Palladium-Catalyzed Sequential Nucleophilic Addition/Oxidative Annulation of Bromoalkynes with Benzoic Acids to Construct Functionalized Isocoumarins

Article abstract of DOI:10.1021/acs.orglett.7b01919

An efficient and robust protocol for the preparation of 3-substituted isocoumarins via palladium-catalyzed nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids has been developed. Remarkably, preliminary mechanistic studies indicated that the transformation might proceed via a stereo- and regioselective nucleophilic addition and C-H functionalization procedure.

Full text of DOI:10.1021/acs.orglett.7b01919

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Sequential Nucleophilic Addition/Oxidative
Annulation of Bromoalkynes with Benzoic Acids To Construct
Functionalized Isocoumarins
Guangbin Jiang, JianXiao Li, Chuanle Zhu, Wanqing Wu,* and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and robust protocol for the preparation of 3-substituted isocoumarins via palladium-catalyzed
nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids has been developed. Remarkably, preliminary
mechanistic studies indicated that the transformation might proceed via a stereo- and regioselective nucleophilic addition and C−
H functionalization procedure.
Scheme 1. Previous Work and This Work
socoumarins, especially 3-substituted isocoumarins, are an
I
important scaffold of various natural products.1,2 They not
only show a broad range of biological and pharmaceutical
activities, such as antitumor,3 anti-inflammatory,4 antibacterial,5
antifungal,6 antidiabetic,7 immunomodulatory, and anti-HIV,8
but also serve as useful and significant precursors for the
synthesis of isocarbostyrils, isoquinolines, and isochromenes.9
Due to the substantial applicability of isocoumarins, remarkable
efforts have been devoted to develop efficient strategies for the
synthesis of this scaffold.10 For instance, Matsubara and co-
workers reported a novel procedure for the synthesis of highly
functionalized isocoumarins via Ni-induced decarboxylation of
anhydrides with alkynes.11 Subsequently, Ackermann and
Warratz reported that isocoumarins were synthesized by
ruthenium-catalyzed annulations of benzoic acids with
alkynes.12 However, most of the reported methods are only
applicable to the synthesis of 3,4-disubstituted isocoumarins.
Hence, it is highly desirable to further develop a novel and
efficient strategy for the construction of 3-substituted
isocoumarins.
During the past decades, haloalkynes have become powerful
and highly versatile building blocks in organic chemistry, which
exhibit abundant and tunable reactivities particularly in the
presence of transition metal catalysts.13 Therefore, remarkable
efforts have been devoted to the synthesis of a valuable scaffold
from haloalkynes.14 Previously, we have reported a series of
nucleophilic addition of fluoride,15 iodide,16 acetate,17 iso-
cyanide18 and sulfide19 to haloalkynes, providing the trisub-
stituted alkenes in excellent yields with exclusive Z-type
configuration (Scheme 1, eq 1). In continuation of our interest
in the field of haloalkyne chemistry, herein, we disclose an
efficient strategy for the synthesis of 3-substituted isocoumarins
via Pd-catalyzed nucleophilic addition/oxidative annulation of
bromoalkynes with benzoic acids (Scheme 1 eq 2).
(Bromoethynyl)benzene 1a and benzoic acid 2a were used as
the model substrate for the studies. A series of Pd catalysts were
initially screened with 15 mol % of ligand and 2.0 equiv of
K2CO3 in 2 mL of solvent (DMSO/EtOH = 2:1) at 120 °C for
20 h. As shown in Table 1, the reaction outcome was highly
dependent on the Pd(0) generated in situ (Table 1, entries 1−
4), and the best result was obtained with Pd(TFA)2.
Furthermore, various phosphine ligands were screened.
Notably, DPEPhos (bis[2-(diphenylphosphino)phenyl] ether)
increased the yield of 3a from 49% to 83% (Table 1, entries 5−
7). Control experiments revealed that both the palladium
catalyst and phosphine ligand were critical for this trans-
Received: June 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01919
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of Isocoumarin Derivatives from a
a
Range of Bromoalkynes and Benzoic Acid
b
entry
catalyst
ligand
PPh3
temp (°C)
base
yield (%)
1
Pd(PPh3)4
PdCl2
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
120
120
120
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
MeONa
Na2CO3
−
9
2
PPh3
37
3
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
−
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
PPh3
41
4
PPh3
49
5
XantPhos
DPEPhos
dppf
65
6
83 (76)
52
7
8
−
n.d.
n.d.
trace
trace
69
9
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhoe
DPEPhos
DPEPhos
DPEPhos
10
11
12
13
14
15
n.d.
76
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
82
c
16
57
d
17
e
59 (54)
46 (41)
18
a
A mixture of 1a (0.2 mmol), 2a (0.1 mmol), base (0.2 mmol),
catalyst (10 mol %), ligand (15 mol %), and DMSO/EtOH = 2:1 (2
mL) was sealed in a 25 mL Schlenk tube at 120 °C for 20 h under N2.
b
GC yield based on 2a using dodecane as internal standard. The
c
number in the parentheses is isolated yield. n.d. = not detected. 6 mol
% of catalyst was used. 4a was used for product 3a. 5a was used for
d
e
a
product 3a.
A mixture of 1 (0.2 mmol), 2a (0.1 mmol), K2CO3 (0.2 mmol),
Pd(TFA)2 (10 mol %), DPEPhos (15 mol %), and DMSO/EtOH =
2:1 (2 mL) was sealed in a 25 mL Schlenk tube at 120 °C for 20 h
b
c
formation (Table 1, entries 8−9). Subsequently, a variety of
different inorganic bases were examined, and the best result was
obtained in the presence of potassium carbonate (Table 1,
entries 10−12). No product was obtained in the absence of the
base (Table 1, entry 13). Additionally, a lower or higher
reaction temperature reduced the yields slightly (Table 1,
entries 14−15). Unfortunately, product 3a was detected in 57%
yield when the reaction was performed with a lower dosage (6
mol %) of Pd(TFA)2 (Table 1, entry 16). With
(chloroethynyl)benzene 4a or (iodoethynyl)benzene 5a as
the substrate, the desired product 3a was also obtained in
reasonable yield (Table 1, entries 17−18). It is noteworthy to
mention that the reaction was rather sensitive to solvent and
DMSO/EtOH = 2:1 was found to be much better than other
solvents (see Supporting Information for details).
With the optimal conditions established, the generality of the
new protocol was subsequently investigated (Scheme 2).
Gratifyingly, a variety of aryl bromoalkynes with different
substituent groups on the phenyl ring underwent annulation
with benzoic acid to furnish the desired products 3a−3t in
moderate to excellent yields. Generally, both electron-donating
and -withdrawing groups at the phenyl ring were compatible
with the catalytic system. Substituents at the para-, ortho-, or
meta-position did not influence the yields dramatically (3a−3r).
Additionally, 2-(bromoethynyl)-1,3-dimethylbenzene worked
well under the standard reaction conditions, converting to the
corresponding isocoumarin 3s in 67% yield. Notably, 2-
(bromoethynyl)naphthalene was also suitable for this catalytic
system and transferred to the desired product 3t in 73% yield.
under N2. Yields refer to isolated yield. 1 mmol scale. 3 equiv of 1ak
were used.
Furthermore, the reaction also proceeded smoothly with
aliphatic bromoalkynes, which gave the corresponding iso-
coumarins in moderate to good yields (3u−3al). Remarkably,
double bromoalkyne was found to yield 3ak in an inferior
isolated yield, albeit 3 equiv of double bromoalkynes were
introduced incrementally. It is worth noting that the alkyl
alkynes derived bromoalkynes that contained the valuable
methoxy group could be converted to the nucleophilic
addition/oxidative annulation product in 66% yield as well
(3al). Finally, a scale-up reaction of (bromoethynyl)benzene 1a
and benzoic acid 2a was tested; delightfully, this transformation
could be achieved on 1 mmol scale and proceeded smoothly to
give desired product 3a with an acceptable decrease in yield
(60%).
To further define the scope of our protocol, we then
evaluated the compatibility of various benzoic acids in this
transformation (Scheme 3). Under the optimized reaction
conditions, various benzoic acid derivatives with p-Me, p-Et, p-t-
Bu, p-Ph, p-OMe, and p-CF3 substituents were explored,
delivering the corresponding isocoumarins 3am−3ar in 65−
83% yields. Furthermore, fluorine and chloride groups were
tolerated, providing the opportunity for further synthetic
applications via classic cross-coupling reactions (3as−3av).
Significantly, various meta-substituted benzoic acids, such as
−CF3, −CH3, and −OCH3 substitutions, were transformed to
the desired products in moderate yields (3aw−3ay) with an
B
DOI: 10.1021/acs.orglett.7b01919
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Isocoumarin Derivatives from a
Range of Benzoic Acids and (Bromoethynyl)benzene
Scheme 4. Control Experiments
a
a
A mixture of 1a (0.2 mmol), 2 (0.1 mmol), K2CO3 (0.2 mmol),
Pd(TFA)2 (10 mol %), DPEPhos (15 mol %), and DMSO/EtOH =
2:1 (2 mL) was sealed in a 25 mL Schlenk tube at 120 °C for 20 h
under N2. Yields refer to isolated yield.
exclusive regioisomer. To our delight, when using the
disubstituted arenecarboxylic acids as the substrates, the
corresponding products could be isolated in 43−59% yields
(3az−3bb).
Scheme 5. Proposed Mechanism
To further clarify the possible mechanism, a series of
mechanistic experiments were performed as shown in Scheme
4. When 2a and bromoalkynes (1) were treated in solvent
(DMSO/EtOH = 2:1) using K2CO3 (2 equiv) as base, low
yields of the corresponding nucleophilic addition products, (Z)-
2-bromovinyl benzoates (6a and 6b), were obtained (Scheme
4, eq 3). Similarly, the reaction of 2,6-dimethoxybenzoic acid
and (bromoethynyl)benzene resulted in the formation of
product 6c in 39% yield (Scheme 4, eq 4). However, when
the Pd(TFA)2 and DPEPhos were used, the isolated yield of 6c
decreased from 39% to 37% (Scheme 4, eq 5), implying that
the Pd(TFA)2 might be uninvolved in the nucleophilic addition
process. Pleasingly, when (Z)-2-bromovinyl benzoates were
subjected to the standard reaction conditions, the desired
products 3a and 3f were produced in 81% and 84% yields,
respectively (Scheme 4, eq 6). Therefore, we presumed that the
consumption of (Z)-2-bromovinyl benzoate A in the catalytic
cycle increased its generation significantly. Finally, the trans-
formation exhibited an intermolecular kinetic isotope effect
both in a competitive experiment (kH/kD = 4.0) and in parallel
reactions (kH/kD = 4.5) (Scheme 4, eq 7), which indicated that
the C−H bond cleavage process should be the turnover-
limiting step in the catalytic cycle.
intermediate B. Finally, the reductive elimination of B affords
the coupling product 3 and regenerates the active Pd(0) species
for the next catalytic cycle.
In summary, we have established the Pd-catalyzed
nucleophilic addition/oxidative annulation of bromoalkynes
with benzoic acids, which provides an efficient strategy to
construct 3-substituted isocoumarins. In addition, the cis-
nucleophilic addition and C−H functionalization were regarded
as the key procedures for this reaction. Remarkably,
commercially available benzoic acids without preactivation
and a one-pot procedure make this strategy attractive and
practical. Further studies will be focused on the synthetic
applications of this method, and the results will be reported in
due course.
In light of the above observations and previous reports,14i,20
a
plausible mechanism for this Pd-catalyzed ortho-C(sp2)−H
functionalization for the synthesis of isocoumarin derivatives is
presented in Scheme 5. Initially, cis-nucleophilic addition of
benzoic acids 2 to bromoalkynes 1 gave the intermediate 6,
which would undergo oxidative addition to Pd(0) species to
generate intermediate A. Next, ortho-C(sp2)−H activation
results in the formation of seven-membered palladacyclic
C
DOI: 10.1021/acs.orglett.7b01919
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01919.
■
S
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
(11) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2008,
130, 17226.
AUTHOR INFORMATION
Corresponding Authors
■
(12) Warratz, S.; Kornhaaβ, C.; Cajaraville, A.; Niepotter, B.; Stalke,
̈
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
D.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 5513.
(13) (a) Wu, W.; Jiang, H. Acc. Chem. Res. 2014, 47, 2483. (b) Jiang,
H.; Zhu, C.; Wu, W. Haloalkyne Chemistry; Springer: Heidelberg,
2016; pp 1−77. (c) Trofimov, A.; Chernyak, N.; Gevorgyan, V. J. Am.
Chem. Soc. 2008, 130, 13538. (d) Yoo, W.-J.; Allen, A.; Villeneuve, K.;
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Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Key Research and Develop-
ment Program of China (2016YFA0602900), the National
Natural Science Foundation of China (21490572 and
21420102003), and Pearl River S&T Nova Program of
Guangzhou (201610010160).
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