& Heterocycles

Heterocycles from a-Aminonitriles

Nicola Otto and Till Opatz*[a]

Dedicated to Professor Helmut Ringsdorf on the occasion of his 85th birthday

Chem. Eur. J. 2014, 20, 13064 – 13077 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim13064

ConceptDOI: 10.1002/chem.201403956

Abstract: Owing to their various modes of reactivity, a-aminonitriles represent versatile building blocks for theconstruction of a wide range of nitrogen heterocycles.The present Concept article focuses on synthetic method-ologies using their bifunctional nature which is the basisof their reactivity as a-amino carbanions and as iminiumions. Reactions exclusively taking place on either theamine or on the nitrile moiety will not be considered.

1. Introduction

Nitrogen heterocycles are fundamental structural elements ofthe biochemical machinery of life. Irrespective of their originfrom a synthetic laboratory or from the metabolism of a livingcreature, many representatives of this large compound classcan influence biological systems. Not surprisingly, the pharma-ceutical and the agrochemical industry heavily rely on the syn-thesis of N-heterocycles. The construction of heterocyclic struc-tures and the development of new methodologies in this con-text have been the subject of intensive research in organicsynthetic chemistry ever since.

In 1850, Adolph Strecker first described the synthesis of a-aminonitriles in his famous three-component reaction of alde-hydes, amines, and hydrogen cyanide.[1] The resulting a-amino-nitriles represent versatile starting materials that can serve askey precursors for a wide range of synthetic applications suchas the synthesis of various nitrogen heterocycles. Since Streck-er’s first report on a-aminonitriles, the reaction has been stud-ied extensively and numerous variations of his synthetic proce-dure as well as stereoselective protocols have been publishedin the literature.[2]

Being bifunctional in nature, a-aminonitriles exhibit severalmodes of reactivity. The carbon atom of the nitrile group em-bodies an electrophilic center and can be attacked by nucleo-philes such as organometallic reagents or hydrides.[3] Hydroly-sis of the nitrile group represents a historical and industriallysignificant method for the straightforward access to a-aminoacids.[1] In contrast, the amine function is nucleophilic and canundergo its well-known reactions with electrophilic agents.

Furthermore, a-aminonitriles bearing a hydrogen atom atthe a-center can be deprotonated resulting in the reversed po-larity of an a-amino carbanion as compared to the electrophilicreactivity of the former iminium carbon (Scheme 1). The result-ing ketene iminate salts can undergo nucleophilic reactionssuch as 1,4-additions to a,b-unsaturated carbonyl compounds,alkylations, 1,2-additions to aldehydes, additions to alkynes,and epoxide ring openings. The scope of this reactivity inver-sion is broader than for the protected cyanohydrins[4] and thefamous 1,3-dithianes. For example, deprotonated a-aminoni-

triles can be alkylated with secondary alkyl halides, whereaslithiated dithianes and, to a lesser extent, cyanohydrin anionslead to elimination in this case.[4a, 5] Moreover, the anions of a-aminonitriles are prone to vinylogous addition, whereas theless polarizable dithiane anions usually require special precau-tions to do so.[5c, 6]

At the same time, a-aminonitriles possess latent iminium ionreactivity. The iminium ion (re)generated by spontaneous or in-duced loss of the cyanide ion can be trapped with various nu-cleophiles, for example, hydrides or organometallic reagents(Bruylants reaction), furnishing a-substituted amines.[7] Theelimination of cyanide can be promoted by copper and silversalts, Brønsted or Lewis acids, and by thermolysis.[8] The imini-um intermediate can be deprotonated to the enamine[9] or hy-drolyzed to the corresponding carbonyl compound.[5c, 10] Thus,deprotonated a-aminonitriles also represent synthetic equiva-lents of acyl anions[11] and can be used for the synthesis of 1,4-dicarbonyl compounds,[6b, 12] which may, for example, serve asprecursors for furans, thiophenes, or pyrroles,[13] as well as forstereoselective nucleophilic acylations.[12c, 14]

Stereoselective modifications of preformed heterocyclesusing aminonitrile chemistry have been developed by variousresearch groups.[15] For example, Husson, Royer and co-workersused their efficient auxiliary-controlled CN(R,S)-method basedon phenylglycinol-derived homochiral bicyclic a-aminonitrilesfor the synthesis of various alkaloids bearing piperidine or pyr-rolidine rings.[16] They achieved high diastereoselectivities in al-kylations, reductions, and Bruylants reactions.

The reactivity of aminonitriles as masked iminium ions hasalso been exploited in natural product synthesis.[17] This ap-proach was elegantly applied in the total synthesis of reserpineby Stork.[18] Other instructive examples are (�)-hirsutine byLounasmaa et al. ,[17a, 19] cis-eburnamonine by Santamaria etal. ,[17b, 20] the synthesis of (�)-gelsemine[17d, 21] and the formalsynthesis of (�)-6a-epipretazettine by Overman and co-work-ers,[22] as well as the synthesis of venenatine and alstovenineby Sarpong and co-workers.[17f]

The above-mentioned methods and synthetic transforma-tions based on a-aminonitriles have in part already been re-viewed by Albright, Enders, Sedl�k, and ourselves.[8, 23]

The present Concept article focuses on synthetic methodolo-gies based on the bifunctional nature of a-aminonitriles whichemploy both the nitrile and the amine moiety for the construc-

Scheme 1. a-Aminonitriles and their modes of reactivity.

[a] N. Otto, Prof. Dr. T. OpatzInstitute of Organic ChemistryJohannes Gutenberg University of MainzDuesbergweg 10–14, Mainz (Germany)E-mail : opatz@uni-mainz.de

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tion of heterocycles. This does not imply that the nitrile func-tion will be contained in the products in all cases but ratherthat its presence is a prerequisite for their formation. Structuralmodifications and decoration of preexisting heterocycles aswell as the sole use of a-aminonitriles as masked iminium ionequivalents will not be covered.

2. Pioneering Examples: The von Miller–PlçchlReaction and the Bucherer–Bergs Synthesis

Von Miller and Plçchl reported as early as in 1898 that a-ami-nonitriles are capable of 1,4-additions to a,b-unsaturated car-bonyl compounds in a basic environment.[24] They observedthe formation of pyrroles 3 from cinnamaldehyde (2) and a,N-diarylaminonitriles 1 in methanolic KOH solution. While they in-itially thought that they had produced 1,2,5-trisubstituted pyr-roles, reinvestigations by Bodforss in 1931 as well as by Treibsand Derra in 1954 revealed the products possessed a 1,2,3-sub-stitution pattern (Scheme 2).[25]

Furthermore, the latter authors recognized the a,N-diaryl-substitution of the starting a-aminonitriles to be essential forpyrrole formation. Presumably, their high CH-acidity makesthese pronucleophiles resistant to the base-induced retro-Strecker reaction under these reaction conditions. For morethan fifty years, the von Miller–Plçchl reaction remained theonly transformation using the anion-stabilizing effect of the ni-trile group in Strecker products for the synthesis of heterocy-cles. Although more than 110 years old, this reaction can com-pete in terms of yield and simplicity with modern proceduressuch as the phosphine-mediated synthesis of polysubstitutedpyrroles from acid chlorides and a,b-unsaturated imines re-ported by Lu et al.[26]

In 1929, Bucherer and Bergs reported on a four-componentreaction involving a ketone, potassium cyanide, and ammoni-um carbonate, which provides access to hydantoins(Scheme 3) and is still widely applied.[27] The imine intermedi-ate 4 combines with HCN to furnish an a-aminonitrile, which,in turn, reacts with carbon dioxide evolved from the ammoni-um carbonate. The resulting carbamate undergoes ring closureby nucleophilic attack to the nitrile carbon to give the 5-imino-oxazolidin-2-one, which rearranges to the hydantoin 5(Scheme 3, path A).

The hydantoin motif is present in diverse natural productsand since it is associated with various biological activities it

became a popular scaffold for drug discovery (see also Section8). As an example, 5,5-diphenylhydantoin (phenytoin) is stillbeing used as an antiepileptic drug. A related approach for thesynthesis of 5,5-disubstituted hydantoins was introduced byShipman and co-workers who exploited two points of diversityin their synthetic procedure. The reaction of nitriles with or-ganometallic reagents such as organolithium and Grignard re-agents furnishes the intermediate metalated imines 6 whichare subsequently reacted in place of ketones under Bucherer–Bergs conditions (Scheme 3, path B).[28]

3. 1,4-Additions of Deprotonated a-Amino-nitriles

Boekelheide, Ainsworth, and Godfrey pioneered the work ondeprotonated Reissert compounds and their reactions withelectrophiles.[29] They demonstrated that upon deprotonation,compounds of type 7 can undergo vinylogous addition toacrylonitrile. The resulting carbanion attacks the amide carbon-yl, and pyrroloisoquinolines such as compound 9 are formedby elimination of water and HCN. Eventually, the remaining ni-trile group is hydrated to the amide moiety under the reactionconditions (Scheme 4).[30] Uff and Budhram successfully usedthe phthalazine-derived Reissert compound for the samepurpose.[30b]

In the 1980s, Cooney and McEwen showed that deprotonat-ed open-chain analogues of Reissert compounds 10 can addto vinyltriphenylphosphonium bromide (Schweizer’s reagent)and provide a direct access to 1,2,5-trisubstituted pyrroles

Scheme 2. The von Miller–Plçchl pyrrole synthesis.

Scheme 3. Bucherer–Bergs synthesis and Shipman’s modification.

Scheme 4. Vinylogous addition to Reissert compounds.

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(Scheme 5).[31] The intermediate phosphonium ylide 11 is con-sumed in an intramolecular Wittig reaction involving theamide carbonyl, and ring closure is followed by dehydrocyana-tion. The method furnishes pyrroles 12 in good to excellentyields. Taking into account the yield of the preparation of un-symmetrical 1,4-dicarbonyls, this method is superior to theclassical Paal–Knorr synthesis.[31] So far, it was not expanded tosubstituted vinylphosphonium salts which should permit theregioselective introduction of substituents to positions 3 and4.

N-Monosubstituted and N-unsubstituted a-aminonitriles aregenerally susceptible to a base-induced retro-Strecker reaction.A significant discovery in this field was made by Meyer et al.who found that a-aminonitriles derived from aromatic or het-eroaromatic aldehydes can be deprotonated quantitatively bystrong bases devoid of Lewis-acidic cations such as KHMDS ir-respective of the number of NH protons. This allows to signifi-cantly broaden the scope of the von Miller–Plçchl pyrrole syn-thesis and, for example, permits the synthesis of N-alkylpyr-roles. After deprotonation of a-aminonitriles 13 with KHMDS inTHF at �78 8C, their vinylogous addition to a,b-unsaturatedcarbonyl compounds yields the cyclic intermediates 15. Theseare unstable and thermally decompose to the von Miller–Plçchl products. Alternatively, their double reduction withNaCNBH3 at low temperature produces the polysubstitutedpyrrolidines 16 in high yields.[32] The established one-pot meth-odology was, for example, applied to the synthesis of the cyto-toxic hexahydropyrrolo[2,1-a]isoquinoline alkaloid (�)-crispineA (17 a) and its C-ring substituted analogues 17 (Scheme 6).[33]

The same research group utilized this method as the keystep of a highly efficient modular total synthesis of various al-kaloids of the lamellarin group (21). Deprotonation of bicyclicaminonitrile 18 available in three steps from homoveratryla-mine, and 1,4-addition to enals 19 furnished 5-hydroxypyrroli-dine-2-carbonitriles, which produced pyrroles 20 in high yieldsupon dehydration and dehydrocyanation. The benchmarkcompound lamellarin G trimethyl ether (21 a) could be pre-pared in 69 % overall yield over seven linear steps(Scheme 7).[34] This represents the most efficient syntheticaccess to the lamellarins known to date.

Kucukdisli et al. recently reported a synthesis of indolizineswith four points of diversity starting from deprotonated 2-(1H-pyrrol-1-yl)nitriles 23 and a,b-unsaturated carbonyl com-pounds based on a one-pot conjugate addition/cyclodehydra-tion/dehydrocyanation reaction sequence (Scheme 8). The

starting materials 23 can be readily prepared in a modifiedClauson–Kaas procedure from commercial 2,5-dimethoxytetra-hydrofuran (22) and ammonia-derived Strecker products.[35]

Tsuge and co-workers first demonstrated that the imines ofammonia-derived Strecker products, a-(alkylideneamino)nitrilesScheme 6. Synthesis of polysubstituted pyrrolidines.

Scheme 7. Modified von Miller–Plçchl reaction and synthesis of lamellarins.

Scheme 5. Vinylogous addition to open-chain analogues of Reissert com-pounds under formation of pyrroles.

Scheme 8. One-pot synthesis of polysubstituted indolizines by an addition/cycloaromatization sequence.

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28, are excellent pronucleophiles for Michael additions.[36] Dueto the extended p-conjugation of their anions, they can evenbe deprotonated with neutral bases such as 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene(TBD) (Scheme 9, path A). Under these conditions, the deproto-nation of CH-acidic electrophiles can be avoided resulting inan extended substrate scope.

Meyer et al. varied the synthetic protocol of Tsuge to pre-pare polysubstituted pyrrolidines. Addition of the deprotonat-ed a-(alkylideneamino)nitriles 29 to enones 30 produces d-keto-a-(alkylideneamino)nitriles 31 which are subjected to anexhaustive reduction with NaCNBH3 in a one-pot procedure(path A). Presumably, the C=N double bond is reduced first,followed by reductive ring closure and reductive decyanationof the iminium species formed by elimination of cyanide tofurnish the polysubstituted pyrrolidines 32 in high yields anddiastereoselectivities ranging from minor to complete(Scheme 9, path A).[37]

When metal bases such as lithium diisopropylamide are em-ployed for deprotonation of compounds 28, N-metalated azo-methine ylides 33 are formed, which undergo a rapid cycload-dition to the electron-deficient double bond of the acceptor tointermediates 34 (Scheme 9, path B). Elimination of LiCN finallyresults in 1-pyrrolines 35.[38] The course of this reaction is de-scribed as a concerted 1,3-dipolar cycloaddition but stepwisemechanisms are also discussed in the literature.[39]

A highly enantioselective catalytic asymmetric approach to2-cyano-pyrrolidines 37 by 1,3-dipolar cycloaddition of a-imi-nonitriles 36 to various dipolarophiles was accomplished byRobles-Mach�n et al. (Scheme 10).[40]

Nitroolefins 38 are another class of suitable reaction partnersfor deprotonated a-(alkylideneamino)nitriles and can, for ex-ample, be employed for the synthesis of tetrasubstituted pyr-roles (Scheme 11). After 1,4-addition, 5-endo-trig cyclization ofthe resulting nitronates 39 produces 2-cyano-4-nitropyrroli-dines which eliminate HCN and HNO2 to yield the 2,3,4,5-tetra-substituted pyrroles 40.[41] Similar cyclizations such as theBarton–Zard reaction, the Montforts synthesis, or van Leusen’s

pyrrole synthesis are limited to the introduction of two orthree substituents, at least one of which needs to be electron-withdrawing.[42] Bergner and Opatz have used a relatedmethod for the synthesis of the pyrrole portion of the top sell-ing lipid-lowering drug atorvastatin.[43]

As first demonstrated by Tsuge et al. , 1-(1-cyanoalkyl)pyridi-nium ylides 41 can undergo formal [3+2]-cycloadditions witholefinic dipolarophiles such as N-substituted maleimides 42 toform endo cycloadducts of type 43 (Scheme 12).[44] The meth-

odology was further developed by Kucukdisli et al. for the syn-thesis of tri- and tetrasubstituted indolizines by formal [3+2]-cycloaddition of 1-(1-cyanoalkyl)pyridinium ylides 46 to nitroo-lefins 38 (Scheme 13). The precursor salts 46 can convenientlybe prepared from pyridines and cyanohydrin triflates 45. Themethod was also employed for the synthesis of various fusedpyrrole-containing heterocycles such as pyrroloisoquinolines,pyrrolophthalazines, pyrroloimidazoles, and pyrrolobenzothia-zoles.[45]

Scheme 9. Synthesis of polysubstituted pyrrolidines via a-(alkylideneamino)-nitriles by Tsuge and Meyer.

Scheme 10. Catalytic asymmetric 1,3-dipolar cycloaddition by Robles-Mach�net al.

Scheme 11. One-pot synthesis of tetrasubstituted pyrroles from a-(alkylide-neamino)nitriles.

Scheme 12. 1,3-Dipolar cycloaddition of heteroaromatic N-ylides with ole-fins.

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Furthermore, a-(alkylideneamino)nitriles can serve as startingmaterials for a transition metal-free route to 1,3-disubstitutedb-carbolines. The reaction of deprotonated a-(alkylideneami-no)nitriles 28 with gramine (49) in the presence of tributyl-phosphine results in the formation of b-indolyl-a-(alkylidene-amino)nitriles 51. The latter compounds can be cyclized underacidic conditions followed by dehydrocyanation and oxidationto afford b-carbolines 52 (Scheme 14).[46] The related nucleo-

philic substitution of gramine derivatives with deprotonatedReissert compounds was first reported by Boekelheide andAinsworth.[29] It is assumed that the electrophilic 3-methyl-eneindolenine (50) is intermediately formed in a base-inducedelimination of dimethylamine in both cases and is subsequent-ly trapped by the respective C-nucleophile.[46]

In addition to the described intermolecular reactions, intra-molecular 1,4-additions of deprotonated a-aminonitriles havebeen used to produce substituted indole-3-acetic acid deriva-tives.[47] This approach was employed for the synthesis of thetetracyclic e-lactam paullone, the parent compound of a classof potent inhibitors of cyclin-dependent kinases that showstrong antiproliferative activity in various human tumor celllines.[48]

4. 1,2-Additions of Deprotonated a-Amino-nitriles

Although deprotonated a-aminonitriles represent soft nucleo-philes, they are also capable of direct additions to C=X double

bonds of sufficient reactivity. Popp and Kant first reported onthe 1,2-addition of deprotonated Reissert compounds to alde-hydes and benzalanilines (Scheme 15). Treatment of carba-mates 53 with benzaldehyde in the presence of nBuLi leads tooxazolidinones 54, which upon dehydrocyanation furnish oxa-zolinones of type 55. Similarly, 1,2-addition of deprotonatedReissert compounds 53 to benzalanilines and subsequent elim-ination of HCN yields isoquinolino-fused imidazolones 57.[49]

The anions of Reissert compounds 58 also react with hetero-cumulenes such as isothiocyanates to yield the thiohydatoins59. The deprotonated phthalazine-derived Reissert compound60 initially produces the open-chain addition product 61,which cyclizes thermally to imidazo[5,1-a]phthalazine 62(Scheme 16).

Kison et al. presented a straightforward modular synthesis oftetrasubstituted imidazoles 69 based on the 1,2-addition of de-protonated N-monosubstituted a-aminonitriles 64 to N-acyli-mines 65 prepared in situ from aldehydes, LiHMDS, and acidchlorides (Scheme 17). Due to the high electrophilicity of N-acylimines, C�C bond formation proceeds smoothly at �78 8C.Thermal dehydrocyanation of the intermediate addition prod-ucts 67 with DBU gives a-(acylamino)imines 68 which cyclizeto imidazoles 69 either spontaneously or upon treatment withPCl5 (Scheme 17, path A). The latter method also permits thesynthesis of trisubstituted oxazoles. Acid hydrolysis of inter-mediates 68 results in a-acylaminoketones 70, which can becyclized to oxazoles 71 by dehydration with PCl5 (Scheme 17,

Scheme 13. Synthesis of tri- and tetrasubstituted indolizines.

Scheme 14. Synthesis of 1,3-disubstituted b-carbolines.

Scheme 15. 1,2-Additions of deprotonated Reissert compound analogues.

Scheme 16. Addition of isothiocyanates to Reissert compound analogues.

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path B).[50] This method allows variation of all four substitutentsand is not limited to acceptor-substituted products.[51] Thesame authors employed the 1,2-addition of deprotonatedStrecker products to unactivated imines 72 (aldimine crosscoupling) for the synthesis of tetrasubstituted 1,2-diaminesand imidazolium chlorides which are precursors to N-heterocy-clic carbenes.

Due to the high basicity of the amide ion produced in the1,2-addition step, a retro-Strecker reaction is induced in theaminonitrile moiety of the primary products 73 under forma-tion of a-aminoimines 74, which tautomerize to enediamines76. Subsequent aerial oxidation of these electron-rich com-pounds furnishes 1,2-diimines 77 with four variable substitu-ents which can be reduced to the corresponding syn- or anti-1,2-diamines with high diastereoselectivity.[52] Alternatively,1,3,4,5-tetrasubstituted imidazolium chlorides 78 can be ob-tained by reaction with paraformaldehyde/HCl or with chloro-methyl esters or ethers (Arduengo cyclization),[53] (Scheme 17,path C).[54] This method provides similar yields as the methodof Hirano et al. for generating imidazolium salts from formami-dines and a-halo ketones but in contrast to the latter proce-dure, unsymmetrical products can be obtained selectively.[55]

5. Alkylations of Deprotonated a-Aminonitriles

While intermolecular alkylations of deprotonated a-aminoni-triles are frequently used for the synthesis of ketones, intramo-lecular variants can provide access to N-heterocycles althoughnot many examples are known for the latter methodology.

Achini used this approach for the preparation of phenyl- andbenzyl-substituted 2-cyanopyrrolidines. Chloroalkyl-substituteda-aminonitriles 81 and 82 give the corresponding 2-cyanopyr-rolidines 83 and 84 upon deprotonation with NaHMDSthrough carbanionic 5-exo-tet ring closure (Scheme 18).[56]

Couty and co-workers reported a related synthesis of the 2-cyano azetidines 89 and 92 starting from b-amino alcohols 85which were converted to the intermediate a-aminonitriles 88and 91. The latter compounds undergo a 4-exo-trig ring clo-sure upon base treatment (Scheme 19). Interestingly, in thecase of phenylglycinol, the rearranged chloride is produced byformation of an intermediate aziridinium salt.[57]

b-Lactams are not only characteristic substructures of a largeclass of antibiotics but also represent versatile intermediates inthe synthesis of b-amino acid derivatives. Laurent and co-work-ers used deprotonated a-aminonitriles for the intramolecularepoxide ring opening to access the western half of the b-lactam antibiotic thienamycin. The 2,3-epoxy butanoate 93 isactivated with oxalyl chloride and reacted with aminonitrile 94.Treatment of the resulting epoxy amide 95 with LiHMDS fur-nishes the diastereomeric azetidin-2-ones 97 in 47 % yield(Scheme 20).[58]

An example for an intermolecular alkylation in heterocyclesynthesis stems from Romek et al. who described a short routeto 4-quinolones 102 by a-alkylation of deprotonated N-aryl-a-aminonitriles 98 with a-bromoesters 99 (Scheme 21). The inter-mediate alkylation products 100 release HCN, furnishing enam-inoesters 101, which form 4-quinolones in a Conrad–Limpach

Scheme 17. Synthesis of imidazoles, oxazoles and imidazolium salts by 1,2-addition of deprotonated a-aminonitriles.

Scheme 19. Intramolecular alkylations using deprotonated a-aminonitriles.

Scheme 18. Intramolecular C-alkylation by Achini.

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cyclization under microwave irradiation.[59] Compared to theclassical Conrad–Limpach synthesis from b-ketoesters and ani-lines,[60] this method is of higher modularity but has limitationswith respect to the steric bulk of the substitutent R3.

6. Electrocyclizations of Deprotonateda-Aminonitriles

The introduction of an additional double bond to a-(alkylide-neamino)nitriles creates the opportunity of electrocyclic ringclosure of the conjugate anions. For example, the Schiff basesobtained by condensation of aminoacetonitrile (104) with a,b-unsaturated ketones 103, can be deprotonated in situ to formstabilized 2-azapentadienyl anions 106. These H�ckel aromaticsystems can undergo a thermal disrotatory 6p-electrocycliza-tion to furnish 3,4-dihydro-2H-pyrrole-2-carbonitriles 108 afterreprotonation in a one-pot procedure (Scheme 22). The prod-ucts are kinetically stable against basic dehydrocyanation andcan, for example, serve as starting materials for the preparationof 1,3,5-trisubstituted pyrrolizidines 110 by vinylogous additionto enones followed by reductive cyclization.[61] However, heat-ing to 250 8C under microwave irradiation transforms com-pounds 108 to 2,4-disubstituted pyrroles 109 in a thermal de-

hydrocyanation.[62] This represents the hitherto most efficiententry to this compound class.

When a-substituted a-aminonitriles 111 are used as theamine component instead of aminoacetonitrile, the analogous2,3,5-trisubstituted cyanopyrrolines 115 are obtained, whichcan be readily converted to the corresponding 2,3,5-trisubsti-tuted pyrroles 116 under microwave irradiation (Scheme 23).An active dehydration is required to effect the initial condensa-tion in this case.[61]

7. Rearrangement of Nitrile-Stabilized Ammo-nium Ylides

Despite their usefulness for the synthesis of N-heterocycles,Stevens rearrangements of nitrile-stabilized ammonium ylideshave relatively rarely been reported. In 2001, Liu and Liang de-veloped a methodology for the one-carbon ring homologationof saturated N-heterocycles such as 2-methyl-1,2,3,4-tetrahy-droisoquinoline 117 to fused benz[d]azepines of type 118. Thereaction sequence comprises an N-alkylation with bromoaceto-nitrile to produce the quaternary ammonium salt, base-in-duced Stevens rearrangement, as well as the reductive decya-nation of the rearrangement product with NaBH4

(Scheme 24).[63] This and related processes open up interestingperspectives for the post-functionalization of tertiary amines.

Soldatova and co-workers employed the same sequence forthe ring homologation of tetrahydroisoquinolinium salts to tet-rahydro-3-benzazepines.[64] Starting from similar tetrahydroiso-

Scheme 20. Intramolecular epoxide ring opening by deprotonated a-amino-nitriles.

Scheme 21. Alkylation of a deprotonated a-aminonitrile and subsequentcyclization to 4-quinolones.

Scheme 22. Synthesis and conversion of 3,4-dihydro-2H-pyrrole-2-carboni-triles.

Scheme 23. 2,3,5-trisubstituted pyrroles from deprotonated a-aminonitriles.

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quinolinium salts 121 in combination with dimethyl acetylene-dicarboxylate, the same authors achieved a ring enlargementby three carbon atoms under formation of 2,3,6,7-tetrahydro-1H-benz[d]azonines 124 (Scheme 25).[65]

More recently, Lahm et al. reported a concise synthesis of

polycyclic alkaloids based on the Stevens rearrangement of ni-trile-stabilized ammonium ylides derived from spirocyclic am-monium salts. Starting from simple cyclic a-aminonitriles 125,the salts 127 were prepared by double N-alkylation with readi-ly available dibromide 126 (two steps from veratrol and diace-tyl). Deprotonation with KHMDS was followed by Stevens rear-rangement even at temperatures as low as 0 8C to furnish com-pounds 129 after reductive decyanation of intermediates 128(Scheme 26). With only five linear steps, this represents theshortest route to the phenanthroindolizidine alkaloid (�)-tylo-phorine (129 a) known so far.[66] Similarly, the tetrahydroproto-berberine alkaloid (�)-xylopinine was synthesized in threesteps from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-bonitrile (18) and 1,2-bis(bromomethyl)-4,5-dimethoxyben-zene.[67]

8. Cyclizations with Incorporation of the NitrileFunction

In addition to its charge-stabilizing effect, the electrophilicityof the nitrile group in conjunction with the nucleophilic aminefunction linked to the same carbon creates further options forthe synthesis of N-heterocycles from a-aminonitriles.

A convenient access to 2,4,4-trisubstituted 5-amino-4H-imi-dazoles 132 by reaction of a-aminonitriles with imidoesters131 was reported by G�mez-Molinero in 1985 (Scheme 27,A).[68] The same authors reported on the synthesis of 4-amino-1H-imidazole-2-carboxylates 135 by reaction of ethyl ethoxy-2-iminoacetate (134) with aminoacetonitrile. When a-substitutedaminonitriles were used as the substrates, the products 135react with another equivalent of the iminoester to furnish thecorresponding amidines (Scheme 27, B).[69]

Scheme 24. Ring enlargement by Stevens rearrangement of nitrile-stabilizedammonium ylides by Liu and Liang.

Scheme 25. Synthesis of 2,3,6,7-tetrahydro-1H-benzo[d]azonines by Solda-tenkov et al.

Scheme 26. Synthesis of (�)-tylophorine and (�)-7-methoxycryptopleurine.

Scheme 27. Various routes to aminoimidazoles.

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Concept

First reported by Bader et al. ,[70] the synthesis of 2,4-disubsti-tuted 5-aminoimidazoles 138 by condensation of a-aminoni-triles and thioiminoether hydrobromides 137 was improved byLam and co-workers who applied microwave irradiation(Scheme 27, C). This method furnishes the desired products inshorter reaction times and high yields. The required thioimi-noethers were in turn conveniently obtained from thioamidesand benzyl bromide under microwave irradiation.[71]

Another efficient route to 4-substituted 5-aminoimidazoles140 from a-aminonitriles involves their condensation with tri-alkyl orthoformates to O-methylimidates. The latter can be co-cyclized with primary amines to yield imidazoles in high yields(Scheme 27, D). This method was first reported by Wright andco-workers and was further developed by McLaughlin et al.who improved the yields and expanded the substrate scopewith respect to both the a-aminonitrile and the amine compo-nent.[72] The reaction starts with the conversion of the imidateportion to an amidine in an addition/elimination sequencewhich is followed by 5-exo-trig-cyclization of the newly intro-duced nitrogen onto the nitrile carbon.

In contrast to the above-mentioned methods, other ap-proaches for the construction of 5-aminoimidazoles have onlyrarely been reported in the literature and are limited to accept-or-substituted products.[73]

Like in the ester series, the electron-withdrawing effect ofthe nitrile function stabilizes neighboring diazo groups. Diazo-tation of a-aminonitriles generates a-diazonitriles 142, whichreadily react with various dipolarophiles. As an example, diazo-acetonitrile and dimethyl acetylenedicarboxylate produce the3-cyano-1H-pyrazole-4,5-dicarboxylate 143,[74] whereas highera-diazonitriles can be cyclized with hydrogen sulfide to 5-amino-1,2,3-thiadiazoles 144 (Scheme 28).[75]

Substituted 2-amino-2,3-dihydroisothiazole-1,1-dioxides areregarded as attractive heterocyclic scaffolds for drug discovery.Marco and co-workers developed a route starting from 2-ami-noisobutyronitrile 145 and alkanesulfonyl chlorides. N-benzyla-tion of the resulting sulfonamides 146 and their deprotona-tion/cyclization furnished the desired compounds 148 in mod-erate to high yields (Scheme 29).[76]

In a similar approach, Postel constructed spiro-[4.4]azaphospholenes 150 from carbohydrate-derived a-ami-nonitriles 149 by N-phosphonylation and intramolecular anion-ic cyclization (Scheme 30).[77] The same authors prepared vari-

ous other spiroheterocyclic products from similar a-aminoni-trile substrates.[78]

Sedl�k and co-workers employed the reaction of aryl isocya-nates with acetophenone-derived a-aminonitriles 151 to 1-(1-aryl-1-cyanoethyl)-3-arylureas 152 as the starting point of theirhydantoin synthesis. Treatment of ureas 152 with anhydrousphosphoric acid results first in the kinetically favored ring clo-sure by attack of the oxygen on the nitrile carbon to furnishphosphate salts of 4-methyl-4-phenyl-2-phenylimino-5-imino-4,5-dihydro-1,3-oxazoles. As in the Edman degradation, hydan-toins (153) are the final and thermodynamically stable reactionproducts (Scheme 31).[79]

Zhong and co-workers presented a synthesis of diverselyfunctionalized imidazoles starting from N-acylated a-aminoni-triles 154, which were reacted with triphenylphosphine anda carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H-imi-dazoles 155 in a single step. Various further functional groupscan be easily introduced in the latter compounds, and structur-al modifications can be carried out (Scheme 32). This methodis superior to other methods which require an additional trans-formation for incorporation of the halide substituent.[80]

Uchibayashi[81] and Blake et al.[82] investigated the Die-ckmann-type cyclization of aminonitrile ester 156 (Scheme 33,A and B). When the deprotonation was carried out under equi-librating conditions, enolate attack to the nitrile carbon atom

Scheme 28. Diazotation of aminonitriles and their reactions with dipolaro-philes.

Scheme 29. Synthesis of 2-amino-2,3-dihydroisothiazole-1,1-dioxides.

Scheme 30. Preparation of spiro[4.4]azaphospholenes.

Scheme 31. Addition of isocyanates to a-aminonitriles.

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Concept

was the dominant process and furnished cyclic enamino ester158 (Scheme 33, C).

2(1 H)-Pyrazinones exhibit diverse biological activities andare a compound class with relevance for pharmaceuticalchemistry. A rapid and versatile access to 1,6-disubstituted 3,5-dichloro-2(1 H)-pyrazinones 160 was developed by Vekemanset al.[83] as well as by Larhed and co-workers.[84] They treated a-aminonitriles 159 with gaseous HCl and oxalyl chloride andachieved closure of the six-membered ring under microwaveirradiation (Scheme 34). Gammill and co-workers reported onan asymmetric synthesis of atropisomeric 6-aryl-3,5-dichloro-1-(1-phenylethyl)-2(1 H)-pyrazinones using the above-mentionedmethod.[85]

A class of heterocycles famous for their biological propertiesare the 1,4-benzodiazepines which exhibit anxiolytic, anticon-vulsant, hypnotic, sedative, and muscle relaxant effects due totheir affinity to GABA receptors in the central nervous system.Hussein and co-workers acylated a-aminonitriles 161 with 2-ni-trobenzoyl chloride to give the corresponding amides (163)which, upon reduction with zinc, furnish the 2-amino-3,4-dihy-dro-5H-1,4-benzodiazepin-5-ones 165 (Scheme 35) in highyields.[86]

9. Miscellaneous Reactions

Apart from classical electrophiles, electron-deficient aromaticrings can also be attacked by deprotonated a-aminonitriles.For example, Arnott et al. reported the spirocyclization of de-

protonated N-isonicotinoyl aminonitriles to the diazaspiro-[5.3]nonanes 168. The starting material 166 was deprotonatedwith lithium diisopropylamide (LDA) and then N-alkoxycarbo-nylated to yield the spirocyclic product in moderate yield. Theaddition of methyl chloroformate was required for the reactionto take place. Under the same conditions, the isomeric N-nico-tinoyl aminonitriles 167 were cyclized to the azaisoindolinones169, which were unstable towards oxidation and produced thearomatic azaisoindolones (Scheme 36).[87]

Unactivated internal alkynes also proved to be suitable reac-tion partners for anions of a-aminonitriles. The intramolecularnucleophilic addition of the lithium salts of compounds 170 tothe triple bond is the key step in a short synthesis of di- andtrisubstituted pyrroles reported by Wang and co-workers. a-Deprotonation with LDA and the following 5-endo-dig cycliza-tion furnishes cyanopyrrolines 171, which are directly isomer-ized to the thermodynamically more stable D2-isomers 172.2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) dehydrogen-ates these intermediates to the corresponding pyrrole-2-car-bonitriles 173 (Scheme 37).[88] While this reaction has a certainresemblance to the electrocyclizations described in Section 6,it should be noted that no conjugation is present here.

The synthesis of 2-methyl substituted oxazole-4-carbonitrile177 starting from imidate 176, first investigated by Cornforth,was further developed by Carey and co-workers.[89] Imidate176 can be prepared from ethyl acetimidate hydrochloride(174) and aminoacetonitrile hydrochloride (175), subsequent

Scheme 32. Synthesis of 2,4-disubstituted 5-halo-1H-imidazoles.

Scheme 33. Dieckmann-type cyclization of an a-aminonitrile ester by Uchi-bayashi and Blake et al.

Scheme 34. Synthesis of 1,6-disubstituted 3,5-dichloro-2(1 H)-pyrazinones.

Scheme 35. 2-Amino-1,4-benzodiazepin-5-ones from a-aminonitriles.

Scheme 36. Spirocyclization of deprotonated N-isonicotinoyl aminonitriles.

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C-formylation with ethyl formate and cyclization with TMSClgives the product 177 in 50 % overall yield (Scheme 38). As de-scribed by Biere and co-workers[90] as well as by Schmidtet al. ,[91] aminoacetonitrile hydrochloride (175) and dimethyl-formamide dimethylacetal form 2-azabuta-1,3-dienes 178,which can be subjected to co-cyclization with anilines to afford1-substituted imidazole-4-carbonitriles 179 (Scheme 39).

10. Conclusion and Outlook

a-Aminonitriles represent powerful building blocks for the con-struction of a large variety of heterocyclic products, the majori-ty of which containing at least one nitrogen atom from thestarting material. Moreover, heterofunctionalized acyclic com-pounds can also be obtained utilizing the same principles asoutlined in this Concept article.

Being the three-component reaction with the oldest history,the Strecker reaction permits the synthesis of a-aminonitrilesfrom commercially available reactants in high yield in a singleoperation. Other ways to prepare aminonitriles are feasible aswell, and the use of cyanide can, for instance, be circumventedby choosing a-amino acids as the starting point.

The nucleophilicity of the amine function, the electrophilici-ty, and steric accessibility of the nitrile group, as well as theability to accommodate a negative charge in a-position and toeliminate cyanide while generating an electrophilic iminiumion confer a unique application potential to this compound

class. In particular in the area of heterocyclic chemistry, com-plex structures can be constructed in a rapid, step-economicalmanner from readily available starting materials.

More than 160 years after Adolph Strecker’s first report ona-aminonitriles, there is still plenty of room for developingnew and efficient synthetic methodology based on these val-uable synthetic intermediates.

Acknowledgments

N.O. is grateful for a PhD scholarship of the “Studienstiftungdes deutschen Volkes”.

Keywords: a-aminonitriles · heterocycles · nitrogenheterocycles · synthetic methods

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Scheme 37. Synthesis of pyrroles by intramolecular cyclization.

Scheme 38. Synthesis of 2-methyloxazole-4-carbonitrile.

Scheme 39. Synthesis of 1-substituted imidazole-4-carbonitriles.

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Received: June 13, 2014Published online on September 12, 2014

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