Alkenylation of pyrroles

SCHEME 10.3 Gaunt s intermolecular regioselective alkenylation of pyrroles. 

Arrayayas and Carretero employed a Af-(2-pyridyl)sulfonyl protecting group to assist in their palladium(II)-catalyzed C2 alkenylation of pyrrole, whereas the research groups of Li and Wang used a A, A-dimethylcarbamoyl group to affect alkenylation of pyrrole at the C2 position under rhodium-catalyzed conditions. ... 

The alkenylations of amide N-protected pyrrole with an excess of acrylate led to dialkenylation at C2 and C5 positions of pyrrole. The successive alkenylation of pyrrole at C2 and C5 positions led to unsymmetrical substituted pyrroles [(Eq. 72)] [156],... 

Using the binuclear ruthenium(II) catalyst [RuBr2(CO)2(PPh3)]2 Wai Yip Fan succeeded to achieve the alkenylation of pyrroles with terminal alkynes under mild conditions at 50°C. This catalyst leads to the reverse regioselectivity for hydroheteroarylation of alkynes and the dialkenylation of pyrrole can be controlled. The mechanism likely involves an electrophilic activation of the alkyne by the Ru (II) species favouring the nucleophilic Markovnikov addition of pyrrole to the alkyne internal carbon [(Eq. 78)] [162]. 

In 2006, Gaunt and co-workers described a regioselective alkenylation of pyrroles under mild aerobic oxidative conditions. A catalytic amount of palladium acetate was able to selectively functionalize tert-butojycarbamate (BOC)-protected pyrrole at the C2-position while a C3-selectivity was achieved with triisopropylsilyl (TIPS)-protected pyrroles (Scheme 9.4). The aerobic conditions worked well for reactive alkenes such as acrylate derivatives, nevertheless the use of peroxide ( BuOOBz) appeared necessary in order to achieve good yields with more challenging substrates [i.e., methyl vinyl sul-fone). Interestingly, intermolecular alkenylation of pyrrole can also be effected with complete selectivity and good yields. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of IV-substitution with bulky groups directing to C-3. The oxidative alkenylation of (V-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the (V-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

A similar reaction of pyrroles 20 with acrylates provides the C-2 substituted a-alkenyl derivatives 21 in 24-91% yield [29]. The 2,6-dichlorobenzoyl protecting group is noteworthy as it prevents cyclization of the phenyl group onto the pyrrole ring (vide infra). 

The one-stage transformation of 3-butenyl-l-methyl ketoxime (63) to 2-methyl-3-(2-propenyl-l)pyrrole (64) and 2-methyl-3-(l-propenyl-l)-l-vinylpyrrole (65) (Scheme 34) (82TL5063) is typical and demonstrates two essential features of this version of the reaction the reaction either can be stopped selectively at the stage of pyrrole ring formation without vi-nylation onto the N—H bond and prototropic isomerization of the alkenyl, or it can form an N-vinylpyrrole in which the double bond of the alkenyl is shifted into conjugation with the pyrrole ring. 

A considerable number of pyrroles 30 with alkyl, alkenyl, or aryl substituents were synthesized by spontaneous cyclization of the enyne precursors 31 (when R = H, Ph, CH2OTHP), or upon treatment of 31 with the catalytic system PdCV KCl (when = H), or alternatively, by treatment of 31 with CuCb (when R H) <03JOC7853>. Treatment of y-ketoalkynes with amines in the presence of catalytic amounts of platinum dichloride constitutes a new route to 1,2,3,5-substituted pyrroles <03AG(E)2681>. An intramolecular rhodium(lI)-catalyzed N-H insertion reaction of 5-amino-7,Y-difluoro-a-diazo-P-ketoesters has been used for the synthesis of a series of 3-fluoropyrroles <03OL745>. 

Abstract This review details recent developments in the Pd-catalyzed C-H bond arylation and alkenylation of indoles and pyrroles, aromatic heterocycles that are frequently displayed in natural products and medicinal agents. 

Pd-Catalyzed C-H Alkenylation of Indole and Pyrrole 4.1 Mechanisms of Pd-Catalyzed C-H Bond Alkenylation... 

Another class of indole syntheses involve annelations of pyrroles. One new example of this type of indole synthesis involved the electrocyelization of a 2-alkenyl-3-allenylpyrrole intermediate <04H(63)1765>. This was exploited for the synthesis of indole-4,7-quinones. 

Regjoselective C—H alkenylation of N-methyl-4-aryl-lH-pyrrole carboxylates (88) with alkenes—primarily acrylamides, acrylates and acrylonitrile—was observed by Lin, Yao, and coworkers to be dependent on the solvent used in the coupling (2014OL4884). As such, C-2 selectivity (89) was achieved when toluene was used as the solvent while inclusion of DMSO favored the C-5 product (87). The authors postulated that the carboxylate-assisted chelation of the palladium catalyst, which occurs readily in toluene, is overridden in the strongly coordinating solvent DMSO and results in an electrophibc C—H activation at the more electron-rich C-5 position. An apphcation of this work to the total synthesis of (it)-rhazinilam was also described in this account. 

Scheme 55 Regioselective Pd-catalyzed C—H alkenylation of IH-pyrrole directed by the steric bulk of the group on nitrogen.

Carretero used a (2-pyridinyl)sulfonyl directing group to achieve efficient palladium-catalyzed C2-alkenylation of IH-indoles and 1 H-pyrroles (117 — 118) with aUcenes as reagent (2009AGE6511) (Scheme 57). High regjoselectivity was obtained with the (2-pyridinyl)sulfonyl moiety on... 

Scheme 57 Pd-catalyzed C2-alkenylation of l- 2-pyridinyl)sulfonyl-substituted IH-in-doles and IH-pyrroles.

This catalytic oxidative annulalion process can also be applied to pyrrole systems. Gaunt and coworkers [29] had described the intermolecular selective alkenylation of C(2) or C(3) of pyrroles based on the nitrogen protecting group (Scheme 9.5 see above). This same concept was implemented in an intramolecular sense to achieve selective annula-tions (Scheme 9.23). When iV-tosyl pyrrole 168 was subjected to oxidative conditions, the cyclization occurred at C(2) to form pyrrole 169. Alternatively, when structurally similar N-triisopropylsilyl pyrrole 170 was treated with the same palladium(II) system, the functionalization occurred at C(4) to afford pyrrole 171. This intriguing differentiation based on the choice of protecting group could have broad implications in selective functionalizations of heterocycles. 

Scheme 7.56 Oxidative alkenylation of a pyrrole en route to dragmacidin F.

Further, Li reported an analogous Cu(I)-catalyzed double alkenylation of amides 304 with 1,4-diiodo-l,3-dienes 303 leading to the formation of tri- and tetra-substi-tuted N-acylpyrroles 30S (Scheme 8.108) [306]. Interestingly, in contrast to Buchwald s approach, employment of alkylcarbamates as the N-nudeophile components in a catalytic reaction provided low yields of the pyrrole products. However, this limitation could be alleviated by performing the reaction in the presence of stoichiometric amounts of Cul and 1,2-diamine ligand L. 

Gomez Arrayas, Carretero, and coworkers [46] investigated the alkenylation of N-[(2-pyridyl)sulfonyl]pyrroles using PdCl2(MeCN)2 and Cu(OAc)2 and disclosed that C2- and C5-dialkenylated products can be selectively synthesized in DMAc at 110°C, while C2-monoalkenylated products are obtained in MeCN at 80 °C (Scheme 18.45). The latter products undergo further alkenylation at the C5 position to form unsymmetrically substituted 2,5-dialkenylpyrrole derivatives. 

---