Rhodium(III)-Catalyzed Decarboxylative Aminomethylation of Glycine Derivatives with Indoles via C-H Activation

Article abstract of DOI:10.1021/acs.joc.9b03365

A rhodium(III)-catalyzed decarboxylative aminomethylation of glycine derivatives with indoles bearing a pyrimidine directing group was developed via C-H activation, exclusively affording the corresponding aminomethylated products with C3 selectivity. In t

Full text of DOI:10.1021/acs.joc.9b03365

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Note
Rhodium(III)-catalyzed decarboxylative aminomethylation
of glycine derivatives with indoles via C-H activation
Ruixing Liu, Yin Wei, and Min Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03365 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
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 14
The Journal of Organic Chemistry
1
2
3
4
5
Rhodium(III)-catalyzed decarboxylative aminomethylation of glycine derivatives
with indoles via C−H activation
6
7
8
Ruixing Liu,a Yin Weia,* and Min Shia,b
9
aState Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Science,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032 China. Email:
weiyin@sioc.ac.cn.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
bShenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen,
Guangdong 518000, China.
NHAr
R
R
H
Rh(III) Ag(I)
Ar-Gly-OH
+
N
H
Activation Relay
20 examples
up to 70% yield
N
DG
C3-selectivity
DG
Abstract: A rhodium(III)-catalyzed decarboxylative aminomethylation of glycine derivatives with
indoles bearing a pyrimidine directing group has been developed via C−H activation, exclusively
affording the corresponding aminomethylated products with C3 selectivity. In this synthetic
protocol, easily available and resourceful arylglycines were utilized as aminomethyl functional
moieties.
In recent years, decarboxylative cross-coupling has been established as a modern strategy for
the formation of C–C and C–heteroatom bond.1 Inexpensive and readily available carboxylic acids
are used as an alternative to expensive organometallic reagents and halides. On the other hand,
due to the worldwide abundance of biomass that incorporates carboxylate functionality (e.g.,
amino acids, α-hydroxy acids, fatty acids etc), there is a strong impetus to invent or discover
chemical transformations that target carboxylic acids as chemoselective leaving groups for new
and valuable C−C bond forming reactions.
Decarboxylative C–H functionalization has emerged as a fascinating field in organic
synthesis. In this realm, silver salt played a pivotal role in the decarboxylative process since
Hunsdicker reaction has been discovered in 1942.2 The seminal studies of Goossen have
demonstrated decarboxylative couplings as a powerful strategy to form C–C or C–heteroatom
bonds starting from carboxylic acids.3 In recent years, Li’s group developed a series of
silver-catalyzed decarboxylative functionalization reactions (Scheme 1a).4 On the basis of their
transformations, various functional groups such as halide, azide, CF3 and SCF3, can be introduced
into the molecules accompanied with decarboxylative process.
C-H bond activation of arenes by transition-metal catalyzed reaction has been extensively
developed as an important synthetic method to provide complex molecular structures.5 Currently,
as a highly efficient method to introduce functional groups, C-H bond functionalizations have
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
1
2
3
4
5
6
7
8
9
significant advantages to construct polycyclic compounds. However, decarboxylation cooperated
in C-H activation paradigm still needs a further exploration. Recently, the groups of Ge and Zhu
have independently displayed the successful exploration of pyruvic acid as the cross-coupling
partners in transition metal (TM)-catalyzed C−H functionalization (Scheme 1b).6 Wang and
co-workers also reported an example of ruthenium-catalyzed decarboxylative meta-selective C−H
acylation with pyruvic acid (Scheme 1c).7 Although meta-selectivity makes this realm
rejuvenating again, the pyruvic acid derivatives are still an obvious limitation of this reaction.
Scheme 1. Examples of carboxylic acid as coupling partners in the decarboxylative
functionalization and C-H activation as well as this work.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
a) Li's work
R COOH
Ag
+
FG
R
FG
FG = t-BuOCl, TsN3,
[CF3], [SCF3]
b) Ge and Zhu's work
O
DG
DG
Pd(II)
Ag
+
R
R
COOH
H
O
c) Wang's work
O
DG
DG
H
Ru
Ag
+
R
COOH
O
R
activation relay
d) This work:
on indole cooperated with glycine decarboxylation
H
NHPh
3
PhNH COOH
Ph-Gly-OH
Rh(III)
Ag
+
H
2
1 N
DG
N
DG
Previously, we reported an example of C-H aminomethylation with triphenylhexahydrotriazine
(THT) under photocatalysis and rhodium catalysis.8 In this finding, we revealed a new activation
relay mode in indole substrate bearing a pyrimidine directing group, in which the reactivity of
indole’s C3 position was enhanced due to the rhodium coordination at the C2 position. Distinct
from C3-cyanation,9 C3-formylation,10 C3-alkynylation11 and C3-alkenylation12 of indole with its
inherent C3 nucleophilicity, this protocol requires a rhodium catalyst to activate its C2 position.
We wonder whether there is a new coupling pattern between decarboxylative species and
cyclometallated intermediate derived from C-H activation. In this report, we present the coupling
of N-pyrimidylindole derivatives with glycine derivatives via a new Rh(III)-catalyzed C-H
activation process to exclusively afford the aminomethylated products with C3 selectivity through
a decarboxylative process in the presence of silver salt (Scheme 1d).
The reaction was carried out with N-pyrimidylindole 1a and N-phenylglycine 2a by using
[Cp*RhIII] complex (4 mol%) and AgSbF6 (20 mol%) as the catalyst combination, AgOAc as an
oxidant (2.0 equiv), acetic acid (2.0 equiv) as the additive in DMF at 120 oC, providing the desired
aminomethylation product 3a in 70% yield (Table 1, entry 1). Noteworthy, the C2 product was not
detected at all. The use of pivalic acid, benzoic acid or adamantanecarboxylic acid as additive
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
afforded 3a in lower yield and only 6% of 3a was formed in the absence of additive, suggesting
that the addition of acetic acid was crucial to this reaction (Table 1, entries 2-5). Then, we
screened several solvents in this transformation and found that the yield of 3a decreased in
acetonitrile and dichloroethane (Table 1, entries 6 and 7). In addition, none of 3a was obtained if
this reaction was carried out in ethanol (Table 1, entry 8). Finally, we extended reaction time to 30
hours, and identified that 3a was obtained in 61% yield under otherwise identical conditions,
indicating that the product 3a may decompose in the acidic media under heating condition (Table
1, entry 9). It should be mentioned here that the starting materials could not be completely
converted when the reaction was quenched after 12 h, giving the desired product in moderate yield.
With regard to the sensitivity test for this protocol,13 we tested the influences of reaction
temperature and under dark condition (for a more detailed condition screening, see Tables S1 and
S2 in the Supporting Information). The reaction could not take place smoothly at 20 oC and 70 oC
(see Table S2, entries 1-2 in Supporting Information); slightly modified reaction temperature from
120 oC to 110 oC and 130 oC led to slight yield decreasing (see Table S2, entries 3-5 in Supporting
Information). Under the dark condition, the yield was not affected (see Table S2, entry 13 in
Supporting Information).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
Table 1 Optimization of the reaction conditions for the reaction of N-pyrimidylindole 1a and
N-phenylglycine 2a.
NHPh
[Cp*RhCl2]2, AgSbF6, AgOAc
PhNH COOH
N
N
+
solvent, additives, 120 o
C
N
Ph-Gly-OH
N
N
N
1a
entrya
2a
3a
solvent
additives
yield of 3a (%)
HOAc
PivOH
70
53
DMF
DMF
DMF
DMF
DMF
DCE
MeCN
1
2
PhCOOH
AdCOOH
-
3
45
51
4
5
6
HOAc
HOAc
6
48
46
-
7
HOAc
HOAc
8
9b
EtOH
DMF
61
a
Substrate 1a (0.10 mmol), 2a (0.15 mmol), HOAc (0.20 mmol), [Cp*RhCl2]2 (4 mol %), AgSbF6 (20 mol %),
AgOAc (0.20 mmol), additives (2 equiv) were added. All the reactions were carried out in a 0.10 mmol scale in
solvent (1.0 mL) at 120 oC for 12 h. b The reaction was carried out for 30 hrs.
After the optimal reaction conditions were established, the substrate scope of various
substituted indoles 1 was subsequently explored, and the results are shown in Scheme 2. When
indole was introduced halide (substrates 1b - 1d) and methoxy group (substrate 1e) at C6 position,
the reaction could proceed smoothly, giving the desired products in 62% to 66% yields. When
indole’s C5-position was substituted with an OBn group (substrate 1f), the reaction also performed
very well to furnish the corresponding product 3f in 58% yield. This aminomethylation protocol
was compatible with substrate 1g and substrate 1h as well, in which the methyl substituent or nitro
substituent was incorporated at indole’s C4-position. We next inspected different directing groups
for this newly developed C-H activation process. The pyrimidine group could be replaced by
pyridine (substrate 1i), thiazole (substrate 1j) and benzoxazole (substrate 1k), affording the
desired products 3i-3k in moderate yields ranging from 51% to 70%. A methyl group could be
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
1
2
3
4
5
6
7
8
9
introduced into pyrimidine directing group (substrate 1l), affording 3l in 53% yield. Its electronic
property or substrate conformation probably affected the coordination of rhodium and substrate.
For substrates 2ma and 2mb having a substituent at C3 position, the reaction did not give the
desired products because the reaction site has been blocked out by the methyl group, and neither
of C2 products were obtained.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
NHPh
4
3
5
2
R
R
NHPh
[RhCp*Cl2]2, AgSbF6
AgOAc, HOAc
N
6
1N
+
7
HOOC
N
(Het)Ar
N
(Het)Ar
DMF, 120 o
C
2a
1b 1m
-
3b 3l
-
NHPh
N
NHPh
N
NHPh
NHPh
N
N
N
N
N
Cl
MeO
Br
N
F
N
N
N
N
3c
3e
(62%)
3b
(66%)
3d
(62%)
(62%)
Me
NO2
NHPh
NHPh
NHPh
N
NHPh
BnO
N
N
N
N
N
N
N
N
N
N
3f
(58%)
3g
(58%)
NHPh
3i
3h
(70%)
R
(51%)
NHPh
NHPh
N
N
N
N
N
N
N
O
N
N
N
S
1
2ma
2mb
R = Me
2
Me
3l
(53%)
R = OMe
3j
(51%)
3k
(51%)
(no reaction)
Scheme 2. Substrate scope of different indole derivatives.a
a Substrate 1 (0.10 mmol), 2a (0.15 mmol), [Cp*RhCl2]2 (4 mol %), AgSbF6 (20 mol %), AgOAc (0.20 mmol), HOAc (0.20 mmol), DMF
(1.0 mL). All the reactions were carried out in a 0.10 mmol scale in DMF (1.0 mL) at 120 oC for 12 h.
Since amino acids are a huge feed stock in the synthetic chemistry, we next investigated the
substrate scope for a varity of substituted N-phenylglycines. The results are demonstrated in
Scheme 3. Various phenyl-substituted glycines bearing electron-donating or electron-withdrawing
groups coupled smoothly with 1a at indole’s C3 position, affording the corresponding
aminomethyl products in moderate yields. For example, methyl group (2n), methoxy group (2o),
isopropyl group (2p) and phenyl group (2q) could be introduced into the para position of
phenylglycines, giving the desired products 3n-3q in moderate yields ranging from 64% to 67%.
To our delight, trifluoromethylthio group (2r) and difluoromethoxy group (2s) substituted glycines
were also tolerated, affording the corresponding products 3r and 3s in 62% and 59% yields,
respectively. For pyrrole tethered phenylglycine (2t), the product 3t could be isolated in 52% yield
o
at 100 C for 10 h with 6 mol% rhodium(III) catalyst. Furthermore, the meta-substituted
phenylglycines were also tested, affording the corresponding indane derivative 3u and
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
chlorine-substituted product 3v in 61% and 70% yields, respectively. Using ortho substituted
glycine 2w, the reaction could took place; however, the corresponding product 3w was obtained in
24% yield.
7
8
NHAr
9
NHAr
[RhCp*Cl2]2, AgSbF6
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
+
AgOAc, HOAc
DMF, 120 oC
HOOC
N
N
N
N
1a
2
3n-3w
H
N
H
N
NH
N
N
N
N
iPr
Me
OMe
N
N
N
N
N
3p
3n
(67%)
(64%)
3o
(66%)
H
H
N
H
N
N
N
N
N
Ph
OCF2H
SCF3
N
N
N
N
N
N
3r
(59%)
3q
(67%)
3s
(62%)
H
N
H
N
H
N
H
N
Me
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
b
3t
(52%)
3w
(24%)
3u
3v
(70%)
(61%)
Scheme 3 Substrate scope of different indole N-phenylglycine derivatives.a
a 1a (0.10 mmol), 2 (0.15 mmol), [Cp*RhCl2]2 (4 mol %), AgSbF6 (20 mol %), AgOAc (0.20 mmol), HOAc (0.20
mmol), DMF (1.0 mL). All the reactions were carried out in a 0.10 mmol scale in DMF (1.0 mL) at 120 oC for 12
h. b The reactions were carried out at 100 oC for 10 h with [Cp*RhCl2]2 (6 mol %)
We also tried plain glycine, but it did not give the desired product under the standard
condition. This observation may reveal the different mechanism from the previously reported
decarboxylative reactions. To further clarify the reaction scope, we attempted to replace the aryl
group with Boc protecting group in our reaction and found that using Boc protected glycine 5 as
substrate14 did not give the coupling product under the standard condition, suggesting the essential
of an aryl group in glycine (Scheme 4a). The control experiment confirmed that this C-H
activation reaction under the optimized conditions was not affected by the addition of the radical
inhibitors such as TEMPO (1.0 equiv), rendering unlikely the intervention of a radical pathway
(Scheme 4b). The control experiments also indicated that none of the desired product was formed
in the absence of rhodium(III) catalyst (Scheme 4c). Using indole substrate 6a or 6b having a
methyl substituent at C2 position, this C-H activation process was completely interrupted,
illustrating that the C-H activation step is indispensable in this synthetic protocol (Scheme 4d).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
1
2
3
4
5
6
7
8
9
The KIE was determined to be kH/kD = 2.7 for the parallel reactions using 1a and 1a-d2 at a low
conversion while the KIE is 1.3 using 1a and 1a-d3. This value indicates that the C2–H cleavage
step is probably involved in the turnover-limiting process (Scheme 4e). Without the co-catalyst
AgSbF6, the reaction also failed.8 A large-scale reaction was carried out to demonstrate the
practical value on synthesis. The yield can be obtained up to 52% in 5 mmol scale (Scheme 4f).
Removal of directing group was achieved upon treatment with NaOEt in DMSO to afford
corresponding product 6 in 81% yield (Scheme 4g).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
Scheme 4 Control experiments and synthetic transformations.
Gly-OH
Failed substrates
4
[RhCp*Cl2]2, AgSbF6
N
no product
+
Boc-Gly-OH
a)
AgOAc, HOAc
DMF, 120 o
N
N
C
1a
5
[RhCp*Cl2]2, AgSbF6
b)
c)
+
Ph-Gly-OH
1a
3a
(63%)
TEMPO
2a
AgOAc, HOAc
DMF, 120 o
C
AgSbF6
1a
no product
no product
+
2a
AgOAc, HOAc
DMF, 120 o
C
Me
N
[RhCp*Cl2]2, AgSbF6
AgOAc, HOAc
or
N
D
2a
d)
+
N
DMF, 120 o
C
N
6a
6b
e)
N
Standard Condition
2a
1a
or
+
3a
KIE = 1.3
N
N
3
1a
-d
D
N
Standard Condition
2a
+
1a
or
3a
KIE = 2.7
N
N
2
1a
-d
[RhCp*Cl2]2, AgSbF6
AgOAc, HOAc
3a
(52%, 780 mg)
1a
(5 mmol, 976 mg)
f)
+
2a
DMF, 120 o
C
NHPh
NHPh
g)
NaOEt
DMSO, 120 o
C
N
N
H
N
3a
N
6 (81%)
Based on the above results and the previous reports, a plausible catalytic cycle has been
shown in Scheme 5. In the presence of AgSbF6, the cationic [Cp*RhIII] complex is initially
generated, which coordinates with substrate 1a, giving a metallacyclic intermediate 7. The
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-phenylglycine 2a undergoes decarboxylation to afford N-methyleneaniline 8 in the presence of
AgOAc and HOAc. For intermediate 7, the reactivity of C3 position has been enhanced due to the
cyclometallation at C2 position.15 The electrophilic addition of 7 on the reactive Mannich acceptor
816 affords the key intermediate 9. Protodemetallation from intermediate 9 produces the
aminomethylation product 3a. The activation of Rh(III) enhanced the nucleophilicity of indole.
Species 8 is a small and highly active imine. The two key factors as cyclometallation at C2
position and formation of active species 8 induce the exclusive C3 site selectivity. The reaction
could not take place if the directing group was changed. This selectivity is irrelevant with
directing group. During optimization of reaction conditions, we found that the loading amount of
AgOAc affected the product yield (see Table S1 in the Supporting Information). AgOAc probably
plays an important role on decarboxylation from 2a to 8. These two parts constitute a relay
catalysis.17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
Scheme 5 A plausible mechanism.
AgOAc
PhN
PhNH
COOH
HOAc
8
2a
Cp*
RhIII
N
N
N
7
NHPh
RhIII
Cp*
N
N
N
1a
[Cp*Rh]III
NHPh
9
HOAc
N
N
N
3a
In summary, a novel rhodium(III)-catalyzed decarboxylative aminomethylation of glycine
derivatives with indoles via C−H activation is developed, which exclusively produces C3
aminomethylation indole products. In this reaction, resourceful arylglycines were utilized as
aminomethyl functional moieties in this rhodium(III)-catalyzed C-H activation. Investigations on
expanding this rhodium-catalyzed cross coupling reaction and application of this method to
synthesize other heterocycles are undergoing in our laboratory.
Experimental Section
1
General information. H NMR spectra were recorded on Agilent and Varian 400 spectrometer
for solution in CDCl3 with tetramethylsilane (TMS) as an internal standard; coupling constants J
are given in Hz. 13C NMR spectra were recorded on Agilent and Varian 400 spectrophotometers
(100 MHz) with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm). Mass and
HRMS spectra were recorded by DART method. Organic solvents used were dried by standard
methods when necessary. Infrared spectra were recorded on a Thermofisher spectrometer with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
1
2
3
4
5
6
absorption in cm-1. Commercially obtained reagents were used without further purification. Flash
column chromatography was carried out using silica gel at increased pressure. All the derivatives
of 1 and 2 were prepared by the reported methods.17
7
8
9
General procedure for the preparation of compound 3a: To a Schlenk tube with a magnetic
stirring bar was added 1-(pyrimidin-2-yl)-1H-indole 1a (0.10 mmol, 19.5 mg), phenylglycine 2a
(0.15 mmol, 47.2 mg), [RhCp*Cl2]2 (4 mol%, 2.5 mg), AgSbF6 (20 mol%, 6.8 mg) and AgOAc
(0.20 mmol, 33.4 mg). Then, DMF (1.0 ml) was injected to the reaction mixture and HOAc (0.20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
o
mmol, 12.0 mg) was added. The reaction was carried out at 120 C in the oil bath. After the
reaction was completed, the solution was concentrated under reduced pressure and the residue was
purified with a silica gel column chromatography to afford the product (petroleum ether / ethyl
acetate = 10 / 1).
Procedure for Scale-Up Preparation of 3a: To a Schlenk tube with a magnetic stirring bar was
added 1-(pyrimidin-2-yl)-1H-indole 1a (5.0 mmol, 975 mg), phenylglycine 2a (7.5 mmol, 2.36 g),
[RhCp*Cl2]2 (4 mol%, 124 mg), AgSbF6 (20 mol%, 343 mg) and AgOAc (10 mmol, 1.67 g). Then,
DMF (25 ml) was injected to the reaction mixture and HOAc (10 mmol, 600 mg) was added. The
o
reaction was carried out at 120 C in the oil bath. After the reaction was completed, the reaction
mixture was filtered through a celite to remove the salts. The solution was concentrated under
reduced pressure and the residue was purified with a silica gel column chromatography to afford
the product (petroleum ether / ethyl acetate = 10 / 1).
1
N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3a).9 yellow oil (21.0 mg, 70%). H
NMR (400 MHz, Chloroform-d) δ 4.00 (s, 1H), 4.51 (s, 2H), 6.72 – 6.80 (m, 3H), 7.01 (dd, J =
4.8 Hz, 1H), 7.22 – 7.31 (m, 3H), 7.40 (dd, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 8.26 (s, 1H),
8.67 (d, J = 4.8 Hz, 2H), 8.83 (d, J = 8.4 Hz, 1H).
N-((6-fluoro-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3b).9 yellow oil (19.7 mg,
62%). 1H NMR (400 MHz, Chloroform-d) δ 3.97 (s, 1H), 4.47 (s, 2H), 6.71 – 6.81 (m, 3H), 6.99 –
7.06 (m, 2H), 7.25 (dd, J = 7.8 Hz, 2H), 7.56 (dd, J = 8.6, 5.4 Hz, 1H), 8.21 (s, 1H), 8.57 (dd, J =
11.1, 2.4 Hz, 1H), 8.61 – 8.71 (m, 2H).
N-((6-chloro-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3c).9 yellow oil (22.1 mg,
66%). 1H NMR (400 MHz, Chloroform-d) δ 3.97 (s, 1H), 4.44 (s, 2H), 6.68 – 6.82 (m, 3H), 7.02
(dd, J = 4.8 Hz, 1H), 7.17 – 7.29 (m, 3H), 7.53 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.64 (d, J = 4.8
Hz, 2H), 8.84 (s, 1H).
N-((6-bromo-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3d).9 yellow oil (23.5 mg,
62%). 1H NMR (400 MHz, Chloroform-d) δ 3.95 (s, 1H), 4.45 (s, 2H), 6.70 – 6.80 (m, 3H), 7.03
(dd, J = 4.8 Hz, 1H), 7.23 (dd, J = 7.7 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H),
8.19 (s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 9.01 (s, 1H).
N-((6-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3e).9 yellow oil (20.5 mg,
62%). 1H NMR (400 MHz, Chloroform-d) δ 3.95 (s, 3H), 4.46 (s, 2H), 6.68 – 6.83 (m, 3H), 6.93
(d, J = 8.9 Hz, 1H), 6.99 (dd, J = 4.4 Hz, 1H), 7.24 (dd, J = 7.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H),
8.15 (s, 1H), 8.46 (s, 1H), 8.65 (d, J = 4.9 Hz, 2H).
N-((5-(benzyloxy)-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3f).9 yellow oil (23.6 mg,
1
58%). H NMR (400 MHz, Chloroform-d) δ 3.94 (s, 1H), 4.47 (s, 2H), 5.11 (s, 2H), 6.71 – 6.79
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
(m, 3H), 7.01 (dd, J = 4.8 Hz, 1H), 7.07 (dd, J = 9.1, 2.6 Hz, 1H), 7.18 – 7.26 (m, 3H), 7.33 (dd, J
= 7.2 Hz, 1H), 7.39 (dd, J = 7.4 Hz, 2H), 7.48 (d, J = 7.3 Hz, 2H), 8.23 (s, 1H), 8.66 (d, J = 4.8 Hz,
2H), 8.71 (d, J = 9.1 Hz, 1H).
7
8
9
N-((4-methyl-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3g).9 yellow oil (18.2 mg,
1
58%). H NMR (400 MHz, Chloroform-d) δ 2.71 (s, 3H), 3.94 (s, 1H), 4.56 (s, 2H), 6.70 – 6.80
(m, 3H), 7.00 – 7.07 (m, 2H), 7.21 – 7.30 (m, 3H), 8.24 (s, 1H), 8.63 – 8.81 (m, 3H).
N-((4-nitro-1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3h).9 yellow oil (17.6 mg, 51%).
1H NMR (400 MHz, Chloroform-d) δ 4.07 (s, 1H), 4.57 (s, 2H), 6.72 – 6.80 (m, 3H), 7.16 (dd, J =
4.8 Hz, 1H), 7.22 (dd, J = 7.6 Hz, 2H), 8.23 (dd, J = 9.3, 2.3 Hz, 1H), 8.41 (s, 1H), 8.59 (d, J = 2.3
Hz, 1H), 8.74 (d, J = 4.8 Hz, 2H), 8.91 (d, J = 9.2 Hz, 1H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
1
N-((1-(pyridin-2-yl)-1H-indol-3-yl)methyl)aniline (3i).9 yellow oil (21.0 mg, 70%). H NMR
(400 MHz, Chloroform-d) δ 3.98 (s, 1H), 4.52 (s, 2H), 6.68 – 6.80 (m, 3H), 7.15 (dd, J = 7.1, 5.1
Hz, 1H), 7.18 – 7.27 (m, 3H), 7.34 (dd, J = 7.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 10.2
Hz, 2H), 7.79 (dd, J = 7.8 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 3.9 Hz, 1H).
1
N-((1-(thiazol-2-yl)-1H-indol-3-yl)methyl)aniline (3j).9 yellow oil (15.5 mg, 51%). H NMR
(400 MHz, Chloroform-d) δ 3.96 (s, 1H), 4.50 (s, 2H), 6.68 – 6.79 (m, 3H), 7.03 (d, J = 2.9 Hz,
1H), 7.20 (dd, J = 7.5 Hz, 2H), 7.27 (dd, J = 7.5 Hz, 1H), 7.39 (dd, J = 7.7 Hz, 1H), 7.57 (d, J =
2.8 Hz, 1H), 7.63 – 7.72 (m, 2H), 8.29 (d, J = 8.3 Hz, 1H).
N-((1-(benzo[d]oxazol-2-yl)-1H-indol-3-yl)methyl)aniline (3k).9 yellow oil (17.3 mg, 51%).
1H NMR (400 MHz, Chloroform-d) δ 4.01 (s, 1H), 4.52 (s, 2H), 6.69 – 6.79 (m, 3H), 7.18 – 7.39
(m, 6H), 7.43 – 7.53 (m, 2H), 7.67 (dd, J = 8.3 Hz, 2H), 7.83 (s, 1H), 8.55 (d, J = 8.3 Hz, 1H).
N-((1-(5-methylpyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3l).9 yellow oil (16.6 mg, 53%).
1H NMR (400 MHz, Chloroform-d) δ 2.31 (s, 3H), 3.99 (s, 1H), 4.51 (s, 2H), 6.69 – 6.79 (m, 3H),
7.20 – 7.29 (m, 3H), 7.37 (dd, J = 7.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 8.24 (s, 1H), 8.51 (s, 2H),
8.79 (d, J = 8.3 Hz, 1H).
4-methyl-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3n).9 yellow oil (20.1 mg,
1
64%). H NMR (400 MHz, Chloroform-d) δ 2.26 (s, 3H), 4.50 (s, 2H), 6.67 (d, J = 7.8 Hz, 2H),
6.99 – 7.08 (m, 3H), 7.25 (dd, J = 5.7 Hz, 1H), 7.38 (dd, J = 7.6 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H),
8.26 (s, 1H), 8.69 (d, J = 4.6 Hz, 2H), 8.82 (d, J = 8.7 Hz, 1H).
4-methoxy-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3o).9 yellow oil (21.8 mg,
66%). 1H NMR (400 MHz, Chloroform-d) δ 3.75 (s, 3H), 4.46 (s, 2H), 6.68 – 6.73 (m, 2H), 6.78 –
6.83 (m, 2H), 7.02 (dd, J = 4.8 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.34 – 7.40 (m, 1H), 7.64 – 7.70 (m,
2H), 8.24 (s, 1H), 8.67 (d, J = 4.8 Hz, 2H), 8.81 (d, J = 8.4 Hz, 1H).
4-isopropyl-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3p). yellow oil (22.9 mg,
67%), petroleum ether/ethyl acetate = 10:1. 1H NMR (400 MHz, Chloroform-d) δ 1.22 (d, J = 6.8
Hz, 6H), 2.82 (hept, J = 6.9 Hz, 1H), 3.86 (s, 1H), 4.49 (s, 2H), 6.65 – 6.73 (m, 2H), 7.03 (d, J =
4.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.37 (dd, J = 8.0 Hz, 1H), 7.67 (d,
J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.68 (d, J = 4.8 Hz, 2H), 8.81 (d, J = 8.0 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 24.3, 33.2, 40.4, 113.0, 116.1, 116.5, 118.3, 119.1, 122.1, 123.9, 124.1,
127.2, 130.2, 136.0, 138.1, 146.5, 157.7, 158.1. IR (neat)  3301, 2924, 2853, 1575, 1509, 1454,
1432, 1413, 1381, 1310, 1211, 1112, 1044 cm-1. HRMS (DART-FTICR) m/z [M-H]+ Calcd. for
C22H21N4 341.1761, Found: 341.1758.
N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)-[1,1'-biphenyl]-4-amine (3q). yellow oil (25.2
1
mg, 67%), petroleum ether/ethyl acetate = 10:1. H NMR (400 MHz, Chloroform-d) δ 4.06 (br,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
1
2
3
4
5
6
7
8
9
1H), 4.55 (s, 2H), 6.80 (d, J = 8.6 Hz, 2H), 7.03 (dd, J = 4.8 Hz, 1H), 7.28 (dd, J = 8.0 Hz, 2H),
7.38 (dd, J = 7.7 Hz, 3H), 7.47 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.67 (d, J = 7.9 Hz,
1H), 8.27 (s, 1H), 8.68 (d, J = 4.8 Hz, 2H), 8.82 (d, J = 8.4 Hz, 1H). 13C{1H} NMR (100 MHz,
Chloroform-d) δ 40.1, 113.2, 116.1, 116.6, 117.9, 119.1, 122.2, 124.0, 124.2, 126.1, 126.4, 128.0,
128.7, 130.2, 130.5, 136.0, 141.3, 147.8, 157.6, 158.2. IR (neat)  3379, 3034, 2811, 1609, 1577,
1560, 1527, 1453, 1430, 1382, 1345, 1324, 1244, 1222, 1207, 1162 cm-1. HRMS (DART-FTICR)
m/z [M-H]+ Calcd. for C25H19N4 375.1604, Found: 375.1602.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)-4-((trifluoromethyl)thio)aniline (3r). yellow
oil (23.6 mg, 59%), petroleum ether/ethyl acetate = 10:1. 1H NMR (400 MHz, Chloroform-d) 4.30
(s, 1H), 4.52 (s, 2H), 6.63 – 6.74 (m, 2H), 7.01 – 7.09 (m, 1H), 7.22 – 7.32 (m, 2H), 7.33 – 7.42
(m, 1H), 7.43 – 7.51 (m, 2H), 7.57 – 7.67 (m, 1H), 8.26 (s, 1H), 8.69 (d, J = 8.0 Hz, 2H), 8.82 (d,
J = 8.0 Hz, 1H). 19F{1H} NMR (377 MHz, Chloroform-d) δ -44.5. 13C{1H} NMR (100 MHz,
Chloroform-d) δ 39.6, 109.8, 113.2, 116.3, 116.6, 117.0, 118.9, 122.3, 124.1, 124.3, 129.8 (q, J =
307 Hz), 129.9, 136.0, 138.3, 150.3, 157.6, 158.2. IR (neat)  3298, 1570, 1509, 1454, 1433, 1384,
1312, 1135, 1111, 1087, 1042 cm-1. HRMS (DART-FTICR) m/z [M-H]+ Calcd. for C20H14F3N4S
399.0886, Found: 399.0881.
4-(difluoromethoxy)-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3s). yellow oil
1
(22.7 mg, 62%), petroleum ether/ethyl acetate = 10:1. H NMR (400 MHz, Chloroform-d) δ 3.97
(br, 1H), 4.46 (s, 2H), 6.38 (t, J = 74.9 Hz, 1H), 6.65 (d, J = 8.7 Hz, 2H), 6.94 – 7.06 (m, 3H),
7.21 – 7.32 (m, 1H), 7.32 – 7.43 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 8.23 (s, 1H), 8.67 (d, J = 4.8
Hz, 2H), 8.81 (d, J = 8.4 Hz, 1H). 19F{1H} NMR (377 MHz, Chloroform-d) δ -80.0, -79.8. 13C{1H}
NMR (100 MHz, Chloroform-d) δ 40.3, 113.5, 116.2, 116.58, 116.64 (t, J = 257 Hz), 117.7, 119.0,
121.5, 122.2, 123.9, 124.2, 130.1, 136.0, 142.6, 146.3, 157.6, 158.2. IR (neat)  3319, 2913, 2845,
1570, 1508, 1453, 1432, 1413, 1381, 1310, 1210, 1132, 1110, 1086, 1066 cm-1. HRMS
(DART-FTICR) m/z [M-H]+ Calcd. for C20H15F2N4O 365.1208, Found: 365.1203.
N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)-4-(1H-pyrrol-1-yl)aniline (3t). yellow oil (19.0
1
mg, 52%), petroleum ether/ethyl acetate = 10:1. H NMR (400 MHz, Chloroform-d) δ 4.07 (br,
1H), 4.54 (s, 2H), 6.32 (d, J = 1.9 Hz, 2H), 7.06 (dd, J = 2.0 Hz, 2H), 7.06 (dd, J = 4.8 Hz, 1H),
7.22 – 7.26 (m, 4H), 7.39 (dd, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 8.28 (s, 1H), 8.70 (d, J =
4.8 Hz, 2H), 8.83 (d, J = 8.4 Hz, 1H). 13C{1H} NMR (100 MHz, Chloroform-d) δ 40.3, 109.4,
113.4, 116.2, 116.6, 117.8, 119.0, 119.8, 122.2, 122.5, 124.0, 124.2, 130.1, 132.1, 136.0, 146.6,
157.6, 158.2. IR (neat)  2922, 2852, 1577, 1561, 1508, 1442, 1428, 1381, 1311, 1266, 1209,
1179, 1134, 1083, 1042 cm-1. HRMS (DART-FTICR) m/z [M-H]+ Calcd. for C23H18N5 requires
(M+-H): 364.1557, Found: 364.1553.
N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)-2,3-dihydro-1H-inden-5-amine (3u). yellow oil
1
(20.7 mg, 61%), petroleum ether/ethyl acetate = 10:1. H NMR (400 MHz, Chloroform-d) δ 2.00
– 2.11 (m, 2H), 2.79 – 2.90 (m, 4H), 3.73 (br, 1H), 4.50 (s, 2H), 6.56 (d, J = 7.9 Hz, 1H), 6.66 (s,
1H), 7.00 – 7.10 (m, 2H), 7.27 (d, J = 9.9 Hz, 2H), 7.38 (dd, J = 7.7 Hz, 1H), 7.68 (d, J = 8.4 Hz,
1H), 8.27 (s, 1H), 8.69 (d, J = 4.7 Hz, 2H), 8.82 (d, J = 8.3 Hz, 1H). 13C{1H} NMR (100 MHz,
Chloroform-d) δ 25.8, 32.0, 33.2, 40.6, 109.1, 111.4, 116.1, 116.5, 118.3, 119.1, 122.1, 123.9,
124.1, 124.8, 130.3, 133.3, 136.0, 145.5, 147.3, 157.7, 158.1. IR (neat)  3356, 2997, 1578, 1561,
1470, 1452, 1434, 1381, 1330, 1311, 1211, 1137, 1121, 1107, 1083 cm-1. HRMS (DART-FTICR)
m/z [M-H]+ Calcd. for C22H19N4 339.1604, Found: 339.1600.
3-chloro-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3v). yellow oil (23.4 mg, 70%),
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
petroleum ether/ethyl acetate = 10:1. 1H NMR (400 MHz, Chloroform-d) δ 4.04 (br, 1H), 4.48 (s,
2H), 6.58 (d, J = 8.2 Hz, 1H), 6.67 – 6.75 (m, 2H), 7.03 (dd, J = 4.8 Hz, 1H), 7.11 (dd, J = 8.2 Hz,
1H), 7.28 (d, J = 7.6 Hz, 2H), 7.40 (dd, J = 7.7 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 8.25 (s, 1H),
8.68 (d, J = 4.7 Hz, 2H), 8.83 (d, J = 8.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 39.9, 111.2,
112.5, 116.2, 116.6, 117.3, 117.4, 119.0, 122.2, 124.0, 124.2, 130.0, 130.3, 135.1, 135.9, 149.4,
157.6, 158.2. IR (neat)  3426, 3126, 1567, 1507, 1472, 1449, 1437, 1428, 1379, 1338, 1329,
1313, 1293, 1267, 1247, 1222, 1206, 1177, 1100, 1069, 1043 cm-1. HRMS (DART-FTICR) m/z
[M-H]+ Calcd. for C19H14ClN4 333.0900, Found: 333.0899.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
2-methyl-N-((1-(pyrimidin-2-yl)-1H-indol-3-yl)methyl)aniline (3w). colorless oil (7.5 mg,
1
24%), petroleum ether/ethyl acetate = 10:1. H NMR (400 MHz, Chloroform-d) δ 2.11 (s, 3H),
3.79 (s, 1H), 4.51 (s, 2H), 6.69 (dd, J = 7.3 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.95 (dd, J = 4.7 Hz,
1H), 7.07 (d, J = 7.2 Hz, 1H), 7.16 (dd, J = 8.0 Hz, 1H), 7.25 (dd, J = 7.5 Hz, 1H), 7.37 (dd, J =
7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 8.24 (s, 1H), 8.62 (d, J = 4.7 Hz, 2H), 8.81 (d, J = 8.4 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 17.7, 40.2, 110.1, 116.2, 116.7, 117.3, 118.1, 119.2,
122.2, 122.3, 124.2, 124.3, 127.4, 130.2, 130.4, 136.1, 146.5, 157.7, 158.2. IR (neat)  3445, 3361,
2845, 1603, 1580, 1560, 1510, 1455, 1444, 1426, 1380, 1347, 1307, 1261, 1230, 1211, 1137, 1084
cm-1. HRMS (DART-FTICR) m/z [M-H]+ Calcd. for C20H17N4 313.1448, Found: 313.1449.
Supporting Information Available: Optimization of Reaction Conditions, KIE experiment,
Procedure for Removing Directing Group and NMR spectra for compounds 3 are included in the
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment
We are grateful for the financial support from the Strategic Priority Research Program of the
Chinese Academy of Sciences (Grant No. XDB20000000), the National Natural Science
Foundation of China (21572052, 21772226, 21772037, 21861132014 and 91956115) and the
Shenzhen Nobel Prize Scientists Laboratory Project.
References
1. (a) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Metal-Catalyzed Decarboxylative C–H Functionalization. Chem. Rev.
2017, 117, 8864-8907; (b) Weaver, J. D.; Recio III, A.; Grenning, A. J.; Tunge, J. A. Transition
Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions. Chem. Rev. 2011, 111, 1846-1913; (c)
Huang, H.; Jia, K.; Chen, Y. Radical Decarboxylative Functionalizations Enabled by Dual Photoredox
Catalysis. ACS Catal. 2016, 6, 4983-4988; (d) Schwarz, J.; König, B. Decarboxylative reactions with and
without light - a comparison. Green Chem. 2018, 20, 323-361; (e) Bloom, S.; Liu, C.; Kölmel, D. K.; Qiao, J.
X.; Zhang, Y.; Poss, M. A.; Ewing, W. R.; MacMillan, D. W. C. Decarboxylative alkylation for site-selective
bioconjugation of native proteins via oxidation potentials. Nat. Chem. 2017, 10, 205-211; (f) Liang, Y.; Zhang,
X.; MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature,
2018, 559, 83-88.
2. Tan, X.; Song, T.; Wang, Z.; Chen, H.; Cui, L.; Li, C. Silver-Catalyzed Decarboxylative Bromination of
Aliphatic Carboxylic Acids. Org. Lett. 2017, 19, 1634-1637.
3. (a) Goossen, L. J. Pd-catalyzed synthesis of arylacetic acid derivatives from boronic acids. Chem. Commun.
2001, 669-670; (b) Goossen, L. J.; Ghosh, K. A new practical ketone synthesis directly from carboxylic acids:
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
2
3
4
5
6
7
8
9
first application of coupling reagents in palladium catalysis. Chem. Commun. 2001, 2084-2085; (c) Goossen, L.
J.; Paetzold, J. Pd-Catalyzed Decarbonylative Olefination of Aryl Esters: Towards a Waste-Free Heck
Reaction. Angew. Chem. Int. Ed. 2002, 41, 1237–1241; (d) Goossen, L. J.; Paetzold, J.; Winkel, L.
Pd-Catalyzed Decarbonylative Heck Olefination of Aromatic Carboxylic Acids Activated in situ with
Di-tert-butyl Dicarbonate. Synlett, 2002, 1721-1723; (e) Goossen, L. J.; Paetzold, J. Decarbonylative Heck
Olefination of Enol Esters: Salt-Free and Environmentally Friendly Access to Vinyl Arenes. Angew. Chem. Int.
Ed. 2004, 43, 1095-1098; (f) Goossen, L. J.; Döhring, A. Lewis Acids as Highly Efficient Catalysts for the
Decarboxylative Esterification of Carboxylic Acids with Dialkyl Dicarbonates. Adv. Synth. Catal. 2003, 345,
943-947; (g) Goossen, L. J.; Ghosh, K. Palladium-Catalyzed Synthesis of Aryl Ketones from Boronic Acids
and Carboxylic Acids Activated in situ by Pivalic Anhydride. Eur. J. Org. Chem. 2002, 3254-3267.
4. a) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. Silver-Catalyzed Decarboxylative Chlorination of Aliphatic
Carboxylic Acids. J. Am. Chem. Soc. 2012, 134, 4258-4563; (b) Liu, C.; Wang, X.; Li, Z.; Cui, L.; Li, C.
Silver-Catalyzed Decarboxylative Radical Azidation of Aliphatic Carboxylic Acids in Aqueous Solution. J.
Am. Chem. Soc. 2015, 137, 9820-9823; (c) Yin, F.; Wang, Z.; Li, Z.; Li, C. Silver-Catalyzed Decarboxylative
Fluorination of Aliphatic Carboxylic Acids in Aqueous Solution. J. Am. Chem. Soc. 2012, 134, 10401-10404;
(d) Liu, X.; Wang, Z.; Cheng, X.; Li, C. Silver-Catalyzed Decarboxylative Alkynylation of Aliphatic
Carboxylic Acids in Aqueous Solution. J. Am. Chem. Soc. 2012, 134, 14330-14333. (e) Hua, A. M.; Mai, D. N.;
Martinez, R.; Baxter, R. D. Radical C−H Fluorination Using Unprotected Amino Acids as Radical Precursors.
Org. Lett. 2017, 19, 2949-2952.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
5. (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C−C Bond Formation via
Heteroatom-Directed C-H Bond Activation. Chem. Rev. 2010, 110, 624-655; (b) He, J.; Wasa, M.; Chan, K. S.
L.; Shao, Q.; Yu, J. -Q. Palladium-Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117,
8754-8786; (c) Song, G.; Li, X. Substrate Activation Strategies in Rhodium(III)-Catalyzed Selective
Functionalization of Arenes. Acc. Chem. Res. 2015, 48, 1007-1020; (d) Satoh, T.; Miura, M. Oxidative
Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis. Chem. Eur. J. 2010, 16,
11212-11222; (e) Song, G.; Wang, F.; Li, X. C–C, C–O and C–N bond formation via rhodium(iii)-catalyzed
oxidative C–H activation. Chem. Soc. Rev. 2012, 41, 3651-3678; f) Kuhl, N.; Schröder, N.; Glorius F. Formal
SN-Type Reactions in Rhodium(III)-Catalyzed C-H Bond Activation. Adv. Synth. Catal. 2014, 356, 1443; (g)
Gulías, M.; Mascareñas, J. L. Metal-Catalyzed Annulations through Activation and Cleavage of C−H Bonds.
Angew. Chem. Int. Ed. 2016, 55, 11000-11019; (h) Ye, B.; Cramer, N. Chiral Cyclopentadienyls: Enabling
Ligands for Asymmetric Rh(III)-Catalyzed C–H Functionalizations. Acc. Chem. Res. 2015, 48, 1308-1318; (i)
Meyer, T. H.; Finger, L. H.; Gandeepan, P.; Ackermann, L. Resource Economy by Metallaelectrocatalysis:
Merging Electrochemistry and CH Activation. Trends Chem. 2019, 1, 63-76.
6. (a) Fang, P.; Li, M.; Ge, H. Room Temperature Palladium-Catalyzed Decarboxylative ortho-Acylation of
Acetanilides with α-Oxocarboxylic Acids. J. Am. Chem. Soc. 2010, 132, 11898-11899; (b) Pan, C.; Jin, H.;
Liu, X.; Cheng, Y.; Zhu, C. Palladium-catalyzed decarboxylative C2-acylation of indoles with α-oxocarboxylic
acids. Chem. Commun. 2013, 2933-2955; (c) Hossian, A.; Manna, M. K.; Manna, K.; Jana, R.
Palladium-catalyzed decarboxylative, decarbonylative and dehydrogenative C(sp2)–H acylation at room
temperature. Org. Biomol. Chem. 2017, 15, 6592-6603; (d) Penteado, F.; Lopes, E. F.; Alves, D.; Perin, G.;
Jacob, R. G.; Lenardao, E. J. α-Keto Acids: Acylating Agents in Organic Synthesis. Chem. Rev. 2019, 119,
7113-7278.
7. Jing, K.; Li, Z.; Wang, G. -W. Direct Decarboxylative Meta-Selective Acylation of Arenes via an
Ortho-Ruthenation Strategy. ACS Catal. 2018, 8, 11875-11881.
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1
2
3
4
5
8. Liu, R.; Liu, J.; Wei, Y.; Shi, M. Activation Relay on Rhodium-Catalyzed C–H Aminomethylation in
Cooperation with Photoredox Catalysis. Org. Lett. 2019, 21, 4077-4081.
9. (a) Ren, X.; Chen, J.; Chen, F.; Cheng, J. The palladium-catalyzed cyanation of indole C–H bonds with the
combination of NH4HCO3 and DMSO as a safe cyanide source. Chem. Commun. 2011, 6725-6727; (b) Yan,
G.; Kuang, C.; Zhang, Y.; Wang, J. Palladium-Catalyzed Direct Cyanation of Indoles with K4[Fe(CN)6]. Org.
Lett. 2010, 12, 1052-1055; (c) Ding, S.; Jiao, N. Direct Transformation of N,N-Dimethylformamide to −CN:
Pd-Catalyzed Cyanation of Heteroarenes via C–H Functionalization. J. Am. Chem. Soc. 2011, 133,
12374-12377; (d) Xu, S.; Huang, X.; Hong, X.; Xu, B. Palladium-Assisted Regioselective C–H Cyanation of
Heteroarenes Using Isonitrile as Cyanide Source. Org. Lett. 2012, 14, 4614-4617.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
10. (a) Wu, W.; Su, W. Mild and Selective Ru-Catalyzed Formylation and Fe-Catalyzed Acylation of Free (N–H)
Indoles Using Anilines as the Carbonyl Source. J. Am. Chem. Soc. 2011, 133, 11924-11927; (b) Chen, J.; Liu,
D.; Liu, B.; Liu, S.; Cheng, J. The Copper-Catalyzed C-3-Formylation of Indole C-H Bonds using Tertiary
Amines and Molecular Oxygen. Adv. Synth. Catal. 2012, 354, 2438-2442.
11. (a) Brand, J. P.; Charpentier. J.; Waser, J. Direct Alkynylation of Indole and Pyrrole Heterocycles. Angew.
Chem. Int. Ed. 2009, 48, 9346-9349; (b) Gu. Y.; Wang, X. Direct palladium-catalyzed C-3 alkynylation of
indoles. Tetrahedron Lett. 2009, 50, 763-766.
12. (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Palladium-Catalyzed Intermolecular
Alkenylation of Indoles by Solvent-Controlled Regioselective C-H Functionalization. Angew. Chem. Int. Ed.
2005, 44, 3125-3129; (b) Xiang, S. -K.; Zhang, B.; Zhang, L. -H.; Cui, Y.; Jiao, N. Morpholine catalyzed
direct C3 alkenylation of indoles with α,β-unsaturated aldehydes. Chem. Commun. 2011, 8097-8099; (c) Chen,
W. -L.; Gao, Y. -R.; Mao, S.; Zhang, Y. -L.; Wang, Y. -F.; Wang, Y. -Q. Palladium-Catalyzed Intermolecular
C3 Alkenylation of Indoles Using Oxygen as the Oxidant. Org. Lett. 2012, 14, 5920-5923; (d) Yu, H.; Yu, Z.
Direct Alkenylation of Indoles with α-Oxo Ketene Dithioacetals: Efficient Synthesis of Indole Alkaloids
Meridianin Derivatives. Angew. Chem. Int. Ed. 2009, 48, 2929-2933.
13. Pitzer, L.; Schäfers, F.; Glorius, F. Rapid Assessment of the Reaction-Condition-Based Sensitivity of Chemical
Transformations. Angew. Chem. Int. Ed. 2019, 58, 8572-8576.
14. (a) Zuo, Z.; MacMillan, D. W. C. Decarboxylative Arylation of α-Amino Acids via Photoredox Catalysis: A
One-Step Conversion of Biomass to Drug Pharmacophore. J. Am. Chem. Soc. 2014, 136, 5257-5260; (b) Yin,
Y.; Dai, Y.; Jia, H.; Li, J.; Bu, L.; Qiao, B.; Zhao, X.; Jiang, Z. Conjugate Addition-Enantioselective
Protonation of N-Aryl Glycines to α-Branched 2-Vinylazaarenes via Cooperative Photoredox and Asymmetric
Catalysis. J. Am. Chem. Soc. 2018, 140, 6083-6087.
15. (a) Leitch, J. A.; Frost, C. G. Ruthenium-catalysed σ-activation for remote meta-selective C–H
functionalisation. Chem. Soc. Rev. 2017, 46, 7145-7153; (b) Leitch, J. A.; Heron, C. J.; Mcknight, J.;
Kociok-Köhn, G.; Bhonoah, Y.; Frost, C. G. Ruthenium catalyzed remote C4-selective C–H functionalisation
of carbazoles via σ-activation. Chem. Commun. 2017, 13039-13042.
16. Li, Z. -L.; Sun, K. -K.; Wu, P. -Y.; Cai, C. Iron-Catalyzed Regioselective α-C–H Alkylation of
N-Methylanilines: Cross-Dehydrogenative Coupling between Unactivated C(sp3)–H and C(sp3)–H Bonds via a
Radical Process. J. Org. Chem. 2019, 84, 6830-6839.
17. (a) Patil, N. T.; Shinde, V. S.; Gajula, B. A one-pot catalysis: the strategic classification with some recent
examples. Org. Biomol. Chem. 2012, 10, 211-224; (b) Pellissier, H., Recent developments in enantioselective
multicatalysed tandem reactions. Tetrahedron, 2013, 69, 7171-7210;
18. (a) Wang, Q.; Xie, F.; Li, X. Rh(III)-Catalyzed Trifluoromethylthiolation of Indoles via C–H Activation. J.
Org. Chem. 2015, 80, 8361-8366; (b) Petry, N.; Vanderbeeken, T.; Malher, A.; Bringer, Y.; Retailleau, P.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
1
2
3
4
5
Bantreil, X.; Lamaty, F. Mechanosynthesis of sydnone-containing coordination complexes. Chem. Commun.
2019, 9495-9498.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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
ACS Paragon Plus Environment