베일리스-힐만 부가생성물의 합성 응용에 관한 연구 = Synthetic Applications of Baylis-Hillman Adducts

다국어 초록 (Multilingual Abstract)

The Baylis-Hillman reaction was found by the German chemists Baylis and Hillman in 1972. The Baylis-Hillman reaction is an effective carbon-carbon bond-forming reaction between the α-position of activated vinyls and some electrophiles like aldehydes and N-tosylimines. The α- position of the activated vinyl compounds is intrinsically nucleophilic although the nucleophilic nature is very weak. However, the nucleophilicity of the α-position of activated vinyls could be increased dramatically by in-situ formation of the corresponding zwitterionic species between the vinyl compounds and DABCO.
The Baylis-Hillman reaction did not received much attention at the earliest stage presumably due to some limitations of the original Baylis-Hillman reaction including slow reaction rate, limitations in electrophilic components, and etc. In the early 1990th Basavaiah and Kim groups started deep investigations on the Baylis-Hillman reaction itself and the chemical transformations using Baylis-Hillman adducts independently. The two research groups shed much light to the Baylis-Hillman and related chemistry by publishing many brilliant research results on the chemical transformations of the Baylis-Hillman adducts.
In this Ph. D. thesis, many useful and novel chemical transformations with Baylis-Hillman adducts and related compounds are described. In Chapter 1, introduction of Baylis-Hillman reaction are provided.
Chapter 2 dealt with the results on the synthesis of five-membered heterocyclic compounds such as pyrazoles, indazoles, isoxazolidinones. An efficient procedure was developed for the regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis-Hillman adducts. These biologically interesting pyrazole derivatives were synthesized by the reaction of Baylis-Hillman adducts of alkyl vinyl ketones and a variety kinds of hydrazines, regioselectively. Some tetrahydroindazole derivatives were synthesized analogously in moderate yields from the Baylis-Hillman adducts of 2-cyclohexen-1-one. These compounds could be oxidized to the corresponding indazoles by using DDQ oxidation protocol. The reaction of tetrahydroindazole and DDQ in benzene at refluxing temperature afforded the synthetically useful indazoles cleanly. During the DDQ oxidation in the presence of carboxylic acid we found an interesting oxidation pathway: oxidation to alcohol and the following ester formation with the carboxylic acid. Such unusual oxidation process was observed for the pyrazoles which could not be oxidized into aromatic nucleus. Thus we could prepare some functionalized pyrazoles by the selective formation of carbocation intermediate with DDQ and the following reaction with carboxylic acids. In the oxidation, resonance stabilization and hyperconjugative stabilization effects played important roles for the selective formation of the more stable carbocation. As the other biologically important five-membered heterocyclic compounds, we prepared some 4-arylidene-2-substituted isoxazolidin-5- ones from the Baylis-Hillman adducts. The synthesis was carried out according to the following process: (i) introduction of N-substituted hydroxylamines at the primary position of the Baylis-Hillman adducts and (ii) LiClO4-assisted cyclization reaction with elimination of methanol.
In Chapter 3, some interesting synthetic applications of N-tosylaziridine derivatives were described. The Baylis-Hillman adducts could be transformed easily into the corresponding cinnamyl bromide derivatives. The cinnamyl bromides could be used as the source of sulfur ylides in the presence of dimethyl sulfide and K2CO3. The in-situ generated sulfur ylides reacted with various N-tosylimines and produced the requisite starting materials, N-tosylaziridines. As the first synthetic applications, We thought that the N-tosylaziridines could be ring-opened by appropriate amine nucleophiles and could afford interesting β,γ-disubstituted-α-arylidene-γ-butyrolactams. As expected we could synthesize the lactam derivatives, fortunately, from the reaction of N-tosylaziridines and anilines under the influence of LiClO4 in CH3CN at refluxing temperature. The reaction produced ring-opened 1,2-diamine derivatives at room temperature first and these 1,2-diamines were converted easily into the corresponding lactam derivatives by elevating the reaction temperature. As a next study we examined the feasibility for the preparation of β,γ-disubstituted-α-arylidene-γ-butyrolactones, which might be formed via the direct intramolecular ring-opening reaction of the aziridine with the oxygen atom of the ester moiety. To our delight, we obtained the desired lactone derivatives from the reaction of N-tosylaziridines directly in the absence of aniline under the same conditions for the synthesis of lactames, LiClO4/refluxing CH3CN. Although the nucleophilicity of the oxygen atom of the ester moiety is small, the intramolecular ring-opening of aziridine ring with this oxygen atom occurred effectively in the presence of LiClO4 (3.0 equiv) at elevated temperature. Next, the N-tosylaziridines were used for the synthesis of 1-arylnaphthalenes. The transformation proceeded via the ring-opening of aziridine and Friedel-Crafts type reaction and the concomitant elimination of p-toluenesulfinic acid to furnish the naphthalene compounds. In addition, the cinnamyl bromides could also be used for the synthesis of biologically interesting arylidene moiety-containing cyclopropane derivatives. When we used MVK instead of N-tosylimine in the reactions with sulfur ylides we obtained the cyclopropane derivatives in moderate yields. However, in this case we have to use strong base, NaOH instead of K2CO3.
In Chapter 4, we described the results on the facile synthetic method of 3-alkylidene-3H-isobenzofuranones from the Baylis-Hillman reaction of 2-carboxybenzaldehyde. Although 2-carboxybenzaldehyde has an aldehyde functional group, the synthesis of the corresponding Baylis-Hillman adduct has not been reported. With catalytic amount of DABCO the reaction will not proceed due to the complete consumption of DABCO catalyst in the acid-base reaction with the carboxylic acid group. Thus, we decided to use excess amounts of DABCO and examined the reaction of 2-carboxybenzaldehyde and ethyl acrylate in CH3CN. Fortunately, we obtained an interesting compound, 3-alkylidene-3H- isobenzofuranone. This compound might be formed via the initial Baylis-Hillman reaction and the following intramolecular cyclization and 1,3-proton transfer process.
Chapter 5 dealt with some unusual reactions of the Baylis-Hillman adducts having ethyl nitroacetate moiety at the secondary position of the Baylis-Hillman adducts. During the continuous examinations on the synthesis of naphthalene derivatives starting from appropriately modified Baylis-Hillman adducts, we introduced ethyl nitroacetate at the secondary position of the Baylis-Hillman adducts and examined the synthesis of naphthalene derivatives with the product thereof. However, to our surprise, we found the formation of unexpected 2-amino-2,3-dihydrobenzofuran derivatives under the influence of H2SO4/TFA in benzene at refluxing temperature. The structure of this unusual compound was confirmed unequivocally by its X-ray crystal structure. These unusual 2-amino-2,3- dihydrobenzofuran derivatives might be produced via the following successive steps: (i) protonation at the nitro group, (ii) intramolecular transfer of oxygen atom from nitrogen to carbon of benzene moiety, (iii) successive 1,3-H shift, (iv) intermolecular Friedel-Crafts type reaction with benzene, and finally (v) formation of the final cyclic aminal derivatives, 2-amino-2,3-dihydrobenzofuran derivatives. In addition, when we used the Baylis-Hillman adducts of alkyl vinyl ketones having ethyl nitroacetate moiety at the secondary position, we obtained fully-substituted furan derivatives. The furan compounds might be produced as follows: (i) protonation at the nitro group, (ii) intramolecular attack of carbonyl group toward protonated nitro group to generate the allylic carbocation intermediate, (iii) intermolecular Friedel-Crafts reaction with benzene, and (iv) the final aromatization process by the elimination of N-hydroxy hydroxylamine species gave the furan derivatives.
In Chapter 6, we described some achievements in general Baylis-Hillman chemistry. The transformation of the Baylis-Hillman adducts into their cinnamyl alcohol derivatives is a useful and important process. Thus, we developed a practical and stereoselective synthetic method of cinnamyl alcohols bearing α-cyano or α-esterfunctionality starting from Baylis-Hillman adducts. The process involved sulfuric acid-mediated simultaneous acetylation and rearrangement followed by partial hydrolysis protocol. We also prepared some Baylis-Hillman adducts bearing the carbamate or amide functional group at the secondary position by applying the DABCO salt concept. During the synthesis we used NaOH in order to increase the reactivity of the nucleophiles and we found that NaOH did not hydrolyze significantly the ester moiety under the reaction conditions. As another trial, we devoted our efforts to the rate increase in the Baylis-Hillman reaction especially in the case of cycloalkenones. Fortunately, we found that the use of N,N,N,'N'-tetramenthyl-1,3- propanediamine (TMPDA) could act very efficiently as the catalyst forthe Baylis-Hillman reaction of cycloalkenone. The increased yields and the rate improvements might be attributed to the stabilizing effect of the zwitterionic intermediate viathe ion-dipole interaction.
Chapter 7 described on the synthesis of substituted cyclopentenes from the Baylis-Hillman adducts via ring-closing metathesis (RCM) reaction. In order to show the synthetic usefulness of the Baylis-Hillman adducts we examined the feasibility for the synthesis of cyclopentene backbone by the combination of Baylis-Hillman chemistry and the ring-closing metathesis (RCM) process catalyzed by the well-known Grubbs catalyst. We prepared the requisite starting materials by functionalization of the Baylis-Hillman adduct with diethyl allylmalonate and the products thereof could be converted into the desired cyclopentene derivatives in high yields.
In Chapter 8, we examined the synthesis of various lactones and lactam derivatives starting from the Baylis-Hillman adducts. we synthesized some β,γ,γ-tri- or γ,γ-disubstituted-α-methylene-γ-butyrolactones starting from the Baylis-Hillman adducts by using the indium chemistry. The reaction of cinnamyl bromides and indium metal produced the corresponding allylindium species. The in-situ generated allylindium species reacted with activated carbonyl compounds and produced the corresponding β,γ,γ-tri- or γ,γ-disubstituted-α-methylene-γ-butyrolactones in a one-pot reaction. Similarly Synthesis of various β,γ-disubstituted-α-methylene-γ-butyro lactam derivatives were carried out via the following sequential process: (i) introduction of primary nitroalkane at the secondary position of the Baylis-Hillman adducts by using the DABCO salt concept and (ii) reductive cyclization with the aid of Fe/AcOH conditions.
Chapter 9 dealt with the chemistry of triple bond-containing compounds. The results described in this chapter were started unexpectedly during the Baylis-Hillman reaction with N-tosylimine derivatives. First of all, we found an efficient method for the effective alkynylation of N-tosylimines with aryl acetylenes. The reaction of N-tosylimines and aryl acetylenes in the presence of ZnBr2 and DIEA (N,N-diisopropylethylamine) in CH3CN afforded the desired N-tosyl propargylamines in moderate to good yields. With these successful results in mind we examined the feasibility for the introduction of aryl acetylenes to other compounds having an electrophilic site such as quinolinium and pyridinium salts, epoxides, and carboxylic acid chlorides. From the reaction of aryl acetylenes and quinolinium or pyridinium salts we could prepare the corresponding 1-acyl-1,2-dihydroquinolines or 1-acyl-1,2-dihydro pyridins. We obtained some homopropargylic alcohols and propargylic alcohols from the reaction of epoxides and aryl acetylenes under the ZnBr2/DIEA/CH3CN conditions. Similarly, α,β-acetylenic ketones were synthesized from the reaction of carboxylic acid chlorides and acetylenic compounds in the presence of ZnBr2 and DIEA in CH3CN. From the acetylenic ketone derivatives having nearby methylene unit, we could obtain very interesting 2,5-disubstituted furan derivatives under the same reaction conditions. During the studies, fortunately, we found that enaminone esters could be prepared in moderate yields when methyl propiolate was reacted with some tertiary amines including DIEA under the influence of ZnBr2 in CH3CN. As an extension to these findings we prepared unusual cyclic and acyclic enaminone esters from Troger's base and some conjugated esters.
As described inthis thesis a variety of chemical transformations for the synthesis of heterocycles, aromatic compounds, and acyclic compounds have been investigated starting from the Baylis-Hillman adducts.

목차 (Table of Contents)

• Contents i
• List of Spectra vi
• List of Tables ix
• List of Abbreviations xi
• Abstract 1
• 1. Introduction
• 1.1. Baylis-Hillman Reaction 8
• 1.2. Origin and Growth 8
• 1.3. Mechanism 9
• 1.4. Chemical Transformations of Baylis-Hillman Adducts 11
• 1.4.1. Synthesis of Alkene Derivatives 11
• 1.4.2. Synthesis of Cyclic Compounds 17
• 1.4.3. Diastereoselective Chemical Transformations 32
• 1.4.4. Miscellaneous 38
• 2. Synthesis of Five-Membered Rings with Two Heteroatoms from Baylis-Hillman Adducts
• 2.1. Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles from Baylis-Hillman Adducts
• 2.1.1. Introduction 45
• 2.1.2. Results and Discussion 47
• 2.1.3. Experimental 53
• 2.2. Synthesis of 2H-Indazole Derivatives Starting from the Baylis-Hillman Adducts of 2-Cyclohexen-1-one
• 2.2.1. Introduction 57
• 2.2.2. Results and Discussion 60
• 2.2.3. Experimental 66
• 2.3. Regioselective Oxidation of 4,5-Disubstituted Pyrazoles
• 2.3.1. Introduction 70
• 2.3.2. Results and Discussion 72
• 2.3.3. Experimental 77
• 2.4. Synthesis of 4-Arylidene-2-substituted Isoxazolidin-5-ones from Baylis-Hillman Adducts
• 2.4.1. Introduction 80
• 2.4.2. Results and Discussion 83
• 2.4.3. Experimental 89
• 3. Synthesis of Three-Membered Ring Compounds from Baylis-Hillman Adducts and Their Synthetic Applications
• 3.1. Synthesis of N-Tosylvinylaziridines from Baylis-Hillman Adducts
• 3.1.1. Introduction 92
• 3.1.2. Results and Discussion 94
• 3.1.3. Experimental 102
• 3.2. Synthesis of α-Arylidene-β-amino-γ-butyrolactones and α-Arylidene-β-amino-γ-butyrolactams
• 3.2.1. Introduction 107
• 3.2.2. Results and Discussion 109
• 3.2.3. Experimental 118
• 3.3. Synthesis of 1-Arylnaphthalenes from N-Tosylvinylaziridines
• 3.3.1. Introduction 122
• 3.3.2. Results and Discussion 125
• 3.3.3. Experimental 129
• 3.4. Synthesis of Vinylcyclopropanes Using Sulfur Ylide Chemistry
• 3.4.1. Introduction 132
• 3.4.2. Results and Discussion 133
• 3.4.3. Experimental 138
• 4. Synthesis of 3-Alkylidene-3H-isobenzofuranones from 2-Carboxy -benzaldehyde under the Baylis-Hillman Conditions
• 4.1. Introduction 142
• 4.2. Results and Discussion 144
• 4.3. Experimental 151
• 5. Synthesis of 2-Amino-2,3-dihydrobenzofurans and Tetrasubstituted Furans from Modified Baylis-Hillman Adducts with Ethyl Nitroacetate
• 5.1. Synthesis of 2-Amino-2,3-dihydrobenzofuran
• 5.1.1. Introduction154
• 5.1.2. Results and Discussion 157
• 5.1.3. Experimental 167
• 5.2. Synthesis of Tetrasubstituted Furans
• 5.2.1. Introduction 173
• 5.2.2. Results and Discussion 178
• 5.2.3. Experimental 183
• 6. Some Principal Problem Solving in Baylis-Hillman Chemistry
• 6.1. Synthesis of Cinnamyl Alcohols Bearing α-Cyano or α-ester Functional Group from Baylis-Hillman Adducts
• 6.1.1. Introduction 190
• 6.1.2. Results and Discussion 192
• 6.1.3. Experimental 196
• 6.2. Synthesis of Baylis-Hillman Adducts Bearing the Carbamate or Amide Functional Group at the Secondary Position
• 6.2.1. Introduction 199
• 6.2.2. Results and Discussion 202
• 6.2.3. Experimental 207
• 6.3. Efficient Synthesis of the Baylis-Hillman Adducts of Cycloalkenones
• 6.3.1. Introduction 210
• 6.3.2. Results and Discussion 213
• 6.3.3. Experimental 222
• 7. Synthesis of Substituted Cyclopentenes from the Baylis-Hillman Adducts via RCM Reaction
• 7.1. Introduction 225
• 7.2. Results and Discussion 227
• 7.3. Experimental 233
• 8. Synthesis of α-Methylene-γ-butyrolactones and α-Methylene-γ-butyrolactams
• 8.1. Synthesis of α-Methylene-γ-butyrolactones
• 8.1.1. Introduction 239
• 8.1.2. Results and Discussion 242
• 8.1.3. Experimental 248
• 8.2. Synthesis of α-Methylene-γ-butyrolactams
• 8.2.1. Introduction 252
• 8.2.2. Results and Discussion 254
• 8.2.3. Experimental 261
• 9. The Chemistry of Triple Bond-Containing Compounds
• 9.1. Synthesis of N-Tosyl Propargylic Amines
• 9.1.1. Introduction 265
• 9.1.2. Results and Discussion 267
• 9.1.3. Experimental 276
• 9.2. Synthesis of 1-Acyl-1,2-dihydroquinolines and 1-Acyl-1,2-dihydro -pyridines
• 9.2.1. Introduction 281
• 9.2.2. Results and Discussion 283
• 9.2.3. Experimental 287
• 9.3. Ring Opening Reaction of Epoxides under Aryl -acetylene/ZnBr2/DIEA Conditions
• 9.3.1. Introduction 290
• 9.3.2. Results and Discussion 292
• 9.3.3. Experimental 297
• 9.4. Synthesis of α,β-Acetylenic Ketones and 2,5-Disubstituted Furans
• 9.4.1. Introduction 299
• 9.4.2. Results and Discussion 302
• 9.4.3. Experimental 312
• 9.5. Cyclic and Acyclic Enaminone Esters from Tröger's Base and Conjugated Esters
• 9.5.1. Introduction 316
• 9.5.2. Results and Discussion 319
• 9.5.3. Experimental 326
• 10. Conclusion 332
• 11. References 338
• Abstract(Korean) 380
• Spectra 387
• Curriculum Vitae 464