A mild and efficient THP protection of indazoles and benzyl alcohols in water

Article abstract of DOI:10.1016/j.tetlet.2018.02.061

A mild and efficient method for THP protection of indazoles and benzyl alcohols has been developed in water, the most environmentally friendly solvent, in which Tween 20 (2% w/w) was added to form aqueous micelles to increase the solubility of starting materials. This aqueous protocol allowed the reaction to proceed smoothly at room temperature and with only 1.2 equiv of DHP, providing moderate to good yields of THP protected products for a wide scope of substrates. In addition, the methodology was highly practical in the large-scale synthesis (1 g synthesis of 2c as an example), wherein the convenient work-up and purification procedure (simple filtration) made the protocol even more attractive.

Full text of DOI:10.1016/j.tetlet.2018.02.061

Accepted Manuscript
A mild and efficient THP protection of indazoles and benzyl alcohols in water
Yang Zhan, Xiao Ding, Hailong Wang, Haihua Yu, Feng Ren
PII:
S0040-4039(18)30263-6
https://doi.org/10.1016/j.tetlet.2018.02.061
TETL 49746
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 January 2018
14 February 2018
23 February 2018
Please cite this article as: Zhan, Y., Ding, X., Wang, H., Yu, H., Ren, F., A mild and efficient THP protection of
indazoles and benzyl alcohols in water, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.061
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A mild and efficient THP protection of indazoles and
benzyl alcohols in water
Leave this area blank for abstract info.
Yang Zhana, †, Xiao Dinga, †, Hailong Wanga, Haihua Yua, and Feng Rena,*
aNeurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road,
Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China.
†contributed equally to this work.



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Water as the solvent
Mild reaction condition
Wide substrate scope
Convenient purification

Tetrahedron Letters
1
Tetrahedron Letters
A mild and efficient THP protection of indazoles and benzyl alcohols in water
Yang Zhana, †, Xiao Dinga, †, Hailong Wanga, Haihua Yua, and Feng Rena,*
aNeurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai
201203, PR China.
*Corresponding author. Tel.: +86 18616743377; fax: +86 021 61590730; e-mail address: feng.q.ren@gsk.com (F. Ren).
†contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Abstract: A mild and efficient method for THP protection of indazoles and benzyl alcohols has
been developed in water, the most environmentally friendly solvent, in which Tween 20 (2%
w/w) was added to form aqueous micelles to increase the solubility of starting materials. This
aqueous protocol allowed the reaction to proceed smoothly at room temperature and with only
1.2 equiv of DHP, providing moderate to good yields of THP protected products for a wide
scope of substrates. In addition, the methodology was highly practical in the large-scale
synthesis (1 g synthesis of 2c as an example), wherein the convenient work-up and purification
procedure (simple filtration) made the protocol even more attractive.
Available online
Keywords:
Indazoles
Benzyl alcohols
THP protection
Aqueous micelles
Tween 20
2009 Elsevier Ltd. All rights reserved.
primary amines in CH2Cl2 at room temperature, but limited
functional group tolerability was evaluated in the examples.11
Introduction
Mezei and co-workers12 developed a solvent- and catalyst-free
protocol for the THP protection of hydroxyl and various
In the syntheses of complex natural products and bioactive
compounds, multiplicity of functional groups requires
a
o
protecting group manipulation to avoid side product formation
and/or to improve reaction efficiency.1 A variety of protecting
groups such as trimethylsilyl (TMS), methoxymethyl (MOM),
tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), and
benzyl (Bn) has been developed to block the corresponding
functional groups including hydroxyl (-OH), amine (-NH-) or
carbolic acid (-COOH).2 Among them, THP represents one of the
most common protective groups, which has been extensively
applied in the synthesis of peptides,3 carbohydrates,4 and other
biologically active molecules.5 The prevalence of using THP as a
protecting group could be attributed to the ease of introduction,
the low cost of the starting material dihydropyran (DHP), and its
excellent stability under various conditions such as strong basic
media, oxidizing and reducing agents.2 Besides, THP group could
be easily removed under mild acidic conditions6 or transferred to
other functional groups7.
heterocyclic amino groups, however high temperature (125 C)
was required for good conversions. Besides, some functional
groups such as indole and pyrrole were not tolerated.12 Up to
date, the reported protocols for THP protection often suffer from
obvious disadvantages such as high reaction temperature, large
excess of the starting material DHP, and narrow substrate scope.
In addition, the THP protection of indazoles was widely used in
pharmaceutical industry including anti-cancer drug Axitinib,
PI3K inhibitors, LRRK2 inhibitors and others.13 However, the
protocol for the THP protection of indazoles was rarely explored.
Herein, we report a mild and efficient method for the THP
protection of indazoles and benzyl alcohols in water, the most
environmentally friendly solvent. This aqueous protocol allowed
the THP protection reactions to proceed smoothly at room
temperature and with only 1.2 equiv of DHP, providing moderate
to high yields of THP protected products with a wide substrate
scope. The methodology was further evaluated in the large-scale
synthesis (1 g scale for 5-methoxy-1H-indazole 1c as an
example), and the desired THP protected product (2c) was
obtained in high yield (90%) with high purity (99%) after a
convenient work-up procedure (simple filtration) without further
purification. The practicability especially for large scale makes
the protocol even more attractive.
Several methods have been reported in the past decades for the
THP protection of different functional groups using acidic
catalysts such as p-toluenesulfonate (TsOH),8 pyridinium p-
toluenesulfonate (PPTS),9 and bismuth triflate10 in aprotic
solvents such as CH2Cl2, THF, and diethyl ether. However, most
of the reported protocols were limited to the protection of the
hydroxyl group, and were not generalized to a broader scope of
other functional groups. Ashok’s group reported a magnesium
halide catalyzed THP protection of alcohols, thiols, phenols and

2
Tetrahedron Letters
Results and discussion
Table 2. Substrate scope of indazoles for THP protection in
watera
To address the ever-increasing health and environmental
concerns, significant progresses have been achieved to replace
organic solvent with the most environmentally friendly solvent,
water, in organic synthesis.14 One focus in this area was adding
readily available surfactants to water to form aqueous micellar
system.15 The “nonreactor” formed by the hydrophobic tail of the
surfactant favored the compartmentalization of organics,
therefore improving the solubility and the local concentration of
organic reagents in the micelles, which resulted in the
enhancement of reactivity and selectivity of organic reactions in
the aqueous micellar system.16 We have developed several novel
protocols in the aqueous micellar system with mild reaction
conditions and high yields, including Ullmann reaction of
indazoles,17 N-alkylation of pyridines,18 and C-H arylation
reactions.19 As our continued efforts to develop environmentally
friendly organic reactions, we started to explore THP protection
of indazoles, the prevalent intermediates in pharmaceutical
industry,13 in water.
conversion
(%)b
isolated yield of 2
entry
1
(%)
1
2
96
2a, 89
2b, 72
87
3
4
5
96
81
75
2c, 84
2d, 75
2e, 62
We initiated our exploration using indazole (1a) as the model
substrate. TPGS-750-M was selected as the surfactant since it has
been successfully utilized in a variety of reactions.20 It was
encouraging that 79% conversion to N-1 THP-protected product
(2a) was observed when using 1.2 equiv of DHP and catalytic
amount (0.1 equiv) of p-toluenesulfonate (TsOH) in TPGS-750-
M/water micellar solvent (2% w/w) after overnight reaction at
room temperature (entry 1, Table 1). Besides, based on HPLC
analysis, only trace amount of N-2 THP-protected product was
detected, indicating high selectivity of this reaction. With this
preliminary result, we then investigated the effect of different
surfactants on the reaction including PTS (entry 2), TritonX-100
(entry 3) and SPGS-550-M (entry 4) and they all resulted in
similar conversions compared to that of TPGS-750-M. Adding
6c
7c
8c
9
88
78
52
64
2f, 82
2g, 58
2h, 44
2i, 44
Table 1. Optimization of reaction conditions for THP protection
of indazolea
10
96
2j, 89
11c
52
2k, 51
entry
catalyst
surfactant
conversion (%)b
aReaction Conditions: Indazoles 1a (1.0 equiv), DHP (1.2 equiv), TsOH
(10 mol%), Tween 20/H2O (2% w/w, 2.5 mL), room temperature,
overnight. bConversion was determined by HPLC peak areas at 214 nm
for indazole 1 and 2 after extraction with EtOAc. cThe reaction was run
at 70 oC. dNot Determined.
1
2
3
TsOH
TsOH
TsOH
TPGS-750-M
PTS
79
76
77
Triton X-100
excess starting material DHP (up to 5 equiv), prolonged reaction
time, and elevated reaction temperature (up to 70 oC) didn’t result
in significant improvement in conversion. To our delight, the
conversion was much improved when using Tweens as the
surfactant, especially Tween 20 (entry 5) and Tween 80 (entry 7)
which provided 96% and 93% conversion, respectively. Tween
20 proved to be the most optimal among the surfactants evaluated
with almost full conversion observed. In addition to the
surfactants, the catalysts also demonstrated significant impact on
the reactivity of THP protection reaction. H2SO4 (entry 8),
trifluoroacetic acid (TFA, entry 9), and pyridinium p-
toluenesulfonate (PPTS, entry 10) resulted in much decreased
reactivity compared to TsOH. Especially for PPTS, only 10%
conversion was observed from HPL analysis, likely due to its
weak activation on DHP in water. On the other hand, Lewis acid
gave moderate to high conversions for the THP protection
reaction, with the highest conversion of 90% using Bi(OTf)3 as
the catalyst and no conversion using Yb(OTf)3. Thus, the most
optimal condition was concluded using Tween 20/water (2% w/w)
as the solvent, TsOH (10 mol%) as the catalyst, and at room
temperature.
4
5
6
7
8
TsOH
TsOH
TsOH
TsOH
H2SO4
SPGS-550-M
Tween 20
Tween 40
Tween 80
Tween 20
75
96
85
93
78
9
TFA
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
79
10
90
40
0
10
11
12
13
PPTS
Bi(OTf)3
Sc(OTf)3
Yb(OTf)3
14
FeCl3
Tween 20
59
aReaction Conditions: Indazole 1a (1.0 eq), DHP (1.2 eq), catalyst (10
mol%), surfactant/H2O (2% w/w, 2.5 mL), room temperature, overnight.
bConversion was determined by HPLC peak areas at 214 nm for indazole
1a and 2a after extraction with EtOAc.

Tetrahedron Letters
3
Table 3. Substrate scope beyond indazoles for THP protection in
benzotriozle (entry 3) and pyrazole (entry 4) all showed much
watera
lower conversions thus lower isolated yields compared indazoles,
even at an elevated temperature (70 C). Benzyl alcohols were
o
also investigated and to our delight, both electron-withdrawing
and electron-donating substitutions on the benzyl ring were well
tolerated for the reaction condition and moderate to high yields of
desired THP protected products were obtained at room
temperature (entries 5‒7). It was noteworthy that the phenol
group of substrate 3f was not affected and the THP protecting
group was selectively on the benzyl alcohol. To further confirm
the result, we subjected the unsubstitutied phenol to the reaction
condition and no THP protected phenol (4h) was detected even
after prolonged reaction time and elevated temperature. This
might be due to the lower nucleophilicity of the phenol alcohol.
isolated yield of 4
entry
1
3
conversion (%)b
51
(%)
4a, 44
2c
3c
33
35
4b, 30
4c, 33
Scheme 1. Large scale synthesis of 5-methoxy-1-(tetrahydro-2H-
pyran-2-yl)-1H-indazole 2c in watera, b
4c
5
66
50
65
4d, 61
4e, 44
4f, 56
6
7
78
4g, 73
8c
trace
4h, NDd
aReaction Conditions: 5-methoxy-1H-indazole 1c (1.0 g), DHP (852 mg, 1.2
equiv), TsOH (128 mg, 10 mol%), Tween/H2O (2% w/w, 35 mL), room
temperature, overnight. bWater was added after the reaction and the solid
precipitated was filtrated to give the compound 2c with high purity (>99%)
and high yield (90%).
aReaction Conditions: Indazole 1a (1.0 equiv), DHP (1.2 equiv), TsOH
(10 mol%), Tween/H2O (2% w/w) 2.5 mL, room temperature,
overnight. bConversion was determined by HPLC peak areas at 214
nm for indazoles 3 and products 4 after extraction with EtOAc.
cThe reaction was run at 70 oC. dNot Determined.
To further evaluate the practicability of this protocol for
industrial applications, a scale-up synthesis was conducted using
1 g of 5-methoxy-1H-indazole (1c) as the substrate (Scheme 1).
The reaction was performed at room temperature with 1.5
equivalents of DHP and catalytic amount of TsOH (10 mol%).
After stirring overnight, more water was added to the reaction
mixture to break the aqueous micellar system, and the product
was directly precipitated out as a solid (please see the picture).
The solid was simply filtered and the desired product (2c) was
obtained with high yield (90%) and high purity (>99%) without
further purification.
We then started to explore the substrate scope of indazoles for
the THP protection reaction (Table 2). A variety of different
substitutions were well tolerated for the reaction condition.
Indazoles bearing the electron-donating substitution (methoxy) at
different positions (4-, 5-, 6-, and 7-position) underwent the
reaction efficiently, providing the corresponding THP protected
products in high conversions and good yields (entries 2‒5).
Compared with the un-substituted indazole, the yields were
slightly decreased which may be due to the lower solubility of
the substrates in the Tween 20/water micellar system. Among
them, the 7-methoxy-1H-indazole (1e) gave the lowest yield,
which was likely attributed to the steric hindrance of the methoxy
group. Introducing electron-withdrawing substituents at the 5-
position of the indazole such as -F, -NO2, and -CF3 (entries 6‒8)
resulted in slower reactions compared with the electron-donating
substituent (1c), and a higher reaction temperature was necessary
Conclusion
In conclusion, we have developed a mild and efficient method
for THP protection of indazoles, benzyl alcohols and other
heterocyclic amino groups in water. Tween 20 (2% w/w) was
added as the surfactant to form aqueous micelles to improve
solubility of substrates and increase local reaction concentration.
This aqueous protocol allowed the reactions to proceed smoothly
at room temperature with only 1.2 equiv of DHP, and showed a
broad substrate scope with moderate to good isolated yields for
the examples examined. In addition, the protocol demonstrated
practicability in the gram-scale synthesis of compound 2c as an
example. The convenient work-up and purification procedure
(simple filtration) made the protocol even more attractive.
Further exploration of aqueous protocols on other protecting
groups is ongoing.
o
(70 C) for reasonable conversions, which might be due to the
reduced nucleophilicity of the indazole nitrogen. Substituents on
the C-3 position of indazole were also tolerated, and moderate
yields were obtained for methyl and nitrile substitutions (entries
9 and 11) and high yield (entry 10) was observed for methoxy
substitution.
We then further expanded the substrate scope to other
heterocyclic amino groups and hydroxyl functionality. As
illustrated in Table 3, indole (entry 1), benzoimidazole (entry 2),

4
Tetrahedron Letters
12.Jawor, M. L.; Ahmed, B. M.; Mezei, G. Green Chem., 2016, 18,
6209-6214.
Acknowledgements
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We thank Dr. Baowei Zhao and Yingxia Sang for helpful
discussions.
Supporting Information
Experimental data, 1H and 13C NMR spectra for the compounds.
The Supporting Information is available free of charge which can
be found:
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Tetrahedron Letters
5
Highlights:
 THP protected indazoles are widely used in
pharmaceutical industry
 Efficient and mild methodology of THP
protection of indazoles is an unmet need
 A mild THP protection of indazoles and
benzyl alcohols in water is reported
 Tween 20 (2% w/w) was added to form
aqueous micelles to improve solubility
 Product could be obtained in high yield and
purity after easy work-up (filtration)