69-1111_Hatakeyama.indd1 Introduction
N Heterocyclic carbenes (NHCs) were rst independently synthesized
by Wanzlick and Öfele in 1968. 1 After two decades, Arduengo et al.
succeeded in the isolation of a stable NHC, 1,3 di(1
adamantyl)imidazol 2 ylidene (IAd). 2 Since then, numerous NHCs and
their precursors have been prepared 3 and applied to various
transition metal catalyzed reactions as a new class of auxiliary
ligands. A variety of late transition metal complexes possessing
NHC ligands have been isolated and have proven to be effective
catalysts in a variety of syn- thetic organic reactions. 4 One of
the most important examples is the ruthenium/NHC catalyst for olen
metathesis developed by Grubbs et al., 5 for which the Nobel Prize
was awarded in 2005. Replacement of one of the two
tricyclohexylphosphine ligands in the rst generation Grubbs
catalyst with 1,3 di(1 mesityl)imidazolin 2 ylidene (SIMes) affords
the second generation Grubbs catalyst, which has signicantly
improved stability and reactivity. Recently, the remarkable
potential of NHC ligands was demonstrated in several palladium
cata- lyzed cross coupling and related reactions, for which the
Nobel Prize was awarded in 2010, just one year ago of this report.
6 Bulky NHC ligands, such as (S)IMes and (S)IPr, were shown to
signicantly improve the performance of the Pd catalyst compared to
traditional phosphine ligands. The catalytic improvements derived
from the NHC type ligands are often attributed to their strong σ
electron donating properties, 7 which result in strong NHC metal
bonds and prevent catalyst
decomposition. The application of NHC ligands in iron group
metal
(IGM) catalysis has attracted considerable attention from aca-
demia and industry due to their practical advantages as well as
unique reactivity. Since the pioneering work of Herrmann on the
nickel NHC catalyzed, Kumada Tamao Corriu coupling reaction, 8 the
use of NHC ligands in IGM catalyzed reactions have been actively
pursued. 9 The successes of these catalysts is attributable to
their strong σ electron donating properties and bulkiness, 7,10
both of which lead to in situ formation of coordinatively
unsaturated reactive species to achieve high cat- alytic
performance. In this report, we describe our recent efforts to
achieve selective C sp 2 C sp 2 cross coupling reactions based on
IGM/NHC catalyst systems, which yielded new cross coupling
reactions with nonconventional reaction mechanisms.
2 Selective Biaryl Cross Coupling Catalyzed by Iron, Cobalt, and
Nickel Fluorides with the Assistance of NHC Ligands
2.1 Background Since functional biaryls constitute a diverse array
of func-
tional materials, such as optoelectronics, drugs and agrochemi-
cals and their intermediates, 11 considerable effort has been
devoted to developing efcient and selective methods for biaryl
synthesis. 12,13 Reductive homocoupling of aryl halides or pseu-
dohalides, i.e., the classical Ullmann reaction, has been devel-
oped to give the desired symmetrical biaryls by using various
transition metals. 12a,c Palladium catalysts in combination
with
Cross Coupling Reactions Catalyzed by Iron Group Metals and N
Heterocyclic Carbenes
via Nonconventional Reaction Mechanisms
International Research Center for Elements Science, Institute for
Chemical Research, Kyoto University Uji, Kyoto, 611 0011,
Japan
(Received September 20, 2011; E mail:
[email protected])
Abstract: New cross coupling reactions catalyzed by iron or iron
group metals (IGMs), consisting of Fe, Co, and Ni with N
heterocyclic carbenes (NHCs), are described in this report. Highly
selective biaryl cross cou- pling reactions between aryl halides
and aryl Grignard reagents were achieved by using a combination of
uo- ride salts of IGMs and NHCs. In the course of the study, an
unexpected alkenylative cross coupling between alkyl aryl suldes
and aryl Grignard reagents was found, in which a typical Ni/NHC
catalyst displayed unprec- edented reactivity toward sulde
substrates. Theoretical studies suggest that the biaryl coupling
and the alke- nylative coupling reactions proceed via two
nonconventional mechanisms, which are substantially different from
the widely accepted cross coupling mechanism: In the biaryl cross
coupling, treatment of the catalyst mixtures of IGM uorides and
NHCs with an excess amount of the aryl Grignard reagent results in
the gen- eration of organometalate complexes, [Ar 1M IIF 2]MgBr
(MFe, Co, and Ni). These organometalate species undergo oxidative
addition of aryl halide substrates to form intermediates in a high
oxidation state (most likely a+IV state) possessing two different
aryl groups, Ar 1Ar 2M IVF 2. The heteroleptic diaryl
organometallic interme- diates collapse easily to afford
unsymmetrical biaryls in a highly selective manner. On the other
hand, the alkenylative coupling reaction using a Ni/NHC catalyst
involves formation of a low oxidation state Ni(0) thioaldehyde
complex, which is transformed to an alkenylnickel species via α
deprotonation of the thioalde- hyde and subsequent C S bond
cleavage of the resulting enethiolate intermediate. The
alkenylnickel species undergoes transmetalation with an aryl
Grignard reagent to form alkenyl/aryl coupling products via
reductive elimination. The present cross coupling reactions
catalyzed by IGMs with NHC ligands provide highly selec- tive C sp
2 C sp 2 coupling methods for the synthesis of unsymmetrical
biaryls and styrene derivatives, offering an opportunity to gain
new mechanistic insights into IGM catalyzed cross coupling
reactions.
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an appropriate terminal reductant such as zinc are currently of
preferred choice. 12b Furthermore, the cross coupling of two
different aryl halides under reducing conditions was devel- oped.
14 The biaryl synthesis under oxidative conditions has been an
alternative since the seminal work of Kharasch and coworkers, who
discovered that aryl Grignard reagents undergo efcient homocoupling
in the presence of catalytic amounts of rst row transition metal
salts, such as the metal halides of chromium, manganese, iron,
cobalt, nickel, and cop- per. 15 Recent progress in oxidative
coupling chemistry extended its utility to the synthesis of various
functionalized biaryls. 16 Notwithstanding the advancements in both
reductive and oxi- dative biaryl coupling reactions, the use of
transition metal catalyzed cross coupling reactions is preferred
because they offer synthetic advantages such as high selectivity,
broad sub- strate scope, and mild reaction conditions. 17 In fact,
a wide range of arylmetal compounds has been successfully used as
the nucleophilic partner in unsymmetrical biaryl coupling reactions
(Scheme 1). While various organometallic com- pounds such as
aryllithium, 18 magnesium, 19 boron, 20 silicon, 21 copper, 22
zinc, 23 or tin compounds 24 have been used in the bia- ryl
coupling reactions, aryl Grignard reagent is likely ideal for
practical synthesis because of their availability, cost perfor-
mance, and environmental innocency. Despite the synthetic
advantages of Grignard reagents, there is one serious draw- back,
the unwanted formation of the symmetrical biaryls via undesired
homocouplings of the Grignard reagents and/or the aryl
electrophiles.
Our research group has been interested in the development of iron
catalyzed reactions, 25 27 and engaged in the develop- ment of
selective iron catalysis to overcome the aforementioned
homocoupling limitation. During the course of the study, it was
found that the combination of iron uoride and NHC ligands resulted
in a highly selective and practical catalyst for the biaryl cross
coupling of aryl Grignard reagents. 28 Although metal uorides are
known to display unique reactiv- ity and selectivity in transition
metal catalyzed carbon car- bon bond forming reactions, 29 and the
“uoride effect” has attracted considerable interest in synthetic
chemistry, 30 their reactivity has remained unstudied in transition
metal cata- lyzed cross coupling reactions. 31,32 Therefore, we
reported the careful investigation of the “uoride effect” in cobalt
33 and nickel catalyzed 34 cross coupling reactions to achieve
selective biaryl cross coupling of aryl halides with arylmagnesium
compounds. The full account of the synthetically useful
unsymmetrical biaryl coupling with the novel IGM uorides/ NHC
ligand catalysts is presented in this chapter. 35
2.2 Iron Fluoride/SIPr Catalyzed Biaryl Cross Coupling The
investigation was initially focused on iron based cata-
lysts because there is no established practical method for Fe
catalyzed biaryl cross coupling reactions. 25 28 While
efcient
homocoupling reactions of arylmagnesium compounds using Fe
catalysts have been reported, 16a,b,donly a few were published in
the same timeframe as our study. 36,37 We began by conduct- ing a
careful and detailed catalyst screening for the reaction of a
simple aryl chloride with an arylmagnesium reagent (Scheme 2). The
benchmark coupling reaction was performed by heating a THF solution
of chlorobenzene 1, p tolylmagne- sium bromide (p TolMgBr, 2.5
equiv), iron salt (5 mol%), and an additive, at 60 for 24 h (Table
1, entry 1). Various addi- tives, including imidazolium and
imidazolinium salts (as shown in Figure 1), as well as typical
phosphine ligands were studied in combination with a catalytic
amount of various iron uoride precursors.
An optimum yield of 98% for 4 methylbiphenyl 2 was achieved by
using 5 mol% of FeF 3·3H 2O and 15 mol% of SIPr·HCl (entry 1). The
undesired homocoupling reaction occurred sluggishly and gave a
negligible amount of biphenyl 3 and a small amount of 4,4’
dimethylbiphenyl 4 (0.018 mmol, 4% yield, based on the amount of p
TolMgBr). As shown in entry 2, when the less sterically demanding
NHC was used, a lower conversion of the starting chlorobenzene 1
was observed. The unsaturated NHC precursors, IPr·HCl and I t
Bu·HCl, were ineffective (entries 3 and 5). The counter anion of
the NHC precursors displayed considerable inuence on the reac-
tivity (entry 4). The use of 10 or 5 mol% of SIPr·HCl resulted in a
selective, but lower conversion (entries 6 and 7). The reac- tion
was sluggish without an NHC precursor (entry 8). As shown in entry
9, N,N,N ’,N ’ tetramethylethylenediamine (TMEDA), one of the most
effective additives for the iron catalyzed cross coupling of aryl
Grignard reagents and non activated alkyl halide, did not promote
the reaction.
A remarkable contrast in the reactivity of various iron pre-
cursors is shown in entries 10 17. FeF 2·4H 2O showed a com-
parable catalytic activity to FeF 3·3H 2O and afforded 2 in 96%
yield. In the presence of a catalytic amount of anhydrous FeF 3 or
FeF 2, the reactions proceeded selectively but did not reach
completion probably owing to their lower solubility in THF (entries
11 and 12). Note that the addition of 15 mol% of water to FeF 3
resulted in only a limited increase in the product yield (entry
13). It was assumed that water or hydroxide might react with the
solid surface of FeF 3 and make it partially solu- ble, thereby
promoting the generation of the catalytically active species. 38 A
mixture of anhydrous FeF 3 and SIPr·HCl (1:2 ratio) was nely ground
in inert atmosphere and this mix- ture showed comparable reactivity
to the FeF 3·3H 2O/SIPr·HCl system. The use of FeCl 3 or Fe(acac) 3
as an iron source resulted in predominant homocoupling with or
without SIPr·HCl (entries 14 16). Pretreatment of FeCl 3 with KF
also generated a catalytically active species, which gave the
unsym- metrical biaryl with the same efciency as that afforded by
the hydrates of iron uorides (entry 17). The experiments indicate
that the involvement of H 2O or metal hydroxide in the catalytic C
C bond forming process is very unlikely.
The procedure described above required a large excess of
Scheme 1. Metal catalyzed unsymmetrical biaryl coupling.
Scheme 2. Iron catalyzed cross coupling between PhCl and p
TolMgBr.
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aryl Grignard reagent to generate the catalytically active iron
species, which prompted us to investigate various organome- tallic
reagents for use as iron based catalyst activators (Scheme 3). 39
For example, the cross coupling between chloro- benzene 1 and p
TolMgBr using reduced amounts of iron u- oride and Grignard reagent
(3 mol% and 1.5 equiv, respec- tively) did not complete, and gave
the cross coupling product in only 72% yield after 24 h at 60
(Table 2, entry 1). Instead of a large aryl Grignard reagent
excess, MeMgBr and EtMgBr were found to activate the catalyst
precursors, suggesting that insufcient basicity of the aryl
Grignard reagent towards deprotonation of the NHC precursors as
well as the reaction with hydrates of iron uorides resulted in slow
substrate con- version. The treatment of FeF 3·3H 2O and SIPr·HCl
with 18 mol% of MeMgBr to quench all protons derived from cata-
lyst precursors enhanced the reaction rate to give 2 in 97% yield
with 1% recovery of 1 (entry 2). Additional MeMgBr slightly
enhanced the reaction rate (entry 3). With EtMgBr (18 mol%), the
reaction reached completion in 12 h to give 98% yield using 1.2
equivalents of p TolMgBr (entry 4). When 27 mol% of EtMgBr was
used, ethylbenzene was produced in 3% yield via cross coupling of
the residual EtMgBr and 1 (entry 5). The lower yield of the
homocoupling product 4 (2%) suggests that some EtMgBr is consumed
for the partial reduc-
tion of the iron(III). 40 Therefore, we propose that EtMgBr is
sufciently basic to react with the water molecules of the metal
uoride hydrates in order to assist in their dissolution.
Table 3 summarizes the scope of this iron catalyzed biaryl cross
coupling reaction under the optimal conditions and the procedures
shown in Scheme 3. The coupling reaction depends strongly on the
nature of the leaving group, where chloroben- zene gave 2
selectively in 98% yield as described above, bromo and iodobenzene
produced larger amounts of the homocou- pling byproduct 4 than the
desired product 2 (entry 1 vs. entries 2 and 3). Phenyl triate
showed lower reactivity, giving 27% yield of 2 (entry 4).
Fluorobenzene did not react under the reaction conditions (entry
5). 4 Chloroanisole reacted with p TolMgBr to give the desired
product in 92% yield (entry 6). Fluorinated biaryls, possessing a
representative mesogen struc- ture of liquid crystal molecules,
were obtained in good yields (entries 7 and 8). Though the
reactions of o tolyl and mesityl- magnesium bromide were rather
sluggish under standard con- ditions, the corresponding biaryl
coupling products were obtained in 90 and 93% yields, respectively,
at elevated reaction temperatures (entries 9 and 10). 4
Fluorophenylmagnesium bromide also reacted smoothly to give the
desired product in 87% yield (entry 11). 1 and 2 naphthylmagnesium
bromide participated in the reaction (entries 12 and 13). The
dimethyl- amino and methylthio groups did not interfere in the
coupling reaction (entries 14 and 15). Note that a small amount of
4,4’’ dimethyl 1,1’’;4’,1’’terphenyl (4%), formed via cleavage of
the Ar SMe bond (via 1:2 cross coupling), which is often observed
in the nickel catalyzed coupling reactions. 41 An ace- tal remained
intact under these reaction conditions (entry 16). 2
Chloroquinoline and 2 bromopyridine took part in the selective
biaryl coupling (entries 17 and 18).
Table 2. Activation of precatalysts by using MeMgBr and
EtMgBr.
Figure 1. NHC precursors.
Table 1. Screening of iron salts and additives in the cross
coupling of chlorobenzene with p tolylmagnesium bromide.
Scheme 3. Activation of iron uoride/SIPr by using EtMgBr.
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2.3 Cobalt and Nickel Fluorides/IPr Catalyzed Biaryl Cross
Coupling
Cobalt and nickel catalysts were examined using the pres- ent
uoride/NHC strategy. Although numerous C C bond forming reactions
based on cobalt 42 and nickel 43 catalysts have been studied, the
corresponding metal uorides have been only sporadically studied in
the cross coupling eld. 44 The reaction of chlorobenzene 1 with p
TolMgBr in the presence of cata- lytic amounts of cobalt and nickel
uorides with various NHCs was investigated as shown in Scheme 4,
comrming that a similar “uoride effect” works in IGMs and is useful
for the selective biaryl synthesis.
Table 4 summarizes the results of the Co and Ni cata-
lyzed reactions. The reaction with CoF 2·4H 2O (3 mol%) and IPr·HCl
(6 mol%) selectively produced the cross coupling product 2 in 95%
yield along with small amounts of homocou- pling products 3 and 4
(3% and 11% yields, respectively, entry 1). Alternatively, the
reaction with CoCl 2·6H 2O gave 2 in a considerably lower yield
(68%) with increased formation of byproducts 3 and 4 (26% yield in
total, entry 2). SIPr·HCl was less effective than IPr·HCl (entry
3). The reaction with NiF 2or NiF 2·4H 2O (1 mol%) and IPr·HCl (2
mol%) gave 2 selectively, but the use of NiCl 2 resulted in less
selectivity (entries 4 6). With a reduced amount of NiF 2 (0.5
mol%), the reaction pro- ceeded to completion after 48 h, affording
2 in 98% yield (entry 7). In contrast to the iron catalyst, the
counter anion of the NHC precursors did not affect the product
yield (entry 8). Decreasing the steric bulkiness of the N aryl
substituent led to a decrease in product yield (entries 9 and 10).
SIPr·HCl was slightly less effective than IPr·HCl (entry 11). It is
noteworthy that addition of KF to NiCl 2 improved the cross/homo
selec- tivity in the reaction of bromobenzene with p TolMgBr
(entries 12 and 13). From these results, we chose SIPr·HCl for iron
uoride and IPr·HCl for cobalt and nickel uorides as the standard
NHC ligands in the subsequent investigations.
Since the seminal work reported by Kumada and Tamao, 34b,c,45
phosphine ligands such as the chelating 1,2
bis(diphenylphosphino)ethane (DPPE) ligand have been effec- tively
used in cross coupling reactions with nickel and palla- dium
catalysts. Therefore, DPPE and NHC ligands in the nickel or cobalt
uoride catalyzed biaryl cross coupling reactions were compared
(Table 5). Interestingly, the bisphos- phine ligand did not promote
the reaction at all when IGM uorides were used as the pre catalyst
(entries 1, 2, and 3). Elongation of the reaction period as well as
higher reaction temperature did not enhance the reaction and
bromobenzene was recovered almost quantitatively. In stark
contrast, NHC ligands promoted the cross coupling reaction
effectively to
Table 4. Screening of cobalt and nickel salts with various NHC
ligands.
Table 3. Iron uoride/NHC catalyzed cross coupling of aryl halides
with aryl Grignard reagents.
Scheme 4. Cobalt and nickel catalyzed cross coupling between PhCl
and p TolMgBr.
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give the desired biaryl in almost quantitative yield (entries 4 6).
As shown in entry 7, when a nickel chloride was used as the pre
catalyst, the biaryl coupling reaction took place in the presence
of a bisphosphine ligand; however, the selectivity was not as high
as that in the reaction with IPr (entry 6) under the same reaction
conditions.
2.4 Scope of Cobalt and Nickel Fluorides/IPr Catalyzed Biaryl Cross
Coupling: Comparisons with Iron Fluoride/ SIPr Catalyst
Under optimized conditions, uoro , bromo , and iodo- benzenes were
examined as electrophiles to determine the scope of the leaving
group in the present reactions (Table 6). Reactions with p TolMgBr
(1.2 equiv) were carried out at 60 in the presence of FeF 3·3H 2O
and SIPr·HCl (3 and 9 mol%, respectively), NiF 2 and IPr·HCl (0.5
and 1 mol%, respectively), or CoF 2·4H 2O and IPr·HCl (0.5 and 1
mol%, respectively).
Fluorobenzene was fully inert under these conditions (entry 1).
While the reaction of chlorobenzene with the iron catalyst
selectively afforded the cross coupling product 2, that of
bromobenzene and iodobenzene generated considerable amounts of
homocoupling product 4 (entries 2 4). As shown in entries 5 7, the
cobalt catalyst was found effective for the reaction with both of
chlorobenzene and bromobenzene, albeit ineffective for that with
iodobenzene. The nickel catalyst showed the broadest scope on the
halide substrate and was found more effective than the iron and
cobalt catalyst in terms of catalytic activity and selectivity
(entries 8 10).
The IGM uoride/NHC catalyzed cross coupling reac- tion is widely
applicable to a broad range of substrates. Table 7 summarizes the
scope of the reactions, which were carried out according to the
procedure described above. Electron rich 4 chloroanisole reacted
smoothly with p TolMgBr to give the desired product in 92%, 94%,
and 88% yields, respectively (entry 1). Fluorine substituted
biaryls, the representative mesogen structure of liquid crystal
molecules, can be synthe- sized using 1 chloro 4 uorobenzene, 1
chloro 3,4 diuo- robenzene, and 1 bromo 3,5 diuorobenzene in medium
to high yields with proper choice of metal catalyst (entries 2 4
and 12). In the case of 1 chloro 3,4 diuorobenzene, the iron and
cobalt catalysts gave high yields of the desired product,
but the nickel catalyst gave a much lower yield with consider- able
generation of the deuorinated biaryl and teraryl com- pounds, via C
F bond cleavage. A similar trend was observed in the reaction with
electron decient 4 uorophenylmagne- sium bromide. While the
reactions of o tolyl and mesityl- magnesium bromides were rather
slow because of their steric bulkiness, elevated reaction
temperatures (80 and 120 ) gave the corresponding products in
medium to high yields (entries 5, 6, and 13). In these cases, the
nickel catalyst showed higher catalytic activity than the other
catalysts. 1 and 2 naphthylmagnesium bromides took part in the iron
catalyzed coupling reaction (92% and 96% yields, respectively,
entries 7 and 8). The reactions of 2 naphthylmagnesium bromide with
the cobalt and nickel catalysts were less selective, giving 70% and
82% yields of the desired product and 24% and 17% of 2,2’
binaphthyl, respectively. As shown in entry 9, the dimethyl- amino
group seems to interfere with the nickel catalyzed coupling
reaction, but not the iron catalyzed coupling. Acetal functionality
remained intact under the reaction conditions (entry 10). In the
presence of the iron catalyst, the reaction of 4 chlorothioanisole
with p TolMgBr took place via a selective C Cl bond cleavage to
give 4 methyl 4’ methylsulfanylbiphe- nyl in 80% yield. The cobalt
and nickel catalyzed reactions were less selective and afforded 55%
and 10% yields with con- siderable amounts of side products such as
4,4’’ dimethyl 1,1’:4’,1’’ terphenyl via C S bond cleavage. 46 As
shown in entry 12, 1 bromo 3,5 diuorobenzene selectively gave the
desired product in the presence of the nickel catalyst owing to the
considerably higher reactivity of the C Br bond as com- pared to
the C F bond. The iron and cobalt catalysts gave 4,4’
dimethylbiphenyl as the major product via the homocou- pling of p
TolMgBr (35% and 46%, respectively). Whereas the reaction of 1
bromo 2 (but 3 enyl)benzene and p TolMgBr with the nickel catalyst
selectively gave the desired product, the reaction with the iron
catalyst gave only 18% yield with 68% yield of 4,4’
dimethylbiphenyl via a homocoupling reaction (entry 14).
Heteroaromatic nucleophiles, as well as electrophiles, took part in
the selective biaryl cross coupling reaction (entries 15 20). In
the presence of cobalt and nickel catalysts, 2 bromo-
Table 5. Comparison between bisphosphine and NHC ligands in IGM
uorides/phosphine catalyed biaryl crosscoupling.
Table 6. Leaving group capabilities of IGM uorides/NHCs.
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pyridine reacted with p TolMgBr at 60 producing the desired product
in 95% and 93% yields, respectively (entry 15). The reaction with
the iron catalyst was less selective, yielding 66% of the desired
product and 30% of 4,4’ dimethylbiphenyl
via the homocoupling of p TolMgBr. In these cases, 2 bromo-
pyridine was not recovered. As shown in entry 16, the reaction
between 3 bromopyridine and p TolMgBr took place selec- tively with
the nickel catalyst but not with the iron or cobalt
Table 7. Substrate scope of iron group metal uoride/NHC catalyzed
baryl crosscoupling reactions.
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catalysts. The reaction between 2 chlorothiophene and p
anisylmagnesium bromide was selective with the cobalt cata- lyst to
give the desired product in 95% yield (entry 17). In the presence
of the iron or nickel catalyst, the reaction did not proceed to
completion, and 2 chlorothiophene was recovered (ca. 90% and 50%,
respectively). 3 Bromothiophene gave the corresponding coupling
product in good yields in the presence of the cobalt and nickel
catalysts (entry 18). The reaction of 2 chloroquinoline with
mesitylmagnesium bromide at 100 yielded the desired product (82%,
entry 19). In the presence of the cobalt and nickel catalysts, the
reaction of 2 bromopyri- dine with 2 thienylmagnesium bromide
proceeded to comple- tion at 80 to give 2 thiophen 2 yl pyridine in
99% yield (entry 20). 2.5 Mechanistic Consideration of the
Catalytic “Fluoride
Effect”: Proposal of New Mechanisms and Theoretical
Evaluation
To gain mechanistic insight into the origin of the high cross/homo
selectivity of the metal uoride catalysts, a series of control
experiments and theoretical studies were conducted. The results of
the control experiments using a variety of metal salts, NHC ligand
precursors (SIPr·HCl or IPr·HCl), and p TolMgBr are summarized in
Scheme 5 and Table 8. The reac- tions were carried out in the
absence of an aryl halide, which has been reported to accelerate
the reductive elimination of neutral organonickel compounds. 47 A
stark difference between the metal chloride and uoride reactivity
towards the Grignard reagent was observed. As shown in Scheme 5,
treatment of FeCl 2 (0.1 mmol) with p TolMgBr (20 equiv) at 0 in
the presence of SIPr·HCl (3.0 equiv) produced 0.096 mmol of 4,4’
dimethylbiphenyl 4 (96% yield based on the amount of FeCl 2).
Similarly, treatment of FeCl 3 with p TolMgBr under the same
conditions resulted in 1.5 times the stoichiometric amount of 4 as
compared to FeCl 2 treated with the Grignard reagent. The results
clearly indicate that p TolMgBr reduces the metal chlorides to give
the corresponding metal(0) species and the biaryl product
simultaneously, which corresponds to the initial activation step in
the cross coupling reaction. Alter- natively, iron (II or III)
uorides did not afford 4 under the same conditions. Only a small
amount of 4 was formed at 60 (with FeF 2 and FeF 3 in 6% and 11%
yields, respectively), while the biaryl cross coupling reaction
proceeded smoothly at the same temperature in the presence of an
aryl halide. Table 8 summarizes the results of similar control
experiments for the cobalt and nickel halides. Treatment of cobalt
and nickel chlorides with p TolMgBr resulted in the rapid homo-
coupling of the Grignard reagents (0 , 1 h) to give 4 in
quantitative yield (entries 3 and 4). However, the corresponding
uorides of these metals did not react with the Grignard reagent
under the same conditions resulting in an 8 11% yield of 4 at 60
.
The thermal instability of homoleptic tetraphenylferrate species,
such as [Ph 4Fe]Li 2,
48 resulted in the assumption that the homoleptic metalate complex
via the transmetalation and addition of an arylmagnesium reagent
was dominant in the reaction of the metal chlorides. Conversely,
the sharp contrast observed in the reactivity of metal uorides (no
signicant biaryl formation) suggests that the uoride counter ion
may interfere with the formation of the fully arylated metalate
complex presumably due to its high electronegativity and strong
uoride coordination to the IGM center.
It should be noted that chlorobenzene 1 did not react in the
presence of a stoichiometric amount of IGM uorides and slight
excess of NHC ligands. 95 99% of the starting material was
recovered without the formation of any byproduct after 24 h at 60 .
The low reactivity provides evidence that oxidative addition of the
aryl halide to the divalent metal uorides does not occur in the
absence of Grignard reagent, even in the pres- ence of NHC ligands
(not the NHC precursors). The genera- tion of reactive
intermediates requires the reaction of corre- sponding metal
uorides with an aryl Grignard reagent.
Based on the control experiments described above and the previously
suggested reaction mechanisms involving the organometalate
complexes of iron, 26o cobalt, 49 and nickel 50 in cross coupling
reactions, two catalytic cycles are proposed in Figures 2 and 3.
Figure 2 depicts a metalate mechanism, which starts with the
formation of heteroleptic metalate(II) complex A from the divalent
metal uoride and arylmagnesium reagent (Ar 1MgX). Complex A
undergoes oxidative addition with an aryl halide to give elusive
higher valent (formally IV oxidation state) species B carrying Ar 1
and Ar 2. 51 Subsequent reductive elimination to give the
unsymmetrical biaryl (Ar 1 Ar 2) gener- ates metal(II) complex C
bearing two uorides and one halo- gen ligand derived from Ar 2X on
the metal center. The reaction of C with Ar 1MgX regenerates
reactive intermediate A. A radi- cal type (II) (III) mechanism has
been reported for iron cata- lyzed cross coupling reactions of
alkyl halides with arylmag- nesium reagents. 52 The catalytic cycle
depicted on the left hand side of Figure 3 shows a canonical “(0)
(II) mechanism,” which consists of the oxidative addition of an
aryl halide to metal(0) intermediate D, transmetalation between
arylmetal halide E and Ar 1MgX, and reductive elimination of Ar 1
Ar 2 from diarylmetal(II) F. 53 We believe that the present
reaction based on the metal uoride catalyst does not take place via
the popular (0) (II) mechanism, but more likely via the higher
valent metalate mechanism, which is analogous to those of cuprate
mediated substitution reactions and catalytic cross coupling
reactions. 54 The nal reductive elimination process in
Scheme 5. Homocoupling of p TolMgBr by IGM halides.
Table 8. Comparison between IGM chlorides and uorides in the
homocoupling of p TolMgBr.
94 J. Synth. Org. Chem., Jpn.1288
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the metalate mechanism is presumed to be much faster than that of
the “(0) (II) mechanism” owing to instability of high valent
intermediate B, thereby, prevailing over the undesirable
transmetalation or formation of ate complexes carrying excess aryl
groups (such as Ar 1 2Ar 2M, G). 55
We employed DFT calculations to evaluate the aforemen- tioned
reaction pathways in the proposed mechanism starting from a
metalate(II) complex. A chemical model consisting of PhMgCl and
PhCl as the nucleophilic and electrophilic coun- terparts, NiF 2 as
the metal catalyst, and 1,3 dimethylimidazol 2 ylidene (IMe) as the
auxiliary ligand was adopted (Figure 4). The widely used B3LYP/6
31G DFT method was employed for the mechanistic studies of the
formation of nickel cata- lyzed C C bonds. 56
The localization of a single reaction pathway that consists of the
formation of a σ complex, the oxidative addition of chlorobenzene
(Ph Cl), and the subsequent reductive elimina- tion of the biphenyl
(Ph Ph) was successful. The energy prole
and structural information for the equilibrium and transition
structures are shown in Figure 5. The nickelate complex (SM1)
interacts with chlorobenzene to form the σ complex (CP1), which is
9.7 kcal/mol higher in energy than the sum of the electron energies
of SM1 and Ph Cl. The uphill energetics are presumably due to the
instability caused by the distortion in the CP1 square pyramidal
structure (angles: F 1 Ni F 276.3°, Cl Ni F 275.0°, Cl Ni C
1175.4°). The bond lengths indi- cate a weak electrostatic
interaction between the nickel center and the lone pair of
electrons in the chloride ligand (Ni Cl2.69, C 2 Cl1.77, cf. C Cl
of Ph Cl1.76). The oxidative addition of Ph Cl via TS1 (C 2 Cl2.12,
Ni C 2
2.11, Ni Cl2.31) requires an activation energy of 18.3 kcal/mol to
form octahedral Ni(IV) intermediate CP2 (Ni C 21.95, Ni Cl2.35).
This process is endothermic (+6.2 kcal/mol), reecting the elusive
nature of tetravalent organonickel species. The reductive
elimination of Ph Ph from CP2 occurs via TS2 with a small
activation energy of +3.5 kcal/mol to form square planar Ni(II)
complex PD1 with a calculated stabilization energy of 49.4
kcal/mol. In light of the low activation barrier, it is expected
that the tetravalent nickel intermediate would not be a stationary
point when the NHC ligand has sterically demanding aryl groups on
the nitro- gen atoms as in the real system.
The same DFT calculations on the iron and cobalt uo- ride/NHC
systems were performed using similar chemical models. The difculty
in the treatment of multiple spin state systems of these metals (a
divalent iron can take S0, 1, and 2 spin states, and a divalent
cobalt can take S1/2 and 3/2 spin states) has been well documented
for the DFT method, 57 resulting in computational evaluation of the
most critical step of the above presented metalate mechanism, which
is oxida- tive addition. The equilibrium structures of the starting
com- plexes (SM1), the high valent oxidative addition product
(CP2), and the transition structures that connect SM1 and CP2 were
optimized. The energies associated with the chloro- benzene
oxidative addition to heteroleptic metalate complexes SM1 Fe and
SM1 Co, were obtained as shown in Figures 6 and 7, respectively.
For the iron system, the reaction coordinates of the quintet state
(S2) and the triplet state (S1) were iso- lated, but the singlet
state (S0) was unsuccessful. As shown in Figure 6, the oxidative
addition of PhCl to ferrate complex SM1 Fe q in the quintet state
took place via TS1 Fe q with a reasonable activation barrier (ΔE
‡+29.5 kcal/mol) to give tetravalent intermediate CP2 Fe q. In the
reaction coordinate of the triplet state (shown with a dashed line
in Figure 6), it was found that tetravalent intermediate CP2 Fe t
is slightly more stable than the one in the quintet state (CP2 Fe
qΔΔE t q -5.5 kcal/mol), whereas the other stationary points (SM1
Fe t and TS1 Fe t) have higher energies than those in the quintet
state. Based on these results, it was assumed that the most sta-
ble SM1 Fe q was the likeliest candidate for the reactive inter-
mediate toward the oxidative addition. This suggests that the cross
coupling reaction should proceed in the quintet state to
tentatively form the elusive iron(IV) intermediates, which may be
prone to rapid reductive elimination to give the cross cou- pling
product (Ph 1 Ph 2). The spin cross over from CP2 Fe q to CP2 Fe t
may be possible but has not been conrmed yet because locating the
conical section of the intersystem crossing is particularly
challenging.
Figure 7 shows the reaction coordinates of the quartet
Figure 2. Catalytic cycle I: metalate mechanism.
Figure 3. Catalytic cycle II: (0) (+II) mechanism.
Figure 4. Chemical model of NiF 2/NHC catalyzed biaryl
coupling.
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state (S3/2) and the doublet state (S1/2) for the cobalt cat-
alyst, for which the energy proles are considerably more com-
plicated than those of iron. The potential energy surfaces of the
quartet state and the doublet state cross over each other during
the oxidative addition process (solid and dashed lines,
respectively). The cobaltate complex in the quartet state, SM1 Co
q, is found to be more stable than the one in the dou- blet state,
SM1 Co d (ΔΔE q d-8.7 kcal/mol). Alternatively, in transition
structure of the oxidative addition, the quartet state TS1 Co q, is
much higher in energy (+16.6 kcal/mol) than the
doublet state TS1 Co d. Likewise, the quartet state CP2 Co q is
much less stable than the doublet state CP2 Co d (ΔΔE q d +19.9
kcal/mol) at the tetravalent cobaltate intermediate. These results
indicate that the crossover of reaction pathways between the
quartet and doublet states may take place during the oxidative
addition process, where the C Cl bond cleavage takes place via TS1
Co d to give CP2 Co d in the doublet state.
Finally, the origin of the “uoride effect” was investigated using
the same DFT calculations on the reactions of nickel
Figure 6. Energy proles of the oxidative addition to Fe II center
based on the B3LYP/6 31G calculations. Relative electron energies
based on SM1Fe q plus PhCl (E, kcal/ mol) are shown in parentheses
(triplet state, S1: the dashed line, quintet state, S2: the solid
line).
Figure 5. Reaction pathway for nickel uoride catalyzed cross
coupling based on the DFT calculation (B3LYP/6 31G ) and its energy
prole. Relative electron energies based on SM1 plus Ph Cl (E,
kcal/mol) are shown in parentheses. Bond lengths are given in
angstroms. Hydrogen atoms are omitted for clarity.
Figure 7. Energy proles of the oxidative addition to Co II center
based on the B3LYP/6 31G calculations. Relative electron energies
based on SM1Co q plus PhCl (E, kcal/ mol) are shown in parentheses
(doublet state, S1/2: the dashed line, quartetstate, S3/2: the
solid line).
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uoride and chloride with arylmagnesium reagents, where chemical
models consisting of a PhMgBr, IMe, and either nickel salts of NiF
2 or NiCl 2 were adopted. This system corre- sponds to the control
experiments described in Scheme 5 and Table 8. The (IMe)NiX 2 (XCl
or F) systems were chosen as models for the starting nickel
complex, and their reactions with phenylmagnesium chloride solvated
with two molecules of dimethyl ether (PhMgCl·2Me 2O) were examined
(Scheme 6 and Figure 8).
In each case of (IMe)NiCl 2 and (IMe)NiF 2 (denoted as SM0 XCl and
SM0 XF, respectively), a single reaction pathway was obtained for
the transmetalation process with PhMgCl·2Me 2O to form (IMe)NiPh 2
(denoted as SM4) via the formation of transmetalation intermediates
SM1 XSM2 X, and SM3 X, as shown in Figure 8. The subsequent
reductive elimination of biphenyl from the common intermediate SM4
gives the (IMe)Ni(0) biphenyl η 4 complex (denoted as PD2 ). The
starting NHC nickel chloride complex SM0 XCl and PhMgCl·2Me 2O
form, upon the release of one molecule of
Me 2O, a nickelate complex (SM1 XC1) with high exothermicity
(ΔΔE-42.7 kcal/mol). Dissociation of MgCl 2·2Me 2O from the
nickelate complex forms the neutral phenylnickel species
(IMe)PhNiCl, SM2 XC1, which is 10.0 kcal/mol higher in energy than
SM1 XC1. The reaction with the second molecule of PhMgCl·2Me 2O
forms another nickelate intermediate car- rying two phenyl groups
(denoted as SM3 XC1) also in an exo- thermic manner (ΔΔE-28.7
kcal/mol). Diphenylnickel SM4 is formed by the endothermic
dissociation of MgCl 2·2Me 2O (ΔΔE+10.9 kcal/mol). SM4 undergoes a
reductive elimina- tion to form a biphenyl complex of the nickel(0)
species, PD2, via a three centered transition structure TS3 with a
reasonable activation barrier and exothermic value (ΔE ‡+15.0
kcal/mol and ΔΔE-10.7 kcal/mol, respectively). The entire process
starting from SM0 XCl to PD2 is exothermic (ΔΔE -61.2 kcal/mol) and
the transformation from the initial nicke- late complex SM1 XCl to
PD2 is exothermic (ΔΔE-18.5 kcal/ mol). Considering the whole
reaction pathway, the DFT study suggests that the reduction of NiCl
2 with a phenyl Grignard reagent is a facile process and strongly
supports the experimen- tal results summarized in Scheme 5 and
Table 8.
The DFT calculations for the nickel uoride system pro- vided a
similar sequence of transformations from the starting SM0 XF to
PD2, but the energy prole was different from that of the nickel
chloride system. Transformation from SM1 XF to SM4 consists of four
steps: 1) formation of monophenylnicke- late complex SM1 XF
(ΔΔE-71.2 kcal/mol) 2) formation of divalent phenylnickel halide
SM2 XF upon the dissociation of MgClF·2Me 2O (ΔΔE+37.0 kcal/mol),
3) formation of diphenylnickelate complex SM3 XF (ΔΔE-42.9
kcal/mol), and 4) formation of diphenylnickel species SM4 upon the
dis-
Scheme 6. Chemical models of homocoupling of aryl Grignard reagent
by nickel halides as shown in entris 4 and 8 in Table 8.
Figure 8. Energy proles of the reaction shown in Scheme 6.
Comparison of the electron energies of the stationary points
(B3LYP/6 31G ) was done by compensating the electron energies of
the metal species and Me 2O molecules shown in the brackets, which
are detached or attached to the intermediates upon the
corresponding transforma- tion, and the energy differences thus
obtained are shown as the relative energies based on SM4 (ΔE,
kcal/mol) in parentheses. The dashed line represents the reaction
pathway of nickel chloride (XCl), and the hashed bold line that of
nickel uoride (XF).
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sociation of MgClF·2Me 2O (ΔΔE+17.6 kcal/mol). After the formation
of SM4, each reaction pathway of nickel chloride and uoride merged
into an identical reductive elimination pathway. Although the
overall process from SM0 XF to PD2 is exothermic (ΔΔE-70.2
kcal/mol), energy minima of the nickel uoride system are at the
stages of the organonickelate intermediates, SM1 XF and SM3 XF
(ΔΔE-1.0 and -6.9 kcal/mol, respectively). The most signicant
difference between the chloride and uoride pathways is the highly
endo- thermic nature of the formation of the phenylnickel halide
intermediates SM2 X from the nickelates SM1 X (ΔΔE +37.0 kcal/mol
and +10.0 kcal/mol from SM1 XF and SM1 XC1, respectively). Cleavage
of a stable Ni F bond is energetically unfavorable and is
presumably the origin of the large endothermic value. The large
electronegativity of uorine may account for the stabilization of
the uorinated nickelate complex and contribute in part to the
enhancement of the uphill energy difference. It should be noted
that the activation barrier of the PhCl oxidative addition to SM1
XF is much lower (ΔE ‡+28.0 kcal/mol as in Figure 5) than the
energy of SM2 XF (ΔΔE+37.0 kcal/mol). The present DFT calcula-
tions show that SM1 XF is a reactive intermediate, preferring the
oxidative addition of an aryl halide substrate rather than the
transmetalation step, and hence, a prime catalytically active
candidate in the nickel uoride/NHC catalyzed biaryl cross coupling.
The similar theoretical evaluation for iron and cobalt uoride/NHC
systems revealed the preference for oxidative addition of the
metalate species, such as SM1 Fe and SM1 Co over the formation of
the corresponding transmetalation prod- ucts.
Based on the results of the control experiments and theo- retical
studies, it was concluded that strong coordination of the uoride
ion to the metal center of iron, cobalt, and nickel sup- presses
the initial transmetalation and reduction processes, which promote
undesired homocoupling reactions. The uo- ride ligands remain
coordinated to the metal center throughout the catalytic cycle even
with a large excess of Grignard reagents under catalytic reaction
conditions. Furthermore, the resulting heteroleptic metalate(II)
complex, such as SM1, undergoes oxidative addition of aryl
chlorides with a reasonable activa- tion energy. A low activation
barrier for the reductive elimina- tion from the resulting high
valent intermediate can account for the characteristically high
cross/homo selectivity of the present IGM uoride/NHC catalyzed
biaryl cross coupling reactions.
3 Nickel Catalyzed Alkenylative Cross Coupling between Alkyl Aryl
Suldes and Aryl Grignard Reagents
3.1 Background Despite a long history starting with independent
publica-
tions by Wenkert 58 and Takei 59 in 1979, organosulfur com- pounds
60 have received far less attention as electrophilic sub- strates
in cross coupling chemistry than other substrates, such as halides,
sulfonates, and phosphates. The underuse of organosulfur compounds
is partly due to their malodorous smell 61 and the perception that
they are a lesser substitute for other electrophiles. Although it
has been shown that their reactivity is virtually the same as those
of the widely used organic halides and pseudohalides, 62 we found a
new reactivity of alkyl aryl sulde toward aryl Grignard reagents
during our study on nickel/NHC catalyzed cross coupling described
in
the preceding section. The ample supply of sulfur sources, 63
especially as renery byproducts in industrial chemistry, has
provided the motivation for a detailed study using organosul- fur
compounds to develop novel Ni catalyzed “alkenylative” cross
coupling reactions. The proposed arylation occurs at the alkyl
substituent of the sulde substrate (not at the aryl sub- stituent)
with the simultaneous addition of an olenic substitu- ent at the
reaction center (Scheme 7). 64
3.2 Alkenylative Cross Coupling: Catalyst Screening and Scope of
the Reaction
Table 9 summarizes the results of the catalyst screening. In the
presence of Ni(cod) 2, the highest yield (92%) of the desired
alkenylative coupling product 6 was obtained after 6 h at 60 by
using saturated type NHC ligand precursor, SIPr·HCl (entry 1). The
reactions using the original NHC ligand, SIPr, or the NHC ligand
precursors, IPr·HCl and SIMes·HCl, dis- played varied selectivity
and decreased yields (entries 2, 3, and 4) as compared to SIPr·HCl.
Ni(acac) 2 and NiCl 2 showed lower catalytic activity and required
a higher reaction tempera- ture, 80 , for complete conversion
(entries 5 and 6). While phosphine ligands improved the yield of
the biaryl coupling product 7, the desired alkenylative coupling
product 6 was not isolated (entries 7 10). In the absence of a
nickel catalyst, the coupling reactions were not effective (entry
11).
The scope of the present nickel catalyzed alkenylative cross
coupling reaction is shown in Table 10. The reactions of dodecyl
suldes possessing an electron rich, electron poor, or bulky aryl
group all afforded the alkenylative coupling prod- ucts in high
yields with excellent E/Z selectivity. The parent dodecyl phenyl
sulde reactions performed optimally with the highest yields
(entries 1 5).
Secondary alkyl aryl suldes display alkenlylative coupling
reactivity, which was investigated using cyclohexyl (or cyclo-
heptyl) phenyl sulde reacted with a variety of aryl Grignard
Scheme 7. Alkenylative cross coupling of alkyl aryl sulde.
Table 9. Catalyst screening on the alkenylative cross coupling of
dodecyl phenyl sulde with p TolMgBr.
98 J. Synth. Org. Chem., Jpn.1292
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reagents bearing dimethylamino, methoxy, methyl, and uoro
substituents to afford the corresponding arylated cycloalkenes in
good to excellent yields (entries 6 9, 13). The reaction was rather
sensitive to steric demands of the aryl nucleophile, and thus, the
coupling product yields using o tolyl and mesityl Grignard reagents
were poor (entries 10 and 11). However, the 2 naphthyl Grignard
reagent participated in the reaction (entry 12).
Excellent E/Z selectivity was achieved in the formation of a di
substituted acyclic olen, exemplied by the stereoselective
synthesis of the E stilbene derivative (entry 14). Conversely, a
low selectivity was observed in the formation of a tri substi-
tuted olen (entry 15). The results may be accounted for by the non
stereoselective formation of enethiolate intermediates (see the
mechanistic discussion below). When a non symmetri- cal secondary
alkyl sulde was subjected to the reaction condi-
tions, the corresponding internal olen 8 and terminal olen 9 were
obtained in a ratio of 46:54. Note that the stereoselectiv- ity of
8 is exceptionally high (entry 16). The olen moiety in the sulde
substrate did not interfere with the coupling reac- tion (entry
17). In entry 18, the reaction of 8 phenylthio 1,4
dioxaspiro[4,5]decane gave a double arylation product, 8,8 diphenyl
1,4 dioxaspiro [4,5]decane (37% yield), and the expected
alkenylative coupling product (43% yield). The gemi- nal
diarylation products were also found as minor by products (1 3%
yields) in all entries. The formation mechanism is dis- cussed in
the next section. 3.3 Mechanistic Considerations: How does the
alkenylation
occur? In Figure 9, we propose a mechanism based on the
experi-
mental observations, 65,66 computational studies (Figures 10 and
11), and related literature reports. 67 72 The catalytic cycle
starts with the oxidative addition of an alkyl phenyl sulde to
Ni(0) species A to afford phenylnickel(II) intermediate B.
Successive β hydride elimination and reductive elimination of the
ben- zene affords Ni(0) thioaldehyde complex C. The use of a bulky
NHC ligand should suppress the conventional biaryl coupling pathway
(A B D). The thioaldehyde then undergoes deprotonation via the
reaction with ArMgBr to produce Ni(0) enethiolate complex E. 67,68
Following C S bond cleavage affords alkenyl nickel(II) F. 69
Transmetalation between F and ArMgBr yields diorganonickel product
G as well as the MgBr 2 and MgS byproducts. 70 Reductive
elimination gives the alke- nylative coupling product, such as 6,
with the regeneration of the active species A. The diarylation may
proceed via addition of an aryl Grignard reagent to thiocarbonyl
intermediate C 71 followed by nickel catalyzed arylation of the
resulting benzyl- thiolate. 72
DFT calculations provide deeper insights into the alkenyla- tive
coupling reaction (Figures 10 and 11 show DFT calcula- tions for
specic parts of Figure 9). Figure 10 shows the reac- tion pathways
for oxidative addition. Ni(0) complex A with π coordination and
Ni(0) complex A’ with sulde coordination are in equilibrium with
each other (where Lthe ethyl phenyl sulde substrate from Figure 9).
Aromatic carbon sulde bond cleavage of A takes place via TS A B
requiring activation energy (ΔG ‡2.0 kcal/mol). The total
activation barrier from A’ to TS A B was calculated as 6.8
kcal/mol, which was lower than the aliphatic carbon sulde bond
cleavage via TS A’ INT (11.5 kcal/mol). The calculations suggest
that the predominant formation species is phenylnickel(II) B.
Regarding the trans- formation from B to C, an unprecedented
transition structure
Figure 9. A plausible mechanism.
Table 10. Substrate scope of alkenylative cross coupling.
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Figure 11. Reaction pathway for the reductive β hydride elimination
process (B to C) and the transmetalation process (B to D) and its
energy proles. Relative Gibbs free energies to B (ΔG, kcal/mol,
B3LYP/6 311+G(d,p) SDD//B3LYP/6 31G- (d) LANL2DZ) are shown in
parentheses. Bond lengths are given in angstroms.
Figure 10. Reaction pathway for oxidative addition process (A to B,
A to INT) and its energy prole. Relative Gibbs free energies to A
(ΔG, kcal/mol, B3LYP/6 311+G(d,p) SDD//B3LYP/6 31G(d) LANL2DZ) are
shown in parentheses. Bond lengths are given in angstroms.
100 J. Synth. Org. Chem., Jpn.1294
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model was obtained (Figure 11). Here, B (where RH, Lnone from
Figure 9) isomerizes to B’, in which an agostic Ni H interaction is
present. A concerted β hydride reductive elimination of benzene
takes place via ve centered transition structure TS B C to form
Ni(0) thioaldehyde complex C. Alter- natively, the transmetalation
from B to D takes place via tran- sition structure TS B D
resembling that in σ bond metathesis. The relative Gibbs free
energy of TS B D was calculated as 3.0 kcal/mol, which is higher
than that of TS B C, probably a result of the steric demand by the
bulky SIPr ligand at TS B D. The computational results are in
accordance with the experi- mental results, indicating the
selective alkenylative coupling product formation in the presence
of SIPr.
4 Conclusions
Two novel C sp 2 C sp 2 cross coupling reactions catalyzed by iron
group metals (IGMs) with N heterocyclic carbene (NHC) ligands were
developed. Combinations of NHCs and IGM uoride salts were
demonstrated to be excellent catalysts for highly selective biaryl
cross coupling reactions between aryl Grignard reagents and aryl or
heteroaryl halides. The forma- tion of homocoupling byproducts,
which often becomes a criti- cal issue in industrial settings, was
suppressed markedly by appropriate choices of the metal uoride/NHC
combination. Based on stoichiometric control experiments and
theoretical studies, the origin of the unique “uoride effect” was
explained by the formation of a higher valent heteroleptic metalate
spe- cies, [Ar 1M IIF 2]MgBr (MFe, Co, Ni) as the key intermediate.
During our continuing exploration for new reactivity of IGM/ NHC
catalysts, an unprecedented alkenylative cross coupling reaction
was developed by using a Ni(0)/SIPr catalyst. The alkyl aryl suldes
cross coupled with aryl Grignard reagents, producing various
styrene derivatives via formal alkyl aryl coupling followed by
dehydrogenation. The IGM/NHC cata- lyzed cross coupling reactions
described in the present report provide a selective and practical
synthetic method for unsym- metrical biaryls and alkenylated
aromatic compounds. Addi- tionally, the results offer new
mechanistic insights into IGM catalyzed cross coupling reactions.
The present study displays new synthetic potentials of IGM/NHC
catalysts by using what were considered non orthodox combinations
of metal cata- lysts, ligands and substrates, and illustrates that
the exploration of new selectivity and reactivity of the catalyst
system can lead us to deeper mechanistic understandings. Although
numerous studies have been conducted on the IGM/NHC catalyst, end-
less selectivity and reactivity properties remain to be discovered
and will be the focus of future work.
Acknowledgment The authors are grateful to Dr. Hirofumi Seike, Mr.
Sigma
Hashimoto, and all the co workers, whose names appear in the
references, for their invaluable intellectual and experimen- tal
contributions to the cross coupling chemistry described in this
article. The present work is based on our research projects, which
are supported by Grant in Aids for Scientic Research from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. Financial support from Tosho Fine Chemi- cal and Tosho
Corporation are gratefully acknowledged.
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Ohsugi, S.; Miyamoto, T. Tetrahedron Lett. 2001, 42, 9207.
62 Selected cross coupling reactions of alkyl aryl suldes: (a)
Melzig, L.; Metzger, A.; Knochel, P. J. Org. Chem. 2010, 75, 2131.
(b) Kanemura, S.; Kondoh, A; Yorimitsu, H.; Oshima, K. Synthesis
2008, 2659. (c) Leconte, N.; Wuillaume, A. K.; Suzenet, F.;
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64 Reactions of dithioacetals with Grignard reagents give olens.:
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Acc. Chem. Res., 1991, 24, 257.
65 The use of dodecanethiol instead of dodecyl phenyl sulde did not
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coupling product, 1 dodecyl 4 methylbenzene (7%), dodecane (24%),
and 1 dodecene (27%), respectively.
66 The reaction of 2,2,4,4,6,6 hexamethyl 1,3,5 trithiane, a trimer
form of propane 2 thione, with 4 (N,N dimethylamino)phenyl Grignard
reagent gave the corresponding alkenylative coupling product, N,N
dimethyl 4 (prop 1 en 2 yl)aniline (17%) with recovery of the tri-
thiane (51%), which indicates the intermediacy of thioketone in the
present alkenylative coupling reaction.
67 The deprotonation of thiocarbonyl compounds: (a) Nocher, A. M.
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489.
68 The tautomerization of thiocarbonyl compounds: Zhang, X. M.;
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69 Cross couplings of aryl thiolates: (a) Cho, Y. H.; Kina, A.;
Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811. (b)
Swindell, C. S.; Blasé, F. R. Tetrahedron Lett. 1990, 31,
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70 Generation of MgS: Nieto, J. T.; Arévalo, A.; Gutiérrez, P. G.;
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72 The reaction of naphthalene 2 ylmethanethiol with 3 equivalents
of p tolyl Grignard reagent under the present reaction conditions
gave the coupling product, 2 (4 methylbenzyl)naphthalene (35%) and
the reduced product, 2 methyl naphthalene (27%). For geminal
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Vol.69 No.11 2011 103 1297
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PROFILE
Takuji Hatakeyama is Assistant Professor of Chemistry at Kyoto
University. He was born in Tokyo in 1977. He received his B.Sc.
(2000) and D.Sc. (2005) from the University of Tokyo. He joined
Prof. Ismagilov group at Chicago University as a postdoctoral
fellow in 2005. He became an assistant professor of Professor
Nakamura’s group at Kyoto Uni- versity in 2006. He became
concurrently a PRESTO researcher of Japan Science and Technology
Agency in 2011. His research in- terests are in the area of
synthetic organic chemistry, organometallic chemistry, and
computational chemistry.
Kentaro Ishizuka is Post doctoral Fellow of Chemistry at Kyushu
University. He was born in Kagoshima in 1980. He received his M.Sc.
(2004) and D.Sc. degree (2007) from Kyushu University. He joined
Prof. Nakamura group at Kyoto University as a postdoctoral fellow
in 2007. He became an assistant professor of Institute of Sustain-
ability Science (ISS) at Kyoto University in 2009. He moved to
Kyushu University as a post doctoral fellow of Institute for
Materi- als Chemistry and Engineering (IMCE) in 2010. His research
interests are in the area of synthetic organic chemistry,
especially asym- metric synthesis.
Masaharu Nakamura is Professor of Chemi- stry at Kyoto University.
He was born in Tokyo in 1967. He received his B.Sc. (1991) from
Tokyo University of Science, and his D.Sc. degree (1996) from Tokyo
Institute of Technology. He became an assistant profes- sor of
Professor Nakamura’s group at the University of Tokyo in 1996, and
then was promoted to a lecturer (2002) and an associ- ate professor
(2004). During this period, he joined Prof. Jacobsen group at
Harvard Uni- versity as a visiting scholar (1999 2000), and then,
became concurrently a PRESTO re- searcher of Japan Science and
Technology Agency (2002 2006). In 2006, He moved to Kyoto
University as a professor of Interna- tional Research Center for
Elements Science, Institute for Chemical Research (ICR). He
received the Chemical Society of Japan Award for Young Chemists in
2001. His re- search eld includes organic reaction, or-
ganometallic, and computational/theoretical chemistries, all of
which focus on the inven- tion and discovery of new molecular
trans- formations for organic synthesis of the next
generation.
104 J. Synth. Org. Chem., Jpn.1298
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