0 Hits

  • Previous / Next

19 Three Carbon—Heteroatom Bonds: Nitriles, Isocyanides, and Derivatives

DOI: 10.1055/sos-SD-019-00001

Murahashi, S.-I.Science of Synthesis, (2004191.

General Introduction

This volume covers the synthesis of compounds with three carbonheteroatom bonds which include nitrile oxides, nitrile sulfides, nitrile imines, nitrilium salts, nitrile ylides, nitriles, phosphaalkynes, and carbon- and heteroatom-bound isocyanides. These are shown in Table 1, together with the sections in which they appear.

Table 1 Structures and Nomenclature for the Three CarbonHeteroatom Bond Containing Compounds Covered in Volume 19

Product Class Structural Formula Section
nitrile oxides R1CN+O 19.1.1
nitrile sulfides R1CN+S 19.1.2
nitrile imines R2CN+NR1 19.2
nitrilium salts R2CN+R1 19.3
nitrile ylides R2CN+CR1 19.4
nitriles R1CN 19.5
phosphaalkynes R1CP 19.6
isocyanides R1N=C 19.7.1
heteroatom-bound isocyanides YN=C (Y=N, S, O, P) 19.7.2

References to reviews on these specific functional groups are given in each section. Discussion of each specific group is generally subdivided into methods that have been selected as the most useful for the preparation of the product class or subclass in question. Each method is presented separately as follows:

1. Introduction: comparison with other methods.

2. Presentation of the scope of the method to include background, discussion of representative examples, safety; mechanistic information where relevant to the use of the method in synthesis; a table of examples (for selected methods); reaction schemes.

3. Representative experimental procedures.

In some cases, methods are further subdivided into variations on a method, each variation being presented according to the above format.

The coverage is not exhaustive, rather the most useful and reliable methods for the synthesis of each functional group have been selected. In some cases, methods that are recommended for limited use, or that have not yet been fully developed, are listed at the end of a section for reference. Tables and representative experimental procedures are given to illustrate the applicability of each approach.

This introduction will outline the individual product classes together with highlighted synthetic methods.

Nitrile oxides are 1,3-dipoles containing the same array of atoms in the functional group as nitrones, but at one oxidation level higher. Nitrile oxides 2 are readily prepared, mainly from hydroximoyl halides 1, which are obtained through the halogenation of aldoximes with a variety of halogenating reagents[‌1‌] or by treatment of activated nitroalkanes with thionyl chloride in the presence of triethylamine (Scheme 1).[‌2‌] As they are difficult to isolate and store, nitrile oxides are normally generated in the presence of a reactive dipolarophile, giving the appropriate adduct directly; however, some nitrile oxides with bulky substituents are stable. Cycloaddition to a substituted ethene proceeds regioselectively, and the products are highly useful as precursors for a variety of other compounds and their functionality is readily unmasked. Typically, metal ion promoted cycloadditions to give dihydroisoxazoles 3 are highly useful reactions (Scheme 1). Stereospecific syntheses of dihydroisoxazoles can be achieved using effective chiral auxiliaries and metal ions. Typically, in the presence of magnesium ions the cycloaddition of nitrile oxides to allylic alcohols proceeds in a highly syn-selective manner when α-chiral dipolarophiles are used.[‌3‌]

Scheme 1 Synthesis of Nitrile Oxides from Hydroximoyl Halides and Stereospecific 1,3-Dipolar Addition to Alkenes[‌2‌‌4‌]

Nitrile oxides can also be prepared directly by oxidation of aldoximes with sodium hypochlorite or N-bromosuccinimide in the presence of a base such as triethylamine. Such oxidations are normally combined with cycloaddition reactions with a suitable dipolarophile already present in the same pot. One typical example is the intramolecular cycloaddition of an aldoxime to give tricycle 4, which contains the ring skeleton of natural product streptazolin (Scheme 2).[‌5‌]

Scheme 2 Direct Synthesis of a Nitrile Oxide and Its Application in the Partial Synthesis of Streptazolin[‌5‌]

Nitrile sulfides are unstable and it is impossible to isolate them. Nitrile sulfides are generated by the thermal decomposition of five-membered heterocyclic compounds, such as 1,3,4-oxathiazol-2-one, and trapped immediately with a suitable dipolarophile, thereby providing access to several classes of heterocycles that are obtained only with difficulty by other means.

Nitrile imines 6, which can be generated by the base-induced dehydrohalogenation of stable hydrazonoyl halides 5, are trapped by a variety of 1,3-dipolarophiles such as alkenes and alkynes to afford 4,5-dihydropyrazoles and pyrazoles, respectively (Scheme 3).[‌6‌,‌7‌]

Scheme 3 Generation of Nitrile Imines from Hydrazonoyl Halides and Entrapment with Alkenes and Alkynes[‌6‌,‌7‌]

Nitrilium salts are intermediates in a number of reactions that include the Beckmann rearrangement producing amides from oximes,[‌8‌,‌9‌] the Ritter reaction producing amides from alcohols and nitriles,[‌10‌‌12‌] the von Braun amide degradation reaction producing alkyl halides and nitriles,[‌13‌] the BischlerNapieralski reaction producing dihydroisoquinolines and related ring-fused imines from amides and arenes,[‌13‌] the Hoesch acylation reaction from arenes and nitriles,[‌14‌] the Gattermann formylation reaction of arenes and hetarenes,[‌15‌] and the Schmidt reaction producing amides from ketones and hydrazoic acid.[‌16‌] In most cases, the nitrilium ions are formed and reacted instantly, but stable nitrilium salts can be isolated. The acid-mediated dehydration of oximes is better known as the Beckmann rearrangement. N-Alkylation of nitriles provides one of the most convenient and direct routes to nitrilium salts. Nitrilium salts are also prepared by the interaction of alkyl chloroformates with Lewis acid complexes of nitriles.

Nitrile ylides are 1,3-dipoles and can be prepared by several methods[‌7‌,‌17‌] including the elimination of hydrogen chloride from imidoyl chlorides, the reaction of carbenes and carbenoids with nitriles, and the photochemical ring opening of aziridines. Pyrroles and dihydropyrroles are obtained by the 1,3-dipolar cycloaddition of nitriles ylides with alkynes and alkenes.

Nitriles are an extremely important class of compounds in organic synthesis. Nitriles have a strong dipole, oriented with the negative end toward the nitrogen, and the cyano group is recognized as a powerful electron-withdrawing substituent. Nitriles have unique properties, and thus various reactions for the synthesis and the unique transformations of nitriles have been developed.

A typical method for the synthesis of nitriles is the construction of the cyano group by functional group transformation from various starting materials, such as aldehydes, carboxylic acids and their derivatives, hydrazones, aldoximes, carboxamides, and thioamides.[‌18‌‌20‌]

The oxidation of hydrazones and aldoximes are important synthetic routes to nitriles, although the direct conversion of aldehydes in a one-pot reaction can be carried out by oxidation of the in situ formed aldimines. One of the most typical transformations is the preparation of nitriles by nucleophilic substitution of alkyl, allyl, and benzyl halides (at the sp3-carbonhalogen bonds) with various cyanide reagents.[‌21‌,‌22‌] Substitution at the sp2-carbonhalogen bonds is very difficult; however, the palladium-catalyzed coupling reaction of Z- and E-vinyl halides with sodium cyanide in the presence of 18-crown-6 was introduced in 1977 as the first transition-metal-catalyzed cyanation reaction of sp2-carbonhalogen bonds to give Z- and E-vinyl cyanides stereospecifically.[‌23‌] This reaction led to the discovery of palladium- and nickel-catalyzed cyanations of aryl halides and vinyl and aryl trifluoromethanesulfonates. The conversion of the aryl chlorides into aryl cyanides is very convenient.[‌24‌]

Aromatic and heteroaromatic nitriles can be prepared by direct cyanation of aromatic and heteroaromatic compounds with cyanogen bromide or trichloroacetonitrile in the presence of FriedelCrafts catalysts.[‌25‌] Heterocyclic N-oxides such as pyridine, quinone, pyrazine, pyrimidine, quinoxaline, or isoquinoline N-oxide undergo reaction with trimethylsilyl cyanide in the presence of a base to give the cyanation products directly. The reactions of pyridine 1-oxide with dimethylcarbamoyl chloride and trimethylsilyl cyanide give the corresponding carbonitriles in excellent yields (modified ReissertHenze reaction).[‌26‌] Catalytic asymmetric Reissert-type reactions of quinoline and isoquinoline derivatives using a Lewis acidLewis base bifunctional catalyst are highly useful; for example, with a catalyst obtained from ligand 7 and diethylaluminum chloride,[‌27‌] 1-(2-furylcarbonyl)-6,7-dimethoxy-1,2-dihydroquinoline-2-carbonitrile (8) is obtained in 91% ee (Scheme 4).

Scheme 4 Aluminum-Catalyzed Asymmetric Reissert-Type Reaction of a Quinoline[‌27‌]

Direct cyanation of the sp-CH bond of acetylenes is performed by treatment with copper(I) cyanide and chlorotrimethylsilane,[‌28‌] or butyllithium and phenyl cyanate.[‌29‌] Direct cyanation of the sp3-CH bond is extremely difficult; however, aerobic oxidative cyanation of tertiary amines with sodium cyanide has been demonstrated. Thus, the treatment of N,N-dimethylaniline with catalytic ruthenium(III) chloride hydrate and sodium cyanide under molecular oxygen (1 atm) gives α-cyanated amine 9 (Scheme 5), which is the precursor of amino acids and 1,2-diamines, in excellent yields. The direct CH activation of an amine α to nitrogen with a ruthenium catalyst forms the intermediate iminium ion and this is the key step of this interesting reaction.[‌30‌]

Scheme 5 Aerobic Ruthenium-Catalyzed Oxidative Cyanation of a Tertiary Amine with Sodium Cyanide[‌30‌]

Introduction of the cyano group by substitution of the metals in organometallic compounds can also be used for nitrile synthesis. Typically, the substitution reaction of organozinc or copper compounds with tosyl cyanide is highly useful.[‌31‌]

Nitriles can also be synthesized by the transformation of other substrates such as amines, alcohols, and nitro compounds. The oxidative transformation of primary amines to nitriles is performed by aerobic oxidation of primary amines in the presence of a hydroxyapatite-bound ruthenium complex [Ru-HAP(II)], which is prepared by mixing calcium hydroxyapatite [Ca10(PO4)6(OH)2] with aqueous ruthenium(III) chloride.[‌32‌]

The synthesis of cyanohydrins and especially the asymmetric synthesis of these compounds are extremely important; therefore, many methods have been developed.[‌33‌] The cyanohydrins of aldehydes are prepared upon treatment with potassium or sodium cyanide/18-crown-6, acetone cyanohydrins with a metal complex catalyst, and trimethylsilyl cyanide with a catalyst. The most significant advances in the area of cyanohydrin chemistry since 1985 have been the development of catalysts for the asymmetric addition of cyanide to aldehydes. The reaction can be induced by a variety of catalysts, of which enzymes, synthetic peptides, and chiral metal complexes are the three most common.[‌34‌‌38‌]

The cyclic dipeptide containing histidine residue catalyzes the asymmetric addition of hydrogen cyanide to benzaldehyde, giving optically active mandelonitrile with up to 90% ee.[‌39‌] A number of organometallic reagents based on chiral complexes of titanium,[‌40‌‌42‌] aluminum, lanthanide,[‌41‌,‌43‌,‌44‌] and other metals[‌45‌] have been found to catalyze the asymmetric addition of hydrogen cyanide or trimethylsilyl cyanide to aldehydes. Typically, the chiral titaniumsalen complex 10 catalyzes the asymmetric addition of potassium cyanide and acetic anhydride to aldehydes affording the cyanohydrin acetates 11 with high enantioselectivities (Scheme 6).

Scheme 6 Titanium-Catalyzed Asymmetric Addition of Potassium Cyanide and Acetic Anhydride to Aldehydes[‌43‌,‌44‌]

The Strecker reaction is a three-component condensation reaction between a carbonyl compound, an amine, and a cyanide to produce an α-aminonitrile. The reaction proceeds via in situ formation of an imine, followed by addition of cyanide to the imine.

The asymmetric addition of cyanide to imines is important in organic synthesis.[‌46‌‌50‌] The enantioselective addition of hydrogen cyanide or trimethylsilyl cyanide to imines in the presence of a chiral catalyst such as a cyclic dipeptide,[‌51‌] or an aluminum,[‌52‌,‌53‌] titanium,[‌54‌] or zirconium[‌55‌] complex is very important in the synthesis of optically active α-aminonitriles. Typically, enantioselective addition of hydrogen cyanide to imines gives aminonitriles 13 using 5mol% of the chiral aluminumsalen complex 12 (Scheme 7).[‌52‌]

Scheme 7 Enantioselective Addition of Hydrogen Cyanide to Imines Catalyzed by a Chiral AluminumSalen Complex[‌52‌]

Hydrocyanation of α,β-unsaturated carbonyl compounds and related compounds is performed upon treatment with diethylaluminum cyanide (prepared from HCN and Et3Al), trimethylsilyl cyanide and a Lewis acid, or acetone cyanohydrin. Hydrogen cyanide itself is normally incapable of adding to Michael acceptors.

The hydrocyanation of alkynes is a very important and useful process since it generates highly versatile α,β-unsaturated nitriles from easily accessible starting materials. The tetrakis(triphenyl phosphite)nickel(II)-catalyzed hydrocyanation of diphenylacetylene gives 1,2-diphenylethanenitrile selectively.[‌56‌,‌57‌]

The Dupont process for the synthesis of adiponitrile (hexanedinitrile, 14) from buta-1,3-diene is the most important application of hydrocyanation. The overall reaction consists of three stages, the first being the synthesis of a mixture of pent-3-enenitrile and 2-methylbut-3-enenitrile (7:3) by the nickel-catalyzed addition of 1 equivalent of hydrogen cyanide to buta-1,3-diene. The isomeric nitriles are separated by distillation, and the unwanted branched product is isomerized in a second step using a similar nickel(0) catalytic system in the presence of a Lewis acid. In the final part of the process, the mixture of unbranched pentenenitriles is isomerized and concomitantly hydrocyanated resulting in the product adiponitrile (14) with selectivities of up to 90% (Scheme 8).[‌58‌‌60‌]

Scheme 8 Nickel-Catalyzed Hydrocyanation of Buta-1,3-diene To Give Adiponitrile[‌58‌‌60‌]

There are many methods for the synthesis of nitriles from other nitriles with retention of the cyano group. The reactions of α-cyano carbanions with electrophiles are one of the fundamental synthetic routes to nitriles, which include reaction with alkyl halides, epoxides, the aldol reaction, the Knoevenagal reaction, the Michael reaction, and the ThorpeZiegler reaction. Usually α-cyano carbanions can be generated upon treatement of nitriles with strong bases such as lithium diisopropylamide and potassium tert-butoxide; however, CH activation α to the nitrogen of nitriles with a low-valent transition-metal catalyst such as dihydridotetrakis(triphenylphosphine)ruthenium(II) is highly useful. The aldol reaction, the Knoevenagel reaction, and the Michael reaction of nitriles can be carried out in a highly selective manner with low-valent transition-metal complexes such as dihydridotetrakis(triphenylphosphine)ruthenium(II) as the redox Lewis acid catalyst under neutral and mild reaction conditions.[‌61‌,‌62‌] Typically, the reaction of ethyl cyanoacetate with 4-hydroxybenzaldehyde gives the product 15 in 98% yield (Scheme 9). The reaction can be carried out under neutral conditions and acidic substrates are tolerated in the reaction. Another example is the Michael addition of ethyl 2-cyanopropanoate (16) to a base-sensitive substrate of prop-2-enal to give 17 (Scheme 9). These reactions provide nonsalt processes that are environmentally benign.[‌63‌]

Scheme 9 Ruthenium-Catalyzed Aldol Condensation and Michael Addition[‌61‌,‌62‌]

The ThorpeZiegler reaction has been carried out using a stoichiometric amount of a strong base, such as sodium hydride, to give aminonitriles from dinitriles; however, pentahydridobis(triisopropylphosphine)iridium(V) can be used instead of a strong base, and the catalytic reaction of 18 can be carried out to give 19 under neutral conditions (Scheme 10).[‌64‌]

Scheme 10 Iridium-Catalyzed ThorpeZiegler Condensation of a Nitrile[‌64‌]

Conjugate additions of reactive nucleophiles to alkenes or alkynes are important CC and carbonheteroatom bond-forming reactions for making a variety of nitriles.[‌65‌,‌66‌] Various nucleophiles such as oxo enolates, ester enolates, enamines, metalated nitriles, metalated nitroalkanes, organometallic compounds, allylsilanes, thiols, and amines add to alkenenitriles selectively to give numerous nitrile compounds.

[2+2] Cycloaddition, 1,3-dipolar cycloaddition, and the DielsAlder reaction are convenient for the stereoselective synthesis of cyclic compounds bearing a nitrile. Iminoacetonitriles, which are readily prepared from alcohols, are useful azodienophiles for intramolecular hetero-DielsAlder reactions (Scheme 11).[‌67‌]

Scheme 11 Aza-DielsAlder Reaction of an Iminoacetonitrile[‌67‌]

The HeckMizoroki reaction, palladium- and nickel-catalyzed cross-coupling reactions with various organometallic compounds, and palladium-catalyzed reactions of allyl esters are extremely useful for the synthesis of nitrile compounds, especially alkenenitriles.

Nitriles have unique properties, and, therefore, various transformations of nitriles have been developed. Functional group transformations of nitriles to amines, imines, aldehydes, ketones, amides, amidines, amidrazones, imidates, and carboxylic acids are widely known, and these transformations have been described in sections of other volumes within Science of Synthesis.

The applications of nitriles in the construction of more complex molecules are also described in this volume. Three-component reactions, one-pot cyclization, cycloaddition, and domino reactions are often used for the synthesis of various heterocyclic compounds. Typically, the reaction of 20 with trimethylsilyl trifluoromethanesulfonate, followed by disiloxydiene 21 affords the open-chain product 22. Treatment of 22 with triethylamine affords the benzopyrano[2,3-b]pyridine 23 (Scheme 12).[‌68‌]

Scheme 12 Reaction of 4-Oxo-4H-1-benzopyran-3-carbonitrile with a Disiloxy-1,3-diene[‌68‌]

One of the unique properties of nitriles is their ability to strongly coordinate to metals. Using this property, new types of practical catalytic reactions of nitriles have been developed. Typically, the ruthenium-catalyzed reaction of amines, nitriles, and water under neutral reaction conditions to give amides and ammonia is an extremely useful reaction which can also be applied to the synthesis of polyamides from diamines and dinitriles (Scheme 13).[‌63‌,‌69‌]

Scheme 13 Ruthenium-Catalyzed Amidation of Nitriles with Amines and Water[‌69‌]

A novel three-component reaction involving nitriles, alkenenitriles, and water in the presence of pentahydridobis(triisopropylphosphine)iridium(V) as a Lewis acid and base ambiphilic catalyst affords glutarimides 24, which are versatile intermediates in the synthesis of biologically active compounds (Scheme 14).[‌64‌]

Scheme 14 Iridium-Catalyzed Three-Component Reaction of Nitriles, Alkenenitriles, and Water To Give Glutarimides[‌64‌]

A wide range of pyridines have been prepared by the [2+2+2] cyclotrimerization of nitriles and alkynes. Cobalt complexes are the most common catalysts.[‌70‌] The complex fused heterocycles can be prepared using cobalt-catalyzed cycloaddition reactions.[‌71‌]

Two alternative approaches to the cyclotrimerization were reported, although both result in the formation of a stoichiometric transition-metal species. Thus, titanium(II) alkoxide [prepared in situ from Ti(OiPr)4 and iPrMgCl][‌72‌] and bis(η5-cyclopentadienyl)(diethyl)zirconium(IV)[‌73‌] promote this type of reaction (Scheme 15).

Scheme 15 Zirconium-Mediated Pyridine Synthesis[‌73‌]

Demko and Sharpless demonstrated the formation of substituted tetrazoles from nitriles and azides by heating neat tosyl cyanide with an unhindered azide, giving quantitative conversion into the 1-substituted 5-tosyltetrazole 25 (Scheme 16), which can be readily elaborated by nucleophilic substitution of the tosyl group.[‌74‌] This is a click chemistry transformation in that no solvent is required.

Scheme 16 The Click Chemistry Approach to Tetrazoles[‌74‌]

Phosphaalkynes are unstable molecules, and their chemistry resembles that of alkynes rather than nitriles. The PC bond system shows a pronounced tendency to undergo cycloaddition and cyclooligomerization reactions.

Methylidynephosphine (26), ethylidynephosphine (27), and fluoromethylidynephosphine (28) (Scheme 17) can be generated and characterized, but must be stored under dry argon at low temperature.[‌75‌]

Scheme 17 Typical Phosphaalkynes[‌75‌,‌76‌]

However, (2,2-dimethylpropylidyne)phosphine (29) is prepared[‌76‌] and isolated as a stable colorless liquid (bp 61°C) and has been employed preferentially in model studies concerning the reactivity of this product class. The most important methods for synthesis of phosphaalkynes are β-elimination reactions. The application of phosphaalkynes in organic synthesis is well documented in many reviews.[‌75‌,‌77‌‌83‌] In analogy to the use of acetylene in cycloaddition reactions, phosphaalkynes are also predominant reaction partners in mainly [2+1], [2+2], [3+2], and [4+2] cycloadditions.[‌77‌,‌79‌,‌80‌,‌84‌]

The [2+1] cycloadditions of electron-deficient species allows the synthesis of unsaturated three-membered phosphorus heterocycles such as 30 (Scheme 18) {see also Science of Synthesis, Vol.9 [Fully Unsaturated Small Ring Heterocycles and Monocyclic Five-Membered Hetarenes with One Heteroatom (Section 9.69.6)]}.[‌85‌] The cycloaddition of phosphaalkynes, e.g. 29, with 1,3-dipoles provides access to a wide range of five-membered heterocyclic systems such as 31.[‌86‌,‌87‌]

Scheme 18 [2+1]- and [3+2]-Cycloaddition Reactions of Phosphaalkynes[‌85‌‌87‌]

Isocyanides have a unique and rather unusual electronic structure. The carbon atom of the isocyano group often exhibits carbene-like reactivity that can be represented by a resonance structure RN=C:; therefore, isocyanides undergo a variety of α-addition reactions with reagents of the type XY, which can be regarded as insertion into the XY bond. On the other hand, the linear structure of isocyanides is well represented by the resonance structure RN+=C, in which the isocyano nitrogen is sp-hybridized.

Isocyanides are usually stable and, hence, distillation and chromatographic separation can be used for isolation of these compounds. The characteristic odor of isocyanides, and in particular of low-boiling isocyanides, is extremely unpleasant, so all experiments should be carried out in a well-ventilated fume hood.

Aliphatic and aromatic isocyanides are synthesized and utilized as reactive synthetic intermediates for organic synthesis.[‌88‌,‌89‌] The nucleophilic substitution of halides or equivalents with metal cyanides such as silver cyanide[‌90‌] and trimethylsilyl cyanide with a Lewis acid[‌91‌,‌92‌] are typical synthetic routes to these compounds (Scheme 19). Isocyanates can be transformed into isocyanides by deoxygenation with appropriate reagents such as triethyl phosphite[‌93‌] (Scheme 19) or by reduction of a carbamate with trichlorosilane/triethylamine.[‌94‌]

The dehydration of formamides by acylating reagents, such as phosgene,[‌95‌] trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), thionyl chloride, and tosyl chloride, and bases, such as triethylamine, is now recognized as the most general method for the preparation of isocyanides due to the ready availability of the starting materials (Scheme 19).[‌96‌]

Scheme 19 Typical Syntheses of Isocyanides[‌90‌‌95‌]

Reactions of isocyanides can be classified into three categories. The first involves the isocyano carbon atom formally behaving like a carbene, undergoing α-addition reactions. Three- or four-component reactions involving the α-addition process have also been developed, leading to development of combinatorial syntheses of amino acid derivatives. The second classification involves generation of a carbanion α to the isocyano group, which is trapped with alkyl halides, epoxides, carbonyl compounds, or Michael acceptors, leading to products in which the isocyano group is retained or converted into other functionalities. Finally, the last category involves cleavage of the CNC bond, that is reductive removal of the isocyano group and isocyanidenitrile rearrangement.

α-Addition of organometallic compounds to isocyanides seems to be the most direct way to compounds such as imidoyllithiums 32, which have been proven to be synthetically useful. The imidoyllithiums 32 are prepared by the reaction of isocyanides with organolithiums (Scheme 20).[‌97‌,‌98‌] It is necessary to use isocyanides that do not carry α-hydrogens to avoid hydrogen abstraction at their α-positions. tert-Alkyl isocyanides and aryl isocyanides are suitable for use in the generation of imidoyllithiums.

Scheme 20 Generation and Reactions of Imidoyllithiums[‌97‌,‌98‌]

The Passerini reaction and the Ugi reaction are highly useful for multicomponent couplings via α-addition reactions. The reaction of isocyanides with carbonyl compounds in the presence of carboxylic acids gives α-acyloxycarboxamides (Passerini reaction).

In addition to the three components used in the Passerini reaction, an amine is used as the fourth component in the Ugi reaction. The condensation of the amines and carbonyl compounds generates imine intermediates, which react with acids and isocyanides to give synthetically useful α-acylaminocarboxamides. Since the Ugi coupling reaction is suitable for combinatorial synthesis of peptide derivatives, e.g. 33 (Scheme 21), much effort has been devoted to expansion of the reaction scope, application to solid-phase synthesis, and increasing the reaction's efficiency.[‌99‌,‌100‌]

Scheme 21 The Ugi Reaction[‌99‌,‌100‌]

Asymmetric dihydrooxazole synthesis has been achieved by using a gold catalyst bearing a chiral ferrocenylphosphine ligand 34 in the reaction of isocyanoacetate with aldehydes (Scheme 22). Enantioselectivity as high as 95% ee is recorded with high trans diastereoselectivity in the reaction of benzaldehyde.[‌101‌]

Scheme 22 Gold-Catalyzed Aldol Reaction of Isocyanoacetates[‌101‌]

Polymerization systems using transition-metal catalysts are commonly utilized, leading to the synthesis of poly(isocyanides) with high stereoregularity. The polymerization mechanism is supposed to involve successive insertion of the isocyano carbon atoms into the transition metalcarbon bond during the propagation stage. Efforts have also been made to develop asymmetric polymerizations that afford optically active helical polymers. Using chiral organopalladium complex 35 as an initiator for asymmetric polymerization[‌102‌,‌103‌] gives a highly stereoselective construction of a helical structure with a single screw-sense. The helical structures of poly(quinoxaline-2,3-diyls) 36 are exceptionally stable (Scheme 23).

Scheme 23 Asymmetric Polymerization of a 1,2-Diisocyanobenzene with a Chiral Palladium Initiator[‌103‌]

Nitrogen-, oxygen-, sulfur-, and phosphorus-bound isocyanides are covered in Section 19.7.2. There are not many known compounds of this class due to the instability of these compounds. Among the heteroatom-bound isocyanides, nitrogen-bound isocyanides have been studied most extensively.

Typically, diazoisocyanide is prepared from the corresponding 1-substituted 3-formyltriaz-1-ene by dehydration with thionyl chloride. The products exhibit exceptional thermal as well as chromatographic stability.