Pyrroles lithiation

The TV-protected pyrrole (212) can be palladated, but not lithiated, in the 3-position to give the stable complex (213) this is readily converted into the 3-methoxycarbonylpyrrole (214) (82JOM(234)l23). The use of palladium derivatives thus further increases the range of transformations made possible through the intermediacy of metallo groups. 

Thieno[2,3-d ]pyrimidin-4(3 H) -one, 3-methyl-synthesis, 4, 1017 Thieno[2,3-d ]pyrimidin-4-ones synthesis, 4, 1017, 1018, 1022 Thieno[2,3-6]pyrrole, 5-aryl-synthesis, 6, 1009 Thieno[2,3-6]pyrrole, N-benzyl- H NMR, 4, 1042 UV spectra, 4, 1044 Thieno[2,3-c]pyrrole, N-ethyl-UV spectra, 4, 1044 Thieno[3,2-6]pyrrole, 5-aryl-synthesis, 6, 1009 Thieno[3,2-6]pyrrole, N-benzyl- H NMR, 4, 1041, 1042 lithiation, 4, 1051 UV spectra, 4, 1044 Thieno[3,2-6]pyrrole, 2,3-dihydro-desulfurization, 6, 984 oxidation, 6, 981... 

Two sequential lithiations and treatments with different bifunctional electrophiles make possible one-pot syntheses of relatively complex molecules. Thus, in the [1+2+2] annulation depicted in Scheme 69, alkylation of 1-benzylbenzotriazole 399 with 2-bromoacetaldehyde diethyl acetal to give intermediate 426 is followed by alkylation with W-benzylideneaniline to produce derivative 427. Following treatment with formic acid causes cyclization to ethoxypyrrolidine 428 that subsequently eliminates ethanol and benzotriazole to give pyrrole 429 <1997JHC1379>. 

Another approach is based on the condensation of lithiated sulfones to unsaturated nitrones (387). Good yields of single stereoisomers of unsaturated hydrox-ylamines (388) are obtained. They undergo a reverse-Cope elimination leading to a single enantiomer of pyrrol idine-/V -oxide (389) (Scheme 2.169) (626). 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

Mono- or bis-bromine-lithium exchange on dibromopyrrole 77 affords stannylpyrroles 78 or 79, respectively, and N-BOC-2-trimethylstannylpyrrole is obtained in 75% yield from N-BOC pyrrole by lithiation with LTMP and quenching with Me3SnCl [15]. 

Direct lithiation of N-(dimethylamino)pyrrole (80) and subsequent quenching with trimethylstannyl chloride affords 81 in excellent yield [67], The N-dimethylamino group can be removed with Cr2(0Ac)4 2H20. 

Although the stannylated pyrroles are normally obtained via lithiation, two other methods to prepare these Stille precursors have been devised. Caddick has found that the addition of tri-n-butylstannyl radical to pyrrole 82 affords stannylpyrrole 83 in good yield [68],... 

Dubac has employed a Stille coupling reaction to synthesize the pyrroles 88 and 89 from stannylpyrrole aldehyde 87 [71]. The latter tin compound was prepared as shown, and related stannylpyrroles were synthesized similarly [72] or using Muchowski s 6-dimethylamino-l-azafulvene dimer lithiation methodology [73]. 

Katritzky et al. <1997JOC4148> described the cyclization of pyrrole derivatives 133 via lithiation at the benzotriazol-1-ylmethyl group and subsequent intramolecular nucleophilic displacement of tosylate to give in good yields dihydropyrrolizines 65, which lead to 3/7-dihydropyrrolizines 68 under treatment with malonate anion (see Section 11.01.5.3). 

Reaction of lithiated methoxyallene 42 with nitriles 97 provided the expected alle-nylimines 98 (Scheme 8.24) however, these products are very labile and only singular examples could be cyclized to afford the expected pyrroles (see Scheme 8.37) [79]. 

These authors also demonstrated that the outcome of analogous additions of lithiated alkoxyallenes 120 to isothiocyanates is highly dependent on the nature of the alkyl group in the isothiocyanates as depicted in Schemes 8.34and 8.35 [88, 91]. Whereas methyl isothiocyanate 134 leads to pyrrole derivative 135, the correspond-... 

Pyrroles are lithiated at the 2-position whether or not the A-protecting group has the ability to coordinate (Scheme 131) . 3-Lithiopyrroles are best obtained by halogen-metal exchange on 3-bromo-A-TIPS pyrrole 275 (Scheme 132). ... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

The usual directing groups such as secondary amides will also successfully direct lateral lithiation at the 2-methyl group of a pyrrole (Scheme 226/° . 

Pyrroles and indoles have one further unique mode of lateral lithiation—deprotonation of an Af-methyl group (also an a lithiation). The reaction works particularly weU with an aldehyde director, temporarily protected as the a-amino alkoxide 565 (Scheme 228)°° . 

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"" . 

SCHEME 26. Addition of lithiated methoxyallene 183 to tosyhmine 196. Synthesis of pyrrole derivatives... 

D. Pyrroles, Indoles. Carbazoles, and Pyrazoles Lithiation in an Al-Phenyl... 

No deprotonation of carbon occurs with pyrroles unsubstituted on nitrogen, so in order for carbanion formation to occur, protection of the nitrogen is essential. However, once protected, the a-lithiation of N-substituted pyrroles occurs readily (790R1 84MI2), and in the case of AT-methylpyr-role, both 2-mono and 2,5-dilithiation can occur, depending upon the reaction conditions (Scheme 5) [79JCS(P1)2845 82SC231]. 

Synthesis of 2-Substituted Pyrroles via a-LiTHiATiON of N-Protected Derivatives... 

In addition to the protected pyrroles mentioned above, the 1-azafulvene dimer formed by Mannich reaction of pyrrole-2-carboxaldehyde with di-methylamine has also been successfully lithiated adjacent to both pyrrole nitrogens (Scheme 10). Reaction with electrophiles and subsequent hydrolysis leads to 5-substituted pyrrole-2-carboxaldehydes in good yield [88TL777 92JOM(423)173]. 

Halogen-metal exchange can also be used as a route to 2-lithiated pyrroles, and because this process can be achieved at much lower temperatures than direct metalation it is now possible to use the /-BOC protecting group with n-butyllithium (87TL6025). 2,5-dilithiation can also be achieved using this system, and the two bromine atoms in l-tcr/-butoxycarbonyl-2,5-dibromopyrrole can both be replaced to give symmetrical products. 

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. 

Metal complexes of pyrrole have also been investigated as substrates for lithiation reactions, with both iron and rhenium Tj -pyrrole derivatives having been found to undergo a-lithiation [90H(31 )383]. Azaferrocene was the first derivative of this type to be studied [83JOM(25l)C41], but it was found that lithiation was not selective and occurred equally in both rings. However, notwithstanding this, it has recently been reported that isomer-ically clean products can be obtained in certain circumstances from reaction with certain carbonyl compounds (Scheme 12) (89MI2). 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

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