Convenient and highly efficient routes to 2 H-chromene and 4-chromanone derivatives: Iodine-promoted and p-toluenesulfonic acid catalyzed cascade cyclizations of propynols

Article abstract of DOI:10.1002/chem.201406100

A convenient strategy is presented for the easy preparation of a series of 2 H-chromenes under mild conditions through iodocyclization of readily accessible propynols. In addition, various 4-chromanones can be synthesized through a p-toluenesulfonic acid catalyzed cascade cyclization with high efficiency (yields up to 99%). Our developed reaction systems are proven to have good functional-group applicability and can be scaled up to gram quantities in satisfactory yields. These systems also provide a new synthetic strategy for two types of important flavonoid skeleton without using costly and toxic metal catalysts. Additionally, the resulting halides could be further exploited in subsequent palladium-catalyzed coupling reactions, so these compounds could act as potential intermediates for the construction of some valuable drug molecules.

Full text of DOI:10.1002/chem.201406100

DOI: 10.1002/chem.201406100
Full Paper
&
Synthetic Methods
Convenient and Highly Efficient Routes to 2H-Chromene and 4-
Chromanone Derivatives: Iodine-Promoted and p-Toluenesulfonic
Acid Catalyzed Cascade Cyclizations of Propynols
Yi-Feng Qiu, Yu-Ying Ye, Xian-Rong Song, Xin-Yu Zhu, Fang Yang, Bo Song, Jia Wang, Hui-
Liang Hua, Yu-Tao He, Ya-Ping Han, Xue-Yuan Liu, and Yong-Min Liang*[a]
Abstract: A convenient strategy is presented for the easy
preparation of a series of 2H-chromenes under mild condi-
tions through iodocyclization of readily accessible propynols.
In addition, various 4-chromanones can be synthesized
through a p-toluenesulfonic acid catalyzed cascade cycliza-
tion with high efficiency (yields up to 99%). Our developed
reaction systems are proven to have good functional-group
applicability and can be scaled up to gram quantities in sat-
isfactory yields. These systems also provide a new synthetic
strategy for two types of important flavonoid skeleton with-
out using costly and toxic metal catalysts. Additionally, the
resulting halides could be further exploited in subsequent
palladium-catalyzed coupling reactions, so these compounds
could act as potential intermediates for the construction of
some valuable drug molecules.
Introduction
2H-Chromene and 4-chroma-
none are vitally important flavo-
noid skeletal structures, which
are found in a wide variety of
natural products and pharma-
ceutically
active
molecules
(Figure 1).[1] Such compounds
have been identified as having
antifungal, antibacterial, antiviral,
anti-inflammatory,
anticancer,
antidepressive, antihypertensive,
antidiabetic, and antioxidant ac-
tivities.[2,3] They are also valuable
intermediates in synthetic and
material chemistry.[2h,4,5] Due to
the outstanding physiological
and pharmaceutical activities of
these compounds, as well as
their important position in syn-
thetic chemistry, the advancing
aspirations of scientists and in-
terest in new routes to construct
Figure 1. Representative bioactive natural products possessing 2H-chromene or 4-chromanone moieties.
benzopyran and benzopyrone rings systems further stimulates
[a] Dr. Y.-F. Qiu,+ Y.-Y. Ye,+ X.-R. Song, X.-Y. Zhu, F. Yang, B. Song, J. Wang,
H.-L. Hua, Y.-T. He, Y.-P. Han, X.-Y. Liu, Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
E-mail: liangym@lzu.edu.cn
[+] These authors contributed equally to this work.
studies in this area. The well-known synthetic route to 2H-
chromenes is by the cyclization of substituted phenolic prop-
argyl ether compounds,[6] whereas the classical methods for
preparing 4-chromanones involve the condensation cyclization
of carbonyl compounds with o-hydroxyacetophenones[5b,7] and
the addition reaction to 4H-chromen-4-ones.[8] With the persis-
tent efforts of many chemists, adequate evolutions have been
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406100.
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achieved on the synthesis of both types of essential molecular
scaffolds.[2f–i,3a,e,f,9,10] Nevertheless, the development of efficient
and straightforward methods in a simple operation and under
mild conditions is still fueled by the strong and growing aspi-
ration for such processes in most areas of chemical synthesis.
It is known that the status of cascade cyclization as a
powerful and ingenious strategy for the synthesis of cyclic
compounds is irreplaceable. Herein, iodocyclization shows
undeniable benefits in most cases, including being metal-free,
having mild conditions, having the potential for further exploi-
tation, and providing economies of time, labor, and cost,[11]
whereas Brønsted acids, as budget and green catalysts, have
emerged as valuable tools for the generation of carbo- and/or
heterocyclic skeletons with unmatched advantages.[12] Alkynols,
as interesting and important starting materials with two
mutual activated functional groups, have become star mole-
cules in synthetic methodology.[13] In the past few years, our
group has successfully developed a series of efficient methods
for the synthesis of carbo- and/or heterocyclic building blocks
through cascade iodocyclization[11] and Brønsted acid catalyzed
cyclization with various alkynols (or alkynones) as the starting
materials.[14] By taking into consideration our current interest in
new approaches to cyclic skeletons with atom economy, as
well as the continued advancement of green chemistry, we
designed an iodocyclization and a Brønsted acid catalyzed
cascade cyclization for the synthesis of 2H-chromene and 4-
chromanone derivatives by using various propynols as the sub-
strates (Scheme 1). Herein, different products derived from the
same starting materials are observed under diverse reaction
systems. Relative to the traditional strategies, our developed
reaction systems could be conveniently operated and avoid
inert-gas protection or toxic transition-metal catalysts, which
may open up a new potential application for these systems in
industrial production.
Results and Discussion
The initial exploration for the synthesis of 2H-chromenes was
started by employing compound 1a (0.1 mmol) as the model
substrate with iodine (2.0 equiv) in MeCN (2.0 mL) at 608C
(Table 1, entry 1). To our delight, our anticipated product, 3,4-
Table 1. Optimization of the iodocyclization for the synthesis of 2a[a]
Entry
Solvent
I2 [equiv]
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
MeCN
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.0
1.2
60
60
60
60
60
60
60
RT
RT
RT
0
79
45
61
N.R.[d]
62
trace[e]
trace[f]
90
98
93
95
MeNO2
1,2-DCE[c]
toluene
THF
DMSO
1,4-dioxane
MeCN
MeCN
MeCN
MeCN
9
10
11
[a] Unless otherwise noted, all reactions were performed with 1a
(0.1 mmol) with I2 in anhydrous solvent (2.0 mL) under an air atmosphere
for 0.5 h. [b] Yields of isolated products. [c] 1,2-DCE: 1,2-dichloroethane.
[d] N.R.: no reaction. [e] 79% of 1-(2-hydroxyphenyl)-2-iodo-3,3-diphenyl-
prop-2-en-1-one was detected. [f] 71% of 1a was recovered.
diiodo-2,2-diphenyl-2H-chromene (2a), was isolated in 79%.
However, no better results were obtained after a brief survey
of various representative solvents (Table 1, entries 2–7).
Lowering of the temperature led to a higher yield of 90%
(Table 1 entry 8). We believe that the higher temperature was
advantageous to the generation of the iodo Meyer–Schuster
rearrangement by-product. Other adjustments indicated that
the most appropriate amount of iodine was 1.2 equivalents,
which gave 98% yield (Table 1, entries 8–10). Afterwards, 95%
yield of 2a was achieved at 08C due to the relatively lower
activity, as expected (Table 1, entry 11). Finally, the optimal
reaction conditions for producing 2a were affirmed as the use
of iodine (1.2 equiv) in MeCN (2.0 mL) at room temperature for
0.5 h (Table 1, entry 9; conditions A).
To verify our concept of the Brønsted acid catalyzed cascade
cyclization for the generation of 4-chromanones, p-TsOH
(10 mol%) was used as the catalyst to initiate a tentative
inquiry in a solution of 1a (0.1 mmol) and MeOH (2.0 mL) at
room temperature. Only 36% of 3a and 59% of 1-(2-hydroxy-
Scheme 1. Our previous work and new anticipation towards the synthesis of
2H-chromene and 4-chromanone derivatives. DDQ: 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; NIS: N-iodosuccinimide; p-TsOH: p-toluenesulfonic acid.
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catalyst. Ultimately, the followed screening of the reaction tem-
perature and catalyst loading (Table 2, entries 12–15) settled
the optimal conditions for the generation of 3a as the addition
of p-TsOH (5 mol%) to a solution of 1a (0.1 mmol) and MeOH
(2.0 mL) at 708C for 4.0 h (Table 2, entry 14; conditions B).
A series of substituted alkynol substrates, including tertiary
(1a–1t, and 1z) and secondary propynols (1u–1y), were pre-
pared to investigate the scope of the cascade iodocyclization.
The corresponding 2H-chromene derivatives 2a–2y, 2a’ and
2a’’ were obtained in moderate to excellent yields under con-
ditions A (Table 3). The structure of 2s was confirmed by X-ray
crystal structure analysis (Figure 2).[15] The influence of substitu-
ent electronic effects on the reaction made little difference for
substituents R1 and R2; in general, tertiary propynols with two
aryl groups gave good yields (2a–2r), whereas decreased
yields were observed with secondary propynols (2u–2y). We
believe that two aryl groups would be much more effective for
the stability of intermediates A and B (see Scheme 5). Further-
more, substrates bearing alkyl groups worked passably for this
transformation (2s and 2t). Despite the fact that only a trace
amount of 2z, with two o-methoxyphenyl groups, was ob-
served due to the combined impact of the particularly strong
electron-donating and steric effects, 52% of 2h was still ach-
ieved with one substituent replaced by a phenyl group. In this
reaction, we observed that more of the iodo Meyer–Schuster
rearrangement product was generated. Notably, the transfor-
mation proceeded smoothly for the substrates with a multiple-
ring group (2-naphthyl group in 1n) or a heterocyclic group
(2-thienyl group in 1o). Substrates with diverse substituents as
the R3 group could also be converted into the corresponding
products in good yields (2p–2r). The final concern was that
the reaction system still worked smoothly with other iodina-
tion reagents; 89 and 77% yields of the corresponding prod-
ucts were obtained in the presence of ICl and IBr, respectively,
which provided another diversified selectivity for further trans-
formations through coupling reactions (2a’ and 2a’’). The
structure of 2a’’ was also confirmed by X-ray crystal structure
analysis (Figure 2).[15]
Table 2. Optimization of the cascade cyclization for the synthesis of 3a[a]
Entry
Catalyst [mol%][b]
T [8C]
Yield [%][c]
1
2
3
4
5
6
7
8
p-TsOH [10]
p-TsOH [10]
TfOH [10]
MsOH [10]
TFA [10]
HI [10][e]
H2C2O4·2H2O [10]
Sc(OTf)3 [10]
Bi(OTf)3 [10]
Zn(OTf)2 [10]
FeCl3 [10]
p-TsOH [10]
p-TsOH [10]
p-TsOH [5]
p-TsOH [2]
RT
80
80
80
80
80
80
80
80
80
80
70
60
70
70
36[d]
92
92
89
83
76
61
88
91
72
89
99
88[f]
99
93
9
10
11
12
13
14
15
[a] Unless otherwise noted, all reactions were performed with 1a
(0.1 mmol) with Brønsted or Lewis acids in methanol (2.0 mL) under an
air atmosphere for 4.0 h. [b] p-TsOH: p-toluenesulfonic acid; TfOH: trifluor-
omethanesulfonic acid; MsOH: methylsulfonic acid; TFA: trifluoroacetic
acid; OTf: trifluoromethanesulfonate. [c] Yields of isolated products.
[d] 59% of the intermediate 1-(2-hydroxyphenyl)-3,3-diphenylprop-2-en-
1-one was detected after 48.0 h. [e] An aqueous solution of 45% HI was
used. [f] 12% of intermediate was detected.
phenyl)-3,3-diphenylprop-2-en-1-one (intermediate
F
in
Scheme 5) without further cyclization came under observation
(Table 2, entry 1). Therefore, the temperature was raised to
808C to facilitate the cyclization process, which gave an excel-
lent yield of 92% (Table 2, entry 2). After subsequent optimiza-
tion experiments with a series of Brønsted and Lewis acids,
TfOH and Bi(OTf)3 were found to be the best two and gave
similar satisfactory yields (Table 2, entries 3–11). Given the
operational convenience and the demand for green chemistry,
p-TsOH was finalized as the most efficient and outstanding
The diversity and applicability of the p-TsOH-catalyzed cas-
cade cyclization for the synthesis of 4-chromanone derivatives
were also surveyed with the same substrates. Gratifyingly,
Figure 2. X-ray structures of 2s, 2a’’, and 3a.[15]
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phenyl groups and unsubstituted phenyl groups as
the substituents R1 and R2 gave excellent yields up to
99%, whereas slightly lower yields were obtained
with electron-rich moieties (3a, 3e–3g, and 3l versus
3b–3d and 3h–3j). We were convinced that electron-
deficient moieties on phenyl groups (R1 and R2) could
be beneficial for the attack of the phenolic hydroxy
group onto the double bond of intermediate F (see
Scheme 5). Similarly, substrates with alkyl groups in-
stead of aryl groups still gave acceptable yields (3s
and 3t). It was an unfortunate fact that substrate 1z
still worked imperfectly in this reaction system: 87%
of the intermediate for 1z was isolated without fur-
ther cyclization, whereas 78% of product 3h was ob-
tained with an o-methoxyphenyl group. The reaction
performed well with secondary propynols 1u–1y,
which gave moderate to good yields under condi-
tions B. It is worth noting that 94% of 3n, with the 2-
naphthyl group, was isolated in this transformation.
This reaction could also be performed with a 2-thienyl
group as the R1 substiuent in a high yield of 88%
(3o). The yield of substrates with representative R3
substituents seems to be good as well, including elec-
tron-rich (methyl-substituted, 3p) and electron-defi-
cient groups (chloro- and bromo-substituted, 3q and
3r).
Table 3. Synthesis of 2H-chromene derivatives 2 from propynols 1.[a]
2a (98%)
2e (78%)
2i (68%)
2m (62%)
2b (78%)
2 f (89%)
2j (75%)
2n (57%)
2c (83%)
2g (82%)
2k (71%)
2o (89%)
2d (92%)
2h (52%)
2l (77%)
2p (93%)
A noteworthy advantage of our methods was that
both reaction systems could be scaled up to gram
quantities; 89% of 3,4-diiodo-2,2-diphenyl-2H-chro-
mene (2a) and 92% of 2,2-diphenylchroman-4-one
(3a) were isolated on the gram scale under the
respective optimal conditions, which might provide
a
potential application for this method in the
synthetic industry (Scheme 2).
2q (88%)
2u (42%)
2r (82%)
2v (54%)
2s (52%)
2w (59%)
2t (49%)
2x (51%)
Another obvious feature of iodocyclization was that
the iodosubstituted 2H-chromenes might be advant-
ageous intermediates for the synthesis of some
natural products through various palladium-catalyzed
reactions. As an example, the Suzuki coupling of 2a
with a variety of phenylboronic acids afforded the
corresponding derivatives (2aa–2ae) in good to
excellent yields (Scheme 3).
In order to investigate the mechanism for both
reactions, some necessary control experiments were
carried out. First of all, as depicted in Table 3, with the
addition of ICl or IBr, the corresponding products 2a’
and 2a’’ were obtained in 89 and 77% yields, respec-
tively. With the confirmation of the structure of 2a’’
by X-ray crystal structure analysis,[15] the sources and
properties of the two iodine atoms in products 2
were demonstrated unequivocally. For the p-TsOH-cat-
2y (41%)
2z (trace)[b]
2a’ (89%)[c]
2a’’ (77%)[d]
[a] Unless otherwise noted, all reactions were performed with 1 (0.1 mmol) with I2
(1.2 equiv) in anhydrous MeCN (2.0 mL) under an air atmosphere at room tempera-
ture for 0.5 h. Yields are given for isolated products. [b] 85% of the iodo Meyer–
Schuster rearrangement product was detected. [c] A solution of iodine chloride in di-
chloromethane (1 molLÀ1) was used instead of iodine. [d] Iodine bromide was used
instead of iodine.
various substituted 4-chromanones were isolated in moderate
to excellent yields under conditions B (Table 4). The structure
of product 3a was confirmed by X-ray crystal structural analy-
sis (Figure 2).[15] This reaction seemed to be more distinct
and sensitive to substituent electronic effects than the above
iodocyclization: substrates with electron-deficient moieties on
alyzed cascade cyclization for the synthesis of 4-chromenones,
compound F (see Scheme 5) was captured and isolated in the
presence of p-TsOH (5 mol%) in MeOH (2.0 mL) at room tem-
perature for 4.0 h. Interestingly, compound F could be isolated
in the same yield even after 48.0 h (Scheme 4, eq. 1). Isolated
compound F was then subjected to conditions B, and product
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we believe that the oxygen atom of the carbonyl
group in 3a probably might come from the initial
intramolecular dehydration of substrate 1a. To
verify this assumption, heavy-oxygen water
(2.0 equiv) was added to the reaction system to-
gether with the catalyst, and a mixture of 18O-
tagged and untagged product 3a could be simulta-
neously detected by GC-MS analysis, which indi-
cates that this transformation could go through
Table 4. Synthesis of 4-chromanone derivatives 3 from propynols 1.[a]
a
Meyer–Schuster
rearrangement
process
(Scheme 4, eq. 4).
The plausible mechanisms that are consistent
with the experimental results mentioned above
and the precedent literature[11,16] are proposed in
Scheme 5. In fact, the propargyl hydroxy group of
substrate 1a is initially activated by an iodine
cation (or proton) and generates propargylic cation
A, which would undergo a subsequent tautomer-
ism to generate the allenic cation B.[11,13d,e] The
attack of iodide (or water) onto B affords C (or E).
The interaction of C and an iodine cation then
gives iodonium cation D, which is attacked by the
phenolic hydroxy group to produce iodo-2H-chro-
mene 2a. Intermediate E undergoes a keto–enol
tautomerization to afford F.[14,16] A subsequent endo
attack of the intramolecular phenolic hydroxy
group onto the carbon–carbon double bond gener-
ates 4-chromanone 3a. The attack of iodide onto E
generates the main by-product I.
3a (99%)
3e (99%)
3i (75%)
3m (80%)
3b (84%)
3 f (99%)
3j (87%)
3n (94%)
3c (82%)
3g (99%)
3k (88%)
3o (88%)
3d (96%)
3h (78%)
3l (99%)
3p (84%)
Conclusion
To sum up, we have disclosed a direct and conven-
ient cascade iodocyclization and Brønsted acid cat-
alyzed cascade cyclization for the synthesis of two
types of important flavonoid skeletons. The respec-
tive processes enable a highly efficient protocol for
preparing various 2H-chromenes or 4-chromanones
from easily prepared propynols. As different nucleo-
philes, diverse reagents were employed to facilitate
cyclization with excellent yields of up to 99%.
Compared to transition-metal-catalyzed reactions,
our developed reaction systems are equipped with
obvious advantages for the continued increasing
requirements of atom economy and green chemis-
try. In addition, the synthetic utility of both reaction
systems has been demonstrated by their applicabil-
ity to a wide range of propynol substrates and
a large reaction scale for potential applications in
industrial production.
3q (86%)
3u (59%)
3r (93%)
3v (74%)
3s (71%)
3w (60%)
3t (43%)
3x (79%)
3y (59%)
3z (trace)[b]
[a] Unless otherwise noted, all reactions were performed with 1 (0.1 mmol) with p-TsOH
in methanol (2.0 mL) under an air atmosphere at 708C for 4.0 h. Yields are given for
isolated products. [b] 87% of 1-(2-hydroxyphenyl)-3,3-bis(2-methoxyphenyl)prop-2-en-1-
one was isolated.
3a was obtained in 92% after 4.0 h (Scheme 4, eq. 2). In addi-
tion, direct heating of the original reaction system could give
Experimental Section
General procedure for the synthesis of product 2a
product 3a in 96% yield (Scheme 4, eq. 3). Therefore, com-
pound F was determined to be the intermediate of the above
reaction. Furthermore, after consulting our previous work,[14]
Iodine (1.2 equiv) was added to a solution of 2-(3-hydroxy-3,3-
diphenylprop-1-yn-1-yl)phenol (1a; 0.1 mmol) in anhydrous MeCN
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Scheme 2. Scale-up experiments.
(2.0 mL), and the resulting mixture was stirred at room tempera-
ture for 0.5 h. The reaction mixture was then diluted with ethyl
ether (2ꢁ15 mL), washed with a saturated aqueous solution of
sodium thiosulfate and saturated brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was further
purified by chromatography on silica gel (petroleum ether/ethyl
acetate, 30:1) to afford the product 3,4-diiodo-2,2-diphenyl-2H-
chromene (2a) in 98% yield.
General procedure for the synthesis of product 3a
Scheme 3. Palladium-catalyzed Suzuki coupling reactions and the products
p-TsOH (5 mol%) was added to a solution of 2-(3-hydroxy-3,3-di-
phenylprop-1-yn-1-yl)phenol (1a; 0.1 mmol) in MeOH (2.0 mL), and
the resulting mixture was stirred at
708C in a sealed tube for 4.0 h.
The reaction mixture was then di-
luted with ethyl ether (2ꢁ15 mL),
washed with a saturated aqueous
solution of sodium bicarbonate
and saturated brine, dried over
Na2SO4, and evaporated under re-
duced pressure. The residue was
further purified by chromatogra-
phy on silica gel (petroleum ether/
ethyl acetate, 50:1) to afford the
product
2,2-diphenylchroman-4-
one (3a) in 99% yield.
Acknowledgements
Financial support was received
from the National Science Foun-
dation
(NSF21272101,
NSF21472074, NSF21472073, and
NSF21302076), the Program for
Changjiang Scholars and Innova-
tive Research Team in University
(IRT1138), and the Fundamental
Research Funds for the Central
Universities (lzujbky-2014–244).
Scheme 4. Verification experiments for the mechanisms.
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Keywords: Brønsted acids · cyclization · flavonoids · iodine ·
propynols · synthetic methods
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Received: November 14, 2014
Published online on && &&, 0000
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FULL PAPER
&
Synthetic Methods
Y.-F. Qiu, Y.-Y. Ye, X.-R. Song, X.-Y. Zhu,
F. Yang, B. Song, J. Wang, H.-L. Hua,
Y.-T. He, Y.-P. Han, X.-Y. Liu, Y.-M. Liang*
&& – &&
A better route: Convenient and highly
efficient strategies are presented for the
easy preparation of 2H-chromenes and
4-chromanones through iodocyclization
and p-toluenesulfonic acid (p-TsOH)
catalyzed cascade cyclization of readily
accessible propynols (see scheme). The
developed systems have good function-
al-group applicability, can be scaled up
to gram quantities in satisfactory yields,
and provide a new synthetic strategy
for two types of important flavonoid
skeleton without using costly and toxic
metal catalysts.
Convenient and Highly Efficient
Routes to 2H-Chromene and 4-
Chromanone Derivatives: Iodine-
Promoted and p-Toluenesulfonic Acid
Catalyzed Cascade Cyclizations of
Propynols
Chem. Eur. J. 2015, 21, 1 – 9
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ