Novel rearrangement in the reaction of 5-methyl-5 H -iso-indolo [2,1-a ]benzimidazole with maleimide derivatives. Stereochemical and X-ray structural study

In the reaction of 5-methyl-5 H -isoindolo[2,1-a ]benzimidazole 2 with N-arylmaleimides 3a–f a novel unexpected rearrangement led to the 3-( E )-1-(2,5-dioxo-1-R -tetrahydro-1 H -3-pyrrolyl)-1- [2-(1-methyl-1 H -benzo[ d ]imidazol-2-yl)phenyl]methylidene-1-R -2,5-pyrrolidinediones 6a–f . A three-step mechanism including Michael addition, Diels–Alder reaction and skeletal rearrangement of tricyclic 7-azanorbornene derivatives 5a–f is proposed to explain the formation of the final products. An X-ray structure analysis of compound 6a shows the presence of a twisted double bond with a torsion angle of 6.42°. In the 1 H NMR spectra the presence of a chirality center and axis in the adducts 6a–f implies the presence of atropodiastereomers.


Introduction
The study of the chemical properties of isoindole derivatives is an important area in heterocyclic chemistry. 1Their most typical reaction is the [4+2]cycloaddition (Diels-Alder reaction), which is well studied for simple isoindoles.1b,c,2 In contrast, the reactions of the corresponding annulated derivatives with dienophiles are more complex and include not only Michael or Diels-Alder reactions but are also usually accompanied with original skeleton rearrangements. 3mong the other annulated isoindoles which are much more delocalized, the heterocyclic system of isoindolo[2,1-a]benzimidazole 2 occupies a special place. 4This is due to a weak interaction between the isoindolic and the benzimidazolic parts of the molecule.It was thus interesting to study their reactions with dienophiles.Herein, we present the original reactions of the 5-methyl-5H-isoindolo[2,1-a]benzimidazole. 5

Results and Discussion
The starting isoindole 2 was obtained in situ from the 5-methyl-5H-isoindolo[2,1a]benzimidazolium iodide 1 using triethylamine as a base (Scheme 1).Reaction of 2 with two equivalents of p-tolylmaleimide leads to the compound 6a (71% yield).Its structure was proved by an X-Ray structure analysis (Figure 1).The analogous compounds (6b-f) were isolated in high yields (72-85%) in the reaction with other N-arylmaleimides, and completely identified by NMR-, mass-, IR-spectra and elemental analysis.

Scheme 1
The main feature concerning the X-ray result is that it permits to ascertain the proposed structural determination.Compound 6a crystallizes with one molecule of chloroform and we observe no noticeable intra or intermolecular short distances.The 5-membered ring C(2)-C(3)-C(4)-N(1)-C(5) in the crystal is nearly planar (no atom deflection from the root-mean-square plane > 0.02 Å) whereas the other succinimide ring C(13)-C(14)-C(15)-N(2)-C(16) present a slight envelope form with C(13) situated at 0.134 Å over the root-mean-square plane of the four other atoms (no deflection > 0.02 Å).The tolyl substituents are staggered to the five membered rings (torsion angles are 50.66 0for С(4)-N(1)-С(6)-С(11) and -70.42 0 for С(16)-N(2)-С(17)-С( 22) ) and quite parallel together.The double bond C(1)-C(2) is twisted (torsion angles С(24)-С(1)-С(2)-С(3) is 6.21 0 ) and is therefore lengthened to 1.351 Å, while a standard double bond length is 1.322 Å. 6 Apparently, this is due to the steric hindrances around the double bond.To explain this unexpected reaction we propose below a probable mechanism.We postulate first a Michael-type reaction of the isoindole 2 with one equivalent of corresponding maleimide (3a-f), forming the succinimide derivative 4. The second step may be a Diels-Alder reaction of the intermediate 4 with the second equivalent of maleimide giving the 7-azanorbornene derivative 5.The latter rearranges in the isolated products 6a-f in one or more additional steps.This is associated to the destruction of two bonds in the strained cycle and the aromatization of the benzimidazole ring.
Interestingly, in spite of their great difference in electronic properties, similar products 8 were obtained in the reaction of pyrido[2,1-a]isoindole 7 with maleimides 3b,c (Scheme 2).In fact, 7 is a 14π-electron heteroaromatic system 4a,b in contrast to the 10π-electronic system of isoindolo[2,1-a]benzimidazole.But there is a weaker interaction between isoindole and the annulated benzimidazole fragments, 4c which makes it more similar to the 10π-electronic system of the simple isoindoles.Thus, the observation of Michael adducts for pyrido[2,1-a]isoindole, using GC-MS and GC-UV spectra 7 and the isolation of 7-azanorbornene derivatives 10 in the reaction of isoindolo[2,1a]quinazolin-5-one 9 with maleimide derivatives 3e (Scheme 3) can be considered as supplementary arguments for the proposed mechanism.

Spectroscopic properties of compounds 6a-f
The 1 H NMR spectra of compounds 6a-f present more signals than expected from the formulae.Moreover, there is only one spot in TLC.This is due to the presence of two chiral elements in the compounds (Scheme 4) -a chiral axis (in bold) and chiral center (marked by an asterisk), which may lead up to four isomeric forms.Furthermore, after treating the products 6a-f with D 2 O we observe in the 1 H-NMR spectra the exchange of a broad singlet near 6 ppm, which indicates the presence of an enol form (Scheme 4) in the reaction mixture.Thus, in all cases, we observed the signals of three isomers -two atropodiastereomers and one enol form.All signals in 1 H-NMR spectra are assigned by 2D NMR and decoupling experiments.The spectra of the aliphatic part (2.00-5.00ppm) of all adducts are similar and this spectral range will be described here for compound 6a.Similar spectra were also observed for compounds 8, 3c with a pyridine instead of the benzimidazole ring.In this case, the existence of a diastereomeric mixture was proved using temperature-dependent NMR spectra 3c in which the coalescence of signals took place with increasing the temperature, thus lowering the rotation barrier about the chiral bond.

Conclusions
The reaction of 5-methyl-5H-isoindolo[2,1-a]benzimidazole with maleimide derivatives leads to rearranged products 6a-f in good yields.The proposed mechanism of the reaction begins by a Michael addition of one equivalent of maleimide to the isoindole followed by a Diels-Alder cycloaddition of the second equivalent of maleimide and subsequent rearrangement of the intermediate tricyclic 7-azanorbornene derivatives 5a-f.From X-ray structure analysis of compound 6a, it appears that the C-C-double bond is twisted (torsion angle 6.42°).A detailed analysis of NMR-spectra of compounds 6a-f shows the presence in solution of a mixture of two diastereomers and one enol form.

Experimental Section
General Procedures.Uncorrected melting points were measured by a Boetius-Thiele apparatus.IR spectra were recorded on a Perkin-Elmer 1760X FT-IR, the EI mass-spectra (70 eV) on a Nermag R10 at the "Service Commun de Spectrométrie de Masse" of the Paul Sabatier University Toulouse, and the 13 C-and other NMR spectra on a Varian Mercury 400 (400 МHz) ( 1 H, 400 MHz, 13 C, 100 MHz) in CDCl 3 , δ values are given in ppm with TMS as internal standard.Elemental analysis were performed at the Department of Chemistry, Kyiv National Taras Shevchenko University.

Figure 1 .
Figure 1.Mercury 1.4.2sticks drawing of the crystal structure of 6a.