Copper-Catalyzed Desaturation of Lactones, Lactams, and Ketones under pH-Neutral Conditions

Article abstract of DOI:10.1021/jacs.9b07932

A copper-catalyzed desaturation method that is suitable for converting lactones, lactams, and cyclic ketones to their α,β-unsaturated counterparts is reported. The reaction does not require strong base/acid or sulfur/selenium reagents and can be carried out through a simple one-step operation. The protocol uses inexpensive catalysts and reagents and exhibits excellent scalability and functional group tolerance. Notably, tert-butyl alcohol is the only stoichiometric byproduct produced, and overoxidation is not observed. The reaction mechanism has been investigated through control experiments, deuterium labeling, radical clock, electron paramagnetic resonance, high-resolution mass spectrometry, and kinetic studies. The data obtained are consistent with a reaction pathway involving reversible α-deprotonation by a Cu(II)-O^tBu species followed by further oxidation of the resulting Cu enolate.

Full text of DOI:10.1021/jacs.9b07932

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Article
Copper-Catalyzed Desaturation of Lactones,
Lactams and Ketones under pH-Neutral Conditions
Ming Chen, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07932 • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 26, 2019
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Page 1 of 15
Journal of the American Chemical Society
Copper-Catalyzed Desaturation of Lactones, Lactams and Ketones under pH-
Neutral Conditions
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Ming Chen† and Guangbin Dong*,†
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†Department of Chemistry, University of Chicago, Chicago, Illinois, 60637, United States
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Abstract
A copper-catalyzed desaturation method is reported, which is suitable for converting lactones, lactams
and cyclic ketones to their α,β-unsaturated counterparts. The reaction does not require strong base/acid
or sulfur/selenium reagents, and can be carried out through a simple one-step operation. The protocol
uses inexpensive catalysts and reagents, exhibits excellent scalability and functional group tolerance.
Notably, t-butanol is the only stoichiometric byproduct produced, and over oxidation is not observed.
The reaction mechanism has been investigated through control experiments, deuterium labelling,
radical clock, EPR, HRMS and kinetic studies. The data obtained are consistent with a reaction pathway
involving a reversible α-deprotonation by a Cu(II)-OtBu species, followed by further oxidation of the
resulting Cu enolate.
Introduction
Methods that prepare and modify carbonyl compounds have been critical in organic synthesis.1
Among numerous carbonyl-involved transformations, desaturation reactions, namely converting a
saturated carbonyl compound to the corresponding α,β-unsaturated counterpart, is of particular
interest for syntheses of complex and biologically relevant molecules.2 First, the electrophilic α,β-
unsaturated structural motif is commonly found in many bioactive natural products (Fig. 1), which has
been an important inspiration for developing new pharmaceutical agents.3 On the other hand, the
desaturation process could be coupled with other transformations, which leads to β-functionalization2a,4
or simultaneous α,β-difunctionalization of carbonyl compounds.5
O
O
O
O
O
O
O
MeOOC
O
N
Ph
(-)-massioalactone
(R)-(+)-goniothalamin
xylogranatopyridine B
O
O
O
OMe
N
O
OMe
O
OMe
piperlongumine
Apocarotenoid
Figure 1. Representative natural products containing α,β-unsaturated carbonyl moieties.
To date, desaturation of ketones and aldehydes has been extensively developed;2 among various
creative strategies, the palladium-catalyzed oxidation offers a direct, efficient and mild approach, and
has been widely utilized in complex molecule syntheses.6 By contrast, the corresponding reactions with
common esters and amides have been much less developed. Classical approaches typically involve
introducing a sulfur or selenium-based leaving group to the α-carbon followed by an elimination
process.7 Recently, through an electrophilic activation approach, an impressive one-pot chemoselective
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selenium(IV)-mediated amide-desaturation was reported by Maulide and co-workers (Scheme 1a).8
Regarding catalytic strategies, Newhouse has systematically developed a suite of palladium-catalyzed
dehydrogenation of esters, amides, nitriles, ketones and carboxylic acids,9 which were effectively
enabled by enolate formation with a novel lithium anilide and subsequent transmetalation to zinc
(Scheme 1b). Alternatively, a soft enolization approach has been adopted by us for direct desaturation
of various esters and amides under either palladium10 or platinum catalysis11 (Scheme 1c). While
effective, these established catalytic methods require either stoichiometric strong bases or strong Lewis
acids for carbonyl enolization due to reduced acidity of the α C−H bonds in esters and amides (compared
to ketones and aldehydes); as a consequence, byproducts are heavily produced in these processes.
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Scheme 1. Recent Advances on Desaturation of Esters and Amides
a) Maulide:
O
O
R'
N
O
Tf2O, 2-I-pyr
Ph SeOH
R
NR'2
R'
R
NR'2
oxidant, base
R
electrophilic activation
b) Newhouse:
O
OLi
O
ZnCl2
LiNR"2
R
XR'
X = O, NR'
R
XR'
R
XR'
Pd cat., oxidant
enolization by strong bases
c) our previous work:
O
O
[B]
Pd or Pt cat.,
oxidant
O
Bu2BOTf, DIPEA
X
X
X
X = O, NR
enolization by strong lewis acids
d) this work:
O
O
waste
R3P-Cu(I) cat
tBuOOtBu
PhH, 80 o
X
tBuOH
2 equiv
X
+
C
X = CH2, O, NR
 strong base and acid free
 sulfur and selenium free
 simple one-step operation
 inexpensive catalyst/reagent
 scalable and chemoselective
 no over-oxidation
[Cu]
[Cu]
O
O
O
H
X
X
catalytic enolization
Inspired by Stahl’s seminal mechanistic studies on the palladium-catalyzed ketone
dehydrogenation,6g an intriguing question is whether catalytic enolization of lactones and lactams could
be realized using a dual functional catalyst that contains a more Lewis acidic metal and a more basic X
ligand (better than carboxylates). Serving as both a Lewis acid and an oxidation catalyst, the metal
complex could first activate the carbonyl substrate through soft enolization and then participate in the
subsequent dehydrogenation process. To continuously supply the base, as well as to maintain a
relatively neutral reaction medium and minimize byproduct formation, it could be strategically attractive
to slowly generate the basic X ligand from the oxidant. In addition, it would also be appealing if earth
abundant first-row transition metals could be employed as catalysts. Herein, we describe our initial
development of a copper-catalyzed oxidation method that can effectively convert a range of saturated
lactones, lactams and ketones to the corresponding unsaturated conjugated carbonyls (Scheme 1d). The
reaction is operated under near pH-neutral conditions with t-butanol as the only stoichiometric
byproduct formed.
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Results and Discussion
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In 2014, Han,12 Patel13 and Hartwig14 independently reported a Cu-catalyzed sequential
dehydrogenation of simple alkanes followed by Kharasch−Sosnovsky-type15 allylic functionalization.
Shortly after, the Antonchick group disclosed a single example of a Cu-catalyzed dehydrogenation of a
special 1,4-diketone.16 Concurrently, the Su group reported a novel Cu/2,2’-bipyridine (bpy)-catalyzed
TEMPO-mediated system for dehydrogenative β-functionalization17 and later multi-desaturation
reactions18 via radical abstractions. While highly efficient, the scope has been mainly focused on
ketones/aldehydes and selective mono-dehydrogenation was difficult. The challenge for the selective
mono-dehydrogenation is likely due to that, comparing to the α C−H bond in the substrate (~89-94
kcal/mol), the allylic C−H bond of the initially formed unsaturated product is typically weaker (~87
kcal/mol) and tends to be more reactive with radical species.19 In addition, from the prospect of polar
effect,20 the α C−H bond is generally more electronically deficient than allylic C−H bonds, therefore less
competitive to be abstracted by an electrophilic oxygen-based radical.
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Table 1. Selected Optimization Studiesa
O
O
20 mol% CuTc
20 mol% CyPPh2
O
O
O
S
1.5 equiv DTBP
O
C7H15
C7H15
PhH, 80 oC, 12 h
'standard' conditions
0.1 M
Cu
CuTc
2a, 82%
1a
(81% isolated)
2aa,b
Entry
Variations from the 'standard' conditions
Yield (%) of
1
2
3
4
5
6
7
8
CuTc
CyPPh
0
trace
Without
Without
2
DTBP
Without
0
C1-6
CuTc
Listed below
Listed below
Listed below
58
instead of
L1-16
Ox1-4
CyPPh
instead of
2
DTBP
instead of
CuTc
CyPPh
and 10 mol%
10 mol%
2
60
solvent = toluene
solvent = PhF
9
68
0
10
solvent = 1,4-dioxane
solvent = DCE
11
12
13
14
15
16
20
76
42
48c
72
82
temp = 70 o
temp = 60 o
C
C
C = 0.05 M
C = 0.2 M
none
Cu(CH3CN)4PF6
Cu2(OTf)2PhMe
CuSPh
C3
CuCl
C2
CuOAc
Cu(OAc)2
C5
C1
C6
, trace
, 78%
, 20%
, 0%
C4
, trace
, 0%
PAr3 (L4-L9)
iPrPPh2
tBuPPh2
L10
Cy3P
Ar = Ph, 64%
L12
, 56%
L11, 82%
, 76%
N
Ar = p-Me-C6H4, 66%
L1
, 10%
L13
SPhos,
, 0%
Ar = p-OMe-C6H4, 72%
Ar = p-F-C6H4, 68%
bpy
L2
L14
XPhos,
, 0%
, 14%
1,10-phen
L3
L15
XantPhos,
, 0%
Ar = p-CF3-C6H4, 48%
Ar = 3,5-di-CF3-C6H3, 28%
L16
dppb,
, 0%
, trace
Ph
O
O
Ph
O
Ph
O
O
Ph
O
OH
Ph
O
O
O
O
Ox3,
Ox4,
0%
0%
Ox1,
Ox2,
0%
58%
a Each reaction was run on a 0.2 mmol scale in a sealed 4 mL vial for 12 h. b Yields were determined by 1H NMR using CH2Br2 as
the internal standard. c 50% of 1a was observed.
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To address the selectivity challenge, we hypothesized that, using a more basic X ligand, such as t-
butoxide, and a softer L ligand (that can have a stronger trans influence), deprotonation of the α C−H
bond could be achieved in a cooperative manner under relatively mild conditions (i.e. lower reaction
temperature). As a consequence, it is expected that the undesired radical-mediated further oxidation
could be minimized. To test this hypothesis, phosphines were first examined as the ancillary ligand and
di-t-butylperoxide (DTBP) was employed as the oxidant in order to slowly generate the basic t-butoxide
ligand. To our delight, when using lactone 1a as the model substrate, the desired α,β-unsaturated
1
2
3
4
5
6
7
8
9
o
lactone product 2a was isolated in 81% yield at 80 C when using copper(I) thiophene-2-carboxylate
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(CuTc)/CyPPh2 (20 mol%) as the metal/ligand combination (Table 1). The role of each reactant was then
explored through control experiments. Clearly, the copper catalyst, the phosphine ligand and DTBP are
all essential to this transformation (entries 1-3). Besides CuTc, a variety of other copper (I) and (II)
complexes has also been tested as catalysts (entry 4). While CuOAc was almost equally effective, other
Cu(I) species, such as CuCl, CuSPh and Cu(MeCN)4PF6, were much less efficient, suggesting the
importance of the carboxylate ligand (vide infra, Mechanistic Studies). Cu(II) complexes, including
Cu2(OTf)2•PhMe and Cu(OAc)2 (effective catalyst in Su’s reactions17,18), gave no or trace desired product.
While the majority of the prior Cu-mediated oxidation reactions employ pyridine-type ligands,21
phosphine ligands were found to be more effective in this transformation (entry 5).22 Pyridine, bpy and
1,10-phen (L1-L3) all gave low yields of the product. Simple triarylphosphines are excellent ligands.
Regarding the electronic effect of the ligand (L4-L9), the more electron-rich PAr3 outperformed the
electron-deficient ones. Interestingly, the monoalkyl diarylphosphines were found most efficient. Both
i
tBu and Pr-substituted phosphines (L10 and L11) can give comparable yields to CyPPh2, but the trialkyl
PCy3 ligand (L12) gave a lower yield. In addition, Buchwald ligands (L13 and L14) and bidentate
phosphine ligands (L15 and L16) have also been examined, whereas all gave low efficiency or no
reactivity.
As one of the most stable peroxide species with decomposition temperature over 100oC, DTBP was
found to be a superior oxidant. Cumyl peroxide (Ox1) delivered the desired product in a moderate yield;
other peroxides, including tBuOOBz (Ox2), BPO (Ox3) and TBHP (Ox4), failed to yield any product (entry
6). Decreasing the catalyst/ligand loading to 10 mol% still afforded 2a in 58% yield (entry 7). A survey of
different solvents suggested aromatic solvents to be optimal (entries 8-11); in contract, the more polar
solvents, e.g. 1,4-dioxane and DCE, gave no product or only 20% yield, respectively. Although 80 oC was
o
the best reaction temperature, the reaction can still proceed even at 60 C (entries 12 and 13). Finally,
running the reaction at a lower concentration gave a lower conversion with most of the starting material
recovered (entry 14), while a higher concentration led to more substrate decomposition (entry 15).
With the optimized conditions in hand, the substrate scope was explored (Table 2). First,
substitutions at the various positions of δ-lactones were tolerated (2a-2ah).23 δ-Alkyl- or aryl-
substituted substrates all worked well, giving satisfactory yields of the corresponding products. In the
presence of an additional enolizable linear ester, the desaturation of δ-lactones (1j) still occurred
selectively at the lactone moiety. The α-phenyl substituted δ-lactone gave no desired product (2k);
instead, the α-dimer was formed as the major side product (vide infra, Scheme 4). When the phenyl
group was replaced with a benzyl group, a pair of isomers of dehydrogenation products was obtained in
low yields (2l). The β-methyl substituted δ-lactone afforded a high yield (2m) using i-PrPPh2 as the ligand.
The fused lactone (1n) was also a suitable substrate. The functional group compatibility was examined
based on β-aryl-substituted δ-lactones (2o-2ah). Gratifyingly, a wide range of functional groups were
Table 2. Substrate Scope with Lactones, Lactams and Ketones
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O
O
O
O
O
O
PG
N
R
PG
R
O
1
N
'standard' conditions
O
R
R
R
R
2
3
4
5
6
7
8
n = 0, 1
1
n = 0, 1
5
n = 0, 1
3
n = 0, 1
4
n = 0, 1
6
n = 0, 1
2
Lactones
O
O
O
O
O
O
O
O
O
O
O
O
O
O
C7H15
Me
, 68%
Ph
OMe
CO2Et
2c
2g
, 78%
2a
2b
, 73%
2d, 71%
2e, 72%
2f, 69%
, 81%
9
O
O
O
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
32
33
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36
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40
41
42
43
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45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
O
O
Ph
O
O
O
Ph
O
Ph
O
Bn
Bn
OEt
Me
2l
2l'
, 9%
, 25%
c
2k
, 0%
c
2h
2i
2m
, 80%
, 73%
O
, 41%
2j
, 72%
O
O
O
O
O
O
Me
O
F
O
O
C7H15
C7H15
C7H15
Ph
C7H15
, 60%
O
Me
2q
, 50%
O
2p
2r
, 57%
O
, 51%
O
2o
2n
, 51%
O
O
OPh
O
O
Br
O
O
O
C7H15
C7H15
C7H15
C7H15
C7H15
I
c
Cl
Br
2w
, 61%
O
2u
2v
, 49%
, 57%
2s
2t
, 55%
, 53%
O
O
O
O
O
O
O
O
O
C7H15
C7H15
C7H15
, 58%
C7H15
C7H15
, 64%
MeO
F3CO
TMS
2ab
, 42%
2aa
2x
2y
2z
, 52%
, 62%
O
O
O
O
O
O
O
O
Me
O
O
O
C7H15
NC
C7H15
C7H15
C7H15
F3C
2ae
, 50%
C7H15
Me
O
N
2ag
, 62%
MeO2C
c
c
2ac
2ad
, 53%
, 44%
2af
, 58%
O
O
O
O
O
O
O
O
Me
O
C7H15
O
Me
N
d
2aj
, 43%
2ai
O
O
2ah
, 54%
, 58%
O
O
O
O
H
H
O
H
H
H
H
H
O
H
H
AcO
AcO
O
H
O
c
c
2am
, 64%
2al
, 75%
2ak
, 56%
Ketones and Lactams
O
O
O
O
O
O
O
O
O
Ts
N
Ts
Ts
C6F5
N
N
C6F5
N
N
O
Me
Ph
4a
c,d
6d, 48%c,d
c
c
c
6e
, 42%
4b
6b
, 52%
, 60%
6a
, 62%
6c
, 59%
4c
, 48%
, 57%
O
O
O
O
Me
CO2Me
Me
H
Me
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
O
Me
Me
MeO
AcO
AcO
AcO
H
c
O
4e
4f
, 52%
, 55%
4g
4h
, 45%
oleanolic acid
4d
, 41%
, 62%
from
from
epiandrosterone acetate
from Dehydroepiandrosterone acetate
from
estrone
a Each reaction was run on a 0.2 mmol scale in a sealed 4 mL vial for 12 h. b Isolated yields. c 20 mol% iPrPPh2 was used.
d The reaction was run at 100 oC. Ts= p-toluenesulfonyl.
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tolerated, including aryl fluoride (2r), chloride (2s), bromide (2t and 2u), iodide (2v), ethers (2w, 2x and
2y), silyl (2z), nitrile (2ad), ester (2ae), trifluoromethyl (2af), electron-rich arenes (2w, 2x and 2ac),
polyaromatic (2ab) and tertiary amides (2ag and 2ah). Five and seven-membered lactones were found
less reactive, though unsaturated γ-lactone (2ai) was still obtained in a moderate yield. Gratifyingly, δ-
lactones derived from bioactive natural products, such as α-tocopherol (2aj), cholesterol (2ak),
androsterone (2al), and dehydroepiandrosterone (2am), also smoothly afforded the desired
desaturation products. Note that the allylic and benzylic C−H bonds in these substrates were tolerated.
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2
3
4
5
6
7
8
9
10
11
12
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The feasibility of desaturating ketones and lactams was also tested with the Cu-catalyzed protocol. β,β-
disubstituted or α,α-disubstituted cyclopentanones and cyclohexanones were competent substrates
(4a-4c). Particularly, this method could be employed to desaturate a number of sterically encumbered
steroid-based substrates (4d-4h). In addition, protected six- or seven- membered lactams could all
afford the corresponding unsaturated products in moderate yields (6a-6e). Reactions with linear esters
and amides were not fruitful under the current conditions likely due to further reduced acidity of the α
hydrogens, which is the topic of the ongoing study.
Scheme 2. Gram-scale Reactions
20 mol% CuTc
O
O
[P]
20 mol%
1.5 equiv tBuOOtBu
O
O
PhH, 80 oC, 24 h
C7H15
C7H15
1a
2a
20 mmol, [P] = CyPPh2
100 mmol, [P] = PPh3
:
86%, 3.4 g
68%, 13.4 g
:
To investigate the practicality of this method, gram and decagram-scale reactions were carried out.
On a 20.0 mmol scale, the desired α,β-unsaturated lactone 2a was isolated in 86% yield when CyPPh2
was used (Scheme 2). The 100 mmol scale reaction employed inexpensive PPh3 as the ligand,24 which
afforded 13.4 g of product 2a.
Mechanistic Studies
Efforts were then carried out to obtain some mechanistic insights into the Cu-catalyzed
dehydrogenation reaction. First, perhaps, the most interesting question is how the α C−H bond is
cleaved. To address this question, a number of control experiments were conducted (Scheme 3).
Running the reaction of substrate 1b under the standard reaction conditions except in the presence of 3
t
equiv BuOD in 4 h provided the desaturated product in 58% yield with 20% D incorporation at the α
position (Eq 1). The recovered 1b was found to contain 40% D at the α position. On the other hand, no
deuterium incorporation was found when running the same reaction in the absence of DTBP or Cu (Eq 2),
suggesting an important role of the proposed [tBuO-Cu] species. The H/D exchange phenomenon
indicates that the copper enolate formation is likely reversible. Thus, from a microscopic reversibility
viewpoint, the cleavage of the α C−H bond should come from a deprotonation process,25,16 which could
be the key for the proposed catalytic enolization. In addition, given that over-oxidation was not
observed even after subjecting the unsaturated product (2a) to the standard condition (Eq 3), as well as
the tolerance of weak benzylic and allylic C−H bonds (2d-2f and 2ak), the alternative α C−H abstraction
pathway by highly reactive free tBuO· radical is unlikely.
Scheme 3. Cleavage of the α C−H Bond
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40%D
O
20%D
O
O
standard condition
3 equiv tBuOD
D
D
1
O
(1)
O
O
D
+
2
3
4 h
1b
2b-d
1b-d
2, 18%
1, 58%
4
5
6
7
0% D
no DTBP
O
O
H
standard condition
3 equiv tBuOD
4 h
2b
(not observed)
(2)
(3)
O
O
H
1b
1b
no CuTc
8
O
9
O
standard condition
12 h
over-oxidation: not observed
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60
2a,
94%
C7H15
2a
proposed:
[Cu]
[Cu]
O
O
O
H
+
HO
O
O
The second question is how the β C−H bond is cleaved. To answer this question, understanding the
property of the generated copper enolate would be important. Similar to Su’s observation,17a the copper
enolate also exhibits sufficient radical character (Scheme 4). First, the reaction of the cyclopropane-
containing lactone (7) gave a transient ring-opening product (8), which decomposed after a longer
reaction time (Eq 4). The C−C cleavage pattern for such a ring-fused cyclopropane is consistent with the
previously reported radical-mediated pathway.26 In addition, a persistent radical, e.g. TEMPO, can
effectively trap the α radical generated in the reaction (Eq 5). Moreover, when the α-phenyl substituted
δ-lactone (1k) was employed, the α dimer was formed in 60% yield (Eq 6). This is likely due to that such
α radical species is stable enough to dissociate and form a dimer. Thus, in addition to being basic, the
copper enolate intermediate also has a notable radical property.
Scheme 4. Radical Character of the Copper Enolate
O
O
standard condition
3 h
O
O
(4)
(5)
+
7
62%
7
8
, 21%
O
O
standard condition
additive
O
O
N
O
2a
+
12 h
1a
9
additive
50 mol% TEMPO :
100 mol% TEMPO:
40%
0%
44%
74%
O
O
O
Ph
Ph
Ph
standard condition
60%
(6)
O
O
O
1k
2k'
X-ray of 2k'
proposed:
[Cux]
O
[Cux-1
]
O
O
[Cux]
O
O
O
Given the radical character of the copper enolate, the β C−H bond of the enolate is anticipated to be
significantly weakened. Early studies by Kochi show that alkyl radicals can react with Cu(II) salts to give
olefins; this process was described as a “oxidative elimination” reaction (Scheme 5).27 A transient Cu(III)-
alkyl intermediate was proposed and carboxylate ligands on copper (e.g. OAc) were critical for this
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transformation. Similarly, in this Cu-catalyzed dehydrogenation reaction, carboxylate-type X ligands
were also found to be essential (vide supra, Table 1). Thus, we questioned whether a similar “oxidative
elimination” process could have occurred in this system.28 A number of experiments were then carried
1
2
3
4
t
out. While it is difficult to quantify the BuOH generated in the reaction, the use of heavier cumyl
5
peroxide (Ox1) afforded the corresponding alcohol 10 in 94% yield based on the desaturated product
generated (Eq 7). In the prior Cu(OAc)2/TEMPO-assisted dehydrogenation, the β C−H abstraction
occurred with an α-oxygenated species (e.g. TMEPO-substituted ketones).17a In our system, the α-
oxygenated species was not observed with lactones. In contrast, the α-tBuO-substituted product (11)
was only observed when treating lactam 5a with stoichiometric CuOAc in the absence of phosphine
ligands (Eq 8); however, subjecting compound 11 to the standard catalytic conditions gave no desired
desaturation product (Eq 9). These results indicate that the α-oxygenated species is unlikely to be an
intermediate in this reaction, which represents a main difference from the Cu(OAc)2/TEMPO system.17a
Hence, in our system the β C−H scission possibly occurs with either the copper enolate or the enolate
radical species.
6
7
8
9
10
11
12
13
14
15
16
17
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20
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22
23
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Cleavage of the β C−H bond
Established: (by Kochi)
OAc
R
R
R
[CuIII
OAc
]
oxidative
elimination
HOAc
[CuIOAc]
H
[Cu(II)(OAc)2]
Ph
O
Ph
O
O
O
Ph
20 mol% CuOAc
20% CyPPh2
PhH, 80 oC, 12 h
x 2
+
(7)
2a
, 62%
HO
10
C7H15
1a
2a)
94% (based on
O
O
O
O
tBuO
5a
, 14%
1 equiv CuOAc
1.5 equiv DTBP
PhH, 80 oC, 12 h
N
C6F5
N
C6F5
+
(8)
(9)
+
6a
, 20%
11
, 27%
5a
O
O
O
O
N
tBuO
N
C6F5
standard condition
12 h
C6F5
not observed
11
6a
proposed:
O
O
O
O
[CuIII
OR
]
oxidative
elimination
[CuII]
OR
O
O
H
H
Kinetic studies. To better understand the catalytic system, the kinetic profiles of the reaction were
obtained (Fig. 2). A short induction period (~10 min) was observed. The reaction then proceeded with a
fast initial rate (0.4 mM/min), and became slower after 3 hours (at around 50% conversion). The
production formation was plateaued after 6 hours. Notably, in the first 6 hours, the mass balance was
nearly perfect, indicating that there was almost no decomposition of the starting material in this period.
The catalyst system then became inactive after 6 hours; the 31P NMR of the reaction mixture suggests
that a significant amount of phosphine oxide was formed at this stage. It is also not surprising that
decomposition of 1a started to occur after the death of the catalyst.
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20 mol% CuTc
20 mol% CyPPh2
1.5 equiv tBuOOtBu
O
O
O
1
2
O
3
4
PhH, 80 o
C
C7H15
C7H15
1a
2a
5
6
7
8
12
10
8
6
4
110
90
2
0
0
10
20
30
9
70
10
11
12
13
14
15
16
17
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50
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54
55
56
57
58
59
60
2a
1a
50
30
10
0
200
400
600
800
-10
t / (min)
Figure 2. The Kinetic Profile of the Cu-Catalyzed Desaturation of Lactone 1a under the Standard
Conditions
0.00045
0.00040
0.00035
0.00030
0.00025
0.00020
DTBP: first order
0.10
0.12
0.14
0.16
0.18
0.20
DTBP ( M )
0.00050
0.00045
0.00040
0.00035
0.00030
0.00025
CuTC-CyPPh : first order
2
0.016
0.020
0.024
0.028
0.032
CuTc-CyPPh ( M )
2
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1
2
3
4
5
6
7
8
0.0010
0.0008
0.0006
0.0004
0.0002
0.0000
0.0002
0.0004
1b : zero order
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0.02
0.04
0.06
0.08
0.10
0.12
0.14
1b (M)
Figure 3. Measurement of the Reaction Rate Dependence of the Oxidant (DTBP), the Copper
Catalyst and the Substrate (1b)
To gain insights into the turnover limiting step (TLS) and the resting state of the catalyst, the
reaction orders of each component have been determined using the initial-rate method (Fig. 3). The rate
of reaction shows first-order dependences on the catalyst and the oxidant (DTBP), but pseudo zero-
order on the lactone substrate (1b). In addition, the parallel kinetic isotope effect (KIE) studies show that
no primary KIE was observed at either the α or β position (Scheme 6), which indicates that C−H bond
cleavage is unlikely involved in the TLS, though a small KH/KD ratio (1.2, repeated twice) was observed at
the α position. The kinetic feature of this reaction represents another difference from the
Cu(OAc)2/TEMPO system,17a which has the α C−H cleavage as the TLS.
Scheme 6. Kinetic Isotope Effect Studies.
A)
B)
O
O
O
O
D
D
O
O
O
O
D
1a-d2
2a-d2
2a
1a
KH / KD = 1.2 0.1
KH / KD = 1.0 0.1


O
O
O
O
D
D
D
D
D
D
O
O
O
O
D
D
D
1a-d2
2a-d2
1a-d4
2a-d4
Based on the results of the kinetic study, further experiments have been carried out to probe the
TLS and resting state of the catalyst. First, the induction period was found to be notably shortened
under a higher concentration of DTBP. In addition, when first mixing CuTc and CyPPh2 in benzene at 80
oC for 0.5 h and then adding the substrate and DTBP, the induction period still existed. However, when
mixing CuTc, CyPPh2 and DTBP at 80 C first before adding the substrate,29 no induction period was
o
observed (for details, see Supporting Information). These results suggest that the copper (I) species, i.e.
[LCu(I)OAc], is unlikely to be involved in the catalytic cycle. To examine whether the TLS involves
participation of the lactone substrate, stoichiometric phosphine ligand, Cu(I)Tc and DTBP were first
stirred at 80 C for 1 h before reacting with substrate 1b at room temperature, 40 C and 50 C,
respectively (Eq 10). No desired desaturation product was observed with most substrate 1b untouched
in all these reactions after 24 h, which implies that the TLS should not be a step before the substrate
enters the catalytic cycle. Considering the pseudo-zero order dependence with the substrate
concentration as well as a small KIE at the α position and no KIE at the β position, we postulated that the
o
o
o
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TLS could be a step after the α C−H deprotonation but before the β C−H cleavage, which also involves
reaction with DTBP (due to the first order dependence on [DTBP]).
1
2
3
O
4
5
6
7
1 equiv CuTc
1 equiv CyPPh2
1.1 equiv DTBP
O
1b
1 equiv
in r.t.
1b
(10)
+
80 oC, 1 h
then r.t.
94-97%
or 40 o
or 50 o
C
C
2b
not observed
8
9
Proposed catalytic cycle. While some mechanistic details of this reaction remain unclear and still
under investigation, the data above allow us to propose a hypothesis for the Cu-catalyzed desaturation
of lactones (Fig. 4). Elegant mechanistic studies by Warren show that Cu(I) could react with DTBP to
generate a LCu(II)OtBu species (B) and a t-butyl oxo-radical that can undergo quick combination with
another equivalent of Cu(I) to give the same species B.21e,f This process is anticipated to be the reason
for the induction period, which is consistent with a fact that higher [DTBP] shortened the induction
period. The LCu(II)OtBu species B could then coordinate to the carbonyl substrate and promote the
subsequent reversible deprotonation of the α-C−H bond. The resulting LCu(II)-enolate D or E could then
react with DTBP to afford a Cu(III) intermediate F that undergoes fast oxidative elimination, according to
Kochi’s study,27,30 to afford the desaturated product and ultimately regenerate the LCu(II)OtBu species
B.31
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11
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2 [LCuIY]
tBuO OtBu
A
O
induction period
X
OtBu
O
2
L
CuII
Y
X
B
Y
L
tBuO
CuII
+ tBuOH
tBuO
O
H
X
L
CuIII
O
[CuIII
]
C
OtBu
G
X
Y
Y
CuII
H
F
O
L
[CuII]
X
+ tBuOH
Y
CuII
O
TLS
tBuO OtBu
X
L
D
H
E
X = O, N, C
Y = OAc, Tc
L = phosphine
O
O
TEMPO
TEMPO
X
A
+
X
H
Figure 4. Proposed Simplified Catalytic Cycle
Based on the kinetic studies, the TLS is proposed to be the reaction between the LCu(II)-enolate and
DTBP. This proposal is consistent with the KIE experiments (vide supra, Scheme 6), as the β C−H cleavage
is expected to be after the TLS and the α C−H cleavage to be before the TLS and reversible (equilibrium
isotope effect). In addition, peroxides are known to be capable of oxidizing Cu(II) to Cu(III),32 though
other pathways involving oxidation of the potential α radical intermediate H cannot be excluded at this
stage. Consequently, the resting state of the catalyst is postulated to be the LCu(II)-enolate and/or other
Cu(II) species (B or C), given that these species could all be in equilibrium. While it remains difficult to
identify the exact Cu(II) species as the resting state(s),33 EPR spectrum of the reaction mixture clearly
indicated the existence of Cu(II) species (see Supporting Information). In addition, ESI high-resolution
mass spec (HRMS) of the reaction mixture captured the masses of the Cu(II) species instead of Cu(I) or
Cu(III) species (see Supporting Information). Taken together, all the data are consistent with the
proposed reaction pathway. Finally, it is noteworthy that copper carboxylates often exist in a dimeric
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form,34 thus it is highly possible that dinuclear copper species are involved and the actual catalytic cycle
is much more complex. Further detailed characterization of the reaction intermediates is underway.
1
2
3
4
Conclusion
5
6
7
8
In summary, the development of a Cu-catalyzed desaturation of lactones, lactams and cyclic ketones
is described. The reaction does not require stoichiometric strong bases or acids, and is sulfur/selenium-
free, showing high functional group tolerance. It uses a first-row transition-metal catalyst and an
inexpensive reagent with t-butanol formed as the only stoichiometric byproduct. In addition, this
method is scalable, operationally simple, and avoids over-oxidation. Preliminary mechanistic studies
reveal an unusual reversible deprotonation of the carbonyl α C−H bonds, radical character of the copper
enolate intermediate, and a critical role of the DTBP oxidant. Future efforts will involve further
enhancement of the reaction efficiency and substrate scope through catalyst design and better
understanding of the structure and reactivity of the copper enolate intermediate.
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ASSOCIATED CONTENT
Text, figures, tables, and CIF files giving experimental procedures, kinetics data, and crystallographic information.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*gbdong@uchicago.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank University of Chicago for the research support. Dr. Jianchun Wang, Dr. Yan Xu, Mr. Chengpeng Wang and
Prof. Guosheng Liu are acknowledged for helpful discussions of the reaction mechanism. Dr. Zhao Wu is thanked
for checking the experiments. We also thank Dr. Ki-Young Yoon for the X-ray crystallography and Mr. Xuanyu Feng
for the EPR experiments.
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(23) The reactions were run with an extended reaction time to allow for full conversions. Otherwise,
separation of pure products from unreacted starting materials would be very difficult.
(24) While the larger scale reactions were always run with caution and protecting equipment, safety
issues with the use of DTBP were not observed in our hands.
5
(25) Bailey, W. D.; Gagnon, N. L.; Elwell, C. E.; Cramblitt, A. C.; Bouchey, C. J.; Tolman, W. B. Revisiting
the Nucleophilic Reactivity of an Anionic Copper-Superoxide Complex. Inorg. Chem. 2019, 58, 4706.
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(28) Notably, direct β-hydrogen elimination of a high valent copper species is rare.
(29) A immediate color change from colorless to green was observed when mixing the Cu(I) complex
with DTBP.
(30) Kochi, J. K. Electron-transfer mechanisms for organometallic intermediates in catalytic reactions.
Acc. Chem. Res. 1974, 7, 351.
(31) The details for the regeneration of Cu(II) species B are unclear at this stage. We hypothesized that
another Cu(II) species is probably involved in this process.
(32) Wang, J.; Liu, C.; Yuan, J.; Lei. A. Copper-Catalyzed Oxidative Coupling of Alkenes with Aldehydes:
Direct Access to α,β-Unsaturated Ketones. Angew. Chem. Int. Ed. 2013, 52, 2256.
(33) 31P NMR of the reaction mixtures showed close and broad peaks. Thus, it was not trivial to use NMR
to identify the resting state.
(34) Brown, G. M.; Chidambaram, R. Dinuclear Copper(II) Acetate Monohydrate: A Redetermination of
the Structure by NeutronDiffraction Analysis. Acta Crystallogr. B 1973, 29, 2393.
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O
O
waste
R3P-Cu(I) cat
tBuOOtBu
X
tBuOH
X
+
PhH, 80 o
C
2 equiv
X = CH2, O, NR
 strong base and acid free
 sulfur and selenium free
 simple one-step operation
 inexpensive catalyst/reagent
 scalable and chemoselective
 no over-oxidation
[Cu]
[Cu]
O
O
O
H
X
X
catalytic enolization
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