Isocyanoalkenes: Occurrence, Syntheses, and Reactivity

Dedication

To Paul Knochel, whose creative genius has transformed functionalized organometallics into a new form of molecular artistry.

Abstract

Isocyanoalkenes are a largely underexplored subset of isocyanides whose natural occurrence, synthesis, and reactivity are elucidated in this review. The discussion begins with an overview of the biosynthesis and natural occurrence, which provides a valuable context for the synthetic approaches to these unusual π-substituted alkenes. Building on this foundation, the review explores the characteristic reactivity of isocyanoalkenes, which is shaped by the strong electron-withdrawing nature of the isocyanide group and an almost complete lack of π-conjugation. Two primary modes of reactivity are highlighted: conjugate additions – especially in systems containing additional electron-withdrawing substituents – and radical additions to the isocyanide, often followed by annulation via iminyl radical intermediates. Special attention is given to two particularly versatile isocyanoalkenes – β-dimethylaminoisocyanoacetates and β-bromoisocyanoacetates – which readily undergo nucleophilic addition–elimination–cyclization sequences to efficiently assemble nitrogen-containing heterocycles. Overall, this review underscores the synthetic potential of isocyanoalkenes and highlights their emerging value in the construction of diverse heterocyclic scaffolds.

Keywords

Isocyanoalkenes - Synthesis - Reactivity - Additions - Heterocycles

1

Introduction

Isocyanoalkenes are rather delicate molecules whose isolation from a diverse array of terrestrial and marine sources requires care to prevent hydrolysis of the divalent isocyanide to the corresponding formamide.[1] Often the terminal isocyanide is the key pharmacophore that typically interacts with biological receptors through hydrogen bonding or via strong binding to transition metals. For isocyanoalkenes, many exhibit strong bioactivity against bacteria, fungi, and parasites.[2] In the case of Xanthocillin X (1),[3] the first isocyanide from natural sources, the antibiotic activity was harnessed in a topical cream marketed under the commercial name Brevicid.[4] The Xanthicillin family[5] continues to attract interest for therapeutic applications,[5a] in part because the unique mode of action is particularly efficacious in combating Gram-negative bacterial infections.[6]

Despite the successful development of Xanthocillin X (1, [Fig. 1]), no subsequent isocyanide-containing pharmaceuticals have reached the market. The limited isocyanoalkene-based research contrasts with the extensive chemistry of isocyanoalkanes. A measure of the disparity is revealed by comparing the 700 or so citations for the top 10 isocyanoalkenes with more than 56,000 citations from publications from the top 10 most highly cited isocyanoalkanes.[7]

Fig. 1 Representative bioactive isocyanoalkenes from natural sources.

The current review collates the scattered reports of isocyanoalkene occurrence, synthesis, and reactions to tease out their inherent reactivity profile. The review begins with a brief survey of naturally occurring isocyanoalkenes followed by synthetic approaches to isocyanoalkenes; the background forms a prelude to covering the reactions of isocyanoalkenes up to early 2025. Attention is focused on the mechanisms and reactivity trends to provide a fundamental understanding of reactivity patterns to encourage future applications. The reactivity profiles and the mechanistic proposals are based on the authors’ insight and experience, which may differ from those of the original authors.

2

Isocyanoalkene Syntheses

2.1

Biosynthesis of isocyanoalkenes

Isocyanoalkenes comprise a niche subset of the 200 or so naturally occurring isocyanides.[1b] [8] The 30 naturally occurring isocyanoalkenes have been isolated from a range of terrestrial and marine sources. The isocyanide nitrogen in isocyanoalkenes appears to be derived solely from amino acids whereas, in isocyanoalkanes, the NC unit can also be biosynthesized by cyanide incorporation.[9]

Detailed labeling studies for the biosynthesis of the isocyanoalkene B-371 (2) and the E-diastereomer 3 demonstrated that the carbon scaffold and the isocyanide nitrogen were derived from tryptophan whereas the isocyanide carbon was derived from ribulose-5-phosphate 4 ([Scheme 1]).[10] Enzymes AmbI1, AmbI2,[11] or IsnA mediate the condensation of l-tryptophan 5 with ribulose-5-phosphate 4 to afford 6 that subsequently undergoes decarboxylation via 7, 8, or 9 to afford 2 or 3.[12] The decarboxylation involves an Fe(II)/2-oxoglutarate(2OG)–dependent oxygenase (IsnB or AmbI3) that is thought to activate the benzylic position by forming the radical 7 or carbocation 8. Subsequent decarboxylation either from one of the reactive intermediates 7 or 8, or via the hydroxycarboxylate 9, installs the olefin.[13] The E/Z-configuration of isocyanoalkenes is likely dictated by the geometry of the enzyme active site for 7 and 8, whereas the configuration of the hydroxyl group in 9 likely determines the alkene geometry via an anti-elimination. A related condensation of l-tyrosine 10 with ribulose-5-phosphate 4 afforded isocyanoacid 11 that suffered the same type of enzyme-mediated oxidative decarboxylation to afford 12, the aglycone of rhabduscin (21), and byelyankacin (22, see [Fig. 3]).[14]

Scheme 1 Biosynthesis of two isocyanoalkenes.

Eq. 1 Isocyanomethylenetriphenylphosphorane olefination.

Eq. 2 Addition of Grignards to isocyanoacrylates.

2.2

Naturally Occurring Isocyanoalkenes

Isocyanides have been isolated from an array of terrestrial and marine organisms.[9] Within these naturally occurring isocyanides, the isocyanoalkenes are a relatively small subset among which xanthocillin X is particularly meritorious in being the first isocyanide obtained from natural sources[4] and the only isocyanide developed into a commercial medicine.[5] Several related dityrosine-derived isocyanoalkenes[15] have been isolated, including the hydroxylated xanthocillins 13 and 14,[16] the reduced xanthocillans 15–17,[17] darlucins A and B (18 and 19, respectively) derived from fermentations of Sphaerellopsis filum ([Fig. 2]),[18] and the structurally related antibiotic MK4588 (20) isolated from Leptosphaeria l-179.[19]

Fig. 2 Xanthocillin-related isocyanoalkenes from natural sources.

Eq. 3 3-Component MCR of 3-dimethylamino-2-isocyanoacrylates.

Several mono-tyrosine-derived isocyanoalkenes have been isolated from terrestrial sources ([Fig. 3]). The isocyanoalkenes rhabduscin (21) and byelyankacin (22) were obtained from nematodes,[20] the bacterial metabolite paerucumarin (23) was extracted from a gene cluster amplified from P. aeruginosa,[21] and the diisocyanides 24–27 were isolated from a liquid culture of the fungus Ophiosphaerella korrae.[22]

Fig. 3 Mono-tyrosine-derived isocyanoalkenes.

Indisocin (28a) and N-methylindisocin (28b) were among the first isocyanoalkene antibiotics to be isolated from natural sources, in this case from cultured actinomycete strain MG323-hF2 ([Fig. 4]).[23] Antibiotic B371 (2),[24] another indole-containing congener, has been isolated from several sources though the geometric isomer 3 was only recently isolated.[25] Cytotoxic activity, as observed for brasilidine A (29), is not common among isocyanoalkenes, suggesting that the isocyanide is not the pharmacophore.[26]

Fig. 4 Indole-derived isocyanoindoles.

Antimalarial, antimicrobial, antibiotic, and antifouling activities are quite common for isocyanides.[2] The isocyanocyclopentenes isolated from Trichoderma soil species are no exception[27] with the isonitrin antibiotics A, B, E,[28] and F[29] (30–33), which contain a highly oxidized cyclopentene core ([Fig. 5]). The clovane isocyanide 34, with an embedded cyclopentene ring, obtained from Australian specimens of the nudibranch Phyllidia ocellata, showed modest antimalarial activity.[30]

Fig. 5 Isocyanocyclopentene-containing natural products.

The welwitindols and hapalindols have garnered significant interest because of the ability of some congeners to reverse multiple-drug resistance, although the isocyanoalkenes in the series do not exhibit this activity ([Fig. 6]).[1e] Welwitindolinone A isonitrile (35) and 12-epi-fischerindole I isonitrile (36) both exhibited fungicidal activity.[31] The related hapalindol I (37) was isolated from the cultured cyanophyte Hapalosiphon fontinalis, an organism with antibacterial and antimycotic activity,[32] whereas the dechloro analogue (38), isolated from Westiellopsis sp., did not show any bioactivity.[33]

Fig. 6 Isocyanoalkene-containing welwitindoles and hapalindols.

The remaining naturally occurring isocyanoalkenes are only vaguely structurally related in containing an oxidized carbon core ([Fig. 7]). The series of mirabilene isonitriles B–E (39–42) were isolated from the blue-green alga Scytonema mirabile and exhibited mild cytotoxic and antifungal activity,[34] whereas A32390A (43), an antimicrobial, was isolated from a Pyrenochaeta culture broth.[35]

Fig. 7 Linear isocyanoalkene with an oxidized carbon core.

The small number of naturally occurring isocyanoalkenes are generally found as congeners within a set of structurally related metabolites. The isocyanide group is thought to contribute to the bioactivities by interacting with nucleophilic sites in biological macromolecules, potentially disrupting essential cellular processes. The common isocyanide core in these natural products underscores the therapeutic potential of isocyanoalkenes, which warrants further investigation into the mode of action and potential for drug development.[3]

2.3

Overview of Isocyanoalkene Syntheses

Cyclohexylisocyanide is the only commercial isocyanoalkene available at less than $50 per gram.[9] All other isocyanoalkenes are synthesized by one of three general strategies involving, in roughly increasing frequency of deployment: eliminations of appropriately substituted isocyanoalkanes ([Scheme 2A], 44 → 45), isocyano-olefinations of aldehydes and ketones ([Scheme 2B], 46 → 47), and the dehydration of vinyl formamides ([Scheme 2C], 48 → 49).[36] The order parallels the ease of accessing the requisite precursors. Each method has specific advantages and disadvantages suited to different synthetic contexts; the main challenge with all three methods is control over the E/Z-geometry.

Scheme 2 The three general strategies to prepare isocyanoalkenes.

Isocyanoalkenes generated by E₂ elimination typically require quite strong bases because the protons adjacent to an isocyanide are only weakly acidic ([Scheme 2A]).[37] Lithium amide bases are the most often employed, which does impose limits on the functionality that is tolerated within the isocyanoalkane scaffold. Generally modest E/Z ratios of isocyanoalkenes are obtained because the small size of the isocyanide, a mere one-eighth the size of a methyl group,[38] leads to minimal bias in the transition structure involved in the E₂ elimination.

Modest steric discrimination results in mixtures of E/Z geometric isomers in most carbonyl olefinations with phosphorous ylide-type or silicon-based isocyanide nucleophiles unless the carbonyl has a significant sterically bias ([Scheme 2B], 46 → 47). The most common method for synthesizing isocyanoalkenes is via the dehydration of vinyl formamides, which has the dual advantages of being more functional group tolerant while faithfully translating the geometry of the vinyl formamide into the corresponding isocyanoalkene (48 → 49); the recent stereoselective synthesis of E- or Z-vinyl formamides makes the latter method particularly attractive.[39]

2.4

Eliminations of β-Substituted Isocyanoalkanes

A variety of β-substituted isocyanoalkanes readily form isocyanoalkenes through ejection of tosylates, phosphates, halides, and ethers. The eliminations are usually performed in THF at −78 °C, which maximizes the stereoselectivity ([Scheme 3]). In the unique case of isocyanoethylene (51), the KOH-induced elimination from benzenesulfonate 50 generates a rather unstable liquid that polymerizes on contact with ground glass joints.[40] A more representative sulfonate elimination is the conversion of mesylate 52 to isocyanoalkene 53 ([Scheme 3]), which is the methyl ester of an isocyanide-containing fungal metabolite (see [Fig. 5], isonitrin E).[30] The sulfonate-elimination strategy has been telescoped into a one-pot addition–sulfonylation–elimination sequence employing the addition of lithiated methylisocyanide to aldehydes (54a, R¹ = H) or ketones (54b); in situ trapping of the alkoxide with TsCl, warming to rt, and treatment with methanolic KOH directly afforded the isocyanoalkenes 55.[41] The closely related elimination of phosphate from the isocyanophosphate 56 afforded 57 as an 86:14 ratio of geometric isomers when performed at room temperature, which improved to 98:2 at −110 °C.[42]

Scheme 3 Isocyanoalkene syntheses involving β-eliminations.

There are surprisingly few eliminations of β-haloisocyanoalkanes, which likely reflects the paucity and instability of many haloisocyanoalkanes.[43] The eliminations are quite facile as illustrated for the quantitative conversion of 58 with KOH to isocyanoalkene 59, presumably as the E-diastereomer ([Scheme 4]).[44] An analogous series of eliminations with cyclic and acyclic iodoisocyanides 60 generated the corresponding isocyanoalkenes 61 with efficiencies that were independent of the relative geometry of the iodine and isocyanide substituents.[45] Even methoxy substituents are efficiently eliminated to afford isocyanoalkenes (62 → 63).[46]

Scheme 4 β-Eliminations of halides and ethers to afford isocyanoalkenes.

Dehydrating electron-rich vinyl formamides to generate isocyanides inverts the electronics with the electron-withdrawing isocyanide often facilitating the elimination of β-substituents under the basic dehydration conditions ([Scheme 5]). The facile elimination of acetate during the dehydration of vinylformamide 64 to 65 is likely facilitated even more because of the conjugating ester moiety.[47] The geometry is likely dictated by an E₂ transition structure in which the methyl group preferentially eclipses the small isocyanide rather than the larger benzyl ester. A very similar elimination occurred during the dehydration of the acetylformamide 66 to give isocyanoalkene 67.[48] In contrast to the acetate eliminations, treatment of 68 under the conventional in situ carbene conditions (CHCl₃, NaOH, Bu₄NBr) afforded primarily the isocyanoalkene 69 resulting from installation of the isocyanide followed by elimination of fluoride.[49]

Scheme 5 Vinylformamide dehydration-elimination to isocyanoalkenes.

The ring opening of epoxyisocyanoalkanes has been employed in the syntheses of several cyclic and acyclic isocyanoalkene natural products ([Scheme 6A]). Originally developed in the context of synthesizing the spirocyclic isocyanoalkene 72, the ring opening of 70 provided the hydroxyisocyanoalkene 71 that was elaborated into 72 isolated from a cultured broth of Trichoderma hamatum.[50] The epoxide-opening strategy was subsequently employed in the synthesis of desepoxyaerocyanidin ([Scheme 6B], 73 → 74).[51] The E/Z geometry derived from the ring opening was strongly dependent upon the nature of the base with lithium bis(trimethylsilyl)amide (LiHMDS) favoring the E-diastereomer and lithium diisopropylamide (LDA) favoring the Z-diastereomer.

Scheme 6 Formation of isocyanoalkenes via epoxides ring opening.

2.5

Carbonyl Olefinations

The direct condensation of aldehydes or ketones with ethyl isocyanoacetate does not afford isocyanoalkenes because the water eliminated during the condensation hydrolyzes the first-formed isocyanoalkene to the corresponding vinyl formamide ([Scheme 7], 54 → 75)[52]; analogous condensation-hydrolyses occur with aldehydes and ketones and metalated isocyanoacetamides[53] or arylsulfonyliso-cyanomethanides.[54] In contrast, isocyano-substituted phosphonates directly generate isocyanoalkenes without hydrolysis (54 → 76).[55] The method was featured in an efficient synthesis of the naturally occurring antibiotic B371 (2), though the E:Z selectively was only 2:3 (77 → 2).[56] Condensation of the unstable chlorophosphonate 78 with aldehydes and ketones 54 afforded α-chloroisocyanoalkenes 79 ([Scheme 7], unspecified yield)[57] and the antibiotics indoscin (28a) and N-methyl indoscin (28b).[58]

Scheme 7 Carbonyl condensations en route to isocyanoalkenes.

Isocyanomethylenetriphenylphosphorane,[59] like the corresponding phosphonates, efficiently converts aldehydes to isocyanoalkenes ([Eq. 1]). The phosphorane is best formed in situ by deprotonating the isocyanomethylphosphonium salt with potassium bis(trimethylsilyl)amide (KHMDS), which permits the olefination of a range of aldehydes (46 → 81). The E/Z selectivity is generally modest except with sterically demanding aldehydes, which provide very good selectivity for the Z-diastereomers.[60]

Most silicon-based olefinating reagents are prepared in situ because the isocyanomethylsilanes are typically unstable ([Scheme 8], 54 → 83).[61] For example, 82 was prepared by deprotonating Tosmic with butyllithium, trapping with Me₃SiCl, and then deprotonating 82 with BuLi before addition of the carbonyl to afford the isocyanoalkene 83.[62] An analogous procedure with the arylsulfanylisocyanide 85 efficiently provided the arythioisocyanoalkenes 86 with modest E/Z selectivity.[63]

Scheme 8 Isocyanoalkenes prepared via siloxide elimination.

2.6

Dehydration of Vinyl Formamides

The dehydration of vinyl formamides is the most common method to prepare isocyanoalkenes ([Scheme 9] provides representative examples).

Scheme 9 Representative vinyl formamide dehydrations to isocyanoalkenes.

The frequency[64] derives from the numerous routes to vinyl formamides and the reproducible, high-yielding dehydration that can be performed with a variety of reagents (in descending order of use): phosphorus oxychloride (87 → 88),[41] triphosgene (89 → 90),[65] phosgene (91 → 92),[66] TsCl (93 → 94),[67] and triflic anhydride (95 → 96).[68] Triflic anhydride is particularly effective for functionalized substrates as illustrated for 95 that was not able to be dehydrated with other reagents.[71] A variety of nitrogenous bases, typically triethylamine and diisopropylethylamine, are employed to neutralize the acid liberated during the dehydration, with diisopropylethylamine being particularly efficacious because the hydrochloride salt is readily removed with an aqueous wash.

In some instances, the vinyl formamides can be prepared and, without isolation, dehydrated to the corresponding isocyanoalkene ([Scheme 10]).[69] For example, addition of an organolithium to aromatic or aliphatic nitriles 97 generated the lithioimine 98 that was formylated and isomerized with CuCN to the vinyl formamide 100. The subsequent dehydration was achieved by the addition of phosphorus oxychloride to the same pot to directly provide isocyanoalkenes 101 from nitriles 97.

Scheme 10 Isocyanoalkenes via an addition–isomerization–dehydration.

2.7

Miscellaneous Isocyanoalkene Syntheses

Several miscellaneous reagents have been employed to access a diverse array of isocyanoalkenes ([Scheme 11]). Isomerizations of readily available “allyl isocyanides”[70] migrate the double bond to afford substituted isocyanoalkenes. Copper oxide is particularly efficacious in isomerizing allylic isocyanides 102 to trisubstituted isocyanoalkenes 103.[42] [71] DBU was employed for the isomerization of 104 to 105 in the context of a synthesis of an isocyanoalkene antibiotic.[30] An analogous isomerization of the propargylic isocyanide 106 employed KOH to afford isocyanoallene 107, which is rather unstable, and this likely caused the modest yield.[72]

Scheme 11 Isomerization routes to isocyanoalkenes.

Two different anionic strategies have been developed to prepare substituted isocyanoalkenes. Sequential deprotonation-trapping of isocyanoalkenes 108 installed an α-substituent on 109; the authors note a propensity for polymerization, which may be why the method has not seen service in the preparation of other isocyanoalkenes ([Scheme 12]).[73] Another deprotonation approach is the ring-opening of oxazoles followed by electrophilic trapping to provide C2-alkoxy-substituted isocyanoalkenes (110 → 111); the main challenge is the substrate- and electrophile-dependent selectivity for trapping on oxygen versus carbon, which limits the reaction scope.[74]

Scheme 12 Miscellaneous syntheses of substituted isocyanoalkenes.

An interesting condensation of the aminoacetal 112 with alkyl isocyanoacetates afforded several isocyanoalkenes 113 [75]; no hydrolysis of the isocyanide was observed, presumably because of consumption of water by the amino-orthoester. The deselenization of vinyl selenocyanates 114 with triethyl phosphite, triphenyl phosphine, or polymer-supported triphenylphosphine was used to access several isocyano-1,3-butadienes 115, the core unit of the xanthocillan antibiotics ([Scheme 12]).[76] Flash vacuum pyrolysis of 116 released reactive trifluoroisocyanoethylene 117 [77] that is stable in the gas phase but readily polymerizes once liquified.[78] The procedure allowed for sufficient material to be crystallized and analyzed by x-ray crystallography, which showed bond lengths similar to those of the isoelectronic trifluoroacrylonitrile.[80] [81]

3

Reactions of Isocyanoalkenes

The chemistry of isocyanoalkenes is very underexplored. The scarcity of reactions correlates with a limited understanding of isocyanoalkenes as an integrated functionality; in most cases, the reactions of the isocyanide and the alkene are independent. Of the two most common reactions of isocyanoalkenes—conjugate additions and radical additions—the former typically incorporate a strongly electron-withdrawing substituent that overrides any influence of the isocyanide on the alkene, while for radical reactions the alkene is generally not involved.

The paucity of reactions that engage both functionalities in one reaction is likely because the isocyanide and alkene functionalities lack essentially any conjugation.[41] Most reagents attack the more reactive isocyanide functionality leaving the alkene unscathed. The virtual absence of conjugation to unactivated isocyanoalkenes reflects the powerful electron-withdrawing effect of an isocyanide that removes more electron density from the α-carbon of the alkene than the β-carbon.[79] The reversed polarization of alkenes substituted with an isocyanide compared to the conjugating electron-withdrawing groups has a profound impact on reactivity. The divergent reactivity is captured in comparable reactions of isocyanoethylene and isoelectronic acrylonitrile with NaOEt; acrylonitrile 118 is rapidly polymerized despite being only weakly conjugated with the alkene,[80] whereas isocyanoethylene 51 is unreactive ([Scheme 13]).[40]

Scheme 13 Divergent reactivity of isocyanoethylene and acrylonitrile.

3.1

Conjugate Additions

Most conjugate additions to isocyanoalkenes require a strong α-substituted electron-withdrawing group such as an ester or sulfoxide ([Scheme 14]). Although the isocyanide is a powerful, inductive, electron-withdrawing group,[84] the polarization is only weakly relayed to the distal β-carbon of the alkene, which makes conjugate addition challenging. Substitution of a strong electron-withdrawing group on the alkene essentially dominates the reactivity by promoting nucleophile attack on the β-carbon ([Scheme 14], 119 → 120). Trapping the resulting anion 120 with an electrophile, either inter- or intra- molecularly (121a and 121b, respectively), affords acyclic or cyclic isocyanoalkanes in which two new bonds have been added to the α- and β-positions of the alkene.

Scheme 14 Conjugate additions to α-EWG-substituted isocyanoalkenes.

3.1.1

Conjugate Additions to α-EWG Substituted-Isocyanoalkenes

Conjugate additions to isocyanoacrylate 122 exhibit a surprising substrate scope.[81] Ethyl- and phenylmagnesium halides efficiently afford isocyanoacetates 123 although MeMgI afforded 123 in low yields ([Eq. 2]). The reaction conditions play a crucial role. In ether, insoluble magnesium enolates form that, upon workup, afforded good yields of 123. Conducting the conjugate addition in tetrahydrofuran (THF), or with Grignard reagents prepared in THF, resulted in homogeneous solutions that led to the isolation of 123 in significantly decreased yield. Presumably, the inductive and conjugating effect of the isocyanide and ester, respectively, create a very electrophilic β-carbon allowing a clean conjugate addition.

Although unstated, the advantageous use of ether might be to precipitate the enolate to prevent a competitive conjugate addition to the isocyanoacrylate 122. Support for this conjecture comes from the condensation of the enolates derived from diethyl malonate 125a or ethyl isocyanoacetate 125b with isocyanoacrylate 124 that afforded the corresponding isocyanoacetates 126a and 126b ([Scheme 15A]).[86] The related addition of isocyanoacetate 125b to 127b or 127c afforded the corresponding pyrroles 130 presumably through the same initial conjugate addition followed by cyclization ([Scheme 15B], 128→129), protonation, elimination of HCN, and isomerization.[86]

Scheme 15 Conjugate addition of enolates to isocyanoacrylates.

The conjugate addition of nitromethane to mono-substituted isocyanovinylsulfones 131 (R¹ ≠ H) proceeds through a similar sequence to afford nitro-substituted pyrroles 135 ([Scheme 16]).[82] The anion of nitromethane adds to 131 to afford the stabilized anion 132 that undergoes a series of proton transfers to afford the nitro-stabilized anion 133. Cyclization onto the pendant isocyanide leads to 134 that eliminates tolylsulfinate culminating, after a series of proton transfers, in the formation of the pyrrole 135. The absence of additions with substituted nitromethanes suggests a specificity that may be challenging to generalize.

Scheme 16 Nitromethane addition to isocyanovinylsulfones.

A closely related addition of primary amines to isocyanovinylsulfones has been used to prepare substituted imidazoles ([Scheme 17]).[83] Primary aliphatic amines work well except for t-BuNH₂, which is presumably too hindered to add conjugately (131 → 136); anilines afforded only traces of the corresponding imidazoles suggesting that they are insufficiently nucleophilic. A series of proton transfers (136 →137), cyclization (137 →138), and elimination of sulfinic acid afforded the imidazoles 139.

Scheme 17 Additions to isocyanovinylsulfones to afford imidazoles.

Isocyanovinylsulfones with a cis-γ-methylene are deprotonated at the γ-position to afford nucleophiles that trap cinnamaldehyde (141a) or electron-deficient N-imines (141b-c) to afford oxazoles or imidazoles, respectively ([Scheme 18A]).[84] The initial trapping occurs α to the isocyanide to generate an alkoxide or sulfonimide 142 that closes onto the isocyanide to afford 143; subsequent elimination of sulfinic acid afforded the oxazoles 144a or imidazoles 144b-c. Trapping the same anions with enones with aromatic substituents R⁴ _, redirected the anionic attack to a conjugate addition ([Scheme 18B]). Cyclization of the resulting enolate 146 onto the isocyanide led to pyrroline 147 that eliminated sulfinic acid to afford pyrrole 148. The γ-deprotonations provide a rapid route to substituted oxazoles and pyrroles that has not been utilized.

Scheme 18 γ-Deprotonation-additions of isocyanoalkenes.

Isocyanoenones 149 reacted with delocalized carbon, sulfur, and nitrogen centered nucleophiles in a CuI-catalyzed conjugate addition sequence leading to oxazoles 153 ([Scheme 19]).[85] Mechanistic analyses suggest that coordination of copper to the isocyanide activated the isocyanoenones 149 toward conjugate addition (150) leading to enolate 151. The subsequent cyclization afforded a C2-cuprated oxazole 152 that deprotonated the pronucleophile to complete the catalytic cycle; deuterium labeling showed that the pro-nucleophile delivered the proton to the cuprated oxazole 152 ([Scheme 19]).

Scheme 19 Cu-catalyzed conjugate addition to isocyanoenones.

3.1.2

Conjugate Additions to Unactivated Isocyanoalkenes

The addition of Ph₂PH and PhPH₂ to isocyanoethylene (51) constitutes two rare, special cases of conjugate additions to an isocyanoalkene devoid of an additional electron-withdrawing group.[86] The reaction benefits from pairing particularly nucleophilic phosphines with an isocyanoethylene having only hydrogen substituents on the alkene. Ph₂PH added once to isocyanoethylene (51) to afford 154 whereas the conjugate adduct 155 from the addition of PhPH₂ subsequently cyclized onto the isocyanide via 156 to form phosphazole 157 ([Scheme 20]). An analogous addition of Ph₂AsH to isocyanoethylene (51) afforded the conjugate adduct much less efficiently.[91]

Scheme 20 Phosphine conjugate additions to isocyanoethylene (51).

Copper salts have been particularly effective in promoting conjugate additions to isocyanoalkenes that are not substituted with electron-withdrawing groups. More than 50 years ago, diethyl malonate was reported to conjugately add to 1-isocyanoalkene 159, generated by in situ isomerization of allylisocyanide 158, to afford the cyclopropane 162 ([Scheme 21]).[87] Presumably Cu₂O serves as the base to facilitate the conjugate addition to afford 160, which is again deprotonated and oxidized by disproportionation with Cu₂O or air to afford 161; reductive elimination from 161 would generate the isocyanocyclopropane 162. The proposed mechanism is consistent with the requirement for stoichiometric Cu₂O. An analogous reaction with methyl or ethyl acetoacetate afforded the corresponding isocyanocyclopropanes in 29% and 17% yield, respectively.

Scheme 21 Copper catalyzed conjugation of allyl isocyanide.

Recently, a more efficient and more general conjugate addition to isocyanoalkenes was reported ([Scheme 22]).[88] NMR evidence supported the in situ formation of a copper Py-Ox complex 163 that reversibly complexed the isocyanoalkene 164 to form the nitrilium-like intermediate 165. The activation is sufficient for a variety of polarizable sulfur, nitrogen, and carbon centered nucleophiles to add to the activated isocyanoalkene 165 to afford 166 whose protonation releases 167 and turns over the catalytic cycle ([Scheme 22]).

Scheme 22 Copper-catalyzed conjugate additions to isocyanoalkenes.

Performing the conjugate addition with bromomalonate nucleophiles triggered a conjugation addition-cyclization producing a series of isocyanocyclopropanes 170 ([Scheme 23]). Key to forming the cyclopropane was intercepting the intermediate copper-stabilized isocyanide anion 169 in an intramolecular displacement ([Scheme 23], 169 → 170). Extending the conjugate addition-cyclization strategy to the allylchloride-malonate 172 efficiently provided the isocyanocyclohexane 173.

Scheme 23 Cu-catalyzed conjugate additions to isocyanoalkenes.

Applying the same copper-Pyox catalyst to conjugate additions of ethyl cyanoacetate to unactivated isocyanoalkenes 174 triggered a [4+1] decarboxylation–cyclization to form 2,3-dihydro-1-H-pyrroles 179 ([Scheme 24]).[89] Experimentally, the process used finely dispersed NaOH in THF (prepared by adding water to NaH, 3 equiv each) to deprotonate ethyl cyanoacetate. The resultant isocyanide-stabilized enolate initiated a conjugate addition to the isocyanoalkene 174 followed by a protonation transfer to generate 175. Subsequent cyclization onto the isocyanide carbon generated an imine anion whose protonation generated 176. The particularly nucleophilic hydroxide attacked the carboxyl to afford 177 that decarboxylated to the stabilized enaminonitrile anion 178 whose protonation afforded the enaminonitrile 179.

Scheme 24 Cu-catalyzed addition–cyclization–decarboxylations.

In an extension of the process, the pronucleophile isocyanonitrile 180 was treated with NaH and isocyanoalkene 174a to provide 183.[94] In this case, the conjugate addition generated the isocyanide-stabilized anion 181 that attacked the nitrile to generate the imine anion 182 that cyclized onto the isocyanide to afford 183 ([Scheme 25]).

Scheme 25 Copper-catalyzed conjugate addition–cyclization cascade.

The difficulty in performing conjugate additions to unactivated isocyanoalkenes led to a complementary strategy employing bromoisocyanoalkenes 184 as π-acceptors via a rare S_NV_π addition ([Scheme 26]).[90] Attack of NaSH on 184 led to the direct displacement of the bromide without causing a conjugate addition–elimination, a mechanism supported by several independent experiments.[91] Progression through the key transition structure 185 may well be facilitated by hydrogen bonding between the isocyanide and hydrogen sulfide during the S_NV_π displacement.[91] The resulting enethiol 186 was deprotonated to afford the nucleophilic enethiolate 187 that cyclized onto the isocyanide to provide a series of 4- or 5-substituted, or 4,5-disubstituted thiazoles 188 ([Scheme 26]).

Scheme 26 S_NV_π addition of NaSH to bromoisocyanoalkenes.

3.2

Radical Additions to Isocyanoalkenes

Isocyanides are excellent radical acceptors. The computed activation energy for the addition of an alkyl radical to an isocyanide is only ~13 kcal mol⁻¹, a low barrier that decreases further as the radical nucleophilicity increases.[92] The addition of a radical to an alkene is predicted to be similar to the rate of addition to an isocyanide[97] but in practice radical additions to isocyanides dominate over the addition of carbon and sulfur radicals to alkenes.[93]

One of the earliest radical additions to an isocyanoalkene was a clever annulation leading to cycloannulated pyridines ([Scheme 27A]).[94] Thermolysis of hexabutylditin in the presence of 5-iodopent-1-yne 190 generated a primary radical that added to isocyanoalkene 189 to form the imidoyl radical 191. A rebound cyclization onto the alkyne generated the vinyl radical 192 whose 6-endo-trig cyclization afforded azadiene radical 193. The conversion of radical 193 to the pyridine 194 is unclear, although air oxidation is likely. An analogous sequence with 5-iodopentanenitrile and isocyanoalkene 189a afforded the pyrazine 195 ([Scheme 27B]).

Scheme 27 Radical cycloannulations with isocyanoalkenes.

A very common strategy for radical additions to isocyanoalkenes is to generate imidoyl radicals via attack on the terminal carbon ([Scheme 28], 196 → 197).[95] The resulting imidoyl radicals are particularly versatile with additions to adjacent π-systems providing a highly delocalized radical 198.[96] Subsequent oxidation to the corresponding cation 199 followed by deprotonation restores the aromaticity to provide heterocycles (199 → 200).

Scheme 28 General design of radical additions to isocyanoalkenes.

3.2.1

Radical Additions to Isocyanoalkenes

Several substituted isoquinolines were prepared by the addition of aryl radicals to the aryl-substituted isocyanoalkene 201 ([Scheme 29]).[97] The requisite aryl radical was generated by reduction of the diaryliodonium salt 202 by a photoexcited iridium complex 207. Attack of the aryl radical onto the isocyanoalkene 201 generated the imidoyl radical 203 that cyclized onto the adjacent aromatic system forming the cyclohexadienyl radical 204. Oxidation of the cyclohexadienyl radical by the Ir^(IV) complex 208 regenerated the iridium catalyst 209 while generating the cation 205 whose deprotonation afforded the arylated isoquinoline 206.

Scheme 29 Photocatalyzed aryl radical addition to isocyanoalkenes.

A very similar addition–cyclization to aryl-substituted isocyanoalkenes 201 was developed using radicals derived from boronic acids ([Scheme 30]).[98] Manganese (III) oxidation of a series of arylboronic acids afforded the corresponding radicals that added to the terminal carbon of isocyanoalkenes 201 to generate the imidoyl radical 210. Subsequent cyclization to the dienyl radical 211, Mn (III) oxidation, and deprotonation of the resulting carbocation 212 provided the substituted isoquinoline 213. The manganese acetate procedure ([Scheme 30]) has the advantage over the corresponding photoredox process ([Scheme 29]) in permitting the incorporation of vinyl substituents from vinyl boronic acids; aliphatic boronic acids only returned unreacted isocyanoalkene. The procedure was further refined by employing hydrazines as the radical precursor and using catalytic manganese (III) with tert-butyl peroxybenzoate (TBPB) as the oxidant.[99]

Scheme 30 Manganese-mediated radical addition to isocyanoalkenes.

A photoredox addition of fluorocarbon radicals to isocyanoalkenes was developed to synthesize fluorine-containing heterocycles in response to the growing demand for diversified strategies to incorporate fluorine – an element found in ~20% of commercial pharmaceuticals.[100] Irradiation of fac-Ir(ppy)₃ (207) in the presence of the radical precursors 214 or 215 and isocyanoalkene 217 led to an efficient synthesis of fluorine-containing pyridines and isoquinolines 221 ([Scheme 31]). The sequence was initiated by reduction of the sulfonium salt 214 [101] or the bromofluorocarbon 215 [102] to generate the fluorocarbon radical 216. Addition of 216 to the isocyanoalkene 217 generated the imidoyl radical 218 whose cyclization onto the proximal alkene or aromatic yielded the delocalized radical 219. Subsequent oxidation by the Ir^(IV) complex 208 generated the carbocation 220 whose deprotonation led to the isoquinoline 221 ([Scheme 31]).

Scheme 31 Radical trifluoromethylation of isocyanoalkenes.

An interesting photoredox addition of trifluoroethyl radicals to isocyanoalkenes is unique among these type of radical additions in allowing both geometric isomers of the isocyanoalkenes to form isoquinolines ([Scheme 32]).[103] The E/Z isomerization occurs through an energy transfer from the excited photocatalyst that most likely occurs in the isocyanoalkene ground state (222 → 223 → 224). In a separate cycle, the excited photocatalyst reduces trifluoroethyl iodide 225 to generate radical 226 and iodide. Addition of 226 to the isocyanoalkene generated the imidoyl radical 227 that cyclized to afford 228. Oxidation of 228 by 208 afforded 229 that was deprotonated to rearomatize the ring and afford isoquinoline 230.

Scheme 32 Radical trifluoroethylation of isocyanoalkenes.

A related fluorination strategy was developed using the iodine (III) reagent 231 as the source of fluorocarbon radical ([Scheme 33]).[104] The initial reduction of 231 was achieved via an electron transfer from t-butyl ammonium iodide (TBAI). Attack of the resulting fluorocarbon radical 232 on the isocyanoalkene 233 generated the imidoyl radical 234 that cyclized to afford 235. Hexadienyl radical 235 is extremely acidic with a computed pK _a of −15.5 for R _f = CF₃.[105] Deprotonation of 235 by the carboxylate led to the radical anion 236 that transferred an electron to 231 to close the catalytic cycle.

Scheme 33 Periodinane-based isocyanoalkene radical addition–cyclization.

Catalytic palladium acetate was employed for the radical difluoroalkylation of several isocyanoalkenes to produce difluoroacylisoquinolines 244 ([Scheme 34]).[106] The palladium-based strategy has a slightly broader reaction scope in allowing a radical addition to trisubstituted isocyanoalkenes 240 with R¹ = H. Mechanistic studies are consistent with a one-electron transfer from palladium to the acyl bromide to produce the diflouroalkyl radical 239 and a Pd(I)Br complex. Attack of the diflouroalkyl radical onto the isocyanoalkene generated imine radical 241 that cyclized to produce the cyclohexadiene radical 242. Based on earlier mechanistic studies (see [Scheme 32]),[109] the rearomatization most likely occurs by deprotonation to form radical anion 243 that reduces Pd(I)Br to generate the isoquinoline and regenerate Pd(0).

Scheme 34 Palladium-catalyzed radical addition to isocyanoalkenes.

A different transition metal-radical approach uses copper and difluoroesters and amides to afford fluorinated isoquinolines ([Scheme 35]).[107] The catalyst 251 derived from CuBr and 4,4′-di-t-butyl-2,2′-dipyridine is suggested to react with B₂Pin₂ and NaOAc to generate the copper(I) complex 252 that abstracts a bromine atom from BrCF₂CO₂Et (245) or BrCF₂CONR₂ to afford the fluorinated radical 246. Addition of radical 246 to the isocyanoalkene 240 afforded imine radical 247 that added to the aromatic ring to generate 248. Reduction of 248 by copper complex 253 returns 251 to the catalytic cycle and affords 249 that is deprotonated to afford the isoquinoline 250. The sequence was also performed using photoredox conditions {fac[Ir(ppy)₃], blue LEDs, Na₂CO₃} to generate radical 246 for isocyanoalkenes in which R¹ = H (3 examples, 72–74%); the catalytic cycle follows that given in [Scheme 32].

Scheme 35 Cu-catalyzed radical addition to isocyanoalkenes.

Microwave irradiation of a benzene solution comprised of t-butyl hydroperoxide (TBHP), Fe(acac)₂ (5 mol%), DBU (10 mol%), isocyanoalkene 254, and 20 equiv of an ether, amine, or thioether afforded a range of substituted isoquinolines 255 ([Scheme 36]).[108] A UV–visible titration is consistent with a strong ligation of DBU to iron suggesting that an iron–DBU complex is involved in reducing TBHP to the t-BuO radical. Subsequent abstraction of a hydrogen atom adjacent to the ether, thioether, or amine 256 (present in a 20-fold excess) facilitated selective formation of the corresponding radical 257. Addition of 257 to the isocyanoalkene 254 generated imidoyl radical 258 that cyclized to afford the cyclohexadienyl radical 259. The precise order in which 259 is converted to the isoquinoline 255 is unclear; either oxidation by Fe³⁺(OH) is followed by deprotonation or DBU may deprotonate the acidic radical followed by oxidation by Fe³⁺(OH) complex. In either case, the net result is loss of one electron and a proton to regenerate the iron catalyst.

Scheme 36 Iron-catalyzed radical addition to isocyanoalkenes.

An iron(II) catalyst allowed the reductive ring opening of cyclobutanone oximes to generate radicals for additions to isocyanoalkenes ([Scheme 37]).[109] Fe(OTf)₂ was found to be the catalyst of choice, which reduced the weak N–O bond of activated cyclobutanone oxime ester 261 to form iminyl radical 262. Ring opening of 262 generated the alkanenitrile-containing radical 263, which added to isocyanoalkene 260 to form iminyl radical 264. Cyclization of 264 to 265 is likely followed by deprotonation and SET to the Fe(III) complex to afford the isoquinoline 266 and regenerate the Fe(II) catalyst ([Scheme 37]).

Scheme 37 Addition of radicals to isocyanoalkenes.

The combination of silver and potassium thiosulfate facilitated a one-electron oxidation–decarboxylation to generate radicals that added to a series of isocyanoacrylates 267 to afford isoquinolines 271 ([Scheme 38A]).[110] The silver-induced decarboxylation generated a radical that added to isocyanoacrylate 267 to generate imidoyl radical 268. Cyclization of 268 to the cyclohexadiene radical 269 was followed by oxidation by peroxydisulfate and/or sulfate radical anion to generate carbocation 270 whose deprotonation generated the isoquinoline 271. The reaction worked best with acids that generate electron-rich radicals, which is consistent with the first step of the mechanism involving nucleophilic attack of the radical onto the isocyanide. The method was subsequently applied to a series of uronic acids, sugar carboxylates, to access glycosylated isoquinolines 273 from 272 ([Scheme 38B]).[111]

Scheme 38 Silver-mediated radical additions to isocyanoalkenes.

A TBHP cyclization cascade was developed using iodide as the radical initiator with ketoxime 274 and isocyanoalkene 277 to afford substituted isoquinolines 280 ([Scheme 39]).[112] Microwave irradiation of TBAI provided the electron to oxidize t-BuOOH to the corresponding t-BuO radical. Subsequent hydrogen atom abstraction from the β,γ-unsaturated ketoxime 274 triggered a 5-exo-trig cyclization from 275 to generate the isoxazole carbon-centered radical 276; subsequent addition to the isocyanoacrylate 277a or amides 277b or 277c afforded the imidoyl radical 278. Cyclization onto the aromatic ring (278 → 279) then generated the cyclohexadiene radical 279. Collapse of the cyclohexadiene radical 279 to the isoquinoline 280 likely occurred through deprotonation to a radical anion followed by reduction of I₂ to regenerate iodide ([Scheme 39]).

Scheme 39 Iodide-catalyzed radical additions to isocyanoalkenes.

The same type of peroxide reduction process was employed to add hydroxyl-stabilized carbon radicals to isocyanoalkenes 281 to generate hydroxylalkylated isoquinolines 286 ([Scheme 40A]).[113] Microwave irradiation of TBPB caused fragmentation to generate a t-butoxy radical that abstracted the α-hydroxyl hydrogen of alcohol 282 to afford the α-hydroxyl-stabilized radical 283.[114] The alcohol, which is employed as the solvent, can be methanol or cyclic or acyclic secondary alcohols; the resulting radical 283 attacked the isocyanide to generate imidoyl radical 284 that cyclized onto the aromatic ring to generate the cyclohexadienyl radical 285. The optimal amount of DBU was 30% suggesting that the deprotonation of 285 generated the cyclohexadienyl radical anion that reduced TBPB to regenerate catalytic t-BuO radical and the isoquinoline. The fate of the benzoyl radical is unclear; at 120 °C decarboxylation to a phenyl radical followed by hydrogen atom abstraction from the alcoholic solvent is likely. The same method was applied to a series of cyclic and acyclic ethers, again used as the solvent, to prepare ether-substituted isoquinolines 286' ([Scheme 40B]).[115]

Scheme 40 Addition of α-hydroxy radicals to isocyanoalkenes.

Scheme 41 Alkyl radical addition to isocyanoalkene.

A closely related peroxide-induced radical addition was developed for the addition of a cyclohexyl radical to isocyanoalkenes 287 ([Scheme 41]).[116] Microwave irradiation of TBPB was employed to generate a t-butoxy radical that abstracted a hydrogen atom from 288 to afford the iminyl radical 289. Attack of the aromatic onto the radical led to the cyclohexadienyl radical 290 whose rearomatization was accomplished with DBU and the t-BuO radical to afford 291.

The addition of acyl radicals to isocyanoalkenes was achieved through hydrogen atom abstraction from aromatic aldehydes to give acyl-substituted isoquinolines ([Scheme 42]).[117] A ligand exchange between phenyliodine(III) diacetate (PIDA) and TMSN₃ generated iodinane 291 containing a weak N-I bond that fragmented under mild heating to azide radical 292 and iodinane radical 293. The azide radical abstracted a hydrogen atom from the aldehyde 294 to generate acyl radical 295 that added to the isocyanoalkene 290 to afford 296. The subsequent cyclization of 296 to the cyclohexadienyl radical 297 was followed by oxidation to 298 whose deprotonation generated the acylisoquinoline 299 ([Scheme 42]).

Scheme 42 Addition of acyl radicals to isocyanoalkenes.

3.3

β-Dimethylaminoisocyanoacetates

β-Dimethylaminoisocyanoacetates 300 are a special type of isocyanoalkene with an ambiphilic push-pull reactivity induced by conjugation between the electron-rich dimethylamine and the electron-deficient ester. The combination increases the electron density adjacent to the isocyanide, increasing the nucleophilicity resulting in facile reactions with electrophiles. For example, alkyl iodides and allyl bromide alkylate the terminal isocyanide carbon of 300a to afford nitriliums 301, which are rapidly attacked by the nucleophilic nitrogen to form ammoniums 302 ([Scheme 43]).[118] Subsequent halide-induced demethylation releases a methyl halide to regioselectively generate methylated imidazoles 303.

Scheme 43 3-Dimethylamino-2-isocyanoacrylate alkylation–cyclization.

Methyl 3-dimethylamino-2-isocyanoacrylate (300a) reportedly reacted with acid chlorides to afford 2-acyl-1-methyl imidazoles by acylation followed by attack by methylamine (cf. [Scheme 43]). However, the acylation of methyl or ethyl 3-dimethylamino-2-isocyanoacrylate (300) with acid chlorides was later found to afford oxazolones 306 ([Scheme 44])[119] via the chloroimidate 304 generated by isocyanide insertion. Facile ionization of 304 to the nitrilium 305 led to preferential attack by the carboxyl oxygen followed by chloride-induced dealkylation. Evidently, the potential amine cyclization in 305 is slower than attack by the carbonyl oxygen, probably because the sp² hybridized nitrogen has an in-plane methyl group preventing attack on the nitrilium (cf. [Scheme 43], 301 → 302), whereas the carbonyl oxygen lone pair is perfectly aligned for a 5-endo-dig cyclization ([Scheme 44], 305 → 306).

Scheme 44 Acylation-cyclization of 3-dimethylamino-2-isocyanoacrylates.

A very similar insertion–cyclization sequence occurs upon exposure of 3-dimethylamino-2-isocyanoacrylates (300) to o-nitroarylsulfenyl chlorides ([Scheme 45]).[120] Isocyanide insertion into the o-nitroarylsulfenyl chloride to generate 307 is followed by ionization to nitrilium 308 that cyclized to afford oxazolone 309 ([Scheme 45]).

Scheme 45 3-Dimethylamino-2-isocyanoacrylate sulfenylation–cyclization.

Arylsulfenyl chlorides lacking the o-nitro substituent react with 3-dimethylamino-2-isocyanoacrylates (300) via two successive additions leading to imidoyloxazolones 316 ([Scheme 46]).[121] The initial isocyanide insertion to afford 310 is followed by sulfenylation of the electron-rich alkene (310 → 311), possibly because cyclization of the ester is no longer favorable because of the greater substitution and because the thioimidoyl chloride is less electrophilic when lacking the electron-withdrawing o-nitro substituent (cf. 304 in [Scheme 44]). The resulting iminium 311 is demethylated by chloride to afford imine 312 that ejects chloride to form the nitrilium 313. The adjacent nucleophilic imine then cyclized onto the nitrilium to afford iminium 314 that was attacked by another equivalent of the isocyanide 300 whose slender terminus is readily able to reach the hindered imine. Cyclization of the resulting nitrilium 315 parallels the earlier cyclization ([Schemes 44] and [45]) leading to the imidoyloxazolone 316. The process is remarkably efficient considering the number of bond constructions.

Scheme 46 Double arylsulfenyl chloride addition to isocyanoacrylates.

Exposure of methyl 3-dimethylamino-2-isocyanoacrylate (300a) to hydrogen sulfide afforded thiazole 319 ([Scheme 47A]).[122] The sequence likely involved protonation of the amine followed by hydrogen sulfide addition and elimination of dimethylamine (317 → 318), based on mechanistic analyses in a related system;[95] the dominant conjugation of the ester dictates the addition–elimination mechanism rather than an S_NV_π addition as occurs with isocyanoalkenes devoid of conjugating substituents[90]. The subsequent cyclization of the enethiol 318 is quite facile leading, after proton transfers, to the thiazole 319. Analogous additions of primary amines to aminoisocyanoacrylate 300a generated the corresponding imidazoles 320 via a similar reaction pathway ([Scheme 47B]).[123]

Scheme 47 Azole formation from 3-dimethylamino-2-isocyanoacrylates.

The high efficiency of the conjugate addition–cyclization to 3-dimethylamino-2-isocyanoacrylate (321) stimulated adapting the method for solid phase synthesis ([Scheme 48]).[124] Employing isocyanoacrylate 321 in which the carboxyl was bound to Wang resin provided a versatile route to 1-substituted 4-imidazole carboxylates 324 ([Scheme 48]).[128] Conjugate additions of several amines were performed at 220 °C to provide 322 that subsequently cyclized onto the isocyanide in a 5-endo-dig process to afford the resin-bound imidazole 323. Subsequent release by exposure to TFA afforded 324.

Scheme 48 Solid phase-tethered 3-dimethylamino-2-isocyanoacrylate.

3.3.1

Multicomponent Reactions of β-Dimethylaminoisocyanoacetates

Several 3-dimethylamino-2-isocyanoacrylates have been employed in multicomponent reactions ([Eq. 3]).[125] A series of 3-dialkylamino-2-isocyanoacrylates 322 were prepared in a high-throughput synthesis program using a secondary amine, N-formylimidazole diethylacetal, and methyl isocyanoacetate. The three-component coupling of the isocyanoacrylates 322, an aldehyde, and an acid afforded a library of 4620 α-oxygenated amides 323.

A four-component condensation of 3-dimethylamino-2-isocyanoacrylate 300 with hydrazoic acid, an aldehyde, and an imine afforded fused tetrazoles 330 ([Scheme 49]).[126] Simply mixing the reagents in methanol, using trimethylsilyl azide as the HN₃ precursor, triggered the condensation to give azide 327 that cyclized via sigmatropic rearrangement to afford 328 (or 329 depending on the substituents); cyclization to 328 is reversable, allowing the reaction to funnel over to 329. In situ 6-endo-trig cyclization of 329 under acidic conditions afforded the tetrazoles 330; under the same conditions, 328 converged to 330 via cycloreversion to 327, cyclization to 329, and then a second cyclization to 330.

Scheme 49 4-Component MCR of 3-dimethylamino-2-isocyanoacrylate.

A direct route to thiazoles was developed by substituting a thiocarboxylic acid in the 4-component condensation with 3-dimethylamino-2-isocyanoacrylate 300, an amine, and an aldehyde ([Scheme 50]).[127] The iminium formed by condensation of an aromatic or aliphatic aldehyde with a primary amine was intercepted by 300 to form a nitrilium that was captured by the thioacid to form the thioamide 331. The thioamide 331 is in equilibrium with the enol form 332 that cyclized via an addition–elimination to form the thiazole 333.

Scheme 50 Thioacid MCR with 300 to afford thiazoles.

The thioacid route to thiazoles was extended to a resin-bound synthesis by using amines bound to the Rink amide resin ([Scheme 51]).[127a] [128] Condensation of methyl 3-dimethylamino-2-isocyanoacrylate (300a) with the Rink amide resin, an aldehyde, and a thioacid afforded resin-bound thiazoles 335 that were cleaved to provide a library of 4-carboxy-2-acylaminomethylthiazoles 336. Various aliphatic, aromatic, and heteroaromatic aldehydes with thioacetic acid and thiobenzoic acid worked well.

Incorporating a thioacid within the amine 337 led to a very clever three-component synthesis of β-lactam-containing thiazoles 342 with 3-dimethylamino-2-isocyanoacrylate (300) and an aldehyde ([Scheme 52]).[129] Condensation of the amine with the aldehyde created an equilibrium between 338 and the iminium 339 that was intercepted by the isocyanide to generate a nitrilium that was attacked by the adjacent thioacid to afford 340. Intramolecular ring contraction via attack on the electrophilic thiolactone with concomitant ring opening afforded the β-lactam 341. Subsequent cyclization of 341 via an addition–elimination installed the thiazole in 342. In an extension of the method [Scheme 52B], the isocyanoalkene 300b was treated with isobutyraldehyde and aminothioacid 337a to afford thiazole 342a in which the thiazole contains a 4-pyridyl substituent rather than an ester (cf. 342 and 342a).

Scheme 51 Solid phase thiazole synthesis with 330a.

Attempts to extend the thiazole synthesis to a three-component condensation with methyl 3-dimethylamino-2-isocyanoacrylate (300a), an aldehyde, and a thioacid have been modestly successful ([Scheme 53]).[130] BF₃.OEt₂ was the best Lewis acid for activating the aldehyde toward attack by the isocyanide, which resulted in the formation of the nitrilium 343. Subsequent attack by the thioacid afforded 344 that underwent intramolecular trans-acylation to 345 via an addition–elimination sequence affording the thiazole 346. The reaction gave modest yields with three thioacids: thioacetic acid, thiotrifluoroacetic acid, and thiobenzoic acid. The inefficiency of the sequence is perhaps, in part, offset by providing a very rapid route to thiazoles 346.

Scheme 52 Three-component couplings to afford β-lactam-thiazoles.

Scheme 53 BF₃-MCR with methyl 3-dimethylamino-2-isocyanoacrylate.

3.4

β-Bromomethyl-2-isocyanoacrylates

3-Bromomethyl-2-isocyanoacrylates (347, BICA) were developed as more reactive alternatives to the 3-dimethylamino-2-isocyanoacrylates (Section 3.3).[131] The β-bromine substituent facilitates the addition–elimination step and avoids protonation, which is required to eject dimethylamine from 3-dimethylamino-2-isocyanoacrylates. The addition of primary amines is facile resulting in 1,5-disubstituted imidazoles 348 ([Scheme 54A]).[132]

Scheme 54 Thiazoles from 3-bromomethyl-2-isocyanoacrylates.

BICA 347 reacts with hydrogen sulfide to produce thiazoles 349 ([Scheme 54B]).[133] The reaction is very efficient with one important caveat: the cyclization requires a cis geometry between bromine and the isocyanide. In some cases, the E-isocyanoalkene is unable to cyclize,[134] although the presence of excess amine allowed in situ equilibration such that both isomers were able to cyclize. [133]

Addition of NaOCH₂Ph in THF to 350 afforded isocyanoester 351 in which both conjugate addition–elimination and transesterification has occurred ([Scheme 55A]).[134] Performing the analogous reaction with NaOMe in MeOH resulted in the formation of the acetal 352 in which two equivalents of methanol added to the olefin, presumably by an addition–elimination followed by addition–protonation ([Scheme 55B]).

Scheme 55 Alkoxide additions to 3-bromomethyl-2-isocyanoacrylates.

The addition of benzyloxyamine or t-butyl carbazate to 353 afforded the corresponding 5-substituted imidazoles 354 and 355, respectively ([Scheme 56]).[135] The addition proceeded smoothly in DMF at room temperature with alkyl- or aryl-substituted 3-bromomethyl-2-isocyanoacrylates.

Scheme 56 Addition of nitrogen nucleophiles to 3-bromomethyl-2-isocyanoacrylates.

Miscellaneous Reactions

Isocyanocyclohexene (356) has been touted as a “convertible isocyanoalkenes” in mulitcomponent reactions where the role of the alkene is to facilitate cleavage of the resulting amide ([Scheme 57]); in these applications, only the terminal isocyanide carbon is incorporated into the target.[136] For example, the four-component reaction of isocyanocyclohexene (356) afforded enamide 357 for which hydrolysis to the corresponding ester 358 was significantly more facile than most amide hydrolyses.[62]

Scheme 57 Isocyanocyclohexene 354 as a “convertible isocyanoalkene.”

The multicomponent reactions of isocyanoethylene (359a) and isocyanoallene (359b) were explored using imines derived from formaldehyde and t-butylamine or allylamine in a four component reaction to afford 360 and a three component reaction to afford 361 ([Scheme 58A],B, respectively).[137] The resulting α-acyloxy amides were formed in yields a little lower than in comparable multicomponent reactions reflecting the high instability of these isocyanoalkenes; vinyl, propargyl, and allenyl isocyanides are not stable for more than a few days at −30 °C with isocyanoallene undergoing explosive polymerization at room temperature.[138]

Scheme 58 Multicomponent reactions with reactive isocyanoalkenes.

A series of three-component condensations employing the isocyanoacrylate 362, a carboxylic acid, and an aldehyde were performed to generate a small library of dehydroamino acid analogues of azinomycin antitumor antibiotics ([Scheme 59A]).[139] Several analogues 363 incorporated an aziridine to mimic the structure of the azinomycins. The presence of pyridine was essential for the condensation, which otherwise afforded only decomposed materials.

Scheme 59 Multicomponent reactions with isocyanoalkenes.

A similar multicomponent condensation to potential anticancer agents employed indole-3-ethenamide 364 analogues as a potential pharmacophore. The strategy employed a series of amino acids as the acid component, premade imines, and an indole-3-ethenamide as illustrated for the synthesis of aspergillamide A 365 ([Scheme 59B]); minimal experimental conditions were provided for the generation of the library of analogues.[140]

[Cp^*RhCl₂]₂ (366) catalyzed the addition of trifluorodiazoethane to isocyanoalkenes 367 to afford isoquinolines 373 by coupling the two carbenoid centers ([Scheme 60]).[141] Complexation of the rhodium catalyst to the isocyanoalkene 367 likely afforded complex 368, which then complexed trifluorodiazoethane and, after nitrogen loss, generated carbene 369. Rhodium-catalyzed coupling of the two carbenoids would generate the ketenimine 370, whose complexation with AgOTf is likely sufficient activation for an intramolecular cyclization 371 → 372. Subsequent deprotonation would afford isoquinoline 373.

Scheme 60 Trifluoroalkylation of isocyanoalkenes via Rh catalysis.

A thermal dimerization of isocyanoalkenes was developed as a rapid route to bipyridines ([Scheme 61]).[142] The dimerization of isocyanides has not been observed directly so the mechanistic details remain unclear.[143] The thermal dimerization of isocyanoalkene 374 is presumed to assemble the core 1,4-diazatriene of 375 which provides two 6-π systems for thermal electrocyclization. The resulting dimer 376 isomerizes to form one pyridine ring, while the other forms a dihydropyridine that is readily oxidized, presumably in air, to afford the dipyridine 377. Particularly interesting is the crossed dimerization of isocyanoalkenes 374 with isocyanoarenes 378 to form nonsymmetrical bis-arenes 379 [Scheme 61B]. The ability to form crossed dimers implies that the crossed dimerization is easier than the homodimerization, which correlates with the higher temperature required for these dimerizations than for analogous reactions of isocyanoalkanes and isocyanoarenes.[144]

Scheme 61 Dimerization and 6 π electron cyclization of isocyanoalkenes.

A palladium-catalyzed addition of an O-benzoyl hydroxylamine to isocyanoalkenes 380 provided an insertion–cyclization route to isoquinolines 386 ([Scheme 62]).[144] The catalytic cycle likely involved coordination of isocyanide to generate the isocyanide-complexed palladium (0) catalyst because palladium, like most transition metals, binds strongly to isocyanides.[145] Subsequent oxidative insertion of palladium complex 381 into the weak N–O bond of 382 increases the oxidation state of palladium in 383, which facilitates insertion into the isocyanide to afford metalated imine 384. A ligand exchange with CsOPiv triggered a concerted metalation–deprotonation to afford the cyclopalladated imidate 385 whose reductive elimination afforded the isoquinoline 386 and returned the zero-valent palladium back to the catalytic cycle.

Scheme 62 Palladium-catalyzed isocyanoalkene insertion–cyclization.

A related palladium insertion with isocyanoalkenes 388 provided imidazolones 392 ([Scheme 63]).[50] The cyclization required preforming a palladium complex from the aryl iodide and TMEDA to afford 20 mol% of the presumed catalyst 387. Complexation of catalyst 387 to the isocyanide 388 afforded 389. Subsequent insertion into the isocyanide to form 390 parallels 382 → 383 → 384 ([Scheme 62]). Formation of 390 positions the electrophilic palladium proximal to the nucleophilic amide that, in the presence of t-BuOK, triggered cyclization to the palladacycle 391. Reductive elimination from 391 released the imidazolone 392 allowing palladium to reinsert into the aryl iodide to regenerate active catalyst 387.

Scheme 63 Isocyanoalkene synthesis mechanism from isocyanoalkenes.

Isocyano-stabilized anions are difficult to form and have a propensity to self-condense; both issues likely contribute to the dearth of deprotonations of isocyanoalkenes.[41] Exposure of 393 to one equivalent of LDA followed by trapping with an alkyl halide afforded the α-alkylated isocyanoalkenes 396 through a sequence of deprotonation–alkylation (394 → 395) followed by isomerization to the more stable tetra-substituted alkene ([Scheme 64], 395 → 396).[48] An analogous deprotonation–acylation with chloroformate required two equivalents of LDA and afforded the deconjugated isocyanoester 397 ([Scheme 64])[47]; in this case, the more stabilized α-anion is protonated to afford the deconjugated isocyanoester 397. The isocyanoalkenes were found to be particularly sensitive to silica gel chromatography resulting in modest isolated yields; subsequent researchers have described the use of silanized “C2-silica” that is particularly useful for purifying sensitive isocyanoalkenes and isocyanoalkanes.[146]

Scheme 64 Alkylation of an isocyanoalkene.

4

Conclusion

Isocyanoalkenes are unusual π-substituted alkenes. About 30 occur naturally in both terrestrial and marine organisms where they are biosynthesized from amino acids. Most of the biochemistry, and the chemistry, is dictated by the isocyanide, which is considerably more reactive than the alkene; the isocyanide has virtually no conjugation with the alkene. The largely inductive polarization of the alkene by the isocyanide has a profound effect on the reactivity, which differs significantly from alkenes substituted with conjugating substituents.

Isocyanocyclohexene is the only commercially available isocyanoalkene at a cost of less than $50/g, so all other isocyanoalkenes must be prepared. There are three main synthesis methods: elimination of β-substituted isocyanoalkanes, olefination, and dehydration of vinyl formamides. Among the three methods, the latter is the preferred synthesis method because several syntheses of vinyl formamides are available with control over the E/Z-geometry, which is otherwise challenging because of the small size of the isocyanide.

The chemistry of isocyanoalkenes is divided into conjugate additions to the alkene carbon, radical addition to the isocyanide carbon, and numerous miscellaneous reactions. Typically, conjugate additions to isocyanoalkenes require strong electron-withdrawing groups to polarize the alkene and stabilize the resulting anion, trapping of which provides a valuable route to substituted isocyanoalkanes. Only recently has a general conjugate addition been extended to substrates devoid of electron-withdrawing groups. The key is activation by a copper complex that reversibly coordinates to the isocyanide, which activates the β-carbon toward conjugate addition.

Several radical additions to β-aryl-substituted isocyanoalkenes have been developed over the last decade. They invariably involve addition to the isocyanide to generate imidoyl radicals that add to adjacent π-systems through a cascade sequence that provides a rapid entry to substituted isoquinolines.

Two particularly versatile isocyanoalkenes are dimethylaminoisocyanoacrylates and bromoisocyanoacrylates. The combination of a nucleophilic isocyanide and a good leaving group on the alkene allows for two sequential additions with bis-nucleophiles in a rapid route to nitrogenous heterocycles: pyrroles, imidazoles, and thiazoles.

Among the miscellaneous reactions of isocyanoalkenes, some take advantage of the relatively facile conversion of isocyanoalkenes to nitrilium ions, which can be harnessed in multicomponent reactions. Other miscellaneous reactions include deprotonation-alkylations and transition metal-catalyzed reactions, which invariably proceed by an initial coordination with the isocyanide.

Several recent advancements in synthesizing isocyanoalkenes are likely to accelerate future developments. Researchers are starting to apply the rich multiple bond-forming sequences of isocyanoalkanes to the lesser-investigated isocyanoalkenes. As more becomes known about the fundamental reactivity profile of this unusual system, there are likely to be an increasing number of advancements to use isocyanoalkenes in forming complex heterocycles, which bodes well for their use in future multiple bond-forming sequences.

Dr. Huan Tian

Huan Tian completed his bachelor’s degree at Arizona State University. After earning his master’s degree, he pursued a Ph.D. under the mentorship of Professor Fraser Fleming at Drexel University, where he explored the reactivity of unsaturated isocyanides. He is currently working in industry, focusing on the design and synthesis of haptens for the development of lateral flow immunoassays.

Fraser Fleming

Fraser Fleming completed a BS (Hons.) at Massey University, New Zealand, before moving to University of British Columbia, Canada where he completed a PhD under the direction of Edward Piers. After postdoctoral research with James D. White at Oregon State University he joined the faculty at Duquesne University, Pittsburgh. In 2013 he took a two-year position as a Program Director at the National Science Foundation working in the Synthesis and the Catalysis Programs before moving to Drexel University in 2015 where he is a Professor of Chemistry. His research interests lie in stereochemistry and organometallics, science and religion, and creativity.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1a Edenborough MS, Herbert RB. Nat Prod Rep 1988; 5: 229-245
• 1b Garson MJ, Simpson JS. Nat Prod Rep 2004; 21: 164-179
• 1c Emsermann J, Kauhl U, Opatz T. Mar Drugs 2016; 14: 16
• 1d Schnermann M, Shenvi RA. Nat Prod Rep 2015; 32: 543-577
• 1e Hohlmann RM, Sherman DH. Nat Prod Rep 2021; 38: 1567-1588
• 2 Massarotti A, Brunelli F, Aprile S, Giustiniano M, Tron GC. Chem Rev 2021; 121: 10742-10788
• 3 Rothe W. Dtsch Med Wochenschr 1954; 79: 1080-1081
• 4 Ahrens CBFW, Bärwald G. PharmacoEconomics 1971; 26: 100-107
• 5a Sakai R, Nakamura T, Nishino T. et al. Bioorg Med Chem 2005; 13: 6388-6393
• 5b Chang CWJ. Prog Chem Org Nat Prod 2000; 3-189
• 6 Hübner I, Shapiro JA, Hoßmann J. et al. ACS Cent Sci 2021; 7: 488-498
• 7 Based on a series of SciFinder searches performed on 19 Jan. 2024
• 8 Emsermann J, Kauhl U, Opatz T. Mar Drugs 2016; 14: 1-83
• 9 Zhang X, Evanno L, Poupon E. Eur J Org Chem 2020; 1919-1929
• 10 Brady SF, Clardy J. Angew Chem, Int Ed 2005; 44: 7045-7048
• 11 Hillwig ML, Zhu Q, Liu X. ACS Chem Biol 2014; 9: 372-377
• 12 Chang W-C, Sanyal D, Huang J-L, Ittiamornkul K, Zhu Q, Liu X. Org Lett 2017; 19: 1208-1211
• 13 Yu C-P, Tang Y, Cha L. et al. J Am Chem Soc 2018; 140: 15190-15193
• 14 Zhu J, Lippa GM, Gulick AM, Tipton PA. Biochemistry 2015; 54: 2659-2669
• 15 Lim FY, Won T, Raffa N. et al. mBio 2018; 9: e00785-18
• 16 Achenbach H, Strittmatter H, Kohl W. Chem Ber 1972; 105: 3061-3066
• 17 Morino T, Nishimoto M, Itou N, Nishikiori T. J Antibiot 1994; 47: 1546-1548
• 18 Zapf S, Hossfeld M, Anke H, Velten R, Steglich W. J Antibiot 1995; 48: 36-41
• 19 Itoh J, Takeuchi Y, Gomi S, Inouye S. J Antibiot 1990; 43: 456-461
• 20 Crawford JM, Portmann C, Zhang X, Roeffaers MBJ, Clardy J. Proc Natl Acad Sci USA 2012; 109: 10821-10826
• 21 Liu W, Christenson SD, Standage S, Shen B. J Bacteriol 2008; 190: 6927-6930
• 22 Pérez-Victoria I, El Aouad N, González-Menéndez V. et al. J Nat Prod 2025; 88: 469-476
• 23 Isshiki K, Takahashi Y, Okada M. et al. J Antibiot 1987; 40: 1195-1198
• 24 Evans JR, Napier EJ, Yates P. J Antibiot 1976; 29: 850-852
• 25 Brady SF, Clardy J. Angew Chem Int Ed 2005; 44: 7063-7065
• 26 Kobayashi J, Tsuda M, Nemoto A, Tanaka Y, Yazawa K, Mikami Y. J Nat Prod 1997; 60: 719-720
• 27 Fujiwara A, Okuda T, Masuda S. et al. Agric Biol Chem 1982; 46: 1803-1809
• 28 Fukuyama T, Yung YM. Tetrahedron Lett 1981; 22: 3759-3760
• 29 Baldwin JE, Kelly DR, Ziegler CBJ. Chem Soc, Chem Commun 1984; 133-134
• 30 White AM, Pierens GK, Skinner-Adams T. et al. J Nat Prod 2015; 78: 1422-1427
• 31 Stratmann K, Moore RE, Bonjouklian R. et al. J Am Chem Soc 1994; 116: 9935-9942
• 32 Moore RE, Cheuk C, Qiang X. et al. J Org Chem 1987; 52: 1036-1043
• 33 Kim H, Lantvit D, Hwang CH. et al. Bioorg Med Chem 2012; 20: 5290-5295
• 34 Carmeli S, Moore RE, Patterson GML, Mori Y, Suzuki M. J Org Chem 1990; 55: 4431-4438
• 35 Marconi GG, Molloy BB, Nagarajan R, Martin JW, Deeter JB, Occolowitz JL. J Antibiot 1978; 31: 27-32
• 36a Fulton JR. Isocyanides and their Heteroanalogs (RZC). In: Comprehensive Organic Functional Group Transformations. 2nd ed. Vol 3. Elsevier; 2005: 705-730
• 36b Suginome M, Ito Y. Sci Synth 2012; 445-531
• 37 Altundas B, Marrazzo J-PR, Fleming FF. Org Biomol Chem 2020; 18: 6467-6482
• 38 Eliel EL, Masilamani D. Rev Lat Quinn 1970; 1: 120-122
• 39 Tian H, Holyoke Jr CW, Fleming FF. Org Lett 2022; 24: 8657-8661
• 40a Matteson DS, Bailey RA. J Am Chem Soc 1968; 90: 3761-3765
• 40b Matteson DS, Bailey RA. Chem Ind 1967; 191-192
• 41 King RB, Borodinsky L. Tetrahedron 1985; 41: 3235-3240
• 42 Bock H, Ugi I. J Prakt Chem 1997; 339: 385-389
• 43a Zinner G, Fehlhammer WP. Angew Chem Int Ed 1985; 24: 979-980
• 43b Lentz D. J Fluorine Chem 1984; 24: 523-530
• 44a Hagedorn I. Angew Chem 1961; 73: 26-27
• 44b Hagedorn I, Eholzer U, Etling H, Isonitrile V. Chem Ber 1965; 98: 193-201
• 45 Baldwin JE, Yamaguchi Y. Tetrahedron Lett 1989; 30: 3335-3338
• 46a Kobayashi K, Irisawa S, Akamatsu H. et al. Bull Chem Soc Jpn 1999; 72: 2307-2313
• 46b Kobayashi K, Akamatsu H, Takada K, Morikawa O, Konishi H. Tetrahedron Lett 1996; 37: 2437-2440
• 47 Fukuda T, Wagatsuma H, Kominami Y. et al. Chem Biodiversity 2016; 13: 1502-1510
• 48 Frippiat S, Sarre C, Baudequin C, Hoarau C, Bischoff L. J Org Chem 2022; 87: 7464-7473
• 49 Liu N, Cao S, Shen L. et al. Tetrahedron Lett 2009; 50: 1982-1985
• 50 Baldwin JE, Adlington RM, Chondrogianni J, Edenborough MS, Keeping JW, Ziegler CBJ. Chem Soc, Chem Commun 1985; 816-817
• 51 Baldwin JE, Chen D, Russell AT. Chem Commun 1997; 2389-2390
• 52a Nunami K, Yamada M, Fukui T, Matsumoto K. J Org Chem 1994; 59: 7635-7642
• 52b Suzuki M, Nunami K, Matsumoto K. et al. Chem Pharm Bull 1980; 28: 2374-2383
• 52c Suzuki M, Nunami K, Moriya T, Matsumoto K, Yoneda N. J Org Chem 1978; 43: 4933-4935
• 52d Schöllkopf U, Harms R, Hoppe D. Liebigs Ann Chem 1973; 1973: 611-618
• 52e Schöllkopf U, Gerhart F, Schröder R. Angew Chem, Int Ed 1969; 8: 672
• 53 Schöllkopf U, Schröder R, Blume E. Liebigs Ann Chem 1972; 766: 130-141
• 54 Schraff S, Trampert J, Pammer F. Inorg Chem 2020; 59: 17171-17183
• 55a Bull S, Stephens L. WO 2022/238694 A1 2022
• 55b Schöllkopf U, Schröder R, Stafforst D. Liebigs Ann Chem 1974; 44-53
• 56 Hoppe I, Schöllkopf U. Liebigs Ann Chem 1984; 600-607
• 57 Isshiki K, Takahashi Y, Sawa T, Naganawa H, Takeuchi T, Umezawa H. J Antibiot 1987; 40: 1199-1201
• 58 Isshiki K, Takahashi Y, Sawa T, Naganawa H, Takeuchi T, Umezawa H. J Antibiot 1987; 40: 1202-1203
• 59 Zinner G, Fehlhammer WP. Angew Chem, Int Ed Engl 1985; 24: 979-980
• 60 Spallarossa M, Wang Q, Riva R, Zhu J. Org Lett 2016; 18: 1622-1625
• 61 Treichel PM, Shaw DB. Inorg Chim Acta 1976; 16: 199-202
• 62 Van Leusen AM, Wildeman J. Rec Trav Pays-Bas 1982; 202-205
• 63 Van Leusen AM, Wildeman J, Moskal J, Van Hemert AW. Rec Trav Chim Pays-Bas 1985; 104: 177-183
• 64 O’Neil IA. In: Comprehensive Func Group Transformations Vol 3 1995; 693-726
• 65 Pirrung MC, Wang J. J Org Chem 2009; 74: 2958-2963
• 66 Richter JM, Ishihara Y, Masuda T. et al. J Am Chem Soc 2008; 130: 17938-17954
• 67 Chenera B, Chuang CP, Hart DJ, Lai CS. J Org Chem 1992; 57: 2018-2029
• 68 Baldwin JE, O’Neil IA. Synlett 1990; 603-604
• 69 Li Y, Fleming FF. Angew Chem, Int Ed 2016; 55: 14770-14773
• 70 El Kaïm L, Grimaud L, Schiltz A. Org Biomol Chem 2009; 7: 3024-3026
• 71 Saegusa T, Murase I, Ito Y. Tetrahedron 1971; 27: 3795-3801
• 72 Møllendal H, Samdal S, Matrane A, Guillemin J-C. J Phys Chem A 2011; 115: 7978-7983
• 73 Schöllkopf U, Stafforst D, Jentsch R. Liebigs Ann Chem 1977; 1977: 1167-1173
• 74a Pirrung MC, Ghorai S. J Am Chem Soc 2006; 128: 11772-11773
• 74b Bayh O, Awad H, Mongin F. et al. J Org Chem 2005; 70: 5190-5196
• 74c Miller RA, Smith RM, Karady S, Reamer RA. Tetrahedron Lett 2002; 43: 935-938
• 74d Boche G, Bosold F, Hermann B, Marsch M, Harms K, Lohrenz JCW. Chem Eur J 1998; 4: 814-817
• 74e Crowe E, Hossner F, Hughes MJ. Tetrahedron 1995; 51: 8889-8900
• 74f Whitney SE, Rickborn B. J Org Chem 1991; 56: 3058-3063
• 74g Dondoni A, Fantin G, Fogagnolo M, Medici A, Pedrini P. J Org Chem 1987; 52: 3413-3420
• 75 Herdeis C, Syväri J. Arch Pharm 1988; 321: 491-496
• 76 Banert K, Toth C. Angew Chem Int Ed 1995; 34: 1627-1629
• 77 Lentz D, Preugschat DJ. Chem Soc, Chem Commun 1992; 1523-1524
• 78 Buschmann J, Kleinhenz S, Lentz D. et al. Inorg Chem 2000; 39: 2807-2812
• 79 Hansch C, Leo A, Taft RW. Chem Rev 1991; 91: 165-195
• 80 Fleming FF, Wang Q. Chem Rev 2003; 103: 2035-2078
• 81 Schollkopf U, Meyer R. Liebigs Ann Chem 1977; 1174-1182
• 82 van Leusen D, Flentge E, van Leusen AM. Tetrahedron 1991; 47: 4639-4644
• 83 van Leusen AM, Schaart FJ, van Leusen D. Rec Trav Chim Pays-Bas 1979; 258-262
• 84 Moskal J, van Stralen R, Postma D, van Leusen AM. Tetrahedron Lett 1986; 27: 2173-2176
• 85 Chao A, Lujan-Montelongo JA, Fleming FF. Org Lett 2016; 18: 3062-3065
• 86a King RB, Efraty AJ. Chem Soc: Perkin I 1974; 1371-1373
• 86b King RB, Efraty A. J Am Chem Soc 1971; 93: 564-565
• 87 Saegusa T, Murase I, Ito Y. Bull Chem Soc Jpn 1972; 45: 1884-1888
• 88 Marrazzo JPR, Chao A, Li Y, Fleming FF. J Org Chem 2022; 87: 488-497
• 89 Marrazzo J-PR, Huynh T, Fleming FF. Synthesis 2024; 56: 2985-2992
• 90 Tian H, Marrazzo J-P, Huynh T, Fleming FF. J Org Chem 2025; 90: 4513-4517
• 91 von Rauge Schleyer P, Allerhand J. Am Chem Soc 1962; 84: 1322-1323
• 92a Gomes GP, Loginova Y, Vatsadze SZ, Alabugin IVJ. Am Chem Soc 2018; 140: 14272-14288
• 92b Minozzi M, Nanni D, Spagnolo P. Curr Org Chem 2007; 11: 1366-1384
• 93a Wang Z, Wei H, Du J, Zuo Z. Green Chem 2024; 26: 10804-10810
• 93b Li L, El Khoury A, Clement BO, Wu C, Harran PG. Org Lett 2022; 24: 2607-2612
• 93c Liu Y, Li S-J, Chen X-L. et al. Adv Synth Catal 2020; 362: 688-694
• 93d Evoniuk CJ, Gomes GDP, Ly M, White FD, Alabugin IV. J Org Chem 2017; 82: 4265-4278
• 93e Evoniuk CJ, Ly M, Alabugin IV. Chem Commun 2015; 51: 12831-12834
• 93f Mitamura T, Iwata K, Ogawa AJ. Org Chem 2011; 76: 3880-3887
• 93g Lamberto M, Corbett DF, Kilburn JD. Tetrahedron Lett 2003; 44: 1347-1349
• 93h Bachi MD, Bar-Ner N, Melman AJ. Org Chem 1996; 61: 7116-7124
• 93i Bachi MD, Balanov A, Bar-Ner NJ. Org Chem 1994; 59: 7752-7758
• 94 Lenoir I, Smith MLJ. Chem Soc: Perkin I 2000; 641-643
• 95 Zhang B, Studer A. Chem Soc Rev 2015; 44: 3505-3521
• 96a Lei J, Huang J, Zhu Q. Org Biomol Chem 2016; 14: 2593-2602
• 96b Sun X, Yu S. Synlett 2016; 27: 2659-2675
• 96c Minozzi M, Nanni D, Spagnolo P. Curr Org Chem 2007; 11: 1366-1384
• 97 Jiang H, Cheng Y, Wang R, Zhang Y, Yu S. Chem Commun 2014; 50: 6164-6167
• 98 Wang H, Yu Y, Hong X, Xu B. Chem Commun 2014; 50: 13485-13488
• 99 Mao H, Gao M, Liu B, Xu B. Org Chem Front 2016; 3: 516-521
• 100 Inoue M, Sumii Y, Shibata N. ACS Omega 2020; 5: 10633-10640
• 101 Cheng Y, Yuan X, Jiang H. et al. Adv Synth Catal 2014; 356: 2859-2866
• 102 Tong K, Zheng T, Zhang Y, Yu S. Adv Synth Catal 2015; 357: 3681-3686
• 103 Liu Y, Kang Y, Wang H. et al. Tetrahedron Lett 2020; 61: 152348
• 104 Zhang B, Studer A. Org Biomol Chem 2014; 12: 9895-9898
• 105 Zhang B, Mück-Lichtenfeld C, Daniliuc CD, Studer A. Angew Chem Int Ed 2013; 52: 10792-10795
• 106 Liu Y, Zhang K, Jiang W. et al. Chem Asian J 2017; 12: 568-576
• 107 Ding F, Jiang Y, Lin K, Shi L. Org Biomol Chem 2018; 16: 1812-1815
• 108 Xu Y, Chen H, Li W, Xie Q, Yu L, Shao L. ChemistrySelect 2017; 2: 8033-8038
• 109 Xue D, Liu R, Zhang D. et al. Org Biomol Chem 2021; 19: 8597-8606
• 110 Yao Q, Zhou X, Zhang X, Wang C, Wang P, Li M. Org Biomol Chem 2017; 15: 957-971
• 111 Han D, Zhou X, Yao Q, Wang P, Li M. J Carbohydr Chem 2020; 39: 75-106
• 112 Xu Y, Chen H, Li W, Xie Q, Yu L, Shao L. Org Biomol Chem 2018; 16: 4996-5005
• 113 Xue D, Chen H, Xu Y. et al. Org Biomol Chem 2017; 15: 10044-10052
• 114 Pasto DJ, Krasnansky R, Zercher C. J Org Chem 1987; 52: 3062-3072
• 115 Qian P, Du B, Zhou J, Mei H, Han J, Pan Y. RSC Adv 2015; 5: 64961-64965
• 116 Xue D, Xue Y, Yu H, Shao L. Synthesis 2019; 51: 874-884
• 117 He Y, Wang X, Xiao J-A. et al. RSC Adv 2018; 8: 3036-3040
• 118 Lau HH, Schöllkopf U. Liebigs Ann Chem 1982; 2093-2095
• 119 Bossio R, Marcaccini S, Pepino R, Paoli P, Polo C. J Heterocycl Chem 1993; 30: 575-577
• 120 Bossio R, Marcaccini S, Pepino RJ. Chem Res: Synop 1993; 1
• 121 Paoli PJ. Heterocycl Chem 1994; 4: 729-732
• 122a Schöllkopf U, Porsch PH, Lau HH. Liebigs Ann Chem 1979; 1444-1446
• 122b Bloom JD, DiGrandi MJ, Dushin RG. et al. Bioorg Med Chem Lett 2003; 13: 2929-2932
• 123a Helal CJ, Lucas JC. Org Lett 2002; 4: 4133-4134
• 123b Atkinson KA, Beretta EE, Brown JA. et al. Bioorg Med Chem Lett 2011; 21: 1621-1625
• 124 Henkel B. Tetrahedron Lett 2004; 45: 2219-2221
• 125 Bienaymé H. Tetrahedron Lett 1998; 39: 4255-4258
• 126 Bienaymé H, Bouzid K. Tetrahedron Lett 1998; 39: 2735-2738
• 127a Kolb J, Beck B, Almstetter M, Heck S, Herdtweck E, Dömling A. Mol Divers 2003; 6: 297-313
• 127b Heck S, Dömling A. Synlett 2000; 424-426
• 128 Henkel B, Sax M, Dömling A. Tetrahedron Lett 2003; 44: 3679-3682
• 129 Kolb J, Beck B, Dömling A. Tetrahedron Lett 2002; 43: 6897-6901
• 130 Henkel B, Beck B, Westner B, Mejat B, Dömling A. Tetrahedron Lett 2003; 44: 8947-8950
• 131a Hiramatsu K, Nunami K-I, Hayashi K, Matsumoto K. Synthesis 1990; 781-782
• 131b Nunami K-I, Hiramatsu K, Hayashi K, Matsumoto K. Tetrahedron 1988; 44: 5467-5478
• 132 Nunami K, Yamada M, Fukui T, Matsumoto K. J Org Chem 1994; 59: 7636-7640
• 133a Bloom JD, DiGrandi MJ, Dushin RG. et al. Bioorg Med Chem Lett 2003; 13: 2929-2932
• 133b Schöllkopf U, Porsch P-H, Lau H-H. Liebigs Ann Chem 1979; 1444-1446
• 134 Yamada M, Fukui T, Nunami K. Tetrahedron Lett 1995; 36: 257-260
• 135 Yamada M, Fukui T, Nunami K. Synthesis 1995; 1365-1367
• 136a Pirrung MC, Ghorai S. J Am Chem Soc 2006; 128: 11772-11773
• 136b Maison W, Schlemminger I, Westerhoff O, Martens J. Bioorg Med Chem 2000; 8: 1343-1350
• 136c Maison W, Schlemminger I, Westerhoff O, Martens J. Bioorg Med Chem Lett 1999; 9: 581-584
• 136d Lindhorst T, Bock H, Ugi I. Tetrahedron 1999; 55: 7411-7420
• 136e Keating TA, Armstrong RW. J Am Chem Soc 1996; 118: 2574-2583
• 137 Quelhas A, Gazzeh H, Roisnel T, Trolez Y, Guillemin JC. Eur J Org Chem 2021; 6002-6005
• 138 Zwikker JW, Stephany RW. Synth Commun 1973; 3: 19-23
• 139 Kim SW, Bauer SM, Armstrong RW. Tetrahedron Lett 1998; 39: 7031-7034
• 140 Beck B, Hess S, Dömling A. Bioorg Med Chem Lett 2000; 10: 1701-1705
• 141 Bu X-B, Wang Z, Wang X-D, Meng X-H, Zhao Y-L. Adv Synth Catal 2018; 360: 2945-2951
• 142 Liu Y, Tan Q, Bao L. et al. Org Lett 2024; 26: 5043-5048
• 143 Marin-Luna M, Alajarin M. Eur J Org Chem 2020; 5496-5500
• 144 Xiong Z, Wang J, Wang Y, Luo S, Zhu Q. Org Chem Front 2017; 4: 1768-1771
• 145 Barnett BR, Figueroa JS. Chem Commun 2016; 52: 13829-13839
• 146 Chao A, Alwedi E, Fleming FF. Synthesis 2019; 51: 2122-2127

Publication History

Received: 05 June 2025

Accepted after revision: 28 July 2025

Article published online:
08 September 2025