Trifluoroacetylation of pyrrolo[1,2-a]pyrazines

Abstract

A study was carried out on the reaction of pyrrolo [1,2-a]pyrazines containing an alkyl, aryl, or aralkyl substituent at C-1 with trifluoroacetic anhydride. Trifluoroacetylation products may be formed either by reaction in the pyrrole ring or at the aryl or aralkyl groups at C-1. Products of electrophilic substitution at C-6 are formed in the trifluoroacetylation of pyrrolo [1,2-a]pyrazines containing at C-1 a substituent bulkier than a methyl group but lacking substituents at C-6 (the α-position of the pyrrole ring).The pyrrolo[1,2-a]pyrazine bicyclic aromatic system has not been studied extensively, perhaps due to the difficulties in its preparation and its relatively low reactivity. The relative stability of the pyrrolo[1,2-a]pyrazine system to the action of weak electrophilic agents is indicated, for example, by the formation of the 6-acetyl derivative in only 16% yield upon heating 1,7-dimethylpyrrolo[1,2-a]pyrazine with excess acetic anhydride at reflux for 24 h [1]. The bromination of unsubstituted pyrrolo[1,2-a]pyrazine leads to a 1:1 mixture of 8-bromo and 6,8-dibromo derivatives [2, 3], while formylation of this model leads to 8-formylpyrrolo[1,2-a]pyrazine in 60% yield as the authors [2] affirm, although the 1 H NMR spectrum given for this compound leaves doubt concerning its structural identification. Paudler and Dunham [3] were unable to formylate unsubstituted pyrrolo[1,2-a]pyrazine by the Vilsmeier-Haack procedure. Attempts to obtain nitroso or azo derivatives of pyrrolo[1,2-a]pyrazines in reactions with nitrous acid and phenyldiazonium chloride also proved unsuccessful [4].Hence, we undertook a systematic study of the behavior of pyrrolo[1,2-a]pyrazines 1-10 in reactions with electrophiles such as acylation with trifluoroacetic anhydride, which is a stronger acylating agent than acetic anhydride. The trifluoroacetyl cation is a rather strong electrophile. Thus, the acylation of pyrroles by trifluoroacetic anhydride proceeds rapidly at 0°C [5]. In previous work [6], we showed that dipyrrolo[1,2-a:2',1'-c]pyrazines form ditrifluoroacetyl derivatives as the major reaction products with excess trifluoroacetic anhydride even at room temperature. On the other hand, much more complicated behavior is found for 3,4-dihydropyrrolo[1,2-a]pyrazines, for which the direction of the reaction depends on the structure of the starting compounds and substrate/reagent ratio [7].The α-position of the pyrrole ring in 1-methylpyrrolo[1,2-a]pyrazine (1) is unoccupied and we might expect that the most likely product in its reaction with trifluoroacetic anhydride would be 6-trifluoroacetylpyrrolo[1,2-a]pyrazine by analogy to acylation by acetic anhydride [1]. However, the reaction of 1 with a 2.5-fold excess of trifluoroacetic anhydride in benzene (method A) yielded three products. NMR spectroscopy and mass spectrometry indicated the formation of 1-(3,3,3-trifluoro-2-oxopropylidene)-__________________________________________________________________________________________ M. V. Lomonosov

Electrophilic acetylation and formylation of pyrrolo[1,2-a]pyrazines: substituent effects on regioselectivity

“…1, 131.3, 130.8, 130.6, 129.1, 128.8, 128.0, 126.3, 124.9, 118.6, 116.7, 114.0, 112.3, 106.3, 55.7; HRMS (ESI-QTOF) m/z [M+Na] + calcd for C23H18N2O2Na 377.1260, found 377.1263. (10). To a stirred solution of 5a (50 mg, 0.22 mmol) in THF (2 mL) were added 2-(1H-pyrrol-1-yl)aniline (41.76 mg, 0.26 mmol) and pdodecylbenezenesulfonic acid (DBSA) (14.36 mg, 0.04 mmol).…”

“…8 To explore new territory based on pyrrolo[1,2-a]pyrazine, we investigated electrophilic acylation to install an acyl unit which could be further elaborated. From several literature precedents, [9][10][11][12][13][14][15] we reasoned that Friedel-Crafts type acylation of 1 would mainly provide 3 having an acyl group at the C6 site (Scheme 1b). Scheme 1.…”