Copper-catalyzed propargylic C–H functionalization for allene syntheses

Abstract

Allenenitriles bearing different synthetically versatile functional groups have been prepared smoothly from 5-alkynyl fluorosulfonamides in decent yields with an excellent chemo- and regio-selectivity under redox neutral conditions. The resulting allenenitriles can be readily converted to useful functionalized heterocycles. Based on mechanistic study, it is confirmed that this is the first example of radical-based non-activated propargylic C–H functionalization for allene syntheses.

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Introduction

Cross coupling reactions represent one of the most straightforward strategies for the construction of complex molecules.¹ As one important class of substrates, the transformations of propargylic compounds are attracting more and more interest.² In the past few decades, catalytic couplings of propargylic alcohol derivatives with organometallic reagents have been established as an effective and very reliable way to synthesize functionalized alkynes^3,4 or allenes^5,6 either via a two-electron or one-electron process (Fig. 1A). However, all these methods apply propargylic alcohol derivatives with an appropriate leaving group. In contrast, direct functionalization of the inert propargylic C–H bonds would provide a straightforward and atom economic approach. In this area, preparation of alkynes has been realized via the Kharasch–Sosnovsky-Type reaction,⁷ intramolecular or intermolecular nitrene insertion,⁸ and coordination-directed deprotonation⁹ (Fig. 1B). Recently Liu et al. reported the benzylic C–H activation of 1-aryl-2-alkynes for arylallene syntheses.¹⁰ We envisioned a strategy of 1,5-hydrogen atom transfer¹¹ for the generation of a propargylic radical, which would be in rapid resonance with an allenyl radical. Trapping with an appropriate reagent would afford alkynes or allenes (Fig. 1C). Such a protocol for selective allene syntheses faces three challenges: (1) the more reactive C≡C bonds may cause undesired transformations such as radical cyclization that complicates the target reaction, (2) the selectivity issue of propargylic radicals vs. allenyl radicals to form either alkyne^7,12 or allene products, and (3) a matched trapping reagent. Allenenitriles could be prepared though the corresponding Wittig reaction,¹³ S_N2′-type substitution of the in situ generated propargylic phosphates,¹⁴ cross coupling of propargylic substrates,^6i,15 and difunctionalization of 1,3-enynes.¹⁶ Herein, we wish to report our results on copper-catalyzed cyanation of non-activated propargylic C–H bonds, affording di- or tri-substituted allenenitriles bearing an attractive remote sulfonamide in decent yields with an excellent chemo- and regio-selectivity tolerating many synthetically versatile functionalities (Fig. 1D).

Fig. 1 Catalytic functionalization of propargylic compounds.

Results and discussion

We began our investigation with fluorosulfonamide^17,181a and TMSCN^15b,16 in the presence of Cu(CH₃CN)₄PF₆ (ref. ¹⁹) and ligand L1 in DCE at 30 °C. To our delight, 17% yield of desired allenenitrile 2a was obtained with 70% recovery of 1a (Table 1, entry 1). Then, attention was focused on the solvent effect (Table 1, entries 2–8): the reaction in CH₃CN for 24 h could deliver a much better yield of 2a of 75%, with only 12% recovery of 1a. By extending the reaction time to 30 hours, 1a could be converted completely, affording 2a in 83% yield (Table 1, entry 9), and the formation of isomeric alkyne product 3a was not observed. When Cu(CH₃CN)₄BF₄ was used instead of Cu(CH₃CN)₄PF₆, the yield of 2a dropped to 61%, with 10% recovery of 1a. This may be attributed to the stronger coordinating ability of BF₄⁻ than that of PF₆⁻,²⁰ which led to a lower catalytic activity. Further screening of other copper catalysts and ligands (Table 1, entries 11–17), didn't give any better results, indicating that Cu(CH₃CN₄)PF₆ and L1 are optimal.

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Copper catalyst	Ligand	Time (h)	Yield of 2a^b (%)	Recovery of 1a^b (%)
a All reactions were run on a 0.1 mmol scale in solvent (1 mL) at 30 °C under a nitrogen atmosphere. b Determined by ^1H NMR analysis with CH3NO2 as the internal standard.
1	DCE	Cu(CH3CN)4PF6	L1	24	17	70
2	Toluene	Cu(CH3CN)4PF6	L1	24	10	67
3	Ethyl acetate	Cu(CH3CN)4PF6	L1	24	29	35
4	MTBE	Cu(CH3CN)4PF6	L1	24	13	56
5	THF	Cu(CH3CN)4PF6	L1	24	13	24
6	Dioxane	Cu(CH3CN)4PF6	L1	24	38	17
7	DMF	Cu(CH3CN)4PF6	L1	24	44	—
8	CH3CN	Cu(CH3CN)4PF6	L1	24	75	12
9	CH3CN	Cu(CH3CN)4PF6	L1	30	83	—
10	CH3CN	Cu(CH3CN)4BF4	L1	36	61	10
11	CH3CN	CuCN	L1	36	69	—
12	CH3CN	CuOAc	L1	36	66	—
13	CH3CN	CuTc	L1	36	61	—
14	CH3CN	Cu(CH3CN)4PF6	L2	36	49	47
15	CH3CN	Cu(CH3CN)4PF6	L3	36	75	7
16	CH3CN	Cu(CH3CN)4PF6	L4	36	71	5
17	CH3CN	Cu(CH3CN)4PF6	L5	36	3	67

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With the optimized conditions in hand, we set out to explore the scope of this propargylic C–H cyanation reaction. As shown in Fig. 2, a variety of fluorosulfonamides bearing a highly sensitive terminal alkyne could be converted to trisubstituted allenes exclusively in decent yields. The R¹ group may be alkyl, cycloalkyl, chloroalkyl, or methoxyalkyl, and 2a–2f were furnished in 77–83% yields. In addition, terminal olefin and differently substituted benzyl groups, such as halide atoms (F, Cl, and Br), methoxy, and trifluoromethyl may be tolerated, affording 2g–2m in 67–76% yields, and the related allyl or benzyl cyanation products were not formed, indicating a perfect chemoselectivity. Furthermore, important heteroaryl groups including thiophene and pyridine are compatible, affording heteraryl-containing products 2n and 2o in 66% and 55% yields.

Fig. 2 Scope. ^aReaction conditions: 1 (0.5 mmol), TMSCN (1.0 mmol), Cu(CH₃CN)₄PF₆ (2 mol%), and L1 (4 mol%) in CH₃CN (5 mL) at 30 °C. ^bReaction on a 4.0 mmol scale. ^cCu(CH₃CN)₄PF₆ (4 mol%), L1 (8 mol%). ^dThe product was a mixture of 2c and its isomer 2g (2c/2g = 97/3), originated from the starting material 1c (1c/1g = 96/4). ^eReaction on a 0.2 mmol scale. ^fAdditional Cu(CH₃CN)₄PF₆ (2 mol%) and L1 (4 mol%) were added to the reaction mixture after stirring for 36 h. ^gCu(CH₃CN)₄PF₆ (10 mol%), L2 (20 mol%).

Compared to the alkyl-substituted substrates, the reaction of the substrate with R¹ being phenyl proceeded more smoothly, affording 2p in 83% yield. The scope could be further expanded to internal alkynes to prepare tetrasubstituted allenes 2q–2u in 58–82% yields after adjusting the reaction conditions slightly. Besides, the R³ group with synthetic versatile functional groups such as acetyl, ester, cyano, nitro, and iodo groups were all intact under the optimal mild reaction conditions (2v–2aa, 66–76% yields). The cyanation reaction could be smoothly implemented for the modification of drug molecules, providing allenenitriles 2ab and 2ac in satisfactory yields. Finally, the reaction may be easily scaled up to the gram-scale (2a), demonstrating the practicality of the protocol.

Moreover, substrates 1ad, 1ae, and 1af were prepared on purpose to check the possibility of 1,4-, 1,6-, or even 1,7-HAT: the reaction of 1ad was complicated (Fig. 3A); the reaction of 1ae underwent 1,6-HAT to result in allenenitrile 2ae in 60% yield with an excellent regioselectivity (Fig. 3B); the reaction of 1af still gave the 1,5-HAT non-allene product 5 in a poor yield (Fig. 3C). Thus, 1,4-HAT and 1,7-HAT do not work while 1,6-HAT works.

Fig. 3 The reactions for 1,n-HAT (n ≠ 5).

Such highly functionalized allenes show great synthetic potential (Fig. 4): 2a may undergo conjugate addition exclusively under a set of mild conditions to afford nitrile 6 bearing a tetrahydropyridine in 88% yield; 2a could also be cyclized with the nitrile group being hydrolyzed to afford amide 7 in 53% yield with NaOH and H₂O₂; NBS promoted electrophilic bromocyclization²¹ of 2a would afford stereodefined brominated alkenenitrile (Z)-8 bearing a tetrahydropyrrole ring in 70% yield with an excellent stereoselectivity, which has been clearly identified by X-ray analysis. The amine functionality could also be easily modified to afford the corresponding N-tosylbenzamide 9 in an excellent yield.

Fig. 4 Transformations of products. Reaction conditions: (i) Cs₂CO₃ (1.0 equiv.), CH₃CN, rt, 17 h. (ii) NaOH (2.0 equiv.), H₂O₂ (4.0 equiv.), EtOH, 80 °C, 7 h. (iii) NBS (1.2 equiv.), DCM/THF = 4/1, rt, 23 h. (iv) 3,5-Dinitrobenzoyl chloride (1.2 equiv.), DMAP (0.1 equiv.), Et₃N (1.5 equiv.), rt, 4 h.

In addition, we found with R¹ being H, both reactions of 1ag and 1ah delivered a mixture of allene 2 and alkyne 3. However, the reactions of substrates with R¹ being a non-H substituent, all afforded the allenenitriles 2 exclusively (Fig. 5A). Thus, we reasoned that the steric effect of R¹ is critical for the observed regioselectivity. To unveil the mechanism, a set of experiments were conducted. Initially, BHT was employed as a radical trapping reagent in the reaction of 1a: the formation of 2a was inhibited gradually with the increase of BHT (Fig. 5B), suggesting a possible radical pathway. To further confirm the existence of any radical intermediates, the reaction of 1ag was conducted under an oxygen atmosphere: the cyanation was inhibited completely, and alkynone 10 was isolated in 27% yield, which couldn't be afforded by the direct oxidation of amine S3ag, confirming the existence of propargylic radical intermediates²² (Fig. 5C). Finally, we investigated the reaction rate of 1a/1a-d to 2a by NMR monitoring (see the ESI†), showing that the primary kinetic isotope effect (KIE) was 1.5 (Fig. 5D).

Fig. 5 Regioselectivity and mechanistic studies.

On the basis of these experiments, a catalytic cycle involving radical intermediates has been proposed (Fig. 6): firstly, the LCu^I species would reduce the N–F bond of 1 to produce the LCu^IIF species and the N-centered radical Int 1. Then Int 1 undergoes a radical 1,5-HAT process to generate the resonance hybrid of propargylic/allenyl radical Int 2, and the LCu^IIF species is converted to the LCu^IICN species by ligand exchange with TMSCN. Subsequently, the allenyl radical, one of the resonance structures of Int 2 with less steric hindrance would be selectively trapped by the LCu^IICN species to afford the allenyl LCu^IIICN species Int 3. Reductive elimination would deliver the desired allene 2 and regenerate the catalytically active LCu^I species.

Fig. 6 Proposed mechanism.

With this approach in hand, we also attempted the enantioselective reaction with different chiral bis(oxazoline) and pyrine-oxazoline ligands. After a series of efforts (for details see Table S6 in the ESI†), the reaction of fluorosulfonamide 1a by using (S,S)-L15* gave (−)-2a in 79% yield and −36% ee. Furthermore, non-terminal alkyne 1r was also subjected to such conditions, which delivered (+)-2r in 33% yield and −23% ee (Fig. 7).

Fig. 7 Preliminary results of catalytic asymmetric propargylic C–H cyanation.

In summary, we have developed the first example of 1,5-HAT-based propargylic C–H activation, providing a highly chemo- and regioselective approach for the construction of allenenitriles, featuring great functionality compatibility. The resulting products may be readily converted to different functionalized heterocycles. Mechanistic studies support the catalytic cycle of Cu^I/Cu^III involving a propargylic radical and allenyl radical. Further studies on other types of 1,5-HAT based propargylic C–H functionalization for allene syntheses and further investigations on the asymmetric version of this propargylic C–H cyanation are ongoing in our laboratory.

Data availability

All detailed procedures, characterization data, and spectra are available in the ESI.†

Author contributions

S. M., X. W. and D. Z. designed the experiments. D. Z., J. F., Y. S and Y. H performed the experiments. D. Z. and S. M. wrote the manuscript. D. Z., C. F. and S. M. checked the experimental data.

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

Financial support from the National Key R&D Program of China (2021YFA1500100) is greatly appreciated. Shengming Ma is a Qiu Shi Adjunct Professor at Zhejiang University. We also thank Qian Zhang in our group for reproducing the results of 2c, 2j, and 2r presented in Fig. 2.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2172810. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc01501g

‡ These authors contributed equally: Junjie Fan, Yaqi Shi, and Yankai Huang.

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