Tandem-type Pd(ii)-catalyzed oxidative Heck reaction/intramolecular C-H amidation sequence: A novel route to 4-aryl-2-quinolinones

Article abstract of DOI:10.1039/c2cc30600j

A novel catalytic method for synthesizing 4-aryl-2-quinolinones is reported. The process involves two mechanistically independent, sequential Pd(ii)-catalyzed reactions - the oxidative Heck reaction and the intramolecular C-H amidation - both of which smoothly proceed in the presence of a single catalytic system in a one-pot manner. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30600j

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COMMUNICATION
Tandem-type Pd(II)-catalyzed oxidative Heck reaction/intramolecular
C–H amidation sequence: a novel route to 4-aryl-2-quinolinonesw
Kiyofumi Inamoto,* Junpei Kawasaki, Kou Hiroya, Yoshinori Kondo and Takayuki Doi*
Received 27th January 2012, Accepted 7th March 2012
DOI: 10.1039/c2cc30600j
A novel catalytic method for synthesizing 4-aryl-2-quinolinones is
reported. The process involves two mechanistically independent,
sequential Pd(II)-catalyzed reactions—the oxidative Heck reaction
and the intramolecular C–H amidation—both of which smoothly
proceed in the presence of a single catalytic system in a one-pot
manner.
2-Quinolinones are an important class of heterocycles, which have
long been known to exhibit a range of biological properties.1
Fig. 1 Synthesis of 2-quinolinones via palladium-catalyzed processes.
In particular, there is increasing interest in several analogues of
4-aryl-2-quinolinones, including natural products2 and compounds
leading to a facile and novel route to 4-aryl-2-quinolinone
that are currently in clinical trials.3 Although various strategies
derivatives [Fig. 1(c)]. In this communication, we describe in detail
the envisioned process in an effort to substantiate it.10
have so far been developed to access 2-quinolinone structural
To probe the viability of the anticipated Pd(II)-catalyzed tandem
motifs, there are only few reports on transition metal-catalyzed
process, we examined the reaction of N-methoxycinnamamide (1a)
approaches, which would provide a more efficient and practical
route.4 Noteworthy examples were recently reported by Kadnikov
and Larock,4f Cacchi and Fabrizi et al.,4d and Willis et al.4b who
successfully developed palladium-catalyzed cyclization processes
for preparing 2-quinolinones. Very recently, Yu et al. found
that 3,3-diarylacrylamides can undergo palladium-catalyzed C–H
functionalization followed by intramolecular amidation, providing
a novel route to 4-aryl-2-quinolinones.4a,5–7
with 2,4,6-triphenylboroxin at 100 1C in the presence of 30 mol%
of the Pd(OAc)2/1,10-phenanthroline (1,10-phen) catalyst system
(Table 1). Using AcOH as the solvent, we first evaluated the effect
of the reoxidant. Interestingly, we found that the use of a copper
salt as reoxidant delivered the 2-quinolinone compound, although
the yields were low (entries 3–5). In these cases, demethoxylation
unexpectedly occurred during the reaction, resulting in the formation
of 2-quinolinone 3. 3,3-Diphenylacrylamide, resulting from Pd(II)-
catalyzed oxidative Heck reaction followed by demethoxy-
lation, was also formed as a minor product.11 The subsequent
screening revealed that the use of 1 equiv. of a silver salt as an
additional reoxidant greatly enhanced the process. Among the silver
salts tested (entries 6–8), Ag2O gave the best results, providing
2-quinolinone 3 in 68% yield (entry 8). Although a reduced amount
of the catalyst provided a decreased yield (entry 8 vs. entry 9),
subsequent screening of the boron source (entries 9–12) indicated
that phenylboronic acid showed better reactivity, generating 3 in
fairly good yield (60%) in the presence of 10 mol% of the catalyst
(entry 12). Further optimization studies resulted in another inter-
esting finding. Namely, the use of increased amounts of Ag2O
(e.g., 4–10 equiv.) completely inhibited demethoxylation, leading to
the formation of 2-quinolinone 2aa (entries 13–16 vs. 12).12 The best
result was obtained when 8 equiv. of Ag2O was employed, affording
2-quinolinone 2aa in 76% yield (entry 15). With this catalyst
system, carrying out the reaction first at 100 1C for 1 h and then
at 120 1C for 10 h provided slightly better results (entry 17). The
reaction under O2 resulted in decreased yield (entry 18). The use
of Ag2O alone as reoxidant was not effective, and 2aa (44%) and
3,3-diphenyl-N-methoxyacrylamide (Heck-product, 44%) were
On the other hand, the rapid construction of complex molecules
through multiple bond-forming reactions in a single step, the
so-called tandem process, can be a powerful tool for synthetic
organic chemists. Such processes reduce the steps in the synthesis
of certain molecules; thus, being attractive from the viewpoint of
developing environmentally benign and economical synthetic
methods. Inspired by the work of Cacchi and Fabrizi, who
employed
a
Pd(0)-catalyzed tandem-type Mizoroki–Heck
reaction/intramolecular Buchwald–Hartwig amidation sequence
for the synthesis of 2-quinolinones [Fig. 1(a)],4d and with the success
of Yu’s as well as ours in using catalytic C–H cyclization in the
synthesis of 2-quinolinones [Fig. 1(b)],4a,5 we envisioned a tandem
process consisting of the oxidative Heck reaction of cinnamamides
with arylboron compounds8,9 followed by the intramolecular C–H
amidation reaction. Both of the above can be catalyzed by Pd(II),
Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
E-mail: inamoto@m.tohoku.ac.jp, doi_taka@mail.pharm.tohoku.ac.jp;
Fax: +81-22-795-5917; Tel: +81-22-795-3906
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral/analytical data. See DOI: 10.1039/c2cc30600j
c
4332 Chem. Commun., 2012, 48, 4332–4334
This journal is The Royal Society of Chemistry 2012

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Table 2 2-Quinolinone synthesis via symmetrical 3,3-diarylacrylamidesa
Table 1 Optimization of reaction conditionsa
Yieldb (%)
Entry Ph–B
X (mol%) Reoxidant (equiv.)
2aa
3
1a
Yieldc
(%)
1
2
3
4
5
(PhBO)3
30
30
30
30
30
K2S2O8 (2)
Oxone (2)
Cu(OAc)2 (2)
Cu(OAc)2ꢀnH2O (2)
Cu(TFA)2ꢀnH2O (2)
Cu(TFA)2ꢀnH2O (2) +
Ag2CO3 (2)
0
0
0
0
0
0
4
19
22
31
0
0
0
0
0
Entry Substrate 1
4 (R)
Conditionsb Product
2
(PhBO)3
(PhBO)3
(PhBO)3
(PhBO)3
1
2
A (t1 = 13)
76
81
4a (H)
2aa
6
7
8
9
(PhBO)3
(PhBO)3
(PhBO)3
(PhBO)3
30
30
30
10
0
0
0
0
50
53
68
49
0
0
0
0
B (t1 = 1,
t2 = 10)
Cu(TFA)2ꢀnH2O (2) +
AgOAc (2)
Cu(TFA)2ꢀnH2O (2) +
Ag2O (2)
3
4
5
4b (4-Me) A (t1 = 16)
2bb 76
2cc 59
Cu(TFA)2ꢀnH2O (2) +
Ag2O (2)
Cu(TFA)2ꢀnH2O (2) +
10
10
10
0
48
0
Ag2O (2)
B (t1 = 3,
4c (4-F)
Cu(TFA)2ꢀnH2O (2) +
Ag2O (1)
t2 = 43)
11
12
13
14
15
16
17c
18d
PhBF3K
0
55
60
0
0
Cu(TFA)2ꢀnH2O (2) +
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2 10
0
0
Ag2O (1)
Cu(TFA)2ꢀnH2O (2) +
Ag2O (4)
66
64
76
65
81
54
0
B (t1 = 3,
4d (4-Cl)
Cu(TFA)2ꢀnH2O (1) +
0
12
0
2dd 61
t2 = 10)
Ag2O (4)
Cu(TFA)2ꢀnH2O (1) +
Ag2O (8)
0
Cu(TFA)2ꢀnH2O (1) +
0
0
Ag2O (10)
Cu(TFA)2ꢀnH2O (1) +
Ag2O (8)
0
0
6
7
4e (4-OMe) A (t1 = 12)
2ee 12d
Cu(TFA)2ꢀnH2O (1) +
0
28
Ag2O (8)
Ag2O (8)
19
20
21
22
PhB(OH)2 10
PhB(OH)2 10
PhB(OH)2
PhB(OH)2
44
0
0
0
0
0
0
0
None
Cu(TFA)2ꢀnH2O (1)
16e
53f
95
0
0
4f (3-OMe) A (t1 = 12)
4g (2-Me) A (t1 = 13)
2ff 68
2gg 0e
Ag2O (8)
0
a
b
Reactions were carried out on a 0.11 mmol scale. Isolated yield.
c
The reaction mixture was first stirred at 100 1C for 1 h and then
d
e
stirred at 120 1C for 10 h. Under an O2 atmosphere. 14% of
demethoxylated cinnamamide was obtained. 22% of demethoxylated
cinnamamide was obtained.
f
8
a
b
Reactions were carried out on a 0.11 mmol scale. Conditions A:
obtained (entry 19). Essentially, the reaction without the
reoxidant did not furnish any cyclized products (entry 20).
Furthermore, performing the reaction without the palladium
catalyst failed to produce any coupling or cyclized products
(entries 21 and 22).13
carried out at 100 1C for t1 h. Conditions B: carried out at 100 1C for
t1 h and then 120 1C for t2 h. Isolated yield. 85% of 1e was
recovered. 34% of 1g was recovered.
c
d
e
To prove the generality of the method, the tandem process
affording 2-quinolinones via the formation of symmetrical
3,3-diarylacrylamides was next examined (Table 2). Reactions
of the substrate that has a methyl group or a halogen atom at
the para-positions of the benzene rings proceeded efficiently
(entries 3–5); whereas that of cinnamamide 1e, possessing a
methoxy group, resulted in the formation of the desired
2-quinolinone 2ee only in 12% yield along with the recovery of
the starting 1e in 85% yield (entry 6). In the case of the reaction of
1f, which possesses a methyl group at the meta-position of the
benzene ring, the C–H cyclization occurred at the less hindered site,
exclusively affording 2-quinolinone 2ff (entry 7). In contrast, the
introduction of a methyl group at the ortho-position of the benzene
ring did not result in the formation of the coupling or cyclized
product (entry 8).
The substrate scope of the process was further examined using a
variety of arylboronic acids (Table 3). Although 4-methoxyphenyl-
boronic acid 4e was not suitable for the process (entry 1), various
arylboronic acids possessing a trifluoromethyl group, a methoxy-
carbonyl group, or a halogen atom on the benzene ring (R2)
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4332–4334 4333

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Table 3 Substrate scope of 2-quinolinone synthesisa
2 (a) Y. Kobayashi and T. Harayama, Org. Lett., 2009, 11, 1603 and
references cited therein; (b) Y. Kitahara, M. Shimizu and A. Kubo,
Heterocycles, 1990, 31, 2085 and references cited therein.
3 (a) J. M. Kraus, H. B. Tatipaka, S. A. McGuffin, N. K. Chennamaneni,
M. Karimi, J. Arif, C. L. M. J. Verlinde, F. S. Buckner and M. H. Gelb,
J. Med. Chem., 2010, 53, 3887; (b) I. Garrido-Laguna, F. Janku,
G. S. Falchook, S. Fu, D. S. Hong, A. Naing, J. Aaron, X. Wang,
M. Kies and R. Kurzrock, Clin. Cancer Res., 2010, 16, 4031; (c) P. R.
Angibaud, M. G. Venet, W. Filliers, R. Broeckx, Y. A. Ligny, P. Muller,
V. S. Poncelet and D. W. End, Eur. J. Org. Chem., 2004, 479.
4 (a) M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058;
(b) A. C. Tadd, A. Matsuno, M. R. Fielding and M. C. Willis, Org.
Lett., 2009, 11, 583; (c) Z. Liu, C. Shi and Y. Chen, Synlett, 2008, 1734;
(d) G. Battistuzzi, R. Bernini, S. Cacchi, I. De Salve and G. Fabrizi, Adv.
Synth. Catal., 2007, 349, 297; (e) R. Bernini, S. Cacchi, G. Fabrizi and
A. Sferrazza, Heterocycles, 2006, 69, 99; (f) D. V. Kadnikov and R. C.
Larock, J. Org. Chem., 2004, 69, 6772; (g) M. Mori, K. Chiba, N. Ohta
and Y. Ban, Heterocycles, 1979, 13, 329; (h) N. A. Cortese, C. B. Ziegler
Jr., B. J. Hrnjez and R. F. Heck, J. Org. Chem., 1978, 43, 2952.
Yield of
c
Entry Substrate 1
4 (R2)
Conditionsb 2+20 (%) (2 : 20)
1
2
4e (4-OMe)
4h (4-CF3)
A (t1 = 9) traced
A (t1 = 12) 57 (57 : 0)
B (t1 = 3,
67 (67 : 0)
t2 = 48)
3
4i (3-CF3)
4
5
4j (4-CO2Me) A (t1 = 17) 64 (64 : 0)
4a (H)
A (t1 = 15) 69 (41 : 28)
5 Following Yu’s report, we also demonstrated that a variety of
4-aryl-2-quinolinones were synthesized from the corresponding
B (t1 = 3,
60 (60 : 0)
t2 = 26)
6
4h (4-CF3)
3-3-diarylacrylamides through
a Pd-catalyzed intramolecular
B (t1 = 3,
48 (48 : 0)
t2 = 48)
7
8
9
4i (3-CF3)
C–H amidation, see: K. Inamoto, T. Saito, K. Hiroya and
T. Doi, J. Org. Chem., 2010, 75, 3900.
6 For selected recent reviews on transition metal-catalyzed C–H functio-
nalization, see: (a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem.
Soc. Rev., 2011, 40, 5068; (b) O. Baudoin, Chem. Soc. Rev., 2011,
4j (4-CO2Me) A (t1 = 17) 57 (57 : 0)
B (t1 = 3,
4c (4-F)
56 (40 : 16)
85 (59 : 26)
66 (50 : 16)
t2 = 43)
B (t1 = 3,
t2 = 48)
B (t1 = 3,
t2 = 43)
10
4d (4-Cl)
40, 4902; (c) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius, Chem.
¨
Soc. Rev., 2011, 40, 4740; (d) A. E. Wendlandt, A. M. Suess and
S. S. Stahl, Angew. Chem., Int. Ed., 2011, 50, 11062; (e) Q. Liu,
H. Zhang and A. Lei, Angew. Chem., Int. Ed., 2011, 50, 10788; (f) E. M.
Beccalli, G. Broggini, A. Fasana and M. Rigamonti, J. Organomet.
Chem., 2011, 696, 277; (g) T. W. Lyons and M. S. Sanford, Chem. Rev.,
2010, 110, 1147; (h) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu,
Angew. Chem., Int. Ed., 2009, 48, 5094.
11
12
13
4k (4-Br)
4a (H)
A (t1 = 13) 62e (62 : 0)
B (t1 = 3,
53e (53 : 0)
t2 = 42)
4h (4-CF3)
14
4d (4-Cl)
A (t1 = 15) 72e (72 : 0)
7 For selected recent examples of Pd-catalyzed aromatic C–H amination,
see: (a) E. J. Yoo, S. Ma, T.-S. Mei, K. S. L. Chan and J.-Q. Yu, J. Am.
Chem. Soc., 2011, 133, 7652; (b) X.-Y. Liu, P. Gao, Y.-W. Shen and
Y.-M. Liang, Org. Lett., 2011, 13, 4196; (c) S. W. Youn, J. H. Bihn and
B. S. Kim, Org. Lett., 2011, 13, 3738; (d) B. Haffemayer, M. Gulias and
M. J. Gaunt, Chem. Sci., 2011, 2, 312; (e) Y. Tan and J. F. Hartwig,
J. Am. Chem. Soc., 2010, 132, 3676; (f) S. Chiba, L. Zhang, S. Sanjaya
and G. Y. Ang, Tetrahedron, 2010, 66, 5692; (g) See also ref. 5.
8 For reviews on oxidative Heck reaction, see: (a) Y. Su and N. Jiao,
Curr. Org. Chem., 2011, 15, 3362; (b) B. Karimi, H. Behzadnia,
D. Elhamifar, P. F. Akhavan, F. K. Esfahani and A. Zamani,
Synthesis, 2010, 1399. For theoretical mechanistic studies of oxi-
dative Heck reaction, see: (c) S. Zhang, L. Shi and Y. Ding, J. Am.
Chem. Soc., 2011, 133, 20218.
a
b
Reactions were carried out on a 0.11 mmol scale. Conditions A:
carried out at 100 1C for t1 h. Conditions B: carried out at 100 1C for t1 h
and then 120 1C for t2 h. Isolated yield. 99% of starting 1a was
recovered. 4-Aryl-6-methoxy-2-quinolinone was exclusively obtained.
c
d
e
successfully underwent reaction, affording different substituted
4-aryl-2-quinolinones generally in good to high yields
(entries 2–14). When cinnamamide 1e was employed, the reaction
sometimes gave a mixture of 2-quinolinones 2 and 20, indicating
that the E-/Z-isomerization could be occurring during the reaction
course (entries 5 and 9–11).
9 For selected recent examples of oxidative Heck reaction using organo-
boron compounds, see: (a) A. Nordqvist, C. Bjorkelid, M. Andaloussi,
¨
A. M. Jansson, S. L. Mowbray, A. Karlen and M. Larhed, J. Org.
´
In conclusion, we have reported a Pd(II)-catalyzed, tandem-type
oxidative Heck reaction/intramolecular C–H amidation sequence,
leading to a conceptually new, efficient method for the construction
of 4-aryl-2-quinolinone scaffolds. Readily available, variously sub-
stituted cinnamamides and arylboronic acids were smoothly reacted
in the presence of the PdCl2/1,10-phen catalyst system along with
the copper/silver reoxidant. Studies to improve the yields as well as
to broaden the substrate scope are currently underway.
Chem., 2011, 76, 8986; (b) Y. Liu, D. Li and C.-M. Park, Angew. Chem.,
Int. Ed., 2011, 50, 7333; (c) E. W. Werner and M. S. Sigman, J. Am.
Chem. Soc., 2010, 132, 13981; (d) Y. Leng, F. Yang, K. Wei and Y. Wu,
Tetrahedron, 2010, 66, 1244; (e) E. W. Ping, K. Venkatasubbaiah, T. F.
Fuller and C. W. Jones, Top. Catal., 2010, 53, 1048; (f) L. R. Odell,
J. Lindh, T. Gustafsson and M. Larhed, Eur. J. Org. Chem., 2010, 2270.
10 For related tandem-type, Pd-catalyzed synthesis of heterocycles
involving C–H functionalization, see: (a) L. Ackermann and
A. Althammer, Angew. Chem., Int. Ed., 2007, 46, 1627;
(b) R. B. Bedford and M. Betham, J. Org. Chem., 2006, 71, 9403.
11 N-Free, demethoxylated cinnamamide is not suitable for the
Pd-catalyzed C–H cyclization. For detailed examination of the effect
of the substituent on the nitrogen atom of cinnamamide 1, see ESIw.
12 Use of a large excess of reoxidants might be inhibiting the undesired
N–O bond cleavage during the process. For selected recent examples of
using N–OR groups as an oxidizing directing group (acting as both a
directing group and an internal oxidant) in transition metal-catalyzed
C–H functionalization processes, see: (a) B. Li, J. Ma, N. Wang, H.
Feng, S. Xu and B. Wang, Org. Lett., 2012, 14, 736; (b) N.
Guimond, S. I. Gorelsky and K. Fagnou, J. Am. Chem. Soc., 2011,
133, 6449; (c) S. Rakshit, C. Grohmann, T. Basset and F. Glorius,
J. Am. Chem. Soc., 2011, 133, 2350.
This work was partly supported by a Grant-in-Aid for
Young Scientists (B) (No. 23790002) from Japan Society for
the Promotion of Science and a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105) from MEXT.
Notes and references
1 For selected recent examples, see: (a) A. K. Gupta, N. Sabarwal,
Y. P. Agrawal, S. Prachand and S. Jain, Eur. J. Med. Chem., 2010,
45, 3472; (b) F. O’Donnell, T. J. P. Smyth, V. N. Ramachandran and
W. F. Smyth, Int. J. Antimicrob. Agents, 2010, 35, 30; (c) B. S.
Jayashree, S. Thomas and Y. Nayak, Med. Chem. Res., 2010, 19, 193.
13 For detailed results of the optimization studies, see ESIw.
c
4334 Chem. Commun., 2012, 48, 4332–4334
This journal is The Royal Society of Chemistry 2012