Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed Suzuki–Miyaura Coupling

Article abstract of DOI:10.1002/anie.202103327

The direct conversion of alkyl esters to ketones has been hindered by the sluggish reactivity of the starting materials and the susceptibility of the product towards subsequent nucleophilic attack. We have now achieved a cross-coupling approach to this transformation using nickel, a bulky N-heterocyclic carbene ligand, and alkyl organoboron coupling partners. 65 alkyl ketones bearing diverse functional groups and heterocyclic scaffolds have been synthesized with this method. Catalyst-controlled chemoselectivity is observed for C(acyl)?O bond activation of multi-functional substrates bearing other bonds prone to cleavage by Ni, including aryl ether, aryl fluoride, and N-Ph amide functional groups. Density functional theory calculations provide mechanistic support for a Ni⁰/Ni^II catalytic cycle and demonstrate how stabilizing non-covalent interactions between the bulky catalyst and substrate are critical for the reaction's success.

Full text of DOI:10.1002/anie.202103327

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Nickel Catalysis
Hot Paper
Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed
Suzuki–Miyaura Coupling
Yan-Long Zheng, Pei-Pei Xie, Omid Daneshfar, Kendall N. Houk,* Xin Hong,* and
Stephen G. Newman*
Abstract: The direct conversion of alkyl esters to ketones has
been hindered by the sluggish reactivity of the starting materials
and the susceptibility of the product towards subsequent
nucleophilic attack. We have now achieved a cross-coupling
approach to this transformation using nickel, a bulky N-
heterocyclic carbene ligand, and alkyl organoboron coupling
partners. 65 alkyl ketones bearing diverse functional groups
and heterocyclic scaffolds have been synthesized with this
method. Catalyst-controlled chemoselectivity is observed for
C(acyl) linkages can be directly obtained, providing a valuable
alternative to traditional acyl substitution reactions.
Ketones are among the most valuable targets in the cross-
coupling of carboxylic acid derivatives due to the challenges
associated with related stoichiometric acyl substitution reac-
tions. For instance, aggressive organometallic nucleophiles
such as Grignard reagents can directly attack carboxylic acid
derivatives; however, the resultant ketones are prone to
subsequent addition.[6] Prior derivatization of the substrate is
generally needed to control this reaction, for instance by using
the Weinreb ketone synthesis protocol (Scheme 1a).[7] In
contrast, cross-coupling approaches use a transition metal
catalyst to activate the acyl group, enabling milder organo-
metallic nucleophiles to participate in the catalytic reaction
while remaining inert to ketone products. For instance, the
seminal works of Stille and Migita on the use of organotin
nucleophiles in cross-coupling demonstrated the synthesis of
ketones from acid chlorides.[8] Another milestone was
reached in 1998 by the Fukuyama group who found Pd
catalysts could activate thioesters towards coupling with
organozinc nucleophiles (Scheme 1b).[9] Further expansion
on the diversity of coupling partners and catalysts that
participate in this type of reactivity continues to progress.[10]
À
C(acyl) O bond activation of multi-functional substrates
bearing other bonds prone to cleavage by Ni, including aryl
ether, aryl fluoride, and N-Ph amide functional groups. Density
functional theory calculations provide mechanistic support for
a Ni0/NiII catalytic cycle and demonstrate how stabilizing non-
covalent interactions between the bulky catalyst and substrate
are critical for the reactionꢀs success.
Introduction
Transition-metal-catalyzed cross-coupling reactions are
widely used in organic and medicinal chemistry to construct
carbon-carbon and carbon-heteroatom bonds.[1] While tradi-
tional electrophilic coupling partners such as aryl bromides
and iodides are most commonly used,[2] this has expanded
recently to include a range of strong carbon-heteroatom bond
activations.[3] For instance, cleavage of C O bonds can enable
À
the use of abundant phenol derivatives to synthesize diverse
C(aryl) linkages in catalytic arylation, alkylation, and amina-
tion reactions.[4] Similar progress has been made in the use of
carboxylic acid derivatives as cross-coupling electrophiles.[5]
When the carbonyl group is retained in these reactions,
[*] Y.-L. Zheng, O. Daneshfar, S. G. Newman
Centre for Catalysis Research and Innovation, Department of
Chemistry and Biomolecular Sciences, University of Ottawa
10 Marie-Curie, Ottawa, Ontario K1N 6N5 (Canada)
E-mail: stephen.newman@uottawa.ca
P.-P. Xie, X. Hong
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
E-mail: hxchem@zju.edu.cn
K. N. Houk
Department of Chemistry and Biochemistry, University of California
Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202103327.
Scheme 1. Strategies for the conversion of carboxylic acid derivatives
to ketones.
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Most recently, amides[11] and esters[12] have been proven to be
catalyst, an unusual NHC ligand with remote steric bulk, and
alkylborane nucleophiles.
viable cross-coupling electrophiles. For example, towards
accessing aryl alkyl ketones, Negishi- and Suzuki–Miyaura-
type coupling reactions have been reported with activated
amides[13] and phenyl esters[14] (Scheme 1c). While these acyl Results and Discussion
ester electrophiles are certainly more robust than acid
chlorides, they are seldom commercially available and must
be synthesized prior to coupling. In contrast, simple methyl
and ethyl esters are abundant and make ideal starting
The coupling of methyl 1-methyl-1H-indole-2-carboxylate
(1a) and B-alkyl-9-BBN[21] reactant 2a was chosen as a model
reaction. Using a Ni catalyst, K3PO4 as base, and toluene as
solvent, the corresponding Suzuki–Miyaura ketone product 3
could be obtained in 80% yield (Table 1 entry 1). The use of
À
materials; however, the relatively strong C(acyl) O bond
which lends them their stability also makes them more
resistant to cleavage by transition metal catalysts.
The first report of the direct cross-coupling of unactivated
esters was in 2016 when Garg and Houk described amide
bond formation from 1-methyl naphthoates using stoichio-
metric Al(OtBu)3 and catalytic Ni.[15] Since then, only modest
progress has been made in expanding the coupling of methyl
esters to include more diverse coupling reactions, hindered by
À
the limited catalysts available for cleaving the strong C O
bond.[16–20] Given the need for improved methods to access
ketones from readily available carboxylic acid derivatives, we
felt that the Suzuki–Miyaura cross-coupling of simple esters
was a particularly important goal (Scheme 1d). Herein, we
describe our endeavors in enabling this reaction using a Ni
Table 1: Optimizing the Suzuki–Miyaura coupling of a methyl ester.[a]
Entry
Deviation from standard conditions
Yield [%]
1
2
3
none
80
0
0
ligand=PnBu3, PtBu3 or PCy3
ligand=dcype or dcypf
ligand=ICy·HBF4
4
0
5
6
7
8
ligand=IPr·HCl
50
45
58
54
60
58
50
51
62
30
44
26
77
ligand=SIPr·HCl
ligand=IPrCHPh2·HBF4
ligand=IPrCPh3·HCl
9
ligand=IPr’·HCl
KF instead of K3PO4
K2CO3 instead of K3PO4
no K3PO4
10
11
12
13
14
15
16
17
Ethyl ester instead of methyl ester
t-Butyl ester instead of methyl ester
Ni(cod)(dq) instead of Ni(cod)2
Ni(OTf)2 + Zn (2.0 equiv)
Reaction at 1008C for 1 h
Scheme 2. Reaction scope of alkylborane reagents. General reaction
conditions: 1a (0.2 mmol), 2 (0.4 mmol), Ni(cod)2 (10 mol%),
IPrCyp·HCl (20 mol%), t-BuOK (20 mol%), K3PO4 (0.4 mmol), toluene
(0.1 M), 100–1308C, 1–16 h (for specific conditions for each substrate,
see the Supporting Information). Isolated yields are reported. Bn:
benzyl, PMB: p-methoxybenzyl.
[a] Reactions run at 0.1 M concentration on 0.2 mmol scale. Yields
determined by H NMR spectroscopy using CH2Br2 as an internal
standard.
1
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the 2,4,6-tricyclopentylaniline-derived N-heterocyclic car-
bine, which we refer to as IPrCyp, was found to be particularly
important.[22] Monodentate (entry 2) and bidentate (entry 3)
phosphines as well as the NHC ligand ICy (entry 4) gave no
detectable product. While IPrCyp is analogous to the more
common ligands IPr and SIPr, these gave consistently lower
yields (entries 5 and 6). Remote steric bulk on ligands has
previously been shown to result in improved activity in both
Pd[23] and Ni-catalyzed[24] couplings. With this in mind,
analogues IPrCHPh2, IPrCPh3 and IPr’[25] were also investigated,
providing moderate yields of 58%, 54%, and 60%, respec-
tively (entries 7–9).
12). The reaction was not limited to use of methyl esters; both
ethyl (entry 13) and t-butyl (entry 14) ester starting materials
led to ketone 3, albeit with reduced yield dependent on the
steric bulk. Towards exploring air stable catalysts to enable
the reaction to be setup outside a glovebox, Ni(cod)(dq)[27]
(entry 15) and Ni(OTf)2/Zn (entry 16) gave 44% and 26%
yield, respectively. Lastly, when exploring the minimum
needed temperature and time required, we observed high
yields at 1008C for 1 h (entry 17). Notably, in all experiments
from Table 1, recovered 1a was found to represent the
majority of the remaining mass balance. Further, the use of
alkylborane nucleophiles was found to be necessary. Exten-
sive studies with arylboronic acids have thus far been
unsuccessful. Further details on the reaction optimization
can be found in the Supporting Information Tables S1–S6.
The choice of base was also important for obtaining high
yields, with KF, K2CO3, and running in the absence of
additional base[26] (beyond the t-BuOK required to deproto-
nate the ligand) all providing yields from 50–58% (entries 10–
Scheme 3. Reaction scope of methyl esters and alkylboranes. General reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Ni(cod)2 (10 mol%),
IPrCyp·HCl (20 mol%), t-BuOK (20 mol%), K3PO4 (0.4 mmol), toluene (0.1 M), 100–1308C, 1–16 h (for specific conditions for each substrate, see
the Supporting Information), isolated yields are reported. [a] KF (0.3 mmol) and KI (0.2 mmol) were used instead of K3PO4. [b] Ethyl ester was
used instead of methyl ester.
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À
With the optimized conditions in hand, we next evaluated
reactive C B bond often resulted in surprisingly large
changes in the yield.
the reaction scope of various alkylborane nucleophiles with
temperatures from 100–1308C and reaction times from 1–
16 h, depending on the substrate (Scheme 2). The model
ketone product 3 could be obtained in 73% yield after
purification. Functionalization of the para position of the
alkylborane with Me, Ph and OMe substituents (4–6) all
provided excellent yields (75–90%). A meta methyl substitu-
ent gave 7 in 80% yield, and an ortho methyl group gave
ketone 8 in 43% yields. With more electron rich arenes on the
organoboron nucleophile, 9 and 10 were isolated in 84% and
92% yield. In contrast, electron withdrawing fluorine (11)
and ester (12) groups on the para position gave slightly lower
yields of 51% and 70%, respectively. Removing the aromatic
ring completely led to a significant drop in yield, as evidenced
by the 31% yield of ketone 13, derived from a cyclohexane-
containing alkylborane nucleophile. Simple styrene deriva-
tives also worked smoothly to give ketones 14–17 in good to
excellent yields (60–81%), though a more sterically hindered
b-methyl alkylborane gave 18 in 24% yield. Longer linear
chains on the nucleophiles were also tolerated, providing 19–
24 in yields ranging from 33–80%. While most yields obtained
during the scope evaluation were good, it is worth noting that
seemingly minor changes to positions remote from the
We next explored the diversity of methyl ester electro-
philes that could participate in the coupling (Scheme 3). First,
simple methyl benzoate derivatives were tested, giving
moderate to good yields of coupling products 25–31. A
boronic ester was also tolerated, giving ketone product 32 in
72% yield and demonstrating chemoselectivity for the C-
(sp ) B bond. An electrophilic acetyl group, (33) an N, N-
3
À
dialkyl amide (34) and an electron-withdrawing methylsul-
fone substituent (35) were all tolerated. Derivatives of the
sulfonamide-containing hyperuricemia drug probenecid were
prepared in 50–55% yield (36–38). Methyl benzoate deriva-
tives bearing remote furan and pyridine groups participated
in coupling to give ketones 39–42 in up to 85% yield. Various
esters bearing polycyclic aromatic backbones also gave the
corresponding ketone products (43–50) in yields ranging from
51–70%. Lastly, we evaluated a variety of heteroaromatic
methyl esters. While unsubstituted methyl nicotinates could
not be directly used, 2,5-disubstituted pyridines 51–53 could
be formed in 44–63% yield. Methyl esters directly attached to
furan (54), carbazole (55 and 56), and the 6-position of indole
(57–61) formed ketones with similar modest efficiency.
Finally, an estrone-derived nucleophile could be used to form
Scheme 4. Orthogonal reactivity studies.
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indole-bearing ketone 62 in 70% yield. Unfortunately, alkyl-
substituted methyl esters could not be successfully alkylated
with our conditions (See Figure S1, Supporting Information).
Methyl esters are generally considered to be inert func-
tional groups for cross-coupling, particularly when compared
to aryl chlorides, bromides, and iodides. Indeed, we found that
these reactive carbon-halogen bonds were not tolerated in our
scope. However, recent efforts have shown that many other
strong bonds can participate in coupling chemistry with
careful selection of the catalyst and nucleophile.[28] Towards
understanding the chemoselectivity, several bifunctional sub-
nucleophiles, this substrate underwent chemoselective cleav-
age at the a-alkyl ester group, giving amide 70 in 65% yield
(Scheme 4c).[29] In contrast, the present conditions for
alkylation showed complete selectivity for the a-aryl ester,
providing ketone 71 in 69% yield. Next, we wanted to
investigate the relative reactivity of amides and esters. N-Ph
amides have been shown to be sufficiently activated to
participate in Ni-catalyzed cross-coupling.[11a] Indeed, ester-
bearing amide 72 has been already shown to undergo selective
À
C N bond cleavage by Rueping and co-workers, forming
ketone 73 and leaving the ester untouched (Scheme 4d).[13b]
Surprisingly, using our conditions with Ni(cod)2/IPrCyp, cou-
pling of the methyl ester occurs to provide ketone 74 in 51%
NMR yield with 46% recovery of starting material, indicating
that orthogonal reactivity between amides and esters is
possible. Lastly, we probed if multiple esters could be
differentiated based on electronics. With trifluoroethyl 4-
methoxycarbonylbenzoate 75 selective cleavage of the tri-
fluoroethanol-derived ester group was observed, affording 73
in 80% yields with no evidence of methyl ester cleavage.
Previous mechanistic studies on the Ni-catalyzed reaction
of methyl esters with amine nucleophiles have suggested that
a Ni0/NiII cross-coupling mechanism is operative, with the Ni0
strates were tested under differing reaction conditions
2
À
(Scheme 4). For example, the C(sp ) O bond of anisoles
can be engaged in Suzuki–Miyaura coupling with a Ni/PCy3
catalyst system and organoboronic ester nucleophile.[28a]
When methyl ether-containing ester 63 was subjected to
2
À
these conditions, a 64% yield of the C(sp ) O bond cleavage
product was observed with no evidence of ester cleavage
(Scheme 4a). Use of our standard conditions from Scheme 3
resulted in a complete switch in chemoselectivity, yielding
ketone 65 in 71% yield with no evidence of ether cleavage.
Similar results were observed with aryl fluoride-bearing ester
66 (Scheme 4b). Established conditions for Suzuki–Miyaura
coupling via C-F bond cleavage[28b] yielded biaryl 67 in 58%
yield. In contrast, our ester coupling conditions resulted in
selective cleavage of the ester, providing 68 in 68% yield. To
probe selectivity in the reaction of diesters, 69 was prepared.
In our previous work on the reaction of esters with amine
oxidatively inserting into the ester C(acyl) O bond.[15,30] This
À
step was calculated to be endothermic and reversible, though
with a reasonable kinetic barrier for the reaction temper-
atures used. Development of the Suzuki–Miyaura reaction
described herein required extensive optimization and devia-
Figure 1. DFT-computed free energy profile of the most favorable pathway for the nickel-catalyzed Suzuki–Miyaura coupling of methyl esters.
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tion from conditions originally developed for amide bond free energy profile suggested that the on-cycle resting state is
formation from methyl esters, suggesting challenges in the the product-coordinated nickel(0) complex 84. The rate-
reaction beyond oxidative addition. DFT studies were thus limiting step is the transmetallation via TS81. The overall
carried out to better understand the similarities and differ- computed barrier of the catalytic cycle is 29.7 kcalmolÀ1 from
ences from this previous work.
the resting state 84 to the transmetallation transition state
The DFT-computed free energy profile of the operative TS81.
pathway of the Ni-catalyzed Suzuki–Miyaura coupling of
Based on the above mechanistic understandings, we next
methyl ester is provided in Figure 1, using methyl 1-methyl- explored the origins of the substituent effect on the reactivity
1H-indole-2-carboxylate (1a) and B-alkyl-9-BBN (2a) as of alkylboranes. In particular, we were curious about the non-
model compounds. From the substrate-coordinated nickel(0) intuitive roles of the remote cyclopentyl ring on the ligand
À
complex 77, oxidative addition via TS78 cleaves the acyl C O and the remote aromatic ring on the organoboron nucleophile
bond, leading to the acylnickel(II) intermediate 79. The (e.g. 3 vs. 13, Figure 2a). In transition state TS81, representing
À
intrinsic barrier of acyl C O bond activation via TS78 is fairly the rate-determining transmetallation towards ketone 3, there
low, which requires 19.6 kcalmolÀ1 from the oxidative addi- exists a C H···p interaction between the cyclopentyl group of
À
tion pre-intermediate 77. This is consistent with previous the IPrCyp ligand and the phenyl substituent of the organo-
mechanistic studies.[14a,30] It should be noted that the bulky boron nucleophile. The C H···p distance is 2.6 ꢁ, and this
À
IPrCyp ligand prevents the formation of the off-cycle resting favorable interaction was further confirmed by IGM analysis
state Ni(NHC)2.[15] Ni(IPrCyp
)
2
cannot be located in our (Figure 2b). Upon changing to a saturated organoboron
À
computations despite extensive efforts. This destabilization nucleophile bearing a cyclohexyl group, the favorable C
of the Ni(NHC)2 state by the bulky IPrCyp ligand also H···p interaction no longer exists. The cyclopentyl group from
contributes to the ligandꢀs high reactivity in the C O bond the IPrCyp ligand and the cyclohexyl ring on the organoboron
À
activation. After the oxidative addition, 79 undergoes the are sterically repulsive to each other in TS85. This increases
transmetallation with the organoboron-K3PO4 complex[31] the overall transmetallation barrier to 29.5 kcalmolÀ1,[32]
through TS81 to generate the NiII(acyl)(alkyl) intermediate which is consistent with the significant drop in reactivity
82. Subsequent acyl-alkyl reductive elimination occurs via when forming ketone 13. These mechanistic understandings
TS83, producing the product-coordinated complex 84. 84 highlight the synergistic design of ligand and substrate in
eventually liberates the alkylated product 3 and regenerates promoting the desired Ni-catalyzed cross-coupling reactions.
species 77 for the next catalytic cycle. The DFT-computed
Figure 2. Optimized transition-state structures and free energy barriers of transmetallation with phenyl- and cyclohexyl-substituted organoboron
nucleophile. Free energy barriers are compared to the substrate-coordinated complex 77. Irrelevant hydrogens are omitted in the structure
diagrams.
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Conclusion
The direct synthesis of ketones by the reaction of
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abundant methyl esters and organometallic nucleophiles is
a long-standing challenge. By employing a Ni0 catalyst
À
capable of oxidatively adding into the strong C(acyl) O bond
of these substrates, an organoboron reagent can react by
transmetallation via a Suzuki–Miyaura-type reaction mecha-
nism. Since these nucleophiles are inert towards ketones, no
secondary addition products are observed as is the case when
more aggressive organometallic reagents are used. The
seldom used ligand IPrCyp, derived from 2,4,6-tricyclopentyl
aniline, is found to be particularly important for obtaining
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in situ undergoes relatively facile oxidative addition into the
À
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Financial support for this work was provided by BASF, the
National Science and Engineering Research Council of
Canada (NSERC), the Canada Research Chair program,
the National Natural Science Foundation of China (21702182
and 21873081, X.H.), Fundamental Research Funds for the
Central Universities (2020XZZX002-02, X.H.), and the State
Key Laboratory of Clean Energy Utilization (ZJU-
CEU2020007, X.H.). Calculations were performed on the
high-performance computing system at the department of
chemistry, Zhejiang University. Martin McLaughlin, Mathias
Schelwies, Stephan Zuend, and Roland Gçtz (BASF) are
thanked for helpful discussions. The Canadian Foundation for
Innovation (CFI) and the Ontario Ministry of Research,
Innovation, & Science are thanked for essential infrastruc-
ture. We thank Jacob Jessiman (Newman lab) for the syn-
thesis of some starting materials.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cross-coupling · esters · ketones · nickel · Suzuki–
Miyaura reactions
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Supporting Information.
Manuscript received: March 7, 2021
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Accepted manuscript online: April 1, 2021
Version of record online: && &&
,
&&&&
Angew. Chem. Int. Ed. 2021, 60, 2 – 10
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Nickel Catalysis
Methyl esters are shown to participate in
intermolecular Suzuki–Miyaura cross-
coupling reactions. Due to the mild
nature of organoboron reagents, the
product ketones are inert to the reaction
conditions, avoiding over reactivity issues
prominent with more aggressive organo-
metallic nucleophiles.
Y.-L. Zheng, P.-P. Xie, O. Daneshfar,
K. N. Houk,* X. Hong,*
S. G. Newman*
&&&& — &&&&
Direct Synthesis of Ketones from Methyl
Esters by Nickel-Catalyzed Suzuki–
Miyaura Coupling
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 10
These are not the final page numbers!