J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996) 147

ORIGINAL

Electrochemical Haloform Reaction Efficient Transformation of Methyl Ketones to Carboxylates

Yoshiharu MATSUBARA * 1, Kazuo FUJIMOTO * 1, Hirofumi MAEKAWA * 2

and Ikuzo NISHIGUCHI * 2

* 1 Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University

(3-4-1 Kowakae, Higashi-Osaka-shi, Osaka-fu, •§ 577) * 2 Osaka Municipal Technical Research Institute

(6-50, 1-Chome, Morinomiya, Jyoto-ku, Osaka-shi, •§ 536)

Abstract : Electrolysis of aliphatic, aromatic, and ƒ¿,ƒÀ-unsaturated methyl ketones in an anhydrous alcohol containing sodium or lithium bromide using an undivided cell equipped with carbon rods as the anode and the cathode brought about electrochemical Haloform reaction to give the corresponding car- boxylates in good to excellent yields. The reaction was found to be mediated with bromonium ion, gen- erated by anodic oxidation of bromide ion. Absence of bromoform in the product mixtures of this reac- tion may be attributed to ready reduction of bromoform to highly volatile compounds, which may pro- vide high simplicity of reaction procedure.

Facile and efficient introduction of carboalkoxyl groups to aromatic rings and olefinic bonds was ac- complished in two steps through initial Friedel-Crafts acetylation followed by the present electrochemi- cal method.

Key words : mediator, methyl ketones, electrolysis, bromonium ion, carboxylates

1 Introduction Haloform reaction has been well known as a method for transformation of methyl ketones to the corresponding carboxylic acids using an aqueous hypohalite solution1) . Synthetic utili- ty of this reaction, however, has been considerably limited owing to use of large amounts of a hazardous halogen and a strong base, troublesome procedure such as separation and pu- rification of the desired carboxylic acid from the resulting haloform, and unsatisfactory yield. In this study, we wish to present a facile and novel method for transformation of a variety of methyl ketones (1) to the corresponding carboxylic esters (2) through electrolysis of 1 in an anhydrous alcohol containing an appropriate alkali halide as a supporting electrolyte.

Corresponding author : Ikuzo NISHIGUCHI

21 148 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996)

2 Experimental 2. 1 General. 1-H-NMR spectra were recorded on a JEOL EX-90 (90 MHz) and a JEOL EX-270 (270.05 MHz) spectrometers in chloroform-d3 with tetramethylsilane as an internal reference. Infrared spectra were measured by a JASCO A-3 or a Shimadzu IR-435 . Mass spectra were obtained using a JEOL JMS-DX 303 HF spectrometer connected with a HP 5890 gas chromatograph with a 30 m TC-1 capillary column and a JMS-DA 5000 data pro- cessing system. Electron impact (EI) of the mass spectra was applied at 70 eV . Gas chro- matograph (GC) was performed on a Shimadzu GC-4 BM equipped with a 2 m x 3 mm col- umn packed with Silicon OV-17 or Polyethylene Glycol (PEG) 20 M on Chromosorb . 2. 2 Materials. Methanol and ethanol were dried using metal sodium and freshly dis- tilled before use. Commercially available starting compounds , such as 2-octanone (la), 2-nonanone (1c), methyl isobutyl ketone (1d) , pinacolone ( le), benzylacetone (1g), 1- chlorobutan-4-one (1h), 1-methoxy-1-methylbutan-3-one (1i) , 1-acetoxybutan-3-one (1j) p- substituted acetophenones (p-substituent : H (1k), CH3 (11), OCH3 (1m), Cl (1n), 1- and 2- acetylnaphthalenes (10 and 1p), mesityl oxide (1q), (E)-hept-3-en-2-one (1r) , (E)-non-3- en-2-one (1s), (E)-5-methylhex-3-en-2-one (1t), (E)-3-methylpent-3-en-2-one (1u) , dime- done (3a) and 1,3-cyclohexanedione (3b) were purchased from Tokyo Chemical Industry Co . Ltd. or Aldrich Chemical Inc.. 1-Acetylcyclohexene (5)2) , 1-acetylcyclopentene (7)3), 2- acetyl-p-cymene (9)4), 5-acetylindan (11)5) and 4,4' -diacetylbiphenyl (13)6) were prepared according to the reported procedures. 2. 3 Typical Procedure for Anodic Haloform Reaction of Methyl Ketones (1a-u) , (3a, b), (5), (7), (9), (11) and (13). Into a solution (80 mL) of anhydrous methanol (or ethanol) containing sodium bromide (0.06 mol) was dissolved an appropriate methyl ketone (0.02 mol), and the solution was in- troduced to a beaker-type of undivided electrolysis cell (100 mL) equipped with carbon rods as the anode and the cathode. Electrolysis was carried out at room temperature (20- 30C ) with magnetical stirring under constant current conditions (current density : 25 - 30 mA/ cm2). After 8-40 F/mol of electricity was passed through the system, the reaction mixture was poured into aqueous saturated sodium chloride solution (200 mL), then was extracted with three 150 mL portions of ethyl ether. After the combined ethereal solution was washed with aqueous saturated sodium chloride solution (200 mL) and was dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent, the residue was isolated by distillation under reduced pressure or by column chro- matography to give the corresponding carboxylic ester in a good yield. All the products were identified by comparison of their gas-chromatographic and spectroscopic behaviours with those of the authentic samples, obtained as follows. Among them, commercially available carboxylic esters , such as methyl and ethyl enan- thates (2a and 2b), methyl octanoate (2c), ethyl isovalerate (2d) methyl and ethyl pivalate (2e and 2f), ethyl 3-phenylpropionate (2g), methyl 3-chloropropionate (2h), ethyl benzoate (2k), methyl p-toluate (21), ethyl p-anisate (2m), methyl p-chlorobenzoate (2n), methyl tiglate (2u), dimethyl glutarate (4b) were also purchased from Tokyo Industry Co . Ltd. or Aldrich Chemical Inc.. The authentic samples of the following products were prepared according to the reported procedures. Methyl 3-methoxyisovalerate (2i) (bp ; 64-70C/20 mm, Lit.7) 57,64C/15 mm) . Ethyl 3-acetoxybutyrate (2j) (bp ; 118-420C/20 mm, Lit.8) 284C/755 mm) . Methyl 1-naphthoate (2o) (bp ; 110-103C/2 mm, Lit.9) 165-166C/17 mm) . Methyl 2-naphthoate (2p) (mp ; 75--.76C, Lit.9) 76 C). Ethyl senecioate (2q) (bp 61,-63C/30 mm, Lit.10) 153- 154 C).

22 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996) 149

Methyl hexenoate (2r) (bp ; 65--67C/20 mm, Lit.11) 56-58C/13 mm). Ethyl (E)-2-octenoate (2s) (bp ; 78-80C/20 mm, Lit.12) 70-72C/15 mm). Ethyl (E)-4-methyl-2-pentenoate (2t) (bp ; 58-60C/20 mm, Lit.13) 60-62C/22 mm). Dimethyl 3,3-glutarate (4a) (bp ; 103-104C/15 mm, Lit.14) 111C/20 mm). Methyl 1-cyclohexenecarboxylate (6) (bp ; 73-75C/20 mm, Lit.15) 78C/25 mm). Ethyl 1-cyclopentenecarboxylate (8) (bp ; 81-83C/20 mm, Lit.16) 73-74C/13 mm). Methyl 2-methyl-4-isopropyl benzoate (10) (bp ; 107-108C/5 mm, Lit.17) 132C/16.2 mm). Methyl 5-indancarboxylate (12) (bp ; 114-116C/5 mm, Lit.18) 106C/4 mm). Dimethyl 4,4' -biphenyldicarboxylate (14) (mp ; 214-215C, Lit.6) 215- 217 C).

3 Results and Discussion Anodic oxidation of methyl ketones (1) was generally carried out in an anhydrous alcohol containing an alkali halide as a supporting electrolyte using an undivided beaker-type elec- trolysis cell equipped with carbon rods as the anode and the cathode at room temperature to give exclusively the corresponding carboxylates (2). It should be cited that contamination of a small amount of water in a solvent resulted in some decrease in the yield of 2 because of formation of the corresponding carboxylic acids. The kind and the amount of alkali halides were found to give a large influence on the con- version of the reaction and the isolated yield of the products 2 as shown in Table 1, where 2-octanone (la) was used as a starting substrate. The results showed that employment of 3 equivalent moles of sodium bromide based on la brought about facile and efficient forma- tion of methyl enanthate (2a) in an optimum yield of 87%. Under the optimum conditions for the reaction of la, a variety of aliphatic methyl ketones (la-j) were subjected to the electrochemical Haloform reaction to form the corresponding carboxylic esters (2a-j) in good to excellent yields as shown in Table 2. The reaction in ethanol required use of lithium bromide instead of sodium bromide because of better solu- bility of the former salt to ethanol. It may be noteworthy that incorporation of some electro- chemically oxidizable functional groups such as a phenyl, a methoxy, an acetoxy group or a chloro atom within the structure of the starting methyl ketones (1g-j) didn't interfere the present anodic reaction to give smoothly the expected products (2g-j) in good yields. In a similar manner, aromatic and a,B-unsaturated methyl ketones (1k-u) were efficiently transformed to the corresponding acrylates (2k-u) through the present anodic oxidation, as shown in Table 3. As the starting conjugated enones are easily prepared through usual Al- dol condensation19), the present method may provide us a useful tool for synthesis of a,B-un-

Table 1 Anodic Oxidation of 2-Octanone using M-X as a Supporting Electrolyte in Me0H.

23 150 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996)

Table 2 Electrochemical Haloform Reaction of Aliphatic Methyl Ketonesa.

Table 3 Electrochemical Haloform Reaction of Aromatic and a,B-Unsaturated Methyl Ketonesa.

saturated esters starting from the corresponding aldehydes and methyl ketones. Anodic oxidation of cyclic 1,3-diketones under the similar conditions led to double cleav- age of both of the carbon-carbon bonds involving the active methylene group to yield ring- opened 1,3-dicarboxylic esters selectively. Thus, dimethyl glutarates (4a, b) were obtained in satisfactory yields from the electrolysis of 1,3-cyclohexanediones (3a, b) in methanol. This anodic Haloform reaction may be applied to development of facile and regioselective introduction of carboalkoxy groups into aromatic rings or carbon-carbon double bonds, which may be rather difficult to accomplish by hitherto known methods20). Thus, Friedel- Crafts acylation of aromatic and olefinic compound followed by anodic oxidation of the re- sulting acetylated products under the similar conditions gave readily the corresponding ben-

24 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996) 151

overall yield 65 %

overall yield 58 %

overall yield 43 %

overall yield 64 %

overall yield 48 %

25 152 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996)

zoates and acrylates, respectively, in satisfactory overall yield. It may be noteworthy from synthetic and mechanistic viewpoints that only a trace amount of bromoform was detected in the product mixture of the present anodic oxidation while con- ventional Haloform reaction requires troublesome procedures to separate and isolate the de- sired carboxylic acids because of formation of a large amount of haloform as the by-prod- ucts. Furthermore, the addition of uniequivalent mole of bromoform or dibromomethane to the starting mixture also resulted in detection of only a trace amount of bromoform or di- bromomethane. These facts indicate rapid consumption of bromoform , dibromomethane, and methyl bromide generated in situ under the reaction conditions .

From these experimental results, the following reaction scheme is proposed as the most plausible pathway of the present electrochemical Haloform reaction. First, the two succes- sive electron transfer from bromide ion to the anode generates a cationic species such as bromonium ion21),22) while sodium methoxide is formed by the reaction of methanol and sodium metal, given through the two-electron transfer from the cathode to a sodium ion . As the second step, a terminal methyl group of methyl ketones is brominated successively by the bromonium ion to give tribromomethyl ketones, which is subjected to nucleophilic substitution by the methoxide anion to yield methyl esters and bromoform . Bromoform is electrochemically reduced at the cathode to highly volatile methyl bromide or methane final- ly through methylene bromide23),24)

In conclusion, from the viewpoint of simple procedure, good yield, and wide generality , the present anodic oxidation may possess high potentiality in organic synthesis.

26 J. Jpn. Oil Chem. Soc. Vol. 45, No. 2 (1996) 153

Acknowledgements This work was supported by the Grant-in-Aid for Scientific Research on Priority of Elec- troorganic Chemistry No. 05235107 from the Ministry of Education, Science and Culture, Japan. (Recieved Oct. 3, 1995 Accepted Nov. 6, 1995)

References 1) a) F. C. Fuson, B. A. Bull, Chem. Rev., 15, 275 (1934). b) H. 0. House, "Modern Synthetic Reac- tions" , 2nd ed., W. A. Benjamine Inc., Menlo Park (Cali., USA), (1972) p. 464. 2) L. Ruzicka, D. R. Koolhaas, A. H. Wind, Helv. Chim. Acta, 14, 1157 (1931). 3) N. Jones, H. T. Taylor, J. Chem. Soc., 1959, 4017. 4) C. F. H. Allen, "Organic Syntheses" , Coll. Vol. 2, 3 (1943) 5) F. C. Uhle, J. E. Krueger, A. E. Rogers, J. Am. Chem. Soc., 78, 1932 (1956). 6) G. J. Sloan, W. R. Vaughan, J. Org. Chem., 24, 750 (1959). 7) D. S. Tarbell, P. Nobe, Jr., J. Am. Chem. Soc., 72, 2657 (1950). 8) M. L. Fein, C. H, Fisher, J. Org. Chem., 13, 750 (1948). 9) P. Fitzgerald, J. Packer, J. Vaughan, A. F. Wilson, J. Chem. Soc., 1956, 170. 10) R. E. Miller, F. F. Nord, J. Org. Chem., 16, 728 (1951). 11) B. R. Baker, M. V. Querry, S. R. Safir, S. Bernstein, J. Org. Chem., 12, 144 (1947). 12) M. Jacobson, J. Am. Chem. Soc., 75, 2584 (1953). 13) L. Foreman, S. M. McElvain, J. Am. Chem. Soc., 62, 1439 (1940). 14) A. I. Vogel, J. Chem. Soc., 1934, 1758. 15) C. G. Overberger, P. Kabasakalian, J. Org. Chem., 21, 1124 (1956). 16) R. L. Kronenthal, E. I. Becker, J. Am. Chem. Soc., 79, 1095 (1957). 17) M. T. Bogert, J. R. Tuttle, J. Am. Chem. Soc., 38, 1349 (1916). 18) I. M. Hunsberger, D. Lendicer, H. S. Gutowsky, D. L. Bunker, P. Taussig, J. Am. Chem. Soc., 77, 2466 (1955). 19) a) A. T. Nielsen, W. J. Houlihan, "Organic Reactions", 16, 1 (1968). b) H. 0. House, "Modern Synthetic Reactions", the 2nd ed, W. A. Benjamine Inc., Menlo Park (Cali., USA) (1972) p. 629. 20) B. M. Trost, I. Fleming, M. E. Sommelhack ed., "Comprehensive Organic Synthesis" , Vol. 4, Pergamon Press, Oxford (England), p. 932, and others are cited therein. 21) Generation of bromonium ion by anodic oxidation of bromide ion, and electrophilic addition of the generated bromonium ion to organic substrates have been well-known according to the reported literatures.22) 22) a) M. M. Baizer, H. Lund ed., "Organic Electrochemistry", the 2nd ed., Marcel Dekker, New York, p. 863 (1983), b) N. L. Weinberg ed., "Technique of Electroorganic Synthesis" , Part I, John Wiley & Sons, New York, p. 368 (1974). c) E. Steckhan, "Topics in Current Chemistry-Electro- chemistry I", Springer-Verlag, Berlin, p. 1 (1987) 23) It is readily expected from reduction potentials of bromoform, methylene bromide and methyl bro- mide that they are subjected to electroreduction under the reaction conditions. Bromoform : -0.64 V, Methylene bromide : -1.48 V, Methyl bromide : -1.96 V vs. SCE in 75% dioxane/0.05 M Et4NBr.24) 24) M. von Stackelberg, W. Stracke, Z. Elektrochem., 53, 118 (1949).

27 196 日本 油 化 学 会 誌 第 45 巻 第 2 号 (1996)

日本油化学会誌本号掲載 論文要 旨

[総説] 新 素 材 「リ ン 脂 質 」

榊 原 敏 之 ・難 波 幸 弘 日本 精 化 株 式 会社 (〒541 大 阪 市 中 央 区 備 後 町2-4-9)

リ ン脂 質 を素 材 と い う見 方 で 見 た とき の現 状 を ま と めた 。 レ シチ ン と称 さ れ る リ ン脂 質 を除 くと,工 業 化 され て い る リ ン脂 質 は グ リセ ロ リン脂 質 の 一 種 の ホ ス フ ァチ ジル コ リンの み で,そ の価 格 は数 十 万 円/kgと 宝 石並 の高 価 品 で あ る。 しか し,こ の10年 間 で リン脂 質 の研 究 が進 み,(1)リ ン脂 質 そ の もの の生 理 活 性(2)リ ボ ソー ム 素材(3) リ ン脂 質複 合 体(4)リ ン脂 質 に よ る化 学 修 飾 の 各分 野 で新 製 品 が 開 発 され て き た。 それ ら を概 説 した 。 リ ン脂 質 を 単 な る化 合 物 と捉 え ず,膜 構 成,複 合体 化,化 学 修 飾 の 成 分 と捉 え る と,リ ン脂 質 は 明 らか に新 素 材 と 言 え る。 今 後 も注 目 され 続 け るだ ろ う。 (連絡 者: 榊 原 敏 之) Vol . 45, No. 2, 127 (1996).

[報文] 糖 脂 質 酵 素 モ デ ル (第 7 報) 糖 脂 質 の 炭 化 水 素 鎖 長 の 酵 素 活 性 へ の 影 響

大 勝 靖 一 ・ 末 吉 孝 工 学 院 大 学 工 学 部 応 用 化 学 科 (〒163-91 東 京 都 新 宿 区 西 新 宿 1- 24- 2)

親 水性 な い し疎 水 性 を有 す る各 種 ア ミノ酸 の 加 水分 解 に及 ぼ す 糖 脂 質 触 媒 の炭 化水 素 鎖 長 の 影 響 を 検 討 した。 糖 脂 質 は 反 応場 と して 添 加 した ボ ス フ ァ チ ジル コ リ ン と相 互 作 用 し,糖 脂 質 の 鎖長 に依 存 して 向 上 した,ま た は 低下 し た 加 水 分解 活 性 を示 した。 また 糖 脂 質 は 鎖長 に 従 って基 質 を識 別 す る能 力 の 異 な る こ とも判 った 。 反 応 場 で あ る脂 質 の 糖脂 質 酵 素 モデ ル 触 媒 に 及 ぼ す 影 響 に つ い て も議 論 す る。 (連 絡 者: 大 勝 靖 一) Vol. 45, No. 2, 137 (1996).

[報文] 電 気 化 学 的 ハ ロ ホ ル ム 反 応 メ チ ル ケ ト ン 類 か ら エ ス テ ル 類 へ の 効 率 的 変 換

松 原 義 治*・ 藤 本 和 男*・ 前 川 博 史**・ 西 口 郁 三** *近 畿 大 学 理 工 学 部 応 用 化学 科 (〒577 東 大 阪 市 小若 江3-4-1) **大 阪 市 立 工 業 研 究 所 (〒536 大阪 市 城 東 区 森 之 宮 1丁 目 6- 50)

脂 肪 族,芳 香 族 お よ び α,β 一不 飽 和 系 な ど種 々の メ チル ケ トン類 を 臭 化 ナ トリウ ム(ま た は臭 化 リチ ウム)を 含 む 無 水 メ タ ノ ー ル(ま た はエ タ ノー ル)中 に て,陽 陰極 と して 炭 素 棒 を 備 え た無 隔膜 セ ル を用 いて 電 解 す れ ば,ホ ロ ホ ル ム 型 反応 が容 易 に起 こ り対 応 す る カル ボ ン酸 の メ チ ルエ ス テル(ま た は エ チ ル エ ス テ ル)が 好 収 率 で 得 られ た 。 反 応 で は 陽極 酸 化 に よ り発 生 す るプ ロモ ニ ウム イ オ ンが メ デ ィエ ー ター と して重 要 な 働 き を果 た して い る と思 われ る。 一 旦生 成す る プ ロモ ホル ムが 陰 極 で の 容 易 な 還 元 に よ り揮 発 性 の 高 い 物 質 に 変 わ り ,反 応 終 了 時 に混 合 物 中 に ほ と ん ど存在 しな い こ と は,反 応 操 作 上 極 め て 高 い 簡便 性 を与 え る。 更 に,芳 香 環 や オ レフ ィ ン結 合 へ の 簡 便 で効 率 的 な カ ル ボ アル コキ シ基 の 導 入 が,最 初 の フ リー デ ル ・ク ラ フ ツ反 応 に よ り,容 易 に可 能 で あ る こ とを 示 した。 (連 絡 者: 西 口郁 三) Vol. 45, No. 2, 147 (1996).

[報文] LC/ MS に よ る ヒ マ シ 油 中 の 遊 離 ヒ ド ロ キ シ 脂 肪 酸 の 定 量

山 本 信 也 ・吉 田 誠 一 ・ 高 松 翼 (株) 資生 堂 研 究 開発 本 部 安 全 性 ・分 析 セ ンタ ー (〒223 横 浜 市 港 北 区 新 羽 町1050)

LC-MSに よ り ヒマ シ油 と硬化 ヒマ シ油 中 の リシ ノ ール 酸 と12一ヒ ドロキ シス テ ア リ ン酸 の定 量 法 を 開 発 した 。 用 い た イ ンタ ー フ ェー ス は 大 気 圧 イ オ ン化(APCI)法 で あ り,こ れ は 疑 分 子 イ オ ンで あ るm/z297と299を モ ニ タ リ ングす る 選択 イオ ンモ ニ タ リ ン グ(SIM)法 に よ り脂 肪 酸 に対 して 高 感 度 を 示 し,検 出限 界 はS/N2～3で1ngで あ った。4 ～100 ng の注 入 範 囲 に お い て,ピ ー ク面 積 とお の お の の ヒ ドロ キ シ脂 肪 酸 量 の 間 に直 線 関 係 がみ られ ,相 関 係 数 は0.999 以 上

70