Aminoiminomethanesulfonic Acid

[1184-90-3]  · CH4N2O3S  · Aminoiminomethanesulfonic Acid  · (MW 124.13)

(parent compound and its derivatives guanylate amines; some derivatives give triazoles with azide and aminoiminoethanenitriles with cyanide as nucleophile)

Alternate Name: formamidinesulfonic acid.

Physical Data: mp 131-131.5 °C when highly pure; around 125 °C with dec before purification.

Solubility: sol water; slightly sol methanol, ethanol; insol ether.

Preparative Methods: by the oxidation of thiourea or aminoiminomethanesulfinic acid (formamidinesulfinic acid) with Peracetic Acid. Many substituted aminoiminomethanesulfonic acids can be prepared in the same way.1,2 Others have utilized Hydrogen Peroxide with sodium molybdate as a catalyst to oxidize the corresponding thioureas to a variety of monosubstituted aminoiminomethanesulfonic acids; the substituents include phenyl, 2-methylphenyl, 4-fluorophenyl, n-propyl,3 cyclohexylmethyl, S-a-methylbenzyl, cyclooctyl, and benzhydryl.4

Purification: recrystallize from glacial acetic acid.

Handling, Storage, and Precautions: stable for at least a few weeks at room temperature. After drying, it remains stable for at least 5 months if kept in a freezer. Thiourea and its metabolites (probably oxidized thiourea) are tumorigenic and cause lung edema. All direct contact with the compound should be avoided; for example, a dust mask should be worn. All residues should be destroyed with strong bleach solution. Many substituted thioureas and their metabolites are also biologically active. Use in a fume hood.

Synthesis of Guanidines from Amines.

Aminoiminomethanesulfonic acid (1) reacts with a variety of primary amines, including t-Butylamine, to give 50 -80% yields of the corresponding guanidines (eq 1). This reaction is more facile than guanidine syntheses starting with S-alkylisothioureas.2 Reactions of primary and secondary amines with monosubstituted (phenylamino)- and (n-propylamino)iminomethanesulfonic acids also give good to excellent yields of the corresponding guanidines. Treatment of (n-propylamino)iminomethanesulfonic acid with a hindered amine, t-butylamine, leads to a good yield of the corresponding triazine instead of the guanidine.3

Reaction of aminoiminomethanesulfonic acid with a variety of amino acids gives yields of guanidino acids ranging from 5 -80%. Reactions of some amino acids do not lead to an isolable product. Similar results are obtained with (phenylamino)iminomethanesulfonic acid and (phenylamino)(phenylimino)methanesulfonic acid.1

Other Nucleophilic Substitution Reactions.

Nucleophilic substitution of a variety of substituted aminoiminomethanesulfonic acids with cyanide leads to the corresponding aminoiminoethanenitriles in 30-87% yield. A number of substituted aminoiminomethanesulfonic acids react with Sodium Azide in acetic acid to give the corresponding 5-aminotetrazole. This reaction is subject to pronounced steric hindrance. Hydroxylamine and Cyanamide also give nucleophilic substitution of the sulfonic acid group.5

Agelasidine-A analogs were prepared in two steps by treatment of a chloroethyl sulfone with Ammonia followed by aminoiminomethanesulfonic acid (eq 2). Direct displacement of chloride using guanidine furnished the dienyl analog in comparable yield.6

Guanylation of 3R-methyl-L-arginine with aminoiminomethanesulfonic acid followed by protection with adamantyloxycarbonyl chloride produced the bis-Adoc protected arginine derivative, a key intermediate in the total synthesis of lavendomycin.7 In contrast, both (3R)- and (3S)-hydroxy-L-arginine have been prepared by guanylation of the tridentate copper complexes of threo- and erythro-2-hydroxy-L-ornithine using S-methylisothiourea.8 Aminoiminomethanesulfonic acid has been used in the synthesis of an a-hydroxy ester C-terminal homo-L-arginine tripeptide for evaluation as a thrombin inhibitor.9 The synthesis of a partially modified retro-inverso T-cell epitope analog required preparation of the malonylarginine intermediate (2) using aminoiminomethanesulfonic acid as the guanylating agent (eq 3).10

Conversion of 3,6-bis(t-butyldimethylsilyl)-N-(3-aminopropyl)normorphine to the corresponding guanidine analog has been accomplished in high yield using aminoiminomethanesulfonic acid. Interestingly, all attempts to convert the N atom of morphine directly to the analogous guanidine were unsuccessful.11 Guanylation of the N-(4-aminobutyl)cinnamanilide (3) with aminoiminomethanesulfonic acid followed by alkylation with prenyl bromide furnished caracasanamide (4) in high yield (eq 4).12 Alternatively, (4) could be prepared by reaction of (3) with cyanamide (5)12 or from guanylation using the bis-Boc S-methylisothiourea (6) followed by cleavage with TFA.13

Related Reagents.

Cyanamide; Guanidine; S-Methylisothiourea; O-Methylisourea; 1H-Pyrazole-1-carboxamidine Hydrochloride.

1. Miller, A. E.; Bischoff, J. J. S 1986, 777.
2. Kim, K.; Lin, Y.-T.; Mosher, H. S. TL 1988, 29, 3183.
3. Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. JOC 1986, 51, 1882.
4. Muller, G. W.; Walters, D. E.; DuBois, G. E. JMC 1992, 35, 740.
5. Miller, A. E.; Feeney, D. J.; Ma, Y.; Zarcone, L.; Aziz, M. A.; Magnuson, E. SC 1990, 20, 217.
6. Suryawanshi, S. N.; Rani, A.; Bhakuni, D. S. IJC(B) 1991, 30B, 1089.
7. Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A. CC 1990, 1216.
8. Wityak, J.; Gould, S. J.; Hein, S. J.; Keszler, D. A. JOC 1987, 52, 2179.
9. Iwanowicz, E. J.; Lin, J.; Roberts, D. G. M.; Michel, I. M.; Seiler, S. M. BML 1992, 2, 1607.
10. Dürr, H.; Goodman, M.; Jung, G. AG(E) 1992, 31, 785.
11. Jackson, W. R.; Copp, F. C.; Cullen, J. D.; Guyett, F. J.; Rae, I. D.; Robinson, A. J.; Pothoulackis, H.; Serelis, A. K.; Wong, M. Clin. Exp. Pharmacol. Physiol. 1992, 19, 17 (CA 1992, 117, 82 892p).
12. Crombie, L.; Jarrett, S. R. M. JCS(P1) 1992, 3179.
13. Delle Monache, G.; Botta, B.; Delle Monache, F.; Espinal, R.; De Bonnevaux, S. C.; De Luca, C.; Botta, M.; Corelli, F.; Carmignani, M. JMC 1993, 36, 2956.

Audrey Miller

University of Connecticut, Storrs, CT, USA

David C. Palmer

R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA

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