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應用硝基苯類化合物為原料並經由分子內還原及環化反應來製備具有生物活性的含氮雜環化合物

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(1)ABSTRACT OF THE THESIS. SYNTHESIS OF BIOLOGICALLY ACTIVE N-HETEROCYCLES VIA INTRAMOLECULAR REDUCTIVE CYCLIZATIONS OF NITROAROMATICS The development of efficient and novel protocols for the construction of Nheterocycles is fascinating and important area of research in synthetic organic chemistry due to their wide spectrum of biological activities and potential application in pharmaceutical field as well as in medicinal chemistry. In this respects, the o-nitro aromatics are readily available starting materials for the construction various nitrogen containing heterocyclic molecules via reductive cyclization.. The contents of this dissertation is divided into four chapters, the Chapter I deals with overview on reductive cyclization and literature survey on intramolecular reductive cyclization in the presence of Fe powder in acetic acid. The Chapter II subdivided into two sections, section A deals with novel synthesis of indolylquinoline derivatives via the C-alkylation of Baylis-Hillman adducts and section B deals with novel synthesis of indolylacridines and indolylcyclopenta[b]quinoline derivatives from the Calkylated cyclic Baylis-Hillman adducts. The Chapter III subdivided into two sections, section A deals with an unprecedented route for the synthesis of 3,3'-biindoles via reductive cyclization of 3-(2-nitro-1-(2-nitrophenyl)ethyl)-1H-indoles mediated by Fe/AcOH and Section B deals with Fe/AcOH mediated carbon degradation: a facile route for the synthesis of quinoline derivatives. The Chapter IV subdivided into two sections, section A deals with a simple and facile route for the synthesis of 2H-1,4benzoxazin-3-(4H)-ones via reductive cyclization of 2-(2-nitrophenoxy)acetonitrile adducts in the presence of Fe/AcOH and section B deals with a highly efficient “ Cl i c k”a ppr oa c ht os y nt he s i s of 1, 4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one moiety via a copper (I)-catalyzed reaction.. i.

(2) Chapter-I: Overview on Reductive Cyclization This chapter describes overview on reductive cyclization and importance of Fe/AcOH as reducing system and literature survey on intramolecular reductive cyclization in the presence of Fe powder in acetic acid. Chapter-II, Section A: Novel synthesis of indolylquinoline derivatives via the C-alkylation of Baylis-Hillman adducts This section A of the work deals with a new and simple method for the C-alkylation of Baylis-Hillman alcohols with various indoles in the presence of catalytic amount of molecular iodine in acetonitrile at room temperature. The obtained reaction products of 2-nitro-Baylis-Hillman alcohols with indoles were subjected to one-pot reductive cyclization to access indolylquinoline derivatives in the presence of Fe powder in acetic acid. The fact that the reactions were clean, devoid of side reaction products constitutes additional attractive features of this methodology.. R O H. O. NO 2. DABCO THF, rt or Proline Imidazole DMF, rt. OH. N H. O. O. Iodine NO 2. ACN, rt. R NO2. 73-89% N H. R = H, Br, Cl, F, Me, Et, Ph, OMe, CO2Me. Fe, AcOH ref lux, 2h 72-83% R. N. NH. R = H, Br, Cl, F, Me, Et, Ph, OMe, CO2Me. Scheme 1. Outline synthetic route to the construction of indolylquinoline derivatives.. ii.

(3) Chapter-II, Section B: Application of the Baylis-Hillman Reaction: An Unprecedented in situ [1,3] sigmatropic rearrangement of indole nucleus to access novel indolylacridines and indolylcyclopenta[b] quinoline derivatives Section B of the work deals with a simple and facile method for the construction of indolylacridines and indolylcyclopenta[b]quinoline derivatives. In which, addition of i ndol e st a ke spl a c ea tα-pos i t i on a swe l la sγ -position of cyclic Baylis-Hillman alcohols in the presence of molecular iodine in acetonitrile at reflux. The obtained reaction products were subjected to reductive cyclization to access indolylacridines and indolylcyclopenta[b]quinoline derivatives in the presence of Fe powder in acetic acid. Particularly worthy of note that in situ [1,3] sigmatropic rearrangement of 2methylindole or 2-phenylindole was occurred during the reductive cyclization of hi g hl yα-regioselective C-alkylated cyclic B-H adducts containing indoles.. OH. O. R. Iodine. R1. NO2. O. ACN, ref lux 77-91%. or NO2. R 1 = H, 1-Me, 2-Me, 2-Ph. R = H, Br, Cl, F n = 0, 1. R1. HN. R. N H. n. NO2. R1. HN. n. n. O R. R = H, Br, Cl, F n = 0, 1 R 1 = H, 1-Me, 2-Me, 2-Ph. R = H, Br, Cl, F n = 0, 1 R 1 = H, 1-Me, 2-Me, 2- Ph. Scheme 2. Regioselective addition of substituted indoles to cyclic Baylis-Hillman adducts.. R1. HN. R1. HN NO2. O R. Fe, AcOH. or NO2. n. O. R. n = 1 (ref lux, 2h) n = 0 (80 oC, 2h). n. R R = H, Br, Cl, F n = 0, 1 R1 = H, 1-Me, 2-Me, 2-Ph. R1. HN. 53-85%. R = H, Br, Cl, F n = 0, 1 R 1 = H, 1-Me, 2-Me, 2-Ph. N. n. R = H, Br, Cl, F n = 0, 1 R 1 = H, 1-Me, 2-Me, 2-Ph. Scheme 3. Synthesis of indolylacridines and indolylcyclopenta[b]quinoline derivati ves via reductive cyclization of indoles containing cyclic B-H adducts.. iii.

(4) Chapter-III, Section A: An unprecedented route for the synthesis of 3,3'-biindoles via reductive cyclization of 3-(2-nitro-1-(2-nitro phenyl) ethyl)-1H-indoles mediated by Fe/AcOH This section A of the work deals with an un precedent route for the synthesis of 3,3'biindoles. In which, the addition of indoles with ortho-β-nitrostyrenes were carried out in the presence of sulfamic acid at 90oC under the neat reaction condition. The obtained reaction products were underwent smooth reductive cyclization and furnished 3,3'-biindoles in good yields in the presence of Fe powder in acetic acid. Both symmetrical and unsymmetrical 3,3'-biindoles were constructed by using this protocol. O2N O2N R. NO2. Sulf amic Acid. R1 NO2 R = H, Br, Cl, F. R. R1. N H. neat, 90 oC. N H. R1 = H, Br, Cl, F, OMe, CH 3, Et, Ph. Fe, AcOH ref lux, 2.5h 79-84% H N R R1 N H R = H, Br, Cl, F R 1 = H, Br, Cl, F, OMe, CH 3, Et, Ph. Scheme 4. Outline synthetic route to the construction of 3,3'-biindolyl derivatives.. Chapter-III, Section B: Fe/AcOH mediated carbon degradation: a facile route for the synthesis of quinoline derivatives This section B of the work describes a new carbon degradation protocol, which results in the formation of quinoline derivatives. The Michael adducts, which obtained from the ortho-β-ni t r os t y r e ne swi t h va r i ousa c y c l i cα-ketones and cyclic enones were. iv.

(5) subjected to reductive cyclization in the presence of Fe powder in acetic acid afforded the quinoline derivatives in good yield via one carbon degradation.. O 2N. O R. Fe, AcOH. . NO 2. N. R. N. R. ref lux, 2h NO 2. Scheme 5. Reaction of 4-nitro-3-(2-nitrophenyl)butan-2-one with Fe powder in acetic acid.. O 2N. O R1. R1. Fe, AcOH. R. R2. ref lux, 2h. NO 2. 41-85%. R = alkyl, Ph-CH2-CH2R 1 = H, Br, Cl, F, OMe, OBn R 2 = H, OMe, OBn. R2. N. R. R = alkyl, Ph-CH2-CH2R 1 = H, Br, Cl, F, OMe, OBn R 2 = H, OMe, OBn. Scheme 6. Synthesis of quinoline derivatives via reductive cyclization of Michael adducts, which derived from ortho-β-ni t r os t y r e ne swi t hva r i ousa c y c l i cα-ketones.. O2N R. O. 1. R2. NO 2 X. X = CH2, O, S R 1 = H, F, OMe R 2 = H, OMe n = 0, 1. n. Fe, AcOH. R1. reflux, 2h. R2. 81-84%. X N. n. X = CH2, O, S R 1 = H, F, OMe R 2 = H, OMe n = 0, 1. Scheme 7. Synthesis of quinoline derivatives via reductive cyclization of Michael adducts, which derived from ortho-β-nitrostyrenes with various cyclic enones.. v.

(6) Chapter-IV, Section A: A simple and facile route for the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones via reductive cyclization of 2-(2-nitro phenoxy)acetonitrile adducts in the presence of Fe/AcOH This section A of the work describes a simple route for the synthesis of 2H-1,4benzoxazin-3-(4H)-ones. In which, the o-alkylation of nitro phenols carried out with bromoacetonitrile or chloroacetonitrile in the presence of K2CO3 in acetone at reflux. The reductive cyclization of 2-(2-nitrophenoxy)acetonitrile adducts afforded the 2H-1, 4-benzoxazin-3-(4H)-ones in good to excellent yields in presence of Fe powder in acetic. acid.. The. present. method. applied. to. synthesis. of. 2-phenyl-4H-. benzo[b]imidazo[1,2-d][1,4]oxazine under microwave condition. This system was compatible with various other functional groups.. R1. R1. R2. NO2. R3. OH. N. X. R2. K 2CO3 R4. acetone, reflux. R 1 = H, Me R 2 = H, Me, Cl, F, OMe, CO 2Et R 3 = H, Me, F, OMe, CO 2Me R 4 = H, Me, Ph, C 3H7, C 2H5, C 2H 4 Cl X = Cl, Br. NO 2 N. R3. O. R4. Fe, AcOH ref lux, 2h 54-95% R1 R2. H N. O. R3. O. R4. Scheme 8. Outline synthetic route to the construction of 2H-1,4-benzoxazin-3(4H)one derivatives.. O N H. O O. Ph. Br. O. K 2CO3 acetone ref lux 77%. N. O O Ph. NH 4OAc (3.0 equiv) 150 oC, neat. O. Microwave, 30min 91%. N. N Ph. Scheme 9. Microwave assisted synthesis of 2-phenyl-4H-benzo[b]imidazo[1,2-d] [1,4]oxazine.. vi.

(7) Chapter-IV, Section B: A Highl yEf f i c i e nt“Cl i c k”Appr o ac ht o Synthesis of 1,4-Disubstituted 1,2,3-Triazole analogues containing 2H-1, 4-benzoxazin-3-(4H)-one Moiety Via a Copper (I)-Catalyzed Reaction We have synthesized bioactive 1,4 disubstituted 1,2,3 triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3 dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields, as a single regioisomer. We have successfully synthesized bis and tris 1,4 disubstituted 1,2,3 triazole analogues containing 2H-1,4benzoxazin-3-(4H)-one derivatives by using this protocol.. R1. O. R3. N. O. R1. CuI (0.3 equiv) R N3. R2. Z. R2. 1,4-dioxane 80oC, 65-98%. Z. O. R3. N. O N N N R. R = alkyl, aryl R 1 = H, F, Me, OMe R 2 = H, Cl, F, Me, OMe, CO2Et R 3 = H, C 2H 5, C3H 7, Ph Z = CH, N. R = alkyl, aryl R1 = H, F, Me, OMe R2 = H, Cl, F, Me, OMe, CO 2Et R3 = H, C2H 5, C3H 7, Ph Z = CH, N. Scheme 10. Our synthetic route towards 1,4 disubstituted 1,2,3-triazole analogues containg 2H-1,4-benzoxazin-3-(4H)-one Moieties.. N3. O. N3. O O. O. O. CuI (0.3 equiv) N. O. N 1,4-dioxane, 1h, 56%. 80 oC. N N N. N N N. N. Scheme 11. Synthesis of 4,4'-(1,1'-(propane-1,3-diyl)bis(1H-1,2,3-triazole-4,1-diyl)) bis (methylene)bis(2H-benzo[b][1,4]oxazin-3(4H)-one).. vii.

(8) N O N3. O. N N. N3 O. CuI (0.3 equiv) N. N. N. N. O. N. O N. 1,4-dioxane, 80 oC 1h, 93 %. O. Scheme 12. Synthesis of 4,4'-(1,1'-(pentane-1,5-diyl)bis(1H-1,2,3-triazole-4,1-diyl)) bis (methylene)bis(2H-benzo[b][1,4]oxazin-3(4H)-one).. O N3. O. N CuI (0.3 equiv). N. O N. O N3. N N N. 1,4-dioxane 80 oC, 1h. N. N N. O. O. 23%. Scheme 13. Synthesis of 4,4'-(1,1'-(1,4-phenylenebis(methylene))bis(1H-1,2,3triazole-4,1-diyl)) bis(methylene)bis(2H-benzo[b][1,4]oxazin-3(4H)-one).. O N. O N. N3 O. N3. CuI (0.3 equiv) 1,4-dioxane 80 oC, 1h. O N N N. N N O N. O N. 91%. Scheme 14. Synthesis of 4,4'-(1,1'-(1,3-phenylenebis(methylene))bis(1H-1,2,3triazole-4,1-diyl)) bis(methylene)bis(2H-benzo[b][1,4]oxazin-3(4H)-one).. viii.

(9) N O N. O. N3. CuI (0.3 equiv). N3. 1,4-dioxane 80 oC, 2h. N N O. N. N. N. O N. N. O. O. 31%. Scheme 15. Synthesis of 4,4'-(1,1'-(1,2-phenylenebis(methylene))bis(1H-1,2,3triazole-4,1-diyl)) bis(methylene)bis(2H-benzo[b][1,4]oxazin-3(4H)-one).. O N O N3 O N. N N O N. N N N. O N. CuI (0.3 equiv). N3. 1,4-dioxane 80 oC, 1h. O N3. N N. 29% N O. N O. Scheme 16. Synthesis of 4,4',4''-(1,1',1''-(benzene-1,3,5-triyltris(methylene))tris(1H1,2,3-triazole-4,1-diyl))tris(methylene)tris(2H-benzo[b][1,4]oxazin-3(4H)-one).. Key Words : Reductive Cyclization, Baylis-Hillman Reaction, N-Heterocyles, Fe/AcOH, Nitroaromatics.. ix.

(10) 中文摘要 在有機化學合成領域的研究中,開發具有高效率和新穎的合成方式來合成含 氮的雜環化合物是相當重要的,因為其具有廣泛的生物活性和在醫藥以及藥物 化學領域的潛在應用性。在這個方面,以鄰位硝基芳香族化合物準備作為可行 的起始物,藉由環化和還原反應來合成建構出多樣性的含氮原子之雜環分子。 本論文主要分為四個章節。在第一章節,回顧有關於使用在醋酸中加入鐵 粉以進行分子內環化和還原反應的相關文獻報導。在第二章節,主要是分為兩 個部分,其中 A 部分是以新的合成方式,使用經過 Baylis-Hillman reaction 所得 到的產物與 indoles 衍生物來進行碳-碳鍵的烷化反應,以合成出具有 indole 取 代基的 quinolines 衍生物;B 部分則是使用經過 Baylis-Hillman reaction 所得到的 產物與 indoles 衍生物來進行碳-碳鍵的烷化和環化反應,以合成出具有 indole 取代基的吖啶以及 indolylcyclopenta[b]quinoline 的衍生物。在第三章節,主要是 分為兩個部分,其中 A 部分是使用嶄新的合成路徑,在鐵粉/醋酸的條件下, 使用 3-(2-nitro-1-(2-nitrophenyl)ethyl)-1H-indoles 來進行環化以及還原反應,合 成出 3,3'-biindoles 之衍生物;B 部分是使用簡潔的合成路徑,在鐵粉/醋酸的條 件底下,合成出 quinolines 的衍生物。第四章節,同樣分為兩個部分,A 部分是 使 用 簡 單 和 便 利 的 合 成 路 徑 , 在 鐵 粉 / 醋 酸 的 條 件 底 下 , 藉 由 2-(2nitrophenoxy)acetonitrile 經 由 環 化 和 還 原 反 應 , 合 成 出 2H-1,4-benzoxazin-3(4H)-ones 的衍生物;B 部分主要是使用具有高效率的“點擊”反應,藉由一價 銅催化反應,將含有 2H-1,4-benzoxazin-3-(4H)-one 基團,合成出在 1 號位和 4 號位具有雙取代的 1,2,3-三氮唑類衍生物。 x.

(11) 關鍵字:還原環化、貝里斯-希爾曼反應、氮雜環、鐵/醋酸、硝基苯. xi.

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