Nickel-Catalyzed C(sp2)-H/C(sp3)-H Oxidative Coupling of Indoles with Toluene Derivatives

Article abstract of DOI:10.1021/acscatal.7b01044

Nickel-catalyzed oxidative C(sp²)-H/C(sp³)-H coupling of indoles with toluene derivatives is successfully achieved in the presence of 2-iodobutane as the oxidant. This method allows the selective C-2 benzylation of indoles with toluene derivatives over the alkylation with 2-iodobutane and permits the coupling of diversified indoles via the monochelation assistance. The reaction proceeded through a single-electron-transfer (SET) process, wherein both the C-H nickelation of indole and the C-H activation of toluene derivatives have a significant effect on the entire reaction rate. The synthetic utility of this nickel-catalyzed protocol is demonstrated by the facile removal of the directing group and by the convenient synthesis of the melatonin receptor antagonist Luzindole derivatives.

Full text of DOI:10.1021/acscatal.7b01044

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Article
2
3
Nickel-Catalyzed C(sp)#H/C(sp)#H Oxidative
Coupling of Indoles with Toluene Derivatives
Vineeta Soni, Shrikant M Khake, and Benudhar Punji
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 15 May 2017
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ACS Catalysis
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NickelꢀCatalyzed C(sp2)‒H/C(sp3)‒H Oxidative Coupling of Indoles
with Toluene Derivatives
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Vineeta Soni, Shrikant M. Khake, and Benudhar Punji*
Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, CSIR–National Chemical Laboratory
(CSIR–NCL), Dr. Homi Bhabha Road, Pune 411 008, Maharashtra, India
ABSTRACT: Nickelꢀcatalyzed oxidative C(sp2)‒H/C(sp3)‒H coupling of indoles with toluene derivatives is successfully achieved
in the presence of 2ꢀiodobutane as the oxidant. This method allows the selective Cꢀ2 benzylation of indoles with toluene derivatives
over the alkylation with 2ꢀiodobutane, and permits the coupling of diversified indoles via the monoꢀchelation assistance. The reacꢀ
tion proceeded through a singleꢀelectronꢀtransfer (SET) process, wherein both the C‒H nickelation of indole and the C‒H activation
of toluene derivatives have a significant effect on the entire reaction rate. The synthetic utility of this nickelꢀcatalyzed protocol is
demonstrated by the facile removal of directing group, and by the convenient synthesis of the melatonin receptor antagonist Luzꢀ
indole derivatives.
KEYWORDS: benzylation, C–H activation, indoles, nickel, oxidative coupling, pincer complex
such conditions, would be an ideal strategy to synthesize the
biologically active benzylatedꢀindoles (Scheme 1).10,11 Herein,
we report on the Niꢀcatalyzed benzylation of indoles with tolꢀ
uene derivatives through the oxidative C(sp2)‒H/C(sp3)‒H
crossꢀcoupling using 2ꢀiodobutane as the oxidant (Scheme 1b).
A variety of indoles can be benzylated regioselectively at the
Cꢀ2 position with numerous functionalized toluene derivatives
via the chelation assistance.
INTRODUCTION
Selective functionalization of indole has attracted considerable
attention owing to the ubiquitous nature of this heterocycle in
natural products, pharmaceuticals and biologically active
compounds.1 Particularly, the direct C‒H bonds functionalizaꢀ
tion to construct C‒C bonds by the transitionꢀmetalꢀcatalysts,
using various organic halides and organometallic compounds
as the coupling partner, has proven a versatile technique for
stepꢀeconomical synthesis, and has significantly been proꢀ
gressed.2 In contrast, the oxidative C‒H/C‒H coupling of inꢀ
doles with the organic coupling partners is relatively less exꢀ
plored,3 though it is an ideal and environmentally benign stratꢀ
egy because the prefunctionalization of substrates is not necesꢀ
sary in this case, and the reaction would not generate halogenꢀ
ated or organometallic byꢀproducts. In the pioneering work,
Fagnou reported on the palladiumꢀcatalyzed oxidative couꢀ
pling of indoles with arenes via the C(sp2)‒H/C(sp2)‒H bonds
activation resulting in the arylation products.4 Subsequently, a
number of reactions on indoles have been reported involving
the oxidative C(sp2)‒H/C(sp2)‒H coupling (Scheme 1a).5 On
the contrary, the C(sp2)‒H coupling of indoles with more
strenuous C(sp3)‒H bond remains challenging.6ꢀ8
Scheme 1. Oxidative C‒H/C‒H Bonds CrossꢀCouplings
and Biologically Active 2ꢀBenzylated Indoles.
Nevertheless,
all
the
C(sp2)‒H/C(sp2)‒H
and
C(sp2)‒H/C(sp3)‒H oxidative couplings of indoles reported till
date use either noble metal catalysts and/or excess amount of
strong oxidants, such as peroxides or secondary transitionꢀ
metals, which remains the critical drawback. Oxidative
C(sp2)‒H/C(sp3)‒H coupling without the use of strong oxiꢀ
dants and precious metals is the most challenging task. In parꢀ
ticular, the C(sp2)‒H/C(sp3)‒H coupling of indoles with toluꢀ
ene derivatives leading to the selective Cꢀ2 benzylation,9 under
RESULTS AND DISCUSSION
Optimization
of
Reaction
Conditions
for
C(sp2)‒H/C(sp3)‒H Coupling of Indole with Toluene. Reꢀ
cently, we have demonstrated the C‒H alkylation of indoles
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with alkyl halides using Niꢀcatalyst 1 (Table 1, footnotes); remained untouched. Substrates bearing both the electronꢀ
1
wherein the mechanistic findings suggested the involvement
of an alkyl radical intermediate.12 A key to the success of
achieving indole benzylation using alkyl halide as an oxidant,
via the oxidative C(sp2)‒H/C(sp3)‒H coupling with toluene
derivatives, would be how to expedite the radical transfer from
alkyl to toluene so that selective benzylation can be obtained
rather than the alkylation. Thus, our initial investigation cenꢀ
tered on the employment of a suitable halide source as well as
the perfect combination of halide and toluene. The reaction of
indole 2a with toluene (10 equiv) and 2ꢀiodobutane (2 equiv),
in the presence of nickel catalyst 1, catalytic amount of
LiHMDS and LiOtBu, afforded the benzylated product 4aa in
32% and alkylated product 4aa’ in 63% (Table 1, entry 1).
Upon increasing the toluene concentration, the selectivity for
the benzylation was enhanced, and with 30 equiv of toluene
the product 4aa was isolated in 69% (entries 2,3). Reducing
the concentration of 2ꢀiodobutane to 1.5 equiv, the product
4aa was obtained in 70% yield (entry 4); however, further
reducing the halide concentration or increasing the toluene
concentration resulted with lowering in yield of benzylation
(Table 1, entries 5,6 and Table S1 in the Supporting Inforꢀ
mation). Though the use of 30 equiv of toluene appears to be a
limitation from the synthetic prospective, this excess amount
is essential to obtain the selective benzylation with toluene
rather than the alkylation with 2ꢀiodobutane. The employment
of other primary and secondary alkyl iodides as oxidant gave
lower yield of 4aa, whereas the electronꢀdeficient halide iC3F7ꢀ
I or aryl iodides afforded a small amount of benzylation (enꢀ
tries 7ꢀ11). The benzylation using ancillary nonꢀpolar solvents,
in addition to toluene (30 equiv), did not help in improving the
selectivity (see Table S2 in the Supporting Information). Surꢀ
prisingly, the reaction in the presence of a small amount of
chlorobenzene (10 equiv) as the solvent afforded 4aa in 82%
yield (Table 1, entry 12). We assume that the chlorobenzene
enhances the solubility of reaction components, hence favors
the reaction. The benzylation in the presence of mild bases,
such as Na2CO3, K2CO3, Cs2CO3 produces trace amount of
4aa (entries 13,14 and Table S1 in the Supporting Inforꢀ
mation). Other nickel precursors as catalyst were less efficient
for the benzylation and produced low to moderate yield of
4aa; however, in the absence of nickel catalyst benzylation
was not observed. The use of base LiOtBu and a relatively
higher reaction temperature of 150 oC for 20 h are essential for
the benzylation reaction to obtain good yield. Though the reacꢀ
tion condition seems severe, this challenging oxidative couꢀ
pling reaction in the presence of mild oxidant 2ꢀiodobutane
has significant advantage. Nonetheless, similar reaction condiꢀ
tions for the Niꢀcatalyzed C‒H functionalizations are necesꢀ
sary and have been well precedented.13
donating as well as electronꢀwithdrawing substituents reacted
smoothly to give the desired benzylation products 4aaꢀ4af.
The halide functionality in the toluene derivatives mostly reꢀ
mained unaffected, and the C(sp3)‒H bond selectively inꢀ
volved in the couplings. The ortho or meta substitutions on
toluene did not stage problem for the benzylation, and delivꢀ
ered the products 4agꢀ4an in moderate to excellent yields. The
substrate 1ꢀmethylnaphthalene reacted with low pace to give
4ao in 51% yield. We were pleased to show that the toluene
derivative containing a heterocycle indole moiety coupled
moderately to afford product 4ap. However, toluene derivaꢀ
tives bearing ester, aldehyde, nitrile or nitro functionality reꢀ
acted sluggishly to give traces of products. The substrates
bearing benzylic C‒H bond, such as ethyl benzene and isoproꢀ
pyl benzene did not couple with the indole derivatives under
the standard reaction conditions. Interestingly, in all the benꢀ
zylation reactions, the oxidative coupling between C(sp2)‒H in
indoles and C(sp2)‒H in toluene derivatives was not observed,
and the competitive alkylation with 2ꢀiodobutane was detected
only in trace amounts.
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Table 1. Optimization of the Reaction Conditions a
entry halide (equiv)
toluene base
(equiv)
4aa
(%)b
32
4aa’
(%)b
63
1
2ꢀiodobutane (2.0)
2ꢀiodobutane (2.0)
2ꢀiodobutane (2.0)
2ꢀiodobutane (1.5)
2ꢀiodobutane (1.0)
2ꢀiodobutane (1.5)
iC3H7I (1.5)
10
20
30
30
30
60
30
30
30
30
30
30
30
30
LiOtBu
2
LiOtBu
LiOtBu
LiOtBu 76 (70)
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
60
34
3
74 (69)
23
4
21
5
60
67
56
39
41
5
19
6
14
7
n.d.
n.d.
n.d.
n.d.
n.d.
10
8
CypꢀI (1.5)
9
1ꢀiodobutane (1.5)
iC3F7I (1.5)
10
11
12c
13
14
C6H5I (1.5)
27
2ꢀiodobutane (1.5)
2ꢀiodobutane (1.5)
2ꢀiodobutane (1.5)
LiOtBu 86 (82)
Na2CO3
Cs2CO3
5
2
5
6
Scope of the Benzylation of Indoles with Toluene Derivaꢀ
tives. With the optimized reaction conditions in hand, the benꢀ
zylation of various indoles was examined either in neat condiꢀ
tion (using 30 equiv of toluene derivatives) or employing 10
equiv of chlorobenzene in addition to toluene derivatives, and
the best results obtained were tabulated. As shown in Scheme
2, the toluene derivatives containing a variety of functional
groups were efficiently reacted with indole via oxidative
C(sp2)‒H/C(sp3)‒H coupling. Notably, selective C(2)‒H benꢀ
zylation was observed in all the cases, and the C(3)‒H bond
aReaction conditions: 2a (0.058 g, 0.3 mmol), halides and
toluene equivalents are w.r.t. 2a, cat 1 (0.0056 g, 0.015 mmol),
LiHMDS (0.010 g, 0.06 mmol), base (0.6 mmol), 150 oC, 20 h.
bGC yields using nꢀdodecane as internal standard. Values in
c
parentheses are isolated yields. Employing chlorobenzene (10
equiv, 0.304 mL) in addition to toluene. n.d. = not determined.
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ACS Catalysis
cle to afford the biologically relevant benzylated indoles. Noꢀ
Scheme 2. Ni(II)ꢀCatalyzed Cꢀ2 Benzylation of Indole with
Toluene Derivatives
1
2
tably, for all the substrates regioselective Cꢀ2 benzylation was
observed, and neither Cꢀ3 nor Cꢀ2/Cꢀ3 double benzylation
encountered, which is significant as the C(3)‒H can further be
functionalized.
3
4
5
6
7
8
Scheme 3. Ni(II)ꢀCatalyzed Cꢀ2 Benzylation of Substituted
Indoles
9
R3
R3
1
cat. (5 mol %)
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11
12
13
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LiHMDS (20 mol %)
R1
R1
H3C
+
H
2ꢀiodobutane
(1.5 equiv)
N
R2
N
R2
LiOtBu (2.0 equiv)
150 oC, 20 h
3
2
4
MeO
F
Me
N
N
N
2ꢀPy
2ꢀPy
4da
2ꢀPy
c
4ca
4ba
: 74%
: 77%
: 79%
Me
Br
N
N
N
2ꢀPy
2ꢀPym
2ꢀPy
a
b
4ea
4fa
: 65%
: 83%
4ga
: 61%
Br
Me
F
N
N
N
2ꢀPym
2ꢀPym
2ꢀPym
b,c
b
b
4ja
: 52%
4ha
: 82%
4ia
: 69%
b
aUsing 10 mol % of cat 1. Employing cat 1 (10 mol %) and
c
chlorobenzene (10 equiv). Compound isolated as a mixture with
b
aEmploying chlorobenzene (10 equiv). Employing cat 1 (10
starting precursor; hence yield was determined and verified by 1H
NMR.
c
mol %) and chlorobenzene (10 equiv). 8% arylation was obꢀ
d
served via C–Br coupling. Compound isolated as a mixture with
starting precursor; hence yield was determined and verified by 1H
NMR.
Mechanistic Aspects of NiꢀCatalyzed C(sp2)‒H/C(sp3)‒H
Oxidative Coupling of Indoles. To gain mechanistic insights,
various controlled experiments were performed (see the Supꢀ
porting Information for details). The benzylation was slightly
affected in the presence of mercury (500 equiv w.r.t cat 1),
which indicates the homogeneous character of nickel catalyst.
Kinetic analysis of the reaction using electronically distinct
indoles and toluene derivatives suggests that the electronicꢀ
factor has little influence on the benzylation (the reaction rates
are almost similar; Scheme 4). These findings dismiss the posꢀ
sibility of electrophilicꢀtype C‒H activation, either on the inꢀ
dole or on the toluene. The initial rates of the benzylation with
toluene and tolueneꢀd8 were determined, wherein the kinetic
isotope effect (KIE) value of 2.7 was obtained (Scheme 5a).
However, the KIE value for indoles 2a and [2ꢀD]ꢀ2a was
found to be 3.1 (Scheme 5b). This indicates that the C‒H bond
nickelation is significant with respect to the turnoverꢀlimiting
step.16 Additionally, H/D scrambling was not observed beꢀ
tween [2ꢀD]ꢀ2a and 2c upon performing the reaction in a sinꢀ
gle vessel (with or without catalyst; Scheme 5c). This reveals
the C‒H activation is irreversible, and does not proceed via a
simple deprotonative path.
Electronically distinct groups on the indole moiety, such as
ether and halides are also well tolerated (Scheme 3). The steriꢀ
cally hindered Cꢀ3 substituted indole 2f was benzylated with
good yield to deliver 4fa. Unfortunately, the indoles bearing
electronꢀwithdrawing groups, such as –CN, –CHO at the Cꢀ3
position did not undergo benzylation with toluene substrate.
Notably, the indoles bearing easily removable 2ꢀpyrimidinyl
group reacted smoothly with toluene to afford moderate to
good yields of the benzylated products 4gaꢀ4ja. However,
indoles containing –C(O)CH3, –C(O)tBu and –OSO2Ph at the
Nꢀcenter as the directing group were not reactive. This sugꢀ
gests that the nitrogen as chelate directing group is essential
for the benzylation reaction. In general, the nickelꢀcatalyzed
regioselective C–H functionalizations are well precedented,
with few exceptions,14 employing the bidentate chelationꢀ
assisted strategy.15 However, herein the benzylation reaction
smoothly proceeded via the monoꢀchelate assistance. This
nickelꢀcatalyzed protocol facilitates the coupling of C(sp3)‒H
bond of toluene derivatives in the presence of a mild oxidant,
and the reaction was tolerated by ether, halides and heterocyꢀ
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1
Scheme 4. Rates of Reactions with Electronically Distinct
Substrates
Upon monitoring the catalytic reaction mixture by the H
NMR in toluene/tolueneꢀd8 employing 25 mol % of the cataꢀ
lyst 1, neither the nickelꢀspecies nor the freeꢀligand were deꢀ
tected; which signals the paramagnetic behavior of active cataꢀ
lyst species. Notably, the benzylation was completely
quenched when the reaction was performed in the presence of
TEMPO or galvinoxyl, which suggests the involvement of a
radical intermediate. Looking at the reaction components, and
our previous findings;12 we assume that a benzyl radical could
be the actual benzylation species, which might evolve by the
radical transfer from the initially formed 2ꢀbutyl radical to
toluene. With this in mind, we observed that the reaction of 2ꢀ
iodobutane with toluene under catalytic conditions, but in the
absence of 2a, produced benzyl iodide and 1,2ꢀdiphenylethane
(PhCH2CH2Ph). Notably, in the absence of nickelꢀcatalyst
neither the benzyl iodide nor the 1,2ꢀdiphenylethane was
formed. These investigations reveal that the nickelꢀspecies is
essential for the generation of 2ꢀbutyl radical (unlike the baseꢀ
promoted radical formation of heptafluoroisopropyl iodide),7n
which is then involved in the production of benzyl radical.
Since, the benzyl iodide formation was not efficient under the
reaction condition, the contribution of benzyl iodide to the
benzylation of indole as the major species is unlikely.
1
2
3
4
5
6
7
8
a) rates of reactions with electronically distinct indoles:
MeO
MeO
H3C
+
H
N
N
(9.0 mmol)
2ꢀPy
4ca
2ꢀPy
cat. 1 (0.015 mmol)
LiHMDS (0.06 mmol)
2c:
(0.3 mmol)
or
or
2ꢀiodobutane (0.45 mmol)
LiOtBu (0.6 mmol)
F
150 o
C
9
H
F
N
10
11
12
13
14
15
16
17
18
19
20
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22
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46
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60
N
2ꢀPy
k
k
4ca = 5.043 x 10ꢀ4 M minꢀ1
4da = 3.866 x 10ꢀ4 M minꢀ1
2ꢀPy
4da
2d: (0.3 mmol)
b) rates of reactions with electronically distinct toluene derivatives:
4ꢀMeOꢀC6H4
H3C
OMe
3c
N
1
cat. (0.015 mmol)
4ac
2ꢀPy
LiHMDS (0.06 mmol)
2a
+
or
or
(0.3 mmol)
2ꢀiodobutane (0.45 mmol)
LiOtBu (0.6 mmol)
150 o
C
4ꢀFꢀC6H4
H3C
F
N
3d
2ꢀPy
4ad
k
k
4ac = 2.895 x 10ꢀ4 M minꢀ1
4ad = 2.371 x 10ꢀ4 M minꢀ1
Scheme 6. Plausible Mechanistic Pathway
O
2a, LiOtBu
LiN(SiMe3)2, HOtBu
LiN(SiMe3
)
2
N
1
Et2N
N
Scheme 5. Kinetic Isotope Effect (KIE) and H/D Scramꢀ
bling Experiments
Ni
LiN(SiMe3
)
2
N(SiMe3
)
2
O
A
Et2N
N
a) rate of reaction with toluene/tolueneꢀd8:
O
N
D
D
Ni
N
4aa'
cat. 1 (0.015 mmol)
LiHMDS (0.06 mmol)
N
toluene
or
D
D
N
H
+
4aa or
Et2N
N
Ni
2ꢀiodobutane
(0.45 mmol)
N
O
B
tolueneꢀd8
D
CD2
E
LiOtBu (0.6 mmol)
I
Et2N
2ꢀPy
N
CH3
N
150 o
C
I
2a
IV
I
N
2ꢀPy
4aa
[D7]ꢀ
Ni
N
4aa
k4aa/k[D7]ꢀ4aa = 2.7
C2H5
CH3
C2H5
CH3
N
CH2
C2H5
C2H5
O
b) rate of reaction for 2a and [2ꢀD]ꢀ2a:
O
N
F
toluene (9.0 mmol)
cat. 1 (0.015 mmol)
Et2N
Ph
LiHMDS (0.06 mmol)
D
H
I
Et2N
IV
N
N
I
N
2ꢀPy
N
2ꢀiodobutane (0.45 mmol)
Ni
or
N
N
LiOtBu (0.6 mmol), 150 o
C
III
Ni
Ph
N
2ꢀPy
2ꢀPy
N
4aa
N
[2ꢀD]ꢀ2a
2a
k2a/k[2ꢀD]ꢀ2a = 3.1
N
C
D
c) H/D scrambling experiment:
(> 95% D)
detected by
MALDIꢀTOFꢀMS
H2C Ph
H3C Ph
C2H5
> 95% D
+
H
Ph
H3C
H3C
C2H5
D
N
D
N
N
2ꢀPy
2ꢀPy
2ꢀPy
On the basis of our mechanistic findings and literature reꢀ
ports,7n,17 a plausible mechanism for the Niꢀcatalyzed benzylaꢀ
tion of indole is presented in Scheme 6. Reaction of 1 with
LiHMDS gives the active amido Ni(II) complex A. Coordinaꢀ
tion of indole 2a to A followed by the crucial C‒H nickelation
would produce species B. This complex would trigger the
generation of 2ꢀbutyl radical by the iodine atom transfer (IAT)
mechanism via a singleꢀelectronꢀtransfer (SET) process.12,17
Next, the butyl radical can have two competing reactions: first
the butyl radical can abstract a hydrogen from toluene to proꢀ
duce the benzyl radical (radical transfer),18 which is then reacts
with species C to afford Ni(IV) complex D. Reductive elimiꢀ
[2ꢀD]ꢀ2a
(0.097 mmol)
(recovered)
(0.10 mmol)
[2ꢀD]ꢀ2a
4aa: trace
cat. 1 (0.01 mmol)
LiHMDS (20 mol %)
+
+
0% D
2ꢀiodobutane (0.3 mmol)
LiOtBu (2 equiv)
MeO
MeO
Ph
MeO
toluene (0.64 mL)
150 oC, 60 min
H
H
+
N
N
N
2ꢀPy
2ꢀPy
2ꢀPy
(0.10 mmol)
2c
4ca: 7% (GC yield)
2c
(0.091 mmol)
(recovered)
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ACS Catalysis
nation of the benzylated product 4aa will deliver Ni(II) speꢀ
CONCLUSION
1
2
3
4
5
6
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cies E, which is then reacts with LiHMDS to complete the
cycle. The MALDIꢀTOFꢀMS analysis of a catalytic reaction
provided evidence for the existance of species D. In the seꢀ
cond case, the butyl radical can rebound with C to produce the
Ni(IV) species F, which leads to undesired alkylation 4aa’.
Alternately, the formation of 2ꢀbutyl radical can be presumed
from an oxidatively added species F. However, such a path
would lead to the major alkylation (4aa’) rather than the radiꢀ
cal creation; hence the production of butyl radical by this
mechanism is unlikely. Although our findings support a
Ni(II)/Ni(III) pathway, probability of a Ni(I)/Ni(III) catalytic
cycle cannot be ruled out at this stage.19
In summary, we have reported a unified strategy for the
C(sp2)‒H/C(sp3)‒H oxidative coupling of indoles with toluene
derivatives using the mild oxidant and a Ni(II)ꢀcatalyst. The
use of 2ꢀiodobutane as the oxidant is very crucial, which funcꢀ
tions as a benzyl radical originator by abstracting Hꢀatom from
the toluene derivatives. The wellꢀdefined, inexpensive nickel
catalyst proved efficient for the coupling of broad indole subꢀ
strates with diverse toluene derivatives. Mechanistic findings
demonstrate that the C‒H activation of indole is significant
with regards to the turnoverꢀlimiting step, and the benzylation
followed a singleꢀelectronꢀtransfer (SET) process. The synꢀ
thetic applicability of this Niꢀcatalyzed strategy is established
by the facile removal of directing groups and by synthesizing
the biologically active Luzindole derivatives.
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Removal of Directing Group and Synthesis of Luzindole
Derivatives. Considering the high synthetic value of free NꢀH
benzylated indoles, we have demonstrated the removal of 2ꢀ
pyridinyl and 2ꢀpyrimidinyl groups from the benzylated prodꢀ
ucts. Hence, the treatments of 4ac and 4ea with MeOTf and
NaOH (aq, 2.0 M) afforded the desired free NH indoles 5ac
and 5ea, respectively, in good yields (Scheme 7).20 Similarly,
the 2ꢀpyrimidinyl group was easily removed from 4ga by the
EXPERIMENTAL SECTION
General Experimental Considerations. All manipulations
were conducted under an argon atmosphere in the glove box
using preꢀdried glassware. The catalytic reactions were perꢀ
formed in flameꢀdried reaction vessels with Teflon screw caps.
Toluene was dried over Na/benzophenone and distilled under
argon. Liquid reagents were flushed with argon prior to use.
The nickel catalyst 1 was synthesized following the reported
protocol.12 Indole derivatives, 5ꢀsubstituted 1ꢀ(pyridinꢀ2ꢀyl)ꢀ
1Hꢀindole,21,23 1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole,24 1ꢀ(pyridinꢀ2ꢀ
o
reaction with EtONa at 110 C in DMSO affording the indole
5aa in 76% yield (Scheme 7).21 The compounds 5aa and 5ac
upon treatment with Nꢀ(2,2ꢀdimethoxyethyl)acetamide proꢀ
duced the melatonin receptor antagonist,22 Luzindole derivaꢀ
tives 6aa and 6ac, respectively, in good yields (Scheme 8).10c
yl)ꢀ1Hꢀindoleꢀ2ꢀd,20
compound
3p,25
and
Nꢀ(2,2ꢀ
dimethoxyethyl)acetamide26 were synthesized according to
previously described procedures. All other chemicals were
obtained from commercial sources and were used without
further purification. High resolution mass spectroscopy
(HRMS) mass spectra were recorded on a Thermo Scientific
QꢀExactive instrument with Accela 1250 pump. Melting
points: Büchi 540 capillary melting point apparatus; values are
uncorrected. MALDIꢀTOFꢀMS analysis was performed using
AB SCIEX TOF/TOF 5800 system. NMR (1H and 13C) spectra
were recorded at 400 or 500 (1H), 100 or 125 {13C, DEPT (disꢀ
tortionless enhancement by polarization transfer)}, 377 (19F)
on Bruker AV 400 and AV 500 spectrometers in CDCl3 soluꢀ
tions, if not otherwise specified; chemical shifts (δ) are given
in ppm. The 1H and 13C NMR spectra are referenced to residuꢀ
al solvent signals (CDCl3: δ(H) 7.26 ppm, δ(C) 77.2 ppm).
Scheme 7. Removal of Directing Group
GC Method. Gas Chromatography analyses were performed
using a Shimadzu GCꢀ2010 gas chromatograph equipped with
a Shimadzu AOCꢀ20s autosampler and a Restek RTXꢀ5 capilꢀ
lary column (30 m x 250 ꢁm). The instrument was set to an
injection volume of 1.0 ꢁL, an inlet split ratio of 10:1, and
inlet and detector temperatures of 250 and 320 °C, respectiveꢀ
ly. UHPꢀgrade argon was used as carrier gas with a flow rate
of 30 mL/min. The temperature program used for all the analꢀ
yses is as follows: 80 °C, 1 min; 30 °C/min to 200 °C, 2 min;
30 °C/min to 260 °C, 3 min; 30 °C/min to 300 °C, 3 min.
Scheme 8. Synthesis of Luzindole Derivatives
Response factors for all the necessary compounds, with reꢀ
spect to standard nꢀdodecane or nꢀhexadecane, were calculated
from the average of three independent GC runs.
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ACS Catalysis
Page 6 of 8
Representative Procedure for the Benzylation of Indoles:
Notes
1
2
3
4
5
6
7
8
The authors declare no competing financial interests.
Synthesis of 2ꢀBenzylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1Hꢀindole (4aa).
Procedure A. To a flame dried screwꢀcap tube (5 mL)
equipped with magnetic stir bar was introduced 1ꢀpyridineꢀ2ꢀ
ylꢀ1Hꢀindole (2a; 0.058 g, 0.3 mmol), 2ꢀiodobutane (0.083 g,
0.45 mmol), cat 1 (0.0056 g, 0.015 mmol, 5.0 mol %),
LiHMDS (0.010 g, 0.06 mmol, 20 mol %), LiOtBu (0.048 g,
0.6 mmol) and toluene (3a; 0.96 mL, 9.0 mmol) inside the
gloveꢀbox. The resultant reaction mixture was stirred at 150
°C in a preheated oil bath for 20 h. At ambient temperature,
the reaction mixture was quenched with distilled H2O (10 mL)
and then neutralized with 2N HCl (0.5 mL). The crude product
was then extracted with CH2Cl2 (20 mL x 3). The combined
organic extract was dried over Na2SO4 and the volatiles were
evaporated in vacuo. The remaining residue was purified by
column chromatography on neutral alumina (petroleum
ether/EtOAc/Et3N: 20/1/0.5) to yield 4aa (0.060 g, 70%) as a
light yellow liquid.
ACKNOWLEDGMENTS
This work was financially supported by SERB, New Delhi, India
(SR/S1/ICꢀ42/2012). We are thankful to the Alexander von Humꢀ
boldt Foundation, Germany for an equipment grant. V.S. and
S.M.K. thank CSIRꢀNew Delhi for research fellowships.
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equiv) was added in addition to the toluene (0.96 mL, 9.0
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Representative Procedure for Kinetic Experiment: Reacꢀ
tion Rate for the Formation of 4ca. To the Teflonꢀscrew cap
tube equipped with magnetic stir bar was introduced cat 1
(0.0056 g, 0.015 mmol, 0.015 M), LiHMDS (0.010 g, 0.06
mmol), LiOtBu (0.048 g, 0.6 mmol), substrate 2c (0.067 g, 0.3
mmol, 0.3 M), 2ꢀiodobutane (0.083 g, 0.45 mmol, 0.45 M) and
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volume 1.0 mL. The reaction mixture was then stirred at 150
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120 min) the reaction vessel was cooled to ambient temperaꢀ
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vial. The sample was diluted with acetone and subjected to GC
analysis. The concentration of the product 4ca obtained in
each sample was determined with respect to the internal standꢀ
ard nꢀhexadecane. The data of the concentration of the product
vs time (min) plot was drawn (Figure S1) and fitted linear with
Origin Pro 8, and the rate was determined by the initial rate
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publication website at DOI: 10.1021.acscatal.xxxxxx
Experimental details and spectroscopic data.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for B.P.: b.punji@ncl.res.in.
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NickelꢀCatalyzed C(sp2)‒H/C(sp3)‒H Oxidative Coupling of Indoles
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