Oxidative C(sp³)–H functionalization of acetonitrile and alkanes with allylic alcohols under metal-free conditions

Abstract

An efficient method for the construction of ketonitriles and α-aryl ketones by tert-butyl peroxybenzoate (TBPB) mediated direct alkylation of acetonitrile and alkanes with α,α-diaryl allylic alcohols has been developed. The reactions involve C(sp³)–H functionalization and radical addition/1,2-aryl migration processes under metal-free conditions.

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Nitriles are versatile intermediates for the synthesis of amides, primary amines, amidines, ketones and carboxylic acids.¹ In particular, ketonitriles are featured in the synthesis of various heterocycles and biologically active compounds,² such as pyridinone derivatives,^2a–e α-hydroxyketones,^2f–h and piperidines.²ⁱ As a result, extensive research effort has been made to develop practical approaches for their facile construction.^3–12

Among them, conjugate addition of a nucleophile to unsaturated nitriles represents one of the most important methods, which is problematic in the substrate compatibility and basic conditions.³ Various precursors, such as α-silylnitrile,⁴ α-bromonitrile,⁵ diazoacetonitrile,⁶ α-aminoacetonitrile,⁷ cyanoacetate salt⁸etc., have been applied to the C–C bond formation by introducing the cyanomethyl group but they are limited by prefunctionalization. In addition, strategies involving transition metal-catalyzed C–H activation of nitrile compounds have been well documented over the past few decades.^9,10 However, catalytic C–H functionalization of simple alkylnitriles (such as acetonitrile, low acidity, pK_a 31.1 in DMSO) remains rare.¹¹ Recently, Liu,^11b Li,^11e Zhu,^11g You^11hetc. have reported elegant direct oxidative cyanomethylation reactions by incorporating the acetonitrile with alkene. From an eco-sustainable and atom economical standpoint, the direct utilization of simple substrates and transition metal-free processes would be more attractive, and further development of new type-reactions toward nitrile derivatives is still highly desirable.¹²

Recently, much attention has been paid to new methods for the C–C bond formation through free-radical-initiated C–H bond functionalization.¹³ Especially the selective activation of C(sp³)–H bonds in ethers, alcohols, amines, alkanes, and other activated compounds has achieved significant success.^14,15 Since 2013, radical-mediated 1,2-migration reactions¹⁶ of α,α-diaryl allylic alcohols have been expanded to CF₃,¹⁷ N₃,¹⁸ POPh₂,¹⁹ and alkyl²⁰ radicals by Wu, Tu, Sodeoka, Han, and our group, and new Csp³–X (X = C, P, N) and Csp³–Csp² bonds have been concomitantly constructed by this type rearrangement (Scheme 1a). Herein, we communicate our recent efforts to present the metal-free oxidative C(sp³)–H functionalization of acetonitrile with α,α-diaryl allylic alcohols, which is initiated with radical addition and terminated by a 1,2-aryl migration (Scheme 1b). The protocol is also efficient when simple alkanes were used as the raw materials instead of acetonitrile.

Scheme 1 Radical-initiated tandem addition/1,2-migration reactions.

The initial study was carried out with allylic alcohol 1a and acetonitrile 2a as the model substrates (Table 1). Fortunately, using TBPB (tert-butylperoxybenzoate) as the radical initiator without any redox catalyst²¹ at 120 °C for 12 h, the direct oxidative alkylation product 4aa could be obtained in 90% GC yield, along with an isolated yield of 87% (Table 1, entry 1). It was found that other oxidants such as DTBP, TBHP or CHP showed low reaction efficiency (Table 1, entries 2–4). Meanwhile, PhI(OAc)₂ and K₂S₂O₈ resulted in no product (Table 1, entries 5 and 6). Lower equivalent of acetonitrile in 1,2-dichloroethane or toluene reduced the yield dramatically (Table 1, entry 7). Further screening of the amount of oxidant (Table 1, entries 8–10), the reaction temperature (Table 1, entry 11) and the reaction time (Table 1, entry 12) revealed that allylic alcohol 1a with 2 equiv. TBPB in 3 mL of acetonitrile at 120 °C for 12 h would be the optimal conditions (Table 1, entry 1).

Table 1 Initial discovery and optimization of reaction conditions^a

Entry	Oxidant (equiv.)	Time (h)	Temp. (°C)	GC-yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (3 mL), and oxidant (1–3 equiv.) (TBPB = tert-butylperoxybenzoate, DTBP = di-tert-butyl peroxide, TBHP = tert-butyl hydroperoxide (70% in aqueous solution), CHP = cumyl hydroperoxide) at 120 °C. b Yields were determined by GC with an internal standard. c Isolated yields. d 2a (10 equiv.) in 1,2-dichloroethane or toluene (3 mL).
1	TBPB (2)	12	120	90(87)^c
2	DTBP (2)	12	120	20
3	TBHP (2)	12	120	<5
4	CHP (2)	12	120	0
5	K2S2O8 (2)	12	120	0
6	PhI(OAc)2 (2)	12	120	<5
7	TBPB (2)	12	120	Trace^d
8	TBPB (1.5)	12	120	71
9	TBPB (2.5)	12	120	89
10	—	12	120	0
11	TBPB (2)	12	80	Trace
12	TBPB (2)	6	120	84

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Encouraged by the above results, we then proceeded to explore the generality of this novel cascade oxidative addition/migration reaction to various α,α-diaryl allylic alcohols. As shown in Table 2, all of the symmetrical substrates with electron-withdrawing groups (F, Cl, Br, and CF₃) were effectively converted to the corresponding ketonitriles 4 in moderate to excellent yields (Table 2, 4ba–da and 4ga). Although the electronic effect on the aromatic rings reduced the reactivity to some extent, the expected products 4ea (Me) and 4fa (OMe) were still furnished in 69% and 58% yields, respectively (Table 2, 4ea–fa). Subsequently, allylic alcohols bearing two different aryl groups were studied in order to obtain information on this type rearrangement. The application of asymmetric alcohol 1h provided an inseparable mixture in 72% total yield with a ratio of 3.7 : 1 determined by ¹H NMR (Table 2, 4ha). In addition, preferential migration of the more electron-poor aryl groups was detected for substrates 1i–k and heterocycle-containing compound 1l (Table 2, 4ia–la). ortho-Substituted aryl rings 1m–1n migrated less effectively with the carbonyl derivatives 4ma–na being isolated in moderate yields (Table 2, 4ma–na). This chemoselective manner suggested that both the electronic character and the steric demand of the substituents affected the migration procedure. Based on this, the reaction is more likely to be a radical (“neophyl”) rearrangement route to the products.^17–20 Furthermore, pentafluorophenyl 1o was almost inert under our conditions (Table 2, 4oa).

Table 2 The reaction of various α,α-diaryl allylic alcohols with acetonitrile^a

a Under the optimal conditions; yields of isolated products. b The ratio of 3 and its isomer determined by ¹H NMR of the isolated product; only the major product is shown.

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We also extended the direct oxidative cyanoalkylation to other types of allylic alcohols (Scheme 2). To our delight, when 1p–r with a 3,4-dihydro-2H-pyran motif were introduced to react with 2a, the reaction went smoothly under the stated conditions to afford products 4pa–ra, albeit in lower yields (29–33%). Regretably, this method was not suitable for the ring expansion of 9-vinyl-9H-fluoren-9-ol 1s.

Scheme 2 Reaction of allylic alcohols 1p–s with 2a.

Next, other nitriles were also tested (Table 3). Cyclopropanecarbonitrile 2b underwent the oxidative C–H activation at the α-position to give the ketonitrile 4ab in a lower yield, probably due to the significant steric effect (Table 3, 4ab). Interestingly, α-substituted alkylnitriles 2c–e (Cl, Br, Ph) failed to participate in the TBPB-promoted addition reaction (Table 3, 4ac–ae). Additionally, activated nitriles were well tolerated, providing the corresponding products 4af–ah in 53–72% yields (Table 3, 4af–ah, the reactivity decreased as follows: X = CN > COOMe > PhCO).

Table 3 Substrate scope for the reaction of other nitriles with 1a^a

a Under the optimal conditions; yields of isolated products. b 2 (10 equiv.) in 3 mL of benzene. c 2 (2 equiv.) in 3 mL of fluorobenzene. d Determined by ¹H NMR of the isolated product.

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As a continuation on the free radical-initiated C(sp³)–H bond functionalization, we next turned our attention to the reaction of α,α-diaryl allylic alcohols with simple alkanes. The results are summarized in Table 4. A series of highly functionalized ketones was synthesized in moderate to excellent yields under the typical conditions (Table 4, 5aa–na). Apart from cyclic alkanes 3b–d, open-chain alkanes such as pentane 3f and hexane 3g could also act as effective substrates in this system (Table 4, 5ab–5ag).

Table 4 The reaction of simple alkanes with diaryl allylic alcohols^a

a Reaction conditions: 1 (0.3 mmol), 3 (4 mL) and TBPB (2 equiv.) at 120 °C for 7 h; yields of isolated products. b The ratio of 5 and its isomer determined by ¹H NMR of the isolated product; only the major product is shown. c 2 (10 equiv.) in 3 mL of benzene.

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The presented methodology can be conveniently used in the synthesis of complicated heterocycles 6 and 7 (Scheme 3). Dihydropyridone derivative 6 was obtained in 50% yield by intramolecular annulation of ketonitrile 4aa, which was an important class of biologically active relevant products.^2a–c Moreover, 4aa could be reduced by LiAlH₄ to give 2,3-diphenylpiperidine 7 in 79% yield.

Scheme 3 Further transformations of the ketonitrile.

To define the possible reaction pathway, 2.0 equiv. of the radical-trapping reagent (TEMPO) was added, the reaction was completely suppressed, and only TEMPO-acetonitrile adduct was observed under the standard conditions (determined by LC-MS analysis), including that an acetonitrile radical was involved in the reaction process (Scheme 4). On the basis of previous studies^19,20 and the results above, a possible mechanism was proposed in Scheme 5. Firstly, TBPB decomposed to give tert-butoxyl radical and benzoate radical at high temperature. Subsequently, hydrogen abstraction of 2a or 3a with tert-butoxyl radical (or benzoate radical) provided a cyanomethyl or alkyl radical I, which was added to allylic alcohol 1, thus affording an alkyl intermediate II. Next, intramolecular 5-ipso cyclization led to generate the spiro[2,5]octadienyl III,^17a followed by 1,2-aryl migration to give radical species IV. Finally, the desired product 4 or 5 was delivered via further oxidation and deprotonation steps.^17–20

Scheme 4 Mechanism studies.

Scheme 5 Possible mechanism.

In conclusion, we have developed a novel and convergent alkylation reaction of acetonitrile and alkanes with allylic alcohols that involves C(sp³)–H functionalization and radical addition/1,2-aryl migration. The direct utilization of commercially available nitrile derivatives and simple alkanes under metal-free conditions represents a practical and straightforward route for access to a variety of highly functionalized ketones.

We gratefully acknowledge the Natural Science Foundation of China (no. 21172162 and 21372174), the Young National Natural Science Foundation of China (no. 21202113), the Ph.D. Programs Foundation of the Ministry of Education of China (2013201130004), Key Laboratory of Organic Synthesis of Jiangsu Province (KJS1211), PAPD, and Soochow University for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00314d

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