Derivatives of pyrido[3´,2´:4,5]pyrrolo[1,2-c ]pyrimidones

Different N -protected dichloromethanimines have been used for the preparation of pyrido[3´,2´:4,5]pyrrolo[1,2-c ]pyrimidines and the results are compared. The preparation of 4-chloro-9-tosylaminopyrido[3´,2´:4,5]pyrrolo[1,2-c ]pyrimidine is described.


Introduction
The synthesis of variolin B 1 1 and derivatives has been one of the important topics developed in our laboratory during the last years. 2Our previous synthetic procedure described for the preparation of deoxyvariolin B 2 is based on the construction of the tricyclic system of pyrido[3´,2´:4,5]pyrrolo[1,2-c]pyrimidone, followed by the transformation of the pyrimidone C ring into an N-protected-aminopyrimidine, halogenation at position 5 of the tricyclic system and finally a palladium cross-coupling reaction for the introduction of the fourth heteroaromatic D ring (Scheme 1).Mercedes Álvarez.Tel.: +34 93 403 70 86; fax: +34 03 403 71 26; e-mail: malvarez@pcb.ub.es.
The application of that procedure to the total synthesis of variolin B 1 required as starting material a properly 4-substituted-7-azaindole. Two different substituents at position four of 7azaindole were used for this purpose, a methoxy group and a chlorine.Both functional groups could be transformed into the hydroxy group, characteristic of the natural product, in a late synthetic step.The hydroxy-functionality could be unmasked by either O-demethylation of the methoxy derivative or by a nucleophilic substitution on the π-deficient pyridine ring. 3In this paper we describe our results on the preparation and use of 4-chloropyrido[3´,2´:4,5]pyrrolo[1,2c]pyrimidine system for the above-mentioned synthesis.
The efficient synthetic procedure described for the preparation of deoxyvariolin B 2a based in the use of triphosgene to afford the tricyclic system had, for its application to the synthesis of variolin B derivatives, the inconvenience of the strong conditions needed for the transformation of the pyrimidone into the aminopyrimidine.In these conditions, either the methoxy or chlorine groups were partially or totally displaced.This made it imperative to modify the conditions of ring C formation using a synthetic equivalent of triphosgene in which a protected nitrogen was introduced at the same time that ring C was formed.In this paper we describe the use of dichloromethanimine with different N-protecting/blocking groups 3a-e for the construction of the properly fuctionalized and protected aminopyrimidine ring C of variolin B and derivatives.

Results and Discussion
The use of N-protected dichloromethanimines 3, as synthetic equivalents of triphosgene, has the advantage of using the same synthetic strategy as described before, but of decreasing the number of steps and, most importantly eliminating the need for the transformation of pyrimidones into the aminopyrimidines and the high pressuree conditions needed for that.The choice of the nitrogen protecting group was crucial for the process because it was required to be stable not only during the formation of the ring C but also in the deprotection of the O-tetrahydropyranyl group, the dehydration of the resulting alcohol, during the halogenation at position 5 of the tricyclic system, and in the cross-coupling reaction employed for the introduction of the fourth aromatic ring.
The procedure for the preparation of these dichloromethanimines was different depending on the N-substituent and the starting material, and three different alternatives were employed.The methods used are summarized in Table 1.Addition of chlorine to acetyl isothiocyanate using TiCl 4 as catalyst to give Nacetyldichloromethanimine 3b was also used for the preparation of Ndichloroacetyldichloromethanimine.The N-tosyldichloromethanimine 3d 6 was obtained from toluene-4-sulfonamide by transformation into N-tosyl-bis(methylsulfanyl)methanimine and then treatment of this derivative with chlorine, following the procedure described by Heukelbach.The N-alkyldichloromethanimines substituted with trityl 3c and p-methoxybenzyl 3e as protecting groups were prepared from the appropriate N-alkylformamides by reaction with a mixture of thionyl chloride and sulfuryl chloride.These reaction conditions also afforded 3c, not previously described, in a good yield and purity.The formation of 3c was verified by comparison of its 1 Hand 13 C-NMR spectra with the comparable signals of the precursor N-tritylformamide, 7 This amide has a characteristic doublet at 8.05 ppm with a coupling constant of 12 Hz due to the formyl proton that disappears in the dichloro-compound; the corresponding carbon signal shifted from 165.9 ppm for the NHCO precursor to 81.3 ppm in TrN=CCl 2 .Dichloro-imine 3c was used without purification in the cyclisation reactions.When the same reaction conditions were used with p-methoxybenzylformamide a mixture of the desired dichloro-imine 3e and a trichloroderivative with an extra chlorine, presumably at the benzylic position, was obtained and the possible use of this dichloroimine was not examined further.
Reaction of aminoethylazaindole 4a 2c with 3a-d for the transformation into the tricyclic system was carried out using comparable reaction conditions for all the dichloromethaninimes (Scheme 2), in DCM as a solvent at room temperature using N,N-diisopropylethylamine (DIPEA).When the N-acetyl or N-dichloroacetyldichloromethanimines were used for the cyclisation, N-deacylation took place during the isolation procedure and only small amounts of the 9-amino-6,7-dihydropyrido[3´,2´:4,5]pyrrolo[1,2-c]pyrimidine 6 could be isolated. 8Additionally, compound 6 was not easy to handle, probably because of its high polarity.The low yields obtained with these protected dichloromethanimines and what would have been a need for a new protection, following the cyclisation, to allow the synthesis to proceed further, persuaded us to change to the use of an alternative dichloromethanimine.
The N-tosyland N-trityldichloromethanimines gave better results.With both these dichloromethanimines, tricyclic systems, 5a and 7a, were obtained in 71% and 58% yields, respectively.From the synthetic point of view it was not a problem to have 5a and 7a as a diastereomeric mixture, as well as compound 4, because the two diasterogenic centres disappear later in the synthetic sequence.The differing polarities of the two 7a diastereomers was enough to allowed the isolation of each isomer during the purification and thence the spectroscopic characterization of each isomer, singly.It is tempting to assign the relative configurations of the stereocenters on the basis of a comparison of the distances (d) in Å 9 between H6 and H2' of both isomers and the percentage increase in the areas of the signals in an NOE-DIF experiment, taking into consideration that the nuclear Overhauser effect (NOE) is a function of the distance between the atoms which give a positive NOE.As show figure 1 the distance between H6 and H2' (d = 3.604 Å) in the (6RS, 2'SR)-7a is larger than in (6SR, 2'SR)-7a (d = 2.078 Å) and correspondingly, the increase in area of H2' on irradiation H6 is smaller (6.61%) than the increase in in the area of H2' on irradiation of H6 in the other stereoisomer, (6SR, 2'SR)-7a (9.45%).The following step required removal of the tetrahydropyranyl-protecting group and was done using 4N aq.HCl in DCM at reflux to give the alcohols 8a 2c and 9a in good yields.At this point we also tested the formation of ring C from 4b using 3c and 3d to give the protected alcohols 5b and 7b which were also deprotected, using the same conditions, to give the alcohols 8b and 9b.With the elimination of the O-protecting group, the resulting alcohols 8a-b and 9a-b gave easily assignable 1 H NMR spectra, with the disappearance of the second chiral centre.The MS of dihydro-derivatives 7a,b and 9a,b did not show molecular ions because of a very favoured fragmentation to generate ions at M+1-TritN as well as at 243 (trityl + ) as the base peak.
Whereas the dehydration of 8a and 8b was achieved by treatment with mesyl chloride and triethylamine (TEA) as base in DCM at room temperature giving the totally aromatic systems 10a or 10b with good yields, the N-trityl protected alcohols 9a and 9b under the same conditions were not significantly changed, even after a longer time and at a higher temperature.The corresponding aromatic compounds were produced, but in low yields and their isolation was difficult, and we were only able to characterize them by 1 H-NMR 10 and MS measurements.The difference in the methansulphonic acid elimination reaction was attributed to the withdrawing character of the tosyl protecting group compared with the donor effect of the trityl.
Much better synthetic results and workability were obtained using the Ts-N=CCl 2 3d and it became the reagent of choice for this key cyclisation process being employed in our total synthesis of the natural compound 1 2c and also for the preparation chloro-compound 9c.
The chloro-compound 9c was of interest to us as a potential precursor of a series of derivatives with different substituents in position 4 of the tricyclic system, to be obtained by nucleophilic displacement of the halogen.
The chloroamine 4c was obtained from the 4-chloro-7-azaindole 11 by reaction of its 2-lithio derivative with 2-phthalimidoacetaldehyde. 12 A lithium-carboxylate was used as N-protecting and ortho-directing substituent for the lithiation at position 2. The yield in this condensation was considerably inferior to those using 7-azaindole or 4-methoxy-7-azaindole.It was possible to recover part of the starting material, but there was a significant overall loss of material probably resulting from a competitive process involving the chlorine.Protection of the alcohol generated, by reaction with dihydropyran, and deprotection of the amino group by hydrazinolysis gave the amino-acetal 4c as a mixture of diastereomers.Cyclization of 4c with Ts-N=CCl 2 under the same conditions as before gave the 9-tosylaminopyrimidine 5c in 68% yield.Removal of the Otetrahydropyranyl protecting group by treatment with 4N HCl followed by elimination of the hydroxyl group through its mesylate gave 10c, with slightly inferior yields than in the comparable steps starting with 7-azaindole or 4-methoxy-7-azaindole.

Conclusions
Several dichloromethanimines 3a-d which differ in the N-protecting/blocking group have been tested for the preparation of amino-protected 9-aminopyrido[3´,2´:4,5]pyrrolo[1,2-c]pyrimidines.This method for the synthesis of the tricyclic common core of the variolins has reduced the number of steps, and the tosyl protecting group was more efficient because it gave better reaction yields and remained untouched throughout the subsequent synthetic steps.
The chloro-compound 9 was prepared starting from the 4-chloro-7-azaindole following the same strategy as before.The overall synthetic yield was lower than the yields obtained in the preparation of analogous compounds without chlorine or with a methoxy in the 4-position, however we now have a procedure which will allow us to synthesise analogues of variolin B, utilising the reactivity of the halogen at the γ-position of the pyridine unit.

N-Tritydichloromethanimine (3c).
To a mixture of SO 2 Cl 2 (0.3 mL, 3.5 mmol) and SOCl 2 (1.1 mL) cooled at 15 ºC was slowly added N-tritylformamide (1 g, 3.5 mmol) and the reaction mixture was stirred at the same temperature for 30 min and after this time at 80 ºC during 2h.The excess of reagents were eliminated under vacuum to leave a yellow solid (1.01g, 86%) which was used without further purification. 13

Table 1 .
Structure and preparation of N-substituted dichloromethanimines 3a-e a A: reaction with Cl 2 catalyzed with TiCl 4 ; B: reaction with SOCl 2 and SO 2 Cl 2 until 1 H NMR analysis indicated the absence of signals for CHO; C: reaction with Cl 2 in CCl 4 as solvent at 0 ºC until 1 H NMR analysis indicated the absence of signals for SMe.