An efficient and simple method for synthesis of 2,2-disubstituted-2H- chromenes by condensation of a phenol with a 1,1-disubstituted propargyl alcohol using BF3·Et2O as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.07.077

An efficient and simple method for the synthesis of 2,2-disubstituted-2H- chromenes by one-step cyclocondensation of a phenol with a variety of 1,1-disubstituted propargyl alcohols using BF₃·Et₂O as the catalyst is described.

Full text of DOI:10.1016/j.tetlet.2012.07.077

Tetrahedron Letters 53 (2012) 5275–5279
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Tetrahedron Letters
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An efficient and simple method for synthesis of
2,2-disubstituted-2H-chromenes by condensation of a phenol with a
1,1-disubstituted propargyl alcohol using BF3ÁEt2O as the catalyst
⇑
Sridhar Madabhushi , Raveendra Jillella, Kondal Reddy Godala, Kishore Kumar Reddy Mallu,
China Ramanaiah Beeram, Narsaiah Chinthala
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple method for the synthesis of 2,2-disubstituted-2H-chromenes by one-step cyclo-
condensation of a phenol with a variety of 1,1-disubstituted propargyl alcohols using BF3ÁEt2O as the cat-
alyst is described.
Received 8 June 2012
Revised 13 July 2012
Accepted 18 July 2012
Available online 27 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2,2-Disubstituted-2H-chromenes
Phenol
Cyclocondensation
1,1-Disubstituted propargyl alcohol
BF3ÁEt2O
Lewis acid catalysis
2,2-Disubstituted-2H-chromenes or 2,2-disubstituted-2H-1-
benzopyrans are found as a parent structure in natural products1
and also in many biologically active molecules, which include
antitumor,2 anti-HIV,3 antibacterial,4 and antifungal agents.5 In
addition, 2,2-dimethyl-2H-chromenes have high importance as
intermediates for the manufacture of several pharmaceutical
compounds6 and 2,2-diaryl-2H-chromenes have applications as
photochromic agents.7 Though several methods are available in
literature for the preparation of 2,2-disubstituted-2H-chromenes,8
a simple and straightforward approach is one-step cyclocondensa-
tion of a phenol and a propargyl alcohol, which are also easily acces-
sible starting materials. In existing methods, however, formation of
2H-chromene from the reaction of a phenol and a propargyl alcohol
was often described as a two-step process.9 The first step is the
preparation of aryl propargyl ether by the reaction of a phenol
and a propargyl alcohol using an acid catalyst such as p-toluene
sulfonic acid and in the second step, aryl propargyl ether was
converted into 2H-chromene via thermal Claisen rearrangement
reaction at 180–220 °C. In literature, relatively few methods were
described for the preparation of 2H-chromenes by one-step
condensation of a phenol and a propargyl alcohol using a Lewis acid
as the catalyst and the methods are as follows: Carreira et al.,10
reported the formation of diaryl-benzopyrans and diaryl-naphtho-
pyrans by the reaction of a diaryl propargyl alcohol with a phenol/
naphthol using pyridinium p-toluenesulfonate(PPTS) as the catalyst
and trimethylorthoformate (two equivalents) as an additive. Heron
and co-workers,11 studied the condensation reaction of 2-naphthol
and a diaryl propargyl alcohol under the catalysis of acidic alumina
to obtain diaryl-naphthopyrans in moderate yields (<45%). In this
reaction, propenylidenenapththalenone was formed as the side
product. Wang and co-workers,12 prepared diaryl-naphthopyrans
in good yields by condensation of 2-naphthol with a 1,1-diaryl
propargyl alcohol using indium(III) chloride as the catalyst. This
study was limited to diaryl-naphthopyrans and the reactions were
observed only under ball milling conditions. McCubbin et al.,13
also studied this reaction using perfluorophenylboronic acid
(C6F5B(OH)2) as the catalyst and obtained naphthopyrans in moder-
ate to good yields. Sartori and co-workers,14 observed the formation
of 2H-chromenes by condensation of a phenol with a propargyl
alcohol using a zeolite (HSZ-360) as the catalyst. This reaction pro-
ceeds only with a 1-methyl substituted propargyl alcohol which
undergoes dehydration in the presence of the zeolite and converts
into corresponding conjugated enyne in the initial step and the
resulting enyne intermediate reacts with phenol to give 2H-
chromene.
Thus, most of the above methods suffer from a lack of generality
as their application was limited to the preparation of either
⇑
Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (S. Madabhushi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.077

5276
S. Madabhushi et al. / Tetrahedron Letters 53 (2012) 5275–5279
R3
R3
O
BF3.Et2O(15 mol%)
R1
R2
R
R1
R
CH2Cl2 or ClCH2CH2Cl
HO R2
OH
6-48h
2
3a-l (72--90%)
1a-l
R=Me, OMe, Br or F R1=R2=Me, R3 = H
R=Me, OMe, Br or F;
R1=R2=Me, R3 = H
4a-j
5a-j (64--82%)
R= Me; R1=R2=Me, CF3, Ph or -(CH2)5-;
R3=H, Ph or SiMe3
R1=R2=Me, CF3, Ph or -(CH2)5-;
R3=H, Ph or SiMe3
Scheme 1. Synthesis of 2,2-disubstituted-2H-chromenes.
benzopyrans or naphthopyrans. Recently, Hua and co-workers,15
developed a general method for preparation of a variety of 2,2-
disubstituted-2H-chromenes by condensation of a phenol and a
1,1-disubstituted propargyl alcohol using ReCl(CO)5 as the catalyst.
Though this method has a good generality, it involves use of highly
expensive catalyst and the reactions were shown to proceed
essentially under heating in a sealed tube. Since the existing meth-
ods suffer from one or more of the disadvantages such as lack of
generality, use of expensive catalyst and poor yields, development
of an efficient and simple general method for preparation of 2,2-
disubstituted-2H-chromenes by condensation of a phenol and
1,1-disubstituted propargyl alcohol is highly desirable. Herein we
report an efficient method for the preparation of a variety of 2,2-
disubstituted-2H-chromenes in high yields (64–90%) by cyclocon-
densation of a phenol and a 1,1-disubstituted propargyl alcohol at
room temperature using an inexpensive Lewis acid BF3ÁEt2O as the
catalyst as shown in Scheme 1.
Table 1
A study of the formation of 2,2-dimethyl-2H-chromene 3a under acid catalysis
OH
Catalyst(15 mol%)
HO
CH2Cl2, r.t.
O
3a
1a
2
S.No.
Catalyst
Reaction time (h)
Yield 3a (%)
1
2
3
4
5
6
7
8
9
10
BF3ÁEt2O
AlCl3
FeCl3
InCl3
ZnCl2
6
82
60
32
12
0
0
0
0
17
0
24
24
24
24
24
24
24
24
24
SbCl3
Yb(OTf)3
Eu(OTf)3
H2SO4
CF3COOH
Table 2
Synthesis of 2,2-dimethyl-2H-chromenes by condensation of a phenol and 2-methylbut-3-yn-2-ol under BF3ÁEt2O catalysis
R
R
BF3.Et2O(15 mol%)
CH2Cl2, r.t.
OH
OH
O
3a-l
1a-l
2
Entry
a
Phenol 1
OH
2H-Chromene 3
Reaction time (h)
6.0
Yielda (%)
82
O
O
O
OH
b
c
6.5
7.5
84
75
OH
OH
OH
d
e
6.5
7.0
90
88
O
O
Br
Br
OH
f
6.5
7.0
6.0
84
72
86
O
F
F
OH
g
h
O
MeO
MeO
OH
O

S. Madabhushi et al. / Tetrahedron Letters 53 (2012) 5275–5279
5277
Table 2 (continued)
Entry
Phenol 1
2H-Chromene 3
Reaction time (h)
5.0
Yielda (%)
OH
O
i
82
O2N
F3C
OH
OH
j
N.R.
N.R.
—
—
—
—
k
OH
l
6.5
80b
O
O
1:1
Isolated yields. All products gave satisfactory 1H, 13C NMR, IR and Mass spectral data.
Corresponds to the mixture of isomers.
a
b
Table 3
Synthesis of 2,2-disubstituted-2H-chromenes by condensation of p-cresol and a 1,1-disubstituted propargyl alcohol under BF3ÁEt2O catalysis
R3
R1
BF3.Et2O(15 mol%)
CH2Cl2, r.t.
OH
R2
R1
R2
OH
4a-j
O
1b
5a-j
Entry
a
Propargyl alcohol 4
2H-Chromene 5
Reaction time (h)
Yielda (%)
82
Ph
Ph
6.0
O
OH
Ph
P
Ph
b
c
6.5
7.5
78
80
O
Ph
OH
Ph
Ph
OH
O
Ph
Ph
Ph
Ph
Ph
d
e
f
6.5
6.5
7.0
8.0
75
75
68
76
OH
Ph
Ph
O
Ph
O
OH
SiMe3
TMS
TMS
O
OH
SiMe3
OH
g
CH3
O
CH3
Ph
Ph
CF3
OH
h
i
36.0
48.0
24.0
65
76
64
CH3
CF3
O
Ph
CF3
Ph
Ph
CF3
OH
CF3
CF3
O
Ph
Ph
CF3
j
OH
Ph
O
CF3
k
l
N.R.
N.R.
24.0
24.0
—
—
OH
OH
a
Isolated yields. All products gave satisfactory 1H, 13C NMR, IR, and Mass spectral data.

5278
S. Madabhushi et al. / Tetrahedron Letters 53 (2012) 5275–5279
Initially, we investigated the condensation reaction of phenol 1a
and 1,1-dimethyl propargyl alcohol(2-methyl-3-butyn-2-ol)
R
R
R
R
R
LA
R
R
2
O
O
O
R
R
OH
using a variety of Lewis and Bronsted acid catalysts such as
BF3ÁEt2O, AlCl3, FeCl3, ZnCl2, SbCl3, InCl3, Yb(OTf)3, Eu(OTf)3, sulfu-
ric acid, and trifluoroacetic acid at room temperature using dichlo-
romethane as solvent to obtain 2,2-dimethyl-2H-chromene 3a and
the results are shown in Table 1. In this study, we observed best re-
sults with BF3ÁEt2O, which gave 2,2-dimethyl-2H-chromene 3a in
82% yield in 6 h in dichloromethane. When this reaction was car-
ried out using other solvents such as 1,2-dichloroethane, n-hexane,
acetonitrile, toluene under similar conditions, 3a was obtained in
65%, 60%, 15%, and 10% yields, respectively in 24 h and no reaction
was observed in methanol.
LA/PhOH
-H2O
LA
H
Claisen
LA= Lewis acid
+H+
R
R
R R
O
R
O
H
H
O
1,5-H shift
[3,3]
Scheme 3. Plausible mechanism for formation of 2,2-disubstituted-2H-chromenes
We also studied the present reaction with a variety of phenols
1a–i, which were reacted with 1,1-dimethyl propargyl alcohol 2
using BF3ÁEt2O as the catalyst in dichloromethane at room temper-
ature to obtain corresponding 2,2-dimethyl-2H-chromenes 3a–i in
72–90% yields as shown in Table 2.16 In this study, however, phe-
nols having electron withdrawing groups such as p-nitrophenol 1j
and p-trifluoromethylphenol 1k were found to be unreactive even
under reflux for 24 h in 1,2-dichloroethane. When an unsymmetri-
cal phenol m-cresol 1l was reacted with 1,1-dimethyl propargyl
alcohol 2 at room temperature in dichloromethane using BF3ÁEt2O
as the catalyst, we did not observe any selectivity and obtained an
inseparable 1:1 mixture of two regioisomeric chromenes (3l, Table
2).
Next, we studied the present reaction using a variety of 1,1-
disubstituted propargyl alcohols 4a–j, which were reacted with
p-cresol 1b under BF3ÁEt2O catalysis in dichloromethane at room
temperature to obtain corresponding 2,2-disubstituted-2H-chrom-
enes 5a–j in 64–82% yields as shown in Table 3. In this study, how-
ever, unsubstituted propargyl alcohol 4k and monosubstituted
propargyl alcohol 4l did not participate in the condensation reac-
tion with p-cresol under similar conditions. Primary and secondary
propargyl alcohols 4k and 4l were unreactive possibly because the
formation of carbocations from these substrates could be energet-
ically not favorable under the reaction conditions when compared
to tertiary propargyl alcohols 4a–j.
We observed that the present condensation reaction to proceed
well also with an allylic alcohol substituted with an electron rich
group such as 1,1-dimethyl allylic alcohol 4m, which was reacted
with p-cresol 1b at room temperature in dichloromethane under
BF3ÁEt2O catalysis to obtain 2,2-dimethyl chroman 5m in 80% yield.
However, 1,1-diphenyl allyl alcohol 4n did not react with p-cresol
1b under similar conditions as shown in Scheme 2.
In the present study, we prepared, for the first time, 4-silyl func-
tionalized 2H-chromenes 5f and 5g in 68 and 76% yields, respec-
tively, which were obtained by the reaction of p-cresol 1b with
1-((trimethylsilyl)ethynyl)cyclohexanol 4f and 2-methyl-4-(tri-
methylsilyl)but-3-yn-2-ol 4g respectively at room temperature
using BF3ÁEt2O as the catalyst in dichloromethane (Table 3). In this
reaction, trimethylsilyl group was found to exhibit good tolerance
to the reaction conditions.
under Lewis acid catalysis.
The functional groups CH3 and CF3 are known as bioisosteres17
in medicinal chemistry. In several existing studies, bioefficacy was
found to improve dramatically when the CH3 group present in a
bioactive molecule was replaced with a CF3 group, which improves
the lipophilicity, bioavailability, and metabolic stability of the mol-
ecule.18 In literature, synthesis and study of trifluoromethyl func-
tionalized 2H-chromenes are so far not known and in present
study, we prepared trifluoromethyl functionalized 2H-chromenes
5h–j (Table 3) by condensation of p-cresol 1b and propargyl alco-
hols19 4h–j using BF3ÁEt2O as the catalyst under reflux in 1,2-
dichloroethane. In this study, trifluoromethyl functionalized prop-
argyl alcohols were found to be relatively sluggish when compared
to methyl functionalized propargyl alcohols, as they required high
temperature (reflux condition in 1,2-dichloroethane) and longer
reaction times (>24 h) to undergo the condensation reaction.
Thermal Claisen rearrangement of aryl propargyl ethers and
their subsequent transformation into 2H-chromenes are exten-
sively studied subjects in literature.20 Sames et al.,21 carried out
this transformation at room temperature using a Lewis acid cata-
lyst PtCl4. In the present study also, we believe that the initial step
of the reaction involves formation of aryl propargyl ether as a tran-
sient intermediate from the reaction of a phenol and a propargyl
alcohols under Lewis acid catalysis. In the subsequent step, the
resulting aryl propargyl ether possibly undergoes rapid Claisen
rearrangement under Lewis acid catalysis and converts into 2H-
chromene as shown in Scheme 3.
In conclusion, we have developed an efficient, simple, and mild
general method for the preparation of 2,2-disubstituted-2H-
chromenes by condensation of a propargyl alcohol and a phenol
using BF3ÁEt2O as the catalyst. In this study, we report the first syn-
thesis of 2-trifluoromethyl functionalized 2H-chromenes and 4-si-
lyl functionalized 2H-chromenes.
Acknowledgement
R.J., K.R.G., K.K.R.M., and C.R.B. are thankful to C.S.I.R., New Delhi
for the award of Senior Research Fellowship. N.C. is thankful to
U.G.C., New Delhi for the award of Senior Research Fellowship.
4m
OH
Supplementary data
O
BF3.Et2O(15 mol%)
CH2Cl2, r.t., 8h
OH
5m (80%)
Supplementary data associated with this article can be found, in
the online version(experimental procedures, characterization data
and 1H & 13C NMR spectra of the compounds), at http://dx.doi.org/
10.1016/j.tetlet.2012.07.077.
Ph Ph
4n
1b
OH
No Reaction
BF3.Et2O(15 mol%)
CH2Cl2, r.t., 12h
References and notes
Scheme 2. A study of the reactivity of 1,1-disubstituted allylic alcohol with p-cresol
under BF3ÁEt2O catalysis.
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28.0; IR (neat):
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t ;
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drop-wise with a syringe at 0 oC and after addition was complete, the mixture
was allowed to stir for 30 min. Next, the mixture was cooled to À78 oC and
then, 2,2,2-trifluoroacetophenone (1.3 mL, 0.9 mmol) was added slowly with a
syringe. After 15 min, the mixture was warmed to 0 oC and stirred for an
additional 30 min. Then, water (10 mL) was added slowly to the mixture,
extracted with diethyl ether (2 Â 15 mL) and the combined organic layer was
dried over anhy. Na2SO4. After removal of the solvent from the mixture under
reduced pressure and purification of the crude product by column
chromatography (silica gel 60–120 mesh, n-hexane) gave 1,1,1-trifluoro-2,4-
diphenyl-3-yn-2-ol 4j (1.49 g, 94%) as an yellow oil. which gave the following
spectral data: 1H NMR (300 MHz, CDCl3): d = 7.83–7.81 (m, 2H), 7.53–7.34 (m,
8H), 3.72 (s, 1H); 13C NMR (75 MHz, CDCl3): d = 135.4, 131.9, 129.4, 128.3,
128.1, 127.1, 120.9, 87.9, 84.4, 73.2; IR (neat):
1450, 1247, 1183, 1066, 694 cmÀ1
ESI-HRMS: Exact mass observed for
11H7F6O : 277.0758 (calculated: 277.0762).
t 3449, 3065, 2959, 2233, 1491,
9. (a) Rao, U.; Balasubramanian, K. K. Tetrahedron Lett. 1983, 24, 5023–5024; (b)
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C
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