Copper(I)-catalyzed intramolecular O-arylation for the synthesis of 2,3,4,9-tetrahydro-1 H -xanthen-1-ones with low loads of CuCl

Article abstract of DOI:10.1021/jo3018318

As little as 0.5 mol % CuCl is sufficient to catalyze the intramolecular O-arylation of easily accessible 2-(2-bromobenzyl)cyclohexane-1,3-diones to provide the corresponding 2,3,4,9-tetrahydro-1H-xanthen-1-ones with yields ranging from 83% to 99%.

Full text of DOI:10.1021/jo3018318

Article
pubs.acs.org/joc
Copper(I)-Catalyzed Intramolecular O‑Arylation for the Synthesis of
2,3,4,9-Tetrahydro‑1H‑xanthen-1-ones with Low Loads of CuCl
Kavitha Sudheendran, Chandi C. Malakar, Jurgen Conrad, and Uwe Beifuss*
̈
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstrasse 30, D-70599 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: As little as 0.5 mol % CuCl is sufficient to catalyze the intra-
molecular O-arylation of easily accessible 2-(2-bromobenzyl)cyclohexane-1,3-
diones to provide the corresponding 2,3,4,9-tetrahydro-1H-xanthen-1-ones
with yields ranging from 83% to 99%.
enamines and 2-hydroxybenzyl alcohols at higher temper-
INTRODUCTION
■
atures,12d the domino reaction between salicylic aldehyde and
1,3-cyclohexanedione catalyzed by p-TSA12c or promoted by
Me3SiI,12a and the reaction of in situ-generated o-quinone
methides with 3-dimethylamino-2-cyclohexen-1-ones in DMF
at higher temperatures.12b
Over the past decade, Cu(I)-catalyzed coupling reactions between
aryl halides and different nucleophiles have experienced a renais-
sance and resulted in the development of more efficient processes
for the formation of C−C as well as C−N, C−O, and C−S
bonds.1,2 The combination of such arylations with other transfor-
mations to domino processes is particularly valuable because it
offers new opportunities for the synthesis of heterocyclic frame-
works.3 Due to their interesting biological activities, xanthenes and
xanthenones have attracted much attention from different fields
including natural product chemistry, synthetic organic chemistry,
and medicinal chemistry.4
Recently, we have discovered that the Cu(I)-catalyzed
domino reaction between 2-bromobenzyl bromides 1 and β-
ketoesters 2 can be used for the efficient and selective synthesis
of 4H-chromenes 4 with yields ranging from 65% to 88%.3b It
was assumed that the domino reaction is based on an inter-
molecular C-benzylation of a 2-bromobenzyl bromide 1 with a
β-ketoester 2 and subsequent intramolecular O-arylation of 3
(Scheme 1).
It is remarkable that upon reaction of 2-bromobenzyl bro-
mides 1 with acyclic β-ketoesters 2 there was no product
resulting from a domino intermolecular O-benzylation/intra-
molecular C-arylation. There was only one exception, namely,
the reaction between 2-bromobenzyl bromide (1a) and 4-
hydroxy-6-methyl-2H-pyran-2-one (5) (Scheme 2). Here, the
formation of 45% of the expected cyclized product 6 was
accompanied by 19% of benzyl ether 7, which originates from
an intermolecular O-benzylation.
Apart from the fully unsaturated xanthenes and xanthenones,
partially saturated compounds such as the tetrahedroxanthe-
nones have attracted a great deal of interest, as many com-
pounds with this structure element exhibit remarkable bio-
logical activities. Typical examples of biologically active tetra-
hydroxanthenones of natural origin include (a) the anti-
bacterial, antifungal, and algicidal blennolides A and B, which
have been isolated from the endophytic fungus Blennoria sp.,5
(b) the monomers of the antitumor agents secalonic acids B
and D, respectively,6 (c) α- and β-diversonolic esters, which
have been isolated from Pencillium diversum,7 (d) globosuxanthone
B from Chaetomium globosum,8 and (e) the antibacterial 3,4-di-
hydroglobosuxanthone A from several endophytic fungi
(Figure 1).9 This is the reason why the synthesis of tetrahydro-
xanthenones is of considerable interest to medicinal chemistry.
Over the years, several synthetic methods have been
developed for the preparation of the 2,3,4,4a-tetrahydro-1H-
xanthen-1-one skeleton (Figure 2, A).4a,10 One of the most
prominent methods is the domino oxa-Michael addition/aldol
reaction between a salicylic aldehyde and a cyclohexenone.10d−f,h
This transformation allows the preparation of enantiomerically
pure 2,3,4,4a-tetrahydroxanthen-1-ones10e,f and has been applied
to the total syntheses of blennolide C11a and diversinol.11b
In contrast, only a few methods are available for the efficient
synthesis of 2,3,4,9-tetrahydro-1H-xanthen-1-ones (Figure 2, B).
They include several one-pot protocols such as the con-
densation of 2-hydroxybenzyl alcohol with 1,3-cyclohexanedione
in HMPA at 185 °C,12e the reaction between β-functionalized
RESULTS AND DISCUSSION
■
On the basis of our previous results, we decided to develop a
domino reaction to 2,3,4,9-tetrahydro-1H-xanthen-1-ones and
related skeletons based on the intermolecular C-benzylation of
a 2-halobenzyl halide with a cyclic 1,3-diketone and subsequent
intramolecular O-arylation. The results of our study are
disclosed in this contribution.
The starting point was the Cu(I)-catalyzed reaction between
1 equiv of 2-bromobenzyl bromide (1a) and 2 equiv of 1,3-
cyclohexanedione (8a). When 1a and 8a were reacted in the
presence of 1 mol % CuCl as the catalyst, 4 equiv of Cs2CO3 as
the base, and 1.2 equiv of pivalic acid, 18% of the xanthenone
9a as well as 29% of the O-benzylated product 10a were
Received: August 27, 2012
Published: October 15, 2012
© 2012 American Chemical Society
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Figure 1. Selected biologically active natural products with a tetrahydroxanthenone core.
In addition, the one-pot approach to 2,3,4,9-tetrahydro-1H-
xanthen-1-one (9a) was also tried using 2-chlorobenzyl bro-
mide (1b) and 2-iodobenzyl bromide (1c) as substrates. When
2-chlorobenzyl bromide (1b) and 1,3-cyclohexanedione (8a)
were reacted with 20 mol % CuI, 4 equiv of Cs2CO3 in DMF at
130 °C for 10 min, 35% of the O-benzylated product (10b) and
26% of the C-benzylated intermediate (11b) could be isolated.
The cyclized product 9a could not be observed. With 2-
iodobenzyl bromide (1c) as the 2-halobenzyl halide, 19% of the
xanthenone 9a, 41% of the O-benzylated product 10c, and 5%
of the C-benzylated intermediate 11c were formed. Obviously,
the nature of the 2-halobenzyl bromide has only little influence
on the extent to which O-benzylation takes place (Scheme 4).
To solve this problem, which is due to the competition
between C- and O-benzylation, we were looking for methods
that allow for the exclusive formation of C-benzylated products
upon reaction between a 2-halobenzyl halide and a 1,3-dicarbonyl.
Figure 2. The structures of the 2,3,4,4a-tetrahydro-1H-xanthen-1-one
(A) and the 2,3,4,9-tetrahydro-1H-xanthen-1-one (B) skeleton.
isolated (Scheme 3). By optimizing the reaction conditions with
respect to Cu(I) source, base, additive, solvent, and reaction
conditions, we were able to increase the combined yield of 9a
and 10a to 71% and the portion of the desired xanthenone to
35% (Table 1, entry 1). It was not possible, however, to suppress
the formation of the O-benzylated product. Similar results were
observed in the reactions between 2-bromobenzyl bromide (1a)
and the substituted 1,3-cyclohexanediones 8b,c,e (Table 1,
entries 2−4).
Scheme 1. Domino Reaction between 2-Bromobenzyl Bromides 1 and β-Ketoesters 2 for the Synthesis of 4H-Chromenes
Scheme 2. Cu(I)-Catalyzed Reaction of 2-Bromobenzyl Bromide (1a) with Pyrone 5
Scheme 3. Initial Experiment for the Cu(I)-Catalyzed Synthesis of 2,3,4,9-Tetrahydro-1H-xanthen-1-ones from 2-Bromobenzyl
Halides and Cyclic 1,3-Diketones
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Table 1. Cu(I)-Catalyzed One-Pot Approach to 2,3,4,9-Tetrahydro-1H-xanthen-1-ones in the Absence of Any Ligand
Scheme 4. Cu(I)-Catalyzed One-Pot Approach to 2,3,4,9-Tetrahydro-1H-xanthen-1-ones Using 2-Halobenzyl Bromides 1b and
1c as Substrates
After several methods were explored,13 the protocol of Marsden
et al. was finally employed.13a It was found that the reaction
between 1 equiv of 1,3-cyclohexanedione (8a) and 1.5 equiv of
2-bromobenzyl bromide (1a) in the presence of 1 equiv of 1 M
aq NaOH at 100 °C exclusively gave 2-(2-bromobenzyl)-
cyclohexane-1,3-dione (11a) in 71% yield (Table 2, entry 1).
However, we did not succeed in combining the reaction
conditions of the successful C-benzylation (1a + 8a → 11a)
with the reaction conditions of the Cu(I)-catalyzed intra-
molecular Ullmann reaction to a new domino process. This
is why we decided to perform the synthesis of xanthenones 9
in two discrete steps. The substrates required for the intra-
molecular Ullmann reaction, i.e., the benzylated cyclic 1,3-
diketones 11b−o, were prepared according to the synthe-
sis of 11a with yields ranging from 45% to 83% (Table 2,
entries 2−15).14
that had proven successful for the reactions between 1a and
8a,c, i.e., 20 mol % CuI, 4 equiv of Cs2CO3, DMF, 130 °C,
10 min (Table 1). The results were disappointing because
the cyclization product 9a was obtained in only 25% yield
(Scheme 5).
In accordance with earlier experience from our own as well as
from other groups,15 further experiments demonstrated that the
yields of xanthenone 9a could be significantly improved when
the reactions were performed in the presence of an acidic
additive such as acetic acid, propionic acid, pivalic acid, or
isovaleric acid. At the same time, the amount of CuI could be
reduced to 1 mol % and the amount of Cs2CO3 could be
reduced to 2 equiv. It turned out that isovaleric acid and pivalic
acid were markedly superior to propionic acid and acetic acid
(Table 3, entries 1−4). Despite our finding that the best yield
was obtained with 0.5 equiv of isovaleric acid, all further
optimizations were performed with pivalic acid as the additive
because isovaleric acid is malodorous. Further experiments
Initial experiments regarding the Cu(I)-catalyzed intramo-
lecular O-arylation of 11a were performed under the conditions
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Table 2. Benzylation of Cyclic 1,3-Diones 8a−h with 2-Halobenzyl Bromides and Related Compounds 1a−g
Scheme 5. Initial Experiment for the Cu(I)-Catalyzed
Intramolecular O-Arylation of 11a
product 9a could be isolated with 95% yield when the
intramolecular O-arylation of 11a was run with 1.2 equiv of
pivalic acid as the additive (Table 3, entry 10). In the
absence of any additive, the yield dropped to 58% (Table 3,
entry 5).
Additional experiments devoted to the influence of the
copper source as well as the amount of the Cu(I)-catalyst
clearly demonstrated that the conversion of 11a to 9a could be
catalyzed not only by CuI but also by CuCl, CuBr, CuCN, and
CuOTf. With all catalysts the yields exceeded 90% (Table 4,
entries 1−5). All further reactions were carried out with CuCl
as the copper source because this is one of the cheapest Cu(I)
revealed that the amount of pivalic acid had a strong impact on
the outcome of the reaction (Table 3, entries 6−10). Increasing
the amount of pivalic acid resulted in higher yields of 9a. The
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0.1 mol %, the yield amounted to 60%. A control experi-
ment underlines the importance of the Cu(I) salt on the out-
come of the O-arylation. In the absence of any copper source
no product formation could be observed (Table 4, entry 9).
Noteworthy, all experiments described in Table 4 were con-
ducted in the presence of no more than 1 equiv of Cs2CO3 as
the base.
Table 3. Influence of Acidic Additives on the Cu(I)-
Catalyzed Intramolecular O-Arylation of 11a
a
Another set of experiments was used to test the influence of
different bases. Cs2CO3 could be replaced with both K2CO3
and K3PO4, but the yields dropped to 75% and 47%, res-
pectively (Table 5, entries 2, 3). NaOEt and DABCO were not
suitable (Table 5, entries 4, 5). Finally, we briefly examined the
entry
acidic additive
additive (equiv)
yield 9a (%)
1
2
3
4
5
6
7
8
9
10
pivalic acid
acetic acid
0.5
0.5
0.5
0.5
0
77
48
63
83
58
61
63
77
78
95
propionic acid
isovaleric acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
Table 5. Influence of the Base and the Amount of Cs2CO3 on
a
the Intramolecular O-Arylation of 11a
0.2
0.3
0.8
1.0
1.2
a
The reactions were performed in a sealed tube with 0.5 mmol 11a in
2 mL DMF.
entry
CuCl (mol %)
base
base (equiv)
yield (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
1
Cs2CO3
K2CO3
K3PO4
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
95
75
Table 4. Influence of the Copper Source and the Amount of
CuCl on the Intramolecular O-Arylation of 11a
a
47
NaOEt
DABCO
Cs2CO3
Cs2CO3
Cs2CO3
2
traces
95
1
91
1
99
a
The reactions were performed in a sealed tube with 0.5 mmol 11a in
entry
catalyst
mol % catalyst
time (h)
yield (%)
2 mL of DMF.
1
2
3
4
5
6
7
8
9
CuI
1
7
98
93
96
96
98
95
51
89
−
CuBr
CuCl
CuCN
CuOTf
CuCl
CuCl
CuCl
−
1
7
influence of the amount of Cs2CO3. Varying its amount in the
range of between 1 and 2 equiv had only little impact on the
yield of 9a (Table 5, entries 6−8).
1
7
1
7
1
7
Finally, it was demonstrated that lowering the reaction tem-
perature from 130 °C to 100 °C resulted in a significantly
decreased yield of 9a (Table 6, entry 2). At 50 °C no product
0.5
0.1
0.1
−
7
7
22
7
a
Table 6. Influence of the Reaction Temperature
a
The reactions were performed in a sealed tube with 0.5 mmol of 11a
in 2 mL of DMF.
salts available. Furthermore, it was found that the cyclization of
11a to 9a tolerates a reduction of the catalyst load from 1 to
0.5 mol % CuCl without loss of yield. A further decrease of the
catalyst load to 0.1 mol % was also possible, but the reaction
time had to be extended to 22 h to achieve high yields (Table 4,
entries 7, 8). In recent years, a number of protocols have been
developed for copper-catalyzed reactions with low loads of the
copper source and N,N′-dimethylethylenediamine (DMEDA),
2,2,6,6-tetramethyl-3,5-heptanedione (TMHD), L-proline, and
4,7-dimethoxy-1,10-phenanthroline as the ligands.2c,16 A prom-
inent example comes from Bolm, who has established that as
little as 0.001 mol % CuO is sufficient to catalyze the inter-
molecular O-arylation of aryl iodides. When the transformation
of 11a to 9a was performed under Bolm’s conditions, i.e., 0.001
mol % CuO, 2 equiv of Cs2CO3, 20 mol % TMHD in DMF at
135 °C for 24 h, the desired cyclization product 9a was isolated
in 45% yield. When the amount of CuO was increased to
entry
T (°C)
yield (%)
1
2
3
130
100
50
95
61
0
a
The reactions were performed in a sealed tube with 0.5 mmol of 11a
in 2 mL of DMF.
was formed (Table 6, entry 3). In summary, the highest yield
of 9a was obtained when the cyclization of 11a was run with
0.5 mol % CuCl, 1.2 equiv of pivalic acid, and 1 equiv of
Cs2CO3 in DMF at 130 °C for 7 h in a sealed vial (Table 4,
entry 6). When 2-(2-chlorobenzyl)-1,3-cyclohexanedione (11b)
was reacted under optimized reaction conditions, only 13% of
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the xanthenone 9a could be isolated (Scheme 6). In addition,
68% of the substrate was reisolated. With the iodo-substituted
substrate 11c, 88% of the xanthenone 9a and only 5% of the
starting material were observed. From these results it is clear
that the bromo-substituted substrate 11a is the most suitable
one.
With the optimized protocol in hand, we studied the sub-
strate scope of the Cu(I)-catalyzed intramolecular O-arylation
of 2-(2-bromoaryl)-1,3-dicarbonyls. It was found that, in addi-
tion to 11a, several substituted 2-(2-bromobenzyl)-1,3-cyclo-
hexanediones 11d−j derived from different 5-monosubstituted
and 5,5-disubstituted 1,3-cyclohexanediones could be reacted to
yield the corresponding xanthenones 9b−h with yields ranging
from 87% to 99% as the sole products (Table 7, entries 2−8). It
was also possible to use 2-(2-bromobenzyl)-1,3-cyclopentane-
dione (11k) as the substrate (Table 7, entry 9). Finally, it was
Scheme 6. CuCl-Catalyzed Intramolecular O-Arylation of
Substituted 2-(2-Halobenzyl)-1,3-dicarbonyls 11b,c
Table 7. CuCl-Catalyzed Intramolecular O-Arylation of Substituted 2-(2-Bromobenzyl)-1,3-dicarbonyls 11a,d−m
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Scheme 7. Plausible Catalytic Cycle for the CuCl-Catalyzed Intramolecular O-Arylation of Substituted 2-(2-Halobenzyl)-1,3-
dicarbonyls in the Presence of Pivalic Acid
demonstrated that several substituted 2-(2-bromoaryl)-1,3-
cyclohexanediones 11l−o derived from different aryl bromides
are tolerated as substrates (Table 7, entries 10−13). These
results suggest that the newly developed method offers a broad
range of potential applications for the synthesis of 2,3,4,9-
tetrahydro-1H-xanthen-1-ones and related O-heterocycles. As
far as we are aware, there is only a single example for the intra-
molecular O-arylation of a 2-(2-halobenzyl)-1,3-dicarbonyl in
the literature. Fang and Li reported that 11a can be cyclized to
9a in 89% yield using 10 mol % CuI as the copper source, 2
equiv of Cs2CO3 as the base, and 20 mol % DMEDA as the
ligand.17 Our studies clearly established that several 2,3,4,9-
tetrahydro-1H-xanthen-1-ones can be obtained in a highly
selective and efficient manner by intramolecular O-arylation of
2-(2-bromobenzyl)-1,3-dicarbonyls using as little as 0.5 mol %
CuCl catalyst and only 1 equiv of Cs2CO3. Therefore, the method
presented here is a valuable supplement to other methods for the
synthesis of 2,3,4,9-tetrahydro-1H-xanthen-1-ones.
Although a mechanistic investigation of the CuCl-catalyzed
intramolecular O-arylation of substituted 2-(2-halobenzyl)-1,3-
dicarbonyls has not been performed, a tentative proposal is
presented in Scheme 7. It is assumed that the mechanism starts
with the reaction of A with Cs2CO3 to give the corresponding
cesium enolate B and CsHCO3. Then the oxidative addition of
the Cu(I) species into the aryl bromide bond of B takes place
with formation of C. This is followed by a bromide/pivalate
exchange to produce the chelated Cu complex D. The required
cesium pivalate is generated from pivalic acid and CsHCO3
which stems from the reaction of enol A with Cs2CO3. Intra-
molecular attack of the cesium enolate on the chelated Cu
center furnishes intermediate E which deliberates cesium
pivalate to give F. It is assumed that chelation of Cu with the
pivalate stabilizes D, thereby facilitating the coupling reaction.
Finally, F undergoes reductive elimination with formation of
the 2,3,4,9-tetrahydro-1H-xanthen-1-one G (≙ 9a) and regen-
eration of CuCl. It is noteworthy that Pd complexes similar to
D and E have been proposed recently.18 The proposal is in
accordance with our finding that the reaction cannot be run
efficiently when the combination of 1 equiv of Cs2CO3 and 1.2
equiv of pivalic acid is replaced by 1 or 1.2 equiv of cesium
pivalate. When the reaction of 11a was run with 1 equiv of
cesium pivalate in the presence of 0.5 mol % CuCl in DMF at
130 °C for 7 h, the yield of 9a amounted only to 52%. The
same outcome was observed with 1.2 equiv of cesium pivalate.
The reason is that with 1 or 1.2 equiv of cesium pivalate the
concentration of cesium ions is not sufficient for the simul-
taneous formation of the cesium enolate B and the formation of
the cesium pivalate required for the chelation of C. With 2 or
2.5 equiv of cesium pivalate, the yield of 9a could be increased
to 88% and 95%, respectively. The proposed mechanism is also
corroborated by the observation that CO2 is formed during the
reaction. It is assumed that CO2 is generated from the reaction
between CsHCO3 and pivalic acid to give cesium pivalate and
H2CO3, which in turn decomposes to CO2 and H2O.
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1
Figure 3. H spin systems and important HMBC correlations (H↔C) for 9m.
were distilled prior to use. Reaction temperatures are reported as bath
temperature. Thin-layer chromatography (TLC) was performed on
TLC silica gel 60 F254. Compounds were visualized with UV light
(λ = 254 nm) and/or by immersion in an ethanolic vanillin solution or
by immersion in a KMnO4 solution followed by heating. Products
were purified by flash chromatography on silica gel, 0.04−0.063 mm.
Melting points were obtained on a melting point apparatus with open
capillary tubes and are uncorrected. IR spectra were measured on a
FT-IR-spectrometer. UV/vis spectra were recorded with a spectropho-
tometer. 1H (13C) NMR spectra were recorded at 300 (75) MHz using
CDCl3, CD3OD, and DMSO-d6 as the solvent. The 1H and 13C
chemical shifts were referenced to residual solvent signals at δ H/C
7.26/77.00 (CDCl3), 3.31/49.10 (CD3OD), and 2.50/39.50 (DMSO-d6)
relative to TMS as internal standard. HSQC-, HMBC-, and
COSY-spectra were recorded on an NMR spectrometer at 300 MHz.
Coupling constants J [Hz] were directly taken from the spectra and
are not averaged. Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), and br
(broad). 1D and 2D homonuclear NMR spectra were measured with
standard pulse sequences. Low-resolution electron impact mass spectra
(MS) and exact mass electron impact mass spectra (HRMS) were
obtained at 70 eV using a double focusing sector field mass spectrom-
eter. Intensities are reported as percentages relative to the base peak
(I = 100%).
The structures of all compounds were unambiguously eluci-
dated by mass spectrometry and NMR spectroscopy. Structure
elucidation of all compounds and full assignment of the 1H and
13C chemical shifts were achieved by evaluating their gCOSY,
gHSQC, and gHMBC spectra. For example, compound 9m
1
contains four H spin systems, one consisting of the protons
attached to carbons C-2, C-3, and C-4 of ring A. The second
spin system contains the two protons attached to C-9 of ring B,
the third spin system contains the three protons of the OCH3
group, and the fourth comprises the aromatic protons 5-H, 6-H,
8-H attached to the aromatic ring C. The sequence of the
protons of the ring A and C spin systems was determined by
analysis of the gCOSY spectrum. To confirm the proposed
structure, we used gHMBC to fix the positions of the six qua-
ternary carbons C-1, C-4a, C-7, C-8a, C-9a, and C-10a. Carbon
C-9a showed strong 3J-HMBC correlations to protons 2-H and
4-H, C-8a to proton 5-H, C-10a to protons 6-H, 8-H, and
9-H, C-7 to protons 1′-H and 5-H, and C-4a to 3-H and 9-H.
These findings established that the two rings A and C are linked
by the four carbons C-4a, C-9a, C-8a, and C-10a as shown in
Figure 3.
General Procedure I for the CuI-Catalyzed Domino Reaction
between 2-Halobenzyl Bromides 1a−c and 1,3-Cyclohexane-
diones 8a-c,e. A dry 10 mL vial was equipped with a magnetic stir
bar, charged with 2-halobenzyl bromide 1 (1 mmol), 1,3-cyclohexa-
nedione 8 (2 mmol), CuI (38 mg, 20 mol %), and Cs2CO3 (1.303 g, 4
mmol), and sealed. The sealed tube was evacuated and backfilled with
argon two times. Then, freshly distilled DMF (2 mL) was added, and
the reaction mixture was stirred at 130 °C for the time given in Table
1. After cooling to room temperature, the reaction mixture was diluted
with water (15 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered,
and evaporated in vacuo. The crude product was subjected to flash
column chromatography over silica gel to yield the products.
Reaction between 1a and 8a. According to general procedure I, 2-
bromobenzyl bromide (1a) (250 mg, 1.0 mmol), 1,3-cyclohexane-
dione (8a) (224 mg, 2.0 mmol), CuI (38 mg, 20 mol %), and Cs2CO3
(1.303 g, 4.0 mmol) were reacted in a sealed tube under argon at
130 °C for 10 min. Column chromatography over silica gel (petroleum
ether/EtOAc = 8:2) afforded 2,3,4,9-tetrahydro-1H-xanthen-1-one
(9a) as a white solid in 35% yield (70 mg, 0.35 mmol) and 3-[(2-bro-
mophenyl)methoxy]-2-cyclohexen-1-one (10a) as a colorless liquid in
36% yield (100 mg, 0.36 mmol).
CONCLUSIONS
■
A simple to execute and efficient method for the synthesis of
substituted 2,3,4,9-tetrahydro-1H-xanthen-1-ones from easily
accessible o-bromobenzyl bromides and cyclic 1,3-dicarbonyls
as starting materials has been developed. 2,3,4,9-Tetrahydro-
1H-xanthen-1-ones can be synthesized in a one-pot reaction
between 2-bromobenzyl bromides and 1,3-cyclohexanediones
via Cu(I)-catalyzed domino intermolecular C-benzylation/intra-
molecular O-arylation. The competing O-benzylation in the
initial step, which could not be suppressed under the conditions
of the Cu(I)-catalyzed domino reaction, gave rise to the forma-
tion of benzyl ethers as side products. The synthesis of the
2,3,4,9-tetrahydro-1H-xanthen-1-ones in two steps has proven to
be a valuable alternative to the domino process, as no side pro-
duct formation occurred. The required C-benzylated 1,3-diones
could be obtained selectively by reacting 2-bromobenzyl bro-
mides with 1,3-diones under basic conditions with yields ranging
from 45% to 83%. Subsequently, the 2-(2-bromobenzyl)-cyclo-
hexane-1,3-diones were cyclized to the corresponding 2,3,4,9-
tetrahydro-1H-xanthen-1-ones by Cu(I)-catalyzed intramolecular
O-arylation in 83% to 99% yield. Best results were obtained
when the cyclizations were performed with 0.5 mol % CuCl as
the catalyst, 1.2 equiv of pivalic acid as an additive, and 1 equiv of
Cs2CO3 as the base.
3-[(2-Bromophenyl)methoxy]-2-cyclohexen-1-one (10a). Rf
=
0.10 (petroleum ether/EtOAc = 8:2); IR (ATR) ν 1651 (s) (C
O), 1600, 1361, 1219, 1176, 1133, 1028, 822, 750 cm−1; UV
(CH3CN) λmax (log ε) 243 (4.30) nm; 1H NMR (300 MHz, CDCl3) δ
2.03 (quin, 3J (5-H, 6-H) = 6.6 Hz, 3J (4-H, 5-H) = 6.3 Hz, 2H, 5-H),
3
3
2.38 (t-like, J (5-H, 6-H) = 6.9 Hz, 2H, 6-H), 2.51 (t-like, J (4-H,
5-H) = 6.3 Hz, 2H, 4-H), 4.97 (s, 2H, CH2), 5.50 (s, 1H, 2-H), 7.24
EXPERIMENTAL SECTION
■
General Remarks. All commercially available reagents were used
without further purification. Glassware was dried for 4 h at 140 °C in
an oven. Solvents used in reactions were distilled over appropriate
drying agents prior to use. Solvents used for extraction and purification
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(ddd, 3J (4′-H, 5′-H) = 6.6 Hz, 3J (3′-H, 4′-H) = 6.0 Hz, 4J (4′-H, 6′-
H) = 1.5 Hz, 1H, 4′-H), 7.34 (ddd, 3J (4′-H, 5′-H) = 7.2 Hz, 3J (5′-H,
Reaction between 1a and 8b. According to general procedure I, 2-
bromobenzyl bromide (1a) (250 mg, 1.0 mmol), 5-methyl-1,3-cyclo-
hexanedione (8b) (252 mg, 2.0 mmol), CuI (38 mg, 20 mol %), and
Cs2CO3 (1.303 g, 4.0 mmol) were reacted in a sealed tube under argon
at 130 °C for 60 min. Column chromatography over silica gel (petroleum
ether/EtOAc = 8:2) afforded 3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-
one (9b) as a white solid in 37% yield (80 mg, 0.37 mmol) and 3-[(2-
bromophenyl)methoxy]-5-methyl-2-cyclohexen-1-one (10d) as a white
solid in 36% yield (105 mg, 0.36 mmol).
3
6′-H) = 7.5 Hz, 1H, 5′-H), 7.42 (dd, J (5′-H, 6′-H) = 7.5 Hz, 1H,
3
6′-H), 7.59 (dd, J (3′-H, 4′-H) = 7.8 Hz, 1H, 3′-H); 13C NMR (75
MHz, CDCl3 ) δ 21.2 (C-5), 28.9 (C-4), 36.7 (C-6), 69.8 (CH ),
2
103.6 (C-2), 122.9 (C-2′), 127.6 (C-5′), 129.2 (C-6′), 129.9 (C-4′),
132.9 (C-3′), 134.4 (C-1′), 177.1 (C-3), 199.6 (C-1); MS (EI, 70 eV)
m/z (%) 280 (8) [M]+, 201 (10) [280 − Br]+, 171 (100), 90 (20), 28
(6); HRMS (EI, M+) calcd for C13H13BrO2 (280.0099), found
280.0094.
Reaction between 1b and 8a. According to general procedure I, 2-
chlorobenzyl bromide (1b) (206 mg, 1.0 mmol), 1,3-cyclohexane-
dione (8a) (224 mg, 2.0 mmol), CuI (38 mg, 20 mol %) and Cs2CO3
(1.303 g, 4.0 mmol) were reacted in a sealed tube under argon at
130 °C for 10 min. Column chromatography over silica gel (petroleum
ether/EtOAc = 8:2) afforded 3-[(2-chlorophenyl)methoxy]-2-cyclo-
hexen-1-one (10b) as a colorless liquid in 35% yield (84 mg, 0.35 mmol)
and 2-[(2-chlorophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one (11b) as
white solid in 26% yield (62 mg, 0.26 mmol).
3-[(2-Bromophenyl)methoxy]-5-methyl-2-cyclohexen-1-one
(10d). mp 42−46 °C; Rf = 0.32 (petroleum ether/EtOAc = 8:2); IR
(ATR) ν 1648 (s) (CO), 1599, 1363, 1214, 1196, 1136, 1031, 988,
1
770, 666 cm−1; UV (CH3CN) λmax (log ε) 243 (4.30) nm; H NMR
3-[(2-Chlorophenyl)methoxy]-2-cyclohexen-1-one (10b). Rf
=
3
0.11 (petroleum ether/EtOAc = 8:2); IR (ATR) ν 1645 (s) (C
(300 MHz, CDCl3) δ 1.10 (d, J (CH3, 5-H) = 6.3 Hz, 3H, CH3),
2.03−2.12 (m, 1H, 6-Hb), 2.25 (dd, 3J (4-Hb, 5-H) = 12.0 Hz, 2H, 4-
Hb and 5-H), 2.42−2.55 (m, 2H, 4-Ha and 6-Ha), 4.96 (s, 2H, CH2),
5.48 (s, 1H, 2-H), 7.22 (ddd, 3J (4′-H, 5′-H) = 6.3 Hz, 3J (3′-H, 4′-H) =
7.5 Hz, 4J (4′-H, 6′-H) = 1.2 Hz, 1H, 4′-H), 7.34 (ddd, 3J (4′-H, 5′-H) =
7.2 Hz, 3J (5′-H, 6′-H) = 7.5 Hz, 1H, 5′-H), 7.42 (dd, 3J (5′-H, 6′-H) =
3
7.5 Hz, 1H, 6′-H), 7.59 (dd, J (3′-H, 4′-H) = 7.8 Hz, 1H, 3′-H);
13C NMR (75 MHz, CDCl3) δ 20.9 (CH3), 28.8 (C-5), 37.0 (C-4), 45.1
O), 1595, 1364, 1223, 1178, 1134, 1057, 846, 756 cm−1; UV
(C-6), 69.8 (CH ), 103.2 (C-2), 122.9 (C-2′), 127.6 (C-5′), 129.2 (C-
1
2
(CH3CN) λmax (log ε) 217 (3.98), 243 (4.27) nm; H NMR (300
6′), 129.9 (C-4′), 132.9 (C-3′), 134.4 (C-1′), 176.5 (C-3), 199.6 (C-1);
3
3
MHz, CDCl3) δ 2.00 (quin, J (5-H, 6-H) = 6.6 Hz, J (4-H, 5-H) =
+
MS (EI, 70 eV) m/z (%) 294 (8) [M]+, 215 (9) [294 − Br] , 170
6.3 Hz, 2H, 5-H), 2.36 (t-like, 3J (5-H, 6-H) = 7.2 Hz, 2H, 6-H), 2.48
(t-like, J (4-H, 5-H) = 6.3 Hz, 2H, 4-H), 4.98 (s, 2H, CH2), 5.49 (s,
(100), 90 (34), 44 (24), 28 (80); Anal. Calcd for C14H15BrO2 (295.17):
C, 56.97; H, 5.12. found: C, 56.93; H, 5.10.
3
1H, 2-H), 7.28 (overlapped, 2H, 4′-H and 5′-H), 7.35−7.43 (m, 2H,
3′-H and 6′-H); 13C NMR (75 MHz, CDCl3) δ 21.1 (C-5), 28.8 (C-
4), 36.6 (C-6), 67.5 (CH2), 103.5 (C-2), 126.9 (C-5′), 129.1 (C-6′),
129.5 (C-4′), 129.6 (C-3′), 132.7 (C-2′), 133.1 (C-1′), 177.2 (C-3),
199.6 (C-1); MS (EI, 70 eV) m/z (%) 236 (10) [M]+, 201 (3) [236-
Cl]+, 125 (100), 28 (96); HRMS (EI, M+) calcd for C13H 13ClO2
(236.0604), found 236.0606.
Reaction between 1c and 8a. According to general procedure I, 2-
iodobenzyl bromide (1c) (297 mg, 1.0 mmol), 1,3-cyclohexanedione
(8a) (224 mg, 2.0 mmol), CuI (38 mg, 20 mol %), and Cs2CO3 (1.303
g, 4.0 mmol) were reacted in a sealed tube under argon at 130 °C for
10 min. Column chromatography over silica gel (petroleum ether/
EtOAc = 8:2) afforded 2,3,4,9-tetrahydro-1H-xanthen-1-one (9a) as a
white solid in 19% yield (38 mg, 0.19 mmol), 3-[(2-iodophenyl)-
methoxy]-2-cyclohexen-1-one (10c) as a white solid in 41% yield
(134 mg, 0.41 mmol) and 2-[(2-iodophenyl)methyl]-3-hydroxy-2-
cyclohexen-1-one (11c) as white solid in 5% yield (17 mg, 0.05 mmol).
3-[(2-Iodophenyl)methoxy]-2-cyclohexen-1-one (10c). mp 106−
107 °C; Rf = 0.09 (petroleum ether/EtOAc = 8:2); IR (ATR) ν 1641
Reaction between 1a and 8c. According to general procedure I, 2-
bromobenzyl bromide (1a) (250 mg, 1.0 mmol), 5,5-dimethyl-1,3-
cyclohexanedione (8c) (280 mg, 2.0 mmol), CuI (38 mg, 20 mol %),
and Cs2CO3 (1.303 g, 4.0 mmol) were reacted in a sealed tube under
argon at 130 °C for 10 min. Column chromatography over silica gel
(petroleum ether/EtOAc = 8:2) afforded 3,3-dimethyl-2,3,4,9-
tetrahydro-1H-xanthen-1-one (9c) as a white solid in 35% yield
(80 mg, 0.35 mmol) and 3-[(2-bromophenyl)methoxy]-5,5-dimethyl-
2-cyclohexen-1-one (10e) as a pale yellow liquid in 36% yield (111
mg, 0.36 mmol).
3-[(2-Bromophenyl)methoxy]-5,5-dimethyl-2-cyclohexen-1-one
(10e). Rf = 0.36 (petroleum ether/EtOAc = 8:2); IR (ATR) ν 1653 (s)
(CO), 1604, 1356, 1220, 1203, 1143, 1022, 820, 750 cm−1; UV
(CH3CN) λmax (log ε) 245 (4.28) nm; 1H NMR (300 MHz, CDCl3) δ
1.09 (s, 6H, 2 × CH3), 2.23 (s, 2H, 6-H), 2.37 (s, 2H, 4-H), 4.96 (s,
3
3
2H, CH2), 5.48 (s, 1H, 2-H), 7.20 (ddd, J (4′-H, 5′-H) = 6.3 Hz, J
(3′-H, 4′-H) = 6.3 Hz, 4J (4′-H, 6′-H) = 1.5 Hz, 1H, 4′-H), 7.33 (ddd,
3J (4′-H, 5′-H) = 7.5 Hz, J (5′-H, 6′-H) = 6.9 Hz, 1H, 5′-H), 7.41
3
3
4
(s) (CO), 1600, 1348, 1223, 1180, 1140, 1011, 818, 748 cm−1; UV
(CH3CN) λmax (log ε) 233 (4.28) nm; 1H NMR (300 MHz, CDCl3) δ
2.03 (quin, 3J (5-H, 6-H) = 6.6 Hz, 3J (4-H, 5-H) = 6.3 Hz, 2H, 5-H),
2.39 (t-like, 3J (5-H, 6-H) = 7.2 Hz, 2H, 6-H), 2.51 (t, 3J (4-H, 5-H) =
6.3 Hz, 2H, 4-H), 4.89 (s, 2H, CH2), 5.51 (s, 1H, 2-H), 7.02−7.08
(dd, J (5′-H, 6′-H) = 6.3 Hz, J (4′-H, 6′-H) = 1.2 Hz, 1H, 6′-H),
7.57 (dd, J (3′-H, 4′-H) = 7.5 Hz, 1H, 3′-H); 13C NMR (75 MHz,
3
CDCl3 ) δ 2 × 28.2 (2 × CH3), 32.5 (C-5), 42.7 (C-4), 50.7 (C-6),
69.8 (CH ), 102.4 (C-2), 122.8 (C-2′), 127.5 (C-5′), 129.0 (C-6′),
2
129.8 (C-4′), 132.8 (C-3′), 134.4 (C-1′), 175.4 (C-3), 199.3 (C-1);
MS (EI, 70 eV) m/z (%) 308 (16) [M]+, 229 (9) [308 − Br]+, 169
(100), 90 (30), 69 (7), 28 (8); HRMS (EI, M+) calcd for C15H17BrO2
(308.0412), found 308.0433.
3
(m, 1H, 4′-H), 7.37−7.41 (m, 2H, 5′-H and 6′-H), 7.87 (d, J (3′-H,
4′-H) = 7.5 Hz, 1H, 3′-H); 13C NMR (75 MHz, CDCl3) δ 21.2 (C-5),
28.8 (C-4), 36.7 (C-6), 74.1 (CH ), 97.8 (C-2′), 103.7 (C-2), 128.4
2
(C-5′), 128.9 (C-6′), 130.1 (C-4′), 137.3 (C-1′), 139.5 (C-3′), 177.2
(C-3), 199.7 (C-1); MS (EI, 70 eV) m/z (%) 328 (94) [M]+, 268
(24), 217 (100), 201 (92), 171 (16), 28 (96); HRMS (EI, M+) calcd
for C13H13IO2 (327.9960), found 327.9948.
Reaction between 1a and 8e. According to general procedure I, 2-
bromobenzyl bromide (1a) (250 mg, 1.0 mmol), 5-phenyl-1,3-cyclo-
hexanedione (8e) (376 mg, 2.0 mmol), CuI (38 mg, 20 mol %), and
Cs2CO3 (1.303 g, 4.0 mmol) were reacted in a sealed tube under argon
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at 130 °C for 60 min. Column chromatography over silica gel
(petroleum ether/EtOAc = 8:2) afforded 3-phenyl-2,3,4,9-tetrahy-
dro-1H-xanthen-1-one (9e) as a white solid in 38% yield (105 mg,
0.38 mmol) and 3-[(2-bromophenyl)methoxy]-5-phenyl-2-cyclo-
hexen-1-one (10g) as a pale yellow liquid in 30% yield (107 mg,
0.30 mmol).
and C-6), 114.2 (C-2), 125.9 (C-2′), 2 × 128.2 (C-4′ and C-5′), 129.5
(C-6′), 133.4 (C-3′), 141.1 (C-1′).
2-[(2-Chlorophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one
(11b). According to general procedure II, 1,3-cyclohexanedione (8a)
3-[(2-Bromophenyl)methoxy]-5-phenyl-2-cyclohexen-1-one
(10g). Rf = 0.23 (petroleum ether/EtOAc = 8:2); IR (ATR) ν 1651
(1.12 g, 10 mmol) was dissolved in aqueous NaOH (400 mg, 1 M,
10 mL) at 0 °C. 2-Chlorobenzyl bromide (1b) (3.08 g, 15 mmol) was
added, and the mixture was heated at 100 °C for 3 h. The crude
product was recrystallized from dichloromethane/methanol (1:1) to
afford 2-[(2-chlorophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one
(11b) as a white solid in 51% yield (1.2 g, 5.1 mmol): mp 191−
193 °C (dichloromethane/methanol); Rf = 0.14 (petroleum ether/
EtOAc = 6:4); IR (ATR) ν 2395 (w) (O−H), 1638 (conjugated CO),
1557, 1383, 1357, 1270, 1187, 1038, 1014, 920, 745, 692 (C−Br)
cm−1; UV (CH3CN) λmax (log ε) 252 (4.02) nm; 1H NMR (300 MHz,
(s) (CO), 1600, 1347, 1215, 1189, 1028, 820, 751, 698 cm−1; UV
(CH3CN) λmax (log ε) 245 (4.28) nm; 1H NMR (300 MHz, CDCl3) δ
2.60 (dd, 2J (6-Ha, 6-Hb) = 16.2 Hz, 3J (5-H, 6-Ha) = 12.0 Hz, 1H, 6-
2
3
Ha), 2.69 (dd, J (6-Ha, 6-Hb) = 16.0 Hz, J (5-H, 6-Hb) = 4.5 Hz,
1H, 6-Hb), 2.70−2.85 (m, 2H, 4-H), 3.45−3.48 (m, 1H, 5-H), 5.01 (s,
3
3
DMSO-d6) δ 1.93 (quin, J (5-H, 6-H) = 6.3 Hz, J (4-H, 5-H) = 6.3
3
3
Hz, 2H, 5-H), 2.42 (overlapped, 4H, 4-H and 6-H), 3.53 (s, 2H, CH2),
2H, CH2), 5.59 (s, 1H, 2-H), 7.23 (ddd, J (4′-H, 5′-H) = 7.5 Hz, J
(3′-H, 4′-H) = 7.5 Hz, 4J (4′-H, 6′-H) = 1.8 Hz, 1H, 4′-H), 7.29−7.31
(m, 3H, 2″-H, 6″-H and 4″-H), 7.34 (overlapped, 3H, 3″-H, 5″-H and
3
4
6.96 (dd, J (5′-H, 6′-H) = 7.2 Hz, J (4′-H, 6′-H) = 2.1 Hz, 1H, 6′-
H), 7.12−7.20 (m, 2H, 4′-H and 5′-H), 7.37 (dd, 3J (3′-H, 4′-H) = 6.9
Hz, 4J (3′-H, 5′-H) = 1.5 Hz, 1H, 3′-H); 13C NMR (75 MHz, DMSO-
3
4
5′-H), 7.42 (dd, J (5′-H, 6′-H) = 7.7 Hz, J (4′-H, 6′-H) = 1.7 Hz,
3
4
d6) δ 20.6 (C-5), 24.9 (CH ), 2 × 32.7 (C-4 and C-6), 111.3 (C-2),
1H, 6′-H), 7.60 (dd, J (3′-H, 4′-H) = 8.0 Hz, J (3′-H, 5′-H) = 1.2
2
Hz, 1H, 3′-H); 13C NMR (75 MHz, CDCl3 ) δ 36.4 (C-4), 39.3 (C-5),
126.8 (C-5′), 127.0 (C-4′), 128.5 (C-6′), 128.6 (C-3′-H), 133.1 (C-
1′), 138.1 (C-2′); MS (EI, 70 eV) m/z (%) 236 (2) [M]+, 201 (60)
[236-Cl]+, 145 (14), 28 (100); HRMS (EI, M+) calcd for C13H 13ClO2
(236.0604), found 236.0604.
43.9 (C-6), 70.1 (CH ), 103.5 (C-2), 122.9 (C-2′), 126.7 (C-2″ and
2
C-6″), 127.1 (C-4″), 127.6 (C-5′), 128.8 (C-3″ and C-5″), 129.2
(C-6′), 129.9 (C-4′), 132.9 (C-3′), 134.3 (C-1′), 142.5 (C-1″), 176.1
(C-3), 198.6 (C-1); MS (EI, 70 eV) m/z (%) 356 (9) [M]+, 277 (9)
[356 − Br] +, 217 (8), 169 (100), 131 (10), 90 (24), 69 (8), 28 (57);
HRMS (EI, M+) calcd for C19H17BrO2 (356.0412), found 356.0386.
General Procedure II for the Synthesis of Starting Materials
11.13a The 1,3-cyclohexanedione 8 (10 mmol) was dissolved in
aqueous NaOH (1 M, 10 mL) at 0 °C. The 2-halobenzyl bromide 1
(15 mmol) was added to the resulting solution. The mixture was
heated at 100 °C for 3 h and then allowed to cool to room tem-
perature. The solid formed was filtered and washed successively with
petroleum ether (5 mL), cold water (5 mL), and cold diethyl ether
(3 mL) until a pale beige solid was obtained. The crude product was
recrystallized from dichloromethane/methanol (1:1) to afford the corres-
ponding 2-[(2-haloaryl)methyl]-3-hydroxy-2-cyclic-1-one 11.
2-[(2-Iodophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one
(11c).13d According to general procedure II, 1,3-cyclohexanedione
(8a) (560 mg, 5 mmol) was dissolved in aqueous NaOH (200 mg,
1 M, 5 mL) at 0 °C. 2-Iodobenzyl bromide (1c) (2.23 g, 7.5 mmol)
was added, and the mixture was heated at 100 °C for 3 h. The crude
product was recrystallized from dichloromethane/methanol (1:1) to
afford 2-[(2-iodophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one (11c)
as a white solid in 60% yield (980 mg, 3.0 mmol): mp 161−162 °C
(dichloromethane/methanol) (lit.13d mp 154−155 °C); Rf = 0.17
Synthesis and Characterization of Starting Materials 11. 2-
[(2-Bromophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one (11a).13b
1
(petroleum ether/EtOAc = 6:4); H NMR (300 MHz, DMSO-d6) δ
1.93 (quin, 3J (5-H, 6-H) = 6.3 Hz, 3J (4-H, 5-H) = 6.3 Hz, 2H, 5-H),
3
3
2.42 (t-like, J (5-H, 6-H) = 6.0 Hz, J (4-H, 5-H) = 6.3 Hz, 4H, 4-H
and 6-H), 3.40 (s, 2H, CH2), 6.88 (overlapped, 2H, 4′-H and 6′-H),
7.23 (ddd, 3J (5′-H, 6′-H) = 7.5 Hz, 3J (4′-H, 5′-H) = 7.5 Hz, 1H, 5′-
3
H), 7.81 (dd, J (3′-H, 4′-H) = 7.8 Hz, 4J (3′-H, 5′-H) = 0.9 Hz, 1H,
3′-H); 13C NMR (75 MHz, DMSO-d6) δ 20.6 (C-5), 32.5 (CH2), 2 ×
33.3 (C-4 and C-6), 101.7 (C-2′), 112.0 (C-2), 127.3 (C-5′), 127.5
(C-4′), 128.0 (C-6′), 138.5 (C-3′), 142.5 (C-1′).
According to general procedure II, 1,3-cyclohexanedione (8a) (1.12 g,
10 mmol) was dissolved in aqueous NaOH (400 mg, 1 M, 10 mL)
at 0 °C. 2-Bromobenzyl bromide (1a) (3.75 g, 15 mmol) was added,
and the mixture was heated at 100 °C for 3 h. The crude product was
recrystallized from dichloromethane/methanol (1:1) to afford 2-[(2-
bromophenyl)methyl]-3-hydroxy-2-cyclohexen-1-one (11a) as a white
solid in 71% yield (2.0 g, 7.1 mmol): mp 190−191 °C (dichloro-
methane/methanol) (lit.13b mp 189−191 °C); Rf = 0.12 (petroleum
ether/EtOAc = 6:4); IR (ATR) ν 2558 (w) (O−H), 1635 (conjugated
CO), 1557, 1359, 1271, 1187, 1067, 1013, 918, 742, 658 (C−Br)
cm−1; UV (CH3CN) λmax (log ε) 251 (4.16) nm; 1H NMR (300 MHz,
2-[(2-Bromophenyl)methyl]-3-hydroxy-5-methyl-2-cyclohexen-1-
one (11d). According to general procedure II, 5-methyl-1,3-cyclo-
hexanedione (8b) (1.26 g, 10 mmol) was dissolved in aqueous NaOH
(400 mg, 1 M, 10 mL) at 0 °C. 2-Bromobenzyl bromide (1a) (3.75 g,
15 mmol) was added, and the mixture was heated at 100 °C for 3 h.
The crude product was recrystallized from dichloromethane/methanol
(1:1) to afford 2-[(2-bromophenyl)methyl]-3-hydroxy-5-methyl-2-
cyclohexen-1-one (11d) as a white solid in 75% yield (2.2 g, 7.5
mmol): mp 205−207 °C (dichloromethane/methanol); Rf = 0.24
3
3
CD3OD) δ 2.04 (quin-like, J (5-H, 6-H) = 6.3 Hz, J (4-H, 5-H) =
6.3 Hz, 2H, 5-H), 2.51 (t-like, 3J (5-H, 6-H) = 6.3 Hz, 3J (4-H, 5-H) =
6.6 Hz, 4H, 4-H and 6-H), 3.64 (s, 2H, CH2), 6.98 (overlapped, 2H,
4′-H and 6′-H), 7.16 (ddd, 3J (5′-H, 6′-H) = 7.5 Hz, 3J (4′-H, 5′-H) =
7.5 Hz, 1H, 5′-H), 7.50 (dd, 3J (3′-H, 4′-H) = 8.1 Hz, 1H, 3′-H); 13
C
NMR (75 MHz, CD3OD) δ 22.1 (C-5), 29.2 (CH2), 2 × 33.9 (C-4
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(petroleum ether/EtOAc = 6:4); IR (ATR) ν 2359 (w) (O−H), 1637
(conjugated CO), 1556, 1314, 1247, 1215, 1145, 1044, 1021, 751,
C-5′), 129.7 (C-6′), 133.4 (C-3′), 141.0 (C-1′); Anal. Calcd for
C16H19BrO2 (323.22): C, 59.45; H, 5.92. found: C, 59.26; H, 5.91.
2-[(2-Bromophenyl)methyl]-3-hydroxy-5-phenyl-2-cyclohexen-1-
one (11g). According to general procedure II, 5-phenyl-1,3-cyclo-
1
678 (C−Br) cm−1; UV (CH3CN) λmax (log ε) 252 (4.14) nm; H
3
NMR (300 MHz, CD3OD) δ 1.12 (d, J (CH3, 5-H) = 5.7 Hz, 3H,
CH3), 2.25−2.32 (m, 3H, 4-Hb, 5-Hb and 6-H), 2.52 (br dd, 2J (4-Ha,
2
4-Hb) = 12.3 Hz, J (6-Ha, 6-Hb) = 12.3 Hz, 2H, 4-Ha and 6-Ha),
3.63 (s, 2H, CH2), 6.95 (dd, 3J (5′-H, 6′-H) = 7.5 Hz, 1H, 6′-H), 7.01
3
3
(ddd, J (4′-H, 5′-H) = 7.5 Hz, J (3′-H, 4′-H) = 7.5 Hz, 1H, 4′-H),
7.16 (ddd, 3J (4′-H, 5′-H) = 7.5 Hz, 3J (5′-H, 6′-H) = 6.9 Hz, 1H, 5′-
H), 7.50 (dd, J (3′-H, 4′-H) = 7.8 Hz, 1H, 3′-H); 13C NMR (75
3
MHz, CD3 OD) δ 21.3 (CH3), 29.2 (CH 2), 30.0 (C-5), 2 × 42.1 (C-6
and C-4), 113.7 (C-2), 125.9 (C-2′), 2 × 128.2 (C-4′ and C-5′), 129.7
(C-6′), 133.4 (C-3′), 141.1 (C-1′); Anal. Calcd for C14H15BrO2
(295.17): C, 56.97; H, 5.12. found: C, 56.77; H, 5.13.
hexanedione (8e) (1.88 g, 10 mmol) was dissolved in aqueous NaOH
(400 mg, 1 M, 10 mL) at 0 °C. 2-Bromobenzyl bromide (1a) (3.75 g,
15 mmol) was added, and the mixture was heated at 100 °C for 3 h.
The crude product was recrystallized from dichloromethane/methanol
(1:1) to afford 2-[(2-bromophenyl)methyl]-3-hydroxy-5-phenyl-2-
cyclohexen-1-one (11g) as a white solid in 56% yield (2.0 g, 5.6
mmol): mp 228−229 °C (dichloromethane/methanol); Rf = 0.36
(petroleum ether/EtOAc = 6:4); IR (ATR) ν 2554 (w) (O−H), 1634
(conjugated CO), 1558, 1331, 1245, 1211, 1041, 912, 748, 701, 656
2-[(2-Bromophenyl)methyl]-3-hydroxy-5,5-dimethyl-2-cyclohex-
en-1-one (11e). According to general procedure II, 5,5-dimethyl-1,3-
1
(C−Br) cm−1; UV (CH3CN) λmax (log ε) 253 (4.11) nm; H NMR
(300 MHz, DMSO-d6) δ 2.56 (br dd, 2J (4-Ha, 4-Hb) = 15.6 Hz, 2J (6-
Ha, 6-Hb) = 15.6 Hz, 2H, 4-Hb and 6-Hb), 2.80 (ddd, 3J (4-Ha, 5-H)
= 11.7 Hz, 3J (5-H, 6-Ha) = 11.7 Hz, 2J (4-Ha, 4-Hb) = 16.2 Hz, 2J (6-
Ha, 6-Hb) = 16.2 Hz, 2H, 4-Ha and 6-Ha), 3.41−3.49 (m, 1H, 5-H),
cyclohexanedione (8c) (1.40 g, 10 mmol) was dissolved in aqueous
NaOH (400 mg, 1 M, 10 mL) at 0 °C. 2-Bromobenzyl bromide (1a)
(3.75 g, 15 mmol) was added, and the mixture was heated at 100 °C
for 3 h. The crude product was recrystallized from dichloromethane/
methanol (1:1) to afford 2-[(2-bromophenyl)methyl]-3-hydroxy-5,5-
dimethyl-2-cyclohexen-1-one (11e) as a white solid in 68% yield
(2.1 g, 6.8 mmol): mp 188−189 °C (dichloromethane/methanol); Rf =
0.33 (petroleum ether/EtOAc = 6:4); IR (ATR) ν 2969 (w) (O−H),
1643 (conjugated CO), 1562, 1370, 1249, 1022, 848, 752, 650 (C−
3
3.54 (br s, 2H, CH2), 6.98 (dd, J (5′-H, 6′-H) = 7.5 Hz, 1H, 6′-H),
7.09 (ddd, 3J (3′-H, 4′-H) = 7.5 Hz, 3J (4′-H, 5′-H) = 7.5 Hz, 1H, 4′-
H), 7.23 (overlapped, 2H, 4″-H and 5′-H), 7.32−7.40 (m, 4H, 2″-H,
3″-H, 5″-H, and 6″-H), 7.56 (dd, 3J (3′-H, 4′-H) = 8.1 Hz, 1H, 3′-H),
10.91 (bs, 1H, 3-H); 13C NMR (75 MHz, DMSO-d6) δ 27.9 (CH2),
38.2 (C-5), 2 × 38.7 (C-4 and C-6), 111.2 (C-2), 124.3 (C-2′), 126.6
(C-4″), 2 × 126.9 (C-2″ and C-6″), 127.3 (C-5′), 127.4 (C-4′), 2 ×
128.5 (C-3″ and C-5″), 128.6 (C-6′), 131.9 (C-3′), 139.4 (C-1′),
143.6 (C-1″); Anal. Calcd for C19H17BrO2 (357.24): C, 63.88; H, 4.80.
found: C, 63.59; H, 4.81.
1
Br) cm−1; UV (CH3CN) λmax (log ε) 253 (4.06) nm; H NMR (300
MHz, CD3OD) δ 1.13 (s, 6H, 2 × CH3), 2.39 (s, 4H, 4-H and 6-H),
3.65 (s, 2H, CH2), 7.01 (overlapped, 2H, 4′-H and 6′-H), 7.16 (ddd, 3
3
J (4′-H, 5′-H) = 7.5 Hz, J (5′-H, 6′-H) = 7.2 Hz, 1H, 5′-H), 7.50
3
(dd, J (3′-H, 4′-H) = 8.1 Hz, 1H, 3′-H); 13C NMR (75 MHz, CD3
2-[(2-Bromophenyl)methyl]-5-(4-chlorophenyl)-3-hydroxy-2-cy-
clohexen-1-one (11h). According to general procedure II, 5-(4-
OD) δ 2 × 28.8 (2 × CH3), 29.1 (CH ), 33.1 (C-5), 2 × 47.7 (C-6
2
and C-4), 113.1 (C-2), 125.8 (C-2′), 128.2 (C-5′), 128.3 (C-4′), 129.9
(C-6′), 133.4 (C-3′), 141.2 (C-1′); Anal. Calcd for C15H17BrO2
(309.20): C, 58.27; H, 5.54. found: C, 58.24; H, 5.56.
2-[(2-Bromophenyl)methyl]-3-hydroxy-5-isopropyl-2-cyclohexen-
1-one (11f). According to general procedure II, 5-isopropyl-1,3-
chlorophenyl)-1,3-cyclohexanedione (8f) (2.23 g, 10 mmol) was
dissolved in aqueous NaOH (400 mg, 1 M, 10 mL) at 0 °C. 2-
Bromobenzyl bromide (1a) (3.75 g, 15 mmol) was added, and the
mixture was heated at 100 °C for 3 h. The crude product was
recrystallized from dichloromethane/methanol (1:1) to afford 2-[(2-
bromophenyl)methyl]-5-(4-chlorophenyl)-3-hydroxy-2-cyclohexen-1-
one (11h) as a white solid in 82% yield (3.2 g, 8.2 mmol): mp 241−
242 °C (dichloromethane/methanol); Rf = 0.30 (petroleum ether/
EtOAc = 6:4); IR (ATR) ν 2516 (w) (O−H), 1620 (conjugated C
O), 1556, 1318, 1246, 1212, 1041, 821, 751, 673 (C−Br) cm−1; UV
cyclohexanedione (8d) (771 mg, 5 mmol) was dissolved in aqueous
NaOH (200 mg, 1 M, 5 mL) at 0 °C. 2-Bromobenzyl bromide (1a)
(1.88 g, 7.5 mmol) was added, and the mixture was heated at 100 °C
for 3 h. The crude product was recrystallized from dichloromethane/
methanol (1:1) to afford 2-[(2-bromophenyl)methyl]-3-hydroxy-5-
isopropyl-2-cyclohexen-1-one (11f) as a white solid in 83% yield (1.35
g, 4.18 mmol): mp 188−189 °C (dichloromethane/methanol); Rf =
0.41 (petroleum ether/EtOAc = 6:4); IR (ATR) ν 2532 (w) (O−H),
1620 (conjugated CO), 1558, 1303, 1245, 1208, 1148, 1038, 750,
1
(CH3CN) λmax (log ε) 253 (4.00) nm; H NMR (300 MHz, DMSO-
d6) δ 2.58 (br dd, 3J (4-Hb, 5-H) = 3.5 Hz, 3J (5-H, 6-Hb) = 3.5 Hz, 2J
(4-Ha, 4-Hb) = 16.2 Hz, 2J (6-Ha, 6-Hb) = 16.2 Hz, 2H, 4-Hb and 6-
Hb), 2.79 (ddd, 3J (4-Ha, 5-H) = 12.0 Hz, 3J (5-H, 6-Ha) = 12.0 Hz, 2J
(4-Ha, 4-Hb) = 16.0 Hz, 2J (6-Ha, 6-Hb) = 16.0 Hz, 2H, 4-Ha and 6-
1
654 (C−Br) cm−1; UV (CH3CN) λmax (log ε) 269 (3.44) nm; H
NMR (300 MHz, CD3OD) δ 0.99 (d, 3J (1″-H, 2″-H) = 6.6 Hz, 6H, 2
× CH3), 1.60−1.67 (m, 1H, 1″-H), 1.93−1.97 (m, 1H, 5-H), 2.32
(ddd, 2J (4-Ha, 4-Hb) = 12.0 Hz, 2J (6-Ha, 6-Hb) = 12.0 Hz, 3J (4-Hb,
3
Ha), 3.42−3.51 (m, 1H, 5-H), 3.54 (br s, 2H, CH2), 6.97 (dd, J (5′-
3
H, 6′-H) = 7.6 Hz, 4J (4′-H, 6′-H) = 1.6 Hz, 1H, 6′-H), 7.09 (ddd, 3J
(3′-H, 4′-H) = 7.6 Hz, 3J (4′-H, 5′-H) = 7.6 Hz, 4J (4′-H, 6′-H) = 1.7
Hz, 1H, 4′-H), 7.22 (ddd, 3J (4′-H, 5′-H) = 7.5 Hz, 3J (5′-H, 6′-H) =
7.5 Hz, 4J (3′-H, 5′-H) = 1.4 Hz, 1H, 5′-H), 7.36−7.45 (m, 4H, 2″-H,
5-H) = 4.8 Hz, J (5-H, 6-Hb) = 4.8 Hz, 2H, 4-Hb and 6-Hb), 2.51
3
(dd, 2J (4-Ha, 4-Hb) = 12.3 Hz, 2J (6-Ha, 6-Hb) = 12.3 Hz, J (4-Ha,
5-H) = 4.8 Hz, 3J (5-H, 6-Ha) = 4.8 Hz, 2H, 4-Ha and 6-Ha), 3.63 (s,
2H, CH2), 6.94 (dd, 3J (5′-H, 6′-H) = 7.2 Hz, 1H, 6′-H), 7.01 (ddd, 3J
(3′-H, 4′-H) = 7.5 Hz, 3J (4′-H, 5′-H) = 7.5 Hz, 1H, 4′-H), 7.16 (ddd,
3
4
6″-H, 3″-H, and 5″-H), 7.56 (dd, J (3′-H, 4′-H) = 7.8 Hz, J (3′-H,
5′-H) = 1.3 Hz, 1H, 3′-H), 10.92 (br s, 1H, 3-H); 13C NMR (75 MHz,
DMSO-d6) δ 27.9 (CH2), 37.6 (C-5), 2 × 38.1 (C-6 and C-4), 111.2
(C-2), 124.3 (C-2′), 127.3 (C-5′), 127.4 (C-4′), 2 × 128.4 (C-2″ and
C-6″), 128.6 (C-6′), 2 × 128.9 (C-3″ and C-5″), 131.2 (C-4″), 131.9
3
3J (4′-H, 5′-H) = 7.5 Hz, J (5′-H, 6′-H) = 6.9 Hz, 1H, 5′-H), 7.50
3
(dd, J (3′-H, 4′-H) = 8.1 Hz, 1H, 3′-H); 13C NMR (75 MHz, CD3
OD) δ 2 × 20.1 (2 × CH3), 29.2 (CH 2), 33.2 (C-1″), 2 × 38.0 (C-6
and C-4), 41.3 (C-5), 113.7 (C-2), 125.9 (C-2′), 2 × 128.2 (C-4′ and
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(C-3′), 139.4 (C-1′), 142.6 (C-1″); Anal. Calcd for C19H16BrClO2
(391.69): C, 58.26; H, 4.12. found: C, 58.30; H, 4.14.
(C-5″), 156.4 (C-2″); Anal. Calcd for C17H15BrO3 (347.20): C, 58.81;
H, 4.35. found: C, 58.62; H, 4.38.
2-[(2-Bromophenyl)methyl]-3-hydroxy-5-(4-methoxyphenyl)-2-
cyclohexen-1-one (11i). According to general procedure II, 5-(4-
2-[(2-Bromophenyl)methyl]-3-hydroxy-2-cyclopenten-1-one
(11k). According to general procedure II, 1,3-cyclopentanedione (8i)
(981 mg, 10 mmol) was dissolved in aqueous NaOH (400 mg, 1 M,
10 mL) at 0 °C. 2-Bromobenzyl bromide (1a) (3.75 g, 15 mmol) was
added, and the mixture was heated at 100 °C for 3 h. The crude
product was recrystallized from dichloromethane/methanol (1:1) to
afford 2-[(2-bromophenyl)methyl]-3-hydroxy-2-cyclopenten-1-one
(11k) as a green solid in 45% yield (1.2 g, 4.5 mmol): mp 172−173 °C
(dichloromethane/methanol); Rf = 0.06 (petroleum ether/EtOAc =
6:4); IR (ATR) ν 2351 (w) (O−H), 1557, 1350, 1258, 1172, 1029,
769, 740, 652 (C−Br) cm−1; UV (CH3CN) λmax (log ε) 239 (4.18)
methoxyphenyl)-1,3-cyclohexanedione (8g) (2.18 g, 10 mmol) was
dissolved in aqueous NaOH (400 mg, 1 M, 10 mL) at 0 °C. 2-
Bromobenzyl bromide (1a) (3.75 g, 15 mmol) was added, and the
mixture was heated at 100 °C for 3 h. The crude product was
recrystallized from dichloromethane/methanol (1:1) to afford 2-[(2-
bromophenyl)methyl]-3-hydroxy-5-(4-methoxyphenyl)-2-cyclohexen-
1-one (11i) as a white solid in 80% yield (3.1 g, 8.0 mmol): mp 218−
219 °C (dichloromethane/methanol); Rf = 0.31 (petroleum ether/
EtOAc = 6:4); IR (ATR) ν 2551 (w) (O−H), 1630 (conjugated C
O), 1558, 1513, 1326, 1245, 1212, 1040, 829, 757, 656 (C−Br) cm−1;
nm; 1H NMR (300 MHz, CD3OD) δ 2.58 (s, 4H, 4-H and 5-H), 3.52
3
1
(s, 2H, CH ), 7.05 (overlapped, 2H, 4′-H and 6′-H), 7.20 (ddd, J
2
UV (CH3CN) λmax (log ε) 252 (4.16) nm; H NMR (300 MHz,
3
3
(4′-H, 5′-H) = 8.1 Hz, 3J (5′-H, 6′-H) = 6.9 Hz, 1H, 5′-H), 7.52 (dd,
DMSO-d6) δ 2.53 (br dd, J (4-Hb, 5-H) = 7.5 Hz, J (5-H, 6-Hb) =
7.5 Hz, 2J (4-Ha, 4-Hb) = 16.5 Hz, 2J (6-Ha, 6-Hb) = 16.5 Hz, 2H, 4-
Hb and 6-Hb), 2.75 (ddd, 3J (4-Ha, 5-H) = 11.7 Hz, 3J (5-H, 6-Ha) =
11.7 Hz, 2J (4-Ha, 4-Hb) = 15.9 Hz, 2J (6-Ha, 6-Hb) = 15.9 Hz, 2H, 4-
Ha and 6-Ha), 3.33−3.42 (m, 1H, 5-H), 3.53 (br s, 2H, CH2), 3.73 (br
s, 3H, OMe), 6.90 (br dd, 3J (2″-H, 3″-H) = 8.7 Hz, 3J (5″-H, 6″-H) =
3J (3′-H, 4′-H) = 7.8 Hz, 1H, 3′-H); 13C NMR (75 MHz, CD3OD) δ
28.4 (CH2), 2 × 31.5 (C-4 and C-5), 115.8 (C-2), 125.6 (C-2′), 128.4
(C-5′), 128.7 (C-4′), 130.6 (C-6′), 133.6 (C-3′), 139.8 (C-1′); Anal.
Calcd for C12H11BrO2 (267.12): C, 53.96; H, 4.15. found: C, 53.83;
H, 4.20.
2-[(1-Bromonaphthalen-2-yl)methyl]-3-hydroxy-2-cyclohexen-1-
one (11l). According to general procedure II, 1,3-cyclohexanedione
3
8.7 Hz, 2H, 3″-H and 5″-H), 6.96 (dd, J (5′-H, 6′-H) = 7.5 Hz, 1H,
6′-H), 7.09 (ddd, 3J (3′-H, 4′-H) = 6.3 Hz, 3J (4′-H, 5′-H) = 7.5 Hz, 4J
(4′-H, 6′-H) = 1.2 Hz, 1H, 4′-H), 7.22 (ddd, 3J (4′-H, 5′-H) = 7.5 Hz,
3J (5′-H, 6′-H) = 7.5 Hz, 1H, 5′-H), 7.30 (br dd, 3J (2″-H, 3″-H) = 8.7
Hz, 3J (5″-H, 6″-H) = 8.7 Hz, 2H, 2″-H and 6″-H), 7.56 (dd, 3 J (3′-H,
4′-H) = 7.5 Hz, 1H, 3′-H), 10.85 (br s, 1H, 3-H); 13C NMR (75 MHz,
DMSO-d6) δ 27.9 (CH2), 37.5 (C-5), 2 × 38.0 (C-6 and C-4), 55.0
(−OCH ), 111.1 (C-2), 2 × 113.8 (C-3″ and C-5″), 124.3 (C-2′),
3
(8a) (560 mg, 5 mmol) was dissolved in aqueous NaOH (200 mg, 1
M, 5 mL) at 0 °C. 1-Bromo-2-(bromomethyl)naphthalene (1d) (2.25
g, 7.5 mmol) was added, and the mixture was heated at 100 °C for 3 h.
The crude product was recrystallized from dichloromethane/methanol
(1:1) to afford 2-[(1-bromonaphthalen-2-yl)methyl-3-hydroxy-2-cy-
clohexen-1-one (11l) as a white solid in 60% yield (1.0 g, 3.0 mmol):
mp 226−227 °C (dichloromethane/methanol); Rf = 0.06 (petroleum
ether/EtOAc = 6:4); IR (ATR) ν 2579 (w) (O−H), 1637 (conjugated
CO), 1558, 1356, 1271, 1184, 1011, 809, 734, 670 (C−Br) cm−1;
UV (CH3CN) λmax (log ε) 276 (3.74), 287 (3.76) nm; 1H NMR (300
MHz, DMSO-d6) δ 1.95 (quin-like, 3J (5-H, 6-H) = 6.3 Hz, 3J (4-H, 5-
H) = 6.3 Hz, 2H, 5-H), 2.44 (t-like, 3J (4-H, 5-H) = 5.7 Hz, 3J (5-H, 6-
H) = 5.7 Hz, 4H, 4-H and 6-H), 3.77 (s, 2H, CH2), 7.13 (dd, 3J (3′-H,
4′-H) = 8.4 Hz, 1H, 3′-H), 7.53 (ddd, 3J (5′-H, 6′-H) = 7.2 Hz, 3J (6′-
H, 7′-H) = 7.5 Hz, 1H, 6′-H), 7.64 (ddd, 3J (6′-H, 7′-H) = 7.2 Hz, 3J
(7′-H, 8′-H) = 7.5 Hz, 1H, 7′-H), 7.80 (dd, 3J (3′-H, 4′-H) = 8.4 Hz,
1H, 4′-H), 7.90 (dd, 3J (5′-H, 6′-H) = 8.1 Hz, 1H, 5′-H), 8.21 (dd, 3J
(7′-H, 8′-H) = 8.4 Hz, 1H, 8′-H), 10.81 (br s, 1H, 3-H); 13C NMR
127.35 (C-5′), 127.40 (C-4′), 2 × 127.9 (C-2″ and C-6″), 128.6 (C-
6′), 131.9 (C-3′), 135.5 (C-1″), 139.4 (C-1′), 157.9 (C-4″); Anal.
Calcd for C20H19BrO3 (387.27): C, 62.03; H, 4.95. found: C, 61.81; H,
4.95.
2-[(2-Bromophenyl)methyl]-5-(furan-2-yl)-3-hydroxy-2-cyclohex-
en-1-one (11j). According to general procedure II, 5-(furan-2-yl)-1,3-
cyclohexanedione (8h) (891 mg, 5 mmol) was dissolved in aqueous
NaOH (200 mg, 1 M, 5 mL) at 0 °C. 2-Bromobenzyl bromide (1a)
(1.88 g, 7.5 mmol) was added, and the mixture was heated at 100 °C
for 3 h. The crude product was recrystallized from dichloromethane/
methanol (1:1) to afford 2-[(2-bromophenyl)methyl]-5-(furan-2-yl)-
3-hydroxy-2-cyclohexen-1-one (11j) as a white solid in 75% yield (1.3 g,
3.75 mmol): mp 231−232 °C (dichloromethane/methanol); Rf =
0.34 (petroleum ether/EtOAc = 6:4); IR (ATR) ν 2550 (w) (O−H),
1640 (conjugated CO), 1559, 1361, 1316, 1251, 1215, 1042, 755,
730, 663 (C−Br) cm−1; UV (CH3CN) λmax (log ε) 253 (4.12) nm; 1H
NMR (300 MHz, DMSO-d6) δ 2.62−2.88 (m, 4H, 4-H and 6-H), 3.49
(75 MHz, DMSO-d6) δ 20.5 (C-5), 29.0 (CH ), 2 × 38.7 (C-4 and
2
C-6), 112.0 (C-2), 122.9 (C-1′), 125.8 (C-6′), 126.1 (C-8′), 126.5
(C-3′), 127.2 (C-4′), 127.6 (C-7′), 128.1 (C-5′), 131.6 (C-8′a), 132.7
(C-4′a), 138.5 (C-2′); MS (EI, 70 eV) m/z (%) 332 (8) [M]+, 251
(100) [332 − Br]+, 195 (7), 152 (5), 126 (6); HRMS (EI, M+) calcd
for C17H15BrO2 (330.0255), found 330.0256.
2-[(6-Bromo-1,3-benzodioxol-5-yl)methyl]-3-hydroxy-2-cyclohexen-
1-one (11m). According to general procedure II, 1.3-cyclohexanedione
3
(br s, 2H, CH2), 3.52−3.58 (m, 1H, 5-H), 6.17 (d, J (3″-H, 4″-H) =
3.3 Hz, 1H, 3″-H), 6.41 (ddd, 3J (3″-H, 4″-H) = 3.0 Hz, 3J (4″-H, 5″-
3
H) = 1.8 Hz, 1H, 4″-H), 6.81 (dd, J (5′-H, 6′-H) = 7.5 Hz, 1H, 6′-
4
3
3
H), 7.06 (ddd, J (4′-H, 6′-H) = 1.2 Hz, J (4′-H, 5′-H) = 6.3 Hz, J
(3′-H, 4′-H) = 7.5 Hz, 1H, 4′-H), 7.16 (ddd, 3J (4′-H, 5′-H) = 6.3 Hz,
3J (5′-H, 6′-H) = 7.5 Hz, 1H, 5′-H), 7.54 (dd, J (3′-H, 4′-H) = 7.8
3
Hz, 1H, 3′-H), 7.59 (br s, 1H, 5″-H), 10.92 (br s, 1H, 3-H); 13C NMR
(75 MHz, DMSO-d6) δ 27.8 (CH2), 31.5 (C-5), 2 × 38.7 (C-4 and
C-6), 104.9 (C-3″), 110.3 (C-4″), 111.3 (C-2), 124.2 (C-2′), 127.3
(C-5′), 127.4 (C-4′), 128.5 (C-6′), 131.9 (C-3′), 139.3 (C-1′), 141.7
(8a) (560 mg, 5 mmol) was dissolved in aqueous NaOH (200 mg,
1 M, 5 mL) at 0 °C. 5-Bromo-6-(bromomethyl)benzo[d][1,3]dioxole
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4
(1e) (2.21 g, 7.5 mmol) was added, and the mixture was heated
at 100 °C for 3 h. The crude product was recrystallized from
dichloromethane/methanol (1:1) to afford 2-[(6-bromo-1,3-benzo-
dioxol-5-yl)methyl]-3-hydroxy-2-cyclohexen-1-one (11m) as a white
solid in 61% yield (1.0 g, 3.08 mmol): mp 191−192 °C (dichloromethane/
methanol); Rf = 0.10 (petroleum ether/EtOAc = 6:4); IR (ATR) ν 2550
(w) (O−H), 1630 (conjugated CO), 1557, 1499, 1475, 1341, 1224,
1177, 1039, 1008, 935, 867 cm−1; UV (CH3CN) λmax (log ε) 203
3J (3′-H, 4′-H) = 5.7 Hz, J (4′-H, 6′-H) = 3.0 Hz, 1H, 4′-H), 7.38
(dd, J (3′-H, 4′-H) = 8.7 Hz, 1H, 3′-H); 13C NMR (75 MHz, CD3
3
OD) δ 22.1 (C-5), 29.2 (CH 2), 2 × 33.9 (C-4 and C-6), 55.8 (OMe),
113.2 (C-4′), 114.2 (C-2), 116.0 (C-6′), 116.3 (C-2′), 133.8 (C-3′),
142.1 (C-1′), 160.5 (C-5′); Anal. Calcd for C14H 15BrO3(311.17): C,
54.04; H, 4.86. found: C, 53.77; H, 4.83.
1-Bromo-2-(bromomethyl)naphthalene (1d).19 In a round-
bottomed flask, 1-bromo-2-methylnaphthalene (3.69 g, 16.7 mmol)
1
(4.55), 248 (4.20), 294 (3.62) nm; H NMR (300 MHz, CD3OD) δ
2.03 (quin, 3J (5-H, 6-H) = 6.3 Hz, 3J (4-H, 5-H) = 6.3 Hz, 2H, 5-H),
3
2.50 (t-like, J (4-H, 5-H) = 6.6 Hz, 3J (5-H, 6-H) = 6.6 Hz, 4H, 4-H
and 6-H), 3.53 (s, 1H, CH2), 5.89 (s, 2H, 2′-H), 6.46 (s, 1H, 4′-H),
6.97 (s, 1H, 7′-H); 13C NMR (75 MHz, CD3OD) δ 22.1 (C-5), 29.0
(CH ), 2 × 33.9 (C-4 and C-6), 102.9 (C-2′), 109.5 (C-4′), 113.2
2
was dissolved in CCl4 (100 mL), followed by N-bromosuccinimide
(2.97 g, 16.7 mmol) and benzoyl peroxide (3 mg). The reaction
mixture was refluxed for 3 h, cooled to room temperature, and washed
with saturated NaHCO3 (50 mL). The organic layer was dried over
MgSO4 and filtered, and the solvent was removed under reduced
pressure. Recrystallization from cyclohexane afforded 1-bromo-2-(bro-
momethyl)naphthalene (1d) as a colorless solid in 72% yield (3.6 g,
12.0 mmol): mp 103−104 °C (lit.19 mp 103−105 °C); 1H NMR (300
MHz, CDCl3) δ 4.87 (s, 2H, 9-H), 7.51−7.62 (m, 3H, 3-H, 6-H and 7-
H), 7.78−7.83 (m, 2H; 4-H and 5-H), 8.34 (br d, 3J (7-H, 8-H) = 8.7
Hz, 1H, 8-H); 13C NMR (75 MHz, CDCl3) δ 34.7 (C-9), 124.9 (C-1),
127.2 (C-8), 127.6 (C-7), 127.7 (C-3), 127.8 (C-6), 128.1 (C-4),
128.3 (C-5), 132.5 (C-2), 134.1 (C-8a), 134.9 (C-4a).
(C-7′), 114.6 (C-2), 115.5 (C-6′), 134.5 (C-5′), 147.8 (C-7′a), 148.8
(C-3′a); Anal. Calcd for C14H13BrO4 (325.15): C, 51.71; H, 4.03.
found: C, 51.61; H, 4.09.
2-[(2-Bromo-5-fluorophenyl)methyl]-3-hydroxy-2-cyclohexen-1-
one (11n). According to general procedure II, 1,3-cyclohexanedione
(8a) (224 mg, 2 mmol) was dissolved in aqueous NaOH (80 mg, 1 M,
2 mL) at 0 °C. 1-Bromo-4-fluorobenzylbromide (1f) (804 mg,
3 mmol) was added, and the mixture was heated at 100 °C for 3 h.
The crude product was recrystallized from dichloromethane/methanol
(1:1) to afford 2-[(2-bromo-5-fluorophenyl)methyl]-3-hydroxy-2-
cyclohexen-1-one (11n) as a white solid in 67% yield (400 mg, 1.34
mmol): mp 199−200 °C (dichloromethane/methanol); Rf = 0.14
(petroleum ether/EtOAc = 6:4); IR (ATR) ν 3126 (w) (O−H), 1590,
1372, 1257, 1187, 1006, 800, 749, 692 (C−Br) cm−1; UV (CH3CN)
5-Bromo-6-bromomethylbenzo[1,3]dioxole (1e).20 A round-bottomed
flask was charged with piperonyl alcohol (15.0 g, 98.7 mmol) and
1
λmax (log ε) 251 (4.13) nm; H NMR (300 MHz, CD3OD) δ 2.05
(quin, 3J (4-H, 5-H) = 6.6 Hz, 3J (5-H, 6-H) = 6.6 Hz, 2H, 5-H), 2.52
(t, 3J (5-H, 6-H) = 6.5 Hz, 3J (4-H, 5-H) = 6.5 Hz, 4H, 6-H and 4-H),
3.62 (s, 2H, CH2), 6.68 (br d, 4J (4′-H, 6′-H) = 3.0 Hz, 3J (5′-H, 6′-F) =
acetic acid (30 mL). After cooling to 0 °C, a mixture of bromine
(2.0 mL, 116.4 mmol) and acetic acid (15 mL) was added slowly. The
reaction mixture was stirred at room temperature for 10 h. The
precipitate was filtered, washed with distilled water, and dried in vacuo
to afford the crude product. Recrystallization from methanol delivered
5-bromo-6-bromomethylbenzo[1,3]dioxole (1e) as a white solid in
86% yield (25 g, 85 mmol): mp 92−93 °C (methanol) (lit.20 mp
3
3
10.1 Hz, 1H, 6′-H), 6.80 (br ddd, J (3′-H, 4′-H) = 8.2 Hz, J (4′-H,
5′-F) = 8.2 Hz, 1H, 4′-H), 7.51 (dd, 3J (3′-H, 4′-H) = 8.8 Hz, 4J (3′-H,
5′-F) = 5.6 Hz, 1H, 3′-H); 13C NMR (75 MHz, CD3OD) δ 22.1 (C-
2
5), 29.4 (CH ), 2 × 33.9 (C-4 and C-6), 113.7 (C-2), 115.1 (d, J
2
2
1
(C−F) = 23.0 Hz, C-4′), 116.5 (d, J (C−F) = 23.7 Hz, C-6′), 119.9
91.5−92.5 °C); H NMR (300 MHz, CDCl3) δ 4.55 (s, 2H, 8-H),
4
3
5.99 (s, 2H, 2-H), 6.91 (s, 1H, 4-H), 7.01 (s, 1H, 7-H); 13C NMR (75
MHz, CDCl3) δ 34.1 (C-8), 102.1 (C-2), 110.5 (C-4), 113.1 (C-7),
115.6 (C-5), 129.9 (C-6), 147.6 (C-7a), 148.7 (C-3a).
(d, J (C−F) = 3.0 Hz, C-2′), 134.6 (d, J (C−F) = 8.2 Hz, C-3′),
143.9 (d, 3J (C−F) = 7.2 Hz, C-1′), 163.7 (d, 1J (C−F) = 243.5 Hz, C-
5′), 2 × 189.5 (C-1 and C-3); Anal. Calcd for C13H12BrFO2(299.14):
C, 52.20; H, 4.04. found: C, 52.01; H, 4.10.
General Procedure III for the CuCl-Catalyzed Domino
Reaction. A dry 10 mL vial was equipped with a magnetic stir bar,
charged with the 2-[(2-haloaryl)methyl]-3-hydroxy-2-cyclic-1-one
derivative 11 (1 mmol), CuCl (0.495 mg, 0.005 mmol), Cs2CO3
(326 mg, 1 mmol), and pivalic acid (123 mg, 1.2 mmol), and sealed.
The sealed tube was evacuated and backfilled with argon two times.
Then, freshly distilled DMF (2 mL) was added, and the reaction
mixture was stirred at 130 °C for 7 h. After cooling to room tem-
perature, the reaction mixture was diluted with water (15 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The
crude product was purified by flash column chromatography over silica
gel to afford the product.
2-[(2-Bromo-5-methoxyphenyl)methyl]-3-hydroxy-2-cyclohexen-
1-one (11o). According to general procedure II, 1,3-cyclohexanedione
(8a) (560 mg, 5 mmol) was dissolved in aqueous NaOH (200 mg,
1 M, 5 mL) at 0 °C. 1-Bromo-4-methoxybenzyl bromide (1g) (2.1 g,
7.5 mmol) was added, and the mixture was heated at 100 °C for 3 h.
The crude product was recrystallized from dichloromethane/methanol
(1:1) to afford 2-[(2-bromo-5-methoxyphenyl)methyl]-3-hydroxy-2-
cyclohexen-1-one (11o) as a white solid in 50% yield (774 mg,
2.5 mmol): mp 149−150 °C (dichloromethane/methanol); Rf = 0.09
(petroleum ether/EtOAc = 6:4); IR (ATR) ν 2550 (w) (O−H), 1675
(conjugated CO), 1569, 1364, 1273, 1186, 1008, 804, 763, 680 (C−
SYNTHESIS AND CHARACTERIZATION OF
■
XANTHENONES AND RELATED COMPOUNDS
2,3,4,9-Tetrahydro-1H-xanthen-1-one (9a).12d,e Synthesis of
9a using 11a as Substrate. Method A. According to general
1
Br) cm−1; UV (CH3CN) λmax (log ε) 233 (4.15), 250 (4.15) nm; H
3
3
NMR (300 MHz, CD3OD) δ 2.05 (quin, J (4-H, 5-H) = 6.6 Hz, J
(5-H, 6-H) = 6.6 Hz, 2H, 5-H), 2.51 (t-like, 3J (4-H, 5-H) = 6.6 Hz, 3J
(5-H, 6-H) = 6.6 Hz, 4H, 4-H and 6-H), 3.59 (s, 2H, CH2), 3.70 (s,
4
3H, OMe), 6.51 (dd, J (4′-H, 6′-H) = 3.0 Hz, 1H, 6′-H), 6.62 (dd,
10206
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procedure III, 11a (281 mg, 1.0 mmol), CuCl (0.495 mg, 0.5 mol %),
Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg, 1.2 mmol)
were reacted in a sealed tube under argon at 130 °C for 7 h. Column
chromatography over silica gel (petroleum ether/EtOAc = 8:2)
afforded 2,3,4,9-tetrahydro-1H-xanthen-1-one (9a) as a white solid in
95% yield (190 mg, 0.95 mmol).
3,3-Dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9c).12c,e Ac-
cording to general procedure III, 11e (309 mg, 1.0 mmol), CuCl
Method B. 11a (281 mg, 1.0 mmol), CuCl (0.495 mg, 0.5 mol %),
and cesium pivalate (585 mg, 2.5 mmol) were reacted in a sealed
tube under argon at 130 °C for 7 h. Column chromatography over
silica gel (petroleum ether/EtOAc = 8:2) afforded 2,3,4,9-tetrahydro-
1H-xanthen-1-one (9a) as a white solid in 94% yield (188 mg,
0.94 mmol).
Synthesis of 9a Using 11b as Substrate. According to general
procedure III, 11b (237 mg, 1.0 mmol), CuCl (0.495 mg, 0.5 mol %),
Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg, 1.2 mmol)
were reacted in a sealed tube under argon at 130 °C for 7 h. Column
chromatography over silica gel (petroleum ether/EtOAc = 8:2)
afforded 2,3,4,9-tetrahydro-1H-xanthen-1-one (9a) as a white solid in
13% yield (25 mg, 0.13 mmol) and 2-[(2′-chlorophenyl)methyl]-3-
hydroxy-2-cyclohexen-1-one (11b) as white solid in 68% (161 mg,
0.68 mmol) was reisolated.
(0.495 mg, 0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid
(123 mg, 1.2 mmol) were reacted in a sealed tube under argon at
130 °C for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 9:1) afforded 3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-
one (9c) as a white solid in 98% yield (224 mg, 0.98 mmol): mp 95−
96 °C (lit.12e mp 96−97.5 °C); Rf = 0.84 (petroleum ether/EtOAc =
1
1:1); H NMR (300 MHz, CDCl3) δ 1.12 (s, 6H, 2 × CH3), 2.33 (s,
2H, 2-H), 2.43 (s, 2H, 4-H), 3.52 (s, 2H, 9-H), 6.95 (dd, 3J (5-H, 6-H) =
7.8 Hz, 1H, 5-H), 7.06 (ddd, 3J (6-H, 7-H) = 6.6 Hz, 3J (7-H, 8-H) =
7.5 Hz, 1H, 7-H), 7.16 (ddd, 3J (5-H, 6-H) = 6.3 Hz, 3J (6-H, 7-H) =
3
7.2 Hz, J (7-H, 8-H) = 7.2 Hz, 2H, 6-H and 8-H); 13C NMR (75
MHz, CDCl3) δ 21.0 (C-9), 2 × 28.4 (2 × CH3), 32.1 (C-3), 41.5 (C-
4), 50.6 (C-2), 108.7 (C-9a), 116.4 (C-5), 120.8 (C-8a), 124.6 (C-7),
127.6 (C-6), 129.7 (C-8), 149.9 (C-10a), 165.1 (C-4a), 197.9 (C-1);
MS (EI, 70 eV) m/z (%) 228 (100) [M]+, 213 (31) [228 − CH3]+,
185 (20) [213 − C2H4]+, 171 (16) [185 − CH2]+, 144 (29), 115 (15),
28 (14).
Synthesis of 9a Using 11c as Substrate. According to general
procedure III, 11c (328 mg, 1.0 mmol), CuCl (0.495 mg, 0.5 mol %),
Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg, 1.2 mmol)
were reacted in a sealed tube under argon at 130 °C for 7 h. Column
chromatography over silica gel (petroleum ether/EtOAc = 8:2)
afforded 2,3,4,9-tetrahydro-1H-xanthen-1-one (9a) as a white solid in
88% yield (175 mg, 0.88 mmol) and 2-[(2′-iodophenyl)methyl]-3-
hydroxy-2-cyclohexen-1-one (11c) as white solid in 5% (16 mg,
0.05 mmol) was reisolated.
3-Isopropyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9d). According
to general procedure III, 11f (323 mg, 1.0 mmol), CuCl (0.495 mg,
mp 92−93 °C (lit.12e mp 90.5−91.5 °C); Rf = 0.49 (petroleum
ether/EtOAc = 1:1); IR (ATR) ν 1637 (s) (CO), 1582, 1454, 1387,
1233, 1183, 1132, 993, 759 cm−1; UV (CH3CN) λmax (log ε) 282
1
3
(3.91) nm; H NMR (300 MHz, CDCl3) δ 2.05 (tt, J (2-H, 3-H) =
6.6 Hz, 3J (3-H, 4-H) = 6.6 Hz, 2H, 3-H), 2.46 (t-like, 3J (2-H, 3-H) =
6.6 Hz, 2H, 2-H), 2.55−2.59 (m, 2H, 4-H), 3.52 (s, 2H, 9-H), 6.95 (d-
like, 3J (5-H, 6-H) = 7.8 Hz, 1H, 5-H), 7.05 (ddd, 4J (5-H, 7-H) = 1.3
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
1.2 mmol) were reacted in a sealed tube under argon at 130 °C for 7 h.
Column chromatography over silica gel (petroleum ether/EtOAc =
9:1) afforded 3-isopropyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9d) as
a white solid in 99% yield (240 mg, 0.99 mmol): mp 74−75 °C; Rf =
0.62 (petroleum ether/EtOAc = 1:1); IR (ATR) ν 1642 (vs) (CO),
1491, 1387, 1226, 1196, 1153, 1137, 761, 661 cm−1; UV (CH3CN)
λmax (log ε) 290 (3.69) nm; 1H NMR (300 MHz, CDCl3) δ 0.96 (dd,
3
3
Hz, J (6-H, 7-H) = 6.6 Hz, J (7-H, 8-H) = 7.5 Hz, 1H, 7-H), 7.15
(partially overlapped, 2H, 6-H and 8-H); 13C NMR (75 MHz, CDCl3)
δ 20.6 (C-3), 21.1 (C-9), 27.7 (C-4), 36.6 (C-2), 110.0 (C-9a), 116.3
(C-5), 120.8 (C-8a), 124.5 (C-7), 127.5 (C-6), 129.6 (C-8), 149.7 (C-10a),
166.8 (C-4a), 198.0 (C-1); MS (EI, 70 eV) m/z (%) 200 (100) [M]+, 172
(12) [200 − C2H4]+, 144 (54) [172 − CO]+, 115 (20), 28 (20).
3-Methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9b). According to
general procedure III, 11d (295 mg, 1.0 mmol), CuCl (0.495 mg,
4
3J (1′-H, CH ) = 4.2 Hz, J (2′-H, 3-H) = 2.7 Hz, 4J (CH , CH3) =
3
3
2.4 Hz, 6H, 2 × CH3), 1.59−1.69 (m, 1H, 1′-H), 1.91−1.99 (m, 1H,
3-H), 2.11−2.21 (m, 1H, 2-Hb), 2.31−2.40 (m, 1H, 4-Hb), 2.51−2.61
(m, 2H, 2-Ha and 4-Ha), 3.45 (d, J (9-Ha, 9-Hb) = 19.8 Hz, 1H, 9-
2
2
3
Hb), 3.54 (d, J (9-Ha, 9-Hb) = 19.8 Hz, 1H, 9-Ha), 6.95 (d-like, J
(5-H, 6-H) = 8.1 Hz, 1H, 5-H), 7.05 (ddd, 3J (6-H, 7-H) = 6.3 Hz, 3J
(7-H, 8-H) = 7.5 Hz, 4J (5-H, 7-H) = 2.1 Hz, 1H, 7-H), 7.15 (partially
overlapped, 2H, 6-H and 8-H); 13C NMR (75 MHz, CDCl3) δ 19.5
(CH3), 19.6 (CH3), 21.2 (C-9), 31.6 (C-4), 32.0 (C-1′), 39.5 (C-3),
40.8 (C-2), 109.5 (C-9a), 116.4 (C-5), 120.8 (C-8a), 124.6 (C-7),
127.6 (C-6), 129.7 (C-8), 149.9 (C-10a), 166.8 (C-4a), 198.4 (C-1);
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
1.2 mmol) were reacted in a sealed tube under argon at 130 °C for 7 h.
Column chromatography over silica gel (petroleum ether/EtOAc =
8:2) afforded 3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9b) as a
white solid in 92% yield (197 mg, 0.92 mmol): mp 97−98 °C; Rf =
0.54 (petroleum ether/EtOAc = 1:1); IR (ATR) ν 1637 (vs) (CO),
1581, 1393, 1235, 1133, 1013, 758, 658 cm−1; UV (CH3CN) λmax (log
ε) 294 (3.32) nm; 1H NMR (300 MHz, CDCl3) δ 1.12 (d, 3J (1′-H, 3-
H) = 6.0 Hz, 3H, 1′-H), 2.09−2.19 (m, 1H, 2-Hb), 2.24−2.34 (m, 2H,
3-H and 4-Hb), 2.50−2.59 (m, 2H, 2-Ha and 4-Ha), 3.49 (d, 2J (9-Ha,
9-Hb) = 19.8 Hz, 1H, 9-Hb), 3.51 (d, 2J (9-Ha, 9-Hb) = 19.8 Hz, 1H,
9-Ha), 6.95 (d-like, 3J (5-H, 6-H) = 7.8 Hz, 1H, 5-H), 7.04 (ddd, 4J (5-
H, 7-H) = 1.8 Hz, 3J (6-H, 7-H) = 5.7 Hz, 3J (7-H, 8-H) = 6.3 Hz, 1H,
7-H), 7.15 (partially overlapped, 2H, 6-H and 8-H); 13C NMR (75
MHz, CDCl3) δ 21.0 (C-1′), 21.1 (C-9), 28.3 (C-3), 35.7 (C-4), 45.0
(C-2), 109.5 (C-9a), 116.4 (C-5), 120.8 (C-8a), 124.5 (C-7), 127.5
(C-6), 129.7 (C-8), 149.8 (C-10a), 166.2 (C-4a), 198.0 (C-1); MS
(EI, 70 eV) m/z (%) 214 (100) [M]+, 199 (18) [214 − CH3]+, 172
(28) [199 − C2H3]+, 144 (76) [172 − CO]+, 115 (35), 28 (16);
HRMS (EI, M+) calcd for C14H14O2 (214.0994), found 214.0984.
MS (EI, 70 eV) m/z (%) 242 (100) [M]+, 199 (28) [242 − C3H ]+,
7
173 (10), 144 (17), 115 (10); HRMS (EI, M+) calcd for C16H18O2
(242.1306), found 242.1307.
3-Phenyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9e). According to
general procedure III, 11g (357 mg, 1.0 mmol), CuCl (0.495 mg,
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
1.2 mmol) were reacted in a sealed tube under argon at 130 °C for
7 h. Column chromatography over silica gel (petroleum ether/EtOAc =
9:1) afforded 3-phenyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9e) as a
white solid in 91% yield (251 mg, 0.91 mmol): mp 108−109 °C;
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Rf = 0.68 (petroleum ether/EtOAc = 1:1); IR (ATR) ν 1639 (vs)
(CO), 1456, 1392, 1227, 1128, 877, 756, 699 cm−1; UV (CH3CN)
λmax (log ε) 295 (3.35) nm; 1H NMR (300 MHz, CDCl3) δ 2.68 (dd,
3J (2-Hb, 3-H) = 12.2 Hz, 2J (2-Ha, 2-Hb) = 16.0 Hz, 1H, 2-Hb), 2.79
(m, 1H, 3-H), 3.51 (d, 2J (9-Ha, 9-Hb) = 19.6 Hz, 1H, 9-Hb), 3.60 (d,
2J (9-Ha, 9-Hb) = 19.6 Hz, 1H, 9-Ha), 3.81 (s, 3H, -OCH3), 6.89−
4
6.92 (m, 2H, 3′-H and 5′-H), 6.95−6.98 (m, 1H, 5-H), 7.07 (ddd, J
(5-H, 7-H) = 1.4 Hz, 3J (6-H, 7-H) = 7.0 Hz, 3J (7-H, 8-H) = 7.9 Hz,
1H, 7-H), 7.15−7.18 (overlapped, 2H, 6-H and 8-H), 7.15−7.21 (m,
2H, 2′-H and 6′-H); 13C NMR (75 MHz, CDCl3) δ 21.2 (C-9), 35.5
(C-4), 38.0 (C-3), 44.0 (C-2), 55.3 (−OCH3), 109.8 (C-9a), 2 ×
114.1 (C-3′ and C-5′), 116.5 (C-5), 120.7 (C-8a), 124.7 (C-7), 3 ×
127.6 (C-6, C-2′ and C-6′), 129.7 (C-8), 134.6 (C-1′), 149.8 (C-10a),
158.6 (C-4′), 165.9 (C-4a), 197.2 (C-1); MS (EI, 70 eV) m/z (%) 306
(100) [M]+, 185 (36) [306 − C8H9O]+, 172 (13), 144 (41), 115 (12),
28 (23); HRMS (EI, M+) calcd for C20H18O3 (306.1256), found
306.1265.
3
2
(dd, J (2-Ha, 3-H) = 4.8 Hz, J (2-Ha, 2-Hb) = 16.0 Hz, 1H, 2-Ha),
2
2.79−2.85 (m, 2H, 4-H), 3.39−3.52 (m, 1H, 3-H), 3.53 (d, J (9-Ha,
9-Hb) = 20.0 Hz, 1H, 9-Hb), 3.61 (d, 2J (9-Ha, 9-Hb) = 20.0 Hz, 1H,
9-Ha), 6.95−7.00 (m, 1H, 5-H), 7.08 (ddd, 3J (6-H, 7-H) = 7.2 Hz, 3J
(7-H, 8-H) = 6.6 Hz, 1H, 7-H), 7.16−7.21 (m, 2H, 6-H and 8-H),
7.25−7.32 (overlapped, 3H, 2′-H, 4′-H, and 6′-H), 7.34−7.42 (m, 2H,
3′-H and 5′-H); 13C NMR (75 MHz, CDCl3) δ 21.2 (C-9), 35.2 (C-
4), 38.7 (C-3), 43.7 (C-2), 109.8 (C-9a), 116.5 (C-5), 120.7 (C-8a),
124.7 (C-7), 2 × 126.7 (C-2′ and C-6′), 127.1 (C-4′), 127.6 (C-6), 2
× 128.8 (C-3′ and C-5′), 129.7 (C-8), 142.5 (C-1′), 149.8 (C-10a),
165.9 (C-4a), 197.1 (C-1); MS (EI, 70 eV) m/z (%) 276 (100) [M]+,
185 (46) [276 − C7H7]+, 158 (18), 144 (30), 115 (16), 28 (5);
HRMS (EI, M+) calcd for C19H16O2 (276.1150), found 276.1165.
3-(4′-Chlorophenyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one (9f).
According to general procedure III, 11h (392 mg, 1.0 mmol), CuCl
3-(Furan-2′-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one (9h). Ac-
cording to general procedure III, 11j (347 mg, 1.0 mmol), CuCl
(0.495 mg, 0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid
(123 mg, 1.2 mmol) were reacted in a sealed tube under argon at 130 °C
for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 9:1) afforded 3-(furan-2′-yl)-2,3,4,9-tetrahydro-1H-xanthen-
1-one (9h) as a white solid in 87% yield (231 mg, 0.87 mmol): mp
113−114 °C; Rf = 0.63 (petroleum ether/EtOAc = 1:1); IR (ATR) ν
1637 (s) (CO), 1490, 1394, 1233, 1176, 1127, 990, 759 cm−1; UV
(CH3CN) λmax (log ε) 292 (3.64) nm; 1H NMR (300 MHz, CDCl3) δ
2.65 (dd, 3J (2-Hb, 3-H) = 11.1 Hz, 2J (2-Ha, 2-Hb) = 16.4 Hz, 1H, 2-
Hb), 2.83 (overlapping, 1H, 2-Ha), 2.77−2.95 (m, 2H, 4-H), 3.49 (d,
2J (9-Ha, 9-Hb) = 20.0 Hz, 1H, 9-Hb), 3.46−3.60 (m, 1H, 3-H), 3.58
(0.495 mg, 0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid
(123 mg, 1.2 mmol) were reacted in a sealed tube under argon at 130 °C
for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 9:1) afforded 3-(4′-chlorophenyl)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (9f) as a brown solid in 93% yield (288 mg, 0.93
mmol): mp 130−132 °C; Rf = 0.61 (petroleum ether/EtOAc = 1:1);
IR (ATR) ν 1639 (s) (CO), 1489, 1391, 1223, 1127, 1013, 820, 760
3
(d, 2J (9-Ha, 9-Hb) = 20.0 Hz, 1H, 9-Ha), 6.10 (dt, J (3′-H, 4′-H) =
3.2 Hz, 4J (3′-H, 5′-H) = 0.8 Hz, 1H, 3′-H), 6.31 (dd, 3J (3′-H, 4′-H) =
3.2 Hz, 3J (4′-H, 5′-H) = 1.8 Hz, 1H, 4′-H), 6.97 (dd, 3J (5-H, 6-H) =
7.8 Hz,1H, 5-H), 7.04−7.09 (m, 1H, 7-H), 7.14−7.19 (m, 2H, 6-H
and 8-H), 7.36 (dd, 3J (4′-H, 5′-H) = 1.8 Hz, 4J (3′-H, 5′-H) = 0.7 Hz,
1H, 5′-H); 13C NMR (75 MHz, CDCl3) δ 21.1 (C-9), 32.2 (C-3),
32.4 (C-4), 40.9 (C-2), 104.8 (C-3′), 109.9 (C-9a), 110.1 (C-4′),
116.4 (C-5), 120.6 (C-8a), 124.7 (C-7), 127.6 (C-6), 129.7 (C-8),
141.7 (C-5′), 149.7 (C-10a), 155.7 (C-2′), 165.1 (C-4a), 196.2 (C-1);
MS (EI, 70 eV) m/z (%) 266 (100) [M]+, 185 (24) [266 − C5H5O]+,
158 (11), 144 (47), 115 (29), 28 (8); HRMS (EI, M+) calcd for
C17H14O3 (266.0943), found 266.0944.
1
cm−1; UV (CH3CN) λmax (log ε) = 292 (3.67) nm; H NMR (300
MHz, CDCl3) δ 2.63 (dd, 3J (2-Hb, 3-H) = 12.3 Hz, 2J (2-Ha, 2-Hb) =
3
2
16.0 Hz, 1H, 2-Hb), 2.74 (dd, J (2-Ha, 3-H) = 4.6 Hz, J (2-Ha, 2-
Hb) = 16.0 Hz, 1H, 2-Ha), 2.74−2.79 (m, 2H, 4-H), 3.37−3.48 (m,
2
2
1H, 3-H), 3.51 (d, J (9-Ha, 9-Hb) = 19.8 Hz, 1H, 9-Hb), 3.60 (d, J
(9-Ha, 9-Hb) = 19.8 Hz, 1H, 9-Ha), 6.94−6.99 (m, 1H, 5-H), 7.08
(ddd, 4J (5-H, 7-H) = 0.9 Hz, 3J (6-H, 7-H) = 7.2 Hz, 3J (7-H, 8-H) =
6.6 Hz, 1H, 7-H), 7.15−7.19 (overlapped, 2H, 6-H and 8-H), 7.15−
7.22 (m, 2H, 2′-H and 6′-H), 7.30−7.36 (m, 2H, 3′-H and 5′-H); 13C
NMR (75 MHz, CDCl3) δ 21.2 (C-9), 35.1 (C-4), 38.1 (C-3), 43.6
(C-2), 109.9 (C-9a), 116.5 (C-5), 120.6 (C-8a), 124.8 (C-7), 127.7
(C-6), 2 × 128.0 (C-2′ and C-6′), 2 × 128.9 (C-3′ and C-5′), 129.7
(C-8), 132.8 (C-4′), 140.9 (C-1′), 149.7 (C-10a), 165.6 (C-4a), 196.6
(C-1); MS (EI, 70 eV) m/z (%) 310 (100) [M]+, 185 (61) [310 −
C7H6Cl]+, 158 (29), 144 (45), 115 (24), 32 (19), 28 (78); HRMS (EI,
M+) calcd for C19H15ClO2 (310.0761), found 310.0767.
2,3-Dihydrocyclopenta[b]chromen-1(9H)-one (9i).12c,e According
to general procedure III, 11k (267 mg, 1.0 mmol), CuCl (0.495 mg,
3-(4′-Methoxyphenyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one
(9g). According to general procedure III, 11i (387 mg, 1.0 mmol),
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
1.2 mmol) were reacted in a sealed tube under atmosphere at 130 °C
for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 7:3) afforded 2,3-dihydrocyclopenta[b]chromen-1(9H)-one
(9i) as a white solid in 54% yield (100 mg, 0.54 mmol): mp 195−
196 °C (lit.12e mp 195−197 °C); Rf = 0.34 (petroleum ether/EtOAc =
1
CuCl (0.495 mg, 0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic
acid (123 mg, 1.2 mmol) were reacted in a sealed tube under argon at
130 °C for 7 h. Column chromatography over silica gel (petroleum
ether/EtOAc = 8:2) afforded 3-(4′-methoxyphenyl)-2,3,4,9-tetrahy-
dro-1H-xanthen-1-one (9g) as a white solid in 95% yield (292 mg,
0.95 mmol): mp 179−181 °C; Rf = 0.56 (petroleum ether/EtOAc =
1:1); IR (ATR) ν 1637 (s) (CO), 1513, 1391, 1249, 1229, 1030,
1:1); H NMR (300 MHz, CDCl3) δ 2.51−2.54 (m, 2H, 2-H), 2.70−
2.73 (m, 2H, 3-H), 3.50 (s, 2H, 9-H), 7.04 (dd, 3J (5-H, 6-H) = 8.1 Hz,
1H, 5-H), 7.09 (ddd, 3J (6-H, 7-H) = 6.6 Hz, 3J (7-H, 8-H) =
8.1 Hz, 1H, 7-H), 7.16−7.22 (m, 2H, 6-H and 8-H); 13C NMR (75 MHz,
CDCl3) δ 20.8 (C-9), 25.8 (C-3), 33.3 (C-2), 114.2 (C-9a), 117.2 (C-5),
119.6 (C-8a), 125.1 (C-7), 128.0 (C-6), 130.4 (C-8), 150.8 (C-4a), 179.2
(C-3a), 203.4 (C-1); MS (EI, 70 eV) m/z (%) 186 (84) [M]+, 158 (24)
[186 − C2H4]+, 128 (13), 44 (54), 28 (100).
1
826, 757 cm−1; UV (CH3CN) λmax (log ε) 291 (3.63) nm; H NMR
(300 MHz, CDCl3) δ 2.62 (dd, 3J (2-Hb, 3-H) = 12.5 Hz, 2J (2-Ha, 2-
10,11-Dihydro-7H-benzo[c]xanthen-8(9H)-one (9j). According to
general procedure III, 11l (331 mg, 1.0 mmol), CuCl (0.495 mg,
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
3
2
Hb) = 16.4 Hz, 1H, 2-Hb), 2.75 (dd, J (2-Ha, 3-H) = 4.4 Hz, J (2-
Ha, 2-Hb) = 16.4 Hz, 1H, 2-Ha), 2.72−2.79 (m, 2H, 4-H), 3.33−3.46
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Article
(75 MHz, CDCl3) δ 20.5 (C-3), 21.5 (C-9), 27.6 (C-4), 36.6 (C-2),
109.0 (C-9a), 114.3 (d, 2J (C−F) = 23.7 Hz, C-6), 115.6 (d, 2J (C−F) =
23.0 Hz, C-8), 117.6 (d, 3J (C−F) = 8.7 Hz, C-5), 122.5 (d, 3J (C−F) =
8.1 Hz, C-8a), 145.8 (d, 4J (C−F) = 2.5 Hz, C-10a), 159.1 (d, 1J (C−F) =
243.0 Hz, C-7), 166.7 (C-4a), 197.8 (C-1); MS (EI, 70 eV) m/z (%)
218 (100) [M]+, 190 (19) [218 − C2H4]+, 162 (46) [190 − CO]+, 133
(26), 28 (9); HRMS (EI, M+) calcd for C13H11FO2 (218.0743), found
218.0742.
1.2 mmol) were reacted in a sealed tube under argon at 130 °C for 7 h.
Column chromatography over silica gel (petroleum ether/EtOAc =
8:2) afforded 10,11-dihydro-7H-benzo[c]xanthen-8-(9H)-one (9j) as a
white solid in 83% yield (207 mg, 0.83 mmol): mp 160−161 °C; Rf =
0.49 (petroleum ether/EtOAc = 1:1); IR (ATR) ν 1645 (s) (CO),
1599, 1379, 1216, 1179, 1129, 1016, 807, 777, 744 cm−1; UV
(CH3CN) λmax (log ε) 223 (4.69), 227 (4.69), 232 (4.64), 264 (3.67),
7-Methoxy-2,3,4,9-tetrahydro-1H-xanthen-1-one (9m). According to
general procedure III, 11o (311 mg, 1.0 mmol), CuCl (0.495 mg,
1
3
312 (3.82) nm; H NMR (300 MHz, CDCl3) δ 2.11 (tt, J (9-H, 10-
H) = 6.3 Hz, 3J (10-H, 11-H) = 6.6 Hz, 2H, 10-H), 2.50 (t-like, 3J (9-
H, 10-H) = 6.3 Hz, 2H, 9-H), 2.66−2.70 (m, 2H, 11-H), 3.65 (br s,
3
2H, 7-H), 7.19 (d-like, J (5-H, 6-H) = 8.4 Hz, 1H, 6-H), 7.45−7.55
0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid (123 mg,
1.2 mmol) were reacted in a sealed tube under argon at 130 °C
for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 8:2) afforded 7-methoxy-2,3,4,9-tetrahydro-1H-xanthen-1-
one (9m) as a white solid in 88% yield (203 mg, 0.88 mmol): mp
113−115 °C; Rf = 0.42 (petroleum ether/EtOAc = 1:1); IR (ATR) ν
1636 (s) (CO), 1495, 1386, 1219, 1181, 1130, 1034, 997, 868, 813
cm−1; UV (CH3CN) λmax (log ε) 285 (4.08) nm; 1H NMR (300 MHz,
CDCl3) δ 2.04 (tt, 3J (3-H, 4-H) = 6.3 Hz, 3J (2-H, 3-H) = 6.6 Hz, 2H,
(overlapped, 3H, 2-H, 3-H and 5-H), 7.78 (dd, 3J (3-H, 4-H) = 7.2 Hz,
4J (2-H, 4-H) = 1.5 Hz, 1H, 4-H), 8.15 (d, 3J (1-H, 2-H) = 7.8 Hz, 1H,
1-H); 13C NMR (75 MHz, CDCl3) δ 20.6 (C-10), 21.7 (C-7), 27.6
(C-11), 36.7 (C-9), 110.2 (C-7a), 115.5 (C-12b), 120.7 (C-1), 123.6
(C-6a), 124.0 (C-2), 126.0 (C-3), 126.2 (C-5), 126.9 (C-6), 127.6 (C-
4), 133.2 (C-4a), 144.2 (C-12a), 166.6 (C-11a), 198.1 (C-8); MS (EI,
70 eV) m/z (%) 250 (100) [M]+, 233 (7), 194 (22), 165 (16); HRMS
(EI, M+) calcd for C17H14O2 (250.0994), found 250.1014.
3
2,3-Dihydro-4H-[1,3]dioxolo[4,5-b]xanthen-1(7H)-one (9k). Ac-
cording to general procedure III, 11m (325 mg, 1.0 mmol), CuCl
3-H), 2.44 (t-like, J (2-H, 3-H) = 6.9 Hz, 2H, 2-H), 2.51−2.56 (m,
2H, 4-H), 3.47 (s, 2H, 9-H), 3.76 (s, 3H, -OCH3), 6.64 (br d, 4J (6-H,
8-H) = 2.7 Hz, 1H, 8-H), 6.69 (overlapped, 1H, 6-H), 6.88 (dd, 3J (5-
H, 6-H) = 8.7 Hz, 1H, 5-H); 13C NMR (75 MHz, CDCl3) δ 20.6 (C-
3), 21.6 (C-9), 27.7 (C-4), 36.6 (C-2), 55.5 (−OCH3), 109.1 (C-9a),
113.3 (C-6), 113.7 (C-8), 117.2 (C-5), 121.6 (C-8a), 143.8 (C-10a),
156.2 (C-7), 166.9 (C-4a), 198.0 (C-1); MS (EI, 70 eV) m/z (%) 230
(100) [M]+, 202 (8) [230 − C2H4]+, 174 (30) [202 − CO]+, 159 (10)
[174 − CH3]+, 28 (7); HRMS (EI, M+) calcd for C14H14O3
(230.0943), found 230.0927.
(0.495 mg, 0.5 mol %), Cs2CO3 (326 mg, 1.0 mmol), and pivalic acid
(123 mg, 1.2 mmol) were reacted in a sealed tube under argon at
130 °C for 7 h. Column chromatography over silica gel (petroleum ether/
EtOAc = 8:2) afforded 2,3-dihydro-4H-[1,3]dioxolo[4,5-b]xanthen-
1(7H)-one (9k) as a buff colored solid in 85% yield (208 mg, 0.85
mmol): mp 162−164 °C; Rf = 0.42 (petroleum ether/EtOAc = 1:1); IR
(ATR) ν 1645 (s) (CO), 1502, 1385, 1215, 1179, 1136, 1027, 999,
926, 853, 764 cm−1; UV (CH3CN) λmax (log ε) 306 (3.82) nm; 1H NMR
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
3
(300 MHz, CDCl3) δ 2.06 (tt, J (2-H, 3-H) = 6.3 Hz, 3J (3-H, 4-H) =
6.6 Hz, 2H, 3-H), 2.45 (t-like, 3J (2-H, 3-H) = 6.9 Hz, 2H, 2-H), 2.50−
2.54 (m, 2H, 4-H), 3.41 (s, 2H, 7-H), 5.92 (s, 2H, 2′-H), 6.49 (s, 1H, 5-
H), 6.56 (s, 1H, 6-H); 13C NMR (75 MHz, CDCl3) δ 20.6 (C-3), 21.5
(C-7), 27.6 (C-4), 36.7 (C-2), 98.3 (C-5), 101.3 (C-2′), 108.0 (C-6),
109.4 (C-7a), 112.7 (C-6a), 144.0 (C-8a), 144.4 (C-5b), 146.6 (C-5a),
166.6 (C-4a), 198.0 (C-1); MS (EI, 70 eV) m/z (%) 243 (100) [M]+,
227 (8) [243 − O]+, 201 (5), 188 (25), 28 (7); HRMS (EI, M+) calcd for
C14H12O4 (244.0736), found 244.0742.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ubeifuss@uni-hohenheim.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
7-Fluoro-2,3,4,9-tetrahydro-1H-xanthen-1-one (9l). According
to general procedure III, 11n (299 mg, 1.0 mmol), CuCl (0.495 mg,
We thank Ms. Sabine Mika for recording of NMR spectra and
Dipl.-Chem. Hans-Georg Imrich and Dr. Alevtina Baskakova
for recording of mass spectra.
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1
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