Photoredox/nickel dual-catalyzed deaminative cross-electrophile for allenylic alkylation with non-activated alkyl katritzky salts

Abstract

Herein, we report the first allenylic alkylation with bench-stable aliphatic amine-derived Katritzky salts via photoredox/nickel dual-catalyzed reductive deaminative cross-electrophile coupling. Non-activated alkyls were efficiently introduced. Abundant substrate sources make this reaction a suitable alternative and widely applicable as it avoids the limitations of rare allenylic alkylations with amino acid derivatives. Meanwhile, the successful involvement of alkyl propargylic electrophiles represents a rare but direct approach for synthesizing polyalkylated allenes without organometallic reagents. Mechanistically, a hypothetical radical–radical coupling between alkyl radical and hybrid allenyl-Ni(I) radical species is proposed.

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Alkylated allenes represent emerging structures in allene chemistry. They serve as key building blocks in diverse natural products, pharmaceuticals,¹ and materials.² Among the classic methods of allene synthesis,³ catalytic alkylation reactions between alkyl organometallic reagents and propargyl derivatives have been proven to be a reliable way to achieve non-activated alkyl-substituted allenes.⁴ However, the limited availability of alkyl sources and the complexity in chemo- and regioselectivity of propargyl precursors is an immediate restriction and fundamental impediment. Meanwhile, with the development of a low-valence transition-metal catalytic reaction, a 1,4-addition reaction of 1,3-enynes, involving alkyl radical species for the synthesis of alkylated allenes, has been reported (Scheme 1a).⁵ However, this indirect method could not effectively synthesize diverse alkylated allenes. In this context, further exploration is in high demand for allenylic alkylation, especially for the introduction of non-activated alkyls with bench-stable alkyl precursors.

Scheme 1 Recent approach to the synthesis of alkylated allenes.

Aliphatic amines are the most prevalent structural motifs in commercially available building blocks.⁶ C–N bond activation of aliphatic amine derivatives, such as diazo⁷ and ammonium compounds,⁸ has exhibited specific synthetic potential for alkylation reactions. Moreover, since the pioneering work by Watson in 2017,⁹ Katritzky pyridinium salts have been employed as excellent alkyl reagents in radical addition,¹⁰ cross-coupling of pseudohalides,^9,11 and cross-electrophile coupling reactions.¹² Although advanced photoredox or electrocatalytic¹³ reactions without stoichiometric metal reductants¹⁴ or photocatalysts in electron donor-acceptor (EDA) complex¹⁵ have been well-developed, only a few alkyl reagents, such as alkyl Katritzky salts that are derived from amino acids, have been successfully applied in allenylic alkylation reactions (Scheme 1b). In 2022, the Zhang group developed a novel nickel-catalyzed allenylation reaction between terminal alkynes and amino acid derivatives with sterically hindered NN₂ pincer ligands.¹⁶ Later, Jubault and Poisson's group discovered straightforward metal-free access to allenoates in 2024.¹⁷ To the best of our knowledge, allenylic alkylation with non-activated alkyl amine derivatives is still elusive and remains challenging. Based on the conversion of Katritzky salts^9–17 and our continuing interest in photocatalysis,¹⁸ herein we describe a distinctive strategy: the first photoredox/nickel dual-catalyzed radical–radical cross-electrophile coupling for the synthesis of alkylated allenes with Katritzky salts (Scheme 1c). This strategy achieved a rare but direct approach for making non-activated alkyl-substituted allenes, which represent a brand-new catalytic system for allenylic functionalization.

Initially, to confirm the regioselective allenyl product with electrophilic alkyl Katritzky salts, highly active propargylic carbonate 1a was chosen as a model substrate^18b,c with NiBr₂·dtbbpy and reductant DIPEA under 390 nm Kessil irradiation in DCM as a solvent. As shown in Table 1, the photocatalyst, 4CzIPN, enabled complete conversion to the desired product 3a with 53% isolated yield as its strong reductive property (E_1/2 = −1.21 V vs. SCE) compared with the redox potential of Katritzky salts (E_1/2 = −0.93 V vs. SCE) (entry 1).¹⁹ Screening of nickel and cobalt catalysts showed that the air-stable NiBr₂·dtbbpy promoted the reaction most efficiently, while NiBr₂·dme/dtbbpy or CoBr₂ exhibited no activity (entries 2–5). Exploration of other light sources and solvents, such as DCE, MeCN or DMA, resulted in substantially decreased reactivity (entries 6–8). Considering the key roles of the photocatalyst and the reductant in the co-catalytic system, a detailed investigation revealed that [Ir(dtbbpy)(ppy)₂]PF₆ (E_1/2 = −1.51 V vs. SCE) and DIPEA exhibited superior reactivity in 63% isolated yield (entries 9–14).¹⁹ Meanwhile, investigation of additives showed that extra 4A MS gave the highest yield in the presence of a mixed DCM/DCE solvent (entries 15 and 16). Control experiments demonstrated that all reaction parameters are essential for such a cross-electrophile coupling, and the optimized reaction conditions were confirmed as 1a (0.2 mmol), 2a (2.0 equiv.), NiBr₂·dtbbpy (20 mol%), [Ir(dtbbpy)(ppy)₂]PF₆ (5 mol%), DIPEA (8.0 equiv.), and 4 Å MS (30 mg) in DCM/DCE under purple Kessil irradiation (390 nm) at room temperature under an argon atmosphere.

Table 1 Optimization of alkylated allenes with Katritzky salts^a

Entries	Catalyst	PC	Reductant	Yield^a (%)
a Reaction conditions: 1a (0.2 mmol), 1c (0.4 mmol), NiBr2·dtbbpy (20 mol%), PC (5 mol%), DIPEA (4.0 equiv.) with 2.0 mL DCM under 390 nm Kessil LEDs at room temperature under argon after 24 h. b Less than 440 nm Kessil LEDs. c With DCE. d With MeCN or DMA. e With DCM/DCE = 4 : 1. f With 4 Å MS (30 mg, 150 g mol^−1). g Without light.
1	NiBr2·dtbbpy	PC_1	DIPEA (4 eq.)	53
2	NiCl2·dtbbpy	PC_1	DIPEA (4 eq.)	31
3	NiBr2·dMeObpy	PC_1	DIPEA (4 eq.)	29
4	CoBr2	PC_1	DIPEA (4 eq.)	0
5	NiBr2·dme/dtbbpy	PC_1	DIPEA (4 eq.)	Trace
6	NiBr2·dtbbpy	PC_1	DIPEA (4 eq.)	48^b
7	NiBr2·dtbbpy	PC_1	DIPEA (4 eq.)	36^c
8	NiBr2·dtbbpy	PC_1	DIPEA (4 eq.)	0^d
9	NiBr2·dtbbpy	PC_2	DIPEA (4 eq.)	59
10	NiBr2·dtbbpy	PC_3	DIPEA (4 eq.)	41
11	NiBr2·dtbbpy	PC_4–6	DIPEA (4 eq.)	0
12	NiBr2·dtbbpy	PC_2	TEA (4 eq.)	23
13	NiBr2·dtbbpy	PC_2	HE (4 eq.)	Trace
14	NiBr2·dtbbpy	PC_2	DIPEA (8 eq.)	63
15	NiBr2·dtbbpy	PC_2	DIPEA (8 eq.)	71^e
16	NiBr2·dtbbpy	PC_2	DIPEA (8 eq.)	79^e^,^f
17	—	PC_2	DIPEA (8 eq.)	0
18	NiBr2·dtbbpy	—	DIPEA (8 eq.)	Trace
19	NiBr2·dtbbpy	PC_2	DIPEA (8 eq.)	0^g

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With the optimized conditions in hand (Table 1, entry 16), we further examined the scope of the deaminative cross-electrophile coupling with alkyl Katritzky salts. Generally, as shown in Scheme 2, propargylic precursors substituted with electron-donating groups exhibited good reactivity. In addition, the electron-rich character of the alkyl groups promoted reactions smoothly in moderate yields (3a–3e). For branched alkyl-substituted precursors that contain isopropyl and tert-butyl, the effect of steric hindrance was limited (3f–3g). Importantly, substrates with alkyl chloride and terminal olefins were well tolerated and exhibited excellent chemoselectivity without the byproduct of hydrodehalogenation and the Heck reaction (3h–3i). Furthermore, secondary and tertiary alkyl-substituted substrates were also applicable to the cross-electrophile coupling, which led to the corresponding products in synthetically useful yields (3j–3n). It should be noted that for phenyl and disubstituted substrates, poor selectivity was noted with only trace amounts of the product, respectively (3o–3p).

Scheme 2 Scope of R¹ in propargylic carbonates. Conditions: 1a–1p (0.2 mmol), 1c (0.4 mmol), NiBr₂·dtbbpy (20 mol%), [Ir(dtbbpy)(ppy)₂]PF₆ (5 mol%), DIPEA (8.0 equiv.), 4 Å MS (30 mg) with 2.0 mL DCM/DCE (4 : 1) less than 390 nm Kessil LEDs at room temperature under argon atmosphere after 24 h. ^a95% substrate recovery rate.

Given the regioselectivity of allenylic and propargylic alkylation, the effect of the electronic properties of the propargylic electrophiles on the reaction was continuously investigated.²⁰ As shown in Scheme 3, for para-substituted precursors, both electron-rich and electron-deficient groups gave the desired products in moderate to good yields smoothly (5a–5h). Moreover, propargylic carbonates with electron-deficient groups, such as chlorine or fluorine, gave a relatively decreased yield, which was probably due to the electron-deficient properties being non-conducive to the stability of the allenylic intermediate (5g–5k). Meanwhile, considering the importance of the deaminative cross-electrophile allenylic alkylation in pharmaceutical synthesis, a derivative of an electrophilic monoterpenoid, Citronellal, was effectively incorporated under this reaction manifold, affording the important building block 5l in allenes chemistry.²¹

Scheme 3 Scope of R² and alkyl Katritzky salts. Conditions: 2a–2s (0.2 mmol), 1c (0.4 mmol), NiBr₂·dtbbpy (20 mol%), [Ir(dtbbpy)(ppy)₂]PF₆ (5 mol%), DIPEA (8.0 equiv.), 4 Å MS (30 mg) with 2.0 mL DCM/DCE (4 : 1) under 390 nm Kessil LEDs at room temperature under argon after 24 h.

Other than the evaluation with respect to propargylic carbonates, the substrate scope of Katritzky salts was also examined. In general, high allenylic selectivity was observed for all inactivated secondary alkyls without any radical stabilizing groups (5m–5q). Of note, for alkyl radicals without a terminal methyl group, a decreased amount of the product was obtained, which may have been due to the negative effect of large steric hindrance during reductive elimination (5o). Furthermore, primary alkyl radicals exhibit low reactivity with both allenylic/propargylic alkylation and hydrogen-capturing mixture products (5r).²² Gratifyingly, alkyl propargylic carbonates showed excellent compatibility under standard conditions, representing the rare example of direct allenylic alkylation with alkyl propargylic precursor to the best of our knowledge (5s). To further expand the application scope of this deaminative cross-electrophile system, the gram-scale reaction with 6 mmol of 1a was employed and 1.24 g of product 3a was successfully obtained in 64% yield with a cheaper photocatalyst, 4CzIPN (Scheme 4).

Scheme 4 Gram-scale reaction.

To gain insight into the mechanism of this reductive deaminative cross-electrophile coupling, a radical capture experiment was first conducted with TEMPO. As shown in Scheme 5, a complete suppression of product 3a revealed the involvement of radical species during the reaction process. Next, the isolated 17% yield byproduct 3aa indicated the potential radical–radical coupling between dihydropyridine radical intermediate and alkyl radical (Scheme 5).^14a,22 The molecular sieves also played important roles in improving reaction yields. The suppressed propargylic hydrogenation byproduct 5ba indicated oxidative addition with Ni(0) to form hybrid propargyl-Ni(I) species before allenyl-Ni(I) species for this structure. Meanwhile, propargylic radical capture produced 6a and two kinds of hydrogen-capturing products, 6b and 6c, which were isolated only in the presence of both nickel catalyst and photocatalyst with DIPEA. These observations further confirmed the involvement of propargyl-Ni(I) species. Finally, an intermolecular EDA complex between DIPEA and Katritzky salts 2a without a photocatalyst was observed accompanied by a red shift, which partially explains the origin of alkyl radicals (see ESI†).

Scheme 5 Radical capture experiments.

Based on the obtained results and previous reports on the reductive cross-electrophile coupling,¹² a hypothetical mechanism for the regioselective cross-electrophile allenylic alkylation has been proposed here (Scheme 6). With irradiation by 390 nm purple light, the excited-state Ir(III)* complex induced a SET process with DIPEA through a reductive quenching cycle, leading to the formation of a reduced-state Ir(II) complex. Furthermore, low-valence nickel species Ni(0) underwent a single electron oxidation addition with 1a to generate a hybrid allenyl-Ni(I) species, namely allenylic radical A.²³ Meanwhile, reduction of Katritzky salt 2a (E_1/2 = −0.93 V vs. SCE) by low-valence Ir(II) (E_1/2 = −1.51 V vs. SCE) generated an alkyl radical C, which then captured the allenylic species A to generate the desired radical–radical coupling product 3a and Ni(I) species.^23e,24 Finally, a complete co-catalytic system was achieved with the reduction of the Ni(I) complex to Ni(0) by the low-valence Ir(II) complex. Notably, despite photocatalysts playing an indispensable role in reactions, the formation of the alkyl radical C from low-valent nickel species^9,25 or the EDA complex with DIPEA²⁶ could not be fully ruled out. Meanwhile, through the reductive reaction atmosphere, the mechanism involving reductive elimination from Ni(III) species could not be ruled out.²⁷ Further investigations to gain a more detailed understanding of the mechanisms are underway in our laboratory.

Scheme 6 Proposed reaction mechanism.

Conclusions

In summary, we have established the first allenylic alkylation with bench-stable aliphatic amine-derived Katritzky salts via photoredox/nickel dual-catalyzed reductive deaminative cross-electrophile coupling. The structurally diverse and efficient activation of non-activated alkyl amine-derived Katritzky salts makes the reaction widely applicable in the absence of stoichiometric metal reductants and strong bases. A rarely reported highly regioselective allenyl alkylation with an alkyl propargylic precursor was also successfully achieved. Mechanistically, a hypothetical radical–radical coupling between the alkyl radical and the hybrid allenyl-Ni(I) radical species is proposed. We expect this protocol to serve as a pioneering work for alkylation reactions and allenylic synthesis.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by Jiangxi Province Key Laboratory of Organic Functional Molecules (No: 2024SSY05141). We gratefully acknowledge the National Natural Science Foundation of China (No. 22001101), the Natural Science Foundation of Jiangxi Province (No. 20224BAB203014, 20212BAB213027, 20212BAB203009, 20212BAB213014 and 20224BAB213007), Jiangxi Province Key Laboratory of Organic Functional Molecules (2023KFJJ01) and Nanchang Normal University (NSBSJJ2020009) for financial support.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo00834k

‡ These authors contributed equally to this article.

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