Reaction of imines with N-iodosuccinimide (NIS): unexpected formation of stable 1 : 1 complexes

Abstract

Imines react with N-iodosuccinimide (NIS) to afford unexpected 1 : 1 complexes and the structure of one of these was determined by single-crystal X-ray diffraction; the reaction seems to be very general for substituted cyclic imines with solid stable complexes obtained in high yields; this is the first reported example of a halogen bonding interaction involving the CLN bond and NIS.As part of a project focussed on the preparation of a small library of derivatives of 1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine 1a we needed to prepare either the 6-bromo or 6-iodo derivatives as appropriate substrates for the Stille and/or Suzuki reactions.1 The reaction with NBS afforded the expected halogenated product 3 (Scheme 1) but under the same conditions, the reaction of 1a with NIS gave a yellow solid compound, the structure of which incorporates the iodo atom and the full heterocyclic and succinimide moieties-as evidenced by NMR spectroscopy and elemental analysis. Further structural analysis allowed us to rule out the co-halogenation compound 2 and we therefore tried to confirm the structure of this apparently simple compound by X-ray analysis. However, all our initial attempts to obtain suitable crystals failed.It was shown that the iminic bond in 1a seems to be critical for the formation of the unexpected reaction product with NIS, since 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine either does not react, or affords the 6-iodo derivative in the presence of NIS. For this reason, we decided to test the reaction with other imines in the hope that we could obtain an appropriate crystal for X-ray diffraction analysis. Fortunately, this aim was achieved in the reaction of 6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1h) with NIS, which allowed us to establish structure 2a for the reaction product between 1a and NIS. We report here further details on the scope of this unprecedented reaction (Scheme 2).First, substitution at the C-1 position of 3,4-dihydropyrrolo[1,2-a]pyrazine was explored with alkyl (methyl and n-propyl), aryl and heteroaryl substituents 3 (Table 1, entries 2-7). Other related bicyclic and tricyclic imines such as 1-substituted 3,4-dihydroisoquinolines (entries 8 and 9) and 2-substituted 3,4-dihydropyrazino[1,2-a]indoles (entries 10-12) were also employed as iminic substrates. 4 The results are summarised in Table 1 and show the reaction to be very general for all aryl (Table 1, entries 4-6, 8, 10 and 12) and heteroaryl (entries 7 and 13) substituted substrates, with complexes being formed in yields of up to 64% and reactions completed within 1 h. The behaviour of alkyl substituted substrates depends of the heterocyclic imine and the nature of the alkyl group. For example, the reaction of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline 1i (entry 9) and 2-methyl-3,4-dihydropyrazino[1,2-a]indole (1k) (entry 11) afforded the addition compounds 2i and 2k in excellent yields (86 and 89%, respectively). However, the methyl derivative 1b gave a complex mixture of products and the n-propyl derivative 1c was ex...

NX⋯Y halogen bonds. Comparison with NH⋯Y H-bonds and CX⋯Y halogen bonds

“…[38][39][40] Most of this data is structural in nature and derives from crystal studies, as recently summarized by Troff et al 41 The N-X XB bond in halosuccinimides [42][43][44] shows up as a short intermolecular contact. 47 Halosaccharins have also been observed to engage in XBs, 48 including with water and pyridine as halogen acceptor. 47 Halosaccharins have also been observed to engage in XBs, 48 including with water and pyridine as halogen acceptor.…”

“…[41][42][43][44][45][46][47][48][49][50] As described below, a wide range of electron donor molecules is considered, including both lone pair and p-donors, and molecules of varying donor ability. We take as a starting point systems where there is available a significant amount of experimental data to serve as a check on the validity of the calculations.…”

Halogen Bonding II

“…Based on infrared spectroscopic investigation of I 3 À in a mixture of 2,3-diaminopyridine and I 2 in dichloromethane solution, Al-Hashimi proposed an asymmetric, bent geometry for I 3 À [117]. By thorough computational investigations applying a variety of solvent models, a general trend for the solvent effect on the symmetry of I 3 À was postulated [118][119][120][121][122][123]. Because of hydrogen bond-induced polarization, protic solvents, such as water, methanol, and ethanol, induce an asymmetric geometry with unequal bond lengths and an asymmetric charge distribution.…”

“…At room temperature, the former was predicted for tetrahydrofuran and the latter for acetonitrile. Symmetry breaking was also predicted to be inducible by lowering the temperature, as a consequence of the temperature dependence of the dielectric constant of common solvents [120,121]. Johnson and Myers, and Lynden-Bell et al, have raised concern that for rate constants equivalent to or larger than 10 cm À1 the antisymmetric mode would be undetectable.…”

“…Some publications mention that the NXS compound (X¼Br, I) can be activated by the addition of a nucleophile [118][119][120]. Halogen bonding adducts of the type shown in Scheme 4 have indeed been characterized structurally for N-iodosuccinimide complexes [121]. However, it is implausible that these complexes constitute the actual "activated species" which is responsible for the halogenation.…”