Visible light promoted coupling of alkynyl bromides and Hantzsch esters for the synthesis of internal alkynes

Abstract

A metal-free visible light promoted C(sp³)–C(sp) coupling reaction of alkynyl bromides and Hantzsch esters was developed, giving internal alkynes with primary, secondary, tertiary alkyl or other functional groups in good to high yields.

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Introduction

Alkynes are essential structural motifs and ubiquitous intermediates in synthetic transformations for building fine chemicals, pharmaceuticals and polymeric photo-/electronic materials.¹ The past several decades have witnessed tremendous development of alkyne synthesis in organic chemistry. The general approaches via the C(sp³)–C(sp) bond formation rely on the addition reaction with organometallic reagents,² and transition-metal-catalyzed coupling reactions using Pd,³ Cu,⁴ Co,⁵ Ni,⁶ Ag⁷ and Fe⁸ complexes (Scheme 1, reaction (a)). However, the tedious reaction conditions and the use of relatively expensive metals led chemists to explore alternative protocols under mild conditions in an environmentally benign manner.⁹

Scheme 1 Synthesis of internal alkynes via C(sp³)–C(sp) coupling.

The visible-light-induced catalysis is becoming a fascinating methodology in modern organic synthesis,¹⁰ including those for C(sp³)–C(sp) coupling reactions (Scheme 1, reaction (b)). For example, in 2014, Chen et al. reported a visible-light-induced deboronative alkynylation reaction with [Ru(bpy)₃](PF₆)₂/BI–OH.¹¹ This reaction worked with alkyl trifluoroborates or boronic acids to generate substituted alkynes. In 2015, Hashmi et al. reported a gold-catalyzed radical C(sp³)–H alkynylation of tertiary aliphatic amines using readily available 1-iodoalkynes as a radical alkynylation reagent in the presence of [Au₂(μ-dppm)₂]²⁺ under photocatalysis conditions.¹² The reaction shows excellent regioselectivity and good functional-group compatibility. However, these reactions require expensive transition metals/ligands and limitations of the substrate scope. In 2015, Li et al. reported a pioneering metal-free coupling of an alkyne and alkyl iodide under ultraviolet irradiation (Scheme 1, reaction (c)).¹³

Recently, Hantzsch esters (HEs)¹⁴ have been extensively used in transfer-hydrogenation reactions and transfer-alkylation reactions, especially in photoredox reactions.¹⁵ In 2011, Nishibayashi and coworkers reported the first visible-light-induced reaction of HEs via alkyl radicals.¹⁶ After that, the reactions of HEs have been successfully used for the C(sp³)–C(sp³)¹⁷ and C(sp³)–C(sp²)¹⁸ bond formation. Very recently, Cheng and co-workers reported the alkynylation of HEs with benziodoxole-activated alkynes under oxidative conditions (Scheme 1, reaction (d)).¹⁹ In this paper, we report a visible-light-induced radical C(sp³)–C(sp) coupling of alkynyl bromides and Hantzsch esters for the synthesis of internal alkynes (Scheme 1, reaction (e)). Our work provides a photocatalytic approach from readily available alkynyl bromides without any additional oxidant, which leads to good tolerance of functional groups.

Results and discussion

Initially, the reaction of 1-bromo-2-phenylacetylene (1a) with 4-cyclohexyl Hantzsch ester (2a) was investigated under photocatalysis (Table 1). We were encouraged to find that the desired cyclohexyl alkyne (3aa) was obtained in 19% yield when the reaction was carried out with 2 mol% of 4CzIPN (2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile) as the photocatalyst in dichloromethane at room temperature for 12 h under the irradiation of blue LEDs (entry 1). The yield was increased to 66% when the reaction time was prolonged to 36 h (entry 2). The addition of a silver salt showed no apparent improvement (entry 3). Screening of solvents and bases revealed that 1,2-dichloroethane is the best choice (entries 4–8), and K₃PO₄ performed best compared to other inorganic and organic bases (entries 8–12). Evaluation of photocatalysts showed that Ir- and Ru-based photocatalysts only afforded the product with a slightly increased yield (entries 13 and 14), while the organic photocatalyst of 10-methyl-9-mesitylacridinium gave only a trace amount of product (entry 15). Considering the environmental benignity of organic photocatalysts compared to transitional metals, the metal-free photocatalyst 4CzIPN was chosen for the reaction. A higher yield was achieved when the loading of Hantzsch ester 2a was increased to two equivalents (entry 16). It is worth noting that the reaction using alkynyl chloride (1a′) or sulfone (1a″) instead of bromide (1a) resulted in some loss of yield (entries 17 & 18).

Table 1 Optimization of the alkynylation reaction^a

Entry	1	PC	Base	Solvent	Yield^b (%)
a Unless otherwise specified, 1a (0.2 mmol), 2a (0.3 mmol), photocatalyst (2 mol%), base (0.6 mmol), solvent (4 mL, [0.5 M]), rt. b Yields determined by ^1H NMR (400 MHz) spectroscopy with CH2Br2 as the internal standard. c The reaction was terminated after 12 h. d AgNO3 (0.2 mmol) was added as an additive. e 2a (0.4 mmol) was used. f Isolated yields in parentheses. DCE = 1,2-dichloroethane, 4CzIPN = 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile, ppy = 2-phenylpyridine, Mes-Acr-Me = 10-methyl-9-mesitylacridinium.
1^c	1a	4CzIPN	K3PO4	CH2Cl2	19
2	1a	4CzIPN	K3PO4	CH2Cl2	66
3^d	1a	4CzIPN	K3PO4	CH2Cl2	67
4	1a	4CzIPN	K3PO4	DMF	Trace
5	1a	4CzIPN	K3PO4	DMSO	45
6	1a	4CzIPN	K3PO4	MeCN	55
7	1a	4CzIPN	K3PO4	Acetone	57
8	1a	4CzIPN	K3PO4	DCE	70
9	1a	4CzIPN	Cs2CO3	DCE	60
10	1a	4CzIPN	NaOAc	DCE	51
11	1a	4CzIPN	t-BuOK	DCE	NR
12	1a	4CzIPN	DBU	DCE	22
13	1a	fac-Ir(ppy)3	K3PO4	DCE	71
14	1a	Ru(ppy)3Cl2	K3PO4	DCE	76
15	1a	Mes-Acr-Me	K3PO4	DCE	3
16^e	1a	4CzIPN	K3PO4	DCE	83(75)^f
17^e	1a′	4CzIPN	K3PO4	DCE	(45)^f
18^e	1a″	4CzIPN	K3PO4	DCE	(21)^f

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With the optimized reaction conditions in hand, we then investigated the substrate scope. A variety of arylethynyl bromides worked well for the reaction (Table 2). Both electron-donating groups (1b–1f) and electron-withdrawing groups (1g–1m) were tolerated at the ortho-, meta- or para-position, giving the internal alkynes 3aa–3ma in good to high yields (entries 1–13). All arylethynyl bromides with 4-phenyl or α-naphthyl and heteroarylethynylbromide derived from indole or thiophene worked as well (3na–3qa) (entries 14–17). Notably, the ester and ketone were also tolerable for the reaction to give the corresponding product (3ra) and estrone-derived alkyne (3sa) in good yields (entries 18 &19). The reaction of a series of 4-alkyl Hantzsch esters is shown in Table 3. It was found that benzyl, acyclic and cyclic secondary alkyl could be easily coupled with the alkynyl bromides to give the products (3db–3ld) in good to high yields (entries 1–4). More importantly, the tertiary alkyl, which is difficult to introduce by the classical nucleophilic substitution reaction, worked best due to the relative stability of their radicals (3ae–3qe) (entries 5–11). It should be noted that Meyer nitrile 2e ²⁰ was used instead of Hantzsch esters due to the difficulty in their synthesis. Furthermore, the reaction of the piperidine-derived Hantzsch ester went smoothly to give product 3df in 65% yield (entry 12).

Table 2 Scope of alkynyl bromides

Entry	1	3	Yield (%)
1	1a (X = H)	3aa	75
2	1b (X = 2-Me)	3ba	87
3	1c (X = 3-Me)	3ca	77
4	1d (X = 4-Me)	3da	84
5	1e (X = 4-MeO)	3ea	85
6	1f (X = 4-t-Bu)	3fa	64
7	1g (X = 2-F)	3ga	76
8	1h (X = 3-F)	3ha	55
9	1i (X = 4-F	3ia	69
10	1j (X = 2-Cl)	3ja	81
11	1k (X = 4-Cl)	3ka	74
12	1l (X = 4-Br)	3la	93
13	1m (X = 4-CF3)	3ma	70
14			79
15			53
16			62
17			45
18			66
19			56

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Table 3 Scope of 4-alkyl Hantzsch esters

Entry	1	2	3	Yield (%)
1	1d			92
2	1d	2c	3dc	89
3	1k	2c	3kc	72
4	1l			91
5	1a	2e	3ae (X = H)	91
6	1e	2e	3ee (X = MeO)	89
7	1l	2e	3le (X = Br)	91
8	1m	2e	3me (X = CF3)	63
9	1n	2e	3ne (X = Ph)	89
10	1r	2e	3re (X = CO2Me)	99
11	1q	2e		51
12	1d			65

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The scale-up reaction using 1.05 g (5 mmol) of alkynyl bromide 1e gave product 3ea in 78% yield (Scheme 2).

Scheme 2 Gram-scale experiment.

The photocatalytic alkynyl–alkyl coupling reaction is believed to proceed via a radical intermediate.²¹ Control experiments revealed that the reaction was completely suppressed with no desired product detected when TEMPO (2,2,6,6-tetramethyl-1-oxylpiperdine) was added as the radical-trapping reagent (Scheme 3).

Scheme 3 Radical-trapping reaction.

The plausible mechanism for the reaction is shown in Fig. 1. The readily available photocatalyst 4CzIPN is irradiated under blue LEDs to the photoexcited state (4CzIPN*), which features a high redox potential  ²² (PC = 4CzIPN) to promote the photooxidative reaction. The substituted Hantzsch esters (E^red_1/2 = +1.08 V vs. SCE)^17a were cleaved by the oxidation of photoexcited 4CzIPN* to generate the alkyl radical I and radical anion II. The addition of alkyl radical I to arylethynylbromide affords the bromoalkenyl radical III,²³ which is collapsed to give alkylalkyne 3 and a bromine radical.²⁴ The reduction of the bromine radical by radical anion species II ²⁵ regenerates the photocatalyst and furnishes the catalytic cycle.

Fig. 1 Plausible reaction mechanism.

Conclusions

In summary, the photocatalytic synthesis of internal alkynes via C(sp³)–C(sp) bond coupling of bromoalkynes and Hantzsch esters was developed. All the primary, secondary and tertiary alkyl radicals generated from the Hantzsch ester derivatives worked well for the reaction. The reaction features good tolerance of many functional groups, including esters and ketones, under metal-free conditions.

Experimental

Unless otherwise indicated, all reactions were carried out with N₂ protection with magnetic stirring. Anhydrous CH₂Cl₂ was distilled from CaH₂. Column chromatography was performed on silica gel (200–300 mesh). All ¹H NMR (300 or 400 or 500 MHz) and ¹³C NMR (75 or 101 or 126 MHz) spectra were recorded on a Bruker-DMX 300 or 400 or 500 spectrometer in CDCl₃, with CH₂Br₂ as an internal standard and reported in parts per million (ppm, δ). ¹H NMR spectroscopy splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q). Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br). Infrared spectra were recorded on a Nicolet 6700 spectrophotometer and reported in wavenumbers (cm⁻¹).

Visible light promoted coupling of alkynyl bromides and Hantzsch esters

General procedure. To a solution of alkynyl bromides 1 (0.2 mmol) in a 10 mL reaction tube were added Hanzsch ester 2 (0.4 mmol, 2.0 equiv.), 4CzIPN (3.15 mg, 0.004 mmol, 2 mol%) and K₃PO₄ (127 mg, 0.6 mmol, 3.0 equiv.) under a nitrogen atmosphere at room temperature. The tube was sealed and 4 mL of DCE were injected. Then the solvent was degassed 3 times. The reaction mixture was stirred for 36 h at room temperature and irradiated by 24 W blue LEDs. After the completion of the reaction, the mixture was diluted with H₂O and extracted with DCM 3 times. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give the desired coupling product 3.

Radical-trapping experiment

To a solution of alkynyl bromides 1e (42 mg, 0.2 mmol) in a 10 mL reaction tube were added Hanzsch ester 2a (134 mg, 0.4 mmol, 2.0 equiv.), 4CzIPN (3.15 mg, 0.004 mmol, 2 mol%), TEMPO (2,2,6,6-tetramethyl-1-oxylpiperidine, 62.5 mg, 0.4 mmol, 2.0 equiv.) and K₃PO₄ (127 mg, 0.6 mmol, 3.0 equiv.) under a nitrogen atmosphere at room temperature. The tube was sealed and 4 mL of DCE was injected. Then the solvent was degassed 3 times. The reaction mixture was stirred for 36 h at room temperature and irradiated by 24 W blue LEDs. No desired product was observed by TLC.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no.: 21425207, 21521002, 21672216) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ob02912a

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