Radical-based regioselective cross-coupling of indoles and cycloalkanes

Article abstract of DOI:10.1039/c5cy01907a

An investigation into the regiochemistry of radical functionalization of indoles using cycloalkanes through di-tert-butyl peroxide (DTBP)-promoted C(sp³)-H activation was conducted. A wide range of indoles bearing substituents at different positions was functionalized directly with simple cycloalkanes in moderate to high regioselectivity. 2-, 4- and 7-positions were mainly functionalized.

Full text of DOI:10.1039/c5cy01907a

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Radical-Based Regioselective Cross-Coupling of Indoles and
Cycloalkanes
Jianmin Xiu,a Wenbin Yia*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
indoles are desirable for both organic synthesis and medicinal
chemistry considerations.
There are numerous methods which have been developed
for the preparation of cycloalkyl substituted indoles, including
multicomponent coupling reaction,[3] Friedel-Craft alkylation,[4]
arylation,[5] and transition-metal catalyzed C-H activation
cross-coupling reaction.[6] The regioselectivity of these
reactions has also been investigated over the years.[7] A more
attractive approach for cycloalkylation of indoles was a
condensation of pre-halogenated indole with cyclanone
followed by reduction with LiAlH4.[8] These strategies can
obtain the target product in high regioselectivity, but they
come with the multiple drawbacks including low atom
utilization, use of toxic reagents and inconvenience of
operations. Therefore, the development of direct
functionalization methods for the selective modification of
An investigation on regiochemistry of radical functionalization of
indoles using cycloalkanes through di-tert-butyl peroxide (DTBP)-
promoted C(sp3)-H activation was conducted. A wide range of
indoles bearing substituents at different position was
functionalized directly with simple cycloalkanes in moderate to
high regioselctivity. 2-, 4- and 7-position were mainly
functionalized.
indoles remains an important practical goal.
Cy
+
(a)
(b)
N
O
Cy
N
O
Cy
Cy
N
O
Cy
NH2
N
NH2
N
N
N
N
N
N
N
Cy
R1
R1
R
R
tBuOOtBu
Scheme 1. Representative bioactive alkylindoles.
+
S
S
Ar
Cy
Ar
(c)
(d)
Ar
S
O
Regiocontrolled functionalization of indole rings has been an
important subject because of the vital role of indole structural
motif in many biologically active natural products (Scheme
1).[1]Some cycloalkyl substituted indoles have exhibited better
metabolic stability than their unsubstituted counterparts.[2]
Consequently, the development of new methods for synthesis
of functionalized indoles including cycloalkyl substituted
H
O
(Cy-H)
H
N
Y
Ar
N
Ar
Y
Cy
metal-free
O
Ar1
(e)
Ar1
Cy
Ar2
Ar2
OH
Previous work
Present work
H
Cy
R3
R3
R4
R4
R2
R2
N
N
R1
R1
J.M. Xiu, Prof. W. B. Yi
School of Chemical Engineering
Nanjing University of Science and Technology
Xiao Ling Wei Street, Nanjing 210094, People’s Republic of China.
E-mail: yiwenbin@mail.njust.edu.cn
Scheme 2. Di-tert-butyl peroxide (DTBP)-Mediated Oxidative Cross-Coupling
reactions.
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
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substituted product could be a harbinger of a new method for
the preparation of indole derivatives with substituents on the
benzene ring.
Afterwards, various oxidants were screened (Table 1,
entries 2-4). The use of tert-butyl hydroperoxide (TBHP) and
potassium persulfate instead of DTBP provided no access to
the desired product 3a. Increasing the amount of DTBP did not
lead to significant difference in the yield of 3a (Table 1, entry
5). Reaction temperature and time were also screened (Table 1,
entries 6-10). The coupling occurred efficiently when heated to
During the last few decades, radical reactions have emerged
as a powerful toolkit for the direct activation of simple alkanes
such as cheap constituents of petroleum ether and nature
gas.[9] The metal-free C(sp3)-H bond functionalization progress
for
C – C (S) bond formation of disulfides, olefins,
heteroaromatics and cycloalkanes promoted by di-tert-butyl
peroxide (DTBP) has also been reported (Scheme 2).[10] With
this in mind and our continuous efforts to develop metal-free
radical syntheses,[11] we envisioned that the formation of
cycloalkyl-substitued indoles in oxidative radical system could
happen, which, if realized, would provide a simple and
practical strategy for the synthesis of cycloalkylindole
derivatives. To verify the feasibility of our proposed
assumption, we started the investigation by selecting the
reaction of indole 1a and cyclohexane 2a as the model
reaction (Table 1).
140
temperature was decreased to 85
°C for 12 hours. There was nearly no reaction when the
°C. Extension of reaction
time may lead to more undesired byproducts. Then we carried
out a screening of various additives, however, none of the
screened additives gave better results (Table 1, entries 11-13).
Furthermore, when the reaction was performed under air
atmosphere, a lower yield was obtained (Table 1, entry 14).
Finally, we used acetonitrile as the solvent with the aim of
decreasing the amount of cyclohexane to 3 equiv., but the
yield was decreased substantially (Table 1, entry 15).
Table 1. Optimization of reaction conditions. [a]
With the above optimized conditions in hand, the scope of
the reaction with respect to indole derivatives was tested and
the results are listed in Table 2.
Table 2. Cross-coupling of Indoles (1) with Cyclohexane (2a)[a]-[c]
Entry
Oxidant
(equiv.)
Addi.
(2 equiv.)
Temp.
(°C)
Time
(h)
Yield
(%)
1
2
3
4
5
6
7
8
140
140
140
140
140
140
140
140
100
85
140
140
140
140
140
12
12
12
12
12
24
8
n. r.
74
n. r.
n. r.
75
73
67
54
10
trace
73
71
70
41
DTBP(1.5)
K2S2O8(1.5)
TBHP(1.5)
DTBP(3)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
DTBP(1.5)
4
9
12
12
12
12
12
12
12
10
11
12
13
14[b]
15[c]
CsCO3
tBuOK
K2CO3
trace
[a] Reaction conditions: indole (1 mmol), cyclohexane (4 mL), under
nitrogen. [b] Under air. [c] Indole (1 mmol), cyclohexane (3 mmol),
acetonitrile (4 mL).
In the absence of radical initiator, the cyclohexyl substituted
indole product was not detected (Table 1, entry 1). To our
surprise, 3a, was obtained in 74% yield in the presence of 1.5
equiv. of DTBP.
According to the reports in the literature, the direct
functionalization of indoles mostly occurs at the 2- or 3-
position.[12] There is almost no report about directly C-H
activation reaction on 4-position of indoles. In 1994, Katritzky
et al. demonstrated aquathermolysis of indole and 2,3-
[a] Reaction conditions: indoles (1 mmol), cyclohexane (4 mL), DTBP (1.5 mmol) at
140 °C for 12 h, under N2. [b] Yield was given as a total yield of mixtures of products,
and the structure was confirmed by NMR. [c] Regioselectivity ratio determined by
GC-MS. [d] Detected by GC-MS.
dimethylindole in cyclo-hexane at 460 °C for 1 h, in which 4-
substituted indole was detected as a significant product.[13]
Our group recently reported the reaction of isochroman with
indoles using DTBP as oxidant provides facile access to 3-
(isochroman-1-yl)-indoles.[14] The unexpected 4-position
2 | J. Name., 2012, 00, 1-3
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Indoles with substituents at 5-position were tested primarily,
To gain insights into the reaction mechanism, several con-
the reaction proceeded predominately at the 4-position in all trol experiments were carried out (Scheme 4). Addition of the
cases (3b-3i), Structure of 3e was confirmed by X-ray crystal radical-trapping reagents 2, 2, 6, 6-tetramethylpiperidine N-
structure analysis (Scheme 3). Although the electrical oxide (TEMPO) could completely inhibit the reaction and 1-
properties of substituents could hardly give any influence on (cyclohexyloxy)-2, 2, 6, 6-tetramethylpiperidine was detected
the regioselectivity, the yields of products (3g and 3h), by using by GC-MS. Moreover, with the absence of 5-chloro-1H-indole,
electron-rich substrates such as 5-methylindole and 5- 1, 1'-bi (cy-clohexane) was detected by GC-MS as the main
methoxyindole were lower than that using electron-deficient product under the reaction conditions. These results indicated
indoles. Substitutes at other positions were also investigated. that the transformation may proceed via a radical course.
N-methylindole could obtained 2-cyclohexyl-1-methyl-1H-
indole and 4-cyclohexyl-1-methyl-1H-indole with the ratio of
74% and 25% respectively. 2-methylindole reacted selectively
at 4-position to give the corresponding products in moderate
or 4-position, the 2-
3m). In the
yields. With
a
substituent at
cyclohexylindole becomes the major product (3l
3
,
case of 6-substituted indole, the reaction displayed a stronger
preference toward the 7-position than the 4-position
selectivity (3n and 3o), compared with 3b and 3c. There was
no significant difference between 2- and 4-position selectivity
in terms of 7-substitued indole.
Scheme 4. Insights into the mechanism.
As shown in table 2, indoles with substituents at different
positions on benzene ring, reaction selectivities were quite
different. Further document research on the selectivity was
conducted. In 2011, Li and co-worker reported a direct para-
selective oxidative cross-coupling of benzene derivatives with
cycloalkanes catalyzed by ruthenium, overwhelming the effect
[15]
of strongly ortho-directing of chelating substituents.
Different substituents also showed diverse ratio of
ortho/meta/para product. They attributed the selectivity to
the stability of resonance of
a
radical-charactered
Scheme 3 X-ray crystal structure analysis of 3e
intermediate and the specific mechanism was not given.
Similarly, we supposed that the position of substituent on the
indoles might have an effect on the stability of the radial
intermediates, thereby leading to selective functionalization.
To test this hypothesis, relative radical stabilities of 1c and 1o
were investigated using density functional theory (DFT)
calculation employing the method B3LYP (Table 4). The
activation energies of radical transition state (TS) varied with
the Breaking bonds. In the case of 1c, the intermediate
generated from breaking C-H4 have the lowest activation
energy than C-H6 and C-H7. While breaking C-H4 and C-H7 could
To expand the scope of the methodology, a range of
cycloalkanes was examined afterwards (Table 3). In a similar
manner to the reaction of 2a, cyclopentane (2b), cycloheptane
(
2c) and cyclooctane (2d) reacted smoothly. 3s was obtained in
a lower yield when 1H-indole-5-carbonitrile was reacted with
n-hexane under the conditions. Interestingly, when
cyclododecane (2e) was used, the corresponding products
were isolated in moderate yields.
Table 3. Cross-coupling of Indoles with Cycloalkanes.[a]-[b]
afford more stable radical transition state than C-H5 for 1o
.
n
The results of theoretic calculation were well coincident with
those of tests.
150% DTBP, N2
R
+
R
°
140 C, 12 h
N
n
H
N
n=0,1,2,3,7
Table 4. Theoretic calculation results of 1c and 1o.
H
1
2
3
Radical TS
energies
(hartree)
Activation
energies
(kJ/mol)
Breaking
bonds
Compounds
C-H4
C-H6
C-H7
C-H4
C-H5
C-H7
-1058.6131
-1058.6105
-1058.6107
-1058.6117
-1058.6083
-1058.6121
41.75
48.57
48.05
45.42
54.35
44.63
[a] Reaction conditions: indole (1 mmol), cycloalkane (4 mL) , DTBP (1.5 mmol)
at 140 °C for 12 h, under N2. [b] Yield was given for the main product, and the
structure was confirmed by NMR.
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Moreover, Frank De Proft et al. reported an electrophilicity of Jiangsu (BK20141394). We also thank the Center for
scale, global as well as local, and a nucleophilicity scale for 35 Advanced Materials and Technology for financial support.
radicals in 2007.[16] In their opinion, radicals can be regarded as
electrophilic/nucleophilic, and the nature of the radical has an
effect on which reactive sites in a substrate are more likely to Notes and references
be attacked. Quite recently, Fionn et al. carried out a
systematic investigation of factors affecting the regio-
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indole derivative to generate the most stable radical
intermediate ( ), affording the final target product
A), which finally reacted with
B
3.
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Scheme 5. Proposed reaction mechanism.
Conclusions
In summary, we have conducted an regiochemistral
investigation on the radical reaction of indoles and
cycloalkanes through C(sp3)-H activation under metal-free
conditions in the presence of tBuOOtBu. A wide range of
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Acknowledgements
We thank the Fundamental Research Funds for the Central
Universities (30920130111002), National Natural Science
[17] Fionn O.; Donna G. B.; Phil S. B. J. Am. Chem. Soc. 2013, 135,
Foundation of China (21476116), Natural Science Foundation 12122.
.
4 | J. Name., 2012, 00, 1-3
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Catalysis Science & Technology
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DOI: 10.1039/C5CY01907A
Radical-Based Regioselective Cross-Coupling of Indoles and
Cycloalkanes
Jianmin Xiu, Wenbin Yi
An investigation on regiochemistry of radical functionalization of indoles using
cycloalkanes through di-tert-butyl peroxide (DTBP)-promoted C(sp3)-H activation
was conducted. A wide range of indoles bearing substituents at different position was
functionalized directly with simple cycloalkanes in moderate to high regioselctivity.
2-, 4- and 7-position were mainly functionalized.