Gold(III)-catalyzed tandem reaction of ketones with phenols: Efficient and highly selective synthesis of functionalized 4H-chromenes

Article abstract of DOI:10.1021/jo902619x

(Chemical Equation Presented) An efficient and highly selective approach for the synthesis of functionalized 4H-chromenes has been developed via gold(III)-catalyzed condensation/annulation tandem reaction of ketones with phenols.

Full text of DOI:10.1021/jo902619x

pubs.acs.org/joc
two classes: (1) transition metal-catalyst involved reactions,
Gold(III)-Catalyzed Tandem Reaction of Ketones
with Phenols: Efficient and Highly Selective Synthesis
of Functionalized 4H-Chromenes
e.g., gold(I)-catalyzed carboalkoxylation reaction of propargyl
esters,4a FeCl3-catalyzed reaction of substituted 2-(hydroxy-
methyl) phenols with β-ketoesters or β-diketones,4b ruthenium-
mediated cycloaddition of propargylic alcohols with phenols,4c
copper-catalyzed intramolecular O-arylation of β-ketoesters,4d
and O-vinylation reaction of phenols with Sn(vinyl)4 followed
by a ruthenium-mediated RCM reaction,4e and palladium-
catalyzed conjugate addition of (2-hydroxyaryl)mercury chlor-
ides with R,β-unsaturated compounds followed by cyclization
and elimination of water;5 (2) organocatalyst involved reac-
tions, e.g., DABCO or phosphine-catalyzed reactions of
salicyclic imines with R,β-unsaturated compounds.4f-h Unfor-
tunately, most of these procedures suffer from using commer-
cially unavailable substrates as starting materials. Therefore,
developing efficient and conventional catalytic processes to
4H-chromenes from simple and readily available substrates
remains a challenging task.
Yunkui Liu,* Jianqiang Qian, Shaojie Lou, Jie Zhu,
and Zhenyuan Xu*
State Key Laboratory Breeding Base of Green Chemistry-
Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, People’s Repubilc of China
ykuiliu@zjut.edu.cn; greensyn@zjut.edu.cn
Received December 11, 2009
On the other hand, tandem reactions,6 compared with
stepwise reactions, usually provide more efficient and envir-
onmentally benign processes to construct molecular diversity
and structural complexity from readily available substrates in a
single step without the separation and purification of the
intermediates. Recently, gold-catalyzed tandem reactions7
have received special attention as gold catalysts8 generally
exhibit extraordinary reactivity and show high selectivity in
An efficient and highly selective approach for the synth-
esis of functionalized 4H-chromenes has been developed
via gold(III)-catalyzed condensation/annulation tandem
reaction of ketones with phenols.
(3) For recent examples on the synthesis of 2H-chromenes, see: (a) Zhou, H.;
Xu, Y.-H.; Chung, W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 1.
€
€
€
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(g) Hershberger, J. C.; Zhang, L.; Lu, G.; Malinakova, H. C. J. Org. Chem. 2006,
Chromenes (2H-chromenes and 4H-chromenes) constitute
an important class of scaffolds found in many naturally
occurring and synthetic molecules exhibiting unique biological
and pharmacological activities.1 Among many approaches for
the construction of chromene structures,2 those involving 2H-
chromenes3 have been well established while those for their
counterpart, 4H-chromenes,4 have been less developed. As
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DOI: 10.1021/jo902619x
r
Published on Web 01/14/2010
J. Org. Chem. 2010, 75, 1309–1312 1309
2010 American Chemical Society

Liu et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
Ph3PAuCl, AuCl3, or AgOTf alone (entries 4-7), indicating
that cationic gold(III) or gold(I) species were essential for the
reaction due to their more electrophilic properties.12 Catalyst
screening experiments revealed that the tandem reaction of
1a with 2a in the presence of other conventional Lewis or
Brønsted acids as catalyst was far less effective even at a
catalyst loading of 30 mol % (entries 8-15), indicating
gold(III) catalyst played a unique role in achieving high
reactivity and selectivity for the present reaction.
entry
catalyst (0.03 mmol)
solvent
DCEb
DCE
DCE
dioxanec
THF
yield of 3aa (%)
Subsequently, both ketones and phenols were surveyed to
investigate the scope and generality of the reaction (Table 2).
First, a variety of ketones 1 were subjected to react with
2-naphthol 2a under the optimized reaction conditions. It
was found that aryl methyl ketones reacted with 2a smoothly
to give the corresponding products 3 in moderate to excellent
yields (67-99%, entries 1-9). The reactions between elec-
tron-deficient aryl methyl ketones (except 1g) and 2a pro-
ceeded faster and gave higher yields of target products
(entries 6, 8, and 9) than those reactions concerning elec-
tron-rich aryl methyl ketones with 2a (entries 2-4). The
reaction of a thiophene-tethered methyl ketone 1j with 2a
under standard conditions furnished 3ja in low yield (35%,
entry 10); however, an enhancement of catalyst loading to 25
mol % resulted in the improvement of the yield of 3ja to 60%
(entry 10). When a more steric hindrance ketone (compared
with methyl ketones), for example, 1k, was used as a substrate,
the reaction gave none of the desired product (entry 11). We
assume that the initial self-condensation of ketones to chal-
cones might be the key step for the reaction (Scheme 2); the
failed reaction of 1k with 2a may be ascribed to the difficult self-
condensation of 1k to chalcone 7.13 In fact, when preparative
chalcone 7, instead of 1k, was subjected to the reaction condi-
tions, a decomposition of 7back to 1k occurred and only a trace
amount of 3ka was detected (entry 11). To our delight, when
less steric hindrance R,β-unsaturated ketones were used as
starting materials to react with 2a, the desired 4H-chromene
products were obtained in moderate to excellent yields under
similar reaction conditions (60-95%, Scheme 1). The reac-
tion of cylcohexanone 1m with 2a resulted in the formation
of a spiro 4H-chromene structure in moderate yield (entry 12).
It is interesting that treatment of ketone 1m with 2a gave
none of the expected product 3ma, whereas a 2H-chromene
isomer 30ma14 was isolated in 45% yield (entry 13). An
unsymmetrical aliphatic ketone 1n was also investigated for
the reaction; unfortunately, a complex mixture of products
was obtained (entry 14). Next, a series of other phenols
were tested for the reaction, and the results indicated that
electron-rich phenols were suitable substrates for the reaction
(entries 15-22). For instance, ketone 1a or 1f underwent the
tandem reaction with electron-rich phenols 2b, 2c, 2d, or 2e
smoothly to afford respective product in good to excellent
yield (entries 15, 17, and 18-22). Unfortunately, the reaction
1
2
3
AuCl/AgOTf
PPh3AuCl/AgOTf
AuCl3/3AgOTf
75
93
99
15
50
95
96
>5
0
0
0
0
0
toluenec
chlorobenzenec
MeCN
DCE
DCE
DCE
4
5
AuCl3
AuCl
6
7
PPh3AuCl
AgOTfd
DCE
DCE
e
8
9
AlCl3 e
ZnCl2
DCE
DCE
0
0
0
26
7
e
10
11
12
13
14
15
16
BiCl3 e
SnCl4e
FeCl3
DCE
DCE
DCE
DCE
e
Cu(OTf)2
HCle,f
HOTfe
none
0
12
DCE
DCE
0g
aCarried out on 2 mmol of 1a and 1 mmol of 2a in the presence of
catalyst in solvent (3 mL) at reflux for 6 h. bDCE = 1,2-dichloroethane.
cThe reaction temperature at 90 °C. dThe amount of catalyst is 0.09
e
f
mmol. The amount of catalyst is 0.3 mmol. Aqueous HCl (37 wt %)
was used. g1a and 2a were recovered quantitatively.
the reactions. In 1986, Kozlikovskii9 reported a tandem
reaction of acetophenone with phenol catalyzed by alumi-
num phenolate in which functionalized 4H-chromene could
be produced, but only one example was investigated and the
reaction gave very low selectivity as in this case a messy
mixture of six products were formed. As part of our ongoing
interest in the construction of chromene structures10 and
gold-catalyzed highly selective reactions,11 we wish to pre-
sent herein a unique gold(III)-catalyzed efficient and highly
selective approach for the synthesis of functionalized 4H-
chromenes from commercially available ketones and phe-
nols via a one-pot tandem reaction manner.
Initially, the reaction of acetophenone 1a and 2-naphthol
2a was investigated to optimize the reaction conditions
(Table 1). When 2 equiv of 1a and 1 equiv of 2a were treated
with AuCl/AgOTf (3 mol % based on 2a) in DCE at reflux
for 6 h, the desired 4H-chromene 3aa was isolated in 75%
yield (entry 1). Under the catalysis of a PPh3AuCl/AgOTf
system, the yield of 3aa was increased to 93% (entry 2).
Gratifyingly, almost quantitative yield of 3aa was obtained
by using AuCl3/3AgOTf as a promotor (entry 3). Solvent
screening showed that toluene and chlorobenzene were
suitable media as well while THF, dioxane, and MeCN were
less effective (entry 3). The reaction could hardly take place
without a catalyst (entry 16), or in the presence of AuCl,
(12) For an excellent review on ligand effects in homogeneous gold
catalysis, see: (a) Grorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
2008, 108, 3351. For silver salt additives in gold catalysis, see for examples:
~
(b) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.; Cardenas,
D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (c) Lemiere,
~
ꢀ
ꢁ
(9) Kozlikovskii, Y. B.; Chemyaev, B. V.; Litvin, A. L. Zh. Org. Khim.
1986, 22, 2389.
(10) Xu, D.-Q.; Wang, Y.-F.; Luo, S.-P.; Zhang, S.; Zhong, A.-G.; Chen,
H.; Xu, Z.-Y. Adv. Synth. Catal. 2008, 350, 2610.
(11) (a) Liu, Y.; Mao, D.; Qian, J.; Lou, S.; Xu, Z.; Zhang, Y. Synthesis
2009, 1170. (b) Liu, Y.; Qian, J.; Lou, S.; Xu, Z. Synlett 2009, 2971.
G. G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.; Aubert, C.;
Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596. (d) Shi,
Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964.
(13) (a) Wayne, W.; Adkins, H. J. Am. Chem. Soc. 1940, 62, 3401.
(b) Muzart, J. Synthesis 1982, 60.
(14) Talley, J. J. Synthesis 1983, 845.
1310 J. Org. Chem. Vol. 75, No. 4, 2010

Liu et al.
JOCNote
TABLE 2. Au(III)-Catalyzed Tandem Reaction of Ketones 1 with Phenols 2a
SCHEME 1. Au(III)-Catalyzed Tandem Reaction of R,β-Unsatu-
rated Ketones with 2-Naphthol 2a
SCHEME 2. Proposed Mechanism
aReaction conditions: 1 (2 mmol), 2 (1 mmol), AuCl3/3AgOTf
(0.03 mmol), DCE (3 mL), reflux. bThe amount of catalyst is
0.25 mmol. cPreparative chalcone 7 was used instead of 1k as the
substrate. d1k was isolated in 96% yield. eThe molar ratio of ketone to
phenol is 4:1.
from two molecules of acetophenone 1a could be detected in
the reaction of 1a with 2a. When the preparative β-methyl
chalcone 4,15 instead of acetophenone, was employed as the
starting material to react with 2-naphthol, the desired pro-
duct 3aa was also obtained in quantitative yield,16 therefore,
we thought 4 might be the key intermediate for the reaction.
between 1a and electron-deficient phenol 2f was not successful
(entry 20). The structure of 3 was established on the basis of
the spectral analysis, which was further confirmed by X-ray
diffraction analysis of a related derivative 3da (Figure S1,
Supporting Information).
(15) Muzart, J. Synth. Commun. 1985, 15, 285.
(16) The reaction between phenol and mesityl oxide in the presence of
HCl has been studied, see: Dianin, A. P. Zh. Russ. Fiz.-Khim. Ova. 1914, 46,
1310.
At present stage, no clear mechanism has been elucidated.
It was found that the condensation product 4 (Scheme 2)
J. Org. Chem. Vol. 75, No. 4, 2010 1311

Liu et al.
JOCNote
On the basis of these facts and previous reports,17 a possible
mechanism concerning the gold(III)-catalyzed tandem reac-
tion of 1a with 2a is proposed (Scheme 2). First, gold(III)-
catalyzed self-condensation of 1a formed intermediate 4.
Then the in situ generated 4 reacted with 2a to give inter-
mediate 5 via gold-activating the enone 4 followed by
an electrophilic aromatic substitution at the 1-position of
2-naphthol and a deprotonation process.17 Protodemetala-
tion of 5 liberated the intermediate 6 and regenerated the
gold catalyst. Intramolecular annulation of 6 with the aid of
the gold catalyst eventually furnished 3aa.
In summary, for the first time we have developed an
efficient and highly selective tandem reaction of ketones
with phenols catalyzed by AuCl3/3AgOTf, which furnished
various functionalized 4H-chromenes in moderate to excel-
lent yields with water as the sole byproduct.
reaction mixture was stirred at reflux. Upon completion, the
resulting mixture was diluted with CH2Cl2 (10 mL) and filtered
through Celite. After evaporation of the solvent under vacuum,
the residue was purified by column chromatography on silica
gel (200-300 mesh) with petroleum ether-EtOAc (20:1) as
eluent to give pure 3aa (0.34 g, 99%). Pale yellow oil; Rf 0.62
(cyclohexane-EtOAc, 20:1); IR (neat) ν 1678 (CdC) cm-1; 1H
NMR (CDCl3/TMS, 500 MHz) δ 7.73-7.68 (m, 4H), 7.54
(d, J = 8.5 Hz, 1H), 7.47-7.09 (m, 11H), 5.29 (s, 1H), 2.17
(s, 3H); 13C NMR (CDCl3/TMS, 125 MHz) δ 150.2, 148.9,
143.0, 133.8, 131.9, 131.5, 129.3, 128.8, 128.6, 128.4, 128.3,
127.1, 126.3, 125.9, 125.6, 124.6, 123.5, 118.9, 118.3, 109.1,
40.8, 29.1; MS (EI, 70 eV) m/z (%) 348(15) [Mþ], 333(100);
HRMS (EI) calcd for C26H20O 348.1514, found 348.1514. For
more details, see the Supporting Information.
Acknowledgment. Financial support from the Natural
Science Foundation of Zhejiang Province (No. Y407168),
the Foundation of Education of Zhejiang Province (No.
Z200803599), and the Opening Foundation of Zhejiang
Provincial Top Key Discipline is gratefully acknowledged.
Experimental Section
AuCl3 (9.1 mg, 0.03 mmol), AgOTf (23.1 mg, 0.09 mmol), and
DCE (2 mL) were added to a 10-mL flask. The mixture was
stirred at rt for 5 min before a DCE solution (1 mL) of 1a
(2.0 mmol, 0.24 g) and 2a (1.0 mmol, 0.14 g) was added. Then the
Supporting Information Available: Experimental proce-
dures and characterization data of all new compounds as well
as X-ray structural data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285.
1312 J. Org. Chem. Vol. 75, No. 4, 2010