Influence of N - s ubstituents of carbamoyl-stabilized azomethine ylides in 1,3-dipolar cycloadditions

Upon treatment with base N-substituted carbamoylmethylphenanthridinium salts were converted into azomethine ylides. These intermediates were intercepted with symmetrically substituted dipolarophiles, and the stereochemistry of the cycloadducts has been found to be dependent on the substitution at the amide nitrogen atom.


Introduction
Carbonyl-stabilized azomethine ylides (1,3-dipoles) derived from phenanthridinium salts are known to undergo versatile 1,3-dipolar cycloaddition reactions with a series of dipolarophiles (fumaronitrile, dimethyl fumarate, and dimethyl maleate).2][3][4][5] We are investigating the stereochemistry of pyrrolidino[1,2-f]phenanthridines resulting from these reactions.In addition, we have revealed that the reactivity of these azomethine ylides and hence the stereoselectivity of the cycloadducts strongly depend on the group attached to the carbonyl group stabilising the ylide.2][3][4][5] Moreover, the cycloadducts obtained from these reactions are often accompanied by dehydrogenated products derived from them.On the other hand, a rather poor reactivity of aminocarbonyl derivatives (amides), was observed, 6,7 the only reactive dipolarophile was fumaronitrile.
4][15] We wanted to study the influence of relatively bulky N-substituents on the stereochemical course of the reaction and the formation of stereoisomers, and in addition, the preparation of products with the above mentioned structures was carried out in anticipation of their biological activity.

Results and Discussion
The reaction of phenanthridine 1 with N-substituted α-bromoacetamides 2 furnished the phenanthridinium bromides 3 as starting materials for the subsequent triethylamine-induced conversion into in situ formed azomethine ylides 4.
The cycloaddition reactions were carried out in an inert atmosphere.The cycloadducts formed in the reaction with the E-configurated dipolarophiles 5a and 5b were influenced by two The yields of cycloadducts 6 and 7 isolated from the reaction of salts 3 with fumaronitrile 5a vary sensibly with temperature at a reaction time of two days (Table 1: Methods 1 and 2, entries 2 and 3; 7 and 8; 11 and 12; 16 and 17; 19 and 20); the slightly increased temperature of boiling dichloromethane (Method 2) significantly increased the cycloadduct yields (except for 6ba).The reactions of salts 3a and 3c (R = bulky N-substituents) with fumaronitrile 5a at ambient temperature (Method 1) barely provided any cycloaddition products after two days (Table 1, entries 1 and 10) but required a rather prolonged reaction period of two months to yield cycloadducts as a mixture of stereoisomers 6 and 7 (Table 1, entries 2 and 11).When the cycloaddition reactions of 3a and 3c with 5a were carried out in boiling chloroform (Method 3), dehydrogenated products 8 and/or 9 were obtained instead of the expected cycloadducts 6 and 7 (Table 1, entries 4 and 13).Remarkably, no partially dehydrogenated products 10 (derived from cycloadducts 6) have been found in these reactions (Method 3) though cycloadducts 6 are the major products at lower reaction temperatures (Methods 1 and 2, vide supra).Obviously, dehydrogenation of 10 (cis-2,3-dihydro structure) and the conversion into the completely unsaturated products 9 occurs faster than the further dehydrogenation of 8 (the trans-2,3-dihydro isomer) into 9.
The reaction of dimethyl fumarate 5b with 3a and 3c (R = bulky N-substituents) at ambient temperature (Method 1) and after a prolonged reaction time of two months furnished the respective cycloadducts 6 and 7 (Table 1, entries 5, 14); at elevated reaction temperature (Method 3) the formation of cycloadducts 6 was strongly favored or was the exclusive product (Table 1, entries 6 and 15, respectively).The salts 3b and 3d (with sterically less demanding Nsubstituents) at ambient reaction temperature (Method 1) gave rise to the formation of cycloadducts 6 exclusively (Table 1, entries 9, 18).The primarily formed cycloadducts resulting from the reaction of salts 3 with dimethyl maleate 5c appear to be very sensitive to dehydrogenation.With the exception of salt 3b giving rise to the formation of cycloadduct 11bc (reflecting the anti-conformation of the azomethine ylide intermediate 4b) all other salts 3a,c-e afforded partially dehydrogenated products 8ac, 8cc, 8dc, and 8ec, respectively (Table 2).Apparently, these products are formed via structure 12 featuring cis-orientation of H-1 and H-12b 1,2 very easily undergo dehydrogenation to the isolated products 8ac, 8cc, 8dc, and 8ec.Product 11bc with trans configuration at C-1, C12b resists dehydrogenation thus enabling its isolation.Obviously, the bulky groups R of the starting materials 3a and 3c retard the cycloaddition reaction with dimethyl maleate 5c at ambient temperature (Method 1), and a slightly higher temperature (Method 2) is required for the reaction to proceed.On the other hand, the reaction of the starting materials 3b and 3d (with sterically less demanding groups R attached to the amide nitrogen atom) reacted already at ambient temperature (Method 1) affording products 8.However, a slightly higher reaction temperature (Method 2) caused a significant decrease in product yield probably because of decomposition.Table 3. Experimental coupling constants ( 3 J exp ) and coupling constants calculated ( 3 J calc ) with the Karplus equation using dihedral angles (Φ) obtained by the semi-empirical AM1 method (SPARTAN program) for cycloadducts 6, 7 and 11bc The assignment of the relative configuration at C-1, C-2, C-3, and C-12b is based on the coupling constants 3 J under the premise that the reaction proceeds with preservation of dipolarophile configuration.The vicinal coupling constants 3 J 1,12b and 3 J 2,3 have been found in the following ranges: 3 J cis = 8.5-11.5 Hz and 3 J trans = 2.5-5.5 Hz. [1][2][3][4][5][6] However, these values 3 J cis and 3 J trans are not applicable to 3 J 1,2 . 16The values reflect conformation of the five-membered ring.
Unfortunately, we were not able to obtain a suitable crystal for X-ray analysis to support the assignments; therefore, we tried to support the structure with data from quantum chemical calculations.The semi-empirical AM1 method (SPARTAN program) was employed for the calculation and optimization of the space arrangement of adducts 6, 7, and 11b.Based on the dihedral angles of the hydrogen atoms attached to the five-membered ring the coupling constants were calculated by application of the Karplus equation; 17 the calculated values together with the experimental coupling constants are listed in Table 3.All calculated results are in a good agreement with experimental data and the structure elucidation by 2D NMR experiments.The value of the coupling constant depends on the conformation of the five-membered ring resulting from the cycloaddition reaction, and therefore, 3 J 1,2 values differ from those found for 3 J 1,12b and 3 J 2,3 .With the dihedral angle H-1-C-1-C-2-H-2 close to 180° 3 J 1,2 is relatively large (compounds 6); when the dihedral angle approaches 90°, the coupling constant 3 J 1,2 is negligible (compounds 7).The experimental coupling constants are in very good agreement with the theoretical values obtained on the basis of the calculated dihedral angle.Differences between experimental and calculated 3 J values are observed only in those cases where the dihedral angle between neighboring hydrogen atoms is very close to zero (Table 3) and C-2 and C-3 are bearing different substituents.This causes divergent values of 3 J 2,3 reflecting the fact that the Karplus equation does not consider electronic effect of adjacent groups.
The 1 H NMR spectra of compounds 6ba and 11bc exhibit duplicate sets of pyrrolidine ring signals owing to mixtures of diastereomers because the starting material 3a was a racemic mixture; integration of the proton signals revealed a 1:1 ratio of the diastereomers.Some adamantly-substituted compounds have been described earlier; 7 the experiments were repeated, the product structures were reinvestigated, and the results are included in order to put them into perspective with those of the other products described herein.

Experimental Section
General Procedures.Melting points were measured on a Kofler hot stage VEB Wägetechnik Rapido 79/2106.IR spectra were recorded as KBr pellets on a FTIR ATI MATTSON spectrophotometer.NMR spectra were recorded on a Bruker Avance DPX 300 apparatus with working frequency 300 MHz for 1 H and 75 MHz for 13 C in CDCl 3 or DMSO-d 6 solution with TMS as an internal standard.Mass spectra were recorded on a FISONS INSTRUMENTS TRIO 1000 spectrometer in positive mode with EI ionization (20eV).TLC was carried out on commercial silica plates Silufol Kavalier, Czech Republic.Column chromatography was carried out on Merck silica (63-100 µm).Dichloromethane (product of Onex, Czech Republic) was dried over CaH 2 and distilled from it.Triethylamine was dried over KOH and rectified through a column with BaO.

General method for the preparation of N-substituted 2-bromoacetamides 2a-e
To a solution of amine (90.98 mmol) in dry dichloromethane (50 mL) cooled to -20 to -30 °C bromoacetyl bromide (9.18 g, 45.49 mmol) was added dropwise under stirring and cooling of the strong exothermic reaction while a white precipitate was formed.The reaction temperature during the addition of bromoacetyl bromide should not exceed -10 °C.After all bromoacetyl bromide was added stirring was continued for another 20 min at the same temperature.Finally, the reaction mixture was filtered, the filtrate was evaporated in vacuo, and the residue was crystallized from an appropriate solvent.
The reaction mixture was concentrated in vacuo, the precipitate was collected, washed with chloroform and diethyl ether, and air-dried at room temperature.

Table 1 .
Products 6-9 from the reaction of salts 3 with fumaronitrile 5a or dimethyl fumarate 5b in the presence of triethylamine as determined by the reaction conditions: inert atmosphere; solvent (dry) and reaction temperature (Methods 1, 2 and 3), and reaction time.