Di-tert-butyl Peroxide (DTBP)-Mediated Oxidative Cross- Coupling of Isochroman and Indole Derivatives

Article abstract of DOI:10.1002/adsc.201500048

A metal-free C-C bond formation method via the oxidative cross-coupling reaction of isochroman and indole derivatives was established. Various α-fuctionalized cyclic ethers were achieved in satisfactory yields using di-tert-butyl peroxide (DTBP) as the oxidant. This method is also a potentially efficient strategy for the construction of cyclic ether-containing targets.

Full text of DOI:10.1002/adsc.201500048

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DOI: 10.1002/adsc.201500048
Di-tert-butyl Peroxide (DTBP)-Mediated Oxidative Cross-
Coupling of Isochroman and Indole Derivatives
Likun Jin,a Jie Feng,a Guoping Lu,a and Chun Caia,*
a
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, Peopleꢀs Republic of
China
Fax: (+86)-25-8431-5030; phone: (+86)-25-8431-5514; e-mail: c.cai@mail.njust.edu.cn
Received: January 19, 2015; Revised: April 15, 2015; Published online: June 10, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500048.
À
Abstract: A metal-free C C bond formation method cient strategy for the construction of cyclic ether-
via the oxidative cross-coupling reaction of isochro- containing targets.
man and indole derivatives was established. Various
a-fuctionalized cyclic ethers were achieved in satis-
factory yields using di-tert-butyl peroxide (DTBP) as Keywords: C C bond formation.; C H activation; a-
the oxidant. This method is also a potentially effi- fuctionalized cyclic ethers; metal-free conditions
À
À
Introduction
oxygen atom of isochroman or analogous heterocyclic
skeletons represents an interesting topic in formal C
À
Progress in methods for the selective functionalization H bond activation reactions. Some recent develop-
of C H bonds has enabled the efficient construction ments have been achieved as follows:[10a–f] Liꢀs group
À
of a tremendous variety of organic compounds of developed a CDC pathway to realize the functionali-
relevance in materials science and medicinal chemis- zation of N-arylated tetrahydroisoquinolines employ-
try.[1] Among them, recently developed dehydrogena- ing copper(I) bromide as the catalyst and tert-butyl
tive cross-coupling (CDC) reactions for the formation hydroperoxide as the oxidant in 2005.[10a] Later, Panꢀs
À
À
of various C C and C heteroatom bonds have at- group demonstrated an iron-catalyzed esterification
tracted much attention.[2] Pioneered by the study of of inactive C(sp ) H bonds in 1,4-dioxane with car-
3
À
Zhao and Li in 2008,[3] great progress has been boxylic acids.[10b] Very recently, Liuꢀs group reported
achieved in this area. Privileged palladium,[4a–c] cop- the selective direct construction of diverse a-function-
per,[4d–f] and iron[4g–i] catalysts were employed owing to alized ethers by use of the trityl ion and a Lewis acid
the highly desirable atom-economy. However, most of catalyst at ambient temperature.[10c]
the reactions were catalyzed by metal salts in combi-
Radical-based reactions lead to mostly spontaneous
nation with stoichiometric oxidants such as TBHP, processes in natural systems ranging from protein
DTBP and DDQ.[4a–i] More recently, organocatalysis damage to aging and diseases.[11] Thus exploring the
has proven to be an alternative to these transition metal-free approach to develop radical reactions[12]
3
À
metal-mediated oxidative couplings involving C(sp )
could be conceived as a more “natural” strategy for
H bond cleavage.[5] Since the oxidative couplings of the synthesis of complicated pharmaceutical com-
glycine derivatives[6] and N-aryltetrahydroisoquino- pounds, whose syntheses traditionally rely on transi-
lines[6] have been well documented, further explora- tion metal-catalyzed reactions. Inspired by that, we
3
À
tions were turned to other cyclic derivatives such as are engaged in discovering the C(sp ) H bond func-
isochroman, 1,3-dithiane and cyclohexane.[7]
tionalization of isochroman in the absence of metal
a-Substituted ethers are common structural motifs catalysts or high-pressure oxygen. To our delight, the
that widely exist in natural products and pharmaceuti- use of DTBP (di-tert-butyl peroxide) allows the easy
3
2
cals with diverse biological activities.[8] 1-Substituted assembly of the C(sp ) C(sp ) bond from isochroman
À
À
isochromans have been demonstrated to have unique and indole derivatives. This C H functionalization
pharmacological activities, similar to the more compli- strategy to synthesize 3-(isochroman-1-yl)-indoles can
cated bioactive compounds.[8a,9] Consequently, func- be regarded as an efficient and practical alternative
3
À
tionalization of C(sp ) H bonds adjacent to the for the formation of a-substituted ethers.
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Likun Jin et al.
Results and Discussion
ished the yields to 47% and 53%, respectively. Be-
sides, increasing the amount of DTBP also did not
show any significant improvement (Table 1, entry 15).
3
À
We initiated our study by investigating the C(sp )
C(sp2) coupling between isochroman 1a and indole 2a Eventually we chose 1.2 equivalents of DTBP without
to generate 3a. We tried to use molecular oxygen as solvent as the optimized conditions for the procedure.
the terminal oxidant at first. Thus ideally, water In order to examine the effect of oxygen, we conduct-
would be only by-product. However, only a 15% yield ed the reaction under an atmosphere of argon which
the desired product was observed and the yield was did not affect the yield (Table 1, entry 17).
not improved obviously though screening of previous-
With the optimized conditions in hand, we next ex-
ly developed conditions.[5a] (Table 1, entries 2–4) The amined the substrate scope for the reaction. Various
low yield and long reaction time indicated the limited indole derivatives were smoothly coupled with iso-
reaction efficiency. Then, chemical oxidants such as chroman, giving the target products in moderate to
TBHP, DTBP and DDQ were tested for the reaction. good yields. Generally, as is shown in Table 2, indoles
After a brief survey of plausible conditions (Table 1, bearing electron-withdrawing (Table 2, 3k–m, 3p–s)
entries 5–9), the desired product 3a was obtained in and eletron-neutral (Table 2, 3d) groups gave good
76% yield along with isochroman-1-one (4) as the by- yields. Electron-donating groups such as methyl and
product using DTBP as the single oxidant under sol- methoxy were tolerated (Table 2, 3b and 3c), but led
vent-free conditions. Solvents were screened to fur- to lower yields as compared to the electron-deficient
ther optimize the reaction. However, we found no sig- indole substrates. It is worth noting that under our
nificant increase of the yield in the presence of DCE, standard conditions, substituents on the 1- and 2-posi-
even slight decreases were observed in PhCl and tions of indoles had a significant influence on the re-
MeCN (Table 1, entries 10–12). It was also found that action. Instead, when indoles were substituted on the
a lower reaction temperature (Table 1, entry 13) and 6- and 7-positions, the electronic effect of the sub-
smaller amount of DTBP (Table 1, entry 14) dimin- stituents played a lesser role on reaction yields,
Table 1. Optimization of the reaction conditions.[a]
Entry
Oxidant
Solvent
Temp. [oC]
Time [h]
Yield of 3a[b] [%]
Yield of 4[b] [%]
1
2
3
4
5
6
7
8
–
O2
O2
O2
–
120
120
120
140
120
120
120
120
120
120
120
120
80
24
24
72
72
24
24
24
24
24
24
24
24
24
24
24
36
24
0
3
0
0
MeCN
MeCN/DCE
MeCN/DCE
–
–
–
–
–
DCE
PhCl
MeCN
–
–
–
–
–
12[c]
15[c]
0[d]
34[e]
76
1
5[c]
10[c]
0[d]
0[e]
5
TBHP (1.2 equiv.)
TBHP (1.2 equiv.)
DTBP (1.2 equiv.)
DDQ (1.5 equiv.)
BPO (1.2 equiv.)
DTBP (1.2 equiv.)
DTBP (1.2 equiv.)
DTBP (1.2 equiv.)
DTBP (1.2 equiv.)
DTBP (0.5 equiv.)
DTBP (3 equiv.)
DTBP (1.2 equiv.)
DTBP (1.2 equiv.)
16
0
7
0
0
9
0
10
11
12
13
14
15
16
17
71
58
47
40
53
9
0
0
120
120
120
120
58
4
78
70[f]
5[f]
[a]
Reaction conditions: isochroman (1.2 mmol) and indole (1 mmol).
GC yield.
Under the conditions of mixed solvent: MeCN/DCE (5:1).
TBHP (70% in water).
TBHP (~5.5M in decane).
Reaction conducted under an argon atmosphere.
[b]
[c]
[d]
[e]
[f]
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Di-tert-butyl Peroxide (DTBP)-Mediated Oxidative Cross-Coupling of Isochroman
Table 2. DTBP-mediated oxidative coupling of isochroman with indoles.[a]
[a]
Reaction conditions: isochroman (1.2 mmol), indoles (1 mmol) and 1.2 mmol DTBP at 1208C in 24 h. Isolated yields.
namely, the target products bearing strong electron- our standard conditions afforded the desired products
withdrawing and electron-donating groups tended to 6f and 6g in 85% and 78% yields, respectively.
show small distinctions on yields (Table 2, 3s vs. 3t).
To gain some insight into the mechanism of this
To further extend the substrate scope, we subse- transformation, control experiments were carried out.
quently turned our attention to investigate ethers and As is shown in Scheme 1, we first conducted the reac-
the analogous heterocycles (Table 3). Besides isochro- tion without indole, which resulted in 4 in 59% yield.
man, other saturated cyclic ethers including 1, 3-dihy- Then, 4 equivalents of TEMPO were added to the re-
droisobenzofuran (5a), 1, 4-dioxane (5d) and THF action as a radical inhibitor. As expected, no desired
(5e) were compatible with the reaction, though lower product was observed, indicating that a radical pro-
yields were obtained. Chroman (5b) and isochroman- cess is involved in the transformation. Meanwhile, the
3-one (5c) were not good substrates for the reaction, coupling between indole (2a) with isochroman (1a)
and only traces of the products were detected. Be- under an argon atmosphere resulted in no significant
sides ether candidates, the scope was further extended decrease of the yield suggesting that oxygen is not es-
to N-substituted tetrahydroisoquinolines (5f and 5g). sential for the procedure. When the reaction was run
To our delight, the cross-couplings of 5f and 5g under under argon without DTBP, neither 3a or 4 was de-
tected.
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Likun Jin et al.
Table 3. Scope of cyclic ethers and heteroatom-containing
According to the results above and recent re-
ports,[6d,10d–g,13] a working hypothesis for the reaction
pathway is depicted in Scheme 2. An electron-cata-
lyzed formal C(sp ) C(sp ) cross-coupling was in-
volved in the process. The tert-butoxyl radical is first
generated by the thermal decomposition of di-tert-
butyl peroxide (DTBP). Then the isochroman-derived
components.[a]
2
3
À
benzylic radical A is formed through hydrogen ab-
3
À
straction of the sp C H bond adjacent to the oxygen
atom. After that, the benzylic radical A adds to
indole at the C-3 position, and it is known that radi-
cals readily react with indoles selectively at the C-3
position. Subsequently, the generated adduct radical
B bearing an acidic NH proton is deprotonated by
tert-butanolate in the chain. After deprotonation, the
radical anion C is then formally liberating an electron
to give the product 3a and meanwhile reducing
DTBP via electron transfer to give the tert-butoxyl
radical and the tert-butanolate. The tert-butanolate
acts as a base in the chain reaction and the tert-butox-
yl radical formed in the process then sustains the
chain.
[a]
Reaction conditions: 5 (1.2 mmol), indoles (1 mmol) and
1.2 mmol DTBP at 1208C in 24 h. Isolated yields.
Scheme 1. Control experiment for the oxidative coupling of isochroman with indoles.
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Di-tert-butyl Peroxide (DTBP)-Mediated Oxidative Cross-Coupling of Isochroman
Acknowledgements
We gratefully acknowledge Natural Science Foundation of
Jiangsu Province (BK 20131346) for financial support. This
work was also supported by National Natural Science Foun-
dation of China (21476116).
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Experimental Section
General Procedure for DTBP-Mediated Oxidative
Cross-Couplings of Isochroman and Indole
Derivatives
Isochroman (1) (1.2 mmol), DTBP (1.2 mmol) and indole
(2) (1 mmol) were sequentially added to a Schlenk tube
with a magnetic stir bar. The resulting mixture was stirred at
1208C for 24 h. After that, the reaction mixture was allowed
to cool to ambient temperature, and then diluted with ethyl
acetate, washed with water, dried over anhydrous Na2SO4.
After the solvent had been removed under reduced pres-
sure, the residue was purified by flash chromatography using
PE-AcOEt (10:1–5:1, v/v) as the eluent to give 3-(isochro-
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