Palladium(II)/polyoxometalate-catalyzed direct C-3 alkenylation of indoles using dioxygen as the terminal oxidant

Article abstract of DOI:10.1002/adsc.201201114

An efficient and practical synthetic method has been developed for the preparation of 3-vinylindoles by the direct C-H olefination of indoles with alkenes. The transformation is catalyzed by palladium acetate combined with 12-molybdophosphoric acid and us

Full text of DOI:10.1002/adsc.201201114

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DOI: 10.1002/adsc.201201114
Palladium(II)/Polyoxometalate-Catalyzed Direct C-3
Alkenylation of Indoles using Dioxygen as the Terminal
Oxidant
Qiufeng Huang,a,b,* Qianqian Song,a Jin Cai,a Xiaofeng Zhang,a and Shen Lina,b,*
a
College of Chemistry & Chemical Engineering, Fujian Normal Univeristy, Fuzhou 350007, Peopleꢀs Republic of China
Fax : (+86)-591-2286-7399; e-mail: qiufenghuang@fjnu.edu.cn or shenlin@fjnu.edu.cn
Fujian Key Laboratory of Polymer Materials, Fuzhou 350007, Fujian, Peopleꢀs Republic of China
b
Received: December 20, 2012; Revised: April 21, 2013; Published online: May 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201114.
Abstract: An efficient and practical synthetic
pounds is of considerable importance in organic syn-
thesis.[5] Metal-catalyzed direct C H olefination is
À
method has been developed for the preparation of
À
3-vinylindoles by the direct C H olefination of in-
a very appealing strategy for the functionalization of
indoles and in pioneering work Gaunt and co-work-
ers[6] have recently described a novel Pd-catalyzed al-
kenylation of indole that allows for selective reaction
at the C-2 or C-3 indole position. In related Pd-cata-
lyzed alkenylation reactions, Ricci et al.[7] reported
a selective reaction of indole at C-2 assisted by a non-
removable N-2-pyridylmethyl group, and Carretero
et al.[8] presented a selective reaction of indole at C-2
assisted by a removable N-(2-pyridyl)sulfonyl protect-
ing group. In addition, Miura et al.[9] reported the Pd-
doles with alkenes. The transformation is catalyzed
by palladium acetate combined with 12-molybdo-
phosphoric acid and uses oxygen as the terminal ox-
idant. 4-Dimethylaminopyridine (DMAP) was ob-
served to be an effective additive for the olefination
reaction. Functional groups such as methoxy,
benzylACHTUNGTRENNUNGoxy, fluoro, bromo, ester, phenyl, and methyl
were tolerated under the reaction conditions.
Keywords: Fujiwara–Moritani reaction; indoles;
palladium; polyoxometalates
À
catalyzed C H alkenylation/decarboxylation of
indole-3-carboxylic acids and Djakovitch et al.[10] de-
scribed
alkenylation of free NH-indole with acrylate. Each of
these procedures required the use of a large excess of
(OAc)2 or t-BuOOBz. These pro-
a heterobimetallic [Pd/Cu]-catalyzed C-3
AHCTUNGTRENNUNG
À
The palladium-catalyzed direct C H olefination (Fuji- oxidant such as Cu
A
wara–Moritani reaction) has received great attention cedures not only could be a problem for applications
in recent years and has emerged as viable alternative on a large scale but also decrease the “green” aspect
to traditional synthetic methods in organic chemis- of the transformation. Herein, we report a highly effi-
try.[1] By eliminating the requirement for prefunction- cient Pd(II)/polyoxometalate-catalyzed C-3 alkenyla-
alized substrates such as alkyl/aryl halides, Fujiwara– tion of indole under mild condition using O2 as the
Moritani reactions offer the prospect of broader sub- terminal oxidant.
strate scope and improved atom-economy. However,
Transition metal oxygen anion clusters (polyoxo-
the majority of palladium-mediated Fujiwara–Morita- metalates or POMs) are generally electron acceptors
ni reactions still require stoichiometric or super-stoi- and can exhibit a wide variety of redox reactions.[11]
chiometric amounts of a terminal oxidant such as cop- Changes in a POMs oxidation state are rarely accom-
per(II) salts,[2] silver(I) salts[3] or benzoquinone.[4] panied by changes in the overall structure of the clus-
These oxidants add expense to the reaction and gen- ter. Importantly, these systems can act as relay species
erate an additional waste stream which may offset the in oxidation reactions in which O2 serves as the termi-
benefits of using a less-functionalized substrate. To nal oxidant. For example, in Pd(II)/Pd(0) catalysis
circumvent these issues, the current trend is to use system, Pd(0) can be oxidized by [POMs]ox to gener-
ecologically benign oxidants such as molecular ate Pd(II)II and [POMs]red. In a subsequent step the
oxygen to provide a sustainable catalytic process.
The indole nucleus is found in a large number of
biologically active natural and unnatural compounds.
Consequently, the synthesis of indole-containing com-
[POMs]red is reoxidized by O2 to [POMs]ox [Eq. (1)].
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Palladium(II)/Polyoxometalate-Catalyzed Direct C-3 Alkenylation of Indoles using Dioxygen
[a]
À
Table 1. Screens for direct C H olefination of indole 1a with n-butyl acrylate 2a.
[a]
Conditions: 1a (0.4 mmol) was allowed to react with 2a (0.8 mmol) in the presence of Pd catalyst
(10 mol%) combined with POMs·nH2O (cat. 5 mol%) and additive (20 mol%) in solvent (1 mL) under
O2 (5 atm) at 808C for 24 h, Hacac=acetylacetone, DMAP=4-dimethylaminopyridine.
GC yields based on 1a used. The number in parentheses shows the isolated yield.
1.2 mmol of 2a.
[b]
[c]
[d]
The reaction was performed with POMs (2.0 mol%) and additive (10 mol%).
Thus, the catalytic use of polyoxometalates along with chose indole 1a and n-butyl acrylate 2a as model sub-
molecular oxygen is an important branch of research. strates to optimize the reaction conditions. Selected
The best-known example of a Pd(II)/POMs/O2-cata- results from these initial studies are summarized in
lyzed reaction is the Wacker-type oxidation of ethyl- Table 1. First, a variety of palladium catalysts was as-
ene to acetaldehyde, which is also applicable to other sayed. The results indicated that Pd
ACHTUNGTRENNUNG
olefins.[12] Recently, Ishii and Obora developed the rior to PdCl2, PdCl
G
oxidative coupling of benzene with a,b-unsaturated tries 1–4). We next evaluated the efficiency of the re-
aldehydes,[13] acrylates,[14] ethylene[15] and acryloni- action with respect to the type of POMs added (en-
trile[16] by the Pd(II)/HPMo11V/O2 system under tries 4–7) and noted best results when H3PMo12O40
À
acidic conditions and Obora has reported C H olefi- was used (28% yield, entry 4). The employment of
nation of aminobenzenes catalyzed by the Pd(II)/ H4PMo11VO40 and H3PW12O40 brought about a slight
HPMo11V/O2 system.[17]
decrease of coupling products 3a (entries 5 and 7),
To investigate the use of POMs/O2 as an oxidant and (NH4)5H4PMo6V6O40, which is partly replaced
for the Pd(II)-catalyzed C-3 alkenylation of indole we with an ammonium cation of the acidic complex, did
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Qiufeng Huang et al.
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not catalyzed the coupling reaction at all (entry 6). reactions of methyl methacrylates, there are two pos-
Not surprisingly, the reaction also failed when POMs sible pathways for b-hydride elimination, one leading
were excluded from the reaction mixture. We also to a 1,1-disubstituted olefin, and the other leading to
noted that additives played a crucial role in the reac- the trisubstituted olefin [Eq. (2)].[19] The reactions of
tion. Omitting Hacac from the reaction mixture re-
sulted in a lower yield (13%, entry 14), N-acetylgly-
cine showed no benefit over Hacac, and Boc-Leu-OH
seemed to inhibit the reaction all together. However,
we were delighted to find that pyridine increased the
product yield substantially, and DMAP was even
more effective at promoting the reaction.[18] In the
presence of DMAP the coupling of 1a with 2a afford-
ed 3a in 54% yield (entry 13). Increasing the amount
of 2a (3 equiv.) relative to 1a resulted in an increase
in the yield of 3a (84%) (entry 15). When the amount
of H3PMo12O40 and DMAP were reduced to 2 mol% indole and 2-methylindole with methyl methacrylate
and 10 mol%, respectively, the yield of 3a was still afforded a mixture of olefinated products in high
high (85%) (entry 16). Among the solvents examined yield. However, when N-methylindole was employed,
in this reaction, DMSO was found to be critical for a moderate yield (59%) of the trisubstituted olefin
the formation of 3a (entries 16 and 18), while the re- was formed selectively; only trace amounts of the dis-
action in DMF, 1,4-dioxane, or HOAc under these re- ubstituted olefin product were observed in the reac-
action conditions afforded 3a in low yields (entries 17, tion mixture. Unfortunately, almost no desired prod-
19–21). When taken together, these results indicated uct was obtained when an internal alkene (methyl cin-
the following as optimal reaction conditions: 1a namate) was employed under the reaction conditions.
(1 equiv.), 2a (3 equiv.), Pd
G
It is thought that the present alkenylation proceeds
H3PMo12O40 (2 mol%), DMAP (10 mol%) in DMF/ via a similar reaction mechanism involving the elec-
DMSO (10%) at 808C.
trophilic attack of a Pd(II) species to indole proposed
To examine the scope of this system, the coupling by Gaunt,[6] and the formed palladium intermediate
reactions of various indoles with olefins were studied reacts with alkene followed by reductive elimination
and the results are shown in Table 2. In the presence to give product and Pd(0). The reduced Pd(0) is re-
of the Pd
doles with various substitution patterns reacted effi-
ciently with n-butyl acrylate 2a to give 3-vinylindoles tion of indoles was performed by PdAHCUTNGTRENNUNG
ACHTUNGTRENNUNG
in moderate to good yields with complete E-stereose- with a catalytic amount of H3PMo12O40 using O2 as
lectivity. It was worthy of noting that the reaction had the terminal oxidant. This method provides an eco-
high functional group compatibility as several func- nomical and environmentally benign process for or-
tional groups, including MeO, PhCH2O, F, Br, CO2R, ganic transformations. Further mechanistic investiga-
Ph, and Me, on the aromatic ring of the indole were tions as well as applications of the present catalytic
tolerated. For example, 2-phenyl-1H-indole reacted system for the oxidative coupling of various aromatic
with 2a to give alkenylation product 3j in 88% yield. compounds are in progress.
More importantly, F and Br substituents were compat-
ible with the catalytic reaction, thus providing
a handle for additional modifications at a later stage.
Neither electron-donating groups nor electron-with-
Experimental Section
drawing groups on the aromatic ring of the indole af-
Representative Procedure for the Oxidative Coupling
fected the efficiency of the reaction. However, with
of Indole (1a) with n-Butyl Acrylate
regard to N-substituents, while N-methylindole was
Formation of (E)-butyl 3-(1H-indol-3-yl)acrylate (3a):
Indole 1a (46.6 mg, 0.4 mmol), n-butyl acrylate (175 mL,
suitable for the reaction; N-tosylindole had no reac-
tivity. As expected, acrylates of various alcohols were
smoothly reacted to afford the corresponding prod-
ucts in good yields. Ethyl acrylate, tert-butyl acrylate
and 2-methoxyethyl acrylate efficiently reacted with
1a to give the corresponding products 3l–n in 60%,
63%, and 65% yields, respectively. In addition, vinyl
phosphonate could reacted with 1a in 56% yield. 1-
Octen-3-one is less reactive than acrylates in this
1.2 mmol),
Pd
(OAc)2
(8.96 mg,
0.04 mmol),
H3PMo12O40·18H2O (18.2 mg, 0.008 mmol), DMAP (4.9 mg,
0.04 mmol), DMSO (0.1 mL) and DMF (0.9 mL) were
placed in a 25-mL stainless steel autoclave under a flow of
argon. O2 was introduced at an initial pressure of 0.5 MPa at
room temperature, and then the autoclave was heated in an
oil bath at 808C with stirring for 24 h. After the autoclave
had cooled to room temperature, O2 was released slowly,
system. Almost no desired product was obtained. In and the crude reaction mixture was diluted with CH2Cl2 to
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Palladium(II)/Polyoxometalate-Catalyzed Direct C-3 Alkenylation of Indoles using Dioxygen
Table 2. Direct C-H olefination of indoles with alkenes.[a]
[a]
Conditions: 1 (0.4 mmol) was allowed to react with 2 (1.2 mmol) in the presence of Pd catalyst
(10 mol%) combined with H3PMo12O40·18H2O (2 mol%) and DMAP (10 mol%) in DMF+10%
DMSO (1 mL) under O2 (5 atm) at 808C for 24 h.
5 mL and C22H46 (0.2 mmol) was added as an internal stan- Acknowledgements
dard for GC analysis. After GC and GC-MS analyses of the
reaction mixture, volatiles were removed under reduced
pressure, and the residue was subjected to silica gel column
chromatography [eluting with petroleum ether (PE) and
then with a EtOAc-PE mixture (1:3)] to afford 3a as
a yellow solid; yield: 73%. The GC analyses of the reaction
mixture disclosed the formation of 3a in 85% yield.
We thank Prof. Matthias Brewer (University of Vermont) for
proofreading of the manuscript and Prof. Ruihu Wang
(Fujian Institute of Research on the Structure of Matter, Chi-
nese Acadamy of Sciences) for assistance with NMR charac-
terization. Financial support from NSFC (Grant Nos.
21103022, 21051003), Natural Science Foundation of Fujian
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Qiufeng Huang et al.
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Provine, China (Grant No. 2011J05019), Foundation of
Fujian Educational Committee (Grant No. JA11063) is grate-
fully acknowledged.
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