Palladium/Acid Relay Catalyzed Tandem Heck Coupling/6-Endo Cyclization between ortho-Halogenated Benzoates and Unactivated Terminal Alkenes for the Synthesis of 1-Isochromanones

Article abstract of DOI:10.1002/adsc.201801507

We report a unique and expeditious route to synthesize 1-isochromanone derivatives through palladium catalyzed tandem Heck coupling/6-endo hydroacyloxylation cyclization between readily available ortho-halogenated benzoates and unactivated alkenes. Various 2-bromo or 2-iodo benzoates can be coupled efficiently with a broad range of alkenes to afford functionalized 1-isochromanones in high yields. Significantly, this cost-efficient and easy-to-handle synthetic methodology will have great prospect application in the synthetic and medicinal chemistry. (Figure presented.).

Full text of DOI:10.1002/adsc.201801507

Title: Palladium/Acid Relay Catalyzed Tandem Heck Coupling/6-
Endo Cyclization between ortho-Halogenated Benzoates
and Unactivated Terminal Alkenes for the Synthesis of 1-
Isochromanones
Authors: Zhenkang Wen, Xiaomin Ge, Zekai Zhao, and Jianbin Chao
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801507
Link to VoR: http://dx.doi.org/10.1002/adsc.201801507

10.1002/adsc.201801507
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium/Acid Relay Catalyzed Tandem Heck Coupling/6-
Endo Cyclization between ortho-Halogenated Benzoates and
Unactivated Terminal Alkenes for the Synthesis of 1-
Isochromanones
Zhen-Kang Wen,*,a Xiao-Min Gea, Ze-Kai Zhaoa and Jian-Bin Chaob
aSchool of Chemistry and Chemical Engineering, Shanxi University,Taiyuan 030006, China. E-mail: zkwen@sxu.edu.cn
bScientific Instrument Center, Shanxi University, Taiyuan 030006, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
due to the specific reaction conditions, which
synthesize 1-isochromanone derivatives through palladium significantly limits their practicality and generality.
Abstract. We report a unique and expeditious route to
catalyzed
tandem
Heck
coupling/6-endo
Therefore, exploitation of novel and general synthetic
methodology for functionalized 1-isochromanones
from readily available starting materials during a
single procedure is highly demand but still remains
great challenges.
hydroacyloxylation cyclization between readily available
ortho-halogenated benzoates and unactivated alkenes.
Various 2-bromo or 2-iodo benzoates can be coupled
efficiently with a broad range of alkenes to afford
functionalized 1-isochromanones in high yields.
Significantly, this cost-efficient and easy-to-handle
synthetic methodology will have great prospect application
in the synthetic and medicinal chemistry.
Scheme 1. Overview and context of work
Keywords: 1-isochromanone; hydroacyloxylation; 6-endo
cyclization; unactivated alkenes; ortho-halogenated
benzoates
Substituted 1-isochromanones, which contain six-
membered cyclic lactone structure motifs (Scheme
1a), are widely found in a large number of bioactive
natural products and pharmaceuticals.[1] Moreover,
molecules bearing isochromanone moieties display a
variety of pharmacological properties,[2] including
antibacterial, antimalarial, anti-inflammatory, anti-
ulcer and antineoplastic properties, etc. Such diverse
biological activities lead this class of compounds to
be one of the most fascinating candidates for new
drug development. During the past decades,
considerable efforts3 have been devoted towards
synthesis
including directed ortho-lithiation of arenes,[3a], [3b] Pd
catalyzed carbonylation of
of
functionalized
isochromanones,
Recently, Lewis acidic metal[4] or Brønsted acid[5]
catalyzed intramolecular hydroalkoxylation of
hydroxyl substituted alkenes has been emerged as a
powerful strategy to effectively construct five- or six-
membered cycloethers through 5-exo or 6-endo
cyclization manner. In this context, intramolecular
hydroacyloxylation[4d, e,g], [6] of alkenyl carboxylic acid
would present a straightforward route to γ- or δ-
lactones with perfect atom economy. However,
examples of hydroacyloxylation of 2-alkenylbenzoic
acids are rarely reported possibly due to the
difficulties in preparation of high polarity and
aromatic alcohol homologues (Scheme 1b path A),[3c],
[3d] selective oxidation[3e] of isochromanes, NHC[3f], [3g]
catalyzed 4+2 annulation of in situ generated o-
quinodimethane intermidiates with ketones (Scheme
1b, path B). Unfortunately, existing approaches
usually suffer from the requiste of additional
synthetic and purification steps to prepare
sophisticated starting materials, and/or the use of
toxic CO under carefully operation, limited substrate
scope as well as poor functional group compatibility
1
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10.1002/adsc.201801507
Advanced Synthesis & Catalysis
relatively unstable carboxylic acids. In 2015,
Shigehisa[7] reported a solution to this problem by
using alkenyl ester as substrates for direct
hydroacyloxylation to afford lactones, although only
several 3-methyl substituted 1-isochromanones were
obtained by this approach (Scheme 1c). These
encouraging achievements led us to consider whether
hydroacyloxylation of ortho-olefinated benzoate ester
could be enabled through 6-endo cyclization process
with Markovnikov selectivity. However, to the best
of our knowledge, there have never been any
examples of 6-endo hydroacyloxylation of 2-
alkenylbenzoate ester to date. Additionally, if tandem
intermolecular Heck coupling and 6-endo cyclization
could occur in one pot (Scheme 1d), this would
provide expeditious synthesis of 1-isochromanone
derivatives between readily available ortho-
halogenated benzoate and simple alkenes, which
avoid the multi-step synthesis of prefunctionalized
substrates. Herein, we report a palladium/acid relay
catalyzed tandem Heck coupling/6-endo cyclization
to afford 1-isochromanones, starting from readily
of 3a. Among them, (4-CF3C6H4)3P proved to be
optimal (entry 7). Solvent effects revealed the mixed
solvent HFIP/o-xylene was superior, while other
solvent system led to decreased yield of 3a formation
(entry 8-11). Notably, when phosphine ligand was
replaced with N-acetyl-protected amino acid[11] along
with addition of DMSO as a minor solvent to
stabilize the Pd(0) complex, the similar results was
also achieved (entry 12-16), wherein Ac-Cys-OH
exhibits the best performance. Thus, two efficient
methods for the facile synthesis of 1-isochromanones
have been established (entry 7 and entry 12), starting
from readily available 2-iodobenzoate and
unactivated alkenes.
Table 1. Optimization Conditionsa,b
entry
1c
2
3
4
5
6
7
8
ligand
-
solvent
yield
0
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
available
ortho-halogenated
benzoates
and
-
33
63
68
67
65
91
30
70
53
0
89
34
70
76
34
unactivated alkenes. Notably, this method displays
outstanding 6-endo regioselectivity with broad
substrate scope and excellent functional group
(C6F5)3P
Cy3P
(2-furyl)3P
tBu3P·HBF4
compatibility, which provides
a
novel bond-
disconnection route to streamline high-value 1-
isochromanones synthesis.
(4-CF3C6H4)3P HFIP/o-xylene (1:1)
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
Ac-Cys-OH
Ac-Cys-OH
Ac-Val-OH
o-xylene
HFIP
HFIP/dioxane (1:1)
HFIP/DCE
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
HFIP/o-xylene (1:1)
Our strategy aims to couple ortho-iodo benzoate ester
with unactivated alkene to generate Heck adducts
(Int-1) in situ, followed by a subsequent 6-endo
hydroacyloxylation of Int-1 to give the desired 1-
isochromanones. The implementation of this strategy
relies on successful addressing the following key
challenges. First, compared with conjugated enones,
disubstituted aliphatic alkenes are challenging
coupling partners in Heck reactions[8] owing to the
lack of electron directing groups to enhance reactivity
and the subtle difference of β-H atoms in the
generated alkyl-Pd species, which usually afforded
linear and branched alkene isomers. Moreover, Heck
coupling typically required stoichiometric bases
which will inevitably inhibit the intramolecular
hydroacyloxylation. Thus, developing a suitable
catalytic system that are compatible with both Heck
coupling and cyclization in a tandem sequence is
essential. Second, undesirable side reactions such as
homo-coupling of aryl halides[9] and dimerization of
olefins[10] must be inhibited by precise control over
reaction conditions.
9
10
11
12d
13e
14d
15d
16d
Ac-Ile-OH
Ac-Gly-OH
aConditions: The reaction was conducted with 1a (0.25
mmol), 2a (2 equiv), Pd(OAc)2 (0.1 equiv), ligand (0.2
equiv), Ag2CO3 (2 equiv), additive (0.1 equiv) in solvent
o
b
c
(1 mL) at 130 C stirred for 24 h. Isolated yield. In the
d
absence of TsOH·H2O Addition of 0.05 mL DMSO as
minor cosolvent. eIn the absence of DMSO.
With the optimized reaction conditions in hand, we
examined the generality of this cascade reaction of 2-
iodobenzoate (1a) with a variety of unactivated
alkenes. As illustrated in Scheme 2, all reactions
proceeded smoothly with either optimized phosphine
ligand or N-acetyl protected amino acid to give
desired products in moderate to high yields. Various
-methyl styrenes bearing substituents with different
electron properties are compatible with the reaction
conditions (3a-3l). In addition, ortho-, meta-, and
para-substituted -methyl styrenes were all tolerated,
and a wide range of functional groups, such as fluoro,
chloro, methoxyl, ester and nitro, are compatible
under the reaction conditions. Other 1,1-disubstituted
alkenes, including 1,1-diphenyl (3m), ethyl (3n), 2-
thiophenyl (3o), 1,1'-biphenyl (3p), 2-naphth (3q)
functionalities, are also efficiently transformed to
We commenced our study by investigating various
reaction conditions for the envisioned reaction of
methyl 2-iodobenzoate (1a) with α-methyl styrene
(2a). The reaction was initially conducted in the
presence of Pd(OAc)2 catalyst, and Ag2CO3 as a base
o
in mixed solvent HFIP/o-xylene at 130 C for 24 h.
Pleasingly, when use of catalytic TsOH·H2O as
Brønsted acid catalyst, the desired product 3a was
obtained in 33% yield (table 1, entry 1-2). The use of
phosphine ligands (entry 3-6) which is expected to
stabilize Pd catalyst dramatically enhanced the yield
2
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10.1002/adsc.201801507
Advanced Synthesis & Catalysis
give the corresponding products. Furthermore, when
methylenecyclohexane derivatives were employed in
this reaction system, the corresponding spirocyclic
products (3r, 3s, 3t) were obtained in reasonable
yields. Additionally, both tert-butyl alcohol[12] and
tert-amyl alcohol[13] are employed as suitable alkene
precursors to give the target products (3u, 3v) in high
yields by using amino acid ligand, in which alcohols
served as olefin equivalents to generate gases
isobutylene and 2-methyl-1-butene in situ
respectively. Furthermore, besides 1,1-disubstituted
alkenes, other monosubstituted alkenes and 1,2-
disubstituted alkenes such as styrene (3w) and
cyclohexene (3v), can also effectively reacted with 2-
iodobenzoate to deliver the desired products in
moderate yields. However, when linear internal
alkene was empoyed as substrate, only trace amount
of the product (3y) was obtained possibly owing to
the electronic and steric effects of 2-methylbut-2-ene.
methylbenzoates was also examined. As shown in
scheme 3, all reactions worked well to give the
desired products in moderate to high yields. 2-bromo
methylbenzoates with different substitutes at the
ortho, para, meta position all reacted well with -
methyl styrene to deliver products. A variety of
functional groups such as alkyl (5b, 5c), methoxyl
(5d), ester (5e), chloro (5f, 5g, 5h) are tolerated under
the reaction conditions. In addition, methyl 3-bromo-
2- naphthoate (5i) also efficiently reacted with -
methyl styrene to furnish the lactonization product.
Scheme 3. Scope of the 2-Bromo Benzoatea,b
Scheme 2. Scope of the Alkene Coupling Componenta,b
aConditions: The reaction was conducted with 4a-4i (0.25
mmol), 2a (0.5 mmol, 2 equiv). bIsolated yield. c12 h.d48 h
To acquire further insight into the mechanism of
palladium
catalyzed
Heck
coupling/hydroacyloxylation cascade reactions, we
became intrigued in exploring its mode of action by
conducting several control experiments. Initially, the
successful transformation of Heck adduct 6 to the
corresponding hydroacyloxylation product 3a (eq 1)
revealed that Heck reaction occurred first in our
protocol, the resulting Heck adduct 6 was possibly
the key intermediate and TsOH was crucial for such
hydroacyloxylation reaction. Further examination of
hydrolyzed Heck product 6b also led to the formation
of 3a (eq 2), thus providing strong support for a
aConditions: The reaction was conducted with 1a (0.25
mmol), 2a-2x (2 equiv), Pd(OAc)2 (0.1 equiv), ligand (0.2
equiv.), Ag2CO3 (2 equiv.), TsOH·H2O (0.1 equiv.) in
hydroacyloxylation
process.
Moreover,
the
employment of radical trapping reagent TEMPO in
the reaction did not significantly affect the yield of
product (eq 3), which ruled out a radical process of
this reaction.[7] Finally, 2 mmol scale reactions of this
protocol (eq 4) demonstrated the potential utility of
our methodology in organic synthesis.
o
HFIP/o-xylene (0.5 mL/0.5 mL) at 130 C stirred for 24 h.
A: (4-CF3C6H4)3P (0.2 equiv.) were added as ligand; B:
Ac-Cys-OH (0.2 equiv.) were added as ligand along with
b
c
d
0.05 mL DMSO. Isolated yield. Stirred for 48 h. 1.5
e
equivalents alkenes. 3 equiv. alcohols served as alkene
equivalents, 0.4 equiv. TsOH·H2O, reaction was conducted
for 6 h. f0.5 equiv Ag2CO3.g0.2 equiv. TsOH·H2O.
It’s known that 2-bromo benzoates are less reactive[14]
in oxidative addition reactions but much cheaper than
their iodo analogues. To our delight, 2-bromo
benzoate (4a, Scheme 3) proved to be viable substrate
in our tandem Heck coupling/hydroacyloxylation
process when using (4-CF3C6H4)3P as the ligand,
whereas amino acid ligand proved to be ineffective to
bromo analogues. Thus, the scope of diverse 2-bromo
3
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10.1002/adsc.201801507
Advanced Synthesis & Catalysis
through p- conjugated effect[15] from esters to give
oxonium intermediate C. Finally, elimination of the
alkyl group from C[7], [16] to afford the desired product
D. The intermediate E was trapped by HRMS
experiment (see supporting information). In addition,
an alternative proposed mechanism (Route B) could
not be rule out. Begin with a subsequent 6-endo
cyclization of Heck adduct (A) , wherein the oxygen
of carbonyl ester served as a nucleophile to attack the
activated alkene moiety (F) to give a 6-membered
benzyl palladium intermediate (G), which undergoes
protonation and elimination of the oxonium alkyl
group to give the desired 1-isochromanones and the
active Pd(II) spiecies.
Scheme 5. Proposed Mechanism
In addition, various benzoate derivatives were
examined with -methyl styrene under reaction
conditions (Scheme 4). Benzoic acid (1aa, 1ab), no
matter its ortho-position is substituted with iodo or
bromo atom, did not furnish the product at all under
the standard reaction conditions. While the
corresponding esters such as ethyl (1ac), tert-butyl
(1ad), tert-pentyl ester (1ae) gave the desired product
with comparable lower yield likely due to the steric
hindrance of alkyl group. Furthermore, 2-iodo
benzamide (1af) also proved to be a suitable substrate
in this process.
In conclusion, we have developed a novel efficient
method for the facile synthesis of 1-isochromanones,
starting from the readily available o-bromo/iodo
benzoate and simple unactivated alkenes. Mechanism
study revealed that this unprecedented reaction
proceed in a Heck coupling/hydroacyloxylation
cascade reactions. A broad range of alkenes including
1,1-disubstituted terminal alkenes, cyclohexene and
monosubstituted styrene are all compatible with this
reaction system to provide the corresponding
isochromanones in moderate to high yields. We
expect that this strategy will provide an efficient and
straightforward route to construct isochromanone
scaffolds with versatile uses in synthetic and
medicinal applications. Further application of this
approach towards total synthesis of useful natural
products are now in progress in our laboratory.
Scheme 4. Mechanistic Insight from O-Alkyl Group
Variance of the Reactiona
aConditions: The reaction was conducted with 1aa-1af
(0.25 mmol), 2a (2 equiv). The yields were determined by
isolated yields. b48 h.
Experimental Section
General Procedure for the Tandem Heck Coupling/6-
endo Cyclization Reactions
A 10 mL reaction tube equipped with a magnetic stirring
bar was added with substituted methyl 2-iodobenzoate
derivative (0.25 mmol), alkene homologues (1.5-2 equiv),
tris[4-(trifluoromethyl)phenyl]phosphine (0.05 mmol, 0.2
equiv), Ag2CO3 (0.5 mmol, 2 equiv), Pd(OAc)2 (0.025
mmol, 0.1 equiv), TsOH·H2O (0.025 mmol, 0.1 equiv) in
0.5/0.5 mL HFIP/o-xylene. The tube was stirred at 130 °C
for 24 h. The reaction mixture was cooled to room
temperature, followed by the addition of water and ethyl
Based on these results, a plausible mechanism of this
cascade reaction was proposed in scheme 5. Once the
Heck adduct A was formed, electrophilic addition of
A with a proton cation was occurred to give a
carbocation intermediate B (Route A), which was
rapidly trapped by oxygen atom in carbonyl group
4
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10.1002/adsc.201801507
Advanced Synthesis & Catalysis
acetate. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3×15 mL). The
combined organic layer was washed with brine and dried
over anhydrous Na2SO4, filtrated and concentrated in
vacuo, the residue was purified through column
chromatography on silica gel to give the desired products.
Y. J. Li, J. L. Wang, S. Q. Wu, W. Xue, S. Yang, Y. R.
Chi, Org. Lett. 2018, 20, 333-336; h) E. T. da Penha, J.
A. Forni, A. F. P. Biajoli, C. R. D. Correia,
Tetrahedron Lett. 2011, 52, 6342-6345; i) S. Crespi, S.
Jager, B. Konig, M. Fagnoni, Eur. J. Org. Chem. 2017,
2147-2153.
Acknowledgements
[4] a) L. Ferrand, Y. Tang, C. Aubert, L. Fensterbank, V.
Mouriꢀs-Mansuy, M. Petit, M. Amatore, Org. Lett.
2017, 19, 2062-2065; b) S. Sultana, N. R. Devi, A. K.
Saikia, Asian J. Org. Chem. 2015, 4, 1281-1288; c) A.
K. Diba, J. M. Begouin, M. Niggemann, Tetrahedron
Lett. 2012, 53, 6629-6632; d) L. A. Adrio, L. S. Quek, J.
G. Taylor, K. K. Hii, Tetrahedron 2009, 65, 10334-
10338; e) T. Ohta, Y. Kataoka, A. Miyoshi, Y. Oe, I.
Furukawa, Y. Ito, J. Organomet. Chem. 2007, 692,
671-677; f) Y. Ito, R. Kato, K. Hamashima, Y. Kataoka,
Y. Oe, T. Ohta, I. Furukawa, J. Organomet. Chem.
2007, 692, 691-697; g) C. G. Yang, N. W. Reich, Z. J.
Shi, C. He, Org. Lett. 2005, 7, 4553-4556; h) L.
Coulombel, I. Favier, E. Duñach, Chem. Commun.
2005, 2286-2288; i) H. Qian, X. Q. Han, R. A.
Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536-9537.
This work was financially supported by the National Natural
Science Foundation of China (21502106), the National Natural
Science Foundation for Young Scientists of Shanxi Province
(201701D221028) and the Ministry of Human Resources and
Social Security Foundation of China for High-level Returned
Talents. We are also very grateful for the test platform provided
by Scientific Instrument Center of Shanxi University.
References
[1] a) For representative examples: a) I. V. Prokhorova, K.
A. Akulich, D. S. Makeeva, I. A. Osterman, D. A.
Skvortsov, P. V. Sergiev, O. A. Dontsova, G.
Yusupova, M. M. Yusupov, S. E. Dmitriev, Sci. Rep.
2016, 6, 27720; b) G. H. Ma, B. Jiang, X. J. Tu, Y.
Ning, S. J. Tu, G. G. Li, Org. Lett. 2014, 16, 4504-4507;
c) S. Pal, V. Chatare, M. Pal, Curr. Org. Chem. 2011,
15, 782-800; d) S. K. Mandal, S. C. Roy, Tetrahedron
Lett. 2007, 48, 4131-4134; e) P. Jiao, J. B. Gloer, J.
Campbell, C. A. Shearer, J. Nat. Prod. 2006, 69, 612-
615; e) T. Yasuda, S. Kayaba, K. Takahashi, T.
Nakazawa, K. Ohsawa, J. Nat. Prod. 2004, 67, 1604-
1607; f) M. Yamato, K. Hashigaki, M. Ikeda, H.
Ohtake, K. Tasaka, J. Med. Chem., 1981, 24, 194-198.
[5] a) N. Tsuji, J. L. Kennemur, T. Buyck, S. Lee, S.
Prévost, P. S. J. Kaib, D. Bykov, C. Farès, B. List,
Science 2018, 359, 1501-1505; b) A. Theodorou, C. G.
Kokotos, Green Chem., 2017, 19, 670-674; c) S. Fujita,
M. Abe, M. Shibuya, Y. Yamamoto, Org. Lett. 2015,
17, 3822-3825; d) D. A. Nicewicz, D. S. Hamilton,
Synlett 2014, 25, 1191-1196; e) D. S. Hamilton, D. A.
Nicewicz, J. Am. Chem. Soc. 2012, 134, 18577-18580;
f) D. C. Rosenfeld, S. Shekhar, A. Takemiya, M.
Utsunomiya, J. F. Hartwig, Org. Lett. 2006, 8, 4179-
4182; g) L. Coulombel, E. Duñach, Green Chem. 2004,
6, 499-501.
[2] a) J. Barbier, R. Jansen, H. Irschik, S. Benson, K.
Gerth, B. Böhlendorf, G. Höfle, H. Reichenbach, J.
Wegner, C. Zeilinger, A. Kirsching, R. Müller, Angew.
Chem. Int. Ed. 2012, 51, 1256-1260; Angew. Chem.
2012, 124, 1282-1286; b) S. Bräse, A. Encinas, J. Keck,
C. F. Nising, Chem. Rev., 2009, 109, 3903-3990; c) P.
Kongsaeree, S. Prabpai, N. Sriubolmas, C. Vongvein, S.
Wiyakrutta, J. Nat. Prod. 2003, 66, 709-711; d) S.
Kamisuki, C. Murakami, K. Ohta, H. Yoshida, F.
Sugawara, K. Sakaguchi, Y. Mizushina, Biochem.
Pharmacol., 2002, 63, 421-427; e) M. Yoshikawa, E.
Uchida, N. Chatani, N. Murakami, J. Yamahara, Chem.
Pharm. Bull. 1992, 40, 3121-3123; f) M. Toshikawa, E.
Uchida, N. Chatani, H. Kobayashi, Y. Naitoh, Y.
Okuno, H. Matsuda, J. Yamahara, N. Murakami, Chem.
Pharm. Bull. 1992, 40, 3352-3354; g) N. Fusetani, T.
Sugawara, S. Matsunaga, H. Hirota, J. Org. Chem.
1991, 56, 4971-4974; h) K. Nozawa, M. Yamada, Y.
Tsuda, K. Kawai, S. Nakajima, Chem. Pharm. Bull.
1981, 29, 2689-2691.
[6] a) X. Chaminade, L. Coulombel, S. Olivero, E. Duñach,
Eur. J. Org. Chem. 2006, 2006, 3554-3557; b) K.
Komeyama, Y. Mieno, S. Yukawa, T. Morimoto, K.
Takaki, Chem. Lett. 2007, 36, 752-753; c) L. J. Gooßen,
D. M. Ohlmann, M. Dierker, Green Chem. 2010, 12,
197-200; d) M. Sakuma, A. Sakakura, K. Ishihara, Org.
Lett. 2013, 15, 2838-2841; e) M. Nagamoto, T.
Nishimura, Chem. Commun. 2015, 51, 13466-13469.
[7] H. Shigehisa, M. Hayashi, H. Ohkawa, T. Suzuki, H.
Okayasu, M. Mukai, A. Yamazaki, R. Kawai, H.
Kikuchi, Y. Satoh, A. Fukuyama, K. Hiroya, J. Am.
Chem. Soc. 2016, 138, 10597-10604.
[8] a) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170-
1214; b) M. S. Sigman, E. W. Werner, Acc. Chem. Res.
2011, 45, 874-884; c) I. P. Beletskaya, A. V.
Cheprakov, Chem. Rev. 2000, 100, 3009-3066. d) P.
Sun, X. M. Qu, T. Y. Li, Y. Zhu, H. L. Yang, Z. Y.
Xing, J. C. Mao, Synlett 2012, 23, 150-154.
[3] a) S. Essig, D. Menche, J. Org. Chem. 2016, 81, 1943-
1966; b) B. A. Egan, M. Paradowski, L. H. Thomas, R.
Marquez, Org. Lett. 2011, 13, 2086-2089; c) Y. Lu, D.
S. Leow, X. S. Wang, K. M. Engle, J. Q. Yu, Chem.
Sci., 2011, 2, 967-971; d) A. Cowell, J. K. Stille, J. Am.
Chem. Soc., 1980, 102, 4193-4198; e) Z. G. Zhang, Y.
Gao, Y. Liu, J. J. Li, H. X. Xie, H. Li, W. Wang, Org.
Lett. 2015, 17, 5492-5495; f) D. Janssen-Müller, S.
Singha, T. Olyschläger, C. G. Daniliuc, F. Glorius, Org.
Lett. 2016, 18, 4444-4447; g) H. L. Wang, X. K. Chen,
[9] D. D. Hennings, T. Iwama, V. H. Rawal, Org. Lett.
1999, 1, 1205-1208.
[10] Z. K. Wen, Y. H. Xu, T. P. Loh, Chem. Sci. 2013, 4,
4520-4524.
[11] a) K. M. Engle, D. H. Wang, J. Q. Yu, J. Am. Chem.
Soc., 2010, 132, 14137-14151; b) Y. Lu, D. H. Wang,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801507
Advanced Synthesis & Catalysis
K. M. Engle, J. Q. Yu, J. Am. Chem. Soc., 2010, 132,
5916-5921; c) D. H. Wang, K. M. Engle, B. F. Shi, J. Q.
Yu, Science, 2010, 327, 315-319.
[14] J. F. Hartwig, In Organotransition Metal Chemistry:
From Bonding to Catalysis; University Science Books:
Sausalito, 2010.
[12] a) J. Buter, D. Heijnen, C. Vila, V. Hornillos, E. Otten, [15] a) D. J. Faizi, A. Issaian, A. J. Davis, S. A. Blum, J.
M. Giannerini, A. J. Minnaard, B. L. Feringa, Angew.
Chem., Int. Ed. 2016, 55, 3620-3624; Angew. Chem.
2016, 128, 3684-3688; b) D. Ley, D. Gerbig, P. R.
Schreiner, Chem. Sci. 2013, 4, 677-684; c) S. N. Rao, R.
A. M. O'Ferrall, S. C. Kelly, D. R. Boyd, R. Agarwal, J.
Am. Chem. Soc. 1993, 115, 5458-5465.
Am. Chem. Soc. 2016, 138, 2126-2129; b) Y. Kita, T.
Yata, Y. Nishimoto, K. Chiba, M. Yasuda, Chem. Sci.
2018, 9, 6041-6052.
[16] a) Y. Kita, T. Yata, Y. Nishimoto, K. Chiba, M.
Yasuda, Chem. Sci., 2018, 9, 6041-6052; b) B. Mir-
Mohamad-Sadeghy, B. Rickborn, J. Org. Chem., 1984,
49, 1477-1481.
[13] a) Á. Molnár, M. Bartók, Tetrahedron 1987, 43, 131-
141; b) C. Uncuta, T. S. Balaban, M. D. Gheorghiu, L.
Stănescu, A. Petride, A. T. Balaban, Tetrahedron Lett.
1985, 26, 4673-4676; c) P. Wolkoff, J. Org. Chem.,
1982, 47 1944-1948.
6
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10.1002/adsc.201801507
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium/Acid Relay Catalyzed Tandem Heck
Coupling/6-Endo Cyclization between ortho-
Halogenated Benzoates and Unactivated Terminal
Alkenes for the Synthesis of 1-Isochromanones
Adv. Synth. Catal. Year, Volume, Page – Page
Zhen-Kang Wen,*,a Xiao-Min Gea, Ze-Kai Zhaoa
and Jian-Bin Chaob
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