Table 2 Optimization of other parametersa
the reaction (Table 3, 3cb–fb). Surprisingly, the alkyl substituted
malonic acid half-thioesters 1g–h also efficiently participated in
the decarboxylation process to generate 4-alkyl thioester 3,4-
dihydrocoumarin 3gb–hb and provided 92% and 88% yields in
12 h. In addition to malonic acid half-thioester 1b–g, several
other α-functionalized carboxylic acids 1i–m, which tolerated
ester, amide, ketone, nitrile and aryl groups, were introduced to
this process and the desired products 3ib–mb were achieved in
high to excellent yields (80–98%).
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
Et2O
DCM
Toluene
EtOAc
Acetone
MeCN
THF
36
<5%
<5%
<5%
46
<5%
66
Conclusions
In summary, we have documented an efficient and convenient
double decarboxylation process for the synthesis of 4-substituted
3,4-dihydrocoumarin in moderate to excellent yields (up to
98%). We hope that the catalytic system and strategy demon-
strated here could be applied to efficiently assemble other syn-
thetic useful chemical structures. Elaboration of above
synthesized products and further applications of our proposed
decarboxylation strategy are now ongoing in our group.
8
9
1,4-Dioxane
DMF
DMF
DMF
DMF
EtOH
H2O
73
82
76
90
90
<5%
<5%
10c
11d
12e
13
14
a Reaction conditions: 1b (0.2 mmol, 1.0 equiv.), 2b (0.24 mmol, 1.2
equiv.), catalyst V (20 mol%), solvent (0.4 mL), 6 h, room temperature.
b Isolated yield after flash column purification. c Cat. V (10 mol%), 12 h.
d 1b (0.24 mmol, 1.2 equiv.), 2b (0.2 mmol, 1.2 equiv.), Cat. V (10 mol
%), 12 h. e 1b (0.3 mmol, 1.5 equiv.), 2b (0.2 mmol, 1.2 equiv.), Cat. V
(10 mol%), 12 h.
Acknowledgements
We gratefully acknowledge the National University of Singapore
and Singapore Ministry of Education for financial support of
this work (Academic Research Grants: R143000408133,
R143000408733, R143000443112, R143000480112, and
NRF-CRP7-2010-03).
secondary amine, pyrrolidine II. Interestingly, pyrrolidine II
afforded a 44% yield (Table 1, entry 2). Followed that, a series
of tertiary amines, such as triethylamine III, N,N-diisopropyl-
ethylamine IV, N-methylmorpholine V and 4-dimethylamino-
pyridine VII, were investigated (Table 1, entries 3–5 and 7). It is
noteworthy that N-methylmorpholine V was approved to be a
more efficient catalyst (Table 1, entry 5, 66%, 6 h). In addition,
several inorganic bases were applied to this reaction and finally
demonstrated no catalytic activation (Table 1, entries 8–11).
In order to achieve a high chemical yield, we did further
investigation on other parameters, such as solvent and ratio of
components. Results showed that less polar solvents were poor
reaction media (Table 2, entries 1–7, <5%–66%). Ethanol and
water led to a sluggish reaction (Table 2, entries 13 and 14).
Finally, a basic polar solvent was generally essential for a good
chemical yield (Table 2, entry 9, 82%). In addition, if the ratio of
1b/2b was adjusted from 1 : 1.2 to 1.2 : 1, a good chemical yield
(90%) was finally obtained (Table 2, entry 11). Moreover, a
lower catalyst loading caused a loss of reaction yield (Table 2,
entry 10, 10 mol%, 76%).
Having established an efficient protocol for the reaction of 1b
and 2b, we subsequently explored the substrate scope of this
transformation. As shown in Table 3, a number of coumarin-3-
carboxylic acids 2b–j bearing electron donating and electron-
withdrawing substituents were successfully applied to the double
decarboxylation process. The corresponding adducts 3bb–bj
were isolated in moderate to excellent yields (60–96%). Further-
more, a diverse set of malonic acid half-thioesters were exam-
ined and demonstrated that the substitution pattern of the phenyl
ring on thioester had limited influence on the catalytic activity of
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