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Synthesis 2024; 56(18): 2925-2932
DOI: 10.1055/a-2338-4243
paper

Photoinduced Aryl Ketone-Catalyzed Phenylation of C(sp3)–H Bonds Attached to the Heteroatom of Ethers and N-Boc-Amines via Concerted Homolytic Aromatic Substitution

Masaya Azami
a   Graduate School of Sciences and Technology for Innovation, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan
,
Michinori Sumimoto
b   Graduate School of Sciences and Technology for Innovation, Yamaguchi University, 2-16-1 Tokiwadai, Ube 755-8611, Japan
,
Reika Nakamura
c   Department of Chemistry, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan
,
Toshihiro Murafuji
a   Graduate School of Sciences and Technology for Innovation, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan
,
Shin Kamijo∗
a   Graduate School of Sciences and Technology for Innovation, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan
› Author Affiliations

This research was supported by the JSPS KAKENHI Grant Number JP22K05096 to S.K.
› Further Information
 
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Abstract

A single-step phenylation at the non-acidic C(sp3)–H bond attached to the heteroatom of ethers and N-Boc-amines has been achieved using photoexcited 4-benzoylpyridine as a hydrogen atom transfer (HAT) catalyst. The design of electron-deficient (trifluoromethylsulfonyl)benzene derivatives, as a phenyl precursor, was critical to realizing the present transformation. Moreover, the DFT calculations indicated that the present transformation proceeds via a concerted homolytic aromatic substitution rather than via a stepwise one involving the formation of a cyclohexadienyl radical intermediate.


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Key words

C–H functionalization - phenylation - photoreaction - aryl ketone - ether - carbamate
Zoom Image
Scheme 1 Representative reaction pathways for homolytic aromatic substitution

The replacement of a leaving group on an aromatic ring by an incoming radical reactant is known as homolytic aromatic substitution.[1] As shown in Scheme [1], initial studies of this type of substitution were often performed using benzene (LG = H) as the radical acceptor and phenyl radical (R• = C6H5 •) as the incoming radical species, and the stepwise mechanisms via the cyclohexadienyl radical intermediate A (R = Ph), which is formed after the addition of phenyl radical to benzene, have been generally accepted. Because of the poor leaving group ability of the hydrogen atom (H•), biphenyl (I, R = Ph) was commonly proposed to be produced either by disproportionation providing 1,4-dihydrobiphenyl (II, R = Ph) as a by-product (path a)[2] or by the set of one-electron oxidation/deprotonation to intervene the cation B [3] or the radical anion C (path b).[4] The intermediacy of the cyclohexadienyl radical A (R = Ph) was clearly demonstrated by the isolation of its dimerized product, tetrahydro-p-quaterphenyl (III), in the report of DeTar and Long in 1958.[2a] [5] A series of studies have also clarified that the reactivity of aryl radicals is much higher than that of alkyl radicals as the incoming radical reactant.[6] The use of benzene derivatives bearing an electron-withdrawing leaving group (LG) has also been widely utilized to improve the reactivity as a radical acceptor and to control the site-selectivity of substitution with an incoming radical reactant in some cases.[7,8] The leaving group, which can be easily eliminated as a radical species (LG•), gives the product I directly from the cyclohexadienyl radical intermediate A (path c). For these electron-deficient benzene derivatives, there is a case where the product I is obtained by one-electron reduction of the starting benzene to generate the radical anion D, followed by addition of an incoming radical species to provide the anion E, and subsequent elimination of LG– (path d).[9] Accordingly, all of the representative homolytic aromatic substitutions have been proposed to proceed in a stepwise sequence involving the formation of either the cyclohexadienyl radical intermediate A or its radical anion analogue D.

During our research program aimed at developing a direct functionalization method for non-acidic C(sp3)–H bonds utilizing a photoexcited aryl ketone as a hydrogen atom transfer (HAT) agent,[10] [11] we found the phenylation at the C–H bond attached to the heteroatom of ethers and N-Boc-amines 1 with combination of (trifluoromethylsulfonyl)benzene derivatives 2 as a phenyl precursor. This is a homolytic aromatic substitution that proceeds by site-selective replacement of the trifluoromethylsulfonyl group on the phenyl precursor with the photochemically generated α-oxy or α-aminocarbon radical, and thus we have succeeded in developing a new preparative method for alkylbenzene derivatives 3.[12] [13] [14] In addition, we elucidated the characteristic feature of the present transformation, which proceeds in a concerted manner (TS1, path e of Scheme [1]), unlike the general stepwise mechanisms, by performing the DFT calculations.

Table 1 Screening of the Phenyl Precursorsa

Entry

Leaving group (LG)

2

Time (h)

Yield (%)b

1

SO2CF3

2a

 4

55c

2

SO2Me

2b

24

22

3

SO2Ph

2c

22

21

4

SO2OPh

2d

24

26

5

CN

2e

24

 7

6

Br

2f

24

 0

a Conditions: 2 (0.2 mmol, 1 equiv), 4-BzPy (0.2 mmol, 1 equiv), THF (1a, 4 mL as solvent, 49 mmol, 247 equiv), K2CO3 (0.2 mmol, 1 equiv), photoirradiation using 365 nm LED light under argon atmosphere at 60 °C.

b Yield was determined by 1H NMR analysis of the crude mixture.

c Isolated yield.

At the early stages of our investigation, we screened the reactivity of benzonitriles 2a–f bearing a variety of potential leaving groups (LG), as a phenyl precursor, by reacting with a solvent amount of THF (1a, 247 equiv) in the presence of a stoichiometric amount of K2CO3 and 4-benzoylpyridine (4-BzPy) under photoirradiation at 60 °C (Table [1]). Among the sulfone-based ones examined,[15] highly electron-deficient 4-(trifluoromethylsulfonyl)benzonitrile (2a) exhibited the highest reactivity and the expected phenylated product 3a was formed in 55% isolated yield (Table [1], entry 1).[16] Methylsulfonylated and phenylsulfonylated benzonitriles, 2b and 2c, respectively, as well as the benzenesulfonate 2d were less reactive and the yields of the desired product 3a remained in 21–26% (entries 2–4). On the other hand, cyano[9] and bromo functionalities, 2e and 2f, respectively, were found to show almost no leaving group ability in the present transformation (entries 5 and 6).

Table 2 Optimization of Reaction Conditionsa

Entry

Solvent

Additive

Time (h)

Yield (%)b

1

THFc

K2CO3

 4

55d

2

THFc

–

22

41

3

CH2Cl2

K2CO3

12

42

4

CH2Cl2

Na2CO3

22

 5

5

CH2Cl2

Cs2CO3

 9

28

6

CH2Cl2

KO t Bu

22

23

7

CH2Cl2

KOAc

22

19

8e

CH2Cl2 f

K2CO3

28

51

9e

CH2Cl2/H2Og

K2CO3 h

 7

48d

a Conditions: THF (1a, 2 mmol, 10 equiv), 2a (0.2 mmol, 1 equiv), 4-BzPy (0.2 mmol, 1 equiv), and additive (0.2 mmol, 1 equiv), solvent (4 mL), photoirradiation­ using 365 nm LED light under argon atmosphere at 60 °C, unless otherwise noted.

b Yield was determined by 1H NMR analysis of the crude mixture.

c THF (4 mL) was used as the starting substance and the solvent.

d Isolated yield.

e 4-BzPy used: 0.2 equiv.

f Solvent used: CH2Cl2 (2 mL).

g Solvent used: CH2Cl2/H2O = 3:1 (2 mL).

h K2CO3 used: 3 equiv.

We further optimized the reaction conditions with a focus on reducing the amount of starting THF (1a) to broaden the substrate applicability and to achieve the catalytic reaction on the aryl ketone (Table [2]). As mentioned in the previous section, the reaction of (trifluoromethylsulfonyl)benzonitrile (2a) with a solvent amount of THF (1a, 247 equiv) in the presence of K2CO3 (1 equiv) and a stoichiometric amount of 4-BzPy (1 equiv) afforded the product 3a in 55% yield in 4 hours (Table [2], entry 1). When the reaction was carried out in the absence of K2CO3, the reaction time was significantly extended to 22 hours (entry 2).[12b] [c] [13b] The amount of starting THF (1a) could be reduced to 10 equivalents using CH2Cl2 as a solvent without significant loss of the product yield although an elongation of the reaction time was observed (42% in 12 h, entry 3).[17] Other additives, including Na2CO3, Cs2CO3, KO t Bu, and KOAc, did not improve the yield of the desired product 3a (entries 4–7). The reaction was successfully catalyzed with 0.2 equivalent of 4-BzPy to afford the product 3a in 51% yield (entry 8). The addition of H2O as a co-solvent and an excess amount of K2CO3 (3 equiv) shortened the reaction time while keeping the yield of 3a at the same level (48% in 7 h, entry 9).[18]

Zoom Image
Scheme 2 Substrate applicability of the C–H phenylation. Reagents and conditions: starting substance 1 (2 mmol, 10 equiv), 2a (0.2 mmol, 1 equiv), 4-BzPy (0.04 mmol, 0.2 equiv), K2CO3 (0.6 mmol, 3 equiv), CH2Cl2/H2O = 3:1 (2 mL), photoirradiation using 365 nm LED light under argon atmosphere at 60 °C. Isolated yields are shown.

After establishing the optimal conditions for the C–H phenylation, a series of ethers and N-Boc protected amine derivatives 1 were reacted with 4-(trifluoromethylsulfonyl)benzonitrile (2a) under photoirradiation (Scheme [2]). Not only five-membered THF (1a), but also seven-membered oxepane (1b) led to the formation of the expected product 3b, with the phenyl group selectively installed on the α-carbon to the oxygen atom, in 61% yield. Acyclic diethyl ether (1c) was a suitable starting substance as well, providing the phenylated product 3c in 55% yield. The phenylation of 1,3-dioxolane (1d) took place at the methylene C–H bond attached to the both two oxygen atoms to give the corresponding product 3d in 52% yield. Despite of the presence of potentially cleavable multiple C–H bonds including the two methines at the ring junctures,[10] [19] the phenylation of ambroxide (1e) occurred chemoselectively at the ethereal C–H bond to afford the product 3e in 62% yield as the sole diastereomer. In this case, the phenyl group was presumably introduced stereoselectively from the less hindered α-face of the molecule to avoid the steric repulsion caused by the methyl group on the tetrasubstituted carbon next to the oxygen atom. Irrespective of the ring size of the azacycles 1f–h, the phenylation took place chemoselectively at the C–H bond adjacent to the nitrogen atom, yielding the corresponding adducts 3f–h in 67–33% yields. The acyclic carbamates 1i and 1j also gave the corresponding phenylated products 3i (40%) and 3j (34%). It is worth mentioning that the present C–H phenylation could be carried out even in the presence of a protic functionality in the starting material, such as N-Boc-butylamine (1j). The phenylation at the methyl group of the N-methylaniline derivative 1k afforded the product 3k in 35% yield without any difficulty.[20]

Next, the applicability of some of the phenyl precursors 2g–l having electron-withdrawing groups (EWG) was investigated (Scheme [3]).[21] As in the case of the para-substituted monocyanated phenyl precursor 2a, the ortho-substituted 2g and the 2,4-disubstituted analogues 2h gave the corresponding products 3l (25%) and 3m (32%) in the same manner. The reaction using the ester-substituted phenyl precursor 2i afforded the expected product 3n (28%) as well. On the contrary, by using 1-(methylsulfonyl)-4-(trifluoromethylsulfonyl)benzene (2j), the site-selective substitution at the carbon center attached to the methylsulfonyl group took place to give the product 3o in 59% yield without the formation of the expected 3o′.[22] The exchange of the methylsulfonyl moiety of 2j to the phenylsulfonyl 2k and the tert-butylsulfonyl group 2l resulted in the formation of the expected products 3p (20%) and 3q (36%), respectively, along with the reduced yield of 3o. Accordingly, the reaction site seemed to be controlled by the steric bulkiness of the sulfonyl moiety when disulfonylated benzenes were employed as a phenyl precursor.

Zoom Image
Scheme 3 C–H phenylation using various phenyl precursors having electron-withdrawing groups. Reagents and conditions: THF (1a; 2 mmol, 10 equiv), 2a (0.2 mmol, 1 equiv), 4-BzPy (0.04 mmol, 0.2 equiv), K2CO3­ (0.6 mmol, 3 equiv), CH2Cl2/H2O = 3:1 (2 mL), photoirradiation using 365 nm LED light under argon atmosphere at 60 °C. Isolated yields are shown.

To obtain mechanistic information, we conducted the radical capture experiment using TEMPO (Scheme [4a]). The reaction between THF (1a) and the phenyl precursor 2a in the presence of a stoichiometric amount of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) for 2 hours[23] resulted in the formation of the TEMPO-adduct of THF 4 (34%),[24] the phenylated THF 3a (8%), together with the recovery of the phenyl precursor 2a (21%). This result clearly showed that the addition of TEMPO was detrimental to the yield of the expected product 3a and that the generation of THF radical (F THF) indeed took place during the reaction course.

Zoom Image
Scheme 4 Investigations to elucidate the reaction pathway for the present C–H phenylation: (a) Radical capture experiment using TEMPO, (b) DFT calculation of the homolytic aromatic substitution step, and (c) A plausible mechanism.

To gain further insight into the detailed reaction pathway for the present C–H phenylation, we performed the dispersion-corrected DFT calculations at the B3LYP-D3 level of theory with the 6-311G+(d) basis sets for N, O, F, and S atoms, the 6-31G(d,p) basis sets for H atom, and CH2Cl2 as the SMD model (Scheme [4b]). Since the generation of the carbon radical species via hydrogen atom abstraction effected by a photoexcited aryl ketone has already been disclosed,[25] [26] our focus has been on the crucial homolytic aromatic substitution step. Our DFT calculation study revealed that the substitution on the aromatic ring of 2a proceeds through a single transition state TS2, in which THF radical (F THF) attacks at the sulfonylated carbon center and simultaneously undergoes homolysis leading to the phenylated product 3a with elimination of trifluoromethylsulfinyl radical G.[15] The energy barrier for this concerted process was calculated to be 10.8 kcal/mol. Intrinsic Reaction Coordination (IRC) analysis of the transition state TS2 revealed no additional intermediates along the reaction pathway from the starting carbon radical F THF to the product 3a, and thus ruling out the involvement of the generally proposed cyclohexadienyl radical intermediate A (see, Scheme [1]).[27] In addition, our attempts to acquire the cyclohexadienyl radical intermediate H bearing the THF ring failed to provide a stable species, suggesting that such an intermediate cannot be formed in the present case.

Taking all the observations into the account, we propose concerted homolytic aromatic substitution as a plausible mechanism for the present photoinduced C–H phenylation of ethers and N-Boc-amines using sulfonylated benzene derivatives as a phenyl precursor (Scheme [4c]). Due to the behavior of photoexcited 4-BzPy as a highly electron-deficient oxyl radical, it abstracts the hydrogen from the C(sp3)–H bond attached to the heteroatom in the starting substance 1, which is electron-rich and has a lower bond energy, and generates the carbon radical F as a nucleophilic incoming reactant. The radical acceptor 2a is electrophilic and contains the readily cleavable electron-withdrawing leaving group (G [15]), so that the addition of the carbon radical F takes place site-selectively at the sulfonylated carbon center in a concerted manner through the transition state TS3, as indicated by the DFT calculation. The eliminated sulfinyl radical G should accept hydrogen from the ketyl radical to regenerate 4-BzPy as a hydrogen atom transfer (HAT) catalyst.[28]

In conclusion, we have developed a single-step preparative method for alkylbenzene derivatives 3 starting from ethers and N-Boc-amines 1 by subjecting to the sulfonylated benzenes 2 as a phenyl precursor in the presence of the photoexcited aryl ketone, 4-BzPy, as a hydrogen atom transfer (HAT) catalyst. The site-selective alkylation proceeds by ipso-substitution of the electron-deficient sulfonylated phenyl precursor 2 with elimination of the sulfinyl radical and the phenyl group is chemoselectively introduced at the carbon atom attached to the heteroatom of the starting substances 1. The DFT calculations strongly indicated that the present transformation proceeds via a concerted homolytic aromatic substitution rather than via a stepwise one involving the formation of a cyclohexadienyl radical intermediate. This study opens a new aspect of homolytic aromatic substitution and provides a simple and mild protocol for alkylating the benzene ring without relying on a metal reagent.

All reactions sensitive to air or moisture were carried out under an argon atmosphere and anhydrous conditions, unless otherwise noted. Analytical TLC was performed on E. Merck silica gel 60 F254 precoated plates. Column chromatography was performed with silica gel (Fuji Silysia) or using a Biotage Isolera system. The 1H and 13C NMR spectra were recorded on a Bruker Avance III-400 (400 MHz) or Bruker DRX500 (500 MHz) spectrometer. Chemical shifts are reported in δ (ppm) relative to residual solvent signals for 1H NMR: CHCl3 (7.26) and 13C NMR: CDCl3 (77.0), and an external reference was used for 19F NMR: C6H5CF3 (-63.7). Signal patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. HRMS were recorded on a Thermo Fisher Scientific Orbitrap Exploris 4800/240/120 instrument. Melting points were measured on a Cornes MPA100 micro melting point apparatus. UV irradiation was carried out by using a Keyence UV-400 LED illuminator with UV-50-A (2.2 W) or UV-50-H (2.6 W) and CCS LV-24UV365-4WPCLTL (3.0 W) lamp at 365 nm.


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Photoinduced Phenylation of C(sp3)–H Bonds; 2-(4-Cyanophenyl)tetrahydrofuran (3a); Typical Procedure (Table [2], entry 9)

[CAS Reg. No. 1588517-28-5]

4-(Trifluoromethylsulfonyl)benzonitrile (2a; 47.0 mg, 0.2 mmol), 4-benzoylpyridine (4-BzPy; 7.3 mg, 0.04 mmol, 0.2 equiv), K2CO3 (82.9 mg, 0.6 mmol, 3 equiv), and THF (0.16 mL, 2.0 mmol, 10 equiv) in CH2Cl2/H2O (3:1, 2 mL) were added to a sealed Pyrex test tube with a rubber septum under an argon atmosphere. The test tube was placed at ca. 1 cm distance from an LED lamp (365 nm) and was irradiated at 60 °C for 7 h. The mixture was extracted with EtOAc, the combined EtOAc layers were washed with H2O and brine, dried (MgSO4), and evaporated. The residue was purified by flash column chromatography (silica gel, hexane/EtOAc 20:1 to 5:1) to provide 2-(4-cyanophenyl)tetrahydrofuran (3a)[11f] as a colorless oil; yield: 16.6 mg (48%).

1H NMR (400 MHz, CDCl3): δ = 1.73 (1 H, ddt, J = 12.2, 7.8, 7.5 Hz), 1.96–2.06 (2 H, m), 2.38 (1 H, ddt, J = 12.2, 7.5, 7.5 Hz), 3.96 (1 H, dt, J = 8.4, 6.9 Hz), 4.09 (1 H, dt, J = 8.4, 6.9 Hz) 4.93 (1 H, dd, J = 7.5, 7.5 Hz), 7.43 (2 H, br d, J = 8.3 Hz), 7.61 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 25.9, 34.6, 68.9, 79.8, 110.8, 118.9, 126.4, 132.1, 149.2.


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2-(4-Cyanophenyl)oxepane (3b)

Yield: 25.5 mg (61%); colorless oil.

IR (ATR): 3020, 2925, 2857, 2227, 1603, 1136, 830, 826, 767, 735 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.50–1.99 (7 H, m), 1.94–2.14 (1 H, m), 3.72 (1 H, ddd, J = 12.3, 7.6, 4.0 Hz), 3.97 (1 H, J = 12.3, 6.4, 4.0 Hz), 4.62 (1 H, dd, J = 8.9, 4.0 Hz), 7.44 (2 H, br d, J = 8.4 Hz), 7.61 (2 H, br d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ = 25.6, 26.6, 30.9, 37.8, 68.9, 80.4, 110.5, 119.0, 126.3, 132.0, 150.0.

HRMS (APCI): m/z calcd for C11H12NO [M + H]+: 202.1226; found: 202.1223.


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1-(4-Cyanophenyl)-1-ethoxyethane (3c)[14b]

[CAS Reg. No. 2016025-14-0]

Yield: 19.3 mg (55%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 1.20 (3 H, t, J = 7.0 Hz), 1.42 (3 H, d, J = 6.5 Hz), 3.34 (1 H, dq, J = 9.2, 7.0 Hz), 3.40 (1 H, dq, J = 9.2, 7.0 Hz), 4.45 (1 H, q, J = 6.5 Hz), 7.42 (2 H, d, J = 8.4 Hz), 7.64 (2 H, d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ = 15.3, 23.9, 64.4, 77.1, 111.1, 118.9, 126.7, 132.3, 149.9.


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2-(4-Cyanophenyl)-1,3-dioxolane (3d)[29]

[CAS Reg. No. 66739-89-7]

Yield: 19.0 mg (52%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 4.02–4.17 (4 H, m), 5.85 (1 H, s), 7.59 (2 H, br d, J = 8.4 Hz), 7.68 (2 H, br d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ = 65.4, 102.4, 112.9, 118.5, 127.1, 132.2, 143.1.


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[2R-(4-Cyanophenyl)]-(–)-ambroxide (3e)

Yield: 47.2 mg (62%); colorless oil.

IR (ATR): 3063, 2989, 2939, 2868, 2843, 2229, 1602, 1079, 840, 768, 689 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.77–0.97 (2 H, m), 0.83 (3 H, s), 0.86 (3 H, s), 0.88 (3 H, s), 0.97–1.07 (1 H, m), 1.07–1.22 (1 H, m), 1.25 (3 H, s), 1.28–1.48 (3 H, m), 1.48–1.77 (4 H, m), 1.77–1.89 (1 H, m), 2.07 (1 H, dt, J = 11.8, 3.3 Hz), 2.33 (1 H, ddd, J = 12.8, 11.0, 9.7 Hz), 5.14 (1 H, dd, J = 9.7, 2.6 Hz), 7.44 (2 H, br d, J = 8.3 Hz), 7.61 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 15.0, 18.2, 20.6, 21.0, 21.6, 32.2, 33.0, 33.5, 36.2, 39.81, 39.85, 42.3, 57.3, 58.5, 76.4, 82.3, 110.5, 119.0, 126.3, 132.1, 150.8.

HRMS (APCI): m/z calcd for C23H32NO [M + H]+: 338.2478; found: 338.2468.


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N-(tert-Butoxycarbonyl)-2-(4-cyanophenyl)pyrrolidine (3f)[30]

[CAS Reg. No. 1440419-03-3]

Yield: 27.9 mg (53%); yellow oil; an inseparable mixture of two rotamers (56:44).

1H NMR (400 MHz, CDCl3): δ = 1.17 (5.04/9 H, br s), 1.45 (3.95/9 H, br s), 1.72–1.84 (1 H, m), 1.84–2.00 (2 H, m), 2.26–2.47 (1 H, m), 3.46–3.79 (2 H, m), 4.78 (0.56/1 H, br s), 4.94 (0.44/1 H, br s), 7.28 (2 H, br d, J = 8.4 Hz), 7.60 (2 H, br d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ (detectable signals) = 23.2, 23.6, 28.1, 28.3, 34.7, 35.8, 47.2, 47.3, 60.7, 61.1, 79.7 (overlapped), 110.4 (overlapped), 118.8 (overlapped), 126.2 (overlapped), 132.1 (overlapped), 150.8 (overlapped), 154.2, 154.4.


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N-(tert-Butoxycarbonyl)-2-(4-cyanophenyl)piperidine (3g)[30]

[CAS Reg. No. 1463887-86-6]

Yield: 19.0 mg (33%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 1.27–1.70 (4 H, m), 1.45 (9 H, s), 1.86–2.00 (1 H, m), 2.25 (1 H, br dd, J = 13.6, 3.3 Hz), 2.73 (1 H, ddd, J = 13.6, 11.9, 3.9 Hz), 4.07 (1 H, br d, J = 13.6 Hz), 5.41 (1 H, br d, J = 3.2 Hz), 7.33 (2 H, br d, J = 8.2 Hz), 7.64 (2 H, d, J = 8.2 Hz).

13C NMR (100 MHz, CDCl3): δ = 19.3, 25.1, 28.1, 28.3, 40.4, 53.4, 80.0, 110.3, 118.8, 127.3, 132.3, 146.7, 155.4.


#

N-(tert-Butoxycarbonyl)-2-(4-cyanophenyl)azepane (3h)[31]

[CAS Reg. No. 2384402-19-9]

Yield: 39.9 mg (67%); yellow oil; an inseparable mixture of two rotamers (54:46).

1H NMR (500 MHz, CDCl3): δ = 1.31 (4.86/9 H, s), 1.39–1.74 (4 H, m), 1.50 (4.14/9 H, s), 1.74–2.06 (3 H, m), 2.21–2.32 (0.46/1 H, m), 2.32–2.46 (0.54/1 H, m), 2.85–2.96 (0.54/1 H, m), 2.96–3.07 (0.46/1 H, m), 3.88–4.03 (0.54/1 H, m), 4.16–4.28 (0.46/1 H, m) 4.94 (0.46/1 H, dd, J = 11.8, 6.5 Hz), 5.22 (0.54/1 H, dd, J = 11.8, 6.6 Hz), 7.29 (0.92/2 H, br d, J = 8.3 Hz), 7.34 (1.08/2 H, br d, J = 8.3 Hz), 7.62 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 25.7, 26.6, 28.2, 28.4, 29.3, 29.4, 29.6, 29.9, 35.3, 36.1, 43.3, 43.5, 58.6, 60.7, 79.8, 79.9, 110.3 (overlapped), 118.8, 118.9, 126.2, 126.4, 132.2, 132.3, 149.5, 150.6, 155.5, 156.0.


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N-(tert-Butoxycarbonyl)-1-(4-cyanophenyl)diethylamine (3i)

[CAS Reg. No. 2680811-25-8]

Yield: 22.2 mg (40%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 1.03 (3 H, br t, J = 7.1 Hz), 1.44 (9 H, br s), 1.56 (3 H, d, J = 7.2 Hz), 2.94 (1 H, br s), 3.16 (1 H, br s), 5.36 (1 H, br s), 7.39 (2 H, br d, J = 8.3 Hz), 7.61 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 15.2, 17.4, 28.4, 38.8, 53.3, 79.9, 110.8, 118.7, 127.5, 132.1, 148.2, 155.5.

HRMS (APCI): m/z calcd for C12H15N2O2 [M – t Bu + 2 H]+ 219.1128; found: 219.1125 (major signal); calcd for C11H15N2 [M – Boc + 2 H]+ 175.1230; found: 175.1227 (minor signal).


#

N-(tert-Butoxycarbonyl)-1-(4-cyanophenyl)butylamine (3j)

Yield: 18.5 mg (34%); yellow solid; mp 76.3–78.0 °C.

IR (ATR): 3359, 3047, 2961, 2933, 2873, 1696, 1608, 1391, 1366, 1164, 840, 757, 680 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.92 (3 H, t, J = 7.4 Hz), 1.22–1.47 (2 H, m), 1.40 (9 H, br s), 1.62–1.75 (2 H, m), 4.63 (1 H, br s), 4.82 (1 H, br s), 7.36 (2 H, br d, J = 8.3 Hz), 7.61 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 13.6, 19.2, 28.2, 38.7, 54.5, 79.9, 110.8, 118.8, 126.9, 132.3, 149.0, 155.1.

HRMS (APCI): m/z calcd for C16H23N2O2 [M + H]+: 275.1755; found: 275.1751.


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N-(tert-Butoxycarbonyl)-N-(4-cyanobenzyl)aniline (3k)

Yield: 16.3 mg (35%); colorless oil.

IR (ATR): 3063, 3042, 2973, 2931, 2852, 2232, 1695, 1597, 1380, 1366, 1149, 862, 758, 696 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.40 (9 H, s), 4.87 (2 H, s), 7.12 (2 H, br d, J = 7.7 Hz), 7.18 (1 H, tt, J = 7.7, 1.6 Hz), 7.29 (2 H, br t, J = 7.7 Hz), 7.36 (2 H, br d, J = 8.6 Hz), 7.60 (2 H, br d, J = 8.6 Hz).

13C NMR (100 MHz, CDCl3): δ = 28.2, 53.7, 81.0, 111.0, 118.7, 126.2, 126.3, 128.0, 128.8, 132.3, 142.4, 144.1, 154.6.

HRMS (APCI): m/z calcd for C19H21N2O2 [M + H]+: 309.1597; found: 309.1595.


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2-(2-Cyanophenyl)tetrahydrofuran (3l)[32]

[CAS Reg. No. 1623476-30-1]

Yield: 8.8 mg (25%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 1.72 (1 H, ddt, J = 12.4, 7.9, 7.7 Hz), 1.97–2.17 (2 H, m), 2.63 (1 H, ddt, J = 12.4, 7.8, 7.7 Hz), 4.03 (1 H, ddd, J = 8.4, 6.8, 6.8 Hz), 4.18 (1 H, ddd, J = 8.4, 6.8, 6.8 Hz), 5.22 (1 H, dd, J = 7.7, 7.7 Hz), 7.77 (1 H, d, J = 8.2 Hz), 7.82 (1 H, dd, J = 8.2, 1.7 Hz), 7.91 (1 H, d, J = 1.7 Hz).

13C NMR (100 MHz, CDCl3): δ = 26.1, 34.3, 69.5, 78.3, 111.2, 112.1, 115.4, 116.7, 127.1 136.0, 136.1, 153.1.


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2-(2,4-Dicyanophenyl)tetrahydrofuran (3m)[32]

[CAS Reg. No. 1623476-42-5]

Yield: 12.6 mg (32%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 1.76 (1 H, ddt, J = 12.4, 7.7, 7.4 Hz), 2.00–2.11 (m), 2.56 (1 H, ddt, J = 12.4, 7.7, 7.7 Hz), 4.00 (1 H, ddd, J = 8.3, 6.8, 6.8 Hz), 4.18 (1 H, ddd, J = 8.3, 6.8, 6.8 Hz), 5.20 (1 H, dd, J = 7.7, 7.7 Hz), 7.31–7.38 (1 H, m), 7.54–7.66 (3 H, m).

13C NMR (100 MHz, CDCl3): δ = 26.1, 34.4, 69.2, 78.8, 109.7, 117.6, 125.9, 127.4, 132.91, 132.94, 147.8.


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2-(4-Methoxycarbonylphenyl)tetrahydrofuran (3n)[32]

[CAS Reg. No. 1623476-31-2]

Yield: 11.6 mg (28%); colorless oil.

1H NMR (400 MHz, CDCl3): δ = 1.77 (1 H, ddt, J = 12.4, 8.0, 7.6 Hz), 2.01 (2 H, m), 2.36 (1 H, ddt, J = 12.4, 7.6, 7.5 Hz), 3.91 (3 H, s), 3.96 (1 H, ddd, J = 8.4, 7.5, 7.5 Hz), 4.11 (1 H, ddd, J = 8.4, 7.5, 7.5 Hz), 4.95 (1 H, dd, J = 7.6, 7.6 Hz), 7.40 (2 H, br d, J = 8.3 Hz), 8.00 (2 H, br d, J = 8.3 Hz).

13C NMR (100 MHz, CDCl3): δ = 25.9, 34.6, 52.0, 68.8, 80.1, 125.4, 128.9, 129.6, 148.9, 167.0.


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2-(4-Trifluoromethylsulfonylphenyl)tetrahydrofuran (3o)

Yield: 29.3 mg (59%); colorless solid; mp 135.2–136.1 °C.

IR (ATR): 3324, 2881, 1591, 1363, 1213, 1190, 1073, 840, 767, 735 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.78 (1 H, ddt, J = 12.3, 8.1, 7.8 Hz), 1.95–2.15 (2 H, m), 2.35–2.57 (1 H, ddt, J = 12.3, 6.7, 6.7 Hz), 4.00 (1 H, ddd, J = 8.5, 6.7, 6.7 Hz), 4.12 (1 H, ddd, J = 8.5, 6.7, 6.7 Hz), 5.02 (1 H, dd, J = 8.1, 8.1 Hz), 7.63 (2 H, br d, J = 8.4 Hz), 7.99 (2 H, br d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ = 25.9, 34.7, 69.1, 79.6, 119.8 (q, 1 J C,F = 323.7 Hz), 126.7, 129.6, 130.9, 152.7.

19F NMR (376 MHz, CDCl3): δ = –78.5.

HRMS (APCI): m/z calcd for C11H12F3O3S [M + H]+: 281.0453; found: 281.0461.


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2-(4-Benzenesulfonylphenyl)tetrahydrofuran (3p)

Yield: 11.3 mg (20%); colorless oil.

IR (ATR): 3058, 2941, 2874, 1602, 1306, 1153, 1059, 833, 741, 687 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.72 (1 H, ddt, J = 12.4, 8.0, 7.6 Hz), 1.64–2.04 (2 H, m), 2.35 (1 H, ddt, J = 12.4, 7.2, 7.2 Hz), 3.94 (1 H, ddd, J = 8.4, 6.8, 6.8 Hz), 4.07 (1 H, ddd, J = 8.4, 6.8, 6.8 Hz), 4.91 (1 H, dd, J = 7.2, 7.2 Hz), 7.43–7.58 (5 H, m), 7.86–7.96 (4 H, m).

13C NMR (100 MHz, CDCl3): δ = 25.9, 34.6, 68.9, 79.7, 126.3, 127.5, 127.7, 129.2, 130.0, 140.1, 141.7, 149.2.

HRMS (ESI): m/z calcd for C16H17O3S [M + H]+: 289.0892; found: 289.0890.


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2-[(4-tert-Butylsulfonyl)phenyl]tetrahydrofuran (3q)

Yield: 9.6 mg (36%); colorless oil.

IR (ATR) 3020, 3003, 2941, 2844, 1636, 1375, 1229, 1150, 1054, 837, 785 cm-1.

1H NMR (500 MHz, CDCl3): δ = 1.33 (9 H, s), 1.77 (1 H, ddt, J = 12.5, 7.3, 7.2 Hz), 2.03 (2 H, quint, J = 7.2 Hz), 2.40 (1 H, ddt, J = 12.5, 7.3, 7.3 Hz), 3.98 (1 H, ddd, J = 8.8, 7.2, 7.2 Hz), 4.12 (1 H, ddd, J = 8.8, 7.2, 7.2 Hz), 4.97 (1 H, dd, J = 7.3, 7.3 Hz), 7.51 (2 H, br d, J = 8.4 Hz), 7.83 (2 H, br d, J = 8.4 Hz).

13C NMR (100 MHz, CDCl3): δ = 23.6, 25.9, 34.7, 59.7, 68.9, 79.9, 125.7, 130.5, 133.9, 149.9.

HRMS (ESI): m/z calcd for C14H21O3S [M + H]+: 269.1205; found: 269.1204.


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Radical Capture Using TEMPO (Scheme [4a])

A CH2Cl2 solution (2.0 mL) of THF (0.16 mL, 2.0 mmol, 10 equiv), 4-(trifluoromethylsulfonyl)benzonitrile (2a; 47.0 mg, 0.2 mmol), 4-benzoylpyridine (4-BzPy, 7.3 mg, 0.04 mmol, 0.2 equiv), K2CO3 (27.6 mg, 0.2 mmol, 1 equiv), and TEMPO (31.3 mg, 0.20 mmol, 1 equiv) in a sealed Pyrex test tube with a rubber septum was purged with argon. The test tube was placed at ca. 1 cm distance from an LED lamp (365 nm) and was irradiated at rt for 2 h. The mixture was extracted with EtOAc, the combined organic extracts were washed with H2O and brine, dried (MgSO4), and evaporated. 1H NMR analysis of the crude mixture revealed the formation of the TEMPO-adduct of THF 4 [10c] (34%), the phenylated THF 3a (8%), and the recovery of the phenyl precursor 2a (21%).


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

HRMS were recorded using an Orbitrap Exploris at the Center for Instrumental Analysis in Yamaguchi University (the program for supporting construction of core facilities: Grant Number JPMXS0440400024). We thank Mr. Ryoji Hatakenaka at Yamaguchi University for an advice on the determination of one of the transition states.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2338-4243.
  • Supporting Information

Corresponding Author

Shin Kamijo
Graduate School of Sciences and Technology for Innovation, Yamaguchi University
1677-1 Yoshida, Yamaguchi 753-8512
Japan   

Publication History

Received: 01 May 2024

Accepted after revision: 04 June 2024

Accepted Manuscript online:
04 June 2024

Article published online:
02 July 2024

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Zoom Image
Scheme 1 Representative reaction pathways for homolytic aromatic substitution
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Scheme 2 Substrate applicability of the C–H phenylation. Reagents and conditions: starting substance 1 (2 mmol, 10 equiv), 2a (0.2 mmol, 1 equiv), 4-BzPy (0.04 mmol, 0.2 equiv), K2CO3 (0.6 mmol, 3 equiv), CH2Cl2/H2O = 3:1 (2 mL), photoirradiation using 365 nm LED light under argon atmosphere at 60 °C. Isolated yields are shown.
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Scheme 3 C–H phenylation using various phenyl precursors having electron-withdrawing groups. Reagents and conditions: THF (1a; 2 mmol, 10 equiv), 2a (0.2 mmol, 1 equiv), 4-BzPy (0.04 mmol, 0.2 equiv), K2CO3­ (0.6 mmol, 3 equiv), CH2Cl2/H2O = 3:1 (2 mL), photoirradiation using 365 nm LED light under argon atmosphere at 60 °C. Isolated yields are shown.
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Scheme 4 Investigations to elucidate the reaction pathway for the present C–H phenylation: (a) Radical capture experiment using TEMPO, (b) DFT calculation of the homolytic aromatic substitution step, and (c) A plausible mechanism.