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Synthesis 2024; 56(21): 3327-3333
DOI: 10.1055/a-2281-2975
paper
Special Issue PSRC-10 (10th Pacific Symposium on Radical Chemistry)

Use of Aliphatic Carboxylic Acid Derivatives for NHC/Photoredox-Catalyzed meta-Selective Acylation of Electron-Rich Arenes

Yamato Goto
a   Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
,
Sho Murakami
b   Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, Japan
,
Yuto Sumida
c   Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
,
Hirohisa Ohmiya  ∗
b   Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, Japan
› Author Affiliations

This work was supported by the Japan Society for the Promotion of Science (JSPS), KAKENHI (Grant Nos. JP21H04681 and JP23H04912) to H.O.
› Further Information
 
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Abstract

We describe the use of acyl imidazoles derived from aliphatic carboxylic acids for the N-heterocyclic carbene/organic photoredox co-catalyzed meta-selective functionalization of electron-rich arenes. Compared to our previous work, a change of the wavelength of the applied LED light from 440 nm to 390 nm promotes this reaction efficiently.


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Key words

N-heterocyclic carbene - photoredox catalysis - meta-selectivity - acylation - arenes

Ketones are extremely common functional groups found in bioactive compounds, pharmaceutical compounds, natural products and materials.[1] They are also regarded as important synthetic intermediates that can be used for Wittig and reduction reactions.[2] Various synthetic methods for constructing ketones have been developed. Among the diverse methods for synthesizing ketones such as alkyl aryl ketones, the Friedel–Crafts acylation of electron-rich arenes is one of the most traditional and powerful tools.[3] Generally, the Friedel–Crafts acylation of electron-rich arenes enables the introduction of an acyl group at ortho- or para-positions relative to the electron-donating group on the aromatic ring (Scheme [1a]). Therefore, the introduction of an acyl group to an arene at the meta-position relative to an electron-donating group in a short number of steps is a challenging goal in terms of obtaining functionalized ketones.

Zoom Image
Scheme 1 (a) Conventional Friedel–Crafts acylation. (b) Our previous work. (c) This work.

Earlier, we developed the meta-selective functionalization of electron-rich arenes through N-heterocyclic carbene (NHC) and organic photoredox co-catalysis to produce ketones (Scheme [1b]).[4] The regioselectivity of the NHC/organic-photoredox-catalyzed acylation is completely different from that of the conventional Friedel–Crafts acylation. The dual catalysis involves a reaction between acyl imidazole III and the NHC catalyst to generate acyl azolium IV and an imidazolide anion. The imidazolide anion adds to the radical cation species II, which is formed by single-electron oxidation of the electron-rich arene I, to generate cyclohexadienyl radical V. The subsequent persistent radical effect (PRE)-based[5] radical–radical coupling of the cyclohexadienyl radical V with the ketyl radical VI, through single-electron reduction of the acyl azolium IV, delivered the desired meta-acylation product.[6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] This protocol could be applied to the meta-selective functionalization of electron-rich arenes using aromatic or aliphatic acyl imidazoles. However, the yields of aliphatic acyl imidazoles were somewhat lower compared to those of aromatic acyl imidazoles. This is due to the higher reduction potential of aliphatic acyl azoliums compared with aromatic acyl azoliums.[25] Based on this background, we re-examined the meta-selective acylation of electron-rich arenes using aliphatic acyl imidazoles to produce alkyl aryl ketones (Scheme [1c]). Compared with the previous reaction conditions, changing the wavelength of the LED light from 440 nm to 390 nm promoted the aliphatic acylation reaction efficiently.

First, we investigated the reaction conditions for the meta-selective functionalization of an electron-rich arene using an aliphatic acyl imidazole (Table [1]). We found suitable reaction conditions that afforded the meta-selective acylation product 3a in a 35% NMR yield using anisole (1a), 1-acetyl imidazole (2a) (derived from acetic acid), the photocatalyst PC1 (5 mol%),[26] [27] [28] triazole-based NHC catalyst N1 (30 mol%), and cesium triazolide (1.3 equiv.) in dichloromethane under visible light irradiation (390 nm) (entry 1). The NMR analysis unambiguously confirmed complete meta-selectivity. An anisole bearing imidazole at the para-position was detected as a byproduct. On the other hand, employing the same reaction conditions as those described in our previous work,[4] using visible light (440 nm), significantly decreased the product yield (5% yield) (entry 2). The same reaction under irradiation using 440 nm blue LED light at 50 ℃ also resulted in a low yield (entry 3). These results suggested that a high temperature was not essential and that using visible light at a wavelength 390 nm was crucial to afford desired product. The use of PC2,[29] which has a lower oxidation potential compared to PC1, under 390 nm blue LED light was not effective (entry 4).

Table 1 Reaction Optimizationa

Entry

Light conditions

PC

Yield (%)b

1

390 nm

PC1

35 (23c)

2

440 nm

PC1

 5

3

440 nm, 50 ℃ (high temperature)

PC1

 4

4

390 nm

PC2

17

a The reaction was carried out with anisole 1 (0.1 mmol), acyl imidazole 2 (0.30 mmol), PC (5 mol%), N1 (30 mol%), cesium 1,2,4-triazolide (0.13 mmol) in dichloromethane (0.3 mL) under 390 nm (Kessil lamp) irradiation for 16 h.

b NMR yields are given.

c Isolated yield.

With optimized reaction conditions in hand, the reactions of various electron-rich arenes with 1-acetyl imidazole (2a) were examined (Scheme [2], top). Electron-rich arenes such as 1,3-dimethoxybenzene and 2,6-dimethoxytoluene showed high reactivity, affording the desired acylation products (3b and 3c) in moderate yields. When electron-poor arenes were used as substrates, the corresponding products were not detected (see the Supporting Information).[30] Our protocol allowed us to utilize a 1,2-disubstituted electron-rich arene, and completely regioselective acylation occurred at the meta-position, having lower steric hindrance, to give 3d. Methoxy benzenes bearing an allyl group, a phenyl group or a pyridyl group were applicable for this reaction, and the acylation occurred selectively at the meta-position of these electron-rich arenes to give products 3e–g.

Zoom Image
Scheme 2 Substrate scope

The scope of aliphatic acyl imidazoles derived from aliphatic carboxylic acids was investigated next (Scheme [2], bottom). The reaction of an acyl imidazole derived from a long-chain fatty carboxylic acid afforded the desired product 3h in 45% yield. Substrates containing a chloro group, an ether group or an alkene moiety were tolerated, giving products 3i–k. A citronellic acid derivative participated in the reaction, albeit affording a low yield of product 3l. When secondary aliphatic carboxylic acids were used as substrates, the acylation reagent derived from cyclopropanecarboxylic acid resulted in a 76% yield of 3m. On the other hand, a relatively hindered cycloheptanecarboxylic acid derivative gave a low yield of 3n. The sterically more hindered 1-methylcyclopropane carboxylic acid derivative was also applicable in this reaction, albeit with a low efficiency towards product 3o. The use of 440 nm blue LED light resulted in lower yields compared with the use of 390 nm blue LED light (3d, 3n and 3o). Arenes that had electron-rich functional groups other than methoxy groups were not applicable for this reaction.

Notably, this reaction was applicable to a one-pot protocol via in situ preparation of the acyl imidazole from the corresponding carboxylic acid and 1,1′-carbonyldiimidazole (CDI). Specifically, the reaction using acetic acid 4 provided the meta-selective acylated arene 3c (Scheme [3])

Zoom Image
Scheme 3 The one-pot procedure

To understand the reason behind the increase in the product yield by changing the blue LED light wavelength from 440 nm to 390 nm, mechanistic studies were performed. We hypothesized that this reaction pathway involved [Mes-Acr•]* (III), which has an extremely high reduction potential, as reported by the Nicewicz group (Scheme [4a]).[31] The single-electron transfer event between [Mes-Acr+]* (I) and the arene was followed by the visible-light excitation of the obtained [Mes-Acr•] II that generates radical species III. This high reduction potential enables a high concentration of the ketyl radical intermediate that promotes this reaction effectively. To confirm whether this pathway was reasonable or not, we added aryl bromide 5 having a high reduction potential (–2.1 V vs SCE[32]), being much higher than the reduction potential of [Mes-Acr•] (II) (–0.6 V vs SCE[31]) (Scheme [4b]). This reaction afforded the reduced product 6 stemming from 5 in 17% yield, together with the ketone 3a (12% yield). This result indicated that [Mes-Acr•]* (III) is formed. Under these reaction conditions, the acyl imidazole could be directly reduced by [Mes-Acr•]* (III). However, the standard reaction without the NHC catalyst did not give the desired product. This result indicated that the acyl azolium intermediate generated from the acyl imidazole and the NHC catalyst was reduced by [Mes-Acr•]* (III) to generate a persistent ketyl radical species.

Zoom Image
Scheme 4 Mechanistic studies

In conclusion, we have developed the use of acyl imidazoles derived from aliphatic carboxylic acids in the NHC/organic-photoredox-co-catalyzed meta-selective functionalization of electron-rich arenes to produce alkyl aryl ketones. Compared to our previous work, a change in the wavelength of the LED light from 440 nm to 390 nm promoted this reaction effectively. The use of 390 nm LED light enabled reduction of the acyl azolium intermediate derived from the aliphatic acyl imidazole by excitation of the reduced photocatalyst to impart an extremely high reduction potential.

NMR spectra were recorded on a Bruker AVANCE NEO 400N spectrometer, operating at 400 MHz for 1H NMR and 100.6 MHz for 13C NMR. Chemical shifts (δ) are reported in ppm. HRMS (ESI) was performed using an impact II (Bruker) spectrometer. TLC analyses were performed on commercial glass plates bearing a 0.25-mm layer of Merck Silica gel 60F254. Silica gel (Wakosil® 60, 64–210 μm) was used for column chromatography. LaboACE LC-5060 (for gel permeation chromatography) was used for purification. IR spectra were recorded with an IRSpirit-X (Shimadzu). Melting points were measured on a Stanford Research Systems MPA100. Reaction set-up and materials: Kessil PR-160 440 nm and Kessil PR-160 390 nm (highest blue and intensity setting) were used as light sources, and a TEKNOS MG9 fan was employed. All reactions were carried out under a nitrogen atmosphere. Materials were obtained from commercial suppliers (Fujifilm Wako Pure Chemical Co., Tokyo Chemical Industry Co., Ltd., BLD Pharmatech Ltd., and Angene) or prepared according to standard procedures unless otherwise noted. The photoredox catalysts PC1,[33] PC2,[29] NHC catalyst N1,[34] acyl imidazole,[4] and cesium 1,2,4-triazolide[35] were prepared according to the literature.


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meta-Selective Acylation; General Procedure

di- t Bu-Mes-Acr+BF4 – (PC1) (5.7 mg, 0.01 mmol) and NHC catalyst N1 (18.9 mg, 0.06 mmol) were placed in an oven-dried screw-top 5 mL vial containing a magnetic stir bar. The vial was then transferred to a nitrogen-filled glovebox and to this was added cesium 1,2,4-triazolide (82.7% purity, 63.2 mg, 0.26 mmol), acyl imidazole 2 (0.60 mmol), electron-rich arene 1 (0.20 mmol), and anhydrous dichloromethane (600 μL). The vial was then removed from the glovebox and the contents stirred for 30 min. After stirring for 20 h at ambient temperature under photoirradiation (390 nm), the reaction mixture was evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give the desired product 3.


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1-(3-Methoxyphenyl)ethan-1-one (3a)

According to the general procedure using anisole (21.6 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (90:10, hexane/Et2O) gave 3a (6.9 mg, 0.046 mmol, 23%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.54 (ddd, J = 8.0, 1.6, 0.8 Hz, 1 H), 7.49 (dd, J = 2.4, 1.6 Hz, 1 H), 7.38 (dd, J = 8.0, 8.0 Hz, 1 H), 7.12 (ddd, J = 8.0, 2.4, 0.8 Hz, 1 H), 3.86 (s, 3 H), 2.60 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 198.0, 159.8, 138.5, 129.5, 121.1, 119.6, 112.3, 55.4, 26.7.

This data is in full agreement with the data previously published in the literature.[36]


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1-(3,5-Dimethoxyphenyl)ethan-1-one (3b)

According to the general procedure using 1,3-dimethoxybenzene (27.6 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 98:2 to 85:15, hexane EtOAc) gave 3b (15.9 mg, 0.088 mmol, 44%) as a yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 2.4 Hz, 2 H), 6.66 (t, J = 2.4 Hz, 1 H), 3.84 (s, 6 H), 2.58 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.8, 160.8, 139.0, 106.1, 105.3, 55.6, 26.7.

This data is in full agreement with the data previously published in the literature.[37]


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1-(3,5-Dimethoxy-4-methylphenyl)ethan-1-one (3c)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 98:2 to 85:15, hexane/EtOAc) gave 3c (20.5 mg, 0.11 mmol, 53%) as a pale yellow solid.

Mp 102–103 ℃.

IR (neat): 1671, 1581, 1458, 1408, 1314, 1247 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.13 (s, 2 H), 3.89 (s, 6 H), 2.60 (s, 3 H), 2.14 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.7, 158.2, 135.6, 120.8, 103.5, 55.8, 26.6, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C11H15O3: 195.1016; found: 195.1005.


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1-[4-(tert-Butyl)-3-methoxyphenyl]ethan-1-one (3d)

According to the general procedure using 1-(tert-butyl)-2-methoxybenzene (32.9 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (95:5, hexane/EtOAc) gave 3d (20.5 mg, 0.053 mmol, 26%) as a yellow oil.

IR (neat): 1681, 1405, 1390, 1357, 1291, 1267 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 1.6 Hz, 1 H), 7.48 (dd, J = 8.8, 1.6 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 3.90 (s, 3 H), 2.59 (s, 3 H), 1.39 (s, 9 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.8, 158.7, 144.2, 136.2, 126.5, 121.4, 109.9, 55.1, 35.3, 29.4, 26.5.

HRMS (ESI): m/z [M + H]+ calcd for C13H19O2: 207.1380; found: 207.1383.


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1-[3-Methoxy-5-[(2-methylallyl)oxy]phenyl]ethan-1-one (3e)

According to the general procedure using 1-methoxy-3-((2-methylallyl)oxy)benzene (35.6 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 95:15, hexane/EtOAc) gave 3e (17.2 mg, 0.078 mmol, 39%) as a yellow oil.

IR (neat): 1683, 1593, 1456, 1432, 1357, 1320 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.11 (dd, J = 2.4, 1.6 Hz, 1 H), 7.09 (dd, J = 2.4, 1.6 Hz, 1 H), 6.68 (dd, J = 2.4, 2.4 Hz, 1 H), 5.11 (m, 1 H), 5.01 (m, 1 H), 4.46 (s, 2 H), 3.84 (s, 3 H), 2.57 (s, 3 H), 1.84 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.8, 160.8, 159.9, 140.4, 139.0, 113.1, 107.1, 106.1, 106.0, 72.0, 55.6, 26.7, 19.4.

HRMS (ESI): m/z [M + H]+ calcd for C13H17O3: 221.1172; found: 221.1165.


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1-(3-Methoxy-5-phenoxyphenyl)ethan-1-one (3f)

According to the general procedure using 1-methoxy-3-phenoxybenzene (40.0 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 90:10, hexane/Et2O) gave 3f (20.4 mg, 0.084 mmol, 42%) as a pale yellow oil.

IR (neat): 1685, 1584, 1490, 1429, 1357, 1333 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.36 (dd, J = 8.4, 7.6 Hz, 2 H), 7.23 (dd, J = 2.4, 1.6 Hz, 1 H), 7.17 (dd, J = 2.0, 1.6 Hz, 1 H), 7.15 (tt, J = 7.6, 1.2 Hz, 1 H), 7.03 (dd, J = 8.4, 1.2 Hz, 2 H), 6.75 (dd, J = 2.4, 2.0 Hz, 1 H), 3.83 (s, 3 H), 2.54 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.3, 161.0, 158.7, 156.4, 139.4, 129.9, 123.9, 119.2, 111.1, 109.5, 107.8, 55.7, 26.8.

HRMS (ESI): m/z [M + H]+ calcd for C15H15O3: 243.1016; found: 243.1002.


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1-[3-Methoxy-5-(pyridin-2-yloxy)phenyl]ethan-1-one (3g)

According to the general procedure using 2-(3-methoxyphenoxy)pyridine (40.2 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)ethan-1-one (66.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 80:20 to 50:50, hexane/Et2O) gave 3g (12.8 mg, 0.05 mmol, 26%) as a colorless oil.

IR (neat): 1685, 1587, 1571, 1467, 1300, 1263 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.20 (ddd, J = 4.8, 2.0, 0.8 Hz, 1 H), 7.72 (ddd, J = 8.0, 7.2, 2.0 Hz, 1 H), 7.34 (dd, J = 2.4, 1.6 Hz, 1 H), 7.31 (dd, J = 2.0, 1.6 Hz, 1 H), 7.04 (ddd, J = 7.2, 4.8, 1.2 Hz, 1 H), 6.96 (ddd, J = 8.0, 1.2, 0.8 Hz, 1 H), 6.91 (dd, J = 2.4, 2.0 Hz, 1 H), 3.85 (s, 3 H), 2.57 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.2, 163.2, 160.8, 155.3, 147.8, 139.6, 139.2, 118.9, 113.8, 112.3, 111.9, 109.4, 55.7, 26.7.

HRMS (ESI): m/z [M + H]+ calcd for C14H14NO3: 244.0968; found: 244.0961.


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1-(3,5-Dimethoxy-4-methylphenyl)octan-1-one (3h)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)octan-1-one (117 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 95:5, hexane/Et2O) gave 3h (24.9 mg, 0.089 mmol, 45%) as a pale yellow solid.

Mp 66–67 ℃.

IR (neat): 1676, 1583, 1452, 1405, 1324, 1237 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.14 (s, 2 H), 3.88 (s, 6 H), 2.94 (t, J = 7.6 Hz, 2 H), 2.14 (s, 3 H), 1.74 (tt, J = 7.6, 7.6 Hz, 2 H), 1.44–1.23 (m, 8 H), 0.89 (t, J = 7.2 Hz, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 200.1, 158.2, 135.5, 120.5, 103.3, 55.8, 38.5, 31.7, 29.3, 29.2, 24.6, 22.6, 14.1, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C17H27O3: 279.1955; found: 279.1947.


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5-Chloro-1-(3,5-dimethoxy-4-methylphenyl)pentan-1-one (3i)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 5-chloro-1-(1H-imidazol-1-yl)pentan-1-one (112 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 95:10, hexane/EtOAc) gave 3i (17.6 mg, 0.065 mmol, 33%) as a white solid.

Mp 90–92 ℃.

IR (neat): 1675, 1584, 1462, 1449, 1411, 1347 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.13 (s, 2 H), 3.89 (s, 6 H), 3.60 (t, J = 6.0 Hz, 2 H), 3.00 (t, J = 6.8 Hz, 2 H), 2.14 (s, 3 H), 1.98–1.83 (m, 4 H).

13C NMR (100.6 MHz, CDCl3): δ = 199.2, 158.2, 135.3, 120.8, 103.2, 55.8, 44.7, 37.4, 32.0, 21.7, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C14H20ClO3: 271.1095; found: 271.1091.


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1-(3,5-Dimethoxy-4-methylphenyl)-3-ethoxypropan-1-one (3j)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 3-ethoxy-1-(1H-imidazol-1-yl)propan-1-one (101 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 80:20, hexane/Et2O) gave 3j (20.4 mg, 0.081 mmol, 40%) as a pale yellow solid.

Mp 58–59 ℃.

IR (neat): 1676, 1584, 1454, 1408, 1306, 1106 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.16 (s, 2 H), 3.872 (s, 6 H), 3.867 (t, J = 6.8 Hz, 2 H), 3.55 (q, J = 6.8 Hz, 2 H), 3.27 (t, J = 6.8 Hz, 2 H), 2.13 (s, 3 H), 1.22 (t, J = 6.8 Hz, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 197.9, 158.2, 135.4, 120.9, 103.3, 66.6, 66.0, 55.8, 38.9, 15.2, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C14H21O4: 253.1434; found: 253.1429.


#

1-(3,5-Dimethoxy-4-methylphenyl)pent-4-en-1-one (3k)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)pent-4-en-1-one (90.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 93:7, hexane/Et2O) gave 3k (10.4 mg, 0.044 mmol, 22%) as a yellow oil.

IR (neat): 1683, 1679, 1584, 1454, 1406, 1309 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.14 (s, 2 H), 5.92 (ddt, J = 17.2, 10.0, 6.8 Hz, 1 H), 5.10 (ddd, J = 17.2, 3.2, 1.6 Hz, 1 H), 5.02 (ddd, J = 10.0, 3.2, 1.2 Hz, 1 H), 3.88 (s, 6 H), 3.06 (t, J = 7.6 Hz, 2 H), 2.51 (tddd, J = 7.6, 6.8, 1.6, 1.2 Hz, 2 H), 2.14 (s, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 198.9, 158.2, 137.4, 135.4, 120.8, 115.3, 103.2, 55.8, 37.7, 28.4, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C14H19O3: 235.1329; found: 235.1326.


#

1-(3,5-Dimethoxy-4-methylphenyl)-3,7-dimethyloct-6-en-1-one (3l)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and 1-(1H-imidazol-1-yl)-3,7-dimethyloct-6-en-1-one (132 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 95:5, hexane/EtOAc) gave 3l (15.1 mg, 0.050 mmol, 25%) as a colorless oil.

IR (neat): 1683, 1676, 1584, 1464, 1456, 1452 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.13 (s, 2 H), 5.11 (m, 1 H), 3.89 (s, 6 H), 2.95 (dd, J = 15.6, 5.6 Hz, 1 H), 2.72 (dd, J = 15.6, 8.0 Hz, 1 H), 2.19 (m, 1 H), 2.14 (s, 3 H), 2.09–1.98 (m, 2 H), 1.68 (s, 3 H), 1.60 (s, 3 H), 1.43 (m, 1 H), 1.29 (m, 1 H), 0.97 (d, J = 6.4 Hz, 3 H).

13C NMR (100.6 MHz, CDCl3): δ = 199.9, 158.2, 135.9, 131.5, 124.4, 120.6, 103.4, 55.8, 45.8, 37.3, 29.8, 25.7, 25.6, 20.0, 17.7, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C19H29O3: 305.2111; found: 305.2096.


#

Cyclopropyl(3,5-dimethoxy-4-methylphenyl)methanone (3m)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and cyclopropyl(1H-imidazol-1-yl)methanone (81.7 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 90:10, hexane/Et2O) gave 3m (33.7 mg, 0.15 mmol, 76%) as a pale yellow solid.

Mp 80–82 ℃.

IR (neat): 1655, 1452, 1409, 1379, 1306, 1245 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.20 (s, 2 H), 3.89 (s, 6 H), 2.66 (tt, J = 7.6, 4.4 Hz, 1 H), 2.15 (s, 3 H), 1.24 (ddd, J = 7.2, 4.4, 3.6 Hz, 2 H), 1.04 (ddd, J = 7.6, 7.2, 3.6 Hz, 2 H).

13C NMR (100.6 MHz, CDCl3): δ = 200.1, 158.2, 136.4, 120.3, 103.2, 55.8, 17.0, 11.7, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C13H17O3: 221.1172; found: 221.1166.


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Cycloheptyl(3,5-dimethoxy-4-methylphenyl)methanone (3n)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and cycloheptyl(1H-imidazol-1-yl)methanone (115 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 93:7, hexane/Et2O) gave 3n (9.6 mg, 0.035 mmol, 17%) as a yellow oil.

IR (neat): 2923, 1675, 1584, 1456, 1452, 1408 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.12 (s, 2 H), 3.88 (s, 6 H), 3.39 (tt, J = 9.6, 4.0 Hz, 1 H), 2.14 (s, 3 H), 1.97–1.90 (m, 2 H), 1.85–1.79 (m, 2 H), 1.76–1.52 (m, 8 H).

13C NMR (100.6 MHz, CDCl3): δ = 203.8, 158.2, 134.8, 120.4, 103.5, 55.9, 46.5, 31.0, 28.4, 26.8, 8.7.

HRMS (ESI): m/z [M + H]+ calcd for C17H25O3: 277.1798; found: 277.1793.


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(3,5-Dimethoxy-4-methylphenyl)(1-methylcyclopropyl)methanone (3o)

According to the general procedure using 1,3-dimethoxy-2-methylbenzene (30.4 mg, 0.2 mmol, 1 equiv.) and (1H-imidazol-1-yl)(1-methylcyclopropyl)methanone (90.1 mg, 0.6 mmol, 3 equiv.) with purification by column chromatography (gradient elution, 100:0 to 95:5, hexane/EtOAc) gave 3o (8.1 mg, 0.024 mmol, 12%) as a yellow oil.

IR (neat): 1670, 1581, 1464, 1456, 1452, 1406 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.03 (s, 2 H), 3.87 (s, 6 H), 2.13 (s, 3 H), 1.47 (s, 3 H), 1.27 (dd, J = 6.4, 4.0 Hz, 2 H), 0.78 (dd, J = 6.4, 4.0 Hz, 2 H).

13C NMR (100.6 MHz, CDCl3): δ = 203.5, 158.0, 135.5, 119.3, 103.8, 55.8, 25.3, 22.3, 15.0, 8.6.

HRMS (ESI): m/z [M + H]+ calcd for C14H19O3: 235.1329; found: 235.1325.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2281-2975.
  • Supporting Information

Corresponding Author

Hirohisa Ohmiya
Institute for Chemical Research, Kyoto University
Gokasho, Uji, Kyoto
Japan   

Publication History

Received: 28 January 2024

Accepted after revision: 05 March 2024

Accepted Manuscript online:
05 March 2024

Article published online:
25 March 2024

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Scheme 1 (a) Conventional Friedel–Crafts acylation. (b) Our previous work. (c) This work.
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Scheme 2 Substrate scope
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Scheme 3 The one-pot procedure
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Scheme 4 Mechanistic studies