Recent Advances in Acyl Suzuki Cross-Coupling

catalysts

Review Recent Advances in Acyl Suzuki Cross-Coupling

Jonathan Buchspies and Michal Szostak *

Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-973-353-5329

Received: 17 December 2018; Accepted: 28 December 2018; Published: 8 January 2019

Abstract: Acyl Suzuki cross-coupling involves the coupling of an organoboron reagent with an acyl electrophile (acyl halide, anhydride, ester, amide). This review provides a timely overview of the very important advances that have recently taken place in the acylative Suzuki cross-coupling. Particular emphasis is directed toward the type of acyl electrophiles, catalyst systems and new cross-coupling partners. This review will be of value to synthetic chemists involved in this rapidly developing ﬁeld of Suzuki cross-coupling as well as those interested in using acylative Suzuki cross-coupling for the synthesis of ketones as a catalytic alternative to stoichiometric nucleophilic additions or Friedel-Crafts reactions.

Keywords: Suzuki cross-coupling; acyl cross-coupling; acylation; ketones; acylative cross-coupling; palladium; nickel; phosphine; N-heterocyclic carbene; Suzuki-Miyaura

1. Introduction The Suzuki cross-coupling represents the most powerful C–C bond forming reaction in organic synthesis [1]. Traditional Suzuki cross-coupling (also referred to as Suzuki–Miyaura cross-coupling) involves the coupling of an organoboron reagent with an aryl halide (pseudohalide) and is most commonly employed for the synthesis of biaryls by a C(sp2)–C(sp2) disconnection using a palladium or nickel catalyst (Figure1A) [ 2,3]. Since the initial report in 1979, many variants of the Suzuki cross-coupling have been discovered [4]. The ability to systematically apply the cross-coupling of organoboron reagents with high predictability, operational-simplicity, and superb functional group tolerance has contributed to the overwhelming success that this reaction enjoys as the key part of the modern chemistry toolbox. The 2010 Nobel Prize in Chemistry is a ﬁtting testament of its impact [5]. Acyl Suzuki cross-coupling involves the coupling of an organoboron reagent with an acyl electrophile (acyl halide, anhydride, ester, amide) (Figure1B), and in parallel to the biaryl counterpart typically proceeds by a C(acyl)–C(sp2) disconnection [6,7]. Since its ﬁrst discovery in 1999, acylative Suzuki cross-coupling has been established as a new and useful technique for the synthesis of ketones as a catalytic alternative to stoichiometric nucleophilic additions of organometallic reagents or Friedel-Crafts reactions of acyl electrophiles [8–11]. In contrast to the traditional Suzuki cross-coupling, the acylative Suzuki cross-coupling has been much less developed. While this trend is not surprising given the paucity of methods for the synthesis of biaryls other than cross-couplings [2,3], the acylative manifold provides a powerful arsenal of catalytic methods for the C–C bond construction at the acyl group with selectivity, precision and functional group tolerance superseding traditional disconnections. As an added advantage, acyl Suzuki cross-couplings often proceed in the absence of an external base since the leaving group may act as a boron activator facilitating transmetallation [12]. In this review, we will provide a timely overview of the very important advances that have recently taken place in the acylative Suzuki cross-coupling. Particular emphasis is directed toward the type of acyl electrophiles, catalyst systems and new cross-coupling partners. The review is organized

Catalysts 2019, 9, 53; doi:10.3390/catal9010053 www.mdpi.com/journal/catalysts Catalysts 2018, 8, x FOR PEER REVIEW 2 of 23

Catalysts 2019, 9, 53 2 of 23 by a type of electrophile undergoing cross-coupling in the order of their electrophilic reactivity [13], namely acyl halides, anhydrides, carboxylic acids, esters, and amides. Thioesters are not covered in this review because excellent monographs on C–S activation have been published [14,15], and the acyl coupling of thioesters typically involves co-activation using stoichiometric Cu(I) (Liebeskind-Srogl coupling). We hope that this review will be of value to synthetic chemists involved in this rapidly developing ﬁeld of acyl Suzuki cross-coupling as well as those interested in using acylative Suzuki Catalystscross-coupling 2018, 8, x FOR for thePEER synthesis REVIEW of ketones by this catalytic method. 2 of 23

Figure 1. Aryl and Acyl Suzuki-Miyaura Cross-Coupling.

In this review, we will provide a timely overview of the very important advances that have recently taken place in the acylative Suzuki cross-coupling. Particular emphasis is directed toward the type of acyl electrophiles, catalyst systems and new cross-coupling partners. The review is organized by a type of electrophile undergoing cross-coupling in the order of their electrophilic reactivity [13], namely acyl halides, anhydrides, carboxylic acids, esters, and amides. Thioesters are not covered in this review because excellent monographs on C–S activation have been published [14,15], and the acyl coupling of thioesters typically involves co-activation using stoichiometric Cu(I) (Liebeskind-Srogl coupling). We hope that this review will be of value to synthetic chemists involved in this rapidly developing field of acyl Suzuki cross-coupling as well as those interested in using acylative Suzuki cross-coupling for the synthesis of ketones by this catalytic method. Figure 1. Aryl and Acyl Suzuki Suzuki-Miyaura-Miyaura Cross Cross-Coupling.-Coupling. 2. Suzuki Cross Cross-Coupling-Coupling of Acyl Halides In this review, we will provide a timely overview of the very important advances that have recentlyIn 1999, taken Bumagin place in developedthe acylative a phosphine-freephosphineSuzuki cross-free-coupling. palladium-catalyzedpalladium Particular-catalyzed emphasis cross cross-coupling-coupling is directed of boronictoward theacids type with of acyl acyl chlorides electrophiles, (Scheme catalyst 11A)A) [[16]16 systems].. The biaryl biaryl and products products new cross were -coupling generated partners. in high The yields review under is organizedmildmild,, room by temperature a type of electrophileconditions using undergoi waterng ascross the-coupling key additive.additive in the. Independently, Independently, order of their a alsoelectrophiliclso in in 1999, reactivityHaddach discovered[13] , namely an acyl anhydrous halides, anhydrides,Suzuki cross cross-coupling carbox-couplingylic acids, of acyl esters, chlorides and amides. (Scheme Thioesters 11B)B) [[17]17].. It are is notimportant covered to innote this that review th theseese becauseanhydrous excellent conditions monographs were possiblepos onsible C –due S activation to the combined have been use publishedof cesium [14,15]carbonate, and and the Pd(PPh acyl coupling3))44 inin refluxing reﬂuxing of thioesters toluene toluene. typically. Both Both involvesBumagin Bumagin’s co’s - andactivation Haddach Haddach’s using’s protocols stoichiometric established Cu(I) (Liebeskinimportant dprecedents -Srogl coupling) in g givingiving. We practical hope that alternatives this review to will direct be ofacyl value additions to synthetic of organomagnesium chemists involved or inorganolithium this rapidly reagentsreagdevelopingents or thefield use of of acyl less Suzuki availableavailable cross organozincsorganozincs-coupling ororas toxictoxicwell organostannanesorganoas thosestannanes interested [[9,10].9, 10in]. using acylative Suzuki cross-coupling for the synthesis of ketones by this catalytic method.

2. Suzuki Cross-Coupling of Acyl Halides In 1999, Bumagin developed a phosphine-free palladium-catalyzed cross-coupling of boronic acids with acyl chlorides (Scheme 1A) [16]. The biaryl products were generated in high yields under mild, room temperature conditions using water as the key additive. Independently, also in 1999, Haddach discovered an anhydrous Suzuki cross-coupling of acyl chlorides (Scheme 1B) [17]. It is important to note that these anhydrous conditions were possible due to the combined use of cesium carbonate and Pd(PPh3)4 in refluxing toluene. Both Bumagin’s and Haddach’s protocols established important precedents in giving practical alternatives to direct acyl additions of organomagnesium or organolithium reagents or the use of less available organozincs or toxic organostannanes [9,10].

Scheme 1. EarlyEarly Studies Studies in Acyl Suzuki Suzuki-Miyaura-Miyaura Cross Cross-Coupling:-Coupling: (A) Bumagin; (B) Haddach. For the firstﬁrst cross-couplingcross-coupling of acyl halides with sodium tetraﬂuoroborates,tetrafluoroborates, see,see, ref.ref. [[18].18].

Suzuki cross-coupling of acyl halides was reviewed in 2013 [19]. For the coverage of the initial studies, the reader is referred to this review. Recent advances in the Suzuki cross-coupling of acyl

Scheme 1. Early Studies in Acyl Suzuki-Miyaura Cross-Coupling: (A) Bumagin; (B) Haddach. For the first cross-coupling of acyl halides with sodium tetrafluoroborates, see, ref. [18].

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Catalysts 2019, 9, 53 3 of 23 Suzuki cross-coupling of acyl halides was reviewed in 2013 [19]. For the coverage of the initial studies, the reader is referred to this review. Recent advances in the Suzuki cross-coupling of acyl halideshalides include include the the development development of new of new ligands, ligands, the use the of easily-recoverableuse of easily-recoverable heterogeneous heterogeneous catalysts andcatalysts eco-friendly and eco solvents,-friendly establishmentsolvents, establishment of new electrophiles of new electrophiles and organoboron and organoboron reagents. reagents. InIn 2015, 2015, in in continuation continuation of of theirtheir studies studies onon 1-benzyl-4-aza-1-azonia-bicyclo[2.2.2]octane1-benzyl-4-aza-1-azonia-bicyclo[2.2.2]octane chloride-palladiumchloride-palladium chloride chloride complex complex [(BeDABCO) [(BeDABCO)2Pd2Pd2Cl2Cl6],6 Rafiee], Raﬁee and and co-workers co-workers found found that thatthis thiscatalyst catalyst was highly was highly active active for acylative for acylative cross-coupling cross-coupling of acyl ofchlorides acyl chlorides with boronic with acids boronic (Scheme acids (Scheme2A) [20].2 ThisA) [ reaction20]. This allowed reaction for allowed the use for of thevarious use ofacyl various chloride acyls and chlorides arylboronic and arylboronic acids under acids mild underand phosphine mild and phosphine-free-free conditions. conditions. At the At same the same time, time, Stepnicka Stepnicka and and co co-workers-workers prepared prepared new phosphinoferrocenesphosphinoferrocenes withwith pendantpendant ureasureas asas supportingsupporting ligandsligands forfor palladium(II)palladium(II) ηη33-allyl-allyl complexescomplexes andand appliedapplied thesethese precatalystsprecatalysts forfor thethe synthesissynthesis ofof ketones byby Suzuki cross-couplingcross-coupling ofof acylacyl chlorides (Scheme(Scheme2 B) 2B) [ 21[21]]. Phosphinoferrocene. Phosphinoferrocene ligands ligands have have unique unique structural structural versatility versatility and, thus, and, have thus, found have severalfound several applications applications in both laboratoryin both laboratory and industrial-scale and industrial catalytic-scale processes. catalytic processes. The catalyst The applied catalyst to thisapplied reaction to this demonstrated reaction demonstrated good reactivity good at reactivity low loading at low at 50loading◦C. at 50 °C.

SchemeScheme 2. Synthesis of of Ketones Ketones from from Acyl Acyl Chlorid Chlorideses using using New New Catalysts: Catalysts: (A ()A (BeDABCO)Pd) (BeDABCO)Pd2Cl26;Cl (B6); ([B(Phosphinoferrocene)Pd(allyl)Cl].) [(Phosphinoferrocene)Pd(allyl)Cl].

InIn 2014,2014, BoraBora describeddescribed aa ligand-freeligand-free Suzuki-typeSuzuki-type cross-couplingcross-coupling reactionreaction ofof aroylaroyl chlorideschlorides andand arylboronicarylboronic acidsacids usingusing aa Pd/CPd/C heterogeneous catalystcatalyst (Scheme(Scheme3 3A)A) [ [22]22].. TheThe useuse ofof 33 mol%mol% of of Pd/C Pd/C ◦ waswas shownshown toto promotepromote thethe cross-couplingcross-coupling atat 6060 °C.C. Moreover,Moreover, thethe heterogeneousheterogeneous catalystcatalyst couldcould bebe recycledrecycled upup toto 77 timestimes withoutwithout lossloss ofof activity.activity. InIn 2014,2014, StepnickaStepnicka preparedprepared immobilizedimmobilized palladiumpalladium catalystscatalysts byby thethe depositiondeposition ofof palladiumpalladium acetateacetate overover functionalizedfunctionalized silicasilica gelgel andand applied thesethese heterogeneous catalystscatalysts toto thethe reactionreaction ofof acylacyl chlorideschlorides withwith boronicboronic acidsacids (Scheme(Scheme3 3B)B) [ [23]23].. InIn 2017,2017, MovassaghMovassagh achievedachieved thethe cross-couplingcross-coupling ofof aroylaroyl chlorideschlorides withwith arylboronicarylboronic acidsacids usingusing aa polystyrenepolystyrene supportedsupported palladium(II)palladium(II) N-heterocyclicN-heterocyclic carbenecarbene complexcomplex (Scheme(Scheme3 3C)C)[ [24]24].. This complex allowed for short reaction times, high efﬁciencyefficiency ◦ underunder mildmild aqueousaqueous conditionsconditions atat 5050 °C,C, andand easeease ofof isolation. TheThe biarylbiaryl ketones synthesized byby thisthis methodmethod were were obtained obtained in inhigh high yields yields and theand catalyst the catalyst could becould reused be up reused to 4 times up to without 4 times signiﬁcant without losssignificant of activity. loss of activity. InIn 2016,2016, BoraBora discovereddiscovered anan eco-friendlyeco-friendly methodmethod relyingrelying onon thethe implementationimplementation ofof bio-derivedbio-derived 2-MeTHF2-MeTHF asas aa solventsolvent to to make make diaryl diaryl ketones ketones (Scheme (Scheme4)[ 4)25 [25]]. The. Th developede developed conditions, conditions, applying applying an

Catalysts 2019, 9, 53 4 of 23 Catalysts 2018, 8, x FOR PEER REVIEW 4 of 23 oximean oxime palladacycle, palladacycle, allowed allowed for for the the use use of of close close to to stoichiometric stoichiometric amounts amounts of of thethe couplingcoupling partners making the reaction highlyhighly atomatom economic,economic, andand gavegave thethe productsproducts inin highhigh yields.yields.

Scheme 3. SynthesisSynthesis of of Ketones Ketones from from Acyl Acyl Chlorides Chlorides using using Heterogeneous Heterogeneous Catalysts: Catalysts: (A)( APd/C;) Pd/C; (B) (PalladiumB) Palladium on S onilica Silica Gel; Gel; (C) (PolymerC) Polymer-Supported-Pd-NHC.-Supported-Pd-NHC.

Scheme 4. Synthesis of Ketones from Acyl Chlorides using an Eco-FriendlyEco-Friendly Solvent.

In 2016, Forbes, Magolan and co-workers reported the Suzuki cross-coupling of acyl chlorides using organotrifluoroborates (Scheme 5A) [26]. Organotrifluoroborates offer high functional group

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tolerance and are moisture-stable making them appealing coupling partners [27]. This coupling offers moderate to excellent yields; however, the reaction appeared to be substrate dependent. More recently the preparation of ketones using acyl fluorides was reported by Sakai and co- workers (Scheme 5B) [28]. Compared to typical acyl chloride electrophiles, acid fluorides are more stable towards oxidative addition. The use of acyl fluorides allowed for high functional group tolerance and a wide substrate scope with high yields. An alternative strategy to the cross-coupling of aroyl halides involves a reversed polarity Catalystsapproach2019, 9 (Scheme, 53 6). In 2014, Lee and co-workers developed the cross-coupling of acylindium5 of 23 reagents prepared in situ from aroyl chlorides and indium (Scheme 6A) [29]. This reaction works well using very mild conditions at 25 °C. The tolerance of ketones, esters, and nitriles is advantageous for furtherIn 2016, functionalization. Forbes, Magolan Krska and and co-workers co-workers reported developed the Suzuki a reverse cross-coupling polarity method of acyl for chlorides the usingsynthesisCatalysts organotrifluoroborates 2018 of, 8 biaryl, x FOR PEERketones REVIEW via (Scheme a Pd-catalyzed5A) [ 26]. cross Organotrifluoroborates-coupling between aryl offer halides high and functional acylsilanes5 of group 23 tolerance(Scheme and 6B) are [30] moisture-stable. The use of a bulky making phospha them- appealingadamantan couplinge was identified partners as [27 an]. optimal This coupling ligand offersfor moderatethetolerance reaction. to and excellent are moisture yields;-stable however, making the them reaction appealing appeared coupling to be partners substrate [27] dependent.. This coupling offers moderate to excellent yields; however, the reaction appeared to be substrate dependent. More recently the preparation of ketones using acyl fluorides was reported by Sakai and co- workers (Scheme 5B) [28]. Compared to typical acyl chloride electrophiles, acid fluorides are more stable towards oxidative addition. The use of acyl fluorides allowed for high functional group tolerance and a wide substrate scope with high yields. An alternative strategy to the cross-coupling of aroyl halides involves a reversed polarity approach (Scheme 6). In 2014, Lee and co-workers developed the cross-coupling of acylindium reagents prepared in situ from aroyl chlorides and indium (Scheme 6A) [29]. This reaction works well using very mild conditions at 25 °C. The tolerance of ketones, esters, and nitriles is advantageous for further functionalization. Krska and co-workers developed a reverse polarity method for the synthesis of biaryl ketones via a Pd-catalyzed cross-coupling between aryl halides and acylsilanes (Scheme 6B) [30]. The use of a bulky phospha-adamantane was identified as an optimal ligand for the reaction. SchemeScheme 5. 5.(A (A) Synthesis) Synthesis of of KetonesKetones fromfrom Acyl Chlorides using using Organotrifluoroborates; Organotrifluoroborates; (B) ( BCross) Cross-- CouplingCoupling of of Acyl Acyl Fluorides. Fluorides.

More recently the preparation of ketones using acyl fluorides was reported by Sakai and co-workers (Scheme5B) [ 28]. Compared to typical acyl chloride electrophiles, acid fluorides are more stable towards oxidative addition. The use of acyl fluorides allowed for high functional group tolerance and a wide substrate scope with high yields. An alternative strategy to the cross-coupling of aroyl halides involves a reversed polarity approach (Scheme6). In 2014, Lee and co-workers developed the cross-coupling of acylindium reagents prepared in situ from aroyl chlorides and indium (Scheme6A) [ 29]. This reaction works well using very mild conditions at 25 ◦C. The tolerance of ketones, esters, and nitriles is advantageous for further functionalization. Krska and co-workers developed a reverse polarity method for the synthesis of biaryl ketonesScheme via5. (A a)Pd-catalyzed Synthesis of Ketones cross-coupling from Acyl between Chlorides aryl using halides Organotrifluoroborates; and acylsilanes (Scheme(B) Cross6-B) [ 30]. The useCoupling of a bulky of Acyl phospha-adamantane Fluorides. was identified as an optimal ligand for the reaction.

Scheme 6. Synthesis of Biaryl Ketones by Polarity Inversion (A) Acyl Indium; (B) Acyl Silanes.

SchemeScheme 6. 6.Synthesis Synthesis of of Biaryl BiarylKetones Ketones byby Polarity Inversion ( (AA) )Acyl Acyl Indium; Indium; (B ()B Acyl) Acyl Silanes. Silanes.

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3. Suzuki Cross-Coupling of Anhydrides In 2001, Gooßen reported the successful use of anhydrides in acyl Suzuki cross-coupling (SchemeCatalysts 2019 7A), 9, 53[31]. This reaction provides a general route to ketones from carboxylic acids using6 of 23 alternative activating reagents to the synthesis from acyl halides. It is important to note that this Catalystsreaction 2018 was, 8 , notx FOR able PEER to REVIEWsupport the use of pivalic anhydride. Based on this mechanistic insight,6 of the 23 3. Suzuki Cross-Coupling of Anhydrides authors developed in situ protocols for acyl Suzuki cross-coupling of carboxylic acids (see Section 4). 3. Suzuki Cross-Coupling of Anhydrides Independently,In 2001, Gooßen Yamamoto reported developed the successful an acyl use crossof anhydrides-coupling ofin carboxylicacyl Suzuki acid cross-coupling anhydrides using(SchemeIn readily 2001,7A) [ Gooavailable31].ßen This reportedPd(PPh reaction3 )4 the providesto successfulform diverse a general use ketone of route anhydrides products to ketones (Scheme in from acyl Suzuki carboxylic7B) [32] cross. This acids-coupling method using (Schemepermittedalternative 7A) for activating [31]high. atomThis reagents reactioneconomy to provides and the synthesisrequired a general no from base. route acyl halides. to ketones It is from important carboxylic to note acids that using this alternativereactionRecently, was activating notSuzuki able cross reagents to support-coupling to the of synthesisuse carboxylic of pivalic from acid anhydride. acyl anhydrides halides. Based hasIt is been onimportant thisdeveloped mechanistic to note using that insight,Ni , this Rh reactionandthe authorsPd catalysis was developed not (Schemeable to in support situ 8A– protocolsC). the use for of acyl pivalic Suzuki anhydride. cross-coupling Based ofon carboxylic this mechanistic acids (see insight, Section the4). authors developed in situ protocols for acyl Suzuki cross-coupling of carboxylic acids (see Section 4). Independently, Yamamoto developed an acyl cross-coupling of carboxylic acid anhydrides using readily available Pd(PPh3)4 to form diverse ketone products (Scheme 7B) [32]. This method permitted for high atom economy and required no base. Recently, Suzuki cross-coupling of carboxylic acid anhydrides has been developed using Ni, Rh and Pd catalysis (Scheme 8A–C).

SchemeScheme 7. 7. EarlyEarly Studies Studies in in Acyl Acyl Suzuki Suzuki-Miyaura-Miyaura Cross Cross-Coupling-Coupling of Carboxylic of Carboxylic Acid Acid Anhydrides: Anhydrides: (A) Goo(A) Gooßen;ßen; (B) Yamamoto. (B) Yamamoto.

Independently, Yamamoto developed an acyl cross-coupling of carboxylic acid anhydrides using readily available Pd(PPh3)4 to form diverse ketone products (Scheme7B) [ 32]. This method permitted for high atom economy and required no base. SchemeRecently, 7. Early Suzuki Studies cross-coupling in Acyl Suzuki of-Miyaura carboxylic Cross acid-Coupling anhydrides of Carboxylic has been Acid developed Anhydrides: using (A) Ni, Rh andGoo Pdßen; catalysis (B) Yamamoto. (Scheme 8A–C).

Scheme 8. Synthesis of Ketones and Esters from Carboxylic Acid Anhydrides: (A) Ni; (B) Rh; (C) Pd.

In 2014, Yang developed a mild method to synthesize biaryl ketones using a nickel(II)-σ-aryl precatalyst (Scheme 8A) [33]. This acyl Suzuki cross-coupling provides an efficient, cost-effective and practical route to making ketones in moderate to good yields. SchemeScheme 8. 8.Synthesis Synthesis of of Ketones Ketones and and Esters Esters from from Carboxylic Carboxylic Acid Acid Anhydrides: Anhydrides: (A (A) Ni;) Ni; (B ()B Rh;) Rh; (C ()C Pd.) Pd. In 2014, Yang developed a mild method to synthesize biaryl ketones using a nickel(II)-σ-aryl precatalystIn 2014, (Scheme Yang developed8A) [ 33]. This a mild acyl method Suzuki cross-couplingto synthesize biaryl provides ketones an efﬁcient, using a cost-effective nickel(II)-σ-aryl and precatalystpractical route (Scheme to making 8A) [33] ketones. This inacyl moderate Suzuki cross to good-coupling yields. provides an efficient, cost-effective and practical route to making ketones in moderate to good yields.

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Catalysts 2018, 8, x FOR PEER REVIEW 7 of 23 In 2015, Liu developed a Rh(I)-catalyzed acyl Suzuki cross-coupling of carboxylic acid anhydrides and potassiumIn 2015, aryltriﬂuoroborates Liu developed a Rh(I) (Scheme-catalyzed8B) [ 34 acyl]. It Suzuki was shown cross- thatcoupling CuI (1.0 of carboxylic equiv) played acid an essentialanhydrides role andand thepotassium reaction aryltrifl could supportuoroborates the use(Scheme of a wide 8B) [3 range4]. It ofwas cross-coupling shown that CuI partners. (1.0 equiv) A nice advantageplayed an of essential this coupling role and includes the reaction low catalyst could loading, support tolerance the use of to a air wide and range moisture, of cross and-coupling the desired productspartners. were A niceobtained advantage in good of to this excellent coupling yields. includes low catalyst loading, tolerance to air and moistureAn effective, and the and desired environmentally-friendly products were obtained protocol in good forto excellent selective yields. aerobic oxidative coupling of arylboronicAn effective acids with and carboxylic environmentally acid anhydrides-friendly protocol in the presence for selective of palladium aerobic oxidative was developed coupling by of Yin (Schemearylboronic8C) [ 35acids]. This with protocol carboxylic involves acid anhydrides a formal scission in the ofpresence the alternative of palladium C–O bondwas developed to afford estersby byYin transmetallation (Scheme 8C) [3 of5] Pd(II). This protocol with boronic involves acid, a formationformal scission of Pd-carboxylate of the alternative and C reductive–O bond elimination.to afford Comparedesters by with transmetallation previous methods of Pd(II) this with reaction boronic can acid, be conducted formation using of Pd ligandless-carboxylate conditions and reductive and low catalystelimination. loading Compared giving good with to previexcellentous methodsyields of thethis ester reaction products. can be conducted using ligandless conditions and low catalyst loading giving good to excellent yields of the ester products. 4. Suzuki Cross-Coupling of Carboxylic Acids 4. Suzuki Cross-Coupling of Carboxylic Acids In 2001, Gooßen reported the direct synthesis of ketones from carboxylic acids by Suzuki cross-couplingIn 2001, viaGoo anßen anhydride reported the intermediate direct synthesis generated of ketones in situ fro (Schemem carboxylic9A) [ 31 acids,36]. by This Suzuki methodology cross- allowedcoupling for via the an engagementanhydride intermediate of an array generated of functionalized in situ (Scheme aryl 9A) and [31,36] alkyl. This carboxylic methodology acids, allowed for the engagement of an array of functionalized aryl and alkyl carboxylic acids, and, as and, as mentioned previously, relied on the use of an unreactive pivalic anhydride activator. mentioned previously, relied on the use of an unreactive pivalic anhydride activator. Independently, Yamamoto developed a related method using dimethyl dicarbonate (DMDC) Independently, Yamamoto developed a related method using dimethyl dicarbonate (DMDC) activator and various carboxylic acids for the synthesis of ketones (Scheme9B) [ 37]. It is important to activator and various carboxylic acids for the synthesis of ketones (Scheme 9B) [37]. It is important to note that these reactions allow for the direct synthesis of ketones from ubiquitous carboxylic acids and note that these reactions allow for the direct synthesis of ketones from ubiquitous carboxylic acids areand easily are compatible easily compatible with meta-substituted with meta-substituted benzoic acids benzoic which acids had whichpreviously had been previously problematic been in theproblematic classical Friedel-Crafts in the classical acylation. Friedel-Crafts acylation.

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More recently, Lindsley reported the use of PyCUI (1-(chloro-1-pyrrolidinylmethylene) pyrrolidiniumhexafluorophosphate in the synthesis of ketones by acyl Suzuki cross-coupling (Scheme 12) [42]. This highly reactive in situ activating reagent allows for the transformation of carboxylic acids into unsymmetrical ketones. Furthermore, this one-pot reaction can be conducted at room temperature with reaction times of 2 h or less and gives moderate to high yields. In 2016, Zeng reported the Suzuki-Miyaura cross-coupling of in situ prepared triazine esters usingScheme CSchemeMDT 9. (29.Early- Earlychloro Studies Studies-4,6-dimethoxy in in Acyl Acyl Suzuki-Miyaura Suzuki-1,3,5-Miyaura-triazine) Cross Cross-Coupling (Scheme-Coupling 13) of of [43]Carboxylic Carboxylic. This Acids:process Acids: (A ()isA Gooßen; )conducted Gooßen; at low catalyst(B)(B Yamamoto.) Yamamoto. loading DMDC DMDCand with = Dimethyl Dimethyl short reaction Dicarbonate. Dicarbonate. times. For Moreover, ForN-BenzoyloxysuccinimideN-Benzoyloxysuccinimide this one-pot, assequ the aseActivator,ntial the Activator,protocol see: gave moderatesee:Ref Reference ereto nceexcellent [38,39] [38,39 . yields]. using functionalized and sterically-hindered substrates. Furthermore, recent progress by Zou in the use of high order aryl boron reagents such as diarylbornicInIn the the past acids past decade, decade,and tetra signiﬁcant significant-arylboronates progress progress in the has acyl been Suzuki achieved achieved cross in in - thecouplin the development developmentg of carboxylic of of selective selective acids is activatingnoteworthyactivating reagents (Schemereagents for for14) acyl acyl [44] Suzuki Suzuki. cross-coupling cross-coupling of carboxylic acids acids (Schemes (Schemes 10 10–14)–14. ). In 2010, Yoon reported the use of EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) as an activating reagent in the Suzuki cross-coupling of carboxylic acids with arylboronic acids to make the desired ketone products (Scheme 10) [40]. EEDQ is a known coupling reagent and serves in this case to make a mixed carboxylic acid anhydride in situ. This simple and efficient method gave diarylketone products in high to excellent yields. In 2013, Sharma reported DMC (2-chloro-1,3-dimethyl imidazolidinium chloride) as an activating reagent for the synthesis of biaryl ketones via acyl Suzuki cross-coupling of carboxylic acids (Scheme 11) [41]. This reaction was compatible with electron-donating and withdrawing substituents on both reaction components; however, aliphatic carboxylic acids were not compatible withScheme the reaction 10. SynthesisSynthesis conditions. of of Ketones Ketones from from Carboxylic Carboxylic Acids Acids using using EEDQ. EEDQ. EEDQ EEDQ = =NN-Ethoxycarbonyl-Ethoxycarbonyl--2- 2-ethoxy-1,2-dihydroquinoline.ethoxy-1,2-dihydroquinoline.

Scheme 11. Synthesis of Ketones from Carboxylic Acids using DMC. DMC = 2-Chloro-1,3- dimethylimidazolinium Chloride.

Scheme 12. Synthesis of Ketones from Carboxylic Acids using PyCIU. PyCIU = 1-(Chloro-1- pyrrolidinylmethylene)pyrrolidinium Hexafluorophosphate.

Catalysts 2018, 8, x FOR PEER REVIEW 8 of 23 Catalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 88 ofof 2323 More recently, Lindsley reported the use of PyCUI (1-(chloro-1-pyrrolidinylmethylene) More recently, Lindsley reportedreported the the use use of PyCUI (1--(chloro(chloro--1--pyrrolidinylmethylene) pyrrolidiniumhexafluorophosphate in the synthesis of ketones by acyl Suzuki cross-coupling pyrrolidiniumhexafluorophosphate in the synthesissynthesis of ketones by acyl Suzuki cross--couplingcoupling (Scheme 12) [42]. This highly reactive in situ activating reagent allows for the transformation of (Scheme(Scheme 12) 12) [42][42].. This This highly reactive inin situ situ activating activating rereagent allows for the transformation of carboxylic acids into unsymmetrical ketones. Furthermore, this one-pot reaction can be conducted at carboxyliccarboxylic acidsacids intointo unsymmetricalunsymmetrical ketones.ketones. Furthermore,Furthermore, thisthis oneone--pot reaction can be conductedconducted at room temperature with reaction times of 2 h or less and gives moderate to high yields. roomroom temperaturetemperature withwith reactionreaction timestimes ofof 22 h or less and gives moderate to high yields. In 2016, Zeng reported the Suzuki-Miyaura cross-coupling of in situ prepared triazine esters InIn 2016,2016, ZengZeng reportedreported thethe Suzuki--Miyaura crosscross--couplingcoupling ofof inin situsitu preparedprepared triazinetriazine estersesters using CMDT (2-chloro-4,6-dimethoxy-1,3,5-triazine) (Scheme 13) [43]. This process is conducted at using CMDT (2--chlorochloro--4,6--dimethoxy--1,3,5--triazine)triazine) (Scheme(Scheme 13)13) [43][43].. This process isis conductedconducted atat low catalyst loading and with short reaction times. Moreover, this one-pot, sequential protocol gave lowlow catalystcatalyst loadingloading andand with short reactionreaction times.times. Moreover,Moreover, thisthis oneone--pot,, sequsequeential protocol gave moderate to excellent yields using functionalized and sterically-hindered substrates. moderate to excellent yields using functionalized and sterically--hindered substrates. Furthermore, recent progress by Zou in the use of high order aryl boron reagents such as Furthermore, recent progress by Zou in the use of high order aryl boron reagents such as diarylbornic acids and tetra-arylboronates in the acyl Suzuki cross-coupling of carboxylic acids is diarylbornic acids and tetra--arylboronates inin thethe acylacyl SuzukiSuzuki crosscross--couplincoupling of carboxylic acids is noteworthy (Scheme 14) [44]. noteworthy (Scheme 14) [44][44]..

Scheme 10. Synthesis of Ketones from Carboxylic Acids using EEDQ. EEDQ = N-Ethoxycarbonyl-2- Scheme 10. SynthesisSynthesis ofof KetonesKetones fromfrom CarboxylicCarboxylic AcidsAcids usingusing EEDQ.EEDQ. EEDQEEDQ == N--Ethoxycarbonyl--22-- Catalystsethoxy2019-,1,29, 53-dihydroquinoline. 8 of 23 ethoxyethoxy--1,21,2--dihydroquinoline.

Scheme 11. Synthesis of Ketones from Carboxylic Acids using DMC. DMC = 2-Chloro-1,3- SchemeScheme 11. SynthesisSynthesisSynthesis of of of Ketones Ketones Ketones from from from Carboxylic Carboxylic Carboxylic Acids Acids Acids using using using DMC. DMC. DMC. DMC DMC DMC = = = 2 2 2-Chloro-1,3---Chloro--1,31,3-- dimethylimidazolinium Chloride. dimethylimidazoliniumdimethylimidazolinium Chloride. Chloride.

Scheme 12. Synthesis of Ketones from Carboxylic Acids using PyCIU. PyCIU = 1-(Chloro-1- SchemeScheme 12. SynthesisSynthesisSynthesis of of of Ketones Ketones Ketones from from from Carboxylic Carboxylic Carboxylic Acids Acids Acids using using using PyCIU. PyCIU. PyCIU. PyCIU PyCIU PyCIU == = 1 1 1-(Chloro-1---(Chloro(Chloro--11-- pyrrolidinylmethylene)pyrrolidinium Hexafluorophosphate. pyrrolidinylmethylene)pyrrolidiniumpyrrolidinylmethylene)pyrrolidinium Hexafluorophosphate. Hexaﬂuorophosphate.

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 23

Scheme 13. SynthesisSynthesis of of Ketones Ketones from from Carboxylic Carboxylic Acids Acids using using CDMT. CDMT. CDMT CDMT = = 2 2-Chloro-4,6--Chloro-4,6- dimethoxy-1,3,5-triazine. NMM = N-Methylmorpholine. dimethoxy-1,3,5-triazine. NMM = N-Methylmorpholine.

SchemeScheme 14. 14. SynthesisSynthesis of of Ketones Ketones from from Carboxylic Carboxylic Acids Acids and and Diarylborinic Diarylborinic Acids Acids using DMDC.

TheseIn 2010, reagents Yoon reported are not only the use more of EEDQcost effective (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) than conventional boronic acids but also showed as an increasedactivating reagentreactivity in thein theSuzuki cross cross-coupling-coupling using of carboxylic DMDC activator. acids with This arylboronic acylative acids Suzuki to make cross the- couplingdesired ketone had a productsremarkably (Scheme broad 10substrate)[40]. EEDQ scope, is affording a known couplingproducts reagentbearing andhydroxy, serves bromo, in this caseand cator makebonyl agroups mixed carboxylicin good to acidhigh anhydride yields [44] in. situ. This simple and efﬁcient method gave diarylketone productsAn interesting in high to excellentapplication yields. of the Ni-catalyzed reductive cross-coupling of carboxylic acids for the synthesisIn 2013, Sharmaof ketones reported was reported DMC (2-chloro-1,3-dimethyl by Gong (Scheme 15) imidazolidinium [45,46]. The coupling chloride) of as benzoic an activating acids withreagent primary for the and synthesis secondary of alkyl biaryl bromides ketones was via performed acyl Suzuki using cross-coupling Ni(acac)2/bipy of catalyst carboxylic system acids in the(Scheme presence 11)[ of41 ].Boc This2O reactionactivator was. Moreover, compatible the withgroup electron-donating demonstrated the and synthesis withdrawing of functionalized substituents Con-glycosides both reaction by the components; direct reductive however, coupling aliphatic of 1-glycosyl carboxylic bromides acids with were carboxylic not compatible acids. with the reaction conditions.

Scheme 15. Synthesis of Ketones from Carboxylic Acids by Reductive Coupling.

5. Suzuki Cross-Coupling of Esters Recently, there have been major developments in the acyl Suzuki cross-coupling of aryl esters (Schemes 16–20). There are several key advantages of using ester electrophiles in the acyl Suzuki cross- coupling, including (i) high-stability, (ii) prevalence in organic synthesis, (iii) opportunities for orthogonal cross-coupling strategies, (iv) reduction of toxic waste produced in the cross-coupling step. In 2017, Newman demonstrated the first example of Suzuki cross-coupling of aryl esters (Scheme 16) [47]. The Pd-NHC catalyst allows for facile insertion into the inactivated C(acyl)–O ester bond, which had proven challenging using Pd-phosphine catalysts. A broad range of phenolic esters and aryl boronic acids were cross-coupled giving ketones in good to excellent yields. In 2017, our group demonstrated the Suzuki cross-coupling of phenolic esters by selective C(acyl)–O cleavage under very mild conditions (Scheme 17A) [48]. The use of bench-stable and commercially-available (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst was critical to achieve high reactivity, affording a wide range of products in good to high yields. Subsequently, we developed conditions for using practical Pd-PEPPSI precatalysts in the acyl Suzuki cross-coupling of phenolic esters (Scheme 17B) [49]. The pyridine “throw-away” family of ligands render this class of Pd-NHC precatalysts an attractive method due to simplicity of synthesis and high reactivity in C(acyl)–O insertion. Later, we demonstrated that the cross-coupling is effectively promoted at remarkably mild room temperature conditions (Scheme 17C), while supporting various Pd-NHC precatalysts as well as Pd(II)-NHC hydroxide dimers (Figure 2) [50]. The preparation of ketones using (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) in the presence of a strong base was reported by Hazari (Scheme 18) [51]. This Pd-NHC effectively coupled esters with aryl boronic acids in good to high yields at room temperature using non-toxic reagents.

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 23

Scheme 13. Synthesis of Ketones from Carboxylic Acids using CDMT. CDMT = 2-Chloro-4,6- dimethoxyCatalysts 2019-1,3,5, 9,- 53triazine. NMM = N-Methylmorpholine. 9 of 23

More recently, Lindsley reported the use of PyCUI (1-(chloro-1-pyrrolidinylmethylene) pyrrolidiniumhexaﬂuorophosphate in the synthesis of ketones by acyl Suzuki cross-coupling (Scheme 12)[42]. This highly reactive in situ activating reagent allows for the transformation of carboxylic acids into unsymmetrical ketones. Furthermore, this one-pot reaction can be conducted at room temperature with reaction times of 2 h or less and gives moderate to high yields. In 2016, Zeng reported the Suzuki-Miyaura cross-coupling of in situ prepared triazine esters using CMDT (2-chloro-4,6-dimethoxy-1,3,5-triazine) (Scheme 13)[43]. This process is conducted at low catalyst loading and with short reaction times. Moreover, this one-pot, sequential protocol gave Schememoderate 14. to Synthesis excellent yieldsof Ketones using from functionalized Carboxylic and Acids sterically-hindered and Diarylborinic substrates. Acids using DMDC. Furthermore, recent progress by Zou in the use of high order aryl boron reagents such as diarylbornic acids and tetra-arylboronates in the acyl Suzuki cross-coupling of carboxylic acids is These reagents are not only more cost effective than conventional boronic acids but also showed noteworthy (Scheme 14)[44]. increased reactivityThese reagents in the are not cross only-coupling more cost effective using thanDMDC conventional activator. boronic This acids acylative but also showedSuzuki cross- couplingincreased had a remarkably reactivity in the broad cross-coupling substrate using scope, DMDC affording activator. products This acylative bearing Suzuki hydroxy, cross-coupling bromo, and carbonylhad groups a remarkably in good broad to high substrate yields scope, [44] affording. products bearing hydroxy, bromo, and carbonyl An groupsinteresting in good application to high yields of [44 the]. Ni-catalyzed reductive cross-coupling of carboxylic acids for the synthesisAn of interesting ketones applicationwas reported of the by Ni-catalyzed Gong (Scheme reductive 15) cross-coupling [45,46]. The of coupling carboxylic of acids benzoic for acids the synthesis of ketones was reported by Gong (Scheme 15)[45,46]. The coupling of benzoic acids with primary and secondary alkyl bromides was performed using Ni(acac)2/bipy catalyst system in with primary and secondary alkyl bromides was performed using Ni(acac)2/bipy catalyst system in the presencethe presence of Boc of2O Boc activator2O activator.. Moreover, Moreover, the the group group demonstrated demonstrated the synthesisthe synthesis of functionalized of functionalized C-glycosidesC-glycosides by the bydirect the direct reductive reductive coupling coupling of of 1 1-glycosyl-glycosyl bromides bromides with with carboxylic carboxylic acids. acids.

SchemeScheme 15. Synthesis 15. Synthesis of Ketones of Ketones from from Carboxylic Carboxylic Acids Acids by Reductiveby Reductive Coupling. Coupling. 5. Suzuki Cross-Coupling of Esters 5. Suzuki Cross-Coupling of Esters Recently, there have been major developments in the acyl Suzuki cross-coupling of aryl esters Recently,(Schemes there 16–20 h).ave There been are major several developments key advantages in of usingthe acyl ester Suzuki electrophiles cross in-coupling the acyl Suzuki of aryl esters (Schemescross-coupling, 16–20). There including are several (i) high-stability, key advantages (ii) prevalence of using in ester organic electrophiles synthesis, (iii) in opportunities the acyl Suzuki for cross- coupling,orthogonal including cross-coupling (i) high-stability, strategies, (iv) (ii) reductionprevalence of toxic in waste organic produced synthesi in thes, cross-coupling (iii) opportunities step. for In 2017, Newman demonstrated the ﬁrst example of Suzuki cross-coupling of aryl esters orthogonal(Scheme cross 16-coupling)[47]. The strategies, Pd-NHC catalyst(iv) reduction allows for of faciletoxic insertionwaste produced into the inactivated in the cross C(acyl)–O-coupling step. In 201ester7, bond,Newman which demonstrated had proven challenging the first using example Pd-phosphine of Suzuki catalysts. cross-coupling A broad range of aryl of phenolic esters (Scheme 16) [47]. estersCatalystsThe Pd and 2018-NHC aryl, 8, x boronicFOR catalyst PEER acids REVIEW allows were cross-coupled for facile insertion giving ketones into inthe good inactivated to excellent C(acyl) yields. –10O ofester 23 bond, which had proven challenging using Pd-phosphine catalysts. A broad range of phenolic esters and aryl boronic acids were cross-coupled giving ketones in good to excellent yields. In 2017, our group demonstrated the Suzuki cross-coupling of phenolic esters by selective C(acyl)–O cleavage under very mild conditions (Scheme 17A) [48]. The use of bench-stable and commercially-available (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst was critical to achieve high reactivity, affording a wide range of products in good to high yields. Subsequently, we developed conditions for usingScheme practical 16. Synthesis Pd-PEPPSI of Ketones precatalyst from Phenolics in Esters the by acyl Newman Suzuki and co-workers.co cross-workers-coupling. of phenolic esters (Scheme 17B) [49]. The pyridine “throw-away” family of ligands render this class of Pd-NHC precatalysts an attractive method due to simplicity of synthesis and high reactivity in C(acyl)–O insertion. Later, we demonstrated that the cross-coupling is effectively promoted at remarkably mild room temperature conditions (Scheme 17C), while supporting various Pd-NHC precatalysts as well as Pd(II)-NHC hydroxide dimers (Figure 2) [50]. The preparation of ketones using (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) in the presence of a strong base was reported by Hazari (Scheme 18) [51]. This Pd-NHC effectively coupled esters with aryl boronic acids in good to high yields at room temperature using non-toxic reagents.

Scheme 17. Synthesis of Ketones from Phenolic Esters by Szostak and co-workers.

Scheme 18. Synthesis of Ketones from Phenolic Esters by Hazari and co-workers.

Figure 2. Structures of Air-Stable Pd-NHC Precatalysts in Cross-Coupling of Phenolic Esters.

In 2018, to further explore the reactivity of phenolic esters in the acyl Suzuki cross-coupling reaction, we have reported the Pd-phosphine-catalyzed cross-coupling of pentafluorophenyl esters (pfp) (Scheme 19) [52]. Due to the activating effect of the fluorine substituents, a mild Pd2(dba)3/PCy3 catalyst was able to effectively activate the C(acyl)–O bond giving products in high yields without the need for a more reactive, albeit less selective, Pd-NHC precatalyst.

Catalysts 2018, 8, x FOR PEER REVIEW 10 of 23 Catalysts 2018, 8, x FOR PEER REVIEW 10 of 23

Catalysts 2019, 9, 53 10 of 23 Scheme 16. Synthesis of Ketones from Phenolic Esters by Newman and co-workers..

SchemeScheme 17. 17. SynthesisSynthesis of of Ketones Ketones from from Phenolic Phenolic Esters Esters by Szostak and co co-workers.-workers.

Catalysts 2018, 8, x FOR PEER REVIEW 11 of 23 Catalysts 2018, 8, x FOR PEER REVIEW 11 of 23

Recently, Rueping and Newman groups reported Ni- and Pd-catalyzed B-alkyl acyl Suzuki cross-coupling of phenolic esters (Scheme 20) [53,54]. Both groups have shown that the catalyst type and reaction conditions dictate whether the process is a decarbonylative or acyl coupling. This novel approach gives alkyl ketones in good to high yields, while also demonstrating the importance of approach gives alkyl ketones in good to high yields, while also demonstrating the importance of ligand selection to promote cross-coupling/decarbonylation of the acyl-metal intermediate. SchemeScheme 18. 18. SynthesisSynthesis of of Ketones Ketones from from Phenolic Phenolic Esters Esters by Hazari and co co-workers.-workers.

Scheme 19. Synthesis of Biaryl Ketones from Pentafluorophenyl Esters. SchemeScheme 19. SynthesisSynthesis of of Biaryl Biaryl Ketones Ketones from from Pentafluorophenyl Pentaﬂuorophenyl Esters. Figure 2. Structures of Air-Stable Pd-NHC Precatalysts in Cross-Coupling of Phenolic Esters.

In 2018, to further explore the reactivity of phenolic esters in the acyl Suzuki cross-coupling reaction, we have reported the Pd-phosphine-catalyzed cross-coupling of pentafluorophenyl esters (pfp) (Scheme 19) [52]. Due to the activating effect of the fluorine substituents, a mild Pd2(dba)3/PCy3 (pfp) (Scheme 19) [52]. Due to the activating effect of the fluorine substituents, a mild Pd2(dba)3/PCy3 catalyst was able to effectively activate the C(acyl)–O bond giving products in high yields without the need for a more reactive, albeit less selective, Pd-NHC precatalyst.

Scheme 20. B-Alkyl Suzuki-Miyaura Cross-Coupling of Phenolic Esters: (A) Rueping; (B) Newman. Scheme 20. B-Alkyl Suzuki-Miyaura Cross-Coupling of Phenolic Esters: (a) Rueping; (b) Newman.

6. Suzuki Cross-Coupling of Amides The ability of transition-metals to catalyze activation of the acyl N–C(O) amide bond was first reported in 2015. Traditionally, the amide bond is the most challenging carboxylic acid derivative to achieve metal insertion due to nN → π*C=O conjugation (15–20 kcal/mol) [55], rendering the classical achieve metal insertion due to nN → π*C=O conjugation (15–20 kcal/mol) [55], rendering the classical amide bond approximately 40% double bond in character. To tackle the challenge of selective metal insertion into the acyl N–C(O) amide bond, we designed a concept of ground-state-destabilization of the amide bond in transition-metal-catalysis (Scheme 21A) [56,57]. We demonstrated a highly chemoselective, Pd(0)-catalyzed, direct acyl Suzuki cross-coupling between boronic acids and geometrically activated amides. A twisted glutarimide diminishes amidic resonance, thus destabilizing the amide ground-state and giving access to versatile ketone products in good to excellent yields. Since the initial report, amide ground state destabilization is considered a prevalent theme in amide bond cross-coupling [58], and all amides thus far have been shown to undergo cross-coupling due to resonance activation [59–62]. Independently, a new methodology for the synthesis of aryl ketones by acyl Suzuki coupling was developed by Zou, in which amides are used to react with arylboronic acids (Scheme 21B) [63]. Amide bond activation was achieved by using modifiable activating groups on the nitrogen atom. The reaction gave good to excellent yields and allowed access to sterically-hindered ketones. At the same time, Garg reported the Ni-catalyzed Suzuki cross-coupling of amide derivatives (Scheme 22) [64]. This coupling is tolerant to significant changes on both amide and boronate substrates and tolerates both heterocycles and epimerizable stereocenters. The scaffolds produced are diverse and the reaction was applied to the synthesis of an antiproliferative agent.

Catalysts 2018, 8, x FOR PEER REVIEW 10 of 23

ewman N Pd IPr cin Cl 3 mol% O B(OH)2 ( )( ) ( ) O K3PO4 + R OPh - R , ° , °, ° THF H2O 90 C R = Ar 1 2 ' ' R R a . e u v - e lkyl (1 0 q i ) 30 95% yi ld Scheme 16. Synthesis of Ketones from Phenolic Esters by Newman and co-workers.

A: Szostak

Pd IPr ind Cl 3 mol% O B(OH)2 ( )( ) ( ) O K CO + 2 3 R OPh , ° R , ° THF 23 C R = Ar 1 alkyl ' ' . R - R (4 5 equiv) 49 98% yield

B: Szostak - - Pd PEPPSI IPr (3 mol%) O B(OH)2 O K2CO3 + R OPh R THF, ° , ° 80 C R = Ar 1 alkyl ' ' . R - R (3 0 equiv) 54 98% yield

C: Szostak - Pd NHC (1 mol%) O B(OH)2 O K2CO3 + Ph OPh - Ph THF H O, 23 °C 2 - Catalysts 2019, 9, 53 ' R' = 4 Me ' 11 of 23 . R - - R (2 0 equiv) Pd PEPPSI IPr 95% [Pd(IPr)(cin)Cl] 73% r n In 2017, our group demonstrated the Suzuki cross-coupling[Pd(IP )( ofi d phenolic)Cl] 94% esters by selective C(acyl)–O cleavage under very mild conditions (Scheme 17A) [48]. The use of bench-stable and Scheme 17. Synthesis of Ketones from Phenolic Esters by Szostak and co-workers. commercially-available (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst was critical to achieve high reactivity, affording a wide rangeazar of products in good to high yields. Subsequently, we developed conditions H i for using practical Pd-PEPPSI precatalysts inPd theIPr acylind C Suzukil 1 mol% cross-coupling of phenolic esters O B(OH)2 ( )( ) ( ) O (Scheme 17B) [49]. The pyridine “throw-away” familyKOH of ligands render this class of Pd-NHC R + precatalysts an attractiveOP methodh due to simplicity of- synthesis, ° andR high reactivity in C(acyl)–O THF H2O 23 C R = Ar ' ' insertion. Later, we demonstrated that theR cross-coupling is effectively promoted R at remarkably mild . e u v - e room temperature conditions (Scheme(1 5 17qC),i ) while supporting various Pd-NHC32 91% y precatalystsi ld as well as Pd(II)-NHC hydroxide dimers (Figure2)[50]. Scheme 18. Synthesis of Ketones from Phenolic Esters by Hazari and co-workers.

Me Me Me Me Me Me Me Me Me Me Me Me Dipp N H N N N N N N N O Cl Dipp Me Me Me Me Me Me Pd Pd Dipp e Pd e eCl Pd Cl e e Pd e M M M M M M Cl O N Cl N Cl H N t u Ph B Dipp Cl r c n - - r r n r µ- [Pd(IP )( i )Cl] Pd PEPPSI IP [Pd(IP )(i d)Cl] [Pd(IP )( OH)Cl]2 FigureFigure 2. 2. StructuresStructures of of Air Air-Stable-Stable Pd Pd-NHC-NHC Precatalysts Precatalysts in in Cross Cross-Coupling-Coupling of of Phenolic Phenolic Esters.

InThe 2018, preparation to further of ketonesexplore usingthe reactivity (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) of phenolic esters in the in theacyl presence Suzuki ofcross a strong-coupling base reaction,was reported we have by Hazari reported (Scheme the Pd 18-phosphine)[51]. This-catalyzed Pd-NHC cross effectively-coupling coupled of pent estersafluorophenyl with aryl boronic esters (pfp)acids (Scheme in good to19) high [52]. yields Due to at the room activating temperature effectusing of the non-toxic fluorine substituents, reagents. a mild Pd2(dba)3/PCy3 catalystIn 2018,was able to further to effectively explore activate the reactivity the C(acyl) of phenolic–O bond esters giving in products the acyl in Suzuki high yields cross-coupling without thereaction, need for we a have more reported reactive, the albeit Pd-phosphine-catalyzed less selective, Pd-NHC cross-coupling precatalyst. of pentaﬂuorophenyl esters (pfp) (Scheme 19)[52]. Due to the activating effect of the ﬂuorine substituents, a mild Pd2(dba)3/PCy3 catalyst was able to effectively activate the C(acyl)–O bond giving products in high yields without the need for a more reactive, albeit less selective, Pd-NHC precatalyst. Recently, Rueping and Newman groups reported Ni- and Pd-catalyzed B-alkyl acyl Suzuki cross-coupling of phenolic esters (Scheme 20)[53,54]. Both groups have shown that the catalyst type and reaction conditions dictate whether the process is a decarbonylative or acyl coupling. This novel approach gives alkyl ketones in good to high yields, while also demonstrating the importance of ligand selection to promote cross-coupling/decarbonylation of the acyl-metal intermediate.

6. Suzuki Cross-Coupling of Amides The ability of transition-metals to catalyze activation of the acyl N–C(O) amide bond was ﬁrst reported in 2015. Traditionally, the amide bond is the most challenging carboxylic acid derivative to achieve metal insertion due to nN → π*C=O conjugation (15–20 kcal/mol) [55], rendering the classical amide bond approximately 40% double bond in character. To tackle the challenge of selective metal insertion into the acyl N–C(O) amide bond, we designed a concept of ground-state-destabilization of the amide bond in transition-metal-catalysis (Scheme 21A) [56,57]. We demonstrated a highly chemoselective, Pd(0)-catalyzed, direct acyl Suzuki cross-coupling between boronic acids and geometrically activated amides. A twisted glutarimide diminishes amidic resonance, thus destabilizing the amide ground-state and giving access to versatile ketone products in good to excellent yields. Since the initial report, amide ground state destabilization is considered a prevalent theme in amide bond cross-coupling [58], and all amides thus far have been shown to undergo cross-coupling due to resonance activation [59–62]. Catalysts 2019, 9, 53 12 of 23 Catalysts 2018, 8, x FOR PEER REVIEW 12 of 23

Catalysts 2018, 8, x FOR PEER REVIEW 12 of 23

SchemeScheme 21.21. StudiesStudies inin SuzukiSuzuki Cross-CouplingCross-Coupling ofof Amides:Amides: ((a)A) Szostak; (b) (B) Zou. Zou.

Independently, a new methodology for the synthesis of aryl ketones by acyl Suzuki coupling was developed by Zou, in which amides are used to react with arylboronic acids (Scheme 21B) [63]. Amide bond activation was achieved by using modiﬁable activating groups on the nitrogen atom. The reaction gave good to excellent yields and allowed access to sterically-hindered ketones. At the same time, Garg reported the Ni-catalyzed Suzuki cross-coupling of amide derivatives (Scheme 22)[64]. This coupling is tolerant to signiﬁcant changes on both amide and boronate substrates and toleratesScheme 22. both Studies heterocycles in Suzuki Cross and epimerizable-Coupling of Amides: stereocenters. Garg. SIPr The = 1,3 scaffolds-bis-(2,6-diisopropylphenyl) produced are diverse- and the4,5-dihydroimidazol reactionScheme was applied 21.-2- ylidine.Studies to thein Suzuki synthesis Cross of-Coupling an antiproliferative of Amides: (a) agent. Szostak; (b) Zou.

Given the indispensable role of the amide bond in chemistry and biology, the amide bond cross- coupling is one of the most rapidly expanding areas of acyl Suzuki coupling [65–72]. The key advances enabling the routine use of this methodology include (1) the development of new amide precursors, (2) the establishment of new catalysts, and (3) the discovery of new types of acyl cross- coupling of amides. These developments are summarized below. To enable a better control of the insertion step and participation of common amides, we have developedSchemeScheme a22. 22. number StudiesStudies in in of Suzuki Suzuki activating Cross Cross-Coupling -Coupling groups forof of Amides: Amides: acyl Suzuki Garg. Garg. SIPr SIPr cross = = 1,3- 1,3-bis-(2,6-diisopropylphenyl)coupling-bis-(2,6-diisopropylphenyl) of amides, including- saccharin,4,5-4,5-dihydroimidazol-2-ylidine.-dihydroimidazol Ms, Boc2, succinimide,-2-ylidine. and Ac functional groups (Scheme 23A–E). N-Acylsaccharins are of interest as bench-stable, highly reactive, and easily prepared amides fromGivenGiven low-costing the the indispensable indispensable saccharin (Scheme role role of ofthe 23A) the amide amide[73] bond. Independently, bond in chemistry in chemistry Zeng and biology, andand biology,co- workersthe amide the reported amidebond cross bond acyl- couplingcross-couplingSuzuki cross is one-coupling is of one the of of most the N- mostacylsaccharins rapidly rapidly expa expanding nding[74]. We areas have areas of also of acyl acyl explored Suzuki Suzuki couplingthe coupling activating [65 [65––72 72effect].]. The The of key keythe advancesadvancesmesyl group enabling enabling and found the the routine routine it to be use use advantageous of of this this methodology to the synthesis include include of ( (1)1 biaryl) the the development ketones using of of highly new new amide amideatom- precursors,precursors,economical (mesyl2 (2)) the the activationestablishment establishment (Scheme of ofnew 23B new catalysts,) [75] catalysts,. andand (3) the (3) discovery the discovery of new of types new typesof acyl of cross acyl- couplincross-couplingN,gN of-Boc amides.2-acti of amides.vation These of Thesedevelopments amides developments was shown are summarized areto be summarized successful below. with below. a combination a Lewis base and palladiumToTo enable catalysis a better , establishing control of a thenew insertion concept forstep activation and participation of amide bondsof of common by cooperative amides, amides, we wecatalysis have have developeddeveloped(Scheme 23C) a a number number [76]. Crucially, of of activating activating this groups method groups for enables acyl for Suzuki acyl the Suzuki use cross-coupling of primary cross-coupling ofamides amides, ofas including amides,starting includingmaterials saccharin,. sMs,Sinceaccharin, Boc primary2, succinimide,Ms, B amidesoc2, succinimide, and are Ac among functional and the Ac mostfunctional groups common (Scheme groups amide 23 (SchemeA–E). derivatives 23A–E) .in pharmaceuticals and biologicallyN-Acyl sacactivecharins intermediates are of interest, this asapproach bench-stable, constitutes highly a reactive,powerful and method easily for prepared the synthesis amides of fromketones low from-costing common saccharin amides (Scheme [77]. 23A) [73]. Independently, Zeng and co-workers reported acyl Suzuki cross-coupling of N-acylsaccharins [74]. We have also explored the activating effect of the mesyl group and found it to be advantageous to the synthesis of biaryl ketones using highly atom- economical mesyl activation (Scheme 23B) [75].

N,N-Boc2-activation of amides was shown to be successful with a combination a Lewis base and palladium catalysis, establishing a new concept for activation of amide bonds by cooperative catalysis (Scheme 23C) [76]. Crucially, this method enables the use of primary amides as starting materials. Since primary amides are among the most common amide derivatives in pharmaceuticals and biologically active intermediates, this approach constitutes a powerful method for the synthesis of ketones from common amides [77].

Catalysts 2019, 9, 53 13 of 23 Catalysts 2018, 8, x FOR PEER REVIEW 13 of 23

Scheme 23. 23. SynthesisSynthesis of Ketones of Ketones from from Amides Amides using using Pd-Phosphine Pd-Phosphine Catalysts: Catalysts: (A) Saccharins; (A) Saccharins; (B) Ms- (Amides;B) Ms-Amides; (C) Boc (2C-Amides;) Boc2-Amides; (D) Succinimides; (D) Succinimides; (E) Ac-Amides. (E) Ac-Amides.

N-Acylsaccharins“Half-twisted” N- areacylsuccinimides of interest as bench-stable, (τ = 46.1°) were highly also reactive, demonstrated and easily as preparedversatile acyl amides transfer from low-costingreagents in Suzuki saccharin cross (Scheme-coupling 23A) (Scheme [73]. Independently, 23D) [78]. This Zeng reaction and relies co-workers on the reportedincrease in acyl reactivity Suzuki cross-couplingof the amide bond of N-acylsaccharins due to the half [-74twist]. We of have the amide also explored bond caused the activating by the effectsuccinimide of the mesyl moiety group (cf. and“fully found perpendicular” it to be advantageous N-acylglutarimide to the synthesiss, τ = 88.6 of biaryl°), which ketones coupl usinged with highly high atom-economical efficiency. Low mesyl cost activationand commercial (Scheme availability 23B) [75]. of succinimides make this process a viable candidate for the formation of biarylN,N-Boc ketones.2-activation Other of catalysts amides washave shown also been to be reported successful for with the a acyl combination cross-coupling a Lewis of base N- andacylsuccinimides palladium catalysis, [79,80]. establishing a new concept for activation of amide bonds by cooperative catalysisMore (Scheme recently, 23 weC) have [76]. reported Crucially, “mono this- methodtwisted” enables N-Ac-amides the use as of highly primary reactive amides acyclic as starting amides materials.in acyl Suzuki Since cross primary-coupling amides (Scheme are among 23E) the [81] most. Incommon this work amide, it was derivatives demonstrated in pharmaceuticals that catalyst andselection biologically dictates active an acyl intermediates, or decarbonylative this approach mechanism. constitutes Due to a powerfulselective methodmono-twist for thedestabilization synthesis of ketonesmechanism from of common the amide amides bond [77(τ ].= 46.1° vs. τ = 5.1°), Ac-amides represent the most reactive acyclic ◦ amides“Half-twisted” developed thus N-acylsuccinimides far for amide bond (τ =cross 46.1-coupling.) were also demonstrated as versatile acyl transfer reagentsOur ingroup Suzuki reported cross-coupling the structural (Scheme characterization 23D) [78]. This and reaction acyl reliesSuzuki on cross the increase-coupling in reactivityof the most of thetwisted amide N- bondacyclic due amides to the prepared half-twist to of date the amide(Figure bond 3) [82] caused. We found by the that succinimide a combined moiety N-carbamate (cf. “fully ◦ perpendicular”and N-Ts or N-Ac N-acylglutarimides, activation results inτ a= near 88.6 perpendicular), which coupled twist with of the high amide efficiency. bond in Lowsimple cost acyclic and amides (τ = 87.2°). These amides for the first time matched the distortion achieved in bridged lactams [83] and represent another class of reactive amides for acyl Suzuki cross-coupling.

Catalysts 2019, 9, 53 14 of 23

commercial availability of succinimides make this process a viable candidate for the formation of biaryl ketones. Other catalysts have also been reported for the acyl cross-coupling of N-acylsuccinimides [79,80]. More recently, we have reported “mono-twisted” N-Ac-amides as highly reactive acyclic amides in acyl Suzuki cross-coupling (Scheme 23E) [81]. In this work, it was demonstrated that catalyst selection dictates an acyl or decarbonylative mechanism. Due to selective mono-twist destabilization mechanism of the amide bond (τ = 46.1◦ vs. τ = 5.1◦), Ac-amides represent the most reactive acyclic amides developed thus far for amide bond cross-coupling. Our group reported the structural characterization and acyl Suzuki cross-coupling of the most twisted N-acyclic amides prepared to date (Figure3)[ 82]. We found that a combined N-carbamate and N-Ts or N-Ac activation results in a near perpendicular twist of the amide bond in simple acyclic amides (τ = 87.2◦). These amides for the ﬁrst time matched the distortion achieved in bridged lactams [83] and Catalysts 2018represent, 8, x FOR another PEER class REVIEW of reactive amides for acyl Suzuki cross-coupling. 14 of 23

Catalysts 2018, 8, x FOR PEER REVIEW 15 of 23 FigureFigure 3. Structures 3. Structures of of the the Most Most TwistedTwisted N-Acyclic N-Acy Amides.clic Amides. catalyst platform.A mechanistically Furthermore, distinct approachthis method to improving demonstr reactivityates the of potential amides in acylfor Suzukicatalytic cross-coupling cross-coupling of inactivatedinvolves the primary development amides of. new catalyst systems (Schemes 24–28).

SchemeScheme 25. Synthesis 24. Synthesis of of Ketones Ketones fromfrom Amides Amides using using Pd-NHC Pd-NHC Catalysts: Catalysts: (A) Pyrroles; (A) Pyrroles; (B) MAPA-Amides; (B) MAPA- Amides;(C) Boc (C2)-Amides. Boc2-Amides.

We further went on to demonstrate the use of N-methylaminopyrimidyl-amides (MAPA) for the acyl Suzuki cross-coupling (Scheme 25B) [91]. With the use of (IPr)Pd(cinnamyl)Cl precatalyst this reaction occurs with high acyl N–C activation chemoselectivity. Of significance, this work provides MAPAScheme as 24.resonance Synthesis-controlled of Ketones (RE from = ca. Amides7 kcal/mol) using practical Pd-NHC alternative Catalysts: to (anilides.A) Pd(NHC)(cin)Cl; (B) More recently, N-Boc2 amides also proved to be highly reactive with the application of Pd(NHC)(ind)Cl; (C) Pd-PEPPSI. For a study using IPr*-type catalysts, see, ref. [85]. (IPr)Pd(cinnamyl)Cl (Scheme 25C) [92]. This reaction demonstrated the synthesis of biaryl ketones under exceedingly mild conditions, achieving a TON of >1000 for the first time in amide acyl Suzuki A mechanistically distinct approach to improving reactivity of amides in acyl Suzuki crosscross-coupling. coupling involves the development of new catalyst systems (Schemes 24–28). The acyl Suzuki cross-coupling of higher order aryl boron reagents with amides was reported Over the past years, we have made significant contributions to the use of strongly σ-donating by Zou (Scheme 26) [93]. With the use of N-3,5(CF3)2C6H3 activating group and Pd(PCy3)2Cl2/PCy3 Pd-NHCscatalyst for system ketone they synthesis were able by to overcomeacyl Suzuki the crosselectronic-coupling and steric of amides factors. forIn the2017, cross we-coupling have reported of (IPr)Pd(cinnamyl)Clamides with diarylbori to nic demonstrate acids or tetra its-arylbor superiorates to reactivity synthesize to ketones all current (Scheme Pd 26A-phosphine). Later, they-based catalystsreported (Scheme the use 24A) of Pd [84-PEPPSI,85]. This-IPr catalystfor the cross supported-coupling a wideof N- alkylrange-amides of substrates with diarylborinic for ketone synthesisacids in good(Scheme to excellent 26B) [94] .yields. The method Subsequently is characterized, we found by a broad that (IPr)Pd( substrateη 3scope-1-t-Bu, affording-indenyl)Cl ketones precatalyst in good not onlyto showedexcellent unprecedentedyields, while it also reactivity uses a commercially, but it also-available allowed Pd for-NHC. very benign reaction conditions (SchemeZeng 24B) reported[48]. Of furtherthe acyl significance, Suzuki cross Pd-coupling-PEPPSI of-IPr N -wasacylsuccinimide used in thes acyl (Scheme Suzuki 27A, cross see- coupling also of anScheme arrays of23D amides and 28, )show [79]. Thising bothreaction excellent gave moderate catalyst to performance good yields in and a short a highly reaction diverse time. Msubstrateore scoperecently, (Scheme they 24C) used [8 structurally6]. The ease-related of synthesis N-acyl-5,5 and-dimethylhydantoins high air- and moisture in the acyl-stability Suzuki of crossPd-NHC- coupling with aryl boronic acids (Scheme 27B) [95]. The use of commercially-available, air- and precatalysts [87–89] are important factors in considering widespread applications in organic moisture-stable (IPr)Pd(allyl)Cl precatalyst as well as good tolerance to several functional groups are synthesis. important features of this protocol. Our group independently studied the structural features of the amideIn 2017, bond we in were N-acyl able-hydantoins to apply (IPr)Pd(cinnamyl)Cl [96], demonstrating that to previously replacement unreact of the ivecarbon N-a cylpyrrolesatom in the and N-acylpyrazolessuccinimide ring (Scheme with nitrogen 25A) [90] to give. The hydantoin cross-coupling results in of a thesesubstantial electronically increase of-activated the amide ( REbond ca. 10 kcal/moldistortion, RE =(additive resonance Winkler energy-Dunitz) plan parameterar amides of is 70°). attributed to the strong σ-donation of the Pd-NHC In 2018, Liu developed the acyl Suzuki cross-coupling of N-acyl-succinimides with aryl boronic

acids using benzothiazole-supported Pd-NHC PEPPSI-type precatalyst (Scheme 28) [97]. This Pd- NHC is easily prepared [98] and provides biaryl ketones in high yields. In 2018, Rhee developed the

Catalysts 2018, 8, x FOR PEER REVIEW 16 of 23 Catalysts 2018,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 16 of 23 first example of using N,N-bis(methanesulfonyl)amides as acyl-transfer reagents in Suzuki cross- firstfirst example example of of using using N,,N--bis(methanesulfonyl)amidesis(methanesulfonyl)amides as as acyl acyl--transfertransfer reagents reagents in in Suzuki Suzuki cross cross-- coupling (Scheme 29) [99]. In addition to using new class of substrates, this reaction works under coupling (Scheme 29) [99][99].. InIn additionaddition toto usingusing newnew classclass ofof substrates,substrates, thisthis reactionreaction worksworks underunder mildCatalysts conditions2019, 9, 53 to provide a wide range of unsymmetrical ketones. 15 of 23 mild conditions to provide a wide range of unsymmetrical ketones.

Scheme 26. Synthesis of Ketones from Amides using Diarylborinic Acids: (A) N-Ts/Ar Amides; (B) Scheme 26. 25. SynthesisSynthesis of of Ketones Ketones from from Amides Amides using using Diarylborinic Diarylborinic Acids: Acids: (A))( AN)--Ts/ArN-Ts/Ar Amides; Amides; (B)) N-Ts/Alkyl Amides. N(B--)Ts/AlkylN-Ts/Alkyl Amides. Amides.

Scheme 27. Synthesis of Biaryl Ketones from Amides: (A) Succinimides; (B) Hydantoins. Scheme 27. 26. Synthesis of Biaryl Ketones from Amides: ( A)) Succinimides; Succinimides; ( (B)) H Hydantoins.Hydantoins.

SchemeScheme 28. 27. SynthesisSynthesis of of Biaryl Biaryl Ketones Ketones from from Amides Amides using using Benzothiazole Benzothiazole-Supported-Supported Pd Pd-NHCs.-NHCs. Scheme 28. Synthesis of Biaryl Ketones from Amides using Benzothiazole--Supported Pd--NHCs. Over the past years, we have made signiﬁcant contributions to the use of strongly σ-donating Pd-NHCs for ketone synthesis by acyl Suzuki cross-coupling of amides. In 2017, we have reported (IPr)Pd(cinnamyl)Cl to demonstrate its superior reactivity to all current Pd-phosphine-based catalysts (Scheme 28A) [84,85]. This catalyst supported a wide range of substrates for ketone synthesis in good to excellent yields. Subsequently, we found that (IPr)Pd(η3-1-t-Bu-indenyl)Cl precatalyst not only showed unprecedented reactivity, but it also allowed for very benign reaction conditions (Scheme 28B) [48]. Of further signiﬁcance, Pd-PEPPSI-IPr was used in the acyl Suzuki cross-coupling of an array of amides, Scheme 29. Synthesis of Ketones from Di-Sulfonyl Amides by Rhee and co-workers. showing bothScheme excellent 29. Synthesis catalyst performanceof Ketones from and Di-- aSulfonyl highly Amides diverse by substrate Rhee and scope co--workers. (Scheme 28C) [86]. The ease of synthesis and high air- and moisture-stability of Pd-NHC precatalysts [87–89] are important factors in considering widespread applications in organic synthesis.

Catalysts 2018, 8, x FOR PEER REVIEW 14 of 23

Catalysts 2019, 9, 53 16 of 23 Figure 3. Structures of the Most Twisted N-Acyclic Amides.

Scheme 28.SchemeSynthesis 24. Synthesis of Ketones of Ketones from from Amides using using Pd-NHC Pd-NHC Catalysts: Catalysts: (A) Pd(NHC)(cin)Cl; (A) Pd(NHC)(cin)Cl; (B) Pd(NHC)(ind)Cl; (C) Pd-PEPPSI. For a study using IPr*-type catalysts, see, ref. [85]. (B) Pd(NHC)(ind)Cl; (C) Pd-PEPPSI. For a study using IPr*-type catalysts, see, ref. [85]. A mechanistically distinct approach to improving reactivity of amides in acyl Suzuki cross- In 2017,coupling we wereinvolves able the development to apply (IPr)Pd(cinnamyl)Cl of new catalyst systems (Scheme to previouslys 24–28). unreactive N-acylpyrroles and N-acylpyrazolesOver the past (Scheme years, we 24 haveA) made [90]. significant The cross-coupling contributions to the of use these of strongly electronically-activated σ-donating (RE ca. 10Pd kcal/mol,-NHCs for REketone = resonance synthesis by energy)acyl Suzuki planar cross- amidescoupling of is amides attributed. In 2017, to thewe ha strongve reportedσ-donation of (IPr)Pd(cinnamyl)Cl to demonstrate its superior reactivity to all current Pd-phosphine-based the Pd-NHCcatalysts catalyst (Scheme platform. 24A) [84,85 Furthermore,]. This catalyst supported this method a wide range demonstrates of substrates for the ketone potential synthesis for catalytic cross-couplingin good of to inactivated excellent yields. primary Subsequently amides., we found that (IPr)Pd(η3-1-t-Bu-indenyl)Cl precatalyst not We furtheronly showed went unprecedentedon to demonstrate reactivity the, but use it of also N-methylaminopyrimidyl-amides allowed for very benign reaction conditions (MAPA) for the acyl Suzuki(Scheme cross-coupling 24B) [48]. Of further (Scheme significance, 24B) [91 Pd].-PEPPSI With- theIPr was use used of (IPr)Pd(cinnamyl)Clin the acyl Suzuki cross-coupling precatalyst this of an array of amides, showing both excellent catalyst performance and a highly diverse substrate reaction occursscope (Scheme with high 24C) acyl [86]. N–CThe ease activation of synthesis chemoselectivity. and high air- and Of moisture signiﬁcance,-stability of this Pd- workNHC provides MAPA asprecatalysts resonance-controlled [87–89] are important (RE = ca. factors 7 kcal/mol) in considering practical widespread alternative applications to anilides. in organic Moresynthesis. recently, N-Boc2 amides also proved to be highly reactive with the application of (IPr)Pd(cinnamyl)ClIn 2017, we (Scheme were able 24 to C)apply [92 (IPr)Pd(cinnamyl)Cl]. This reaction demonstratedto previously unreact theive synthesis N-acylpyrroles of biaryl and ketones N-acylpyrazoles (Scheme 25A) [90]. The cross-coupling of these electronically-activated (RE ca. 10 under exceedinglykcal/mol, RE mild= resonance conditions, energy) plan achievingar amides is a attributed TON of to >1000the strong for σ-donation the ﬁrst of the time Pd- inNHC amide acyl Suzuki cross-coupling.

The acyl Suzuki cross-coupling of higher order aryl boron reagents with amides was reported by Zou (Scheme 25)[93]. With the use of N-3,5(CF3)2C6H3 activating group and Pd(PCy3)2Cl2/PCy3 catalyst system they were able to overcome the electronic and steric factors for the cross-coupling of amides with diarylborinic acids or tetra-arylborates to synthesize ketones (Scheme 25A). Later, they reported the use of Pd-PEPPSI-IPr for the cross-coupling of N-alkyl-amides with diarylborinic acids (Scheme 25B) [94]. The method is characterized by a broad substrate scope, affording ketones in good to excellent yields, while it also uses a commercially-available Pd-NHC. Zeng reported the acyl Suzuki cross-coupling of N-acylsuccinimides (Scheme 26A, see also Schemes 23D and 27)[79]. This reaction gave moderate to good yields in a short reaction time. More recently, they used structurally-related N-acyl-5,5-dimethylhydantoins in the acyl Suzuki cross-coupling with aryl boronic acids (Scheme 26B) [95]. The use of commercially-available, air- and moisture-stable (IPr)Pd(allyl)Cl precatalyst as well as good tolerance to several functional groups are important features of this protocol. Our group independently studied the structural features of the amide bond in N-acyl-hydantoins [96], demonstrating that replacement of the carbon atom in the Catalysts 2018, 8, x FOR PEER REVIEW 16 of 23 first example of using N,N-bis(methanesulfonyl)amides as acyl-transfer reagents in Suzuki cross- coupling (Scheme 29) [99]. In addition to using new class of substrates, this reaction works under mild conditions to provide a wide range of unsymmetrical ketones.

Scheme 26. Synthesis of Ketones from Amides using Diarylborinic Acids: (A) N-Ts/Ar Amides; (B) N-Ts/Alkyl Amides.

Catalysts 2019, 9, 53 17 of 23 Scheme 27. Synthesis of Biaryl Ketones from Amides: (A) Succinimides; (B) Hydantoins. succinimide ring with nitrogen to give hydantoin results in a substantial increase of the amide bond distortion (additive Winkler-Dunitz parameter of 70◦). In 2018, Liu developed the acyl Suzuki cross-coupling of N-acyl-succinimides with aryl boronic acids using benzothiazole-supported Pd-NHC PEPPSI-type precatalyst (Scheme 27)[97]. This Pd-NHC is easily prepared [98] and provides biaryl ketones in high yields. In 2018, Rhee developed the ﬁrst example of using N,N-bis(methanesulfonyl)amides as acyl-transfer reagents in Suzuki cross-coupling (Scheme 29)[99]. In addition to using new class of substrates, this reaction works under mild conditions to provideScheme a wide 28. Synthesis range of of unsymmetrical Biaryl Ketones from ketones. Amides using Benzothiazole-Supported Pd-NHCs.

Catalysts 2018, 8, x FOR PEER REVIEW 17 of 23

In 2018, three groups reported independently B-alkyl Suzuki cross-coupling of amides by selectiveScheme N–C(O) 29. acyl Synthesis cleavage of (SchemeKetones 30).from The Di Di-Sulfonyl -RuepingSulfonyl group Amides explored by Rhee the and alkyl co-workers.co ketone-workers. synthesis from anilides with the use of alkylboranes and a nickel catalyst (Scheme 30A) [100]. This process In 2018,allows three comparatively groups reported mild reaction independently conditions and B-alkyl support Suzukis various cross-coupling functional groups. of amides The by Zou selective N–C(O)group acyl reported cleavage the (Scheme use of Pd -30PEPPSI). The-IPrRueping in the cross group-coupling explored of N-tosylamides the alkyl with ketone trialkylboranes synthesis from anilidesor with alkyl the-9-BBN use reagents of alkylboranes (Scheme 30B) and [101 a nickel]. This highly catalyst efficient (Scheme acylative 30A) cross [100-coupling]. This processmethod allows gives also access to unsymmetrical di-alkyl ketones. Our group reported (IPr)Pd(cinnamyl)Cl- comparatively mild reaction conditions and supports various functional groups. The Zou group catalyzed cross-coupling of alkyl-9-BBN reagents with different types of amides, including even the reported the use of Pd-PEPPSI-IPr in the cross-coupling of N-tosylamides with trialkylboranes or more challenging Boc2-amides derived directly from common primary amides (Scheme 30C) [102]. alkyl-9-BBNThe efficiency reagents of (Scheme this process 30B) was [101 highlighted]. This highly in a sequential efﬁcient acylative C(sp2)–C(sp cross-coupling2)/C(acyl)–C(sp3) method cross- gives also accesscoupling to unsymmetrical of common amides di-alkyl. ketones. Our group reported (IPr)Pd(cinnamyl)Cl-catalyzed cross-couplingIn a ofcomplementary alkyl-9-BBN approach, reagents the with Garg differentgroup reported types Ni of-catalyzed amides, cross including-coupling even of α-C the- more aliphatic amides with arylboronic acid pinacol esters (Scheme 31) [103]. This methodology relies on challenging Boc2-amides derived directly from common primary amides (Scheme 30C) [102]. an electron-rich N-alkyl-NHC supporting ligand, and successfully addressed the difficulty of using The efﬁciency of this process was highlighted in a sequential C(sp2)–C(sp2)/C(acyl)–C(sp3) α-C-aliphatic amide derivatives. Furthermore, the method was highlighted in the synthesis of a cross-couplingbioactive ofspiroindolenine common amides. precursor.

SchemeScheme 30. B-Alkyl 30. B-Alkyl Suzuki-Miyaura Suzuki-Miyaura Cross-CouplingCross-Coupling of Amides: of Amides: (A) Anilides; (A) Anilides; (B) Tosylamides; (B) Tosylamides; (C) (C) N-BocN-Boc Amides, Amides, Glutarimides Glutarimides and and Saccharins. Saccharins.

Scheme 31. Synthesis of Ketones from Aliphatic Amides by Garg and co-workers.

Catalysts 2018, 8, x FOR PEER REVIEW 17 of 23

In 2018, three groups reported independently B-alkyl Suzuki cross-coupling of amides by selective N–C(O) acyl cleavage (Scheme 30). The Rueping group explored the alkyl ketone synthesis from anilides with the use of alkylboranes and a nickel catalyst (Scheme 30A) [100]. This process allows comparatively mild reaction conditions and supports various functional groups. The Zou group reported the use of Pd-PEPPSI-IPr in the cross-coupling of N-tosylamides with trialkylboranes or alkyl-9-BBN reagents (Scheme 30B) [101]. This highly efficient acylative cross-coupling method gives also access to unsymmetrical di-alkyl ketones. Our group reported (IPr)Pd(cinnamyl)Cl- catalyzed cross-coupling of alkyl-9-BBN reagents with different types of amides, including even the more challenging Boc2-amides derived directly from common primary amides (Scheme 30C) [102]. The efficiency of this process was highlighted in a sequential C(sp2)–C(sp2)/C(acyl)–C(sp3) cross- coupling of common amides. In a complementary approach, the Garg group reported Ni-catalyzed cross-coupling of α-C- aliphatic amides with arylboronic acid pinacol esters (Scheme 31) [103]. This methodology relies on an electron-rich N-alkyl-NHC supporting ligand, and successfully addressed the difficulty of using α-C-aliphatic amide derivatives. Furthermore, the method was highlighted in the synthesis of a bioactive spiroindolenine precursor.

Catalysts 2019, 9, 53 18 of 23

In a complementary approach, the Garg group reported Ni-catalyzed cross-coupling of α-C-aliphatic amides with arylboronic acid pinacol esters (Scheme 31)[103]. This methodology relies on an electron-rich N-alkyl-NHC supporting ligand, and successfully addressed the difﬁculty of usingSchemeα-C-aliphatic 30. B-Alkyl amide Suzuki derivatives.-Miyaura Furthermore,Cross-Coupling the of methodAmides: was(A) Anilides; highlighted (B) Tosylamides; in the synthesis (C) of a bioactiveN-Boc spiroindolenine Amides, Glutarimides precursor. and Saccharins.

Scheme 31. Synthesis of Ketones from Aliphatic AmidesAmides byby GargGarg andand co-workers.co-workers. Catalysts 2018, 8, x FOR PEER REVIEW 18 of 23 The groups of Molander and Pan developed the synthesis of ketones by acyl-type cross-couplingThe groups of amides of Molander (Scheme and 32Pan). developed The Molander the synthesis group developedof ketones by a acyl photoredox/Ni-catalyzed-type cross-coupling cross-coupling of amides (Scheme of N-acyl-succinimides 32). The Molander with group alkyl developed trifluoroborates a photoredox for/Ni the-catalyzed synthesis cross of aliphatic-coupling ketones of (SchemeN-acyl 32-A)succinimides [104]. This with reaction alkyl trifluoroborates provides mild for conditionsthe synthesis and of aliphatic tolerance ketones for a(Scheme widevariety 32A) of functional[104]. This groups reaction on both provides coupling mild conditions partners. and The tolerance Pan group for a demonstrated wide variety of thefunctional first example groups of a reductiveon both cross-coupling coupling partners of amides. The byPan acyl group cleavage demonstrated (Scheme the32B) first [105 example]. The reaction of a reductive is mechanistically cross- coupling of amides by acyl cleavage (Scheme 32B) [105]. The reaction is mechanistically significant significant because Ni-catalyst allowed for selective activation of the amide bond instead of the C–I because Ni-catalyst allowed for selective activation of the amide bond instead of the C–I bond, bond,preventing preventing self self-coupling-coupling under under reductive reductive conditions conditions.. Additional Additional methods for methods the synthesis for the of ketones synthesis of ketonesby cross by cross-coupling-coupling of amides of amides have been have reported been reported [106,107] [.106 ,107].

SchemeScheme 32. Synthesis 32. Synthesis of Ketones of Ketones from from Amides: Amides: ((AA)) Ir/Ni-Cooperative Ir/Ni-Cooperative Catalysis Catalysis;; (B) (NiB)-Catalyzed Ni-Catalyzed ReductiveReductive Coupling. Coupling.

7. Conclusions7. Conclusions In summary,In summary, signiﬁcant significant advances advances have have recently recently taken taken place place in the infield the of acylative ﬁeld of acylativeSuzuki cross Suzuki- cross-coupling.coupling. This This is highlighted is highlighted by a by rapid a rapid discovery discovery of new of acyl new electrophiles, acyl electrophiles, catalyst catalystsystems and systems and cross-couplingcross-coupling partners. partners. In In a a broad broaderer perspective, perspective, the the acyl acyl Suzuki Suzuki cross cross-coupling-coupling allows allows for the for the synthesis of ketones as a catalytic alternative to stoichiometric nucleophilic additions and Friedel- synthesis of ketones as a catalytic alternative to stoichiometric nucleophilic additions and Friedel-Crafts Crafts reactions, but also to using less available or toxic organometallic reagents such as organozincs reactions, but also to using less available or toxic organometallic reagents such as organozincs or organostannanes. The major advance has undoubtedly been the development of previously or organostannanes.considered as unreactive The majorcommon advance ester and has amide undoubtedly electrophiles been in the the cross development-coupling. This of allows previously consideredfor utilization as unreactive of bench common-stable carboxylic ester and acid amide electrophiles electrophiles that are in prevalent the cross-coupling. in organic synthesis. This allows for utilizationThe ubiquity of of bench-stable the amide bond carboxylic in natural acid products, electrophiles pharmaceuticals that are and prevalent biomolecules in organic provides synthesis. a The ubiquitystrong motivation of the amide for the bond further in development natural products, of acyl pharmaceuticalscross-couplings of andcarboxylic biomolecules acid derivatives provides a strongof motivationmajor practical for importance. the further development of acyl cross-couplings of carboxylic acid derivatives of major practicalDespite importance. progress being considerable, numerous challenges remain. Future research will need to address the development of more reactive catalyst systems, expansion of the substrate scope, development of new sustainable protocols and application to the synthesis of natural products and pharmaceuticals. Future mechanistic studies together with a better understanding of the underlying elementary steps could potentially lead to the general acyl Suzuki platform that is routinely considered for the construction of key structural motifs.

Author Contributions: The manuscript was written through the contributions of all authors.

Funding: Rutgers University and the NSF (CAREER CHE-1650766) are gratefully acknowledged for support.

Conflicts of Interest: The authors declare no conflict of interest.

Catalysts 2019, 9, 53 19 of 23

Despite progress being considerable, numerous challenges remain. Future research will need to address the development of more reactive catalyst systems, expansion of the substrate scope, development of new sustainable protocols and application to the synthesis of natural products and pharmaceuticals. Future mechanistic studies together with a better understanding of the underlying elementary steps could potentially lead to the general acyl Suzuki platform that is routinely considered for the construction of key structural motifs.

Author Contributions: The manuscript was written through the contributions of all authors. Funding: Rutgers University and the NSF (CAREER CHE-1650766) are gratefully acknowledged for support. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

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