Transition-Metal-Catalyzed Alkyl Heck-Type Reactions

988Syn thesisReviewD. Kurandina et al.The first intramolecular Heck reaction of benzyl halideswas developed by Negishi to access five- to seven-membered cyclic compounds (Scheme 4).20 The initial screeningof the leaving group on the o-allylbenzyl electrophile 27 revealed that Cl, Br, and OMs were acceptable leaving groups,leading almost exclusively to the formation of 2-methyleneindane (28). In the cases of I and OCO2Me leaving groups,the cyclization occurred quite efficiently but with low regioselectivity, as the formation of regioisomer 29 was detected in significant amounts.Negishi, 1989XH 5 mol% Pd(PPh3)4Et3N, MeCNreflux27Bu3SnHAIBN, PhHrefluxX Br, I29time, h yield 28 (%)1820.5820.5641605 days262 days 1XClBrIOMsOCO2MeOAcXSnBu3Me28yield 29 (%) 1 118 123 1disclosed a straightforward synthesis of isochromene derivatives 37 via the intramolecular Heck reaction of benzyl halides and vinylogous carbonates (Scheme 4).1b2.2 α-Carbonyl Alkyl HalidesIn the 1980s, Ban and Mori performed the initial studyon the Pd(PPh3)4-catalyzed intramolecular alkylation of olefins using α-carbonyl alkyl halides 38.23 The reaction proceeded with low selectivity, delivering mixtures of atomtransfer radical cyclization (ATRC) and Heck products (39and 40, respectively) in moderate yields (Scheme 5). In2003, Glorius reported an intermolecular Heck reaction of2-chloroacetamides 41 with 2,3-dihydrofuran (24a), butylvinyl ether (43) and styrenes 45 (Scheme 5, eq 1).24 Alkylation of 24a and 43 led to the exclusive formation of α-alkylated olefins 42 and 44, respectively, thus supporting thereaction mechanism involving palladium enolates ratherthan alkyl radical intermediates. Conversely, the reaction of30Scope, representative examples:Ban & Mori, 1982 & 1985I31RR H, 65%R Me, 72%Chen, 2008CO2EtCO2Et323364%R1OHR1OON38n 1 or 2ONnN4039nn48–75%Gharpure, 2014N-R235 N36–91%CO2Et0%0%Pan, 2011R2CO2Et34IPd(PPh3)43643–95%Glorius, 2003R1OO24aCO2R4OR237365–88% RR'65-75%42OScheme 4 Intramolecular Pd-catalyzed Heck reactions of benzyl halides(1)Lastly, o-allylbenzyl acetate was practically unreactive.Interestingly, attempts to induce this cyclization under typical radical conditions led to the hydrostannation product30 only, thus illustrating the superiority of the Heck reaction pathway for this type of cyclization. The developed intramolecular Heck reaction was also able to deliver six- andseven-membered cyclic compounds 31 and 32 from thecorresponding benzyl chlorides in good yields and regioselectivity. However, attempts to obtain four- and eightmembered rings using this strategy (33 and 34, respectively) were unsuccessful (Scheme 4).In 2008, Chen applied an intramolecular Heck-type approach for the synthesis of 3-alkyl-1H-quinolin-2-ones 35via cyclization of benzyl halides with α,β-unsaturated amides.21 In 2011, Pan introduced another regioselective intramolecular Heck-type coupling for the assembly of a biologically important core compounds, i.e., 4-aryldihydropyrroles36.22 In this case, cyclization favored products with an endocyclic double bond, so that most of these dihydropyrroleswere obtained as single regioisomers. In 2014, GharpureONRRClNR' 41R Et, Hex, t-BuR' H, EtO5 mol%Pd(PPh3)2Cl2OBu(i-Pr)2NEtMeCN, 110 C43RMeOBu44H44a, R n-Hex, 53%44b, R t-Bu, 63%NOAr45(2)NCBr4724a5 mol% Pd(PPh3)2Cl2(i-Pr)2NEtMeCN, 110 Cn-HexArN46H46a, Ar Ph, 39%46b, Ar p-MeOC6H4, 35%NC48O30%Gevorgyan, 2018R2R1R3EtO2C49(i-Pr)2NEtbenzene, rt10Scope, representative examples:R1EtO2CR110 mol% Pd Xantphos G3BrArEtO2CR2EtO2C50R3ONEtO2C50a, R1 Me, Ar Ph, 92%50c, 47%50b, R1 CO2Et, Ar 4-MeOC6H4, 54%EtO2CEtO2C50d, 51%Scheme 5 Pd-catalyzed Heck reactions of α-carbonyl alkyl halidesGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

989Syn thesisbromoacetonitrile (47) with 24a produced β-alkylated 2,3dihydrofuran 48 in 30% yield as a single product (Scheme 5,eq 2). This reaction was suggested to proceed via a radicalpathway.More recently, Gevorgyan showed that activated tertiaryalkyl bromides possessing an α-carbonyl moiety 49 can efficiently react with styrenes and electron-rich alkenes atroom temperature (Scheme 5).25 Catalyzed by a Pd Xantphos G3 complex, the reaction furnished the Heck products50a–d in moderate to high yields. A radical clock experiment suggested that the catalytic cycle might involve analkyl Pd-radical hybrid species.2.3ReviewD. Kurandina et al.Chen, 1988R2I1 mol% Pd(PPh3)4IRfR351In 1988, Chen reported the first Pd-catalyzed additionof perfluorinated alkyl iodides 51 to alkenes 52 leading toalkyl iodides 53, i.e., the atom transfer radical addition(ATRA) products (Scheme 6).26 The radical nature of thistransformation was strongly supported by the mechanisticstudies, which led the authors to propose the involvementof a Pd(0) complex in a radical initiation event. In 2012, Reutrakul developed the Pd(PPh3)4-catalyzed Heck reaction of(bromodifluoromethyl)sulfones 54 with alkenes (Scheme6).27 The reaction proceeded smoothly in toluene at 100 Cdelivering the coupling products 55a–f in moderate yields.Later, Zhang reported the first Heck reaction of perfluorinated alkyl halides with vinyl arenes/heteroarenes (57a–g),diene (57h), and electron-rich olefins (57i,j) (Scheme 6).28The reaction features a quite general scope leading to valuable fluoroalkylated alkenes in good to excellent yields.Moreover, this method was shown to be effective for thesynthesis of complex molecules possessing fluorinatedfragments (57k,l). In follow-up work, the same groupdemonstrated that a similar catalytic system involving aPd(II)-precatalyst and Xantphos as the ligand enabled aHeck-type coupling of secondary trifluoromethylated alkylbromides (Scheme 6, products 59a–c).29 The performedmechanistic studies supported a hybrid Pd-radical mechanism and ruled out the possible involvement of the corresponding ATRA products (bromide-containing analogues of53) for both reactions.28,292.4 α-Functionalized Alkyl HalidesIn 2014, Gevorgyan reported the Pd-catalyzed endo-selective Heck-type reaction of iodomethylsilyl ethers 61 employing ferrocene-derived bidentate phosphine ligand 64(Scheme 7).30 The reaction was able to deliver seven-, eight-,and nine-membered siloxycycles 62a–i in good yields,which could further be converted into the correspondingallylic alcohols (see 63g,i as examples) via oxidation. Formally, this transformation provides a tool for the selective(Z)-hydroxymethylation of phenols and alkenols 60. TheR2R3R1 5334–97%52R1Reutrakul, 2012R1R2PhO2SF10 mol% Pd(PPh3)4Br54R3FR1 52R2PhO2SK2CO3PhCH3, 100 CFF R355Scope, representative examples:PhO2SPhO2SArFOFFFFRfR3SPhFF55f, 69% (E/Z 1.7:1)AlkylRfBr(I), 56Br585 mol%Pd(PPh3)2Cl2F3CR25 mol% Pd(PPh3)2Cl2 or10 mol% Pd(MeCN)2Cl210–20 mol% Xantphos R1 52M2CO3 or KOAc1,4-dioxane or DCE, 80 CR1 57PhPhO2S55d, 41%Zhang, 2015 & 2017R2PhF55e, 45%PhO2S5555a, Ar Ph, 41%55b, Ar 4-ClC6H4, 60%55c, Ar 4-MeC6H4, 52%Fluoroalkyl HalidesRfAlkyl R2R3F3CR37.5 mol% XantphosKOAC, DCE, 80 CR1 59OScope, representative examples:F3C(F2C)4F2CNF3CF3C(F2C)4F2C57i, 81%57a, R H, 89%57b, R t-Bu, 87%57c, R t-BuO, 94%57d, R CO2Me, 55%57e, R CHO, 80%57h, 47%ROMeF3C(F2C)4F2CNF3C(F2C)4F2CN57j, 57%EtO2CF2C57f, 40% SO57g, 69%CO2MeFFO57l, 49% HHHNHO57k, 75%F3COMeCF3OCF3NHO59b, 61%CF359a, 85%CNPhPh59c, 71%Scheme 6 Pd-catalyzed Heck reactions of fluoroalkyl halidesmechanistic studies suggested a hybrid Pd-radical mechanism for this Heck reaction. Also, the silicon atom wasfound to be crucial for the observed endo selectivity.In 2017, Gevorgyan’s group developed the first visiblelight-induced Pd-catalyzed Heck reaction of alkyl halides atambient temperature under exogenous photosensitizerfree conditions to furnish valuable allylic systems of diverseelectronic nature (Scheme 7).31 Allylic silanes (66a,b,k–o),boronates (66c,j), germane (66d), stannane (66e), pivalate(66f), phosphonates (66g,p), phthalimide (66h), and tosylate (66i) derivatives were easily synthesized from primary and secondary α-functionalized alkyl halides and vinylGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

990Syn thesisReviewD. Kurandina et al.Gevorgyan, hMe, 75 C6160O SiI10 mol% Pd(OAc)220 mol% LP(t-Bu)2L, 646263Scope, representative examples:i-Pri-Pri-Pr62a, R H, 79%62b, R 3-MeO, 87%62c, R 3-F, 74%62d, R 4-O2N, 33%62e, R 2-MeO, 90%SiO7OOHi-Pri-Pri-PrO SiSiOH[O]8787%62g, 60%62f, 75%R63gMeMei-Pri-PrHSiO9HHHHOPh7i-Pr62h, 44%Si Oi-PrH[O]H80%HO63i62i, 82%Gevorgyan, 2017 & 2018R1R3GI(Br) R26510 mol% Pd(OAc)220 mol% Xantphos10 mol%Pd Xantphos G3orR1R3R2GCs2CO3 or (i-Pr)2NEtPhH, Blue LED, rt10Scope, representative examples:66OMeBpinG66a, G TMS, 88%, 55% (from AlkBr)66b, G Si(OEt)3, 65%66c, G Bpin, 70%TMS66d, G GeMe3, 68%66e, G SnBu3, 71%TMS66f, G OPiv, 76%66k, 90%66g, G P(O)(OEt) , 58%Me2PhSiPh66j, 90%DMETiCl455%BpinMe67 Ph(no light)66q, G Ts, 85% (from AlkBr)66r, G Bpin, 99%66s, G P(O)(OEt)2, 85%G266h, G NPhthl, 72%66i, G Ts, 61%TMSR66l, R OMe, 82%66m, R CN, 80%66n, R Br, 59%66o, R F, 73%(EtO)2(O)PN66p, 77%OMeScheme 7 Pd-catalyzed Heck reactions of α-functionalized alkyl halidesarenes/heteroarenes. The obtained allylic systems can befurther modified, for example, via a Hosomi–Sakurai reaction (66j 67). Later, the same group applied these photoinduced conditions for the Heck reactions of α-heteroatomsubstituted tertiary alkyl iodides with styrene (Scheme 7,products 66q–s).25Notably, in this case, presumably due to the insufficiently low reduction potentials of the activated tertiarysubstrates, activation by light was not necessary to obtainthe Heck reaction products. The performed radical clockand radical trapping experiments described in these reports25,31 support a radical-type mechanism. It was alsoshown that Pd(0)Ln complexes were the single light-absorbing species in this reaction. The excited state is quenched byan alkyl halide, presumably via a SET event, which was calculated to be ‘barrierless’,12c to form the alkyl Pd hybrid species 68 that adds to an alkene producing the new radicalspecies 69 (Scheme 8). Subsequent β-H elimination fromthe latter delivers the product 66, while the base regenerates the Pd(0) catalyst.LnPd(0)hvLnPd0B X69Scheme 8 Gevorgyan’s mechanism for the visible-light-induced Pdcatalyzed Heck reactionGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

991Syn thesis2.5ReviewD. Kurandina et al.Unactivated Alkyl Electrophileshigh yields and regioselectivities from the correspondingunsaturated alkyl bromides and even chlorides 73 at elevated temperatures. The stereochemical outcome of this transformation supports the SN2 mechanism for the oxidativeaddition step, thus eliminating involvement of radical intermediates in this reaction.The first Heck reaction of unactivated alkyl halides withalkenes was reported by Waegell and de Meijere in 1998(Scheme 9).32a In this report, 1-bromoadamantane (70), asubstrate which is not disposed to β-hydrogen elimination,was employed. Upon this Pd/C-catalyzed reaction at 120 C,a number of substituted olefins 72 were obtained in low tomoderate yields. In 2007, Fu introduced the first protocolfor the Heck reaction of unactivated alkyl bromides andchlorides containing eliminable β-hydrogens (Scheme10).32b The employment of the bulky NHC-ligand 75 on thePd catalyst was the key for the success of this transformation, allowing an intramolecular insertion of the alkyl-Pdspecies into a double bond to proceed faster than the premature β-hydrogen elimination. Cyclopentane derivativespossessing an exo-alkene moiety 74a–g were obtained inWaegell & de Meijere, 1998Br10 mol% Pd/CArRK2CO3DMF, 120 C7071Scheme 9 Waegell and de Meijere’s first Pd-catalyzed Heck reaction ofunactivated alkyl halidesIn 2011, Alexanian developed a protocol for an intramolecular alkyl-Heck reaction, which relied on radical reactivity (Scheme 10).33 Following his previous work on the car-Fu, 20075 mol% Pd2(MeO-dba)320 mol% SIMes·HBF420 mol% KOt-BuXCs2CO3 or K3PO4RRX Br, Cl73MesN MesNBF4–75 HSIMes·BF4–74Scope, representative examples:AlkBr (MeCN, 65 C)a or AlkBr (NMP, 110 C)bEtO2CEtO2C74a, Ar 2-naphthyl, 73%a74b, Ar 4-MeOC6H4, 78%a, 72%b74c, Ar 4-F3CC6H4, 79%a74d, Ar 2-benzofuranyl, 83%bArn-Oct74f, 75%a, 71%b74e, 85%a, 80%b74g, 81%aAlexanian, 2011 & 2017first generationannRRsecond generationbn10 mol% Pd(PPh3)4R10 atm COO(i-Pr)2NEtPhMe, 130 CX I7879, not observedX 5 mol% Pd(allyl)Cl220 mol% dtbpfnREt3NPhCF3, 100 CX Br76, X I77, X Br78Scope, representative examples:4-MeOC6H4OOBuHEtO2CMeTsNHEtO2COHOHMe78a, 80%a, 90%b78b, 73% (d.r. 83:17),a73% (d.r. 89:11)b78c, 70%,a82%b78d, 66% (d.r. 95:5),a93% (d.r. 95:5)b78e, 74%,a77%bR1Liu, gcyclizationTsN10 mol% Pd(dppf)Cl2Cy2NMePhMe, 110 CArR72, 15–41%R2Ar83R1R1R2Ar81R1 H, Ph, i-Pr, i-Bu, or MeR2 H or MeAr Ph, 3-MeOC6H4, 4-NCC6H4, 4-FC6H4, 4-ClC6H4, etc.R2TsNAr 8251–89%Scheme 10 Pd-catalyzed intramolecular Heck reactions of unactivated alkyl halides; d.r. diastereomeric ratioGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

992Syn thesisReviewD. Kurandina et al.bonylative Heck-type reaction,34 he showed that under increased CO pressure, Pd(PPh3)4 was capable of catalyzingthe 5- or 6-exo-trig cyclization reaction of alkenyl iodides76, leading to the exclusive formation of Heck reactionproducts 78a–e rather than the corresponding cycloalkenones 79. Interestingly, in the absence of CO, the reaction proceeded as well, albeit with lower efficiency andregioselectivity. In contrast to Fu’s work,32b mechanisticstudies, including a radical trapping experiment, indicatedthe formation of radical species under these conditions. Accordingly, a hybrid Pd-radical mechanism was postulated.In 2017, the same group introduced a second-generationPd-based catalytic system for an intramolecular Heck-typereaction, thus enabling efficient carbocyclization of unsaturated alkyl bromides 77 under CO-free conditions (Scheme10).35 Moreover, in this work, the authors investigated thedifference in the reactivity of alkyl iodides versus alkyl bromides in this cyclization. It was hypothesized that, in thecase of alkyl bromides, the cyclization proceeds via autotandem catalysis (Scheme 11). Initiated by the Pd(0) complex, ATRC leads to the formation of alkyl bromide 86,which could be isolated from the reaction mixture. Subsequently, the Pd(0)-catalyzed dehydrohalogenation of 86 delivers the Heck reaction product. Alternatively, for alkyl iodides, the radical chain mechanism initiated by the Pd(0)catalyst was suggested as a more likely scenario.In 2016, Liu reported a related Pd-catalyzed radicalHeck-type cyclization utilizing alkyl iodides 80 possessing a1-aryl-substituted alkene moiety (Scheme 10).36 The use ofthese specific substrates resulted in the exceptional endoselective cyclization. This outcome is attributed to a muchhigher stability of the forming tertiary benzyl radical intermediate 81 versus a non-stabilized primary radical species83, which would arise via an alternative 5-exo-trig cyclization. Thus, a number of 5-aryl-1,2,3,6-tetrahydropyridines82, which are structural motifs found in a variety of naturalproducts and pharmaceutical compounds, were synthesized using this approach.In 2014, Alexanian developed an intermolecular versionof alkyl Heck reaction of unactivated alkyl iodides (Scheme12).37 By employing Pd(dppf)Cl2 as a catalyst, both primaryand secondary alkyl iodides 88 reacted smoothly with styrene and acrylonitrile derivatives producing alkylated olefins 91a–k in moderate to excellent yields. Shortly after,Zhou applied a combination of a Pd(0) precatalyst and dppfas a ligand, which allowed intermolecular Heck reactions ofstyrenes to proceed with alkyl iodides 88, bromides 89 andeven chlorides 90 (Scheme 12).38 The use of LiI as an additive in the reaction was crucial for achieving higher yieldswith halides 89 and 90, presumably due to in situ generation of more reactive iodide species. As a result, the corresponding Heck reaction products 91a,h–k were obtained inyields comparable to those reported by Alexanian employing alkyl iodides. Similar to the previously described Heck-B ticatom transferL Pd(0)dehydrohalogenation nradical BrScheme 11 Alexanian’s mechanism for the Pd-catalyzed carbocyclization of unactivated alkyl bromides via auto-tandem catalysistype cyclization reactions, the mechanistic studies in bothreports were consistent with a hybrid Pd-radical pathway,thus further illustrating the prominence of this pathway forovercoming premature β-hydrogen elimination in alkylHeck reactions.Until recently, all the reported methods for the Heck reaction of unactivated alkyl halides required elevated temperatures. In 2017, Gevorgyan’s group demonstrated thepossibility of achieving a room temperature Heck reactionof unactivated primary and secondary alkyl halides undervisible-light-induced exogeneous photosensitizer-free conditions employing a Pd(0)/Xantphos catalytic system(Scheme 12, products 92a–c).31 Shortly after, the groups ofShang and Fu independently developed a similar methodfor the reactions of primary and secondary unactivated alkyl bromides with styrenes to provide the Heck reactionproducts 92d–h in excellent yields and E/Z ratios.39Moreover, challenging tertiary alkyl bromides were alsofound to be capable coupling partners (products 92i–n). Inaddition to styrenes, unactivated tertiary alkyl bromides reacted with electron-deficient alkenes in a highly efficientmanner (products 92o,p). The mechanistic studies of thiswork strongly supported a radical pathway, which was initiated by a SET event from the photoexcited Pd(0) complexto an alkyl halide (see Scheme 8). Furthermore, the performed X-ray photoelectron spectroscopy studies detectedpalladium in three oxidation states: Pd(0), Pd(I), and Pd(II),thus demonstrating that the Pd(0)–Pd(I)–Pd(II) catalytic cycle is a highly feasible scenario for these visible-light-induced conditions. Shortly after, Gevorgyan independentlyreported analogous efficient alkyl Heck reactions of unactivated tertiary alkyl iodides with styrenes and acrylonitrile(Scheme 12, products 92q–v).25Very recently, Gevorgyan’s group reported a photoinduced, Pd-catalyzed radical relay Heck reaction at remoteunactivated C(sp3)–H sites of aliphatic alcohols, which synergistically combines a C–H activation via a hydrogen atomGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

993Syn thesisReviewD. Kurandina et al.abstraction (HAT) process and an alkyl Heck reaction(Scheme 13).40 The control of the β-, γ-, or δ-sites in this regioselectiv

mediated and transition-metal-catalyzed approaches. This review sum-marizes the advances in alkyl Heck-type reactions from its discovery early in the 1970s up until the end of 2018. 1 Introduction 2 Pd-Catalyzed Heck-Type Reactions 2.1 Benzylic Electrophiles 2.2 α-Carbonyl Alkyl Halides 2.3 Fluoroalkyl Halides 2.4 α-Functionalized Alkyl Halides