取代反应

第4章 取代反应,1. Arbuzov (阿尔布佐夫) 反应2. Gabriel 合成3. Chichibabin 氨基化反应4. Friedel-Crafts 反应5. Sandmeyer 反应6. Meerwein Arylation 反应7. Reimer-Tiemann 反应8. Grob 碎片化反应9. Mitsunobu 反应10. Stork 烯胺合成法11. Hunsdiecker 反应12. 其它取代,Arbuzov 阿尔布佐夫反应：,反应通式：,由醇(或亚磷酸酯)制备磷酸酯类化合物、卤代烷的很好方法,The synthesis of pentavalent alkyl phosphoric acid esters from trivalent phosphoric acid esters and alkyl halides is known as the (also known as Michaelis-Arbuzov reaction).,反应机理：,卤代烷反应时，其活性次序为：RI RBr RCl RF。 除了卤代烷外，烯丙型或炔丙型卤化物、-卤代醚、- 或 -卤代酸酯、对甲苯磺酸酯等也可以进行反应。 当亚磷酸三烷基酯中三个烷基各不相同时，总是先脱除体积较小的基团。,反应实例：(习题),J. Org. Chem. 2007, 72, 10551057,Org. Lett. 2003, 5, 16611664,研究新进展：,实例1：,The phosphonic acid analog of NSAID (Non-steroidal anti-inflammatory drug) diclofenac was successfully synth. by Mugrage et al. using a novel acid cat. as the key step followed by a TMSBr promoted dealkylation.,Mugrage, B. et al. Tetrahedron Lett. 2000, 41, 2047-2050.,NSAID (Nonsteroidal Antiinflammatory Drugs)为非甾体抗炎药，是一类不含有甾体结构的抗炎药。 NSAIDs自阿司匹林于1898年首次合成后，100多年来已有百余种上千个品牌上市，这类药物包括： 阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布等。,Schmidt et al. design. and synthesized. a novel class of glycosyl-transferase inhibitors. The key synth. steps involve an followed by a coupling with uridine-5-morpholidophosphate as the activat. deriv.,Schmidt, R. R. et al. Design and synthesis of aryl/hetarylmethyl phosphonate-UMP derivatives as potential glucosyltransferase inhibitors. Tetrahedron Lett. 2001, 42, 5393-5395.,糖基转移酶是糖蛋白、糖脂中糖链生物合成的关键酶之一,其活性的非正常表达与肿瘤、免疫系统等疾病的发生、发展有密切关系。其抑制剂可以用于抗肿瘤、抗免疫系统等疾病。,实例2：,A novel enantioselect. synth.of an antagonist of the NMDA receptor, LY235959, was achiev. in 13% overall yield and 17 steps from (R)-pantolactone. The phosphoric acid portion of the target was highly yield. by .,Hansen, M. M., et al. J. Org. Chem. 1998, 63, 775-785.,实例3：,NMDA receptor,NMDA受体的全称为N-甲基-D-天门冬氨酸受体。在90年代中期，该受体被发现是一种特殊类型的谷氨酸神经递质 离子型受体。,NMDA受体涉及包括学习和记忆形成等在内的关键过程，其功能丧失会导致很多疾病，包括帕金森氏症、精神分裂症和中风等。,NMDA受体是中枢神经系统内一类重要的兴奋性氨基酸受体。研究表明，它不仅在神经系统发育过程中发挥着重要生理作用；在神经元回路形成过程中亦起关键作用。,研究NMDA受体在神经药理方面有着广阔的前景。,Gabriel Synthesis (制脂肪伯胺),反应通式：,Transform 1 RX into 1 amines using potassium phthalimide. Now it include the alkylation of sulfonamides and imides. The 1st technique often produces bad yields or side products; separation of phtalhydrazide can be unpleasant. Many alternative reagents have been developed. e.g. the sodium salt of saccharin (邻磺酰苯甲酰亚胺), are similar to the phthalimide salts, hydrolyze more readily; extend the reactivity to 2 RX.,反应机理：,反应实例：,J. Agric. Food Chem. 2009, 57, 2849-2855.,The total synth. of the insect feeding deterrent (昆虫拒食剂) peramine was accomplish. by Dumas at du Pont lab. The was successfully employ. in the last steps of the synthesis.,Dumas, D. J. Total synthesis of peramine. J. Org. Chem. 1988, 53, 4650-4653.,实例1：,是一类能使害虫接触后丧失饲食能力，直到被饿死，而不是直接将其毒杀的化合物,During the synth. of swainsonine (苦马豆素(一类抗癌药) and castano-spermine (栗树精胺(一类抗艾滋病病毒药) analogues, Burgess et al. introduc. the N-atom by replacing a 1 -OH using phthalimide under the Mitsunobu cond. The phthalyl group was not immediately removed.,Burgess, K., et al. Tetrahedron Lett. 1990, 31, 6949-6952.,实例2：,苦马豆素(Swainonine),最初由Colegate从灰苦马豆中分离出来，属于多羟基吲哚兹定生物碱，在吲哚兹定环的1, 2, 8位上各带一个-OH，被命名为1, 2, 8- 三羟基八氢吲哚兹定(1, 2, 8-trihydroxyoctahydro indolizidine)。 该物质有毒。但最近研究表明它是一种新的抗癌药物，它具有杀伤肿瘤细胞作用。,苦马豆,Nunami, K.-i. et al. Tetrahedron Lett.1996, 37, 4957-4960.,A dynamic kinetic resolution was utiliz. for the highly stereoselect. Gabriel synth. of-amino acids by Nunami and co-workers.,实例3：,The enantioselect. prepar. of vicinal diamines is a challenging task. Rossi et al. undertook the synth. of a -benzoylamino-phenylalanine (2,3-diamino acid), which is an analogue of the taxol side chain.,Rossi, F. M. et al. Tetrahedron 1996, 52, 10279-10286.,实例4：,Chichibabin Amination Reaction,The direct amination of PyH and its derivatives at their electron-deficient positions via nucleophilic aromatic substitution (SNAr) is known as .,反应通式：,反应机理：(略),In the lab of Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1H-imidazo4,5- bpyridine (PHIP), a mutagenic (致突变的) compd. isolat. from cooked beef, and its 3-methyl isomer have been accomplished.,Felton, J. S. et al. Heterocycles 1986, 24, 1815-1819.,实例1：,Palucki et al. synth. 2-3-aminopropyl-5,6,7,8-tetrahydronaph-thyridine (四氢二萘叮) in large quantities for clinical studies via a one-pot double Suzuki react. follow. by deprotect. and a highly regioselect. intramol. .,Palucki, M. et al. Tetrahedron Lett. 2001, 42, 6811-6814.,实例2：,Vedernikov et al. designed and synth. tridentate facially chelating ligands of the 2.n.1-(2,6)-pyridinophane family.,The key step in their synth. of these tripyridine macrocycles was a double Chichibabin-type condensation of 1,2-bis(2-pyridyl)ethanes with lithiated 2,6-dimethylpyridines.,Vedernikov, A. N. et al. J. Org. Chem. 2003, 68, 4806-4814.,实例3：,In 1877, Friedel and Crafts treated amyl chloride with thin aluminum strips in benzene and observed the formation of amylbenzene. The reaction of RX with ArH was found to be general, and AlCl3 was identified as the catalyst. The substitution of aromatic and aliphatic substrates with various alkylating agents (alkyl halides, alkenes, alkynes, alcohols, etc.) in the presence of catalytic amounts of Lewis acid is called . Lewis acids catalysts: BeCl2, CdCl2, BF3, BBr3, GaCl3, AlBr3, FeCl3, TiCl4, SnCl4, SbCl5, LaX3, AlRX2.,Friedel-Crafts Reaction,1) Friedel-Crafts Alkylation,反应机理：(略),反应通式：,2) Friedel-Crafts Acylation,The introduction of a keto group into an aromatic or aliphatic substrate by using an acyl halide or anhydride in the presence of a Lewis acid catalyst is called . The reaction is closely related to the F-C alkylation.,反应通式：,反应机理：(略),The key step was a regioselective F-C alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide.,Schreiber et al. carried out the total synthesis of the potent cytotoxin ()-tri-O-methyl dynemicin A methyl ester.,Schreiber, S. L. et al. Total syntheses of di- and tri-O-methyl dynemicin A methyl esters. J. Am. Chem. Soc. 1993, 115, 10378-10379.,实例1：,In the lab of Posner, semisynthetic antimalarial trioxanes in the artemisinin (青蒿素) family were prepared via an efficient F-C alkylation using a pyranosyl fluoride derived from the natural trioxane lactone artemisinin.,Posner, G. H. et al. Orally Active, Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin Family. J. Med. Chem. 1999, 42, 300-304.,实例2：,Artemisinin (青蒿素),从中药黄花蒿(Artemisa annua)中提取的一种抗疟有效成分，具有抗白血病和免疫调节功能。 研究发现，青蒿还对乳腺癌、红斑狼疮、风湿等有疗效，因此它的利用前景非常广阔,During the synthesis of anti-HIV cosalane analogues, Cushman et al. attached substituted benzoic acid rings to the pharmacophore through methylene and amide linkers.,Cushman, M. et al. Synthesis and Anti-HIV Activity of Cosalane Analogues with Substituted Benzoic Acid Rings Attached to the Pharmacophore through Methylene and Amide Linkers. J. Org. Chem. 1999, 64, 5858-5866.,实例3：,Overman et al. accomplished the enantioselective total synthesis of ()-Hispidospermidin by utilizing an aliphatic intramolecular F-C acylation as the key step to assemble the rigid tricyclic core.,Overman, L. E., Tomasi, A. L. Enantioselective Total Synthesis of Hispidospermidin. J. Am. Chem. Soc. 1998, 120, 4039-4040.,实例4：,During the total synthesis of phomazarin, Boger and co-workers closed the B ring of the natural product with a F-C acylation reaction.,Boger, D. L., Hong, J., Hikota, M., Ishida, M. Total Synthesis of Phomazarin. J. Am. Chem. Soc. 1999, 121, 2471-2477.,实例5：,Krohn et al. found the total synthesis of phytoalexine ()-lacinilene C methyl ether was completed.,In order to prepare the core of the natural product, an intermolecular F-C acylation was carried out between succinic anhydride and an aromatic substrate, followed by an intramolecular acylation.,Krohn, K. et al. J. Org. Chem. 1998, 63, 4140-4142.,实例6：,The first synthesis of the macrotricyclic core of roseophilin was carried out by A. Frstner and co-workers. An intramolecular F-C acylation was used to close the third ring of the macrotricycle.,Frstner, A., Weintritt, H. Total Synthesis of the Potent Antitumor Agent Roseophilin: A Concise Approach to the Macrotricyclic Core. J. Am. Chem. Soc. 1997, 119, 2944-2945.,The first compound was converted into the acid chloride under neutral conditions usingthe highly convenient -chloroenamine reagent,实例7：,Sandmeyer Reaction,The substitution of aryldiazonium salts with halides or pesudohalides is known as .,In 1884, T. Sandmeyer intended to prepare phenylacetylene by reacting benzenediazonium chloride with Cu(I) acetylide, but the major product of the reaction was chlorobenzene, and no trace of the desired product was detected.,It was also found that bromobenzene was formed by using CuBr, and CuCN led to benzonitrile.,反应通式：,反应通式：,反应机理：(芳基自由基中间体),The neurotoxic quaterpyridine natural product Nemertelline was successfully synthesized by S. Rault et al. using a Suzuki cross-coupling as the key step.,The boronic acid coupling partner was prepared by first subjecting 3-amino-2-chloropyridine to the conditions of the Sandmeyer reaction followed by a Li Br exchange and trapping the lithiopyridine derivative with B(OPri)3.,实例1：,M. Nakata et al. completed the concise total synthesis of (+/-)-A80915G , which belongs to the napyradiomycin family of antibiotics.,A Sandmeyer reaction was used to introduce the iodine substituent to the substrate in order to obtain the required trihalogenated 1,4-dimethoxy-benzene precursor.,Nakata, M. et al. Tetrahedron Lett. 1999, 40, 7501-7505.,实例2：,1) deprotection of the carboxy-terminal N-methylamide with N2O4 followed by a pH neutral hydrolysis; 2) global demethylation at r.t. using AlBr3/EtSH with concomitant N-terminal trifluoroacetamide hydrolysis.,Deprotection:,In the lab of D.A. Evans the total synth. of the teicoplanin aglycon was accomplished.,Evans, D. A. et al. J. Am. Chem. Soc. 2001, 123, 12411-12413.,实例3：,Meerwein Arylation,The arylation of substituted alkenes with aryldiazonium halides (formally the addition of an aryl halide to a C-C double bond) in the presence of a metal salt catalyst is known as .,反应通式：,反应机理：(芳基自由基中间体),In the lab of Bihovsky, a series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P2 and P3 amino acids were replaced with substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate-1,1-dioxides,Bihovsky, R. et al. J. Med. Chem. 2001, 44, 3488-3503.,实例1：,The research team of Baldwin developed the first synthetic sequence for the preparation of N(5)-ergolines. The key step was a hetero-D-A reaction of a substituted phenyl butadiene to form the piperidine ring.,The phenyl butadiene substrate was prepared via the Meerwein arylation of 1,4-butadiene and a diazonium salt derived from 2,6-dinitrotoluene. The initially formed chlorinated product was subjected to dehydrochlorination using DBU as the base.,Baldwin, J. E. et al. J. Chem. Soc., Chem. Commun. 1985, 1586-1587.,实例2：,The synth. of the aglycone of the antibiotic gilvocarcin-M was accomplish. by McKenzie et al. by a sequential Meerwein arylation- D-A cycloaddition.,The substrate was first subjected to diazotization and then the resulting diazonium chloride was coupled to 2,6-dichlorobenzoquinone in water to afford the quinone product in moderate yield. It is important to mention that the Meerwein arylation was conducted in water at 80 C in the absence of a catalyst.,McKenzie, T. C. et al. Tetrahedron Lett. 1987, 28, 5435-5436.,实例3：,Sohda et al. prepar. a series of novel thiazolidinedione deriv. of the potent antidiabetic (抗糖尿病的) pioglitazone (吡格列酮, AD-4833, U-72, 107). The p-substit. aniline was diazotized with NaNO2/HBr, and the diazonium was used to arylate methyl acrylate in the presence of Cu2O.,The bromopropionate product was first treated with thiourea, and the resulting iminothiazolidinone hydrolyzed with aq. HCl to afford the desired thiazolid inedione derivative.,Sohda, T. et al. J. Med. Chem. 1992, 35, 2617-2626.,实例4：,Reimer-Tiemann 甲酰化反应,The formylation of phenols and heterocyclic phenols using chloroform in an aqueous alkaline medium is known as .,Ciamician-Dennstedt rearrangement,反应机理：,Zimmermann et al. develop. an efficient synth. of 2-amino-1,8-naphthyridines that can serve as building blocks for host-guest and self-assembling systems.,实例1：,A series of indatraline deriv. containing methoxy groups were synth. and their monoamine transporter binding site affinities were measured in the lab of Rice.,Rice, K. C. et al. Design, Synthesis, and Monoamine Transporter Binding Site Affinities of Methoxy Derivatives of Indatraline. J. Med. Chem. 2000, 43, 4868-4876.,实例2：,The development of a novel hapten for radioimmunoassay of the lignan, enterolactone in plasma (serum) was accomplish. by Makela etal.,Makela, T. et al. Tetrahedron 2000, 56, 1873-1882.,实例3：,Grob Fragmentation 碎片化反应,In the 1950s, C. A. Grob firstly systematically investigate the regulated heterolytic cleavage reactions of molecules containing certain combinations of carbon and heteroatoms (e.g., B, O, N, S, P, halogens). The general formula of “ a-b-c-d-X” represents three embedded components:,Cleavage reactions of this type are referred to as , and as a result, 3 fragments (products) are formed.,1) “ a-b” is the electrofuge(离电体), which leaves without the bonding electron pair and becomes the electrofugal fragment;2) “c-d” will become the unsaturated fragment at the end of the reaction; 3) “ X” is the nucleofuge (离核基), which leaves with a bonding electron pair.,包括典型碎片化反应、逆Aldol反应及类似反应,反应机理：(略),Paquette et al. accomplish. the first total synth. of the antileukemic (抗白血病的) agent Jatrophatrione (假白榄三酮). This nat. prod. has a 5.9.5 fused tricyclic skeleton with a trans-B/C ring fusion.,The key step in the approach was the to obtain the tricyclo5.9.5 skeleton.,Paquette, L. A. et al. J. Am. Chem. Soc. 2002, 124, 6542-6543.,假白榄,实例1：,In the lab of Winkler, the synth. of the carbon framework of the Eleutherobin Aglycon was developed using a tandem D-A reaction and a Grob fragmentation as key steps.,Winkler, J. D. et al. Org. Lett. 2003, 5, 1805-1808.,实例2：,逆Aldol反应,实例3：,Mitsunobu Reaction,The substitution of 1 and 2 alcohols with nucleophiles promoted by dialkyl azodicarboxylate and a trialkyl- or triaryl phosphine is known as .,反应通式：,The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using R3P and DEAD. The alcohol undergoes an inversion of stereochemistry. The nucleophile employed should be acidic, since one of the reagents (DEAD) must be protonated during the course of the reaction to prevent from side reactions.,Mitsunobu Reaction,应用：,水解,反应机理：,J. Org. Chem., 2008, 73, 4882-4887.,Org. Lett., 2006, 8, 5069-5072.,反应实例：,Org. Lett. 2009, 11, 807-810.,Synthesis 1995, 756-758.,J. Org. Chem. 2003, 68, 8261-8263.,Tetrahedron 2002, 58, 5979-5982.,The architectural. novel macrolide (+)-zampanolide was synth. in the lab of A.B. Smith.,The required PT-sulfone was prepared from the corresponding primary alcohol via a 2-step protocol employing sequential Mitsunobu reaction and S-S oxidation.,Smith, A. B., III. et al. J. Am. Chem. Soc. 2001, 123, 12426-12427.,A key Intermediate,实例1：,A key Intermediate,The total synth. of the bioactive indole alkaloid ent-WIN 64821 was accomplished by Overman et al.,The stereospecific incorporation of two C-N bonds was achieved using to convert two 2 alcohol functionalities to the corresponding alkyl azides with inversion of configuration.,Overman, L. E., et al. J. Am. Chem. Soc. 2001, 123, 9465-9467.,实例2：,ADDP: 偶氮二甲酰二哌啶,The nat. potent antitumor antibiotic (+)-duocarmycin A, its epimer, and unnat. enantiomers were prepar. by Boger et al. The last step was the elaboration of the reactive cyclopropane moiety, which was carried out via a transannular spirocyclization using .,Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2301-2302.,实例3：,The total synth. of the tricyclic marine alkaloid ()-fasicularin was firstly completed by Kibayashi et al. The 2 alcohol functionality was invert. using protocol.,Kibayashi, C. et al. J. Am. Chem. Soc. 2000, 122, 4583-4592.,实例4：,Stork 烯胺合成法,The synthesis of -alkyl- or acyl- carbonyl compounds via the alkylation or acylation of the corres. enamines is known as the Stork enamine synthesis,反应通式：,反应机理：,The total synth. of the phenolic sesquiterpene ()-parviflorine was accomplish. by Maldonado and co-workers.,The key step in the synthetic sequence was the reaction of an enamine with acrolein to form a bicyclic intermediate, which was then subjected to a Grob fragmentation to afford the 8-membered ring of the natural product.,Maldonado, L. A. et al. A Total Synthesis of the Racemic Sesquiterpene Parvifoline. J. Org. Chem. 1998, 63, 2918-2921.,实例1：,The biomimetic synth. of the structural. novel bisesquiterpenoid ()-biatractylolide was report. by Baldwin et al. The atractylolide precursor was prepar. from a bicyclic ketone using .,Baldwin, J. E. et al. Biomimetic Synthesis of Biatractylolide and Biepiasterolide. Org. Lett. 2003, 5, 3049-3052.,实例2：,In the lab of A.B. Smith, the synth. of (+)-jatropholone A and B was achiev. using a high-pressure D-A cycloadd. between a tetra-substit. furan and a homochiral enone.,The -benzyloxy cyclopentanone was convert. to the morpholine enamine in quant. yield. The enamine was isolat. as a single regioisomer. In contrast, the corres. piperidine or pyrrolidine enamines were obtain. always as a mixture of