Facile synthesis of 3-benzylsulfinyl- and 3-benzylsulfonyl-7- diethylaminocoumarins

Article abstract of DOI:10.3184/174751914X14054403315001

The efficient synthesis of a 3-benzylsulfinylcoumarin and a 3-benzylsulfonylcoumarin starting from thiobenzyl alcohol using solvent-free Knoevenagel reaction as the key step is reported. Moreover, the molecular structure of 3-benzylsulfonyl-7-diethylamino

Full text of DOI:10.3184/174751914X14054403315001

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 AUGUST, 493–495
RESEARCH PAPER 493
Facile synthesis of 3‑benzylsulfinyl‑ and 3‑benzylsulfonyl‑7‑
diethylaminocoumarins
Xiaolong Wang*, Ziyan Xue, Yanying Ma and Fang Yang
The School of Chemical and Biological Engineering, Lanzhou Jiaotong University, 88 West Anning Road, Lanzhou 730070, P.R. China
The efficient synthesis of a 3‑benzylsulfinylcoumarin and a 3‑benzylsulfonylcoumarin starting from thiobenzyl alcohol using
solvent‑free Knoevenagel reaction as the key step is reported. Moreover, the molecular structure of 3‑benzylsulfonyl‑7‑
diethylaminocoumarin is confirmed by X‑ray crystal analysis.
Keywords: coumarin, sulfide, oxidation, Knoevenagel reaction, X‑ray analysis
Coumarins are important organic compounds that have been
widely studied. Many of these compounds exhibit a diverse
array of biological properties such as antibacterial, anti‑HIV,
anticancer, antioxidant and anti‑inflammatory activities.1 In
addition, owing to their thermal stability and optical properties,
coumarin derivatives are widely used as nonlinear optical
chromophores, laser dyes, fluorescent whiteners, fluorescent
probes and solar energy collectors.2 Therefore, the design and
synthesis of coumarin derivatives is a popular research topic in
organic chemistry.
Traditionally, coumarins can be synthesised by various
methods including the Perkin, Knoevenagel, Pechmann and
Wittig reactions.3 The Knoevenagel reaction has been one of
the most popular methods in which substituted salicylaldehydes
are condensed with active methylene compounds in the
presence of a base to afford coumarins. Various active
methylene compounds, such as β‑keto esters, diethyl malonate
and ethyl (2‑benzthiazolyl)acetate, have been employed in
this reaction.4,5 Since we have previously applied the sulfones
in the Ramberg–Bäcklund reaction,6 we reasoned that the
α‑sulfinylester and α‑sulfonylester derived from sulfides could
react with salicylaldehyde readily to give the corresponding
coumarins.
Merchant and Shah7 prepared a series of 3‑phenylsulfonyl
coumarins by oxidising the corresponding sulfides, which were
obtained via the condensation of salicylaldehydes and sodium
S‑phenylthioacetate. Some of the sulfides could be oxidised
only to the sulfoxide stage (i.e. the sulfinylcoumarins) even
with excess oxidising agent. Recently, Zhu and coworkers8
achieved 3‑polyfluoroalkanesulfonyl coumarins by L‑proline
catalysed Knoevenagel reaction of salicylaldehydes and ethyl
perfluorobutylsulfonylacetate in more than 15 hours, wherein
the latter substrate was generated from the reaction of methyl
nonafluorobutyl sulfone and methyl chloroformate.8 These
methodologies are associated with several drawbacks such as
long reaction time, high temperature and limited availability of
substrates. Consequently, it is desirable to develop a practical
and convenient method for the synthesis of sulfinyl and
sulfonyl coumarins from readily available materials. Here we
present the facile synthesis of a 3‑benzylsulfinylcoumarin and
a 3‑benzylsulfonylcoumarin from commercially available and
inexpensive thiobenzyl alcohol.
The synthesis of the target coumarins was carried out as
outlined in Scheme 1. Initially, we conducted the reaction
of thiobenzyl alcohol (1) and ethyl chloroacetate at room
temperature in DMF promoted by a base in the hope of
preparing the corresponding sulfide. The use of KOH proved
to be unsuccessful, the reaction was sluggish and considerable
A literature survey revealed that studies on the synthesis
of sulfinyl and/or sulfonyl coumarins were very limited.
S
O
3
CO2Et
b
c
a
S
CO2Et
SH
S
CO2Et
O
O
1
2
4
O
S
CHO
d
S
CO2Et
+
O
(C2H5)2N
OH
(C2H5)2N
O
O
5
3
6
O
O
CHO
OH
d
S
S
CO2Et
+
O
O
(C2H5)2N
(C2H5)2N
O
O
5
4
7
Scheme 1 Reagents and conditions: (a) ClCH2CO2Et, NaH, DMF, room temperature, 1 h, 92%; (b) 30% aq. H2O2, AcOH, room temperature, 5 h, 86%; (c) 30%
aq. H2O2, AcOH, 60 °C, 7 h, 83%; (d) piperidine, solvent‑free, room temperature to 50 °C, 0.5 h, 6: 78%, 7: 82%.
* Correspondent. E‑mail: wangxl@mail.lzjtu.cn
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494 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 Crystal data and structure refinement of 7
Empirical formula C20H21NO4S
Formula weight
amounts of starting materials were recovered even after
prolonged reaction time. However, when NaH was employed,
the desired sulfide 2 was obtained as the sole product in 92%
yield. The next synthetic challenge was the selective oxidation
of the sulfide to form the corresponding sulfoxide and sulfone,
respectively. It was reported that sulfides can be oxidised to
sulfoxides or sulfones by m‑chloroperbenzoic acid (MCPBA),
oxone or metal oxide catalyst‑H2O2 system.9 Fortunately, in
a simple and cost effective manner, sulfide 2 was smoothly
oxidised to ethyl benzylsulfinylacetate (3) in 86% yield
by 30% H2O2 without any catalyst in acetic acid at room
temperature. Then, we reasoned that the sulfide 2 could be
converted to the corresponding sulfone via oxidation at higher
temperatures. However, the oxidation under reflux condition
led to extensive decomposition and did not give the desired
product. After systematic exploration of reaction temperature,
we found that the oxidation proceeded optimally at 60 °C
to produce ethyl benzylsulfonylacetate (4) in 83% yield.
Subsequently, compounds 3 and 4 were respectively subjected
to Knoevenagel reaction with 4‑(diethylamino)salicylaldehyde
(5) catalysed by piperidine under solvent‑free conditions to
afford the corresponding 3‑benzylsulfinylcoumarin 6 and
3‑benzylsulfonylcoumarin 7 in good yields (Scheme 1). We
also examined the same Knoevenagel reactions in refluxing
ethanol, wherein the desired products were obtained in
unsatisfactory yields along with appreciable quantities of by‑
products.
Fortunately, suitable single crystals of 7 were obtained
by recrystallisation from petroleum ether/ethyl acetate for
X‑ray analysis (Fig. 1), whereby the molecular structure
and stereochemistry of this coumarin was unambiguously
confirmed. A summary of the crystallographic data and
structure refinement details is shown in Table 1, and the
selected bond lengths and bond angles are listed in Table 2.
Crystallographic data for 7 has been deposited at the Cambridge
Crystallographic Data Centre with the deposition number
CCDC 1009941. These data can be obtained free of charge on
application to CCDC via www.ccdc.cam.ac.uk.
371.44
293(2)
Temperature/K
Wavelength/Å
0.71073
Crystal system
Space group
Monoclinic
P 21/n
Unit cell dimensions/ Å
a=13.2890(7)
b=10.5679(5)
c=13.3597(7)
α=90°
β=90.606(5) °
γ=90°
1876.09(17)
4
Volume/Å3
Z
Calculated density/Mg m–3
Absorption coefficient/mm–1
F(000)
1.315
0.197
784
Crystal size
2Θ range for data collection
Limiting indices
0.29×0.26×0.12 mm
6.1 to 52.04°
–16≤h≤16
–13 ≤k≤13
–15 ≤l≤16
Reflections collected/unique
Refinement method
Data/restraints/parameters
Goodness‑of‑fit on F2
10020/3612 [R(int)=0.0644]
Full‑matrix least‑squares on F2
3612/25/256
1.077
Final R indices [I>2σ (I)]
R indices (all data)
Largest diff. peak and hole/e Å–3
R1 =0.0624, wR2 = 0.1350
R1 =0.1085, wR2 = 0.1724
0.23 and –0.31
Table 2 Selected structural parameters for compound 7
Bond lengths (Å)
S1–O3
S1–O4
S1–C8
S1–C14
O1–C5
O1–C7
1.431(2)
1.436(2)
1.754(3)
1.775(3)
1.381(4)
1.385(4)
O2–C7
C1–N1
C7–C8
C8–C9
C4–C9
C14–C15
1.211(4)
1.362(4)
1.439(4)
1.365(4)
1.401(4)
1.505(4)
In
summary,
the
efficient
synthesis
of
a
3‑benzylsulfinylcoumarin and a 3‑benzylsulfonylcoumarin
from readily available thiobenzyl alcohol has been described,
in which the sulfide was oxidised to sulfoxide and sulfone
by H2O2 without any catalyst and the Knoevenagel reactions
were conveniently performed under solvent‑free conditions.
The structure of 3‑benzylsulfonyl‑7‑diethylaminocoumarin
(7) was further confirmed by X‑ray single crystal analysis.
This synthetic approach should provide a succinct route to a
diverse array of sulfinyl‑ and sulfonylcoumarins for biological
or optical studies. Further work is in progress in our laboratory.
Bond angles (°)
O3–S1–O4
O3–S1–C8
O3–S1–C14
O4–S1–C8
O4–S1–C14
C8–S1–C14
C5–O1–C7
O1–C5–C4
117.57(17)
106.62(15)
108.24(17)
109.57(15)
108.51(17)
105.69(16)
122.6(2)
C15–C14–S1
N1–C1–C2
N1–C1–C6
C6–C1–C2
C6–C5–O1
O1–C7–C8
O2–C7–O1
O2–C7–C8
110.0(2)
120.5(3)
121.9(3)
117.6(3)
116.2(3)
116.4(3)
116.3(3)
127.3(3)
120.1(3)
Fig. 1 The molecular structure of compound 7. Non‑hydrogen atoms are shown at the 30% probability level.
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JOURNAL OF CHEMICAL RESEARCH 2014 495
3-Benzylsulfinyl-7-diethylaminocoumarin (6):
A
mixture of
Experimental
4‑(diethylamino)salicylaldehyde (5, 0.29 g, 1.5 mmol), ethyl
benzylsulfinylacetate (3, 0.34 g, 1.5 mmol) and piperidine (0.5 mL)
in a mortar was ground well with a pestle at room temperature. The
reaction was heated at 50 °C and ground for 30 min. Then, the mixture
was dissolved in ethyl acetate (50 mL), neutralised with 3N HCl and
extracted with brine (3×50 mL). The organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
resulting residue was purified by column chromatography using
petroleum ether/ethyl acetate (v/v=2:1) as eluent to afford 6 (0.41 g,
yield 78%) as a yellow solid, m.p. 160–162 °C. IR (KBr) cm–1: 1718,
Reagents and solvents were all from commercial sources and used
without further purification. 1H NMR and 13C NMR spectra were
recorded on a Mercury Plus 400 MHz spectrometer. Chemical shifts
were reported relative to internal tetramethylsilane (δ 0.00 ppm) or
1
CDCl3 (δ 7.26 ppm) for H and CDCl3 (δ 77.0 ppm) for 13C. Coupling
constants (J) are given in Hertz (Hz). Melting points were measured
on a Kofler apparatus and uncorrected. Column chromatography
purifications were performed on 200–300 mesh silica gel. Analytical
TLC was performed on silica gel GF254 plates. X‑ray crystallographic
analysis was performed on
a SuperNova, Dual, Cu at zero,
1
1616, 1511, 1249, 1130, 1076, 1048, 700, 633. H NMR (400 MHz,
Eos diffractometer. The crystal was kept at 293(2) K during data
collection. Using Olex2, the structure was solved with the ShelXS
structure solution program using direct methods and refined with
the ShelXL refinement package using least squares minimisation.
High resolution mass spectra (HRMS) were determined on a Bruker
Daltonics APEX II 47e spectrometer.
CDCl3): δ 7.67 (s, 1H), 7.27–7.18 (m, 6H), 6.58 (dd, J=8.8 and
2.0 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 4.41 (d, J=12.8 Hz, 1H), 4.10
(d, J=12.8 Hz, 1H), 3.44 (q, J=7.2 Hz, 4H), 1.21 (t, J=7.2 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 158.6, 157.2, 152.0, 143.1, 130.7, 130.1,
129.6, 128.5, 128.4, 120.6, 109.7, 108.3, 97.3, 58.0, 45.2, 12.6. HRMS
calcd for C20H22NO3S [M+H]+: 356.1315; found: 356.1316.
Ethyl benzylsulfidylacetate (2): Thiobenzyl alcohol (1.24 g,
10.0 mmol) was dissolved in dry DMF (15 mL), NaH (0.48 g, 60%
in mineral oil, 12.0 mmol) was added and the resulting mixture was
stirred at room temperature for 15 min. Then, ethyl chloroacetate
(1.23 g, 10.0 mmol) was added and the resulting solution was stirred
for 1 h at room temperature. On completion of the reaction (monitored
by TLC), AcOEt (50 mL) was added to the mixture and washed with
brine (3×50 mL). The organic layer was dried (Na2SO4), filtered
and concentrated under reduced pressure. The resulting residue was
purified by column chromatography using petroleum ether/ethyl
acetate (v/v=10:1) as eluent to afford 2 (1.93 g) as a colourless oil in
3-Benzylsulfonyl-7-diethylaminocoumarin (7):
A mixture
of 4‑(diethylamino)salicylaldehyde (5, 0.29 g, 1.5 mmol), ethyl
benzylsulfonylacetate (4, 0.36 g, 1.5 mmol) and piperidine (0.5 mL)
in a mortar was ground well with a pestle at room temperature. The
reaction was heated at 50 °C and ground for 30 min. Then, the mixture
was dissolved in ethyl acetate (50 mL), neutralised with 3N HCl and
extracted with brine (3×50 mL). The organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
resulting residue was purified by column chromatography using
petroleum ether/ethyl acetate (v/v=2:1) as eluent to afford 7 (0.46 g,
yield 82%) as a yellow‑greenish solid, m.p. 172–173 °C. IR (KBr) cm–1:
1
92% yield. H NMR (400 MHz, CDCl3): δ 7.34–7.23 (m, 5H), 4.15
1
(q, J=7.2 Hz, 2H), 3.81 (s, 2H), 3.04 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 170.4, 137.3, 129.2, 128.5, 127.2, 61.3,
36.3, 32.2, 14.2. HRMS calcd for C11H15O2S [M+H]+: 211.0787; found:
211.0792.
1717, 1620, 1509, 1352, 1131, 700, 633. H NMR (400 MHz, CDCl3):
δ 8.10 (s, 1H), 7.40–7.29 (m, 6H), 6.62 (dd, J=8.8 and 2.4 Hz, 1H),
6.51 (d, J=2.4 Hz, 1H), 4.74 (s, 1H), 3.48 (q, J=7.2 Hz, 4H), 1.26 (t,
J=7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 158.5, 157.5, 153.4,
148.2, 131.6, 130.8, 128.7, 128.3, 115.4, 110.0, 106.7, 96.8, 59.3, 45.2,
12.4. HRMS calcd for C20H22NO4S [M+H]+: 372.1264; found:
372.1272.
Ethyl benzylsulfinylacetate (3): Sulfide 2 (0.42 g, 2.0 mmol) was
dissolved in glacial acetic acid (5 mL). Then, H2O2 (30% w/v, 2 mL)
was added and the resulting solution was stirred for 5 h at room
temperature. When the reaction was judged to be complete (TLC
monitoring), the mixture was dissolved in ethyl acetate (50 mL).
The solution was washed with brine (3×50 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure. The resulting
residue was purified by column chromatography using petroleum
ether/ethyl acetate (v/v=1:1) as eluent to afford 3 (0.39 g, yield 86%)
We are grateful for the financial support from the ‘Qing Lan’
talent engineering funds (QL‑06‑01A) of the Lanzhou Jiaotong
University.
1
Received 21 April 2014; accepted 8 July 2014
Paper 1402603 doi: 10.3184/174751914X14054403315001
Published online: 12 August 2014
as a colourless solid, m.p. 44–46 °C. H NMR (400 MHz, CDCl3): δ
7.41–7.32 (m, 5H), 4.27–4.21 (m, 3H), 4.11 (d, J=13.2 Hz, 1H), 3.57
(d, J=14.0 Hz, 1H), 3.47 (d, J=14.0 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 165.3, 130.5, 129.2, 129.1, 128.8, 62.2,
58.1, 53.7, 14.2. HRMS calcd for C11H15O3S [M+H]+: 227.0736; found:
227.0744.
References
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Ethyl benzylsulfonylacetate (4): Sulfide 2 (0.42 g, 2.0 mmol) was
dissolved in glacial acetic acid (5 mL). Then, H2O2 (30% w/v, 2 mL)
was added and the resulting solution was stirred at 50 °C for 7 h.
Upon completion of the reaction (TLC monitoring), the mixture
was dissolved in ethyl acetate (50 mL) and then extracted with brine
(3×50 mL). The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography using petroleum ether/ethyl
acetate (v/v=5:1) as eluent to afford 4 (0.40 g) as a colourless oil in 83%
2
3
4
5
6
1
7
8
yield. H NMR (400 MHz, CDCl3): δ 7.46–7.35 (m, 5H), 4.48 (s, 2H),
4.24 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 1.28 (t, J=7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 163.0, 130.8, 128.9, 128.7, 127.5, 62.3, 59.1, 54.8,
13.7. HRMS calcd for C11H15O4S [M+H]+: 243.0686; found: 243.0693.
9
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