Nickel-Catalyzed Reductive Arylation of Redox Active Esters for the Synthesis of -Aryl Nitriles – Role of a Chlorosilane Additive Nicholas W. M. Michel§, Racquel K. Edjoc§, Emmanuel Fagbola§, Jonathan M. E. Hughes‡, Louis- Charles Campeau‡, Sophie A. L. Rousseaux§* AUTHOR ADDRESS § Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, CANADA ‡ Department of Process Research and Development, Merck & Co. Inc., Rahway, New Jersey 07065, United States KEYWORDS nickel catalysis, reductive cross-coupling, chlorosilane, α-aryl nitrile, arylation, radical, NHP ester ABSTRACT: A nickel-catalyzed reductive cross-coupling of redox-active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted -aryl nitriles, an important scaffold in pharmaceutical sciences. Mechanistic studies reveal that decarboxylation of the NHP ester to the reactive radical intermediate is accomplished by a combination of a chlorosilane additive and Zn dust. The reaction exhibits a broad scope as many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents. Scheme 1. α-Aryl nitrile synthesis via cross-coupling intermediates and their prevalence in pharmaceutical agents. Thus, considerable efforts have been dedicated to their synthesis.2 Traditionally, feedstock chemicals such as aliphatic nitriles3 or cyanoacetate salts4 can undergo α-arylation as a nucleophilic reagent in the presence of an aryl(pseudo)halide coupling partner with a transition-metal catalyst such as Pd (Scheme 1a, left). However, these established α-arylation methods require strongly basic reaction conditions and/or high temperatures to generate the nucleophilic coupling partner, which limits both their functional group compatibility and their use in late-stage diversification of complex molecules. In contrast, cross-coupling reactions using - (pseudo)halo nitriles as electrophilic coupling partners address these limitations as the reactions tend to be milder. As such, -(pseudo)halo nitriles have been elegantly employed in traditional5 (Scheme 1a, right), and reductive6,7 (Scheme 1b, left) cross-coupling reactions. The main drawback to these methods is that starting material preparation can be undesirable since they are typically synthesized from a Nickel-catalyzed reductive cross-couplings (RCC) have cyanohydrin intermediate which requires the use of a toxic garnered considerable interest over the past decade since they cyanide equivalent. As an alternative approach, we envisioned allow for the construction of C–C bonds from two distinct using cyanoacetic acid derived electrophiles in a RCC as these electrophilic reagents.1 Compared to traditional cross– are feedstock starting materials and easily derivatized coupling reactions, reductive methods tend to avoid the (Scheme 1b, blue box). Specifically, we envisioned using the discrete formation of anionic species which often leads to redox properties of N-hydroxyphthalimide (NHP) esters to milder reaction conditions that exhibit exceptional functional generate an -cyano radical that can engage in Ni-catalyzed group tolerance. Thus, reductive cross-coupling reactions that arylation.8 target substrates containing base-sensitive functional groups RCC reactions of NHP esters are powerful methods that have are highly attractive as they elegantly showcase the been used to prepare a diverse range of C–C bonds.9 Notably, advantages of this cross-coupling strategy. One such example while there are many examples in the literature describing the that would benefit from this strategy is the synthesis of α-aryl functionalization of alkyl substituted NHP ester derivatives, nitriles. These scaffolds are of importance to the synthetic examples of NHP esters bearing additional functional group community due to their versatile nature as synthetic handles in the –position are rare.10 Herein we describe the phenol (3c), sulfonamide (3d, 3u, 3y), benzyl alcohol (3g, 3t), development of a reductive decarboxylative arylation reaction and ketone (3h, 3z). of cyanoacetic-derived NHP esters. Mechanistic studies of the Notably, the unprotected alcohols in 3c, 3g, and 3t are reaction revealed a unique reduction mechanism for the NHP silylated over the course of the reaction, and either the free ester substrate and indicated that an -cyano radical alcohol (3c, 3g), or the TMS-protected adduct (3t) can be intermediate is generated in the combined presence of a isolated directly.13 Aryl iodides containing N-heterocycles chlorosilane additive and Zn dust. This finding has (3i, 3s, 3u) were efficiently cross-coupled, as well as 5- implications on the field of NHP ester functionalization, as the iodobenzothiophene (3j, 3r). Tertiary amide substrate (3l), role of halosilane additives in previous investigations are not 9b and secondary amide (3t) bearing a free N-H were good fully understood. coupling partners. Strongly electron-donating groups on the We began reaction optimization by exploring the RCC of iodoarene are tolerated such as alkoxy (3a, 3m, 3q) and amino NHP ester 1a and iodoarene 2. Initial experiments led to low (3e, 3o) substituents. An ortho-substituted iodoarene gave the conversions of aryl iodide and none of the desired product 3a desired α-aryl nitrile (3f) in 46% yield. Structurally complex (Table 1, entry 1). However, when 1 equivalent of a mono- aryl iodides, bearing a diverse range of functional groups (3s- chlorosilane additive such as TBSCl or TMSCl was added, u) were also suitable substrates in the reaction, which low to moderate yields (24% and 55%, respectively) of α-aryl highlights the synthetic utility of this method within the nitrile 3a were obtained (Table 1, entries 2-3). Di– and tri– context of late-stage diversification. In particular, - chlorosilanes generally resulted in increased product hydroxyamide 3t, is an intermediate towards an anti- t formation, with the notable exception of Si( Bu)2Cl2, which hypercholesterolemic compound which features a selective resulted in no detectable formation of 3a (Table 1, entries 4- Ar-I over Ar-Br functionalization en route towards those 7). Ultimately, when 3 equivalents of TMSCl were added in medicinal agents.14 combination with NiCl2bpy (10 mol %) as the pre-catalyst, Other NHP esters of functionalized cyanoacetic acids can also and superstoichiometric Zn dust (8 equiv), 3a was obtained in 11 be used in this transformation. -Aryl nitriles with pendant 82% yield (Table 1, entry 8). Decreasing the amount of Zn alkyl chains (3v) or an allyl substituent (3w) were prepared in to 2 equivalents resulted in reduced conversion to 3a (Table moderate to good yields from the corresponding NHP ester. 1, entry 9). The reaction is very rapid and occurs within 15 Nitrile 3x was prepared in good yield from the NHP ester minutes at room temperature (vide infra), potentially containing a free N-H indole without requiring protecting signifying that rapid Zn-mediated reduction of the Ni catalyst group manipulations.15 Bulky isopropyl (3k-3r, 3t, 3u) and is essential for productive catalysis. Control reactions in the cyclohexyl (3y) substituted NHP esters were also suitable absence of Ni, ligand or Zn resulted in no detectable product substrates for this transformation, as well as substrate 3z formation. bearing a cyclopropane ring.16 Table 1. Effect of chlorosilane additive NiCl2bpy (10 mol %) CN Ph 3 CN [Si]–Cl (1 equiv) Ph 3 Zn (8.0 equiv) + I OMe DMA (0.2 M) NHP O r.t., 1 h 1a 2 3a OMe (1.5 equiv) (1 equiv) Entry [Si–Cl] yield 3a (%)a conv. 2 (%)a 1 None 0 16 2 TBSCl 24 53 3 TMSCl 55 66 4 SiCyMeCl2 65 100 i 5 Si( Pr)2Cl2 74 100 t 6 Si( Bu)2Cl2 0 8 7 SiPhCl3 75 100 8 TMSCl (3 equiv) 83 100 b 9 TMSCl (3 equiv) 53 83 aCalibrated yields determined by GC-MS using dodecane as an internal standard. Reactions performed on a 0.1 mmol scale. bReaction performed using 2 equiv Zn instead of 8 equiv. After establishing the optimal reaction conditions, we set out to explore the scope of the reaction (Scheme 2). Notably, the reaction was selective for aryl iodides over other common cross-coupling partners such as aryl bromides (3t, 3v), aryl chlorides (3n), aryl tosylates (3b, 3k), and aryl pivalates (3w). Functionalization at the other reactive position of these substrates was never observed.12 Aryl iodides bearing base- sensitive functional groups were also compatible, including a Scheme 2. Reaction Scopea NiCl2bpy (10 mol %) O TMSCl (3 equiv) Zn (8 equiv) R CN CN + Ar–I NHP DMA (0.2 M) Ar R r.t., 1 h 1 [standard conditions] 3 (1.5 equiv) (1 equiv) Aryl Iodide Scope Pharmaceutical Agents CN CN CN CN CN CN Ph Ph Ph Ph Ph 3 3 3 3 3 NC CH Ph 3 3 O N O Ph N O NHP 3 1a NH O OMe OTs OH S NBn2 H2N O 3s 29%d 3a 70%b 3b 59% 3c 43% 3d 75% 3e 57% CN CN CN CN CN Ph Ph Ph 3 3 3 Ph 3 Ph 3 Me CN HO N iPr O OTMS N S Me O OEt N 3f 46% 3g 53%c 3h 53% 3i 92% 3j 70% H Aryl Iodide Scope Br i CN i OTBDMS Pr iPr CN Pr CN iPr CN F NHP O 1b 3t 30%e,f OTs N Ph OBn Me 3k 55% 3l 72% O 3m 65% i iPr CN iPr CN iPr CN iPr CN Pr CN NC N O NHtBu nPr S iPr O N OEt Cl O S NBn2 O OMe 3u 60% 3n 65% 3o 65% 3p 34% 3q 72% 3r 55% NHP Ester Scope CN CN CN NH CN CN O CN Me Ph O NHP R Me Br PivO S S 1c-g H N 2 O O 3v 48% 3w 57% 3x 60% 3y 79% 3z 65% (4:1 d.r.) aReactions performed on a 0.2 mmol scale.