A novel de-O-chloroacetylation reagent: 1-seleonocarbamoylpiperidine

Article abstract of DOI:10.1016/j.tetlet.2006.07.009

1-Selenocarbamoylpiperidine 2 chemoselectively cleaves the O-chloroacetyl group in the presence of other acyl groups such as acetyl, pivaloyl, and Fmoc without the assistance of a base. The high lipophilicity of 2 allowed us to use 1,4-dioxane, THF, and D

Full text of DOI:10.1016/j.tetlet.2006.07.009

Tetrahedron Letters 47 (2006) 6603–6606
A novel de-O-chloroacetylation reagent:
1-seleonocarbamoylpiperidine
Shingo Sogabe,a Hiromune Ando,b,* Mamoru Koketsub and Hideharu Ishiharaa,*
aDepartment of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
bDivision of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 31 May 2006; revised 3 July 2006; accepted 6 July 2006
Available online 28 July 2006
Abstract—1-Selenocarbamoylpiperidine 2 chemoselectively cleaves the O-chloroacetyl group in the presence of other acyl groups
such as acetyl, pivaloyl, and Fmoc without the assistance of a base. The high lipophilicity of 2 allowed us to use 1,4-dioxane,
THF, and DMF as reaction solvents, thereby enabling dechloroacetylation at high temperature. A comparative experiment with
other dechloroacetyl reagents showed that selenourea 2 has a high potential as a dechloroacetylation reagent.
Ó 2006 Elsevier Ltd. All rights reserved.
The chloroacetyl (CAc) group has been widely used for
the protection of hydroxyl group during organic synthe-
sis. In particular, the chemoselective deprotection of the
CAc group in the presence of other acyl functionalities
such as the acetyl, benzoyl, and levulinoyl groups serves
as a critical method for the synthesis of complex oligo-
saccharides. Thus far, thiourea,1 hydrazine dithio-
carbonate (HDTC),2 pyridine,3 and diazabicyclo[2.2.2]
octane (DABCO)4 are representative of dechloroacetyl-
ation reagents. Thiourea and HDTC are believed to
deprotect the CAc group by following the cyclization
mechanism. This mechanism is illustrated in Scheme 1:
the nucleophilic atom (X) of the reagent replaces the
chlorine atom of the CAc group, and then another
nucleophilic atom (Y) attacks the carbonyl carbon to
break the C–O bond, thereby resulting in the production
of free hydroxyl. In contrast, tertiary-amine-containing
reagents such as pyridine and DABCO presumably
attack the a-carbon to form onium salt, which is then
solvolyzed by water, MeOH, or EtOH to produce naked
hydroxyl group.
Among the reagents, although thiourea is most widely
used, it is usually difficult to achieve complete deprotec-
tion at the hindered position. On the other hand, HDTC
performs fast and with clear deprotection. However, it is
critical that the HDTC be used immediately after its
preparation due to it poor chemical stability. The
recently reported DABCO also cleaves CAc in a fast
and clean manner even at the hindered position, but
the reaction media is limited to alcoholic solvents due
to the solvent-assisted reaction mechanism. This limita-
tion sometimes hampers its application to the deprotec-
tion of the CAc group installed in the fully protected
lipophilic oligosaccharide. In this study, we demonstrate
that 1-seleonocarbamoylpiperidine 2 serves as a new
de-O-chloroacetylation reagent.
X
O
X
Cyclization
R
Y
O
R
Y
O
HO
Cl
ROH
O
R
O
N
R
Solvolysis
R
N
R
O
R
R
Scheme 1. Plausible mechanism of dechloroacetylation.
Se
Se
LiAlH4
HCl
N
NH2
N
N
C
THF
0 °C
91% (2 steps)
THF
0 °C
Keywords: Chloroacetyl group; Selenourea; Chemoselective
deprotection.
2
1
*
Corresponding authors. Tel./fax: +81 58 293 2617; e-mail: hando@
cc.gifu-u.ac.jp
Scheme 2. Preparation of 1-selenocarbamoylpiperidine 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.009

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S. Sogabe et al. / Tetrahedron Letters 47 (2006) 6603–6606
Table 1. Examination of dechloroacetylation of glucoside 4 with 2
Previously, we reported the facile and high-yielding
synthesis of 2 by reaction of 1-cyanopiperidine 1 with
LiAlHSeH that is generated in situ by the action of
LiAlH4 and selenium5, (Scheme 2); furthermore, we
recently reported its application to selenium-containing
Se
NH2
2
or
OCAc
O
OH
O
3
CAcO
BnO
HO
OSE
OSE
heterocycle formation.6 As
a
dechloroacetylation
BnO
OBn
4
OBn
5
reagent, we expected this compound to exhibit higher
reactivity than thiourea because of the high nucleo-
philicity of selenium and expected a higher lipophilicity
because of the piperidine skeleton within 2.
Entry Reagenta Solvent
Baseb
Temp Time Yield
(°C)
DIEA rt
rt
DIEA 50
(h)
(%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
3
THF
THF
THF
THF
Diox
DMF
CH2Cl2
THF
19
24
3
7
6
6
6
6
81
99
88
99
95
90
64
0
—
To evaluate the potential of 2 as a dechloroacetylation
reagent, 4,6-di-O-chloroacetyl glucoside 4 (1.0 equiv)
was reacted with 2 (2.4 equiv) under various conditions
(Table 1). In entries 1–4, the reactions were conducted in
THF with or without the presence of N,N-diisopropyl-
ethylamine (DIEA) (2.4 equiv). In the presence of
DIEA, miscellaneous byproducts were accompanied
with the deprotected product 5 (entries 1 and 3). On
the other hand, without the use of DIEA, 2 cleaved
the CAc group quantitatively (entries 2 and 4).à Simi-
larly, both the reactions conducted in 1,4-dioxane and
DMF proceeded smoothly to yield 4,6-diol in high yields
(entries 5 and 6). However, in less polar CH2Cl2, the
yield of 5 diminished to 64% (entry 7). In entry 8, sele-
noamide 37 was reacted with 4. As a result, 3 did not
cleave the CAc group at all; this suggests that the urea
skeleton was critical for CAc group cleavage.
—
—
—
—
—
50
50
80
50
50
DIEA = N,N-diisopropylethylamine.
Diox = 1,4-dioxane.
a 2.4 equiv for compound 4.
b 2.4 equiv for compound 4.
Table 2. Comparative experiment on dechloroacetylation
OH
O
OCAc
O
BnO
BnO
BnO
BnO
BnO
BnO
Reagent
(1.2 equiv)
O
MeO
O
O
OTIPS
O
OTIPS
O
MeO
O
reflux
OSE
OSE
Next, we conducted a comparative experiment with sel-
enourea 2 and other dechloroacetylating reagents. Thus,
the dechloroacetylation of the C-2 axial position of
disaccharide 6 was attempted with 2, thiourea, DABCO,
and 1-thiocarbamoylpiperidine (TCP)8 (Table 2). Under
the optimal conditions reported in the literatures,1,4
thiourea and DABCO cleaved the CAc group in 41%
and 91% yields, respectively (entries 1 and 2). Further,
we confirmed that DABCO did not react with the CAc
functionality in THF (entry 3). On the other hand,
dechloroacetylations with selenourea 2 in refluxed
THF and 1,4-dioxane proceeded smoothly to produce
a monohydroxy compound 7 in 85% and 96% yields,
O
O
OMe
6
OMe
7
Entry
Reagent
Solvent
Bath
Temp (°C)
Time
Yield
(%)
(h)
1
2
3
4
5a
6a
Thiourea
DABCO
DABCO
2
MeOH
EtOH
THF
THF
Diox
70
80
80
80
110
110
17
7
20
8
7
15
41
91
0
85
96
39
2
TCP
Diox
SE = 2-(trimethylsilyl)ethyl.
TIPS = triisopropylsilyl.
DABCO = diazabicyclo[2.2.2]octane.
TCP = 1-thiocarbamoylpiperidine.
a 2.4 equiv of reagents was used.
Preparation of 1-selenocarbamoylpiperidine 2 (modified protocol of
Ref. 5). Step 1: To a solution of 1-piperidinecarbonitrile (1; 1.5 mL,
10.0 mmol) in THF (100 mL), a 1 M solution of hydrogen chloride in
diethylether (20.0 mL, 20.0 mmol) was added at 0 °C under an argon
atmosphere; this mixture (mixture A) was stirred for 2 h. Step 2: To a
suspension of black selenium powder (800 mg, 10.0 mmol) in THF
(100 mL), lithium aluminum hydride (380 mg, 10.0 mmol) was added
in portions at 0 °C under an argon atmosphere, and the suspension
was stirred for 30 min. The suspension turned grayish. Step 3: To the
stirred grayish suspension, mixture A was added dropwise at 0 °C.
After stirring for 3 h, the reaction mixture was extracted with CH2Cl2,
and the organic layer was washed with water, dried over Na2SO4, and
concentrated. The resulted residue was crystallized from CH2Cl2 and
nHex to give 2 as yellow crystals (ꢀ70%).
respectively (entries 4 and 5). In the case of the corre-
sponding thio-homolog TCP, the CAc group was
cleaved in 39% yield (entry 6), suggesting that the high
reactivity of 2 is endowed with a selenocarbonyl moiety.
In the next step, to examine the chemoselectivity of
dechloroacetylation by selenourea 2, several substrates
bearing the CAc group with other acyl functionalities
were reacted. The results are summarized in Table 3.
The CAc group at the C4 hydroxyl of glucoside 8, which
was hampered by a bulky pivalate group at C6, was
exclusively deprotected in high yield, and gratifyingly,
a base-labile Fmoc group mounted on the C6 hydroxyl
of glucoside 9 was also insusceptible to selenourea 2,
thus affording 13 in 90% yield (entries 1 and 2). Simi-
larly, the CAc group within Fmoc-protected serine allyl
à Typical procedure of dechloroacetylation (the case of entry 4): To a
solution of compound 4 (105 mg, 0.171 mmol) in THF (2.0 mL), 2
(78 mg, 0.410 mmol) was added, and the reaction mixture was stirred
for 7 h at 50 °C and monitored by TLC (EtOAc/nHex = 2/3). The
reaction mixture was filtered through CeliteÒ and concentrated in
vacuo. The resulting residue was chromatographed on silica gel
(EtOAc/nHex = 1/3) to yield 5 (78 mg, 99%).

S. Sogabe et al. / Tetrahedron Letters 47 (2006) 6603–6606
Table 3. Examination of chemoselective deprotection of CAc with 2
6605
R
R
O
O
2
O
O
O
OH
CAc
Entry
Substrate
Equivalents of 2
Solvent
Temp (°C)
Time (h)
Product
Yield (%)
1
2
3
4
8
1.2
2.0
1.2
1.2
THF
Diox
THF
Diox
50
60
70
10
3
8
12
13
14
15
90
90
99
99
9
10
11
100
5
OPiv
O
OFmoc
O
RO
RO
BnO
OSE
OSE
BnO
OBn
8 R = CAc
12 R = H
OBn
9 R = CAc
13 R = H
OR
OR
COOMe
AcO
O
SPh
AcHN
AcO
CO2All
FmocHN
OAc
10 R = CAc
14 R = H
11 R = CAc
15 R = H
ester 10 was also cleanly deprotected to give 14 in an
almost quantitative yield (entry 3). Further, CAc at
the hindered C8 position of sialic acid 11 was also quan-
titatively cleaved in refluxed 1,4-dioxane without the
cleavage and migration of acetyl groups, thereby
producing 8-OH sialoside 15, as indicated by the spectra
of 2 allowed the usage of DMF, THF, and 1,4-dioxane
as reaction solvents. Moreover, 2 proved to be stable for
three months when it was stored in a freezer. These fea-
tures reinforce the application of 2 to the deprotection
of the CAc group within lipophilic oligosaccharides.
1
of H NMR.9
Acknowledgements
Finally, we conducted the reaction of 4-O-CAc-gluco-
side 16 with 2 to discuss the reaction mechanism. This
reaction concomitantly produced selenazolone deriva-
tive 186 in the yield of 97%, with 4-OH glucoside 17
(95%) (Scheme 3). This result strongly suggests that
dechloroacetylation by 2 proceeds via the cyclization
mechanism.
This work was supported by MEXT of Japan (Grant-in-
Aid for Scientific Research to H.A., No. 16780083) and
the Mitsubishi Chemical Corporation Fund (H.A.).
References and notes
1. Naruto, M.; Ohno, K.; Naruse, N.; Takeuchi, H. Tetra-
hedron Lett. 1979, 20, 251–254.
2. van Boeckel, C. A. A.; Beetz, T. Tetrahedron Lett. 1983, 24,
3775–3778.
In conclusion, we have demonstrated that 2 deprotects
the O-CAc group with high chemoselectivity via the
cyclization mechanism. The lipophilic piperidine moiety
3. Johnson, F.; Starkovsky, N. A.; Paton, A. C.; Carlson, A.
A. J. Am. Chem. Soc. 1964, 86, 118–119.
4. Lefeber, D. J.; Kamerling, J. P.; Vliegenthart, F. G. Org.
Lett. 2000, 2, 701–703.
5. (a) Koketsu, M.; Fukuta, Y.; Ishihara, H. Tetrahedron Lett.
2001, 42, 6333–6335; (b) Ishihara, H.; Kokestu, M.;
Fukuda, Y.; Nada, F. J. Am. Chem. Soc. 2001, 123,
8408–8409.
Se
O
O
OBn
O
Se
Cl
H
N
O
O
N
+
OSE
NH
N
BnO
THF
40 °C
H
OBn
2
16
(1.2 equiv)
(1.0 equiv)
6. (a) Koketsu, M.; Kanoh, K.; Ando, H.; Ishihara, H.
Heteroat. Chem. 2006, 17, 88–92; (b) Koketsu, M.; Tanaka,
H.; Ishihara, H. Chem. Lett. 2005, 34, 1260–1261; (c)
Koketsu, M.; Nada, F.; Ishihara, H. Synthesis 2002, 195–
198.
7. (a) Ishihara, H.; Yosimura, K.; Kouketsu, M. Chem. Lett.
1998, 1287–1288; (b) Ogawa, A.; Miyake, J.; Karasaki, Y.;
Murai, S.; Sonoda, N. J. Org. Chem. 1985, 50, 384–386.
Se
OBn
O
O
HO
BnO
N
N
OSE
+
OBn
17
95%
18
97%
(based on 16)
Scheme 3. Proposed mechanism of dechloroacetylation with 2.

6606
S. Sogabe et al. / Tetrahedron Letters 47 (2006) 6603–6606
8. Ziegler, T.; Pantkowski, G. J. Carbohydr. Chem. 1993, 12,
J3ax,4 = J4,5 = 11.4 Hz, H-4), 5.14 (dd, 1H, J6,7 = 5.8,
J7,8 = 1.7 Hz, H-7), 4.66 (dd, 1H, J5,6 = 10.3 Hz, H-6),
4.10 (m, 4H, H-5, H-9, H-9, H-8), 3.56 (s, 3H, COOMe),
2.69 (dd, 1H, Jgem = 13.7 Hz, H-3eq), 2.13, 2.08, 2.04, and
1.93 (4s, 12H, 4Ac); 13C NMR (CDCl3, 100 MHz) d 171.2,
171.1, 171.0, 170.5, 168.0, 135.8, 129.7, 129.4, 129.0, 89.2,
72.5, 70.6, 69.2, 69.1, 65.8, 52.6, 49.5, 37.8, 23.1, 20.9.
357–370.
1
9. (a) H NMR analysis showed the cleavage of the chloro-
acetyl group (d 4.10; d, 2H) and the shift of H-8 from 5.04
to 4.10 ppm; (b) NMR data of 15: 1H NMR (CDCl3,
500 MHz)
d 7.51–7.32 (m, 5H, Ph), 6.10 (d, 1H,
J5,NH = 9.8 Hz, NH), 5.39 (td, 1H, J3eq,4 = 4.6,