Synthesis of 2-Acylated Indoles through Palladium-Catalyzed Dehydrogenative Coupling of N -Pyrimidine-Protected Indoles with Aldehydes and Ethyl Glyoxylate

Article abstract of DOI:10.1055/s-0034-1379935

C2-Acylated indoles have been synthesized in good yields through palladium-catalyzed dehydrogenative coupling of N-pyrimidine-protected indoles using aldehydes as the source of acyl reagent and tert-butyl hydroperoxide as the oxidant. 2-Indole carboxylate

Full text of DOI:10.1055/s-0034-1379935

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 771–778
letter
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W. Wang et al.
Letter
Synlett
Synthesis of 2-Acylated Indoles through Palladium-Catalyzed De-
hydrogenative Coupling of N-Pyrimidine-Protected Indoles with
Aldehydes and Ethyl Glyoxylate
Wenduo Wang
N
Jidan Liu
N
N
O
N
Qingwen Gui
Ze Tan*
O
N
Pd catalyst
N
R1
H
R2
+
R1
R2
TBHP, 125 °C
EtOAc
State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan Univer-
sity, Changsha 410082, P. R. of China
52–83%
ztanze@gmail.com
Received: 09.10.2014
Accepted after revision: 24.11.2014
Published online: 09.02.2015
run in a one-pot fashion, the need to use CO2 and organo-
lithium reagent requires stringent exclusion of air and
moisture, thus making the reaction less user friendly.
Moreover, the use of strong base can severely limit the
scope of the reaction.
DOI: 10.1055/s-0034-1379935; Art ID: st-2014-w0850-l
Abstract C2-Acylated indoles have been synthesized in good yields
through palladium-catalyzed dehydrogenative coupling of N-pyrimi-
dine-protected indoles using aldehydes as the source of acyl reagent
and tert-butyl hydroperoxide as the oxidant. 2-Indole carboxylates can
be synthesized when aldehydes are substituted by ethyl glyoxylate.
Recently, several palladium-catalyzed acylation reac-
tions of arenes have been developed by using aldehyde as
the source of the acyl group.10,11 The installation of a car-
bonyl group on the arenes, i.e., the synthesis of aryl ketones
and carboxylates from benzene derivatives through palladi-
um-catalyzed dehydrogenative coupling, has been an area
of intense research.11 For example, Li and others reported
dehydrogenative couplings between 2-aryl pyridines and
aryl aldehydes to produce aryl ketones.11a,b Later, Kwong11c
successfully extended this protocol to the dehydrogenative
coupling between acetanilides with aryl aldehydes. Li, Deng
and co-workers were able to successfully use alcohols in-
stead of aldehydes in similar couplings.11d,e Even more im-
pressive is that Sun and Patel were able to use toluene de-
rivatives as the acyl source, thus increasing the overall reac-
tion efficiency further.12 Whereas various protocols based
on palladium-catalyzed C–H activation of arenes have been
developed for the synthesis of aryl ketones and esters from
benzene derivatives, only a few examples involving the use
of heterocycles are known.13,9e,f Thus it would be highly de-
sirable for palladium-catalyzed dehydrogenative coupling
to be applied in the synthesis of acylated heteroaromatic
compounds such as indoles.
Key words palladium, dehydrogenative coupling, aldehyde, acyla-
tion, indoles
Acylated indoles are important substructures in a num-
ber of biologically active natural products and pharmaceu-
tical compounds1 and they have been shown to possess an-
tidiabetic,1a anticancer,1c and anti-HIV activities.1b They
have also been frequently used as valuable intermediates in
the synthesis of dyes2a and pharmaceuticals.2b Compared
with 2-acylindoles, 3-acylindoles can be conveniently syn-
thesized through Friedel–Crafts reaction,3 Vilsmeier–Haack
reaction,4 and indole Grignard reaction.5 In addition, they
can be prepared through alternative procedures such as
transition-metal-catalyzed formylation6 or acylations.7 For
example, Wang recently disclosed an elegant copper-pro-
moted decarboxylative C3-selective acylation of N-substi-
tuted indoles with α-oxocarboxylic acids.8 Despite this
progress, only a few methods exist for the preparation of 2-
acylindoles.9 The most common method for preparation of
2-acylindole is the Katritsky procedure.9a It involves the use
of CO2 to protect the indole nitrogen atom after the hydro-
gen on the nitrogen atom is abstracted by an organolithium
reagent. This in situ protected indole will react further with
a strong base such as t-BuLi to generate a carbanion at the
C2-position, which will subsequently react with an acyl
electrophile to generate the desired 2-acylindole. Although
the C2-acylation transformation is very efficient and can be
Pyrimidine has been used as a removable protecting
group for phenols14 and anilines.15 More importantly, it has
been shown to be a competent directing group in various
transition-metal-catalyzed C–H activations. Hence, a vari-
ety of C–C and C–X bond formation reactions based on py-
rimidine-directed transition-metal-catalyzed C–H activa-
tion have been developed.16 Inspired by these results, we
considered whether pyrimidine could be used to both pro-
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W. Wang et al.
Letter
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tect the nitrogen atom of the indole molecules and serve as
the directing group for palladium-catalyzed C2-selective
acylation using aldehyde as the acylation reagent. Herein,
we report that C2-selective acylation can indeed be
achieved in good yields through palladium-catalyzed dehy-
drogenative coupling between pyrimidine-protected in-
doles and aldehydes.
Table 1 Optimization of the Reaction Conditionsa
N
CHO
N
PdX2
N
O
N
N
ligand, additive
+
N
initiator
24 h
We commenced our study by using the reaction of N-
pyrimidine-protected indole 1 and p-methylbenzaldehyde
as the model reaction. When 1 was treated with 2 (1.5
equiv) in the presence of Pd(OAc)2 (10 mol%), TBHP (70% in
H2O, 4 equiv) in toluene under N2 at 125 °C for 24 h, the de-
sired acylation product 3aa was isolated in 23% yield (Table
1, entry 1). When we replaced the aqueous TBHP with an-
hydrous TBHP (5 M in decane), the yield increased to 56%
(entry 2). A yield of 83% could be obtained when the sol-
vent was switched to EtOAc (entry 3) whereas other sol-
vents such as DMF, DMSO, and MeCN all gave much inferior
results (entries 4–6). Given that phosphine ligand was
shown to have a beneficial effect on the reaction yield in
other palladium-catalyzed acylations, we included phos-
phine ligands such as dppp, dppe, dppf, and PPh3 to the re-
action mixture as additives. However, the yield actually suf-
fered (entries 7–10). Substituting the catalyst Pd(OAc)2
with PdCl2 or Pd(TFA)2 did not improve the yield (entry 11
and 12). When the reaction temperature was reduced to
100 °C, the yield of 3aa also dropped, whereas running the
reaction at 135 °C gave a yield of 72% (entries 13 and 14). A
control reaction also confirmed that no desired product 3aa
was formed when palladium catalyst was absent (entry 15).
Based on these results, we established the reaction in EtOAc
at 125 °C under N2 in the presence of Pd(OAc)2 as our stan-
dard reaction conditions.17
Me
1
2
3aa
Me
Entry Catalyst
Temp (°C) Ligand Initiator Solvent
Yield (%)b
1c
2
3
4
5
6
7
8
9
Pd(OAc)2
125
125
125
125
125
125
125
125
125
125
125
125
100
135
125
–
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
toluene
toluene
EtOAc
DMF
23
56
83
19
30
38
53
55
48
32
21
60
57
72
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
–
–
–
–
DMSO
MeCN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
–
dppp
dppe
dppf
PPh3
–
10
11
12
13
14
15
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
–
–
–
–
–
a Reaction conditions: indole (1 equiv), PdX2 (10 mol%), anhydrous TBHP
(ca. 5 M in decane, 4 equiv), p-tolualdehyde (1.5 equiv), solvent (3 mL mmol–1),
ligand (10 mol%), under N2, 24 h.
b Isolated yield.
c TBHP (70% in H2O) was added.
With the optimized protocol in hand, we next set out to
explore the scope and the limitations of the reaction (Table
2). We found that the reaction worked satisfactorily with a
range of aromatic aldehydes. The desired C2-acylated in-
doles were obtained in yields ranging from 52 to 83% (Table
2, entries 1–10, 22, and 23) when substituents such as Me,
MeO, Ph, NO2, Br, Cl, and F, as well as acetamino group were
placed on the aromatic ring of the aldehyde. Moreover, 1-
and 2-naphthaldehyde as well as 2-furfuraldehyde can also
participate in the coupling, affording the desired C2-acylat-
ed product in 48–78% yields (Table 2, entries 9, 10, 12, and
18). Much to our disappointment, aliphatic aldehydes such
as 1-octanal were not viable substrates for this type of cou-
pling (Table 2, entry 11). We surmise that this is due to the
fact that alkyl aldehydes can be easily oxidized to acids by
the oxidant.18 We found that substituents such as methyl,
fluoro, bromo, chloro, methoxy, cyano, and even carboxyl-
ate groups were all well tolerated on the phenyl ring of in-
dole, affording the desired acylated product in 59–85%
yields (Table 2, entries 12–21). Notably, a methyl group on
the C3-position of the indole did not hinder the desired C2-
acylation, demonstrating the versatility of this protocol (Ta-
ble 2, entry 20).
Given that we have shown that ethyl glyoxylate can also
be used to participate in the palladium-catalyzed decarbo-
nylative–dehydrogenative coupling with anilides, and that
aryl carboxylate instead of ketones will be obtained,19 we
considered whether ethyl glyoxylate could also be used in
our newly developed reaction. Much to our satisfaction, we
found that by replacing the aryl aldehyde with ethyl glyox-
ylate and running the reaction under our standard condi-
tions, decarbonylation indeed took place to give the desired
2-indole carboxylates in good yields; the results are sum-
marized in Table 3. A range of substituted indoles could be
used in the palladium-catalyzed decarbonylative-dehydro-
genative coupling with ethyl glyoxylate to generate the de-
sired 2-indole carboxylates in 64–82% yields (Table 3, en-
tries 1–9). It is important to note that this type of product is
not readily accessible through Friedel–Crafts reaction.
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Table 2 Synthesis of 2-Acylated Indoles through Palladium-Catalyzed Dehydrogenative Coupling of N-Pyrimidine-Protected Indoles with Aldehydesa
N
N
O
N
N
O
+
N
N
Pd(OAc)2 (10 mol%)
H
R2
R1
R1
R2
TBHP (4 equiv), EtOAc
N2, 24 h, 125 °C
1
2
3
Entry Indole
Product
Yield Entry Indole
(%)b
Product
Yield
(%)b
N
N
N
N
N
O
N
O
N
N
N
N
N
N
1
83
80
61
13
14
15
59
63
76
N
N
Br
Br
Me
Cl
Br
3aa
3al
N
N
N
N
N
N
N
O
O
N
N
2
N
N
Cl
Cl
3ab
3am
N
N
N
N
N
O
N
O
N
N
N
Me
Me
Me
Me
3
N
N
NC
NC
3ac
3an
N
N
N
N
N
N
O
O
N
N
N
N
4
52
16
85
N
N
MeOOC
MeOOC
NO2
Me
3ao
3ad
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Table 2 (continued)
Entry Indole
Product
Yield Entry Indole
(%)b
Product
Yield
(%)b
N
N
N
N
N
O
N
N
F
N
O
N
N
5
72
17
70
F
N
N
Ph
3ap
3ae
N
N
N
N
N
N
Cl
N
O
N
O
N
N
N
N
N
6
63
65
61
62
18
19
20
21
72
78
82
80
Br
Cl
N
N
3af
3aq
N
N
N
N
N
N
N
O
O
O
N
O
N
7
N
N
MeO
Cl
MeO
3ar
3ag
3ah
3ai
N
N
N
N
N
N
N
N
N
N
O
N
8
N
F
N
3as
N
N
N
N
N
N
N
O
N
9
N
N
3at
N
N
N
N
N
O
N
N
N
O
N
10
78
22
76
N
N
O
3aj
OMe
3au
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Table 2 (continued)
Entry Indole
Product
Yield Entry Indole
(%)b
Product
Yield
(%)b
N
N
O
N
N
N
N
N
N
N
11
0
23
67
O
N
N
N
O
(CH2)6
HN
3av
N
N
O
N
N
N
12
61
N
F
F
3ak
a Reaction conditions: indole (0.3 mol), aldehyde (0.45 mmol), Pd(OAc)2 (10 mol%), TBHP (4 equiv), EtOAc (2.0 mL), 125 °C, 24 h.
b Isolated yield.
To demonstrate the synthetic utility of our reaction and
authenticate the product, 3ab was treated with NaOEt for
24 hours,20 the pyrimidine group was removed, and 6a was
isolated in 80% yield (Equation 1). The identity of 3ab was
confirmed by comparison of its 1H NMR spectrum with re-
ported data.9e This result proved that acylation took place at
the C2-position.
mechanism cannot explain the loss of one molecule of CO
during the reaction with ethyl glyoxylate. Based on these
results, we reason that the reaction may be initiated with
the palladium(II)-mediated ortho-palladation of the indole
to form intermediate A (Scheme 1). TBHP is decomposed
into RO· radicals, which subsequently abstract the hydrogen
from the aldehyde to form acyl radicals. As in the case of
glyoxylate, an extra step of decarbonylation is involved after
the hydrogen abstraction. The generated acyl radicals will
subsequently react with intermediate A to produce a palla-
dium(IV)22 or palladium(III) intermediate B (B1 for glyoxyl-
ate and B2 for benzaldehyde).23 After reductive elimination,
B will be transformed into the desired ketone and ester
products, and palladium(II) is regenerated, thus completing
the catalytic cycle.
N
N
H
O
N
O
N
NaOEt
DMSO, N2
100 °C
3ab
6a
Equation 1
N
Although the exact mechanism remains unclear, some
information has been gathered. When a free-radical scav-
enger (e.g., TEMPO) was added to the reaction mixture, the
reaction was almost completely stopped (Equation 2), sug-
gesting this reaction may involve a radical intermediate.
This observation is consistent with reports by oth-
ers.10e,11a,c,21 On the other hand, the usually invoked pallada-
tion–addition to the carbonyl group–dehydropalladation
CHO
Me
N
N
O
N
N
Pd(OAc)2
+
N
TEMPO, TBHP
EtOAc, N2
125 °C, 24 h
Me
(trace)
Equation 2
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Table 3 (continued)
Entry Indole
Table 3 Synthesis of 2-Indole Carboxylates through Palladium-Cata-
lyzed Dehydrogenative/Decarbonylative Coupling of N-Pyrimidine-Pro-
tected Indoles with Ethyl Glyoxylatea
Product
Yield
(%)b
70
N
N
N
N
Pd(OAc)2
(10 mol%)
N
N
O
N
+
N
OEt
6
O
O
N
N
N
N
H
TBHP, EtOAc
N2, 125 °C, 24 h
O
OEt
OEt
MeOOC
5af
MeOOC
5
4
1
Entry Indole
Product
Yield
(%)b
N
N
N
N
7
73
78
64
F
O
N
F
N
N
N
N
N
N
OEt
1
82
67
5ag
O
N
OEt
N
5aa
N
N
N
8
Cl
O
OEt
N
Cl
N
N
N
N
N
N
N
5ah
2
O
N
N
OEt
F
5ab
N
F
N
N
N
9
O
N
N
N
N
OEt
N
MeO
5ai
MeO
3
68
72
65
O
OEt
N
N
a Reaction conditions: indole (0.3 mol), ethyl glyoxylate (0.45 mmol),
Pd(OAc)2 (10 mol%), TBHP (4 equiv), EtOAc (2.0 mL), 125 °C, 24 h.
b Isolated yield.
Br
5ac
Br
N
In summary, a novel way of synthesizing C2-acylated in-
doles was developed with palladium catalysis using TBHP
as the oxidant and aldehydes as the source of acyl reagent.
We also found that 2-indole carboxylates can be synthe-
sized when aldehydes were substituted with ethyl glyoxyl-
ate.9f This method offers an alternative route for the synthe-
sis of 2-acylated indoles because the pyrimidine group can
be easily removed. Efforts are underway to elucidate the re-
action mechanism and the results will be reported in due
course.
N
N
4
O
N
N
OEt
Cl
5ad
Cl
N
N
N
N
5
O
N
N
OEt
NC
5ae
NC
Acknowledgment
Z.T. would like to thank the National Science Foundation of China (No.
21072051), NCET program (NCET-09-0334) and the Fundamental Re-
search Funds for the Central Universities, Hunan university, for finan-
cial support.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 771–778

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Letter
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N
N
N
N
N
O
N
N
O
N
/
N
OEt
H
5aa
1
Pd(II)
3ab
HOAc
N
N
N
OAc
Pd
(II)
A
N
N
N
N
OAc
L
OAc
L
(III) or (IV)
O
(III) or (IV)
O
N
N
Pd
Pd
/
EtO
B1
O
OEt
B2
•
•
•
/
CO
O
t-BuOOH/H2O
O
O
OEt
H
t-BuOH/H2O
t-BuOOH
t-BuOOH
t-BuO• / •OH
O
O
2
O
OEt
t-BuO• / •OH
H
4
Scheme 1 Proposed mechanism for palladium-catalyzed dehydrogenative coupling of N-pyrimidine-protected indoles with aldehydes and ethyl glyox-
ylate
Supporting Information
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Cailly, T.; Fabis, F. Tetrahedron 2010, 66, 5008.
Supporting information for this article is available online at
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S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
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[3-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)metha-
none (3as): Yield: 82%; white solid; mp 153–154 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.63 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 4.0 Hz,
2 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.48–7.40
(m, 2 H), 7.32 (q, J = 8.0 Hz, 3 H), 6.84 (t, J = 4.0 Hz, 1 H), 2.37 (s,
3 H). 13C NMR (101 MHz, CDCl3): δ = 189.4, 157.5, 157.0, 139.2,
136.4, 133.2, 132.2, 130.2, 128.5, 128.3, 126.1, 122.5, 121.7,
120.1, 116.1, 115.2, 9.3; HRMS: m/z [M]+ calcd for C20H15N3O:
313.1207; found: 313.1210.
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11339.
[7-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)metha-
none (3at): Yield: 80%; yellow solid; mp 36–37 °C. 1H NMR (400
MHz, CDCl3): δ = 8.85 (d, J = 4.0 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 2 H),
7.60–7.55 (m, 2 H), 7.48–7.45 (m, 2 H), 7.39 (t, J = 4.0 Hz, 1 H),
7.20 (s, 1 H), 7.13–7.11 (m, 2 H), 1.96 (s, 3 H). 13C NMR (101
MHz, CDCl3): δ = 187.0, 159.7, 158.1, 138.3, 138.2, 136.0, 132.4,
129.6, 129.2, 128.2, 127.2, 122.4, 121.9, 121.1, 120.1, 116.4,
19.3. HRMS: m/z [M]+ calcd for C20H15N3O: 313.1207; found:
313.1210.
(4-Methoxyphenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]meth-
anone (3au): Yield: 76%; white solid; mp 39–40 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.61 (d, J = 4.0 Hz, 2 H), 8.39 (d, J = 8.0 Hz,
1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.41 (t, J =
8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 7.02 (t, J =
4.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 2 H), 3.83 (s, 3 H). 13C NMR (101
MHz, CDCl3): δ = 186.4, 163.3, 157.9, 157.2, 138.0, 137.2, 131.8,
130.7, 127.9, 126.1, 122.6, 122.2, 117.3, 114.5, 114.1, 113.5,
55.4; HRMS: m/z [M]+ calcd for C20H15N3O2: 329.1152; found:
329.1159.
N-{4-[1-(Pyrimidin-2-yl)-1H-indole-2-carbonyl]phenyl}acet-
amide (3av): Yield: 67%; yellow solid; mp 138–139 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.11 (s, 1 H), 8.56 (d, J = 4.0 Hz, 2 H), 8.37
(d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.68–7.61 (m, 3 H),
7.41 (t, J = 8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 6.99
(t, J = 4.0 Hz, 1 H), 2.09 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ =
186.8, 169.4, 157.8, 157.0, 142.9, 138.0, 136.9, 132.7, 130.7,
127.8, 126.4, 122.7, 122.3, 118.7, 117.3, 115.1, 114.1, 24.28;
HRMS: m/z [M]+ calcd for C21H16N4O2: 356.1273; found:
356.1268.
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2011, 2325. (c) Heo, Y.; Hyun, D.; Kumar, M. R.; Jung, H. M.; Lee,
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S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009,
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(17) General Procedure: To a 25-mL sealed tube were added indole
(0.3 mmol), aldehyde (0.45 mmol), Pd(OAc)2 (6.72 mg, 10
mmol%), anhydrous TBHP (ca. 5 M in decane, 4 equiv), and
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