Ultrasound-assisted Wittig reaction and synthesis of 5-alkyl- and 5-alkenyl-resorcinols

Article abstract of DOI:10.3184/030823409X417306

Some 5-alkyl- and 5-alkenyl-resorcinols were synthesised from commercially available 3,5-bis(benzylo×y)benzaldehyde by ultrasound-assisted Wittig reaction with alkyltriphenyl phosphonium bromides in basic aqueous condition, followed by debenzylation and simultaneously reduction of a double bond of the styrene type with Na/n-BuOH in overall yields of 62-72%.

Full text of DOI:10.3184/030823409X417306

JOURNAL OF CHEMICAL RESEARCH 2009
MARCH, 183-185
RESEARCH PAPER 183
Ultrasound-assisted Wittig reaction and synthesis of 5-alkyl- and
5-alkenyl-resorcinols
Li-Qiang Wu*, Chun-Guang Yang, Li-Ming Yang and Li-Juan Yang
School of Pharmacy, Xinxiang Medical College, Xinxiang, Henan 453003, P.R. China
Some 5-alkyl- and 5-alkenyl-resorcinols were synthesised from commercially available 3,5-bis(benzyloxy)benzaldehyde
by
ultrasound-assisted
Wittig reaction with alkyltriphenyl phosphonium
bromides in basic aqueous condition, followed
by debenzylation and simultaneously
reduction of a double bond of the styrene type with Na/n-BuOH in overall
yields of 62-72%.
Keywords: 5-alkylresorcinol, 3,5-bis(benzyloxy)benzaldehyde, Wittig reaction, ultrasound irradiation, 5-alkenylresorcinols
5-Alkylresorcinols are non-isoprenoid phenolic lipids that
carry an n-alkyl side chain at C-5 of the resorcinol ring.
They are of a great importance owing to their biological
activity such as antibacterial and antifungal activity, cytotoxic
activity, antioxidant activity and 5-lipoxygenase inhibitory
activity.! Olivetol(la),2 grevillol(lb),3 adipostatin A(lc)4 and
5-heptadecyllresorcinol (ld)5 and the 5-alkenylresorcinols
ardisinol II(le)6 and bilobol (lff (Fig. 1) have been isolated
from natural sources.
There are three strategies for synthesis of 5-alkenyl-
resorcinols: (i) elaboration of the side-chain on the aromatic
ring. This route is complicated and has a lower yield;8.10(ii)
aromatisation of cyclohexane derivatives. This method is
not suitable for synthesis of 5-alkenylresorcinols;II.12 (iii)
direct alkylation of the aromatic ring by Suzuki coupling.
The necessity for a terminal alkene as the starting material
for the reaction limits the number of compounds available
for this kind of approach to 5-alkenylresorcinols synthesis
in genera1.13We now report a simple and efficient route to
5-alkylresorcinols and some 5-alkenylresorcinols based on an
ultrasound-assisted Wittig reaction.
olivetol
grevillol
adipostatinA
5-heptadecyIlresorcni oI
1a R=CH3(CH2h
1b R=CH3(CH2)1O
1c R=CH3(CH2)12
1d R=CH3(CH2)14
1e R=CH3(CH2hCH~CH(CH2ls
ardisinoiII
bilobol
1f R=CH3(CH2)sCH§CH(CH2)s
Fig. 1 Some 5-alkyl-and 5-alkenyl-resorcinols
ethers functionalities were cleaved and the conjugated double
bond was reduced but the isolated one was not affected. 14
The Wittig reaction is one of the most versatile
synthetic methods for preparation of olefins from carbonyl
compounds and it is classically carried out using a hydride
or organometallic base in anhydrous aprotic solvents under
an inert atmosphere. During synthesis of 2, we applied
the solid-liquid transfer technique to the Wittig reaction.
This salt-free system is a more environmentally-friendly
Compounds la-fwere prepared starting from commercially
available 3,5-bis(benzyloxy) benzaldehyde, as outlined in
Table 1. Ultrasound-assisted Wittig reaction of alkyltriphenyl
phosphonium bromides with 3,5-bis(benzyloxy) benzaldehyde,
in the presence of K2C03 and using DMSO/water as solvent,
afforded the styrenes 2a-f in 81-90% yields. Cleavage of
the benzyl ethers and reduction of the conjugated double
bond of compounds 2a-f were attempted by catalytic
hydrogenolysis over Pd/C, but this method was not suitable
for synthesis of 5-alkenylresorcinols as the isolated double
bond was reduced. However, compounds 2a-f were treated
with metallic sodium in n-butanol to obtain the 5-alkyl- and
alkenyl-resorcinols in 75-81% yields, where two benzyl
strategy than methods utilising lithium bases.15 Scheme
details the solid-liquid phase-transfer process.
1
To establish simple and suitable conditions for the
synthesis of compounds analogous to 2 the reaction of
butyltriphenyl phosphonium bromide with 3, 5-bis(benzyloxy)
benzaldehyde was chosen as a model, and its behaviour was
studied under a variety of conditions by TLC andl IH NMR
and 13CNMR spectroscopy (Table 2).
According to Table 2, the best result was obtained in
the presence of K2C03, ultrasound irradiation and using
DMSO/water as solvent (entry 7). The results also emphasised
the importance of using ultrasound irradiation (entries 1,3,5
and 7), which shortened reaction times and improved yields.
Table 1 The synthesis of 5-alkyl-and 5-alkenyl-resorcinols
B n0'(Y C H O
H O y<C H 2hR
y_ R C H 2PPh3 B rK. 2C O ~B2n0O_~CyH =C H RNaln-~uOH
I
A
OBn
DMSO. )). 90-100 C
OBn
80-90 C.lh
OH
2
1
Yield/%b
Entry
R
2
Yield/Yo"
1
2
3
CH3(CH2h
CH3(CH2ho
CH3(CH2)12
CH3(CH2h4
2a
2b
2c
2d
2e
2f
89
85
86
90
82
81
1a
1b
1c
1d
1e
1f
81
76
79
77
75
77
4
5
6
Z
CH3(CH2hCH=CH(CH2)5
CH3(CH2)5CH~CH(CH2)5
"Totalyield of the Zand Emixture.
blsolated yield.
* Correspondent.E-mail:wliq1974@sohu.com

184 JOURNAL OF CHEMICAL RESEARCH 2009
Ax
R
\ c=c/
+
+
/
\
H
H
Scheme 1 Solid-liquid
phase-transfer process.
Table 2 The reactions of butyltriphenylphosphonium
bromide and 3,5-bis(benzyloxy)benzaldehyde under different conditions"
Yield/%b
Time/h Ultrasound
Entry
Base
Solvent
1
2
3
4
5
6
7
8
NaOH
NaOH
NaOH
NaOH
KZC03
KZC03
KZC03
KZC03
Dioxane/water
Dioxane/water
DMSO/water
DMSO/water
Dioxane/water
Dioxane/water
DMSO/water
DMSO/water
1
5
1
5
1
5
1
5
+
+
+
+
26
<10
28
<10
38
30
85
55
"3,5-Bis(benzyloxy)benzaldehyde:
alkyltriphenylphosphonium
bromide: KZC03: water = 1: 1: 1.3: 2; the reaction carried out at 90-100°C.
bTotal yield of the Zand Emixture.
cooled to 25°C, treated with 10 mL of water and extracted with two
15 mL portions of ether. The combined organic layer was washed
successively with water and brine and then dried over anhydrous
magnesium sulfate, filtered and concentrated. The crude product was
chromatographed on silica gel eluting using hexane:ethyl acetate
(10:1) to yield 2 as colourless oil.
In summary, we have developed
a
general methodology
to
in
synthesise a number of 5-alkyl- and 5-alkenyl-resorcinols
excellent yield. The key steps include ultrasound-accelerated
Wittig reaction, followed by debenzylation
and simultaneous
reduction of the conjugated double bond with Na/n-BuOH.
Sodium metal (9.2 g, 400 mmol) was added to a solution of 2 in
anhydrous n-BuOH (100 mL) at room temperature. The resulting
mixture was heated at 80-90°C and stirred for I h. The reaction was
quenched by addition of20% aqueous HOAc (50 mL). After hexane
(100 mL) was added to this mixture, it was heated at reflux and
the aqueous layer was removed with a Dean-Stark trap overnight.
The organic layer then was filtered and concentrated under reduced
pressure. The crude product was chromatographed on silica gel
eluting using hexane:ethyl acetate (4: I) to yield 1.
Experimental
NMR spectra were determined on FT-NMRAvance 400 spectrometer
in CDCI3 or DMSO-d and were expressed in delta values relative
6
to tetramethylsilane, coupling constants (J) were measured in Hz;
Elemental analyses were recorded on a Vario EL III elemental
analyser; melting points were determined on a Mel-Temp capillary
tube apparatus and were uncorrected; ultrasound irradiation was
effected in a water bath of a CQ250 ultrasonic cleaner (frequency:
40 kHz, power 250 W); Commercially available reagents were used
throughout without further purification unless otherwise stated;
Dioxane and DMSO were fresWy distilled from sodium.
Olivetol (Ia): Colourless oil. 'H NMR (400 MHz, DMSO-d6)
8: 9.07 (brs, exch. Dp, 2H), 6.22 (d, 2H, J
= 2.0 Hz), 6.15 (t, 1H,
J= 2.0 Hz), 2.42 (t, J= 7.6 Hz, 2H), 1.55-1.50 (m, 2H), 1.33-1.26 (m,
4H), 0.85 (t, J= 7.0 Hz, 3H). l3C NMR (100 MHz, CDCI3) 8: 156.6
(2C), 146.2, 108.3 (2C), 100.2, 35.8, 31.5, 30.5, 22.5, 14.1. Anal.
Calcd for CllH'602 C, 73.30; H, 8.95. Found: C, 73.38; H, 8.89%.
Grevillol (Ib): Colourless solid, m.p. 85-86°C (lit.lO, m.p. 81-
83°C). 'H NMR (400 MHz, DMSO-d6) 8: 9.07 (brs, exch. Dp, 2H),
6.20 (d, 2H, J= 2.1 Hz), 6.15 (t, 1H, J= 2.1 Hz), 2.30 (t, J= 7.4 Hz,
2H), 1.53-1.46 (m, 2H), 1.30-1.25 (m, 20H), 0.87 (t, 3H, J= 7.2 Hz).
l3C NMR (100 MHz, CDCI3) 8: 156.4 (2C), 147.2, 108.6 (2C),
Preparation ofl: General procedure
The alkyltriphenylphosphonium
carbonate (20 mmol), DMSO (10 mL) containing water (0.5 mL),
and 3,5-bis(benzyloxy)benzaldehyde (15 mmol) were successively
introduced into a 100 mL reaction vessel. The mixture was irradiated
in a water bath of the ultrasonic cleaner at 90-100 °C for I h, then
bromide (15 mmol), potassium

JOURNAL OF CHEMICAL RESEARCH 2009
185
100.2,35.8,31.9,31.0,29.7-29.0
(8C), 22.7, 14.1. Anal. Calcd for
We are pleased to acknowledge the financial support from
Cl9H3P2 C, 78.03; H, 11.03. Found: C, 78.00; H, 11.01%.
Xinxiang Medical College (No. 04GXLP05).
Adipostatin A (Ie): Colourless solid, m.p. 88-89°C (lit.4, m.p. 91-
92°C). IHNMR(400 MHz, DMSO-d6) 8: 9.02 (brs, exch. DP, 2H),
6.05 (d, 2H, J= 2.0 Hz), 6.00 (t, lH, J= 2.0 Hz), 2.35 (t, J= 7.4 Hz,
2H), 1.60-1.55 (m, 2H), 1.25-1.20 (m, 24H), 0.87 (t, 3H, J= 7.2 Hz).
l3C NMR (l00 MHz, CDC13) 8: 156.8 (2C), 146.8, 108.1 (2C),
Received 12 October 2008; accepted 27 January 2009
Paper 08/0220 doi: 10.3184/030823409X417306
Published online: 6 April 2009
100.7,35.6,31.9,31.0,29.7-29.0
(l0C), 22.7, 14.1. Anal. Calcd for
C21H3602 C, 78.69; H, 11.32. Found: C, 78.56; H, 11.35%.
References
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m.p. 92-93°C). IH NMR (400 MHz, DMSO-d6,) 8: 8.97 (brs, exch.
DP, 2H), 6.14 (d, 2H, J= 2.2 Hz), 6.09 (t, lH, J= 2.2 Hz), 2.45 (t,
J = 7.5 Hz, 2H), 1.55-1.50 (m, 2H), 1.30-1.20 (m, 28H), 0.88 (t, 3H,
J= 7.0 Hz). 13CNMR (100 MHz, CDCl3) 8: 156.7 (2C), 146.2, 107.9
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130.9, 130.6, 107.3 (2C), 104.1, 36.2, 32.1, 31.1, 29.9-29.0 (4C),
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= 2.2 Hz), 6.28 (t,
lH, J = 2.2 Hz), 5.80 (brs, exch. D20, 2H), 5.45 (t, 2H, J = 4.7 Hz),
2.58-2.51 (m, 2H), 2.05-1.98 (m, 4H), 1.52-1.20 (m, 18H), 0.90 (t,
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