Copper-catalyzed intramolecular oxidative 6-exo-trig cyclization of 1,6-enynes with H2O and O2

Article abstract of DOI:10.1002/anie.201104082

The novel CuCl₂-catalyzed title reaction of enynes has been developed for synthesizing substituted naphthoquinones (see scheme; DMA=dimethylacetamide). The method represents the first example of a copper-catalyzed enyne oxidative cyclization for constructing 1,4-naphthoquinones by the incorporation of two oxygen atoms into the organic framework from molecular oxygen and water.

Full text of DOI:10.1002/anie.201104082

Communications
DOI: 10.1002/anie.201104082
Synthetic Methods
Copper-Catalyzed Intramolecular Oxidative 6-exo-trig Cyclization of
1,6-Enynes with H2O and O2**
Zhi-Qiang Wang, Wen-Wu Zhang, Lu-Bin Gong, Ri-Yuan Tang, Xu-Heng Yang, Yu Liu, and
Jin-Heng Li*
Transition-metal-catalyzed cyclization of 1,n-enynes has
attracted significant interest because of their synthetic utility,
and it is now used as a rapid and powerful approach to
prepare cyclic derivatives in organic synthesis.[1–8] In partic-
ular, these cyclization transformations are highly efficient and
atom economical, and provide opportunities to discover new
reactions. Despite considerable progress in the field, the
development of mild 1,n-enyne cyclization routes using
inexpensive catalytic materials to construct new, complex
compounds remains a challenge. Copper catalysts are widely
used in organic synthesis;[2] however, examples of copper-
catalyzed 1,n-enyne cyclizations are rare and all reports to
date focus on the use of CuI salts.[3] The key obstacle to CuI
catalysts is that they have a far stronger affinity for alkynes
than alkenes,[2a,4a–d] which results in the addition of more
nucleophilic reagents (often H2O, amines, acids, and alcohols)
rather than alkenes to alkynes.[2,4] Although this obstacle does
not favor the classical 1,n-enyne cyclization reaction, it may
facilitate 1,n-enyne cyclizations that include the simultaneous
Scheme 1. Routes to substituted 1,4-naphthoquinones. DMA=di-
introduction of other more nucleophilic reagents and alkenes
to alkynes. After a series of trials, we found that Ce(SO4)2
facilitated CuCl2-catalyzed oxidative 6-exo-trig cyclization of
enynes with H2O for preparing 1,4-naphthoquinones using O2
as an oxidant and a reactant under mild reaction conditions
(Scheme 1a).[5,6] The method is the first example of using a
CuII catalyst for the oxidative cyclization of enynes, in which
1,4-naphthoquinones are constructed by the incorporation of
two oxygen atoms from molecular oxygen[5c] and water into
the organic framework of the product.
methylacetamide, LG=leaving group.
(most notably Vitamin K), and functional materials (dyes
and pigments).[7] The traditional route to 1,4-naphthoqui-
nones is the oxidation of substituted naphthols, naphthyl
amines, or naphthalenes.[8] However, this method often
furnishes products in low to moderate yields, and has low
functional group compatibility. Owing to these drawbacks,
several powerful alternative methods have arisen, including
(Scheme 1b): 1) the Diels–Alder reaction of substituted 1,3-
dienes with preexisting quinones (path a),[9] 2) the reaction of
alkynes with metal carbonyls (path b),[10] 3) thermo cyclo-
isomerization of cyclobutenones (path c),[11] and 4) the
annulation of Fischer carbene complexes with alkynes (path
d).[12] As shown in Scheme 1, we herein describe an efficient
example of achieving 1,4-naphthoquinones by catalytic oxi-
dative 6-exo-trig cyclization of enynes with H2O and O2 using
a simple and inexpensive copper salt as the catalyst.
(Scheme 1).
Our investigation began with the reaction of (E)-3-
phenyl-1-(2-(2-phenylethynyl)phenyl)prop-2-en-1-one (1a)
with CuCl2 and O2 in THF at 808C; however, only a trace
amount of the target 6-exo-trig cyclization product 2a was
observed (Table 1, entry 1).[13] Substrate 1a could be success-
fully cyclized with 10 mol% CuCl2 and 1 atm O2 at 808C, thus
affording the desired product 2a in 42% yield, using DMF as
the solvent (entry 2). It is noteworthy that the yield is reduced
to 38% using air instead of O2 (entry 3). The yield was
increased to 60% when the reaction was carried out in DMA
Quinones, particularly 1,4-naphthoquinones, are valuable
synthetic intermediates, and important structural units found
in numerous natural products, pharmaceutical molecules
[*] Z.-Q. Wang, L.-B. Gong, X.-H. Yang, Y. Liu, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan University
Changsha 410082 (China)
E-mail: jhli@hunnu.edu.cn
Z.-Q. Wang, L.-B. Gong, X.-H. Yang
Key Laboratory of Chemical Biology & Traditional Chinese Medicine
Research (Ministry of Education), Hunan Normal University
Changsha 410081 (China)
W.-W. Zhang, R.-Y. Tang
College of Chemistry and Materials Engineering
Wenzhou University, Wenzhou, 325035 (China)
[**] We thank the Natural Science Foundation of China (No. 20872112)
and the Scientific Research Fund of Hunan Provincial Education
Department (No. 08A037) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104082.
8968
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Angew. Chem. Int. Ed. 2011, 50, 8968 –8973

Table 1: Screening optimal conditions.[a]
(N,N-dimethylacetamide; entry 4). In light of these results, a
series of other copper catalysts, CuBr2, Cu(OTf)2, Cu(OAc)2,
and CuCl, were evaluated. Only CuBr2 displayed high
catalytic activity, whereas the other copper catalysts were
less effective.[13] Screening revealed that the yield was
enhanced slightly to 65% when 150 mol% K2S2O8 was
added (entry 5). We found that the amount of CuCl2 has an
effect on the reaction: the yield of 2a using 20 mol% CuCl2
was the same as when 10 mol% CuCl2 was used (entry 6), but
was lowered to 58% when 5 mol% CuCl2 was used (entry 7).
Notably, the reaction cannot take place without either Cu
catalysts or O2 (entries 8 and 9). Examination of the reaction
temperature revealed that the optimal temperature was 808C
(entries 5, 10, and 11). Satisfactory yields are still obtained
from the reaction of 1 mmol of substrate 1a with CuCl2, O2,
and K2S2O8 (entry 12). Prompted by the above results, a
number of other oxidative additives, such oxone, PhI(OAc)2,
BPO, mCPBA, (NH4)2Ce(NO3)6, and Ce(SO4)2·4H2O, were
investigated (entries 13–18). Although five additives, oxone,
PhI(OAc)2, BPO, mCBPA, and (NH4)2Ce(NO3)6, displayed
the same effect as K2S2O8 (entries 13–17), Ce(SO4)2 was the
most efficient and enhanced the yield to 80% (entry 18).
Finally, the amount of CuCl2 was tested without any additives
(entries 19 and 20). The results showed yield identical to that
of 10 mol% CuCl2 when using 50 mol% CuCl2 (entry 19), but
the yield was decreased to 47% when the amount of CuCl2
was enhanced to 100 mol% (entry 20).
Entry [Cu]
(mol%)
Gas Additive
T [oC] Solvent Yield [%][b]
1
2
3
4
5
6
7
8
9
10
CuCl2 (10) O2
–
–
–
–
80
80
80
80
80
80
80
80
80
THF
trace
42
38
60
65
67
58
0
CuCl2 (10) O2
CuCl2 (10) air
CuCl2 (10) O2
CuCl2 (10) O2 K2S2O8
CuCl2 (20) O2 K2S2O8
DMF
DMF
DMA
DMA
DMA
DMA
DMA
DMA
CuCl2 (5)
–
O2 K2S2O8
O2 K2S2O8
CuCl2 (10) Ar
K2S2O8
0
CuCl2 (10) O2 K2S2O8
100 DMA
67
52
68
63
60
58
70
55
80
56
47
11[c] CuCl2 (10) O2 K2S2O8
60
80
80
80
80
80
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
12[d] CuCl2 (20) O2 K2S2O8
13
14
15
16
17
18
19
20
CuCl2 (10) O2 oxone
CuCl2 (10) O2 PhI(OAc)2
CuCl2 (10) O2 BPO
CuCl2 (10) O2 mCPBA
CuCl2 (10) O2 (NH4)2Ce(NO3)6 80
CuCl2 (10) O2 Ce(SO4)2·4H2O 80
CuCl2 (50) O2
CuCl2 (100) O2
–
–
80
80
[a] Reaction conditions: 1a (0.2 mmol), [Cu], gas (1 atm), additive
(1.5 equiv), and solvent (3 mL) for 24 h. About 0.1% (v/v) of water is
contained in solvent. [b] Yield of isolated product. [c] For 36 h. [d] 1a
(1 mmol). BPO=benzoyl peroxide; mCPBA=meta-chloroperbenzoic
acid, DMF=N,N’-dimethylformamide, THF=tetrahydrofuran.
The scope was explored under the optimal reaction
conditions and the results are summarized in Table 2.[13]
Initially, substituents on the aromatic moiety at the terminal
alkyne were investigated: the activity of the substrates with
substituents is: para position > meta position > ortho posi-
Table 2: CuCl2-catalyzed synthesis of 1,4-naphthoquinones 2.[a]
Entry 1,4-Naphthoquinone 2
Yield CuCl
T
t
Entry 1,4-Naphthoquinone 2
Yield CuCl
T
t
[%][b] [mol%] [8C] [h]
[%][b] [mol%] [8C] [h]
1[c]
2b
2c
2d
2e
8
30
10
10
30
100 48
13
2n 70
2o 75
2p 73
2q 63
10
10
30
30
80
80
24
24
2
3
4
50
70
85
80
80
24
24
14
15
16
100 30
100 30
100 24
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Communications
Table 2: (Continued)
Entry 1,4-Naphthoquinone 2
Yield CuCl
T
t
Entry 1,4-Naphthoquinone 2
Yield CuCl
T
t
[%][b] [mol%] [8C] [h]
[%][b] [mol%] [8C] [h]
5
6
2 f
65
80
50
10
100 24
17
2r
65
30
50
100 24
100 24
2g
80
80
24
24
18
2s
2t
61
80
7
2h
2i
55
45
50
10
50
50
19
20
21
30
50
30
100 24
100 24
100 24
8[c]
100 48
100 48
2u 67
9[c]
2j
2v
39
2w 36
10[d]
2k
43
76
50
100 48
22
23
10
50
80
24
4w 26
11
12
2l
10
10
80
80
24
24
2x
51
100 48
2m 69
[a] Reaction conditions: 1a (0.2 mmol), CuCl2 (10 mol%), O2 (1 atm), Ce(SO4)2·4H2O (150 mol%), and DMA (0.1% v/v of water; 3 mL) at 808C.
[b] Yield of isolated product. [c] Substrate was consumed completely, and some unidentified products were observed by GC/MS analysis. [d] A by-
product, (E)-1-(2-cinnamoylphenyl)-2-cyclohexenylethane-1,2-dione (3k), was isolated in 16% yield.
tion. While substrates bearing an ortho- or meta-methyl group
were treated with CuCl2, O2, and Ce(SO4)2 to afford the
corresponding 6-exo-trig cyclization products 2b and 2c in
low to moderate yields, the substrate with a para-methyl
group provided the desired product 2d in a good yield. Other
substituents, such as Cl and NO2 groups, were found to be
tolerated under the optimal conditions (2e–2g). Notably, the
thiophen-2-yl-substituted substrate successfully underwent
the annulation reaction with CuCl2, O2, and Ce(SO4)2 in
moderate yield (2h). Moderate yields were found to be still
achievable from terminal alkynes, aliphatic alkynes, and
enynes under the same reaction conditions (2i–2k). By
using (E)-1-(2-ethynylphenyl)-3-phenylprop-2-en-1-one (a
terminal alkyne), for instance, the cyclization reaction
proceeded smoothly to form the corresponding 2-benzoyl-
naphthalene-1,4-dione (2i) in 45% yield. Suprisingly, treat-
ment of (E)-1-(2-(cyclohexenylethynyl)phenyl)-3-phenyl-
prop-2-en-1-one, bearing a cyclohexenyl group, with CuCl2,
O2, and Ce(SO4)2 afforded the cyclization/cyclohexenyl
epoxidation product 2k in 43% yield together with a by-
product, (E)-1-(2-cinnamoylphenyl)-2-cyclohexenylethane-
1,2-dione (3k), in 16% yield.[14] Substrates with substituents
such as Me, CF3, and F, on the aromatic ring adjacent to a
ketone were also suitable for the reaction (2l–2n). For
example, an F-substituted substrate furnished the desired
product 2n in 70% yield. The results disclosed that several
functional groups, such as methyl, chloro, nitro, methoxy,
iodo, and bromo groups on the aryl ring at the terminal prop-
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Angew. Chem. Int. Ed. 2011, 50, 8968 –8973

2-en-1-one were perfectly compatible with the optimal
conditions, affording the corresponding products 2o–2u in
moderate to good yields.
[18O2]-3k containing two 18O atoms [Eq. (1)].[14] Unfortu-
nately, the product [18O2]-3k could not be converted into the
desired cyclization product under standard conditions. It was
interesting to disclose that the reaction of substrate 1a with
10 equivalents of H218O, CuCl2, and O2 furnished the 18O-
atom-containing product [18O]-2a as determined by GC/MS
and HRMS (ESI) analysis in the presence/absence of
additives [Eq. (2)]. The results reveal the source of two new
oxygen atoms in product 2: one oxygen atom is from water
through a Wacker-type oxidation reaction,[14] and the other
oxygen atom is from O2.[5b] Moreover, the oxygen atom of the
2-benzoyl moiety is from H2O according to authoritative
13C NMR spectra of products 2a and [18O]-2a.[17] The reaction
between substrates 1a and ethyl 2-diazoacetate (5) was
carried out to examine whether the copper carbene inter-
mediate exists:[18] only product 2a (45% yield) together with
product 6 (93% yield) were obtained [Eq. (3)]. The carbene
product 7k was not observed from the reaction of 1k with 5
[Eq. (4)]. The cyclization reactions of substrates 8, either (E)-
Importantly, the chloro, iodo, and bromo substitutions (2p
and 2r–2u) can be tolerated in this annulation reaction,
thereby facilitating additional modifications at the halogen-
ated positions. Moreover, some heterocycles (2u, 2w, and 2x)
or olefins (2v) were introduced into this system, which also
makes this methodology more useful for the preparation of
pharmaceuticals and natural products.[15] Interestingly,
another 5-exo-dig cyclization product 4w was isolated from
the reaction of (E)-3-(furan-2-yl)-1-(2-(phenylethynyl)-
phenyl)prop-2-en-1-one besides the desired product 2w.
However, aliphatic alkyne only furnished the 6-exo-trig
cyclization product 2x in 51% yield. The reason may be
that the vinylfuran moiety is highly active, thus resulting in the
occurrence of a Diels–Alder reaction with arylalkynes in the
presence of Lewis acids.[16]
To elucidate the mechanism, some control experiments
were carried out (Scheme 2).[13] It was surprising to find that
the reaction of substrate 1k with H218O, CuCl2, an additive
(Ce(SO4)2 or K2S2O8), and O2 afforded the diketone product
3-phenyl-1-(2-(2-phenylacetyl)phenyl)prop-2-en-1-one
or
(E)-1-phenyl-2-(2-(3-phenylacryloyl)phenyl)ethane-1,2-dione,
did not take place under the optimal reaction conditions and
only a trace of olefin Wacker oxidation products 9 was
observed [Eq. (5)], thus indicating that the reaction does not
include the alkyne hydrolysis.[14,19] Notably, a stoichiometric
amount of two radical inhibitors, TEMPO or 1,1-diphenyle-
thene, were also tested with substrate 1a: greater than 90% of
1a was recovered together with a trace of target product 2a,
thereby suggesting that the reaction proceeds through a
radical process.
Consequently, a possible mechanism as outlined in
Scheme 3 is proposed.[1,2,4,5] Complexation of CuCl2 with
substrate 1a yields the intermediate A, followed by sequen-
À
tial Wacker oxidation of the C C double bond with H2O
(intermediate B)[14] and intramolecular cyclization to afford
intermediate C. Oxidation of intermediate C with O2 leads to
the peroxycopper(III) intermediate D with the aid of the
oxidative additive.[5] Reductive elimination of intermediate D
gives rise to the formation of the peroxycopper(II) com-
plex E.[5] Finally, the O O bond cleavage of the peroxycop-
À
per(II) complex E and oxidization of the alcohol delivers the
desired product 2a and Cu(OH)Cl. The active CuII species
can be regenerated by the reaction of Cu(OH)Cl with HCl.
Scheme 2. Control experiments.
Scheme 3. Possible mechanism.
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Communications
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There are at least two roles of the oxidative additives in this
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In summary, we have described that inexpensive CuCl2
can catalyze the intramolecular oxidative carbocyclization of
(E)-3-aryl-1-(2-(arylethynyl)aryl)prop-2-en-1-ones with high
substituent compatibility using O2 as both the terminal
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[6] Until now, only few examples of the oxidative 1,n-enynes
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substrates. See: a) L. L. Welbes, T. W. Lyons, K. A. Cychosz,
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Experimental Section
Typical experimental procedure for the CuCl2-catalyzed intramolec-
ular oxidative cyclization of alkynes with alkenes: (E)-3-aryl-1-(2-(2-
arylethynyl)phenyl)prop-2-en-1-one 1 (0.2 mmol), CuCl2 (10 mol%),
Ce(SO4)2·4H2O (150 mol%), and DMA (3 mL) were added to a
Schlenk tube. The tube was then charged with O2 (1 atm), and the
reaction mixture stirred at 808C (oil bath temperature) for the
indicated time until complete consumption of starting material as
monitored by TLC and GC/MS analysis. After the reaction was
finished, the reaction mixture was cooled to room temperature,
diluted in ethyl acetate, and washed with brine. The aqueous phase
was re-extracted with ethyl acetate. The combined organic extracts
were dried over Na2SO4, concentrated under vacuum, and the
resulting residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate 4:1) to afford the desired product 2.
Received: June 14, 2011
Published online: August 19, 2011
Keywords: copper · enyne · heterocycles · oxidative cyclization ·
.
oxygen
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Angew. Chem. Int. Ed. 2011, 50, 8968 –8973
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www.angewandte.org
8973