Copper-catalyzed vinylogous aerobic oxidation of unsaturated compounds with air

Article abstract of DOI:10.1021/jacs.8b01886

A mild and operationally simple copper-catalyzed vinylogous aerobic oxidation of β,γ- and α,β-unsaturated esters is described. This method features good yields, broad substrate scope, excellent chemo- and regioselectivity, and good functional group tolerance. This method is additionally capable of oxidizing β,γ- and α,β-unsaturated aldehydes, ketones, amides, nitriles, and sulfones. Furthermore, the present catalytic system is suitable for bisvinylogous and trisvinylogous oxidation. Tetramethylguanidine (TMG) was found to be crucial in its role as a base, but we also speculate that it serves as a ligand to copper(II) triflate to produce the active copper(II) catalyst. Mechanistic experiments conducted suggest a plausible reaction pathway via an allylcopper(II) species. Finally, the breadth of scope and power of this methodology are demonstrated through its application to complex natural product substrates.

Full text of DOI:10.1021/jacs.8b01886

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Copper-Catalyzed Vinylogous Aerobic
Oxidation of Unsaturated Compounds with Air
Hai-Jun Zhang, Alexander W. Schuppe, Shi-Tao Pan, Jin-
Xiang Chen, Bo-Ran Wang, Timothy R. Newhouse, and Liang Yin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01886 • Publication Date (Web): 16 Mar 2018
Downloaded from http://pubs.acs.org on March 16, 2018
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Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated
Compounds with Air
HaiꢀJun Zhang,1 Alexander W. Schuppe,2 ShiꢀTao Pan,1 JinꢀXiang Chen,1 BoꢀRan Wang,1 Timothy R.
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Newhouse,2,* Liang Yin1,*
1CAS Key Laboratory of Synthetic Chemistry of Natural Substances, 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
2Department of Chemistry, Yale University, 225 Prospect, New Haven, Connecticut 06520ꢀ8107, United States
Supporting Information Placeholder
ABSTRACT: A mild and operationally simple copperꢀcatalyzed vinylogous aerobic oxidation of β,γꢀ and α,βꢀunsaturated esters is described.
This method features good yields, broad substrate scope, excellent chemoꢀ and regioselectivity and good functional group tolerance. This method is
additionally capable of oxidizing β,γꢀ and α,βꢀunsaturated aldehydes, ketones, amides, nitriles and sulfones. Furthermore, the present catalytic
system is suitable for bisvinylogous and trisvinylogous oxidation. TMG was found to be crucial in its role as a base, but we also speculate it serves
as a ligand to copper(II) triflate to produce the active copper(II) catalyst. Mechanistic experiments conducted suggest a plausible reaction pathway
via an allyl copper(II) species. Finally, the breadth of scope and power of this methodology is demonstrated through application to complex natural
product substrates.
oxidation reactions.11 In synthetic chemistry, copperꢀcatalyzed or ꢀ
mediated aerobic hydroxylations have been intensively studied and
led to a number of important synthetically useful oxidation reactions,
which have been applied in numerous industrial settings.12,13
INTRODUCTION
Selective oxidation is one of the most critical reaction types utiꢀ
lized in both academic and industrial settings,1 which allows converꢀ
sion of petroleumꢀbased feedstocks to useful chemicals of higher
oxidation state such as alcohols, carbonyl compounds and epoxides.
Among various oxidants, oxygen represents the most easily accessible
and abundant oxidant, which can lead to an environmentally benign
Scheme 1. Copper-Catalyzed Vinylogous Aerobic Oxidation of
β,γ-Unsaturated Esters and Undesired Oxidation Pathways
source for the oxidative functionalization of organic molecules.2
A
catalyst is indispensable to achieve a selective transformation due to
the high activation energy of oxygen.3 Moreover, poor selectivity and
limited substrate scope, as well as overꢀoxidation are found as signifiꢀ
cant limitations.4
Recently, noteworthy advances have been achieved in transition
metalꢀcatalyzed selective aerobic oxidation of CꢀH bonds to CꢀC, CꢀN
and CꢀO bonds and oxidation or cleavage of CꢀC double bonds.5,6
Furthermore, various heterocycles have been synthesized by metalꢀ
catalyzed aerobic oxidation.7 Considering the issues of relative safety,
extremely low cost, sustainable abundance and ease of manipulation,
performing aerobic oxidation using air is highly preferred. However,
it is often challenging to employ air instead of oxygen in metal cataꢀ
lyzed aerobic oxidations due to reduced reactivity at lower oxygen
concentration.8 Although a significant number of transitionꢀmetalꢀ
catalyzed aerobic oxidations have been developed, practical and effiꢀ
cient hydroxylations with air as the oxidant are still highly desirable.
Among the various transition metal catalysts used in selective oxiꢀ
dation with oxygen, copper is widely recognized as ideal due to its
natural abundance, cost effectiveness and sustainability.9,10 More
importantly, copper shows excellent reactivity: Cu0, CuI, CuII, and
CuIII oxidation states can be easily accessed, which enables radical
pathways or twoꢀelectron bond formations. In addition to its redox
properties, copper has the additional possibility of acting as a Lewis
acid either through σ−coordination to basic oxygen functionality or
through π–coordination with numerous functional groups. Such reacꢀ
tivity is leveraged by metalloenzymes, possessing copper in the active
site, which are utilized by nature as efficient catalysts for aerobic
One particular class of oxidation reaction is the oxidation of enoꢀ
lates, which is a direct and efficient way to obtain αꢀhydroxyl carbonꢀ
yl compounds.14 In the classic oxidation of steroids, αꢀhydroxylation
has been possible using molecular oxygen as an oxidant:15 generation
of an enolate in the presence of a strong base (such as LDA), nucleoꢀ
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Cu salt
base
reductant (1.5 equiv)
O2 balloon
(5 mol %)
(1.2 equiv)
philic attack of oxygen by the enolate and reduction of newly formed
peroxide by a trialkyl phosphite.16 Phaseꢀtransfer catalysis has also
been applied for aerobic oxidation of ketones and 2ꢀoxindoles.17 Sevꢀ
eral other oxidants, such as oxaziridines18ꢀ20 and MoOPH,21 compliꢀ
ment αꢀhydroxylation of enolates with molecular oxygen.
O
O
O
1
2
3
4
5
6
7
8
Ph
HO
OR
OR
Ph
THF (0.2 M), rt, 4-48 h
Ph Me
6a-10a
Me
1a-5a
11
entry
1
substrate
reductant
Cu salt
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
base
TMG
yield (%)b yield of 11 (%)b
More recently, copperꢀcatalyzed αꢀhydroxylation of ketones has
emerged as an efficient and sustainable alternative to the use of stoiꢀ
chiometric oxidations in the preparation of αꢀhydroxyl carbonyl comꢀ
pounds (Scheme 1A).22 Although significant advances have been
achieved in the aerobic oxidation of enolates via copper catalysis22 or
other transition metal catalysts,23 there is no report of a transitionꢀ
metalꢀcatalyzed vinylogous oxidation of dienolates. Due to competiꢀ
tive αꢀhydroxylation and other deleterious side reactions related to the
proximal olefin in both the starting material and product, it is chalꢀ
lenging to simultaneously control both chemoselectivity and regioseꢀ
lectivity while solving the problem of overꢀoxidation (Scheme 1B).
1a, R = Bn
1a, R = Bn
1a, R = Bn
1a, R = Bn
1a, R = Bn
1a, R = Bn
1a, R = Bn
2a, R = Me
3a, R = Et
4a, R = tBu
5a, R = Ph
2a, R = Me
2a, R = Me
-
33
82
0
21
8
2
PPh3
P(OEt)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
TMG
3
TMG
0
4
TMG
85
0
8
5
iPr2NEt
Barton's Base
hppH
TMG
0
9
6
43
9
22
30
8
10
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7
8
87
82
72
53
87
87
87
90
87
0
9
TMG
10
13
15
8
10
11
12c
13d
TMG
γꢀHydroxylꢀα,βꢀ(E)ꢀalkenoic esters are important motifs present in
naturally occurring compounds, such as macrolides.24 These functionꢀ
al groups play an important role as Michael acceptors for thiol conꢀ
taining side chains in enzymatic binding sites.25 Moreover, they
served as versatile intermediates in a wide range of chemical manipuꢀ
lations in organic synthesis.26 One of the most commonly employed
methods for the oxidation of dienolates employs oxygen and P(OEt)3,
in which the dienolates are generated by deprotonation of β,γꢀ
unsaturated or α,βꢀunsaturated ketones or esters in the presence of
LDA.27 However, very strong bases, such as LDA, are significantly
limited in their functional group tolerance as a result of poor regioseꢀ
lectivity, low efficiency and overꢀoxidation. In 2017, two of us (A. W.
S. and T. R. N.) utilized a vinylogous hydroxylation reaction with
molecular oxygen to afford a γꢀhydroxylꢀα,βꢀ(E)ꢀalkenoic ester moieꢀ
ty, which was a key intermediate in the total synthesis of (±)ꢀ
andirolide N.28 Here, we report a copperꢀcatalyzed vinylogous aerobic
oxidation of γ,γꢀdisubstituted β,γꢀ and/or α,βꢀunsaturated compounds
under air, leading to a broad array of γꢀhydroxylꢀα,βꢀ(E)ꢀunsaturated
compounds (including esters, aldehydes, ketones, amides, nitriles and
sulfones) in high yield.
TMG
TMG
TMG
8
14d,e 2a, R = Me
15d,e,f 2a, R = Me
16d,f,g 2a, R = Me
17d,e,f 2a, R = Me
18d,e,f 2a, R = Me
TMG
8
TMG
8
TMG
10
0
TMG
Cu(OTf)2
-
0
0
a1a-5a: 0.2 mmol. bDetermined by 1H NMR analysis of reaction crude mixture. cAir balloon
employed. dUndried THF (water content ≤ 1000 ppm) and air balloon employed. e0.8 equiv TMG
employed. f1.3 equiv PPh3 employed. g0.3 equiv TMG employed. 60 h. TMG
= tetramethyl
guanidine. Barton's Base = 2-tBu-1,1,3,3-tetramethylguanidine. hppH = 1,3,4,6,7,8-Hexahydro-2H-
pyrimido[1,2-a]pyrimidine.
A stronger amine base was indispensable as weaker bases (such as
iPr2NEt, Et3N, and Cy2NMe) were ineffective (entry 5 and see SI).
Barton’s base and hppH gave inferior results (entries 6–7). Studies on
the identity of the ester group determined that a methyl ester was
optimal (entry 8). The use of other ester substituents such as ethyl,
tertꢀbutyl and phenyl also led to product formation, albeit in lower
yield (entries 9–11). It is very encouraging for process chemistry
applications that under an atmosphere of air the vinylogous oxidation
proceeded with comparable yield (entry 12). Adding water to the
catalytic oxidative system did not affect the reaction outcome, which
successfully enabled the vinylogous oxidation to proceed using
undried THF under air (entry 13). 0.8 Equiv TMG was found to be
ideal to promote the reaction to finish in 24 h without impacting the
yield (entry 14). Reducing the amount of PPh3 resulted in a slightly
increased yield (entry 15). A catalytic amount of TMG (0.3 equiv)
was also effective but prolonged reaction time was required (entry 16).
Control experiments indicated that both copper(II) triflate and TMG
were crucial in the present vinylogous oxidative system (entries 17
and 18). Furthermore, other metal salts including Lewis acids (such as
Ni(OTf)2, Sc(OTf)3, Yb(OTf)3 and InBr3) and redoxꢀactive metal salts
(such as FeSO4·7H2O, FeCl3, Mn(OAc)2·4H2O and Mn(OAc)3·2H2O)
were completely ineffective, highlighting the power of the copper
catalyst system (see SI).
RESULTS AND DISCUSSION
1. Optimization of Reaction Conditions. Based on our previously
disclosed asymmetric vinylogous Mannichꢀtype reaction catalyzed by
a chiral copper(I) complex,29 we envisioned that a copperꢀdienolate,
generated upon deprotonation by a base, might be selectively oxidized
by oxygen to produce a γꢀhydroxylꢀα,βꢀ(E)ꢀalkenoic ester. In line
with the above hypothesis, we commenced the investigation by using
γ,γꢀdisubstituted β,γꢀunsaturated ester 1a as the substrate and
Cu[(CH3CN)4]PF6 as the catalyst (Table 1). Addition of a reductant
proved to be crucial, as the oxidation without any reductant resulted
in 33% yield (entry 1), while the addition of PPh3 as a reductant led to
the product in 82% yield (entry 2). Other reductants were less sucꢀ
cessful, including the commonly employed reductant P(OEt)3 (entry
3),30 PBu3 and Ph2PMe (see SI). Other triaryl phosphines were also
investigated and PPh3 outperformed these reductants.31 Various other
commercially available copper salts and solvents were found to be
less successful (see SI). Although all copper salts examined catalyzed
the desired aerobic oxidation, the use of Cu(OTf)2 resulted in an inꢀ
creased yield (entry 4 and see SI).
Scheme 2. Vinylogous Aerobic Oxidation of 2a under Reported
Reaction Conditions (1H NMR yield was given)
Table 1. Optimization of the Reaction Conditions with γ,γ-
Disubstituted β,γ-Unsaturated Esters under Oxygen Atmospherea
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Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
O
O
O
air balloon
Ph
HO
Ph
2a
OMe
OMe
Ph
THF (0.2 M), rt, 16 h
this work
Me
Me
2a
7a, 90%
11, 8%
0%
4
5
6
7
8
9
Cs2CO3
P(OEt)3
O2 (1 atm)
(0.2 equiv)
(2.0 equiv)
O
O
O
O
Ph
Ph
HO
Ph
2a
OMe
OMe
OMe
OMe
Ph
DMSO (0.2 M), rt, 20 h
ref 15e
Me
Me
Me
2a
2a
7a, 14%
11, 0%
0%
KOtBu
air balloon
(1.0 equiv)
O
O
HO
Ph
2a
10
11
12
13
14
15
16
17
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20
21
22
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Ph
DMSO (0.2 M), rt, 24 h
ref 15f
Me
7a, 0%
11, 0%
0%
Cu2O
hppH
O2 (1 atm)
(5 mol %)
(1.1 equiv)
O
O
O
O
Ph
Ph
HO
Ph
2a
OMe
OMe
OMe
OMe
Ph
DMSO (0.2 M), rt, 24 h
ref 22b
Me
Me
Me
2a
2a
7a, <5%
11, 0%
22%
DBU
P(OMe)3
O2 (1 atm)
(2.0 equiv)
(1.5 equiv)
O
O
HO
Ph
2a
CH3CN (0.2 M), 40 oC, 20 h
ref 28
Ph
Me
7a, 46%
11, 20%
0%
The reported reaction conditions for the aerobic oxidation of carꢀ
bonyl compounds15e,15f,22b and vinylogous aerobic oxidation of β,γꢀ
unsaturated compound28 were also investigated for the γꢀ
hydroxylation of 2a (Scheme 2). Jiao’s transitionꢀmetalꢀfree condiꢀ
tion,15e for the αꢀhydroxylation of carbonyl compounds, was not effiꢀ
cient for the vinylogous oxidation of dienolates, as only 14% 7a
was obtained. Gnanaprakasam’s transitionꢀmetalꢀfree system15f was
unproductive and product 7a was not detected. Schoenebeck’s cataꢀ
lytic system22b using Cu2O as the catalyst was not effective for this
transformation either. At last, the condition reported from the total
synthesis of (±)ꢀandirolide N28 was less effective to produce 7a (46%
yield in addition to 20% acetophenone).
Table 2. Substrate Scope of γ,γ-Disubstituted β,γ-Unsaturated
Esters in Copper-Catalyzed Vinylogous Oxidation under Air
Atmospherea
2. Investigation of the Substrate Scope. The substrate scope of
γ,γꢀdisubstituted β,γꢀunsaturated esters was evaluated under the optiꢀ
mized reaction conditions (Table 2). In most cases, pure (E)ꢀβ,γꢀ
unsaturated esters were employed. However, due to the difficulty of
obtaining a single alkene isomer, in some instances (E)ꢀ/(Z)ꢀmixtures
were directly subjected to vinylogous oxidation for the exploration of
the substrate scope. A series of aromatic substituents were well tolerꢀ
ated at the R1 position. Both electronꢀdonating groups, such as methyl
(7b, 7n), phenyl (7c), methoxy (7d, 7o), dimethylamino (7e); and
electronꢀwithdrawing groups, such as fluoride (7f), chloride (7g, 7p),
bromide (7h, 7q), trifluoromethyl (7i), trifluoromethoxy (7j), methyl
ester (7k), nitro (7l) and cyano (7m), did not have a significant effect
on the yield. However, orthoꢀchlorophenyl led to moderate yield
possibly due to the increased steric hindrance (7r). Both 2ꢀnaphthyl
(7s) and 2ꢀthienyl (7t) were compatible, affording corresponding
products in good yield.
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The substituent at the R2 position was extended from methyl to
panded to the long alkyl chains containing various functional groups.
ethyl (7u), isopropyl (7v) and cyclopropyl (7w) successfully. In the
cases of substrates with bisꢀaliphatic substituents, vinylogous oxidaꢀ
tion was sluggish at room temperature. Thus an elevated reaction
temperature and oxygen balloon were required to obtain oxidized
products in moderate yield (7x–7aa). It is noteworthy that a trisubstiꢀ
tuted alkene was tolerated in the present oxidative conditions (7y).
Furthermore, β,γꢀunsaturated esters with other oxidation prone funcꢀ
tional groups, such as ketone (7ab) and unprotected secondary and
tertiary alcohols (7ac, 7ad), were also suitable substrates.
Product 7ah was generated in 32% yield presumably due to interferꢀ
ence of a primary alcohol unit. The reaction of TBSꢀprotected subꢀ
strate 12ai proceeded smoothly to give the product 7ai in 67% yield.
An acetal group was also tolerated under the present condition (7aj).
The ester 12ak containing a monoꢀsubstituted olefin was also a comꢀ
petent substrate, giving the product 7ak in 80% yield. The substrates
with two aliphatic substituents at the γꢀposition were completely inert
under the current catalytic system, presumably due to the increased
pKa of the γꢀproton in 12.
1
2
3
4
5
6
7
8
Table 3. Substrate Scope of γ,γ-Disubstituted α,β-Unsaturated
Esters in Copper-Catalyzed Vinylogous Oxidation under Air
Atmospherea
Table 4. Preliminary Substrate Scope of γ,γ-Disubstituted α,β-
Unsaturated Aldehydes and Ketones in Copper-Catalyzed Vi-
nylogous Oxidation under Air Atmospherea
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
28
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Unsaturated aldehydes and ketones were also submitted to the preꢀ
sent catalytic vinylogous aerobic oxidation condition (Table 4). α,βꢀ
Unsaturated aldehydes bearing an aryl and a methyl group at the γꢀ
position were smoothly converted to the corresponding γꢀhydroxylꢀ
α,βꢀ(E)ꢀunsaturated aldehydes in reasonably good yield (15a–15d).
The substrate derived from melonal (13e) was also suitable, leading to
15e in 52% yield in only 20 min. Moreover, both β,γꢀunsaturated
phenyl ketone and α,βꢀunsaturated phenyl ketone provided the same
product in good yield (16a), 67% and 54% yield respectively. The
oxidation of α,βꢀunsaturated methyl ketone afforded 16b in 76%
yield. Subjecting a prenyl phenyl ketone to the current catalytic sysꢀ
tem led to 16c in 70% yield. Both β,γꢀunsaturated and α,βꢀ
unsaturated cyclic ketones were oxidized to generate γꢀhydroxylꢀγꢀ
phenyl cyclohexanone (16d) in good yield. Again, γ,γꢀdialkylꢀ
substituted α,βꢀunsaturated ketone was completely inert under the
present condition.33
As α,βꢀunsaturated esters (12) are more commonly encountered in
organic synthesis, we wanted to extend the reaction conditions to
these substrates. However, the pKa of the γꢀproton in 12a is signifiꢀ
cantly higher than the pKa of αꢀprotons in 2a,32 which results in a
more challenging deprotonation step. By increasing the amount of
TMG to 1.2 equiv, the current catalytic system was successfully apꢀ
plied to γ,γꢀdisubstituted α,βꢀunsaturated esters (12) (Table 3). Variꢀ
ous α,βꢀunsaturated esters containing an aryl and a methyl substituent
at the γꢀposition were efficiently oxidized to generate γꢀhydroxylꢀα,βꢀ
(E)ꢀalkenoic esters in good yield (7a–7q, 7ae–7ag). However, a bulky
aryl group, such as orthoꢀmethyl phenyl (7af), had a diminishing
effect on the yield. It is encouraging that 2ꢀnaphthyl (7s) and 2ꢀthienyl
(7t) groups were wellꢀtolerated. The aliphatic substituent was not
limited to methyl, as substrates with ethyl (7u) and cyclopropyl (7w)
were competent substrates. The aliphatic substituent was further exꢀ
Table 5. Preliminary Substrate Scope of γ,γ-Disubstituted β,γ-
Unsaturated Nitriles, Amides and Sulfones in Copper-Catalyzed
Vinylogous Oxidation under Air Atmospherea
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Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
yield (21d). Moreover, a conjugated Weinreb amide substrate was
oxidized without difficulty (21a). As for the β,γꢀunsaturated phenyl
sulfones, several examples were studied, which gave γꢀhydroxylꢀα,βꢀ
(E)ꢀunsaturated sulfones in good yield (22a–22d). Moreover, vinyloꢀ
gous oxidation of trifluoromethyl sulfone proceeded smoothly to
afford product 22e in 55% yield.
1
2
3
4
5
6
7
8
R1
EWG
air balloon
HO
R1
EWG
R2
R2
THF (0.2 M), rt, t h
20-22
17-19
only
Me
E
A. EWG = CN, t = 16 h
Scheme 3. Copper-Catalyzed Bisvinylogous and Trisvinylogous
Aerobic Oxidation under Air Atmosphere
HO
Me
CN
HO
CN
HO
Ph Me
CN
9
20a, 86%
88%b
MeO
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
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27
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29
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
20b, 84%c
20c, 78%
HO
CN
HO
CN
Me
HO
CN
Et Et
Me
Me
Me
20d, 85%
20e, 71%d
20f, 54%d
B. EWG = amide, t = 12 h
O
Me
N
Me
X =
X =
N
O
HO
O
X
Me
Me
Ph Me
21a, 77%
21a, 81%e
X =
X =
N
Ph
N
X =
Bn
N
H
Bn
Since the vinylogous oxidation of unsaturated esters, aldehydes, keꢀ
tones, amides, nitriles and sulfones proceeded smoothly, we attempted
the more challenging selective bisvinylogous and trisvinylogous oxiꢀ
dation. As shown in Scheme 3, 23 was subjected to copperꢀcatalyzed
oxidation system and product 24 was isolated in 80% yield. It was
found that two equivalents of TMG was required for complete conꢀ
version. α,β,γ,δꢀUnsaturated aldehyde 25 was also tested under the
current catalytic system. To our delight, product 26 was obtained in
87% yield and the aldehyde functionality was left untouched under
the oxidation conditions. As for α,β,γ,δꢀunsaturated ketone 27, prodꢀ
uct 28 was generated in 81% yield. Encouragingly, a more challengꢀ
ing remote oxidation of substrate 29 to product 30 was successfully
achieved in 82% yield. Additionally, monoꢀγꢀsubstituted α,βꢀ
unsaturated or β,γꢀunsaturated esters were also studied and no satisꢀ
factory results were obtained.34
21d, 71%h
21b, 74%f
21c, 81%g
C. EWG = sulfone, 1.2 equiv TMG, 1.5 equiv PPh3, t = 16-48 h
O
O
O
O
HO
S
HO
S
O
O
Ph
Ph
HO
Ph Me
S
Ph
Me
Me
Cl
Me
22a, 85%
22b, 76%
22c, 75%
O
O
HO
S
Ph
O
O
HO
Ph Me
22e, 55%i
S
Me
CF3
22d, 82%
As shown in Tables 2ꢀ5, many substrates required slightly modified
reaction conditions. Generally, the substrates with higher pKa of αꢀ
protons or γꢀproton or steric hindrance at γꢀposition need increased
reaction time, such as 2d, 2e, 2r, 2u, 2v, 2w, 12b, 12d, 12e, 12u, 12w,
12afꢀ12ak. While α,βꢀunsaturated aldehydes and ketones needed less
TMG, β,γꢀunsaturated amides and sulfones required more equivalents
of TMG than corresponding esters. Moreover, α,βꢀunsaturated comꢀ
pounds require more TMG than β,γꢀunsaturated compounds, for exꢀ
ample, 2 (Table 2) vs 12 (Table 3), 16a and 16d (Table 4B), 20a (Taꢀ
ble 5A) and 21a (Table 5B). β,γꢀUnsaturated compounds with twoꢀ
alkyl substituents, such as 2xꢀ2aa, 17e and 17f, requires increased
amount of TMG and more forcing reaction conditions (refluxing and
oxygen instead of air). It is evident now that both the ease of deprotoꢀ
nation and the steric hindrance at the γꢀposition contributed to the
ease of reaction.
aIsolated yield reported on 0.2 mmol scale. , -Unsaturated , 1.2 equiv TMG and 1.5
b
17
equiv PPh3 were used. 12 h. c36 h. d3.0 equiv TMG and O2 were used. Reflux, 48 h. e , -
f
and 1.2 equiv TMG were used. 48 h. 1.2 equiv TMG was used. 50 oC, 54
18
Unsaturated
h. g1.2 equiv TMG was used. 79 h. h3.0 equiv TMG was used. 32 h. 0.4 equiv TMG and
i
1.3 equiv PPh3 were used. 5 h.
The applicability of the reaction conditions was further expanded to
unsaturated nitriles, amides and sulfones, which are showcased in
Table 5. β,γꢀUnsaturated nitriles bearing one aryl and one methyl
substituent were competent substrates and afforded corresponding
products in decent yield (20a–20d). An α,βꢀunsaturated nitrile was
also hydroxylated at γꢀposition successfully (20a). The propensity of
substrates containing two aliphatic substituents to undergo vinylogous
oxidation was diminished. Therefore, refluxing the reaction mixture
under an oxygen atmosphere and prolonged reaction time were reꢀ
quired to obtain the product in good yield of these difficult substrates
(20e–20f). A nitrile bearing two allylic methyl groups was also a
competent substrate under the current catalytic system (20f).
3. Insights to the Reaction Mechanism and Proposed Reaction
Pathways. Aside from facilitating deprotonation of the substrate,
TMG may also act as a ligand to a copper(II) salt to form a Cu(II)
complex,35 which may be the real catalyst. In the case of employing
Cu(I) salt, the oxidative atmosphere may transform it to correspondꢀ
ing Cu(II) salt and then Cu(II) catalyst could be accessed. Furtherꢀ
more, TMG may act as a weak reductant, as hppH has been reported
as a reductant in the oxidation of carbonyl compounds.22b,36 As shown
in Table 1 (entry 1), the γꢀhydroxylation without PPh3 led to the forꢀ
β,γꢀUnsaturated amides, including Weinreb amide (18a), pyrroliꢀ
dine amide (18b), dibenzyl amine amide (18c), were also evaluated.
The vinylogous oxidation of these amides proceeded smoothly to
afford products in reasonably good yield. The functional group comꢀ
patibility of the current catalytic system was further highlighted when
the aniline amide (18d), containing a free NꢀH, was oxidized in 71%
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Journal of the American Chemical Society
Page 6 of 11
mation of the product 7a in 33% yield. Additionally, when 31P NMR
of the reaction mixture was acquired the signals for PPh3 and P(O)Ph3
were observed, but no signal for a copperꢀPPh3 complex was detected.
It is therefore hypothesized that the role of PPh3 is to act as a stoichiꢀ
ometric reductant.
1
2
3
4
5
6
7
8
The performance of both (Z)ꢀ2a and (Z)ꢀ12a in the vinylogous oxiꢀ
dation were also evaluated (Scheme 4). Under the optimal reaction
1
conditions, the same product 7a was obtained in 78% H NMR yield
with 5% (Z)ꢀ2a recovered after the reaction was run for 82 hours,
which indicated that (Z)ꢀ2a was less reactive than (E)ꢀ2a. (Z)ꢀ12a was
the most inert, which afforded product 7a in 10% yield together with
88% recovered (Z)ꢀ12a in 90 h. These results suggest that the alkene
geometry effected the ease of deprotonation and thus had an imꢀ
portant influence on the reaction time. Moreover, the geometry of the
generated copper(II)ꢀdienolate complexes may also affect the reaction
rate.
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. 18O Labeling Experiment
Scheme 4. Catalytic Vinylogous Aerobic Oxidation of (E)-/(Z)-β,γ-
Unsaturated Esters and (E)-/(Z)-α,β-Unsaturated Esters (1H
NMR yield was given)
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
O
O
O
air balloon
Ph
HO
Ph
(E)-2a
OMe
OMe
Ph
THF (0.2 M), rt, 16 h
Me
Me
(E)-2a
7a, 90%
11, 8%
0%
E only
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
Scheme 6. Treating Product 7a with the Reaction Condition
O
O
O
air balloon
Me
HO
Ph
(Z)-2a
OMe
OMe
Ph
THF (0.2 M), rt, 82 h
Me
Ph
(Z)-2a
7a, 78%
11, 12%
5%
E only
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
O
O
O
air balloon
Ph
HO
Ph
(E)-12a
OMe
OMe
Ph
THF (0.2 M), rt, 60 h
An 18O labeling experiment was performed with 19a as the subꢀ
strate as shown in Scheme 5, which demonstrated that the oxygen
atom in the newly formed hydroxyl group originates from O2 rather
than surreptitious water. Experiments using mass spectrometry led to
the detection of 18Oꢀincorporated triphenyl phosphine oxide. These
observations demonstrate the fate of molecular oxygen is incorporaꢀ
tion into the alcohol product and oxidation of the terminal reductant.
In order to probe how the acetophenone (11) byproduct in the reaction
arises, product 7a was subjected to the standard reaction conditions
(Scheme 6), and 100% 7a was recovered without any 11. This control
experiment demonstrated that the formation of acetophenone was not
generated from decomposition or overꢀoxidation of 7a, which sugꢀ
gests that 11 is formed by an alternative pathway from the starting
material 2a.
Me
Me
(E)-12a
7a, 82%
11, 18%
0%
E only
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
Ph
Me
O
O
O
air balloon
HO
Ph
(Z)-12a
OMe
OMe
Ph
THF (0.2 M), rt, 90 h
Me
(Z)-12a
7a, 10%
11, 1.5%
88%
E only
The vinylogous oxidation of 2a proceeded in equal efficiency with
TEMPO or 1,1ꢀdiphenylethylene as an additive. These two experiꢀ
mental observations argue against a radical based mechanism and
suggest a twoꢀelectron process is operative (Table 6, entry 2 and 3).
Vinylogous oxidation of 2a also proceeded nicely in the dark or in the
presence of DABCO, indicating that singlet oxygen was not involved
in the reaction process (Table 6, entry 4 and 5).15e, 37
Scheme 7. Efforts to Capture a Peroxide Species through an In-
tramolecular Oxo-Michael Addition
Table 6. Catalytic Vinylogous Aerobic Oxidation under Some
Special Conditionsa
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1
2
3
4
5
6
7
Journal of the American Chemical Society
A. Capture of a Peroxide Species
O
Scheme 8. Proposed Mechanism for the Copper-Catalyzed Aero-
bic Vinylogous Oxidation
O
O
Ph
O
Cu(OTf)2
TMG
(5 mol %)
(1.2 equiv)
Ph
Ph
OMe
OMe
OMe
OH
O
air balloon
THF (0.2 M), rt
O
Me
Me
O
Me
O
31
32
33
with PPh3 (1.5 equiv), 36 h
without PPh3, 11 h
40%, dr = 1/1
80%, dr = 1/1
23%, dr = 1/1
0%, dr = 1/1
8
9
B. 18O Labeling Experiment
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
Cu(OTf)2
TMG
(5 mol %)
(1.2 equiv)
Ph
Ph
OMe
OMe
O2/18O2 (1/1) balloon
OH
O
SM
THF (0.2 M), rt, 24 h
Me
O
Me
O
32, 68%, dr = 1/1
normal product
relative intensity: 100%
5%
31
[M+Na]+
[M+Na+4]+
[M+Na+2]+
18O product
relative intensity: 68%
relative intensity: 5%
C. Possible Pathways to Generate 32 and 33
O
Although speculative at this juncture,16 we proposed a plausible reꢀ
action pathway for this vinylogous oxidation as shown in Scheme 8.
The copper(II) complex V is formed through the coordination of
TMG to copper(II) triflate.35 In the presence of TMG, copper(II)
dienolate W is generated, which would have an equilibrium with allyl
copper(II) species X. It would be expected that oxidation of W would
result in αꢀoxidation, while oxidation of X would result in γꢀoxidation
and lead to the formation of a copper(II) peroxide species Y. Peroxide
Y would be reduced through attack of PPh3 at the less hindered distal
peroxide oxygen atom to generate an alkoxide, which would be proꢀ
tonated to afford the final product 7a and regenerate the copper(II)
complex V. Alternatively, the intermediate Y could afford a fourꢀ
membered endoꢀperoxide Z by an intramolecular oxaꢀMichael addiꢀ
tion, which collapses to give the side product acetophenone (11) and
regenerate the copper(II) complex V. An additional possibility that
cannot be ruled out at this time is the role of bimetallic copper comꢀ
plexes, including those with bridging oxygen ligands.38
O
O
Ph
Ph
O
Ph
OMe
OMe
OMe
O
O
H
32
O
O
O
O
Me
Me
C
Me
A
B
O
O
O
O
O
Ph
Ph
Ph
OMe
OMe
OMe
O
O
O
O
O
PPh3
H
O
33
Me
Me
A
D
E
O
Dienone 31, containing an additional α,βꢀunsaturated ketone unit,
was designed to capture the suspected peroxide species (Scheme 7A).
In accord with literature precedent on the oxidation of enolates with
molecular oxygen,16 it was our expectation that the present vinylogous
oxidation proceeds via a peroxide intermediate such as A (Scheme
7C). When compound 31 was subjected to the standard reaction conꢀ
dition, products 32 and 33 were separately formed in 40% and 23%
yield, respectively, as mixtures of diastereomers (1:1 dr) (Scheme 7A).
The expected product 33 presumably arises via an oxaꢀMichael reacꢀ
tion after γꢀhydroxylation occurs, while product 32 represents an
overꢀoxidation product. Product 32 could be formed as outlined in
Scheme 7C, wherein the initially formed γꢀperoxy intermediate A
undergoes an oxaꢀMichael reaction before reduction of the peroxide
can occur. The resulting intermediate B would then be expected to
decompose to the observed product 32 via the alkoxide C. It was
therefore hypothesized that in the absence of PPh3 a greater quantity
of 32 would be formed. Indeed, in the absence of PPh3 product 32 was
isolated in 80% yield and 1:1 dr (Scheme 7A).
Scheme 9. Copper-Catalyzed 10 g-Scale Vinylogous Aerobic Oxi-
dation
4. Scalability of Vinylogous Oxidation Condition. The robustness
of the present vinylogous hydroxylation was showcased by a 10 gꢀ
scale oxidation of 2a. As shown in Scheme 9, 8.93 grams of product
7a was isolated in 82% yield, which demonstrated that the 10 gꢀscale
reaction had the same efficiency as the milligramꢀscale reaction.
Moreover, the vinylogous oxidation performed in 10 gꢀscale in the
open air also proceeded in the same efficiency (see SI). An initial
clear pale yellow mixture gradually changed to green, finally to dark
green.
The decomposition of the endoperoxide B to the product 32 via this
pathway would require that both oxygen atoms incorporated are deꢀ
rived from the same molecule of O2. To evaluate whether this is the
case or if the two oxygen atoms are introduced independently, we
conducted an experiment using a 1:1 mixture of O2 and 18O2 (Scheme
7B). If the oxygen atoms are derived from one molecule of O2, as in
endoperoxide B, we would expect a distribution of the doubly labeled
16O product and the doubly labeled 18O product. While if the epoxide
32 is formed by an alternative other pathway involving two discrete
molecules of O2, we would expect a statistical distribution of products.
Analysis of the mass spectrum data provided direct evidence that one
molecule of O2 leads to the product 32 consistent with the intermediaꢀ
cy of the endoperoxide B.
Scheme 10. Application of the Present Catalytic Vinylogous Aer-
obic Oxidation to Structure Modification and Total Synthesis of
Natural Products
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Page 8 of 11
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.2 equiv)
(1.3 equiv)
servations. It was postulated that TMG is not only a base for the
deprotonation but also a ligand for copper(II) salt to form the real
Me
Me
O
O
1
2
3
4
5
6
7
8
H
H
HO
copper (II) catalyst. Finally, the utility of this hydroxylation methodꢀ
ology was showcased with the selective modification of natural prodꢀ
uct derivatives and the preparation of an advanced synthetic intermeꢀ
diate for the total synthesis of (±)ꢀandirolide N. Application of the
vinylogous oxidation to other problems in multistep synthesis, as well
as development of a catalytic asymmetric version is currently under
investigation in our laboratories.
air balloon
H
H
THF (0.2 M), rt, 17 h
H
H
O
O
O
O
34
35, 56%
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.2 equiv)
(1.3 equiv)
Me
Me
OH
OH
H
H
HO
air balloon
H
H
H
H
THF (0.2 M), rt, 20 h
Me
Me
ASSOCIATED CONTENT
Supporting Information
9
36
37, 56%
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
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.2 equiv)
(1.3 equiv)
Me
Me
OH
O
O
The Supporting Information is available free of charge on the ACS
Publications website at:
H
H
Me
Me
air balloon
HO
HO
Experimental procedures, Xꢀray diffraction, spectroscopic
data for all new compounds including 1H, 19F and 13C NMR
spectra (PDF)
H
H
THF (0.2 M), rt, 24 h
H
H
38
39, 55%
Crystallographic data (CIF)
Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.8 equiv)
(1.3 equiv)
O
O
H
AUTHOR INFORMATION
Corresponding Author
H
H
O
O
air balloon
O
O
Me
O
Me
iso-odoratin (40)
Me
H
H
THF (0.2 M), rt, 5 h
*liangyin@sioc.ac.cn
*timothy.newhouse@yale.edu
ORCID
Liang Yin: 0000ꢀ0001ꢀ9604ꢀ5198
Timothy R. Newhouse: 0000ꢀ0001ꢀ8741ꢀ7236
Notes
Me
O
OH
H
41, 65%
5. Application of the Present Methodology. The utility of this γꢀ
hydroxylation methodology was showcased for the modification of
natural product derivatives (Scheme 10). For example, estrꢀ5(10)ꢀeneꢀ
3,17ꢀdione (34) was selectively oxidized under the standard condition
to afford 10βꢀhydroxyestrꢀ4ꢀeneꢀ3,17ꢀdione (35) in 56% yield. Both
the allylic and tertiary CꢀH bonds were left intact under the oxidation
condition. Tibolone (36), a synthetic steroid drug used mainly for
treatment of endometriosis, was submitted to standard vinylogous
oxidation condition and oxidized to 37 in 56% yield, which represents
a fast and effective method to access Tibolone derivatives. Moreover,
3βꢀhydroxyandrostaꢀ5,15ꢀdienꢀ17ꢀone (38) was also a competent
substrate for the current vinylogous oxidation reaction, which was
selectively oxidized to give 3β,14βꢀdihydroxyandrostaꢀ5,15ꢀdienꢀ17ꢀ
one (39) in 55% yield. The spectral data for products 3539 and 3940 are
in agreement with the data previously reported; product 37 was charꢀ
acterized by Xꢀray crystallography. The prevalence of unsaturated
carbonyl functionalities in synthetic intermediates and natural prodꢀ
ucts makes the present method very attractive to carry out remote
oxidation rapidly and efficiently.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the “Thousand
Youth Talents Plan”, the National Natural Sciences Foundation of
China (No. 21672235), the Strategic Priority Research Program of the
Chinese Academy of Sciences (No. XDB20000000), the “Shanghai
RisingꢀStar Plan” (No. 15QA1404600), CAS Key Laboratory of Synꢀ
thetic Chemistry of Natural Substances, the National Institutes of
Health (1R01ꢀGM118614ꢀ01A1), the National Science Foundation
(GRFP to A.W.S.), Bristol Myers Squibb (fellowship to A.W.S.),
Nalas Engineering, the Sloan Foundation, Yale University, and
Shanghai Institute of Organic Chemistry. Additionally, Professor Dr.
Jinꢀhan Gui and Dr. Kai Ding at Shanghai Institute of Organic Chemꢀ
istry are acknowledged for their generous offer of some commercially
available steroids.
REFERENCES
The present vinylogous oxidation system was also employed in the
synthesis of a natural product (Scheme 10). Isoꢀodoratin (40), which
has multiple sites of potential oxidation, was subjected to the standard
oxidation condition and selectively transformed to the corresponding
γꢀhydroxylated compound (41), a lateꢀstage intermediate in the synꢀ
thesis of (±)ꢀandirolide N,28 in 65% yield. The success of the standard
reaction condition with this complex substrate suggests that these
conditions may be quite general and see use in numerous other conꢀ
texts.
(1) (a) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D.
H. B. Chem. Rev. 2006, 106, 2943–2989. (b) Piera, J.; Bäckvall, J.ꢀE.
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GarciaꢀBosch, I.; Company, A.; Frisch, J. R.; TorrentꢀSucarrat, M.;
Cardellach, M.; Gamba, I.; Güell, M.; Casella, L.; Que, L.; Ribas, X.;
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Chem., Int. Ed. 2014, 53, 3205–3209. (d) Liang, Y.ꢀF.; Jiao, N. Acc.
Chem. Res. 2017, 50, 1640–1653.
CONCLUSION
In conclusion, an operationally simple and highly efficient catalytic
system, using copper(II) triflate, TMG, PPh3 and air, was developed.
The present catalytic system for vinylogous aerobic oxidation was
suitable for both γ,γꢀdisubstitutedꢀβ,γꢀunsaturated esters and γ,γꢀ
disubstitutedꢀα,βꢀunsaturated esters. A series of functional groups
(such as tertiary amine, nitro, ester, nitrile, ketone, primary, secondary
and tertiary alcohol, TBSꢀether, acetal and olefin) were well tolerated.
Unsaturated aldehydes, ketones, amides, nitriles and sulfones were
also viable substrates. Furthermore, a mechanism for the vinylogous
aerobic oxidation has been proposed based on the experimental obꢀ
(4) Foote, C. S.; Valentine, J. S.; Greenberg, A.; Liebman, J. F. Eds.,
Active Oxygen in Chemistry, Blackie Academic & Professional:
London, 1995.
(5) For some recent reviews on transition metalꢀcatalyzed aerobic oxidaꢀ
tion: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420. (b)
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Journal of the American Chemical Society
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1
2
3
4
5
6
7
8
(13) For some very recent examples on copperꢀcatalyzed aerobic oxidaꢀ
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(22) (a) Arai, T.; Sato, T.; Noguchi, H.; Kanoh, H.; kaneko, K.; Yanagꢀ
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(30) The γꢀhydroxylation of 2a with P(OEt)3 failed at room temperature.
However, 40% 7a was obtained when the reaction was heated at 55
oC for 24 h.
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(35) The complex of TMG and Cu(II) was reported, see : Longhi, R.;
Drago, R. S. Inorg. Chem. 1965, 4, 11ꢀ14.
(36) Both TMG and hppH belong to guanidine, whose structures were
depicted below.
(31) Several triaryl phosphines were examined in the γꢀhydroxylation of
2a. Except for the electronꢀrich P(4ꢀMeOꢀC6H4)3, other phosphines
led to 7a in good yield. Particularly, both (R)ꢀBINAP and (R)ꢀTolꢀ
BINAP (0.65 equiv) worked with equal efficiency as PPh3. The
product 7a was obtained in good yield but without any asymmetric
induction. Therefore, it is less likely that the complex of phosphine
and copper(II) or copper(I) was involved as a catalyst in the present
vinylogous hydroxylation.
(37) Quannes, C.; Wilson, T. J. Am. Chem. Soc. 1968, 90, 6527–6528.
(38) Elwell, C. E.; Gagnon, N. L.; Neisen, B. D.; Dhar, D.; Spaeth, A. D.;
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(39) Buděšínský, M.; Fajkoš, J.; Günter, J.; Kasal, A. Collect. Czech.
Chem. Commun. 2005, 70, 507ꢀ518.
Cu(OTf)2
TMG
(5 mol %)
(0.8 equiv)
phosphine (1.3 equiv)
air balloon
O
O
O
(40) Reich, I. L.; Reich, H. J.; Kneer, N.; Lardy, H. Steroids 2002, 67,
221ꢀ233.
Ph
HO
Ph
OMe
OMe
Ph
11
THF (0.2 M), rt, t h
Me
7a
Me
2a
entrya
phosphine
PPh3
t
yield of 7a
91%
yield of 11
8%
10
18
10
11
10
9
1
86%
P(Tol)3
13%
8%
2
90%
P(4-F-C6H4)3
P(4-CF3-C6H4)3
P(4-MeO-C6H4)3
(R)-BINAP
3
77%
4
14%
trace
8%
5b
6c
7c
trace
81%, 0% ee
82%, 0% ee
(R)-Tol-BINAP
9
7%
a1H NMR yield reported on 0.2 mmol scale. b2a remained and unchanged. c0.65
equiv bisphosphine employed.
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Cu(OTf)2
TMG
PPh3
(5 mol %)
(0.2-2.0 equiv)
(1.3-1.5 equiv)
R1
R1
EWG
EWG
1
2
3
4
R2
R2
HO
R1 R2
EWG
air balloon
or
THF (0.2 M), rt
E only
>90 examples
32-92%
5
6
EWG = aldehyde, ketone, ester,
amide, nitrile, sulfone
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