Ligand-Controlled Chemoselective C(acyl)-O Bond vs C(aryl)-C Bond Activation of Aromatic Esters in Nickel Catalyzed C(sp2)-C(sp3) Cross-Couplings

Article abstract of DOI:10.1021/jacs.7b12865

A ligand-controlled and site-selective nickel catalyzed Suzuki-Miyaura cross-coupling reaction with aromatic esters and alkyl organoboron reagents as coupling partners was developed. This methodology provides a facile route for C(sp²)-C(sp³) bond formation in a straightforward fashion by successful suppression of the undesired β-hydride elimination process. By simply switching the phosphorus ligand, the ester substrates are converted into the alkylated arenes and ketone products, respectively. The utility of this newly developed protocol was demonstrated by its wide substrate scope, broad functional group tolerance and application in the synthesis of key intermediates for the synthesis of bioactive compounds. DFT studies on the oxidative addition step helped rationalizing this intriguing reaction chemoselectivity: whereas nickel complexes with bidentate ligands favor the C(aryl)-C bond cleavage in the oxidative addition step leading to the alkylated product via a decarbonylative process, nickel complexes with monodentate phosphorus ligands favor activation of the C(acyl)-O bond, which later generates the ketone product.

Full text of DOI:10.1021/jacs.7b12865

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Article
Ligand-Controlled Chemoselective C(acyl)-O bond
vs. C(aryl)-C bond Activation of Aromatic Esters in
Nickel Catalyzed C(sp2)-C(sp3) Cross-Couplings
Adisak Chatupheeraphat, Hsuan-Hung Liao, Watchara Srimontree, Lin
Guo, Yury Minenkov, Albert Poater, Luigi Cavallo, and Magnus Rueping
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12865 • Publication Date (Web): 20 Feb 2018
Downloaded from http://pubs.acs.org on February 20, 2018
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Ligand-Controlled Chemoselective C(acyl)-O bond vs. C(aryl)-
C bond Activation of Aromatic Esters in Nickel Catalyzed
C(sp2)-C(sp3) Cross-Couplings
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Adisak Chatupheeraphat,§,† HsuanꢀHung Liao,§† Watchara Srimontree,† Lin Guo,† Yury Minenkov,‡
Albert Poater,‡,# Luigi Cavallo,‡ and Magnus Rueping†,‡
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡King Abdullah University of Science and Technology (KAUST), KAUST Catalysis Center (KCC), Thuwal 23955ꢀ6900,
Saudi Arabia
#Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Campus Montilivi, 17003
Girona, Catalonia, Spain
KEYWORDS. Nickel catalysis, C-C bond formation, cross coupling
ABSTRACT: A ligandꢀcontrolled and siteꢀselective nickel catalyzed SuzukiꢀMiyaura crossꢀcoupling reaction with aromatic esters
and alkyl organoboron reagents as coupling partners was developed. This methodology provides a facile route for C(sp2)ꢀC(sp3)
bond formation in a straightforward fashion by successful suppression of the undesired ßꢀhydride elimination process. By simply
switching the phosphorus ligand, the ester substrates are converted into the alkylated arenes and ketone products respectively. The
utility of this newly developed protocol was demonstrated by its wide substrate scope, broad functional group tolerance and appliꢀ
cation in the synthesis of key intermediates for the synthesis of bioactive compounds. DFT studies on the oxidative addition step
helped rationalizing this intriguing reaction chemoselectivity: whereas nickel complexes with bidentate ligands favor the C(aryl)ꢀC
bond cleavage in the oxidative addition step leading to the alkylated product via a decarbonylative process, nickel complexes with
monoꢀdentate phosphorus ligands favor activation of the C(acyl)ꢀO bond, which later generates the ketone product.
Conventionally, halocarbon electrophiles are the most applied
ꢀ INTRODUCTION
coupling partners in SuzukiꢀMiyaura reactions. However, the
corrosive halideꢀcontaining waste production does not meet
the modern synthetic chemistry expectations with the growing
interest in environmentally friendly protocol development
nowadays. In this context, aroyl compounds, due to their ubiqꢀ
uitous nature, have received considerable attention to further
complement organic halides as coupling partners in the realm
of transition metal catalyzed reactions.6ꢀ8 Early examples of
using aroyl electrophiles in a decarbonylative manner focused
on “active” species, such as acid chlorides,6 anhydrides,7 or
twisted amides.8 The concept of using naturally abundant and
“nonꢀactivated” esters in decarbonylative crossꢀcouplings is
still in its infancy,9 perhaps due to the difficulty in finding a
suitable catalyst for the activation of inert bonds.
The discovery and development of transition metal catalyzed
crossꢀcoupling reactions is one of the most successful chapters
in modern organic chemistry. Among the disclosed transforꢀ
mations, the SuzukiꢀMiyaura crossꢀcoupling reaction has
emerged as a powerful tool1 to forge linkages between carbon
atoms. To date most coupling reactions show superior ability
for the synthesis of nonꢀsymmetric biaryls via C(sp2)ꢀC(sp2)
crossꢀcoupling,2 while the development of C(sp2)ꢀC(sp3) bond
formations is still more difficult to accomplish,3,4 and suffers
from several undesired reaction pathways. For example, ßꢀ
hydride elimination and protodeboration5 plague the transfer
of the alkyl residue from the organometallic reagent to the
organic framework, which makes the development of C(sp2)ꢀ
C(sp3) couplings a tedious exercise.
Scheme 1. Ligand-Controlled Ni-Catalyzed Suzuki-Miyaura cross-coupling reaction: C(acyl)-O bond vs. C(aryl)-C bond
activation.
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Palladium catalysis has historically dominated the field of Cꢀ
ꢀ RESULTS AND DISCUSSION
halogen bond activation; however, first row transition metals,
such as nickel, were found to be more effective alternatives to
harness less reactive electrophiles.10 For example, the electronꢀ
rich nature renders nickel to be more reactive toward strong
bond activation, such as CꢀO bonds, in the oxidative addition
step. Furthermore, ßꢀhydride elimination is a minor issue with
nickel compared with palladium due to the high energy barrier
of nickelꢀcarbon bond rotation.11
Guided by the theory mentioned above, survey coupling exꢀ
periments with phenyl benzofuranꢀ2ꢀcarboxylate 1a and Bꢀ
alkylꢀ9ꢀBBN 2a under Ni(cod)2 [cod = 1,5ꢀcyclooctadiene]
catalysis were carried out and the results are summarized in
Table 1. Preliminary experiments were conducted with a series
of trialkylꢀmonodentate phosphine ligands, including PnBu3
and PCy3 which resulted in a mixture of ketone A and decarꢀ
bonylative product B (Table 1, entries 1ꢀ2). Carbene ligands
such as 1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolidinꢀ2ꢀylidene
(SIPr) did not provide any trace of product (Table 1, entry 3).
Further evaluation of a range of bidentate phosphine complexꢀ
es revealed the complete suppression of undesired ketone byꢀ
product formation (Table 1, entries 4ꢀ5). The most competent
ligand was identified as dcype [1,2ꢀbis (dicyclohexꢀ
ylphosphino) ethane] providing the product in 75% yield (Taꢀ
ble 1, entry 5). Regarding the effect of different bases (Table
1, entries 5ꢀ7), the best result in terms of reactivity was obꢀ
tained with CsF as base (Table 1, entry 5). The base plays a
crucial role in the transmetalation step, where a higher free
bond enthalpy of the newly formed boronꢀbase bond could
provide a better driving force for the transmetalation process.
Owing to the fact that boronꢀfluorine bonds are the strongest
single bonds (BꢀF bond is 146 kcal/mol),22 the fluoride salt
shows superior ability among the others.
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Hence, the development of a nickel catalyzed SuzukiꢀMiyaura
decarbonylative crossꢀcoupling variant12 with alkylboron
compounds and phenyl esters as crossꢀcoupling partners
would enable an important advancement in the formation of
C(aryl)ꢀC(alkyl) bonds (Scheme 1). On the other hand, alkyl
ketones are important motifs in many natural products and
pharmaceutical compounds. Besides, their propensity to unꢀ
dergo further functional group interconversion makes them
valuable synthetic intermediates. Commonly used transition
metal catalyzed methods to synthesize ketones include: 1)
transitionꢀmetalꢀcatalyzed carbonylation of organic halides
(RX) with CO; 2) nucleophilic addition of organometallics to
carboxylic acid derivatives. However, the manipulation of
toxic carbon monoxide under high pressure conditions limits
the carbonylation strategy and the overaddition of hard organꢀ
ometallic reagents to carboxylic acid derivatives often results
in the formation of undesired tertiary alcohols instead of keꢀ
tones.13 Therefore, a userꢀfriendly synthetic operation which
can produce solely ketone products is highly desired. Transiꢀ
tionꢀmetalꢀcatalyzed SuzukiꢀMiyaura crossꢀcoupling is an
ideal platform for such transformations14 and progress in acylꢀ
ation reactions was accomplished by using reactive acylating
reagents such as acid chlorides,15 acid anhydrides16 and thioeꢀ
sters.17 In addition, amide CꢀN bond cleavage became a recent
topic;18 however, the reaction outcome is highly dependent on
the protecting group on the amide moiety. In contrast, the
activation of the acyl CꢀO bond of esters remains elusive.
Inspired by Yamamoto’s pioneering work in 1980,19 who
reported the CꢀO bond cleavage of esters with stoichiometric
amounts of Ni, Chatani’s activation of pyridyl esters and their
reaction with organoboron nucleophiles,20 as well as Yamaguꢀ
chi and Itami's report on the Ni catalyzed decarbonylative
coupling of azoles with aromatic esters9f we questioned
whether a SuzukiꢀMiyaura coupling system could be extended
to simple and unactivated phenyl esters, suppressing the loss
of carbonyl moiety (CO) for the ketone formation.
Table 1. Optimization of the nickel catalyzed decarbonyla-
tive Csp2-Csp3 couplinga
Entry Ni cat.
Ligand
Base
Yieldb (%)
(1 equiv)
A
B
1
2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
NiCl2/Zn
ꢀ
PnBu3
PCy3
CsF
CsF
CsF
CsF
CsF
Cs2CO3
K3PO4
ꢀ
5
10
ꢀ
14
ꢀ
3
SIPr
ꢀ
4
dcypf
dcype
dcype
dcype
dcype
dcype
dcype
dcype
dcype
dcype
dcype
ꢀ
40
5
ꢀ
75
6
ꢀ
6
The development of readily tunable and chemoselective transꢀ
formations in the presence of multiple possible reactive sites is
a challenge in modern organic synthesis. Transition metal
catalyzed reactions are effective in addressing this problem by
changes in the coordination geometry of the catalytic center
using diverse ligand effects. Herein, we describe a ligand
switchable SuzukiꢀMiyaura crossꢀcoupling variant with ester
and alkyl organoboron components as coupling partners. This
newly developed methodology provides an unconventional
route for C(sp2)ꢀC(sp3) bond formation in a straightforward
fashion, which successfully suppresses the undesired ßꢀ
hydride elimination. Furthermore, the judicious choice of
different phosphorus ligands delivers the decarbonylative and
ketone products respectively (Scheme 1).21
7
ꢀ
39
8
ꢀ
23
9c
10d
11
12
13e
CsF
CsF
CsF
CsF
CsF
CsF
ꢀ
41
ꢀ
66
ꢀ
20
ꢀ
ꢀ
Ni(cod)2
ꢀ
98(95)f
97(95)f
14d,e Ni(cod)2
ꢀ
i-Pr
N
i-Pr
N
PCy2
PCy2
Fe
P
P
i-Pr
SIPr
i-Pr
dcypf
dcype
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b
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
150 °C for 65 h, yield for isolated products. dcype (40 mol %)
was used. cCs2CO3 (2 equiv). dReaction was stirred for 5 days.
mol %), ligand (40 mol %), base (1.o equiv), toluene (1 ml), 150
1
2
3
°C, 16 h. bNMR yield, 1,3,5ꢀ(OMe)3C6H3 as internal standard.
d
e
cReaction in iꢀPr2O. dcype (20 mol %). Reaction performed for
72 h. fYield of isolated product.
4
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9
Initially, esters incorporating a series of different heterocyclic
patterns, including benzofuran, benzothiophen and indole,
were tested and the corresponding products 3a-c were isolated
with high yields (95, 82, and 67% yield respectively). Switchꢀ
ing to structurally simpler furan and thiophene based esters
still provided the products 3d-i with pleasing results. Further
efforts focused on nonꢀheteroatom containing aromatic moieꢀ
ties on the ester group. Substrates with nonꢀsubstituted (1j),
electronꢀrich (1k, 1m) and ꢀdeficient (1l) phenyl esters were
tested and participated ideally in this process, furnishing the
corresponding adducts 3j-m in moderate to good yields. In
addition, substrates with πꢀextended aromatic rings, including
biphenyl, 2ꢀnaphthyl and 1ꢀnaphthyl esters (1n-p) were also
studied and provided satisfying results. Lastly, the chemoseꢀ
lectivity between different esters was also investigated. Notaꢀ
bly, only the phenylꢀcontaining ester moieties had been reꢀ
placed and delivered the corresponding substituted product 3r.
Interestingly, a baseꢀfree reaction still successfully delivered
the desired product, albeit with a much lower yield (Table 1,
23% vs. 75% yield, entry 8 vs. 5). Further optimization foꢀ
cused on solvent screening; switching the solvent from toluene
to diisopropyl ether, however, afforded a lower yield (Table 1,
entry 9). In situ generation of the Ni (0) catalyst from NiCl2
and zinc dust was evaluated; however, a significantly deꢀ
creased reactivity was observed (Table 1, 20% vs. 75% yield,
entry 11 vs. 5). Control reactions showed that no product is
obtained in the absence of the nickel catalyst (Table 1, entry
12). Notably, extending the reaction time afforded the product
in better yield (Table 1, entry 5 vs. 13 and entry 10 vs. 14).
To further demonstrate the generality of this novel protocol,
we evaluated the scope of the nickel catalyzed Suzukiꢀ
Miyaura crossꢀcoupling reaction between esters and Bꢀalkylꢀ9ꢀ
BBNs. As revealed in Table 2, a variety of ester substrates
with different electronic properties and substitution patterns
provided the corresponding decarbonylative products 3 with
excellent reactivity.
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Table 3. Scope of organoborane in the nickel catalyzed
decarbonylative aryl-alkyl cross-couplinga
Table 2. Ester scope in the nickel catalyzed decarbonyla-
tive aryl-alkyl cross-couplinga
aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Ni(cod)2 (10
mol %), dcype (20 mol %), CsF (1.0 equiv) in toluene (0.2 M) at
150 °C for 65 h, yield for isolated products.
After testing the tolerance with different ester precursors, our
efforts focused on applying various Bꢀalkylꢀ9ꢀBBNs 2 in this
newly developed SuzukiꢀMiyaura reaction. Different substituꢀ
tion patterns and electronic properties on the Bꢀalkylꢀ9ꢀBBNs
were evaluated to establish the reaction scope. As shown in
Table 3, all alkylborane reagents were well tolerated and the
decarbonylative products 3s-y were isolated in good yields.
Furthermore, the silyl and ester group containing alkylborane
nucleophiles were also suitable for the crossꢀcoupling protoꢀ
col, which features the possibility for further functional group
interconversion.
In addition to the in situ prepared Bꢀalkylꢀ9ꢀBBN nucleoꢀ
philes, commercial available triethylborane (BEt3) has also
proved itself as an ideal alkylborane reagent for this demandꢀ
ing transformation. A series of different esters with aromatic
and heteroatom containing aromatic moieties were employed
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
mol %), dcype (20 mol %), CsF (1.0 equiv) in toluene (0.2 M) at
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in this reaction under the optimized conditions and the correꢀ
sponding products 5a-g were obtained in good yields (Table
desired alkylated products 3a, 3j with 58% and 34% yields
respectively.
1
4).
2
3
4
5
6
Table 6. Scope of the nickel catalyzed decarbonylative
aryl-alkyl cross-coupling with amidesa
Table 4. Scope of the nickel catalyzed decarbonylative
aryl-alkyl cross-coupling: Triethylborane as organoborane
reagenta
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aReaction conditions: 6 (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
mol %), dcype (20 mol %), CsF (1.0 equiv) in toluene (0.2 M) at
150 °C for 65 h, NMR yield, 1,3,5ꢀ(OMe)3C6H3 as internal standꢀ
ard. b160 °C, 120 h.
We next turned our attention to the development of a general
protocol for the ketone formation, which was isolated as a side
product in our initial studies. The ketone product can be obꢀ
tained from transmetallation with the Bꢀalkylꢀ9ꢀBBN without
CO extrusion. Based on this observation, we hypothesized that
the ketone might indeed become the sole product by varying
the reaction parameters. Our initial efforts focused on screenꢀ
ing various ligands.
aReaction conditions: 1 (0.2 mmol), 4a (0.4 mmol), Ni(cod)2 (10
mol %), dcype (40 mol %), CsF (1.0 equiv) in toluene (0.3 M) at
150 °C for 48 h, yield for isolated products.
Microwave irradiation has become a popular technique in
modern transition metal catalysis, not only because it provides
a highly efficient energy source, but also prevents the decomꢀ
position of sensitive catalysts.23 Therefore, we became interꢀ
ested in a microwaveꢀassisted procedure for our newly develꢀ
oped nickel catalyzed decarbonylative Csp2ꢀCsp3 coupling.
When compared to the batch reaction, an enormous process
acceleration was observed (Table 5, entry 1 vs entry 2).
Table 7. Optimization of the nickel catalyzed Suzuki-
Miyaura cross-coupling reaction for ketone formationa
O
R
R
O
Ni(cod)2 (10 mol %)
ligand (20 mol %)
A'
B'
OPh
+
B
+
base (2 equiv)
toluene, T (°C), 10 h
Table 5 Nickel catalyzed decarbonylative Csp2-Csp3 cou-
R
plings: MW vs. Batcha
1o
2a:
R = CH2PMP
Entry
Ligand
Base
T (°C)
Yieldb (%)
(2 equiv)
A'
B'
1
2
SIPr
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ꢀ
110
110
150
150
150
150
110
110
110
110
110
110
110
80
ꢀ
ꢀ
ꢀ
ꢀ
dcype
dcype
dcype
dcype
dcype
PPh3
Entry
Conditions
MW
Time (h)
Yieldb (%)
3
4c
5c,d
6d,e
7
ꢀ
32
42
53
61
ꢀ
ꢀ
1
5
5
5
82
39
64
ꢀ
2
3c
Batch
ꢀ
MW
12
82
90
50
40
81
62
90
75
ꢀ
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
mol %), dcype (20 mol %), CsF (1.0 equiv), toluene (1 ml).
bNMR yield, 1,3,5ꢀ(OMe)3C6H3 as internal standard. cWith
Cs2CO3 (2 equiv) as base.
8
PCy3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
ꢀ
ꢀ
9
ꢀ
10
11
12
13f
14
15
16g
17
18
ꢀ
ꢀ
Inspired by the successful development of nickel catalyzed
decarbonylative reactions with amide substrates reported indeꢀ
pendently by Szostak and Shi last year,24 we also applied our
optimal reaction conditions to amides as substrates in this new
SuzukiꢀMiyaura crossꢀcoupling reaction (Table 6). Within this
area, we were interested to forge linkages between C(sp2) and
C(sp3) atoms from unꢀactivated amides which is challenging
and difficult to achieve. To our delight, the benzofurylꢀ and
phenylꢀbased amides were successfully transformed into the
ꢀ
ꢀ
ꢀ
40
ꢀ
80
ꢀ
80
ꢀ
ꢀ
PnBu3
80
ꢀ
ꢀ
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aReaction conditions: 1o (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
b
mol %), ligand (20 mol %), base (2 equiv), toluene (1 ml). Yield
1
2
3
after purification. 65 h. ddcype (40 mol %). eReaction in MW for
c
5 h. fReaction in iꢀPr2O. gWithout Ni(cod)2.
4
5
6
7
8
9
However,
the
carbene
ligand,
1,3ꢀbis
(2,6ꢀ
Table 8. Ester scope for the nickel catalyzed cross-coupling
reaction for ketone formationa
diisopropylphenyl)imidazolidinꢀ2ꢀylidene (SIPr), and the
bidentate phosphine ligand, 1,2ꢀbis (dicyclohexylꢀphosphino)
ethane (dcype), did not provide the desired ketone product
(Table 7, entries 1 and 2). In contrast, the corresponding deꢀ
carbonylative product B' was obtained when the temperature
of the reaction was raised to 150 °C and when the reaction was
performed under microwave irradiation (Table 7, entries 3ꢀ6).
Switching to monodentate phosphine ligands, including PPh3,
PCy3 and PnBu3, provided a significant improvement with
regard to the reactivity and the desired ketone A' was isolated
as the only product with 12%, 82% and 90% yield respectively
(Table 7, entries 7ꢀ9), which indicates that the nature of the
ligand has a dramatic effect on the reaction outcome. Continuꢀ
ing with the most promising ligand, PnBu3, various bases were
evaluated next. However, changing the base from cesium
carbonate to other bases had a deleterious effect on the yield
(Table 7, entries 10ꢀ12). Use of diisopropyl ether as solvent,
provided a decrease in the reaction yield (Table 7, entry 13).
Further optimization focused on the reaction temperature;
lowering the reaction temperature to 80 °C was not detriꢀ
mental for the ketone formation (Table 7, entry 14). Decreasꢀ
ing the reaction temperature further to 40 °C resulted in a
lower yield (Table 7, entry 15). Lastly, a series of control
experiments indicated that the presence of nickel catalyst,
phosphorus ligand and base are crucial for the reaction (Table
7, entries 16ꢀ18).
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Having established an optimal reaction protocol, an investigaꢀ
tion of the substrate scope for the ketone formation was carꢀ
ried out. The results summarized in Table 8 show that a wide
range of ester substrates are well tolerated in this C (acyl)ꢀO
bond activation protocol to afford the desired ketones 7a-s
with excellent reactivity.
Compared to the naphthyl substituted ketone 7a (94%), the
phenyl substituted ketone 7b was also obtained with high yield
(87%). This result indicated that reactive fused aromatic rings
containing substrates are not necessary in this methodology.
Therefore, we decided to examine the scope tolerance with
simple phenyl substituted esters. Next, various phenylꢀ based
esters bearing substituents with different electronic and steric
properties in the para position were tested and the adducts 7c-i
were isolated in good to excellent yields (64ꢀ89%). Furtherꢀ
more, phenylꢀbased esters with substitution on either ortho or
meta positions also reacted nicely to furnish the desired ketone
products 7j-k with good yields (76ꢀ78%). In addition, the
benzylꢀbased ester, methyl ketone and amine substitutions
remained intact (7l-n). These versatile products show potential
for further diversification via additional chemical transforꢀ
mations. Lastly, we also have evaluated substrates with heterꢀ
ocyclic moieties, including furan, benzofuran, thiophene and
indole, which also gave the desired products with pleasing
results (7o-s). The next aim was the application of this newly
developed strategy to a variety of alkylborane reagents. In
order to demonstrate the superiority of our protocol with reꢀ
spect to substrate scope tolerance, both the phenylꢀ and naphꢀ
thylꢀbased esters were examined simultaneously.
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Ni(cod)2 (10
mol %), PCy3 (20 mol %), Cs2CO3 (2.0 equiv) in toluene (0.2 M)
b
at 80 °C for 10 h, yield for isolated products. PnBu3 was used as
ligand instead of PCy3.
Firstly, various phenylꢀbased Bꢀalkylꢀ9ꢀBBNs 2 bearing subꢀ
stituents with different electronic properties in either ortho or
para position were tested. Excellent results were achieved and
adducts 7t-aa were isolated in good to high yields (72ꢀ91%).
Subsequently, aliphaticꢀbased alkylborane reagents were apꢀ
plied, which also reacted nicely to furnish the corresponding
ketones 7ab-ae with high yields (76ꢀ90%). Furthermore, we
also applied the silyl protected ether containing alkylborane
reagent in the reaction system, which delivered the desired
products 7af, 7ag with acceptable results (82ꢀ87% yield).
Lastly, a chiral carbon containing reagent was found also
suitable for the crossꢀcoupling protocol. Subsequently, comꢀ
mercial available triꢀalkyl boranes were subjected to the nickꢀ
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elꢀcatalyzed reaction and coupled with a series of esters bearꢀ To show the synthetic applicability of our newly developed
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ing different electronic properties (Table 10). To our delight,
all applied substrates were successfully converted into the
corresponding ketone products with good to excellent yields.
Table 9. Organoborane scope of the nickel catalyzed cross-
coupling reaction for ketone formationa
method, an intramolecular version of the nickel catalyzed
SuzukiꢀMiyaura reaction was investigated. Conventionally,
transition metal catalyzed intramolecular reactions sometimes
suffer from undesired problems, e.g. selfꢀdimerization. Howꢀ
ever, after reaction examination we were able to overcome the
obstacle of undesired side product formation and to obtain the
desired product 10 in good yield (Table 11).
In a scaleꢀup process, a gram scale reaction was carried out in
order to demonstrate the scalability of our newly developed
method. Importantly, the cheap and air stable NiCl2 was found
to be able to provide the ketone 7a in high yield (86%),25
which offers a great opportunity for further application in
industry (Scheme 2).
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The power of this methodology is exemplified through its
application to the synthesis of bioactive reagents (Scheme 3).
For examples, ester 1o could be coupled with piperdineꢀ
derived organoborane reagent 11 under our optimal nickel
catalyzed reaction conditions, which successfully provided
ketone 12a in 87% yield. Ketone 12a is an intermediate for the
synthesis of 13a, a potent antagonist of αvβ3/αvβ5 integrins26
and our crossꢀcoupling strategy provides an alternative route
for its synthesis. Compound 13b which showed high affinity
for selective serotonin reuptake inhibitors (SSRIs),27 is expectꢀ
ing to produce a new generation of antidepressants with faster
onset of action and greater efficiency and safety than the curꢀ
rent marketed reagents. Therefore, we also applied our newly
developed strategy to the synthesis of its ketone precursor 12b,
which was isolated in 82% yield.
Table 11. Nickel catalyzed intramolecular Suzuki-Miyaura
cross-coupling reaction
1) 9-BBN dimer, toluene
reflux for 16 h
Conc. [M] Yield (%)
O
O
aReaction conditions: 1o or 1j (0.2 mmol), 2 (0.4 mmol), Ni(cod)2
(10 mol %), PCy3 (20 mol %), Cs2CO3 (2.0 equiv) in toluene (0.2
M) at 150 °C for 10 h, yield for isolated products.
0.12
5
OPh
2) Ni(cod)2 (10 mol %)
PnBu3 (20 mol %)
Cs2CO3 (2 equiv)
60 °C, 72 h
0.065
0.048
0.038
32
67
74
9
10
Table 10. Scope of the nickel catalyzed cross-coupling
reaction for ketone formation: Trialkylborane as organo-
borane reagentsa
Scheme 2. Gram scale coupling: NiCl2 as economical cata-
lyst
O
O
R
O
O
Ni(cod)2 (10 mol %)
PCy3 (20 mol %)
NiCl2 (10 mol %)
PnBu (40 mol %)
R
OPh
Ralkyl
OPh
+
B
Ar
Ar
B(Ralkyl
)
+
3
Cs2CO3 (2 equiv)
Cs2CO3 (2 equiv)
toluene, 60 °C, 16h
toluene, 60 °C, 72 h
1
4
8a-h
O
1o, 4.03 mmol (1g)
2a: R = CH2PMP
6.04 mmol
7a: 86%
O
O
Me
Me
Me
Price comparsion (Sigama Aldrich):
2 g Ni(cod)2 vs. 50 g NiCl2: 80.06 euro vs. 61.1 euro
tBu
R
8a, 89%b
8b, R = H: 97%
8c, R = Ph: 80%
8d, 90%
Scheme 3. The developed alkylation method enables the
facile synthesis of bioactive compounds
O
O
Me
Me
R
O
Me
O
F3C
8e, 64%
8h, 85%
8f, R = H, 76%
8g, R = Ph, 63%
aReaction conditions: 1 (0.2 mmol), 4a,b (0.4 mmol), Ni(cod)2
(10 mol %), PCy3 (40 mol %), Cs2CO3 (2.0 equiv) in toluene (0.3
b
M) at 60 °C for 16 h, yield for isolated products. Reaction at 40
°C.
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Boc
N
O
NBoc
Ni(cod)2 (10 mol %)
Pcy3 (20 mol %)
O
1
2
OPh
Cs2CO3 (2 equiv)
toluene, 80 °C, 10 h
+
B
3
4
12a, naphthyl: 87%
1o, 1j
11
12b
, phenyl: 82%
5
6
7
8
9
MeO
CO2H
Boc
N
O
N
N
H
N
O
10
11
12
13
13a
potent antagonist of αvβ3/αvβ5 integrins
13b
potential antidepressant drug
With this experimental background in mind28 we performed
DFT calculations29 to rationalize the selective activation of the
C(acyl)ꢀO bond with monoꢀdentate phosphorus ligands versus
the selective activation of the C(aryl)ꢀC bond with biꢀdentate
phosphorus ligands.30
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As model system we investigated the reactivity of 1o with
Ni(PnBu3)2 and Ni(dcype).
Focusing on Ni(PnBu3)2, the reaction starts with coordination
of the aryl ester 1o to the Ni center to form complex IN0 (Figꢀ
ure 1a). Oxidative addition of the C(acyl)ꢀO bond to the metal
via transition state TS1 requires an activation free energy of
22.7 kcal/mol to generate the acylꢀNi intermediate IN1. The
overall step is endergonic by 10.7 kcal/mol. The competitive
oxidative addition of the C(aryl)ꢀC bond via transition state
TS2, generating intermediate IN2, has an activation barrier of
26.5 kcal/mol and it is endergonic by 11.1 kcal/mol. Thus,
with Ni(PnBu3)2 C(acyl)ꢀO activation is favored over C(aryl)ꢀ
C bond activation by 3.8 kcal/mol (22.7 vs. 26.5 kcal/mol).
Oxidative addition at the OꢀC(phenyl) bond, via transition
state TS3, has an activation energy of 31.9 kcal/mol, excludꢀ
ing this route.
Figure 1. DFTꢀcomputed Gibbs free energy profile (in
kcal/mol) for the oxidative addition of 1o to: (a) Ni(PnBu3)2
and (b) Ni(dcype). Blue pathway: C(acyl)−O bond activation.
Red pathway: C(aryl)−C bond activation. Green pathway: Oꢀ
C(phenyl) bond activation.
Moving to Ni(dcype), coordination of 1o to the Ni center to
form complex IN0 is exergonic by 30.5 kcal/mol (Figure 1b).
Oxidative addition of the C(acyl)ꢀO bond to the metal via
transition state TS1 requires an activation free energy of 30.4
kcal/mol to generate the acylꢀNi intermediate IN1, the overall
step being endergonic by 11.9 kcal/mol. The competitive
oxidative addition of the C(aryl)ꢀC bond via transition state
TS2, generating intermediate IN2, has an activation barrier of
28.1 kcal/mol and it is endergonic by 16.9 kcal/mol. Thus,
Ni(dcype) activation of the C(aryl)ꢀO bond is favored over
activation of the C(acyl)ꢀC bond by 2.3 kcal/mol (28.1 vs. 30.4
kcal/mol). Again oxidative addition of the OꢀC(phenyl) bond,
via transition state TS3 and an activation energy of 36.7
kcal/mol is at clearly higher energy, and thus it can be ruled
out.
Having validated the computational protocol to reproduce the
experimental selectivities, we moved to rationalize the origin
of the different behavior. Comparison of the free energy proꢀ
files reported in Figures 1a and 1b indicates that the Ni(dcype)
complex coordinates the substrate 15.5 kcal/mol stronger than
the Ni(PnBu3)2 complex, and that the oxidative addition activaꢀ
tion barriers are approximately 25 kcal/mol with Ni(PnBu3)2,
while they are 3ꢀ5 kcal/mol higher with Ni(dcype). The reꢀ
markable difference in the coordination energy can be rationꢀ
alized considering that the Ni(PnBu3)2 moiety has to deform
from a PꢀNiꢀP angle ≈180° to ≈110° upon coordination, see
Figure 2b, whereas the geometry of the Ni(dcype) moiety,
with a PꢀNiꢀP angle ≈90° enforced by the chelating ligand, see
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Figure 2d, is nearly unchanged upon substrate coordination.
in Å and angles in deg. See Figure S1 for a different view of
transition state TS2b.
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8
Thus, we calculated the energy required to deform the metal
fragment from the geometry it has before substrate coordinaꢀ
tion to the geometry it has after substrate coordination. Acꢀ
cording to these calculations deforming the relaxed Ni(PnBu3)2
moiety to the geometry it has upon coordination costs 10.9
kcal/mol more than deforming the Ni(dcype) moiety, almost
accounting for the difference of 15.0 kcal/mol in the free enerꢀ
gies of coordination. This conclusion is in line with similar
considerations in the context of oxidative addition of aryl
iodides to Au(I) complexes.31
Analysis of the transition state geometries, see Figure 2, alꢀ
lows understanding the origin of the different selectivity. In
the C(acyl)ꢀO activation transition states the substrate is oriꢀ
ented perpendicular to the PꢀNiꢀP plane, with a η3 coordinaꢀ
tion of the substrate involving the activated CꢀO bond and the
ipso C atom of the naphthyl moiety (Figures 2a and 2c). The
forming NiꢀC and NiꢀO bonds and the NiꢀP bonds assume an
almost tetrahedral arrangement around the Ni atom, minimizꢀ
ing interaction between the substrate and the alkyl Pꢀ
substituents. Differently, in the C(aryl)ꢀC activation transition
states the substrate is oriented in the PꢀNiꢀP plane, with a η2
coordination of the substrate involving only the activated CꢀC
bond (Figures 2b and 2d). The forming NiꢀC bonds and the
NiꢀP bonds assume an almost square planar arrangement
around the Ni atom, maximizing interaction between the subꢀ
strate and the alkyl Pꢀsubstituents. This is particularly relevant
with the Ni(PnBu3)2 system, due to the larger PꢀNiꢀP angle,
≈110°, versus an angle ≈90° with the Ni(dcype) system. This
is also evidenced by the steric maps reported (Figure S1),32
which indicate steric pressure by the PnBu3 ligands in the
coordination plane defined by the PꢀNiꢀP bonds. The increased
steric repulsion between the substrate and the PnBu3 ligands
destabilizes the C(aryl)ꢀC activation transition state favoring
C(acyl)ꢀO activation.
Hammett Correlation Studies. In order to study the influꢀ
ence of the electronic effects of the substituents on the selecꢀ
tive SuzukiꢀMiyaura coupling protocol, the magnitude of
stabilization that occurred in the transition state for the couꢀ
pling was determined from the Hammett analysis. Hammett
plots were obtained by plotting log(k/k0) against substituent
parameter σp for the nickel catalyzed reaction of paraꢀ
substituted phenolic ester derivatives with Bꢀalkylꢀ9ꢀBBN
2a.33 The plot of log(k/k0) and σp for ketone formation gave a
linear correlation with a slope ρ= +1.2 (Figure 3). The linear
regression with σp value indicated that an inductive effect was
mainly responsible for the stabilization of the transition state.
The positive slope (ρ= 1.2) of the line indicated that oxidaꢀ
tive addition of ester to Ni(0) was sensitive to the electronic
effect of the substituents and weakening of the C(acyl)ꢀO bond
occurred. A positive nonzero slope for the Hammett indicates
that oxidativeꢀaddition is the rateꢀdetermining step in ketone
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formation pathway In contrast, for the decarbonylative proꢀ
.
cess, the plot of log(k/k0) against σp gave a linear correlation
with a slope ρ= ꢀ0.28 (Figure 3). The linear regression with
σp value indicated that oxidative addition is not the rateꢀ
determining step. Therefore, we considered investigating the
full reaction mechanism by DFT calculations in the next stage.
The possible DFT free energy profiles for the conversion of 1o
to the final products are displayed in Figures 4a and 4b for
Ni(PnBu3)2 and Ni(dcype), respectively.20c,30.Only the most
favorable oxidative addition step (Figure 1) was considered for
both catalysts. As discussed above, for Ni(PnBu3)2 the favored
oxidative addition step leads to IN1. The following steps, from
IN1 to IN9, can be associated to the transmetallation section.
It starts with PBu3 dissociation, IN1 to IN4, which costs only
10.6 kcal/mol in terms of Gibbs free energy, as the enthalpic
penalty for PnBu3 dissociation is compensated by a large inꢀ
crease in entropy. IN4 can react with Cs2CO3 to remove
n
CsOPh from the metal, leading to IN5. Coordination of Prꢀ
BBN to IN5 leads to IN6, and the transmetallation step occurs
via transition state TS4 and an energy barrier of 21.2 kcal/mol
from IN5.
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
Figure 2. Parts a and b, geometry of transition states TS1 and
TS2 for C(acyl)ꢀO and C(aryl)ꢀC activation with Ni(PnBu3)2.
Parts c and d, geometry of transition states TS1 and TS2 for
C(acyl)ꢀO and C(aryl)ꢀC activation with Ni(dcype). Distances
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
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for the competitive decarboxylation of IN2 is calculated to be
Figure 3. Hammett analysis of nonꢀdecarbonylative and deꢀ
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8
carbonylative SuzukiꢀMiyaura coupling using σp values.
11.1 kcal/mol above TS6, and thus this mechanistic option can
be ruled out. The following steps, from IN12 to IN17, correꢀ
spond to the transmetallation section, with a mechanism strictꢀ
ly similar to that calculated for Ni(PnBu3)2, steps from IN1 to
IN9. Considering that reactivity with Ni(dcype) occurs with
Cs2(CO)3 as well (see Table 5), for the sake of easier compariꢀ
son with the Ni(PnBu3)2 energy profile we used Cs2(CO3)
instead of the better performing CsF. Details on the
transmetallation step with CsF can be found in Figure S6.
Transmetallation starts with dissociation of a P atom from
Nickel, IN12 to IN13, a step that costs 26.2 kcal/mol in terms
of Gibbs free energy, as the tether between the two P atoms
prevents a large increase in entropy that could compensate the
enthalpic penalty. The high energy intermediate IN13 can
react with Cs2CO3 to remove CsOPh from the metal, leading
Dissociation of Cs(CO3)BBN and coordination of a free PnBu3
ligand leads to IN9 and completes the transmetallation section.
The last step is reductive elimination from IN9 via transition
state TS5 and an energy barrier of 4.4 kcal/mol only. Dissociaꢀ
tion of the formed product from IN10 requires 11.4 kcal/mol
and regenerates the starting Ni(PnBu3)2 species. The reaction
profile in Figure 4a indicates that, with Ni(PnBu3)2, the initial
oxidative addition can be considered as the rate determining
step, since it corresponds to the highest in energy transition
state (TS1 at 7.7 kcal/mol) and to the largest energy barrier
(22.2 kcal/mol) from IN0 to TS1. The transmetallation transiꢀ
tion state TS4 is at the same energy of TS1, but we can asꢀ
sume TS4 as an upper bound limit, since more favorable
pathways, eventually involving different aggregation states of
the base, can be involved. To further support this scenario
DFT Hammett plots were obtained by plotting ꢀꢀꢀE≠ /RT
against the substituent parameter σp of paraꢀsubstituted pheꢀ
nolic ester derivatives of 1o (ꢀꢀE≠ is the difference in the
energy of activation for oxidative addition of the C(acyl)ꢀO
bond to Ni between paraꢀsubstituted and unsubstituted 1o).
The linear correlation between ꢀꢀꢀG≠/RT and σp with a posiꢀ
tive slope (Figure S2) is in agreement with the experimental
trend thus supporting the mechanistic rationalization.
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n
to IN14. Coordination of PrꢀBBN to IN14 leads to IN15, and
the transmetallation step occurs via transition state TS7 and an
energy barrier of 28.5 kcal/mol from IN15. Dissociation of
Cs(CO3)BBN from IN16 and coordination of the dangling P
atom leads to IN17 completes the transmetallation section.
The last step is reductive elimination from IN17 via transition
state TS8 and an energy barrier of 16.3 kcal/mol. Dissociation
of the formed product from IN18 requires 24.7 kcal/mol and
regenerates the starting Ni(PnBu3)2 species. The reaction proꢀ
file in Figure 4b indicates that, with Ni(dcype), the highest in
energy structure corresponds to the P dissociated intermediate
IN13, an event triggering the transmetallation step. The
transmetallation transition state TS7 is at approximately the
same energy of IN13. Again, we can assume TS7 as an upper
bound limit, since more favorable pathways eventually involvꢀ
ing different aggregation states of the base can be involved.
Moving to Ni(dcype), the favored oxidative addition step leads
to IN2. Differently from the Ni(PnBu3)2 profile, calculations
suggest that the next step is easy decarbonylation of IN2 to
IN11, via transition state TS6 and an energy barrier of 11.8
kcal/mol, see Figure 4b. Exergonic CO dissociation leading to
IN12 completes the decarbonylation step. The transition state
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Figure 4. Full DFTꢀcomputed Gibbs free energy (in kcal/mol) mechanism for the ligandꢀcontrolled nickel catalyzed Suzukiꢀ
n
Miyaura crossꢀcoupling reactions with substrate 1o, Cs2CO3 as the base, C3H7ꢀBBN as the organoboron reagent, for the a)
Ni(PnBu3)2 and b) Ni(dcype) catalysts.
To further support this scenario DFT Hammett plots were
obtained by plotting ꢀꢀꢀEDiss/RT against the substituent paꢀ
rameter σp of paraꢀsubstituted phenolic ester derivatives of 1o
(ꢀꢀEDiss is the difference in the dissociation energy of the P
atom from IN12 to give IN13, between paraꢀsubstituted and
unsubstituted 1o). The linear correlation between ꢀꢀꢀEDiss/RT
and σp with a negative slope (Figure S3) is in agreement with
the experimental trend. In contrast, DFT Hammett plots of ꢀ
ꢀꢀE≠ /RT for the oxidative addition of the C(aryl)ꢀC(acyl)
bond to Ni via TS2, and for the decarbonylation step via TS6,
gave a linear correlation with a positive slope (see Figures S4
and S5), at odd with the experimental trend.
termediate IN2 irreversible, as the dissociated CO can escape
from solution, the mechanistic rationalization emerging from
Figures 3b and 4b suggests that the product selectivity deterꢀ
mining step is the initial oxidative addition, while the rate
limiting step is connected to the transmetallation step.
CONCLUSIONS
In summary, the results reported herein represent the first
example of ligandꢀcontrolled and siteꢀselective nickel cataꢀ
lyzed SuzukiꢀMiyaura crossꢀcoupling reaction with aromatic
ester and alkyl organoboron components as coupling partners.
This newly developed methodology enables a facile route for
Considering decarbonylation of the oxidative addition inꢀ
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C(sp2)ꢀC(sp3) bond formation in a straightforward fashion by
Chem. Rev. 2011, 111, 1417ꢀ1492. (c) Cherney, A. H.; Kadunce, N.
T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587ꢀ9652.
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successful suppression of the undesired ßꢀhydride elimination
process. The switch in selectivity is attributed to the judicious
choice of different phosphorus ligands, which notably conꢀ
verted the esters into the alkylated and ketone products respecꢀ
tively. The utility of this newly developed protocol has been
demonstrated by the broad functional group tolerance and the
application in the synthesis of bioactive compounds. DFT
studies on the oxidative addition step of phenyl 2ꢀnaphthoate
with different nickel complexes were carried out in order to
rationalize this intriguing reaction chemoselectivity. When
monoꢀdentate phosphorus ligands, such as PnBu3 and PCy3,
were used, the nickel complex favors activation of the C(acyl)ꢀ
O bond, which later generates the ketone product. On the other
hand, the nickel complex with biꢀdentate dcype ligand favors
the C(aryl)ꢀC bond cleavage in the oxidation addition step,
leading to the alkylated product via a decarbonylative process.
Complete DFT energy profiles indicate that, consistently with
the experimental Hammett plots, the initial oxidative addition
of the substrate is the rate limiting and product selectivity
determining step when PnBu3 is used as ligand. Differently,
when dcype is used the initial oxidative addition of the subꢀ
strate, followed by easy irreversible decarbonylation, is the
product selectivity determining step, while transmetallation is
rate limiting.
(4) For pioneer works which utilized Bꢀalkylꢀ9ꢀBBNs as crossꢀ
coupling partners in nickel catalyzed carbonꢀhalogen bond activation,
see: (a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602ꢀ9603.
(b) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694ꢀ6695. (c)
Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11908ꢀ11909.
(d) Lu Z.; Fu, G. C. Angew. Chem. Int. Ed. 2010, 49, 6676ꢀ6678. (e)
Lu Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154ꢀ
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■ ASSOCIATED CONTENT
*Supporting Information
Experimental and computational details, full characterization of
the products and spectra, Cartesian coordinates of the optimized
geometries.
■ AUTHOR INFORMATION
Corresponding Author
* magnus.rueping@rwthꢀaachen.de *luigi.cavallo@kaust.edu.sa
Author Contributions
§A.C. and H.ꢀH.L. contributed equally.
Notes
The authors declare no competing financial interest.
ꢀ ACKNOWLEDGMENTS
H.ꢀH.L. thanks the DAAD for a doctoral fellowship. A.P. thanks the
Spanish MINECO for a project CTQ2014ꢀ59832ꢀJIN. This research
was supported by the KAUST Office of Sponsored Research under
Award No. URF/1/3030ꢀ01. LC thanks the King Abdullah University
of Science and Technology (KAUST) for supporting this work. For
computer time, this research used the resources of the KAUST Superꢀ
computing Laboratory (KSL) at KAUST.
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product was observed.
Cross-experiment
Ni(cod)2 (10 mol %)
PnBu3 (40 mol %)
PMP
PMP
O
Cs2CO3 (2 equiv)
12%
toluene, 150 o
C
OPh
B
+
Ni(cod)2 (10 mol %)
dcype (20 mol %)
starting material
92% recovery
CsF (2 equiv)
toluene, 80 o
C
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