Free carbenes from complementarily paired alkynes

Abstract

Carbenes (R¹R²C:) like radicals, arynes and nitrenes constitute an important family of neutral, high-energy, reactive intermediates-fleeting chemical entities that undergo rapid reactions. An alkyne (R³C≡CR⁴) is a fundamental functional group that houses a high degree of potential energy; however, the substantial kinetic stability of alkynes renders them conveniently handleable as shelf-stable chemical commodities. The ability to generate metal-free carbenes directly from alkynes, fuelled by the high potential (that is, thermodynamic) energy of the latter, would constitute a considerable advance. We report here that this can be achieved simply by warming a mixture of a 2-alkynyl iminoheterocycle (a cyclic compound containing a nucleophilic nitrogen atom) with an electrophilic alkyne. We demonstrate considerable generality for the process: many shelf-stable alkyne electrophiles engage many classes of (2-alkynyl)heterocyclic nucleophiles to produce carbene intermediates that immediately undergo many types of transformations to provide facile and practical access to a diverse array of heterocyclic products. Key mechanistic aspects of the reactions are delineated.

Fig. 1 |. The high potential energy (thermodynamic instability) of alkynes can drive the formation of reactive intermediates.

a, A C≡C has characteristically high potential energy when compared with its more saturated C=C and C–C analogs; it has relatively higher kinetic stability compared with reactive intermediates (RIs). b, Classical methods for carbene generation: Free carbenes and carbenoids are frequently produced with the ejection of N₂ gas as the driving force. Base-promoted eliminations are employed to generate dihalocarbenes and NHCs. c, The alkyne units in dimethyl acetylenedicarboxylate molecules can fuel formation of a free carbene intermediate under thermal-only conditions. d, Three alkyne units can fuel formation of an (reactive) aryne intermediate under thermal-only conditions. ^aNHC = N-heterocyclic carbene

Fig. 2 |. Two early reactions suggest the formation of carbene intermediates (further supported by DFT computations) enroute to indolizine-containing products.

a, Reaction between the pyridine derivative 15 and the HDDA-benzyne 16 gave rise to the polycyclic product 17 via 1,5-C–H insertion from the carbene 19. b, Reaction between the pyridine derivative 20 and DMAD (9) furnished the indolizine 22 via 1,2-C–H insertion from the carbene intermediate 21. c, Potential energy surface of the reaction between model compounds 23 and 24 that leads to the indolizine 27 computed by DFT [SMD (dichloroethane)/B3LYP-GD3BJ/6–311++G(d,p)]. ^aNumbers in red and blue indicate the progression (from 23 to 26 to 27) in the change in bond length (longer) and bond order (lower) between the red () and green () atoms. ^bBond orders obtained using the Wiberg bond index.

Fig. 3 |. Insertion (a-d) and 1,3-dipolar cycloaddition (e-g) reactions of the carbene intermediates.

a, Carbene insertion into an isopropyl C–H bond. b, Carbene insertion into OMe or SMe C–H bond. c, Carbene insertion into an O–H bond. d, Formation of a strained 5,5,6-trycyclic product via C–H insertion. e, 1:2 Adducts between 2-ethynyl pyridines and DMAD via interception of the carbene by an ester carbonyl oxygen and subsequent 1,3-dipolar cycloaddition. f, Isolation of the bridged ether product 46 and its rearrangement to its tricyclic ketone isomer 47 provide support for the proposed reaction pathway. g, Intramolecular 1,3-dipolar cycloaddition provides a tetracyclic ketone. ^a##%s indicate the isolated yields following chromatographic purification (silica gel). ^bE = CO₂Me (from DMAD, 9, EC≡CE).

Fig. 4 |. Scope of electrophilic alkynes.

a, Identification of OAc as an ideal carbene trapping group. b, A variety of electrophilic alkynes, including benzyne can engage with 2-ethynyl pyridine derivatives. c, Unproductive alkyne substrates. ^aTFT = α,α,α-trifluorotoluene; ^bPBP = p-bromophenyl; ^cPCP = p-chlorophenyl.

Fig. 5 |. Examples in which various arrays of a carbene-capture process, of an electron-deficient alkyne, and of an alkynyl iminoheterocycle are melded.

a, O–H insertion reactions of a series of homologous alkynol substrates 60a–d engaged by an ynone 61. b, 1,3-Dipolar cycloaddition reaction between isoquinoline substrate 63 and DMAD. c, 1,3-Dipolar cycloaddition reaction between thiazole substrate 65 and DMAD. d, 1,2-C–H insertion using 2-alkynyl pyrroline 58i and a diyne 56d. e, 1,5-C–H insertion using pyrimidine substrate 68 and ynoate 69.

Fig. 6 |. A series of unusual transformations.

a, Sequential generation of two carbene intermediates from the reaction between bipyridine 71 and DMAD. b, Formation of two distinct products 77 and 78 provides experimental evidence for the delocalization of the carbene character onto both C● and C▼. c, Selective and exclusive propynylidene carbene trapping at the remote carbon (C▼) within 79 can be achieved by using an HDDA benzyne (derived from 14) as the electrophile. d, Formation of 84 and 84-D indicates a carbene metathesis process that has a significant H/D kinetic isotope effect. e, An example of a three-component, cyclopropanation reaction.