View Article Online / Journal Homepage / Table of Contents for this issue J. Chern. SOC.(C), 1970 Published on 01 January 1970. Downloaded by Christian Albrechts Universitat zu Kiel on 27/10/2014 17:10:29. 2510 Sequential Attack by a Diketone on a Polyhydrazine; the Reaction of Triaminoguanidine with Acetylacetone By R. N. Butler,t F. L. Scott,* and R. D. Scott, Department of Chemistry, University College, Cork, Ireland The reaction of triaminoguanidine with acetylacetone involves a sequential attack of the diketone on the hydrazine groupings of the triaminoguanidine. The reaction provides a new route to substituted tetrazines and dipyrazolyl ketone hydrazones, but it cannot be used to provide a hydrazidinating reagent comparable with the amidinating agents obtained from similar reactions of diketones with monoacylhydrazines. WE examined, some time ago, the mechanistic patterns of cleavage of l-acylpyrazoles and evolved from these studies a variety of useful synthetical procedures.1.2 The acyl groups we used were principally nitrogencontaining such as carbamoyl, thiocarbamoyl, amidino, etc., and the deacylation processes proved to be efficient means of transacylation. In particular, the l-amidinopyrazoles proved t o be useful amidinating agents for both organic synthesis l y 3 and biochemical purpose^.^ Because of this latter use especially, we considered the possibility of synthesising a l-acylpyrazole containing a hydrazidino-group [C(:N*NH,)-NH*NH,] so that its use in novel modification of amino-acids might be examined. A ready synthesis of our l-amidinopyrazolesinvolved the reaction of p-diketones with monoacylhydrazines. A similar reaction with the polyhydrazine triaminoguanidine would give the desired hydrazidino-transferring agent (I). Hence we investigated the reaction of triaminoguanidine with acetylacetone as a means of preparing materials such as compounds (I). On treatment of triaminoguanidine nitrate with acetylacetone a complex reaction occurred giving rise to a number of products, the proportions of which varied t Present address: sligo Regional Technical College, SligO, Ireland. F. L. Scott, D. O’Donovan, and J. Reilly, J . Anzer. Chern. SOG.,1953, 75, 4053. F. L. Scott, J . Org. Chem.,, 1957, 22, 1568. Reagents for Organic Synthesis,’ Wiley, New York, 1967, p. 738. * A. F. S. A. Habeeb, Biochinz. Biophys. A d a , 1959, 34, 294; Canad. J . Biochenz. Physiol., 1960, 38, 493. 2 3 L. F. Fieser and M. Fieser, View Article Online 2511 Published on 01 January 1970. Downloaded by Christian Albrechts Universitat zu Kiel on 27/10/2014 17:10:29. Org. with the conditions of the reaction (Table). I n the presence of sufficient acetylacetone, a t ambient temperatures the dipyrazolylmethylenehydrazono-derivative (111) was the main product, whereas under reflux conditions considerable decomposition occurred and a pale yellow compound with the dihydrotetrazine structure (IV) was isolated in highest yield. Small quantities of 3,5-dimethylpyrazole were also isolated from these reactions. Hence this procedure provides a new route to substituted tetrazines. By using two, or less, molar proportions of acetylacetone, the product (111)could be excluded from the reaction entirely. Under these conditions, prolonged stirring of the reactants a t ambient temperatures or gentle heating of the solutions favoured formation of the product (IV). It was also noted that a stoicheiometry of 2 : 1 (acetylacetone to triaminoguanidine) appeared to be operating in the reaction, since when less than two molar proportions of acetylacetone were used, a quantity close to the expected both as its benzylidene derivative (V) and as its acetylacetone derivative (111). Treatment of the material (11) with dilute nitric acid or hydrochloric acid yielded the dihydrotetrazine (IV) (30-50~0) and 3,5-dimethylpyrazole (90%); thus the origin of these materials is explained. Hence the overall reaction can be represented as a coherent process involving sequential attack of the diketone at the hydrazine-groupings of the substrate (Scheme). Attack of acetylacetone on each hydrazine grouping, followed by elimination of a molecule of water (cf. ref. 5) leads to the material (11), probably via the hydrazidinopyrazole derivative (I).* This latter material, however, if present a t all, is apparently extremely reactive and is rapidly converted into the material (11)and hence cannot be used as an effective hydrazidinating agent. Subsequent reaction of the material (11) with acid or excess of acetylacetone accounts for the other products observed. EXPERIMENTAL Me NHiNH-C-N H-NH,,HNO, II N o=c( t CH2 o=c / I NH2 PY \ ,C=N-NH2 PY N-N (Nl ‘Me - ( A c ) ~ G H ~ Py-C-NH* II NH2 I IY I R’ Pv 1 2 (ml R=Me,R=CH2Ac 1 (Y) R = H , R2=Ph P y = 3,5-dimethylpyrazol-l-yl SCHEME quantity of triarninoguanidine nitrate was recovered unchanged in each case. This suggested the presence of an intermediate, a possible precursor of compound (IV), and this was subsequently isolated in yields up to 50:/, by a brief stirring of the reactants (15 min.) at ambient temperatures followed by immediate work-up, thereby intercepting it prior to its conversion into compound (IV)* This intermediate was identified as the novel dipyrazolyl ketone hydrazone (11). It was characterised 5 The reactions of diketones with monsubstituted hydrazines t o give substituted pyrazoles are well documented: F. Kurzer and K. Douraghi-Zadeh, J . Chem. SOC.( C ) , 1966, 6 ; H. Beyer and K. Pommerening, Chern. Bey., 1966, 99, 2937; H. Beyer, E. Bulka, W. Dietz, and H.-G. Potzwaldt, ibid., 1963, 96, 1996; D. T. Manning and H. A. Coleman, J . Oyg. Chern., 1969,34, 2747. M.p.s are corrected. Molecular weights were determined by cryoscopic methods. 1.r. spectra were measured with a Perkin-Elmer Infracord (model 137E) spectrophotometer with sodium chloride optics. Solids were examined as discs with potassium bromide. U.V. spectra were measured with a Perkin-Elmer (model 137) spectrophotometer with 95% ethanol as solvent. Reaction of Triaminoguanidine Nitrate with A cetylacetone. -The following is a typical example. A solution of triaminoguanidine nitrate (2.25 g.) in slightly warmed water (60 ml.) was cooled to ambient temperature and treated with acetylacetone (1.75 ml.) in 95% ethanol (15 ml.). The mixture was stirred for 1 hr. and set aside for 3 days, during which time successive crops of pale yellow crystals of 1,2-dihydro-3,6-bis-(3,5-dimethyl~yrazol-l-yZ)tetrazine (IV) (total yield 593 mg., 32.5%) separated, m.p. 147-149’ (from aqueous ethanol) (Found: C, 53.05; H , 5.95; N, 41.75%; M ,269. C,,H,,N, requires C, 52.9; H, 5.9; N, 41.15%; M , 272). A solution of the material in 95% ethanol developed a red colour and showed a characteristic tetrazine U.V. absorptions a t 528 nm. resulting from oxidation of the compound. The fully oxidised tetrazine was obtained as described later. Also in accord with structure (IV) was a strong N-H i.r. absorption a t 3320 cm.-l. The filtrate from this material was treated with water (50 ml.) and extracted with ether (4 x 70 ml.). The yellow extracts were separated from the aqueous portion [solution (A)], combined, dried, and evaporated. The residue, a white crystalline solid with a sticky yellow gum was repeatedly shaken with small portions of cold ether to remove the gum. The white solid (521 mg., 28%) was bis- (3,5-dimethylpyrazol1-yZ) ketone hydrazone (11), m.p. 119-121’ [from light petroleum (b.p. 40-60°)] (Found: C, 56.75; H , 6.7; N, 35-85. C1lH,,N, requires C, 56.9; H, 6.9; N, 36.2%). The i.r. spectrum of the material showed characteristic primary amine bands, vmaX. 3300 and 3410 (NH stretching) and 1630 cm.-l (NH, deformation). * Attempts t o isolate this material b y using excess of triaminoguanidine were unsuccessful (see Table). 6 C. H. Lin, E. Lieber, and J. P. Hotwitz, J . Amer. Chem. SOC.,1954, 76, 427. View Article Online Published on 01 January 1970. Downloaded by Christian Albrechts Universitat zu Kiel on 27/10/2014 17:10:29. 2512 J. Chem. SOC. (C), 1970 The aqueous solution (A) was brought to pH 6 with Nsodium hydroxide and slowly evaporated a t 40" under vacuum. Successive crops of triaminoguanidine nitrate separated (total recovery 615 mg., 27%). The solution was finally evaporated to dryness and the brown sticky residue was dissolved in water (10ml.). The solution was extracted with ether (10 x 20 ml.). Work up of the extracts yielded white plates (51 mg., 9%) of 3,5-dimethylpyrazole (m.p. 107-109"). The results of a number of such reactions are summarised in the Table. Conditions Molar ratio (triaminoguanidine to acetylacetone) 1 : 1.1la Temp. Products (%) (reaction time) (11) (1111 (IV~ Ambient 28 <1 32.5 (3 days) 1:2b 50 <1 1.5 Ambient (15 min.) 2.5 <1 <1 Ambient 4: 1 c (15 min.) <1 64-70 4 Ambient (30 min.) Reflux <1 11 13 (30 rnin.) a Triaminoguanidine nitrate recovered, 28%. 3,5-dimethylpyrazole was isolated in 9% yield. A sticky reddish yellow oil was also obtained. 6 No triaminoguanidine nitrate recovered. A reddish yellow oil was obtained. 0 Triaminoguanidine nitrate recovered, 75-80%. Sticky yellow gums again formed. d No triaminoguanidine nitrate recovered. 3,5-Dimethylpyrazole isolated, 5% . 6 Considerable quantities of resinous decomposition products were encountered. A previous report (cf. F. L. Scott, M. F. Cashman and J. Reilly, J . Amer. Clzem. SOL, 1953, 75, 1510) of a 58% yield of compound (IV) under these conditions is in error. The figure should probably have been 5.8. A Reactions of t h Hydrazone (11).-(a) With aldehydes. Benzaldehyde (0.057 ml.) was added to a solution of compound (11) (100 mg.) in 95% ethanol and the mixture was heated a t 70" for 15 min., treated with a few drops of water, and stirred for 3 hr. a t ambient temperature. The solution was then heated to boiling, treated with water until cloudiness appeared, and set aside for 24 hr. White crystals (106 mg., 77%) of bis-(3,5-divtzethylpyrazol-l-y1) ketone benzylidenehydrazone (V) separated, m.p. 102-103" (from aqueous ethanol) (Found: C, 67.1; H, 6.5; N, 26.2. C18H2,,N, requires C, 67-5; H, 6-25; N, 26.25%). A similar reaction with acetylacetone yielded bis-(3,5dimethylfiyrazol-l-yl) ketone (l-methyl-3-oxobutylidene)hydrazone (111),m.p. 103-104" (from aqueous ethanol),identical (mixed m.p. and i.r. spectra) with that obtained from the reaction of triaminoguanidine with acetylacetone (Found : C, 60.95; H, 7.3; N, 26.7. C1,H2ZN,0 requires C, 61.1; H, 7.0; N, 26.75%). (b) With acids. A solution of compound (11) (200 mg.) in 95% ethanol was treated with water (3 ml.) followed by hydrochloric acid ( 0 . 0 1 ~ ;0.5 ml.), and the mixture was stirred a t ambient temperature for 2 hr. It was then heated to boiling and treated with water until crystals began to appear. On cooling the solution, pale yellow crystals (35 mg., 30-6y0)of compound (IV) separated, m.p. 144-147', identical (mixed m.p. and i.r. spectra) with that obtained previously. The filtrate from this material was extracted with ether but the ethereal solution yielded only an intractable brown gum. The aqueous solution remaining was evaporated to dryness ; i t deposited white crystalline 3,5-dimethylpyrazole hydrochloride (103 mg., go%), m.p. 236-240" (shrinks and turns brown), identical (mixed m.p. and i.r. spectra) with a sample prepared by dissolving a small quantity of 3,5dimethylpyrazole in a few ml. of dilute hydrochloric acid and evaporating the solution (Found: C, 45.2; H, 7.15; C1, 26.55; N, 20.85. Calc. for C,H,C1N2: C, 45.3; H, 6-8; C1, 26.8; N, 21.15%). A similar reaction with nitric acid yielded compound (IV) (51yo)and 3,5-dimethylpyrazole (40%). Oxidation of the Dihydrotetrazine (IV).-A solution of the diliydrotetrazine (IV) (340 mg.) in acetic acid (15 ml.) was treated with hydrogen peroxide (20 vol.; 1-5ml.) and the mixture was heated a t 70" for 1.75 hr. The dark red solution was cooled, treated with water (10 ml.) and set aside for 18 hr.; red crystals (20 mg., 6%) of 3,6-bis-(3,5dimethylpyrazol-l-y I) tetrazine separated, m.p . 223-225" (from aqueous alcohol) (Found: C, 53.5; H, 5.15; N, 40.9% ; M , 269. C1,Hl,N, requires C, 53.35; H, 5.2; N, 41.5%; N , 270), hmxs (95% ethanol) 528 nm. (c 390). Further work-up of the reaction mixture yielded only decomposition products and some 3,5-dimethylpyrazole, A similar decomposition was found to occur when compound (IV) was heated similarly in acetic acid; this explains the low yield of the tetrazine. A cleaner but more tedious dehydrogenation of compound (IV) was effected by oxidation with air in toluene. A solution of compound (IV) (2-4g.) in dry toluene (40ml.) was set aside for 20 weeks in an air-filled stoppered vessel. It gradually turned red and long red needles (300 mg., 12.5%) of the tetrazine separated. We thank the Irish Government for a research fellowship (to R. N. B.). [0/701 Received, April 30th, 19701