Selective synthesis of fluorinated carbohydrates using N,N-diethyl-α, α-difluoro-(m-methylbenzyl)amine

Article abstract of DOI:10.1016/j.tetlet.2003.11.121

Deoxyfluorination of a hydroxy group in carbohydrates was carried out using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine. A primary hydroxy group in carbohydrates was effectively converted to the corresponding fluoride under microwave irradiation or at 100°C. Deoxyfluorination of hydroxy groups at the anomeric position proceeded at below room temperature, and glycosyl fluorides could be obtained in good yields. The reaction chemoselectively proceeded, and various protecting groups of carbohydrates can survive under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2003.11.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1287–1289
Selective synthesis of fluorinated carbohydrates using
N,N-diethyl-a,a-difluoro-(m-methylbenzyl)amine
Shingo Kobayashi, Atushi Yoneda, Tsuyoshi Fukuhara and Shoji Hara*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 24 September 2003; revised 7 November 2003; accepted 21 November 2003
Abstract—Deoxyfluorination of a hydroxy group in carbohydrates was carried out using N,N-diethyl-a,a-difluoro-(m-methyl-
benzyl)amine. A primary hydroxy group in carbohydrates was effectively converted to the corresponding fluoride under microwave
irradiation or at 100 °C. Deoxyfluorination of hydroxy groups at the anomeric position proceeded at below room temperature, and
glycosyl fluorides could be obtained in good yields. The reaction chemoselectively proceeded, and various protecting groups of
carbohydrates can survive under the reaction conditions.
Ó 2003 Elsevier Ltd. All rights reserved.
Fluorinated carbohydrates have recently received much
attention because of their important role for the study of
the enzyme–carbohydrate interactions as well as their
interesting biological activities.1 We found that N,N-
diethyl-a,a-difluoro-(m-methylbenzyl)amine (1)2 is a
selective reagent for a fluorinated carbohydrate synthe-
sis (Eq. 1).
72 h.4 On the other hand, the reaction proceeded more
quickly under the micro-wave irradiation conditions6
and 3 was isolated in 70% yield in 20 min (Table 1).7 The
reaction of methyl 2,3-O-isopropylidene-b-D-ribofura-
nose (4) with N,N-diethylaminosulfur trifluoride
(DAST) was previously reported to cause migration of
the methoxy group from 1- to 5-position, and an
unexpected 5-O-methyl-2,3-O-isopropylidene-b-D-ribo-
furanosyl fluoride was obtained instead of the expected
5-deoxy-5-fluoro derivative (5).9 In the reaction of 4
with 1 under the micro-wave irradiation conditions, 5
could be obtained in 51% yield with the methoxy group
migrated product (20% yield). Migration of the methoxy
group could be prevented by carrying out the reaction in
dioxane at 100 °C in the presence of KF to selectively
give 5 in 67% yield. Similarly, an a-isomer (7) could be
stereospecifically obtained in 63% yield from an a-ribose
derivative (6). Under the same conditions, 1,2,3,4-tetra-
F
F
NEt2
OH
O
F
O
O
1
O
O
O
O
NEt2
+
O
O
O
O
2
3
ð1Þ
O-acety-a-
D
-glucopyranose (8) could be converted to
-glucopyra-
1,2,3,4-tetra-O-acety-6-deoxy-6-fluoro-a-
D
nose (9) in 68% yield. DFMBA 1 can be also used for
the deoxyfluorination of nucleosides and 20,30-O-iso-
propylideneuridine (10) could be converted to 50-deoxy-
50-fluoro derivative (11) in 55% yield without migration
of the uracil ring under the micro-wave irradiation
conditions.10
The deoxyfluorination of 1,2;3,4-di-O-isopropylidene-a-
-galactopyranose (2) by 1 slowly proceeded under the
thermal conditions in a hydrocarbon solvent and only
D
20% of 2 was converted to 6-deoxy-6-fluoro-1,2;3,4-di-
O-isopropylidene-a- -galactopyranose (3) at 150 °C in
D
DFMBA 1 is also applicable for the selective synthesis
of glucosyl fluorids.11 Deoxyfluorination reaction of
hydroxy groups at the anomeric position in various
carbohydrates with 1 proceeded at below room tem-
perature and the corresponding glycosyl fluorides could
Keywords: Carbohydrates; Halogenation; Microwave heating.
* Corresponding author. Tel./fax: +81-11-706-6556; e-mail: hara@
org-mc.eng.hokudai.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.121

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S. Kobayashi et al. / Tetrahedron Letters 45 (2004) 1287–1289
Table 1. Deoxyfluorination of primary hydroxy group in sugars and a
nucleoside using DFMBAa
Table 2. Deoxyfluorination of anomeric hydroxy group in sugars
using DFMBAa
Substrate
Condition
Product
Yield (%)b
Sugar
Product
Yield (%)b
90c
OH
O
F
MW 20 min
heptane
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
F
70
O
OH
α only
13
O
12
O
2
3
O
α : β = 43 : 57
OBn
OBn
O
BnO
BnO
O
OMe
HO
OMe
F
F
O
O
O
F
85
80
100 °C 16 h
dioxane
67c;d
OH
α only
BnO
14
BnO
O
4
O
O
O
15
O
5
α : β = 40 : 60
OAc
HO
OAc
O
O
AcO
AcO
AcO
F
63c;d
O
100 °C 24 h
dioxane
OMe
OH
OMe
O
O
O
AcO
β only
7
OAc
OAc
17
16
6
α : β = 60 : 40
OH
O
F
tBuMe2SiO
AcO
AcO
tBuMe2SiO
AcO
AcO
O
O
O
100 °C 6 h
dioxane
68c
OH
F
80d
OAc
OAc
OAc
OAc
O
O
O
O
9
8
18
19
α : β = 10 : 90
α : β = 75 : 25
O
N
O
N
NH
NH
HO
ArCOO
O
O
F
OH
O
HO
O
F
70d;e
O
O
MW 10 min
heptane
55
O
O
O
O
20
21
O
O
O
O
10
11
α : β = 10 : 90
α : β = 70 : 30
Ar = m-tolyl
a If otherwise not mentioned, 2 equiv of DFMBA to substrate was
used.
b Isolated yield based on substrate used.
c 4 equiv of KF to substrate was added.
d 2.5 equiv of DFMBA to substrate used.
HO
F
ArCOO
O
O
OH
60c;f ;g
HO
22
ArCOO
ArCOO
OH
β only
23
Ar = m-tolyl
a If otherwise not mentioned, the reaction was carried out in CH2Cl2 at
room temperature for 1 h with 1.2 equiv of DFMBA.
b Isolated yield based on sugar used.
be obtained in good yields (Table 2). Most of the pro-
tecting groups of the carbohydrates such as acetonide
(12), benzyl ether (14), acetate (16), and silyl ether (18)
can tolerate the reaction conditions. Moreover, hydroxy
groups at other than the anomeric position were not
converted to fluoride by 1 at below room temperature.
c The reaction was carried out without any solvent.
d The reaction was carried out at 0 °C.
e 2.4 equiv of DFMBA to sugar was used.
f 8 equiv of DFMBA to sugar was used.
g The reaction was carried out for 12 h.
For instance, 2,3-O-isopropylidene-
reacted with 2.4 equiv of 1 at 0 °C to give 2,3-O-iso-
propylidene-5-O-m-methylbenzoyl- -ribofuranosyl
D-ribofuranose (20)
References and notes
D
fluoride (21) in 70% yield. Under the reaction condi-
tions, only the hydroxy group at the anomeric position
was selectively deoxyfluorinated and the hydroxy group
at the 5-position was only acylated. Furthermore,
1. Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Carbohydr.
Res. 2000, 327, 47–86.
2. Previously, N,N-dimethyl-a,a-difluorobenzylamine was
used for the deoxyfluorination of simple alcohols and
carboxylic acids3.
3. Dmowski, W.; Kaminski, M. J. Fluorine Chem. 1983, 23,
219–228.
4. DFMBA is a thermally stable fluorinating regent and its
exothermic starting point (ARC) is 180.0 °C.5
5. Yoshimura, T.; Fushimi, N.; Hidaka, T.; Kawai, K. WO
03/020685 A1, 2003.
D
-xylose (22), having four free hydroxy groups, can be
directly converted to 2,3,4-tri-O-m-methylbenzoyl-
-xylopyranosyl fluoride (23) in 60% yield by the reac-
tion with 8 equiv of 1.
D
6. As for the effect of micro-wave in organic synthesis, see:
Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH:
Weinheim, 2002.
7. Into a reactor consisting of a TeflonTM PFA tube with a
diameter of 10 mm sealed at one end, were introduced
heptane (1 mL), 1 (213 mg, 1 mmol), and 2 (130 mg,
Acknowledgements
We are grateful to Mitubishi Gas Chemical Company
Inc. for their donation of DFMBA and its ARC data.

S. Kobayashi et al. / Tetrahedron Letters 45 (2004) 1287–1289
1289
0.5 mmol). The open end of the reactor was connected to a
port in a domestic microwave oven and the port was
connected to a reflux condenser located outside the oven.8
Then, the reaction mixture was submitted to microwave
irradiation for 20 min. During the irradiation, the reaction
mixture was refluxed vigorously. After the reaction, the
reaction mixture was poured into aq NaHCO3 and
extracted with ether three times. The combined ethereal
layers were dried over MgSO4, concentrated under
reduced pressure. Purification by column chromatography
(silica gel/hexane–Et2O) gave 3 in 70% yield. IR (neat)
5.1 Hz, 1H), 4.48–4.65 (3H, m), 5.56 (d, J ¼ 4:9 Hz, 1H);
19FNMR (376 MHz, CDCl3) d )231.73 (dt, J ¼ 14:0,
47.6 Hz, 1F); 13CNMR (100 MHz, CDCl3) d 24.39, 24.88,
25.90, 26.00, 66.60 (d, J ¼ 22:3 Hz), 770.39, 70.47, 70.55,
82.04 (d, J ¼ 167:9 Hz), 96.15, 108.78, 109.63; HRMS
calcd for C12H19O5F 262.1216, found 262.1215.
8. Inagaki, T.; Fukuhara, T.; Hara, S. Synthesis 2003, 1157–
1159.
9. Lloyd, A. E.; Coe, P. L.; Walker, R. T.; Howarth, O. W.
J. Fluorine Chem. 1993, 60, 239–250.
10. As for a review of fluorinated nucleosides, see: Pankiewicz,
K. W. Carbohydr. Res. 2000, 327, 87–105.
2990, 1184, 1256, 1213, 1072 cmꢀ1 1HNMR (400 MHz,
;
CDCl3) d 1.34 (s, 6H), 1.45 (s, 3H), 1.55 (s, 3H), 4.07–4.10
(m, 1H), 4.27 (dd, J ¼ 2:0, 8.1 Hz, 1H), 4.35 (dd, J ¼ 2:4,
11. As for a review of glycosyl fluorides, see: Shimizu, M.;
Togo, H.; Yokoyama, M. Synthesis 1998, 799–822.