Sonogashira Cross-Coupling of Aryltrimethylammonium Salts

Article abstract of DOI:10.1021/acscatal.9b00218

A protocol for C(sp)-C(sp²) bond formation via the Sonogashira coupling reaction involving C-N bond cleavage with aryltrimethylammonium triflate as an electrophilic coupling partner is described in this work. The reactions proceeded well under mild conditions with a stoichiometric ratio of alkyl, aryl, or heteroaryl acetylenes and provided yields of up to 93%. Numerous useful functional groups were tolerated under the reaction conditions. Direct amine alkynylation can be achieved through a one-pot process without the isolation of ammonium salt. The protocol can be performed on a gram scale. Density functional theory calculations were performed to investigate the reaction mechanism that involved oxidative addition, alkyne coordination, deprotonation, and reductive elimination, which yielded the cross-coupling product.

Full text of DOI:10.1021/acscatal.9b00218

Subscriber access provided by Stockholm University Library
Article
Sonogashira Cross-Coupling of Aryltrimethylammonium Salts
Qianwei Chen, Fengchen Gao, Huiling Tang, Miao Yao, Qian
Zhao, yanhui Shi, Yanfeng Dang, and Changsheng Cao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00218 • Publication Date (Web): 18 Mar 2019
Downloaded from http://pubs.acs.org on March 18, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
ACS Catalysis
1
2
3
4
5
6
7
8
9
Sonogashira Cross-Coupling of Aryltrimethylammonium Salts
†
†
†
†
†
*,†
Qianwei Chen, Fengchen Gao, Huiling Tang, Miao Yao, Qian Zhao, Yanhui Shi, Yanfeng
*
,‡
*,†
Dang and Changsheng Cao
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†School of Chemistry and Material Science, Jiangsu Normal University, Xuzhou 221116, China
‡Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China
2
ABSTRACT: A protocol for C(sp)–C(sp ) bond formation via the Sonogashira coupling reaction involving C–N bond cleavage with
aryltrimethylammonium triflate as an electrophilic coupling partner was described in this work. The reactions proceeded well under
mild conditions with stoichiometric ratio of alkyl, aryl, or heteroaryl acetylenes and provided yields of up to 93%. Numerous useful
functional groups were tolerated under the reaction conditions. Direct amine alkynylation can be achieved through a one-pot process
without the isolation of ammonium salt. The protocol can be performed on the gram scale. Density functional theory calculations
were performed to investigate the reaction mechanism that involved oxidative addition, alkyne coordination, deprotonation, and
reductive elimination, which yielded the cross-coupling product.
Keywords: C–N bond activation, Sonogashira, Cross-coupling, Pd–NHC complex, DFT
INTRODUCTION
Scheme 1. Songashira Cross-coupling Reactions via
Activation of a C-N Bond
Transition-metal catalyzed cross-coupling reactions have
been widely applied in organic synthesis as a powerful tool for
C–C bond construction. Most of these cross-coupling
Previous work
1
NHNH2
PdCl2 (5 mol%),
R1
R2
R2
21 examples
2
3
+
+
+
H
H
H
reactions, for example, the Suzuki–Miyaura, Kumada,
PPh3 (30 mol%)
O2 (1 atm), AcOH (3 eq.)
50 °C, 12 h
R1
4
5
6
Negishi, Mizoroki–Heck , and Stille reactions, focus on the
2
2
1 eq.
Ar
3.5 eq.
(ref. 15)
formation of C(sp )–C(sp ) bonds. The Sonogashira cross-
coupling reaction plays an irreplaceable role as a unique method
diversified catalyst
and conditions
N2
2
for C(sp)–C(sp ) bond formation in the preparation of aryl
Ar
R
R
R
X
alkynes or enynes, which are often encountered in natural
products, pharmaceuticals, biologically important molecules,
and molecular organic materials. Aryl halides, triflates, and
tosylates are the most commonly used electrophilic coupling
partners in the Sonogashira reaction. Recently, the
(
ref. 18)
7
This work:
NMe3
OTf
SIPr-PdCl -Py (10 mol%)
2
Ar
R
Ar
8
t-BuONa (2-3 eq.), THF
development of new coupling partners has received widespread
attention, the cross-coupling reactions involving the activation
N2, 45-70 °C, 4-24 h
1
eq.
1 eq.
33 examples
9
10
11
12
of C–O, C–S, C–P and C–N bonds have been investigated.
Given the abundance of C–N bonds in biomacromolecules,
availability from various inexpensive amines, including
1
3
drugs, and materials, the transition-metal-catalyzed C–N bond
activation reaction has considerable potential for application in
organic synthesis. Despite the synthetic challenge posed by the
high dissociation energy of the C–N bond, many cross-coupling
reactions that occur via the cleavage of inert C–N bonds have
19
primary, secondary, and tertiary amines.
Since Wenkert first used aryltrimethylammonium iodides as
an electrophilic coupling partner in the Ni-catalyzed Kumada
20
reaction, various Ni or Pd-catalyzed reactions involving
quaternary ammonium salts have been reported for the
1
4-15
been discovered in the last 20 years.
One of the attractive
2
2
3
2
construction of C(sp )–C(sp ) or C(sp )–C(sp ) bonds. These
approaches for these cross-coupling reactions is the activation
of an inert C–N bond to an activated C–N bond, e.g. the
transformation of amines into their corresponding diazonium
2
1
22
23
reactions include the Kumada,
Suzuki,
Negishi,
2
4
25
Buchwald−Hartwig, and Stille reactions, as well as various
2
6
2
other reactions. Nevertheless, C(sp)–C(sp ) bond formation
via the Sonogashira cross-coupling reaction with quaternary
ammonium salts as reactants remains challenging. Herein, we
report the first example of the use of aryltrimethylammonium
salts in Sonogashira cross-coupling reactions catalyzed by the
stable Pd–NHC complex. Our approach provides a potential
protocol for the activation of the C–N bonds of primary,
secondary, and tertiary amines. Furthermore, we investigated
the reaction
16
17
salts
or pyridinium salts.
Unlike pyridinium salts,
arenediazonium salts have been successfully employed as
arylation reagents in numerous cross-coupling reactions,
1
8
including the Sonogashira reaction (Scheme 1). These
compounds, however, are unstable and can only be converted
from primary amines. Quaternary ammonium salts are
attractive alternatives to arenediazonium salts because of their
sufficient stability; long shelf life; and
ACS Paragon Plus Environment

ACS Catalysis
entries 5-6) provided 3 at yields of less than 30%.
Page 2 of 7
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. The Effect of the Counterion of Ammonium Salts
Table 1. Optimization of the Reaction Conditions
SIPr-PdCl -Py (10 mol%)
t-BuONa (2.0 equiv.)
2
cat. (10 mol%),
ligand (10 mol%)
N
N
+
X
+
THF (1 mL), 45 °C,
OTf
base(2.0 equiv.), N2
solvent, 45 °C
1
(a-g)
2
4 h, N2
X = OTf, Cl, Br, I, BF , OMs, OTs)
3
1a
2
3
(
4
Entry cat.
ligand
XPhos
base
solvent time yield
Entrya
Yield (%)b
Salts
1a
1b
1c
1d
1e
X
OTf
Cl
Br
I
b
(h)
(%)
1
2
3
4
5
6
7
78
65
60
20
76
54
52
1
2
3
4
5
6
7
8
9
10
Ni(PPh
Pd(PPh
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
PdCl
IMes-PdCl
IPr-PdCl -Py
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
SIPr-PdCl
3
)
2
Cl
Cl
2
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuOLi
t-BuOK
THF
THF
THF
THF
THF
THF
THF
THF
THF
10
10
10
10
10
10
10
10
10
10
2
0
2
trace
18
15
29
20
41
57
3
)
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
BF
4
PCy
3
1f
1g
OMs
OTs
IPr·HCl
SIPr·HCl
SIPr·HCl
2
a
0.2 mmol scale reactions. HPLC yield with biphenyl as the internal standard.
b
2
-Py
2
2
2
2
2
2
2
2
2
2
2
2
2
2
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
-Py
THF
THF
74
72
1
1
1
2
Yield decreased when PdCl
2
was used as a precursor instead of
THF
4
78
Pd(OAc) (Table 1, entries 6–7). Furthermore, we tested the
2
13
THF
6
75
catalytic performances of three well-defined Pd–NHC
complexes. Moderate product yields were generated when
IMes–PdCl –Py (41%) and IPr–PdCl –Py (57%) were utilized
1
1
1
4
5
6
THF
8
76
THF
THF
4
4
trace
53
2
2
2
17
Cs
2
CO
3
THF
4
0
(
Table 1, entries 8–9). The SIPr–PdCl
best catalytic activity among all tested catalysts and generated
a good yield of 74% (Table 1, entry 10). In contrast to IMes–
–Py, IPr–PdCl –Py provided good yields. This result
2 2
implies that the presence of a ligand with steric hindrance
facilitates the reaction. The negligible effects on the reaction
when the reaction time was shortened from 10 h to 4 h suggests
that the reaction reached completion within 4 h (Table 1, entries
–Py complex showed the
1
1
8
9
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
EtOH
DMF
MeCN
dioxane
toluene
4
4
4
4
trace
trace
trace
12
20
2
2
1
2
PdCl
4
19
2
7
a
.2 mmol scale reactions. b HPLC yield with biphenyl as the internal standard.
0
N
N
N
N
1
0–14). Our following results indicate that the base and solvent
PCy2
played a crucial role in the success of the reaction. t-BuOK
provided only modest yields of the desired product (53%), and
t-BuOLi and Cs CO severely inhibited the reaction (Table 1,
2 3
entries 14–17). Although THF provided good product yields,
dioxane and toluene only provided 12%–19% product yields
(Table 1, entry 21–22). In addition, only trace amounts of the
product were obtained with N,N-dimethylformamide (DMF),
acetonitrile (MeCN) and ethanol (EtOH).
SIPr
IPr
XPhos
N
N
N
N
N
N
Cl Pd Cl
N
Cl Pd Cl
N
Cl Pd Cl
N
The counterion effect of the ammonium salts on the reactivity
of Sonogashira reaction was examined in the reaction of
phenyltrimethylammonium salts (1a-g) with 4-ethynyltoluene
SIPr-PdCl -Py
IPr-PdCl -Py
IMes-PdCl -Py
2
2
2
mechanism of our approach through density functional theory
(DFT) calculations.
(2) under the optimized reaction conditions. As shown in Table
2
, the tested counterions have slightly effect on the yield of 3
RESULTS AND DISCUSSION
except for I ion. The good reactivity of very soluble triflate salt
1a (78% yield) and poor soluble tetrafluoroborate salt 1e (76%
yield) in THF were observed, suggesting that the solubility of
the salts has insignificantly effect on the reaction. Over 60%
yield of 3 was detected with the halide salts (1b and 1c) and
around 54% yield was observed with the sulfonate salts (1f and
1g). However, the iodide salt 1d reacted much more slowly
under the same conditions, leading to low yield of 3 (20%) with
a large amount of recovered 1d.
The successful employment of Ni and Pd catalysts in many
coupling reactions of quaternary ammonium salts suggests that
Ni(0) or Pd(0) could insert into the C–N bond of an aryl
ammonium. We began our studies by attempting to alkynylate
phenyltrimethylammonium triflate (1a) by using 4-
ethynyltoluene (2) with different Pd or Ni catalysts (Table 1).
Initially, we examined the feasibility of using moisture- and air-
stable Ni(PPh ) Cl and Pd(PPh ) Cl (10 mol%) as the catalyst
3 2 2 3 2 2
precursor. The reactions were performed with t-BuONa (2 eq.)
as the base and THF as the solvent at 45 ℃ for 10 h. However,
Furthermore, the scope and generality of the protocol was
explored. First, a variety of terminal alkynes were reacted with
ammonium salt 1a under the optimized reaction conditions
Ni(PPh
provided a 1-methyl-4-(phenylethynyl)benzene (3) yield of 2%
Table 1, entries 1–2). Therefore, we examined the effects of
increasing the amount of Pd precatalyst (Table 1, entries 3–10).
The reactions catalyzed by Pd(OAc) with the phosphine ligand
PCy and XPhos (Table 1, entries 3–4) and with the N-
heterocycle carbene (NHC) ligands SIPr and IPr (Table 1,
3 2 2 3 2 2
) Cl was completely ineffective, and Pd(PPh ) Cl
(Table 3, 3-18). The results showed that various substituted
(
phenylacetylenes could be successfully converted to the
corresponding diaryl acetylenes in moderate to excellent yields.
Either electron-rich or electron-deficient aryl acetylenes were
suitable for the reaction. Generally, good yields were obtained
2
3
ACS Paragon Plus Environment

Page 3 of 7
ACS Catalysis
Table 3. The Sonogashira Cross-coupling of Terminal Alkyne with Aryltrimethylamonium Triflate
1
2
3
4
5
6
7
8
9
N
SIPr-PdCl -Py (10 mol%)
2
Ar
+
H
R
Ar
R
OTf
0.5 mmol)
t-BuONa (2.0 eq.)
THF , 45 C, 4 h
(
(0.5 mmol)
3-33
n-Bu
3
. 79%
4. 68% (4.5 h)
5. 73%
6. 93%
7. 62%
OMe
NMe2
F
Cl
NHPiv
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8. 92%
9. 82%
10. 53% (12 h)
11. 72%
12. 71% (6 h, 3 eq. Base)
S
S
Cl
1
3. 54%
8. 50%
14. 60%
15. 73%
16. 64%
17. 28%
F
F
Ph
F
OMe
OMe
OMe Cl
OMe NC
NC
OMe
1
19. 73%
20. 87%
21. 56% (22 h)
22. 53%
Cl
OMe
OMe
OMe F3C
OMe
23. 63%
24. 25% (24 h)
25. 13% (70 oC, 12 h)
26. 61% (70 oC)
27. 72%
N
S
S
EtOOC
OMe
OMe F3C
NC
Cl
28. 6% (21 h)
29. 74% (15 h)
30. 60% (15.5 h)
31. 69%
32. 24% (13 h)
F3C
NHPiv
33. 59% (13 h, 3 eq. Base)
a
2
Unless specified indication in brackets, SIPr-PdCl -Py (0.05 mmol), alkyne (0.50 mmol), aryltrimethylammonium triflate (0.50 mmol) and t-
BuONa (1 mmol) were employed in 2.5 mL of THF at 45 °C for 4 h under N
2
atmosphere; b Isolated yields.
Scheme 2. Alkynylation of Dimethylaniline in One-pot
Process
Scheme 5. Proposed Catalytic Cycle for the Palladium-
Catalyzed C-C Coupling
SIPr
SIPr-PdCl2-Py (10 mol%),
Cl Pd Cl
Py
N
MeOTf (1.0 eq.)
t-BuONa (2.0 eq.)
THF (1 mL), N2
r.t., 30 min
4-ethynyltoluene (1.0 eq.)
t-BuONa
0
.5 mmol
THF (2 mL), N2, 45 C, 4 h
3
. 73%
N
Ph
Ph
Ph
SIPr Pd Py
Scheme 3. Amplification Reaction
reductive
elimination
oxidative
addition
NMe3
N
SIPr-PdCl2-Py (10 mol%)
+
Step 4
Step 1
OTf
a. 5.0 mmol
THF (25 mL), Under N2
45 oC, 4 h
1
2. 5.0 mmol
3. 0.7 g (75 %)
Ph
SIPr
Ph
Pd SIPr
Py
Ph Pd Py
Scheme 4. Competition Reaction
Step 3
Step 2
H
SIPr-PdCl2-Py (10 mol%)
t-BuONa (2.0 eq.)
substrate
coordination
N
deprotonation
+
OTf
THF (25 mL), Under N2
t-BuOH
SIPr
Ph Pd Py
Ph
Ph
4
5 °C, 4 h
1
a. 0.5 mmol
0.5 mmol
34. 55%
35. 73%
H
t-BuO
SIPr-PdCl2-Py (10 mol%)
N
t-BuONa (2.0 eq.)
+
TMS
OTf
THF (25 mL), Under N2
TMS
4
5 °C, 4 h
1
a. 0.5 mmol
0.5 mmol
whereas 10 was isolated with a yield of 53% within 12 h when
p-fluorophenylacetylene was applied in the reaction. Notably,
1
1 was generated with a yield of 72% when para-chloro
with phenylacetylenes that bear an electron-donating group.
Meanwhile, the reaction time must be prolonged to achieve
satisfactory yields of aryl acetylenes with a withdrawing group.
For example, 8 was isolated with a yield of 92% within 4 h when
p-methoxyphenylacetylene was used in the reaction,
phenylacetylene was used. This result indicates that the
potentially labile Cl was inert in the reaction and thus facilitated
further transformation. The C–N bond of ammonium could be
selectively functionalized given that amine and amide groups
remained intact during the reaction (Table 3, 9 and 12). Hetero
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 7
SIPr
Pd
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Gsol
TS1'
32.9
(kcal/mol)
NMe3
SIPr
Pd
TS1
23.8
Py
NMe3
Py
oxidative
addition
SIPr
NMe3
IN3
0.7
Ph Pd Py
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
SIPr
Ph Pd Py
Ph
N
IN2
6.6
IN4
.2
Ph
6
SIPr
SIPr
Pd
IN1
0.0
Pd Py
Ph
IN6
-1.2
Ph
Py
SIPr
Pd
NMe3
IN7
-3.5
IN5
4.3
t-BuO-
SIPr
Pd
-
Py
SIPr
Ph Pd
Py Ph
SIPr
Ph Pd
Py
SIPr
Py
Ph Pd Py
i-Pr
i-Pr
TS2
-40.1
N
N
Ph
SIPr :
Py :
t-BuOH
Ph
reductive
elimination
i-Pr
i-Pr
IN8
-50.4
SIPr
Pd
Ph
IN9
-50.5
SIPr
N
Py
Ph Pd
Py
Ph
IN1
-77.7
Ph
Figure 1. DFT-computed free energy profiles for the Pd-catalyzed C-C coupling reaction. Energies are relative to the active
catalyst IN1, and are mass balanced.
cycles, such as thiophene, can be tolerated under the optimized
reaction conditions (Table 3, 13–14). Interestingly, terminal
alkyl alkynes were also applicable in this reaction and can be
successfully converted to the corresponding alkynes in
moderate yields (Table 3, 15–16 and 18). However, Cl
substitution on the alkyl group interfered with the reaction and
resulted in the low yield of the desired product 17.
Interestingly, amines can be directly alkynylated through a
two-step one-pot process. For example, dimethylaniline can be
converted to 3 with a 73% overall yield via methylation by
methyl triflate followed by the Pd-catalyzed Sonogashira
reaction with 4-ethynyltoluene (Scheme 2).
Furthermore, 0.7 g of 3 was obtained (yield: 75%) when the
reaction scale of the alkynylation of 1a with 2 was enlarged 10
times. This yield is comparable with the yield of the small-scale
reaction (Scheme 3).
Furthermore, the use of various aryltrimethylammonium
triflates in the ammonium Sonogashira coupling reaction with
-ethynylanisole was examined (Table 3, 19–29). The results
4
We also performed the competition experiments of the
Sonogashira reaction with the Heck and Hiyama reaction
showed that reactions performed with active electron-poor
aryltrimethylammonium triflates occurred smoothly and
provided the corresponding diphenyl alkynes in moderate to
good yields (Table 3, 19–23). By contrast, reactions conducted
with electron-rich aryltrimethylammonium triflates were
sluggish and generated the desired products at low yields (Table
3, 24–25). For example, 19 was obtained at the yield of 73%
when 4-fluorophenyltrimethylamonium triflate was used,
whereas 24 was obtained at the yield of 25% when 4-
methylphenyltrimethylamonium triflate was utilized. The low
yield in the case of 4-ethoxycarbonyl-phenyltrimethylamonium
triflate was attributed to the decomposition of ester groups
(Scheme 4). Competition between vinyl and ethynyl group
showed that only the arylation of ethynyl occurred in the
reaction of 1-ethynyl-4-vinylbenzene with 1a. Likewise, in the
reaction of (4-ethynylphenyl)trimethylsilane with 1a, the TMS
group remained intact, whereas acetylene underwent arylation.
2
8
under the employed conditions (Table 3, 28). Some interesting
tolerances of functional groups, including fluoro, chloro, ether,
amine, amide, cyano, pyridinyl and thiophene groups, were
noted.
ACS Paragon Plus Environment

Page 5 of 7
ACS Catalysis
butoxide acts as base to deprotonate the C‒H bond. However,
1
2
3
4
5
6
7
8
9
the transition state for the deprotonated H−C(≡CPh) step
assisted by t-BuO in IN6 appears nonexistent, as the attempted
−
optimizations all converged to IN8 + t-BuOH. This is probably
due to an extremely flat potential energy surface arising from
that the activation of alkyne C‒H bond by the strong base t-
−
BuO is too easy to occur, and tracking the C‒H bond
deprotonation process by means of scan coordinates analysis
demonstrates this point (see Figure S1 in Supporting
Information for detail). The deprotonated step is highly
exergonic by 49.2 kcal/mol. Although IN5 is more stable than
Pd(II) intermediates IN4 and IN6, it will not have an important
effect on the energy profile, because the deprotonated product
(IN9) derived from IN5 must isomerize to IN8 to promote C-C
coupling. Finally, IN8 undertakes feasible reductive
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
≠
elimination at the Pd(II) center (TS2, ∆G = 10.3 kcal/mol) to
form a new carbon-carbon bond (Figures 1 and 2), providing
the cross-coupling product and regenerating the active catalyst
IN1.
Figure 2. DFT-optimized structures of selected intermediates
and transition states for the Pd-catalyzed C-C coupling reaction.
All the H atoms are hidden for simplicity.
Taken the complete reaction pathway into consideration
+
(Figure 1), the C−N oxidative addition of substrate Ph-NMe
3
(TS1) is found to be the turnover-limiting step, which is 23.8
kcal/mol. This energy barrier would be achievable at the
experimental condition (45 °C), thereby accounting for the
good yield of the reactions shown in Table 3 (up to 93 % yield).
In addition, the transformation shown in Figure 1 is highly
exergonic (‒77.7 kcal/mol), driving the reaction into next
catalytic cycle.
To gain insight into the reaction mechanism, we performed
2
9
DFT studies with Gaussian 09 package. The reaction shown
in Scheme 5 was chosen as a representative for the mechanistic
3
0
investigation. BP86 and a mixed basis set of SDD for Pd and
-31G(d,p) for other atoms were used in geometry
optimizations and frequency calculations. Single-point energies
6
3
1
CONCLUSION
were calculated with M06 and a mixed basis set of SDD for
Pd and 6-31++G(d,p) for other atoms. Solvation energy
corrections were calculated using the SMD32 model with THF
as the solvent. Note that the catalytic precursor
In conclusion, the Pd–NHC-catalyzed cross-coupling of
terminal alkynes with aryltrimethylammonium triflate was
established. To the best of our knowledge, this transformation
is the first example of the alkynylation of quaternary
ammonium salts. The reaction occurred under mild conditions
with stoichiometric ratios of reactants and provided moderate to
good product yields. A variety of alkyl, aryl, and heteroaryl
substituents on the alkyne substrate can be used, and many
useful functional groups can be tolerated. Amines can be
directly alkynylated through a one-pot process without the
isolation of ammonium salts. The protocol is compatible on a
gram scale. Computational mechanistic studies indicated that
the reaction occurred through oxidative addition, alkyne
coordination, deprotonation, and C–C reductive elimination,
which yielded the final cross-coupling product.
2
(SIPr)(Py)Pd(II)(Cl) can be easily reduced to Pd(0) species
under the experimental condition (t-BuONa). Accordingly,
(SIPr)Pd(0)(Py) was employed as the active catalyst in the
following computational studies.
Scheme 5 illustrates our proposed catalytic cycle, which can
be characterized by four steps, namely, oxidative addition (step
1
), substrate coordination (step 2), deprotonation (step 3), and
C-C reductive elimination to provide the final coupling product
step 4). The free energy profiles for steps 1-4 are presented in
Figure 1.
As shown in Figure 1, the 14e Pd(0) catalyst IN1 initially
undergoes substrate coordination leading to the 16e π-bound
(
2
+
3
complex IN2 [(SIPr)Pd(Py)(η -PhNMe ) ]. Relative to the
active catalyst IN1, the coordination is thermodynamically
ASSOCIATED CONTENT
Supporting Information
unfavorable by 6.6 kcal/mol. Then, the oxidative addition of
+
quaternary ammonium (Ph-NMe
3
) takes place via transition
≠
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
state TS1 (∆G = 23.8 kcal/mol) giving the T-shaped Pd(II)
intermediate IN3 and releasing NMe . The oxidative addition
occurs through an S 2 back-side attack type transition state,
3
Detailed experimental procedures, H and 13C NMR spectra, and
1
N
DFT results.
where the optimized structures of TS1 and its precursor IN2 are
shown in Figure 2. This is different from the general mechanism
in Pd-catalyzed oxidative addition of R-X (X = Cl, Br, or I), for
which this-type transition state (i.e., TS1’ in Figure 1) is 9.1
kcal/mol higher than that of TS1. The higher energy barrier of
TS1’ may attribute to the steric influence arising from the bulky
AUTHOR INFORMATION
Corresponding Author
Yanhui Shi: yhshi@jsnu.edu.cn
Yanfeng Dang: yanfeng.dang@tju.edu.cn.
3
NMe group. Complex IN3 could isomerize to its more stable
isomer IN4 or IN5. The coordination of the PhC≡CH substrate
to Pd(II) center transforms IN4 to IN6 to facilitate the
succeeding deprotonation and C-C coupling. Control reactions
shown in Table 2 (Entry 1 and 5) indicate that the sodium tert-
Changsheng Cao: chshcao@jsnu.edu.cn.
ORCID
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 7
Qianwei Chen: 0000-0003-3262-4144
Yanfeng Dang: 0000-0002-9297-9759
Yanhui Shi: 0000-0003-0577-8674
(17) (a) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.; Tomlin, J.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
W.; Garnsey, M. R.; Watson, M. P. Transforming Benzylic Amines
into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts
via C–N Bond Activation. Org. Lett. 2018, 20, 3030-3033. (b) Basch,
C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl
Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C–
N Bond Activation. J. Am. Chem. Soc. 2017, 139, 5313-5316. (c)
Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy for the
Visible-Light-Mediated Generation of Alkyl Radicals. Angew. Chem.,
Int. Edit. 2017, 56, 12336-12339. (d) Buszek, K. R.; Brown, N. N-
Vinylpyridinium and -ammonium Tetrafluoroborate Salts: New
Electrophilic Coupling Partners for Pd(0)-Catalyzed Suzuki Cross-
Coupling Reactions. Org. Lett. 2007, 9, 707-710.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT .
We are grateful to the National Natural Science Foundation of
China (NSFC Nos: 21571087 and 21673156), and Major
Projects of Natural Science Research in Jiangsu Province
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(15KJA150004). Q. C. appreciate Prof. Jingfen Li (HUTC)
(18) (a) Fabrizi, G.; Goggiamani, A.; Sferrazza, A.; Cacchi, S.
and Dr. Chao Chen (HUTC) for their encouragement and
guidance.
Sonogashira Cross-Coupling of Arenediazonium Salts. Angew. Chem.,
Int. Ed. 2010, 49, 4067-4070. (b) Cai, R.; Lu, M.; Aguilera, E. Y.; Xi,
Y.; Akhmedov, N. G.; Petersen, J. L.; Chen, H.; Shi, X. Ligand-
Assisted Gold-Catalyzed Cross-Coupling with Aryldiazonium Salts:
Redox Gold Catalysis without an External Oxidant. Angew. Chem., Int.
Ed. 2015, 54, 8772-8776. (c) Barbero, M.; Cadamuro, S.; Dughera, S.
REFERENCES
(1) Seechurn, C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V.
Palladium-Catalyzed Cross-Coupling: Historical Contextual
A
Copper-
and
Phosphane-Free
Sonogashira
Coupling
of
Perspective to the 2010 Nobel Prize. Angew. Chem., Int. Edit. 2012, 51,
5062-5085.
Arenediazonium o-Benzenedisulfonimides. Eur. J. Org. Chem. 2014,
2014, 598-605. (d) Panda, B.; Sarkar, T. K. Gold and palladium
combined for the Sonogashira-type cross-coupling of arenediazonium
salts. Chem. Commun. 2010, 46 , 3131-3133. (e) Tlahuext-Aca, A.;
Hopkinson, M. N.; Sahoo, B.; Glorius, F. Dual gold/photoredox-
catalyzed C(sp)-H arylation of terminal alkynes with diazonium salts.
Chem. Sci. 2016, 7, 89-93.
(19) (a) Lator, A.; Gaillard, S.; Poater, A.; Renaud, J.-L. Well-Defined
Phosphine-Free Iron-Catalyzed N-Ethylation and N-Methylation of
Amines with Ethanol and Methanol. Org. Lett. 2018, 20, 5985-5990.
(b) Guyon, C.; Duclos, M.-C.; Metay, E. Lemaire, M., Reductive N-
methylation of amines with calcium hydride and Pd/C catalyst.
Tetrahedron Lett. 2016, 57, 3002-3005. (c) Wang, W.; Buchholz, A.;
Ivanova, I. I.; Weitkamp, J.; Hunger, M. Synthesis and immobilization
of quaternary ammonium cations in acidic zeolites. Chem. Commun.
2003, 2600-2601.
(2) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
Catalysts for Suzuki-Miyaura coupling processes: Scope and studies of
the effect of ligand structure. J. Am. Chem. Soc. 2005, 127, 4685-4696.
(3) Heravi, M. M.; Hajiabbasi, P. Recent advances in Kumada-Tamao-
Corriu cross-coupling reaction catalyzed by different ligands. Monatsh.
Chem. 2012, 143, 1575-1592.
(
4) Phapale, V. B.; Cardenas, D. J. Nickel-catalysed Negishi cross-
coupling reactions: scope and mechanisms. Chem. Soc. Rev. 2009, 38,
598-1607.
1
(5) Beletskaya, I. P.; Cheprakov, A. V. The heck reaction as a
sharpening stone of palladium catalysis. Chem. Rev. 2000, 100, 3009-
3
(
066.
6) Carsten, B.; He, F.; Son, H. J.; Xu, T.; Yu, L. Stille
Polycondensation for Synthesis of Functional Materials. Chem. Rev.
011, 111, 1493-1528.
2
(20) Wenkert, E.; Han, A. L.; Jenny, C. J. Nickel-induced conversion
of carbon nitrogen into carbon carbon bonds - one-step transformations
of aryl，quanternary ammonium-salts into alkylarenes and blaryls. J.
(7) Chinchilla, R.; Nájera, C. The Sonogashira Reaction:ꢀ A Booming
Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, 107,
8
74-922.
Chem. Soc., Chem. Commun. 1988, 975-976.
(8) Littke, A. F.; Fu, G. C. Palladium-catalyzed coupling reactions of
(21) (a) Reeves, J. T.; Fandrick, D. R.; Tan, Z. L.; Song, J. J.; Lee, H.;
aryl chlorides. Angew. Chem., Int. Edit. 2002, 41, 4176-4211.
(9) Cornella, J.; Zarate, C.; Martin, R. Metal-catalyzed activation of
ethers via C-O bond cleavage: a new strategy for molecular diversity.
Chem. Soc. Rev. 2014, 43, 8081-8097.
Yee, N. K.; Senanayake, C. H. Room Temperature Palladium-
Catalyzed Cross Coupling of Aryltrimethylammonium Triflates with
Aryl Grignard Reagents. Org. Lett. 2010, 12, 4388-4391. (b) Guo, W.
J.;
Wang,
Z.
X.
Iron-catalyzed
cross-coupling
of
(10) Wang, L. D.; He, W.; Yu, Z. K. Transition-metal mediated carbon-
aryltrimethylammonium triflates and alkyl Grignard reagents.
Tetrahedron. 2013, 69, 9580-9585. (c) Guisan-Ceinos, M.; Martin-
Heras, V.; Tortosa, M. Regio- and Stereospecific Copper-Catalyzed
Substitution Reaction of Propargylic Ammonium Salts with Aryl
Grignard Reagents. J. Am. Chem. Soc. 2017, 139, 8448-8451.
sulfur bond activation and transformations. Chem. Soc. Rev. 2013, 42,
599-621.
(11) (a) Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S.
Tetraarylphosphonium halides as arylating reagents in Pd-catalyzed
heck and cross-coupling reactions. Angew. Chem., Int. Ed. 2005, 44,
(
22) (a) Blakey, S. B.; MacMillan, D. W. C. The first Suzuki cross-
couplings of aryltrimethylammonium salts. J. Am. Chem. Soc. 2003,
25, 6046-6047. (b) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P.
6
166-6169. (b) Deng, Z.; Lin, J.-H.; Xiao, J.-C. Nucleophilic arylation
with tetraarylphosphonium salts. Nat. Commun. 2016, 7, 10337.
(12) (a) Ouyang, K. B.; Hao, W.; Zhang, W. X.; Xi, Z. F. Transition-
Metal-Catalyzed Cleavage of C-N Single Bonds. Chem. Rev. 2015, 115,
1
A.; Sirianni, E. R.; Watson, M. P. Nickel-Catalyzed Cross Couplings
of Benzylic Ammonium Salts and Boronic Acids: Stereospecific
Formation of Diarylethanes via C-N Bond Activation. J. Am. Chem.
Soc. 2013, 135, 280-285. (c) Shacklady-McAtee, D. M.; Roberts, K.
M.; Basch, C. H.; Song, Y.-G.; Watson, M. P. A general, simple
catalyst for enantiospecific cross-couplings of benzylic ammonium
triflates and boronic acids. No phosphine ligand required. Tetrahedron
2014, 70, 4257-4263.
1
2045-12090. (b) Wang, Q. J.; Su, Y. J.; Li, L. X.; Huang, H. M.
Transition-metal catalysed C-N bond activation. Chem. Soc. Rev. 2016,
5, 1257-1272.
4
(13) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-
Catalyzed C–N Cross-Coupling Reactions. Chem. Rev. 2016, 116,
1
2564-12649.
(14) Hosseinian, A.; Mohammadi, R.; Ahmadi, S.; Monfared, A.;
(23) (a) Xie, L. G.; Wang, Z. X. Nickel-Catalyzed Cross-Coupling of
Rahmani, Z. Arylhydrazines: novel and versatile electrophilic partners
in cross-coupling reactions. RSC Adv. 2018, 8, 33828-33844.
(15) Zhao, Y.; Song, Q. Palladium-catalyzed aerobic oxidative cross-
coupling of arylhydrazines with terminal alkynes. Chem. Commun.
Aryltrimethylammonium Iodides with Organozinc Reagents. Angew.
Chem., Int. Edit. 2011, 50, 4901-4904. (b) Zhang, Q.; Zhang, X. Q.;
Wang, Z. X. Nickel complexes supported by quinoline-based ligands:
synthesis, characterization and catalysis in the cross-coupling of
arylzinc reagents and aryl chlorides or aryltrimethylammonium salts.
Dalton Transactions. 2012, 41, 10453-10464. (c) Wu, D.; Tao, J. L.;
Wang, Z. X. Highly efficient pincer nickel catalyzed cross-coupling of
aryltrimethylammonium triflates with arylzinc reagents. Org. Chem.
2
015, 51, 13272-13274.
(16) Oger, N.; d'Halluin, M.; Le Grognec, E.; Felpin, F. X. Using Aryl
Diazonium Salts in Palladium-Catalyzed Reactions under Safer
Conditions. Org. Process Res. Dev. 2014, 18, 1786-1801.
ACS Paragon Plus Environment

Page 7 of 7
ACS Catalysis
Front. 2015, 2, 265-273.
(24) Zhang, X. Q.; Wang, Z. X. Nickel-catalyzed cross-coupling of
aryltrimethylammonium triflates and amines. Org. Biomol. Chem.
Coupling of Aryl Esters. J. Am. Chem. Soc. 2017, 139, 1311-1318.
(29) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.,
Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand,
J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi,
J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross,
J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann,
R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.
W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian
09, Rev. A.01; Gaussian, Inc.: Wallingford, CT, 2010.
(30) (a) Becke, A. D. A New Mixing of Hartree–Fock and Local
Density‒Functional Theories. J. Chem. Phys. 1993, 98, 1372-1377. (b)
Becke, A. D. Density‒Functional Thermochemistry. III. The Role of
Exact Exchange. J. Chem. Phys. 1993, 98, 5648-5652. (c) Perdew, J.
P.; Chevary, J. A.; Vosko, S. H.; Jackson, K. A.; Pederson, M. R.; Singh,
D. J.; Fiolhais, C. Atoms, Molecules, Solids, and Surfaces:
Applications of the Generalized Gradient Approximation for Exchange
and Correlation. Phys. Rev. B 1992, 46, 6671-6687.
1
2
3
4
5
6
7
8
9
2
014, 12, 1448-1453.
(25) Wang, D. Y.; Kawahata, M.; Yang, Z. K.; Miyamoto, K.;
Komagawa, S.; Yamaguchi, K.; Wang, C.; Uchiyama, M. Stille
coupling via C-N bond cleavage. Nat. Commun. 2016, 7, 12937.
(26) (a) Zhu, F.; Tao, J.-L.; Wang, Z.-X. Palladium-Catalyzed C–H
Arylation of (Benzo)oxazoles or (Benzo)thiazoles with
Aryltrimethylammonium Triflates. Org. Lett. 2015, 17, 4926-4929. (b)
Li, J.; Wang, Z. X. Nickel catalyzed alpha-arylation of ketones with
aryltrimethylammonium triflates. Org. Biomol. Chem. 2016, 14, 7579-
7
584. (c) Uemura, T.; Yamaguchi, M.; Chatani, N.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phenyltrimethylammonium Salts as Methylation Reagents in the
Nickel-Catalyzed Methylation of C-H Bonds. Angew. Chem., Int. Edit.
2
016, 55, 3162-3165. (d) Yu, S. J.; Liu, S.; Lan, Y.; Wan, B. S.; Li, X.
W. Rhodium-Catalyzed C-H Activation of Phenacyl Ammonium Salts
Assisted by an Oxidizing C-N Bond: A Combination of Experimental
and Theoretical Studies. J. Am. Chem. Soc. 2015, 137, 1623-1631. (e)
He, F.; Wang, Z. X. Nickel-catalyzed cross-coupling of aryl or 2-
menaphthyl quaternary ammonium triflates with organoaluminum
reagents. Tetrahedron. 2017, 73, 4450-4457. (f) Moragas, T.; Gaydou,
M.; Martin, R. Nickel-Catalyzed Carboxylation of Benzylic C-N Bonds
with CO2. Angew. Chem., Int. Edit. 2016, 55, 5053-5057. (g) Hu, J. F.;
Sun, H. Q.; Cai, W. S.; Pu, X. H.; Zhang, Y. M.; Shi, Z. Z. Nickel-
Catalyzed Borylation of Aryl- and Benzyltrimethylammonium Salts
via C-N Bond Cleavage. J. Org. Chem. 2016, 81, 14-24. (h) Yi, Y. Q.
Q.; Yang, W. C.; Zhai, D. D.; Zhang, X. Y.; Li, S. Q.; Guan, B. T.
Nickel-catalyzed C-N bond reduction of aromatic and benzylic
quaternary ammonium triflates. Chem. Commun. 2016, 52, 10894-
(31) (a) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals
for Main Group Thermochemistry, Thermochemical Kinetics,
Noncovalent Interactions, Excited States, and Transition Elements:
Two New Functionals and Systematic Testing of Four M06-Class
Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120,
1
0897. (i) Yang, Z. K.; Wang, D. Y.; Minami, H.; Ogawa, H.; Ozaki,
2
15-241. (b) Zhao, Y.; Truhlar, D. G. Density Functionals with Broad
Applicability in Chemistry. Acc. Chem. Res. 2008, 41, 157-167.
32) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation
T.; Saito, T.; Miyamoto, K.; Wang, C.; Uchiyama, M. Cross-Coupling
of Organolithium with Ethers or Aryl Ammonium Salts by C-O or C-
N Bond Cleavage. Chem.-Eur. J. 2016, 22, 15693-15699.
(
Model Based on Solute Electron Density and on A Continuum Model
of the Solvent Defined by the Bulk Dielectric Constant and Atomic
Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-6396.
(27) Organ, M. G.; Chass, G. A.; Fang, D. C.; Hopkinson, A. C.;
Valente, C. Pd-NHC (PEPPSI) complexes: Synthetic utility and
computational studies into their reactivity. Synthesis. 2008, 2776-2797.
(28) Ben Halima, T.; Zhang, W.; Yalaoui, I.; Hong, X.; Yang, Y.-F.;
Houk, K. N.; Newman, S. G. Palladium-Catalyzed Suzuki-Miyaura
TOC graphic
Z
N
SIPr-PdCl2-Py (10 mol%)
Z
R1
R2
R2
+
H
OTf
t-BuONa (2-3 eq.), THF, N2
R1
·
45-70 °C, 4-24 h
33 examples
· up to 93% yield
(Z = CH, N; R1 = H, F, Cl,
CH3, CF3, CN, COOEt,; R2
1 eq.
1 eq.
=
aryl or alkyl)
ACS Paragon Plus Environment