Cu-catalyzed sequential dehydrogenation-conjugate addition for β-functionalization of saturated ketones: Scope and mechanism

Article abstract of DOI:10.1021/jacs.6b01337

The first copper-catalyzed direct β-functionalization of saturated ketones is reported. This protocol enables diverse ketones to couple with a wide range of nitrogen, oxygen and carbon nucleophiles in generally good yields under operationally simple conditions. The detailed mechanistic studies including kinetic studies, KIE measurements, identification of reaction intermediates, EPR and UV-visible experiments were conducted, which reveal that this reaction proceeds via a novel radical-based dehydrogenation to enone and subsequent conjugate addition sequence.

Full text of DOI:10.1021/jacs.6b01337

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Article
Cu-Catalyzed Sequential Dehydrogenation-Conjugate Addition for
#-Functionalization of Saturated Ketones: Scope and Mechanism
Xiaoming Jie, Yaping Shang, Xiaofeng Zhang, and Weiping Su
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01337 • Publication Date (Web): 11 Apr 2016
Downloaded from http://pubs.acs.org on April 11, 2016
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Page 1 of 11
Journal of the American Chemical Society
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Cu-Catalyzed Sequential Dehydrogenation-Conjugate Addition for
β-Functionalization of Saturated Ketones: Scope and Mechanism
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Xiaoming Jie, Yaping Shang, Xiaofeng Zhang and Weiping Su*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002 (PR China)
ABSTRACT: The first copper-catalyzed direct β-functionalization of saturated ketones is reported. This protocol enables
diverse ketones to couple with a wide range of nitrogen, oxygen and carbon nucleophiles in generally good yields under
operationally simple conditions. The detailed mechanistic studies including kinetic studies, KIE measurements, identifi-
cation of reaction intermediates, EPR and UV-Visible experiments were conducted, which reveal that this reaction pro-
ceeds via a novel radical-based dehydrogenation to enone and subsequent conjugate addition sequence.
INTRODUCTION
Scheme 1. Overview of Ketone Dehydrogenation and
Saturated Ketone β-Functionalization
α,β-Unsaturated ketones are ubiquitous in bioactive
compounds and generally regarded as versatile synthetic
intermediates in the syntheses of fine chemicals, phar-
maceuticals and materials.1 Traditionally, approaches to
access enone architecture involve α,β-dehydrogenation of
the parent saturated ketones, which require multistep
preparation routes2 or use of stoichiometric reagents such
as 2-iodoxybenzoic acid (IBX)3 and 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ),4 and often suffer from
limited functional group compatibility and poor regiose-
lectivity. Recently, transition-metal-catalyzed C-H func-
tionalization reactions have shown their powerful ability
to convert carbonyl compounds to the corresponding
unsaturated derivatives. For example, Pd(II)-catalyzed
aerobic dehydrogenation methods5 provide a facile access
to α,β-unsaturated ketones (Scheme 1). Efforts have fur-
ther been made to develop Pd-based catalyst for the de-
hydrogenation of more challenging aliphatic esters, ni-
triles and amides.6 Besides the widely used palladium cat-
alyst, the iridium and ruthenium catalysts have shown
their powerful ability to promote alkane dehydrogena-
tion.7 However, reports of applying these catalysts to ke-
tone dehydrogenation are rare.8 These Pd, Ir and Ru cata-
lysts generally capitalize on their inherent catalytic at-
tributes to form metal-enolate intermediate and subse-
quent β-hydride elimination to generate desired enones.
Although this type of catalytic manners have appeared
frequently in the literature, examples of first-row metal
catalysts capable of effecting ketone desaturation via radi-
cal type mechanism are much less common and their re-
action mechanisms have been less studied in depth.
employing such metals are expected to exhibit higher cost
economy as well as more diverse substrate scope. Actually,
of the few approaches reported, the majority requires
stoichiometric first-row metals that serve as oxidants and
the conversions are only applicable to specific substrates.9
Consequently, the invention of first-row-metal-catalyzed
protocol to achieve regio- and chemoselective desatura-
tion of unactivated ketones in a broadly applicable man-
ner would be highly desirable.
As our ongoing interest in the development of C-H
functionalization reactions10 to promote efficient ketone
couplings, we have recently reported several methods for
Pd-catalyzed dehydrogenative olefination of (het-
ero)arenes via olefin intermediates generated in situ from
saturated ketones and nitroalkanes.11 In the Pd-catalyzed
As a matter of fact, first-row metals such as Cu, Ni and
Mn are not only earth-abundant and inexpensive, but also
insensitive to catalyst poisoning caused by strong coordi-
nating heteroatom functionalities. Catalytic systems
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RESULTS AND DISCUSSION
decarboxylative olefination of carboxylic acid with satu-
rated ketones,11b Cu(OAc)2 was much more efficient than
other oxidants such as Ag salts, implying that Cu(OAc)2
might play dual roles. Here, we report a 2,2’-bipyridine
(bpy)-supported Cu catalyst system that enables direct,
selective and controlled desaturation of ketones to enones
and subsequent conjugate addition with sulfonamides,
amides, amines and anilines to generate Mannich-type
products, as well as alcohols, phenols and 1,3-dicarbonyl
compounds to form β-oxygenated or β-alkylated ketones
(Scheme 1). To the best of our knowledge, our findings
represent the first example of intermolecular reaction for
directly installing heteroatom functionalities to the β-C-H
(sp3) bonds of unactivated ketones.
1
2
3
4
5
6
7
8
Considering β-Amino ketones are well accepted as key
synthetic intermediates of pharmaceutical interest,23 we
decided to initiate our studies with exploring reaction
conditions suitable for the direct β-amination of saturated
ketones.24 Conventional methods for accessing β-Amino
ketones include aza-Michael addition and Mannich reac-
tion.25 For conjugate addition reactions, preparation and
isolation steps of activated enones were required. Particu-
larly, if the enones were vinyl ketones, they would be un-
stable and prone to polymerization. On the other hand,
electron-deficient amides were deactivated substrates in
Mannich reaction and the employment of unsymmetrical
ketones usually gave rise to regioisometric mixtures. In
this context, propiophenone (1a) was chosen as model
substrate to surrogate its corresponding unstable vinyl
ketone. Additionally, N-methyl-p-toluene sulfonamide
(2a) was selected as the amide source for the reason that
benzenesulfonamide scaffolds are prevalent in medicinal
molecules. Copper salts were chosen as our catalyst can-
didates because copper complexes were widely used in
conjugate addition of enones.26 Also, copper catalysts
have shown their ability to effect alkane dehydrogenation
to alkene27 and oxidative condensation of cyclic enones
with alcohol to aryl ethers.28 However, these precedents
often require non-selective peroxides as stoichiometric
oxidants and are not applicable to dehydrogenation of
linear ketone. These limitations prompted us to investi-
gate a mild and broadly applicable copper-catalyzed pro-
tocol that could not only facilitate ketone dehydrogena-
tions to enone but also benefit subsequent conjugate ad-
dition of enone intermediate.
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The strategy to combine initial substrate dehydrogena-
tion to olefin intermediate with secondary olefin trans-
formations represents a new avenue to the direct C-H
functionalization reactions, and has a tremendous poten-
tial to rapidly construct diverse complex molecular
frameworks from simple starting materials owing to ver-
satile reactivity of olefins.12-17 Since 1,4-conjugate addition
of nucleophiles to α,β-unsaturated ketones is the most
commonly used approach to β-functionalized ketones,18
we envisioned that a novel ketone dehydrogenation pro-
cess in combination with subsequent conjugate addition
would provide an appealing, atom-economical alternative
to traditional methods by elimination of the need for
troublesome pre-preparation and isolation of α,β-
unsaturated ketones. The potential of this strategy in the
synthesis of β-functionalized carbonyls has been illustrat-
ed by the recent pioneering studies, such as the transition
metal-catalyzed ketone β-amination,12a ketone β-
arylation,12c-e, 13 β-arylation of β-keto esters,14 α-substituted
esters15 and aldehydes19, and multi-dehydrogenation of
ketone to benzenes.12g The directing group-assisted C-H
activation methods has also been established to function-
alize β-C-H (sp3) bonds of carboxylic acid derivatives (e.g.
amides and esters).20 Meanwhile, the organocatalysts (e.g.
N-heterocyclic carbenes and amines) have been success-
fully used to effect β-functionalization of saturated esters
and aldehydes.21 The photoredox catalysis, in combination
with organocatalysis, also proves to be a promising ap-
proach to the β-C-H (sp3) functionalization of aldehydes
and cyclic ketones.22 These prominent advances provided
useful starting points for our investigation of other inno-
vative β-functionalization protocols.
To examine the feasibility of our proposed protocol, a
variety of copper precursors, ligands, solvents and addi-
tives were evaluated (Table 1). After extensive screening,
we found that the use of copper acetate as the catalyst,
bpy (2,2’-bipyridine) as the ligand and TEMPO (2,2,6,6-
tetramethylpiperidine-N-oxyl) as the oxidant in 1,2-
dichlorobenzene was optimal to form the desired carbon-
nitrogen bond at the β-position of 1a. The afforded β-
amidation product 3a could be isolated in 95% yield
without significant overoxidation (< 5 %) (entry 1). Nota-
bly, although 3.0 equiv of ketone was used, nearly half of
the starting 1a remained intact after the reaction was fin-
ished (see Table S1 in the Supporting Information). Re-
ducing the amount of 1a to 1.5 equiv led to a decrease in
reaction efficiency but still afforded a synthetically useful
yield (72%) (entry 2). Control experiments revealed that
no product was obtained in the absence of either
Cu(OAc)2 or TEMPO, implying the indispensable roles of
these two reaction components (entries 3 and 4). The
reaction conducted without bpy ligand could still gener-
ate 3a in 62% yield (entry 5). Of the ligands tested, 1,10-
phenanthroline showed similar yield to bpy, and mono-
dentate pyridine could also enhance the efficiency of Cu
catalyst when its loading was increased to 0.5 equiv (en-
tries 6-8). Attempts to utilize catalytic amount of TEMPO
lead to inferior results (entry 9). Other TEMPO deriva-
tives with diverse electronic characters also exhibited low
To achieve the desired general β-functionalization of
saturated ketones via tandem ketone dehydrogenation-
conjugate addition sequence, the catalyst system must
meet the following requirements: (1) the catalyst system is
capable of facilitating both ketone desaturation and con-
jugate addition; (2) the catalyst system selectively dehy-
drogenates ketone starting material over β-functionalized
ketone products to avoid overoxidation of products; (3)
the oxidative dehydrogenation conditions are compatible
with conjugate addition donor ( a nucleophilic coupling
partner).
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Table 1. Selected Reaction Development
Scheme 2. Substrate Scope of Nitrogen and Oxygen
Nucleophilesa
1
2
3
4
5
6
7
8
9
H
Cu(OAc)2 (10 mol%)
bpy (10 mol%)
TEMPO (1.0 equiv)
O
O
O
N
R1 R2
or
R1
R3
O
N
or
+
1,2-dichlorobenzene (0.1 M)
120 oC, N2, 24 h
R2
R3OH
1a
2
3
Isolated
yield (%)
variations from standard condi-
tions
entry
O
O
O
O
S
O
O
S
O
S
O
O
3a
95
72
0
0
62
94
3a'
< 5
<5
0
0
< 5
< 5
N
N
N
Me
1
none
1a (1.5 equiv)
w/o Cu(OAc)2
w/o TEMPO
Me
Me
Me
Ph
Me
Me
Me
3a, 95%
3b, 68%
3c, 74%
2
3
4
5
6
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
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40
41
42
43
44
45
46
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58
59
60
O
O
O
O
O
O
O
N
O
O
O
S
S
S
N
N
Me
Ph
Ph
w/o bpy
3d, 88%
3e, 83%
3f, 90%
1,10-phenanthroline instead of
bpy
0.2 equiv of pyridine instead of
bpy
0.5 equiv of pyridine instead of
bpy
0.2 equiv of TEMPO
2.0 equiv of TEMPO
0.2 equiv of TEMPO, O2 (1 atm)
atmosphere
air atmosphere
1.0 equiv of NHPI instead of
TEMPO
2.0 equiv of tBuOOH (5.0-6.0 M
in decane) instead of TEMPO
2.0 equiv of tBuOOtBu instead of
TEMPO
CuSO4 instead of Cu(OAc)2
Cu(OTf)2 instead of Cu(OAc)2
CuCl2 instead of Cu(OAc)2
O
O
O
O
O
N
N
N
O
7
76
87
< 5
< 5
O
3g, 73%
3h, 68%
3i, 63%
O
Cl
NO2
O
O
8
Boc
Bn
N
O
N
N
Me
Me
N
3j, 57%
3k, 60%
3l, 62%
9
10
11
54
79
0
0
16
0
CO2Me
O
O
O
N
N
N
Me
Me
CO2Me
Ph
3n, 75%
3m, 81%
3o, 60%
12
13
50
0
< 5
0
O
O
O
N
N
N
O
Me
N
O
Me
3r, 75%
14
15
0
0
0
0
3q, 56%
3p, 73%
O
O
F
O
O
Bn
S
N
N
N
H
H
Bn
Me
3s, 62%
3t, 67%
3u, 71%
16
17
18
19
0
15
0
0
0
0
0
Br
Cl
O
O
O
N
N
H
N
N
H
H
PhCl
dichlorobenzene
DME instead
dichlorobenzene
DMF instead
dichlorobenzene
instead
of
of
of
1,2-
1,2-
1,2-
1,2-
90
3v, 76%
3w, 70%
3x, 61%
O
O
N
O
Me
Me
O
Me
N
N
20
21
49
45
0
0
O
H
3z, 37%b
3aa, 36%b
3y, 60%
O
O
O
Me
O
O
O
22
23
24
DMSO
instead
of
< 5
49
73
0
3ac, 32%b
3ab, 41%b
dichlorobenzene
1,4-dioxane instead of 1,2-
dichlorobenzene
3ad, 44%c
0
a
toluene
instead
of
1,2-
< 5
Reaction conditions: 1a (0.6 mmol), 2 (0.2 mmol),
Cu(OAc)2 (0.02 mmol), bpy (0.02 mmol), TEMPO (0.2
mmol), 1,2-dichlorobenzene (2 mL), 120 C, N2 atmosphere,
24 h. All isolated yields.
dichlorobenzene
o
b
1a (0.5 mmol), 2 (5 mmol),
efficiency (see Table S1 in the Supporting Information).
Increasing the amount of TEMPO led to a decrease in
yield due to overoxidation of the desired product (entry
10). Although Cu/TEMPO catalyzed aerobic oxidations
are well established by Stahl et al,29 the oxygen atmos-
phere completely shut down this transformation (entry 11).
Moreover, the yield dropped dramatically when the mod-
el reaction was carried out under air atmosphere (entry
12). Thus, these experimental data suggest that our reac-
tion proceeds through a mechanism different from the
systems of Stahl et al. The choice of additives also proved
to be pivotal for the formation of 3a since other previous-
ly reported oxidants in copper-catalyzed dehydrogenation
reactions such as NHPI (N-hydroxyphthalimide) and
Cu(OAc)2 (0.1 mmol), bpy (0.1 mmol), Li2CO3 (0.5 mmol)
o
TEMPO (0.5 mmol), 1,2-dichlorobenzene (2 mL), 120 C, N2
atmosphere, 24 h. c 1a (0.2 mmol), 2 (1.0 mmol) were used.
peroxides did not work for this reaction (entries 13-15).
Changing the acetate counterion of the copper catalyst
resulted in decreased yields (entries 16-18). Finally, we
surveyed the effects of solvent and observed that chloro-
benzene was slightly less efficient than 1,2-
dichlorobenzene and other screened solvents led to slug-
gish conversion to 3a (entries 19-24).
With this catalytic system in hand, we initially investi-
gated the substrate scope with respect to a wide range of
nitrogen-containing nucleophiles (Scheme 2). As illus-
trated, secondary sulfonamides with various substituted
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groups at the nitrogen atom participated in this transfor-
Scheme 3. Substrate Scope of Ketonesa
1
mation (3a-3f). Particularly, a terminal alkene substituent
of sulfonamides could be tolerated to give 3e in 83% yield,
highlighting the excellent functional group compatibility
of the reaction conditions. In addition to sulfonamides,
amides and Boc-protected alkoxylamine also proved to be
suitable substrates (3g-3j). Secondary anilines bearing
chloro, nitro or ester functionalities smoothly underwent
the reaction to produce the desired β-amination products
(3k-3m). Heterocyclic nitrogen nucleophiles like N-
methyl 2-aminopyridine and a 3-substituted indole were
also effective coupling partners (entries 3n and 3o), indic-
ative of the robustness of the Cu catalytic system against
the poisoning caused by Lewis basic heterocycles. Alt-
hough the nitrogen-vicinal and benzylic positions of ali-
phatic amines are prone to be oxidized, the established
oxidative conditions enabled both cyclic and acyclic ali-
phatic amines to participate in the reaction in good yields
with no side-product from oxidation of these amines ob-
served (3p-3s). To our delight, primary sulfonamides, ani-
lines and heteroanilines all served well under the current
conditions to give high yields of N,N-disubstituted prod-
ucts (3t-3y). Primary alkyl amine such as butylamine
didn’t give the target product due to the decomposition of
substrate under current conditions. Both primary and
secondary alcohols could serve as nucleophiles to give β-
alkoxylation products (3z-3ac) in moderate yields. The
low yields in the reaction of alcohols probably stemmed
from their weak nucleophilicity and competitive alcohol
oxidation. Finally, phenol served as a substrate to furnish
the desired product in 44% yield (3ad).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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45
46
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48
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50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions: 1 (0.6 mmol), 2 (0.2 mmol),
Cu(OAc)2 (0.02 mmol), bpy (0.02 mmol), TEMPO (0.2
o
mmol), 1,2-dichlorobenzene (2 mL), 120 C, N2 atmosphere,
24 h. All isolated yields. b Conducted at 100 oC. c No bpy add-
d
e
ed. Cu(OAc)2 (30 mol%) and bpy (30 mol%) were used.
1
f
(0.2 mmol) and 2 (0.6 mmol) were used. Cu(OAc)2 (10
Subsequently, we evaluated the substrate scope with re-
spect to various ketones (Scheme 3). A variety of electron-
ically diverse functionalities on the phenyl ring of propio-
phenones were well tolerated to give desired β-amination
products in excellent yields (4a-4g). Additionally, het-
eroaromatic ketones such as 3-propionylpyridine, 2-
propionylfuran and 2-propionylthiophene smoothly un-
derwent the reaction without side-reactions at their reac-
tive C-2 or C-3 positions of heteroaromatic rings, demon-
strating high chemo- and regioselectivity of this trans-
formation (4h-4j). Moreover, the generality of this proto-
col can be further demonstrated by its compatibility with
aliphatic ketones and its ability to effect β-amination of
challenging β-substituted ketones (4k-4p). As demon-
strated, aliphatic ketones served as suitable substrates in
this transformation (4k-4n) in the presence of higher
loadings of Cu(OAc)2 and bpy, which circumvented the
formidable synthesis of aliphatic vinyl ketones used in
traditional conjugate addition reactions and exhibited
high selectivity comparing with Mannich reaction. For β-
substituted ketones (4o and 4p), the relatively low con-
version was attributed to retardation of the conjugate
addition step due to steric hindrance, rather than a less
effective dehydrogenation (see p. S60 in the Supporting
Information). To further test the practicability and scala-
bility of this reaction, a large scale reaction was conduct-
ed to synthesize commercial drug dyclonine (an oral an-
aesthetic medicine), which furnished 0.94g of product in
mol%), bpy (20 mol%) and Na2CO3 (0.5 equiv) were used. g
mmol scale.
5
65% yield (4q). Unfortunately, cyclic ketones such as cy-
clohexanone gave rise to none of the desired β-amination
products (4r). Finally, attempts to apply this strategy to
esters and amides were unsuccessful, probably due to
their higher pKa value of the α-C-H bonds (4s and 4t).
To show the generality of this transformation, we next
explored the possibility of extending this Cu(II)-catalyzed
dehydrogenation-conjugate addition approach to the syn-
thesis of β-alkylated ketones using 1,3-dicarbonyl com-
pounds as carbon nucleophiles (Scheme 4). Initial at-
tempts with our standard conditions only provided low
conversions. Considering that 1,3-dicarbonyl compounds
had the tendency to chelate copper salt and therefore
deactivate the Cu catalyst, we raised the Cu(II)/bpy load-
ings to prevent catalyst from poisoning. Gratifyingly,
when 20 mol% Cu(OAc)2/bpy was used, the reactions
displayed a broad substrate scope for both ketones and
1,3-dicarbonyl compounds, similarly to that observed with
nitrogen nucleophiles. As revealed in Scheme 4, aryl-
containing β-diketones and β-ketoesters served well to
afford the corresponding products in good to excellent
yields (6a-6e). Dimethyl malonate, a relatively weak nu-
cleophile, also delivered the product 6f in moderate yield.
Once again, heteroaryl ketones, halogen-containing
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Scheme 4. Substrate Scope of Ketones and 1,3-
Dicarbonyl Compoundsa
1
2
3
4
Cu(OAc)2 (20 mol%)
bpy (20 mol%)
TEMPO (1.0 equiv)
O
R2 R3
O
O
O
R1
O
+
R1
R2
R3
R4
R4
O
1,2-dichlorobenzene (0.1 M)
120 oC, N2, 24 h
5
1
5
6
6
O
O
O
O
O
O
7
8
9
Ph
Ar1
Ar2
Ph
Ar1 = p-OMeC6H4
Ar2 = p-tBuC6H4
O
Ph
O
O
tBu
6c, 92%
6a, 91%
6b, 97%
O
O
O
O
O
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
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
in 35% yield after 10 h with 65% of 1a recovered (eq 1).
Then, we observed that the conjugate addition reaction of
pre-prepared phenyl vinyl ketone 1a’ with sulfonamide 2a
gave 3a in 92% yield under the standard conditions (eq 2).
Further control experiment revealed that copper salt as a
Lewis acid catalyst was indispensable to the conjugate
addition step. The observed ketone dehydrogenation to
generate 1a’ and the conjugate addition of Michael donor
to 1a’ support our original hypothesis that ketone β-
functionalization may proceed via a tandem dehydro-
genation-conjugate addition sequence.
CO2Et
CO2Et
Ph
CO2Me
tBu
CO2Me
O
O
O
O
tBu
6g, 96%
6f, 51%
6d, 70%
6e, 60%
O
O
O
O
O
O
O
O
S
O
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
F
O
O
O
Me
O
6h, 93%
6i, 90%
6j, 94%
6k, 99%
O
O
O
O
O
O
O
O
tBu
tBu
tBu
tBu
tBu
tBu
O
tBu
MeO
O
Cl
O
tBu
Br
O
6m, 94%
NO2
O
6l, 99%
6o, 71%
6n, 73%
O
O
O
O
O
CO2Et
CO2Et
O
Ph
Me
Ph
Since the Lewis acid-promoted conjugate addition is a
well-known process, we focused our attention on the de-
tailed mechanism of ketone dehydrogenation process.
This mechanistic investigation would be of interest be-
cause the copper-catalyzed ketone dehydrogenation to
enones remained an unknown transformation. We chose
3-phenylpropiophenone (7) as a mechanistic probe for
ketone dehydrogenation process because chalcone (8),
the expected dehydrogenation product, was of low reac-
tivity towards Michael addition (see p.S60 in the Support-
ing Information), nonvolatile and easy to handle. The
reaction of 3-phenylpropiophenone (7) under the stand-
ard conditions produced chalcone (8) in 90% isolated
yield. Further analysis of this reaction residue showed
that 2,2,6,6-tetramethylpiperidine were generated in 50%
yield (eq 3). Additionally, neither chlorobenzene nor ben-
zene was detected. These observations revealed that
TEMPO was the sole oxidant during the reaction.30 And
because the ultimate reduced form of TEMPO, 2,2,6,6-
tetramethylpiperidine, was detected, it could explain the
observation that 1.0 equiv of TEMPO was enough to effect
the dehydrogenation. Control experiments revealed that
both Cu(OAc)2 and TEMPO are indispensable for the
dehydrogenation. Therefore, these results, in combina-
tion with the above observations, disclosed that Cu(OAc)2
simultaneously catalyzed both dehydrogenation and con-
jugate addition, and TEMPO as oxidant functioned only
in the dehydrogenation process.
O
O
Ph
O
O
Ph
6q, 48%b
6p, 51%b
6r, 43%c
6s, 41%c,d
Ph
CO2Me
O
O
Ph
O
CO2Me
CO2Me
O
Me
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
6u, 52%e
CO2Me
6w, 54%e
6t, 50%e
6v, 70%c
a
Reaction conditions: 1 (0.6 mmol), 2 (0.2 mmol),
Cu(OAc)2 (0.04 mmol), bpy (0.04 mmol), TEMPO (0.2
o
mmol), 1,2-dichlorobenzene (2 mL), 120 C, N2 atmosphere,
24 h. b Cu(OAc)2 (30 mol%) and bpy (30 mol%) were used. c
1
(0.6 mmol), 2 (0.2 mmol), Cu(OAc)2 (0.2 mmol), TEMPO
(0.4 mmol) and Li2CO3 (0.2 mmol) were used. Cs2CO3 (0.2
mmol) was used instead of Li2CO3. 1 (0.2 mmol), 5 (0.6
mmol), Cu(OAc)2 (0.2 mmol), TEMPO (0.5 mmol) and
Cs2CO3 (0.2 mmol) were used.
d
e
ketones and aliphatic ketones all participated in the reac-
tion, exhibiting high functional-group tolerance (6g-6q).
Sterically encumbered substrates such as tertiary 1,3-
dicarbonyl compounds and β-substituted ketones were
difficult to undergo efficient couplings in the presence of
catalytic amount of Cu(OAc)2, however, stoichiometric
Cu(OAc)2 enabled efficient conversions of these challeng-
ing substrates (6r-6w). It should be mentioned that the
syntheses of 6r and 6s offered a facile avenue to construc-
tion of quaternary carbon centers at the γ-position of sat-
urated ketones. Moreover, β-substituted ketones includ-
ing γ-keto ester and 1,4-diketone were also alkylated at
the positions β to keto-group using dimethyl malonate as
a coupling partner (6v and 6w).
In view of the fact that our reaction did not occur under
aerobic conditions, we began to wonder if a radical pro-
cess was involved in this transformation. As a matter of
fact, precedent IBX-mediated dehydrogenation of ketones
was reported to form an intermediate with a carbon radi-
cal at the α-position of carbonyl groups.3d To probe this
possibility, we synthesized 9, a radical-clock probe and
observed that 9 was converted, in 73% yield, to conjugat-
ed diene 10 under the standard conditions (Scheme 5A).31
Additionally, to further assess the potential intermediacy
EXPERIMENTAL MECHANISTIC STUDIES
To gain in-depth insights into the reaction mechanism,
we carried out a series of experimental investigations. At
first, we checked the behavior of propiophenone 1a under
our standard conditions without adding any nucleophiles,
and observed that phenyl vinyl ketone could be generated
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of α-radical carbonyl, 3-phenylpropiophenone (7) was
Page 6 of 11
1
2
3
4
5
6
7
8
exposed to the standard conditions in the presence of
CBr4, which formed α-bromosubstituted product 11 in 71%
yield (Scheme 5B). Collectively, the observed ring-
opening product 10 and α-bromosubstituted product 11
provided strong evidences to support that this copper-
catalyzed ketone dehydrogenation to enone involved α-
radical intermediate formation. Notably, these results also
help make a distinction between our catalytic conditions
and Stahl’s system since it has been proved that no radical
intermediates is involved in Stahl’s Cu/nitroxyl-catalyzed
aerobic alcohol oxidation.32
9
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
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Experiments to Probe the Proposed Radi-
cal Intermediate
A)
O
O
standard conditions
12 h
10
, 73%
9
O
O
Ring
Opening
B)
O
O
standard conditions
+
CBr4
Br
11, 71%
(2.0 equiv)
7
Kinetic Studies. To provide further information about
the reaction mechanism, kinetic experiments were per-
formed to establish the rate laws of the dehydrogenation
process by monitoring the concentration of chalcone (8)
generated from 3-phenylpropiophenone (7) dehydrogena-
tion (Figure 1). All the kinetic data were taken at the time
points in the early stage of reaction (the early period of 6-
24 mins). The measurement of initial rate of dehydro-
genation of 3-phenylpropiophenone (7) as a function of
concentration of 7 displayed a first-order kinetic depend-
ence with respect to 7 (Figure 1A). Furthermore, the initial
reaction rate exhibited a first-order kinetic dependence
with respect to Cu(II)/bpy (Figure 1B, the ratio of Cu(II)
to bpy is 1 : 1). The effect of TEMPO concentration on the
reaction rate showed a zero-order dependence with
TEMPO (Figure 1C).
Figure 1. Dependence of Cu(OAc)2/bpy-catalyzed ketone
dehydrogenation on initial (A) 3-phenylpropiophenone
concentration, (B) Cu/bpy concentration and (C) TEMPO
concentration. Standard reaction conditions: 0.1 M 3-
phenylpropiophenone, 10 mM Cu(OAc)2, 10 mM bpy, 0.1
M TEMPO, 2.0 mL 1,2-dichlorobenzene, N2, 120 oC.
Kinetic Isotope Effects. After the kinetic data of each
reaction components in the dehydrogenation process
were obtained, we turned our attention to the identifica-
tion of turnover-limiting step in this conversion. For this
purpose, both α- and β-deuterated 7 were synthesized.
Then, 7, α- and β-deuterated 7 were subjected to identical
standard conditions in separate reaction vessels, and the
initial reaction rates of their dehydrogenation to chalcone
(8) were measured from parallel experiments, as shown in
Figure 2. Comparison of the initial reaction rates between
7 and α-deuterated 7 revealed a significant primary kinet-
ic isotope effect of 5.32, while the dehydrogenation of β-
deuterated 7 exhibited no significant kinetic isotope effect
(kH/kD = 1.02). These observations mean that C-H bond
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Journal of the American Chemical Society
ble of capturing the active radical species, we reasoned
KIE from parallel experiments
1
that the formed ketone α-radical intermediate could be
intercepted by TEMPO to deliver α-TEMPO-substituted
ketone.34 To verify this, the α-TEMPO-substituted ketone
12 was prepared and its reactivity was investigated. As a
result, we observed that 12 underwent rapid TEMPOH
(hydroxylamine) elimination to generate 8 in 95% yield
under standard conditions within 1 h (eq 4). Accordingly,
we speculated that 12 was likely formed as an intermedi-
ate prior to final enone formation. However, the fast
TEMPOH-elimination makes it difficult to directly ob-
serve this possible transient intermediate. Moreover, the
similar polarity of 7 and 12 impedes the separation of the-
se compounds via conventional column chromatography.
Being aware of the fact that the ketone dehydrogenation
is first-order in Cu(II)/bpy, we envisioned that increasing
the amount of Cu(II)/bpy could lead to a more rapid for-
mation of 12 for convenient monitoring. Actually, with an
increased Cu(II)/bpy loadings, we indeed observed the
2
3
4
5
6
7
8
9
O
O
H
H
D
D
D
α
-d1-8
α
-d2-7
kH/kD = 5.32
O
O
H
H
H
D
H
8
7
k
H/kD = 1.02
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
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
D
D
H
H
β
-d1-8
-d -7
β
2
1
formation of 12 by H NMR analysis (eq 5 and Figure 3).
This observation thus provides solid evidence to support
that α-TEMPO-substituted ketone 12 is the reaction in-
termediate in ketone dehydrogenation to enone. It is
worth to mention that the direct formations of α-
TEMPO-substituted ketones under catalytic conditions
were rare and the TEMPOH-elimination to generate al-
kene was sporadically observed as side reactions with low
efficiencies in precedent literatures.35 Consequently, our
copper-catalyzed dehydrogenation process represents a
unique and unprecedented transformation that is differ-
ent from the previously reported metal-catalyzed β-
hydride elimination to enone pathway.
Figure 2. Kinetic profiles for the dehydrogenation of 7
(red), α-d2-7 (blue), β-d2-7 (green) by
(bpy)Cu(OAc)2/TEMPO. Yields were obtained by GC
analysis. Standard reaction conditions: 10 mM Cu(OAc)2,
10 mM bpy, 0.1 M TEMPO, 2.0 mL 1,2-dichlorobenzene, N2,
120 oC.
O
O
standard conditions
O
(4)
N
1 h
8
95%
12
cleavage at the α-position of carbonyl group is involved in
the turnover-limiting step of the dehydrogenation pro-
cess. This conclusion is consistent with the zero-order
dependence of initial rate on TEMPO that was observed
in the aforementioned kinetic investigations.
Cu(OAc)2 (1.0 equiv)
bpy (1.0 equiv)
O
TEMPO (1.0 equiv)
7
12
8
+
+
(5)
1,2-dichlorobenzene (0.1 M)
120 oC, N2, 1 h
separated as
mixtures
44%
7
Detection of Reaction Intermediate. Although the
α-radical intermediate and the rate-determining step of
this copper-catalyzed dehydrogenation have been identi-
fied, more efforts are still needed to clarify the more de-
tailed dehydrogenation pathway after the α-radical in-
termediate is formed. In literature reports, the IBX-
mediated ketone dehydrogenation, the alkane dehydro-
genation promoted by copper-peroxide systems and other
radical initiated dehydrogenation processes33 were pro-
posed to proceed via hydrogen atom abstraction to form
alkyl radical, then oxidation of the alkyl radical to alkyl
cation, and final deprotonation of alkyl cation to form
alkene. Such a dehydrogenation pathway, however, is
unlikely operative in our current dehydrogenation pro-
cess because the ketone radical cation located at α-
position is hard to generate due to its high instability.
Since TEMPO is well known as a radical scavenger capa-
EPR and UV-Visible Experiments. EPR and UV-visible
spectroscopic studies were conducted to gain more in-
formation about the nature of the copper catalyst (Figure
4 and 5). To mimic the catalysis process, we used 10 mol%
of Cu(OAc)2, 10 mol% bpy and 50 mol% TEMPO in the
EPR studies of the dehydrogenation of 7. As shown in
Figure 4, a decrease of both Cu(II) and TEMPO signals
could be observed as the reaction proceeded. This trend
was also observed via UV- visible experiments, in which
Cu(II) signal dropped along with Cu(I) signal rose.
Proposed Mechanism. Based on the above-mentioned
mechanistic studies, a plausible mechanism was proposed
(Scheme 6). At first, Cu(OAc)2 as Lewis acid reacts with
ketone to form metal-enolate complex 13. Then, homoly-
sis of the Cu(II)-enolate bond generates Cu(I) species and
ketone intermediate 15 is captured by TEMPO to form
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Page 8 of 11
phenylpropiophenone, 10 mM Cu(OAc)2, 10 mM bpy, 0.1
M TEMPO, 2.0 mL 1,2-dichlorobenzene, N2, 120 oC.
1
2
3
4
5
6
7
8
9
α-TEMPO-substituted ketone 16 that undergoes fast
TEMPOH-elimination to form enones. Since only trans-
enone is formed, the TEMPOH-elimination likely occurs
via β-H abstraction assisted by another molecule of
TEMPO (17). Then, enone reacts with various nucleo-
philes under copper catalyst to achieve the overall direct
β-functionalization of ketones. Finally, oxidation of Cu(I)
species by TEMPO or TEMPOH regenerates Cu(II) spe-
cies with 2,2,6,6-tetramethylpiperidine and water released.
To clarify the regeneration of Cu(II) species from oxida-
tion of Cu(I), reactions of CuOAc/bpy complex with
TEMPO or TEMPOH have been performed, which
demonstrated that both TEMPO36 and TEMPOH37 could
oxidize Cu(I) to Cu(II) (see Figure S26-S29 in the Sup-
porting Information). Additionally, control experiments
using Cu(I) salt as catalyst precursor have also been done
to verify that the CuOAc/bpy as a catalyst system effects
the dehydrogenation of 3-phenylpropiophenone in the
presence of TEMPO (eq. 6). In contrast, in the presence
of TEMPOH as an oxidant, CuOAc/bpy did not promote
the dehydrogenation of 3-phenylpropiophenone (eq 7),
although oxidization of the CuOAc/bpy system to Cu(II)
species by TEMPOH has been established. No dehydro-
genation to occur in the experiment described in eq. 7
may stem from the lack of TEMPO component in the re-
action system, which probably provides a clue for the oxi-
dation of Cu(I) by TEMPOH. There are two possible ways
for oxidation of Cu(I) by TEMPOH: 1) oxidative addition
of N-O bond to Cu(I) species to generate Cu(III) species,
followed by the reaction of Cu(III) species with another
Cu(I) species to regenerate Cu(II) species; 2) oxidation of
Cu(I) species by the oxoammonium from disproportiona-
tion of TEMPOH.36 The latter way would involve for-
mation of TEMPO. Consequently, no dehydrogenation in
the reaction of eq. 7 suggested that the oxidation of Cu(I)
by TEMPOH did not involve generation of TEMPO and
therefore rose the possibility that the oxidation of Cu(I)
by TEMPOH proceeded via Cu(III) intermediate.
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
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. The 1H NMR spectra of (A) pure 3-
phenylpropiophenone 7, (B) pure α-TEMPO-adducted 3-
phenylpropiophenone 12 and (C) mixtures of 7 and 12
isolated from the reaction described in eq 5.
Figure 4. EPR spectra acquired from the dehydrogenation
of 3-phenylpropiophenone at (A) 0.5 h, (B) 1.0 h and (C)
2.0 h. Reaction conditions: 0.1 M 3-phenylpropiophenone,
10 mM Cu(OAc)2, 10 mM bpy, 50 mM TEMPO, 2.0 mL 1,2-
dichlorobenzene, N2, 120 oC.
CONCLUSIONS
In summary, we have developed a copper-catalyzed
method for direct β-functionalization of unactivated ke-
tones with a wide range of nitrogen, oxygen and carbon
nucleophiles, which proceeds through a tandem ketone
dehydrogenation-conjugate addition sequence. This pro-
tocol obviates the need for additional preparation steps
and carefully handing of α,β-unsaturated ketones, and
therefore opens up a new door to construction of β-
functionalized ketones in a highly efficient fashion. This
coupling also shows excellent functional group tolerance
as well as high chemo- and regioselectivity due to its mild
oxidative conditions. Mechanistic studies were carried out
to provide in-depth insight into this transformation using
control experiments, kinetic studies, identification of re-
action intermediates and KIE measurements. As disclosed
by mechanistic studies, our Cu-catalyzed dehydrogena-
tion of ketones represents an unprecedented radical-
based process. We expect that our mechanistic findings
Figure 5. UV-visible spectra acquired from the dehy-
drogenation of 3-phenylpropiophenone at (A) 0.5 h, (B)
1.0 h and (C) 2.0 h. Reaction conditions: 0.1 M 3-
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8
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36
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54
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58
59
60
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ASSOCIATED CONTENT
1
Detailed experimental procedures, H, 13C and 19F NMR spec-
tra data for compounds, kinetic data, and additional experi-
ment data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wpsu@fjirsm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Prof. Armido Studer for the fruitful discussion of
mechanism and Prof. Zhongning Chen for the helpful discus-
sion of UV-visible spectra. We also thank reviewers for their
helpful comments on an early version of this paper. Financial
support from NSFC (21431008, 21332001, 21402196 and
21401197), and the CAS/SAFEA International Partnership
Program for Creative Research Teams is greatly appreciated.
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