Disubstituted pyrroles intermediate

The [,4 + 2] cycloaddition of dienophiles with 1-substituted pyrroles is also a reversible reaction, which has been utilized in the synthesis of 3,4-disubstituted pyrroles (b-77MI305oq) and, via the initial reaction of the pyrrole with benzyne, for the synthesis of isoindoles (81 AHC(29>341). The retro-reaction can be controlled and aided by a 1,3-dipolar cycloaddition of the intermediate adduct with benzonitrile oxide (74TL2163, 76RTC67) (Scheme 61). 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

Aza-l, 3-l i5(triphenylphosphoranyhdene)propane (24), a novel syn-thon, was prepared in situ by reaction of the iminophosphorane (21) with methylenetriphenylphosphorane (22) followed by treatment of the intermediate (23) with n-butylhthium. Reaction of yhde (24) with dialdehydes (e.g., 25) or diketones (e.g., 26) gave good yields of 3H-2-benzazepine (27) and 2,3-disubstituted pyrroles (28a—c), respectively (Scheme 8) (1994JOC4551). 

Reported examples of the second reaction occur at the j8-position in an a,a -disubstituted pyrrole. Whilst for the second reaction there is no evidence to indicate the intermediate formation of ethyl methylenemalonate, followed by Michael addition, pyrroles can participate in such additions. Examples are the ready reaction with ethynyl ketones , with quinones" and with acrylic esters (in the presence of boron trifluoride etherate)" ... 

Padwa and coworkers realized the synthesis of 2,4-disubstituted pyrroles using rearrangements of 2-fiiranyl carbamates via 5-methoxy-3-pyrrolin-2-one intermediates. 2-Furanyl carbamate 593 was treated with iodine and sodium bicarbonate followed by methyl iodide and silver oxide to give the N-substituted 5-methoxy-3-pyrrolin-2-one 595 via the iodinated intermediate 594 (Scheme 173 20090L1233). Padwa employed this method to synthesize 5-methoxypyrrol-2-ones, which were then treated with alkyl hthiates to give tricycHc products (2009T6720). 

Crabtree and co-workers discovered the dehydrogenative Paal-Knorr synthesis the reaction of 1,4-diols with primary amines in the presence of a Ru diphosphine diamine complex at 125 °C to afford 2,5-disubstituted pyrroles (Scheme 12.37)." Kempe and Milstein developed dehydrogenative conditions for the synthesis of pyrroles via C-N and C-C coupling of alcohols with vicinal amino alcohols (Scheme 12.37). These reactions require the use of KOfBu, which may facilitate a-deprotonation of the intermediate imine. 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

A proposed trimerization of disubstituted cyanamides occurs during the reaction of cyanogen chloride with diphenylamine the supposed intermediate diphenylcyanamide should trimerize to give hexaphenylmelaminc.232 There is a similar reaction when cyanogen chloride is treated with pyrrole.233... 

Perhaps the most important new development in the ac-biladiene route has been the synthesis of discrete unsymmetrical tripyrrene intermediates. Russian workers had shown that a,a -disubstituted pyrromethanes could be condensed successively with one and two formyl pyrrole units to form first a tripyrrene and then a symmetrical ac-biladiene, which could be cyclized to porphyrin. The Liverpool group, however, showed that by use of unsymmetrical differentially protected pyrromethane diesters, condensation could be effected with two different formyl pyrroles to yield first tripyrrenes and then unsymmetrical ac-bi-ladienes. Cyclization of the latter afforded unsymmetrically substituted porphyrins. This procedure represents the first truly stepwise rational porphyrin synthesis, as exemplified by the synthesis of isocoproporphyin (26) (cf. Scheme... 

Pyrroles and indoles react readily with aldehydes and ketones. The initially formed carbinol usually generates a reactive intermediate, which is attacked by another equivalent of substrate to yield a disubstituted methane. The reliable synthesis of aryldipyrromethanes from the direct... 

Both 1-methylpyrrole and 1-methylindole can be easily lithiated and the resulting intermediates have been used extensively in synthesis. The range of electrophiles which can be used with lithiated pyrroles and indoles is quite broad. Aldehydes and ketones give carbinols. A,A-Disubstituted formamides give aldehydes. Carbon dioxide and alkyl chloroformates have been used to make carboxylic acid derivatives. Alkyl halides, sulfates and sulfonates can be used to introduce alkyl groups. Interestingly, even t-butyl bromide has been used successfully for alkylation (see entry 3, Table 7). Some examples are given in Table 7. 

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