Synthesis of symmetrical bisquinolones via nickel(0)-catalyzed homocoupling of 4-chloroquinolones

Article abstract of DOI:10.1002/adsc.200700081

A method for the gram-scale preparation of functionalized 4,4′-bisquinolones using a microwave-assisted Ullmann-type homocoupling reaction is described. The method is catalytic in nickel(O) which is generated in situ by reduction from an inexpensive nickel(II) source and utilizes readily available 4-chloroquinolin-2(1H)-ones as starting materials. In contrast to the alternative palladium(0)-catalyzed one-pot borylation/Suzuki crosscoupling reaction, the new method avoids the use of an expensive catalyst and cross-coupling partner such as bis(pinacolato)diboron.

Full text of DOI:10.1002/adsc.200700081

UPDATES
DOI: 10.1002/adsc.200700081
Synthesis of Symmetrical Bisquinolones via Nickel(0)-Catalyzed
Homocoupling of 4-Chloroquinolones
Jamshed Hashima and C. Oliver Kappea,*
a
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)and Institute of Chemistry, Karl-Franzens University
Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Phone: (+43)-316-380-5352; fax: (+43)-316-380-9840; e-mail: oliver.kappe@uni-graz.at
Received: February 2, 2007; Revised: August 3, 2007
Abstract: A method for the gram-scale preparation
of functionalized 4,4’-bisquinolones using a micro-
wave-assisted Ullmann-type homocoupling reaction
is described. The method is catalytic in nickel(0)
which is generated in situ by reduction from an in-
expensive nickel(II)source and utilizes readily
available 4-chloroquinolin-2(1H)-ones as starting
materials. In contrast to the alternative palladi-
um(0)-catalyzed one-pot borylation/Suzuki cross-
coupling reaction, the new method avoids the use
of an expensive catalyst and cross-coupling partner
such as bis(pinacolato)diboron.
In view of the substantial interest and broad appli-
cation of symmetrical biaryls,[1–11] considerable efforts
have been undertaken to achieve efficient, economi-
cal, safe, and environmentally benign methods for
their preparation in many academic and industrial
laboratories.[12] Since the first biaryl couplings per-
formed by Ullmann over a century ago applying stoi-
chiometric amounts of copper metal,[13] the catalytic
use of transition metals, especially of palladium and
nickel, in the formation of symmetrical biaryls is now
well established.[12] In this context we recently report-
ed the first synthesis of 4,4’-bisquinolones of type 1.[14]
These novel, symmetrical bis-heterocycles are of con-
siderable interest as aza-analogues of biscoumarin
natural products (e.g., 4,4’-biisofraxidin),[2] because of
their anticipated fluorescent properties as push-pull
carbostyrils (1, R3 =R4 =OMe),[15] and as starting ma-
terials for the synthesis of novel aza-BINAP ana-
logues (Figure 2).[16]
Keywords: homocoupling; homogeneous catalysis;
microwave heating; nickel; quinolones; reduction
Introduction
In our recent publication we have outlined the gen-
eration of 4,4’-bisquinolones 1, employing both a pal-
The structural subunit of symmetrical biaryls plays an ladium(0)-catalyzed one-pot borylation/Suzuki cross-
important role in organic and medicinal chemistry, coupling method, and a nickel(0)-mediated homocou-
and is found in a wide variety of natural products in- pling protocol using the corresponding 4-chloroquino-
cluding alkaloids such as the anti-HIV alkaloid mi- lin-2(1H)-ones 2 as precursors.[14] Both methods did in
chellamine B,[1] coumarins (4,4’-biisofraxidin),[2] poly- fact allow the successful, high-yielding preparation of
ketides[3] and terpenes (Figure 1).[4] Compounds incor- a variety of bisquinolones of type 1, in addition to
porating symmetrical biaryl moieties also find applica- 4,4’-biscoumarin and a range of other symmetrical bi-
tions as conductors for thin film transistor applica-
C
ceuticals (e.g., in the laxative agent 4,4’-biphenol),[9]
and in agrochemicals (e.g., in the non-selective broad- avoids the use of a cross-coupling partner and there-
spectrum herbicide paraquat).[10] Related biaryl het- fore appears to be more favorably from the stand-
erocycles are also well known in the literature and point of atom economy,[18] our original nickel-mediat-
often display similarly interesting biological and phys- ed method utilized stoichiometric amounts of a nick-
ical properties.[11]
el(II)source (1.3 equivalents of NiCl )and required 4
2
equivalents of triphenylphosphine as ligand.[14] The
Adv. Synth. Catal. 2007, 349, 2353 – 2360
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Jamshed Hashim and C. Oliver Kappe
UPDATES
Figure 1. Important symmetrical biaryl products.
subsequent complex chromatographic separation of lies in the fact that these heteroaryl chlorides are
the desired product from triphenylphosphine and its comparatively unreactive as coupling partners. It is
oxide impurity in fact only allowed the preparation of well known that aryl chlorides, despite the fact that
quantities of bisquinolones 1 on a less than 50-mg those substrates would generally be the most useful
scale.[19] We now report an improved method for the ones because of their low cost and the wide availabili-
homocoupling of 4-chloroquinolin-2(1H)-ones 2 (see ty,[20] are comparatively unreactive as coupling part-
Table 1, Table 2 and Table 3)that utilizes a compara-
ners in transition metal-catalyzed processes when
tively inexpensive combination of a nickel catalyst [25 compared to aryl bromides and iodides.[20] General
mol% of NiCl2(PPh3)2] and an additional bidentate and efficient protocols employing aryl chlorides as
N
ligand (25 mol% of DPEphos).[17] Importantly, using starting materials in such transformations have only
this method good isolated product yields can in many recently emerged in the literature.[20–23] The low reac-
cases be obtained without purification by chromatog- tivity of aryl chlorides is usually attributed to the
À
raphy, allowing the preparation of bisquinolones 1 in strength of the C Cl bond (Àb1ond dissociation energies
À1
À
gram-scale quantities.
for Ph X: Cl=96 kcalmol ; Br=81 kcalmol ; I=
65 kcalmolÀ1)which leads to a reluctance of aryl
chlorides toward oxidative addition to transition
metal centers, a critical step in many transition metal-
catalyzed coupling reactions.[20]
Results and Discussion
The main problem in the reported cross- and homo-
In our original nickel-mediated reductive homocou-
couplings involving 4-chloroquinolin-2(1H)-ones[14] pling, the active nickel(0)complex was generated
Figure 2. 4,4’-Bisquinolones and 4,4’-biscoumarins.
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Adv. Synth. Catal. 2007, 349, 2353 – 2360

Synthesis of Symmetrical Bisquinolones
UPDATES
Scheme 1. Proposed mechanism of Ni(0)-mediated homocouplings of aryl halides using Ni(0) species.[26]
from a nickel(II)salt and Zn dust as reducing agent
All optimization studies were performed on a 0.25-
in the presence of triphenylphosphine as ligand.[14] In mmol scale using sealed vessel microwave heating in
order to simplify and possibly to improve this proce- order to extend the available temperature range
dure we have now considered the direct use of a above the boiling point of the individual solvent.[27]
nickel(0)source. The successful use of the commer-
An extensive optimization of the reaction parameters
cially available zerovalent nickel complex Ni(COD)2 included the amount of the nickel reagent, the type
AHCTREUNG
(COD=1,5-cyclooctadiene)in related homocoupling
and concentration of additional ligands, the use of
reactions of aryl bromides or iodides (Scheme 1)[24,25] other additives, different solvents, reaction time and
prompted us to apply these conditions also to the ho- temperature. While aryl bromides and iodides have
mocoupling of 4-chloro-1-methylquinolin-2-(1H)-one been shown to undergo this type of coupling with rel-
2a as a model substrate (Table 1).[24,25]
ative ease,[24,25] only one example of a reductive homo-
coupling which involves an aryl chloride is known,
Table 1. Reaction optimization for the nickel(0)-mediated reductive homocoupling of 4-chloroquinolone 2a using Ni-
(COD)2.[a]
ACHTREUNG
Entry Ni
(COD)2
2,2ꢁ-Dipyridyl ligand
(equivs.)
KI additive
(equivs.)
Time
[min]
Solvent/temperature Product distribution
[8C]
(equivs.)
(%)[b]
1
2
3
4
5
6
7
8
0.50
0.75
0.75
0.75
0.75
0.75
0.75
0.75
1.0
1.0
-
1.0
1.0
0.5
1.0
1.0
-
-
-
-
0.5
0.5
0.5
0.5
25
25
25
35
35
35
35
55
DMF/195
DMF/195
DMF/195
dioxane/130
dioxane/130
dioxane/130
THF/120
40/52/8
0/97/3
20/75/5
10/90/0
0/99/1c
5/94/1
9/80/11
17/73/10
DMSO/160
[a]
[b]
[c]
Reaction conditions: 0.25 mmol chloroquinolone 2a, Ni(COD)2, 2,2’-dipyridyl, KI, 1.5 mL dry solvent, sealed vessel single
A
mode microwave irradiation. See the Experimental Section for further information.
Product distribution refers to relative peak area (%)ratios of crude HPLC-UV (215 nm)traces: starting material 2a/
product 1a/dehalogenated product.
Product isolation by filtration through Celite, evaporation, and subsequent recrystallization furnished a 93% yield of bis-
quinolone 1a.
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Jamshed Hashim and C. Oliver Kappe
UPDATES
providing a mere 14% product yield.[24] In these less ligand which would greatly simplify the purifica-
transformations, the oxidative addition generally is tion process and thus make this method scalable. A
the rate-limiting step (Scheme 1). Aryl halides which number of examples involving the Ni-mediated homo-
have comparatively small dissociation energies (e.g., coupling of aryl chlorides to biphenyls have been re-
aryl iodides)will undergo faster oxidative addition to
ported in the literature.[29,30] In this context, several
the metal center and ultimately will show a higher re- sources of nickel(II)were evaluated under the origi-
activity in the reductive homocoupling.[24] Since there nally reported in situ reductive conditions using zinc
is no regeneration mechanism in this homocoupling, dust.[14] In addition, in light of the results obtained
stoichiometric amounts of Ni
N
N
ployed in order to achieve full conversion. In the case DMF to dioxane. In our originally reported protocol
of 4-chloro-1-methylquinolin-2-(1H)-one 2a the use of requiring stoichiometric amounts of an Ni source
0.75 equivs. of the sensitive Ni
(1.5 equivs. per biaryl product)provided the best re-
sults. Lowering the amount of Ni(COD)2 led to in- ing the regeneration of the active Ni(0)species. The
A
elimination step is not favorable, therefore not allow-
AHCTREUNG
complete conversions (Table 1, entry 1), with the only use of DMF or other coordinating dipolar aprotic sol-
observed by-product being the dehalogenated quino- vents will likely lead to de-coordination of ligands
lone.[14] Nickel(0)-mediated homocoupling reactions from the Ni(0)complex and to the formation unde-
routinely rely on additional ligands,[12,24–26,28] which sta- sired side products.[30] Employing dioxane as solvent,
bilize the catalyst and the arylnickel species during most of the tested nickel(II)salts/complexes such as
the reaction sequence and restrict decomposition. In NiCl2, NiCl2
A
(dppe), NiCl2
A
the present case, 1.0 equivalent of 2,2’-dipyridyl ex- (acac)2 were effective in the desired homocoupling
AHCTREUNG
hibited an optimum effect on the observed conversion (Table 2). In all cases the only by-product was the de-
(compare entries 2 and 3). Close to quantitative con- halogenated quinolone. By adding an additional
versions were observed by heating the reaction mix- amount of a bidentate ligand (see mechanistic discus-
ture in DMF at 1958C for 25 min. Under these condi- sion below), such as bis(2-diphenylphosphinophenyl)
tions, only very small amounts of the dehalogenated ether (DPEphos)or diphenylphosphinoferrocene
side-product, 1-methylquinolin-2-(1H)-one, were ob- (dppf)(Figure 3)to the reaction mixture, the amount
served by HPLC monitoring. Ultimately, we found of the required nickel(II)complex could be reduced
that optimum results were achieved by switching to to 20 mol% and the dehalogenation pathway could
anhydrous dioxane as a solvent, which allowed reduc- be largely suppressed (entries 3 and 7).
tion of the reaction temperature to 1308C. Further
improvements were made by adding 0.5 equivalents ployed 20 mol% of NiCl
One of the best sets of conditions (entry 3)em-
AHCTREUNG
of potassium iodide as an additive since it is known and 20 mol% of dppf as ligand employing the tradi-
that iodide ions enhance the reaction rate of nickel- tional reductive environment (1.3 equivs. Zn dust,
catalyzed homocoupling reactions (compare entries 4 1.8 equivs. KI). Microwave heating of the reaction
and 5).[28] Under optimized reaction conditions mixture at 1308C for 30 min provided full conversion
(Table 1, entry 5), full conversion to bisquinolone 1a to the bisquinolone product with less than 10% of the
was observed within a 35 min reaction time with only dehalogenated by-product being formed (86% isolat-
1% of the dehalogenated by-product formed. Gratify- ed yield by flash chromatography). Equally high se-
ingly, product isolation in this case did not require lectivity and efficiency toward homocoupling was dis-
chromatography and simply involved filtration played employing DPEphos as a ligand system, albeit
through a Celite pad, evaporation of solvent, and re- using
crystallization of the crude product from acetonitrile (entry 7).
to provide a 93% isolated product yield of the desired While both methods required only 0.20–0.25 equivs.
bisquinolone 1a. This protocol could be scaled to of the relatively inexpensive nickel(II)complex NiCl
a 25 mol% catalyst and ligand loading
2
1.0 mmol to provide 1a in ca. 100 mg quantity. De-
spite this fact, the high cost and pronounced air sensi- fact that here chromatography is not required to sepa-
tivity of the Ni
(COD)2 reagent,[17] employed in almost rate triphenylphosphine and the additional dppf/DPE-
A
ACHTREUNG
stoichiometric amounts, precluded this method from phos ligands from the bisquinolone product. Notably,
being used for the preparation of larger quantities of the use of DPEphos (entry 7)provides equally high
bisquinolones.
conversions as dppf (entry 3), but is the ligand of
We therefore turned our attention again to our choice due to the significantly lower cost.[17] We have
original reductive homocoupling protocol starting therefore performed a ca. 40-fold scale-up of the ex-
from a nickel(II)source in the hope to turn the stoi-
periment described in entry 7 employing 11 mmol of
chiometric method into a catalytic version that would chloroquinolone 2 as starting material employing a
require less metal, and therefore also a smaller larger microwave process vial (11-mL reaction
amount of the reducing agent and, most importantly, volume). Gratifyingly, monitoring the crude reaction
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Synthesis of Symmetrical Bisquinolones
UPDATES
Table 2. Catalyst/ligand screening for the nickel(0)-mediated
reductive homocoupling of 4-chloroquinolone using Ni(II)
complexes.[a]
Figure 3. Structures of bidentate ligands DPEphos and dppf.
In order to evaluate the general applicability of this
homocoupling protocol, a number of different 4-
chloroquinolone substrates (in addition to 4-chloro-
coumarin)[14] were subjected to the optimized cou-
pling protocol outlined above (Table 2). Utilizing the
optimized catalytic method detailed in Table 2
(entry 7), all substrates did undergo homocoupling to
the respective biaryl derivatives in >98% conversion
and with very high selectivity. The amount of dehalo-
genated by-products in most cases was below 5% In
fact, we find that this new protocol involving catalytic
Entry Catalyst
(mol%)
Additive
(mol%)
Product distribution
(%)[b]
1
2
3
4
5
NiCl2
(10)
NiCl
(20)
NiCl
(20)
NiCl2
(20)
N
61/39
87/13
91/9[c]
68/32
71/29
dppf (20)0/
dppf (25)0/
amounts of NiCl2(PPh3)2 in combination with DPE-
A
NiCl
(25)
2(dppf)
phos as ligand provides equally high isolated product
yields (71–92%)compared to our previously pub-
6
7
Ni
NiCl2
(25)
N
1/
65/34
lished method employing stoichiometric amounts of a
0/91/9[d]
[14]
Ni(II)source.
In most cases, the extractive work-
up/purification elaborated above specifically for bis-
quinolone 1a was also successful for other biaryl de-
[a]
[b]
Reaction conditions: 0.25 mmol chloroarene 2a, Ni cata-
lyst, ligand, 1.3 equivs. Zn dust, 1.8 equivs. KI, 1 mL dry
dioxane, sealed vessel single mode microwave irradiation
at 1308C for 30 min.
Product distribution refers to relative peak area (%)
ratios of crude HPLC-UV (215 nm)traces: starting mate-
rial 2a/product 1a/dehalogenated product.
Product isolation by flash chromatography provided a
86% yield of bisquinolone 1a.
For an 11-mmol run, product isolation by an extractive
work-up and recrystallization led to a 74% yield of iso-
lated pure product.
Table 3. Nickel(0)-mediated reductive homocoupling of 4-
chloroquinolone using NiCl2
(PPh3)2 and DPEphos.[a]
G
[c]
[d]
Substrate
Yield [%][b]
mixture by HPLC demonstrated the full scalability of
this process: again, less than 10% of the unwanted
dehalogenated quinolone was observed, with HPLC
traces being nearly identical to those of the small-
scale experiment. In the purification procedure, the
dioxane solvent was evaporated under reduced pres-
sure. After addition of acetonitrile and warming to ca.
808C the crude reaction mixture was filtered through
a pad of Celite. Since DPEphos is nearly insoluble
under those conditions, most of the ligand material
could be removed. Evaporation of the acetonitrile sol-
vent furnished the crude bisquinolone product which
was subsequently dissolved in dichloromethane and
washed three times with saturated aqueous ammoni-
um chloride solution. Evaporation of dichlorome-
thane and recrystallization of the crude material from
acetonitrile provided bisquinolone 1a in 74% yield
(purity>99% by HPLC at 215 nm).
2a; R1 =Me, R2 =R3 =R4 =H
2b; R1-R2 =(CH2)3, R3 =R4 =H
2c; R1 =Me, R2 =R3 =H, R4 =OMe
2d; R1 =Me, R2 =R4 =H, R3 =OMe
2e; R1 =Me, R2 =H, R3 =R4 =OMe
2f; 4-chlorocoumarin
85 (69)
92 (39)
71 (À)c
79 (45)
83 (34)
92 (73)
[a]
Reaction conditions: 0.50 mmol chloroarene 2, 25 mol%
NiCl2(PPh3)2, 25 mol% DPEphos, 1.3 equivs. Zn dust,
AHCTREUNG
1.8 equivs. KI, 0.8 mL dry dioxane, sealed vessel single
mode microwave irradiation at 1308C for 30 min.
Isolated yields of pure product using flash chromatogra-
phy. In parenthesis, isolated yields obtained by extractive
work-up and recrystallization (see Experimental Sec-
tion).
[b]
[c]
Due to the insolubility of this material in acetonitrile, the
extraction procedure was not successful in this case.
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Jamshed Hashim and C. Oliver Kappe
UPDATES
the success was a change of solvent and the combined
use of bidentate and monodentate ligands providing
more active Ni(0)catalytic species. The method is
therefore scalable and will allow us to further study
the properties of these novel types of bisheterocylces.
Experimental Section
General Remarks
All homocoupling reactions involving air-sensitive reagents
were carried out under an atmosphere of dry argon. Dry
flash chromatography[33] was performed on Merck silica gel
60 H (<45 nm particle size). TLC analyses were performed
on pre-coated (Merck Silica gel 60 HF254)plates. 1H NMR
and 13C NMR spectra were recorded on a Bruker 360 MHz
instrument at 360 and at 90 MHz, respectively. FT-IR spec-
tra were recorded using KBr pellets. Low resolution mass
spectra were obtained on an Agilent 1100 LC/MS instru-
ment using atmospheric pressure chemical ionization
(APCI)in positive or negative mode. Analytical HPLC
analysis was carried out on a Merck C18 reversed-phase
(RP)analytical column (119”3 mm, particle size 5 mm)or a
Pathfinder-AS100 reversed-phase column (150”4.6 mm,
particle size 5 mm)at 25 8C using mobile phase A [water/
acetonitrile 90:10 (v/v)+0.1% TFA] and B (MeCN+0.1%
TFA)at a flow rate of 0.5–1.0 mLmin À1. The following gra-
dient was applied: linear increase from solution 30% B to
100% B in 7 min, hold at 100% solution B for 2 min.
Zn powder (Merck 108789, <60 mm particle size)was
used for the Ni(0)-catalyzed homocouplings. All anhydrous
solvents, catalysts and ligands were obtained from Aldrich
Chem. Co. and were used without any further purification.
Microwave irradiation experiments were carried out on an
Initiator Eight EXP or Emrys Synthesizer single-mode
cavity instrument, producing controlled microwave irradia-
tion at 2450 MHz (Biotage AB, Uppsala). Reaction times
refer to hold times at the temperature indicated, not to total
irradiation times. The temperature was measured with an IR
sensor on the outside of the reaction vessel.
Figure 4. Difference in catalytic activity of coordinatively
unsaturated and saturated Ni(0)complexes.
rivatives, although the isolated yields using this non-
chromatographic method were not always as high as
when using standard flash chromatography (Table 3).
Mechanistic Discussion
It is known that bidentate ligands such as dppf
(Figure 3)increase the electron density on low-valent
transition metals, making the metal more nucleophil-
ic, thus facilitating oxidative addition and reducing
the propensity for reductive elimination.[26,31] The use
of NiCl2(dppf)in the presence of an additional
R
amount of dppf (Table 2, entry 5)may lead to the for-
mation of a rather stable coordinatively saturated
Ni(0)ligand complex (Figure 4)with tetrahedral ge-
ometry having large ligand bite angles (dppf=968).
This reduces the accessibility for oxidative addition.[32]
In contrast, a coordinatively unsaturated Ni(0)com-
plex generated from NiCl2(PPh3)2 and dppf (Figure 4)
A
is more efficient toward oxidative addition and will
enhance the overall efficiency of the catalytic cycle.[32]
In the specific homocoupling reaction described in
Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-
one 2a using Bis(1,5-cyclooctadiene)nickel(0)
Table 2, NiCl
and selective than the bidentate ligand catalyst NiCl2
(dppf)(compare entries 3 and 5). NiCl 2(PPh3)2 is sur-
T
A
ACHTREUNG
A mixture containing 48.4 mg (0.25 mmol)of 4-chloro-1-
methylquinolin-2(1H)-one (2a),[34] 51.7 mg (0.188 mmol,
rounded by monodentate ligands and is thus more ef-
ficient to generate coordinatively reactive Ni(0) in
situ in the presence of an additional dppf ligand.
0.75 equivs.)of Ni (COD)2, 39.0 mg (0.25 mmol, 1.0 equiv.)
E
of 2,2’-dipyridyl, and 20.8 mg (0.125 mmol, 0.50 equivs.)of
KI was suspended in 1.0 mL of anhydrous dioxane under an
argon atmosphere in a 5-mL Pyrex microwave vial equipped
with a magnetic stirring bar. The vial was sealed, stirred for
4 min at room temperature, and then heated for 35 min at
1308C. Thereafter, the solvent was removed under reduced
pressure, the remaining residue dissolved in CH2Cl2 and fil-
tered through a small pad of Celite. Evaporation of the sol-
vent and recrystallization of the resulting crude material
from acetonitrile delivered pure bisquinolone 1a; yield:
36.8 mg (93%).
Conclusions
In summary, we have developed a Ni(0)-catalyzed re-
ductive homocoupling reaction of easily accessible 4-
chloroquinolin-2(1H)-ones that provides 4,4’-bisquino-
lones in good yields. In contrast to our previous proto-
col,[14] this new method only requires 0.25 equivalents
of a comparatively inexpensive Ni source and does not
The reaction was also performed on a 1.0-mmol scale
rely on chromatography for product isolation. Key to (1308C for 55 min)providing the same product yield.
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Synthesis of Symmetrical Bisquinolones
UPDATES
4 min at room temperature, and then heated by microwave
irradiation for 30 min at 1308C. Thereafter, the solvent was
removed under reduced pressure. The products were isolat-
ed by gradient dry flash chromatography using EtOAc/ace-
tone as solvent mixture to obtain the pure biaryls 1a–f;
yield: 71–92%.
Alternatively, products were isolated using an extractive
work-up/purification method as described above for com-
pound 1a. Yields for both protocols are given in Table 3.
Spectroscopic and analytical data for biaryls 1a–f were as
previously reported in ref.[14]
Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-
one 2a using Bis(triphenylphosphine)nickel(II)
Dichloride and Diphenylphosphinoferrocene
A mixture containing 48.4 mg (0.25 mmol)of 4-chloro-1-
methylquinolin-2(1H)-one (2a), 32.7 mg (0.05 mmol, 20
mol%)of NiCl 2(PPh3)2, 27.7 mg (0.05 mmol, 20 mol%)of
G
diphenylphosphinoferrocene (dppf), 21.2 mg (0.324 mmol,
1.3 equivs.)of Zn powder and 74.7 mg (0.45 mmol,
1.8 equivs.)of KI was suspended in 1.0 mL anhydrous diox-
ane under an argon atmosphere in a 5-mL Pyrex microwave
process vial equipped with a magnetic stirring bar. The vial
was sealed, the mixture was stirred for 4 min at room tem-
perature, and then heated by microwave irradiation for
30 min at 1308C. Thereafter, the solvent was removed under
reduced pressure. The product was isolated by gradient dry
flash chromatography using EtOAc/acetone as solvent mix-
ture to obtain pure bisquinolone 1a; yield: 34.0 mg (86%).
Acknowledgements
J. H. thanks the Higher Education Commission ofPakistan
for a Ph.D. scholarship. We also thank Biotage AB (Uppsala,
Sweden) for the provision of microwave instrumentation.
Homocoupling of 4-Chloro-1-methylquinolin-2(1H)-
one 2 using Bis(triphenylphosphine)nickel(II)
Dichloride and DPEphos
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NiCl2(PPh3)2, 1.48 g (2.75 mmol, 25 mol%)of DPEphos,
A
935 mg (14.3 mmol, 1.3 equivs.)of Zn powder and 3.29 g
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hydrous dioxane under an argon atmosphere in a 20-mL
Pyrex microwave vial equipped with a magnetic stirring bar.
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phine ligand. Evaporation of the acetonitrile solvent furnish-
ed the crude bisquinolone product contaminated with small
quantities of triphenylphosphine which was subsequently
dissolved in 400 mL of dichloromethane and washed three
times with 150 mL of saturated aqueous ammonium chloride
solution (to remove inorganic potassium iodide). Drying of
the organic phase over anhydrous MgSO4, filtration through
a pad of Celite, evaporation of dichloromethane and subse-
quent recrystallization (2 times)from acetonitrile provided
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A
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Adv. Synth. Catal. 2007, 349, 2353 – 2360
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2359

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A
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2360
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2353 – 2360