Synthesis of Indolines by Palladium-Catalyzed Intermolecular Amination of Unactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.9b02386

A new palladium-catalyzed C(sp³)-H amination reaction has been developed. 1-(tert-Butyl)-2-iodobenzene and its derivatives undergo palladium-catalyzed C-H activation to form palladacycles. The palladacycles are aminated with diaziridinone to form indolines as the final products. The reaction represents a new method for the synthesis of 3,3-disubstituted indolines, which are essential structural motifs in many bioactive compounds and pharmaceutical targets.

Full text of DOI:10.1021/acs.orglett.9b02386

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Indolines by Palladium-Catalyzed Intermolecular
3
Amination of Unactivated C(sp )−H Bonds
Xueliang Sun, Zhuo Wu, Weixin Qi, Xiaoming Ji, Cang Cheng, and Yanghui Zhang*
School of Chemical Science and Engineering, Shanghai Key Laboratory of Chemical Assessment and Sustainability, Tongji
University, 1239 Siping Road, Shanghai, 200092, P. R. China
*
S Supporting Information
3
ABSTRACT: A new palladium-catalyzed C(sp )−H amina-
tion reaction has been developed. 1-(tert-Butyl)-2-iodoben-
zene and its derivatives undergo palladium-catalyzed C−H
activation to form palladacycles. The palladacycles are
aminated with diaziridinone to form indolines as the final
products. The reaction represents a new method for the
synthesis of 3,3-disubstituted indolines, which are essential
structural motifs in many bioactive compounds and
pharmaceutical targets.
8
ransition-metal-catalyzed C−H amination represents an
group, and with alkyl halides and hexamethyldisilane by our
9
T
innovative method for the formation of C−N bonds and
has great advantages over classical amination reactions. Over
the past decades, C−H amination has gained considerable
group. We envisioned that such C,C-palladacycles could also
react with diaziridinone. The reaction would represent a new
type of C(sp )−H amination reaction.
3
1
interest, and a number of reactions have been developed. The
Indolines represent an important class of N-containing
heterocycles and privileged scaffolds that are extensively found
in natural products. Many indoline derivatives exhibit essential
biological activities and are often employed as pharmaceutical
current transition-metal-catalyzed C−H amination reactions
can be generally classified into two categories: (1) C−H
insertion reaction. This type of reactions relies on the use of
metal-nitrenoid intermediates. The intermediates insert into
C−H bonds and form C−N bonds. (2) C−H activation
reaction. For this reaction, C−H bonds are first cleaved to
form metal−carbon bonds that are then converted into C−N
1
0
targets. Therefore, the development of efficient synthetic
methods for indolines has been the topic of extensive
investigations. C−H amination has been applied to the
synthesis of indolines, and many reactions have been
2
2
11
3
bonds. While a variety of C(sp )−H amination reactions have
developed. In this context, C(sp )−H amination reactions
12
3
been developed, the majority of the current C(sp )−H
amination reactions are primarily limited to those through a
C−H insertion mechanism. Amination reactions via C(sp )−H
activation are still rare and remain to be exploited.
have also been reported. These reactions are limited to
intramolecular amination and rely on the use of substrates that
are preinstalled with amino groups (Scheme 1). It is still
desirable to develop innovative C−H amination reactions for
the synthesis of indolines. Herein, we report a new synthetic
3
3
The Shi group discovered that diaziridinone can react with
4
3
method for indolines through Pd-catalyzed C(sp )−H
amination.
We commenced studies by investigating the reaction of 1-
tert-butyl)-2-iodobenzene (1a) with N,N-di-tert-butyl-
diaziridinone (2). After extensive condition survey, desired
indoline product 3a was obtained in 10% yield under the
conditions as shown in entry 1 of Table 1. Only a trace amount
of the product was observed when the amount of
triphenylphosphine was reduced to 0.2 or 0.5 equiv (entries
and 3). The yield was improved to 16% when Cs CO was
used as the base (entry 4). Other bases such as Na CO and
C,C-palladacycles efficiently. It is noted that the C,C-
2
palladacycles are obtained through Pd-enabled C(sp )−H
activation, so the reaction represents an innovative C−H
amination reaction. Furthermore, while common C−H
amination reactions from one C−N bond, in Shi’s reaction,
the two C−Pd bonds of the C,C-palladacycles are aminated to
yield two C−N bonds and generate cyclic amine products.
Inspired by this innovative reaction, our group developed
several C−H amination reactions, which provide new methods
(
5
2
for the synthesis of cyclic amines. All of these reactions
2 3
2
3
involve C(sp )−H activation, and the C(sp )−H activation-
2 3
Li CO almost failed to give the product (entries 5 and 6).
initiated reactions still remain to be investigated.
2
3
3
Solvent screening showed that the yield decreased or no
C,C-Palladacycles can also be synthesized through C(sp )−
6
H activation, and a few intermolecular reactions of the
resulted C,C-palladacycles have been reported, including those
with aryl iodides by Dyker, with carbene by the Martin
Received: July 10, 2019
7
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
Scheme 1. Synthesis of Indolines by C(sp )−H Amination
47% by replacing triphenylphosphine with tricyclohexyl-
phosphine (entry 12). A yield of 82% was obtained by adding
1
equiv of CsOAc as the second base (entry 13). While the
exact roles of CsOAc remain to be investigated, it has been
reported that an acetate can accelerate palladium-catalyzed C−
13
H activation. It should be noted that when the reaction was
scaled up to 1 mmol, the product was still formed in 71% yield
(
entry 13). The yield could be slightly improved in the
presence of 3 equiv of 2 (entry 14). The yield decreased
dramatically to 54% when 0.5 equiv of PCy was used (entry
3
15), which indicated the necessity of 1 equiv of ligand. 1-
Bromo-2-(tert-butyl)benzene was also reactive, albeit giving a
t
much lower yield (entry 16). P Bu suppressed the amination
3
reaction of the aryl bromide, and product 3a was not observed
(
entries 17 and 18).
Having developed an efficient protocol for the synthesis of
indolines, we then investigated the substrate scope of this Pd-
3
catalyzed C(sp )−H amination reaction. Although 3 equiv of 2
give a higher yield, 2 equiv are sufficient to provide satisfactory
yields. Therefore, 2 equiv of 2 were used for the examination of
substrate scope. A range of 1-(tert-butyl)-2-iodobenzene
derivatives bearing various functionalities were subjected to
the optimal conditions. As shown in Scheme 2, the substrates
a
Table 1. Optimization of Reaction Conditions
a
Scheme 2. Substrate Scope
solvent
(1 mL)
yield of 3a
a
entry
bases (equiv)
K CO (4)
ligand (equiv)
(%)
1
2
3
4
5
6
7
8
9
PPh (1.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DCE
toluene
1,4-dioxane
DMSO
DMSO
DMSO
10
2
3
3
K CO (4)
PPh (0.2)
trace
trace
16
trace
0
13
0
11
0
2
3
3
K CO (4)
PPh (0.5)
2
3
3
Cs CO (4)
PPh (1.0)
2
3
3
Na CO (4)
PPh (1.0)
2
3
3
Li CO (4)
PPh (1.0)
2
3
3
Cs CO (4)
PPh (1.0)
2
3
3
Cs CO (4)
PPh (1.0)
2
3
3
Cs CO (4)
PPh (1.0)
2
3
3
10
11
12
13
Cs CO (4)
PPh (1.0)
2
3
3
Cs CO (4)
PPh (1.0)
30
2
3
3
Cs CO (4)
PCy (1.0)
47
82 (71
2
3
3
,
bd
Cs CO (4)/CsOAc PCy (1.0)
)
2
3
3
(
1)
c
d
14
15
16
17
18
Cs CO (4)/CsOAc PCy (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
88 (83 )
54
2
3
3
(
1)
Cs CO (4)/CsOAc PCy (0.5)
2
3
3
(
1)
e
Cs CO (4)/CsOAc PCy (1.0)
44
2
3
3
(
1)
t
e
Cs CO (4)/CsOAc P Bu (1.0)
0
2
3
3
(
1)
t
e
Cs CO (4)/CsOAc P Bu ·HBF
0
2
3
3
4
(
1)
(1.0)
a
The yields were determined by 1H NMR analysis of the crude
b
reaction mixture using CH Br as the internal standard. 1 mmol of
1
2
2
c
d
e
a was used. 3 equiv of 2 were used. Isolated yield. 1-Bromo-2-
(tert-butyl)benzene was used.
desried product was formed when the reaction was carried out
in most common organic solvents such as DMA, 1,2-
dichloroethane, toluene, and 1,4-dioxane (entries 7−10).
However, the use of DMSO as the solvent enhanced the
yield to 30% (entry 11). The yield was further improved to
a
b
Isolated yield. The corresponding aryl bromides were used. All the
reactions of aryl bromides were carried out twice, and the outcomes of
two reactions were the same. 1 mmol of 1m was used as the
substrate.
c
B
DOI: 10.1021/acs.orglett.9b02386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing a methyl group underwent the amination reactions
efficiently, affording the corresponding indoline product in
(TKI) and P-glycoprotein (P-gp) inhibitor, and can antagonize
14
multidrug resistance. BRL 46470A (compound B) is a highly
15
7
4% yield (3b). The methoxy group was compatible, and the
potent, selective, and long acting 5-HT receptor antagonist.
3
reaction was high-yielding (3c). The chloro group was
tolerated under the conditions, but the yield was low.
Gratefully, the yield was improved to 76% when 2-bromo-1-
A series of 3,3-dimethylindoline derivatives (compound C)
have been reported to be potent and highly selective
16
norepinephrine reuptake inhibitors (NRIs). Furthermore,
(tert-butyl)-4-chlorobenzene was used (3d). It should be noted
compound D is an effective aromatic bioisostere in the
17
that the substrate containing a dimethylamino group was
suitable (3e). Even a free amino group was also compatible,
although the yield was low (3f). The performance of substrates
bearing electron-withdrawing groups was then examined. The
presence of an ester group led to a slightly lower yield (3g),
imidazole class of 5-HT receptor antagonists.
3
The tert-butyl group of the indoline products could be
4
removed under conditions as shown in Scheme 3. The
Scheme 3. Deprotection of the Indoline Product
3
and a nitro group suppressed the C(sp )−H amination
reaction completely (3h). Unexpectedly, a tert-butyl group
has a great impact on the reaction, and the indoline product
was formed in a much lower yield (3i). Furthermore, while 1-
bromo-2-(tert-butyl)-4-chlorobenzene gave a higher yield than
its corresponding iodide 1d, the reactions of the corresponding
bromides of 1g and 1i failed to form the desired products.
However, the aryl bromide bearing a para-ester group was
reactive, affording indoline 3j in 58% yield. While the reason
remains to be investigated, it could be that the electron-
withdrawing para-ester group accelerated the oxidative
addition of the aryl bromide to Pd(0). This outcome implies
that this amination reaction should be very sensitive to
electronic properties of substrates. The substrate bearing two
methoxy groups was also compatible, yielding disubstituted
indoline derivatives (3k). As a comparison, for the
corresponding cyclic analog 1l, two isomers were formed in
a ratio of around 1:3 (3l-1 and 3l-2). In this reaction, the
palladacycle, which was formed through intramolecular
resulting free amine can be readily manipulated, which allows
easy access to various indoline derivatives. It should be
mentioned that the synthesis of compounds C and D rely on
the free indoline as the key intermediate.
To gain some insight into the reaction mechanism, we
18
prepared palladacycle 5. When palladacycle 5 was subjected
to the standard conditions, desired product 3a was formed
(
Scheme 4, eq 1). However, the yield was much lower than
Scheme 4. Mechanistic Studies
3
C(sp )−H activation, decomposed to generate an
alkylpalladium(II) species before it could react with diazir-
idinone. The resulted alkylpalladium(II) species then cleaved
aryl C−H bond to form a second palladacycle. The
palladacycle then reacted with diaziridinone to afford isomer
3l-2 (Scheme 6). The compatibility of the derivatized tert-butyl
group was also examined. The methoxy-substituted tert-butyl
group exhibited high reactivity, and the product was formed in
8
8% yield (3m). A yield of 76% was still obtained when the
reaction was scaled up to 1 mmol. Even one methyl group was
sufficient to be aminated (3n), which expands the indoline
scope. However, an ester group suppressed the reaction (3o).
1
-Iodo-2-isopropylbenzene and 1-iodo-2-methoxybenzene
were not suitable (3p and 3q).
It should be noted that 3,3-dimethylindolines are essential
structural motifs in many bioactive compounds and
pharmaceutical targets. For example, motesanib (AMG706)
that in the catalytic reaction of 1a. The lower yield could be
caused by ligand cycloocta-1,5-diene (COD). The yield was
(Figure 1, compound A) is a potent tyrosine kinase inhibitor
improved to 90% when 5 equiv of PCy were added (eq 2),
3
and the product was not formed in the absence of the
phosphine ligand (eq 3). These experimental results support
that palladacycle 5 is a likely intermediate in the amination
reaction, and PCy played crucial roles in the amination step.
3
Then we investigated the kinetic isotope effect in the
reaction. Deuterated 1m-D and 1m-D were synthesized. 1m-
3
6
D and the mixture of 3m and 1m-D (1:1) was subjected to
3
6
the standard conditions (Scheme 5). Therefore, the
intermolecular KIE value was 3 to 1, and the intramolecular
KIE was 7 to 1. Parallel reactions of 1m and 1m-D were also
6
carried out, and the KIE value was 2.1. These results suggest
that C−H activation should be the rate-determining step.
Based on the above experimental results and previous
4
,5b
Figure 1. Bioactive compounds containing indoline motifs.
report,
a mechanism is proposed as shown in Scheme 6 for
C
DOI: 10.1021/acs.orglett.9b02386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
Scheme 5. Kinetic Isotope Effect Studies
the C(sp )−H amiantion reaction. The reaction should start
with the oxidative addition of aryl iodide 1a to Pd(0) to yield
Pd(II) species A. The Pd(II) species then cleaves the methyl
3
C(sp )−H bond of the tert-butyl group, generating pallada-
cycle B. The palladacycle then undergoes an oxidative addition
reaction with diaziridinone to provide pallada(IV)cycle C. The
subsequent reductive elimination affords a cyclic compex D-1
or D-2 (pathway a). Final product 3a is formed by β-N
elimination and reductive elimination. A Pd−nitrene could be
the intermedidate in this indoline-forming reaction (pathway
b).
In conclusion, we have successfully developed the palladium-
catalyzed amination reaction of 1-(tert-butyl)-2-iodobenzene
3
and its derivatives through C(sp )−H activation. In this
reaction, the palladacycles obtained through intramolecular
3
C(sp )−H activation should act as the key intermediate. The
palladacycles were aminated with diaziridinone, and two C−N
bonds were formed. The reaction represents a new method for
the synthesis of indolines.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02386.
Detailed experimental procedures, spectroscopic data of
authentic compounds, and characterization of products
(PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: zhangyanghui@tongji.edu.cn.
■
*
Scheme 6. Proposed Mechanism
ORCID
Yanghui Zhang: 0000-0003-2189-3496
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the National Natural Science
Foundation of China (No. 216721626) and the Shanghai
Science and Technology Commission (14DZ2261100).
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