A catalyst-free one-pot construction of skeletons of 5-methoxyseselin and alloxanthoxyletin in water

Article abstract of DOI:10.1021/ol401581p

In refluxing water and without an additional catalyst, electron-rich phenols could react with alkynoic acids or alkynoates to provide coumarin structures. The skeletons of two natural pyranocoumarins, 5-methoxyseselin and alloxanthoxyletin, could be constructed (total yield up to 76%) in an aqueous multicomponent reaction in which isoprenyl acetate, propiolic acid, and phloroglucinol were simply mixed and refluxed in water.

Full text of DOI:10.1021/ol401581p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Catalyst-Free One-Pot Construction
of Skeletons of 5‑Methoxyseselin and
Alloxanthoxyletin in Water
Jin-Li Cao, Su-Li Shen, Peng Yang, and Jin Qu*
The State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
qujin@nankai.edu.cn
Received June 5, 2013
ABSTRACT
In refluxing water and without an additional catalyst, electron-rich phenols could react with alkynoic acids or alkynoates to provide coumarin
structures. The skeletons of two natural pyranocoumarins, 5-methoxyseselin and alloxanthoxyletin, could be constructed (total yield up to 76%) in
an aqueous multicomponent reaction in which isoprenyl acetate, propiolic acid, and phloroglucinol were simply mixed and refluxed in water.
Multicomponent reactions (MCRs) in which three or
more small building blocks react together following their
intrinsic reactivities offer a quick solution in the syntheses
of complicated molecules.1 Most MCRs require activation
by a catalyst and are operated in organic solvents, but it
was found that several MCRs, such as the Passerini and
Ugi reaction, could efficiently proceed in aqueous solution
without an additional catalyst.2 Actually, in Robinson’s
synthesis of bridged bicyclic alkaloid tropinone reported in
1917, which was later regarded as the pioneering work of
biomimetic total synthesis, glutaraldehyde, methylamine,
and calcium acetone dicarboxylate were simply mixed in
an aqueous buffer solution and the catalyst-free MCR
produced the skeleton of tropinone with great simplicity
(Scheme 1).3 The aqueous MCRs in the literature normally
use relatively reactivesubstratessuchasaldehydes, amines,
1,3-dicarbonyl compounds, and 1,3-dinitriles. Neverthe-
less, examples of aqueous MCRs using less reactive sub-
strates such as arenes, olefins, and alkynes are quite
limited.1g,2,4 Furthermore, after Robinson’s synthesis of tro-
pinone, the catalyst-free one-pot synthesis of the skeleton of
natural products in aqueous solution was rarely reported and
it is of general interest to broaden the scope of the natural
products that can be accomplished in nature’s solvent.5
Pyranocoumarins with a phloroglucinol core such as
(þ)-calanolide A, (þ)-pseudocordatolide C, and norden-
tatin have diverse bioactivities such as anti-HIV and
antibacterial activities.6 The angled 5-methoxyseselin (1)
and alloxanthoxyletin (2) are active antibacterial agents,
and linear xanthoxyletin (3) is used in the perfume industry
(Figure 1).7 The traditional methods for syntheses of
€
(1) For reviews on MCRs, see: (a) Domling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168. (b) Syamala, M. Org. Prep. Proced. Int.
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2009, 41, 1. (c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (d)
Yu, J.; Shi, F.; Gong, L. -Z. Acc. Chem. Res. 2011, 44, 1156. (e) Jiang, B.;
Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem.;Asian J. 2010, 5, 2318. (f)
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r
10.1021/ol401581p
XXXX American Chemical Society

Scheme 1. One-Pot Synthesis of Tropinone in Aqueous Solution
coumarins, such as the Perkin, Pechmann, or Knoevenagel
reaction, were usually conducted under harsh reaction
conditions.8 The modern atom-economic syntheses of
coumarins by hydroarylation reactions of alkynoates were
carried out under mild conditions, but using expensive
transition metals such as Pd,7i,9aꢀe Pt,9f,g and Au9h
as catalysts. It was also reported that inexpensive metal
salts such as Fe10a,b or Zn7j,10cꢀe could also be efficient
catalysts. Due to our long-lasting interest in water-
promoted organic reactions,11 we investigated the reac-
tions of electron-rich phenols with alkynoic acids or
alkynoates in water and reported herein that the hydro-
arylation reactions of propiolic acid or propiolate worked
in refluxing water and gave coumarin products in high
yields. We further presented that the skeletons of two
Figure 1. Natural pyranocoumarins.
natural pyranocoumarins could be constructed in one step
through an aqueous tricomponent reaction.
Since many coumarins contain a phloroglucinol (4a)
core (Figure 1),6 the preliminary trial was carried out by
adding 4a and 1.2 equiv of propiolic acid (5a) in water
(both of the two reactants can dissolve in water).12 As
the reaction proceeded under refluxing conditions, 5,7-
dihydroxycoumarin (6a, a natural coumarin first isolated
in 1982,13 83% yield) formed as a light yellow precipitate
(entry 1, Table 1). The minor product of reaction was
bicoumarin 7 (5% yield, Scheme 2). At 75 °C, only a 57%
yield of 6a was obtained with 61% conversion of phloro-
glucinol (entry 2). The reaction barely took place
in room-temperature water or in refluxing methanol
(entries 3, 4). 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP)
also has high ionizing power like water but can dissolve
most organic compounds. When replacing water with the
mixed solvent ofHFIPandH2O (v:v= 1:1), a 63% yield of
6a was obtained with 64% conversion of phloroglucinol
(entry 5). We also tested the neat conditions by heating
solid 4a in liquid 5a in an oil bath at 110 °C. It turned out
that the neat reaction gave a parallel yield with that held in
aqueous solution (entry 6). For practical reasons and
because of our interest of investigating the possible role
of water in the natural occurrence of complicated natural
products, water was chosen as the reaction medium in the
current study. When using 3 equiv of propiolic acid, all
phloroglucinol could be converted within 4 h under reflux-
ing conditions (entry 7) and the cleaner but slower reaction
at 75 °C gave the highest yield of 96% (entry 8). The
reaction using ethyl propiolate (5b) proceeded equally well
in refluxing water and gave an 81% yield of 6a after 24 h
(entry 9). A control experiment showed that this reaction
did not proceed under neat conditions. The reaction of
monomethylated phloroglucinol 4b was slower compared
with 4a, which was probably due to its lower aqueous
solubility (entry 10). Notably, the regioselectivity of the
(5) The catalyst-free one-pot synthesis of natural products in alco-
ꢀ
holic solvents: (a) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullie,
M. M. J. Am. Chem. Soc. 1980, 102, 7505. (b) De Laszlo, S. E.; Williard,
P. G. J. Am. Chem. Soc. 1985, 107, 199. (c) Tsuchida, K.; Mizuno, Y.;
Ikeda, K. Heterocycles 1981, 15, 883. The catalyst-free one-pot synthesis
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P. R. Org. Lett. 2007, 9, 5035. (e) De Silva, R. A.; Santra, S.; Andreana,
P. R. Org. Lett. 2008, 10, 4541. (f) Santra, S.; Andreana, P. R. J. Org.
Chem. 2011, 76, 2261. (g) Santra, S.; Andreana, P. R. Angew. Chem., Int.
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(7) The previous total syntheses of pyranocoumarins 1, 2, 3: (a)
Ganguly, A. K.; Joshi, B. S.; Kamat, V. N.; Manmade, A. H. Tetrahedron
1967, 23, 4777. (b) Ahluwalia, V. K.; Bhat, M. K.; Prakash, C.; Bala, S.
Bull. Chem. Soc. Jpn. 1980, 53, 1070. (c) Tsukayama, M.; Sakamoto, T.;
Horie, T.; Masumura, M.; Nakayama, M. Heterocycles 1981, 16, 955. (d)
Murray, R. D. H.; Jorge, Z. D. Tetrahedron Lett. 1983, 24, 3403. (e)
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Y.; Xie, L.; Cosentino, L. M.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1997,
7, 2573. (g) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K.-H. J. Med.
Chem. 1999, 42, 2662. (h) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker,
A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939. (i) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc.
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Fedorov, A. Y.; Nyuchev, A. V.; Beletskaya, I. P. Chem. Heterocycl.
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(b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074. (c)
Kitamura, T.; Yamamoto, K.; Kotani, M.; Oyamada, J.; Jia, C.;
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(12) The water we used to carry out the reactions was double distilled
water. The pH value of the double distilled water is 5.5ꢀ6 because of the
dissolved CO2. The possible effect of dissolved CO2 in water was
evaluated by conducting the reactions under a nitrogen atmosphere
with degassed water, but no difference in reactivity was found.
ꢀ
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Compd. 1982, 18, 616.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Reactions of Phloroglucinol or Its Ethers with
Propiolic Acid or Ethyl Propiolate
Table 2. Reactions of Other Electron-Rich Phenols with
Propiolic Acid
a General procedure: reactions were performed with 1.0 mmol of 4
and 3 mmol of 5 in water (2 mL). b Isolated yield based on the quantity of 4.
Scheme 2. Proposed Mechanism
a General procedure: reactions were performed with 1.0 mmol of 4
and 5 in solvent (2 mL). b Isolated yield. c In water (1 mL). d By isolated
yield. e By 1H NMR.
formation of 6b-1 and 6b-2 (6b-1:6b-2 = 1:4) was better
compared with the Pd2dba3-catalyzed hydroarylation re-
action of the similar substrates.7i The dimethoxy substituted
4c reacted even worse due to its even poorer aqueous
solubility. It is interesting to test if 1,3,5-trimethoxy benzene
(4d) can react with ethyl propiolate (5b) in water since no
acidic proton presents in both substrates and the reaction
cannot be self-catalyzed. 1,3,5-Trimethoxy benzene (4d)
does not dissolve in water, and hence no reaction took place
in water. However, 4d and 5b did react in refluxing HFIP
slowly but cleanly and gave a 1:6 mixture of 6d-1 and 6d-2 in
28% total yield and 1% of disubstituted product 8(entry12).
Clearly, a protic solvent with high ionizing power such as
HFIP could promote the hydroarylation of alkynoates.
Other electron-rich phenols could also react with pro-
piolic acid but some of the reactions gave a different type
of product (Table 2). For sesamol 4e, a 44% yield of
4,40-ethylidene-bisphenol 9e was obtained as the major
product. Similar products were also obtained by using
resorcinol (4f) orm-guaiacol (4g). But for 5-methylresorcinol
(4h), the reaction gave coumarin 6h as the major product.
The reactions between phloroglucinol and 2-butynoic acid or
3-phenylpropiolic acid did not work due to steric hindrance.
A plausible mechanism of the reactions is drawn in
Scheme 3. The electron-rich phloroglucinol attacked the
Org. Lett., Vol. XX, No. XX, XXXX
C

triplebond of propiolic acid toform the phenyl-substituted
R,β-unsaturated acid (I) which wasimmediately cyclizedto
give a coumarin product since no R,β-unsaturated acid was
observed during the whole reaction followed by NMR
techniques. However, if the phenolic hydroxyl group at the
ortho position of the arene (such as that in 4e, 4f, and 4g) is
not nucleophilic enough to afford the coumarin product,
the formed R,β-unsaturated acid would undergo a decar-
boxylation reaction14 and produce the substituted styrene
which was then attacked by another molecule of phenol to
give 4,40-ethylidene-bisphenol. The formation of 5% of
byproduct 7 can be explained as being due to the direct
attack of phenol at the triple bond of propiolic acid
generating an anion. This anion attacks the triple bond
of another molecule of propiolic acid that is nearby
to give the diacid (II). After the lactonization and
decarboxylation, the substituted styrene further re-
acted with coumarin formed in the reaction system
Scheme 3. Stepwise Synthesis of Pyranocoumarins in Water
Table 3. Synthesis of Pyranocoumarins by an Aqueous MCR
0
and gave C3ꢀC8 linked bicoumarins.
The aqueous synthesis of coumarin could be combined
with an aqueous FriedelꢀCrafts reaction in constructing
the pyranocoumarin skeleton. The reported synthesis of
2,2-dimethylchroman (11) from phloroglucinol (4a) and
isoprenyl acetate (10) was catalyzed by Lewis acids or
Brønsted acids.15 To our delight, this reaction proceeded in
refluxing water and gave 11 in 88% yield (isoprenyl acetate
(10) was not stable in refluxing water, so an excess amount
of 4a was needed to convert 10 in a short period of time).
The isolated 11 could react with propiolic acid in refluxing
water toprovideamixtureof regioisomeric compounds12,
13, and 14 (12:13:14 = 1:3:0.4) with a total yield of 60%
(Scheme 3). The above stepwise synthesis was then carried
out as an aqueous MCR. By adding 10,4a,and5a (10:4a:5a =
1:1:1.2) in water and heating the reaction mixture, a 1:3.3
mixture of regioisomers 12 and 13 (40% total yield; the
amount of linear type product 14 was too small to be
isolated) precipitated out as a light yellow powder. We
found that 21% of 6a and 6% of compound 15, which is
the synthetic precursor of the antibiotic natural product
dipetalolactone,16 also formed in the one-pot reaction
(entry 1, Table 3). Because 6a did not react with 10 in
refluxing water and a very small amount of 11 presented in
the final product, the reaction sequence in the one-pot
synthesis should be as follows: 10 and 4a first reacted and
gave 2,2-dimethylchroman (11), which was then reacted
with 5a to give compounds 12 and 13. Upon using an
excess amount of substrates 4a and 5a, most of 10 was
converted and the total yield of compounds 12 and 13
based on 10was76%(entry 5). Compounds12and 13were
methylated and dehydrogenated using the reported
method7i to finish the total syntheses of 5-methoxyseselin
1 and alloxanthoxyletin 2 in three steps.
ratio of
11
6a
15
entry
10:4a:5a
(%)
(%)c
(%)
12þ13 (%) (12:13)a,b
1
2
3
4
5
1:1:1.2
1:1:2
0
0
5
0
0
21
20
74
71
70
6
3
6
3
3
40 (1:3.4)
42 (1:3.2)
56 (1:3.3)d
71 (1:3.4)d
76 (1:3.4)d
1:1.7:2
1:5:4
1:5:6
a General procedure: 1 mmol of 10 with 4a and 5a were refluxed in
water (2 mL). b Isolated yield based on the quantity of 10. c Isolated yield
based on the quantity of 4a. d Compound 5a was added 4 h later.
Water is an ideal solvent for MCRs involving a polar
transition state/intermediate since the polarity and the
ionizing power of water compared to organic solvents
are far larger. For the first time, our group found that
the reaction between propiolic acid (or its ester) and
phloroglucinol derivatives worked in refluxing water with-
out an additional catalyst. In an aqueous MCR, phloro-
glucinol, isoprenyl acetate, and propiolic acid could be
self-assembled to form the skeletons of two natural pyra-
nocoumarins. This work demonstrated the power of an
aqueous MCR in the construction of the core structures of
natural products, which has not been fully explored yet.
Acknowledgment. This work was financially supported
by the NSFC (21072098), Program for New Century
Excellent Talents in University.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
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~
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX