Reactions of glyoxals with hydrazones: a new route to 4-hydroxypyrazoles

摘要

J. CHEM.SOC. PERKIN TRANS. I 1985 Reactions of Glyoxals with Hydrazones: A New Route to 4-Hydroxypyrazoles Mikael Begtrup" and Hans Peter NytoftDepartment of Organic Chemistry, Technical University of Denmark, OK-2800 Lyngby, Denmark N-Substituted hydrazones of aldehydes react with glyoxals under non-aqueous conditions to give N- substituted 4- hydroxypyrazoles; fourteen such products are described. In the presence of water, N-substituted 3-acyl-4- hydroxypyratoles are produced from 2-oxoaldehyde hydrazones and glyoxals. It is shown that glyoxals combine in a 1 :1 ratio with N-monosubstituted hydrazines to give 2-hydrazonoaldehydes as the kinetically controlled products. At room temperature or lower, these hydrazonoaldehydes rearrange to the more stable 2-oxoaldehyde hydrazones and react with glyoxals to give N-substituted 3-acyl-4- hydroxypyrazoles; sixteen such products are described.This synthesis, involving easily accessible starting materials, opens up a new, and for certain derivatives exclusive, route to 4-hydroxypyrazoles. The discovery of pyrazomycin (l), an antiviral, microbial compound,' has stimulated interest in 4-hydroxypyrazoles (2), a class of compound less well explored than their 3- and 5-hydroxy-substituted counterparts. Reported syntheses of 4- hydroxypyrazoles (2) fall into two categories, one characterised by the formation of C-N bonds ~nly,~-~ the other Pand involving C-C bond formation(s). The combinations of a-CHZOH diazoesters with alkyl malonates,*-" or of alkyl hydra- zinoacetates with a-oxoesters,' ' to give 4-hydroxypyrazoles, seem to be the only known examples of the C-C bond-forming type of synthesis.The inherent limitations in the substitution patterns attain- able through the known methodology motivated our search for alternative routes to the 4-hydroxypyrazoles (2), all involving C-C bond-forming reactions. We describe our results here. Results and Discussion A retrosynthetic inspection of structure (2) suggests the reaction of aldehyde hydrazones (3)and glyoxals (4) to be an obvious, though apparently neglected, synthetic possibility (Scheme 1). In fact, we found that the aldehyde hydrazones (3; R' = Me or Ph, R2= H, Me, Et, Pr, or Ph) and the glyoxals (4; R3= H, Me, or Ph), when heated together under anhydrous conditions in butyl acetate containing acetic acid, afforded moderate to excellent yields of the 4-hydroxypyrazoles (2); fourteen representatives of these are listed in Table 1 (entries 1-14).The structural assignment of these rests on (i) agreement in m.p.s mixed m.p. in the case of (2; R' = Ph, R2= H, R3 = Me) with eight previously described compounds of this series, and (ii) comparison of the 'H and 13C n.m.r. spectra with those recorded for the authentic specimens (entries 3,4,6-9, 13, and 14 in Table 1) The "C n.m.r. spectral results are given in Table 2. The 'H n.m.r. results are available as a supplementary Publication (SUP No. 56091,2 pp.).* The hydrazones of lower aldehydes, (3; R' = Me or Ph; R2= H, Me, Et, or Pr), are of limited In the experiments where they were generated in situ from the reaction of the aldehyde and N-substituted hydrazine followed by the addition of the glyoxal, the expected 4-hydroxypyrazoles (2R2 = Me, Et, or Pr) were invariably accompanied by the corresponding 3- unsubstituted analogues (2; R2 = H), suggesting the corn- petitive involvement of the formaldehyde hydrazones (3; R2= H).Conceivably, these could arise by 'transhydrazonation', followed by C-C bond fission, as indicated in Scheme 2 (path a). * For details of the Supplementary Publications Scheme see Instructions for Authors (1985) in J. Chem. SOC.,Perkin Trans. 1, 1985, Issue 1. (2) Scheme 1. H H IQJ Scheme 2. When conducted in the presence of water, the reaction between compounds (3) and (4) afforded 3-acyl-4-hydroxy- pyrazoles, obviously deriving from the reaction between the glyoxal hydrazones and the glyoxals (4), the former compounds arising from (3) and (4) by 'transhydrazonation' (Scheme 2, 82 J.CHEM. SOC. PERKIN TRANS. I 1985 Table 1. Preparation of the 4-hydroxypyrazoles (2) and (8) from the hydrazones (3) and (7), respectively Product (2), from starting materials (3)and (4) Analysis () Found Yield of M.p. of pure Reported (Required)Entry Reaction" Work-up crude product M.p. Recrystallization compoundC m.p. 7A7 no. R' R2 R3 conditions conditions (023 medium c.C> ("C) c H N(OC) 1 Me H Me 31 112-1 18 E 120-122 53.35 7.4 24.75 (53.55) (7.2) (25.0)2 Me H Ph 35 140-142 C 149-150 68.65 5.75 15.95 (68.95) (5.8) (16.1)3 Me Me Me 23 174-177 F 18 1-1 83 I 87-1 89' 4 Me Me Ph 15' 149-154 C 153-1 55 160' 70.0 6.5 14.75 (70.2) (6.45) (14.9)5 Me Ph Me 46 177-1 79 C 178-180 69.8 6.45 14.8 14 175-177 (70.2) (6.45) (14.9)6 Me Ph Ph 86 142-149 C 170-172 175-177' 7 Ph H Me 35 124-126 D 136 137-13gk31 124-126 8 Ph H Ph 66 157-161 C 180-182 179' 76.55 5.2 12.0 (76.25) (5.1) (1 1.85)9 Ph Me Me 23 Oi1 h 138-140' 10 Ph Et Me 27 1 22- 125 I 134-135 71.0 7.1 13.7 19' 122-125 (71.25) (7.0) ( 13.85)11 Ph Pr" Me 14/ 63-7 1 I 88-90 72.2 7.55 12.65 (72.2) (7.45) (1 2.95) 12 Ph Ph Me 35 119-133 C 144 76.75 5.65 11.0 (76.8) (5.65) (1 1.2)13 Ph Me Ph 459 153-1 58 C 170 175' 76.65 5.65 11.0 (76.8) (5.65) (11.2)14 Ph Ph Ph 70 148-149 G,J 148-149 252' 80.6 5.2 8.7 (80.8) (5.15) (8.95) Product (8), from starting materials (4) and (7) 15 Me Me H 90 85--90 A 92 51.1 5.75 19.85 (51.4) (5.75) 20.0) 16 Me Me Me 53 48-6 1 B 66-67 54.15 6.5 17.9 (54.55) (6.55) (18.15) 17 Me Me Ph 74 110-1 15 A 119-121 66.95 5.65 12.85 (66.65) (5.6) 1 (12.95) 18 Me Ph H 66 64-66 A 68-69 65.2 5.0 13.75 (65.35) (5.0) (13.85) 19 Me Ph Me 82 6 1-67 B,H 87-88 67.1 5.55 12.6 57 67-68 (66.65) (5.6) (12.95) 20 Me Ph Ph 52 92-98 B 107-108 73.55 5.05 10.15 0 (73.35) (5.05) ( 10.05) 21 Ph H H 42 132-136 C,H 143-145 63.5 4.2 14.8 (63.8) (4.3) (14.9) 22 Ph H Me 46 76-80 A 81-82 65.55 5.05 13.95 35 76-80 (65.35) (5.0) (13.85) 23 Ph H Ph 100 122-1 25 C,H 130 72.7 4.55 10.65 22 122-125 (72.7) (4.6) (10.6)24 Ph Me H 40 92-98 A 98-100 65.4 5.0 13.85 (65.35) (5.0) (13.85)25 Ph Me Me 61 79-80 A 79-8 1 66.8 5.65 12.9 38 76-80 (66.65) (5.6) (12.95)26 Ph Me Ph 91 121-122 H 121 73.25 5.05 10.0 (73.35) (5.05) (10.05) 27 Ph Ph H 84 101-105 B 106-107 72.85 4.55 10.6 (72.7) (4.6) (10.6)28 Ph Ph Me 46 98-99 B 101-103 73.75 5.15 9.95 26 101-I03 (73.35) (5.05) (10.05) See Experimental section for details.The hydrazones (3)and (7) were prepared in siru when reaction conditions (b), (e),or (f)were used. A, hexane; B, ligroin (b.p. 80-1 10 "C);C, ethyl acetate; D, ethyl acetate-hexane; E, propan-2-01; F, ethanol; G, chloroform; H, methanol; I, toluene; and J, toluene-hexane. Most of the 4-hydroxypyrazoles were colourless with a few exceptions which were slightly yellow.In addition, compound (2; R' = R3 = Me, R2 = H) (27) was present in the combined ether and ethyl acetate extracts (n.m.r.). In addition, compound (8;R' = Me, R2= R3 = Ph) (46) was isolated from the dichloromethane extract of the basic solution. The dichloromethane was removed and the residue worked up as in (e). f In addition, compound (2R' = Ph, R2 = H, R3 = Me) was formed. Yields are specified under the work-up conditions. In addition, compound (8; R' =R2 = R3 = Ph) (26) was isolated as described in work-up conditions (h). The product was converted into its crystalline 0-acetyl derivative as described under work-up conditions (t). Ref. 8. j Ref. 26. Ref. 6. J. CHEM.SOC. PERKIN TRANS. I 1985 83 Table 1 (conrinued) Product (2), from starting materials (3) and (4) Analysis () Found Yield of M.p. of pure Reported (Required)Entry Reaction Work-up crude product M.p. Recrystallization compound' m.p. /pA-, no. R' RZ R3 conditions conditions () ("C) medium ("C) ("C) C H N 29 Ph Ph Ph (c) (4) 87 154-1 59 C 159-160 77.55 4.7 8.05 (77.65) (4.75) (8.25) 30 Bn Me Me (.f) (1) 39 4651 B 45 67.6 6.05 12.15 (67.8) (6.15) (1 2.15) Table2. '3CN.m.r. shifts (in p.p.m. relative to the CDCI, centre peak at 6 76.90 p.p.m.) of the 4-hydroxypyrazoles (2) and (8)dissolved in OS~M-CDCI, Compound (2) G/p.p.m. 3-Me or 5-Me R' R2 R3 C--O c-3 C-4 c-5 c-1' c-2' c-3' C-4' NMe /-A-, COMe Me H Me 126.8 138.3 125.4 36.2 7.8 Me Me Me H Me" Phb 136.0 127.2 135.6 138.8 125.6 129.8 128.6 129.1 128.1 35.8 37.5 10.0 8.0 Me Me Ph Me Ph H Phb Me Me 135.6 133.9 129.7 136.8 136.7 139.5 130.9 126.4 125.8 135.9 139.4 128.5 125.3 124.3 129.0 128.1 129.0 128.0 126.2 127.4 36.9 36.6 9.9 8.2 9.1 Ph Me Me 136.9 139.4 125.3 139.4 123.9 128.6 126.7 9.7 9.1 Ph Ph Ph" 132.8 137.6 131.5 Compound (8) Me Me Me Me Me Me H Me Ph 197.9 197.8 198.0 136.3 135.2 135.5 146.6 142.9 143.2 115.7 123.3 127.5 128.0 128.6 128.6 128.3 40.1 37.3 7.6 25.3 25.2 Me Ph H 190.1 135.1 149.4 115.4 136.2 128.1 130.2 132.9 40.4 Me Ph Me 190.1 134.5 145.6 122.8 136.4 128.0 130.2 132.8 37.5 7.6 Me Ph Ph 190.0 135.0 146.4 127.7 39.1 Ph H H" 185.6 139.0 144.7 113.4 138.7 118.2 128.6 126.6 Ph Ph H H Me Ph 189.4 189.6 137.7 138.1 142.9 143.2 124.5 127.2 139.1 124.4 129.1 128.6 8.9 Ph Me H 198.5 137.8 147.0 112.4 139.6 119.2 129.3 127.3 25.5 Ph Me Me 198.5 136.9 143.5 123.8 139.4 124.6 129.1 128.4 9.0 25.5 Ph Me Ph 198.7 137.2 143.8 127.3 25.6 a Solvent: CDC13-(CD3)zS0 (12: 1).Saturated solution. path b). This casual observation prompted a more detailed H R2 study of the synthesis of z-oxoaldehyde hydrazones (7) as the starting materials for the production of the potentially useful 3-acyl-4-hydroxypyrazoles (8). At 0 "C or below, methylglyoxal combines with methyl- or phenyl-hydrazine (5;R' = Me or Ph) (Scheme 3) to give the hydrazonoaldehydes (6;R' = Me or Ph, R2 = Me) in a kinetically controlled reaction.In acidic solution, isomerisation to the more stable oxohydrazones (7; IR' = Me or Ph,R2 = Me) occurs at room temperature, making the last-named compounds easily accessible starting materials for the synthesis of the 3-acyl-4-hydroxypyrazoles (8). Six oxohydrazones (7;R1 = Me, Ph, or PhCH,, R2 = H, Me, or Ph) were thus prepared and converted into the sixteen new 3-acyl-4-hydroxypyrazoles (8) listed in Table 1 (entries 15-30); R2 they were characterised by comparisons of their 'H and 13C n.m.r. spectra with those of compound (8;R' = Ph, R2 = H, R3 = Me) (entry 22), the structure of which was established by Scheme 3.oxidation to the carboxylic acid, followed by decarboxylation to give a product identical with an authentic specimen of 4-In no case did the obviously rearrangement to the oxohydrazones (7) took placehydroxy-5-methyl- 1-phenylpyra~ole.~ hydrazonoaldehyde (6;R' = Me or Ph, R2 = Me) give rise to before the condensation reaction. the formation of N-substituted 5-acetyl-4-hydroxypyrazoles; Careful n.m.r. monitoring of a mixture of methylglyoxal and Me Me(10) (111 compound (5; R' = Me) (Scheme 3) as a function of time revealed the sequential appearance of (6 R' = R2 = Me), (7;R' = R2= Me), a diketone, isolated and identified as (9),and, finally, the 3-acyl-4-hydroxypyrazole(8; R' = R2 = R3= Me), accompanied by the formaldehyde aminal (10) which was identified by comparison with a specimen synthesized from compound (7; R' = R2 = Me) and formaldehyde by a known method.14 The diketone (9) is apparently not an intermediate in the pathway to compound (8; R' = R2 = R3= Me), as neither the expected 3-acetyl-5-hydroxy-l,4-dimethylpyrazole,nor the possible 5-acetyl-4-hydroxy- 1-methylpyrazole, were observed in the reaction mixture.The formation of compound (10) requires the intermediacy of formaldehyde, or its equivalent, conceivably arising from the reaction of compounds (7;R' = R2= Me) and (4 R3= Me) as outlined in Scheme 2. Interestingly, the hydrazonoaldehyde (6 R' = R2 = Me) reacted with formaldehyde in the ratio 1 :1 to give a product possessing the characteristics expected for the dihydro-1,3,4- oxadiazine derivative (11).In summary, aldehyde hydrazones and glyoxals, both easily accessible starting materials, serve well for the synthesis of 4- hydroxypyrazoles, including the 3-acyl derivatives. The choice between non-aqueous or aqueous conditions depends on the structure of the target molecules and can easily be made on the basis of the above discussion. ExperimentalSolvents were removed under reduced pressure. Flash chromatography was performed as described in ref. 15. The purity and identity of all compounds were confirmed using t.l.c., m.p.s, and i.r., 'H n.m.r., and mass spectra. 'H N.m.r. spectra were recorded on a Bruker HX-90 instrument. "C N.m.r. spectra were obtained on a Bruker WH-90 instrument and assigned as described previously.'6 Mass spectra were obtained on a V.G.Micromass 7070 F instrument. Benzylhydrazine,' ' formaldehyde phenylhydrazone,' gly-oxal phenylhydrazone, ' 1-phenylhydrazono-2-phenylethan-one,2o benzaldehyde methylhydrazone,2 ' and benzaldehyde phenylhydrazone,22 were prepared by literature methods. Anhydrous methylglyoxal was prepared by stirring a com- mercial50 aqueous solution (2.60 ml), n-butyl acetate (10 ml), and anhydrous sodium sulphate (2 g) for 15 min. The organic solution was decanted off, stirred for 15 min with anhydrous magnesium sulphate (2 g), and filtered. Anhydrous phenylgly- oxal was obtained by distilling its hydrate.23 Ether refers to diethyl ether. J. CHEM. SOC. PERKIN TRANS.I 1985 Preparation of 4-Hydroxypyrazoles.-Reaction conditions. (a) The hydrazone (3)or (7) (7.75 mmol) was mixed at 0 "Cwith the glyoxal (4) (15.7 mmol), dissolved in dry n-butyl acetate, magnesium sulphate (1.0 g), and acetic acid (1.0 ml). Stirring was continued at 20 "C for 10 min and then at 110 "Cfor 1h. (b) The hydrazone (3) was prepared in situ by adding the aldehyde (7.75 mmol) with stirring at 0 "Cto the hydrazine (7.75 mmol) in butyl acetate (3.0 ml). Stirring was continued at 0 "C for 10 min and then at 20 "Cfor 1 h. In the case of formaldehyde a 40 aqueous solution (0.58 ml) was used and anhydrous sodium sulphate (1.0 g) was added. This was decanted off and extracted with butyl acetate (2 x 1 ml). (c) The hydrazone (3) or (7) (7.75 mmol), the glyoxal (7.75 mmol) (glyoxal in 40, methyl glyoxal in 50 aqueous solution), and acetic acid (21 ml) were stirred at 110 "C for 1 h.(d) As in (c) but replacing acetic acid with water (40ml).(e)The hydrazine (5)(7.75 mmol), the glyoxal(4) (23.3 mmol) in aqueous solution, and water (40ml) were heated to reflux for 3 h. cf) As in (e) but replacing water with acetic acid (40 ml) and lwhydrochloric acid (40 ml). Work-up conditions. (a) The reaction mixture was filtered while still hot. Extraction with boiling butyl acetate (2 x 5 ml) and removal of the solvent gave a residue which was dissolved in lw-aqueous sodium hydroxide (20 ml). Washing with dichloromethane (2 x 20 ml), acidification to pH ca. 2 with conc.hydrochloric acid, extraction with dichloromethane (2 x 10 ml), washing with saturated aqueous hydrogen carbonate (2 x 5 ml) (this washing was necessary only when phenylglyoxal was used as the 2-oxo-aldehyde), drying (MgS04), and removal of the dichloromethane gave a residue which was extracted with boiling ethyl acetate (20 + 4 x 5 ml). The hot extracts were filtered through silica gel (2.5 g) and activated carbon (1 g). Removal of the ethyl acetate afforded the crude product. (6) In cases where the sodium salt of the hydroxypyrazole does separate it was isolated and washed with ethyl acetate (2 x 20 ml). The aqueous filtrate was washed with dichloromethane (2 x 20 ml) and combined with the washed salt. The mixture was acidified and work-up continued as in (a).(c) Alternatively, the sodium salt was dissolved by addition of water (20 ml). Washing with dichloromethane (2 x 20 ml), acidification to pH ca. 2 with conc. hydrochloric acid, extraction with dichloromethane (3 x 20 ml), drying (MgS04), filtration through silica gel (1 g) and activated carbon (0.5 g), and removal of the dichloromethane gave a residue which was extracted with boiling ligroin (b.p. 80-1 10 "C) (3 x 5 ml). The volume was reduced to ca. 2 ml and the mixture cooled to 0 "C. Filtration gave the crude product. (d) When the hydroxypyrazole is slightly soluble in di- chloromethane and separates in the crystalline state, work-up was performed as in (a). However, after the acidification the mixture was left overnight.Filtration, washing with water (2 x 2 ml), drying, extraction with boiling ethyl acetate (20 + 4 x 5 ml), filtration of the hot extract through silica gel (2.5 g) and activated carbon (1 g), and removal of the ethyl acetate gave a residue which was triturated with boiling hexane (3 x 5 ml) and with 20 "Cchloroform (2 + 3 x 1mi), and the residue collected on a filter. (e) In cases where the hydroxypyrazole is less acidic the reaction was followed by careful removal of the solvent at 0.1 kPa and 40°C. The residue was stirred for 10 min with IM- aqueous potassium hydroxide (40 ml) and ether (10 ml). Filtration, separation of the ether, and successive washing of the precipitate and the aqueous solution with ether (2 x 10 ml) was followed by acidification of the combined precipitate and aqueous solution, and work-up was continued as in (a).cf)When the potassium salt was slightly soluble, the solvent J.CHEM. SOC. PERKIN TRANS. I 1985 was removed as in (e), followed by stirring with boiling 2~- potassium hydroxide (10 ml) for 2-3 min. Cooling to 0 "C, filtration, stirring with ether (20 ml), filtration, and washing with dichloromethane (3 x 5 ml) gave a residue which was stirred with boiling conc. hydrochloric acid (5 ml) for 2-3 min. Cooling to O"C, filtration, and washing with water (5 ml) afforded the crude product. (g)Work-up was initiated as in (a),but since the hydroxy- pyrazole is relatively basic the acidification with conc. hydro- chloric acid was stopped at pH 6.Then the water was removed and the residue was extracted with ethanol (3 x 5 ml). Removal of the ethanol left a residue which was triturated with boiling acetone (5 x 10 ml). Removal of the acetone, dissolution of the residue in methanol (10 ml), filtration through silica gel and activated carbon as in (a), removal of the methanol, and washing of the residue with hexane (2 x 10 ml) and ether (2 x 2.5 ml) gave the crude product. (h) Work-up was initiated as in (a).The material which did not dissolve in sodium hydroxide was filtered off. Procedure (a) was continued for the filtrate which produced 4-hydroxy-3- methyl-1,5-diphenylpyrazole(2R' = R3= Ph, R2 = Me). The residue was stirred with ether and work-up continued as in cf)to give 3-benzoyl-4-hydroxy- 1,5-diphenylpyrazole (8;R = R2 = R3 = Ph).(i) As in (g), but the washing with ether was followed by washing with ethyl acetate (2 x 1 ml) which left the crude product. (j)The reaction mixture was extracted with dichloromethane (3 x 25 ml). Removal of the dichloromethane gave the crude product.(k)As in G), but the resulting material was worked up as in (a). (1) As in (k). The material obtained was dissolved in ethyl acetate-hexane (1 :4; 7.8 ml). The solution was filtered through silica gel (2 g) and the silica gel extracted twice with the eluant (2.5 ml). The filtrate was evaporated to dryness. (m)The reaction mixture was diluted with water (60ml) and 33 aqueous sodium hydroxide was added until the solution reached pH 6.The mixture was cooled to 0 "C and filtered. The residue was extracted with boiling ligroin (3 x 5 ml) and the product isolated as in (c). (n) As in (m),but filtration was replaced by extraction with dichloromethane (4 x 25 ml) followed by removal of the dichlorome thane. (0)33 Aqueous sodium hydroxide was added until pH 10 was reached, keeping the temperature below 30 "C. Filtration, washing with water (20 ml), acidification of the filtrate to pH ca. 2 (conc. hydrochloric acid), extraction with dichloromethane, and work-up as in (n) gave the crude product. (p) Work-up was performed as in (a)with acidification to pH 6. The crude product was then flash-chromatographed (ethyl acetate-hexane, 1 : 1). The third fraction (RF0.19) contained the 4-h ydrox ypyrazole.(4)Work-up was performed as in (a).Then flash chromato- graphy (ethyl acetate-hexane 1 :1) first gave 3-ethyl-4-hydroxy- 5-methyl-1-phenylpyrazole(2; R' = Ph, R2 = Et, R3 = Me), then 4-hydroxy-5-methyl-1-phenylpyrazole(2R' = Ph, R2 = H; R3 = Me). (r) Similarly, flash chromatography (ethyl acetate-hexane 1:1) was used for separating the products (2; R' = Ph, R2 = Et, It3 = Me) and (2; R' = Ph, R2 =H, R3 = Me). (s)Flash chromatography (ethyl acetate-hexane 1:2) served to separate 3-acetyl-4-hydroxy-5-methyl-l-phenylpyrazole(8; R' = Ph, R2 = R3 = Me), 4-hydroxy-5-methyl-3-propyl-1-phenylpyrazole (2; R' = Ph, R2 = Pr", R3 = Me), and compound (2; R' = Ph, R2 = H, R3 = Me). (t)Procedure (a)was followed, but as the hydroxypyrazole was relatively basic the acidification was stopped at pH 6. Extraction with dichloromethane (2 x 10 ml), drying (MgSO,), removal of the dichloromethane, and preparative t.1.c.on plates kept for 0.5 h over conc. aqueous ammonia and then immediately eluted with ethyl acetate-hexane (1 :l) gave 4- hydroxy-3,5-dimethyl-l-phenylpyrazole(2; R' = Ph, R2 = R3 = Me) (RF0.21) as a yellow oil. Hydrochloride, m.p. 165- 167 "C (propan-2-01). 0-Acetyf derivative, m.p. 55-56 "C (hexane) (Found: C, 68.0; H, 6.15; N, 12.15. Cl,H14N202 requires C, 67.8; H, 6.15; N, 12.15); 6 (CDC13) 7.45-7.2 (5 H, m, Ph), 2.29 (3 H, s, MeC02), 2.17 (3 H, s, 3- or 5-Me), 2.16 (3 H, s, 5- or 3-Me). The next fraction contained 4-hydroxy-1,5- diphenylpyrazole (2; R' = Ph, R2 = H, R3 = Ph).(u) The solvent was removed to give a residue which was flash-chromatographed (dichloromethane) to give 4-hydroxy- 1,3,5-triphenylpyrazole (2; R' = R2 = R3 = Ph) (RF0.47). Conversion of Compound (8; R' = Ph, R2 = H, R3 = Me) into Compound (2; R' = Ph, R2 = H, R3 = Me).-A solution of silver nitrate (5.2 g) in water (10 ml) was added to a solution of compound (8; R' = Ph, R2 = H, R3= Me) (2.33 g) in 33 sodium hydroxide (5 ml). Heating of the mixture to 80 "C for 10 min, filtration, and extraction of the residue with water (2 x 20 ml) gave a filtrate which was acidified (conc. hydrochloric acid) to pH 2 and extracted with dichloromethane (50 + 10 ml). The organic solution was extracted with 4 aqueous potassium hydrogen carbonate (2 x 50 ml) and the aqueous solution was washed with dichloromethane (3 x 25 ml), acidified as above, and extracted with dichloromethane (3 x 50 ml).Removal of the dichloromethane gave 4-hydroxy-5-methyl- 1-phenyl- pyrazole-3-carboxylic acid (2; R' = Ph, R2 = C02H, R3 =Me) (1.08 g, 43) 6 (CDCI,) 7.88br (2 H, s, exchangeable, C02H and OH), 7.46 (5H,s, Ph), and 2.26 (3 H, s, Me). The material was heated to 24G245 "C for 45 min, and the residue was extracted with dichloromethane (50 ml). The solution was extracted with 1M-sodium hydroxide (50 ml) and the aqueous extract was washed with dichloromethane (3 x 25 ml), acidified as above, and extracted with dichloromethane (2 x 50 ml). Removal of the dichloromethane gave a brown oil (0.30 g), which was flash chromatographed (ethyl acetate-hexane, 1:1) to give two unidentified compounds in minor amounts, followed by compound (2; R' = Ph, R2 = H, R3 =Me) (0.10 g, 1273, m.p.136"C (ethyl acetate) (lit.,6 137-138 "C).The mixed m.p. and the i.r., and 'H and 13C n.m.r. spectra were identical with those of an authentic sample. Preparation of Hydrazones of the a-Oxoaldehydes.-(a) A mixture of water (200 ml), methanol (50 ml), acetic acid (20 ml), and 40 aqueous methylglyoxal (14.6 ml) was cooled to -15 "C. Methylhydrazine (10 ml) was added with stirring and the temperature kept below -12 "C. Stirring was continued for 30 min at -12 to -15 "C. 33 Sodium hydroxide was added until pH 7 was reached keeping the temperature below -9 "C. Rapid extraction with dichloro- methane (200 + 2 x 75 ml) and removal of the dichloro- methane gave a semicrystalline mass which was kept at -25 "C for 2 h and filtered to give yellow 2-methylhydrazonopropanal (6; R' = R2 = Me) (4.26 g, 26), m.p.58-64 "C. Recrystallization (toluene-hexane, 1 :4) raised the m.p. to 68- 70 "C(Found: C, 47.15; H, 8.0; N, 27.35. C,H,N20 requires C, 48.0; H, 8.05; N, 28.0);6 (CDCI,) 9.29 (1 H, s, CHO), 6.18br (1 H, s; exchangeable, NH), 3.31 (3 H, d, J 3.8 Hz, collapses on irradiation at 6 6.18, NMe), and 1.78 (3 H, s, CMe); m/z 100 (loo, M+).(6) A solution of methylhydrazine (8.34 ml) and acetic acid (15 ml) in water (100 ml) was added with stirring during 15 min to a 1.0 aqueous solution of methylglyoxal (925 ml).The mixture was kept for 1 day at 20°C and extracted with dichloromethane (4 x 150 ml). The organic solution was washed with water (4 x 40 ml), and the dichloromethane was 86 removed to give l-methylhydrazonopropanone(7; R' = RZ = Me) (4.16 g, 33), as yellow crystals, m.p. 63-65 "C (toluene- ligroin, 1 :2). After sublimation the m.p. was 67-49 "C (Found C, 47.4; H, 8.05; N, 27.7. C4C8N20 requires C, 48.0; H, 8.05; N, 28.0); 6 (CDCl,) 6.86 (1 H, s, HC), 6.61br (1 H, s, exchangeable, NH), 2.96 (3 H, dd, JHNMc4.4 and 0.7 Hz, MeN), and 2.31 (3 H,s, MeC); m/z 100 (loo, M+).(c) Water (200 ml), methanol (50 ml), acetic acid (20 ml), and 40 aqueous methylglyoxal (14.6 ml) were cooled to 0 "C.Phenylhydrazine (9.8 ml) was added during 1 min with stirring and cooling in an ice-bath. After being stirred at 0 "C for 10 min the mixture was extracted at 0 "C with dichloromethane (200 ml). The organic solution was washed with saturated aqueous sodium hydrogen carbonate (30 ml) and evaporated to dryness. The residue was washed with boiling hexane (3 x 50 ml) and recrystallized from toluene (29 ml), with cooling to -25 "C, producing 2-phenylhydrazonopropanal(6;R' = Ph, R2 = Me) (7.62 g, 48), m.p. 123-124 "C (lit.,24 126 "C); 6(CDC1,) 9.45 (1 H, s, CHO), 8.0br (1 H, s, exchangeable, NH), 7.5-4.9 (5 H, m, Ph), and 1.98 (3 H, s, Me); m/z 169 (loo, M'). (d) 40 Aqueous methylglyoxal (7.7 ml) and then 1~-hydrochloric acid was added to a solution of phenylhydrazine (4.9 ml) in methanol (100 ml).The mixture was heated to reflux for 4 h and kept at 20 "C for 1 h. After filtration the residue was washed with 50 aqueous methanol (25 ml), 25 methanol (50ml), and water (50 ml) to give 1 -phenylhydrazonopropan-2-one (7; R' = Ph, R2 = Me) (5.3 g, 65), m.p. 134-142°C. Recrystallization (toluene) gave m.p. 149 "C (lit.,25 148- 149 "C). (e) Phenylglyoxal (1.00 ml), methanol (50 ml), acetic acid (6 ml), methylhydrazine (0.51 ml), and water (50 ml) were mixed and kept for 1 day. Extraction with dichloromethane (3 x 20 ml), removal of the dichloromethane, and drying at 0.13 kPa over P,O, produced light brown 1 -methylhydrazono-2-phenyl-ethanone (7; R' = Me, R2= Ph) (1.33 g, 93) as a 3: 1 mixture of the Z-and E-forms (Found: C, 66.45; H, 6.1; N, 16.35.C9HloN,0 requires C, 66.65; H, 6.2; N, 17.25); 6 (CDCl,) 8.0-7.7 and 7.55-7.2 (2 H, m, and 4 H, m; Ph and HGN), 3.33 and 3.02 3 H, two d (3: l), J 4.0 and 3.0 Hz, collapse upon exchange with D,O, Me in the Z-and E-form, respectively; m/z 162 (55, M'), 161 (30, M-l), 147 (45), 119 (73, 105 (60),91 (loo), and 77 (95). (f) Methylhydrazine (8.34 ml), acetic acid (15 ml), and water (100 ml) were added during 15 min with stirring to 50 aqueous methylglyoxal (37.4 ml) in water (900 ml). After 1 day the mixture was washed with toluene (4 x 150 ml). Removal of the water at 20 "C gave a residue (9.72 g) which contained 1- N-acetyl(hydroxy)methyl-N-methylhydrazonopropanone (9) (70 by 'H n.m.r.) l-methylhydrazonopropanone(7; R' = R2 Me) (lo), and 1,l'-methylenebis(l-methyl-2-(2-oxopropyl-idene)hydrazine (10) (20).Attempts to purify compound (9) were unsuccessful. The n.m.r. spectrum of an unpurified specimen of (9) exhibited the following signals; S (CDC1,) 6.97 (1 H, q, J 0.9 Hz, HC=N), 5.21 (1 H,s, HCO), 4.4br (1 H, exchangeable,OH), 2.93 (3 H, d, J0.9 Hz, NMe), 2.28 (3 H, s, MeCO), and 2.22 (3 H, s, OCMe); 6, (CDCl,) 202.5 (s, GO), 197.1 (s, conj. GO), 132.2 (d, J 167 Hz, HC=N), 89.9 (d, CO), 33.5 (9, NMe), 25.1 (9, Me), and 23.8 p.p.m. (4, Me). Reactions between the Hydrazones of the a-Oxoaldehydes and Formaldehyde.-(a) 40 Aqueous formaldehyde (0.075 ml) and acetic acid (1.0 ml) were added to a solution of 1-methylhydrazonopropanone (7; R' = R2 = Me) (0.10 g) in water (10 ml).After 2 h the mixture was extracted with dichloromethane (2 x 5 ml). Removal of the dichloromethane afforded me thylenebis 1 -methyl-2-( 2-oxopropy1idene)hydra- J. CHEM. soc. PERKIN TRANS. I 1985 zine (10) (0.098 g, 92), m.p. 106-107 "C. Recrystallization (toluene-ligroin, 1 :5) did not change the m.p. (Found C, 58.5; H, 8.8; N, 15.15. C9HI6N4O2 requires C, 58.65; H, 8.75; N, 15.2); 6 (CDCl,) 6.67 (2 H q, J 0.9 Hz, 2 CH=N), 5.03(2 H, S, CH2), 2.91 (6 H, d, J0.9 Hz, 2 MeN), and 2.31 (6 H, s, 2 Mew), 6, (CDC13) 197.1 (s,GO), 130.0 (d, CH=N), 80.7 (t, CH,), 34.4 (q, MeN), and 23.8 p.p.m. (9, Me-); m/z212 (2, M+),and 113 (100).(b) 2-Methylhydrazonopropanal(6;R' = R2 = Me) (1.00 g) and 4 aqueous formaldehyde (10 ml) were kept for 3.5 h. Extraction with dichloromethane (2 x 50 ml), drying (MgS04), and removal of the dichloromethane gave 6-hydroxy-3,5- dimethyl-3,6-dihydro-2H-1,3,4-oxadiazine (1 1) (0.74 g), m.p. 94-101 "C. Recrystallization at 20 "C (dichloromethane-hexane, without heating) gave the pure product (0.40 g, 31), m.p. 112-114°C (Found: C, 46.35; H, 7.85; N, 21.3. C,HloN202 requires C, 46.15, H, 7.75; N, 21.55); 6 (CDCl,) 4.92br(l H,s,HC),4.35(1 H,d,J7.8Hz)and4.03(1 H,d,J7.8 Hz) (CH,), 3.13br (1 H, s, exchangeable, OH), 2.79 (3 H, s, MeN), and 1.99 (1 H, s, MeC); 6, (CDC1,) 146.1 (s, GN), 85.6 (d, HC), 73.7 (t, CH,), 40.2 (4, MeN), and 19.5 p.p.m.(4, MeC); m/z 130 (78, M+) and 113 (7, M -OH). Acknowledgements Thanks are due to Dr. J. (Dgaard Madsen for the mass spectra and to Prof. A. Kjaer for help with the manuscript. The 13C n.m.r. spectrometer was provided by the Danish Natural Science Research Council and the mass spectrometer by the Danish Council for Scientific and Industrial Research. 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