Reductive cyclization nitro ketones

A recent adaptation of this type of approach involves the spontaneous intramolecular cyclization of imino ketones, formed by the reduction of nitro ketones through the action of tributylphosphine/diphenyl sulfide (Scheme 6.14). When the corresponding esters (R = OR) are used, pyrrolin-2-ones are formed (Scheme 6.15). 

In contrast to ammonia, primary, secondary, and tertiary amines can add to aldehydes and ketones to give different kinds of products. Primary amines give imi-nes and secondary amines gives enamines (10-69). This section will focus on imines. Reduction of co-azido ketones leads to the amino-ketones, which cyclizes to form a 2-substituted pyrroline. Reduction of nitro-ketones in the presence... 

Conjugated nitrones are formed by intramolecular reductive cyclizations of nitro groups onto ketones the resulting nitrones give starting materials for preparing azasteroids. An example is shown in Eq. 8.43.66... 

Condensation of methyl ketones with (3 -dimethylaminonitroethylene gives y-nitro-a,/3-unsaturated enones which can be reductively cyclized to pyrroles. This method was first applied to substituted acetophenones, giving 2-arylpyrroles (equation 84) (74CB1499, 71CB440). 

As reported in Figure 2.5, nitroolefins (26), easily obtained by nitroaldol condensation between 5-nitro ketones (24) and aldehydes (25), are converted directly into the spiroketals (29) by reduction with sodium boronhydride in methanol. The one-pot reduction-spiroketalization of nitroalkenes (26) probably proceeds via the nitronate (27) that by acidification is converted into carbonyl derivatives, which spontaneously cyclize to emiketals (28). Removal of the tetrahydropyranyl group, by heating the acidic mixture during the workup, affords, in a one-pot reaction from (26), the desired spiroketals in 64-66% overall yields. The spiroketalization of (26)-(29b) proceeds in high ( )-diastereoselectivity. 

Deoxygenation of a nitrone. Some years ago Todd and co-workers noted that 1-pyrroline-1-oxides can be obtained by reductive cyclization of a y-nitro ketone. This reaction was used recently in a synthesis of chlonns related to vitamin B,. Thus the nitro ketone 1 on reduction with zinc and acetic acid gives the pyrroline N-oxide 2 in high yield. The N-oxide is stable to triphenylphosphiue or trimethyl phosphite, but is reduced to the imine 3 in high yield by TiCl,. 

Similar reduction of a 1,4-nitro ketone results in an intramolecular cyclization to a pyrrole (equation 1). 

Reductive cyclization of 2-(t>/X t>-nitro)phenyl imidazoles 817, 819 (Scheme 203) in the presence of an orthoester or a ketone is promoted by a low-valent titanium reagent TiCU-Zn to afford imidazo[l,2-f]quinazolines 818 and 5,6-dihydroimidazo[l,2-r ]quinazolines 820 <2005JHC173>. Notably, halogens are not reduced under these conditions. 

Other synthetic applications derive from various cyclizations that occur during reduction of the substrates that contain a reactive function at a specific position. These cyclizations proceed through the intermediate imine or amine to the cyclic amine. Various functional units such as olefins, heterocyclic rings, ketones, acids, amides, amines, nitrile, and nitro have been involved. Palladium, Rh, and finely divided Ni (Raney Ni) under more vigorous conditions are commonly used. Reductive cyclization of ketonitrile 1 over Raney Ni gives myosmine 2 along with some nomicotine 3 as overreduced product ... 

If other active groups are present y or S to the reducible nitro group, hydrogenation can result in formation of nitrogen heterocyclic products. Several such cyclizations provide an entry to indoles, such as reductive cyclizations of dinitrostyrene 1 [equation (a)], of o-nitrobenzyl ketone 2 [equation (b)], and of nitro nitrile 3 [equation (c)] , all of them carried out on palladium-on-carbon. 

The sheer number of o-nitrophenyl ketone reductive cychzations to form indoles necessitates an abbreviated section of this material. It is obvious that the challenge in this methodology is the preparation of the precursor nitro ketone because its cyclization is fait accompli. Scheme 7 [48-75] illustrates a range of indoles synthesized by... 

Scheme 7 Indoles Formed by Reductive Cyclization of Nitro Ketones...

Several unusual reductive cyclizations of nitro ketones are tabulated in Scheme 11. Tilve s group anployed a double reductive cyclization to synthesize 67f-indolo[2,3-ii]... 

As alluded to earlier, the reductive cyclization of nitro ketones often leads to A-hydroxyindoles when the intermediate reduction prodnct, a hydroxylamine, undergoes cyclization. This path can be made dominant if desired. Thus, as shown in Scheme 12, several researchers have developed such a methodology. Acheson may have been the first chemist to achieve this reaction. A two-phase zinc reduction of o-nitrophenylacetaldehyde yields the unstable N-hydroxyindole, which was trapped as the more stable (distillable) A-acetoxyindole (equation 1) [85]. Wong and colleagues use a lead-promoted reductive cyclization approach to Al-hydroxyindoles in excellent yields (equation 2 and 34-37) [86]. Wojciechowski s team employed a VNS synthesis of the A-hydroxyindole precursors (equation 3) [87]. 

A new synthetic route into the piperidine series, involving reductive cyclization of 5-nitro-ketones (Scheme 25), has been used for the syn-... 

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