An organocatalyst from renewable materials for the synthesis of coumarins and chromenes: Three-component reaction and multigram scale synthesis

Article abstract of DOI:10.1039/c4ra00673a

A new concept of catalysts which are prepared from renewable materials is demonstrated. It is known that amino acids (e.g., proline and hydroxyproline) are robust organocatalysts for several reactions. Bovine tendons which are proteins rich in hydroxyproline and proline were used as a source of amino acids. An acid hydrolysate of tendons (a TH catalyst) could catalyze two reactions: (i) the synthesis of coumarins and chromenes under solvent-free conditions and (ii) the synthesis of densely functionalized 4H-chromenes via a three-component reaction. Moreover, an economical and easily accessible TH catalyst is applicable in a multigram scale synthesis of coumarins and chromenes, as well as in the three-component reaction for chromene synthesis. A catalytic activity of hydroxyproline for the synthesis of 4H-chromenes via the three-component reaction was also discovered. The present work demonstrates not only the green catalysts from renewable materials, but also an environmentally benign preparation of coumarins and chromenes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00673a

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PAPER
An organocatalyst from renewable materials for the
synthesis of coumarins and chromenes:
three-component reaction and multigram scale
synthesis†
Cite this: RSC Adv., 2014, 4, 13708
Rapeepat Sangsuwan,a Sasithorn Sangher,b Thammarat Aree,c Chulabhorn Mahidol,ab
abd
Somsak Ruchirawatabd and Prasat Kittakoop
*
A new concept of catalysts which are prepared from renewable materials is demonstrated. It is known that
amino acids (e.g., proline and hydroxyproline) are robust organocatalysts for several reactions. Bovine
tendons which are proteins rich in hydroxyproline and proline were used as a source of amino acids. An
acid hydrolysate of tendons (a TH catalyst) could catalyze two reactions: (i) the synthesis of coumarins
and chromenes under solvent-free conditions and (ii) the synthesis of densely functionalized
4H-chromenes via a three-component reaction. Moreover, an economical and easily accessible TH
catalyst is applicable in a multigram scale synthesis of coumarins and chromenes, as well as in the three-
component reaction for chromene synthesis. A catalytic activity of hydroxyproline for the synthesis of
4H-chromenes via the three-component reaction was also discovered. The present work demonstrates
not only the green catalysts from renewable materials, but also an environmentally benign preparation of
coumarins and chromenes.
Received 23rd January 2014
Accepted 21st February 2014
DOI: 10.1039/c4ra00673a
www.rsc.org/advances
compounds and drug leads.14–18 The examples of drugs
currently used are warfarin 3a and cromoglicic acid 3b as
Introduction
anticoagulants and anti-asthmatic agents, respectively (Fig. 2).
Because of their important use in pharmaceuticals, there are
many synthetic methods towards the synthesis of these privi-
leged structures.
Several synthetic routes have been reported for the synthesis
of coumarins.19–21 Whereas, chromene derivatives were synthe-
sized by various methods, for example, DBU-catalyzed reaction
between salicylic aldehydes and ethyl 2-methylbuta-2,3-dien-
oate;22 tandem benzylation and cyclization by FeCl3;23 Cu(I)-
catalyzed domino reactions;24 and triazine functionalized
ordered mesoporous organosilica as an organocatalyst.25
The benzopyran chemical class, formed from the fusion of a
benzene ring and a pyran ring with various levels of saturation
and oxidation, appears in many natural products.1 1-Benzo-
pyran skeletons including coumarin 1 and 4H-chromene 2
(Fig. 1) are important scaffolds in many drugs and bioactive
natural products.
Coumarins (2H-chromen-2-one derivatives) possess many
biological activities including anticoagulant, anticancer,
enzyme inhibition, vasorelaxant, antimicrobial, antioxidant,
and anti-inammatory, and anti-HIV activities.2–12 In addition
to the biological properties, they have been used in food addi-
tives, cosmetics, optical brightener, and uorescent and laser
dyes.13 4H-Chromene moiety is present in many bioactive
aChulabhorn Graduate Institute, Chemical Biology Program, Kamphaeng Phet 6 Road,
Laksi, Bangkok 10210, Thailand. E-mail: prasat@cri.or.th; Fax: +66-2-5538545; Tel:
+66-86-9755777
Fig. 1 Structure of coumarin 1 and 4H-chromene 2.
bChulabhorn Research Institute, Kamphaeng Phet 6 Road, Laksi, Bangkok 10210,
Thailand
cDepartment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok
10330, Thailand
dCenter of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry
of Education, Thailand
† Electronic supplementary information (ESI) available. CCDC 952576–952579.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra00673a
Fig. 2 Structure of warfarin 3a cromoglicic acid 3b.
13708 | RSC Adv., 2014, 4, 13708–13718
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However, these procedures are not green methods since metals provided better yields of products than that of ethyl acetoace-
and hazardous solvents are used in the synthesis. Recently, tate. To ensure that the reaction was not catalyzed by the
green methods were developed for the synthesis of chromene residue of base or acid which was probably present in the
and coumarin, for example, four-component catalyst-free reac- prepared catalyst, portions of the TH catalyst were dissolved in
tion in water26 and biocatalytic domino reaction with the water, and pH of solutions were found to be at 6.5–7.2, con-
enzyme alkaline protease.27 However, the development of new rming that the reaction was not due to the activity of base or
methods and catalysts, which provide economical and envi- acid.
ronmentally friendly routes, is still required for both coumarin
and chromene syntheses.
Next, we investigated the inuence of the molar ratio of
substrates (salicylaldehyde 4a to methyl acetoacetate 5) on the
Among various organocatalysts, amino acids play an product ratios of coumarin (6a) to chromene (7a). As shown in
important role in asymmetric organocatalysis. L-Proline and Table 1, increasing the molar ratio of methyl acetoacetate (5)
derivatives have been extensively used as efficient organo- gave a slightly increase in chromene (7a) production. We next
catalysts,28,29 and they are employed in several asymmetric investigated the effect of temperature for the reaction, and the
organic syntheses.30 L-Proline and other amino acids have been reactions were conducted at room temperature (26–28 C), 55
ꢀ
demonstrated to be powerful catalysts for various reactions, i.e., ꢀC, and 80 ꢀC. It was found that the times used for the reaction
aldol reactions, Mannich reactions, Michael reaction, and at room temperature, 55 ꢀC, and 80 ꢀC were 96 h, 29 h, and 19 h,
a-functionalizations of carbonyl compounds.31 Utilization of respectively (the yields were >96% as indicated by 1H NMR
renewable materials for ne and industrial chemicals is one of spectrum). Although increasing temperature could shorten the
the important topics in green chemistry,32–36 because renewable time for the reactions, performing the reaction at 55 ꢀC was
resources provide not only the reduction of environmental more reasonable, in term of the reduction of energy consump-
ꢀ
impacts, but also economical feasibility and sustainable tion, than that at 80 C. We therefore decided to carry out the
ꢀ
productions. Normally, tendons are composed of various reaction at 55 C for further experiments.
collagen bers, which are proteins rich in hydroxyproline and
Next, we investigated the reaction of methyl acetoacetate (5)
proline;37–39 both amino acids are known as robust organo- and a variety of salicylaldehyde derivatives (4), using the molar
catalysts.28–31,40 In the present work, we demonstrate a new ratio 1 : 3 of salicylaldehyde derivatives (4) to methyl acetoace-
concept of catalysts which are prepared from renewable mate- tate (5) with 20% of the TH catalyst (at 55 ꢀC). As shown in Table
rials. We used bovine tendons as a source of amino acids, and 2, both coumarins and chromenes were obtained in low to
found that a tendon hydrolysate (TH) served as an excellent moderate yields (3–54%). Unsubstituted salicylaldehyde and
organocatalyst, catalyzing the synthesis of coumarins and 4H- those bearing electron-donating groups (Table 2, entries 1–4
chromenes under solvent-free conditions. The TH catalyst also and 8) favored the formation of chromenes (7a, 7b, 7c, 7d, and
efficiently catalyzed the three-component reactions for the 7h) with respect to coumarins (6a, 6b, 6c, 6d, and 6h). In
construction of densely functionalized 4H-chromenes, recently contrast, salicylaldehyde bearing an electron-withdrawing
reported by Gu and coworkers.41 Moreover, the cheap and easily group (Table 2, entries 5 and 6) provided coumarins (6e and 6f)
accessible TH catalyst was applicable in a multigram scale more than chromenes (7e and 7f). 5-Nitrosalicylaldehyde and 2-
synthesis of coumarins and chromenes, as well as in a multi- hydroxy-1-naphthaldehyde did not provide chromenes (7i and
gram scale chromene synthesis via the three-component 7k), therefore only coumarins (6i and 6k) were obtained (Table
reactions.
2, entries 9 and 11). This could be because the nitro group
increases the acidity of the hydroxyl group, which is likely to be
deprotonated, and thus reducing the electrophilicity of the
aldehyde group. It was found that 4-(diethylamino)salicylalde-
hyde (4j) did not give both coumarin (6j) and chromene (7j)
(Table 2, entry 10). This could be because a diethylamino group
of 4j probably makes an aldehyde group less reactive via para-
donating electron from a nitrogen atom.
Results and discussion
The TH catalyst was simply prepared from the acid hydrolysis of
bovine tendons. The hydrolysate obtained from acid hydrolysis
was neutralized by base, and then extracted with MeOH to give
the TH catalyst. The reaction between salicylaldehyde (4a)
methyl acetoacetate (5) catalyzed by the TH catalyst under
As mentioned earlier, this reaction gave two diastereomers of
chromene products with the ratio of ca. 1.5–2.0 to 1 for the
ꢀ
solvent-free condition (at 55 C) was initially investigated; this
reaction gave coumarin 6a and two diastereomers of chromene
7a as products (Fig. 3). We also found that methyl acetoacetate
Table 1 Effects of the molar ratio of 4a : 5 on the yield of 6a and 7aa
Entry
4a : 5
Time (h)
6a : 7ab
1
2
3
4
1 : 1
1 : 3
1 : 5
1 : 7
65
65
65
65
15 : 8
3 : 4
7 : 11
1 : 2
a
Reactions were performed using salicylaldehyde (50 mg, 0.41 mmol)
b
Fig. 3 Reaction of salicylaldehyde (4a) and methyl acetoacetate (5)
catalyzed by the TH catalyst.
and 20% (by weight) of the TH catalyst. The ratio of 6a : 7a was
determined by 1H NMR spectrum.
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Table 2 Synthesis of coumarins and chromenes from salicylaldehyde derivatives (4) and methyl acetoacetate (5) using the TH catalysta
Paper
Entry 4
Coumarin (% yield) Chromenef (% yield) Time (h) Entry 4
Coumarin (% yield) Chromenef (% yield) Time (h)
1
29
25
7
8
72
23%e
38%h,d
40%b
17%i,e
2
72
28%c
14%c
46%h,d
3%e
21%i,e
3
4
72
25
9
24
26%h,b
41%b
0%
10
72g
28%c
42%h,d
Trace amount
0%
0%
5
72
72
11
36
54%b
31%h,d
42%c
6
39%b
33%h,d
a
b
Reactions contained ca. 4.09 mmol of salicylaldehyde derivatives (4), ca. 12.28 mmol of 5, and 20% of the TH catalyst (at 55 ꢀC). Yield of the
c
product that was precipitated and obtained without chromatographic separation. Yield from product precipitation and chromatographic
separation. Yield from crystallization and chromatographic separation. Yield from chromatographic separation. Before crystallization, the
d
e
f
g
h
ratios of ca. 1.5–2.0 to 1 for the major diastereomer to minor diastereomer were observed. Substrate was recovered. Yield of the major
diastereomer of chromene. i Yield of two diastereomers of chromene.
1
major diastereomer to minor diastereomer. H NMR spectrum of chromenes 7a–f (26–46% yield) were obtained aer crystal-
(ESI, Fig. 1S†) of the two diastereomers (0.429 g) of chromene 7b lization. It should be noted that chromenes 7g and 7h could not
indicated the ratio of 2 to 1 (a major isomer to a minor isomer). be crystallized, and unfortunately they could not be separated
However, aer crystallization from EtOH–CH2Cl2, a large by chromatographic techniques; therefore, percentage yields of
amount (0.397 g) of the major diastereomer of chromene 7b was chromenes 7g and 7h were of a mixture of the two diastereo-
obtained, leaving only 0.029 g of the ltrate containing the two mers (Table 2, entries 7 and 8).
chromene diastereomers at the ratio of 5 : 3 (ESI, Fig. 2S†). This
The structure of a major diastereomer of chromene 7a was
result suggested that only the major diastereomer could be elucidated by analysis of spectroscopic data; extensive analysis
crystallizable, and that the minor diastereomer was converted of 2D NMR data established a planar structure of 7a. Fortu-
to the major diastereomer during crystallization. As shown in nately, appropriate crystals of the major diastereomer of chro-
Table 2 (entries 1–6), large amounts of the major diastereomer menes 7a, 7b, 7e, and 7f were obtained, and they were subjected
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between the two chromene diastereomers proceeds via an enol
intermediate (ESI, Fig. 3S†). It is worth mentioning that this is
the rst report on the preparation of a single 4S,20R-diaste-
reomer of chromenes (e.g. 7a–f), particularly under environ-
mentally benign conditions.
Tendons are proteins rich in hydroxyproline and proline
amino acids.37–39 The fact that both proline and hydroxyproline
are robust organocatalysts,28–31,40 we therefore propose that the
two amino acids in the TH catalyst are possibly responsible for
the catalytic activity. Analysis of an amino acid content in the
TH catalyst revealed that, among 20 natural amino acids, the
percentage of proline and hydroxyproline were 15.89% and
13.12%, respectively (ESI, Table 2S†), which were relatively
high as compared to other amino acids, except glycine
(19.23%). To prove our hypothesis, we then used L-proline
(20% mol) as a catalyst for the reaction entries 1, 2, and 5
(Table 2). Indeed, we found that L-proline gave the same
coumarins and chromenes as that obtained from the TH
catalyst; respective yields of coumarins 6a, 6b, and 6e were
29%, 28%, and 50%, while those of chromenes 7a, 7b, and 7e
were 40%, 18%, and 24%, respectively. However, hydroxypro-
line (20% mol) did not catalyze such reaction, possibly due to
the insolubility of hydroxyproline in solvent-free conditions
(its precipitate was observed). This result conclusively indi-
cated that hydroxyproline did not involve in the reaction under
solvent-free conditions. We then performed the reaction in
EtOH : H2O (9 : 1), in which hydroxyproline could be
completely dissolved; the reaction proceeded under this
condition, giving respective yields of 23%, 14%, and 24% for
coumarins 6a, 6b, and 6e and 9%, 17%, and 8% for chromenes
7a, 7b, and 7e. Therefore, hydroxyproline also had a catalytic
activity for the formation of chromenes and coumarins under a
relatively polar condition that could dissolve hydroxyproline,
but not under solvent-free conditions as shown in Table 2. A
proposed mechanism for the formation of coumarin and
chromene catalyzed by amino acids is shown in Fig. 5. The
reaction starts with a condensation of an aldehyde and a
catalyst (represented as L-proline), giving rise to an iminium
intermediate A, which subsequently reacts with methyl ace-
toacetate (5), to give the intermediate B. Lactonization of B
leads to the formation of the intermediate C. A release of a
catalyst from the intermediate C gives rise to a coumarin D.
Alternatively, a phenolic group of the intermediate B intra-
molecularly attacks a carbonyl to give the intermediate E; a
release of a catalyst from the intermediate E yields the inter-
mediate F. Loss of water assisted by lone pair electrons on
oxygen gives the oxonium intermediate G, which in turn reacts
with methyl acetoacetate (5) to give a chromene H (Fig. 5).
Fig. 4 ORTEP plots (30% probability level) of chromenes 7a, 7b, 7e,
and 7f (color codes: C ¼ cyan, O ¼ red, Br ¼ orange, Cl ¼ green,
H ¼ white).
Fig. 5 A proposed mechanism for the formation of coumarin and
chromene.
to a single crystal X-ray analysis, which conclusively disclosed
the relative conguration of S* and R* for the positions 4 and 20,
respectively (Fig. 4). We proposed that the isomerization
Table 3 Multigram scale synthesis of coumarin 6a and chromene 7a
Weight of
4a (g)
Temperature
Yield of 6a
(g) (%)
Yield of 7a
(g) (%)
Entry
Ratio of 4a : 5
(ꢀC)
Time (h)
1
2
3
10.0
10.6
10.4
1 : 3
1 : 7
1 : 7
55
55
80
72
72
15
4.3 (28%)
6.8 (41%)
4.8 (30%)
8.6 (33%)
10.4 (37%)
9.9 (36%)
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Table 4 Three-component reaction of salicylaldehyde derivatives (4), Table 4 (Contd.)
dimedone derivatives (8), and nucleophiles (NuH) by the TH catalyst
Entry
NuH
Product
Time (h)
Yield (%)
Entry
1
NuH
Product
Time (h)
24
Yield (%)
67
9
16
73
2
3
24
24
79
56
10
4
70
Since the TH catalyst is inexpensive, we performed multi-
gram scale synthesis of coumarin 6a and chromene 7a with
three separated (solvent-free) conditions (Table 3). With ca. 10 g
of a substrate 4a, respective yields of 28–41% and 33–37% for
coumarin 6a and chromene 7a were obtained (Table 3), indi-
cating that a practical multigram scale synthesis of coumarins
and chromenes is feasible with the TH catalyst. The TH catalyst
is a green catalyst derived from renewable materials (bovine
tendons), and the solvent-free conditions employed for this
multigram scale synthesis is also environmentally friendly.
Next we used the TH catalyst for the synthesis of densely
functionalized 4H-chromenes via a three-component reaction.
Gu et al. reported the elegant green chemistry route for the
synthesis of densely functionalized 4H-chromenes via a three-
component reaction of salicylaldehydes, 1,3-cyclohexanediones,
and nucleophiles, employing L-proline as catalyst, and some
products could be easily isolated by ltration, avoiding the use
of chromatographic separations.41 We followed Gu method for
the synthesis of 4H-chromenes, using our TH catalyst. As shown
in Table 4, the reaction of salicylaldehyde derivatives (4),
dimedone derivatives (8), and nucleophiles (NuH) gave chro-
menes (9a–j) with yields of 43–95%. It should be noted that
chromene products (9a–j) were obtained by ltration and
washing with ethanol (without chromatographic separations).
Chromenes 9a–c were previously synthesized by Gu and
coworkers with respective yields of 98, 88, and 87%,41 however,
these chromenes (9a–c) obtained from the present work (by the
TH catalyst) were 67, 79, 56%, respectively (Table 4, entries 1–3).
It should be noted that Gu and coworkers cooled the reaction
mixture to 0 ꢀC before ltration and washing with ethanol,41
however, in the present work, this process was performed at
4
5
24
24
95
76
6
7
24
16
43
66
8
16
73
ꢀ
room temperature (26–28 C). This may be the reason that the
yields of 9a–c were lower than Gu method.41 Compounds 9d–j
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were new chromenes (Table 4, entries 4–10) obtained from the
Since hydroxyproline was also present in the TH catalyst (ESI,
TH catalyst with yields $ 70%, except 9f (43%) and 9g (66%). Table 2S†), we then performed the three-component reaction
Although chromene products were simply obtained by ltration for the synthesis of 4H-chromenes 9n and 9p using hydrox-
and washing with ethanol, we observed that the derivatives that yproline as a catalyst. Surprisingly, quantitative yields of the
are relatively polar (e.g., 9c and 9f, Table 4, entries 3 and 6) had chromenes 9n (99.5%) and 9p (99.8%) were obtained from the
substantial yield losses from ethanol washing. Whereas non- reaction; this result indicated that hydroxyproline in the TH
polar products (e.g., 9d) did not have much yield losses from catalyst should also involve in the formation of chromenes. This
ethanol washing, and thus providing good yield (95%).
Apart from the chromene synthesis reported by Gu and synthesis of 4H-chromenes via the three-component reaction.
coworkers,41 there were other works recently reported for the
Overall, the present study highlights a feasible eco-friendly
is the rst report on a catalytic activity of hydroxyproline for the
synthesis of densely functionalized 4H-chromenes using ZnO multigram scale synthesis of coumarins and chromenes with a
nanoparticles,42 tetrabutylammonium uoride,43 L-proline,44 green catalyst from renewable materials, bovine tendons. It
and iron(III) chloride and triphenylphosphine45 as catalysts. The should be noted that bovine tendons are used as food ingredi-
TH catalyst is much cheaper than those catalysts previously ents in some countries in Asia, but they are waste from meat
employed for such chromene synthesis,41–45 and we therefore industry in Western countries. The multigram scale synthesis of
used the TH catalyst for multigram scale synthesis of chro- coumarins and/or chromenes reported here could be performed
menes. As shown in Fig. 6, a scale of ca. 10 g salicylaldehyde under solvent-free conditions (Table 3) or without chromato-
derivatives was used with 20% of the TH catalyst. Aer stirring graphic separations of the products (Fig. 6). Therefore, both the
ꢀ
the reaction mixture at 80 C for 15–18 h, chromene products catalyst and the synthetic method are green and friendly to the
(9k–p) were simply obtained by ltration and washing with environment.
ethanol, giving yields of 56, 91, 74, 85, 96, and 97%, respectively
(Fig. 6). This result indicates that the economical and green TH
Conclusions
catalyst is applicable in the multigram scale synthesis of chro-
menes; the products were easily obtained without chromato-
The economical, easily accessible, and environmentally friendly
graphic separations.
TH catalyst was prepared from the acid hydrolysis of bovine
tendons which are renewable materials. The TH catalyst cata-
lyzed the synthesis of coumarins and chromenes (e.g., 7a–h)
under the solvent-free conditions, and it also catalyzed the
synthesis of densely functionalized 4H-chromenes via the three-
component reaction. Moreover, the TH catalyst is applicable in
the multigram scale synthesis of coumarins and chromenes, as
well as in the three-component reaction for the construction of
the 4H-chromenes. A multigram scale preparation of chro-
menes with a single 4S,20R-diastereomer was demonstrated for
the rst time. Proline, not hydroxyproline, in the TH catalyst
possibly catalyzes the formation of coumarins and chromenes
under solvent-free conditions. In addition to proline, hydrox-
yproline was also found to catalyze the three-component reac-
tion for the synthesis of 4H-chromenes. To the best of our
knowledge, this is the rst report on the green catalyst prepared
from renewable materials.
Experimental section
Instruments
Melting points were measured on Buchi 535 Melting Point
Apparatus and reported without correction. UV-Vis spectra were
obtained from Shimadzu UV-1700 PharmaSpec Spectropho-
tometer. FTIR data were obtained using a universal attenuated
total reectance (UATR) attachment on a Perkin-Elmer Spec-
trum One spectrometer. 1H and 13C NMR spectra were recorded
on a Bruker AM 300 NMR instrument (operating at 300 MHz for
1H and 75 MHz for 13C) and a Bruker AVANCE 400 NMR spec-
1
trometer (operating at 400 MHz for H and 100 MHz for 13C).
APCI TOF MS spectra were obtained from a Bruker MicroTOFLC
Fig. 6 Multigram scale synthesis of chromenes 9k–p.
spectrometer.
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with 100% MeOH), followed by silica gel preparative TLC
(developed with 20% EtOAc in hexane) to obtain coumarin 6a
and a mixture of the two diastereomers of chromene 7a. The
mixture of the two diastereomers of chromene 7a was dissolved
in a mixture of EtOH–CH2Cl2 (2 : 1) and le at room tempera-
ture, and the major diastereomer of chromene 7a again crys-
tallized from a solution.
Preparation of the TH catalyst
Two batches of the TH catalyst were prepared, and the TH
catalysts from both batches had the same catalytic properties.
Amino acid content in the TH catalyst is in Table 2S (ESI).†
The rst batch. Bovine tendon (135 g) was hydrolyzed in
110 mL of 6 M HCl. A mixture was stirred and reuxed for 12 h;
pH of the mixture was adjusted to 7 with saturated NaOH. The
mixture was dried by a rotary evaporator, vacuum-dried, and
then dissolved in methanol. The methanol soluble part was
collected and dried to yield 7 g of the TH catalyst.
The second batch. Bovine tendon (256 g) was hydrolyzed in
90 mL of 6 M HCl. The mixture was stirred and reuxed for 18 h,
and its pH was adjusted to 7 with saturated NaOH. The mixture
was dried by a rotary evaporator, vacuum-dried, and extracted
with 100 mL of MeOH (eleven times, a total volume of 1100 mL).
The MeOH extracts were combined and dried, giving 24 g of the
TH catalyst.
(S*)-Methyl 4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-
4H-chromene-3-carboxylate (7a). Colorless crystals; mp 119–122 ꢀC;
UV (MeOH) lmax (log 3) 268 (3.68); IR (UATR) nmax: 3002, 2952, 2840,
1713, 1640, 1584, 1488, 1459, 1434, 1381, 1356, 1291, 1218, 1188,
1
1154, 1106, 1064, 990, 947, 822, 758 cmꢁ1; H NMR (400 MHz,
CDCl3) d: 2.21 (s, 3H), 2.44 (s, 3H), 3.44 (s, 3H), 3.65 (d, J ¼ 4.5 Hz,
1H), 3.76 (s, 3H), 4.76 (d, J ¼ 4.5 Hz, 1H), 6.98 (dd, J ¼ 1.0 Hz, 8.1
Hz, 1H), 7.05 (td, J ¼ 1.2 Hz, 7.5 Hz, 1H), 7.19 (td, J ¼ 1.1 Hz, 8.0 Hz,
1H) 7.29 (dd, J ¼ 1.5 Hz, 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
19.7, 29.5, 34.6, 51.5, 51.9, 66.1, 103.4, 115.8, 121.4, 124.3, 128.2,
129.1, 151.2, 163.9, 167.1, 168.9, 201.6; APCI-TOF MS: calcd for
C17H18NaO6, m/z 341.0996 (M + Na)+, found 341.1000.
General procedure for the synthesis of coumarins and
chromenes using the TH catalyst
Synthesis of coumarin 6b and chromene 7b
A mixture of a salicylaldehyde derivative (500 mg, 1 equiv.) and
methyl acetoacetate (3 equiv.) was added the TH catalyst (20%
by weight of a salicylaldehyde derivative). The reaction was
stirred at 55 ꢀC, and the progress of a reaction was monitored by
TLC. Aer the reaction was complete (the time for each reaction
is indicated in Table 2), if coumarin product precipitated, it was
collected by ltration. However, if the coumarin product did not
precipitate, the reaction mixture was le at room temperature,
in order to crystallize chromene product. In case that both
chromene and coumarin did not crystallize or precipitate, the
reaction mixture was subjected to chromatographic separations
(i.e., Sephadex LH-20 column chromatography (CC), silica gel
CC, and preparative TLC). In some cases, chromene or
coumarin in the fractions obtained from chromatographic
separations were recrystallized from EtOH–CH2Cl2.
Multigram scale synthesis of coumarin 6a and chromene 7a
was performed with ca. 10 g of salicylaldehyde 4a, using 20% of
the TH catalyst. The ratio of substrates 4a and 5, time, and
temperature for the reaction were indicated in Table 3. Aer the
reaction was complete, it was added an equal volume of CH2Cl2
and H2O; compounds 6a and 7a were in the CH2Cl2 layer, while
the TH catalyst was in the H2O layer. The CH2Cl2 layer was le at
room temperature, and chromene 7a crystallized from the
mixture, followed by coumarin 6a. Finally, a mother liquid was
separated by Sephadex LH-20 CC (eluted with MeOH); fractions
were le at room temperature, and 6a or 7a individually crys-
tallized from the fractions.
Compounds 6b and 7b were prepared according to the general
procedure. Coumarin 6b precipitated from the reaction
mixture. Aer removing coumarin 6b, the reaction mixture was
washed with water to remove a catalyst, dried under vacuum,
and further puried by Sephadex LH-20 CC (eluted with 100%
MeOH) to obtain additional amounts of coumarin 6b and the
mixture of two diastereomers of chromene 7b. The mixture of
two diastereomers of chromene 7b was dissolved in a mixture of
EtOH–CH2Cl2 (2 : 1) and le at room temperature, and the
major diastereomer of chromene 7b crystallized from a
solution.
(S*)-Methyl 6-methoxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-
yl)-2-methyl-4H-chromene-3-carboxylate (7b). Yellow crystals;
mp 97–98 ꢀC; UV (MeOH) lmax (log 3) 279 (3.83); IR (UATR) nmax
:
2997, 2952, 2838, 1713, 1636, 1601, 1496, 1433, 1380, 1351,
1283, 1244, 1204, 1155, 1106, 1068, 1034, 992, 947, 870, 814,
1
774, 721, 696 cmꢁ1; H NMR (300 MHz, CDCl3) d: 2.16 (s, 3H),
2.38 (s, 3H), 3.41 (s, 3H), 3.62 (d, J ¼ 6 Hz, 1H), 3.71 (s, 6H), 4.69
(d, J ¼ 3 Hz, 1H), 6.68 (dd, J ¼ 3 Hz, 9 Hz, 1H), 6.80 (d, J ¼ 3 Hz,
1H), 6.86 (d, J ¼ 9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 19.3,
29.0, 34.4, 51.0, 51.6, 55.0, 65.7, 102.1, 112.6, 114.0, 116.1, 121.7,
144.9, 155.7, 163.8, 166.7, 168.6, 201.3; ESI-TOF MS: calcd for
C
18H20NaO7, m/z 371.1101 (M + Na)+, found 371.1106.
Synthesis of coumarin 6c and chromene 7c
Compounds 6c and 7c were prepared according to the general
procedure. The major diastereomer of chromene 7c precipi-
tated from the reaction mixture. Aer removing precipitate of
7c, the resulting mixture was le at room temperature, and
Synthesis of coumarin 6a and chromene 7a
Both 6a and 7a were prepared according to the general proce- coumarin 6c was precipitated. Aer removing coumarin 6c, the
dure. The crude reaction mixture was le at room temperature, reaction mixture was puried by Sephadex LH-20 CC, eluted
and the major diastereomer of chromene 7a crystallized from with 100% MeOH, to obtain fractions that contained coumarin
the mixture. Aer removing crystals of 7a, the reaction mixture 6c, and these fractions were combined. A combined fraction
was then washed with water to remove a catalyst, dried under containing 6c was dried by a rotary evaporator, and dissolved in
vacuum, and further puried by Sephadex LH-20 CC (eluted EtOH–CH2Cl2; coumarin 6c crystallized from EtOH–CH2Cl2.
13714 | RSC Adv., 2014, 4, 13708–13718
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(S*)-Methyl 7-methoxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-
RSC Advances
ꢀ
mp 119–120 C; UV (MeOH) lmax (log 3) 272 (3.73); IR (UATR)
nmax: 3003, 2953, 2922, 1714, 1645, 1578, 1480, 1435, 1382, 1344,
1279, 1221, 1189, 1161, 1116, 1069, 993, 894, 826, 775 cmꢁ1; 1H
NMR (300 MHz, CDCl3) d: 2.21 (s, 3H), 2.43 (s, 3H), 3.48 (s, 3H),
3.64 (d, J ¼ 3 Hz, 1H), 3.77 (s, 3H), 4.72 (d, J ¼ 3 Hz, 1H), 6.87 (d,
J ¼ 9 Hz, 1H), 6.29 (m, 1H), 7.46 (s, 1H); 13C NMR (75 MHz,
CDCl3) d: 19.7, 29.5, 34.3, 51.7, 52.2, 65.9, 103.3, 116.7, 117.6,
123.6, 131.2, 131.9, 150.5, 163.9, 166.9, 168.8, 201.24; ESI-TOF
MS: calcd for C17H17BrNaO6, m/z 419.0101 (M + Na)+, found
419.0093.
yl)-2-methyl-4H-chromene-3-carboxylate (7c). White solid; UV
(MeOH) lmax (log 3) 271 (3.75), 222 (4.21); IR (UATR) nmax: 3003,
2952, 2841, 1705, 1638, 1583, 1508, 1437, 1385, 1358, 1337,
1288, 1260, 1243, 1206, 1189, 1157, 1140, 1069, 1035, 1005, 952,
1
849, 805, 778, 715 cmꢁ1; H NMR (300 MHz, CDCl3) d: 2.21 (s,
3H), 2.43 (s, 3H), 3.47 (s, 3H), 3.64 (d, J ¼ 3 Hz, 1H), 3.76–3.77 (s,
6H), 4.70 (d, J ¼ 3 Hz, 1H), 6.54 (d, J ¼ 3 Hz, 1H), 6.80 (d, J ¼ 3
Hz, 1H), 6.63 (d, J ¼ 9 Hz, 1H), 7.19 (d, J ¼ 6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d: 19.8, 29.6, 34.2, 51.6, 52.1, 55.4, 66.1, 101.1,
103.8, 110.8, 113.3, 129.8, 152.1, 159.6, 164.0, 167.3, 169.2,
202.0; ESI-TOF MS: calcd for C18H20NaO7, m/z 371.1101 (M +
Na)+, found 371.1109.
Synthesis of coumarin 6f and chromene 7f
Compounds 6f and 7f were prepared according to the general
procedure. Coumarin 6f precipitated from the reaction mixture.
Aer removing coumarin 6f, the reaction mixture was le at
room temperature, and the major diastereomer of chromene 7f
crystallized from the mixture. Aer removing crystals of 7f, the
reaction mixture was washed with water to remove a catalyst,
dried under vacuum, and puried by silica gel preparative TLC
(developed with 25% EtOAc in petroleum ether) to obtain a
mixture of the two diastereomers of 7f. The mixture of two
chromene diastereomers 7f was dissolved in EtOH–CH2Cl2 and
le at room temperature; the major diastereomer of chromene
7f crystallized from EtOH–CH2Cl2.
Synthesis of coumarin 6d and chromene 7d
Compounds 6d and 7d were prepared according to the general
procedure. Coumarin 6d precipitated from the reaction mixture.
Aer removing coumarin 6d, the reaction mixture was le at
room temperature, and the major diastereomer of chromene 7d
crystallized from the mixture. Aer removing crystals of 7d, the
reaction mixture was washed with water to remove a catalyst,
dried under vacuum, and further puried by Sephadex LH-20 CC
(eluted with 100% MeOH), followed by silica gel CC (eluted with
20% EtOAc in petroleum ether) to obtain additional amounts of
coumarin 6d and a mixture of two chromene diastereomers 7d.
The mixture of the two chromene diastereomers 7d was dissolved
in EtOH–CH2Cl2 (2 : 1) and le at room temperature; the major
diastereomer of chromene 7d crystallized from EtOH–CH2Cl2.
(S*)-Methyl 8-hydroxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-
yl)-2-methyl-4H-chromene-3-carboxylate (7d). Colorless crystals;
(S*)-Methyl 6-chloro-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-
2-methyl-4H-chromene-3-carboxylate (7f). Colorless crystals;
ꢀ
mp 111–113 C; UV (MeOH) lmax (log 3) 271 (3.48); IR (UATR)
nmax: 3003, 2953, 2841, 1716, 1694, 1643, 1582, 1483, 1435, 1381,
1351, 1281, 1223, 1190, 1158, 1116, 1069, 992, 950, 887, 820,
775, 664 cmꢁ1; 1H NMR (400 MHz, CDCl3) d: 2.21 (s, 3H), 2.43 (s,
3H), 3.48 (s, 3H), 3.64 (d, J ¼ 4.4 Hz, 1H), 3.77 (s, 3H), 4.72 (d, J ¼
4.2 Hz, 1H), 6.92 (d, J ¼ 8.7 Hz, 1H), 7.16 (dd, J ¼ 2.5 Hz, 8.7 Hz,
1H), 7.32 (d, J ¼ 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 19.6,
29.5, 34.4, 51.6, 52.1, 65.9, 103.2, 117.1, 123.1, 128.2, 129.0,
129.2, 150.0, 163.9, 166.9, 168.8, 201.3; ESI-TOF MS: calcd for
ꢀ
mp 124–126 C; UV (MeOH) lmax (log 3) 286 (3.62), 267 (3.65),
205 (4.20); IR (UATR) nmax: 3420, 3002, 2953, 2845, 1712, 1641,
1617, 1598, 1480, 1435, 1382, 1356, 1211, 1160, 1084, 995, 843,
781, 734 cmꢁ1; 1H NMR (400 MHz, CDCl3) d: 2.21 (s, 3H), 2.49 (s,
3H), 3.47 (s, 3H), 3.64 (d, J ¼ 4.9 Hz, 1H), 3.78 (s, 3H), 4.76 (d, J ¼
4.8 Hz, 1H), 5.44 (s, 1H), 6.79–6.86 (m, 2H), 6.92–6.98 (m, 2H);
13C NMR (100 MHz, CDCl3) d: 19.6, 29.5, 34.7, 51.6, 52.1, 66.0,
104.2, 114.6, 119.9, 122.1, 124.5, 139.1, 143.5, 163.3, 167.1,
168.9, 201.7; ESI-TOF MS: calcd for C17H18NaO7, m/z 357.0944
(M + Na)+, found 357.0952.
C
17H17ClNaO6, m/z 375.0606 (M + Na)+, found 375.0603.
Synthesis of coumarin 6g and chromene 7g
Compounds 6g and 7g were prepared according to the general
procedure. Coumarin 6g precipitated from the reaction mixture.
Aer removing coumarin 6g, the reaction mixture was washed
with water to remove a catalyst, dried under vacuum, and
Synthesis of coumarin 6e and chromene 7e
Compounds 6e and 7e were prepared according to the general puried by preparative TLC (50% EtOAc in petroleum ether) to
procedure. Coumarin 6e precipitated from the reaction mixture. obtain the mixture of two diastereomers of chromene 7g.
Aer removing coumarin 6e, the reaction mixture was le at
3-Acetyl-5-bromo-8-methoxy-2H-chromen-2-one (6g). Yellow
room temperature, and the major diastereomer of chromene 7e solid; UV (MeOH) lmax (log 3) 320 (3.80), 259 (3.62), 213 (4.08); IR
crystallized from the mixture. Aer removing crystals of 7e, the (UATR) nmax: 3084, 2942, 1733, 1686, 1592, 1563, 1466, 1437,
reaction mixture was then washed with water to remove a 1358, 1328, 1264, 1227, 1202, 1152, 1095, 953, 924, 832, 765
1
catalyst, dried under vacuum, and further puried by silica gel cmꢁ1; H NMR (300 MHz, CDCl3) d: 2.74 (s, 3H), 3.97 (s, 3H),
preparative TLC (developed with 25% EtOAc in petroleum ether) 7.04 (d, J ¼ 9 Hz, 1H), 7.47 (d, J ¼ 6 Hz, 1H), 8.73 (s, 1H); 13C
to obtain the mixture of two chromene diastereomers 7e. The NMR (75 MHz, CDCl3) d: 30.5, 56.5, 113.9, 116.1, 118.5, 125.3,
mixture of the two chromene diastereomers 7e was dissolved in 128.2, 145.7, 146.5, 146.6, 158.0, 195.0; ESI-TOF MS: calcd for
EtOH–CH2Cl2 and le at room temperature; the major diaste-
reomer of chromene 7e crystallized from EtOH–CH2Cl2.
C
12H9BrNaO4, m/z 318.9576 (M + Na)+, found 318.9587.
Methyl 5-bromo-8-methoxy-4-(1-methoxy-1,3-dioxobutan-2-
(S*)-Methyl 6-bromo-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)- yl)-2-methyl-4H-chromene-3-carboxylate (7g). Yellow viscous oil;
2-methyl-4H-chromene-3-carboxylate (7e). Colorless crystals; UV (MeOH) lmax (log 3) 292 (3.82), 265 (4.01), 202 (4.61); IR
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(UATR) nmax: 2997, 2951, 2841, 2172, 1717, 1644, 1602, 1578,
1477, 1435, 1382, 1357, 1312, 1237, 1210, 1155, 1096, 1062, 883,
800 cmꢁ1; The major diastereomer: 1H NMR (300 MHz, CDCl3) d:
2.36 (s, 3H), 2.51 (s, 3H), 3.54 (s, 3H), 3.73 (s, 3H), 3.86 (s, 3H),
3.95 (d, J ¼ 3 Hz, 1H), 4.81 (d, J ¼ 3 Hz, 1H), 6.71–6.75 (m, 1H),
7.27–7.31 (m, 1H); 13C NMR (75 MHz, CDCl3) d: 19.4, 30.0, 36.2,
51.3, 52.0, 56.2, 62.3, 101.5, 111.9, 112.4, 122.4, 127.4, 127.8,
147.3, 163.7, 167.1, 167.8, 201.1; The minor diastereomer: 1H
NMR (300 MHz, CDCl3) d: 2.11 (s, 3H), 2.47 (s, 3H), 3.66 (s, 3H),
3.79 (s, 3H), 3.87 (s, 3H), 3.94–3.97 (m, 1H), 4.85 (d, J ¼ 3 Hz, 1H),
6.71–6.75 (m, 1H), 7.27–7.31 (m, 1H); 13C NMR (75 MHz, CDCl3)
d: 19.1, 30.1, 36.8, 51.7, 52.3, 56.3, 62.4, 103.8, 111.4, 112.4, 122.4,
Synthesis of coumarin 6k and chromene 7k
The synthesis was performed according to the general proce-
dure. Coumarin 6k precipitated from the reaction mixture. Aer
removing coumarin 6k, the resulting reaction mixture was then
puried by silica gel preparative TLC (100% CH2Cl2) to obtain
additional amounts of coumarin 6k. Chromene 7k was not
formed from this reaction.
General procedure of three-component reactions of
salicylaldehyde derivatives (4), 1,3-cyclohexanedione
derivatives (8), and nucleophiles (NuH) by the TH catalyst
127.4, 127.8, 147.2, 162.9, 167.1, 168.2, 201.2; ESI-TOF MS: calcd A mixture of salicylaldehyde derivatives (4) (1.0–1.7 mmol; 1
for C18H19BrNaO7, m/z 449.0206 (M + Na)+, found 449.0215.
equiv.), 1,3-cyclohexanedione derivatives (8) (1 equiv.), NuH
(1 equiv.) and the TH catalyst (20% by weight) in ethanol (3 mL)
was stirred at 80 ꢀC. The time for each reaction was indicated in
Table 4. The reaction mixture was cooled to room temperature,
and it was ltered and washed with ethanol to yield chromenes.
Spectroscopic data of chromenes 9a–c,41 9d,43 and 9e (ref. 46)
were identical to those reported in the literature.
Multigram scale synthesis of chromenes was performed in
the same manner as that mentioned above. Amounts of ca. 10 g
of salicylaldehyde derivatives (4), with 1 equivalent of 1,3-
cyclohexanedione derivatives (8) and NuH, were used in the
experiment; the reaction time was 15–18 h (Fig. 6). Spectro-
scopic data of chromene 9k were in good agreement with those
in the literature.42,44,45
7-Bromo-9-(1H-indol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-
one (9f). White solid; UV (MeOH) lmax (log 3) 280 (4.34) 221
(4.78); IR (UATR) nmax: 3747, 3403, 3331, 3056, 2949, 2303, 1638,
1575, 1474, 1456, 1422, 1375, 1338, 1233, 1181, 1135, 1097,
1068, 997, 912, 816, 795, 739 cmꢁ1; 1H NMR (300 MHz, CDCl3) d:
1.62–2.06 (m, 2H), 2.32–2.36 (m, 2H), 2.57–2.79 (m, 2H), 5.28 (s,
1H), 6.96–7.01 (m, 2H), 7.07–7.14 (m, 2H), 7.22–7.30 (m, 3H),
7.36 (d, J ¼ 8 Hz, 1H), 8.15 (s, 1H); 13C NMR (75 MHz, CDCl3) d:
20.3, 27.7, 29.6, 37.0, 111.4, 113.6, 117.2, 118.0, 118.8, 119.5,
119.7, 121.7, 122.7, 125.5, 127.4, 130.5, 132.8, 136.5, 148.6,
165.7, 197.1; ESI-TOF MS: calcd for C21H16BrNNaO2, m/z
416.0257 (M + Na)+, found 416.0256.
Synthesis of coumarin 6h and chromene 7h
Compounds 6h and 7h were prepared according to the general
procedure. The reaction mixture was washed with water to
remove a catalyst, dried under vacuum, and puried by
Sephadex LH-20 CC (eluted with 100% MeOH) to obtain the
mixture of two chromene diastereomers 7h and the fractions
that contained coumarin 6h. The fractions containing 6h were
combined and puried again by preparative TLC (40% hexane
in CH2Cl2) to give coumarin 6h.
Methyl 6,8-di-tert-butyl-4-(1-methoxy-1,3-dioxobutan-2-yl)-2-
methyl-4H-chromene-3-carboxylate (7h). Yellow viscous oil; UV
(MeOH) lmax (log 3) 276 (3.83); IR (UATR) nmax: 2954, 2870, 1716,
1643, 1598, 1435, 1380, 1361, 1274, 1246, 1213, 1199, 1170, 1074,
994, 883, 832, 774 cmꢁ1; The major diastereomer: 1H NMR (400
MHz, CDCl3) d: 1.28–1.29 (s, 9H), 1.42 (s, 9H), 2.21 (s, 3H), 2.50
(s, 3H), 3.45 (s, 3H), 3.55 (d, J ¼ 6.1 Hz, 1H), 3.75 (s, 3H), 4.72 (m,
1H) 7.15 (m, 1H), 7.22 (m, 1H); 13C NMR (100 MHz, CDCl3) d:
19.5, 29.4, 30.0, 30.4 (3C), 31.4 (3C), 34.8, 36.1, 51.4, 52.0, 66.4,
103.8, 121.6, 122.4, 123.9, 127.3, 136.1, 146.3, 163.9, 167.1, 169.0,
201.7; the minor diastereomer: 1H NMR (400 MHz, CDCl3) d:
1.28–1.29 (s, 9H), 1.42 (s, 9H), 1.78 (s, 3H), 2.49 (s, 3H), 3.64 (d, J
¼ 6.5 Hz, 1H) 3.71 (s, 3H), 3.77 (s, 3H), 4.72 (m, 1H) 7.15 (m, 1H),
7.22 (m, 1H); 13C NMR (100 MHz, CDCl3) d: 19.3, 29.5, 29.7, 30.0
(3C), 31.4 (3C), 34.5, 36.7, 51.4, 52.2, 64.9, 104.2, 121.8, 122.5,
123.7, 127.2, 136.4, 146.6, 163.4, 167.1, 168.6, 202.3; ESI-TOF MS:
calcd for C25H34NaO6, m/z 453.2248 (M + Na)+, found 453.2261.
9-(1H-Indol-3-yl)-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydro-
1H-xanthen-1-one (9g). Orange solid; UV (MeOH) lmax (log 3)
283 (4.09), 223 (4.65), 203 (4.59); IR (UATR) nmax: 3408, 3336,
3050, 2958, 2869, 1637, 1582, 1542, 1505, 1456, 1421, 1374,
1336, 1284, 1264, 1190, 1167, 1145, 1112, 1096, 1035, 1013, 957,
1
838, 782, 738, 704 cmꢁ1; H NMR (300 MHz, CDCl3) d: 0.95 (s,
Synthesis of coumarin 6i and chromene 7i
3H), 1.10 (s, 3H), 2.17 (d, J ¼ 16 Hz, 1H), 2.25 (d, J ¼ 16 Hz, 1H),
2.51 (d, J ¼ 18 Hz, 1H), 2.59 (d, J ¼ 17 Hz, 1H), 3.76 (s, 3H), 5.25
(s, 1H), 6.56 (dd, J ¼ 9, 3 Hz, 1H), 6.63 (d, J ¼ 3 Hz, 1H), 6.98 (td, J
¼ 8, 1 Hz, 1H), 7.05 (m, 2H), 7.15 (d, J ¼ 2 Hz, 1H), 7.25 (d, J ¼ 8
Hz, 1H), 7.37 (d, J ¼ 8 Hz, 1H), 8.02 (brs, 1H); 13C NMR (75 MHz,
CDCl3) d: 27.6, 28.9, 29.0, 32.0, 41.5, 50.9, 55.4, 101.2, 111.2,
111.5, 113.0, 117.3, 119.0, 119.2, 120.5, 121.5, 122.3, 125.6,
130.6, 136.5, 150.0, 158.8, 164.1, 197.4; ESI-TOF MS: calcd for
Compound 6i was prepared according to the general procedure.
The reaction mixture was added ethanol to precipitate
coumarin 6i, and 6i was then collected by ltration. Chromene
7i was not obtained from this reaction.
Synthesis of coumarin 6j and chromene 7j
C
24H23NNaO3, m/z 396.1570 (M + Na)+, found 396.1574.
The synthesis was performed according to the general proce-
3-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-
dure. However, the reaction did not give coumarin 6j and 1H-indole-2-carboxylic acid (9h). White solid; UV (MeOH) lmax
chromene 7j.
(log 3) 296 (3.77), 227 (4.01); IR (UATR) nmax: 3261, 2937, 2877,
13716 | RSC Adv., 2014, 4, 13708–13718
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1676, 1644, 1579, 1547, 1485, 1446, 1417, 1376, 1350, 1319, 1289, 148.6, 169.2, 196.0; ESI-TOF MS: calcd for C19H14ClN3NaO2, m/z
1257, 1227, 1201, 1183, 1143, 1199, 1034, 1015, 913, 875, 758, 374.0667 (M + Na)+, found 374.0658.
736, 710, 682 cmꢁ1; 1H NMR (300 MHz, DMSO-d6) d: 0.87 (s, 3H),
9-Benzotriazol-1-yl-8-bromo-5-methoxy-2,3,4,9-tetrahydro-
1.05 (s, 3H), 1.98 (d, J ¼ 16 Hz, 1H), 2.24 (d, J ¼ 16 Hz, 1H), 2.60 xanthen-1-one (9n). White solid; UV (EtOH) lmax (log 3) 293
(d, J ¼ 18 Hz, 1H), 2.68 (d, J ¼ 18 Hz, 1H), 6.25 (s, 1H), 6.87 (t, J ¼ (3.96), 264 (4.26), 207 (4.61); IR (UATR) nmax: 2962, 2940, 2838,
7 Hz, 1H), 6.99 (td, J ¼ 8, 3 Hz, 1H), 7.09–7.17 (m, 3H), 7.20–7.27 1659, 1609, 1578, 1476, 1443, 1386, 1332, 1312, 1278, 1263, 1231,
(m, 2H), 7.34 (d, J ¼ 8 Hz, 1H), 11.50 (s, 1H), 13.18 (brs, 1H); 13
C
1205, 1187, 1158, 1149, 1139, 1125, 1101, 1092, 1064, 1002, 941,
1
NMR (75 MHz, DMSO-d6) d: 26.8, 27.3, 28.8, 31.5, 40.5, 50.3, 917, 873, 818, 802, 776, 764, 735, 743, 702, 657 cmꢁ1; H NMR
111.5 (2C), 112.7, 116.2, 119.2, 119.9, 123.7, 124.0, 124.7, 124.9, (300 MHz, CDCl3) d: 1.95–2.10 (m, 2H), 2.36–2.40 (m, 2H), 2.80–
125.2, 127.7, 129.7, 136.1, 148.6, 163.6, 164.1196.0; ESI-TOF MS: 2.97 (m, 2H), 3.96 (s, 3H), 6.85 (d, J ¼ 8.8 Hz, 1H), 7.11 (s, 1H),
calcd for C24H22NO4, m/z 388.1543 (M + H)+, found 388.1554.
7.28 (d, J ¼ 8.9 Hz, 1H), 7.32 (td, Jt ¼ 8.1 Hz, Jd ¼ 0.7 Hz, 1H), 7.55
7-Bromo-9-((4-methoxybenzyl)thio)-2,3,4,9-tetrahydro-1H- (td, J ¼ 7.9 Hz, Jd ¼ 0.7 Hz, 1H), 7.95 (d, J ¼ 8.4 Hz, 1H), 8.15 (d, J
xanthen-1-one (9i). White crystals; mp 115–117 ꢀC; UV (MeOH) ¼ 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 20.0, 27.6, 36.4, 48.1,
lmax (log 3) 279 (3.57), 205 (4.13); IR (UATR) nmax: 2951, 2830, 56.4, 111.2, 111.7, 112.9, 114.1, 119.3, 120.4, 123.6, 127.2, 128.4,
1641,1608, 1574, 1509, 1474, 1411, 1374, 1301, 1233, 1170, 1133, 133.5, 142.2, 144.8, 147.7, 168.8, 196.2; ESI-TOF MS: calcd for
1033, 995, 908, 814, 734, 670 cmꢁ1; 1H NMR (300 MHz, CDCl3): C20H16BrN3NaO3, m/z 448.0267 (M + Na)+, found 448.0267.
1.81–2.02 (m, 2H), 2.27–2.49 (m, 4H), 3.57 (d, J ¼ 14 Hz, 1H),
5-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-
3.66 (d, J ¼ 14 Hz, 1H), 3.79 (s, 3H), 4.94 (s, 1H), 6.80–6.89 (m, 1,3-dimethyl-pyrimidine-2,4,6-trione (9o). White solid; UV
3H), 7.17–7.20 (m, 3H), 7.28 (dd, J ¼ 9.2 Hz, 1H); 13C NMR (75 (EtOH) lmax (log 3) 267 (3.30), 222 (3.38), 204 (3.50); IR (UATR)
MHz, CDCl3): 19.9, 27.6, 34.7, 34.8, 36.8, 55.3, 111.8, 113.8 (2C), nmax: 3749, 2957, 2886, 1746, 1675, 1643, 1582, 1457, 1421, 1387,
117.5, 117.9, 124.8, 129.9 (2C), 130.2, 131.1, 132.5, 149.5, 158.6, 1319, 1289, 1230, 1185, 1114, 1034, 775, 756 cmꢁ1; 1H NMR (300
166.9, 196.2; ESI-TOF MS: calcd for C21H19BrNaO3S, m/z MHz, CDCl3) d: 1.13 (s, 3H), 1.18 (s, 3H), 2.30 (d, J ¼ 17.3 Hz,
453.0131 (M + Na)+, found 453.0133.
1H), 2.36 (d, J ¼ 16.3 Hz, 1H), 2.48 (d, J ¼ 17.7 Hz, 1H), 2.56 (d, J
5-(3,3-Dimethyl-7-nitro-1-oxo-2,3,4,9-tetrahydro-1H-xanthen- ¼ 17.6 Hz, 1H), 3.07 (s, 3H), 3.21 (s, 3H), 3.85 (d, J ¼ 2.7 Hz, 1H),
9-yl)-1,3-dimethylpyrimidine-2,4,6-(1H,3H,5H)-trione
(9j). 4.87 (s, 1H), 7.03 (d, J ¼ 8.22 Hz, 1H) 7.08–7.09 (m, 2H), 7.22–
White solid; UV (MeOH) lmax (log 3) 318 (3.94), 231 (4.23), 203 7.29 (m, 1H); 13C NMR (75 MHz, CDCl3) d: 27.2, 28.1, 28.2, 29.2,
(4.51); IR (UATR) nmax: 3744, 3070, 2960, 2869, 1747, 1675, 1651, 32.0, 36.3, 41.4, 50.5, 54.9, 108.8, 116.6, 120.5, 124.9, 127.9,
1584, 1526, 1446, 1422, 1381, 1343, 1287, 1235, 1209, 1194, 129.0, 150.4, 151.1, 166.9, 167.2, 168.0, 192.7; ESI-TOF MS: calcd
1147, 1127, 1089, 1031, 905, 840, 801, 749, 735, 702 cmꢁ1; H for C21H22N2NaO5, m/z 405.1421 (M + Na)+, found 405.1430.
1
NMR (300 MHz, CDCl3) d: 1.13 (s, 3H), 1.15 (s, 3H) 2.29 (d, J ¼ 16
5-(7-Chloro-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-
Hz, 1H), 2.37 (d, J ¼ 16 Hz, 1H), 2.55 (s, 2H), 3.21 (s, 3H), 3.26 (s, 9-yl)-1,3-dimethyl-pyrimidine-2,4,6-trione (9p). White solid; UV
3H), 3.90 (d, J ¼ 2 Hz, 1H), 4.97 (s, 1H), 7.17 (dd, J ¼ 8.2 Hz, 1H), (EtOH) lmax (log 3) 265 (4.24), 225 (4.31), 206 (4.42); IR (UATR)
8.1–8.2 (m, 2H); 13C NMR (75 MHz, CDCl3) d: 26.9, 28.5, 28.6, nmax: 2959, 2876, 1734, 1677, 1645, 1449, 1420, 1382, 1287 1234,
29.4, 32.1, 34.6, 41.3, 50.6, 55.4, 108.9, 117.7, 123.2, 124.4, 124.6, 1187, 1119, 1033, 827, 757 cmꢁ1; H NMR (300 MHz, CDCl3) d:
1
144.5, 151.0, 154.6, 166.6, 166.7, 167.2, 197.5; ESI-TOF MS: calcd 1.12 (s, 3H), 1.14 (s, 3H), 2.28 (d, J ¼ 15.9 Hz, 1H), 2.35 (d, J ¼
for C21H21N3NaO7, m/z 450.1272 (M + Na)+, found 450.1262.
16.1 Hz, 1H), 2.47 (d, J ¼ 18.5 Hz, 1H), 2.54 (d, J ¼ 17.8 Hz, 1H),
8-Bromo-9-(1H-indol-3-yl)-5-methoxy-2,3,4,9-tetrahydro- 3.16 (s, 3H), 3.24 (s, 3H), 3.85 (d, J ¼ 2.5 Hz, 1H), 4.84 (s, 1H), 6.98
xanthen-1-one (9l). White solid; UV (EtOH) lmax (log 3) 291 (d, J ¼ 8.7 Hz, 1H), 7.16 (d, J ¼ 2.3 Hz, 1H), 7.21 (dd, Ja ¼ 8.7 Hz,
(4.36), 273 (4.40), 221 (4.96), 213 (4.96); IR (UATR) nmax: 3338, Jb ¼ 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 27.1, 28.3, 28.4,
2319, 1644, 1573, 1471, 1428, 1372, 1311, 1217, 1182, 1135, 29.3, 32.0, 35.5, 41.4, 50.5, 55.1, 108.5, 118.0, 122.9, 127.9, 129.0,
1092, 1062, 869, 800, 745 cmꢁ1; 1H NMR (300 MHz, DMSO-d6) d: 130.0, 148.9, 151.1, 166.8, 167.0, 167.8, 197.4; ESI-TOF MS: calcd
1.66–1.97 (m, 2H), 2.17–2.36 (m, 2H), 2.60–2.76 (m, 2H), 3.87 (s, for C21H21ClN2NaO5, m/z 439.1031 (M + Na)+, found 439.1036.
3H), 5.30 (s, 1H), 6.86–7.01 (m, 3H), 7.08 (d, J ¼ 2.4 Hz, 1H), 7.28
(d, J ¼ 8.6 Hz, 2H), 7.35 (d, J ¼ 7.9 Hz, 1H), 10.90 (s, 1H); 13C
Single crystal X-ray analysis
NMR (75 MHz, DMSO-d6) d: 19.9, 26.7, 29.5, 36.3, 55.9, 111.6,
X-ray diffraction data for chromenes 7a, 7b, 7e, and 7f were
111.9, 113.7, 114.3, 116.4, 118.3, 118.6, 120.5, 124.7, 125.2 (2C),
collected at 296(2) K on a Bruker X8 APEX II KAPPA CCD
128.2, 136.0, 140.2, 147.1, 165.5, 195.9; ESI-TOF MS: calcd for
22H18BrNNaO3, m/z 446.0362 (M + Na)+, found 446.0363.
diffractometer using graphite monochromatized Mo-Ka radia-
C
˚
tion (l ¼ 0.71073 A). The structures were solved using SHELXS-
9-Benzotriazol-1-yl-7-chloro-2,3,4,9-tetrahydro-xanthen-1-one
9747 and rened using full-matrix least squares on F2 with
SHELXL-97.47 Final R-values and selected renement details of
7a, 7b, 7e, and 7f are given in Table 1S (ESI).†
(9m). Yellow solid; UV (EtOH) lmax (log 3) 265 (4.45); IR (UATR)
nmax: 3747, 2942, 1732, 1648, 1583, 1480, 1421, 1383, 1240, 1182,
1
1079, 1001, 823, 747 cmꢁ1; H NMR (300 MHz, CDCl3) d: 2.03–
2.17 (m, 2H), 2.39–2.44 (m, 2H), 2.73–2.97 (m, 2H), 7.02 (s, 1H),
7.18–7.31 (m, 3H), 7.36 (d, J ¼ 7.5 Hz, 1H), 7.51 (t, J ¼ 7.5 Hz,
1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 8.01 (d, J ¼ 8.4 Hz, 1H); 13C NMR
Acknowledgements
(75 MHz, CDCl3) d: 20.1, 27.8, 36.4, 48.2, 109.3, 109.6, 118.7, P. K. is supported by The Thailand Research Fund and the
120.0, 120.9, 123.9, 127.6, 128.8, 130.3, 130.5, 132.3, 145.7, Center of Excellence on Environmental Health and Toxicology,
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Science & Technology Postgraduate Education and Research 17 K. S. Shih, J. H. Wang, Y. W. Wu, C. M. Teng, C. C. Chen and
Development Office (PERDO), Ministry of Education. T. A. C. R. Yang, PLoS One, 2012, 7, e42389.
acknowledges nancial support by the Higher Education 18 S. A. Patil, J. Wang, X. S. Li, J. Chen, T. S. Jones, A. Hosni-
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Ahmed, R. Patil, W. L. Seibel, W. Li and D. D. Miller,
of Thailand, Office of the Higher Education Commission,
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