HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 4, 2014, pp. 995-1007
Received, 26th January, 2014, Accepted, 27th February, 2014, Published online, 14th March, 2014.
DOI: 10.3987/COM-14-12952

■ New 1,2- and 1,3-Aza-ylides of 3-Amino-2-substituted-1H-isoindoles

Hatem A. Abdel-Aziz,* Tilal Elsaman, Khalid A. Al-Rashood, and Hoong-Kun Fun

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-11451, Saudi Arabia

Abstract

The reaction of 2-(bromomethyl)benzonitrile (5) with hydrazides 6a-f or heterocyclic amines 14a-c gave isoindolium bromides 7a-f and 15a-f, respectively. Deprotonation of the latter salts afforded the 1,2-aza-ylides 8a-f and 1,3-aza-ylides 16a-c instead of the analogous imines 9a-f or 17a-c, respectively. Single crystal X-ray and NMR analyses confirmed the stable ylide structures of 8a-f and 16a-c and established the presence of a complete benzenoid unit in the isoindole moiety, in both the solid state and solution phase.

INTRODUCTION
Isoindoles are particularly useful for treating diseases caused or aggravated by excessive or unregulated levels of tumour necrosis factor alpha (TNF-α), interleukin-beta (IL-β), interleukin-10 (IL-10) or lymphocytes (T-cells). For example, these compounds are effective for treating cancer, viral, genetic, inflammatory, allergic, autoimmune and bacterial diseases.1,2 Thalidomide, an isoindole derivative, is an emerging immunotherapeutic agent. In addition to its utility in treating a variety of inflammatory disorders, it is useful for treating cancers and has been shown to inhibit the production of both TNF-α and IL-β while simultaneously increasing the production of IL-10 and T-cells. The teratogenic properties of thalidomide have limited its use and driven efforts to discover new related inhibitors of TNF-α production with improved therapeutic activity and reduced toxicity.3-6 Despite this research, there remains a need for non-toxic and high-potency compounds that treat or prevent cancer, inflammatory disorders, and autoimmune diseases. Therefore, the synthesis and chemical reactivity of isoindole derivatives have received considerable interest.7,8
The 2H-isoindole tautomer (1) (Figure 1a) is the predominant form in solution and is associated with lower aromaticity, as its six-membered ring is not a complete benzenoid unit. The alternative 1H-isoindole tautomer (2) (Figure 1a), which contains a complete benzenoid unit, exists in an appreciable percentage in equilibrium with the 2H-isoindole tautomer (1). The position of this equilibrium can be altered by changing the solvent. Solvents such as dimethylsulphoxide (DMSO) tend to favour the 2H-isoindole tautomer, while protic solvents such as methanol favour the 1H-isoindole tautomer.9-12

On the other hand, there has been a rapid increase in the use of ylides in organic synthesis. Despite the instability of nitrogen ylides, they are highly reactive intermediates and have a rich chemistry that can be used for the rapid preparation of highly functionalised compounds from relatively simple components. N-Ylide chemistry now includes a large area of research and embodies a broad range of synthetic and mechanistic work concerning both the generation and reactions of ylides.13 1,2-Aza-ylides, or 1,2-dipole aza compounds, are neutral dipolar molecules containing a negatively charged nitrogen atom directly attached to another nitrogen atom with a positive charge, with both nitrogen atoms having full octets of electrons. When 1,2-dipole aza compounds are attached to a carbon atom, they form 1,3-dipole molecules represented as an allyl structure (-C=N-N-) in which the 1,3-dipole shares four π-system electrons over three atoms, such as in ylides 3 (Figure 1b).13

In continuation of our interest in the construction of novel heterocycles of chemical and/or pharmaceutical interest,14-21 in this work we aimed to study the reaction of 2-(bromomethyl)benzonitrile (5) with hydrazides 6a-f or heterocyclic amines 14a-c (Schemes 1 and 2), which produced stable 1,2- and 1,3-aza-ylides of isoindole containing a complete benzenoid unit in the solid state and solution phase.

RESULTS AND DISCUSSION
The reaction of 2-(bromomethyl)benzonitrile (5) with the appropriate hydrazides 6a-f in methanol under microwave irradiation (200 W, 90 °C) for 4 min gave, in each case, a single product in good yield (75-92%). The products were identified as isoindolium bromides 7a-f (Scheme 1) based on single crystal X-ray analysis of compound 7f22 (Figure 2). Salts 7a-f were also prepared conventionally in refluxing methanol for 10 h in 40-68% yield.

Interestingly, deprotonation of bromides 7a-f with sodium carbonate at ambient temperature afforded the 1,2-aza-ylides 8a-f based on single crystal X-ray analysis of compound 8a22 (Figure 3), which excluded the possibility of the formation of imines 9a-f in the solid state. IR spectra of compounds 8a-f revealed two sharp absorption bands characteristic of a quaternary ammonium cation (≡N+-) in the region of 2362-2339 cm-1. A carbonyl absorption band also appeared at 1699-1676 cm−1 in addition to the NH2 absorption band at 3405-3047 cm−1. The 1H NMR (DMSO-d6) spectra of 8a-f did not indicate the presence of a pyrrole -CH= proton due to the expected equilibrium with 10a-f. However, the spectra contained a singlet signal due to -CH2- protons in the region of δ 5.23-5.40 in addition to a D2O-exchangeable singlet signal due to an -NH2 in the region of δ 8.89-9.10. 13C NMR (DMSO-d6) of 8a-f revealed an aliphatic -CH2- carbon signal in the region of δ 56.9-57.38.

However, NMR spectra of 8a-f acquired in MeOD contained the same pattern of signals as in DMSO-d6. Furthermore, using different protic or aprotic solvents to grow a single crystal of compound 8a suitable for X-ray analysis resulted in the same structure in the solid state. These results established the complete stable benzenoid unit of 1,2-aza-ylides 8a-f in the solid state and solution phase.

The above reaction is assumed to proceed via the initial reaction of the NH2 moiety of hydrazides 6a-f with the bromomethyl branch of 5, followed by addition of the resulting acyclic quaternary amines 11a-f to the ortho-cyano functionality. The carbon atom of the cyano group becomes C3 of the resulting isoindole skeleton, while the nitrogen atom is converted to the amino group. Reversing the sequence of the latter pathway and the formation of phthalazine 12a-f are less probable (Scheme 1). However, when we added potassium carbonate to the reaction of 5 with 6a-f, 8a-f were obtained in very poor yields (5-12%). The relative stability of 1,2-aza-ylides is somewhat dependent on the substituent pattern. Electron-withdrawing groups stabilise the negative centre, while electron-donating groups stabilise the positive centre.23 The carbonyl and amino groups play an important role in the formation of the isolable and stable 1,2-dipole ylene form of ylides 8a-f. However, NMR and X-ray measurements excluded the formation of 8a-f or 13a-f (Figure 4).

The X-ray analysis measurements of 8a established the aromaticity of the 1H-isoindole moiety, which appeared to be almost planar and had bond lengths in the benzene ring that are within the normal range of an ideal complete benzenoid unit24 (Figure 5a). The bond lengths for N3-C15 (1.468(2) Å), C8-C9 (1.460(2) Å) and C14-C15 (1.496(2) Å) in the five-membered ring of the 1H-isoindole moiety are in the range of single bond lengths, and the bond length of N3-C8 (1.310(2) Å) is in the range of the Csp2=N double bond distance.24 Moreover, the crystal structure of 8a is stabilised by an extensive network of intermolecular hydrogen bonds, in which the carbonyl O1 atom is hydrogen bonded to the amino N atom through N2−H1(N2)···O1 and N2−H2(N2)···O1ii hydrogen bonds (Figure 5b).

Encouraged by the above results, we reacted 2-(bromomethyl)benzonitrile (5) with the appropriate heterocyclic amines 14a-c in a similar manner to give isoindolium bromides 15a-c (Scheme 2), according to single crystal X-ray analysis of compound 15a22 (Figure 6).

Deprotonation of the latter bromide salts 15a-c yielded their free bases, but trials of growing a single crystal of these free bases failed. However, the 1,3-aza-ylide structures of compounds 16a-c were confirmed based on their IR and 1H NMR spectra. The IR spectra of the latter compounds exhibited sharp absorption bands due to the quaternary ammonium cation (≡N+-) in the region of 2361-2340 cm-1, while their 1H NMR spectra did not contain the characteristic signal from an NH in a heterocyclic ring (pyrazole, triazole or imidazole) in the region of δ 10-14.27-29 In addition, the 1H NMR spectra (DMSO-d6) of 16a-c contained singlet signals due to methylene protons in the region of δ 5.35-5.66 while their 13C NMR spectra (DMSO-d6) contained methylene group carbon signals in the region of δ 42.74-55.5. These data excluded the tautomerisation of 16a-c to their corresponding incomplete benzenoid structures 18a-c in the solution phase whereas the appearance of a D2O-exchangeable signal from the NH2 group in the region δ 7.21-9.5 excluded structures 17a-c. However, the azole moiety and amino group supported the formation of 1,3-aza-ylides 16a-c.23

In conclusion, we herein report the convenient synthesis and an interesting configuration of the newly synthesised 1,2- and 1,3-aza-ylides of 1H-isoindole in the solid state and solution phase.

EXPERIMENTAL
Infrared (IR) spectra were recorded using KBr disks with the Perkin Elmer FT-IR Spectrum BX apparatus. Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. NMR spectra were obtained in DMSO-d6 on a Brucker NMR spectrometer operating at 500 MHz for 1H and 125 MHz for 13C. Chemical shifts are expressed in δ-values (ppm) relative to TMS as an internal standard. Coupling constants (J) are expressed in Hz. D2O was added to confirm the presence of exchangeable protons. Mass spectra were obtained using a Varian MAT CH-5 spectrometer (70 eV). Elemental analyses were carried out at the Microanalytical Center of Cairo University. The X-ray diffraction measurements were obtained using a Bruker SMART APEX diffractometer. The microwave irradiations were carried out in an Explorer-48 microwave reactor from CEM, USA.
Synthesis of isoindolium bromides 7a-f and 15a-c. A mixture of 2-(bromomethyl)benzonitrile (5) (1.96 g, 10 mmol) and the appropriate hydrazide 6a-f or heterocyclic amine 14a-c (10 mmol) in absolute MeOH (10 mL) was added to a closed vessel in a microwave reactor. The closed vessel was irradiated with microwaves at 200 W and 90 °C, with 250 psi maximum pressure for 4 min. The vessel was cooled and the solid that formed was collected by filtration and washed with methanol to give isoindolium bromides 7a-f and 15a-c, respectively, in 75-92% yields, which were used for the next step without any further purification. Compounds 7a-f and 15a-c were synthesized conventionally by refluxing a mixture of 5 (1.96 g, 10 mmol) and the appropriate hydrazide 6a-f or heterocyclic amine 14a-c (10 mmol) in absolute MeOH (30 mL) for 10 h and then left to cool. The separated solid was filtered and washed with methanol to give isoindolium bromides 7a-f and 15a-c, respectively in 40-68% yields.
3-Amino-2-benzamido-1H-isoindolium bromide (7a). White solid, yield (92%); mp 297-299 °C; IR (KBr): ν 3450-3075 (NH+NH2), 2360, 2340 (-C=N+-), 1669 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.34 (s, 2H, CH2), 7.29-7.40 (m, 3H, ArHs), 7.51-7.58 (m, 1H, ArH), 7.62-7.66 (m, 2H, ArHs), 8.05-8.10 (m, 3H, ArHs), 8.96 (s, D2O exch., 2H, NH2), 11.23 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 57.21 (CH2), 121.84, 122.81, 127.23, 127.78, 127.87, 128.86, 131.10, 140.29, 154.32, 169.34; EI MS m/z: 334 [M+2]+. Anal. Calcd for C15H14BrN3O (332.20): C, 54.23; H, 4.25; N, 12.65. Found: C, 54.44; H, 4.16; N, 12.79.
3-Amino-2-(4-methylbenzamido)-1H-isoindolium bromide (7b). White solid, Yield (85%); mp 327-329 °C; IR (KBr): ν 3480-3070 (NH+NH2), 2361, 2340 (-C=N+-), 1693 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 2.32 (s, 3H, CH3), 5.30 (s, 2H, CH2), 7.15 (d, J = 7.5 Hz, 2H, ArHs), 7.54-7.64 (m, 1H, ArH), 7.63-7.66 (m, 2H, ArHs), 7.99 (d, J = 7.5 Hz, 2H, ArHs), 8.08 (d, J = 7.5 Hz, 1H, ArH), 8.98 (s, D2O exch., 2H, NH2), 11.47 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 20.97 (CH3), 57.08 (CH2), 121.86, 122.80, 127.9, 127.87, 128.65, 131.08, 136.01, 138.35, 140.28, 154.27, 169.83; EI MS m/z: 347 [M+1]+. Anal. Calcd for C16H16BrN3O (346.22): C, 55.51; H, 4.66; N, 12.14. Found: C, 55.74; H, 4.71; N, 12.328.
3-Amino-2-(4-methoxybenzamido)-1H-isoindolium bromide (7c). White solid, Yield (82%); mp 325-327 °C; IR (KBr): ν 3420-3070 (NH+NH2), 2361, 2339 (-C=N+-), 1666 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 3.78 (s, 3H, CH3), 5.29 (s, 2H, CH2), 6.89 (d, J = 7.5 Hz, 2H, ArHs), 7.50-7.58 (m, 1H, ArH), 7.61-7.66 (m, 2H, ArHs), 8.0-8.05 (m, 3H, ArHs), 8.94 (s, D2O exch., 2H, NH2), 11.87 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 56.05 (CH3), 56.78 (CH2), 112.50, 121.85, 123.11, 127.65, 128.49, 130.54, 131.12, 140.21, 154.56, 159.98, 169.75; EI MS m/z: 364 [M+2]+. Anal. Calcd for C16H16BrN3O2 (362.22): C, 53.05; H, 4.45; N, 11.60. Found: C, 52.93; H, 4.42; N, 11.74.
3-Amino-2-(4-chlorobenzamido)-1H-isoindolium bromide (7d). White solid, yield (84%); mp 358-360 °C; IR (KBr): ν 3430-3060 (NH+NH2), 2361, 2339 (-C=N+-), 1668 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.33 (s, 2H, CH2), 7.39 (d, J = 7.5 Hz, 2H, ArHs), 7.50-7.60 (m, 1H, ArH), 7.62-7.64 (m, 2H, ArHs), 8.05-8.08 (m, 1H, ArH), 8.12 (d, J = 7.5 Hz, 2H, ArHs), 8.94 (s, D2O exch., 2H, NH2), 11.91 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 57.11 (CH2), 121.54, 122.74, 127.16, 128.12, 128.31, 129.63, 131.27, 133.41, 138.72, 141.02, 154.17, 169.84; EI MS m/z: 368 [M+2]+. Anal. Calcd for C15H13BrClN3O (366.64): C, 49.14; H, 3.57; N, 11.46. Found: C, 48.98; H, 3.56; N, 11.54.
3-Amino-2-(4-nitrobenzamido)-1H-isoindolium bromide (7e). Pale yellow solid, yield (75%); mp 300-302 °C; IR (KBr): ν 3375-3090 (NH+NH2), 2361, 2340 (-C=N+-), 1698 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.38 (s, 2H, CH2), 7.50-7.59 (m, 1H, ArH), 7.61-7.70 (m, 2H, ArHs), 8.02-8.04 (m, 1H, ArH), 8.21 (d, J = 8.5 Hz, 2H, ArHs), 8.32 (d, J = 8.5 Hz, 2H, ArHs), 9.11 (s, D2O exch., 2H, NH2), 11.32 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 57.10 (CH2), 122.13, 122.63, 123.21, 128.14, 128.89, 131.40, 140.39, 146.20, 147.62, 154.13, 169.46; EI MS m/z: 379 [M+1]+. Anal. Calcd for C15H13BrN4O3 (377.19): C, 47.76; H, 3.47; N, 14.85. Found: C, 47.69; H, 3.55; N, 14.93.
3-Amino-2-(2-(2,3-dimethylphenylamino)benzamido)-1H-isoindolium bromide (7f). Colorless crystals, yield (85%); mp 311-313 °C; IR (KBr): ν 3445-3060 (2NH+NH2), 2361, 2340 (-C=N+-), 1669 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 2.15 (s, 3H, CH3), 2.26 (s, 3H, CH3), 5.28 (s, 2H, CH2), 6.66-6.70 (m, 1H, ArH), 6.80-6.82 (m, 1H, ArH), 6.97-7.05 (m, 2H, ArHs), 7.14-7.21 (m, 2H, ArHs), 7.57-7.60 (m, 1H, ArH), 7.60-7.71 (m, 2H, ArHs), 8.10 (d, J = 7.5 Hz, 1H, ArH), 8.34 (d, J = 7.5 Hz, 1H, ArH), 9.13 (s, D2O exch., 2H, NH2); 10.84 (s, D2O exch., 1H, NH), 11.39 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 13.76 (CH3), 20.37 (CH3), 57.23 (CH2), 113.42, 116.26, 117.20, 122.02, 122.30, 122.89, 123.32, 125.46, 127.95, 128.49, 129.72, 131.21, 131.38, 137.76, 140.43, 140.71, 145.29, 154.45, 170.99; EI MS m/z: 453 [M+2]+. Anal. Calcd for C23H23BrN4O (451.36): C, 61.20; H, 5.14; N, 12.41. Found: C, 61.01; H, 5.03; N, 12.43.
3-Amino-2-(3-phenyl-1H-pyrazol-5-yl)-1H-isoindolium bromide (15a). Colorless crystals, yield (75%); mp 340-342 °C; IR (KBr): ν 3380-3000 (NH+NH2), 2361, 2339 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.35 (s, 2H, CH2), 7.08 (s, 1H, pyrazole), 7.42-7.24 (m, 3H, ArHs), 7.66-7.68 (m, 1H, ArH), 7.81-7.89 (m, 4H, ArHs), 8.41 (d, J = 7.5 Hz, 1H, ArH), 9.12 (s, D2O exch., 2H, NH2), 13.20 (s, D2O exch., H, NH); 13C NMR (125 MHz, DMSO-d6): δ 56.01 (CH2), 93.84, 123.42, 123.94, 125.51, 128.65, 129.05, 129.43, 133.74, 141.36, 143.82, 148.34, 159.15; EI MS m/z: 357 [M+2]+. Anal. Calcd for C17H15BrN4 (355.23): C, 57.48; H, 4.26; N, 15.77. Found: C, 57.55; H, 4.29; N, 15.68.
3-Amino-2-(1H-1,2,4-triazol-5-yl)-1H-isoindolium bromide (15b). White solid, yield (75%); mp 255-257 °C; IR (KBr): ν 3320-3050 (NH+NH2), 2361, 2339 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.64 (s, 2H, CH2), 7.47-7.58 (m, 1H, ArH), 7.69-7.80 (m, 2H, ArHs), 7.89-7.94 (m, 1H, ArH), 8.72 (s, 1H, triazole), 8.91 (s, D2O exch., 2H, NH2), 12.75 (s, D2O exch., H, NH); 13C NMR (125 MHz, DMSO-d6): δ 53.76 (CH2), 111.66, 117.32, 124.00, 127.93, 130.98, 133.57, 138.81, 144.08, 159.36; EI MS m/z: 282 [M+2]+. Anal. Calcd for C10H10BrN5 (280.12): C, 42.88; H, 3.60; N, 25.00. Found: C, 42.75; H, 3.63; N, 24.92.
3-Amino-2-(1H-benzo[d]imidazol-2-yl)-1H-isoindolium bromide (15c). White solid, yield (88%); mp 308-310 °C; IR (KBr): ν 3290-3050 (NH+NH2), 2361, 2340 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.33 (s, 2H, CH2), 6.86-6.88 (m, 2H, ArHs), 6.95 (s, D2O exch., 2H, NH2), 7.48-7.68 (m, 3H, ArHs), 7.90-7.94 (m, 2H, ArHs), 12.17 (s, D2O exch., H, NH); 13C NMR (125 MHz, DMSO-d6): δ 45.65 (CH2), 108.87, 111.46, 117.43, 120.62, 127.54, 127.94, 131.87, 133.45, 142.23, 155.54; EI MS m/z: 331 [M]+. Anal. Calcd for C15H13BrN4 (329.19): C, 54.73; H, 3.98; N, 17.02. Found: C, 45.71; H, 4.59; N, 16.93.

Synthesis of isoindolium ylides 8a-f and 16a-c. An aqueous solution of sodium carbonate (10%, 15 mL) was added to a solution of the appropriate isoindolium bromide 7a-f or 15a-c (1 mmol) in distilled water (15 mL). The reaction mixture was stirred for 24 h. The formed precipitate was filtered off, washed with distilled water, dried and recrystallised from EtOH/DMF to give ylides 8a-f and 16a-c, respectively.
(3-Amino-1H-isoindolium-2-yl)(benzoyl)amide (8a). Colorless crystals, yield (63%); mp 230-232 °C; IR (KBr): ν 3405, 3052 (NH2), 2361, 2340 (-C=N+-), 1677 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.32 (s, 2H, CH2), 7.30-7.40 (m, 3H, ArHs), 7.50-7.60 (m, 1H, ArH), 7.64-7.67 (m, 2H, ArHs), 8.07-8.11 (m, 3H, ArHs), 9.01 (s, D2O exch., 2H, NH2); 1H NMR (500 MHz, MeOD): δ 5.15 (s, 2H, CH2), 7.41-7.45 (m, 3H, ArHs), 7.56-7.59 (m, 1H, ArH), 7.67-7.71 (m, 2H, ArHs), 7.98-8.00 (m, 1H, ArHs), 8.07-8.08 (m, 2H, ArHs), 8.59 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 57.22 (CH2), 121.84, 122.80, 127.21, 127.80, 127.87, 128.86, 131.12, 140.31, 154.30, 167.64; 13C NMR (125 MHz, MeOD): δ 58.09 (CH2), 123.38, 124.12, 128.93, 129.10, 129.46, 129.84, 131.24, 133.40, 138.55, 142.12, 158.60, 174.24; EI MS m/z: 251 [M]+. Anal. Calcd for C15H13N3O (251.28): C, 71.70; H, 5.21; N, 16.72. Found: C, 71.55; H, 5.13; N, 16.49.
(3-Amino-1H-isoindolium-2-yl)(4-methylbenzoyl)amide (8b). White solid, Yield (56%); mp 228-230 °C; IR (KBr): ν 3392, 3047 (NH2), 2361, 2340 (-C=N+-), 1699 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 2.33 (s, 3H, CH3), 5.27 (s, 2H, CH2), 7.15 (d, J = 7.5 Hz, 2H, ArHs), 7.55-7.64 (m, 1H, ArH), 7.63-7.65 (m, 2H, ArHs), 7.98 (d, J = 7.5 Hz, 2H, ArHs), 8.05 (d, J = 7.5 Hz, 1H, ArH), 9.00 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 20.95 (CH3), 57.10 (CH2), 121.86, 122.81, 127.81, 127.87, 128.66, 131.14, 135.95, 138.35, 140.28, 154.31, 167.63; EI MS m/z: 266 [M+1]+. Anal. Calcd for C16H15N3O (265.31): C, 72.43; H, 5.70; N, 15.84. Found: C, 72.71; H, 5.52; N, 16.03.
(3-Amino-1H-isoindolium-2-yl)(4-methoxybenzoyl)amide (8c). White solid, Yield (47%); mp 235-237 °C; IR (KBr): ν 3385, 3064 (NH2), 2361, 2340 (-C=N+-), 1676 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 3.79 (s, 3H, CH3), 5.23 (s, 2H, CH2), 6.89 (d, J = 7.5 Hz, 2H, ArHs), 7.50-7.60 (m, 1H, ArH), 7.62-7.66 (m, 2H, ArHs), 8.00-8.05 (m, 3H, ArHs), 8.90 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 55.05 (CH3), 56.97 (CH2), 112.52, 121.86, 122.82, 127.87, 128.80, 129.33, 131.12, 140.23, 154.50, 160.19, 167.42; EI MS m/z: 281 [M]+. Anal. Calcd for C16H15N3O2 (281.31): C, 68.31; H, 5.37; N, 14.94. Found: C, 68.47; H, 5.43; N, 15.15.
(3-Amino-1H-isoindolium-2-yl)(4-chlorobenzoyl)amide (8d). White solid, yield (80%); mp 255-257 °C; IR (KBr): ν 3389, 3067 (NH2), 2361, 2340 (-C=N+-), 1676 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.35 (s, 2H, CH2), 7.39 (d, J = 8.0 Hz, 2H, ArHs), 7.50-7.60 (m, 1H, ArH), 7.63-7.66 (m, 2H, ArHs), 8.06-8.08 (m, 1H, ArH), 8.10 (d, J = 8.0 Hz, 2H, ArHs), 8.97 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 57.35 (CH2), 121.83, 122.81, 127.15, 127.92, 128.31, 129.63, 131.20, 133.41, 138.38, 140.34, 153.71, 166.37; EI MS m/z: 286 [M+1]+. Anal. Calcd for C15H12ClN3O (285.73): C, 63.05; H, 4.23; N, 14.71. Found: C, 63.20; H, 4.26; N, 14.89.
(3-Amino-1H-isoindolium-2-yl)(4-nitrobenzoyl)amide (8e). Pale yellow solid, yield (78%); mp 266-268 °C; IR (KBr): ν 3308, 3115 (NH2), 2361, 2340 (-C=N+-), 1697 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.40 (s, 2H, CH2), 7.50-7.60 (m, 1H, ArH), 7.60-7.70 (m, 2H, ArHs), 8.02-8.03 (m, 1H, ArH), 8.21 (d, J = 8.5 Hz, 2H, ArHs), 8.34 (d, J = 8.5 Hz, 2H, ArHs), 9.10 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 57.38 (CH2), 121.94, 122.52, 122.89, 128.00, 128.89, 131.41, 140.39, 146.20, 147.64, 153.94, 167.60; EI MS m/z: 297 [M+1]+. Anal. Calcd for C15H12N4O3 (296.28): C, 60.81; H, 4.08; N, 18.91. Found: C, 60.63; H, 4.10; N, 19.13.
(3-Amino-1H-isoindolium-2-yl)(2-(2,3-dimethylphenylamino)benzoyl)amide (8f). White solid, yield (82%); mp 213-215 °C; IR (KBr): ν 3404-3066 (NH+NH2), 2362, 2340 (-C=N+-), 1672 (C=O) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 2.16 (s, 3H, CH3), 2.26 (s, 3H, CH3), 5.26 (s, 2H, CH2), 6.66-6.69 (m, 1H, ArH), 6.80-6.82 (m, 1H, ArH), 6.97-7.04 (m, 2H, ArHs), 7.13-7.20 (m, 2H, ArHs), 7.57-7.59 (m, 1H, ArH), 7.6-7.7 (m, 2H, ArHs), 8.10 (d, J = 7.0 Hz, 1H, ArH), 8.34 (d, J = 7.0 Hz, 1H, ArH), 9.00 (s, D2O exch., 2H, NH2); 10.86 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 13.74 (CH3), 20.37 (CH3), 57.21 (CH2), 113.39, 116.26, 117.22, 121.98, 122.30, 122.88, 123.32, 125.46, 127.95, 128.47, 129.51, 130.76, 131.38, 137.23, 140.40, 140.71, 145.29, 154.21, 170.84; EI MS m/z: 370 [M+1]+. Anal. Calcd for C23H22N4O (370.45): C, 74.57; H, 5.99; N, 15.12. Found: C, 74.53; H, 6.07; N, 15.04.
5-(3-Amino-1H-isoindolium-2-yl)-3-phenylpyrazol-1-ide (16a). White solid, yield (75%); mp 255-257 °C; IR (KBr): ν 3248-2965 (NH2), 2360, 2337 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.35 (s, 2H, CH2), 7.07 (s, 1H, pyrazole), 7.44-7.25 (m, 3H, ArHs), 7.66-7.68 (m, 1H, ArH), 7.80-7.88 (m, 4H, ArHs), 8.40 (d, J = 7.5 Hz, 1H, ArH), 9.50 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 55.50 (CH2), 93.66, 123.43, 123.94, 125.51, 128.70, 128.99, 129.11, 133.62, 141.32, 143.70, 148.02, 159.34; EI MS m/z: 274 [M]+. Anal. Calcd for C17H14N4 (274.32): C, 74.43; H, 5.14; N, 20.42. Found: C, 74.29; H, 5.11; N, 20.57.
5-(3-Amino-1H-isoindolium-2-yl)-1,2,4-triazol-1-ide (16b). White solid, yield (45%); mp 146-148 °C; IR (KBr): ν 3200-3067 (NH2), 2361, 2340 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.66 (s, 2H, CH2), 7.47-7.58 (m, 1H, ArH), 7.69-7.79 (m, 2H, ArHs), 7.89-7.94 (m, 1H, ArH), 8.71 (s, 1H, triazole), 8.85 (s, D2O exch., 2H, NH2); 13C NMR (125 MHz, DMSO-d6): δ 50.58 (CH2), 111.27, 117.08, 123.30, 127.89, 130.98, 133.31, 138.81, 144.08, 159.33; EI MS m/z: 199 [M]+. Anal. Calcd for C10H9N5 (199.21): C, 60.29; H, 4.55; N, 35.16. Found: C, 60.30; H, 4.52; N, 35.00.
2-(3-Amino-1H-isoindolium-2-yl)benzo[d]imidazol-1-ide (16c). White solid, yield (66%); mp 160-162 °C; IR (KBr): ν 3347-3247 (NH2), 2361, 2340 (-C=N+-) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 5.35 (s, 2H, CH2), 6.87-6.88 (m, 2H, ArHs), 7.21 (s, D2O exch., 2H, NH2), 7.47-7.66 (m, 3H, ArHs), 7.90-7.92 (m, 2H, ArHs); 13C NMR (125 MHz, DMSO-d6): δ 42.74 (CH2), 106.52, 110.35, 117.28, 120.67, 127.06, 128.04, 131.39, 133.28, 140.93, 152.77; EI MS m/z: 248 [M]+. Anal. Calcd for C15H12N4 (248.28): C, 72.56; H, 4.87; N, 22.57. Found: C, 72.39; H, 4.82; N, 22.39.

ACKNOWLEDGEMENTS
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no. RGP-VPP-321.

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