical purifications were performed using SiO 2 (0.040-0.063 mm, 230-400 mesh) from Merck. Unless otherwise noted, commercial available starting materials were purchased from commercial sources and used without further purification. Preparation of N-arylacrylamides 1were prepared according to literature procedures. [7a] General Procedure for the Synthesis of Oxindoles with 3 o Nitrile Moiety vacuo. The residue was purified by flash chromatography on silica gel to afford the corresponding oxindole with 3 o nitrile moiety in yields listed in Schemes 1 and 2.