One pot synthesis of unsymmetrical ketones from carboxylic and boronic acids via PyClU-mediated acylative Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2017.01.064

A synthetic procedure for the preparation of ketones from easily accessible carboxylic acids has been developed. This methodology proceeds via in situ activation of the carboxylic acid with PyClU, followed by the palladium-catalyzed acylative cross-coupling with boronic acids. The reaction is performed in one pot, without the need of phosphine ligands, at room temperature and in reaction times of 2 h or less. The scope of the reaction is robust with aryl boronic and carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2017.01.064

Tetrahedron Letters 58 (2017) 898–901
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Tetrahedron Letters
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One pot synthesis of unsymmetrical ketones from carboxylic and
boronic acids via PyClU-mediated acylative Suzuki coupling
⇑
Pedro M. Garcia-Barrantes, Kevin McGowan, Steven W. Ingram, Craig W. Lindsley
Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville, TN 37232, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic procedure for the preparation of ketones from easily accessible carboxylic acids has been
developed. This methodology proceeds via in situ activation of the carboxylic acid with PyClU, followed
by the palladium-catalyzed acylative cross-coupling with boronic acids. The reaction is performed in one
pot, without the need of phosphine ligands, at room temperature and in reaction times of 2 h or less. The
scope of the reaction is robust with aryl boronic and carboxylic acids.
Received 14 December 2016
Revised 19 January 2017
Accepted 20 January 2017
Available online 22 January 2017
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
PyClU
Suzuki-Miyaura
One pot
Cross-coupling
Boronic acid
The ketone functional group is a common moiety found in mul-
tiple substances with applications in diverse fields, such as phar-
maceutical, agrochemical and materials. Ketone-containing
compounds, and especially unsymmetrical aryl and/or heterobiaryl
ketones, are important intermediates in organic synthesis that
have been elaborated into both simple small molecule compounds
as well as highly complex natural products and polymers. Due to
their versatility and wide applicability, numerous methods and
strategies for their preparation have been published.1 However,
many of these approaches have caveats, especially when it comes
to the synthesis of unsymmetrical ketones, as they occur in either
a multi-step fashion, under harsh conditions, or with low tolerance
for pendant functional groups.
The preparation of aryl ketones has been facilitated significantly
with the introduction of Suzuki cross-coupling reactions between
acyl chlorides and organoboranes.2–4 This approach has the advan-
tage of being operationally simple, without the necessity of ligands
for the metal, and often at room temperature; however, the use of
acyl chlorides has its disadvantages: they usually need to be pre-
pared in a prior step, chemical instability in open atmosphere,
and they are not as ubiquitous in commercial catalogs as other car-
boxylic acid derivatives. In order to bypass the use of acyl halides
and expand the applicability of this reaction, various approaches
have been developed where the carboxylic acid is pre-activated
to form a suitable species that can enter in the catalytic cycle of
this transformation.
Representative of these latter pre-activation strategies, the use
of di(N-succinimidyl) carbonate 1,5 dimethyl dicarbonate 2,6–8 N-
ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline 3,9 and 2-chloro-
1,3-dimethylimidazolidinium chloride
4 have been reported
(Scheme 1).10 These reagents allow the conversion of carboxylic
acids to mixed anhydrides, activated esters, or acyl chlorides, spe-
cies which can take part of the reaction with boronic acids in a
Suzuki coupling. However, long reaction times and thermal heating
(60–90 °C) are required for the reaction to occur when using these
methodologies, as well as phosphine ligands, that can complicate
purification. More recently, the use of 1 to form unsymmetrical
ketones at room temperature has been highlighted; however, this
transformation still required reaction times between 12 and 24 h
and employs high-order aryl boron reagents, which are far less
available than boronic acids.11
In the course of our drug discovery efforts, an early lead series
required the synthesis of unsymmetrical ketone intermediates;
therefore, we took the opportunity to develop new methodology
for the in situ activation of carboxylic acids in acylative Suzuki cou-
plings with boronic acids. Based on the broad substrate scope in
amide coupling paradigms, we focused on PyClU, which can effi-
ciently generate the acyl chloride species in situ. Also, the urea
by-product derived from the PyClU is not likely to interfere in
the reaction. In an initial pilot of this approach, we assessed the
coupling using benzoic acid and 5 as model system, which pro-
vided 6 in good yield (70%, Scheme 1). Direct comparison of this
⇑
Corresponding author.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
http://dx.doi.org/10.1016/j.tetlet.2017.01.064
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

P.M. Garcia-Barrantes et al. / Tetrahedron Letters 58 (2017) 898–901
899
Table 1
Screening of bases for PyClU-mediated acylative Suzuki coupling.a
Entry
Base
Equiv.
Yieldb
1
2
3
4
5
6
7
8
No base
K2CO3
Na2CO3
Cs2CO3
K3PO4
CsF
KOH
NaOH
t-BuOK
Et3N
DIEA
2,4,6-Collidine
K2CO3
K2CO3
Na2CO3
Na2CO3
K3PO4
K3PO4
–
0
79
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
3.0
1.0
3.0
1.0
3.0
59 (70)
47
57
23
2
23
0
36
22
0
83
78
79
55
59
50
9
10
11
12
13
14
15
16
17
18
a
Reactions were run in a 0.5 mmol scale, using benzoic acid (1.0 equiv.), 4-
phenosyphenylboronic acid (1.0 equiv.), PyClU (1.1 equiv.), 5 mol% Pd(OAc)2 in
acetone (0.2 M), 2 h of reaction time at room temperature.
b
Yields were determined by LC-MS, using as IS 3-phenoxybenzoic acid.
Table 2
Screening of palladium sources for optimization of the PyClU-mediated acylative
Suzuki coupling.a
Entry
Catalyst
Mol%
Yieldb
Scheme 1. Formation of ketones via cross-coupling of carboxylic and boronic acids.
1
2
3
4
5
6
7
8
No palladium
Pd/C
PdCl2
–
5
5
5
5
5
5
5
5
2
1
2
1
0
15
89
7
14
0
Pd(acac)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(P(t-Bu)3)2
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
PdCl2
9
41
15
49c
43c
74c
60c
9
10
11
12
13
PdCl2
a
b
c
Reactions were run as indicated in Table 1, using K2CO3 (1.0 equiv.) as base.
Yields were determined by LC-MS, using 3-phenoxybenzoic acid as IS.
4 h of reaction time.
Scheme 2. Comparison of the Suzuki coupling conditions employing benzoyl
chloride and via PyClU-activated benzoic acid.
new this methodology to the classical approach with benzoyl chlo-
ride, demonstrated that the two approaches were comparable
(84%, Scheme 2).
CuBr and CuI) and nickel (NiCl2, Ni(acac)2, Ni(COD)2 and Ni(PPh3)2Cl2)
sources failed to deliver the desired product 6. In contrast,
palladium catalysts gave mixed results; however, PdCl2 stood out
(entry 3, Table 2), providing improved conversion relative to Pd
(OAc)2. Importantly, these data demonstrated that additional
phosphine ligands are not necessary for a successful reaction.
Attempts to decrease the catalyst loading from 5 mol% to either 1
or 2 mol% resulted in diminished yields and slower conversion to
product (entries 10–13, Table 2). Overall, these data support the
use of 5 mol% PdCl2 as the optimal catalyst in the PyClU-mediated
acylative Suzuki coupling.
With the optimal base (K2CO3) and catalyst (5 mol% PdCl2) iden-
tified, we next explored the effect of solvents on the reaction
(Table 3). Interestingly, we observed that the reaction could be per-
formed in in moderate yields both non-polar and polar aprotic sol-
vents obtaining moderate yields, while protic solvents negatively
impacted yields and further diminished as the dielectric constant
increased. Competent solvents from this effort were toluene (entry
2, Table 3) and THF (entry 4, Table 3); however, despite achieving
yields in excess of 60%, neither produced an improvement over
acetone (entry 1, Table 3).
As initial results demonstrated that using PyClU was a viable
strategy to perform the reaction with the carboxylic acid in situ,
we proceeded to screen conditions to optimize the yield of the
transformation. The first step of our screening included the use
of different bases (Table 1). This effort demonstrated that the use
of base was essential, as without this reaction component, no pro-
duct was observed. Also, it was found that carbonate and phos-
phate bases (entries 2–5 and entries 13–18, Table 1) were
superior to organic bases (entries 10–12, Table 1) and alkoxides
(entries 7–9, Table 1). The equivalents of base also affected the out-
come of the reaction, with one equivalent affording comparable or
improved results relative to three equivalents of base. Thus, the
first optimization parameter identified that one equivalent of
potassium carbonate provided the best results (83% yield, entry
13, Table 1), and these conditions would be employed in subse-
quent optimization parameters.
Then, we explored different catalysts previously used in Su-zuki
cross-couplings (Table 2). The use of copper (Cu2O, CuOAc, CuCl,

900
P.M. Garcia-Barrantes et al. / Tetrahedron Letters 58 (2017) 898–901
Table 3
groups (chlorine). The different toluic acid (8–10, Table 4) showed
little difference in their yields, indicating that electron-donating
substituents generally allowed. In the case of the electron-with-
drawing chlorine atom, the 2-chloro substitution (11) led to lower
yields (56%), compared the 3- and 4-substituted congeners, 12
(85%) and 13 (74%), respectively. Our survey of reaction scope
was expanded to include a broader array of electron-donating
and withdrawing substituents, predominantly 4-position of the
benzoic acid component. The optimized conditions tolerated the
presence of electron withdrawing substituents such as fluoro
(14,15), trifluoromethyl (18), trifluoromethoxy (19), cyano
(16,17) and nitro (20). From this effort, it was observed that the
nitro and cyano led to lower yields while other substituents
afforded isolated yield between 61 and 76%. Electron-donating
substituents such as methoxy (21) also provided good isolated
yields, as well as the use of the Boc-protected aniline (22). Based
on these data, we expanded the scope further to survey hetero-
cyclic ring systems; however, limited tolerance to heteroatoms in
the ring was noted. The best results were obtained, with furan
(23), thiophene (24) and MeO-pyridine (25). Basic heterocycles
such as naked pyridine, imidazole, as well as NH-containing rings
systems, such as pyrazole and indole, failed to deliver the desired
product.
Screening of solvents for optimization of the PyClU-mediated acylative Suzuki
coupling.a
Entry
Solvents
Yieldb
1
2
3
4
5
6
7
8
Acetone
Toluene
1,4-Dioxane
THF
DME
EtOAc
DMF
ACN
i-PrOH
EtOH
MeOH
H2O
89
62
47
68
49
57
0
39
40
40
25
0
9
10
11
12
a
Reactions were performed as in Table 1, using K2CO3 (1.0 equiv.), 5 mol% PdCl2
in the respective solvent (0.2 M).
b
Yields were determined by LC-MS, using as IS 3-phenoxybenzoic acid.
Then, we proceeded to test the scope of the PyClU-mediated
acylative Suzuki coupling with the optimized conditions gener-
ated.12 Initially, we explored a broad range of substituents in both
the carboxylic acid and the boronic acid reaction components.
Quickly, we found that sp3 coupling partners, either carboxylic acid
or boronic acid, did not afford the desired ketones; thus, reaction
scope was limited to aromatic and heteroaromatic coupling part-
ners (Table 4). To explore electronic effects on the aryl/heteroaryl
carboxylic acid coupling partner in this reaction, we selected both
electron donating groups (methyl) and electron withdrawing
To explore the effect of electron donating or electron with-
drawing substituents on the boronic acid (Table 4) in this reaction,
the methoxy (26–28) and cyano (29,30) moieties were initially
evaluated. The different anisole boronic acids showed similar
yields though the 2-methoxy (26) had a low conversion rate at
the two hour time point. The electron-withdrawing cyano
Table 4
Scope of PyClU-mediated acylative Suzuki coupling.
Cpd
R1
R2
Conversionb
Yieldc
7
8
9
Ph
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
4-PhOPh
2-MeOPh
3-MeOPh
4-MeOPh
3-CNPh
91
89
92
77
86
56
85
74
63
76
80
38
61
70
50
78
79
50
69
68
29
51
54
60
44
67
45
59
79
49
60
2-MePh
3-MePh
4-MePh
2-ClPh
3-ClPh
4-ClPh
>98
>98
>98
68
>98
>98
>98
>98
85
62
79
81
71
>98
>98
77
79
71
54
86
82
95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
3-FPh
4-FPh
3-CNPh
4-CNPh
4-CF3Ph
4-CF3OPh
4-NO2Ph
3-MeOPh
4-NHBocPh
2-Furan
5-Me-2-Thiophene
6-MeO-3-Pyridine
Ph
Ph
Ph
Ph
Ph
3-PhOPh
3-PhOPh
3-PhOPh
3-PhOPh
3-PhOPh
3-PhOPh
4-CNPh
4-MePh
4-FPh
4-ClPh
4-CF3Ph
4-CF3OPh
3-Thiophene
77
86
92
86
90
82
80
a Reactions were run as in Table 1, using K2CO3 (1.0 equiv.), 5 mol% PdCl2.
b
Conversion with respect to the boronic acid.
Isolated yields.
c

P.M. Garcia-Barrantes et al. / Tetrahedron Letters 58 (2017) 898–901
901
to unsymmetrical ketones at room temperature, without the need
of phosphine ligands, and in short reaction times (up to 2 h). The
methodology has proved to be robust to synthesize different
unsymmetrical aryl ketones in moderate to high yields, and with
tolerance for electron-withdrawing and electron-releasing
substituents.
Acknowledgments
The authors gratefully acknowledge support from the Warren
Family and Foundation for support of our research programs and
for establishing the William K. Warren, Jr. Chair in Medicine.
Scheme 3. Production of unsymmetrical ketones with higher-order boron reagents
and PyClU mediated conditions.
References
1. Dieter RK. Tetrahedron. 1999;55:4177–4236.
substituent provided comparable yields in either the 3- (29) or
4-position (30), but the 2-CN congener afforded no product. We
further expanded our scope by introducing a range of electron-
donating and electron-withdrawing groups at the 4-position
(31–35), which were all tolerated under our optimized conditions.
We then tried to broaden our scope to heterocyclic boronic acids,
but only the thiophene derivative (36) proved productive.
Lastly, we wanted to assay higher-order boron reagent part-
ners, as Zou and collaborators demonstrated that the acylative
Suzuki coupling could be performed also with aryl borinic acids
and tetraarylboronates.11 Performing the reaction with p-tolyl-
borinic acid 7 under our optimized conditions provided ketone 8
in yields comparable to those reported Zou.11 Furthermore, the
use of tetraphenylboronate 9 also delivered ketone 10 in good
yields (87%), suggesting broad generality amongst boron species
(Scheme 3).
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12. General experimental procedure. In
a
vial, 4-phenoxyphenylboronic acid
0.020 mmol), 1-(chloro-1-
(87 mg, 0.410 mmol), PdCl2 (3.7 mg,
pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU) (150 mg,
0.450 mmol), K2CO3 (57.41 mg, 0.410 mmol) were added and dissolved in 1 ml
of acetone. Then, a solution of benzoic acid (50 mg, 0.410 mmol) in 1 ml of
acetone was added. The mixture was stirred at room temperature for 2 h.
Consumption of starting materials and formation of product was confirmed by
LC-MS. The reaction was worked up filtration through a small pad of celite and
evaporating the volatiles in vacuo. The crude product was obtained as a white
In summary, we have developed a novel approach for the acyla-
tive Suzuki coupling between readily available and stable car-
boxylic and boronic acids, as well as higher order boron reagents
(e.g. borinic acids).11 By using PyClU as the in situ activating
reagent of the carboxylic acid, we accomplish the transformation
solid (100 mg, 89% yield) after flash chromatography purification using
a
gradient hexanes and ether, 0 to 5% ether. 1H NMR (400 MHz, CDCl3): d (ppm)
= 7.85 (2H, d, J = 8.6 Hz), 7.81 (2H, d, J = 8.4 Hz), 7.60 (1H, t, J = 7.36 Hz), 7.50
(2H, t, J = 7.3 Hz), 7.43 (2H, t, J = 7.7 Hz), 7.23 (1H, t, J = 7.4 Hz), 7.13 (2H, d,
J = 7.7 Hz), 7.06 (2H, d, J = 8.8 Hz). LRMS: m/z = 275 [MH+]