Manganese catalyzed cross-coupling of allylic alcohols and nitriles: an elegant route for access to δ-hydroxynitriles

Abstract

Alcohols and nitrile derivatives are highly important skeletons, widely applied in both organic and bioorganic chemistry. Cross coupling of alcohols and nitriles through formal conjugated addition is a powerful and environmentally friendly strategy for access to long carbon chain tethered nitriles, due to its 100% atom economy and readily available starting materials. Herein, we reported a first example of the pincer manganese(I) catalyzed redox-neutral coupling of nitriles with allylic alcohols to forge a variety of δ-hydroxynitriles. The reaction featured a broad substrate scope with good functional group tolerance under simple conditions (43 examples, 50–94% yields). Remarkably, the mildness and practicality of this protocol were further demonstrated by the successful synthesis of anipamil and verapamil via a one or two-cascade borrowing hydrogen procedure.

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Introduction

Nitrile derivatives have found widespread applications as pharmaceuticals, natural products and organic materials.^1,2 Especially, δ-hydroxynitriles are frequently used as versatile building blocks for the synthesis of diols, lactones, lactams, amino alcohols and cyclic amine derivatives.^3–7 Typically, δ-hydroxynitriles are often encountered in various biologically active molecules, pharmaceuticals, and natural products, as shown in Fig. 1. 5-Hydroxy-2,3-diphenylpentanonitrile (Compound A ⁸) was used as a herbicide and plant growth regulator. Additionally, δ-aminonitriles derived from δ-hydroxynitriles exhibited diverse biological activities, such as compound B ⁹ employed for the identification of non-peptide malignant brain tumor (MBT) and compound C ¹⁰ used as an antagonist for autoimmune diseases. Furthermore, verapamil is a calcium channel blocker for the treatment of cerebrovascular disease, while anipamil is used to cure high blood pressure. In view of these considerations, tremendous efforts have been poured into the development of efficient methodologies for synthesizing δ-hydroxynitriles, in which the base-mediated 1,4-Michael addition of nitriles to α,β-unsaturated carbonyl compounds followed by carbonyl reduction remains the foremost method.¹¹ Nevertheless, this conjugate addition reaction has disadvantages including poor functional group tolerance, inevitable waste production and requiring prefunctionalized starting materials Thus, seeking straight-forward and sustainable approaches in a simple manipulation to achieve the synthesis of δ-hydroxynitriles is an appealing yet difficult, task.

Fig. 1 δ-Hydroxynitriles in various biologically active molecules and pharmaceuticals.

Recently, the strategy of borrowing hydrogen (BH), first proposed by Williams and colleagues,¹² has experienced a renaissance in organic chemistry since it takes advantage of readily available alcohols as sustainable and safe coupling partners by using simple metal catalysis, avoiding the demand for oxidants, reducing agents, toxic bases or multistep reactions. Over the past few decades, noble metals like Ru, Rh, Ir, and Pd have been demonstrated as efficient catalysts in hydrogen borrowing reactions,¹³ realizing the easy transformation of primary or secondary alcohols as green alkylative and arylative reagents. As a testament to this, the cross coupling of nitriles and alcohols via a BH process is a fantastic way to construct nitrile derivatives. Very recently, Gunanathan and co-workers reported a Ru-catalyzed conjugate addition reaction to construct δ-hydroxynitriles from nitrile and allylic alcohols.¹⁴ However, the low availability of scarce metals as well as the cost of removal of such metals from the product and the creation of environmental pollution has encouraged chemists to mine alternative catalysts based on 3d metals with abundant sources on Earth.

Being the third most abundant transition metal in the earth's crust, manganese¹⁵ has recently been found to be a valuable alternative to realize the preparation of nitrile skeletons via borrowing hydrogen transformations with less toxic and less expensive properties than the typically used 4d- and 5d-transition metal compounds (Scheme 1A).¹⁶ In 2017, Milstein and co-workers demonstrated that a PNP–Mn complex catalyzed the olefination reaction to deliver the α-olefinated nitrile.¹⁷ An elegant work reported by Maji¹⁸ and co-workers in 2018 realized the first example of manganese catalyzed α-alkylation of nitriles with primary alcohols by using a bidentate ligand, despite its substrate limitation (secondary alcohols and methanol cannot be used as an alkylating reagent). Later, Rueping and El-Sepelgy¹⁹ reported a manganese PNP pincer complex²⁰ capable of enabling the catalytic α-methylation of nitriles using methanol as a methyl source. Despite this great success, expanding base metal-catalyzed BH processes involving secondary alcohols as well as formal conjugate additions of allylic alcohols to nitriles remains a challenging task to be solved. With our continuing interest in BH reactions,²¹ we envisioned a formal conjugate addition of allylic alcohols with nitriles as carbon nucleophiles and regeneration of hydroxyl groups through hydrogenation of in situ formed carbonyl skeletons (Scheme 1B). The control of deleterious side reactions including the aldol type self-coupling of in situ generated α,β-unsaturated carbonyl compounds and 1,2-addition versus 1,4-addition of nitriles to α,β-unsaturated carbonyl compounds and expansion to more challenging secondary alcohols and nitriles are the main tasks remaining to be achieved. Herein, we report a first example of a manganese pincer complex enabled efficient synthesis of δ-hydroxynitriles through formal conjugate addition of nitriles with allylic alcohols with 100% atom economy (Scheme 1C). This protocol has a wide substrate scope with good functional group tolerance under simple conditions (43 examples, 50–94% yields), and could be applied in the gram-scale total synthesis of the drugs anipamil and verapamil.

Scheme 1 Mn catalyzed borrowing hydrogen transformations of alcohols with nitriles.

Results and discussion

At the outset of our investigations, the reaction of the selected model substrates phenyl acetonitrile (1, 0.5 mmol, 1 equiv.) and cinnamyl alcohol (2, 1.0 mmol, 2 equiv.) using Mn-1 (1 mol%) as the catalyst and 10 mol% KO^tBu as the base at 110 °C (Table 1, entry 1) was performed. Gratifyingly, the complete conversion of phenyl acetonitrile was observed, and the anticipated conjugate addition product 3 was isolated in 66% yield. Notably, the α-alkylation product was not detected in this catalysis reaction. Other tridentate ligand coordinated manganese compounds, Mn-2 ²² and Mn-3,²³ showed dramatically low efficiency in this reaction (Table 1, entries 2 and 3). Reducing the reaction temperature from 110 °C to 90 °C resulted in a drop in yield, whereas a higher temperature had no obvious effect (Table 1, entries 4 and 5). Next, a set of bases were screened, and K₂CO₃ proved to be the optimal one to give the desired product 3 in 85% yield with a short reaction time of 4 h (Table 1, entries 6–8). Moreover, decreasing the dose of K₂CO₃ to 5 mol% had little influence on the reaction outcomes (Table 1, entry 9). In addition, reactions performed in tert-amyl alcohol or 1-butanol afforded product 3 in a diminished yield (Table 1, entry 10). It is worth noting that reaction with a low catalyst loading of 0.5 mol% still occurred smoothly to offer the targeted 3 in a relatively lower yield (Table 1, entry 11). As expected, no coupled product was observed when the reaction was carried out in the absence of Mn-1 (Table 1, entry 12).

Table 1 Optimization of reaction conditions^a

Entry	Cat	Base	Temp (°C)	T (h)	Yield^c (%)
a Reaction conditions: 1 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.), toluene (1.0 mL), [Mn] (1 mol%), and base (10 mol%) under heating and a nitrogen atmosphere. b 5 mol% K2CO3 was used. c Isolated yield. d tert-Amyl alcohol was used as solvent. e 1-Butanol was used as solvent. f 0.5 mol% Mn-1 was used. g ND = not detected.
1	Mn-1	KO^tBu	110	24	66
2	Mn-2	KO^tBu	110	24	5
3	Mn-3	KO^tBu	110	24	0
4	Mn-1	KO^tBu	90	24	45
5	Mn-1	KO^tBu	130	12	63
6	Mn-1	K2CO3	110	4	85
7	Mn-1	Cs2CO3	110	24	52
8	Mn-1	KOH	110	24	48
9^b	Mn-1	K2CO3	110	4	82
10	Mn-1	K2CO3	110	4	65^d, 58^e
11^f	Mn-1	K2CO3	110	24	80
12	––	K2CO3	110	24	ND^g

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With the optimized reaction conditions in hand, the scope of the formal conjugate addition reactions was investigated (Scheme 2). The variation of Ar adjacent to the nitrile group was first examined. Benzene rings with electron-donating groups (CH₃O- and ^tBu-) gave relatively higher yields (5, 90%;7, 85%) than that bearing an electron-withdrawing group (CF₃-, 4, 50%). Notably, the halide group, chlorine (6), was retained under the reaction conditions, delivering products in 78% yields. The substituent position had little influence on the reaction outcomes, and all substrates can forge the target products 8 and 9 in 84% and 85% yields, respectively. Similarly, nitriles containing naphthyl and thienyl groups could also be utilized for the conjugate addition reactions, leading to the corresponding products 10 and 11 in moderate yields. Next, a variety of internal aryl allyl alcohols were examined. No obvious electronic and steric effects were observed, leading to the targeted products 12–16 in 76–85% yields. Notably, multiple substituents of aryl moieties were also allowed in this reaction, in which the di ortho substituted substrate gave a lower yield (17, 62% vs.18, 86%). Moreover, the naphthalene tethered allyl alcohol coupled with phenylacetonitrile smoothly to produce 19 in 85% yield. It is worth noting that the secondary ally alcohol was also tolerated to give the corresponding δ-hydroxynitrile 20 in 85% yield. Delightfully, internal alkyl allyl alcohols were compatible with this transformation, delivering 21–25 in good yields. Encouragingly, this reaction was capable of constructing quaternary carbon centers to offer 26 and 27 in excellent yields. Subsequently, the scope of terminal allyl alcohols was investigated. No matter whether the R² group was an alkyl or aryl moiety, this process still occurred successfully to afford 28–32 in 79–88% yields. Furthermore, vinyl aryl methanols were demonstrated as suitable coupling partners to react with phenylacetonitrile to provide the coupled products 33–35 in 80–87% yields. Finally, propylene alcohol proceeded in this reaction efficiently with plenty of primary and secondary nitriles to generate the expected products 36–44 in moderate to good yields.

Scheme 2 Mn-catalyzed cross-coupling of allylic alcohols and nitriles. Reaction conditions: 1 (0.5 mmol, 1 equiv.), 2 (1.0 mmol, 2 equiv.), toluene (1.0 mL), [Mn] (1 mol%), and base (10 mol (%) at 110 °C. d.r. was analyzed by ¹H NMR, n.d = not determined. Reported yields were calculated for pure isolated products after column chromatography.

To demonstrate the scalability and utility of this method, we applied it in the gram-scale synthesis of two important drugs (Scheme 3). Initially, 10 mmol of 3-methoxy phenylacetonitrile 45 was combined with 1-dodecanol as the first BH reaction to offer the secondary nitrile 46 in 2.69 g/80% yield under modified reaction conditions. The second BH coupling of 46 with propylene alcohol proceeded smoothly to produce tertiary nitrile 47 in 1.84 g/67% yield. Nitrile 47 underwent bromination with PBr₃ then nucleophilic substitution by 48 to form the calcium channel blocker anipamil 49 in a combined yield of 1.56 g/58% (Scheme 3-1).²⁴ In addition, the synthesis of the drug verapamil 53 can also be accomplished by using this strategy (Scheme 3-2). Using a similar procedure, nitrile 50 was coupled with propylene alcohol to forge the δ-hydroxynitrile 42 in 1.8 g/77% yield. Subsequent bromination/nucleophilic substitution of 51 occurred to give the δ-aminonitrile 51 in 1.52 g/48% yield. Introducing an isopropyl unit at the benzylic nitrile carbon on 51 according to a reported procedure can lead to verapamil 52.²⁵

Scheme 3 Application of catalytic formal conjugate addition reactions in drug synthesis.

In order to obtain a preliminary understanding of the reaction mechanism, we carried out several control experiments. First, the reaction of phenyl acetonitrile and 4-phenylbut-3-en-2-one with base (10 mol% K₂CO₃) alone occurred inefficiently to give the 1,4-conjugate addition product 54 in 25% yield (Scheme 4-1). As a comparison, addition of a catalytic amount of Mn-1 resulted in an 87% yield, which suggested that Mn-1 might accelerate this 1,4-conjugate addition reaction. Second, performing the above reaction in the presence of iso-propanol led to the formation of the desired product 20 in 87% yield with the catalyst Mn-1, however no product was observed without the use of Mn-1 (Scheme 4-2). These results indicated that a hydrogen transfer process from iso-propanol to 54 occurred via Mn catalysis. Third, a deuterium labeling reaction using deuterated cinnamyl alcohol 55 (94% D) was performed, which gave the deuterated product 56 in 85% yield with 65% deuteration at the adjacent carbon atoms near the hydroxyl group.

Scheme 4 Control experiments.

Based on these observations and the previous literature on Mn(II)-based borrowing hydrogen reactions, a plausible mechanism for Mn-1 catalyzed 1,4-conjugate addition can be proposed as shown in Fig. 2. Initially, an active Mn-1′ catalyst was formed with the assistance of a base, which triggered the dehydrogenative process of cinnamic alcohol to form the cinnamaldehyde 57 and Mn–H species III. 1,4-Conjugate addition of 57 by phenyl acetonitrile resulted in aldehyde 58. Subsequently, hydrogenation of the aldehyde group of 58 by the Mn–H species through several transient states produced the desired product 3 and regeneration of the active Mn-1′ catalyst.

Fig. 2 Plausible reaction mechanism for Mn-I catalyzed 1,4-conjugate addition of allyl alcohols and nitriles.

Conclusions

In conclusion, we have developed a manganese(I) pincer complex catalyzed efficient and facile method for the cross coupling of nitriles and allyl alcohols to form δ-hydroxynitriles. This protocol featured a broad substrate scope with a good functional group tolerance under simple conditions (43 examples, 50–94% yields). Remarkably, the mildness and practicality of this protocol were further demonstrated by the syntheses of anipamil and verapamil via a one or two-cascade borrowing hydrogen procedure. Mechanistic studies confirmed that the reaction follows a hydrogen-borrowing pathway, leading to the concept of exploiting the diagonal relationship between Ru(II) and Mn(I) to design efficient catalysts with manganese as a benign metal component. The present cheap metal-catalyzed hydrogen borrowing strategies are expected to be of high interest to scientists in academia and industry.

Experimental

General procedure for the synthesis of δ-hydroxynitrile

To a mixture of Mn-1 catalyst (1 mol%), K₂CO₃ (10 mol%), nitriles (0.5 mmol) and cinnamyl alcohol (1.0 mmol), 1.0 mL of toluene was added. Then, the reaction was stirred at 110 °C for 4 h under Ar in a pressure tube (ACE pressure tube, 15 mL). After cooling to room temperature, the reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL) three times. The combined organic layers were washed with brine and dried over magnesium sulfate, and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5 : 1–2 : 1) to give the desired product δ-hydroxynitrile.

Author contributions

D. Song designed this project and S. Wang performed most of the experiments. S. Wang and D. Song wrote this paper. The other authors participated in parts of the experiments, data analysis and the results discussion.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 22078298, 21978271 and 22178315), Natural Science Foundation of Zhejiang Province (No. LY21B020007) and key research and development program of Zhejiang Province (No. 2022C03169) for financial support.

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Footnotes

† Electronic supplementary information (ESI) available: experimental procedures and characterization data of all the compounds. See DOI: https://doi.org/10.1039/d2gc03679g

‡ S. Wang and D. Song contributed equally to this work.

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