K2CO3-catalyzed synthesis of chromones and 4-quinolones through the cleavage of aromatic C-O bonds

Article abstract of DOI:10.1021/ol300908g

Phenol-derived electrophiles are favorable substrates because phenols are naturally abundant or can be readily prepared from other aromatic compounds. However, the cleavage of aromatic C-O bonds is a great challenge because of their high energy. K₂CO₃-catalyzed intramolecular cyclization of 1-(2-alkoxyphenyl)-3-akylpropane-1,3-dione and 3-(alkylimino)-1-(2-methoxyphenyl)-2-methylpropan-1-one derivatives via the selective cleavage of aromatic C-O bonds is reported. The corresponding chromone and 4-quinolone derivatives were obtained in reasonable yields.

Full text of DOI:10.1021/ol300908g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
K2CO3-Catalyzed Synthesis of Chromones
and 4-Quinolones through the Cleavage of
Aromatic CÀO Bonds
Jie Zhao,† Yufen Zhao,†,‡ and Hua Fu*,†,§
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R.
China, Key Laboratory for Chemical Biology of Fujian Province, Department of
Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, P. R. China, and Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received April 9, 2012
ABSTRACT
Phenol-derived electrophiles are favorable substrates because phenols are naturally abundant or can be readily prepared from other aromatic
compounds. However, the cleavage of aromatic CÀO bonds is a great challenge because of their high energy. K2CO3-catalyzed intramolecular
cyclization of 1-(2-alkoxyphenyl)-3-akylpropane-1,3-dione and 3-(alkylimino)-1-(2-methoxyphenyl)-2-methylpropan-1-one derivatives via the selec-
tive cleavage of aromatic CÀO bonds is reported. The corresponding chromone and 4-quinolone derivatives were obtained in reasonable yields.
Transition-metal-catalyzed aromatic nucleophilic sub-
stitutions are ubiquitous in modern organic synthesis,1 and
most of the reactions use aryl halides as electrophiles
because of their high reactivity.2 However, aryl halides
are far less available from natural sources, and they are
certainly not used as coupling partners in biosynthesis
pathways.3 In addition, some drawbacks accompany the
reactions by using aryl halides as electrophiles. For exam-
ple, aryl halides and halide byproducts are environmentally
unfriendly, and some of aryl halides are often unavailable
and difficult to prepare. Therefore, it is highly desirable to
develop some alternatives of aryl halides. Phenol-derived
electrophiles are favorable substrates because phenols are
naturally abundant or can be readily prepared from other
easily accessed aromatic species, and over 50000 phenol
derivatives are commercially available.3,4 However, the
cleavage of aromatic CÀO bonds often is not easy because
of a higher aryl CÀO bond energy relative to CÀX (X =
Cl, Br, I) bonds in aryl halides.5 Therefore, activations of
CÀO bonds in phenols are required. Typically, phenols are
converted into corresponding sulfonates,6 sulfamates,7
phosphates,8 carboxylates,9 and carbamates10 to improve
cleavage of aromatic CÀO bonds together with assistance
(4) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH: Weinheim,
2003.
(5) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255–263.
€
(6) (a) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609–
† Department of Chemistry, Tsinghua University.
612. (b) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818–11819. (c) Limmert, M. E.; Roy, A. H.; Hartwig, J. F.
J. Org. Chem. 2005, 70, 9364–9370.
‡ College of Chemistry and Chemical Engineering, Xiamen University.
§ Graduate School of Shenzhen, Tsinghua University.
(1) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359–1469.
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Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem.
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Reactions; Wiley-VCH: Weinheim, 1997.
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A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416.
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Y.; Katauro, Y.; Kumada, M. Synthesis 1981, 1001–1003.
r
10.1021/ol300908g
XXXX American Chemical Society

of expensive transition metals. Recently, the selective cleav-
age of aromatic CÀO bonds from alkyl aryl ethers has been
investigated in the presence of transition metals,11 particu-
larly nickel catalysts.12 Herein, we report base-catalyzed
synthesis of chromone and 4-quinolone derivatives via
selective cleavage of aromatic CÀO bonds.
Table 1. Intramolecular Cyclization of 1-(2-Methoxyphenyl)-3-
p-tolylpropane-1,3-dione (1a) to 2-p-Tolyl-4H-chromen-4-one
(2a): Optimization of Conditionsa
As shown in Table 1, intramolecular cyclization of 1-(2-
methoxyphenyl)-3-p-tolylpropane-1,3-dione (1a) to 2-p-
tolyl-4H-chromen-4-one (2a) was chosen as the model
reaction to optimize the reaction conditions including
transition-metal salts, bases, and solvents under nitrogen
atmosphere. Four solvents were tested in the presence of
highly pure K2CO3 (here, K2CO3 with 99.997% purity was
used from Alfa Aesar Co.13 in order to avoid the involve-
ment of other metals in the reaction) (entries 1À4), and
DMSO (entry 1) and DMF (entry 2) gave better results.
DMF provided the highest yield (95%). The effect of bases
was investigated (entries 5À8), and K2CO3 provided the
highest efficiency (compare entries 2, 5À8). Interestingly,
organic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
also afforded the target product (2a) in 71% yield (entry 8),
and use of the organic base further avoided involvement of
othermetals. The solventinthe resultingsolution of entry 2
was removed, the residue was determined by inductively
coupled plasma mass spectroscopy (ICP-MS), and only
trace amounts of Ni (8.41 ppm), Pd (1.98 ppm), Rh (0.47
ppm), Ru (0.63 ppm), and Cu (2.52 ppm) were found. We
changed the amount of K2CO3 (entries 9À11), and a small
amount of K2CO3 also afforded the target product (2a) in
higher yields. The results showed that K2CO3 acted as the
catalyst in this reaction. When volume of DMF was
changed to 1 mL from 2 mL, a 86% yield was provided
(entry 11). The reaction under air gave a low yield (17%)
with some byproduct appearing (entry 12). We attempted
cyclization of 1-(2-methoxyphenyl)-3-p-tolylpropane-1,3-
dione (1a) in the presence of different transition-metal
salts, and the results showed that addition of these transi-
tion-metal salts decreased the efficiency of this reaction
(entries 13À15). Therefore, the standard reaction condition
for the base-catalyzed synthesis of chromone derivatives is
as follows: 20 mol % of K2CO3 as the catalyst and DMF as
the solvent under nitrogen atmosphere.
entry tm saltb base (equiv)
solvent
DMSO
time (h) yieldc (%)
1
2
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
Cs2CO3 (1)
K3PO4 (1)
KOH (1)
24
24
24
24
24
24
24
24
40
40
40
40
40
40
40
90
DMF
95
3
1,4-dioxane
NMP
trace
57
4
5
DMF
81
6
DMF
64
7
DMF
18
8
DBU (1)
DMF
71
9
K2CO3 (0.8) DMF
K2CO3 (0.4) DMF
K2CO3 (0.2) DMF
K2CO3 (0.2) DMF
K2CO3 (0.2) DMF
K2CO3 (0.2) DMF
88
10
11
12
13
14
15
86
84 (86d)
17d,e
68d
73d
5d
CuI
NiCl2
Pd(OAc)2 K2CO3 (0.2) DMF
a Reaction conditions: 1-(2-methoxyphenyl)-3-p-tolylpropane-1,3-
dione (0.5 mmol), base (0.5 mmol), solvent (2 mL), tm salt (no addition
of tm salt for entries 1À16; 0.05 mmol for 17À20) under nitrogen
atmosphere in a sealed Schlenk tube. Reaction temperature (125 °C).
Reaction time (24 or 40 h). b tm = transition metal. c Isolated yield.
d Solvent (1 mL). e Under air.
We investigated the substrate scope of the base-cata-
lyzed intramolecular cyclization. As shown in Table 2, the
examined substrates provided good to excellent yields. For
substituent R1, the substrates with electron-withdrawing
groups showed higher reactivity than those with electron-
donating groups (compare entries 2À5). For substituent
R2, the substrates containing electron-donating groups on
aromatic rings provided higher yields than those contain-
ing electron-withdrawing and neutral groups on aromatic
rings, and the reactivity decreased when R2 was an alipha-
tic alkyl (entry 6). In general, the intramolecular cycliza-
tion afforded slightly lower yields when 2-methoxyl was
replaced with 2-ethanoxyl (entry 7) or 2-phenoxyl (entries
8À12). It is well-known that the chromone derivatives are
important natural products and have exhibited various
biological and medicinal activities,14 and the acid-catalyzed
synthesis of chromones is a common strategy via the reac-
tion of 1-(2-hydroxyphenyl)-3-akylpropane-1,3-dione deri-
vatives.15 The present base-catalyzed intramolecular
nucleophilic substitution is a transition-metal-free process,
and this transition-metal-free method solves the problem
that trace amount of toxic transition-metals remained in the
(9) (a) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am.
Chem. Soc. 2008, 130, 14468–14470. (b) Quasdorf, K. W.; Tian, X.;
Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422–14423. (c) Quasdorf,
K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009,
131, 17748–17749.
(10) (a) Sengupta, S.; Leite, M.; Raslan, D. S. J. Org. Chem. 1992, 57,
4066–4068. (b) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am.
Chem. Soc. 2009, 131, 17750–17752.
(11) (a) Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S.
J. Am. Chem. Soc. 2004, 126, 2706–2707. (b) Ueno, S.; Mizushima, E.;
Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516–16517.
(12) (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43,
1486–1495. (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am.
Chem. Soc. 1979, 101, 2246–2247. (c) Dankwardt, J. W. Angew. Chem.,
Int. Ed. 2004, 43, 2428–2432. (d) Tobisu, M.; Shimasaki, T.; Chatani, N.
Angew. Chem., Int. Ed. 2008, 47, 4866–4869. (e) Sergeev, A. G.; Hartwig,
J. F. Science 2011, 332, 439–443.
(13) K2CO3 (99.997%), Mg (2 ppm), Na (8 ppm), other elements
including Al, Sb, As, Ba, Bi, B, Cd, Ca, Cr, Co, Cu, In, Fe, Pb, Li, Mn,
Mo, Ni, P, Si, Te, Sn, Ti, V, Zn, Zr (sought but not detected) (the data
were provided by Alfa Aesar Co.).
(14) (a) Havsteen, B. H. Pharmacol. Ther. 2002, 96, 67–202. (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893–930. (c) deAzevedo, W. F.; Mueller-Dieckmann, H. J.; Schulze-
Gahmen, U.; Worland, P. J.; Sausville, E.; Kim, S. H. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 2735–2740.
(15) (a) Banerji, A.; Goomer, N. C. Synthesis 1980, 874. (b) Hirao, I.;
Yamaguchi, M.; Hamada, M. Synthesis 1984, 1076.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. K2CO3-Catalyzed Intramolecular Cyclization Leading
to Chromone Derivativesa
Scheme 1. K2CO3-Catalyzed Intramolecular Cyclization of
Substituted 1-(2-(1H-Imidazol-1-yl)phenyl)-3-phenylpropane-
1,3-diones Leading to Flavones
(1t) and 1-(2-(1H-imidazol-1-yl)phenyl)-3-(4-methoxy-
phenyl)propane-1,3-dione (1u), and the corresponding
chromones 2a and 2b were obtained in 81 and 70% yields,
respectively (Scheme 1). In the previous organic synthesis,
aromatic compounds with nitrogen-containing groups as
leaving groups were limited. For example, diazo com-
pounds were used as electrophiles,16 but preparation of
the diazo compounds needed environmentally unfriendly
HNO2 as the partner. In addition, aryl ammonium salts
were also applied in the coupling reactions, and transition-
metal catalysts were required.17 It is well-known that
cleavage of the aromatic CÀN bonds in neutral arylamines
is very difficult, so the present finding is different from
traditional aromatic nucleophilic substitution reactions.
In our previous research on the synthesis of chromone
derivatives from substituted 1-(2-halophenyl)-3-p-tolyl-
propane-1,3-diones,18 we performed various control ex-
periments in order to explore the base-mediated mecha-
nism. The results showed that the substrates containing
2-bromo or chloro almost exhibited similar reactivity.
Here, alkoxyl and 1H-imidazol-1-yl were used as the
leaving groups, and the reactions worked well. Obviously,
the present reaction mechanism is different from the
traditional nucleophilic substitution reactions of aryl
CÀX (X = halo and their alternates). A possible mechan-
ism on the base-catalyzed intramolecular nucleophilic
substitutions of 1 leading to chromone derivatives (2) is
proposed in Scheme 2. Enolization of the R-carbonyl
group in 1 leads to intermediate I in the presence of base
(K2CO3), and intrmolecular cycloaddition of I gives II.
Rearomatization of II by elimination of KY provides the
target product (2). Treatment of KY with KHCO3 regen-
erates K2CO3 leaving HY.
Inspired by the excellent results above, we investigated
reactions of 3-(2-methoxyphenyl)-2-methyl-3-oxopropa-
nal with primaryamines leading to 4-quinolone derivatives
(See Table 3). The whole process was divided into two steps:
coupling of aldehyde with primary amine first formed
imine intermediate, 3-(alkylimino)-1-(2-methoxyphenyl)-
2-methylpropan-1-one (III), and then intramolecular cy-
clization of the imine yielded 4-quinolone derivative (see
Scheme 3). Formation of imines was performed in DMSO
a Reaction conditions: dione (1) (0.5 mmol), K2CO3 (0.1 mmol),
DMF (1 mL) under nitrogen atmosphere in a sealed Schlenk tube.
b Isolated yield.
final target products after purification by the previous
isolation procedures. Therefore, the present transition-
metal-free and aryl-halide-free base-catalyzed method is
environmentally friendly.
Similarly, we attempted intramolecular cyclization of
1-(2-(1H-imidazol-1-yl)phenyl)-3-p-tolylpropane-1,3-dione
(16) (a) Darses, S.; Jeffrey, J. P.; Genet, J. P.; Brayer, J. L.; Demoute,
J. P. Tetrahedron Lett. 1996, 37, 3857–3860. (b) Roglans, A.; Pla-
Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622–4643.
(17) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
6046–6047.
~
(18) Zhao, J.; Zhao, Y.; Fu, H. Angew. Chem., Int. Ed. 2011, 50,
3769–3773.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Possible Mechanism on Base-Catalyzed Intramole-
cular Cyclization of 1 Leading to Chromone Derivative (2)
Scheme 3. Possible Mechanism on Coupling of 3 with 4 Fol-
lowed Intramolecular Cyclization under Base-Catalysis Lead-
ing to 4-Quinolone Derivative (5)
and aliphatic amines were effective in the reactions, and no
evident difference was observed. As chromone derivatives,
4-quinolone derivatives were of biological and medicinal
function.19 Therefore, the present method will find wide
application in chemistry, biology, and medicine.
Table 3. Reactions of 3-(2-Methoxyphenyl)-2-methyl-3-oxo-
propanal with Primary Amines Leading to 4-Quinolone Deri-
vatives under Catalysis of K2CO3
a
According to the previous results, a possible mechanism for
synthesis of 4-quinolone derivatives is suggested in Scheme 3.
Reaction of aldehyde 3 with primary amine 4 provides imine
III, and then enolization of carbonyl group in III leads to IV in
the presence of base (K2CO3). Intramolecular cycloaddition
of IV gives V. Rearomatization of V by elimination of
KOCH3 provides the target product 5. Treatment of KOCH3
with KHCO3 regenerates K2CO3 leaving CH3OH.
In summary, we have developed a convenient and effi-
cient base-catalyzed method forsynthesisofchromone and
4-quinolone derivatives. The protocol uses K2CO3 as the
catalyst, readily available substituted 1-(2-alkoxyphenyl)-
3-akylpropane-1,3-diones 3-(2-methoxyphenyl)-2-methyl-3-
oxopropanal, and primary amines as the starting materials,
the reactions underwent the selective cleavage of the aromatic
CÀO bonds, and the corresponding chromone and 4-quino-
lone derivatives were obtained in reasonable yields. The
method did not need the aid of any transition metal which
avoided contamination of toxic metals to the products. Thus,
the inexpensive and environmentally benign approaches to
heterocycles will find wide application and attract much
attention in academic and industrial research.
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 20972083 and
21172128) and the Ministry of Science and Technology of
China (Grant No. 2012CB722605) for financial support.
Note Added after ASAP Publication. Errors were cor-
rected in Table 3, Scheme 3, TOC/Abstract graphic; this
reposted May 17, 2012.
a Reaction conditions: 3-(2-methoxyphenyl)-2-methyl-3-oxopropanal
(3) (0.5 mmol), amine (4) (0.55 mmol), K2CO3 (0.2 mmol), DMSO
(1 mL) under nitrogen atmosphere in a sealed Schlenk tube. b Isolated yield.
Supporting Information Available. Synthetic procedures,
characterization data, and 1H and 13C NMR spectra of these
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org. The authors
declare no competing financial interest.
at 90 °C under nitrogen atmosphere. After completeness of
imine formation (TCL determination) (about 3 h), 40 mol %
K2CO3 was added to the resulting solution, and the
following reaction was carried out at 130 °C under nitrogen
atmosphere. To our delight, the corresponding 4-quinolone
derivatives were obtained in moderate yields. Both aromatic
(19) (a) Anderson, V. E.; Osheroff, N. Curr. Pharm. Des. 2001, 7,
337–353. (b) Ziegler, C. B.; Bitha, P.; Kuck, N. A.; Fenton, T. J.;
Petersen, P. J.; Lin, Y. I. J. Med. Chem. 1990, 33, 142–146.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX