In situ phosphonium-containing Lewis base-catalyzed 1,6-cyanation reaction: a facile way to obtain α-diaryl and α-triaryl acetonitriles

Abstract

We present a phosphonium-containing catalyst generated in situ from phosphine and tert-butyl acrylate that serves as an unusual Lewis base catalyst. It was applied for the promotion of a remote 1,6-cyanation reaction of p-quinone methides and fuchsones employing trimethylsilyl cyanide as the cyanide source. A diverse range of α-diaryl and α-triaryl acetonitriles was obtained in high yields under mild reaction conditions with low catalyst loading (5 mol%). The practicality and utility of this protocol were demonstrated via the gram-scale preparation and facile elaboration of products. Mechanistic investigations (in situ NMR and ESI-MS analysis) were employed to characterize the active zwitterionic phosphonium intermediate, which was the “true” active catalyst.

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In recent decades, organophosphine-participating nucleophilic catalysis has emerged as one of the most flourishing and attractive research field, and also as a powerful tool for the preparation of structurally diverse molecules.¹ In a general mode of phosphine catalysis, the reaction between a nucleophilic phosphine and a suitable electrophile initially generates a zwitterionic species A, and then captures appropriate electrophiles such as aldehydes or imines,² electron-deficient alkenes,³ or allenes⁴ to afford many useful products. Alternatively, the basic nature of such zwitterionic intermediates can be utilized to deprotonate pronucleophiles, leading to the Michael addition⁵ or γ-addition⁶ (Fig. 1a). Limited by this traditional activation mode, the application and development of organophosphine catalysis has been restricted. Interestingly, recent studies have shown that the zwitterion A generated in situ from phosphines and active electrophiles could be utilized as organic base catalysts for chemical synthesis. In 2008, Tian and colleagues reported a Henry reaction using an phosphonium salt in situ as a Brønsted base catalyst by combining triphenylphosphine and methyl acrylate.⁷ Zhao and coworkers established chiral phosphine-acrylate dual-reagent catalysis for many asymmetric transformations whereby the zwitterionic A generated in situ from a chiral amino acid-based phosphine and acrylate were rightfully utilized as Brønsted base catalysts.⁸ Recently, our research team also developed a novel and efficient in situ phosphonium-containing Brønsted base catalyst assembled with dipeptide-based phosphine and allenoate to enable a facile asymmetric decarboxylative Mannich reaction between cyclic ketimines and β-keto acids with excellent yields and enantioselectivities (Fig. 1b, left).⁹ The phosphine-acrylate dual-reagent from the work of Zhao and colleagues could also serve as a Lewis base catalyst to achieve enantioselective Strecker-type reactions.¹⁰ Accordingly, Wu and coworkers reported cyanosilylation of α,α-dialkoxy ketones by phosphine-acrylate dual-reagent catalysis.¹¹ Recently, Zhang and Liu reported the 1,4-conjugate addition of β-trifluoromethyl enones with analogous strategy (Fig. 1b, right).¹² Despite such impressive progress in this field, the novel catalytic model is underdeveloped and remains challenging. In particular, application of an in situ phosphonium-containing organic base catalyst to promote a remote 1,6-cyanation has not been reported. Thus, focusing on replenishing novel reactions and challenging substrates to achieve diverse organic synthesis by such in situ Lewis base catalysis is worthwhile.

Fig. 1 (a) General phosphine catalysis; (b) an in situ phosphonium catalyst serving as an organic base catalyst; and (c) an in situ phosphonium-containing Lewis base catalyst enabling a remote 1,6-cyanation reaction (this work).

Conversely, α-diaryl and α-triaryl nitriles have emerged as essential scaffolds present in many pharmaceutical agents and biologically active molecules (Fig. 2).¹³ Accordingly, efforts have been directed toward the development of a new process to furnish these scaffolds.¹⁴ The direct cyanation reaction of p-quinone methides (p-QMs)¹⁵ is a straightforward and attractive way to construct such structural motifs.¹⁶ We have conducted considerable research on phosphonium-containing organocatalysis.^9,17,18 We hypothesized that combining an organophosphine with a suitable acrylate for in situ formation of a phosphonium species might be employed as an impactful Lewis base catalyst to activate trimethylsilyl cyanide. That hypothesis was inspired by the natural affinity of silicon to oxygen or fluorine anions. Herein, we present an efficient and applicative methodology for preparing functionalized α-diaryl and α-triaryl nitrile molecules. In this strategy, an in situ phosphonium salt generated from tricyclohexylphosphine and tert-butyl acrylate was employed as a novel Lewis base catalyst for promoting 1,6-cyanation of p-QMs and fuchsones using trimethylsilyl cyanide (TMSCN) as a safe and convenient cyanide source (Fig. 1c).

Fig. 2 Representative bioactive molecules containing α-diaryl- or α-triaryl nitrile units.

We began our studies by using PPh₂Me (P1) and ethyl acrylate (E1) as catalyst partners to investigate the 1,6-cyanation reaction between p-QM (1a) and TMSCN (2a) in CHCl₃ at room temperature (Table 1). Gratifyingly, the desired product 3a was isolated in 65% yield after 12 h (entry 1). Encouraged by this initial result, we next screened various phosphines with ethyl acrylate (E1) as the in situ phosphonium salt catalyst (entries 2–8). Finally, P(Cy)₃ (P6) was found to be the most effective one, and gave the desired product in 94% yield (entry 6). PAr₃-type phosphines could not initiate this reaction likely due to the low activity of phosphine itself (entries 7 and 8). Then, we fixed P6 as the phosphine moiety to evaluate different electrophiles (E) for this transformation (entries 9–11). Tert-butyl acrylate (E3) was the best partner, offering the desired product in 98% yield (entry 10). Besides, we investigated allenoate E4 as the electrophile partner combined with phosphine P6 as the in situ catalyst for this reaction, but a product was not obtained (entry 11). This may have been because this in situ phosphonium species generated from phosphine and allenoate was inclined to be π₃⁴ carbon anion rather than enolate oxygen anion, so it may have been unable to act as a Lewis base catalyst.⁹ In addition, we investigated the solvent type but this did not elicit a better result (entries 12–15). Upon reducing the catalyst load to 5 mol%, the model reaction was also completed smoothly after 24 h, and afforded the target product without loss of yield (entry 16).

Table 1 Reaction optimization^a,b

Entry	P	E	Solvent	Time (h)	Yield (%)
a Reaction conditions: 1a (0.10 mmol), 2a (0.2 mmol), P (10 mol%), and E (10 mol%) in CHCl3 (1.0 mL) at room temperature. b Yields of isolated products of 3a. c 5 mol% P6 and E3 were used.
1	P1	E1	CHCl3	12	65
2	P2	E1	CHCl3	12	76
3	P3	E1	CHCl3	12	74
4	P4	E1	CHCl3	12	32
5	P5	E1	CHCl3	12	86
6	P6	E1	CHCl3	12	94
7	P7	E1	CHCl3	12	Trace
8	P8	E1	CHCl3	12	Trace
9	P6	E2	CHCl3	12	55
10	P6	E3	CHCl 3	12	98
11	P6	E4	CHCl3	12	NR
12	P6	E3	CH2Cl2	12	89
13	P6	E3	Et2O	12	91
14	P6	E3	Hexane	12	88
15	P6	E3	Toluene	12	75
16^c	P6	E3	CHCl3	24	98

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With the optimal reaction conditions in hand, the scopes of p-QMs for synthesis of α-diaryl acetonitriles were investigated (Table 2). In general, p-QMs bearing electron-donating groups (R = Me, OMe) on the phenyl ring regardless of the position were perfectly compatible with the reaction conditions, and afforded the desired cyanation products in high yields (92–99%). Halogenated substituents at the ortho, meta, or para position of the phenyl ring could be excellent substrates and afford the corresponding products in high yields (88–93%). Substrates bearing an electron-withdrawing group (R = CN, CF₃) were also well tolerated to the reaction conditions, and furnished the corresponding α-diaryl nitriles in 92% yield (3q) and 86% yield (3r), respectively. Furthermore, disubstitution on the benzene ring of p-QMs gave the corresponding products (3s) in 99% yield and (3t) 98% yield, respectively. To our delight, heterocyclic-substituted p-QMs such as 1-naphthyl and thienyl were also amenable to this protocol, and delivered the corresponding α-diaryl acetonitriles in 84–89% yields (3u–3v). Notably, p-QMs bearing two isopropyl groups at the ortho position were also well tolerated, and afforded the product (3w) in 85% yield with prolongation of the reaction time to 32 h. When methyl-substituted p-QMs were used as the substrate, the desired product (3x) was not obtained due to the instability of the substrate.

Table 2 Synthesis of α-diaryl nitriles^a,b

a Unless stated otherwise, reactions were carried out with 1 (0.10 mmol), TMSCN (0.2 mmol), P6 (5 mol%), and E3 (5 mol%) in CHCl₃ (1.0 mL) at room temperature for 24 h. b Isolated yields.

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Based on successful implementation of direct cyanation of p-QMs with TMSCN for preparing α-diaryl nitriles, we used this 1,6-cyanation reaction of fuchsones towards constructing fully substituted α-triaryl acetonitriles. This is a big challenge because of the steric hindrance and low reactivity of fuchsone substrates. To overcome this difficulty, we adjusted slightly the reaction temperature to 45 °C. To our delight, all the fuchsones tested underwent this reaction efficiently, and produced the expected α-triaryl acetonitriles in moderate-to-good yields (Table 3). In general, fuchsones with a methyl substituent group at the ortho position, regardless of their electronic properties on the aromatic moiety (Ar³), were perfectly compatible with the reaction conditions, and delivered the corresponding α-triaryl nitrile products (5a–5c) in 82–87% yields. By increasing the catalyst loading to 10 mol%, isopropyl and tert-butyl substitutional fuchsones could also be suitable substrates, and the corresponding products bearing a quaternary carbon center (5d–5g) were obtained in 80–83% yields after 36 h.

Table 3 Synthesis of α-triaryl nitriles^a,b

a Unless stated otherwise, reactions were carried out with 4 (0.10 mmol), TMSCN (0.2 mmol), P6 (5 mol%), and E3 (5 mol%) in CHCl₃ (1.0 mL) at 45 °C for 24 h. b Isolated yields. c P6 (10 mol%) and E3 (10 mol%) were used.

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To verify the utility and practicality of this protocol, the gram-scale reaction between p-QM 1f (3.5 mmol, 1.13 g) and TMSCN was undertaken, and gave the α-diaryl acetonitrile product 3f with 97% yield (1.23 g) under standard conditions. Besides, the fuchsone 4a could be accomplished under a large-scale reaction system to offer the quaternary-centered product 5a in 85% yield (Scheme 1A). Further transformations of product 3f were carried out. The CN group could be reduced readily to form primary amine 6a in 91% yield. The α-diaryl nitrile 3f could be oxidized by activated MnO₂ to give the cyan-containing quinone 6b in 89% yield. Furthermore, a similar 1,6-cyanation reaction of product 6b by in situ phosphonium provided the dicyano-substituted compound 6c in 84% yield. Besides, the p-quinone methide 6b underwent a hydrophosphonylation reaction to give the phosphorus-containing cyanide 6d in 97% yield. Analogously, sulfur-containing cyanide 6e was obtained in 92% yield by a nucleophilic addition reaction of p-quinone methide 6b with thiophenol (Scheme 1B).

Scheme 1 The gram-scale synthesis and synthetic elaboration of products.

Then, a preliminary study on the enantioselective version of this 1,6-cyanation reaction was conducted. We first carried out the model reactions of p-QMs 1a or fuchsone 4b employing a dipeptide-based chiral organophosphine P9 with acrylate E3 to produce the in situ phosphonium salt catalyst (Table 4). Regrettably, both of the corresponding desired products (3a and 5b) were generated in low yields but with 0% ee. Afterwards, we prepared chiral acrylate E5. This was selected as a catalyst partner with P(Cy)₃ for in situ formation of a chiral phosphonium catalyst to provide the enantioselectivity of this reaction. However, no chiral induction was shown. In addition, chiral phosphine (P9) and chiral acrylate (E5) were assembled together for this reaction, but promising results were not obtained (see ESI† for more details). We speculated that the long distance between the reaction site and chiral control site, as well as the flexible cyanion, may have hampered enantioselective control.

Table 4 Preliminary study of the enantioselective 1,6-cyanation reaction

Entry	Cat.	Product	Yield (%)	ee (%)
1	P9 + E3	3a	48	0
2	P9 + E3	5b	31	0
3	P6 + E5	3a	89	0
4	P6 + E5	5b	67	1
5	P9 + E5	3a	39	2
6	P9 + E5	5b	22	1

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Important control experiments were carried out to gain insight into the mechanism of this reaction. When the model substrates were used with only phosphine or tert-butyl acrylate, the reaction did not occur. This demonstrated the importance of phosphine and tert-butyl acrylate in this catalytic system. A Brønsted base, such as triethylamine, could not promote this reaction (Scheme 2A). We wished to further understand the role of an in situ-generated phosphonium catalyst from phosphine and tert-butyl acrylate. Hence, we employed electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (³¹P NMR) spectroscopy for characterization of active species. First, P(Cy)₃ and tert-butyl acrylate generated a zwitterion Ain situ, which was tested by ESI-MS (ESI Fig. S2†), and ³¹P NMR was employed to track the reaction intermediate (Fig. 3). In particular, when P(Cy)₃ and tert-butyl acrylate were added together, the expected zwitterion A was generated rapidly, and showed a new ³¹P NMR signal at δ = 32.78 ppm. Then, TMSCN was added and another new ³¹P NMR signal at δ = 32.95 ppm arose. We inferred that the oxygen anion of zwitterion A may act as a Lewis base to activate TMSCN, thereby likely forming a new species B (Scheme 2B).¹¹

Scheme 2 Control experiments and in situ³¹P NMR studies.

Fig. 3 The proposed reaction mechanism.

According to the mechanistic results stated above, we proposed a plausible reaction pathway for this 1,6-cyanation reaction (Fig. 3). First, the Michael-type addition of P(Cy)₃ to tert-butyl acrylate generated zwitterion A rapidly, which acted as a Lewis base to activate TMSCN via species B. Then, the new zwitterion B released the active CN anion, which attacked the δ-carbon of p-QM or fuchsone to accomplish 1,6-addition/aromatization, thus affording the intermediate C that could be quenched further by acid to give the target product.

In summary, we demonstrated the synthesis of an efficient in situ phosphonium salt catalyst via combining P(Cy)₃ and tert-butyl acrylate for the direct 1,6-cyanation reaction of p-QMs and fuchsones under mild reaction conditions and low catalyst loading. It provided facile access to a diverse range of α-diaryl and α-triaryl nitriles in good-to-excellent yields. Mechanistic studies showed that the zwitterion A generated in situ served as a Lewis base to activate the silicon of TMSCN. We hope that this elegant work strongly supplements the application of phosphine-acrylate catalysis. We also expect that this novel catalytic protocol might aid the construction of α-diaryl and α-triaryl nitrile scaffolds. Further development of asymmetric processes for such in situ phosphonium catalysis is ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (21971165, 21921002, 21772035, 22101189), National Key R&D Program of China (2018YFA0903500), and National Natural Science Foundation of Hunan (2021JJ40150). We also acknowledge the comprehensive training platform of the Specialized Laboratory in the College of Chemistry at Sichuan University and the Analytical & Testing Center of Sichuan University for compound testing.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Complete experimental procedures and characterization data for the prepared compounds. See DOI: 10.1039/d1qo01501j

‡ These authors contributed equally.

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