Palladium-Catalyzed Chemo- and Enantioselective C?O Bond Cleavage of α-Acyloxy Ketones by Hydrogenolysis

Article abstract of DOI:10.1002/anie.201603590

A chemoselective C?O bond cleavage of the ester alkyl side-chain of α-acyloxy ketones was realized for the first time by a highly efficient palladium-catalyzed hydrogenolysis (S/C=6000, the highest catalytic efficiency by far). Furthermore, a kinetic resolution of α-acyloxy ketones was first developed by enantioselective hydrogenolysis with good yields and up to 99 % ee.

Full text of DOI:10.1002/anie.201603590

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International Edition: DOI: 10.1002/anie.201603590
German Edition: DOI: 10.1002/ange.201603590
Kinetic Resolution
À
Palladium-Catalyzed Chemo- and Enantioselective C O Bond
Cleavage of a-Acyloxy Ketones by Hydrogenolysis
Jianzhong Chen, Zhenfeng Zhang, Delong Liu, and Wanbin Zhang*
À
Abstract: A chemoselective C O bond cleavage of the ester
alkyl side-chain of a-acyloxy ketones was realized for the first
time by a highly efficient palladium-catalyzed hydrogenolysis
(S/C = 6000, the highest catalytic efficiency by far). Further-
more, a kinetic resolution of a-acyloxy ketones was first
developed by enantioselective hydrogenolysis with good yields
and up to 99% ee.
T
he a-acyloxy ketones, which can be readily obtained by
a classic benzoin condensation or a cross-benzoin reaction,[1]
are of great interest and commonly found as useful synthetic
intermediates.[2] Generally, further derivation tends to occur
À
selectively at the keto carbonyl group or at the C O bond in
the ester carbonyl side-chain.[3] While the selective C O bond
À
cleavage of an ester alkyl side-chain is considered to be
disfavored and has only garnered little attention, the corre-
sponding products of simple ketone products have a wider
use.[4] Previously, to realize the selective cleavage of an
À
Scheme 1. Cleavage of C O bonds by hydrogenolysis. TFE=2,2,2-
trifluoroethanol.
À
inactive C O bond, either a large excess of reducing agents or
photolysis was needed, and always suffered from low
(OCOCF3)2 (1.0 mol%) and racemic DTBM-Segphos
(1.1 mol%), under 30 bar H2 pressure at room temperature
in different solvents (Table 1). Only the hydrogenated
product 3a was obtained in TFE and DCM with full
conversion (entries 1 and 2), and almost no reaction occurred
efficiency and high cost.[5] In addition, no reports on
enantioselective C O bond cleavage of ester alkyl side-
chains have been published thus far, despite chiral a-acyloxy
ketones being important structural elements in many optically
active substances.[2c,d] Therefore, to further extend the uti-
lization of a-acyloxy ketones, a more efficient and convenient
À
À
methodology for chemo- and enantioselective C O bond
cleavage is desired.
Table 1: Optimization of the reaction conditions.[a]
Recently, our group has developed an efficient palladium-
=
catalyzed asymmetric hydrogenation of C O bonds of a-
acyloxy-1-arylethanones (Scheme 1).[6] During studies on
À
these reactions, a small amount of a C O bond-cleavage
product was observed. This unexpected discovery inspired the
current research utilizing palladium-catalyzed hydrogenolysis
Entry
Solvent
Conv. [%][b]
2a
À
for the chemo- and enantioselective C O bond cleavage of
3a
ester alkyl side-chains.[7]
1
2
3
4
5
TFE
DCM
DCE
CHCl3
MeOH
EtOH
0
0
>95
>95
Initially, we carried out the hydrogenolysis of 2-oxo-2-
phenylethyl pivalate (1a) using a catalytic system of Pd-
0
0
trace
0
17
83
6
13
87
[*] Dr. J. Chen, Prof. W. Zhang
7
8
9
iPrOH
toluene
acetone
acetone
acetone
trace
trace
>95
>95
>95
27
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P.R. China)
E-mail: wanbin@sjtu.edu.cn
trace
trace
trace
trace
10[c]
11[d]
Homepage: http://wanbin.sjtu.edu.cn
Dr. Z. Zhang, Dr. D. Liu, Prof. W. Zhang
School of Pharmacy, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P.R. China)
[a] Reaction conditions: 1a (0.1 mmol), Pd(OCOCF3)2 (1.0 mol%),
DTBM-Segphos (1.1 mol%), solvent (1.0 mL), RT, 24 h. [b] Determined
by 1H NMR analysis. [c] S/C=1000, 0.33 g 1a, 6.0 mL acetone, RT, H2
(60 bar), 24 h. [d] S/C=6000, 2.0 g 1a, 15.0 mL acetone, H2 (60 bar),
608C, 30 h. DCE=1,2-dichloroethane, DCM=dichloromethane.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603590.
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in DCE and CHCl3 (entries 3 and 4). Alcohols such as MeOH,
EtOH, and iPrOH gave the desired product 2a in low yield
with a large amount of 3a (entries 5–7). The less polar
solvents, for example, toluene, only provided low activity
(entry 8). To our surprise, the most promising result was
obtained using acetone, a solvent not commonly used in
hydrogenation reactions (entry 9). Moreover, different
ligands and palladium precursors were also tested in acetone.
However no good alternatives to the DTBM-Segphos/Pd-
(OCOCF3)2 catalyst system were discovered (for details, see
Table S1 in the Supporting Information). To examine the
efficiency of our current catalytic system, the hydrogenolysis
of 1a was tested with a relatively low catalyst loading
(entries 10 and 11). To our delight, when the S/C ratio was
increased to 6000, the reaction proceeded smoothly with
quantitative conversion, albeit requiring a higher reaction
temperature and H2 pressure. The example represents, by far,
the highest catalytic efficiency for the palladium-catalyzed
homogeneous hydrogenation.[6]
The substrate scope of the catalytic system was explored
using the optimized reaction conditions (Schemes 2 and 3).
All the tested a-acyloxy ketone substrates were converted
into their corresponding products in excellent conversions
(Scheme 2). The position of the substituents on the phenyl
Scheme 2. Chemoselective hydrogenolysis of a-acyloxy ketones. [a] 60
bar, 608C.
Scheme 3. Chemoselective hydrogenolysis of acyloins. Bz=benzoyl.
ring (R1) did not alter the reaction efficiency as shown with
methoxy substrates (1b–d). Similarly, different R1 groups had
no influence on the overall yields (1e–i, 1k–n). For complete
transformation of 1j, 60 bar H2 pressure and 608C were
needed because of its low reaction activity. In addition,
different R2 groups were also evaluated with the catalyst
system. This method was efficient for the chemoselective
hydrogenolysis of methyl-substituted substrates (1o) under
60 bar H2 pressure at 608C. Other substrates with different R2
groups, including Ph, 2-ClC6H4 and 2-MeOC6H4, 3-MeOC6H4,
and 4-MeOC6H4, were successfully reacted under standard
reaction conditions (1p–t).
of Pd(OCOCF3)2 and racemic DTBM-Segphos, with 30 bar
H2 pressure at 358C in acetone, the three substrates bearing
different ester groups, such as OAc, OPiv, and OBz, showed
distinguished reactivities (1u–w). The compound 1w with an
OBz was the most active. When the OBz was decorated with
4-Me or 4-CF3 (1x,y), the reaction went to completion in
24 hours. Changing R1 to 4-ClC6H4 (1z) also gave a good
result, albeit with a low reaction activity. Substrates bearing
a Cl group at the 2-, 3-, or 4-position on the aromatic ring (R3)
also gave excellent yields (1aa–ac). Other substrates with
different substituents, such as 2-FC6H4 and 2-MeC6H4 (1ad
and 1ae), also underwent complete hydrogenolysis within
24 hours. Substrates with disubstituted aromatic rings at R3
were investigated in the hydrogenolysis and the correspond-
To further extend the substrate scope, the a-acyloxy-a-
substituted-1-arylethanones (acyloins) were subjected to the
hydrogenolysis reaction (Scheme 3). Under a catalytic system
2
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ing products were obtained with quantitative conversions
The chiral compounds 1 have the potential for use in
(1af–ah), however a higher H2 pressure and reaction temper-
ature were required. When R3 was replaced by 1-naphthalene
(1ai), excellent chemoselectivity was also observed. When R1
and R3 were 3-chlorophenyl and 4-methylphenyl, respec-
tively, the substrates were transformed completely after
24 hours (1aj,ak). Changing R1, R2, and R3 to 4-methylphenyl
groups had no effect on the reaction conversion (1al).
Furthermore, it was very interesting that the acyloins can
be kinetically resolved using (R)-DTBM-Segphos as a chiral
ligand (Scheme 4). A substrate bearing OBz [(Æ)-1w] was
reacted under 30 bar hydrogen pressure for 6 hours to recover
1w with 82% yield and 4% ee. By lowering the reaction
simple transformations for the synthesis of unsymmetrical
chiral 1,2-diol structural motifs commonly found in various
biologically active compounds and chiral ligands.[8] By using
the same catalytic system of hydrogenolysis but replacing
acetone with TFE, (S)-1ac was hydrogenated smoothly to
give the corresponding products (S,R)-4 (36% yield) and
(S,S)-4 (55% yield) without loss in the ee value (Scheme 5).
The corresponding unsymmetrical chiral 1,2-diol (S,R)-5 was
obtained by removal of the ester in 91% yield and 99% ee.[9]
Meanwhile, according to a reported literature,[10] (S,S)-4 could
be cyclized directly using Pd(OAc)2/X-Phos and hydrolyzed
to give the dihydrobenzofuran derivative (S,S)-6 in 67% yield
and 99% ee.[11]
Scheme 5. Product derivatization. Reagents and conditions: a) (S)-1ac
(0.4 mmol), Pd(OCOCF3)2 (1.0 mol%), (R)-DBTM-Segphos
(1.1 mol%), TFE (4.0 mL), H2 (30 bar), RT, 24 h. b) (S,R)-4 (0.1 mmol),
MeOH (2.0 mL), THF (2.0 mL), 10% K2CO3 aq. (2.0 mL), RT, 8 h.
c) (S,S)-4 (0.1 mmol), 7.0 mol% Pd(OAc)2, 7.0 mol% X-Phos, Cs2CO3
(1.2 equiv), 1,4-dioxane (3.0 mL), 908C, 12 h. d) MeOH (1.0 mL), THF
(1.0 mL), 10% Cs2CO3 aq. (1.0 mL), RT, 18 h. THF=tetrahydrofuran,
X-Phos=dicyclohexyl[2’,4’,6’-tris(prop-2-yl)biphenyl-2-yl]phosphane.
In conclusion, under mild reaction conditions, a chemo-
Scheme 4. Kinetic resolution of acyloins by enantioselective hydro-
genolysis.
À
selective C O bond cleavage of an ester alkyl side-chain of a-
acyloxy ketones by palladium-catalyzed hydrogenolysis has
been reported for the first time. A variety of substrates were
investigated with almost quantitative conversions. And
reducing the catalyst loading to 1/6000 still provided a quanti-
tative yield of the product, and represents, by far, the lowest
catalyst loading for homogeneous palladium-catalyzed hydro-
temperature to 08C, enantioselectivity increased slightly to
6% ee (37% yield). Reducing the H2 pressure to 15 bar
increased the enantioselectivity to 36% ee (52% yield).
Substrates with a Cl group at the 4- and 3-positions on the
benzene ring also displayed less than promising results under
30 bar H2 pressure (1aa and 1ab), while a substrate bearing Cl
at the 2-position on the benzene ring of R3 showed excellent
performance (99% ee for (S)-1ac in 46% yield). Similarly
excellent enantioselectivities were achieved for the substrates
bearing 2-F and 2-Me at the benzene ring when a suitable H2
pressure was used [(S)-1ad and (S)-1ae]. Substrates in which
R3 possessed two functional groups in different positions on
the benzene ring were also explored in the enantioselective
hydrogenolysis. The recovered substrates were obtained with
excellent enantioselectivities and good yields [(S)-1af, (S)-
1ag, and (S)-1ah]. To the best of our knowledge, this is the
first report on kinetic resolution by catalytic enantioselective
hydrogenolysis.
À
genation. Furthermore, an enantioselective C O bond cleav-
age of ester alkyl side-chain was also reported for the first
time and further applied to the kinetic resolution of some
acyloins with up to 99% ee. The corresponding chiral
products could serve as important intermediates for the
preparation of some useful optically active substances.
Acknowledgments
This work was partially supported by the National Natural
Science Foundation of China (No. 21232004, 21372152,
21472123, and 21572131), Science and Technology Commis-
sion of Shanghai Municipality (No. 14XD1402300), and the
China Postdoctoral Science Foundation (No. 2014M551397).
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We also thank the Instrumental Analysis Center of SJTU for
characterization.
Keywords: cleavage reactions · hydrogenolysis · ketones ·
kinetic resolution · palladium
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Received: April 13, 2016
Revised: May 11, 2016
Published online: && &&, &&&&
4
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Kinetic Resolution
J. Chen, Z. Zhang, D. Liu,
W. Zhang*
&&&& — &&&&
Palladium-Catalyzed Chemo- and
À
À
À
Enantioselective C O Bond Cleavage of
a-Acyloxy Ketones by Hydrogenolysis
A break of C O: A chemoselective C O
bond cleavage of the ester alkyl side-chain
of a-acyloxy ketones by a palladium-cat-
alyzed hydrogenolysis is reported. Fur-
kinetic resolution of some acyloins with
up to 99% ee. The example (S/C=6000)
represents by far the highest catalytic
efficiency for a palladium-catalyzed
homogeneous hydrogenation.
À
thermore, an enantioselective C O bond
cleavage was successfully applied to the
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