2.4- Disubstituted pyrroles

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

The thermal transformations observed with these systems can be rationalized in terms of an equilibration of the 1-azirine with a transient vinylnitrene which subsequently rearranges to the 2,5-disubstituted pyrrole (56). 

Kaiser and Muchowski (41) reduced A -(r-butoxycarbonyl) pyrroles to the corresponding pyrrolidines over 5% Pt-on-C at room temperature and atmospheric pressure. Under these conditions 0-benzyl groups are retained and 2,5-disubstituted pyrroles are reduced mainly or exclusively to thecis-2,5-disubstituted pyrrolidines. In some cases Pt-on-C proved superior to either Rh-on-C or PtO,. 

Scheme 3 Synthesis of 1,4-disubstituted pyrroles via Paal-Knorr reaction...

PPy was the first conducting polymer to be structurally analyzed. The discovery that a,a -disubstituted pyrroles did not electropolymerize led to the conclusion that the pyrrole units in PPy are a-linked Magic angle spinning C-NMR... 

Vinamidinium salts have been used for the preparation of 2,3- or 2,5-disubstituted pyrroles. Thus, reaction of sarcosine ethyl ester with 18 results in an amine-exchange reaction at the least hindered position. Anion mediated cyclization and elimination of dimethylamine leads to 19 <96T6879>. 

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 [1-nitro acetates. 

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. 

Tertiary A-allylthioamides have been converted into thioamidium salts by the formation of complexes with Lewis acid. Further treatment with lithium hexamethyldisilazide (LiHMDS) affords the corresponding 1,2-disubstituted pyrroles (Scheme 25).52... 

Banwell s group has provided an alternative strategy [32] for obtaining the lamellarin framework and it is presented in Scheme 10. The methodology involves the formation of a 2,4-disubstituted pyrrole (53) containing an acid... 

Alkynes can also serve as the recipient of cycloamination protocols. For example, 2,4-disubstituted pyrroles 180 are formed in high yields from Pd-cataJyzed cyclization of aminoalkynes 179 [127]. Less effective is Pd(Ph3P)4 but Pd(OAc)2 works as well as PdCh. 

Pyrrolines. This diene undergoes a [4 + ljannelation with primary amines to form a pyrrolidine 2 that can be converted to a 3-(3-phenylsulfonyl)pyrroline (3) in high yield. These pyrrolines are oxidized by DDQ to pyrroles (4), which can be converted readily to 2,3-disubstituted pyrroles (5). 

A reaction of JV-alkyl-and N-phenyl-2,5-disubstituted pyrroles with complex 219 at 0 °C gave the best yields of the corresponding pentathiepins 221 under conditions which include treatment with non-premixed sulfur monochloride and DABCO and with complex 220 (2005OL5725 Scheme 117). 

Although it was not attempted, the second bromine atom could presumably have been replaced by a second lithiation step prior to the hydrolysis, thereby giving rise to a variety of unsymmetrical 2,5-disubstituted pyrroles. 

Disubstituted thiophenes 96 and 1,2,5-tri- and 2,5-disubstituted pyrrole derivatives 97 are available readily from m-3,6-disubstituted-3,6-dihydro-l,2-dioxins in a one-pot synthesis. The reaction proceeds by an initial Kornblum-de la Mare rearrangement of the 3,6-dihydro-l,2-dioxin to its isomeric 1,4-diketone followed by the condensation with Lawesson s reagent, ammonium carbonate, or a primary amine (Scheme 21) <2002TL3199>. 

Narasaka has utilized a Heck-type intramolecular aminopalladation of the olefinic moiety of r,5-unsaturated ketone 0-pentafluorobenzoyloximes 9 to afford 2,5-disubstituted pyrroles 10 (R = CH3, C02Et) <99CL45>. The use of the O-pentafluorobenzoyl group was found necessary to preclude competing Beckmann rearrangements. 

The Mukaiyama reaction with the dimethoxy acetal of azidoacetaldehyde gives 2,3-disubstituted pyrroles (Scheme 50) (90AG(E)777). 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Reaction of an -substituted pyrrole with an alkynic dienophile provides access to a 3,4-disubstituted pyrrole through a Diels-Alder/retro-Diels-Alder cycloaddition process (73CJC1089). The 3,4-pyrroledicarboxylic ester (206) prepared in this way has been converted to the antimitotic agent Verrucarin E (207 Scheme 44). 

The reductive coupling of phenacyl bromides using nickel carbonyl (68CC33) or an electrolytic procedure (81S625) provides excellent yields of 2,4-diarylfurans. Coupling of a-bromoaldimines with sodium or lithium provides mainly 3,4-disubstituted pyrroles, whereas isopropylmagnesium bromide yields mainly 2,4-disubstituted pyrroles (Scheme 77)... 

Michael adducts are also formed from the reactions of pyrroles with ethyl propiolate and with but-l-yn-3-one. In addition to the expected acrylic ester, 1-methylpyrrole also yields ethyl 3,3-bis(l-methyl-2-pyrrolyl)propanoate in its reaction with ethyl propiolate (67MI30500, 67MI30501), whilst if both a -positions of the pyrrole ring are unsubstituted, a twofold Michael addition with but-l-yn-3-one occurs to give the 2,5-disubstituted pyrrole (76JHC1145). 

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... 

The reduction of pyrroles by zinc in acetic acid or hydrochloric acid gives, initially, as the major product, A-pyrroline, together with A1- and A2-pyrrolines, all of which are further reduced to pyrrolidine (Scheme 54) (B-77MI30507). Reduction of 2,5-disubstituted pyrroles produces both the cis- and the trans- A3-pyrrolines, (206) and (207). 

Disubstituted pyrroles generally react with alkoxycarbonylcarbenes to give the 5-pyrrolylacetic esters (B-77MI30500, 79JA4410), but when both the 2- and 5-positions are substituted the /3-substitution products are formed. 

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