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Article

Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones

by
Hideyasu China
1,2,*,
Nami Kageyama
2,
Hodaka Yatabe
2,
Mihoyo Fujitake
3,
Yusei Matsumoto
2,
Zhihan Jing
2 and
Toshifumi Dohi
2,*
1
Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, 97-1, Minamihokotate, Kodo, Kyotanabe 610-0395, Kyoto, Japan
2
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Shiga, Japan
3
Center for Pharmaceutical Research and Development, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2026, 31(1), 199; https://doi.org/10.3390/molecules31010199
Submission received: 12 December 2025 / Revised: 26 December 2025 / Accepted: 30 December 2025 / Published: 5 January 2026
(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)
Browse Figures
Versions Notes

Abstract

Haloketoesters are synthetic intermediates in various cyclization reactions that facilitate the production of biologically active compounds. Nonetheless, the selective synthesis of dihaloketoesters and trihaloketoesters, which are expected to be highly versatile, presents significant challenges. In this study, we designed a new synthetic approach that selectively and efficiently produces haloketoesters through the halogenative C–C bond cleavage and ring-opening reactions of cyclic 1,3-diketones. This convenient method enables the direct synthesis of di- and trichloro-functionalized ketoesters from 1,3-cyclohexadiones under mild conditions. Na2HPO4, employed as a buffer salt, proved to be effective in facilitating the alcoholytic ring-opening reaction of 2,2-dichloro-1,3-cyclohexadiones, which were generated as synthetic intermediates.

1. Introduction

Acyclic keto acids and ketoesters are amenable to a range of cyclization reactions, resulting in diverse ring structures including disubstituted lactams [1,2,3,4], acyllactams [5], disubstituted cyclic amines [6,7], monosubstituted lactones [8,9,10,11], gem-disubstituted lactones [12,13], monosubstituted enol lactones [14], acyllactones [15,16], other heterocycles [17,18], and carbocyclic compounds [19]. These acyclic molecules can be synthesized through various strategies such as the retro-Claisen reaction [20,21,22,23], Michael reaction [24,25,26], directed oxidation reaction [27], oxidative ring-opening reaction [28,29,30,31], cross-coupling reaction [32,33], and insertion reaction [34]. These methodologies facilitate the introduction of diverse substituents and enable a variety of synthetic approaches from the appropriate starting materials.
Keto acids and ketoesters are recognized for their inclusion in various bioactive compounds, such as duazomycin (N-acetyl DON) [35], esonarimod (KE-298) [36], (R)-flobufen [37], kynurenine [38], tanomastat (BAY 12-9566) [39], and 3F-5-AL [40], rendering them significant synthetic targets. Furthermore, keto acids and ketoesters serve as excellent synthetic building blocks, possessing at least two reactive sites with distinct chemical properties. Indeed, numerous synthetic methodologies have been developed utilizing these compounds as key molecules for the synthesis of bioactive compounds, including cytosporanone A, massoialactone, preussin, hexadecanolide, tetrahydrolipstatin, ezetimibe, shimobashiric acid A, ubrogepant, and several unnamed substances (Figure 1) [1,15,41,42,43,44,45].
In particular, functionalized haloketoesters are highly versatile in their derivatization. Dihaloacyl groups are applicable to asymmetric reduction [46,47,48], aldol reactions [49,50,51,52], Z-alkenoate formation [53,54,55], [4+3] cycloaddition [53,55], and various heterocycle formations [53,56,57,58,59]. Furthermore, trihaloacyl groups have been employed in asymmetric Mannich-type reactions [60,61,62], asymmetric reduction followed by Jocic-type reactions [63], radical addition reactions [64], and Grignard reactions [65]. Trihaloacyl groups also serve as leaving groups during alcoholysis [66] and aminolysis [67]. Our previous research demonstrated that haloketoesters, which possess both a haloacyl moiety and an ester moiety, provide additional versatility in derivatizations [68,69,70].
However, the selective synthesis of di- and trihaloketoesters via ketoester halogenation presents significant challenges. This difficulty arises because the introduction of halogen atoms at the ketone α-position competes with halogenation at the alternative α’-position. Additionally, overreactions such as trihalogenation (e.g., haloform reactions) complicate the synthesis of dihalogenated compounds, rendering it exceedingly difficult to control both the regioselectivity and the number of halogen atoms introduced.
This study focuses on selective halogenation via ring-opening reactions of cyclic 1,3-diketones, which are readily synthesized using various methodologies [71,72,73,74,75,76,77]. Traditional approaches to reagent-controlled ring-opening reactions employ strong bases, as well as metal-catalyst-controlled retro-Claisen condensations [20], albeit requiring elevated temperatures. These methods facilitate the formation of non-functionalized ring-opening products from cyclic 1,3-diketones (Scheme 1a). Integrating halogenation under harsh conditions is not conducive to the selective synthesis of haloketoesters. In this study, we successfully developed a direct and selective synthesis method for di- and trihaloketoesters from cyclic 1,3-diketones, eliminating the need for transition metals, through convenient halogenative ring-opening esterification under mild conditions (Scheme 1b). Notably, the synthesis of dichloroketo acids was accomplished without using chromatography. Our approach for synthesizing functionalized ketoesters has the potential to advance the molecular transformation of 1,3-cyclohexadiones into diverse heterocyclic compounds.

2. Results and Discussion

2.1. Optimization of Buffer Salt for Halogenative Ring-Opening Reaction

The gem-dihalomethylketone moiety is a potent site for C–C bond cleavage. Initial halogenative C–C bond cleavage reactions of acyclic molecules are primarily of interest for their degradative fragmentation properties [78]. In recent years, however, synthetically valuable C–C bond cleavage reactions have been developed, including gem-difluorination [79,80], dichlorination [81,82,83,84,85], and dibromination [81,83], through the use of halogenating agents and nucleophiles. Analogous reactions have been implicated in the biosynthesis of biologically active compounds [86,87]. However, halogenative C–C bond cleavage reactions involving the ring opening of cyclic molecules have not been extensively explored for synthetic applications. Although such reactions have been conducted using alcohols [88,89,90], water [91], and amines [92,93,94] as nucleophiles, they are generally restricted to ring-strained substrates and often require harsh conditions such as high temperatures and strong bases. The dichloroacetylation of amines, employing cyclic gem-dichlorodiester as the sacrificial agent, utilizes a comparable C–C bond cleavage process [95].
Building upon the product analysis of multiple reactions observed during the monochlorodimedone assay [69], we previously demonstrated the stepwise cleavage of the C–C bond in a cyclic substrate devoid of ring strain [70]. Nevertheless, C–C bond cleavage accompanied by the dichlorination of cyclic diketones under one-pot conditions has not been demonstrated.
This study focuses on the direct synthesis of di- or trichloroketo acid methyl esters from cyclic 1,3-diketones under considerably mild conditions in an alcoholic medium containing N-chlorosuccinimide (NCS) and buffer salts at ambient temperature. Initially, the influence of buffer salts on the conversion of cyclohexadione 1a to dichloroketoester 2a in the presence of MeOH was assessed, and the results are presented in Table 1. The sodium salt exhibited a higher product yield than the potassium salt. Moreover, weakly basic salts such as Na2HPO4, NaHCO3, and AcONa (entries 1, 5, and 9, respectively) were determined to be more effective than NaH2PO4, a weakly acidic salt (entry 3), and Na2CO3, a relatively strong base (entry 7). Consequently, Na2HPO4 was identified as the optimal salt for the halogenative ring cleavage. When a catalytic amount of the base was used, the reaction was stopped after 30 min. Therefore, a minimum of 0.5 equivalents of Na2HPO4 was required for the reaction to proceed completely.

2.2. Substrate Scope

The substrate scope was evaluated under the optimized conditions using Na2HPO4 (Table 2). For the synthesis of 5-substituted dichloroketo acid methyl esters 2b–g from the corresponding 1,3-cyclohexadiones 1b–g, 2.0 equivalents of NCS were used in the presence of 0.5 equivalents of Na2HPO4. This direct synthesis yielded monosubstituted dichloroketoesters 2b–d and gem-disubstituted dichloroketoesters 2e–g with high efficiency (Table 2). The comparable yields of methyl-substituted products 2b,e and phenyl-substituted products 2c,f indicate that the 5-position of the corresponding substrates 1b,c,e,f was not significantly influenced by steric hindrance in this reaction. Furthermore, p-anisyl-substituted product 2d and p-tolyl-substituted product 2g demonstrated the potential to introduce additional substituents at the aryl moiety. However, this method is unsuitable for the synthesis of dibromoketoesters because the buffer salt induces debromination of the synthetic intermediate 2,2-dibromo-1,3-cyclohexadiones [69,96].
By contrast, the utilization of 3.6 equivalents of NCS facilitated the synthesis of trichloroketo acid methyl esters 3a–g. This reaction requires excess NCS beyond the stoichiometric quantities. When only 3.0 equivalents of NCS were employed, small amounts of the corresponding dichloroketoesters 2a–g persisted within the reaction system as synthetic intermediates, complicating the purification of the desired corresponding trichloroketoesters 3a–g. This approach successfully yielded trichloroketoesters without substituent 3, with monosubstituents 3b–d and gem-disubstituents 3e–g in high yields (Table 3). The yields of trichloroketoesters 3a–g were comparable to those of the corresponding dichloroketoesters 2a–g (see Table 2).
Additionally, alcohols that functioned as co-solvents were screened. The ester moiety of the product in this reaction depends on the alcohol used. For the synthesis of dichloroketo acid alkyl ester, 2.0 equivalents of NCS and Na2HPO4 were used in a dehydrated alcohol with 3 Å molecular sieves, as detailed in Table 4. Ring-cleavage reactions with EtOH, nPrOH, and 2-methoxyethanol yielded the corresponding ethyl ester 4, n-propyl ester 5, and 2-methoxyethyl ester 6, respectively, with high efficiency (entries 1–3). Conversely, ring cleavage using nBuOH and iBuOH afforded the corresponding n-butyl ester 7 and i-butyl ester 8, respectively, in low yields (entries 4 and 5). As mentioned above, these esters are produced in the presence of primary alcohols. However, when the secondary alcohol iPrOH or the tertiary alcohol tBuOH was employed, the corresponding esters were not formed; instead, the reactions resulted in the formation of dichloroketo acids. This indicates that the steric hindrance of the alcohol side chain significantly influences the nucleophilic reaction of alcohols with gem-dichlorinated synthetic intermediates.
The dichlorinative ring cleavage of 1,3-cycloheptadione 9 afforded the corresponding product 10 in good yield, whereas 1,3-cyclooctadione 11 produced the corresponding dichloroketoester 12 along with trichloroketoester 13 as a byproduct (Scheme 2a,b). This implies that the chlorination of 1,3-cyclooctadione 11 is the rate-determining step of the dichlorinative ring-cleavage reaction. On the other hand, 1,3-cyclopentanone 14 did not undergo chlorination at ambient temperature; however, the corresponding dichloroketoester 15 was obtained in low yield under reflux conditions (Scheme 2c). The inability to synthesize 15 using Cs2CO3, a stronger base, indicates that Na2HPO4, a weaker base, is more suitable for this reaction.

2.3. Mechanism

Mixed trihaloketoesters can be synthesized through a stepwise approach involving gem-chlorination of cyclic 1,3-diketones, followed by alcoholic ring cleavage of the resulting cyclic dichloro-1,3-diketones. For instance, dichloromonobromoketoester 16 was obtained in 98% yield via gem-chlorination of cyclic diketone 1a, followed by the addition of Na2HPO4 in the presence of NBS (Scheme 3, path a). However, the addition of NBS after the ring-cleavage reaction with Na2HPO4 resulted in a reduced yield of 39% (Scheme 3, path b). This observation indicates that the enolate generated immediately prior to the ring-cleavage reaction served as a highly reactive intermediate for the third subsequent halogenation.
Halogenative ring cleavage of cyclic 1,3-diketones involves two independent processes: gem-dichlorination and alcoholic ring opening (Figure 2). In the gem-dichlorination process, the reaction proceeds quantitatively—even in the absence of Na2HPO4—because the succinimide anion generated from NCS during chlorination acts as a base. The carbonyl group of the cyclic 1,3-diketone, which completely suppresses enol–enol isomerization via gem-dichlorination, regains its electrophilicity, thereby facilitating nucleophilic reactions with alcohols. However, the alcohol ring-opening process requires Na2HPO4. The recarbonylation of the alkoxy anion generated by the nucleophilic reaction of alcohols drives the irreversible cleavage of the C–C bond, while the intramolecular gem-chloroacetyl moiety aids in charge stabilization. Consequently, an environment with excess halogenating agent for gem-dichlorination resulted in the formation of a trihaloketoester from the enol anion, whereas an environment lacking excess halogenating agent yielded a dihaloketoester, as the enol anion was readily protonated by the surrounding protic solvent. Although the reaction mechanism is similar to the classical Lieben haloform reaction, it differs in the number of required halogen atoms and the reaction selectivity for C–C bond cleavage. Our method requires dihalogenation for the cleavage of cyclic 1,3-diketones, whereas the haloform reaction typically requires trihalogenation for substrates containing an acetyl group. Another distinction is that the trihaloacetyl moiety in the trihaloketoesters is retained without further fragmentation in our method. This unique chemoselectivity is synthetically advantageous.

3. Materials and Methods

3.1. General Information

5-(p-Methoxyphenyl)-1,3-cyclohexanedione 1d [97] was prepared from 4-(p-methoxyphenyl)-3-butene-2-one and diethyl malonate according to the literature. 5-Methyl-5-phenyl-1,3-cyclohexanedione 1f [98] and 5-methyl-5-p-tolyl-1,3-cyclohexanedione 1g were prepared from 5-methylresorcinol according to the literature. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on an ECS 400 and ECX 500 NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated chloroform (CDCl3) as the solvent. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (δ = 0) as an internal standard. The coupling constants (J) are reported in Hertz, and the multiplicity is reported according to the following convention: singlet (s), doublet (d), double doublet (dd), triplet (t), quintet (quin), sextet (sext), octet (o), broad singlet (br), and multiplet (m). The chemical shifts (number of protons, multiplicity, and coupling constants) are reported. Infrared (IR) spectra were recorded using a JASCO FT/IR-4200 spectrometer (JASCO, Tokyo, Japan) using the diffuse reflectance method with KBr powder. Absorption is expressed in units of reciprocal centimeters (cm−1). High-resolution mass spectra (HRMS) were obtained using the electron ionization (EI) method and recorded using a JMS-700 spectrometer (JEOL Ltd., Tokyo, Japan).

3.2. Synthesis of Haloketo Acid Alkyl Esters

3.2.1. General Procedure for Synthesizing Dichloroketo Acid Methyl Esters

To a solution of a 1,3-cyclohexadione (1.0 mmol) and NCS (267.1 mg, 2.0 mmol) in MeOH (10 mL), Na2HPO4 (71 mg, 0.5 mmol) was added. After stirring the mixture at room temperature for 0.5 h, the solvent was evaporated. The product was dissolved in CH2Cl2, and the extract was filtered through filter paper for dehydration. After evaporation to remove the solvent, the product was dissolved in hexane by sonication, and the extract was filtered through filter paper. The removal of the solvent by evaporation afforded the purified product.

3.2.2. 6,6-Dichloro-5-oxo-hexanoic Acid Methyl Ester (2a)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.00 (2H, quin, J = 7.2 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.92 (2H, t, J = 7.1 Hz), 3.69 (3H, s), 5.84 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 18.9, 32.6, 33.9, 51.7, 69.7, 173.3, 196.7 ppm. IR (ATR, KBr): ν 3649, 3545, 3456, 2953, 2848, 2596, 2411, 2068, 1733, 1606, 1438, 1372, 1210, 1088, 1053, 892, 867, 782, 727 cm−1. HRMS (EI, m/z) calcd for C7H11Cl2O3 [M + 1]+: 213.0085; found: 213.0079.

3.2.3. 6,6-Dichloro-3-methyl-5-oxo-hexanoic Acid Methyl Ester (2b)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.04 (3H, d, J = 6.9 Hz), 2.30 (1H, dd, J = 15.6, 7.3 Hz), 2.38 (1H, dd, J = 15.6, 6.4 Hz), 2.57 (1H, o, J = 6.9 Hz), 2.79 (1H, dd, J = 17.8, 7.3 Hz), 2.91 (1H, dd, J = 17.9, 6.2 Hz), 3.68 (3H, s), 5.82 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 19.8, 26.2, 40.2, 41.1, 51.6, 70.0, 172.6, 195.9 ppm. IR (ATR, KBr): ν 3656, 3620, 3539, 3456, 2968, 2845, 2741, 2610, 2019, 1736, 1437, 1370, 1171, 1078, 1039, 1009, 957, 858, 784, 733, 663, 551 cm−1. HRMS (EI, m/z) calcd for C8H13Cl2O3 [M + 1]+: 227.0242; found: 227.0240.

3.2.4. 6,6-Dichloro-5-oxo-3-phenyl-hexanoic Acid Methyl Ester (2c)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.68 (1H, dd, J = 15.6, 7.4 Hz), 2.74 (1H, dd, J = 16.0, 7.3 Hz), 3.23 (2H, d, J = 7.3 Hz), 3.61 (3H, s), 3.74 (1H, quin, J = 7.3 Hz), 5.71 (1H, s), 7.20–7.26 (3H, m), 7.28–7.34 (2H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 37.0, 40.1, 41.0, 51.7, 69.9, 127.2, 127.2, 128.7, 142.1, 172.0, 195.0 ppm. IR (ATR, KBr): ν 3063, 3030, 3005, 2952, 2845, 1954, 1878, 1735, 1604, 1496, 1455, 1438, 1368, 1336, 1265, 1221, 1161, 1127, 1081, 1028, 993, 889, 845, 793, 764, 733, 700, 562, 522 cm−1. HRMS (EI, m/z) calcd for C13H14Cl2O3 [M]+: 288.0320; found: 288.0323.

3.2.5. 6,6-Dichloro-3-(4-methoxy-phenyl)-5-oxo-hexanoic Acid Methyl Ester (2d)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.64 (1H, dd, J = 15.1, 7.8 Hz), 2.70 (1H, dd, J = 16.0, 7.3 Hz), 3.18 (2H, d, J = 7.3 Hz), 3.60 (3H, s), 3.78 (3H, s), 5.70 (1H, s), 6.83 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 36.3, 40.3, 41.2, 51.7, 55.2, 69.9, 114.0, 128.3, 134.0, 158.5, 172.0, 195.0 ppm. IR (ATR, KBr): ν 3659, 3562, 3459, 3002, 2954, 2838, 2602, 2549, 2493, 2426, 2059, 1883, 1736, 1612, 1583, 1514, 1439, 1366, 1250, 1084, 1031, 830, 794, 743, 556, 539 cm−1. HRMS (EI, m/z) calcd for C14H16Cl2O4 [M]+: 318.0426; found: 318.0426.

3.2.6. 6,6-Dichloro-3,3-dimethyl-5-oxo-hexanoic Acid Methyl Ester (2e)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.14 (6H, s), 2.50 (2H, s), 2.97 (2H, s), 3.65 (3H, s), 5.83 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 28.1, 32.6, 44.0, 44.3, 51.3, 70.5, 172.4, 195.7 ppm. 1H and 13C NMR data are consistent with those reported in the literature [67].

3.2.7. 6,6-Dichloro-3-methyl-5-oxo-3-phenyl-hexanoic Acid Methyl Ester (2f)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.88 (1H, d, J = 15.1 Hz), 2.98 (1H, d, J = 15.1 Hz), 3.43 (1H, d, J = 17.8 Hz), 3.50 (1H, d, J = 17.8 Hz), 3.58 (3H, s), 5.61 (1H, s), 7.20–7.25 (1H, m), 7.30–7.35 (4H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 26.1, 39.0, 44.5, 44.9, 51.5, 70.4, 125.2, 126.7, 128.5, 145.4, 171.9, 194.7 ppm. IR (ATR, KBr): ν 3673, 3561, 3455, 3091, 3060, 2952, 2844, 2602, 1952, 1874, 1730, 1602, 1582, 1497, 1444, 1382, 1351, 1209, 1078, 1011, 956, 850, 766, 738, 697, 633, 560, 540, 525 cm−1. HRMS (EI, m/z) calcd for C14H16Cl2O3 [M]+: 302.0476; found: 302.0470.

3.2.8. 6,6-Dichloro-3-methyl-5-oxo-3-p-tolyl-hexanoic Acid Methyl Ester (2g)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.88 (3H, s), 2.31 (3H, s), 2.86 (1H, d, J = 15.1 Hz), 2.95 (1H, d, J = 15.1 Hz), 3.40 (1H, d, J = 17.9 Hz), 3.46 (1H, d, J = 17.8 Hz), 3.58 (3H, s), 5.60 (1H, s), 7.13 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.7 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 20.9, 26.2, 38.7, 44.5, 45.1, 51.4, 70.4, 125.1, 129.2, 136.2, 142.4, 171.9, 194.8 ppm. HRMS (EI, m/z) calcd for C15H18Cl2O3 [M]+: 316.0633; found: 316.0628.

3.2.9. General Procedure for Synthesis of Trichloroketo Acid Methyl Esters

To a solution of 1,3-cyclohexadiones (1.0 mmol) and NCS (480.7 mg, 3.6 mmol) in MeOH (10 mL), Na2HPO4 (71.0 mg, 0.5 mmol) was added. After the mixture was stirred at room temperature for 0.5 h, the solvent was removed by evaporation. The product was dissolved in CH2Cl2, and then the extract was filtered through filter paper for dehydration. After evaporation for the removal of the solvent, the product was dissolved in hexane by sonication, and then the extract was filtered through filter paper. The concentrated filtrate by evaporation was purified by silica gel chromatography with AcOEt/hexane solution.

3.2.10. 6,6,6-Trichloro-5-oxo-hexanoic Acid Methyl Ester (3a)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.08 (2H, quin, J = 7.2 Hz), 2.44 (2H, t, J = 7.1 Hz), 3.11 (1H, t, J = 7.2 Hz), 3.69 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 19.9, 32.4, 32.9, 51.7, 96.2, 173.0, 190.1 ppm. IR (ATR, KBr): ν 3482, 2957, 2880, 2846, 2364, 2357, 2330, 1737, 1438, 1370, 1266, 1171, 1104, 1062, 1010, 958, 877, 821, 752, 699, 650, 634, 591, 561 cm−1. HRMS (FAB, m/z) calcd for C7H10Cl3O3 [M + H]+: 246.9696; found: 246.9697.

3.2.11. 6,6,6-Trichloro-3-methyl-5-oxo-hexanoic Acid Methyl Ester (3b)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.07 (3H, d, J = 6.9 Hz), 2.34 (1H, dd, J = 15.5, 7.5 Hz), 2.43 (1H, dd, J = 15.5, 6.9 Hz), 2.64 (1H, o, J = 6.8 Hz), 2.98 (1H, dd, J = 17.8, 7.5 Hz), 3.11 (1H, dd, J = 17.6, 5.9 Hz), 3.69 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 19.5, 27.0, 39.9, 40.1, 51.6, 96.4, 172.4, 189.3 ppm. IR (ATR, KBr): 3820, 3661, 3481, 2953, 2880, 2845, 2741, 2616, 2017, 1738, 1437, 1370, 1267, 1173, 1102, 1063, 1009, 957, 876, 819, 754, 704, 592, 553 cm−1. HRMS (FAB, m/z) calcd for C8H12Cl3O3 [M + H]+: 260.9852; found: 260.9854.

3.2.12. 6,6,6-Trichloro-5-oxo-3-phenyl-hexanoic Acid Methyl Ester (3c)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.71 (1H, dd, J = 16.0, 7.3 Hz), 2.80 (1H, dd, J = 16.0, 7.3 Hz), 3.41 (2H, d, J = 7.3 Hz), 3.61 (3H, s), 3.80 (1H, quin, J = 7.4 Hz), 7.20–7.33 (5H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 37.0, 40.1, 40.2, 51.7, 55.2, 96.2, 114.0, 128.4, 133.6, 158.6, 171.9, 188.4 ppm. IR (ATR, KBr): 3474, 3447, 3085, 3063, 3031, 3008, 2956, 2933, 2905, 2848, 1968, 1953, 1889, 1731, 1693, 1603, 1583, 1496, 1455, 1438, 1425, 1378, 1362, 1258, 1218, 1166, 1102, 1077, 989, 918, 903, 876, 824, 764, 700, 610, 557, 542 cm−1. HRMS (EI, m/z) calcd for C14H13Cl3O3 [M]+: 321.9930; found: 321.9928.

3.2.13. 6,6,6-Trichloro-3-(4-methoxy-phenyl)-5-oxo-hexanoic Acid Methyl Ester (3d)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.68 (1H, dd, J = 15.9, 7.9 Hz), 2.75 (1H, dd, J = 16.0, 7.3 Hz), 3.36 (2H, d, J = 6.9 Hz), 3.61 (3H, s), 3.70–3.83 (1H, m), 6.83 (2H, d, J = 8.7), 7.17 (2H, d, J = 8.7) ppm. 13C NMR (100 MHz, CDCl3): δ 37.0, 40.1, 40.2, 51.7, 55.2, 96.2, 114.0, 128.4, 133.6, 158.6, 171.9, 188.4 ppm. IR (ATR, KBr): 3003, 2953, 2838, 1738, 1612, 1583, 1514, 1438, 1366, 1301, 1250, 1179, 1114, 1089, 1035, 874, 833, 747, 708, 549 cm−1. HRMS (EI, m/z) calcd for C15H15Cl3O4 [M]+: 352.0036; found: 352.0037.

3.2.14. 6,6,6-Trichloro-3,3-dimethyl-oxo-hexanoic Acid Methyl Ester (3e)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.17 (6H, s), 2.58 (2H, s), 3.23 (2H, s), 3.66 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 27.7, 32.8, 42.7, 44.1, 51.3, 96.7, 172.3, 189.2 ppm. IR (ATR, KBr): 3672, 3477, 3241, 2953, 2844, 2629, 2021, 1739, 1437, 1392, 1352, 1227, 1076, 1011, 881, 833, 748, 697, 652, 626, 560 cm−1. HRMS (EI, m/z) calcd for C9H14Cl3O3 [M + H]+: 275.0008; found: 275.0016.

3.2.15. 6,6,6-Trichloro-3-methyl-5-oxo-3-phenyl-hexanoic Acid Methyl Ester (3f)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.63 (3H, s), 2.91 (1H, d, J = 15.6 Hz), 3.05 (1H, d, J = 15.1 Hz), 3.58 (3H, s), 3.71 (1H, d, J = 18.8 Hz), 3.77 (1H, d, J = 18.8 Hz), 7.20–7.25 (1H, m), 7.30–7.38 (4H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 25.7, 39.1, 42.9, 44.7, 51.5, 96.5, 125.3, 126.6, 128.5, 145.2, 171.8, 188.2 ppm. IR (ATR, KBr): ν 3670, 3489, 3091, 3060, 3026, 2952, 2843, 2602, 2017, 1949, 1873, 1731, 1602, 1583, 1498, 1436, 1383, 1347, 1277, 1206, 1082, 1013, 958, 874, 821, 758, 698, 632, 551, 535 cm−1.

3.2.16. 6,6,6-Trichloro-3-methyl-5-oxo-3-p-tolyl-hexanoic Acid Methyl Ester (3g)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.60 (3H, s), 2.31 (3H, s), 2.94 (1H, d, J = 15.1 Hz), 3.03 (1H, d, J = 15.1 Hz), 3.59 (3H, s), 3.64 (1H, d, J = 18.8 Hz), 3.74 (1H, d, J = 18.8 Hz), 7.13 (2H, d, J = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 20.9, 25.8, 38.8, 42.9, 44.7, 51.5, 96.6, 125.2, 129.2, 136.2, 142.3, 171.9, 188.2 ppm. IR (ATR, KBr): ν 3508, 2952, 1901, 1735, 1517, 1436, 1417, 1381, 1347, 1277, 1204, 1097, 1077, 1013, 959, 877, 858, 816, 751, 708, 681, 661, 630, 602, 593, 551 cm−1. HRMS (EI, m/z) calcd for C15H17Cl3O3 [M]+: 320.0243; found: 320.0244.

3.2.17. General Procedure for Synthesis of Dichloroketo Acid Alkyl Esters

To a solution of a 1,3-cyclohexadione (1.0 mmol) and NCS (267.1 mg, 2.0 mmol) in alcohol (10 mL), Na2HPO4 (71.0 mg, 0.5 mmol) was added. After stirring the mixture at room temperature for 0.5 h, the solvent was evaporated. The product was dissolved in CH2Cl2, and the extract was filtered through filter paper for dehydration. After evaporating the solvent, the product was dissolved in hexane via sonication, and the extract was filtered through filter paper. The filtrate was concentrated by evaporation and purified by silica gel chromatography using an ethyl acetate (AcOEt)/hexane solution.

3.2.18. 6,6-Dichloro-5-oxo-hexanoic Acid Ethyl Ester (4)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J = 7.3 Hz), 2.00 (2H, quin, J = 7.3 Hz), 2.38 (2H, t, J = 7.3 Hz), 2.92 (2H, t, J = 7.3 Hz), 4.14 (2H, q, J = 7.3 Hz), 5.83 (1H, s) ppm 13C NMR (100 MHz, CDCl3): δ 4.2, 18.9, 32.9, 33.8, 60.5, 69.8, 172.8, 196.7 ppm. IR (ATR, KBr): ν 3643, 3451, 2983, 1731, 1448, 1376, 1190, 1094, 1029, 858, 789, 735 cm−1. HRMS (EI, m/z) calcd for C8H13Cl2O3 [M + H]+: 227.0242; found: 227.0244.

3.2.19. 6,6-Dichloro-5-oxo-hexanoic Acid Propyl Ester (5)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J = 7.5 Hz), 1.65 (3H, sext, J = 7.3 Hz), 2.00 (2H, quin, J = 7.3 Hz), 2.39 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.1 Hz), 4.05 (2H, t, J = 6.9 Hz), 5.83 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 10.4, 18.9, 21.9, 32.8, 33.8, 66.2, 69.8, 172.9, 196.7 ppm. IR (ATR, KBr): ν 3446, 2969, 2880, 1732, 1459, 1395, 1379, 1314, 1185, 1089, 1061, 1002, 912, 849, 788, 736 cm−1. HRMS (EI, m/z) calcd for C9H14Cl2O3 [M + H]+: 241.0398; found: 241.0400.

3.2.20. 6,6-Dichloro-5-oxo-hexanoic Acid 2-Methoxy-Ethyl Ester (6)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.01 (2H, q, J = 7.3 Hz), 2.44 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.1 Hz), 3.39 (3H, s), 3.58–3.61 (2H, m), 4.24–4.26 (2H, m), 5.84 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 18.9, 32.7, 33.8, 59.0, 63.6, 69.8, 70.4, 172.8, 196.7 ppm. 1 IR (ATR, KBr): ν 3632, 3449, 2936, 1732, 1452, 1407, 1380, 1127, 1033, 861, 784, 734, 534 cm−1. HRMS (EI, m/z) calcd for C9H14Cl2O4 [M + H]+: 257.0347; found: 257.0344.

3.2.21. 6,6-Dichloro-5-oxo-hexanoic Acid Butyl Ester (7)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J = 7.5 Hz), 1.38 (2H, sext, J = 7.6 Hz), 1.61 (2H, quin, J = 7.2 Hz), 2.00 (2H, quin, J = 7.3 Hz), 2.39 (2H, t, J = 7.3 Hz), 2.92 (2H, t, J = 7.1 Hz), 4.09 (2H, t, J = 6.9 Hz), 5.83 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 13.7, 18.9, 19.1, 30.6, 32.9, 33.9, 64.5, 69.8, 172.9, 196.7 ppm. IR (ATR, KBr): ν 3620, 3449, 2961, 2874, 1732, 1457, 1394, 1314, 1188, 1063, 1024, 966, 845, 788, 731, 518 cm−1. HRMS (EI, m/z) calcd for C10H16Cl2O3 [M + H]+: 255.0555; found: 255.0552.

3.2.22. 6,6-Dichloro-5-oxo-hexanoic Acid Isobutyl Ester (8)

Colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (6H, d, J = 6.8 Hz), 1.88–1.98 (1H, m), 2.00 (2H, quin, J = 7.3 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.1 Hz), 3.87 (2H, d, J = 6.9 Hz), 5.83 (1H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 18.9, 19.1, 27.7, 32.8, 33.9, 69.8, 70.7, 172.9, 196.7 ppm. IR (ATR, KBr): ν 3650, 3450, 2961, 2875, 1732, 1470, 1382, 1189, 1088, 1014, 946, 782, 728, 521 cm−1. HRMS (EI, m/z) calcd for C10H16Cl2O3 [M + H]+: 255.0555; found: 255.0552.

3.2.23. 7,7-Dichloro-5-oxo-heptanoic Acid Methyl Ester (10)

Colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.67–1.72 (4H, m), 2.36 (2H, t, J = 6.9 Hz), 2.86 (2H, t, J = 6.9 Hz), 3.68 (3H, s), 5.84 (1H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 23.1, 24.1, 33.6, 34.5, 51.6, 69.8, 173.6, 196.9 ppm. HRMS (EI, m/z) calcd for C8H13Cl2O3 [M + H]+: 227.0242; found: 227.0243.

3.2.24. 8,8-Dichloro-5-oxo-octanoic Acid Methyl Ester (12)

Colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.35–1.41 (2H, m), 1.63–1.72 (4H, m), 2.33 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.2 Hz), 3.67 (3H, s), 5.82 (1H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 23.4, 24.5, 28.3, 33.8, 34.6, 51.5, 69.9, 174.0, 197.1 ppm. HRMS (EI, m/z) calcd for C9H15Cl2O3 [M + H]+: 241.0398; found: 241.0404.

3.2.25. 8,8,8-Trichloro-5-oxo-octanoic Acid Methyl Ester (13)

Colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.41 (2H, quin, J = 7.7 Hz), 1.68 (2H, quin, J = 7.6 Hz), 1.77 (2H, quin, J = 7.4 Hz), 2.34 (2H, t, J = 7.5 Hz), 3.00 (2H, t, J = 7.5 Hz), 3.68 (3H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 24.4, 24.5, 28.3, 33.66, 33.75, 51.6, 96.4, 173.9, 190.5 ppm.

3.2.26. 5,5-Dichloro-5-oxo-pentanoic Acid Methyl Ester (15)

Colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.70 (2H, t, J = 6.6 Hz), 3.16 (2H, t, J = 6.6 Hz), 3.70 (3H, s), 5.93 (1H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 27.9, 30.2, 52.0, 69.7, 172.4, 195.9 ppm. HRMS (EI, m/z) calcd for C6H9Cl2O3 [M + H]+: 198.9929; found: 198.9929.

3.2.27. 6-Bromo-6,6-dichloro-5-oxo-hexanoic Acid Methyl Ester (16)

Colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.06 (2H, quin, J = 7.2 Hz), 2.42 (2H, t, J = 7.5 Hz), 3.14 (2H, t, J = 7.2 Hz), 3.67 (3H, s) ppm. 13C NMR (125 MHz, CDCl3): δ 20.1, 32.4, 32.8, 51.7, 80.8, 173.1, 190.4 ppm. HRMS (EI, m/z) calcd for C7H10BrCl2O3 [M + H]+: 290.9190; found: 290.9194.

4. Conclusions

In this study, we identified a unique reaction system that facilitates the direct synthesis of di- and trichloroketoesters from cyclic 1,3-diketones at ambient temperatures. The use of Na2HPO4, which plays a key role in the alcoholytic ring-opening reactions of the 2,2-dichloro-1,3-diketones generated as intermediates, was demonstrated to yield haloketo acid methyl esters with high efficiency. The selective synthesis of dichloro and trichloro products can be modulated by the stoichiometry of the NCS. Although the mechanism by which Na2HPO4 influences C–C bond cleavage remains unclear, this method has significant potential for further derivatization. The integration of this method with various heterocycle formation techniques utilizing haloketo acids and their esters is anticipated to aid in the synthesis of diverse new compounds functionalized with or without halogen atoms.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/1420-3049/31/1/199/s1, 1H and 13C NMR spectra of compounds 2a−g, 3a−g, 4−8, 10, 12, 13, 15, and 16.

Author Contributions

H.C. found the direct synthesis of di- or trichloroketo acid methyl esters from cyclic 1,3-diketones and drafted the manuscript; N.K., H.Y., M.F., Y.M., and Z.J. also contributed to the experiments; T.D. directed this study as a project and finalized the manuscript with critical discussion. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by JST CREST (grant number JPMJCR20R1) and the Ritsumeikan Global Innovation Research Organization (R-GIRO) project. H.C. also acknowledges support from a Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI grant number 24K09738) from JSPS.

Data Availability Statement

The data supporting this work is in the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 31 00199 g001
Figure 1. Bioactive compounds synthesized using δ-keto acids and ketoesters as intermediates.
Figure 1. Bioactive compounds synthesized using δ-keto acids and ketoesters as intermediates.
Molecules 31 00199 g001
Molecules 31 00199 sch001
Scheme 1. Ring-cleavage reactions of cyclic 1,3-diketones: (a) Retro-Claisen condensations; (b) This work: Halogenative ring-opening strategy.
Scheme 1. Ring-cleavage reactions of cyclic 1,3-diketones: (a) Retro-Claisen condensations; (b) This work: Halogenative ring-opening strategy.
Molecules 31 00199 sch001
Molecules 31 00199 sch002
Scheme 2. Ring-size scope for halogenative ring cleavage, of (a) 1,3-cycloheptadione, (b) 1,3-cyclooctadione, and (c) 1,3-cyclopentadione.
Scheme 2. Ring-size scope for halogenative ring cleavage, of (a) 1,3-cycloheptadione, (b) 1,3-cyclooctadione, and (c) 1,3-cyclopentadione.
Molecules 31 00199 sch002
Molecules 31 00199 sch003
Scheme 3. Control experiment for trihalogenative ring-cleavage reactions.
Scheme 3. Control experiment for trihalogenative ring-cleavage reactions.
Molecules 31 00199 sch003
Molecules 31 00199 g002
Figure 2. Mechanism of halogenative ring-cleavage reaction producing trihaloketoester.
Figure 2. Mechanism of halogenative ring-cleavage reaction producing trihaloketoester.
Molecules 31 00199 g002
Table 1. Effect of buffer salt on the halogenative ring-cleavage reaction.
Table 1. Effect of buffer salt on the halogenative ring-cleavage reaction.
Molecules 31 00199 i001
EntryBuffer SaltYield (%)
1Na2HPO4100
2K2HPO480
3NaH2PO460 (10) 1
4KH2PO414 (21) 1
5NaHCO391
6KHCO382
7Na2CO371
8K2CO357
9AcONa95
10AcOK92
1 The numerals in parentheses are the yield of 2,2-dichloro-1,3-cyclohexadione.
Table 2. Substrate scope of the halogenative ring-cleavage reaction producing dichloroketoesters.
Table 2. Substrate scope of the halogenative ring-cleavage reaction producing dichloroketoesters.
Molecules 31 00199 i002
EntryProductYield (%)
12b (1R = H, 2R = Me)98
22c (1R = H, 2R = Ph)99
32d (1R = H, 2R = p-MeOC6H4)87
42e (1R, 2R = Me)97
52f (1R = Ph, 2R = Me)93
62g (1R = p-Me C6H4, 2R = Me)95
Table 3. Halogenative ring-cleavage reaction producing trichloroketoesters 3a–g.
Table 3. Halogenative ring-cleavage reaction producing trichloroketoesters 3a–g.
Molecules 31 00199 i003
EntryProductYield (%)
13a (1R, 2R = H)91
23b (1R = H, 2R = Me)99
33c (1R = H, 2R = Ph)90
43d (1R = H, 2R = p-MeOC6H4)85
53e (1R, 2R = Me)98
63f (1R = Ph, 2R = Me)100
73g (1R = p-Me C6H4, 2R = Me)98
Table 4. Synthesis of dichloroketo acid alkyl esters.
Table 4. Synthesis of dichloroketo acid alkyl esters.
Molecules 31 00199 i004
Entry (Alcohol)ProductYield (%)
1 (EtOH)4 (R = Et)86
2 (nPrOH)5 (R = nPr)77
3 (2-methoxyethanol)6 (R = CH2CH2OCH3)78
4 (nBuOH)7 (R = nBu)40
5 (tBuOH)8 (R = tBu)27
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China, H.; Kageyama, N.; Yatabe, H.; Fujitake, M.; Matsumoto, Y.; Jing, Z.; Dohi, T. Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones. Molecules 2026, 31, 199. https://doi.org/10.3390/molecules31010199

AMA Style

China H, Kageyama N, Yatabe H, Fujitake M, Matsumoto Y, Jing Z, Dohi T. Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones. Molecules. 2026; 31(1):199. https://doi.org/10.3390/molecules31010199

Chicago/Turabian Style

China, Hideyasu, Nami Kageyama, Hodaka Yatabe, Mihoyo Fujitake, Yusei Matsumoto, Zhihan Jing, and Toshifumi Dohi. 2026. "Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones" Molecules 31, no. 1: 199. https://doi.org/10.3390/molecules31010199

APA Style

China, H., Kageyama, N., Yatabe, H., Fujitake, M., Matsumoto, Y., Jing, Z., & Dohi, T. (2026). Chemoselectively Functionalized Ketoesters by Halogenative C–C Bond Cleavage of Cyclic Diketones. Molecules, 31(1), 199. https://doi.org/10.3390/molecules31010199

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