Highly efficient deprotection of phenolic tetrahydropyranyl and methoxymethyl ethers and sequel cyclization to indanones using Sn(IV)Cl 4 catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.05.009

Sn(IV)Cl₄ catalyst provided a rapid and efficient deprotection method for the phenolic THP and MOM ethers and sequel intramolecular Friedel-Crafts alkylation reaction of THP and MOM protected chalcone epoxides under mild conditions. The reaction took 2-3 min to give the products in excellent yield (90-98%) at 0 °C without affecting the other functional groups.

Full text of DOI:10.1016/j.tetlet.2014.05.009

Accepted Manuscript
Highly efficient deprotection of phenolic tetrahydropyranyl and methoxymethyl
ethers and sequel cyclization to indanones using Sn(IV)Cl4 catalyst
Naseem Ahmed, Gulab Khushalrao Pathe, B. Venkata Babu
PII:
S0040-4039(14)00785-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.009
TETL 44599
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 February 2014
3 May 2014
4 May 2014
Please cite this article as: Ahmed, N., Pathe, G.K., Venkata Babu, B., Highly efficient deprotection of phenolic
tetrahydropyranyl and methoxymethyl ethers and sequel cyclization to indanones using Sn(IV)Cl4 catalyst,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.009
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Highly efficient deprotection of phenolic tetrahydropyranyl and methoxymethyl ethers and
sequel cyclization to indanones using Sn(IV)Cl4 catalyst
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Naseem Ahmed*, Gulab Khushalrao Pathe and B. Venkata Babu
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247 667, India
Fax: +91 1332 285745.
E-mail: nasemfcy@iitr.ac.in
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Abstract:
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Sn(IV)Cl4 catalyst provided a rapid and efficient deprotection method for the phenolic THP and
MOM ethers and sequel intramolecular Friedel-Crafts alkylation reaction of THP and MOM
protected chalcone epoxides under mild conditions. The reaction took 2-3 min to give the
products in excellent yield (90-98%) at 0 0C without affecting the other functional groups.
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Keywords: Alcohol, Phenol, SnCl4, detetrahydropyranylation, demethoxymethylation, Friedel-
Crafts alkylation.
Protection-deprotection of the functional groups is the most frequent used strategies in
the multi-steps organic syntheses. In particular, the protection and the deprotection of hydroxyl
group is extremely important because of its enormous demand for the synthesis of a number of
compounds of biological and synthetic interest such as carbohydrates, macrolides, peptides,
steroids, nucleotides and polyethers.1 The protection of hydroxyl groups with 3,4-dihydro-2H-
pyran is the most frequent used method due to stability of the resulting 2-tetrahydropyranyl
ethers (THPEs) in the presence of strong bases or nucleophiles such as Grignard reagents,
organolithium compounds, metal hydrides, catalytic hydrogenation, alkylating and acylating
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agents.2 Similarly, methoxymethyl chloride (MOMCl) is an another important reagent for the
hydroxyl group protection.3
The deprotection of THP and MOM ethers therefore required efficient methods to avoid
the decomposition of the products and/or loss of other functional groups in the products under
harsh reaction conditions. Therefore, several catalysts have been explored for the
detetrahydropyranylation of alcohols and phenols that include protic acids,4 Lewis acids like
9
BF3-etherate,5 LiBr,6 LiBF4,7 LiOTf,8 LiClO4, Sc(OTf)3,10 In(OTf)3,11 I2,12 InCl3,13 ZrCl4,14
CuCl2,15 and NH4Cl,16 expansive graphite,17clay materials,18 silica-supported sulfuric acid,19 and
other miscellaneous catalysts.20-25 Similarly, many catalysts have been used for the
demethoxymethylation of alcohols and phenols such as HCl, BBr3, pyridinium p-toluene
sulphonate under strong acidic condition, mild Lewis acids ZnBr2, and TiCl4 in aprotic
conditions and BBr3 derivatives Me2BBr, and (i-PrS)2BBr.26 Most of these methods have
different drawbacks such as longer reaction time, low yields, refluxing at high temperature and
the tedious work-up procedures. Hence, there is still a scope to develop mild and efficient
methods in the deprotection of tetrahydropyranyl and methoxymethyl ethers.
In continuation of our interest to develop new methods for the synthesis and the acid
catalysis reactions,27 herein, we report an efficient deprotection method of the THP and the
MOM ethers and sequel Friedel-Crafts alkylation reaction of the protected THP and MOM
chalcone epoxides using SnCl4 catalyst under mild reaction conditions.
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The catalytic efficiency of different metal halides was screened (Table 1). The metal
halides (Table 1, entries 1-5) showed poor to moderate catalytic activity. InCl3 (Table 1, entry 6)
was found to be a better catalyst at 10 mol% catalyst loading, which gave 90% yield of the
cyclized products without deprotecting the THP or the MOM ethers. However, the reaction was
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completed in 4-5 hours. SnCl4 (Table 1, entries 7, 8) at less than 10 mol% catalyst loading gave
lower yields in a longer reaction time. SnCl4 (Table 1, entry 9) at 10 mol% catalyst loading was
found to be the most efficient catalyst, which gave the optimal yield (98%) with deprotecting the
THP and the MOM ethers within 2-3 min. Further, increase in the catalyst loading of SnCl4
(Table 1, entry 10) gave the side-product as 3-(4-chlorophenyl)-2-chloro-2,3-dihydro indan-1-
one along with the desider product. We also applied SnI4 and SnBr4 in 5, 10, and 20 mol%
catalysts loading during the deprotection of THP and MOM ethers. However, it gave the desired
products only 5-10% yields after stirring for 2-6 h at 0 oC.
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[Table 1]
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55
We observed the solvent effects using different solvents like CH3COCH3, CHCl3, CH2Cl2
and THF. CHCl3 and CH2Cl2 were found to be the desired solvents (Table 2, entries 4, 6).
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[Table 2]
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Under optimized reaction conditions, the deprotection of THP and MOM ethers in
phenols, chalcone and chalcone epoxides were achieved using 10 mol% of SnCl4 in excellent
0
yields (90-98%) within 2-3 min at 0 C in the presence of other functional groups. However, in
the case of alcoholic THP and MOM ethers, even 20 mol% of catalyst loading gave less yield 10
and 25% respectively (Table 3, entry 1). In case of chalcones 6-13, only THP or MOM removal
was observed without intramolecular Friedel-Crafts alkylation. These products were
characterized by comparing their physical and spectral data with the literature values.22,28
Interestingly, the THP and MOM removal followed by the Friedel-Crafts alkylation was
observed for the chalcone epoxides which gave the corresponding indanones 14-19 in excellent
yield (90-98%) within 2-3 min at 0oC (Table 3).
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[Table 3]
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The stereochemistry and the diastereomeric excess ratio of the indanone derivatives 14-19 were
determined by the chiral column separation of racemic mixture of diastereomers. For example, in
the synthesis of racemic indanone 3-(4-bromophenyl)-2-hydroxy-2, 3-dihydroindan-1-one
(Scheme 1), the chiral HPLC purification gave peaks at 40.14 (51%) and 56.43 (49%) min. for
the diastereomers (See Supporting Information). Then, we synthesized enantiomerically excess
(ee) trans-chalcone epoxide of 2R, 3S-configuration from chalcone with α,α'-diphenyl-L-prolinol
and TBHP in hexane which gave a good yield (58%) with 77.6% ee (Scheme 1). Asymmetric
1
epoxides were characterized by comparing with the literature value of H-NMR and
enantiomeric excess was determined by chiral HPLC column and optical rotation in
chloroform.24
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[Scheme 1]
It was observed that during the ring opening of epoxides, the C-2 configuration remained same
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while the C-3 configuration changed due to SN1-like mechanism therefore it gave the regio- and
stereoselective intramolecular Friedel-Crafts alkylation. The protons at C-2 and C-3 positions are
1
in trans-orientation which is confirmed by the coupling constant (J = 2.0 Hz) in H-NMR
spectrum. 24 The absolute configurations at C-2 and C-3 are confirmed as 2R and 3S respectively.
The stereoselectivity and high yields for 1-indanones under acidic condition (SnCl4) might be
due to the variable oxidation state and availability of relatively low energy 5d-orbitals on tin. On
ligation with epoxide oxygen, the tetrahedron structure of SnCl4 was converted to a trigonal
bipyramid/octahedron structure. This geometrical change enhanced the steric hindrance which
results in a faster epoxide ring opening from β-carbon due to considerable electron deficient
character at benzylic carbon. Therefore, the nucleophile attacked at β-carbon of carbonyl group.
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A proposed reaction mechanism is shown in Scheme 2 for the MOM ether deprotection and the
sequel intramolecular Friedel-Crafts alkylation, where ligation of SnCl4 with MOM oxygen
resulted in the removal of the methyl (methylene) oxonium group followed by its reaction with
Cl− generated the MOMCl.23 Same time, the epoxide oxygen ligation with SnCl4 might change
the tetrahedron structure of SnCl4 into trigonal bipyramid/octahedron structure. The geometry
changes enhanced the steric hindrance which results in faster epoxide ring opening from β-
carbon due to considerable electron deficient character at benzylic position not on α-carbon due
to a 4-membered cyclobutanone (unstable intermediate). Therefore, the nucleophilic attack took
place at β-carbon of carbonyl which gave a resonance stabilized benzyl intermediate. Finally, a
base hydrolysis regenerated SnCl4 catalyst which is used in the next catalytic-cycle.
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[Scheme 2]
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In conclusion, we have illustrated an optimized reaction conditions for the rapid and efficient
deprotection of the phenolic THP and MOM ethers and sequel intramolecular Friedel-Crafts
alkylation reaction of chalcone epoxides. All reactions were completed within 2-3 min and gave
0
excellent yield (90-98%) at 0 C for both the THP and the MOM ethers and sequel cyclization
reactions without affecting the other functional groups.
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Acknowledgements
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Financial support and award of junior research fellowship (JRF) by the Department of science
and Technology (DST), New Delhi, India is gratefully acknowledged.
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Supplementary Material
5

1 13
Experimental procedures and the characterization data H, C NMR spectra and chiral HPLC
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chromatogram associated with this article are available.
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References and Notes
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27. (a) Ahmed, N.; Van Lier, J. E. Tetrahedron Lett. 2007, 48, 5407;
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N. K. Beilstein J. Org. Chem. 2012, 8, 177; (d) Konduru, N. K.; Ahmed, N. Synth.
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2471.
28. General procedure for the deprotection of tetrahydropyranyl and methoxymethyl ethers of
alcohols and phenols: SnCl4 (10 moles %) was added to a stirred solution of THP/MOM
7

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169
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ethers (1 mmol) in CH2Cl2 (5 mL) at 0 °C. TLC monitoring, the reaction mixture was
poured into 10% aqueous Na2CO3 solution and extracted with CH2Cl2. The combined
organic layer was washed with brine solution, dried with anhyd. Na2SO4 and concentrated
in vacuo to afford the corresponding alcohol or phenol, which was purified by silica gel
column chromatography with hexane-EtOAc eluent to obtain the products 1-19 in excellent
yield (90-98%). Characterization for example, (E)-1-(4-chlorophenyl)-3-(4-hydroxy
1
phenyl)prop-2-en-1-one(11): H NMR (CDCl3, 500 MHz) δppm7.87 (d, J = 8.5 Hz, 2H),
7.54 (d, J = 8.5 Hz, 1H), 7.06 (d, 9 Hz, 1H), 6.95 (d, J = 9 Hz, 2H), 6.40 (s, 1H ) 5.29 (t,7
13
Hz,1H), 5.22 (d, J = 1.5 Hz,1H). C NMR (CDCl3, 125 MHz) δ ppm 195.55, 161.83,
137.36, 131.82, 131.42, 129.79, 125.99, 123.01, 116.23, 76.32, 63.53. GC-MS(m/z): 258
[M+.,C15H11FO3]. 3-(4-bromophenyl)-2,5-dihydroxy-2,3-dihydroinden-1-one (13): 1H NMR
(CDCl3, 500 MHz) δppm 7.86 (d, J = 8.5 Hz, 2H), 7.54-7.52 (m, 1H ), 7.05 (t, 7 Hz,1H ),
6.95 (d, J = 9 Hz, 2H), 6.42 (s, 1H), 5.29 (t,7 Hz,1H), 5.22 (d, J = 1.5 Hz,1H). 13C NMR
(CDCl3, 125 MHz) δ ppm 195.57, 161.85, 137.38, 131.84, 131.45, 129.81, 126.01, 123.04,
116.25, 75.40, 63.55. GC-MS (m/z): 318 [M+., C15H11BrO3], 320 [M+2].
Caption to illustrations
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Table 1. Optimization conditions in deprotection of the THP and the MOM ethers and sequel
cyclization of phenolic compounds with different catalysts
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Table 2. Solvent effects on yields in deprotection of the THP and the MOM ethers and sequel
cyclization reaction
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Table 3. Examples of the THP and MOM ethers deprotection and sequel cyclization reaction
Scheme 1. Synthesis of diastereoisomerically pure trans-3-(4-bromophenyl)-2-hydroxy-2,3-
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dihydroindan-1-one
Scheme 2. A propose mechanism for the deprotection of MOM ethers followed by cyclization
with SnCl4
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Table 1. Optimization conditions in deprotection of the THP and the MOM ethers and sequel
cyclization of phenolic compounds with different catalysts
O
O
OH
Catalysts (mol %) / DCM
0 oC
R1O
O
HO
R1= MOM/THP
Cl
Cl
186
187
188
189
190
191
Entry Catalyst Mol %
Time
20-24 h
6 h
Yield (%)
28a
1
2
3
4
5
6
7
8
9
SbCl3
SnI4
10
10
10
10
10
10
1
7b
SbCl5
MgCl2
SnBr4
InCl3
SnCl4
SnCl4
SnCl4
20-24 h
18-24 h
6 h
20a
18a
192
193
194
195
196
197
198
199
200
201
202
203
204
10b
90a
4-5 h
3 min
2 min
3 min
75b
5
90b
98b
10
10
SnCl4
20
3 min
70+20c
a Gave only cyclization.
b Gave both THP and MOM ethers deprotection and sequel cyclization.
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205
206
207
C Other product as 3-(4-chlorophenyl)-2-chloro-2,3-dihydro indan-1-one
(20%).
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Table 2. Solvent effects on yields in deprotection of the THP and the MOM ethers and sequel
cyclization reaction
O
O
OH
R1O
SnCl4 (mol%) / solvents
0 0C, 2-3 min.
O
HO
R1= MOM/THP
Cl
Cl
210
Entry
Mol%
Solvents
Acetone
Acetone
DCM
Yield (%)
40a
1
2
3
4
5
6
7
8
1
5
45 a
2
80 b
10
2
DCM
98 b
CHCl3
CHCl3
THF
85 c
10
5
96 c
52 d
10
THF
60 d
211
212
Reaction time: a 2h, b,c 3 min, d 3 h.
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Table 3. Examples of the THP and MOM ethers deprotection and sequel cyclization reaction
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O
O
OH
R1O
SnCl4 (10 mol %) / DCM
00C, 2-3 min
O
HO
R2
R2
R1= THP/MOM
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Entry
ROTHP/MOM
Time Yield Yield
(min) (%)a (%)b
ROH
1
2
10
25
2
3
2
95
92
2
96
95
O
H
OH
3
4
5
2
2
92
90
95
92
6
7
3
3
98
96
94
98
11

8
9
2
2
3
97
96
95
94
93
10
92
11
12
13
14
3
2
3
3
96
90
95
96
95
92
95
93
15
2
98
98
12

16
2
95
94
17
3
96
93
18
3
95
92
19
2
92
92
b
215 Yield (1-19): a R-OTHP and R-OMOM ethers deprotection.
216
217
218
Scheme 1. Synthesis of diastereoisomerically pure trans-3-(4-bromophenyl)-2-hydroxy-2,3-
dihydroindan-1-one.
13

O
O
OH
SnCl4 (10 mol%)
O
A
A
CH2Cl2, 0 oC
2-3 min
B
B
(2R,3S)
77.6% ee
Br
(2R, 3S)
90% yield
upto 75% ee
Br
219
220
221
Scheme 2. A propose mechanism for the deprotection of MOM ethers followed by cyclization
222
223
with SnCl4
O
H
O
1
Cl
Sn
Cl
Cl
Sn
Cl
+δ
O
+δ
O
Cl
Cl
Cl
Cl
+δ
O
O
O
Cl Sn Cl
Cl
2
O
Cl Sn Cl
Cl Cl
1
R2
e
t
Cl
R2
u
o
r
O
Cl
-
O
Cl
Cl
Sn
Cl
O
O
- HCl
Cl Sn Cl
route 2
Cl
O
O
R2
Cl
OH
Sn Cl
Cl
O
HO
O
Cl Sn Cl
Cl
base hydrolysis
-SnCl4
R2
R2
224
225
226
227
14

228
Graphical Abstract
229
230
Highly efficient deprotection of phenolic tetrahydropyranyl and methoxymethyl ethers and
sequel cyclization to indanones using Sn(IV)Cl4 catalyst
231
Naseem Ahmed*, Gulab Khushalrao Pathe and B. Venkata Babu
O
O
O
SnCl4 (10 mol%), DCM
SnCl4 (10 mol%), DCM
OH
O
0 0C, 2-3 min
H3C
0 0C, 2-3 min
HO
O
O
O
O
O
R1
R1
R1
232
15