1H-Pyrazole-1-carboxamidine Hydrochloride

[4023-02-3]  · C4H7ClN4  · 1H-Pyrazole-1-carboxamidine Hydrochloride  · (MW 146.60)

(electrophilic agent capable of specific reaction with nitrogen nucleophiles such as amines and hydrazines, yielding substituted guanidines and aminoguanidines by displacement of pyrazole;1,2 synthesis of substituted s-triazines1,3)

Alternate Name: 1-guanylpyrazole hydrochloride.

Physical Data: mp 167-168 °C.

Solubility: insol ether, hexane; very sol H2O, DMF, alcohol; in the presence of 1 equiv Diisopropylethylamine (free base), very sol (>1.5 M) DMF, H2O, and alcohol, and sol CH2Cl2, CHCl3, THF, acetone, and acetonitrile; the free base is slightly sol EtOAc, ether.

Form Supplied in: nonhygroscopic, white crystalline solid.

Preparative Method: to a mixture of pyrazole (0.36 mol) Cyanamide (0.36 mol), and 320 mL of p-dioxane is added 95 mL of 4 N HCl in p-dioxane. The mixture is gradually warmed to 55-60 °C with mechanical stirring under N2. After about 1 h the product crystallizes and the mixture is cooled to rt. Ether (100 mL) is added with stirring and the product is collected by filtration, washed with ether, and dried in vacuo, yielding 51.2 g (97%).

Handling, Storage, and Precautions: indefinitely stable (at least two years) at rt in a tightly sealed bottle. Cool, dry, and dark conditions are recommended for long term storage. The toxicological properties are not known, but pyrazole is considered a possible teratogen. Use in a fume hood.

Synthesis of Substituted Guanidines.

1H-Pyrazole-1-carboxamidine (1) reacts with many amines and hydrazines at room temperature under a variety of conditions to give substituted guanidines in good yields (eq 1).1,2 In this context, the carboxamidine (1) is significantly more reactive than 3,5-dimethylpyrazole-1-carboxamidine nitrate4 and other commercially available guanylating agents (see also Cyanamide, O-Methylisourea, and S-Methylisothiourea).2 Because of its superior reactivity, good solubility properties, stability, and ease of preparation, the carboxamidine (1) is the guanylating agent of choice for many applications, including solid-phase peptide synthesis of arginine-containing peptides by quantitative guanylation of the d-amino group(s) of ornithine-containing precursor sequences.2 The general use of the guanylating agent (1) for the preparation of various arginine peptides by such a strategy (eq 2) in this author's laboratory has not yet necessitated the evaluation of commercially unavailable Aminoiminomethanesulfonic Acid,5,6 with questionable stability7 and solubility properties, as an alternative guanylating agent for this purpose.

For amine guanylation, the reactivity of the carboxamidine (1) appears to be limited to primary, secondary, and aryl amines that are not deactivated by steric, electronic, or resonance effects. For example, guanidine products cannot be obtained from diisopropylamine, dicyclohexylamine, 2,2,2-trifluoroethylamine, p-nitroaniline, and a- or b-naphthylamine. In these cases only the diguanidine (2), formed by slow self condensation of (1), can be isolated (eq 3).2 The diguanidine (2) also slowly forms at room temperature in the presence of tertiary amines and is unreactive with cyclohexylamine at room temperature.2

Modification of Proteins.

Like 3,5-dimethylpyrazole-1-carboxamidine nitrate, the carboxamidine (1) in aqueous buffer can guanylate the ε-amino groups of lysine residues (and to a lesser extent the N-terminal a-amino group) in proteins to produce homoarginine residues.8 The extent of guanylation by these reagents depends on molar ratio, concentrations, pH, temperature, and time.8 These reagents are particularly suitable when extensively modified proteins are desired. For more specific, less extensive lysine modification, the use of other less reactive, water soluble reagents may be advantageous.

Synthesis of N,N-Disubstituted and Diprotected Guanidines.

The N-allyl derivative (3) of the reagent (1) has been prepared (eq 4)9 and, although less reactive, has been found to react slowly, specifically and essentially completely at room temperature with the d-amino group of L-ornithine (eq 5) to allow facile isolation of NG-allyl-L-arginine (4) in 70% yield.9 This result suggests that other N,N-dialkylguanidines may be obtainable via the appropriate N-alkyl derivatives of the reagent (1).

The N,N-bis-Cbz and bis-Boc derivatives (5a,b) of the carboxamidine (1) have been recently prepared in good yields by two sequential acylations (eq 6).10,11 These derivatives are substantially more reactive than the parent carboxamidine (1) and react readily with aniline and 2,2,2-trifluoroethylamine at room temperature to give N,N-bis-protected guanidines that can be smoothly deprotected under typical conditions to provide otherwise inaccessible monosubstituted guanidines in good yields (eq 7).10 Although the N,N-bis-urethane-protected carboxamidines (5a,b) fail to guanylate diisopropylamine and dicyclohexylamine,10 they nonetheless represent a valuable and complementary alternative to the use of the reagent (1) when the guanylation of relatively nonnucleophilic amines under mild conditions is required, they also provide more flexibility in the formulation of synthesis schemes targeting complex guanidine-containing molecules. Alternative reagents reported for the preparation of N,N-bis-Boc-guanidines from amines are N,N-bis-Boc-thiourea12 and N,N-bis-Boc-S-methylisothiourea.13

Synthesis of 2-Amino-Substituted s-Triazines.

The carboxamidine (1) reacts readily with 1,3,5-Triazine yielding 2-(pyrazol-1-yl)-s-triazine (6) which reacts with Ammonia, many amines, and Hydrazine to produce 2-monosubstituted s-triazines (7) in good yields (eq 8).1,3

Related Reagents.

Aminoiminomethanesulfonic Acid; Diphenyl Cyanocarbonimidate; S-Methylisothiourea; O-Methylisourea.

1. Bredereck, H.; Effenberger, F.; Hajek, M. CB 1965, 98, 3178.
2. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. JOC 1992, 57, 2497.
3. Bredereck, H.; Effenberger, F.; Hofmann, A.; Hajek, M. AG 1963, 75, 825.
4. Bannard, R. A. B.; Casselman, A. A.; Cockburn, W. F.; Brown, G. M. CJC 1958, 36, 1541.
5. Miller, A. E.; Bischoff, J. J. S 1986, 777.
6. Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. M.; Mills, J. E. JOC 1986, 51, 1882.
7. Kim, K.; Lin, Y.-T.; Mosher, H. S. TL 1988, 29, 3183.
8. Habeeb, A. F. S. A. Methods Enzymol. 1972, 25b, 558.
9. Bernatowicz, M. S.; Matsueda, G. R. SC 1993, 23, 657.
10. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. TL 1993, 34, 3389.
11. Wu, Y.; Matsueda, G. R.; Bernatowicz, M. S. SC 1993, in press.
12. Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. TL 1992, 33, 5933.
13. Bergeron, R. J.; McManis, J. S. JOC 1987, 52, 1700.

Michael S. Bernatowicz

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.