One-step transformation of tetrahydropyranyl ethers using indium(III) triflate as the catalyst

Article abstract of DOI:10.1248/cpb.57.1167

A convergent one-step transformation of tetrahydropyranyl (THP) ethers is described. According to our earlier experiments, indium(III) triflate has proven to be an efficient catalyst for the transformation of THP ethers into their corresponding acetates.

Full text of DOI:10.1248/cpb.57.1167

October 2009
Notes
Chem. Pharm. Bull. 57(10) 1167—1170 (2009)
1167
One-Step Transformation of Tetrahydropyranyl Ethers Using Indium(III)
Triflate as the Catalyst
b
Tomoko MINENO, ,a,b Nana NIKAIDO,b and Hisao KANSUI
*
a Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare; 60 Nakaorui,
Takasaki, Gunma 370–0033, Japan: and b Laboratory of Organic Chemistry, Faculty of Pharmaceutical Sciences, Sojo
University; 4–22–1 Ikeda, Kumamoto 860–0082, Japan.
Received June 26, 2009; accepted July 18, 2009; published online July 27, 2009
A convergent one-step transformation of tetrahydropyranyl (THP) ethers is described. According to our
earlier experiments, indium(III) triflate has proven to be an efficient catalyst for the transformation of THP
ethers into their corresponding acetates. In further intensive work, we have developed a useful transforming re-
action of THP ethers using various anhydride moieties. Indium(III) triflate was confirmed as a suitable catalyst,
furnishing good to excellent yields. The details of this one-step transformation are described.
Key words tetrahydropyranyl ether; indium(III) triflate; catalyst; one-step transformation
Tetrahydropyranyl (THP) group is a well-utilized moiety, acetic anhydride (Chart 1). In both cases, the reaction
mainly as a tool to protect alcohol units due to its feasibility proceeded and produced excellent yields in a shorter
of installation and low cost. Stirring the free alcohols with time when indium(III) triflate was employed as the catalyst
3,4-dihydro-2H-pyran (DHP) under acidic conditions can (Table 1, entries 1 and 3), as compared with indium(III)
easily produce THP-protected alcohols.1—8) Also, THP-pro- chloride (Table 1, entries 2 and 4). Giving the satisfactory
tected alcohols are generally stable under a wide range of re- results with indium(III) triflate, we then expanded our in-
action conditions and reagents, such as metal hydrides, alkyl- vestigation to the other types of anhydrides. The reactions
lithiums, Grignard reagents, and catalytic hydrogenation.9—13) were carried out with THP-protected benzyl alcohol, N-(2-
For the THP ethers, a number of deprotecting methods have hydroxyethyl)phthalimide, and a wide range of anhydrides
been introduced.14) Various acids, including AcOH,15) pyri- (Chart 2).
dinium para-toluenesulfonate (PPTS),1) boric acid,16) and
As expected, the reactions with another aliphatic anhy-
TsOH,17) can cleave THP ethers to regenerate free alcohols dride of isobutyric anhydride generated similar satisfactory
with high efficacy. Although some of the metal reagents can results (Table 2, entries 1 and 7). In the case of benzoic anhy-
be expensive and toxic, the cleavage of THP ethers using dride, the reaction required an extended period of time, al-
transition metal reagents, such as PdCl2(CH3CN)2,18) though acceptable results were obtained (Table 2, entries 2
CuCl2·2H2O,19,20) and CuSO4·5H2O,21) has also been re- and 8). With the exception of entry 5, these conditions were
ported.
then applied to the cyclic anhydrides, and the reactions pro-
Previously, we have reported a couple of convenient reac- duced entirely poor yields. These results were presumably
tion methods using indium or indium-related reagents.22—25) due to the low reaction temperature. When reactions were re-
The authors have recently developed a practical approach to sumed at reflux using THF as the solvent, good to excellent
tetrahydropyranylation and depyranylation of various alco- outcomes were yielded. Meanwhile, the reaction was com-
hols using indium(III) triflate.26) It is worth noting that with pleted in the case of cis-1,2-cyclohexanedicarboxylic anhy-
the same catalyst, the reactions proceed in directions of both dride (Table 2, entry 5) without stirring at reflux, which was
protection and deprotection. In the presence of a catalytic
amount of indium(III) triflate, protection of alcohols is car-
ried out using CH2Cl2 as the solvent, whereas deprotection
uses MeOH/H2O as the solvent. Kamal et al. also reported
that tetrahydropyranylation can be controlled using catalytic
aluminum(III) triflate.27) Another report has shown the cleav-
age of THP ethers using titanium(III) triflate in good
yields.28) According to our earlier experiments, indium(III)
triflate was revealed to be an efficient catalyst for the trans-
formation of THP ethers into their corresponding acetates. In
further intensive work, we have developed a useful trans-
forming reaction of THP ethers using various anhydride moi-
eties with indium(III) triflate as the catalyst. Herein, we re-
port the details of this one-step transformation.
Chart 1
Results and Discussion
THP-protected benzyl alcohol and N-(2-hydroxyethyl)-
phthalimide were used as the starting materials. First, the
suitability of the catalysts was examined by reactions with
Chart 2
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: mineno@takasaki-u.ac.jp

1168
Vol. 57, No. 10
Table 1. Reactions to Compare the Catalysts
Temp.
(°C)
Yieldb)
(%)
Entry
1
Starting Material
Product
Catalysta)
In(OTf)3
Solvent
CH2Cl2
Time
1 h
r.t.
93
2
3
InCl3
CH2Cl2
CH2Cl2
r.t.
r.t.
24 h
61
96
In(OTf)3
40 min
4
InCl3
CH2Cl2
r.t.
24 h
67
a) The reactions were performed using 0.05 eq of the catalysts. b) Isolated yields.
Table 2. Reactions with Indium(III) Triflatea)
Temp.
(°C)
Yieldb)
(%)
Entry
Starting material
Reactant
Product
Solvent
Time
1
2
3
CH2Cl2
CH2Cl2
THF
r.t.
50 min
22 h
82
69
86
r.t.
Reflux
50 min
4
5
THF
Reflux
r.t.
22 h
18 h
94
90
CH2Cl2
6
THF
Reflux
21 h
60
7
8
CH2Cl2
CH2Cl2
r.t.
r.t.
50 min
20 h
96
76
9
THF
Reflux
17 h
54
10
11
THF
THF
Reflux
Reflux
22 h
26 h
61
73
a) The reactions were performed using 0.05 eq of indium(III) triflate. b) Isolated yields.
driven presumably by the release of a steric strain of the not produce satisfactory results regardless of the solvent. It is
5-member ring of 1,2-cyclohexanedicarboxylic anhydride. worth noting that no major structural isomerization was ob-
However, the reaction of THP-protected N-(2-hydroxyethyl) served in the cases of maleic anhydride (Table 2, entries 4
phthalimide with 1,2-cyclohexanedicarboxylic anhydride did and 10) or cis-1,2-cyclohexanedicarboxylic anhydride (Table

October 2009
1169
1.86—1.75 (m, 2H), 1.59—1.37 (m, 4H); 13C-NMR (125 MHz, CDCl3)
d: 180.0, 173.3, 135.9, 128.4, 128.0, 127.9, 66.2, 42.4, 42.3, 26.1, 25.9,
23.6, 23.5; MS (ESI): [MꢁH]ꢁ Calcd for C15H17O4 m/z: 261.1132, Found
261.1153.
2, entry 5).
Conclusion
In summary, we have developed a valid method for a one-
pot transformation of THP ethers. The reaction is not struc-
turally restricted, and it is widely applicable to transforma-
tions with the various types of anhydrides. Compared with
indium(III) chloride, another possible catalyst, indium(III)
triflate suitably catalyzed the transformation and furnish-
ed high yields. Further utility for these methods is being
studied.
Benzyl Phthalate: Colorless oil; yield 60%; IR (neat) n: 3036, 2940, 2866,
1724, 1701, 1288, 1126, 1072, 741 cmꢁ1 1H-NMR (500 MHz, CDCl3) d:
;
7.90 (d, 1H, Jꢃ7.5 Hz), 7.72 (d, 1H, Jꢃ7.5 Hz), 7.61—7.54 (m, 2H), 7.44—
7.28 (m, 5H), 5.37 (s, 2H); 13C-NMR (125 MHz, CDCl3) d: 172.0, 167.9,
135.2, 133.1, 132.0, 130.8, 130.0, 129.7, 128.7, 128.5, 128.4, 128.3, 67.7;
MS (FAB): [MꢂH]ꢂ Calcd for C15H13O4 m/z: 257.0808, Found 257.0826.
2-Phthalimidoethyl Isobutyrate: Colorless oil; yield 96%; IR (neat) n:
2974, 2943, 1775, 1717, 1470, 1427, 1393, 1366, 1192, 1153, 999,
721 cmꢁ1 1H-NMR (500 MHz, CDCl3) d: 7.76 (dd, 2H, Jꢃ5.8, 2.9 Hz),
;
7.64 (dd, 2H, Jꢃ5.8, 2.9 Hz), 4.24 (t, 2H, Jꢃ5.2 Hz), 3.87 (t, 2H, Jꢃ5.2 Hz),
2.40 (hep, 1H, Jꢃ6.9 Hz), 1.01 (d, 6H, Jꢃ6.9 Hz); 13C-NMR (125 MHz,
CDCl3) d: 176.5, 167.8, 133.8, 131.7, 123.1, 61.1, 36.9, 33.6, 18.6; MS
(FAB): [MꢂH]ꢂ Calcd for C14H16NO4 m/z: 262.1074, Found 262.1072.
2-Phthalimidoethyl Benzoate: White solid; yield 76%; mp 103.0—
104.8 °C; IR (KBr) n: 3055, 1775, 1767, 1709, 1424, 1393, 1277, 1119,
Experimental
General Information 1H- and 13C-NMR spectra were recorded on a
JEOL JNM-ECA-500. The Chemical shifts (d) are reported in parts per mil-
lion (ppm) and J values in Hz. High resolution mass spectra were measured
on a JEOL JMS-BU20 (EI), JEOL JMS-700 MStation (FAB), and Shimadzu
LCMS-IT-TOF (ESI). Infrared spectra were recorded on a Shimadzu FTIR-
8400S spectrometer. Melting points were measured on a Yanaco MP-S3
melting points apparatus and were uncorrected. All commercially available
chemicals were used without purification.
999, 714 cmꢁ1 1H-NMR (500 MHz, CDCl3) d: 7.96 (dd, 2H, Jꢃ8.6,
;
1.2 Hz), 7.83 (dd, 2H, Jꢃ5.8, 2.9 Hz), 7.69 (dd, 2H, Jꢃ5.8, 2.9 Hz), 7.50 (t,
1H, Jꢃ7.5 Hz), 7.38 ( t, 2H, Jꢃ7.5 Hz), 4.52 (t, 2H, Jꢃ5.2 Hz), 4.10 (t, 2H,
Jꢃ5.2 Hz); 13C-NMR (125 MHz, CDCl3) d: 167.9, 166.2, 134.0, 132.9,
131.8, 129.6, 129.5, 128.3, 123.3, 62.2, 36.9; MS (FAB): [MꢂH]ꢂ Calcd for
C17H14NO4 m/z: 296.0917, Found 296.0935.
Representative Experimental Procedure N-(2-Hydroxyethyl)phthal-
imide THP ether (143 mg, 0.52 mmol, entry 3, Table 1) was taken in dry
CH2Cl2 (5 ml) under argon atmosphere at 0 °C, to which Ac2O (63 mg,
0.62 mmol) and In(OTf)3 (15 mg, 0.026 mmol) were added and stirred at
the same temperature for 10 min and then at room temperature for 40 min.
The reaction mixture was diluted with water and extracted with CH2Cl2
(3ꢀ10 ml). The combined organic layers were washed with brine and dried
over anhydrous Na2SO4. The mixture was filtered and concentrated by rotary
evaporation. Purification by flash chromatography using hexane/ethyl acetate
(8 : 2) furnished acetyl-protected N-(2-hydroxyethyl)phthalimide as a white
solid (116 mg, 96% yield).
2-Phthalimidoethyl Succinate: White solid; yield 54%; mp 106.9—
107.3 °C; IR (KBr) n: 3040, 2951, 2932, 1736, 1709, 1694, 1424, 1397,
1204, 1161, 725 cmꢁ1; 1H-NMR (500 MHz, CDCl3) d: 7.86 (dd, 2H, Jꢃ5.2,
2.9 Hz), 7.73 (dd, 2H, Jꢃ5.2, 2.9 Hz), 4.34 (t, 2H, Jꢃ5.2 Hz), 3.96 (t, 2H,
Jꢃ5.2 Hz), 2.66—2.58 (m, 4H); 13C-NMR (125 MHz, CDCl3) d: 177.5,
171.9, 168.1, 134.1, 131.9, 123.4, 62.0, 36.9, 28.70, 28.65; MS (FAB):
[MꢂH]ꢂ Calcd for C14H14NO6 m/z: 292.0816, Found 292.0828.
2-Phthalimidoethyl Maleate: Colorless oil; yield 61%; IR (neat) n: 3366,
1
1773, 1713, 1586, 1427, 1397, 1223, 1177, 721 cmꢁ1; H-NMR (500 MHz,
MeOH-d4) d: 7.84 (dd, 2H, Jꢃ5.8, 2.9 Hz), 7.79 (dd, 2H, Jꢃ5.8, 2.9 Hz),
6.52 (d, 1H, Jꢃ12.0 Hz), 5.71 (d, 1H, Jꢃ12.1 Hz), 4.35 (t, 2H, Jꢃ5.7 Hz),
3.96 (t, 2H, Jꢃ5.7 Hz); 13C-NMR (125 MHz, MeOH-d4) d: 174.3, 169.5,
167.2, 143.6, 135.4, 133.2, 124.2, 118.9, 62.4, 37.8; MS (FAB): [MꢂNa]ꢂ
Calcd for C14H11NO6Na m/z: 312.0479, Found 312.0489.
Benzyl Acetate: Colorless oil; yield 93%; IR (neat) n: 3067, 3034, 2955,
1
1740, 1381, 1364, 1229, 1026, 750, 698 cmꢁ1; H-NMR (500 MHz, CDCl3)
d: 7.38—7.31 (m, 5H), 5.12 (s, 2H), 2.09 (s, 3H); 13C-NMR (125 MHz,
CDCl3) d: 170.3, 135.7, 128.2, 127.92, 127.87, 65.9, 20.5; MS (EI): [M]ꢂ
Calcd for C9H10O2 m/z: 150.0681, Found 150.0666.
2-Phthalimidoethyl Phthalate: White solid; yield 73%; mp 159.0—
159.5 °C; IR (KBr) n: 2953, 1742, 1702, 1697, 1427, 1399, 1292, 991,
2-Phthalimidoethyl Acetate: White solid; yield 96%; mp 88.5—89.1 °C;
IR (KBr) n: 1775, 1740, 1709, 1429, 1397, 1371, 1358, 1244, 1036,
1
721 cmꢁ1; H-NMR (500 MHz, MeOH-d4) d: 7.84 (dd, 2H, Jꢃ5.2, 2.9 Hz),
721 cmꢁ1 1H-NMR (500 MHz, CDCl3) d: 7.84 (dd, 2H, Jꢃ5.7, 2.9 Hz),
;
7.80—7.74 (m, 3H), 7.62—7.54 (m, 3H), 4.52 (t, 2H, Jꢃ5.2 Hz), 4.04 (t,
2H, Jꢃ5.2 Hz); 13C-NMR (125 MHz, MeOH-d4) d: 170.1, 169.7, 169.6,
135.4, 133.9, 133.3, 133.0, 132.4, 132.0, 130.2, 129.6, 124.2, 63.9, 37.9; MS
(FAB): [MꢂH]ꢂ Calcd for C18H14NO6 m/z: 340.0816, Found 340.0832.
7.72 (dd, 2H, Jꢃ5.8, 2.9 Hz), 4.30 (t, 2H, Jꢃ5.2 Hz), 3.94 (t, 2H, Jꢃ5.2 Hz),
2.00 (s, 3H); 13C-NMR (125 MHz, CDCl3) d: 170.8, 168.1, 134.0, 131.9,
123.3, 61.5, 37.0, 20.7; MS (FAB): [MꢂH]ꢂ Calcd for C12H12NO4 m/z:
234.0761, Found 234.0767.
Benzyl Isobutyrate: Colorless oil; yield 82%; IR (neat) n: 2974, 2938,
1
1736, 1470, 1456, 1190, 1152, 750, 698 cmꢁ1; H-NMR (500 MHz, CDCl3)
Acknowledgments The authors are grateful to Professor T. Kunieda
(Sojo University) for his kind suggestions.
d: 7.38—7.31 (m, 5H), 5.14 (s, 2H), 2.63 (hep, 1H, Jꢃ7.5 Hz), 1.22 (d, 6H,
Jꢃ7.5 Hz); 13C-NMR (125 MHz, CDCl3) d: 176.6, 136.1, 128.3, 127.9,
127.8, 65.8, 33.8, 18.8; MS (EI): [M]ꢂ Calcd for C11H14O2 m/z: 178.0994,
Found 178.0974.
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