Key words
alkyne difunctionalization - Ni-catalyzed - cross-coupling -
anti-selective - mechanistic studies - alkenylnickel
1
Introduction
Transition-metal-catalyzed alkyne hydro- and difunctionalization reactions are commonplace
in modern synthetic chemistry. These reactions are popular because they produce synthetically
relevant alkenes in a manner that is often regioselective and/or stereoselective.
Because these reactions generally involve migratory insertion at the catalytic metal,
syn selectivity is expected. A variety of different Ni-catalyzed alkyne functionalization
reactions have, however, demonstrated anti stereoselectivity. These reactions are highlighted in this Short Review (Scheme [1]), and their mechanisms are described whenever possible. The anti-selective reactions described in this review frequently (but not exclusively) rely
on the isomerization of catalytic alkenylnickel intermediates. The penultimate section
of this review focuses on the different mechanisms that can lead to alkenylnickel
isomerization since these processes are a common unifying feature for many anti-selective alkyne functionalization reactions.
Dale Wilger(left) was born in 1984 in Buffalo, New York. He obtained his undergraduate degree
in chemistry at Fredonia State. He pursued his graduate studies at the University
of North Carolina at Chapel Hill within the lab of Professor Marcey Waters (2006–2011).
After performing postdoctoral research with Professor David Nicewicz, he became a
professor of chemistry at Samford University in Birmingham, Alabama (2015). Dr. Wilger’s
research interests include the development of novel Ni-catalyzed cross-coupling reactions
and mechanistic studies related to these important transformations.
Sydney Bottcher (middle) was born in 1999 in Ft. Benning, Georgia. In 2018, she began an undergraduate
degree in chemistry and biochemistry at Samford University where she joined the group
of Professor Dale Wilger. Her research focuses on anti-selective alkyne hydroarylation reactions and subsequent modifications to form triaryl
alkenes.
Lauren Hutchinson (right) was born in 2000 in Orlando, Florida. After receiving her high school diploma
from The Master’s Academy, she went on to study chemistry and biochemistry at Samford
University. Lauren joined the research group of Professor Dale Wilger in 2019. Lauren’s
research focuses on organometallic chemistry and the Ni-catalyzed synthesis of indenones.
Scheme 1 Transition-metal-catalyzed alkyne hydroarylation reactions typically yield syn stereoselectivity
anti-Selective Hydroarylation
2
anti-Selective Hydroarylation
Transition-metal-catalyzed alkyne hydroarylation is a well-established approach for
the stereoselective synthesis of alkenes.[1] Catalytic systems employing Cr,[2] Mn,[3] Fe,[4] Co,[5] Ni,[6] Cu,[7] Rh,[8] and Pd[9] have all been previously reported. Even though the mechanisms for these reactions
vary, migratory insertion is often implicated as the key stereodefining step. Therefore,
syn selectivity is commonly observed.[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] However, notable exceptions do exist. Fujiwara has reported an anti-selective alkyne hydroarylation reaction that directly activates C–H bonds in aromatic
compounds.[10] The report by Fujiwara in 2000 was the first example of this reaction class to produce
high anti stereoselectivity.[10] More recently, several Au-catalyzed alkyne hydroarylation reactions have demonstrated
comparable anti selectivity with similar substrates.[11] This has helped to shed light on the mechanism of the Fujiwara hydroarylation, which
likely proceeds through alkyne coordination and intermolecular nucleophilic attack
by the arene (Wacker-type or Friedel–Crafts-type mechanisms).[11]
[12]
[13]
Similar to Pd, Ni is well known for being able to provide syn-selective alkyne hydroarylations within a variety of substrate classes.[14] Still, several different examples of anti-selective alkyne hydroarylation have been reported within the last decade. In 2011,
Robbins and Hartwig reported two different sets of conditions for Ni-catalyzed alkyne
hydroarylation, both of which provided moderate anti stereoselectivity with certain substrates.[15] Both sets of conditions required Ni(cod)2 as a precatalyst (cod = 1,5-cyclooctadiene). The first preparation employed arylboronic
acid derivatives 1 and diphenylacetylene 2 (Scheme [2]). Triphenylphosphine was found to be the optimal supporting ligand under those conditions.
Certain arylboronic acid derivatives with electron-withdrawing substituents provided
trisubstituted alkenes 3 in high yields and high anti stereoselectivity. Clear trends regarding the observed anti stereoselectivity are challenging to identify. For example, ester and ketone groups
at the para position of 1 provided low anti selectivity (3b, 3c: ca. 3:1 Z/E), while an aldehyde and a nitrile group provided moderate and high anti selectivity, respectively (3f, 3g: 11.8:1 and >20:1 Z/E).
Scheme 2 Ni-catalyzed alkyne hydroarylation with arylboronic acids[15]
The second synthetic procedure reported by Robbins and Hartwig engaged aryl bromides
4 and required triethylsilane as an added reductant (Scheme [2]).[15] The optimal ligand in that preparation was tributylphosphine. The scope for this
procedure was less extensive, but low to moderate anti stereoselectivity was observed when aryl bromides with ortho substituents were examined (3j, k). The primary focus of this report by Robbins and Hartwig was a new method for the
high-throughput discovery of transition-metal-catalyzed reactions. A Cu-catalyzed
oxidative (Chan–Lam) coupling reaction and a Cu-catalyzed alkyne hydroamination reaction
were also reported. No potential mechanism for the hydroarylation reactions was discussed.
In 2017, Reddy et al. reported a Ni-catalyzed hydroarylation procedure for propargyl
and homopropargyl alcohols (Scheme [3]).[16a] Arylboronic acids served as the aryl donors. When terminal alkynes 5 were employed, hydroarylation products 6, with linear regioselectivity and syn stereoselectivity, were obtained. When otherwise similar internal alkynes 7 were examined, hydroarylation products 8 were isolated with the opposite regioselectivity and stereoselectivity. Reddy proposed
a hydroarylation mechanism that operated entirely within the Ni(I) oxidation state.
This proposed mechanism was based on findings previously reported by Liu (see below).[17]
Scheme 3 Hydroarylation with propargyl and homopropargyl alcohols[16]
The mechanism described by Reddy et al. involved transmetalation, syn-selective migratory insertion to give 9, and protodenickelation to give 8 (Scheme [4]). Interestingly, the change in regioselectivity observed for internal alkynes suggested
that the orientation for migratory insertion depended on steric factors and not on
directing group coordination, or at least that steric factors could override the stabilization
provided by directing group coordination. Reddy proposed that isomerization of the
alkenylnickel intermediate syn-9 allowed for the formation of the anti hydroarylation product. Coordination of the directing group to the metal center would
stabilize anti-9 and provide the thermodynamic driving force for the observed stereoselectivity. This
same rationale was provided by Cheng et al. to explain the anti stereoselectivity observed when propargylic substrates were employed in a Co-catalyzed
alkyne hydroarylation procedure.[18] In that report, Cheng et al. observed syn selectivity with nearly all other alkyne substrates. Both Cheng et al. and Reddy
et al. reported no stereoselectivity (1:1 Z/E) when alkynes lacking coordinating directing groups were examined.[16]
[18]
Scheme 4 Hydroarylation mechanism proposed by Reddy et al.[16]
Scheme 5 Ni-catalyzed alkyne hydroarylation with air-stable reagents[19]
In 2019, Wilger et al. reported a Ni-catalyzed alkyne hydroarylation procedure that
required only air-stable precatalysts, reagents, and substrates (Scheme [5]; phen = 1,10-phenanthroline).[19] This reaction supplied trisubstituted alkenes 3 under operationally simple and inherently scalable conditions. Aryl bromides 4 served as aryl donors under reductive conditions with Zn and water. Certain aryl
bromides provided moderate anti stereoselectivity, similar to previous reports, although numerous substrates behaved
differently. Aryl bromides with ortho substituents provided adequate anti stereoselectivity (3l–p). Aryl bromides with meta substituents provided low anti stereoselectivity (3q,r). Aryl bromides with a para substituent provided good yields, but no measurable stereoselectivity (1:1 Z/E). This stood in stark contrast to the report by Hartwig and Robbins, which recorded
high anti stereoselectivity with several different para-substituted arylboronic acids.[15]
Wilger et al. performed deuterium-labeling experiments with D2O, d
7-DMF, and d
8-toluene in order to better define the mechanism for Ni-catalyzed alkyne hydroarylation
(Scheme [6]). These experiments indicated that the vinyl hydrogen atom in 3 was primarily derived from added water. Small quantities (<20%) of 3 were likely created via Ni–C bond homolysis and hydrogen-atom transfer, especially
under anhydrous conditions. The hydrogen atom donor was not the solvent under any
of the conditions examined. Hydrogen atom abstraction most likely occurred from benzylic
groups in 3 or 4 since added d
8-toluene could contribute to product deuteration.
Scheme 6 Deuterium-labeling experiments for alkyne hydroarylation[19]
Wilger et al. also performed mechanistic experiments with a Ni(II) aryl bromide complex,
Ni(tBubpy)(o-tol)Br 10 (Scheme [7]; tBubpy = 4,4′-di-tert-butyl-2,2′-dipyridyl). The complex 10 was competent as a precatalyst when compared to Ni(
t
Bubpy)Cl2 11, indicating that a Ni(II) aryl halide complex is a likely catalytic intermediate.[14d] Stoichiometric experiments with 2, 4l, and 10 indicated that Zn was required for adequate chemical yield. This suggested that at
least one of the relevant catalytic intermediates exists in the Ni(I) oxidation state.[14d]
[20] Additional mechanistic experiments indicated that an arylzinc intermediate was not
likely. Other protic donors (such as MeOH, EtOH,
i
PrOH, and
t
BuOH) gave similar Z/E ratios, indicating that the diastereoselectivity of these reactions was not affected
by the rate of protodenickelation.
Scheme 7 Mechanistic experiments with a Ni(II) aryl bromide complex[19]
Wilger et al. proposed the mechanism shown below for Ni-catalyzed alkyne hydroarylation
(Scheme [8]).[19] Off cycle, the Ni(II) precatalyst is reduced to an active Ni(0) species 12 by Zn. Oxidative addition into the C–Br bond of 4 would produce an intermediate analogous to 10. Subsequent reduction with Zn and alkyne coordination would give a Ni(I) complex
13. Migratory insertion would produce syn-14. Isomerization of the alkenylnickel isomer syn-14 to anti-14 and protodenickelation would provide 3, and the net effect of an anti-selective hydroarylation. Reduction of 15 by Zn would facilitate catalytic turnover. It has been shown that Zn is capable of
reducing Ni(II) aryl halide complexes to Ni(I) aryl complexes.[21] Therefore, Wilger et al. proposed that single-electron reduction occurs with 10 before migratory insertion and other subsequent steps. Since the complex 10 can produce non-negligible quantities of 3 without reductant, it may be possible that the requisite alkene-forming steps can
occur from both the Ni(I) and Ni(II) oxidation states, but that product formation
is faster from the Ni(I) oxidation state.
Scheme 8 Mechanism proposed for Ni-catalyzed alkyne hydroarylation[19]
The substrate scope for this reaction suggested that the thermodynamic driving force
for isomerization was steric repulsion within the alkenylnickel intermediates syn-14 and anti-14. Aryl groups with ortho substituents are more sterically demanding, and equilibration through reversible
isomerization would therefore tend to position these groups further away from the
Ni center. This explains why ortho substituents on the aryl donors led to higher diastereoselectivity, while meta substituents led to low levels of selectivity, and para substituents led to no measurable selectivity. If the hydroarylation reaction reported
by Hartwig and Robbins operates with a similar mechanism, then para-substituted aryl donors may have provided better selectivity because phosphine ligands
were used. Bipyridyl ligands are planar and possibly capable of rotating away from
the substituted aryl group. Phosphine ligands are trigonal pyramidal and therefore
present a greater three-dimensional steric profile. The observation that the more
sterically hindered
t
Bubpy ligand provided higher anti stereoselectivity compared to phenanthroline is consistent with this hypothesis.
Steric repulsion is often implicated as the driving force for alkenylnickel isomerization
in other catalytic reactions (see below).
Scheme 9 Ni-catalyzed alkynylboration[22]
anti-Selective Carboborylation
3
anti-Selective Carboborylation
Organoboron compounds are viewed as some of the most versatile cross-coupling partners
available to synthetic chemists. Aryl- and vinylboron reagents can be employed in
a vast array of C–C bond-forming reactions. This has led to an interest in synthesizing
organoboron reagents with increasing functionalization. In 2005, Suginome et al. reported
an anti-selective Ni-catalyzed alkynylboration reaction (Scheme [9]).[22] This cross-coupling was developed based on observations from a previously reported
syn-selective cyanoboration reaction.[23] Chloroboryl homopropargylic ethers 16 and alkynylstannanes 17 underwent clean 5-exo cyclization and carboboration across the alkyne triple bond, forming substituted
alkene derivatives 18. The precatalyst used for this transformation was Ni(cod)2. Triphenylphosphine was found to be the optimal supporting ligand for catalytic reactions.
The products 18 were moisture sensitive and were therefore converted into pinacolborane derivatives
19 before silica gel chromatography.
Suginome et al. proposed a mechanism that began with oxidative addition into the B–Cl
bond to give 20. Migratory insertion of the alkyne into the Ni–B bond would give syn-21. Isomerization would produce anti-21, then transmetalation would produce 22, and reductive elimination would produce 18. Steric repulsion between the diisopropylamino group and the phosphine-ligated Ni
center in syn-21 was proposed to drive the isomerization process. This hypothetical mechanism was
strongly bolstered by the isolation and characterization of anti-21d, which was synthesized via a stoichiometric reaction between 16d, Ni(cod)2, and the ligand PMe3 (Scheme [10]). X-ray analysis of anti-21d clearly showed the trans configuration of the C–B and C–Ni bonds.
Scheme 10 Ni-catalyzed alkynylboration mechanism[22]
anti-Selective Dicarbofunctionalization
4
anti-Selective Dicarbofunctionalization
4.1
Carbocyanative Cyclization
In 2013, Arai et al. reported a Ni-catalyzed cyclative carbocyanation for enynes (Scheme
[11]).[24] This procedure used Ni(P(OPh)3)4 as a precatalyst and acetone cyanohydrin as a HCN source. The enynes 23 underwent carbocyanative 5-exo-cyclization to produce 24. In certain cases, stoichiometric quantities of the P(OPh)3 ligand were found to be beneficial. When less sterically congested enynes were examined,
24 was obtained with low syn selectivity (3–5:1 Z/E). More sterically congested enynes gave 24 with very high anti selectivity (>20:1 E/Z). The substrate scope for this transformation was somewhat limited, but importantly,
this study provided the first example of an anti-selective carbocyanation.
Scheme 11 Ni-Catalyzed carbocyanative cyclization of enynes[24]
Scheme 12 Carbocyanative cyclization mechanism[24]
Arai et al. proposed a mechanism beginning with oxidative addition of HCN or the cyanohydrin
(Scheme [12]). Migratory insertion of the alkene group in 23 would produce 25 and subsequent alkyne carbometalation would produce syn-26. Isomerization of the alkenylnickel intermediate syn-26 is likely driven by steric repulsion between the bulky silyl group and α-substituents
on the enyne scaffold. Reductive elimination of anti-26 would provide the product 24. Some evidence for migratory insertion of the alkene with the opposite regioselectivity
(6-exo cyclization products) was observed during optimization. In addition to influencing
alkenylnickel isomerization, bulky silyl groups were also necessary to discourage
an initial migratory insertion of the more reactive C–C triple bond, a reaction that
did not result in cyclization.
4.2
Cyclization with Aryl Donors
In 2016, Liu et al. reported a Ni-catalyzed cyclization of alkynyl nitriles 27 to produce 1-naphthylamines 28 (Scheme [13]).[17] This transformation was necessarily facilitated by the isomerization of an alkenylnickel
intermediate. Arylboronic acids 1 served as the aryl donors. Yields for the reaction were good when a wide variety
of different arylboronic acids 1 and substituted alkynyl nitriles 27 were used. Arylboronic acids with either electron-donating or electron-withdrawing
substituents were tolerated, as were sensitive functional groups such as ketones,
esters, nitriles, and halides. A similarly wide scope was observed for substituents
on 27, although alkyl substituents on the alkyne moiety resulted in substantially lower
yields.
Scheme 13 Ni-Catalyzed cyclization of alkynyl nitriles[17]
Liu et al. performed several mechanistic experiments and found the Ni precatalyst
Ni(acac)2, arylboronic acid 1, KOtBu, and the ligand IPr produced a Ni(I) species IPrNi(acac) 29 (Scheme [14]; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene). The Ni(I) complex 29 was characterized by X-ray analysis. The complex 29 was found to be catalytically competent (yield = 53%) when compared to mixtures of
Ni(acac)2 and the IPr ligand (yield = 64%). This suggested that a Ni(I) complex analogous to
29 is a catalytic intermediate in the cyclization reaction.
Liu et al. proposed a catalytic mechanism that began with transmetalation to form
a Ni(I) aryl species. Migratory insertion with the C–C triple bond would produce syn-30. Isomerization to the alkenylnickel isomer anti-30 must occur before cyclization with the nitrile C–N triple bond. Protonolysis of
31 and tautomerization would produce 28. The regioselectivity of the alkyne migratory insertion step is critical to the transformation.
Substrates lacking the OTBS group provided very low yields (ca. 10%), implying that
the substituent might play a role in directing the regioselectivity of alkyne migratory
insertion. To our knowledge, this report by Liu was the first example of a catalytic
reaction in which equilibrating alkenylnickel species are trapped via a cyclization
event that is specific to the anti stereoisomer. Several other examples described below share this mechanistic feature.
Scheme 14 Mechanism for Ni-catalyzed cyclization of alkynyl nitriles[17]
In 2016, nearly concurrently with Liu’s seminal example, Lam et al. reported a highly
enantioselective catalytic cyclization reaction that was also facilitated by an alkenylnickel
isomerization process (Scheme [15]).[25a] Alkynyl 1,3-diketones 32 underwent enantioselective cyclization with arylboronic acids 1 as aryl donors. The chiral bicyclic β-hydroxyketone products 34 were obtained with excellent yields and enantioselectivities when the phosphinooxazoline
ligand 33 was used in conjunction with a Ni(OAc)2·4H2O precatalyst. Lam et al. proposed a mechanism that began with transmetalation and
alkyne migratory insertion to produce syn-35. The isomerization of syn-35 is driven by the removal of anti-35 from the reaction mixture via cyclization with the pendant carbonyl group. Protonation
of the Ni alkoxide intermediate 36 provides the product 34 and catalyst turnover. Additionally, cyclohexane-1,3-diones 37 and cyclohexa-1,3-dienones 39 provided the cyclic products 38 and 40, respectively, with high yields and enantioselectivities.
Scheme 15 Ni-Catalyzed cyclization of alkynyl ketones and enones[25a]
The Lam group has reported several other enantioselective cyclization reactions that
operate with similar mechanistic principles (Scheme [16]). In 2017, Lam et al. reported a Ni-catalyzed cyclization with amine-tethered 1,6-enynes
41 and arylboronic acid donors 1. In this case, Ni(OAc)2·4H2O and the NeoPHOX ligand 42 provided cyclic amine products 43 with high yields and enantioselectivities.[25b] The Z-configuration of the alkene moiety in 41 was found to be critical for cyclization to occur. In 2018, Lam et al. reported a
Ni-catalyzed desymmetrization of propargyl-substituted malonate esters 44 to produce cyclic products 45.[25c] The ligand 33 once again provided high yields and enantioselectivities. The substrate scope for
the arylboronic acids and aryl alkynes was extensive in this report. This procedure
allowed for gram-scale enantioselective syntheses. In 2018, Lam et al. reported a
Ni-catalyzed cyclization for propargyl-substituted amides 46.[25d] The pyrrole products 47 in this report were achiral, but yields were high and a wide variety of different
aryl groups could be incorporated. All three reactions shown in Scheme [16] are proposed to occur through a similar mechanism involving transmetalation (from
1), regioselective and syn-selective alkyne migratory insertion, alkenylnickel isomerization, and cyclization
of the anti alkenylnickel stereoisomer. In 2018, Reddy et al. reported a Ni-catalyzed cyclization
reaction for alkynyl azides that synthesized diarylquinolines in a closely related
manner.[16b]
Scheme 16 Ni-Catalyzed cyclization of bifunctional substrates[25b]
[c]
[d]
4.3
Cyclization with CO2
In 2015, Martin et al. reported a cyclative carboxylation for unactivated primary
and secondary alkyl halides with CO2 (Scheme [17]).[26a] As a C1 synthon, CO2 is ideal in terms of its cost, availability, and environmental impact. Martin et
al. found that the precatalyst NiBr2·diglyme was effective in combination with bipyridyl ligands such as bathophenanthroline,
bathocuproine, or neocuproine. Mn was used as a reductant. Primary alkyl bromides
48 provided syn-selective cyclization products 49. Bathocuproine was found to be the optimal ligand for primary alkyl bromides. Secondary
bromides 48 formed anti-selective cyclization products 49. Neocuproine was found to provide the highest anti selectivity when secondary alkyl bromides were employed. Similar to previously described
examples, steric repulsion appeared to play a role in the diastereoselectivity of
this transformation. Stoichiometric experiments with Ni(0) precursors provided no
product, indicating that a simple Ni(0)/Ni(II) catalytic cycle was not likely. Martin
et al. proposed that a Ni(I) intermediate was relevant. The mechanism for alkenylnickel
isomerization in this reaction is described in Section 6. In 2016, Martin et al. reported
a related Ni-catalyzed carboxylation for unactivated primary, secondary, and even
tertiary alkyl chlorides with CO2;[26b] an impressive feat given the recalcitrant nature of these electrophiles in cross-coupling
reactions. Several secondary alkyl chlorides demonstrated similar anti selectivity in that report as well.[26b]
Scheme 17 Ni-Catalyzed cyclization and carboxylation with CO2
[26a]
4.4
Intermolecular Dicarbofunctionalization
The Nevado group has reported several intermolecular alkyne difunctionalization reactions
that provide anti stereoselectivity through mechanisms that are distinct from those described above.[27] In 2016, Nevado et al. reported that terminal alkynes 50, arylboronic acids 1, and alkyl halides 51 could serve as carbon-based building blocks for stereoselective alkene synthesis
(Scheme [18]).[27b] The chemical yields for alkenes 52 were good and the anti stereoselectivities were excellent (>99:1 in most cases). Moreover, the substrate
scope for this cross-coupling was extensive. Even tertiary halides such as tert-butyl iodide could be used as alkyl donors within this procedure. Control experiments
indicated that free radical inhibitors such as TEMPO or BHT halted reactivity. Reactions
with both Ni(0) and Ni(II) precursors failed to provide vinyl halides without 1 or with substoichiometric quantities of 1. Nevado et al. hypothesized that a catalytic N(I)/Ni(III) cycle was operating. It
was proposed that transmetalation with 1 would produce a Ni(I) aryl species 53 capable of intercepting 51. This reaction would generate a Ni(II) aryl halide species 54 and a carbon-centered radical. The carbon-centered radical would add to the terminal
alkyne 50 in an intermolecular fashion and produce a freely interconverting vinyl radical 55. Selective radical recombination of 55 with 54 would provide the Ni(III) complex 56 and explain the observed diastereoselectivity. Reductive elimination from 56 would furnish the product 52 and regenerate the Ni(I) catalyst.
Scheme 18 Ni-Catalyzed dicarbofunctionalization[27b]
anti-Selective Carbosulfonylation
5
anti-Selective Carbosulfonylation
In 2017, Nevado et al. reported a Ni-catalyzed anti-selective alkyne carbosulfonylation reaction (Scheme [19]).[27c] Terminal alkynes 50, arylboronic acids 1, and sulfonyl chlorides 57 combined to produce highly substituted vinyl sulfones 58 in high yields and high anti stereoselectivities. In this case, a preformed catalyst with a unique ligand 59 was optimal (59 = 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine). The substrate scope for this reaction was broad.
Nevado et al. proposed a mechanism very similar to the previously reported Ni-catalyzed
dicarbofunctionalization reaction shown above (Scheme [18]). A Ni(I) aryl complex was hypothesized to react with 57 to produce sulfonyl radicals. These sulfonyl radicals would add to 50 to generate freely interconverting vinyl radicals in much the same way. Selective
recombination of these carbon-centered radicals with a Ni(II) aryl halide complex
and reductive elimination would explain product formation and the observed diastereoselectivity.
These alkyne difunctionalization mechanisms are unique compared to the other examples
covered in this review. These reports have so far been limited to terminal alkynes,
but the anti stereoselectivities have been exceptional. Similar approaches will likely be used
to develop future anti-selective alkyne functionalization reactions.
Alkenylnickel Isomerization
6
Alkenylnickel Isomerization
Many of the anti-selective alkyne functionalization reactions described above rely on the isomerization
of key alkenylnickel intermediates to provide adequate stereoselection. Numerous thermodynamic
and kinetic factors influence the relative abundance of these alkenylnickel isomers,
including steric repulsion, directing group coordination, and/or subsequent irreversible
reactions. While these relationships that dictate the relative differences between
alkenylnickel stereoisomers are often easily inferred, the kinetic factors that render
one alkenylnickel species configurationally stable, and another configurationally
labile, are more challenging to determine. It should be emphasized that C=C double-bond
isomerization is not inherent to all alkenylnickel species. Numerous syn-selective alkyne functionalizations and other cross-coupling reactions require alkenylnickel
species that are configurationally stable.[14]
[28] Understanding how alkenylnickel complexes undergo isomerization is highly important
since it may allow further reaction development. Furthermore, in some cases the isomerization
of alkenylnickel intermediates has led to the loss of stereochemical integrity.[28] Therefore, there are compelling arguments for being able to both selectively facilitate
and prevent alkenylnickel isomerization. It should also be emphasized that C=C double-bond
isomerization is not entirely unique to Ni. Alkenylcobalt,[18] alkenylruthenium,[29] alkenylrhodium,[30] alkenylpalladium,[31] and alkenylosmium[32] complexes are also known to undergo isomerization processes that can help inform
the discussion regarding alkenylnickel intermediates.
Scheme 19 Ni-Catalyzed carbosulfonylation[27c]
In 1979, Huggins and Bergman demonstrated that the rapid isomerization of alkenylnickel
species can explain the observation of kinetic products with apparent anti stereoselectivity (Scheme [20]).[33] The authors elegantly showed that Ni(acac)(PPh3)Me and Ni(acac)(PPh3)Ph add to diphenylacetylene 2 and 1-phenylpropyne 60, respectively, to give the same kinetic product 61. Moreover, Huggins and Bergman went on to show that reactions with isotopically labelled
components (60 and d
3-60) undergo an initial addition reaction with measurable syn selectivity and then equilibrate to form a statistical mixture of isomers (d
3-61). This report by Huggins and Bergman was the first to experimentally determine that
anti-selective alkyne functionalization reactions could be explained by the isomerization
of alkenylnickel species.
Scheme 20 Seminal studies on alkenylnickel isomerization[33]
The report by Huggins and Bergman was also innovative because they carefully investigated
the mechanism for alkenylnickel isomerization.[33] The authors noted that direct unimolecular rotation about the alkenylnickel C=C
double bond was the most straightforward explanation conceptually, but ultimately
discredited this mechanism based on experimental evidence (see below).[33] A wide variety of mechanisms could explain the isomerization of alkenylnickel species.
Several of these possible mechanisms are illustrated in Scheme [21]. We suggest that mechanisms involving: (a) direct unimolecular rotation, (b) reversible
nucleophilic attack, (c) reversible protonation, and (d) reversible bond homolysis
are the most relevant for consideration here. This is not meant to be an exhaustive
list of all possible isomerization mechanisms. Since direct unimolecular rotation
about an alkenylnickel double bond is arguably the simplest mechanism for isomerization,
it is discussed first.
Huggins and Bergman proposed that charge-separated resonance contributors might lower
the barrier for unimolecular rotation about the alkenylnickel C=C double bond since
they would impart more single-bond character to these species (Scheme [21a]). Often referred to using different terms (dipolar,[30b] bipolar,[31a] zwitterionic,[31b] and/or carbene[31c]), similar resonance structures have been proposed to contribute to the isomerization
of other alkenylmetal species.[18]
,
[29]
[30]
[31]
[32] Huggins and Bergman proposed a resonance structure in which the metal center has
significant π-acidity and accepts electron density from the alkenyl ligand.[33] This is consistent with the final conclusion of Huggins and Bergman regarding the
isomerization mechanism (see below).
Scheme 21 Possible isomerization mechanisms for alkenylnickel species
Resonance structures proposed for alkenylrhodium and alkenylpalladium species are
more typically represented with significant π-basicity and back-donation from the
metal center to the alkenyl ligand.[30]
[31] These representations are consistent with the established π-donating abilities of
these metals. There are several instances in which the extent of isomerization can
be directly correlated with the electron density present at the metal center. For
example, alkenylrhodium complexes with substituted triphenylphosphine ligands (P(C6H4X)3) undergo isomerization with rates reflecting the relative electron-donating ability
of the phosphine ligand (X = F < H < OCH3).[30b] In other instances, isomerization can be directly linked to the π-accepting ability
of the alkenyl ligand. Alkynes with conjugated carbonyl substituents will often undergo
isomerization, while alkynes lacking these substituents are configurationally stable
under identical conditions.[30a]
[b]
[31b]
Catalytic intermediates in the Ni(I) oxidation state may facilitate isomerization
in several of the difunctionalization reactions described above. A Ni(I) complex would
possess greater electron density compared to a Ni(II) complex, and that would presumably
facilitate back-donation consistent with the examples above. The isomerization process
observed by Huggins and Bergman occurred within the Ni(II) oxidation state, but the
ancillary ligand was anionic (acac = acetylacetonate). That isomerization reaction
was also found to be phosphine-catalyzed (see below). Importantly, a catalytic intermediate
that is formally a Ni(I) complex may be more accurately described as a Ni(II) complex
with a reduced (radical-anion) ligand.[34] That electronic structure would resemble the Ni complexes studied by Huggins and
Bergman more closely. It should be noted that Liu,[17] Wilger,[19] and Martin[26] have all independently reported alkenylnickel isomerization and each of these reports
implicated Ni(I) species as key catalytic intermediates. Because Ni(I) species are
odd-electron intermediates it may be prudent to consider resonance contributors that
distribute spin density throughout the alkenyl ligand.
Huggins and Bergmans’ study of alkenylnickel isomerization provided compelling evidence
that the process was catalyzed by free phosphine ligand (Scheme [22]). Reversible phosphine exchange was evident by NMR analysis of the Ni reactants
62. The rate of addition to alkynes was inversely proportional to the concentration
of added phosphine. The structure of the phosphine ligand in the Ni species also affected
the rate of addition. Those observations implied that ligand substitution to form
63 was at least partially rate-limiting in the carbonickelation process. Huggins and
Bergman suggested an associative mechanism for alkyne/phosphine exchange. Since the
observed products were formed by phosphine coordination to 64 after carbonickelation, it would be expected that the concentration of the ligand
should have substantially influenced the observed stereoselectivity. However, the
diastereomeric ratios observed for kinetic product mixtures displayed minimal dependence
on the concentration of added phosphine. For example, the rates for addition reactions
with added phosphine ligand displayed a linear dependence on 1/[PPh3], but changing the added phosphine concentration one order of magnitude changed the
diastereomeric ratio approximately 10%. These observations were consistent with a
mechanism in which free phosphine catalyzed the isomerization of the alkenylnickel
species syn-64 to anti-64. In other words, if the alkenylnickel intermediate were capable of undergoing isomerization
by a direct unimolecular pathway, then higher phosphine concentrations would be expected
to favor the trapping of syn-64 (and the observed syn-65/
anti-65 ratio). Huggins and Bergman envisioned a mechanism in which free phosphine could
reversibly attack the alkenyl carbon atom β to the metal center in 64, and thereby allow rotation around the Cα–Cβ bond.[33] A phosphine-catalyzed isomerization mechanism could be operating in many of the
Ni-catalyzed reactions reported above. In catalytic procedures that do not require
added phosphines, it may be possible that another nucleophilic species such as dissociated
pyridyl ligand, halide anion, or base could participate in this manner.
Scheme 22 Phosphine-catalyzed alkenylnickel isomerization[33]
Acid-catalyzed processes may also contribute to the isomerization of alkenylnickel
species (Scheme [21c]). Several of the Ni-catalyzed reactions reported above require protodenickelation
as a product-forming step. Tanke and Crabtree hypothesized that acidic species could
catalyze the isomerization of alkenyliridium intermediates within a hydrosilylation
reaction.[35] Control experiments that included exogenous base disproved this hypothesis. Since
protonolysis is often a productive step in the reported anti-selective alkyne functionalization reactions catalyzed by Ni, the effects of exogenous
base would be challenging to interpret. Tanke and Crabtree eventually supported an
isomerization mechanism that involved direct unimolecular rotation of an alkenyliridium
intermediate. Nelson and Gagné later demonstrated that rapid proton transfer steps
can interconvert alkenylplatinum regioisomers 66 and d-66 in an enyne cycloisomerization reaction (Scheme [23]).[13] One could envision a similar sequence of proton transfer steps leading to the stereochemical isomerization of an alkenylnickel species. In the example reported by Nelson and
Gagné, deuterated acids left a residual isotopic label in the product 67. This type of deuterium-labeling experiment would be challenging to perform or uninformative
in many of the Ni-catalyzed alkyne functionalization reactions described above.
Scheme 23 Acid-catalyzed alkenylplatinum isomerization[13]
Scheme 24 Alkenylnickel isomerization via reversible bond homolysis[26a]
Martin et al. proposed that reversible Ni–C bond homolysis could explain the isomerization
of alkenylnickel species in the carboxylation reaction described in Section 4.3 (Scheme
[24]).[26a] Martin et al. proposed that after oxidative addition and alkyne migratory insertion
with 48, an alkenylnickel species such as syn-68 may undergo bond homolysis to create a vinyl radical syn-69. The carbon-centered radical syn-69 would isomerize to anti-69, and then radical recombination with the Ni(I) center would produce anti-68 (and then eventually anti-49). Perhaps most interesting, the isomerization process appeared to be strongly dependent
upon the choice of supporting ligand (neocuproine versus bathocuproine). Martin et
al. suggested that redox-noninnocent ligand behavior may be partially responsible
for this observation.[34] The mechanistic studies reported by Wilger et al. indicated that irreversible Ni–C bond homolysis did occur under catalytic alkyne hydroarylation conditions. However,
the extent of reversible bond homolysis could not be assessed. Direct unimolecular bond rotation and reversible
Ni–C bond homolysis are perhaps the most challenging isomerization processes to differentiate.
Detailed mechanistic studies, including crossover experiments with well-defined alkenylnickel
complexes, should help to differentiate direct unimolecular rotation and reversible
bond homolysis in the future.
7
Conclusions
A large sampling of recently reported Ni-catalyzed anti-selective alkyne functionalization reactions has been summarized. In many instances,
the proposed mechanisms for these transformations have suggested alkenylnickel isomerization
as the cause for their unusual stereoselectivity. Key outliers include the anti-selective intermolecular alkyne difunctionalization reactions reported by Nevado
et al. Both of these mechanistic umbrellas hold promise for future reaction development.
Because the isomerization of alkenylnickel species facilitates stereoselectivity in
many of the examples described above, this topic was briefly reviewed as well (Section
6). Several possible mechanisms for alkenylnickel isomerization were described in
the context of reported catalytic reactions. Further understanding these isomerization
processes will lead to improvements in Ni-catalyzed cross-coupling procedures and
to the creation of new alkyne functionalization reactions.
Given the broad range of possible mechanisms that could explain alkenylnickel isomerization,
we believe that further experimentation will greatly elucidate this field of study.
As noted above, several of the isomerization mechanisms are very difficult to differentiate
between. Numerous questions regarding the oxidation state of configurationally unstable
species (Ni(I) versus Ni(II)) remain. Other questions relate to the role that nucleophilic
and acidic species might play in catalyzing isomerization. Although challenging, the
synthesis and characterization of discreet alkenylnickel complexes should be pursued.
Catalytic and stoichiometric control experiments with these complexes should help
to fully define the relevant mechanisms. We hope this Short Review inspires further investigations in this area.
