Deprotection of durable benzenesulfonyl protection for phenols — efficient synthesis of polyphenols

Article abstract of DOI:10.1080/00397911.2017.1393088

A robust protection method for phenol was demonstrated by the use of durable benzenesulfonyl group, which survives various harsh reaction conditions using Grignard reagent, organolithium reagent, metal alkoxide, phosgene, mineral, and Lewis acids. A facile deprotection condition utilizing pulverized KOH (5 equiv) and t-BuOH (10 equiv) in hot toluene makes this protocol as a practical method, which can be applied to the multistep synthesis of biologically and medicinally important polyphenol compounds.

Full text of DOI:10.1080/00397911.2017.1393088

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An International Journal for Rapid Communication of Synthetic Organic
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Deprotection of durable benzenesulfonyl
protection for phenols — efficient synthesis of
polyphenols
Mohammad Shariful Alam & Sangho Koo
To cite this article: Mohammad Shariful Alam & Sangho Koo (2018) Deprotection of durable
benzenesulfonyl protection for phenols — efficient synthesis of polyphenols, Synthetic
Communications, 48:3, 247-254, DOI: 10.1080/00397911.2017.1393088
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 3, 247–254
https://doi.org/10.1080/00397911.2017.1393088
Deprotection of durable benzenesulfonyl protection
for phenols — efficient synthesis of polyphenols
Mohammad Shariful Alama and Sangho Kooa,b
b
aDepartment of Energy Science and Technology, Myongji University, Yongin, Korea; Department of Chemistry,
Myongji University, Yongin, Korea
ABSTRACT
ARTICLE HISTORY
Received 10 September 2017
A robust protection method for phenol was demonstrated by the use
of durable benzenesulfonyl group, which survives various harsh
reaction conditions using Grignard reagent, organolithium reagent,
KEYWORDS
Benzenesulfonyl group;
deprotection; phenols;
polyphenols; protecting
group
metal alkoxide, phosgene, mineral, and Lewis acids.
A facile
deprotection condition utilizing pulverized KOH (5 equiv) and t-BuOH
(10 equiv) in hot toluene makes this protocol as a practical method,
which can be applied to the multistep synthesis of biologically and
medicinally important polyphenol compounds.
GRAPHICAL ABSTRACT
Introduction
Selection of an appropriate protecting group is essential in organic synthesis, and some-
times a key to success for total syntheses of biologically active, highly functionalized natural
products. The essential elements for successful protecting groups are easy installation and
efficient deprotection, not to mention of durability during chemical transformations.
Alcohol is an important functional group, which often requires protection under basic
and nucleophilic conditions. Etheral protections are widely used due to their stability under
basic conditions.[1,2] On the other hand, the fact that etheral groups are unstable under
acidic conditions can be utilized in designing deprotection methods. It would be often
desirable to select a universal protecting group for alcohols, which survives under both
acidic and basic conditions, especially for multistep syntheses.
Polyphenols such as quercetin, catechin, hesperetin, cyanidin, daidzein, caffeic acid, and
ferulic acid are important antioxidants, which are known to exhibit preventive effects on
CONTACT Sangho Koo
sangkoo@mju.ac.kr
Department of Energy Science and Technology; Department of
Chemistry, Myongji University, Myongji-Ro 116, Cheoin-Gu Yongin, Gyeonggi-Do, 17058, Korea.
Supplemental data (Full experimental detail, 1H and 13C NMR spectra for the synthesis of 7) can be accessed on the
publisher’s website.
© 2017 Taylor & Francis

248
M.S. ALAM AND S. KOO
Figure 1. Sulfonate protecting groups for amines and phenols.
cardiovascular diseases, cancers, diabetes, and so on.[3,4] The polyphenol natural products
require multistep syntheses consisting protection/deprotection for the phenolic groups.
Phenol is more troublesome in the selection of proper protecting groups due to the more
acidic nature of phenolic hydrogen. Resonance stabilization of phenoxide ions through the
benzene ring makes them good leaving groups. It is, thus, necessary to use a durable
protecting group for phenols in multistep syntheses, which survives various harsh reaction
conditions using the Grignard reagent, alkyl lithium, metal alkoxide, phosgene, mineral,
and Lewis acids.
A benzenesulfonyl group as stabilized ester seems to be an excellent candidate to fulfill
the requirement for durability under various conditions. It is also imperative to remove the
protecting group in a selective and timely manner while not affecting the other functional
groups in the molecules. Several selective deprotection methods of the benzenesulfonyl
group for amino compounds have been reported using Cs2CO3 in THF/EtOH,[5] SmI2/
amine/water,[6] and electrochemical reduction.[7] Activated benzenesulfonyl groups with
2-formyl-,[8] 4-methyl, 4-nitro-, and pentafluoro-substitutions,[9] and the modified sulfonyl
groups such as methanesulfonyl, trifluoromethanesulfonyl,[10] and benzylsulfonyl
groups[11] have been used for phenol protection to facilitate selective removal of the
sulfonate esters (Fig. 1).
There are, however, only a few examples demonstrating the efficacy of the more durable
benzenesulfonyl protecting group for phenols presumably because of the difficulty in
selective deprotection.[12,13] In the course of our research directed towards the synthesis
of carotenoids containing phenolic substituents for improved antioxidant activity, we
found an efficient deprotection condition of the parent benzenesulfonyl group for phenols
by utilizing pulverized KOH and t-BuOH in toluene. We herein report the scope of the
deprotection method and demonstrate an efficient synthetic application to biologically
and medicinally important all-trans-1,6-di(40-hydroyphenyl)-hexa-1,3,5-triene.[14–16]
Discussion
Deprotection of the benzenesulfonyl group for phenols requires cleavage of S-O bond in
sulfonate esters.[17,18]A couple of conditions were reported in the literature studies, which
utilized either aqueous KOH in refluxing MeOH[12] or n-PrSLi in HMPA at 180 °C.[13]
Instead of utilizing unusual nucleophile (n-PrSLi) under a very harsh condition,[13] the con-
dition using KOH would be preferable as long as homogeneity of the reaction system is
guaranteed.[19] The mechanistic study using aqueous KOH at 50 °C revealed that hydrolysis
of benzenesulfonate ester followed either concerted or stepwise addition/elimination

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process depending on the acidity of phenols.[20] Regardless of the mechanism, it was
conceived that the effective nucleophilicity of KOH, which is supported by homogeneity
of the reaction system, is a key factor to produce high yield of deprotection. We, thus,
carefully studied the deprotection conditions of phenyl benzenesulfonate (2a) using KOH
in various combinations of reaction solvents (Table 1).
Aqueous KOH in MeOH at 70 °C produced 78% yield of phenol (1a) (entry 1).[12] KOH
in MeOH or EtOH gave slightly improved yields of 81 ∼ 83% (entries 2–3). t-BuOH
becomes sticky liquid when it melts and makes a homogeneous solution with toluene,
which would provide enough thermal energy for the hydrolysis at its boiling point as well
as solubility to sulfonate esters. It was anticipated that KOH and t-BuOH together with
toluene would make an excellent deprotection condition as a homogeneous medium for
benzenesulfonate esters. Optimization studies (entries 4–8) showed that at least 5 equiv.
of KOH and 10 equiv. of t-BuOH in toluene was required for one equiv. of the sulfonate
ester, in which almost quantitative yield (98%) of phenol was obtained at 100 °C for 30 min
(entry 5). Other lower boiling solvents such as CH2Cl2 and EtOAc were not effective to
generate enough thermal energy for the cleavage of S–O bond (entries 9–10). There
was no additional effect of toluene when MeOH or EtOH was used as a solvent (entries
11–12). On the other hand, the yield was decreased when toluene was absent in the
optimized condition (entry 13). It was also noteworthy that t-BuOK would be the nucleo-
phile for the cleavage of sulfonate ester (entries 14–15), but the deprotection yield was not
as good as the optimized case, in which KOH might act as the major nucleophile.
The scope of the above deprotection condition was investigated for various benzenesul-
fonate esters, prepared from diverse phenols of different electronic and steric natures
(Table 2). Benzenesulfonate esters 2 were prepared by the reaction of benzenesulfonyl chlor-
ide and Et3N in CH2Cl2 from phenols 1 with ortho-, meta-, and para-substituents of methyl,
Table 1. Deprotection conditions of phenyl benzenesulfonate (2) utilizing KOH as a nucleophile.a
Entry
KOH (equiv)
Solvent-1 (equiv)
Solvent-2
T (°C)
t (h)
Yield (%)
1b
2
5
H2O
MeOH
70
70
80
0.5
0.5
0.5
1
0.5
1
1
0.5
1
2
0.5
0.5
0.5
0.5
0.5
78
83
81
95
98
74
60
61
0
5
none
MeOH
3
5
none
EtOH
4
5
t-BuOH (10)
t-BuOH (10)
t-BuOH (10)
t-BuOH (10)
t-BuOH (5)
t-BuOH (10)
t-BuOH (10)
EtOH (10)
MeOH (10)
t-BuOH (10)
none
toluene
toluene
toluene
toluene
toluene
CH2Cl2
EtOAc
100
100
100
100
100
45
5
5
6
3
7
2
8
5
9
5
10
11
12
13
14
15
5
77
0
5
toluene
toluene
none
toluene
toluene
100
100
80
81
74
62
66
70
5
5
t-BuOK, 5
t-BuOK, 5
100
100
t-BuOH (10)
aPhenyl benzenesulfonate (2) (1.0 g, 4.6 mmol) was treated with KOH (equiv.), Solvent-1 (equiv.), and Solvent-2 (23 mL). The
reaction mixture was heated at the designated temperature for the designated time.
b4 mL of H2O was used in CH3OH (20 mL).

250

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Scheme 1. Application of the benzenesulfonyl protection to the Synthesis of 1,6-di(40-hydroyphenyl)-
hexa-1,3,5-triene (7).
methoxy, bromo, formyl, acetyl, and nitro groups.[21] Excellent preparation yields were
obtained for benzenesulfonate esters except for ortho-acetyl phenol 1n (45% yield).
There seems to be a good agreement of the yield of deprotection with the mechanistic
pathway of the reaction. It was reported that the reaction proceeded via stepwise mech-
anism for the sulfonate ester with a poor leaving group; on the other hand, it occurred
via concerted mechanism for a good leaving group.[20] Phenols of the poor leaving group
(pKLG > 8) include those with methyl, methoxy, and bromo-substituents (left section in
Table 2). The deprotection yields ranged from 70% to high 80 s except for the case of
ortho-bromo substituent 2h (96% yield). Phenols with formyl, acetyl, and nitro-
substituents are considered to be a good leaving group (pKLG < 8), and decent yields (high
80’s up to 100%) were obtained for deprotection (right section in Table 2) except for the
case of ortho-formyl substituent 2k (57% yield). It is very interesting to note the opposing
neighboring group effects that ortho-bromine gives a high yield of deprotection product by
facilitating the cleavage of S-O bond, but ortho-formyl group provides a low yield of
phenol, presumably by undergoing side reactions.
The utility of the above protection/deprotection protocol for phenol was demonstrated
for the synthesis of all-trans-1,6-di(40-hydroyphenyl)-hexa-1,3,5-triene (7), which was
reported to exhibit anti-oxidant and cancer-preventive effects[14] as well as biological roles
as a tyrosinase inhibitor[15] and a probe for alpha-amyloid plagues.[16] The synthesis com-
menced from 4-hydroxylbenzaldehyde (1m) by the protection with benzenesulfonyl group
to give 2m (93% yield), which was stable enough to produce a quantitative yield of vinyl
carbinol 3 under the condition using strongly nucleophilic vinyl Grignard reagent
(Scheme 1). The protection also survived under strongly acidic condition of PBr3 to afford
allylic bromide 4 (84% yield), in which hydrobromic and phosphoric acids were generated
during the work-up process. The allylic bromide 4 was smoothly converted into the corre-
sponding allylic sulfone 5 (93% yield), and they were coupled at − 78 °C by the action of
strongly basic n-BuLi to produce the coupling product 6 in 95% yield.
It was envisioned that the final two steps of base-promoted elimination and hydrolysis
(deprotection) of benzenesulfonyl groups can be carried out in one-pot using the above

252
M.S. ALAM AND S. KOO
optimized deprotection condition. In fact, desulfonylations by KOH (10 equiv)
proceeded in t-BuOH (20 equiv) and toluene at 80 °C for 30 min to give rise to the desired
1,6-di(40-hydroyphenyl)-hexa-1,3,5-triene (7) in 65% yield, in which EtOH (20 equiv.) was
also added to facilitate the base-promoted elimination process.
In summary, an efficient deprotection of the durable benzenesulfonyl group for phenols
was demonstrated utilizing pulverized KOH (5 equiv) in t-BuOH (10 equiv) and toluene at
80 ∼ 100 °C. The benzenesulfonyl protection is stable enough to survive through various
chemical transformations under harsh conditions, which offers a new entry for the efficient
syntheses of biologically and medicinally important polyphenol compounds.
Experimental section
General procedure for the preparation of aryl benzenesulfonates
To a stirred solution of phenol (1a) (5.00 g, 53.1 mmol) in CH2Cl2 (100 mL) at 0 °C,
benzenesulfonyl chloride (8.21 mL, 63.8 mmol) and Et3N (8.83 mL, 63.8 mmol) were
added. The reaction mixture was warmed to room temperature and stirred for 6 h. The
mixture was quenched with 1 M HCl solution, extracted with CH2Cl2, dried over Na2SO4,
and concentrated under reduced pressure. The crude product was purified by SiO2 flash
column chromatography (hexane:EtOAc ¼ 9:1 � 3:1) to give phenyl benzenesulfonate 2a
1
(12.1 g, 51.7 mmol) in 97% yield as colorless viscous liquid. Data[20]: H NMR (CDCl3,
400 MHz) δ ¼ 7.82 (d, J ¼ 7.2 Hz, 2H), 7.66 (t, J ¼ 6.4 Hz, 1H), 7.51 (t, J ¼ 7.6 Hz, 2H),
7.30–7.22 (m, 3H), 6.96 (d, J ¼ 7.6 Hz, 2H) ppm.
General procedure for deprotection of aryl benzenesulfonate
To a stirred solution of phenyl benzenesulfonate 2a (5.00 g, 21.4 mmol) in toluene (80 mL),
KOH (5.99 g, 0.107 mol) and t-BuOH (15.8 g, 0.204 mol) were added. The mixture was
heated at 100 °C for 30 min and cooled to room temperature. Most of solvent was removed
under reduced pressure. The residue was treated with 1 M HCl solution, extracted with
EtOAc (50 mL � 4), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was pure enough to give phenol (1a) (1.97 g,
20.9 mmol) as colorless crystal in 98% yield.
4-formylphenyl benzenesulfonate (2m)
Following the general procedure for protection, 2m was obtained in 93% yield as white
solid (Rf ¼ 0.25, 4:1 hexane/EtOAc). Data: 1H NMR (CDCl3, 400 MHz) δ ¼ 7.82–7.88
(m, 4H), 7.68–7.73 (m, 1H), 7.53–7.59 (m, 2H), 7.16–7.20 (m, 2H) ppm; 13C NMR (CDCl3,
100 MHz) δ ¼ 190.6, 153.7, 135.0, 134.9, 134.6, 131.3, 129.3, 128.4, 123.0 ppm; HRMS (EI):
m/z [262.03] calcd for C13H10O4S 262.0300, found 262.0300.
4,40-((1E,3E,5E)-hexa-1,3,5-triene-1,6-diyl)diphenol (7)
To a stirred solution of the coupling product 6 (1.00 g, 1.45 mmol) in toluene (20 mL),
t-BuOH (2.14 g, 29.0 mmol), KOH (0.81 g, 14.5 mmol), and EtOH (1.33 g, 29.0 mmol) were
added as the general deprotection procedure. The mixture was then heated at 80 °C for
30 min, and cooled to room temperature. Most of solvent was removed under reduced
pressure. The residue was dissolved in EtOAc and washed with 1 M HCl solution. The

SYNTHETIC COMMUNICATIONS®
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aqueous layer was extracted with EtOAc (50 mL � 4). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography (Rf ¼ 0.55, 1:1 hexane/
EtOAc) to afford diphenol 7 (0.25 g, 0.95 mmol) in 65% yield as a light pink solid. Data:
IR (KBr) 3362, 2922, 1603, 1510, 1446, 1249, 1170, 1148, 1092, 991, 865, 820, 745,
529 cm−1; 1H NMR (acetone-d6, 400 MHz) δ ¼ 8.35 (s, 2H), 7.14 (d, J ¼ 8.4 Hz, 4H),
6.62 (d, J ¼ 8.4 Hz, 4H), 6.58–6.66 (m, 2H), 6.36 (d, J ¼ 15.2 Hz, 2H), 6.25–6.34 (m, 2H)
ppm; 13C NMR (acetone-d6, 100 MHz) δ ¼ 158.8, 134.4, 133.5, 131.0, 129.3, 128.3, 117.2 ppm;
HRMS (EI): m/z [264.12] calcd for C18H16O2, 264.1150, found 264.1148.
Acknowledgement
This work was supported by 2017 research fund of Myongji University.
ORCID
Sangho Koo
http://orcid.org/0000-0003-4725-1117
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