Cyclization reactions cathodic

Cathodic cyclization reactions have supphed and continue to provide a fertile territory for the development and exploration of new reactions and the determination of reaction mechanism. Two areas that appear to merit additional exploration include the application of existing methodology to the synthesis of natural products, and, more significantly, a systematic assessment of the factors associated with the control of both relative and absolute stereochemistry. Until there is a solid foundation to which the non-electrochemist can confidently turn in evaluating the prospects for stereochemical control, it seems somewhat unlikely that electrochemically-based methods will see widespread use in organic synthesis. Fortunately, this comment can be viewed as a challenge and as a problem simply awaiting creative solution. 

Kariv-Miller and coworkers have developed indirect electroreductive cyclizations with the dimethyl-pyrrolidinium ion (DMP") as a mediator. Preparative electrolysis of 6-hepten-2-one (9) at a graphite cathode afforded cu-dimethylcyclopentanol (10) in 90% yield (equation 5). The reduction is believed to occur via the ketyl radical anion, which cyclizes onto the alkenic bond. In the absence of DMP simple reduction to 6-hepten-2-ol takes place.Very recently it was shown that instead of DMP several aromatic hydrocarbons can be used as mediators to initiate the cyclization reaction. The carbonyl group can also be cyclized onto an alkynic bond and even an aromatic ring. - ... 

The principle of contrast enhancement by photobleachable layers has been known in photography for quite a long time. New formulations were developed for application in lithography and used for the production of cathode ray tubes More recently, a family of arylnitrones have been investigated and described as effective contrast-enhancing materials (CEM) for use in IC-lithography The photochemical reaction which occurs is a cyclization reaction ... 

For cases directly comparable to the cyclization originating from (27) above, the yields of the product were not as high. However, a related reaction used in the synthesis of an 11-substituted dibenzo[a,d]-cycloheptenimine derivative was very successful as shown in Scheme 11 (Eq. 2) [32]. In this reaction, a controlled potential electrolysis of (33) led to the formation of the tetracyclic (34) in an 85% isolated yield. The reaction was performed on a 1 g scale using an undivided cell, a graphite felt anode, a stainless steel cathode, a saturated calomel reference electrode, and a 1% NaBF4 in 70 30 THF/water electrolyte solution. The electrolysis was scaled up further with the use of a flow cell. In this experiment, 200 g of (33) were oxidized in order to afford a 75% isolated yield of (34). 

Electroreduction of y- and 5-cyano ketones in isoPrOH with a Sn cathode gave a-hydroxyketones with good diastereo-selectivities as cyclization products. The reaction has been used as a key step for the synthesis of, for example, guaiazulene, triquinanes, and dihydrojasmone. Similarly, the corresponding intermolecular couplings were realized [315]. 

In this article we address cyclizations that are initiated by reduction at a cathode. A wide variety of ring systems have been constructed in this manner. Given its importance in the development of organic electrochemistry, it is appropriate to begin our discussion with the electrohydrocyclization (EHC) reaction pioneered in the 1960s by Baizer and co-workers [8-10]. 

As noted previously, many of the cathodic cyclizations discussed in this article are variations on the electrohydrocyclization theme developed by Baizer and coworkers [8-14,16,17,21], The next section of this article, for example, deals with what has been referred to as the electroreductive cyclization (ERC) reaction, a process that leads to cycUzation between an electron-deficient alkene and an aldehyde or ketone. With this thought in mind, several of the section titles are formulated to highlight the functional groups to be joined the following is representative. 

Pyridinium salts tethered to ketones also undergo cathodic cyclization [1]. The reaction provides a convenient diastereoselective route to quinolizidine and indolizidine derivatives such as 203, 204 and 206, 208, and 209, and appears to hold significant promise as a route to alkaloids. Examples are portrayed and the optimal conditions are listed below the equations. A mercury cathode is preferred, as passivation occurs when lead is used, and the reaction does not occur... 

The direct reduction of haloalkynes using either mercury or vitreous carbon as the cathode has been examined in considerable detail [80-84] one example is portrayed in Eq (77). The influence of reduction potential, current consumption, proton donor, electrode, and substrate concentration on the course of the process has been examined. Vitreous carbon electrodes are preferred, though mercury has been used in many instances. Unfortunately, these reactions suffer from the formation of diorganomercurials. While both alkyl iodides and bromides can be used, the former is generally preferred. Because of their higher reduction potential, alkyl chlorides react via a different mechanism, one involving isomerization to an allene followed by cyclization [83]. 

In order to illustrate the application of LSV in mechanistic analysis we can look at the redox behavior of the formazan-tetrazolium salt system which we studied some years ago [17], 1,3,5-Triphenyl formazane was oxidized at controlled potential in CH3CN-Et4NC104 solution to 2,3,5-triphenyl tetrazolium perchlorate which was then isolated in quantitative yield. Coulometry showed that the overall electrode reaction was a two-electron oxidation. It has been shown that the rate of variation of Ep with log v was 30 mV per decade of sweep rate and that there was no variation of the peak potential with the concentration of 1,3,5-triphenylformazan. According to Saveant s diagnostic criteria (Table 1), four mechanistic schemes were possible e-C-e-p-p, e-C-d-p-p, e-c-P-e-p and e-c-P-d-p. If cyclization is the rate-determining step, then the resulting e-C-e-p-p and e-C-d-p-p mechanisms would not imply variation of Ep with the concentration of base. However, we have observed the 35 mV shift of Ep cathodically in the presence of 4-cyanopyridine as a b e. These observations ruled out the first two mechanisms. The remaining possibilities were then e-c-P-e and e-c-P-d, as shown in Scheme 3. 

A series of bicyclo[3.3.0]octanols are accessible by electroreductive tandem cyclization of linear allyl pentenyl ketones 189, as shown by Kariv-Miller et al. [189]. The electrolyses are carried out with an Hg-pool cathode and a Pt-flag anode. As electrolyte, tetrabutylammonium tetrafluororborate is used. The reaction is stereoselective, yielding only two isomers 192 and 193. In a competing reaction, a small amount of the monocyclic alcohol is formed. Since all the monocycles have the 1-allyl and the 2-methyl group in trans geometry it is assumed that this terminates the reaction. The formation of a bicyclic product requires that the first cyclization provides the cis radical anion which leads to cis-ring juncture [190] (Scheme 37). 

The intramolecular reaction of activated alkenes of the type 8 leads to the formation of 5- or 6-membered rings [26] and has been carried out only at a mercury cathode in a divided cell. In these processes, the activated alkene radical-anion is formed at a less negative potential than that required for cleavage of the carbon-bromine bond. Cyclization then occurs by nucleophilic substitution. 

Radical intermediates are also trapped by intramolecular reaction with an alkene or alkyne bond. At a mercury cathode this process competes with formation of the dialkylmercury [51], At a reticulated vitreous carbon cathode, this intramolecular cyclization of radicals generated by reduction of iodo compounds is an important process. Reduction of l-iododec-5-yne 5 at vitreous carbon gives the cyclopentane... 

Reductive cyclizations were reported by Shono as early as 1971. The success of the reaction is highly dependent on the nature of the cathodic material. Carbon rod has been found to give both high yields and diastereoselectivities. See T. Shono and M. Mitani, J. Am. Chem. Soc., 93, 5284 (1971) T. Shono, I. Nishiguchi, H. Ohmizu, and M. Mitani, J. Am. Chem. Soc., 100, 545 (1978). 

Reverse annulation reactions of bromoacetaldehyde cyclohexenyl acetals 261 catalyzed by 255 using NaBUt as the stoichiometric reducing agent provided bicycles 262 in 40-71% yield (Fig. 64, entry 5) [314, 315]. Cathodic reduction at — 1.8 V was also successfully applied to regenerate 255 or vitamin B12 247 in radical 5-exo cyclizations of 261 under optimized conditions (entry 6) [316, 317]. Less than 10% of the cyclic reduced products 263 were detected. 

Hisaeda and coworkers subsequently reported radical (macro)cyclizations of oo-bromoalkyl acrylates 300 catalyzed by modified vitamin B12 301a under photo-lytic conditions (Fig. 71) [334], The active Co(I) catalyst is generated by electroreduction at platinum cathodes and subsequently substitutes the halide in 300. The resulting organocobalt(III) intermediate was characterized by UV and MS techniques in the dark. Photolysis triggers 6-endo, 10-endo, or 16-endo cyclizations affording the products 302 in 95, 15, and 43% yield, respectively. The reaction was inhibited by addition of the radical trap PBN 303 and the derived radical adducts were detected by ESR-spectroscopy. 

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