TW593273B - Process for acyl substitution of anhydride by vanadyl salt catalyst - Google Patents

Abstract

A process for acyl substitution of an anhydride with an active-hydrogen-containing compound includes reacting the anhydride with the active-hydrogen-containing compound in the presence of a vanadyl salt catalyst to obtain a high yield of acyl substitution reaction product with high chemoselectivity.

Description

593273

FIELD OF THE INVENTION The present invention relates to a method for performing hydrazone substitution of an anhydride using an active hydrogen-containing compound, and more particularly, to a method for hydrazone substitution of an anhydride using an active hydrogen-containing compound in the presence of a monooxanadium salt catalyst. Method to obtain a high yield of highly chemoselective fluorenyl substitution reaction products. Background of the invention

The halogenation of alcohols, amines, and thiols is an important and commonly used transformation in organic synthesis. In these roles, fluorenyl groups or anhydrides are often used as the source of fluorenyl groups in the test medium or in Lewis bases or acid catalysts. In the past, trisium silicon (TMS) and metal trifluoromethanesulfonates, such as indium trifluoromethanesulfonate, rhenium trifluoromethanesulfonate, copper trifluoromethanesulfonate, and bismuth trifluoromethanesulfonate It has been found to be effective in catalyzing this dehydration of alcohols having anhydrides. However, among the substrates that have been studied and have a wider range of anhydrides and 6 ^ -sensitive groups, such as propyl isopropyl compounds and allyl groups, only some of them may not be completely compatible. In addition, most of these catalysts have encountered some difficulties. For example, the tritiation of an allyl alcohol (cinnamyl alcohol) catalyzed by europium trifluoromethanesulfonate can result in rearranged by-products. The tritiated reaction catalyzed by difloxacin difluoromethylxanthate should be carried out at a temperature of 0 or lower which inhibits the hydrolysis of functional groups on the substrate. In addition, the actual role of the aforementioned catalyst in the catalytic pathway is not fully understood. In particular, the preparation of the metal trifluoromethanesulfonic acid salt often requires the direct mixing of a metal oxide with an excess of thermally continuous acid. From the metal trifluoromethanesulfonate 4 593273 V. Description of the invention (5) Examples Example 1: Preparation of vanadyl trifluoromethanesulfonate [V (0) (0Tf) 2-x (H20)] Vanadium sulfate (V (0) S04 · 3H20) (342 mg, 2.1 mmole) was added to a two-necked flask (50 mL, dried under vacuum), and then dissolved in methanol (2 mL). A solution of barium trifluoromethanesulfonate in methanol (2M, 2mL) was added at room temperature and homogeneously mixed for 30 minutes. A barium sulfate precipitate was formed. The precipitate was filtered through diatomaceous earth, and the filtrate was collected. The solvent remaining in the filtrate was removed under vacuum (120 ° C, 4 hours) to obtain a dark blue solid (622 mg, yield 85%). The obtained vanadyl trifluoromethanesulfonate can be directly used for the halogenation. Example 2: Preparation of vanadyl acetate [V (0) (0Ac) 2-x (H20)] In a dry 5 ml, double-necked, round-bottomed reaction flask, the sulfate trihydrate (114.0 mg, 0.53 mmole), followed by the addition of methanol (1 mL). A solution of Ba (OAc) 2 (130.3 mg, 0.51 mmol) in methanol (1 mL) was added to the reaction flask at room temperature. After 30 minutes of stirring, a precipitate of barium sulfate was observed, which was filtered out through a short filling of diatomaceous earth. The filtrate was concentrated and dried under vacuum at 120 ° C for 4 hours, and produced 109.5 mg (90% yield) of acetic acid famine salt like a cyan solid. Example 3: Preparation of vanadyl chloride salt [V (0) (C1) 2_x (H20)] In a dry 5 ml, double-necked, round-bottomed reaction flask, the oxygen sulfate was 5327273. 5. Description of the invention Hungry salt trihydrate (114.0 mg, 0.53 mmole) was placed, followed by the addition of aqueous methanol (Me0H / H20, 1 / 0.3 mL). A solution of BaCl2-2H20 (122.1 mg, 0.50 mmol) in methanol (1 mL) was added to the reaction flask at room temperature. After 30 minutes of stirring, a precipitate of barium sulfate was observed. The precipitate was filtered through a short filling of diatomaceous earth. The filtrate was concentrated and dried under vacuum at 120 ° C for 4 hours, and produced 86.4 mg (90% yield) of vanadyl chloride salt as a lavender solid. Example 4: Preparation of vanadyl azide [V (0) (N3) 2-x (H20)] In a dry 5 ml, double-necked, round-bottomed reaction flask, the sulfate trihydrate ( 114.0 mg, 0.53 mmole) was left, followed by the addition of methanol (1 mL). A solution of Ba (N3) 2 (112.5 mg, 0.51 mmol) in methanol (1 mL) was added to the reaction flask at room temperature. After 30 minutes of stirring, a precipitate of barium sulfate was observed, which was filtered out through a short filling of diatomaceous earth. The filtrate was concentrated and dried under vacuum at 120 ° C for 2 hours, and produced 91.5 mg (88% yield) of vanadyl azide as a brown solid. Example 5: Preparation of vanadyl hexafluoroantimonate [V (0) (SbF6) 2-x (H20)] In a dry 5 ml, double-necked, round-bottomed reaction flask, let the sulfuric acid # 1 salt three The water compound (88.0 mg, 0.50 mmole) was left, followed by the addition of THF (2 mL). A solution of AgSbF6 (343.5 mg, 1.0 mmol) in THF (1 mL) was added to the reaction flask at room temperature. After 30 minutes of stirring, a precipitate of barium sulfate was observed. The precipitate was filtered through diatomaceous earth 9 593273 V. Description of the invention (7) A short filling. The filtrate was concentrated and dried under vacuum at 120 ° C for 4 hours, and 254.6 mg (86% yield) of vanadyl hexafluoroantimonate was produced as a red-brown solid. Example 6: Preparation of vanadium peroxyacid salt [v (〇) (c 丨 〇4) 2-x (H2〇)] Preparation of a vanadium sulfate sulfate in a dry 5 l, double neck, round bottom reaction flask The dihydrate (114.00 mg, 0.553 mm) was placed, followed by the addition of methanol (1 mL). A solution of Ba (clO4) 2 (171 5 mg, 0.51 mmol) in one of methanol (1 mL) was added to the reaction flask at room temperature. After stirring for so minutes, a precipitate of barium sulfate was observed, and the precipitate was filtered through a short filling of diatomaceous earth. The filtrate was concentrated and dried in a vacuum under i2 (rc for 2 hours, and produced 130.6 mg (80% yield) of peroxovanadate salt as a brown solid. Example 7: Tetracyanoplatinum vanadate salt [v (〇) pt (CN) 4-x (H20)] Preparation In a dry 5 liter, double-necked, round-bottomed reaction flask, the oxygen sulphate dihydrate (114.0 mg, 0.53 mmole) was placed and continued. Add methanol (1 mL). Let a solution of BaPt (CN) 4-xH20 (222.5 mg, 0.51 mmol) in methanol (1 mL) be added to the reaction flask at room temperature. After 30 minutes of stirring, A precipitate of barium sulfate was observed. The precipitate was filtered through a short filling of diatomaceous earth. The filtrate was concentrated and dried under vacuum at 120 ° C for 4 hours, and produced a brown color. 190.8 mg (89% yield) of solid tetracyanoplatinum vanadium salt. 10 V. Description of the invention (8) Example 8: Preparation of vanadyl titanate salt [V (0) Ti〇3_x (H20)] In a 5 ml, double-necked, round-bottomed reaction flask, the sulfate trihydrate (114.0 mg, 0.53 mmole) was placed, followed by the addition of methanol (1 mL). One of the methanol (imL) was Ba Ti03 (118.9mg, 0.51mmol) was added to the reaction flask at room temperature. After 30 minutes of stirring, a precipitate of barium sulfate was observed, and the precipitate was filtered through a short filling of diatomaceous earth. The filtrate was concentrated and dried under vacuum at 120 ° C for 4 hours, and produced 10 L of 9 mg (92% yield) oxygen titanate salt as a cyan solid. Example 9: Oxyvanium salt catalyst Chemical reaction In this example, four different vanadyl oxide catalysts were tested by the tritiation of 2-phenylethanol. Record 1: The tritiation of the vanadyl salt of acetopyruvate in a dry 50 In a 1-liter, double-necked, round-bottomed reaction flask, place acetic acid vanadyl acetate (B.Tmg, 0.05mmole) in 3mL of anhydrous CH2C12 and place 'acetic anhydride (153.1mg, 141.5 // L, 1.5mmol) in It was slowly added to the above solution at room temperature. After about 10 minutes, a 2-phenylethanol solution (i22mg, 119.3 / zL, 1.0 mmol) in CH2Cl2 (2mL) was slowly added to the above dark green solution. And the reaction mixture was stirred for 5 hours. Followed by TLC. After the reaction was completed, the reaction was allowed to react. The combined solution was rapidly cooled with a cold, saturated liquid NaHC03 solution (5mL). The resulting separated organic layer was washed with brine, dried (MgS04), filtered, and evaporated. 593273 V. Description of the invention (11) Table 1: Catalytic dehydration of 2-phenylethanol with various anhydrides in the presence of various vanadyl oxide catalysts 0 〇1 II II 1 mol% V (0) L, Ph ^, 〇C (〇) R_ Qian Ren 〇 Ren Qian ch2ci2 Record V (〇) L Anhydride (R,) Time (h) Yield, α% 1 V (0) (acac) /, c ch3 5 85 2 V (0) C12 ch3 7.5 94 3 V (0) S0 / CH3e 24 92 4 V (0) (0Tf) 2 ch3 0.5 98 5 V (0) (0Tf) / ch3 0.75 98 6 V (0) (0Tf) 2 cf3 3 98 7 V (0) ( 0Tf) 2 i-? T 1 98 8 V (0) (0Tf) 2 tert-Bu 11 99 9 V (0) (0Tf) 2 tert-BnO 28 95 10 V (0) (0Tf) 2 Ph 26 92 11 V (0) (0Tf) 2 Succinic anhydride 42 93 12 V (0) (0Tf) 2 Benzoic anhydride 96 75A, β-isolated yield & acetic acid pyruvate " Use five mole percentages of catalyst a Use The trihydrate e was recovered from the aqueous layer using CH3CN as a solvent 7 catalyst system, and was repeatedly used in five consecutive processes. The separation rate of the diphenyl ester was 16%. 14 5. Description of the invention (12) " The test results with 5 mol% of vanadyl acetonylpyruvate (v〇 (acac) 2) and vanadyl sulfate are valid, respectively within 5 hours and 24 hours, The tritiation was completed in the presence of 1.5 Ac # 0 at room temperature. Vaporized oxonium salts and vanadium trifluoromethanesulfonate salts, which were prepared from oxosulfate and appropriate barium salts, were found to be more active. The dehydration of ν (〇) α2 used and v (〇) (〇Tf) 2 with 15 equivalents of Ac2 in CH2Cl2 was completed in 7.5.5 hours, yielding at least 94% The phenethylacetic acid. It should be noted that the corresponding VCh and v (〇Tf) 2 are catalytically inactive, supporting the role of the V = 0 unit in the oxovanadium catalyst. It is expected that since the residual acetic anhydride and trifluoromethyl lutein oxonium salt can be quickly removed by direct liquid washing, there is no need to use this dehydration process for chromatographic purification. More importantly, V (0) (0Tf) 2 is completely water-soluble, which can be recovered from the concentration of this aqueous layer 'and has similar catalytic activity and is reused for at least five consecutive processes. As shown in Table 1, in addition to acetic anhydride, the catalytic system can be used for non-bad, cyclic, aliphatic and aromatic anhydrides. Generally speaking, the more this field is obstructed, the lower the randomization rate (that is, CH3 > I-Pr >t-BU; refer to Table 1, "· Jilu 4, 7 and 8). The halogenation of aromatic anhydrides (such as R-Ph in record 10 of Table 1) is up to 50 times slower than the halogenation of aliphatic anhydrides (in records 4 and 6 to 8 of Table 1). The halogenation with bis-tertiary-butyl nitrogen carbonate is also well performed and has a rate similar to that of the benzylation (in record 9 of Table i). Cyclic anhydrides, such as succinic anhydride and phthalic anhydride, are the least active (in records u and 12 in Table i). 593273 V. Description of the invention (13 Example 10: Using the best existing catalyst trifluoromethyl lutein oxyacute salt, the affinity of acetic acid and pivalic anhydride for the substitution of fluorenyl groups was tested in this example ' : Acetic anhydride and pivalic anhydride have a space for variation and the need for electron transfer = shellfish nucleophiles. The matrix, reaction time and yield of this example are summarized in Table 2 below. 16 593273 V. Description of the invention (15 ) — In almost all cases, with the exception of cinnamyl alcohol (85%) and methanol valerate, the chemical yield of the tritiation is at least 95%. In general: the tritiation proceeds more than the corresponding pivalate Much faster. The dehydration of primary, secondary and acid-sensitive allyl and phenyl alcohols progresses very smoothly. In the case of o-secondary alcohols and 10, u_dihydroxy_benzophenone cycloheptane Medium (in records 2 and 5 of Table 1), no by-products of rearrangement of allyl or ortho secondary alcohols were observed. Tertiary alcohols, such as tertiary butyl alcohol and trityl, are inactive. Even so, the corresponding tertiary butyl mercaptan is quite alive (in Table 1 Record 10). In the quantitative production in nature, aromatic alcohols, amines and thiols (such as 2-hydroxide, 2-amine and thiothio-naphthalene) can be used for tritiation (record 6 in Table 2) -8). Example 11:

The tritium and / or pivalate effects of various functional matrices were tested in this example. The matrix, reaction time, and yield for this test are summarized in Table 3 below. 18 593273

19 593273 V. Description of the invention (17) --1 b Unless otherwise stated, 1.5 equivalents of anhydride are used. The yield of '7 separation is described with a spectroscope. · The values in parentheses are relative to pivalic acid. d uses two equivalents of anhydride. e uses three equivalents of anhydride. f is performed at -5 ° (:). g no solvent is used. h the reaction is marked with an asterisk. 1 For effective monohydration, the product of dihydration using 0.95 equivalents of J10% yield was isolated. _ · As shown in Table 3, the halogenation process can accept functional groups, such as hydrazine, ester, lactone, _, imine, propyl g and the same compound as Jing Jijun (Records 1 to 9 in Table 3 ) Proton nucleophiles. Their fermentation progresses smoothly and has a yield of 75 to 100%. The α-hydroxyl and α-amino groups are listed in Tables 2 and 3 in Table 3, and stone and base vinegar. In ketones (in records 4 and $ in Table 3), side effects, such as oxidation (dehydrogenation) and dehydration, have not been observed. Although tritiated effects on the -class radicals are unavoidable This primary hydroxyl group has a concomitant migration effect of acetone compound units, but at a temperature of -5 ° C, the hydration of diacetone-D-glucose (in record 7 of Table 7) is performed. No sign of C-0 cleavage has been observed. | The high catalytic efficiency of vanadyl difluoromethanesulfonate is further illustrated in the polymer base molecule, Such as the pre-fermentation of uridine, lactose and cyclodextrin (21 OH group). In all cases, although it has a long reaction time (2.5 to 4 days), the reaction is in acetic acid or in pure Acetic anhydride is completed. By utilizing the different reactivity between nucleophiles, the chemoselective chelation of 3-hydrocarbon methylnaphthalene can be carried out. The first hydroxyl group is completely used 20 593273

Is chemically selective and tritiated and has a yield of at least 95% (in record 10 of Table 3). The tritiated effect of tertiary leucine on the spatially masked amine element is suitable for selection. The corresponding I tritiated product is provided at a yield of 60%. Nonetheless, the similar meaning of pivalic acid proceeded with full selectivity (97%). Example 12:

Since this formic acid if is the least activated non-cyclic anhydride, it can be directly reacted with fatty acids in the presence of benzyl formate.

In this example, the mixed anhydride produced in situ acts as a reactant for the actual fermentation. The reaction of the mixture of 1-phenethyl-3 -butane-1 -alcohol and oleic acid and stearic anhydride and the reaction of Fmoc-L-leucine and fluorenyltri-leucine are as shown in the following scheme 2 As shown. As shown in Scheme 2, the ethyl ethyl-3-butane-1-enzyme was treated with a mixture of oleic acid and phenylarsinic anhydride in CH2C12 with 5 mol% of digas methyl luteinate salt for 2 hours. The produced oleic acid with a yield of 82% was formed smoothly. As exemplified in the direct coupling of Fmoc-L-leucine and methyl t-tri-leucine with a yield of 93%, this mixed anhydride technology can also be used for the synthesis of bis-peptide. 21 593273 V. Description of the invention (l9) Scheme 2: In the synthesis of oleic acid and bis-peptide, it has the dehydration effect of mixed anhydride.

5 mol% V (〇) (〇Tf) 2 (PhC (〇)) 2〇

Example 13: It is known that amines, sulfur, primary alcohols, and aromatic alcohols can be used for phenylhydrazone. However, the benzamidines of secondary alcohols are slightly restricted and require more severe reaction conditions. Regarding the benzoylation of alcohols, amines, and sulfur, the substrate, reaction time, and yield of the test are summarized in Table 4 below. As shown in Table 4, the only active secondary alcohol, which has a yield of 52% when subjected to benzamidine at 50 ° C, is shown in record 8 of Table 4. 593273 V. Description of the invention (20) Table 4: Benzolation of alcohols, amines and sulfur

Record matrix a time, hourly yield /% 1 Ph (CH2) 2OH 26 92 2 ca0H 80 99 3 Cp OH 96 99 4 caNH2 96 99 5 (/ -Pr) 2NH 18 95 6 OCX 96 96 7 T ^ rZ-BuSH 36 97 8 (7〇H v0C (0) Ph 72c 52 9 f-Bu 〇 H2NM〇Me 0.5 100 10 coc; 60 " 83 11 6d'c 7 3 i-Bu y \ H2N ^ OH a Unless otherwise specified, use 1.5 equivalents of anhydride. B Separated yield and descriptive characteristics by spectroscope. ° Performed in THF at 50 ° C with 2 mol% catalyst. D The reaction is marked with an asterisk. E For effective monofluorination, use 0.95 equivalent of anhydride.

twenty three

Claims (1)

593ZB Announcement I — ~ ~ 1 Supplement ___ VI. Application for Patent Scope No. 091 105433 Patent Application Amendment for Patent Scope Amendment Date: April 1993 1 · A method of using an active hydrogen-containing compound to perform an anhydride A method for a fluorenyl substitution reaction, which comprises reacting the anhydride with the active hydrogen-containing compound in the presence of a monooxanadium salt catalyst, wherein the vanadium salt catalyst has the following chemical formula: (vo) x2 where X2 is selected from In the group consisting of: (〇Tf) 2, so3_aryl, S04, (acac) 2, (CH3C02) 2, (f) 2, (ci) 2, (Br) 2, (I) 2, A1203, (N3) 2, SbF6, HP04, M04, (Nb03) 2, (N03) 2, C204, (C104) 2, Se04, Pt (CN) 4, Ti03, W04, and Zr03 . 2. The method according to item 丨 in the scope of the patent application, wherein the active hydrogen-containing compound has the following chemical formula: (Rik-RHn-C-YH, where Y is selected from the group consisting of: 0, NH And S; R is a hydrocarbylene group; the parent-Ri is selected from the group consisting of an olefin element, an Ss element, a lactone element, a pyrene element, an imine element, and a propyl compound Element and hydroxy aldehyde element; m is 0, 1, 2 or 3; η is 0, 1, 2 or 3; and m + n is 3. 3 according to the method described in the first patent claim, wherein the anhydride With -25- "-Su added six The chemical formula under the patent claim range: (R, C0) 20 Each R is selected from the group consisting of: non-cyclic lipid element, cyclolipid element, and aromatic element. 4. The method according to item i of the patent claim, wherein the reaction step is performed in the presence of methylene chloride. 5. The method according to item 丨 of the patent application, wherein the oxygen starved salt is a di-II-fluorenyl acid salt. 6. The method according to item 5 of the scope of patent application, wherein the vanadyl trifluoromethanesulfonate is generated by reacting vanadyl sulfate and barium trifluoroammonium sulfonate. 7. The method according to item 5 of the scope of the patent application, wherein the vanadyl triflate is produced by reacting vanadium oxide with an excess of trifluoromethylphosphonic acid. 8. The method according to item 1 of the scope of patent application, wherein the method is a tritiated reaction selected from at least one of the group consisting of: sorbitol, glycerol, fatty acids, and Benzoic acid. 9. The method according to item 1 of the scope of patent application, wherein the method is a brewing effect of one of the @ 1 categories. 10. The method according to item 1 of the scope of patent application, wherein the method is a synthesis of one of the peptides. ·