Pd/C-catalyzed synthesis of isoquinolones through C-H Activation

Article abstract of DOI:10.1002/cctc.201403059

The direct synthesis of isoquinolones from benzamides and alkynes through C-H activation was developed by using Pd/C as a heterogeneous catalyst without a ligand under mild conditions. A variety of isoquinolones were obtained in good yields with excellent regioselectivities. The Pd/C catalyst could be recycled three times without a significant decrease in the activity (yields as high as 85). Activation complete: The direct synthesis of isoquinolones from benzamides and alkynes through C-H activation is developed by using Pd/C as a heterogeneous catalyst. The Pd/C catalyst can be recycled three times without a significant decrease in the activity.

Full text of DOI:10.1002/cctc.201403059

DOI: 10.1002/cctc.201403059
Communications
Pd/C-Catalyzed Synthesis of Isoquinolones through CÀH
Activation
Zhen Shu, Wei Li,* and Baiquan Wang*[a]
The direct synthesis of isoquinolones from benzamides and al-
kynes through CÀH activation was developed by using Pd/C as
a heterogeneous catalyst without a ligand under mild condi-
tions. A variety of isoquinolones were obtained in good yields
with excellent regioselectivities. The Pd/C catalyst could be re-
cycled three times without a significant decrease in the activity
(yields as high as 85%).
As one of the most active research topics, transition-metal-cat-
alyzed CÀH bond activation has attracted much attention over
Scheme 1. Direct synthesis of isoquinolones from benzamides and alkynes.
Piv=pivaloyl.
the last decades as a result of an increase in the awareness of
atom economy and green chemistry. CÀH activation can
reduce the number of steps of a synthesis and decrease the
amount of waste produced; in certain cases, a reaction may
even be made waste free. Among CÀH activation reactions,
Pd-catalyzed CÀH bond activation has been developed rapidly
with great progress.[1] However, most of the described proce-
dures require the use of a homogeneous palladium catalyst.
The requirement of precious palladium often hampers com-
mercial access to such methodology. In contrast, the use of
a heterogeneous palladium catalyst to practice this chemistry
enables facile recovery of palladium and eliminates contamina-
tion of the product by the metal.[2] In recent years, heterogene-
ous palladium on activated carbon (Pd/C) has been applied
successfully in coupling reactions,[2] including Heck,[3] Sonoga-
shira,[2e,4] and Suzuki–Miyaura[2b,5] reactions; the construction of
nitrogen and oxygen heterocycles;[6,7] and in other coupling re-
actions.[8] However, Pd/C-catalyzed CÀH activation reactions
are still limited.[9,10]
ganic catalysts[17] can all be used in this reaction [Scheme 1,
Eq. (1)]. Although these catalysts can afford good yields, the re-
covery and reuse of the catalysts are still problematic. Herein,
we report an effective heterogeneous catalytic system for the
direct synthesis of isoquinolones from benzamides and alkynes
[Scheme 1, Eq. (2)].
At the beginning of our study, we used N-methoxybenza-
mide (1a) and diphenylacetylene (2a) as starting materials, 5%
Pd/C as the catalyst, air as the oxidant, NaI·2H2O as the addi-
tive, DMF as the solvent, and 1208C as the reaction tempera-
ture. To our delight, corresponding isoquinolone 3a was ob-
tained in 42% yield (Table 1, entry 1). Using oxygen as the oxi-
dant instead of air, the yield did not increase significantly
(Table 1, entry 3), whereas the yield decreased markedly if the
reaction was performed under an argon atmosphere (Table 1,
entry 2). Upon decreasing the reaction temperature to 1008C,
the reaction did not proceed (Table 1, entry 4), whereas an in-
crease in the reaction temperature did not improve the yield
(Table 1, entry 5). By using N-methyl-2-pyrrolidone (NMP), di-
methylacetamide (DMA), or DMSO as the solvent instead of
DMF, similar yields were obtained (Table 1, entries 6–8). In con-
trast, the use of MeOH, toluene, H2O, or CH2Cl2 as the solvent
gave no product (Table 1, entries 9–12). Next, the influence of
iodide was investigated. The addition of nBu4NI or KI instead
of NaI·2H2O afforded similar yields of the product (Table 1, en-
tries 13 and 16), whereas the use of PhI(OAc)2 or I2 gave no
product (Table 1, entries 14 and 15). Clearly, the iodide with
a valence of À1 was the best choice, and we selected
NaI·2H2O as the standard additive in our later tests. Unexpect-
edly, reducing the number of equivalents of NaI·2H2O from
1 to 0.5 increased the yield of the product to 64% (Table 1,
entry 17), whereas the use of 2 equivalents of NaI·2H2O de-
creased the yield to 32% (Table 1, entry 18). Different bases
were also tested. To our delight, the yield of the product in-
creased to 92% in the presence of Na2CO3 (Table 1, entry 19).
The isoquinolone skeleton exists widely in natural products
and can be found in N-methylcoryaldine, coryaldine alkaloids,
and other complex natural compounds. Isoquinolone and its
derivatives show good biological activities and can be used as
drugs and biologics.[11] The direct synthesis of isoquinolones
from benzamides and alkynes through CÀH activation has
been recently achieved. Rh,[12] Ru,[13] Pd,[14] Ni,[15] Co,[16] and or-
[a] Z. Shu, Prof. Dr. W. Li, Prof. Dr. B. Wang
College of Chemistry
State Key Laboratory of Elemento-Organic Chemistry
Key Laboratory of Advanced Energy Materials Chemistry
(Ministry of Education)
Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin)
College of Chemistry, Nankai University
Tianjin 300071 (China)
E-mail: weili@nankai.edu.cn
bqwang@nankai.edu.cn
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201403059.
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Table 1. Optimization
of
the
reaction
conditions.[a]
Table 2. Reaction scope.[a]
Entry
Solvent
RI
Base
Yield
[%][b]
[(equiv.)]
1
DMF
DMF
DMF
DMF
DMF
NMP
DMA
DMSO
MeOH
toluene
H2O
CH2Cl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
NaI·2H2O (1)
nBu4I (1)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
42
12
47
trace
41
42
2[c]
3[d]
4[e]
5[f]
6
7
8
9
40
26
n.r.
n.r.
trace
n.r.
41
trace
n.r.
39
64
32
92
73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PhI(OAc)2 (1)
I2 (1)
KI (1)
NaI·2H2O (0.5)
NaI·2H2O (2)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
NaI·2H2O (0.5)
–
–
Na2CO3
NaHCO3
K2CO3
K2HPO4
LiOH
KHCO3
Et3N
24
64
68
50
n.r.
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), 5% Pd/C
(10 mol%), base (0.3 mmol), solvent (1.0 mL), 48 h, air. [b] Yield of isolated
product. n.r.=no reaction. [c] Under an atmosphere of argon. [d] Under
an atmosphere of O2. [e] At 1008C. [f] At 1408C.
Using NaHCO3, K2HPO3, LiOH, or KHCO3 as the base afforded
moderate yields (Table 1, entries 20 and 22–24), whereas the
use of K2CO3 or Et3N gave a low yield or no product (Table 1,
entries 21 and 25).
With the optimal reaction conditions (Table 1, entry 19) in
hand, various substituted benzamides were treated with differ-
ent alkynes to give the corresponding isoquinolone derivatives
(Table 2). Benzamides with electron-donating groups worked
well and afforded the corresponding products in good yields
(see products 3b–d and 3 f–k). The position of the substituent
had an important influence on the yield of the product. Clearly,
substrates with para substitution showed higher activities than
substrates with meta and ortho substitutions (see products
3b–d). Steric effects in the para position were not evident, as
products 3h and 3i were obtained in yields of 64 and 86%, re-
spectively. Interestingly, upon employing meta-substituted or
3,4-disubstituted benzamides 1c, 1j, and 1k, single regioiso-
meric products 3c, 3j, and 3k were obtained, which revealed
the excellent regioselectivity of this reaction. Unfortunately,
benzamides with electron-withdrawing groups showed much
lower reactivities. The para-chloro-substituted benzamide only
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), 5% Pd/C (10 mol%),
NaI·2H2O (0.15 mmol), Na2CO3 (0.3 mmol), DMF (1.0 mL), 48 h, air.
gave 22% yield of product 3e, whereas substrates with
a strong electron-donating group such as p-NO2 and p-CF3
gave no product.
The competition reaction of benzamides 1e and 1g with di-
phenylacetylene (2a) under the standard conditions further in-
dicated that the product formation favors isoquinolone 3g de-
rived from the more electron-rich benzamide (Scheme 2).
To further demonstrate the efficiency and practicality of this
reaction, a scale-up reaction was performed. Thus, gram-scale
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Experimental Section
General procedure for the synthesis of isoquinolones
A Schlenk tube equipped with a stir bar was charged with a mix-
ture of substituted benzamide 1 (0.3 mmol, 1.0 equiv.), alkyne 2
(0.9 mmol, 3.0 equiv.), 5% Pd/C (0.03 mmol, 10 mol%), NaI·2H2O
(27.9 mg, 0.15 mmol, 0.5 equiv.), and Na2CO3 (31.8 mg, 0.3 mmol,
1.0 equiv.). DMF (1.0 mL) was added, and the mixture was stirred at
1208C for 48 h in air. Afterwards, the mixture was filtered, washed
with H2O (30 mL), and extracted with CH2Cl2 (3ꢁ30 mL). The com-
bined organic phase was dried with anhydrous Na2SO4. After re-
moval of the solvents under reduced pressure, the residue was ab-
sorbed to a small amount of silica gel. Purification was performed
by flash column chromatography on silica gel.
Scheme 2. Competition reaction of different substrates.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21372122, 21376123, 21121002, and U1403293) for finan-
cial support.
Keywords: alkynes · CÀH activation · heterogeneous catalysis ·
palladium · synthetic methods
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Scheme 3. Proposed catalytic cycle.
synthesis of 3a was achieved in 88% yield. At last, recycling of
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obtained in yields of 92, 87, and 85% after the first, second,
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bond adjacent to the amide through directing group participa-
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Pd intermediate B, which can readily undergo coordination
and insertion into the PdÀC bond of an alkyne to afford corre-
sponding seven-membered cyclic Pd intermediate C. After re-
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can be reoxidized by air to regenerate the PdII species for the
next catalytic cycle.
In summary, we developed an effective heterogeneous and
recyclable catalytic system for the direct synthesis of isoquino-
lones from benzamides and alkynes through CÀH activation
under mild conditions. A broad range of substituted benza-
mides and alkynes were used in this reaction, and the products
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Received: December 29, 2014
Published online on && &&, 0000
&
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
4
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATIONS
Z. Shu, W. Li,* B. Wang*
&& – &&
Pd/C-Catalyzed Synthesis of
Isoquinolones through CÀH Activation
Activation complete: The direct synthe-
sis of isoquinolones from benzamides
and alkynes through CÀH activation is
developed by using Pd/C as a heteroge-
neous catalyst. The Pd/C catalyst can be
recycled three times without a signifi-
cant decrease in the activity.
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
5
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ