Mild and efficient C2-alkenylation of indoles with alkynes catalyzed by a cobalt complex

Article abstract of DOI:10.1002/anie.201200019

Direct alkenylation of the C2-position of indoles bearing an easily removable N-pyrimidyl group with alkynes has been achieved by using a cobalt catalyst complexed with a phosphine-pyridine bidentate ligand. This reaction has wide substrate scope and is highly efficient and stereoselective at room temperature. The alkenylated indoles serve as useful platforms for further synthetic transformations (some products of these transformations are shown in the scheme). Copyright

Full text of DOI:10.1002/anie.201200019

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Angewandte
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DOI: 10.1002/anie.201200019
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C H Bond Functionalization
Mild and Efficient C2-Alkenylation of Indoles with Alkynes Catalyzed
by a Cobalt Complex**
Zhenhua Ding and Naohiko Yoshikai*
Indole represents a privileged core structural motif that
occurs in biologically active natural and unnatural products.[1]
Consequently, direct functionalization of the indole nucleus
has long attracted interest of synthetic chemists.[2] While the
C3-position of indole is the inherently reactive site for
Table 1: Screening of reaction conditions.[a]
Friedel–Crafts-type chemistry,[3] the recent emergence of
[4]
À
transition-metal-catalyzed C H bond functionalization has
Entry
Ligand (mol%)
Yield [%][b]
not only expanded the scope of C3-functionalization but also
has opened the door to a variety of methods for C2-
functionalization. Nevertheless, compared with arylation,[5,6]
catalysts that allow alkenylation of the C2-position are still
limited despite the potential utility of such products.[7,8] While
disubstituted and trisubstituted olefin products have been
accessed by oxidative Heck olefination[9] and hydroarylation
of internal alkynes,[10] respectively, there remain significant
limitations that warrant further catalyst development, partic-
ularly for the latter type of reaction. For example, the nickel
catalysis of Nakao, Hiyama et al. needs an electron-with-
drawing substituent at the C3-position,[10a,b] while the rhodium
catalysis of Schipper, Hutchinson, and Fagnou does not allow
the use of dialkylacetylenes.[10c] We report herein efficient C2-
alkenylation of indoles bearing an easily removable N-
pyrimidyl group[11] under room-temperature conditions with
a versatile cobalt catalyst. The alkenylated indoles serve as
useful platforms for further synthetic manipulations, such as
1
2
3
4
5
6
7
8
PMePh2 (20)
PCy3 (10)
IMes·HCl (10)
DPEphos (10)
Xantphos (10)
1,10-phenanthroline (10)
P(3-ClC6H4)3 (20)
P(3-ClC6H4)3 (20) + pyridine (80)
pyphos (10)
3
8
5
4
13
1
55, 24[c]
66[c]
9
97,[c] 96[d]
2
10
dppp (10)
pyphos (5)
11[e]
93[d]
[a] Reaction was performed on a 0.3 mmol scale. [b] Determined by GC
using n-tridecane as an internal standard. [c] Yield obtained at the
reaction time of 2 h. [d] Isolated yield. [e] Performed on a 5 mmol scale
using 1.2 equiv of 2a and 5 mol% of the catalyst. Cy=cyclohexyl.
À
cycloaddition, Friedel–Crafts condensation, and direct C H
functionalization reactions.
With the recent success of cobalt catalysis[12] for aromatic
product 3aa in a moderate yield of 55% but with rather poor
mass balance (> 90% conversion of 1a) because of formation
of unidentified by-products (Table 1, entry 7).[16] As we
reported recently for alkenylation of an aromatic imine,[14f]
the use of pyridine (80 mol%) as a coligand accelerated the
reaction and modestly improved the product yield (66% with
2 h reaction) yet with unsatisfactory mass balance (Table 1,
entry 8). This acceleration effect eventually prompted us to
find that a phosphine-pyridine bidentate ligand, 2-(diphenyl-
phosphinoethyl)pyridine (pyphos),[17] effected very clean
conversion of the starting materials within two hours,[16]
affording 3aa in 97% yield with exclusive (> 50:1) E ster-
eochemistry (Table 1, entry 9). Note that the amount of the
Grignard reagent (60 mol%) was critical to the catalytic
activity, as the reduction of the amount of Grignard reagent
led to a significant drop in the product yield (50 mol%, 20%;
40 mol%, 4%; 30 mol%, 1% for 12 h reaction).[18] 1,3-
Bis(diphenylphosphino)propane (dppp), a bidentate phos-
phine that has a bite angle similar to that of the pyphos ligand,
was far less effective (Table 1, entry 10). The reaction could
be performed on a 5 mmol scale by using 1.2 equiv of 2a and
5 mol% of the catalyst without significant decrease in the
product yield (Table 1, entry 11).
À
and heteroaromatic C H bond functionalization demon-
strated by us[13,14] and others,[15] we commenced our study
with the reaction of N-pyrimidylindole 1a (0.3 mmol) and 4-
octyne 2a (1.5 equiv) in the presence of CoBr2 (10 mol%),
ligand (10–20 mol%), and neopentylmagnesium bromide
(60 mol%) at 208C for 12 h (Table 1). Most of the phosphine,
N-heterocyclic carbene, and nitrogen ligands that we pre-
viously employed for the cobalt catalysis poorly promoted the
reaction (Table 1, entries 1–6), except that the use of tris(3-
chlorophenyl)phosphine[14f] afforded the desired alkenylation
[*] Z. Ding, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371, Singapore
E-mail: nyoshikai@ntu.edu.sg
Homepage: http://www3.ntu.edu.sg/home/nyoshikai/yoshi-
kai_group/Home.html
[**] We thank Singapore National Research Foundation (NRF-RF2009-
05), Nanyang Technological University, and JST, CREST for financial
support, and Dr. Yongxin Li (Nanyang Technological University) for
assistance in X-ray crystallographic analysis.
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With the effective catalytic system in hand, we moved on
to exploration of the scope of the alkenylation reaction. First,
addition of 1a to various alkynes was examined (Table 2). The
present reaction tolerated a variety of alkynes including
Table 2: Addition of indole 1a to various alkynes.[a]
Entry
R1
R2
3
Yield [%][b]
r.r.[c]
1
2
3
4
5
6
7
8
nPr
CH2SiMe3
iPr
tBu
Ph
4-MeOC6H4
4-ClC6H4
Ph
nPr
CH2SiMe3
Me
nBu
Me
Me
Me
Et
c-C3H5
Et
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
96 (93)
88
88
57
91
89
40
92
93
88
96 (92)
81
91
79
–
–
8:1
>50:1
12:1
19:1
13:1
1.6:1
1.4:1
2.5:1
–
>50:1
>50:1
>50:1
>50:1[d]
9
Ph
10
11
12
13
14
15
2,6-Me2C6H3
Ph
SiMe3
SiMe3
SiMe3
SiMe3
Me
nBu
Ph
4-CNC6H4
62
[a] Reaction was performed on a 0.3 mmol scale. [b] Yield of isolated
product. In parentheses the yield of isolated product is shown for
a 5 mmol scale reaction using 1.2 equiv of the alkyne and 5 mol% of the
catalyst. [c] Regioisomeric ratio determined by 1H NMR spectroscopy.
[d] E/Z ratio was 4:1.
Scheme 1. Addition of various indoles to 2a. Reaction was performed
on a 0.3 mmol scale, and yields of isolated products are shown. [a]
NR2 =morpholino. Reaction time was 40 h. [b] Reaction was performed
using 100 mol% of tBuCH2MgBr.
dialkyl alkynes (Table 2, entries 1–4), aryl alkyl alkynes
(entries 5–10), diphenylacetylene (entry 11), and silyl-substi-
tuted alkynes (entries 12–15), and afforded the corresponding
alkenylation products in good to excellent yields with
exclusive E stereochemistry. As was the case with 4-octyne,
the reaction of diphenylacetylene was also easily scaled up to
5 mmol scale without problem (Table 2, entry 11). High levels
of regioselectivity (8:1 to > 50:1) were achieved for alkynes
such as 4-methylpent-2-yne, 2,2-dimethyloct-3-yne, 1-aryl-1-
propynes, and silyl-substituted alkynes (Table 2, entries 3–7
in good to excellent yields. Both electron-withdrawing and
-donating substituents, including fluoro (3ba and 3ga), chloro
(3ca and 3ha), methoxy (3da and 3la), cyano (3ea and 3ia),
tertiary amide (3 fa), and alkyl (3ja and 3ka) groups could be
tolerated. Alkyl substituents at the 3- and 7-positions did not
cause any steric inhibition, and the alkenylated products 3ja
and 3ka were afforded in 92 and 81% yields, respectively. N-
Pyrimidyl benzimidazole also participated in the reaction
with an increased loading of the Grignard reagent
(100 mol%) to afford the alkenylated product 3ma in 82%
yield.
Removal of the pyrimidyl group on the alkenylation
product was easily achieved by treatment with NaOEt in
dimethylsulfoxide (DMSO) at 1008C,[11] with the stereochem-
istry of the olefin moiety untouched. Thus, the 4-octyne and
diphenylacetylene adducts 3aa and 3ak were converted to
their free indole derivatives 4aa and 4ak in 87 and 93%
yields, respectively (Scheme 2a), which served as useful
starting materials for further synthetic transformations.
First, Diels–Alder reaction of 4aa and 4ak with N-phenyl-
maleimide took place smoothly in the presence of a catalytic
amount of BF3·OEt2, and the following oxidation using DDQ
À
and 12–15), where the C C bond formation took place at the
less hindered acetylenic carbon atom. However, the sensitiv-
ity of the catalyst toward steric change became apparent when
the methyl group of 1-phenyl-1-propyne was replaced by an
ethyl or a cyclopropyl group (Table 2, entries 8 and 9). Thus,
such alkynes exhibited only modest regioselectivity (ca.
1.5:1). The regioselectivity was improved to 2.5:1 by intro-
ducing a bulky aryl group (Table 2, entry 10). It is notable that
the regioselectivity for 1-aryl-2-trimethylsilylacetylene
(Table 2, entries 14 and 15) was the opposite of that observed
for the rhodium(III)-catalyzed reaction of N-carbamoyl
indole.[10c,19]
Next, we explored the reaction of various indole deriva-
tives with 4-octyne 2a (Scheme 1). N-pyrimidyl indoles
substituted at the 3–7-positions all participated smoothly in
the reaction to afford the corresponding alkenylated products
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functionalization and their applications to the design of new
catalytic systems are currently underway.
Received: January 2, 2012
Revised: March 1, 2012
Published online: April 3, 2012
À
Keywords: alkyne · C H activation · cobalt · hydroarylation ·
indoles
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[19] The regio- and stereochemistry of 3an was confirmed by X-ray
crystallographic analysis (see the Supporting Information).
CCDC 859819 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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