New deprotection method of the 2,2,2-trichloroethoxycarbonyl (Troc) group with (BU3Sn)2

Article abstract of DOI:10.1016/j.tetlet.2005.08.026

The 2,2,2-trichloroethoxycarbonyl (Troc) group was efficiently removed in high yields with (Bu₃Sn)₂ in DMF under microwave heating. The present method was applied to deprotection of the Troc group on solid support.

Full text of DOI:10.1016/j.tetlet.2005.08.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6831–6832
New deprotection method of the
2,2,2-trichloroethoxycarbonyl (Troc) group with (Bu3Sn)2
Hiroomi Tokimoto and Koichi Fukase*
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
Received 12 July 2005; revised 2 August 2005; accepted 4 August 2005
Available online 19 August 2005
Abstract—The 2,2,2-trichloroethoxycarbonyl (Troc) groupwas efficiently removed in high yields with (Bu 3Sn)2 in DMF under
microwave heating. The present method was applied to deprotection of the Troc group on solid support.
Ó 2005 Elsevier Ltd. All rights reserved.
The 2,2,2-trichloroethoxycarbonyl (Troc) grouphas
been frequently used for the protection of amino and
hydroxyl groups in organic synthesis, especially oligo-
saccharide synthesis.1 For example, b-selective glycosyl-
ation of the glucosaminyl donor is readily effected by
virtue of neighboring participation of the 2-N-Troc
group.2 The Troc groupis generally removed via a
reductive elimination process, such as Zn in AcOH,
Zn–Cu in AcOH, Zn–Pb in THF, Zn–N-methylimidaz-
ole,3 Li in liquid NH3, SmI2 in THF, Cd in AcOH–
DMF, or electrolysis.1 Most of these methods are
carried out under heterogeneous conditions and hence
are difficult to apply to solid-phase synthesis. In addition,
we have sometimes observed that significant amounts of
dichloroethoxycarbonylated byproducts were formed by
the cleavage of the Troc groupwith Zn or Zn–Cu in
AcOH.
the application of the present method to solid-phase
synthesis. Previously, we reported solid-phase synthesis
of indol-2-ones (2-oxindoles) by means of aryl radical
cyclization of resin-bound N-(2-bromophenyl)acryl-
amides using Bu3SnH.4 We found that DMF was the
best choice for the radical cyclization on solid support
inducing a reagent concentration effect of Bu3SnH on
the polymer support, whereas the same reaction in
DMF under liquid-phase condition did not proceed.
Surprisingly, the Troc group was removed quantitatively
by using (Bu3Sn)2 (0.6 equiv) in DMF without any effect
on the allyl group. The resulting amino group was then
acetylated for easy purification to give the desired 2 in
99% yield. AIBN and Bu3SnH in DMF gave many
byproducts, including dichloroethoxycarbonylated
compounds (yield of 2 was 17%). Et3B also cleaved the
Troc groupbut afforded the ethyl groupadduct to the
allyl group.
We assumed that the Troc groupwould be removed via
a radical intermediate formed by abstraction of the
chlorine atom and, therefore, expected that the radical
generating reagents could cleave the Troc group. We
first examined the reaction by using N-Troc-glucos-
amine allyl glycoside 1 and AIBN (0.1 equiv) and
Bu3SnH (1.1 equiv), Et3B (1.1 equiv), or (Bu3Sn)2 in
benzene or toluene under reflux, but the cleavage of
the Troc groupproceeded very slowly to give only a tiny
amount of the desired product. We then checked the
cleavage reaction of the Troc groupin DMF considering
Ph
Ph
O
O
(Bu3Sn)2, DMF
100˚C, 1 day
O
O
O
O
BnO
BnO
TrocNH
H2N
OAllyl
OAllyl
1
Ph
O
O
Ac2O
O
BnO
AcNH
99%
OAllyl
2
We next examined the removal of the Troc groupwith
(Bu3Sn)2 under microwave irradiation to reduce the
reaction time. Deprotection in benzene hardly pro-
ceeded even under microwave irradiation (Table 1, entry
1). Microwave irradiation dramatically accelerated
Keywords: Protective group; Deprotection; Radical reaction;
Microwave.
*
Corresponding author. Tel.: +81 6 6850 5388; fax: +81 6 6850
5419; e-mail: koichi@chem.sci.oska-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.026

6832
H. Tokimoto, K. Fukase / Tetrahedron Letters 46 (2005) 6831–6832
Table 1. Deprotection of Troc group under microwave irradiation
Ph
Ph
O
O
O
Ph
(Bu3Sn)2
Ac2O
O
O
O
O
O
O
solvents
Microwave
BnO
BnO
BnO
OR
OR
OR
TrocNH
H2N
AcNH
(50 W, 20 psi, 200˚C)
2 ; R = α-Allyl
4 ; R = β-Bn
1 ; R = α-Allyl
3 ; R = β-Bn
Entry
Solvent
Substrate
(Bu3Sn)2 (equiv)
Time (min)
Product
Yield (%)
1
2
3
4
5
Benzene
DMF
DMF
DMF
DMF
1
1
3
1
3
0.6
0.6
0.6
0.1
0.1
500
50
40
50
40
2
2
4
2
4
Trace
89
94
82
99
deprotection of the Troc group in DMF (entries 2 and
3).5,6
polystyrene by amide bond formation. N-Troc glucos-
amine was then introduced to solid support by the tri-
chloroacetimidate method.7 Deprotection of the Troc
groupon solid phase was carried out by the use of
(Bu3Sn)2 (0.1 equiv) in DMF under microwave irradia-
tion. The resulting resin was acetylated and cleaved by
NaOMe in THF/MeOH to give the desired 7 in 88%
for five steps.
Interestingly, a catalytic amount of (Bu3Sn)2 was enough
to complete the deprotection reaction (Table 1, entries 4
and 5). Probably, Bu3SnCl formed by the reaction was
reacted with the tributylstannyl radical to regenerate
(Bu3Sn)2 and form a chlorine radical, which might be
reduced by DMF. Addition of excess radical trapping
agent anthracene prevented the cleavage reaction of
the Troc group. This result proved that the present
cleavage of the Troc groupis radical-promoted reaction.
As described, we have established a new deprotection
method of the Troc groupby using (Bu Sn)2 in DMF.
3
The present method did not afford dichloroethoxycar-
bonylated byproducts.
Acknowledgements
The present work was financially supported in part by
Grant-in-Aid for Scientific Research No. 15310149 from
the Japan Society for the Promotion of Science.
Referencesand notes
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
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´
´
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5. DiscoverTM Focused Microwave Synthesis (CEM Corpora-
tion) was used for focused microwave irradiations. A vessel
for microwave reaction was filled with 1, DMF and
(Bu3Sn)2, and then sealed with a Teflon septum. The vial
was positioned in the cavity of the microwave reactor and
irradiated with maximum power of 50 W for 50 min. After
cooling, Ac2O was added. The mixture was concentrated in
vacuo and the residue was washed with n-hexane to give 2.
6. Reviews for microwave-assisted organic synthesis: (a)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–
6284; (b) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem.
Res. 2002, 35, 717–727.
We then applied the present method to solid-phase syn-
thesis, since the cleavage reaction is carried out under
homogeneous conditions. The reaction sequence began
with the introduction of linker 5 to aminomethylated
7. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212–
235.