InBr3-catalyzed annulations of cyclic 1,3-diketones with aryl propargyl alcohols: a novel synthesis of 2,4-diaryldihydropyrans

Article abstract of DOI:10.1016/j.tetlet.2009.04.088

The cyclic 1,3-dicarbonyl compounds undergo smooth cyclization with aryl propargyl alcohols in the presence of 10 mol % indium tribromide in refluxing dichloroethane to produce 2,4-diarylpyran derivatives in good yields with high selectivity.

Full text of DOI:10.1016/j.tetlet.2009.04.088

Tetrahedron Letters 50 (2009) 3963–3965
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Tetrahedron Letters
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InBr3-catalyzed annulations of cyclic 1,3-diketones with aryl propargyl
alcohols: a novel synthesis of 2,4-diaryldihydropyrans
*
J. S. Yadav , B. V. Subba Reddy, K. V. Raghavendra Rao, R. Narender
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclic 1,3-dicarbonyl compounds undergo smooth cyclization with aryl propargyl alcohols in the
presence of 10 mol % indium tribromide in refluxing dichloroethane to produce 2,4-diarylpyran deriva-
tives in good yields with high selectivity.
Received 5 January 2009
Revised 18 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium(III) halides
Arylpropargyl alcohols
1,3-Dicarbonyls
Cyclization
Lewis acid catalyzed carbon–carbon bond-forming reactions are
of great significance in organic synthesis because of their high
reactivity, selectivity, and mild reaction conditions.1 Aryl propargyl
methanols are well-known carbon electrophiles capable of reacting
with various nucleophiles and their ability to undergo nucleophilic
substitution reactions contributes largely to their synthetic va-
lue.2,3 The direct nucleophilic substitution of the hydroxy group
in alcohols with nucleophiles generally requires preactivation of
the alcohol because of its poor leaving ability.4 Consequently, hy-
droxyl groups are transformed into the corresponding halides, car-
boxylates, carbonates, phosphonates, or related compounds.5
Recently, acid catalysts such as BF3ÁOEt2, InCl3, Bi(OTf)3, Yb(OTf)3,
FeCl3, and H-montmorillonite have been employed to perform
nucleophilic substitution of benzylic alcohols with active methy-
lene compounds.6,7 In most cases, either a high reaction tempera-
ture or a promoter is required to enhance the leaving ability of
the hydroxyl group. However, only few methods have been
reported for the direct substitution of propargylic alcohols with
Recently, indium tribromide has received increasing attention
as a water-tolerant Lewis acid catalyst for organic synthesis dem-
onstrating highly chemo-, regio-, and stereo-selective results.11
Compared to conventional Lewis acids, it has advantages of water
stability, recyclability, operational simplicity, strong tolerance to
oxygen, and nitrogen-containing substrates and functional groups,
and it can often be used in catalytic amounts.12
Following our interest in catalytic uses of indium tribro-
mide,13,14 we herein, report for the first time, an efficient alkylation
of cyclic 1,3-dicarbonyl compounds with propargylic alcohols
using a catalytic amount of InBr3. Accordingly, we first attempted
the alkylation of cyclopentane-1,3-dione (1) with 1,3-diphenyl-2-
propyn-1-ol (2) in 1,2-dichloroethane in the presence of 10 mol %
of InBr3. The reaction went to completion in 2.0 h and the desired
product, 2,4-diphenyl-6,7-dihydrocyclopenta-[b]pyran-5(4H)-one,
3a was obtained in 85% yield (Scheme 1).
Encouraged by this result, we turned our attention to various
cyclic 1,3-diketones and aryl propargyl alcohols. Interestingly,
cyclic 1,3-diketones such as cyclohexane-1,3-dione and 5,5-di-
methyl-1,3-cyclohexanedione (dimedone) reacted well with
1,3-diphenyl-2-propyn-1-ol to give the corresponding 2,4-diphe-
nyl-7,8-dihydro-4H-chromen-5(6H)-one derivatives in good yields
(Table 1, entries b and c). Various aryl propargyl alcohols such as
1,3-dicarbonyls.8 The coupling of 1,3-diketones with
a,b-unsaturated
ketones has been reported for the synthesis of 5-oxo-tetrahydro-4H-
benzo-[b]-pyrans.9 Recently, the coupling of cyclopentanediones with
propargyl alcohols has been achieved using Ru/TFA catalyst system.10
Therefore, the development of simple, convenient, and one-pot
approaches for direct catalytic substitution of alcohols with cyclic
1,3-dicarbonyls would extend its use in the synthesis of biologically
interesting heterocycles.
O
Ph
O
OH
10 mol% InBr3
DCE, 80 ºC
+
Ph
Ph
O
3a
Ph
O
1
2
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.088

3964
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3963–3965
Table 1
Indium tribromide-catalyzed synthesis of 2,4-disubstituted pyrans
Entry
a
Propargyl alcohol
1,3-Diketone
Producta
Time (h)
2.0
Yieldb (%)
85
O
R
O
OH
R = phenyl
Ph
O
Ph
O
O
O
R
OH
b
c
d
e
f
R = phenyl
2.0
1.5
2.5
2.0
2.0
2.5
2.0
1.5
1.0
1.5
1.0
83
80
89
86
88
90
87
85
82
86
85
Ph
O
O
O
Ph
O
R
OH
R = phenyl
Ph
O
O
Ph
O
R
OH
O
R = 2-naphthyl
R = 2-naphthyl
R = 2-naphthyl
R = tolyl
Ph
Ph
O
Ph
O
O
O
R
OH
O
Ph
O
O
O
R
O
OH
OH
Ph
Ph
Ph
O
O
R
O
g
h
i
O
Ph
Me
OH
O
O
O
R
R = 2-thienyl
R = 2-thienyl
R = 2-naphthyl
R = 2-thienyl
S
Ph
Ph
O
O
O
Ph
O
R
O
OH
S
O
Ph
O
R
OH
O
j
O
R
O
O
O
OH
OH
k
l
S
O
O
O
O
O
O
O
O
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
O
OH
O
Ph
m
n
5.0
1.0
1.5
89
90
88
Ph
O
O
O
OH
O
O
O
O
Ph
Ph
R = n-butyl
R = n-butyl
Ph
Ph
R
O
OH
Me
Me
o
Me
Me
R
a
All products were characterized by 1H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3963–3965
3965
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O
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O
O
Ph
OH
I2
DCE, 80 ºC
I
+
Ph
O
O
Ph
Ph
4
Scheme 3.
9. Hu, X. Y.; Fan, X. S.; Zhang, X. Y.; Qu, G. R.; Li, Y. Z. Can. J. Chem. 2006, 84, 1054.
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44, 6055; (b) Yadav, J. S.; Reddy, B. V. S.; Gakul, B. Green Chem. 2003, 5, 264; (c)
Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Parimala, G. Synthesis 2003, 2390.
15. Experimental procedure: A mixture of 1,3-dicarbonyl compound (2.0 mmol),
alcohol (1.0 mmol), and InBr3 (10 mol %) in dichloroethane (5 mL) was refluxed
to 80 °C for appropriate time. After completion of the reaction as indicated by
TLC, the reaction mixture was filtered and diluted with water and extracted
with dichloromethane (2 Â 15 mL). The combined organic layers were dried
over anhydrous Na2SO4, concentrated in vacuo, and purified by column
chromatography on silica gel (Merck, 100–200 mesh, ethyl acetate–hexane,
1:9) to afford pure products as shown in Table 1. The spectroscopic data of the
products were identical with the data reported in the literature. Spectral data
for selected products:
1-(naphthalen-2-yl)-3-phenylprop-2-yn-1-ol, 1-(naphthalen-2-
yl)hept-2-yn-1-ol, 3-phenyl-1-p-tolylprop-2-yn-1-ol, 3-phenyl-1-
(thiophen-2-yl)prop-2-yn-1-ol, and 1-(thiophen-2-yl)hept-2-yn-
1-ol reacted effectively with cyclic 1,3-diketones to furnish the
respective dihydropyran derivatives (Table 1, entries d–k). In case
of acyclic 1,3-diketones such as acetyl acetone and 1,3-diphenyl-
propane-1,3-dione, no cyclized products were obtained under
identical conditions (Scheme 2, Table 1, entries l–o).
Next, we attempted alkylation of cyclohexane-1,3-diketone
with 1,3-diphenyl-2-propyn-1-ol using molecular iodine as a cata-
lyst. The reaction proceeded smoothly in the presence of equimolar
amount of iodine in refluxing 1,2-dichloroethane. The reaction
went to completion in 3 h and the product, 3-iodo-2,4-diphenyl-
7,8-dihydro-4H-chromen-5(6H)-one, 4 was obtained in 75% yield
(Scheme 3).
However, in the absence of iodine or indium tribromide, the
above reactions (Schemes 1–3) did not proceed even after 12 h.
No addition or rearranged products were observed in this reaction.
The hydroxyl group was simply replaced by 1,3-diketone. Further-
more, propargylic alcohols derived from aliphatic aldehydes such
as 1-cyclohexylhept-2-yn-1-ol did not undergo the expected cycli-
zation. This method was successful only with propargylic alcohols
derived from aromatic aldehydes. As solvent, dichloroethane ap-
peared to give the best results. The products were characterized
by 1H, 13C NMR, IR, and mass spectroscopy. Among various metal
halides such as InCl3, CeCl3Á7H2O, SmCl3, and YbCl3, indium tribro-
mide was found to give the best results. The scope and generality
of this process were illustrated with respect to various 1,3-dike-
tones and aryl propargyl alcohols and the results are presented
in Table 1.15
In summary, we have developed a novel method for the prepa-
ration of dihydropyrans from cyclic 1,3-diketones and aryl propar-
gyl alcohols using catalytic amount of indium tribromide as
catalyst. In addition to its simplicity and efficiency, this method
provides high yields of products with high selectivity, which makes
it a useful and attractive process for the preparation of dihydropy-
ran derivatives in a single step operation.
Compound 3a: 2,4-diphenyl-4,5,6,7-tetrahydrocyclopenta[b]pyran-5-one: Pale
yellow color solid, mp 166–168 °C; IR (KBr): mmax 2923, 2852, 2254, 2127,
1698, 1668, 1627, 1386, 1230, 1026, 1001, 826, 761, 694 cmÀ1 1H NMR
;
(200 MHz, CDCl3):
d 2.41–2.46 (m, 2H), 2.75–2.82 (m, 2H), 4.40 (d, 1H,
J = 4.4 Hz), 5.64 (d, 1H, J = 4.4 Hz), 7.15–7.41 (m. 8H), 7.58–7.62 (m, 2H); 13C
NMR (75 MHz, CDCl3): d 25.5, 33.4, 35.5, 103.9, 117.0, 124.6, 126.9, 128.1,
128.4, 129.0, 130.9, 132.7, 143.0, 148.3, 178.4, 202.7; EIMS (M+Na): m/z: 311.
Compound 3d: 4-(2-naphthyl)-2-phenyl-4,5,6,7-tetrahydro-cyclopenta[b]pyran-
5-one: Colorless solid, mp 181–184 °C; IR (KBr): mmax 2923, 2854, 1670, 1626,
1387, 1232, 1129, 1004, 817, 759, 695, 594, 477 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 2.47–2.51 (m, 2H), 2.82–2.87 (m, 2H), 4.63 (d, 1H, J = 3.7 Hz), 5.75 (d,
1H, J = 4.5 Hz), 7.37–7.51 (m, 6H), 7.65–7.82 (m, 6H). 13C NMR (75 MHz,
CDCl3): d 25.5, 33.3, 35.7, 103.7, 116.9, 124.6, 125.5, 125.9, 126.4, 126.6, 127.5,
127.7, 128.2, 128.4, 129.0, 132.5, 132.6, 133.3, 140.4, 148.4, 178.5, 202.6; EIMS
(M+Na): m/z: 361.
Compound 3g: 4-(4-methylphenyl)-2-phenyl-4,5,6,7-tetrahydro- cyclopenta[b]-
pyran-5-one: Colorless solid, mp 180–182 °C; IR (KBr): mmax 2922, 2852, 1703,
1674, 1628, 1386, 1231, 1002, 816, 763, 696, 513 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 2.31 (S, 3H), 2.42–2.46 (m, 2H), 2.74–2.79 (m, 2H), 4.38 (d, 1H,
J = 4.1 Hz), 5.62 (d, 1H, J = 4.1 Hz), 7.06–7.09 (d, 2H, J = 7.9 Hz), 7.15–7.18 (d, 2H,
J = 8.1 Hz), 7.31–7.39 (m, 3H), 7.57–7.61 (m, 2H); 13C NMR (75 MHz, CDCl3): d
21.0, 25.6, 33.3, 35.2, 104.0, 117.2, 124.7, 127.9, 128.4, 128.9, 129.2, 132.7, 136.5,
140.1, 148.2, 178.3, 202.7; EIMS (M+Na): m/z: 325.
Compound 3h: 2-phenyl-4-(2-thienyl)-5,6,7,8-tetrahydro-4H-5-chromenone:
Brown liquid, IR (Neat): mmax 3065, 2923, 2853, 1662, 1625, 1379, 1213, 1185,
Acknowledgment
1022, 764, 694, 555, 522 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.01–2.10 (m, 2H),
;
2.30–2.49 (m, 2H), 2.55–2.74 (m, 2H), 4.82 (d, 1H, J = 5.2 Hz), 5.78 (d, 1H,
J = 5.2 Hz), 6.85–6.87 (m, 1H), 6.92 (d, 1H, J = 3.0 Hz), 7.07–7.09 (dd, 1H, J = 5.2,
1.5 Hz), 7.29–7.38 (m, 3H), 7.56–7.59 (m, 2H); 13C NMR (75 MHz, CDCl3): d 20.3,
27.6, 29.7, 37.0, 103.5, 113.7, 124.1, 124.4, 124.6, 126.7, 128.4, 128.9, 132.8,
147.5, 149.6, 166.1, 197.2; EIMS (M+Na): m/z: 331.
K.V.R. thanks CSIR, New Delhi for the award of fellowship.
References and notes
Compound 3m: 2-(1,3-diphenyl-2-propynyl)-1,3-diphenyl-1,3-propanedione:
1. Kobayashi, S. Eur. J. Org. Chem. 1999, 15–27.
Colorless, solid, mp 91–92 °C; IR (KBr):
m
max 3062, 2923, 2853, 1686, 1658, 1591,
1490, 1446, 1285, 1253, 1196, 988, 755, 687, 561, 523 cmÀ1
;
1H NMR (300 MHz,
2. (a) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem. Soc. 1980, 102, 2508–
2512; (b) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214; (c) Nishibayashi, Y.;
Milton, M. D.; Inada, Y.; Yoshikawa, M.; Wakiji, I.; Hidai, M.; Uemura, S. Chem.
Eur. J. 2005, 11, 1433–1451; (d) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R.
F.; Yang, W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298–8301.
CDCl3): d5.14 (d, 1H, J = 9.8 Hz), 5.76 (d, 1H, J = 10.5 Hz), 6.98–7.02 (m, 2H), 7.09–
7.30 (m, 8H), 7.39–7.58 (m, 6H), 7.72–7.76 (m, 2H), 8.08–8.11 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 38.7, 62.9, 85.0, 89.3, 122.8, 127.3, 127.8, 128.3, 128.5, 128.8,
129.0, 131.3, 133.3, 133.4, 136.3, 136.8, 139.1, 192.4; EIMS (M+Na): m/z: 437.