Neodymium-catalyzed intramolecular alkyne-hydroarylation with arenes

Article abstract of DOI:10.1016/j.tetlet.2016.06.053

A Nd(OTf)₃-catalyzed alkyne-hydroarylation with arenes is reported. This reaction shows a wide range of functional group tolerance. Such a catalytic methodology enriches lanthanide element chemistry and provides a new route for synthesizing phe

Full text of DOI:10.1016/j.tetlet.2016.06.053

Tetrahedron Letters 57 (2016) 3235–3238
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Tetrahedron Letters
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Neodymium-catalyzed intramolecular alkyne-hydroarylation with
arenes
⇑
Dawen Xu, Ruiwen Jin, Wangsheng Liu, Feifei Ba, Yawei Li, Aishun Ding, Hao Guo
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Nd(OTf) -catalyzed alkyne-hydroarylation with arenes is reported. This reaction shows a wide range of
3
Received 30 April 2016
Revised 11 June 2016
Accepted 13 June 2016
Available online 14 June 2016
functional group tolerance. Such a catalytic methodology enriches lanthanide element chemistry and
provides a new route for synthesizing phenanthrene derivatives.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Lanthanide element
Hydroarylation
Phenanthrene
Lewis acid
Phenanthrene and its derivatives are a class of important com-
pounds in organic chemistry. A large portion of phenanthrenes
have been found as natural products in plants belonging to the
Table 1
a
Optimization of reaction conditions
1
Orchidaceae, Betulaceae, and Combretaceae families. Such biolog-
2
ically active natural products have been used to prepare antiviral,
Nd(OTf)3
solvent
anticancer, antianxietic,4 anti-HIV,5 and Anti-inflammatory
3
6
agents. Apart from medical usage, they have also been widely
applied in photoconducting, photochemical, electroluminescent,
OMe
7
and fluorescent materials. Numerous strategies have been devel-
OMe
oped for the synthesis of phenanthrenes.8 However, most of these
protocols are faced with low compatibility of functional groups or
harsh reaction conditions. Lewis acid catalysis in this field has
attracted much attention from organic chemists for its 100% atom
economy and relatively mild reaction condition. Numerous
,9
1a
2a
Entry Solvent
Temperature
Nd(OTf)3 (mol
%)
Time
(h)
Yield
(%)
b
(°C)
0 (99)c
1
Ethyl
rt
100
30
1
0,11
11a
11b
achievements
have been reported, among which In,
Hf,
acetate
Acetone
EtOH
1
1c
11e
Rh,11f Au,
11g,k
11h
11i
2
3
4
5
6
7
8
9
1
1
rt
rt
rt
rt
rt
rt
100
100
100
100
100
20
20
5
30
27
30
12
9
24
3
9
0 (99)c
Pd,
Fe,
Ag,
and Ru showed nice catalytic
c
0 (99)
activity in the hydroarylation of alkynes. Lanthanide elements
have wide applications in organic chemistry owing to their
relative abundance in nature and nontoxicity to environment.
Those elements have predominarily one stable oxidation state (3
CH
CH
3
CN
Cl
8 (92)c
92
2
2
CH NO2
3
95
CH
CH
CH
CH
CH
3
NO
3
NO
3
NO
3
NO
3
NO
2
2
2
2
2
3 (97)c
99
115
115
115
115
+) which is quite different from transition metals and main
98
group metals. The trivalent lanthanide salts, like lanthanide
triflates, generally show strong Lewis acidity and are insensitive
to air and moisture, which is superior to main group metal and
transition metal salts. To date, a series of transformations can be
catalyzed by lanthanide Lewis acid,12 such as hydroamination
0d
1
e
5
0
10
10
99 (99)
d
0 (99)c
a
The reaction of 1a (0.2 mmol) and Nd(OTf)
3
in anhydrous solvent (5 mL) in a
sealed tube was carried out at tested temperature under argon atmosphere.
13
b
Yield was determined by 1H NMR analysis of the crude product using CH
2 2
Br as
internal standard.
c
Recovered yield of 1a.
⇑
Corresponding author. Tel./fax: +86 21 55664361.
E-mail address: Hao_Guo@fudan.edu.cn (H. Guo).
d
1a (0.5 mmol) in anhydrous CH
3 2
NO (12.5 mL) was applied.
e
Isolated yield of 2a.
http://dx.doi.org/10.1016/j.tetlet.2016.06.053
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

3
236
D. Xu et al. / Tetrahedron Letters 57 (2016) 3235–3238
Table 2
D
D
Scope of this hydroarylationa
R3
R
2
R3
R2
5
mol% Nd(OTf)
3
H
5 mol% Nd(OTf)3
, 115 oC, 8 h
, 115 o
H
CH
3
NO
2
C
3 2
CH NO
R1
OMe
36%
R1
OMe
2
a-d4
1a'
1
2
D
OMe
OEt
1
2%
2
a
2b
2c
OMe
OMe
5
mol% Nd(OTf)
NO
, 115 oC, 8 h
3
2a-d10
D
1
0 h, 99%
14 h, 75%
68 h, 45%
CH
3
2
OMe
H-D exchange
product
1a'
H
Cl
5
2%
2
d
2e
2f
2a
7
2 h, 57%
72 h, 22% (78%)b
47.5 h, 74%
2
a-d %
4
Conversion = 100%
Total yield = 99%
K
H/D
=
= 0.6
2
a-d10% + 2a%
OH
0
Scheme 1. Isotope experiment of deuterated 1a under standard condition.
OMe
OMe
2h
OMe
and hydroalkoxylation.14 However, lanthanide Lewis acid-cat-
alyzed hydroarylation of alkynes remains unexplored. With regard
to enriching the methodology, a deep investigation of the catalytic
activity of lanthanide elements in this reaction is highly desired.
2
g
2i
2
6.5 h, 92%
13.3 h, 97%
14.5 h, 89%
O
Herein, we wish to report the Nd(OTf)
alkyne-hydroarylation with arenes. The reaction proceeded effi-
ciently with catalytic amount of Nd(OTf) and exhibited good func-
3
-catalyzed intramolecular
OH
3
tional group tolerance, providing a novel method for the synthesis
of phenanthrenes.
OMe
OMe
OMe
The initial reaction was carried out at room temperature using
-((4-methoxyphenyl)-ethynyl)-1,1 -biphenyl 1a as the model
2
j
2k
27 h, 93%
2l
0
2
3
7 h, 97%
16.5 h, 96%
substrate and 1 equiv of Nd(OTf)
reactions in ethyl acetate, acetone, or EtOH did not proceed at all
Table 1, entries 1–3). Fortunately, when the reaction was con-
ducted in CH CN, an 8% NMR yield of the desired hydroarylation
product 2a was formed, although the conversion rate was very
low (Table 1, entry 4). When CH Cl or CH NO was used as the
3
as the catalyst. Disappointingly,
Br
COOMe
(
3
2
2
3
2
OMe
OMe
OMe
solvent, we were delighted to see that the yield increased signifi-
cantly (Table 1, entries 5 and 6). Considering that the highest yield
2
m
2n
2o
and reaction speed were observed in CH
CH NO was chosen as the optimized solvent for this reaction.
Next, we tried to decrease the catalyst loading. Unfortunately,
the reaction with 20 mol% of Nd(OTf) yielded only 3% of 2a
Table 1, entry 7). Therefore, an elevated temperature was applied,
which gave a 99% NMR yield of 2a in the presence of 20 mol % of
Nd(OTf) at 115 °C (Table 1, entry 8). Further study indicated that
5 mol % of Nd(OTf) was enough to catalyze this transformation,
3 2
NO (Table 1, entry 6),
1
7 h, 99%
16.5 h, 92%
37 h, 94%
3
2
NO
2
CN
3
(
3
OMe
OMe
3
affording 2a in nearly quantitative yield (Table 1, entry 9). Subse-
quently, we conducted the reaction at a larger scale, the reaction
efficiency remained the same (Table 1, entry 10). Finally, the reac-
tion at 115 °C without catalyst was tested. The fact that no reaction
2
p
2q
3
5 h, 81%
44 h, 79%
a
All reactions were carried out using 1 (0.5 mmol) and Nd(OTf)
3
(0.025 mmol) in
anhydrous CH NO (12.5 mL) in a sealed tube at 115 °C under argon atmosphere.
3
2
occurred demonstrated that Nd(OTf)
this reaction (Table 1, entry 11).
3
was indeed the catalyst for
Isolated yield was reported.
b
Recovered yield of 2e.

D. Xu et al. / Tetrahedron Letters 57 (2016) 3235–3238
3237
Nd(OTf)
3
TfO
TfO
Nd
OTf
C-H activation
HOTf
1a
OTf
Coordination
OMe
OMe
A
A
H
Electrophilic aromatic
substitution
C-H activation
Nd(OTf)3
Nd(OTf)
2
TfO Nd
TfO
B
OMe
OMe
D
Protonlysis
Insertion
2a
TfO Nd
OTf
TfO Nd
OTf
H
OMe
OMe
C
C
Scheme 2. Plausible mechanism for this reaction.
With the optimized reaction conditions in hand, we started to
investigate the substrate scope (Table 2). In general, strong elec-
tron-donating groups were favored on R position. Substrates bear-
only hydrogen source, we assumed that there might be some
H-D exchange with CH NO . As shown in Scheme 1, the kinetic
3
2
1
constant KH/D was found to be 0.6. This value clearly indicated a
secondary, inverse kinetic isotope effect, which meant that C–H
activation was not involved in the rate-determining step.17
Based on the above experimental evidence, two reaction path-
ing methoxy or ethoxy group gave their corresponding cyclized
products in 99% or 75% isolated yields, respectively (2a and 2b).
The structure of 2 was determined by 2a which is a known com-
1
5
18
pound. Substrates bearing a weak electron-donating group or H
ways, electrophilic aromatic substitution (EAS) and C–H activa-
1
9
atom afforded the desired products in moderate yields (2c and
tion, are depicted as shown in Scheme 2. For the EAS reaction
pathway, the electrophilic Nd(OTf) initiates the reaction by coor-
dination with the alkyne, where the coordination of Nd(OTf) with
2
d). While for substrates with electron-withdrawing groups, the
reaction speed was very low, affording phenanthrene derivative
e in only a 22% isolated yield after 72 h. The above data clearly
3
3
2
alkyne renders the increased electrophilicity of alkyne. The follow-
ing intramolecular 6-endo-dig electrophilic addition results in the
Wheland intermediate B which will generate the vinylneodymium
intermediate C via deprotonation. Finally, protonlysis of C yields
the phenanthrene product and regenerates the catalyst. For the
C–H activation reaction pathway, four key steps are involved. (i)
1
indicated that electron-withdrawing R group would reduce the
reaction speed, which might be due to the lower coordination abil-
ity of electron deficient alkyne moiety. When R was 2-methyl, the
2
reaction proceeded smoothly to produce 2f in a 74% yield. Then a
series of disubstituted substrates were applied in this reaction
(2g–2j). Strong electron-donating groups, like hydroxyl, could be
3
coordination of Nd(OTf) with alkyne to afford (Nd-alkyne) com-
well tolerated, affording the corresponding product 2g in a 92%
yield. Weak electron-donating substrates could also be efficiently
converted to their corresponding products (2h and 2i). Notably,
the reaction of reactants with strong electron-withdrawing groups,
like acetyl, could proceed smoothly, generating the phenanthrene
derivative 2j in an excellent yield. Subsequently, several trisubsti-
tuted substrates were also applied in this reaction (2k–2q). It was
worthy to note that many functional groups, such as hydroxyl,
bromo, methoxycarbonyl, nitro, and cyano, could be well tolerated,
yielding trisubstituted phenanthrenes in good to excellent yields
plex A, (ii) C–H activation to form arylneodymium intermediate
D, (iii) insertion of C–C triple bond into C–Nd bond to yield the
vinylneodymium intermediate C, and (iv) protonlysis of C to give
the product and regenerate the catalyst.
In conclusion, we have investigated lanthanide element Lewis
3
acid Nd(OTf) -catalyzed intramolecular alkyne-hydroarylation
with arenes. The reaction yielded a series of phenanthrene deriva-
tives in good to excellent yields. A lot of functional groups were
tolerated in this reaction.
(
2k, 2n, 2o, 2p, and 2q). Furthermore, the fact that electron-donat-
2
Acknowledgments
ing R groups could accelerate the reaction speed might suggest a
Friedel–Craft mechanism (vide infra).
We greatly acknowledge the financial support from National
Basic Research Program of China (973 Program, 2012CB720300),
To gain an insight into the reaction mechanism, a deuterated
0
model substrate 1a was synthesized and applied under the stan-
dard condition. After full conversion, a quantitative total yield of
the desired products was obtained. Careful exploration of
NMR spectra (see Page S44 in Supplementary data) of the product
mixtures demonstrated that 2a was formed in a 52% yield, which
meant that 52% of deuterium was missing during the whole trans-
formation. The fact that the ortho-hydrogen was scrambled usually
indicates significant C–H activation by a metal species, which has
been observed in other types of rare earth metal-catalyzed C–H
International Science
China (2014DFE40130), and Shanghai Rising-Star Program
14QA1400500).
& Technology Cooperation Program of
1
H
(
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
053.
1
6
3 2
addition reactions. Considered that the solvent CH NO was the

3
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