Palladium-catalyzed intramolecular amidation of C(sp2)-H bonds: Synthesis of 4-aryl-2-quinolinones

Article abstract of DOI:10.1021/jo100557s

Figure presented A catalytic synthetic approach for the synthesis of 2-quinolinone compounds through a Pd-catalyzed C(sp²)-H functionalization/intramolecular amidation sequence is described. The cyclization process efficiently proceeds in the p

Full text of DOI:10.1021/jo100557s

pubs.acs.org/joc
4-aryl-2-quinolinone derivatives, including several natural
Palladium-Catalyzed Intramolecular Amidation of
C(sp2)-H Bonds: Synthesis of 4-Aryl-2-quinolinones
products1 and compounds that are currently in clinical
trials,2 have attracted much attention in recent years.1-4
Moreover, 2-quinolinones serve as valuable synthetic inter-
mediates because they can be easily transformed into 2-
(pseudo)haloquinolines (e.g., 2-Cl, 2-OTf), which can under-
go further functionalization, such as nucleophilic aroma-
tic substitutions and Pd-catalyzed coupling reactions.5
Although many strategies for the construction of the 2-qui-
Kiyofumi Inamoto,* Tadataka Saito, Kou Hiroya, and
Takayuki Doi*
Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
nolinone ring rely on cyclization approaches,6,7 including
6a
inamoto@mail.pharm.tohoku.ac.jp; doi_taka@mail.pharm.
tohoku.ac.jp
€
classic base-catalyzed Friedlander and acid-catalyzed
Knorr synthesis,6b few synthetic methods based on transi-
tion-metal catalysis exist. However, such methods would
provide a more facile, versatile, and practical route.
Received March 24, 2010
Several research groups recently demonstrated the suc-
cessful use of a palladium catalyst in 2-quinolinone
synthesis.8-10 Larock et al. reported the carbonylative an-
nulation of alkynes with 2-iodoanilines and CO in the
presence of Pd(OAc)2, leading to 3,4-disubstituted 2-quino-
linones.8e More recently, Cacchi, Fabrizi, and co-workers
developed a protocol for preparing 4-aryl-2-quinolinones
from 2-bromocinnamamides and aryl iodides through a
tandem-type Heck reaction/Buchwald-Hartwig amination
sequence.8c Willis’ group also reported a one-pot formation
of 2-quinolinones from 2-(2-haloalkenyl)aryl halides and
A catalytic synthetic approach for the synthesis of 2-qui-
nolinone compounds through a Pd-catalyzed C(sp2)-H
functionalization/intramolecular amidation sequence is
described. The cyclization process efficiently proceeds in
the presence of a catalytic amount of PdCl2 and Cu(OAc)2
under an O2 atmosphere, providing practical access to a
range of variously substituted 4-aryl-2-quinolinones.
(4) (a) Cheng, P.; Zhang, Q.; Ma, Y.-B.; Jiang, Z.-Y.; Zhang, X.-M.;
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and natural products with unique biological activities, con-
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3900 J. Org. Chem. 2010, 75, 3900–3903
Published on Web 05/06/2010
DOI: 10.1021/jo100557s
r
2010 American Chemical Society

Inamoto et al.
JOCNote
TABLE 1. Pd-Catalyzed 2-Quinolinone Synthesis: Effect of Reaction
Parameters
TABLE 2. Pd-Catalyzed 2-Quinolinone Synthesis: Effect of Substitu-
ent on Nitrogen Atom
yielda (%)
entry
Cu(OAc)2 (mol %)
atmosphere
yielda (%)
1
2
3
4
5
6
7
8
100
100
50
30
15
0
Ar
O2
O2
O2
O2
O2
air
air
53 (45)b
82
85
entry
R
2
3
recovered 1
1
2
3
4
5
6
7
Ts (1a)
Ac (1b)
Boc (1c)
H (1d)
Me (1e)
85
53
36
25
0
0
0
0
0
0
0
0
0
0
0
88
47 (53)b
0 (96)b
97
23 (1d)
68 (1e)
78 (1f)
0
21 (1h)
trace (1i)
0
24 (3e)
0 (3f)
99 (3g)
62 (3h)
58 (3i)
82 (3j)
50
30
iPr (1f)
65 (25)b
OMe (1g)
Ph (1h)
4-OMeC6H4 (1i)
4-NO2C6H4 (1j)
aYield of isolated product from reaction on a 0.13 mmol scale.
8b
9b
10b
bRecovered yield of starting material in parentheses.
0
aYield of isolated product from reaction on a 0.13 mmol scale.
amines in the presence of CO by means of a Pd-catalyzed
intermolecular aminocarbonylation/intramolecular amida-
tion sequence.8a
b100 mol % of Cu(OAc)2.
During the past several years, Pd-catalyzed functional
group-directed C-H functionalization has been intensively
studied, with most investigations focused on carbon-
carbon, carbon-oxygen, and carbon-halogen bond for-
mation.11 Carbon-nitrogen bond formation through
Pd-catalyzed C-H functionalization (C-H amination) has
so far been less studied,12-14 but it would be a complemen-
tary approach to the Buchwald-Hartwig (C-X, X = halo-
gen atom) amination reaction.15
Several reports have shown the potential of Pd-catalyzed
C-H amination for the synthesis of nitrogen atom-based
heterocycles that makes use of the intramolecular variant of
the process.16 In 2005, Buchwald’s group reported that an
intramolecular C-H amination of 2-acetaminobiphenyl
compounds can be realized in the presence of a catalytic
amount of Pd(OAc)2, leading to an efficient formation of
carbazoles.12k After this pioneering work, several groups,
including ours, successfully expanded the method for synthe-
sizing some nitrogen atom-based heterocycles, such as indo-
lines,12a,b oxindoles,12c,e indoles,12h indazoles,12i and carba-
zoles.12d,f,g Yu et al. recently developed an efficient method
for the synthesis of lactams via intramolecular C-H
amination.12e In light of these successful precedents for Pd-
catalyzed intramolecular C-H amination, we anticipated
that the cyclization of 3-arylacrylamides through a C-H
amination process would lead to an efficient protocol for the
synthesis of 2-quinolinone compounds. Herein, we address
the details of this subject.
Initial studies were performed using N-tosyl-3,3-dipheny-
lacrylamide (1a) to determine the optimal reaction condi-
tions (Table 1). On the basis of our recent reports about Pd-
catalyzed C-H amination,12h,i we examined various com-
binations of a catalytic palladium and a copper salt as a
stoichiometric reoxidant in DMSO solvent. The use of
10 mol % of PdCl2 and 100 mol % of Cu(OAc)2 resulted
in the formation of the cyclized product. Unexpectedly,
detosylation of 2-quinolinone also occurred during the
course of the reaction, generating 4-phenyl-2-quinolinone
(2) in fairly good yield (53%, entry 1).17,18
(11) For recent reviews on transition-metal-catalyzed C-H functionali-
zation, see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–
1169. (b) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540–548. (c) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. (d) Ackermann, L.;
Vincente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (e)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094–5115. (f ) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074–1086. (g) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344. (h)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447–2464. (i)
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. ( j) Li, B.-J.;
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949–957. (k) Kakkiuchi, F.; Kochi, T.
Synthesis 2008, 3013–3039. (l) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem.
Rev. 2007, 107, 3117–3179. (m) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichim. Acta 2007, 40, 35–41.
(12) (a) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
€
10806–10807. (b) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew.
Chem., Int. Ed. 2009, 48, 6892–6895. (c) Miura, T.; Ito, Y.; Murakami, M.
Chem. Lett. 2009, 38, 328–329. (d) Jordan-Hore, J. A.; Johansson, C. C. C.;
Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184–
16186. (e) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058–14059. (f )
Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 7603–7610. (g) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (h) Inamoto, K.; Saito, T.;
Hiroya, K.; Doi, T. Synlett 2008, 3157–3162. (i) Inamoto, K.; Saito, T.;
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Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048–9049.
(k) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
14560–14561.
Unfortunately, further optimization of this initial lead
using a range of solvents, palladium sources, and reoxidants
did not improve the yield. Various metal salts, aryliodonium
(13) (a) For a recent review on catalytic C-H amination, see: Collet, F.;
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061–5074. (b) For Pd-
catalyzed allylic C-H amination, see: Rice, G. T.; White, M. C. J. Am.
Chem. Soc. 2009, 131, 11707–11711. (c) For Pd-catalyzed dehydrogenative
diamination of terminal alkenes, see: Wang, B.; Du, H.; Shi, Y. Angew.
Chem., Int. Ed. 2008, 47, 8224–8227.
(16) For recent reviews on the construction of heterocyclic compounds
via C-H functionalization, see: (a) Thansandote, P.; Lautens, M. Chem.;
Eur. J. 2009, 15, 5874–5883. (b) Zhang, M. Adv. Synth. Catal. 2009, 351,
2243–2270.
(17) Heating independently prepared 1-tosyl-4-phenyl-2-quinolinone at
120 °C in DMSO in the absence of palladium and copper salts resulted in the
detosylation, producing compound 2 in quantitative yield. Similar detosyla-
tion has been previously reported; see ref 8e.
(14) Examples of C-S bond formation via catalytic C-H functionaliza-
ꢀ
tion are much rarer in the literature; see: (a) Zhao, X.; Dimitrijevic, E.; Dong,
V. M. J. Am. Chem. Soc. 2009, 131, 3466–3467. (b) Joyce, L. L.; Batey, R. A.
Org. Lett. 2009, 11, 2792–2795. (c) Inamoto, K; Hasegawa, C.; Hiroya, K.;
Doi, T. Org. Lett. 2008, 10, 5147–5150. (d) Inamoto, K.; Arai, Y.; Hiroya, K.;
Doi, T. Chem. Commun. 2008, 5529–5531.
(15) Janey, J. M. In Name Reactions for Functional Group Transforma-
tions; Li, J. J., Corey, E. J., Eds.; Wiley: New York, 2007; pp 564-604.
(18) For detailed results of screening, see the Supporting Information.
J. Org. Chem. Vol. 75, No. 11, 2010 3901

Inamoto et al.
JOCNote
TABLE 3. Pd-Catalyzed 2-Quinolinone Synthesis: Substrate Scope
TABLE 4. Pd-Catalyzed 2-Quinolinone Synthesis: Unsymmetrical
Substrates
aYield of isolated product from reaction on a 0.13 mmol scale.
bRecovered yield of starting material in parentheses. c140 °C.
salts, benzoquinone, and Oxone were used as a reoxidant,
but none of them yielded better results. However, we were
pleased to find that the use of an O2 atmosphere greatly
enhanced the process (entry 1 vs 2)19,20 and reduced the
amount of Cu(OAc)2 to 30 mol % (entry 4). From a practical
point of view, it is noteworthy that the catalytic activity of the
(19) Molecular oxygen (O2), because of its nontoxic, readily available,
and easy-to-handle character, can be considered as one of the most ideal
reoxidants and has often been employed as a terminal co-reoxidant for
similar catalytic C-H functionalization processes; see ref 12c,12f,12g,12k.
For other selected recent examples, see: (a) Ueda, S.; Nagasawa, H. J. Org.
Chem. 2009, 74, 4272–4277. (b) Brasche, G.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 1932–1934. (c) Brasche, G.; García-Fortanet, J.; Buchwald,
S. L. Org. Lett. 2008, 10, 2207–2210. (d) Ferreira, E. M.; Zhang, H.; Stoltz, B. M.
Tetrahedron 2008, 64, 5987–6001. (e) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137–3139. (f ) Chen, X.; Hao, X.-S.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790–6791.
(20) For selected reviews on Pd-catalyzed oxidation reactions using
molecular oxygen, see: (a) Gligorich, K. M.; Sigman, M. S. Chem. Commun.
2009, 3854–3867. (b) Muzart, J. Chem. Asian J. 2006, 1, 508–515. (c) Stahl,
S. S. Science 2005, 309, 1824–1826. (d) Punniyamurthy, T.; Velusamy, S.; Iqbal, J.
Chem. Rev. 2005, 105, 2329–2363. (e) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400–3420. (f ) Nishimura, T.; Uemura, S. Synlett 2004, 201–216.
aYield of isolated product from reaction on a 0.13 mmol scale.
b140 °C. c15 mol % of PdCl2 was used. dRecovered yield of starting
material in parentheses. Obtained as a 1:2.7 mixture of E-/Z-isomers.
e
fA 1.4:1 mixture of E-/Z-isomers was used. gA 2.6:1 mixture of E-/Z-
isomers was used.
3902 J. Org. Chem. Vol. 75, No. 11, 2010

Inamoto et al.
JOCNote
system was also found in the reaction conducted under an air
atmosphere (entry 7).
isomerization, providing 2v-a and 2v-b as sole products in
high yields (entries 7 and 8).22,23
We next explored the effect of the substituent on the
nitrogen atom of an amide moiety (Table 2). As the tosyl
group described above (entry 1), cyclization of the substrate
possessing an electron-withdrawing acetyl (Ac) or a tert-
butoxycarbonyl (Boc) group proceeded with concomitant
loss of an Ac or a Boc group, thereby producing depro-
tected 2-quinolinone (2) (entries 2 and 3). The use of free
amide (1d, entry 4) or alkyl amides (1e and 1f, entries 5
and 6) resulted in poor yields, whereas a methoxy substi-
tuent significantly enhanced this process (entry 7). The
benzene ring was also found to be a suitable substituent
on a nitrogen atom (entries 8-10). Interestingly, the yield
increased as the electron density of the benzene ring on the
nitrogen atom diminished, suggesting that the nucleophili-
city of the nitrogen atom plays an important role in the
process.
In summary, we have demonstrated that the cyclization of
3,3-diarylacrylamides through intramolecular C-H amina-
tion can be performed in the presence of a palladium catalyst
to produce variously substituted 2-quinolinones generally in
high yields. The use of an O2 atmosphere along with a
semicatalytic amount of Cu(OAc)2 as a reoxidation system
proved to be crucial for the process. The method provides a
novel and efficient protocol to construct a pharmaceutically
important 2-quinolinone nucleus, and this technique should
be a valuable tool in the fields of medicinal chemistry as well
as organic synthesis. Further studies of the application of
the Pd-catalyzed intramolecular C-H amination process for
the synthesis of other nitrogen atom-based heterocycles are
currently underway.
Experimental Section
This new method for 2-quinolinone synthesis can be
applied to cyclization of a range of substrates possessing
various functional groups on the benzene ring (Table 3).
Halogen atoms, including bromine, are well tolerated under
the reaction conditions employed (entries 1-3). The sub-
strate 1n, which contains two electron-withdrawing cyano
groups at the para-position, was not suitable for this process
(entry 4), whereas amides 1o-q, which have two electron-
donating methoxy groups at the ortho-, meta-, or para-
position, produced the corresponding 2-quinolinone com-
pounds 2o-q in high yields (entries 5-7).
The scope of the catalytic conditions developed above was
further investigated using several unsymmetrical substrates
(Table 4). The reaction of the Z-isomer of the substrate 1r,
which had one cyano group at the para-position, gave
2-quinolinone 2r-a as a sole product in high yield (entry 1).
Similarly, the use of its E-isomer (1r-E) resulted in the
successful formation of 2r-b (entry 2). The E-isomer is much
more reactive than the Z-isomer in the case of the m-cyano-
substituted compound 1s (entries 3 and 4). From the former
(1s-E), quinolinone 2s-b was produced in quantitative yield
(entry 4), whereas the cyclization of the latter (1s-Z) pro-
vided 2s-a in only 18% yield along with the recovery of 1s as a
1:2.7 mixture of E-/Z-isomers (61%, entry 3). Although the
reason for the difference in the reactivity is unknown at
present, a plausible rationale for these results might involve
the relatively slow rate of isomerization compared to that of
cyclization and deactivation of the catalyst system employed
during the reaction course.21 Due to the difficulty of separa-
tion, a mixture of isomers was used for the reactions of 1t and
1u. Both compounds smoothly underwent the cyclization,
affording a mixture of regioisomers that included 2t-a
and 2t-b and 2u-a and 2u-b, respectively (entries 5 and 6).
Reactions of 1v-Z and 1v-E proceeded efficiently without
Representative Procedure for Pd-Catalyzed 2-Quinolinone
Synthesis (Table 1, Entry 4). Compound 1a (50.0 mg, 0.13
mmol), PdCl2 (2.3 mg, 0.013 mmol), and Cu(OAc)2 (7.2 mg,
0.040 mmol) were weighed in a pear-shaped flask. The flask
was evacuated and refilled with Ar. Under a positive Ar
pressure, DMSO (2.6 mL) was added via syringe. The flask
was again evacuated and refilled with O2. The reaction mixture
was then stirred at 120 °C for 14 h under an O2 atmosphere
(balloon). After being cooled to room temperature, the reaction
mixture was extracted with ethyl acetate (10 mL ꢀ 3), and the
combined organic layer was washed with brine (10 mL) and
dried over MgSO4. The solvent was evaporated, and the
residue was purified by silica gel column chromatography
[hexane-ethyl acetate (4:1)] to give 2 (25.8 mg, 88%) as a
colorless solid.
4-Phenyl-1H-quinolin-2-one (2): mp 259-260 °C (white nee-
dles from EtOH, lit.8c mp 252-254 °C); IR ν (film, cm-1) 2849,
1
1659; H NMR (400 MHz, CDCl3) δ 6.70 (1H, s), 7.14-7.18
(1H, m), 7.46-7.56 (8H, m), 12.56 (1H, br s); 13C NMR (100
MHz, CDCl3) δ 116.7, 119.5, 120.7, 122.5, 126.6, 128.5, 128.7,
128.8, 130.6, 137.0, 138.8, 153.3, 164.1; MS m/z 221 (Mþ, 100);
HRMS calcd for C15H11NO 221.0841, found 221.0831. Anal.
Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C,
81.16; H, 5.23; N, 6.33.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (B) from the Japan
Society for the Promotion of Science (JSPS).
Supporting Information Available: Experimental details and
spectroscopic and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) Although extensive mechanistic studies have yet to be conducted,
experiments with the isotopically labeled substrates revealed primary kinetic
isotope effects (kH/kD) of 3.5 (intramolecular) and 2.7 (intermolecular),
indicating that cleavage of the C-H bond is involved in the rate-determining
step. Similar KIE values (intramolecular: 3.5, intremolecular: 2.6) were
previously observed in a related aromatic palladation process; see: Cher-
nyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636–5637. For
experimental details, see the Supporting Information.
(21) E-/Z-Isomerization of 1s was observed when either 1s-Z or 1s-E was
heated in DMSO at 120 °C for 8 h, resulting in the formation of a 1:1.9
mixture of E-/Z-isomers from both isomers.
(23) Compared with an air atmosphere, the use of an O2 atmosphere for the
reactions of 1k-v gives better results in terms of the yield and the reaction time.
J. Org. Chem. Vol. 75, No. 11, 2010 3903