An atom-economical approach to the synthesis of potentially bioactive 2 H-chromenes via CuI-catalyzed reactions of Alkyl/Aryl-(E)-(o-propargyloxy)styryl ketones

Article abstract of DOI:10.1055/s-0031-1290769

A series of potentially bioactive 2H-chromenes have been synthesized in good yields (60-82%) via CuI-catalyzed reactions of alkyl/aryl-(E)-(o- propargyloxy)styryl ketones in an atom-economical approach. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290769

LETTER
▌1225
Letter
An Atom-Economical Approach to the Synthesis of Potentially Bioactive
2H-Chromenes via CuI-Catalyzed Reactions of Alkyl/Aryl-(E)-(o-Propar-
gyloxy)styryl Ketones
Potentially Bioactive 2H-Chromenes
K. C. Majumdar,*a,b Inul Ansary,a Pranab K. Shyam,a B. Roya
a
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
b
Department of Chemical Sciences, Tezpur University, Napaam 784028, Assam, India
E-mail: kcm@klyuniv.ac.in
Received: 24.01.2012; Accepted after revision: 23.02.2012
2H-chromene moiety. In addition to biological applica-
Abstract: A series of potentially bioactive 2H-chromenes have
tions, these are also widely used as photochromic materi-
been synthesized in good yields (60–82%) via CuI-catalyzed reac-
als.10
tions of alkyl/aryl-(E)-(o-propargyloxy)styryl ketones in an atom-
economical approach.
The bioactivity and application potential of these com-
Keywords: aldol
oxy)styryl ketones, copper(I) iodide, 2H-chromenes, atom economy
condensation,
alkyl/aryl-(E)-(o-propargyl- pounds has attracted a number of research groups to de-
velop several methodologies for the synthesis of this class
of compounds. The approaches in use include intramolec-
ular cyclization of Wittig intermediates,11 microwave-as-
sisted reaction of salicylaldehyde with enamines,12
catalytic Petasis reaction of salicylaldehydes,13 ring-clos-
ing olefin metathesis,14 Baylis–Hillman reaction of sali-
cylaldehydes with methyl vinyl ketones,15 Claisen
rearrangement of propargyl phenyl ethers,16 Pd-catalyzed
ring closure of 2-isoprenyl phenols,17 electrocyclic ring
closure of vinylquinone derivatives,18 ylide annulation re-
2H-Chromenes (2H-benzopyrans) are an important class
of oxygenated heterocyclic compounds.1 Many naturally
occurring pharmacologically active compounds possess
the 2H-chromene moiety, for example, 5,7-dimethoxy-2-
methyl-2H-benzopyran (1) and 5,7-dimethoxy-2,8-di-
methyl-2H-benzopyran (2, Figure 1). Both 1 and 2 were
isolated from the leaf essential oil of Calyptranthes trico-
na.2 Calanolide F (3, Figure 1), isolated from Calophyl-
lum teysmannii var. inophylloide,3 also contain the 2,2-
dimethylchromene moiety and exhibits anti-HIV activity.
On the other hand, 3-(6-chloro-2H-chromen-3-yl)propen-
1-one (4, Figure 1), a synthetic compound bearing the 2H-
chromene unit, exhibits in vitro antileishmanial activity at
noncytotoxic concentrations.4
21
action,19 molecular iodine20 as well as Ph3PAuNTf2 -cat-
alyzed cyclization of aryl propargyl ethers, reaction of
salicylaldehyde and potassium vinyltrifluoroborate in the
presence of secondary amine,22 iron-catalyzed intramo-
lecular alkyne–aldehyde metathesis of the alkynyl ether of
salicylaldehydes,23 and the reaction of 5-chloro-2-
hydroxybenzaldehyde with acrolein in the presence of po-
tassium carbonate followed by Claisen–Schmidt conden-
sation with various acetophenones in ethanolic NaOH.4
All these routes were not devoid of any drawback. Some
required the use of expensive catalysts14,17,18,21 or re-
agents,13,14b,22 some involved greater number of reaction
steps14b and also longer reaction time13a for the cyclization
step. To avoid these problems, there is a demand for even
an improved protocol for the synthesis of this class of
compounds. Herein, we report a convenient and efficient
approach for the synthesis of 2H-chromenes from the re-
action of readily accessible substrates alkyl/aryl-(E)-(o-
propargyloxy)styryl ketones in the presence of CuI as a
catalyst.
R
O
MeO
O
HO
O
O
O
OMe
1 R = H
2 R = Me
O
3
calanolide F
Cl
R
O
4 R = Cl, F, OMe
The starting precursors, alkyl/aryl-(E)-(o-propargyl-
oxy)styryl ketones 7a–j were prepared in 68–85% yields
from the reaction of their corresponding alkyl/aryl-(E)-(o-
hydroxy)styryl ketones 6a–j with propargyl bromide in
refluxing acetone for 5–6 hours in the presence of anhy-
drous K2CO3 and a catalytic amount of NaI (Scheme 1).
The compounds 6a–h24,25 (R5 = Me, Et) were, in turn, pre-
pared by the aldol condensation of 2-hydroxybenzalde-
hydes 5a–f with K2CO3 in acetone or ethyl methyl ketone
under reflux for 10–12 hours. The compounds 6i,j (R5 =
aryl) were prepared from 2-hydroxybenzaldehydes by the
Figure 1
Moreover, it is also found that several compounds with
antitumor,5 antibacterial/antimicrobial,6 fungicidal,7 in-
secticidal,8 and also antioxidant9 properties contain the
SYNLETT 2012, 23, 1225–1229
Advanced online publication: 20.04.2012
DOI: 10.1055/s-0031-1290769; Art ID: ST-2012-B0068-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1226
K. C. Majumdar et al.
LETTER
aldol condensation with acetophenones and methanolic
KOH at room temperature for 2–3 hours followed by acid-
ification with dilute HCl. Similarly, the starting precur-
sors 7k and 7l (inseparable mixture) were also synthesized
in 70% overall yield in the ratio of 7k/7l = 1.4:1.0 (deter-
O
O
i
O
O
7a
9a 54%
1
O
mined from the H NMR spectrum) following the same
+
reaction sequence from the inseparable mixture of 2-hy-
droxy benzaldehydes 5g and 5h, Reimer–Tiemann prod-
ucts of 4-chloro-3-methyl phenol.
O
O
R1
R1
O
R2
R3
CHO
OH
R2
R3
i or ii
O
R5
10a
not found
O
OH
R5
R4
R4
Scheme 2 Reagents and conditions: (i) CuI (5 mol%), DMF, 100 °C,
4 h.
5a R1 = H, R2 = Me, R3 = H, R4 = H
5b R1 = H, R2 = H, R3 = H, R4 = H
5c R1 = H, R2 = Cl, R3 = H, R4 = H
5d R1 = H, R2 = t-Bu, R3 = H, R4 = H
5e R1 = Me, R2 = H, R3 = Me, R4 = H
5f R1 = Me, R2 = H, R3 = H, R4 = Me
5g R1 = H, R2 = Cl, R3 = Me, R4 = H
5h R1 = Me, R2 = Cl, R3 = H, R4 = H
iii
To optimize the reaction conditions we then performed a
series of experiments by changing the variable parameters
such as solvent, catalyst, reaction temperature, and reac-
tion time (Table 1). Thus, the substrate (E)-4-[5-methyl-2-
(prop-2-ynyloxy)phenyl]but-3-en-2-one (7a) was made to
R1
O
R2
R3
R5
O
R4
7a–l
Table 1 Optimization of the Reaction Conditions
O
O
Cl
CHO
iv
catalyst
5g
5h
+
solvent, Δ
O
O
O
inseparable
mixture
7a
9a
8g
inseparable
mixture and
unstable
+
Entry Solvent
Catalyst
(mol%)
Temp
(°C)
Time Yield
(h)
(%)
Cl
CHO
O
1
2a
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMSO
CuI (5)
100
4
2
2
5
2
3
5
5
5
5
5
2
4
2
6
54
CuI (10)
CuI (15)
CuI (10)
CuI (10)
CuI (10)
100
68
8h
Scheme 1 Reagents and conditions: (i) (when R5 = Me, Et): K2CO3,
reflux, 10–12 h; (ii) (when R5 = aryl): KOH, MeOH, r.t., 2–3 h, then
4 N HCl; (iii) propargyl bromide, anhyd K2CO3, NaI (cat.), dry ace-
tone, reflux, 5–6 h; (iv) propargyl bromide, anhyd K2CO3, NaI (cat.),
dry MeCN, reflux, 2 h.
100
68
80
43
130
36
100
63
Products of every step were inseparable; therefore, an
alternative reaction pathway was explored for their syn-
thesis. When the inseparable mixture of 2-hydroxybenzal-
dehydes 5g and 5h were made to react with a propargyl
bromide–K2CO3 mixture in refluxing acetonitrile in the
presence of a catalytic amount of NaI, again an insepara-
ble mixture of the expected o-propargyloxy benzalde-
hydes 8g and 8h were obtained that readily underwent
decomposition.
1,4-dioxane CuI (10)
reflux
reflux
reflux
reflux
100
n.r.
n.r.
n.r.
n.r.
DCE
CuI (10)
MeCN
THF
CuI (10)
10
CuI (10)
11
12
13
14
15
toluene
DMF
DMF
DMF
DMF
CuI (10)
n.r.
b
FeCl3 (10)
CuCl2·2H2O (10)
InCl3 (10)
100
We have used compound 7a as a model precursor for our
study. The substrate 7a was treated with 5 mol% of CuI in
DMF at 100 °C for four hours (Table 1, entry 1) and 2H-
chromene 9a26 was isolated in 54% yield, without the for-
mation of expected product 1,3-diyne27 derivative 10a
(Scheme 2).
100
n.r.
c
100
d
100
n.r.
–
a Optimized reaction conditions.
b Several inseparable spots formed.
c Decomposition of the starting material occurred.
d Absence of catalyst; n.r. = no reaction occurred.
Synlett 2012, 23, 1225–1229
© Georg Thieme Verlag Stuttgart · New York

LETTER
Potentially Bioactive 2H-Chromenes
1227
react with 10 mol% of CuI in DMF at 100 °C for only two Surprisingly, the reaction of the inseparable mixture of the
hours to complete the reaction giving the 2H-chromene 9a substrates 7k and 7l under the optimized reaction condi-
in 68% yield (Table 1, entry 2).
tions afforded only one isolable product, the 2H-
chromene 9k (Table 2, entry 11). Although three spots,
one for 9k (Rf = ca. 0.5), one deep spot on the base line
(perhaps from decomposition), and another spot with
higher Rf value (ca. 0.9) were observed on the TLC (silica
gel, 1:9 EtOAc–PE). However, during chromatographic
separation and also on keeping the upper fraction, the
products underwent rapid decomposition and thereby we
failed to characterized the product from 7l.
Further increase in the amount of CuI did not improve the
yield of the product 9a (Table 1, entry 3). The yield of the
2H-chromene 9a was found to be appreciably lower when
the reaction was carried out at either higher or lower than
100 °C (Table 1, entry 4, 5). Different solvents viz.
DMSO, 1,4-dioxane, 1,2-dichloroethane (DCE), MeCN,
THF, and toluene were also examined, but only the
DMSO gave the 2H-chromene 9a in a higher yield (63%,
Table 1 entry 6). The other solvents did not give even a The structures of 2H-chromenes 9 were determined from
trace of the 2H-chromene 9a, and the starting material 7a their spectral and analytical data, and the final assignment
was recovered (Table 1, entries 7–11). Again, FeCl3, was made from the NOESY (1H–1H correlation) experi-
CuCl2·2H2O, and InCl3 were also tested for their catalytic ment (Figure 2).
activity but these were found to be ineffective for this re-
action (Table 1, entries 12–14).
NOE
NOE
In the absence of CuI as catalyst, the substrate 7a re-
mained unaffected (Table 1, entry 15). Thus a combina-
tion of (E)-4-[5-methyl-2-(prop-2-ynyloxy) phenyl]but-3-
en-2-one (7a), and 10 mol% of CuI in DMF at 100 °C pro-
vides the best result (Table 1, entry 2).
Ha
Hd
He
O
Cl
Hf
Hb
O
Hc
To test the generality of the reaction, other substrates 7b–
j were treated under the optimized reaction conditions,
and the 2H-chromene derivatives 9b–j were obtained in
60–82% yields (Table 2).
9c
Figure 2 NOESY correlation of the compound 9c
Table 2 Synthesis of 2H-Chromene Derivatives
R1
O
R1
O
R2
R3
R2
R3
R5
R5
CuI (10 mol%)
O
DMF, 100 °C
1.5–2 h
O
R4
R4
7a–l
9a–k
R1
R2
R3
R4
R5
Yield (%)a
Entry
Substrate
Product
Time (h)
1
2
7a
7b
7c
7d
7e
7f
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
9a
9b
9c
9d
9e
9f
2
68
73
82
64
65
62
71
69
60
63
H
H
2
3
H
Cl
t-Bu
H
H
2
4
H
H
2
5
Me
Me
H
Me
H
2
6
H
2
7
7g
7h
7i
H
H
9g
9h
9i
2
8
H
Me
H
H
Et
2
9
H
H
Ph
1.5
1.5
2
10
11
12
7j
H
Cl
Cl
Cl
H
2-ClC6H4
Me
Me
9j
7kb
7lb
69c
–
H
Me
H
9k
–
Me
2
a Isolated yield of the product.
b Inseparable mixture of 7k and 7l was used.
c Isolated yield of the product of 9k with respect to the starting material 7k.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1225–1229

1228
K. C. Majumdar et al.
LETTER
The NOESY spectrum of the compound 9c shows two im-
portant NOE interactions, one between Ha (δH = 7.05, d,
J = 2.8 Hz) and Hd (δH = 6.70, s) and the other between Hd
(δH = 6.70, s) and He (δH = 7.19, d, J = 16.0 Hz). Moreover,
the spectral data and melting point of the compound 9j
were also consistent with the literature reported values.4
Acknowledgment
We thank CSIR (New Delhi) and DST (New Delhi) for financial as-
sistance. Two of us are grateful to UGC (New Delhi, I.A.) and to
CSIR (New Delhi, P.K.S.) for their research fellowships. We also
thank DST (New Delhi) for providing Bruker DPX-400 NMR and
Perkin-Elmer L 120-000A IR spectrometers and a Perkin-Elmer
2400 series II CHN-analyzer under the DST-FIST programme.
A probable reaction mechanism for the formation of 2H-
chromene 9 is depicted in Scheme 3. Initially the CuI may
facilitate a 1,5-propargyl shift of 7 via the intermediate 11
to form the intermediate 12 which may readily undergo an
intramolecular [4+2] cycloaddition28 to generate the fused
species 13. The strained species 13 may then isomerize to
produce 14 that on facile electrocyclic ring opening29 may
give the product 9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
References and Notes
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CuI
R1
O
R1
O
R2
R3
R2
R3
1,5-propargyl
shift
R5
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CuI
O
O
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11
O
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H
intramolecular
[4+2]
cycloaddition
R2
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isomerization
O
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13
CuI
CuI
12
O
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electro-
cyclic ring
opening
R1
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In short, the product of the reaction can be regarded as the
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oxy)styryl ketone catalyzed by CuI.
In conclusion, a series of potentially bioactive 2H-
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catalyzed reactions of easily available alkyl/aryl-(E)-(o-
propargyloxy)styryl ketones of which the compound 9j is
known to exhibit in vitro antileishmanial activity at non-
cytotoxic concentration.4 The attractive features of this
methodology are the mild reaction conditions, high atom-
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friendly catalyst. Moreover, this protocol can introduce
α,β-unsaturated carbonyl functionality in the 2H-
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Synlett 2012, 23, 1225–1229
© Georg Thieme Verlag Stuttgart · New York

LETTER
Potentially Bioactive 2H-Chromenes
1229
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(26) Typical Procedure for the Synthesis of (E)-4-(6-Methyl-
2H-chromen-3-yl)but-3-en-2-one (9a): A mixture of
compound 7a (150 mg, 0.70 mmol), and CuI (14 mg, 10
mol%) was stirred in dry DMF (4 mL) at 100 °C for 2 h. The
reaction mixture was cooled to r.t., and then it was poured
into H2O (10 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 20 mL), the organic layer was washed with H2O
(3 × 15 mL), brine (20 mL), and then dried over anhyd
Na2SO4. The solvent was removed under reduced pressure to
give a crude mass which was chromatographed over silica
gel (230–400 mesh) using EtOAc–PE (1:19 v/v) as an eluent
to afford the 2H-chromene 9a as a sole product; yield 68%;
mp 68 °C. IR (KBr): νmax = 2918, 1682 cm–1. 1H NMR (400
MHz, CDCl3): δ = 2.26 (s, 3 H), 2.33 (s, 3 H), 4.93 (s, 2 H),
6.03 (d, 1 H, J = 16.4 Hz), 6.73–6.75 (m, 2 H), 6.89 (s, 1 H),
6.99 (dd, 1 H, J = 8.4, 1.6 Hz), 7.21 (d, 1 H, J = 16.4 Hz). 13
C
NMR (100 MHz, CDCl3): δ = 20.5, 27.7, 65.0, 115.6, 121.6,
125.5, 128.3, 128.7, 131.1, 131.6, 132.0, 140.4, 152.4,
198.0. ESI-HRMS: m/z calcd for C14H14O2Na [M + Na]:
237.0892; found: 237.0931.
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