Earth-abundant metals

Among the transition metal used in organic synthesis, the late transition metals like rhodium, palladium, and iridium have taken center stage when it comes to methodology development. Although these late-stage transition metals have contributed immensely to synthetic organic and organometallic chemistry, increasing societal awareness in terms of sustainable developments and resource management has prompted chemists to explore the use of environmentally benign, inexpensive, and earth-abundant metals [18-27]. In this section, we summarize recent progress in Ni, Fe, Cu, and Co-catalyzed domino reactions of strained bicyclic alkenes.

Nickel-catalyzed reactions

Without close inspection, nickel might seem like the peculiar younger sibling of palladium within the field of transition-metal catalysis. Nickel lies directly above palladium in the periodic table, as such, it readily performs many of the same elementary reactions. Because of their reactive commonalties, nickel is often seen as the budget-friendly replacement; however, this misconception will clearly be refuted in this section, showcasing several diverse nickel-catalyzed domino reactions.

In 2001, Rayabarapu and co-workers investigated the Ni-catalyzed ring-opening/cyclization cascade of heterobicyclic alkenes 1 with alkyl propiolates 2 for the synthesis of coumarin derivatives 3 (Scheme 1) [28]. The reaction initiates with the in situ reduction of Ni(II) to Ni(0) followed by the side-on coordination of the alkene and alkyne substrates to the metal center with subsequent oxidative cyclometallation to form a nickel metallacycle, similar to several reported Ni-catalyzed [2 + 2] cycloadditions [29,30]. Rather than undergoing reductive elimination to afford to [2 + 2] adduct, β-oxygen elimination followed by E/Z isomerization and intramolecular lactonization generates the annulated coumarin scaffold. In 2003, the Cheng lab extended on this Ni-catalyzed ring-opening strategy [31]. It was noted the addition of 1.5 equivalents of water interrupted the cyclization step and led entirely to reductively coupled alkenylated ring-opened products. Interestingly, when this methodology was applied to the ester-bearing oxabicyclic 1a, the anticipated reductive coupling product was not detected; instead, bicyclic γ-lactone 4 was solely observed (Scheme 1). This unprecedented lactone is presumed to be generated through the expected reductive coupling to generate the ring-opened intermediate 5 which undergoes subsequent intramolecular lactonization with the distal ester group. In the same year, Cheng and co-workers observed the identical reactivity when exploring the Pd- and Ni-catalyzed asymmetric reductive ring opening of heterobicyclic alkenes, ultimately generating the bicyclic product 7 (Scheme 1) [32].

Scheme 1: Ni-catalyzed ring-opening/cyclization cascade of heterobicyclic alkenes 1 with alkyl propiolates 2 to generate coumarin 3 and bicyclic γ-lactone 4 derivatives.

In 2003, the Cheng laboratory continued studying Ni-catalyzed routes towards coumarin cores through the Ni-catalyzed ring-opening/cyclization cascade of heterobicyclic alkenes 1 with β-iodo-(Z)-propenoates and o-iodobenzoates 9 (Scheme 2) [33]. The authors noted the ring-opening/cyclization cascade proceeded smoothly for a variety of heterobicyclic alkenes including both oxa- and azabenzonorbornadienes as well as oxanorbornenes; however, the latter two substrates did not undergo dehydrogenation, generating cis-selective annulated coumarins (10b and 10d). In 2006, the same group applied this methodology for the total synthesis of arnottin I (10h), a coumarin-type natural product isolated from the bark of the Xanthoxylum arnottianum Maxim which possesses some antibiotic properties [34]. Mechanistically, the authors proposed the reaction begins with the in situ reduction of Ni(II) to Ni(0) by zinc to generate Ni(0) which undergoes oxidative addition with the organo iodide to yield Ni(II) intermediate 11. Coordination of 11 to the bicyclic alkene followed by migratory insertion affords intermediate 12 which undergoes β-oxygen elimination to form 13. Rearrangement of 13 via β-hydride elimination and enolization generates a 1-naphthol species which undergoes intramolecular cyclization with the ester to form the final product 10. The selectivity for the non-dehydrogenated coumarins 10d is not understood, but 10b likely does not undergo dehydrogenation because there is no formation of aromaticity to drive the reaction forward. When the bicyclic alkene is substituted unsymmetrically at the bridgehead position, the reaction is entirely regioselective for the formation of a 1,2,4-trisubstituted pattern. The observed regioselectivity arises from the preferential migratory insertion of the aryl group distal to the bridgehead substituent.

Scheme 2: Ni-catalyzed ring-opening/cyclization cascade of heterobicyclic alkenes 8 with β-iodo-(Z)-propenoates and o-iodobenzoates 9.

In 2010, Ogata and Fukuzawa explored the Ni-catalyzed two- and three-component difunctionalization of norbornene derivatives 15 with alkynes (Scheme 3) [35]. It was noted the reaction is amenable to both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs); however, yields were diminished with increasing electron deficiency. Moreover, the use of the bulkier tert-butyldimethylsilyl-protecting group resulted in the corresponding 1,5-enyne only being produced in a 33% yield. Several different norbornene derivatives were explored and gave the anticipated exo,exo-difunctionalized product in good yield. In contrast, when using an ethylene-bridged bicycloalkene to generate the product 19c, the latter was obtained in a greatly reduced yield, perhaps due to less ring strain providing a thermodynamic driving force.

Scheme 3: Ni-catalyzed two- and three-component difunctionalizations of norbornene derivatives 15 with alkynes 16 and 17.

In 2013, Mannathan et al. discussed a Ni-catalyzed intermolecular three-component difunctionalization of oxabicyclic alkenes 1 with organoboronic acids 20 and alkynes 17 (Scheme 4) [36]. While broadly successful, when electron-deficient arylboronic acids were used, slightly diminished yields were observed. Moreover, when 3-hexyne was used, the reaction failed to afford any product. The reaction likely begins similarly to Cheng’s 2003 report (Scheme 1) [31] where the coordination of the alkyne 17 and alkene 1 to the Ni(0) center, followed by oxidative cyclometallation, yields the following nickelocycle 24. Unlike Cheng’s 2003 report, which proposes subsequent β-oxygen elimination (Scheme 1) [31], alkoholysis by MeOH affords an alkyl(methoxy)nickel intermediate 25. Transmetalation of 25 with the organoboronic acid gives intermediate 26, which upon reductive elimination affords the difunctionalized product 21 and regenerates the Ni(0) catalyst.

Scheme 4: Ni-catalyzed intermolecular three-component difunctionalization of oxabicyclic alkenes 1 with alkynes 17 and organoboronic acids 20.

In 2019, the Stanley laboratory explored the Ni-catalyzed intermolecular three-component carboacylation of norbornene derivatives 15 using imides 27 and tetraarylborates 28 (Scheme 5) [37]. The method utilizes C–N bond activation to trigger the reaction. The authors demonstrated a broad reaction scope. Electron-deficient amides were shown to perform worse than their electron-rich counterparts with the p-trifluoromethyl substituent forming the ketone product in <10% yield. While substitution of the norbornene was tolerated, both EWGs and EDGs hindered the reaction. Upon several mechanistic studies, the authors proposed the catalytic cycle begins with the oxidative addition of the active Ni(0) catalyst to imide 27 to afford the acyl–Ni(II)–amido intermediate 30. Side-on coordination followed by migratory insertion of the bicyclic alkene selectively generates the exo-alkyl–Ni(II)–amido complex 31. Transmetalation with triarylborane affords 32 which undergoes reductive elimination to form the carboacylated product 29 as well as regenerates the Ni(0) catalyst. In 2022, the Tobisu group explored a two-component carboacylation of norbornene derivatives. Exploiting a Ni/NHC system, the authors were able to develop an entirely atom-economic carboacylation process utilizing N-indoyl arylamides [38].

Scheme 5: Ni-catalyzed intermolecular three-component carboacylation of norbornene derivatives 15.

In 2019, Gutierrez and Molander reported the coupling 4-alkyl-1,4-dihydropyridines 31 with heterobicyclic alkenes 30 under photoredox/Ni dual catalysis (Scheme 6) [39]. In contrast to other photoredox-mediated transformations, the authors utilized the inexpensive organic photosensitizer 4-CzIPN (Scheme 6 and Scheme 7) instead of the more commonly, and expensive, metal-based photocatalysts. While broadly successful, tertiary radicals failed to deliver any desired product. Of note, the reaction was amenable to a broad scope of derivatized heterobicyclic alkenes with mono- and disubstituted bridgeheads having little effect on the reaction (32b) with reactions involving unsymmetrically substituted bicyclic alkenes demonstrating complete regioselectivity for either 1,2,3- or 1,2,4-trisubstitued products (32a, 32f). DFT calculations were used to explain the syn-1,2-substitution experimentally observed rather than the possible syn-1,4-substituted product. It was found the reductive elimination transition state leading to the 1,4-disubstituted product TS33-P1 would require an increase in distortion energy compared to TS35-P2 which contributes to an overall greater kinetic barrier.

Scheme 6: Photoredox/Ni dual-catalyzed coupling of 4-alkyl-1,4-dihydropyridines 31 with heterobicyclic alkenes 30.

The following year, Lautens and Renaud expanded the scope of the photoredox/Ni dual-catalyzed coupling of alkyl nucleophiles 36 with heterobicyclic alkenes 30 to include α-amino radicals (Scheme 7) [40]. The authors noted the electron-rich oxabenzonorbornadiene derivatives provided the corresponding ring-opened adducts in good yields (63–68% yield) while those bearing EWG led to poor product formation. Unlike Gutierrez and Molander’s work (Scheme 6) [39], it was found mono- and disubstituted bridgeheads affected the efficacy of the reaction with the demethylated bridgehead oxabenzonorbornadiene only delivering the product in a 20% yield. Although yields were slightly diminished, unsymmetrical bridgehead-monosubstituted oxabenzonorbornadiene led solely to the 1,2,4-trisubstituted regioisomer (Scheme 7), similar to that observed by Gutierrez and Molander [39]. Selected substituents on the aniline motif were found to hamper reactivity with a few examples failing to provide the desired product when 4-CzIPN was used as the photocatalyst; however, the products were isolated when [Ir(dF(CF3)ppy)2(bpy)]PF6 was used. Based on experimental observations and control reactions, the authors proposed the reaction begins with the photoexcitation of the photosensitizer 43 to form 44 which can oxidize aniline 36a to give radical cation 46 (Scheme 7). Deprotonation by DBU produces the radical 40. The radical anion photosensitizer 45 can reduce Ni(I) to Ni(0), closing the first catalytic cycle. The Ni(0) complex can undergo oxidative addition into the C–O bond of the oxabicyclic alkene 30a to afford the σ-allyl intermediate 38 which can isomerize to the more stable π-allyl intermediate 39. Addition of the α-amino radical to the Ni(II) center generates the Ni(III) complex 41. Reductive elimination, followed by protodemetalation, leads to the final ring-opened adduct 37.

Scheme 7: Photoredox/Ni dual-catalyzed coupling of α-amino radicals with heterobicyclic alkenes 30.

Copper-catalyzed reactions

In 2009, Pineschi and co-workers explored the Cu-catalyzed rearrangement/allylic alkylation of 2,3-diazabicyclo[2.2.1]heptenes 47 with Grignard reagents 48 (Scheme 8) [41]. The reaction is thought to proceed via the Lewis acid-catalyzed [3,4]-sigmatropic rearrangement of the diazabicycle 47 to form the allylic carbazate intermediate 51. Nucleophilic attack of an organomagnesium, or organocuprate, in an anti SN2’ fashion on 52 furnish the final ring-opened product 49. The authors note the use of a carbamate protecting group was crucial for the success of the reaction, hypothesizing it inhibited the classical [3,3]-sigmatropic Lewis acid-catalyzed rearrangement often observed. Both alkyl and aryl Grignard reagents were amenable to the reaction; however, heteroaryl Grignard reagents resulted in poor conversion.

Scheme 8: Cu-catalyzed rearrangement/allylic alkylation of 2,3-diazabicyclo[2.2.1]heptenes 47 with Grignard reagents 48.

The Cu-catalyzed borylative difunctionalization of π-systems is a power tool for the facile synthesis of complex boronate-containing compounds [42]. Generally, these reactions proceed through the generation of a Cu–boryl species via σ-bond metathesis, followed by migratory insertion with a π-system. The subsequent alkyl–Cu intermediate is intercepted by an electrophile to generate the difunctionalized system. This methodology has been applied several times to strained bicyclic alkenes with a variety of electrophiles.

In 2015, Hirano and Miura developed a Cu-catalyzed aminoboration of bicyclic alkenes 1 with bis(pinacolato)diboron (B2pin2) (53) and O-benzoylhydroxylamine derivatives 54 (Scheme 9) [43]. While the scope of bicyclic alkenes was quite extensive with aza-, carbo-, and oxabicyclic alkenes being amenable to the reaction, electron-deficient substrates resulted in lowered yields. Of note, the reaction is highly regioselective with the unsymmetrically methyl-substituted bicyclic alkene producing a single regioisomer 55a. The authors noted the aminoborylated products bearing a BPin moiety were not always stable upon isolation, so they were either converted into the more stable Bdan (dan = 1,8-diaminonaphthalenyl) or Bpin-Bdan was used directly which showed comparable yields. The authors also reported preliminary results for an asymmetric variant of the reaction using (R,R)-Ph-BPE as a chiral ligand. Although the use of the chiral phosphine ligand resulted in slightly diminished yields, the authors were able to achieve ees up to 88%. The authors proposed the reaction begins with the generation of the tert-butoxide Cu salt which undergoes σ-bond metathesis with B2Pin2 generating the Cu–boryl species 59 (Scheme 9). Side-on coordination on the exo face of the bicyclic alkene followed by migratory insertion generates the alkyl–Cu species 60 which after electrophilic amination with the O-benzoylhydroxylamine 54 liberates the final aminoborylated product 55 and a benzoyl–Cu complex 61. To close the catalytic cycle a transmetalation of 61 with LiOt-Bu regenerates the active catalyst.

Scheme 9: Cu-catalyzed aminoboration of bicyclic alkenes 1 with bis(pinacolato)diboron (B2pin2) (53) and O-benzoylhydroxylamine derivatives 54.

In 2017, Xiao and Fu studied the Cu-catalyzed borylalkynylation of oxabenzonorbornadiene (30b) with B2pin2 (53) and bromoalkynes 62 (Scheme 10) [44]. The scope of the reaction was limited to only two examples of bromoalkynes reacting with oxabenzonorbornadiene (30b). Notably, the yield of the reaction dramatically diminished when the terminal triisopropylsilyl (TIPS) group in 63a was swapped for a Ph (63b). Mechanistically, the reaction operates in a similar manner reported by Hirano and Miura (Scheme 9) [43]; however, the alkyl–Cu species 60 is intercepted by the bromoalkyne rather than an O-benzoylhydroxylamine.

Scheme 10: Cu-catalyzed borylalkynylation of oxabenzonorbornadiene (30b) with B2pin2 (53) and bromoalkynes 62.

In the same year, the Brown laboratory investigated the Cu-catalyzed borylacylation of bicyclic alkenes 1 (Scheme 11) [45]. Like the previous borylative difunctionalization reactions, it was found the reaction generated a single exo,exo diastereomer. A brief investigation into an enantioselective variant of the borylacylation was investigated; however, the methodology was not applied to bicyclic alkenes.

Scheme 11: Cu-catalyzed borylacylation of bicyclic alkenes 1.

In 2019, the Yang lab examined the Cu-catalyzed diastereoselective 1,2-difunctionalization of oxabenzonorbornadienes 30 for the synthesis of β-thiocyanato thioethers 68 (Scheme 12) [46]. In contrast to the previous difunctionalization reactions, the authors noted the reaction was stereoselective for the trans-addition product. Mechanistically, the authors proposed the reaction begins with the Cu-mediated substitution reaction of iodobenzene (66a) with KSCN to afford phenyl thiocyanate (70). The Cu complex can then undergo oxidative addition into the S–C bond of the thiocyanate 70 to afford intermediate 71 which can side-on coordinate to the exo face of 30b. Subsequently, the thiocyanate attacks the olefin from the endo face via 72 to give complex 73. Reductive elimination furnishes the final difunctionalized product and regenerates the active Cu(I) catalyst. The reaction was broadly successful with the steric and electronic nature of the aryl iodide having little effect on the reaction.

Scheme 12: Cu-catalyzed diastereoselective 1,2-difunctionalization of oxabenzonorbornadienes 30 for the synthesis of β-thiocyanato thioethers 68.

Iron-catalyzed reactions

Being the most earth-abundant d-block element, as well as orders of magnitude less expensive than other transition-metal catalysts, iron is bringing a renaissance to the idea of sustainable, green catalysis. In 2011, Ito et al. reported a diastereoselective Fe-catalyzed carbozincation of heterobicyclic alkenes 1 with diphenylzinc (74a) (Scheme 13) [47]. Using an ortho-phenylene diphosphine ligand L3, the authors were able to suppress β-heteroatom elimination enabling sequential electrophilic trapping of the alkylzinc complex. Although this reaction would more closely fall under the definition of a telescoped reaction than a strict domino reaction, this methodology allowed for the synthesis of difunctionalized strained alkenes. While broadly successful, strongly electron-withdrawing groups lowered the yield of the reaction. In 2021, Isozaki and Nakamura reinvestigated the reaction and established an asymmetric variant of the Fe-catalyzed carbozincation of azabicyclic alkenes 77 (Scheme 13) [48]. Using (S,S)-chiraphos, the authors were able to achieve enantioselectivities of up to 99%. Unfortunately, only two examples of electrophilic capturing were explored, using CD3CO2D to give deuterated products and I2. Most reports simply underwent protodemetalation upon quenching to afford the monosubstituted bicyclic alkene. The catalytic cycle starts with a diaryl Fe(II)–(S,S)-chiraphos complex 80 being generated through the reduction of FeCl3 with excess diarylzinc in the presence of the phosphine ligand. Side-on coordination to the exo face of the azabicycle 77a generates 81 where subsequent migratory insertion affords the alkyl–Fe(II) complex 82. Transmetalation with an organozinc produces 78a which can be trapped by an electrophile to generate the final product 79a.

Scheme 13: Fe-catalyzed carbozincation of heterobicyclic alkenes 1 with arylzinc reagents 74.

Cobalt-catalyzed reactions

In 2014, the Yoshikai lab investigated the Co-catalyzed addition of arylzinc reagents 83 of norbornene derivatives 15 (Scheme 14) [49]. In contrast to the 1,2-difunctionalization of bicyclic alkenes via arylzinc reagents reported by Nakamura under Fe catalysis (Scheme 13) [48], this reaction is considered to undergo a 1,4-Co migration ultimately generating 1,4-difunctionalization species. Mechanistically, the reaction likely proceeds similarly to Nakamura’s Fe-catalyzed methodology (Scheme 13) [48].

Scheme 14: Co-catalyzed addition of arylzinc reagents of norbornene derivatives 15.

In 2017, the Cheng laboratory investigated the Co-catalyzed ring-opening/dehydration of oxabicyclic alkenes via the C–H activation of arenes (Scheme 15) [50]. First, the group explored the ortho-naphthylation of N-pyrimidinylindole derivatives 85. The reaction was amenable for both electron-rich and deficient indoles. When the reaction was attempted on electron-deficient oxabicyclic alkene derivatives, it was observed the reaction did not undergo dehydration to give the 2-naphthyl product, rather the ring-opened 1,2-hydroxy adduct. When the Lewis acid cocatalyst AgSbF6 was removed from the reaction mixture, it was noted only ring-opened 1,2-hydroxy adducts were formed, so it is likely the Lewis acid is required for dehydration. In contrast, when N-pyrimidinylbenzimidazole derivatives were used, the 1,2-C–H addition product was observed exclusively. By slightly altering the reaction conditions, 2-arylpyridines 85a were able to undergo the ring-opening/dehydration reaction with oxabicyclic alkenes to afford ortho-naphthylated products 86a.

Scheme 15: Co-catalyzed ring-opening/dehydration of oxabicyclic alkenes 30 via C–H activation of arenes.

Concurrently, the Li group investigated the same ortho-naphthylation of N-pyrimidinylindole derivatives 85 (Scheme 15) [51]. In contrast to Cheng’s report, it’s noted the addition of AcOH rather than CsOAc enabled the same ring-opening/dehydration cascade to occur; however, acidic conditions seem to require less energy to drive the dehydration step.

In 2019, the Zhai Group investigated the Co-catalyzed [3 + 2] annulation/ring-opening/dehydration domino reaction of oxabicyclic alkenes 30 with 2-(1-methylhydrazinyl)pyridine (MHP) directed arenes 87 for the synthesis of benzo[b]fluorenones 88 (Scheme 16) [52]. C–H bond functionalization with heterobicyclic alkenes as annulation partners has received considerable attention in recent years. Several different arene and directing groups have been investigated; however, they typically result in the exo-selective addition product with the bridge heteroatom intact. Although this limits the applicability of the reaction, the authors noted the use of 5.0 equivalents of Cs2CO3 provided the naphthalene core via sequential dehydration. Based on preliminary mechanistic experiments, the authors proposed the reaction begins with the oxidation of Co(II) to Co(III) by O2. MHP-directed C–H activation of the ortho-C–H position generates 90 which can coordinate to the bicyclic alkene forming 91. Migratory insertion of the olefin affords 92 which undergoes intramolecular nucleophilic addition followed by protodemetalation and elimination of MHP to afford 94. Base-mediated ring opening of the bridging ether generates 95 which undergoes an elimination reaction to afford the naphthalene product 88a.

Scheme 16: Co-catalyzed [3 + 2] annulation/ring-opening/dehydration domino reaction of oxabicyclic alkenes 1 with 2-(1-methylhydrazinyl)pyridine (MHP) directed arenes 22.

Inspired by Zhao’s seminal report on the racemic carboamination of bicyclic alkenes [53], the Cramer laboratory studied the Co-catalyzed enantioselective carboamination of bicyclic alkenes 1 via C–H functionalization in 2021 (Scheme 17) [54]. The authors noted decreasing the steric bulk of the amide moiety of the substrate from isopropyl to ethyl to methyl decreased the enantioselectivity of the reaction. Carbon- and nitrogen-bridging bicyclic alkenes were also identified as competent substrates. In this respect, norbornadiene was found to give the desired carboaminated product in slightly diminished yields while azabicyclic alkenes generated the targeted products in excellent yield, albeit with slightly reduced enantioselectivity. To showcase the synthetic capabilities of this methodology, the authors synthesized the non-natural amino acid derivative 98j in good diastereoselectivity.

Scheme 17: Co-catalyzed enantioselective carboamination of bicyclic alkenes 1 via C–H functionalization.

Ruthenium-catalyzed reactions

In 2006, the Tam laboratory investigated the Ru-catalyzed cyclization of oxabenzonorbornene derivatives 30 with propargylic alcohols 99 for the synthesis of isochromenes 100 (Scheme 18) [55]. After coordination of the Ru-center to the exo face of 30b, oxidative cyclization can afford the ruthenacycle 101. Unlike previous works studying Ru-catalyzed cyclizations involving bicyclic alkenes and alkynes [56-59], the reaction preferentially undergoes β-hydride elimination to generate 102 rather than reductive elimination which would afford the [2 + 2] adduct. Hydroruthenation of the allene produces 103 which can either undergo reductive elimination to afford the cyclopropanated bicyclic alkene or undergo a [2 + 2] cycloreversion to generate the Ru–carbene 104. The Ru–carbene 104 can rearrange to 100 through a 1,3-migration of the alkoxy group which can finally reductively eliminate the isochromene product. Based on control reactions, the authors proposed the active catalytic species is cationic, as the use of the cationic precatalyst [Cp*Ru(CH3CN)3]PF6 in THF afforded the isochromene as the major product, suggesting a similar cationic species may be generated in MeOH [60].

Scheme 18: Ru-catalyzed cyclization of oxabenzonorbornene derivatives with propargylic alcohols for the synthesis of isochromenes.

In 2011, Tenaglia and co-workers investigated the Ru-catalyzed coupling of oxabenzonorbornene derivatives 30 with propargylic alcohols and ethers 106 to access benzonorcaradienes 107 (Scheme 19) [61]. While discriminating between the neutral and cationic active ruthenium species, the authors noted the use of [Cp*Ru(CH3CN)3]PF6 as the precatalyst produced the cyclopropanated bicyclic alkene adducts exclusively. This contrasts with Tam’s report (Scheme 18) [55] which found cationic Ru species formed the isochromene 100 preferentially which may be attributed to the solvent playing a more impactful role in the reaction than previously anticipated. Of note, the reaction was amenable to a broad scope of derivatized heterobicyclic alkenes. Electron-deficient bicyclic alkenes were found to react much slower, ultimately affording products in diminished yields. Mono- and disubstituted bridgehead variants were applicable, but with reduced efficacy with the former producing a dihydronaphthofuran 107i as the major product.

Scheme 19: Ru-catalyzed coupling of oxabenzonorbornene derivatives 30 with propargylic alcohols and ethers 106 to access benzonorcaradienes 107.

In 2019, the Cramer group continued studying this reaction and developed an enantioselective variant utilizing a chiral Cp* derivative (Scheme 19) [62]. Similar reactivity trends were observed in both accounts. Mechanistically, the transformation was proposed to begin with the coordination of Cp*RuI to the exo face of the bicyclic alkene. Oxidative addition into the C–O bond, which is proposed to be the enantiodetermining transition state, followed by coordination to the alkyne generates intermediate 109. Migratory insertion of the alkyne results in the ruthenacycle 110. Subsequent reductive elimination generates putative allyl vinyl ether 111 and regenerates the active ruthenium complex. The allyl vinyl ether intermediate undergoes a Claisen rearrangement to afford the endo-isomer 112. Thermal isomerization of 113a by a 6π-electrocyclic ring-opening/closing cascade leads to the to the final exo-isomer 107.

In 2018, the Zhang lab investigated the Ru-catalyzed ring-opening/dehydration of oxabicyclic alkenes 30 via the C–H activation of anilides 114 (Scheme 20) [63]. When the optimized conditions were applied to azabenzonorbornadiene derivatives, the dehydrative naphthylation sequence did not occur with the reaction being exclusive for exo-ring-opened products, similar to that observed in a typical Rh-catalyzed ring-opening reaction (vide infra). The reaction seems to be sensitive to the steric bulk of the amide functionality with n-propyl and isopropylamides having diminished yields. While the scope of anilides was quite extensive, electron-deficient substrates resulted in lowered yields.

Scheme 20: Ru-catalyzed ring-opening/dehydration of oxabicyclic alkenes via the C–H activation of anilides.

In 2022, the Jeganmohan group investigated the Ru-catalyzed ring-opening/lactamization of azabenzonorbornadiene derivatives 30 with arylamides 116 (Scheme 21) [64]. Weinreb amides outperformed other arylamides, likely serving as a better directing group for the initial aryl-C–H activation. While the scope of functionalized aryl Weinreb amides was quite wide, including different EWGs and EDGs, as well as heterocycles, ortho-substitution was not tolerated. The authors applied the methodology for the synthesis of biologically important benzo[c]phenanthridine derivatives 117. Through methylation and subsequent aromatization of the phenanthridinones produced, the authors were able to quickly afford novel fagaronine 117j and nitidine 117k derivatives.

Scheme 21: Ru-catalyzed of azabenzonorbornadiene derivatives with arylamides.

Rhodium-catalyzed reactions

In 2002, the Lautens laboratory reported a tandem cyclization of arylboronate esters 118 with a variety of bicyclic alkenes 15 using a water-soluble Rh-catalytic system (Scheme 22) [65]. The authors reported the reaction proceeded smoothly with a limited variety of substituted norbornenes and boronate esters.

I