Synthesis of functionalized chromones via organocatalysis

Article abstract of DOI:10.1016/j.tet.2014.10.045

A facile and versatile organocatalytic approach to access 2-substituted and 2,3-disubstituted chromone derivatives under mild conditions was developed, which was effectively catalyzed by novel proline phenylsulphonylhydrazide or pyrrolidine. As a result, diversely functionalized chromones were obtained in up to 99% yield. In addition, further modification of the corresponding chromones afforded novel polycyclic chromones.

Full text of DOI:10.1016/j.tet.2014.10.045

Tetrahedron 70 (2014) 9314e9320
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized chromones via organocatalysis
*
Sai-Shuai Wen, Jing Wang, Yi-Ming Luo, Hua Yang
College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and versatile organocatalytic approach to access 2-substituted and 2,3-disubstituted chromone
derivatives under mild conditions was developed, which was effectively catalyzed by novel proline
phenylsulphonylhydrazide or pyrrolidine. As a result, diversely functionalized chromones were obtained
in up to 99% yield. In addition, further modification of the corresponding chromones afforded novel
polycyclic chromones.
Received 6 September 2014
Received in revised form 14 October 2014
Accepted 20 October 2014
Available online 23 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Chromone
Proline phenylsulphonylhydrazide
1. Introduction
Chromones are one of the most important classes of naturally
occurring heterocyclic compounds, which widely exist in nature1,2
and have been found as the secondary metabolites distributed in
plant.3 These kinds of compounds have drawn much attention in
the past decades due to their considerable biological and phar-
macological activities such as antimicrobial, antioxidant, antifungal
and anticancer properties.3e9
Until now, a large number of synthetic methods have been de-
veloped to prepare chromones and their derivatives, including
classic Claisen condensation,10e18 BakereVenkatamaran rear-
rangement,19e25 KostaneckieRobinson reaction19,23,24,26e31 and so
on (Scheme 1, Eq. a & b). Besides, other efforts involving metallic
catalysts32e35 or microwave18,36 were also made in order to secure
more efficient pathways. However, for most of the present
methods, strong bases or acids were usually used and sometimes
high temperatures were inevitable, which might lead to the un-
satisfactory yield due to the formation of side-products and severe
decomposition of starting materials.1,3 On the other hand, although
various synthetic approaches have been extensively studied, most
of these developed synthetic methods were focused on the syn-
Scheme 1. Synthetic routes of substituted chromones.
thesis of flavones (R2¼aryl group in Scheme 1).
A general
synthetic method under mild reaction conditions is highly desir-
able for preparing diversely functionalized chromones, especially
In the past decade, organocatalysis has evolved to be a versatile
and powerful tool in organic synthesis since it possesses such ad-
vantages as low cost, easy operation, insensitivity to moisture and
air, mild reaction condition, and environment-friendliness.41,42
However, this useful strategy has been rarely employed in the
synthesis of chromones. In 2002, Samant et al. found that a stoi-
chiometric amount of morphline can convert 1-(2-hydroxyphenyl)-
1,3-butanedione into 2-methylchromone when the reaction was
for
2-alkyl-substituted,
2,3-disubstituted
and
polycyclic
chromones.37e40
* Corresponding author. Tel.: þ86 731 88830833; e-mail address: hyangchem@
csu.edu.cn (H. Yang).
http://dx.doi.org/10.1016/j.tet.2014.10.045
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
9315
refluxed in ethanol;43 and very recently, Tilve and co-workers re-
ported the synthesis of flavones from aryl aldehyde and 2’-
hydroxyacetophenone by using pyrrolidine as the catalyst, iodine
as the oxidant in DMSO at high temperature (Eq. c).44 Apparently,
the organocatalytic preparation of structurally diversified chro-
mones under mild conditions still remains an unsolved problem.
Thus, our continued interest on the organocatalysis prompted us to
seek an effective solution for this everlasting problem. We envi-
sioned that the specifically designed organocatalysts with sec-
ondary amine motif might effectively activate the carbonyl group in
1,3-dioxophenoxy substrates, leading to the formation of chro-
mones under mild conditions (Scheme 1, Eq. d). Consequently,
a novel proline phenylsulphonylhydrazide was designed and pre-
pared for this conversion. It was found that proline phenyl-
sulphonylhydrazide and pyrrolidine can efficiently catalyze this
reaction complementarily. As a result, a wide range of chromones
were achieved in excellent chemical yields under quite mild con-
ditions. Furthermore, this strategy was also extended to construct
other polycyclic skeletons including tetrahydroxanthones (THXs).
catalyst loading (10 mol %) severely eroded the chemical yield of
2a (entry 8). The reaction temperature was also investigated for
this reaction and a higher temperature of 55 ꢀC can afford the
maintained yield compared with room temperature (entry 10). But
its reaction time can be significantly shortened to 12 h. It is worth
noting that an unwanted by-product was also observed at higher
temperature.45 Herein, the optimum yield of 83% was reached
with 0.2 equiv of 3 in MeOH containing 0.1 equiv of water at 55 ꢀC.
In addition, piperidine 4 and aniline 5 were also tested in this
work, and the comparatively lower yields of 69% and 37% were
obtained, respectively (entries 11e12). Prolinosulphonamide 6,
possessing the significantly improved solubilities in regular sol-
vents and versatile catalytic activities, also showed mediocre cat-
alytic activity toward this reaction with the yield of 37% (entry 13).
Ultimately,
a novel proline phenylsulphonylhydrazide 7 was
designed and prepared from the direct coupling of Boc-protected
proline and p-dodecylphenylsulphonylhydrazide followed by
deprotection. Gratifyingly, proline phenylsulphonylhydrazide 7
can effectively catalyze this reaction and provide the highest yield
of 99% under the optimized conditions despite a relatively longer
reaction time of 36 h (entry 14). Accordingly, proline phenyl-
sulphonylhydrazide 7 would be chosen as the superior organo-
catalyst for this transformation.
2. Discussion
Initially, (2-hydroxyphenyl)-1,3-butanedione 1a was chosen as
the model reaction to investigate this reaction (Table 1). We were
pleased to observe that the cyclization of diketone 1a smoothly
proceeded to afford the desired chromone 2a, which was cata-
lyzed by pyrrolidine 3. Then, different solvents were firstly eval-
uated, and the highest yield of 66% was obtained in MeOH (entries
1e4). It was also found that H2O could improve the yield when
using THF as the solvent (entries 2 and 4). So the effect of water
was also investigated (entries 5e7). As a result, the presence of
0.1 equiv of H2O provided the optimum yield of 84% (entry 5).
Next, the loading of catalyst 3 was studied. Higher catalyst loading
(40 mol %) slightly decreased the yield of 2a (entry 9) and low
With the optimal conditions in hand, scope of this reaction was
next explored (Table 2). It is worth noting that the commercial
availability and inexpensive cost of catalyst 3 necessitated its fur-
ther investigation on the substrate tolerance. Consequently, cata-
lyst 7 and 3 were subjected to the evaluation of various substrates
side by side. In general, the cyclization of alkyl-substituted sub-
strates (R1¼H, R2¼alkyl group) catalyzed by either 3 or 7 afforded
the corresponding products in good yields (2aee), no matter with
steric effects of alkyl groups. Besides, higher yields were usually
obtained by using catalyst 7, except that a comparably higher yield
was achieved for 2c catalyzed by 3. Surprisingly, a poor yield (37%)
was observed on the carboxylated substrate 2f using catalyst 3 as
the catalyst. However, the employment of 7 significantly improved
the yield to 87%. It should be noted that no matter, which catalyst
was used, yields of flavone 2g and styrylchromone 2h were rela-
tively lower due to the formation side-products and poor solubil-
ities of starting materials. Moreover, as for the di-substituted
substrates, good yields were generally achieved in widely varied
reaction times from 12 to 108 h. Again, for most of the studied
substrates, higher yields were achieved by using catalyst 7 (2k, 2l,
2m and 2n). However, quite poor yield (35%) was obtained for 2j by
employing catalyst 7. Pleasingly, using catalyst 3 afforded a satis-
factory yield (71%). It seems that catalyst 3 could serve as a bene-
ficial complement of catalyst 7 for specific substrates, although
catalyst 7 generally performed better in this reaction.
Table 1
Optimization of the reaction conditionsa
Tetrahydroxanthones (THXs) and their hydrogenated de-
rivatives are the core structure of natural products with important
biological activities. Synthetic routes for this class of compounds
are surprisingly limited and undeveloped.38,46 Accordingly, prepa-
ration of THXs via this developed methodology was also in-
vestigated. Diketone 10 was prepared in reasonable yield starting
from the aldol reaction between salicylic aldehyde 8 and cyclic
ketone 9 followed by oxidation of the resulting alcohol. Satisfyingly,
cyclizations of diketone 10aec catalyzed by 3 or 7 proceeded
smoothly to furnish the corresponding THX derivatives 11aec. In-
terestingly, only low to moderate yields were obtained using cat-
alyst 7. However, excellent yields (>95%) were achieved for the
reaction catalyzed by pyrrolidine 3 in even shorter reaction dura-
tion (Scheme 2). Presumably, the steric effect of substrate 10 might
dramatically erode the catalytic effectiveness of the more steric-
demanding catalyst 7. Apparently, this developed protocol
employing catalyst 3 could serve as an efficient pathway to prepare
this class of polycyclic chromone derivatives.
Entry
Catalyst
(mol %)
H2O (mol %)
Solvent
T
ꢀC
Time
(h)
Yield of
2ab (%)
1
2
3
4
5
6
7
8
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (10)
3 (40)
3 (20)
4 (20)
5 (20)
6 (20)
7 (20)
0
0
0
MeOH
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
55
55
55
55
55
52
36
36
36
24
24
24
24
12
12
24
24
24
36
66
30
28
42
84
81
80
51
74
83
69
37
37
99
Toluene
H2O/THF (2:1)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
d
10
20
40
10
10
10
10
10
10
10
9
10
11
12
13
14
a
Unless otherwise noted, all reactions were carried out in sealed reaction vials at
the designated temperature with diketone 1a (0.50 mmol), pyrrolidine, and addi-
tives in solvent (5 mL).
b
Isolated yields after silica gel chromatography.

9316
S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
Table 2
Synthesis of 2-substituted and 2,3-disubstituted chromone derivativesa
Scheme 3. Transformation of chromone 2n to various tricyclic ring systems.
(12) in excellent yield. Heating 12 in1,4-dioxane and H2O at reflux
for 3 h furnished 1H-furo[3,4-b]benzopyran-3,9-dione (13) in 35%
yield, which was previously synthesized as a byproduct with ex-
tremely poor yield (5% yield) in the literature.47 A reaction se-
quence on bromide 12 including substitution by sodium azide and
reduction by triphenylphosphine afforded 1,2-dihydro-[1]benzo-
pyrano[2,3-c]pyrrole-3,9-dione (14) in 55% yield. Refluxing 12 with
benzylamine exclusively gave 1,2-dihydro-2-(phenylmethyl)-[1]
benzopyrano[2,3-c]pyrrole-3,9-dione (15) in 76% yield. Since these
tricyclic chromone skeletons were rarely investigated before, these
results might open the door for further studies on these classes of
polycyclic compounds.
3. Conclusion
In summary, an efficient organocatalytic approach to access 2-
substituted and 2,3-disubstituted chromones under mild condi-
tions was accomplished, which was effectively catalyzed by the
newly designed proline phenylsulphonylhydrazide 7 or easily
available pyrrolidine. Notably, proline phenylsulphonylhydrazide 7
was prepared and employed as an organocatalyst for the first time.
As a consequence, a wide range of chromones with diverse struc-
tural features have been prepared in high yields (up to 99% yield).
Moreover, further modification of the corresponding chromones
led to the construction of novel polycyclic ring skeletons. This
versatile protocol would pave the pathway for broad application of
organocatalysis in the synthesis of chromone heterocycles.
a Unless otherwise noted, all reactions were carried out in sealed reaction vials
at 55oC with diketone 1 (0.50 mmol), organocatalyst (0.10 mmol), and
water(0.05 mmol) in MeOH (2.5 mL).
bIsolated yields after silica gel chromatography.
c 5.0 mL of MeOH was used.
d The reaction was performed at reflux.
4. Experimental section
4.1. General
Unless otherwise noted, all the reagents were purchased from
commercial suppliers and used without further purification. 1H
NMR spectra were recorded at 400 MHz. The chemical shifts were
recorded in parts per million relative to tetramethylsilane and with
the solvent resonance as the internal standard. Data were reported
as follows: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet), coupling constants (Hz), in-
tegration. 13C NMR data were collected at 100 MHz with complete
proton decoupling. Chemical shifts were reported in ppm from the
tetramethylsilane with the solvent resonance as internal standard.
Infrared spectra (IR) were measured by FTIR apparatus. High res-
olution mass spectroscopy (HRMS) was recorded on TOF MS ESþ
mass spectrometer and acetonitrile and methanol were used to
dissolve the sample. Column chromatography was carried out on
silica gel (200e300 mesh).
Scheme 2. Synthesis of tetrahydroxanthone and its derivatives.
Ultimately, efforts were directed to synthesize novel tricyclic
chromone systems via further transformations (Scheme 3). Bro-
mination of 2,3-disubstituted chromone 2n gave the corresponding
3-(bromomethyl)-4-oxo-4H-chromene-2-carboxylate methyl ester
Diketone 1a,48 1b,49 1c,50 1d,51 1e,52 1f,53 1g,54 1h,55 1i,56 and
catalyst 657 were prepared according to the reported procedures.

S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
9317
4.2. General experimental procedure for diketone (1jen)
(s, 3H), 3.43 (q, J¼6.8 Hz,1H),1.22 (d, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz, ketone form) d (ppm) 191.6,168.5,156.9,136.0,126.6,122.3,
To a solution of 20-hydroxy-3-phenylpropiophenone (2.7 g,
18 mmol) in toluene (50 mL) was added NaH (2.5 g, 63 mmol) and
the resulting mixture was stirred for 10 min at room temperature.
Then, the corresponding ester (28 mmol) was added dropwise to it.
The reaction mixture was heated at reflux for 1 h. After being
cooled to 0 ꢀC, the reaction mixture was quenched with H2O,
acidified with HCl (3 N), and extracted with ethyl acetate. The
combined organic layer was dried over anhydrous Na2SO4, con-
centrated, and purified by silica gel column chromatography using
petroleum ether/ethyl acetate (19/1 to 99/1) as the eluent to pro-
vide diketone 1.
120.5, 118.0, 100.8, 54.2, 46.0, 8.6; HRMS (TOF-ESþ) m/z: [MþNa]þ
calcd for C12H12O5Na 259.0582, found 259.0588.
4.3. General experimental procedure for the cyclization
reaction using 3 as the catalyst
A mixture of diketone 1 (0.50 mmol), pyrrolidine 3 (8.1
mL,
0.10 mmol) and water (0.9
m
L, 0.05 mmol) was heated at 55 ꢀC for
the given time. After completion of the reaction monitored by TLC,
the solvent was removed under reduced pressure. The crude mix-
ture was purified via silica gel column chromatography using pe-
troleum ether/ethyl acetate (9/1 to 19/1) as the eluent to give the
corresponding substituted chromones 2.
4.2.1. 1-(2-Hydroxyphenyl)-2-methyl-1,3-hexanedione (1j). Orange
solid (1.4 g, 35% yield); mp 95e96 ꢀC; 1H NMR (CDCl3, 400 MHz,
mixture of ketone and enol forms)
d
(ppm) 12.14 (s, 1H), 7.86e7.89
4.4. General experimental procedure for the cyclization
reaction using 7 as the catalyst
(m, 1H), 7.40 (dd, J¼8.0, 1.6 Hz, 1H), 7.45e7.53 (m, 2H), 7.00e7.06
(m, 2H), 6.92e6.95 (m, 2H), 4.50 (q, J¼7.0 Hz, 1H), 2.93e2.96 (m,
0.6H), 2.73e2.78 (m, 0.8H), 2.64 (d, J¼2.0 Hz, 0.6H), 2.48e2.56 (m,
1H), 2.35e2.43 (m, 1H), 1.82e1.97 (m, 2H), 1.54e1.65 (m, 5.2H), 1.47
(d, J¼6.8 Hz, 3H), 1.31 (d, J¼6.8 Hz, 2H), 1.20 (d, J¼7.6 Hz, 1.2H),
0.99e1.06 (m, 3H), 0.86 (t, J¼7.4 Hz, 3H); HRMS (TOF-ESþ) m/z:
[MþNa]þ calcd for C13H16O3Na 243.0997, found 243.0990.
A
mixture of diketone
1
(0.50 mmol), proline phenyl-
L,
sulphonylhydrazide 7 (44 mg, 0.1 mmol) and water (0.9
m
0.05 mmol) was heated at 55 ꢀC for the given time. After comple-
tion of the reaction monitored by TLC, the solvent was removed
under reduced pressure. The crude mixture was purified via silica
gel column chromatography using petroleum ether/ethyl acetate
(9/1 to 19/1) as the eluent to give the corresponding substituted
chromones 2.
4.2.2. 1-(2-Hydroxyphenyl)-2,4-dimethyl-1,3-pentanedione
(1k). White solid (2.2 g, 55% yield); mp 109e110 ꢀC; 1H NMR
(CDCl3, 400 MHz, mixture of ketone and enol forms) d (ppm) 12.10 (s,
1H), 7.85e7.89 (m, 1H), 7.75 (dd, J¼8.4, 1.6 Hz, 1H), 7.46e7.53 (m,
2H), 6.99e7.06 (m, 2H), 6.91e6.95 (m, 2H), 4.64 (q, J¼6.8 Hz, 1H),
3.03e3.09 (m, 0.5H), 2.73e2.85 (m, 2H), 2.55 (s, 0.5H), 2.27e2.34
(m, 0.5H), 2.14e2.20 (m, 0.5H), 1.47 (d, J¼6.8 Hz, 3H), 1.30 (d,
J¼7.2 Hz, 2H),1.11e1.18 (m, 9H), 1.06 (d, J¼6.8 Hz, 3H), 0.99 (d,
J¼7.2 Hz, 1.2H); HRMS (TOF-ESþ) m/z: [MþNa]þ calcd for
4.4.1. 2-Methylchromone (2a). White solid (81 mg, 99% yield); mp
69e71 ꢀC (lit. 69e72 ꢀ 58); 1H NMR (DMSO-d6, 400 MHz)
C d (ppm)
8.01 (dd, J¼8.0, 1.6 Hz, 1H), 7.76e7.80 (m, 1H), 7.61 (d, J¼8.4 Hz, 1H),
7.47 (t, J¼7.6 Hz, 1H), 6.26 (s, 1H), 2.40 (s, 3H).
4.4.2. 2-Propylchromone (2b). Yellowish oil59 (94 mg, 99% yield);
C
13H16O3Na 243.0997, found 243.0989.
1H NMR (CDCl3, 400 MHz)
7.62e7.67 (m, 1H), 7.36e7.44 (m, 2H), 6.19 (s, 1H), 2.61 (t, J¼7.2 Hz,
2H), 1.76e1.81 (m, 2H), 1.03 (t, J¼7.2 Hz, 3H).
d
(ppm) 8.19 (dd, J¼8.0, 1.6 Hz, 1H),
4.2.3. 1-Cyclohexyl-3-(2-hydroxyphenyl)-2-methyl-1,3-
propanedione (1l). White solid (2.7 g, 58% yield); mp 167 ꢀC; 1H
NMR (CDCl3, 400 MHz, mixture of ketone and enol forms)
d
(ppm)
4.4.3. 2-Isopropylchromone (2c). Yellow oil59 (83 mg, 88% yield); 1H
12.15 (s, 1H), 8.22 (dd, J¼8.0, 1.2 Hz, 0.3H), 7.89 (td, J¼8.0, 1.6 Hz,
0.6H), 7.76 (d, J¼8.0 Hz, 1H), 7.61e7.65 (m, 0.3H), 7.46e7.55 (m,
1.6H), 7.43 (d, J¼8.8 Hz, 0.3H), 7.34e7.38 (m, 0.3H), 6.93e7.07 (m,
3H), 4.64 (q, J¼7.0 Hz, 1H), 3.08 (q, J¼7.0 Hz, 0.3H), 2.81e2.93 (m,
0.8H), 2.48e2.54 (m, 1.2H), 2.31e2.38 (m, 4H), 1.66e1.97 (m, 23H),
1.42e1.51 (m, 14H), 1.17e1.38 (m, 21H), 0.90e0.91 (m, 4H); HRMS
(TOF-ESþ) m/z: [MþNa]þ calcd for C16H20O3Na 283.1310, found
283.1299.
NMR (CDCl3, 400 MHz)
7.63e7.68 (m, 1H), 7.44e7.46 (m, 1H), 7.36e7.40 (m, 1H), 6.21 (s,
1H), 2.82e2.93 (m, 1H), 1.33 (d, J¼6.8 Hz, 6H).
d
(ppm) 8.18 (dd, J¼8.0, 1.6 Hz, 1H),
4.4.4. 2-Cyclohexylchromone (2d). Colorless oil60 (109 mg, 95%
yield); 1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.18 (dd, J¼8.0, 1.6 Hz,
1H), 7.62e7.66 (m, 1H), 7.43 (d, J¼8.4 Hz, 1H), 7.37 (t, J¼7.6 Hz, 1H),
6.18 (s, 1H), 2.50e2.57 (m, 1H), 2.03e2.06 (m, 2H), 1.87e1.90 (m,
2H), 1.76e1.79 (d, J¼12.4 Hz, 1H), 1.23e1.54 (m, 5H).
4.2.4. 1-(2-Hydroxyphenyl)-2-methyl-4-phenyl-1,3-butanedione
(1m). Colorless solid (3.2 g, 72% yield); mp 87e88 ꢀC; 1H NMR
4.4.5. 2-Benzylchromone (2e). White solid (112 mg, 95% yield); mp
(CDCl3, 400 MHz, mixture of ketone and enol forms)
d
(ppm) 12.05 (s,
88e90 ꢀC (lit. 86e87 ꢀC59); 1H NMR (CDCl3, 400 MHz)
d (ppm) 8.16
0.3H), 7.88 (dd, J¼8.0, 1.8 Hz, 0.8H), 7.84 (dd, J¼7.6, 1.6 Hz, 1H),
7.30e7.49 (m, 12H), 7.24e7.26 (m, 2H), 7.19e7.29 (m, 1.7H),
7.12e7.14 (m, 0.8H), 6.96e7.04 (m, 2.3H), 6.90e6.93 (m, 1.8H),
6.78e6.82 (m, 0.4H), 4.57 (q, J¼7.0 Hz, 0.4H), 3.82 (d, J¼15.6 Hz,
0.4H), 3.72 (d, J¼15.6 Hz, 0.4H), 3.38 (d, J¼14.0 Hz, 0.8H), 3.28 (d,
J¼14.0 Hz, 1H), 3.18 (d, J¼14.0 Hz, 1H), 2.81e2.92 (m, 4H), 1.45 (d,
J¼6.8 Hz, 1H), 1.41 (d, J¼6.8 Hz, 3H), 1.32 (d, J¼7.2 Hz, 2H); HRMS
(TOF-ESþ) m/z: [MþH]þ calcd for C17H17O3 269.1178, found
269.1186.
(dd, J¼8.0, 1.6 Hz, 1H), 7.61e7.66 (m, 1H), 7.30e7.43 (m, 7H), 6.14 (s,
1H), 3.93 (s, 2H).
4.4.6. Methyl chromone-2-carboxylate (2f). White solid (89 mg, 87%
yield); mp 126e129 ꢀC (lit. 122e123 ꢀC61); 1H NMR (CDCl3,
400 MHz)
d
(ppm) 8.20 (dd, J¼8.0, 1.2 Hz, 1H), 7.73e7.77 (m, 1H),
7.60e7.62 (m, 1H), 7.44e7.48 (m, 1H), 7.12 (s, 1H), 4.02 (s, 3H).
4.4.7. Flavone (2g). Yellow solid (75 mg, 67% yield); mp 96e97 ꢀC
(lit. 96e97 ꢀC58); 1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.25 (dd, J¼8.0,
4.2.5. Methyl 4-(2-hydroxyphenyl)-3-methyl-2,4-dioxobutanoate
1.2 Hz, 1H), 7.94e7.96 (m, 2H), 7.70e7.74 (m, 1H), 7.59 (d, J¼8.4 Hz,
(1n). White solid (3.0 g, 70% yield); mp 140e141 ꢀC; IR (KBr)
n
1H), 7.54e7.60 (m, 3H), 7.44 (t, J¼7.4 Hz, 1H), 6.85 (s, 1H).
3386, 2987, 2912, 1750, 1676, 1461, 972, 752 cm-1; 1H NMR (CDCl3,
400 MHz, ketone form)
(ppm) 7.90 (dd, J¼8.0,1.6 Hz,1H), 7.48e7.52
(m,1H), 7.08 (t, J¼7.2 Hz,1H), 6.94e6.97 (m,1H), 4.55 (br s,1H), 3.98
d
4.4.8. 2-Styrylchromone (2h). Yellow solid (63 mg, 51% yield); mp
142e144 ꢀC (lit. 141 ꢀ 62); 1H NMR (CDCl3, 400 MHz)
C d (ppm) 8.21

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S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
(dd, J¼8.0,1.6 Hz,1H), 7.54e7.72 (m, 5H), 7.38e7.46 (m, 4H), 6.81 (d,
J¼16.0 Hz, 1H), 6.35 (s, 1H).
brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified via silica gel column chromatography
using petroleum ether/ethyl acetate (3/1 to 9/1) as the eluent to
give N-Boc proline phenylsulphonylhydrazide 16 as colorless oil
4.4.9. 2,3-Dimethylchromone (2i). White solid (83 mg, 95% yield);
mp 95e97 ꢀC (lit. 97 ꢀC63); 1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.19
(4.1 g, 51% yield); IR (KBr)
n
3329, 3232, 2962, 2929, 1699, 1402,
(ppm) 8.01e8.05 (m,
(dd, J¼8.0, 1.6 Hz, 1H), 7.58e7.62 (m, 1H), 7.32e7.38 (m, 2H), 2.41 (s,
1170, 773 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
d
3H), 2.06 (s, 3H).
2H), 7.25e7.33 (m, 2H), 4.47 (br, s, 2H), 3.48e3.55 (m, 1.8H),
3.27e3.42 (m, 3H), 3.47e2.57 (m, 1.8H), 2.28e2.35 (m, 1H), 1.99 (br,
s, 4.2H), 1.71e1.86 (m, 7H), 1.45e1.62 (m, 16.2H), 1.32e1.39 (m, 6H),
1.08e1.25 (m, 21.8H), 0.72e0.88 (m, 7.3H); 13C NMR (DMSO-d6,
4.4.10. 3-Methyl-2-propylchromone (2j). White solid (72 mg, 71%
yield); mp 60e62 ꢀC; IR (KBr)
n
2960, 2928, 2869, 1632, 1463, 1166,
760 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.22 (dd, J¼8.0,1.2 Hz,
100 MHz) d (ppm) 174.8, 174.3, 153.9, 153.5, 130.1, 127.9, 79.0, 59.1,
1H), 7.61e7.65 (m,1H), 7.35e7.42 (m, 2H), 2.72 (t, J¼7.6 Hz, 2H), 2.11
58.9, 46.7, 46.5, 37.4, 30.7, 29.1, 28.6, 28.4, 27.4, 27.1, 23.6, 22.5, 22.4,
(s, 3H), 1.77e1.86 (m, 2H), 1.06 (t, J¼3.4 Hz, 3H); 13C NMR (CDCl3,
21.2, 20.5, 14.5 14.3; HRMS (TOF-ESþ) m/z: [MþNa]þ calcd for
100 MHz)
d
(ppm) 178.3, 165.2, 155.9, 132.9, 125.9, 124.4, 122.6,
C28H47N3O5SNa 560.3134, found 560.3121.
117.6, 116.8, 34.1, 20.6, 13.8, 9.9; HRMS (TOF-ESþ) m/z: [MþNa]þ
calcd for C13H14O2Na 225.0891, found 225.0899.
4.6. Experimental procedure for proline phenyl-
sulphonylhydrazide (7)
4.4.11. 2-Isopropyl-3-methylchromone (2k). White solid (100 mg,
99% yield); mp 54e57 ꢀC; IR (KBr)
n
3056, 2966, 2934, 1632, 1467,
1398, 1371, 763 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.20 (d,
J¼8.0 Hz, 1H), 7.61 (t, J¼8.0 Hz, 1H), 7.33e7.43 (m, 2H), 3.21e3.31
(m, 1H), 2.10 (s, 3H), 1.32 (d, J¼6.8 Hz, 6H); 13C NMR (CDCl3,
100 MHz)
d (ppm) 178.4, 168.6, 155.9, 132.9, 125.8, 124.4, 122.6,
117.6, 115.1, 30.6, 19.7, 9.4; HRMS (TOF-ESþ) m/z: [MþNa]þ calcd for
C
13H14O2Na 225.0891, found 225.0898.
To a solution of 16 (2.7 g, 5.0 mmol) in DCM was added tri-
fluoroacetic acid (1.8 mL, 25 mmol). After being stirred for 2 h, the
mixture was neutralized with ammonia solution (28%), washed
with water. The organic layer was dried over anhydrous Na2SO4,
concentrated in vacuo. The crude product was purified by silica gel
column chromatography using methanol/dichloromethane (1/9) as
4.4.12. 2-Cyclohexyl-3-methylchromone (2l). White solid (105 mg,
87% yield); mp 52 ꢀC; IR (KBr)
2966, 2934, 1632, 1610, 1397, 1371,
1107, 763 cmꢁ1 1H NMR (CDCl3, 400 MHz)
(ppm) 8.19e8.21 (m,
n
;
d
1H), 7.59e7.62 (m, 1H), 7.41 (d, J¼8.4 Hz, 1H), 7.34 (t, J¼7.2 Hz, 1H),
2.84e2.92 (m,1H), 2.10 (s, 3H),1.67e1.91 (m, 7H),1.30e1.46 (m, 3H);
the eluent to afford 7 as colorless oil (1.3 g, 59% yield); IR (KBr)
3162, 2958, 2926, 2855, 1677, 1202, 1167, 836, 722 cmꢁ1 1H NMR
(DMSO-d6, 400 MHz)
n
13C NMR (CDCl3, 100 MHz)
d
(ppm) 178.5, 168.2, 155.9, 132.8, 125.8,
;
124.4, 122.6, 117.6, 115.3, 40.8, 29.6, 26.1, 25.8, 9.5; HRMS (TOF-ESþ)
d
(ppm) 7.72 (d, J¼8.0 Hz, 2H), 7.30 (d,
m/z: [MþNa]þ calcd for C16H18O2Na 265.1204, found 265.1200.
J¼8.0 Hz, 2H), 3.42 (q, J¼5.2 Hz, 1H), 2.68e2.71 (m, 2H), 2.51e2.60
(m, 1H), 1.72e1.80 (m, 1H), 1.31e1.58 (m, 8H), 0.99e1.23 (m, 16H),
4.4.13. 2-Benzyl-3-methylchromone (2m). White solid (123 mg, 98%
yield); mp 121e125 ꢀC (lit. 125.7e126.5 ꢀC64); 1H NMR (CDCl3,
0.66e0.81 (m, 7H); 13C NMR (DMSO-d6, 100 MHz)
d (ppm) 172.1,
151.9, 136.1, 128.5, 128.1, 59.2, 47.1, 45.7, 36.6, 31.7, 30.7, 29.2, 27.0,
400 MHz)
d
(ppm) 8.20 (d, J¼8.0, 1.6 Hz, 1H), 7.58e7.62 (m, 1H),
25.9, 22.5, 20.5, 14.3, 12.2; HRMS (TOF-ESþ) m/z: [MþH]þ calcd for
7.26e7.38 (m, 7H), 4.05 (s, 2H), 2.16 (s, 3H).
C23H40N3O3S 438.2790, found 438.2768.
4.4.14. 3-Methyl-4-oxo-4H-chromene-2-carboxylatemethyl
ester
4.7. General experimental procedure for diketone (10aec)
(2n). White solid (89 mg, 82% yield); mp 106e107 ꢀC (lit. 99 ꢀC65);
1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.21 (dd, J¼8.0, 1.6 Hz, 1H),
To a solution of salicylaldehyde 9 (0.6 mg, 5.0 mmol) in MeOH/
H2O (1:1, 100 mL) was added diketone 10 (50 mmol) and pyrroli-
dine (0.41 mL, 5.0 mmol) and the resulting mixture was stirred at rt
overnight. Then the mixture was acidified with HCl (3 N), extracted
with DCM, washed with H2O and saturated brine, dried over
Na2SO4, and concentrated under reduced pressure to obtain the
crude intermediate aldol product. It was then dissolved in DCM.
Pyridinium chlorochromate (25 mmol) was added to the mixture
solution and stirred at rt overnight. The reaction mixture was fil-
tered, evaporated, and purified by silica gel column chromatogra-
phy using petroleum ether/ethyl acetate (9/1 to 19/1) as the eluent
to afford the corresponding diketone 10.
7.69e7.74 (m, 1H), 7.51 (d, J¼8.4 Hz, 1H), 7.39e7.44 (m, 1H), 4.02 (s,
3H), 2.38 (s, 3H).
4.5. Experimental procedure for N-Boc proline phenyl-
sulphonylhydrazide (16)
To a solution of p-dodecylbenesulfonyl chloride (5.0 g, 15 mmol)
in DCM (6 mL) was added hydrazine hydrate (80%, 9.1 mL, 0.15 mol)
at rt. After being stirred vigorously for 2 h, the reaction solution was
concentrated to remove most of the solvent in vacuo. The residue
was then dissolved in ethyl acetate, washed with water and brine,
dried over anhydrous Na2SO4, and concentrated to afford benze-
nesulfonyl hydrazide, which was dissolved in DCM (80 mL) sub-
4.7.1. 2-(2-Hydroxybenzoyl)cyclohexanone
(0.52 g, 48% yield); mp 159e161 ꢀC; 1H NMR (CDCl3, 400 MHz,
mixture of ketone and enol forms) (ppm) 7.84e7.90 (m, 1.4H),
(10a). White
solid
d
7.45e7.52 (m,1.5H), 6.91e7.05 (m, 3H), 3.11 (br s,1H), 2.76e2.79 (m,
1H), 2.57e2.61 (m, 1H), 2.22e2.56 (m, 0.5H), 2.13e2.16 (m, 1.1H),
1.99e2.03 (m, 1H), 1.87e1.91 (m, 1.7H), 1.57e1.81 (m, 6.1H),
1.26e1.37 (m, 2.1H); HRMS (TOF-ESþ) m/z: [MþH]þ calcd for
sequently. To the resulting mixture was added Boc-
L-proline (3.9 g,
C13H15O3 219.1021, found 219.1027.
18 mmol), 4-dimethylaminopyridine (0.4 g, 3.0 mmol) and EDC$HCl
(4.2 g, 22 mmol), respectively. The reaction mixture was stirred at rt
for 3 h. Then the mixture was filtered, washed with half-saturated
4.7.2. 2-(2-Hydroxybenzoyl)-4-methylcyclohexanone (10b). White
solid (0.29 g, 25% yield); mp 135e136 ꢀC; 1H NMR (CDCl3, 400 MHz,

S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
9319
mixture of ketone and enol forms)
d
(ppm) 7.86e7.91 (m, 1H),
400 MHz)
7.56 (d, J¼8.4 Hz, 1H), 7.45e7.49 (m, 1H), 4.91 (s, 2H), 4.08 (s, 3H);
13C NMR (CDCl3, 100 MHz)
(ppm) 176.3, 161.2, 155.1, 149.9, 135.1,
d
(ppm) 8.25 (dd, J¼8.0, 1.6 Hz, 1H), 7.74e7.78 (m, 1H),
7.45e7.52 (m, 1H), 7.00e7.06 (m, 1H), 6.92e6.98 (m, 1H), 2.82e2.86
(m, 1H), 2.77 (s, 0.3H), 2.66 (dd, J¼13.2, 4.4 Hz, 0.3H), 2.41 (s, 1H),
2.20e2.41 (m, 1H), 1.97e2.15 (m, 2.2H), 1.73e1.82 (m, 2H),
1.53e1.58 (m, 1H), 1.29e1.46 (m, 2.2H), 1.03 (d, J¼6.4 Hz, 2.3H), 0.94
(d, J¼6.8 Hz, 0.7H); HRMS (TOF-ESþ) m/z: [MþH]þ calcd for
d
126.3, 126.2, 125.0, 122.9, 118.5, 53.7, 21.3; HRMS (TOF-ESþ) m/z:
[MþNa]þ calcd for C12H9O4BrNa 318.9582, found 318.9576.
C
14H17O3 233.1178, found 233.1180.
4.10. Experimental procedure for 1H-furo[3,4-b][1]benzo-
pyran-3,9-dione (13)
4.7.3. 3-(2-Hydroxybenzoyl)dihydro-2H-pyran-4(3H)-one
(10c). Colorless oil (0.23 g, 21% yield); 1H NMR (DMSO-d6,
A mixture of 12 (60 mg, 0.20 mmol) and calcium carbonate
(0.12 mg, 1.2 mmol) in water (2 mL) and 1,4-dioxane (2 mL) was
heated at reflux for 3 h. Then the reaction mixture was filtered, and
the filtrate was concentrated in vacuo to afford compound 13 as
a yellowish solid (14 mg, 35% yield); mp 265e266 ꢀC (lit.
400 MHz, mixture of ketone and enol forms)
d (ppm) 8.32 (s, 0.3H),
7.74 (dd, J¼8.0, 1.6 Hz, 1H), 7.68 (dd, J¼7.6, 1.6 Hz, 1H), 7.54e7.63 (m,
2H), 7.42 (s, 1H), 7.00e7.11 (m, 5H), 4.14 (dd, J¼11.2, 4.8 Hz, 1H),
3.89e3.93 (m, 2H), 3.81 (dd, J¼11.2, 5.2 Hz, 1H), 3.43e3.66 (m, 4H),
3.27e3.31 (m, 1H), 2.75 (dd, J¼10.4, 5.2 Hz, 1H), 2.08e2.20 (m, 2H),
1.98 (d, J¼12.8 Hz, 1H), 1.77e1.81 (m, 1H); HRMS (TOF-ESþ) m/z:
[MþNa]þ calcd for C13H16O3Na 243.0997, found 243.0986.
240e242 ꢀC66); 1H NMR (DMSO-d6, 400 MHz)
d (ppm) 8.19 (d,
J¼8.0 Hz, 1H), 7.95e7.99 (m, 1H), 7.90 (d, J¼8.4 Hz, 1H), 7.64 (t,
J¼7.6 Hz, 1H), 5.36 (s, 2H).
4.8. General experimental procedure for tetrahydrox-
4.11. Experimental procedure for 1,2-dihydro-[1]benzopyrano
anthones (11aec)
[2,3-c]pyrrole-3,9-dione (14)
A mixture of diketone 10 (0.20 mmol), pyrrolidine (8.1
m
L,
To a solution of 12 (60 mg, 0.20 mmol) in DMF/H2O (5:1, 1.2 mL)
was added NaN3 (14 mg, 0.22 mmol) and the resulting mixture was
stirred at reflux for 4 h. After being cooled to room temperature, the
mixture was added triphenylphosphine (58 mg, 0.22 mmol), and
stirred at 50 ꢀC for 24 h. And the resulting reaction solution was
then concentrated in vacuo. The residue was washed with ethyl
ether and purified by silica gel column chromatography using pe-
troleum ether/ethyl acetate (1/1) as the eluent to afford 14 as
0.10 mmol) and water (0.9
m
L, 0.05 mmol) was heated at 55 ꢀC for
the given time. After completion of the reaction monitored by TLC,
the solvent was removed under reduced pressure. The crude mix-
ture was purified via silica gel column chromatography using pe-
troleum ether/ethyl acetate (9/1 to 19/1) as the eluent to give the
corresponding tetrahydroxanthones 11.
4.8.1. Tetrahydroxanthone (11a). White solid (95 mg, 95% yield);
a yellow solid (22 mg, 55% yield); decomposed at 209 ꢀC; IR (KBr)
3229, 3099, 2933, 1728, 1679, 1659, 1463, 1290, 1223, 1036, 890,
764 cmꢁ1 1H NMR (DMSO-d6, 400 MHz)
(ppm) 9.38 (br s, 1H),
n
mp 103 ꢀC (lit. 102e103 ꢀC65); 1H NMR (CDCl3, 400 MHz)
d (ppm)
8.20 (dd, J¼8.0, 1.6 Hz, 1H), 7.59e7.63 (m, 1H), 7.33e7.40 (m, 2H),
2.68 (t, J¼6.4 Hz, 2H), 2.59 (t, J¼6.2 Hz, 2H), 1.86e1.92 (m, 2H),
1.74e1.80 (m, 2H).
;
d
8.17 (dd, J¼8.0,1.2 Hz,1H), 7.89e7.93 (m,1H), 7.85 (dd, J¼8.4, 0.8 Hz,
1H), 7.58e7.62 (m, 1H), 4.29 (d, J¼0.8 Hz, 2H); 13C NMR (DMSO-d6,
100 MHz)
d (ppm) 174.7, 164.1, 135.4, 126.6, 126.5, 125.8, 124.7,
4.8. 2. 1, 2, 3,4-Tetrahydro-2-methyl-9H-xanthꢀen-9-one
119.6; HRMS (TOF-ESþ) m/z: [MþH]þ calcd for C11H8NO3 202.0504,
(11b). Yellowish solid (104 mg, 97% yield); mp 141e143 C; IR (KBr)
found 202.0519.
n
2953, 2928, 1636, 1612, 1567, 1464, 1291, 1138, 762 cmꢁ1; 1H NMR
(CDCl3, 400 MHz)
d
(ppm) 8.20 (dd, J¼7.6, 1.2 Hz, 1H), 7.59e7.63 (m,
4.12. Experimental procedure for 1,2-dihydro-2-(phenyl-
methyl)-[1]benzopyrano[2,3-c]pyrrole-3,9-dione (15)
1H), 7.32e7.39 (m, 2H), 2.84 (dd, J¼16.8, 4.8 Hz, 1H), 2.71e2.75 (m,
2H), 2.02e2.10 (m, 1H), 1.91e1.98 (m, 1H), 1.78e1.85 (m, 1H),
1.44e1.55 (m, 1H), 1.11 (d, J¼6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
A mixture of 12 (60 mg, 0.2 mmol), benzylamine (24
mL,
d
(ppm) 177.8, 163.7, 155.9, 132.9, 125.8, 124.4, 123.1, 117.9, 117.6,
0.22 mmol), and triethylamine (31 L, 0.22 mmol) in acetonitrile
m
29.9, 29.2, 28.07, 28.05, 21.2; HRMS (TOF-ESþ) m/z: [MþNa]þ calcd
(1.8 mL) was refluxed for 24 h. Then the solvent was removed in
vacuo. And the residue was purified via silica gel column chroma-
tography using petroleum ether/ethyl acetate (9/1) as the eluent to
afford the product 15 as a yellow solid (44 mg, 76% yield); mp
for C14H14O2Na 237.0891, found 237.0884.
4.8.3. Xanthenone 11c. White solid (95 mg, 95% yield); mp 103 ꢀC;
IR (KBr)
n
2952, 2902, 2842, 1653, 1609, 1469, 1405, 1322, 1168, 863,
258e259 ꢀC; IR (KBr)
n
3068, 2931, 1719, 1662, 1463, 1442, 1263,
(ppm) 8.27 (dd,
738 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
(ppm) 8.19 (dd, J¼8.0,1.6 Hz,
1228, 882, 753 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
1H), 7.63e7.68 (m, 1H), 7.37e7.44 (m, 2H), 4.67 (t, J¼1.2 Hz, 2H),
J¼8.0,1.2 Hz,1H), 7.70e7.92 (m, 2H), 7.50 (t, J¼7.2 Hz,1H), 7.31e7.39
4.03 (t, J¼5.6 Hz, 2H), 2.78e2.81 (m, 2H); 13C NMR (CDCl3,100 MHz)
(m, 5H), 4.81 (s, 2H), 4.24 (s, 2H); 13C NMR (CDCl3, 100 MHz)
d
(ppm) 175.7, 160.8, 156.0, 133.4, 125.6, 124.9, 123.5, 117.8, 117.1,
d (ppm) 174.2, 162.1, 156.6, 155.0, 135.6, 134.6, 129.1, 128.4, 128.3,
63.8, 62.6, 27.7; HRMS (TOF-ESþ) m/z: [MþNa]þ calcd for
126.1, 126.0, 125.0, 124.2, 119.1, 47.2, 44.8; HRMS (TOF-ESþ) m/z:
C
12H10O3Na 225.0528, found 225.0522.
[MþNa]þ calcd for C18H13NO3Na 314.0793, found 314.0801.
4.9. Experimental procedure for 3-(bromomethyl)-4-oxo-4H-
Acknowledgements
chromene-2-carboxylate methyl ester (12)
We gratefully acknowledge the financial support from Central
South University, National Natural Science Foundation of China
(21376270 & 21276282) and Hunan Provincial Science and Tech-
nology Department (2012WK2007).
To a solution of 2n (0.10 g, 0.46 mmol) in CCl4 (6 mL) was added
N-bromosuccinimide (84 mg, 0.47 mmol) and a catalytic amount of
AIBN, and the mixture was refluxed for 5 h. The solvent was re-
moved in vacuo to give the crude product. Then the purified
product 12 was obtained via silica gel column chromatography
using petroleum ether/ethyl acetate (19/1) as the eluent as a white
Supplementary data
solid (0.13 g, 96% yield); mp 147e149 ꢀC; IR (KBr)
1733, 1652, 1465, 1387, 1254, 868, 765 cmꢁ1 1H NMR (CDCl3,
n
3076, 2954,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.045.
;

9320
S.-S. Wen et al. / Tetrahedron 70 (2014) 9314e9320
28. Yamaguchi, S.; Mutoh, M.; Shimakura, M.; Tsuzuki, K.; Kawase, Y. J. Heterocycl.
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