Acetylation of N-heteroaryl bromides via PdCl2/(o-tolyl) 3P catalyzed heck reactions

Article abstract of DOI:10.1055/s-2008-1032193

A new user-friendly and convenient method for the acetylation of N-heteroaryl bromides is described. This process is based on the palladium-catalyzed olefination of an N-heteroaryl bromide with butyl vinyl ether, followed by acid hydrolysis of the intermediate heteroaryl vinyl ether in situ. Isopropanol at 85°C, in the presence of K₃PO ₄·3H₂O (2 equiv), PdCl₂ (2 mol%) and (o-tolyl)₃P (4 mol%), provided the best conditions, giving yields of N-heteroaryl bromides up to 75%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032193

PAPER
887
Acetylation of N-Heteroaryl Bromides via PdCl2/(o-tolyl)3P Catalyzed Heck
Reactions
Acetylation of
N
i
-Heter
a
oaryl Brom
n
ides xiong He,a Xiaochun Tao,*a Xinyan Wu,a Lisheng Cai,*b Victor W. Pikeb
a
Laboratory of Organometallic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. of China
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
E-mail: LishengCai@mail.nih.gov; E-mail: xctao@ecust.edu.cn
b
Received 24 October 2007; revised 12 December 2007
catalyst and ligand used is large. These two factors also
make the method inconvenient and costly. Santelli et
al.15,16 developed an efficient catalytic system for the
Heck olefinic coupling reaction, but the ligand they used,
Abstract: A new user-friendly and convenient method for the
acetylation of N-heteroaryl bromides is described. This process is
based on the palladium-catalyzed olefination of an N-heteroaryl
bromide with butyl vinyl ether, followed by acid hydrolysis of the
intermediate heteroaryl vinyl ether in situ. Isopropanol at 85 °C, in namely cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphino-
the presence of K3PO4·3H2O (2 equiv), PdCl2 (2 mol%) and (o-
tolyl)3P (4 mol%), provided the best conditions, giving yields of N-
heteroaryl bromides up to 75%.
methyl)cyclopentane, is difficult to obtain. The palladi-
um-catalyzed Heck reaction of heteroaryl bromides with
butyl vinyl ether in ionic liquids using 1,3-bis(diphe-
nylphosphino)propane (dppp) as a ligand was reported.17
Key words: acetylation, butyl vinyl ether, isopropanol, N-hetero-
aryl bromides
meso-2,4-Bis(diphenylphosphino)pentane showed much
better regioselectivity than dppp.18 Regioselective and
fast Pd(0)-catalyzed internal a-arylation of ethylene gly-
Heteroaryl methyl ketones are of significant interest in or-
ganic chemistry,1–5 since versatile transformations of the
acetyl function make them important intermediates in the
synthesis of agrochemicals, pharmaceuticals and natural
products.6–10 In general, the introduction of the acetyl
function is the most direct and versatile route through
which to prepare functionalized heteroaryl methyl ke-
tones. Wright et al. reported the first example of a palla-
dium-catalyzed acetylation of heteroaryl bromides with
butyl vinyl ether,11 as outlined in Scheme 1.
col vinyl ether with aryl halide has been accomplished in
water.19 Herein, we report a new, more convenient and
eco-friendly palladium-catalyzed Heck olefinic coupling
of heteroaryl bromides with vinyl ether, in the synthesis of
heteroaryl methyl ketones.
We typically used the reaction described in Scheme 2 for
optimization of the conditions. Initially we used Wright’s
conditions,11 where the reaction was carried out with (5-
bromopyridin-2-yl)dimethylamine (2.0 mmol) and butyl
vinyl ether (10 mmol), using Pd(OAc)2 (8 mol%) as cata-
lyst and (o-tolyl)3P (16 mol%) as ligand, triethylamine as
base, and acetonitrile as solvent. However, even when the
reaction was refluxed for ten hours under Ar, no product
was produced. Since the PdCl2/i-PrOH system was report-
ed to catalyze the coupling reaction efficiently,20 the reac-
tion was then carried out with (5-bromopyridin-2-
yl)dimethylamine (2.0 mmol) and butyl vinyl ether (2.4
mmol), with PdCl2 (2 mol%) as catalyst, K2CO3 as base,
and i-PrOH as solvent. The reaction mixture was refluxed
for six hours under Ar but, again, no desired product was
found (Table 1, entry 4), however, the addition of PPh3 as
ligand gave the desired product in 35% yield (Table 1, en-
The heteroaryl bromide A is transformed to intermediate
heteroaryl vinyl ether B in a palladium-catalyzed
Heck12,13 olefinic coupling with butyl vinyl ether.14 Acid
hydrolysis of the intermediate furnishes the heteroaryl
methyl ketone C. This process offers several advantages
including mild reaction conditions that are tolerant of
many functional groups, a two-step one-pot reaction, and
acceptable yields. Nevertheless, some drawbacks still ex-
ist. For example, the chosen solvent, acetonitrile, is toxic
and unfriendly to the environment. Moreover, the butyl
vinyl ether is required to be present in five-fold greater
amounts than the heteroaryl bromide, and the quantity of
Bu
Bu
O
O
O
Pd(OAc)2 (8 mol% )
(o-tolyl)3P (16 mol%)
+
HCl, H2O, 20 °C
R1,R2
R1,R2
Br
Et3N, MeCN, 80 °C
18 h
N
R1,R2
N
N
A
B
C
Scheme 1
SYNTHESIS 2008, No. 6, pp 0887–0890
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032193; Art ID: M08007SS
© Georg Thieme Verlag Stuttgart · New York

888
T. He et al.
PAPER
O
Br
HCl
PdCl2, ligand
Bu
+
O
H2O, 20 °C
base, i-PrOH, 85 °C, 6 h
N
N
N
N
Scheme 2 The reaction used to optimize conditions
try 5). Therefore, we examined a series of bases contain- The success of K3PO4·3H2O as the base in the reaction is
ing potassium ions instead of K2CO3. KH2PO4, KOAc, consistent with the recent proposal of ‘ionic’ versus ‘neu-
and KOH failed completely, yielding no desired product; tral’ mechanism in the Heck reaction of electron-rich ole-
only starting material was recovered (Table 1, entries 9– fins.21 K3PO4·3H2O must have less solubility than
11). KF·2H2O, t-BuOK, and K2HPO4 all gave the desired K2HPO4·3H2O or KH2PO4, reducing the base’s tendency
products, but the yields were low (Table 1, entries 6–8). to quench ionic intermediates during catalysis. This is in
Inspired by the different effects of KH2PO4 and K2HPO4 contrast with the anion-assisted Heck reaction reported by
on the yields of the desired product, we used K3PO4·3H2O Jeffery et al.,22 which was studied mechanistically by
as base in the reaction. To our delight, we isolated the de- Amatore and Justand.23 It has been reported that ionic liq-
sired product in 60% yield (Table 1, entry 2). Then we uid as solvent and ammonium salts that can act as hydro-
substituted (o-tolyl)3P for PPh3 and the isolated yield in- gen-bond donors, exert a remarkable accelerating effect
creased to 75% (Table 1, entry 1). However, chelated on the rates of the regioselective arylation of electron-rich
phosphine ligands, such as 1,2-bis(diphenylphosphi- olefins by aryl halides.24 The isopropanol used as solvent
no)ethane (dppe), gave a very low yield (Table 1, entry 3). in our system may function analogously.
This is in contrast with some recent reports where diphos-
In most cases, the catalyst used in the Heck reaction is
phines have been used successfully.16,18,19
generated in situ. Various claims have been made about
palladium(II/IV) catalytic cycles25,26 and, indeed, some
Table 1 Optimization of the Acetylation of 5-Bromo-2-dimethyl-
palladium(IV) species have been isolated.21 However, all
aminopyridine with Butyl Vinyl Ethera
current evidence seems to point to a palladium(0/II) cycle.
Entry
Ligand
P(o-MeC6H4)3
PPh3
Base (equiv)
K3PO4·3H2O (2)
K3PO4·3H2O (1.5)
K3PO4·3H2O (1.5)
K2CO3 (2)
Yield (%)b
This means that the first step of the reaction is the reduc-
tion of the palladium(II) precursor into active palladi-
um(0) species.
1
2
75
60
trace
0
We propose a reasonable pathway for catalyst reduction in
Scheme 3. L2PdCl2 reacts with isopropanol in the pres-
ence of base to generate a palladium isopropanolate inter-
mediate.27–30 Elimination of the b-H from the intermediate
forms a L2PdHCl species and acetone. Elimination of HCl
from L2PdHCl produces a L2Pd(0)species, which is the
proposed catalytic species for the reaction.
3
dppe
4
none
5
PPh3
K2CO3 (2)
35
27
15
25
0
6
PPh3
KF·2H2O (2)
t-BuOK (2)
After optimizing the catalytic conditions, we evaluated
the scope and limitations of the reaction. Generally, PdCl2
(2 mol%), (o-tolyl)3P (4 mol%), butyl vinyl ether (1.2
equiv), and K3PO4·3H2O (2 equiv) were used, and the re-
action was conducted in isopropanol at 85 °C for 6–10
hours. The results are summarized in Table 2. Substrates
with primary amino groups gave low yields (Table 2, en-
tries 3 and 6), however, when the amino groups of 5-bro-
mo-2-aminopyridine and 5-bromo-2-aminopyrimidine
were protected by methyl or acetyl groups, the yields
increased significantly (Table 2, entries 1, 2, 4 and 5).
7
PPh3
8
PPh3
K2HPO4·3H2O (2)
KH2PO4 (2)
9
PPh3
10
11
PPh3
KOAc (2)
0
PPh3
KOH (2)
0
a Reactions were carried out in refluxing i-PrOH (5 mL) for 6 h under
argon. The molecular ratio of N-heteroaryl halides, butyl vinyl ethers,
PdCl2, (o-tolyl)3P, and base was 1:1.2:0.02:0.04:1.5–2.0.
b Isolated yield.
OH
L
base
HCl
O
base
L
O
H
H
L
L2PdCl2
+
L
H
Pd Cl
L
L2Pd
Pd
Pd
HCl
L
O
Cl
Cl
L = (o-tolyl)3P, Ph3P
Scheme 3
Synthesis 2008, No. 6, 887–890 © Thieme Stuttgart · New York

PAPER
Acetylation of N-Heteroaryl Bromides
889
Table 2 Heck Acetylation of Heteroaryl Halides with Butyl Vinyl
5-Bromo-1-methylindoline, 5-bromo-1-acetylindoline, 4-
bromoindole and 5-bromoindole also showed good reac-
tivity, and the corresponding products were isolated in
55–63% yield (Table 2, entries 7–10).
Ethersa (continued)
Entry Substrate
Obtained or expected Time Yield
product
(h)
(%)b
Table 2 Heck Acetylation of Heteroaryl Halides with Butyl Vinyl
O
Ethersa
Br
9
6
63
Entry Substrate
Obtained or expected Time Yield
product
(h)
(%)b
N
N
H
H
9
O
O
Br
Br
1
6
75
10
6
60
N
N
N
N
N
N
N
H
H
1
10
O
a Reactions were carried out in refluxing i-PrOH (5 mL), using het-
eroaryl halides (2.0 mmol), butyl vinyl ethers (2.4 mmol), PdCl2 (0.04
mmol), (o-tolyl)3P (0.08 mmol), and K3PO4·3H2O (4.0 mmol) at
85 °C for 6–10 h under argon.
Br
2
10
10
63
N
N
H
N
H
b Isolated yield.
2
O
Br
In summary, we have developed a novel method for the
acetylation of N-heteroaryl bromides. Using the catalytic
system of PdCl2/(o-tolyl)3P in isopropanol, we have trans-
formed N-heteroaryl bromides into N-heteroaryl methyl
ketones in medium to high yields. Strongly coordinating
groups, such as primary amino groups, are not tolerated.
The use of isopropanol as solvent is very attractive in its
cost and environmental friendliness.
3
trace
N
NH2
N
N
NH2
3
O
Br
N
N
4
6
75
N
N
N
4
All reagents and solvents were purchased from commercial sources
and used without further purification. Products were purified by sil-
ica gel column chromatography. 1H NMR spectra were recorded in
CDCl3 using a Bruker Avance 500 spectrometer at 500 MHz, with
chemical shifts (d) reported versus TMS as an internal standard.
Melting points were obtained in open capillary tubes and are uncor-
rected.
O
Br
N
N
N
N
5
10
10
65
N
N
H
N
N
N
H
5
O
Br
Heck Coupling Reactions of Heteroaryl Bromides; 1-(6-Di-
methylaminopyridin-3-yl)ethanone (1);9 Typical Procedure
To a pre-dried Schlenk tube was added, sequentially, 5-bromo-2-
dimethylaminopyridine (402 mg, 2.0 mmol), butyl vinyl ether (240
mg, 2.4 mmol), PdCl2 (7 mg, 0.04 mmol), (o-tolyl)3P (24 mg, 0.08
mmol), K3PO4·3H2O (800 mg, 4.0 mmol) and anhydrous i-PrOH (5
mL). The mixture was stirred at reflux for 6–10 h; TLC analysis
(petroleum ether–EtOAc, 10:1) showed complete conversion of 5-
bromo-2-dimethylaminopyridine. The mixture was then cooled to
r.t. and the solvent was recovered under vacuum. The residue was
taken up in HCl (6 M, 5 mL ) and stirred for 15 min. The mixture
was then neutralized to pH 8 with aq NaOH (6 M). The product was
extracted into EtOAc (3 × 10 mL) and the combined organic layers
were washed with sat. brine (2 × 6 mL), dried with MgSO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (petroleum ether–EtOAc,
10:1) to afford 1.
6
trace
N
NH2
NH2
6
O
Br
7
8
62
55
N
N
O
O
7
O
Br
8
10
N
N
8
Yield: 247 mg (75%); yellow solid; mp 63.8–64.2 °C.
1H NMR (CDCl3, 500 MHz): d = 2.5 (s, 3 H), 3.2 (s, 6 H), 6.5 (d,
J = 9.1 Hz, 1 H), 8.0 (dd, J = 9.1, 2.2 Hz, 1 H), 8.8 (d, J = 2.2 Hz,
1 H).
Synthesis 2008, No. 6, 887–890 © Thieme Stuttgart · New York

890
T. He et al.
PAPER
(4) Murray, T. J.; Zimmerman, S. C.; Kolotuchin, S. V.
1-(6-Methylaminopyridin-3-yl)ethanone (2)9
Mp 129.8–130.2 °C.
Tetrahedron 1995, 51, 635.
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57, 2507.
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H. J. Med. Chem. 1994, 37, 57.
1H NMR (CDCl3, 500 MHz): d = 2.5 (s, 3 H), 3.0 (d, J = 4.5 Hz,
3 H), 5.3 (br s, 1 H), 6.4 (d, J = 8.8 Hz, 1 H), 8.0 (d, J = 8.8 Hz,
1 H), 8.7 (s, 1 H).
1-[2-(Dimethylamino)pyrimidin-5-yl]ethanone (4)9
Mp 92.0–92.9 °C.
1H NMR (CDCl3, 500 MHz): d = 2.5 (s, 3 H), 3.3 (s, 6 H), 8.8 (s,
2 H).
(9) Matulenko, M. A.; Lee, C. H.; Jiang, M.; Frey, R. R.;
Cowart, M. D.; Bayburt, E. K.; DiDomenico, S.; Gfesser, G.
A.; Gomtsyan, A.; Zheng, G. Z.; Mckie, J. A.; Stewart, A.
O.; Yu, H. X.; Kohlhaas, K. L.; Alexander, K. M.;
McGaraughty, S.; Wismer, C. T.; Mikusa, J.; Marsh, K. C.;
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Dougherty, R. W.; Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.;
James, M. K.; Johnson, M. F.; Queen, K. L.; Sherrill, R. G.;
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1-[2-(Methylamino)pyrimidin-5-yl]ethanone (5)
Mp 168.8–170.4 °C.
1H NMR (CDCl3, 500 MHz): d = 2.5 (s, 3 H), 3.1 (d, J = 5.1 Hz,
3 H), 5.9 (br s, 1 H), 8.8 (s, 1 H), 8.9 (s, 1 H).
1-(1-Acetylindolin-5-yl)ethanone (7)31
Mp 138.6–140.2 °C (Lit. 140–141 °C).
1H NMR (CDCl3, 500 MHz): d = 2.3 (s, 3 H), 2.6 (s, 3 H), 3.2 (m,
2 H), 4.1 (m, 2 H), 7.8 (m, 2 H), 8.2 (d, J = 8.1 Hz, 1 H).
1-(1-Methylindolin-5-yl)ethanone (8)27
Mp 59.5–60.2 °C (Lit. 59.5–60 °C).
1H NMR (CDCl3, 500 MHz): d = 2.5 (s, 3 H), 2.8 (s, 3 H), 3.0 (m,
2 H), 3.5 (m, 2 H), 6.3 (d, J = 8.3 Hz, 1 H), 7.7 (s, 1 H), 7.9 (m,
1 H).
1-Indol-4-ylethanone (9)32
Mp 161.5–162.4 °C (Lit. 163–164 °C).
1H NMR (CDCl3, 500 MHz): d = 2.7 (s, 3 H), 7.3 (m, 1 H), 7.4 (d,
J = 2.6 Hz, 2 H), 7.6 (d, J = 7.9 Hz, 1 H), 7.8 (d, J = 7.4 Hz, 1 H),
8.4 (br s, 1 H).
1-Indol-5-ylethanone (10)33
Mp 72.8–75.4 °C (Lit. 73–75 °C).
1H NMR (CDCl3, 500 MHz): d = 2.7 (s, 3 H), 6.7 (s, 1 H), 7.3 (m,
1 H), 7.4 (d, J = 8.6 Hz, 1 H), 7.9 (d, J = 8.6 Hz, 1 H), 8.3 (s, 1 H),
8.5 (s, 1 H).
Acknowledgment
Dr L. Cai and Dr V. W. Pike were supported by the Intramural
Research Program of the National Institutes of Health (NIMH).
Professor Xiaochun Tao received support for this research from
East China University of Science and Technology.
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861.
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Synthesis 2008, No. 6, 887–890 © Thieme Stuttgart · New York