Divergent route to access structurally diverse 4-quinolones via mono or sequential cross-couplings

Article abstract of DOI:10.1021/jo1014504

A divergent route was developed to access 3-iodo- and 6-chloro-3-iodo-4(1H) -quinolones for further elaboration via mono and/or sequential Suzuki-Miyaura cross-coupling to generate novel and medicinally important 4(1H)-quinolones. Copper- and palladium-ca

Full text of DOI:10.1021/jo1014504

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various natural products.6 In the past decade, 4-quinolones have
Divergent Route to Access Structurally
Diverse 4-Quinolones via Mono or Sequential
Cross-Couplings
resurfaced as antimalarial agents.7 Using in vitro activity assays
against erythrocytic stages of multidrug-resistant isolates and
clones of P. falciparum, Kyle, Manetsch, and Riscoe recently
demonstrated that 3-substituted 4(1H)-quinolone derivatives
display antimalarial activity at low to single-digit nanomolar
concentrations.7 Herein, we report a divergent synthetic proto-
col for the rapid preparation of functionalized 3-substituted
4(1H)- and 4(1alkyl)-quinolones.
R. Matthew Cross and Roman Manetsch*
Department of Chemistry, University of South Florida,
CHE205, 4202 East Fowler Avenue, Tampa, Florida 33620,
United States
Most routes to access 4-quinolones rely on traditional
reactions such as the Gould-Jacobs,8 Conrad-Limpach,9
Niementowski,10 or Camps cyclizations.11 However, these
transformations are limited by elevated reaction temperatures,
unsatisfactory yields, and poor regioselectivities. Furthermore,
several mild synthetic approaches focusing primarily on 2-sub-
stituted 4-quinolones have been developed utilizing transition
metal catalysis12 as well as base-promoted Camps cyclization of
N-(ketoaryl)amides.13 Among the entire repertoire of 4-quino-
lone syntheses, the Conrad-Limpach cyclization is the most
prevalent reaction for the preparation of 3-substituted 4-quino-
lones involving 2-substituted-β-ketoesters and anilines as start-
ing materials. Nevertheless, the cyclization step using sterically
hindered and/or acid-sensitive 2-substituted β-ketoesters com-
monly generates 3-substituted-4-quinolones in poor yields and
requires difficult purification protocols.
manetsch@usf.edu
Received August 3, 2010
The need to access structurally diverse 3-aryl-4-quinolones, in
conjunction with the lack of a contemporary synthetic approach
to such compounds, motivated us to devise a reliable and
divergent synthetic route (Scheme 1). The key step of our method
involves substitution of the quinolone core at the 3-position
using a Suzuki-Miyaura cross-coupling. Strikingly, our
approach further demonstrates the utility of sequential
cross-couplings with dihalogenated quinolones culminat-
ing in the synthesis of structurally diverse analogues. The
quinolone intermediate is obtained by a combination
of easily synthesized or commercially available anilines and
ethyl acetoacetate cyclized through a high-yielding Conrad-
Limpach reaction (Scheme 1). Subsequent regioselective halo-
genation of the quinolone core provides the Suzuki-Miyaura
A divergent route was developed to access 3-iodo- and
6-chloro-3-iodo-4(1H)-quinolones for further elaboration
via mono and/or sequential Suzuki-Miyaura cross-cou-
pling to generate novel and medicinally important 4(1H)-
quinolones. Copper- and palladium-catalyzed cyanations
were used to functionalize the 4-quinolone core further.
Substituted 4-quinolones are relevant for various medic-
inal applications including inhibition of tubulin formation,1
antimicrobial2 and antiviral therapies,3 antiallergy treatments,4
and cancer chemotherapies5 and are common scaffolds found in
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Published on Web 11/17/2010
DOI: 10.1021/jo1014504
r
2010 American Chemical Society

Cross and Manetsch
JOCNote
SCHEME 1. Sequential Pd-Catalyzed Cross-Coupling of Iodo-
chloro Quinolones
TABLE 2. Optimization of Cross-Coupling Conditions
entry
R
R0
X
Pd/ligand
solvent
toluene
% yielda
1
2
3
4
5
6
7
8
9
H
Me Br Pd(PPh3)4
85
92
90
88
H
H
H
H
H
H
Me Br Pd2(dba)3/SPHOSc toluene
Me Br Pd2(dba)3/XPHOSd toluene
Me Br Pd(OAc)2/SPHOS
Me
H
toluene
toluenee
toluene
DMFe
I
I
I
I
I
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
95
<25
72b
50b
85b
H
6-Cl Me
6-Cl Me
2-butanole
DMFe
TABLE 1. Methylation of Halo-quinolones
aReaction conditions: 1a (0.4 mmol), Pd source (4 mol %), ligand
(8 mol %), K3PO4 (2 equiv), PhB(OH)2 (1.5 equiv), solvent (3 mL), 80 °C.
b110 °C. cSPHOS (2-dicyclohexylphosphino-20,60-dimethoxy-1,10-biphenyl.
d XPHOS (2-(dicyclohexylphosphino)-20,40,60-tri-isopropyl-1,10-biphenyl.
eSolvent (1 mL).
entry
R
X
time (h)
% yield
(a:b)
N-methylated quinolone substrates was found to be superior,
whereas the couplings with 4(1H)-quinolones required DMF
for complete conversion, although resulting in modest yields
(entry 6 and 7). Similarly, 6-chloro-N-methyl-quinolones re-
quired the use of DMF as a solvent, and 2-butanol was found to
be suboptimal (entry 8 and 9).
1
2
3
4
5
6
7
6-H
6-H
6-F
6-Cl
6-0 Me
6-Me
5,7-diCl
Br
I
Br
I
Br
I
I
8
12
16
12
14
19
15
99
95
94
97
99
85
90
1.67:1
2.37:1
2.05:1
3.20:1
2.51:1
1.95:1
12.0:1
Next, the substrate scope of the coupling reaction was
studied in detail. Couplings with various phenylboronic acids
with both N-methylated 3-bromo- and 3-iodo-quinolones
(Table 3, entries 1 and 2) resulted in 92% and 95% yields of
quinolones, respectively. DMF was required for the less
soluble 4(1H)-quinolone (entry 3), providing a 72% yield.
Halides were efficiently coupled with electron-rich boronic
acids (entries 4-6) in a short amount of time. 4-Methoxyphe-
nyl boronic acid was also reacted with N-methyl- and N-H-3-
bromo-6-fluoro-quinolones (entries 7 and 8), furnishing the
corresponding products in 95% and 73% yields, respectively.
Sterically hindered boronic acids were coupled smoothly with
electron-deficient and electron-neutral quinolones (entries 9
and 10). meta-Substituted arylboronic acids (entries 11-14)
including 3-(dimethylcarbamoyl)phenylboronic acid (entries
13 and 14) provided yields of 95% and 65% for both the
N-alkyl- and the N-H-quinolone. A fluorinated quinolone was
cross-coupled with 4-fluorophenyl boronic acid (entries 15 and
16) in 81% and 73% yields.
Although furan-2-boronic acids have been reported to be
problematic with the Pd/SPHOS catalyst/ligand system,
Molander and co-workers realized these problematic couplings
by the use of 2-furanyl organotrifluoroborates.17 Strikingly, the
substitution of N-methyl- and N-H-4-quinolones with furan-
2-boronic acids provided the desired products in 97% and 75%
yields, respectively (Table 3, entries 19 and 20). Finally,
E-phenylethenylboronic acid (entry 25) was installed at the
3-position in excellent yields with a trans:cis ratio of 12:1.
Conveniently, this set of conditions was effective for coupling
our quinolones with all of the major subclasses of substrates
including heteroaryl, both electron-rich and -deficient, alkenyl,
coupling precursor.14 These halides and their N-methyl ana-
logues could be directly subjected to cross-coupling conditions.
4(1-alkyl)-Quinolones have also found utility in medicinal
applications15 and their preparations have been explored.
Standard alkylation conditions were screened using the
group 1 and silver carbonates at various temperatures.
Heating of the reaction mixtures resulted in both lower
selectivities and yields due to reduction of the halide sub-
stituent to the 3-H-4-quinolone. Likewise, the use of cold
reaction conditions resulted in poor yields due to the de-
creased solubility of the quinolones at lower temperatures.
Ultimately, the use of Cs2CO3 in DMF at room temperature
provided excellent yields albeit with modest chemoselectiv-
ities (Table 1, entries 1-7).
Screening of appropriate Suzuki-Miyaura conditions
applicable to our substituted quinolones commenced with a
study of different catalyst systems and solvents. The choice
to use SPHOS as the ligand and K3PO4 as the base was
suggested by previous and extensive work of Buchwald16
et al. Couplings using quinolones 1a and the standard catalyst
Pd(PPh3)4 furnished quinolone 2a in good yields (Table 2,
entry 1). However, reactions were completed in less time using a
Pd/SPHOS system and resulted in higher yields of the 3-sub-
stituted quinolones (Table 2, entries 2-4). When applying the
same conditions to a quinolone with an iodo- substituent rather
than a bromo- substituent, an improvement in yield was
obtained (Table 2, entry 5). The use of toluene as solvent for the
(15) (a) Capparelli, M. V.; Charris, J. E.; Dominguez, J. N. J. Chem.
Crystallogr. 2006, 36, 389–398.
(16) (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358–3366. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
(17) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009,
74, 973–980.
J. Org. Chem. Vol. 75, No. 24, 2010 8655

Cross and Manetsch
JOCNote
TABLE 3. Scope 3-Halo-4-quinolone Cross-Couplings
TABLE 4. Scope of 6-Chloro-4-quinolone Cross-Couplings
a3.5 equiv of Ar0B(OH)2. bToluene. c2 equiv of Ar0B(OH)2. d100 °C.
coupled with 4-fluorophenylboronic acid smoothly in 94%
yields for the N-methylated and in 72% yields with N-H-
quinolone (Table 4, entries 1 and 2). 3-Phenyl-6-chloroquino-
lone was next coupled with 4-(hydroxymethyl)phenylboronic
acid (entries 3 and 4) in good yields for both amino forms.
3-Furanyl-6-chloro quinolones reacted well in the N-methyl
form with a 92% yield for phenylboronic acid (entry 5) and
91% for the sterically encumbered 2,5-dimethylphenylboronic
acid (entry 7). The free N-H containing 3-furanyl-6-chloro
quinolones only produced modest yields when coupled with
phenyl and dimethylphenylboronic acids (entries 6 and 8) of
41% and 47%, respectively. 3-Pyrimidine-6-chloro-4-quino-
lone (entry 9) was coupled with 3-pyridylboronic acid in 88%
yield to generate a 3-pyrimidine-6-pyridyl-4-quinolone hetero-
cycle.
To build in additional avenues for diversity, we explored
the possibilities of installing cyano groups at both the 3- and
6-positions (Table 5, entries 1 and 2). 6-Chloro-3-cyano-
quinolones could provide an intermediate to diversify the
benzenoid ring of the quinolone while enabling a potential
transformation to a 3-carboxylate group similar to cipro-
floxacin. An extension of the method developed by Eli Lilly
using a Pd/dppf catalyst with Zn0 as the in situ reductant18
efficiently transformed the 6-chloro-4-quinolone to 3-furan-
yl-6-cyano quinolone (Table 5, entry 1) in high yields. The
same conditions failed to catalyze the cyanation of 3-iodo-
quinolone. Previous work shows that many palladium-cat-
alyzed methods proceed with only low to moderate yields of
the product.19 Ultimately, switching to a copper iodide/
DMEDA system20 with sodium cyanide resulted in cyana-
tion of the 3-position with excellent yields (Table 5, entry 2).
aDMF, 1.5 equiv of ArB(OH)2, 110 °C. b2-Butanol, 1.5 equiv of
ArB(OH)2, 110 °C. DMF, 3.5 equiv of ArB(OH)2, 110 °C. DMF, 2.0
equiv of ArB(OH)2, 85°C. eToluene, 2.0 equiv of ArB(OH)2. fDMF, 5 equiv
of ArB(OH)2, 110 °C.
c
d
fluorinated, and pyridyl, as well as sterically hindered substrates
(Table 3).
6-Chloro-3-aryl-4-quinolones (Table 3, entries 9 and
17-24) were studied to highlight the divergent nature of this
synthetic route further by taking advantage of the reactivity
differences between the iodo and chloro substituents. The
3-position could be subjected to Suzuki-Miyaura coupling
followed by a subsequent coupling with a different boronic
acid at the 6-position, providing the capability of building
complex 4-quinolones. 3-Phenyl-6-chloroquinolones were
(18) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271–3273.
(19) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224–8228.
(20) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
2890–2891.
8656 J. Org. Chem. Vol. 75, No. 24, 2010

Cross and Manetsch
JOCNote
TABLE 5. Cyanation of 4-Quinolone
125.3, 124.6, 123.3,115.3, 35.3, 20.2. HRMS (ESI) calcd for
C17H15NO [M þ H]þ 250.12264, found 250.12372.
Procedure for 6-Chloro-4-quinolone Cross-Couplings. In a
flame-dried Schlenk tube backfilled with argon (3ꢀ), a mixture
of 6-chloro-2-methyl-3-phenylquinolin-4(1H)-one (100 mg,
0.37 mmol), 4-(hydroxymethyl)phenylboronic acid (197 mg,
1.29 mmol), K3PO4 (158 mg,0.74 mmol), Pd2(dba)3 (17 mg,
0.019 mmol), and SPHOS (23 mg, 0.056 mmol) was heated to
110 °C in DMF (1 mL) for 21 h. The reaction was cooled to room
temperature and then diluted with 20 mL of chloroform and
20 mL of methanol. This mixture was brought to a boil and then
filtered over a pad of Celite, an additional 10 mL of boiling
DMF was then poured over the pad, and the combined eluent
was concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (DCM/
MeOH gradient) to provide the title compound in 73% yield
(92 mg) as a light yellow solid, mp = 341-344 °C. Character-
ization data for Table 4, entry 4: 1H NMR (400 MHz, DMSO) δ
11.73 (s, 1H), 8.32 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.66 (dd, J=
20.1, 8.2 Hz, 3H), 7.41 (dd, J=14.9, 7.6 Hz, 4H), 7.29 (dd, J=
19.8, 7.2 Hz, 3H), 5.23 (s, 1H), 4.55 (s, 2H), 2.24 (s, 3H). 13C
NMR (101 MHz, DMSO) δ 174.9, 146.5, 141.7, 138.6, 137.9,
136.2, 134.5, 131.0, 130.1, 127.8, 127.2, 126.5, 126.2, 124.6,
122.5, 121.0, 118.4, 62.6, 18.9. HRMS (ESI) calcd for
C23H20NO2 [M þ H]þ 342.14886, found 342.14981.
In summary, using the Pd/SPHOS catalyst/ligand system,
we have designed and optimized a divergent synthetic
route to structurally diverse 3-aryl-4-quinolones resulting
in medicinally important heterocyclic scaffolds. A 6-chloro-
3-iodo-quinolone was used as a core intermediate to diversify
the quinolone scaffold via mono or sequential Suzuki-
Miyaura cross-couplings including fluoro, pyridyl, sterically
hindered, heteroaryl, electron-rich, and electron-poor sub-
strates. In addition, iodo-4-quinolones were subjected to
cyanations via Pd-catalysis, and chloro-4-quinolones were
transformed by copper catalysis. Ongoing efforts at prepar-
ing 3-aryl-4-quinolones via this route led to the identification
of several analogues displaying antimalarial activity in the
nanomolar range.21
Procedure for 6-Chloro-4-quinolone Cross-Couplings. To a
flame-dried Schlenk tube backfilled with argon (3ꢀ) was added
a mixture of 6-chloro-3-iodo-1,2-dimethylquinolin-4(1H)-one (100
mg, 0.3 mmol), CuI (6 mg, 0.03 mmol), DMEDA (32 μL, 0.3
mmol), and sodium cyanide (18 mg, 0.36 mmol). The reaction was
heated to 90 °C in toluene (1 mL) for 23 h. The reaction was cooled
to room temperature, diluted with 20 mL of chloroform, filtered
through a pad of Celite, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel
(EtOAC/MeOH 5%) to provide 6-chloro-1,2-dimethyl-4-oxo-1,4-
dihydroquinoline-3-carbonitrile in 90% yield (63 mgs) as a light
brown solid, mp = 255-256 °C. Characterization data for Table 5,
entry 2: 1H NMR (400 MHz, DMSO) δ 8.06 (d, J = 2.4 Hz, 1H),
7.97 (d, J= 9.2 Hz, 1H), 7.86 (dd, J= 9.2, 2.4 Hz, 1H), 3.82 (s, 3H),
2.74 (s, 3H). 13C NMR (101 MHz, DMSO) δ 172.7, 159.9, 139.4,
133.3, 130.1, 126.0, 124.1, 120.4, 116.8, 96.0, 36.5, 21.0.
Experimental Section
Procedure for 3-Halo-4-quinolone Cross-Couplings. In a
flame-dried Schlenk tube backfilled with argon (3ꢀ) a mixture
of 3-iodo-1,2-dimethylquinolin-4(1H)-one (100 mg, 0.4 mmol),
phenylboronic acid (97 mg, 0.59 mmol), K3PO4 (168 mg, 0.79
mmol), Pd2(dba)3 (14.5 mg, 0.016 mmol), and SPHOS (13 mg,
0.032 mmol) was heated to 80 °C in toluene (1 mL) for 45 min.
The reaction was cooled to room temperature and then diluted
with 20 mL of chloroform and 20 mL of methanol, and this
mixture was brought to a boil and then filtered over a pad of
Celite. The eluent was concentrated under reduced pressure, and
the residual oil was purified via flash chromatography on silica
gel (hexanes/EtOAc gradient) to provide the title compound in
95% yield (94 mg) as an off-white solid, mp = 208-210 °C.
Characterization data for Table 3, entry 2: 1H NMR (400 MHz,
CDCl3) δ 8.46 (dd, J = 8.0, 1.5, 1H), 7.61 (dd, J = 9.4, 7.8, 1H),
7.48 (d, J = 8.6, 1H), 7.40-7.27 (m, 4H), 7.24-7.17 (m, 2H),
3.75 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 176.1,
148.5,141.6, 137.3, 132.14, 131.1, 128.5, 127.5, 127.2, 126.4,
Acknowledgment. We thank Medicines for Malaria Venture
(MMV) and the Florida Center of Excellence for Biomolecular
Identification and Targeted Therapeutics (FCoE-BITT) for
financial support. We thank Dr. David L. Flanigan for help in
preparing the manuscript.
Supporting Information Available: Detailed experimental
procedures including 1H, 13C, and 19F NMR, HRMS, and
melting points. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Cross, R. M.; Flanigan, D. L.; Monastyrskyi, A.; Mutka, T.; Kyle,
D. E.; Manetsch, R. Abstracts of Papers, 239th National Meeting of the
American Chemical Society, San Francisco, CA, March 21-25, 2010;
American Chemical Society: Washington, DC, 2010; ORGN-316.
J. Org. Chem. Vol. 75, No. 24, 2010 8657