Nickel catalyzed electrochemical heteroarylation of activated olefins

Article abstract of DOI:10.1055/s-2002-33654

Conjugate addition reaction of heteroaryl halides to activated olefins has been successfully achieved by nickel catalysis combined with the consumable anode procedure and provides access to various functionalized heteroaryl compounds with potential biolog

Full text of DOI:10.1055/s-2002-33654

1752
PAPER
Nickel Catalyzed Electrochemical Heteroarylation of Activated Olefins
H
eteroarylatio
y
n
of
A
ctivate
l
d
O
lef
v
ins ie Condon,* Daniel Dupré, Isabelle Lachaise, Jean-Yves Nédélec
Laboratoire d'Electrochimie Catalyse et Synthèse Organique CNRS, Université Paris XII- UMR 7582, 2 rue Henri Dunant 94320 Thiais,
France
Fax +33(1)49781148; E-mail: condon@glvt-cnrs.fr
Received 2 April 2002; revised 29 May 2002
As part of our investigations devoted to the heteroaryl ha-
Abstract: Conjugate addition reaction of heteroaryl halides to acti-
lide chemistry, we report in this paper the heteroarylation
vated olefins has been successfully achieved by nickel catalysis
of activated olefins mediated by nickel catalysis
combined with the consumable anode procedure and provides ac-
(Scheme 1). This straightforward, mild, and efficient re-
action is compatible with a large number of functional
groups9 and easily implemented.11
cess to various functionalized heteroaryl compounds with potential
biological activity.
Key words: catalysis, nickel, heteroaryl halide, electrochemistry,
alkenes
NiII / e- (anode)
HetAr
+
HetArX
EWG
EWG
60-80°C
Functionalized heteroaromatic structures are important
building blocks for the synthesis of biologically active
molecules as pharmaceuticals or agrochemicals. Het-
eroaromatic compounds have also found applications in
material science and supramolecular chemistry. One gen-
eral access to functionalized heteroaryl compounds uses
heteroaryl metal intermediates. These can be obtained ei-
ther by directed hydrogen-metal exchange1a b (lithium or
magnesium) or by halogen-metal exchange2a d (e.g. with
iPrMgX or BuLi) eventually followed by transmetallation
with CuCN,2d ZnCl23a or nBu3SnCl.3a These intermediates
are further reacted with electrophiles in coupling or addi-
tion reactions eventually in the presence of transition met-
EWG: electrowithdrawing group
Scheme 1
This reaction is a very convenient method to tether a func-
tional group separated by two methylene groups to an aryl
moiety with the aim of either modifying the physical
properties of the substrate (polar group) or enabling fur-
ther grafting to another moiety.
The reaction mechanism (Scheme 2) includes i. the elec-
trochemical reduction of NiBr2 into Ni(0) which is stabi-
lized in the solution by complexation to weak ligands
(pyridine, acetonitrile, the activated olefin) along with the
release of iron ions from anode oxidation, ii. the oxidative
addition of ArX to Ni(0), iii. the insertion of activated ole-
fin into the Ar Ni bond.
2a
b
3a–b
al catalyst. Pyridyl,
imidazoyl,
or pyrazoyl4
halides were functionalized according to these two-step
procedures. Though efficient, these procedures usually re-
quire very restrictive reaction conditions, notably low or
even quite low temperature.1,2c,d Alternatively, cross-cou-
pling reactions5a–5b mediated by transition metal catalysts
involving organometallics and heteroaryl halides have
been described in the literature for alkylation and aryla-
tion of heterocyclic compounds.
Ni0Ln
EWG
-1.0 V/SCE
[ Ni0]
NiII + 2 e-
EWG
Ar-X
nL
X
X
NiII Ln
EWG
NiIILn
More importantly, however, transition metal catalysis of-
fers very interesting prospects in that one-pot procedures
can be carried out directly from readily available heteroar-
yl halides when the catalytic process can be combined
with a reducing agent operating in situ.6 We have already
developed this approach by combining the transition met-
al catalyzed electroreductive activation of organic halides
and the use of a sacrificial anode. We have applied this
methodology to aryl or alkenyl halides in cross-coupling
with organic halides7 in addition reaction to aldehydes8 or
to activated olefins9a–9c and more recently to heteroaryl
halides in homo- and cross-coupling reactions.10
Ar
Ar
EWG
Scheme 2
The final organonickel intermediate can be either proto-
nated in situ to give the product and Ni(II) or converted
into an alkyl iron intermediate by transmetallation with
iron ions (Scheme 3).
The interest of heterocyclic structures in bioactive com-
pounds prompted us to examine if this approach
(Scheme 1) is compatible with the presence of heteroat-
oms (N, S, O) in the aromatic ring. The key points in this
investigation are the nature and the number of heteroat-
oms in the aromatic ring, the nature of the halogen, as well
as its position relative to the heteroatom.
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-2096,E;2002,0,12,1752,1758,ftx,en;Z05902ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

PAPER
Heteroarylation of Activated Olefins
1753
lower than those previously obtained in the arylation of
activated olefins.9b
X
MXn
MXn-1
EWG
NiIILn
EWG
- NiX2Ln
path A
Ar
Ar
The presence of the heteroatom in the ring can account for
differences in efficiency between arylation and the het-
eroarylation reactions. Indeed the heteroatom in the sub-
strate can compete with the weakly coordinating ligands
like acetonitrile, pyridine or the activated olefin to form a
new nickel species. Also, as compared to nitrogen, sul-
phur (entries 16-20) may exhibit a stronger affinity for
nickel species leading possibly to fully coordinated unre-
active nickel complexes. Finally, the consistent difference
in reactivity when the halogen is located in position 2 as
compared to position 3 can be rationalized by a stronger
coordination of the corresponding adduct to nickel species
in structure (I) than in (II) (Scheme 4) again leading to un-
reactive species.
in situ
protonation
in or ex situ
protonation
path B
- NiII
Ar
EWG
Scheme 3
We first investigated the reactivity of heteroaryl halides
bearing a single heteroatom i.e. the 2- and 3-halo-deriva-
tives of pyridine, quinoline, and thiophene. Methyl vinyl
ketone (MVK) which is a good Michael acceptor in the
arylation process9b was selected as the activated olefin and
the conjugate addition reactions were first performed ac-
cording to either of the two protocols previously reported,
that is, in DMF pyridine, 9:19a–b (method A) or in DMF
acetonitrile, 1:19c (method B).
The reactions are typically carried out in an undivided
electrolysis cell flushed with argon and fitted with an iron
or stainless steel rod as the anode and a concentric nickel
foam as the cathode. A short preelectrolysis, conducted at
constant current density (0.5 A/dm2) involving the oxida-
tion of the anode, along with the reduction of 1, 2-dibro-
moethane (0.7 mmol) added in the solvent mixture
containing NBu4Br NBu4I, is run at room temperature
prior to the successive addition of the heteroaryl halide (1
equiv), MVK (2.5 equiv) and the catalyst precursor
NiBr2 3H2O (0.1 equiv). We previously found that this
short preelectrolysis9c enhances the yields thanks to the
presence of iron salts at the beginning of the reaction. The
electrolysis is conducted at constant current intensity
(0.15 A) and at 60 °C until full consumption of the het-
eroaryl halide. The cathode potential throughout the elec-
trolysis is at ca –1.0 V versus SCE.
X
-O
X
[Ni]
O-
[Ni]
X: heteroatom
(I)
(II)
Scheme 4
On the basis of these assumptions we have been able to
improve the yields by working at a higher temperature and
in the presence of both excess of MVK (10 instead of 2.5
equiv) and the catalyst. The increase of the concentration
of nickel species in the solution can be easily obtained
from a stainless steel rod (Fe:Cr:Ni, 72:18:10) as the an-
ode in place of the iron rod previously used. We thus can
have a continuous release of nickel salts along with iron
salts allowing for the maintenance of the minimum
amount of efficient catalytic species over the electrolysis
procedure. These new reaction conditions are defined in
method C (Table 1) when the solvent is the DMF–pyri-
dine, 9:1 and the reaction temperature is 75 °C.
In Table 1 are reported the results of the nickel-catalyzed
electrochemical heteroarylation of MVK. In most cases
the electrochemical conjugate addition reaction occurs af-
fording the desired adduct with moderate to high yields.
The main by-product is the reduction product of the het-
eroaryl halide. Table 1 allows us to make three prelimi-
nary remarks: i. when the halogen is to the heteroatom
(N or S) yields are higher from the chloro than from the
bromo derivative, ii. on the contrary, bromine is required
at the position to nitrogen or sulfur to provide significant
yields of the addition product, iii. azines give higher
yields of the addition product than thiophene. If we now
look at the reaction conditions, striking differences are ob-
served depending on the nature of the solvents with sub-
stantial advantages of one method (A or B) over the other
according to the nature of the reagent (Table 1, entries 3,
4, 12, 13). As a general trend, method A leads to higher
yields from 2-chloro compounds (Table 1, entries 3, 4)
whereas method B is more convenient with 3-bromo com-
pounds (Table 1, entries 12, 13). These previously defined
reaction conditions however are not very satisfactory no-
tably with 2-halo substituted compounds as yields are
As shown in Table 1, this procedure is the most suitable
for -chloroazines (entries 5, 8, 11) giving yields in the
range of 80%. Slight improvement is also observed in the
case of 2-chlorothiophene (Table 1, entry 19). In the case
of 3-bromo substituted compounds there is no such an ad-
vantage in using method C as observed with 3-bromo-
quinoline (Table 1, entries 13-14).
We next focused on the application to heteroaryl halides
bearing two or more heteroatoms in their ring such as di-
azines (pyrazyl and pyrimidyl chlorides), chlorobenzox-
azole, and bromocafeine. The results are reported in
Table 2. Activation of chloropyrazine 1l by nickel catalyst
and further reaction with MVK gives similar results from
either method A or B (Table 2, entries 1, 2). We also
found that the reaction of 1l can be carried out in pure ac-
etonitrile as solvent (procedure D), which is not appropri-
ate for the standard arylation process, affording a
substantial improvement of the yield (Table 2, entry 3).
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York

1754
S. Condon et al.
PAPER
Table 1 Nickel-Catalyzed Conjugate Addition Reaction of Pyridyl, Quinolyl, and Thienyl Halides to Methyl Vinyl Ketone (MVK)a
HetAr
10% NiBr2.3H2O
+
HetArX
e-
O
O
solvents
3 a-i
1 a-k
2 a
Entry
HeteroArX
MVK (equiv)
Methodb
Reaction Time (h) Product
Yield (%)
1
2
2-Bromopyridine 1a
1a
2.5
2.5
A
B
7
5
3a
3a
30
16
3
4
5
2-Chloropyridine 1b
1b
1b
2.5
2.5
10
A
B
C
6
8
7
3a
3a
3a
52
30
83
6
2-Chloro-5-CF3-pyridine 1c
2.5
B
6
3b
56
7
8
2-Chloro-6-MeO-pyridine 1d
1d
2.5–10
10
B
C
8
7
3c
3c
18
72
9
3-Bromopyridine 1e
2.5
B
3.5
3d
73
10
11
2-Chloroquinoline 1f
1f
2.5
10
A
C
5
3.5
3e
3e
42
86
12
13
14
3-Bromoquinoline 1g
1g
1g
2.5
2.5
10
A
B
C
8.5
4.1
3.5
3f
3f
3f
49
76
85
15
4-Chloro-2-Me-quinoline 1h
2.7
B
4
3g
45
16
17
2-Bromothiophene 1i
1i
2.5
10
B
C
11
6
3h
3h
15
0
18
19
2-Chlorothiophene 1j
1j
2.5
10
B
C
10
13
3h
3h
10
31
20
3-Bromothiophene 1k
2.5
B
8
3i
43
a Reactions conditions: heteroarylhalide (7 mmol), MVK (2.5–10 equiv), NiBr2 3H2O (0.1 equiv), I = 0.15 A.
b Method A: DMF pyridine, 9:1, 60 °C, iron anode. Method B: DMF MeCN (1:1), 60 °C, iron anode. Method C: DMF pyridine, 9:1, 75 °C,
stainless steel anode.
With 2-chloropyrimidine 1m neither method A or B af- The conjugate addition reaction is less efficient with di-
fords satisfactory results. We hypothesized that a highly substituted olefins (entries 4 8, Table 3) even with dime-
efficient complexation of the catalyst by the heterocyclic thyl maleate and dimethyl fumarate which were good
reagent could hamper its reaction thus leading to a low substrates in the arylation.9a–b
turnover. Excess olefin (10 equiv) as well as a higher tem-
In conclusion the general method previously reported for
perature (method C) did not afford significant improve-
arylation reaction9a–b of activated olefins can be applied to
ment. However using acetonitrile as solvent as in the case
heteroaryl halides, though less efficiently, when conduct-
of chloropyrazine 1l enabled to get a satisfactory 53%
ed under standard reaction conditions (A or B). Reaction
conditions have to be optimized for every type of struc-
tures since yields are closely dependent on the nature and
number of heteroatoms in the ring and on the position of
yield. Excess of MVK was also necessary in the case of
chlorobenzoxazole 1n and 30% is the highest yield ob-
tained in DMF–MeCN, 1:1 (method B) while no product
was formed in DMF–pyridine, 9:1 (method C). Finally the
the halogen. Thus four experimental parameters can be
conjugate addition reaction with 2-bromocafeine as sub-
tuned in the optimization experiments: the solvent, the
strate was possible at 80 °C in DMF–MeCN, 1:1 when the
olefin/heteroaryl halide ratio, the anode, and the tempera-
iron rod (entry 10, Table 2) was replaced by a stainless
ture. 3-Heteroaryl halides mostly behave as aryl halides
steel rod (entry 11, Table 2, method E).
and can be reacted in typical reaction conditions referred
Lastly, synthetic application of the standard method B to in method B. Because of the nickel affinity of the het-
was extended to other various electron deficient olefins eroatom in the aromatic nucleus and eventually of the
(Table 3). For this study, we chose 3-bromoquinoline 1g, functionalized chain, reaction conditions have been suc-
a good substrate to alkylate (see entry 13, Table 1). The cessfully redefined for the substrates containing nitrogen.
best results were obtained with mono-substituted olefins This is clearly illustrated by the reactions of 2-halohet-
(methyl vinyl ketone, acrylonitrile, and ethyl acrylate). eroaryl compounds (Table 1) and 2-bromocafeine
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York

PAPER
Heteroarylation of Activated Olefins
1755
Nickel-Catalyzed Electroreductive Coupling; General Proce-
dure
Table 2 Extension to Nickel-Catalyzed Conjugate Addition Reac-
tion of Substrates Containing Two or More Heteroatoms with MVKa
A single-compartment electrochemical cell11 was equipped with a
nickel grid (area 30 cm2) as the cathode and a cylindrical iron or
stainless steel rod (diameter 1 cm) as the anode. Under a slow
stream of argon, tetrabutylammonium bromide (100 mg, 0.31
mmol) and tetrabutylammonium iodide (75 mg, 0.20 mmol) were
dissolved as supporting electrolytes in a mixture of DMF (15 mL)
and MeCN (15 mL) or DMF (27 mL) and pyridine (3 mL). 1,2-Di-
bromoethane (60 L, 0.70 mmol) was added. A short electrolysis
was performed at r.t. and at constant current density (0.5 A/dm2)
during 15 min. Then the current was turned off. The activated olefin
(2.5 to 10 equiv), the heteroaryl halide (7.0 mmol), and nickel bro-
mide hydrate (153 mg, 0.70 mmol) were successively added. The
reaction mixture was then heated (60 °C 80 °C). The electrolysis
was run at constant current density (0.5 A/dm2). The reaction was
monitored by GC and discontinued when most of the heteroaryl ha-
lide was consumed (3.5 to 11 h).
HetAr
10% NiBr2.3H2O
+
HetArX
e-
O
O
solvents
2 a
1 l-o
3 j-m
O
CH3
N
N
H3C
O
N
N
Br
Cl
N
N
1l
Cl
N
N
Cl
N
O
1m
1n
1o
CH3
Entry Hetero MVK
Methodb Reaction Product Yield
ArX
(equiv)
time (h)
(%)
1
2
3
1l
1l
1l
2.5
2.5
2.5
A
B
D
5
5
5
3j
3j
3j
50
50
65
For compounds 3a, 3b, 3c, 3d, 3e, 3f, 3k, 3l, 3o the work-up was
performed as follows: the reaction mixture was poured into sat.
NaHCO3 soln (100 mL) and the cell was rinsed with CH2Cl2 (30
mL). The resulting mixture was then extracted with CH2Cl2
(2 100 mL). The combined extracts were evaporated to dryness
under reduced pressure. The residue was purified by silica-gel col-
umn chromatography to give the desired compound.
4
5
6
7
1m
1m
1m
1m
2.5
2.5
10
A
B
C
D
10
6.5
4
3k
3k
3k
3k
18
21
27
53
10
6.5
8
9
1n
1n
10
10
B
C
6
3
3l
3l
30
0
For compounds 3g, 3h, 3i, 3n, 3p, 3q the work-up was performed
as follows: the reaction mixture was poured into Et2O (100 mL),
eventually decanted and filtered, and the cell was rinsed with HCl
(1 N, 30 mL). The combined Et2O solutions were then washed with
HCl (1 N, 3 70 mL). The combined aqueous layers were neutral-
ized and rendered basic by adding NaHCO3 powder, filtered and ex-
tracted with Et2O (4 70 mL). The combined extracts were dried
over Na2SO4 and the solvent removed under reduced pressure. The
residue was purified by silica-gel column chromatography to give
the desired compound.
10c
11c
1o
1o
6 10
10
B
E
5.5
3.5
3m
3m
Traces
68
a Reactions conditions: heteroarylhalide (7 mmol), MVK (2.5 10
equiv), NiBr2 3H2O (0.1 equiv) I = 0.15 A.
b Method A: DMF pyridine, 9:1, 60 °C, iron anode. Method B: DMF
MeCN, 1:1 at 60 °C, iron anode. Method C: DMF pyridine 9:1,
75 °C, stainless steel anode. Method D: MeCN, 60 °C, iron anode,
NBu4BF4 as supporting electrolyte. Method E: DMF MeCN, 1:1,
stainless steel anode.
For compounds 3m, 3j the work-up was performed as follows: The
mixture was quenched with sat. NH4Cl soln (60 mL) and extracted
with EtOAc (3 70 mL for compound 3m) or CH2Cl2 (3 70 mL
for compound 3j). The combined organic layers were dried over
Na2SO4 and the solvent was evaporated. The residue thus obtained
was purified by column chromatography to give desired compound.
c Reaction performed with 5 mmol of 2-bromocafeine at 80 °C.
(Table 2) with MVK, where a large excess of the activated
olefin and constant supply of the catalyst precursor by an-
odic dissolution of a stainless steel anode can compensate
the loss of the catalytic nickel species. The readily avail-
ability of the starting reagents and the simplicity of the
procedure makes this methodology a convenient and
straightforward way to provide new elaborated products
of great importance, notably in bio-organic chemistry.
4-(5-Trifluoromethylpyridin-2-yl)-butan-2-one (3b)
The residue was purified by column chromatography on silica-gel
(70 230 mesh) with an increasing elution polarity (15 to 50%,
Et2O pentane) to afford 0.87g (56%) of 3b as a colorless liquid.
Anal. Calcd for C10H10F3NO: C, 55.30; H, 4.64; N, 6.45. Found: C,
54.95; H, 4.76; N, 6.28.
4-(6-Methoxypyridin-2-yl)-butan-2-one (3c)
All reactions were carried out under argon atmosphere. All reagents
unless indicated and supporting electrolytes were used as received
without further purification. DMF and MeCN were dried over 3 Å
molecular sieves and stored under argon. Melting point determina-
tions were performed with a capillary melting point device (Electro-
thermal IA9100 Digital Melting Point Apparatus) and are
uncorrected. Infrared spectra (IR) were recorded on a Perkin-Elmer
283B spectrophotometer. NMR spectra were obtained with Bruker
AC 200 spectrometer (1H at 200 MHz, 13C NMR at 50.32 MHz).
The mass spectra were measured (EI) with a gas chromatography
coupled mass spectrometer at 70 eV (GCQ ThermoQuest) using a
30 m DB-5MS capillary column. Elemental analysis was deter-
mined by the Service Central d’Analyses (CNRS 69-Vernaison
France) for novel compounds.
The residue was purified by column chromatography on silica-gel
(70–230 mesh) with a mixture of pentane CH2Cl2,1:1 as eluent to
give 0.902 g (72%) of 3c as a colorless liquid .
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
66.74; H, 7.36, N, 7.81.
4-Quinolin-2-yl-butan-2-one (3e)
The residue was purified by column chromatography on silica-gel
(70–230 mesh) with a mixture of EtOAc pentane, 2:1 as eluent to
give 1.20 g (86%) of 3e as a colorless liquid.
4-Quinolin-3-yl-butan-2-one (3f)
The solid residue was purified by column chromatography on silica-
gel (230–400 mesh) with a mixture of EtOAc pentane, 2:1 as elu-
ent to give 1.18 g (85%) of 3f as shiny white crystals.
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York

1756
S. Condon et al.
PAPER
Table 3 Reaction of 3-Bromoquinoline (1g) with Various Activated Olefins according to Method Ba
Br
EWG
10% NiBr2.3H2O
e- / Fe anode
EWG
+
N
N
DMF/CH3CN, 60°C
1g (7 mmol)
2a-h (2.5 equiv)
3f, 3n-s
Entry
Olefin
Reaction Time (h)
3.7
Product
Yield (%)
76
COCH3
1
2
3
4
3f
2a
CO2Et
4.25
4.5
4
3n
3o
3p
44
51
25
2b
CN
2c
O
2d
MeO2C
CO2Me
5
6
7
8
3q
3q
16
18
2e
CO2Me
MeO2C
2f
CH3
CO2Me
7
4.5
3r
5
2g
H3C
CO2Me
8
5
3s
5
2h
a Reactions conditions: 3-bromoquinoline (7 mmol), activated olefin (2.5 equiv), NiBr2 3H2O (0.1 equiv), I = 0.15 A, DMF MeCN, 1:1, 60 °C,
iron anode.
Anal. Calcd for C13H13NO: C, 78.37; H, 6.58; N, 7.03. Found: C,
78.47; H, 6.58; N, 7.16.
2(3-Oxobutyl)benzoxazole (3l)
The solid residue was purified by column chromatography on silica-
gel (230–400 mesh) with an increasing elution polarity (10% to
30%, EtOAc pentane) to afford 0.40g (30%) of 3l as white crystals.
4-(2-Methylquinolin)-4-yl-butan-2-one (3g)
The solid residue was purified by flash chromatography (silica-gel,
230–400 mesh, eluent EtOAc pentane, 2:1) to give 0.67g (45%) of
3g as shiny white crystals.
Anal. Calcd for C11H11O2N: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.77; H, 5.96; N, 7.40
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.53; H, 7.02; N, 6.59.
3-Oxobutylcafeine (3m)
The solid residue was purified by column chromatography on silica-
gel (70–230 mesh) with 1% MeOH CH2Cl2 as eluent to give 1.35
g (68%) of 3m as white crystals.
4-Pyrazin-2-yl-butan-2-one (3j)
The compound was purified by column chromatography on silica-
gel (70–230 mesh) with 2% MeOH in Et2O as eluent to give 0.68 g
(65%) of 3j as a colorless liquid.
3-Quinolin-3-yl-propanenitrile (3o)
The residue was purified by column chromatography on silica-gel
erased (230–400 mesh) silica using EtOAc pentane, 1:1 as eluent
to give 0.65 g (51%) of 3o as a colorless liquid.
4-Pyrimidin-2-yl-butan-2-one (3k)
The residue was purified by column chromatography on silica-gel
(70–230 mesh, eluent: CH2Cl2) to give 0.55 g (53%) of slightly pale
liquid 3k which tends to darken over time.
Anal. Calcd for C12H10N2: C, 79.10; H, 5.53; N, 15.37. Found: C,
78.91; H, 5.52; N, 15.27.
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York

PAPER
Heteroarylation of Activated Olefins
1757
3-Quinolin-3-yl-cyclohexanone (3p)
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
66.11; H, 5 49; N, 4.89.
The compound was purified by column chromatography on silica-
gel (70–230 mesh) with 0.5% MeOH CH2Cl2 as eluent to give 0.40
g (25%) of 3p as a colorless liquid.
Spectral data are given in Table 4.
The following products were identified by comparison of their spec-
tral data with those given in literature: 4-pyridin-2-yl-butan-2-
one,12 4-pyridin-3-yl-butan-2-one,13 4-thiophene-2-yl-butan-2-
one,14 4-thiophen-3-yl-butan-2-one,14 ethyl 3-quinolin-3-yl-pro-
panoate.15
Dimethyl -(quinolin-3-yl)-succinate (3q)
The residue was purified by column chromatography on silica (70–
230 mesh) with 0.5% MeOH CH2Cl2 as eluent to give 0.35 g (18%)
of 3q as a solid (from dimethylfumarate)
Table 4. Physical and Spectroscopic Data of Compounds 3b q
Product Mp
(°C)
IR (NaCl)
(cm–1)
1H NMR (200 MHz, CDCl3)
ppm, J (Hz)
13C NMR
(50.32 MHz, CDCl3), ppm
MS, m/z (%)
3b
liquid 1720, 1610, 8.79 (s, 1 H), 7.84 (dd, 1 H, J = 7.3, 2.2), 7.37 (d, 1 H, 207.1, 164.4, 145.9, 145.8 133.2, 218 (base peak),
1575
J = 8.1), 3.17 (t, 2 H, J = 6.5), 3.03 (t, 2 H, J = 6.5), 2.23 133.1, 122.9, 41.4 31.3, 29.3
202, 174
(s, 3 H)
3c
3e
liquid 3030, 1720, 7.37 (t, 1 H, J = 7.7), 6.65 (d, 1 H, J = 7.7), 6.46 (d, 1 H, 208.1, 163.5, 157.9, 138.7 115.2, 180 (base peak)
1590 J = 7.7), 3.61 (s, 3 H), 2.87 (m 4 H), 2.12 (s, 3 H) 107.6, 53.0, 42.0 31.3, 29.8
liquid 3030, 1720, 7.87 (d, 1 H, J = 8.3), 7.86 (d, 1 H, J = 8.4), 7.60 (d, 1 H, 207.6, 160.5, 147.4 135.9, 129.0, 200, 184,
1600, 1560, J = 8.3), 7.52 (td, 1 H, J = 7.5, 1.2), 7.31(t, 1 H, J = 7.5), 128.4 127.2, 126.5, 125.5, 121.4, 156 (base peak),
1500
7.13 (d, 1 H, J = 8.4), 3 11(t, 2 H, J = 7.0), 2.90 (t, 2 H, 41.5, 32.1, 29.9
J = 7.0), 2.08 (s, 3 H)
128
3f
75
3030, 1710, 8.66 (s, 1 H), 7.94 (d, 1 H, J = 8.3), 7.82 (s, 1 H), 7.63 (d, 206.8, 151.7, 146.8, 134.3,
1600, 1570, 1 H, J = 7.6), 7.54 (td, 1 H, J = 7.6 1.4), 7.39 (t, 1 H,
1490 J = 7.6), 2 96 (t, 2 H, J = 7.2), 2.75 (t, 2 H, J = 7.2), 2.04 126.6, 44.2, 29.9, 26.7
(s, 3 H)
199 184
133.7, 129.0, 128.7, 127.9, 127.3 (base peak)
156, 142, 129,
115
3g
92
3040, 1720, 8.11 (m, 1 H), 8.02 (m, 1 H), 7.75 (td, 1 H, J = 7.6, 1.2), 206.8, 158.6, 147.9, 146.7,
1605, 1565, 7.58 (td, 1 H, J = 7.6, 1.2), 7.22 (s, 1 H), 3.40 (t, 2 H, 129.4, 129.1, 125.6, 125.4,
1515 J = 7.6), 2.97 (t, 2 H, J = 7.6), 2.78 (s, 3 H), 2.26 (s, 3 H) 122.9, 121.5, 43.2, 29.9, 25.5,
25.2
213, 170
(base peak)
3j
3k
3l
liquid
8.30–8.43 (m, 3 H), 2.93 (m, 4 H), 2.10 (s, 3 H)
207.0, 156.0, 144.8 143.7, 142.1, 151, 135, 107
41.2, 29.8 28.5 (base peak)
liquid 3060, 1720, 8.56 (d, 2 H, J = 4.9), 7.05 (t, 1 H, J = 4.9), 3.20 (t, 2 H, 207.1, 169.2, 156.5, 118.1, 40.1, 151, 135, 107
1580, 1440 J = 6.9), 2.94 (t, 2 H, J = 6.9), 2.16 (s, 3 H)
32.4, 29.5
(base peak)
89
7.56 (m, 1 H), 7.38 (m, 1 H), 7.20 (m, 2 H), 3.06 (m, 4 205.8, 165.9, 150.6, 141.0,
191 (base peak),
H), 2.16 (s, 3 H)
124.4, 124.0, 119.2, 110.1, 39.2, 146
29.6, 22.2
3m
3o
141
3.88 (s, 3 H), 3.44 (s, 3 H), 3.29 (s, 3 H), 2.92 (m, 4 H), 206.7, 155.2, 153.1, 151.7,
264, 221
(base peak)
2.16 (s, 3 H)
147.8, 107.4, 39.7, 31.6, 30.0,
29.7, 27.8, 23.8
liquid 2250, 1605, 8.65 (d, 1 H, J = 1.8), 7.94 (d, 1 H, J = 8.4), 7.88 (d, 1 H, 150.9, 147.2, 134.7, 130.7,
182,
1570, 1490 J = 1.8), 7.65 (dd, 1 H, J = 8.2, 1.2), 7.56 (td, 1 H,
J = 7.6, 1.3), 7.40 (td, 1 H, J = 7.6, 1.3), 2.99 (t, 2 H,
J = 7.3), 2.58 (t, 2 H, J = 7.3)
129.3, 129.1, 127.7, 127.6,
126.9, 118.8, 28.6, 18.8
142 (base peak),
115
3p
3q
liquid 1740, 1625, 8.74 (d, 1 H, J = 2.2), 8.00 (d, 1 H, J = 8.4), 7.86 (d, 1 H, 209.9, 150.4, 147.1, 136.8,
1590, 1520 J = 2.2), 7.71 (m, 1 H), 7.61 (m, 1 H), 7.46 (m, 1 H), 3.16 132.5, 129.1, 129.0, 128.0,
(br m, 1 H), 2.61 (m, 2 H), 2.41 (m, 2 H), 2.09 (m, 2 H), 127.6, 126.9, 48.1, 42.1, 41.0,
226, 197, 182,
168 (base peak),
154, 140
1.89 (m, 2 H)
32.3, 25.2
67
3020, 1750, 8.80 (s, 1 H), 8.05–7.99 (m, 2 H), 7.73 (dd, 1 H, J = 8.1, 172.6, 171.4, 150.5, 147.5,
274, 273, 241
213 (base peak),
198, 183,
1605, 1575, 1.5), 7.65 (td, 1 H, J = 7.4, 1.5), 7.49 (td, 1 H, J = 7.4, 134.3, 134.2, 130.5, 129.6,
1500 1.5), 4.26 (dd, 1 H, J = 9.4, 5.9), 3.64 (s, 3 H), 3.61 (s, 3 129.2, 127.7, 127.0, 52.6,
H), 3.27 (dd, 1 H, J = 17.0, 9.4), 2.75 (dd, 1 H, J = 17.0, 52.0, 44.7, 37.1
5.9)
172, 154, 140,
128
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York

1758
S. Condon et al.
PAPER
(8) Durandetti, M.; Périchon, J.; Nédélec, J. Y. Tetrahedron
References
Lett. 1999, 40, 9009.
(1) (a) Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059.
(b) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G.
Tetrahedron 2001, 57, 4489.
(9) (a) Condon-Gueugnot, S.; Léonel, E.; Nédélec, J. Y.;
Périchon, J. J. Org. Chem. 1995, 60, 7684. (b) Condon, S.;
Dupré, D.; Falgayrac, G.; Nédélec, J. Y. Eur. J. Org. Chem.
2002, 105. (c) Condon-Gueugnot, S.; Dupré, D.; Nédélec, J.
Y.; Périchon, J. Synthesis 1997, 1457.
(10) (a) Cannes, C.; Condon, S.; Durandetti, M.; Périchon, J.;
Nédélec, J. Y. J. Org. Chem. 2000, 65, 4575. (b) Gosmini,
C.; Lasry, S.; Nédélec, J. Y.; Périchon, J. Tetrahedron 1998,
54, 1289. (c) Gosmini, C.; Nédélec, J. Y.; Périchon, J.
Tetrahedron Lett. 2000, 41, 201. (d) Durandetti, M.;
Périchon, J.; Nédélec, J. Y. Tetrahedron Lett. 1997, 38,
8683. (e) de França, K. W. R.; Navarro, M.; Léonel, E.;
Durandetti, M.; Nédélec, J. Y. J. Org. Chem. 2002, 67, 1838.
(11) Chaussard, J.; Folest, J. C.; Nédélec, J. Y.; Périchon, J.;
Sibille, S.; Troupel, M. Synthesis 1990, 369.
(12) Ferles, M.; Kafka, S.; Silhánková, A.; Sputová, M. Collect.
Czech. Chem. Commun. 1981, 46, 1167.
(13) Wenkert, E.; Chang, C. J.; Chawla, H. P. S.; Cochran, D. W.;
Hagaman, E. W.; King, J. C.; Orito, K. J. Am. Chem. Soc.
1976, 98, 3645.
(14) Tamaru, Y.; Yamada, Y.; Yoshida, Z. I. Tetrahedron 1979,
35, 329.
(15) Griesgraber, G.; Kramer, M. J.; Elliot, R. L.; Nilius, A. M.;
Ewing, P. J.; Raney, P. M.; Bui, M. H.; Flamm, R. K.; Chu,
D. T. W.; Plattner, J. J.; Or, Y. S. J. Med. Chem. 1998, 41,
1660.
(2) (a) Trécourt, F.; Breton, G.; Bonnet, V.; Mongin, F.;
Marsais, F.; Quéguiner, G. Tetrahedron Lett. 1999, 40,
4339. (b) Trécourt, F.; Breton, G.; Bonnet, V.; Mongin, F.;
Marsais, F.; Quéguiner, G. Tetrahedron 2000, 56, 1349.
(c) Bérillon, L.; Leprêtre, A.; Turck, A.; Plé, N.; Quéguiner,
G.; Cahiez, G.; Knochel, P. Synlett 1998, 1359. (d)Abarbri,
M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40,
7449.
(3) (a) Jetter, M. C.; Reitz, A. B. Synthesis 1998, 829.
(b) Turner, R. M.; Lindell, S. D. J. Org. Chem. 1991, 56,
5739.
(4) Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.;
Vedso, P.; Begtrup, M. J. Org. Chem. 1999, 64, 4196.
(5) (a) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.
Tetrahedron 1982, 38, 3347. (b) Chi, S. M.; Choi, J. K.;
Yum, E. K.; Chi, D. Y. Tetrahedron Lett. 2000, 41, 919.
(6) (a) For homocoupling see: Iyoda, M.; Otsuka, H.; Sato, K.;
Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80. (b)
For conjugate addition reaction see: Sustmann, R.; Hopp, P.;
Holl, P. Tetrahedron Lett. 1989, 30, 689.
(7) Durandetti, M.; Nédélec, J. Y.; Périchon, J. J. Org. Chem.
1996, 61, 1748.
Synthesis 2002, No. 12, 1752–1758 ISSN 0936-5214 © Thieme Stuttgart · New York