Pd-Catalyzed Enantioselective Double Heck Reaction

Article abstract of DOI:10.1021/acs.orglett.9b03517

An asymmetric Pd-catalyzed intramolecular followed by an intermolecular double Heck reaction of arenediazonium salts with simple alkenes is disclosed. This reaction features mild reaction conditions, simple operation, and excellent functional group tolera

Full text of DOI:10.1021/acs.orglett.9b03517

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Enantioselective Double Heck Reaction
Baihang Ju, Shigui Chen,* and Wangqing Kong*
The Center for Precision Synthesis (CPS), Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s
Republic of China
S
* Supporting Information
ABSTRACT: An asymmetric Pd-catalyzed intramolecular
followed by an intermolecular double Heck reaction of
arenediazonium salts with simple alkenes is disclosed. This
reaction features mild reaction conditions, simple operation,
and excellent functional group tolerance and provides a rapid
access to functionalized dihydrobenzofurans bearing all-
carbon quaternary centers in good regioselectivity (>95/5)
and enantioselectivity (90−99% ee).
he fused tricyclic dihydrobenzofuran framework repre-
sents a prevalent core structure present in a large number
of natural products such as Isoabietenin A, Parviflorene J,
Morphine, and its derivatives (Codeine, Thebaine, and
Codeinone), which show a wide range of important bio-
logically activities (Figure 1).1 Therefore, it is not surprising
Scheme 1. Transition-Metal-Catalyzed Double Heck
Reaction
T
Figure 1. Representative examples of biologically active molecules
and natural products.
that enormous efforts have been devoted to developing new
transformations to synthesize this privileged structural
skeleton.2 Nevertheless, efficient methods for their enantiose-
lective preparation are still rare. Therefore, it is highly desirable
to develop new strategies to access these scaffolds.
transition metal catalyzed redox-neutral aryl-alkenylation
reaction of aryl halides with vinylmetallic reagents has also
been well investigated (Scheme 1A, bottom).5 However,
asymmetric transformation has not been reported.6 Only
recently, the Zhang group reported the Pd-catalyzed
enantioselective aryl-alkenylation reaction of aryl halides with
vinyl boronic acids.7 However, the above-mentioned methods
are limited to the use of pregenerate coupling partners (the
vinylmetallic reagents or vinylhalides), which require many
stoichiometric transformations for their preparation.
On the other hand, catalytic asymmetric dicarbofunctional-
ization of alkenes by simultaneously installing two carbon
groups on each side of the double bond has experienced
remarkable progress and emerged as a powerful synthetic tool
for constructing molecules containing quaternary stereo-
centers.3 Among them, the double Heck reaction is a
particularly appealing transformation, since it not only offers
a facile route to diverse cyclic scaffolds having all-carbon
quaternary centers, but also the introduced alkenyl group can
be further functionalized. Our group recently reported the first
example of a highly enantioselective aryl-alkenylation reaction
by Ni-catalyzed reductive cyclizative cross-coupling of an aryl
bromide with a vinyl bromide (Scheme 1A, top).4 In addition,
The direct double Heck reaction with nonfunctionalized
olefins is a significantly more efficient and atom-economical
Received: October 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03517
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
strategy. A single racemic example of a double Heck reaction of
aryl iodide with methyl acrylate has been reported; however, a
mixture of products was obtained (Scheme 1B),8 which draws
into question the generality of this approach. To solve this
problem, we anticipated that a mild generation of active
arylmetallic species is critical for success. Inspired by the
seminal contributions by Correia9 as well as Sigman and
Toste10 on enantioselective Heck−Matsuda reactions, we
expected to achieve an enantioselective double Heck reaction
of aryldiazonium salts with simple alkenes by utilizing the
ability of aryldiazonium salts to be easily available and highly
reactive.11 Herein, we report the first catalytic enantioselective
double Heck reaction that provides access to functionalized
dihydrobenzofurans bearing all-carbon quaternary centers
(Scheme 1C). This protocol reported in this work proceeds
under open flask and mild conditions without requiring
anhydrous solvents and air-sensitive chiral phosphines ligands.
Our investigations commenced with the coupling of
arenediazonium salt 1a and methyl acrylate 2a. Gratefully,
the desired E-configuration dihydrobenzofuran 3aa was
obtained exclusively in 74% yield using Pd(OAc)2 (10 mol
%) as a catalyst in the absence of ligand (Table 1, entry 1).
This result may indicate that controlling the enantioselectivity
of the reaction is challenging because of the background
reaction. Facing the challenge, we decided to employ the same
protocol to test the asymmetric transformation using (S)-tBu-
Pyrox (L1) as a chiral ligand, affording 3aa in 75% yield, albeit
with only 9% ee (entry 2). Subsequently, we found that the
anions in palladium catalysts had a great influence on both the
efficiency and enantioselectivity (entries 3−5). PdCl2 was
found to be particularly effective in terms of enantioselectivity
(entry 5, 77% ee), albeit with a lower yield. Attempts to add
DTBMP, a highly efficient organic base in asymmetric Heck−
Matsuda reaction,12 or the addition of carbonates such as
Na2CO3 or K2CO3 as base,13 inhibited the desired domino
process (entries 6−8). To our surprise, noteworthy improve-
ment of the yield to 90% was observed when Ag2CO3 was used
as an additive (entry 9). Next, the chiral ligands L2−L14 were
examined (entries 11−23), and L14 proved to be the most
effective, delivering 3aa in 65% yield with 82% ee (entry 23).
Gratefully, when lowering the reaction temperature to 10 °C,
the enantioselectivity of 3aa could be improved to 94% (3aa/
3aa′ > 95/5, entry 24).14 We assume that the cationic pathway
might be established by removing chloride ions through
Ag2CO3, so only catalytic amounts of silver salt are sufficient.
To our surprise, the enantioselectivity was significantly reduced
with 10 mol % of Ag2CO3 (entry 25, 60% ee). Obviously, the
addition of Ag2CO3 was beneficial for both the reactivity and
enantioselectivity. Although the role of Ag2CO3 is unclear, we
suspect that it may play a dual role, not only as a Lewis acid to
promote the oxidative addition of Pd(0) to arenediazonium
salt but also as a chloride scavenger.
Table 1. Optimization of the Reaction Conditions
yield of 3aa
ee of 3aa
b
c
entry
[Pd]
additive
ligand
(%)
(%)
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(dba)2
PdCl2
−
−
−
−
−
L1
L1
L1
74
75
26
28
−
9
20
37
77
−
5
−
L1
9
6
7
8
9
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DTBMP
Na2CO3
K2CO3
Ag2CO3
Ag3PO4
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
trace
trace
trace
90
83
trace
14
71
56
31
83
89
57
62
85
87
52
65
79
−
−
74
69
−
67
69
70
73
67
1
79
17
48
69
81
82
94
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
L9
L10
L11
L12
L13
L14
L14
L14
PdCl2
PdCl2
PdCl2
PdCl2
d
24
25
e
76
a
1a (0.1 mmol), 2a (0.2 mmol), Pd-catalyst (10 mol %), ligand (20
mol %), additive (0.1 mmol) in solvent (1 mL) at 40 °C for 24 h,
b
c
3aa/3aa′ > 95/5. Isolated yields. Determined by HPLC analysis
d
with a chiral column. Reaction was performed at 10 °C for 4 days.
e
Reaction was conducted with 10 mol % of Ag2CO3. DTBMP = 2,6-
di-tert-butyl-4-methylpyridine.
distinguished by an exquisite chemoselectivity profile, as
methoxyl (3ae, 3ap, and 3as), fluoro (3ag, 3ar, and 3at),
nitro (3ah), trifluoromethyl (3ai), trifluoromethoxyl (3am),
ester (3al), or chloro (3aq) could all be perfectly
accommodated. Particularly interesting was the observation
that the presence of bromo atom on the aromatic ring did not
interfere, affording 3ak and 3ao in good yields without traces
of the further competing Heck coupling product being
observed, thus providing opportunities for further derivatiza-
tion by cross-couplings.
The substrate scope of arenediazonium salts 1 was examined
next (Scheme 3). Dihydrobenzofurans 3bk−fk were obtained
in good yields and high enantioselectivities (90%−92% ee)
regardless of whether the para-substitutions of arenediazonium
salts are electron-donating or electron-withdrawing groups.
The meta-substituted arenediazonium salts all posed no
With the optimized reaction conditions in hand (Table 1,
entry 24), the substrate scope of alkenes 2 was first explored
(Scheme 2). Gratifyingly, the reaction showed excellent
regioselectivity to produce the E-configuration linear product
3 rather than the branched product 3′ in almost all cases (3/3′
> 95/5). In addition to acrylates, both the electron-rich and
electron-deficient styrenyl derivatives can undergo cyclizative
cross-coupling to provide the desired dihydrobenzofurans
3ac−at in good yields with high enantioselectivities (90%−
97% ee). Notably, the inclusion of an ortho-substituent did not
hinder the reaction (3aq). The reaction was rather general and
B
DOI: 10.1021/acs.orglett.9b03517
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of Alkenes 2
Scheme 4. Gram-Scale Reaction and Synthetic Applications
a
3-Chloro-2-methylprop-1-ene (1.5 equiv), K2CO3 (3 equiv),
b
c
acetone, 65 °C. Zn0, MeOH/NH4Cl. HBF4, NaNO2 (2.5 equiv),
H2O, 0 °C, 68% (three steps). m-CPBA = meta-chloroperbenzoic
acid.
nium salt 1a was synthesized from inexpensive and
commercially available 2-nitrophenol in three steps without
the need for column chromatographic separation. The
preparative utility of this key double Heck reaction was
evaluated using 1.3 g of substrate 1a to afford the desired
product 3ac in 80% yield with 94% ee value. The double bond
was then epoxidized in the presence of m-CPBA to afford the
corresponding epoxide 4 in 80% yield (1.1/1 dr). Further
investigations with other Brønsted or Lewis acids found that
BF3·Et2O was the best to furnish product 5 with high
diastereoselectivity (100/13).15
In summary, we have demonstrated a facile and efficient
protocol for the construction of functionalized dihydrobenzo-
furans through the Pd-catalyzed double Heck reaction of
arenediazonium salts with simple alkenes. This reaction
features mild reaction conditions, simple operation, and
excellent functional group tolerance and exhibits exquisite
regioselectivity (>95/5) and enantioselectivity (90%−99% ee).
In addition, this reaction has been applied to efficient synthesis
of athe enantiopure tricyclic dihydrobenzofuran scaffold from
commercially available and inexpensive 2-nitrophenol.
a
b
3/3′ > 95/5, unless noted otherwise. 5 equiv of 2t were used; 3at/
3at′ = 92/8.
a
Scheme 3. Substrate Scope of Arenediazonium Salts 1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03517.
Experimental procedures and spectra data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sgchen@whu.edu.cn.
*E-mail: wqkong@whu.edu.cn.
ORCID
Wangqing Kong: 0000-0003-3260-0097
Notes
a
3/3′ > 95/5, unless noted otherwise.
The authors declare no competing financial interest.
problems (3gk−hk). However, the reaction of arenediazonium
salt with a monosubstituted olefin was unsuccessful (3ik).
Given the wide structural diversity of chiral fused tricyclic
dihydrobenzofurans in target compounds as illustrated in
Figure 1, a further synthetic application of this catalytic double
Heck reaction was proven by efficient synthesis of fused
tricyclic dihydrobenzofuran 5 (Scheme 4). The arenediazo-
ACKNOWLEDGMENTS
■
This work was supported by the “1000-Youth Talents Plan”,
National Natural Science Foundation of China (Nos.
21702149, 21702153), Wuhan University, and Fundamental
Research Funds for the Central Universities (2042018kf0012,
2042018kf0003).
C
DOI: 10.1021/acs.orglett.9b03517
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Li, Y.; Huang, B.; Liang, R.; Jia, Y.-X. Enantioselective Dearomative
Difunctionalization of Indoles by Palladium-Catalyzed Heck/Sonoga-
shira Sequence. Angew. Chem., Int. Ed. 2017, 56, 7475−7478.
(m) Zhang, Z.; Xu, B.; Qian, Y.; Wu, L.; Wu, Y.; Zhou, L.; Liu, Y.;
Zhang, J. Palladium-Catalyzed Enantioselective Reductive Heck
Reactions: Convenient Access to 3,3-Disubstituted 2,3-Dihydroben-
zofuran. Angew. Chem., Int. Ed. 2018, 57, 10373−10377. (n) Zhang,
Z.; Xu, B.; Wu, L.; Zhou, L.; Ji, D.; Liu, Y.; Li, Z.; Zhang, J.
Palladium/XuPhos-Catalyzed Enantioselective Carboiodination of
Olefin-Tethered Aryl Iodides. J. Am. Chem. Soc. 2019, 141, 8110−
8115. (o) Shen, C.; Zeidan, N.; Wu, Q.; Breuers, C. B. J.; Liu, R.; Jia,
Y.-X.; Lautens, M. Pd-catalyzed dearomative arylborylation of indoles.
Chem. Sci. 2019, 10, 3118−3122.
REFERENCES
■
(1) (a) Gomez, F.; Quijano, L.; Calderon, J. S.; Rodriquez, C.; Rios,
T. Prenylflavans from Tephrosia watsoniana. Phytochemistry 1985, 24,
1057−1059. (b) Tamaki, M.; Sadhu, S. K.; Ohtsuki, T.; Toume, K.;
Koyano, T.; Kowithayakorn, T.; Hayashi, M.; Komiyama, K.;
Ishibashi, M. Parviflorene J, a Cytotoxic Sesquiterpene Dimer with
a New Rearranged Skeleton from Curcuma parviflora. Heterocycles
2007, 72, 649−654. (c) Yang, J.-H.; Du, X.; He, F.; Zhang, H.-B.; Li,
X.-N.; Su, J.; Li, Y.; Pu, J.-X.; Sun, H.-D. Bioactive Abietane and ent-
Kaurane Diterpenoids from Isodon tenuifolius. J. Nat. Prod. 2013, 76,
256−264.
(2) For reviews on the total synthesis of morphine and its
derivatives, see: (a) Chida, N. Recent Advances in the Synthesis of
Morphine and Related Alkaloids. Top. Curr. Chem. 2010, 299, 1−28.
(b) Rinner, U.; Hudlicky, T. Synthesis of Morphine Alkaloids and
Derivatives. Top. Curr. Chem. 2011, 309, 33−66. (c) Li, Q.; Zhang, H.
Research Progress on the Synthesis of Morphine Alkaloids. Youji
Huaxue 2017, 37, 1629−1652. For references on total synthesis of
morphine and its derivatives by intramolecular Heck reaction, see:
(d) Hong, C. Y.; Kado, N.; Overman, L. E. Asymmetric Synthesis of
Either Enantiomer of Opium Alkaloids and Morphinans. Total
Synthesis of (−)- and (+)-Dihydrocodeinone and (−)- and
(+)-Morphine. J. Am. Chem. Soc. 1993, 115, 11028−11029.
(e) Liou, J. P.; Cheng, C. Y. Total synthesis of ( )-desoxycodeine-
D: a novel route to the morphine skeleton. Tetrahedron Lett. 2000, 41,
915−918. (f) Trost, B. M.; Tang, W. P. Enantioselective Synthesis of
(−)-Codeine and (−)-Morphine. J. Am. Chem. Soc. 2002, 124,
14542−14543. (g) Trost, B. M.; Tang, W. P.; Toste, F. D. Divergent
Enantioselective Synthesis of (−)-Galanthamine and (−)-Morphine.
J. Am. Chem. Soc. 2005, 127, 14785−14803. (h) Uchida, K.;
Yokoshima, S.; Kan, T.; Fukuyama, T. Total Synthesis of
( )-Morphine. Org. Lett. 2006, 8, 5311−5313. (i) Omori, A. T.;
Finn, K. J.; Leisch, H.; Carroll, R. J.; Hudlicky, T. Chemoenzymatic
Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck
Cyclizations via C-B-D Ring Construction. Synlett 2007, 2007, 2859−
2862. (j) Varin, M.; Barre, E.; Iorga, B.; Guillou, C. Diastereoselective
Total Synthesis of ( )-Codeine. Chem. - Eur. J. 2008, 14, 6606−6608.
(3) For reviews on asymmetric alkene dicarbofunctionalization
reactions, see: (a) Ping, Y.; Li, Y.; Zhu, J.; Kong, W. Construction of
Quaternary Stereocenters by Palladium-Catalyzed Carbopalladation-
Initiated Cascade Reactions. Angew. Chem., Int. Ed. 2019, 58, 1562−
1573. (b) DeLuca, R. J.; Stokes, B. J.; Sigman, M. S. The Strategic
Generation and Interception of Palladium-Hydrides for Use in Alkene
Functionalization Reactions. Pure Appl. Chem. 2014, 86, 395−408.
(c) Giri, R.; KC, S. Strategies toward Dicarbofunctionalization of
Unactivated Olefins by Combined Heck Carbometalation and Cross-
Coupling. J. Org. Chem. 2018, 83, 3013−3022. (d) Dhungana, R. K.;
KC, S.; Basnet, P.; Giri, R. Transition Metal-Catalyzed Dicarbofunc-
tionalization of Unactivated Olefins. Chem. Rec. 2018, 18, 1314−
1340. For selected examples, see: (e) Cong, H.; Fu, G. C. Catalytic
Enantioselective Cyclization/Cross-Coupling with Alkyl Electrophiles.
J. Am. Chem. Soc. 2014, 136, 3788−3791. (f) Stokes, J. B.; Liao, L.; de
Andrade, A. M.; Wang, Q.; Sigman, M. S. A Palladium-Catalyzed
Three-Component-Coupling Strategy for the Differential Vicinal
Diarylation of Terminal 1,3-Dienes. Org. Lett. 2014, 16, 4666−4669.
(g) Shen, C.; Liu, R.-R.; Fan, R.-J.; Li, Y.-L.; Xu, T.-F.; Gao, J.-R.; Jia,
Y.-X. Enantioselective Arylative Dearomatization of Indoles via Pd-
Catalyzed Intramolecular Reductive Heck Reactions. J. Am. Chem. Soc.
2015, 137, 4936−4939. (h) Yue, G.; Lei, K.; Hirao, H.; Zhou, J. S.
Palladium-Catalyzed Asymmetric Reductive Heck Reaction of Aryl
Halides. Angew. Chem., Int. Ed. 2015, 54, 6531−6535. (i) You, W.;
Brown, M. K. Catalytic Enantioselective Diarylation of Alkenes. J. Am.
Chem. Soc. 2015, 137, 14578−14581. (j) Kong, W.; Wang, Q.; Zhu, J.
Palladium-Catalyzed Enantioselective Domino Heck/Intermolecular
C-H Bond Functionalization: Development and Application to the
Synthesis of (+)-Esermethole. J. Am. Chem. Soc. 2015, 137, 16028−
16030. (k) Kong, W.; Wang, Q.; Zhu, J. Water as a Hydride Source in
Palladium-Catalyzed Enantioselective Reductive Heck Reactions.
Angew. Chem., Int. Ed. 2017, 56, 3987−3991. (l) Liu, R.; Wang, Y.;
(4) (a) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W. Ni-Catalyzed
Enantioselective Reductive Diarylation of Activated Alkenes by
Domino Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2018, 140,
12364−12368. (b) Li, Y.; Ding, Z.; Lei, A.; Kong, W. Ni-Catalyzed
enantioselective reductive aryl-alkenylation of alkenes: application to
the synthesis of (+)-physovenine and (+)-physostigmine. Org. Chem.
Front. 2019, 6, 3305−3309. (c) Tian, Z.; Qiao, J.; Xu, G.; Pang, X.;
Qi, L.; Ma, W.; Zhao, Z.; Duan, J.; Du, Y.; Su, P.; Liu, X.; Shu, X.
Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of
Unactivated Alkenes. J. Am. Chem. Soc. 2019, 141, 7637−7643.
(5) (a) Seashore-Ludlow, B.; Somfai, P. Domino Carbopalladation-
Cross-Coupling for the Synthesis of 3,3-Disubstituted Oxindoles. Org.
Lett. 2012, 14, 3858−3861. (b) Zhou, M.-B.; Huang, X.-C.; Liu, Y.-Y.;
Song, R.-J.; Li, J.-H. Alkylation of Terminal Alkynes with Transient σ-
Alkylpalladium(II) Complexes: A Carboalkynylation Route to Alkyl-
Substituted Alkynes. Chem. - Eur. J. 2014, 20, 1843−1846. (c) Packer,
G.; Lepre, K.; Kankanala, J.; Sridharan, V. Bimetallic (Cu/Pd)
catalytic cascade reactions to 3,3-disubstituted oxindole analogues.
RSC Adv. 2014, 4, 3457−3460. (d) Vachhani, D. D.; Butani, H. H.;
Sharma, N.; Bhoya, U. C.; Shah, A. K.; Van der Eycken, E. V. Domino
Heck/borylation sequence towards indolinone-3-methyl boronic
esters: trapping of the σ-alkylpalladium intermediate with boron.
Chem. Commun. 2015, 51, 14862−14865. (e) Liu, R.-R.; Xu, T.-F.;
Wang, Y.-G.; Xiang, B.; Gao, J.-R.; Jia, Y.-X. Palladium-catalyzed
dearomative arylalkynylation of indoles. Chem. Commun. 2016, 52,
13664−13667. (f) You, W.; Brown, M. K. Diarylation of Alkenes by a
Cu-Catalyzed Migratory Insertion/Cross-Coupling Cascade. J. Am.
Chem. Soc. 2014, 136, 14730−14733. (g) Wu, L.; Wang, F.; Wan, X.;
Wang, D.; Chen, P.; Liu, G. Asymmetric Cu-Catalyzed Intermolecular
Trifluoromethylarylation of Styrenes: Enantioselective Arylation of
Benzylic Radicals. J. Am. Chem. Soc. 2017, 139, 2904−2907. (h) Gao,
P.; Chen, L.; Brown, M. K. Nickel-Catalyzed Stereoselective
Diarylation of Alkenylarenes. J. Am. Chem. Soc. 2018, 140, 10653−
10657. (i) Shrestha, B.; Basnet, P.; Dhungana, R. K.; KC, S.; Thapa,
S.; Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective 1,2-
Dicarbofunctionalization of Olefins by Intercepting Heck Intermedi-
ates as Imine-Stabilized Transient Metallacycles. J. Am. Chem. Soc.
2017, 139, 10653−10656. (j) Li, W.; Boon, J. K.; Zhao, Y. Nickel-
catalyzed difunctionalization of allyl moieties using organoboronic
acids and halides with divergent regioselectivities. Chem. Sci. 2018, 9,
600−607. (k) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.;
Engle, K. M. Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl
Carbonyl Compounds via Conjunctive Cross-Coupling. J. Am. Chem.
Soc. 2017, 139, 10657−10660. (l) Liu, Z.; Zeng, T.; Yang, K. S.;
Engle, K. M. β,γ-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl
Compounds via Directed Nucleopalladation. J. Am. Chem. Soc. 2016,
138, 15122−15125.
(6) (a) Fretwell, P.; Grigg, R.; Sansano, J. M.; Sridharan, V.;
Sukirthalingam, S.; Wilson, D.; Redpath, J. Palladium Catalysed
Tandem Cyclisation−Anion Capture Processes. Part 4: Organotin-
(IV) Transfer Agents. Tetrahedron 2000, 56, 7525−7539. (b) Li, Y.;
Wang, K.; Ping, Y.; Wang, Y.; Kong, W. Nickel-Catalyzed Domino
Heck Cyclization/Suzuki Coupling for the Synthesis of 3,3-
Disubstituted Oxindoles. Org. Lett. 2018, 20, 921−924. (c) Piou,
T.; Neuville, L.; Zhu, J. Spirocyclization by Palladium-Catalyzed
Domino Heck-Direct C-H Arylation Reactions: Synthesis of
D
DOI: 10.1021/acs.orglett.9b03517
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Spirodihydroquinolin-2-ones. Org. Lett. 2012, 14, 3760−3763.
(d) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Pd-Catalyzed Heck-Type
Cascade Reactions with N-Tosyl Hydrazones: An Efficient Way to
Alkenes via in Situ Generated Alkylpalladium. Org. Lett. 2013, 15,
4814−4817. (e) Gao, Y.; Wu, W.; Jiang, H.; Yang, X.; Liu, W.; Li, C.-
J. Palladium-Catalyzed Tandem Oxidative Arylation/Olefination of
Aromatic Tethered Alkenes/Alkynes. Chem. - Eur. J. 2017, 23, 793−
797. (f) Schempp, T. T.; Daniels, B. E.; Staben, S. T.; Stivala, C. E. A
General Strategy for the Construction of Functionalized Azaindolines
via Domino Palladium-Catalyzed Heck Cyclization/Suzuki Coupling.
Org. Lett. 2017, 19, 3616−3619 and references therein.
(7) Zhang, Z.; Xu, B.; Wu, L.; Wu, Y.; Qian, Y.; Zhou, L.; Liu, Y.;
Zhang, J. Enantioselective Dicarbofunctionalization of Unactivated
Alkenes by Palladium-Catalyzed Tandem Heck/Suzuki Coupling
Reaction. Angew. Chem., Int. Ed. 2019, 58, 14653−14659.
(8) Szlosek-Pinaud, M.; Diaz, P.; Martinez, J.; Lamaty, F. Efficient
synthetic approach to heterocycles possessing the 3,3-disubstituted-
2,3-dihydrobenzofuran skeleton via diverse palladium-catalyzed
tandem reactions. Tetrahedron 2007, 63, 3340−3349.
Anion Phase-Transfer of Aryl Diazonium Salts. Angew. Chem., Int. Ed.
2017, 56, 5806−5811. (h) Reddi, Y.; Tsai, C.; Avila, C. M.; Toste, F.
D.; Sunoj, R. B. Harnessing Noncovalent Interactions in Dual-
Catalytic Enantioselective Heck-Matsuda Arylation. J. Am. Chem. Soc.
2019, 141, 998−1009.
(11) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Diazonium
̃
Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions.
Chem. Rev. 2006, 106, 4622−4643.
(12) (a) Angnes, R. A.; Oliveira, J. M.; Oliveira, C. C.; Martins, N.
C.; Correia, C. R. D. Stereoselective Synthesis of Aryl Cyclopentene
Scaffolds by Heck-Matsuda Desymmetrization of 3-Cyclopentenol.
Chem. - Eur. J. 2014, 20, 13117−13121. (b) Kattela, S.; Heerdt, G.;
Correia, C. R. D. Non-Covalent Carbonyl-Directed Heck−Matsuda
Desymmetrizations: Synthesis of Cyclopentene-Fused Spirooxindoles,
Spirolactones, and Spirolactams. Adv. Synth. Catal. 2017, 359, 260−
267. (c) de Oliveira, J. M.; Angnes, R. A.; Khan, I. U.; Polo, E. C.;
Heerdt, G.; Servilha, B. M.; da Silva, V. H. M.; Braga, A. A. C.;
Correia, C. R. D. Enantioselective, Noncovalent, Substrate-Directable
Heck−Matsuda and Oxidative Heck Arylations of Unactivated Five-
Membered Carbocyclic Olefins. Chem. - Eur. J. 2018, 24, 11738−
11747.
(9) (a) Correia, C. R. D.; Oliveira, C. C.; Salles, A. G., Jr.; Santos, E.
A. F. The first examples of the enantioselective Heck−Matsuda
reaction: arylation of unactivated cyclic olefins using chiral bisoxazo-
lines. Tetrahedron Lett. 2012, 53, 3325. (b) Oliveira, C. C.; Angnes, R.
A.; Correia, C. R. D. Intermolecular Enantioselective Heck−Matsuda
Arylations of Acyclic Olefins: Application to the Synthesis of β-Aryl-γ-
lactones and β-Aryl Aldehydes. J. Org. Chem. 2013, 78, 4373−4385.
(c) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Quaternary
Stereogenic Centers through Enantioselective Heck Arylation of
Acyclic Olefins with Aryldiazonium Salts: Application in a Concise
Synthesis of (R)-Verapamil. Angew. Chem., Int. Ed. 2015, 54, 14036−
14039. (d) de Azambuja, F. de; Carmona, R. C.; Chorro, T. H. D.;
Heerdt, G.; Correia, C. R. D. Noncovalent Substrate-Directed
Enantioselective Heck Reactions: Synthesis of S-and P-Stereogenic
Heterocycles. Chem. - Eur. J. 2016, 22, 11205−11209. (e) Khan, I. U.;
Kattela, S.; Hassan, A.; Correia, C. R. D. Enantioselective total
synthesis of the highly selective sphingosine-1-receptor VPC01091 by
the Heck desymmetrization of a non-activated cyclopentene-fused
spiro-pyrrolidinone. Org. Biomol. Chem. 2016, 14, 9476−9480.
(f) Silva, A. R.; Polo, E. C.; Martins, N. C.; Correia, C. R. D.
Enantioselective Oxy-Heck-Matsuda Arylations: Expeditious Syn-
thesis of Dihydrobenzofuran Systems and Total Synthesis of the
Neolignan (−)-Conocarpan. Adv. Synth. Catal. 2018, 360, 346−365.
(13) Although ZnCO3 is widely used in asymmetric Heck−Matsuda
reactions, it is not commercially available.
(14) Gao, Y.; Xiong, W.; Chen, H.; Wu, W.; Peng, J.; Gao, Y.; Jiang,
H. Pd-Catalyzed Highly Regio- and Stereoselective Formation of C-C
Double Bonds: An Efficient Method for the Synthesis of Benzofuran-,
Dihydrobenzofuran-, and Indoline-Containing Alkenes. J. Org. Chem.
2015, 80, 7456−7467.
̈
(15) Muhlthau, F.; Schuster, O.; Bach, T. High Facial Diaster-
eoselectivity in Intra- and Intermolecular Reactions of Chiral Benzylic
Cations. J. Am. Chem. Soc. 2005, 127, 9348−9349.
̈
(g) Carmona, R. C.; Koster, O. D.; Correia, C. R. D. Chiral N,N
Ligands Enabling Palladium-Catalyzed Enantioselective Intramolecu-
lar Heck-Matsuda Carbonylation Reactions by Sequential Migratory
and CO Insertions. Angew. Chem., Int. Ed. 2018, 57, 12067−12070.
(10) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a
Redox-Relay Strategy. Science 2012, 338, 1455−1458. (b) Stokes, J.
B.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. A Palladium-
Catalyzed Three-Component-Coupling Strategy for the Differential
Vicinal Diarylation of Terminal 1,3-Dienes. Org. Lett. 2014, 16,
4666−4669. (c) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu,
Y.-D.; Sigman, M. S.; Wiest, O. Mechanism, Reactivity, and Selectivity
in Palladium-Catalyzed Redox-Relay Heck Arylations of Alkenyl
Alcohols. J. Am. Chem. Soc. 2014, 136, 1960−1967. (d) Yamamoto,
E.; Hilton, M. J.; Orlandi, M.; Saini, V.; Toste, F. D.; Sigman, M. S.
Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-
Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer. J.
Am. Chem. Soc. 2016, 138, 15877−15880. (e) Nelson, H. M.;
́
Williams, B. D.; Miro, J.; Toste, F. D. Enantioselective 1,1-
Arylborylation of Alkenes: Merging Chiral Anion Phase Transfer
with Pd Catalysis. J. Am. Chem. Soc. 2015, 137, 3213−3216.
(f) Orlandi, M.; Hilton, M. J.; Yamamoto, E.; Toste, F. D.; Sigman,
M. S. Mechanistic Investigations of the Pd(0)-Catalyzed Enantiose-
lective 1,1-Diarylation of Benzyl Acrylates. J. Am. Chem. Soc. 2017,
139, 12688−12695. (g) Avila, C. M.; Patel, J. S.; Reddi, Y.; Saito, M.;
Nelson, H. M.; Shunatona, H. P.; Sigman, M. S.; Sunoj, R. B.; Toste,
F. D. Enantioselective Heck-Matsuda Arylations through Chiral
E
DOI: 10.1021/acs.orglett.9b03517
Org. Lett. XXXX, XXX, XXX−XXX