Guanidine1

[113-00-8]  · CH5N3  · Guanidine  · (MW 59.09) (acetate)

[593-87-3]  · C3H9N3O2  · Guanidine Acetate  · (MW 119.15) (carbonate)

[593-85-1]  · C3H12N6O3  · Guanidine Carbonate  · (MW 180.21) (hydrochloride)

[50-01-1]  · CH6ClN3  · Guanidine Hydrochloride  · (MW 95.55) (nitrate)

[506-93-4]  · CH6N4O3  · Guanidine Nitrate  · (MW 122.11) (sulfate)

[1184-68-5]  · C2H12N6O4S  · Guanidine Sulfate  · (MW 216.27) (thiocyanate)

[593-84-0]  · C2H6N4S  · Guanidine Thiocyanate  · (MW 118.19)

(synthesis of heterocycles;2 selective deacetylating agent;3 synthesis of primary amines4)

Physical Data: mp 48-49 °C; pKa 13.6.

Solubility: free base readily sol alcohols, water; guanidinium salts of strong acids, e.g. HCl or HNO3, sol water, DMF, alcohol; guanidinium carbonate water sol but virtually insol alcohol; guanidine acetate sl sol ether, while guanidine nitrate moderately sol acetone; guanidinium salts, in general, insol aliphatic or aromatic hydrocarbons.

Form Supplied in: commercially available salts include the acetate, carbonate, hydrochloride, nitrate, sulfate, and thiocyanate.

Preparative Methods: substituted guanidines can be prepared by several methods. The reaction of an S-alkylisothiourea with an amine is one of the oldest and most useful methods but it suffers from production of noxious side products, namely an alkanethiol.7 An O-alkylisourea can also function in a similar manner,8 although these reagents, generally, are not as reactive as the S-alkylisothioureas. Direct oxidation of Thiourea and substituted thioureas to sulfonic acids prior to reaction with amines avoids the problems of thiol production. The intermediate sulfonic acids are at least as reactive as the S-alkylisothioureas.9 Cyanamide and substituted cyanamides react with amines or ammonium salts to produce guanidines.10 This approach can be useful to prepare certain hindered guanidines, e.g. derivatives of t-Butylamine.11 Addition of amines or ammonia to a disubstituted carbodiimide yields guanidines, but this method is limited by the availability of the carbodiimide.11 Reaction of amines with either 1-guanyl-3,5-dimethylpyrazole nitrate10 or 1-guanylpyrazole hydrochloride12 affords good yields of substituted guanidines.

Handling, Storage, and Precautions: the free base is very hygroscopic and readily absorbs CO2 from the air. It is liberated from a salt and used in situ. Hydrolysis occurs slowly at room temperature but more rapidly at elevated temperatures or in the presence of alkali to yield urea, then CO2 and NH3. Guanidinium salts of strong acids are stable to boiling water. Toxic fumes of NOx are given off when guanidine is heated to decomposition. Use in a fume hood. Guanidine hydrochloride liberates toxic fumes of HCl and NOx when heated to decomposition.5 Guanidine nitrate is both a powerful oxidant and high explosive; a warning cautioning against its preparation has been published.6

Heterocycle Synthesis: Five-Membered Rings.

Synthesis of five-membered heterocycles proceeds well from guanidine and various bis-electrophiles. Glyoxal dihydrate condenses with monosubstituted guanidinium salts in aqueous solution to yield a mixture of cis/trans 1:1 adducts identified as 2-amino-4,5-dihydro-4,5-dihydroxy-1-substituted imidazolium salts.13 Similarly, 1,1-disubstituted guanidinium salts react with 1-phenyl-1,2-propanedione in methanol to afford 2-(disubstituted amino)-4-hydroxy-4-methyl-4H-imidazoles, from which the corresponding imidazoles are available via catalytic hydrogenolysis.14 A series of 2-amino-4-arylimidazoles has been prepared from cyclization of guanidine with an acetophenone using bromine as a condensing agent. Under these reaction conditions, the in situ generated phenacyl bromide reacts rapidly with guanidine to yield the product (eq 1).15 When benzil is condensed with guanidine carbonate in ethanolic KOH, a good yield of 5,5-diphenyl-2-iminohydantoin is obtained. When 1-methylguanidine was used, this reaction afforded a 2.2:1 mixture of 5,5-diphenyl-2-methyliminohydantoin and 3-methyl-5,5-diphenyl-2-iminohydantoin (eq 2).16

Guanidine ring-opening of 1-methylcarbamoylisatin afforded an a-keto acylguanidine which cyclized under the reaction conditions to produce a 3:2 mixture of the disubstituted quinazolin-2-one and the spirohydantoin, respectively (eq 3).17

When 2,2-disubstituted propionitriles were cyclized with guanidine in DMF, a series of 5,5-disubstituted imidazolidine-2,4-diimines, including spiro analogs, were obtained.18 Diethyl Oxomalonate and guanidine in ethanol give 2-amino-5-ethoxycarbonyl-5-hydroxy-4H-imidazolin-4-one in good yield (eq 4).19 Use of isopropylguanidine affords the corresponding 2-isopropylamino derivative. L-Dehydroascorbic acid undergoes similar reactions. In this case the initially isolated products were refluxed in ethanol to effect dehydration as well.

Heterocycle Synthesis: Six-Membered Rings.

Cyclization of guanidine with 1,3-bis-electrophiles is one of the oldest and most common methods available for the preparation of 2-aminopyrimidines.1,2 Isocytosine (1) is readily prepared from reaction of guanidine sulfate and formylacetic acid, generated from malic acid under the reaction conditions (eq 5).20 It can also be prepared by nucleophilic addition of guanidine to C-6 of 1,3-dimethyluracil, with subsequent ring cleavage and cyclization with loss of 1,3-dimethylurea.21 The cyclization of guanidine with 1,3-diketones, leading to 2-amino-4,6-dialkyl substituted pyrimidines, is pH dependent with optimum conditions found to be pH 9-10.22 Conjugate addition of guanidine to 1,3-bis(heteroaryl)-2-propenones followed by cyclization affords 2-amino-4,6-bis(heteroaryl)pyrimidines in good yields.23

Condensation of cyanoacetic esters24 or alkoxymethylene nitriles25 with guanidine leads to 2,4-diaminopyrimidines in high yield. Cyclization of guanidine with ethyl acetamidocyanoacetate yields the expected 5-acetamidopyrimidine in high yield.26 Extension of this methodology to reaction with diethyl ureidomalonate or 5-ethoxycarbonylhydantoin produced the 5-ureidopyrimidine analogs. The ureidomalonates did not react with O-Methylisourea or S-alkylisothioureas (see S-Methylisothiourea).27 The pyrimidines obtained from reaction of Ethyl Ethoxymethylenecyanoacetate with guanidine were greatly influenced by the stoichiometry of the reaction, with a fourfold excess of guanidine leading almost exclusively to (2) (eq 6).28

A simple, one-pot synthesis of 2-substituted 5-vinylpyrimidines involves cyclization of 1-vinylpiperidylacrolein (4) with amidines, including guanidine and 1,1-dimethylguanidine (eq 7).29 Cyclization of acrylates and methacrylates with guanidine in t-butyl or isopropyl alcohol at room temperature provides a high-yield synthesis of the rather inaccessible dihydropyrimidines (eq 8).30 With guanidine and methylguanidine the reaction proceeds in a few hours, whereas both 1,1- and 1,2-dimethylguanidine require 48 h and 1,2,3-trimethylguanidine is unreactive. No reaction was observed using methyl 3,3-dimethylacrylate. [15N3]Guanidine has been prepared and used to prove the mechanism for cyclization of heterocyclic o-aminonitriles to fused 2,4-diaminopyrimidines.31

A general synthesis of 2-amino- and 2-substituted amino-1,3,5-triazines involves cyclization of the appropriate guanidine sulfate with Tris(formylamino)methane, a precursor to N-formylformamidine, the actual species involved in the reaction (eq 9).32 Best results were obtained using a 1:2 ratio of guanidine to tris(formamido)methane. To prepare 2,4-diamino-1,3,5-triazine, guanidine has been treated with N,N-dimethylformamide dimethyl acetal (see N,N-Dimethylformamide Diethyl Acetal).33 This method could be used to prepare 2,4-bis(alkyl)- and -(aryl)amino-1,3,5-triazines from the corresponding monosubstituted guanidine, although mixtures of products and modest yields were reported in some cases. Guanidine reacts with an azirineacrylate in DMSO via addition to C-2 followed by C-C bond cleavage to yield, ultimately, a trisubstituted 1,3,5-triazine (for R = H) after air oxidation (eq 10).34

For R = Me, with oxidation no longer possible a bicyclic lactam was isolated, although it was not possible to distinguish between the regioisomers. In the presence of excess NaOMe, guanidine reacts with some benzaldehydes to produce 2,4-diamino-6-aryl-1,3,5-triazines.35 These have been postulated to arise via an intramolecular oxidation-reduction of the initially formed bis-aldimine. Deuterium labeling studies and isolation of Cannizzaro reaction products support this hypothesis. Reaction of guanidine carbonate with a pyridinesulfonyl chloride gave a sulfonylguanidine, which was cyclized to 3-amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (5) (eq 11).36 The 3-monoalkylamino analogs, evaluated as potassium channel openers, were prepared by amine displacement of the 3-methylmercapto derivative, presumably to avoid regioisomer formation expected using a monosubstituted guanidine.

A key step in the synthesis of ptilocaulin (7), an antitumor antibiotic isolated from a marine sponge, is conjugate addition of guanidine to enone (6) with subsequent cyclodehydration (eq 12).37 In an alternative approach, the tricyclic guanidine was prepared by guanylation of an amino ketone and subsequent cyclization.38

Selective Deacetylating Agent.

Guanidine selectively deacetylates phenolic acetates in the presence of benzylic acetates.3 Acetamides, methyl esters, benzoates, and pivalates are stable to the reaction conditions. Peracetylated carbohydrates can be instantaneously and quantitatively deacetylated using a 1:1 molar ratio of carbohydrate to guanidine. The stereochemical integrity of the products was not described.

Synthesis of Primary Amines.

Treatment of primary bromides, allylic and benzylic halides with guanidine followed by base affords the corresponding primary amine.4

Miscellaneous.

Acylation of guanidine by a-amino esters produces amino acid acylguanidines which were explored as intermediates in peptide bond formation.39 Guanidine has been used to effect both ester hydrolysis and epoxide ring opening in a single step.40 Direct phosphorylation of guanidine can be accomplished in good yield using diisopropyl phosphite in CCl4 in the presence of NaOH.41 The reaction also works well with S-alkylisothioureas.

Related Reagents.

Aminoiminomethanesulfonic Acid; Formamidine Acetate; S-Methylisothiourea; O-Methylisourea; 1H-Pyrazole-1-carboxamidine Hydrochloride.


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David C. Palmer

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



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