molecules

Review On the Use of Iron in Organic Chemistry

Arnar Guðmundsson 1 and Jan-E. Bäckvall 1,2,*

1 Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden; [email protected] 2 Department of Natural Sciences, Mid Sweden University, Holmgatan 10, 85179 Sundsvall, Sweden * Correspondence: [email protected]; Tel.: +46-08-674-71-78



Received: 2 March 2020; Accepted: 10 March 2020; Published: 16 March 2020


Abstract: Transition metal catalysis in modern organic synthesis has largely focused on noble transition metals like palladium, platinum and ruthenium. The toxicity and low abundance of these metals, however, has led to a rising focus on the development of the more sustainable base metals like iron, copper and nickel for use in catalysis. Iron is a particularly good candidate for this purpose due to its abundance, wide redox potential range, and the ease with which its properties can be tuned through the exploitation of its multiple oxidation states, electron spin states and redox potential. This is a fact made clear by all life on Earth, where iron is used as a cornerstone in the chemistry of living processes. In this mini review, we report on the general advancements in the field of iron catalysis in organic chemistry covering addition reactions, C-H activation, cross-coupling reactions, cycloadditions, isomerization and redox reactions.

Keywords: iron; organic synthesis; C-H activation; C-C coupling

1. Introduction Iron is the most abundant element on Earth by mass and is used ubiquitously by living organisms [1]. The ability of iron to assume many oxidation states (from 2 up to +6) coupled with its low toxicity − makes it an attractive, versatile and useful catalyst in organic synthesis. The wide range of oxidation states available for iron and its ability to promote single electron transfer (SET) allows it to cover a wide range of transformations. In low oxidation states, iron becomes nucleophilic in character and takes part in reactions such as nucleophilic substitutions, reductions and cycloisomerizations. At higher oxidation states, iron behaves as a Lewis acid, activating unsaturated bonds and at very high oxidation states (+3 to +5) iron complexes can take part in C-H activation. Due to iron’s central position in the periodic table, it can have the property of both an “early” and “late” transition metal and with the many oxidation states available, any type of reaction is, in principle, within reach. Iron cations also bind strongly to many N- and O-based ligands, and these ligands can replace phosphine ligands in iron chemistry. As the atmosphere on Earth changed following the Great Oxidation Event about 2.4 billion years ago, ferrous (+2) iron complexes became less stable and ferric (+3) complexes became predominant [2]. Iron in its ferric oxidation state typically forms complexes that are water-insoluble like hematite (Fe2O3) or magnetite (Fe3O4), especially under basic conditions when exposed to air. This propensity of iron complexes to precipitate can be a hindrance for catalysis, although, despite the fact that ferric complexes are mostly water-insoluble at biological pH, iron is still the most common transition metal in living organisms and is indispensable for the chemical processes of life—oxygen binding, electron transport, DNA synthesis, and cell proliferation, to name only a few. Modern catalysis has been dominated by noble transition metals, such as palladium, platinum, ruthenium and iridium, and these metals have been used in a wide range of reactions. The main

Molecules 2020, 25, 1349; doi:10.3390/molecules25061349 www.mdpi.com/journal/molecules Molecules 2020, 25, 1349 2 of 20 advantage that noble transition metals have over their base counterparts is their preference for undergoing two-electron processes. They do, however, have significant drawbacks: high cost, non-renewable supply and/or precarious toxicological and ecological properties. These factors may not pose too much of a problem for academic research, but have profound implications for industry and for the future of sustainable chemistry. It is for these reasons that attention has shifted towards base transition metals like iron, copper and nickel. Iron is particularly well suited as it is the second most abundant metal in the Earth’s crust after aluminum and is consequently attractive economically and ecologically. Despite these advantages of iron, organoiron catalysts tend to suffer from serious drawbacks such as difficult synthetic pathways, lack of robustness, poor atom economy and low activity or enantioselectivity. Although circumventing these limitations will be necessary for iron catalysis to reach its full potential, base metal catalysis will no doubt gain importance in the future and it is reasonable to think that base metals such as iron will eventually supplant the traditional dominance of noble transition metals as the field matures. In recent times, the area of iron catalysis has exploded and Beller in 2008 and Bolm in 2009 declared that the age of iron has begun [3,4]. An intriguing outlook on the future of homogeneous iron catalysis was published in 2016 by Fürstner [5]. This review focuses on the recent advancements in iron catalysis pertaining to organic chemistry from 2016 to February 2020. An excellent and comprehensive review from 2015 by Knölker on all the types of iron-catalyzed reactions discussed in this review in addition to others can be consulted for the interested reader [6]. Other more specialized reviews may be found in each respective subsection. It should be mentioned that metathesis reactions are omitted from this review.

2. Iron in Organic Synthesis Organoiron chemistry began in 1891 with the discovery of iron pentacarbonyl by Mond and Berthelot [7,8]. It was used sixty years later industrially in the Reppe process of hydroformylation of ethylene to form propionaldehyde and 1-propanol in basic solutions [9]. An important event was the discovery of ferrocene in 1951 [10], the structure of which was determined in 1952 [11,12] and led to the Nobel prize being awarded to Wilkinson and Fischer in 1973. The discovery of the Haber–Bosch process was an additional milestone in iron chemistry. The latter process uses an inorganic iron catalyst for the production of ammonia and sparked an agricultural revolution [13,14]. In modern organoiron chemistry, iron is used in a great number of diverse reactions, as will be apparent from this review, though perhaps, just as in the chemistry of life, its most ubiquitous role is in redox chemistry.

2.1. Addition Reactions The first example of an iron-catalyzed racemization of alcohols was reported in 2016 with the use of an iron pincer catalyst [15]. Between 2016 and 2017, the groups of Bäckvall [16] and Rueping [17] independently reported the dynamic kinetic resolution (DKR) of sec-alcohols using a combination of iron catalysis for racemization and a lipase for resolution, which demonstrates a useful combination of enzyme and transition metal catalysis (Scheme1). In one study, Knölkers complex ( II) was used directly [17], and in the other study, a bench-stable precursor to Knölkers complex (II), iron tricarbonyl complex I, was used, which was activated through oxidative decarbonylation with TMANO to form coordinatively unsaturated iron complex I’ [16]. In the latter study, various benzylic and aliphatic esters could be produced in good to excellent yields with excellent ee. Two different enzymes, Candida antarctica lipase B (CalB/Novozyme 435) and Burkholderia cepasia (PS-C), could be used and the procedure could be reproduced on gram-scale. The group of Zhou also reported a related work using hexanoate as the acyl donor [18]. Rodriguez published a review on the synthesis, properties and reactivity of this interesting class of iron catalysts in 2015 [19]. Molecules 2020, 25, x FOR PEER REVIEW 3 of 20 Molecules 2020, 25, 1349 3 of 20 Molecules 2020, 25, x FOR PEER REVIEW 3 of 20

90 90 91 Scheme 1.1. Bäckvall’s and Rueping’s DKR of sec-alcohols. 91 Scheme 1. Bäckvall’s and Rueping’s DKR of sec-alcohols. 92 The indoleindole ring ring is ais ubiquitous a ubiquitous heterocyclic heterocyclic motif inmotif natural in productsnatural andproducts methods and for methods constructing for 9392 chiralconstructingThe polycyclic indole chiral systemsring polycyclic is a with ubiquitous systems indole with skeletonsheterocyclic indole has skeletons attractedmotif in has considerablenatural attracted products considerable attention. and methodsattention. In 2017, thefor In 9493 group2017,constructing the of Zhou group chiral reported of polycyclic Zhou the reported first systems intramolecular the with first indole intram enantioselective skeletonsolecular has enantioselective cyclopropanation attracted considerable cyclopropanation of indoles attention. that was Inof 9594 catalyzedindoles2017, the that eithergroup was by catalyzedof iron Zhou or coppereitherreported by in iron thethe presence orfirst copper intram of in a olecularthe chiral presence ligand enantioselective of (Scheme a chiral2)[ ligand 20cyclopropanation]. Many (Scheme functional 2) [20]. of 9695 groupsManyindoles functional werethat was tolerated catalyzedgroups and were variouseither tolerated by cyclopropanated iron and or coppervariou sin indolescyclopropanated the presence were prepared of aindoles chiral in highligandwere to prepared (Scheme excellent in2) yields high[20]. 9796 andtoMany excellent in functional almost yields all casesgroups and with in were almost excellent tolerated all cases ee. and The with variou mechanism excellents cyclopropanated of ee the. The enhancement mechanism indolesof ofwere the the enantioselectivity preparedenhancement in high of 9897 istheto currentlyexcellent enantioselectivity unknown,yields and is although in currently almost the allunknown, R cases2 group with wasalthough excellent found the to ee R be. 2The importantgroup mechanism was and foundhad of tothe to be beenhancement important different from and of 9998 hydrogenhadthe enantioselectivityto be different for the reaction from is currentlyhydrogen to proceed. unknown,for the reaction although to proceed. the R2 group was found to be important and 99 had to be different from hydrogen for the reaction to proceed.

100 100 101 Scheme 2.2. Zhou’s enantioselective cyclopropanation. 101 Scheme 2. Zhou’s enantioselective cyclopropanation. Hydroamination of alkenes is an atom-economic approach and the amines produced are some of 102 Hydroamination of alkenes is an atom-economic approach and the amines produced are some the most common functionalities found in fine chemicals and pharmaceuticals. Hydroamination of 103102 of theHydroamination most common functionalities of alkenes is an found atom-economic in fine chemicals approach and and pharmaceuticals. the amines produced Hydroamination are some terminal alkenes typically gives the Markovnikov product selectivity, but in 2019 the group of Wang 104103 of theterminal most alkenescommon typically functionalities gives thefound Markovnikov in fine chemicals product and selectivity, pharmaceuticals. but in 2019 Hydroamination the group of reported the first iron-catalyzed anti-Markovnikov addition of allylic alcohols [21]. For this purpose, 105104 Wangof terminal reported alkenes the firsttypically iron-catalyzed gives the Markovnikovanti-Markovnikov product addition selectivity, of allylic but alcohols in 2019 [21].the group For this of an iron-PNP pincer complex was used. The reaction proceeds through a hydrogen-borrowing strategy 106105 purpose,Wang reported an iron-PNPthe first iron-catalyzed pincer complex anti-Markovnikov was used. additionThe reaction of allylic proceeds alcohols [21].through For this a where the iron complex temporarily activates the alcohol by dehydrogenation to the α,β-unsaturated 107106 hydrogen-borrowingpurpose, an iron-PNP strategy pincer where complex the iron was complex used. temporarilyThe reaction activates proceeds the throughalcohol bya carbonyl compound. The latter compound reacts with an amine to form an iminium ion, which 108107 dehydrogenationhydrogen-borrowing to the strategy α,β-unsaturated where the carbonyl iron complexcompound. temporarily The latter activatescompound the reacts alcohol with byan undergoes conjugate additon at the β-position with another amine followed by hydrolysis and 109108 aminedehydrogenation to form an toiminium the α,β ion,-unsaturated which undergoes carbonyl conjugatecompound. additon The latter at the compound β-position reacts with withanother an reduction to give the product. Various amines were produced in good yields with this method. 110109 amine followedto form an by iminium hydrolysis ion, and which reduction undergoes to give conjugate the product. additon Various at the amines β-position were with produced another in Interestingly, hydroamidation could also be performed (Scheme3). 111110 goodamine yields followed with by this hydrolysis method. Interestingly,and reduction hydroamidation to give the product. could Various also be aminesperformed. were produced in 111 good yields with this method. Interestingly, hydroamidation could also be performed.

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112 112 113 Scheme 3. Wang’s iron-catalyzed anti-Markovnikov hydroamination. 113 SchemeScheme 3.3. Wang’sWang’s iron-catalyzediron-catalyzed anti-Markovnikovanti-Markovnikov hydroamination. hydroamination. 114 C-C and C-N bonds are important bonds in organic chemistry and one of the most effective 114 C-CC-C and and C-N C-N bonds bonds are are important important bonds bonds in organicin organic chemistry chemistry and and one one of the of mostthe most effective effective ways 114115 waysC-C of creating and C-N these bonds bonds are simultaneouslyimportant bonds is inth roughorganic the chemistry carboamination and one of of olefins. the most In 2017,effective the 115 ofways creating of creating these bonds these simultaneouslybonds simultaneously is through is th therough carboamination the carboamination of olefins. of olefins. In 2017, In the 2017, group the of 115116 waysgroup of of creatingBao reported these thebonds diastereoselective simultaneously construction is through theof amines carboamination and disubstituted of olefins. β-amino In 2017, acids the 116 Baogroup reported of Bao the reported diastereoselective the diastereoselective construction construction of amines of and amines disubstituted and disubstitutedβ-amino β-amino acids through acids 116 group of Bao reported the diastereoselective construction of amines and disubstituted β-amino acids 117 through the carboamination of olefins (Scheme 4) [22]. Aliphatic acids were used as an alkyl source 117 thethrough carboamination the carboamination of olefins (Schemeof olefins4)[ (Scheme22]. Aliphatic 4) [22]. acidsAliphatic were acids used were as an used alkyl as source an alkyl and source nitriles 118 and nitriles as a nitrogen source. The protocol could be performed on a gram-scale and various 118 asand a nitrogen nitriles source.as a nitrogen The protocol source. couldThe protocol be performed could onbe aperformed gram-scale on and a gram-scale various carboamination and various 119 carboamination products were obtained in good yields and excellent diastereoselectivity. The choice 119 productscarboamination were obtained products in goodwere yieldsobtained and in excellent good yields diastereoselectivity. and excellent diastereoselectivity. The choice of acid The was choice found 120 of acid was found to have a strong effect on the diastereoselectivity. TsOH was used for the 120 toof have acid a strongwas found effect to on have the diastereoselectivity. a strong effect on TsOH the diastereoselectivity. was used for the carboamination TsOH was used of olefins, for the but 121 carboamination of olefins, but for the carboamination of esters, binary and ternary acids had a more for the carboamination of esters, binary and ternary acids had a more positive effect over monoacids, 121122 carboamination of olefins, but for the carboamination2 4 of esters, binary and ternary acids had a more 122 positive effect over monoacids, with H2SO4 giving the best result. The addition of the nitrile group 122 withpositive H2SO effect4 giving over themonoacids, best result. with The H2SO addition4 giving of the the best nitrile result. group The addition was found, of the through nitrile Densitygroup 123 was found, through Density Functional Theory (DFT) calculations, to be 123 Functionalwas found, Theory through (DFT) calculations, Density to beFunctional diastereoselectivity-determining, Theory (DFT) calculations, and hyperconjugation to be 124 diastereoselectivity-determining, and hyperconjugation was proposed to account for the 124 wasdiastereoselectivity-determining, proposed to account for the anti-selectivity. and hyperconjugation was proposed to account for the 125 anti-selectivity. 125 anti-selectivity.

126 126 Scheme 4. Bao’s carboamination. 127 Scheme 4. Bao’s carboamination. 127 Scheme 4. Bao’s carboamination. Organosilicon compounds have significant chemical, physical and bioactive properties and an 128 Organosilicon compounds have significant chemical, physical and bioactive properties and an 128 exampleOrganosilicon of these compounds compounds is have 1-amino-2-silylalkanes, significant chemical, whichphysical have, and inbioactive recent properties times, emerged and an as 129 example of these compounds is 1-amino-2-silylalkanes, which have, in recent times, emerged as 129 candidatesexample of for these pharmaceutical compounds is development. 1-amino-2-silylalk Silicon-containinganes, which have, compounds in recent aretimes, generally emerged made as 130 candidates for pharmaceutical development. Silicon-containing compounds are generally made 130 throughcandidates hydrosylilation for pharmaceutical or dehydrogenative development. silylation, Silicon-containing but in 2017 thecompou groupnds of are Luo generally reported themade first 131 through hydrosylilation or dehydrogenative silylation, but in 2017 the group of Luo reported the 131 iron-catalyzedthrough hydrosylilation synthesis of or 1-amino-2-silylalkanes dehydrogenative silylati throughon, but the in 1,2-difunctionalization 2017 the group of Luo of reported styrenes the and 132 first iron-catalyzed synthesis of 1-amino-2-silylalkanes through the 1,2-difunctionalization of 132 conjugatedfirst iron-catalyzed alkenes (Scheme synthesis5)[ of23 ].1-amino-2-silylalkanes Di-tert-butyl-peroxide through (DTBP) the was 1,2-difunctionalization used as an oxidant in of the 133 styrenes and conjugated alkenes (Scheme 5) [23]. Di-tert-butyl-peroxide (DTBP) was used as an 133 reaction.styrenes Amines, and conjugated amides and alkenes carbon (Scheme nucleophiles 5) [23]. could Di-tert be employed-butyl-peroxide and delivered (DTBP) thewas corresponding used as an 134 oxidant in the reaction. Amines, amides and carbon nucleophiles could be employed and delivered 134 productsoxidant in mostlythe reaction. good Amines, yields. The amides reaction and carb wason proposed nucleophiles to proceed could viabe employed a silicon-centered and delivered radical 135 the corresponding products in mostly good yields. The reaction was proposed to proceed via a 135 fromthe corresponding oxidative cleavage products of the in Si-Hmostly bond good followed yields. byThe addition reaction acrosswas proposed the C=C to bond proceed and avia N-H a 136 silicon-centered radical from oxidative cleavage of the Si-H bond followed by addition across the 136 oxidativesilicon-centered functionalization radical from cascade. oxidative cleavage of the Si-H bond followed by addition across the 137 C=C bond and a N-H oxidative functionalization cascade. 137 C=C bond and a N-H oxidative functionalization cascade.

138 138 Scheme 5. Luo’s silylation.

Molecules 2020, 25, x FOR PEER REVIEW 5 of 20 MoleculesMolecules 20202020,, 2525,, 1349x FOR PEER REVIEW 55 ofof 2020 139 Scheme 5. Luo’s silylation. 139 Scheme 5. Luo’s silylation. 2.2. C-H Bond Activation 140 2.2. C-H Bond Activation 140 2.2. C-H Bond Activation 141 The firstfirst example of a C-HC-H activationactivation was a Friedel–CraftsFriedel–Crafts reaction reported by Dimroth in 141 The first example of a C-H activation was a Friedel–Crafts reaction reported by Dimroth in 142 1902,1902, where where benzene benzene reacted reacted with with mercury mercury (II) (II)acetate acetate to give to givephenylmercury phenylmercury (II) acetate (II) acetate [24]. Later, [24]. 142 1902, where benzene reacted with mercury (II) acetate to give phenylmercury (II) acetate [24]. Later, 143 Later,in 1955, in 1955,Murahashi Murahashi reported reported the cobalt-catalyzed the cobalt-catalyzed chelation-assisted chelation-assisted C-H C-H functionalization functionalization of 143 in 1955, Murahashi reported the cobalt-catalyzed chelation-assisted C-H functionalization of 144 of(E)-N-1-diphenylmethanei (E)-N-1-diphenylmethaneiminemine to to2-phenylisoindolin-1-one 2-phenylisoindolin-1-one [25]. [25 ].A Agreat great advance advance in in the the fieldfield 144 occurred(E)-N-1-diphenylmethanei in 1966 when Shilovmine reported to 2-phenylisoindolin-1-one that K2PtCl4 could induce [25]. isotope A scramblinggreat advance between in the methane field 145 occurred in 1966 when Shilov reported that K2PtCl4 could induce isotope scrambling between 145 occurred in 1966 when Shilov reported that K2PtCl4 could induce isotope scrambling between 146 andmethane heavy and water heavy [26, 27water]. Shilov’s [26,27]. discovery Shilov’s led discovery to the so led called to “Shilovthe so called system”, “Shilov which system”, remains towhich this 146 methane and heavy water [26,27]. Shilov’s discovery led to the so called “Shilov system”, which 147 dayremains as one to ofthis the day few catalyticas one of systems the few that catalyti can accomplishc systems selective that can alkene accomplish functionalizations selective alkene under 147 remains to this day as one of the few catalytic systems that can accomplish selective alkene 148 mildfunctionalizations conditions. In under 2008, themild synthetic conditions. power In of 2 C-H008, activationthe synthetic was expandedpower of toC-H include activation organoiron was 148 functionalizations under mild conditions. In 2008, the synthetic power of C-H activation was 149 catalysisexpanded by to Nakamura include organoiron in his arylation catalysis of benzoquinolines by Nakamura in (Scheme his arylation6)[ 28 ].of An benzoquinolines excellent review (Scheme on the 149 expanded to include organoiron catalysis by Nakamura in his arylation of benzoquinolines (Scheme 150 subject6) [28]. ofAn iron excellent in C-H review activation on reactionsthe subject by of Nakamura iron in C-H was activation published reactions in 2017 [ 29by] andNakamura a review was on 150 6) [28]. An excellent review on the subject of iron in C-H activation reactions by Nakamura was 151 oxidativepublished C-H in 2017 activation [29] and was a review published on oxidative by Li in 2014 C-H [activation30]. was published by Li in 2014 [30]. 151 published in 2017 [29] and a review on oxidative C-H activation was published by Li in 2014 [30].

152 152 153 Scheme 6. Nakamura’s C-H activation. 153 SchemeScheme 6.6. Nakamura’sNakamura’s C-H activation. 154 The group of Arnold has in the past used engineered cytochrome P450, which is a type of enzyme 154 TheThe group ofof ArnoldArnold hashas in the past used engineeredengineered cytochrome P450,P450, whichwhich isis aa type of enzyme 155 that uses a heme cofactor, to enantioselectively α-hydroxylate arylacetic acid derivatives via C-H 155 thatthat usesuses aa hemeheme cofactor,cofactor, toto enantioselectivelyenantioselectively αα-hydroxylate-hydroxylate arylaceticarylacetic acidacid derivativesderivatives viavia C-HC-H 156 activation [31]. In 2017, they reported the directed evolution of cytochrome P450 monooxygenase, for 156 activationactivation [[31].31]. In 2017, they reported the directeddirected evolution of cytochrome P450P450 monooxygenase,monooxygenase, forfor 157 enantioselective C-H activation to give C-N bonds (Scheme 7) [32]. It uses a variant of P411 based on 157 enantioselectiveenantioselective C-H C-H activation activation to to give give C-N C-N bonds bonds (S (Schemecheme 7)7 )[[32].32 ].It uses It uses a variant a variant of ofP411 P411 based based on 158 the P450 monooxygenase which has an axial serine ligand on the haem iron instead of the natural 158 onthethe P450 P450 monooxygenase monooxygenase which which has has an an axial axial serine serine ligand ligand on on the the haem haem iron iron instead instead of the naturalnatural 159 cysteine. The method utilizes a tosyl azide as a nitrene source which generates an iron nitrenoid that 159 cysteine.cysteine. The method utilizes a tosyl azide as a nitrenenitrene source whichwhich generatesgenerates an ironiron nitrenoidnitrenoid thatthat 160 subsequently reacts with an alkane to deliver the C-H amination product. The P411 variant has a 160 subsequentlysubsequently reacts with an alkanealkane toto deliverdeliver thethe C-HC-H aminationamination product.product. The P411 variantvariant has aa 161 turnover number (TON) of 1300, which is considerably higher than the best reported, to our 161 turnoverturnover numbernumber (TON) (TON) of 1300,of 1300, which which is considerably is consider higherably thanhigher the than best reported,the best toreported, our knowledge, to our 162 knowledge, for traditional chiral transition metal complexes, which is a chiral manganese porphyrin 162 forknowledge, traditional for chiral traditional transition chiral metal transition complexes, metal which complexes, is a chiral which manganese is a chiral porphyrin manganese with aporphyrin turnover 163 with a turnover number of 85 [33]. A variety of benzylic tosylamines could be produced with excellent 163 numberwith a turnover of 85 [33 number]. A variety of 85 of [33]. benzylic A variety tosylamines of benzylic could tosylamines be produced could with be produced excellent ees.with excellent 164 ees. 164 ees.

165 165 166 Scheme 7.7. Arnold’s C-H amination. 166 Scheme 7. Arnold’s C-H amination. 167 In 2019,2019, ArnoldArnold and and coworkers coworkers extended extended their their methodology methodology using using another another variant variant of P411 of P411 in C-H in 167 In 2019, Arnold and coworkers extended their methodology using another variant of P411 in 168 alkylationC-H alkylation using using diazoesters diazoesters (Scheme (Scheme8)[ 34 ].8) The [34]. diazo The substratediazo subs scopetrate could scope be could extended be extended beyond 168 C-H alkylation using diazoesters (Scheme 8) [34]. The diazo substrate scope could be extended 169 ester-basedbeyond ester-based reagents toreagents Weinreb to amides Weinreb and amides diazoketones and diazoketones and gave the and corresponding gave the corresponding products with 169 beyond ester-based reagents to Weinreb amides and diazoketones and gave the corresponding 170 excellentproducts eewiths and excellent with total ees turnover and with numbers total turnover (TTN) ofnumbers up to 2330. (TTN) These of up studies to 2330. together These show studies the 170 products with excellent ees and with total turnover numbers (TTN) of up to 2330. These studies 171 potentialtogether show for generating the potential C-H alkylationfor generating enzymes C-H thatalkylation can emulate enzymes the scopethat can and emulate selectivity the ofscope Natures and 171 together show the potential for generating C-H alkylation enzymes that can emulate the scope and 172 C-Hselectivity oxygenation of Natures catalysts. C-H oxygenation catalysts. 172 selectivity of Natures C-H oxygenation catalysts.

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173 173 3 174 Scheme 8.8. Arnold’sArnold’s sp sp3 C-HC-H activation.activation. 174 Scheme 8. Arnold’s sp3 C-H activation. 3 175 C(sp3)-H)-H alkylation alkylation via via an an isoelectronic isoelectronic iron iron carbene carbene intermediate intermediate was was first first reported reported in in 2017 2017 by by 3 175176 the group C(sp )-H ofof WhiteWhitealkylation usingusing via anan an ironiron isoelectronic phthalocyaninephthalocyanine iron carbene (Scheme(Scheme intermediate9 9))[ [35].35]. Iron was ca carbenes firstrbenes reported generally in 2017 prefer by 3 176177 thecyclopropanation group of White over using C-H an oxidation, iron phthalocyanine but, in thisthis case,case, (Scheme allylicallylic 9) andand [35]. benzylicbenzylic Iron ca C(spC(sprbenes3)-H)-H generally bonds could prefer be 3 177178 cyclopropanationalkylated with a broad over C-H scope.scope. oxidation, Mechanistic but, instudies studies this case, indicated indicated allylic that thatand anbenzylic electrophilic C(sp )-H iron bonds carbene could was be 178179 alkylatedmediating with homolytichomolytic a broad C-HC-H scope. cleavage cleavage Mechanistic followed followed studies by by recombination recombination indicated that with with an the electrophilic the resulting resulting alkyl iron alkyl radical carbene radical to formwas to 179180 mediatingformthe new the C-Cnew homolytic bond. C-C bond. The C-H C-H The cleavage cleavageC-H cleavage followed was found was by found torecombination be to partially be partially rate with determining. rate the determining. resulting alkyl radical to 180 form the new C-C bond. The C-H cleavage was found to be partially rate determining.

181 181 182 Scheme 9.. White’sWhite’s isoelectronicisoelectronic carbenecarbene C(spC(sp3)-H oxidation. 182 Scheme 9.9. White’s isoelectronic carbene C(sp3)-H)-H oxidation. oxidation. 183 In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed In 2018, the group of Ackermann reported on an allene annulation through an iron-catalyzed 183184 C-H/N-H/C-O/C-HIn 2018, the group functionalization of Ackermann sequence reported (Soncheme an allene 10) annulation[36]. The mechanism through an wasiron-catalyzed shown to C-H/N-H/C-O/C-H functionalization sequence (Scheme 10)[36]. The mechanism was shown to involve 184185 C-H/N-H/C-O/C-Hinvolve an unprecedented functionalization 1,4-iron migrationsequence (SC-chemeH activation 10) [36]. manifold. The mechanism Alkyl chlorideswas shown were to an unprecedented 1,4-iron migration C-H activation manifold. Alkyl chlorides were tolerated under 185186 involvetolerated an under unprecedented these reaction 1,4-iron conditions, migration with C- Hno activation cross-coupling manifold. being Alkyl observed. chlorides Various were these reaction conditions, with no cross-coupling being observed. Various dihydroisoquinolones could 186187 tolerateddihydroisoquinolones under these could reaction be produced conditions, through with the no use cross-coupling of this method beingin excellent observed. yields Variousand the be produced through the use of this method in excellent yields and the modular nature of the triazole 187188 dihydroisoquinolonesmodular nature of the couldtriazole be groupproduced allowed through for the usesynthesis of this ofmethod exo-methylene in excellent isoquinolones yields and the as group allowed for the synthesis of exo-methylene isoquinolones as well. 188189 modularwell. nature of the triazole group allowed for the synthesis of exo-methylene isoquinolones as 189 well.

190 190 Scheme 10. Ackermann’s allene annulation. 191 Scheme 10.. Ackermann’sAckermann’s alleneallene annulation.annulation. 191 Scheme 10. Ackermann’s allene annulation. In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of 192 In late 2019, the group of Wang demonstrated an iron-catalyzed α-C-H functionalization of π-bonds in the hydroxyalkylation of alkynes and olefins (Scheme 11)[37]. Propargylic and allylic C-H 192193 π-bondsIn late in the2019, hydroxyalkylation the group of Wang of alkynes demonstrated and olefins an iron-catalyzed (Scheme 11) [37].α-C-H Propargylic functionalization and allylic of bonds were functionalized with this method and a wide variety of homopropargylic and homoallylic 193194 πC-H-bonds bonds in thewere hydroxyalkylation functionalized with of alkynes this method and olefins and a(Scheme wide variety 11) [37]. of Propargylichomopropargylic and allylic and alcohols could be produced in excellent yields, although with modest stereoselectivity. The key to the 194195 C-Hhomoallylic bonds alcoholswere functionalized could be produced with this in excellenmethodt yields,and a althoughwide variety with of mo homopropargylicdest stereoselectivity. and success of this approach is the fact that coordination of the iron catalyst to the unsaturated bond is 195196 homoallylicThe key to thealcohols success could of bethis produced approach in is excellen the factt yields, that coordination although with of mothedest iron stereoselectivity. catalyst to the known to lower the pKa of a propargylic or allylic proton from 38 and 43, respectively, to <10 [38]. 196197 Theunsaturated key to thebond success is known of this to lowerapproach the pKais the of facta propargylic that coordination≈ or allylic≈ of proton the iron from catalyst ≈38 and to ≈the43, An (α-allenyl)iron or (π-allyl)iron complex for propargylic or allylic complexes, respectively, is then 197198 unsaturatedrespectively, bondto <10 is known[38]. An to (lowerα-allenyl)iron the pKa ofor a( πpropargylic-allyl)iron complexor allylic forproton propargylic from ≈38 orand allylic ≈43, formed in the presence of a base, which is utilized as the coupling partner. 198199 respectively,complexes, respectively, to <10 [38]. is Anthen ( αformed-allenyl)iron in the orpres (πence-allyl)iron of a base, complex which foris utilized propargylic as the orcoupling allylic 199200 complexes,partner. respectively, is then formed in the presence of a base, which is utilized as the coupling 200 partner.

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201 201 202 Scheme 11.11. Wang’s α-C-H functionalization. 202 Scheme 11. Wang’s α-C-H functionalization. 3 203 In 2018, the group of Liu reported the unprecedentedunprecedented iron(II)-catalyzed fluorinationfluorination ofof C(spC(sp3)-H 203 In 2018, the group of Liu reported the unprecedented iron(II)-catalyzed fluorination of C(sp3)-H 204 bonds usingusing alkoxyl alkoxyl radicals radicals (Scheme (Scheme 12)[ 12)39]. [39]. The procedureThe procedure was applied was applied to a wide to range a wide of substratesrange of 204 bonds using alkoxyl radicals (Scheme 12) [39]. The procedure was applied to a wide range of 205 andsubstrates it was and found it was that found a range that of a functional range of functional groups were groups tolerated, were includingtolerated, including halide and halide hydroxyl and 205 substrates and it was found that a range of functional groups were tolerated, including halide and 206 groups.hydroxyl N-fluorobenzenesulfonamide groups. N-fluorobenzenesulfonamide (NFSI) was (NFSI) used as was the fluorideused as source the fluoride and the source substrate and scope the 206 hydroxyl groups. N-fluorobenzenesulfonamide (NFSI) was used as the fluoride source and the 207 couldsubstrate be extendedscope could from be extended fluorination from to fluorinati chlorination,on to amination chlorination, and amination alkylation. and The alkylation. authors alsoThe 207 substrate scope could be extended from fluorination to chlorination, amination and alkylation. The 208 demonstratedauthors also demonstrated a one-pot application a one-pot of application their protocol of their starting protocol from starting a simple from alkane. a simple alkane. 208 authors also demonstrated a one-pot application of their protocol starting from a simple alkane.

209 209 210 Scheme 12. Liu’s C-H fluorination. 210 Scheme 12.12. Liu’s C-H fluorination. fluorination. 211 2.3. Cross-Coupling Reactions 211 2.3. Cross-Coupling Reactions 212 Transition-metal-catalyzed cross cross coupling coupling protocols protocols have have become become an important an important tool in tool the organicin the 212 Transition-metal-catalyzed cross coupling protocols have become an important tool in the 213 chemist‘sorganic chemist‘s arsenal. arsenal. This area This has area been has important been impo inrtant chemistry in chemistry for about for five about decades, five decades, and in 2010and in it 213 organic chemist‘s arsenal. This area has been important in chemistry for about five decades, and in 214 received2010 it received formal recognitionformal recognition when Richard when Heck,Richard Akira Heck, Suzuki Akira and Suzuki Ei-ichi and Negishi Ei-ichi received Negishi the received Nobel 214 2010 it received formal recognition when Richard Heck, Akira Suzuki and Ei-ichi Negishi received 215 prizethe Nobel for palladium-catalyzed prize for palladium-catalyzed cross-couplings cross-coupli in organicngs synthesis. in organic Although synthesis. a powerful Although technique, a powerful its 215 the Nobel prize for palladium-catalyzed cross-couplings in organic synthesis. Although a powerful 216 applicationstechnique, its have applications been dominated have by been the use domina of expensiveted by palladium- the use andof nickel-basedexpensive palladium- catalysts, which and 216 technique, its applications have been dominated by the use of expensive palladium- and 217 arenickel-based often toxic. catalysts, The most which common are often types toxic. of cross The coupling most common reactions types using of cross iron arecoupling those involvingreactions 217 nickel-based catalysts, which are often toxic. The most common types of cross coupling reactions 218 Grignardusing iron reagents are those as theinvolving transmetalating Grignard nucleophile. reagents as Thethe firsttransmetalating example of an nucleophile. alkenylation The of alkylfirst 218 using iron are those involving Grignard reagents as the transmetalating nucleophile. The first 219 Grignardexample of reagents an alkenylation with organic of alkyl halides Grignard using reagents iron(III) chloridewith organi wasc halides reported using in 1971 iron(III) by Kochi chloride and 219 example of an alkenylation of alkyl Grignard reagents with organic halides using iron(III) chloride 220 Tamurawas reported (Scheme in 131971)[40 ].by A Kochi review and on theTamura subject (Scheme of iron-catalyzed 13) [40]. cross-couplingA review on reactionsthe subject with of a 220 was reported in 1971 by Kochi and Tamura (Scheme 13) [40]. A review on the subject of 221 focusiron-catalyzed on mechanistic cross-coupling studies was reactions published with in 2016a focus by Byerson mechanistic [41]. A more studies focused was review published on the in use 2016 of 221 iron-catalyzed cross-coupling reactions with a focus on mechanistic studies was published in 2016 222 iron-catalyzedby Byers [41]. A cross-coupling more focused for review the synthesis on the use of pharmaceuticalsof iron-catalyzed was cross-coupling released in 2018 for the by Szostaksynthesis [42 of]. 222 by Byers [41]. A more focused review on the use of iron-catalyzed cross-coupling for the synthesis of 223 pharmaceuticals was released in 2018 by Szostak [42]. 223 pharmaceuticals was released in 2018 by Szostak [42].

224 224 225 Scheme 13. Kochi’s and Tamura’s original alkenylation. 225 Scheme 13. Kochi’s and Tamura’s original alkenylation. 226 In 2016, Bäckvall and coworkers reported the coupling of propargyl carboxylatescarboxylates and Grignard 226 reagentsIn 2016, using Bäckvall the environmentally and coworkers benign reported Fe(acac) the couplingto synthesize of propargyl substituted carboxylates allenes andand protectedGrignard 227 reagents using the environmentally benign Fe(acac)3 to synthesize substituted allenes and protected 227 reagentsα using the environmentally benign Fe(acac)3 to synthesize substituted allenes and protected 228 α-allenols (Scheme(Scheme 14 14))[43 [43,,4444].]. The The mild mild reaction reaction conditions conditions tolerate tolerate a broad a broad range ofrange functional of functional groups 228 α-allenols (Scheme 14) [43,44]. The mild reaction conditions tolerate a broad range of functional 229 (silylgroups ethers, (silyl carbamates ethers, carbamates and acetals) and and acetals) could and be appliedcould be to applied more complex to more molecules complex suchmolecules as steroids. such 229 groups (silyl ethers, carbamates and acetals) and could be applied to more complex molecules such 230 Trias steroids. and tetra Tri substituted and tetra allenes substitu wereted allenes obtained were in excellent obtained yields, in excellent whereas yields, the yield whereas was foundthe yield todrop was 230 as steroids. Tri and tetra substituted allenes were obtained in excellent yields, whereas the yield was 231 forfound less to substituted drop for less allenes. substituted A variety allenes. of alkyl A and variety aryl of Grignard alkyl and reagents aryl Grignard could be appliedreagents and could it was be 231 found to drop for less substituted allenes. A variety of alkyl and aryl Grignard reagents could be 232 demonstratedapplied and it thatwas thedemonstrated protocol can that be the readily protocol performed can be onreadily a gram-scale. performed on a gram-scale. 232 applied and it was demonstrated that the protocol can be readily performed on a gram-scale.

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233 Scheme 14. Bäckvall’s synthesis of substituted allenes and protected α-allenols from carboxylates. 234 Scheme 14.. Bäckvall’sBäckvall’s synthesissynthesis ofof substitutedsubstituted allenesallenes andand protectedprotected α-allenols-allenols fromfrom carboxylates.carboxylates. In 2016, the group of Frantz reported on a highly stereoselective iron-catalyzed cross coupling 235 InIn 2016,2016, thethe groupgroup ofof FrantzFrantz reportedreported onon aa highlyhighly stereoselectivestereoselective iron-catalyzediron-catalyzed crosscross couplingcoupling using FeCl to couple Grignard reagents and enol carbamates (Scheme 15)[45]. Many functional 236 using FeCl3 to couple Grignard reagents and enol carbamates (Scheme 15) [45]. Many functional 236 using FeCl3 to couple Grignard reagents and enol carbamates (Scheme 15) [45]. Many functional groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost 237 groups, such as ethers, silanes, primary bromides, alkynes and alkenes, were tolerated. In almost all all cases, the yield and E/Z selectivity was excellent, with (E)-carbamates leading to (E)-acrylates 238 cases,cases, thethe yieldyield andand E/ZE/Z selectivityselectivity waswas excellent,excellent, withwith (E)-carbamates(E)-carbamates leadingleading toto (E)-acrylates(E)-acrylates andand and (Z)-carbamates leading to (Z)-acrylates. This study constitutes the only example so far of an 239 (Z)-carbamates(Z)-carbamates leadingleading toto (Z)-acrylates.(Z)-acrylates. ThisThis ststudy constitutes the only example so far of an iron-catalyzed cross-coupling, where an oxygen-based electrophile is favored over a vinylic halide 240 iron-catalyzediron-catalyzed cross-coupling,cross-coupling, wherewhere anan oxygen-basedoxygen-based electrophile is favored over a vinylic halide (a (a Cl group at R in Scheme 15). 241 Cl group at R2 in2 Scheme 15). 241 Cl group at R2 in Scheme 15).

242 Scheme 15. Frantz’ stereoselective synthesis of acrylates. 243 Scheme 15.15. Frantz’Frantz’ stereoselectivestereoselective synthesissynthesis ofof acrylates.acrylates. Aryl C-glycosides are interesting pharmaceutical candidates because of their biological activities 244 Aryl C-glycosides are interesting pharmaceutical candidates because of their biological and resistance to metabolic degradation. In 2017, the group of Nakamura developed a highly 245 activities and resistance to metabolic degradation. In 2017, the group of NakamuraNakamura developeddeveloped aa diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to form 246 highly diastereoselective iron-catalyzed cross-coupling of glycosyl halides and aryl metal reagents to these compounds using FeCl in conjunction with a SciOPP ligand (Scheme 16)[46]. A variety of aryl, 247 form these compounds using2 FeCl2 in conjunction with a SciOPP ligand (Scheme 16) [46]. A variety 247 form these compounds using FeCl2 in conjunction with a SciOPP ligand (Scheme 16) [46]. A variety heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could be applied. 248 of aryl, heteroaryl and vinyl metal reagents based on magnesium, zinc, boron and aluminium could The reaction was found to proceed through the generation and stereoselective trapping of glycosyl 249 be applied. The reaction was found to proceed throughrough thethe generationgeneration andand stereoselectivestereoselective trappingtrapping radical intermediates and represents a rare example of a highly stereoselective carbon-carbon bond 250 of glycosyl radical intermediates and represents aa rarerare exampleexample ofof aa highlyhighly stereoselectivestereoselective formation based on iron catalysis. 251 carbon-carboncarbon-carbon bondbond formationformation based on iron catalysis.

252

Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2. 253 Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2. 253 Scheme 16. Nakamura’s diastereoselective synthesis of aryl C-glycosides using (Sciopp) FeCl2.

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254 Heterocyclic motifs are common in biologically active compounds and the presence of Heterocyclic motifs are common in biologically active compounds and the presence of heteroatoms 255 heteroatoms arranged around a quaternary carbon center often endows a certain spacial definition arranged around a quaternary carbon center often endows a certain spacial definition that can be 256 that can be useful, for example, in enhancing drug-binding. These types of spirocyclic motifs are useful, for example, in enhancing drug-binding. These types of spirocyclic motifs are most often 257 most often generated through [2 + 3] cycloadditions, but, in 2017, the group of Sweeney developed generated through [2 + 3] cycloadditions, but, in 2017, the group of Sweeney developed an elegant 258 an elegant cross-coupling cascade reaction to generate these motifs with inexpensive Fe(acac)3 as the 258 an elegant cross-coupling cascade reaction to generate these motifs with inexpensive Fe(acac)3 as the cross-coupling cascade reaction to generate these motifs with inexpensive Fe(acac)3 as the catalyst 259 catalyst directly from feedstocks chemicals directly available from plant sources (Scheme 17) [47]. directly from feedstocks chemicals directly available from plant sources (Scheme 17)[47]. The protocol 260 The protocol delivered diastereomerically enriched nitrogen- and oxygen-containing delivered diastereomerically enriched nitrogen- and oxygen-containing cis-heterospirocycles and was 261 cis-heterospirocycles and was applicable to substrates with typically sensitive functionalities like applicable to substrates with typically sensitive functionalities like esters and aryl chlorides. 262 esters and aryl chlorides.

263 Scheme 17. Sweeney’s cyclization. 264 Scheme 17.. Sweeney’sSweeney’s cyclization.cyclization. Palladium catalysts have traditionally been ubiquitous in cross-coupling reactions. Utilizing iron 265 Palladium catalysts have traditionally been ubiquitous in cross-coupling reactions. Utilizing for the Suzuki coupling to provide simple biaryl compounds remained elusive until recently, when the 266 iron for the Suzuki coupling to provide simple biaryl compounds remained elusive until recently, group of Bedford showed that simple π-coordinating N-pyrrole amides on the aryl halide substrate 267 when the group of Bedford showed that simple π-coordinating N-pyrrole amides on the aryl halide could facilitate activation of the relatively unreactive C-X bond (Scheme 18)[48]. The use of an NHC 268 substrate could facilitate activation of the relatively unreactive C-X bond (Scheme 18) [48]. The use of ligand with the appropriate steric bulk proved crucial. A variety of biaryl products were obtained 269 an NHC ligand with the appropriate steric bulk proved crucial. A variety of biaryl products were in excellent yields. This study demonstrates that iron-catalyzed Suzuki couplings to give biaryls are 270 obtained in excellent yields. This study demonstrates that iron-catalyzed Suzuki couplings to give achievable, though to make the procedure general, efforts will have to be made to develop non-directed 271 biaryls are achievable, though to make the procedure general, efforts will have to be made to halide bond activation. 272 develop non-directed halide bond activation.

273 Scheme 18. Bedford’s cross-coupling. 274 Scheme 18.. Bedford’sBedford’s cross-coupling.cross-coupling. 2.4. Cycloadditions 275 2.4. Cycloadditions 2.4. CycloadditionsMedium-sized rings (7–11 membered) are important structural motifs with applications 276 in theMedium-sized synthesis of rings polymers, (7–11 membered) fragrances are and important other specialty structural chemicals. motifs with Among applications these in cyclic the 277 compounds,synthesis of eight-memberedpolymers, fragrances rings areand particularly other specialty useful chemicals. for the synthesis Among of these polyethylene cyclic compounds, derivatives. 278 Metal-catalyzedeight-membered [4rings+ 4]-cycloaddition are particularly of useful two butadienes for the synthesis to produce of 1,5-cyclooctadienepolyethylene derivatives. is well 279 established,Metal-catalyzed although [4 + the4]-cycloaddition use of 1,3-dienes of istwo challenging butadienes owing to toproduce unwanted 1,5-cyclooctadiene side-products including is well 280 linearestablished, oligomers, although [2 + 2]- the and use [4 + of2]-cycloadducts, 1,3-dienes is aschallenging well as regio- owing and stereoisomeric to unwanted [4 side-products+ 4] products. 281 Catalystincluding design linear must oligomers, be guided [2 + with2]- and these [4 + concerns 2]-cycloadducts, in mind. as Recently, well as theregio- group and of stereoisomeric Chirik developed [4 + 282 an4] products. iron-catalyzed Catalyst [4 + 4]-cycloadditiondesign must be ofguided 1,3-dienes with tothese access concerns these compounds in mind. Recently, using (imino)pyridine the group of 283 ironChirik bis-olefin developed and anα-diimine iron-catalyzed iron complexes [4 + 4]-cycloaddition (Scheme 19)[ 49of]. 1,3-dienes A wide variety to access of 1,5-cyclooctadienes these compounds 284 couldusing be(imino)pyridine produced in good iron tobis-olefin excellent and yields α-diimine and with iron controlled complexes chemo- (Scheme and 19) regioselectivity. [49]. A wide variety Kinetic 285 analysisof 1,5-cyclooctadienes and Mößbauer could spectroscopy be produced provided in good evidence to excellent for a mechanism yields and in with which controlled oxidative chemo- cyclization and 286 ofregioselectivity. the two dienes Kinetic determines analysis the and regio- Mößbauer and diastereoselectivity. spectroscopy provided evidence for a mechanism in 287 which oxidative cyclization of the two dienes determines the regio- and diastereoselectivity.

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288 288 289 SchemeScheme 19.19. Chirik’sChirik’s iron-catalyzediron-catalyzed [4[4 ++ 4]-cycloaddition. 289 Scheme 19. Chirik’s iron-catalyzed [4 + 4]-cycloaddition. 290 IndolinesIndolines areare pharmaceuticallypharmaceutically significantsignificant aza-heterocyclesaza-heterocycles andand thethe firstfirst exampleexample ofof aa synthesissynthesis 290 Indolines are pharmaceutically significant aza-heterocycles and the first example of a synthesis 291 ofof thesethese compoundscompounds viavia anan iron-catalyzediron-catalyzed decarboxylativedecarboxylative [4[4 ++ 1]-cycloaddition1]-cycloaddition was describeddescribed inin 291 of these compounds via an iron-catalyzed decarboxylative [4 + 1]-cycloaddition was described in 292 20162016 byby thethe groupgroup ofof Xiao.Xiao. A widewide rangerange ofof functionalizedfunctionalized indolines could be preparedprepared fromfrom vinylvinyl 292 2016 by the group of Xiao. A wide range of functionalized indolines could be prepared from vinyl 293 benzoxazinanonesbenzoxazinanones and sulfur sulfur ylides ylides in in good good to to exce excellentllent yields yields in inhigh high diastereoselectivity diastereoselectivity using using the 293 benzoxazinanones and sulfur ylides in good to excellent yields in high diastereoselectivity using the 294 thenucleophilic nucleophilic Bu4N[Fe(CO) Bu4N[Fe(CO)3(NO)]3(NO)] (TBAFe) (TBAFe) catalyst catalyst (Scheme (Scheme 20) [50]. 20 )[The50 authors]. The authorspostulated postulated that the 294 nucleophilic Bu4N[Fe(CO)3(NO)] (TBAFe) catalyst (Scheme 20) [50]. The authors postulated that the 295 thatreaction the reactionproceeds proceeds via the via formation the formation of an of electrophilic an electrophilic (π-allyl) (π-allyl) iron iron complex, complex, which which wouldwould 295 reaction proceeds via the formation of an electrophilic (π-allyl) iron complex, which would 296 subsequentlysubsequently reactreact with with the the sulfur sulfur ylide ylide and undergoand undergo an intramolecular an intramolecular SN2 displacement SN2 displacement of dimethyl of 296 subsequently react with the sulfur ylide and undergo an intramolecular SN2 displacement of 297 sulfidedimethyl by sulfide the tosyl by amide the tosyl anion. amide This studyanion. is This noteworthy study is and noteworthy constitutes and the constitutes first example the of first the 297 dimethyl sulfide by the tosyl amide anion. This study is noteworthy and constitutes the first 298 exploitationexample of the of anexploitation interesting of reverse-electron-demand an interesting reverse-electron-demand (π-allyl) iron species. (π-allyl) iron species. 298 example of the exploitation of an interesting reverse-electron-demand (π-allyl) iron species.

299 299 300 Scheme 20. Xiaos’ [4 + 1]-cycloaddition. 300 SchemeScheme 20.20. Xiaos’ [4 + 1]-cycloaddition. 301 Oxidative [4 + 2] annulations of imines and alkynes for the synthesis of isoquinolines are well 301 Oxidative [4 + 2] annulations of imines and al alkyneskynes for the synthesis of isoquinolines are well 302 established [51] but an interesting redox-neutral variant was reported in 2016 by the group of Wang 302 established [[51]51] but an interesting redox-neutral va variantriant was reported in 2016 by the group of Wang 303 involving an iron-carbonyl-catalyzed C-H transformation of an arene (Scheme 21) [52]. A wide 303 involving anan iron-carbonyl-catalyzed iron-carbonyl-catalyzed C-H C-H transformation transformation of an of arene an arene (Scheme (Scheme 21)[52 21)]. A [52]. wide A variety wide 304 variety of isoquinolines were isolated in good to excellent yield and only the cis-stereoisomer was 304 ofvariety isoquinolines of isoquinolines were isolated were isol in goodated toin excellentgood to excellent yield and yield only and the cis-stereoisomeronly the cis-stereoisomer was observed. was 305 observed. Mechanistic studies revealed that there was an essential synergy of dinuclear irons in the 305 observed. Mechanistic studies revealed that there was an essential synergy of dinuclear irons in the 306 oxidative C-H addition and turnover-limiting H-transfer to the alkyne in the catalytic cycle. 306 oxidative C-H addition and turnover-limiting H-transfer to the alkyne in the catalytic cycle.

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Mechanistic studies revealed that there was an essential synergy of dinuclear irons in the oxidative Molecules 2020, 25, x FOR PEER REVIEW 11 of 20 C-HMolecules addition 2020, 25 and, x FOR turnover-limiting PEER REVIEW H-transfer to the alkyne in the catalytic cycle. 11 of 20

307 Scheme 21. Wang’s [4 + 2] annulation/C-H activation. 308 Scheme 21. Wang’sWang’s [4[4 ++ 2]2] annulation/C-Hannulation/C-H activation.activation. Cyclotrimerization of alkynes mediated by transition metals is a key approach towards the 309 Cyclotrimerization of alkynes mediated by transition metals is a key approach towards the synthesis of substituted aromatic compounds. In 2017, the group of Jacobi von Wangelin reported the 310 synthesis of substituted aromatic compounds. In 2017, the group of JacobiJacobi vonvon WangelinWangelin reportedreported iron-catalyzed trimerization of terminal alkynes in the absence of a reducing agent (Scheme 22)[53]. 311 thethe iron-catalyzediron-catalyzed trimerizationtrimerization ofof terminalterminal alkynesalkynes inin thethe absenceabsence ofof aa reducingreducing agentagent (Scheme(Scheme 22)22) The approach was based on having a simple Fe (II) precatalyst and an internal bulky basic ligand 312 [53].[53]. TheThe approachapproach waswas basedbased onon havinghaving aa simplesimple FeFe (II)(II) precatalystprecatalyst andand anan internalinternal bulkybulky basicbasic which could mimic the effect of an external reductant. Terminal alkynes readily reacted, whereas 313 ligandligand whichwhich couldcould mimicmimic thethe effecteffect ofof anan externalexternal reductant.reductant. TerminalTerminal alkynesalkynes readilyreadily reacted,reacted, internal ones did not, which is in accordance with the mechanistic postulate that the reaction is initiated 314 whereas internal ones did not, which is in accordance with the mechanistic postulate that the through alkyne deprotonation. Good regioselectivity was observed with almost exclusive formation of 315 reaction is initiated through alkyne deprotonation. Good regioselectivity was observed with almost the 1,2,4-substituted product over the 1,3,5-substituted and a wide variety of arenes were produced in 316 exclusive formation of the 1,2,4-substituted product over the 1,3,5-substituted and a wide variety of mostly excellent yields. 317 arenes were produced in mostly excellent yields.

318 Scheme 22. Jacobi van Wangelin’s cyclotrimerization. 319 Scheme 22.. JacobiJacobi vanvan Wangelin’sWangelin’s cyclotrimerization.cyclotrimerization. 2.5. Isomerizations 320 2.5. Isomerizations 320 2.5. IsomerizationsIron-catalyzed isomerization of unsaturated alcohols to carbonyls was first reported by Emerson 321 and PettitIron-catalyzedIron-catalyzed in the 1960s isomerizationisomerization [54]. In this study, ofof unsaturatedunsaturated butadiene-(tricarbonyl)iron alalcohols to carbonyls complexes was were first exposed reported to strong by 322 acidsEmerson to form and their Pettit corresponding in the 1960sπ -allyl[54]. ironIn this complexes. study, butadiene-(tricarbonyl)iron When these were reacted with complexes water, η2 -(allylwere 323 alcohol)ironexposed to strong complexes acids formed, to form which their isomerized corresponding to the π enol-iron-allyl-allyl ironiron complex. complexes.complexes. Upon WhenWhen decomposition, thesethese werewere 2 324 butanonereacted with was water, obtained. η2-(allyl-(allyl alcohol)ironalcohol)iron complexescomplexes formed,formed, whichwhich isomerizedisomerized toto thethe enol-ironenol-iron 325 complex.Between Upon 2017 decomposition, and 2019, the groupsbutanone of Bäckvall was obtained. [55,56] and Rueping [57,58] independently reported 326 the iron-catalyzedBetween 2017 cycloisomerizationand 2019, the groups of allenolsof Bäckvall and allenic[55,56][55,56] sulfonamidesandand RuepingRueping using[57,58][57,58] iron independentlyindependently tricarbonyl 327 complexreported Ithe(Scheme iron-catalyzed 23). An analogous cycloisomerization ruthenium-catalyzed of allenolsallenols cyclization andand allenicallenic of αsulfonamidessulfonamides-allenols had using previouslyusing ironiron 328 beentricarbonyltricarbonyl reported complexcomplex by Bäckvall I (Scheme(Scheme [59 ].23).23). In AnAn these analogousanalogous protocols, ruthenium-catalyzedruthenium-catalyzedI is activated by TMANOcyclizationcyclization to ofof form α-allenols-allenols the active hadhad 329 catalystpreviouslyI’. Thebeen protocols reported have by Bäck a widevall scope[59]. In and these deliver protocols, the corresponding I isis activatedactivated heterocycles byby TMANOTMANO intoto excellentformform thethe 330 yields.active catalyst Interestingly I’. The it protocols was found have that a through wide scope the introductionand deliver the of a corresponding substituent in theheterocycles R2 position in 331 excellent yields. Interestingly it was found that through the introduction of a substituent in the R2 331 ofexcellent the allene, yields. the Interestingly reaction was it made was diastereoselective,found that through giving the introduction the trans-product of a substituent predominantly in the R in2 332 theposition case ofof dihydrofurans the allene, the or exclusivelyreaction was in themade case diastereoselective,diastereoselective, of dihydropyrroles givinggiving [54,55 ]. thethe The trans-producttrans-product origin of the 333 diastereoselectivity,predominantly in the revealed case of dihydrofurans through DFT or calculations, exclusively was in the the case participation of dihydropyrroles of the non-innocent [54,55]. The 334 cyclopentadienylorigin of the diastereoselectivity, ligand of the catalyst revealed lowering through the transitionDFT calculations, state, leading was tothe the participation trans product. of the 335 non-innocent cyclopentadienyl ligand of the catalyst lowering the transition state, leading to the 336 transtrans product.product.

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337337 Scheme 23. Bäckvall’s and Rueping’s cycloisomerizations. 338 Scheme 23. Bäckvall’s and Rueping’s cycloisomerizations. 338338 SchemeScheme 2323.. Bäckvall’sBäckvall’s andand Rueping’sRueping’s cycloisomerizations.cycloisomerizations. According to the Woodward–Hofmann rules, [2 + 2] cycloadditions of two olefins are 339 According to the Woodward–Hofmann rules, [2 + 2] cycloadditions of two olefins are 339339 photochemicallyAccordingAccording toto allowed, thethe Woodward–HofmannWoodward–Hofmann but thermally forbidden rules,rules, [60 ]. [2[2 Due ++ to2]2] this cycloadditionscycloadditions restriction, photochemical ofof twotwo olefinsolefins[2 +areare2] 340 photochemically allowed, but thermally forbidden [60]. Due to this restriction, photochemical [2 + 2] 340340 photochemicallycycloadditionphotochemically between allowed,allowed, two butbut olefins thermallythermally is the forbiddenforbidden most common [60][60].. DueDue strategy toto thisthis to restriction,restriction, form cyclobutanes. photochemicalphotochemical In 2018, [2[2 ++ the 2]2] 341 cycloaddition between two olefins is the most common strategy to form cyclobutanes. In 2018, the 341341 cycloadditiongroupcycloaddition of Plietker betweenbetween reported twotwo anolefinsolefins unusual isis thethe cycloisomerization mostmost cocommonmmon strategystrategy of enynes toto formform using cyclcycl aobutanes.obutanes. cationic iron InIn 2018,2018, nitrosyl thethe 342 group of Plietker reported an unusual cycloisomerization of enynes using a cationic iron nitrosyl 342342 groupcatalystgroup ofof (Scheme PlietkerPlietker 24 reportedreported)[61]. Their anan unusualunusual 1,6- and cycloisomeri 1,7-enyneacetatescycloisomerizationzation were ofof enynesenynes expected usingusing to isomerize aa cationiccationic to ironiron allenes, nitrosylnitrosyl but 343 catalyst (Scheme 24) [61]. Their 1,6- and 1,7-enyneacetates were expected to isomerize to allenes, but 343343 catalystinsteadcatalyst isomerized (Scheme(Scheme 24)24) to [61].[61]. their TheirTheir corresponding 1,6-1,6- andand 1,7-enyneace1,7-enyneace bicyclo [3.2.0]tatestates or [4.2.0] werewere alkylamidesexpectedexpected toto isomerize inisomerize good to excellenttoto allenes,allenes, yield butbut 344 instead isomerized to their corresponding bicyclo [3.2.0] or [4.2.0] alkylamides in good to excellent 344344 insteadunderinstead mild isomerizedisomerized conditions. toto theirtheir The correspondingcorresponding reaction tolerates bicyclobicyclo esters, [3[3.2.0] amides.2.0] oror [4.2.0][4.2.0] and halides, alkylamidesalkylamides and aff ininorded goodgood the toto productsexcellentexcellent 345 yield under mild conditions. The reaction tolerates esters, amides and halides, and afforded the 345345 yieldgenerallyyield underunder in goodmildmild toconditions.conditions. high yields. TheThe reactionreaction toleratetoleratess esters,esters, amidesamides andand halides,halides, andand affordedafforded thethe 346 products generally in good to high yields. 346346 productsproducts generallygenerally inin goodgood toto highhigh yields.yields.

347347 348 Scheme 24. Plietker’s cycloisomerization cycloisomerization of enynes. 348348 SchemeScheme 24.24. Plietker’sPlietker’s cycloisomerizationcycloisomerization ofof enynes.enynes.

349 Iron carbonyl complexes have been used in th thee isomerization of allylic alcohols, but a major 349349 IronIron carbonylcarbonyl complexescomplexes havehave beenbeen usedused inin ththee isomerizationisomerization ofof allylicallylic alcohols,alcohols, butbut aa majormajor 350 drawback associatedassociated with with the the use use of theseof these complexes comple isxes the is fact the that fact they that require they UVrequire light UV for activationlight for 350350 drawbackdrawback associatedassociated withwith thethe useuse ofof thesethese complecomplexesxes isis thethe factfact thatthat theythey requirerequire UVUV lightlight forfor 351 activationand are thus and not are amenable thus not to amenable industrial to synthesis industrial [62 ].synthesis In 2018, the[62]. group In 2018, of de the Vries group reported of de the Vries use 351351 activationactivation andand areare thusthus notnot amenableamenable toto industrialindustrial synthesissynthesis [62].[62]. InIn 2018,2018, thethe groupgroup ofof dede VriesVries 352 reportedof a pincer the PNP-iron use of a complexpincer PNP-iron for the isomerization complex for the of allylicisomerization alcohols of and allylic found alcohols it to be and an excellentfound it 352352 reportedreported thethe useuse ofof aa pincerpincer PNP-ironPNP-iron complexcomplex forfor thethe isomerizationisomerization ofof allylicallylic alcoholsalcohols andand foundfound itit 353 toracemization be an excellent catalyst racemization in conjunction catalyst with in tBuOK conjun (Schemection with 25 )[tBuOK63]. Both (Scheme benzylic 25) and[63]. aliphatic Both benzylic allylic 353353 toto bebe anan excellentexcellent racemizationracemization catalystcatalyst inin conjunconjunctionction withwith tBuOKtBuOK (Scheme(Scheme 25)25) [63].[63]. BothBoth benzylicbenzylic 354 and aliphatic homoallylic allylic alcohols and homoallylic could be isomerized alcohols could in mostly be isomerized excellent yields.in mostly The excellent sterically yields. hindered The 354354 andand aliphaticaliphatic allylicallylic andand homoallylichomoallylic alcoholsalcohols couldcould bebe isomerizedisomerized inin mostlymostly excellentexcellent yields.yields. TheThe 355 stericallytrans-sobrerol hindered could trans-sobrerol be reduced as could well, be although reduced in as a modestwell, although yield of in 36%. a modest A two-step yield of hydrogen 36%. A 355355 stericallysterically hinderedhindered trans-sobreroltrans-sobrerol couldcould bebe reducedreduced asas well,well, althoughalthough inin aa modestmodest yieldyield ofof 36%.36%. AA 356 two-stepborrowing hydrogen mechanism borrowing involving mechanism dehydrogenation-hydrogenation involving dehydrogenation-hydrogenation isomerization was proposed isomerization on the 356356 two-steptwo-step hydrogenhydrogen borrowingborrowing mechanismmechanism involvinginvolving dehydrogenation-hydrogenationdehydrogenation-hydrogenation isomerizationisomerization 357 wasbasis proposed of DFT calculations. on the basis of DFT calculations. 357357 waswas proposedproposed onon thethe basisbasis ofof DFTDFT calculations.calculations.

358358 Scheme 25. de Vries’ allylic alcohol isomerization. 359 Scheme 25. de Vries’ allylic alcohol isomerization. 359359 SchemeScheme 2525.. dede Vries’Vries’ allylicallylic alcoholalcohol isomerization.isomerization.

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Molecules 2020, 25, x FOR PEER REVIEW 13 of 20 An elegant cascade reaction involving cross-coupling and cycloisomerization forming two C-C 360 bondsAn and elegant highly cascade functionalized reaction 1,3-dienesinvolving withcross-coupling a stereodefined and cycloisomerization tetrasubstituted alkene forming unit, two which C-C is 361 bondsdifficult and to highly obtain functionalized by other means, 1,3-dienes was developed with a stereodefined in 2016 by the tetrasubstituted group of Fürstner alkene (Scheme unit, 26 which)[64]. 362 isA difficult series of to X-ray obtain structures by other showedmeans, was that developed the substituent in 2016 delivered by the group by the of GrignardFürstner ( reagentScheme and26) 363 [64]the. transferredA series of X-ray alkenyl structures substituent showed were that on the the substituent same side delivered of the central by the tetrasubstituted Grignard reagent alkene and 364 theunit. transferred Any loss alkenyl of stereoselectivity substituent were is likely on the the same result side of aof secondary the central isomerization tetrasubstituted process. alkeneMany unit. 365 Anyvariously loss of substituted stereoselectivity 1,3-dienes is likely could the be result produced of a secondary with this isomerization method in good process. to excellent Many variously yield and 366 substitutedenantioselectivity 1,3-dienes and bothcould primary be produced and secondary with Grignardthis method reagents in good could to be excellent used. yield and 367 enantioselectivity and both primary and secondary Grignard reagents could be used.

368 369 SchemeScheme 26. 26. Fürstner’sFürstner’s cycloisomerization/cross-coupling cycloisomerization/cross-coupling cascade cascade reaction. reaction.

2.6. Redox Reactions 370 2.6. Redox Reactions Redox chemistry is what iron has traditionally been most known for, due to its multiple possible 371 Redox chemistry is what iron has traditionally been most known for, due to its multiple oxidation states. It is a very important field, not only for organic synthesis but also for biochemistry 372 possible oxidation states. It is a very important field, not only for organic synthesis but also for and industrial applications. A review on the use of iron (and other base metals) in borrowing hydrogen 373 biochemistry and industrial applications. A review on the use of iron (and other base metals) in strategies was released by Morrill in 2019 [65]. A review on iron in reduction and hydrometalation was 374 borrowing hydrogen strategies was released by Morrill in 2019 [65]. A review on iron in reduction published in 2019 by Darcel [66]. 375 and hydrometalation was published in 2019 by Darcel [66]. One of the main bottlenecks in synthetic fuel production powered by sunlight or electricity is 376 One of the main bottlenecks in synthetic fuel production powered by sunlight or electricity is the oxidation of water. The use of abundant and environmentally benign metals for this purpose 377 the oxidation of water. The use of abundant and environmentally benign metals for this purpose is is desireable and, to this end, the group of Masaoka, in 2016, reported the use of a pentanuclear 378 desireable and, to this end, the group of Masaoka, in 2016, reported the use of a pentanuclear iron II III 3+ iron catalyst [Fe 4Fe (µ3-O)(µ-L)6] ((L = 3,5-bis(2-pyridyl)pyrazole) [67]. A multinuclear core 379 catalyst [FeII4FeIII(μ3-O)(μ-L)6]3+ ((L = 3,5-bis(2-pyridyl)pyrazole) [67]. A multinuclear core typically typically gives rise to a redox flexibility that would be expected to be favourable in a reaction involving 380 gives rise to a redox flexibility that would be expected to be favourable in a reaction involving multi-electron transfer, such as water oxidation, as is known from enzyme examples in nature such as 381 multi-electron transfer, such as water oxidation, as is known from enzyme examples in nature such photosystem II in plants where Mn4Ca clusters are used. The turnover frequency was found to be 1900 382 as photosystem II in plants where Mn4Ca clusters are used. The turnover frequency was found to be per second, which is about three orders of magnitude greater than that of other iron-based systems, 383 1900 per second, which is about three orders of magnitude greater than that of other iron-based but despite the advantage of this system, it required a H2O/MeCN mixture and a large overpotential of 384 systems, but despite the advantage of this system, it required a H2O/MeCN mixture and a large 0.5 V, preventing it from practical use. These findings do, however, clearly indicate that efficient water 385 overpotential of 0.5 V, preventing it from practical use. These findings do, however, clearly indicate oxidation protocols can be developed based on multinuclear iron catalysts. 386 that efficient water oxidation protocols can be developed based on multinuclear iron catalysts. Oxidation reactions are of fundamental interest in organic chemistry, and an ideal oxidant to use 387 Oxidation reactions are of fundamental interest in organic chemistry, and an ideal oxidant to in such processes is O2. To this end, the group of Bäckvall in 2020 reported the first example of a 388 use in such processes is O2. To this end, the group of Bäckvall in 2020 reported the first example of a 389 biomimeticbiomimetic oxidation oxidation of of alcohols alcohols (Scheme (Scheme 27)27)[ [68].68]. Various Various primary primary and and secondary secondary alcohols alcohols could could be be 390 oxidizedoxidized to to their their corresponding corresponding aldehydes aldehydes and and ketone ketoness with with this this method method in in good good to to excellent excellent yields. yields. 391 TheThe process waswas inspired inspired by by the the electron electron transport transpor chaint chain used used in living in living organisms organisms and involves and involves coupled 392 coupledredox processes redox processes that lead tothat a low-energy lead to a pathwaylow-energy through pathway a stepwise through oxidation a stepwise using oxidation electron transfer using mediators (ETMs) with O2 as the terminal oxidant. An iron(II)-catalyst was used for this purpose, 393 electron transfer mediators (ETMs) with O2 as the terminal oxidant. An iron(II)-catalyst was used for which exhibited surprising stability in the presence of O2, in addition to a benzoquinone-derivative 394 this purpose, which exhibited surprising stability in the presence of O2, in addition to a 395 benzoquinone-derivativeand a Co(salen)-type complex and a as Co(salen)-type ETMs. complex as ETMs.

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396 397396 Scheme 27. Bäckvall’s biomimetic oxidation of alcohols. Scheme 27. Bäckvall’s biomimetic oxidation of alcohols. 397 Scheme 27. Bäckvall’s biomimetic oxidation of alcohols. 398 The oxidation of alcohols to carboxylic acids typically involves the use of stoichiometric 399 amountsThe of oxidation toxic oxidants, of alcohols such to carboxylicas KMnO4acids or CrO typically3. In 2016, involves the the group use ofof stoichiometric Ma developed amounts an 398 The oxidation of alcohols to carboxylic acids typically involves the use of stoichiometric 400 iron-catalyzedof toxic oxidants, aerobic such oxidation as KMnO of alcohols4 or CrO to3. carboxylic In 2016, the acids group to circumvent of Ma developed this problem an iron-catalyzed (Scheme 399 amounts of toxic oxidants, such as KMnO4 or CrO3. In 2016, the group of Ma developed an 401 28)aerobic [69]. A oxidation wide variety of alcohols of alcohols to carboxylic (and aldehy acids todes) circumvent could be this oxidized problem to (Scheme their corresponding 28)[69]. A wide 400 iron-catalyzed aerobic oxidation of alcohols to carboxylic acids to circumvent this problem (Scheme 402 carboxylicvariety ofacids alcohols and synthetically (and aldehydes) useful could groups be oxidizedsuch as halides, to their alkynes, corresponding olefins, carboxylic esters and acids ethers and 401 28) [69]. A wide variety of alcohols (and aldehydes) could be oxidized to their corresponding 403 weresynthetically tolerated. The useful synthetic groups application such as halides, of this alkynes, protocol olefins, was also esters demonstrated and ethers werethrough tolerated. the first The 402 carboxylic acids and synthetically useful groups such as halides, alkynes, olefins, esters and ethers 404 totalsynthetic synthesis application of the naturally of this protocoloccurring was allene, also demonstratedphlomic acid, throughand in a the55 g first synthesis total synthesis of palmitic of the 403 were tolerated. The synthetic application of this protocol was also demonstrated through the first 405 acid.naturally occurring allene, phlomic acid, and in a 55 g synthesis of palmitic acid. 404 total synthesis of the naturally occurring allene, phlomic acid, and in a 55 g synthesis of palmitic 406 405 acid. 406

407

408407 SchemeScheme 28. 28.Ma’sMa’s iron-catalyzed iron-catalyzed aerobic aerobic oxidation oxidation of alcohols. of alcohols. 408 Scheme 28. Ma’s iron-catalyzed aerobic oxidation of alcohols. 409 CyclicCyclic -epoxideα-epoxide enones enones are are structures structures found found routinely routinely in natural in natural products products and and are are also also useful useful 410 synthons.synthons. Producing Producing these these compounds compounds through through enantios enantioselectiveelective epoxidation epoxidation is notoriously is notoriously difficult. difficult. 409 Cyclic -epoxide enones are structures found routinely in natural products and are also useful 411 In In2016, 2016, the the groupgroup ofof Costas Costas reported reported the firstthe iron-catalyzedfirst iron-catalyzed and highly and enantioselective highly enantioselective epoxidation 410 synthons. Producing these compounds through enantioselective epoxidation is notoriously difficult. 412 epoxidationof these compounds of these compounds using a bulky using tetradentate a bulky iron tetr catalystadentate (Scheme iron catalyst 29)[70 ].(Scheme The reaction 29) [70]. was The found 411 In 2016, the group of Costas reported the first iron-catalyzed and highly enantioselective 413 reactionto proceed was found via the to generation proceed via of anthe electrophilic generation of oxidant, an electrophilic which is unusual oxidant, for which this classis unusual of reactions, for 412 epoxidation of these compounds using a bulky tetradentate iron catalyst (Scheme 29) [70]. The 414 thiswhere class nucleophilicof reactions, oxidantswhere nucleophilic usually account oxidan forts the usually reaction account through fora the Weitz–Sche reaction ffthrougher-type mechanism.a Weitz– 413 reaction was found to proceed via the generation of an electrophilic oxidant, which is unusual for 415 Scheffer-type2-Ethylhexanoic mechanism. acid (2-eha) 2-Ethylhexanoic was found to acid be necessary(2-eha) was as found an additive to be tonecessary help activate as an H additive2O2. Various to 414 this class of reactions, where nucleophilic oxidants usually account for the reaction through a Weitz– 416 helpepoxides activate could H2O2 be. Various produced epoxides in mostly could excellent be produced yields in and mostly excellent excellentees. yields and excellent ees. 415 Scheffer-type mechanism. 2-Ethylhexanoic acid (2-eha) was found to be necessary as an additive to 416 help activate H2O2. Various epoxides could be produced in mostly excellent yields and excellent ees.

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417 417 Scheme 29. Costas’ enantioselective epoxidation. 418 Scheme 29. Costas’ enantioselective epoxidation. 418 Scheme 29. Costas’ enantioselective epoxidation. A number of pharmaceutically active compounds for psychiatric therapy or cardic arrythmias 419 A number of pharmaceutically active compounds for psychiatric therapy or cardic arrythmias 419 haveA optically number active of pharmaceutically alcohols or oxaheterocycle active compounds motifs. for The psychiatric standard methods therapy ofor synthesizingcardic arrythmias these 420 have optically active alcohols or oxaheterocycle motifs. The standard methods of synthesizing these 420 havecompounds optically rely active on expensivealcohols or andoxaheterocycle partly toxic motifs. noble metalsThe standard and it methods would thus of synthesizing be advantageous these 421 compounds rely on expensive and partly toxic noble metals and it would thus be advantageous to 421 compoundsto employ base rely metals on expensive for this and purpose. partly In toxic 2018, noble the groupmetals ofand Gade it would developed thus be an advantageous enantioselective to 422 employ base metals for this purpose. In 2018, the group of Gade developed an enantioselective 422 employreduction base of functionalizedmetals for this ketonespurpose. to In form 2018, these the compoundsgroup of Gade (Scheme developed 30)[ 71an]. enantioselective A chiral pincer 423 reduction of functionalized ketones to form these compounds (Scheme 30) [71]. A chiral pincer 423 “boxmi”-typereduction of functionalized iron catalyst with ketones a low catalystto form loading these ofcompounds 0.5 mol% was(Scheme used which30) [71]. provided A chiral access pincer to a 424 “boxmi”-type iron catalyst with a low catalyst loading of 0.5 mol% was used which provided access 424 “boxmi”-typebroad range of iron functionalized catalyst with halohydrins, a low catalyst oxaheterocycles loading of 0.5 and mol% amino was alcohols used which in excellent provided yields access and 425 to a broad range of functionalized halohydrins, oxaheterocycles and amino alcohols in excellent 425 tomostly a broad excellent rangeee s.of Thefunctionalized protocol could halohydrins, also be performed oxaheterocycles on a gram and scale amino to form alcohols a chiral in halohydrin excellent 426 yields and mostly excellent ees. The protocol could also be performed on a gram scale to form a 426 yieldsthat forms and themostly basis excellent for the preparation ees. The protocol of the antidepressant could also be (R)-fluoxetine.performed on a gram scale to form a 427 chiral halohydrin that forms the basis for the preparation of the antidepressant (R)-fluoxetine. 427 chiral halohydrin that forms the basis for the preparation of the antidepressant (R)-fluoxetine.

428 428 429 Scheme 30. Gade’s enantioselective reduction of functionalized ketones. 429 Scheme 30 30.. Gade’sGade’s enantioselective reduct reductionion of functionalized ketones.

430 Transfer hydrogenation processes are attractive alternatives to classical catalytic hydrogenation 430 Transfer hydrogenation processes are attractive alternatives to classical catalytic hydrogenation 431 since the use of high pressure and expensive reactors can be avoided. The group of de Vries in 2019 431 since the the use use of of high high pressure pressure and and expensive expensive reactors reactors can canbe avoided. be avoided. The group The groupof de Vries of de in Vries2019 432 reported the base-free transfer hydrogenation of esters using EtOH as the hydrogen source (Scheme 432 reportedin 2019 reportedthe base-free the transfer base-free hydrogenation transfer hydrogenation of esters using of EtOH esters as using the hydrogen EtOH as source the hydrogen (Scheme 433 31) [72]. It is interesting to note that EtOH can be used as the reductant, which is usually a problem, 433 31)source [72]. (Scheme It is interesting 31)[72 ].to Itnote is interestingthat EtOH can to note be used that as EtOH the reductant, can be used which as theis usually reductant, a problem, which 434 since the acetaldehyde formed can potentially deactivate the catalyst by decarbonylation. Various 434 sinceis usually the acetaldehyde a problem, sinceformed the can acetaldehyde potentially deac formedtivate can the potentially catalyst by deactivate decarbonylation. the catalyst Various by 435 aliphatic and aromatic esters, including lactones, could be reduced to their corresponding alcohols in 435 aliphaticdecarbonylation. and aromatic Various esters, aliphatic including and lactones, aromatic could esters, be reduced including to their lactones, corresponding could be reducedalcohols in to 436 good to excellent yields. In addition the reaction could be scaled up tenfold. Similar iron-based 436 goodtheir correspondingto excellent yields. alcohols In addition in good the to excellent reaction yields.could be In scaled addition up the tenfold. reaction Similar could iron-based be scaled 437 protocols using a base are known to reduce C=C bonds [73], but in this base-free protocol, esters 437 protocolsup tenfold. using Similar a base iron-based are known protocols to reduce using C=C bo ands base [73], are but known in this to base-free reduce C =protocol,C bonds esters [73], 438 were selectively reduced. One important topic in green chemistry is the recycling of polymers by 438 werebut in selectively this base-free reduced. protocol, One important esters were topic selectively in green reduced.chemistry is One the importantrecycling of topic polymers in green by 439 conversion to their monomers. This study shows the first transfer-hydrogenation-catalyzed 439 conversionchemistry isto the their recycling monomers. of polymers This bystudy conversion shows the to their first monomers.transfer-hydrogenation-catalyzed This study shows the 440 depolymerization of a polyester (Dynacol 7360, made from adipic acid and 1,6-hexanediol), 440 depolymerizationfirst transfer-hydrogenation-catalyzed of a polyester (Dynacol depolymerization 7360, made offrom a polyester adipic (Dynacolacid and 7360,1,6-hexanediol), made from 441 demonstrating the possibility of using iron-catalysis for the recycling of plastic waste. 441 demonstratingadipic acid and the 1,6-hexanediol), possibility of demonstratingusing iron-catalysis the possibility for the recycling of using of iron-catalysis plastic waste. for the recycling of plastic waste.

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442442 Scheme 31. de Vries’ transfer hydrogenation of esters. 443443 SchemeScheme 3131.. dede Vries’Vries’ transfertransfer hydrogenationhydrogenation ofof esters.esters. Simple carboxylic acids are excellent carbonyl donors for functionalized carboxylic acid derivatives. 444444 SimpleSimple carboxyliccarboxylic acidsacids areare excellentexcellent carbonylcarbonyl donorsdonors forfor functionalizedfunctionalized carboxyliccarboxylic acidacid Generating the enolate, enediolate, of a carboxylic acid is, however, quite challenging, due to the low 445445 derivatives.derivatives. GeneratingGenerating thethe enolate,enolate, enediolate,enediolate, ofof aa carboxyliccarboxylic acidacid is,is, however,however, quitequite challenging,challenging, acidity of the α-proton. The Brønsted acidity of the carboxylic acid is a further complication for the 446446 duedue toto thethe lowlow acidityacidity ofof thethe αα-proton.-proton. TheThe BrBrønstedønsted acidityacidity ofof thethe carboxyliccarboxylic acidacid isis aa furtherfurther deprotonation of the α-proton, and therefore two equivalents of a strong base such as LDA are normally 447447 complicationcomplication forfor thethe deprotonationdeprotonation ofof thethe αα-proton,-proton, andand thereforetherefore twotwo equivalentsequivalents ofof aa strongstrong basebase required for efficient enolization. In 2020, the group of Ohshima reported the α-functionalization of 448448 suchsuch asas LDALDA areare normallynormally requiredrequired forfor efficientefficient enenolization.olization. InIn 2020,2020, thethe groupgroup ofof OhshimaOhshima reportedreported carboxylic acids through an iron-catalyzed 1e- radical process [74]. The use of molecular sieves was 449449 thethe αα-functionalization-functionalization ofof carboxyliccarboxylic acidsacids throughthrough anan iron-catalyzediron-catalyzed 1e1e-- radicalradical processprocess [74].[74]. TheThe useuse found to be crucial in suppressing undesired decarboxylation and the alkali metal salt component of 450450 ofof molecularmolecular sievessieves waswas foundfound toto bebe crucialcrucial inin suppressingsuppressing undesiredundesired decarboxylationdecarboxylation andand thethe alkalialkali the sieves (sodium or potassium carboxylate) was found to play a crucial role in promoting the reaction. 451451 metalmetal saltsalt componentcomponent ofof thethe sievessieves (sodium(sodium oror popotassiumtassium carboxylate)carboxylate) waswas foundfound toto playplay aa crucialcrucial The reaction had wide scope and functional groups typically sensitive to oxidation conditions, such as 452452 rolerole inin promotingpromoting thethe reaction.reaction. TheThe reactionreaction hahadd widewide scopescope andand functionalfunctional groupsgroups typicallytypically primary benzylic alcohols and thioethers were tolerated. This study constitutes the first example of 453453 sensitivesensitive toto oxidationoxidation conditions,conditions, suchsuch asas primaryprimary benzylicbenzylic alcoholsalcohols andand thioethersthioethers werewere tolerated.tolerated. the generation of redox-active heterobimetallic enediolates from unprotected carboxylic acids under 454454 ThisThis studystudy constitutesconstitutes thethe firstfirst exampleexample ofof thethe generationgeneration ofof redox-activeredox-active heterobimetallicheterobimetallic catalytic conditions (Scheme 32). 455455 enediolatesenediolates fromfrom unprotectedunprotected carboxyliccarboxylic acidsacids underunder catalyticcatalytic conditions.conditions.

456456 457 457 Scheme 32. Ohshima’s α-oxidation of carboxylic acids. 458 Scheme 32. Ohshima’s -oxidation of carboxylic acids. 458 3. Conclusions Scheme 32. Ohshima’s -oxidation of carboxylic acids.

459459 3.3. ConclusionsConclusionsThis review has highlighted recent advances in iron-catalysis with respect to organic synthesis. This field has expanded greatly in recent years and giving a detailed account of each reaction category 460460 ThisThis reviewreview hashas highlightedhighlighted recentrecent advancesadvances inin iriron-catalysison-catalysis withwith respectrespect toto organicorganic synthesis.synthesis. is an impossible task for a short review of this type. Herein, only key representative examples are 461461 ThisThis fieldfield hashas expandedexpanded greatlygreatly inin recentrecent yearsyears andand givinggiving aa detaileddetailed accountaccount ofof eacheach reactionreaction given, and interested readers are advised to look into the reviews referenced throughout the text. 462462 categorycategory isis anan impossibleimpossible tasktask forfor aa shortshort reviewreview ofof thisthis type.type. Herein,Herein, onlyonly keykey representativerepresentative As is clear from the examples given in this review, iron complexes are capable of catalyzing a 463463 examplesexamples areare given,given, andand interestedinterested readersreaders areare advisedadvised toto looklook intointo thethe reviewsreviews referencedreferenced wide range of reactions in organic synthesis. This potential of iron catalysis has not been fully realized, 464464 throughoutthroughout thethe text.text. however, and noble transition metal protocols continue to define the state of the art when it comes to 465465 AsAs isis clearclear fromfrom thethe examplesexamples givengiven inin thisthis rereview,view, ironiron complexescomplexes areare capablecapable ofof catalyzingcatalyzing aa transition metal catalysis. The field is still in its infancy, but it is fair to say that iron (and other base 466466 widewide rangerange ofof reactionsreactions inin organicorganic synthesis.synthesis. ThisThis potentialpotential ofof ironiron catalysiscatalysis hashas notnot beenbeen fullyfully metals) may very well challenge this dominance of noble transition metals in the foreseeable future. 467467 realized,realized, however,however, andand noblenoble transititransitionon metalmetal protocolsprotocols continuecontinue toto defidefinene thethe statestate ofof thethe artart whenwhen itit 468468 Authorcomescomes to Contributions:to transitiontransition metalmetalConceptualization, catalysis.catalysis. TheThe writing, fieldfield isis editing stillstill inin and itsits infancy,infancy, reviewing—A.G. butbut itit isis and fairfair J.-E.B. toto saysay All thatthat authors ironiron (and have(and 469469 readotherother and basebase agreed metals)metals) to the may publishedmay veryvery version wellwell ofchallengechallenge the manuscript. thisthis dominancedominance ofof noblenoble transitiontransition metalsmetals inin thethe 470470 Funding:foreseeableforeseeableThis future.future. research was funded by the Swedish Research Council (grant number 2016-03897), The European Union, and the Knut and Alice Wallenberg Foundation (grant number KAW 2016.0072). 471471 AuthorAuthor Contributions:Contributions: Conceptualization,Conceptualization, writing,writing, editingediting andand revireviewing—A.G.ewing—A.G. andand J.E.B.J.E.B. BothBoth authorsauthors havehave Conflicts of Interest: The authors declare no conflict of interest. 472472 readread andand agreedagreed toto thethe publispublishedhed versionversion ofof thethe manuscriptmanuscript 473473 Funding:Funding: ThisThis researchresearch waswas fundedfunded byby thethe SwedishSwedish ReResearchsearch CouncilCouncil (grant(grant numbernumber 2016-03897),2016-03897), TheThe 474474 EuropeanEuropean Union,Union, andand thethe KnutKnut andand AliceAlice WalleWallenbergnberg FoundationFoundation (grant(grant numbernumber KAWKAW 2016.0072).2016.0072). 475475 ConflictsConflicts ofof Interest:Interest: TheThe authorsauthors declaredeclare nono conflictconflict ofof interest.interest.

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