Manganese Catalyzed α-Olefination of Nitriles by Primary Alcohols

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Manganese Catalyzed α‑Olefination of Nitriles by Primary Alcohols Subrata Chakraborty, Uttam Kumar Das, Yehoshoa Ben-David, and David Milstein* Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel S Supporting Information *

Scheme 1. Transition Metal Catalyzed Dehydrogenative Coupling of Alcohols and Nitriles

ABSTRACT: Catalytic α-olefination of nitriles using primary alcohols, via dehydrogenative coupling of alcohols with nitriles, is presented. The reaction is catalyzed by a pincer complex of an earth-abundant metal (manganese), in the absence of any additives, base, or hydrogen acceptor, liberating dihydrogen and water as the only byproducts. α,β-Substituted acrylonitriles serve as valuable intermediates in the synthesis of a variety of products including dyes, herbicides, fragrances, pharmaceuticals, and natural products.1,2 Several drugs, for example entacapone (for Parkinson’s disease), and CC-5079, a potent antitumor agent, contain a crucial α,βunsaturated nitrile moiety.2d They are also used in the synthesis of high electron affinity polymers for light emitting diodes with air stable electrodes.3 Moreover, they are key building blocks for various synthetic transformations.4 Traditional syntheses of α,β-unsaturated nitriles involve Knoevenagel condensation of aldehydes and arylacetonitriles in the presence of stoichiometric5 or catalytic bases.6 However, base mediated condensation reactions have several drawbacks: self-condensation of the nitriles, aldol reaction of the carbonyl group bearing enolizable α-hydrogens, Cannizzaro reaction, potential attack of aldehyde (bearing α-hydrogen) by the nitrile, and poor tolerance of a wide range of functional groups toward base.5c,7 Alternative reagents and catalysts are also reported for the condensation of aldehydes and nitriles, including several other routes to obtain α,β-unsaturated nitriles.8,9 However, most of them suffer from toxicity issues, expensive starting reagents, poor yield, limited accessibility of starting materials, and generation of copious waste. Acceptorless dehydrogenative coupling (ADC) emerged as a powerful tool for various sustainable organic transformations.10 ADC of alcohols with nitriles can offer an attractive “green” route for the synthesis of unsaturated nitriles; alcohols are environmentally benign, cheap, abundant feedstocks that can be obtained industrially or from renewable resources such as lignocellulosic biomass.11 Hydrogen and water are the only byproducts in this methodology. Formation of C−C and C−N bonds using alcohols, based on the so-called “borrowing hydrogen” methodology, is an important synthetic approach.12a C−C bond formation using alcohols as alkylating agents was recently reported by several groups.12 Few examples of direct α- alkylation of nitriles using primary alcohols catalyzed by noble-metal based complexes of Ru, Rh, Ir, Pd, Os (Scheme 1) are also described, requiring catalytic bases in most cases.13 Concerns regarding economic constraints, limited availability, and toxicity issues of noble metals attracted much current © 2017 American Chemical Society

interest in homogeneous catalysis by earth-abundant, metal complexes (Fe, Co, Ni, Mn).14,15 In fact, much progress in catalysis by complexes of base metals has been achieved in various (de)hydrogenation reactions. Manganese offers an attractive alternative to noble metals since it is the third most abundant metal in the earth’s crust after iron and titanium. In 2016, we reported the dehydrogenative coupling of alcohols and amines to aldimines,16a catalyzed by a pincer Mn(PNP)tBu complex 1 (Figure 1). Several other reports on Mn

Figure 1. Manganese pincer complexes explored in this study.

catalyzed reactions based on alcohol dehydrogenation appeared subsequently, namely C-alkylation of ketones,17a N-alkylation of amines,17b alcohol to esters,17c dehydrogenation of aq. methanol to H2 and CO2,18 and pyrimidine, quinoline, and pyrrole synthesis.19 Hydrogenations of ketones, nitriles, esters, CO2, and amides were also reported.20−23 Very recently we reported Mn-catalyzed N-formylation of amines using methanol24 and deoxygenation of alcohols,25 catalyzed by MnPNP pincer complex 2 (Figure 1). Previously, we demonstrated that complex 1 is an efficient catalyst for the C−C bond formation of α,β unsaturated carbonyl compounds with nonactivated nitriles (Michael reaction). Remarkably, the reaction takes place at room temperature, in the absence of base, by nitrile activation via metal−ligand cooperation.26 Intrigued by these recent developments, we explored the possibility of dehydrogenative coupling of alcohols and nitriles bearing α-hydrogens. To our knowledge, transition metal Received: July 5, 2017 Published: August 9, 2017 11710

DOI: 10.1021/jacs.7b06993 J. Am. Chem. Soc. 2017, 139, 11710−11713

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Table 2. α-Olefination of Nitriles by Primary Alcohols Catalyzed by 2a

catalyzed acceptorless dehydrogenative coupling of alcohols and nitriles to form α-alkenylnitriles with the extrusion of H2 and water had not been reported thus far. Reaction of benzyl alcohol (0.25 mmol), phenylacetonitrile (0.25 mmol), and complex 1 (4 mol %) in 1 mL of toluene at 135 °C in a closed Schlenk tube resulted after 45 h in formation of 2,3-diphenylacrylonitrile in poor (13%) yield (Table 1, entry Table 1. α-Olefination of Phenylacetonitrile by Benzyl Alcohol Catalyzed by Complexes 1−3a

entrya

cat.

solvent

time (h)

conv.b (%)

yieldb

c

1 2 2 3 2 2 2 2 4 4

toluene toluene p-xylene toluene toluene THF dioxane toluene toluene toluene

45 39 45 48 20 48 48 45 40 40

13 93 78 7 67 79 78 32 86 63

13 87 66 7 60 73 76 32 73 52

1 2d 3d,e 4 5 6 7 8f 9g 10g a

0.01 mmol catalyst, 0.25 mmol benzyl alcohol, 0.25 mmol phenylacetonitrile, 1 mL of toluene in 50 mL Schlenk flask heated at 135 °C bath temperature. bConv. and yield were determined using GC or NMR using N,N-dimethylaniline as internal standard. cAverage of two runs. dIsolated yield. eThe reaction was carried out using 8.9 mmol of benzyl alcohol, 8.9 mmol of phenylacetonitrile, and 4 mol % catalyst 2 in an open system. f110 °C. gSee mechanistic part and Scheme 2.

1). However, using complex 2 as catalyst resulted in formation of 2,3-diphenylacrylonitrile in 87% yield, as revealed by GC-MS and NMR (Table 1, entry 2). The 1H NMR is in accord with the Z geometric isomer. 27 Only traces of the CC hydrogenation product 2,3-diphenylpropionitrile, along with traces of another product, most likely the E isomer, were detected by GC-MS. Analysis of the gas phase by GC indicated formation of H2. It is noteworthy that the reaction does not require any additives or a hydrogen acceptor. Moreover, the reaction takes place in the absence of base, indicating the capability of the MnPNP pincer complex for α-C−H activation of nitriles, likely generating a metal stabilized carbanion (vide inf ra).28 A large scale reaction (8.9 mmol phenylacetonitrile and 8.9 mmol benzyl alcohol) in an open system was also carried out using catalyst 2, giving a 66% yield of the isolated 2,3-diphenylacrylonitrile (entry 3). Complex 3 was not an effective catalyst, leading to only 7% of 2,3-diphenylacrylonitrile (Table 1, entry 4). Using polar solvents such as THF or dioxane, the corresponding products were obtained in 73% and 76% yields, respectively (Table 1, entries 6 and 7). Lowering the temperature to 110 °C furnished only 32% of the corresponding alkenyl nitrile (Table 1, entry 8). Next, the scope of this new catalytic reaction was probed. As shown in Table 2, various electron-donating and -withdrawing substituents at the para position of the benzyl alcohol (p-OMe, p-Cl, p-CF3) dehydrogenatively coupled with phenylacetonitrile to give α,β substituted acrylonitriles in excellent yields with Zselectivity (Table 2, entries 1−3). Dehydrogenative coupling of

a

Conditions: alcohol (0.25 mmol), nitrile (0.25 mmol), 2 (0.01 mmol), toluene (1 mL) heated in a 50 mL closed Young Schlenk tube at 135 °C bath temperature. bConversion determined by GC or NMR analysis using N,N-dimethylaniline as internal standard. cIsolated yields. dYield by GC or NMR analysis using N,N-dimethylaniline internal standard. e8 mol % catalyst was used.

various substituted benzyl cyanides with benzyl alcohols also proceeded well (Table 2, entries 4−8). Notably, dehydrogenative coupling of benzyl alcohol with heteroaromatic 3pyridylacetonitrile, and also that of 1-naphthyl methanol with benzyl nitrile gave the corresponding unsaturated nitriles in moderate yields (Table 2, entries 9, 11). 11711

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temperature the alkoxo complex A (Scheme 2) along with 4methoxybenzaldehyde and the hydride complex 2 as revealed by 1H and 31P NMR spectra.25 Considering our experimental findings, and based on recent mechanistic investigations of the Mn-catalyzed dehydrogenative coupling of amines and methanol,24 and on deoxygenation of primary alcohols catalyzed by 2,25 the catalytic cycle depicted in Scheme 2 is plausible. Initial dihydrogen liberation from complex 2 leads to the amido complex 4, which undergoes intramolecular C−H activation to form the thermodynamically more stable C-metalated complex 4′.24 O−H activation of the alcohol by complex 4 or 4′ via proton transfer, to either the amido nitrogen or benzylic carbon, results in the formation of the alkoxo complex A. The following β-hydride elimination step29 releases the aldehyde, which, unlike the dearomatized Mn(PNPtBu) system, apparently does not bind with the amido complex 4.16a In a competitive pathway, the nitrile bearing αhydrogens likely forms complex B by ligand-based deprotonation, generating a nitrile carbanion. Intermediates A and B are expected to be in equilibrium with the amido complex 4. Nucleophilic attack of the carbanion at the aldehyde followed by water elimination leads to the α,β-unsaturated nitriles and regenerates the amido complex 4, thus completing the catalytic cycle. In conclusion, unprecedented transition metal catalyzed olefination of nitriles by acceptorless dehydrogenative coupling of alcohols and nitriles is demonstrated, leading to a range of substituted acrylonitriles. Moreover, the reaction is catalyzed by an earth-abundant metal (Mn) complex. This CC double bond formation proceeds without any additives, such as bases, or hydrogen acceptors, using the pincer catalyst (iPr-PNHP)Mn(H)(CO)2 2. A plausible mechanism, involving a ligandbased deprotonation of a nitrile, is provided.

Aliphatic alcohols also underwent dehydrogenative coupling with nitriles. Thus, reaction of 1-hexanol with phenylacetonitrile afforded 59% of 2-phenyl-2-octenenitrile (Table 2, entry 12). However, a small amount of the CC hydrogenated product (12%) was also observed. Phenylethanol and 3-methylbutanol coupling with benzyl cyanide produced 47% and 58% yields of the corresponding acrylonitriles, respectively (Table 1, entries 13−14). Cinnamyl alcohol dehydrogenatively coupled with phenylacetonitrile to give (2Z,4E)-2,5-diphenylpenta-2,4dienenitrile in 81% yield; notably, both CC bonds remain intact (Table 2, entry 15). Finally, the dehydrogenative coupling of benzyl alcohol and the more challenging aliphatic 3-phenylpropionitrile resulted in only 20% of the corresponding product after 45 h with a loading of 8 mol % catalyst (Table 2, entry 16). Regarding the mechanism, we believe that the amido complex 424 (Scheme 2) is involved in the catalytic cycle. Scheme 2. Proposed Mechanism

Indeed, when freshly prepared 4 (4 mol %) was employed as catalyst in the dehydrogenative coupling of benzyl alcohol and benzyl cyanide at 135 °C, a 73% yield of 2,3-diphenylacrylonitrile was obtained after 40 h (Table 1, entry 9). Complex 4′ also catalyzes the reaction giving a slightly lower yield (52%) compared to complex 2 or 4 (Table 1, entry 10). Significantly, treatment of 4 with 4-fluorophenylacetonitrile (1 equiv) in tol-d8 at room temperature resulted in partial formation of a new complex, which exhibited two broad 31 1 P{ H} NMR signals at δ = 59 and 91 ppm. Cooling to −40 °C resulted in sharpening of the broad signals to form two doublet signals at δ = 59.8 (2JPP = 89 Hz) and 91.8 (2JPP = 89 Hz) ppm, indicating reversibility of the reaction at room temperature (see Supporting Information (SI)). This new complex is plausibly a cationic complex B (Scheme 2), in which abstraction of the acidic α-proton from 4-fluorophenylacetonitrile by the basic amido moiety of complex 4 generates a nitrile carbanion, which may be stabilized by coordination to the cationic metal center or remain as a counteranion. In the 1H NMR spectrum a singlet signal at 4.3 ppm is likely due to a CH proton of the nitrile carbanion. In the 19F NMR, a signal at −133.6 ppm was observed for the fluorine atom of the likely carbanion, along with the signal of 4-fluorophenylacetonitrile at δ −116 ppm. To further support these assignments, 4fluorophenylacetonitrile was reacted with KH in THF at room temperature and the observed 1H NMR (4.4 ppm) and 19 F NMR (−133.7 ppm) signals were in accord with the suggested nitrile carbanion (see SI, Figures S4 and S5). Thus, these observations represent a rare direct observation of C−H activation of arylacetonitrile by an amido-amine MLC. In addition, we have previously reported that the amido complex 4 reacts with excess 4-methoxybenzyl alcohol to form at room

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06993. Experimental details, GCMS, and NMR spectra of products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected]. ORCID

David Milstein: 0000-0002-2320-0262 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the European Research Council (ERC AdG 692775), and by the Israel Science Foundation. D.M. holds the Israel Matz Professorial Chair. S.C. thanks the committee of the Swiss Friends of the Weizmann Institute of Science for a generous postdoctoral fellowship. U.K.D. is thankful to Govt. of India for the DST SERB Overseas Postdoctoral Fellowship.

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REFERENCES

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