A novel and convenient chemoselective deprotection method for both silyl and acetyl groups on acidic hydroxyl groups such as phenol and carboxylic acid by using a nitrogen organic base, 1,1,3,3-tetramethylguanidine

Article abstract of DOI:10.1021/ol027263d

(Matrix presented) 1,1,3,3-Tetramethylguanidine (TMG)¹, a nitrogen organic base, is a convenient and useful reagent for chemoselective deprotection of both silyl and acetyl groups on acidic hydroxyl groups such as phenol and carboxylic acid without affecting aliphatic silyl and acetyl groups. The chemoselectivity is dependent on the acidity of the hydroxyl group.

Full text of DOI:10.1021/ol027263d

ORGANIC
LETTERS
2003
Vol. 5, No. 2
209-212
A Novel and Convenient Chemoselective
Deprotection Method for Both Silyl and
Acetyl Groups on Acidic Hydroxyl
Groups Such as Phenol and Carboxylic
Acid by Using a Nitrogen Organic Base,
1,1,3,3-Tetramethylguanidine
,‡
Kin-ichi Oyama† and Tadao Kondo*
Chemical Instrument Center, Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan,
and Graduate School of Bioagricultural Sciences, Nagoya UniVersity, Chikusa,
Nagoya 464-8601, Japan
kondot@agr.nagoya-u.ac.jp
Received November 11, 2002
ABSTRACT
1,1,3,3-Tetramethylguanidine (TMG)1, a nitrogen organic base, is a convenient and useful reagent for chemoselective deprotection of both silyl
and acetyl groups on acidic hydroxyl groups such as phenol and carboxylic acid without affecting aliphatic silyl and acetyl groups. The
chemoselectivity is dependent on the acidity of the hydroxyl group.
Silyl and acetyl groups are widely used for protection of
phenolic hydroxyl groups in the synthesis of biologically
significant products.2 Phenolic compounds such as flavonoid
glycosides, lignan glycosides, anthracycline glycosides, and
phenolic glycopeptide antibiotics have attracted considerable
attention due to their antioxidant, antitumor, and antibacterial
activities.3 For synthesis of these phenolic glycoconjugates,
selective deprotection is an essential synthetic tool. TBAF
is used as a typically desilylating reagent,2 but it generally
has no selectivity4 and side-reactions may occur due to the
nucleophilicity of the fluoride ion.5 Only a few types of
selective desilylation of phenolic TBDMS ether have been
realized by treatment with basic reagents, often accompanied
by deacylation,6-9 though many selective desilylations of
(4) A method of chemoselective cleavage of the phenolic silyl ether by
using TBAF has been reported, but carefully controlled conditions were
required: Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985,
26, 681.
(5) Ranu, B. C.; Jana, U.; Majee, A. Tetrahedron Lett. 1999, 40, 1985
and references therein.
(6) For a review of selective desilylation: Nelson, T. D.; Crouch, R. D.
Synthesis 1996, 1031.
† Chemical Instrument Center, Nagoya University.
(7) Basic reagents for selective deprotection of phenolic TBDMS ether
are reported inorganic bases such as KF,7a,b K2CO37c,d, and NaOH7e and
triethylamine N-oxide/CH3OH:7f (a) Just, G.; Zamboni, R. Can. J. Chem.
1978, 56, 2725. (b) Schmittling, E. A.; Sawyer, J. S. Tetrahedron Lett.
1991, 32, 7207. (c) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett.
1994, 35, 7565. (d) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1997, 38,
187. (e) Crouch, R. D.; Stieff, M.; Frie, J. L.; Cadwallader, A. B.; Bevis,
D. C. Tetrahedron Lett. 1999, 40, 3133. (f) Zubaidha, P. K.; Bhosale, S.
V.; Hashmi, A. M. Tetrahedron Lett. 2002, 43, 7277.
‡ Graduate School of Bioagricultural Sciences, Nagoya University.
(1) Berning, D. E.; Noll, B. C.; DuBois, D. L. J. Am. Chem. Soc. 1999,
121, 11432.
(2) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley and Sons: New York, 1999. (b) Kocienski, P. J.
Protecting Groups; George Thieme Verlag: New York, 1994.
(3) Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds. Glycoscience:
Chemistry and Chemical Biology III; Springer: Berlin, 2001.
10.1021/ol027263d CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003

aliphatic TBDMS ether with acidic reagents have been
developed.6,10 Selective deacylation of phenolic acetates,
among polyacylates, needs strictly controlled conditions or
specific reagents, despite a number of reports of success.2,11
Herein we document an efficient chemoselective deprotection
method for both silyl and acetyl groups on acidic hydroxyl
groups such as phenol and carboxylic acid using a nitrogen
organic base, TMG.
Table 2. Chemoselective Desilylation of the Various Phenolic
Silyl Ethers by Using TMG
In general, the Si-O bond is stable to nitrogen organic
bases such as Et3N, (i-Pr)2NEt, pyridine, collidine, and
1,1,3,3-tetramethylurea. Surprisingly, methyl p-coumarate
TBDMS ether (1) was desilylated completely by treatment
with TMG in CH3CN (Table 1, entry XIV). To study this
Table 1. Desilylating Reactions of the Phenolic Silyl Ether by
Using TMG
entry
solvent
TMG (equiv)
temp (°C)
yield (%)a,b
I
II
CH2Cl2
toluene
THF
CH3OH
DMF
1
1
1
1
1
1
0.1
rt
rt
rt
rt
rt
rt
rt
nr
nr
trace
44
69
III
IV
V
VI
VII
DMSO
CH3CN
67
66 (25)c
66 (21)d
87 (4)e
72
VIII
IX
X
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0.1
1
2
4
1
50
rt
rt
75
78
78
83
XI
rt
XII
XIII
XIV
50
50
50
2
4
92
a Isolated yield. b Value in parentheses is the recovery of the starting
material. c Reaction was performed for 13 h. d Reaction was performed in
the presence of H2O (2 equiv) for 13 h. e Reaction was performed in the
presence of H2O (2 equiv) for 8 h.
reaction in detail, the solvent effect was examined. Polar
aprotic solvents such as DMF, DMSO, and CH3CN were
effective for this reaction (Table 1, entries V, VI, and IX).
In contrast, nonpolar aprotic solvents such as CH2Cl2,
toluene, and THF were ineffective (Table 1, entries I-III).
The protic solvent, CH3OH, demonstrated a moderate effect
(Table 1, entry IV). Among the described solvents, CH3CN
was the most effective.
a Isolated yield. b Value in parentheses is the recovery of the starting
material. c Reaction was performed by using TMG (0.1 equiv) for 13 h.
d Reaction was performed by using TMG (0.1 equiv) in the presence of
H2O (2 equiv) for 13 h. e Reaction was performed by using TMG (0.1 equiv)
in the presence of H2O (2 equiv) for 24 h. f Solvent was 1/1 (v/v) TMG/
CH3CN. g Reaction was performed for 4 h. h Reaction was performed for
49 h. i Reaction was carried out at room temperature for 20 min. j TMG
was used 12 equiv. k Solvent was 1/1 (v/v) THF/CH3CN.
Further, the effects of temperature, H2O as an additive,
and the amount of TMG were examined (Table 1) so that
optimized reaction conditions could be determined (4 equiv
of TMG in CH3CN at 50 °C for 1 h; Table 1, entry XIV).12
This novel method for desilylation could be applied to a
variety of silylated compounds. The desilylation of silyl
ethers 1, 3-7, 11 by using TMG in CH3CN afforded the
corresponding phenols in virtually quantitative isolated yields
(Table 1, entry XIV; Table 2, entries I-V and VIV). Notably,
the desilylation of silyl ether 11 had no influence on acetyl
groups. Further, it should be noted that the desilylation of
(8) A method of chemoselective cleavage of the phenolic silyl ether by
using DMSO/H2O/90 °C has been reported, but this has no chemoselectivity
between benzylic and phenolic TBDMS ethers: Maiti, G.; Roy, S. C.
Tetrahedron Lett. 1997, 38, 495.
210
Org. Lett., Vol. 5, No. 2, 2003

TBDMS ether 5 bearing an electron-donating group was very
slow in comparison with the desilylation of TBDMS ethers
1 and 4. Phenolic silyl ethers bearing an electron-withdrawing
group were deprotected more easily than those bearing an
electron-donating group. Therefore, it was found that more
acidic phenolic silyl ethers are deprotected easily.6 The
chemoselective desilylation of bis-silyl ethers 8-10 bearing
both phenolic silyl and aliphatic silyl groups in the same
moleclue was also investigated.13 Phenolic TBDMS or
TBDPS ethers were completely desilylated without affecting
aliphatic TBDMS or TBDPS ethers (Table 2, entries VI-
VIII).14-16 To the best of our knowledge, this is the first
successful chemoselective desilylation of phenolic TBDPS
ethers in the presence of an aliphatic TBDPS ether.17
Table 3. Chemoselective Desilylation of Various Silyl Esters
by Using TMG
This desilylation reaction was applied to silyl esters. As
expected, the desilylation of TBDPS esters 20 and 21 by
using TMG could be performed smoothly to give high yields
(Table 3, entries I and II). The desilylation of 22 bearing
both carboxylic and aliphatic silyl groups gave only the
corresponding carboxylic acid, without affecting the aliphatic
TBDPS group, in high yield (Table 3, entry III).13
a Isolated yield. b Solvent was 1/1 (v/v) THF/CH3CN.
(9) Two examples of chemoselective cleavage of the phenolic TBDMS
ether by using acidic reagents, 10% HCl (aqueous)9a and camphorsulfonic
acid,9b have been reported, but these examples are special cases. Generally,
it is known that basic conditions favor the chemoselective cleavage of
phenolic silyl ether, while acidic conditions favor the chemoselective
cleavage of aliphatic silyl ether:6 (a) Davis, F. A.; Clark, C.; Kumar, A.;
Chen, B.-C. J. Org. Chem. 1994, 59, 1184. (b) Angle, S. R.; Wada, T.
Tetrahedron Lett. 1997, 38, 7955.
Furthermore, we found that this method was applicable
for chemoselective deacetylation. When phenolic acetates
26-28 were examined, the phenolic acetyl group was
selectively deprotected (Table 4, entries I-III).16
(10) For the selective deprotection of aliphatic TBDMS by using acidic
conditions: (a) Lee, A. S.-Y.; Yeh, H.-C.; Tsai M.-H. Tetrahedron Lett.
1995, 36, 6891. (b) Lee, A. S.-Y.; Shie, J.-J. Tetrahedron Lett. 1998, 39,
5249. (c) Lipshutz, B. H.; Keith, J. Tetrahedron Lett. 1998, 39, 2495. (d)
Lee, A. S.-Y.; Yeh, H.-C.; Shie, J.-J. Tetrahedron Lett. 1998, 39, 5249. (e)
Oriyama, T.; Kobayashi, Y.; Noda, K. Synlett 1998, 1047.
Table 4. Chemoselective Deacetylation of the Various
Phenolic Acetates by Using TMG
(11) For the selective deprotection of phenolic acetyl esters: (a) Gonza´lez,
A. G.; Jorge, Z. D.; Dorta, H. L.; Luis, F. R. Tetrahedron Lett. 1981, 22,
335. (b) Kunesch, N.; Miet, C.; Poisson, J. Tetrahedron Lett. 1987, 28,
3569. (c) Ono, M.; Itoh, I. Tetrahedron Lett. 1989, 30, 207. (d) Bandgar,
B. P.; Uppalla, L. S.; Sagar, A. D.; Sadavarte, V. S. Tetrahedron Lett. 2001,
42, 1163.
(12) Typical procedure: to a solution of TBDMS ether 1 (58 mg, 0.2
mmol) in CH3CN (1.0 mL) was added TMG (1,1,3,3-tetramethylguanidine)
(92 mg, 0.8 mmol) at room temperature. The solution was stirred for 1 h
at 50 °C. The reaction was then quenched by addition of saturated aqueous
NH4Cl, and the mixture was extracted with AcOEt. The combined extract
was dried over anhydrous MgSO4, and evaporation of the solvent afforded
the crude product. This was purified by thin-layer chromatography (1:1
hexane-AcOEt) to afford the corresponding phenol (33 mg, 92%).
(13) Because 10 and 22 were insoluble in CH3CN, 1:1 THF/CH3CN was
used as a solvent.
(14) The desilylation position of the TBDMS group was determined by
1H NMR. The tert-butyl signals of aliphatic TBDMS ethers and phenolic
TBDMS ethers were found to be 0.85 and 0.98 ppm, respectively.7c
(15) In the case of TBDPS ethers, there is no crucial difference in the
chemical shift for the tert-butyl group between aliphatic TBDPS and
phenolic TBDPS ethers. Therefore, the desilylation position was determined
by acetylation of the desilylated compounds 17 and 18 to acetates (see
Supporting Information).
(16) The position of the acetyl group was determined by acylation shift
and methyl signals of acetyl esters. Hydroxyl methylene and methine signals
of the compounds did not show any acylation shift. The methyl signals of
aliphatic acetyl esters and phenolic acetyl esters are 2.02-2.10 and 2.25-
2.36 ppm, respectively: (a) Santaniello, E.; Fiecchi, A. J. Chem. Soc., Perkin
Trans. 1 1983, 2765. (b) Paradisi, M. P.; Zecchini, G. P.; Torrini, I.
Tetrahedron Lett. 1986, 27, 5029. (c) Allevi, P.; Ciuffreda, P.; Longo, A.;
Anastasia, M. Tetrahedron: Asymmetry 1998, 9, 2915. (d) Yang, J.;
Breslow, R. Tetrahedron Lett. 2000, 41, 8063.
a Isolated yield. b Solvent was 1/1 (v/v) TMG/CH3CN.
To clarify the mechanism of the deprotection reaction,18
1
it was followed by H NMR. A 1:1 mixture of 1 and TMG
in CD3CN was observed at room temperature. The methyl
signal of TMG was downfield-shifted by 0.07 ppm in
comparison with that in CD3CN, while the proton signals of
(17) Selective deprotection of aliphatic TBDPS without affecting phenolic
TBDPS ethers has been reported,10c-e but selective deprotection of phenolic
TBDPS without affecting aliphatic TBDPS ethers has not been reported.
Org. Lett., Vol. 5, No. 2, 2003
211

reaction. From these results, we assume the catalytic mech-
anism for our desilylation reaction in the presence of H2O
as shown in Scheme 1.
Scheme 1. Proposed Mechanism for Desilylation by Using
TMG
In conclusion, we have demonstrated that TMG, a nitrogen
organic base, is a convenient and useful reagent for chemose-
lective deprotection of both silyl and acetyl groups on acidic
hydroxyl groups such as phenol and carboxylic acid, without
affecting aliphatic silyl and acetyl groups. We believe that
this novel chemoselective deprotection method will serve as
a useful tool for the synthesis of biologically significant
products.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (COE) No. 07CE2004 and
for Scientific Research on a Priority Area No. 12045234 from
the Ministry of Education, Culture, Sports, Sciences, and
Technology of Japan.
Supporting Information Available: Spectroscopic char-
1
acterization of new compounds and copies of H NMR
spectrum of 1, 2, TMG, and a 1:1 mixture of 1 and TMG in
CD3CN. This material is available free of charge via the
Internet at http://pubs.acs.org.
the aromatic ring of the phenolate were upfield-shifted by
ca. 0.18 ppm in comparison with those of 2 in CD3CN. It
was ascertained that intermediate A is formed, as shown in
Scheme 1. Therefore, this desilylation might involve nu-
cleophilic attack of TMG on the Si atom.19 Next, the effect
of H2O was examined in the desilylation reaction with silyl
ethers 1 and 4 by using 0.1 equiv of TMG in the presence
of 2.0 equiv of H2O. As shown in Tables 1 and 2, it turned
out that the addition of H2O accelerated the desilylation
OL027263D
(18) Verkade et al. have reported the desilylating reagent, P(MeNCH2-
CH2)3N, as a nonionic base. Although TMG is also a nonionic base, its
reactivity is different from that of P(MeNCH2CH2)3N. In the case of
P(MeNCH2CH2)3N, chemoselectivity is not observed between phenolic and
aliphatic TBDMS ethers and the desilylation of phenolic TBDPS ethers
gives only a low yield: Yu, Z.; Verkade, J. G. J. Org. Chem. 2000, 65,
2065.
(19) (a) Chaudhry, S. C.; Kummer, D. J. Organomet. Chem. 1988, 339,
241. (b) Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002, 8, 553.
212
Org. Lett., Vol. 5, No. 2, 2003