Amino nitrile cyclizations

Intramolecular amino-nitrile cyclization in synthesis of aminopyrroles, -azoles, -azines, and -azepines 87MI1. 

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

TABLE 7.1. SYNTHESIS OF 5(2//)-OXAZOLONES VIA CYCLIZATION OF AMINO ACIDS OR AMINO NITRILES... 

Cyclizations with perfluoroacylating agents seem to be quite general for the synthesis of 5(2i7)-oxazolones with aromatic substituents directly bonded to the heterocyclic ring. For example, perfluoroacylation of a solution of an arylgly-cine containing a phosphorus trihalide affords 4-aryl-2-(perfluoroalkyl)-5(2//)-oxazolones (Table 7.1, Fig. 12) Similar results were obtained when amino nitriles were used as starting materials. ... 

An unusual reaction leading to the formation of 4-thioxopyrazolo[3,4-d]-pyrimidines has been reported. 1-Substituted 4-cyano-5-aminopyrazoles (103, R = H) react with phenyl isothiocyanate in dimethylformamide (DMF) saturated with hydrogen chloride to yield 1-substituted 4(5//)-pyrazolo[3,4-d]-pyrimidinethione (110). A proposed reaction sequence involved an initial nucleophilic addition of phenyl isothiocyanate to the protonated o-amino-nitrile to give an o-aminothioamide (108), followed by formylation by the dimethylformamide-hydrogen chloride mixture affording 109, which then cyclizes to the final product 110 (70MI1). 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

Treatment of ethyl l- 2-[(tm-butyl, dimethylsilyl)oxy]-l-phenylethyl -6-alkylpiperidine-2-carboxylates with 10% HF in MeCN afforded diastereo-meric mixtures of 4-phenyl-6-substituted perhydropyrido[2,l-c][l,4]oxazin-1-ones (94JOC3769). Dieckmann cyclization of ethyl 4-(3-ethoxy-carbonylpropyl)morpholine-3-carboxylate with ferf-BuOK in Et20 and subsequent ester hydrolysis and decarboxylation furnished perhydropy-rido[2,l-c][l,4]-oxazin-9-one (82EUP57536 92BMC1293). Mild acidic hydrolysis of the nitrile moiety of amino nitrile 185 gave pyrido[2,l-c][l,4]ox-azin-l-one 60 (96TL4001). 

An intramolecular reductive coupling of ketones with nitriles has been reported for acyclic and monocyclic substrates y9-amino nitriles were isolated from acyclic malononitrile adducts [87]. The Sml2-initiated reductive cyclization of cyclic a-cyanoalkyl-substituted ketones leads to acyloin products in high yields. In this instance further irradiation of the reaction mixtures was performed to afford complete conversion (Scheme 27) [88]. More applications have been collected in several excellent reviews [89-92]. 

The target compound 8 is derived from a known carboxylic acid 54 [85], which is obtained via reductive cleavage of the carbon-sulfur bond of bicyclic amide 53 whose carboxylic acid congener is an intermediate of the Merck s approach [85]. The compound 53 is obtained through amidation and subsequent cyclization of 5y -a-amino nitrile syn-Sl. The compound syn-51 should be prepared stereoselectively by Strecker reaction of a-amino aldehyde 51 that can be readily prepared from L-cysteine. 

All attempts [heating with or without a base such as NaOH, potassium carbonate (K2CO3) or DBU] to effect cyclization of a-amino nitriles 52a and 52b to bicyclic compound 58 failed possibly due to such side reactions as those initiated by retro Strecker reaction (Fig. (23)). The compounds 52a and 52 b were thus converted to amides 59a and 59b before the ring closure (Fig. (24)). 

When stirred in 85% H3P04, the triptophan derived a-amino nitrile 356 underwent a stereospecific cyclization cascade to give 357 in nearly quantitative yield (Scheme 67) (04OL2641). The formation of tetracyclic 357 is interesting because this compound incorporates both the tetrahydropyrrolo[2,3-Z>]indole structure, which is found in physostigmine and related alkaloids, and the tetrahydroimidazo[l,2-a] indole skeleton, which is present in asperlicin and related natural products. 

Good yields of pvrido[2,3-d] pyrimidines (37) were also obtained by the action of formamide on o-amino nitriles (36).16 Reduction of 2-amino-4,6-dimethyInicotinitriIc yields the 3-aminomcthyl compound (38). Acylation to the 3-acylaminomethyl derivative (39), followed by cyclization, by means of beat or phosphoryl chloride, yielded the diliydiopyrido[2,3-d]pyrimidin s (40).29... 

Silver nitrate. 18,320 19, 305-306. j Cyclization. 2-AlkynylbenzoK Substituted isocoumarins are the majo Carbonyl compounds from t the a-amino nitrile derivatives of enal drolysis of the products. ... 

Eliminations. Treatment of o-alkyl A -(r-butylthio)azoarenes with r-BuOK accomplishes cyclization and delivers l//-indazoles. Unsaturated a-amino nitriles are obtained on alkylation of 2-(N-methylanilino)-2-benzenesulfenylacetonitrile, due to elimination of benzenethiol in situ. 

The use of guanidine for cyclization gives amino substituted derivatives (e.g. 212) (52CB1012), and in this case o-aminonitriles may be used to furnish diamines (e.g. 8UOC1394). An unusual reaction involving nitriles occurred during the preparation of nicotinonitrile from the amide and ammonium sulfamate, when a 60% yield of the dimeric by-product (213) was formed via the nitrile (69BSB289). Similar products have been obtained from... 

The only reaction of this type noted involved the reaction of pteridines, e.g. (415), with malonodinitrile (or cyanoacetamide), via ring opening to (416), with final [6 + 0 ( )] cyclization to give the 6-amino-7-nitrile (amide) (417) (73JCS(P1)1615, 73JCS(P1)1974). 

Cyclization reactions effected by intramolecular attack of the heteroatom on a nitrile group provide a useful source of 2-amino heterocycles. Some illustrative examples are depicted in Scheme 16. 

The C-coordinated thiazolium complexes are the result of the proton-induced cyclization reactions (980M513). Thus, complex 1 on protonation with tetrafiuoroboric acid yields the C-coordinated thiazolium structure 2. In turn, the nitrile complex 3 under these conditions is transformed to the thiazolium cationic species 4. Protonation of the amido complex 5 with tetrafiuoroboric acid also results in a cyclization but it proceeds differently. The amino group of the CONH2 moiety is lost and BF3-framework is coordinated via the carbonyl oxygen in an overall neutral complex 6. 

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