Baba, Naomichi

Hamada, Masayuki

Kawahara, Seiichi

Oda, Jun'ichi

Kyoto University Research Information Repository

TitleHydroperoxidation of 9-Hexylfluorene and Weitz-Scheffer,Epoxidation of Cyclohexenones under Phase TransferCondition (Commemoration Issue Dedicated to ProfessorShinzaburo OKA On the Occasion of His Retirement)Author(s)Baba, Naomichi; Oda, Jun'ichi; Kawahara, Seiichi; Hamada,MasayukiCitationBulletin of the Institute for Chemical Research, KyotoUniversity (1989), 67(3): 121-127Issue Date1989-11-30URL http://hdl.handle.net/2433/77304RightType Departmental Bulletin PaperTextversionpublisherKyoto UniversityBull. Inst. Chem. Res., Kyoto Univ., Vol. 67, No. 3, 1989  Hydroperoxidation of 9-Hexylfluorene and Weitz-Scheffer        Epoxidation of Cyclohexenones under Phase                  Transfer Condition          Naomichi BABA*, Jun'ichi ODA**, Seiichi KAWAHARA***                      and Masayuki HAIVIADA****                              ReceivedAugust21, 1989   A single-pot oxidation system involving hydroperoxidation of 9-hexylfluorene and epoxidation of cyclohexenones therewith under phase transfer condition was devised and applied tentatively to asym-metric synthesis of optically active epoxyketones.    KEY WORDS: Phase transfer catalyst/ Hydroperoxidation/ Single-pot ep-                 oxidation! Asymmetric Epoxidation/                          INTRODUCTION    Utillization of molecular oxygen to epoxide synthesis without involving any isolation procedure of hazadous hydroperoxides as epoxidizing agent has been an important problem standing on the safty and effective use of natural resources. A number of studies in this field have been reported including metal catalyzed hydro-peroxidation and epoxide formation in situ,' photochemical method,~1 P-450 model system') and phase transfer-catalyzed oxidations') in all of which molecular oxygen was used as one oxygen atom source.    We report here a single-pot epoxidation of cyclohexenones in which both 9-hexylfluorenyl hydroperoxide formation via anion oxidation with molecular oxygen and the epoxidation are conducted successively under phase transfer condition. In due course, the system was tentatively extended to the asymmetric synthesis of op-tically active epoxyketones by use of chiral phase transfer catalyst (PTC).                      RESULT AND DISCUSSION    Our previous work showed that 9-hydroperoxy-9-hexylfluorene(1) was a good candidate for the Weitz-Scheffer type epoxidation (eq. 1) improving the enantio-selectivity of asymmetric epoxidation of cyclohexenone by use of a optically active bis-type phase transfer catalyst') This hydroperoxide (1) was prepared previously by Sprinzak from 9-hexylfluorene and dry oxygen gas in the presence of triton B   *  'il i : Present address: Faculty of Agriculture, Okayama University, Tsushimanaka, Oka-    yama 700.  ** Ii\mJI1 — Laboratory of Plant Product Chemistry, Institute for Chemical Research, Kyoto     University, Uji, Kyoto 611.  *** ?cgs— Presentaddress: Takasago Koryo Kogyo Co. Ltd., Chuo-ku, Tokyo 104. **** : Present address: Department of Agriculture, Kinki University, Nakamachi, Nara 631. (121)                     N.  BABA,  J. ODA, S. KAWAHARA, and M. HAMADA        o(1) , (2a) or (2b)        II'C0eq. 1                      10N-NaOH, toluene 00                     ..N+X-                 CI                                                            CH2—  0 0 HO                                                            CH2 —      H00 (CH2)5CH3HH'X                                                   (2a): Y= Br      (1)O(2b): Y= Cl Fig. 1. in dry pyridine (eq.2).6) In order to find more convenient reaction conditions, we examined the fluorenyl anion-mediated hydroperoxidation by use of benzyltrimethyl-ammonium chloride (BTEAC) in two phase condition instead of using triton B in dry pyridine (eq. 3). Thus, oxygen gas was introduced to a solution of BTEAC, 9-hexylfluorene and trace of 10N-NaOH in a mixture of pyridine/toluene (2:3) with 02, triton B, dry pyridineH30+ OOO-----> (1) eq. 2    H (CH2)5CH3 02, BTEAC, aq, NaOH, pyridine/toluene ----------------------------------------------------> (1) eq. 3                                      Fig. 2. vigorous stirring at r.t. for 4 h. After evaporation of the solvent, the concentrate was acidified and 9-hydroperoxy-9-hexylfluorene was isolated by column chroma-tography. From this experiment, the hydroperoxide was obtained with 89% chemi-cal yield.    An important point of this system was the use of small amount of aq. NaOH solution with very high concentration otherwise the hydroperoxidation was unsuc-cessful under typical PTC conditions where comparable amount of water to organic solvent is used. The advantages over the triton B method are that the present procedure did not require dry solvent, dry oxygen gas and low temperature. More-over, oxygen gas could be replaced by air affording the hydroperoxide in 77% yield.    This result suggested that both the PTC-catalyzed hydroperoxidation of 9-hexylfluorene (eq. 3) and the PTC-catalyzed Weitz-Scheffer epoxidation7 (eq. 1) must be conducted at the same time by use of the one PTC in a single flask. To test this posibility, oxygen gas was introduced for more than 20 h to a solution of cyclohexenone as a substrate of the epoxidation, 9-hexylfluorene as a precursor of the hydroperoxide, BTEAC and small amount of 10N-NaOH in a mixture of ben-zene and pyridine (2/3).    Unexpectedly, however, cyclohexenone 2,3-epoxide with only 27% c.y. was produced mostly leaving the starting materials. Search for the cause of this low yield revealed that existence of cyclohexenones in the reaction mixture strongly (122)               PTC-catalyzed Single-pot Hydroperoxidation and Epoxidation           Table 1. Inhibition of  Peroxidation, of 9-Hexylfluorene by Cycloalkenones*           run cycloalkenone (cycloalkenone\chem. yield of 9-hexyl-                                    9-hexylfluorene J fluorenyl hydroperoxide          1 9093%   290.1847                     0          3     90.5324    4II1.0016 0 51.0011 0    61.0013 0 71.0027                       0 801.0034         ®. 9o1.002            *) In runs 1 - 4 and 5'-9, 0.05 and 0.02 mol equivalent of benzyltriethyl-               ammonium chloride to 9-hexylfluorene wereused,respectively.           **) The hydroperoxide content was determined by iodometry. depressed the formation of the hydroperoxide even in a catalytic manner to some extent (Table 1). For example, as run 2 shows, yield of the hydroperoxide decreased to 47% from 93% (run 1) in the presence of /8% mol of 2, 3-cyclohexenone to 9-hexylfluorene. With equivalent mole of cyclohexenone, the formation of the hydro-peroxide dropped to 16% (run 4). Furthermore, no addition product from the possible 1,4-nucleophilic attack of fluorenyl anion to cyclohexenones was detected at all, and most of 9-hexylfluorene was recovered.8) Taking account of this inhibi-tory action of cyclohexenones, a possible route for effective hydroperoxidation and epoxidation in a single pot may be an addition of cyclohexenone after completion of the hydroperoxide formation. Thus, as described above, 9-hexylfluorene was oxidized first to the hydroperoxide (1) according to eq. (2), and then the substrate was added to the oxidation mixture followed by stirring for 24 h at room tempera-ture. As shown in Table 2, it was found that the corresponding epoxyketones were obtained in reasonable yield after usual work-up. On the other hand, when air was used instead of oxygen gas, the yields reduced to 15-.75 %. However, removing of carbon dioxide from the air by bubbling it through aq. NaOH improved the (123)                     N.  BABA, J. Onn, S. KAWAHARA, and M. HAMADA            Table 2. Peroxidation and Epoxidation in a Single Pot with Benzyl-                    triethylammonium Chloride                                                % chem. yield*            run substrate epoxide 02 air air without CO2      1l ~, C)0 100 48100 00       20100 60100        0 0       30100 75100 00 4 ~ ~0 725762 00 00      54.0711563 0 0               *) conversion yield by v.p.c. conversion yield to the same level as with oxygen gas. As seen in runs 4 and 5, 4,4-dimethylcyclohexanone and vitamine K3 afforded relatively low conversion yields (60,70%). Although the reason for the former may be ascribed to steric hindrance by the two methyl groups, for the latter, it is unknown.    As an extension of the above oxidation system, asymmetric epoxidation of cyclo-hexenones was undertaken by use of chiral bis(PTC) (2a or 2b) under the same condition except for the temperature of the epoxidation. As shown " in Table 3, the optically active epoxides were obtained with the chemical yield ranging over 13-85%. Cyclohexenone afforded (2S, 3S) cyclohexenone 2,3-epoxide with 44 (run 1) and 54 (run 6) % e.e. by use of (2a) and (2b) respectively.9) On the other hand, for 5,5-dimethylcyclohexanone (runs 2 and 7) and 3-methylnaphthoquinone (runs 3 and 8), the stereoselectivities were found to be small whereas reaosnable chemical yields (57,82%) were observed. The other substrates, 4-methylcyclohexenone (runs 4 and 9) and 4,4-dimethylcyclohexenone (runs 5 and 10) also afforded the optically active 2,3-epoxyketones whose optical purities and absolute configuration were unknown.    Thus, it was demonstrated that chiral PTC's which have been used as catalyst for asymmetric epoxidations5) were also feasible for the hydroperoxidation of 9-he-xylfluorene and the both processes could successively be performed in a single flask to give optically active epoxides. Although the stereoselectivities were unsatisfactory as a method for asymmetric synthesis, the present study constitutes a first example for utillization of molecular oxygen and preparation of chiral epoxide in a single flask by use of chiral PTC. The use of PTC constitutes one of the most important techniques of organic chemistry1) and a number of asymmetric syntheses using chiral PTC have also been reported. It appaers, however, that examples of very (124)               PTC-catalyzed Single-pot Hydroperoxidation and Epoxidation            Table 3. Asymmetric Epoxidation with  Chiral PTC (2a) and (2b)   run X substrate product rteaetemp.%yiechemld°.o/e.e. configuration      . 1 Brgo —20°C 3444 2S, 3S O 0  2 Bro—20 579 00 00  3 Br ®. ®/ 0 —20 764 2S, 3R 0 0  4 Brr.t. 82 (-24.8°)* —         I ~o O 0  5 Brr.t. 51 (-17.10)* —                               0 O 0  6 Clgo—20 8554 2S, 3S O 0 7 Cl0—20 807 O 0 O 0 8 C1®So—20 821 2S, 3R O 0  9 Cl 0r.t. 68 (-29.4°)*—           rf)00   10 Clar.t. 13 (-19.9°)* —       O 0    *) Optical rotation at 578 nm in methylene chloride high stereoselectivity have been rather scarce and the selectivity seems to depend subtly on the structure of PTC5'11) as well as of reactant,s.12) solvent,9.13) and type of reaction.'2 In the present study, further variation of PTC structure might be of prime importance so far as concerning with improvement of the stereoselectivities.                       EXPERIMENTAL    Optical rotations were taken on a Perkin-Elmer 241 polarimeter. VPC were on a Shimadzu GC-4CM and a Varian Aerograph Model 920 for preparative scale chromatography. Preparation of chiral bis(PTC) (2) was described in our previous study.5) 4,4-Dimethyl-2,3-cyclohexane,15) 4-methy1-2,3-cyclohexane,16) and 5,5-dim-ethyl-2,3-cyclohexanone'7 were prepared according to the literature methods. Preparation of the hydroperoxide (1) under phase transfer condition.    Into a solution of benzyltriethylammonium chloride (38 mg, 0.17 mmol), 9-hexylfluorene (1.3 g, 5.2 mmol) and 10N-NaOH (124 sal) in a mixture (17 ml) of (125)                     N. BABA, J. ODA, S.  KAWAHARA, andM. HAMADA pyridine/toluene (2/3), oxygene gas was bubbled with vigorous stirring for 4 h. After evaporation of the solvent, the residue was purified by chromatography (silica gel, CH2C12/hexane (5/1)). Chem. yield, 1.30 g (89%). When air was used in-stead of oxygen gas, the hydroperoxide swas obtained in 77% yield. Inhibition of hydroperoxidation of 9-hexylfluorene by cyclohexanones.    The hydroperoxidation was conducted under the same condition described above in the presence of varying amount cyclohexanones as shown in Table 1. After the reaction, the hydroperoxide contents were determined by iodometry. Hydroperoxidation and subsequent epoxidation in a single flask.    After the hydroperoxidation of 9-hexylfluorene (0.15 g, 0.59 mmol) in pyridine/ toluene (2/3) (5 ml) for 2 h in the presence of benzyltriethylammonium chloride (5.5 mg, 0.024 mmol) and ION-NaOH (36 ,44), alkyl cyclohexenone (0.45 mmol) was added and stirred overnight at room temperature. The chemical yield was determined by gaschromatography (5%-XE-60, 2 m, 140°C). Hexane (20 ml) was added with shaking to the reaction mixture and filtered. The filtrate was concen-trated and the residue was distilled at 20 mm by Kugel Rohr apparatus to separate epoxide containing fraction from 9-hexylfluorenol and benzyltriethylammoniu chlo-ride. From the distillate, epoxide were isolated pure by preparative VPC (5%- XE-60, 2 m, 160°C). Proton NMR spectra confirmed the purity and structural in-tegrity of the epoxide.91 Hydroperoxidation and asymmetric epoxidation in a single flask.    The same procedure as described above was conducted in the presence of bis (PTC) (2) instead of benzyltriethylammonium chloride. Since the catalytic activity of the bis(PTC) seemed to be lower than benzyltriethylammonium chloride, addi-tional bis(PTC) of the same amount was supplemneted before addition of cyclo-hexenone. The epoxide was isolated pure as described above and the optical purity was determined from its optical rotation.9)                           REFERENCES(1) R.A. Sheldon and J.K. Kochi, "Metal-Catalyzed Oxidation of Organic Compound", Academic      Press, New York, 1982. (2) W. Adam, A. Griesbeck and E. Staab, Tetrahedron Lett., 27, 2839 (1986). S.C. Sethi, A.D.      Natu and M.S. Wadia, Heterocycles, 18 221 (1982). (3) M. 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Hydroperoxidation of 9-Hexylfluorene and Weitz-Scheffer, Epoxidation of Cyclohexenones under Phase Transfer Condition (Commemoration Issue Dedicated to Professor Shinzaburo OKA On the Occasion of His Retirement)

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Hydroperoxidation of 9-Hexylfluorene and Weitz-Scheffer, Epoxidation of Cyclohexenones under Phase Transfer Condition (Commemoration Issue Dedicated to Professor Shinzaburo OKA On the Occasion of His Retirement)

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