Potassium cyanate synthesis

Mono-substituted and unsymmetrical di-substituted ureas may be prepared by a modification of Wohler s urea synthesis, salts of primary or secondary amines being used instead of the ammonium salt for interaction with potassium cyanate. Thus when an aqueous solution containing both aniline hydrochloride and potassium cyanate is heated, aniline cyanate is first formed, and then C,HjNH,HCl -h KCNO = C,H6NHj,HCNO -h KCl C,HsNH HCNO = C.H NHCONH, by the usual molecular rearrangement is converted into monophenyburea. 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

The first reported synthesis of hydroxyurea (24) consists of the condensation of hy-droxylamine with potassium cyanate (Scheme 7.14) [87]. Condensation of hydroxy-lamine with ethyl carbamate also gives pure hydroxyurea in good yield after recrystallization (Scheme 7.14) [88]. Nitrogen-15 labeled hydroxyurea provides a useful tool for studying the NO-producing reactions of hydroxyurea and can be prepared by the condensation of N-15 labeled hydroxylamine with either potassium cyanate or trimethylsilyl isocyanate followed by silyl group removal (Scheme 7.14) [89, 90]. Addition of hydroxylamine to alkyl or aryl isocyanates yields alkyl or aryl N-hydroxyureas (Scheme 7.14) [91, 92]. The condensation of amines with aromatic N-hydroxy carbamates also produces N-substituted N-hydroxyureas (Scheme 7.14) [93]. 

Surprisingly it was reported that when potassium cyanate is substituted for sodium cyanate the yields of carbamates are reduced to less than 5 %. The reason for this drastic effect is not known at this time. In addition, the use of other alkali or alkaline metal cyanates in this reaction has not been investigated. The Loev [28] procedure appears applicable to the synthesis of carbamates from primary, secondary, and tertiary alcohols (2 hr reaction time affords 60-90% yields), cyclic and acyclic 1,3-diols, phenols, oximes, ald-oximes, and ketoximes, and primary, secondary, and tertiary mercaptans. Carbamates could not be obtained from diphenylethylcarbinol (dehydrated to 1,1-diphenylethylene) or trichloro- and trifluoromethylcarbinols. 

URECH HYDANTOIN SYNTHESIS. Formation of hydantoins from o -amino acids by treatment with potassium cyanate in a aqueous solution and heating of the salt of the intermediate hydantoic acid with 25% hydrochloric acid. 

Potassium cyanate, carbonic and chlorocarbonic esters, phosgene, or urea are used as cyclizing agents in the synthesis of perimidine-2-one 430 (X = X = NR, Y = O) and its derivatives from 1,8-naphthylene-diamines. Naphtho[substituted amino group in position 2 (X = Y = NH or Y = NR) are obtained on interaction of 1,8-naphthylenediamines with bromocyanogen, cyanoamide, 5-methylisothiourea, arylisothiocyanates, or dimethyltri-chloromethylamine. 

Ureidobenzoic acids and derivatives 1 which are readily available from anthranilic acid derivatives and potassium cyanate (cf. p 27) can be cyclized to quinazoline-2,4(l/f,3//)-diones 2 in generally excellent yields. This method makes possible the synthesis of some quinazoline-2,4(1//,3//)-diones on a kilogram scale. The cyclization is usually performed in alkaline medium although cyclizations in acidic mediumhave also been reported. A detailed mechanistic and kinetic study of intramolecular nucleophilic displacement by the ureido func-tional group at the carbonyl carbon of esters and amides of 2-urcidobenzoic acidsand 2-ureidobenzoic acid itself " is available. 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

The historical S3mthesis of urea by heating potassium cyanate and ammonium sulfate is analogous to the synthesis of substituted ureas from amines and the cyanate ... 

The Strecker synthesis starting from a-amino nitriles and potassium cyanate yields useful hydantoins as intermediates. They are hydrolyzed at neutral pH to hydantoic acids and to amino acids (not shown) (Scheme 9.4.3)... 

Imidazolidin-2,4-diones 4 have the trivial name hydantoins. They are made by a two-step synthesis from cir-amino acids and potassium cyanate ... 

As in the Wohler urea synthesis, addition takes places to the C-N double bond of the isocyanic acid which is in hydrolytic equilibrium with potassium cyanate. The cyclodehydration is brought about by heating with hydrochloric acid. 

Its structure was established by an independent synthesis (E. Fischer and Ach, 1895) from malonic acid and urea giving barbituric acid (see p 404) and its 5-amino derivative 37. On treatment with potassium cyanate, 37 yielded pseudouric acid 38 which on cyclodehydration gave uric acid 33 ... 

The condensation of appropriately substituted o-ketoanilines with cyanate also has been used to prepare quinazolinones. For example, in the synthesis of novel reverse transcriptase inhibitors, 3-trifluoromethylquinazo ine derivative 98 was synthesized by Corbett and coworkers <01BMCL211>. Treatment of trifluoromethyl ketone 96 with potassium cyanate yielded aminol 97, which was subsequently dehydrated in refluxing xylenes to give the quinazolinone 98. 

Employment of potassium cyanate for mechanochemical synthesis of ureas was described by Colacino et al. [30]. Reaction carried out in the planetary mill with KNCO/H2O, without addition of any supplementary base afforded pure phenylalanyl urea 154 in high yield (97%) without need of purification (Scheme 3.43). From an environmental point of view, regarding atom and solvent economy, this procedure for the preparation of urea derivative was very advantageous, hi contrast, an excess of potassium cyanate and heating were necessary to afford phenylalanylurea in solution in 78% yield. 

This method was successfully apphed to the sterically hindered diphenylglycine methyl ester hydrochloride (entry 8) to prepare the antiepileptic dmg phenytoin 22. In this synthesis, trimethylsilyl isocyanate (TMS-NCO), a more reactive alternative to potassium cyanate was used in the first step. The decomposition of TMS-NCO... 

The starting point for his synthesis was N,]SF-dimethylurea, the reaction of which with malonic acid gave N,N-dimethylbarbituric acid. With nitrous acid (sodium nitrite and a mineral acid) he produced dimethylvioluric acid, which gave dimethylpseudouric acid upon reduction and further reaction with potassium cyanate. Ring closure by heating with hydrochloric acid then led to 1,3-di-methyluric acid. [518] Its reaction with phosphorus pentachloride and reduction with hydrogen iodide then produced the supposed theophylline final... 

The annulation of a pyrimidin-2,4-dione ring to the anthranilic acid and its analogues 132 was successfully achieved upon the treatment with potassium cyanate and acetic acid in PEG 400 (Scheme 76) [107]. The scope of the reaction included synthesis of substituted quinazolin-2,4-diones and their aza-analogues 133. 

Basic principle for the synthesis of optically pure l- and o-amino acids via Strecker synthesis of racemic hydantoins and their (dynamic) kinetic resolution and stepwise hydrolysis toward the amino acids. KOCN, potassium cyanate HYD, hydantoin 28 CARB-AA,... 

A phase-transfer catalysed nucleophilic displacement reaction on chloro-acetanilides by cyanate ions, followed by ring-closure (Scheme 5.10), provides a simple and viable synthesis of hydantoins [41], The formation of the hydantoins is inhibited by substituents in the orf/to-position of the aryl ring, but the addition of potassium iodide, or tetra-n-butylammonium iodide, generally increases the overall rate of formation of the cyclic compounds, presumably by facilitating the initial nucleophilic substitution step. 

The synthesis of a C-labelled version of naratriptan (3b) is highlighted in Scheme The indole ring of naratriptan hydrochloride (3) was oxidatively cleaved using sodium periodate to give ketoformanilide 45. Cyanation of 45 with potassium [ C]cyanide in aqueous ethanol gave the intermediate amidine 46, which was reduced directly with NaBH4 in acetic acid to afford C-labelled naratriptan (3b), which was isolated as the hydrochloride salt. 

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