Reactions with heteroaromatic compounds

W Schroth, H Kluge, R Frach, W Hode and H-D Schadler, J. Prakt. Chem., 1983,325, 787. 

The reactivity of heterocyclic systems with carbenes, generated under phase-transfer catalytic conditions, has been reviewed for the period up to 1983 [1]. Most unsaturated non-heteroaromatic systems react with carbenes in the manner expected of alkenes, amines, amides, ketones, etc. (see Sections 7.3,7.5 and 7.6). 

Selected examples of the reaction of pyrroles and indoles with dihalocarbenes 

Analogous reactions with bromoform produces the corresponding 3-bromo derivatives [6], while the reaction of alkylindoles with chlorofluorocarbene produces a complex mixture of halogenated heterocycles (Table 7.18) [9]. 

Method C The azole (0.5 mol) and TEBA-C1 (0.23 g, 1 mmol) in CH2C12 (15 ml) are mixed with aqueous NaOH (50%, 20 ml) at 0°C and the mixture is stirred for 1-2 h. CHC12F in CH2C12 (ca. 50%, 33 ml) is then added dropwise. The two-phase system is stirred at room temperature for 12 h and the product is isolated as described in 7.7.I.A. 

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A -Sulphonylation of pyrroles and indoles, using a liquidtliquid two-phase procedure [3, 48, 50-54], is superior to the traditional methods, which frequently require preformation of the heteroaryl sodium derivative, whereas A-sulphonylation of indole using a sulphonyl chloride in the presence of pyridine leads to the formation of the l,4-dihydro-4-indol-3-ylpyridine [49], The liquid liquid two-phase procedure outlined below is suitable for most A -Sulphonylation reactions with heteroaromatic compounds, but it is sometimes advisable to add a second quantity of the sulphonyl chloride during the course of the reaction [22,47]. 

Finet JP (1998) Ligand Coupling reactions with Heteroaromatic Compounds. Perga-mon, Oxford (Tetrahedron Organic Chemistry Series, vol 18)... 

The outcome of the reaction with heteroaromatic compounds is also affected by the manner of mixing. For example, the reaction with thiophene using a microflow system took place smoothly to give the monoalkylation product exclusively, while the reaction in a macrobatch reactor gave a significant amount of the dialkylation product. A similar tendency was also observed for the reaction of furan and N-methylpyrrole. These results indicate that the reactions with such heteroaromatic compounds also suffer from the problem of disguised chemical selectivity... 

Probably, the diversity of nitrile oxide chemistry is not conducive to writing reviews related to all aspects of their reactivity. Therefore, only several references can be mentioned, which are connected with several topics in this section. Among these are the reviews devoted to the photochemistry of N-oxides (including nitrile oxides) (100) and reactions of nitrilium betaines with heteroaromatic compounds (101). Other references on reviews will be given in corresponding subsections or paragraphs. 

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. 

As described in the previous sections, a variety of nucleophiles attack the Cy atom of ruthenium-allenylidene intermediates. Aromatic compounds should also be suitable candidates and this was found to be the case [30]. Thus, reactions of propargylic alcohols with heteroaromatic compounds such as furans, thiophenes, pyrroles, and indoles in the presence of a diruthenium catalyst such as la proceeded smoothly to afford the corresponding propargylated heteroaromatic compounds in high yields with complete regioselectivity (Scheme 7.25). The reaction is considered to be an electrophilic aromatic substitution if viewed from the side of aromatic compounds. 

The reactions of 2-iodopyrazine, 2-methylsulfanyl-4-iodopyrimidine and 3-iodo-6-phenylpyridazine with lithium tributylmagnesate resulted in very efficient iodine-magnesium exchange to yield the corresponding heteroarylmagnesium species (equations 35-37)" °. The reactions with carbonyl compounds and diphenyl disulfide proceeded with good yields. The reactions proceeded smoothly, and neither the starting iodide nor any butylated compounds derived from nucleophilic addition to the heteroaromatic nuclei were observed. 

The most interesting compounds described in this paragraph are meso-ionic naphtho[reactions with olefinic compounds. For instance, the reaction with acetylenedicarboxylates gives rise to adducts 458, which are dehydrogenated spontaneously to the new heteroaromatic systems 459 with the aromatic 147r-electron contour [75JCS(PI)556]. 

As shown in Table 2, reaction of heteroaromatic compounds with alkynoates occurs under very mild conditions [4, 6]. Heteroaromatic compounds such as pyrroles, furans, and indoles readily hydroarylate alkynoates at room temperature in the presence of a catalytic amount of Pd(OAc)2 in acetic acid or CH2C12, usually affording ds-heteroarylalkenes. This reaction provides a synthetic route to hetero-arylalkenes, especially ds-alkenes, from simple heteroaromatic compounds. 

Takagi, J., Sato, K., Hartwig, J. F., Ishiyama, T., Miyaura, N. Iridium-catalyzed C-H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron regioselective synthesis of heteroarylboronates. Tetrahedron Lett. 2002,43, 5649-5651. 

N-Acyliminium ions are versatile intermediates in organic synthesis they not only react with various nucleophiles such as electron-rich aromatic and heteroaromatic compounds but also undergo cycloaddition reactions with unsaturated compounds.It is especially noteworthy that N-acyliminium ions serve as electron-deficient 4t7 components in [4 + 2] cycloaddition with alkenes and alkynes. " This reaction serves as a useful method for the construction of heterocyclic rings containing a nitrogen atom. Acyclic structures containing amino and hydroxyl groups can also be synthesized from the initially formed cyclic compounds. 

Thermal (2 + 2)-cycloaddition reactions have never been reviewed so far, although occasionally a few reactions have been discussed in other review articles.20,21 The literature on this subject is summarized here in four subsections. First the mechanistic aspects of thermal (2 + 2)-cyclo-addition reactions are dealt with and subsequently a review is given of (2 + 2)-cycloadditions of heterocycles with olefins and compounds having other double bonds, with acetylenes, and with heterocumulenes. The reactions with acetylenes are discussed under two separate headings, covering (1) reactions with nonaromatic heterocycles and (2) reactions with heteroaromatics. The reactions included are exclusively inter-molecular (2 + 2)-cycloadditions. No examples are known of intramolecular thermal (2 + 2)-cycloadditions of two isolated -electron systems or of thermal electrocyclizations of conjugated 4/r-electron systems of heterocyclic compounds (Appendix). 

Reactions of electron-r/cA acetylenes with heteroaromatic compounds are rare. Such (2 + 2>cycloadditions have been proposed as the first step in the boron-trifluoride-catalyzed reaction of isoquinoline with l-dimethylamino-2-phenylacetyleneM and in the reaction of 1,2,4-triazines with 1-diethylamino-l-propyne, 1 but no experimental... 

A variety of organometallic compounds can be used for the coupling reaction with heteroaromatics possessing a-leaving groups. 

Summary Pure and mixed substituted indoyl-, pyrroyl-, and furanyl-silanes are formed in the reaction of heteroaromatic compounds with lithium alkyls and halosilanes (1-3). Chains of silyl-bridged molecules are available (7). The crystal structure of a lithium derivative (10) is presented and the 1,2-silyl group migration from nitrogen to carbon is proved. Formation of a 16-membered macrocycle (12) containing four indole molecules is described. 

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

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