Trichloroacetimidate as an efficient protective group for alcohols

Article abstract of DOI:10.1055/s-1999-2736

The trichloroacetimidate is disclosed to be a general and efficient protective group for alcohols, which can be deprotected under mild acidic, basic, or neutral conditions, and has orthogonal stability with the acetate and tert-butyldimethylsilyl (TBS) protections.

Full text of DOI:10.1055/s-1999-2736

LETTER
753
Trichloroacetimidate as an Efficient Protective Group for Alcohols
Biao Yu,a* Hai Yu,b Yongzheng Hui,a Xiuwen Hanb
aState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
bState Key Laboratory of Catalyst, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Fax +21 64166128; E-mail: byu@pub.sioc.ac.cn
Received 19 March 1999
ro-reaction of the addition of an alcohol to
Abstract: The trichloroacetimidate is disclosed to be a general and
trichloroacetonitrile involves.11 (C) Reductive elimination
efficient protective group for alcohols, which can be deprotected
conditions (neutral conditions) (Zn, NH4Cl, EtOH); the
under mild acidic, basic, or neutral conditions, and has orthogonal
same mechanism as in the deprotection of the 2,2,2-
trichloroethoxycarbonyl (TrOC) group12 and the 2,2,2-
trichloro-ethyl ester works.13
stability with the acetate and tert-butyldimethylsilyl (TBS) protec-
tions.
Key words: trichloroacetimidate, protective group, alcohol
Protection of hydroxyl function is one of the main themes
in the protective group chemistry, and is decisive in many
synthetic works.1 Although a very large number of protec-
tive groups for alcohols have been developed, new and ef-
ficient protection manipulation continues to be the focus
of attention and will certainly open up new possibilities
for performing the art of organic synthesis.1,2 The trichlo-
roacetimidate, which can be readily generated from an al-
cohol by addition with trichloroacetonitrile in the
presence of a base, has widely been used for two purpos-
es: (1) serves as an excellent leaving group to liberate a
useful cation, such as in glycosyl,3 benzyl,4 p-methoxy-
benzyl,5 allyl,4b,c tert-butyl,6 and 2-phenylisopropyl
trichloroacet-imidate6b; (2) serves as a neighboring nu-
cleophilic nitrogen surrogate to deliver an aza-Claisen re-
arrangement (Overman rearrangement)7 or an addition to
a trigonal site (an epoxy8 or a Hg2+ or I+ activated carbon-
carbon double bond9). To the best of our knowledge, so
far only two papers mentioned the use of the trichloroace-
timidate as a temporary protective group for hydroxyl
function.10 Both cases involved in the course of execution
of the Schmidt glycosylation;3 therein the anomeric
trichloroacetimidate at the same time was employed as a
leaving group. The trichloroacetimidate protection re-
mained intact during the glycosylation under the promo-
tion of TMSOTf and BF3∑OEt2, and was removed
afterwards under acidic conditions (1N HCl/MeOH and
80% HOAc) in moderate to good yields (51% and 87%,
respectively). Herein, we report that trichloroacetimidate
can be used as a general and efficient protective group for
alcohols, which can be deprotected under mild acidic, ba-
sic, or neutral conditions, and has orthogonal stability
with the acetate and TBS ether protections.
Scheme 1
Three conditions worked very well on the cleavage of the
trichloro-acetimidate on a relatively robust substrate 1b
(entries 1-3).14,15 However, treatment of 1b with TsOH
under longer time also resulted in the partial cleavage of
the 4,6-isopropylidene. The trichloroacet-imidate was
found to be selectively removed under acidic (condition
A) and reductive elimination conditions (condition C) in
the presence of an acetate counterpart (entries 4, 6). Pro-
longing the reaction time under Zn/NH4Cl in ethanol
(condition C) also led to the cleavage of the acetate (entry
7), which was likely effected by the eliminated fragment
(i.e. HN=C=CCl2); because it has been found that acetate
remained stable under these conditions.16 Interestingly, it
was also found that the acetate was removed selectively in
the presence of its trichloroacetimidate counterpart under
the action of DBU in methanol (condition B, entry 5). The
trichloroacetimidate in between an acetyl and benzoyl
groups was also selectively removed under the action of
TsOH (substrate 4b, entry 13); while under the action of
Zn/NH4Cl in EtOH, both the trichloroacetimidate and the
acetate were removed with the benzoate remained intact
According to the intrinsic properties of the trichloroace-
timidate, three types of conditions were sought to release
the masking hydroxyl function (Scheme 1 and Table): (A)
Acidic conditions (TsOH-H2O, MeOH/CH2Cl2, rt); the
same mechanism as in the acid catalyzed hydrolysis of es-
ters proceeds. (B) Basic conditions (DBU, MeOH); a ret-
Synlett 1999, No. 6, 753–755 ISSN 0936-5214 © Thieme Stuttgart · New York

754
B. Yu et al.
LETTER
As depicted in scheme 2,17 the use of trichloroacetimidate
as a protective group for hydroxyl function is particular
useful in the oligosaccharide synthesis. To prepare the
disaccharide acceptor 9, a protective group should be in-
troduced onto the 3-OH of 4a18 first, which should be sta-
ble under the conditions for converting the anomeric allyl
group to the trichloroacetimidate and for the subsequent
glycosylation (conditions a-c), and then has to be removed
afterwards without effecting the acetyl, benzoyl, anomer-
ic thioether, and the glycosidic bond. It was not easy to
find a perfect protective group to meet all these requests;
nevertheless, herein the trichloroacetimidate protection
was demonstrated unequivocally to be a very nice and
straightforward choice.
Acknowledgement
This work is supported by the Ministry of Science and Technology
of China. BY thanks a Research Grant from NSFC (No. 29802008).
References and Notes
(1) (a) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2056. (b) Protecting Groups, 1st ed;
Kocienski, P. J. Ed.; Thieme, Stuttgart, 1994.
(2) Protective Groups in Organic Synthesis, 2nd ed; Greene, T.
W. and Wuts, P. G. M. Ed.; John Wiley & Sons, Inc. 1991.
(3) Schmidt glycosylation (using glycosyl trichloroacetimidates
as glycosyl donors) is one of the most successful glycosylation
protocols. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986,
25, 212.
(4) (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Common.
1981, 1240. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J.
Chem. Soc. Perkin Trans. 1 1985, 2247. (c) Kokotos, G.;
Chiou, A. Synthesis, 1997, 168. (d) S. Hanessian, S.; Xie, F.
Tetrahedron Lett. 1998, 39, 733.
(5) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O.
Tetrahedron Lett. 1988, 29, 4139.
(6) (a) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk,
J. M. Synthesis, 1987, 568. (b) Thierry, J.; Yue, C.; Potier, P.
Tetra-hedron Lett. 1998, 39, 1557.
(7) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. (b)
Overman, L. E. Ibid. 1976, 98, 2901. (c) Overman, L. E. Acc.
Chem. Res. 1980, 13, 218. (d) Nishikawa, T.; Asai, M.;
Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63, 188.
(8) (a) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J.;
Fisher, P. Synthesis, 1989, 256. (b) Hatakeyama, S.;
Matsumoto, H.; Fukuyama, H.; Mukugi, Y.; Irie, H. J. Org.
Chem. 1997, 62, 2275.
(entry 14). Moreover, it was also found that the trichloro-
acetimidate has excellent orthogonal stability with anoth-
er commonly used protective group – TBS ether (entries
9-12): the trichloroacetimidate was selectively removed
under all three conditions in the presence of an TBS coun-
terpart (entries 9-11), while in turn the TBS ether was se-
lectively cleaved under TBAF without affecting its
trichloroacetimidate counterpart (entry 12), giving the
corresponding deprotection products in excellent yields.
(9) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
(10) (a) Lassaletta, J. M; Carlsson, K.; Garegg, P. J.; Schmidt, R.
R. J. Org. Chem. 1996, 61, 6873. (b) Qiu, D.; Koganty, R. R.
Tetra-hedron Lett. 1997, 38, 961.
(11) (a) Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem.
1984, 1343. (b) Schmdit, R. R.; Michel, J. Tetrahedron Lett.
1984, 25, 821.
(12) Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1967,
2555.
(13) Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;
Oppolzer, W.; Ramage, R.; Ranganathan, S, Vorbruggen, H.
J. Am. Chem. Soc. 1966, 88, 852.
(14) Typical procedures for the deprotection of
trichloroacetimidates. Condition A: to a solution of 1b (120
mg, 0.30 mmol) in CH2Cl2-MeOH (4 mL, 1:1) at rt was added
Scheme 2
Synlett 1999, No. 6, 753–755 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Trichloroacetimidate as an Efficient Protective Group for Alcohols
755
TsOH-H2O (28 mg, 0.15 mmol). After being stirred at rt for 5
(16) (a) Yu, B.; Zhang, J.; Lu, S.; Hui, Y. Synlett 1998, 29. (b)Yu,
B.; Li, B.; Zhang, J.; Hui, Y. Tetrahedron Lett. 1998, 39, 487.
(17) 1H NMR (300 MHz, CDCl3) data for compounds 5-9. 5: 8.05
(2 H, m), 7.60 (1H, m), 7.46 (2H, m), 5.26 (1H, m), 5.16-5.09
(2H, m), 4.26 (2H, m), 3.23 (1H, d, J = 4.1), 2.44 (1H, d, J =
9.7), 2.19 (3H, s), 1.28 (3H, d, J = 6.2);
min, the reaction was quenched by addition of Et3N (0.2 mL),
and then concentrated. The residue was purified by a silica gel
column chromatography (petroleum ether-EtOAc, 2:1) to give
1a as a white solid (76 mg, 98%). Condition B: to a solution
of 1b (49 mg, 0.12 mmol) in dry MeOH at rt was added DBU
(0.02 ml, 0.12 mmol). After being stirred for 2 h, the solution
was concentrated to a residue, which was purified by a silica
gel column to give 1a (32 mg, 100%). Condition C: to a
solution of 1b (83 mg, 0.21 mmol) in dry EtOH (2 mL), was
added Zn powder (67 mg, 1.0 mmol) and NH4Cl (27 mg, 1.0
mmol). After being refluxed for 5 min, the mixture was
filtered. The filtrates were concentrated to a residue, which
was purified by a silica gel column to give 1a (53 mg, 99%).
(15) 1H NMR of trichloroacetimidates (1b-4b) (300 MHz, CDCl3).
1b: 8.55 (1H, s), 5.92 (1H, d, J = 3.7), 5.32 (1H, d, J = 2.6),
4.62 (1H, d, J = 3.6), 4.38 (1H, t, J = 6.2), 4.30 (1H, dd, J =
7.5, 2.5), 4.13 (1H, t, J = 7.2), 4.02 (1H, m), 1.53, 1.41, 1.32,
1.29 (3H each, s each).
6: 8.79 (1H, s), 8.57 (1H, s), 8.01 (2H, m), 7.60 (1H, m), 7.46
(2H, m), 6.47 (1H, d, J = 1.6), 5.69-5.57 (3H, m), 4.26 (1H,
m), 1.89 (3H, s), 1.32 (3H, d, J = 6.3);
8: 8.02 (4H, m), 7.56 (2H, m), 7.43 (4H, m), 5.48-5.26 (5H,
m), 5.12 (2H, m), 4.37 (1H, dd, J = 9.7, 3.4), 4.30 (1H, m),
4.12 (1H, m), 2.66 (2H, m), 2.29 (3H, s), 1.78 (3H, s), 1.27
(9H, m);
9: 8.04 (4H, m), 7.57 (2H, m), 7.47 (4H, m), 5.41 (2H, m),
5.27 (3H, m), 4.95 (1H, d, J = 1.5), 4.32 (2H, m), 4.04 (1H, m),
3.78 (1H, m), 2.63 (2H, m), 2.23 (3H, s), 1.89 (3H, s), 1.26
(9H, m).
(18) Auzanneau, F. -I.; Forooghian, F.; Pinto, B. M. Carbohydr.
Res. 1996, 291, 21.
2b: 8.20 (1H, brs), 4.27 (2H, t, J = 6.5), 4.03 (2H, t, J = 6.8),
2.03 (3H, s), 1.78 (2H, m), 1.59 (2H, m), 1.43-1.25 (12H, m);
3b: 8.21 (1H, brs), 4.27 (2H, t, J = 6.5), 3.59 (2H, t, J = 6.5),
1.76 (2H, m), 1.51-1.28 (14H, m), 0.88 (9H, s), 0.03 (6H, s).
4b: 8.45 (1H, s), 8.02-7.80 (5H, m), 5.93 (1H, m), 5.60 (3H,
m), 5.32 (2H, m), 4.88 (1H, s), 4.24 (1H, dd, J = 12.8, 5.1),
4.10 (2H, m), 2.14 (3H, s), 1.31 (3H, d, J = 6.3).
Article Identifier:
1437-2096,E;1999,0,06,0753,0755,ftx,en;Y05599ST.pdf
Synlett 1999, No. 6, 753–755 ISSN 0936-5214 © Thieme Stuttgart · New York