Base-free nickel-catalysed decarbonylative Suzuki–Miyaura coupling of acid fluorides

Article abstract of DOI:10.1038/s41586-018-0628-7

The Suzuki–Miyaura cross-coupling of organoboron nucleophiles with aryl halide electrophiles is one of the most widely used carbon–carbon bond-forming reactions in organic and medicinal chemistry^1,2. A key challenge associated with these transformations is that they generally require the addition of an exogenous base, the role of which is to enable transmetallation between the organoboron nucleophile and the metal catalyst³. This requirement limits the substrate scope of the reaction because the added base promotes competitive decomposition of many organoboron substrates^3–5. As such, considerable research has focused on strategies for mitigating base-mediated side reactions^6–12. Previous efforts have primarily focused either on designing strategically masked organoboron reagents (to slow base-mediated decomposition)^6–8 or on developing highly active palladium precatalysts (to accelerate cross-coupling relative to base-mediated decomposition pathways)^10–12. An attractive alternative approach involves identifying combinations of catalyst and electrophile that enable Suzuki–Miyaura-type reactions to proceed without an exogenous base^12–14. Here we use this approach to develop a nickel-catalysed coupling of aryl boronic acids with acid fluorides^15–17, which are formed in situ from readily available carboxylic acids^18–22. This combination of catalyst and electrophile enables a mechanistic manifold in which a ‘transmetallation-active’ aryl nickel fluoride intermediate is generated directly in the catalytic cycle^13,16. As such, this transformation does not require an exogenous base and is applicable to a wide range of base-sensitive boronic acids and biologically active carboxylic acids.

Full text of DOI:10.1038/s41586-018-0628-7

Letter
https://doi.org/10.1038/s41586-018-0628-7
Base-free nickel-catalysed decarbonylative Suzuki–
Miyaura coupling of acid fluorides
Christian A. Malapit1, James r. Bour1, Conor e. Brigham1 & Melanie S. Sanford1*
The Suzuki–Miyaura cross-coupling of organoboron nucleophiles presence of exogenous base (MX*). The role of the base (Fig. 1b, cycle I)
with aryl halide electrophiles is one of the most widely used is to convert the ‘transmetallation-inactive’ [Ar–Pd–X] intermediate
carbon–carbon bond-forming reactions in organic and medicinal (where X = chloride, bromide or iodide) to a ‘transmetallation-
chemistry1,2. A key challenge associated with these transformations active’ intermediate [Ar–Pd–X*] (where X*=hydroxide or fluoride).
is that they generally require the addition of an exogenous base, the [Ar–Pd–X*] then participates in fast transmetallation with a boronic
role of which is to enable transmetallation between the organoboron acid23–25. However, the base also mediates the off-cycle formation
nucleophile and the metal catalyst3. This requirement limits the of organoboronate intermediates that competitively decompose via
substrate scope of the reaction because the added base promotes protodeboronation, oxidation and/or homocoupling4,5. Inspired by
competitive decomposition of many organoboron substrates3–5. As several literature reports13,16, we proposed that the combination of a
such, considerable research has focused on strategies for mitigating nickel catalyst and an acid fluoride electrophile would directly form a
base-mediated side reactions6–12. Previous efforts have primarily ‘transmetallation-active’ intermediate [Ar–Ni–F] via oxidative addition
focused either on designing strategically masked organoboron and subsequent decarbonylation (Fig. 1b, cycle II). Importantly, Ni0 is
reagents (to slow base-mediated decomposition)6–8 or on developing well-known to participate in oxidative addition reactions with carbox-
highly active palladium precatalysts (to accelerate cross-coupling ylic acid derivatives15,26–30. Furthermore, with appropriate selection of
relative to base-mediated decomposition pathways)10–12. An supporting ligands, the resulting NiII-acyl intermediates are known to
attractive alternative approach involves identifying combinations undergo decarbonylation26–30. This approach offers several advantages,
of catalyst and electrophile that enable Suzuki–Miyaura-type which include eliminating the requirement for exogenous base; using
reactions to proceed without an exogenous base12–14. Here we highly electrophilic ArC(O)F substrates, which should undergo rapid
use this approach to develop a nickel-catalysed coupling of aryl oxidative addition under mild conditions (compared to, for example,
boronic acids with acid fluorides15–17, which are formed in situ the corresponding aryl fluorides13,31–33, esters26,28 or amides27); and
from readily available carboxylic acids18–22. This combination using readily available and inexpensive carboxylic acid derivatives as
of catalyst and electrophile enables a mechanistic manifold in coupling partners. Notably, a similar strategy was recently applied to
which a ‘transmetallation-active’ aryl nickel fluoride intermediate the palladium-catalysed decarbonylative coupling of acid fluorides with
is generated directly in the catalytic cycle13,16. As such, this triethyltrifluoromethylsilane16.
transformation does not require an exogenous base and is applicable
Stoichiometric studies were first conducted to assess the viability of
to a wide range of base-sensitive boronic acids and biologically each step of the proposed catalytic cycle. To investigate oxidative addi-
active carboxylic acids.
tion and decarbonylation, benzoyl fluoride 1 was reacted with Ni(cod)2
The traditional Suzuki–Miyaura reaction involves the palladium- and PCy3 (Fig. 2a) (cod, 1,5-cyclooctadiene; PCy3, tricyclohexylphos-
catalysed coupling of an aryl halide (Ar–X) with a boronic acid in the phine). The benzoyl nickel fluoride intermediate 2 was formed rapidly
Pd catalyst
R′
B(OR) 2
Ni catalyst
R′
B(OR)2
a
R
X
R
R′
R
CO2H
Base
Suzuki–Miyaura reaction
Pharmaceuticals
Agrochemicals
Organic materials
Organo(pseudo)halides
X = I, Br, Cl, OTs, OTf
This work
Carboxylic acids
Highly abundant
O
b
O
II
II
X* (base)
X–
X
Ni
F
Ar Pd
Ar
X
Ar
Ar
–CO
X*
F
II
I
II
Ar [M ]
[Ni0]
[Pd0]
Suzuki-Miyaura
reaction
This work
(no base)
Transmetallation-active
intermediates
Off-cycle
decomposition
via ArB(OH)3
M = Pd or Ni
X* = OH or F
–
X*
Ar Ar′
Ar′ B(OH)2
Ar Ar′
II
II
Ar Ni Ar′
Ar Pd Ar′
Base
Fig. 1 | Suzuki–Miyaura reaction and mechanistic design for the direct
generation of transmetallation-active [Ar–M–X*] intermediates.
a, Cross-coupling reactions with organoboron reagents. b, Mechanistic
design for directly accessing transmetallation-active intermediates for the
base-free decarbonylative coupling of acid fluorides with organoboron
reagents. R, alkyl or aryl group; Ar, aryl group.
1Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. *e-mail: mssanfor@umich.edu
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reSeArCH Letter
a
PCy3
Ni
O
Oxidative addition
THF, RT
Decarbonylation
O
PCy3
F
Ni(cod)2
and PCy3
F
+
F
Ni
PCy3
THF, RT
–CO
PCy3
2, >95%, 10 min
1
3, 90%, 15 h
2b (PEt3 as ligand)
3
b
Transmetallation
Reductive elimination
–Ni0Ln
PCy3
NiII Ar′
PCy3
Fn
NiII
F
PCy3
Ar′–B(OH)2
+
RT, 1 h, THF
NiII
X
PCy3
PCy3
5/6
4
3
PCy3
(not observed)
Transmetallation active
7, X = Cl
8, X = Br
F
Transmetallation inactive
Ar′–B(OH) 2
(HO)2B
F
(HO)2B
F
F
Yield, 5/6
5, 90%
6, >95%
c
Non-
selective
Highly
selective
Moderately
selective
O
O
Ar′
10 mol% Ni(cod)2
20 mol% P ligand
Ar′
+
F
PCy3
PPh2Me
Ligand
PEt3
+
Ar′–B(OH)2
THF, 100 °C, 16 h
95
>99:1
Yield (%)
Selectivity
(11:12)
15
30:70
82
85:15
MeO2C
MeO2C
MeO2C
9
10
11
12
O
d
Ar′
O
NMe2 NMe2
OH
–
PF6
NMe2
1
2
F
Ar
F
MeO2C
11, 86% yield
+
MeO2C
Activation in situ
TFFH, Proton Sponge
THF, RT, 15 min
Cross-coupling
Ar′–B(OH)2 (10)
catalyst Ni(cod)2/PPh2Me
Me2N
9
13
TFFH
Proton Sponge
THF, 100 °C, 16 h
Fig. 2 | Discovery of transmetallation-active nickel fluoride
intermediates generated from decarbonylation enables Suzuki–
Miyaura reaction of carboxylic acids and aryl boronic acids.
a, Oxidative addition and decarbonylation of acid fluoride 1 at room
temperature generates an Ar–Ni–F intermediate 3. b, Transmetallation
and reductive elimination of 3 and aryl boronic acids. c, Base-free nickel-
catalysed decarbonylative Suzuki–Miyaura-type reaction. d, Direct
conversion of aryl carboxylic acid to Suzuki–Miyaura biaryl product
via in situ generation of acid fluoride. Yields are based on 19F NMR
spectroscopy (a, b) and gas chromatography (c). Cy, cyclohexyl; RT, room
temperature; THF, tetrahydrofuran. For details on reaction conditions, see
Supplementary Information.
(within 10 min at room temperature), and this complex underwent of various deoxyfluorinating reagents and bases revealed that the
decarbonylation to afford phenyl nickel fluoride complex 3 in 90% yield combination of tetramethylfluoroformamidinium hexafluorophosphate
after 15 h. To confirm that 3 is ‘transmetallation-active’, this complex (TFFH) and 1,8-bis(dimethylamino)naphthalene converts carboxylic
was treated with 4-fluorophenyl boronic acid. As predicted, biaryl 5 acid 13 to acid fluoride 9 within 15 min at room temperature. The
(the product of transmetallation and subsequent C–C bond-forming subsequent addition of nickel catalyst and boronic acid 10 to the same
reductive elimination) was formed in 90% yield after 1 h at room pot and heating for 16 h at 100°C then affords biaryl product 11 in
temperature. An analogous reaction with 2,4,6-trifluorophenylboronic 86% yield. Various aromatic and heteroaromatic carboxylic acids
acid (which is known to undergo rapid protodeboronation under participate in this one-pot nickel-catalysed coupling with arylboronic
basic conditions)4,10 provided 6 in >95% yield, indicating that acids (Fig. 3). Esters, nitriles, trifluoromethyl groups, methyl- and
transmetallation with 3 is faster than protodeboronation. Notably, the phenyl ethers, sulfonamides, amides, alkenes, imidazoles, oxazoles
analogous phenyl nickel chloride 7 and phenyl nickel bromide 8 do not and pinacolboronate esters are tolerated. Aryl chlorides and phenyl
react with aryl boronic acids to form 5 and 6, respectively, even when esters26,28—common electrophiles in other nickel-catalysed cross-
heated at 100°C.
coupling reactions—are also compatible, demonstrating the ortho-
These stoichiometric studies were next translated to a nickel- gonality of the current method. Moderate yields were obtained with
catalysed decarbonylative coupling between acid fluoride 9 and acid fluorides bearing electron-donating substituents (products 17–23)
4-methoxyphenyl boronic acid (10). The use of 10 mol% Ni(cod)2 as well as those with ortho-substituents (products 20–23). For the
and 20 mol% PCy3 as catalyst afforded biaryl 11 along with a former, analysis of the crude reaction mixtures by gas chromatogra-
ketone by-product 12 (11:12 =85:15). Triethylphosphine afforded phy coupled with mass spectrometry showed ketone side products,
poorer selectivity (11:12 =30:70), whereas methyl(diphenyl)phos- indicating that decarbonylation is relatively slow with electron-rich
phine (PPh2Me) provided 11 as a single detectable product in 95% substrates. With the latter, unreacted starting material remained, sug-
yield. These changes in selectivity as a function of phosphine arise gesting that oxidative addition is sluggish when the acid fluoride is
from ligand effects on the decarbonylation step (see Supplementary sterically hindered. Heteroaromatic carboxylic acids, including thio-
Information for details).
phene, benzofuran, indole, pyridine and quinoline derivatives, are also
A key advantage of acid fluoride electrophiles is that they are directly effective coupling partners. Finally, various carboxylic acid-containing
accessible from carboxylic acids via deoxyfluorination. Evaluation bioactive molecules, including probenecid, bexarotene, tamibarotene,
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Letter reSeArCH
10 mol % Ni(cod)2
20 mol % PPh2Me
O
F
O
TFFH (1 equiv.)
+
Ar
(HO)2B
OMe
Ar
OMe
Ar
Proton Sponge (1 equiv.)
THF, RT, 15–30 min
THF, 100 °C, 16 h
OH
10
Isolated or in situ
A
Ar
Activation
Cross-coupling
O
A
O
A
A
N
C
A
F3C
A
MeO
A
11, 95% (in situ 86%)
14, (in situ 76%)
16, (in situ 69%)
18, (in situ 51%)
15, 58%
17, 35%
OMe
A
A
A
A
O
A
A
22, (in situ 46%)
24, (in situ 92%)
19, 59%
20, 52%
21, 60%
23, 45%
O
B
O
O
A
A
A
A
A
Cl
PhO
S
O
26, (in situ 83%)
27, (in situ 84%)
25, 65%
28, 65%
29, 54%
A
CF3
A
O
F3C
A
S
N
N
N
O
A
N
A
Me
30, 68% (in situ 45%)
31, (in situ 69%)
32, (in situ 73%)
Probenecid 33
Bexarotene 34
96% (in situ 92%)
(in situ 78%)
A
A
A
O
O
O
S
N
N
A
NH
N
N
N
N
O
N
A
O
Me
S
O
Tamibarotene 35
(in situ 83%)
Telmisartan 36
(in situ 42%)
RARβ2 agonist 37
(in situ 52%)a
Flavone 38
(in situ 92%)b
Febuxostat 39
(in situ 88%)b
Fig. 3 | Scope of the nickel-catalysed decarbonylative Suzuki–Miyaura
reaction with various carboxylic acids. A (in green), p-anisyl. aContains
inseparable protodecarbonylated carboxylic acid fluoride (7%) as
impurity. bTributyl(4-methoxyphenyl)stannane was used as the coupling
partner. For details of reaction conditions and for examples of acid
fluorides that did not undergo high-yielding decarbonylative coupling, see
Supplementary Information.
telmisartan, flavone and febuxostat, participate in this one-pot decar- Data availability
The main data supporting the findings of this study are available within the
bonylative cross-coupling.
article and its Supplementary Information. Additional data are available from
the corresponding author upon request. Metrical parameters for the structures
of complexes 2b and 3 (see Supplementary Information) are available free of
charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.
cam.ac.uk/) under reference numbers CCDC 1837039 and CCDC 1837038,
respectively.
The generality of this method with respect to the boronic acid
coupling partner was explored using probenecid as the substrate
(Fig. 4a). Aryl boronic acids containing fluorine, ester and methyl
ketone substituents were compatible. Alkenyl boronic acids underwent
coupling to generate 45 and 46. Cyclopropyl, allyl and benzyl boronic
acids reacted under the optimized conditions to afford moderate
yields of 47–49. Additionally, without any modification on the condi-
tions, arylstannane nucleophiles afforded the flavone and febuxostat
analogues 36 and 37 (Fig. 3). Base-sensitive α-heteroaryl boronic acids,
including furans, thiophenes and pyrroles, also underwent coupling
(Fig. 4b). Finally, highly base-sensitive ortho-difluorophenyl boronic
acids4,10 underwent high-yielding coupling with probenecid acid
fluoride.
Received: 14 April 2018; Accepted: 22 August 2018;
Published online xx xx xxxx.
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reSeArCH Letter
O
R
(HO)2B
R
(2 equiv.)
OH
O
O
S
10 mol % Ni(cod)2
20 mol % PPh2Me
O
TFFH (1 equiv.)
S
N
N
O
Proton Sponge (1 equiv.)
THF, RT, 15–30 min
O
P
THF, 100 °C, 16 h
F
P
Isolated or in situ
Activation
Cross-coupling
R
P
CO2H
40
Probenecid analogues
Probenecid
a
F
OMe
O
P
P
P
P
O
P
O
41, 80% (in situ 82%)
42, 75%
43, 89%
44, 92% (in situ 74%)
45, 69%
P
P
P
P
OMe
46, 73%
47, 56%
48, 42%
49, 51%
b
O
N
CF3
P
N
N
P
P
P
O
S
P
O
P
P
S
Boc
50, 58%
51, 82% (in situ 79%)
52, 71%
53, 83%
54, 43%, 60 °C (58%, b.r.s.m.)
55, 77%
56, 93%
F
F
F
F
CF3
F
OMe
F
F
F
O
F
F
F
F
P
P
P
P
P
P
F
F
F
F
F
57, 67%a
58, 86%
61, 85%
59, 72% (in situ 69%)
60, 60% (in situ 66%)
62, 75% (in situ 72%)
F
F
c
O
F
O
F
Air stable,
commercial
B(OH)2
F
F
O
Me
Method A or B
F
PPh2Me
F
+
O
S
THF, 100 °C, 16 h
N
Ni Cl
S
O
N
F
O
O
PPh2Me
Cross-coupling
61
40
64
A: 93%19F NMR, 85% isolated
B: 77%19F NMR, 66% isolated
63
Fig. 4 | Scope of the nickel-catalysed decarbonylative Suzuki–Miyaura
coupling with various organoboron reagents. a, (Hetero)aryl, alkenyl,
and alkyl boronic acids. b, Organoboron reagents that undergo facile
protodeboronation. b.r.s.m., based on recovered starting material. c, Use
of a commercial, air-stable precatalyst 63. Method A involves standard
conditions and is operated in a dry box. Method B: 10 mol% 63, 10 mol%
CsF, all catalysts and reagents are handled on the benchtop. P (in blue),
probenecid aryl fragment; Boc, tert-butoxycarbonyl. aIsolated product
contains inseparable ketone by-product (5%). For details on reaction
conditions and for examples of organoboron reagents that did not undergo
high yielding decarbonylative coupling, see Supplementary Information.
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Letter reSeArCH
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reactions. C.A.M. discovered and developed the catalytic reactions. C.A.M.,
J.R.B. and M.S.S. conceived and designed the investigations. M.S.S. directed
and supported the research. C.A.M., J.R.B. and M.S.S. wrote and revised the
manuscript.
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Competing interests The authors declare no competing interests.
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Acknowledgements We acknowledge financial support from National Institutes
of Health NIGMS (GM073836) and the Danish National Research Foundation
(Carbon Dioxide Activation Center; CADIAC). We acknowledge J. Kampf for X-ray
crystallographic analyses of 2b and 3.
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