One-pot synthesis of 4 h -chromenes by tandem benzylation and cyclization in the presence of sodium bisulfate on silica gel

Article abstract of DOI:10.1055/s-0033-1339026

A simple and efficient method has been developed for the synthesis of 4H-chromenes from o-hydroxybenzylic alcohols and dicarbonyl compounds containing active methylene groups by using silica gel supported sodium bisulfate. Various dicarbonyl compounds suc

Full text of DOI:10.1055/s-0033-1339026

LETTER
▌1571
letter
One-Pot Synthesis of 4H-Chromenes by Tandem Benzylation and Cyclization
in the Presence of Sodium Bisulfate on Silica Gel
One-Pot Synthesis of 4H-Chromenes
Tadashi Aoyama,*a,b Takumi Yamamoto,a Saki Miyota,a Mamiko Hayakawa,a Toshio Takido, Mitsuo Kodomaric
a
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku,
Tokyo 101-8308, Japan
Fax +81(3)32590818; E-mail: aoyama.tadashi@nihon-u.ac.jp
b
The Center for Creative Materials Research, Research Institute of Science and Technology, College of Science and Technology, Nihon
University, Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
c
The Institute of Natural Sciences, College of Humanities and Science, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550,
Japan
Received: 05.03.2014; Accepted after revision: 06.04.2014
in the presence of sodium bisulfate on silica gel (Scheme
1).
Abstract: A simple and efficient method has been developed for
the synthesis of 4H-chromenes from o-hydroxybenzylic alcohols
and dicarbonyl compounds containing active methylene groups by
O
O
using silica gel supported sodium bisulfate. Various dicarbonyl
compounds such as diketones, keto esters, and keto amides can be
used in the synthesis of the 4H-chromenes.
Y = H
O
O
Ph
Ph
Key words: cyclizations, benzylations, supported reagents,
chromenes, one-pot syntheses
NaHSO4–SiO2
+
Ph
O
O
OH
Y = OH
Ph
Derivatives of 4H-chromene have attracted growing inter-
est in recent years because of their wide range of pharma-
cological and biological activities, including diuretic,
spasmolytic, anticoagulant, anticancer, and anti-anaphy-
lactic activities.1 As a result, many methods have been de-
veloped for the synthesis of 4H-chromene derivatives,
including three-component reactions catalyzed by L-pro-
line,2 reactions of salicylic aldehydes with β-dicarbonyl
compounds in the presence of iodo(trimethyl)silane,3
gold(III)-catalyzed tandem reaction of ketones with phe-
nols,4 p-toluenesulfonic acid monohydrate catalyzed reac-
tions of acetophenones with 3-methoxybenzene-1,2-diol,5
1,4-diazabicyclo[2.2.2]octane-catalyzed reactions of sali-
cyl N-tosylimines with allenic esters or ketones,6 iron(III)
chloride catalyzed benzylation and cyclization of 1,3-di-
carbonyl compounds,7 copper(I) iodide catalyzed intra-
molecular coupling of aryl bromides with 1,3-dicarbonyl
compounds,8 intramolecular ring-closing metathesis in
the presence of the second-generation Grubbs catalyst,9
tetrahydrothiophene-catalyzed ylide annulation,10 and
other methods.11
Y
Scheme 1 Reactions of acetylacetone with benzylic alcohols
A similar reaction using a Brønsted acid as a catalyst in an
ionic liquid has been reported by Funabiki and co-work-
ers;13 however, their procedure involves laborious workup
to obtain a pure product. We therefore attempted to devel-
op a simpler method for the synthesis of 4H-chromenes
from various alcohols and dicarbonyl compounds such as
diketones, keto esters, or keto amides. Here, we describe
a one-pot synthesis of 4H-chromenes by a tandem ben-
zylation and cyclization in the presence of sodium bisul-
fate on silica gel (Scheme 2).
OH
O
OH OH
O
O
R1
R2
OH
H+
R3
+
R1
R2
O
– H2O
+
1
R3
2
+OH
We recently reported C–C bond formation reactions of
1,3-dicarbonyl compounds with benzylic alcohols in the
presence of sodium bisulfate supported on silica gel.12 In
the course of this study, we found out that 4H-chromene
derivative were easily formed when 2-[hydroxy(phe-
nyl)methyl]phenol was used instead of diphenylmethanol
R1
R2
R3
O
O
R3
O
R3
– H+
R2
R2
R1
OH
– H2O
OH
O
R1
3
SYNLETT 2014, 25, 1571–1576
Advanced online publication: 20.05.2014
DOI: 10.1055/s-0033-1339026; Art ID: st-2014-u0193-l
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of chromenes in the presence of sodium bisul-
fate on silica gel
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1572
T. Aoyama et al.
LETTER
Conditions such as the solvent, the acid catalyst, and the We then examined the reactions of various β-diketones,
amount of sodium bisulfate for alkylation of 1,3-dicarbon- keto esters, and keto amides with diol 2a (Table 2). In the
yl compounds had previously been optimized, as de- reaction of symmetrical diketones with diol 2a, 2,6-di-
scribed in our earlier report.12 In the construction of methylheptane-3,5-dione (1c) gave the corresponding
chromenes, compound 3aa was obtained in high yield chromene 3ca in 63% yield, along with 6% of a structural
when the reaction of acetylacetone (1a; 2 mmol) with 2- isomer (entry 1). 2,2,6,6-Tetramethylheptane-3,5-dione
[hydroxy(phenyl)methyl]phenol (2a; 2 mmol) was carried (1d) did not give 3da at all; in this reaction, alkylation of
out in the presence of 2.1 mmol of sodium bisulfate on sil- 1d with 2a did not occur, and dimers, trimers, and tetra-
ica gel at 60 °C for 0.5 hours (Table 1, entry 1). The cor- mers of 2a were formed by self-alkylation (entry 2). On
responding reaction of ethyl acetoacetate (1b) gave the the other hand, the reaction of 1,3-diphenylpropane-1,3-
chromene 3ba in low yield; however, by using five equiv- dione (1e) with diol 2a gave the corresponding chromene
alents of 1b, we obtained chromene 3ba in 90% yield (en- 3ea in excellent yield (entry 3). Cyclic diketones 1f–h also
try 5).
gave the corresponding chromenes 3fa, 3ga, and 3ha in
moderate to good yields (entries 4–6). In the reaction of
the nonsymmetrical cyclic diketone 1h, chromene 3ha
was formed selectively, and no structural isomer was ob-
tained.
Table 1 Reaction of Diol 2a with Acetylacetone (1a) or Ethyl Ace-
toacetate (1b)
Ph
O
OH OH
O
O
On the basis of these results, we examined the reactions of
various aliphatic nonsymmetrical diketones (1i, 1j, and
1k) with diol 2a to determine whether the corresponding
chromenes could be obtained selectively (entries 7–9).
Not all the diketones gave the corresponding chromenes
selectively. The reactions of 1i and 1k gave mixtures of
the corresponding chromenes and their regioisomers in
83% and 94% total yields. In contrast, the reaction of di-
ketone 1j gave the expected chromene in 23% yield, along
an unexpected product, 2-tert-butyl-4-phenyl-4H-
chromene (4), in 29% yield.
R
NaHSO4–SiO2
Ph
+
R
O
1a or 1b
2a
3aa or 3ba
Entry
R
1/2a
(mmol) (°C)
Temp
Time Product Yielda
(h)
(%)
1
2
3
4
5
Me
2:2
2:2
2:2
6:2
10:2
60
80
80
80
80
0.5
0.5
3
3aa
3ba
3ba
3ba
3ba
94
28
52
69
90
OEt
OEt
OEt
OEt
5
5
a Isolated yield.
Table 2 Reaction of Diol 2a with Various β-Dicarbonyl Compounds
OH OH
Ph
O
O
O
NaHSO4–SiO2
R1
Ph
R1
R2
+
1c–r
DCE
80 °C, 5 h
O
R2
2a
3ca–ra
Entry
1
Diketone
1/2a (mmol)
Product
Yield (%)a
Ph
O
O
O
O
O
1c
6:2
3ca
63
O
Ph
3′ca
6
O
Ph
O
O
2
1d
6:2
3da
N.D.
O
Synlett 2014, 25, 1571–1576
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of 4H-Chromenes
1573
Table 2 Reaction of Diol 2a with Various β-Dicarbonyl Compounds (continued)
OH OH
Ph
O
O
O
NaHSO4–SiO2
R1
Ph
R1
R2
+
1c–r
DCE
80 °C, 5 h
O
R2
2a
3ca–ra
Entry
3
Diketone
1/2a (mmol)
Product
Yield (%)a
98
Ph
O
O
O
Ph
1e
1f
6:2
6:2
3ea
3fa
Ph
O
Ph
O
Ph
O
Ph
O
4
5
89
66
O
Ph
O
O
O
O
O
1g
6:2
3ga
O
Ph
O
O
O
6
7
1h
1i
6:2
6:2
3ha
3ia
86
47
O
Ph
O
O
O
Ph
3ia′
3ja
4
36
23
29
O
Ph
O
O
O
8
1j
6:2
O
Ph
O
Ph
O
O
O
O
Ph
9
1k
6:2
3ka
3ka′
3la
72
22
78
Ph
O
Ph
O
Ph
O
Ph
O
O
OEt
10
1l
10:2
OEt
O
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1571–1576

1574
T. Aoyama et al.
LETTER
Table 2 Reaction of Diol 2a with Various β-Dicarbonyl Compounds (continued)
OH OH
Ph
O
O
O
NaHSO4–SiO2
R1
Ph
R1
R2
+
1c–r
DCE
80 °C, 5 h
O
R2
2a
3ca–ra
Entry
11
Diketone
1/2a (mmol)
Product
Yield (%)a
Ph
O
O
O
OEt
OEt
1m
10:2
10:2
3ma
3na
51
OEt
O
Ph
O
O
O
O
12
1n
6
OEt
O
Ph
3na′
3oa
3pa
3qa
3ra
10
84
88
82
61
O
O
O
Ph
O
O
OEt
13
14
15
16
1o
1p
1q
1r
6:2
6:2
6:2
6:2
Ph
OEt
NMe2
NEt2
O
Ph
O
Ph
O
O
O
O
NMe2
NEt2
O
Ph
O
O
O
O
O
Ph
Ph
N
H
Ph
N
H
O
a Isolated yield.
In the reactions of β-keto esters, yields of the products de- We also tested other benzylic diols instead of 2a in the re-
creased as the number of methyl group attached to the ace- action with acetylacetone (1a) (Table 3). Reaction of ace-
tyl carbon increased (Table 1, entry 5 and Table 2, entries tyl acetone (1a) with diol 2b gave 3ab in 58% yield (Table
10–12). The reaction of ethyl acetoacetate (1b) gave 3, entry 1). Other secondary benzylic alcohols 2c and 2d
chromene 3ba in 90% yield, whereas the reaction of keto also reacted with 1a to give the corresponding chromenes
ester 1l gave chromene 3la in 78% yield and keto ester 1m (entries 2 and 3).
gave 3ma in 51% yield (Table 2, entries 10 and 11). In the
However, the reaction of diol 2e did not give the corre-
reaction of keto ester 1n, intramolecular cyclization oc-
sponding chromene 3ae, and 2,2,3-trimethyl-2,3-dihydro-
curred at the carbons of the carbonyl group and the ester
benzofuran (5) was obtained instead in 54% yield (Table
3, entry 4). In a plausible pathway for this reaction
(Scheme 3), the cationic intermediate 2′e is generated by
sodium bisulfate on silica gel and undergoes a methyl
group, and a mixture of the expected chromene 3na and
the chroman derivatives 3na′ was obtained (entry 12).
The use of three equivalents of ethyl benzoylacetate (1o)
or β-keto amides 1p–r was necessary to obtain good
shift to give 2′′e, which cyclizes intramolecularly to form
yields of the corresponding chromene derivatives (entries
5.
13–16).
Synlett 2014, 25, 1571–1576
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of 4H-Chromenes
1575
When diol 2g was used in the reaction, the expected
chromene 3ag was obtained in only 15% yield, along with
the unexpected chromane 6 in 70% yield (Table 3, entry
6). The formation of 6 can be explained as follows
(Scheme 4): dehydration of diol 2g in the presence of so-
dium bisulfate gives enol 7, which reacts with a further
molecule of diol 2g to form the ene diol 8;14 this then un-
dergoes intramolecular cyclization to give chromane 6 as
the final product.
Table 3 Reactions of Acetylacetone (1a) with o-Hydroxybenzylic
Alcohols
R1 R2
OH OH
R2
O
NaHSO4–SiO2
R1
+
1a
DCE
80 °C, 5 h
O
2b–h
3ab–ah
Entrya
1
Diol
Product
Yieldb (%)
58
OH OH
2b
3ab
OH
NaHSO4–SiO2
1a
2g
3ag
+
+
O
OH OH
OH OH
OH OH
OH OH
OH OH
OH OH
6 70%
2
3
4
5
6
7
2c
2d
2e
2f
3ac
3ad
3ae
3af
58
OH
OH
2g
HO
40
7
8
Scheme 4 Plausible reaction path for the formation of chromane 6
N.D.c
The formation of chromane ring systems by coupling of
alcohols is not a known reaction, and this represents a
novel method for the synthesis of chromanes. In the reac-
tion of diol 2h, the corresponding chromene was not
formed, and the dehydration product, 2-(1-phenylvi-
nyl)phenol, was obtained as the main product (Table 3,
entry 7).
6
In conclusion, we have developed a simple method for the
synthesis of 4H-chromenes by tandem benzylation and
cyclization in the presence of sodium bisulfate on silica
gel. Various diketones, keto esters, and keto amides can
be used in the synthesis of 4H-chromenes. In addition, we
discovered novel routes to 2,3-dihydrobenzofurans and
chromanes; these are now under investigation.
2g
2h
3ag
3ah
15d
N.D.e
Ph
a A 1a/2 ratio of 6:2 was used in all the reactions.
b Isolated yield.
Supporting Information for this article is available online
c 2,2,3-Trimethyl-2,3-dihydrobenzofuran (5) was obtained instead;
see Scheme 3.
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
d Chromane 6 was the main product; see Scheme 4.
e The dehydration product, 2-(1-phenylvinyl)phenol, was the main
product.
References
(1) (a) Schweizer, E. E.; Meeder-Nycz, D. In The Chemistry of
Heterocyclic Compounds; Vol. 31; Ellis, G. P., Ed.; Wiley &
Sons: New York, 1977, 11. (b) Shaheen, F.; Ahmad, M.;
Khan, S. N.; Hussain, S. S.; Anjum, S.; Tashkhodjaev, B.;
Turgunov, K.; Sultankhodzhaev, M. N.; Choudhary, M. I.;
Rahman, A. Eur. J. Org. Chem. 2006, 2371. (c) Kidwai, M.;
Saxena, S.; Khan, M. K. R.; Thukral, S. S. Bioorg. Med.
Chem. Lett. 2005, 15, 4295.
NaHSO4–SiO2
1a
+
2e
O
5 54%
OH
OH
+
(2) Li, M.; Zhang, B.; Gu, Y. Green Chem. 2012, 14, 2421.
(3) Wang, F.; Qu, M.; Chen, F.; Li, L.; Shi, M. Chem. Commun.
2012, 48, 437.
methyl shift
– H+
+
(4) Liu, Y.; Qian, J.; Lou, S.; Zhu, J.; Xu, Z. J. Org. Chem. 2010,
75, 1309.
2'e
2''e
(5) Xue, W.-J.; Li, Q.; Gao, F.-F.; Zhu, Y.-P.; Wang, J.-G.;
Zhang, W.; Wu, A.-X. ACS Comb. Sci. 2012, 14, 478.
Scheme 3 Plausible reaction path for the formation of 2,2,3-trimeth-
yl-2,3-dihydrobenzofuran (5)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1571–1576

1576
T. Aoyama et al.
LETTER
(6) Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 3057.
(7) Fan, J.; Wang, Z. Chem. Commun. 2008, 5381.
(8) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
(9) van Otterlo, W. A. L.; Ngidi, E. L.; Kuzvidza, S.; Morgans,
G. L.; Mollele, S. S.; de Koning, C. B. Tetrahedron 2005, 61,
9996.
(11) (a) Liu, C.; Zhang, X.; Wang, R.; Wang, W. Org. Lett. 2010,
12, 4948. (b) Alemán, J.; Alvarado, C.; Marcos, V.; Núñez,
A.; Ruano, J. L. G. Synthesis 2011, 1840.
(12) Aoyama, T.; Miyota, S.; Takido, T.; Kodomari, M. Synlett
2011, 2971.
(13) Funabiki, K.; Komeda, T.; Kubota, Y.; Matsui, M.
Tetrahedron 2009, 65, 7457.
(14) Aoyama, T.; Koda, S.; Takeyoshi, Y.; Ito, T.; Takido, T.;
Kodomari, M. Chem. Commun. 2013, 49, 6605.
(10) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006,
8, 3853.
Synlett 2014, 25, 1571–1576
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.