Reductive cyclization methods

Several syntheses of 1-hydroxymethylpyrrolizidines have been reported. Borch and Ho1 have utilized a reductive cyclization method for their synthesis of ( )-isoretronecanol (6) and ( )-trachelanthamidine (7). The cycloheptenone ester (1), prepared by a novel route (Scheme 1), was reductively aminated to give a mixture of the diastereoisomeric amino-esters (2) and (3) in 48% yield. These esters could not be separated. Oxidative cleavage of the double bond of the esters, followed by reductive cyclization, gave a 35% yield of the pyrrolizidine esters (4) and (5). Separation of these compounds was achieved by preparative t.l.c., and a final reduction step afforded the racemic alkaloids (6) and (7). The second reductive amination process was stereoselective, because reduction of the unseparated ester mixture (4) and (5) gave a 1 2 ratio (g.l.c.) of the 1-hydroxymethylpyrrolizidines. 

Syntheses of the heterocycle from 2-nitrobenzenethiol involving reductive cyclization methods have been employed by a number of research groups. 

BusP as ligand.Poor yields in the reductive cyclization method—when competitive cyclization is possible—and also the need for milder reaction conditions in the cyclization step urged Emoto et al. to report an alternative method based on sequential palladium-catalyzed aryl amination (Scheme 10). The substrate for the cyclization was 2-amino-2 -bromo-diphenylamine, obtained by selective bromination and reduction of the well-known 2-nitrodiphenyl-amines or by coupling of 2-bromoaniline with a l-bromo-2-nitrobenzene and subsequent reduction. Treatment of 2-bromo-2 -nitrodiphenylamine with catalytic amounts of palladium(II) and BINAP as ligand afforded the desired phenazines in good yields. ... 

In the work of Jarman and coworkers, a more reliable reductive cyclization method was studied (Scheme 9.60). Starting from resin-bound ortho-ammo acid nitro benzene derivative 506 and subsequent cleavage from the resin using TFA/DCM method provides intermediate 507. Repeated treatment with zinc powder in acetic acid was used for reduction to form 508. 

Scheme 93 Reductive cyclization methods for the synthesis of spiroacetals...

A two-step synthesis of indoles from o-nitrobenzaldehydes proceeds by condensation with nitromcthanc followed by reductive cyclization. Like the Leim-gruber Batcho method, the principal application of the reaction is to indoles with only carbocyclic substituents. The forniation of the o,p-dinitrostyrenes is usually done under classical Henry condensation conditions but KF/18-crown-6 in propanol was found to be an advantageous reaction medium for acetoxy-substituted compounds[1]. The o,p-dinitrostyrenes can also be obtained by nitration of p-nitrostyrenes[2]. 

An oxidative cyclization, (151) -> (152), with azodicarboxylate (78CC764) is balanced by the synthesis of 5-deazaalloxazines from aryl bis(6-aminouracilyl)methanes, which involves azodicarboxylate in an intermediate electrophilic capacity (153 -> 154) (79CPB2507). Other methods involve reductive cyclizations (72AP751). 

An old and satisfactory method is the Riedel synthesis in which o-nitrobenzaldehyde is converted to its bisformaraido derivative followed by reductive cyclization with zinc and acetic acid, or with iron and hydrochloric acid. This synthesis has been used to make... 

Perhaps the most reliable method for the reductive cyclization of a nitro ester to a hydroxamic acid is that which involves treatment with sodium horohydride in the presence of palladium on charcoal. Although under these conditions aromatic nitro compounds are reduced to amines, o-nitro esters such as 53, in which the ester group is suitably oriented with respect to the nitro group, give good yields of cyclic hydroxamic acids (54). Coutts and his co-... 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

Scheme 10. Synthesis of compound 49 by the reductive hydroxy ketone cyclization method.

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

In another procedure, 2-aminobenzophenone is acylated with an sc-azido acid in the presence of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and the product 23 is converted into a benzodiazepinone by reductive cyclization with propane-1,3-dithiol (Method F).200... 

As in the porphycene series one method to obtain an isocorroie is based on the McMurry coupling of a tetrapyrroledicarbaldehyde, e.g. 1.2 4 The reductive cyclization forms a C —C double bond bridge leading directly to the isocorroie, e.g. 2, which is at the correct oxidation level. 

A general method for the synthesis of N-unsubstituted aziridine-2-carboxylates involves a triphenylphosphine-mediated reductive cyclization of hydroxy azido esters [17-22]. A recent example involves the treatment of [1-hydroxy-a-azido ester 15 (Scheme 3.6) with PPh3 to give aziridine 16 in 90% yield [19]. a-Hydroxy- 3-azido esters undergo similar reactions to give aziridine-2-carboxylates [20-22],... 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

A useful and simple method for the one-pot preparation of highly functionalized, enanhomerically pure cyclopentanes from readily accessible carbohydrate precursors has been designed by Chiara and coworkers [73]. The procedure depends on a samarium(II) iodide-promoted reductive dealkoxyhalogenahon of 6-desoxy-6-iodo-hexopyranosides such as 7-160 to produce a 6,e-unsaturated aldehyde which, after reductive cyclization, is trapped by an added electrophile to furnish the final product. In the presence of acetic anhydride, the four products 7-161 to 7-164 were obtained from 7-160. 

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of a-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford a-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73... 

Similar to the Fisher indole synthesis, reductive cyclization of nitro aromatics offers a powerful means of forming indoles. Reductive cyclization of ortho, 2 -dinitrostyrenes has occurred in many ways, by TiCl3, NaBH4-Pd/C, H2-Pcl/C, and other reductive methods.89 Corey and coworkers have used the Borchardt modification (Fe-AcOFI, sihca gel, toluene at reflux for the reductive cyclization of o-ji-dinitrostyrenes) to prepare 6,7-dimethoxyindole (Eq. 10.65) in a total synthesis of aspidophytine (see Schemes 3.3 and 3.4 in Section 3.2.l).89d... 

Battersby and coworkers have developed selective methods for total synthesis of chlorins on a model system, as shown in Scheme 10.15, in which the Michael addition of 5-(2-nitroethyl) pyrrole to enone and reductive cyclization are used as key steps.112... 

The carbinolamine-containing pyrrolo[2,l-c][l,4]benzodiazepine family of antitumor antibiotics is produced by various Streptomyces species well-known members include abthramy-cine, tomay mycine, and DC-81,138 Various approaches to the synthesis of these compounds have been investigated over past years reductive cyclization of suitably substituted nitroaldehydes is the frequently used method (Eq. 10.81).139... 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

In a related cobalt-catalyzed transformation, 1,3-dienes tethered to ally lie ethers engage in Et2AlCl-mediated reductive cyclization.463 Exposure of benzylic ether 22a to Co(acac)3-PPh3 in the presence of Et2AlCl results in formation of divinylcyclopentane 22b with excellent /raar-diastereoselectivity. As demonstrated by the conversion of 23a to 23b, this method is also applicable to the stereocontrolled formation of six-membered rings (Scheme 16). 

Recently, the silane-mediated reductive cyclization of activated alkynes with tethered ketones using Stryker s reagent as a catalyst was reported.112,90b Alkynyl ketone substrate 84a was treated with a catalytic amount of Stryker s reagent in the presence of polymethylhydrosiloxane (PMHS) to afford the cA-fused hydrindane 84b as a single diastereomer. This method is applicable to both five- and six-membered ring formation, but often suffers from competitive over-reduction of the reaction products (Scheme 59). 

The vinylsilane C-Si bond can also be formed from a silane by reductive cyclization/hydrosilylation of a 1,6- or 1,7-diyne. Reductive cyclization of diynes is an important ring-forming method catalyzed by transition metals, and silanes are common reductants in this process. However, in many cases the silane serves only as a hydride source, and the silyl group is not retained in the isolated product.95 Here, the focus is on the more rare methods which allow simultaneous C-C bond formation and vinylsilane installation. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

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