Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
REACTIONS OF 4-CYANOBENZO[c]PYRYLIUM SALTS WITH NITROGENCONTAINING NUCLEOPHILES S. L. Bogza1, S. Yu. Suikov2, N. M. Bogdan2, Yu. A. Nikolyukin2, and V. I. Dulenko2 The recyclization reactions of 4-cyanobenzo[c]pyrylium salts with ammonia, primary amines,and hydrazines have been studied. New derivatives of isoquinoline, benzo-2,3-diazepine, and pyrazolo[5,4-c]isoquinoline have been obtained. Keywords: benzo-2,3-diazepine, benzo[c]pyrylium, pyrazolo[5,4-c]isoquinoline, recyclization. Conversions of 4-acetyl- and 4-ethoxycarbonylbenzo[c]pyrylium salts have been described in [1-3]. While continuing the investigation of the reactivity of benzo[c]pyrylium cation involving electron-withdrawing substituents, we studied the recyclization of 4-cyanobenzo[c]pyrylium perchlorates  under the action of nitrogen-containing nucleophiles. The presence of the nitrile group, as well as other withdrawing substituents , in the pyrylium nucleus enables its conversion under mild conditions. 1,3-Dialkyl- (1a-c) and 4-cyano-1-methyl-3-phenylbenzo[c]pyrylium (1d) perchlorates, like 4-acetyl- and 4-ethoxycarbonyl derivatives, are converted into 4-cyanoisoquinolines 2a-d at room temperature in aqueous alcoholic ammonia solution. CN O
R2 ClO4 1a–d
1, 2 a R1 = R2 = Me, b R1 = Me, R2 = Et; c R1 = Me, R2 = Pr; d R1 = Ph, R2 = Me
Salts 1a and 1d were used to study the reaction with other nitrogen-containing nucleophiles. Compounds 1a and 1d were isolated in preparatively acceptable yields on acylation of the appropriate β-keto nitriles. The yields of perchlorates 1b,c with ethyl and propyl substituents in position 1 were low as a result of the formation of side products, viz. 4(3H)-oxo-1,3-oxazinium perchlorates . Reactions of perchlorates 1a and 1d with ptoluidine, primary aliphatic amines, hydrazine hydrate, and phenylhydrazine have been investigated. On interacting equimolar amounts of salt 1a and primary amine or hydrazine in 2-propanol at 20-40°C 2-R-4-cyanoisoquinolinium perchlorates 3a-e were formed in high yields. __________________________________________________________________________________________ 1
Moscow A. N. Kosygin State Textile University, Moscow 117983, Russia; e-mail: [email protected]
2 L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk 83114, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1645-1651, November, 2004. Original article submitted March 5, 2002. 0009-3122/04/4011-1421©2004 Springer Science+Business Media, Inc.
1 mol/l RNH2
3 a R = p-Tol, b R = CH2Ph, c R = furfuryl, d R = NH2, e R = NHPh
Heating salt 1a with fivefold amount of p-toluidine was also completed by the formation of compound 3a, which was not subjected to further conversions in the presence of highly basic amines (benzylamine, butylamine). This may be caused by the redistribution of electron density of the isoquinolinium cation involving the π-electron sextet of the N-aryl substituent. On using an excess of benzylamine the recyclization of the pyran ring of salt 1a into pyridinium cation is accompanied by substitution of the 6-methoxy group by residue of amine and 2-benzyl-6-benzylamino-4-cyano-7-methoxy-1,3-dimethylisoquinolinium perchlorate (4) is formed. Compound 4 was also obtained on treating 2-benzyl-4-cyanoisoquinolinium salt 3b with an excess of benzylamine, which enables compound 3b to be considered as an intermediate in the conversion of 1 → 4. The IR and 1H NMR spectra of isoquinolinium salt 4 and the data of elemental analysis correspond to the proposed structure. In the known recyclization of 4-ethoxycarbonylbenzo[c]pyrylium derivatives with primary amines the 2-R-4-ethoxycarbonylisoquinolinium cation is also an intermediate in one of the conversions, however the reaction products are derivatives of 1-naphthylamine . When heating salt 1a or perchlorates 3d,e with excess of hydrazine or phenylhydrazine the compounds are formed, the spectral and analytical characteristics of which correspond to benzo-2,3-diazepine derivatives 5a,b. Absorption bands are present in the IR spectrum of 5-cyano-7,8-dimethoxy-1,4-dimethylbenzo-2,3(3H)diazepine (5a) for the nitrile group (2200), for C=C and C=N bonds of seven-membered ring (1640, 1610, 1585), and there is also an absorption band at 3250 cm-1, that corresponds to the vibrations of an N–H bond.
1a NC 3d,e
Me N R N
O Me 5a,b 5 a R = H, b R = Ph
In the 1H NMR spectrum recorded in DMSO-d6 solution there were singlets for two methyl and for two methoxy groups and two signals for the aromatic protons of the benzene nucleus. The singlet with chemical shift of 6.02 ppm and integral intensity 1H belongs to the H-3 proton of the diazepine ring. On heating a solution of sample from 18 to 40°C a drift of the proton signal occurs from 6.02 to 5.9 ppm, which in view of the presence in the IR spectrum of an absorption band for the N–H bond, confirms the attachment of the proton to the 1422
nitrogen atom at position 3 and the character of the disposition of the bonds in the seven-membered ring. A strong low field shift is observed of the singlet for the H-6 proton (8.92 ppm) in the spectrum of diazepine 5b. This effect is caused most of all by the reduction in the distance between the H-6 proton and the nitrile group due to distortion of the diazepine ring geometry as a result of the introduction of a bulky phenyl substituent into it. CN Ph
NH2 _ Me ClO4
N Ac2O / HClO4 NH
TABLE 1. Physicochemical Characteristics of Compounds 2-8 Compound
Found, % —————— Calculated, % H N 4 5
69.7 69.4 70.0 70.3 71.3 71.1 75.1 75.0 55.6 55.8
5.9 5.8 6.4 6.2 6.5 6.7 5.2 5.3 5.1 5.2
11.5 11.6 11.2 11.0 10.5 10.4 9.5 9.4 6.9 6.8
219-221 (dec.) 220-222 (dec.) 198-200 (dec.) 283-285 (dec.) 241-243 (dec.)
86 80 69 87 77
TABLE 1 (continued) 1
237-238 (dec.) 203-204
65.6 65.3 72.0 72.0 79.0 79.1 51.9 51.5 71.5 71.5
5.9 5.9 5.6 5.7 5.5 5.6 4.2 4.3 5.6 5.3
16.3 16.3 12.7 12.6 7.3 7.1 16.9 16.7 13.3 13.2
On replacing the methyl group at position 3 of the 4-cyanobenzo[c]pyrylium cation by phenyl substituent the direction of the reaction is changed. Interaction of perchlorate 1d with benzylamine leads to 1-benzylamino-4-cyano-6,7-dimethoxy-3-phenylnaphthalene (6) irrespective of the reactant ratio. 2-Amino-4-cyano-6-hydrazino-7-methoxy-1-methyl-3-phenylisoquinolinium perchlorate (7) and 7,8-dimethoxy-5-methyl-1-phenylpyrazolo[3,4-c]isoquinoline (8) were isolated on heating salt 1d with hydrazine hydrate at a ratio of 1:10. The structure of pyrazoloisoquinoline (8) was also confirmed by an alternate synthesis, by the acylation of 5-amino-4-(3,4-dimethoxyphenyl)-3-phenylpyrazole  in acetic anhydride in the presence of perchloric acid. Probably, on interaction of salt 1d with hydrazine under conditions of excess of reactant, the coordinated effect of the substituents on the electron sheath of the benzo[c]pyrylium cation makes possibility of the equally probable attack of hydrazine molecule at atoms C(1) and C(6). This determines the further course of the reaction and the structure of the final products. The practically equal yields of compounds 7 and 8 are indirect confirmation of the reliability of this hypothesis. We discovered an analogous result, caused by the close reactivity of the C(1) and C(6) atoms, in the case of the interaction of 1,3-dialkyl-4-ethoxycarbonylbenzo[c]pyrylium perchlorates with benzylamine . The reactions of 4-cyanobenzo[c]pyrylium salts studied show that the introduction of cyano group, as well as other electron-withdrawing substituents, into the benzo[c]pyrylium cation facilitates its recyclization and broadens the possibilities of converting it.
TABLE 2. Spectral Characteristics of Compounds 2-8 Compound 1
IR spectrum, ν, cm-1 2
2220, 1620, 1100
Н NMR spectrum, δ, ppm (J, Hz)* 3
2.57 (3Н, s, СН3); 2.73 (3Н, s, СН3); 3.67 (3Н, s, ОСН3); 3.80 (3Н, s, ОСН3); 7.07 (1Н, s, Н arom.); 7.17 (1Н, s, Н arom.) 1.07 (3Н, t, СН3); 2.50 (3Н, s, СН3); 3.03 (3Н, q, СН2); 3.67 (3Н, s, ОСН3); 3.77 (3Н, s, ОСН3); 7.07 (1Н, s, Н arom.); 7.15 (1Н, s, Н arom.) 0.60 (3Н, t, СН3); 1.50 (2Н, m, СН2); 2.50 (3Н, s, СН3); 2.97 (2Н, t, СН2); 3.63 (3Н, s, ОСН3); 3.73 (3Н, s, ОСН3); 7.07 (1Н, s, Н arom.); 7.15 (1Н, s, Н arom.); 7.05 (1Н, s, Н arom.); 7.17 (1Н, s, Н arom.) 2.83 (3Н, s, СН3); 3.90 (3Н, s, ОСН3); 3.97 (3Н, s, ОСН3); 7.16-7.85 (7Н, m, Н arom.) 2.47 (3Н, s, СН3); 3.13 (3Н, s, СН3); 3.45 (3Н, s, СН3); 3.98 (3Н, s, ОСН3); 4.15 (3Н, s, ОСН3); 7.53-7.75 (3Н, m, Н arom.); 7.85 (1Н, s, Н arom.); 8.08 (2Н, d, Н arom.)
TABLE 2 (continued) 1
2225, 1620, 1100
2225, 1625, 1100
3370, 3300, 2230, 1635, 1100 3250, 2220, 1630, 1100
3.10 (3Н, s, СН3); 3.27 (3Н, s, СН3); 4.20 (3Н, s, ОСН3); 4.30 (3Н, s, ОСН3); 6.03 (2Н, s, СН2); 7.10-7.55 (5Н, m, Н arom.); 7.67 (1Н, s, Н arom.); 7.83 (1Н, s, Н arom.) 2.57 (3Н, s, СН3); 2.72 (3Н, s, СН3); 3.85 (3Н, s, ОСН3); 3.90 (3Н, s, ОСН3); 4.06 (2Н, s, СН2 Fur); 6.07 (1Н, s, Н arom. Fur); 6.55 (1Н, s, Н arom. Fur); 6.68 (1Н, s, Н arom. Fur); 7.09 (1Н, s, Н arom.); 8.01 (1Н, s, Н arom.) 2.90 (3Н, s, СН3); 3.13 (3Н, s, СН3); 3.96 (3Н, s, ОСН3); 4.03 (3Н, s, ОСН3); 7.23 (1Н, s, Н arom.); 7.67 (1Н, s, Н arom.)
3320, 2230, 1605, 1100
3250, 2200, 1640
3200, 2225, 1640, 1610, 1100 1620
2.56 (3Н, s, СН3); 3.14 (3Н, s, СН3); 4.07 (3Н, s, ОСН3); 4.09 (3Н, s, ОСН3); 6.58 (2Н, d, Н arom.); 6.99 (1Н, t, Н arom.); 7.12 (1Н, s, Н arom.); 7.32 (2Н, t, Н arom.); 7.82 (1Н, s, Н arom.); 11.72 (1Н, br. s, N–H) 2.83 (3Н, s, СН3); 2.95 (3Н, s, СН3); 3.97 (6Н, s, 2ОСН3); 4.55 (2Н, s, СН2); 5.63 (2Н, s, СН2); 6.60 (1Н, s, Н arom.); 6.77-7.27 (11Н, m, Н arom.) 1.57 (3Н, s, СН3); 1.88 (3Н, s, СН3); 3.73 (3Н, s, ОСН3); 3.76 (3Н, s, ОСН3); 6.02 (1Н, br. s, N–Н); 6.69 (1Н, s, Н arom.); 6.91 (1Н, s, Н arom.) 1.93 (3Н, s, СН3); 3.78 (3Н, s, ОСН3); 3.82 (3Н, s, ОСН3); 6.84 (1Н, s, Н arom.); 7.05-7.20 (1Н, t, J = 7.5, Н arom.); 7.43 (2Н, t, J = 7.5, Н arom.); 7.73 (2Н, d, J = 7.5, Н arom.); 8.92 (1Н, s, Н arom.) 3.54 (3Н, s, ОСН3); 3.61 (3Н, s, ОСН3); 4.00 (2Н, d, СН2, J = 6.2); 6.52-6.67 (3Н, m, Н arom.); 7.04-7.32 (10Н, m, Н arom.); 10.50 (1Н, t, J = 6.2, N–H) 3.17 (3Н, s, СН3); 4.10 (3Н, s, ОСН3); 7.43-7.87 (7Н, m, Н arom.) 3.23 (3Н, s, СН3); 3.80 (3Н, s, ОСН3); 4.07 (3Н, s, ОСН3); 7.67 (7Н, s, Н arom.)
_______ * The 1H NMR spectra were taken in CF3COOH (for compounds 2a-d, 3a,b,d, 4, 7, and 8) and in DMSO-d6 (for compounds 3c,e, 5a,b, and 6).
EXPERIMENTAL The IR spectra were recorded in nujol on a UR 20 spectrophotometer, and the 1H NMR spectra were taken on a Varian Gemini 200 (200 MHz) spectrometer, internal standard was TMS. The physicochemical and spectral characteristics of the compounds synthesized are given in Tables 1 and 2. 4-Cyano-6,7-dimethoxyisoquinolines 2a-d. Perchlorate 1 (5 mmol) was added in one portion to mixture of aqueous 25% ammonia solution (5 ml) and 2-propanol (8 ml). The reaction mixture was stirred for 1-2 h, isoquinoline 2 was filtered off, washed with water, and crystallized from alcohol. 1,3-Dialkyl-4-cyano-6,7-dimethoxy-2-R-isoquinolinium Perchlorates 3a-e. Perchlorate 1 (5 mmol) was added to solution of primary amine or hydrazine (5.5 mmol) in 2-propanol (10 ml) and the mixture stirred at 20-40°C until complete dissolution. After 4-6 h solid isoquinoline perchlorate 3 was filtered off, washed with alcohol, and with ether, and dried. 2-Benzyl-6-benzylamino-4-cyano-7-methoxy-1,3-dimethylisoquinolinium Perchlorate (4). A. Mixture of perchlorate 1 (5 mmol) and benzylamine (25 mmol) was boiled in ethanol for 6 h, then left overnight. The precipitated solid was filtered off, and crystallized from ethanol. 1425
B. Mixture of isoquinolinium perchlorate 3b (5 mmol) and benzylamine (25 mmol) was boiled in ethanol for 6 h. The reaction mixture was treated as in method A. 1-Benzylamino-4-cyano-6,7-dimethoxy-3-phenylnaphthalene (6) was obtained by the recyclization of perchlorate 1d under the conditions described for compound 4. 5-Cyano-7,8-dimethoxy-1,4-dimethyl-3-R-benzo-2,3(3H)-diazepines (5a,b). Perchlorate 1a or isoquinolinium perchlorates 3d,e were heated with fivefold quantity of appropriate hydrazine in ethanol for 5-6 h and left overnight. The reaction mixture was poured into water, the precipitate was filtered off, washed with water, dried, and crystallized from xylene. 7,8-Dimethoxy-5-methyl-1-phenylpyrazolo[3,4-c]isoquinoline (8) and 2-Amino-4-cyano-6hydrazino-7-methoxy-1-methyl-3-phenylisoquinolinium Perchlorate (7). Mixture of perchlorate 1d (3 mmol) and hydrazine hydrate (30 mmol) in acetonitrile was boiled for 2 h and cooled. The precipitated solid pyrazoloisoquinoline 8 was filtered off, dried, and crystallized from m-xylene. The filtrate was poured into ether (50 ml), and the precipitated oil triturated with water. Perchlorate 7 was filtered off, washed with water, and dried, then crystallized from ethanol.
REFERENCES 1. 2. 3. 4. 5. 6.
S. L. Bogza and Yu. A. Nikolyukin, Khim. Geterotsikl. Soedin., 1475 (1993). S. L. Bogza, Yu. A. Nikolyukin, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1290 (1994). S. L. Bogza, Yu. A. Nikolyukin, M. Yu. Zubritskii, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 317 (1995). S. L. Bogza, Yu. A. Nikolyukin, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 465 (1990). E. V. Kuznetsov, I. V. Shcherbakova, and A. T. Balaban, Adv. Heterocycl. Chem., 50, 158 (1988). Yu. A. Nikolyukin, L. V. Dulenko, and V. I. Dulenko, Khim. Geterotsikl. Soedin., 1092 (1990).