Amine-catalyzed cascade synthesis of 3,4-diunsubstituted coumarins

Article abstract of DOI:10.1002/ejoc.201300538

We disclose an efficient route to synthesize 3,4-diunsubstituted coumarins through a cascade organocatalytic reaction. The reaction is catalyzed by using of a combination of benzylamine (10 mol-%) and triethylamine (10 mol-%). Various salicylaldehydes were tested, and the corresponding coumarin products were obtained in good to high yields under mild and metal-free reaction conditions. We disclose an efficient route to synthesize 3,4-diunsubstituted coumarins through a cascade organocatalytic reaction. The reaction is catalyzed by using of a combination of benzylamine (10 mol-%) and triethylamine (10 mol-%). Various salicylaldehydes are tested, and the corresponding coumarin products are obtained in good to high yields under mild and metal-free reaction conditions. Copyright

Full text of DOI:10.1002/ejoc.201300538

Job/Unit: O30538
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Date: 11-06-13 18:03:23
Pages: 5
SHORT COMMUNICATION
Domino Reactions
J. Wei, P. Wang, Q. Jia, J. Huang,
Z. Du,* K. Zhang, J. Wang* ............ 1–5
Amine-Catalyzed Cascade Synthesis of 3,4-
Diunsubstituted Coumarins
We disclose an efficient route to synthesize
3,4-diunsubstituted coumarins through a
cascade organocatalytic reaction. The reac-
tion is catalyzed by using of a combination
of benzylamine (10 mol-%) and triethyl-
amine (10 mol-%). Various salicylaldehydes
are tested, and the corresponding coumarin
products are obtained in good to high
yields under mild and metal-free reaction
conditions.
Keywords: Natural products / Organoca-
talysis
/ Domino reactions / Decarb-
oxylation / Amines
0000, 0–0
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Job/Unit: O30538
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Date: 11-06-13 18:03:23
Pages: 5
J. Wei, P. Wang, Q. Jia, J. Huang, Z. Du, K. Zhang, J. Wang
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300538
Amine-Catalyzed Cascade Synthesis of 3,4-Diunsubstituted Coumarins
Jia Wei,[a] Pengcheng Wang,[b] Qianfa Jia,[a] Jiaoyao Huang,[b] Zhiyun Du,*[a]
Kun Zhang,[a] and Jian Wang*[a,b]
Keywords: Natural products / Organocatalysis / Domino reactions / Decarboxylation / Amines
We disclose an efficient route to synthesize 3,4-diunsubsti-
tuted coumarins through a cascade organocatalytic reaction.
The reaction is catalyzed by using of a combination of benz-
ylamine (10 mol-%) and triethylamine (10 mol-%). Various
salicylaldehydes were tested, and the corresponding couma-
rin products were obtained in good to high yields under mild
and metal-free reaction conditions.
Introduction
As one of the prominent medicinal scaffolds, the couma-
rin is featured in numerous synthetic compounds and natu-
ral products that are used as drugs,[1] anticoagulants,[2a–2d]
and pesticides.[2e] Coumarin and its derivatives have varied
bioactivities including antimicrobial activity,[3a] antithrom-
botic activity,[3b] antipsoriasis activity,[3c] anticancer ac-
tivity,[3d] anti-HIV activity,[3e] antiproliferative activity,[3f]
inhibitory activity on viral proteases,[3g] estrogen-like ef-
fects,[3h] and central nervous system modulating activity.[3i]
These important findings have attracted considerable atten-
tion to the functionalization of the coumarin skeleton. As
exemplified in Figure 1, natural products A–D were re-
ported to possess some biological properties. Herniarin (A)
has been used as a sensitizer in German chamomile.[4] Mar-
min (B), a coumarin isolated from Aegle marmelos Correa,
has shown antiallergic effects.[5] Aesculin (C) is used in mi-
crobiology laboratories to aid in the identification of bacte-
rial species.[6] Aesculetin (D) is present in many toxic and
medicinal plants, in the form of glycosides and caffeic acid
conjugates, and can have an anticoagulant effect.[7] Thereby,
the synthesis of this coumarin scaffold is of much interest.
Coumarins have been synthesized by several routes, in-
cluding Pechmann synthesis,[8] Perkin synthesis,[9] Knoeven-
agel condensation,[10] the Reformatsky reaction,[11] the Wit-
tig reaction,[12] and so on. Among these, the Pechmann re-
action is the most widely used method, as the reaction in-
volves the use of simple starting materials, such as phenols
Figure 1. Representative examples of natural 3,4-diunsubstituted
coumarins.
and β-keto esters, in the presence of acidic condensing
agents. The use of various reagents such as H2SO4, FeCl3,
ZnCl2, POCl3, AlCl3, HCl, phosphoric acid, trifluoroacetic
acid, montmorillonite, and other clays are all well docu-
mented in the literature.[13] Most of these methods suffer
from severe drawbacks including the use of a large amount
of catalysts, long reaction times, and high temperatures.
Some of the recent achievements in the efficient construc-
tion of this nucleus include the development of cation-ex-
change resins,[14a] solid acid catalysts and metal nitrates,[13]
heteropolyacid-supported polyaniline catalysts,[14c,14d] mi-
crowave irradiation, ionic liquids as efficient catalysts,[14e]
and very recently the Pt-catalyzed hydroarylation of propi-
olic acids with phenols.[14f] Consequently, there is ample
room for further development of milder reaction condi-
tions, increased variation in the substituents of both com-
ponents, and better yields.
Recently, the scope of metal-free organocatalysts to pro-
mote cascade reactions has expanded.[15] It is noteworthy
that a number of useful cascade reactions were reported.[16]
Undoubtedly, the utilization of cascade reactions provides
a useful synthetic tool for organic synthesis. It offers the
possibility to form multiple chemical bonds in a one-pot
process without isolating intermediates, changing reaction
conditions, or adding reagents. Finally, this strategy reduces
[a] Allan H. Conney Laboratory for Anticancer Research, Guang
Dong University of Technology,
Guang Dong 510006, China
[b] Department of Chemistry, National University of Singapore,
Block S15, Level 5, 3 Science Drive 3, Singapore 117543
Fax: +65-6779-1691
E-mail: chmwangj@nus.edu.sg
Homepage: http://www.chemistry.nus.edu.sg/people/academic_
staff/Wangjian.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300538
2
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Cascade Synthesis of 3,4-Diunsubstituted Coumarins
the synthetic costs and simplifies synthetic steps and pro- Table 1. Evaluation of organocatalysts.[a]
cesses. Inspired by the advantages and significances of this
cascade strategy, we became interested in exploring a new
cascade reaction for our targeted coumarins. Recently, our
group reported the facile synthesis of 4-substituted 3,4-di-
hydrocoumarins and 3-hydroxyoxindoles through an
organocatalytic decarboxylation process.[17] These reports
revealed that the decarboxylative process[18] is a practical
and efficient method for C–C bond formation. Herein, we
report a cascade organocatalytic method for the facile syn-
Entry
Catalyst
Yield [%][b]
thesis of 3,4-diunsubstituted coumarins.
1
2
3
4
5
6
I
52
42
40
23
34
60
II
III
IV
V
Results and Discussion
In an initial investigation, we conducted a model reaction
between salicylaldehyde (1a) and malonic acid half-thioes-
ter 2a by employing pyrrolidine I (20 mol-%) as an organ-
ocatalyst and Et3N (20 mol-%) as a cocatalyst to afford de-
sired product 3a in 52% isolated yield (Table 1). To further
improve the reaction yield, a series of commercially avail-
able, simple amines II–VI were examined. The yield slightly
improved to 60% in the presence of primary benzylamine
(VI; Table 1, entry 6), whereas all other tested amine cata-
lysts resulted in low yields (Table 1, entries 2–5). In ad-
dition, base as the cocatalyst was found to have an impor-
tant effect on the reaction yield (Table 2). A substantial de-
crease in the reaction yield was observed for stronger or-
ganic (Table 2, entry 3) and inorganic bases (17–51%;
Table 2, entries 4–6). More importantly, the solvent was
found to be a critical factor for changing reactivity (Table 3,
entries 1–7). Among the solvents tested, CHCl3 proved to
be the best medium with respect to catalytic activity and
yield (90%, 48 h, r.t.; Table 3, entry 2). Further changes in
reaction temperature did have a significant effect on the re-
activity (97%, 55 °C, 4 h; Table 3, entry 8). Notably, a cata-
lyst loading of 5 mol-% provided the product in 95% yield
in 10 h (Table 3, entry 10).
VI
[a] Reaction conditions: CH2Cl2 (0.4 mL), salicylaldehyde (1a;
0.1 mmol, 1.0 equiv.), malonic acid half-thioester 2a (0.2 mmol,
2 equiv.), Et3N (20 mol-%, 0.2 equiv.), and catalyst (20 mol-%) at
room temperature for 48 h. [b] Yield of isolated product after col-
umn chromatography.
Table 2. Evaluation of bases.[a]
Entry
Base
Yield [%][b]
[c]
1
2
3
4
5
6
–
31
54
48
38
17
51
2,6-lutidine
DBU[d]
LiOH
Na2CO3
Cs2CO3
[a] Unless specified, see the Exp. Section for reaction conditions.
[b] Yield of isolated product after column chromatography. [c] No
base. [d] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
With the optimized reaction conditions in hand, the sub-
strate scope of this transformation was examined by varying
salicylaldehyde 1 (Table 4). Salicylaldehydes 1b–s were suc-
cessfully partook in the reaction, and corresponding ad-
ducts 3b–s were obtained in good to excellent yields (80–
96%, 3–12 h; Table 4, entries 2–18). Salicylaldehydes having
both electron-donating and electron-withdrawing substitu-
ents can be efficiently catalyzed in this transformation.
Thus, the substitution pattern of the arene had a limited
influence on the reaction activity. Additionally, naphthyl-
based salicylaldehyde also reacted in this process to form
desired product 3s (86%, 48 h; Table 4, entry 19). Lastly, we
examined malonic half-thioesters 2b–d (Table 5). Phenyl-
substituted 2b and 2c and alkyl-substituted 2d had limited
influence on the reactivity (89–92% yield, 4 h; Table 5, en-
tries 1–3). All these results indicate that the formation of
the ester group by lactonization is not the rate-determining
step.
Table 3. Evaluation of solvents.[a]
Entry
Solvent
Yield [%][b]
1
2
3
4
5
6
CH2Cl2
CHCl3
toluene
EtOAc
CH3CN
Et2O
60
90
58
48
52
60
73
97
94
95
7
DMSO
CHCl3
CHCl3
CHCl3
8[c]
9[d]
10[e]
[a] Unless specified, see the Exp. Section for reaction conditions.
[b] Yield of isolated product after column chromatography.
[c] 55 °C, 4 h. [d] 10 mol-% of IV, 10 mol-% Et3N, 55 °C, 6 h.
Notably compound 3d, named Herniarin (A), is a meth-
oxy analogue of umbelliferone and can be found in natural [e] 5 mol-% of IV, 5 mol-% Et3N, 55 °C, 10 h.
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J. Wei, P. Wang, Q. Jia, J. Huang, Z. Du, K. Zhang, J. Wang
SHORT COMMUNICATION
Table 4. Scope of substrates.[a]
Table 5. Scope of malonic half-thioesters.[a]
Entry
R
Time [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
3-OMe
3-OEt
4-OMe
4-OBn
5-Me
5-OMe
5-tBu
3-OMe, 5-Br
3-OMe, 5-NO2
5-F
5-Cl
5-Br
6
3
3
3
9
9
3
12
3
9
9
3
9
10
3
12
3
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
93
90
94
92
83
95
95
86
88
87
93
90
91
96
91
85
89
80
86
9
10
11
12
13
14
15
16
17
18
19
[a] Unless specified, see the Exp. Section for reaction conditions.
5-NO2
With regard to the reaction mechanism, two plausible
pathways are proposed (Scheme 1). As shown in pathway a
(Scheme 1), catalyst VI reacts with salicylaldehyde 1a to
form intermediate AA through a Knoevenagel reaction.
Then, Et3N triggers a decarboxylation elimination step to
create intermediate BB. Finally, subsequent lactonization
leads to target product 3a. Without sufficient evidence in
hand, the reaction can also be postulated to proceed
through pathway b. Malonic acid half-thioester 2a directly
reacts with 1a to generate intermediate CC in the presence
of Et3N. Subsequently, a Knoevenagel reaction affords con-
struct intermediate DD. Finally, decarboxylation allows in-
termediate DD to be converted into coumarin 3a.
3,5-Cl2
3,5-Br2
3-Br, 5-Cl
3-Br, 5-NO2
2-naphthyl
48
[a] Unless specified, see the Exp. Section for reaction conditions.
[b] Yield of isolated product after column chromatography.
resources, such as Herniaria glabra, Ayapana triplinervis,
and Prunus.[19] To show the potentially practical synthesis
of our method, a half-gram scale synthesis was performed
to assemble natural product Herniarin (3d, also A). By
combination of 1d and 2a under standard conditions, de-
sired product 3d was rapidly produced [Equation (1), 81%,
24 h].
Conclusions
In conclusion, we have documented an efficient route to
synthesize 3,4-diunsubstituted coumarins through an or-
ganocatalytic cascade reaction. The reaction is catalyzed by
using of a combination of benzylamine (10 mol-%) and tri-
ethylamine (10 mol-%). A number of salicylaldehydes were
tested, and the corresponding coumarin products were ob-
(1) tained in good to high yields under mild and metal-free
Scheme 1. Proposed mechanism.
4
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Cascade Synthesis of 3,4-Diunsubstituted Coumarins
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Acknowledgments
The authors acknowledge financial support from the National Uni-
versity of Singapore and Singapore Ministry of Education,
National Research Foundation (Academic Research Grants:
R143000443112, R143000532112, and NRF-CRP7-2010-03).
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Received: April 13, 2013
Published Online: ᭿
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