A deprotection procedure using SO3H silica gel to remove non-silyl protecting groups

Article abstract of DOI:10.1080/00397911.2018.1548023

Protecting groups are indispensable in organic synthesis and there is a great need for a variety of deprotection methods. Here, we investigated the scope of the application of a deprotection procedure using SO₃H silica gel, which we have previously reported as a desilylation procedure. Under these conditions, -OMOM, -OSEM, -OTHP, and -OAc groups and dimethyl acetal were cleaved. Pivaloyloxy, benzyloxy and methoxy carbonyl groups remained intact and selective deprotection of TBS groups in the presence of other protecting groups was accomplished. We succeeded in cleaving an acetyl group on a secondary alcohol in a highly polar nortropine derivative. Our findings here provide another deprotection option and would be helpful in the synthesis of multifunctional compounds.

Full text of DOI:10.1080/00397911.2018.1548023

Synthetic Communications
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Chemistry
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A deprotection procedure using SO3H silica gel to
remove non-silyl protecting groups
Fumika Karaki, Miki Kuwada, Saki Tajiri, Misaki Kanda, Mari Yanai, Mitsuhiro
Kamimura, Kennosuke Itoh & Hideaki Fujii
To cite this article: Fumika Karaki, Miki Kuwada, Saki Tajiri, Misaki Kanda, Mari Yanai, Mitsuhiro
Kamimura, Kennosuke Itoh & Hideaki Fujii (2019) A deprotection procedure using SO3H silica
gel to remove non-silyl protecting groups, Synthetic Communications, 49:2, 212-220, DOI:
10.1080/00397911.2018.1548023
To link to this article: https://doi.org/10.1080/00397911.2018.1548023
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2019, VOL. 49, NO. 2, 212–220
https://doi.org/10.1080/00397911.2018.1548023
A deprotection procedure using SO3H silica gel to remove
non-silyl protecting groups
Fumika Karakia,b , Miki Kuwadaa, Saki Tajiria, Misaki Kandaa, Mari Yanaia,
Mitsuhiro Kamimurac, Kennosuke Itoha,b , and Hideaki Fujiia,b
b
aLaboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo, Japan; Medicinal
c
Research Laboratories, School of Pharmacy, Kitasato University, Tokyo, Japan; FUJI SILYSIA CHEMICAL
LTD., Kasugai-Shi, Aichi, Japan
ABSTRACT
ARTICLE HISTORY
Received 26 September 2018
Protecting groups are indispensable in organic synthesis and there is
a great need for a variety of deprotection methods. Here, we investi-
gated the scope of the application of a deprotection procedure
using SO3H silica gel, which we have previously reported as a desily-
lation procedure. Under these conditions, -OMOM, -OSEM, -OTHP,
and -OAc groups and dimethyl acetal were cleaved. Pivaloyloxy, ben-
zyloxy and methoxy carbonyl groups remained intact and selective
deprotection of TBS groups in the presence of other protecting
groups was accomplished. We succeeded in cleaving an acetyl group
on a secondary alcohol in a highly polar nortropine derivative. Our
findings here provide another deprotection option and would be
helpful in the synthesis of multifunctional compounds.
KEYWORDS
SO3H silica gel; solid-
supported catalyst; acid-
catalyzed deprotection
GRAPHICAL ABSTRACT
Introduction
Protection and deprotection sequences are indispensable in organic synthesis, even in
the 21st century.[1,2] As the number of reactive functional groups increases in propor-
tion to the complexity of the molecules, selective protection and deprotection methods
have been adopted in synthesizing these molecules.[3–7] However, only a limited number
of methods to cleave protecting groups are available in the arsenal of the chemist:
acidic,[8,9] basic,[10,11] oxidative and reductive conditions,[12–15] nucleophilic
CONTACT Hideaki Fujii
fujiih@pharm.kitasato-u.ac.jp
Laboratory of Medicinal Chemistry, School of Pharmacy,
Kitasato University, 5–9–1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Supplemental data for this article can be accessed on the publisher's website.
ß 2019 Taylor & Francis Group, LLC

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213
substitutions,[16–18] etc. With this limited number of procedures, we must selectively
cleave the desired groups.
We have previously reported a desilylation method using SO3H silica gel, an alkylsul-
fonic acid-functionalized silica gel.[19,20] This procedure is environmentally friendly
since the SO3H silica gel could be reused for deprotection without pretreatment.
Moreover, simple filtration and elution processes were sufficient to obtain the crude
product. No aqueous workup was required. As the obtained crude products contained
no silyl residues in almost all cases, no additional purification processes were needed.
These features allowed us to reduce the usage of organic solvent and to limit the emis-
sion of polluted water. Although this method has been applied only to the cleavage of
silyl ethers thus far, it has the potential to cleave a wider variety of protecting groups by
extending the scope of application. Also, information on the tolerance of various func-
tional groups toward SO3H silica gel would be useful in achieving selective deprotection
of a desired protecting group in the construction of highly functionalized complex mol-
ecules. In this report, we explored the tolerance and lability of various protecting groups
to our deprotection procedure using SO3H silica gel.
Results and discussion
To determine the relative lability of protected alcohols and ketones to SO3H silica gel,
we treated them with the TBS-cleaving conditions in our previous report[19,20] (Tables 1
and 2). Although we identified heptane as an optimal solvent in that report, undesired
dimers contaminated the product when the procedure was applied to MOM or SEM
protected alcohols 1a and 1 b.1 To circumvent this problem, we employed another con-
dition: 50 ꢀC, 2 h in methanol. Under these conditions, production of dimer was com-
Table 1. Deprotection of protected alcohols.
Entry
Starting material
R
Yield (%)a
1
2
3
4
5c
6
7
1a
1b
1c
1d
1e
1f
MOM
SEM
THP
Bn
Tr
Ac
88
81b
93b
0
28d (21)e
93
1g
Piv
1 (51)f
aIsolated yields; bNo purification process was needed; Toluene was used as a solvent instead of methanol; d3 h; e24 h;
c
f120 ꢀC, 24 h.
1This dimer may be produced through the elimination of the protonated alkoxide moiety and the subsequent addition
of the deprotected alcohol to the resulting oxonium cation (see Scheme 1). Methanol used in these reaction was not
dehydrated grade and contained several amounts of water. It is possible that this water hydrolyzed the oxonium cation
intermediate and suppressed the formation of the dimers.

214
F. KARAKI ET AL.
Scheme 1. Proposed mechanism for the production of the dimers. R ¼ Me or CH2CH2SiMe3.
Table 2. Deprotection of protected ketones.
Entry
Starting material
R
Yield (%)a
1
2
3a
3b
Me
—(CH2)2—
92b
29 (0)c
aIsolated yields; bNo purification process was needed; 8 h. The reaction gave a complex mixture.
c
pletely suppressed in the case of SEM-protected alcohol 1 b (Table 1, entry 2). On the
other hand, the crude product was contaminated with ca. 4% of dimer in the case of
MOM ether 1a, and column chromatography was required to obtain pure alcohol 2
(Table 1, entry 1). Tetrahydropyranyl groups were cleanly cleaved in methanol and no
purification was needed in this case (Table 1, entry 3). The benzyl group, another ether
protecting group, remained completely intact (entry 4). Our attempt to test more acid-
labile trityl-protected alcohol 1e failed due to the poor solubility of the compound in
methanol. Instead, we used toluene as a solvent and treated with SO3H silica gel for 3 h,
which is another TBS-cleaving condition we have reported earlier[19] (entry 5). The
deprotected alcohol 2 was obtained in 28% yield in 3 h. However, even after 24 h, the
starting material 1e did not disappear and product yield was not improved. As the
formed trityl cation is stable, this should rebind to the hydroxy group of the product 2.
As for acyl protecting groups, while the acetyl group was deprotected cleanly (entry 6),
the more bulky pivaloyl group was almost intact under this condition (entry 7).
Although pivaloyl-protected 1 g was consumed under harsh conditions (120 ꢀC, 24 h),
the yield of 2 was not satisfactory.2 We next applied our procedure to protected ketones
(Table 2). Dimethyl acetal was deprotected efficiently to furnish the ketone 4 (entry 1).
In the case of more acid-resistant 1,3-dioxolane (entry 2), a large portion of the starting
material remained in the crude mixture. Complete consumption of 3 b was accom-
plished after 8 h, but this condition gave a complex mixture.
Next, we attempted to convert esters to carboxylic acids using SO3H silica gel.[21]
When the procedure was applied to benzyl 4-methoxyphenylacetate or tert-butyl 4-
methoxyphenylacetate, a ca. 6:4 mixture of the desired 4-methoxyphenylacetic acid and
2By adding methanol solutions of the substrates to SO3H silica gel, we obtained fluffy powder of silica gel. Then the
powder was heated at the indicated temperatures. Thus the reactions could be performed above the boiling points of
the solvents.

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SYNTHETIC COMMUNICATIONSV
215
Scheme 2. Selective deprotection of dimethyl acetal in the presence of TBS group.
undesired methyl 4-methoxyphenylacetate was furnished after consumption of the start-
ing materials. Production of methyl ester could not be suppressed even when the reac-
tion was performed in toluene (benzyl ester: 120 ꢀC, 24 h, tert-butyl ester: 50 ꢀC, 3 h)
and the crude product was eluted with 1% acetic acid in chloroform, i.e. under the con-
ditions in the absence of methanol.3 We applied this procedure to the methyl 4-methox-
yphenylacetate (methanol, 50 ꢀC, 2 h), and found that this group was almost intact
under these conditions.
With information on lability and tolerance of various functional groups to SO3H sil-
ica gel in hand, we next attempted selective deprotection of highly acid-labile protecting
groups in the presence of the TBS group. At 0 ꢀC, the TBS group remained intact for
5 min and selective conversion of dimethyl acetal to ketone was accomplished
(Scheme 2). This result encouraged us to apply the procedure to the selective deprotec-
tion of acid-cleavable alcohol protecting groups (Table 3). Unfortunately, acetyl, SEM,
and MOM groups remained unchanged under these conditions (entries 1–3). Although
the selective deprotection of the THP group in 7d partially progressed under the condi-
tion (5 min), prolonged reaction time did not give pure mono-protected alcohol 8 due
to the concomitant production of diol 9 (entry 4).
We turned our attention to the selective deprotection of TBS groups in the presence
of other protecting groups (Table 4). In the presence of pivaloyloxy, benzyloxy, and
methoxy carbonyl groups, the TBS groups were cleaved cleanly (entries 1–3).
To show the utility of our deprotection procedure in constructing multi-functional mol-
ecules, we applied this procedure to the selective deprotection of the TBS group in the
presence of N-Fmoc and methoxycarbonyl groups (Scheme 3). Tetrabutylammonium
fluoride, the gold standard to cleave silyl ethers, was not considered as an option due to
the lability of the Fmoc group.[1] Basic aqueous conditions and Lewis acid conditions were
not applicable either due to the presence of methoxycarbonyl group. By using SO3H silica
gel, the desired product 13 was obtained in excellent yield although column purification
was needed to remove the silyl residue. Contamination of the silyl residue could not be
supressed by using twice as much SO3H silica gel as the standard procedure. Although we
have reported that some amount of silyl residue remained in the crude product in the case
of the desilylation of compounds possessing basic nitrogens,[19,20] the substrate 12 has no
basic nitrogen. It is now difficult to make out the cause of this contamination.
As our deprotection procedure does not need aqueous workup, it would be applicable to
highly hydrophilic compounds. Therefore, we applied this procedure to nortropine deriva-
tive 14. The product 15 is so polar (cLogP = ꢁ1.794) that it is difficult to extract from
water. As expected, standard solvolysis and extraction from the aqueous layer using
3SO3H silica gel is produced by modifying the surface of silica gel using a trimethoxy-type silane coupling agent. The
residual methoxy group may cause the conversion.
4The cLogP value was calculated using ChemDraw Professional version 16.0.

216
F. KARAKI ET AL.
Table 3. Attempt to selective deprotection of protected alcohols in the presence of TBS group.
Entry
Starting material
R
7:8:9a
1
7a
7b
7c
7d
Ac
100:0:0
100:0:0
100:0:0
2
SEM
MOM
THP
3b
4
73:27:0
(26:42:31)c
aThe composition ratio was determined from 1H NMR of the crude products; b20 min; 2 h.
c
Table 4. Selective deprotection of TBS group in the presence of acid-resistant groups.
Entry
Starting material
R
Yield (%)a
1
2
3
10a
10b
10c
CH2OPiv
CH2OBn
CO2Me
96
98
100
aIsolated yields.
Scheme 3. Selective deprotection of TBS group in the presence of other functional groups.
Table 5. Comparison of two O-deacetylation protocols.
Condition
Yield (%)a
A
B
K2CO3, MeOH, rt, 3 h
33
75
SO3H silica gel, MeOH, 100 ꢀC, 6 h
aNo purification process was needed.

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217
dichloromethane gave only low yield of 15 (Table 5, condition A). In sharp contrast, our
deprotection procedure gave a moderate yield of 15, although rather harsh condition was
needed to deprotect the acetyl group on a secondary alcohol moiety (condition B).
Conclusions
We have explored the scope of application of a deprotection procedure using SO3H
silica gel to remove non-silyl protecting groups. Conventional protecting groups for
alcohols (MOM, SEM, THP and acetyl groups) and dimethyl acetal were cleaved
cleanly. O-Pivaloyl, O-benzyl, and methoxycarbonyl groups, on the other hand,
remained intact. Based on these findings, selective deprotection was accomplished. In
addition, the superiority of this procedure in synthesizing polar compounds was shown.
Our finding here will present SO3H silica gel as a choice in the development of syn-
thetic strategies for complex multi-functional compounds.
Experimental
General information
All reagents and solvents were obtained from commercial suppliers and were used with-
out further purification. IR spectra were recorded on a JASCO FT/IR-460Plus. NMR
1
spectra were recorded on an Agilent Technologies VXR-400NMR for H- and 13C-
NMR. Chemical shifts were reported as d values (ppm) referenced to tetramethylsilane.
MS were obtained on a JEOL JMS-100LP or JMS-AX505HA by applying an electrospray
ionization (ESI) or electron impact (EI) method. The progress of the reaction was deter-
mined on Merck Silica Gel Art. 5715 (TLC). Column chromatographies were carried
out using CHROMATOREX PSQ 60B (Fuji Silysia) or Hi-FlashTM Column M or L
R
V
(Yamazen Cooperation). SCAVENGER SO3H SILICA (Fuji Silysia), which contains
5%wt of water, was used for the deprotection reactions. The reactions were performed
under an argon atmosphere unless otherwise noted.
Deprotection protocol using SO3H silica gel
Deprotection using SO3H silica gel was conducted according to our previous reports.[19,20]
A solution of substrates with protective groups (0.4 mmol) in the indicated solvent (1 mL)
was treated with SO3H silica gel (2 g, 0.2 mmol/g). After shaking for 1 min, resulting pow-
der was left to stand at the indicated temperature. Then, the powder was put on the pad of
Celite and eluted with MeOH (30 mL). The obtained eluate was concentrated under
reduced pressure to yield the products. No purification process was required when com-
pounds 1 b, 1c, 3a, 10a–c and 14 were used as starting materials. In the case of compound
12, although 0.1 mmol/g of SO3H silica gel was used, silyl residues were not completely
trapped by silica gel and purification process was required.

218
F. KARAKI ET AL.
Characterization of deprotected products
4 -Methoxyphenethyl alcohol (2)
The spectral data for this compound coincided with those of commercially obtained one.
4 -Methoxyphenylacetone (4)
The spectral data for this compound coincided with those of commercially obtained one.
4 -Hydroxyphenethyl pivalate (11a)
The spectral data for this compound coincided with the literature.[22]
4 -(2-(Benzyloxy)ethyl)phenol (11b)
A colorless oil. 1H NMR (400 MHz, CDCl3): d 2.86 (t, J ¼ 7.2 Hz, 2H), 3.65 (t,
J ¼ 7.2 Hz, 2H), 4.52 (s, 2H), 4.63 (s, 1H), 6.74 (d, J ¼ 8.4 Hz, 2H), 7.08 (d, J ¼ 8.4 Hz,
2H), 7.21–7.44 (5 H, m). 13C NMR (100 MHz, CDCl3): d 35.3, 71.4, 72.9, 115.2, 127.6,
127.7, 128.4, 129.9, 130.6, 138.1, 154.1. HR-MS (ESI): Calcd for C15H16NaO2 [MþNa]þ:
251.1048. Found: 251.1055. IR (neat, cmꢁ1): 3348, 1613, 1515, 1453, 1230, 1075, 471.
Methyl 2-(4-hydroxyphenyl)acetate (11c)
The spectral data for this compound coincided with the literature.[23]
Methyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tyrosinate (13)
The crude product was purified with column chromatography (Hi-Flash M; n-hexane/
ethyl acetate, 62:28 to 51:49) to eliminate contaminated silyl residues. The spectral data
coincided with the literature.[24]
1 -((1R,3r,5S)-3-Hydroxy-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one (15)
1
A colorless solid. Mp 115.0–117.6 ꢀC. H NMR (400 MHz, CDCl3): d 1.74–1.81 (m, 1H),
1.83–1.94 (m, 2H), 1.94–2.04 (m. 2H), 2.05 (s, 3H), 2.10–2.35 (m, 4H), 4.07–4.12 (m,
1H), 4.12–4.17 (m, 1H), 4.61–4.66 (m, 1H). 13C NMR (100 MHz, CDCl3): d 21.4, 27.2,
28.8, 38.6, 39.9, 50.6, 54.7, 64.8, 166.0. HR-MS (ESI): Calcd for C9H15NNaO2
[M þ Na]þ: 192.1000. Found: 192.0999. IR (KBr, cmꢁ1): 3361, 2945, 1609, 1467, 1090,
1045, 976, 901, 648.

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Deacetylation of compound 14 by solvolysis
A suspension of 14 (83.0 mg, 0.393 mmol) and potassium carbonate (1.10 g, 7.96 mmol)
in methanol (10 mL) was stirred at ambient temperature for 3 h. Then the reaction mix-
ture was filtered through a pad of Celite, and the filtrate was concentrated under
reduced pressure. Water was added to the residue and the whole was extracted with
dichloromethane. The combined organic layer was washed with brine, dried over
sodium sulfate and concentrated under reduced pressure. Compound 15 (22.2 mg,
0.131 mmol, 33.3%) was obtained without purification. The yield was improved to
92.7% by using chloroform/2-propanol ¼ 3:1 as an extraction solvent.
Acknowledgments
We are grateful to Dr. Kenichiro Nagai (Analytical Unit for Organic Chemistry of Kitasato
University) for help with the structure determination of the newly synthesized compounds.
ORCID
Fumika Karaki
Kennosuke Itoh
Hideaki Fujii
https://orcid.org/0000-0002-3815-713X
http://orcid.org/0000-0002-6096-304X
https://orcid.org/0000-0002-0049-0084
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