C2-Alkylation of N-pyrimidylindole with vinylsilane via cobalt-catalyzed C-H bond activation

Article abstract of DOI:10.3762/bjoc.8.174

Direct C2-alkylation of an indole bearing a readily removable N-pyrimidyl group with a vinylsilane was achieved by using a cobalt catalyst generated in situ from CoBr₂, bathocuproine, and cyclohexylmagnesium bromide. The reaction allows coupling between a series of N-pyrimidylindoles and vinylsilanes at a mild reaction temperature of 60 °C, affording the corresponding alkylated indoles in moderate to good yields.

Full text of DOI:10.3762/bjoc.8.174

C2-Alkylation of N-pyrimidylindole with vinylsilane
via cobalt-catalyzed C–H bond activation
Zhenhua Ding and Naohiko Yoshikai*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1536–1542.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
doi:10.3762/bjoc.8.174
Received: 13 June 2012
Accepted: 11 July 2012
Email:
Published: 14 September 2012
Naohiko Yoshikai* - nyoshikai@ntu.edu.sg
This article is part of the Thematic Series "C–H Functionalization".
Guest Editor: H. M. L. Davies
* Corresponding author
Keywords:
alkylation; C–H functionalization; cobalt; indole; vinylsilane
© 2012 Ding and Yoshikai; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Direct C2-alkylation of an indole bearing a readily removable N-pyrimidyl group with a vinylsilane was achieved by using a cobalt
catalyst generated in situ from CoBr2, bathocuproine, and cyclohexylmagnesium bromide. The reaction allows coupling between a
series of N-pyrimidylindoles and vinylsilanes at a mild reaction temperature of 60 °C, affording the corresponding alkylated indoles
in moderate to good yields.
Introduction
The indole ring ubiquitously occurs in biologically active base or indol-2-yl radicals generated from 2-halogenated
natural and unnatural compounds [1-3]. Consequently, there has indoles [12-17]. Examples of direct C2-alkylation via transition-
been a strong demand for catalytic methods allowing efficient metal-catalyzed C–H activation are still limited [18-20], while
and regioselective functionalization of indole derivatives [4-6]. Jiao and Bach recently reported an elegant palladium-catalyzed,
Over the past decade, transition-metal-catalyzed direct function- norbornene-mediated C2-alkylation reaction with a broad spec-
alization has emerged as a powerful strategy for the direct intro- trum of alkyl bromides [21].
duction of aryl and alkenyl groups to the C2 and C3 positions of
indole [7-9]. The situation is different when it comes to direct Over the past few years, our group and others have explored
C–H alkylation [10,11]. The intrinsically nucleophilic C3 posi- C–H bond functionalization reactions using cobalt complexes as
tion of indole is amenable to a variety of catalytic alkylation inexpensive transition-metal catalysts [22], which often feature
reactions such as Friedel–Crafts reaction [5]. On the other hand, mild reaction conditions and unique regioselectivities [23-32].
C2-alkylation of indoles has traditionally required 2-lithio- As a part of this research program, we have recently reported a
indoles generated by C2-lithiation with a stoichiometric lithium C2-alkenylation reaction of N-pyrimidylindoles with internal
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Beilstein J. Org. Chem. 2012, 8, 1536–1542.
Scheme 1: (a) Cobalt-catalyzed C2-alkenylation of N-pyrimidylindole, (b) ortho-alkylation of aryl imine, and (c) C2-alkylation of N-pyrimidylindole.
alkynes catalyzed by a cobalt–pyridylphosphine complex Additional screening of N-heterocyclic carbene (NHC) and
(Scheme 1a) [33], in which the pyrimidyl group functions as a phosphine ligands did not lead to an improvement of the
readily removable directing group [34]. We also reported an catalytic efficiency (Table 1, entries 7–9). The reaction turned
ortho-alkylation reaction of aromatic imines with vinylsilanes out to be sensitive to the amount of the Grignard reagent, as
and simple olefins using a cobalt–phenanthroline catalyst reduction of its loading from 100 to 60 mol % improved the
(Scheme 1b) [35]. Building on these studies, we have devel- yield of 3aa while suppressing the formation of byproduct 4
oped a cobalt–bathocuproine catalyst for the direct C2-alkyl- (Table 1, entry 10).
ation reaction of N-pyrimidylindoles with vinylsilanes, which is
reported herein (Scheme 1c).
Next, we performed screening of Grignard reagents using
bathocuproine as the ligand (Table 2). Among Grignard
reagents without β-hydrogen atoms, neopentyl- and phenylmag-
Results and Discussion
Our study commenced with the optimization of the reaction of nesium bromides afforded 3aa in comparable yields (Table 2,
N-pyrimidylindole 1a with vinyltrimethylsilane (2a). The entries 1 and 4), while trimethylsilylmethyl- and methylmagne-
combination of CoBr2 (10 mol %), 1,10-phenanthroline (phen, sium chlorides gave much poorer results (Table 2, entries 2 and
10 mol %) and neopentylmagnesium bromide (100 mol %), 3). Primary and secondary alkyl Grignard reagents also
which was effective for ortho-alkylation of aromatic imines promoted the reaction, in which the reaction efficiency was
[35], afforded the desired adduct 3aa in only 17% yield accom- strongly dependent on the alkyl group (Table 2, entries 5–10).
panied by a small amount of a C2-neopentylated product 4 We identified cyclohexylmagnesium bromide as the optimum
(Table 1, entry 1). Subsequent examination of phenanthroline Grignard reagent, which afforded 3aa in 69% isolated yield
and bipyridine-type ligands (Table 1, entries 2–5) revealed that without formation of the cross-coupling product 4 between 1a
2,9-dimethyl-1,10-phenanthroline (neocuproine) and 2,9- and the Grignard reagent.
dimethyl-4,7-diphenylphenanthroline (bathocuproine)
improved the yield of 3aa, while the byproduct 4 could not be With the optimized catalytic system in hand, we explored the
suppressed (Table 1, entries 3 and 4). The P,N-bidentate ligand scope of the reaction (Scheme 2). A variety of N-pyrimidylin-
pyphos, which was the optimum ligand for the alkenylation doles participated in the reaction with vinyltrimethylsilane to
reaction [33], was poorly effective (Table 1, entry 6). afford the alkylation products 3ba–3ia in moderate yields, with
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Beilstein J. Org. Chem. 2012, 8, 1536–1542.
Table 1: Screening of ligands.a
entry
ligand (mol %)
yield (%)b
3aa
4
1
phen (10)
17
11
32
34
1
7
2
bathophen (10)
neocup (10)
bathocup (10)
dtbpy (10)
7
3
12
20
3
4
5
6
pyphos (10)
IMes·HCl (10)
PPh3 (20)
2
3
7
4
2
8
9
5
9
P(3-ClC6H4)3 (20)
bathocup
23
50
11
10
10c
aReaction was performed on a 0.3 mmol scale. bDetermined by GC using n-tridecane as an internal standard. c60 mol % of t-BuCH2MgBr was used.
Table 2: Screening of Grignard reagents.a
entry
RMgX
yield (%)b
3aa
4
1
2
3
4
5
t-BuCH2MgBr
Me3SiCH2MgCl
MeMgCl
50
26
14
46
28
10
5
4
PhMgBr
5
EtMgBr
3
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Beilstein J. Org. Chem. 2012, 8, 1536–1542.
Table 2: Screening of Grignard reagents.a (continued)
6
BuMgBr
45
0
3
0
0
0
7
i-PrMgBr
49
8
c-C3H5MgBr
c-C5H9MgBr
c-C6H11MgBr
13
9
46
10
67 (69)c
aReaction was performed on a 0.3 mmol scale. bDetermined by GC using n-tridecane as an internal standard. cIsolated yield.
Scheme 2: Addition of N-pyrimidylindoles to vinylsilanes.
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Beilstein J. Org. Chem. 2012, 8, 1536–1542.
Scheme 3: Addition of N-pyrimidylindole to norbornene (a) and 1-octene (b).
tolerance of electron-withdrawing (F and Cl) and electron- with norbornene (2d) afforded the alkylation product 3ad in
donating (OMe) substituents and steric hindrance at the C3 and 30% yield (Scheme 3a). The reaction of 1-octene (2e) was even
C7 positions. Unlike the cobalt-catalyzed C2-alkenylation reac- more sluggish, affording the alkylation product 3ae in only 9%
tion (Scheme 1a) [33], the reaction did not tolerate a cyano yield (Scheme 3b). Styrene also reacted rather sluggishly to
group on the indole substrate. In addition, N-pyrimidyl benzimi- afford only a small amount of the alkylation product (3% as
dazole did not participate in the present alkylation reaction, estimated by GC and GCMS), the regiochemistry (branched
although it was a good substrate for the C2-alkenylation reac- versus linear) of which has yet to be determined. An acrylate
tion. A pyridyl group served as an alternative directing group to ester was not tolerable as an olefinic reaction partner because of
the pyrimidyl group, affording the alkylation product 3ka in the presence of excess Grignard reagent.
80% yield. On the other hand, an N,N-dimethylcarbamoyl
group, which was previously used as a directing group for The present alkylation reaction could be performed on a prepar-
rhodium-catalyzed C2-alkenylation [36], was entirely ineffec- atively useful scale. Thus, alkylation of 1a with vinyltrimethyl-
tive. Vinylsilanes bearing dimethylphenylsilyl and triphenyl- silane (2a) on a 5 mmol scale afforded the adduct 3aa in 68%
silyl groups were amenable to the addition reaction with 1a, yield (Scheme 4). Furthermore, the pyrimidyl group on 3aa
affording the adduct 3ab and 3ac in modest yields. Vinyltri- could be readily removed by heating with NaOEt in DMSO,
ethoxysilane also reacted with 1a in 20% yield, although the affording the free indole 4aa in 85% yield.
product could not be separated in a pure form.
Conclusion
Unfortunately, the present catalytic system was not very effec- In summary, we have developed a cobalt–bathocuproine cata-
tive for C2-alkylation with simple olefins. The reaction of 1a lyst for C2-alkylation of N-pyrimidyl indoles with vinylsilanes.
Scheme 4: Gram-scale reaction and deprotection of N-pyrimidyl group.
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(1a) (58.6 mg, 0.3 mmol), CoBr2 (6.6 mg, 0.03 mmol), and
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reaction mixture was stirred at 60 °C for 12 h, and then
quenched with saturated aqueous solution of NH4Cl (1.5 mL).
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