摘要
取代基苯硼酸(substituent phenylboronic acids)是有芳香气味的硼酸,其种类繁多,发展非常快,被广泛应用于电子、化学、医药、生物等领域,特别是在糖类传感器方面。本文首先介绍了各种取代基苯硼酸的合成与应用研究,展望了其发展趋势,然后对对位取代基苯硼酸的制备及工艺改进进行了研究,重点研究和改进了对叔丁基、对异丙基苯硼酸和对氯苯硼酸的制备工艺,从而确定了各自的优化合成条件。应用正交设计实验和灰色关联度分析法对影响对叔丁基苯硼酸产率的诸因素如反应时间、反应温度和反应物的物质的量比进行了分析,确定影响对叔丁基苯硼酸产率的因素中,影响最大的为反应温度,其余依次为反应时间和反应物的物质的量比,结合正交实验确定优化合成条件为:亲核取代温度为-20℃,反应物质对溴叔丁基苯与硼酸三甲酯的物质的量之比为1/1.4,反应时间为160 min,总产率高达69.5%;对影响对异丙基苯硼酸产率的诸因素如反应温度和反应物的物质的量的比也进行了分析,确定优化合成条件为:反应物配比对异丙基溴苯与硼酸三丁酯的摩尔比为1/1.5,反应温度为-10℃,酸性水解后总产率56.6%;对影响对氯苯硼酸产率的诸因素如反应时间、反应温度和反应物的物质的量的比也进行了分析,确定优化合成条件为:对氯溴苯与硼酸三丁酯的摩尔比为1/2,反应温度为-40℃,反应时间为160 min,最终产率高达87.77%。此外我们还对对溴苯硼酸的合成条件进行了初步研究。应用质谱、核磁共振光谱、红外光谱和高效液相色谱对上述每个产品进行了分析表征,结果表明所得产物与目标产物结构一致。
There are various kinds of substituent phenylboronic acids which smell sweet, are being developed rapidly and have been widely used in the fields of electronics, chemistry, medicine and biology, especially in glucose sensors. In this thesis, the synthesis, the application and the prospect of substituent phenylboronic acids were summarized, and the synthesises of 4-tert-Butylphenylboronic acid, 4-iso-propylphenyl boronic acid and 4-chlorophenylboronic acid and their improvement were studied in detail. The influencing factors such as temperature, reaction time, reactants molar ratio were analyzed with the orthogonal experiment and the Grey Correlation Degree method, an optimized process for the preparation of 4-tert-Butylphenylboronic acid was thus obtained as follows: the reactant molar ratio of 1-bromo-4-tert-butylbenzene to the trimethyl borate was 1/1.4, the temperature was -20℃, and the reaction time was 160 min. The final yield was 69.5%. An optimized process was obtained by investigating the influence of the temperature, reactant proportion on the yield of 4-iso-propylphenyl boronic acid: The molar ratio of reactants is n(C8H9Br): n(B(OC4H9)3)=1/1.5, the temperature is -10℃,and the isolated total yield is 56.6%. An optimized process for the synthesis of 4-chlorophenylboronic acid was also obtained as follows: the reactant molar ratio of p-chlorobromobenzene to the tributylborate was 1/2, the temperature was -40℃, and the reaction time was 160 min. The final yield was 87.77%. Meanwhile, the preliminary synthesis of 4-bromophenylboronic acid was investigated too. Each of the above products was identified by mass spectrum, 1HNMR, IR and HPLC.
引文
[1] Scott E, Collibee, Jiaxin Yu. A facile and convenient synthesis of functionalized ortho-nitrophenylboronic acids[J].Tetrahedron Letters, 2005,46 :4453–4455
[2] Steffen Haber, Meudt Andreas, Scherer Stefan, et al. Process for the preparation of substituted phenylboronic acids[P].US: 6576789B1,2003-6-10.
[3]Hao Fang, Gurpreet Kaurb, Jun Yanb, et al. An efficient synthesis of sterically hindered arylboronic acids[J].Tetrahedron Letters, 2005,46(10) :1671-1674
[4]Lo Young S. Process for preparing tetrazolylphenylboronic acid intermediates[P]. US:5206374,1993-04-27
[5]Haishi Cao, Tom McGill, Michael D. Heagy. Substituent Effects on Monoboronic Acid Sensors for Saccharides Based on N-Phenyl-1,8-naphthalenedicerboximid- es [J]. J. Org. Chem. 2004, 69, 2959-2966
[6] Anne Marie Schoevaars, Wim Kruizinga, Robert W. J. Zijlstra, et al. Toward a switchable molecular rotor: Unexpected dynamic behavior of functionalized overcrowded alkenes[J]. J Org Chem 1997,62: 4943-4948.
[7] Wayne J. Thompson, John Gaudino. A General Synthesis of 5-Arylnicotinates [J]. J.Org.Chem.1984,49,5237-5243.
[8] Ahman Jens, Wolfe John P, Kamikawa Ken, et al. Ligands for metals and improved metal-catalyzed processes based thereon[P].EP:1354887, 2003-10-22
[9] Decamp Ann E, Grabowski Edward J J, Huffman Mark A, et al. Preparation of 2-aryl carbapenems[P].WO:9531461,1995-11-23
[10]Wenjie Li, Dorian P. Nelson, Mark S. Jensen, et al. An Improved Protocol for the Preparation of 3-Pyridyl- and Some Arylboronic Acids [J]. J. Org. Chem.,2002, 67 (15), 5394 -5397
[11]王积涛,宋礼成.金属有机化学[M].北京:高等教育出版社,1989.p11-13, 45-47
[12] Reitz David B, Li Jinglin, Norton Monica B. Substituted biphenyl compounds for the treatment of inflammation[P]. WO:9616934,1996-06-06.
[13]Derick D. Winkle, Kevin M. Schaab. Suzuki Reaction of a Diarylborinic Acid: One-Pot Preparation and Cross-Coupling of Bis(3,5-dimethylphenyl)borinic Acid[J]. Organic Process Research & Development,2001, 5, 450-451
[14]黄世文,单自兴,赵德杰.“一锅法”简便合成一芳基硼酸和二芳基硼酸[J].有机化学,1995,15(1):64-67
[15]安忠维,陈新兵.多环芳烃类单取代硼酸的合成研究[J]. 精细化工,2000,17(5):297-298,309
[16]Tatsuo Ishiyama, Miki Murata, Norio Miyaura. Palladium(0)-Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloarenes: A Direct Procedure for Arylboronic Esters [J]. J. Org. Chem.,1995,60, 7508-7510
[17]Weijuan Ni, Hao Fang, Greg Springsteen,et al. The Design of Boronic Acid Spectroscopic Reporter Compounds by Taking Advantage of the pKa-Lowering Effect of Diol Binding: Nitrophenol-Based Color Reporters for Diols[J]. J. Org. Chem., 2004, 69, 1999-2007
[18]Lei Zhu, Jason Duquette, Mingbao Zhang. An Improved Preparation of Arylboronates: Application in One-PotSuzuki Biaryl Synthesis [J]. J. Org. Chem., 2003, 68, 3729-3732
[19] 邓友节,田秋峰,康杰.3,5-二氟-4-氰基苯硼酸酯类化合物、其制备方法及其在液晶化合物中的用途[P].CN:02153545, 2004-06-16.
[20] Thibaud Biadatti, Pascal Collette.Preparation of substituted biaryl benzoic acids as inhibitors of RAR receptors and use thereof in human medicine and in cosmetics[P]. WO:03101928, 2003-12-11.
[21] Harald Walter. Pyrazolecarboxamides and pyrazolethioamides as agricultural fungicides [P].WO:0142223, 2001-06-14.
[22] Michael Draper, Mark L. Nelson. Substitued tetracycline compounds for the treatment of malaria [P].WO:38001, 2004-05-06.
[23] Stuart B. Levy, Michael Draper, Graham Jones, et al. Methods of using substituted tetracycline compounds to modulate RNA, and therapeutic use[P].WO:38000, 2004-10-24.
[24] Edwin Thurston David ,Philip Wilson Howard. Preparation of pyrrolobenzodiazepines as anticancer agents [P]. WO: 43963, 2004-05-27.
[25] Xiang Zhou, Man Kin Tse , Wan Terence S. M. et al. Synthesis of β-Mono-,Tetra-,and Octasubstituted Sterically Bulky Porphyrins via Suzuki Cross-Coupling[J].J. Org .Chem., 1996, 61(11): 3590-3593.
[26] Ishiyama Tatsuo,Kizaki Hiroe , Miyaura Norio , et al. Synthesis ofunsymmetrical biaryl ketones via palladium-catalyzed carbonylative cross-coupling reaction of arylboronic acids with iodoarenes[J].Tetrahedron Lett.,1993,34(47),7595-7598.
[27] Thibaud Biadatti, Pascal Collette.Preparation of substituted biaryl benzoic acids as inhibitors of RAR receptors and use thereof in human medicine and in cosmetics[P]. WO:03101928, 2003-12-11.
[28] Kricka Larry Jan, Organoboron compounds as chemiluminescence enhancers[P]. WO: 9316 195, 1993-08-19.
[29] Kricka Larry Jan, Enhancers for the chemiluminescent reactions[P]. Brit.UK: 2276721, 1994-10-05.
[30] C. F. Poole , S. Singhawangcha and A. Zlatkis.Comparison of Electron-capturing Boronic Acid for the selective analysis of Bifunctional Compounds[J].J. Chromatogr. ,1979(186): 307-316.
[31] Koehler KA, Lienhard GE. 2-Phenylethaneboronic acid, a possible transition-state analog for chymotrypsin[J]. Biochemistry ,1971, 10:2477-2483.
[32] Philipp M, Bender ML. Inhibition of serine proteases by arylboronic acids[J]. Proc Natl Acad Sci USA 1971, 68:478-480.
[33] Matthews DA, Alden RA, Birktoft JJ ,et al. X-ray crystallographic study of boronic acid adducts with subtilisin BPN0 (Novo). A model for the catalytic transition state[J]. J Biol Chem.,1975,250:7120-7126.
[34] Matteson DS, Majumdar D. Homologation of boronic esters to a-chloro boronic esters[J]. Organometallics,1983, 2:1529-1535.
[35] Matteson DS, Sadhu KM. Synthesis of 1-amino-2-phenylethane-1-boronic acid derivatives[J].Organometallics,1984,3:614-618.
[36] Matteson DS, Jesthi PK, Sadhu KM. Synthesis and properties of pinanediol a-amido boronic esters[J].Organometallics, 1984,3:1284-1288.
[37] Kinder DH, Katzenellenbogen JA. Acylamino boronic acids and difluoroborane analogues of amino acids: Potent inhibitors of chymotrypsin and elastase[J]. J. Med. Chem.,1985,28:1917-1925.
[38] Jagannathan S, Forsyth TP, Kettner CA. Synthesis of boronic acid analogues of a-amino acids by introducing side chains as electrophiles[J]. J. Org. Chem.2001,66:6375-6380.
[39] Angyal S J, Greeves D, Pickles V A. The stereochemistry of complex formation of polyols with borate and peridate anions, and with metal cations[J]. Carbohydr. Res.,1974, 35:165-173.
[40] Greg S, Binghe W. A detailed examination of boronic acid-diol complexation[J]. Tetrahedron, 2002,58 (26):5291-5300.
[41] Kazunori K,Hiroaki M. Sensitive glucose-induced change of the lower critical solution temperature of poly [N,N–dimethylacrylamide–co-3-(acrylamido) phenyl-boronic acid][J]. Macromolecules, 1994,27:1061-1062.
[42] Daijiro S, Yoshishige M, Kazunori K, et al. Preparation and characterization of a glucose-responsive insulin-releasing polymer device[J]. Biomaterials, 1994,15 (2): 121-128.
[43] Kazunori K,Hiroaki M,Masayuki B,et al. Totally synthetic polymer gels responding to external glucose concentration:their preparation and application to on-off regulation of insulin release[J]. J. Am. Chem. Soc., 1998,120:12694-12695.
[44] Kazuki A,Takeo Y. Molecular recognition gating membranes made by plasma-graft polymerization[J]. J. Photopolym. Sci. Technol.,2005, 18 (2):229-232.
[45] Tsukagoshi K, Hashimoto M, Otsuka M,et al. Separation behavior of biological constituents having cis-diol groups through interactions with phenylboronic acid sites introduced on the inner wall of a fused-silica capillary[J]. B. Chem. Soc. JPN., 1998,71 (12):2831-2836.
[46] Liebich H M, DiStefano C, Wixforth A, et al. Quantitation of urinary nucleosides by high-performance liquid chromatography[J]. J.Chromatogr. A, 1997,763 (1/3):193-197.
[47] Uda I , Sugai A , Kon K . Isolation and characterization of novel neutral glycolipids from Thermoplasma acidophilum[J]. Biochim. Biophys . ACTA, 1999,1439:363-370.
[48] Zheng Y F , Xu G W , Yang J , et al. Determination of urinary nucleosides by direct injection and coupled-column high-performance liquidchromatography[J] . J.Chromatogr.B, 2005,819:85-90.
[49] Senel S,Camli S T,Tuncel M,et al. Nucleotide adsorption-desorption behaviour of boronic acid functionalized uniform-porous particles[J]. J. Chromatogr. B,2002,769 (2):283–295.
[50] 李方楼,赵欣捷,许国旺.硅胶基硝化苯硼酸亲和色谱材料的合成及应用[J].分析化学,2006,34(10):1366-1370.
[51] 李莉,赫荣乔.间氨基苯硼酸亲和层析法纯化的糖基化蚓激酶及纯化方法[P].CN 1448508A,2003-10-15
[52] Di Luccio M,Smith B D,Kida T,et al. Separation of fructose from a mixture of sugars using supported liquid membranes[J]. J.Membrane Sci., 2000,174 (2):217-224.
[53] Ma Y, Yang X R. One saccharide sensor based on the complex of the boronic acid and the monosaccharide using electrochemical impedance spectroscopy[J]. J.of Electroanal. Chem., 2005,580 (2):348-352.
[54] Takahashi S,Kashiwagi Y,Hosni T,et al. Voltammetric response of phenylboronic acid monolayer-modified gold electrode to sugars[J].Anal. Sci., 2004,20 (5):757-759.
[55] Takahashi S, Anzai J. Phenylboronic acid monolayer-modified electrodes sensitive to sugars[J]. Langmuir, 2005, 21 (11):5102-5107.
[56] Lee M C, Kabilan S, Hussain A. Glucose-sensitive holographic sensors for monitoring bacterial growth[J]. Anal. Chem.,2004,76(19):5748-5755.
[57] Yasumasa Kanekiyo, Hiroaki Sato, Hiroaki Tao. Saccharide Sensing Based on Saccharide-Induced Conformational Changes in Fluorescent Boronic Acid Polymers[J].Macromolecular Rapid Communications,2005,26,1542-1546.
[58] Wang W, Gao X, Wang B.Boronic acid-based sensors[J]. Current Org. Chem., 2002,6:1285-1317.
[59] Hao F,Gurpreet K,Binghe W. Progress in boronic acid-based fluorescent glucose sensors[J]. J. Fluoresc., 2004,14:481-489.
[60] Haishi C,Michael D H. Fluorescent Chemosensors for Carbohydrates:A Decade’s Worth of Bright Spies for Saccharides in Review[J]. J. Fluoresc., 2004,14:569-584.
[61] Elizabeth A M,Bethel V S,Sapna K D,et al. Fluorescence Glucose Detection:Advances Toward the Ideal In Vivo Biosensor[J]. J.Fluoresc., 2004,14:535-547.
[62] 王积涛,张宝申,王永梅等.有机化学(第二版)[M].天津:南开大学出版社,2003.222-223
[63] 王积涛,宋礼成.金属有机化学[M].北京:高等教育出版社,1989.11-13, 45-47
[64] 王玉炉.有机合成化学[M].北京:科学出版社.2005,86~88.
[65] 初玉霞.有机化学[M].北京:化学工业出版社.2002,130.
[66] Bean, F. R.; Johnson, J. R. Derivatives of phenylboric acid , their preparation and action upon bacteria. II. Hydroxyphenylboric acids. J. Am. Chem. Soc. 1952,54, 4415-25.
[67] Osamu Nozak, Xiaoying Ji, Larry J Kricka. New enhancers for the chemiluminescent peroxidase catalyzed chemiluminescent oxidation of pyrogallol and purpurogallin[J].J.Biolumin. Chemilumin , 1995, 10(3):151-156.
[68] Jeffrey Douglas Lloyd, Allison Kathleen Deane-Wray.Wood preservatives containing boronic, diboronic,or boronic acids[P] .Brit.UK :2281210, 1995-03-01.
[69] Pamela R. Westmark, Bradley D. Smith. Boronic acids facilitate the transport of Ribonucleosides through lipid bilayers[J]. J. Pharm. Sci.1996, 85(3):266-269.
[70] Galla Rao, Manfred Philipp.Boronic acids catalyze the hydrolysis of mandelonitrile[J]. Bioorg.Chem.Enzym.Catal.1992, 129-142
[71] Xiang Zhou, Zhong-yuan Zhou,Thomas C.W.Mak, et al.Synthesis of β- Octasubstituted Sterically Bulky Porphyrins by Suzuki Cross Coupling[J]. J.Chem.Soc.Perkin Trans.1994, 1:2519-2520
[72] Amanda E. Sutton, Jon Clardy. The synthesis of potentially selective inhibitors of dihydroorotatedehydrogenase.The utilization of chemoselective Suzuki Cross-Coupling reactions in a parallel synthesis[J].Tetrahedron Letters, 2001,42:547-551
[73] Beerli Renem, Tommasi Ruben Alberto, Weiler Sven, et al. Quinazoline derivativ- -es [P]. WO:02102782,2002-12-27
[74] Sebti Said, Hamilton Andrew. Inhibitors of prenyl transferases [P].WO:9621456,1996-07-18
[75] Peter Blurton, Frank Burkamp,et al. Preparation of amino heterocycles as vanilloid receptor modulators(VR1),in particular antagonists,for treating pain and/or inflammation[P]. WO :2004 46133,2004-06-03.
[76] Madras Bertha Kalifon, Meltzer Peter Claude. Non-amine tropane analogues [P]. GB:2380733,2003-04-16
[77] Allen Darin, Fahr Bruce, Oslob Johan, et al. Caspase-1 inhibitors and methods for their use[P]. WO:03103599,2003-12-18
[78] Daugan Alain Claude-Marie. Benzamide derivatives and their use as APOB-100 secretion inhibitors[P]. WO:0032582,2000-06-08
[79] Murugesan Natesan, Hunt John T. Phenyl Sulfonamide and their use as endothelin antagonists [P].EP:0569193, 1993-11-10.
[80] Vikram Paul,Brian P. Roberts. Homolytic Reactions of Ligated Boranes.Part 10.Electron Spin Resonance Studies of Radicals derived from Ligated Arylboranes[J].J. Chem. Soc. Perkin Trans.Ⅱ,1988,8:1900.
[81]Chan Ming F, Raju Bore G, Kois Adam, et al. Thienyl-, furyl- and pyrrolyl sulfona- -mides and derivatives thereof that modulate the activity of endothelin[P]. US: 5594021 ,1997-01-14
[82] 王伯原主编.新编中级无机化学实验[M].南京:南京大学出版社,1998,3.
[83] Aldrich. Handbook of fine chemicals and laboratory Equipment[M].Shanghai:Sigma-Aldrich,2003.363.
[84] 王学萌,张继忠,王荣. 灰色系统分析及实用计算程序[M]. 武汉:华中科技大学出版社,1996.
[85] 简春雨.田口式品质工程对有机合成之应用[D] .中国台北:朝阳科技大学应用化学系, 2002.
[86] 黄枢,谢如刚,田宝芝,秦圣英.有机合成试剂制备手册[M].成都:四川大学出版社,1988.p375-377
[87] Jean Jacques Bourguignon, Claire Lugnier, Mustapha Abarghaz ,et al. Benzodiazepinone inhibitors of cyclic nucleotide phosphodiesterase PDE2 for use in treatment of nervous system disorders[P]. FR:2846653, 2004-05-07.
[88] Shomir Ghosh, Amy M. Elder, Kennth G.Carson, et al. Preparation of tetrahydroquinolinyl PGD2 receptor antagonists for the treatment of inflammatory disease [P].WO:32,848, 2004-04-22.
[89] Kin Shing Chan, Xiang Zhou,Bao-sheng Luo, et al. Synthesis of β-aryl substituted Porphyrins by Palladium-catalysed Cross-Coupling reactions[J]. J. Chem. Soc . ,Chem.Commun., 1994,271-272.
[91] Aldrich. Handbook of fine chemicals and laboratory Equipment[M].Shanghai:Sigma-Aldrich.2003-2004.461.
[92] Fukushima Yukihiro, Babasaki Mitsue, Horikawa Yukio. Preparation of optically-active ketones and chiral smectic liquid-crystal compositions containing them[P]. JP 05 294 898 .1993-11-09
[93] Batenburg Amir Maximiliaan, Van der Hijden,Hendrikus Theodorus W. M. Detergent composition containing lipolytic enzyme ands tabilizer[P]. EP 478050.1992-04-01.
[94] Rao Galla, Philipp Manfred .Boronic acids catalyze the hydrolysis of mandelonitrile[J]. Bioorg. Chem.Enzym. Catal. 1992,129-142.
[95] Kopf A ., Schalkhammer T.,Kirchner G ., et al. Is there a correlation of structure and activity of lipases under various reaction conditions[J]? Biocatalysis. 1994,9(1~4):261-268.
[96] Nielsen Donald R., McEwen William E. Benzenediboronic acids[J] . J. Am. Chem. Soc. 1957, 79:3681-3684.