Aryne Multicomponent Reactions by Directed C?H Activation

Article abstract of DOI:10.1002/chem.202100205

Arylation via ortho C?H activation by the aid of directing groups has been explored recently by many researchers. Herein, a palladium-catalyzed C?H arylation using 8-aminoquinoline as a bidentate directing group has been developed. The reaction furnishes only C?H arylation, unlike previous methods where cyclization to corresponding isoquinolones is observed. More interestingly, sequential C?H functionalization was observed when methylacrylate and acrylonitrile was added; this led to C?H olefination with the aryl group, which was installed from the aryne precursor.

Full text of DOI:10.1002/chem.202100205

Accepted Article
Accepted Article
Title: Aryne Multicomponent Reactions by Directed C-H Activation
Authors: Sunil Kumar Sunnam and Jitendra D Belani
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202100205
Link to VoR: https://doi.org/10.1002/chem.202100205
01/2020

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
Aryne Multicomponent Reactions by Directed C-H Activation
Dr. Sunil Kumar Sunnam*, and Dr. Jitendra D. Belani*
Dedicated to Prof. Dr. Bernhard Wünsch on the occasion of his 61st birthday
[a]
Dr., Sunil Kumar, Sunnam
Thomas Jefferson University, College of Pharmacy
1020 Locust street, Philadelphia, PA 19107 (USA)
E-mail: sunilkumarsunnam@gmail.com
Present address: Dr. Reddy’s Laboratories, IPDO, Sy No 42 45 46 & 54, Bachupally, Hyderabad, Telangana-500090 (India)
[b]
Dr., Jitendra, Belani
Thomas Jefferson University, College of Pharmacy
1020 Locust street, Philadelphia, PA 19107 (USA)
E-mail: jitendra.belani@jefferson.edu
Supporting information for this article is given via a link at the end of the document
Abstract: Arylation via ortho C-H activation by the aid of directing
non-heterocyclic C-C bond in the C-H activation chemistry of
arynes remains elusive. We aimed to test the feasibility of third
coupling partners other than carbon monoxide (CO) in three
component reactions of arynes in C-H activation. Herein, we
report the use of arynes for biaryl synthesis in a 2-component
fashion and further extended our studies to use them in 3-
component reactions with acrylates and acrylonitriles via C-H
activation process.
groups is explored recently by many researchers. Herein, we have
developed
a
palladium-catalyzed C-H arylation using 8-
aminoquinoline as a bidentate directing group. We have overserved
that the reaction furnishes only C-H arylation unlike previous methods
where cyclization to corresponding isoquinolones is observed. More
interestingly, we have observed sequential C-H functionalization
when methylacrylate and acrylonitrile was added which underwent C-
H olefination with the aryl group which was installed from aryne
precursor.
Xu, 2014, 2015; Jeganmohan, 2014, Zhang 2017, Wang 2019
O
O
R1
R2
OMe
Pd(OAc)2
,
R1
R2
OMe
N
N
H
+
and/or Cu(OAc)2 or K2S2O8,
or
H
Introduction
blue LED
Greaney, 2007
R1
, 2003, 2004
Catellani
Ortho directed transition metal catalysis has emerged as a fine
craft in the C-H functionalization through chelation assistance.[1]
Biaryl synthesis is one of the major research area using these
R1
O
CO2Me
Br
R1
OMe
R1
R2
I
I
strategies due to its importance in pharmaceuticals/biology.[2]
A
R2
, Pd(OAc)2
Pd(OAc)2
variety of coupling partners were employed for the arylation of the
activated sp2 C-H bonds including aryl halides,[3] aryl boronic
acids[4a-d] and boronates,[4e,f] aryl grignards,[5] aryliodonium salts,[6]
arenediazonium salts,[7] aryl carbamates,[8] more recently aryl
silanes.[9]
Ever since the introduction of mild reaction conditions to generate
arynes by Kobayashi,[10] aryne chemistry has been
comprehensively developed by many researchers including
Larock, Greaney, Cheng and Biju.[11] Recently, the arynes
generated by this simple method were used to couple to the
metallated arenes generated via ortho C-H activation and all of
them resulted in the formation of heterocycles, mostly
phenanthridinones (Scheme 1).[12]
R2
R2
Initiated by oxidative addition
no C-H activation involved
This Work
R1
O
R1
O
R1
O
Q
Q
N
N
Q
Pd(OAc)2,
Pd(TFA)2
N
H
H
+
H
BQ,
NaOPiv
BQ,
H
NaOPiv + KOTf
R2
R2
R2 = CO2Me, CN
2-component
3-component
Scheme 1. Arynes in C-H activation reactions.
In this context, we wonder whether we could utilize an aryne as
an arylating reagent in a C-H activation process without forming
any heterocycles and would extend the scope to a three
component reactions involving a C-H activation process. Whilst
three component reactions involving C-H activation and an aryne
with a third coupling partner are not common, a solitary report by
Feng et al. described the utilization of carbon monoxide (CO) as
a third component which also resulted in phenanthridinone
heterocycles.[13] However, a third component which may form a
Results and Discussion
We started our studies by preparing a mono ortho-substituted
benzoic acid derivative 1 with a metal directing group. Our first
choice for the ortho directing group is the 8-aminoquinoline,
because of its versatility with coupling partners[14] and Pd(OAc)2
was chosen as the transition metal from previous reports with
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
arynes. We were glad to observe biphenyl product 3 in 19%
isolated yield when we employed 10 mol% of Pd(OAc)2, 1.0
equivalent 1,4-benzoquinone as oxidant, 1.5 equivalent aryne
precursor 2 and 3.0 equivalents of CsF for a trial reaction on
carboxamide 1 (Scheme 2) at 100 °C for 24 hours in acetonitrile.
Four other metals NiCl2, Ni(OTf)2, [Ru (p-cymeneI)Cl2]2, [RhCp*Cl]2
were screened for this transformation and found to be ineffective.
Other solvents such as toluene, DCM, DCE, DME did not yield any
biphenyl 3, while THF solvent showed traces of products. Next,
fluoride sources CsF, KF, NaF, LiF and TBAF were examined, among
them only CsF (19%) and KF (25.4%) yielded 3, while others showed
no conversion of the starting material. It is noteworthy to understand
that the rate of generation of benzyne should be slow enough to match
with that of the C-H activation step. As demonstrated by Jiang et al.[15]
KF releases aryne slower than CsF, which also was in good
agreement with our results. Next, we turned our attention to study the
effect of additives. We first tried the effect of 20 mol% addition of silver
salts AgSbF6 and AgNTf2 into the reaction and they lowered the yield
of the biphenyl 3 (Table 1, entries 2 and 3). Then the effect of protic
sources like acetic acid and its steric congener pivalic acid was
examined and it was observed that they both improved the yield of 3
significantly with pivalic acid being slightly better (38.7% vs 42.3%,
table 1, entries 4 and 5).
6a
TFA (0.2 eq.)
20.0
28.3
32.5
50 .6
64.8
52.2
79.3
7a
Na(TFA) (0.2 eq.)
KOAc (0.2 eq.)
8a
9b
Pivalic acid (0.5 eq)
Pivalic acid (1.0 eq)
NaOPiv (0.5 eq)
NaOPiv (1.0 eq)
10b
11b
12c
Conditions: [a] Quinolineamide (0.2 mmol, 1.0 eq.), aryne precursor (0.3
mmol, 1.5 eq.), Pd(OAc)2 (2.3 mg, 10 mol%), 1,4-benzoquinone (0.3 mmol, 1.5
eq.), KF (0.6 mmol, 3.0 eq.), additive, acetonitrile (3 mL, 0.066
M of
[b]
quinolineamide), 100 °C, 24 h.; Quinolineamide (0.2 mmol, 1.0 eq.), aryne
precursor (0.6 mmol, 2.0 eq.), Pd(OAc)2 (2.3 mg, 10 mol%), 1,4-benzoquinone
(0.3 mmol, 1.5 eq.), KF (0.6 mmol, 3.0 eq.), additive, acetonitrile (3 mL, 0.066
M of quinolineamide), 100 °C, 24 h. [c] reaction time 15 h. * Isolated yields.
A variety of quinolineamides were prepared and screened for the
substrate scope of these reaction conditions (Figure 1) with yields
moderate 35% (14) to good 85% (18). The scope was extended on
the aryne precursor variants (15–18, 20–24). A 1:1 ratio of positional
isomers was observed when 4-Methyl-2-(trimethylsilyl)phenyl
trifluoromethanesulfonate
and
4-(Trimethylsilyl)-1H-indol-5-yl
A more acidic source TFA (20%) and its sodium salt Na(TFA) (28.3%)
lowered the yield of 3 (table 1, entries 6 and 7) and the potassium salt
of acetic acid, KOAc gave slightly lesser yield than with its protic form
acetic acid (table 1, entry 8 vs 4). Among these additives pivalic acid
gave better yield, therefore the effect of molar concentration of pivalic
acid was investigated. 0.5 equivalent addition of pivalic acid on 2.0
equivalent addition of aryne improved the yield of 3 to 50.6% and
further increase of pivalic acid to 1.0 equivalent gave 64.8% yield of
3. At this point we were curious to learn if NaOPiv brings any
improvement in the yield. Accordingly, 0.5 equivalent addition of
NaOPiv gave a very slight better yield of 52.2% compared to the yield
with 0.5 equivalent addition of the corresponding acid (table 1, entry
11 vs 9), but gratifyingly, 1.0 equivalent addition of NaOPiv gave 3 in
79.3% yield and also reduced the reaction time to 15 h.
trifluoromethanesulfonate were used as the aryne precursors (Figure
1, entries 21 and 23, 24) and 4:1 ratio of regio isomers was observed
when 2-methyl-6-(trimethylsilyl)phenyl trifluoromethanesulfonate was
used as the aryne precursor (Figure 1, entry 22). With benzamides
containing no ortho substituents on either side, bis-arylation was
observed. However, we never were able to isolate any mono-arylated
products in these cases (Figure 1, entries 11, 19 and 20) and the bis
arylation was observed in low yields. So, we employed double the
stoichiometry of all the other reagents (aryne precursors (4 eq.), 1,4-
benzoquinone (3 eq.), Pd(OAc)2 (0.2 mol%), KF (6.0 eq.) and
sodiumpivalate (2 eq.)) to get only the bis-arylated products. In a
particular case, where N-(quinolin-8-yl)furan-2-carboxamide was the
starting material, 75% Diels-Alder product 5 was formed owing to the
lower rate of C-H activation compared to that of Diels-Alder reaction.
This experiment is in agreement with the formation of aryne
intermediate in the reaction. Next we turned our focus on a bigger
challenge, the study of an additional coupling partner in the reaction
medium. Based on an earlier report on non C-H activation variant,[11d]
we were curious to study methylacrylate involvement as the third
coupling partner in the C-H activation reactions involving arynes as
alkene coupling by DG assisted C-H activation is an active research
recently.[11e-g] We wanted to fix the aryne precursor stoichiometry to
2.0 equivalents since it gave the best yield in 2-component reaction.
The remaining reaction conditions such as stoichiometry of Pd(OAc)2,
oxidant, fluoride, solvent concentration, temperature were kept the
same and arbitrarily 2.0 eq. of methylacrylate were used. A test
reaction without any additive was performed and we were pleased to
observe that a 3-component coupled product 6 in 26% with exclusive
(E)-selectivity at the newly formed cinnamyl bond, together with 2-
component product 3 in 11% and unreacted starting material 1 in 45%
(Scheme 3, Table 2, entry 1). Though it was not surprising to observe
the formation of 3, the challenge was identified as finding the
conditions to improve the yield of 6 over 3 with concurrent complete
consumption of the starting material. Consequently, we chose to study
the effects of some additives and decided to test the effect of the same
CH3O
O
H
CH3O
O
TMS
OTf
Q
Q
Pd(OAc)2,
N
H
N
H
+
BQ, additive,
KF, ACN, 100 °C,
15 - 24 h.
1
2
3
Scheme 2. Optimization of 2-component reactions involving arynes and DG-
assisted benzamides
Table 1. Optimization of 2-component reaction with arynes and 2-Methoxy-N-
(quinolin-8-yl)benzamide
Entry
Additive
Yield %*
1a
2a
3a
4a
5a
None
25.4
6
AgSbF6 (0.2 eq.)
AgNTf2 (0.2 eq.)
Acetic acid (0.2 eq.)
Pivalic acid (0.2 eq.)
14.4
38.7
42.3
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
exclusive (E)-selectivity was observed at the newly formed cinnamyl
bonds and additionally we never observed the acrylate coupled
product 4.
additives (Pivalic acid and NaOPiv) which gave better yields in two
component reactions.
H3CO
H3CO
O
NHQ
OCH3
OCH3
O
NHQ
O
NHQ
O
NHQ
OCH3
OCH3
H3CO
H3C
TMS
CH3O
O
CH3O
O
CH3O
O
H
H3CO
O
Q
Q
3, 79.3%
NHQ
11, 75.9%
NHQ
16, 68.2%
20, 63.9%
Q
OTf
2
N
N
H
N
O
H
H
O
O
NHQ
OCH3
OCH3
NHQ
CH3
OCH3
H3CO
3
H3C
F
H3CO
OCH3
O
O
OCH3
[Pd], BQ,
additive, KF,
ACN, 100 °C, 24 h
OCH3
O
7, 76.8%
12, 69%
17, 78%
21, 71% (1:1 3' / 4' isomers)
NHQ
4, Not observed
1
6
O
NHQ
O
NHQ
OCH3
OCH3
O
O
S
NHQ
F
CF3
H3CO
Scheme 3. 3-component reactions involving arynes, 8AQ benzamides and
CH3
22, 68% (4:1 3' / 2' isomers)
methylacrylate.
8, 73.9%
13, 81.8%
18, 71.8%
O
NHQ
O
NHQ
O
NHQ
O
NHQ
Table 2. Optimization of 5-component reaction with arynes and 2-Methoxy-N-
CF3
H3CO
NH
(quinolin-8-yl)benzamide and methylacrylate.
11,
9, 77.8%
14, 34.7%
23, 74% (1:1 indol-4-yl / -5-yl isomers)
75.9% (by mono arylation)
78% (by bis arylation)
Metal
(10 mol%)
Pd(OAc)2
Additive
Serial
No
O
NHQ
O
NHQ
OCH3
O
NHQ
6
3
5
1
O
NHQ
O2N
H3CO
H3C
OCH3
NH
1
-
26
45
10, 41.9%
15, 77.9%
24, 54.8% (1:1 indol-4-yl / -5-yl isomers)
H3CO
19, 67.8%
O
2
Pd(OAc)2
Pivalic
acid (1.0
eq)
33.6
29.1
29.2
Q
N
O
5,
H
74.7%
3
Pd(OAc)2
NaOPiv
(1.0 eq)
44.0
51.3
42.4
18.7
11.8
38
20.4
17.3
16
Figure 1. Scope of 2-component reactions. (Isolated yields under standard
4
5
Pd(TFA)2
Pd(TFA)2
NaOPiv
(1.0 eq)
conditions b) in Table 1.
NaOPiv
(0.5 eq)
Accordingly, 1.0 eq. of Pivalic acid addition increased 6 to 33.6% and
3 to 29% and 1.0 eq. of NaOPiv further increased 6 to 44% with 3 still
formed at 18.7% proving again that NaOPiv is superior in 3-
component reactions as well. Switching to Pd(TFA)2 instead of
Pd(OAc)2 increased the yield of 6 to 51.3% and minimized 3 to 11.8%
(table2, entry 4). In a quest to further improve the yield of 6, two
phosphines PPh3 (20%) and XPhos (20%) were screened and both
ended up giving 6 in 11.4% and 8% yields respectively. Retrospecting
the entries 4 and 5 in table 1, it is evident here and also well known
that the acetate or pivalate anions are assisting the C-H activation
processes in the literature,[15] therefore we thought of testing an anion
which is stable and milder such as a triflate. Hereupon a test reaction
with 20 mol% Sc(OTf)3 (60 mol% triflate content) was conducted and
we were delighted that 37% 6 was formed with 60% unreacted starting
material and surprisingly 3 was not observed. Though Sc(OTf)3 gave
only 37% yield of 6, the mass balance was excellent. This encouraged
us to test other triflate anions such as NaOTf (50 mol%) and KOTf (50
mol%) . Delightedly, they gave 6 in 55% and 56.4% yields respectively
with KOTf being the best among all and with excellent selectivity for 6
and good mass balance. Nevertheless, this moderate yield still is not
satisfactory. Keeping in mind that NaOPiv consumed most of the
starting material in two component reactions (entry 11 and 12, table
1) and in three component reactions as in earlier entries 3–5 (table 2),
and the fact that triflate salts giving exclusive selectivity, a reaction
was set up with both additives, 0.5 eq. KOTf and 0.5 eq. NaOPiv.
Gratifyingly, 76% of 6 was observed with no starting material left. We
are satisfied with this yield owing to the labile nature of aryne
intermediates and their assembly in a C-H activated three component
reaction. It is noteworthy to mention that in all these conditions,
6
7
8
9
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
PPh3
11.4
8
n.d.
n.d.
n.o.
n.d.
n.d.
60
XPhos
Sc(OTf)3
37
NaOTf
(0.5 eq)
55
n.o.
n.o.
40
40
10
11
Pd(TFA)2
Pd(TFA)2
KOTf (0.5
eq)
56.4
KOTf (0.5
eq)
NaOPiv
(0.5 eq)
+
76
n.o.
n.o.
Conditions: Quinolineamide (0.2 mmol, 1.0 eq.), aryne precursor (0.4 mmol, 2.0
eq.), Metal (10 mol%), 1,4-benzoquinone (0.3 mmol, 1.5 eq.), KF (0.6 mmol, 3.0
eq.), additive, acetonitrile (3 mL, 0.066 M of quinoloneamide), methylacrylate
(0.2 mmol), 100 °C, 24 h.
These standard conditions were imposed on variety of quinoline
amides, substituted arynes and methylacrylate to give 25 to 34 in 48–
84% yields (Figure 2). The scope of the third component was
extended to acrylonitrile to give cinnamonitriles 35 to 42 in 53–74%
yields. It was observed that in most cases (5 out of 8 substrates) of
cinnamonitriles, an inseparable E:Z ratios (with E-isomer being major,
36, 38, 40–42) were formed. The formation of the 3-component
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
reaction product is supported by its X-ray crystal structure (Figure
3).[16]
Figure 3. ORTEP diagram of 6, showing thermal ellipsoids at 50% probability
level.
O
NHQ
O
NHQ
O
NHQ
O
NHQ
CH3
Pd(TFA)2
1
H3CO
O2N
H3C
H3CO
6
-TFA
BQ + 2 TFA
R
, R = CO2Me, 75.9%
35, R = CN, 64.8%
R
R
R
CH3O
O
6
25
26
27
, R = CO2Me, 70.2%
37, R = CN, 57.2%
, R = CO2Me, 48%
, R = CO2Me, 78.1%
36, R = CN, 69%
CH3O
O
N
OCH3
N
N
O
NHQ
O
NHQ
NHQ
O
Pd
TFA
O
NHQ
OCH3
N
Pd
H
H3CO
F
OMe
H3CO
S
O
2 + KF
-TFA
OCH3
30
, R = CO2Me, 75.1%
R
R
R
R
31, R = CO2Me, 84%
28
38
29
39
, R = CO2Me, 82%
, R = CN, 74.2%
, R = CO2Me, 77.9%
, R = CN, 65%
40
, R = CN, 53%
CH3O
O
O
NHQ
O
NHQ
Q
NH
O
N
H
N
CF3
O
CH3O
N
H3CO
Pd
N
R
R
N
Pd
R
32
41
33
42
, R = CO2Me, 73%
, R = CN, 70.3%
, R = CO2Me,67.7%
, R = CN, 59.1%
OMe
34, R = CO2Me, 65.5%
O
O
OMe
Scheme 4: Possible pathway of 3-Component reactions.
Figure 2. Scope of 3-component reactions. Isolated yields under standard
conditions (entry 11 conditions) in Table 2.
H3CO
H3CO
TMS
OTf
O
O
CD3O
D3
CH3O
CH3O
O
H
CD3O
O
D
Q
Q
Q
D
Q
N
N
43
N
N
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
D
O
O
2
A reaction mechanism was proposed (Scheme 4) and we performed
kinetic isotopic studies on the 3-component reaction to understand
whether the acrylate coupling is a regular Heck or a Michael addition
type. Accordingly, deuterated analogue of 1 was synthesized based
on the available literature.[17] When equal molar quantities of 1 and 1-
D were reacted under standard 3-component reaction conditions, a
kinetic isotopic effect (kH/kD) of 3 (see supporting information for the
1H NMR spectrum of the mixture of 31 and 31-D) was observed and
incorporation of deuterium on the acrylate alkene carbons was not
observed (Scheme 5), suggesting that acrylate coupling did not
happen via a Michael addition but by a regular Heck type mechanism
procedure at the newly formed cinnamoyl bond.
D
O
Standard conditions
OCH3
OCH3
1
1-D
31
31-D
(no D incorporation)
Scheme 5. Deuterium labelling experiments of 3-component reaction in
standard conditions.
Conclusion
To summarize, we employed arynes in 2-component ortho C-H
activation reactions for biaryl synthesis without the formation of
any heterocycles as reported in previous reports and further
extended this strategy for three component reactions involving
methylacrylate and acrylonitrile as third coupling partners. We
hope that these findings open up new challenges in multi-
component reactions of arynes in C-H activation chemistry.
Acknowledgements
JDB acknowledges the Dean Rebecca Finley, College of
Pharmacy at TJU. JDB and SKS are also grateful to TJU for the
facilities and financial support for this work. SKS specially thanks
Prof. Jason Sello, Dept. of Chemistry, Brown University, USA for
allowing to repeat a few experiments in his laboratory.
Keywords: aryne • biaryl • biarylacrylate • multi-component •
ortho C-H activation reaction.
[1]
a) Ł.Woz´niak, N. Cramer, Trends Chem. 2019, 1, 471–484; b) P.
Gandeepan, L. Ackermann, Chem 2018, 4, 199 –222; c) Y. Park,Y. Kim,
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
S. Chang, Chem. Rev. 2017, 117, 9247–9301; d) Q.-Z. Zheng, N. Jiao,
Chem. Soc. Rev. 2016, 45, 4590–4627; e) B. Ye, N. Cramer, Acc.Chem.
Res. 2015, 48, 1308 –1318; f) G. Rouquet, N. Chatani, Angew.Chem. Int.
Ed. 2013, 52, 11726–11743; Angew.Chem. 2013, 125, 11942–11959; g)
J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369–375. h) P. Sehnal,
R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev. 2010, 110, 824–889; i) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew.Chem. Int. Ed. 2009, 48,
9792–9826; Angew.Chem. 2009, 121, 9976–10011; j) X. Chen, K. M.
Engle, D.-H. Wang, J. -Q. Yu, Angew.Chem. Int. Ed. 2009, 48, 5094–
5115; Angew.Chem. 2009, 121, 5196–5217; k) O. Daugulis, H. -Q. Do,
D. Shabashov, Acc. Chem. Res. 2009, 42, 1074–1086. l) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169. m) P. Gandeepan, T.
Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem. Rev. 2019,
119, 2192–2452. n) J. Yamaguchi, A. D. Yamaguchi, K. Itami,
Angew.Chem. Int. Ed. 2012, 51, 8960−9009.
2006, 8, 3391–3394. c) Y. Feng, G. Chen, Angew. Chem. 2010, 122,
970–973; Angew. Chem. Int. Ed. 2010, 49, 958–961. d) D. Shabashov,
O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965–3972. e) Y. Ano, M.
Tobisu, N. Chatani, J. Am. Chem. Soc. 2011, 133, 12984–12986. f) W.
R. Gutekunst, R. Gianatassio, P. S. Baran, Angew. Chem. 2012, 124,
7625–7628; Angew. Chem. Int. Ed. 2012, 51, 7507–7510. g) T. Truong,
K. Klimovica, O. Daugulis, J. Am. Chem. Soc. 2013, 135, 9342 – 9345.
h) M. Corbet, F. De Campo, Angew. Chem. Int. Ed. 2013, 52, 9896–9898.
h) S. Rej, Y. Ano, N. Chatani, Chem. Rev. 2020, 120, 1788 – 1887.
[15] M. Feng, B. Tang, N. Wang, H. –X. Xu, X. Jiang, Angew. Chem. Int. Ed.,
2015, 54, 14960–14964.
[16] Deposition Number 2024054 (for compound 6) contains the
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access Structures
service www.ccdc.cam.ac.uk/structures.
[2]
a) J. –A. G. –Lo´pez, M. F. Greaney, Chem. Soc. Rev. 2016, 45, 6766–
6798. b) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem.
Rev. 2011, 111, 563–639.
[17] A. M. Suess, M. Z. Ertem, C. J. Cramer, S. S. Stahl, J. Am. Chem. Soc.
2013, 135, 9797−9804.
[3]
[4]
A. Yokota, Y. Aihara, N. Chatani, J. Org. Chem. 2014, 79, 11922–11932.
a) R. K. Chinnagolla, M. Jeganmohan, Org. Lett., 2012, 14, 5246–5249.
b) Y. -C. Yuan, C. Bruneau, T. Roisnel, R. Gramage-Doria, J. Org. Chem.
2019, 84, 12893−12903. c) T. Vogler, A. Studer, Org. Lett., 2008, 10,
129–131. d) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin, Y.
Wang, Angew. Chem., Int. Ed. 2007, 46, 5554–5558. e) F. Kakiuchi, S.
Kan, N. Chatani, S. Murai, J. Am Chem. Soc., 2003, 125, 1698–1699. f)
B. Zhang, H. –W. Wang, Y. –S. Kang, P. Zhang, H. –J. Xu, Y. Lu, W. –
Y. Sun, Org. Lett. 2017, 19, 5940–5943.
[5]
L. Ilies, S. Asako, E. Nakamura, J. Am. Chem. Soc. 2011, 133,
7672−7675.
[6]
[7]
T. E. Storr, M. F. Greaney, Org. Lett. 2013, 15, 1410–1413.
L. Huang, D. Hackenberger, L. J. Goossen, Angew. Chem. Int. Ed. 2015,
54, 12607–12611.
[8]
[9]
M. Tobisu, K. Yasui, Y. Aihara, N. Chatani. Angew. Chem. Int. Ed. 2017,
56, 1877–1880.
H. Luo, Q. Xie, K. Sun, J. Deng, L. Xu, K. Wang, X. Luo, RSC Advances
2019, 32, 18191–18195.
[10] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett., 1983, 12, 1211–
1214.
[11] a) N. Chatani, A. Kamitani, M. Oshita, Y. Fukumoto, S. Murai, J. Am.
Chem. Soc. 2001, 123, 12686–2687. b) Z. Liu, R. C. Larock, Angew.
Chem. Int. Ed. 2007, 46, 2535–2538. c) J. L. Henderson, A. S. Edwards,
M. F. Greaney, J. Am. Chem. Soc., 2006, 128, 7426–7427. d) J. L.
Henderson, A. S. Edwards, M. F. Greaney. Org. Lett. 2007, 9, 5589-
5592. e) H. Yoshida, T. Morishita, H. Fukushima, J. Ohshita, A. Kunai,
Org. Lett. 2007, 9, 3367–3370. f) M. Jeganmohan, C. -H, Cheng, Org.
Lett. 2004, 6, 2821–2824. (early MCR) g) A. Bhunia, T. Roy, P. Pachfule,
P. R. Rajamohanan, A. T. Biju, Angew. Chem. Int. Ed. 2013, 52, 10040–
10043. e) A. Deb, S. Bag, R. Kancherla, D. Maiti, J. Am Chem. Soc.,
2014, 136, 13602–13605. f) K. Seth, M. Bera, M. Brochetta, S. Agasti, A.
Das, A. Gandini, A. Porta, G. Zanoni, D. Maiti, ACS Catal. 2017, 7, 7732–
7736. g) S. Maity, R. Kancherla, U. Dhawa, E. Hoque, S. Pimparkar, D.
Maiti. ACS Catal. 2016, 6, 5493–5499.
[12] a) S. Pimparkar, M. Jeganmohan, Chem. Commun. 2014, 50, 12116–
12119. b) X. -L. Peng, W. -G. Wang, C. Jiang, D. Sun, Z. -H. Xu, C.-H.
Tung, Org. Lett. 2014, 16, 5354–5357. c) W. Wang, X. Peng, X. Qin, X.
Zhao, C. Ma, C. –H. Tung, Z. Xu, J. Org. Chem. 2015, 80, 2835–2841.
d) T. –Yu. Zhang, J. –B. Lin, Q. –Z. Li, J. –C. Kang, J. –L. Pan, S. –H.
Hou, C. Chen, S. –Y. Zhang, Org. Lett. 2017, 19, 1764–1767. e) T. –Y.
Zhang, C. Liu, C. Chen, J. –X. Liu, H. –Y. Xiang, W. Jiang, T. –M. Ding,
S. –Y. Zhang, Org. Lett. 2018, 20, 220–223. f) J. Zhao, H. Li, P. Li, L.
Wang. J. Org. Chem. 2019, 84, 9007–9016. g) M. Asamdi, P. M.
Chauhan, J. J. Patel, K. H. Chikhalia, Tetrahedron 2019, 75, 3485–3494.
h) S. Feng, S. Li, J. Li, J. Wei, Org. Chem. Front. 2019, 6, 517–522. i) C.
Chen, Y. Hao, T. –Yu, Zhang, J. –L. Pan, J. Ding, H. –Y. Xiang, M. Wang,
T. –M. Ding, A. Duan, S. –Y. Zhang, Chem. Commun. 2019, 55, 755–
758.
[13] M. Feng, B. Tang, H. –X. Xu, X. Jiang, Org. Lett. 2016, 18, 4352–4355.
[14] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005,
127, 13154–13155. b) B. V. S. Reddy, L. R. Reddy, E. J. Corey, Org. Lett.
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202100205
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
Arynes were known to undergo multi-component reactions in non C-H activation variants. The present article provides the application
of in-situ generated arynes in multi-component C-H activation reactions catalyzed by palladium and assisted by a combination of
additives sodium pivalate and potassium triflate. Unlike the earlier versions, phenanthridinones (heterocycles) were not observed in 2-
component fashion.
6
This article is protected by copyright. All rights reserved.