Iron-Catalyzed Carbonyl–Alkyne and Carbonyl–Olefin Metathesis

catalysts

Review Iron-Catalyzed Carbonyl–Alkyne and Carbonyl–Oleﬁn Metathesis Reactions

Benedikt W. Grau and Svetlana B. Tsogoeva *

Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-9131-85-65573; Fax: +49-9131-85-65501

Received: 20 August 2020; Accepted: 4 September 2020; Published: 21 September 2020

Abstract: Construction of carbon–carbon bonds is one of the most important tools for the synthesis of complex organic molecules. Among multiple possibilities are the carbonyl–alkyne and carbonyl–olefin metathesis reactions, which are used to form new carbon–carbon bonds between carbonyl derivatives and unsaturated organic compounds. As many different approaches have already been established and offer reliable access to C=C bond formation via carbonyl–alkyne and carbonyl–olefin metathesis, focus is now shifting towards cost efficiency, sustainability and environmentally friendly metal catalysts. Iron, which is earth-abundant and considered as an eco-friendly and inexpensive option in comparison to traditional metal catalysts, fulfils these requirements. Hence, the focus of this review is on recent advances in the iron-catalyzed carbonyl–alkyne, carbonyl–olefin and related C–O/C–O metathesis reactions. The still large research potential for ecologically and economically attractive and sustainable iron-based catalysts is demonstrated.

Keywords: iron catalysts; carbonyl-olefin metathesis; carbonyl-alkyne metathesis; C=C bond formations

1. Introduction The formation of carbon–carbon bonds is one of the most important goals in chemistry [1]. For fast, efficient and selective coupling, catalysis via metal salts or metal complexes is an elegant option with versatile applications in academic research or industry [2–4]. Among known efficient C–C bond formation methods are metal-catalyzed cycloadditions, which provide attractive alternatives to photochemical [5], radical [6] or thermal [7,8] cyclization reactions, as they do not require expensive photosensitizers and mostly work under mild conditions. One of the most important methodologies is the metal-catalyzed olefin–olefin metathesis reaction (Scheme1a), which is a powerful tool for the formation of carbon–carbon double bonds with a wide range of applications [9–12]. It provides access to unsaturated compounds which are otherwise impossible to prepare, pharmaceutics in particular [13]. In addition to the olefin metathesis reaction, carbonyl–alkyne and carbonyl–olefin metathesis reactions offer an alternative possibility to generate carbon–carbon bonds. In contrast to olefin–olefin metathesis (as shown in Scheme1a), carbonyl–alkyne (Scheme1b) and carbonyl–olefin metathesis (Scheme1c) do not follow the Chauvin mechanism, even though the reaction proceeds via a formal [2 + 2] cycloaddition with an oxetene or oxetane as the intermediate [14,15]. As the reaction mechanism differs from olefin metathesis, use of a different type of catalyst is required. Most common metal catalysts for these reactions are Lewis acids, which activate both the carbonyl and the oxetene/oxetane species during the reaction [16,17]. A special case is the C–O/C–O metathesis reaction (as depicted in Scheme1d), which forms a new C–O bond resulting in cyclic ether derivatives. Even though the reaction does not form a new C–C bond, the reaction can be considered as a ring-closing C–O/C–O metathesis of aliphatic ethers [18].

Catalysts 2020, 10, 1092; doi:10.3390/catal10091092 www.mdpi.com/journal/catalysts Catalysts 2020, 10, x FOR PEER REVIEW 2 of 13

Catalysts 2020, 10, 1092 2 of 13

While many catalytic systems have already been reported, mainly employing organic Lewis acids [19] or metal-based Lewis acids [20], the development of new sustainable, cost-saving, earth-abundant metal-containing catalysts is highly desirable in today’s chemistry [21,22]. Recently, FeCl3, which fulfils the abovementioned requirements, has been established for carbonyl-olefin and carbonyl-alkyne metathesis as a reliable catalyst. Therefore, the current review summarizes all recent Catalystsdevelopments 2020, 10, x in FOR this PEER field REVIEW of research and related Fe-catalyzed C–O/C–O metathesis reaction. 2 of 13 Scheme 1. Selected metathesis reactions: (a) olefin–olefin metathesis, (b) carbonyl–alkyne metathesis, (c) carbonyl–olefin metathesis and (d) ring-closing C–O/C–O metathesis.

A special case is the C–O/C–O metathesis reaction (as depicted in Scheme 1d), which forms a new C–O bond resulting in cyclic ether derivatives. Even though the reaction does not form a new C–C bond, the reaction can be considered as a ring-closing C–O/C–O metathesis of aliphatic ethers [18]. While many catalytic systems have already been reported, mainly employing organic Lewis acids [19] or metal-based Lewis acids [20], the development of new sustainable, cost-saving, earth- abundant metal-containing catalysts is highly desirable in today’s chemistry [21,22]. Recently, FeCl3, which fulfils the abovementioned requirements, has been established for carbonyl-olefin and

carbonyl-alkyne metathesis as a reliable catalyst. Therefore, the current review summarizes all recent Scheme 1. Selected metathesis reactions: (a) olefin–olefin metathesis, (b) carbonyl–alkyne metathesis, developmentsScheme 1. Selectedin this field metathesis of research reactions: and ( are) olefin–olefinlated Fe-catalyzed metathesis, C–O/C–O (b) carbonyl–alkyne metathesis reaction.metathesis, ((cc)) carbonyl–olefin carbonyl–olefin metathesis and ( d) ring-closing C–OC–O/C–O/C–O metathesis. 2. Results Results A special case is the C–O/C–O metathesis reaction (as depicted in Scheme 1d), which forms a new2.1. Iron-Catalyzed Iron-CatalyzedC–O bond resulting C–O/C–O C–O/C–O in cyclic Ring-Closing ether derivatives. Metathesis Even though the reaction does not form a new C–C bond, the reaction can be considered as a ring-closing C–O/C–O metathesis of aliphatic ethers 3 3 [18]. As the first first example of a related related metathesis metathesis reaction we chose the C(sp )–O/C(sp)–O/C(sp )–O)–O ring-closing ring-closing reactionWhile reported many bycatalytic Morandi systems and co-workers have already [[18].18]. b Th Thiseenis reported,single single bond mainly “metathesis” “metathesis” employing reaction organic is a Lewis acidsacid-catalyzed [19] or metal-based ring closing, Lewis which acids transforms [20], the linear development diethers into of new five- five- sustainable, or six-membered cost-saving, cyclic earth-ethers (Scheme2 2).). abundant metal-containing catalysts is highly desirable in today’s chemistry [21,22]. Recently, FeCl3, which fulfils the abovementioned requirements, has been established for carbonyl-olefin and carbonyl-alkyne metathesis as a reliable catalyst. Therefore, the current review summarizes all recent developments in this field of research and related Fe-catalyzed C–O/C–O metathesis reaction.

2. Results Scheme 2. GeneralGeneral equation equation of the reaction developed by Morandi and co-workers.

2.1. Iron-CatalyzedDifferentDifferent substitution C–O/C–O patterns,Ring-Closing including Metathesis benzyl groups with electron donating and electron withdrawing groups as well as methyl groups an andd heteroatoms in the chain, are tolerated in the As the first example of a related metathesis reaction we chose the C(sp3)–O/C(sp3)–O ring-closing reaction system. To To investigate if the the generation generation of of dimethyl-ether dimethyl-ether is is the the driving driving force force of of the the reaction, reaction, reaction reported by Morandi and co-workers [18]. This single bond “metathesis” reaction is a Lewis experiments werewere performedperformed with with 1,5-pentanediol 1,5-pentanediol etherified etherified with with diff differenterent alcohols alcohols (MeOH, (MeOH, PrOH PrOH and acid-catalyzed ring closing, which transforms linear diethers into five- or six-membered cyclic ethers andButOH). ButOH). As the As yield the ofyield the cycloetherof the cycloether was identical, was iden it couldtical, beit could concluded be concluded that dimethyl-ether that dimethyl-ether formation (Scheme 2). formationis not the key is not driving the key force driving of the reaction.force of the Additional reaction. investigations Additional investigations showed also thatshowed generation also that of generationthe cyclic ether of the is irreversible.cyclic ether Inis conclusionirreversible. the In authors conclusion suggest the a authors bimolecular suggest mechanism, a bimolecular which wasmechanism, supported which by a crossoverwas supported experiment by a withcrossove methyl-r experiment and propyl-ether with methyl- derivatives. and Thepropyl-ether proposed derivatives.mechanismCatalysts 2020, 10 isThe, depictedx FOR proposed PEER in REVIEW Schememechan 3ism: is depicted in Scheme 3: 3 of 13

Scheme 2. General equation of the reaction developed by Morandi and co-workers.

Different substitution patterns, including benzyl groups with electron donating and electron withdrawing groups as well as methyl groups and heteroatoms in the chain, are tolerated in the reaction system. To investigate if the generation of dimethyl-ether is the driving force of the reaction, experiments were performed with 1,5-pentanediol etherified with different alcohols (MeOH, PrOH Scheme 3. Proposed mechanism for the C–O/C–O metathesis reaction. and ButOH). As theScheme yield of3. Proposedthe cycloether mechanism was idenfor thetical, C–O/C–O it could metathesis be concluded reaction. that dimethyl-ether formation is not the key driving force of the reaction. Additional investigations showed also that The reaction also works with different Lewis acids, such as e.g., AlCl3 or Sc(OTf)3, stressing the generation of the cyclic ether is irreversible. In conclusion the authors suggest a bimolecular role of iron in the proposed mechanism. Although the mechanism is bimolecular and yields cross- mechanism, which was supported by a crossover experiment with methyl- and propyl-ether products, the metal catalyst only activates the oxygen and therefore strongly deviates from the derivatives. The proposed mechanism is depicted in Scheme 3: Chauvin mechanism. In conclusion, the iron-catalyzed C–O/C–O ring-closing reaction is the first of its kind which gives access to cyclic ethers, even though it cannot be considered a classical metathesis reaction.

2.2. Iron-Catalyzed Carbonyl-Alkyne Metathesis The carbonyl–alkyne metathesis (oxygen transfer from carbonyl to carbon–carbon triple bond) is an atom-efficient reaction which had its rush time in the early 2000s as a gold-catalyzed reaction [23]. In contrast to stabilized Wittig reagents, the carbonyl–alkyne metathesis reaction offers a favorable alternative as it possesses full atom efficiency for the synthesis of highly functionalized alkene derivatives. The discovery of the reaction being catalyzed by AgSbF5 led the focus to less expensive Lewis acids [24]. Even though the reaction has also been described to occur with other Lewis acids, iron-based Lewis acids have been found to be one of the most favorable, which can be explained by the HSAB theory: [25] FeIII can be considered as a “harder” Lewis acid than e.g., InIII, as it has a smaller ionic radius and, therefore, a more concentrated charge, which can be beneficial for interaction, resulting in better catalytic performance [26]. It is important to notice here that iron(III)chloride is only used to activate the aldehyde and the oxetene inside the—concerted, albeit non-synchronous—[2 + 2] cycloaddition, as depicted in Scheme 4. Iron d-orbitals do not take part in the cycloaddition step. Consequently, the reaction does not follow the Chauvin mechanism, as the metal is not included in the cycle formed in the transition structure. In general, the reaction itself is better described as an economical catalytic alternative to the Wittig reaction [27]. Nevertheless, carbonyl-alkyne metathesis consists of formal [2 + 2] and retro [2 + 2] cycloadditions and enables access to multiple heterocycles similar to olefin–metathesis and will be discussed in the following part.

Scheme 4. Reaction mechanism of carbonyl–alkyne metathesis.

The first example of carbonyl-alkyne metathesis catalyzed by iron was described by Jana and co-workers in 2011 (Scheme 5) [17].

Scheme 5. FeCl3-catalyzed carbonyl–alkyne metathesis reaction towards 2H-chromenes.

Similar reactions yielding 2H-chromene derivatives were described with different catalysts before, e.g., Ru- [28] and Au-based [29] catalysts. While former methodologies suffer from their usage of an expensive metal catalyst, the new method employing iron as Lewis acid decreases the costs of

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Catalysts 2020, 10, 1092 3 of 13 Scheme 3.. ProposedProposed mechanismmechanism forfor thethe C–O/C–OC–O/C–O metathesismetathesis reaction.reaction.

The reaction also works with different Lewis acids, such as e.g., AlCl3 or Sc(OTf)3, stressing the The reaction reaction also also works works with with differ diﬀerentent Lewis Lewis acids, acids, such such as ase.g., e.g., AlCl AlCl3 or Sc(OTf)or Sc(OTf)3, stressing, stressing the role of iron in the proposed mechanism. Although the mechanism is bimolecular3 and yields3 cross- rolethe roleof iron of ironin the in proposed the proposed mechanism. mechanism. Althou Althoughgh the mechanism the mechanism is bimolecular is bimolecular and yields and yieldscross- products, the metal catalyst only activates the oxygen and therefore strongly deviates from the products,cross-products, the metal the metalcatalyst catalyst only onlyactivates activates the ox theygen oxygen and andtherefore therefore strongly strongly deviates deviates from from the Chauvin mechanism. In conclusion, the iron-catalyzed C–O/C–O ring-closing reaction is the first of Chauvinthe Chauvin mechanism. mechanism. In conclusion, In conclusion, the iron-catalyzed the iron-catalyzed C–O/C–O C–O ring-closing/C–O ring-closing reaction reaction is the first is the of its kind which gives access to cyclic ethers, even though it cannot be considered a classical metathesis itsﬁrst kind of itswhich kind gives which access gives to access cyclic ethers, to cyclic even ethers, though even it cannot though be it considered cannot be considered a classical metathesis a classical reaction. reaction.metathesis reaction.

2.2. Iron-Catalyzed Iron-Catalyzed Carbonyl-Alkyne Metathesis The carbonyl–alkynecarbonyl–alkyne metathesismetathesis (oxygen(oxygen transfer transfer from from carbonyl carbonyl to to carbon–carbon carbon–carbon triple triple bond) bond) is isanis anan atom-e atom-efficientatom-efficientfficient reaction reactionreaction which whichwhich had hadhad its rushitsits rushrush time timetime in the inin the earlythe earlyearly 2000s 2000s2000s as a asas gold-catalyzed aa gold-catalyzedgold-catalyzed reaction reactionreaction [23]. [23].In contrast In contrast to stabilized to stabilized Wittig reagents,Wittig reagents, the carbonyl–alkyne thethe carbonyl–alkynecarbonyl–alkyne metathesis metathmetath reactionesis oreactionffers a favorable offers a favorablealternative alternative as it possesses as it possesses full atom full effi atomciency effi forciency the synthesisfor the synthesis of highly of functionalizedhighly functionalized alkene alkene derivatives. The discovery of the reaction being catalyzed by AgSbF5 led the focus to less alkenederivatives. derivatives. The discovery The discovery of the reaction of the reaction being catalyzed being catalyzed by AgSbF by5 led AgSbF the focus5 led tothe less focus expensive to less expensiveLewis acids Lewis [24]. acids Even though[24]. Even the though reaction the has reacti alsoon been has described also been to described occur with to other occur Lewis with acids,other Lewisiron-based acids, Lewis iron-based acids haveLewis been acids found have been to be foun oned of to the be mostone of favorable, the most whichfavorable, can which be explained can be III III explainedby the HSAB by the theory: HSAB [25 theory:] FeIII can [25] be Fe consideredIII cancan bebe consideredconsidered as a “harder” asas aa “harder”“harder” Lewis acid LewisLewis than acidacid e.g., thanthan InIII e.g.,e.g.,, as it InIn hasIII,, asas a itsmallerit hashas aa ionicsmallersmaller radius ionicionic and, radiusradius therefore, and,and, therefore,therefore, a more concentrated aa moremore concentratedconcentrated charge, which charge,charge, can whichwhich be beneficial cancan bebe for beneficialbeneficial interaction, forfor interaction,resultinginteraction, in resulting betterresulting catalytic inin betterbetter performance catalyticcatalytic performanceperformance [26]. [26].[26]. It is importantimportant to notice here thatthat iron(III)chlorideiron(III)chloride is only used to activateactivate the aldehyde and the oxetene insideinside the—concerted,the—concerted, albeit albeit non-synchronous—[2 non-synchronous—[2+ +2] 2] cycloaddition, cycloaddition, as as depicted depicted in in Scheme Scheme4. 4.Iron Iron d-orbitals d-orbitals do do not not take take part part in the in cycloaddition the cycloaddition step. step. Consequently, Consequently, the reaction the reaction does not does follow not followthe Chauvin the Chauvin mechanism, mechanism, as the metal as the is metal not included is not includedincluded in the cycle inin thethe formed cyclecycle in formedformed the transition inin thethe transitiontransition structure. structure.In general, In the general, reaction the itself reaction is better itselfitself describedisis betterbetter describeddescribed as an economical asas anan econecon catalyticomical catalytic alternative alternative to the Wittig to the Wittigreaction reaction [27]. Nevertheless, [27]. Nevertheless, carbonyl-alkyne carbonyl-alkyne metathesis metathesisthesis consists consistsconsists of formal ofof formalformal [2 + 2] [2[2 and ++ 2]2] retroandand retroretro [2 + [22][2 +cycloadditions 2] cycloadditions and and enables enables access access to multiple to multiple heterocycles heterocycles similar similar to olefin–metathesis to olefin–metathesis and and will will be bediscussed discussed in thein the following following part. part.

Scheme 4.4.. ReactionReaction mechanismmechanism of of carbonyl–alkyne carbonyl–alkyne metathesis. metathesis.

The ﬁrstfirst exampleexample of carbonyl-alkynecarbonyl-alkyne metathesis catalyzed by iron was described by Jana and co-workers in 2011 (Scheme5 5))[ [17].17].

Scheme 5. FeCl3-catalyzed-catalyzed carbonyl–alkyne carbonyl–alkyne metathesis metathesis reaction towards 2H-chromenes. Scheme 5. FeCl3-catalyzed carbonyl–alkyne metathesis reaction towards 2H-chromenes. Similar reactions yielding 2H-chromene derivatives were described with different catalysts before, Similar reactions yielding 2H-chromene derivatives were described with different catalysts e.g., Ru- [28] and Au-based [29] catalysts. While former methodologies suffer from their usage of an before, e.g., Ru- [28] and Au-based [29] catalysts. While former methodologies suffer from their usage expensive metal catalyst, the new method employing iron as Lewis acid decreases the costs of the of an expensive metal catalyst, the new method employing iron as Lewis acid decreases the costs of reaction drastically. One year later, the research group of Jana published a novel procedure towards phenanthrene derivatives (Scheme6). In this case the metathesis reaction is exploited to directly yield completely conjugated ring systems. In addition to the straightforward synthesis of precursors (two steps, palladium cross-coupling reactions), the method possesses a good tolerance with respect to functional groups, including methoxy, methyl, fluorine, chloride and ester moieties. Catalysts 2020, 10, x FOR PEER REVIEW 4 of 13 Catalysts 2020, 10, x FOR PEER REVIEW 4 of 13 the reaction drastically. One year later, the research group of Jana published a novel procedure towards phenanthrene derivatives (Scheme 6).

Catalysts 2020, 10, 1092 4 of 13

An additional approach for the carbonyl–alkyne metathesis was reported by Bera et al. in 2013Catalysts (Scheme 2020, 10, 7x). FOR ByPEER applying REVIEW 2,2 0 functionalized diarylesters it was possible to synthesize4 of 13 dibenzo[b,f ]oxepine and benzo[b]oxepine core structures, which possess many applications in medicinal Scheme 6. Iron(III)-catalyzed carbonyl–alkyne metathesis reaction towards phenanthrenes. chemistry.the reaction Additionally, drastically. One these year ring later, systems the representresearch group the ﬁrst of examplesJana published of artiﬁcially a novel synthesized procedure seven-memberedtowardsIn this phenanthrene case the heterocycles metathesis derivatives reported reaction (Scheme in is the 6).exploite literature d to to directly this date. yield completely conjugated ring systems. In addition to the straightforward synthesis of precursors (two steps, palladium cross- coupling reactions), the method possesses a good tolerance with respect to functional groups, including methoxy, methyl, fluorine, chloride and ester moieties. An additional approach for the carbonyl–alkyne metathesis was reported by Bera et al. in 2013 (Scheme 7). By applying 2,2′ functionalized diarylesters it was possible to synthesize dibenzo[b,f]oxepine and benzo[b]oxepine core structures, which possess many applications in medicinal chemistry. Additionally, these ring systems represent the first examples of artificially medicinal chemistry. Additionally, these ring systems represent the first examples of artificially synthesized seven-membered heterocycles reported in the literature to this date. Scheme 6. Iron(III)-catalyzedIron(III)-catalyzed carbonyl–alkyne metathesis reaction towards phenanthrenes.phenanthrenes.

In this case the metathesis reaction is exploited to directly yield completely conjugated ring systems. In addition to the straightforward synthesis of precursors (two steps, palladium cross- coupling reactions), the method possesses a good tolerance with respect to functional groups, including methoxy, methyl, fluorine, chloride and ester moieties. An additional approach for the carbonyl–alkyne metathesis was reported by Bera et al. in 2013

(Scheme 7). By applying 2,2′ functionalized diarylesters it was possible to synthesize dibenzo[b,f]oxepineScheme and 7. Synthesis benzo[b of ]oxepine dibenzo[ coreb,f]oxepine]oxepine structures, and and benzo[ benzo[ whichb]oxepine]oxepine possess compounds. many applications in medicinal chemistry. Additionally, these ring systems represent the first examples of artificially synthesizedIn 2014,2014, seven-membered the the research research group group heterocycles of Jana of Jana further reported further expanded inexpanded the the literature applicability the toapplicability this of date. iron-catalyzed of iron-catalyzed carbonyl– alkynecarbonyl– metathesis alkyne metathesis by synthesizing by synthesizing precursors precursors inspired by inspired their work by publishedtheir work inpublished 2011 (Scheme in 20115). By(Scheme replacement 5). By replacement of oxygen byof oxygen nitrogen by and nitrogen variation and variation of the chain of the length chain of length the alkyl of the bridge alkyl bridge to the alkyneto the alkyne moiety, moiety, a new librarya new library of six- or ofseven-membered six- or seven-membered nitrogen-containing nitrogen-containing heterocycles heterocycles was reported was (Schemereported8 ).(Scheme Again, these8). Again, classes these of compounds classes of were compounds already wellwere established already well in pharmacological established in applicationspharmacological and mayapplications lead to noveland may bioactive lead to compounds. novel bioactive compounds.

Scheme 7. Synthesis of dibenzo[b,f]oxepine and benzo[b]oxepine compounds.

In 2014, the research group of Jana further expanded the applicability of iron-catalyzed carbonyl– alkyne metathesis by synthesizing precursors inspired by their work published in 2011 (Scheme 5). By replacement of oxygen by nitrogen and variation of the chain length of the alkyl bridge Scheme 8. Carbonyl–alkyne metathesis reaction towards dihydroquinolines, quinolines and to theScheme alkyne 8.moiety, Carbonyl–alkyne a new library metathesis of six- or reactionseven-membered towards dihydroquinolines, nitrogen-containing quinolines heterocycles and was dihydrobenzo[b]azepines. reporteddihydrobenzo[ (Schemeb ]azepines.8). Again, these classes of compounds were already well established in pharmacological applications and may lead to novel bioactive compounds. The last work concerning alkyne–oleﬁn metathesis was reported by Jalal et al. in 2017. In this The last work concerning alkyne–olefin metathesis was reported by Jalal et al. in 2017. In this publication, the focus was laid on the conversion of indole-derived compounds towards benzocarbazole publication, the focus was laid on the conversion of indole-derived compounds towards and azepinoindole core structures as depicted in Scheme9. As these are known to exhibit antitumor [ 30] benzocarbazole and azepinoindole core structures as depicted in Scheme 9. As these are known to and antiestrogenic [31] properties, the expansion of the scope towards novel compounds is highly exhibit antitumor [30] and antiestrogenic [31] properties, the expansion of the scope towards novel desirable. By varying conformation of aldehyde and alkyne function, the carbonyl–alkyne metathesis compounds is highly desirable. By varying conformation of aldehyde and alkyne function, the gave facile access to the desired core structures, which were only accessible via expensive synthetic routes or toxic reagents before.

An additional advantage of this methodology is the straightforward precursor synthesis, whichScheme consists 8.of Carbonyl–alkyne only two steps. metathesis reaction towards dihydroquinolines, quinolines and Indihydrobenzo[ summary, theb]azepines. carbonyl–oleﬁn metathesis reaction is a useful tool for the synthesis of novel, uncommon heterocyclic compounds or for straightforward synthesis of phenanthrene aldehydes. As synthesisThe last ofwork precursors concerning involves alkyne–o simplelefin reaction metathesis steps andwas thereported metathesis by Jalal catalyst et al. is in non-toxic 2017. In andthis publication, the focus was laid on the conversion of indole-derived compounds towards benzocarbazole and azepinoindole core structures as depicted in Scheme 9. As these are known to exhibit antitumor [30] and antiestrogenic [31] properties, the expansion of the scope towards novel compounds is highly desirable. By varying conformation of aldehyde and alkyne function, the

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carbonyl–alkyne metathesis gave facile access to the desired core structures, which were only accessible via expensive synthetic routes or toxic reagents before. Catalysts 2020, 10, 1092 5 of 13

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 13 cheap, this methodology might be useful for the discovery or development of novel pharmaceutically activecarbonyl–alkyne compounds. metathesis An overview gave of facile all reported access reactions to the desired and that core of resulting structures, derivatives which iswere depicted only inaccessible Scheme via10. expensive synthetic routes or toxic reagents before.

Scheme 9. FeCl3-catalyzed reaction towards benzocarbazoles and azepino[1,2-a]indoles.

An additional advantage of this methodology is the straightforward precursor synthesis, which consists of only two steps. In summary, the carbonyl–olefin metathesis reaction is a useful tool for the synthesis of novel, uncommon heterocyclic compounds or for straightforward synthesis of phenanthrene aldehydes. As synthesis of precursors involves simple reaction steps and the metathesis catalyst is non-toxic and cheap, this methodology might be useful for the discovery or development of novel pharmaceutically active compounds. An overview of all reported reactions and that of resulting derivatives is depicted in Scheme 10. Scheme 9. FeCl3-catalyzed-catalyzed reaction reaction towards towards benzocarbazoles benzocarbazoles and azepino[1,2- a]indoles.

Scheme 10. Overview of the reported carbonyl–alkyne metathesis reactions. Scheme 10. Overview of the reported carbonyl–alkyne metathesis reactions. 2.3.2.3. Iron-Catalyzed Iron-Catalyzed Carbonyl-Olefin Carbonyl-Olefin Metathesis Metathesis Similar to carbonyl–alkyne metathesis and olefin–olefin metathesis, carbonyl–olefin metathesis Similar to carbonyl–alkyne metathesis and olefin–olefin metathesis, carbonyl–olefin metathesis is a powerful tool for C=C bond formation [16]. The early carbonyl–olefin metathesis protocols is a powerful tool for C=C bond formation [16]. The early carbonyl–olefin metathesis protocols required harsh conditions, like the first described example employing a two-step sequence including a photoinduced [2 + 2] cycloaddition, known as the Paternò-Büchi reaction [32,33], and an acidic or thermal retro-cyclization to yield the desired products (Scheme 11A) [34]. Another possibility of yielding the desired metathesis products is the stoichiometric use of a metal catalyst (Scheme 11B), which is oxidized during the reaction, as was described by the research group of Grubbs in 1990 [35]. Since this process is not catalytic, it is not suitable for industry due to its low atom economy. In 1983, Schopov and co-workers reported the first catalytic procedure employing tungsten chloride for theScheme synthesis 10. ofOverview polyconjugated of the reported polymers carbonyl–alkyne [36]. Even metathesis though this reactions. was the first catalytic approach, the reaction has a strong limitation as it requires a conjugated C=C and C=O bond. Only one2.3. Iron-Catalyzed year later, Snider Carbonyl-Olefin and co-workers Metathesis published a modified version of the oxetane-forming reaction of Similar to carbonyl–alkyne metathesis and olefin–olefin metathesis, carbonyl–olefin metathesis is a powerful tool for C=C bond formation [16]. The early carbonyl–olefin metathesis protocols

Catalysts 2020, 10, x FOR PEER REVIEW 6 of 13 Catalysts 2020, 10, x FOR PEER REVIEW 6 of 13 required harsh conditions, like the first described example employing a two-step sequence including arequired photoinduced harsh conditions, [2 + 2] cycloaddition, like the first known described as the example Paternò-Büchi employing reaction a two-step [32,33], sequence and an including acidic or thermala photoinduced retro-cyclization [2 + 2] cycloaddition, to yield the knowndesired as products the Paternò-Büchi (Scheme 11A) reaction [34]. [32,33], Another and possibility an acidic orof yieldingthermal retro-cyclizationthe desired metathesis to yield products the desired is the productsstoichiometric (Scheme use 11A)of a metal[34]. Anothercatalyst (Schemepossibility 11B), of whichyielding is oxidizedthe desired during metathesis the reaction, products as was is the described stoichiometric by the researchuse of a groupmetal catalystof Grubbs (Scheme in 1990 11B), [35]. Sincewhich this is oxidized process duringis not catalytic, the reaction, it is notas was suitable described for industry by the researchdue to its group low atom of Grubbs economy. in 1990 [35]. SinceIn this 1983, process Schopov is not and catalytic, co-workers it is not reported suitable thefor industryfirst catalytic due to procedure its low atom employing economy. tungsten chlorideIn 1983, for the Schopov synthesis and of co-workers polyconjugated reported polyme thers first [36]. catalytic Even though procedure this was employing the first tungstencatalytic approach,chloride for the the reaction synthesis has of a polyconjugatedstrong limitation polyme as it requiresrs [36]. aEven conjugated though C=Cthis wasand theC=O first bond. catalytic Only approach, the reaction has a strong limitation as it requires a conjugated C=C and C=O bond. Only Catalystsone year2020 later,, 10, 1092Snider and co-workers published a modified version of the oxetane-forming reaction6 of 13 one year later, Snider and co-workers published a modified version of the oxetane-forming reaction of an aldehyde and an olefin - employing SnCl4 as catalyst (Scheme 11C) [37,38]. The modified version of an aldehyde and an olefin - employing SnCl4 as catalyst (Scheme 11C) [37,38]. The modified version used a 1:2 ratio of Me2AlCl:MeAlCl2 yielding the desired diene in 30% yield. Further experiments used a 1:2 ratio of Me2AlCl:MeAlCl2 yielding the desired diene in 30% yield. Further experiments anwith aldehyde different and ratios an olefin of the - employing catalytic mixture SnCl4 as alre catalystady gave (Scheme evidence 11C) [37that,38 ].the The catalytic modified activity version is with different ratios of the catalytic mixture already gave evidence that the catalytic activity is usedconnected a 1:2 ratioto the of strength Me2AlCl:MeAlCl of the Lewis2 yielding acid. theIn th desirede following diene years in 30% different yield. Further approaches experiments with Lewis with connected to the strength of the Lewis acid. In the following years different approaches with Lewis diacids,fferent for ratios example of the with catalytic EZP-10 mixture (solid already Lewis gaveacid catalyst) evidence or that BF the3·OEt catalytic2 were activity published is connected [19,39]. As to theacids,already strength for described example of the Lewisin with the acid.previousEZP-10 In the (solid section following Lewis for the yearsacid carbonyl–alkyne dicatalyst)fferent approachesor BF metathesis3·OEt2 with were Lewisreaction, published acids, the for [19,39].Lewis example acid As already described in the previous section for the carbonyl–alkyne metathesis reaction, the Lewis acid withactivates EZP-10 the (solidoxygen Lewis of the acid carbonyl catalyst) and or also BF3 OEtin th2 ewere transition published structure [19,39 indu]. Ascing already the retro-[2 described + 2]- in · theactivatesaddition previous [40].the sectionoxygen forof thethe carbonyl–alkynecarbonyl and also metathesis in the transition reaction, structure the Lewis indu acidcing activates the retro-[2 the oxygen + 2]- ofaddition the carbonyl [40]. and also in the transition structure inducing the retro-[2 + 2]-addition [40].

Scheme 11. Types of carbonyl-olefin metathesis: (A) photochemical; (B) stoichiometric transition Scheme 11. Types of carbonyl-oleﬁn metathesis: (A) photochemical; (B) stoichiometric transition Scheme 11. Types of carbonyl-olefinmetal-mediated; metathesis: (C) catalytic (A) photochemical; cross metathesis. (B) stoichiometric transition metal-mediated; (C) catalyticmetal-mediated; cross metathesis. (C) catalytic cross metathesis.

The first catalytic carbonyl–olefin metathesis approach employing the Lewis acid FeCl3 as an The ﬁrst catalytic carbonyl–oleﬁn metathesis approach employing the Lewis acid FeCl3 as an The first catalytic carbonyl–olefin metathesis approach employing the Lewis acid FeCl3 as an environmentally friendly catalyst in a ring-closing reaction was published by the research group of environmentally friendly catalyst in a ring-closing reaction was published by the research group of Schindler, which presented a widewide scopescope ofof almostalmost 5050 examplesexamples withwith moderate-to-excellentmoderate-to-excellent yields Schindler, which presented a wide scope of almost 50 examples with moderate-to-excellent yields under mild reaction conditions (Scheme(Scheme 1212):): [[40]40] under mild reaction conditions (Scheme 12): [40]

Scheme 12. General equation of the reac reactiontion reported by Schindler. Scheme 12. General equation of the reaction reported by Schindler. In a small review, Saá highlighted the most important features of the new approach: the reaction In a small review, Saá highlighted the most important features of the new approach: the reaction tolerates various aromatic substituents, while bulky olefin moieties decrease product formation. toleratesIn a smallvarious review, aromatic Saá highlighted substituents, the while most importantbulky olefin features moieties of the decrease new approach: product the formation. reaction Moreover, metal enolates were not necessary to yield the desired products, as moieties bearing toleratesMoreover, various metal enolatesaromatic weresubstituents, not necessary while tobulk yieldy olefin the desiredmoieties products, decrease asproduct moieties formation. bearing quaternary carbons in α-position are viable towards the reaction [41]. Nevertheless, compared to olefin quaternaryMoreover, metalcarbons enolates in α-position were not are necessary viable towards to yield the the reaction desired [41]. products, Nevertheless, as moieties compared bearing to metathesis, the versatility of the reaction is still poor, as the already existing metathesis catalyst pool olefinquaternary metathesis, carbons the in versatility α-position of arethe reactionviable towards is still poor, the reactionas the already [41]. Nevertheless,existing metathesis compared catalyst to makes the design of suitable reaction conditions for almost every substitution pattern possible. poololefin makes metathesis, the design the versatility of suitable of reaction the reaction conditio is stillns poor, for almost as the every already substitution existing metathesis pattern possible. catalyst pool Inmakes the the same design year of further suitable applications reaction conditio of iron-catalyzedns for almost every carbonyl–olefin substitution metathesispattern possible. were demonstrated by Li and co-workers, published in 2016, providing access to highly substituted five-membered carbocycles and six-membered heterocycles (Scheme 13)[42]. As the authors hypothesized that bulky benzoyl and phenyl groups play a key role in the formation of the transition structure, mainly these were chosen for R1,R2 and R3. Extending the previous scope, modification of the conditions was also employed to provide five-membered nitrogen heterocycles in poor to excellent yields. The reaction temperature was lowered to 0◦ and allyltrimethylsilane was used as an additive (5 eq.), as the reaction did not proceed by only using iron(III)chloride (Scheme 14). The role of allyltrimethylsilane could not be clarified in the studies, but it is suggested that both functional groups, the trimethylsilyl and allyl group, are required for the transformation. The authors further suggested two possible roles of the additive: first, it might promote coordination of the catalyst and therefore the formation and ring opening of the oxetane intermediate, and second, it may support the separation of the aldehyde, as the bisallylated product was found as the by-product. Catalysts 2020, 10, x FOR PEER REVIEW 7 of 13

In the same year further applications of iron-catalyzed carbonyl–olefin metathesis were demonstrated by Li and co-workers, published in 2016, providing access to highly substituted five- membered carbocycles and six-membered heterocycles (Scheme 13) [42].

Catalysts 2020, 10, x FOR PEER REVIEW 7 of 13

In the same year further applications of iron-catalyzed carbonyl–olefin metathesis were demonstrated by Li andScheme co-workers, 13. General published equations in of 2016, the published providing reactions access byto Li.highly substituted five- Catalysts 2020, 10, 1092 7 of 13 membered carbocycles and six-membered heterocycles (Scheme 13) [42]. As the authors hypothesized that bulky benzoyl and phenyl groups play a key role in the formation of the transition structure, mainly these were chosen for R1, R2 and R3. Extending the previous scope, modification of the conditions was also employed to provide five-membered nitrogen heterocycles in poor to excellent yields. The reaction temperature was lowered to 0° and allyltrimethylsilane was used as an additive (5 eq.), as the reaction did not proceed by only using Scheme 13. General equations of the published reactions by Li. iron(III)chloride (Scheme 14). As the authors hypothesized that bulky benzoyl and phenyl groups play a key role in the formation of the transition structure, mainly these were chosen for R1, R2 and R3. Extending the previous scope, modification of the conditions was also employed to provide five-membered nitrogen heterocycles in poor to excellent yields. The reaction temperature was lowered to 0° and allyltrimethylsilane was used as an additive (5 eq.), as the reaction did not proceed by only using iron(III)chlorideScheme 14.(Scheme General 14). reaction equation of published reactions employing allyltrimethylsilane. Scheme 13. GeneralGeneral equations equations of of the the published published reactions by Li. The role of allyltrimethylsilane could not be clarified in the studies, but it is suggested that both As the authors hypothesized that bulky benzoyl and phenyl groups play a key role in the functional groups, the trimethylsilyl and allyl group, are required for the transformation. The authors formation of the transition structure, mainly these were chosen for R1, R2 and R3. Extending the further suggested two possible roles of the additive: first, it might promote coordination of the previous scope, modification of the conditions was also employed to provide five-membered catalyst and therefore the formation and ring opening of the oxetane intermediate, and second, it may nitrogen heterocycles in poor to excellent yields. The reaction temperature was lowered to 0° and support the separation of the aldehyde, as the bisallylated product was found as the by-product. allyltrimethylsilaneScheme 14. General Generalwas used reaction reaction as an equation additive of published (5 eq.), as reactions the reaction employing did not allyltrimethylsilane. proceed by only using Another example of carbonyl–olefin metathesis was reported by Schindler and co-workers in iron(III)chloride (Scheme 14). 2017,TheAnother expanding role exampleof allyltrimethylsilane the scope of carbonyl–oleﬁn of FeCl3 catalysis could metathesis not to bepolycyclic clarif wasied reported aromatic in the studies, by compounds Schindler but it and is(Scheme suggested co-workers 15) that[43]. in 2017,bothThis functionalexpandingwork also includedgroups, the scope the the of trimethylsilyl isolation FeCl3 catalysis of an and oxetane to allyl polycyclic grouintermediatep, aromatic are required as compounds evidence for the for transformation. (Scheme the cycloaddition 15)[43 ].The This reactionauthors work furtheralsostep. included suggested the isolation two possible of an oxetaneroles of intermediate the additive as: first, evidence it might for the promot cycloadditione coordination reaction of step.the catalyst and therefore the formation and ring opening of the oxetane intermediate, and second, it may support the separation of the aldehyde, as the bisallylated product was found as the by-product.

Another example of carbonyl–olefin metathesis was reported by Schindler and co-workers in Scheme 14. General reaction equation of published reactions employing allyltrimethylsilane. 2017, expanding the scope of FeCl3 catalysis to polycyclic aromatic compounds (Scheme 15) [43]. This work also included the isolation of an oxetane intermediate as evidence for the cycloaddition reaction The role of allyltrimethylsilane could not be clarified in the studies, but it is suggested that both step. functional groups, the trimethylsilylScheme 15. General and allyl equation grou for p, arethe required synthesis offor polycycles. the transformation. The authors further suggested two possible roles of the additive: first, it might promote coordination of the catalystTo getandget deeper deepertherefore insightsinsights the formation intointo thethe and reactionreaction ring mechanismopeninmechangism of the of theoxetanethe carbonyl–olefincarbonyl–olefin intermediate, ring-closing and second, reaction it may supportdepicted the in separation Scheme 1212, of, Zimmermanthe aldehyde, and as the Schindler bisallylated cooperated product to was investigate found as theby by-product. computational, kineticAnother and synthetic example analysis of carbonyl–olefin the nature of metathesis the LewisLewis was acid-catalyzed reported by reaction Schindler (Figure and1 1))[co-workers [44].44]. For the in 2017,computations, expanding ZStruct, the scope a DFT-based of FeCl3 catalysis program to which polycyclic is able aromatic to detect compounds reaction pathways (Scheme by 15) generating [43]. This computations, ZStruct, a DFT-based program which is able to detect reaction pathways by generating worka range also of included intermediatesintermediates the isolation and calculate of an oxetane their inte thermodynamicrmediate as evidence availability, for the independent cycloaddition from reaction bond Scheme 15. General equation for the synthesis of polycycles. step.forming andand breaking,breaking, waswas usedused [[45].45]. InIn thethe syntheticsynthetic analysis, analysis, it it was was possible possible to to identify identify acetone acetone as as a by-product in reactions with R3 = R4 = methyl via NMR spectroscopy, which lends further support to To get deeper insights into the reaction mechanism of the carbonyl–olefin ring-closing reaction the proposed mechanism. depicted in Scheme 12, Zimmerman and Schindler cooperated to investigate by computational, To identify the role of the Lewis acid, especially FeIII, to differentiate between a stepwise, cationic kinetic and synthetic analysis the nature of the Lewis acid-catalyzed reaction (Figure 1) [44]. For the reaction mechanism and a concerted, non-synchronous mechanism in the formation and dissociation computations, ZStruct, a DFT-based program which is able to detect reaction pathways by generating of the oxetane and for the determination of the turnover-limiting step, experiments like cation trapping, a range of intermediates and calculate their thermodynamic availability, independent from bond EPR measurements, determination of the secondary kinetic isotope effect and ZStruct calculations forming and breaking, was used [45]. In the synthetic analysis, it was possible to identify acetone as were carried out. Scheme 15. General equation for the synthesis of polycycles. The results were summarized as follows (Figure1): concerning Fe III as catalyst, the efficiency is relatedTo toget the deeper Lewis insights acidity ofinto the the catalyst reaction used, mechan and theism best of resultsthe carbonyl–olefin were obtained ring-closing for iron(III)chloride, reaction depictedwhich binds in Scheme to the carbonyls 12, Zimmerman without anand electron Schindler transfer cooperated event, whileto investigate small impurities by computational, or usage of kineticiron(III)chloride and synthetic hydrate analysis did notthe nature affect the of the yield Lewis of the acid-catalyzed metathesis reaction. reaction It(Figure was also 1) [44]. possible For the to computations,exclude the influence ZStruct, of a possibleDFT-based HCl program formation which on theis able reaction to detect rate. reaction pathways by generating a rangeConcerning of intermediates turnover and limitation: calculate the their transition thermodynamic state, governing availability, the turnover independent of the cycle, from is highlybond formingordered andand displaysbreaking, high was levels used of[45]. bond In reorganizationthe synthetic analysis, energy, andit wasB-SKIE possible analysis to identify indicated acetone oxetane as formation as the turnover-limiting step. In this step, the π system of the aryl group stabilizes the HOMO through electron delocalization. The activation barriers of the rate-limiting step of the two Catalysts 2020, 10, 1092 8 of 13

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 13 suggested mechanisms were found to be almost identical, but as cation-trapping experiments were not asuccessful, by-product a stepwisein reactions reaction with R was3 = R excluded.4 = methyl via NMR spectroscopy, which lends further support to theConcerning proposed mechanism. dissociation mechanism: experiments gave different yield results vs. conversion for benzyl-To identify and alkyl-substituted the role of the Lewis olefins, acid, indicating especially that Fe bothIII, to differentiate mechanisms between are possible, a stepwise, depending cationic on reactionthe substitution mechanism pattern. and a Styrenyl-derivedconcerted, non-synchronous substrates seemmechanism to prefer in the formation cationic-stepwise and dissociation reaction, ofas theythe oxetane are able and to delocalize for the determination the positive charge of the via turnover-limiting mesomerism. In step, conclusion, experiments FeIII as like catalyst cation in trapping,carbonyl–olefin EPR measurements, metathesis provides determination a simple andof th straightforwarde secondary kinetic road toisotope versatile effect compounds and ZStruct via calculationsring-closing were metathesis. carried out.

Enthalpic Profile a)

Ph Cl3Fe CO2Et O Me Ph Me CO2Et Cl Fe 3 O 24.0 Me

) Me -1

TS-II Ph Cl3Fe CO Et Ph O Cl Fe 2 TS-I CO2Et 3 Cl3Fe 15.3

H (kcal molH (kcal O 14.5 O Me Me + Me Me CO2Et Ph

4.3 3.8 0.0 oxetane

Reaction Coordinate

FigureFigure 1. 1. ReactionReaction profiles proﬁles of of the the two two possible possible reaction reaction pa pathwaysthways calculated calculated by bythe the research research group group of Zimmermann.of Zimmermann.

TheIn 2019, results Schindler were summarized and co-workers as follows reported (Figure an 1): additional concerning type FeIII of as carbonyl–olefin catalyst, the efficiency synthesis, is relatedwhich allowsto the the Lewis manipulation acidity of of functionalizedthe catalyst used, decalin and derivatives the best [results46]. These were compounds obtained canfor iron(III)chloride,be synthesized by which three-step binds modification to the carbonyls of naturally without occurring an electron steroids. transfer In contrast event, towhile previously small reported carbonyl–olefin metathesis reactions, two additional side-paths occur during the reaction, impurities or usage of iron(III)chloride hydrate did not affect the yield of the metathesis reaction. It waswhich also may possible result to in exclude carbonyl–ene the influence metathesis of possible product HCl or formation tetrahydrofuran on the reaction compounds rate. instead of the desiredConcerning product turnover (Scheme limitation: 16), which the are transition also interesting state, governing in their similarity the turnover to biologically of the cycle, active is highlymolecules. ordered Interestingly, and displays by changing high levels the catalyzingof bond reorganization Lewis acid, a selectivityenergy, and towards Β-SKIE the analysis desired III indicatedmolecules oxetane can be achieved.formation Feas theturned turnover-limiting out to work step. best forIn this the step, desired the carbonyl–olefinπ system of the aryl metathesis group stabilizes the HOMO through electron delocalization. The activation barriers of the rate-limiting step of the two suggested mechanisms were found to be almost identical, but as cation-trapping experiments were not successful, a stepwise reaction was excluded.

Catalysts 2020, 10, x FOR PEER REVIEW 9 of 13

Concerning dissociation mechanism: experiments gave different yield results vs. conversion for benzyl- and alkyl-substituted olefins, indicating that both mechanisms are possible, depending on the substitution pattern. Styrenyl-derived substrates seem to prefer the cationic-stepwise reaction, as III they are able to delocalize the positive charge via mesomerism. In conclusion, FeIII as catalyst in carbonyl–olefin metathesis provides a simple and straightforward road to versatile compounds via ring-closing metathesis. In 2019, Schindler and co-workers reported an additional type of carbonyl–olefin synthesis, which allows the manipulation of functionalized decalin derivatives [46]. These compounds can be synthesized by three-step modification of naturally occurring steroids. In contrast to previously reported carbonyl–olefin metathesis reactions, two additional side-paths occur during the reaction, which may result in carbonyl–ene metathesis product or tetrahydrofuran compounds instead of the desired product (Scheme 16), which are also interesting in their similarity to biologically active Catalysts 2020, 10, 1092 9 of 13 molecules. Interestingly, by changing the catalyzing Lewis acid, a selectivity towards the desired III molecules can be achieved. FeIII turned out to work best for the desired carbonyl–olefin metathesis product, albeit it was not possible to to suppress suppress the the formation formation of of tetrahydrofura tetrahydrofurann derivative derivative formation. formation. Total selectivityselectivity cancan bebe achievedachieved byby usingusing alcoholalcohol asas RR inin thethe decalindecalin derivativesderivatives insteadinstead ofof acetate.acetate.

Scheme 16. Overview of possible outcomes for the conversion of chosen decalin derivative.

With the the optimized optimized conditions conditions in hand, in hand, the scope the of scope reaction of reactionwas performed, was performed, which resulted which in yieldsresulted up in to yields84%; the up general to 84%; equation the general is depicted equation in isScheme depicted 17. inFor Scheme this purpose, 17. For cyclodecenones this purpose, werecyclodecenones synthesized were starting synthesized from starting the fromreadily the readilyavailable available steroids steroids cholesterol, cholesterol, stigmasterol, stigmasterol, dehydroepiandrosterone and pregnenolone.pregnenolone.

Scheme 17. General equation for the transannular carbonyl-oleﬁn metathesis. Scheme 17. General equation for the transannular carbonyl-olefin metathesis. Additional to experimental investigations of the mechanism, computational investigations were CatalystsAdditional 2020, 10, x FORto experimental PEER REVIEW investigations of the mechanism, computational investigations10 were of 13 performed. In summary, the results suggest that the mechanism diﬀers from the already established performed. In summary, the results suggest that the mechanism differs from the already established types: after after activation activation of of carbon carbonyl-oxygen,yl-oxygen, two reversible transformationstransformations are possible. While the kinetic pathway yields the carbonyl-ene product (whi (whichch can also be isolated at lower temperatures under otherwise standard conditions),conditions), [2[2+2]-cycloaddition+ 2]-cycloaddition can can lead lead to to the the tetrahydrofuran tetrahydrofuran product via elimination or yield the desired product via retro-[2retro-[2 ++ 2]-cycloaddition. In their their recent recent approach, approach, the research group of Sc Schindlerhindler focused on the synthesis of novel chiral tetrahydropyridine derivatives (Scheme 1818).). The The prec precursorsursors were synthesized via three steps, starting starting from commercially available amino acids.

Scheme 18. GeneralGeneral equation equation for for synthesis synthesis of tetrahydropyridine derivatives.

Further screening of the catalytic conditions and additional investigations indicated that the choice of the protecting group and the olefin subunit has a crucial influence on the reaction outcome. Furthermore, the deprotection of the synthesized products is straightforward: treatment with SmI2, H2O and NEt3 in THF grants facile access to the desired secondary amine. In conclusion, this method offers a simple route towards chiral tetrahydropyridines. To expand the scope of FeIII-catalyzed carbonyl–olefin reactions towards 2,5- and 3,5- hexadienals, analog to the Schindler’s work (Scheme 19), Zhu and co-workers performed computational investigations to get information on how substitution patterns of those derivative may have beneficial influence on the outcome of the reaction [47].

Scheme 19. Carbonyl–olefin metathesis developed by Schindler and diene model systems investigated by Zhu and co-workers.

The results can be summarized as follows: first, electron density donating groups like methyl, as already reported in the example in Scheme 19, decrease energy of the cycloaddition barriers; second, cycloreversion barriers can be lowered by using substituents bearing an electron-donating, hyperconjugative effect (like X = SiH3, Scheme 19). Additionally, the substitution for R1 = Ar is beneficial for the cycloreversion, even though it increases the cycloaddition barrier slightly (which is not considered as a major drawback by the authors). As 10 out of 33 designed systems were identified as promising candidates, this work gives strong evidence that carbonyl–olefin metathesis might be realized in future work.

3. Conclusions Iron, one of the most abundant elements in the earth’s crust, is the focus of extensive research in catalysis. Many applications employing iron in heterogeneous and homogeneous systems as a catalyst have already been realized. Among already established reactions are carbonyl–olefin and carbonyl–alkyne metathesis, which are catalyzed in solution by FeCl3, functioning as Lewis acid and providing a wide scope of reactions. The theoretical investigations of carbonyl–olefin metathesis reactions may give hints for the design of new procedures to even further expand the family of iron-

Catalysts 2020, 10, x FOR PEER REVIEW 10 of 13

types: after activation of carbonyl-oxygen, two reversible transformations are possible. While the kinetic pathway yields the carbonyl-ene product (which can also be isolated at lower temperatures under otherwise standard conditions), [2+2]-cycloaddition can lead to the tetrahydrofuran product via elimination or yield the desired product via retro-[2 + 2]-cycloaddition. In their recent approach, the research group of Schindler focused on the synthesis of novel chiral tetrahydropyridine derivatives (Scheme 18). The precursors were synthesized via three steps, starting from commercially available amino acids.

Catalysts 2020, 10, 1092 10 of 13 Scheme 18. General equation for synthesis of tetrahydropyridine derivatives.

Further screeningscreening of the the catalytic catalytic conditions conditions andand additionaladditional investigations investigations indicatedindicated that the the choicechoice of the protecting group and the olefinolefin subunit has a crucial influence influence on the reaction outcome. Furthermore,Furthermore, the deprotectiondeprotection ofof thethe synthesizedsynthesized productsproducts isis straightforward:straightforward: treatment with SmISmI22, H22O and NEt 3 inin THF THF grants grants facile facile access to the desired secondary amine. In conclusion, this methodmethod ooffersffers aa simplesimple routeroute towardstowards chiralchiral tetrahydropyridines.tetrahydropyridines. III To expand expand the the scope scope of Fe of-catalyzed FeIII-catalyzed carbonyl–olefin carbonyl– reactionsolefin reactions towards 2,5- towards and 3,5- 2,5 hexadienals,- and 3,5- analoghexadienals, to the analog Schindler’s to the work Schindler’s (Scheme work 19), Zhu(Scheme and 19),co-workers Zhu and performed co-workers computational performed investigationscomputational to investigations get information to get on information how substitution on how patterns substitution of those patterns derivative of those may derivative have beneficial may influencehave beneficial on the influence outcome on of thethe reactionoutcome [ 47of]. the reaction [47].

Scheme 19.19Carbonyl–oleﬁn. Carbonyl–olefin metathesis metathesis developed developed by Schindler by Schindler and diene and model diene systems model investigated systems byinvestigated Zhu and co-workers. by Zhu and co-workers.

The resultsresults cancan bebe summarizedsummarized asas follows:follows: first,first, electron density donating groups like methyl, as already already reported in the the example example inin Scheme Scheme 19 19,, decrease decrease energy of the the cycloaddition cycloaddition barriers;barriers; second,second, cycloreversion barriers can be lowered by usingusing substituentssubstituents bearing an electron-donating,electron-donating, 11 hyperconjugative eeffectffect (like (like X X = = SiH SiH33,, Scheme Scheme 19 19).). Additionally Additionally,, the substitution substitution for for R R == Ar is is beneficialbeneficial forfor thethe cycloreversion, eveneven thoughthough it increases thethe cycloaddition barrierbarrier slightlyslightly (which(which is not considered asas aa major drawback byby thethe authors). As 10 out of 33 designed systems were identifiedidentified as promisingpromising candidates,candidates, this workwork givesgives strongstrong evidenceevidence thatthat carbonyl–olefincarbonyl–olefin metathesismetathesis mightmight bebe realizedrealized inin futurefuture work.work.

3.3. Conclusions Iron,Iron, one of the most most abundant abundant elements elements in in the the earth earth’s’s crust, crust, is isthe the focus focus of ofextensive extensive research research in incatalysis. catalysis. Many Many applications applications employing employing iron iron in in heterogen heterogeneouseous and and homogen homogeneouseous systems systems as asa acatalyst catalyst have have already already been been realized realized.. Among Among already already established established reactions reactions are carbonyl are carbonyl–olefin–olefin and andcarbonyl carbonyl–alkyne–alkyne metathesis, metathesis, which which are cataly arez catalyzeded in solution in solution by FeCl by3, functioning FeCl3, functioning as Lewis asacid Lewis and acidproviding and providing a wide scope a wide of reactions. scope of reactions.The theoretical The theoretical investigations investigations of carbonyl of–olefin carbonyl–olefin metathesis metathesisreactions may reactions give hints may for give the hintsdesign for of the new design procedures of new to procedures even further to expand even further the family expand of iron the- family of iron-catalyzed carbonyl–olefin metathesis reactions. By exploiting the described procedures, the synthesis of novel bioactive molecules or derivatives of already known drugs can be realized, which becomes more and more important in the light of increasing resistance towards already established pharmaceutics.

Author Contributions: All authors have read and agreed to the published version of the manuscript. Writing—original draft preparation, B.W.G.; writing—review and editing, S.B.T. Funding: This research received no external funding. Acknowledgments: We thank the Interdisciplinary Center for Molecular Materials (ICMM) and the Graduate School Molecular Science (GSMS) for research support. Conﬂicts of Interest: The authors declare no conﬂict of interest. Catalysts 2020, 10, 1092 11 of 13

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