Symmetrical bisquinolones via metal-catalyzed cross-coupling and homocoupling reactions

Article abstract of DOI:10.1021/jo052283p

Functionalized 4,4′-bisquinolones can be efficiently synthesized by microwave-assisted palladium(0)-catalyzed one-pot borylation/Suzuki cross-coupling reactions or via nickel(0)-mediated homocouplings of 4-chloroquinolin-2(1H)-one precursors. Both methods are also applicable to other types of symmetrical biaryls.

Full text of DOI:10.1021/jo052283p

Symmetrical Bisquinolones via Metal-Catalyzed
Cross-Coupling and Homocoupling Reactions
Jamshed Hashim, Toma N. Glasnov,
Jennifer M. Kremsner, and C. Oliver Kappe*
Institute of Chemistry, Karl-Franzens-UniVersity Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
oliVer.kappe@uni-graz.at
ReceiVed NoVember 3, 2005
Here we report two different methods for the synthesis of
bisquinolones of type 1 that are based either on Pd(0)-catalyzed
one-pot borylation/Suzuki cross-couplings or on Ni(0)-mediated
homocouplings (Ullmann reaction) of 4-chloroquinolin-2(1H)-
one precursors. Both methods rapidly deliver bisquinolones in
good to excellent yields employing controlled microwave
irradiation (MW) and are applicable not only toward the
preparation of the desired symmetrical bisquinolones but also
as general methods for a symmetrical biaryl synthesis.
Several recently developed protocols for the preparation of
symmetrical biaryls from arylhalides via cross-coupling chem-
istry involve the use of bis(pinacolato)diboron as a reagent.9-11
In these Pd(0)-catalyzed one-pot transformations, arylboronic
esters are formed as intermediates, which are not isolated, and
undergo subsequent Suzuki coupling to directly form the desired
biaryls.9-11 The preferred catalyst for this transformation is
PdCl2(dppf) (dppf ) diphenylphosphinoferrocene).9,11
Functionalized 4,4′-bisquinolones can be efficiently synthe-
sized by microwave-assisted palladium(0)-catalyzed one-pot
borylation/Suzuki cross-coupling reactions or via nickel(0)-
mediated homocouplings of 4-chloroquinolin-2(1H)-one
precursors. Both methods are also applicable to other types
of symmetrical biaryls.
As a starting point for the synthesis of bisquinolones 1, we
investigated the one-pot borylation/Suzuki cross-coupling of
readily available 4-chloro-1-methylquinolin-2(1H)-one 2a6 as
a model substrate (Table 1). All initial optimization studies were
performed on a 0.25 mmol scale using automated sequential
microwave processing to allow for shorter reaction times and
higher yields.10-12 An extensive optimization of the reaction
parameters included the amount of bis(pinacolato)diboron
reagent, the type and the concentration of the Pd catalyst, and
the required base, solvent, reaction time, and temperature.
An initial attempt to adapt the previously reported protocols
where aryl iodides,9 bromides,9,11 triflates,9 and reactive 2-chlo-
roazaheterocycles10 have been employed as precursors quickly
demonstrated that the use of the suggested K2CO3 or KF base
was not successful. Under the published reaction conditions,9-11
only trace amounts of the desired bisquinolone product 1a were
obtained from the chloro precursor 2a, regardless of the catalyst,
solvent system, and the reaction temperature. Gratifyingly, we
discovered that the use of the much stronger base KOH (4.5
Substituted biaryls play an important role in organic chem-
istry.1,2 Many natural products, pharmaceuticals, herbicides, and
fine chemicals contain symmetrical or unsymmetrical biaryl
units. In addition, biaryls are applied as chiral ligands in
catalysis, as liquid crystals or organic conductors.1 Bis-
heterocycles are also well-known in the literature and often
display similarly interesting biological and physical properties.2-5
Important structural motifs are, for example, bipyridines,3
bithiophenes,4 and bipyrroles.5
In the context of our ongoing interest in the chemistry of
functionalized quinolin-2(1H)-ones (carbostyrils),6 we became
interested in the generation of the corresponding 4,4′-bisqui-
nolones of type 1. This novel class of bis-heterocycles are of
interest both as aza-analogues of biscoumarin natural products
(e.g., 4,4′-biisofraxidin)7 and because of their anticipated
fluorescent properties as push-pull carbostyrils (R3 ) R4 )
OMe).8
* To whom correspondence should be addressed. Phone: +43-316-380-5352.
Fax: +43-316-380-9840.
(1) For reviews on biaryls, see: (a) Hassan, J.; Se´vignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (b) Shimizu, H.;
Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405. (c) Bringmann, G.;
Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning,
M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(2) Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265.
(3) (a) Leadbeater, N. E.; Resouly, S. M. Tetrahedron Lett. 1999, 40,
4243. (b) Tiecco, M.; Tingoli, M.; Testaferri, L.; Bartoli, D.; Chianelli, D.
Tetrahedron 1989, 45, 2857.
(7) (a) Pharkphoom, P.; Hiroshi, N.; Wanchai, D. E. Planta Med. 1998,
64, 774. (b) Lei, J.-G.; Lin, G.-Q. Chin. J. Chem. 2002, 20, 1263.
(8) (a) Strohmeier, G.; Fabian, W. M. F.; Uray, G. HelV. Chim. Acta
2004, 87, 215. (b) Lee, H.-K.; Cao, H.; Rana, T. M. J. Comb. Chem. 2005,
7, 279.
(9) (a) Nising, C. F.; Schmid, U. K.; Nieger, M.; Bra¨se, S. J. Org. Chem.
2004, 69, 6830. See also: (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron
Lett. 1997, 38, 3841. (c) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org.
Chem. 1995, 60, 7508. (d) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N.
Tetrahedron Lett. 1997, 38, 3447.
(4) (a) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627. (b) Hassan,
J.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1999, 40, 857.
(5) Grigg, R.; Johnson, A. W. J. Chem. Soc. 1964, 3315.
(6) Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005,
70, 3864.
(10) De Borggraeve, W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.;
Compernolle, F.; Van der Eycken, E.; Hoornaert, G. Synlett 2005, 777.
(11) Melucci, M.; Barbarella, G.; Zambianchi, M.; Di Pietro, P.; Bongini,
A. J. Org. Chem. 2004, 69, 4821.
(12) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
10.1021/jo052283p CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/12/2006
J. Org. Chem. 2006, 71, 1707-1710
1707

TABLE 1. Catalyst/Ligand Screening for the Pd(0)-Catalyzed
Bisquinolone Synthesisa
TABLE 2. Effect of Iodide Additives on Ni(0)-Mediated
Homocouplings of 4-Chloroquinolonesa
iodide additive
(equiv)
product
catalyst
(mol %)
additive
(mol %)
product
distributionb (%)
entry
distributionb (%)
entry
1
2
3
4
5
NaI (1.8)
KI (1.8)
0/88/12
1/95/4c
21/76/3
19/78/3
11/85/4
1
2
3
4
5
6
7
8
9
PdCl2(dppf) (5)
PdCl2(dppf) (10)
PdCl2(dppf) (10)
Pd(OAc)2 (5)
dppf (7)
22/61/17
3/89/8
dppf (7)
dppf (10)
0/97/3c
0/92/8
KI (1.0)
KI (1.6)
Pd(PPh3)4 (8)
1/91/8
palladacycled (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
dppf (10)
0/63/37
0/60/40
0/84/16
0/86/14
0/88/12
a Reaction conditions: 0.25 mmol chloroarene 2a, 1.3 equiv NiCl2, 1.3
equiv Zn dust, 4.0 equiv PPh3, iodide additive, 1.5 mL dry DMF, sealed-
vessel, single-mode, microwave irradiation at 205 °C for 25 min. See
Supporting Information for further details. b Product distribution refers to
relative peak area (%) ratios of crude HPLC-UV (215 nm) traces: starting
material/product/dehalogenated product. c Product isolation by flash chro-
matography provided a 90% yield of bisquinolone 1a.
dppf (7)
t-Bu3PHBF4 (5)
PCy3 (5)
10
a Reaction conditions: 0.25 mmol chloroarene 2a, 4.5 equiv KOH, 0.7
equiv bis(pinacolato)diboron, 1.5 mL n-BuCl, sealed-vessel, single-mode,
microwave irradiation at 130 °C for 30 min. See Supporting Information
for further details. b Product distribution refers to relative peak area (%)
ratios of crude HPLC-UV (215 nm) traces: starting material/product/
dehalogenated product. c Product isolation by flash chromatography provided
an 85% yield of bisquinolone 1a. d Herrmann’s palladacycle.
efficient, leading to a higher percentage of the dehalogenated
product, although the use of Pd(OAc)2/dppf or Pd(PPh3)4
furnished product yields that were also high (Table 1).
Importantly, the conversions determined by the HPLC
monitoring of the crude reaction mixtures (Table 1) nicely
matched isolated product yields. From the experiment described
in entry 3, for example, an 85% yield of bisquinolone 1a was
obtained after flash chromatography. Our optimized one-pot
borylation/Suzuki cross-coupling conditions were applicable to
a series of 4-chloroquinolin-2(1H)-one substrates, allowing the
preparation of various functionalized symmetrical bisquinolones
(cf. Table 3).
The high costs of the required bis(pinacolato)diboron reagent
and the Pd catalyst in the above-mentioned cross-coupling
protocols prompted us to explore an alternative homocoupling
method such as the Ullmann reaction,2 which would not require
the use of an additional cross-coupling partner. Among the many
different available protocols for successful bi(hetero)aryl syn-
thesis via homocoupling methods,2-5 we were particularly
attracted by Ni-mediated reductive homocouplings, where the
active Ni(0) complex is prepared directly from an inexpensive
Ni(II) salt and a reducing reagent such as Zn dust in the presence
of triphenylphosphine.2,14
equiv) in conjunction with PdCl2(dppf) as catalyst (10 mol %)
provided excellent conversions (>90%), depending on the
solvent system used (dioxane, 115 °C, 30 min).13
When several of the commonly used solvents for this type
of transformation were screened, such as DMSO, DMF, or
toluene, we noticed that, while the starting material was
consumed, the major reaction product with these solvents was
the dehalogenated product, 1-methylquinolin-2(1H)-one. Suit-
able solvents for the one-pot borylation/Suzuki cross-coupling
that minimized dehalogenation (<10%) included dioxane, CH2-
Cl2, and 1,2-dichloroethane. The best solvent identified in our
studies, however, was 1-chlorobutane. Under optimized reaction
conditions (see Table 1, entry 3), full conversion to the
bisquinolone 1a was achieved within a 25 min reaction time,
with only 3% of the dehalogenated product formed. It should
be noted that reducing the amount of KOH to, for example, 2.0
equiv also led to an increased formation of the dehalogenated
product.
Substantial efforts were made to identify the optimum
catalyst, reaction temperature, and time for this reaction (Table
1). After considerable experimentation, it was found that a 130
°C reaction temperature allowed the one-pot bisquinolone
coupling to proceed within less than half an hour. Whereas lower
reaction temperatures resulted in longer reaction times, higher
temperatures produced more side and decomposition products.
Among the many catalysts tested, PdCl2(dppf) proved to be
optimal. However, a 10 mol % loading of the catalyst was
required to achieve acceptable conversions. In fact, best results
were obtained upon the addition of a further amount of 7 mol
% of the free dppf ligand to slow catalyst decomposition.9 Many
other Pd catalyst/ligand systems proved significantly less
As with the cross-coupling protocol, a careful optimization
of the reaction conditions with respect to the solvent, molar
ratios (reagents and additives), time, and temperature was
performed for the homocoupling of chloroquinolone 2a (Table
2). Initial experiments indicated that the general procedures for
aryl halide homocouplings2,14,15 involving dry DMF as the
solvent, NiCl2 as the metal source, PPh3 as the ligand, and Zn
dust as the reducing reagent were also applicable to bisquinolone
(14) (a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Monta-
nucci, M. Synthesis 1984, 736. (b) Ford, A.; Sinn, E.; Woodward, S. J.
Chem. Soc., Perkin Trans. 1 1997, 927. (c) For a recent report on iron-
catalyzed homocouplings, see: Cahiez, G.; Chaboche, C.; Mahuteau-Betzer,
F.; Ahr, M. Org. Lett. 2005, 7, 1943.
(13) The effect of stronger bases such as KOH probably lies in their
stronger nucleophilicity. For a detailed description of the reaction mechanism
in these biaryl formations and the role of the base, see ref 9.
(15) (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem.
1995, 60, 176. (b) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995,
60, 1060.
1708 J. Org. Chem., Vol. 71, No. 4, 2006

TABLE 3. Synthesis of Biaryls via Microwave-Assisted Cross- and
Homocoupling of (Hetero)Aryl Chlorides and Bromides
synthesis under microwave irradiation conditions. Acceptable
product yields of the homocoupled bisquinolone 1a were
obtained within 25 min at about a 205 °C reaction temperature;
the only observed byproduct being again the dehalogenated
quinolone. As a result of the unreactive nature of the aryl
chloride precursor, it was necessary to use Ni in stoichiometric
amounts (1.3 equiv). Lowering the amount of Ni led to
incomplete conversions. Similarly, we found that the presence
of 1.3 equiv of Zn proved optimal for this transformation, with
both lower and higher amounts of Zn resulting in more
dehalogenated product. Ligands such as PPh3 are essential in
Ni-mediated homocoupling reactions to stabilize the in situ
generated Ni(0) catalyst and aryl Ni species during the reaction
sequence.15 In the present case, 4.0 equiv of PPh3 provided
optimum product yields.
Nevertheless, by applying the above-mentioned reagent
mixtures, it proved difficult to achieve high conversions in the
desired short time frames. It is well-known that halide ions,
especially iodide, enhance the reaction rate of Ni-catalyzed
homocoupling reactions.2,15 The iodide ion is believed to
function as a bridging ion between Ni and Zn in the electron-
transfer process and/or as a donor ligand for the highly
coordinately unsaturated Ni(0) complex.15 The screening of
several iodide sources in our model reaction finally resulted in
the use of 1.8 equiv of KI as an additive (Table 2, entry 2).
Under these optimized conditions, the formation of the deha-
logenated byproduct could be kept to a minimum (ca. 4%),
allowing the desired bisquinolone homocoupling product 1a to
be isolated in 90% yield after flash chromatography.
Having two different optimized protocols for the efficient
generation of symmetrical bisquinolones from readily available
4-chloroquinolin-2(1H)-one substrates at hand, we next pro-
ceeded to investigate the scope of these coupling procedures
for (i) the preparation of a variety of functionalized bisquino-
lones and (ii) the use of these methods as general high-speed
symmetrical biaryl coupling methods. Gratifyingly, both meth-
ods provided moderate to excellent isolated product yields for
all the quinolone systems, 2a-f, tested (Table 3). For the
electron-rich mono- or disubstituted methoxy analogues 2d-f,
somewhat higher reaction temperatures (145 °C) were applied
in the cross-coupling protocol (Method A) to achieve good
yields.16 The required 4-chloroquinolone precursors were readily
available from the known 4-hydroxyquinolones by microwave-
assisted chlorination using POCl3 as the chlorinating reagent
(for details, see Supporting Information).6 For the examples
displayed in Table 3, the Pd-catalyzed cross-coupling method
(Method A) proved to be somewhat more reliable, furnishing
higher isolated product yields (68-85%) as compared to those
of the Ni-mediated homocoupling method (Method B, 39-
90%). A clear disadvantage of the Ni method additionally lies
in the required extensive purification process, removing large
quantities of the PPh3 ligand by flash chromatography.
a Isolated yields of pure product. For further details see Supporting
Information. b Reaction conditions: 0.30 mmol substrate, 10 mol %
PdCl2(dppf), 7 mol % dppf, 0.7 equiv bis(pinacolato)diboron, 4.5 equiv
KOH, 2.0 mL n-BuCl, sealed-vessel, single-mode, microwave irradiation
at 130 °C for 35 min. c Reaction conditions: 0.25 mmol substrate, 1.3 equiv
NiCl2, 4.0 equiv PPh3, 1.3 equiv Zn, 1.8 equiv KI, 1.5 mL DMF, sealed-
vessel, single-mode, microwave irradiation at 205 °C for 25 min. d Reaction
conditions: 10 mol % Pd(OAc)2, 20 mol % dppf, 1.5 mL dioxane.
e Reaction temperature: 145 °C. f Reaction conditions: 6 mol % Pd(PPh3)4,
2.5 equiv CsCO3, 1.5 mL toluene.
changing to a toluene/Cs2CO3 solvent/base system in the Pd-
catalyzed one-pot borylation/Suzuki cross-coupling (Method A),
we achieved the preparation of 4,4′-biscoumarin in a moderate
67% yield. The standard reaction conditions employing KOH
as base furnished only very small amounts of the desired
product, presumably a result of the hydrolysis/destruction of
the sensitive coumarin heterocycle. When our base-free Ni(0)-
mediated homocoupling protocol was used, a near quantitative
98% yield of 4,4′-biscoumarin was obtained.17,18
While both our protocols were optimized for the rather
specific and comparatively unreactive 4-chloroquinolin-2(1H)-
one precursors 2a-f, we were interested to see if these
procedures could also be used as general high-speed biaryl
We next attempted to synthesize 4,4′-biscoumarin starting
from 4-chlorocoumarin using both coupling methods. Biscou-
marins are of interest because of their physiological properties
and their presence as important structural units in a variety of
biologically active natural products (i.e., 4,4′-biisofraxidin).7 The
generation of biscoumarins via cross-coupling chemistry to our
knowledge has not been reported in the literature.16,17 By
(17) For Suzuki and related cross-coupling reactions involving 4-sul-
fonyloxy-substituted coumarins, see: (a) Boland, G. M.; Donnelly, D. M.
X.; Finet, J.-P.; Rea, M. D. J. Chem. Soc., Perkin Trans. 1 1996, 2591. (b)
Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J.; Rea, M. D. Synth. Commun.
1999, 29, 2719. (c) Yao, M.-L.; Deng, M.-Z. Heteroat. Chem. 2000, 11,
380. Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642.
(16) Beletskaya, I. P.; Ganina, O. G.; Tsvetkov, A. V.; Fedorov, A. Y.;
Finet, J.-P. Synlett 2004, 2797.
(18) For Ni-catalyzed homocouplings of 4-sulfonyloxy-substituted
coumarins, see: Lei, J.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2004, 2364.
J. Org. Chem, Vol. 71, No. 4, 2006 1709

4,4′-Bis-(1-phenylquinolin-2(1H)-one), 1c. Mp > 400 °C dec
coupling methods. Gratifyingly, we were pleased to find that
both microwave-assisted coupling methods were also applicable
to the more commonly used hetero(aryl) bromide substrates,
such as 3-bromoquinoline, 2-bromothiophene, and 1-bromonaph-
thalene (Table 3). Without any further optimization, good to
excellent yields of the corresponding bis(hetero)aryls were
obtained. Again, the Pd-catalyzed one-pot borylation/Suzuki
cross-coupling conditions generally provided somewhat higher
product yields (ca. 90%) compared with those of the Ni-
mediated Ullmann homocoupling procedure.
In summary, we have developed two generally applicable
high-speed methods for the preparation of symmetrical (hetero)-
biaryls using either Pd(0)-catalyzed cross-coupling or Ni(0)-
mediated homocoupling principles. The procedures are particu-
larly valuable for the preparation of novel types of bisquinolones,
which are presently under investigation as fluorescent probes
in our laboratories. Results from these studies will be published
elsewhere. We are currently investigating alternative catalytic
cross- and homocoupling protocols to access unsymmetrical
bisquinolones.
1
(CCl4); IR (KBr) νmax 1661 cm-1; H NMR (360 MHz, CDCl3) δ
6.81 (d, J ) 8.4 Hz, 2H), 6.91 (s, 2H), 7.14 (t, J ) 7.6 Hz, 2H),
7.38-7.45 (m, 8H), 7.60 (t, J ) 7.4 Hz, 2H), 7.68 (t, J ) 7.6 Hz,
4H); 13C NMR (90 MHz, CDCl3) δ 116.6, 119.4, 122.4, 122.6,
127.0, 128.9, 129.2, 130.4, 130.9, 137.4, 141.2, 147.0, 161.5; MS
(positive APCI, m/z) 441 [25, (M + 1)], 440 (100, M).
4,4′-Bis-(6-methoxy-1-methylquinolin-2(1H)-one), 1d. Mp 256-
1
258 °C (ethanol); IR (KBr) νmax 1648 cm-1; H NMR (360 MHz,
DMSO-d6) δ 3.58 (s, 6H), 3.69 (s, 6H), 6.57 (d, J ) 2.8 Hz, 2H),
6.66 (s, 2H), 7.34 (dd, J ) 9.3 and 2.8 Hz, 2H), 7.62 (d, J ) 9.3
Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 55.8, 110.0, 115.9,
119.4, 120.4, 122.5, 134.7, 145.5, 154.8, 161.1; MS (positive APCI,
m/z) 377 [25, (M + 1)], 376 (100, M).
4,4′-Bis-(7-methoxy-1-methylquinolin-2(1H)-one), 1e. Mp 232-
1
234 °C (ethanol); IR (KBr) νmax 1658 cm-1; H NMR (360 MHz,
DMSO-d6) δ 3.67 (s, 6H), 3.89 (s, 6H), 6.45 (s, 2H), 6.76 (d, J )
8.7 Hz, 2H), 7.04-7.07 (m, 4H); 13C NMR (90 MHz, CDCl3) δ
29.8, 56.2, 99.7, 110.8, 113.5, 117.9, 128.8, 142.0, 146.3, 161.5,
162.3; MS (positive APCI, m/z) 377 [25, (M + 1)], 376 (100, M).
Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found:
C, 70.23; H, 5.26; N, 7.37.
4,4′-Bis-(6,7-dimethoxy-1-methylquinolin-2(1H)-one), 1f. Mp
1
276-277 °C dec (ethanol); IR (KBr) νmax 1642 cm-1; H NMR
Experimental Section
(360 MHz, DMSO-d6) δ 3.45 (s, 6H), 3.74 (s, 6H), 3.96 (s, 6H),
6.46 (s, 2H), 6.57 (s, 2H), 7.09 (s, 2H); 13C NMR (90 MHz, CDCl3)
δ 30.0, 56.2, 56.4, 97.6, 108.2, 112.7, 119.1, 136.1, 145.2, 145.8,
152.8, 162.0; MS (positive APCI, m/z) 437 [50, (M + 1)], 436
(100, M).
General Procedure for the One-Pot Borylation/Suzuki Cross-
Coupling of Haloarenes (Method A, Table 3). A mixture
containing 0.30 mmol of the corresponding haloarene (Table 3),
24.5 mg (0.03 mmol, 10 mol %) of PdCl2(dppf), 11.6 mg (0.021
mmol, 7 mol %) of dppf, 53.3 mg (0.21 mmol, 0.7 equiv) of bis-
(pinacolato)diboron, and 75.7 mg (1.35 mmol, 4.5 equiv) of finely
crushed KOH powder (analytical grade) was suspended in 2.0 mL
of anhydrous 1-chlorobutane under an argon atmosphere in a 5 mL
microwave vial (Pyrex) equipped with a magnetic stirring bar. The
vial was sealed, stirred for 4 min at room temperature, and then
heated for 35 min at 130 °C (see Table 3 for deviations). Thereafter,
the solvent was removed under reduced pressure. The product was
directly isolated by gradient dry flash chromatography, using
appropriate solvents. For yields, see Table 3.
General Procedure for the Homocoupling of Haloarenes
(Method B, Table 3). A mixture containing 0.25 mmol of the
corresponding haloarene (Table 3), 42.1 mg (0.325 mmol, 1.3 equiv)
of anhydrous NiCl2, 262.3 mg (1 mmol, 4.0 equiv) of PPh3, 21.2
mg (0.324 mmol, 1.3 equiv) of Zn powder (<60 µm particle size),
and 74.7 mg (0.45 mmol, 1.8 equiv) of KI was suspended in 1.5
mL anhydrous DMF under an argon atmosphere in a 5 mL
microwave vial (Pyrex) equipped with a magnetic stirring bar. The
vial was sealed, stirred for 4 min at room temperature, and then
heated for 25 min at 205 °C. Thereafter, the solvent was removed
under reduced pressure. The product was isolated by gradient dry
flash chromatography using appropriate solvents. For yields, see
Table 3.
4,4′-Bis-(2H-chromen-2-one). Mp 215-216 °C (acetonitrile;
1
lit.19 215 °C); H NMR (360 MHz, CDCl3) δ 6.50 (s, 2H), 7.22-
7.24 (m, 4H), 7.47 (d, J ) 8.4 Hz, 2H), 7.60-7.65 (m, 2H). MS
(positive APCI, m/z) 291 [95, (M + 1)], 290 (45, M), 252 [100,
(M - 38)], 236 (M - 54).
1
3,3′-Bisquinoline. Mp 269-271 °C (ethanol; lit.20 271 °C); H
NMR (360 MHz, CDCl3) δ 7.70 (t, J ) 7.25 Hz, 2H), 7.85 (t, J )
7.42 Hz, 2H), 8.01 (d, J ) 8.0 Hz, 2H), 8.29 (d, J ) 8.4 Hz, 2H),
8.57 (s, 2H), 9.33 (s, 2H). MS (positive APCI, m/z) 257 [20, (M +
1)], 256 (100, M).
2,2′-Bisthiophene. Mp 30-32 °C (diethyl ether; lit.21 32-34
1
°C); H NMR (360 MHz, CDCl3) δ 7.02 (dd, J ) 3.70 and 4.95
Hz, 2H), 7.19-7.24 (m, 4H). MS (positive APCI, m/z) 166 (100,
M).
1,1′-Bisnaphthalene. Mp 158-159 °C (acetone; lit.22,23 158.8-
159 °C); 1H NMR (360 MHz, CDCl3) δ 7.29-7.32 (m, 2H), 7.40
(d, J ) 8.40 Hz, 2H), 7.47-7.52 (m, 4H), 7.59-7.63 (m, 2H),
7.96 (dd, J ) 3.00 and 8.10 Hz, 4H).
Acknowledgment. This work was supported by the Austrian
Science Fund (FWF, P15582, and I18-N07). J.H. thanks the
Higher Education Commission of Pakistan for a scholarship.
We also thank Biotage AB (Uppsala, Sweden) for the provision
of an Initiator 8 microwave reactor and W. Stadlbauer for
assistance in obtaining the quinolone precursors.
4,4′-Bis-(1-methylquinolin-2(1H)-one), 1a. Mp 283-284 °C
(acetonitrile). IR (KBr) νmax 1648 cm-1 1H NMR (360 MHz,
;
DMSO-d6) δ 3.71 (s, 6H), 6.67 (s, 2H), 7.11-7.17 (m, 4H), 7.64-
7.67 (m, 4H); 13C NMR (90 MHz, DMSO-d6) δ 29.8, 115.8, 119.6,
121.6, 122.7, 127.3, 131.8, 140.2, 146.1, 160.9; MS (positive APCI,
m/z) 317 [25, (M + 1)], 316 (100, M). Anal. Calcd for
C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C, 75.95; H, 4.98;
N, 8.78.
Supporting Information Available: Materials and methods,
experimental procedures, and H NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
JO052283P
(19) Deshmukh, R. S. K.; Paradkar, M. V. Synth. Commun. 1988, 18,
589-596.
(20) Uyeda, K. J. Pharm. Soc. Jpn. 1931, 51, 495-501; Chem. Abstr.
1931, 25, 5427.
(21) Nishihara, Y.; Ikegashira, K.; Toriyama, F.; Mori, A.; Hiyama, T.
Bull. Chem. Soc. Jpn. 2000, 73, 985.
(22) Ibuki, E.; Ozasa, S.; Fujioka, Y.; Mizutani, H. Bull. Chem. Soc.
Jpn. 1982, 55, 845-851.
(23) Collet, A.; Brienne, M. J.; Jacques, J. Bull. Soc. Chim. Fr. 1972, 1,
127-142.
7,7′-Bis-(2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one),
1
1b. Mp 270 °C dec (acetonitrile); IR (KBr) νmax 1637 cm-1; H
NMR (360 MHz, DMSO-d6) δ 2.02-2.13 (m, 4H), 2.99 (t, J )
5.7 Hz, 4H), 4.13 (t, J ) 5.7 Hz, 4H), 6.62 (s, 2H), 6.96 (d, J )
7.6 Hz, 2H), 7.02 (t, J ) 7.6 Hz, 2H), 7.40 (d, J ) 7.0 Hz, 2H);
13C NMR (90 MHz, DMSO-d6) δ 20.6, 27.8, 42.6, 119.7, 121.4,
121.9, 125.3, 125.4, 130.5, 136.8, 146.4, 161.2; MS (positive APCI,
m/z) 368 (100, M).
1710 J. Org. Chem., Vol. 71, No. 4, 2006