The Nitro Group in Organic Synthesis

5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METAL CATALYSIS 141

The monoanions of primary nitroalkanes, phenylnitromethane, and α-nitro esters are all preferentially C-alkylated by cinnamyl acetate and 2-butenyl acetate in 50–89% yield in the presence of Pd catalyst (Eq. 5.51).75 The α-nitro ester gives the C-alkylate in 89% yield, but 2-nitropropane gives the C-alkylate in only 29% yield. The main product is cinnamaldehyde, which is derived from O-alkylation.75a

+Pd(PPh3)4

Wade and coworkers have found that α-nitro sulfones are useful reagents in organic synthesis because they are converted into nitroalkanes, nitriles, or carboxylic acids (see Eq. 5.52).76

(Phenylsulfonyl)nitromethane is preferentially C-alkylated by allylic acetates in the presence of Pd(PPh3)4 (5 mol%) to give various α-nitro sulfones as shown in Eq. 5.53.76

H H O

Allylic carbonates are better electrophiles than allylic acetates for the palladium-catalyzed allylic alkylation.77 Reaction of Eq. 5.54 shows the selective allylic alkylation of α-nitro ester with allylic carbonates without affecting allylic acetates.78

(5.54)

5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METAL CATALYSIS 143

Rajappa and co-workers have reported synthesis of dipeptides with an α,α-bisallylglycine residue at the NH2-terminal, which are biologically important.83 Their strategy is based on (1) nitroacetylation of an amino acid derivative, (2) regioselective bisallylation by Pd-catalyzed reaction, and (3) generation of the free terminal NH2 from the NO2 group as shown in Scheme 5.8. Esters of L-proline, L-valine, and L-phenylalanine are converted into the corresponding N-nitroacetyl derivatives using 1,1-bis(methylthio)-2-nitroethylene84 (see Section 4.2, Michael addition). Subsequent palladium-catalyzed allylation followed by reduction with Zn in AcOH gives the desired dipeptides.

Ph OAc

O N

DBU, Pd(PPh3)4

PhH2CO2C

95%

Scheme 5.8.

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85

Scheme 5.9.

144 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

Scheme 5.10.

1,4-cis-Disubstituted cyclopentene precursors of carbocyclic nucleosides are prepared by acyl-nitroso hetero Diels-Alder reaction and subsequent Pd(0)-catalyzed allylic alkylation. Acylnitroso dienophiles derived from amino acids are used for asymmetric hetero Diels-Alder reaction. The alcohol in Scheme 5.10, prepared by this route,86 is converted into the corresponding nitromethyl group by Pd(0)-mediated alkylation.87 Removal of the L-alanine side chain followed by the Nef reaction leads to an important intermediate for the preparation of carbovir, aristermycin, and related analogs, which show potent and selective anti-HIV activity.88a A short, enantioselective synthesis of the carbocyclic nucleoside carbovir is also reported, in which the reaction of Pd catalyzed allylation of nitro compounds is used in a key step.

Miller and coworker report a total synthesis of carbocyclic polyoxin C from cis-(N-tert- butylcarbamoyl)cyclopent-2-en-1-ol, as shown in Scheme 5.11.89 This synthesis features a

O

HO OH

Scheme 5.11.

146 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

Scheme 5.13.

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphinoxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereoand enantioselective allylation of substituted nitroalkanes has also been reported.95b

(5.62)

148 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

are summarized. 1-Nitronaphthalene reacts with the anion of nitromethane to give the nitromethylated product, as shown in Eq. 5.64.102 Suzuki and coworkers have extended this reaction to m-dinitrobenzene (Eq. 5.65). Although the reaction proceeds slowly, this is the first example of nitromethylation of monocyclic nitrobenzenes. The reaction of Eq. 5.64 requires additional oxidizing agents to complete the reaction, but that of Eq. 5.65 does not need the external oxidizing agents.103

In general, heterocyclic nitro compounds undergo cine substitution reactions more readily than nitrobenzenes. For example, the reaction of 5-acyl- or 5-alkoxycarbonyl-2-nitrofurans with the anion of nitroalkanes gives cine substitution products in excellent yields (Eq. 5.66).104

O

O

90%

The reaction of 1,2-dimethyl-5-nitroimidazole with 2-nitropropane anion gives the new highly branched imidazole derivative, which is formed via cine-substitution and SRN1 substitution (Eq. 5.67).51b

Me

Barton and coworkers have explored the arylation of various nucleophiles including nitroalkanes using bismuth reagents.105 Reaction of 2-nitropropane with triphenylbismuth carbonate gives 2-nitro-2-phenylpropane in 80% yield.106 Recently, this arylation has been used for the synthesis of unusual amino acids. Arylation of α-nitro esters with triphenylbismuth dichloride followed by reduction gives unique α-amino acids (Eq. 5.68).107

Me O

77%

150 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS

Scheme 5.15.

simple, except for fluorination. The widespread interest in halogenated nitro compounds mainly stems from their antimicrobial and insecticide activities.116b

The reaction of α-bromo or α-iodonitroalkanes with sodium benzenesulfinate gives α-nitro sulfones in 85–95% yields (Eq. 5.73), which proceeds via SRN1 reaction (Section 5.4).117

α-Nitrosulfones react with various nucleophiles to give the SRN1-alkylated products, as discussed in Section 5.4. α,α-Dinitro compounds, α-nitrosulfones, and α-nitronitriles are prepared in excellent yields when nitroalkane salts are coupled to nitrite, benzensulfinate, and cyanide ions in the presence of potassium ferricyanide (Eqs. 5.74 and 5.75) (see Section 5.4).

Bowman has surveyed the reactions of α-substituted aliphatic nitro compounds with nucleophiles, which undergo either SRN1 substitution or polar reaction (Scheme 5.16).118 The reactions

electrophilic center, and only Me2S attacks the carbon electrophilic center.

Bromonitromethane is used for the preparation of nitrocyclopropane. The reaction of N-benzylmaleimide and bromonitromethane in the presence of base gives the azabicyclo[3.1.0] hexane ring system. Many bases have been tried to improve the yield; however, amidine base, particularly 1,2-dimethyl-1, 4, 5, 6-tetrahydropyrimidine (DMTHP), gives the best yield

Scheme 5.16.