Iron-Mediated C−H Functionalization of Unactivated Alkynes for the Synthesis of Derivatized Dihydropyrrolones: Regioselectivity Under Thermodynamic Control

Abstract

Cyclopentadienyliron dicarbonyl-based complexes present opportunities for underexplored disconnections in synthesis. Access to challenging dihydropyrrolone products is achieved by propargylic C−H functionalization of alkynes for the formation of cyclic organoiron species. Excellent regioselectivity for unsymmetrical alkynes is observed in many cases. Notably, regioselectivity under these stoichiometric conditions diverges from those observed previously under catalysis, occurring at the more-substituted terminus of the alkyne, and allowing for methine functionalization and the formation of quaternary centers. Divergent demetallation of the intermediate organoiron complexes gives access to chemically diverse products which are further amenable to functionalization.

Entry for the Table of Contents

Cyclopentadienyliron species mediate propargylic C−H functionalization of simple, unactivated alkynes for the synthesis of densely substituted and diversely functionalized dihydropyrrolones. High regioselectivities are observed under conditions of thermodynamic control.

Introduction

Partially unsaturated heterocycles occupy an interesting niche in the medicinal chemist’s tool kit as the field moves to escape the flatland of predominantly sp²-hybridized small molecules.^[1] Natural^[2] and synthetic products containing dihydropyrrolone cores^[3] have demonstrated antibacterial,^[4] antifungal,^[5] and anti-tubercular^[6] properties as well as potential for biological applications in immunomodulation,^[7] cancer therapeutics,^[8] and bacterial quorum sensing^[9] (Scheme 1a). While a number of strategies for dihydropyrrolone synthesis have been developed in recent years,^[10] few methods allow for rapid access to polyfunctionalized products with this core using simple starting materials.^[11] Correspondingly, the development of new multicomponent syntheses that produce densely functionalized heterocycles are of significant interest as they allow for rapid access to underexplored scaffolds.^[12] Methods that allow for divergent functionalization are generally more suitable for elaboration, library development, and exploring the chemical space around a core scaffold. These modern challenges inspire the creation of new, sustainable methods for rapidly introducing chemical complexity through the multi-component assembly of readily available starting materials and reagents.

Scheme 1.

(a) Examples of bioactive dihydropyrrolones. (b) Precedented reactivity of Fp-based allyliron species with both cationic and dipolar electrophiles. (c) [3+2] cycloaddition with allenyliron species gave access to a diversifiable dihydrofuranyliron species. (d) Stoichiometric regioselective α-C–H functionalization of the more substituted position for [3 + 2] cycloaddition.

The alkyne is a simple and abundant functional group that has been employed in numerous polyfunctionalization and annulation strategies.^[13] Reactions that functionalize both the alkyne and the neighboring propargylic position are also well-developed,^[14] but few exploit the direct C−H functionalization of the α-C−H bond.^[15] Our group previously reported the use of substituted cyclopentadienyl iron dicarbonyl (Fp^R) species as mediators of C–H functionalization of unsaturated hydrocarbons to allow for electrophilic bond formation at the α-position. These explorations drew heavy inspiration from precedented transformations of allyl- and allenyliron Fp-species developed by Rosenblum and Wojcicki among others (Scheme 1b).^[16] In 2020, we reported an Fp^R-mediated [3 + 2] cycloaddition which coupled alkynes and their derived stoichiometric Fp^R-complexes with various 1,2-dipolar electrophiles. This cycloaddition was used to produce cyclic η¹-vinyliron species that were transformed into a limited family of dihydrofurans by electrophilic demetallation (Scheme 1c).^[17] These studies were conducted in the context of our group’s development of catalytic α-C−H functionalization reactions using Fp^R-based complexes to achieve allylic, allenic, and propargylic C−H to C−C bond transformations that retain the original alkene, allene, or alkyne, respectively.^[18]

In these catalytic processes, the C−H functionalization of dialkylalkynes is often challenging, particularly when sterically hindered alkyl groups are employed. Moreover, when multiple propargylic C−H positions are present, the distribution of regioisomeric products is under kinetic control. In contrast, we report in the present work that under stepwise conditions developed for stoichiometric [3+2]-cycloaddition, the regiochemical outcome of propargylic functionalization was found to be under thermodynamic control, leading to preferential functionalization at the more substituted alkyl group. In addition to the novel regioselectivity, these stoichiometric conditions allowed for the first time the functionalization of 3° propargylic C−H bonds to give products with quaternary carbon centers. Additionally, we have developed several novel demetallative transformations of these cyclic vinyliron complexes including fluorodemetallation, chlorodemetallation, and proto(deutero)demetallation for the synthesis of an array of diversified products from common vinyliron intermediates. This tandem cyclization-demetallation approach allows for the rapid generation of a family of organic dihydropyrrolone products and their relatives from simple alkynes (Scheme 1d).

Results and Discussion

Regioselectivity of catalytic vs. stepwise stoichiometric functionalization

Our group’s previously reported mechanistic experiments showed that deprotonation is turnover limiting and irreversible under catalytic conditions in which trityl cation [Ph₃C⁺] was used as the electrophile.^[18] Thus, the regioisomeric outcome is believed to reflect the kinetic acidities of propargylic C−H bonds. In the case of 2-heptyne, there was an appreciable selectivity for methyl functionalization over methylene functionalization, giving linear and branched α-tritylation products 4a-L and 4a-B in an 8.2:1 ratio (Scheme 2a). We were surprised to find, however, that when cationic Fp*−(2-heptyne) complex 2 (Fp* = (C₅Me₅)Fe(CO)₂) was subjected to stoichiometric deprotonation with various amine bases then reacted with Ph₃C⁺BF₄⁻, essentially exclusive functionalization at the methylene position (>20:1 r.r.) was observed. The deprotonation step was monitored by in situ ¹H-NMR; stoichiometric 2-heptyne complex 2 was synthesized and subjected to a variety of organic bases. In all cases, though allenyliron 3a-L could be observed within the first hour, the signal intensity decreased with a corresponding increase in the signal corresponding to 3a-B (see the Supporting Information). This result indicates that, in the absence of an electrophile to irreversibly trap the allenyliron intermediate, deprotonation is reversible, and deprotonation of the more substituted position (H_t of 2) is thermodynamically favorable. Furthermore, when the equilibrated mixture of allenyliron species is subjected to trapping with a model electrophile, 4a-B is observed as the major product with excellent regioselectivity (Scheme 2b).

Scheme 2.

(a) Under catalytic conditions, methyl functionalization is preferred to methylene functionalization. (b) Stoichiometric deprotonation of asymmetric iron complex 2 gives predominantly allenyliron 3a-B after equilibration. Trapping of the resultant nucleophile with trityl cation gives 4a-B as the major product.

With the observation of this unprecedented selectivity for the more substituted position, we sought to apply this technology to the synthesis of organic derivatives of these organometallic intermediates. We saw our group’s alkyne-dipole [3 + 2] cycloaddition as a potential application for this newly observed selectivity. In optimizing this multicomponent/multi-step process, we investigated both multi-pot and single-pot procedures, each of which led to useful yields of functionalized dihydropyrrolones.

Access to Fp*-Dihydropyrrolonyl Complexes

We began by evaluating the compatibility of reagents using 2-heptyne as a model alkyne, tosylisocyanate (TsNCO) as the electrophilic reagent,^[19] and complex 1a as a convenient Fp*⁺ source^[20] for the synthesis of cyclic organoiron species which we envisioned could be further transformed into diverse organic products (Scheme 3).

Scheme 3.

(a) One-pot stoichiometric functionalization of asymmetric alkynes with an isocyanate dipole produces a mixture of tautomeric iron complexes. (b) A modified multi-pot procedure allows for access to the more desirable enamine tautomer. (c) Direct comparison of the reactivity of complexes 5 and 5’ to bromination; while enaminyliron 5 is consumed within an hour, no detectable bromination products are detected when subjecting 5’ to NBS. After 2 h, 88% of 5’ is detected by 1H-NMR.

Functionalization of the more substituted methylene position was the exclusive pathway observed, with the potential products of methyl functionalization never being detected. Under reaction conditions, 5-endo-dig aminometallation gave 5 as the initial product; subsequent isomerization of the enamine isomer 5 to the conjugated enone isomer 5’ was observed to varying extent. While changing the identity and equivalents of base, solvent, reaction time, temperature, and workup conditions affected the ratio of 5:5’, in all cases 5’ was the major product observed. Enonyliron 5’ is significantly less reactive to electrophilic functionalization for demetallation compared to enaminyliron 5, and as such, we soon recognized that its formation was undesirable with respect to the goal of synthesizing organic products from the formed metal complexes. In a side-by-side comparison, when subjected to N-bromosuccinimide (NBS, 1.0 equiv), 5 was consumed in under thirty minutes at 0 °C, while treatment of 5’ to the same conditions did not afford any organic bromination products (Scheme 3c).

Following an observation that isomerization of 5 to 5’ was promoted with mild acid, a strategy for partial purification of the mixture of allenyliron species (3aB+3aL) was developed for removal of the conjugate acid of the amine base formed in the deprotonation step. We found that filtration of the solution of the mixture of allenyliron species through either neutral or basified (Et₃N) silica effectively removed the ammonium salt without significant material loss. The optimal base for material throughput was found to be dimethylcyclohexylamine (Me₂NCy). Unhindered pyridines and secondary amines (with the exception of 2,2,6,6-tetramethylpiperidine) were incompatible, though Et₃N was a suitable replacement that delivered slightly reduced yields. Additionally, this purification of the allenyliron intermediate(s) improved the reaction profile of the cycloaddition. Similarly, using shorter reactions times with a larger excess of TsNCO allowed for consumption of the allenyliron nucleophile before significant isomerization of 5 to 5’ was observed. Critically, we found that quenching the reaction with ethylenediamine before an aqueous workup was effective at scavenging both unreacted cationic iron and TsNCO and allowed for purification of the intermediate complex with standard organic techniques (Scheme 3b).

In addition to the isomerizable complexes formed from methylene (-CH₂-) functionalization, we postulated that the observed regioselectivity may extend to tertiary propargylic positions over secondary or primary. The previously encountered isomerization of these products is not possible due to the lack of an allylic methine in the cyclized product, so a single-pot, stepwise-addition process was revisited. Pleasingly, exclusive methine functionalization was observed, and the cyclization complex 6 could be isolated in high yields (Scheme 4). Notably, this streamlined procedure could also be applied for the synthesis of Fp-derived complex 6’, also observed as a single regioisomer, albeit in lower yields. The incorporation of the pentamethyl-substituted ligand (Cp*) in place of parent Cp significantly improved both the stability of intermediates for isolation and general reaction profile for demetallation when compared to Fp. Infrared spectroscopic and crystallographic data are consistent with the electron-rich Cp* ligand allowing for enhanced π-basicity (backbonding ability) of the Fe center and possibly contributing to the more facile demetallation of the Fp*-based intermediates compared to their Fp-based analogues. These results are consistent with our previous stoichiometric and catalytic investigations into propargylic functionalization.

Scheme 4.

Methine functionalization using a modified one-pot process. ORTEP renderings of Fp- and Fp*- based complexes 6 and 6’ (ellipsoids at 50% probability level).

The Development of Novel Demetallation Conditions for the Synthesis of Organic Products

With a method in hand for the synthesis of these vinyliron species, we sought to produce useful organic products. While several methods for electrophilic fluorination of organometallic species are precedented, the C−Fe to C−F bond transformation is, to our knowledge, unreported. We subjected a rigorously purified sample of 6 to various electrophilic fluorine reagents (Table 1). The strongly oxidative fluorinating reagent Selectfluor partially consumed the starting complex, but the reaction profile indicated low selectivity and decomposition of the desired product under reaction conditions. The use of more polar solvents to improve reagent solubility and conversion further complicated the reaction profile. Less reactive reagents like NFSI did not consume the starting material, and, upon heating, the slow demetallation consisted mainly of competitive protodemetallation for the formation of 6h. Among the N-fluoropyridinium reagents, we found that 1-fluoro-2,6-dichlorofluoropyridinium tetrafluoroborate (NFP-4) outperformed the related electron-rich pyridinium reagents as well as the triflate salt. Importantly, an excess of this reagent was tolerated without product decomposition, allowing for improved consumption of the starting complex 6 without significant byproduct formation. Counterintuitively, though NFP-4 appears to be more soluble in acetonitrile, the best F- vs. H- selectivity was observed using freshly distilled THF.

Table 1.

Optimization of the fluoro-demetallation of complex 6.

F+ Source[a]	Equiv.	Solvent	Time, Temp	Results/Comment [b][c]
Selectfluor	1.0	MeCN	25°C, 18h	6 (>50%), trace 6f, decomposition
Selectfluor	2.0	MeCN	25°C, 18h	significant decomposition
NFSI	2.0	MeCN	25°C, 12h	6 (>85%), no 6f
NFSI	2.0	MeCN	60°C, 12h	6, trace 6f, 6h (~20%)
NFP-1	1.1	MeCN	25°C, 12h	6, 6f (~15%), 6h (~40%)
NFP-1	1.1	MeCN	65°C, 12h	6f (~15%), 6h (~20%)
NFP-2	1.1	MeCN	25°C, 12h	6, 6f (<5%), 6h (~30%)
NFP-3	1.1	MeCN	25°C, 12h	6, 6f (~20%), 6h (~20%)
NFP-4	1.1	MeCN	25°C, 12h	6, 6f (~30%), 6h (~20%)
NFP-4	1.1	THF	25°C, 12h	6, 6f (~45%), 6h (~5%)
NFP-4	2.0	THF	25°C, 12h	6f (~55%), 6h (<5%)
NFP-4	2.0	THF	0–25°C, 4h	6f (~65%, 59% isolated[d])

^[a]Abbreviations: Selectfluor = 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate, NFSI = N-fluorobenzenesulfonamide, NFP-1 = N-fluoropyridinium triflate, NFP-2 = N-fluoro-2,4,6-trimethylpyridinium triflate, NFP-3 = N-fluoro-2,6-dichloropyridinium triflate, NFP-4 = N-fluoro-2,6-tetrafluoroborate

^[b]RS = recovered or observed unreacted complex

^[c]yields and conversions are approximated by 1H-NMR of the reaction mixture using 1,1,2,2-tetrachloroethane as internal standard.

^[d]Screening was carried out using 0.05 mmol 6; isolation was carried out on 0.2 mmol scale.

While protodemetallation was often observed as a side product in the presence of various electrophilic reagents, subjecting 6 directly to various H⁺ sources such as TsOH, AcOH, and aqueous acids, led to significant material loss and the formation of a number of other products. Trimethylsilyl chloride (TMSCl) was found to be efficient for protodemetallation via in situ generation of HCl using undried CH₂Cl₂. This method proved superior to others as the reaction profile better tolerated an excess of the silyl reagent, and the by-product iron-chloride complex (Fp*Cl) could be separated from the organic product chromatographically. This method could be further extended to deuterodemetallation using distilled THF as the solvent with added D₂O as the source of D⁺, allowing for excellent D-incorporation (95%) at this position. These direct C(sp²)−Fe to C−H and C−D transformations serve as another novel expansion to the demetallation tool kit and generate a scaffold with a previously unreported deuteration pattern. With both cyclization and demetallation systems in hand, we prepared a number of organic products using enaminyliron species as intermediates (Table 2).

Table 2.

A variety of densely substituted products were obtained using a stepwise cyclization/demetallation approach, sorted by demetallation. X-ray structure of 10c. (a) 1-Fluoro-2,6-dichloropyridinium tetrafluoroborate (2 equiv), THF, 0 °C to 25 °C. (b) TMSCl, 3:1 THF:D₂O, 0 °C to 25 °C. (c) TMSCl, THF, −20 °C to 25 °C then K₂CO₃ (d) TMSCl, THF, 25 °C then H₂O (e) N-Bromosuccinimide (1.0 equiv), THF, 0 °C, 30 min then 25 °C. (f) I₂ (1.5 equiv), THF, 0 °C to 25 °C, in dark. (g) N-Chlorosuccinimide (1.5 equiv), THF, 0 °C to 25 °C. (h) Br₂ (3.5 equiv), THF, 0 °C to 25 °C, 12 h, then Bu₄NBr (3 equiv), CH₂Cl₂, 40 °C, 6 h. (i) N-Bromosuccinimide (3.0 equiv), THF, 0 °C, 30 min then 25 °C. (j) N-Iodoosuccinimide (3.0 equiv), THF, 0 °C, 30 min then 25 °C. (k) Cerium ammonium nitrate (1.5 equiv), 1:1 MeOH:THF, K₂CO₃ (powdered, 10 equiv.), CO balloon.

We previously reported bromo- and iododemetallation of related vinyliron species using halosuccinimides as electrophilic halogen sources; we found these conditions applicable with slight modification here to give vinyl bromide 6c and iodide 6i in good yields. However, when complex 6 was subjected to excess Br₂, a second allylic halogenation was often observed as a competitive pathway and the major isolated product was 6c. The formation of this product did not depend on whether the reaction was carried out in the dark or with exposure to light. Moreover, upon scale-up of this transformation, gem-dibromo regioisomer 6c’ was identified as a minor product, suggesting that the mechanism of dibromide 6c formation involved an alkene bromination followed by bromide-mediated allylic rearrangement (Scheme 5a). We found that addition of a bromide ion source (Bu₄NBr) to the mixture pushed the reaction forward; this two-step, single pot sequence allows for isolation of dibromide regioisomer 6c in good yields. The double bromination strategy was expanded to an extended scaffold for the formation of 10c, the structure of which was confirmed by X-ray crystallography (Table 2).

Scheme 5.

Proposed mechanisms for the formation of 6c, 5c, and 5b.

A second oxidative event was also observed upon subjecting isomerizable complex 5 to excess halogenating reagent. Under these conditions, bromo-diene 5b was observed as the major product (Scheme 5b). While the order of elimination steps is unclear, we propose that a second halogenation followed by a double elimination gives the doubly unsaturated product. Accordingly, NBS outperforms elemental bromine for this transformation. This manifold was extended to access the corresponding iododiene 5j. During isolation of isomerizable demetallation products, the enaminyl species completely tautomerizes to the enonyl species; while bromide 5b’ was observed to form in situ by analysis of the reaction mixture, 5b was the exclusive product isolated after workup.

This strategy for electrophilic halogenation was successfully extended to chlorodemetallation with excess NCS for the synthesis of 6k; mild heating allows for full consumption of complex 6 without the observation of further chlorination or product decomposition of the vinyl chloride, albeit with lower overall yield. Lastly, C−Fe to C−C bond transformation was achieved through oxidative demetallation following a similar strategy to Reger^[21] to generate ester products 6a and 11a. Critically, the addition of powdered K₂CO₃ minimized competitive protodemetallation.

With respect to the scope of alkyne, we first examined various alkyl isopropyl acetylenes, as the resultant gem-dimethyl moiety is attractive in the context of medicinal chemistry.^[22] Extended alkyl chains likewise demonstrate excellent C−H regioselectivity for the methine position, and the resultant complexes are compatible with the variety of demetallation conditions. A regioisomeric mixture of alkene isomers was observed during initial attempts to protodemetallate substrates with longer chains. This isomerization to the exo-methylene bearing isomer could be minimized by cooling the mixture during addition of acid to give endo products like 6h, 15h, or 16h. Conversely, isomerization was promoted by heating, increasing reaction time, or adding additional equivalents of acid to give alkenes 10h’ and 16h’ as single isomers. The alkene geometry was confirmed by NOESY spectroscopy (see the Supporting Information). Pleasingly, functionalization and demetallation of the methine position of a cyclopentylalkyne could also be achieved to give spirocyclic products 13b, 13h, and 13d.

Aryl isopropyl acetylenes could also be functionalized under these conditions, though the conditions for demetallation needed to be modified to allow for functionalization of the less reactive vinyliron moiety in the organoiron complex. Protonation, deuteration, halogenation, and alkoxycarbonylation are all compatible to give an array of products. A variety of electronically diverse alkynes substituted with esters (17, 18, 24), ethers (23), sulfonamides (22), and nitro groups (20) can be readily cyclized and demetallated, though strongly electron-withdrawing groups appear to decrease the amount of initial alkyne-iron coordination complex formed, lowering the overall yield. Strongly coordinating functional groups also appear to interrupt the initial alkyne-iron coordination; consequently, substrates that contained nitriles, alcohols, and amines functions were unsuccessful.

Using the multi-pot cyclization method (Scheme 3b), enaminyliron complexes generated from C−H functionalization of propargylic methylene groups were also transformed into attractive organic products. Bromodemetallation (5b), iododemetallation (5i), protodemetallation (5h), deuterodemetallation (5d) and fluorodemetallation (5f) products were all accessible through analogous conditions, though in all cases, tautomerization of the product to the enone isomer was observed upon workup and isolation. In addition to regioselective functionalization of unsymmetrical dialkylalkynes, symmetrical alkynes can be de-symmetrized to give densely substituted products (9, 19).

To further demonstrate the utility of these densely functionalized heterocycles, selected products were subjected to further diversification (Scheme 6). The pendant allylic bromide of 6c could be further diversified with various pharmaceutically attractive partners including morpholine (6c1), azide (6c2), and phenol (6c3). Complementarily, the vinyl iodide of 6i could be diversified readily using more traditional approaches such as Suzuki (6i1), Heck (6i2), or Sonogashira (6i3) cross couplings. Markovnikov hydration of 6h gives access to 6h1 in good yields. Reduction of 6h gives access to related pyrrole derivatives. Lactam 6h2 is accessed through catalytic hydrogenation; catalytic acid promotes isomerization of the double bond to the exo position and the less sterically hindered alkene is readily reduced in mild conditions. On the other hand, reduction of the amide moiety with NaBH₄/MeOH followed by aqueous workup gives sulfonamide hemiaminal 6h3.

Scheme 6.

(a) Cerium ammonium nitrate (1.5 equiv), 1:1 MeOH:THF, K₂CO₃ (powdered, 10 equiv.), CO balloon. (b) N-Bromosuccinimide (1.0 equiv), THF, 0 °C, 30 min then 25 °C, 2 h. (c) Br₂ (3.5 equiv), THF, 0 °C to 25 °C, 12 h, then Bu₄NBr (3 equiv), CH₂Cl₂, 40 °C, 6 h. (d) TMSCl, 3:1 THF:D₂O, 0 °C to 25 °C. (e) 1:1 HCl (1.0M aqueous):CH₂Cl₂, 25 °C, 4 h. (f) 1-Fluoro-2,6-dichloropyridinium tetrafluoroborate (2 equiv), THF, 0 °C to 25 °C, 4 h. (g) Pd/C (10% w/w suspension, 0.05 equiv), EtOAc, AcOH (2 drops), H₂ balloon, 12 h. (h) TMSCl, THF, 0 °C to 25 °C (i) I₂ (1.5 equiv), THF, 0 °C to 25 °C, 18 h, in dark. (j) NaBH₄ (3 equiv), MeOH, 0 °C, 1 h. (k) N-Chlorosuccinimide (1.5 equiv), THF, 0 °C to 25 °C, 18 h (l) Morpholine (2.0 equiv), DMF, 50 °C, 2 h. (m) NaN₃ (1.2 equiv), DMSO, 0 °C to 25 °C, 6 h. (n) PhOH (2 equiv), K₂CO₃ (powdered, 5 equiv), DMSO, 50 °C, 2 h. (o) 4-(Triflouromethyl)-phenylboronic acid (1.5 equiv), Pd(PPh₃)₄ (0.1 equiv), Cs₂CO₃ (2 equiv), 4:1 dioxane:H₂O, 25 °C, 16 h. (p) Ethyl acrylate (1.5 equiv), Pd(OAc)₂ (0.05 equiv), P(o-Tol)₃ (0.1 equiv), DIPEA (neat), 16 h. (q) TMS-acetylene (3.0 equiv), Pd(PPh₃)₂Cl₂ (0.02 equiv), CuI (0.05 equiv) 3:1 Et₃N:CH₂Cl₂, 0 °C to 25 °C, 18 h.

Conclusion

The development of base metal-mediated processes that rapidly introduce chemical complexity to simple starting materials is of significant interest to the field. Our group has developed a method for iron-mediated regioselective propargylic C−H functionalization for the synthesis of densely substituted dihydropyrrole scaffolds using a deprotonation-cyclization-demetallation cascade strategy. Notably, under stoichiometric conditions, functionalization of the more-substituted propargylic position proceeded with excellent C−H regioselectivity and also allowed for previously unreported propargylic functionalization of methine C−H bonds for the formation of products containing all-carbon quaternary centers. Following cycloaddition, the product organoiron species can be demetallated under divergent conditions to afford a host of diverse dihydropyrrolone products and their derivatives.

Experimental Section

General information, detailed experimental procedures, characterization data, crystallographic data, and copies of ¹H and ¹³C NMR spectra of all newly reported compounds are included in the Supporting Information. Deposition Numbers 2256673 (for 6), 2256674 (for 6’), 2256675 (for 10c), and 2256676 (for 11b) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe <url href=“http://www.ccdc.cam.ac.uk/structures”> Access Structures service</url>.

Representative examples for cycloaddition and demetallation procedures are shown below.

Complex 5. In a nitrogen-filled glovebox, a flame-dried flask equipped with a stir bar was charged with Fp*I (100 mg, 267 μmol), AgBF₄ (54.7 mg, 281 μmol, 1.05 equiv), then 2-heptyne (79.3 μL, 1.5 equiv) and dry toluene (500 μL). The mixture was stirred for 30 minutes then dry dichloromethane (500 μL) was added. The color changes from deep black to red to brown over 2 hours and was left to stir overnight (14h). The solution was cooled in an ice bath, and to the stirring solution was added Me₂NCy (121 μL, 3.0 equiv) causing an immediate color change to a lighter brown. The mixture was warmed to room temperature with stirring for 3 hours. A short column of neutral alumina (activated, Brockmann Activity I, Supelco) was equilibrated with diethyl ether. The reaction mixture was flushed through this column with a solvent system of 1:1 diethyl ether: CH₂Cl₂ to remove brown and grey precipitate at the baseline of the column until the orange eluent ran colorless. The filtrate was quickly concentrated to ¼ volume under reduced pressure and a stir bar was added to the orange solution. The vessel was capped with a rubber septum, purged with N₂, dissolved in distilled dichloromethane (5 mL), and cooled to 0 °C under a nitrogen ballon for use within 5 minutes. TsNCO (61.3 μL, 1.5 equiv) was withdrawn with a syringe from a container in a nitrogen-filled glovebox and added dropwise to the orange solution with stirring. The mixture was warmed to room temperature and monitored in 30-minute intervals for the disappearance of the orange allenyliron species by TLC (R_f = 0.9, SiO₂, 85:15 hexanes:EtOAc). After 2 hours, the reaction mixture was quenched by the dropwise addition of ethylene diamine (200 μL) with vigorous stirring at 0 °C causing the reaction mixture to change from brown to orange-yellow in color immediately and form a yellow-white sticky precipitate. (Leaving the reaction mixture for longer reaction times often results in significant tautomerization and formation of the organometallic species complex 5’). The mixture was added to a separatory funnel with cold water (20 mL) and extracted thrice with CH₂Cl₂ (3 × 10 mL) . The combined organic layers were diluted with an equal volume of hexanes (30 mL) while a silica column was packed and equilibrated with hexanes. The organic extract solution was applied to the column using flash chromatography techniques creating a deep red-orange band at the baseline. The column was eluted first with several column volumes of 1:1 hexanes: CH₂Cl₂ then with a gradient of hexanes:EtOAc (9:1 to 7:3) which elutes the desired organometallic product as a bright yellow band. Upon concentration, the yellow oil solidifies to glittery yellow solid (94.4 mg, 65.4%) that can be further recrystallized from Et₂O:CH₂Cl₂ for characterization. The complex was dried under vacuum for <1 h before use in subsequent demetallative transformations. ¹H NMR (601 MHz, CDCl₃) δ 7.96 (d, J = 7.8 Hz, 2H, tosyl), 7.28 (d, J = 7.9 Hz, 2H, tosyl), 4.43 (broad q, J = 5.8 Hz, 1H, allylic methine), 2.40 (s, 3H, tosyl), 2.33 (broadened, 1H, diasterotopic allylic H_a), 2.02 (broadened, 1H, diasterotopic allylic H_b), 1.72 (s, 15H, Cp*), 1.59 – 1.55 (broadened, 1H), 1.53 (d, J = 6.5 Hz, 3H), 1.33 (broadened, 1H), 0.89 (t, J = 7.2 Hz). ¹³C NMR (151 MHz, CDCl₃) δ 216.5, 216.1, 167.2, 143.9, 143.4, 137.3, 129.7, 129.3, 127.9, 126.5, 97.0, 32.0 , 21.6, 21.1, 14.3, 9.8. HRMS (ESI) calc’d for C₂₇H₃₄O₅NFeS [M+H]⁺: 540.1501, found: 540.1491. IR (ATR, neat): ν(CO) = 1998, 1946 cm⁻¹.

5b, 4-Bromo-5-methyl-3-propyl-1-tosyl-1,5-dihydro-2H-pyrrol-2-one. To a solution of complex 5 (66.0 mg, 122 μmol) in distilled THF (2.0 mL) at 0 °C was added dropwise over 5 minutes a solution of N-bromosuccinimide (21.0 mg, 117 μmol, 0.96 equiv) in distilled THF (2.0 mL). The reaction mixture is stirred at 0 °C for 4 h at which point a solution of sodium bisulfite (1.0 M, 5.0 mL) is added. The mixture is extracted with EtOAc (3 × 5 mL), and the combined organic layers are dried over MgSO₄, filtered, and concentrated. The crude mixture is purified by column chromatography (SiO₂, 19:1 to 4:1, hexanes:EtOAc) to give the desired product as a white crystalline solid (25.0 mg, 54.9%). ¹H NMR (601 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.16 (bs, 1H), 2.43 (s, 3H), 2.21 (td, J = 8.2, 2.8 Hz, 2H), 2.02 (s, 3H), 1.54 – 1.44 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 164.8, 145.4, 143.8, 136.3, 135.8, 129.6, 128.5, 92.1, 26.8, 26.6, 21.7, 20.3, 13.8. HRMS (ESI) calc’d for C₁₅H₁₉O₃NBrS [M+H]⁺: 372.0264, found: 372.0263.

5c, 4-Bromo-5-methylene-3-propyl-1-tosyl-1,5-dihydro-2H-pyrrol-2-one. To a solution of complex 5 (66.0 mg, 122 μmol) in distilled THF (2.0 mL) at 0 °C was added dropwise over 5 minutes a solution of N-bromosuccinimide (66.0 mg, 367 μmol, 3.0 equiv) in distilled THF (2.0 mL). The reaction mixture is stirred at 0 °C for 10 minutes then warmed to room temperature. The solution was monitored by TLC for disappearance of 5b at which point a solution of sodium bisulfite (1.0 M, 5.0 mL) is added. The mixture is extracted with EtOAc (3 × 5 mL), and the combined organic layers are dried over MgSO₄, filtered, and concentrated. The crude mixture is purified by column chromatography (SiO₂, 19:1 to 4:1, hexanes:EtOAc), and fractions containing the desired product are concentrated in the dark and wrapped in foil for drying. The product when pure is a white crystalline solid (38.4 mg, 84.7%), that turns dark brown and appears to decompose upon prolonged exposure to light. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.18 (overlapping, J = 14.4, 7.1 Hz, 3H), 7.07 (d, J = 7.0 Hz, 2H), 6.23 (d, J = 2.1 Hz, 1H), 5.39 (d, J = 2.1 Hz, 1H), 2.83 – 2.74 (dd, J = 9.1, 6.6 Hz, 2H), 2.63 (dd, J = 9.1, 6.6 Hz, 2H), 2.45 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 165.2, 145.6, 140.2, 139.0, 135.4, 134.8, 132.9, 129.8, 128.4, 128.4, 128.0, 126.3, 103.3, 33.0, 27.6, 21.7. HRMS (ESI) calc’d for C₂₀H₁₉O₃NBrS [M+H]⁺: 432.0264, found: 432.0265.

5f, 4-Fluoro-5-methyl-3-propyl-1-tosyl-1,5-dihydro-2H-pyrrol-2-one. In a nitrogen-filled glovebox, a flame-dried flask equipped with a stir bar was charged with 2,6-dichloro-1-fluoropyridinium tetrafluoroborate (24.8 mg, 97.9 μmol, 1.1 equiv) and was added recently-distilled THF (500 μL) then the solution cooled under a nitrogen balloon in an ice bath. To this solution was added via syringe a recently-prepared solution of complex 5 (48 mg, 890 μmol) in recently-distilled THF (two portions of 500μL). The reaction was brought to room temperature and stirred for 16 h. The reaction mixture was flushed through silica with 1:1 hexanes:EtOAc and the eluent concentrated. The material was purified by flash column chromatography (SiO₂, 9:1 to 4:1 hexanes:EtOAc) to give the product as a colorless oil (22.6 mg, 59.4%). ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J = 8.3 Hz, 2H, tosyl), 7.33 (d, J = 8.1 Hz, 2H, tosyl), 4.68 (q, J = 6.3 Hz, 1H, NCH), 2.43 (s, 3H, tosyl), 2.11 (t, J = 7.6 Hz, 2H), 1.66 (d, J = 6.5 Hz, 3H), 1.54 – 1.45 (m, apparent sextet, 2H), 0.86 (t, J = 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 173.6 (d, J = 293.9 Hz), 167.7 (d, J = 18.0 Hz), 145.1, 136.1, 129.7, 128.1, 112.6 (d, J = 4.8 Hz), 55.1 (d, J = 25.8 Hz), 23.0 (d, J = 2.1 Hz), 21.7, 20.3 (d, J = 1.7 Hz), 17.5, 13.7. ¹⁹F NMR (471 MHz, CDCl₃) δ −113.2. HRMS (ESI) calc’d for C₁₅H₁₉O₃NFS [M+H]⁺: 312.1064, found: 312.1065.

Complex 6. In a nitrogen-filled glovebox, a flame-dried flask equipped with a stir bar was charged with Fp*(thf)BF₄ (100 mg, 246 μmol), 4-methyl-2-pentyne (42.7 μL, 373 μmol, 1.5 equiv) and dry dichloromethane (1.0 mL). The mixture was stirred for 12 h causing a change of color from bright red to yellow-brown. Dimethylcyclohexylamine (111 μL, 739 μmol, 3.0 equiv) was added dropwise causing a faint lightening of the solution and the mixture was stirred for 4 h. The mixture was cooled to 0 °C and tosyl isocyanate (75 μL, 493 μmol, 2.0 equiv) was added dropwise over 3 minutes via syringe. The mixture was warmed to 25°C for 1 h at which point disappearance of the allenyliron intermediate is observed by TLC (R_f = 0.9 , SiO₂, 9:1 hexanes:EtOAc). The reaction was cooled to 0 °C and quenched with the addition of ethylene diamine (300 μL) and stirred for 5 minutes, then partitioned between water (10 mL) and dichloromethane (10 mL). The aqueous layer was extracted thrice with CH₂Cl₂ (3 × 10 mL) and the organic layers were combined. To the organic mixture was added an equal volume of hexanes and the mixture swirled to homogeneity. This mixture was poured over a silica column equilibrated with hexanes and flushed with two column volumes of 1:1 hexanes:CH₂Cl₂, trapping the desired product at the baseline. The column was then eluted with a gradient (SiO₂, hexanes:EtOAc 9:1 to 3:1, R_f = 0.25 in 3:1) to give the desired product as a yellow oil that crystallized to a glittery yellow foam under high vacuum (120 mg, 93%). The product could be recrystallized from a mixture of CH₂Cl₂ and Et₂O at 20 °C for single-crystal X-ray crystallographic analysis. Increasing the scale of the above procedure to 1.00 g Fp*(thf)BF₄, (10-fold increase) gave the product at a somewhat reduced yield (1.01 g, 78.0%). ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 1.71 (s, 15H), 0.94 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 185.8, 144.1, 137.8, 136.9, 132.3, 129.4, 127.6, 96.7, 55.1, 10.2. HRMS (ESI) calc’d for C₂₆H₃₂O₅NFeS [M+H]⁺: 526.1345, found: 526.1349. IR (ATR, neat): ν(CO) = 1992, 1935 cm⁻¹.

6c, 4-Bromo-5-(bromomethyl)-3,3-dimethyl-1-tosyl-1,3-dihydro-2H-pyrrol-2-one. To a solution of complex 6 (50.0 mg, 98.4 μmol) in distilled THF (1.0 mL) at 0 °C was added dropwise a freshly prepared solution of bromine (portion of a stock solution, 14.7 μL, 300 μmol, 3.0 equiv) in distilled THF (2.0 mL). The reaction mixture is warmed to room temperature and stirred for 4 h at which point the reaction mixture has changed from bright yellow to deep orange and starting material 6 is consumed by TLC. Tetrabuylammonium bromide (Bu₄NBr, 95 mg, 3 equiv) and dichloromethane (2.0 mL) were added, and the mixture was stirred in the sealed vessel for an additional 2 h at 40 °C. A solution of chilled sodium bisulfite (1.0 M, 5.0 mL) is added, and the mixture is extracted with EtOAc (3 × 5 mL), and the combined organic layers are dried over MgSO₄, filtered, and concentrated. The crude mixture is purified by column chromatography (SiO₂, 39:1 to 9:1, hexanes:EtOAc) to give the desired product as a white crystalline solid. (31.1 mg, 75.1%). ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.72 (s, 2H), 2.45 (s, 3H), 1.13 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 145.7, 135.0, 134.9, 129.6, 128.8, 116.3, 49.2, 22.7, 22.5, 21.8. HRMS (ESI) calc’d for C₁₄H₁₆O₃NBr₂S [M+H]⁺: 435.9212, found: 435.9216.

6d, 3,3,5-Trimethyl-1-tosyl-1,3-dihydro-2H-pyrrol-2-one-4-d. To a solution of complex 6 (50.0 mg, 98.4 μmol) in distilled THF (5.0 mL) and D₂O (1.0 mL, NMR solvent grade) at 0 °C was added dropwise neat chlorotrimethylsilane (TMSCl, 50 μL, 3.3 equiv). The reaction mixture is stirred at 0 °C for 10 minutes then slowly warmed to room temperature over the course of 12 h. Upon addition of the TMSCl, the reaction partitions into layers which must be stirred vigorously to allow for intermixing. Separately, into a separatory funnel was added a 1.0M sodium carbonate solution and some ice chunks. The reaction mixture is transferred to the separatory funnel and the bright orange organic layer is separated. The aqueous layer is extracted with two additional volumes of CH₂Cl₂ (2 × 10 mL). The combined organic layers are washed once with brine then diluted with an equal volume of hexanes and loaded onto a silica column. The column is eluted with a gradient of hexanes:EtOAc (95:5 to 4:1) to give the 6d which crystallizes upon concentration (19.2 mg, 70%, 95% D incorporation). ¹H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.00 (s, J = 1.4 Hz, 0.05H, protodemetallation product), 2.36 (s, 3H), 2.20 (d, J = 1.4 Hz, 3H), 1.01 (s, 3H). ¹³C NMR (151 MHz, CDCl3) δ 181.2, 144.9, 137.0, 136.1, 129.7, 127.8, (116.2, 116.0, 115.9 (t, J = 26.8 Hz, C-D), 45.2, 23.7, 21.7, 16.6. HRMS (ESI) calc’d for C₁₄H₁₇DO₃N₂ [M+H]+: 281.10709, found: 281.10647.

6f, 4-Fluoro-3,3,5-trimethyl-1-tosyl-1,3-dihydro-2H-pyrrol-2-one. In a nitrogen-filled glovebox, a flame-dried flask equipped with a stir bar was charged with 1-fluoro-2,6-dichloropyridinium tetrafluoroborate (50.0 mg, 197 μmol, 2.0 equiv). The vessel was sealed, removed from the glovebox, and placed into an ice bath under a nitrogen balloon. Separately, a solution of complex 6 (40 mg, 98.5 μmol, 1.0 equiv) was prepared with freshly distilled THF (2.0 mL). The freshly prepared yellow solution was added dropwise to the sealed vessel through the septum such that the material runs down the side of the flask and is cooled before reaching the solid at the bottom. The mixture was stirred for 30 minutes before being removed from the ice bath and then is stirred at room temperature overnight (25°C, 14 h). The crude reaction mixture is loaded directly onto a short silica plug and flushed through silica gel with 5 column volumes of 4:1 hexanes:EtOAc then the filtrate is concentrated to dryness. The crude product is purified by chromatography (SiO₂, 9:1 to 4:1 hexanes:EtOAc) to give 6a as a white crystalline solid (19.0 mg, 64.9%). ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.37 (s, 2H), 2.15 (d, J = 3.4 Hz, 3H), 1.07 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 175.9 (d, J = 9.8 Hz), 151.1 (d, J = 265.9 Hz, F-C), 145.2, 135.6, 129.8, 127.7, 117.4 (d, J = 25.1 Hz), 44.2 (d, J = 19.8 Hz), 21.7, 21.0 (d, J = 2.6 Hz), 10.2. ¹⁹F NMR (471 MHz, CDCl₃) δ −163.66. HRMS (ESI) calc’d for C₁₄H₁₆O₃NFS [M+H]⁺: 297.0829, found: 297.0825.

6i, 4-Iodo-3,3,5-trimethyl-1-tosyl-1,3-dihydro-2H-pyrrol-2-one. To a solution of complex 6 (50.0 mg, 98.4 μmol) in distilled THF (1.0 mL) at 0 °C in a foil-wrapped container was added dropwise a freshly prepared solution of iodine (31.3 mg, 1.0 equiv, measured by mass) in distilled THF (2.0 mL). The reaction mixture is stirred at 0 °C for 4 h at which point a solution of sodium bisulfite (1.0 M, 5.0 mL) is added. The mixture is extracted with EtOAc (3 × 5 mL), and the combined organic layers are dried over MgSO₄, filtered, and concentrated in the dark. The crude mixture is purified by column chromatography (SiO₂, 19:1 to 4:1, hexanes:EtOAc) to give the desired product as a white crystalline solid (29.3 mg, 58.7%). ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 2.44 (s, 2H), 2.39 (s, 2H), 1.04 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 178.2, 145.4, 135.6, 129.8, 127.9, 49.7, 24.0, 21.8, 18.1. HRMS (ESI) calc’d for C₁₄H₁₇O₃NIS [M+H]⁺: 405.9968, found: 405.9963.

6k, 4-Chloro-3,3,5-trimethyl-1-tosyl-1,3-dihydro-2H-pyrrol-2-one. To a flame-dried screw-top vessel with stir bar was added N-chlorosuccinimide (26.3 mg, 197 μmol, 2.0 equiv). The vessel was sealed and thrice purged with a nitrogen atmosphere. Separately, a solution of complex 6 (40 mg, 98.5 μmol, 1.0 equiv) was prepared with freshly distilled THF (2.0 mL). The freshly prepared yellow solution was added to the sealed vessel then the vessel was heated to 50 °C for 16 hours. The solution changes from a bright yellow color to an orange color. The crude reaction mixture is loaded directly onto a short silica plug and flushed through silica gel with 5 column volumes of 4:1 hexanes:EtOAc then the filtrate is concentrated to dryness. The crude product is purified by chromatography (SiO₂, 9:1 to 4:1 hexanes:EtOAc) to give 6k as a white crystalline solid (15.5 mg, 50.1%). ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 1.12 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 178.1, 145.4, 135.7, 132.0, 129.8, 127.8, 120.1, 47.9, 22.0, 21.7, 12.9. HRMS (ESI) calc’d for C₁₄H₁₇O₃NClS [M+H]+: 314.0612, found: 314.0666.