HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 10, 2009, pp. 2509-2522
Received, 20th May, 2009, Accepted, 30th June, 2009, Published online, 1st July, 2009.
DOI: 10.3987/COM-09-11760

■ Tetrazolium N-Aminides: Complementary Studies on Synthesis and Properties

Dietrich Moderhack* and Matthias Noreiks

Institute of Pharmaceutical Chemistry, Technical University, Beethovenstrasse 55, D-38106 Braunschweig, Germany

Abstract

Attempts are made to access the title compounds from N-amido/urei¬dotetrazoles (A, B; 1H- / 2H-system). These materials are provided by acylation of the respective N-aminotetrazoles (A in one step, B partly by hydrolysis of diacylat¬ed derivatives which are obtained directly). On treatment with excess dimethyl sul¬fate only A undergoes the necessary ring quaternization, giving rise to two isomers (ratio ca. 4 : 1); work-up with base allows isolation of the major aminide (X). This technique requires that the (slow) quaternization process be fully completed, since at pH > 7 dimethyl sulfate rapidly affects the side chain of A. Concluding experi¬ments pertain to protonation and methylation of the title compounds (X–XII).

INTRODUCTION
Three series of tetrazolium N-aminides (X–XII) stabilized by an electron-withdrawing group have been recently prepared in straightforward manner from the respective aminotetrazolium salts (I–III) (Scheme 1).1 The conversion, performed as one-pot synthesis, proceeded as follows: (i) deprotonation of I–III to generate the parent aminides (IV–VI), (ii) acylation of the latter to yield the amidotetrazolium salts (VII–IX), and (iii) deprotonation of VII–IX to afford the target aminides (X–XII). The abridgment (I–III → VII–IX) was not feasible because of insufficient nucleophilicity of the amino group.1,2 This contrasts with the reactivity of 1(3)-aminoimidazolium 3 and both 4- and 1-amino-1,2,4-triazolium salts 4 which can be directly acylated. An alternate approach constitutes quaternization of N-amidotetrazoles like A and B — a principle that has been verified with 4-amido- 4a, 5 and 1-amido-1,2,4-triazoles.4d Having pointed to the viability of the route (A → VII → X) marginally,1 we provide a detailed account which includes the sequences (A → VIII → XI) and (B → IX → XII) and, finally, describes properties of X–XII not dealt with in our previous paper.1

RESULTS AND DISCUSSION
N-Amido/Ureidotetrazoles
As candidates we chose derivatives having R = Me / Ph and R' = Me / Ph / NHPh most of which were unknown materials. Access was sought by acylation of the respective N-aminotetrazoles (1, 2) (Scheme 2). While this kind of functionalization is amply documented for N-aminoazoles in general,6 the experience with tetrazoles is scarce. Directly relevant examples are limited to the reactions of 1-aminotetrazole (1; R = H) with phenyl isocyanate 7 and of 2-amino-5-phenyltetrazole (2b) with phthaloyl chloride.8
Regarding acetylation, 1a,b were treated at elevated temperature with a slight excess of acetic anhydride in acetic acid. While the derivative (A1a) was formed smoothly, the 5-phenyl congener (A1b) arose less readily (heating with the neat reagent proved inappropriate as this modification caused twofold acetylation giving A'1a,b9, 10). However, when submitting the isomeric tetrazoles (2a,b) to the conditions suitable for A1a,b, no reaction occurred. This lack of nucleophilicity reflects the stronger electron-withdrawing influence exerted by the 2H-tetrazol-2-yl system.11 Thus, to prepare B1a,b we attempted acetyl chloride in diethyl ether in the presence of triethylamine and commenced using an equimolar amount of the reagent.

But since this led to a mixture of mono- and diacetyl derivatives accompanied by starting material, we sought for exhaustive acetylation by adjusting the proportions. The diacetyl derivatives (B'1a,b), now formed exclusively, could be in turn hydrolyzed to the required amides (B1a,b).
Benzoylation of 1a,b was achieved with benzoyl chloride using pyridine as solvent (→ A2a,b); 12 again, the 5-phenyl substituted derivative (1b) proved less reactive. The two isomeric amines (2a,b), by contrast, turned out to be fully inert. In parallel to acetylation, reactivity was observed only on employing triethylamine and here too the process did not stop at the stage of monoacylation: as final products the isoimides (3a,b) were formed (instead of dibenzamides of type B'); their structure was deduced from comparison of the 13C NMR data with those of analogous compounds of the 1,2,3-triazole series.13 On hydrolysis of these materials (made by use of excess reagent) the target benzamides (B2a,b) arose in good yield.
Phenylcarbamoylation by the treatment with phenyl isocyanate proceeded well at room temperature in the cases of 1a and 2a,b to afford the ureas (A3a) and (B3a,b), respectively. With 1a the reaction could be accomplished in dichloromethane as solvent, whereas pyridine was compulsory for the conversion of 2a,b. This applies to 1b as well, but here also heating was required because of the poor solubility.

Tetrazolium N-Aminides
Exploring to what extent the above tetrazoles (A) and (B) are suitable materials for aminide making, we first studied the 5-methyl derivatives (A1a–A3a) and (B1a–B3a). Since in preliminary experiments 1 methyl iodide has proved inappropriate for ring quaternization,14 dimethyl sulfate was used throughout to effect the following (Scheme 3):
The isomers (A1a–A3a), while reacting more slowly than the parent (1a),1 gave, in line with the ambident behavior of 1H-tetrazoles, ca. 4 : 1 mixtures of the quaternary salts (5a-c) and (6a-c). Attempts to isolate them were vitiated: In the case of 5a / 6a the acidic medium arising on removal of excess reagent with water–diethyl ether induced hydrolysis of the acetamido group to leave behind the respective amino salts of type (I / II) (R = R" = Me). The side chains of 5b / 6b and 5c / 6c withstood this work-up, but when, for convenience, the solution of 5b / 6b was submitted to an anion exchange procedure (MeOSO3 → Br), in addition to the target bromides substantial amounts of the aminides (4b / 7b) were formed and separated as solids on the exchange resin. Hence we treated the original reaction mixtures (5b / 6b) and (5c / 6c) with aqueous alkali carbonate. This immediately caused precipitation of the pure aminides (4b) and (4c);15 the minor components (7b) and (7c), however, eluded isolation. The same technique was then applied to the couple (5a / 6a). But here the liberated aminides (4a / 7a) proved susceptive of alkylation by the dimethyl sulfate still present in the reaction mixture, giving rise to irremovable by-products identified as the methyl sulfate analogues of the iodide salts (14a / 15a) which were prepared separately (see later). Yet another impurity, the N-methylacetamide (9a), will form if that base-assisted work-up is set about untimely, i.e. before the initial quaternization process (which is very slow !) has been fully completed: According to a model experiment dimethyl sulfate at pH > 7 rapidly attacks unconsumed starting material at the functional group.16, 17 Since the educts (A2a) and (A3a) are likewise susceptible to this kind of conversion giving 9b and 9c, respectively, an appropriate check should precede isolation of the aminides (4b) and (4c).
In striking contrast to the behavior of A1a–A3a towards dimethyl sulfate, no reaction took place with the isomers (B1a–B3a), even on prolonged exposure. These substrates, like all 2H-tetrazoles, are extremely weak nucleophiles, and here the acyl moiety further impairs reactivity so as to prevent the formation of the desired salts (8a–c). The only conversion of which B1a–B3a were found capable was side chain methylation yielding the derivatives (10a-c).18

Turning to substrates having R = Ph, we treated the urea (A3b) with dimethyl sulfate. Unlike its methyl congener (A3a) it displayed only negligible reactivity. This resembles our earlier observation in which the quaternization of the parent (1b) proceeded considerably more slowly than that of 1a.1 In view of this inertness the experiments with the 5-phenyl-2H-tetrazoles (B1b–B3b) were unpromising and omitted.
Addendum to aminide synthesis from I–III: In pursuit of our former aminide synthesis 1 we have found that intermediates of type (VI), viz. the derivatives (12a,b), are isolable compounds.19 The corresponding representatives of type (IV) and (V), however, proved elusive. The obtained substances form slightly hygroscopic crystals. Their relative stability is rationalized in terms of the stronger electron-withdrawing effect (inductively and by resonance) of the 1H-tetrazolium-3-yl system (cf. ref.20). Basicity measurements, performed by UV spectrometry at 260 nm and 20 °C in water, showed pKa = 9.27 (12a) and 8.76
(12b).21 On addition of hydrobromic acid to 12b, the starting salt (11b) was recovered in 78% yield.

N-Amidotetrazolium Salts
Isolation of the intermediary salts (5) and (6), dispensible in the preceding part, was required for comparative purposes. We therefore tried to approach the species from the aminide side and extended the method to the isomer (8). When the acetyl derivatives (4a,e) and (7e) were treated in ethanol with hydrobromic acid, followed by addition of diethyl ether, instead of the respective acetamido salts (5) and (6) the products of hydrolysis [i.e. type (I) and (II)] were found. This confirms the sensitivity experienced above with 5a / 6a after having quaternized A1a. Complete hydrolysis of the functionality also occurred on the attempt to prepare the benzamido salt (5b).

Stability was encountered only with its congeners having R = Ph, i.e. the derivatives (5d), (6d), and (8d) (X = Br; made accordingly from 4d, 7d, and 13d).22 As expected, these compounds are strong acids; we determined pKa = 2.92 (5d), 2.87 (6d), and 3.19 (8d) (all values by potentiometric titration of 0.002 molar solutions with 0.01 N NaOH in water at 20 °C). Judging from the pKa's of the (5-methylated) phenacyltetrazolium bromides which show 10.17, 9.64, and 9.05, respectively,20 the tetrazolium N-aminides are by 106–107 less basic than their N-ylidic counterparts.23 But while the pKa's of the phenacyl salts follow the electron-withdrawing effect of the tetrazolium moieties 20 (which increases in the order as these units are grouped in Scheme 1), the pKa's of 5d, 6d, and 8d do not.
To provide the remaining reference material (14 / 15) (cf. above) we adopted the method that has proved fruitful with tetrazolium N-phenacylides,20 i.e. treatment of the aminides (4) and (7) with methyl iodide in dimethylformamide as solvent.24 At room temperature the derivatives (14a,b) and (15a,b) were obtained within 24 hours. Yet, applying the procedure to 13, several days were required for the products (16a,b). This again reflects the enhanced acceptor character of the 1H-tetrazolium-3-yl system: for the total atomic charge of the aminide nitrogen of 13a we found –0.382, compared to –0.422 (4a) and –0.418 (7a) [values refer to optimized geometries calculated at the B3LYP/6-31G(d) level of theory (cf. ref.1)]. Apart from 15b which could not be isolated pure because of extreme hygroscopicity, all of the methylation products are stable solids. This led us to doubt a literature note 26 stating that the triazolium N-aminide (17a) forms a 'very unstable salt with methyl iodide' — apparently compound (18a) — which releases the reagent 'even at room temperature.' Preparing this derivative, we could not confirm the alledged sensitivity, but found that the substance, including its congener (18b), matches the stability of the above tetrazolium salts.

EXPERIMENTAL
Mp: Linström apparatus; elemental analysis: CHN Analyzer 1106 Carlo Erba; IR: Philips PU-9800 FTIR, Thermo Nicolet FT-IR 200; NMR: Bruker DRX-400 (400.1 and 100.6 MHz for 1H and 13C, respective­ly); UV/VIS: Philips PU-8730, Analytik Jena Specord 200; MS: Finnigan-MAT 90 (70 eV). The following compounds were prepared by reported procedures: (i) Tetrazolamines (1a),1 (1b),9b (2a),1 and (2b);9b (ii) tetrazolium aminides (4a,b,d), (7a,b,d), and (13a,b,d,e);1 (iii) aminotetrazolium bromides (11a,b);1 (iv) 1,2,4-triazolium aminides (17a) 4a and (17b).4d

N-(5-Methyl/5-Phenyl-1H-tetrazol-1-yl)acetamide (A1a,b). General procedure: Adopting the method of ref.,4a a mixture of the appropriate tetrazol-1-amine (1a) or (1b) (5 mmol), acetic anhydride (0.61 g, 6 mmol), and acetic acid (5 mL) was heated at reflux for 6 h. Removal of the solvent left an oil that slowly solidified; in the case of A1b, it was purified on silica gel (Et2O). For data, see Tables 1 and 2.

N-Acetyl-N-(5-methyl/5-phenyl-1H-tetrazol-1-yl)acetamide (A'1a,b). General procedure: Adopting the method of ref.,9b the appropriate tetrazol-1-amine (1a) or (1b) (5 mmol) and acetic anhydride (4.08 g, 40 mmol) were heated at reflux for 4 h. Evaporation of excess reagent in vacuo afforded an oil that slowly solidified. For the data of A'1a, see Tables 1 and 2; for A'1b, see below.

A'1b: 0.16 g (21%); mp 86–88 °C (benzene–Et2O; lit.,9a mp 90 °C; lit.,9b mp 88–89 °C); IR (KBr): ν 1760, 1743 cm–1; 1H NMR (DMSO-d6): δ 2.36 (s, 6H), 7.53–7.58 (m, 2H), 7.60–7.65 (m, 1H), 7.72–7.76 (m, 2H) [lit.,9b 2.38 (s, 6H), 7.6–8.0 (m, 5H)]; 13C NMR (DMSO-d6): δ 24.7 (q, 2C), 121.6 (s), 127.7 (d, 2C), 129.8 (d, 2C), 132.7 (d), 153.5 (s), 168.6 (s, 2C).

N-(5-Methyl/5-Phenyl-1H-tetrazol-1-yl)benzamide (A2a,b). General procedure: To a stirred solution of the respective tetrazol-1-amine (1a) or (1b) (4 mmol) in pyridine (10 mL) was added dropwise benzoyl chloride (0.56 g, 4 mmol) at 20 °C. In the case of A2a, the mixture was allowed to stand at room temperature for 1 h; for A2b, it was heated at reflux for ≥ 6 h. After concentration to dryness the resultant oil was treated with water (5 mL) and the solid formed was collected by filtration.
A2b: 0.99 g (93%); mp 135–136 °C (EtOH–water; lit.,12a mp 134–135 °C; lit.,12b mp 136–138 °C); IR (KBr): ν 3169, 1704 cm–1; 1H NMR (DMSO-d6): δ 7.58–7.64 (m, 5H), 7.70–7.75 (m, 1H), 7.94–8.03 (m, 4H), 13.27 (s, 1H); 13C NMR (DMSO-d6): δ 122.2 (s), 127.8 (d, 2C), 127.9 (d, 2C), 129.1 (d, 2C), 129.4 (d, 2C), 129.9 (s), 132.0 (d), 133.5 (d), 153.2 (s), 165.6 (s). — For the data of A2a, see Tables 1 and 2.

1-(5-Methyl-1H/2H-tetrazol-1-yl/2-yl)-3-phenylurea (A3a / B3a), 1-phenyl-3-(5-phenyl-1H/2H-tetrazol-1-yl/2-yl)urea (A3b / B3b). General procedure: (i) To a stirred solution of 2 mmol of the appropriate tetrazolamine (1a) in CH2Cl2 (5 mL) or (1b), (2a), (2b) in pyridine (2 mL) was slowly added phenyl isocyanate (0.24 g, 2 mmol). After continued stirring at 20 °C (1 h for A3a, B3a; 2 h for B3b) or 115 °C (6 h for A3b) the solvent was evaporated. The derivative (A3a) was directly crystallized from the residue, whereas the other products were first purified on silica gel (EtOAc). For data, see Tables 1 and 2.

N-Acetyl-N-(5-methyl/5-phenyl-2H-tetrazol-2-yl)acetamide (B'1a,b), N-(5-me¬thyl/5-phenyl-2H-tetrazol-2-yl)benzimidoyl benzoate (3a,b). General procedure: To a stirred solution of the appropriate tetrazol-2-amine (2a) or (2b) (10 mmol) and triethylamine (2.20 g, 22 mmol) in Et2O (40 mL) was slowly added in the same solvent (10 mL): acetyl chloride (1.57 g, 20 mmol) and benzoyl chloride (2.81 g, 20 mmol), respectively. After 1 h the mixture was cooled to 4 °C, the solid was filtered off and the filtrate concentrated. The resultant oil readily crystallized on scratching. For data, see Tables 1 and 2.

N-(5-Methyl/5-Phenyl-2H-tetrazol-2-yl)acetamide (B1a,b), N-(5-methyl/5-phenyl-2H-tetrazol-2-yl)benzamide (B2a,b). General procedure: A suspension of the appropriate derivative (B'1a), (B'1b), (3a) or (3b) (5 mmol) in 2 N KOH (30 mL) was stirred at 80 °C (2 h with B'1a,b, 4 h with 3a,b). The clear solution was acidified with 12 N HCl to afford the product which was isolated by filtration or extraction with CH2Cl2. For data, see Tables 1 and 2.

N-Benzoyl-1,5-dimethyl-1H-tetrazolium-4-aminide (4b), 1,5-dimethyl-N-(phenylcarbamoyl)-1H-tetrazolium-4-aminide (4c). General procedure: A suspension of the amide (A2a) or urea (A3a) (1 mmol) in dimethyl sulfate (1 mL, ca. 10 mmol) was allowed to stand at 20 °C for 3 d. Then the mixture was diluted with Et2O (20 mL) and the solvent was decanted to afford ca. 0.3 g of a colorless oil [1H NMR (DMSO-d6): s (N-Me) at δ 4.34 (5b) / 4.61 (6b) or 4.35 (5c) / 4.73 (6c)]. On adding aqueous K2CO3 (10 mL, 5%) the pure aminide (4b) (0.08 g, 36%) or (4c) (0.16 g, 65%) precipitated and was filtered off. The data (mp, IR, 1H and 13C NMR) were consistent with those of ref.1

4-Benzamido-1-methyl-5-phenyl-1H-tetrazolium bromide (5d). The aminide (4d) (1 mmol) was dissolved in water (5 mL) followed by addition of ca. 9 N HBr (0.25 g). Then the mixture was extracted with CH2Cl2 (2 x 20 mL); the organic layer was concentrated to dryness and the residue was recrystallized. For data, see Tables 1 and 2.

4-Benzamido-2-methyl-5-phenyl-2H-tetrazolium bromide (6d), 3-benzamido/ 3-acetamido-1-methyl-5-phenyl-1H-tetrazolium bromide (8d,e). General procedure: The appropriate aminide (7d), (13d) or (13e) (1 mmol) was dissolved in EtOH (5 mL) followed by addition of ca. 9 N HBr (0.25 g). After the mixture had been cooled to 4 °C, it was cautiously diluted with Et2O and set aside to allow crystallization of the product. For data, see Tables 1 and 2.

N-Methyl-N-(5-methyl-1H/2H-tetrazol-1-yl/2-yl)acetamide (9a / 10a). General procedure: To a solution of the appropriate acetamide (A1a) or (B1a) (0.18 g, 1 mmol) in CHCl3 (50 mL) were added K2CO3 (1.00 g) and dimethyl sulfate (0.13 g, 1 mmol). The mixture was heated at reflux for 4 h with vigorous stirring. Then the solid was removed and the filtrate was concentrated. The residual mass was purified on silica gel (CH2Cl2). For data, see Tables 1 and 2.

N-Methyl-N-(5-methyl-1H/2H-tetrazol-1-yl/2-yl)benzamide (9b / 10b), 1-(5-methyl-1H/2H-tetrazol-1-yl/2-yl)-3-phenylurea (9c / 10c). General procedure: To a vigorously stirred solution of K2CO3 (1.00 g) in water (10 mL) were added, successively, the appropriate benzamide (A2a) or (B2a) or the phenylurea (A3a) or (B3a) (1 mmol) and dimethyl sulfate (0.5 mL, ca. 5 mmol). After 30 min the solid was removed and the filtrate was concentrated to dryness. The residual material was purified on silica gel (CH2Cl2). For data, see Tables 1 and 2.

1,5-Dimethyl-1H-tetrazolium-3-aminide (12a), 1-methyl-5-phenyl-1H-tetrazol-3-aminide (12b). General procedure: The respective tetrazolium salt (11a) or (11b) (1 mmol) and K2CO3 (0.35 g, ca. 2.5 mmol) were dissolved in water (10 mL). The mixture was immediately extracted with CH2Cl2 (3 x 15 mL) and the organic layers were dried. Evaporation of the solvent afforded slightly hygroscopic crystals giving microanalytical figures only approximate (because of moisture and gradual decomposition); attempts to recrystallize the material failed.
12a: 0.04 g (49%); mp 56–57 °C; UV (MeOH / CH2Cl2): λmax (log ε) 285 (ca. 3.47) / 287 (ca. 3.91) nm; MS (m/z, %): 113 (M+, 100), 98 (29), 69 (76), 56 (44), 43 (50); for IR and 1H / 13C NMR, see Table 2.
12b: 0.10 g (57%); mp 75–76 °C; UV (MeOH / CH2Cl2): λmax (log ε) 276 (ca. 3.76) / 287 (ca. 4.10) nm; MS (m/z, %): 175 (M+, 25), 160 (54), 118 (41), 104 (62), 77 (100); for IR and 1H / 13C NMR, see Table 2.

1,5-Dimethyl-4-(N-methylacetamido/N-methylbenzamido)-1H-tetrazolium iodide (14a,b), 2,5-di¬methyl-4-(N-methylacetamido/N-methylbenzamido)-2H-tetrazolium iodide (15a,b), 1-benzyl/1-methyl-4-(N-methylacetamido)-1H-1,2,4-triazolium iodide (18a,b). General procedure: To a solution of the appropriate aminide (4a), (4b), (7a), (7b), (17a) or (17b) (1 mmol) in anhydrous DMF (5 mL) was added methyl iodide (0.36 g, 2.8 mmol) and the mixture was allowed to stand for 24 h. After removal of the solvent in vacuo the residue was dissolved in EtOH, followed by addition of Et2O for crystallization of the product which was filtered off (15b liquefied instantaneously). For data, see Tables 1 and 2.

1,5-Dimethyl-3-(N-methylacetamido/N-methylbenzamido)-1H-tetrazolium iodide (16a,b). General procedure: The appropriate aminide (13a) or (13b) (1 mmol) was treated as above except that work-up was performed after 3 d. For data, see Tables 1 and 2.

ACKNOWLEDGMENT
The authors thank T. Peters for assistance in providing compound (15b).

References

1. Cf. D. Moderhack and M. Noreiks, Heterocycles, 2004, 63, 2605. CrossRef
2. M. Noreiks, Dissertation, Technical University of Braunschweig (Germany), 2006, pp. 18–19.
3. Y. Tamura, H. Hayashi, J. Minamikawa, and M. Ikeda, J. Heterocycl. Chem., 1974, 11, 781. CrossRef
4. a) H. G. O. Becker, N. Sauder, and H.-J. Timpe, J. Prakt. Chem., 1969, 311, 897; CrossRef b) Y. Tamura, H. Hayashi, and M. Ikeda, Chem. Pharm. Bull., 1976, 24, 2568; c) C. R. Arnold, T. Melvin, W. M. Nelson, and G. B. Schuster, J. Org. Chem., 1992, 57, 3316; CrossRef d) D. Moderhack and M. Noreiks, Heterocycles, 2006, 68, 2113. CrossRef
5. a) H. G. O. Becker and H.-J. Timpe, J. Prakt. Chem., 1970, 312, 1112; CrossRef b) H. G. O. Becker, K. Heimburger, and H.-J. Timpe, J. Prakt. Chem., 1971, 313, 795; CrossRef c) A. Narayanan, D. R. Chapman, S. P. Upadhyaya, and L. Bauer, J. Heterocycl. Chem., 1993, 30, 1405; CrossRef d) B. Pirotte, P. de Tullio, B. Masereel, M. Schynts, J. Delarge, L. Dupont, and L. Thunus, Can. J. Chem., 1993, 71, 1857. CrossRef
6. V. V. Kuzmenko and A. F. Pozharskii, 'Advances in Heterocyclic Chemistry: N-Aminoazoles,' Vol. 53, ed. by A. R. Katritzky, Academic Press, Inc., London, 1992, pp. 85–231. CrossRef
7. I. Hagedorn and H.-D. Winkelmann, Chem. Ber., 1966, 99, 850 (also tosyl chloride gave the appropriate amidotetrazole, but acetylating and benzoylating agents caused ring transformation into 1,3,4-oxadiazole derivatives). CrossRef
8. T. L. Gilchrist, G. E. Gymer, and C. W. Rees, J. Chem. Soc., Perkin Trans. 1, 1975, 1747. CrossRef
9. For the conversion (1b → A'1b), cf.: a) R. Stollé, J. Prakt. Chem., 1933, 138, 1; CrossRef b) R. Raap, Can. J. Chem., 1969, 47, 3677. CrossRef
10. See also the behavior of 1,5-diaminotetrazole: a) Ref.9bb) P. N. Gaponik and V. P. Karavai, Khim. Geterotsikl. Soedin., 1984, 1683; Chem. Heterocycl. Compd. (USSR) (Engl. Transl.), 1984, 20, 1388. CrossRef
11. P. Bouchet, C. Coquelet, and J. Elguero, J. Chem. Soc., Perkin Trans. 2, 1974, 449. CrossRef
12. Compound (A2b) is long known as the product formed on hydrolysis of 5-phenyltetrazoles having at N(1) benzimidoyl cyanide and chloride functionalities, respectively: a) R. Fusco and S. Rossi, Ann. Chim. (Rome), 1960, 50, 277; b) H. Behringer and H. J. Fischer, Chem. Ber., 1962, 95, 2546. CrossRef
13. N. A. Rodios, J. Heterocycl. Chem., 1984, 21, 1169. CrossRef
14. In contrast to quaternization of 4- and 1-amido-1,2,4-triazoles4a,d,5a.
15. In ref.,1 p. 2608, instead of the process (A2a → 4b), the conversion (A1a → 4a) has been inadvertently quoted. — Additional corrections on p. 2612: (i) line 14 should read '8d,f,h, 9d,f,h, and 10b,d,f,h:', (ii) line 17 should read 'After 1 h (4 h for 9f) the'.
16. Cf. methylation of 1-amidoimidazoles: A. Hetzheim, O. Peters, and H. Beyer, Chem. Ber., 1967, 100, 3418. CrossRef
17. As 9a exhibits considerable proclivity for quaternization giving 14a / 15a (MeOSO3 for I), pure
material was preferentially made in an organic solvent; this variant also facilitated isolation of the water-soluble product.
18. For side chain methylation of A1b–A3b and B1b–B3b, see ref.,2 pp. 20–21.
19. Isolable hetarenium aminides lacking a stabilizing N-substituent are rare: a) S. F. Gait, C. W. Rees, and R. C. Storr, Chem. Commun., 1971, 1545; CrossRef S. F. Gait, M. E. Peek, C. W. Rees, and R. C. Storr, J. Chem. Soc., Perkin Trans. 1, 1975, 19; CrossRef b) M. Stumpf and H. Balli, Liebigs Ann. Chem., 1994, 1049. CrossRef
20. D. Moderhack and A. Lembcke, J. Chem. Soc., Perkin Trans. 1, 1986, 1157 (see also p. 2009). CrossRef
21. Cf. N-unsubstituted pyridinium 1-aminide: pKa = 11.2 (by potentiometric titration of 1-aminopyridinium iodide): T. Okamoto, M. Hirobe, Y. Tamai, and E. Yabe, Chem. Pharm. Bull., 1966, 14, 506.
22. Of the latter tetrazolium series the acetamido congener (8e) could be isolated too, albeit in low yield (see Table 1).
23. Reduced basicity also exists with respect to N-aminides of the 1,2,4-triazole series: N-acetyl-1-benzyl(butyl)-1,2,4-triazolium-4-aminide shows pKa = 4.5 (4.9): a) H.-J. Timpe, Z. Chem., 1972, 12, 250; b) H.-J. Timpe, 'Advances in Heterocyclic Chemistry: Heteroaromatic N-Imines,' Vol. 17, ed. by A. R. Katritzky and A. J. Boulton, Academic Press, Inc., London, 1974, pp. 213–253.
24. Employment of acetone or ethyl acetate at elevated temperature (partly at 20 °C), which works excellently with imidazolium N-aminides,25 had no appreciable effect (exemplified with 4a).
25. M. de las Heras, A. Molina, J. J. Vaquero, J. L. Garcia Navio, and J. Alvarez-Builla, J. Org. Chem., 1993, 58, 5862. CrossRef
26. P. Zalupsky and A. Martvon, Collect. Czech. Chem. Commun., 1984, 49, 1713.