Next Article in Journal
The Recognition Pathway of the SARS-CoV-2 Spike Receptor-Binding Domain to Human Angiotensin-Converting Enzyme 2
Previous Article in Journal
Analysis of Volatile Aroma Components in Different Parts of Shiitake Mushroom (Lentinus edodes) Treated with Ultraviolet C Light-Emitting Diodes Based on Gas Chromatography–Ion Mobility Spectroscopy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 8
10.3390/molecules29081874
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Natsumi Hanazawa
,
Masami Kuriyama
,
Kosuke Yamamoto
and
Osamu Onomura
*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(8), 1874; https://doi.org/10.3390/molecules29081874
Submission received: 15 March 2024 / Revised: 17 April 2024 / Accepted: 18 April 2024 / Published: 19 April 2024
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
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.

1. Introduction

Chloro-substituted ketones are versatile building blocks in the synthesis of drug-candidate 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].
Alkoxy radicals are known as highly reactive species, involved in inert C(sp3)−H and C(sp3)−C(sp3) bond functionalization through 1,5-hydrogen atom transfer and β-scission reactions [11,12,13,14]. The ring-opening chlorination of cycloalkanols has proven to be an efficient strategy for the synthesis of distally chloro-substituted ketones through β-scission. tert-Cyclopropanols and cyclobutanols are useful precursors for β- and γ-chlorinated ketones since the ring-strain energies of these cycloalkanols are highly favorable for promoting the β-scission of the alkoxy radical species [15,16,17,18]. On the other hand, similar ring-opening reactions of unstrained cycloalkanols have also attracted attention as efficient synthetic methods for ω-functionalized ketones [19,20,21]. For example, Zhang and Qi reported the synthesis of ω-chloroalkyl aryl ketones from corresponding cycloalkanols using t-BuOCl as a Cl source (Scheme 1) [22]. The group of Zhu and Bao developed the ring-opening reaction with NCS (Scheme 2) [23]. In both cases, a precious transition-metal catalyst is required. In addition, there are not many examples of chlorinated-ketone synthesis from unstrained cycloalkanols [24,25,26,27,28]. Therefore, the development of alternatively greener and more efficient protocols is still desired. Hypochlorite salts are classical and versatile oxidants [29,30,31,32,33,34], and phase-transfer catalysts have often been employed in efficient hypochlorite-mediated oxidation methods [32,33,34]. Tetramethylammonium hypochlorite (TMAOCl) is easy to prepare from tetramethylammonium hydroxide by chlorine 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 ring-opening chlorination of N-protected cyclic amines with the use of TMAOCl as an oxidant (Scheme 3) [37]. Herein, we describe the metal-free C(sp3)−C(sp3) bond cleavage of tert-cycloalkanols for the synthesis of ω-chloroalkyl aryl ketones with TMAOCl (Scheme 4).

2. Results and Discussion

2.1. 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 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].

2.2. 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].

2.3. 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.

2.4. 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 tert-alkyl 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.

3. Materials and Methods

3.1. Chemicals and Instruments

1H, 13C{1H}, and 19F NMR spectra were recorded with a JNM ECA400II spectrometer (JEOL, Tokyo, Japan) (400 MHz for 1H NMR, 100 MHz for 13C{1H} NMR, 376 MHz for 19F NMR). Chemical shift values are expressed in parts per million (ppm) relative to internal TMS (δ 0.00 ppm for 1H NMR) or CDCl3 (δ 77.0 ppm for 13C{1H} NMR). Abbreviations are as follows: s, singlet; d, doublet; t, triplet; and m, multiplet. Low- and high-resolution mass spectra (LRMS and HRMS) were recorded using a Xevo QTof MS system (Waters, Tokyo, Japan) using the electrospray ionization (ESI) method. Infrared (IR) spectra were recorded on a Spectrum Two spectrometer (Perkin–Elmer, Yokohama, Japan). Data are expressed as frequency of absorption (cm−1). The products were isolated by silica-gel column chromatography (Sfär Silica D Duo 60 µm, Biotage, Uppsala, Sweden). Commercially available chemicals were purchased from Sigma–Aldrich (Tokyo, Japan), Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan) and FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan), and used as received. A strong acid cation-exchange resin, Amberlite IR120B Na, was purchased from Organo Corporation (Tokyo, Japan). Aqueous tetramethylammonium hypochlorite (TMAOCl) was prepared from aqueous tetramethylammonium hydroxide (TMAOH) by ion-exchange method (14.0 wt% TMAOCl, 7.86 wt% available chlorine, pH = 11.5) [36]. Compounds 1b [20], 1c [45], 1d–1g [20], 1h [46], 1i [47], 1j–1k [20], 1l [48], and 1m–1o [20] were synthesized according to the reported methods.

3.2. 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 CH2Cl2 (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to give the corresponding ω-chloroalkyl aryl ketones.

3.3. Procedure for the Scale-Up Experiment

1-Phenylcyclohexanol 1a (5.7 mmol, 1.0 g) was added to a 20 mL vial, and then CH2Cl2 (5.7 mL), TMAOCl (0.67 mL, 8.55 mmol), and AcOH (684 mg, 0.65 mL, 11.4 mmol) were successively added at rt. After stirring for 1 h at rt, the reaction mixture was extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (hexane/AcOEt = 97:3) to produce 0.96 g of chloro-1-phenylhexan-1-one 2a (4.56 mmol, 80%).

3.4. 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 Me4NOH 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 Me4N type. Aqueous NaOCl·5H2O solution (8.0 wt% as available chlorine) was then passed through the column to afford the aqueous TMAOCl solution.

3.5. Characterization Data

  • Chloro-1-phenylhexan-1-one (2a) [26]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 89 mg of 2a (0.42 mmol, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.97−7.95 (m, 2H), 7.58−7.55 (m, 1H), 7.48−7.45 (m, 2H), 3.56 (t, J = 6.6 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 1.86−1.76 (m, 4H), 1.56−1.52 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.0, 136.9, 133.0, 128.6, 128.0, 44.9, 38.3, 32.4, 26.6, 23.4; LRMS (ESI) m/z: 211 [M + H]+.
  • 6-Chloro-1-(4-chlorophenyl)hexan-1-one (2b) [22]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 103 mg of 2b (0.42 mmol, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.91–7.88 (m, 2H), 7.46–7.42 (m, 2H), 3.56 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.85–1.75 (m, 4H), 1.56–1.53 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.7, 139.4, 135.2, 129.4, 128.9, 44.8, 38.2, 32.4, 26.5, 23.3; LRMS (ESI) m/z: 245 [M + H]+.
  • 6-Chloro-1-(3-chlorophenyl)hexan-1-one (2c): Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 103 mg of 2c (0.42 mmol, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.55–7.51 (m, 1H), 7.43–7.39 (m, 1H), 3.56 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 1.86–1.75 (m, 4H), 1.56–1.52 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.5, 139.8, 132.5, 128.4, 117.9, 116.3, 44.7, 38.6, 32.3, 26.4, 23.1; IR (ATR): 2939, 2865, 1686, 1570, 1420, 1206 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C12H15Cl2O 246.1529, found 246.1530.
  • 6-Chloro-1-(4-trifluoromethylphenyl)hexan-1-one (2d): Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 96 mg of 2d (0.35 mmol, 69%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 1.86–1.77 (m, 4H), 1.57–1.53 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.9, 139.5, 134.3 (q, J = 32.4 Hz), 128.3, 125.7, 123.6 (q, J = 270.7 Hz), 44.8, 38.6, 32.4, 26.4, 23.1; 19F NMR (376 MHz, CDCl3): δ −66.3; IR (ATR): 2941, 2868, 1690, 1409, 1322, 1125, 1065 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C13H15ClF3O 279.7058, found 279.7057.
  • 4-(5-Chloropentanoyl)benzonitrile (2e): Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 84 mg of 2e (0.36 mmol, 71%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 1.86–1.77 (m, 4H), 1.57–1.55 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.5, 139.8, 132.5, 128.4, 117.9, 116.3, 44.7, 38.6, 32.3, 26.4, 23.1; IR (ATR): 2947, 2866, 2229, 1695, 1402, 1272, 1191 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C13H15ClNO 236.7173, found 236.7172.
  • 6-Chloro-1-(4-methylphenyl)hexan-1-one (2f) [23]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 94 mg of 2f (0.42 mmol, 84%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.87–7.84 (m, 2H), 7.27–7.25 (m, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 2.41 (s, 3H), 1.85–1.77 (m, 4H), 1.56–1.53 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.7, 143.7, 134.5, 129.2, 128.1, 44.9, 38.2, 32.5, 26.6, 23.5, 21.6; LRMS (ESI) m/z: 225 [M + H]+.
  • 3-(2-Chloroethoxy)-1-phenyl-1-propanone (2g): Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 54 mg of 2g (0.26 mmol, 51%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.98–7.95 (m, 2H), 7.57–7.49 (m, 1H), 7.49–7.45 (m, 2H), 3.97–3.94 (m, 2H), 3.76–3.74 (m, 2H), 3.63–3.60 (m, 2H), 3.31–3.27 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 136.8, 133.2, 128.6, 128.0, 71.2, 66.3, 42.7, 38.6; IR (ATR): 2961, 2873, 1661, 1596, 1446, 1213, 1116 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C11H14ClO2 213.6807, found 213.6807.
  • 6-Chloro-4-methyl-1-phenyl-1-hexanone (2i) [23]: Silica-gel column chromatography (hexane/toluene = 4/6) gave 58 mg of 2i (0.26 mmol, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.98–7.95 (m, 2H), 7.57–7.55 (m, 1H), 7.49–7.45 (m, 2H), 3.63–3.55 (m, 2H), 3.03–2.97 (m, 2H), 1.84–1.76 (m, 3H), 1.67–1.58 (m, 2H), 0.97 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.2, 136.9, 133.0, 128.6, 128.0, 43.0, 39.5, 36.0, 30.7, 30.1, 18.9; LRMS (ESI) m/z: 225 [M + H]+.
  • 5-Chloro-1-phenylpentan-1-one (2j) [26]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 53 mg of 2j (0.27 mmol, 54%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.97–7.95 (m, 2H), 7.57–7.56 (m, 1H), 7.49–7.45 (m, 2H), 3.59 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.91–1.89 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.6, 136.8, 133.1, 128.6, 128.0, 44.7, 37.5, 32.0, 21.5; LRMS (ESI) m/z: 197 [M + H]+.
  • 7-Chloro-1-phenylheptan-1-one (2k) [26]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 81 mg of 2k (0.36 mmol, 72%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.97–7.95 (m, 2H), 7.58–7.54 (m, 1H), 7.48–7.44 (m, 2H), 3.54 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 1.82–1.75 (m, 4H), 1.50–1.42 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.3, 137.0, 132.9, 128.6, 128.0, 45.0, 38.4, 32.4, 28.5, 26.7, 24.0; LRMS (ESI) m/z: 225 [M + H]+.
  • 8-Chloro-1-phenyloctan-1-one (2l) [26]: Silica-gel column chromatography (hexane/AcOEt = 97:3) gave 50 mg of 2l (0.36 mmol, 42%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.98–7.95 (m, 2H), 7.59–7.52 (m, 1H), 7.49–7.44 (m, 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 1.80–1.73 (m, 8H), 0.93–0.82 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.4, 137.0, 132.9, 128.5, 128.0, 45.1, 38.5, 32.5, 29.1, 28.7, 26.7, 24.2; LRMS (ESI) m/z: 239 [M + H]+.

4. Conclusions

In conclusion, we developed the C–C bond cleavage of tert-cycloalkanols for the direct approach for ω-chloroalkyl aryl ketones using TMAOCl as an oxidant. TMAOCl demonstrated a higher reactivity rather than the combination of NaOCl/Me4NCl, which might indicate the usefulness of TMAOCl as not only a hypochlorite but also as a phase-transfer reagent. In this reaction, we successfully obtained a variety of ω-chloroalkyl aryl ketones in good to high yields, even on a gram scale.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29081874/s1, Copies of 1H, 13C{1H}, and 19F NMR spectra of compounds 2a–2g and 2i–2l.

Author Contributions

Conceptualization, O.O.; methodology, O.O.; investigation, N.H.; writing—original draft preparation, N.H.; writing—review and editing, O.O., M.K., K.Y. and N.H.; visualization, N.H.; supervision, O.O.; project administration, K.Y. and M.K.; funding acquisition, O.O., M.K. and K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by JSPS (KAKENHI: 22K06528, 22K15255, and 19K05459).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Supplementary Materials.

Acknowledgments

We are grateful to Tokuyama Corporation for the generous gift of TMAOCl.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Van Wijngaarden, I.; Kruse, C.G.; van der Heyden, J.A.M.; Tulp, M.T.M. 2-Phenylpyrroles as conformationally restricted benzamide analogs. A new class of potential antipsychotics. 2. J. Med. Chem. 1988, 31, 1934–1940. [Google Scholar] [CrossRef]
  2. Perrone, R.; Berardi, F.; Colabufo, N.A.; Lacivita, E.; Leopoldo, M.; Tortorella, V. Synthesis and structure-affinity relationships of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]-1-aryl ketones as 5-HT7 receptor ligands. J. Med. Chem. 2003, 46, 646–649. [Google Scholar] [CrossRef]
  3. Chen, C.-A.; Jiang, Y.; Lu, K.; Daniewska, I.; Mazza, C.G.; Negron, L.; Forray, C.; Parola, T.; Li, B.; Hegde, L.G.; et al. Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits. J. Med. Chem. 2007, 50, 3883–3890. [Google Scholar] [CrossRef] [PubMed]
  4. Yang, D.; Yan, Y.-L.; Lui, B. Mild α-halogenation reactions of 1,3-dicarbonyl compounds catalyzed by Lewis acids. J. Org. Chem. 2002, 67, 7429–7431. [Google Scholar] [CrossRef]
  5. Frantz, R.; Hintermann, L.; Perseghini, M.; Broggini, D.; Togni, A. Titanium-catalyzed stereoselective geminal heterodihalogenation of β-ketoesters. Org. Lett. 2003, 5, 1709–1712. [Google Scholar] [CrossRef]
  6. Marigo, M.; Bachmann, S.; Halland, N.; Braunton, A.; Jørgensen, K.A. Highly enantioselective direct organocatalytic α-chlorination of ketones. Angew. Chem. Int. Ed. 2004, 43, 5507–5510. [Google Scholar] [CrossRef] [PubMed]
  7. Shibatomi, K.; Soga, Y.; Narayama, A.; Fujisawa, I.; Iwasa, S. Highly enantioselective chlorination of β-ketoesters and subsequent SN2 displacement of tertiary chlorides: A flexible method for the construction of quaternary stereogenic centers. J. Am. Chem. Soc. 2012, 134, 9836–9839. [Google Scholar] [CrossRef] [PubMed]
  8. Noguchi, T.; Hasegawa, M.; Tomisawa, K.; Mitsukuchi, M. Synthesis and Structure–Activity Relationships of 5-Phenylthiophenecarboxylic Acid Derivatives as Antirheumatic Agents. Bioorg. Med. Chem. 2003, 11, 4729–4742. [Google Scholar] [CrossRef] [PubMed]
  9. Close, W.J. An Improved Synthesis of Cyclopropyl Phenyl Ketone and Related Substances. J. Am. Chem. Soc. 1957, 79, 1455–1458. [Google Scholar] [CrossRef]
  10. Lukin, K.; Hsu, M.C.; Chambournier, G.; Kotecki, B.; Venkatramani, C.J.; Leanna, M.R. Development of a Large Scale Asymmetric Synthesis of Vanilloid Receptor (TRPV1) Antagonist ABT-102. Org. Process Res. Dev. 2007, 11, 578–584. [Google Scholar] [CrossRef]
  11. Majetich, G.; Wheless, K. Remote intramolecular free radical functionalizations: An update. Tetrahedron 1995, 51, 7095–7129. [Google Scholar] [CrossRef]
  12. Čeković, Ź. Reactions of δ-carbon radicals generated by 1,5-hydrogen transfer to alkoxy radicals. Tetrahedron 2003, 59, 8073–8090. [Google Scholar] [CrossRef]
  13. Chiba, S.; Chen, H. sp3 C−H oxidation by remote H-radical shift with oxygen- and nitrogen-radicals: A recent update. Org. Biomol. Chem. 2014, 12, 4051–4060. [Google Scholar] [CrossRef] [PubMed]
  14. Murakami, M.; Ishida, N. β-Scission of Alkoxy Radicals in Synthetic Transformations. Chem. Lett. 2017, 46, 1692–1700. [Google Scholar] [CrossRef]
  15. Kapustina, N.I.; Sokova, L.L.; Nikishin, G.I. Electrochemical oxidative ring opening of 1-methylcyclobutanol. Russ. Chem. Bull. 1996, 45, 1246–1248. [Google Scholar] [CrossRef]
  16. Allen, B.D.W.; Hareram, M.D.; Seastram, A.C.; McBride, T.; Wirth, T.; Browne, D.L.; Morrill, L.C. Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals. Org. Lett. 2019, 21, 9241–9246. [Google Scholar] [CrossRef] [PubMed]
  17. Yang, Z.; Yang, D.; Zhang, J.; Tan, C.; Li, J.; Wang, S.; Zhang, H.; Huang, Z.; Lei, A. Electrophotochemical Ce-Catalyzed Ring-Opening Functionalization of Cycloalkanols under Redox-Neutral Conditions: Scope and Mechanism. J. Am. Chem. Soc. 2022, 144, 13895–13902. [Google Scholar] [CrossRef] [PubMed]
  18. Huan, L.; Zhu, C. Manganese-catalyzed ring-opening chlorination of cyclobutanols: Regiospecific synthesis of γ-chloroketones. Org. Chem. Front. 2016, 3, 1467–1471. [Google Scholar] [CrossRef]
  19. Kapustina, B.I.; Spektor, S.S.; Nikishin, G.I. Oxidative cleavage of tertiary cycloalkanols by the lead tetraacetate-metal halide system. Russ. Chem. Bull. 1983, 32, 1394–1398. [Google Scholar] [CrossRef]
  20. Yamamoto, K.; Toguchi, H.; Kuriyama, M.; Watanabe, S.; Iwasaki, F.; Onomura, O. Electrophotochemical Ring-Opening Bromination of tert-Cycloalkanols. J. Org. Chem. 2021, 86, 16177–16186. [Google Scholar] [CrossRef] [PubMed]
  21. Han, W.-J.; Zhan, J.-L.; Yang, F.-L.; Liu, L. Ring-Opening Functionalization/Cyclization Reactions of Cycloalkanols under Transition-Metal-Free Conditions. Eur. J. Org. Chem. 2024, 27, e202301215. [Google Scholar] [CrossRef]
  22. Huang, F.-Q.; Xie, J.; Sun, J.-G.; Wang, Y.-W.; Dong, X.; Qi, L.-W.; Zhang, B. Regioselective Synthesis of Carbonyl-Containing Alkyl Chlorides via Silver-Catalyzed Ring-Opening Chlorination of Cycloalkanols. Org. Lett. 2016, 18, 684–687. [Google Scholar] [CrossRef] [PubMed]
  23. Fan, X.; Zhao, H.; Yu, J.; Bao, X.; Zhu, C. Regiospecific synthesis of distally chlorinated ketones via C−C bond cleavage of cycloalkanols. Org. Chem. Front. 2016, 3, 227–232. [Google Scholar] [CrossRef]
  24. Yayla, H.G.; Wang, H.; Tarantino, K.T.; Orbe, H.S.; Knowles, R.R. Catalytic Ring-Opening of Cyclic Alcohols Enabled by PCET Activation of Strong O–H Bonds. J. Am. Chem. Soc. 2016, 138, 10794–10797. [Google Scholar] [CrossRef] [PubMed]
  25. Wu, P.; Ma, S. Halogen-Substituted Allenyl Ketones through Ring Opening of Nonstrained Cycloalkanols. Org. Lett. 2021, 23, 2533–2537. [Google Scholar] [CrossRef] [PubMed]
  26. Liu, S.; Bai, M.; Xu, P.-F.; Sun, Q.-X.; Duan, X.-H.; Guo, L.-N. Copper-catalyzed radical ring-opening halogenation with HX. Chem. Commun. 2021, 57, 8652–8655. [Google Scholar] [CrossRef] [PubMed]
  27. Geng, Y.; Ma, Y.; Huang, R.; Li, X.; Yu, S. N-Haloimide-enabled halogenation via halogen-bond-assisted C–C activation of alkanols. Green Chem. 2023, 25, 221–228. [Google Scholar] [CrossRef]
  28. Wilt, J.W.; Hill, J.W. On the Rearrangement of t-Cycloalkyl Hypochlorites. J. Org. Chem. 1961, 26, 3523–3525. [Google Scholar] [CrossRef]
  29. Stevens, R.V.; Chapman, K.T.; Stubbs, C.A.; Tam, W.W.; Albizati, K.F. Further Studies on the Utility of Sodium Hypochlorite in Organic Synthesis. Selective Oxidation of Diols and Direct Conversion of Aldehydes to Esters. Tetrahedron Lett. 1982, 23, 4647–4650. [Google Scholar] [CrossRef]
  30. McDonald, C.E.; Nice, L.E.; Shaw, A.W.; Nestor, N.B. Calcium hypochlorite-mediated oxidation of primary alcohols to methyl esters. Tetrahedron Lett. 1993, 34, 2741–2744. [Google Scholar] [CrossRef]
  31. Wuts, P.G.M.; Cabaj, J.E.; Havens, J.L. Use of a Δ1-Piperidine for the Synthesis of a Differentially Protected Diamine Intermediate for the Preparation of the Iron Siderophore Desferrioxamine. J. Org. Chem. 1994, 59, 6470–6471. [Google Scholar] [CrossRef]
  32. Kirihara, M.; Okada, T.; Sugiyama, Y.; Akiyoshi, M.; Matsunaga, T.; Kimura, Y. Sodium Hypochlorite Pentahydrate Crystals (NaOCl·5H2O): Convenient and Environmentally Benign Oxidant for Organic Synthesis. Org. Process Res. Dev. 2017, 21, 1925–1937. [Google Scholar] [CrossRef]
  33. Lee, G.A.; Freedman, H.H. Phase transfer catalyzed oxidations of alcohols and amines by aqueous hypochlorite. Tetrahedron Lett. 1976, 17, 1641–1644. [Google Scholar] [CrossRef]
  34. Ishii, F.; Kishi, K.-i. Oxidation of Hydroquinone and Catechols with Aqueous Sodium Hypochlorite under Phase-Transfer Catalysis. Synthesis 1980, 1980, 706–708. [Google Scholar] [CrossRef]
  35. Shimoda, A.; Kikkawa, Y.; Sato, T.; Negishi, T. Quaternary Alkylammonium Hypochlorite Solution, Manufacturing Method Thereof, and Semiconductor Wafer Processing Method. JP Patent JP 2021-90051 A, 10 June 2021. [Google Scholar]
  36. Murata, A.; Umezu, N.; Tono, S.; Taira, H. Process for Producing Tetraalkylammonium Salt, and Process for Producing Tetraalkylammonium Hydroxide Using Same as Raw Material. PCT Int. Appl. WO 2012/090699 A1, 5 July 2012. [Google Scholar]
  37. Kaieda, Y.; Yamamoto, K.; Toguchi, H.; Hanazawa, N.; Kuriyama, M.; Onomura, O. Oxidative C–N Bond Cleavage of Cyclic Amines with Ammonium Hypochlorite. Synthesis 2023, eFirst. [Google Scholar] [CrossRef]
  38. Reger, D.L.; Habib, M.M.; Fauth, D.J. Use of phase-transfer reaction conditions for the hydrogenation of conjugated dienes and α,β-unsaturated ketones with a homogeneous metal hydride catalyst. J. Org. Chem. 1980, 45, 3860–3865. [Google Scholar] [CrossRef]
  39. Sasson, Y.; Negussie, S.; Royz, M.; Mushkin, N. Tetramethylammonium chloride as a selective and robust phase transfer catalyst in a solid–liquid halex reaction: The role of water. Chem. Commun. 1996, 297–298. [Google Scholar] [CrossRef]
  40. Dailey, J.I.; Hays, R.S.; Lee, H.; Mitchell, R.M.; Ries, J.J.; Landolt, R.G.; Husmann, H.H.; Lockridge, J.B.; Hendrickson, W.H. β-Scission of Tertiary Alkyl Hypochlorites Promoted by Phase-Transfer Catalysis. J. Org. Chem. 2000, 65, 2568–2571. [Google Scholar] [CrossRef] [PubMed]
  41. The reaction of 1-(2-chlorophenyl)cyclohexanol afforded an inseparable mixture of the desired product (22% NMR yield) and unknown compounds. 2024; Unpublished work.
  42. Greene, F.D.; Savitz, M.L.; Osterholtz, F.D.; Lau, H.H.; Smith, W.N.; Zanet, P.M. Decomposition of tertiary alkyl hypochlorites. J. Org. Chem. 1963, 28, 55–64. [Google Scholar] [CrossRef]
  43. Fonouni, H.E.; Krishnan, S.; Kuhn, D.G.; Hamilton, G.A. Mechanisms of epoxidations and chlorinations of hydrocarbons by inorganic hypochlorite in the presence of a phase-transfer catalyst. J. Am. Chem. Soc. 1983, 105, 7672–7676. [Google Scholar] [CrossRef]
  44. Kurouchi, H.; Andujar-De Sanctis, I.L.; Singleton, D.A. Controlling Selectivity by Controlling Energy Partitioning in a Thermal Reaction in Solution. J. Am. Chem. Soc. 2016, 138, 14534–14537. [Google Scholar] [CrossRef] [PubMed]
  45. Zhao, C.-Y.; Li, L.-G.; Liu, Q.-R.; Pan, C.-X.; Su, G.-F.; Mo, D.-L. Synthesis of β-Acetoxy Alcohols by PhI(OAc)2-Mediated Metal-Free Diastereoselective β-Acetoxylation of Alcohols. Org. Biomol. Chem. 2016, 14, 6795–6803. [Google Scholar] [CrossRef] [PubMed]
  46. Reddy, B.P.; Reddy, K.R.; Reddy, A.P.; Krupadanam, G.L.D.; Mukkera, V.; Sudhakar, N.; Subrahmanyam, L.V.L. Preparation of Novel Substituted Betulinic Amide Derivatives as HIV Inhibitors. PCT Int. Appl. WO 2017017630 Al, 2 February 2017. [Google Scholar]
  47. Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. N-Bromosuccinimide-mediated reaction of cyclic styrenes with chloramine-T. Tetrahedron Lett. 2014, 55, 4767–4770. [Google Scholar] [CrossRef]
  48. Deng, W.; Ye, C.; Li, Y.; Li, D.; Bao, H. Iron-Catalyzed Oxyalkylation of Terminal Alkynes with Alkyl Iodides. Org. Lett. 2019, 21, 261–265. [Google Scholar] [CrossRef] [PubMed]
Molecules 29 01874 sch001
Scheme 1. Regiospecific synthesis of carbonyl-containing alkyl chlorides with t-BuOCl.
Scheme 1. Regiospecific synthesis of carbonyl-containing alkyl chlorides with t-BuOCl.
Molecules 29 01874 sch001
Molecules 29 01874 sch002
Scheme 2. Regiospecific synthesis of carbonyl-containing alkyl chlorides with NCS.
Scheme 2. Regiospecific synthesis of carbonyl-containing alkyl chlorides with NCS.
Molecules 29 01874 sch002
Molecules 29 01874 sch003
Scheme 3. Our previous work: oxidative C–N bond cleavage of cyclic amines with TMAOCl.
Scheme 3. Our previous work: oxidative C–N bond cleavage of cyclic amines with TMAOCl.
Molecules 29 01874 sch003
Molecules 29 01874 sch004
Scheme 4. This work: oxidative C–C bond cleavage of tert-cycloalkanols with TMAOCl.
Scheme 4. This work: oxidative C–C bond cleavage of tert-cycloalkanols with TMAOCl.
Molecules 29 01874 sch004
Molecules 29 01874 sch005
Scheme 5. Substrate scope and limitations for C–C bond cleavage of tert-cycloalkanols. Reagents and conditions: 1 (0.5 mmol), TMAOCl (1.5 equiv), AcOH (2.0 equiv), CH2Cl2 (1.0 M), rt, 1 h. Isolated yields are shown.
Scheme 5. Substrate scope and limitations for C–C bond cleavage of tert-cycloalkanols. Reagents and conditions: 1 (0.5 mmol), TMAOCl (1.5 equiv), AcOH (2.0 equiv), CH2Cl2 (1.0 M), rt, 1 h. Isolated yields are shown.
Molecules 29 01874 sch005
Molecules 29 01874 sch006
Scheme 6. Scale-up experiment.
Scheme 6. Scale-up experiment.
Molecules 29 01874 sch006
Table 1. Optimization of reaction conditions.
Table 1. Optimization of reaction conditions.
Molecules 29 01874 i001
EntryTMAOCl
(Equiv)		Acid
(Equiv)		SolventYield (%) a
11.535% HCl (1.5)CH2Cl247
21.5TFA (1.5)CH2Cl277
31.5AcOH (1.5)CH2Cl279
41.5H3PO4 (0.75)CH2Cl276
51.5NaH2PO4 (1.5)CH2Cl275
61.5AcOH (2.0)CH2Cl285
71.5AcOH (2.25)CH2Cl283
82.0AcOH (2.0)CH2Cl270
9 b1.5AcOH (2.0)CH2Cl285
10 c1.5AcOH (2.0)CH2Cl285 (83)
11 c,d1.5AcOH (2.0)CH2Cl284
12 c1.5AcOH (2.0)ClPh70
13 c1.5AcOH (2.0)AcOEt67
14 c1.5AcOH (2.0)MeCN62
15 c,e-AcOH (2.0)CH2Cl256
16 c,f-AcOH (2.0)CH2Cl274
17 c,g-AcOH (2.0)CH2Cl279
181.5-CH2Cl2trace
19 h1.5AcOH (2.0)CH2Cl277
a Determined by 1H 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.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hanazawa, N.; Kuriyama, M.; Yamamoto, K.; Onomura, O. Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite. Molecules 2024, 29, 1874. https://doi.org/10.3390/molecules29081874

AMA Style

Hanazawa N, Kuriyama M, Yamamoto K, Onomura O. Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite. Molecules. 2024; 29(8):1874. https://doi.org/10.3390/molecules29081874

Chicago/Turabian Style

Hanazawa, Natsumi, Masami Kuriyama, Kosuke Yamamoto, and Osamu Onomura. 2024. "Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite" Molecules 29, no. 8: 1874. https://doi.org/10.3390/molecules29081874

APA Style

Hanazawa, N., Kuriyama, M., Yamamoto, K., & Onomura, O. (2024). Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite. Molecules, 29(8), 1874. https://doi.org/10.3390/molecules29081874

Article Metrics

Back to TopTop