Distal Alkenyl C-H Functionalization via the Palladium/Norbornene Cooperative Catalysis

Article abstract of DOI:10.1021/jacs.9b11479

A distal-selective alkenyl C-H arylation method is reported through a directed palladium/norbornene (Pd/NBE) cooperative catalysis. The key is to use an appropriate combination of the directing group and the NBE cocatalyst. A range of acyclic and cyclic c

Full text of DOI:10.1021/jacs.9b11479

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Communication
Distal Alkenyl C-H Functionalization via the
Palladium/Norbornene Cooperative Catalysis
Zhao Wu, Nina Fatuzzo, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11479 • Publication Date (Web): 29 Jan 2020
Downloaded from pubs.acs.org on January 29, 2020
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Journal of the American Chemical Society
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Distal Alkenyl C−H Functionalization via the Palladium/Norbornene
Cooperative Catalysis
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Zhao Wu, Nina Fatuzzo, and Guangbin Dong*
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
consequently enrich methods for regioselective synthesis
of trisubstituted alkenes. Herein, we describe our initial
development of a distal alkenyl C−H functionalization
strategy via the palladium/norbornene (NBE) cooperative
catalysis (Scheme 1c).
ABSTRACT: A distal-selective alkenyl C−H arylation
method
is
reported
through
a
directed
palladium/norbornene (Pd/NBE) cooperative catalysis.
The key is to use an appropriate combination of the
directing group and the NBE co-catalyst. A range of
acyclic and cyclic cis-olefins are suitable substrates, and
the reaction is operated under air with excellent site-
selectivity. Preliminary mechanistic studies are consistent
with the proposed Pd/NBE-catalyzed C−H activation
instead of the Heck pathway. Initial success on distal
alkylation has also been achieved using MeI and methyl
bromoacetate as electrophiles.
Scheme 1. Trisubstituted Olefins
a) Common approaches for preparing trisubstituted olefines
C
H
B
A
P
[
]
O
C
B
H
B
A
HX
X
C
Y
A
C
H
H
B
A
B
A
b) Directed alkenyl CH activation
FG
H
Trisubstituted olefins are prevalent structural motifs
found in numerous natural products1 and other
biologically active compounds;2 they often serve as
versatile synthetic intermediates to access various other
functional groups, such as epoxides, aziridines and
cyclopropanes as well as tertiary stereocenters.3 Typically,
trisubstituted olefins are prepared through olefination of
carbonyls, hydrofunctionalization of alkynes, cross
couplings and olefin metathesis, etc. (Scheme 1a).
Despite the efficacy of these established approaches, it is
nontrivial to control regio- and stereoselectivity for
synthesis of unsymmetrical trisubstituted olefins
(comparing to disubstituted olefins) in the absence of
steric or electronic bias.4 Alternatively, direct
functionalization of an unactivated alkenyl C−H bond in
1,2-disubstiuted olefins represents an attractive approach
for preparing unsymmetrical trisubstituted alkenes. In
particular, the use of directing groups (DGs) offers a
convenient approach to enhance reactivity and site-
selectivity for the alkenyl C−H activation due to
proximity effect (Scheme 1b).5 To date, a number of
transition metal complexes, e.g. Ru,6 Pd,7 Rh,8 Ir,9 Fe10
and Co11, have been reported to be efficient for
functionalization of the proximal alkenyl C−H bonds.
However, it would be attractive if a complementary
approach can be developed to allow site-selective
activation of the distal alkenyl C−H bonds, which would
H
DG
DG
proximal
distal
established
proximal
H
H
R
DG
metal cat.
FG
R
?
distal
R
c) This work: distal activation
Ar
H
H
H
DG
O
DG
O
Pd
R
R
NBE
ArI
ArI
DG
O
H
Pd
I
Pd
H
NBE
Pd
O
DG
R
O
DG
R
R
II
six-membered
palladacycle
alkenyl-norbornyl
palladacycle
Recently, the Pd/NBE catalysis, originally discovered
by Catellani, has emerged as a powerful tool for arene
functionalization.12 In 2015, the Yu13 and our14 groups
independently reported complementary methods for the
Pd/NBE-catalyzed meta-selective C−H activation
initiated by directed ortho-palladation. An intriguing
question is whether such a distal C−H functionalization
strategy could be extended beyond aromatic substrates,
such as alkenes (Scheme 1c). Started with a directed C−H
palladation at the proximal alkene position, followed by
NBE insertion and a second C−H palladation at the distal
position, an alkenyl-norbornyl palladacycle II would be
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formed, which could react with electrophiles to install a
functional group at the distal carbon. Subsequent NBE
extrusion and re-protonation at the proximal position
complete the catalytic cycle.
Page 2 of 8
To address these challenges, it would be beneficial to
realize fast and reversible proximal C−H palladation
with appropriate DGs. In addition, the structure of NBE
could also be important to minimize undesired side
reactions by serving as a reactive ligand. Moreover, the
DG should be easily installable and removable. To
e x p l o r e t h e p r o p o s e d d i s t a l a l k e n e C − H
functionalization, cis-alkene 1a with an “exo”-type DG17
based on oxime ethers18 was chosen as the initial
substrate and arylation was studied as the model reaction
(Table 1). After careful evaluation of various reaction
parameters, ultimately, the desired C−H arylation
product (3a) was obtained in 76% yield with
Pd(OAc)2/N4 as the catalyst combination, 3-CF3-2-
pyridone as the additive19 and AgOAc as the halide
scavenger in CHCl3 under air (See Supporting
Information for detailed optimization). Other oxime
1
2
3
4
5
6
7
8
However, compared with arenes, several challenges
could be anticipated for activating alkene C−H bonds
with the proposed pathway. The primary concern comes
from the more reactive olefin π bond. Due to the lack of
stability by aromaticity, the C=C bond in alkenes could
easily undergo various π-breaking transformations, such
as reactions with oxidants or electrophiles, leading to
undesired background reactions. Second, the π bond of
alkenes is typically considered to be a better ligand for Pd
than arenes, thus a number of Pd-mediated side reactions,
including 2π-insertion and nucleophilic attack of
coordinated olefins, could compete with the desired C−H
palladation step. Third, after NBE insertion, the alkyl−Pd
intermediate is known to form cyclopropanes easily with
the alkene via migratory insertion, instead of palladation
with the distal C−H bond.15 Hence, limited examples are
known for the Catellani-type reaction of regular alkenyl
substrates.16
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e
t
h
e
r
s
w
e
r
e
a
l
s
o
Table 2. Alkene Scope a
Table 1. Selected Optimization for the C−H Arylation
DG
10 mol % Pd(OAc)2
20 mol % 3-CF3-2-pyridone
DG
H
O
H
O
I
H
Ar
N4
30 mol %
2.0 equiv AgOAc
air
R
CO2Me
R
+
CHCl3 (0.2 M),
100 °C, 12 hrs
standard conditions
1a
1.0 equiv
2a
2.0 equiv
3a
R = CH2CH2Ph
Me
Me
Ar = o-CO2MePh
DG
=
N
DG1
79% isolated
% Yielda
Entry
Variation from standard conditions
None
1
2
3
76%
listed below
0%
-
instead of
DG1
DG2 5
w/o Pd(OAc)2
w/o pyridone ligand
4
5
6
7
16%
0%b
w/o
N4
instead of
listed below
11%
N1-N7
N4
CsOAc instead of AgOAc
F
OMe
MeO
N
N
N
N
N
F
OMe
DG5
68%
DG2
0%
DG3
3%
DG4
0%
O
N
Ph
CN
O
NHMe
O
N1
28%
N2
14%
N3
65%
N4
76%
O
O
CO2Me
CO2Me
MeO
MeHN
N5
65%
N6
60%
N7
26%
a Unless otherwise noted, reactions were run on a 0.2 mmol
1
scale. Yields were determined by H NMR analysis using
CH2Br2 as the internal standard. b 52% Heck product (Z)-3a
observed.
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10 mol % Pd(OAc)2
20 mol % 3-CF3-2-pyridone
30 mol % N4
also delivered the desired product (entry 6),20 though the
imide-based N4 was most reactive.21 Moreover,
replacement of AgOAc with the corresponding cesium
salt was not effective under the standard conditions (entry
7).
DG1
DG1
H
O
H
O
1
2
3
4
5
6
7
8
Ar
R1
H
R1
+
ArI
2.0 equiv AgOAc
CHCl3 (0.2 M), air
100 °C, 12 hrs
3
1
Ar = o-CO2MePh
derived from 2o alcohols:
DG1
O
DG1
O
DG1
O
With the optimized conditions in hand, the alkene scope
was first investigated (Table 2). A range of styrenyl
alkenes bearing both electron-deficient (3b) and -rich (3c)
substituents afforded the desired products in good yields
and excellent regio- and diastereoselectivity. Besides
aliphatic alcohols, benzylic alcohol-derived substrates
also reacted well. It is surprising that the phenyl-
substituted substrate still gave the desired distal alkene-
arylation product (3f) despite the potential side reaction
on the arene, e.g. meta-arylation. It is likely that the
chelation between the cis alkene and the DG inhibited
undesired ortho palladation on the phenyl group. In
addition, cis 1,2-dialkyl-substituted alkenes are
competent substrates (3g-k). Apart from secondary
alcohols, primary alcohol-derived substrates also reacted.
Cyclic alkenes containing six- or eight-membered rings
(3l, 3o) provided the desired products in moderate to good
yields. Reactions with the more challenging linear
alkenes derived from primary alcohols (3p, 3q) showed a
slightly lower efficiency due to the flexibility of the
substrates. Moreover, allylic and homoallylic protected
amines (3r-t) worked well with a modified DG.
Ar
Ar
Ph
Ph
Ar
Ph
CF3
OMe
9
3c, 66%
E only
3a, 79%
E only
3b, 75%
E only
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11
12
13
14
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DG1
F
DG1
O
DG1
O
O
Ar
Ar
Ar
Me
F
OMe
3e, 60%
E only
3f, 63%
E only
3d, 67%
E only
DG1
DG1
DG1
O
O
O
Ar
Ar
Ar
Ph
Ph
Ph
Me
Me
TBSO
3g, 68% b
E/Z = 9 : 1
3h, 74% b
3i, 66% c
Z/E = 15 : 1
E/Z = 18 : 1
DG1
DG1
O
O
Ar
Ar
Ph
Ph
BnO
3j, 52% c
Z/E = 14 : 1
3k, 58% b
E/Z > 20 : 1
derived from 1o alcohols:
O
DG1
O
O
DG1
CO2Me
DG1
CO2Me
CO2Me
The scope of aryl iodides was then explored (Table 3).
Aryl iodides with an ortho electron-withdrawing group
proved to be most efficient, consistent with the typical
Catellani arylation reaction.22 Interestingly, methyl 2,5-
diiodobenzoate can be coupled to give the mono-
alkenylated product 4a in 63% yield, where the iodide
ortho to the ester group reacted exclusively. Electron-
deficient aryl iodides (4b-4e, 4h) generally afforded the
distal arylation products in good yield and excellent E/Z
selectivity, while slightly electron-rich ones (4f and 4g)
gave lower yields and moderate selectivity. Besides esters,
other ortho groups, such as nitro (4d-f), ketone (4i),
tertiary amide (4j) and Weinreb amide (4k), also
delivered the desired products in good yields.
Heteroarenes, such as thiophene (4g) and pyridine (4h),
as well as iodide (4a), bromide (4e) and chloride (4c)
substituents, were tolerated. Aryl iodides without an
ortho electron-withdrawing group were much less
reactive under the current conditions,23 likely due to the
difficulty of the oxidative addition step between the aryl
electrophile and the alkenyl-norbornyl palladacycle.
Beyond arylation, under slightly modified conditions, the
distal C−H alkylation with methyl iodide and methyl
bromoacetate can be achieved in moderate yields (4l-n).
I
CO2Me
3l, 75%
3m, 83%
3n, 57%
Ar
Ar
Ar
O
DG1
O
DG1
O
Me
DG1
3q, 59% b
3p, 69%
E/Z > 20 : 1
3o, 47%
E/Z = 20 : 1
derived from amines:
DG6
Cbz
Ar
N
DG6
Ar
DG6
N
Cbz
N
Cbz
Me
Me
Ar
3s, 84% d
E only
3t, 50% d
E/Z > 20 : 1
3r, 83% d
a Unless otherwise noted, reactions were run on a 0.2 mmol
scale in a 4 mL vial under the standard conditions. Numbers
1
are the isolated yields and E/Z ratio was determined by H
NMR analysis of the reaction crude. b 36 hrs. c 24 hrs. d DG6
= 3-methyl-2-pyridyl, see Supporting Information for
detailed conditions.
investigated as the DG (entry 2). While the aldehyde-
derived ones (DG2-4) were much less reactive, the
cyclohexanone-derived DG5 showed a comparable result.
Control experiments indicate that both palladium and
NBE are essential to this reaction, and diminished yield
was observed in the absence of the pyridone additive
(entries 3-5). Note that the normal Heck product (Z)-3a
was formed dominantly in the absence of NBE (entry 5);
in contrast, under the standard conditions the Heck
reaction was significantly suppressed (vide infra, Scheme
2). In addition, simple NBE and other substituted NBEs
Table 3. Electrophile Scopea
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Page 4 of 8
10 mol % Pd(OAc)2
20 mol % 3-CF3-2-pyridone
alkene substrate (E)-1n gave no desired arylation product,
and Z/E isomerization was not observed under the
standard reaction conditions (Scheme 2d), which rule out
the pathways involving alkene isomerization-then-Heck
or Heck-then-alkene isomerization.
DG1
DG1
H
O
1
2
3
H
O
30 mol % N4
RX
R
+
H
R
R
2.0 equiv AgOAc
CHCl3 (0.2 M), air
100 °C, 12 hrs
Ph
Ph
2
4
1a
2.0 equiv
R = CH2CH2Ph
4
5
6
7
arylation:
CO2Me
DG1
DG1
O
I
Scheme 2. Mechanistic Studies.
O
DG1
O
O
O
R
R
a) Heck pathway:
R
MeO2C
Ph
MeO2C
Ph
Me
Me
MeO2C
Ph
Me
8
9
DG1
-H
elimination
3a, 79%
E only
4a
4b, 80%
E only
, 63%
H
O
N
Ar
N
O
Pd
Ar-Pd-I
Me
H
O
E only
Ph
Et
H
Ph
H
R
H
- Pd–H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
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45
46
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49
50
51
52
53
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57
58
59
60
R
Cl
Ar
Ar
DG1
DG1
Br
R
Ph
DG1
O
1a
3a
(Z)-
O
b) NBE equivalency effect:
R
R
R
DG1
DG1
NO2 Ph
NO2 Ph
DG1
O
O
O
MeO2C
MeO
Ph
standard conditions
Ar
+
ArI
2a
4c, 81%
E only
4d, 74%
E only
4e
, 67%
E only
+
N5
X mol %
34 hrs
Et
Et
3q
3q
(E)-
(Z)-
1o
DG1
DG1
DG1
O
O
Heck product
Catellani product
S
N
R
R
R
3q
3q
(Z)-
(E)-
X mol %
E/Z ratio
MeO2C
NO2 Ph
MeO2C
Ph
Ph
—
0
25
0
70%
14%
4h, 61% b,c
4f, 63%
E only
4g, 61%
E/Z = 4 : 1
2.5 : 1
20 : 1
35%
E only
50
51%
55%
2.5%
< 1 %
DG1
DG1
DG1
O
O
O
100
> 50 : 1
R
R
R
Ph
O
c) deuterium labeling studies
Ph
O
Ph
O
Et2N
Me
MeOMeN
0.22 D
DG1
O
DG1
4j, 59% c
E only
4k, 76%
E only
O
4i, 75%
E only
standard conditions
0.20 D
R
R
w/ 3.0 equiv CD3CO2D
Ph
Ph
w/o ArI
alkylation:
81% yield
1a
DG6
Cbz
DG1
DG1
N
O
O
0.27 D
Ph
Me
Ph
MeO
DG1
R
R
O
DG1
O
O
Ph
54% yield
Ar
Me
R
4l, 31% d
Z only
4m, 65% e
Z only
standard conditions
4n, 25% d
R
ArI
+
3 hrs
Ph
0.14 D
DG1
w/ 1.0 equiv CD3CO2D
2a
1a
O
0.10 D
a Unless otherwise noted, reactions were run on a 0.2 mmol
scale in a 4 mL vial under the standard conditions. Numbers
R
23% yield
d) control experiments
Ph
1
O
no rxn
standard conditions
are the isolated yields and E/Z ratio was determined by H
DG1
Ph
ArI
2a
+
NMR analysis of the reaction crude. b 110 °C. c 24 hrs. d MeI
was used. e Methyl bromoacetate was used.
(E)-1n
w/ 85% RSM
Ph
Ar
standard conditions
w/o ArI
A major competing reaction pathway is the directed
Heck reaction (Scheme 2a). The aryl-Pd(II) species could
undergo directed migratory insertion to the alkene
O
O
DG1
Ar
DG1
Ph
(E)-3p
(Z)-3p
no
w/ 89%
(Z)-3p
훽
followed by -H elimination to give the Z-alkene
From the view of practicality, the Pd loading can be
reduced to 5 mol% on a larger scale (Scheme 3a). The
arylation product can undergo various transformations
(Scheme 3b). For example, the oxime-ether DG can be
easily removed by treatment with Zn and acetic acid. The
olefin moiety can be hydrogenated by Pd/C to deliver
product 6. The Raney nickel-catalyzed condition can
remove the DG and reduce the alkene simultaneously in
a quantitative yield. Gratifyingly, the proximal position
could undergo a further directed C−H/Heck coupling,
which furnished an unsymmetrical tetrasubstituted alkene
(7).26 The linear arylation products after saponification
can be converted to the corresponding substituted
phthalides27 in good yields (8-10, Scheme 3c). In addition,
using methyl bromoacetate as the electrophile, a two-step
2-hydroxyethylation was realized in an efficient manner
(Scheme 3d). Note that LiAlH4 chemo-selectively
reduced the ester moiety instead of the oxime DG. Finally,
an initial silver-free condition was identified for the allyl
product.24 It was interesting to observe that, by increasing
the loading of the NBE co-catalyst, the undesired Heck
pathway was significantly inhibited (Scheme 2b). To gain
insights into the reaction mechanism, deuterium labeling
studies were carried out. In the absence of the aryl iodide,
upon addition of 3.0 equiv of CD3CO2D, 81% of the
alkene substrate was recovered with 20% and 22%
deuterium incorporation at the distal and proximal vinyl
positions, respectively (Scheme 2c). This indicates
reversible formation of C−H palladation intermediates I
and II (vide supra, Scheme 1c). In addition, a four-
membered ring side product25 was obtained in 10% yield
under these conditions, implying the formation of
alkenyl-norbornyl palladacycle II. In the presence of the
aryl iodide and CD3CO2D, deuterium incorporation was
observed in the vinyl C−H bonds of both the arylation
product as well as the recovered alkene substrate (Scheme
2c), which suggests protonation occurred at the proximal
position. In addition, control experiments with the trans
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Journal of the American Chemical Society
*gbdong@uchicago.edu
amine substrate (Scheme 3e), which replaced AgOAc
with CsOAc using methyl t-butyl ether (MTBE) as
solvent.
1
2
3
4
5
6
7
8
Notes
The authors declare no competing financial interest.
Scheme 3. Synthetic Utility
ACKNOWLEDGMENT
a) Scale up:
5 mol % Pd(OAc)2
DG1
DG1
10 mol % 3-CF3-2-pyridone
N4
O
O
The authors thank the University of Chicago and NIGMS
(1R01GM124414–01A1) for financial supports. N.F. thanks
Metcalf fellowship for the financial support. Mr. Renhe Li is
acknowledged for checking the reproducibility of the
experimental procedure.
30 mol %
+
Ar
ArI
Ph
Ph
2.0 equiv AgOAc
CHCl3 (0.2 M), air
100 °C, 28 hrs
Ph
Ph
2a
0.32 g
1a
, 1 mmol
72% yield
9
b) Elaboration of the arylation product:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
Zn, HOAc
79%
Pd(OAc)2 (cat.)
AgOAc
methyl acrylate
REFERENCES
Ar
5
O
DG1
Ar
DG1
1
For selected syntheses of natural products that contain
CO2Me
99%
1.5 : 1 dr
Pd/C
H2
trisubstituted olefins, see: a) Wipf, P.; Kim, S. Total Synthesis of the
Enantiomer of the Antiviral Marine Natural Product Hennoxazole
A. J. Am. Chem. Soc. 1995, 117, 558-559. b) White, J. D.; Carter, R.
G.; Sundermann, K. F.; Wartmann, M. Total Synthesis of Epothilone
B, Epothilone D, and cis- and trans-9,10-Dehydroepothilone D. J.
Am. Chem. Soc. 2001, 123, 5407-5413. c) Smith III, A. B.; Qiu, Y.;
Jones, D. R.; Kobayshi, K. Total Synthesis of (-)-Discodermolide. J.
Am. Chem. Soc. 1995, 117, 12011-12012.
Ar
7
3l
OH
Raney Ni,
B(OH)3, H2
tetrasubstituted
alkene
99%
2 : 1 dr
Ar
6
c) Access to substituted phthalides:
O
O
R1
1) LiOH
DG1
2
For selected syntheses of drugs that contain trisubstituted
R1
O
OMe
O
2) PhSeSePh
R3
olefins, see: Ishikawa, H.; Suzuki, T.; Hayashi, Y. High-Yielding
Synthesis of the Anti-Influenza Neuramidase Inhibitor
(−)-Oseltamivir by Three “One-Pot” Operations. Angew. Chem. Int.
Ed. 2009, 48, 1304-1307. b) Wang, H.; Zheng, X.; Cia, Z.; Yu, O.;
Zheng, S.; Zhu, T. Synthesis and Evaluation of an Injectable
Everolimus Prodrug. Bioorg. Med. Chem. Lett. 2017, 27, 1175-1178.
c) Nemoto, H.; Shiraki, M.; Nagamochi, M.; Fukumoto, K. A Concise
Enantiocontrolled Total Synthesis of (−)-α-Bisabolol and (+)-4-
epi-α-Bisabolol. Tetrahedron. Lett. 1993, 34, 4939-4942.
R3
then H2O2
R2
R2
O
DG1
R1= Me, R2= Ph
R1= H, R2= Me
R1= H, R2=
72%, dr=2:1
69%, dr=2:1
79%, dr=2:1
8,
9,
10,
d) Distal 2-hydroxylethylation:
DG1
O
DG1
DG1
11
O
O
Br
CO2Me
LiAlH4
R3
OMe
R3
R
see Table 3
0 °C, 30 min
Ph
1a
Ph
O
Ph OH
3
a) Verendel, J. J.; Pamies, O.; Dieguez, M.; Andersson, P. G.
4m
, 65% yield
R= CH2CH2Ph
Asymmetric Hydrogenation of Olefins Using Chiral Crabtree-type
Catalysts: Scope and Limitations. Chem. Rev. 2014, 114, 2130-2169.
b) Etayo, P.; Vidal-Ferran, A. Rhodium-Catalysed Asymmetric
Hydrogenation as a Valuable Synthetic Tool for the Preparation of
Chiral Drugs. Chem. Soc. Rev. 2013, 42, 728-754.
Z only
98% yield
e) Silver-free condition:
DG6
10 mol % Pd(OAc)2
20 mol % 5-CF3-2-pyridone
100 mol % N3
DG6
Cbz
N
Cbz
N
+
ArI (3 equiv)
4 Nguyen, T. T.; Koh, M. J.; Mann, T. J.;Schrock, R. R.; Hoveyda, A.
H. Synthesis of E- and Z-Trisubstituted Alkenes by Catalytic Cross-
Metathesis. Nature, 2017, 552, 347-354.
3 equiv CsOAc
MTBE (0.1 M)
100 °C, N2, 24 hrs
Ar
2a
3r
71%
5
For alkenyl C−H activation reviews, see: a) Shang, X.; Liu, Z.
In summary, a Pd/NBE-catalyzed strategy for distal
C−H functionalization of alkenes is developed, which
provides a convenient way to prepare trisubstituted
olefins. The reaction is regio- and stereoselective, and can
operate in air. The use of easily removable exo-DGs in
alkene C−H activation could have implications beyond
this transformation. Further optimization of the distal
alkylation reaction and expansion of the electrophile
scope are the topics of the ongoing investigation.
Transition Metal-Catalyzed Cvinyl–Cvinyl Bond Formation via Double
Cvinyl–H Bond Activation Chem. Soc. Rev., 2013, 42, 3253-3260. b)
Wang, K.; Hu, F.; Zhao, Y.; Wang, J. Directing Group-Assisted
Transition-Metal-Catalyzed Vinylic C-H bond Functionalization. Sci.
China Chem. 2015, 58, 1252-1265. c) Maraswami, M.; Loh, T.-P.
Transition-Metal-Catalyzed Alkenyl sp2 C–H Activation: A Short
Account. Synthesis, 2019, 51, 1049-1062.
6 For selected examples, see: a) Trost, B. M.; Imi, K.; Davies, I. W.
Elaboration of Conjugated Alkenes Initiated by Insertion into a
Vinylic C-H Bond. J. Am. Chem. Soc. 1995, 117, 5371-5372. b)
Kakiuchi, F.; Tanaka, Y.; Sato, T.; Chatani, N.; Murai, S. Catalytic
Addition of Olefinic C–H Bonds to Olefins. Chem. Lett. 1995, 679-
680. c) Zhang, J.; Loh, T.-P. Ruthenium- and Rhodium-Catalyzed
Cross-Coupling Reaction of Acrylamides with Alkenes: Efficient
Access to (Z,E)-Dienamides. Chem. Commun. 2012, 48, 11232-
11234. d) Hu, X. H.; Zhang, J.; Yang, X. F.; Xu, Y. H.; Loh, T.-P. Stereo-
and Chemoselective Cross-Coupling between Two Electron-
Deficient Acrylates: An Efficient Route to (Z,E)-Muconate
Derivatives. J. Am. Chem. Soc. 2015, 137, 3169-3172.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures; spectral data (PDF)
7 For leading references, see: a) Zhou, H.; Xu, Y.; Chung, W.; Loh,
T.-P. Palladium-Catalyzed Direct Arylation of Cyclic Enamides with
Aryl Silanes by sp2 C-H Activation. Angew. Chem. Int. Ed. 2009, 48,
5355-5357. b) Pankajakshan, S.; Xu, Y.; Cheng, J. K.; Low, M. T.; Loh,
T.-P. Palladium-Catalyzed Direct C-H Arylation of Enamides with
AUTHOR INFORMATION
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14
Simple Arenes. Angew. Chem. Int. Ed. 2012, 51, 5701-5705. c)
Dong, Z.; Wang, J.; Dong, G. Simple Amine-Directed Meta-
Selective C–H Arylation via Pd/Norbornene Catalysis J. Am. Chem.
Soc. 2015, 137, 5887-5890.
Liang, Q.; Yang, C.; Meng, F.-F.; Jiang, B.; Xu, Y.-H.; Loh, T.-P.
Chelation versus Non-Chelation Control in the Stereoselective
Alkenyl sp2 C−H Bond Functionalization Reaction. Angew. Chem.
Int. Ed. 2017, 56, 5091-5095. d) Liu, M.; Yang, P.; Karunananda, M.
K.; Wang, Y.; Liu, P.; Engle, K. M. C(alkenyl)–H Activation via Six-
Membered Palladacycles: Catalytic 1,3-Diene Synthesis. J. Am.
Chem. Soc. 2018, 140, 5805-5813. e) Luo, Y.-C.; Yang, C.; Qiu, S.-Q.;
Liang, Q.-J.; Xu, Y.-H.; Loh, T.-P. Palladium(II)-Catalyzed
Stereospecific Alkenyl C–H Bond Alkylation of Allylamines with
Alkyl Iodides. ACS Catal. 2019, 9, 4271-4276.
1
2
3
4
5
6
7
8
15
a) Catellani, M.; Chiusoli, G. P. Competitive Processes in
Palladium-Catalyzed C−C Bond Formation. J. Organomet. Chem.
1982, 233, C21-C24. b) Khanna, A.; Premachandra, I. D. U. A.; Sung,
P. D.; Van Vranken, D. L. Palladium-Catalyzed Catellani
Aminocyclopropanation Reactions with Vinyl Halides. Org. Lett.
2013, 15, 3158-3161.
16
For alkenyl Catellani-type reactions: a) Wang, J.; Dong, Z.;
Yang, C.; Dong, G. Modular and Regioselective Synthesis of All-
Carbon Tetrasubstituted Olefins Enabled by an Alkenyl Catellani
Reaction. Nat. Chem. 2019, 11, 1106-1112. b) Yamamoto, Y.;
Murayama, T.; Jiang, J.; Yasui, T.; Shibuya, M. The Vinylogous
Catellani Reaction: a Combined Computational and Experimental
Study. Chem. Sci. 2018, 9, 1191−1199.
9
8 For selected examples, see: a) Besset, T.; Kuhl, N.; Patureau, F.
W.; Glorius, F. RhIII-Catalyzed Oxidative Olefination of Vinylic C-H
Bonds: Efficient and Selective Access to Di-unsaturated α-Amino
Acid Derivatives and Other Linear 1,3-Butadienes. Chem. Eur. J.
2011, 17, 7167-7171. b) Wang, H.; Beiring, B.; Yu, D.; Collins, K. D.;
Glorius, F. [3]Dendralene Synthesis: Rhodium(III)-Catalyzed
Alkenyl C-H Activation and Coupling Reaction with Allenyl
Carbinol Carbonate. Angew. Chem. Int. Ed. 2013, 52, 12430-12434.
c) Boultadakis-Arapinis, M.; Hopkinson, M. N. Glorius, F. Using
Rh(III)-Catalyzed C–H Activation as a Tool for the Selective
Functionalization of Ketone-Containing Molecules. Org. Lett. 2014,
16, 1630-1633. d) Lei, Z.; Ye, J.; Sun, J.; Shi, Z. Direct Alkenyl C–H
Functionalization of Cyclic Enamines with Carboxylic Acids via Rh
Catalysis Assisted by Hydrogen Bonding. Org. Chem. Front. 2014,
1, 634-638.
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23
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
Xu, Y.; Dong, G. sp3 C–H Activation via exo-type Directing
Groups Chem. Sci. 2018, 9, 1424-1432.
18
For earlier works, see: a) Desai, L. V.; Stowers, K. J.; Sanford,
M. S. Insights into Directing Group Ability in Palladium-Catalyzed
C−H Bond Functionalization. J. Am. Chem. Soc. 2008, 130, 13285-
13293. b) Ren, Z.; Mo, F.; Dong, G. Catalytic Functionalization of
Unactivated sp3 C–H Bonds via exo-Directing Groups: Synthesis of
Chemically Differentiated 1,2-Diols. J. Am. Chem. Soc. 2012, 134,
16991-16994.
19
For the first use of substituted 2-pyridone as the concerted
9
For selected examples, see: a) Zhang, Y. J. Skucas, E.; Krische,
metalation deprotonation (CMD) promotor, see: Wang, P.; Farmer,
M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J. E.;
Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q. Ligand-Promoted Meta-
C–H Arylation of Anilines, Phenols, and Heterocycles. J. Am. Chem.
Soc. 2016, 138, 9269-9276.
M. J. Direct Prenylation of Aromatic and α,β-Unsaturated
Carboxamides
via
Iridium-Catalyzed
C−H
Oxidative
Addition−Allene Insertion. Org. Lett. 2009, 11, 4248-4250. b) Ye,
K.; He, H.; Liu, W.-B.; Dai, L; Helmchen, G.; You, S.-L. Iridium-
Catalyzed Allylic Vinylation and Asymmetric Allylic Amination
Reactions with o-Aminostyrenes. J. Am. Chem. Soc. 2011, 133,
19006-19014.
20
a) For the first use of a substituted NBE in the Pd/NBE
catalysis, see: Dong, Z.; Wang, J.; Ren, Z.; Dong, G. Ortho C−H
Acylation of Aryl Iodides by Palladium/Norbornene Catalysis.
Angew. Chem. Int. Ed. 2015, 54, 12664-12668. b) For the first use
of a substituted NBE in the C−H activation-initiated Pd/NBE
catalysis, see: Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q.
Ligand-Enabled Meta-C–H Alkylation and Arylation Using a
Modified Norbornene J. Am. Chem. Soc. 2015, 137, 11574-11577.
21 Liu, Z.-S.; Qian, G.; Gao, Q.; Wang, P.; Cheng, H.-G.; Wei, Q.; Liu,
Q.; Zhou, Q. Palladium/Norbornene Cooperative Catalysis to Access
Tetrahydronaphthalenes and Indanes with a Quaternary Center.
ACS Catal. 2018, 8, 4783-4788.
10 For selected examples, see: a) Ilies, L.; Matsubara, T.; Ichikawa,
S.; Asako, S.; Nakamura, E. Iron-Catalyzed Directed Alkylation of
Aromatic and Olefinic Carboxamides with Primary and Secondary
Alkyl Tosylates, Mesylates, and Halides. J. Am. Chem. Soc. 2014, 136,
13126-13129. b) Monks, B. M.; Fruchey, E. R. Cook, S. P.
Iron-Catalyzed C(sp2)-H Alkylation of Carboxamides with Primary
Electrophiles. Angew. Chem. Int. Ed. 2014, 53, 11065-11069. c)
Ilies, L.; Ichikawa, S.; Matsubara, T.; Nakamura, E. Iron-Catalyzed
Directed Alkylation of Alkenes and Arenes with Alkylzinc Halides.
Adv. Synth. Catal. 2015, 357, 2175-2179. d) Cera, G.; Haven, T.;
22
a) Motti, E.; Della Ca’, N.; Deledda, S.; Fava, E.; Panciroli, F.;
Ackermann,
L.
Expedient
Iron-Catalyzed
C−H
Catellani, M. Palladium-Catalyzed Unsymmetrical Aryl Couplings in
Sequence Leading to O-Teraryls: Dramatic Olefin Effect on
Selectivity. Chem. Commun. 2010, 46, 4291-4293. b) Martins, A.;
Candito, D. A.; Lautens, M. Palladium-Catalyzed Reductive ortho-
Arylation: Evidence for the Decomposition of 1,2-
Dimethoxyethane and Subsequent Arylpalladium (II) Reduction.
Org. Lett. 2010, 12, 5186-5188.
Allylation/Alkylation by Triazole Assistance with Ample Scope.
Angew. Chem. Int. Ed. 2016, 55, 1484-1488.
11 For selected examples, see: a) Gensch, T.; Vasquez-Cespedes,
S.; Yu, D.-G. Glorius, F. Org. Lett. 2015, 17, 3714-3717. b) Wang, H.;
Zhang, S.; Wang, Z.; He, M.; Xu, K. Cobalt-Catalyzed Monoselective
Ortho-C–H
Functionalization
of
Carboxamides
with
Organoaluminum Reagent. Org. Lett. 2016, 18, 5628-5631. c) Li, T.;
Shen, C.; Sun, Y.; Zhang, J.; Xiang, P.; Lu, X.; Zhong, G. Cobalt-
Catalyzed Olefinic C–H Alkenylation/Alkylation Switched by
Carbonyl Groups. Org. Lett. 2019, 19, 7772-7777.
23 For example, p-nitrophenyl iodide gave the desired product
albeit in 8% yield.
O
DG1
12
For selected reviews, see: a) Ye, J.; Lautens, M. Palladium-
Catalysed Norbornene-Mediated C–H Functionalization of Arenes.
Nat. Chem. 2015, 7, 863−870. b) Della Ca’, N.; Fontana, M.; Motti,
E.; Catellani, M. Pd/Norbornene: A Winning Combination for
Selective Aromatic Functionalization via C–H Bond Activation. Acc.
Chem. Res. 2016, 49, 1389−1400. c) Wang, J.; Dong, G.
Palladium/Norbornene Cooperative Catalysis. Chem. Rev. 2019,
119, 7478-7528. d) Cheng, H.-G.; Chen, S.; Chen, R.; Zhou, Q.
Palladium (II)-Initiated Catellani-Type Reactions. Angew. Chem.
Int. Ed. 2019, 58, 5832-5844.
8%
NO2
24
Romine, A. M.; Yang, K. S.; Karunannanda, M. K.; Chen, J. S.;
Engle, K. M. Synthetic and Mechanistic Studies of a Versatile
Heteroaryl Thioether Directing Group for Pd(II) Catalysis. ACS
Catal. 2019, 9, 7626-7640.
25
A typical side product was observed in this reaction, which
supports a Catellani pathway.
Ph
13 Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.;
Yu, J.-Q. Ligand-Enabled meta-C–H Activation Using a Transient
Mediator. Nature, 2015, 519, 334-338.
O
N
O
DG1
O
R
Ph
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J. (eds) Progress in the Chemistry of Organic Natural Products,
2017, 104. 127-246. Springer, Cham.
Attempts to realize
a
direct distal/proximal
1
2
difunctionalization of the alkene substrates, e.g. distal
arylation/proximal Heck, only resulted in a low yield.
27
León, A.; Del-Ángel, M.; Ávila, J. L.; Delgado, G. Phthalides:
3
4
5
Distribution in Nature, Chemical Reactivity, Synthesis, and
Biological Activity. In: Kinghorn A.D., Falk H., Gibbons S., Kobayashi
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Me
distal
proximal
H
E
H
O
1
2
3
H
Me
DG
DG
O
N
Ph
O
N
R
Pd
O
E
E: Ar, Me or CH2CO2Me
R
4
E
5
6
7
8
DG
O
H
Pd
Pd
NBE
Pd
H
O
DG
R
O
DG
R
R
9
 simple removable DG
 distal alkenyl C-H activation
 stereo- and regioselective synthesis of trisubstituted alkenes
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