Palladium-catalyzed site-selective arylation of aliphatic ketones enabled by a transient ligand

Article abstract of DOI:10.1039/c8cc00980e

Transition metal-catalyzed direct C-H bond functionalization enabled by transient ligands has become an attractive topic. Here we report a palladium-catalyzed site-selective arylation of β-C(sp³)-H bonds in aliphatic ketones with β-alanine as the transient ligand.

Full text of DOI:10.1039/c8cc00980e

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Palladium-Catalyzed Site-Selective Arylation of Aliphatic Ketones
Enabled by A Transient Ligand
Lei Pana†, Ke Yanga,b†, Guigen Lib,c* and Haibo Gea*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Transition metal-catalyzed direct C–H bond functionalization
enabled by transient ligands has become an attractive topic. Here
we report a palladium-catalyzed site-selective arylation of β-
C(sp3)–H bonds in aliphatic ketones with β-alanine as the transient
ligand.
O
OH
O
O
O
OH
O
O
O
Nabumetone
Warfarin
Loxoprofen
Figure 1. Selected examples of biologically active drugs.
Aliphatic ketones are key intermediates in chemical synthesis
and ubiquitous structural units in biologically active natural
products and pharmaceuticals, such as the marketed drugs
nabumetone1, warfarin2 and loxoprofen3 (Figure 1). Among
various synthetic methods for aliphatic ketones, transition
metal-catalyzed C–H bond functionalization has become one
of the most efficient tactics in organic synthesis. In the past
decade, the auxiliary group-based strategy has been
Previous work
cat. 2-amino-3-picoline
cat. RhCl(PPh3)3
PhMe, 150 oC, 24h
(a)
O
R1CHO +
R2
R1
R2
cat.
R2
O
N
N
O
H
(b)
(c)
R2
cat. Rh(coe)2Cl2
+
extensively explored to achieve
a series of C–H bond
cat. IMes, cat. TsOH.H2O
functionalization reactions with high site-selectivity4. Despite
the great progress has been made in this area, this approach is
still far from satisfaction because installation and removal of
the directing ligands on substrates add additional synthetic
steps, and thus diminish the overall efficiency of the reaction
process. For this reason, the development of novel and
powerful methodologies without attaching an internal
directing group is highly desirable.
PhMe, 120 o
C
R1
R1
H2N
cat. Pd(OAc)2
CO2H
cat.
O
O
R1
R1
Ar
I
R2
+
R2
AgTFA, HFIP/HOAc
H
Ar
O
This work:
CO2H
H N
cat.
2
H
O
Ar
cat. Pd(OAc)2
+
ArI
R1
R2
R1
R2
AgTFA, HFIP/HOAc
Scheme 1. Transition metal-catalyzed C–H bond
functionalization of aldehydes/ketones enabled by transient
ligands.
A strategy based on the in situ generated directing groups has
proven successful in transition metal-catalyzed C–H bond
functionalization reactions. In 1997, Jun’s group demonstrated
for the first time the Rh(I)-catalyzed functionalization of C–H
bonds of aldehydes by employing 2-amino-3-picoline as a
transient ligand (Scheme 1a)5. Recently, Dong’s group
established
a novel Rh(I)-catalyzed alkylation process of
ketones with a secondary amine as a transient ligand (Scheme
1b)6. In the meanwhile, the use of catalytic amounts of
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phosphinite ligands was also proven effective in Rh(I)- amounts of AgTFA with β-alanine (L1) as a transient ligand at
catalyzed selective C–H functionalization of phenols, alcohols 130 oC under nitrogen atmosphere (Table 1). Initial solvent
and anilines7. However, the catalytic site-selective screening showed that mixture of hexafluoro-2-propanol and
functionalization of unactivated C(sp3)–H bonds is a challenge acetic acid at the volume ratio of 3:1 could provide the desired
process8. Very recently, Yu and co-workers established the Pd- arylated product 3a in decent yield (entry 5). It is believed that
catalyzed arylation of o-alkyl benzaldehydes and aliphatic this co-solvent system facilitates the ligand association and
ketones with α-amino acids as transient ligands (Scheme 1c)8a. dissociation, and cyclopalladation in the process.10 Next, the
In spite of a powerful approach, this method suffers from a effect on selected ligands towards the process was examined.
restricted substrates scope, and only terminal -C(sp3)–H bonds It turned out that the reactions gave low yields with an
α-
could be functionalized with linear ketones. On the basis of amino acid (L2 or L3) as the ligand, indicating that a [5,5]-
previous study in our group, herein we report a palladium- bicyclic palladium intermediate may not be suitable in this
catalyzed arylation of unactivated β-methylene C–H bonds of process (entries 6-7). Following the above investigations,
aliphatic ketones with 3-aminopropanoic acid as the transient screening of silver salts was conducted, and low yields were
ligand9.
observed with AgOAc, Ag2CO3 or Ag2O (entries 14-16). Further
study showed that this reaction could also be catalyzed by
PdCl2, Pd(TFA)2, Pd(acac)2 or Pd(PhCN)2Cl2 with moderate
yields (entries 17-20). It is noteworthy that no desired product
3a was obtained in the absence of a silver salt or a ligand
(entries 21-22). Moreover, a lower yield was obtained at a
lower reaction temperature (entry 23).
Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Aliphatic Ketonesa
a
Reaction conditions:
1 (0.20 mmol), Pd(OAc)2 (10 mol%), 2a
a
(0.4 mmol), AgTFA (0.3 mmol), β-alanine (40 mol%), HFIP (1.5
b
Reaction conditions: 1a (0.2 mmol), Pd source (10 mol%), 2a
mL), HOAc (0.5 mL), 130 oC, N2, 36 h. Isolated yields. PhI (0.8
(0.4 mmol), additives (0.3 mmol), ligands (40 mol%), solvent
(2.0 mL), 130 oC, N2, 36 h. b Yields are based on 1a, determined
mmol). c HFIP (1.6 mL), HOAc (0.4 mL). d β-alanine (0.14 mmol).
1
c
by H-NMR using dibromomethane as internal standard. 110
oC. d Isolated yields.
As shown in Scheme 2, this strategy could be used for the
unsymmetric double C–H arylation of ketones. Two different
aryl groups could be consecutively installed to provide
Very recently, our group discovered the palladium-catalyzed
direct β-arylation of aliphatic aldehydes with β-alanine as a
transient ligand in hexafluoro-2-propanol and acetic acid8b. On
the basis of this report, we commenced our investigation on
compound
4
with glycine and β-alanine as the transient ligands
respectively.
the cross coupling of 2-pentanone (1a) and iodobenzene (2a
)
in the presence of catalytic Pd(OAc)2 and stoichiometric
2 | J. Name., 2012, 00, 1-3
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A
to a palladium species generates the corresponding six-
membered palladium complex Cyclometalation of
intermediate
activates the β-C(sp3)–H bond, giving rise to a
[5,6]-bicyclic palladium intermediate Then, oxidative
addition of the intermediate with an aryl iodide produces the
palladium (IV) species . Finally, reductive elimination of the
palladium complex will occur, followed by ligand dissociation
and iodide abstraction to give the β-imino acid , which
releases the desired product and the ligand β-alanine.
B
.
B
C
.
C
D
D
F
3
Scheme 2. Unsymmetric double C H arylation of butan-2-one
−
Next, we carried out the substrate scope study on aryl iodides
(Table 3). As expected, unactivated β-secondary C–H bond of
2-pentanone could be arylated with different aryl iodides with
great functional group compatibility. Aryl iodides bearing an
electron-withdrawing or electron-donating group on phenyl
ring at the o-, m- or p-positions underwent arylation smoothly
to produce the desired products in good yields (3p-z). It is also
noteworthy that halogens (F, Cl, or Br) were well tolerated,
enabling further manipulations of the initial products.
Furthermore, 5-iodo-2-(trifluoromethyl)pyridine was also a
suitable substrate for this reaction (3za).
Table 3. Scope of Aryl Iodidesa
Figure 2. Proposed catalytic cycle.
In summary, a direct arylation of β-C(sp3)–H bonds of aliphatic
ketones has been developed via a palladium catalysis under
atmospheric nitrogen with cheap and commercially available
β-alanine as the transient ligand with good functional group
compatibility. A great preference for functionalizing the C H
−
bonds of β-sp3 carbons over those of γ-carbons and relatively
reactive α-carbons is observed. The detailed mechanistic study
of this transformation is currently undergoing in our laboratory.
Acknowledgements
We greatly appreciate the financial support for this work by
NSF (CHE-1350541) and Indiana University Purdue University
Indianapolis. G. L. is also grateful for financial support from
Robert Welch Foundation (D-1361).
a
Reaction conditions: 1a (0.20 mmol), Pd(OAc)2 (10 mol%),
2
(0.4 mmol), AgTFA (0.3 mmol), β-alanine (40 mol%), HFIP (1.5
b
mL), HOAc (0.5 mL), 130 oC, N2, 36 h. Isolated yields. β-
alanine (0.12 mmol), HFIP (1.6 mL), HOAc (0.4 mL).
Conflicts of interest
On the basis of the above obtained results and previous
reports8b,11, a plausible reaction mechanism is proposed
(Figure 2). It is believed that this process is initiated by the
There are no conflicts to declare.
reversible imine formation from aliphatic ketone
catalytic transient ligand β-alanine, providing the imine
intermediate . Then, coordination of the imine intermediate
1 with the
Notes and references
A
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H
O
Ar
O
cat. Pd, ArI
R1
R2
R2
CO2H
R1
H N
2
cat.
R1
[5,6]-bicyclic
palladium intermediate
N
PdII
R2
O
O
C-H Arylation of ketones enabled by a cheap and commercially available transient ligand with
high site-selectivity and functional group compatibility.