Photoredox-Catalyzed Amidation via Alkylsilicates and

Letter Cite This: ACS Catal. 2017, 7, 7957-7961

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Nickel/Photoredox-Catalyzed Amidation via Alkylsilicates and Isocyanates Shuai Zheng, David N. Primer, and Gary A. Molander* Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States S Supporting Information *

ABSTRACT: A nickel/photoredox, dual-catalyzed amidation reaction between alkylsilicate reagents and alkyl/aryl isocyanates is reported. In contrast to the previously reported reductive coupling process, this protocol is characterized by mild reaction conditions and the absence of a stoichiometric reductant. A mechanistic hypothesis involving a nickel-isocyanate adduct is proposed based on literature precedent and further validation by experimental results. KEYWORDS: amidation, radicals, nickel/photoredox dual catalysis, alkylsilicates, isocyanates

R

Scheme 1. Mechanistic Similarities between Reductive and Photoredox Cross-coupling

eductive coupling has been a powerful tool for the construction of a variety of structures, including those accessed via Csp2−Csp3 cross-coupling.1 Compared to crosscoupling reactions utilizing organometallic reagents as nucleophiles,2 reductive cross-coupling reactions generate “radical nucleophiles” in situ from the corresponding halides, significantly expanding the functional group tolerance for both partners. Despite this clear advantage in substrate scope, the need for a sacrificial amount of a stoichiometric reductant (hydride sources, metals, etc.) is a systemic drawback regarding atom economy and sustainability that limits the widespread implementation of reductive couplings. According to the most widely accepted catalytic cycle for reductive coupling, these transformations proceed through a putative single-electron transfer (SET) process involving radical rebound oxidative addition at the metal center.3 Even though both coupling partners in reductive cross-coupling are electrophiles, the mechanism of these transformations merges with that of photoredox-mediated cross-coupling reactions, in which a radical is generated via photoredox catalysis before oxidative capture by the metal center, generating a Ni(III) intermediate (I) that is common to both approaches (see Scheme 1).4 Indeed, photoredox catalysis has drawn a significant amount of attention in recent years. The ability to replace difficult, twoelectron processes with discrete, successive, single-electron transfer events results in methods with far greater control of reaction rate.5 Furthermore, these approaches often succeed in diminishing radical chain processes by obviating the requirement for stoichiometric radical generation. Recently, our group reported the merging of such photoredox processes with Ni cross-coupling reactions, utilizing oxidatively generated radical precursors.6 Given the mechanistic similarities between these two emerging fields, we pondered whether lessons learned from the reductive coupling literature could inform the design of new © XXXX American Chemical Society

chemistry in the photoredox cross-coupling realm. In particular, it seemed reasonable to explore whether other electrophilic partners previously employed in reductive coupling processes could be translationally applied to unexplored photoredox systems.1c The main advantage here would be that the transformation would be overall redox-neutral: the reduced photocatalyst formed upon reductive quenching would turn over the nickel catalytic cycle, obviating the need for a sacrificial reductant. Several electrophiles have been incorporated within photoredox cross-coupling, including (pseudo)aryl halides,6a,c−e,7 alkenyl halides,8 acyl chlorides,9 acyl imides,10 and activated carboxylic acids.11 However, unsaturated carbonyl-type electrophiles have not been explored extensively, with most efforts focusing on CO2.12 Inspired by work from Martin et al. in the formation of amides from alkyl halides and isocyanates Received: August 17, 2017 Revised: October 20, 2017

7957

DOI: 10.1021/acscatal.7b02795 ACS Catal. 2017, 7, 7957−7961

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ACS Catalysis Table 1. Optimization of Reaction Conditionsa

(Scheme 2a),13 we decided to explore the ability of isocyanates to be engaged in a Ni/photoredox dual catalytic cycle to generate amide groups. Scheme 2. Previous Research and Present Projecta

a

Data taken from refs 13 and 16.

entry

photocatalyst

ligand

[M]

yieldb (%)

1 2c 3 4 5 6 7 8 9 10 11 12 13f 14g 15h 16i 17

[Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 4CzIPNd [Ir]e

dtbbpy dtbbpy 6-Mebpy dppf phen phen phen phen phen phen

Ni(DME)Cl2 Ni(DME)Cl2 Ni(DME)Cl2 Ni(DME)Cl2 Ni(DME)Cl2 Co(OAc)2 Fe(acac)3 Ni(DME)Cl2 Ni(DME)Cl2 Ni(DME)Cl2

phen phen dtbpej

Ni(phen)Cl2 Ni(phen)Cl2 Ni(phen)Cl2 Ni(phen)Cl2 Ni(phen)Cl2 Ni(DME)Cl2

46 30 15 24 97 trace trace 48 65 0 0 98 0 0 42 30 30

[Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 [Ru(bpy)3][PF6]2 4CzIPN [Ir]e [Ru(bpy)3][PF6]2

a

1a (0.1 mmol, 1.0 equiv), 1b (0.2 mmol, 2.0 equiv), photocatalyst (1.5 mol %), [M] (2.5 mol %), ligand (2.5 mol %), DMF (1 mL, 0.1 M) at room temperature (rt) under blue LED irradiation. bHPLC yield. cUsing diisopropylammonium cyclohexylbis(catecholato)silicate as radical precursor. d4CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6dicyanobenzene. e[Ir] = {Ir[dF(CF3)ppy]2[bpy]}[PF6]. fIn darkness. g 1.0 equiv of TEMPO was added. hUsing diethyl 4-cyclohexyl-2,6dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as radical precursor. i Using cyclohexyl-BF3K as radical precursors. jdtbpe = 1,2-bis(di-tertbutylphosphino)ethane.

Amides are highly prevalent in biomedically related molecules. In fact, over 30% of bond-forming reactions in medicinal chemistry publications are amidations.14 Despite the fact that amidation methods are well-represented, many are predicated on sensitive reagents, harsh conditions, or stoichiometric amounts of activating agents.15 As a representative example, in a contribution from Bode et al. (Scheme 2b),16 alkyl and aryl isocyanates reacted with Grignard reagents to form sterically hindered amides. However, utilization of organometallic reagents limits the functional group tolerance of this approach (i.e., ketones, esters, etc., were not incorporated within the nucleophile). Because Ni/photoredox dual catalysis is known for its mild reaction conditions, processes based on this mechanistic paradigm would be expected to allow formation of the same bond without the need to preform an organometallic reagent, thus overcoming major limitations of traditional organometallic-based approaches. To begin our investigations, we selected cyclohexyl bis(catecholato)silicate (1a) and phenethyl isocyanate (1b) as radical partner and electrophile, respectively. Use of [Ru(bpy)3][PF6]2 as a photocatalyst and [(dtbbpy)Ni(H2O)4]Cl2 as the nickel precatalyst afforded the desired amide product in 46% yield (Table 1, entry 1). For organosilicates, the use of iPr2NH2+ as a counterion proved detrimental because of the tendency of the associated conjugate base to form an N,Ndiisopropyl urea upon reaction with the isocyanates, resulting in lower yields (Table 1, entry 2). This problem was circumvented by altering the silicate counterion to Et3NH+ or Me3NH+, the conjugate bases of which are non-nucleophilic. At this point, a rigorous optimization effort was carried out, utilizing highthroughput experimentation.17 Unsurprisingly, the choice of ligand for the Ni catalyst exerted a significant influence in the reaction outcome. Although bidentate phosphine ligands afforded poor yields (entries 4 and 16 in Table 1), with a significant amount of radical homocoupling byproducts, bispyridyl-type ligands (entries 1−3 in Table 1) gave better results. It came to our attention that the use of the flexible

dtbbpy ligand afforded modest yields (entries 1 and 2), whereas the previously employed 6-Mebpy13 gave a yield of only 15% (entry 3 in Table 1). Given that substitution at the 6-position of the bpy ligand should cause distortion of the backbone,13 this suggested that a more rigid system might be beneficial for this catalysis. In this vein, the use of phenanthroline resulted in quantitative product formation, while successfully suppressing the formation of off-cycle products (entry 5 in Table 1). To improve the operational simplicity, the use of preformed (Phen)NiCl2 led to similar results (entry 12 in Table 1). Further optimization of catalyst loading indicated the feasibility of reducing the catalyst loading to 2.5 mol % of Ni-precatalyst and 1.5 mol % of the Ru-photocatalyst in DMF. Other radical precursors, such as 4-alkyl-1,4-dihydropyridines and alkyltrifluoroborates were also attempted under the conditions developed for the alkylsilicates (entries 14 and 15 in Table 1),6c,e however, significantly lower yields were observed using these radical precursors. Encouraged by these results, we explored the substrate scope. As shown in Table 2, primary (2a), secondary (2b) and tertiary (2c) isocyanate species all rendered comparable yields, indicating the low influence of steric factors regarding the isocyanate counterpart. Notably, even for a sterically demanding 2,6-diisopropylphenyl isocyanate (2h), the yield was not compromised. When using aromatic isocyanates, only one equivalent was required to render comparable yields (2n), likely because of their enhanced stability under the reaction conditions. Concerning the alkylsilicates, we observed that both 7958

DOI: 10.1021/acscatal.7b02795 ACS Catal. 2017, 7, 7957−7961

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ACS Catalysis Table 2. Isocyanate Scope

Table 3. Silicate Scope

a

Reaction conditions: alkylsilicate (0.5 mmol, 1.0 equiv), isocyanate (1.0 mmol, 2.0 equiv for alkyl isocyanates; 0.5 mmol, 1.0 equiv for aryl isocyanates), DMF (5 mL, 0.1 M). bHNMe3+ was used as a counterion. cNMR yield. d36 h is needed for a complete conversion. a

Reaction conditions: alkylsilicate (0.5 mmol, 1.0 equiv), isocyanate (1.0 mmol, 2.0 equiv for alkyl isocyanates, 0.5 mmol, 1.0 equiv for aryl isocyanates), (phen)NiCl2 (0.0125 mmol, 2.5 mol %), [Ru(bpy)3][PF6]2 (0.0075 mmol, 1.5 mol %), DMF (5 mL, 0.1 M). bNMR yield. c Obtained via Tamao−Fleming oxidation of the corresponding Si(OEt)3 species: 30% H2O2 (1 mL) KF (1.5 mmol, 3.0 equiv) KHCO3 (1.5 mmol, 3.0 equiv), MeOH (5 mL), THF (5 mL), 0 °C. d Yield of gram-scale reaction.

addition reactions, allyl isocyanate afforded a good yield of 2e without any evidence of radical addition. Next, we sought to understand the intricacies of the reaction pathway. First, control experiments were performed. Unsurprisingly, in the absence of photocatalyst or light, no conversion was observed (Table 1, entries 10−13). By the addition of TEMPO in the reaction (Table 1, entry 14), no product was formed, which supported the radical pathway. The lack of product formation without a nickel catalyst (Table 1, entry 10) ruled out the direct radical addition pathway, suggesting a necessary interaction between the isocyanate and the nickel complex. Alternative metal catalysts (e.g., Fe, Co) and aprotic silicate counterions only rendered trace amounts of product, thus highlighting both the need for a proton source to turn over the catalytic cycle and the unique role of nickel.17 Furthermore, preliminary computational studies were carried out to enlighten the interaction between isocyanate and (Phen)Ni0 complex.24 A barrierless oxidative addition of Ni(0) to the isocyanate appears to be more favorable than the slightly uphill alkyl radical addition to a Ni(0) center.4 Based on these results and our previous understanding of photoredox/nickel dual catalysis,4 a plausible mechanism was proposed (Scheme 3), where Ni(II) carbonyl-amido intermediate 4b20,21 is formed upon oxidative addition of Ni(0) to the isocyanate. Subsequently, intermediate 4c will be generated upon radical addition.4,6a The generated Ni(III) complex then undergoes reductive elimination to generate the new C−C bond, followed by protonation with the ammonium counterion. The resulting Ni(I) complex is then reduced by Ru(bpy)3+ to turn over both the nickel and photoredox catalytic cycles.22 Although attempts to synthesize complex 4b with bipyridine supporting ligands failed because of the instability of this complex, by mixing a stable Ni(0) source, Ni(COD)2, in the presence of phenanthroline and 2,6-diisopropylphenyl iso-

primary and secondary alkylsilicates worked well, with slightly higher yields using secondary alkylsilicates, probably as a consequence of the higher stability of the intermediate radical. A gram-scale reaction generating 2n was also carried out, and a comparable yield of 69% was observed, indicating that this reaction is scalable. A variety of functional groups were well accommodated on both the silicate and isocyanate coupling partners. According to results presented in Tables 2 and 3, enolizable ketones (2i), esters (2d, 3f, and 3i), ethers (3e), fluorides (3c, 3d), nitriles (2l, 3a), and amides (3g) were accommodated in moderate to good yields. These functional handles were not tolerated under previously reported protocols.16 Isothiocyanate species could also be employed in the reaction (2g), and heteroaromatic systems were readily accommodated as well. Despite a longer reaction time, the pyridyl moiety (3k) afforded a reasonable yield. Notably, although both pyrrole (3h) and thiophene (2m) ring systems are known for radical polymerization reactivity,18 the desired products were successfully isolated. The functional group tolerance of this reaction also provides possibilities for sequential functionalization. For example, an aryl chloride (2j) was accessed in good yield, providing a handle for further elaboration via traditional cross-coupling. The (EtO)3Si group was also compatible, which led to installation of a hydroxy group (2f) in 68% yield after a one-pot, Tamao−Fleming oxidation.19 Although alkenyl moieties are vulnerable to radical 7959

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ACS Catalysis

cyclohexyl radical generated during reaction. Notably, these CO extrusion-derived side products further support the viability of 4b and 4c as intermediates along the reaction pathway. Overall, the proposed mechanism and experiments are consistent with previous work by Martin, in which a reductive coupling strategy was used.13,25 In their cases, coupling was validated to occur via a radical pathway, using superstoichiometric zinc, both to generate the alkyl radical and to reduce the nickel catalyst. In conclusion, a nickel-catalyzed photoredox amidation of alkylsilicates and aryl/alkyl isocyanates has been developed. Under these mild conditions, this reaction utilizes a similar pathway to that previously used in reductive couplings, but eliminates the required stoichiometric reductant by using a photocatalyst for both radical generation and nickel cycle turnover. With a series of electrophilic functional groups tolerated, this reaction is complementary to those afforded by conventional methods, such as acylation of amines and isocyanate alkylation via organometallic reagents. Most excitingly, the recognition regarding the mechanistic similarities between Ni/photoredox dual cross-coupling and nickel reductive couplings can serve as a foundation for developing new chemistry in both fields. As such, a closer examination of the literature between these two related regimes can help inform and allow the development of new transformations.

Scheme 3. Plausible Mechanisms of Nickel-Catalyzed Photoredox Amidation

cyanate, we were able to observe rapid changes by NMR and IR, corresponding to the disappearance of the isocyanate and the formation of a new carbonyl peak. These appear to be indicative of an oxidative addition intermediate. Indeed, the corresponding product was observed by reaction of the in-situgenerated 5a with cyclohexylsilicate under photoredox conditions (see Scheme 4a).20

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Scheme 4. Mechanistic Investigation

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b02795. Experimental procedures, HTE data, mechanistic studies, compound characterization data, and NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shuai Zheng: 0000-0001-9085-4410 Gary A. Molander: 0000-0002-9114-5584 Funding

The authors are grateful for the financial support provided by NIGMS (No. R01 GM 113878). We thank the NIH (No. S10 OD011980) for supporting the University of Pennsylvania (UPenn) Merck Center for High Throughput Experimentation, which funded the equipment used in screening efforts. Notes

The plausibility of this proposal is also consistent with the work by Hillhouse on the synthesis of related, isolable (dtbpe)Ni(II)-DippNCO oxidative addition complexes.21,24 As noted in our optimization, the same, sterically bulky, bisphosphino ligand was viable in the catalysis, affording a moderate 30% yield of the desired coupled product (Table 1, entry 16).23 Interestingly, during the reaction between the cyclohexylsilicate and diisopropylphenyl isocyanate, diisopropylphenyl urea (6a) was isolated (Scheme 4b). This off-cycle product suggests a reaction pathway where CO extrusion from 4b results in the formation of a Ni-imido complex,20 which can then react with another equivalent of isocyanate to generate the observed urea.21 In addition, detection of dicyclohexyl ketone 6b in the GC-MS demonstrates the capture of CO by

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We sincerely thank Dr. Alvaro Gutierrez-Bonet [University of Pennsylvania (UPenn)] for helpful discussion. We thank Professor Osvaldo Gutierrez (University of Maryland) for preliminary computational results concerning the energy of the proposed reaction intermediates. Dr. Charles W. Ross, III (UPenn) is acknowledged for obtaining HRMS data.

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REFERENCES

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ACS Catalysis

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DOI: 10.1021/acscatal.7b02795 ACS Catal. 2017, 7, 7957−7961