Ethynylation of Pyrroles

5 Cross-Coupling of Pyrroles with Haloacetylenes 2.1.5.1 Ethynylation of Pyrroles 

The mechanism of the reaction involves the addition-elimination seqnence [514,516]. 

The intermediates, 2-(2-acyl-l-bromovinyl)pyrroles (Table 2.6), isolated from the reaction mixture, are converted into the corresponding 2-(2-acylethynyl)pyrroles over AI2O3 surface [516]. 

Side products of the cross-coupling, 2-acyl-l,l-di(pyrrol-2-yl)ethenes (Table 2.6), are likely formed via the substitution of bromine atom by the second pyrrole molecule in 2-(2-acyl-l-bromovinyl)pyrroles [516]. Their yields are normally up to 20% but expectedly increase (to 40%), when excess pyrrole, higher temperatures, or longer reaction times are employed [514]. 

Products of Reaction of Pyrroles with 1 -Alkylthio-2-Chloroacetylenes 

---

Direct ethynylation of pyrroles results from the use of bromoethynyl ketones at room temperature on alumina (Scheme 51) the process may involve initial addition to the alkyne followed by elimination of HBr from 112... 

Trofimov, B.A. and L.N. Sobenina. 2009. Ethynylation of pyrrole nucleus with haloacet-ylenes on active surfaces. In Targets in Heterocyclic Systems Chemistry and Properties, vol. 12, eds. O.A. Attanasi and D. Spinelli, pp. 92-119. Rome, Italy Societa Chemica Italian a. 

Trofimov, B.A., Z.V. Stepanova, L.N. Sobenina et al. 2004. Ethynylation of pyrroles with l-acyl-2-bromoacetylenes on alnmina A formally inverse Sonogashira coupling . Tetrahedron Lett 34 6513-6516. 

Attractive for further development and understanding is the palladium- and copper-free ethynylation of the pyrrole and indole rings with haloacetylenes on alumina at room temperature (Section 3.02.2.3.8). This promises to become an alternative to the Sonogashira coupling, particularly due to inaccessibility and low stability of halopyrroles and indoles. 

The pyrroles 209 react with 2-(alkylsulfanyl)-l-chloroacetylenes in the KOH/DMSO system to give 1-ethynyl-l//-pyrroles 210 (yield up to 58%) as a substitution product along with l,l -(l,Tethenediyl)bis-l//-pyrroles 211 and l,l -(l,2-ethenediyl)bis-l/7-pyrroles 212. These compounds resulted from further nucleophilic addition of excess pyrrole to the triple bond of the initial product (Equation 48) <1999RJ0916, 2002COR1121>. 

Experimentally obtained data confirm the order of pATa values of the ethynyl proton 4 > 3 > 5 for pyrazoles predicted in (75KGS821) on the basis of calculations of the energy of CH bond cleavage. Of interest is also a tendency of a pyrrole nitrogen to increase the acidity of ethynyl-substituted compounds as compared with a pyridine nitrogen. The difference in the activity of pyrrole and pyridine nitrogen is about 2 log units. 

Furan-2-yl)-pyrroles were readily ethynylated with acylbromoacetylenes on solid AI2O3 medium (no solvent, room temperature, 1 h) to afford 5-(furan-2-yl)-2-acylethynylpyrroles in 39-74% yields. In the case of 2-(furan-2-yl)pyr-roles, an alternative ethynylation of the furan ring took place, in which the ratio of the furan and pyrrole ring ethynylation products was 1 5-7 (14T9506). 

The discussed variants of novel ethynylation of the pyrrole nucleus look even more attractive taking into account that the standard transition metal-catalyzed reactions, including the Sonogashira cross-coupling, do not allow the ethynylpyrroles with electron-withdrawing functions in acetylene substituent to be synthesized [525]. 

Using a gold catalyst, the direct alkynylation of pyrroles, indoles, and thiophenes may be achieved using ethynyl benziodoxolones, (135). Extensive mechanistic studies were not conclusive but favour a r-activation process, or an oxidative mechanism. " ... 

To further suppress the insertion of dyes into the channels from the substrate side, the channels can be sealed on one side by adsorption of a polymer onto the substrate [48,49]. Alternatively, stopcocks can be functionalised specifically with electroreactive constituents like ethynylic [50] vinylic [51], or pyrrolic groups [52,53]. The substrate serves as electrode under the influence of an electrochemical potential and only the adjacent heads of the stopcocks react to form a covalently cross-linked structure. The stopcocks are then removed from the other side of the crystals to unblock the channels for the dye insertion. 

The methylheptenones aie intermediates for the synthesis of linalool (3). A continuous ethynylation with sodium hydroxide and methyl pyrrol id in one has been developed (eq. 3) (29). 

The isomerization of vinyl- or ethynyl-oxiranes is a frequently exploited source of dihydrofurans or furans, as illustrated by (163) — (164) (73JA250) and (165) — (166) (69JCS(C)12). Vinylazirine similarly gives pyrrole (Section 3.5.2.2). 

Treatment of 6-chloro-4-methylpyrrolo[2,3-6]pyridine with methoxide ion resulted in only 39% yield of the product from chloride displacement, even under very harsh conditions (300 °C). Ethynyl-ation of the halogenated pyrrolopyridines was also carried out. The reaction was successful using compound (73), after protection of the pyrrole nitrogen, and trimethylsilylethyne. However, with unsubstituted ethyne only the iodo derivative was reactive. In this case a disubstituted ethyne derivative (74) was obtained (Scheme 22) <68RCR55i>. 

The isomerization of ethynyl-oxiranes 223 leads to furans 224, as illustrated in Scheme 128 <1969JCC12>. A similar reaction of ethynyl-oxiranes with amines gives pyrroles (see Scheme 86 in Section 4.2.3.3.1). Aziridine 225 reacts with bis(trimethylsilyl)acetylene upon heating to provide pyrrole 226 (Scheme 129) <1999JOC1630>. 

The mechanism of this new ethynylation involves an addition-elimination sequence, probably promoted by the coordinatively unsaturated center (electrophilic assistance) and by mechanoactivation (grinding up the reactants with AI2O3) <2004TL6513, 2006RJ01348>. The intermediates of this reaction, 2-(l-bromo-2-acylethenyl)pyrroles 700, are isolated and converted upon AI2O3 to 2-ethynylpyrroles 699 (Scheme 136) <2006RJ01348>. 

Cycloaddition of 7V-Boc-pyrrole with ethynyl / -tolyl sulfone generated the bicyclic system selective reduction of a double bond then conjugate addition of 5-lithio-2-methoxypyridine produced an intermediate, with the required stereochemistry, requiring only straightforward manipulations to produce epibatidine. 

The 6-endo-dig ring closure of l-[2-(substituted-ethynyl)phenyl]-li/-pyrroles and... 

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)" ... 

Fig. 14 Dyad prepared by direct coupling of a a [Ru(bpy)2] group to porphyrins bearing enaminoketone group (M = or Zn ) b an ethynyl(ferrocenyl)(dppe) complex at the meso-position and c a mthenocene on a M-OEP pyrrole ring...

Like the pyrrole synthesis, the assembly of 4-methylene-3-oxa-l-azabicyclo[3.1.0]hexanes is likely triggered by the formation of O-vinyl oxime (detected by GLC and NMR). The deprotonation of O-vinyl oxime in a-position relative to the oxime function and the further intermolecular nucleophilic substitution of the vinyloxy group can lead to azirine A (Scheme 1.178). The latter reacts with acetylene (in the form of carbanion) to give acetylenic ethynyl aziri-dine B (the nitrogen analog of the Favorsky reaction), which is added to the third... 

---