Palladium-catalyzed C2-acylation of indoles with α-diketones assisted by the removable N-(2-pyrimidyl) group

Article abstract of DOI:10.1002/ejoc.201500304

An effective and practical palladium-catalyzed C2-acylation method was successfully developed for the synthesis of 2-acylindoles. A variety of 2-acylindoles were readily prepared from N-pyrimidyl indoles in moderate to good yields. This methodology offers

Full text of DOI:10.1002/ejoc.201500304

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201500304
Palladium-Catalyzed C2-Acylation of Indoles with α-Diketones Assisted by the
Removable N-(2-Pyrimidyl) Group
Chunpu Li,[a,b] Wei Zhu,[b] Shuangjie Shu,[b] Xiaoming Wu,*[a] and Hong Liu*[a,b]
Keywords: Synthetic methods / Acylation / C–H activation / Palladium / Nitrogen heterocycles
An effective and practical palladium-catalyzed C2-acylation
method was successfully developed for the synthesis of 2-
methodology offers several advantages, which include ease
of handling, mild reaction conditions, and use of an efficient
acylindoles. A variety of 2-acylindoles were readily prepared and cheap catalyst. In particular, challenging 2-acetylindoles
from N-pyrimidyl indoles in moderate to good yields. This
were synthesized in good yields.
common method for their synthesis,[12] however, this
method suffers from air- and moisture-sensitive organo-
Introduction
C–H functionalization of indoles, such as acylation,[1] lithium reagents. In past decades, innovative methods have
alkynylation[2] and alkenylation,[3] occur preferentially at been developed to synthesize 2-acylindoles under various
the more reactive C3 position of indoles because of inherent catalytic conditions. Beller and co-workers described an
electronic bias.[4] To alter the natural regioselectivity from efficient ruthenium-catalyzed carbonylative C–H-bond aryl-
C3–H to the C2–H of indoles, suitable directing groups are ation process to provide 2-acylindole derivatives, however,
usually introduced into the N1 position of the indole.[5] the essential use of carbon monoxide limits the application
Transition-metal-catalyzed direct C–H bond functionaliza- of this method.[13] Li and co-workers demonstrated oxidat-
tion reactions recently emerged as a powerful method of ive C2 acylation of indoles by using an expensive rhodium
functionalizing indoles at the C2 position. Several transi- catalyst.[14] Recently, Saxena[15] and Zhu[16] reported palla-
tion metal complexes that contain palladium,[6] copper,[7] dium-catalyzed decarboxylative C2 acylation of indoles by
cobalt,[8] ruthenium,[9] and rhodium,[5c,5d,10] have been ex- using α-oxocarboxylic acids under different conditions.
plored as active catalysts in these reactions.
Therefore, the pursuit of regioselective C–H acylation reac-
2-Acylindole derivatives are found in many natural prod- tions at the C2 position of indoles remains an extremely
ucts and biologically active molecules.[11] The coupling of attractive and challenging task for organic chemists. Cheng
nitrogen-protected 2-lithioindoles with acyl chloride is a and co-workers described Pd-catalyzed oxidative ortho-acyl-
Scheme 1. Direct C2-acylation reaction of indoles through C–H bond functionalization.
[a] Department of Medicinal Chemistry, China Pharmaceutical
ation reactions between arene C–H bonds that bore conven-
University,
tional directing groups and aldehydes as acyl reagents.[17]
24 Tong Jia Xiang, Nanjing 210009, P. R. China
[b] CAS Key Laboratory of Receptor Research, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, P. R. China
E-mail: hliu@mail.shcnc.ac.cn
Such ortho-acylation reactions were also realized by using
alcohols,[18] carboxylic acids,[19] benzylic ethers,[20] benzyl-
amines,[21] α-diketones,[22] α-oxocarboxylic acids,[23] or
toluene derivatives[24] as acylation reagents. Inspired by
these strategies, we report herein efficient C2-acylation of
indoles that have an easily removable N-pyrimidyl group
http://sourcedb.simm.cas.cn/yw/zjrcyw/201111/t20111121_
3399263.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500304.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
C. Li, W. Zhu, S. Shu, X. Wu, H. Liu
FULL PAPER
with a versatile palladium catalyst (Scheme 1). Our method Table 1. Optimization of the reaction conditions.[a]
proceeds under mild conditions with easy operation and
broad substrate scope. In particular, challenging 2-acet-
ylindoles, which are key intermediates for pharmaceutical
products, are synthesized in good yields.
Results and Discussion
Entry Acyl
reagents
Acyl reagents TBHP Solvent
Yield
[%][b]
To begin we focused on the reaction of 1-(pyrimidin-2-
yl)-1H-indole (1a) with toluene in the presence of
Pd(OAc)2 and an oxidant (Table 1). To our disappointment,
only a low yield of the product was isolated in the presence
of tert-butyl hydroperoxide (TBHP) as oxidant (Table 1,
Entry 1). The optimization process of acylation of 1-(pyr-
imidin-2-yl)-1H-indole (1a) with other acylation reagents,
such as benzylic ether, benzylamine, benzyl alcohol and
benzil, were investigated (Table 1, Entries 2–5). The acyl-
ation product could be obtained in 56% yield by reaction
of 1-(pyrimidin-2-yl)-1H-indole (1a) with benzil (2a) with
TBHP as the oxidant in tetrahydrofuran (THF; Table 1,
Entry 5). A systematic screening of the reaction conditions
was undertaken. When the catalyst loading was decreased
to 3 mol-%, the desired product was obtained at a lower
yield of 54% (Table 1, Entry 6). The ratio of 1-(pyrimidin-
2-yl)-1H-indole (1a) to TBHP played a critical role in the
reaction efficiency. For example, when this ratio was
changed from 1:3 to 1:4 and 1:6, the yields of the desired
products changed from 56 to 60 and 48%, respectively
(Table 1, Entries 5, 7, and 8). These results indicated that
the ratio of 1:4 was the best choice (Table 1, Entry 7). In
addition, the ratio of 2a relative to 1a was investigated, and
two equivalents of 2a provided the best result (Table 1, En-
tries 7 and 9). Other solvents were screened, and THF pro-
vided the highest yield (Table 1, Entries 9–13). No desired
product could be obtained in the absence of Pd(OAc)2
(Table 1, Entry 14). Therefore, the standard conditions for
the Pd-catalyzed C2-acylation of indoles are as follows:
[mmol]
[mmol]
1
2
PhMe
Bn2O
–
1.2
1.2
1.2
1.2
1.2
1.2
1.6
2.4
1.6
1.6
1.6
1.6
1.6
1.6
–
20[c]
n.r.
n.r.
40[d]
56
1.2
1.2
1.2
0.5
0.5
0.5
0.5
0.8
0.8
0.8
0.8
0.8
0.8
DCE
PhCl
PhCl
THF
THF
THF
THF
THF
PhCl
DME
dioxane
PhMe
THF
3
4
BnNH2
BnOH
5
6
7
8
benzil (2a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
54[e]
60
48
71
n.r.
54
25
9
10
11
12
13
14
35
n.r.[f]
[a] Reaction conditions: 1a (0.4 mmol), acyl reagents, TBHP
(ca. 5.5 m in decane), Pd(OAc)2 (0.02 mmol), solvent (1.6 mL),
100 °C, 24 h. [b] Isolated yield. [c] Toluene as solvent. [d] PdCl2
(0.02 mmol). [e] Pd(OAc)2 (0.012 mmol). [f] Without Pd. DCE =
dichloroethene; DME = dimethoxyethane.
Table 2. Scope of direct C2-acylation of 1-(pyrimidin-2-yl)-1H-ind-
oles with α-diketones.[a]
Pd(OAc)2 (5 mol-%) as catalyst, TBHP (4 equiv.) as oxi- Entry R1, 1
R2, 2
3
Yield [%][b]
dant, benzil (2a; 2 equiv.) as partner of 1-(pyrimidin-2-yl)-
1H-indole (1a), and reactions were performed at 100 °C in
THF without exclusion of air.
1
2
3
4
5
6
7
8
H,1a
C6H5, 2a
3a
71
68
73
55
75
77
67
71
61
70
66
67
73
46
65
68
70
75
H,1a
2-OMe-C6H5, 2b 3b
H,1a
2-Cl-C6H5, 2c
4-OMe-C6H5, 2d 3d
4-Me-C6H5, 2e
4-F-C6H5, 2f
CH3, 2g
3c
H,1a
With optimized reaction conditions established, the
scope of various substrates was examined (Table 2). As
shown in Table 2, α-diaryl ketones that bear different sub-
stituted groups on the benzene rings, such as methyl, meth-
oxy, fluoro, and chloro, could react with 1-(pyrimidin-2-yl)-
1H-indole (1a) to afford products 3b–3f in moderate to
good yields (Table 2, Entries 2–6). α-Diaryl ketones that
possess electron-withdrawing groups (3c and 3f) gave higher
yields than those with electron-donating groups (3b, 3d, and
3e). For α-di(aliphatic)ketone derivatives the reaction also
proceeded well (Table 2, Entries 7 and 8). Under standard
reaction conditions, challenging 2,3-butanedione 2g and
3,4-hexanedione 2h also afforded products 3g and 3h in 67
and 71% yields, respectively. This provides an efficient route
H,1a
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H,1a
H,1a
H,1a
CH3CH2, 2h
C6H5, 2a
9
5-F, 1b
5-Cl, 1c
5-Br, 1d
5-Me, 1e
5-OMe, 1f
5-CN, 1g
5-COOMe, 1h
6-F, 1i
7-Me, 1j
10
11
12
13
14
15
16
17
18
C6H5, 2a
C6H5, 2a
C6H5, 2a
C6H5, 2a
C6H5, 2a
C6H5, 2a
C6H5, 2a
C6H5, 2a
3-CH2COOEt, 1k C6H5, 2a
[a] Reaction conditions: 1a (0.4 mmol),
(1.6 mmol, ca. 5.5 m in decane), Pd(OAc)2 (0.02 mmol), THF
2 (0.8 mmol), TBHP
to the synthesis of 2-acetylindoles, which are key intermedi- (1.6 mL), 100 °C, 24 h. [b] Isolated yield.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
Palladium-Catalyzed C2-Acylation of Indoles with α-Diketones
ates in pharmaceutical products.[25] Subsequently, an inves- When the asymmetric aromatic α-diketone with an elec-
tigation into different substituted indoles showed that a tron-withdrawing group (Cl) on the benzene ring was inves-
number of functional groups could be introduced into the tigated, a yield of 55% was obtained with a 3a/3s ratio of
indoles to afford the corresponding products in good yields. 2.7:1.
The use of electron-donating indoles with methyl (1e and
To extend the synthetic practicability of this protocol,
1j) and methoxy (1f) substituents gave corresponding prod- removal of the 2-pyrimidyl groups from the acylation prod-
ucts 3l, 3q, and 3m, respectively, in good yields (Table 2, ucts was then conducted (Scheme 2). Upon treatment of 3a
Entries 12, 13, and 17), whereas indoles with electron-with- with NaOEt in dimethyl sulfoxide (DMSO) at 100 °C for
drawing groups, such as fluoro, chloro, bromo, nitrile, and 24 h, corresponding product 3t was obtained in 72% yield.
methyl ester, provided the corresponding products in mod-
erate to good yields (Table 2, Entries 9–11 and 14–16). The
tolerance of the reaction to these active groups in the sub-
strates meant that they could be further transformed into
other different functional groups. Steric hindrance on the
indole had no effect on the reaction, and the desired prod-
uct was provided in good yield (Table 2, Entry 18; 75%
yield).
The protocol was not limited to indoles as heteroarom-
atic substrates for C–H bond functionalization, and the re-
sults are summarized in Table 3. For example, 2-pyrimidyl-
substituted pyrrole was efficiently converted into desired
Scheme 2. Deprotection of the 2-pyrimidyl director.
products 3aa and 3ab in 41 and 18% yields, respectively.
Asymmetric α-diketones, such as 1-phenylpropane-1,2-di-
To gain more understanding of this reaction, certain con-
one and 1-(4-chlorophenyl)-2-phenylethane-1,2-dione, re- trol experiments were performed. When 1-(pyrimidin-2-yl)-
acted with 1-(pyrimidin-2-yl)-1H-indole (1a) smoothly to 1H-indole (1a) was treated with benzil (2a) in the presence
generate products in good yields and moderate selectivities. of a radical scavenger (1,4-benzoquinone), almost no acyl-
A yield of 65% was obtained with a 3g/3a ratio of 1.6:1. 2- ation product was produced, which indicated that a radical
Acetylindole product 3g was obtained as the majority. was likely involved in the catalytic cycle (Scheme 3). Based
Table 3. Direct C2-acylation of heterocycles with α-diketones or asymmetric α-diketones.[a]
[a] Reaction conditions: 1a (0.4 mmol), acyl reagents, TBHP (ca. 5.5 m in decane), Pd(OAc)2 (0.02 mmol), solvent (1.6 mL), 100 °C, 24 h,
isolated yield. [b] R2 = R3 = Ph. [c] R2 = Ph, R3 = Me. [d] R2 = Ph, R3 = 4-Cl-Ph.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
C. Li, W. Zhu, S. Shu, X. Wu, H. Liu
FULL PAPER
Scheme 3. Control experiment.
Scheme 4. A plausible reaction mechanism.
on these observations and previous studies,[16,22] we pro- zation. The remarkable features of this methodology in-
posed a possible mechanism, as illustrated in Scheme 4. Co- clude good product yields and wide tolerance of various
ordination of the nitrogen atom of 1a to PdII and directed functional groups, which renders this methodology as a
cyclopalladation reaction provide palladacycle, A. α-Di- highly versatile and atom-economical alternative to existing
phenyl ketone is oxidized to give benzoyl radicals through methods for building the biologically important 2-acylind-
C–C bond cleavage by TBHP. Then, palladacycle A reacts ole unit. Furthermore, deprotection of the metal-directing
with a benzoyl radical to produce PdIII or PdIV intermediate pyrimidyl group is very simple and straightforward. The
B, which can undergo reductive elimination to give desired generality, high efficiency, and operational simplicity of this
product 3a and regenerate the PdII catalyst.
method make it attractive for the alternative construction
of 2-acylindoles.
Conclusions
Experimental Section
In summary, we have demonstrated a protocol for the
synthesis of substituted 2-acylindole derivatives in good
General Information: Unless otherwise stated, all reagents used
were commercially purchased without further purification. THF is
yields through palladium-catalyzed C–H bond functionali- commercially available and was used without further evaporation.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
Palladium-Catalyzed C2-Acylation of Indoles with α-Diketones
Substrates 1a–1k and 2-(1H-pyrrol-1-yl)pyrimidine were prepared
according to literature procedures.[6c,7b,9a,10a,16] Analytical TLC was
performed with HSGF 254 (0.15–0.2 mm thickness). Compound
spots were visualized by UV light (254 nm). Column chromatog-
raphy was performed with silica gel FCP 200–300. NMR spectra
were recorded with a 400 or 500 MHz instrument. Chemical shifts
are reported relative to tetramethylsilane. Proton coupling patterns
are described as singlet (s), doublet (d), triplet (t), quartet (q), mul-
tiplet (m), and broad (br.). HRMS was measured with a Micromass
Ultra Q-TOF spectrometer.
2 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.35–7.25
(m, 3 H), 7.13 (s, 1 H), 7.11–7.06 (m, 1 H), 2.44 (s, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 187.48, 158.08, 157.44, 143.67,
138.31, 137.43, 135.45, 129.88, 129.18, 128.14, 126.47, 122.88,
122.53, 117.47, 115.16, 114.31, 21.82 ppm. MS (ESI): m/z = 314.0
[M + H]+.
(4-Fluorophenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (3f):
Yellow solid, yield 97 mg (77 %), m.p. 113–114 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.64 (d, J = 4.8 Hz, 2 H), 8.42 (d, J =
8.5 Hz, 1 H), 8.06–7.94 (m, 2 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.46
General Procedure for the Synthesis of Phenyl[1-(pyrimidin-2-yl)- (t, J = 7.8 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.16–7.04 (m, 4
1H-indol-2-yl]methanone (3a): To a dry sealed tube was added 1-
(pyrimidin-2-yl)-1H-indole (1a; 78 mg, 0.40 mmol), benzil (168 mg,
0.80 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and TBHP (290 μL,
1.6 mmol, ca. 5.5 m in decane) and dissolved in THF (1.6 mL). The
resulting mixture was stirred for 24 h at 100 °C. After cooling to
room temperature, the reaction mixture was concentrated under
reduced pressure, and the obtained residue was purified by column
chromatography (silica gel) to give 3a; yield: 85 mg (71%).
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 186.27, 165.65 (d, J =
254.8 Hz), 158.11, 157.32, 138.37, 136.96, 134.45 (d, J = 2.9 Hz),
132.22, 132.15, 128.07, 126.73, 123.05, 122.62, 117.55, 115.72,
115.54, 115.43, 114.42 ppm. MS (ESI): m/z = 318.0 [M + H]+.
HRMS (ESI): calcd. for C19H13FN3O [M + H]+ 318.1043; found
318.1037.
1-[1-(Pyrimidin-2-yl)-1H-indol-2-yl]ethanone (3g): Yellow solid,
yield 64 mg (67%), m.p. 155–158 °C. 1H NMR (500 MHz, CDCl3):
Phenyl[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (3a):[16] White δ = 8.79 (d, J = 4.8 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 1 H), 7.71 (d, J
solid, yield 85 mg (71%). 1H NMR (400 MHz, CDCl3): δ = 8.64 = 7.9 Hz, 1 H), 7.43–7.36 (m, 1 H), 7.34 (s, 1 H), 7.29–7.19 (m, 2
(d, J = 4.8 Hz, 2 H), 8.40 (d, J = 8.5 Hz, 1 H), 7.98 (d, J = 8.0 Hz,
H), 2.60 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 190.72,
2 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.59–7.52 (m, 1 H), 7.49–7.40 (m, 158.43, 157.97, 139.47, 137.93, 127.49, 127.08, 122.91, 122.73,
3 H), 7.33–7.27 (m, 1 H), 7.14 (s, 1 H), 7.06 (t, J = 4.8 Hz, 1 118.45, 114.62, 113.24, 28.17 ppm. MS (ESI): m/z = 238.0 [M +
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 187.70, 158.09, 157.40,
138.40, 138.08, 137.29, 132.82, 129.67, 128.46, 128.12, 126.64,
122.95, 122.62, 117.50, 115.56, 114.34 ppm. MS (ESI): m/z = 300.0
[M + H]+.
H]+. HRMS (ESI) calcd. for C14H12N3O [M + H]+ 238.0980; found
238.0982.
1-[1-(Pyrimidin-2-yl)-1H-indol-2-yl]propan-1-one (3h): Yellow solid,
1
yield 71 mg (67%), m.p. 76–78 °C. H NMR (500 MHz, CDCl3): δ
(2-Methoxyphenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone = 8.82–8.75 (m, 2 H), 8.01 (d, J = 8.5 Hz, 1 H), 7.71 (d, J = 7.9 Hz,
(3b): White solid, yield 89 mg (68 %), m.p. 94–96 °C. 1H NMR 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.29 (s, 1 H), 7.28–7.20 (m, 2 H),
(400 MHz, CDCl3): δ = 8.65 (d, J = 4.8 Hz, 2 H), 8.39 (d, J =
8.5 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.58–7.52 (m, 2 H), 7.45
(t, J = 7.8 Hz, 1 H), 7.37–7.27 (m, 2 H), 7.15 (s, 1 H), 7.13–7.06
(m, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
2.97 (q, J = 7.3 Hz, 2 H), 1.23 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 194.57, 158.43, 158.03, 139.18, 137.81,
127.69, 126.81, 122.79, 122.71, 118.36, 113.39, 33.90, 8.71 ppm. MS
(ESI): m/z = 252.1 [M + H]+. HRMS (ESI): calcd. for C15H14N3O
187.41, 159.75, 158.11, 157.44, 139.38, 138.43, 137.26, 129.45, [M + H]+ 252.1137; found 252.1134.
128.10, 126.66, 122.95, 122.65, 119.66, 117.52, 115.62, 114.34,
[5-Fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3i):
113.51, 55.59 ppm. MS (ESI): m/z = 330.0 [M + H]+. HRMS (ESI):
White solid, yield 77 mg (61 %), m.p. 146–147 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.61 (d, J = 4.8 Hz, 2 H), 8.42 (dd, J =
9.2, 4.5 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 2 H), 7.55 (t, J = 7.2 Hz, 1
H), 7.44 (t, J = 7.6 Hz, 2 H), 7.34 (dd, J = 8.6, 2.3 Hz, 1 H),
7.18 (td, J = 9.0, 2.4 Hz, 1 H), 7.11–6.99 (m, 2 H) ppm. 13C NMR
calcd. for C20H16N3O2 [M + H]+ 330.1243; found 330.1236.
(2-Chlorophenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (3c):
White solid, yield 97 mg (73 %), m.p. 91–93 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.70 (d, J = 4.8 Hz, 2 H), 8.29 (d, J =
8.5 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), (126 MHz, CDCl3): δ = 187.69, 159.34 (d, J = 239.8 Hz), 158.11,
7.47–7.39 (m, 2 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.31–7.20 (m, 2 H),
157.14, 138.62, 137.88, 134.59, 133.00, 129.62, 128.81 (d, J =
7.15 (s, 1 H), 7.09 (t, J = 4.8 Hz, 1 H) ppm. 13C NMR (126 MHz, 10.2 Hz), 128.54, 117.58, 115.81 (d, J = 8.9 Hz), 114.75 (d, J =
CDCl3): δ = 185.69, 158.14, 157.37, 138.99, 137.92, 137.65, 133.04, 25.6 Hz), 114.40 (d, J = 4.4 Hz), 107.31 (d, J = 23.7 Hz) ppm. MS
131.89, 130.78, 130.70, 127.83, 127.26, 126.30, 123.02, 122.96, (ESI): m/z = 318.0 [M + H]+. HRMS (ESI): calcd. for C19H13FN3O
117.79, 117.17, 114.20 ppm. MS (ESI): m/z = 334.0 [M + H]+.
HRMS (ESI): calcd. for C19H13ClN3O [M + H]+ 334.0747; found
334.0756.
[M + H]+ 318.1043; found 318.1034.
[5-Chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3j):
White solid, yield 94 mg (70 %), m.p. 109–110 °C. 1H NMR
(4-Methoxyphenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (400 MHz, CDCl3): δ = 8.62 (d, J = 4.8 Hz, 2 H), 8.38 (d, J =
(3d):[16] White solid, yield 72 mg (55 %). 1H NMR (400 MHz,
CDCl3): δ = 8.64 (d, J = 4.8 Hz, 2 H), 8.40 (d, J = 8.5 Hz, 1 H),
7.99 (d, J = 8.7 Hz, 2 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.43 (t, J =
9.0 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 2 H), 7.71–7.64 (m, 1 H), 7.56
(t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.39 (dd, J = 8.9,
1.9 Hz, 1 H), 7.07 (t, J = 4.8 Hz, 1 H), 7.03 (s, 1 H) ppm. 13C NMR
7.7 Hz, 1 H), 7.34–7.24 (m, 1 H), 7.15–7.03 (m, 2 H), 6.94 (d, J = (126 MHz, CDCl3): δ = 187.61, 158.14, 157.07, 138.34, 137.81,
8.8 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ 136.47, 133.06, 129.64, 129.27, 128.56, 128.46, 126.69, 121.78,
= 186.63, 163.51, 158.09, 157.48, 138.25, 137.46, 132.06, 130.93,
117.71, 115.81, 113.92 ppm. MS (ESI): m/z = 334.0 [M + H]+.
128.20, 126.36, 122.87, 122.46, 117.46, 114.78, 114.33, 113.75, HRMS (ESI): calcd. for C19H13ClN3O [M + H]+ 334.0747; found
55.62 ppm. MS (ESI): m/z = 330.0 [M + H]+.
334.0739.
[1-(Pyrimidin-2-yl)-1H-indol-2-yl](p-tolyl)methanone (3e):[16] White
[5-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone
solid, yield 94 mg (75%). 1H NMR (400 MHz, CDCl3): δ = 8.66 (3k):[16] White solid, yield 100 mg (66 %). 1H NMR (400 MHz,
(d, J = 4.4 Hz, 2 H), 8.42 (d, J = 8.5 Hz, 1 H), 7.92 (d, J = 7.7 Hz,
CDCl3): δ = 8.62 (d, J = 4.8 Hz, 2 H), 8.33 (d, J = 8.9 Hz, 1 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
C. Li, W. Zhu, S. Shu, X. Wu, H. Liu
FULL PAPER
7.95 (d, J = 7.8 Hz, 2 H), 7.83 (d, J = 1.8 Hz, 1 H), 7.59–7.49 (m, 121.25, 120.34, 116.61, 19.52 ppm. MS (ESI): m/z = 314.0 [M +
2 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.08 (t, J = 4.8 Hz, 1 H), 7.03 (s, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 187.59, 158.14, 157.06,
138.18, 137.80, 136.78, 133.07, 129.86, 129.64, 129.28, 128.56,
124.90, 117.73, 116.19, 116.05, 113.77 ppm. MS (ESI): m/z = 378.0
[M + H]+.
H]+.
Ethyl 2-[2-Benzoyl-1-(pyrimidin-2-yl)-1H-indol-3-yl]acetate (3r):
Yellow solid, yield 116 mg (75 %), m.p. 129–131 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.65 (d, J = 8.4 Hz, 1 H), 8.45 (dd, J =
4.8, 1.1 Hz, 2 H), 7.80–7.73 (m, 2 H), 7.71 (d, J = 7.9 Hz, 1 H),
7.51–7.45 (m, 1 H), 7.43–7.38 (m, 1 H), 7.37–7.32 (m, 1 H), 7.29
(t, J = 7.7 Hz, 2 H), 6.90–6.83 (m, 1 H), 4.04 (q, J = 7.1 Hz, 2 H),
3.91 (s, 2 H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 189.32, 170.61, 157.73, 157.00, 139.24, 136.28, 134.73,
132.44, 129.36, 128.62, 128.38, 126.38, 123.10, 120.42, 118.16,
116.59, 115.43, 61.08, 30.40, 14.14 ppm. MS (ESI): m/z = 386.1 [M
+ H]+. HRMS (ESI): calcd. for C23H20N3O3 [M + H]+ 386.1505;
found 386.1498.
[5-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3l):
Yellow solid, yield 84 mg (67 %), m.p. 136–138 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.65–8.58 (m, 2 H), 8.29 (d, J = 8.6 Hz, 1
H), 8.00–7.92 (m, 2 H), 7.57–7.50 (m, 1 H), 7.47 (s, 1 H), 7.43 (t,
J = 7.6 Hz, 2 H), 7.29–7.24 (m, 1 H), 7.07–7.00 (m, 2 H), 2.47 (s, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 187.78, 158.04, 157.43,
138.20, 137.33, 136.77, 132.75, 132.43, 129.63, 128.44, 128.38,
128.29, 122.17, 117.29, 115.35, 114.11, 21.48 ppm. MS (ESI): m/z
= 314.0 [M + H]+. HRMS (ESI): calcd. for C20H16N3O [M + H]+
314.1293; found 314.1286.
(4-Chlorophenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone
(3s):[16] White solid, yield 20 mg (15%). 1H NMR (500 MHz,
CDCl3): δ = 8.63 (d, J = 4.8 Hz, 2 H), 8.42 (dd, J = 8.5, 0.6 Hz, 1
H), 7.95–7.87 (m, 2 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.49–7.43 (m, 1
H), 7.43–7.39 (m, 2 H), 7.33–7.28 (m, 1 H), 7.12 (s, 1 H), 7.07 (t,
J = 4.8 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 186.51,
158.11, 157.30, 139.19, 138.37, 136.85, 136.50, 130.96, 128.81,
128.09, 126.80, 123.09, 122.65, 117.55, 115.48, 114.49 ppm. MS
(ESI): m/z = 334.0 [M + H]+.
[5-Methoxy-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone
(3m):[16] White solid, yield 96 mg (73 %). 1H NMR (400 MHz,
CDCl3): δ = 8.60 (d, J = 4.8 Hz, 2 H), 8.34 (d, J = 9.1 Hz, 1 H),
7.95 (d, J = 7.8 Hz, 2 H), 7.54 (t, J = 7.3 Hz, 1 H), 7.43 (t, J =
7.6 Hz, 2 H), 7.14–7.11 (m, 1 H), 7.11–7.06 (m, 1 H), 7.05 (s, 1 H),
7.02 (t, J = 4.8 Hz, 1 H), 3.88 (s, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 187.75, 158.01, 157.32, 156.11, 138.20, 137.75, 133.33,
132.76, 129.59, 128.85, 128.44, 117.25, 116.61, 115.56, 115.03,
103.59, 55.83 ppm. MS (ESI): m/z = 330.0 [M + H]+.
Phenyl[1-(pyrimidin-2-yl)-1H-pyrrol-2-yl]methanone (3aa): Yellow
solid, yield 41 mg (41%), m.p. 105–107 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.60 (d, J = 4.8 Hz, 2 H), 7.98–7.91 (m, 2 H), 7.75–
7.69 (m, 1 H), 7.56–7.50 (m, 1 H), 7.46–7.40 (m, 2 H), 7.11 (t, J =
4.8 Hz, 1 H), 6.83 (dd, J = 3.6, 1.6 Hz, 1 H), 6.39–6.34 (m, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 186.01, 158.34, 156.95,
138.35, 132.50, 132.33, 129.75, 128.33, 128.04, 122.77, 118.56,
110.56 ppm. MS (ESI): m/z = 250.0 [M + H]+. HRMS (ESI): calcd.
for C15H12N3O [M + H]+ 250.0980; found 250.0987.
2-Benzoyl-1-(pyrimidin-2-yl)-1H-indole-5-carbonitrile (3n): Yellow
solid, yield 60 mg (46%), m.p. 152–154 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.66 (d, J = 4.8 Hz, 2 H), 8.51 (d, J = 8.8 Hz, 1 H),
8.05 (s, 1 H), 7.96 (d, J = 8.2 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 1 H),
7.59 (t, J = 7.4 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.19–7.09 (m, 2
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 187.30, 158.32, 156.72,
139.47, 139.11, 137.36, 133.39, 129.69, 128.90, 128.68, 128.01,
127.70, 119.80, 118.37, 115.58, 113.84, 106.27 ppm. MS (ESI): m/z
= 325.0 [M + H]+. HRMS (ESI): calcd. for C20H13N4O [M + H]+
325.1089; found 325.1081.
[1-(Pyrimidin-2-yl)-1H-pyrrole-2,5-diyl]bis(phenylmethanone) (3ab):
Yellow solid, yield 25 mg (18%), m.p. 139–142 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.77 (d, J = 4.9 Hz, 2 H), 7.98–7.89 (m, 4
H), 7.63–7.55 (m, 2 H), 7.52–7.45 (m, 4 H), 7.39–7.33 (m, 1 H),
6.84 (s, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 185.84,
158.54, 158.32, 137.60, 136.27, 133.02, 129.79, 128.54, 120.22,
119.35 ppm. MS (ESI): m/z = 354.0 [M + H]+. HRMS (ESI): calcd.
for C22H16N3O2 [M + H]+ 354.1243; found 354.1233.
Methyl 2-Benzoyl-1-(pyrimidin-2-yl)-1H-indole-5-carboxylate
(3o):[16] Yellow solid, yield 93 mg (65 %). 1H NMR (400 MHz,
CDCl3): δ = 8.65 (d, J = 4.8 Hz, 2 H), 8.45 (s, 1 H), 8.41 (d, J =
8.9 Hz, 1 H), 8.12 (d, J = 8.9 Hz, 1 H), 7.97 (d, J = 7.4 Hz, 2 H),
7.57 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.17 (s, 1 H),
7.11 (t, J = 4.8 Hz, 1 H), 3.95 (s, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 187.44, 167.48, 158.26, 157.07, 140.65, 138.45, 137.69,
133.16, 129.73, 128.60, 127.79, 127.56, 125.26, 124.96, 118.07,
115.53, 114.13, 52.27 ppm. MS (ESI): m/z = 358.0 [M + H]+.
The Procedure of Removal of the 2-Pyrimidyl Directing Group:
Based on literature reports,[16] the procedure for removal of the 2-
pyrimidyl directing group is as follows: a mixture of 3a (30 mg,
0.1 mmol), NaOEt (20 mg, 0.3 mmol) and DMSO (3 mL) was
stirred in a reaction tube at 100 °C under an argon atmosphere for
24 h. The resulting mixture was then quenched with water. The
mixture was extracted with ethyl acetate, and the combined organic
layer was dried with sodium sulfate. The solvent was evaporated
under reduced pressure and the residue was purified by column
chromatography (silica gel) to give product 3t as a yellow solid
(16 mg, yield 72%).
[6-Fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone
(3p):[16] White solid, yield 87 mg (68 %). 1H NMR (400 MHz,
CDCl3): δ = 8.64 (d, J = 4.8 Hz, 2 H), 8.14 (dd, J = 10.5, 2.1 Hz,
1 H), 7.97 (d, J = 7.5 Hz, 2 H), 7.63 (dd, J = 8.7, 5.5 Hz, 1 H),
7.56 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.12–7.02 (m,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 187.23, 162.41 (d, J
= 243.2 Hz), 158.16, 157.23, 138.83 (d, J = 13.0 Hz), 137.94, 137.86
(d, J = 3.9 Hz), 132.92, 129.68, 128.52, 124.50, 123.59 (d, J =
10.3 Hz), 117.72, 115.48, 111.90 (d, J = 24.9 Hz), 101.41 (d, J =
28.6 Hz) ppm. MS (ESI): m/z = 318.0 [M + H]+.
(1H-Indol-2-yl)(phenyl)methanone (3t):[16] Yellow solid, yield 16 mg
(72%). H NMR (400 MHz, CDCl3): δ = 9.41 (s, 1 H), 8.01 (d, J
= 7.4 Hz, 2 H), 7.73 (d, J = 8.1 Hz, 1 H), 7.67–7.60 (m, 1 H), 7.58–
7.46 (m, 3 H), 7.43–7.35 (m, 1 H), 7.22–7.13 (m, 2 H) ppm.
1
Supporting Information (see footnote on the first page of this arti-
[7-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone
(3q):[16] White solid, yield 88 mg (70 %). 1H NMR (500 MHz,
CDCl3): δ = 8.88 (d, J = 4.9 Hz, 2 H), 7.96–7.91 (m, 2 H), 7.63–
7.56 (m, 2 H), 7.51–7.46 (m, 2 H), 7.42 (t, J = 4.9 Hz, 1 H), 7.21
(s, 1 H), 7.15–7.12 (m, 2 H), 1.98 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 187.19, 159.86, 158.30, 138.54, 138.37,
1
cle): Copies of the H and 13C NMR spectra for all final products.
Acknowledgments
The authors gratefully acknowledge financial support from the
136.13, 132.56, 129.81, 129.40, 128.41, 127.36, 122.64, 122.05, National Natural Science Foundation of China (NSFC) (grant
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
Palladium-Catalyzed C2-Acylation of Indoles with α-Diketones
Chem. Soc. 2014, 136, 5424–5431; d) B. Punji, W. Song, G. A.
numbers 21021063, 91229204, and 81025017) and National S&T
Shevchenko, L. Ackermann, Chem. Eur. J. 2013, 19, 10605–
10610; e) W. Song, L. Ackermann, Angew. Chem. Int. Ed. 2012,
51, 8251–8254; Angew. Chem. 2012, 124, 8376–8379; f) B. Sun,
T. Yoshino, S. Matsunaga, M. Kanai, Adv. Synth. Catal. 2014,
356, 1491–1495; g) T. Yoshino, H. Ikemoto, S. Matsunaga, M.
Kanai, Chem. Eur. J. 2013, 19, 9142–9146.
a) L. Ackermann, A. V. Lygin, Org. Lett. 2011, 13, 3332–3335;
b) B. Li, J. Ma, W. Xie, H. Song, S. Xu, B. Wang, J. Org. Chem.
2013, 78, 9345–9353; c) J. Pospech, A. Tlili, A. Spannenberg,
H. Neumann, M. Beller, Chem. Eur. J. 2014, 20, 3135–3141; d)
M. Schinkel, I. Marek, L. Ackermann, Angew. Chem. Int. Ed.
2013, 52, 3977–3980; Angew. Chem. 2013, 125, 4069–4072; e)
L. Q. Zhang, S. Yang, X. Huang, J. You, F. Song, Chem. Com-
mun. 2013, 49, 8830–8832; f) V. Lanke, K. R. Prabhu, Org.
Lett. 2013, 15, 2818–2821.
a) B. Gong, J. Shi, X. Wang, Y. Yan, Q. Li, Y. Meng, H. E.
Xu, W. Yi, Adv. Synth. Catal. 2014, 356, 137–143; b) X. Hong,
H. Wang, G. Qian, Q. Tan, B. Xu, J. Org. Chem. 2014, 79,
3228–3237; c) M. Kim, J. Park, S. Sharma, S. Han, S. H. Han,
J. H. Kwak, Y. H. Jung, I. S. Kim, Org. Biomol. Chem. 2013,
11, 7427–7434; d) X. Li, S. Yu, F. Wang, B. Wan, X. Yu, Angew.
Chem. Int. Ed. 2013, 52, 2577–2580; Angew. Chem. 2013, 125,
2637–2640; e) M. Z. Lu, P. Lu, Y. H. Xu, T. P. Loh, Org. Lett.
2014, 16, 2614–2617; f) K. Parthasarathy, A. R. Azcargorta, Y.
Cheng, C. Bolm, Org. Lett. 2014, 16, 2538–2541; g) J. Ryu, K.
Shin, S. H. Park, J. Y. Kim, S. Chang, Angew. Chem. Int. Ed.
2012, 51, 9904–9908; Angew. Chem. 2012, 124, 10042–10046.
a) A. Brancale, R. Silvestri, Med. Res. Rev. 2007, 27, 209–238;
b) E. Yamuna, R. A. Kumar, M. Zeller, K. J. Rajendra Prasad,
Eur. J. Med. Chem. 2012, 47, 228–238; c) S. Mahboobi, S.
Teller, H. Pongratz, H. Hufsky, A. Sellmer, A. Botzki, A.
Uecker, T. Beckers, S. Baasner, C. Schachtele, F. Uberall, M. U.
Kassack, S. Dove, F. D. Bohmer, J. Med. Chem. 2002, 45,
1002–1018; d) M. A. Tarselli, K. M. Raehal, A. K. Brasher,
J. M. Streicher, C. E. Groer, M. D. Cameron, L. M. Bohn,
G. C. Micalizio, Nat. Chem. 2011, 3, 449–453; e) F. Yu, R. L.
Wolin, J. Wei, P. J. Desai, P. M. McGovern, P. J. Dunford, L.
Karlsson, R. L. Thurmond, J. Receptor Ligand Channel Res.
2010, 3, 37–49.
a) M. G. Saulnier, G. W. Gribble, J. Org. Chem. 1982, 47, 757–
761; b) R. J. Sundberg, H. F. Russell, J. Org. Chem. 1973, 38,
3324–3330.
J. Pospech, A. Tlili, A. Spannenberg, H. Neumann, M. Beller,
Chem. Eur. J. 2014, 20, 3135–3141.
B. Zhou, Y. X. Yang, Y. C. Li, Chem. Commun. 2012, 48, 5163–
5165.
S. Sharma, I. A. Khan, A. K. Saxena, Adv. Synth. Catal. 2013,
355, 673–678.
C. Pan, H. Jin, X. Liu, Y. Cheng, C. Zhu, Chem. Commun.
2013, 49, 2933–2935.
X. Jia, S. Zhang, W. Wang, F. Luo, J. Cheng, Org. Lett. 2009,
11, 3120–3123.
F. H. Xiao, S. A. Qi, F. Zhao, O. Basle, G. J. Deng, C. J. Li,
Org. Lett. 2011, 13, 1614–1617.
J. Lu, H. Zhang, X. Chen, H. Liu, Y. Jiang, H. Fu, Adv. Synth.
Major
Projects
(grant
numbers
2012ZX09103101-072,
2012ZX09301001-005, 2013ZX09507-001, and 2014ZX09507002-
001).
[1] a) D. M. Ketcha, G. W. Gribble, J. Org. Chem. 1985, 50, 5451–
5457; b) T. Okauchi, M. Itonaga, T. Minami, T. Owa, K. Ki-
toh, H. Yoshino, Org. Lett. 2000, 2, 1485–1487; c) O. Ottoni,
A. V. Neder, A. K. Dias, R. P. Cruz, L. B. Aquino, Org. Lett.
2001, 3, 1005–1007; d) A. R. Katritzky, K. Suzuki, S. K. Singh,
H. Y. He, J. Org. Chem. 2003, 68, 5720–5723; e) J. Chen, B.
Liu, D. Liu, S. Liu, J. Cheng, Adv. Synth. Catal. 2012, 354,
2438–2442; f) E. Kianmehr, S. Kazemi, A. Foroumadi, Tetrahe-
dron 2014, 70, 349–354; g) Y. Ma, J. You, F. Song, Chem. Eur.
J. 2013, 19, 1189–1193; h) C. Wang, S. Wang, H. Li, J. Yan, H.
Chi, X. Chen, Z. Zhang, Org. Biomol. Chem. 2014, 12, 1721–
1724; i) W. Wu, W. Su, J. Am. Chem. Soc. 2011, 133, 11924–
11927; j) Q. Xing, P. Li, H. Lv, R. Lang, C. Xia, F. Li, Chem.
Commun. 2014, 50, 12181–12184.
[2] a) J. P. Brand, J. Charpentier, J. Waser, Angew. Chem. Int. Ed.
2009, 48, 9346–9349; Angew. Chem. 2009, 121, 9510–9513; b)
J. P. Brand, C. Chevalley, R. Scopelliti, J. Waser, Chem. Eur. J.
2012, 18, 5655–5666; c) Y. Gu, X.-M. Wang, Tetrahedron Lett.
2009, 50, 763–766; d) J. L. Ruano, J. Aleman, L. Marzo, C.
Alvarado, M. Tortosa, S. Diaz-Tendero, A. Fraile, Angew.
Chem. Int. Ed. 2012, 51, 2712–2716; Angew. Chem. 2012, 124,
2766–2770.
[3] a) N. P. Grimster, C. Gauntlett, C. R. Godfrey, M. J. Gaunt,
Angew. Chem. Int. Ed. 2005, 44, 3125–3129; Angew. Chem.
2005, 117, 3185–3189; b) H. Yu, Z. Yu, Angew. Chem. Int. Ed.
2009, 48, 2929–2933; Angew. Chem. 2009, 121, 2973–2977; c)
S. K. Xiang, B. Zhang, L. H. Zhang, Y. Cui, N. Jiao, Chem.
Commun. 2011, 47, 8097–8099; d) Q. Yang, L. Wang, T. Guo,
Z. Yu, J. Org. Chem. 2012, 77, 8355–8361; e) Q. Huang, Q.
Song, J. Cai, X. Zhang, S. Lin, Adv. Synth. Catal. 2013, 355,
1512–1516; f) Y. P. Shang, X. M. Jie, J. Zhou, P. Hu, S. J. Hu-
ang, W. P. Su, Angew. Chem. Int. Ed. 2013, 52, 1299–1303; An-
gew. Chem. 2013, 125, 1337–1341; g) W. L. Chen, Y. R. Gao,
S. Mao, Y. L. Zhang, Y. F. Wang, Y. Q. Wang, Org. Lett. 2012,
14, 5920–5923.
[4] a) S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont, T.
Boubaker, A. R. Ofial, H. Mayr, J. Org. Chem. 2006, 71, 9088–
9095; b) R. J. Sundberg, Indoles; Academic Press: San Diego,
1996; p. 190; c) R. J. Sundberg, Comprehensive Heterocyclic
Chemistry: (Eds.: A. R. Katritzky, C. W. Rees), Pergamon, Ox-
ford, UK, 1984; vol. 4, p. 313–376.
[5] a) E. Capito, J. M. Brown, A. Ricci, Chem. Commun. 2005,
1854–1856; b) A. Garcia-Rubia, R. Gomez Arrayas, J. C. Car-
retero, Angew. Chem. Int. Ed. 2009, 48, 6511–6515; Angew.
Chem. 2009, 121, 6633–6637; c) B. Li, J. Ma, W. Xie, H. Song,
S. Xu, B. Wang, Chem. Eur. J. 2013, 19, 11863–11868; d) S.
Sharma, S. Han, M. Kim, N. K. Mishra, J. Park, Y. Shin, J. Ha,
J. H. Kwak, Y. H. Jung, I. S. Kim, Org. Biomol. Chem. 2014, 12,
1703–1706; e) S. Yu, X. Li, Org. Lett. 2014, 16, 1200–1203.
[6] a) A. Garcia-Rubia, B. Urones, R. Gomez Arrayas, J. C. Carre-
tero, Chem. Eur. J. 2010, 16, 9676–9685; b) Z.-L. Yan, W.-L.
Chen, Y.-R. Gao, S. Mao, Y.-L. Zhang, Y.-Q. Wang, Adv.
Synth. Catal. 2014, 356, 1085–1092; c) S. Xu, X. Huang, X.
Hong, B. Xu, Org. Lett. 2012, 14, 4614–4617.
[7] a) X. Kou, M. Zhao, X. Qiao, Y. Zhu, X. Tong, Z. Shen, Chem.
Eur. J. 2013, 19, 16880–16886; b) M. Nishino, K. Hirano, T.
Satoh, M. Miura, Angew. Chem. Int. Ed. 2012, 51, 6993–6997;
Angew. Chem. 2012, 124, 7099–7103; c) C. Pan, H. Jin, P. Xu,
X. Liu, Y. Cheng, C. Zhu, J. Org. Chem. 2013, 78, 9494–9498;
d) H. Xu, X. Qiao, S. Yang, Z. Shen, J. Org. Chem. 2014, 79,
4414–4422.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
Catal. 2013, 529–536.
S. Han, S. Sharma, J. Park, M. Kim, Y. Shin, N. K. Mishra,
J. J. Bae, J. H. Kwak, Y. H. Jung, I. S. Kim, J. Org. Chem. 2014,
79, 275–284.
Q. Zhang, F. Yang, Y. Wu, Chem. Commun. 2013, 49, 6837–
6839.
W. Zhou, H. J. Li, L. Wang, Org. Lett. 2012, 14, 4594–4597.
M. Li, H. Ge, Org. Lett. 2010, 12, 3464–3467.
a) Z. Xu, B. Xiang, P. Sun, RSC Adv. 2013, 3, 1679; b) S. Guin,
S. K. Rout, A. Banerjee, S. Nandi, B. K. Patel, Org. Lett. 2012,
14, 5294–5297.
[21]
[22]
[23]
[24]
[8] a) Z. Ding, N. Yoshikai, Beilstein J. Org. Chem. 2012, 8, 1536–
1542; b) Z. Ding, N. Yoshikai, Angew. Chem. Int. Ed. 2012, 51,
4698–4701; Angew. Chem. 2012, 124, 4776–4779; c) H. Ikem-
oto, T. Yoshino, K. Sakata, S. Matsunaga, M. Kanai, J. Am.
[25]
a) N. S. Kumar, E. A. Amandoron, A. Cherkasov, B. B. Finlay,
H. Gong, L. Jackson, S. Kaur, T. Lian, A. Moreau, C. Labriere,
N. E. Reiner, R. H. See, N. C. Strynadka, L. Thorson, E. W.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
C. Li, W. Zhu, S. Shu, X. Wu, H. Liu
FULL PAPER
Wong, L. Worrall, R. Zoraghi, R. N. Young, Bioorg. Med.
Chem. 2012, 20, 7069–7082; b) R. K. Tiwari, D. Singh, J. Singh,
V. Yadav, A. K. Pathak, R. Dabur, A. K. Chhillar, R. Singh,
G. L. Sharma, R. Chandra, A. K. Verma, Bioorg. Med. Chem.
Lett. 2006, 16, 413–416; c) H. Zhao, A. C. Donnelly, B. R. Kus-
uma, G. E. Brandt, D. Brown, R. A. Rajewski, G. Vielhauer, J.
Holzbeierlein, M. S. Cohen, B. S. Blagg, J. Med. Chem. 2011,
54, 3839–3853.
Received: March 6, 2015
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50304
/KAP1
Date: 05-05-15 12:37:08
Pages: 9
Palladium-Catalyzed C2-Acylation of Indoles with α-Diketones
C–H Functionalization
C. Li, W. Zhu, S. Shu, X. Wu,*
H. Liu* ............................................. 1–9
Palladium-Catalyzed C2-Acylation of
Indoles with α-Diketones Assisted by the
Removable N-(2-Pyrimidyl) Group
Keywords: Synthetic methods / Acylation /
C–H activation / Palladium / Nitrogen
heterocycles
A variety of 2-acylindoles were readily
prepared from N-pyrimidyl-substituted
indoles in moderate to good yields by an
effective palladium-catalyzed C2-acylation
method. The remarkable features of this
methodology include good product yields
and wide tolerance of various functional
groups.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9