The Nitro Group in Organic Synthesis

5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS 133

Ring enlargement of α-nitrocycloalkanones has been extensively used for the synthesis of macrocyclic compounds, as exemplified in Eq. 5.22.37

(5.22)

The retro-Henry reaction of 2-nitrocycloalkanols gives ω-nitro ketones, as shown in Eq. 5.23.38

5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS

The ability of a nitro group in the substrate to bring about electron-transfer free radical chain nucleophilic substitution (SRN1) at a saturated carbon atom is well documented.39 Such electron transfer reactions are one of the characteristic features of nitro compounds. Kornblum and Russell have established the SRN1 reaction independently; the details of the early history have been well reviewed by them.39 The reaction of p-nitrobenzyl chloride with a salt of nitroalkane is in sharp contrast to the general behavior of the alkylation of the carbanions derived from nitroalkanes; here, carbon alkylation is predominant. The carbon alkylation process proceeds via a chain reaction involving anion radicals and free radicals, as shown in Eq. 5.24 and Scheme 5.4 (SRN1 reaction).40

Scheme 5.4. SRN1 reaction.

134 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

SRN1 reactions using related p-nitrophenyl or p-nitrocumyl systems41 as reductive alkylating agents have been studied by Kornblum and co-workers; these are well summarized in the reviews.39 At the same time, Russell discovered the SRN1 reaction of geminal halonitroalkanes with stabilized carbanions (see Eq. 5.25).42 The products are readily converted into alkenes via elimination of nitro groups (see Section 7.3).

The cyano group is also a good electron acceptor for SRN1 substrates, as shown in Eq. 5.2643 and Eq. 5.27,44 but a nitro group is a better electron acceptor than a cyano group.

Geminal dinitro compounds,45 α-nitro sulfones,46 α-nitro esters,47 or α-nitro nitriles48 react with anions derived from nitroalkanes to give the SRN1 products, as shown in Eqs. 5.28, 5.29, 5.30 and 5.31, respectively (Section 7.1).

70%

The anion of nitromethane is particularly reactive in SRN1 reactions. Various kinds of tertiary nitro groups are replaced by a nitromethyl group on treatment with the anion of nitromethane (Section 7.1).49 2-Iodoadamantane reacts with the anion of nitromethane in the presence of acetone enolate (entrainment reaction) under irradiation of a 400-W UV lamp to give 2-ni- tromethyladamantane in 68% yield, (see Eq. 5.32).50a 1-Iodoadamantane also reacts with the anion of nitromethane in a similar way.50b

Crozet and co-workers have used SRN1 reactions for synthesis of new heterocycles, which are expected to be biologically active (see also Section 7.3, which discusses synthesis of alkenes). For example, 2-chloromethyl-5-nitroimidazole reacts with the anion of 2-nitropropane to give 2-isopropylidene-5-nitroimidazole. It is formed via C-alkylation of the nitronate ion

followed by elimination of HNO2 (Eq. 5.33).51a Other derivatives of nitroimidazoles are also good substrates for SRN1 reactions.51b,c

Reactions of nitrothiazole derivatives with anions of nitroalkanes, such as shown in Eq. 5.34, proceed via a SRN1 mechanism.52

The anion derived from ethyl 2-nitropropionate reacts with various reductive alkylating agents (SRN1 substrates) to give new unsymmetrically disubstituted nitro esters (Eq. 5.35), which are interesting precursors for unusual amino acids.53

70%

136 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

Gem-nitro imidazolyl alkanes undergo SRN1 reactions with the anion of various nitroalkanes, as shown in Eq. 5.36.54 The nitro group is replaced by hydrogen in 80–90% yield on treatment with Bu3SnH (see Chapter 7, which discusses radical denitration).

SRN1 reactions are generally accelerated by irradiation with tungsten lamps (200–500 W) or fluorescent lamps. They are retarded in the presence of oxygen or other radical inhibitors. Recently, microwave irradiation has been shown to be effective in inducing SRN1 reactions; the reaction of Eq. 5.37 proceeds under microwave irradiation (900 W, 5 min) in the presence of trace amounts of water.55

(5.37)

Alkyl mercury halides participate in a photo-stimulated radical chain reaction of the anion of nitroalkanes (see Eq. 5.38) in which a 275-W sun lamp is used.56a–c Primary, secondary, and

tertiary alkyl radicals generated from alkyl mercury halides react with the anion of nitroalkanes to form new C-C bonds.

Branchaud and coworkers have used cobaloximes as alkyl radical precursors for the cross-coupling reaction with nitronates.57 This method is very useful for producing branchedchain monosaccharides, as shown in Eq. 5.39.57b

Martin and coworkers have used this strategy for synthesis of α- and β-(1,6)-linked C-disaccharides (Eq. 5.40).58

5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METAL CATALYSIS 139

Scheme 5.5. Catalytic cycle in the palladium-catalyzed telomerization of 1,3-butadiene

telomerization of 1,3-butadiene is shown in Scheme 5.5; a wide range of H-X trapping reagents (X = nucleophilic carbon, oxygen, nitrogen, or sulfur) are used.69

When nitromethane is used as a trapping reagent in the telomerization of butadiene using Pd(OAc)2 and Ph3P, mono-, diand trialkylated compounds of nitromethane are formed (Eq. 5.47).70 They are selectively formed by changing the ratio of nitromethane and butadiene. As the nitro groups are transformed into various functional groups, the reaction of Eq. 5.47 is very useful in organic synthesis.

Butadiene telomerization using nitroethane as a trapping reagent is applied to the total synthesis of the natural product, recifeiolide, where the secondary nitro group is converted into the ketogroup by the Nef reaction, and the terminal double bond is converted into the iodide via hydro alumination (Scheme 5.6).71

Extension to carbocyclization of butadiene telomerization using nitromethane as a trapping reagent is reported (Eq. 5.48).72 Palladium-catalyzed carbo-annulation of 1,3-dienes by aryl halides is also reported (Eq. 5.49).73 The nitro group is removed by radical denitration (see Section 7.2), or the nitroalkyl group is transformed into the carbonyl group via the Nef reaction (see Section 6.1).

73%

140 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

I

70%

O O

I

82%

Scheme 5.6. Synthesis of recifeiolide

Nitronate anions react with (π-allyl)cobalt complexes prepared from acylation of 1,3-dienes by acetylcobalt tetracarbonyl to produce nitro enones (Eq. 5.50).74

5.5.2 Pd-Catalyzed Allylic C-Alkylation of Nitro Compounds

The palladium-catalyzed allylic alkylation of soft nucleophiles (Tsuji-Trost reaction) represents one of the most useful organic transformations. Various allylating reagents and nucleophiles can participate in this reaction, as summarized in Scheme 5.7. Although allyl acetates, allyl carbonates, or 1,3-dienemonoepoxides are generally used as alkylating reagents, allylic nitro compounds also can be used as alkylating reagents (see Section 7.1). Active methylene compounds are generally used as nucleophiles in Tsuji-Trost reaction. Nitroalkanes, α-nitro ketones, α-nitro esters, and α-nitro sulfones can be also used as nucleophiles for this transformation.

X = OAc , OC(O)OR, SO2Ph, NO2, OP(O)(OR)2, NR2, SR, etc.

NuH = CH2(CO2R)2, CH2(CN)CO2R, CH2(SO2Ph)CO2R, CH2(NO2)CO2R, CH2(NO2)SO2Ph,

CH2(SO2Ph)2, etc.

Scheme 5.7. Pd(0) catalyzed allylic alkylation