Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
‡ These authors contributed equally.
Key words
Heck reaction - cross-coupling - alkyl halides - alkenes - transition-metal catalysis
1
Introduction
The Mizoroki–Heck reaction[1] is one of the most powerful approaches towards multisubstituted alkenes. This reaction
represents the first example of Pd-catalyzed C–C bond-forming reactions,[2] which follow a classical Pd(0)/Pd(II) catalytic cycle enabling coupling of aryl
and vinyl electrophiles with olefins.
The Heck reaction has been exhaustively employed in organic synthesis, drug discovery,
electronics, and in industry,[3] which has led to its recognition with a Nobel Prize in 2010. Current research in
this area is directed towards the use of decreased loadings of palladium,[4] the employment of low-cost transition metals,[5] and the development of asymmetric protocols.[6] Historically, aryl halides/pseudohalides were the electrophiles of choice for all
cross-coupling reactions, thus, not surprisingly, they were also extensively used
in Heck reactions. Throughout years, this research has been summarized in many excellent
reviews.[7] In contrast, alkyl electrophiles were found to be more challenging coupling partners,
mostly due to the competing β-H elimination process[2] and the slower rates of the oxidative addition step.[8] Nonetheless, under more recently developed conditions, alkyl halides[9] were shown to be suitable partners for this transformation. However, the number
of reports on alkyl Heck reactions remains scarce compared to those employing aryl
substrates.
In general, alkyl Heck reactions feature the same mechanism as the classical Heck
reaction between aryl halides and alkenes, involving: (1) oxidative addition, (2)
migratory insertion, (3) β-hydrogen elimination, and (4) catalyst regeneration steps
(Scheme [1]). However, in contrast to the aryl Heck reaction, its alkyl version is often presumed
to involve radical intermediates, thus operating via a hybrid organometallic–radical
scenario. Mechanistic studies, such as radical trapping,[10] radical clock experiments,[11] as well as ESR studies, have proved the presence of radical species in some alkyl
Heck reactions. The mechanisms of their formation, which may depend on the nature
of the alkyl component, the leaving group, and the metal catalyst, are still not completely
understood. It was shown that employment of visible light allows alkyl Heck reactions
to be accomplished under milder conditions; over recent years this area of research
has grown significantly. Various complexes of Co, Ir/Ru, Au, Pd, and other transition
metals were found to catalyze this reaction under visible-light irradiation, with
significantly expanded scope. This review highlights the advances in the field of
alkyl Heck-type reactions of alkyl electrophiles with alkenes since its discovery
in the early seventies.[1d] It is organized by the type of electrophile used, such as benzylic, activated (possessing
a carbonyl or equivalents at the β-position), perfluorinated, and unactivated alkyl
electrophiles. Related transformations, such as Heck-type reactions involving a β-X
elimination step and cascade transformations commencing with radical addition to an
alkene moiety are not discussed herein.[12]
Scheme 1 Mechanism of transition-metal-catalyzed alkyl Heck-type reactions
Pd-Catalyzed Heck-Type Reactions
2
Pd-Catalyzed Heck-Type Reactions
2.1
Benzylic Electrophiles
The first example of the coupling of an alkyl halide with an olefin was reported by
Heck in his original seminal work in 1972 (Scheme [2]).[1d] Benzyl chloride (1) reacted with methyl acrylate (2) in the presence of 1 mol% of Pd(OAc)2 and Bu3N as the base to deliver a regiomeric mixture of alkenes 3. In 1995, Zhuangyu and co-workers developed a base-free alkyl Heck reaction of benzyltris(n-butyl)ammonium bromide salts 4 toward exclusive formation of the conjugated products 6 (Scheme [2]).[13] Both electron-rich and electron-deficient alkenes 5 were efficiently benzylated under these conditions. Based on ESR studies, the authors
suggested the involvement of benzyl radicals, which would form via the reductive cleavage
of the benzyl quaternary ammonium salt in the presence of the palladium(0) species.
Later, the coupling of benzyl chlorides with olefins was elegantly utilized by Kita
to obtain the key intermediate 8 in the synthesis of beraprost, a vasodilator and antiplatelet agent (Scheme [2]).[14] In this work, the Heck reaction followed by hydrogenation was shown to be superior
over other methods tested for installation of an alkyl chain at the benzylic position
of compound 7.
Scheme 2 Pd-catalyzed Heck reactions of benzyl halides; r.r. = regiomeric ratio
In 2000, Pan and co-workers observed an interesting Pd-catalyzed rearrangement in
the vinylation reaction of α-chloromethylnaphthalene (9) (Scheme [2]).[15] In reactions with N-vinylimides, besides the expected Heck products 11, a product with an olefin attached at the peri position of the naphthalene ring was detected. This unusual rearrangement product
12 was proposed to form via the cyclopalladation intermediate 14, when the nitrogen-containing alkene served as a stabilizing ligand for benzylpalladium
species 13. Later, Pan described the Pd-catalyzed cascade reaction of benzyl halides with N-allyl-N-(2-butenyl)-p-toluenesulfonamide (17) to furnish dihydropyrroles 18 with excellent regioselectivity (Scheme [2]).[16]
In addition to benzyl halides, benzyl trifluoroacetates were also found to be compatible
coupling partners for the Heck reaction. In 1999, Yamamoto reported that mixing benzyl
trifluoroacetate with phosphine-coordinated Pd(0) led to the formation of an oxidative
addition complex.[17] In 2004, Shimizu showed that the reaction of this complex with ethyl acrylate under
heating produced the corresponding Heck reaction product.[18] Based on these initial discoveries, the catalytic benzylation of olefins with benzyl
trifluoroacetates 19 was developed (Scheme [3]).[18] Moreover, the authors were able to achieve the benzylation of p-methylstyrene (22) with p-methoxybenzyl alcohol (21) using trifluoroacetic anhydride as an additive. Later, Zhou introduced an asymmetric
Heck reaction of benzyl trifluoroacetates 19 with five-membered cyclic olefins 24.[19] In the presence of Pd/phosphoramidite ligand 26, 2,3-, and 2,5-dihydrofurans, N-Boc-2,3-pyrroline, and cyclopentene (24a–c) were smoothly alkylated with electronically diverse benzyl trifluoroacetates leading
to the corresponding products 25a–f in high yields, and with high degrees of regioselectivity and enantioselectivity
(Scheme [3]).
Scheme 3 Pd-catalyzed Heck reactions of benzyl fluoroacetates; r.r. = regiomeric ratio
The first intramolecular Heck reaction of benzyl halides was developed by Negishi
to access five- to seven-membered cyclic compounds (Scheme [4]).[20] The initial screening of 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.
Scheme 4 Intramolecular Pd-catalyzed Heck reactions of benzyl halides
Lastly, o-allylbenzyl acetate was practically unreactive. Interestingly, attempts to induce
this cyclization under typical radical conditions led to the hydrostannation product
30 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- and seven-membered cyclic compounds 31 and 32 from the corresponding benzyl chlorides in good yields and regioselectivity. However,
attempts to obtain four- and eight-membered 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 35 via 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-aryldihydropyrroles
36.[22] In this case, cyclization favored products with an endocyclic double bond, so that
most of these dihydropyrroles were obtained as single regioisomers. In 2014, Gharpure
disclosed a straightforward synthesis of isochromene derivatives 37 via the intramolecular Heck reaction of benzyl halides and vinylogous carbonates
(Scheme [4]).[1b]
2.2
α-Carbonyl Alkyl Halides
Scheme 5 Pd-catalyzed Heck reactions of α-carbonyl alkyl halides
In the 1980s, Ban and Mori performed the initial study on 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 atom transfer
radical cyclization (ATRC) and Heck products (39 and 40, respectively) in moderate yields (Scheme [5]). In 2003, Glorius reported an intermolecular Heck reaction of 2-chloroacetamides
41 with 2,3-dihydrofuran (24a), butyl vinyl 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 the reaction mechanism involving palladium enolates
rather than alkyl radical intermediates. Conversely, the reaction of bromoacetonitrile
(47) with 24a produced β-alkylated 2,3-dihydrofuran 48 in 30% yield as a single product (Scheme [5], eq 2). This reaction was suggested to proceed via a radical pathway.
More recently, Gevorgyan showed that activated tertiary alkyl bromides possessing
an α-carbonyl moiety 49 can efficiently react with styrenes and electron-rich alkenes at room temperature
(Scheme [5]).[25] Catalyzed by a Pd Xantphos G3 complex, the reaction furnished the Heck products
50a–d in moderate to high yields. A radical clock experiment suggested that the catalytic
cycle might involve an alkyl Pd-radical hybrid species.
2.3
Fluoroalkyl Halides
In 1988, Chen reported the first Pd-catalyzed addition of perfluorinated alkyl iodides
51 to alkenes 52 leading to alkyl iodides 53, i.e., the atom transfer radical addition (ATRA) products (Scheme [6]).[26] The radical nature of this transformation was strongly supported by the mechanistic
studies, which led the authors to propose the involvement of 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 (Scheme [6]).[27] The reaction proceeded smoothly in toluene at 100 °C delivering 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]).[28] The 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 the synthesis of complex molecules possessing fluorinated fragments (57k,l). In follow-up work, the same group demonstrated that a similar catalytic system
involving a Pd(II)-precatalyst and Xantphos as the ligand enabled a Heck-type coupling
of secondary trifluoromethylated alkyl bromides (Scheme [6], products 59a–c).[29] The performed mechanistic studies supported a hybrid Pd-radical mechanism and ruled
out the possible involvement of the corresponding ATRA products (bromide-containing
analogues of 53) for both reactions.[28]
[29]
Scheme 6 Pd-catalyzed Heck reactions of fluoroalkyl halides
2.4
α-Functionalized Alkyl Halides
In 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 corresponding allylic alcohols
(see 63g,i as examples) via oxidation. Formally, this transformation provides a tool for the
selective (Z)-hydroxymethylation of phenols and alkenols 60. The mechanistic studies suggested a hybrid Pd-radical mechanism for this Heck reaction.
Also, the silicon atom was found to be crucial for the observed endo selectivity.
Scheme 7 Pd-catalyzed Heck reactions of α-functionalized alkyl halides
In 2017, Gevorgyan’s group developed the first visible-light-induced Pd-catalyzed
Heck reaction of alkyl halides at ambient temperature under exogenous photosensitizer-free
conditions to furnish valuable allylic systems of diverse electronic 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 vinyl arenes/heteroarenes. The obtained allylic systems can be further
modified, for example, via a Hosomi–Sakurai reaction (66j → 67). Later, the same group applied these photoinduced conditions for the Heck reactions
of α-heteroatom-substituted tertiary alkyl iodides with styrene (Scheme [7], products 66q–s).[25]
Notably, in this case, presumably due to the insufficiently low reduction potentials
of the activated tertiary substrates, activation by light was not necessary to obtain
the Heck reaction products. The performed radical clock and radical trapping experiments
described in these reports[25]
[31] support a radical-type mechanism. It was also shown that Pd(0)Ln complexes were the single light-absorbing species in this reaction. The excited state
is quenched by an 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 radical species 69 (Scheme [8]). Subsequent β-H elimination from the latter delivers the product 66, while the base regenerates the Pd(0) catalyst.
Scheme 8 Gevorgyan’s mechanism for the visible-light-induced Pd-catalyzed Heck reaction
2.5
Unactivated Alkyl Electrophiles
The first Heck reaction of unactivated alkyl halides with alkenes was reported by
Waegell and de Meijere in 1998 (Scheme [9]).[32a] In this report, 1-bromoadamantane (70), a substrate 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 to moderate yields. In 2007, Fu introduced the first protocol
for the Heck reaction of unactivated alkyl bromides and chlorides containing eliminable
β-hydrogens (Scheme [10]).[32b] The employment of the bulky NHC-ligand 75 on the Pd catalyst was the key for the success of this transformation, allowing an
intramolecular insertion of the alkyl-Pd species into a double bond to proceed faster
than the premature β-hydrogen elimination. Cyclopentane derivatives possessing an
exo-alkene moiety 74a–g were obtained in high yields and regioselectivities from the corresponding unsaturated
alkyl bromides and even chlorides 73 at elevated temperatures. The stereochemical outcome of this transformation supports
the SN2 mechanism for the oxidative addition step, thus eliminating involvement of radical
intermediates in this reaction.
Scheme 9 Waegell and de Meijere’s first Pd-catalyzed Heck reaction of unactivated alkyl halides
Scheme 10 Pd-catalyzed intramolecular Heck reactions of unactivated alkyl halides; d.r. = diastereomeric
ratio
In 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 carbonylative Heck-type reaction,[34] he showed that under increased CO pressure, Pd(PPh3)4 was capable of catalyzing the 5- or 6-exo-trig cyclization reaction of alkenyl iodides 76, leading to the exclusive formation of Heck reaction products 78a–e rather than the corresponding cycloalkenones 79. Interestingly, in the absence of CO, the reaction proceeded as well, albeit with
lower efficiency and regioselectivity. In contrast to Fu’s work,[32b] mechanistic studies, including a radical trapping experiment, indicated the formation
of radical species under these conditions. Accordingly, a hybrid Pd-radical mechanism
was postulated. In 2017, the same group introduced a second-generation Pd-based catalytic
system for an intramolecular Heck-type reaction, thus enabling efficient carbocyclization
of unsaturated alkyl bromides 77 under CO-free conditions (Scheme [10]).[35] Moreover, in this work, the authors investigated the difference in the reactivity
of alkyl iodides versus alkyl bromides in this cyclization. It was hypothesized that,
in the case of alkyl bromides, the cyclization proceeds via auto-tandem 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 radical Heck-type cyclization utilizing
alkyl iodides 80 possessing a 1-aryl-substituted alkene moiety (Scheme [10]).[36] The use of these specific substrates resulted in the exceptional endo-selective cyclization. This outcome is attributed to a much higher stability of the
forming tertiary benzyl radical intermediate 81 versus a non-stabilized primary radical species 83, which would arise via an alternative 5-exo-trig cyclization. Thus, a number of 5-aryl-1,2,3,6-tetrahydropyridines 82, which are structural motifs found in a variety of natural products and pharmaceutical
compounds, were synthesized using this approach.
Scheme 11 Alexanian’s mechanism for the Pd-catalyzed carbocyclization of unactivated alkyl
bromides via auto-tandem catalysis
Scheme 12 Pd-catalyzed intermolecular Heck reactions of unactivated alkyl halides
In 2014, Alexanian developed an intermolecular version of alkyl Heck reaction of unactivated
alkyl iodides (Scheme [12]).[37] By employing Pd(dppf)Cl2 as a catalyst, both primary and 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 dppf as a ligand, which allowed intermolecular Heck reactions of styrenes
to proceed with alkyl iodides 88, bromides 89 and even chlorides 90 (Scheme [12]).[38] The use of LiI as an additive in the reaction was crucial for achieving higher yields
with 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 in yields comparable to those reported by Alexanian employing alkyl
iodides. Similar to the previously described Heck-type cyclization reactions, the
mechanistic studies in both reports were consistent with a hybrid Pd-radical pathway,
thus further illustrating the prominence of this pathway for overcoming premature
β-hydrogen elimination in alkyl Heck reactions.
Until recently, all the reported methods for the Heck reaction of unactivated alkyl
halides required elevated temperatures. In 2017, Gevorgyan’s group demonstrated the
possibility of achieving a room temperature Heck reaction of unactivated primary and
secondary alkyl halides under visible-light-induced exogeneous photosensitizer-free
conditions employing a Pd(0)/Xantphos catalytic system (Scheme [12], products 92a–c).[31] Shortly after, the groups of Shang and Fu independently developed a similar method
for the reactions of primary and secondary unactivated alkyl bromides with styrenes
to provide the Heck reaction products 92d–h in excellent yields and E/Z ratios.[39]
Moreover, challenging tertiary alkyl bromides were also found to be capable coupling
partners (products 92i–n). In addition to styrenes, unactivated tertiary alkyl bromides reacted with electron-deficient
alkenes in a highly efficient manner (products 92o,p). The mechanistic studies of this work strongly supported a radical pathway, which
was initiated by a SET event from the photoexcited Pd(0) complex to an alkyl halide
(see Scheme [8]). Furthermore, the performed X-ray photoelectron spectroscopy studies detected palladium
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 independently reported analogous efficient alkyl Heck reactions
of unactivated tertiary alkyl iodides with styrenes and acrylonitrile (Scheme [12], products 92q–v).[25]
Very recently, Gevorgyan’s group reported a photoinduced, Pd-catalyzed radical relay
Heck reaction at remote unactivated C(sp3)–H sites of aliphatic alcohols, which synergistically combines a C–H activation via
a hydrogen atom abstraction (HAT) process and an alkyl Heck reaction (Scheme [13]).[40] The control of the β-, γ-, or δ-sites in this regioselective Heck reaction was achieved
by the employment of easily installable/removable iodomethyl silyl tethers on alcohols
93. These tethers are known to engage in a SET process with the photoexcited Pd complex
to form the Pd-radical hybrid species 95.[30]
[31] Remarkably, 95 bypasses the potential side-reaction processes, such as hydrodehalogenation or premature
Heck reaction (97), but rather undergoes a selective 1,5-, 1,6- or 1,7-HAT to produce the translocated
Pd-radical hybrid species 96. Subsequently, the latter is able to couple with acrylonitrile, acrylate or styrene
derivatives to afford the remote Heck reaction products 94a–m in good yields. Interestingly, the iodine-atom transfer intermediate 96′ was observed during this reaction, which presumably is formed via a reversible I-atom
transfer from the Pd(I)I species.
Scheme 13 Pd-catalyzed aliphatic radical relay Heck reaction at unactivated C(sp3)–H sites of alcohols
Lately, the scope of alkyl electrophiles in the Heck reaction has been expanded. Thus,
in 2018, Zhou’s group reported a Heck-type reaction of cyclic (98) and acyclic (99) epoxides using a Pd(0)-Xantphos catalytic system (Scheme [14]).[41] Styrenes, conjugated dienes, and electron-deficient olefins were efficiently alkylated
to give ring-opening products 100a–h and 101a,b with retention of the stereochemistry of the original epoxides. The authors proposed
that the reaction proceeds via the in situ generation of β-iodohydrins 104 from the epoxide 98g and Et3N·HI, which undergoes a SET reduction by the Pd(0) complex to form the alkyl Pd-hybrid
radical species 105 (Scheme [15]). Subsequently, this species adds to the double bond of alkene to form a new radical
species 106, which gives the reaction product via recombination with Pd(I) and subsequent β-H
elimination. The measured redox potentials of the reaction components are consistent
with this hypothesis, thus ruling out an alternative radical polar crossover pathway
involving oxidation of benzyl radical species 106 by Pd(I) into the corresponding benzyl cation 108.
Scheme 14 Pd-catalyzed intermolecular Heck reactions of epoxides and redox-active esters
Scheme 15 Zhou’s mechanism for the Pd-catalyzed Heck reaction of epoxides
In addition to alkyl halides and epoxides, the redox-active esters have also been
found to undergo an efficient Heck-type reaction. In 2018, the groups of Shang, Fu
and Glorius independently discovered a photoinduced Pd-catalyzed Heck reaction of
redox active esters, aliphatic N-(acyloxy)phthalimides 102, with styrenes (Scheme [14]).[42]
The reactions of primary, secondary and tertiary substrates proceeded smoothly at
room temperature (products 103a–s), thus providing an alternative approach towards alkylated alkenes starting from
readily available carboxylic acids. Overall, the scope of these transformations was
comparable with that of the visible-light-induced Heck reactions of alkyl halides.
Likewise, mechanistic studies have proven a radical-type mechanism initiated by a
SET event between a photoexcited Pd(0) complex and a redox-active ester, followed
by its decarboxylative fragmentation towards an alkyl hybrid Pd-radical species. The
latter would be engaged in the hybrid Pd-radical catalytic cycle, ultimately generating
the corresponding Heck reaction products. Furthermore, photophysical studies revealed
that the Pd complex is the only light-absorbing species in this transformation, while
N-(acyloxy)phthalimides 102 showed no absorption in the visible light region.
Ni-Catalyzed Heck-Type Reactions
3
Ni-Catalyzed Heck-Type Reactions
3.1
Benzylic Electrophiles
Following his work on the Ni-catalyzed allylic alkenylation,[43] in 2011, Jamison introduced a protocol for Heck coupling of benzyl chlorides with
terminal aliphatic alkenes. A number of branched Heck reaction products 110 were efficiently obtained at room temperature in the presence of Ni(COD)2, the monodentate phosphine ligand PCy2Ph and TESOTf as an additive (Scheme [16]).[44] The reaction was proposed to occur via a cationic Heck reaction pathway (Scheme
[17]). First, the oxidative addition complex 115 undergoes counteranion exchange with TESOTf to generate the cationic benzyl-Ni(II)
species 116, followed by an olefin coordination and sterics-controlled migratory insertion. Subsequent
β-H elimination of the formed alkyl-Ni(II) complex 117 affords the branched Heck reaction product 110 and HNi(II)OTf, which upon reduction to Ni(0) returns to the catalytic cycle. This
protocol is unique for alkyl Heck reactions as it provides access to 1,1-dialkyl-substituted
alkenes 110a–i in excellent yields and regioselectivities (>95:5 for most cases). Two years later,
the same group discovered the precatalyst 111 that allows this reaction to proceed much faster and, most remarkably, to be carried
out under open-flask conditions, where no exclusion of air, water, or degassing of
solvents and reagents is required.[45] Relying on these new conditions, a diverse range of allylbenzene derivatives 110h–j was efficiently synthesized in comparable yields to those reported under the previous
protocol conditions (Scheme [16]).
Scheme 16 Ni-catalyzed Heck reactions of benzylic electrophiles
Scheme 17 Jamison’s mechanism for the Ni-catalyzed Heck reaction of benzylic chlorides
In 2014, Jarvo developed a highly efficient, stereospecific, Ni-catalyzed intramolecular
Heck reaction of chiral methyl benzyl ethers 112 to give methylenecyclopentanes 113 (Scheme [16]).[46] The stereochemical outcome of this reaction arose from inversion during the oxidative
addition event, thus providing a single enantiomer of the key alkyl-Ni intermediate
114. The stereochemistry at this carbon center remained unchanged throughout the following
steps.
Recently, Hu and Huang reported the Ni-catalyzed Heck reaction of benzylamines 118 proceeding via a C–N bond activation (Scheme [18]).[47]
Scheme 18 Ni-catalyzed Heck reaction of benzylamines
The reaction is believed to occur via a charge transfer (CT) complex 121, which undergoes an SET with the Ni(0) catalyst to form alkyl radical species 122. The latter can be captured with styrene derivatives to produce Heck reaction products
120a–i in moderate to good yields.
3.2
α-Carbonyl Alkyl Halides
In 2012, Lei reported the Ni-catalyzed Heck-type reaction of α-carbonyl-substituted
alkyl halides 123 with styrenes to construct α-alkenyl carbonyl derivatives 124 (Scheme [19]).[48] Both amide- and ester-possessing secondary and tertiary alkyl bromides were reactive
under Ni(PPh3)4/dppp-catalyzed conditions leading to the products 124a–k. Interestingly, the authors showed that a Ni(I)-complex such as Ni(PPh3)4Cl was able to catalyze this reaction, as well. Thus, the following radical-type mechanism
has been proposed (Scheme [20]). Presumably, the Ni(I) species is generated in situ from the Ni(0)-catalyst and
an alkyl bromide via a SET event. The second SET event would produce the Ni(II)-complex
and alkyl radical species 125, which undergoes radical addition to the alkene to form benzylic radical 126. A subsequent radical polar crossover process would regenerate the active Ni(I)-catalyst
and produce cationic intermediate 127, which upon base-assisted deprotonation provides the final product. The involvement
of a radical polar crossover pathway was supported by the presence of the lactam cyclization
by-product in significant amounts in the reaction towards 124f (Scheme [19]).
Scheme 19 Ni-catalyzed Heck reaction of α-carbonyl alkyl halides
Scheme 20 Lei’s mechanism for the Ni-catalyzed Heck reaction of α-carbonyl alkyl halides
3.3
Unactivated Alkyl Halides
The first example of Ni-catalyzed Heck reactions of unactivated alkyl halides was
reported by Beletskaya in 1988 (Scheme [21]). The Ni(PPh3)4Cl2/Zn/pyridine system was shown to be capable of catalyzing the reaction of unactivated
primary and secondary alkyl bromides with styrene toward the Heck reaction products
129a–c in low to moderate yields.[49]
Scheme 21 Ni-catalyzed Heck reactions of unactivated alkyl halides
In 2012, Álvarez de Cienfuegos and Cuerva introduced a Heck-type cyclization of alkyl
iodides 130 under Ni/Ti-synergetic catalysis at room temperature (Scheme [21]).[50] Interestingly, depending on the conditions, the reaction could provide either normal
or reductive Heck products (131a–d or 132, respectively). In the case of standard Heck reaction conditions, the Ni(I) complex
is suggested to be the active catalyst that initiates the radical-type mechanism via
SET with an alkyl iodide; whereas the role of Ti(III) is believed to execute a hydrogen
atom transfer (HAT) from the intermediate 133. The latter hypothesis seems to be consistent with the results on the more efficient
production of 132 in the reactions of less hindered alkenes. This outcome is attributed to the ability
of Ti(III) to irreversibly trap less bulky radical intermediates 133, thus providing the corresponding reduced products upon acidic quenching. Recently,
Alexanian developed the Ni-catalyzed intramolecular and intermolecular Heck reactions
of alkyl bromides 134 (Scheme [21]).[51] Employing a Ni/Xantphos catalyst and Mn reductant, this reaction produced cyclized
products 135a–d in good yields and enhanced alkene regioselectivity compared to the previously developed
Pd-catalyzed carbocyclizations.[35] Moreover, using these conditions, an intermolecular coupling of primary and secondary
alkyl bromides with electron-deficient alkenes was accomplished (products 135e–g). Mechanistic studies suggested a radical-type scenario commenced by SET between
Ni(0) and an alkyl bromide. In contrast to the Pd-catalyzed carbocyclization of alkyl
bromides,[35] no ATRC product was observed in the course of this transformation.
Co-Catalyzed Heck-Type Reactions
4
Co-Catalyzed Heck-Type Reactions
The area of Co-catalyzed alkylation reactions has arisen after the seminal discovery
by Tada on the generation of alkyl radicals from alkyl halides in the presence of
cobaloxime(I) as the catalyst.[52] A number of reports on intramolecular Co-catalyzed Heck reactions by Scheffold[53] and others,[54] as well as on the intermolecular version by Branchaud,[55] appeared at the early stage of its development (Scheme [22]). These initial protocols usually employed strong reductive conditions, and electrochemical
or photoinduced activation of hydroxocobalamin (vitamin B12a) or cobaloxime complexes. In 2002, and his follow-up work in 2006, Oshima reported
the Co-catalyzed Heck reaction of alkyl halides in the presence of Grignard reagents
such as TMSCH2MgCl (Scheme [22]).[56] Alkyl iodides, bromides, and even chlorides reacted efficiently with styrene derivatives,
producing the Heck reaction products 140a–i in good yields. Spectroscopic and crystallographic studies supported a SET process
between the in situ generated Co(0) complex and an alkyl halide leading to the alkyl
radical species engaged in the hybrid-radical mechanism. In 2004, the same group applied
these conditions towards Heck reactions of epoxides 98 and 99 (Scheme [22]).[57] The reaction proceeded through in situ generation of 2-bromomagnesium methoxide
143 followed by the Co-catalyzed Heck reaction of alkyl bromides analogous to the prior
work.[56] The reaction was fairly effective for Heck reactions of symmetrical epoxides 141a–d, while asymmetrical substrates yielded a mixture of regioisomers 142a and 142a′.
Scheme 22 Co-catalyzed Heck reactions using strong reducing reagents
In 2011, Carreira developed a room-temperature visible-light-induced intramolecular
Heck reaction employing a cobaloxime catalyst 148 (Scheme [23]).[58] In contrast to the previously reported Co-catalyzed Heck reactions, the method relied
on the Hunig’s base [N(i-Pr)2Et]-promoted Co(I)-catalyst turnover via deprotonation of the Co(III)–H intermediate.
Therefore, strong reductants such as RMgX or Zn were no longer required, which significantly
expanded the functional group compatibility of the Co-catalyzed Heck reaction. Excitingly,
the authors were able to apply this mild protocol for the late-stage cyclization step
in the total synthesis of (+)-daphmanidin.[58] Later, Carreira reported an intermolecular version of this coupling using 2,2,2-trifluoroethyl
iodide (146) and styrene derivatives (Scheme [23]).[59] The intramolecular and intermolecular Heck reactions proceeded uneventfully, generating
the Heck products 145a–d and 147a–e in good to excellent yields. Sensitive functionalities such as amides, esters, ketones,
and aldehydes were well tolerated. Recently, Wu and co-workers developed a room temperature
Heck reaction of widely available alkyl carboxylic acids 149 using organo photoredox/cobaloxime dual catalysis (Scheme [24]).[60] The scope of this reaction was fairly broad as primary, secondary and tertiary alkyl
radicals, generated from carboxylic acids, could be efficiently coupled with vinyl
arenes/heteroarenes leading to the corresponding products 150a–g in good to excellent yields. Vinyl boronates and vinyl silanes (products 150h and 150i, respectively) were also shown to be competent alkene coupling partners in this reaction,
which further extended the synthetic utility of this protocol.
Scheme 23 Carreira’s Co-catalyzed Heck reaction using Hunig’s base
Scheme 24 Wu’s Co-catalyzed Heck reaction of carboxylic acids
Moreover, under the developed conditions, an unprecedented three-component coupling
of alkyl carboxylic acid, acrylates, and styrenes was demonstrated to afford highly
functionalized vinyl arenes in good yields and as single regioisomers with exclusive
E configuration (products 150j and 150k). Mechanistic studies, as well as DFT calculations, supported a radical-type mechanism
(Scheme [25]). According to which, a SET process from the carboxylate to the excited Mes-Acr+* species is followed by radical decarboxylation to produce the alkyl radical species
151. Subsequent trapping of the latter by an alkene, and then by the Co(II)-catalyst,
leads to alkyl-Co(III) species 153, which undergoes β-H elimination towards the Heck reaction product 150 and a Co(III)-H species. Deprotonation of this species, followed by an SET with the
reduced photocatalyst regenerates both active catalysts, Co(II)Ln, and Mes-Acr+. This represents the first method for the Heck reaction of unactivated alkyl carboxylic
acids, with H2 and CO2 being the only by-products.
Scheme 25 Wu’s mechanism for the Co-catalyzed Heck reaction of carboxylic acids
Cu-Catalyzed Heck-Type Reactions
5
Cu-Catalyzed Heck-Type Reactions
In 2013, Chemler reported the first Cu-catalyzed alkyl Heck reaction (Scheme [26]). In contrast to many alkyl Heck reactions, this reaction employed alkyl nucleophiles,
such as alkyltrifluoroborates 154, as coupling partners for the alkenes.[61]
Scheme 26 Chemler’s Cu-catalyzed Heck reaction of alkyl trifluoroborates
The outcome of TEMPO-trapping and radical clock experiments indicated the radical
nature of this transformation. The authors proposed that, under oxidative conditions,
generation of alkyl radical species 157 and a Cu(I) species occurred via homolysis of the Cu–C bond in the complex 156, which formed via transmetalation of the Cu(II) catalyst with alkyl trifluoroborate
154 (Scheme [27]). Addition of 157 to an alkene, followed by subsequent oxidation and deprotonation produced the Heck
reaction product 155. Yet, to regenerate the catalyst, the Cu(I) species had to be oxidized by an external
oxidant such as MnO2. This oxidative transformation features a quite general scope with regards to the
trifluoroborate salt, as benzylic, unactivated primary, and secondary alkyl substrates
could efficiently react with styrene derivatives to afford the Heck products 155a–i in good yields.
Scheme 27 Chemler’s mechanism for the Cu-catalyzed Heck reaction of alkyl trifluoroborates
In the same year, Nishikata developed the Cu(I)/triamine (161)-catalyzed Heck reaction of activated tertiary alkyl bromides 159 with styrenes (Scheme [28]).[62] Ester-, nitro-, or keto-group-possessing tertiary alkyl bromides were demonstrated
to couple with electron-rich styrenes (products 160a–e) under mild conditions, presumably via the formation of ATRA intermediate 162. A TEMPO-trapping experiment confirmed the intermediacy of a tertiary alkyl radical
species in this reaction. Later, the same group introduced a modified Cu(I)/triamine-based
catalytic system to accomplish the Heck reaction of amido-possessing alkyl bromides,
which were unreactive under the previous conditions,[62] with both electron-rich and electron-deficient styrene derivatives (Scheme [28]).[63] The reaction required higher temperatures and tri-(2-picolyl)amine (TMPA) as a ligand
to furnish products 160f–k in reasonable yields. In 2014, Lei developed the Cu(I)/1,10-phen-catalyzed Heck reaction
of primary benzylic and activated secondary and tertiary alkyl bromides with electron-rich
styrenes (Scheme [28], products 163a–k).[64] An EPR experiment supported the SET event between the Cu(I) catalyst and an alkyl
bromide.
Scheme 28 Cu-catalyzed Heck reactions of activated alkyl halides
In 2014, Chu and Tong synthesized CuB23 alloy short nanotubes, which were found to be capable of catalyzing the Heck reaction
of unactivated alkyl iodides 88 under ligand-free conditions (Scheme [29]).[65] Under these conditions, unactivated primary and secondary substrates reacted smoothly,
presumably via a radical pathway (products 164a–e). This method provided slightly superior yields compared to the Pd-catalyzed Heck
reaction.[37] Moreover, the catalyst showed a great recycling performance.
Scheme 29 Cu-catalyzed Heck reaction of unactivated alkyl halides
Regioselectivity has been an issue in the Heck reactions of unactivated aliphatic
olefins due to the undifferentiated C–H sites for β-H elimination. Very recently,
the first regioselective Heck reaction of alkyl bromides with unactivated aliphatic
olefins was reported by Bi and co-workers (Scheme [30]).[66]
Scheme 30 Fu, Guan and Bi’s directed Cu-catalyzed Heck reaction of unactivated olefins
The high reactivity and regioselectivity of this transformation were governed by the
aminoquinolone directing group (AQ) on the alkene 165, coordination of which to the Cu(I) catalyst activated the double bond (167) and also provided control of the regioselectivity for the β-H elimination step (168). Detailed mechanistic studies and DFT calculations indicated a radical pathway involving
a dimethyl sulfoxide assisted concerted H–Br elimination event from a conformationally
strained Cu(III) cyclic transition state. Activated primary, secondary and tertiary
alkyl bromides were suitable substrates in this reaction leading to products 166a–h.
Other Metals in Heck-Type Reactions
6
Other Metals in Heck-Type Reactions
In 2003, Kambe reported the titanocene-catalyzed Heck-type reaction of alkyl halides
with vinyl arenes (Scheme [31]).[67] The reaction proceeded efficiently at 0 °C for unactivated primary and secondary
alkyl bromides and even chlorides (products 169a–e), however, considerable amounts of by-products were observed in some cases. The Ti(III)-complex
formed in situ from the Ti(IV)-catalyst and the Grignard reagent is believed to generate
alkyl radicals, as well as to trap the benzylic radical intermediate towards an alkyl
Ti(IV) species 170, which upon β-H elimination delivers the Heck product 169.
Scheme 31 Ti-catalyzed Heck reaction
In 2013, Lei’s group applied Rh- and Ir-photoredox catalysis for the Heck reaction
of activated alkyl bromides with vinyl arenes (Scheme [32]).[68] The reaction operates via a radical-polar crossover pathway, where a photoredox
catalyst is involved in SET with an alkyl bromide, and in oxidation of the benzylic
radical intermediate towards the carbocation 172. Activated tertiary and secondary alkyl bromides reacted efficiently under the Rh-catalyzed
conditions (171a–f), whereas activated primary alkyl bromides required Ir-catalyzed conditions for the
same coupling (171g–k). Later, Cho employed ethyl 2-bromo-2,2-difluoroacetate (173) in a photoinduced Ir-catalyzed Heck reaction (Scheme [32]).[69] Besides styrene derivatives (products 174a–c), unactivated aliphatic alkenes (products 174d–f) were also suitable partners in reactions with alkyl bromide 173, which is quite rare for alkyl Heck reactions.
Scheme 32 Rh- and Ir-catalyzed Heck reactions
In 2015, the Fe-catalyzed Heck reaction of benzyl chlorides 175 under UV irradiation was reported by Mankad (Scheme [33]).[70] The authors favored a classical Heck reaction mechanism for this transformation,
where UV irradiation promoted the CO dissociation to reveal reactive, coordinatively
unsaturated Fe-containing intermediates. A radical-type process was considered to
be an unproductive pathway under these conditions, competing with the Heck reaction
and leading to decomposition. Therefore, the reaction suffered from moderate yields
and regioselectivity due to alkene isomerization (products 176a–g). In 2017, Bao reported another Fe-catalyzed Heck reaction using peresters 177 as the source of alkyl radicals (Scheme [33]).[71] This reaction was proposed to occur via a radical-polar crossover mechanism initiated
by the Fe(II)-catalyst. Methylated and ethylated styrene derivatives 178a–g, enyne 178h, and diene 178i were obtained in reasonable yields under these conditions.
Scheme 33 Fe-catalyzed Heck reactions
In 2014, decarbonylative Heck-type reactions employing tert-butyl peroxide and a catalytic amount of MnBr2 were reported by Li (Scheme [34]).[72] Peroxide-induced H-atom abstraction from aldehyde 179 gives the carbonyl radical 181, which upon releasing CO fragments into an alkyl radical 182 (Scheme [35]). Subsequent radical addition of the latter to the alkene, followed by oxidation
and deprotonation furnishes the Heck-type product 180. The reaction proceeds well with primary, secondary, and tertiary aldehydes, however,
it is limited to 1,1-disubstituted styrenes (products 180a–f).
In 2016, Hashmi’s group showed that dinuclear gold complex 186 could catalyze the Heck reaction of alkyl bromides under UVA irradiation (315–400
nm) (Scheme [36]).[73] In this reaction, electron-rich vinyl arenes were efficiently alkylated with primary,
secondary, and tertiary alkyl bromides to afford Heck products 185a–f in good yields. The method was also applicable for the late-stage functionalization
of a complex molecule, e.g., pregnenolone derivative 185c. Mechanistic studies supported an Au-catalyzed radical polar-crossover mechanism
induced by SET from the photoexcited Au(I)–Au(I) complex to an alkyl bromide.
Scheme 34 Mn-catalyzed Heck reaction
Scheme 35 Li’s mechanism for the Mn-catalyzed Heck reaction
Scheme 36 Au-catalyzed Heck reaction
7
Conclusion
Although the first alkyl Heck reaction was reported by Richard Heck in his original
work,[1d] this transformation has remained underdeveloped until recently, especially for unactivated
hindered alkyl halides possessing eliminable β-hydrogens. However, a merger of radical-
and transition-metal-catalyzed approaches has significantly driven this area. Nowadays,
in addition to Pd, other transition metals such as Ni, Co, Cu, Fe, and others have
been shown to efficiently catalyze Heck-type reactions, generally following a hybrid-organometallic
radical mechanism. Unactivated alkyl electrophiles possessing eliminable β-hydrogens
appeared to be non-problematic for this mechanism. Moreover, the employment of mild
photoinduced conditions has further broadened the scope of the alkyl Heck reaction.
Although, significant effort has been made to expand the scope with regards to the
alkyl component, the scope of the alkenes remains mostly limited to good radical acceptors
such as styrenes and acrylate derivatives. Examples of the alkylation of unactivated
aliphatic alkenes are rare. Therefore, the future direction of this transformation
may rely on the development of new systems that enable unactivated alkenes to undergo
selective and efficient Heck-type reactions. Obviously, detailed mechanistic studies
are warranted for better understanding of alkyl Heck-type reactions.
