Photoredox-Enabled Synthesis of α-Alkylated Alkenylammonium Salts

Abstract

The development of novel synthetic methods for quaternary ammonium salts is highly demanded since the current synthesis heavily relies on the conventional Menshutkin reaction. Herein, we report photoredox-catalyzed alkylation of α-brominated alkenylammonium salts. Mechanistically, the generation of a highly reactive α-ammoniovinyl radical is the key to our method. This reaction enables the synthesis of various unprecedented α-alkylated alkenylammonium salts.

Key words

alkenylammonium salts - photoredox catalyst - alkylation - halogen-atom transfer - quaternary ammonium salts

Quaternary ammonium salts are important chemical compounds, which are widely used as surfactants, pharmaceuticals, and organocatalysts (Scheme [1a]).[1] In most cases, these compounds are synthesized through the Menshutkin reaction: quaternarization of tertiary amines.[2] Although this reaction is a practical method for the synthesis of tetraalkylammonium salts, it is difficult to synthesize alkenylammonium salts. This is because the alkylation of the corresponding tertiary enamines is known to proceed on the carbon atom, not on the nitrogen atom (Scheme [1b]).[3] While the synthesis of trimethylvinylammonium salt, the simplest alkenylammonium salt, was attained by Kleine in 1904,[4] a versatile synthetic method for α-substituted alkenylammonium salts has not been developed. Because of the lack of reliable synthetic methods, the chemistry of alkenylammonium salts is behind compared to that of alkylammonium salts. Recently, we developed Suzuki–Miyaura or Sonogashira coupling of α-brominated alkenylammonium salts, which leads to structurally new α-arylated or α-alkynylated alkenylammonium salts (Scheme [1c]).[5] However, the synthesis of α-alkylated alkenylammonium salts proved to be difficult under these Pd-catalyzed conditions.

Scheme 1 (a) Examples of functional quaternary ammonium salts. (b) Synthesis of quaternary ammonium salts using the Menshutkin reaction. (c) Previous work. (d) This work.

Herein, we report the photoredox-catalyzed[6] synthesis of α-alkylated alkenylammonium salts from α-brominated alkenylammonium salts and 1,1-diarylethylenes (Scheme [1d]). The halogen-atom transfer (XAT)[7] mediated generation of highly reactive α-ammoniovinyl radical enables this process.

The reaction conditions for the synthesis of α-alkylated alkenylammonium salts were initially screened with α-brominated alkenylammonium salt 1a and 1,1-diphenylethylene (2a) (Table [1]). The use of (TMS)₃SiNHAd, which is reported by MacMillan and co-workers as a broadly useful XAT reagent,[8] with 4CzIPN (PC1) in MeOH under 456 nm LED irradiation gave α-alkylated alkenylammonium salt 3a in 54% yield along with 32% of reduced byproduct 4 (entry 1). Byproduct 4 would be generated through hydrogen atom transfer[9] between α-ammoniovinyl radical and MeOH or (TMS)₃SiNHAd. A survey of photoredox catalysts revealed that [Ru(phen)₃]Cl₂ (PC2) and Ir(ppy)₃ (PC3) were not effective, and the conversion of 2a decreased (entries 2 and 3). In this transformation, dramatic solvent effects were observed. With aprotic polar solvents, such as MeCN, acetone, and THF, the yield and selectivity of 3a were not satisfactory (entries 4–6), though the exact reason for this is unclear. In addition, ^t BuOH was also not an appropriate solvent; on the other hand, the generation of byproduct 4 was almost suppressed by using HFIP as a solvent (entries 7 and 8). By increasing the amount of (TMS)₃SiNHAd and prolonging the reaction time, the yield of 3a improved to 45% still suppressing the generation of 4 (entries 9 and 10). Another XAT reagent, (TMS)₃SiNH( ^t Bu), afforded product 3a in 92% yield while triisobutylamine, which has been used for the generation of C(sp²) radical,[10] failed to provide 3a (entries 11 and 12). Finally, the conditions using 6.0 mol% of PC1 gave the best result where 93% of 3a was obtained with good reproducibility (entry 13). Furthermore, the use of 5.0 equivalents of 2a proved essential for achieving a high yield (entry 13 vs entries 14 and 15).

Table 1 Investigation of the reaction conditions

Entry	Photo- catalyst	XAT reagent	Solvent	Yield (%) of 3a a	Yield (%) of 4 a
1	PC1	(TMS)3SiNHAd	MeOH	54	32
2	PC2	(TMS)3SiNHAd	MeOH	12	15
3	PC3	(TMS)3SiNHAd	MeOH	9	25
4	PC1	(TMS)3SiNHAd	MeCN	12	40
5	PC1	(TMS)3SiNHAd	acetone	35	29
6	PC1	(TMS)3SiNHAd	THF	45	48
7	PC1	(TMS)3SiNHAd	t BuOH	43	13
8	PC1	(TMS)3SiNHAd	HFIP	13	3
9b,c,d	PC1	(TMS)3SiNHAd	HFIP	40	0
10b,c,e	PC1	(TMS)3SiNHAd	HFIP	45	0
11b,c,e	PC1	(TMS)3SiNH( t Bu)	HFIP	92	0
12b,c,e	PC1	i Bu3N	HFIP	0	0
13b,c,e,f	PC1	(TMS)3SiNH( t Bu)	HFIP	93	0
14b,c,e,f,g	PC1	(TMS)3SiNH( t Bu)	HFIP	24	8
15b,c,e,f,h	PC1	(TMS)3SiNH( t Bu)	HFIP	44	7

^{a 1}H NMR yield using C₂H₂Cl₄ as the internal standard.

^b Reaction time of 16 h.

^c Using 1.5 mL of HFIP.

^d Using 2.0 equivalents of XAT reagent.

^e Using 2.5 equivalents of XAT reagent.

^f Using 6.0 mol% of PC1.

^g Using 1.0 equivalents of 2a.

^h Using 3.0 equivalents of 2a.

A proposed mechanism for this alkylation reaction of α-brominated alkenylammonium salts is described in Scheme [2a]. Upon irradiation with blue light, the photoredox catalyst is converted into the long-lived triplet excited state PC*.[6f] Since the excited-state photocatalyst has high oxidation ability, single-electron oxidation of (TMS)₃SiNH( ^t Bu) proceeds smoothly, and subsequent deprotonation gives N-centered radical A. Then, the electron-rich α-amino silicon-centered radical B is generated through the radical aza-Brook rearrangement of radical A.[8] As radical B possesses strong halogen abstraction ability, bromine atom transfer from 1a to radical B furnishes the highly reactive α-ammoniovinyl radical D, and the reaction of radical D with 2a gives radical intermediate E. The resulting radical E is reduced to anion intermediate F by PC^•–,[6g] and protonation of F gives alkylated product 3a. In the radical addition step (the reaction of radical D with 2a), when MeOH is used as a solvent, the highly reactive α-ammoniovinyl radical D would abstract hydrogen atom from an α-C–H bond of MeOH, which competes with radical addition to 2a. In contrast, the α-C–H bond of HFIP is less reactive for hydrogen atom abstraction than that of MeOH because of the polar and electrostatic influence of fluorine substituents.[11] The undesired reduction pathway, therefore, is suppressed by using HFIP as the solvent. To confirm the generation of anion intermediate F, this reaction was performed in HFIP/D₂O (Scheme [2b]). As a result, deuterated product 3a-D was obtained in 23% (¹H NMR yield), along with 40% recovery of 1a. The result indicates that PC^•– reduces radical E to anion intermediate F, which is then quenched with D₂O.

Scheme 2 (a) Proposed mechanism. (b) Anion intermediate trapping experiment.

With the optimal reaction conditions in hand, we investigated the substrate scope of the synthesis of α-alkylated alkenylammonium salts (Scheme [3]). For ease of isolation, the product α-alkylated alkenylammonium salts were collected as the PF₆ salts. In addition to 1,1-diphenylethylene (2a), 1,1-diarylethylenes having various substituents, such as a methoxy, phenyl, fluoro, or chloro group, at the para position were applicable for this transformation, and the corresponding products 3b–3e were obtained in moderate to good yields (56–79%). Both meta- and ortho-chlorinated olefins (2f and 2g) were smoothly converted into α-alkylated alkenylammonium salts (3f and 3g). Not only unsymmetrical olefins, but also a symmetrical olefin provided the alkylated product 3h in 50% yield. Notably, trisubstituted olefin and methyl atropate were compatible with our procedure (3i and 3j), while methyl acrylate and styrene derivatives did not give the corresponding products (3k–3m). Next, we explored alternative α-brominated alkenylammonium salts in conjunction with 1,1-diphenylethylene (2a) as a model olefin. The reaction of the bulkier isopropyldimethylammonium salt gave 3n in 28% yield. Heterocyclic ammonium salts were also tolerated by this reaction, and 3o–3q were obtained in 48–65% yield.

Considering that there had been no prior examples for the preparation of α-alkylated alkenylammonium salts, we then demonstrated synthetic applications using 3a. First, a scale-up synthesis was accomplished, where 59% of 3a was obtained on a 2.0-mmol scale (Scheme [4a]). Then, derivatizations of obtained 3a were conducted (Scheme [4b]). Hydrogenation of 3a using Pd/C gave 5 in 24% yield, which is a methylated analogue of plant biostimulant 6 discovered by our group.[12] [13] Moreover, selective N-demethylation of 3a occurred in the presence of DABCO, and the corresponding enamine reacted with benzaldehyde to give the condensation product 7 in 79% yield. This result highlights the utility of α-alkylated alkenylammonium salts as a new stable precursor of enamines.

Scheme 3 Scope of the reaction (N.D. = not detected). ^a hexafluorophosphate salt 1c was used as the starting material.

Scheme 4 (a) Scale-up experiment. (b) Transformations of α-alkylated alkenylammonium salt 3a.

In summary, we have developed a new synthetic method for α-alkylated alkenylammonium salts. Our photocatalytic conditions enable access to various α-alkylated alkenylammonium salts from α-brominated alkenylammonium salts and 1,1-diarylethylenes under mild conditions. Additionally, the scale-up synthesis and derivatizations of product 3a further enhance the synthetic potential of our method. Further investigation of the physical properties and bioactivity of the obtained products is ongoing in our lab.

General experimental details are given in the Supporting Information.

α-Alkylated Alkenylammonium Salt 3a; Typical Procedure

A dried reaction tube with a stirring bar was charged with 1-bromo-N,N,N-trimethylethenammonium tetrafluoroborate (1a, 50 mg, 0.20 mmol, 1.0 equiv.), 4CzIPN (9.6 mg, 0.012 mmol, 6.0 mol%), and (TMS)₃SiNHAd( ^t Bu) (160 mg, 0.50 mmol, 2.5 equiv.). The tube was filled with nitrogen by employing the usual Schlenk technique (evacuate–refill cycle). HFIP (1.5 mL) and 1,1-diphenylethylene (2a, 180 mg, 1.0 mmol, 5.0 equiv.) were added to the tube and the mixture was stirred under blue light irradiation with a cooling fan (a 40 W Kessil PR160 blue LED was placed 1 cm below the reaction vial) for 16 h. The crude mixture was concentrated in vacuo and purified by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH = 80:20) to provide the product. To exchange the counter anion, the obtained product was dissolved in CH₂Cl₂ and washed with saturated aqueous KPF₆ solution three times. The organic layer was dried with Na₂SO₄, filtered, and concentrated in vacuo. The crude product was recrystallized (CH₂Cl₂/Et₂O) to give 3a (52.1 mg) as a white solid, which contained 0.25 mg of acetone, 0.28 mg of MeOH, and 0.94 mg of CH₂Cl₂. The yield of 3a was calculated as 62%. Note: the ratio of 3a, acetone, MeOH, and CH₂Cl₂ was determined by ¹H NMR since acetone, MeOH, and CH₂Cl₂ were not completely removed after drying in vacuo for 24 h.

Mp 190 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.16–3.18 (m, 11 H), 4.36 (t, J = 8.0 Hz, 1 H), 5.26 (brs, 1 H), 5.59 (d, J = 5.5 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 4 H), 7.37 (d, J = 7.5 Hz, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.8, 49.6, 54.9, 111.8, 127.7, 128.6, 129.7, 144.1, 152.1.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₄N: 266.1909 [M]⁺; found: 266.1919.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9644.

3b

Synthesized according to the typical procedure from 1a (51 mg, 0.20 mmol) using 1-(4-methoxyphenyl)-1-phenylethene (2b, 220 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (160 mg, 0.50 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3b (69.9 mg) as a pale yellow solid, which contained 0.27 mg of Et₂O. The yield of 3b was calculated as 79%. Note: the ratio of 3b and Et₂O was determined by ¹H NMR since Et₂O was not completely removed after drying in vacuo for 24 h.

Mp 119 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.13 (d, J = 8.0 Hz, 2 H), 3.16 (s, 9 H), 3.74 (s, 3 H), 4.30 (t, J = 8.0 Hz, 1 H), 5.25 (brs, 1 H), 5.59 (d, J = 4.0 Hz, 1 H), 6.87 (d, J = 9.0 Hz, 2 H), 7.22 (t, J = 7.0 Hz, 1 H), 7.27 (d, J = 8.5 Hz, 2 H), 7.31–7.36 (m, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 34.0, 48.9, 54.9, 55.8, 111.7, 114.9, 127.6, 128.5, 129.6, 129.7, 136.0, 144.5, 152.2, 159.4.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 707 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₀H₂₆NO: 296.2014 [M]⁺; found: 296.2014.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9636.

3c

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using 4-(1-phenylethenyl)-1,1′-biphenyl (2c, 260 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (180 mg, 0.55 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 95:5 to 90:10) and recrystallization (CH₂Cl₂/Et₂O) afforded 3c (62.8 mg) as a yellow solid, which contained 1.6 mg of Et₂O, 1.1 mg of acetone, and 0.33 mg of MeOH. The yield of 3c was calculated as 60%. Note: the ratio of 3c, Et₂O, acetone, and MeOH was determined by ¹H NMR since Et₂O, acetone, and MeOH were not completely removed after drying in vacuo for 24 h.

Mp 134 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.19 (s, 9 H), 3.22 (d, J = 7.5 Hz, 2 H), 4.41 (t, J = 7.5 Hz, 1 H), 5.30 (brs, 1 H), 5.62 (d, J = 4.5 Hz, 1 H), 7.24 (t, J = 7.5 Hz, 1 H), 7.34–7.37 (m, 3 H), 7.40–7.47 (m, 6 H), 7.61 (d, J = 8.0 Hz, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.8, 49.3, 55.0, 111.8, 127.7, 127.8, 128.2, 128.4, 128.6, 129.1, 129.79, 129.83, 140.3, 141.1, 143.4, 144.0, 152.1.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 707 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₅H₂₈N: 342.2222 [M]⁺; found: 342.2205.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9637.

3d

Synthesized according to the typical procedure from 1a (51 mg, 0.20 mmol) using 1-(4-fluorophenyl)-1-phenylethene (2d, 210 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (190 mg, 0.58 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3d (48.8 mg) as a pale yellow solid, which contained 0.24 mg of acetone and 0.85 mg of CH₂Cl₂. The yield of 3d was calculated as 56%. Note: the ratio of 3d, acetone, and CH₂Cl₂ was determined by ¹H NMR since acetone and CH₂Cl₂ were not completely removed after drying in vacuo for 24 h.

Mp 152 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.13–3.18 (m, 11 H), 4.37 (t, J = 8.0 Hz, 1 H), 5.25 (brs, 1 H), 5.60 (d, J = 5.0 Hz, 1 H), 7.07 (t, J = 8.5 Hz, 2 H), 7.23 (t, J = 6.5 Hz, 1 H), 7.32–7.39 (m, 6 H).

¹³C NMR (126 MHz, CD₃CN): δ = 34.1, 48.9, 55.0, 112.0, 116.3 (d, J = 21.6 Hz), 127.9, 128.6, 129.8, 130.4 (d, J = 8.4 Hz), 140.2 (d, J = 3.6 Hz), 143.9, 152.0, 162.5 (d, J = 244 Hz).

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 707 Hz, 6 F), –116.2 (m, 1 F).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₃FN: 284.1815 [M]⁺; found: 284.1825.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9648.

3e

Synthesized according to the typical procedure from 1a (51 mg, 0.20 mmol) using 1-(4-chlorophenyl)-1-phenylethene (2e, 220 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (210 mg, 0.67 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3e (66.0 mg) as a yellow solid, which contained 3.7 mg of Et₂O and 2.8 mg of CH₂Cl₂. The yield of 3e was calculated as 67%. Note: the ratio of 3e, Et₂O, and CH₂Cl₂ was determined by ¹H NMR since Et₂O and CH₂Cl₂ were not completely removed after drying in vacuo for 24 h.

Mp 129.4–134.2 °C.

¹H NMR (500 MHz, CD₃CN): δ = 3.14–3.16 (m, 11 H), 4.36 (t, J = 8.0 Hz, 1 H), 5.24 (brs, 1 H), 5.60 (d, J = 4.5 Hz, 1 H), 7.22–7.26 (m, 1 H), 7.32–7.37 (m, 8 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.8, 49.0, 55.0, 112.0, 128.0, 128.6, 129.7, 129.8, 130.3, 133.0, 143.0, 143.6, 151.9.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₃ClN: 300.1519 [M]⁺; found: 300.1504.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9644.

3f

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using 1-(3-chlorophenyl)-1-phenylethene (2f, 220 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (160 mg, 0.52 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 90:10) and recrystallization (CH₂Cl₂/n-hexane) afforded 3f (49.0 mg, 0.110 mmol, 55%) as a pale yellow solid.

Mp 144 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.15–3.17 (m, 11 H), 4.37 (t, J = 8.0 Hz, 1 H), 5.24 (brs, 1 H), 5.60 (d, J = 5.0 Hz, 1 H), 7.23–7.26 (m, 2 H), 7.31–7.38 (m, 6 H), 7.43 (s, 1 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.5, 49.2, 54.9, 111.9, 127.2, 127.8, 128.0, 128.5, 128.6, 129.8, 131.3, 134.9, 143.2, 146.5, 151.8.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 707 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₃ClN: 300.1519 [M]⁺; found: 300.1516.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9639.

3g

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using 1-(2-chlorophenyl)-1-phenylethene (2g, 220 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (210 mg, 0.67 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/ MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3g (54.5 mg, 0.122 mmol, 60%) as a pale yellow solid.

Mp 134 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.15–3.18 (m, 11 H), 4.84 (t, J = 8.0 Hz, 1 H), 5.19 (brs, 1 H), 5.60 (d, J = 5.5 Hz, 1 H), 7.26 (t, J = 7.5 Hz, 2 H), 7.33–7.38 (m, 5 H), 7.43 (dd, J = 7.5, 1.5 Hz, 1 H), 7.50 (dd, J = 7.5, 1.5 Hz, 1 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.8, 45.5, 55.0, 111.8, 128.0, 128.6, 129.1, 129.3, 129.4, 129.7, 130.8, 134.4, 140.8, 142.3, 151.8.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 704 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₃ClN: 300.1519 [M]⁺; found: 300.1519.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9643.

3h

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using 1,1-bis(4-fluorophenyl)ethene (2h, 220 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (180 mg, 0.55 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH, 95:5 to 86:14) and recrystallization (CH₂Cl₂/Et₂O) afforded 3h (46.0 mg) as a white solid, which contained 0.32 mg of Et₂O, 0.51 mg of acetone, and 0.35 mg of CH₂Cl₂. The yield of 3h was calculated as 50%. Note: the ratio of 3h, Et₂O, acetone, and CH₂Cl₂ was determined by ¹H NMR since Et₂O, acetone, and CH₂Cl₂ were not completely removed after drying in vacuo for 24 h.

Mp 150 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.11 (d, J = 7.5 Hz, 2 H), 3.15 (s, 9 H), 4.38 (t, J = 8.0 Hz, 1 H), 5.24 (brs, 1 H), 5.61 (d, J = 4.5 Hz, 1 H), 7.06–7.11 (m, 4 H), 7.35–7.38 (m, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 34.2, 48.0, 54.9, 112.0, 116.3 (d, J = 21.6 Hz), 130.4 (d, J = 8.4 Hz), 139.9 (d, J = 3.6 Hz), 151.7, 162.5 (d, J = 244 Hz).

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz, 6 F), –116.1 (m, 2 F).

HRMS (ESI-MS, positive): m/z calcd for C₁₉H₂₂F₂N: 302.1720 [M]⁺; found: 302.1721.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9637.

3i

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using 1,1-diphenylpropene (2i, 190 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (170 mg, 0.54 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3i (41.5 mg) as a pale yellow solid, which contained 0.75 mg of Et₂O. The yield of 3i was calculated as 48%. Note: the ratio of 3i and Et₂O was determined by ¹H NMR since Et₂O was not completely removed after drying in vacuo for 24 h.

Mp 134 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 1.21 (d, J = 7.0 Hz, 3 H), 2.90 (s, 9 H), 3.36–3.40 (m, 1 H), 4.10 (d, J = 11.5 Hz, 1 H), 5.76–5.79 (m, 2 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.22–7.31 (m, 5 H), 7.39 (t, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 2 H).

¹³C NMR (126 MHz, CD₃CN): δ = 24.3, 38.7, 54.6, 59.6, 111.9, 127.77, 127.82, 129.3, 129.4, 129.7, 130.0, 143.0, 143.4, 158.0.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₀H₂₆N: 280.2065 [M]⁺; found: 280.2068.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9639.

3j

Synthesized according to the typical procedure from 1a (50 mg, 0.20 mmol) using methyl atropate (2j, 98 mg, 0.60 mmol, 3.0 equiv.) and (TMS)₃SiNH( ^t Bu) (170 mg, 0.54 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂­/MeOH, 25:75) and recrystallization (MeOH/Et₂O) afforded 3j (20.8 mg, 0.0529 mmol, 26%) as a white solid.

Mp 169.1–169.9 °C.

¹H NMR (500 MHz, CD₃CN): δ = 2.76 (dd, J = 17.5, 6.0 Hz, 1 H), 3.15 (dd, J = 17.5, 9.5 Hz, 1 H), 3.21 (s, 9 H), 3.63 (s, 3 H), 4.06 (dd, J = 9.5, 6.0 Hz, 1 H), 5.33 (brs, 1 H), 5.64 (d, J = 5.0 Hz, 1 H), 7.33–7.41 (m, 5 H).

¹³C NMR (126 MHz, CD₃CN): δ = 32.3, 50.0, 53.0, 54.9, 110.7, 128.8, 129.0, 129.9, 138.2, 151.7, 173.5.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 707 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₁₅H₂₂NO₂: 248.1651 [M]⁺; found: 248.1652.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9636.

3n

Synthesized according to the typical procedure from 1-bromo-N-(2-propyl)-N,N-dimethylethenammonium tetrafluoroborate (1b, 56 mg, 0.20 mmol) using 1,1-diphenylethylene (2a, 180 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (170 mg, 0.52 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH, 95:5) and recrystallization (CH₂Cl₂/Et₂O) afforded 3n (24.8 mg, 0.0566 mmol, 28%) as a white solid.

Mp 137 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 1.17 (d, J = 6.5 Hz, 6 H), 2.99 (s, 6 H), 3.13 (d, J = 7.5 Hz, 2 H), 3.95–4.00 (m, 1 H), 4.39 (t, J = 7.5 Hz, 1 H), 5.44 (brs, 1 H), 5.55 (d, J = 5.0 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 4 H), 7.39 (d, J = 7.5 Hz, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 16.3, 34.0, 48.1, 49.6, 65.7, 113.4, 127.8, 128.5, 129.7, 144.2, 150.9.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₁H₂₈N: 294.2222 [M]⁺; found: 294.2231.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9639.

3o

Synthesized according to the typical procedure from N-(1-bromoethenyl)-N-methylpyrrolidinium hexafluorophosphate (1c, 68 mg, 0.20 mmol) using 1,1-diphenylethylene (2a, 180 mg, 0.98 mmol) and (TMS)₃SiNH( ^t Bu) (160 mg, 0.51 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl_2­/MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3o (56.9 mg, 0.130 mmol, 65%) as a pale yellow solid.

Mp 148 °C (dec).

¹H NMR (500 MHz, CD₂Cl₂): δ = 2.21–2.28 (m, 4 H), 3.08 (s, 3 H), 3.16 (d, J = 7.5 Hz, 2 H), 3.53–3.58 (m, 2 H), 3.68–3.72 (m, 2 H), 4.27 (t, J = 7.5 Hz, 1 H), 5.35 (brs, 1 H), 5.55 (d, J = 5.0 Hz, 1 H), 7.24 (t, J = 7.0 Hz, 2 H), 7.30–7.36 (m, 8 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 20.9, 35.4, 49.8, 50.9, 64.5, 112.7, 127.6, 127.9, 129.4, 142.6, 150.6.

¹⁹F NMR (471 MHz, CD₂Cl₂): δ = –73.0 (d, J = 711 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₁H₂₆N: 292.2065 [M]⁺; found: 292.2074.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9642.

3p

Synthesized according to the typical procedure from N-(1-bromoethenyl)-N-methylmorpholinium tetrafluoroborate (1d, 59 mg, 0.20 mmol) using 1,1-diphenylethylene (2a, 180 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (160 mg, 0.51 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3p (49.8 mg, 0.110 mmol, 55%) as a pale yellow solid.

Mp 160 °C (dec).

¹H NMR (500 MHz, CD₃CN): δ = 3.10 (d, J = 7.5 Hz, 2 H), 3.12 (s, 3 H), 3.48–3.53 (m, 2 H), 3.71–3.76 (m, 2 H), 3.79–3.82 (m, 2 H), 3.89–3.92 (m, 2 H), 4.40 (t, J = 7.5 Hz, 1 H), 5.51 (brs, 1 H), 5.60 (d, J = 5.0 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 4 H), 7.39 (d, J = 7.5 Hz, 4 H).

¹³C NMR (126 MHz, CD₃CN): δ = 33.8, 49.4, 53.4, 60.7, 62.1, 114.8, 127.8, 128.5, 129.8, 144.0, 148.8.

¹⁹F NMR (471 MHz, CD₃CN): δ = –71.4 (d, J = 705 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₁H₂₆NO: 308.2014 [M]⁺; found: 308.2007.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9640.

3q

Synthesized according to the typical procedure from N-(1-bromoethenyl)quinuclidium tetrafluoroborate (1e, 60 mg, 0.20 mmol) using 1,1-diphenylethylene (2a, 180 mg, 1.0 mmol) and (TMS)₃SiNH( ^t Bu) (160 mg, 0.51 mmol). Purification by flash column chromatography on NaBr-treated silica gel (CH₂Cl₂/MeOH, 80:20) and recrystallization (CH₂Cl₂/Et₂O) afforded 3q (44.2 mg, 0.0954 mmol, 48%) as a white solid.

Mp 194 °C (dec).

¹H NMR (500 MHz, CD₃OD): δ = 2.02–2.05 (m, 6 H), 2.19–2.20 (m, 1 H), 3.25 (d, J = 8.0 Hz, 2 H), 3.62 (t, J = 8.0 Hz, 6 H), 4.37 (t, J = 7.5 Hz, 1 H), 5.34 (brs, 1 H), 5.65 (d, J = 4.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 4 H), 7.38 (d, J = 7.5 Hz, 4 H).

¹³C NMR (126 MHz, CD₃OD): δ = 20.6, 25.1, 35.4, 50.7, 56.5, 113.3, 127.9, 129.0, 129.8, 144.5, 152.7.

¹⁹F NMR (471 MHz, CD₃OD): δ = –72.5 (d, J = 708 Hz).

HRMS (ESI-MS, positive): m/z calcd for C₂₃H₂₈N: 318.2222 [M]⁺; found: 318.2236.

HRMS (ESI-MS, negative): m/z calcd for PF₆: 144.9642 [M]^–; found: 144.9639.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1a Bureš F. Top. Curr. Chem. 2019; 377: 14
• 1b Brycki B, Szulc A, Brycka J, Kowalczyk I. Molecules 2023; 28: 6336
• 1c Tischer M, Pradel G, Ohlsen K, Holzgrabe U. ChemMedChem 2012; 7: 22
• 1d Novacek J, Waser M. Eur. J. Org. Chem. 2013; 637
• 1e Hashimoto T, Maruoka K. Chem. Rev. 2007; 107: 5656
• 1f Qian D, Sun J. Chem. Eur. J. 2019; 25: 3740
• 2 Menschutkin N. Z. Phys. Chem. 1890; 5U: 589
• 3 Stork G, Brizzolara A, Landesman H, Szmuszkovicz J, Terrell R. J. Am. Chem. Soc. 1963; 85: 207
• 4 Kleine G. Justus Liebigs Ann. Chem. 1904; 337: 81
• 5 Yoshita A, Sakakibara Y, Murakami K. Bull. Chem. Soc. Jpn. 2023; 96: 303
• 6a Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
• 6b Matsui JK, Lang SB, Heitz DR, Molander GA. ACS Catal. 2017; 7: 2563
• 6c Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
• 6d Wang C.-S, Dixneuf PH, Soulé J.-F. Chem. Rev. 2018; 118: 7532
• 6e Sakakibara Y, Murakami K. ACS Catal. 2022; 12: 1857
• 6f Vega-Peñaloza A, Mateos J, Companyó X, Escudero-Casao M, Dell’Amico L. Angew. Chem. Int. Ed. 2021; 60: 1082
• 6g Wiles RJ, Molander GA. Isr. J. Chem. 2020; 60: 281
• 7 Juliá F, Constantin T, Leonori D. Chem. Rev. 2022; 122: 2292
• 8 Sakai HA, Liu W, Le CC, MacMillan DW. C. J. Am. Chem. Soc. 2020; 142: 11691
• 9a Sarkar S, Cheung KP. S, Gevorgyan V. Chem. Sci. 2020; 11: 12974
• 9b Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
• 9c Capaldo L, Ravelli D. Eur. J. Org. Chem. 2017; 2056
• 9d Cao H, Tang X, Tang H, Yuan Y, Wu J. Chem Catal. 2021; 1: 523
• 10 Constantin T, Zanini M, Regni A, Sheikh NS, Juliá F, Leonori D. Science 2020; 367: 1021
• 11 Cradlebaugh JA, Zhang L, Shelton GR, Litwinienko G, Smart BE, Ingold KU, Dolbier WR. Jr. Org. Biomol. Chem. 2004; 2: 2083
• 12a Yakhin OI, Lubyanov AA, Yakhin IA, Brown PH. Front. Plant Sci. 2017; 7: 2049
• 12b Ahmad A, Blasco B, Martos V. Front. Plant Sci. 2022; 13: 862034
• 13 Kinoshita T, Sakakibara Y, Hirano T, Murakami K. ChemRxiv 2023; preprint DOI: DOI: 10.26434/chemrxiv-2023-bwm63.

Publication History

Received: 27 March 2024

Accepted after revision: 09 April 2024

Accepted Manuscript online:
09 April 2024

Article published online:
23 April 2024