Superbase-promoted selective carbon-carbon bond cleavage driven by aromatization

Article abstract of DOI:10.1039/c9ob00606k

A novel selective carbon-carbon single bond cleavage has been disclosed through the copper-catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine hydrochlorides with substituted 1-(bromomethyl)-2-iodobenzenes leading to fused N-heterocycles. Mechanistic studies showed that the intrinsic drive of aromatization and the action of the superbase derived from sodium tert-butoxide and dimethylsulfoxide were the key factors leading to the carbon-carbon single bond cleavage. Furthermore, the obtained N-heterocycles are indoloquinoline derivatives with wide biological activities.

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ARTICLE TYPE
Superbase-promoted selective carbon-carbon bond cleavage driven by
aromatization†
Can Liu,a,b Xianjin Zhu,b Yongzhen Han,b Haijun Yang,b Changjin Zhua and Hua Fu*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel selective carbon-carbon single bond cleavage has been disclosed through the copper-
catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine hydrochlorides with substituted 1-
(bromomethyl)-2-iodobenzenes leading to fused N-heterocycles. Mechanistic studies showed that
the intrinsic drive of aromatization and the action of superbase derived from sodium tert-butoxide
10 and dimethylsulfoxide were the key factors leading to the carbon-carbon single bond cleavage.
Furthermore, the obtained N-heterocycles are indoloquinoline derivatives with wide biological
activities.
Carbon-carbon (C-C) bonds are ubiquitous, and the enzymatic
of our knowledge, this is the first example of superbase-promoted
selective C-C bond cleavage is a fairly common issue in nature.1 40 chemoselective carbon-carbon single bond cleavage driven by
15 However, this pathway is a great challenge in organic synthesis
due to the inert nature of C-C bonds.2 Recently, the
chemoselective cleavage of C-C bonds has become a hot issue in
organic chemistry.3 In the successful examples for the cleavage of
C-C bonds, the common methods include insertion of a metal into
20 C-C bonds through intramolecular chelation by the introduction
of pincer-type ligands,4 metal-promoted C-C bond activation of
strained skeletons (three or four-membered rings) through the
relief of ring-strain energy,5 β-carbon elimination of tertiary
alcohols,6 or aerobic oxidation of C-C bonds.7
aromatization.
Table 1 Optimization of conditions for copper-catalyzed reaction of 3-
benzyl-1-methylindolin-2-imine hydrochloride (1a) with 2-iodobenzyl
bromide (2a)a
45
Temp
(oC)
100
100
100
100
100
Yields of
3a/4ab
48/23
5/73
Entry
Cu Cat.
Base
Solvent
1
2
3
4
5
CuCl
CuCl
CuCl
CuCl
CuCl
KOH
KOH
KOH
KOH
KOH
DMF
DMSO
tBuOH
CH3CN
toluene
1,4-
43/14
26/52
24/13
25
6
CuCl
KOH
100
13/10
Scheme 1 Copper-catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine
hydrochlorides (1) with substituted 1-(bromomethyl)-2-iodobenzenes (2).
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
7
CuBr
CuI
KOH
KOH
100
100
100
100
100
100
100
100
100
80
16/58
20/46
17/61
22/48
21/46
6/74
Herein, we report a novel superbase-promoted chemoselective
carbon-carbon single bond cleavage driven by aromatization. As
30 shown in Scheme 1, we had planned to perform copper-catalyzed
reaction of 1-alkyl-3-alkylindolin-2-imine hydrochlorides (1)
with substituted 1-(bromomethyl)-2-iodobenzenes (2) leading to
fused N-hetercycles (3).8 Surprisingly, the aromatization products
(4) were obtained in high yields when tBuONa and
35 dimethylsulfoxide (DMSO) were used as the base and solvent,
8
9
Cu2O
KOH
10
11
12
13
14
15
16
17
Cu(OAc)2
Cu(TFA)2
CuCl
KOH
KOH
NaOH
tBuOLi
tBuONa
tBuOK
tBuONa
tBuONa
CuCl
0/78
CuCl
0/83
CuCl
0/80
respectively. Mechanistic investigations indicated that
transformed into 4 in DMSO in the presence of BuONa at room
3
CuCl
0/71
t
CuCl
120
0/82
temperature without addition of any transition metal. To the best
a
Reaction conditions: under nitrogen atmosphere, 3-benzyl-1-
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methylindolin-2-imine hydrochloride (1a) (0.22 mmol, 1.1 equiv),
2-iodobenzyl bromide (2a) (0.2 mmol, 1.0 equiv), Cu catalyst (20
µmol, 10 mol%), base (0.8 mmol, 4.0 equiv), solvent (2.0 mL),
temperature (80-120 oC), time (20 h) in a sealed Schlenk tube.
3
4
5
6
7
2a
2a
2a
2a
2a
1
Structure of 4a was confirmed by H and 13C NMR spectra and
comparing structure of 4e (structure of 4e was assigned by X-ray
diffraction analysis). b Isolated yield.
Figure 1 Crystal structure of 4e.
At first, the copper-catalyzed one-pot reaction of 3-benzyl-1-
methylindolin-2-imine hydrochloride (1a) with 2-iodobenzyl
bromide (1a) was used as the model to optimize conditions
including copper catalysts, bases, solvents and temperature. As
shown in Table 1, six solvents were tested using CuCl as the
catalyst, KOH as the base under a nitrogen atmosphere at 100 oC
5
8
2a
2a
2a
2a
2a
2a
4a (70%)
4a (65%)
4a (80%)
4a (83%)
4a (81%)
4a (85%)
10 for 20 h (entries 1-6), we found two products 3a and 4a (from a
C-C single bond cleavage of 3a). The structure of 4a was
1
confirmed by H and 13C NMR spectra and comparing single-
9
crystal X-ray analysis of 4e (structure of 4e was assigned by X-
ray diffraction analysis (Figure 1, see Supporting Information for
15 details). Reaction conditions with dimethylsulfoxide (DMSO)
provided 4a in the highest yield (73%) (entry 2). Subsequently,
other copper catalysts were screened using DMSO as the solvent
(entries 7-11), and the results showed that they were inferior to
CuCl. Further, four other bases were surveyed (entres 12-15), and
20 tBuONa gave 4a in 83% yield without 3a appearing (entry 14).
Variation of temperature was attempted (entries 16 and 17), and
we found that 100 oC was a suitable temperature.
10
11
12
13
Table 2 Substrate scope for the copper-catalyzed reaction of 1-alkyl-3-
alkylindolin-2-imine hydrochlorides (1) with substituted 1-
25 (bromomethyl)-2-iodobenzenes (2)a
Entry
1
1
2
4
14
2a
4a (81%)
2
2a
2
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15
16
2a
2a
4a (70%)
4a (73%)
27
28
29
1a
1a
1a
30
31
1a
1n
4a (38%)
4a (35%)
2f
17
18
2a
2a
4a (41%)
32
2a
4a (12%)
33
34
2a
2a
4a (17%)
4a (24%)
a Reaction conditions: under nitrogen atmosphere, 1 (0.22 mmol,
1.1 equiv), 2 (0.2 mmol, 1.0 equiv), CuCl (20 µmol, 10 mol%),
tBuONa (0.8 mmol, 4.0 equiv), DMSO (2.0 mL), temperature (100
oC), time (20 h) in a sealed Schlenk tube.
19
20
21
2a
2a
2a
With the optimized conditions in hand, the substrate scope for
the copper-catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine
hydrochlorides (1) with substituted 1-(bromomethyl)-2-
iodobenzenes (2) was investigated. As shown in Table 2,
variation of substituents R2 in 1 was first surveyed using 2-
iodobenzyl bromide (2a) as the partner, several N-alkyl indolin-2-
imines including methyl, ethyl, propyl, butyl, benzyl,
phenylpropyl and allyl were feasible, and the substrates 1a-g
afforded the corresponding aromatization products 4a-g in high
5
10 yields (71-83%). Product 4g underwent a C=C double bond
transfer during the copper-catalyzed reaction of substrates 1g
with 2a (entry 7). For substituents R3 with different substituted
aromatics including p-methylphenyl, p-methoxyphenyl, p-
22
23
2a
2a
fluorophenyl,
p-chlorophenyl,
p-bromophenyl
and
p-
15 trifluoromethylphenyl, the C-C bond cleavage occurred without
exception (entries 8-13). Increasing the 3-position alkyl chain
length led to C-C bond cleavage, albeit in diminished yield
(entries 14-17). Subsequently, we explored variation of
substituents R1 in 1 including strong electron-donating groups
20 (entries 18-21), poor electron-withdrawing groups (entries 22 and
23) and strong electron-withdrawing groups (entry 24), and found
that the substrates containing electron-withdrawing R1 groups
exhibited slightly higher reactivity than those containing electron-
donating groups. Finally, several substituted 2-iodobenzyl
25 bromide (2) were tested, and they also showed high reactivity
(entries 26-29). Yields obviously decreased when 1-
(bromomethyl)-2-bromobenzenes (2f) was used as the partner of
1a or 1n (entries 30 and 31). We attempted three substrates 1z,
1aa and 1ab without the terminal phenyl groups for substituents
30 R3, and the reaction gave lower yields (entries 32-34). The
present method exhibited some functional group tolerance
24
2a
2a
25
26
1a
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t
tBuONa as the base. (e) Treatment of 3a in DMSO with BuONa as the
40 base.
including C-F (entries 10, 22, 27 and 28), C-Cl (entries 11, 23
and 29), C-Br bonds (entries 12 and 16), and CF3 (entries 13 and
24) and ether groups (entries 21 and 26). The obtained N-
heterocycles (4) are indoloquinoline derivatives, and they have
been well established to be the anticancer, antibacterial,
antifungal, antiplatelet, aggregation, antimalarial, analgesic,
antihypertensive agents9 and DNA intercalating agents10 and
topoisomerase II inhibitors.11 Therefore, the present method is a
novel strategy for synthesis of indoloquinoline derivatives.
To explore the formation process of products 4, some control
experiments were performed. Here, the formation of 4a was used
as the example (Scheme 2). When one equiv of 2a (relative to
amount of 1a) was applied as the partner of 1a, the reaction in
DMSO gave 5 in 95% yield with 2.5 equiv of K2CO3 as the base
To further investigate the reaction mechanism, more
experiments were carried out as shown in Scheme 3. No reaction
occurred when BuOH replaced DMSO as the solvent (Scheme
3a) or NEt3 was used as the base instead of tBuONa (Scheme 3b).
t
5
t
45 The results above indicated the possibililty that BuONa/DMSO
acted as a superbase. In order to avoid involvement of trace
amounts of transition metals in the reaction system, 0.2 equiv of
Na2S was added, and the reaction also worked well (Scheme 3c),
which excluded the doubt that transition metals could promote
50 the reaction. No unfavourable influence was observed in the
presence of 2.0 equiv of 2,2,6,6-tetramethylpiperidinooxy
(TEMPO) as the radical quenching agent (Scheme 3d), which
indicated that the reaction was not a radical process. As shown in
10
15 at room temperature (Scheme 2a). Reaction of 1a with 2.2 equiv
of 2a under the similar condition produced 5 and 6 in 86% and
8% yields, respectively (Scheme 2b). The results above showed
that the reaction started at 3-position of 1. Copper-catalyzed
intramolecular N-arylation of 5 provided 3a in 93% yield using
20 tBuOH as the solvent and K2CO3 as the base without C-C bond
cleavage occurring (Scheme 2c). However, the copper-catalyzed
reaction in DMSO gave 4a in 90% yield with tBuONa as the base
(Scheme 2d). Interestingly, 4a was obtained in 95% yield after
t
Scheme 3e, copper-catalyzed reaction of 1l with 2a in BuOH
55 with K2CO3 as the base provided 7, and the Suzuki coupling of 7
with 2-naphthaleneboronic acid (8) gave 9. Treatment of 9 with
the superbase (tBuONa/DMSO) afforded 4a and 10 in 90% and
87% yields, respectively, which showed that an intramolecular
elimination occurred.
60
t
treatment of 3a in DMSO in the presence of BuONa for only 5
25 min at room temperature (Scheme 2e). The results above
indicated that DMSO/tBuONa could act as a superbase12 and
played a key role in aromatization of 3a leading to 4a. To reveal
whether our tBuONa contains trace amount of transition metals, it
was tested by inductively coupled plasma-mass spectrometry
30 (ICP-MS), and transition metals almost were not found,13 which
indicated that the reaction did not need assistance of transition
metals.
Scheme
3 Further investigations on the reaction mechanism: (a)
t t
Treatment of 3a in BuOH with two equiv of BuONa as the base. (b)
Treatment of 3a in DMSO with one equiv of NEt3 as the base. (c)
65 Treatment of 3a in DMSO with BuONa as the base in the presence of
t
t
Na2S. (d) Treatment of 3a in DMSO with BuONa as the base in the
presence of two equiv of TEMPO. (e) Synthesis and aromatization of 9.
Scheme 2 Investigations on formation process of 4a: (a) Reaction of 1a
35 with one equiv of 2a in DMSO with K2CO3 as the base. (b) Reaction of
1a with 2.2 equiv of 2a in DMSO with K2CO3 as the base. (c) Copper-
t
catalyzed intramolecular N-arylation of 5 in BuOH with K2CO3 as the
base. (d) Copper-catalyzed intramolecular cyclization of 5 in DMSO with
4
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45
50
55
60
65
70
75
80
85
90
95
4
5
Scheme 4 A possible mechanism for the superbase-promoted C-C bond
cleavage.
According to the experiments above, a possible pathway of this
5
copper-catalyzed reaction of 1 with 2 leading to 4 is proposed in
t
6
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Scheme 4. First, treatment of BuONa with DMSO forms a
superbase M+-OtBu.12 Under the basic conditions, reaction of 1
with 2 first gives intermediate I, and then copper-catalyzed
intramolecular N-arylation leads to II. Deprotonation of II under
10 treatment of the superbase provides III leaving HOtBu, and an
alkyl elimination of III afforded the target product (4) freeing IV.
Finally, treatment of IV with DMSO or HOtBu yields V.
In summary, we have developed a novel chemoselective
carbon-carbon single bond cleavage. Mechanistic studies
15 indicated that the intrinsic drive of aromatization combining with
the action of superbase derived from sodium tert-butoxide and
dimethylsulfoxide made the carbon-carbon single bond cleavage
feasible. Furthermore, the obtained N-heterocycles are
indoloquinoline derivatives with various biological activities. We
20 believe that the present superbase-promoted aromatization
method should provide an unprecedented and useful strategy for
construction of diverse molecules.
7
8
9
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The authors would like to thank Dr. Haifang Li in Department
of Chemistry at Tsinghua University for her great help in high
25 resolution mass spectrometric analysis, and the National Natural
Science Foundation of China (Grant No. 21772108) for financial
support.
Notes and references
a School of Chemistry and Chemical Engineering , Beijing Institute of
30 Technology, Beijing 100081, P. R. China. Fax: (+86) 10-62781695; E-
mail: fuhua@mail.tsinghua.edu.cn
100 13 Data determined by ICP-MS: Pd (6.4 ppb), Cu (40.1 ppb), Fe (75.9
ppb), Ni (2.3 ppb), Ru (0.14 ppb), Co (<0.10 ppb) and Ir (<0.10 ppb).
b Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, P. R. China.
35
† Electronic Supplementary Information (ESI) available: Full
experimental details, characterization and NMR spectra of the target
products are provided. See DOI: 10.1039/b000000x/
40 1 F. P. Guengerich and F. K. Yoshimoto, Chem. Rev., 2018, 118, 6573.
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