Development of 3-methoxy-4-benzyloxybenzyl alcohol (MBBA) resin as polymer-supported synthesis support: Preparation and benzyl ether cleavage by DDQ oxidation

Article abstract of DOI:10.1007/s12039-010-0023-x

3-Methoxy-4-benzyloxybenzyl alcohol (MBBA) resin was synthesized by a two-step sequence under microwave irradiation involving the reaction of commercially available Merrifield resin with vanillin, followed by reduction with sodium borohydride. MBBA resin was treated with bromides in the presence of sodium hydride to afford the corresponding resin-bound benzyl ethers. Cleavage of the resin-bound benzyl ethers from the MBBA resin was carried out using 2,3-dichloro-5,6-dicyanobenzoqunone (DDQ) to give the corresponding alcohols in good yields. Moreover, the recovery, regeneration, and reuse of this polymer support could be achieved easily. MBBA resin can be developed as a kind of solid-phase synthesis bead of alcohols. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0023-x

J. Chem. Sci., Vol. 122, No. 2, March 2010, pp. 203–207. © Indian Academy of Sciences.
Development of 3-methoxy-4-benzyloxybenzyl alcohol (MBBA)
resin as polymer-supported synthesis support: Preparation and
benzyl ether cleavage by DDQ oxidation
1
QIANG HUANG *, BAO-ZHONG ZHENG and QUAN LONG
,
1
2
1
Department of Materials Science and Engineering, Yunnan University, Kunming, Yunnan 650091,
PR China
2
School of Chemical Science and Engineering, Yunnan University, Kunming, Yunnan 650091,
PR China
e-mail: huangqiang@ynu.edu.cn
MS received 17 April 2009; revised 13 September 2009; accepted 23 December 2009
Abstract. 3-Methoxy-4-benzyloxybenzyl alcohol (MBBA) resin was synthesized by a two-step se-
quence under microwave irradiation involving the reaction of commercially available Merrifield resin
with vanillin, followed by reduction with sodium borohydride. MBBA resin was treated with bromides in
the presence of sodium hydride to afford the corresponding resin-bound benzyl ethers. Cleavage of the
resin-bound benzyl ethers from the MBBA resin was carried out using 2,3-dichloro-5,6-dicyano-
benzoqunone (DDQ) to give the corresponding alcohols in good yields. Moreover, the recovery, regen-
eration, and reuse of this polymer support could be achieved easily. MBBA resin can be developed as a
kind of solid-phase synthesis bead of alcohols.
Keywords. Solid-phase organic synthesis; polymer support; linker; 3-methoxy-4-benzyloxybenzyl
alcohol resin; DDQ oxidation; recycling.
1
. Introduction
the synthesis, so that the target molecule can be re-
3b,3d
leased from the resin into solution.
On the other hand, 4-methoxybenzyl (MPM) and
Solid-phase organic synthesis (SPOS) continues to
be important in the development of libraries of new 3,4-dimethoxybenzyl (DMPM) protecting groups are
molecules since it offers advantages such as the ease widely applied in solution phase synthesis for their
1
of reaction work-up and automation. The success of benzyl formations readily removed by 2,3-dichloro-
a SPOS strategy depends on the properties of the 5,6-dicyano-benzoqunone (DDQ) oxidation under
2
4
solid supports in many critical ways. The solid sup- mild and neutral conditions. Thus, one of the pre-
ports used most widely in SPOS are Merrifield resin sent authors (Zheng et al) used them skillfully for
5
and their derivatives with various linkers which are the synthesis of the complex natural products.
the structural bridges between the polymer frame- Resin-bound MPM protecting groups, whose p-
work and a substrate. Most linkers for solid-phase alkoxylbenzyl system could be selectively cleaved
chemistry are derived from known protecting by DDQ oxidation for the release of target mole-
groups, and hereby they have been described as the cules, have been applied for SPOS of alcohols and
6
immobilized protecting groups since many of them amines. However, DMPM group, a more sensitive
4b
group than MPM group for DDQ removing, has
not been developed for any SPOS strategies in our
knowledge. In this work, we prepared a novel 3-
methoxy-4-benzoxybenzyl alcohol (MBBA) resin,
and it was reacted with various bromides to form the
benzyl ether systems which contain the resin-bound
DMPM group. The benzyl ether systems cleaved by
DDQ oxidation were studied for the potential appli-
cation of SPOS for alcohols.
bear some similarities to protecting groups in solu-
3
tion phase synthesis. For example, they are required
to be stable to the reaction conditions when used
during the elaboration of the target molecule, and be
cleaved selectively and orthogonally at the end of
*
For correspondence
2
03

2
2
2
04
Qiang Huang et al
. Experimental
.1 Genneral
(1) was determined by N elemental analysis involv-
ing DNP derivative reaction. Resin (1) (20 mg) was
placed in a tube and swelled in DMF (3 mL) for
5 min. DNP (3 equiv.) and a catalytic amount of
1
Merrifield resin (200–400 mesh, 1% DVB cross-
linked, 1⋅24 mmolCl/g) was obtained from Tianjin
Nankai Hecheng Technological Com. Ltd., China,
and was extracted by EtOH before it was used. Va-
nillin, DDQ, 4-nitrobenzyl bromide, 4-cyanobenzyl
bromide, 3-bromoethyl cyanide, and N,N-diethyl-2-
bromo-acetamide were purchased from Merck,
Germany. Other chemicals were obtained locally.
THF and DCM were distilled before using. Micro-
wave reactions were conducted using a CEM Dis-
cover Synthesis Unit. Reactions were performed in
glass vessels. DDQ oxidation cleavages were per-
formed using KEM-6 Parallel Synthesizer. Elemen-
tal analysis was carried out by GmbH Vario EL.
Agilent 1100 was used for HPLC. FT-IR spectra
acetic acid were added to the tube, then it was sealed
and placed in an oscillator for 30 min at room tem-
perature. The mixture was filtered, washed and dried
–1
under vacuum. Theoretical loading = 1⋅087 mmol g .
Found: C, 78⋅59; H, 6⋅35; N, 6⋅06.
2
.2b MBBA resin (2): Resin (1) (992 mg,
–
1
1
⋅081 mmol g , 1⋅074 mmol) was placed in a reac-
tion vessel and allowed to swell in THF (5 mL) for
0min under N . NaBH
(150 mg, 3⋅97 mmol) and
TBAI (75 mg, 0⋅203 mmol) were dissolved in mixed
solvent containing THF (10 mL) and H O (2 mL)
and the mixture was injected. The contents were
stirred and heated in the microwave at reflux for
0 min. The resultant solid was filtered, washed
with ethyl acetate (20 mL), water (3 × 10 mL), ace-
tone (2 × 10 mL), CH Cl (2 × 20 mL) and ether
2 × 10 mL). The resin was dried at 50°C for one
3
2
4
2
1
(
KBr tableting) were recorded on Thermo Nicolet
1
TFIR AVATAR 360. H-NMR spectra were recor-
ded using Bruker AVANCE DRX500 spectrometer
with special high resolution magic angle spinning
2
2
(
–
1
hour to give white beads. IR (KBr): 3108, 3312 cm .
1
(
HR-MAS) probe and the resin was placed in a
mm rotor. Chemical shifts were recorded in parts
H-NMR (500 MHz, CDCl
br s, PS), 6⋅60 (3H br s, H-Ar), 4⋅92 (2H br s,
CH O), 2⋅05 (1H, s OH),
O), 3⋅82 (3H, br s, CH
⋅69 (br s, PS), 1⋅33 (br s, PS). The loading of resin
2) was determined by N elemental analysis involv-
3
): δ 7⋅13 (br s, PS), 7⋅01
4
(
per million (δ: ppm) referenced to TMS (δ: 0) as an
internal standard. Coupling constants (J) are given
in Hertz (Hz).
2
3
1
(
ing 4-nitrobenzoyl chloride derivative reaction.
Resin (2) (20 mg) was placed in a tube and swelled
in DMF (2 mL) for 15 min. 4-Nitrobenzoyl chloride
2
2
.2 Syntheses and characterization
(
3 equiv.), a catalytic amount of 4-dimethylamino
.2a 3-methoxy-4-benzoxylbenzyl aldehyde resin
–
1
pyridine (DMAP) and pyridine were added to the
tube, then it was sealed and placed in an oscillator
for 30 min at room temperature. The mixture was
filtered, washed and dried under vacuum. Theoreti-
(
1): Merrifield resin (1 g, 1⋅24 mmol g , 1⋅24
mmol) was placed in a reaction vessel and allowed
to swell in DMF (5 mL) for 30 min under N . Vanil-
lin (300 mg, 1⋅972 mmol), CO (400 mg,
⋅894 mmol), and tetrabutyl ammonium iodide
TBAI, 54 mg, 0⋅146 mmol) were dissolved in DMF
15 mL) and added via syringe to the reaction ves-
2
K
2
3
–1
cal loading = 1⋅086 mmol g . Found: C, 80⋅13; H,
⋅35; N, 1⋅49.
2
8
(
(
sel. The mixture was stirred and heated in the mi- 2.3 General procedure for the preparetion of
crowave at 120°C for 5 min. After cooling to room the resins (3a–d)
temperature, the beads were transferred to a sintered
–
1
tube and washed successively with acetone–CH
O (1 : 1 : 1) (10 mL × 5), acetone (10 mL × 3), was added NaH (15⋅4 mg, 0⋅642 mmol) under N
THF (10 mL × 3), CH OH (10 mL × 3), then dried atmosphere. One of the bromides (4⋅0 equiv.) in dry
under vacuum at 50°C for one hour to give some- DMF (5 mL) was injected. The contents were
3
OH– To resin (2) (200 mg, 1⋅064 mmol g , 0⋅210 mmol)
H
2
2
3
–
1
what yellow beads. IR (KBr): 1688 cm (C=O), shaken for 6 h at 60°C. The resultant solid was fil-
–
1
1
2
760 cm (O=C–H). H-NMR (500 MHz, CDCl
⋅78 (1H, s, CHO), 7⋅30 (2H, br s, H-Ar), 6⋅98 (br s, (2 × 5 mL), H
PS), 5⋅11 (2H, br s, CH O), 3⋅70 (3H, br s, CH O), CH Cl (2 × 5 mL) and ether (2 × 5 mL). The resins
⋅73 (br s, PS), 1⋅38 (br s, PS). The loading of resin were dried in vacuum to corresponding resin-bound
3
): δ tered, washed with H
2
O (2 × 5 mL), 3% acetic acid
9
2
O (2 × 5 mL), acetone (2 × 5 mL),
2
3
2
2
1

Development of 3-methoxy-4-benzyloxybenzyl alcohol resin as polymer-supported synthesis support
205
Scheme 1. The synthetic process of MBBA resin.
1
benzyl ethers. Theoretical loading: (3a), 0⋅930 nance at 9⋅78 ppm in the H MAS-NMR spectrum.
–
1
–1
mmol g ; (3b), 0⋅948 mmol g ; (3c), 1⋅007 Loading of the aldehyde group was determined by
–
1
–1
mmol g ; (3d), 0⋅950 mmol g . Found: (3a), C, nitrogen analysis involving 2,4-dinitrophenyl hydra-
7
1
1
6⋅52, H, 8⋅13, N, 1⋅28; (3b), C, 81⋅90, H, 8⋅46, N, zine (DNP) derivative, to be 1⋅081 mmol/g, corre-
⋅30; (3c), C, 78⋅93, H, 9⋅55, N, 1⋅36; (3d), 79⋅11, sponding to 99% yield. Next, reduction of the resin
0⋅10, N, 1⋅24.
(1) with NaBH
transfer catalytic condition in mixed solvent
THF/H O at reflux temperature for 10 min afforded
4
under microwave-assisted phase
2
2
.4 General procedure for the DDQ cleavage
the MBBA resin (2) according to our work reported
of resin-bound benzyl ethers
8
recently. The monitoring of reaction was performed
by the FTIR spectrum resorting the disappearance of
benzaldehyde group stretching frequency and the
appearance of OH vibrational frequency and by
To resin-bound benzyl ethers (3a–d, 200 mg) was
respectively added DDQ (1⋅2 equiv.) in CH
O (10 : 1, 5 mL). The contents were shaken for
0 min at room temperature. The solid was filtered,
washing with CH Cl –H
O (10 : 1, 2 × 5 mL). The
combined filtrate was analysed by HPLC.
2 2
Cl –
H
2
1
the H MAS-NMR spectrum with the help of the
3
disappearance of aldehydic resonance at 9⋅78 ppm.
The OH loading of resin (2) was determined to be
2
2
2
1
4
9
⋅064 mmol/g by nitrogen analysis involving
-nitrobenzoyl chloride derivative, corresponding to
8% yield.
3
. Results and discussion
The syntheses of 4-benzoxylbenzyl alcohol resins
9
3
.1 Synthesis of MBBA resin
have been reported earlier. The methoxide-
catalysed displacement of benzyl chlorine of Merri-
MBBA resin was prepared by a two-step sequence field resin by 4-hydroxybenzyl alcohol (Wang
9a
under microwave irradiation involving the reaction resin) or 2-methoxy-4-hydroxybenzyl alcohol (Sasrin
9
b
of commercially available Merrifield resin with va- resin) was performed. Accordingly, MBBA resin
nillin, followed by reduction with sodium boro- would be synthesized by the reaction of chloro-
hydride as shown in scheme 1. In the first step, methyl resin with 3-methoxy-4-hydroxybenzyl alco-
Merrifield resin was reacted with vanillin in the hol (vanillic alcohol) under the similar condition.
presence of non-nucleophilic base K
lytic amount of TBAI as phase transfer catalyst, and be attained when we prepared the MBBA resin by
DMF as solvent under microwave irradiation at the reaction of commercially available Merrifield
20°C only for 5 min as described in our previous resin with vanillic alcohol under methoxide-
2 3
CO , a cata- However, we found that the target resin could hardly
1
7
work. 3-Methoxy-4-benzoxyl benzaldehyde resin catalysed condition. It was likely to be the instability
(
1) was simply obtained by filtration of the reaction and polymerization of p-hydroxy-benzyl alcohols in
10
mixture and washing the resultant solid by various base. Furthermore, the electronic effects of the 3-
solvents. The formation of resin (1) was monitored methoxy group of vanillic alcohol may deleteriously
–1
by the appearance of C=O (1688 cm ) and O=C–H facilitate the polymerization in alkali medium com-
–
1
(
2760 cm ) stretching frequency of polymer- pared with the species without methoxy group.
supported benzaldehyde group in FTIR analysis, fur- Since the direct loading of vanillic alcohol to poly-
ther verified by the characteristic aldehydic reso- mer support was unsuccessful, a relatively indirect

2
06
Qiang Huang et al
method involving functional group transformation accelerate the processing and greatly decreased the
would be taken into account. Resin (1) could be reaction time.
readily prepared by the phase transfer catalysed re-
action of Merrifield resin with vanillin in good
3
.2 Cleavage of resin-bound benzyl ethers
1
1
yield. Vanillin being different from vanillic alco-
hol, the electronic effects of vanillin’s o-methoxy
group may significantly enhance the nucleophilicity
of the phenolic OH because of the existence of for-
myl group, and can promote the formation of corre-
Various bromides containing nitrogen, including 4-
nitrobenzyl bromide, p-cyanobenzyl bromide, 3-
bromoethyl cyanide, or N,N-diethyl-2-bromo-
acetamide, was respectively reacted with resin (2) in
the presence of NaH so as to provide the corre-
sponding polymer-supported benzyl ethers (3a–d).
The separation and purification of polymer-
supported benzyl ethers were simply treated by fil-
tration and washing. The loading rates of various
solid-supported benzyl ethers were determined by
elemental analysis. The results presented in table 1.
As can be seen, the loading rates of various benzyl
ethers exceed 90%, and the good loadings were ob-
tained.
1
1a
sponding benzaldehyde resins. Then, reduction of
solid-supported aldehyde to corresponding benzyl
alcohol could obtain the MBBA resin (1). Though a
tow-step sequence was involved in current process,
the microwave irradiation assisted method could
Table 1. Etherization of (2) with bromated species
Then, the resin-bound 3-methoxy-4-benzoxyl-
benzyl ether systems were cleaved with DDQ (1⋅2
equiv.) oxidation in dichloromethane containing a
small amount of water at room temperature for a
quite short time to lead to formation of the corre-
sponding alcohols (4a–d) in high yield (table 2).
Comparison with the previous report of Deegan and
Reaction
time/h
Yield
(%)
Entry
RBr
1
6
6
98
98
2
3
4
5
6
6a
his coworkers, the benzyl ether system of MBBA
a
98
b
resin cleaved by DDQ exhibited similar yields
though the AgroGel-Wang derived ether resins have
a PEG chain spacer which makes its activity
97
c
95
6
12
b
97
93
1
2
higher.
7
a
With the first regenerated resin (2). With the second re- 3.3 Regeneration and recycling
c
generated resin (2). With the third regenerated resin (2)
One of the major advantages for development of the
current strategy is the potential recovery of the
polymer beads for subsequent reuse. The 3-
methoxy-4-benzoxyl benzaldehyde resin (1) could
be recovered quantitatively by simple filtration and
washing with organic solvents after DDQ cleavage
Table 2. Cleavage of the resin-bound benzyl ethers.
1
was performed. Transmittance FTIR and H-NMR
a
Reaction
time/min.
Yield
(%)
spectra of the recovered polymer beads showed the
restoration of the aldehyde functional group, with a
loading similar to the original value. Next, the
MBBA resin (2) could be regenerated by reduction
Entry
ROH
1
2
30
30
98
99
4
with NaBH . The process of the regeneration and re-
cycling for the polymer beads was schematically
presented in figure 1. The OH loading of the first,
second, and third-hand resin 2 was hardly decreased
to compare that of the freshly resin, and the recov-
ered resin could be reused for the same reactions
3
4
60
45
91
94
a
Yield according to HPLC data, product was not isolated

Development of 3-methoxy-4-benzyloxybenzyl alcohol resin as polymer-supported synthesis support
207
Figure 1. Repeated use of the polymer beads.
2
002 J. Comb. Chem. 4 1; (c) Huang Q, Long Q and
Zheng B-Z 2004 Prog. Chem. 16 236; (d) James I W
999 Tetrahedron 55 4855; (d) Brown A R,
without loss of chemical yield of the resin-bound
etherification products (table 1, Entry 3–5).
1
Hermkens P H H, Ottenheijm H C J and Rees D C
1998 Synlett 817
4
. Conclusion
4
. (a) Oikawa Y, Yoshioka T and Yonemistu O 1982
Tetrahedron Lett. 23 885; (b) Horyta K, Yoshioka T,
Tanaka T, Oikawa Y and Yonemistu O 1986 Tetra-
hedron. 42 3021
In summary, a simple and efficient two-step sequence
synthesis of a novel 3-methoxy-4-benzoxylbenzyl
alcohol (MBBA) resin involving linking vanillin to
5
. (a) Zheng B-Z, Yamauchi M, Dei H, Kusaka S, Ma-
tsui K and Yonemitsu O 2000 Tetrahedron Lett. 41
4
Merrifield resin, followed by reduction with NaBH ,
and effective DDQ cleavage of solid-supported benzyl
ethers were successfully carried out to obtain alcohol
products. Moreover, recovery, regeneration, and reuse
of the resin were achieved. In short, MBBA resin can
be developed as a kind of solid-phase synthesis beads
of alcohols and others, and the polymer beads can be
duty-cycle operation.
6
441; (b) Matsui K, Zheng B-Z, Kusaka S, Kuroda
M, Yoshimoto K, Yamada H and Yonemitsu O 2001
Eur. J. Org. Chem. 3615; (c) Zheng B-Z, Maeda H,
Mori M, Kusaka S, Matsushima T, Nakajima N, Uen-
ishi J and Yonemitsu O 1999 Chem. Pharm. Bull. 47
1
288; (d) Zheng B-Z, Yamauchi M, Dei H and
Yonemitsu O 2000 Chem. Pharm. Bull. 48 1761
6. (a) Deegan T L, Gooding O W, Baudart S and Porco
J A 1997 Tetrahedron Lett. 38 4973; (b) Kobayashi
S and Aoki Y 1998 Tetrahedron Lett. 39 7345; (c)
Kobayashi S and Akiyama R 1998 Tetrahedron Lett.
Acknowledgements
3
9 9211
. Huang Q, Li Z, Ma X, Long Q and Zheng B-Z 2007
Acta Polym. Sin. 7 681
8. Huang Q, Long Q and Zheng B-Z 2008 Acta Polym.
Sin. 5 487
. (a) Lu G S, Mojsov S, Tam J P and Merrifield R B
981 J. Org. Chem. 46 3433; (b) Mergler M, Tanner
R, Gosteli J and Grogg P 1988 Tetrahedron Lett. 32
005
. (a) Boldt G E, Dickerson T J and Janda K D 2006 10. Katritzky A R, Toader D, Watson K and Kiely J S
Drug Discovery Today 11 143; (b) Diaz-Garcia M E,
1997 Tetrahedron Lett. 38 7849
Pina-Luis G and Rivero I A 2006 Trends Anal. Chem. 11. (a) Sarhan A A, El-Shehawy A A and Abdelaal M Y
We are grateful to the financial support from Na-
tional Natural Science Foundation of China (Grant
No. 20172044) and Provincial Natural Science foun-
dation of Yunnan, China (Grant No. 2005E0008Q).
7
9
1
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