LETTER
1105
Facile Removal Strategy for Allyl and Allyloxycarbonyl Protecting Groups
Using Solid-Supported Barbituric Acid under Palladium Catalysis
F
acile Removal St
i
rategy
for
Allyl
o
and
A
llyloxy
k
carbonyl Pr
a
otecting
G
r
z
oups u Tsukamoto,* Takamichi Suzuki, Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)2176849; E-mail: hirokazu@mail.pharm.tohoku.ac.jp
Received 6 April 2003
X
Abstract: Solid-supported barbituric acid can be used for the palla-
dium(0)-catalyzed deprotection of allyl amines, carbamates, car-
bonates, esters and ethers. This solid-supported reagent facilitates
isolation and purification of the deprotected compounds, especially
acids and amines.
R
R
X = CO2, NR', O
Filtration
1a
X
O
R
XH
cat. Pd(0)
O
1a, 2a, 3a
X = NR', O
Key words: allyl and allyloxycarbonyl groups, palladium(0)-cata-
lyzed deprotection, solid-supported barbituric acid, facile isolation,
highly polar compounds
Facile Isolation
O
O
N
1a: R=R'=H
2a: R, R'=Allyl, H
3a: R=R'=Allyl
N
R
O
O
R'
N
N
Protection and deprotection strategies are unavoidable
and ubiquitous in modern organic synthesis.1 The latter
process frequently produces highly polar deprotected
compounds such as acids and amines difficult to isolate. It
is desirable for their isolation and purification to avoid
aqueous work up and column chromatography. On the
other hand, solid-supported reagents have been often em-
ployed for solution-phase organic synthesis to save labor
in isolation and purification of the products and facilitate
parallel synthesis in solution-phase.2 These reagents are
the most suitable for the deprotection strategy because the
deprotected products can be isolated by filtration and sub-
sequent evaporation without aqueous work up. We recent-
ly reported the palladium(0)-catalyzed mild and selective
deprotection of allyl ethers employing N,N¢-dimethylbar-
bituric acid (DMBA, 1),3 which can also deprotect other
allyl derivatives such as allyl amines,4a carbamates4b and
esters.4c Herein we describe the facile deprotection strate-
gy for allyl derivatives using solid-supported barbituric
acid 1a (Scheme 1).
O
= Polymer Support
O
N, N'-Dimethylbarbituric Acid
(DMBA, 1)
Scheme 1 Facile deprotection strategy for allyl derivatives using
solid-supported barbituric acid 1a.
malonic acid to give N,N¢-dicyclohexylbarbituric acid.10
To our surprise, this method was applicable to the less re-
active polymer-supported urea 5a,b and provided the bar-
bituric acid 1a,b in good conversion even when a little
excess of reagents were used.11 Loading of 1a was deter-
mined by elemental analysis of chlorine after derivatiza-
tion to 6a with 1-(4¢-chlorophenyl)-prop-2-enyl methyl
carbonate 912 under palladium catalysis. The formation of
the barbituric acid 1a and its derivative 6a was confirmed
by spectra data13 of the cleaved residue 7 and 8 from the
corresponding Rink amide resin 1b and 6b respectively.
X
O
N
N
NH
NH
Initially, we carried out the synthesis of the solid-support-
ed barbituric acid 1a,b based on condensation of malonic
acid with polymer-supported urea 5a,b (Scheme 2).5 The
urea 5a,b was prepared by treatment of aminomethyl resin
4a or glycinated Rink amide resin 4b with n-propyl isocy-
anate. Conventional methods for the synthesis of barbitu-
ric acids in solution-phase using malonic acid and acetic
anhydride6 or diethyl malonate and sodium ethoxide7
were found to be unsuitable for the polymer-supported
urea 5a,b.8 Fushiya reported an unconventional method,9
in which N,N¢-dicyclohexylcarbodiimide (DCC) condens-
es an urea composed of only acyclic primary amines with
malonic acid selectively though DCC itself can react with
a)
b)
R
R
O
O
NH2
4a–b
O
d)
5a–b
4a : Aminomethyl Resin
1a–b : X=PS → 7 : X=CONH2
1.44 mmol/g
R=H
c)
PS
4b : Glycinated Rink Amide Resin
NHCOCH2NH2
NH2
d)
6a–b : X=PS → 8 : X=CONH2
0.57 mmol/g
R=
Cl
Cl
PS
O
MeO
OMe
MeO2CO
PS = Polystyrene
9
Scheme 2 Synthesis of solid-supported barbituric acid 1a,b
Reactions and conditions: a) n-PrNCO (4 equiv), CH2Cl2, 30 °C,
24 h; b) 0.45 M Malonic Acid (3 equiv for 5a, 6 equiv for 5b), 0.90
M DCC (6 equiv for 5a, 12 equiv for 5b) in THF, 0 °C to r.t., 4 h, loa-
ding: 1.15 mmol/g for 1a; c) 9 (10 equiv), 25 mol% Pd(PPh3)4, THF,
r.t., 12 h, loading: 0.85 mmol/g for 4a; d) 95% aq TFA, r.t., 2 h, 84%
yield of 7 for 1b, 70% yield of 8 for 6b.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1105,1108,ftx,en;U06303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York