Peculiarities of the cascade cleavage of the polarized C ≡ C-fragment in α -ketoacetylenes on reaction with ethylene diamine

The reaction of diarylketoacetylenes with ethylenediamine (EDA) leads to arylmethylketones and 2-substituted imidazoline derivatives. This transformation involves complete cleavage of the triple bond via initial intermolecular Michael-addition with subsequent intramolecular Michael-addition. Final fragmentation can be presented as a retro-Mannich reaction, accompanied by three formal reductive stages (formation of three C-H bonds), while the other carbon undergoes a formal oxidation, in which three C-N bonds (C-N and C=N) are formed.


Introduction
The high and unique reactivity of compounds with a triple bond motivates their extensive application in organic synthesis, medicinal chemistry, biotechnology and material science. 1 α-Ketoacetylenes possess additional synthetic potential: 2,3 Owing to the increased electrophilicity of the acetylenic fragment and its proximity to the carbonyl group, these compounds represent excellent models for studying the factors controlling regioselectivity of their addition reactions.In the reactions with nucleophilic reagents, such structures are prone to facile heterocyclization. 4rom the fundamental point of view, this contributes to a deeper understanding of their reactivity and allows the data relating to Baldwin's rules (explaining the directions of cyclization under alternative routes of reactions) to be extended.This area of organic chemistry has attracted considerable research attention. 5arlier we reported 6,7 that the reaction of diarylketoacetylenes with EDA affords acetophenones and 2-substituted imidazoline derivatives.This fragmentation involves total cleavage of the triple bond via three formal reductive stages to form three C-H bonds, whereas other carbon undergoes formal oxidation, i.e. three C-N bonds (C-N and C=N) are formed (Scheme 1).Scheme 1. Proposed pathway for the complete disproportionation of alkyne moiety.

Results and Discussion
In previous work we studied α-ketoacetylenes bearing aryl substituents in the ketone and alkyne counterparts of the molecule, in all cases the above cleavage of the substrate to a 2-substituted imidazoline being observed.
To confirm the generality of this reaction as well as to elucidate the effects of electronic and steric factors, we chose substrates containing 5-membered heterocyclic donor substituents (pyrazole, pyrrole) and 6-membered acceptor p-bromophenyl fragment.
The necessity for a more detailed investigation of this reaction was dictated also by the literature 8 from which it follows that α-ketoacetylenes of similar "push-pull" character (due to the +M-effect of the nitrogen atom) can undergo other transformations in the reactions with EDA.For example, it has been reported 9 that 4-dialkylamino-3-butyn-2-ones react with this reagent to furnish 2-(2-hydroxyprop-1-enyl)imidazoline, a product of EDA addition, without elimination of a ketone molecule (Scheme 2).
In addition, in the same work it is mentioned that such substrates can react not only with participation of carbon β-atom of the triple bond, but also with involvement of the carbonyl group, i.e. with the formation of diazepine derivatives.

Scheme 3. Two approaches to the preparation of ketoalkynes 3a-d.
The reaction of α-ketoacetylenes 3a-d with EDA was carried out by heating under reflux their equimolar mixture in dioxane until disappearance of the starting acetylene (TLC-control).As expected, in the case of ketoacetylene 3a with the two acceptor substituents, the reaction was the fastest (2 h).Pyrazole derivative 3b turned out to be less reactive (requiring 28 h) due to the +M-effect of the pyrrole nitrogen atom in the initial heterocycle.The most deactivating +Meffect was observed for tetrahydroindole derivatives 3c and 3d (reaction time was 40 h).The increase in reaction time may also be attributed to steric hindrance.
As a whole, the process comprises a series of consecutive transformations.The composition and structure of the formed (detected by GCMS, Table 1) and isolated products allow the previously proposed sequence of cascade reactions (Scheme 1) 7 to be confirmed.Namely, the process involves the intermolecular addition of amine to give monoadducts A1 inter , the subsequent intramolecular Michael-addition (5-exo-trig-cyclization) and fragmentation of intramolecular cyclization products A1 intra (retro-Mannich) to deliver ketones 6 and 7 and 2substituted imidazolines 8a-d (Scheme 4).Along with these processes, the intermolecular addition of the free amino group of the А1 inter monoadduct to the triple bond of ketoacetylenes 3a-d gives rise to bisadducts 9a-d.It should be emphasized that the composition of products recorded by GCMS (Table 1) and preparatively isolated products is different: In all the reaction mixtures analyzed by GCMS, the compounds 9a-d, the products of addition of ketoacetylenes 3a-d to EDA were not detected.Presumably, this was attributed to the low volatility of these higher molecular weight adducts under the chromatographic conditions.Nevertheless, adducts 9a-d have been isolated and characterized (see Experimental Section).
On the other hand, it was shown that upon recording the GCMS of compound 10d, splitting of the А1 inter monoadduct took place (owing to the high temperature -300 °C).These results are in agreement with our previous finding, 7 which support that an increase in temperature during the reaction between ketoacetylenes and EDA even by 25 °C (from 100 °C to 125 °C) leads to significantly larger yields of monoadduct А1 inter fragmentation products (by 20-40%).
In the IR spectra of compounds 9a-d the carbonyl stretching vibration ν(C=O) was shifted to 1591-1595 cm -1 (in the starting ketoacetylenes this band was observed at 1608-1635 cm -1 ) due to hydrogen bond formation N-H … O=C.This is in good agreement with data previously reported, 11 where the authors explained a similar shift by the chelation of the C=O bond (Scheme 5).

Scheme 5. Formation of hydrogen bonds in 9a-d.
The low content of acetophenone 7 may be attributed to its high volatility.Apparently, the losses of low-boiling acetophenone occur during the sample preparation (in the course of solvents distillation in vacuum) for MS recording.In addition, separation of the reaction mixture leads to the problems with isolation of acetophenone 7. Therefore a method for the preparation of acetophenone 2,4-dinitrophenylhydrazone was employed for identification of acetophenone 7.
The results of investigations have revealed the peculiar behavior of the tetrahydroindole derivatives 3c and 3d.Besides the expected fragmentation products (acetophenone 7 and imidazoline 8c), azepines 11c and 11d were detected for the first time.Additionally, compound 11d was isolated in preparative yield (13%; Scheme 6).
We propose that the diazepines 11c and 11d from the tetrahydroindole derivatives 3c and 3d, respectively, can be formed by either of two routes: Addition of EDA to the acetylene carbon β to the carbonyl affords the monoadducts 10c and 10d, respectively that subsequently undergo intramolecular cyclodehydration at the carbonyl or EDA initially adds at the carbonyl group to give Schiff bases 11′c and 11′d, respectively that then undergo an intramolecular ring closure on the acetylene β-carbon (Scheme 6).
Moreover, for benzyl derivative 3d formation of imidazoline 8d is not practically realized.The fragmentation products, ketone 7 and imidazoline 8d, are formed under the conditions of mass spectrum recording (the increased temperature).
Indeed, when the reaction of ketone 3d was carried out with three-fold excess EDA, mainly monoadduct 10d was isolated in 70% yield.The products of the triple bond cleavage, acetophenone and imidazoline 8d as well as diazepine 11d were not found in the reaction mixture (TLC).At the same time, when of the GCMS of this sample was recorded, the reaction mixture contained acetophenone 7 (6%), imidazoline 8d (24%) and diazepine 11d (35%).

Conclusions
In conclusion, the generality of α-ketoacetylene cleavage under the action of EDA, leading to the corresponding 2-substituted imidazolines and arylmethylketones, is confirmed.Peculiarities of the substrates bearing strong donor substituents in the acetylene counterpart of the molecule were found.These peculiarities are responsible for alternative directions of the reaction, viz.formation of the azepine and products of its rearrangement -1(R)-2-(4,5-dihydro-1H-pyrrol-2-yl)-4,5,6,7tetrahydro-1H-indole.

Figure 1 .
Figure 1.Determination of Z-configuration of compound 10d by the NOESY spectrum.

Scheme 6 .
Scheme 6. Possible pathways for the formation of dihydrodiazepines 11c and 11d.