Copper-catalyzed C-H [3 + 2] annulation of: N-substituted anilines with α-carbonyl alkyl bromides via C(sp3)-Br/C(sp2)-H functionalization

Article abstract of DOI:10.1039/d0ob00399a

A copper-catalyzed C-H [3 + 2] annulation of N-substituted anilines with α-carbonyl alkyl bromides for the synthesis of 3,3′-disubstituted oxindoles is developed. Tandem C-H cycloamidation reactions of various α-carbonyl alkyl bromide derivatives including tertiary-α-bromoalkyl ketone esters, malonic esters and cycloalkanes, with N-Aryl or alkyl substituted anilines, can be performed using this system, affording a vast array of valuable 3,3′-disubstituted oxindoles in moderate to good yields.

Full text of DOI:10.1039/d0ob00399a

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FULL PAPER
Copper-Catalyzed C-H [3+2] Annulation of N-Substituted Anilines with α-Carbonyl
3
2
Alkyl Bromides via C(sp )-Br/C(sp )-H Functionalization
a
a
a
a
a
ab
An-Zhu Cao, Yu-Ting Xiao, Yan-Chen Wu, Ren-Jie Song,* Ye-Xiang Xie,* and Jin-Heng Li*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A copper-catalyzed C-H [3+2] annulation of N-substituted
anilines with α-carbonyl alkyl bromides for the synthesis of 3,3’-
disubstituted oxindoles is developed. This system performs 50 difuoro-2-oxindole through a visible-light-induced photoredox
In the same year, Zhang and co-works7b described an efficient
and synthetically convenient method for synthesis of 3,3’-
8
tandem C-H cycloamidation reaction between various of α-
carbonyl alkyl bromides derivatives including tertiary-α-
bromoalkyl, ketone esters, malonic esters and cycloalkane, with
N-aryl or alkyl substituted anilines, affording a vast array of
difuoromethylation-amidation (Scheme 1b).
Despite those methods provide effective tool to produce
1
0
substituted
indolineones,
only
bromodifluoroacetate
(BrCF CO Et) and N-alkyl substituted anilines can transformed to
2
2
valuable 3,3’-disubstituted oxindoles with moderate to good 55 the corresponding product. When we first tested the [3+2]
yields. annulation by the use of di-p-tolylamine (1a) reacted with ethyl
-bromo-2-methylpropanoate (2a) under Song or Zhang’s
2
15
20
25
30
Substituted oxindoles are widely found in biologically-active
conditions, only 5% or trace yield of [3+2] annulation product
was obtained (Scheme 1c). Thus, aryl substituted anilines is still
challenging for this transformation because of the steric
disadvantage as well as the entropy. Herein, we reported our
study on the synthesis of 3,3’-disubstituted oxindoles, using
natural products and pharmaceuticals, especially 3,3-
disubstituted oxindoles show important biological activities such
as anti-tumor and anti-cardiovascular disease . Therefore, the
6
0
1
interest in development of simple, efficient protocol for the
synthesis of substituted oxindoles have rapidly increased2-5. In
the past decade, various methods for the systhese of substituted
oxindoles have been established, including Pd-catalyzed
cyclization reactions of N-(o-haloaryl)amides (Mizoroki–Heck
9
copper-promoted C-H [3+2] annulation of alkyl radicals to N-
substituted anilines (Scheme 1d).
6
5
Previous works:
a) Intra/Intermolecular Cyclization Leading to the Formation of Oxindoles
1
2
R1
X
R2
R
R2
couplings and arylations) , base-promoted cyclization reactions
Intramolecular
Cyclization
Intermolecular
Cyclization
R
Ar
Ar
O
Ar
+
Radical
3
of α-activated-N-arylamides , radical cyclization reactions of N-
N
R
O
N
N
R
O
4
R
arylamides , and tandem radical addition-cyclization reactions of
b) Intermolecular C-H Difluoracetylation-Cycloamidation of Anilines Leading to the Formation of Oxindoles
5
Zhang group in 2017
N-arylacrylamides (Scheme 1a).
F
fac-Ir(ppy)3 (0.5 mol%)
Na2CO3 (2 equiv)
F
H
Transition-metal-catalysis promoted intermolecular addition
of radicals to electron-rich aromatic rings to achieve C-H
cyclization reaction has been becoming an ideal and powerful
+
BrCF CO R'
2 2
Ar
Ar
O
CH2Cl2, Blue LED (12 W), r.t.
NH
R
then EtOH, 60 o
N
C
R = H, Alkyl Group
R
Song group in 2017
F
F
Cu(OAc)2 H2O(10 mol%)
4,4'-di-tert-butyl-2,2'-bipyridine (10 mol%)
6
H
way to synthesize heterocyclic compounds . In 2017, Song and
Ar
+
BrCF2CO2R'
Ar
O
NaOAc (2 equiv), DCE
B2pin2 (30 mol%)
7
a
co-works
reported
a
copper/Bpin
2
-Catalyzed
NH2
N
H
1
00 oC, 16 h
difuoroacetylation of anilines via C-H activation followed by
c) C-H Cycloamidation of Anilines with -Carbonyl Alkyl Bromides under Zhang or Song's Conditions
intramolecular amidation.
O
O
p-tolyl
Zhang's
Conditions
Song's
OEt Conditions
NH
N
3
5
N
+
Br
p-tolyl
p-tolyl
O
3
aa, 5%
a
3aa, trace
2a
Key Laboratory of Jiangxi Province for Persistent Pollutants
1a
Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, China
This work: d) Copper Catalyzed [3+2] Annulation of N,N-Disubstituted Anilines with -Carbonyl Alkyl
Bromides
R2
R3
R4
O
Cu(OAc)2 (10 mol%)
2,2'-bipyridine, L1 (20 mol%)
b
H
R3
Br
State Key Laboratory of Chemo/Biosensing and Chemometrics,
OR5
R2
Ar
O
Ar
+
K CO (2 equiv)
CH3CN, 120 C,12 h
2
3
N
R1
4
4
0
5
Hunan University, Changsha 410082, China
E-mail: srj0731@hnu.edu.cn, xieyexiang520@126.com and
jhli@hnu.edu.cn
R4
NH
R1
R1 = H, Alkyl, Aryl Group
†
Electronic Supplementary Information (ESI) available: [details
Scheme 1 The protocols for construction of 3,3’-disubstituted
of any supplementary information available should be included
here]. See DOI: 10.1039/b000000x/
oxindoles
7
0
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In this transformation, tertiary a-bromoalkyl, ketone esters,
malonic esters and cycloalkane could react with N-alkyl
substituted- and aryl substituted anilines leading to N-
substituted 3,3’-disubstituted oxindoles in moderate to good
yields.
17% in DMF (entries 16-18). We found the optimum
temperature to be 120 C, while the content of 3aa was
79% (entry 1 vs entries 19-20).
o
35
5
Table 2. Variation of N-substituted anilines (1) and α-carbonyl alkyl
bromides (2) a
Table 1 Screening of optimal reaction conditionsa
O
Cu(OAc)2 (10 mol%)
2,2'-bipyridine (20 mol%)
OEt
N
+
Br
O
N
H
K2CO3 (2 equiv)
CH CN, 120 oC, 12 h
3
O
Cu(OAc)2 (10 mol%)
2a
OEt 2,2'-bipyridine, L1 (20 mol%)
N
1a
3aa
+
Br
N
K2CO3 (2 equiv)
H
O
CH CN, 120 oC, 12 h
3
O
2a
O
1a
3aa
N
N
Entry
Variation from the standard conditions
none
Isolated yield (%)
Ph
tBu
1
2
3
4
5
6
7
8
9
79
0
tBu
Ph
3
ba, 74%
3ba
3ca, 80%
without Cu(OAc)
Cu(acac) instead of Cu(OAc)
CuBr instead of Cu(OAc)
CuOAc instead of Cu(OAc)
Cu O instead of Cu(OAc)
Cu(OAc) (20 mol%)
Cu(OAc) (5 mol%)
without 2,2’-bipyridine
1,10-phenanthroline L2 instead of L1
PPh L3 instead of L1
without K CO
instead of K
2
O
O
O
N
2
2
49
51
57
32
80
40
38
42
10
0
13
17
17
58
48
17
50
45
N
tBu
N
2
2
Ph
OMe
tBu
2
Ph
MeO
2
2
3da, 59%
3ea, 76%
3fa, 66%
O
O
O
O
2
N
N
N
2
HN
F
Br
Cl
F
OMe
Br
Cl
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
3ga, 66%
3
ha, 67%
3ia, 53%
3ja, trace
O
O
O
O
3
2
3
N
N
N
N
N
Et
nBu
n-hexyl
OMe
OMe
OMe
OMe
OMe
Cs
2
CO
3
2
CO
CO
CO
DCE instead of CH CN
dioxane instead of CH CN
CN
3
3
ka, 73%
3la, 53%
3ma, 70%
3na, 51%
t
KO Bu instead of K
Et
2
3
O
O
O
O
3
N instead of K
2
3
N
N
N
allyl
Bn
tBu
3
OMe
3
3oa, 53%
3pa, 62%
3qa, 50%
3ra, 48%
Et
Et
O
O
DMF instead of CH
3
O
O
o
N
at 130 C
N
N
N
O
o
Ph
at 110 C
O
a
3sa, 45%
3ta, 44%
3ua, 52%
3ab, 67%
Reaction conditions: 1a (0.3 mmol), 2a (2 equiv), Cu(OAc)
2
(10
O
mol%), 2,2’-bipyridine (20 mol%), K
2
CO
3
(0.6 mmol), CH
3
CN (2 mL) at
O
F
F
O
N
O
OEt
O
o
O
1
20 C for 12 h under Ar atmosphere.
OEt
N
N
N
1
1
2
2
3
0
5
0
5
0
Initial studies into the new annulation were performed
with di-p-tolylamine (1a), ethyl 2-bromo-2-
methylpropanoate (2a), Cu(OAc) (10 mol%), 2,2-bipyridine
L1 (20 mol%), and K CO in CH CN, 79% yield of cyclization
product 3,3,5-trimethyl-1-(p-tolyl)indolin-2-one (3aa) was
isolated (Table 1, entry 1). However, no desired product
was obtained in the absence of copper catalyst (entry 2).
3
ac, 76%
3ad, 74%
3ae, 39%
3af, 38%
a
2
Reaction conditions: 1a (0.3 mmol), 2a (2 equiv), Cu(OAc) (10 mol%),
2
o
2,2’-bipyridine (20 mol%), K
2 h under Ar atmosphere.
2 3 3
CO (0.6 mmol), CH CN (2 mL) at 120 C for
2
3
3
1
The scope of this tandem reaction was subsequently
40
45
50
evaluated with the optimized conditions (Table 2). A series of N-
substituted anilines 1 and α-carbonyl alkyl bromides 2 reacted
well, forming the desired N-substituted oxindoles in moderate
yields. A series of substrates containing consubstituents, such as
Several other copper catalysts, including Cu(acac)
CuOAc and Cu O, exhibited reactivity, but they were all
inferior to Cu(OAc) (entries 3-6). A higher loading (20 mol%)
of Cu(OAc) had no obvious improvement on the yield
entry 7), while the yield of desired product decreased to
2 2
, CuBr ,
2
2
2
3 3 3 2 3 2 2 3 3
C(CH ) , C(CH ) Ph, C(CH ) CH C(CH ) , Ph, OMe, Br, Cl and F, on
(
the para-position of N-arylsubstituted anilines, have shown good
reactivity under the optimized reaction conditions. For example,
substrates bearing tertiary butyl group 1b or phenyl group 1e
were compatible with the reaction conditions and provided
products 3ba and 3ea in 74% and 76% yields, respectively. To
our delight, Br, Cl and F groups were compatible to optimal
conditions, thus providing products 3ga-ia which can be
subsequent modified at the halogenated position.
Unfortunately, N-free aniline 1j was not suitable for this
transformation. Interestingly, the standard conditions were
4
2 .
0% in the presence of 5 mol% Cu(OAc) (entry 8) Screening
of the ligands showed that ligand play major role in this
transformation (entry 9) Ligands 1,10-phenanthroline L2
and PPh L3 showed inferior reactivity (entries 10-11). We
could not isolate the desired product 3aa without K CO
entry 12). After screening of the bases, we found that
.
3
1
0
2
3
(
t
2 3
different inorganic bases, such as Cs CO and KO Bu, and
3
organic base Et N displayed lower reactivity (entries 13-15).
The solvents also influenced the reactivity, moderate yield
of product 3aa was obtained in DCE or dioxane, while gave
2
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Organic & Biomolecular Chemistry
applicable with N-alkyl, N-aryl substituted substrates 1k-p, which
can also be smoothly transformed to N-alkyl substituted
oxindoles. For instance, 4-methoxy-N-methylaniline 1l reacted
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), Which were well-
known radical scavengers, was added in this conversion under
the standard conditions, and the results showed that the
with ethyl 2-bromo-2-methylpropanoate 2a to afford the desired 40 formation of the products was completely inhibited (Scheme 2,
5
product 5-methoxy-1,3,3-trimethylindolin-2-one 3la in 53%
yield. Various functional groups, such as Me, Bu, and Ph, on the
aryl rings of N-methyl anilines were well tolerated to form the
corresponding products 3qa-sa in 45-50% yields. Like the aniline,
eq3). Subsequently, we have used (1-cyclo-propylvinyl)benzene
(1x) to react with α-carbonyl alkyl bromides (2b), mono
alkylation/ringopening/cyclization product 4 was observed with
13% yield, which confirmed this C-H cycloamidation involved a
t
N-methylnaphthalen-1-amine 1t also underwent the C-H 45 radical process (Scheme 2, eq4). We examined the sequence of
10
15
20
25
amination reaction, producing corresponding product 1,3,3-
trimethyl-1,3-dihydro-2H-benzo[g]indol-2-one 3ta in 44% yield.
Furthermore, heterocyclic aniline 1u was also tolerated well,
giving the desired product 5-ethyl-7,7-dimethyl-5,7-dihydro-6H-
the tandem reaction by using 2-bromo-2-methyl-N,N-di-p-
tolylpropanamide (5) as starting materials under the standard
condition. Interestingly, the desired product was not obtained.
Instead, the compound 6 was observed in 66% yield (Scheme 2,
[
1,3]dioxolo[4,5-f]indol-6-one 3ua in 52% yield. Unfortunately, 50 eq5), which has confirmed activation of C-H bond should be
no quaternary benzofuranone has been detected in GC-MS
when we tested the phenol under this condition. Subsequently,
we examined the scope of the tandem cyclization with a variety
of α-carbonyl alkyl bromides 2. As shown in Table 2, the method
tolerates a wide range of tertiary-α-bromoalkyl malonic esters,
ketone esters and cycloalkanes. For example, α-bromo
cycloalkane, ethyl 1-bromocyclobutane-1-carboxylate (2c)
prior to the formation of lactam.
O
O
OEt
OEt
Br
1b
1
Cu(II)L
SET
Cu(III)L
COOEt
N
H
reacted with di-p-tolylamine (1a) in the presence of Cu(OAc)
2
,
H
1a
N
COOEt
2
,2-bipyridine, and K CO to give the corresponding product 5'-
2
3
Base
H
methyl-1'-(p-tolyl)spiro[cyclobutane-1,3'-indolin]-2'-one 3ac in
76% yield. Importantly, bromodifluoroacetate (3f) was
compatible with the reaction conditions and provided 3,3-
difluoro-2-oxindole derivative 3af in 38% yield.
N
3
H+
2
COOEt
O
H
EtOOC
N
N
Base
O
Cu(OAc)2 (10 mol%)
O
NH
OEt
2,2'-bipyridine (20 mol%)
N
+
Br
N
(eq 1)
K2CO3 (2 equiv)
CH3CN, 120 oC, 12 h
+
O
4
3aa
2a
EtOOC
COOEt
1v
3va, 46%
3va', 0%
MeO
Scheme 3 Possible mechanism
O
O
Cu(OAc)2 (10 mol%)
2,2'-bipyridine (20 mol%)
55
OEt
N
N
NH
+
Br
+
(eq 2)
Based on the control experiments and previous works 11
,
K2CO3 (2 equiv)
O
CH3CN, 120 oC, 12 h
2
a
the mechanisms for the copper-mediated C-H
cycloamidation reaction was proposed (Scheme 3). Firstly,
the alkyl radical A was formed by a single-electron transfer
MeO
OMe
3wa
6
1w
3wa'
3% yield (3wa:3wa' = 2:1)
O
TEMPO (3 equiv)
Cu(OAc)2 (10 mol%)
2,2'-bipyridine (20 mol%)
60 (SET) process from ethyl 2-bromo-2-methylpropanoate 2a,
and then reacts with di-p-tolylamine 1a to deliver the
intermediate B. Subsequently, intermediate B was oxidized
by Cu(III)L to produce the intermediate C, following by
deprotonation of C by base can furnish the product D.
N
OEt
+
Br
(eq 3)
(eq 4)
N
K2CO3 (2 equiv)
CH3CN, 120 oC, 12 h
H
O
3aa, 0%
1a
2a
O
Et
Br
Et
Cu(OAc)2 (10 mol%)
2,2'-bipyridine (20 mol%)
OEt
OEt
+
K2CO3 (2 equiv)
CH3CN, 120 oC, 12 h
Et Et
O
2b
1x
4,13%
6
5
Finally, intramolecular cycloamidation of the amino group
with the ester afforded the substituted oxindole 3aa under
the basic conditions.
In summary, we have developed the copper promoted
C-H cycloamidation of N-substituted anilines with α-
Br
O
O
O
Cu(OAc)2 (10 mol%)
,2'-bipyridine (20 mol%)
2
N
N
+
N
(eq 5)
K2CO3 (2 equiv)
CH3CN, 120 oC, 12 h
3
aa, trace
6, 66%
5
Scheme 2 Control experiments
3
0
2
70 carbonyl alkyl bromides under Bpin -Free conditions. In this
In order to gain mechanistic information about this C-H
cycloamidation, several control experiments were carried out
transformation, various of N-substituted anilines (especially
aryl substituted) and α-carbonyl alkyl bromides were
transformed to the corresponding 3,3’-disubstituted
oxindoles derivatives in moderate to good yields under
(Scheme 2). Competition experiments using N-substituted
anilines with different electronic properties revealed that this C-
3
5
H cycloamidation could preferentially occurs in electron-rich 75 simple conditions. More importantly, a new C-C bond and
aromatic ring (Scheme 2, eq1, eq2). A stoichiometric amount of
C-N bond were formed in this transformation and this
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Page 4 of 4
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group. Wide substrate scope make this strategy have
implications in drugs discovery and development.
5
.
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6
7
7
8
8
9
9
5
0
5
0
5
0
5
Acknowledgment
5
We thank the Natural Science Foundation of China (Nos.
5
1878326, 21762030, 21625203 and 21871126), and Jiangxi
Province Science and Technology Project (Nos. 20171BCB23055
and 20171ACB21032) for financial support.
5
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