A mild palladium-catalyzed Suzuki coupling reaction of quinoline carboxylates with boronic acids

Article abstract of DOI:10.1002/adsc.201100141

A palladium-catalyzed cross-coupling between aryl carboxylates and boronic acids has been achieved for the first time by taking advantage of the enhanced reactivity of quinoline 4-carboxylates. Also for the first time a Suzuki coupling reaction via a self-activation of boronic acids without addition of base is described. The reactions proceed under mild conditions (25-65°C) to give excellent yields, and a wide range of functionalities is tolerated. Copyright

Full text of DOI:10.1002/adsc.201100141

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DOI: 10.1002/adsc.201100141
A Mild Palladium-Catalyzed Suzuki Coupling Reaction of
Quinoline Carboxylates with Boronic Acids
Wenjie Li,a,* Joe J. Gao,a Yongda Zhang,a Wenjun Tang,a Heewon Lee,a
Keith R. Fandrick,a Bruce Lu,a and Chris H. Senanayakea
a
Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/PO Box 368, Ridgefield, CT 06877-0368, USA
Fax : (+1)-203-791-6168; e-mail: wenjie.li@boehringer-ingelheim.com
Received: February 26, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100141.
Abstract: A palladium-catalyzed cross-coupling be-
tween aryl carboxylates and boronic acids has been
achieved for the first time by taking advantage of
the enhanced reactivity of quinoline 4-carboxylates.
Also for the first time a Suzuki coupling reaction
via a self-activation of boronic acids without addi-
tion of base is described. The reactions proceed
under mild conditions (25–658C) to give excellent
yields, and a wide range of functionalities is tolerat-
ed.
since been published.[6] Despite these achievements,
Suzuki–Miyaura coupling reactions with phenolic
esters remain as an underdeveloped area. Notably, no
such palladium-facilitated coupling reaction has been
reported. The versatility of palladium catalysts and
the vast availability of ligands may allow the fine-
tuning of the reaction to enable mild conditions, low
catalyst loadings, broad substrate scope, and wide
functional group tolerance. Herein, we report the first
examples of palladium-catalyzed cross-coupling reac-
tions between activated aryl esters and boronic acids.
Quinoline and pyridine moieties are widely present
in synthetic drug substances and biologically active
natural products.[7] Functionalized heteroaromatic
compounds containing quinoline and pyridine scaf-
folds have been of great interest to pharmaceutical in-
dustries,[8] and many methodologies have been devel-
oped for their synthesis.[9] As part of our program to
Keywords: monophosphanes; palladium; quino-
lines; room temperature reaction; Suzuki–Miyaura
cross-coupling
Transition metal-catalyzed cross-coupling reactions prepare 4-arylquinolines as drug candidates, we realiz-
have been widely utilized in both academia and indus- ed that such derivatives were often synthesized via
tries.[1] In particular, the Suzuki–Miyaura reaction is cross-coupling reactions from 4-chloroquinolines,[10]
one of the most powerful methodologies for the con- which were usually prepared from the readily avail-
struction of biaryl functionalities.[2] The traditional able 4-hydroxylquinolines. Based on the advantages
Suzuki–Miyaura reaction involves arylboronic acids mentioned above, it is highly desirable to use the
and aryl halides as coupling partners, and significant ester derivatives as cross-coupling partner. Consider-
success has been accomplished towards using aryl ing that 4-quinoline carboxylates have much different
chlorides in coupling reactions.[3] Phenol derivatives electronic properties from the corresponding phenol
have also been used and they were usually activated esters and that they are significantly more reactive
by forming sulfonate derivatives.[4] The phenolic due to the electron-deficient nature of quinoline
esters are attractive coupling partners because they (Figure 1), we envisioned that it might be feasible to
are extremely economical, easy to prepare, and envi-
ronmentally friendly. The apparent challenge for this
À
application is the fact the aryl C O bond of the O-
acylated phenol is usually unreactive toward the de-
sired oxidative metal insertion and readily undergoes
hydrolysis under Suzuki–Miyaura reaction conditions.
Recently, Gargꢀs and Shiꢀs groups have reported
Suzuki–Miyaura coupling with aryl pivalates using
Figure 1. Enhanced reactivity of quinoline 4-carboxylates
nickel catalysts,[5] and a couple of review articles have over naphthalene 1-carboxylates.
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Scheme 1. Cross-coupling between 4-hydroxyquinoline benzoate and phenylboronic acid in the absence of base.
carry out such a cross coupling reaction using palladi- thoxybenzoate was as effective (Table 1, entry 1) as
um as catalyst.
the benzoate itself. The more electron-donating p-di-
modest yield
We initiated our study with 4-hydroxylquinoline methylaminobenzoate gave only
a
benzoyl ester (1) and were pleased to find that it (entry 3). The electron-withdrawing p-CF3-benzoate
readily underwent a cross-coupling reaction with phe- was slightly less effective (entry 2), whereas the p-
nylboronic acid (2) in toluene at 708C with catalytic nitro group was detrimental (entry 4). The 2,4,6-tri-
Pd2dba3/S-Phos.[11] Interestingly, the reaction proceed- methylbenzoate also gave a low yield (entry 5), prob-
ed to completion without any addition of base ably due to the increased steric hindrance. Aliphatic
(Scheme 1). We believe that the following two key esters were also suitable for this transformation (en-
factors in the catalytic cycle contribute to the success- tries 6 and 7) and gave excellent yields.
ful outcome of this reaction: (i) the enhanced reactivi-
Focusing on the benzoyl derivative, we surveyed
ty of quinoline 4-carboxylates allows the oxidative in- the ligands for optimum reaction conditions. The
À
sertion of the C O bond by palladium(0) to give 4; most commonly used arylphosphine ligands such as
and (ii) the transmetallation is facilitated by the for- Ph3P, tri
G
G
mation of a six-membered transition state 5, in which failed to promote the coupling reaction. On the other
the boronic acid is activated by the carbonyl group of hand, as shown in Table 2, electron-rich dialkyl biaryl-
the ester in the absence of base (Scheme 2). To the monophosphanes (entries 1, 3, and 4)[12] gave excel-
best of our knowledge this was the first example of lent yields, and the yield decreased with less electron-
Suzuki coupling without base or fluoride as activating rich ligands (entries 5–10). The biarylmonophospho-
agents for boronic acids. Under these mild conditions rus ligand developed by our department (BI-DIME,
the potential pathway of ester hydrolysis was mini- entry 2)[13] exhibited superior reactivity and drove the
mized and therefore the overall reaction efficiency reaction to completion within 30 min. A brief solvent
was greatly improved.
survey was performed and it was found that the reac-
Next we investigated different substituents on the
phenyl group of the carboxylate and found that p-me-
Table 1. Cross-coupling between various 4-quinoline carbox-
ylates and phenylboronic acid.
Entry
R
Time [h][a] Yield [%][b]
1
2
3
4
5
6
7
4-MeO-C6H4 (1a)[c]
4-CF3-C6H4 (1b)[c]
4-Me2N-C6H4 (1c)[c]
4-NO2-C6H4 (1d)[d]
1
1
3
15
98
84
57
31
22
95
98
2,4,6-trimethyl-C6H2 (1e)[e] 15[f]
CH3 (1f)[c]
t-Bu (1g)[c]
2
1
[a]
Time for complete conversion of 1a–1g by HPLC analy-
sis unless noted otherwise.
Yield determined by HPLC assay.
1.5 equiv. of PhB(OH)2 added.
2 equiv. of PhB(OH)2 added.
5 equiv. of PhB(OH)2 added.
[b]
[c]
[d]
[e]
[f]
Scheme 2. Proposed mechanism for the cross-coupling be-
tween 4-hydroxyquinoline benzoate and phenylboronic acid.
Complete conversion of 1e was not achieved.
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A Mild Palladium-Catalyzed Suzuki Coupling Reaction of Quinoline Carboxylates with Boronic Acids
Table 2. Ligand survey for the cross-coupling reaction between 4-hydroxyquinoline benzoate and phenylboronic acid.
Entry Ligand
Reaction time[a] Yield[b] Entry Ligand
Reaction time[a] Yield[b]
1
G
1 h
98%
98%
6
7
3 h
3 h
80%
80%
2
3
4
2 h
2 h
3 h
98%
98%
80
8
Cy3P
3 h
3 h
3 h
75%
9
(t-Bu)3P·HBF4
69%[c]
41%[c]
5
10
[a]
Time for complete conversion of 1.
Yield determined by HPLC assay.
Complete conversion of 1 not achieved.
[b]
[c]
tion proceeded very well in a variety of solvents such
as dioxane, THF, 2-methyl-THF, IPAc, acetonitrile,
DMAc, and 2-butanone.
The remarkable reactivity of BI-DIME prompted
us to search for even milder reaction conditions. We
[14]
soon found out that when PdACHTUNTRGENNUG(CH3CN)4ACHTUNGTREN(NUGN BF4)2 was
used as palladium source instead of Pd2dba3, BI-
DIME catalyzed the cross-coupling reaction to com-
plete conversion even at room temperature. In the
parallel studies, BI-DIME demonstrated superior re-
activity to other dialkyl-biarylmonophosphanes such
as S-Phos, which failed to drive the reaction to com-
plete conversion under the same conditions
(Figure 2).
The scope of the reaction was investigated under
our optimized conditions (Table 3). A wide range of
boronic acids readily underwent the cross-coupling re-
action to give the desired products. In most cases the
Figure 2. Comparison of reactivity of BI-DIME and S-Phos
reactions were carried out at 658C to expedite the for the cross-coupling reaction.
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Wenjie Li et al.
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Table 3. Cross-coupling reaction of 4-hydroxyquinoline ben-
zoates and boronic acids.
as they were able to drive the reaction to complete
conversion at low temperature (conditions b and c) in
several selected examples (3b, 3c, 3d, 3e). Both elec-
tron-rich (3d, 10b) and electron-deficient (3c, 3f, 3g)
boronic acids performed well in the cross-coupling. o-
Substituted boronic acids also proceeded to give the
desired products (3i, 3j, 3k), although in slightly lower
yields. A wide range of functional groups was tolerat-
ed in the reaction, including ketone (3e), nitrile (3f),
nitro (3g), aldehyde (3j), and ester (10a). The aryl
chloride functionality was also tolerated to give de-
sired products in high yield (10c, 11a, 11b) without
forming the coupling product at the chloride site.
In summary, we have discovered and developed a
palladium-catalyzed cross-coupling reaction between
acylated 4-hydroxyquinoline and boronic acids in the
absence of base or fluoride. The reaction not only
offers synthetic applications for the preparation of
functionalized quinolines, but also has mechanistic
significance with self-activation of boronic acids. Ap-
plying the BI ligand BI-DIME, the reaction could
proceed under very mild conditions. Studies aimed at
extending the scope and further understanding the
mechanistic aspect of the reaction are underway.
93%[a]
90%[a]
90%[b]
80%[c]
92%[a]
91%[c]
91%[a]
85%[c]
89%[a]
88%[c]
95%[a]
82%[a]
81%[a]
Experimental Section
General Procedure for Cross-Coupling Reactions
To an oven-dried flask (50 mL) under an argon atmosphere
were charged of 2-methyl-THF (5 mL), 4-hydoxylquinoline
benzoate (1 mmol), boronic acid (1.2 mmol), Pd
ACHTUGNRTNE(NUNG CH3CN)4
AHCTUNGTREN(NGUN BF4)2 (0.01 mmol) and the BI-DIME (0.02 mmol). The mix-
ture was degassed with argon for 5 min, and then agitated at
258C for 48–60 h. To the agitated solution was charged ethyl
acetate (20 mL), followed by 5% NaOH (10 mL).The mix-
ture was stirred for 10 min. The aqueous phase was cut. The
organic phase was washed with 10% brine (10 mL) and
dried with anhydrous sodium sulfate. The product was puri-
fied by flash silica chromatography (Combi-Flash, EtOAc/
hexanes, 1/4).
76%[a]
83%[a]
92%[a]
96%[a]
88%[a]
91%[a]
94%[a]
96%[a]
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[a]
Isolated yield. Reaction conditions: Pd2dba3 (1 mol%), S-
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Isolated yield. Reaction conditions: PdACHTUNTRGENNUG(CH3CN)4ACHUTGNTREN(NUNG BF4)2
(1 mol%), BI-DIME (2 mol%), RB(OH)2 (1.2 equiv.), 2-
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