Synthesis of Novel Fused Heterocycles Based on Pyrano[2,3-c]pyrazole

M. E. A. ZakiN ational Research Centre, Dokki, Cairo, EgyptTel: 002-02 5838479, Fax: 002-02-3370931Dedicated to Professor W. ZielinskeiReceived:30 October 1997 / Accepted: 18 January 1998 / Published: 23 February 1998Abstract: 3-Substituted 1,2,4-triazole derivatives (5, 9, 13, 16b, 19), pyrimidinium salts (21 ), triazines (24 ),and aryl methylene hydrazono pyrazolopyrano-pyrimidine ( 27a,b ) which are rearranged in basic medium to30a,b , were afforded via the reaction of 6-amino 1,4,5,6-tetrahydro-5-imino-3-methyl-1-phenyl-4 (p-chlorophenyl) pyrazolo [4', 3' : 5,6]-pyrano [2,3-d] pyrimidine ( 3) with different reagents.Keywords: Condensed pyrazoles, cyclocondensation, Dimorth rearrangement.IntroductionCondensed pyrazoles are biologically interestingcompounds and their chemistry has received considerableattention [1,2]. Several pyrano[2,3-c]pyrazoles are reportedto have useful biological effects, such as analgesic andanti-inflammatory activities [3]. Moreover, the biologicalactivity of fused azoles has led to intensive research ontheir synthesis [4-6].Results and DiscussionIn the present study, we report on the synthesis ofpyrazolo [4`, 3` : 5,6] pyrano [3,2-e] [1,2,4]-triazolo [1,5-c] pyrimidine and pyrazolo [4``, 3`` : 4`,5`] pyrano [2` 3` :4,5] pyrimido [1,6-b] [1,2,4]- triazine derivatives via thereaction of 6-amino-1,4,5,6- tetrahydro-5-imino-3-methyl-1-phenyl-4-(p-chlorophenyl) pyrazolo [4`, 3` : 5,6] pyrano[2,3-d] pyrimidine ( 3) with different reagents.


Introduction
Condensed pyrazoles are biologically interesting compounds and their chemistry has received considerable attention [1,2].Several pyrano [2,3-c]pyrazoles are reported to have useful biological effects, such as analgesic and anti-inflammatory activities [3].Moreover, the biological activity of fused azoles has led to intensive research on their synthesis [4][5][6].

N N O
The cyclocondensation of compound 3 with the appropriate carboxylic acid derivatives was performed by heating compound 3 with an excess of neat formic acid 4 to afford 8,11-dihydro-10-methyl-8-phenyl-11 (5) in a 65% combined yield.An improvement in the preparation of this compound was achieved using triethylorthoformate (6) by refluxing neat at 140°C, or by reacting of compound (3) with ethoxymethelyene malononitrile (7) to afford 80-82% yield (Scheme 2).
When triethylorthoacetate (8) was used in the above cyclocondensation, [1,2,4] triazolo [1,5-c] pyrimidine (9) was produced.Compound 9 was also produced via the reaction of 3 with acetic anhydride (10) as carboxylic acid anhydride and acetyl chloride (11) as acid chloride.The structure of 9 was based on the absence of NH and NH 2 absorption in the i.r.spectrum.(Scheme 2).
The subsequent incorporation of a one-carbon unit carrying an amino group into 3 to form the triazolo component was performed via two facile procedures.The first one consisted in applying cyanogen bromide (14) condensation to compound 3 and the second one involved refluxing the compound 3 and S-methyl isothiourea sulfate (15) [13] to afford 3-amino-10-methyl-8,11-dihydro-11 [1,5-c] pyrimidine (16b).That compound 16b exists in the 2-amino tautomeric form and not in the 2iminoform was shown by the appearance of an intense absorption band at 3400 cm -1 and a two proton singlet as broad band at 3.7 ppm due to NH 2 in the i.r. and 1H nmr spectra respectively.In the case involving the condensation of compound 3 with cyanogen bromide (14) and S-methyl isothiourea sulfate (15), the intermediates formed might bear a cyanimino (17) or guanidino function (18).These intermediates (17 and 18) were cyclized ) in an alkaline medium to give the target molecule 16b as expected (Scheme 2).However because of the different electronic influence on each reaction centre, 16b was obtained in different yields.
The activity of compound 3 towards the reaction product was active methylene was also tested [17].Thus, with ethyl cyanoacetate ( 23 ,b) followed by the loss of malononitrile [18].Also the same product (27b) was isolated from the reaction of compound 3 with ptolulaldehyde and p-anisaldehyde 29a,b respectively.Based on their spectral data no cyclization took place (Scheme 3).From this experiment, it can be concluded that a Taylor-Löeffler transformation has occured [9].Because the reaction was carried out in basic medium as catalyst which facilitates the Dimorth rearrangement, the formal structure 30a,b is preferable (Scheme 3).
For convenience of the readers, the spectroscopic data are also collected in Table 1. (5)

General
Melting points are uncorrected and were taken on a Boetius melting point microscope.Microanalyses were performed by the Micro-analytical unit Cairo University I.R. spectra were recorded on a Mattson 5000 FIR spectrometer 1 H NMR spectra were determined on a Varian EM NMR spectrometer using tetra-methylsilan as an internal standand.Mass spectra (MS) were recorded on a Finigan SSQ 7000 mass spectrometer.
To a solution of 2 (2g, 0.005 mol) in methanol (25 ml) a solution of hydrazine hydrate (5 ml) was added and the mixture stirred for 1 hr.Then it is allowed to stand overnight.The precipitate formed is filtered, dried and crystallized from methanol to afford.55% of 3. M.p. 213-214°C: 1

Method A
A mixture of 3 (1.01g,0.0025 mol) and (32 ml, 0.7 mol) of formic acid 4 was refluxed for 10 hrs. and then cooled poured onto ice-water to give a white precipitate which was filtered, washed several times by water, dried.and then crystallized from ethanol to afford 55% of 5. M.p. 324-325°C. 1

Method B
A solution of 3 (1.01 g; 0.0025 mol) and (2.2 g, 0.02 mole) of triethylorthoformate 6 neat was refluxed for 8 hrs.A precipitate was formed, filtered while and recrystallized from ethanol to give 0.83g (80%) of 5.

Method C
To a solution of 3 (1.01g,0.0025 mol) in absolute ethanol (30 ml) was added ethoxymethylene malononitrile 7 and the mixture was refluxed for 6 hr (TLC control).On cooling, a solid product separated, which was filtered and recrystallized from ethanol to give 0.85g (82%) of 5.

Method B
A solution of 3 (1.01g,.0025mol) and 10 ml of acetic anhydride (10) was refluxed for 10 hrs.A precipitate was formed, filtered while hot, and recrystallized from ethanol to give 0.8g (75%) of 9.

(NH)
Method A A solution of 3 (1.01 g, 0.0025 mol) in 50 ml dimethylformamide was kept at 0°C and treated with cyanogen bromide 14 (0.6 g, 0.005 mol).The mixture was refluxed for 5 hrs, then cooled and poured onto water to give a white precipitate, filtered, washed with water and crystallized from dimethylformamide to yield 0.54 g (50%) of 16b.M.p.>300 C. 1

pyrimidine (19)
A mixture of 3 (1.01 g, 0.0025 mol) and 0.49 g (0.003 mol) of trichloroacetic acid (22) in 15 ml of freshly distilled phosphorus oxychloride, was refluxed on a water bath for 4 hrs, cooled then poured onto ice -water to give a precipitate which was filtered off, and washed with water.The solid that collected by filteration, was recrystallized in dioxane to afford 0.7 g (51%) of (19).m.p. 270-271°C. 1

pyrimidine (30a,b).
Method A A mixture of 3 (1.01 g, 0.0025 mol) and ptolylmalononitrile (25a) or p-anisylmalononitrile (25b) (0.0025 mol) in dioxane, in the presence of piperidine as a catalyst was refluxed for 8 hours.After cooling, the solid product formed was collected and crystallized from dioxane to yield 70% and 80% of 30a,b respectively.