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Article

Sodium Hypochlorite Pentahydrate as a Chlorinating Reagent: Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones

by
Michio Iwaoka
1,2,*,
Reo Shimada
1,
Masaki Kuroda
1,
Takehito Ikeda
1 and
Eduardo E. Alberto
3
1
Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka 259-1292, Kanagawa, Japan
2
Institute of Advanced Biosciences, Tokai University, Kitakaname, Hiratsuka 259-1292, Kanagawa, Japan
3
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
*
Author to whom correspondence should be addressed.
Processes 2024, 12(6), 1102; https://doi.org/10.3390/pr12061102
Submission received: 1 May 2024 / Revised: 21 May 2024 / Accepted: 25 May 2024 / Published: 27 May 2024
(This article belongs to the Special Issue Advances and Prospects in Organic Synthesis)
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Abstract

:
Sodium hypochlorite pentahydrate (NaClO·5H2O, 1) has recently been employed in organic synthesis as an oxidant for alcohols, sulfides, glycols, etc. In most of these reactions, however, reagent 1 functions just as a simple oxidant, and the variations of the reactions have not been well explored. In this study, we report another useful and fascinating reaction, in which reagent 1 functions as a green chlorinating reagent toward β,γ-unsaturated carboxylic acid (2). When substrate 2 was stirred at room temperature with 1 (2 eq) in acetonitrile for 1 h, α,β-unsaturated lactone (3) was obtained in moderate yields (up to 62%). The same reaction proceeded in various organic and aqueous solvents as well. When excess reagent 1 was employed, lactone 3 was further oxidized to the corresponding epoxide (4) for some cases. The conversion is initiated by electrophilic attack of HOCl to the C=C bond of 2 to generate a chloronium ion intermediate, which is cyclized to β-chlorolactone (5) and then 3 through the elimination of HCl. The usefulness of 1 as a chlorinating reagent was further demonstrated in the electrophilic substitution of activated aromatic compounds.

1. Introduction

Sodium hypochlorite (NaClO) is widely used in our daily life as a bleach and an antibacterial agent. However, this oxidizing reagent is chemically unstable, and hence it has to be preserved in a diluted aqueous solution. Therefore, NaClO has been limitedly applied in organic synthesis [1,2]. Nevertheless, NaClO has the potential as a useful and green reagent because it produces only non-toxic NaCl as a byproduct after the oxidation reaction. The conventional use of NaClO (or HOCl) in organic synthesis includes oxidation of alcohols to aldehydes and ketones [3,4,5,6,7]; oxidation of alkenes to epoxides [8,9,10] and glycols [11]; oxidation of sulfoxides to sulfones [12]; chlorination of allenes [13]; phenols [14,15], and amine [16,17,18]; etc. [19,20,21,22,23,24,25,26,27]. However, chlorination of simple alkenes using NaClO has not been reported in the literature. Recently, sodium hypochlorite pentahydrate (NaClO·5H2O, 1) has become available as stable crystals [28,29]. This has stimulated researchers to explore new processes of organic substances into valuable compounds using 1. For example, selective oxidation of alcohols [30,31,32], oxidation of sulfides to sulfoxides and sulfones [33,34], oxidative cleavage of glycols [35], oxidation of imines to oxaziridines [36], oxidative 1,2-diamination of alkenes [37], etc. [38,39,40,41], were reported. In most of these reactions, however, reagent 1 functions just as a simple oxidant, and the variations of the reactions have not been widely explored. Organic reaction processes, in which unique reactivities of NaClO as a chlorinating reagent are exerted, have been largely left to be studied. In this context, we demonstrate here that 1 is a potentially useful chlorinating reagent for the tandem conversion of β,γ-unsaturated carboxylic acids (2) to α,β-unsaturated lactones (3), as well as for the electrophilic chlorination of activated aromatic compounds.
The intramolecular cyclization reactions of unsaturated carboxylic acids are important processes in organic synthesis and have been extensively studied in the literature [42,43,44]. For example, Cheng reported iron-catalyzed radical annulation of unsaturated carboxylic acids in the presence of PhSSPh or PhSeSePh (Scheme 1A) [45]. Wirth reported the transformation of unsaturated carboxylic acids into unsaturated lactones using a hypervalent iodine reagent with two equivalents of trimethylsilyl triflate (TMSOTf) (Scheme 1B) [46]. Electrochemical oxidative bromination and cyclization sequences of unsaturated carboxylic acids were reported by Kim (Scheme 1C) [47]. However, in most of the cyclization reactions, the use of complex transition metal catalysts [48], harmful sulfur or selenium reagents [45,49,50,51,52,53,54,55,56,57], halogenating agents with poor atom economy such as N-halosuccinimide and derivatives [58,59], or expensive hypervalent iodide reagents [46,60] was necessary. Most of them would have environmental risks to some extent. On the other hand, the reactions developed in this study do not have such risks nor need any difficult experimental procedures. Indeed, the reaction products can be obtained only by mixing the substrates and 1 in a solvent without using any other reagents (Scheme 1D).

2. Results and Discussion

We started our investigation using (E)-4-phenylpent-3-enoic acid (2a) as a substrate and acetonitrile as a solvent. Since NaClO·5H2O (1) is not soluble in the solvent, the mixture was stirred vigorously. The reaction progress was monitored by TLC, which indicated that 2a completely disappeared within 5 min. After 1 or 3 h, the reaction mixture was evaporated, and the residual material was transferred onto a silica gel column. The products were separated through the gel. The results are summarized in Table 1.
When 1 (1 eq) was employed at 0 °C, only products with unknown structures were obtained, except for a trace amount of the expected product 3a, which was identified by 1H NMR (entry 1). When the amount of 1 was increased to 2 eq, 3a was obtained in a yield of 53% (entry 2). However, the yield decreased significantly upon increasing the reaction time from 1 h to 3 h (entry 3). When 3 eq of 1 was employed, the yield of 3a increased, but epoxide 4a was also generated (entry 4). A similar result (lower yields of 3a and 4a) was obtained using 5 eq of 1 (entry 5). Subsequently, the reaction temperature was increased to room temperature (entries 6–9). Under these conditions, the yield of 3a was raised up to 62% (entry 7). Again, when 1 was employed in excess, the formation of epoxide 4a was observed (entries 8 and 9). The molecular structure of 4a was confirmed by X-ray analysis (Figure S1), which clearly shows that the epoxide oxygen is placed on the opposite side of the phenyl group, probably due to the greater steric repulsion of the benzene ring than that of the methyl group during the formation of the oxirane ring. Other products were also detected in the reaction mixture, but their structures could not be characterized.
Examining the reaction conditions, we determined that the optimal conditions were the use of 2 eq of 1 at room temperature for 1 h (Table 1, entry 7). Applying these conditions, we subsequently carried out the reaction in various organic and aqueous solvents. The results are summarized in Table 2. The yields of 3a were higher in more polar organic solvents (entries 1–8), suggesting the involvement of HOCl, which would be liberated to the solvent by the acid–base reaction between NaClO and 2a. Indeed, 1 dissolved in MeOH, DMF, and EtOH, while in acetone it was partially soluble. For other solvents, such as hexane, toluene, and DCM, 1 did not dissolve. It is of interest that the reaction took place even in such non-polar solvents. However, only modest amounts of 3a (up to 62%) were obtained in these reactions due to the progression of complex side reactions.
More interestingly, 3a was obtained even in aqueous solutions (Table 2, entries 9–11). The yield of 3a significantly increased at pH 4.0, accompanying the formation of chloride 5a. The total yield was 73%, which was slightly improved from that in acetonitrile (Table 2, entry 1). The pH dependence supports the involvement of HOCl, not NaClO, as a reactive species. The formation of 5 is facilitated by its insolubility in aqueous solutions. The reaction was also carried out under a biphasic condition (Table 2, entry 12). However, the yield of 3a decreased, whereas that of 4a increased slightly. It should be noted that chloride 5a contained only one stereoisomer as revealed by 1H NMR analysis, suggesting the stereoselective formation from the three-membered ring chloronium ion intermediate.
Next, the scope of substrate 2 was explored using acetonitrile as a solvent (Table 3). Although the yields of 3 were not high, the desired cyclized products 3b–f were obtained from both aromatic and aliphatic β,γ-unsaturated carboxylic acids 2b–f, except for 3-butanoic acid (2d) (entry 3), for which chloride 6, instead of α,β-unsaturated γ-butyrolactone (3d), was produced. When (E)-4-phenylbut-3-enoic acid (2b) was employed as a substrate, 5-phenylfuran-2(5H)-one (3b) was obtained in 21% yield along with side product 3b′ in 17% yield (entry 1). Formation of such a rearranged isomer has been reported in similar reactions [61]. When a longer reaction time was employed, rearrangement of 3b to 3b’ was observed. When the reaction was carried out in a larger scale, product 3b was obtained in a similar yield. On the other hand, for substrate 2c, which has a methoxy group at the para position of the benzene ring of 2b, the yield of the cyclized product 3c became higher (entry 2), supporting the participation of the electrophilic addition of HOCl to the C=C bond in the initial stage of the reaction. When aliphatic substrates 2e and 2f were employed, the reaction became sluggish (Figure S2). Unsaturated lactones 3e and 3f were obtained in low yields along with epoxides 4e and 4f (entries 4 and 5). It should be noted that the reaction conditions, i.e., temperature, amounts of 1, and reaction time, were optimized for each substrate to increase the yield of the desired product, i.e., 3. For example, when the reaction of 2b was carried out at 0 °C, 3b was not obtained. Similarly, when the reaction of 2e was carried out at 0 °C, the reaction proceeded very slowly due to the low reactivity of the aliphatic substrate. On the other hand, the desired product was not obtained when the reaction of 2f was carried out at room temperature, probably due to the decomposition of products 3f and 4f.
Several control experiments were performed to obtain more information about the reaction mechanism. When alkenes 7 and 8 (Figure 1) were employed as substrates, no cyclization products were obtained although the substrate disappeared quickly after initiation of the reaction. Thus, only unsaturated carboxylic acids can be employed as a substrate in this reaction. Further, when styrene 9 was employed in methanol, methoxide 10 was obtained at 40 °C after 1 day (Scheme 2). In this reaction, the formation of a trace amount of chloride 11, which would be generated by dehydration of the HOCl adduct of 9, was also observed by 1H NMR, suggesting the occurrence of complex side reactions [62].
Summing up all observations, the reaction mechanism was delineated as shown in Scheme 3. HOCl, which is formed by the reaction between acidic substrates 2 and 1 [28,38], attacks the C=C bond of the substrate to generate a three-membered ring chloronium ion intermediate 12. In this intermediate, an intramolecular nucleophilic attack of the COO− group takes place stereoselectively, resulting in the formation of chloride 5. In the reaction of styrene 9 in methanol, the solvent worked as a nucleophile. However, for substrate 1a, such a methoxide product was not obtained when the reaction was carried out in MeOH (Table 2, entry 2). Subsequently, HCl is eliminated from 5 to generate product 3 by reacting with the hydroxide anion, which has been liberated from HOCl. In the presence of excess 1, lactone 3 is oxidized to epoxide 4. According to Scheme 3, unsaturated lactone 3 can be obtained from 2 using only 1 equivalent of 1 as observed in Table 1, entry 6, and Table 3, entry 4. The total reaction formula is 2 + NaClO·5H2O (1) → 3 + NaCl + 6H2O, indicating that the reaction is a sustainable green process. However, the reaction usually required 2 equivalents of 1 as observed in Table 1, Table 2 and Table 3. This would be due to the insolubility of 1 in organic solvents or insolubility of 2, 3, and 5 in aqueous mixtures.
To demonstrate the usability of 1 as a chlorinating reagent, we attempted to carry out electrophilic substitutions of activated aromatic compounds (Scheme 4 and Scheme 5). When 1,3,5-trimethoxybenzene (13) was reacted with 1 in acetonitrile at room temperature for 2 h, chloride 14 was obtained in 55% yield along with a trace amount of dichloride 15 as expected. Similarly, N,N-dimethylaniline (16) was also chlorinated to 4-chloro-N,N-dimethylaniline (17) in 17% yield along with unknown byproducts. In these reactions, we assume that the same HOCl participates as an active chlorinating reagent. Although the conversion yields were not so high as compared to those reported in the literature [63,64,65,66,67,68,69], in which more than 90% conversions were achieved by using an elaborate chlorinating reagent, such as N-chlorosuccinimide, lithium chloride–H2O2, or fullerene derivatives, and a catalyst, the reaction using 1 has an advantage in that it requires no additional reagent nor catalyst. Similar chlorination reactions of phenols and aromatic ethers, including 13, using HOCl was reported previously [14,15,70].

3. Conclusions

In this study, we demonstrated two novel reactions using NaClO·5H2O (1). In the first reaction, the transformation of unsaturated carboxylic acids (2) to unsaturated lactones (3) was achieved through chlorination of the substrate with 1 in various solvents (Table 1, Table 2 and Table 3). Although the yields of 3 were modest (up to 62%), it should be stressed that this is the first report to show the potential usefulness of NaClO or HOCl as an electrophilic chlorinating reagent toward simple alkenes. Since the transformation from 2 to 3 is an important reaction in organic synthetic processes (Scheme 1), it is also of note that such tandem reactions can be simply realized by using only 1 as a reagent. In the second reaction, electrophilic chlorination of 13 and 16 was achieved by applying the same reaction conditions (Scheme 4 and Scheme 5). Thus, NaClO·5H2O (1) was found to be a potentially useful and sustainable green chlorinating reagent in organic synthesis.

4. Materials and Methods

NaClO·5H2O (1) was purchased from Tokyo Chemical Industry Co., Ltd., Tokyo, Japan, and was used as obtained. It should be noted that this reagent is deliquescence. Substrates 2a, 2c, and 2f were synthesized according to the literature methods [55,71]. All other substrates and chemicals were commercially available and were used as purchased without further purification. Progressions of the reactions were monitored by thin-layer chromatography (TLC) using pre-coated sheets of silica gel 60 (Merck Millipore, Merck KGaA, Darmstadt, Germany), and also by 1H NMR using a Magritek Spinsolve60 spectrometer at 60 MHz in some cases. To identify the reaction products, 1H NMR spectra were measured at 500 MHz on a Bruker AV-500 spectrometer at 298 K in CDCl3 using the solvent signal as an internal standard of the chemical shifts.

4.1. General Procedure

To a mixture of a substrate (0.23 mmol) and acetonitrile (1 mL), we added 1 (76 mg, 2 eq). After rigorous stirring at room temperature for 1 h, the mixture was evaporated. When aqueous solvents were employed, the reaction mixture was added to water and extracted with ethyl acetate, and the combined organic layers were dried with magnesium sulfate, filtered, and evaporated. The residual materials thus obtained were put on a silica gel column and eluted with a mixture of hexane and ethyl acetate (usually at the ratio of 4:1). Fractionated products were collected. The structures of the main products were assigned based on the NMR spectra.

4.2. Reaction of (E)-4-Phenylpent-3-Enoic Acid (2a)

Following the general procedure, 5-methyl-5-phenylfuran-2(5H)-one (3a) was obtained (24.8 mg, 62%) as a colorless oil. Spectral data for 3a: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 5.5 Hz, 1H), 7.39–7.31 (m, 5H), 6.06 (d, J = 5.5 Hz, 1H), 1.83 (s, 3H). The spectrum was consistent with the literature [72].
When the reaction was carried out using 1 (124 mg, 3 eq), 4-methyl-4-phenyl-3,6-dioxabicyclo[3.1.0]hexan-2-one (4a) was obtained (10.8 mg, 25%) as a white solid, in addition to 3a (14.9 mg, 37%). Spectral data for 4a: m.p. 90–92 °C. 1H NMR (500 MHz, CDCl3) δ 7.46–7.37 (m, 5H), 4.10 (d, J = 2.5 Hz, 1H), 3.78 (d, J = 2.5 Hz, 1H), 1.82 (s, 3H). 13C NMR (125.8 MHz, CDCl3) δ 170.1, 139.7, 129.1, 128.8, 124.6, 85.1, 61.4, 51.1, 22.6. The molecular structure of 4a was determined by single-crystal X-ray diffraction analysis (see below).
When the reaction was carried out in pH 4.0 phthalate buffer, (4S/R,5R/S)-4-chloro-5-methyl-5-phenyldihydrofuran-2(3H)-one (5a) was obtained (12.0 mg, 25%) as a colorless oil, in addition to 3a (19.4 mg, 48%). Spectral data for 5a: 1H NMR (500 MHz, CDCl3) δ 7.41–7.33 (m, 5H), 4.69 (dd, J = 6.5 and 3.0 Hz, 1H), 2.96 (dd, J = 18.0 and 6.5 Hz, 1H), 2.79 (dd, J = 18.0 and 3.0 Hz, 1H), 1.83 (s, 3H). The spectrum was consistent with the literature [61].

4.3. Reaction of (E)-4-Phenylbut-3-Enoic Acid (2b)

Following the general procedure, 5-phenylfuran-2(5H)-one (3b) was obtained (7.8 mg, 21%) as a colorless oil along with 5-phenylfuran-2(3H)-one (3b′) (6.3 mg, 17%) as a slightly yellow oil. Spectral data for 3b: 1H NMR (500 MHz, CDCl3) δ 7.54 (dd, J = 5.5 and 1.5 Hz, 1H), 7.41–7.38 (m, 3H), 7.28–7.26 (m, 2H), 6.24 (dd, J = 5.5 and 2.5 Hz, 1H), 6.02 (t, J = 2.0 Hz, 1H). Spectral data for 3b′: 1H NMR (500 MHz, CDCl3) δ 7.62–7.59 (m, 2H), 7.43–7.38 (m, 3H), 5.79 (t, J = 3.0 Hz, 1H), 3.43 (d, J = 3.0 Hz, 2H). These spectra were consistent with the literature [61].

4.4. Reaction of (E)-4-(4-Methoxyphenyl)But-3-Enoic Acid (2c)

The reaction was carried out at 0 °C for 3 h to yield 5-(4-methoxyphenyl)furan-2(5H)-one (3c) (24.3 mg, 56%) as a colorless oil. Spectral data for 3c: 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 5.5 and 1.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.22 (dd, J = 5.5 and 2.0 Hz, 1H), 5.96 (t, J = 2.0 Hz, 1H), 3.80 (s, 3H). The spectrum was consistent with the literature [73].

4.5. Reaction of But-3-Enoic Acid (2d)

The reaction was carried out in a 1.1 mmol scale at 0 °C for 1 h to yield 4-(chloromethyl)oxetan-2-one (6) (14.5 mg, 11%) as a colorless oil. Spectral data for 6: 1H NMR (500 MHz, CDCl3) δ 4.74 (m, 1H), 3.83 (m, 2H), 3.60 (dd, J = 16.5 and 6.0 Hz, 1H), 3.40 (dd, J = 16.5 and 4.0 Hz, 1H). The spectrum was consistent with the literature [74].

4.6. Reaction of (E)-Hex-3-Enoic Acid (2e)

The reaction was carried out in a 1.0 mmol scale using 1 eq of 1 at room temperature for 1 day to yield 5-ethylfuran-2(5H)-one (3e) (17.8 mg, 16%) as a colorless oil along with (1S/R,4S/R,5S/R)-4-ethyl-3,6-dioxabicyclo[3.1.0]hexan-2-one (4e) (30.9 mg, 24%) as a colorless oil. Spectral data for 3e: 1H NMR (500 MHz, CDCl3) δ 7.45 (dd, J = 5.5 and 1.5 Hz, 1H), 6.11 (dd, J = 5.5 and 2.0 Hz, 1H), 5.00 (m, 1 H), 1.88–1.79 (m, 1H), 1.77–1.68 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H). The spectrum was consistent with the literature [75]. Spectral data for 4e: 1H NMR (500 MHz, CDCl3) δ 4.51 (m, 1H), 3.97 (d, J = 2.5 Hz, 1H), 3.77 (dd, J = 2.5 and 1.0 Hz, 1H), 1.80–1.66 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H). 13C NMR (125.8 MHz, CDCl3) δ 170.4, 80.8, 57.8, 49.8, 25.3, 8.6.

4.7. Reaction of (E)-5-Phenylpent-3-Enoic Acid (2f)

The reaction was carried out in a 0.92 mmol scale at 0 °C for 2 h to yield 5-benzylfuran-2(5H)-one (3f) (13.4 mg, 8%) as a colorless oil along with (1S/R,4S/R,5S/R)-4-benzyl-3,6-dioxabicyclo[3.1.0]hexan-2-one (4f) (4.4 mg, 3%) as a colorless oil. Spectral data for 3f: 1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 6.0 and 1.5 Hz, 1H), 7.27–7.13 (m, 5H), 6.01 (dd, J = 6.0 and 2.0 Hz, 1H), 5.16 (m, 1H), 3.08 (dd, J = 13.5 and 6.0 Hz, 1H), 2.89 (dd, J = 14.0 and 7.0 Hz, 1H). The spectrum was consistent with the literature [54]. Spectral data for 4f: 1H NMR (500 MHz, CDCl3) δ 7.37–7.22 (m, 5H), 4.82 (m, 1H), 3.99 (d, J = 2.0 1H), 3.63 (dd, J = 2.5 and 1.0 Hz, 1H), 3.12 (dd, J = 14.0 and 5.5 Hz, 1H), 3.00 (dd, J = 14.0 and 7.0 Hz, 1H). 13C NMR (125.8 MHz, CDCl3) δ 170.0, 133.6, 129.5, 129.0, 127.6, 79.3, 57.6, 49.8, 38.3.

4.8. Reaction of Styrene (9)

The reaction was carried out in methanol at 40 °C for 1 day to yield (2-chloro-1-methoxyethyl)benzene (10) (11.4 mg, 29%) as a colorless oil along with a trace amount of (E)-(2-chlorovinyl)benzene (11). Spectral data for 10: 1H NMR (500 MHz, CDCl3) δ 7.41–7.32 (m, 5H), 4.36 (dd, J = 8.0 and 4.5 Hz, 1H), 3.68 (dd, J = 11.5 and 8.0 Hz, 1H), 3.59 (dd, J = 11.5 and 4.5 Hz, 1H), 3.32 (s, 3H). The spectrum was consistent with the literature [76]. Spectral data for 11: 1H NMR (500 MHz, CDCl3) δ 7.33–7.28 (m, 5H), 6.83 (d, J = 13.5 Hz, 1H), 6.64 (d, J = 13.5 Hz, 1H). The spectrum was consistent with the literature [77].

4.9. Reaction of 1,3,5-Trimethoxybenzene (13)

Following the general procedure, 2-chloro-1,3,5-trimethoxybenzene (14) (25.5 mg, 55%) was obtained as a white solid along with a trace amount of 2,4-dichloro-1,3,5-trimethoxybenzene (15) as a white solid. Spectral data for 14: 1H NMR (500 MHz, CDCl3) δ 6.18 (s, 2H), 3.88 (s, 6H), 3.81 (s, 3H). Spectral data for 15 as a mixture with 14: 1H NMR (500 MHz, CDCl3) δ 6.38 (s, 1H), 3.91 (s, 6H), 3.89 (s, 3H). These spectra were consistent with the literature [78].

4.10. Reaction of N,N-Dimethylaniline (16)

Following the general procedure, 4-chloro-N,N-dimethylaniline (17) (6.2 mg, 17%) was obtained as a pale yellow solid along with unknown byproducts. Spectral data for 17: 1H NMR (500 MHz, CDCl3) δ 7.17 (td, J = 9.0 and 2.7 Hz, 2H), 6.63 (td, J = 9.0 and 2.7 Hz, 2H), 2.93 (s, 6H). The spectrum was consistent with the literature [79].

4.11. X-ray Analysis for 4a

The compound was recrystallized from hexane–dichloromethane to yield fine crystals. The single crystal X-ray diffraction data were recorded on a Rigaku XtaLAB PRO P200 diffractometer using graphite monochromated Mo Kα radiation. The collected data were processed with CrysAlisPro (Rigaku Oxford Diffraction: Tokyo, Japan, 2015). The initial structures were solved by SHELXT (Version 2018/2) [80]. The structure refinement was performed by the full-matrix least-squares method on F2 using SHELXL (Version 2018/3) [81]. The CIF files for these compounds were deposited on CCDC (2323420).

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/pr12061102/s1. Figure S1: X-ray structure for 4a. Figure S2: A series of 1H NMR spectra monitoring the reaction of 2e with NaClO·5H2O (1). Table S1: Crystallographic data for 4a; spectroscopic characterization of the reaction products.

Author Contributions

Conceptualization, M.I.; conceptional support, E.E.A.; methodology and investigation, R.S. and M.K.; X-ray analysis, T.I.; writing—original draft preparation, M.I.; writing—review and editing, E.E.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by JSPS KAKENHI, grant number 22K05466 (M.I.), and CAPES-PRINT, grant number 88887.833186/2023-00 (M.I. and E.E.A.).

Data Availability Statement

The original contributions presented in the study are included in the article and Supplementary Materials, further inquiries can be directed to the corresponding author.

Acknowledgments

E.E.A. thanks CAPES, CNPq, and FAPEMIG for their financial support.

Conflicts of Interest

The authors declare no conflicts of interest.

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Processes 12 01102 sch001
Scheme 1. Lactonization reactions of unsaturated carboxylic acids (A–D) [45,46,47].
Scheme 1. Lactonization reactions of unsaturated carboxylic acids (A–D) [45,46,47].
Processes 12 01102 sch001
Processes 12 01102 g001
Figure 1. Unusable substrates.
Figure 1. Unusable substrates.
Processes 12 01102 g001
Processes 12 01102 sch002
Scheme 2. The reaction of styrene 9.
Scheme 2. The reaction of styrene 9.
Processes 12 01102 sch002
Processes 12 01102 sch003
Scheme 3. The proposed reaction mechanism.
Scheme 3. The proposed reaction mechanism.
Processes 12 01102 sch003
Processes 12 01102 sch004
Scheme 4. Chlorination of 13 using NaClO·5H2O (1).
Scheme 4. Chlorination of 13 using NaClO·5H2O (1).
Processes 12 01102 sch004
Processes 12 01102 sch005
Scheme 5. Chlorination of 16 using NaClO·5H2O (1).
Scheme 5. Chlorination of 16 using NaClO·5H2O (1).
Processes 12 01102 sch005
Table 1. Optimization of the reaction conditions for the oxidative cyclization of 2a to 3a using NaClO·5H2O (1) in CH3CN a.
Table 1. Optimization of the reaction conditions for the oxidative cyclization of 2a to 3a using NaClO·5H2O (1) in CH3CN a.
Processes 12 01102 i001
EntryNaClO·5H2O (1)TempReaction Time (h)Yields of 3a (%) bYields of 4a (%) b
11 eq0 °C1trace–
22 eq0 °C153–
32 eq0 °C336–
43 eq0 °C3457
55 eq0 °C3175
61 eqrt148–
72 eqrt162–
83 eqrt13725
95 eqrt242620
a Reactions were carried out using 2a (40 mg, 0.23 mmol) in CH3CN (1 mL). b Isolated yields.
Table 2. Examination of various solvents for the oxidative cyclization of 2a to 3a using NaClO·5H2O (1) a.
Table 2. Examination of various solvents for the oxidative cyclization of 2a to 3a using NaClO·5H2O (1) a.
Processes 12 01102 i002
EntrySolventsYields of 3a (%) bYields of 5a (%) b
1CH3CN62–
2MeOH61–
3DMF59–
4EtOH39–
5Acetone25–
6Hexane18–
7Toluene17–
8DCM11–
9H2O24trace c
10Buffer pH 6.9 d2110
11Buffer pH 4.0 e4825
12Buffer pH 4.0—Et2O1732
a Reactions were carried out using 2a (40 mg, 0.23 mmol) in the corresponding solvent (1 mL). b Isolated yields. c Estimated by 1H NMR. d 25 mM phosphate buffer was used. e 50 mM potassium hydrogen phthalate buffer was used.
Table 3. The scope of the substrate for the oxidative cyclization of 2 using NaClO·5H2O (1) a.
Table 3. The scope of the substrate for the oxidative cyclization of 2 using NaClO·5H2O (1) a.
Processes 12 01102 i003
EntrySubstrateRConditionsYield of 3 bSide Products (Yields) b
12bPhrt, 1 h21%Processes 12 01102 i004
rt, 6 h–(30%)
rt, 1 h c23%(trace)
22c4-CH3O-C6H40 °C, 3 h56%
32dH0 °C, 1 h d0%Processes 12 01102 i005
42eCH3CH2rt, 1 d d,e16%Processes 12 01102 i006
52fPhCH20 °C, 2 h d8%Processes 12 01102 i007
a Reactions were carried out using 2 (0.23 mmol) and 1 (2 eq) in CH3CN (1 mL). b Isolated yields. c A 10 times larger scale was applied using 2 (2.3 mmol) and 1 (2 eq) in CH3CN (10 mL). d A 4–5 times larger scale was applied. e Using 1 eq of 1.
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Iwaoka, M.; Shimada, R.; Kuroda, M.; Ikeda, T.; Alberto, E.E. Sodium Hypochlorite Pentahydrate as a Chlorinating Reagent: Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones. Processes 2024, 12, 1102. https://doi.org/10.3390/pr12061102

AMA Style

Iwaoka M, Shimada R, Kuroda M, Ikeda T, Alberto EE. Sodium Hypochlorite Pentahydrate as a Chlorinating Reagent: Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones. Processes. 2024; 12(6):1102. https://doi.org/10.3390/pr12061102

Chicago/Turabian Style

Iwaoka, Michio, Reo Shimada, Masaki Kuroda, Takehito Ikeda, and Eduardo E. Alberto. 2024. "Sodium Hypochlorite Pentahydrate as a Chlorinating Reagent: Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones" Processes 12, no. 6: 1102. https://doi.org/10.3390/pr12061102

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