An efficient route from coumarins to highly functionalized N-phenyl-2-quinolinones via Buchwald-Hartwig amination

Article abstract of DOI:10.1016/S0040-4039(03)00884-0

Multiple substituted N-phenyl-2-quinolinones were obtained in a convenient four-step route from a variety of commercially available coumarins, utilizing customised Buchwald-Hartwig amination protocols for the key reaction. Whereas simple aminolysis of cou

Full text of DOI:10.1016/S0040-4039(03)00884-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4207–4211
An efficient route from coumarins to highly functionalized
N-phenyl-2-quinolinones via Buchwald–Hartwig amination
Thomas Ullrich* and Francis Giraud
Novartis Forschungsinstitut GmbH, Medicinal Chemistry Unit, Brunner Strasse 59, A-1235 Wien, Austria
Received 17 March 2003; accepted 4 April 2003
Abstract—Multiple substituted N-phenyl-2-quinolinones were obtained in a convenient four-step route from a variety of
commercially available coumarins, utilizing customised Buchwald–Hartwig amination protocols for the key reaction. Whereas
simple aminolysis of coumarins is limited to non-electron-deficient, sterically unhindered derivatives of aniline under harsh
conditions, the present method allows for conversions with multiple substituted aromatic amines, as demonstrated by the example
of chlorinated aminosalicylates. © 2003 Elsevier Science Ltd. All rights reserved.
Substituted N-phenyl-2-quinolinones represent the
structural basis of many biologically active compounds,
such as protein kinase inhibitors, immunomodulators,
anti-ulcer agents, hypoglycemics, farnesyl transferase
inhibitors, and antiviral agents.1a–f We had specific
interest in the substance class for the evaluation of
potential immunosuppressors and sought a synthetic
route that would introduce as much structural diversity
as possible, with a focus on salicylic acid derivatives as
the N-phenyl moiety, and variability of the quinolinyl
substitution pattern.
Known procedures for the synthesis of N-phenyl-2-
quinolinones (Scheme 1) report the coupling of nor-
Scheme 1.
* Corresponding author. Tel.: +43-1-86634-436; fax: +43-1-86634-354; e-mail: thomas.ullrich@pharma.novartis.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00884-0

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T. Ullrich, F. Giraud / Tetrahedron Letters 44 (2003) 4207–4211
Scheme 2. Reagents and conditions: (a) NaOEt, EtOH, reflux, 4 h; (b) Tf2O, Et3N, CH2Cl2, rt, 2 h; (c) see Table 1; (d) NaOMe,
MeOH, reflux, 1–4 h (see also Table 2).
quinolinones with aryl halides,2 boronic acids,3 or
organolead reagents4 in the presence of copper catalysts
(Route A). Few examples were given where coumarins
were directly aminolyzed upon treatment with substi-
tuted anilines5 (Route B). Both of these methods bear
significant limitations. Route A is certainly compro-
mised by the low number of commercially available,
functionalized 2-quinolinones, and structurally diverse
boronic acids or organolead reagents are either expen-
sive or hazardous, or have to be synthesized in a
lengthy process. Aryl halides do not necessarily fall
under these limitations but give very poor yields in this
type of coupling reactions. When applying Route B in
Figure 1. SK-CC01-A.

T. Ullrich, F. Giraud / Tetrahedron Letters 44 (2003) 4207–4211
Table 1. Buchwald–Hartwig amination
4209
Entry
R1
R2
R3
R4
Prod.
Ma
Time (h)
Yield (%)
4a/5a
4a/5b
4a/5c
4b/5d
H
H
H
6-Me
H
H
H
Cl
H
H
CO2Me
CO2Me
H
OMe
H
6a
6b
6c
6d
A
A
A
A
B
C
A
B
C
A
A
A
20
20
24
24
24
0.3
24
24
0.3
24
24
24
73
79
60
45
80
47
42
77
38
73
48
51
OMe
4c/5d
6-NO2
Cl
CO2Me
OMe
6e
4d/5e
4d/5d
4e/5d
7-Me
7-Me
7-OMe
H
Cl
Cl
CO2Me
CO2Me
CO2Me
OMe
OMe
OMe
6f
6g
6h
a Methods: A, Pd2(dba)3 (25 mol%), ( )-BINAP, Cs2CO3, toluene, reflux; B, SK-CC01-A (5 mol%), Cs2CO3, toluene, reflux; C, Pd2(dba)3 (25
mol%), ( )-BINAP, Cs2CO3, acetonitrile, 150°C, microwave irradiation.
Table 2. Cyclization of aminoesters
Entry
R1
R2
R3
R4
Pr.
Time (h)
Yield (%)
6a
6b
6c
6d
6e
6f
H
H
H
6-Me
6-NO2
7-Me
7-Me
7-OMe
H
H
H
Cl
Cl
H
Cl
Cl
H
H
H
OMe
H
OMe
OMe
OMe
OMe
OMe
1a
1b
1c
1d
1e
1f
4
3
3
3
1
4
4
4
72
64
67
50
84
64
63
43
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
6g
6h
1g
1h
our laboratory, we observed that aminolysis of cou-
marin did not take place with anilines featuring elec-
tron-withdrawing groups in the para position or any
ortho-substituents for sterical reasons, both crucial
structural features in our series.
Furthermore, Route B usually requires harsh conditions
(extensive reflux in high-boiling solvents) to overcome
the pronounced sluggishness of the reactions; a number
of functional or protective groups necessary for diver-
sity would not tolerate such conditions. For these rea-

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T. Ullrich, F. Giraud / Tetrahedron Letters 44 (2003) 4207–4211
heating and addition of fresh catalyst. We therefore
investigated this particular reaction with a new catalyst
that has been recently described as a very valuable tool
in CꢀC and CꢀN coupling reactions, [bis(bicyclo-
[2.2.1]hept-2-yl)phosphine]chloro[2%-(dimethylamino-kN)-
[1,1%-biphenyl]-2-yl-kC]palladium (SK-CC01-A) (Fig.
1).10 The reaction proceeded with a faster rate to yield
80% of 6d and 6e, respectively, after 24 h, using 4 mol%
of catalyst. When applied to other substrates, SK-CC01-
A could not elevate yields up to more than 80% but
shortened the required reaction time for this conversion
to some extent.
sons we sought an alternative route that would be
accomplished in only few synthetic steps from a variety
of cheap starting materials, providing good yields while
tolerating a large variety of functional groups. A promis-
ing pathway (Route C) was envisaged considering the
ease at which diarylamines can be synthesized under
Buchwald–Hartwig conditions.6 Providing a useful syn-
thon for amination, bearing a carboxyl side chain for
final stage cyclization, we opted for triflated o-hydroxy-
cinnamates that would be readily available from cou-
marins.
The presented synthetic route is primarily based on a
Buchwald–Hartwig palladium-catalyzed aryl-amino
coupling reaction between triflates of the general formula
4 and anilines of the general formula 5 (Scheme 2).
Triflates 4 were obtained by ethanolysis of commercially
available coumarins 27 and subsequent sulfonylation of
o-hydroxycinnamates 3. 1H NMR analysis indicated that
the double bond conformation in 3 was exclusively (E).
The Buchwald–Hartwig amination was in general per-
formed following a literature protocol,8 using Pd2(dba)3
as catalyst (4 mol%) and ( )-BINAP as ligand in the
presence of Cs2CO3 and toluene (reflux). Although these
conditions reportedly give good to excellent yields for
many substrates, and we ourselves obtained yields of
60–80% for meta- and/or para-substituted anilines after
24 h, we observed a significant decrease of the conversion
rate when employing the sterically hindered aniline 5d
(R2=Cl).9 Products 6d, 6e, 6g and 6h could not be
afforded in more than 50% yield even after prolonged
Another improvement, although limited to the small
loading capacity of the used equipment, was offered by
conducting the Buchwald amination under microwave
irradiation, as described for aryl bromides by Wan et al.11
Thus, upon replacement of toluene with acetonitrile,
similar yields as achieved with conventional synthesis
were obtained after only 15 min at 150°C,12 which
underlines the striking superiority of microwave-assisted
technology for small-scale procedures in the field of
palladium-catalyzed coupling reactions. An overview of
all substrates and reaction conditions of Buchwald–
Hartwig amination reactions is presented in Table 1.
In the final step, aminoesters 6a–h underwent base-trig-
gered cyclization, taking advantage of the relative acidity
of the secondary amine hydrogen. Simple treatment with
NaOMe/MeOH afforded products 1a–h in moderate to
good yields.13 It was evident that the electronic nature
of both aromatic rings had a significant impact
Table 3. Analytical data for 1b–h
Compd.
1H NMR (400 MHz; CDCl3) l (ppm)
13C NMR (400 MHz; CDCl3) l (ppm)
HR-MS m/z
1b
7.79 (d, 1H, 9.5), 7.59 (dd, 1H, 7.7, 1.4), 7.51 (t,
1H, 8.1), 7.35 (td, 1H, 8.2, 1.5), 7.20 (td, 1H, 8.2,
0.8), 7.07 (dd, 1H, 2.4, 8.4), 6.88 (m, 1H), 6.82 (t,
1H, 2.3), 6.79 (d, 1H, 9.5), 6.70 (d, 1H, 8.5), 3.83
(s, 3H)
162.2, 161.1, 141.1, 139.8, 138.7, 130.9, 130.2, 128.2,
122.3, 122.2, 120.8, 120.3, 116.0, 115.0, 114.1, 55.4
252.1 (M+H)+
1c
1d
8.3 (d, 2H, 7.3), 7.80 (d, 1H, 9.6), 7.6 (dd, 1H, 7.5, 166.6, 162.4, 142.2, 141.1, 140.5, 132.0, 131.2, 130.8,
280.1 (M+H)+
358.1 (M+H)+
1.3), 7.40 (d, 2H, 7.3), 7.35 (td, 1H, 4.1, 1.7), 7.22
(t, 1H, 7), 6.80 (d, 1H, 9.6), 6.60 (d, 1H, 8.5), 4.0
(s, 3H)
129.6, 128.9, 123.0, 122.5, 120.7, 116.0
8.06 (s, 1H), 7.77 (d, 1H, 9.6), 7.42 (s, 1H), 7.20
(dd, 1H, 7.6, 2.0), 6.95 (s, 1H), 6.76 (d, 1H, 9.6),
6.46 (d, 1H, 8.60), 3.94 (s, 3H), 3.87 (s, 3H), 2.41
(s, 3H)
164.9, 161.2, 158.9, 140.3, 139.4, 137.6, 133.5, 132.6,
131.9, 128.4, 124.3, 122.1, 121.9, 120.2, 114.8, 114.4,
56.6, 52.5, 20.6
1e
1f
8.57 (d, 1H, 2.5) 8.25 (dd, 1H, 9.2, 2.5), 8.11 (s,
1H), 7.95 (d, 1H, 9.5), 6.98 (s, 1H), 6.94 (d, 1H,
9.5), 6.71 (d, 1H, 9.2), 4.0 (s, 3H), 3.9 (s, 3H)
8.02 (d, 1H, 8.2), 7.75 (d, 1H, 8.5), 7.48 (d, 1H,
165.0, 164.2, 161.1, 159.4, 143.9, 140.2, 138.5, 134.1,
125.7, 124.9, 124.6, 124.3, 123.3, 120.2, 116.1, 114.5,
57.1, 53.0
389.1 (M+H)+
324.1 (M+H)+
166.5, 162.5, 160.9, 142.8, 141.7, 141.2, 140.3, 133.7,
7.9), 7.04 (dd, 1H, 7.9, 1.4), 6.96–6.88 (m, 2H), 6.70 128.6, 124.4, 121.3, 121.1, 121.0, 118.5, 116.1, 113.3,
(d, 1H, 9.5), 6.43 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 56.6, 52.6, 22.4
2.41 (s, 3H)
1g
1h
8.06 (s, 1H), 7.77 (d, 1H, 9.6), 7.50 (d, 1H, 8.0),
7.05 (dd, 1H, 8.0, 1.4), 6.94 (s, 1H), 6.70 (d, 1H,
9.6), 6.31 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.32
(s, 2H)
165.3, 161.8, 159.3, 142.1, 140.7, 140.2, 139.9, 133.8,
128.9, 124.8, 124.7, 122.7, 121.1, 118.5, 115.3, 114.9,
57.0, 52.8, 22.4
358.1 (M+H)+
374.1 (M+H)+
8.1 (s, 1H), 7.75 (d, 1H, 10.5), 7.55 (d, 1H, 8.6),
6.95 (s, 1H), 6.85 (dd, 1H, 6.3, 2.3), 6.61 (d, 1H,
165.2, 162.3, 162.1, 159.4, 141.7, 140.7, 139.8, 134.0,
130.4, 124.6, 122.5, 119.1, 114.9, 114.8, 110.6, 99.9,
12.5), 6.0 (d, 1H, 2.3), 3.95 (s, 3H), 3.9 (s, 3H), 3.7 57.0, 55.9, 52.9
(s, 3H)

T. Ullrich, F. Giraud / Tetrahedron Letters 44 (2003) 4207–4211
4211
on the conversion rate and the yield after several hours
of reflux. A reaction period longer than indicated was
considered disadvantageous due to decomposition
(TLC), also the reason for which no quantitative con-
versions were observed. With both R1 and R3 being
electron-withdrawing groups, such as –NO2 and
–COOMe (1e), located in the para position of the
amino substituent, the promoted acidity enhanced the
rate as compared to ‘neutral’ or electron-donating
groups. This manifested in a time/yield profile as
demonstrated in Table 2. Analytical data for 1b–h are
presented in Table 3. 1a Has been synthesized via Route
A and thoroughly characterized by Wawzonek et al.2
Inoue, Y.; Sato, K.; Miki, S. JP 97-183870, 1999; (e) End,
D. W.; Venet, M. G.; Angibaud, P. R.; Sanz, G. C. WO
96-EP4661, 1997; (f) Afonso, A.; Weinstein, J.; Gentles,
M. J. WO 91-US6251, 1995.
2. Wawzonek, S.; Van Truong, T. J. Heterocycl. Chem.
1988, 25, 381–382.
3. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux,
D. Tetrahedron 1999, 55, 12757–12770.
4. Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J.
Chem. Soc., Perkin Trans. 1 1997, 3, 229–233.
5. El Kihel, A.; Benchidmi, M.; Essassi, E. M.; Bauchat, P.;
Danion-Bougot, R. Synth. Commun. 1999, 29, 2435–2445.
6. Hartwig, J. F. In Modern Amination Methods; Ricci, A.,
Ed.; Wiley-VCH: Weinheim, 2000; pp. 195–262.
7. Fries, K.; Klostermann, W. Justus Liebigs Ann. Chem.
1908, 362, 1–29.
8. Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6363–6366.
9. This compound was synthesized according to:
Ehrenkaufer, R. L.; Scripko, J. G.; Hoffman, P. L. Org.
Prep. Proced. Int. 1992, 24, 64–66.
In conclusion, we have discovered an efficient and
convenient route to convert commercial coumarins into
multiple substituted N-phenyl-2-quinolinones without
the limitations usually observed in this process. A great
potential of time and yield optimization was offered by
the choice of catalyst and microwave irradiation in the
key step of the pathway. The present work should be
easily reproducible with other amine substrates, includ-
ing heterocyclic scaffolds, with a good chance of being
broadly applied.
10. Indolese, A.; Schnyder, A. EP 1132361, 2001.
11. Wan, Y.; Alterman, M.; Hallberg, A. Synthesis 2002, 11,
1597–1600.
12. A representative procedure is described: A mixture of 4c
(100 mg, 0.27 mmol), 5d7 (76 mg, 0.35 mmol), cesium
carbonate (135 mg, 0.41 mmol), Pd2(dba)3 (7.8 mg, 0.008
mmol), BINAP (7.8 mg, 0.012 mmol) and HPLC grade
acetonitrile (2 mL) is placed in a 5mL high-pressure glass
vial and reacted in an Emrys™ microwave optimizer
(150°C, 15 min). After cooling, the mixture was poured
on 1N HCl (10 mL) and extracted with EtOAc (3×10
mL). The combined organic layers are washed with brine
(1×20 mL), dried (Na2SO4/charcoal) and evaporated. The
residue is purified by flash chromatography (appr. 10 g of
silica gel, eluent: toluene/EtOAc=3:1) to yield 73 mg
(84%) of 6e. TLC: toluene/EtOAc=3:1 (Rf=0.5).
13. A representative procedure is described: 6g (4.11 g, 10.2
mmol) and NaOMe (1.11 g, 20.4 mmol) are dissolved in
anhydrous MeOH (100 mL) and refluxed in an argon
atmosphere for 4 h. After cooling, the mixture is poured
on 1N HCl (200 mL) and extracted with EtOAc (2×200
mL). The combined organic layers are washed with brine
(2×200 mL), dried (Na2SO4) and evaporated. The residue
is purified by flash chromatography (appr. 100 g of silica
gel, eluent: toluene/EtOAc=1:1) to yield 2.14 g (63%) of
1g. TLC: toluene/EtOAc=1:1 (Rf=0.2).
Acknowledgements
We thank the Leonardo DaVinci fellowship program
for financial support, Solvias AG (Switzerland) for
kindly providing us with a free sample of SK-CC01-A,
and K. Ho¨genauer and K. Weigand for a thorough
review of the manuscript.
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