Reactions of 1,3-dioxoimidazo1,5-bisoquinolinium bromides with nucleophiles

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1991 Reactions of I,3-Dioxoimidazo[l,5-6] isoqu in01 inium Bromides with Nucleophi les loannis Niopasa and Gordon A. Smail *eb a Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 540 06, Greece Department of Pharmacy, University of Strathclyde, Glasgow G I IXW, UK Treatment of 10- bromo-I ,3-dioxoimidazo[l,5-6] isoquinolinium bromides 2, 1,3-dioxoimidazo-[I ,5-61 isoquinolinium bromides 4, and tetrahydro-I ,3-dioxo-I H-imidazo[l,5-61 isoquinolinium bro- mides 7 with selected nucleophiles gave adducts which were respectively 5-substituted 10- bromo- imidazo[l,5-6] isoquinoline-I ,3(2H,5H) -diones 3,5-substituted imidazo[l,5-6] isoquinoline- 1,3(2H, 5H) -diones 5 and 5-substituted 10,l Oa-dihydroimidazo[l,5-61 isoquinoline-I ,3(2H,5H) -diones 8.The adduct with cyanide (Reissert compound) 5i reacted with benzyl chloride to yield 5-benzyl- 1,2,3,5-tetrahydro-I ,3-dioxo-2-propylimidazo[1,5-6] isoquinoline-5-carbonitrile 6. Both adducts 5i and the dihydro-Reissert compounds 81and 8m were hydrolysed to the corresponding carboxylic acids. Reaction of isoquinolinium bromide 7a with phenylmagnesium bromide afforded 2,3,10,1 Oa-tetra- hydro- 3- hydroxy -2-methyl -3,5-dip henylimidazo [1,5-61 isoqu ino1 in -1 (5H) -one 9. Bromination of 10,10a-dihydroimidazo[ 1,5-b]isoquinoline- 1,3(2H,SH)-diones 1under various conditions has been shown ' to yield, inter alia, a series of 1,3-dioxoimidazo[ 1,5-b]iso- quinolinium salts, e.g., 2, 4, or 7 or mixtures of 2 and 4.The addition reactions of these quaternary salts with selected nucleophiles is now described. Results and Discussion Treatment of the 10-bromo-2,3-dihydro-1,3-dioxo-1H-imid-azo[ 1,5-b]isoquinolinium bromides 2a-2d with methanol or ethanol gave the adducts 3a-3e. The IR spectra of the products exhibited a characteristic band at or near 1630 cm-' for the 10,lOa double bond, which is some 30 cm-' lower than the corresponding band in the non-brominated adducts 5. In the 'H NMR, spectra 5-H appeared as a sharp singlet in the range 6 6.4Cb6.68, comparing favourably with the cited 2,3 values of analogous compounds. The 9-H appeared downfield of the other aromatic protons, presumably reflecting deshielding by the neighbouring bromine atom.The N-unsubstituted adducts 3a and 3b [in (CD,),SO and (CD,),CO], showed no observable signal for the NH moiety, either because of peak broadening by the nitrogen quadruple, or because of a rapid proton exchange with water contained in the solvents; similar observations have been reported for related structure^.^,^ Accurate mass measurement of the molecular ion at m/z 324/322 (1 : 1) in compound 3c gave the appropriate formula; the base peak occurred at m/z 293/291 (1:1) corresponding to the loss of OMe. N-Alkylisoquinolinium or N-acylisoquinolinium salts are well to react with water to give pseudobases and with alcohols to form the corresponding ethers. The latter can also be prepared by reaction of the pseudobase with the appropriate alcohol. Reaction of the isoquinolinium salts 4Wd with methanol or ethanol afforded the corresponding adducts 5a-5d, which were characterised by IR and 'H NMR spectroscopy.Their IR spectra showed a band at 1660 cm-' for the 10,lOa double bond; the 5-H and 10-H protons appeared as sharp singlets in the ranges 6 6.49-6.63 and 6.83-6.98, respectively. Ammonia and amines are known6" to add to C-1 of isoquinolinium salts and the factors that influence this addition are similar to those of the addition of water and alcohols. Treatment of the mixture of imidazoc 1,5-b]isoquinolinium salts 2b' and 4a' with diethylamine, followed by chrom-atography on silica gel, afforded a yellow solid, which on TLC showed two overlapping spots. The IR and 'H NMR spectral characteristics of the mixture were in agreement with the expected adducts 3f and 5e.The IR spectrum of the mixture exhibited two bands at 1660 and 1635 cm-', whereas the 'H NMR spectrum showed the signal for 10-H of compound 5e as a singlet at 6 6.6 and that for 9-H of compound 3f at 6 7.767.87, downfield of the other aromatic protons. Treatment of the mixture 3f and 5e with ethereal hydrogen bromide gave the starting material 2b/4a, indicating that the amination of isoquinolinium salts is reversible in acids.' Further elution of the column afforded the pseudobase 5f. The IR spectrum exhibited two bands at 3440 (OH) and 1660 cm-' (C=C) and the 'H NMR spectrum [in (CD,),SO] showed the 5-OH group resonating as an exchangeable broad singlet at 6 3.28. Treatment of compound 4b with triethylamine resulted in the isolation of the pseudobase 5g as the only identifiable product.The 'H NMR spectrum (in CDCl,) showed the 5-H and 5-OH as doublets (J 6 Hz). Accurate mass measurement of the molecular ion at m/z 244 gave the appropriate formula. Attack of cyanide ion on isoquinolinium salts also occurs at C-1 9*10 to give adducts. Treatment of the isoquinolinium bromides 4b and 4c with aqueous potassium cyanide in dichloromethane ' ' gave, respectively, the Reissert compounds 5h and 5.The analytical and spectroscopic data were consistent with the assigned structures. The IR spectra showed no detectable absorption for the cyano group in the range 22W 2400 cm-' in common with other Reissert compounds.12 The mass spectrum of adduct 5h gave the molecular ion and the principal fragment arose through loss of cyanide radical, which loss is a recognised fragmentation pathway of Reissert compound^.'^ Column chromatography (silica gel) of the ethereal filtrate, after the isolation of adduct 5h, afforded the pseudobase 5g.When 5-nitroisoquinoline is treated with potassium cyanide and benzyl chloride in water4ichloromethane, the N-acyl pseudobase is formed in high yield, rather than the expected Reissert compound which is formed in less than 2% It seems that the effect of the 5-nitro group enhances the 'hardness' of the C-1 centre, thus favouring attack by the hard base water rather than the softer base CN-.' 5.1 Treatment of the l0-bromoimidazo[1,5-b]isoquinolinium bromide 2d with aqueous potassium cyanide in dichloromethane 120 J.CHEM. SOC. PERKIN TRANS. I 1991 Br Br R2 0 2 3 a;R=H b; R=Me c;R=Et d; R=Ph a; R’ = H, R2 = OMe b; R’ = H, R2 = OEt c; R’ = Me, R2 = OMe d; R‘ = Et, R2 = OMe f; R’ = Me, R2 = NEt2 g; R’ = Ph, R2 = OH e; R’ = Ph, R2 = OMe R2 0 0 5 6 a; R’ = Et, R2= OMe g; R’ = Et, R2 = OH b; R’ = Et, R2 = OEt h; R’ = Et, R2 = CN c; R’ = Pr”, R2 = OMe i; R’ = Prn, R2 = CN d; R’ = Ph, R2= OMe j; R’ = Prn, R2= CONH2 e; R’ = Me, R2 = NEt2 k; R’ = Pr“, R2 = C02H f; R’ = Me, R2 = OH 0 R2 0 7 8 a; R = Me b; R = Ph a; R’ = Me, R2 = OMe g; R’ = Ph, R2= SEt m; R’ = Ph, R2 = CN b; R’ = Me, R2 = OEt h; R’ = Me, R2= ON=CHMe n; R’ = Me, R2 = C02H c; R’ = Ph, R2 = OMe i; R’ = Me, R2 = NMe2 p; R’ = Ph, R2 = C02H d; R’ = Ph, R2 = OEt j; R’ = Ph, R2 = NEt2 q; R’ = Me, R2 = C02Me e; R’ = Ph, R2 = OPr’ k; R’ = Me, R2 = I(.J[CH2CH2]0[CH2CH2]J r; R’ = Ph, R2 = C02Me f; R’ = Me, R2 = SPh I; R’ = Me, R2 = CN Ph Ph Ph 9 10 afforded the brominated pseudobase 3g which on refluxing with (DMF) containing sodium hydride,*’ under nitrogen, afforded methanol gave the corresponding ether 3e.It is possible that the the 5-benzyl cyanide adduct 6. The ‘H NMR spectrum showed ureido moiety of the isoquinolinium salts 2 and 4 together with the benzylic protons, adjacent to the asymmetric C-5, as an AB the C-10 bromine atom increase the ‘hardness’ of the C-5 centre, quartet (J 14 Hz); the 10-H appeared as a singlet at 6 6.16, permitting competitive attack by the harder base water. upfield of the corresponding proton in the parent compound 5i Reissert compounds usually undergo acid-catalysed hydro- (6 6.77).This may be explained by a conformation of compound lysis to give aldehydes plus the corresponding heterocyclic 6 in which the benzene ring of the C-5 benzyl group is situated carboxylic acid. ’ Acid-catalysed hydrolysis of the cyanide underneath the C-10 proton to cause shielding of that proton. adduct 5i with concentrated hydrochloric acid afforded the 3,4-Dihydroisoquinolinium salts react at C- 1 with nucleo- corresponding amide 5j in good yield. The cyano group in philes, in a manner similar to ‘fully’ aromatic isoquinolinium adduct 5i is hindered and hydrolysis to the corresponding acid salts, to give a variety of 1-substituted tetrahydroisoquino- 5k is difficult.However, hydrolysis to the acid 5k was finally lines.2 Quantitatively the 3,4-dihydroisoquinolinium system achieved by treatment of the amide Sj with sulphuric acid is more susceptible to attack than the ‘fully’ aromatic containing acetic acid” and followed the mechanism of isoquinolinium system since there is less loss of conjugation ordinary nitriles. The mass spectrum of acid 5k gave the energy. The stability of the adducts derived from 3,4-molecular ion at mjz 286 (M+, 15.6%) and a principal fragment dihydroisoquinolinium salts varies with the nature of C-1 at nzjz 241 (94.6%) arising through loss of the carboxy group.substituent; for the most part, however, treatment with acid Alkylation of Reissert and dihydro-Reissert compounds is results in the loss of the substituent and regeneration of the known to proceed via the corresponding carbanions which, in quaternary salt. turn, can effect nucleophilic substitution of alkyl halides 18,19 to Treatment of the I H-imidazo[ 1,5-b]isoquinolinium bromides give the C-l-substituted derivatives. Treatment of the Reissert 7a and 7b with methanol, ethanol, or isopropyl alcohol gave the compound 5i with benzyl chloride in dry dimethylformamide corresponding adducts 8a -8e. The products were obtained in J. CHEM. soc PERKIN TRANS. 1 1991 121 Table 1 Analytical data for the 10-brominated adducts 3a-3e Found % (Required) Compound Yield (Formula) (% Solvent M.p.("C) C H Br N 68 MeOH 236-238 46.85 2.9 25.75 9.0 (46.6 2.95 25.85 9.05) 65 EtOH 252" 48.2 3.2 24.6 8.65 (48.3 3.45 24.75 8.65) 67 MeOH 142b 48.75 3.55 24.75 9.05 (48.3 3.45 24.75 8.65) 57 MeOH 126-127 49.25 3.65 24.2 7.95 (49.85 3.9 23.7 8.3) 61 MeOH 199-200 56.05 3.5 20.95 7.6 (56.1 7.25)3.4 20.75 " Over range. Resolidified and then remelted at 250-253 "C. Table 2 Spectroscopic data for the 10-brominated adducts 3a-3e IR 'H NMR" (6) Compound (v,,,/cm-' 5-H 9-H Other protons 3ab 3210 (NH), 1760 (CO), 6.40s 7.75m 3.19 (3 H, s, 5-OMe), 1710 (CO), 1630 (CS) 7.52-7.62 (3 H, m, ArH) 3b' 3190 (NH), 1760 (CO), 6.50s 7.83m 1.05 (3 H, t, OCH,Me), 3.66 1710 (CO), 1630 (CS) (2 H,q,OCH,Me), 7.35-7.65 (3 H, m, ArH) 3Cd 1760 (CO), 1710 (CO), 6.45s 7.91-8.02m 3.20 (3 H, s, NMe), 3.36 1635 (CS) (3 H, s, 5-OMe), 7.45-7.65 (3 H, m, ArH) 3d 1760 (CO), 1720 (CO), 6.41s 7.89-7.99m 1.30(3 H, t, NCH,Me), 3.34 1630 (C=C) (3 H, s, 5-OMe), 3.74 (2 H, q.NCH,Me), 7.41-7.60 (3 H, m, ArH) 3e 1765 (CO), 1725 (CO), 6.51s 7.968.07m 3.44 (3 H, s, 5-OMe), 1635 (C=C) 7.43-7.66 (9 H, m, ArH) a Spectra were recorded in CDCl, unless otherwise indicated. Spectrum in (CD,),SO. Spectrum in (CD,),Co. M+,323.9926. C,,H, ,"BrN,O, requires M, 323.9934; and M+, 321.9946. Cl3Hl 179BrN,03 requires M, 321.9953. good yields as white solids and were easily characterised by 'H NMR spectroscopy.All of the adducts showed an ABX pattern arising from splitting of 10a-H, which appeared as double doublets (J 6 and 13 Hz), with the C-10 non-equivalent methylene protons which occurred as doublets of quartets. Treatment of compound 7a with thiophenol afforded the adduct 8f and reaction of compound 7b with ethanethiol afforded the adduct 8g. The adduct 8g gave a very weak molecular ion at m/z 338 (O.lY(,) and the base peak corresponded to m/z 177 (M -SEt). Compound 7a reacted with acetaldoxime to yield the corresponding adduct 8h as a semi-solid at room temperature; the analytical and spectroscopic characteristics of the product were consistent with its structure 8h. Reaction of salts 7a and 7b with dimethylamine, diethylamine and morpholine afforded the adducts 8i-8k.In the 'H NMR spectra 6-H appeared downfield of the other aromatic protons through deshielding by the neighbouring amino group. Treatment of the morpholino adduct 8k with DCl, in the NMR tube, shifted the signals downfield and after 12 h gave a yellow precipitate 7b, indicating the reversibility of the amination reaction of salts 7 in acidic solution. Treatment of the salt 7a with an excess of freshly prepared phenylmagnesium bromide gave compound 9 as the only identifiable product. The IR spectrum exhibited two new bands at 3250 (OH)and at 1685 cm-I (CO) but not the usual carbonyl bands of the hydantoin ring.22 The 'H NMR spectrum showed the signal for 10a-H as a double doublet (J 6 and 13 Hz) at 6 3.87, upfield of the analogous proton signal of the hydantoins 8, reflecting the loss of deshielding by the hydantoin ring; the C- 3 hydroxy proton appeared as an exchangeable singlet at 6 5.06.The mass spectrum of the product 9 gave the molecular ion at mjz 370 (M', 26.4%) and the base peak at mjz 352 (M -H20), corresponding to the mesoionic structure Reaction of salts 7a and 7b with potassium cyanide in water-dichloromethane afforded the dihydro-Reissert compounds 81 and 8m, respec-tively. Their IR spectra exhibited a very weak band at ca. 2240 cm-' for the cyano group. Refluxing of compounds 81 and 8m with a mixture of hydrochloric and acetic acid afforded directly the respective acids 8n and 8p, which were esterified with freshly prepared diazomethane to the esters 8q and 8r.Experimental IR spectra were recorded in KCl pellets on a Perkin-Elmer 197 instrument and 'H NMR spectra were obtained with a Perkin- Elmer R32 (90 MHz) spectrometer, with tetramethylsilane as internal standard. J Values are given in Hz. Mass spectra were run on a AEI-MS 902 double-focussing, high-resolution spectrometer. M.p.s were determined on a Kofler hot-stage apparatus and are uncorrected. Preparation of 5-Afkoxy- lO-hromoimiduzo[ 1.5-blisoquino- fine-l,3-(2H,SH)-diones 3a-3e.-Crude lO-brom0-2,3-dihydro-1,3-dioxo-1H-imidazo[1,5-b]isoquinoliniumbromide2( 1 mmol) was dissolved in freshly distilled dry methanol or absolute ethanol (5 cm3) with the aid of heat and the solution was left at room temperature for 3 h.The white solid which formed was collected by filtration, washed with cold dry J. CHEM. SOC. PERKIN TRANS. 1 1991 Table 3 Analytical data for the adducts 5a-5d Found % (Required)Compound (Formula) Yield (%I Solvent M.p. ("C) C H N 62 MeOH 92-93 64.95 5.3 11.0 58 EtOH 8&87 (65.1 66.4 5.45 6.0 10.85) 10.1 58 MeOH 84" (66.15 66.35 5.9 6.05 10.3) 10.05 79 MeOH 202-203 (66.15 70.7 5.9 4.6 10.3) 9.15 (70.6 4.6 9.15) a Lit.,24 m.p. 85 "C; resolidified and then remelted at 205-210 "C. Table 4 Spectroscopic data for the adducts 5a-5d IR 'H NMR" (6) Compound (vrnax/cm-7 5-H 9-H Other protons 5a 1760 (CO), 1710 (CO), 6.50s 6.85s 1.30 (3 H, t, NCH,Me), 3.33 1660 (CX) (3 H, s, 5-OMe), 3.74 (2 H q, NCH,Me),7.47(4 H,s, ArH) 5b 1760 (CO), 1710 (CO), 6.51s 6.83s 1.06-1.37 (6 H, two 1660 (CX) overlapping triplets, NCH,Me and OCH,Me), 3.54-3.83 (4 H, two overlapping quartets, NCH,Me and OCH,Me), 7.43 (4 H, s, ArH) 5c 1770 (CO), 1710 (CO), 6.50s 6.87s 0.96 (3 H, t, NCH,CH,Me), 1660 (CS) 1.74 (2 H, m, NCH,CH,Me), 3.32 (3 H, s, 5-OMe), 3.63 (2 H, t, NCH,CH,Me), 7.47 (4 H, s, ArH) 5d 1765 (CO), 1720 (CO), 6.58s 6.98s 3.42 (3 H, s, 5-OMe), 1660 (CX) 7.42-7.56 (9 H, m, ArH) " Spectra were recorded in CDCl,.methanol or absolute ethanol and recrystallised from the cm-l (CO)] was identical with that of the material 2b and 4a. appropriate solvent to give the 5-alkoxy- 10-bromoimidazo[ 13- Further elution of the column afforded 5-hydroxy-2-methyl- blisoquinoline- 1 ,3(2H75H)-diones 3a-3e (Tables 1 and 2).imidazo[ 1,5-b]isoquinoline- 1,3(2H,SH)-dione 5f (0.06 g), m.p. 189-190°C (Found: C, 63.25; H, 4.5; N, 12.4%; Mf, Preparation of 5-Alkoxyimidazo[ 1,5-b]isoquinoline-1,3- 230. CI2Hl0N2O3 requires C, 63.7; H, 4.45; N, 12.4%; M, 230); (2H,5H) -diones 5a-5d.-A crudeN-substituted-2,3-dihydro-1,3-v,,,/cm-' 3440 (OH), 1760 (CO), 1710 (CO) and 1660 (CS); 6 dioxo- 1H-imidazo[ 1,5-b]isoquinolinium bromide 4 (1 mmol) [(CD,),SO] 3.02 (3 H, s, NMe), 3.28 (1 H, br s, exchanged with was treated, as described above, with dry methanol or absolute D,O, 5-OH), 6.59 (1 H, s, 5-H), 6.99 (1 H, s, 10-H) and 7.50 (4 H, ethanol (5cm3) to give the 2-substituted 5-alkoxy-imidazo[ 13- s, ArH).b]isoquinoline- 1,3(2H,SH)-diones 5a-5d (Tables 3 and 4). Reaction of 2-Ethyl 2,3-dihydro-1,3-dioxo-lH-imidazo[1,5-b]-Reaction of the Mixture of lO-Brorno-2,3-dihydro-2-methyl-isoquinolinium Bromide 4b with Triethy1amine.-A suspension of 173-dioxo-1H-imidazo[ 1,5-b]isoquinolinium Bromide and 2,3-Di- the salt 4b (0.307 g, 1 mmol) in dry chloroform (5 cm3) was hydro-2-methyl- 1,3-dioxo- 1 H-imidazoc 1,5-b] isoquinolinium treated, as described above, with triethylamine (0.1 g, 1 mmol). Bromide 2b and 4a with Diethylamine.-A suspension of the Further work-up and column chromatography on silica gel, mixture 2b and 4a (0.5 g) in dry, ethanol-free chloroform (5 with chloroform-diethyl ether (4 : 1) as eluant, gave 2-ethyl-5- cm3) was treated with diethylamine (0.25 g) and the resultant hydroxyimidazoc 175-b]isoquinoline- 1,3(2H,SH)-dione 5g (0.04 yellow solution was shaken occasionally for 0.5 h.The reaction g), m.p. 144-145 "C (Found: C, 63.55; H, 5.0; N, 11.6%; Mf, 244. mixture was flooded with anhydrous diethyl ether, the C13H12N203requires C, 63.9; H, 4.95; N, 11.45%; M, 244); v,,,. diethylamine hydrobromide was filtered off,and the filtrate, after cm-' 3375 (OH), 1760 (CO), 1710 (CO) and 1665 (C=C); concentration, was chromatographed on a silica gel column G(CDC1,) 1.28 (3 H, t, NCH2Me), 3.69 (2 H, q, NCH,Me), 4.02 with chloroform-diethyl ether (1 : 1) as eluant to give yellow (1 H, d, J 6, exchanged with D20, SOH), 6.79-6.85 [2 H, d, J 6 crystals, which on TLC showed two overlapping spots; v,,,/ (collapsed to a singlet at 6 6.82 on addition of D,O), 5-H, cm-' 1760 (CO), 1720 (CO), 1660 (C=C) and 1635 (C=C); overlapping with a singlet centred at 6 6.81, lO-H] and 7.39-7.50 G(CDC1,) 0.98 [t, N(CH2Me),], 2.442.78 [two overlapping (4 H, m, ArH).quartets, N(CH,Me),], 3.1 1-3.14 (two singlets, NMe), 6.23 (br s, 5-H), 6.60 (s, 10-H), 7.29-7.50 (m, ArH) and 7.76-7.87 (m, 9-Preparation of Reissert Compounds 5h and Si.-To a stirred H). Treatment of the product with ethereal hydrogen chloride suspension of 2-ethyl-2,3-dihydro-1,3-dioxo-1H-imidazoc 13- gave a yellow solid whose IR spectrum [1835 (CO) and 1755 b]isoquinolinium bromide '4b (1.23 g, 4 mmol) in dichlorometh- J. CHEM.soc PERKIN TRANS. 1 1991 123 Table 5 Analytical data for the (&)-dihydro-adducts 8a4k Found % (Required) Compound (Formula) Yield" (%I Solvent M.p. ("C) C H N 5 53 MeOH 107- 109 63.0 5.6 11.3 54 EtOH 130-131 (63.4 64.2 5.75 6.35 11.35) 11.15 (64.6 6.2 10.75) 48 MeOH 196198 70.2 5.05 8.95 51 EtOH 143-145 (70.1 71.1 5.25 5.55 9.1) 8.9 (70.8 5.65 8.7) 41 Pr'OH 121-123 71.0 5.75 8.05 61 AcOEt 190-191 (7 1.4 66.45 6.0 5.1 8.35) 8.85 9.8 (66.65 4.95 8.65 9.9) 51 AcOEt 165.5-167 67.6 5.35 7.95 9.45 (67.45 5.35 8.25 9.45) 6 1.05 5.55 15.15 50 Et20 127-128 (61.5 64.8 5.55 6.9 15.95 15.4) 43 Et20 116118 (64.85 72.15 6.6 6.45 16.2) 11.65 32 Et20 195-197 (72.2 69.75 6.65 5.85 12.0) 11.2 (69.4 5.8 11.55) " Yield is based on the appropriate lO,lOa-dihydroimidazo[ 1,5-b]isoquinoline-l,3(2H,5H)-dione 1.The (-)-isomer. 'The product was a semi-solid at room temperature. The products were purified by column chromatography on silica gel, with chloroform-diethyl ether (8: 2) as eluant. 'The product was purified by column chromatography on neutral alumina, with chloroform-diethyl ether (9: 1) as eluant. ane (150 cm3) was added dropwise a solution of potassium cyanide (0.32 g) in water (4 cm3). The reaction mixture was stirred until all of the reactants had dissolved and the solution was left overnight before being treated with anhydrous sodium sulphate, filtered and evaporated to give an oil, which on trituration with anhydrous diethyl ether yielded 2-ethyl-1,2,3,5-tetrahydro-1,3-dioxoimidazo[1,5-b]isoquinoline-5-carbonitrile 5h (0.26 g, 26%), m.p.175-176 "C (from MeOH) (Found: C, 66.15; H, 4.2; N, 16.2%; M', 253. C14HllN302 requires C, 66.4; H, 4.4; N, 16.6%; M, 253); v,,,/cm-' 1765 (CO), 1720 (CO) and 1665 (C=C; G(CDC1,) 1.29 (3 H, t, NCH2Me), 3.72 (2 H, q, NCH,Me), 6.25 (1 H, s, 5-H), 6.74 (1 H, s, 10-H) and 7.42 (4 H, s, ArH). Column chromatography of the ethereal filtrate on silica gel, with chloroform-diethyl ether (9:l) as eluant, gave the pseudobase 5g (0.19 g) (also isolated from the reaction of compound 4b with triethylamine). Similar treatment of 2,3-dihydro- 1,3-dioxo-2-propyl-lH- imidazo[ 1,5-b]isoquinolinium bromide 4c (1.28 g, 4 mmol) with potassium cyanide (0.32 g) afforded 1,2,3,5-tetrahydro-l,3-dioxo-2-propylimidazo[ 1,5-b]isoquinoline-5-carbonitrile 5i (0.49 g, 46%), m.p.159-161 "C (lit.,24 160-161 "C) (Found: C, 67.05; H, 4.8; N, 15.45%. Calc. for C,,H,,N,O,: C, 67.4; H, 4.9; N, 15.7%); v,,,/cm-' 1770 (CO), 1715 (CO) and 1665 (C==C); G(CDC1,) 0.95 (3 H, t, NCH2CH2Me), 1.73 (2 H, m, NCH,CH,Me), 3.62 (2 H, t, NCH2CH2Me), 6.28 (1 H, s, 5-H), 6.77 (1 H, s, 10-H) and 7.45 (4 H, s, ArH). Reaction of l0-Bromo-2,3-dihydro-1,3-dioxo-2-phenyl-lH-imidazoc 1,5-b]isoquinolinium Bromide 2d with Cyanide.-Treat- ment of crude lO-brom0-2,3-dihydro- 1,3-dioxo-2-phenyl- 1 H-imidazoc 1,5-b]isoquinolinium bromide ' 2d (0.5 g) with potas- sium cyanide (0.1 g) in water (1 cm3) and dichloromethane (50 cm3) gave, after the usual work-up, a white solid (from acetonitrile) which was tentatively assigned as the pseudobase 3g, v,,,/cm-' 3440 (OH), 1760 (CO), 1710 (CO) and 1630 (M); S[(CD,),SO] 6.68 (1 H, d, J 7, after addition of D20 collapsed to a singlet, 5-H), 7.09 (1 H, d, J 7, exchanged with D,O, 5-OH), 7.42-7.58 (8 H, m, ArH) and 7.81-7.96 (1 H, m, 9- H).The product was refluxed with dry methanol for 4 h to give the corresponding ether 3e. Benzylation of 1,2,3,5-Tetrahydro-1,3-dioxo-2-propylimidazo-[1,5-b]isoquinoline-5-carbonitrile5i.-A suspension of com-pound 5i (0.267 g, 1 mmol) in freshly distilled, dry DMF (3 cm3) was stirred at 0 "C under nitrogen. Benzyl chloride (0.19 g, 1.5 mmol) and sodium hydride (0.036 g, 1.5 mmol) were added successively and the mixture was stirred for 3 h, poured onto crushed ice, then extracted with chloroform and the extracts were dried (MgSO,) and evaporated to afford 5-benzyl- 1,2,3,5- tetrahydro-1,3-dioxo-2-propylimidazo[1,5-b]isoquinoline-5-carbonitrile 6 (0.16 g, 4573, m.p.196197 "C (from MeOH) (Found: C, 73.45; H, 5.15; N, 11.75%; M+, 357. C22Hl,N,02 requires C, 73.9; H, 5.35; N, 11.45%; M, 357); v,,,/cm-' 1765 (CO), 1715 (CO) and 1680 (M);S(CDC1,) 0.99 (3 H, t, NCH2- CH,Me), 1.75 (2 H, m, NCH,CH,Me), 3.214.10 (4 H, a triplet centred at 6 3.61, NCH2CH,Me, overlapping with an ABq, J 14, CH,Ph), 6.16 (1 H, s, 10-H) and 6.51-7.63 (9 H, m, ArH). Reaction of ( k)-1,2,10,10a-7- Tetrahydro- 1,3-dioxo- 1H-imi- dazo[ 1,5-b]isoquinolinium Bromides 7 with Various Nucleo- phi1es.-A suspension of the appropriate (-+)-l0,lOa- tetrahy- droimidazo[ 1,5-b]isoquinoline-l,3(2H,5H)-dione la or Id (10 mmol) in dry tetrachloromethane (10 cm3) was treated with a solution of bromine (1.6 g, 10 mmol) in dry tetrachloromethane (5 cm3) '.The resultant crude (+)-1,2,10,10a-tetrahydro-1,3-dioxo-1 H-imidazo[ 1,5-b]isoquinolinium bromide 7was treated with dry methanol, absolute ethanol, or isopropyl alcohol (10 cm3) to give the (+)-2-substituted 5-alkoxy-10,lOa-dihydroimidazo[ 1,5-b]isoquinoline- 1,3(2H,SH)-diones 8a-8e, which were recrystallised from an appropriate solvent. Treatment, by this procedure, of the salts 7 with thiophenol, ethanethiol, and acetaldoxime in dry, ethanol-free chloroform afforded the corresponding adducts 8f4h.Treatment of the salts 7, under similar conditions, with dimethylamine, diethyl- amine, and morpholine afforded the adducts 8i-8k, which were purified by column chromatography on silica or neutral alumina, with chloroformAiethy1 ether (9 : 1) as eluant. The 124 J. CHEM. SOC. PERKIN TRANS. I 1991 Table 6 Spectroscopic data for the (a)-dihydro-adducts 8a-8k IR 'H NMR" (6) Compound (v,,,/cm-' 1 5-H" IOa-H' 10-H,d 8a 1760 (CO), 1710 (CO) 6.02 4.30 2.64 3.38 8b 1760 (CO), 1710 (CO) 6.10 4.30 2.65 3.33 8c 1770 (CO), 1720 (CO) 6.12 4.49 2.81 3.50 8d 1770 (CO), 1720 (CO) 6.21 4.50 2.82 3.50 8e 1780 (CO), 17 15 (CO) 6.27 4.50 2.80-3.48 8f 1770 (CO), 1710 (CO) 6.60 4.37 2.55- 3.40 8gS 1770 (CO), 1710 (CO) 6.57 4.66 2.86-3.52 8i 1770 (CO), 1710 (CO) 5.75 4.15 2.58 3.37 gj 1770 (CO), I7 10 (CO) 5.99 4.29 2.78 3.47 8kg 1770 (CO), 1715 (CO) 5.85 4.29 2.82 -3.49 Other protons 3.06 (3 H, s, NMe), 3.52 (3 H, s, 5-OMe), 7.18 7.5 1 (4 H, m, ArH) 1.25 (3 H, t, OCH,Me), 3.03 (3 H, s, NMe), 3.8 I (2 H, q, OCH,Me), 7.15 7.50 (4 H, m, ArH) 3.60 (3 H, s, 5-OMe), 7.25 7.52 (9 H, m, ArH) 1.30 (3 H, t, OCH,Mt.), 3.90 (2 H, q, OCH,Me), 7.25-7.51 (9 H, m, ArH) 1.20 (3 H, d, J 6 Hz, CH- Me). 1.40 (3 H, d, J 6 Hz, CH Mc.), 4.1 3-4.29 (1 H, m, CHMe,), 7.23 7.48 (9 H, m, ArH) 2.90 (3 H, s, NMe), 7.15-7.59 (9 H, m, ArH) 1.32 (3 H, t, SCH,Mc), 2.82 (2 H, q, SCH,Me).7.2c7.48 (9 H, m, ArH) 2.29 (6 H, s, 5-NMe2), 3.07 (3 H, s, NMe), 7.18 7.32 (3 H, m, ArH), 7.59--7.70 (1 H, m, 6-H) 1.10 [6 H, t, N(CH, ~WMC)~J, 2.62 [4 H, q, N(CH,Me),l,7.2G7.48 (8 H, m, ArH), 7.63-7.74 (1 H, m, 6-H) 2.62 2.75 [4 H, two overlapping triplets N(CH,)], 3.69 [4 H, t, O(CH,)], 7.24-7.51 (8 H, m, ArH), 7.7s7.81 (1 H, m, 6-H) a Spectra were recorded in CDCI,. Singlet. 'Doublet of quartets. Double doublets. '(-)-Isomer, [x] k0-62.4" (c, 1.0, CHCl,). M', 338.1 127. CI9 H,8N20,32S requires M, 338.1089. Addition of DCI shifted the signals downfield and after 12 h gave a yellow precipitate. analytical and spectral data of the adducts 8a-8k are given in Tables 5 and 6.Reaction of ( & )-2,3,10-10a- Tetrahydro-2-methyl- 1,3-dio~o- 1H-imidazo[1,5-b]isoquinoliniumBromide 7a with Phenylmag- nesium Bromide.-To a stirred solution of phenylmagnesium bromide in dry diethyl ether, which was freshly prepared from bromobenzene (3.14 g, 20 mmol) and magnesium turnings (0.53 g, 22 mmol), was added crude powdered compound 7a (2.36 g, 8 mmol) portionwise. The reaction was continued for 0.5 h and then water (30 cm3) was added slowly; dil. hydrochloric acid was added until two layers resulted, followed finally by ammonium chloride (1.5 g) and sufficient ammonia to make the aq. phase alkaline. The organic layer was separated, washed with water, and dried (Na,SO,).Evaporation of the solvents gave an off-white solid (1.1 g), which was chromatographed on a silica gel column, with chloroform-diethyl ether-methanol suspension of crude ( & )-2,3,10,1 Oa-tetrahydro-2-methyl- 1,3- dioxo-1 H-imidazo[ 175-b]isoquinolinium bromide 7a, obtained from the bromination of compound lb (2.16 g, 10 mmol) in tetrachloromethane,' was treated as described previously for the preparation of Reissert compounds 5h and 5i with a solution of potassium cyanide (1 g) in water (5 cm3) to give (*)-1,2,3,5,10,1 Oa-hexahydro-2-methyl- l13-dioxoimidazo[ 1,5-b] iso- quinoline-5-carbonitrile 81 (0.6 g, 25% based on lb), m.p. 230- 231 "C (Found: C, 64.5; H, 4.5; N, 17.75%; M', 241. C13HI1N3O, requires C, 64.5; H, 4.6; N, 17.4%; M, 241); v,,,/ cm-' 2240vw (CN), 1770 (CO) and 1710 (CO); G(CDC1,) 2.70- 3.47 (5 H, dq, 10-H, overlapping with a s centred at 6 3.09, NMe), 4.28 (1 H, dd, J 6 and 13, IOa-H), 6.02 (1 H, s, 5-H) and 7.25-7.52 (4 H, m, ArH).By a similar procedure (+)-1,2,3,5,10,1Oa-hexahydro-1,3-dioxo-2-phen~ilimi~~a~o[1,5-h]isoquinoline-5-carbonitrile8m was obtained from the salt 7b, m.p. 229-231 "C (from MeOH) (85: 10:5) as eluant, to afford (~)-2,3,lO,lOa-te~rahydro-3-hyd-(Found: C, 71.6; H, 4.5; N, 13.7. Cl,H13N30, requires C, 71.25; roxy-2-methyl-3,5-diphenylimidazo[1,5-b] isoquinolin- 1 (5H)-one 9 m.p. 188-190 "C(Found: C, 77.35; H, 6.1; N, 7.6%; M', 370. C,,H2,N,0, requires C, 77.8; H, 6.0; N, 7.55%; M, 370); v,,,/ cm-' 3250 (OH) and 1685 (CO); G(CDC1,) 2.50 (3 H, s, NMe), 2.85-3.15 (2 H, dq, 10-H,), 3.87 (1 H,dd, J 6 and 13, 10a-H), 5.06 (1 H, s, exchanged with D,O, 3-OH), 5.78 (1 H, s, 5-H) and 7.05-7.46 (14 H, m, ArH).Preparation of Dihydro- Reissert Compounds 81 and 8m.-A H, 4.3; N, 13.85%); v,,,/cm-' 2250vw (CN), 1780 (CO) and 1715 (CO); G(CDC13) 2.85-3.56 (2 H, dq, lO-H,), 4.42 (1 H, dd, J 6 and 13, 10a-H), 6.11 (1 H, s, 5-H) and 7.32-7.43 (9 H, m, ArH). Hydrolysis of Reissert and Dihydro- Reissert Compounds 5i, 81 and 8m.-A solution of the Reissert compound 5i (0.67 g, 3 mmol) in conc. hydrochloric acid (20 cm3) was refluxed for 2 h. After cooling, the white product which separated out was J. CHEM soc'. PERKIN TRANS. 1 1991 collected by filtration and recrystallised from acetone to give 1,2,3,5- tttruhydro- 1,3-dioxo-2-propylimidazo[1,541isoquinoline-5-carboxumide Sj as a solid (0.64 g, 89.5%), m.p.287-289 "C (Found: C, 63.65; H, 5.25; N, 14.55. C15H15N303requires C, 63.35;H, 4.95; N, 14.75%); v,,,/cm-' 3395 and 3225 (NH,), 1775 (CO), 1715 (CO), 1685 (amide I), 1670 (C=C) and 1635 (amide 11); S[(CD,),SO] 0.88 (3 H, t, NCH2CH,Me), 1.60 (2 H, m, NCH,CH,Me), 3.49 (2 H, t, NCH,CH,Me), 4.3M.55 (2 H, br s, exchanged with D,O, SCONH,), 5.22 (1 H, s, 5-H), 6.61 (1 H, s, 10-H) and 7.21-7.65 (4 H, m, ArH). The amide Sj (0.3 g) was further hydrolysed by being refluxed for 4 h with a mixture of sulphuric acid, glacial acetic acid and water (1 5 cm3; 1 :1 :1). The resultant clear solution, after cooling to room temperature, was poured onto crushed ice and extracted with diethyl ether; the extract was washed with water, dried (Na,SO,), and evaporated to give an oil, which was dissolved in 5% aq.sodium hydroxide and acidified with 6 mol dm-3 hydrochloric acid to yield 1,2,3,5-tetrahydro- 1,3-dioxo-2- propq~fimiu'ax[1,5-b]isoquinofine-5-carboxylicacid Sk (0.17 g, 5779, m.p. 182-184°C (Found: C, 62.9; H, 4.95; N, 9.9"/,; M', 286. C1sH14N204requires C, 62.9; H, 4.95; N, 9.8%; M. 286); v,,,,'cm-' 1760 (CO), 1710 (CO) and 1675 (C=C); G[(CD,),SO] 0.87 (3 H, t, NCH,CH,Me), 1.62 (2 H, m, NCH,CH,Me), 3.50 (2 H, t, NCH,CH,Me), 4.354.95 (br s, exchange signal of 5-C0,H with water in solvent), 5.60 (1 H, s, 5-H), 6.72 (1 H, s, 10-H) and 7.25- 7.55 (4 H, m, ArH). Compound 81(1.2 g, 5 mmol) was refluxed for 3 h in a mixture of conc. hydrochloric acid (35 cm3) and glacial acetic acid (15 cm3).The solution was cooled, extracted with diethyl ether and the extract was washed with water and dried (Na,SO,). Evaporation gave an oil, which when triturated with dry diethyl ether afforded ( +)-1,2,3,5,10,1Oa-hexahydro-2-methyl-I ,3-dioxoir?ziduzo[1,5-b]isoquinoline-5-carboxylicacid 8n (0.9 g, 70:/;), m.p. 189.5-191 "C (Found: C, 60.1; H, 4.95; N, 10.85%. Cl3HI2N2O4requires C, 60.0; H, 4.65; N, 10.75%); vmaX,'cm-' 1770 (CO), 1735 (CO)and 1690 (CO); F(CDC1,) 2.70-3.41(5 H, dq, 10-H, overlapping with a s centred at 6 3.05, NMe), 4.51 (1 H, dd, J 6 and 13, 10a-H), 5.70 (1 H, s, 5-H), 7.20-7.34 (3 H, m, ArH), 7.51-7.66 (1 H, m, 6-H), 10.20(1 H, s, exchanged with D,0,5-CO,H).By an identical procedure compound 8m (1.21 g, 4 mmol) gave ( _+ )-1,2,3,5,lO,lOa-hexahydro-1,3-dioxo-2-phenylimidazo-[1,5-h]isoquinoline-5-carboxylicacid 8p (0.96 g, 7573,m.p. 246 248 "C (Found: C, 66,75; H, 4.45; N, 8.8%; M', 322. C,8Hl,N20, requires C, 67.05; H, 4.4; N, 8.75%; M, 322); v,,,/cm-' 1775 (CO), 1735 (CO) and 1700 (CO); S[(CD,),SO] 3.13-3.30 (2 H, m, 10-H,), 4.68 (1 H, dd, J 6 and 13, 10a-H), 5.62 (1 H, s, 5-H) and 7.30-7.69 (9 H, m, ArH). The acid 8n (0.53 g, 2 mmol) was treated with a freshly prepared solution of diazomethane in dichloromethane to yield (k)-methyl 1,2,3,5,10,1 Oa-hexahydro-2-methyl- 1,3-dioxoimida- zo[ 1,5-b]isoquinoline-5-carboxyfate8q (0.48 g, 88%), m.p.11 8-119 "C (Found: C, 60.9; H, 5.25; N, 9.85. C,4H14N204requires C, 61.3; H, 5.15; N, 10.2%); v,,,/cm-' 1775 (CO), 1740 (CO) and 1710 (CO); G(CDC1,) 2.72-3.45 (5 H, dq, 1GH2 overlapping with a s centred at 6 3.08, NMe), 3.78 (3 H, s, 5-C02Me),4.59 (1 H, dd, J 6 and 13, 1Oa-H), 5.72 (1 H, s, 5-H), 7.20-7.35 (3 H, m, ArH) and 7.53-7.64 (1 H, m, 6-H). Similar treatment of acid 8p with diazomethane (0.644 g, 2 mmol) gave ( f)-methyl 1,2,3,5,10, 1 Oa-hexahjdro- 1,3-dio.uo-2- phenylimidazo[ 1,5-b]isoquinoline-5-carboxylate8r (0.63g, 94%), m.p. 167-169°C (from MeOH) (Found: C, 68.25; H, 4.95; N, 8.65. ClgHl6N2O4 requires C, 67.85; H, 4.8; N, 8.35%); vmax/cm-l1780 (CO), 1750 (CO) and 1710 (CO); G(CDC1,) 2.89-3.55 (2 H, dq, 10-H,), 3.80 (3 H, s, 5-C02Me),4.76 (1 H, dd, J 6 and 13, 10a-H), 5.80 (1 H, s, 5-H) and 7.23-7.68 (9 H, m, ArH).References I I. Niopas and G. A. Smail, preceding paper. 2 J. W. Bunting and W. G. Meathrel, Can. J. Chem.. 1972,50,917. 3 B. C. Uff, J. R. Kershaw and S. R. Chhabra, J. Chcm. Soc.. Perkin Trans. 1, 1974, 1146. 4 R. A. Corral and 0.0.Orazi, Spectrochim. Acta, 1965,21,2119. 5 R. H. Barker, G. J. Bourdeaux and S. L. Vail, .4ppl. Spectrosc., 1966, 20,414. 6 C. K. Bradsher, Quaternary Isoquinoliniuni Salts. in /soquinolines, Part 1, ed. G. Grethe, Heterocyclic Compounds, John Wiley, London, 1981, vol. 38, p. 381. 7 F. Krohnke and I. Vogt, Chem. Ber., 1957,90,2227 8 D. Beke, Adu. Heterocycl. Chem., 1963, 1, 167. 9 M. D. Johnson, J. Chem. Soc., 1964,200. 10 R. D. Haworth and W. H. Perkin, J. Chem. Soc., 1925,127. 1434. 11 F. D. Popp and W. Blount, Chem. Ind. (London),1961,550. 12 W. E. McEven and R. L. Cobb, Chem. Ret.., 1955,55511 13 F. D. Popp, K. T. Potts and R. Armbruster, Org. .Mas.\ Spectrom., 1970, 3, 1075. 14 R. Chenevert, E. Lemieux and N. Voyer, Synlh. Conimun., 1983, 13, 1095. 15 1. Fleming, Frontier Orbitals and Organic Chemical Hractions, Wiley, 1976, p. 33. 16 R. G. Pearson, J. Chem. Educ., 1968,45581,643. 17 C. Schuerch and E. H. Huntress, J. Am. Chem. Soc.. 1948.70,2824. 18 R. Piccivili and F. D. Popp, Can. J. Chem., 1969,47, 3261. 19 B. C. Uff, J. R. Kershaw and J. L. Neumeyer, Org. Stwth., 1977,56, 19. 20 M. Makosza, Tetrahedron Lett., 1969,677. 21 W. J. Gender, Heterocyclic Compounds, ed. R. C. Elderfield, John Wiley, London, 1952, vol. 4, p. 344. 22 S. Cortes and H. Kohn, f.Org. Chem., 1983,48, 2246. 23 W. D. Ollis and C. A. Ramsden, Adt. Heterocycl. Chcwi., 1976, 19, 1. 24 E. C. Weir, Ph.D. Thesis, University of Strathclyde, 1979. Paper 0/03543B Received 2nd August 1990 Accepted 9th August 1990