The Nitro group in organic sysnthesis - Feuer

330 SYNTHESIS OF HETEROCYCLIC COMPOUNDS

pyrroles with various substituents (R1 and R2) at the β-positions. The limitation of this reaction is that pyrroles unsubstituted in the 2-position, cannot be prepared. The yields are generally excellent (80–90%), but the yield is moderate, if R1 is H. Nonionic strong bases such as DBU and guanidine are generally used in the Barton-Zard reaction.

H

52%

The reaction pathways for the pyrrole formation are summarized in Scheme 10.3. The group that is eliminated at the final stage is a nitrite ion (Barton-Zard reaction) or a toluenesulfinate ion (Leusen reaction), depending on the reaction pattern.

Benzyl isocyanoacetate is a useful reagent for the preparation of benzyl 5-unsubstituted pyrrole-2-carboxylates, which are widely used in the synthesis of porphyrins.23 Ono and coworkers have prepared pyrroles substituted with various substituents at the β-positions.23a Because the requisite β-nitro acetates (or nitroalkenes) are readily available by the Henry

N

N H

Scheme 10.3.

10.1 PYRROLES 331

reaction, various substituents are easily introduced into the 3- and 4-positions of pyrroles (Eqs. 10.20 and 10.21).

H

82%

The Barton-Zard pyrrole synthesis has now been extensively applied to synthesis of natural and unnatural products containing pyrrole units. Methyl 4-methylpyrrole-2-carboxylate is the trail-maker pheromone of the Texas leaf-cutting ant Atta texana.24 It is readily prepared by the Barton Zard method in 60% yield (Eq. 10.22).22

Pyrrolostatin is a novel lipid peroxidation inhibitor, which is isolated from Streptomyces chrestomyceticus. Its structure consists of a pyrrole-2-carboxylic acid with a geranyl group at the 4-position. It is readily prepared by applying the Barton-Zard pyrrole synthesis, as shown in Eq. 10.23.24

Many other biologically active pyrroles have been prepared by this reaction. 2-Cyano-3,4- disubstituted pyrroles are prepared by the reaction of isocyanoacetonitrile with β-nitro acetates.

332 SYNTHESIS OF HETEROCYCLIC COMPOUNDS

This is used for synthesis of porphobilinogen (Eq. 10.24).25 Porphobilinogen is the key building block in the biosynthesis of pigments of life such as porphyrins, heme, and vitamin B12. Interesting application of porphobiliogen to synthesis of immunocomponents for the measurement of lead (Pb) by fluorescence polarization immunoassay has been reported.26

Total synthesis of (+)-deoxypyrrolorine, a potential biochemical marker for diagnosis of osteoporosis, is shown in Eq. 10.25.27 Osteoporosis is a crippling degenerative bone disease that affects the aged population, particularly postmenopausal women.

CO2H

Total synthesis of phytochromobilin starting from 2-tosylpyrroles, which are prepared by β-nitro acetates with TosMIC (Scheme 10.4) has been reported.28 Phytochrome is a chromoprotein concerned in a variety of processes in higher plants such as growth, development, and morphogenesis.29

Barton-Zard pyrrole synthesis is also applied to synthesis of pyrroles with a variety of substituents. Pyrroles substituted with long alkyl substituents at the 3 and 4 positions,30 pyrroles with β-CF3 (Eq. 10.26),31 3,4-diarypyrroles (Eq. 10.27),32 and pyrrole-2-phophonates (Eq. 10.28)33 are prepared in a similar manner based on isonitrile cyclization.

60%

Nitroalkenes derived from galactose or other carbohydrates are converted directly into pyrroles substituted with such carbohydrates at the β-position. They are important precursors for water-soluble porphyrins (Eq. 10.29).34 Such kinds of porphyrins are good candidates for photodynamic therapy of cancer and have been extensively studied.

63%

334 SYNTHESIS OF HETEROCYCLIC COMPOUNDS

Aida and coworkers have used the Barton-Zard reaction in the synthesis of axially dissymmetric pyrroles as shown in Eq. 10.30.35

The combination of the Diels-Alder reaction of β-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons (Eq. 10.31).36 Pyrroles fused with bicyclo[2.2.2]octodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction (Eq. 10.32).37

For example, 2,7-diformylisoindole is obtained in quantitative yield by heating the corresponding pyrrole fused with bicyclo ring. Certain aromatic nitro compounds are reactive enough to undergo the Barton-Zard reaction. For instance, polycyclic aromatic nitro compounds are generally reactive toward the anion of ethyl isocyanoacetate to give pyrroles fused with polycyclic aromatic rings, as shown in Eqs. 10.33 and 10.34.38

CNCH2CO2Et

(10.33)

87%

Monocyclic nitro aromatics such as m-dinitrobenzene and its derivatives also react with ethyl isocyanoacetate to give the corresponding isoindoles (Eq. 10.40).44

Polymer-supported reagents and other solid sequestering agents may be used to generate an array of 1,2,3,4-tetrasubstituted pyrrole derivatives using the Barton-Zard reaction as a key pyrrole formation reaction. Pure pyrroles are obtained without any chromatographic purification steps.45

Nitroalkenes can be replaced by α,β-unsaturated sulfones in the Barton-Zard pyrrole synthesis. Each method has its own merit. Nitroalkenes are more reactive than α,β-unsaturated sulfones; therefore, nitroalkenes should be used in less reactive cases. On the other hand, cyclic α,β-unsaturated sulfones are more easily prepared than cyclic nitroalkenes; pyrrole synthesis using sulfones is the method of choice in such cases, as shown in Eq. 10.41.46

Pyrroles prepared by the Barton-Zard reaction are very important as precursors of porphyrins and also of conducting polymers. The ester group at the 2-position is readily removed on heating

with KOH in ethylene glycol at 170 °C to give α-free pyrroles, which are useful for preparing porphyrins (Eq. 10.42)47 or polypyrroles (Eq. 10.43).38a,48

20%

In 1988, Ono and Maruyama reported a very simple synthesis of octaethylporphyrin (OEP) from 3,4-diethylpyrrole-2-carboxylate, as shown in Eq. 10.44.49 Reduction of this pyrrole with LiAlH4 gives 2-hydroxyethylpyrrole, which is converted into OEP on treatment with acid and an oxidizing agent. This route is very convenient for synthesis of porphyrins. This method is now used extensively for synthesis of β-substituted porphyrins.50 For example, a highly conjugated porphyrin, shown in Eq. 10.45, has been prepared by this route.51 The requisite pyrroles are prepared from nitro compounds or sulfones; thus, various substituents are readily introduced into porphyrins.

Reduction of nitrostyrene with aqueous TiCl3 gives a 3,4-diarypyrrole directly in moderate yield (Eq. 10.46).52 The reaction proceeds via dimerization of anion radicals of nitrostyrene and reduction of the nitro function in the dimer to imines. Reduction of dinitrile with diisobutylaluminum hydride (DIBAL) gives α-free pyrroles (Eq. 10.47);53 both reactions may proceed in a similar mechanism. These pyrroles are useful intermediates for functionalized porphyrins.