Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite

An oxidative C–C bond cleavage of tert-cycloalkanols with tetramethylammonium hypochlorite (TMAOCl) has been developed. TMAOCl is easy to prepare from tetramethylammonium hydroxide, and the combination of TMAOCl and AcOH effectively promoted the C–C bond cleavage in a two-phase system without additional phase-transfer reagents. Unstrained tert-cycloalkanols were transformed into ω-chloroalkyl aryl ketones in moderate to excellent yields under metal-free and mild reaction conditions.


Introduction
Chloro-substituted ketones are versatile building blocks in the synthesis of drugcandidate compounds [1][2][3].Therefore, the development of an efficient synthetic method for chlorinated ketones is highly desirable.While a number of reliable protocols for the synthesis of chlorinated ketones have been developed [4][5][6][7], the straightforward introduction of a chlorine atom into the remote position of a carbonyl group is still challenging.Although the Friedel-Crafts reaction is one of the direct approaches for chlorinated carbonyl compounds, stoichiometric strong Lewis acids and moisture-sensitive acyl chlorides are required [8][9][10].

Optimization of Reaction Conditions
We started the initial study with the use of 1-phenylcyclohexanol (1a) as a model substrate (Table 1).When 1a (0.5 mmol) was treated with TMAOCl (1.5 equiv) and 35% HCl aq.(1.5 equiv) in CH2Cl2 at room temperature for 1 h, the desired ω-chloroalkyl aryl ketone 2a was obtained in 47% yield (Table 1, entry 1).Among a series of acids tested, AcOH provided a superior result (entries 1-5).We further optimized the reaction conditions, and 2a was obtained in a higher yield by employing 2.0 equiv of AcOH (entry 6).The yield of 2a slightly decreased with the use of 2.25 equiv of AcOH (entry 7), and the use of 2.0 equiv of TMAOCl and AcOH led to an obvious decrease in yield (entry 8).When the reactions were carried out at higher reaction concentrations, the reaction outcomes were not affected (entries 9 and 10), and 2a was isolated in 83% yield (entry 10).Extending the reaction time did not improve the yield of 2a (entry 11).Other solvents such as ClPh, AcOEt, and MeCN were less suitable for the reaction, providing 2a in lower yields (entries gas injection or the ion-exchange method [35,36].In addition, TMAOCl is a unique hypohalite salt requiring no additional phase-transfer reagents.Recently, we disclosed the ringopening chlorination of N-protected cyclic amines with the use of TMAOCl as an oxidant (Scheme 3) [37].Herein, we describe the metal-free C(sp 3 )−C(sp 3 ) bond cleavage of tertcycloalkanols for the synthesis of ω-chloroalkyl aryl ketones with TMAOCl (Scheme 4).

Optimization of Reaction Conditions
We started the initial study with the use of 1-phenylcyclohexanol (1a) as a model substrate (Table 1).When 1a (0.5 mmol) was treated with TMAOCl (1.5 equiv) and 35% HCl aq.(1.5 equiv) in CH2Cl2 at room temperature for 1 h, the desired ω-chloroalkyl aryl ketone 2a was obtained in 47% yield (Table 1, entry 1).Among a series of acids tested, AcOH provided a superior result (entries 1-5).We further optimized the reaction conditions, and 2a was obtained in a higher yield by employing 2.0 equiv of AcOH (entry 6).The yield of 2a slightly decreased with the use of 2.25 equiv of AcOH (entry 7), and the use of 2.0 equiv of TMAOCl and AcOH led to an obvious decrease in yield (entry 8).When the reactions were carried out at higher reaction concentrations, the reaction outcomes were not affected (entries 9 and 10), and 2a was isolated in 83% yield (entry 10).Extending the reaction time did not improve the yield of 2a (entry 11).Other solvents such as ClPh, AcOEt, and MeCN were less suitable for the reaction, providing 2a in lower yields (entries gas injection or the ion-exchange method [35,36].In addition, TMAOCl is a unique hypohalite salt requiring no additional phase-transfer reagents.Recently, we disclosed the ringopening chlorination of N-protected cyclic amines with the use of TMAOCl as an oxidant (Scheme 3) [37].Herein, we describe the metal-free C(sp 3 )−C(sp 3 ) bond cleavage of tertcycloalkanols for the synthesis of ω-chloroalkyl aryl ketones with TMAOCl (Scheme 4).

Optimization of Reaction Conditions
We started the initial study with the use of 1-phenylcyclohexanol (1a) as a model substrate (Table 1).When 1a (0.5 mmol) was treated with TMAOCl (1.5 equiv) and 35% HCl aq.(1.5 equiv) in CH2Cl2 at room temperature for 1 h, the desired ω-chloroalkyl aryl ketone 2a was obtained in 47% yield (Table 1, entry 1).Among a series of acids tested, AcOH provided a superior result (entries 1-5).We further optimized the reaction conditions, and 2a was obtained in a higher yield by employing 2.0 equiv of AcOH (entry 6).The yield of 2a slightly decreased with the use of 2.25 equiv of AcOH (entry 7), and the use of 2.0 equiv of TMAOCl and AcOH led to an obvious decrease in yield (entry 8).When the reactions were carried out at higher reaction concentrations, the reaction outcomes were not affected (entries 9 and 10), and 2a was isolated in 83% yield (entry 10).Extending the reaction time did not improve the yield of 2a (entry 11).Other solvents such as ClPh, AcOEt, and MeCN were less suitable for the reaction, providing 2a in lower yields (entries gas injection or the ion-exchange method [35,36].In addition, TMAOCl is a unique hypohalite salt requiring no additional phase-transfer reagents.Recently, we disclosed the ringopening chlorination of N-protected cyclic amines with the use of TMAOCl as an oxidant (Scheme 3) [37].Herein, we describe the metal-free C(sp 3 )−C(sp 3 ) bond cleavage of tertcycloalkanols for the synthesis of ω-chloroalkyl aryl ketones with TMAOCl (Scheme 4).

Optimization of Reaction Conditions
We started the initial study with the use of 1-phenylcyclohexanol (1a) as a model substrate (Table 1).When 1a (0.5 mmol) was treated with TMAOCl (1.5 equiv) and 35% HCl aq.(1.5 equiv) in CH2Cl2 at room temperature for 1 h, the desired ω-chloroalkyl aryl ketone 2a was obtained in 47% yield (Table 1, entry 1).Among a series of acids tested, AcOH provided a superior result (entries 1-5).We further optimized the reaction conditions, and 2a was obtained in a higher yield by employing 2.0 equiv of AcOH (entry 6).The yield of 2a slightly decreased with the use of 2.25 equiv of AcOH (entry 7), and the use of 2.0 equiv of TMAOCl and AcOH led to an obvious decrease in yield (entry 8).When the reactions were carried out at higher reaction concentrations, the reaction outcomes were not affected (entries 9 and 10), and 2a was isolated in 83% yield (entry 10).Extending the reaction time did not improve the yield of 2a (entry 11).Other solvents such as ClPh, AcOEt, and MeCN were less suitable for the reaction, providing 2a in lower yields (entries Scheme 4. This work: oxidative C-C bond cleavage of tert-cycloalkanols with TMAOCl.

Optimization of Reaction Conditions
We started the initial study with the use of 1-phenylcyclohexanol (1a) as a model substrate (Table 1).When 1a (0.5 mmol) was treated with TMAOCl (1.5 equiv) and 35% HCl aq.(1.5 equiv) in CH 2 Cl 2 at room temperature for 1 h, the desired ω-chloroalkyl aryl ketone 2a was obtained in 47% yield (Table 1, entry 1).Among a series of acids tested, AcOH provided a superior result (entries 1-5).We further optimized the reaction conditions, and 2a was obtained in a higher yield by employing 2.0 equiv of AcOH (entry 6).The yield of 2a slightly decreased with the use of 2.25 equiv of AcOH (entry 7), and the use of 2.0 equiv of TMAOCl and AcOH led to an obvious decrease in yield (entry 8).When the reactions were carried out at higher reaction concentrations, the reaction outcomes were not affected (entries 9 and 10), and 2a was isolated in 83% yield (entry 10).Extending the reaction time did not improve the yield of 2a (entry 11).Other solvents such as ClPh, AcOEt, and MeCN were less suitable for the reaction, providing 2a in lower yields (entries 12-14).A commercially available NaOCl•5H 2 O was found to be a less effective oxidant for this ring-opening reaction (entry 10 vs. entry 15).The addition of Me 4 NCl exhibited a positive effect on the reaction outcome [38,39], but the yield was slightly low, even with 2.0 equiv of NaOCl•5H 2 O, compared with that obtained from TMAOCl (entry 10 vs. entries 16 and 17).On the other hand, the reaction did not proceed well without an acid (entry 18).The reaction under the N 2 atmosphere provided 2a in 77% yield, indicating that the presence of oxygen did not have a significant effect on the reaction outcome (entry 19) [40].12-14).A commercially available NaOCl•5H2O was found to be a less effective oxidant for this ring-opening reaction (entry 10 vs. entry 15).The addition of Me4NCl exhibited a positive effect on the reaction outcome [38,39], but the yield was slightly low, even with 2.0 equiv of NaOCl•5H2O, compared with that obtained from TMAOCl (entry 10 vs. entries 16 and 17).On the other hand, the reaction did not proceed well without an acid (entry 18).The reaction under the N2 atmosphere provided 2a in 77% yield, indicating that the presence of oxygen did not have a significant effect on the reaction outcome (entry 19) [40].a Determined by 1 H NMR analysis using maleic acid as an internal standard.Isolated yield is given in parentheses.b 0.5 M. c 1.0 M. d 4 h.e NaOCl•5H2O (1.5 equiv).f NaOCl•5H2O (1.5 equiv), Me4NCl (1.5 equiv).g NaOCl•5H2O (2.0 equiv), Me4NCl (2.0 equiv).h Under N2 atmosphere.

Substrate Scope
With optimized conditions in hand, the scope and limitation of this reaction were investigated (Scheme 5).The substrate 1b with a p-chloro group provided the desired product 2b in 84% yield.Moreover, 1-(3-Chlorophenyl)cyclohexanol (1c) was converted into the corresponding product 2c in a high yield, and 1-Phenylcyclohexanols, substituted with electron-withdrawing groups such as trifluoromethyl (1d) and cyano (1e) groups participated well in this ring-opening reaction, affording the corresponding products (2d and 2e) in good yields.The substrate with an electron-donating group, such as a p-methyl group, provided the desired product 2f in 84% yield.While the tetrahydro-4-pyranol derivative 1g was successfully transformed into the corresponding product 2g in a moderate yield, the N-Boc-4-piperidinol derivative 1h afforded a trace amount of the desired

Substrate Scope
With optimized conditions in hand, the scope and limitation of this reaction were investigated (Scheme 5).The substrate 1b with a p-chloro group provided the desired product 2b in 84% yield.Moreover, 1-(3-Chlorophenyl)cyclohexanol (1c) was converted into the corresponding product 2c in a high yield, and 1-Phenylcyclohexanols, substituted with electron-withdrawing groups such as trifluoromethyl (1d) and cyano (1e) groups participated well in this ring-opening reaction, affording the corresponding products (2d and 2e) in good yields.The substrate with an electron-donating group, such as a p-methyl group, provided the desired product 2f in 84% yield.While the tetrahydro-4-pyranol derivative 1g was successfully transformed into the corresponding product 2g in a moderate yield, the N-Boc-4-piperidinol derivative 1h afforded a trace amount of the desired product 2h.The reaction of 4-methyl-1-phenylcyclohexanol 1i led to the formation of 2i in 52% yield.Furthermore, cycloalkanols with different ring sizes were converted into the desired products (2j-2l) in moderate to high yields.The substrates with p-methoxyphenyl (1m), 4-pyridyl (1n), and benzothiazolyl (1o) groups were not suitable substrates for the present reaction conditions, and most of the starting materials remained unreacted [41].

Scale-Up Experiment
To evaluate the scalability of the present reaction, the reaction was carried out using 5.7 mmol of 1a (Scheme 6).The desired product 2a was obtained in 80% yield.

Scale-Up Experiment
To evaluate the scalability of the present reaction, the reaction was carried out using 5.7 mmol of 1a (Scheme 6).The desired product 2a was obtained in 80% yield.

Scale-Up Experiment
To evaluate the scalability of the present reaction, the reaction was carried out using 5.7 mmol of 1a (Scheme 6).The desired product 2a was obtained in 80% yield.Scheme 6. Scale-up experiment.

Control Experiment
A control experiment was conducted to gain insight into the details of the present transformation.The reaction of 1a under the standard reaction conditions with 1.5 equiv of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) provided the ring-opening product 2a in 42% yield, and a TEMPO adduct was not detected in the crude reaction mixture by HRMS analysis.The previous literature reports proposed that the fragmentation of tertalkyl hypochrolite proceeds through alkoxy radical formation [28,[40][41][42][43][44].However, the control experiment suggests that a radical process may be not necessarily involved in the present reaction.

General
Procedure for the Oxidative C-C Bond Cleavage of tert-Cycloalkanol tert-Cycloalkanol 1 (0.5 mmol) was added to a 9 mL vial, and then CH 2 Cl 2 (0.5 mL), TMAOCl (0.673 mL, 0.75 mmol), and AcOH (60.0 mg, 57.2 µL, 1.0 mmol) were successively added at rt.After stirring for 1 h at the same temperature, the reaction mixture was extracted with AcOEt.The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.The residue was purified by silica-gel column chromatography to give the corresponding ω-chloroalkyl aryl ketones.

Preparation of Aqueous TMAOCl Solution
IR120B Na (0.5 L) was packed in a glass column (φ44 mm × 100 cm) and washed with ultrapure water (2.0 L) followed by 1M HCl (4.2 L) and additional ultrapure water (2.5 L).Aqueous Me 4 NOH solution (2.5 wt%, 4.2 L) and ultrapure water (4.0 L) were successively passed through the column to adjust the resin to a Me 4 N type.Aqueous NaOCl•5H 2 O solution (8.0 wt% as available chlorine) was then passed through the column to afford the aqueous TMAOCl solution.

n n Scheme 3 .
Scheme 3. Our previous work: oxidative C-N bond cleavage of cyclic amines with TMAOCl.
n n

n n Scheme 2. Regiospecific
synthesis of carbonyl-containing alkyl chlorides with NCS.

Table 1 .
Optimization of reaction conditions.

Table 1 .
Optimization of reaction conditions.