Expedient Synthesis of Ketones via N-Heterocyclic Carbene/Nickel-Catalyzed Redox-Economical Coupling of Alcohols and Alkynes?

Article abstract of DOI:10.1002/cjoc.202000019

An N-heterocyclic carbene/nickel-catalyzed direct coupling of alcohols and internal alkynes to form α-branched ketones has been developed. This methodology provides a new approach to afford branched ketones, which are difficult to access through the hydroacylation of simple internal alkenes with aldehydes. This redox-neutral and redox-economical coupling is free from any oxidative or reductive additives as well as stoichiometric byproducts. These reactions convert both benzylic and aliphatic alcohols and alkynes, two basic feedstock chemicals, into various α-branched ketones in a single chemical step.

Full text of DOI:10.1002/cjoc.202000019

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Expedient Synthesis of Ketones via NHC/Nickel-Catalyzed Redox-Economical
Coupling of Alcohols and Alkynes
Authors: Yu-Qing Li, Feng Li, and Shi-Liang Shi*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000019.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202000019.
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Chinese Journal
of Chemistry
Nickel catalysis, Ketone synthesis, Hydrogen transfer, Alkynes, Alcohols，
N-heterocyclic carbene ligand
Report
CJC
中
国 化 学 - An International Journal
Expedient Synthesis of Ketones via NHC/Nickel-Catalyzed Redox-
Economical Coupling of Alcohols and Alkynes
Yu-Qing Li, # Feng Li, # and Shi-Liang Shi *
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
#Y.-Q. Li and F. Li contributed equally.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
An NHC/nickel-catalyzed direct coupling of alcohols and internal alkynes to form α-branched ketones has been developed. This methodology provides a
new approach to afford branched ketones, which is difficult to access through the hydroacylation of simple internal alkenes with aldehydes. This redox-
neutral and redox-economical coupling is free from any oxidative or reductive additives as well as stoichiometric byproducts. These reactions convert both
benzylic and aliphatic alcohols and alkynes, two basic feedstock chemicals, into various α-branched ketones in a single chemical step.
The ketone is a fundamental functional group of high synthetic
utility. The direct preparation of ketones from readily available
starting materials via carbon-carbon bond formations represents
one of the most critical challenges in organic synthesis. The
transition-metal-catalyzed hydroacylation of alkenes, usually
achieved by the addition of an aldehyde C-H bond across an olefin
π-bond, is one straightforward strategy for the construction of
ketones from simple precursors.[1] Despite the high efficiency of
this transformation, however, several longstanding limitations
exist. For instance, these processes are typically catalyzed by noble
metals, most often Rh.[2] Moreover, a coordinating group is usually
needed on either the alkene or aldehyde substrate to provide
chelation assistance and suppress the undesired decarbonylation
reaction.[3] More importantly, most current hydroacylation
methods are only applicable to terminal alkenes, strain-activated
cyclic alkenes, or electronically activated alkenes (Figure 1a). [2d, 3d,e,
We noted that in our proposed catalytic cycle, a single nickel
catalyst would have to perform two catalytic cycles simultaneously,
and it was unclear whether a suitable ligand could be found to
allow this single-catalyst, dual-catalytic process to take place.
Furthermore, the success of our strategy was hinged on addressing
three challenges (Figure 1b): (i) competitive trimerization of
Figure 1. Direct synthesis of ketones from internal alkenes and alkynes. (a)
Hydroacylation of internal alkenes. (b) Direct coupling of alcohols with
alkynes to form ketones.
4]
Unactivated internal alkenes continue to pose a formidable
challenge to hydroacylation chemistry.[5]
As an alternative strategy to access the hydroacylation
products of simple internal alkenes, we considered changing the
oxidation state of the starting materials. In particular, we reasoned
that the direct coupling of alcohols and alkynes, two basic
feedstock chemicals, would probably lead to the same product as
alkene hydroacylation (Figure 1b). In more detail, we envisioned
that a direct hydrogen transfer of an alcohol in the presence of a
nickel catalyst would give catalytic amounts of nickel hydride
species and an aldehyde.[6] The alkyne would then be
hydroacylated by the aldehyde via an oxanickelacyclic
intermediate[7,8] to form a carbon-carbon bond affording an
enone.[9] We further postulated that the enone would be
eventually hydrogenated by the initially formed nickel hydride
species to deliver the α-branched ketone product.
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Yu-Qing Li et al.
Breaking Report
4a, which is consistent with our initial proposal. Notably, SIPr was
found to be superior to other NHC ligands furnishing 3a in 84%
yield with a high ratio of 3a/4a (88:12, entry 2). The use of IPr
provided the product in the same ratio of 3a/4a but with other
byproducts mainly derived from the trimerization of 4-octyne
(entry 3)[10]. Other NHC ligands such as IMes and IPr*OMe, as well as
phosphine ligands (see SI), gave both lower reactivity and
selectivity (entries 4-5). Using SIPr as the optimized ligand, we then
focused on lowering the amount of enone 4a. As we had proposed
that 4a might be selectively reduced to 3a by using alcohol as a
reductant in the presence of the nickel catalyst, we gradually
increased the equivalent of alcohol. As expected, the amount of
enone decreased dramatically (entries 6-8). When 1.5 equivalent
of alcohol (1a) was employed, the enone (4a) was undetectable,
and the ketone product (3a) could be isolated in 90% yield (entry
8).
Table 1. Optimization of reaction conditionsa
mol%)
Ni(cod)2 (5
O
O
NHC/HCl mol%)
(5
nPr
OH
tBuONa
mol%
5
+
+
Ph
nPr
Ph
nPr
(
)
nPr
N
Ph
nPr
3a
nPr
4a
toluene M)
(1
100 o 12 h
C,
1a
2a
R1
R1
R1
R1
R1
R2 Me: IMes
R1 Me, R H: IPr
=
=
H,
N
N
N
2
=
=
1
2
OMe
R2
2 R Ph, R OMe: IPr*
=
=
R1
R1
R
R1
R1
SIPr
Entry
1a/2a
NHC
none
SIPr
IPr
Yield of 3a (%)b
3a/4ab
--
1
2
3
4
5
6
7
8
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1
0
84
88:12
88:12
79:21
73:27
94:6
79
IMes
67
IPr*OMe
SIPr
64
a.
of internal alkenes
Hydroacylation
88
O
R2
or
Rh, Ru etc.
+
R3
activated
R1
aldehydes
H
1.2:1
1.5:1
SIPr
91
98:2
cyclic
to
internal alkenes
inapplicable simple
internal alkenes
SIPr
92 (90)c
>99:1
oxidation state
changing
b. Reaction design:
a Reactions were performed on 0.2 mmol scale.b Determined by 1H
NMR analysis using an internal standard. c Isolated yield.
work)
(This
O
R3
OH
+
NHC/Ni(0)
(cat.)
R1
R3
R2
internal
R1
Redox-economical
process
R2
alkynes[10], which is facile under nickel catalysis, would need to be
suppressed; (ii) desired formation of oxametallacyclic
intermediates should be fast enough to avoid competitive aldol
reaction and Tishchenko reaction of transient aldehydes[11]; (iii) the
conjugate reduction catalyzed by the nickel hydride species, which
has been rarely studied[12], would need to be highly chemo- and
α
alcohols
simple
alkynes
-branched ketones
H
[Ni]
R3
H
NiII
R2
NiII
O
O
O
Ni0
R3
O
R1
R3
R1
R3
R1
R1
regioselective to avoid unproductive reductions of alkynes[13]
,
R2
R2
R2
transiently formed aldehydes and enones, as well as ketone
products. Capitalizing on newly designed N-heterocyclic carbene
(NHC) ligands[14], we recently reported a Ni-catalyzed redox-
economical coupling of benzylic alcohols and alkynes for the direct
preparation of chiral allylic alcohols.[6a] As part of our continuing
effort in the field of NHC/metal catalysis, we report here the use of
an NHC-ligated nickel catalyst to achieve the alcohol-alkyne
coupling as a means of obtaining the ketone products of an elusive
hydroacylation of unactivated internal olefins.[15] This base-metal-
catalyzed hydrogenative transfer process[16] free from any
additives makes the reaction atom-, step- and redox-economical.[17]
We first test the feasibility of the proposed redox-economical
coupling utilizing benzylic alcohol (1a) and 4-octyne (2a) as the
model substrates to form ketone 3a in the presence of 5 mol% of
Ni(cod)2, tBuONa, and a range of NHC precursor imidazolium salts
under heating conditions (100 oC). We found that the in-situ
generated Ni/NHC catalyst indeed deliver the desired ketone
product (3a), while no reaction occurred in the absence of NHC
ligands (Table 1, entry 1). We also observed the formation of enone
R3
Potential challenges:
R2
R3
R2
R3
R3
OH
OH
O
O
R1
R3
R1
H
R1
O
R1
R2
R2
R
R2
alkyne
trimerization
aldol
reaction
Tishchenko
reaction
unproductive
reductions
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
With the optimized conditions in hand, we next examined the
Table 2. Nickel-catalyzed coupling of benzylic alcohols with alkynesa
generality of this nickel-catalyzed coupling reaction using an array
of benzyl alcohols and alkynes. As shown in Table 2, various
benzylic alcohols with electron-donating substituents such as
methyl or alkoxyl groups at ortho-, meta-, and para-position
efficiently coupled with 4-octyne (2a) to give the corresponding
ketones in high yields (86-94%, 3a–3h). As for benzylic alcohols
with electron-withdrawing substituents such as fluoro and
trifluoromethyl groups, bulkier ligand IPr*OMe was used instead of
SIPr, and ketone products were obtained in high yields (84-90%, 3i
and 3j). In addition to 4-octyne, symmetric internal alkynes
including 3-hexyne, 5-decyne, 7-tetradecyne, and a cyclic alkyne
(cyclododecyne), were all competent substrates for this redox-
economical transformation (3k–3n). Moreover, unsymmetric
internal alkynes also served as viable substrates, and the products
were generated in high yields (77-87%, 3o–3r) as regioisomeric
mixtures. Given that the similar size of alkyl substituents on the
alkynes, the reactions using 3-octyne or 2-hexyne gave products in
reasonable levels of regioselectivity (1.9-3.5:1, 3o, 3p). In the case
of 4-methyl-2-pentyne, the catalyst could effectively differentiate
the isopropyl and methyl group substituents furnishing the product
in regioselectivity of 6.7:1 (3q), while the use of an aryl-alkyl
internal alkyne (1-phenyl-1-hexyne) afforded the product in
excellent regioselectivity (12.5:1, 3r). Importantly, a gram-scale (8
mmol) was successfully performed to deliver products in high
yields (84%, 3a). It bears mentioning that in all these cases, enones
4 were not observed in the reaction mixture(3/4 > 20/1), further
highlight the efficiency and robustness of the transformation.
Next, we surveyed the possibility of expanding the reaction to
simple aliphatic alcohol substrates. Due to the more challenging
dehydrogenation of aliphatic alcohols compared to that of benzylic
alcohols, and more labile of the transiently formed aliphatic
aldehydes to undergo aldol reaction and Tishchenko reaction, the
application of simple aliphatic alcohols to this novel coupling
reaction was non-trivial. Fortunately, we identified IPr*OMe as a
suitable ligand to efficiently couple aliphatic alcohols and alkynes
for the synthesis of alkyl-alkyl ketones. As shown in Table 3,
aliphatic alcohols, including long linear alcohols (6a-6e), α- or β-
branched alcohols (6g and 6h), β-amino alcohols (6i), and ethanol
(6j), were all viable substrates for this protocol affording products
in moderate to high yields (45-89%). Functional groups such as
ethers (6k and 6l), silyl-ethers (6m), fluoride (6k), trifluoromethoxy
(6l) group, and aniline (6i), are well tolerated under the catalytic
conditions. Alcohols bearing pyridine or thiophene heterocycles
were compatible, giving products in moderate yields (6n and 6o).
In the case of α-branched alcohol, ester byproduct was observed,
which is formed by the Tishchenko reaction of a transient aldehyde;
and the desired ketone product was obtained in moderate yield
(6g). Notably, coupling reactions involving both labile aldehydes
(phenylacetaldehyde (6f), amino acetaldehyde (6i), and
acetaldehyde (6j)) and the corresponding ketone products with
acidic α-protons, which are more inclined to go aldol reaction,
were performed smoothly to give products in synthetically useful
yields.
mol%)
Ni(cod)2 (5
O
O
OH
R3
SIPr/HCl mol%)
(5
tBuONa
toluene
5
R3
mol%
+
Ar
+
Ar
R3
(
)
R2
Ar
R2
R2
M)
(1.0
1
2
100 o 12 h
3
4
C,
mmol)
eq.)
(1.5
>
cases
20/1 in all
(0.2
3 4
/
O
O
O
nPr
Me
nPr
Ph
nPr
nPr
nPr
3c
, 86%
nPr
90%
Me
3b
3a
8
, 89%
,
mmol scale)
(84%,
O
O
O
O
O
nPr
nPr
nPr
MeO
MeO
nPr
nPr
nPr
MeO
3d
94%
,
,
3e
,
3f
,
85%
O
88%
O
O
F3C
nPr
nPr
nPr
O
O
nPr
90%
nPr
93%
nPr
90%b
Ph
3g
3h
,
3i
,
O
O
O
F
Ph
Ph
nBu
nPr
Ph
Et
nBu
nPr
84%b
Et
3k
3l
84%
,
3j
, 88%
,
O
O
O
Ph
nHex
Et
12
nHex
nBu
Me
c
3m
3o
79%
,
, 82%,
(1.9:1)
3n
69%
,
O
O
O
Ph
Ph
Ph
3p
Me
Ph
Me
nPr
nPr
iPr
3q
, 84%,
c
c
c
, 77%,
3r
, 87%,
(3.5:1)
(12.5:1)
(6.7:1)
a Isolated yields on 0.2 mmol scale reactions. b Using IPr*OMe instead
of SIPr as the ligand. c Ratio of regioisomers.
Chin. J. Chem. 2019, 37, XXX－XXX
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Yu-Qing Li et al.
Breaking Report
a.
The observation of
intermediates
possible
O
O
Table 3. Nickel-catalyzed coupling of aliphatic alcohols and alkynes a
mol%)
Ph
Ph
nPr Ph
nPr
nPr
Ni(cod)2 (5
nPr
SIPr/HCl mol%)
nPr
(5
OH
+
tBuONa
toluene
5
,
15%
mol%
4a
3a
60%
,
(
)
nPr
Ph
M)
(1.0
C
mol%)
Ni(cod)2 (10
O
OH
mmol)
100 o
R
OH
eq.)
O
(0.2
(1.5
IPr*OMe/HCl
tBuONa
mol%)
nPr
(10
+
"Standard conditions"
5 mins
Alkyl
O
R
Ph
H
mol%)
Alkyl
R
nPr
6%
(10
R
toluene
M)
7a
4%
,
2
(1.0
5
eq.)
6
120 o 12 h
-
mmol)
7a
3a
to ketone
b. Transformation of
OH
alcohol E
C,
(0.2
(1.0
allylic
O
O
O
above conditions
0.5 hours
Ph
nPr
Ph
nPr
nHex
nHex
88%
nPr
Me
nPent
Me
nPr
mmol)
nPr
3a
, 99%
Me
nPr
-
nPent
7a
E
(0.2
6c
,
6b
84%
,
6a
,
86%
c.
enone
4a to
3a
ketone
Transformation of
O
E-
O
O
O
O
OH
+
above conditions
2 hours
Ph
nPr
Ph
nPr
nPr
Ph
nPr
Me
Ph
nPr
Ph
1a
nPr
mmol)
10
nPr
nPr
nPr
6f 57%
nPr
83%
E-4a
3a 74%
,
eq)
(0.2
(1.5
6e
,
,
89%
O
6d
,
d.
catalytic
cycles
Proposed
O
Me
O
Mechanism 1
Me
N
Ni
nPr
nPr
O
nPr
nPr
Ph
OH
Ph
Me
nPr
nPr
nPr
54%b,
nPr
81%
Ph
nPr
nPr
H
nPr
nPr
Ni0
d
c
59%b,
6i
,
6g
,
6h
,
A
O
OH
F
O
Ph
O
Ph
O
4
OCF3
O
Ph
OH
Ni
O
nPr
Ni0
nPr
Me
O
Ph
nPr
nPr
nPr
nPr
nPr
4
nPr
46%e
B
6j
,
6k
76%
,
6l 76%
,
O
OH
[Ni]
H
nPr
OH
Ni
Ph
nPr
Ph
O
O
4
nPr
O
O
nPr
Ph
nPr
S
nPr
nPr
nPr
nPr
Ph
H
TBSO
N
nPr
d
nPr
6m 70%
nPr
C
51%b,
d
65%b,
6o
,
6n
,
,
Mechanism 2
nPr
OH
O
+
a Isolated yield on 0.2 mmol scale reactions; the ratio of ketone: enone is
nPr
Ph
Ph
H
b
all > 20:1 unless otherwise indicated. Using 15 mol% of catalyst and
base. c Reaction runs at 40 ℃. d Reaction runs at 80 ℃. e Reaction runs
at 25 ℃, the ratio of ketone: enone is 12:1.
Ni
O
nPr
Ph
nPr
H
A
Ni0
C-C
cycle
cycle
Hydrogen-transfer
coupling
[Ni]-H
O
To get insight into the reaction mechanism, we performed
additional experiments. We first examined the coupling of benzyl
alcohol (1a) and 4-octyne (2a) under the standard conditions.
When the reaction was heated for just 5 minutes, we obtained the
ketone (3a) in a 60% NMR yield, alone with enone 4a, allylic alcohol
7a, and benzaldehyde in 15%, 6%, and 4% NMR yield, respectively
(Figure 2a). When heating the reaction mixture for 1 hour, the
enone 4a and allylic alcohol 7a were not detected. These results
suggest that enone and allylic alcohol may be the intermediates
H
O
Ni
Ph
nPr
nPr
O
D
nPr
Ph
nPr
Ph
nPr
nPr
to a ketone with alcohol as a reductant in this reaction (Figure 2c).
These results proved that enone and allylic alcohol both could be
the intermediate of ketone in this reaction.
It has been reported the nickel-catalyzed coupling of alcohols
and alkynes to furnish allylic alcohols by our group[6a,c], and the
nickel-catalyzed coupling of aldehydes and alkynes to form
enones.[7b,9] Based on these works and our observations in this
reaction, we proposed two possible mechanisms, as shown in
Figure 2d. In the mechanism 1, the alkyne and in-situ formed
aldehyde first go cyclometallation with Ni(0) catalyst to afford an
oxanickelacycle A. Then the protonation of A by alcohol delivers
acyclic nickel intermediate B, which subsequently goes β-H
elimination to provide nickel hydride intermediate C, meanwhile
regenerates an aldehyde. Then reductive elimination of C gives
Figure 2. Mechanism investigation
of the reaction. Then we performed transformations of enone and
allylic alcohol to ketone products under standard conditions. The
reaction of allylic alcohol (7a) can give ketone (3a) quantitively in
just 0.5 hours (Figure 2b), suggesting that the isomerization of
allylic alcohol to the ketone[18] is a facile reaction under the
standard conditions. When treated enone 4a with benzyl alcohol
(1a) under standard conditions for 2 hours, we obtained the ketone
product (3a) in 74% yield, which suggests that 4a can be reduced
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
allylic alcohol, which isomerizes to afford the ketone. Alternatively,
the oxanickelacycle A can undergo β-H elimination to give an
enone, which is shown in the mechanism 2, and then the conjugate
reduction by nickel hydride species affords the ketone product.
Although both mechanisms are possible, we think the mechanism
1 is the major pathway because the isomerization of allylic alcohol
7a to the ketone is faster than the conjugate reduction of enone.
In conclusion, we have developed a novel NHC/nickel-
catalyzed coupling of alcohols and alkynes for the expedient
synthesis of ketones. A variety of α-branched aryl alkyl ketones and
dialkyl ketones, which are difficult to access through a metal-
catalyzed hydroacylation of simple internal alkenes with aldehydes,
were readily prepared in one chemical step. This hydrogenative
transfer protocol is free from any oxidative or reductive additives,
rendering this reaction atom-, step- and redox-economical. Further
expanding the scope of this type of reaction is underway in our
laboratory.
formation via carbon-hydrogen activation. Intermolecular
hydroacylation: the addition of aldehydes to alkenes. Organometallics.
1988, 7, 1451-1453; (f) Schwartz, J.; Cannon, J. B. Hydroacylation.
Synthesis of ketones from olefins using metal hydride reagents. J. Am.
Chem. Soc. 1974, 96, 4721-4723.
(a) Suggs, J. W.; Activation of aldehyde carbon-hydrogen bonds to
oxidative addition via formation of 3-methyl-2-aminopyridyl
aldimines and related compounds: rhodium based catalytic
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Dialkylacrylamides with Aldehydes Catalyzed by
a Cationic
Rhodium(I)/dppb Complex. Org. Lett. 2007, 9, 1215-1218; (f) Murphy,
S. K.; Bruch, A.; Dong, V. M. Substrate-Directed Hydroacylation:
Rhodium-Catalyzed Coupling of Vinylphenols and Nonchelating
Aldehydes. Angew. Chem. Int. Ed. 2014, 53, 2455-2459; (g) Coulter, M.
M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. Regio- and Enantioselective
Intermolecular Hydroacylation: Substrate-Directed Addition of
Salicylaldehydes to Homoallylic Sulfides. J. Am. Chem. Soc. 2010, 132,
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Acknowledgment
This work is supported by the NSFC (91856111, 21690074,
21871288, 21821002), the CAS (XDB 20000000), and the “1000-
Youth Talents Plan”.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Oriented Synthesis, Step Economy, and Drug Design. Acc. Chem. Res.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Yu-Qing Li et al.
Breaking Report
Entry for the Table of Contents
Page No.
O
R2
Expedient Synthesis of Ketones via NHC/Nickel-
Catalyzed Redox-Economical Coupling of
Alcohols and Alkynes
OH
NHC/Ni(0)
(cat.)
and
+
R1
R2
R3
R1
atom-,
step-,
R3
redox-economical
α
internal
alcohols
simple
alkynes
alkyl
-branched ketones
=
R2
R1
alkyl
=
aryl,
aryl,
R3 alkyl
=
An NHC/Ni-catalyzed direct coupling of alcohols and internal alkynes for a convenient synthesis of
α-branched ketones is reported. This novel hydrogenative transfer protocol provides an atom-, and
redox-economical approach to α-branched ketones, products that are difficult to access through the
hydroacylation of unactivated internal alkenes with aldehydes, in one chemical step.
Yu-Qing Li, # Feng Li, # and Shi-Liang Shi *
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.