Cu-catalyzed intramolecular hydroarylation of alkynes

Article abstract of DOI:10.1039/c4ra12258e

An efficient Cu-catalyzed intramolecular hydroarylation reaction of alkynes has been developed. The reaction is accomplished under mild conditions and shows good tolerance to both electron-rich and electron-deficient aryl nucleophiles. A series of aryl, h

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Cu-Catalyzed Intramolecular Hydroarylation of Alkynes
Yun-Long Wang, Wen-Man Zhang, Jian-Jun Dai, Yi-Si Feng,* Hua-Jian Xu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient Cu-catalyzed intramolecular hydroarylation
reaction of alkynes has been developed. The reaction is
accomplished under mild conditions and shows good
tolerance to both of electron-rich and electron-deficient aryl
nucleophiles. A series of aryl, heteroaryl, alkyl, and even the
N-group attached alkynes are all suitable substrates for the
intramolecular hydroarylation.
Scheme 1 Cu-catalyzed intramolecular hydroarylation reaction of
Introduction
alkynes
Transition metal-catalyzed hydroarylation of alkynes represents a
practical and atom-economical method to form new C(sp2)-C(sp2)
bonds via aromatic C-H activation.1-2 In addition, the
intramolecular hydroarylation reaction has been recognized as an
efficient approach to construct polycyclic aromatic frameworks.
Many groups have studied this reaction. For instance, Pd, Pt, Au,
Ru, and others precious-metal catalysts catalyzed intramolecular
hydroarylation reaction of alkynes have been reported in the past
decades.3 Nonetheless, some problems remained to be solved
with these reactions. Expensive and/or poisonous catalysts were
normally used to promote the reaction in previous studies, which
limited the development of large-scale application. The
selectivity of exo- and endo-type cyclization products still needs
to be controlled. Recently, the Fe-catalyzed intramolecular
hydroarylation of alkynes have also been reported,4 but there are
still limitations in the types of substrates. For instance, electron-
rich aryl nucleophiles are necessary for the intramolecular
hydroarylation in Campagne’s work.5 On the other hand, the
electron-rich aryl nucleophiles underwent the transformation with
a very low yield (4-MeO and 2-MeO, 19% and 13%) in Takaki’s
work.6 Besides, the aryl attachment on the alkyne terminal plays
an essential role in above reactions. Therefore, the development
of a nontoxic and inexpensive catalyst system with universal
functional group compatibility is an interesting challenge.
Herein, we describe an general and efficient Cu-catalyzed
intramolecular hydroarylation reaction of alkynes under mild
conditions (Scheme 1).7 Both of electron-rich and electron-
deficient aryl nucleophiles are well tolerated in the reaction to
give the 6-endo products in moderate to good yields. Not only the
aryl, alkyl, but also the N-group attached alkynes are suitable
substrates for the Cu-catalyzed intramolecular hydroarylation.
Meanwhile, polycyclic dihydronaphthalenes and chromenes
derivatives, which are valuable organic skeleton,8 can be
synthesized by present protocol.
Table 1. Optimization of the Reaction Conditionsa
Yield
(%)b
Entry
CuX
Solvent
T (oC)
Time (h)
1
2
3
4
5
6
7
8
Cu
CuCl
CuI
CuCl2
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
60
30
60
60
60
60
60
12
12
12
12
12
12
12
12
12
12
12
12
12
12
1
NR
trace
NR
NR
NR
22
5
48
87
18
95
trace
94
7
6
Cu(OAc)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
Cu(OTf)2
---
DCE
MeOH
DCE/MeOH (1:1)
DCE/MeOHc
MeNO2
PhCH3
1,4-dioxane
PhCH3
9
10
11
12
13
14
15
16
17
18 e
19
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
3
4
12
12
63
94 (89)d
trace
NR
PhCH3
a Reaction conditions: I (0.01mmol), [Cu] (10 mol%), solvent (1 mL) under Ar atmosphere.
b Yield determined by GC. c 10 equiv of MeOH in DCE. d Isolated yield. e In air.
gave inferior results (Table 1, entries 1-5). In order to improve
the product yield, a series of organic solvents were tested (entries
7-13). The mixed solvent of DCE/MeOH showed a better result
than either DCE or MeOH (entry 8). When 10 equiv of MeOH
was added in DCE as the reaction solvent, the product yield was
improved to 87% (entry 9).9 Surprisingly, PhCH3 showed the best
efficiency for this reaction, and the yield of desired product was
further increased to 95% (entry 11). In addition, it was our goal to
achieve this reaction under milder conditions. It was delighted
that when we reduced the temperature to 60 oC, the yield of
product was not significantly reduced (entry 13). However, the
reaction at 30 oC showed a much low activity under the same
We began our study by examining the intramolecular
hydroarylation of 1-methoxy-4-(4-phenylbut-1-ynyl)benzene (I).
First, different copper catalysts (entries 1-8) were examined in
o
DCE under 80 C. As a uniquely effective catalyst, Cu(OTf)2
showed commendable catalytic effect, and the target product was
obtained in 22% yield (Table 1, entry 6). Other copper catalysts
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Table 2. Scope of aryl nucleophilesa
Table 3. Scope of terminal alkyne attachmentsa
View Article Online
DOI: 10.1039/C4RA12258E
COOEt
CF3
COOEt
O
O
O
O
O
2ve, 56%
2sc, 52%
2td, 70%
2ue, 64%
2wc, 86%
O
O
N
S
O
OMe
2aac, 65%
2ab, 0%
2x, 65%
2yb
, 68%
2z, 62%
a Reaction conditions: 1 (0.01 mmol), Cu(OTf)2 (10 mol%), PhCH3 (1 mL) at 60°C for 4 h
under Ar atmosphere. Isolated yield. b the solvent is DCE. c 10 equiv of MeOH in DCE as
the solvent. d DCE, 100°C. e DCE/ PhCH3(1:1), 80°C, 12 h.
ketone (2i, 2n), trifluoromethyl (2j, 2m), ester (2k, 2l), lactone
(2q), were well-tolerated in the reaction.
Moreover, arene rings carrying fluoro-, chloro-, and bromo-
substituents are compatible with the reaction, enabling additional
modifications at the halogenated positions (2c-2f, 2o). Notably,
we found that the phenanthrene derivatives can also be achieved
in high yield via the cyclization of o-alkynyl biaryls under present
reaction conditions (2r). In addition, the successful synthesis of
heterocyclic and polycyclic compounds (2p, 2q) made the
protocol be potentially used in late-stage intromolecular
cyclization. Importantly, the intramolecular hydroarylation of the
meta-substitutent substrate 1p regioselectively gave the product
2p in 77%. Furthermore, a seven-membered ring can also be
formed by this reaction, albeit the yield is relatively lower (2s).10
However, the five-membered ring indene derivative couldn’t be
formed (2t).
Besides, the effect of terminal attachments R2 in the substituent
was investigated (Table 3). In addition to the PMP group, the
simple phenyl group as terminal alkyne attachments was also
sufficiently reactive, providing a moderate to good yield of the
corresponding products (2u, 2y). Compared with the previously
developed cationic iron-catalyzed intramolecular hydroarylation
alkyne,6 the present method showed a better functional group
compatibility, because the substrates with electron-deficient
aromatic rings R2 were difficult to obtain the desired products in
Takaki’s work. However, in our reaction, the R2 group with
strong electon-withdrawing CF3 and ester substitued was also
well-tolerated and give the product in excellent yield (2v-2x). The
substrates with heterocyclic and polycyclic attachments on
terminal alkyne, such as thiophene group, oxazolidinone group11
and naphthalene groups, could undergo the hydroarylation
reaction to get the product in good yield (2z, 2ab, 2ac). Note that
the substrate of oxazolidinone-substituted could be tolerated
successfully, which pave a route for the construction of more
complex polycyclic aromatic compounds. Surprisingly, alkyne
with terminal attachments was also achieved the reaction
effectively to obtain the target product in 68% yield (2aa). Yet,
there was no reaction occurred when the unsubstituted alkynes
was used (2ad).
a Reaction conditions: 1 (0.01mmol), Cu(OTf)2 (10 mol%), PhCH3 (1 mL) at 60 °C for 4 h
c
under Ar atmosphere. Isolated yield. PMP = p-methoxyphenyl. b the solvent is DCE.
f
DCE. 1 h. d 10 equiv of MeOH in DCE as the solvent. e DCE, 80°C toluene, 80 °C.g
DCE/ PhCH3(1:1), 80°C. h DCE/ PhCH3(1:4), 60°C, 8h.
optimized conditions (entry 14). Finally, the time of this reaction
was also examined (entries15-17). Gratifyingly, the reaction was
completed with an extremely high yield just in 4 hours (entry 17).
Disappointedly, no detectable product was obtained when the
reaction was underwent in air conditions (entry 18). Furthermore,
in the absence of Cu-catalyst, we did not observe the desired
product (entry 19).
With the optimized reaction conditions in hand, we next
examined the substrate scope of aryl nucleophiles (Table 2). The
O-tethered substrate bearing phenyl group afforded the
cyclization product in 84% yield (2g). Not only the electron-rich
aryl nucleophiles which commonly were used in previous works,
were found to undergo the desired reaction in high efficiency, but
also the electron-deficient aryl nucleophiles could give the
products in moderate to good yields. Many synthetically
important functional groups, including ether (2a, 2h), methyl (2b),
2
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functional group tolerance. a nontoxic and inexpensive catalyst,
Cu(OTf)2, was successfully used in this hydroarylation reaction,
View Article Online
and showed wonderful catalytic effect. Not only the aryl, but also
DOI: 10.1039/C4RA12258E
the alkyl and N-group attached alkynes are suitable substrates for
this reaction. Numerous 2H-naphthalene and 2H-chromene
derivatives can be prepared in good to excellent yields via the
straightforward, practically useful method.
Scheme 2 Gram-scale reaction.
Experimental
General procedure for the synthesis of the Products.
A
10 mL over-dried Schlenk tube was charged with
corresponding alkyne (0.1 mmol) (if solid), Cu(OTf)2 (10 mol%,
3.62 mg). The tube was evacuated and backfilled with argon (this
procedure was repeated three times). Under a counter flow of
argon, corresponding alkyne (0.1 mmol) (if liquid) and solvent (1
mL) were added by syringe. The tube was sealed and the mixture
o
was allowed to stir in a preheated oil bath at 60 C for 4 h. The
mixture was cooled to room temperature when the reaction was
completed. Next, the organic solvent was concentrated under
reduced pressure. The crude product was purified by
chromatography on silica gel with petroleum ether/ethyl acetate
to give the product 2.
Scheme 3 Transformation of model product.
Acknowledgements
To probe the synthetic utility of this newly developed protocol,
a scaled-up reaction was conducted with an aim on evaluating
practical aspects. In this experiment, the hydroarylation of 1a was
conducted on 1.33 g scale, and product 2a can be obtained in
gram quantity with a satisfactory yield of 86% (Scheme 2).12
Notably, a lower loading of Cu catalyst (5 mol %) was used in
this gram-scale reaction. Besides, in order to further demonstrate
the worth of the products, the further transformation of the model
product was also studied (Scheme 3).12 The product II was
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21272050, 21371044,
21472033) and the Program for New Century Excellent Talents
in University of the Chinese Ministry of Education (NCET-11-
0627).
Notes and references
School of Chemistry and Chemical Engineering, School of Medical
Engineering, Hefei University of Technology, Hefei 230009, P. R. China.
E-mail: hjxu@hfut.edu.cn
successfully
oxidized
by
DDQ
(1,2-dichloro-4,5-
dicyanobenzoquinone) to a polyaromatic naphthalenes III. Then,
the hydrogenation of product II can also be occurred smoothly
(IV) with good yield. Next, the compound V, which may be an
important difluorocyclopropanes derivatives in organofluorine
chemistry,13 was obtained by 1,1-difluorocyclopropanation of
product II. A series of applications with model product provided
a new method to construct the more complicated and valuable
polycyclic derivatives.
†Electronic Supplementary Information (ESI) available: Experimental
details, characterization data, and H and 13C NMR spectra of products.
1
See DOI: 10.1039/b000000x/
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Scheme 4 Isotope labeling experiment.
To better understand the reaction mechanism, we performed
the kinetic isotope experiment (Scheme 4). The KH/KD values of
intramolecular KIE (kinetic isotope experiments) indicated that
the C-H cleavage is not the rate-determine step (KH/KD = 0.96).
These results suggest that the present Cu-catalyzed cyclization
may proceed via a Friedel-Crafts type process.2h, 2u, 6, 14
Conclusions
In summary, we have reported an efficient Cu-catalyzed
intramolecular hydroarylation reaction of alkynes with good
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Yields of II using various solvents: DCE (1 mL)/MeOH (10 equiv)
(87%) > DCE (1 mL)/MeOH (20 equiv) (83%) > DCE (1 mL)/MeOH
(5 equiv) (64%) > DCE (1 mL)/MeOH (2 equiv) (55%).
10 The yield of remainder material is 58%.
11 3,4-Dihydronaphthalen-1(2H)-one was got with the yield of 26%,
when the reaction was accomplished.
12 The specific procedure of experiment. Please see supporting
information.
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4
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