The Nitro Group in Organic Synthesis

10.2 SYNTHESIS OF INDOLES 341

3-nitroindoles in good yields.71 The regioselective synthesis of nitroindoles is important for functionalization of indoles.72

(10.53)

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of α-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford α-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73

The cyanomethylation of nitroarenes followed by alkylation and reductive cyclization yields indoles (see Chapter 9, which discusses the VNS reactions) (Eq. 10.56).74

Improvement was reported in the synthesis of 7-alkoxyindoles by reaction of alkoxynitrobenzenes with vinylmagnesium bromide (Eq. 10.57).75 This reaction proceeds via the addition of the Grignard reagent ortho to the nitro group and subsequent [3,3]sigmatropic rearrangement (Bartori indole synthesis).76 This indole synthesis is applied to a short synthesis of the pyrrolophenanthridone alkaloid hippadine, as shown in Scheme 10.8.77

OCHPh2 Ph2CHO

57%

The previously unknown 2-nitroindoles have been conveniently prepared from o-nitroben- zaldehyde via the Sundberg indole synthesis (Eq. 10.61).84

Soderberg and coworkers have developed a palladium-phosphine-catalyzed reductive N-het- eroannulation of 2-nitrostyrenes forming indoles in good yields.85 For example, reaction of 6-bromo-2-nitrostyrene with carbon monoxide in the presence of a catalytic amount of palladium diacetate (6 mol%) and triphenylphosphine (24 mol%) in acetonitrile at 70 °C, gives 4-bromoindole in 86% yield (Eq. 10.62). Several functional groups, such as esters, ethers, bromides, triflates, and additional nitro groups, have been shown to be compatible with the reaction conditions.

With the use of this methodology, 2,4-dimethylindole, 4-(hydroxymethyl)-2-methylindole, and 4-(methoxymethyl)-2-methylindole are readily obtained, as shown in Eq. 10.63.86 These indoles have been recently isolated from European Basidmycetes.87 Watanabe and coworkers have used a catalytic amount of PdCl2(PPh3)2-SnCl2 under carbon monoxide for reductive N-heterocyclization of o-nitrostyrenes.88

66%

HN

42%

Scheme 10.9.

Rawal and Kozmin have utilized a Reissert type reaction in the total synthesis of tabersonine. The requisite nitro ketone is prepared by SNAr reaction of o-nitrophenylphenyliodonium fluoride with ketone silyl enol ether (Scheme 10.10).96

The reductive cyclization of o-nitrophenylacetic acids or esters gives oxyindoles, which has been applied to preparation of 6-hydroxy-7-methoxyoxyindole in a synthesis of (+)-paraher- quamide B (Scheme 10.11).42

The pyrrolo[2,3-d]pyrimidine anticancer agent is prepared utilizing, as a key sequence, Michael condensation of 2,6-diamino-4(3H)-pyrimidinone with nitroalkenes, followed by the Nef reaction that leads to the annulated pyrrole ring (Eq. 10.67).98

Annulation of pyridine to indole is accomplished by a tandem aza-Wittig/electrocyclization strategy as shown in Eq. 10.68.99

Scheme 10.10.

10.3 SYNTHESIS OF OTHER NITROGEN HETEROCYCLES 347

cycloaddition using nitroalkenes provides an excellent route to stereoselective synthesis of pyrrolidines. This section describes the routes to the synthesis of pyrrolidines based on the Michael addition. The Michael addition of nitro compounds to α,β-unsaturated carbonyl compounds or esters followed by reduction gives pyrrolidines or related compounds. cis-2,3- Disubstituted pyrrolidines are available from nitro ketones, which are prepared by the Michael addition of nitromethane to enones. Reduction of the nitro ketones with Raney Ni gives the pyrrolines, which, on NaBH3CN reduction, give quantitative yields of cis-2,3-disubstituted pyrrolidines (Eq. 10.71).107

cis

Ruthenium complex catalyzes reductive N-heterocyclization of γ-nitroketones to give pyrroline derivatives (Eq. 10.72).108

cis-2,5-Disubstituted pyrrolidines are prepared by the Michael addition of nitro compounds to enones followed by reduction with H2-Pd/C. This strategy has been widely used for synthesis of various alkaloids. Stevens and Lee have reported stereoselective total synthesis of the tail pheromone of the Pharaoh ant (Scheme 10.12)109 and gephyrotoxin 223, neurotoxic alkaloids

NaCNBH3

N

H

Me (CH2)3CH3

68%

Scheme 10.12.

Scheme 10.13.

(Scheme 10.13).110 New alkaloids from ants, (3R, 5S, 9R)-3-butyl-5-(1-oxopropyl)indolizidine and (3R, 5R, 9R)-3-butyl-5-(1-oxopropyl)indolizidine, are identified and synthesized as outlined in Scheme 10.14.111

Battersby and coworkers have developed selective methods for total synthesis of chlorins on a model system, as shown in Scheme 10.15, in which the Michael addition of 5-(2-nitroethyl) pyrrole to enone and reductive cyclization are used as key steps.112

O

EtONa

Scheme 10.14.

Scheme 10.16.

The pyrrolizidines and indolizidines are a group of alkaloids that are characterized by the presence of the basic azabicyclo[3.3.0]octane and azabicyclo[4.3.0]nonane frameworks, respectively. These alkaloids exhibit remarkably diverse types of biological activity and have been reported to act as antitumor, hypotensive, anti-inflammatory, carcinogenic, or hepatoxic agents. Various pyrrolizidines and indolizidines have been prepared by 1,3-dipolar cycloaddition.115 Synthesis of these is described in the section 8.2 discussing cycloaddition.

An interesting strategy for the synthesis of pyrrolizidines and indolizidines has been developed by Brandi and co-workers. Cycloaddition between nitrones or nitrile oxides with methylenecyclopropanes generates strained tricyclic spiro compounds, which are prone toward

further transformations, such as rearrangement, ring opening, and new ring closure (Scheme 10.17).116

The Michael reaction of nitromethane with methyl vinyl ketone and 1-decene-3-one followed by reductive cyclization gives two isomeric pyrrolizidines, depending on reduction conditions (Eq. 10.74).117

Scheme 10.17.