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Due to the importance of pyrroles, there have been many methodologies developed to access them,63 and as such, only a select few examples will be highlighted in this section.

1.5.2.1 Paal-Knorr pyrrole synthesis

One of the earliest and most well known synthesis of pyrroles is the classic Paal-Knorr synthesis (Scheme 1-43). In 1884, Paal and Knorr independently found that 1,4-diketone 1-180 can react with ammonia or primary amine 1-118 to access pyrrole 1-181 (Scheme 1-43). The reaction has been greatly studied with many modifications discovered.64 The amine can be varied greatly, but generally a diketone is required as 1,4-dialdehydes or keto aldehydes are unstable.

1.5.2.2 Hantzsch pyrrole synthesis

A few years later, one of the earliest multi-component synthesis of pyrroles was developed by Arthur Hantzsch (Scheme 1-44).65 _{Addition of α-haloketone 1-184, β-keto}

ester 1-182 and ammonia, or a primary amine, give pyrrole 1-185. A key mechanistic feature of the reaction is the enamine intermediate (1-183) attacking the α-haloketone. As this has become another classic pyrrole synthesis, many modifications of this procedure have been developed.

Scheme 1-44 General Hantzsch pyrrole synthesis

One recent example of a Hantzsch type pyrrole synthesis comes from the Wu group. They were able to access polysubstituted pyrroles (1-188) in a one pot procedure from enamines (1-186) and α-bromo ketones (1-187); however, unlike the traditional mechanism, the pyrrole synthesis is initiated through a photoinduced electron transfer from Ir(ppy)3 (Scheme 1-45).66 In their optimization, they were fortunate to obtain a 92%

yield of pyrrole when a mixture of enamine, ketone, and Ir(ppy)3 in DMSO were

irradiated with visible light; failure to include one of these components resulted in no pyrrole. To confirm a radical process, TEMPO was placed into the reaction mixture and a significant drop in yield occurred (29%). With a relatively short optimization, they were then able to expand the scope of the methodology to access a variety of pyrroles. Unfortunately, only aryl substituents on the enamine and the α-bromo ketone were tested. Moderate yields were obtained for their pyrroles, but generally electron donating substituents offered greater yields than electron withdrawing, for example when R1 = p- NO2-C6H4 there was a 57% yield of pyrrole, but when R1 = p-OMe-C6H4 there was an

84% yield. The proposed mechanism begins with the excitation of Ir(ppy)3 to Ir(ppy)3*,

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Ir(ppy)3+ and the reduced carbonyl. Reduced 1-189 then gets debrominated to give

radical 1-190. Radical 1-190 reacts with the enamine to form intermediate 1-192, which then self catalyzes the reaction by reducing ketone 1-189. Cyclization of 1-193, followed by dehydration of 1-194 leads to the pyrrole 1-188.

Scheme 1-45 Wu group’s light initiated Hantzsch synthesis of pyrroles

1.5.2.3 Davies pyrrole synthesis

Among the classics, modern ways have also been developed to access pyrroles. Inspired by the process developed by the Hashmi et al.67 to access furans from alkynyl epoxides, the Davies group set out to develop conditions to obtain pyrroles from a gold catalyzed, ring expansion of N-tosyl alkynyl aziridines (1-195) (Scheme 1-46).68 They found during their optimization that they could influence the pyrrole regioisomer by modifying the solvent, and the counter ion of the gold catalyst (PPh3AuCl). When AgOTs in DCE was

used, 2-5 substituted pyrrole 1-196 was formed exclusively. When AgOTf in dichloromethane was used, the 2-4 substituted pyrrole 1-197 was the major, or sole product. Lastly, when AgOTf in toluene was used it resulted in a mixture of regioisomers. The regioselectivity can be explained by intermediate 1-199 in the proposed mechanism. A basic counter ion, such as AgOTs, would facilitate in the elimination to form 2,5-disubstituted pyrroles (pathway A). The lack of a basic counter ion would require a Lewis basic solvent to facilitate in this role, as seen in the case with AgOTf, and toluene. Absence of either a basic counter ion or solvent would result in sole formation of the rearranged product (pathway B). The effect of the counter ion on gold catalyst is not surprising to this case, as it has previously been reported in the literature.69

Scheme 1-46 Davies group’s synthesis of pyrroles from alkynyl aziridines

1.5.2.4 Glorius pyrrole synthesis

In 2010, the Glorius group expanded on the work developed by Dr. Keith Fagnou’s indole synthesis,70 to access pyrroles by a allylic sp3 C-H activation, or vinylic sp2 C-H activation, of enamines and their subsequent coupling with alkynes (Scheme 1-47).71 The optimized conditions were found to be [Cp*RhCl2]2, AgSbF6, and Cu(OAc)2 in DCE; a

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non-coordinating solvent, and choice of oxidant were important to the reaction (many Cu salts were not tolerable of the reaction conditions). The requirement for Cu(OAc)2 was

confirmed whereby a reaction without copper gave a 2% yield (1H NMR yield), which then increased to 48% after addition of Cu(OAc)2 (1H NMR yield). It was also found that

SbF6 was the superior counter ion, and some anions, such as chloride anion, resulted in

no reaction. The reaction scope was tolerable of various aryl internal alkynes with N- acetyl enamine (R= CO2Me; R1= H; R2= Ac) in 38-70% yields, and of various enamines

with 1-phenyl-1-butyne, or diphenylacetylene. Since only one regioisomer was formed when R=CO2Me (1-206a), it was speculated that the reaction must be proceeded through

intermediate 1-209 (whereby the rhodium coordinates with the carbonyl of the ester). This was confirmed when an enamine with R=CN was used. Since there is only one mode for coordination (as seen in intermediate 1-210), pyrrole 1-207a was formed exclusively.