Facile synthesis of 4-arylsulfanylcoumarin library through reaction of 4-tosyloxycoumarins with thiols on solid phase

Article abstract of DOI:10.1246/cl.2006.562

Diversified 4-urylsulfanylcoumarins were generated under extremely mild conditions on solid phase with a silyl linker based macro-beads by base-promoted reaction of 4-tosyloxycoumarins with thiols. Copyright

Full text of DOI:10.1246/cl.2006.562

562
Chemistry Letters Vol.35, No.6 (2006)
Facile Synthesis of 4-Arylsulfanylcoumarin Library through Reaction
of 4-Tosyloxycoumarins with Thiols on Solid Phase
Jie Wu
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
(Received March 6, 2006; CL-060266; E-mail: jie wu@fudan.edu.cn)
Diversified 4-arylsulfanylcoumarins were generated under
Tosylates
extremely mild conditions on solid phase with a silyl linker
based macro-beads by base-promoted reaction of 4-tosyloxycou-
marins with thiols.
OTs
OTs
OTs
HO
HO
O
O
HO
O
O
O
O
1b
1a
1c
Benzenethiols
SH
The introduction of sulfur as a heteroatom in many mole-
cules was shown to be an effective method for imparting signifi-
cant biological activity.1 Coumarin, an important class of drug-
like molecule with unique pharmaceutical and biological proper-
ties, has generated a considerable interest both in academia and
industry. As a result, there have been numerous efforts to devel-
op efficient methodologies for its synthesis.2 In light of our inter-
est in coumarin chemistry,3 we required an efficient method to
generate a 4-sulfide based coumarin library with a hope to find
some interesting lead compounds for our particular biological
assays. In this paper, we report a superior method for the synthe-
sis of diversified 4-arylsulfanylcoumarins from the correspond-
ing 4-tosyloxycoumarins and thiols under extremely mild condi-
tions with excellent yields, which ultimately led to a 4-arylsulfa-
nylcoumarin library on a silyl linker based macrobeads.
R1
B1: R1 = H; B2: R1 = 2-Br; B3: R1 = 3-Br; B4: R1 = 4-Br; B5: R1 = 2-Me;
B6: R1 = 3-Me; B7: R1 = 2-Cl; B8: R1 = 4-Me; B9: R1 = 3-Cl; B10: R1 = 4-Cl;
B11: R1 = 2-OMe; B12: R1 = 3-OMe; B13: R1 = 2,4-difluoro; B14: R1 = 4-OMe;
B15: R1 = 2-Et; B16: R1 = 3-F; B17: R1 = 4-F; B18: R1 = 2,4-dimethyl;
B19: R1 = 3,4-dimethyl; B20: R1 = 2-F; B21: R1 = 2,6-dimethyl; B22: R1 = 2-tBu;
B23: R1 = 2,5-dichloro; B24: R1 = 2,5-dimethyl; B25: R1 = 2,6-dichloro;
B26: R1 = 3,4-dichloro; B27: R1 = 2-naphthyl; B28: R1 = 4-SMe;
B29: R1 = 2,5-dimethoxy; B30: R1 = 3,5-dimethyl; B31: R1 = 4-tBu.
Organothiols
SH
SH
SH
Cl
SH
SH
SH
Cl
MeO
C1
C7
C2
C3
C4
C5
C6
SH
SH
O
SH
SH
C8
C9
C10
Although 4-arylsulfanylcoumarins have been synthesized
repeatedly either for biological evaluation or as key intermedi-
ates in synthesizing complex molecules, their syntheses suffer
from multiple synthetic steps, harsh reaction conditions (such
as the use of stoichiometric amounts of bases, or toxic reagents
often under high temperatures), and poor substituent tolerance.4
Since we are interested in synthesizing libraries on a silyl linker
based high-capacity polystyrene macro-beads5 as an indispensa-
ble requirement to realize a key element in a one-bead, one-com-
pound per well technology platform,5b we could not utilize the
conditions illustrated above. This is due to the incompatibility
between the extreme conditions used for the functionalization
of the coumarin scaffold and the selected solid support. There-
fore, we had to search for alternative mild reaction conditions
that not only are compatible with substrates and the solid sup-
port, but could also proceed at room temperature as a require-
ment to prevent fracturing of the polystyrene based macro-
beads, which normally occurs at an elevated temperature.
Recently, we identified 4-tosyloxycoumarin as an ideal elec-
trophile in palladium-catalyzed cross-coupling reactions to gen-
erate 4-substituted coumarins.3 We assumed that this substrate
may also under 1,4-addition, followed by elimination when re-
acted with nucleophiles since the structure of this enol tosylate
is in ꢀ,ꢁ-conjugated system.
Figure 1.
could be carried out at room temperature under air atmosphere.
To demonstrate the generality of this method, we next investi-
gated the scope of this reaction (Scheme 1). This reaction
was highly efficient. When substituted benzenethiol B1–B10
(Figure 1) were used, all reactions were completed in two mi-
nutes to give the corresponding products in almost quantitative
yields. While, when organomercaptans C7–C10 were employed,
the reaction time was extended to 4–24 h, and usually a yield of
desired products higher than 95% was obtained in all the cases.
The exceptional efficiency for this base accelerated reaction
led us to apply this methodology on solid-phase synthesis of 4-
arylsulfanylcoumarin library. In order to link the tosylates sub-
strates to the silyl linker based macrobeads (500–600 mm, gener-
ated based on the method described by Schreiber5a from unfunc-
tionalized polystyrene, which was purchased from Rapp Poly-
mere GmbH), the substrates (1a–1c) (Figure 1) were synthe-
sized7 and then loaded on the solid support (loading: 100–
120 nmol).5 (Scheme 2) These on beads tosylates were first
reacted in parallel with 31 benzenethiols (B1{31, 5 equiv.) and
R2SH (1.0 equiv.)
(B1-B10: < 2 min;
C7-C10: 4-24 h)
SR2
OTs
Similar nucleophilic vinylic substitutions of this kind of
structure were observed previously.6 To test this idea, 4-tosyl-
oxycoumarin (1a) was prepared and reacted with benzenethiol in
the presence of triethylamine in CH2Cl2. To our delight, this
reaction was finished in less than 2 min at room temperature in
almost quantitative yields. It is also noteworthy that this reaction
R1
R1
CH2Cl2, Et3N (1.1 equiv.)
r.t., air
O
O
O
O
1
>95% yield
1a: R1 = H; 1b: R1 = 6-Me;
1c: R1 = 6-Cl; 1d: R1 = 6-F; 1f: R1 = 7-OMe
Scheme 1.
Copyright ꢀ 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.6 (2006)
563
(Table 1). It is interesting to notice that all the benzenethiols-
based reactions gave the corresponding products in high yields
(more than 90%) as was confirmed with LC-MS, and the reac-
tions only needed 6 h at room temperature under air atmosphere
for completion. On the other hand, the organothiols-based reac-
tions proceeded extremely slowly and no significant conversions
were observed when the reactions proceeded at room tempera-
ture for 4 days. This library was synthesized only in two days.
The operation is very simple and the compounds were released
by treating with HFÁpyridine and TMSOMe subsequently. The
purity of this library was analyzed by LCMS and the results were
almost perfect. Most of them were over 90% pure which could
be directly used for biological assay. Further investigation for
this category of substrates is underway in our lab.
1) TMSCl, imidazole
iPr
Si
iPr
RT, DCM, 2h
2) TfOH, DCM, r.t. 1.5h
OMe
3) 2,6-lutidine, DCM
r.t. 4h, 1a-c
OTs
O
SAr
R
R
ArSH (B1-31
)
O
O
TEA, DCM
r.t. 6h
O
O
O
3(a-c)B1-31
2(a-c)
1) HF/pyridine, THF, 1h
2) TMSOMe, 5 min
SAr
R
HO
O
O
In conclusion, we have developed a highly efficient and con-
venient approach for the synthesis of diversified 4-arylsulfanyl-
coumarins library under extremely mild reaction conditions.
This method should allow us to construct a larger 4-arylsulfanyl-
coumarins library fast and effectively. The screening for biolog-
ical activity of these small molecules is under investigation in
our laboratory.
4(a-c)B1-31
Scheme 2. Library synthesis on solid phase.
Table 1. Solid-phase library synthesisa
Product
Purity
Product
Purity
Product
Purity
4a-B1
4a-B2
4a-B3
4a-B4
4a-B5
4a-B6
4a-B7
4a-B8
4a-B9
4a-B10
4a-B11
4a-B12
4a-B13
4a-B14
4a-B15
4a-B16
4a-B17
4a-B18
4a-B19
4a-B20
4a-B21
4a-B22
4a-B23
4a-B24
4a-B25
4a-B26
4a-B27
4a-B28
4a-B29
4a-B30
4a-B31
94.1% 4b-B1
94.6% 4b-B2
91.8% 4b-B3
>99% 4b-B4
89.2% 4b-B5
83.6% 4b-B6
96.5% 4b-B7
90.9% 4b-B8
93.1% 4b-B9
>99%
98.9%
>99%
>99%
96.9%
97.6%
>99%
>99%
>99%
4c-B1
4c-B2
4c-B3
4c-B4
4c-B5
4c-B6
4c-B7
4c-B8
4c-B9
4c-B10
4c-B11
4c-B12
4c-B13
4c-B14
4c-B15
4c-B16
4c-B17
4c-B18
4c-B19
4c-B20
4c-B21
4c-B22
4c-B23
4c-B24
4c-B25
4c-B26
4c-B27
4c-B28
4c-B29
4c-B30
4c-B31
98.4%
>99%
95.3%
98.9%
>99%
97.8%
>99%
95.7%
96.3%
97.4%
>99%
>99%
>99%
>99%
97.7%
>99%
>99%
91.6%
90.0%
>99%
96.4%
93.6%
>99%
98.0%
>99%
97.0%
98.2%
97.0%
>99%
94.9%
85.0%
We thank Professor Zhen Yang for his invaluable advice
during the course of this research. Financial support from
National Natural Science Foundation of China (No. 20502004),
Ministry of Education of China, the Science and Technology
Commission of Shanghai Municipality (No. 05ZR14013), and
Fudan University is gratefully acknowledged.
References
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2
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´
97.7% 4b-B10 >99%
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>99% 4b-B11
>99% 4b-B12
>99% 4b-B13
94.3% 4b-B14 >99%
95.4% 4b-B15 >99%
>99% 4b-B16
>99% 4b-B17
85.9% 4b-B18 >99%
77.8% 4b-B19
97.9% 4b-B20
87.0% 4b-B21
88.0% 4b-B22
94.2% 4b-B23 >99%
94.5% 4b-B24 97.7%
97.7% 4b-B25 >99%
93.8% 4b-B26 98.0%
98.2% 4b-B27 >99%
94.1% 4b-B28 >99%
95.3% 4b-B29
83.5% 4b-B30
74.9% 4b-B31
93.6%
98.5%
94.8%
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4
96.4%
98.3%
92.3%
95.5%
92.2%
72.9%
5
6
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97.7%
94.3%
84.5%
aPurities were determined by LC-MS.
7
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10 organothiols (C1{10, 5 equiv.), respectively, (Figure 1) and
then cleaved from the beads. The results are summarized below
Published on the web (Advance View) April 25, 2006; doi:10.1246/cl.2006.562