Ring construction intramolecular

Keywords chiral lanthanoid complexes, rare earth complexes, carbocyclic ring construction via intramolecular Diels-Alder reaction... 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

F. Ring-Construction by Intramolecular C-H Insertion of (Phenylthio)carbenes... 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Intramolecular nucleophilic aromatic substitution on 243 allowed l,4-dihydropyridazin-3(2//)-one ring construction (Equation 58) . Similarly, a tetrahydropyridazine unit could be constructed starting from 244 (Equation 59) . 

Many of the limitations of C—C bond formation by C —H insertion outlined for intermolecular reactions (Section 1.2.1.) can be overcome by making the reaction intramolecular. Thus, hydrogen atom abstraction followed by intramolecular radical-radical coupling or radical addition to an alkene are increasingly popular processes. Two-electron carbene insertions, either thermal or transition metal catalyzed, have also been used extensively. In either case, ring construction involves net C—C bond formation at a previously unactivated C-H site. 

In the last ten years C—C bond formation by intramolecular C—II insertion has evolved from a laboratory curiosity to an effective tool for molecular construction. Procedures for C —C bond formation with control of relative and. in some cases, absolute configuration are now available. The greatest growth has been in the development of rhodium-catalyzed diazocarbonyl insertion reactions. The development of effective cnantioselective catalysts for this process will make it an even more valuable method for ring construction. 

TABLE 1. Examples of medium/Large ring construction via the Sml2-promoted intramolecular Reformatsky-type reaction (the new —C bond is highlighted by the disconnection curve)... 

The intramolecular Diels-Alder reaction has long been a powerful method for polycyclic ring construction. A1 Padwa of Emory University reports (J. Org. Chem. 68 227, 12003) that on Rh catalysis, a diazoalkyne such as 1 is smoothly converted into the reactive furan 2. Cyclization of 2 leads via 3 to the angularly-arylated product 4. 

Intramolecular carbene insertion (e.g. 1 —> 3) has long been a useful method for ring construction. Masahisa Nakada of Waseda University in Tokyo now reports (J. Am. Chem. Soc. 125 2860, 2003) that with the addition of the ligand 2 this process can be made highly enantioselective. As the starting diazo ketone 1 is easily prepared by diazo transfer to the sulfonyl ketone, this should allow facile entry to enantioenriched cyclopentanones and cyclohexanones. 

Deacetoxyalcyonin acetate 1 and cuncellin 2 are representative members of the euniccllin class of diterpenes. The synthesis of deacetoxyalcyonin acetate 2 by Gary Molander of the University of Pennsylvania (J. Am. Chem. Soc. 2004, /26,1642) illustrates the power of intramolecular organometallic carbonyl addition for ring construction. 

Intramolecular alkylation is an attractive method for ring construction. Helena M.C. Ferraz of the University of Sao Paulo and Marcos N. Eberlin of the State University of Campinas report (J. Org. Chem. 2005, 70, 110) that the intramolecular displacement of the iodide 1 proceeds by way of the tethered enamine 2, delivering the quaternary center of the keto ester 3 with high diastereocontrol. 

Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, /26,8664) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbenc or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol. 

In a very significant development, the parent 277-azepine 85 was prepared for the first time (Scheme 10) <1995AGE1469>. A ring construction was adopted involving A-BOC deprotection of 84 followed by treatment with strong base to afford 85 after intramolecular imine formation and base-induced elimination of acetate. While the yield was only 1%, the azepine was sufficiently stable at 25 °C for 48 h to allow for H and 13C NMR spectroscopic characterization. 

In a different type d ring-construction process, base-induced intramolecular cyclization of the ester derived from the acids 242 gave the 1-benzazepines 243 in moderate to excellent yields (Scheme 31). The yields were affected by the nature of the substituent group R1 on nitrogen, with the best yield being obtained with an iV-benzyl derivative (243 R1 =CH2Ph, R2 = Br, R3 = Et) <2004TL9335>. 

Further application of the powerful intramolecular reductive Heck reaction has been realized in the efficient microwave-assisted synthesis (Pd(PPh3)4, 3 mol%, HCOONa, 1.5 equiv, DMF HzO 3 1, 110 °G) of the important 3-benzazepine system. The precursors were A-ethynoyl derivatives of N-substituted n-bromophenethylamines, which afforded, via a type c ring construction, 3-benzazepin-2-ones with a substituted exocyclic methylene group at the Cl position <20070L3017>. 

The use of a zirconium complex (dibutylzirconocene, — 78 °C to rt, 2 h) to induce intramolecular co-cyclization of A-methyl-5-azanona-l,8-diene to an intermediate zirconacycle was a key step in a new azepane synthetic route hydrolysis (MeOH, aq. NaHC03) of this intermediate then realized the trans- 1,4,5-trimethylazepane in 75% yield the active reagent for the initial cyclization was zirconocene (1-butene). The overall transformation represents a type d ring construction process <2006SL3439>. This synthetically versatile process is also applicable to aza eneyne and aza diyne precursors as well as benz-fused analogues. 

Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T (2007) Chemoenzymatic Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck Cyclizations via C-B-D Ring Construction. Synlett 2859... 

Omori AT, Finn KJ et al (2007) Chemoenzymatic total synthesis of (+)-codeine by sequential intramolecular Heck cyclizations via C-B-D ring construction. Synlett 2007 2859-2862... 

The H mode of the pyrimidine ring construction assuming the stepwise formation of the N(l)-C(2) and C(2)-N(3) bonds as a result of the insertion of a component serving as the source of the C(2) atom is more often used in practice. The simplest modification involves intramolecular condensation of 3-(acylamino)thienopyri-dines produced by acylation of 3-amino-2-carbamoylthieno[2,3-Z>]pyridines or their structural analogs (1995PS83). An example is the synthesis of pyrimidothienobenzo-quinoline 98 from chloroacetamide 99. 

An alternative ring construction approach to 1,4-oxazepin-7-ones (e.g. 241) utilises the Baylis-Hillman product 240, subsequent reaction with a p-aminoalcohol, and ester hydrolysis followed by DCC-mediated intramolecular coupling to afford 241. This sequence can be generalised to give a range of analogues [02S2232],... 

As part of a study of ring construction through transposition of activated cyclo-propanes, Danishefsky s group has scrutinized the feasibility of intramolecular homoconjugate nucleophilic additon.64 Two of the substrates examined were 34 and 35 and these were found to undergo rather efficient closure to bicyclo[3.3.0]octane derivatives when treated with strong base. The somewhat elevated temperatures allow both the cyclopropane fission and subsequent Dieckmann condensation to proceed at respectable rates. 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

Intramolecular carbon-carbon bond formation is an effective means of creating a variety of functionalized carbocyclic and heterocyclic ring systems. Apparently, proper choice of Lewis acid promoters and conditions enables stereoselective ring construction by use of la and other Lewis acids. 

The known approaches to the synthesis of thienopyrimidines can be divided into two main groups construction of the pyrimidine ring by intramolecular cyclization of thiophene derivatives and thiophene ring closure in pyrimidine derivatives. 

Using this method, synthesis of functionalized substituted cyclopropanes can be achieved via nucleophilic alkylation of the monoacetates of but-2-ene-l,4-diols 18 with malonates (and similar stabilized) carbanions in the presence of a palladium(0) catalyst. Subsequent acylation of the second hydroxyl function and subsequent treatment with base in the presence of the palladium(0) catalyst leads to intramolecular nucleophilic alkylation. This method and similar conversions have been applied to numerous other cyclopropane ring constructions. - - ... 

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