Cathodic cyclizations

The cathodic cyclization of several types of A -(5-oxoalkyl)pyridinium salts in 1 M sulfuric acid afforded quinolizine derivatives. For example, compound 256, prepared from 4-methylpyridine, gave a diastereomeric mixture of quinolizines 257 and 258. Differential pulse polarographic studies allowed a mechanism to be proposed, which is outlined in Scheme 53 <2003EJ02919>. 

Scheme 21 Cathodic cyclization of unsaturated esters yield (alcohol) 60%, yield (TMS ether) 67%.

Scheme 28 Cathodic cyclization of unsaturated acids in the presence of triphenyl phosphine alkyl, H, aryl, R H, aryl, yields 11 -49%.

Scheme 34 Cathodic cyclization of unsaturated ketones R alkyl, yields 75-98%.

Scheme 36 Intramolecular cathodic cyclization of ketones with aryl rings R alkyl, yields 21-74%.

It is worth noting that anodic oxidations often give electrophilic and/or acidic centers, whereas cathodic reductions lead to nucleophihc and/or basic centers. Moreover, we must keep in mind that the mechanisms of many anodic and cathodic cyclizations are not accurately known. 

Cathodic cyclizations also involve various reactive intermediates. 

Scheme 62 Cathodic cyclization of N-keto a Iky I pyridinium salts.

Scheme 72 Butenolides hy cathodic cyclization of allene and ketone.

Scheme 83 Benzo[c]cinnoline by cathodic cyclization of 2,2 -dinitrobiphenyl.

An electrochemical synthesis of apor- derivatives [85]. phines via cathodic cyclization of iodo benzylisoquinolinium salts has been re-... 

Diastereoselective cathodic cyclizations Cathodic reductions of 1-substituted-of l-(4-oxoalkyl) and l-(3-oxoalkyl) 3-nicotinamides (1-methylnicotinamide,... 

Scheme 152 Aporphine by cathodic cyclization of a iodobenzylisoquinolinium salt. O...

Fig. 21 Regio- and stereoselective cathodic cyclization of a 4-oxoalkyl pyridinium salt [114, 115].

Scheme 69 Nickel-catalyzed cathodic cyclization of unsaturated ethers.

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. 

When cyclization occurs between an electron-deficient allene and a ketone, as is the case with 27, butenolides are produced [19]. Given the importance of this functional group in cardiac glycoside natural products, the simplicity of the starting materials, and the facility of the cathodic cyclization, it may be worth noting the opportunity to utilize this transformation in the construction of these natural products. 

The transformation has been employed extensively in the preparation of precursors to a number of natural products (note Schemes 10-15), including, guaiazulene (148), dihydrojasmone (150), rosaprostol (155), and convergent syntheses of ( — )-valeranone (159), hirsutene (162), and A -capnellene (167) [57]. The key cathodic cyclization step is illustrated for each natural product. 

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... 

Given the large number of tandem cyclization processes that have been explored [63], it is disappointing to note that so few have been promoted electrochemi-cally. There appears to be a significant opportunity for additional exploration. Two tyiws of tandem cathodic cyclizations are discussed below. The first involves generation of a ketyl, and its subsequent cyclization onto a pendant alkene to afford a new radical that closes onto a second alkene [64,65]. The second focuses on chemistry not yet discussed involving the reductive cyclization of enol phosphates of 1,3-dicarbonyl compounds [66]. 

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. 

The Use of Anodically Generated Intermediates for Promoting Cathodic Cyclizations... 

The synthesis of iminium salt 85 by soda-lime pyrolysis through an intermediate enamine (83CJC2016) is inferior to that of salt 60 (Scheme 16). Cathodic cyclization of l-(E-oxoalkyl)pyridinium salts gives dia-stereomeric hydroxy compounds 86 and 87 in yields of 14-16% each (95AGE2007). 

Another superior synthesis of aporphines is that devised by Neumeyer and Gottlieb it proceeds through the cathodic cyclization of a l-(o-iodobenzyl)iso-quinoline methiodide (Scheme 5). Electrolysis of (34) followed by reduction gave rise to 10,11-dimethoxyaporphine (35). Aporphine itself has also been prepared, by a parallel route.3... 

The cathodic cyclization of 5-enones leads regio- and stereoselectively to cyclo-pentanols (Eqs. 22, 23) [161]. The reduction of the non-conjugated dienone affords in a tandem reaction a bicyclic alcohol (Eq. 24) [162]. 

C. Cathodic Cyclizations Involving at Least One Tosylate Function.. . . 559... 

Intramolecular cathodic cyclization of dithiocarboxylic esters was studied the cathodic reduction of (175) was found to give the benzothiepine (176) as shown (Scheme 30) <92CBI27>. 

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