Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2026 Jan 15.
Published in final edited form as: J Am Chem Soc. 2025 Sep 8;147(37):33923–33931. doi: 10.1021/jacs.5c10617

Synthesis of Bicyclo[2.1.0]pentanes and Vinylcyclopropanes Using Palladium Carbenes: Ligand-Controlled Carbene Reactivity

Isaiah K Eckart-Frank 1, Emily S Arnold 2,‡, Liam P Murphy 3,‡, Sidney M Wilkerson-Hill 4
PMCID: PMC12801349  NIHMSID: NIHMS2133842  PMID: 40921025

Abstract

Once physical organic curiosities, bicyclo[2.1.0]pentanes (colloquially termed housanes) are useful strain-release reagents and are unique structural motifs for medicinal chemistry campaigns because of their high Fsp3 content. Despite this, methods to synthesize housanes are lacking due to their highly strained nature. Herein, we report an intramolecular cyclopropanation strategy to obtain functionalized housanes using palladium carbenes (20 substrates, up to 89% yield). Key to the success of this reaction was the insight that the reactivity of Pd(0) carbenes is controlled by the supporting ligand. Strongly donating N-heterocyclic carbine ligands promote cyclopropanation reactivity, while some π-accepting phosphoramidite ligands (e.g., rac-MonoPhos) afford C–H insertion products (8 examples, up to 20:1 selectivity). Deuterium-labeling studies revealed a KIE of 2.1 at 80 °C, suggesting a palladium carbene is involved in the C–H insertion step, and the independent synthesis of alkyldiazenes confirms that they are not relevant intermediates in this reaction. The housane products were amenable to late-stage cross-coupling reactions and ring-opening reactions to provide cyclopentanes.

Graphical Abstract

graphic file with name nihms-2133842-f0001.jpg

INTRODUCTION

Cyclopropanes are indispensable tailoring elements encountered in medical chemistry campaigns because the physical properties of these strained rings often translate into desirable function.1 These rigid carbocycles increase Fsp3,2 have well-defined exit vectors,3 and contain strong C–H bonds that are less susceptible to oxidation by cytochrome P450s.4 Ring-fused cyclopropane groups are particularly valuable chemotypes because they serve as “rigidified” versions of saturated heterocyclic and carbocyclic rings while maintaining the compound’s general topology. Specifically, bicyclo[2.1.0]pentanes (colloquially termed housanes), which have a ring strain of 57.3 kcal/mol, have been recognized as rigidified cyclopentanes.5 The synthesis of cyclopropanes is most readily accomplished by [2 + 1] cycloaddition reactions between alkenes and metal carbenes (Figure 1A) because these reactions are both convergent and modular.6 So, catalytic methods to obtain cyclopropane groups in more complex environments are needed to address the ever-increasing structural complexity of active pharmaceutical ingredients.

Figure 1.

Figure 1.

Open in a new tab

Background on cyclopropane synthesis and housanes. (A) Common disconnections for cyclopropane synthesis using carbenes. (B) Previous reports to make housanes using intramolecular cyclopropanation reaction. (C) Divergent reactivity of palladium(0) carbenes.

The synthesis of more highly strained cyclopropanes, such as those embedded within housanes,7 using intramolecular [2 + 1] cycloaddition reactions with metal carbene intermediates is challenging because of the steric and conformational demands imposed by the structures of these small rigid systems and the need to overcome unwanted C–H insertion reactions that lead to less strained vinylcyclopropane products.8 Indeed, there are only three reports detailing the scope of intramolecular cyclopropanation reactions to obtain housanes, which underscores the difficulty of this transformation (Figure 1B).9 Consequently, other strategies based on transannular C–C bond formation,5,10 intermolecular and intramolecular cyclopropanation of cyclobutenes,11 photochemical [2 + 2] cycloadditions with cyclopropenes,12 and N2 extrusion from cyclic alkyldiazenes13 have been used to obtain housanes.

As a part of a research program centered on the synthesis of strained molecules, we previously demonstrated the ability of Pd carbenes to produce spirocyclic cyclobutanes and cyclopropanes.14 During these studies, we observed a dramatic effect of the metal oxidation level and ligand on the outcome of the reaction and demonstrated the formation of bicyclo[2.1.0]pentanes from Pd(0) carbene intermediates. We hypothesized that Pd-catalyzed cyclopropanation reactions could be a general platform to obtain housanes since they proceed through metallacyclobutane intermediates15–18 and are thus mechanistically distinct from reactions of diazo compounds with Rh(II) complexes.19 Additionally, the judicious choice of ligands on Pd would enable the selective formation of housanes over C–H insertion products. We hypothesized based on observations in our initial report that strong σ-donor ligands would favor housane formation, while strong π-accepting ligands would favor C–H insertion. Herein, we report an approach to housanes and vinylcyclopropanes using palladium carbenes (Figure 1C). By studying the synthesis of these carbocycles, we have also gained additional insight into the reactivity of Pd-carbenes20,21 and showed that ligand electronics influence cyclopropanation versus C–H insertion selectivity in these transformations.

RESULTS AND DISCUSSION

Reaction Optimization.

We began these studies by synthesizing allyl hydrazone 1a and cinnamyl hydrazone 1b derived from methyl N-tosylpiperidine-4-carboxylate and testing the impact of the transition metal catalyst identity on cyclopropanation reactivity (Table 1). We initially focused on catalysts known to affect intramolecular cyclopropanation reactions using diazoesters. We found that many of these catalysts were less selective for cyclopropanation products 2a and 2b and instead primarily produced the isomeric vinylcyclopropanes (VCPs) 3a and 3b via an intramolecular insertion to the allylic C–H bond. Rh2(OAc)4, for example, gave 12% yield of housane 2a and 67% yield of VCP 3a (1:5.6 selectivity) (Table 1, Entry 1). A CuTp′ catalyst22 also produced mostly VCP 3a (48% yield, 1:2.1 selectivity) (Table 1, Entry 2). Ni(0) with an N-heterocyclic carbene (NHC) ligand afforded low yields of the desired housane 2a (15% by 1H NMR), but without the formation of the isomeric VCP 3a (Table 1, Entry 3).

Table 1.

Optimization of Reaction Conditionsa

graphic file with name nihms-2133842-t0003.jpg
entry catalyst M R % yield 2 % yield 3 ratio 2:3
1b Rh2(OAc)4 Li H 12 67 1:5.6
2b CuTp′ Li H 23 48 1:2.1
3b Ni(COD)2, SIPr·HCl Li H 15 nd >20:1
4 Pd(dba)2, no ligand added Li H 34 17 2.0:1
5 Pd(dba)2, P(tBu)3·HBF4 Na H 56 6 9.3:1
6 Pd(dba)2, P(Ad)3 Na H 64 5 12.8:1
7 Pd(dba)2, IPr Na H 85 1 >20:1
8 Pd(dba)2, IPr·HCl Li H 94 2 >20:1
9 Pd(COD) (DQ), IPr·HCl Na H 92 1 >20:1
10 Pd(dba)2, IPr·HCl Li/Na Ph >20:1 to 4:1
11 IPr PEPPSI Na Ph 88 1 >20:1
12c [(IMes) Pd(NQ)]2 Na Ph 96 1 >20:1
13c [(IMes) Pd(NQ)]2 Na H 77 <3 >20:1
14 Pd(dba)2, rac-MonoPhos Na H 16 63 1:4.0
Open in a new tab
a

Yields are 1H NMR yields of the crude reaction mixture measured using mesitylene or hexamethyldisiloxane as an internal standard.

b

10 mol % catalyst loading.

c

2.5 mol % catalyst loading.

We then investigated Pd(0) precatalysts and ligand combinations. Bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) without additional added ligand resulted in low selectivity for housane 2a (34% 1H NMR yield, 2.0:1 ratio, entry 4). The use of Pd(dba)2 with electron-rich, bulky phosphines such as P(tBu)3·HBF4 or P(Ad)3 resulted in moderate selectivity for housane 2a (9.3:1 and 12.8:1 ratios, respectively) (Table 1, Entries 5 and 6). Pd(dba)2 with strong σ-donating NHC ligands such as IPr or its imidazolium salt produced housane 2a with high yield and selectivity (>90% 1H NMR yield, >20:1) from hydrazone 1a (Table 1, Entries 7 and 8). The catalyst and ligand loading in this case could be reduced to 1.0 mol %. Other Pd(0) precatalysts such as Pd(COD)(DQ) also provided high yield and selectivity for housane 2a (Table 1, Entry 9).23 While the Pd(dba)/IPr metal–ligand combination was effective for allyl hydrazone 1a, cinnamyl-derived hydrazones (e.g., 1b) produced inconsistent housane/VCP ratios across multiple runs (from >20:1 to 4:1, Table 1, Entry 10).24 We proposed the low reproducibility with Pd(dba)2 and NHC ligands or precursors was due to competitive coordination of Pd to the styrenyl π-bond and side reactions like nucleophilic addition of the NHC to dba and to the hydrazone substrate (vide infra).25,26 These processes decreased the concentration of the desired active Pd NHC catalyst and produced species of less selective Pd complexes in solution. As such, we investigated the use of precomplexed commercial Pd(0) NHC catalysts. The IPr PEPPSI catalyst produced phenyl housane 2b in 88% yield and >20:1 ratio (Table 1, Entry 11). We also investigated the commercial Pd(0) NHC dimer [(IMes)Pd(NQ)]227 and observed good yields and high selectivity for phenyl housane 2b with retained selectivity for housane 2a (Table 1, Entries 12, 13). Using the phosphoramidite rac-MonoPhos28 with Pd(dba)2 resulted in a reversal of product selectivity, favoring VCP 3a (63% yield, 1:4 ratio, Table 1, Entry 14).16e,f These results demonstrated the unique ability of Pd carbenes to produce highly strained housanes from alkene-tethered hydrazones with excellent ligand control when compared with other transition metal catalysts. Changing additional variables, such as solvent, inorganic base, and temperature, had a negative or minimal impact on selectivity.

Scope of the Intramolecular Cyclopropanation Reaction.

We then used the data from our reaction optimization campaign to inform our selection of hydrazone substrates to produce housane compounds. We found that the intramolecular cyclopropanation reaction was quite general. First, we tested hydrazones derived from methyl N-tosylpiperidine-4-carboxylate with varied alkene identities (Figure 2, top). We found that Z-cinnamyl hydrazone 1c produced the corresponding housane 2c containing an endo-phenyl group in 67% yield and 8.2:1 ratio of housane to VCP. An allylic methyl group was tolerated, yielding methyl housane 2d isolated in 80% yield as a 2:1 mixture of diastereomers, but with high housane to VCP selectivity (>20:1 ratio). Using hydrazone 1e bearing a 1,1-disubstituted alkene afforded [2.1.0]-bicycle 2e bearing an angular methyl group isolated in 78% yield. Trisubstituted alkene substrate 1f was also viable in the reaction, producing substituted product 2f in 88% yield (>20:1 ratio). Notably, the cyclopropanation reaction of prenyl hydrazone 1g was much more challenging, and dimethyl housane 2g and VCP isomer 3g were isolated as a mixture in 68% yield (1:1.2 ratio). We tested the effect of the tether length using homoallyl hydrazone 1h. This compound produced the corresponding cyclopropane 2h isolated in 70% yield. Significant amounts of the diazene, which arises from a thermal [3 + 2] cycloaddition reaction of the diazo intermediate and alkene, were obtained in this reaction (vide infra). A variety of housane products (2i–2l) derived from E-cinnamyl hydrazones containing different arene electronics (1i–1l) were also obtained (Figure 2, left of center). Electron-rich, electron-neutral, and electron-deficient arenes performed well in this reaction and each aryl housane was obtained in good yields and in >20:1 ratio. The reaction conducted using E-cinnamyl hydrazone (1b) on a 1.0 mmol scale produced the product 2b in 70% yield (>20:1 selectivity).

Figure 2.

Figure 2.

Open in a new tab

NHC-Pd-catalyzed cyclopropanation tolerates substitution at each carbon of the housane motif. Conditions: [(IMes)Pd(NQ)]2 (2.5 mol %), NaOtBu (2.0 equiv), PhMe (0.1 M), 80 °C, 2 h. Yields from reactions were obtained on a 0.100 mmol scale unless otherwise stated. Yields in parentheses are 1H NMR yields measured using mesitylene as an internal standard. Cyclopropanation: C–H insertion selectivity >20:1 unless otherwise stated. (a) Isolated yield refers to the combined yield of the inseparable mixture of 2 and 3. (b) Reaction run with 5 mol % [(IMes)Pd(NQ)]2. (c) Substrate repeated for comparison purposes. Second yield refers to an experiment performed on a 1.0 mmol scale.

We also investigated how changing both the hydrazone compound and the alkene component affected reactivity (Figure 2, center, α-aryl, and α-alkyl cinnamyl substrates). Specifically, hydrazones 1m and 1n produced their corresponding housanes in 89% and 87% yield, respectively. For these substrates, we did not observe significant amounts of products resulting from migration of the α-groups (phenyl migration for substrate 1m and methyl migration for substrate 1n) to produce the corresponding dienes. We rationalized this effect was due to a faster rate of [2 + 2] to form the metallacyclobutane than group migration due to precoordination of the pendant alkene to Pd.16a

We also investigated how the groups on the hydrazone backbone affected the reactivity (Figure 2, bottom). For example, using a hydrazone with nonidentical α-alkyl groups (e.g., Me and Bn in hydrazone 1o) produced the corresponding housane product 2o with high housane/VCP selectivity, but as a mixture of diastereomers (2.6:1 d.r.). We found that ketone-derived hydrazones also performed moderately well in the reaction, affording housane 2p in 39% yield. Using hydrazones containing α-aryl groups, such as compounds 1q and 1r, gave housane 2q and 2r in 76% and 47% yield, respectively. No aryl migration products were observed for 1q; however, fluorenyl hydrazone 1r afforded a substantial amount of 9-allylphenanthrene (4.5:1 selectivity). Lastly, we changed the saturated heterocyclic backbone of the substrates to afford an unsymmetrical N-tosyl piperidine housane 2s and a tetrahydropyran-containing housane product 2t isolated in 83% (1:1 dr) and 49% yield, respectively. We found azetidines could be tolerated to produce the highly strained N-tosyl spiro[azetidine-3,2′-bicyclo[2.1.0]pentane] 2u isolated in 36% yield as the major product without significant ring expansion into the Pd carbene.29 The structure of azetidine 2u was confirmed by X-ray crystallographic analysis (Figure 2, center right).

Effect of Phosphoramidite Ligands on Product Selectivity.

We then sought to test the scope of the C–H insertion reaction using phosphoramidite ligands (Figure 3). Using rac-MonoPhos as a ligand, we found that we could obtain selectivity for C–H insertion products using some of the same hydrazone substrates that gave housanes using NHC ligands; however, these reactions were much less general, and product distributions were highly dependent on the structure of the alkene group and phosphoramidite ligand. For example, hydrazone 1a produced vinylcyclopropane 3a in 75% combined yield with good selectivity over the cyclopropanation product (4.0:1 selectivity). The cinnamyl hydrazone 1b produced vinylcyclopropane 3b in a 2.6:1 ratio and a 78% yield combined with the housane, whereas the opposite alkene stereoisomer 1c produced vinylcyclopropane 3c isolated in 70% yield in >20:1 ratio. Allyl methyl hydrazone 1d provided tetrasubstituted cyclopropane 3d in a 64% combined yield (2.0:1 product ratio). Using the more sterically encumbered alkene 1g produced the prenylated VCP 3g in a 76% combined yield (13.3:1 selectivity). We also demonstrated C–H insertion reactions on substrates lacking the alkene that was necessary for housane formation. Hydrazone 1v, for example, produced the corresponding C–H insertion product 3v isolated in 35% yield. Allylic C–H insertion prevails in this case since this pathway produces the less strained cyclopropane isomer, whereas benzylic C–H insertion would produce a more strained spirocyclopropane ring fusion. Next, we demonstrated that these carbenes are capable of effecting C–H insertion into unactivated C–H bonds. Hydrazone 1w, containing a pendant methyl group, afforded compound 3w in 51% yield. Surprisingly, cyclohexenyl hydrazone 1x exclusively produced spirocyclic cyclopropane 3x in 75% yield in >20:1 ratio with respect to other C–H insertion or intramolecular cyclopropanation products, suggesting 1,3-C–H insertion is kinetically favorable over other insertions or cyclopropanation reactions. Finally, the reaction of hydrazone substrate 1m, containing α-aryl groups, with Pd(dba)2 in the presence of rac-MonoPhos exclusively gave the aryl migration product 4 (96% 1H NMR yield, 7.3:1 E/Z). This result underscores the importance of ligand electronics on the outcome of Pd carbene reactions.

Figure 3.

Figure 3.

Open in a new tab

Scope of C–H insertions. Conditions: yields refer to the isolated yields of product mixtures. Selectivity refers to ratio of C–H insertion to cyclopropanation products and is determined by analysis of the crude reaction mixture by 1H NMR. (a) LiOtBu was used as the base for this reaction.

When a chiral nonracemic phosphoramidite ((R)-MonoPhos) was used, substrate 1b yielded vinylcyclopropane 3b in 31% ee (82% yield and 3.0:1 selectivity with respect to the housane 2b) (eq 1).16c Chiral phosphoramidite ligands containing substitution at the 3,3′-positions of the binaphthol ring produced lower selectivity for vinylcyclopropane over housanes and in some cases were selective for housanes. We are currently working to understand the impact of sterics and electronics of the ligands on C–H insertion selectivity, improving the enantioselectivity of the reaction for vinylcyclopropanes, determining the absolute stereochemistry of the products, and elucidating whether housane products can be obtained enantioselectively.24

graphic file with name nihms-2133842-f0002.jpg

Deuterium-Labeling Studies.

To obtain further mechanistic insights into the C–H insertion step, we conducted deuterium-labeling studies (Figure 4). We rationally designed monodeuterated hydrazone 1y to test aspects of the palladium carbene reactivity. When deuterated cinnamyl hydrazone 1y was subjected to our standard C–H insertion reaction conditions, we observed a 1:1.8 mixture of deuterated housane to VCP isomers. Deuterated housane 2y was observed with expected 1:1 d.r. (24% 1H NMR yield) without observable D-scrambling. Deuterated vinylcyclopropane 3y, resulting from carbene C–H insertion, was observed in 29% 1H NMR yield alongside the isomeric products cis-3y′ (10% 1H NMR yield) and trans-3y′ (4% 1H NMR yield) that result from carbene C–D insertion. For the VCP isomers, D was incorporated exclusively into the carbene carbon. From the ratio of compound 3y to the sum of cis-3y′ and trans-3y′, we calculated a kinetic isotope effect (KIE) of 2.1 at 80 °C, which is consistent with known metal carbene-catalyzed C–H/D insertion KIE values.30 Due to this agreement with literature data for metal carbene C–H insertions, this normal, primary KIE lends support to a C–H insertion step mediated by a Pd carbene.

Figure 4.

Figure 4.

Open in a new tab

Hydrazone deuterium-labeling studies reveal KIE of the intramolecular C–H insertion reaction. (a) Conditions are the optimized reaction conditions shown in Table 1. Pd(dba)2 (5 mol %), rac-MonoPhos (6 mol %), NaOtBu (2.0 equiv), PhMe, 80 °C, 2 h. Yields and ratios were calculated from an average of two experiments. The stereochemical indicators cis and trans refer to the relative stereochemistry between tertiary methine H and D in this case. For additional data supporting this KIE, see the Supporting Information.

Further support for the reaction mechanism comes from stereochemical probes (i.e., alkene geometry) within hydrazone substrates 1b and 1c. We found that 1b produced the product 2b with an exo-phenyl geometry. The analogous reaction using 1c produced the endo-phenyl cyclopropane product 2c. These results suggest that the reaction is both stereospecific and stereoselective.

Testing the Reactivity of Diazene Intermediates and Isolation of an NHC-Adduct.

It is well-established that alkyldiazene intermediates can be formed by thermal [3 + 2] cycloaddition reactions, and these intermediates convert to cyclopropanes both thermally and photochemically.13,31 Therefore, it was necessary to consider whether the housane products formed in our reaction arose from the intermediate alkyldiazenes. To gain further insight into the mechanism, we tested whether Pd-NHC complexes could catalyze the conversion of alkyldiazenes to the observed housane products (Figure 5, eq 2) by independently synthesizing compounds 5 and 6. Compound 5 was obtained using the method of Taber and was observed in the crude reaction mixture of 2h.31 Upon subjecting diazene 5 to the optimized reaction conditions, we did not observe the corresponding cyclopropane 2h, suggesting that it is not likely an intermediate en route to the product. Similarly, bridged bicyclic diazene 6 also failed to convert to the corresponding cyclopropane 2e (Figure 5, eq 3). Tautomerization of compound 5 to compound 7 was observed in aliquots of the crude reaction mixture using hydrazone 1h and attempts to isolate compound 7 afforded aldehyde 8. Unfortunately, we could not synthesize or observe the isomeric diazene 9, from which product 2a could also be formed, using thermal- or Lewis-acid-promoted reaction conditions. Therefore, it is unlikely this intermediate is produced during our reaction.

Figure 5.

Figure 5.

Open in a new tab

Independently synthesized alkyl diazenes do not react with Pd(0)-NHC catalysts to give housanes. N-Heterocyclic carbenes react with hydrazones to form diazene adducts. Yields in parentheses are 1H NMR yields measured using mesitylene as an internal standard.

Given the variability of the reactions of cinnamyl hydrazone substrates 1b and 1i–1n when conducted with Pd(dba)2 and IPr, we hypothesized the free NHC ligand could react with dba32 or with our hydrazone substrates (Figure 5). When palladium was omitted from the reaction mixture, we observed the unexpected addition of IPr into 1b to produce the stable adduct 10 (Figure 5, eq 4).33 These results underscore the importance of ensuring efficient complexation of NHC and palladium before adding hydrazone substrates.

Housane Functionalization Reactions.

Next, we demonstrated the utility of our substrates by functionalizing our housane compounds (Figure 6). More functionalized housanes have only been reported in limited studies,9a,b,10a,12a and many of the housanes obtained to date have electron-withdrawing groups at the ring fusion position, making them valuable strain release reagents.10b We synthesized and tested a hydrazone substrate (1z) bearing an aryl chloride, which could be used for late-stage cross-coupling reactions (Figure 6, top). As anticipated, the optimal reaction conditions produced an inseparable mixture of housane 2z alongside the protodehalogenation product 2b in 85% combined yield (3.5:1 ratio of 2z:2b). Shortening the reaction time to 1 h gave a comparable yield (75% combined isolated yield) with a greater ratio of 2z:2b (6.8:1). The chlorinated product, however, was amenable to palladium-catalyzed cross-coupling reactions (Figure 6, bottom). A Buchwald–Hartwig reaction with 1-methylpiperazine afforded product 11 in 80% isolated yield, and a Suzuki–Miyaura reaction with pyrimidine-5-boronic acid afforded product 12 in 72% yield. These functionalizations highlight the potential for a rapid increase in structural complexity from our hydrazone starting materials and occur without appreciable ring-opening of the [2.1.0]-bicycle.

Figure 6.

Figure 6.

Open in a new tab

(Top) hydrazone 1z containing an aryl chloride was tolerated under reaction conditions, with some dechlorinated product 2b formed. (a) [(IMes)Pd(NQ)]2 (2.5 mol %), NaOtBu (2.0 equiv), PhMe, 80 °C, 2 h. (b) 1 h reaction time. (Bottom) housane 2z is competent in Buchwald–Hartwig and Suzuki–Miyaura cross-couplings. (c) Pd(dba)2 (5 mol %), DavePhos (10 mol %), 1-methylpiperazine (1.2 equiv), NaOtBu (1.5 equiv). (d) Pd2(dba)3 (5 mol %), PCy3 (15 mol %), K3PO4 (2.0 equiv), and pyrimidine-5-boronic acid (1.5 equiv).

Additionally, we sought to define the ring-opening reactivity of structurally complex alkyl-substituted housane derivatives, which lack activating groups (Figure 7). We found that the C–C bond in 2a could be hydrogenated to produce cyclopentane 13 isolated in 95% yield. Conversely, the hydrogenation of the corresponding housane bearing a bridgehead methyl group (2e) did not proceed readily under these conditions to produce methyl cyclopentane, returning 80% starting material after 24 h. Upon treating methylhousane 2e with AgBF4, we observed the formation of cyclopentene 14 as a single regioisomer isolated in 90% yield.34 Interestingly, treatment of the unsubstituted housane 2a with AgBF4 resulted in a complex mixture of products and did not fully consume the housane starting material even after 116 h.24 A difunctionalization of the ring-fused C–C bond could also be accomplished. Reaction of 2e with BBr3 in the presence of phenylsilane afforded boronic ester 15 isolated in 39% yield (1.26:1 d.r.) after reaction with 3,4-diethylhexane-3,4-diol (Epin) and Et3N.35 When pinacol was used instead of Epin, borylated cyclopentane decomposed during purification. The lack of stereocontrol suggests a stepwise reduction and intermediate tertiary carbocation. Finally, removal of the tosyl group of housane 2b was affected using magnesium metal in methanol,36 affording spirocyclic piperidine 16 in 60% yield while preserving the bicyclo[2.1.0]pentane moiety.

Figure 7.

Figure 7.

Open in a new tab

(Top) Functionalizations of housanes 2a and 2e enable spiro cyclopentane synthesis. (Bottom) Piperidine deprotected using a mild Mg/MeOH reduction system.

CONCLUSION

In conclusion, we have demonstrated the ligand-controlled divergent reactivity of Pd(0) carbenes in intramolecular cyclopropanation and C–H insertion reactions to obtain strained bicyclic and spirocyclic cyclopropanes using non-stabilized carbenes. This intramolecular cyclopropanation method provides general access to alkyl-substituted housanes, tolerating varied substitution at each carbon of the housane. We have shown the reactivity of Pd(0) carbenes is impacted by the supporting ligand on palladium—strongly σ-donating ligands facilitate the formation of cyclopropanation products, while π-accepting phosphoramidites resulted primarily in C–H insertion products, though the effect was less general. Deuterium-labeling studies suggested that the C–H insertion occurs through a Pd carbene intermediate. Resubjection of cyclic alkyldiazenes to the reaction conditions showed that these species are likely not the intermediates that lead to the product in this reaction. Lastly, the strained C–C bond in the bicyclo[2.1.0]pentanes were leveraged for different ring-opening reactions. Future studies will be directed at developing a more detailed structural basis for the divergent reactivity of Pd carbenes, enantioselective variations of this reaction, and developing intermolecular reactions of palladium alkylidenes.

Supplementary Material

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c10617.

Experimental details, additional experimental results, and compound characterization (PDF)

ACKNOWLEDGMENTS

We thank the University of North Carolina’s Department of Chemistry NMR Core Laboratory and the Mass Spectrometry Core Laboratory for their assistance with characterization. These materials are based upon work supported by the National Science Foundation under Grant Nos. CHE-0922858, CHE-1828138, and CHE-1726291. We thank the University of North Carolina’s Department of Chemistry X-ray Crystallography Core and Dr. Chun-Hsing Chen for single-crystal analysis of 2u. This material is based upon work supported by the National Science Foundation under Grant No. CHE-2117287. We thank Prof. Keary Engle (Scripps Research) for his generous donation of the Pd(COD)(DQ) precatalyst used in this study.

Funding

S.M.W.-H. is grateful to the National Institutes of General Medicines (5R35GM155260), the Alfred P. Sloan Foundation (FG-2024-22218) for funding.

Footnotes

Accession Codes

Deposition Number 2434824 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

The authors declare no competing financial interest.

Complete contact information is available at: https://pubs.acs.org/10.1021/jacs.5c10617

NOTE ADDED IN PROOF

A new approach to synthesize housanes by Suero and coworkers37 appeared online in this journal on the day this study was accepted.

Contributor Information

Isaiah K. Eckart-Frank, Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States; Present Address: Process Research and Development, Abbvie, Inc., North Chicago, Illinois 60064, United States

Emily S. Arnold, Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Liam P. Murphy, Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Sidney M. Wilkerson-Hill, Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

REFERENCES

  • (1).(a) Shearer J; Castro JL; Lawson ADG; MacCoss M; Taylor RD Rings in Clinical Trials and Drugs: Present and Future. J. Med. Chem 2022, 65, 8699–8712. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Talele TT The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. J. Med. Chem 2016, 59, 8712–8756. [DOI] [PubMed] [Google Scholar]; (c) Taylor RD; MacCoss M; Lawson AD Rings in Drugs. J. Med. Chem 2014, 57, 5845–5859. [DOI] [PubMed] [Google Scholar]
  • (2).(a) Lovering F Escape from Flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515–519. [Google Scholar]; (b) Lovering F; Bikker J; Humblet C Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem 2009, 52, 6752–6756. [DOI] [PubMed] [Google Scholar]
  • (3).Carreira EM; Fessard TC Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities. Chem. Rev 2014, 114, 8257–8322. [DOI] [PubMed] [Google Scholar]
  • (4).(a) Suzuki M; Iwasaki H; Fujikawa Y; Kitahara M; Sakashita M; Sakoda R Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors. Bioorg. Med. Chem 2001, 9, 2727–2743. [DOI] [PubMed] [Google Scholar]; (b) Blanksby SJ; Ellison GB Bond dissociation energies of organic molecules. Acc. Chem. Res 2003, 36, 255–263. [DOI] [PubMed] [Google Scholar]
  • (5).(a) Semeno VV; Vasylchenko VO; Vashchenko BV; Lutsenko DO; Iminov RT; Volovenko OB; Grygorenko OO Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids. J. Org. Chem 2020, 85, 2321–2337. [DOI] [PubMed] [Google Scholar]; (b) Anslyn EV; Dougherty DA Modern Physical Organic Chemistry; University Science Books, 2006. [Google Scholar]
  • (6).(a) Kulinkovich OG Chapter III. Synthesis of Cyclopropanes. In Cyclopropanes in Organic Synthesis; Wiley: Hoboken, NJ, 2015; pp 57–98. [Google Scholar]; (b) Corey EJ; Cheng X-M The Logic of Chemical Synthesis; Wiley, 1995. [Google Scholar]
  • (7).(a) Carpenter BK Bicyclo[2.1.0]pentanes and Bicyclo[2.2.0]-hexanes. In The Chemistry of Cyclobutanes; Rappoport Z, Liebman JF, Eds.; PATAI’S Chemistry of Functional Groups; Wiley, 2009. [Google Scholar]; (b) Wiberg KB Small Ring Bicyclo[n.m.0]alkanes. Adv. Alicycl. Chem 1968, 2, 185–254. [Google Scholar]
  • (8).(a) Jiang L; Wang Z; Armstrong M; Suero MG β-Diazocarbonyl Compounds: Synthesis and their Rh(II)-Catalyzed 1,3 C–H Insertions. Angew. Chem., Int. Ed 2021, 60, 6177–6184. [DOI] [PubMed] [Google Scholar]; (b) Shi W; Zhang B; Zhang J; Liu B; Zhang S; Wang J Stereoselective Intramolecular 1,3 C–H Insertion in Rh(II) Carbene Reactions. Org. Lett 2005, 7, 3103–3106. [DOI] [PubMed] [Google Scholar]
  • (9).For examples of intramolecular cyclopropanation reactions to obtain housanes, see:; (a) Coto D; Suárez-García D; Mata S; Fernández I; López LA; Vicente R From Cyclopropene to Housane Derivatives via Intramolecular Cyclopropanation. Angew. Chem., Int. Ed 2024, 63, No. e202409226. [DOI] [PubMed] [Google Scholar]; (b) Sharland J; Davies HML One Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates. Org. Lett 2023, 25, 5214–5219. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Shi G-Q; Cia W-L Rhodium-Catalyzed Decomposition of δ,ε-Unsaturated β,β-Difluoro-α-Diazo Esters, The Direct Formation of Bicyclo[2.1.0]pentane ring systems via Intramolecular Cyclopropanation Reaction. J. Chem. Soc., Perkin Trans 1 1996, 47, 2337–2338. [Google Scholar]
  • (10).For examples of transannular bond formation see:; (a) Liu Y; Tranin S; Chang Y-C; Piper EB; Fessard T; Van Hoveln R; Salome C; Brown MK Facile Synthesis of Housanes by an Unexpected Strategy. J. Am. Chem. Soc 2025, 147, 6318–6325. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Jung M; Lindsay VNG One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones. J. Am. Chem. Soc 2022, 144, 4764–4769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (11).For seminal reports of cyclobutene cyclopropanation reactions, see:; (a) Gassman PG; Mansfield KT Bridgehead substituted bicyclo[2.1.0]pentanes. J. Org. Chem 1967, 32, 915–920. [Google Scholar]; (b) Kinstle TH; Welch RL; Exley RW Substituted bicyclo[2.1.0]pentanes. J. Am. Chem. Soc 1967, 89, 3660–3661. [Google Scholar]; (c) Lin Si-L.; Chen Y-H; Liu H-H; Xiang S-H; Tan B Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs. J. Am. Chem. Soc 2023, 145, 21152–21158. [DOI] [PubMed] [Google Scholar]; (d) He J; Snapper ML New Cycloaddition/Fragmentation Strategies for Preparing 5,7,5 and 5,7,6 Fused Tricyclic Ring Systems. Tetrahedron 2013, 69, 7831–7839. [Google Scholar]; (e) Williams MJ; Deak HL; Snapper ML Intramolecular Cyclobutadiene Cycloaddition/Cyclopropanation/Thermal Rearrangement: An Effective Strategy for the Asymmetric Syntheses of Pleocarpenene and Pleocarpenone. J. Am. Chem. Soc 2007, 129, 486–487. [DOI] [PubMed] [Google Scholar]; (f) Deak HL; Stokes SS; Snapper ML New Approach to Bicyclo[5.3.0] Ring Systems. J. Am. Chem. Soc 2001, 123, 5152–5153. [DOI] [PubMed] [Google Scholar]; (g) Franck-Neumann M; Miesch M; Gross L Synthesis of the angular triquinane (±)-pentalenene via small ring intermediates. Tetrahedron Lett. 1992, 33, 3879–3882. [Google Scholar]
  • (12).(a) Keen B; Cong C; Castanedo A; Davies GHM; Knowles RR; Davies HML Stereoselective Synthesis of Highly Functionalized Bicyclo[2.1.0]pentanes by Sequential [2 + 1] and [2 + 2] Cycloadditions. Org. Lett 2025, 27, 1673–1678. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Mondal ARS; Bapat NA; Mishra H; Hari DP Highly Stereoselective Synthesis of Polysubstituted Housanes and Spiro-Oxa-Housanes: Application and Mechanistic Insights. Chem. Sci 2025, 16, 12350. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Suárez-Garcia D; Rodríguez MA; Barbolla I; Vincente R Synthesis of Fused-Housane Derivatives via Intramolecular [2 + 2] Photocycloaddition. Org. Lett 2025, 27, 3825–3830. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Reilly SD; Wamser CC Reactions of Methylene with hexamethyl(Dewar benzene). J. Org. Chem 1991, 56, 5232–5234. [Google Scholar]; (e) Wiberg KB; Kass SR; Bishop KC III Electrophilic Cleavage of Cyclopropanes. Acetolysis of Bicyclo[2.1.0]pentane and Bicyclo[3.1.0]-hexane. J. Am. Chem. Soc 1985, 107, 996–1002. [Google Scholar]
  • (13).(a) Adam W; Harrer HM; Werner MN; Peters K Electronic Substituent Effects on the Acid-Catalyzed [4 + 2] Cycloaddition of Isopyrazoles with Cyclopentadiene and the Photochemical and Thermal Denitrogenation of the Resulting 1,4-Diaryl-7,7-dimethyl-2,3-diazabicyclo[2.21]hept-2-ene Azoalkanes to Bicyclo[2.1.0]pentanes. J. Org. Chem 1994, 59, 3786–3797. [Google Scholar]; (b) Adam W; Finzel R; Kita F Benzophenone-sensitized Two-Photon Chemistry of Azoalkanes in the “Laser/Liquid Jet”: Evidence for Photoinduced Hydrogen 1,2-Shift in 1,3-Cyclopentadiyl Triplet Diradicals. Tetrahedron Lett. 1991, 32, 2211–2214. [Google Scholar]; (c) Dauben WG; Wiseman JR Solvolysis of bicyclo[2.1.0]pentanyl-1-methyl p-nitro-benzoate. J. Am. Chem. Soc 1967, 89, 3545–3549. [Google Scholar]; (e) Criegee R; Rimmelin A Darstellung und Eigenschaften von Bicyclo-[0.1.2]-Pentan. Chem. Ber 1957, 90, 414–417. [Google Scholar]
  • (14).(a) Eckart-Frank IK; Wilkerson-Hill SM Palladium-Catalyzed Trans-Selective Synthesis of Spirocyclic Cyclobutanes using α,α-Dialkylcrotyl- and Allylhydrazones. J. Am. Chem. Soc 2023, 145, 18591–18597. [DOI] [PubMed] [Google Scholar]; (b) Ritchie NFC; Zahara AJ; Wilkerson-Hill SM Divergent Reactivity of α,α-Disubstituted Alkenyl Hydrazones: Bench Stable Cyclopropylcarbinyl Equivalents. J. Am. Chem. Soc 2022, 144, 2101–2106. [DOI] [PubMed] [Google Scholar]
  • (15).(a) Brookhart M; Studabaker WB Cyclopropanes from Reactions of Transition-Metal-Carbene Complexes with Olefins. Chem. Rev 1987, 87, 411–432. [Google Scholar]; (b) Doyle MP Catalytic Methods for Metal Carbene Transformations. Chem. Rev 1986, 86, 919–939. [DOI] [PubMed] [Google Scholar]
  • (16).For mechanistic studies, see:; (a) Martín C; Molina F; Alvarez E; Beldarrain TR Stable N-Heterocyclic Carbene (NHC)-Palladium(0) Complexes as Active Catalysts for Olefin Cyclopropanation Reactions with Ethyl Diazoaceate. Chem. - Eur. J 2011, 17, 14885–14895. [DOI] [PubMed] [Google Scholar]; (b) Straub BF Pd(0) Mechanism of Palladium-Catalyzed Cyclopropanation of Alkenes by CH2N2: A DFT Study. J. Am. Chem. Soc 2002, 124, 14195–14201. [DOI] [PubMed] [Google Scholar]; (c) Denmark SE; Stavenger RA; Faucher A-M; Edwards JP Cyclopropanation with Diazomethane and Bis(oxazoline)palladium(II) Complexes. J. Org. Chem 1997, 62, 3375–3389. [DOI] [PubMed] [Google Scholar]; (d) Salvado O; Dominguez-Molano P; Fernández E Stereoselective Cyclopropanation of 1,1-Diborylalkenes via Palladium-Catalyzed (Trimethylsilyl)-diazomethane Insertion. Org. Lett 2022, 24, 4949–4953. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Solé D; Amenta A; Mariani F; Bennasar M-L; Fernández I Transition Metal-Catalysed Intramolecular Carbenoid C–H Insertion for Pyrrolidine Formation by Decomposition of α-Diazoesters. Adv. Synth. Catal 2017, 359, 3654–3664. [Google Scholar]; (f) Solé D; Mariani F; Bennasar M-L; Fernández I Palladium-Catalyzed Intramolecular Carbene Insertion into C(sp3)–H Bonds. Angew. Chem., Int. Ed 2016, 55, 6467–6470. [DOI] [PubMed] [Google Scholar]; (g) Yang Y; Li J; Du B; Yuan C; Liu B; Qin S An entry to vinylcyclopropane through palladium-catalyzed intramolecular cyclopropanation of alkenes with unstabilized allylic tosylhydrazones. Chem. Commun 2015, 51, 6179–6182. [DOI] [PubMed] [Google Scholar]; (h) Yuan C; Du B; Yang L; Liu B Bioinspired Total Synthesis of Bolivianine: A Diels–Alder/Intramolecular Hetero-Diels–Alder Cascade Approach. J. Am. Chem. Soc 2013, 135, 9291–9294. [DOI] [PubMed] [Google Scholar]
  • (17).For mechanistic studies on the reactivity of Cu carbenes, see:; (a) Straub BF; Hofmann P Copper(I) Carbenes: The Synthesis of Active Intermediates in Copper-Catalyzed Cyclopropanation. Angew. Chem., Int. Ed 2001, 40, 1288–1290. [DOI] [PubMed] [Google Scholar]; (b) Straub BF; Rominger F; Hofmann P A Fluxional α-Carbonyl Diazoalkane Complex of Copper Relevant to Catalytic Cyclopropanation. Organometallics 2000, 19, 4305–4309. [Google Scholar]; (c) Evans DA; Woerpel KA; Hinman MM; Faul MM Bis(oxazolines) as Chiral Ligands in Metal-Catalyzed Asymmetric Reactions. Catalytic, Asymmetric, Cyclopropanation of Olefins. J. Am. Chem. Soc 1991, 113, 726–728. [Google Scholar]
  • (18).For an example of bicyclopropane formation that uses cobaltacyclobutane, see:; Zhang Z-Z; Han Y-Q; Zhan B-B; Wang S; Shi B-F Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed Multiple C(sp3)–H Activation Strategy. Angew. Chem., Int. Ed 2017, 56, 13145–13149. [DOI] [PubMed] [Google Scholar]
  • (19).(a) Wei B; Sharland JC; Lin P; Wilkerson-Hill SM; Fullilove FA; McKinnon S; Blackmond DG; Davies HML In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings. ACS Catal. 2020, 10, 1161–1170. [Google Scholar]; (b) Nowlan DT; Singleton DA Mechanism and Origin of Enantioselectivity in the Rh2(OAc)(DPTI)3-Catalyzed Cyclopropenation of Alkynes. J. Am. Chem. Soc 2005, 127, 6190–6191. [DOI] [PubMed] [Google Scholar]; (c) Nowlan DT; Gregg TM; Davies HML; Singleton DA Isotope Effects and the Nature of Selectivity in Rhodium-Catalyzed Cyclopropanations. J. Am. Chem. Soc 2003, 125, 15902–15911. [DOI] [PubMed] [Google Scholar]; (d) Doyle MP; Griffin JH; Bagheri V; Dorow RL Correlations between Catalytic Reactions of Diazo Compounds and Stoichiometric Reactions of Transition-Metal Carbenes with Alkenes. Mechanism of the Cyclopropanation Reaction. Organometallics 1984, 3, 53–61. [Google Scholar]; (f) Fu Z; Wang C; Zhou C-Y Alkylcarbene mediated intramolecular alkene cyclopropanation to construct aza[3.1.0] bicycles. Org. Chem. Front 2023, 10, 699–704. [Google Scholar]; (g) Torres Ó; Roglans A; Pla-Quintana A An Enantioselective Cascade Cyclopropanation Reaction Catalyzed by Rhodium(I): Asymmetric Synthesis of Vinylcyclopropanes. Adv. Synth. Catal 2016, 358, 3512–3516. [Google Scholar]
  • (20).For an early report using Pd to catalyze diazo transfer reactions, see:; Anciaux AJ; Hubert AJ; Noels AF; Petiniot N; Teyssié P Transition Metal-Catalyzed Reactions of Diazo Compounds 1. Cyclopropanation of Double Bonds. J. Org. Chem 1980, 45, 695–702. [Google Scholar]
  • (21).(a) Xiao Q; Zhang Y; Wang J Diazo Compounds and N-Tosylhydrazones: Novel Cross-Coupling Partners in Transition-Metal-Catalyzed Reactions. Acc. Chem. Res 2013, 46, 236–247. [DOI] [PubMed] [Google Scholar]; (b) Greenman KL; Carter DS; Van Vranken DL Palladium-Catalyzed Insertion Reactions of Trimethylsilyldiazomethane. Tetrahedron 2001, 57, 5219–5225. [Google Scholar]
  • (22).(a) Díaz-Requejo MM; Pérez P Coinage Metal Catalyzed C–H Bond Functionalization of Hydrocarbons. Chem. Rev 2008, 108, 3379–3394. [DOI] [PubMed] [Google Scholar]; (b) Pérez PJ; Brookhart M; Templeton JL A copper(I) catalyst for carbene and nitrene transfer to form cyclopropanes, cyclopropenes, and aziridines. Organometallics 1993, 12, 261–262. [Google Scholar]
  • (23).He W-J; Qin W-Z; Yang S; Ma S; Kim N; Schultz JE; Palkowitz MD; He C; Ma A; Schmidt MA; Gembicky M; Wisniewski SR; Engle KM “Pd(COD)(DQ): A Stable, Versatile, and Monometallic Palladium(0) Source for Organometallic Synthesis and Catalysis”. ChemRxiv 2024. [Google Scholar]
  • (24). See the Supporting Information for more details.
  • (25).Clement ND; Cavell KJ; Ooi L-L Zerovalent N-Heterocyclic Carbene Complexes of Palladium and Nickel Dimethyl Fumarate: Synthesis, Structure, and Dynamic Behavior. Organometallics 2006, 25, 4155–4165. [Google Scholar]
  • (26).(a) Astakhov AV; Khazipov OV; Chernenko AY; Pasyukov DV; Kashin AS; Gordeev EG; Khrustalev VN; Chernyshev VM; Ananikov VP A New Mode of Operation of Pd-NHC Systems Studied in a Catalytic Mizoroki–Heck Reaction. Organometallics 2017, 36, 1981–1992. [Google Scholar]; (b) Zalesskiy SS; Ananikov VP Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis. Organometallics 2012, 31, 2302–2309. [Google Scholar]
  • (27).Selvakumar K; Zapf A; Spannenberg A; Beller M Synthesis of Monocarbenepalladium(0) Complexes and Their Catalytic Behavior in Cross-Coupling Reactions of Aryldiazonium Salts. Chem. - Eur. J 2002, 8, 3901–3906. [DOI] [PubMed] [Google Scholar]
  • (28).Teichert JF; Feringa BL Phosphoramidites: Privileged Ligands In Asymmetric Catalysis. Angew. Chem., Int. Ed 2010, 49, 2486–2528. [DOI] [PubMed] [Google Scholar]
  • (29).(a) Holzschneider K; Kirsch S [1,2]-Migration Reactions Catalyzed by Gold Complexes and their Applications in Total Synthesis. Isr. J. Chem 2018, 58, 596–607. [Google Scholar]; (b) Markham JP; Staben ST; Toste FD Gold(I)-Catalyzed Ring Expansion of Cyclopropanols and Cyclobutanols. J. Am. Chem. Soc 2005, 127, 9708–9709. [DOI] [PubMed] [Google Scholar]; (c) Bishop KC III Transition metal catalyzed rearrangements of small ring organic molecules. Chem. Rev 1976, 76, 461–486. [Google Scholar]
  • (30).(a) Clark JS; Dossetter AG; Wong Y-S; Townsend RJ; Whittingham WG; Russell CA Anomalous Intramolecular C–H Insertion Reactions of Rhodium Carbenoids: Factors Influencing the Reaction Course and Mechanistic Implications. J. Org. Chem 2004, 69, 3886–3898. [DOI] [PubMed] [Google Scholar]; (b) Sulikowski GA; Lee S Kinetic isotope effects in the intramolecular insertion of a metal carbene into a C–H bond adjacent to nitrogen. Tetrahedron Lett. 1999, 40, 8035–8038. [Google Scholar]; (c) Wang P; Adams J Model Studies of the Stereoelectronic Effect in Rh(II) Mediated Carbenoid C-H Insertion Reactions. J. Am. Chem. Soc 1994, 116, 3296–3305. [Google Scholar]
  • (31).For examples using homoallyl hydrazones, see:; (a) Taber DF; Guo P; Guo N Intramolecular [1 + 4 + 1] Cycloaddition: Establishment of the Method. J. Am. Chem. Soc 2010, 132, 11179–11182. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Taber DF; Guo P Convenient Access to Bicyclic and Tricyclic Diazenes. J. Org. Chem 2008, 73, 9479–9481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (32).Enders D; Breuer K; Raabe G; Runsink J; Teles JH; Melder J-P; Ebel K; Brode S Preparation, Structure, and Reactivity of 1,3,4-Triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene, a New Stable Carbene. Angew. Chem., Int. Ed 1995, 34, 1021–1023. [Google Scholar]
  • (33).DiRocco DA; Oberg KM; Rovis T Isolable Analogues of the Breslow Intermediate Derived from Chiral Triazolyidene Carbenes. J. Am. Chem. Soc 2012, 134, 6143–6145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (34).(a) Chou SK Acid and Transition Metal Promoted Rearrangement of 1-Phenylbicyclo[2.1.0]pentanes. Ph.D. Dissertation; Marquette University, 1975. [Google Scholar]; (b) Paquette LA; Henzel RP; Wilson SE Ag+-Catalyzed Rearrangements. XIV. Influence of Structural Features of the Course of Bicyclo[1.1.0]butane Rearrangements Catalyzed by Silver(I) Ion. J. Am. Chem. Soc 1972, 94, 7780–7788. [Google Scholar]; (c) Gassman P; Meyer G; Williams F Transition Metal Complex Promoted Rearrangements. The Effect of the Metal and of the Attached Ligands on the Mode of Cleavage of Methylated Bicyclo[1.1.0]butanes. J. Am. Chem. Soc 1972, 94, 7741–7748. [Google Scholar]
  • (35).(a) Oka N; Yamada T; Sajiki H; Akai S; Ikawa T Aryl Boronic Esters are Stable on Silica Gel and Reactive under Suzuki–Miyaura Coupling Conditions. Org. Lett 2022, 24, 3510–3514. [DOI] [PubMed] [Google Scholar]; (b) Wang D; Xue X-S; Houk KN; Shi Z Mild Ring-Opening 1,3-Hydroborations of Non-Activated Cyclopropanes. Angew. Chem., Int. Ed 2018, 57, 16861–16865. [DOI] [PubMed] [Google Scholar]
  • (36).Prysiazhniuk K; Datsenko OP; Polishchuk O; Shulha S; Shablykin O; Nikandrova Y; Horbatok K; Bodenchuk I; Borysko P; Shepilov D; Pishel I; Kubyshkin V; Mykhailiuk PK Spiro[3.3]heptane as a Saturated Benzene Bioisostere. Angew. Chem., Int. Ed 2024, 63, No. e202316557. [DOI] [PubMed] [Google Scholar]
  • (37).Esteve Guasch J; Pal D; Suero MG Catalytic Oxidative Ligand Transfer of Rh-Carbynoids and Alkyl Iodides. J. Am. Chem. Soc 2025, 147, 31444. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information
NIHMS2133842-supplement-Supporting_Information.pdf (12.3MB, pdf)

RESOURCES