One pot synthesis of bioactive benzopyranones through palladium-catalyzed C-H activation and CO insertion into 2-arylphenols

Article abstract of DOI:10.1039/c3cc47197g

Palladium-catalyzed oxidative carbonylation of 2-arylphenols through C-H bond activation and C-C and C-O bond formation under acid-base free and mild conditions has been developed. The reaction tolerates a variety of substrates and provides biologically important benzopyranone derivatives in up to 87% isolated yield.

Full text of DOI:10.1039/c3cc47197g

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One pot synthesis of bioactive benzopyranones
through palladium-catalyzed C–H activation and
CO insertion into 2-arylphenols†
Tai-Hua Lee,a Jayachandran Jayakumar,b Chien-Hong Cheng*b and Shih-Ching Chuang*a
Cite this: Chem. Commun., 2013,
49, 11797
Received 20th September 2013,
Accepted 25th October 2013
DOI: 10.1039/c3cc47197g
www.rsc.org/chemcomm
Palladium-catalyzed oxidative carbonylation of 2-arylphenols materials, [60]fulleroazepines.10 In this system, we have also succeeded
through C–H bond activation and C–C and C–O bond formation in the preparation of phenanthridinones through Pd-catalyzed oxida-
under acid–base free and mild conditions has been developed. The tive CO insertion into N-sulfonyl-2-aminobiaryls under acid-free con-
reaction tolerates a variety of substrates and provides biologically ditions.11 Due to their importance in biological and materials science
important benzopyranone derivatives in up to 87% isolated yield. fields,12 the syntheses of benzopyranones have received substantial
attention. Previous approaches relied on multistep procedures for [3+3]
The methodology of transition-metal-catalyzed C–H bond activation cyclization of silyl enol ethers with 3-silyloxy-2-en-1-ones,13 oxidation of
has evolved as a powerful tool for covalent C–X bond formation 6H-benzo[c]chromene,14 Cu(I)-mediated cyclization of 2-halobiaryl-
(X = C, N, O) with features of step-economy and green chemistry carboxylic acid,15 Suzuki–Miyaura cross-coupling of o-bromoaryl-
primarily because halogenated materials are not required as starting carboxylates and o-hydroxyarylboronic acids,16 and Pd-catalyzed CO
substrates. Many of these reactions have been extensively used for the insertion into 10-hydroxy-10,9-boroxarophenanthrenes.17 Very
syntheses of various natural products and bioactive molecules.1 recently, Inamoto et al.18 and Shi et al.19 independently demon-
In this scope, metal-catalyzed carbonylation of organic compounds strated ruthenium and palladium-catalyzed CO insertion into
in the presence of carbon monoxide in combination with C–H bond 2-arylphenols via C–H activation. These related reports utilized
activation has become an important tool for C–C and C–X bond- conditions with bases (K2CO3 or Cs2CO3 or Na2CO3) or carbene
forming processes.2 Yu et al. have recently demonstrated the ortho- ligands (IPr) as additives in mesitylene at >100 1C.8a Our continuing
carbonylation of anilides and carboxylic acids through Pd(II)-catalyzed interest in the C–H activation reactions of 2-substituted biaryls
C–H bond activation under a CO atmosphere.3 Other recent reports relevant to our developed fulleroazepines and phenanthridinone
also revealed the synthesis of phthalimides4 through tandem C–H syntheses10,11 prompts us to scrutinize the reaction conditions for
bond activation and carbonylation of benzamides catalyzed by the syntheses of benzopyranones from 2-arylphenols by Pd-catalysis.
palladium, ruthenium or rhodium complexes. Similarly, Lei et al. Herein we report the oxidative insertion of carbon monoxide into
achieved Pd-catalyzed oxidative dual C–H functionalization– 2-arylphenols through C–H bond activation without extra addition
carbonylation of diaryl ethers for the synthesis of xanthones.5 of acid, base or ligand at lower reaction temperature (Scheme 1).
In addition to the C–H activation–functionalization on the same aryl
We optimized the studied carbonylation reaction using biphenyl-2-ol
ring as the directing group, the metal-catalyzed C–H activation of (1a) as a model substrate and summarized the results in Table 1. We
neighbouring aryl rings, the 2-directing group substituted biaryl started with previously successful conditions with 10 mol% of Pd(OAc)2
systems, has also emerged for the syntheses of fluorenones,6 carba- and silver acetate as oxidants in anhydrous CH3CN for carbonylation of
zoles,7 dibenzofurans8 and phenanthridinones.9 We recently reported 1a and observed the formation of 6H-benzo[c]chromen-6-one (2a) in
the annulation of N-sulfonyl-2-aminobiaryls with [60]fullerenes 37% isolated yield (entry 1). The catalytic reaction in other solvents such
through palladium(II)-catalyzed C–H bond activation to afford n-type as DMF, toluene, DMSO, THF or butyronitrile gave lower product
yields than that in CH3CN (entries 2–6). We noted that reactions
a Department of Applied Chemistry, National Chiao Tung University,
Hsinchu 30010, Taiwan, R.O.C. E-mail: jscchuang@faculty.nctu.edu.tw;
Fax: +886-35723764; Tel: +886-35731858
b Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan,
R.O.C. E-mail: chcheng@mx.nthu.edu.tw; Fax: +886-35724698;
Tel: +886-35715131 ext 33381
† Electronic supplementary information (ESI) available. CCDC 949418 and
Scheme 1 Palladium-catalyzed C–H bond activation–carbonylation of 2-arylphenols
951032. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc47197g
for syntheses of benzopyranones.
c
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Table 1 Optimization of reaction conditionsa
Table 2 Palladium-catalyzed synthesis of benzopyranone derivativesa
Oxidant
Entry (equiv.)
Temp Time Yieldb
Entry
1
Substrate 1
Product 2
Yieldb (%)
68
Additive
Solvent (1C)
(h)
(%)
1
2
3
4
5
6
7
8
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (3)
Ag2O (2)
Ag2CO3 (2)
KHSO5 (2)
K2S2O8 (2)
Cu(OAc)2 (2)
BQ (2)
AgOAc (3)
AgOAc (4)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3CN
DMF
Toluene
DMSO
THF
80
80
80
80
80
110
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
72
96
24
24
48
24
24
48
48
48
37
23
11
Trace
28
31
35
25
24
33
36
28
50
42
68
60
49
27
29
59
—
Pr-CN
2
3
4
5
70
85
87
77
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
—
NaOAc (1)
KOAc (1)
2,4,6-Collidine CH3CN
TFA (5)
AcOH (2)
—
—
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
40
47
38
46
6
70
62
68
65
72
a
All the reactions were performed with 1a (50 mg, 0.29 mmol), 10 mol%
of Pd(OAc)2 (6.6 mg, 0.029 mmol) under CO in freshly distilled solvents
(4 mL) unless otherwise noted. Isolated yields. 15 mol% of Pd(OAc)2
was employed. PdCl2(PPh3)2 was used as a catalyst. Reaction was
carried out with undistilled CH3CN.
7
b
c
d
e
8
with Ag2O, K2S2O8 and Cu(OAc)2 as oxidants produced comparable
yields to that with AgOAc (entries 7–12) and concluded that AgOAc
and Cu(OAc)2 can be suitable oxidants in CH3CN. This notion is
quite different to our previously studied carbonylation of N-sulfonyl-
2-aminobiaryls since it only worked better with AgOAc.11 We further
investigated the relative stoichiometric amounts of reactants and
reaction time for achieving optimal yields. The reaction with a higher
amount of silver acetate (3 and 4 equiv.) provided 2a in 50% and
42% yields (entries 13 and 14) and those with prolonged reaction
times of 48, 72 and 96 h gave 68, 60 and 49% yields, respectively
(entries 15–17). The demand for a longer reaction time than 24 h is
9
10
11
12
13
87
74
78
likely due to the slow C–O reductive elimination process.8a Our naıve
¨
thought to use bases as additives to quench the slightly acidic
conditions, such as using NaOAc, KOAc and 2,4,6-collidine, did
not improve the yields (entries 18–20). Neither the explored reaction
took place under more acidic conditions with extra acidic additives
such as TFA or AcOH (entries 21 and 22). The above observation is
consistent with Liu’s conclusion that the phenol moiety behaved as a
neutral s-donor.8a We further found that an increase of the catalyst
loading and replacement of the catalyst with PdCl2(PPh3)2 did not
help (entries 23 and 24). Our control experiment showed that the
reaction conditions have to be anhydrous since the use of non-
distilled acetonitrile only gave 46% yield (entry 25).
14
15
16
75
81
86
Under the standard reaction conditions (Table 1, entry 14),
substrates 1b–d without substituents on the Ar1 ring and with an
electron-donating group (EDG), methyl or methoxy moiety, on the
c
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Table 2 (continued )
(entries 17 and 18). It is worthwhile to point out that the present
C–H activation–carbonylation is not compatible with substrates
equipped with a methyl group on Ar1—no desired CO insertion
spots were observed by TLC analysis (entries 19 and 20). The benzylic
C–H bonds of these substrates could be easily activated followed by
CO insertion and reductive elimination with another 2-arylphenol to
give esters. Repetitiously the intermolecular process will give poly-
meric species. The present catalytic reaction was applicable to
substrates with Ar2 of the 2-naphthyl moiety to give substituted
6H-naphtho[2,3-c]chromen-6-ones in good yields regioselectively
(entries 21 and 22). Furthermore, the reaction of 1-phenylnaphtha-
lene-2-ol (1w) with CO proceeded effectively to give 2w in 75% yield
(entry 23). Finally, difluoro-substituted 2-arylphenols did not pro-
duce the expected CO insertion products likely due to the instability
of the intermediates having more electron-withdrawing groups on
the phenol ring in the catalytic process (entries 24 and 25).
Entry
17
Substrate 1
Product 2
Yieldb (%)
75
18
19
85
—
In conclusion, we have demonstrated an efficient Pd-catalyzed
oxidative carbonylation of 2-arylphenols via one O–H and C–H bond
cleavage, and one new C–C and C–O bond formation under mild
conditions with tolerance of a variety of substrates in good yields.
We thank the National Science Council of Taiwan, NCTU
and NTHU for financial support of this research.
20
21
22
—
72
74
Notes and references
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75
—
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a
All reactions were carried out with substrate 1 (50 mg), Pd(OAc)2
(10 mol%), and AgOAc (3 equiv.) in 4 mL of anhydrous CH3CN at 80 1C
b
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regioselectively to generate benzopyranones 2b–d, respectively, in
70–87% yields (Table 2, entries 2–4). This reaction was also applied
to substrates 1 with a chloro substituent on Ar2 (entry 5) and
heterocycles such as 2-furyl and 2-thienyl on Ar2 (entries 6 and 7).
In addition, benzopyranone 2h with a 3,4-methylenedioxy moiety
can be prepared in 68% yield (entry 8). Compound 2h was prepared
11 V. Rajeshkumar, T.-H. Lee and S.-C. Chuang, Org. Lett., 2013, 15, 1468.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 11797--11799 11799