Ammonium chloride-catalyzed three-component reaction for the synthesis of fused 4H-chromene derivatives in aqueous medium

Article abstract of DOI:10.1055/s-0033-1340082

An efficient one-pot process was developed to synthesize 4H-chromene derivatives using a three-component reaction involving salicylaldehydes, cyclic 1,3-diketones, and thiols in an aqueous medium at room temperature. This protocol was accomplished using the inexpensive and readily available catalyst NH₄Cl. The attractive features of this protocol are: use of inexpensive catalyst NH₄Cl, good yields, and mild and environmentally benign reaction conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340082

PAPER
▌73
paper
Ammonium Chloride-Catalyzed Three-Component Reaction for the Synthesis
of Fused 4H-Chromene Derivatives in Aqueous Medium
Synthesis of Fused 4H-Chromene Derivatives
Suchandra Bhattacharjee, Deb K. Das, Abu T. Khan*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
Fax +91(361)2582349; E-mail: atk@iitg.ernet.in
Received: 17.07.2013; Accepted after revision: 10.10.2013
This work is dedicated to Professor Gautam Barua, former Director of the Indian Institute of Technology, Guwahati for his immense
contribution in setting up and developing the Science Department of IIT Guwahati.
mation of 4H-chromene compounds. The other methods
Abstract: An efficient one-pot process was developed to synthe-
available for the synthesis of 4H-chromene derivatives are
size 4H-chromene derivatives using a three-component reaction in-
cycloaddition of propargylic alcohols,16a or ketones16b
volving salicylaldehydes, cyclic 1,3-diketones, and thiols in an
aqueous medium at room temperature. This protocol was accom-
with phenols, reactions of allenic esters and ketones with
plished using the inexpensive and readily available catalyst NH4Cl. salicyl-N-tosylimines,17 ring-closing metathesis reaction
of aryl vinyl ethers,18 copper-catalyzed intra-19a and
The attractive features of this protocol are: use of inexpensive cata-
lyst NH4Cl, good yields, and mild and environmentally benign re-
action conditions.
intermolecular19b coupling of aryl bromides with 1,3-di-
carbonyl compounds, tetrahydrothiophene-catalyzed
ylide annulation reaction,20 organocatalytic sequential
Key words: 4H-chromenes, salicylaldehydes, cyclic 1,3-diketones,
thiols, ammonium chloride, aqueous medium, multicomponent re-
actions (MCRs)
one-pot reaction of 1,3-diones with salicylaldehydes,21
and tandem benzylation and cyclization of 1,3-dicarbonyl
compounds using benzylic alcohols.22 A survey of the lit-
erature shows that the majority of the strategies for the
Multicomponent reaction (MCR) offers a remarkable
synthesis of 4H-chromene derivatives involve either ex-
pensive catalysts,16a,b,18,21 or multistep sequences,18,20 pro-
longed reaction time,19b and harsh reaction
conditions.18,19,22 Consequently, there is a need to develop
a synthetic method using inexpensive and environmental-
ly benign catalyst.
handy protocol to construct new heterocyclic molecules
with relevant biological activity.1 Water is truly the na-
ture’s reaction medium playing a crucial role in various
life-sustaining processes. Needless to say, water is found
in high abundance, hence cost-effective, and is a green
solvent in organic transformations2 owing to its nonflam-
mable and nontoxic nature. Further, it exhibits unique
properties like high dielectric constant, and its cohesive
energy density puts an extraordinary effect on reaction
rates with unique selectivity and reactivity.3 Designing
MCRs using water as the reaction medium to synthesize
heterocyclic scaffolds with medicinal traits is one of the
trending research amongst synthetic organic chemists in
view of green chemistry.4
SR2
O
OH
O
H
R1
O
N
HO
O
O
II
I
gastric antisecretory agent
antibacterial agent
The chromene scaffold and its derivatives exhibit useful
biological and pharmacological activities such as antibac-
terial,5 antitumor,6 anticancer,7 anticonvulsant,8 apoptosis
inducers,9 Chk1-inhibitors,10 and anti-anaphylactic activi-
ties.11 Some of them are found as natural products, for ex-
ample, the antibacterial rhodomyrtone (I)12 and the gastric
antisecretory agent II13 as shown in Figure 1.
Figure 1 Some natural compounds containing chromene skeleton
Ammonium chloride is readily available and is an inex-
pensive catalyst. In aqueous medium, it is a good proton
source, which can activate the carbonyl group through hy-
drogen bonding.23 Moreover, it can react with carbonyl
groups in the presence of amines to form imines, which
can act as dienophiles in Diels–Alder reactions.24 Thus,
NH4Cl was considered to be a promising catalyst in view
of its remarkable ability to catalyze a manifold of organic
transformations by way of multicomponent reactions for
the synthesis of pyrrolo[3,4-b]pyridin-5-ones,23a di- and
Literature search reveals that salicylaldehyde reacts with
an active methylene compound such as cyclic 1,3-
diketones14 or malononitrile15 to form a Knoevenagel
product, which can react with a suitable nucleophile such
as thiols, indoles, benzotriazoles, and 4-hydroxycouma-
rins followed by ring-closure reaction leading to the for-
tetrapeptides,25a
spirochromenes,25c 4-imino-4H-3,1-benzoxazines,25d tet-
rahydrofuro[2,3-c]pyridine,25e
and tetrahydroben-
zo[α]xanthen-11-one derivatives.25f
3,4-dihydropyrimidin-2-(1H)-ones,25b
SYNTHESIS 2014, 46, 0073–0080
Advanced online publication: 07.11.2013
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0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
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DOI: 10.1055/s-0033-1340082; Art ID: SS-2013-N0491-OP
© Georg Thieme Verlag Stuttgart · New York

74
S. Bhattacharjee et al.
PAPER
SR3
O
In continuation of our investigations on the synthesis of
novel heterocyclic compounds under aqueous condi-
tions,26 we conceived to investigate the synthesis of 4H-
chromene compounds using more environmentally be-
nign reaction conditions. We report herein a new, conve-
nient, and highly efficient greener protocol for the
synthesis of 4H-chromenes 4 via three-component con-
densation of salicylaldehydes 1, cyclic 1,3-dicarbonyl
compounds 2, and aromatic or aliphatic thiols 3 catalyzed
by ammonium chloride in water at room temperature as
shown in Scheme 1.
O
CHO
OH
NH4Cl
(20 mol%)
+
R2
R2
R2
R2
R1
H2O, r.t.
O
R1
O
n
n
1
4
R3SH
3
n = 0, 1
2
R
1 = H (1a), 5-Br (1b), 5-OMe (1c)
3-OMe (1d), 3-OEt (1e)
R
R
2 = Me (2a), H (2b), n = 1
2 = H (2c), n = 0
R3 = aryl, alkyl, benzyl
Scheme 1 One-pot three-component synthesis of 4H-chromene de-
In our initial efforts to synthesize 4H-chromene derivative
4b, a reaction was carried out with an equimolar mixture
of salicylaldehyde (1a), dimedone (2a), and 4-chlorothio-
phenol (3a) in water in the absence of catalyst at room
temperature. The reaction did not proceed to completion
even after 12 hours and resulted in the isolation of product
rivatives
4H-chromene derivative 4b and 1-oxohexahydroxanthene
derivative 527 in 22% and 48% yield (Table 1, entry 1), re-
spectively, which was confirmed from IR and H NMR
1
Table 1 Optimization of Reaction Conditions for the Synthesis of 3,3-Dimethyl-9-(4-chlorophenylthio)-2,3,4,9-tetrahydro-1H-xanthen-1-one
(4b)a
Cl
HO
O
O
S
O
SH
O
O
O
Cl
4b
5
3a
Cl
CHO
OH
+
O
S
Cl
1a
2a
S
OH
6
Entry
Catalyst (mol%)
Solvent
Time (h)
Yield (%)b
4b
5
6
1
2
none
H2O
H2O
H2O
H2O
EtOH
neat
H2O
H2O
H2O
H2O
H2O
12
12
5
22
67
78
74
29
46
74
37
38
42
38
48
–
NH4Cl (10)
NH4Cl (20)
NH4Cl (30)
NH4Cl (20)
NH4Cl (20)
NH4Br (20)
TBAB (20)
TBAI (20)
BETAC (20)
TBATB (20)
7
–
3
trace
trace
14
–
4
5
–
5
5
17
–
6
16
6
8
7
trace
36
–
8
12
16
12
12
26
20
24
42
9
26
10
11
22
18
a Reaction conditions: salicylaldehyde (1a), dimedone (2a), and 4-chlorothiophenol (3a) were taken in a 1:1:1 ratio at r.t.
b Isolated yields after column chromatography.
Synthesis 2014, 46, 73–80
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Fused 4H-Chromene Derivatives
75
spectra. The same reaction was also carried out in the These results show that the catalyst NH4Cl has a remark-
presence of 10 mol% of NH4Cl in water, which afforded able effect in suppressing the formation of by-products
the product 4b along with the formation of a trace amount and controlling the reaction selectivity in water. To exam-
of compound 5 in 67% and 7% yield (Table 1, entry 2), re- ine the efficacy of the catalyst, several reactions were also
spectively. To reduce the formation of the by-products as performed in the presence of other mild acid catalyst such
well to increase the yield of the desired 4H-chromene 4b, as TBAB, TBAI, BETAC, and TBATB under identical re-
a similar reaction was executed using 20 and 30 mol% of action conditions, but all of them delivered poorer results
NH4Cl to afford compound 4b in 78% and 74% yield, re- in terms of yield and selectivity toward 4b (Table 1, en-
spectively. It was noted that the yield of the product 4b tries 8–11) and gave 2-{bis[(4-chlorophenyl)thio]meth-
had increased from 67 to 78% by increasing the amount of yl}phenol (6) as another by-product. It is worthwhile to
catalyst from 10% to 20% with the formation of only a mention that the same reaction gave comparatively simi-
trace amount of product 5, which also shortened the reac- lar yields when 20 mol% of NH4Br was used in water
tion time significantly (Table1, entry 3). However, in- (Table 1, entry 7). Since the yield has not increased signif-
creasing the amount of catalyst from 20% to 30% did not icantly and cost of the NH4Br is higher as compared to
improve the yield of the product (Table 1, entry 4). The re- NH4Cl, all the reactions were performed using 20 mol%
actions were very sluggish and incomplete even after 16 of NH4Cl in water.
hours, when the same reaction was carried out in the pres-
The above observations indicate that the reaction pro-
ence of 20 mol% of NH4Cl under solvent-free conditions
ceeds well in the presence of 20 mol% of NH4Cl in aque-
(Table 1, entry 6).
ous media. The mild reaction conditions and clean TLC
pattern are the main advantages of the present reaction in
Table 2 Substrate Scope for the Synthesis of 4H-Chromene Derivatives 4a
SR3
O
O
CHO
OH
NH4Cl
(20 mol%)
+
R2
R2
R2
R2
R1
H2O, r.t.
R1
O
O
n
n
n = 0, 1
1
2
4
R3SH
3
Entry
1
2
R3
Ph
Time (h)
Product
Yield (%)b
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1e
1a
1b
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
2c
2c
5.0
5.0
4.5
4.0
4.0
6.0
5.0
4.5
5.0
4.0
4.0
3.0
4.0
4.0
3.0
3.0
4a
4b
4c
4d
4e
4f
79
78
76
71
74
70
77
75
55
62
75
71
79
77
72
69
4-ClC6H4
4-BrC6H4
4-MeC6H4
3
4
5
4-MeOC6H4
6
2-naphthyl
7
Et
4g
4h
4i
8
Pr
9
Bn
10
11
12
13
14
15
16
4-MeC6H4
4j
4-ClC6H4
4k
4l
Pr
Ph
Ph
Ph
Ph
4m
4n
4o
4p
a Reaction conditions: salicylaldehyde 1, 1,3-cyclic ketone 2, and thiol 3 were taken in a 1:1:1 ratio in the presence of 20 mol% of NH4Cl in 5
mL of H2O at r.t.; entries 15 and 16 were conducted at reflux.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 73–80

76
S. Bhattacharjee et al.
PAPER
water. With the optimized conditions in hand, we next All the synthesized compounds were characterized by IR,
embarked on an investigation of the substrate scope of the NMR, and elemental analysis. The products 4a–p exhib-
present multicomponent reaction for the synthesis of 4H- ited a diagnostic signal in the range of δ = 4.96–5.38 as-
chromene derivatives 4 with different salicylaldehydes 1, signable to H-9 at the point of attachment of 4H-chromene
cyclic 1,3-diketones 2, and thiols 3. Performing the reac- to the thiol moiety depending on the nature of the substit-
tion with a mixture of salicylaldehyde, dimedone, and uent in salicylaldehydes and thiols. Finally, the structure
thiophenol under identical conditions, the desired product of one of the representative compounds such as 9-[(4-
4a was obtained in 79% yield (Table 2, entry 1). To ex- chlorophenyl)thio]-7-methoxy-3,3-dimethyl-2,3,4,9-tet-
plore the synthetic scope and the generality of the present rahydro-1H-xanthen-1-one (4k) was confirmed unambig-
protocol, various reactions were performed with a wide uously by single crystal X-ray diffraction analysis (Figure
variety of aromatic thiols containing different substituents 2) (see Supporting Information).
in the aromatic ring such as Br, Me, and OMe with sali-
cylaldehyde and dimedone. The reaction time and per-
centage yield of the products 4c–f are shown in Table 2
(entries 3–6). Likewise, aliphatic thiols such as ethane thi-
ol and propane thiol were tested under identical reaction
condition to provide the desired 4H-chromene products
4g,h in good yields (entries 7 and 8, Table 2).
For verifying the generality of the present method, other
substituted salicylaldehyde derivatives bearing Br, MeO,
and OEt substituent in the ring were also examined with
dimedone and different aliphatic or aromatic thiols under
identical reaction conditions to provide the desired 4H-
chromene products 4i–n in moderate to good yields (Ta-
ble 2, entries 9–14). Furthermore, the reactions with other
cyclic 1,3-diketones such as cyclohexa-1,3-dione and cy-
clopenta-1,3-dione with salicylaldehydes and thiophenol
Figure 2 X-ray crystal structure of 4H-chromene 4k28
were also performed to give the desired products 4i,j and
4o,p (entries 9, 10 and 15, 16). It was observed that the
similar transformation failed in the case of acyclic 1,3-
diketone such as acetylacetone and also for malononitrile.
The formation of the product may be explained as fol-
lows: The first step is believed to be the condensation re-
action between salicylaldehyde 1 with cyclic 1,3-diketone
2 to give a Knoevenagel product C, which can act as a
suitable Michael acceptor. The role of ammonium chlo-
ride is a source of proton, which activates carbonyl group
through hydrogen bonding. Then a nucleophile such as
thiol reacts at the exocyclic benzylidene double bond of
the Knoevenagel product C to form the intermediate D,
which further undergoes intramolecular ring-closure reac-
tion followed by dehydration to give the desired 4H-
chromene compounds 4 as shown in Scheme 2.
The present protocol was further examined by carrying
out two consecutive reactions with salicylaldehyde (1a),
dimedone (2a), and with a nucleophile such as indole (7a)
and β-naphthol (7b), and the desired products 8a and 8b
were isolated in 81% and 58% yield, respectively, as
shown in Table 3.
Table 3 Substrate Scope for the Synthesis of 4H-Chromene Deriva-
tives 8a
O
Nu
O
CHO
OH
NH4Cl
In conclusion, we have demonstrated an efficient and eco-
friendly protocol for the synthesis of 4H-chromene deriv-
atives by employing the environmentally benign catalyst
NH4Cl via one-pot three-component condensation reac-
tion from wide variety of salicylaldehydes, cyclic 1,3-di-
ketones, and aromatic or aliphatic thiols employing water
as the reaction medium. This new method is endowed
with advantages such as green reaction medium, environ-
mentally benign reaction conditions with good yields, su-
perior atom economy, the easy accessibility of the
catalyst, and its cost effectiveness.
(20 mol%)
+
H2O, r.t.
O
O
1a
2a
8
NuH
7
Entry
NuH 7
Time (h)
Product
Yield (%)b
1
2
indole
5.0
6.0
8a
8b
81
58
2-naphthol
a Reaction conditions: salicylaldehyde (1a), dimedone (2a), and nu-
cleophile 7 were taken in a 1:1:1 ratio in the presence of 20 mol% of
NH4Cl in 5 mL of H2O. For entry 1, the reaction was carried out at
r.t., whereas in the case of entry 2 the reaction mixture was refluxed.
b Isolated yields.
Melting points were determined on a Büchi melting point apparatus
and are uncorrected. IR spectra were recorded on PerkinElmer 281
1
IR spectrophotometer. H and 13C NMR spectra were recorded on
Varian 400 spectrometer with TMS as internal reference; chemical
1
shifts (δ scale) are reported in parts per million (ppm). H NMR
spectra are reported in the order: multiplicity, coupling constant
Synthesis 2014, 46, 73–80
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Synthesis of Fused 4H-Chromene Derivatives
77
H
O
H3N
H
O
O
O
R1
R2
R2
R2
R2
H
R1
OH
HO
O
1
OH
2
A
NH4Cl
NH4
Cl
O
HO
R3
H
R3
O
S
S
O
R2
R2
R1
R1
R2
R2
O
R2
R2
R1
OH
OH
H
B
O
O
H2O
D
H
NH3
4
R3-SH
O
3
R1
R2
R2
O
OH
C
Scheme 2 Proposed NH4Cl-catalyzed formation of 4H-chromene derivatives 4
(J value) in hertz (Hz) and number of protons. Standard abbrevia-
tions were used to denote signal multiplicities. Mass spectrometry
data was collected on Agilent Technologies 6520 Accurate-Mass
Q-TOF LC/MS spectrometer. Elemental analyses were carried out
using PerkinElmer 2400 Series II CHNS/O analyzer at the Depart-
ment of Chemistry, Indian Institute of Technology, Guwahati. The
X-ray crystal structure was determined with a Siemens P-4 diffrac-
tometer.
2-{Bis[(4-chlorophenyl)thio]methyl}phenol (6) (Table 1, Entry
8)
Yield: 0.101 g (26%); brown liquid.
IR (film): 3446, 2924, 1641, 1474, 1092 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.25 (m, 4 H), 7.20–7.12 (m,
6 H), 6.81 (d, J = 7.6 Hz, 2 H), 5.71 (s, 1 H).
Anal. Calcd for C19H14Cl2OS2 (393.35): C, 58.02, H, 3.59. Found:
C, 58.08; H, 3.56.
4H-Chromene Derivatives 4a–p; General Procedure
A mixture of salicylaldehyde 1 (1 mmol), cyclic 1,3-diketone 2 (1
mmol), aliphatic or aromatic thiol 3 (1 mmol), and NH4Cl (0.2
mmol) in H2O (5 mL) was stirred at r.t. for 3–6 h in a 25 mL round-
bottomed flask. The progress of the reaction was monitored by TLC
(eluent: EtOAc–hexane, 1:9). After the completion of the reaction,
the crude reaction mixture was extracted with EtOAc (2 × 10 mL),
the combined organic layers were washed with H2O (10 mL), and
dried (Na2SO4). The solvent was removed in vacuo and the residue
was chromatographed on silica gel (60–120 mesh, eluent: EtOAc–
hexane, 1:9) to afford the pure products in 55–79% yields (Table 1).
9-(4-Bromophenylsulfanyl)-3,3-dimethyl-2,3,4,9-tetrahydro-
1H-xanthen-1-one (4c)
Yield: 0.315 g (76%); orange liquid.
IR (film): 3061, 2958, 2871, 1668, 1645, 1582, 1485, 1470, 1384,
1235, 1177, 1144, 1090, 1067, 1010, 925, 872, 820 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.25 (dd, J = 8.4, 1.6 Hz, 1 H),
7.22 (d, J = 8.0 Hz, 1 H), 7.19–7.08 (m, 3 H), 6.90 (dd, J = 8.4, 1.6
Hz, 2 H), 6.83 (d, J = 8.0 Hz, 1 H), 5.28 (s, 1 H), 2.40–2.27 (m, 4
H), 1.15 (s, 3 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.5, 166.2, 150.5, 137.5 (2 C),
131.3, 131.2 (2 C), 129.3, 128.2, 125.0, 123.3, 122.2, 116.1, 109.5,
50.7, 41.2, 40.9, 31.9, 28.3, 28.2.
Compounds 4a and 4b have been previously reported.15b The data
for the by-products 5 and 6 obtained in the screening reactions are
also described below.
Anal. Calcd for C21H19BrO2S (415.34): C, 60.73; H, 4.61. Found: C,
60.83; H, 4.66.
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimeth-
yl-2,3,4,9-tetrahydro-1H-xanthen-1-one (5) (Table 1, Entry 1)
Yield: 0.175 g (48%); white solid; mp 219–221 °C.
IR (KBr): 3208, 2954, 1645 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.46 (s, 1 H), 7.17–7.14 (m, 1 H),
7.13–6.99 (m, 3 H), 4.66 (s, 1 H), 2.60 (d, J = 17.6 Hz, 1 H), 2.47
(d, J = 17.6 Hz, 1 H), 2.38–2.32 (m, 4 H), 1.99 (d, J = 16.8 Hz, 1 H),
1.93 (d, J = 8 Hz, 1 H), 1.12 (s, 3 H), 1.03 (s, 3 H), 0.99 (s, 3 H),
0.98 (s, 3 H).
3,3-Dimethyl-9-(p-tolylthio)-2,3,4,9-tetrahydro-1H-xanthen-1-
one (4d)
Yield: 0.248 g (71%); orange liquid.
IR (film): 3020, 2958, 2926, 2875, 1662, 1644, 1582, 1486, 1460,
1383, 1293, 1235, 1177, 1019, 910, 873, 809, 751, 663 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.6 Hz, 2 H), 7.18–
7.09 (m, 2 H), 6.96 (d, J = 8 Hz, 2 H), 6.93 (d, J = 8 Hz, 1 H), 6.81
(d, J = 8.4 Hz, 1 H), 5.26 (s, 1 H), 2.38–2.35 (m, 4 H), 2.31 (s, 3 H),
1.17 (s, 3 H), 1.07 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.9, 166.3, 150.6, 136.4 (2 C),
128.0, 129.5, 129.1 (2 C), 128.5, 128.2, 125.0, 122.8, 116.1, 109.8,
50.9, 41.3, 40.7, 32.1, 28.5, 28.4, 21.3.
Anal. Calcd for C23H26O4 (366.45): C, 75.38; H, 7.15. Found: C,
75.44; H, 7.12.
© Georg Thieme Verlag Stuttgart · New York
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S. Bhattacharjee et al.
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MS (ESI): m/z [M + Na]+ calcd for C22H22O2S + Na: 373.1233;
found: 373.1358.
5.02 (s, 1 H), 2.59–2.46 (m, 2 H), 2.40–2.19 (m, 4 H), 1.48–1.41 (m,
2 H), 1.17 (s, 3 H), 1.13 (s, 3 H), 0.85 (t, J = 7.2 Hz, 3 H).
Anal. Calcd for C22H22O2S (350.47): C, 75.39; H, 6.33. Found: C,
75.46; H, 6.28.
13C NMR (100 MHz, CDCl3): δ = 195.3, 165.2, 150.2, 129.1, 127.6,
124.7, 122.4, 115.7, 110.4, 50.1, 40.8, 34.4, 31.4, 31.2, 28.9, 26.6,
22.0, 13.2.
MS (ESI): m/z [M + Na]+ calcd for C18H22O2S + Na: 325.1200;
found: 325.1286.
9-[(4-Methoxyphenyl)thio]-3,3-dimethyl-2,3,4,9-tetrahydro-
1H-xanthen-1-one (4e)
Yield: 0.270 g (74%); orange solid; mp 107–108 °C.
Anal. Calcd for C18H22O2S (302.43): C, 71.48; H, 7.33. Found: C,
71.55; H, 7.38.
IR (KBr): 2954, 1659, 1640, 1589, 1462, 1380, 1232, 1172, 1030,
758, 533 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.26 (m, 2 H), 7.17–7.12 (m,
1 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.79 (dd, J = 8, 1.6 Hz, 1 H), 6.67
(d, J = 8.8 Hz, 2 H), 5.22 (s, 1 H), 3.78 (s, 3 H), 2.39–2.28 (m, 4 H),
1.18 (s, 3 H), 1.07 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.4, 165.8, 160.1, 150.4, 137.8
(2 C), 129.3, 127.7, 124.6, 122.3, 121.9, 115.7, 113.5 (2 C), 109.3,
54.9, 50.5, 40.9, 40.5, 31.7, 28.2, 28.1.
9-(Benzylthio)-7-bromo-2,3,4,9-tetrahydro-1H-xanthen-1-one
(4i)
Yield: 0.220 g (55%); colorless liquid.
IR (film): 2928, 1659, 1640, 1473, 1410, 1377, 1231, 1166, 1130,
995, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.18 (m, 7 H), 6.88 (d,
J = 8.8 Hz, 1 H), 4.96 (s, 1 H), 3.61 (s, 2 H), 2.43–2.29 (m, 4 H),
1.19–1.18 (m, 2 H).
MS (ESI): m/z [M + Na]+ calcd for C22H22O3S + Na: 389.1182;
found: 389.1198.
13C NMR (100 MHz, CDCl3): δ = 196.4, 167.1, 149.8, 138.5, 132.7,
131.4, 129.0 (2 C), 128.5 (2 C), 127.1, 124.7, 118.0, 117.7, 111.8,
36.8, 35.1 (2 C), 27.7, 20.0.
Anal. Calcd for C22H22O3S (366.47): C, 72.10; H, 6.05. Found: C,
72.18; H, 6.10.
MS (ESI): m/z [M + Na]+ calcd for C20H17 BrO2S + Na: 425.0025;
found: 425.0139.
3,3-Dimethyl-9-(naphthalen-2-ylthio)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (4f)
Yield: 0.270 g (70%); orange liquid.
Anal. Calcd for C20H17BrO2S (401.32): C, 59.86; H, 4.27. Found: C,
59.92: H, 4.33.
IR (film): 2956, 2926, 1665, 1643, 1581, 1498, 1460, 1381, 1266,
1176, 1143, 1129, 1031, 1013, 943 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 7.2 Hz, 1 H), 7.69–
7.58 (m, 2 H), 7.54 (s, 1 H), 7.52–7.41 (m, 2 H), 7.28–7.23 (m, 1 H),
7.21–7.09 (m, 3 H), 6.73 (d, J = 7.8 Hz, 1 H), 5.39 (s, 1 H), 2.47–
2.31 (m, 4 H), 1.15 (s, 3 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 196.0, 166.4, 150.6, 136.1, 133.2,
133.0, 132.7, 129.5, 129.4, 128.2, 127.7, 127.6, 126.6, 126.5, 126.2,
125.1, 122.8, 116.1, 109.7, 50.8, 41.3, 41.0, 32.0, 28.6, 28.3.
7-Methoxy-9-(p-tolylthio)-2,3,4,9-tetrahydro-1H-xanthen-1-
one (4j)
Yield: 0.218 g (62%); orange solid; mp 145–146 °C.
IR (KBr): 2952, 2927, 1654, 1637, 1493, 1459, 1339, 1260, 1225,
1198, 1033, 998, 874, 808, 753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.97 (d, J = 8 Hz, 2 H), 6.93 (d,
J = 8.4 Hz, 2 H), 6.75–6.72 (m, 3 H), 5.25 (s, 1 H), 3.77 (s, 3 H),
2.41–2.37 (m, 4 H), 2.32 (s, 3 H), 2.01–2.04 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 196.2, 168.3, 156.7, 144.9, 139.2,
137.0 (2 C), 129.1 (2 C), 128.1, 123.6, 117.0, 115.3, 112.4, 109.9,
55.8, 41.2, 37.0, 27.7, 21.4, 20.4.
MS (ESI): m/z [M + Na]+ calcd for C25H22O2S + Na: 409.0233;
found: 409.0143.
Anal Calcd for C25H22O2S (386.51): C, 77.69; H, 5.74. Found: C,
77.74; H, 5.78.
MS (ESI): m/z [M + Na]+ calcd for C21H20O3S + Na: 375.1025;
found: 375.1018.
9-(Ethylthio)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthene-1-
one (4g)
Yield: 0.221 g (77%); orange solid; mp 63–64 °C.
Anal. Calcd for C21H20O3S (352.45): C, 71.56; H, 5.72. Found: C,
71.60; H, 5.78.
IR (KBr): 2960, 1662, 1645, 1458, 1380, 1235, 1176, 1141, 1017,
754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39 (dd, J = 7.6, 1.2 Hz, 1 H),
7.27–7.15 (m, 2 H), 7.03 (dd, J = 8, 1.2 Hz, 1 H), 5.04 (s, 1 H),
2.59–2.47 (m, 2 H), 2.45–2.27 (m, 4 H), 1.17 (s, 3 H), 1.13 (s, 3 H),
1.10 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 196.0, 165.8, 150.5, 129.4, 127.9,
125.1, 122.6, 116.0, 110.7, 50.5, 41.2, 34.8, 31.8, 29.2, 27.1, 23.5,
13.9.
9-[(4-Chlorophenyl)thio]-7-methoxy-3,3-dimethyl-2,3,4,9-tet-
rahydro-1H-xanthen-1-one (4k)
Yield: 0.300 g (75%); orange solid; mp 112–113 °C.
IR (KBr): 2955, 1659, 1643, 1497, 1380, 1216, 1038, 824 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.15 (d, J = 8.4 Hz, 2 H), 7.02 (d,
J = 8 Hz, 2 H), 6.80–6.73 (m, 2 H), 6.69 (d, J = 2.8 Hz, 1 H), 5.28
(s, 1 H), 3.76 (s, 3 H), 2.40–2.31 (m, 4 H), 1.15 (s, 3 H), 1.08 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 195.9, 166.7, 156.6, 144.9, 137.5
(2 C), 135.2, 130.7, 128.5 (2 C), 123.0, 117.3, 115.3, 112.3, 108.8,
55.7, 50.9, 41.7, 41.4, 32.1, 28.6, 28.4.
MS (ESI): m/z [M + Na]+ calcd for C17H20O2S + Na: 311.1076;
found: 311.1143.
Anal. Calcd for C17H20O2S (288.40): C, 70.80; H, 6.99. Found: C,
70.86; H, 6.92.
Anal. Calcd for C22H21ClO3S (400.92): C, 65.91; H, 5.28. Found: C,
65.89: H, 5.34.
3,3-Dimethyl-9-(propylthio)-2,3,4,9-tetrahydro-1H-xanthene-
1-one (4h)
Yield: 0.226 g (75%); orange liquid.
5-Methoxy-3,3-dimethyl-9-(propylthio)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (4l)
Yield: 0.235 g (71%); orange solid; mp 128–129 °C.
IR (film): 2959, 1662, 1645, 1582, 1457, 1379, 1291, 1234, 1176,
1144, 1012, 871, 754, 701, 663, 542 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 7.6 Hz, 1 H), 7.21 (d,
J = 7.6 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H),
IR (KBr): 3009, 2955, 1655, 1639, 1612, 1582, 1485, 1381, 1271,
1228, 1124, 1094, 764, 734, 544 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.10 (t, J = 8 Hz, 1 H), 6.98 (dd,
J = 7.6, 1.2 Hz, 1 H), 6.81 (dd, J = 8.0, 1.2 Hz, 1 H), 5.01 (s, 1 H),
Synthesis 2014, 46, 73–80
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Fused 4H-Chromene Derivatives
79
3.91 (s, 3 H), 2.66 (d, J = 17.2 Hz, 1 H), 2.56 (d, J = 17.6 Hz, 1 H),
2.41–2.19 (m, 4 H), 1.48–1.39 (m, 2 H), 1.17 (s, 3 H), 1.13 (s, 3 H),
0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.8, 165.3, 147.1, 140.2, 124.7,
123.5, 120.7, 110.4, 109.9, 55.8, 50.5, 41.1, 34.7, 31.8, 31.3, 29.1,
27.0, 22.2, 13.5.
Anal. Calcd for C18H14O2S (294.37): C, 73.44; H, 4.79. Found: C,
73.53; H, 4.82.
7-Bromo-9-(phenylthio)-2,3-dihydrocyclopenta[b]chromen-
1(9H)-one (4p)
Yield: 0.257 g (69%); brown solid; mp 182–183 °C.
IR (KBr): 2920, 1700, 1649, 1470, 1437, 1384, 1245, 1194, 1160,
1119, 1014, 823, 740, 697 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 2.4 Hz, 1 H), 7.36–
7.31 (m, 2 H), 7.19 (t, J = 7.8 Hz, 2 H), 7.00 (d, J = 8.4, 1.2 Hz, 2
H), 6.75 (d, J = 9.0 Hz, 1 H), 5.07 (s, 1 H), 2.62–2.51 (m, 4 H).
MS (ESI): m/z [M + Na]+ calcd for C19H24O3S + Na: 355.1338;
found: 355.1335.
Anal. Calcd for C19H24O3S (332.46): C, 68.64; H, 7.28. Found: C,
68.72; H, 7.36.
13C NMR (100 MHz, CDCl3): δ = 201.1, 179.5, 150.3, 136.8 (2 C),
133.5, 131.7, 130.4, 129.5, 128.6 (2 C), 124.3, 118.3, 118.1, 113.7,
40.1, 33.6, 25.3.
5-Methoxy-3,3-dimethyl-9-(phenylthio)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (4m)
Yield: 0.289 g (79%); orange solid; mp 102–105 °C.
IR (KBr): 3055, 2958, 1670, 1645, 1583, 1470, 1385, 1274, 1228,
1186, 1124, 1093, 954, 841, 789, 737, 665 cm–1.
MS (ESI): m/z [M + Na]+ calcd for C18H13BrO2S + Na: 396.9692;
found: 396.9662.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.27 (m, 1 H), 7.16 (t,
J = 7.2 Hz, 2 H), 7.11–7.02 (m, 3 H), 6.85 (d, J = 7.8 Hz, 1 H), 6.76
(d, J = 7.8 Hz, 1 H), 5.30 (s, 1 H), 3.82 (s, 3 H), 2.48–2.28 (m, 4 H),
1.15 (s, 3 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.8, 166.0, 147.4, 140.5, 136.1
(2 C), 131.9, 128.8, 128.2 (2 C), 124.7, 123.5, 120.9, 110.5, 109.6,
56.1, 50.8, 41.3, 40.8, 32.0, 28.4 (2 C).
Anal. Calcd for C18H13BrO2S (373.26): C, 57.92; H, 3.51. Found: C,
57.98; H, 3.55.
9-(1H-Indol-3-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-
1-one (8a)
Yield: 0.277 g (81%); orange solid; mp 200–202 °C.
IR (KBr): 3329, 1643, 1467, 1421, 1375, 1228, 1179 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.39 (d, J = 7.5 Hz,
2 H), 7.32–7.22 (m, 2 H) 7.20–7.05 (m, 3 H), 6.96 (d, J = 4.5 Hz, 2
H), 5.32 (s, 1 H), 2.64–2.15 (m, 4 H), 1.11 (s, 3 H), 1.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 197.4, 164.3, 149.4, 136.5, 130.1,
127.3, 125.5, 125.2, 124.8, 122.4, 121.4, 120.1, 119.1, 118.9, 116.1,
112.6, 111.2, 50.8, 41.4, 32.0, 29.4, 29.0, 27.5.
MS (ESI): m/z [M + Na]+ calcd for C22H22O3S + Na: 389.1182;
found: 389.1198.
Anal. Calcd for C22H22O3S (366.47): C, 72.10; H, 6.05. Found: C,
72.18; H, 6.10.
5-Ethoxy-3,3-dimethyl-9-(phenylthio)-2,3,4,9-tetrahydro-1H-
xanthen-1-one (4n)
Yield: 0.292 g (77%); orange liquid.
MS (ESI): m/z [M + Na]+ calcd for C23H21NO2 + Na: 366.1455;
found: 366.1467.
IR (film): 2957, 1664, 1645, 1582, 1473, 1438, 1383, 1275, 1226,
1189, 1083, 750, 692 cm–1.
Anal. Calcd for C23H21NO2 (343.15): C, 80.44; H, 6.16. Found: C,
80.47; H, 6.18.
1H NMR (300 MHz, CDCl3): δ = 7.29 (d, J = 6.6 Hz, 1 H), 7.17 (t,
J = 7.8 Hz, 2H), 7.13–7.09 (m, 2 H), 7.02 (t, J = 7.8 Hz, 1 H), 6.80
(d, J = 7.8 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.29 (s, 1 H), 4.14–
3.92 (m, 2 H), 2.48–2.32 (m, 4 H), 1.38 (t, J = 6.9 Hz, 3 H), 1.16 (s,
3 H), 1.07 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 195.9, 166.2, 146.6, 140.8, 136.1
(2 C), 132.1, 128.6, 128.2 (2 C), 124.6, 123.6, 120.9, 112.3, 109.6,
64.8, 50.8, 41.2, 40.9, 32.1, 28.4, 28.3, 14.7.
9-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3,4,9-tetra-
hydro-1H-xanthen-1-one (8b)
Yield: 0.214 g (58%); white solid; mp 229–231 °C.
IR (KBr): 3204, 2960, 1655, 1634, 1484, 1431, 1382, 1182, 1143
cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.27 (s, 1 H), 7.79 (d, J = 9 Hz, 2
H), 7.66 (d, J = 7.5 Hz, 1 H), 7.37 (q, J = 5.7 Hz, 3 H), 7.01 (s, 2 H),
6.60 (s, 2 H), 5.77 (s, 1 H), 2.61 (s, 2 H), 2.39 (d, J = 5.7 Hz, 2 H),
1.15 (s, 3 H), 0.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 200.6, 166.8, 152.7, 147.7, 132.6,
131.4, 131.0, 129.0, 128.7, 128.1, 127.8, 127.4, 125.2, 123.3, 121.4,
118.7, 117.3, 116.5, 113.8, 50.1, 41.5, 32.3, 28.9, 27.9, 27.1.
MS (ESI): [M + Na]+ calcd for C23H24O3S + Na: 403.1338; found:
403.1375.
Anal. Calcd for C23H24O3S (380.49): C, 72.60; H, 6.36. Found: C,
72.68; H, 6.44.
MS (ESI): m/z [M + H]+ calcd for C25H22O3: 371.1642; found:
371.1642.
9-(Phenylthio)-2,3-dihydrocyclopenta[b]chromen-1(9H)-one
(4o)
Yield: 0.211 g (72%); brown liquid.
Anal. Calcd for C25H22O3 (370.15): C, 81.06; H, 5.99. Found: C,
81.09; H, 5.94.
IR (film): 2923, 1704, 1651, 1574, 1438, 1393, 1249, 1163, 1119,
744, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.49 (m, 1 H), 7.31–7.27 (m,
1 H), 7.25–7.20 (m, 2 H), 7.14 (t, J = 7.2 Hz, 2 H), 6.94 (d, J = 8 Hz,
2 H), 6.85–6.83 (m, 1 H), 5.13 (s, 1 H), 2.57–2.36 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 201.5, 179.9, 151.3, 136.8 (2 C),
131.0, 130.9, 129.2, 128.8, 128.4 (2 C), 125.8, 122.2, 116.6, 114.0,
40.5, 33.6, 25.3.
Acknowledgment
S.B. is thankful to IIT Guwahati for her research fellowship.
D.K.D. is thankful to CSIR, New Delhi for his research fellowship.
The authors are grateful to the Department of Science and Techno-
logy, New Delhi for financial assistance for creating single XRD fa-
cility in the Department of Chemistry under FIST program. The
authors also acknowledge the Director, IIT Guwahati for providing
laboratory facility.
MS (ESI): m/z [M + Na]+ calcd for C18H14O2S + Na: 317.0607;
found: 317.0610.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 73–80

80
S. Bhattacharjee et al.
PAPER
(13) Bristol, J. A.; Gold, E. H.; Gross, I.; Lovey, R. G. J. Med.
Chem. 1981, 24, 1010.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are X-ray crystallographic data (CIF files) of 4k, spectral data of all
(14) (a) Ghosh, P. P.; Das, A. R. J. Org. Chem. 2013, 78, 6170.
(b) Li, M.; Zhang, B.; Gu, Y. Green Chem. 2012, 14, 2421.
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Angew. Chem. Int. Ed. 2004, 43, 115.
1
compounds and copies of H, 13C NMR, and MS spectra of pro-
ducts.SungIifo
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Synthesis 2014, 46, 73–80
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