Pyrroles reaction with aldehydes

The condensation of 2,5-diunsubstituted pyrroles with formic acid20 is a viable method to produce porphyrins. However, the most common procedure21 22 involves the heating of the corresponding pyrroles 1 with aldehydes and aldehyde derivatives like imines or a Mannich reagent in the presence of acid. The reaction is initiated by electrophilic attack of the aldehyde (or aldehyde derivative) to the pyrrole 1. The formed (hydroxyalkyl)pyrrole 3 then undergoes electrophilic substitution with another pyrrole to form a dipyrrylmethane 4. Repeated addition of aldehyde and pyrrole finally forms a tetrameric (hydroxyalkyl)bilane 5. 

The acid-catalyzed addition of aliphatic ketones to 2,3,4- or 2,3,5-trisubstituted pyrroles generally produces bispyrrolylalkanes, analogous in structure to the products of the corresponding reactions with aldehydes, whereas 2,5-disubstituted pyrroles react with acetone to form a 2 3 adduct (113). Pyrrole and 3,4-disubstituted pyrroles react with aliphatic ketones to give porphyrinogens (114), which, unlike the macrocycles obtained from the... 

Likewise, pyrroles are accessible if in the last cyclocondensation step a primary amine is applied. Therefore, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of primary amines 96 or ammonium chloride and glacial acetic acid, the 1,2,3,5-tetrasubstituted or 2,3,5-trisubstituted pyrroles 97 are obtained in good yields in a one-pot procedure (Scheme 52) [259, 260]. 

Reaction with Aldehydes and Ketones. The pyrryl carbinols can also be synthesized by another approach the reaction of the electrophilic carbonyl group of aldehydes and ketones with pyrroles. This reaction (Scheme 7.10) is found also in benzene chemistry where the ring is activated, e.g., by the electron-releasing hydroxyl group in phenols. 

If pyrrole formation occurs with an amino acid, this product can react further (Formula 4.63) to yield a bicychc lactone (V in Formula 4.59). Other secondary products of 3-deoxyosone are compounds with a pyranone structure. In fact, P-pyranone (VI in Formula 4.59) is under discussion as the most important intermediate. It can be formed from the pyranose hemiacetal form of 3-deoxyosone (Formula 4.64). This compound has been identified only in the full acetal form (e. g., with carbohydrates on drying) because only this structure makes a relatively stable end product possible. The compounds mentioned have acidic hydrogen atoms in position 4, easily allowing condensation reactions with aldehydes and polymerization or the formation of brown dyes. 

Transmetallation of 1-6 or treatment of 1-6 with Lewis acid further broadens the scope of its reaction chemistry. In the presence of CuCl, the reaction of 1-6 with diazo dicarboxylate affords pyridazine derivatives [27]. In the presence of CuCl or nickel complexes, the reaction of 1-6 with alkynes leads to benzene derivatives [28, 29]. Transmetallation of 1-6 with Bids allows further reaction with 2-oxo malonate to give 2/7-pyran derivatives [27]. Transmetallation of 1-6 with CrCls followed by reaction with isocyanates affords pyridine derivatives [30]. Transmetallation of 1-6 with AICI3 followed by reaction with aldehydes affords pentasubstimted cyclo-pentadiene derivatives [31]. Under the similar condition, 1-6 reacts with nitroso compounds to form pyrrole derivatives [32]. Addition of n-butyl lithium activates 1-6 and allows further reaction with carbon monoxide, which leads to carbonylation and affords 2-cyclopentenone upon hydrolysis [33]. 

Fundamentally similar to pyrromethene formation are two of the classical colour reactions associated with pyrroles. The redness produced by pyrroles with an acid-moistened pine shaving is due to reaction with aldehydes in the wood, but it is not specific for pyrroles " . Ehrlich s reaction depends on the formation of coloured products by the reaction of a pyrrole with j -dimethylaminobenzaldehyde in acid solution. The nature of the reaction is indicated by the isolation of a salt of the cation (26) after treatment of (27) with the Ehrlich reagent, a carboxyl group being eliminated (26) gives red solutions, the disodium salt of the derived free base produces yellow solutions, and treatment of (26) with excess acid the colourless di-protonated salt . ... 

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

The reaction of alkynyllithium compounds with alkoxycarbene tungsten complexes leads to anionic propargyl tungsten complexes (Figure 2.33 see also Figure 3.9). These intermediates are stable at low temperatures and react upon Lewis acid catalysis with aldehydes or A -sulfonyl imines to yield five-membered heterocycles [280]. Oxidative methoxycarbonylation [375] of the intermediate vinyl tungsten complex, followed by elimination of methanol leads to pyrroles or furanes (Figure 2.33 Entry 6, Table 2.22). 

If secondary AAs are heated in the presence of aldehydes containing a proximate terminal double or triple bond and then condensed, decarboxylation and intramolecular cycloaddition tri-, tetra-, penta-, or hexa-cyclic cycloadducts with a condensed pyrrole ring are formed. An example is the reaction with sarcosine (Scheme 55) (88T4953). 

When, instead of aldehydes, A-tosyl imine 196 is used as an electrophile in a reaction with lithiated methoxyallene 183, allenyl imines 197 result. As shown in Scheme 26, they can be converted into pyrrole derivatives 198 and 199"" . 

Wittig reactions with pyrrole-2-aldehyde led to the esters (79) which were cyclisized to 3a-azaazulen-4-ones (80).104,105 4-Methylene-3a-aza-azulenes (81) have been obtained from 80 with stabilized phos-phoranes.36 Reaction of dimethyl acetylenedicarboxylate with 81 could not be achieved. A similar cycloaddition was successful in the synthesis of cycl[3,3,3]azines (2) (Section V). 

When the reactions of pyrroles and indoles with aldehydes are catalyzed by hydriodic acid, the initially formed carbinols or azafulvenes are reduced to yield the corresponding alkylpyrroles and alkylindoles (68CJC3291,70CJC139). The reductive alkylation of the pyrrole ring, using a range of aliphatic and aromatic aldehydes and ketones, may also be accomplished with phosphonium iodide, with hydrochloric acid and zinc amalgam, or with tin(II) bromide in hydrobromic acid. 

The Schotten-Baumann acylation of pyrroles and indoles is discussed in Section 3.05.1.2.6 and reactions of the heteroaryl anions with aldehydes and ketones are presented in Section... 

Although less reactive than many aromatic aldehydes, formyl-pyrroles and -indoles undergo base-catalyzed reactions with a variety of activated methylene compounds to yield compounds of the type (431) and (432), where, for example, X, Y = C02Et, C02Et COMe,... 

The lithium derivatives of 1-substituted pyrroles and indoles provide another general route of access to 2-acyl pyrroles and indoles. The ketones can be obtained directly by reaction with aryl nitriles or acid halides but, at least for 1-benzenesulfonylindole, a two-step procedure involving reaction with an aldehyde followed by oxidation of the carbinol to the ketone is frequently more convenient (equation 179) (73JOC3324, 75JOC2613). This method is probably the most general route to 2-acylindoles, although many have also been prepared by direct Fischer cyclization (see Section 3.06.3.4.2). 

This above result was only obtained with maleimide as the dipolarophile. With dimethyl fumarate and fumaronitrile, A2-pyrrolines are obtained, probably because of the acidity of the hydrogen atoms a- to ester and nitrile functionalities. Reaction with alkynes produces pyrrole derivatives in good to excellent yields and with aromatic aldehydes leads regioselectively to oxazolidines in moderate yields.263... 

Two routes for the synthesis of a four-terminal wire compound based on a central porphyrin unit are presented in Scheme 10.25 [13b], In one route, the tetrabro-mide 75 was treated with potassium thioacetate, which resulted in the substitution product 76. Alternatively, reaction of aldehyde 77 with pyrrole 78 at room temperature using mixed acid catalysis conditions provided 76 after oxidation with DDQ. 

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