Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C-Br/C-H Functionalization

Article abstract of DOI:10.1021/acs.orglett.8b01962

Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)₄PF₄ catalyst and 1,10-phenanthroline (1,10-Phen) ligand enables the formation of three new C-C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency.

Full text of DOI:10.1021/acs.orglett.8b01962

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[4 + 2] Annulation Cascades of 2‑Bromo-1-arylpropan-1-ones with
Terminal Alkynes Involving C−Br/C−H Functionalization
Xuan-Hui Ouyang,†,§ Chao Hu,†,§ Ren-Jie Song,*,† and Jin-Heng Li*,†,‡
†Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: Straightforward access to various substituted
naphthalenones by copper-catalyzed [4 + 2] annulation
cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes
is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10-
phenanthroline (1,10-Phen) ligand enables the formation of
three new C−C bonds in a single reaction via [4 + 2]
annulation of a 2-bromo-1-arylpropan-1-one with an alkyne
followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step
efficiency.
aphthalenones are an important class of structural motifs
found in bioactive compounds and natural products.1 As
an example, Perenniporide A (Figure 1) showed antifungal
bromo-1,3-dicarbonyl compounds in the presence of Ir-
(ppy)2(dtbbpy)PF6 catalysis (Scheme 1a).5 Recently, the
N
Scheme 1. Tandem Annulation of 2-Bromo-1-arylpropan-1-
ones and Alkynes
application of α-bromo carbonyl compounds6,7 have long
attracted attention from our group and other chemists. In light
of the role of naphthalenones and our interest in the
development of the annulation reactions of α-bromo carbonyl
compounds, herein, we reported a copper-catalyzed cascade [4
+ 2] annulation8 of 2-bromo-1-arylpropan-1-ones with
terminal alkynes leading to the construction of substituted
naphthalenones (Scheme 1b).
We commenced our studies using 2-bromo-1-phenylpropan-
1-one (1a) and ethynylbenzene (2a) as reaction components
to give 2-methyl-2-(1-oxo-1-phenylpropan-2-yl)-4-phenyl-
naphthalen-1(2H)-one 3aa (Table 1). Treatment of substrate
1a with alkyne 2a, Cu(MeCN)4PF6, and K2CO3 in toluene
under argon at 120 °C afforded the desired annulation product
3aa in a 61% yield (entry 1). A higher yield was achieved with
Figure 1. Representative bioactive examples of naphthalenones.
activity against five plant pathogens,1g including Fusarium
moniliforme, Verticillium alboatrum, Gibberella zeae, Fusarium
oxysporum, and Alternaria longipes. Classical protocols for the
syntheses of naphthalenone derivatives mainly focus on the
intramolecular tandem cyclization of α-alkynyl aryl ketones
enabled by palladium, copper, manganese, or peroxide.2
However, the substituted groups in substrates limited these
protocols for accessing the structural diversity of naphthale-
nones. Therefore, the development of new general strategies to
selectively construct the polysubstituted naphthalenone
skeletons from simple starting materials would be interesting.3
Carbocyclizations of alkynes with arenes and alkenes has
unarguably become an importantly strategy for the synthesis of
heterocyclic and carbocyclic compounds.4 In 2013, Zhang, Yu
and co-workers reported the synthesis of naphthols via a
visible-light promoted tandem coupling of alkynes with 2-
Received: June 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01962
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Organic Letters
Letter
a
a
Table 1. Screening of Optimal Conditions
Scheme 2. Variation of the Terminal Alkynes (2)
b
entry
[Cu salt]
ligand
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
CuI

L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Ag2CO3
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCl
61
82
76
21
trace
74
57
46
83
73
57
54
trace
0
79
74
77
80
78
75
CuCl
CuBr2
c
9
10
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
d
11
12
13
14
15
16
17
18
19
19

K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN
dioxane
toluene
toluene
toluene
a
Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), K2CO3 (0.4
mmol), Cu(MeCN)4PF6 (10 mol %) and L1 (20 mol %), toluene (2
mL) at 120 °C under argon atmosphere for 16 h. The dr value is
given in the parentheses determined by GC-MS analysis of the crude
products.
e
f
g
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), [Cu] (0.01
mmol), ligand (0.02 mmol), base (0.4 mmol), solvent (2 mL) at 120
electron-withdrawing group 2e were compatible with the
reaction conditions and provided products 3ab and 3ae in 78%
and 54% yields, respectively. Moreover, the disubstituted
alkyne 2i smoothly underwent the tandem reaction with 1a,
affording the desired product 4-(3,5-dimethylphenyl)-2-meth-
yl-2-(1-oxo-1-phenylpropan-2-yl)naphthalen-1(2H) -one 3ai
in 80% yield. In particularly, the electron-rich heterocycle
alkyne 3j was a suitable substrate for the reaction, affording the
corresponding product 3aj in 74% yield. It was noteworthy
that the reaction performed using 3-ethynylcyclohex-1-ene 2k
resulted in the formation of the desired product 3ak in 58%
yield with excellent diastereoselectivities. Interestingly, ali-
phatic alkynes 2l and 2m could convert to the corresponding
products 3al and 3am in 49% and 53% yields, respectively, and
also had excellent diastereoselectivity under the present
reaction conditions.
We next evaluated the scope of the tandem cyclization
protocol with regard to 2-bromo-1-arylpropan-1-ones 1 in the
presence of ethynylbenzene (2a) or 3-ethynylthiophene (2j),
Cu(MeCN)4PF6, 1,10-Phen (L1), and K2CO3 (Scheme 3). In
general, para-substituted α-bromo aryl ketones 1b−f were well
tolerated under the optimal conditions. Various functional
groups, such as methoxyl, methyl, bromo, chloro, and fluoro,
were compatible with the standard reaction conditions and
afforded the corresponding products 3ba−fa in 59−78%
yields. Importantly, halogen groups, Br, Cl, and F, were well-
tolerated, thus providing opportunities for additional mod-
ification of the products (3da−fa). The annulation protocol
was applicable to meta-substituted α-bromo aryl ketone 1g,
giving 3ga in 63% yield. However, the benzo[b]thiophene 4ha,
not the expected annulation product 3ha, was obtained from 2-
°C under argon atmosphere for 16 h. The dr value of 3aa is about
b
1.1:1 determined by GC-MS analysis of the crude products. Isolated
c
yield. Cu(MeCN)4PF6 (20 mol %) and L1 (40 mol %).
d
e
f
Cu(MeCN)4PF6 (5 mol %) and L1 (10 mol %). At 130 °C. At
g
110 °C. 1a (4 mmol), 2a (2 mmol), toluene (5 mL) for 48 h.
1,10-phenanthroline L1 (82%, entry 2). Other ligands, such as
2,2′-bipyridine L2, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]-
azepine L3, and triphenylphosphane L4, were tested, and the
results show that they were less effective than ligand L1 in
terms of yield (entries 3−5). We found that Cu(MeCN)4PF6 is
superior to other copper salts, such as CuI, CuCl, and CuBr2
(entry 1 vs entries 6−8). Further optimization revealed that 10
mol % of copper salt gave the best result (entries 9−10). A
series of other bases, such as Na2CO3, Ag2CO3, and Et3N, were
subsequently examined (entries 11−13): Na2CO3 and Ag2CO3
displayed high catalytic activity, but they were less efficient
than K2CO3, while only a trace yield of 3aa was detected in the
presence of Et3N. However, only a trace yield of product 3aa
was detected in the absence of a base (entry 14). Solvent
screening showed that toluene was the best solvent compared
to PhCl, MeCN, and dioxane (entry 1 vs entries 15−17). We
also tested different reaction temperatures and observed that
120 °C was the most efficient (entry 1 vs entries 18−19).
Gratifyingly, a reaction scale up to 2 mmol of 2a succeeded in
accessing 3a in good yield (entry 20).
Under the optimal conditions, the substrate scope of alkynes
was explored in Scheme 2. Various electron-donating and
electron-withdrawing functional groups, such as Me, Cl, Br,
and COMe, on the aryl rings of alkynes were well tolerated.9
For example, substrates bearing electron-donating group 2b or
B
DOI: 10.1021/acs.orglett.8b01962
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Organic Letters
Letter
Based on the above results and previous reports,4−7 the
possible mechanism for the copper-catalyzed tandem cycliza-
tion is proposed in Scheme 5. A Cu(II) species A was formed
Scheme 3. Variation of the 2-Bromo-1-arylpropan-1-ones
(1)
a
Scheme 5. Possible Mechanisms
with the aid of the base, and then oxidative addition of Cu(II)
species A to alkynes leading to intermediate B, followed by the
cyclization of intermediate B to give intermediate C. Reductive
elimination of intermediate C formed the intermediate D.
Finally, intermediate D reacted with the α-bromo ketone to
give the desired product 3aa in the presence of a base.
Alternatively, we also proposed a radical mechanism. Cleavage
of the C−Br bond of substrate 1a with the Cu(I) species under
heating affords the alkyl radical A′ and the Cu(II) species. A
radical addition of alkyl radical A′ with alkyne 2a produces the
radical intermediate B′, which is then converted to radical
intermediate C′, which upon intramolecular cyclization
constructs intermediate D. The last step is the same.
In summary, we have developed a new copper-catalyzed
tandem annulation reaction of 2-bromo-1-arylpropan-1-ones
with alkynes for the straightforward synthesis of naphtha-
leones, in which two-component α-bromo ketones participate
in the reaction. Importantly, three new C−C bonds were
formed in the reaction; this method is highly efficient and
various functional groups are well-tolerated. Work on the
detailed mechanistic study and application of the tandem
annulation strategy is currently underway in our laboratory.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), K2CO3 (0.4
mmol), Cu(MeCN)4PF6 (10 mol %) and L1 (20 mol %), toluene (2
mL) at 120 °C under argon atmosphere for 16 h. The dr value is
given in the parentheses determined by GC-MS analysis of the crude
products. 2-((5-Methyl-7-phenylbenzo[b]thiophen-4-yl)oxy)-1-
(thiophen-3-yl)propan-1-one (4ha) was obtained in 77% yield.
b
bromo-1-(thiophen-3-yl)propan-1-one 1h in 77% yield,
possibly because the aromaticity of thiophene is less than
that of benzene.
To gain insight into the mechanism, the standard reaction
was performed in the presence of a stoichiometric amount of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), hydroqui-
none, 2,6-ditert-butyl-4-methylphenol (BHT), and ethene-
1,1-diyldibenzene which are well-known radical scavengers,
and the results show that the formation of product was
completely inhibited, implicating a radical process. Substrate
1a and substrate 2a were treated with ethene-1,1-diyldibenzene
to form 2-methyl-1,4,4-triphenylbut-3-en-1-one (4aa) in 68%
yield (eq 1 in Scheme 4). We can isolate the naphthol
derivative 5aa in 48% yield when the excess alkyne 2a was used
in this reaction. However, compound 5aa could not converted
to the product 3aa, which showed this reaction not process a
naphthol intermediate (eq 2 in Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01962.
Scheme 4. Control Experiments
Descriptions of experimental procedures for compounds
and analytical characterization (PDF)
Accession Codes
CCDC 1851204 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: srj0731@hnu.edu.cn.
*E-mail: jhli@hnu.edu.cn.
C
DOI: 10.1021/acs.orglett.8b01962
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Ren-Jie Song: 0000-0001-8708-7433
Jin-Heng Li: 0000-0001-7215-7152
Author Contributions
§X.-H.O. and C.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (Nos.
21402046, 21625203, and 21472039), the Jiangxi Province
Science and Technology Project (Nos. 20171BCB23055,
20171ACB21032, 20171ACB20015, and 20165BCB18007),
and the Jiangxi Educational Committee Foundation of China
(No. GJJ160725) for financial support.
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