1978 1297 Polyaza-azulenes. Part 1. Synthesis and Reactions of Some 2,3,3a,6- Tetrahydropyrazolo [3,4-d] [I,2]diazepines By Jonathan R. Frost and Jacques Streith,' Laboratoire de Synthhse et de Photochimie Organiques AssociB au CNRS, Ecole Nationale Superieure de Chimie de Mulhouse, Universitb du Haut-Rhin, 3, rue A. Werner, 68093 Muihouse CBdex, France The reactions of 2,3,3a.6-tetrahydropyrazolo[3,4-d] [1,2]diazepines (2) with methanolic sodium carbonate have been investigated. 4-Vinylpyrazoles (3) and (4). 2,4,5,6-tetrahydropyrazolo[3,4-d] [1,2]diazepines (5), 1(2),4,5,6-tetrahydropyrazolo[3,4-d] [1,2]diazepines (6). and 1 (2).6-dihydropyrazolo[3,4-d] [1,2]diazepines (7) are obtained, the nature of the product being dependent upon the way in which (2) is substituted.The mechanism by which the above compounds are formed is discussed. THEsynthesis of polyaza-azulenes is of interest when nitrogen atoms upon the properties of azulene. Along studying the effect of methine group replacement by these lines Hafner,l in his elegant work in the field of K. Hafner, J. Heterocyclic Cham., 1975, 12, Suppl. vol. 3, heterocyclic aromatic systems, synthesised some mono- s-33. and di-aza-azulene systems and showed the similarities of their electronic spectra with those of azulene. We describe here our first results obtained in the field of polyaza-azulene synthesis. The photochemically accessible lH-[1,2]diazepines (1)273 were chosen as starting materials for our synthetic work since these compounds, as recently reported,* undergo ready cycloaddition with diazomethane to J.C.S. Perkin I anion upon the immonium ion-Mannich type inter- mediate which is presumably initially formed in this reaction.Thus, starting from the diazepines (la-d) we obtained in good overall yield the stable crystalline adducts (2a-f) (see Table 1). lH N.m.r. data (see Table 2) and an X-ray structure for a related compound 697 show quite 8R3 C (R2)=NNHR1 @ !!!H (3) a; R1 = Ts, R2 = H a; R1 = Ts, R2 = H,R3 = Ac a; R1 = Ts,R2 = H,R3 = vinyl (Z-isomer) b; R1 = SOzPh, R2 = H b; R1 = S02Ph, R2 = H,R3 = Ac b; R' = S02Ph,R2 = H,R3 = vinyl c; R1 = SOzPh, R2 = Me c; R1 = S02Ph, R2 = Me, R3 = Ac c; R1 = SOzPh, R2 = Me, R3 = vinyl d; R1 = Bz,R2 = Me d; R1 = Bz,R~= Me,R3 =Ac d; R1 = Ts,R2 = H,R3 = vinyl (€-isomer) e;R1 =Bz,R2 =Me,R3 =Ts e; R1 = Ts,R2 = H,R3 = Et f; R1 = Ts, R2 = H,R3=MeOCH2 (numbering of the side-chains is non -systematic 1 afford unstable tetrahydro-1,2,6,7-tetra-aza-azulenede-rivatives (2; R3 = H) (hereafter referred to as 2,3,3a,6- tetrahydropyrazolo[3,4-d][1,2]diazepines).As reported earlier the cycloaddition reaction affords initially the expected l-pyrazoline in the first step; however this rapidly isomerises to the more conjugated 2-pyrazoline (2). These unstable adducts (2) may be stabilized by acetylation, methoxymethylation, or tosylation at the N-2 nitrogen atom. Acetylation and tosylation of the adducts (2; R3 = H) were carried out using standard procedures. Attempted N-2 methylation of (2; R1 = Ts, R2= R3 = H) using methanolic formaldehyde and sodium borohydride led unexpectedly to the 2-methoxy- methyl derivative (2f).Formation of this compound may be visualized as occurring via attack by methoxide 2 J. Streith and J. &I.Cassal, Angew. Chem. Internat. Edn., 1968, 7, 129. M. Nastasi, Heterocycles, 1976, 4, 1509. G. Kiehl, J. Streith, and G. Taurand, Tetrahedron, 1974, SO, 2851. Ha vinyl = )6=i(Hb Hc clearly that diazomethane adds site-specifically and regiospecifically to the A4-double bond of diazepines (1). Having achieved the synthesis of stable 2,3,3a,6-tetra- hydropyrazolo[3,4-d] [1,2]diazepine derivatives we next turned our attention to the chemistry of these novel heterocycles. We now report that on treatment with methanolic sodium carbonate the 2,3,3a,6-tetrahydro- pyrazolo[3,4-d][1,2]diazepines (2a-f) afford a series of products the nature of which depends upon the way in which the bicyclic molecules (2) are substituted.When the tetrahydropyrazolo[3,4-d][1,2]diazepines (2a-c), which all bear arylsulphonyl groups at N-6 and acetyl groups at N-2, are treated with methanolic sodium carbonate the corresponding 4-vinylpyrazole-3(5)-carb-5 B. L. Sondengani, J. Hentchoya HBmo, and G. Charles, Tetrahedron Letters, 1973, 261. R. Allmann and T. Debaerdemaecker, Cryst. Struct. Comm., 1974, 8, 205. 7 J. Streith, G. Kiehl. and H. Fritz, Tdvahedron IAters, 1974, 631. 1978 1299 TABLE1 Elemental analyses and physical data for compounds (2)-( 7) Yield Found (yo) Requires (yo1 Cryst. solvent M.P.("C) (%) c H N Formula C H N EtOH-H2O 178 60 54.1 5.0 16.7 C16H16N403S 54.2 4.85 16.9 EtOH-H 20 179-180 56 52.8 4.5 17.6 C14H1,N,O,S 52.8 4.4 17.6 MeOH 147 49 54.15 4.85 16.9 C&1&4O,S 54.2 4.85 16.9 EtOH 167-1 68 57 65.1 5.3 19.0 C1,H16N402 64.85 5.4 18.9 EtOH 161 52 61.9 4.9 13.7 C2,H2,N40,S 61.75 4.9 13.7 EtOH 144-145 39 54.0 5.3 17.1 Cl,Hl,N40,S 53.9 5.4 16.75 EtOH-H2O 143 58 53.6 5.0 19.4 Cl,H14N,0,S 53.8 4.9 19.3 EtOH-H2O 142 56 52.3 4.4 20.2 C12H1zN*O,S 52.2 4.4 20.3 EtOH 138 30 53.7 4.7 19.3 C1,H1,N402S 53.8 4.9 19.3 EtOH-H2O 159-161 100 53.8 4.9 19.2 Cl,Hl,N,02S 53.8 4.9 19.3 EtOH 149 75 53.3 5.5 19.3 Cl,Hl,N,O,S 53.4 5.5 19.2 53 53.7 5.6 16.8 C16Hl,N,O,S 53.9 5.4 16.75 EtOH 154-155 21 54.1 5.5 16.8 C15Hl,N40,S 53.9 5.4 16.75 MeOH 248 24 66.25 5.6 21.8 C14H14N40 66.1 5.55 22.0 179-1 80 78 66.65 4.9 22.1 C14Hl,N40 66.7 4.8 22.2C6H6 TABLE2 1H N.m.r.,* i.r., and U.V.spectra of compounds (2a-f) lH N.m.r. 1.r. U.V. H-3 and LlLlX. (EtOH)/R1 R2 (4 R3 H-3a (m) H-4 (dd) $ H-5 (dd) $ vmaX./cm-l nm (logloc) 2.44 (s),7.38 and 7.88 t 7.62 2.24 (s) 3,70-4.40 5.17 6.90 1 670 328 (4.22) 7.55-8.12 (m) 7.70 2.25 (s) 3.70-4.50 5.18 6.91 1677 328 (4.19) 7.50-8.10 (m) 2.22 2.25 (s) 3.80-4.35 5.22 6.81 1 650 323 (4.21) 7.35-7.80 (m) 2.20 2.30 (s) 3.80-4.40 5.36 7.24 1660 331 (4.26) 7.20-7.93 (m) 2.20 2.50 (s) 7.33 and 3.60-4.23 5.23 7.20 1675 328 (4.13) 7.90 t 2.43 (s),7.30, and 7.83 t 7.48 3.30 (s) 3 H 3.06-4.83 5.06 6.71 1599 336 (4.10) 4.60 (s)2 H * Determined for CDC1, solutions.t AA'BB' system J = 8 Hz. $ J3a,4 = J3a,5 ca. 2 Hz, J4,6 ca. 8 Hz. TABLE 3 1H N.m.r.,* i.r. and U.V. spectra of compounds (3a-e) lH N.m.r. NHbr (s, 1.r. R' R2/H-5(s) R3 exchangeable) vmax. Icm-l 2.40 (s),7.34, and 7.85 t 7.48 6.68 Ha 12.32 3 150, 1630 7.80 5.24 Hb (dd) $ 13.46 5.52 H, 7.23-8.06 (m) 7.23-8.06 6.64 Ha 12.40 3 160, 1 629 263 (4.23) 5.13 Hb (dd) $ 13.10 5.48 H, 7.30-7.95 (m) 2.23 6.60 Ha 12.20 3 140, 1630 262 (4.11) 7.65 5.10 Hb (dd) $ 13.00 5.30 H, 2.40 (s), 7.27, and 7.82 7.62 6.90 Ha 11.07 3 260, 3 150, 284 (4.41) 8.00 5.15 Hb (dd) $ 12.60 1632 5.55 H, 2.40 (s),7.40, and 7.80 t 7.46 1.14 (t)5 12.37 3 295, 3 050, 273 (4.13) 7.73 2.57 (9) 13.77 1612 * Determined for (CD,),SO-CDCI, solutions. t AA'BB system J = 8 Hz.$ Jar, = 11 Hz, Jac = 18 H~,J,,, = 2 H~.5 J = 8 Hz. TABLE4 1% N.m.r. spectra of compounds (3a, b, d, e) and (4) C-8 Ar Compd. C-3 c-4 c-5 C- 6 c-7 C-8 'J(CH) s 0 m p ArMe (3a) 142.18 120.30 127.14 124.97 115.22 132.29 182 135.84 127.14 129.29 143.80 20.92 (3b) 142.34 120.48 127.22 125.12 115.47 132.59 182 138.97 127.22 129.41 133.41 (3d) 140.03 118.57 129.90 126.82 113.81 141.45 164 135.61 127.36 129.64 143.81 20.89 (3e)* 142.82 123.57 127.71 15.55 15.15 132.83 182 135.96 127.11 129.76 143.86 20.97 (4) 142.43 120.76 ca. 128 124.75 114.28 131.95 181 135.68 126.94 129.95 143.71 20.99 * Also signals at 82.12 (N-CH,-0) and 56.43 (MeO).aldehyde tosyl and phenylsulphonylhydrazones (3a-c) function was further confirmed by its catalytic hydrogen- were obtained. Compounds (3a-c) exhibited character- ation to the 4-ethylpyrazole (3e). The stereochemistry istic lH n.m.r. chemical shifts and coupling constants for of the hydrazone function in these molecules follows from the three protons of the vinyl moiety (see Table 3). In the 13C n.m.r. lJ(C,H) coupling constant for C-8 (see the case of compound (3a) the presence of a vinyl Table 4). Values of lJ(C,H) for C-8 of cu. 180 Hz correspond to Z-isomers whereas values of ca. 160 Hz correspond to E-isomers.s The stereochemistry of the hydrazone function of compound (3c) could not be determined since this compound bears a methyl group at C-8. When the Z-tosylhydrazone (3a) was set aside in (CD3),S0 containing deuterium oxide and water for three weeks it isomerised quantitatively (13C n.m.r.) to the E-isomer (3d).In order to elucidate the mechanism of this base- promoted ring cleavage compound (2a) was treated with sodium carbonate at reflux in monodeuteriomethanol. The n.m.r. spectrum of the product clearly showed that deuterium had been incorporated into the vinyl moiety affording a ca. 1 :1 mixture of monodeuteriated vinyl pyrazoles (3a; Hb =D) and (3a; H, =D) together with (3a;R3=Hb=D) + 3(3a;R =H,=D) a little undeuteriated material. The Figure shows the n.m.r. spectrum of the mixture in the range 6 5.0-7.2.The lH n.m.r. spectrum of compound (3a) is also re- produced over the same range of chemical shift for comparison purposes. It will be noted that the lH n.m.r. spectrum of the mixture lacks the geminal coupling (Jbc=2 Hz) between protons Hb and H,. These protons now appear as sharp doublets having coupling constants of 11and 18 Hz respectively. Proton Ha in the mixture appears essentially as two super- imposed doublets having coupling constants of 11 and 18 Hz. From this data we conclude that deuterium has been incorporated at C-7 of compound (3a) via the intermediacy of anion (9) (Scheme) in a non-stereo-specific manner. The mechanism depicted in the Scheme J.C.S. Perkin I accounts for these findings provided that the first step in the reaction is a base-catalysed deprotonation of the doubly allylic H-3a of compound (2).That this is indeed the case was shown by the following lH n.m.r. experiment with compounds (2a). Treatment of a tetradeuteriomethanol solution of compound (2a) contained in an n.m.r. tube with a small piece of metallic sodium resulted in the loss of the vicinal and allylic couplings, Jsa,4 and J3%,5 =2 Hz at H-4 and H-5 respectively (see Table 2). Signals due to these protons now appear as sharp doublets, = 8 Hz, showing that H-3a of compound (2a) had been removed. It will be noticed that the acetyl stabilizing group is lost when (2a-c) are treated with methanolic sodium carbonate. Although it is not clear at which stage along the reaction path this group is removed it has been reported that N-acetylpyrazoles would be easily solvo- lysed under the reaction conditions employed, Methyl acetate formed from the solvolysis of the acetyl function was detected by V.P.C. in the distilled reaction solvent residues.Treatment of the methoxymethyl derivatives (2f) with methanolic sodium carbonate afforded the corres- ponding vinylpyrazole (4) (53%) together with compound (5) (21%). This result prompted a careful re-examin- ation of the reaction of compound (2a) with methanolic sodium carbonate. Chromatography on preparative plates afforded a small quantity (4%) of what we believe to be the corresponding l(2) ,4,5,6-tetrahydropyrazolo-[3,4-d][1,2]diazepine [(5),MeOCH, replaced by H)] which was identified by lH n.m.r.spectroscopy only. Compound (2d) on treatment with methanolic sodium carbonate afforded the pyrazolo[3,4-d]diazepine (6) albeit in low yield. Methyl benzoate and methyl acetate were also formed during this reaction indicating that solvo- lysis occurred at both the N-2 and N-6 positions of compounds (2d). Other products were formed in this reaction but these could not, in our hands, be isolated in a pure form. In order to explain the formation of these pyrazolo- [3,4-d]diazepines (5) and (6) we assume that the initial steps in the reaction sequence are the same as those shown in Scheme for vinylpyrazole formation. If instead of ring-opening intermediate (10) undergoes aromatisation leading to anion (12) via a base-induced double-bond migration or (12) is formed by recyclisation of the proposed intermediate (11)then compounds of type (5) and (6) may be obtained as depicted in the Scheme.That anion (12) is most likely to be involved in the form- ation of compounds of type (5) and (6) was shown by a second deuterium incorporation experiment. Thus reaction of compound (2d) with sodium carbonate in tetradeuteriomethanol resulted in the formation of compound (14) (Scheme). Integration of the lH n.m.r. spectrum of (14) indicated that one deuterium had been * N. Naulet, M. L. Filleux, G. J. Martin, and J. Pornet, Org.Magnetic Resonance, 1975, 7, 326. 9 H. A. Staab, Angew. Chem. Intemat. Edn., 1962, 1,351. 1978 1301 incorporated at both C-4 and C-5 in a non-stereospecific of suitably substituted compounds of type (2) with a manner. view to achieving the synthesis of 1,2,6,7-tetra-aza-An understanding of the mechanistic pathways leading azulene is continuing in this laboratory. HH HH 4(2) -R3-NT)I-Rl -R3--N yTi-Rl"N* R2 R* (8) (9 1 R3 =TsJ Me and MeOAc (14) SCHEME to compounds (3)-(6) enabled US to design suitably substituted tetrahydropyrazolo[3,4-d]diazepinesof type (2) which could undergo elimination affording 1(2),6-di-hydropyrazolo [3,4-a] [1,2]diazepinesm These compounds are Potentially tetra-aza-azulene Precursors* these lines we syntllesised the N-2 tosyl derivative (2e).On treatment with methanolic sodium carbonate at reflux this compound afforded the 1(2),6-dihYdro-pyrazolo[3,4-d] [1,2]diazepine (7), presumably via the intermediacy of (8) and (15) (see Scheme).The design EXPERIMENTAL lH N.m.r. spectra were determined at 60 MHz with tetra- as reference. N*m*r*spectrawere determined at 20.1 and 25 MHz for (CD,),SO solutions with tetramethylsilane as internal reference. Unless otherwise stated i.r. spectra were determined for KBr discs and column chromatography was carried out with Mer& Kieselgel 60, 70-230 mesh ASTM using a mixture of ethyl acetate and cyclohexane 8 : 2 (v/v) as eluant. Preparative t.1.c. was carried out on 20 x 20 cm plates coated with Merck Kieselgel HF,,, (type 60). A Girdel 75 gas chromato- graph (N, carrier gas, flame ionisation detector, column packed with FFAP on Chromosorb WHMDS) was used for analytical V.P.C.; i.v. refers to evaporation under water- pump vacuum. 2,3,3a,6-TetrahydroPyrazolo[3,4-d][1,2]diazepines (2a-f). -To ice-cold ethereal diazomethane (prepared from 43 g of 9-tosylmethylnitrosamide lo)was added a saturated chloro- form solution of the appropriate 1H-1,2-diazepine (2.0 g).l1*l2.* The reactants were maintained at 0 "C for 18 h after which time the solvent was removed by i.v. evapor- ation and the residual oil, crude (2; R3 = H), was treated as described under (i)-(iii) below. (i) It was treated with a mixture of acetic anhydride (2 ml) and pyridine (20 ml) at 50 "C for 18 h. The reaction mixture was poured onto crushed ice (ca. 100 g) and the resulting mixture was extracted with chloroform (3 x 100 ml).Evaporation of the chloroform extracts i.v. afforded an oil which was freed from residual pyridine by warming at 50 "C and 0.1 mmHg and finally column chromatographed t to give 2-acetyl-2,3,3a,6-tetrahydropyrazolo[3,4-d][1,2]diaze-pines (2a-d); see Tables 1 and 2. (ii) It was treated with p-toluenesulphonyl chloride (4.0 g) in pyridine (12 ml) at reflux for 15 min. The reaction mixture was cooled, poured into water (ca. 100 ml), and extracted with chloroform (3 x 75 ml). Evaporation of the chloroform extracts i.v. afforded a brown oil which was freed from pyridine at 50 "C and 0.1 mmHg and finally column chromatographed to give 6-benzoyZ-8-methyZ-2-tosyl-2,3,3a,6-tetrahydropyrazolo[3,4-d][1, 2ldiazepine (2e); see Tables 1 and 2.(iii) It was treated with methanolic formaldehyde (35- 40% ; 9 ml) in methanol (25 ml) at reflux for 30 min. The reaction mixture was cooled and sodium borohydride (1.04 g) was added portionwise with cooling. On stirring for ca. 1 h a pale yellow solid precipitated and this was filtered off and crystallized to afford 2-methoxymethyl-6-tosyZ-2,3,3a,6-tetrahydropyrazoZo[3,4-d][1,2]diazepine (2f) ; see Tables 1 and 2. 4- Vinylpyrazole-3( 5)-carbaldehyde Phenylsulphonyl- and Tosyl-hydrazones (3a-c) .The appropriate tetrahydro- pyrazolo[3,4-d][1,2]diazepine [(2a), (0.98 g); (2b), (0.99 g); and (2c), (0.77 g)] was heated at reflux in methanol [50 ml per g of (2)] containing sodium carbonate [l g per g of (2)] for 3 h.Filtration and evaporation of the solvent i.v. afforded a residue which was column chromatographed to give C-vinylpyrazole-3(5)-carbaldehyde phenylsulphonyl-and tosyl-hydrazones (3a-c) ; see Tables 1, 3, and 4. An investigation (v.P.c.) of the reaction solvent obtained from the evaporation of the above reaction indicated the presence of methyl acetate. Suspected 6-Tosyl-1(2),4,5,6-tetrahyd~o~yrazolo[3,4-d][1,2]-* The diazepine (Id) was prepared by photolysis of the corres- ponding N-iminopyridinium ylide in toluene and had a m.p. of 73 OC.13 t For compounds (2a-c) a small quantity of yellow material was eluted first in each case. This was identified spectroscopically as the corresponding 2-acetyl-2,6-dihydropyrazolo[3,4-d][1,2]-diazepine.For example, the preparation of (2a) afforded 2- acetyl-6-tosyl-2,6-dihydropyrazolo[3,4-d][1,2]diazepine (1.5y0), m.p. 205-215 "C (decomp.) (xylene) (Found: C, 54.5; H, 4.3; N, 17.0. C,,H,,N,O,S requires C, 54.5; H, 4.3; N, 17.0y0),i.r. vmax. 3 160, 1 742, and 1 675 cm-l; U.V. h,,,.(CHCl,) 289 nm (log,, E = 3.93); M+ = 330; lH n.m.r. G(CDC1,) 2.47 (s, Me), 2.57 (s, Me), 5.28 (d, J = 9.6 Hz, H-4). 6.40 (d, J = 9.6 Hz, H-5),7.28 (s, H-3), 7.61 (s, H-8), 7.37 (d) and 7.87 (d) (AA'BB' sys- tem, Ts). J.C.S. Perkin 1 diazepine.-Compound (3a) (0.97 g) was heated at reflux in methanolic sodium carbonate for 2.5 h under identical conditions to those described above. The residue obtained from evaporation of the reaction filtrate was applied to eighteen preparative t.1.c.plates. Elution with ethyl acetate-cyclohexane (8 : 2 v/v) gave compound (3a) (0.59 g, 69%) and a mixture (0.095 g) which was re-chromato-graphed on preparative t.1.c. plates. Two elutions with the same solvent mixture afforded crude suspected 6-tosyl- 1(2),4,5,6-tetrahydropyrazoZo[3,4-d][1, 2Idiazepine (0.036 g, 4%) which was identified from the following lH n.m.r. spectrum only, G[CDCl,-(CD,),SO] 2.41 (s), 7.33 and 7.86 (AA'BB', Ts), 2.90-3.2 (m, 2 x H-4) and 3.46-3.66 (m, 2 x H-5), 7.43 (s, H-3), and 7.73 (s, H-8), and 8.0br (s, NH). 4- VinyZpyrazole-3( 5) -carbaldehyde (E)-Tosylhydrazone (3d). -4-Vinylpyrazole-3( 5)-carbaldehyde (2)-tosylhydrazone (3a) was set aside in (CD,),SO containing deuterium oxide and water for 3 weeks whence it was observed by 13C n.m.r.to isomerise quantitatively to its (E)-isomer (3d). Addition of the (CD,),SO solution to water gave a white precipitate which was filtered off and crystallised to afford 4-vinyl- pyrazole-3( 5)-carbaldehyde (E)-tosylhydrazone (3d) ; see Tables 1, 3, and 4. 4-Ethylpyrazole-3(5) -curbaldehyde (2)-Tosylhydrazone (3e). -Hydrogen was bubbled through a solution of the vinyl- pyrazole (3a) (0.18 g) in ethanol (100 ml) containing 10% palladium charcoal (0.1 g) until all the starting material had been consumed (ca. 2 h t.1.c.). The reaction mixture was filtered and the filtrate evaporated i.v. to yield a white solid which was crystallized to afford 4-ethylpyrazole-3(5)- carbaldehyde (2)-tosylhydrazone (3e) ; see Tables 1, 3, and 4.l-MethoxymethyZ-4-vinyZ~yrazole-3-carbaldehyde(2)-Tosyl-hydrazone (4) and 2-Methoxymethyl-6-tosyl-2,4,5,6-tetrahydro-$yrazolo[3,4-d][ 1,2]dzazepine (5) .-2-Methoxymethyl-6- tosyl-2,3,3a,6-tetrahydropyrazolo[3,4-d][1,2]diazepine (2f) (0.33 g) was heated under reflux in methanol (12.5 ml) containing sodium carbonate (0.3 g) for 3 h. The reaction mixture was cooled, filtered, and evaporated i.v. to afford an oil which was applied to ten preparative t.1.c. plates. Elution with ethyl acetate-cyclohexane (6 : 4 v/v) afforded l-methoxymethyl-4-vinylpyrazole-3-carbaldehyde(2)-to-sylhydrazone (4) (see Tables 1 and 4) [RF0.7; i.r.vmae (liq. film) 3 120 and 1630 cm-l; lH n.m.r. G(CDC1,) 2.39 (s), 7.25 (d) and 7.83 (d) (AA'BB', Ts), 7.30 (s, H-5), 7.63 (s, H-8), 6.53 (dd, Ha), 5.21 (dd, Hb), 5.46 (dd, Hc), 11.83br (s, NH exchangeable), 3.38 (s, OMe), 5.40 (s, OCH,N) (Jab = 11 Hz, Jac = 17, Jbc = 1.5 Hz)] and 2-methoxy-methyl-6-tosyl-2,4,5,6-tetrahydropyrazoZo[3,4-d][1, 2Idiazepine , (5) (see Table 1) [RE'0.46; i.r. vmx. 1620 cm-l; lH n.m.r. G(CDC1,) 2.41 (s),7.30 (d) and 7.90 (d) (AA'BB', Ts), 2.90-3.20 (m, 2 x H-4) and 3.50-3.80 (m, 2 x H-5), 7.44 (s, H-3) and 7.70(s,H-8), 3.30 (s,OMe),and 5.33 (s,O-CH,-N). 6-Benzoyl-8-methyl-1(2),4,5,6-tetrahydropyrazoZo[3,4-d]-[1,2]diaze~ine (6).-2-Acetyl-6-benzoyl-8-methyl-2,3,3a,6-tetrahydropyrazolo[3,4-d][1,2]diazepine (2d) (1.00 g) was heated at reflux in methanol (50 ml) containing sodium carbonate (1.0 g) for 2 h. The reaction mixture was cooled, filtered, and the filtrate evaporated i.v. to afford lo Th.J.de Boer and H. J. Backer, Organic Synth., Coll. Vol. IV, 1963, 250. l1 J. Streith and J. M. Cassal, Tetrahedron Letters, 1968, 4541. l2 R. A. Abramovitch and T. Takaya, J. Org. Chem., 1973, 88, 3311. l3 J. Streith and S. Syren, personal communication. an oil which was column chromatographed giving methyl benzoate (0.155 g, 29%) followed by a pale yellow solid mixture (0.336 g) which afforded 6-benzoyl-&methyl-1(2),4,5,6-tetrahydropyrazoZo[3,4-d][1,21diazepine (6) (0.207 g) on crystallisation (see Table l), i.r. vmx. 3 160 and 1 620 cm-l, U.V.AmX.(EtOH)295 nm (log,, E = 3.95); lH n.m.r. G[CDCl,-(CD,),SO] 2.40 (s, Me), 2.85-3.15 (m, 2 x H-4), and 3.90-4.18 (m, 2 x H-5), 7.20-7.60 (m, ArH + H-3), and 13.2br (s, NH exchangeable). Continued elution with ethyl acetate-cyclohexane followed by ethanol afforded a crude yellow solid (0.434 g) which was not investigated further. An investigation (v.P.c.) of the reaction solvent obtained from the evaporation of the above reaction indicated the presence of methyl acetate. 6-BenzoyZ-8-methyl- 1 (2),6-dihydropyrazolo[3,4-d][1,2]di-azepine (7).-6-Benzoyl-8-methyl-2-tosyl-2,3,3a,6-tetra-hydropyrazolo[3,4-d] [1,2]diazepine (2e) ( 1.00 g) was heated at reflux in methanol (60 ml) containing sodium carbonate (1.0 g) for 1 h. The reaction mixture was cooled, filtered, and the filtrate evaporated i.v.The residue was column chromatographed to afford 6-benzoyE-8-methyl-1(2),6-di-hydro~yrazolo[3,4-d][1,2]diaze~ine(7) (see Table l), i.r. vmx. 3 140 and 1660 cm-'; U.V. &,(EtOH) 237 nm (log,, E = 4.32); IH n.m.r. G[CDCl,-(CD,),SO] 2.40 (s, Me), 6.41 (AB quartet, Ja~ 8 Hz, H-4 and H-5), 7.20- = 7.70 (m, ArH -t H-3), and 7.50br (s, NH exchangeable). Deuteriation Experiments.-(i) The reaction of 2-acetyl-6-tosyl-2,3,3a,6-tetrahydro~yrazolo[3,4-d][1,2]diazepine (2a) with sodium carbonate an monodeuteriomethanol (CH,OD) . Compound (2a) (0.352 g) was heated at reflux in mono- deuteriomethanol (5 ml) containing sodium carbonate (0.3 g) for 2.5 h. The reaction was cooled, filtered, and the filtrate evaporated i.v.to afford a residue which was column 1303 chromatographed. Elution with a mixture of ethyl acetate and cyclohexane (6 : 4; v/v) gave a white solid (0.142 g) which on crystallisation from aqueous ethanol afforded a mixture (0.081 g) of vinylpyrazole-3(5)-carb-aldehyde tosylhydrazones [(3a; Hb = D) and (3a; H, = D) ca. 1 : 1 major products and (3a) minor product]; M+ 291; lH n.m.r. [(CD,),SO] (see Figure). (ii) The reaction of 2-acetyZ-6-benzoyl-8-nzethyE-2,3,3a,6-tetrahydro~yrazolo[3,4-d][1,2]diazepine (2d) with sodium carbonate in tetradeuteriovnetha?zoZ (CD,OD) . Compound (2d) (0.398 g) was heated at reflux in tetradeuteriomethanol (4 ml) containing sodium carbonate (0.4 g) for 3 h.The reaction was set aside overnight at room temperature and then filtered. Evaporation of the filtrate i.v. gave an oil which was applied to eight preparative t.1.c. plates. Elution with a mixture of ethyl acetate and cyclohexane (8: 2; v/v) gave deuteriomethyl benzoate (0.047 g) and a mixture (0.22 g). A portion of the latter (0.103 g) was rechromato- graphed over Merck silica gel 60 under pressure (ca. 5 bar). Elution with a mixture of ethyl acetate and acetonitrile (95 : 5; v/v) afforded 6-benzoyl-8-methyl-4,5-dideuterio-l(2),6-dihydropyrazolo[3,4-d][l,2]diazepine(14) (0.031 g), M+256; IH n.m.r. (80 MHz Fourier transform) G[(CD,),SO- CDCl,] 2.45 (s, Me), 3.05 (m, CHD), 4.10 (m, CHD), 7.30- 7.65 (m, ArH + H-3), and 12.95br (s, NH). We thank Professor Fritz, Ciba-Geigy A. G., Basel, and H. Strub, ENSCM, for determining and interpreting 13C n.m.r. spectra, Dr. Teller, laboratoire de chimie organique, spectromktrie de masse, Institut de Chimie de Strasbourg, for determining mass spectra and the C.N.R.S. for a research fellowship. [7/1808 Received, 14th October, 19773
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