Chemistry of L-ascorbic acid. IV. Regioselective O-alkylation of 5,6-O-isopropylidene-L-ascorbic acid using CsF

Article abstract of DOI:10.1081/SCC-120039489

The regioselective 3-O-alkylation of 5,6-O-isopropylidene-L-ascorbic acid is achieved under mild conditions using CsF as a base.

Full text of DOI:10.1081/SCC-120039489

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Chemistry of L‐Ascorbic
Acid. IV. Regioselective
O‐Alkylation of
5,6‐O‐Isopropylidene‐L‐ascorbic
Acid Using CsF
a
a
Mukund G. Kulkarni & Sandesh D. Kate
a
Department of Chemistry , University of Pune ,
Pune, 411007, India
Published online: 10 Jan 2011.
To cite this article: Mukund G. Kulkarni & Sandesh D. Kate (2004) Chemistry of
L‐Ascorbic Acid. IV. Regioselective O‐Alkylation of 5,6‐O‐Isopropylidene‐L‐ascorbic
Acid Using CsF, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:13, 2365-2370, DOI: 10.1081/
SCC-120039489
To link to this article: http://dx.doi.org/10.1081/SCC-120039489
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 13, pp. 2365–2370, 2004
Chemistry of L-Ascorbic Acid. IV.
Regioselective O-Alkylation of 5,6-O-
Isopropylidene-L-ascorbic Acid Using CsF
#
*
Mukund G. Kulkarni and Sandesh D. Kate
Department of Chemistry, University of Pune, Pune, India
ABSTRACT
The regioselective 3-O-alkylation of 5,6-O-isopropylidene-L-ascorbic
acid is achieved under mild conditions using CsF as a base.
Key Words: L-Ascorbic acid (vitamin C); Alkyl halides; O-Alkylation;
Ethers; Cesium fluoride.
INTRODUCTION
Selective manipulation of diols and polyols is one of the central problems
in synthetic organic chemistry, particularly, in the area of carbohydrates and
#
[1]
See Ref. .
Correspondence: Mukund G. Kulkarni, Department of Chemistry, University of Pune,
*
Pune 411007, India; Fax: þ91-020-2569-1728; E-mail: mgkulkarni@chem.unipune.
ernet.in.
2
365
DOI: 10.1081/SCC-120039489
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2
366
Kulkarni and Kate
[
2]
polyhydroxy compounds. Alkylation of L-ascorbic acid is fairly sensitive to
alkylation reagent, base, solvent and reaction conditions, as well as the deriva-
tive used. The problem becomes even more complicated as the alkylation of
L-ascorbic acid or its 5,6-O-protected derivatives may lead to 3-O-alkylation,
2
3
-O-alkylation, di-O-alkylation, and/or C-alkylation. Preparation of either
-O-alkyl or 2,3-di-O-alkyl derivatives of L-ascorbic acid was effected
[3]
using sodium hydrogen carbonate and alkyl mesylates/triflates or under
[
4]
Mitsunobu conditions. O-Alkylation of L-ascorbic acid using fluoride ion
as a base under aprotic conditions has not been reported.
The importance of fluoride ion as a catalyst for the promotion of various
[5]
types of base catalyzed reactions has been previously recognized. The work
of Clark and Miller, in particular, revealed that the fluoride ion has an effect on
[5]
[6]
coupling reactions because of hydrogen bond formation. A recent report
involves the synthesis of ethers and esters using CsF–Celite as a solid
supported base. Fluoride ion catalyzed selective O-alkylation of tetronic
[7]
acid is known. It was of interest for us to check whether the O-alkylation
of L-ascorbic acid using fluoride ion as a base would give 2-O-alkylation or
3-O-alkylation and/or 2-C-alkylation, and further what will be the extent of
selectivity in this alkylation reaction.
RESULTS AND DISCUSSION
Initial efforts to effect the reactions with L-ascorbic acid using cesium
fluoride as a base and alkyl halides/tosylates as alkylating agents gave the
3
-O-alkyl derivatives, albeit in low yields. Later, it was found that the 3-O-
alkyl derivatives could be obtained in good yields when 5,6-O-isopropylidene
derivative of L-ascorbic acid was used. The results indicated that the reactions
with primary alkylating agents such as methyl iodide, ethyl iodide, propyl
tosylate, butyl bromide/tosylate, octyl bromide/tosylate, n-tetradecyl
bromide, methoxymethyl chloride, allyl bromide, and benzyl bromide gave
the moderate yields of the corresponding 3-O-alkyl derivatives (3a–3i).
Under the conditions used, di-O-alkylation was observed in ,5% with the
above alkylating reagents. The secondary alkylating agent such as isopropyl
bromide gave the corresponding 3-O-alkyl derivative (3j) in low yield.
The products from C-alkylation were not obtained. The method is selective
favoring the 3-O-alkyl derivative rather than the 2-O-alkyl derivative.
The structures of all the products were confirmed from their physical and
spectral data.
In summary, we have developed a novel methodology for the preparation
of 3-O-alkyl derivatives of 5,6-O-isopropylidene-L-ascorbic acid employing
CsF as a base under mild conditions (Sch. 1).

Chemistry of L-Ascorbic Acid. IV
2367
Scheme 1.
EXPERIMENTAL SECTION
All solvents were distilled prior to use. Dimethyl sulfoxide was dried over
˚
calcium hydride and stored on 4-A molecular sieves. Reagents and materials
were either obtained from commercial suppliers or prepared by standard
methods. Silica gel (100–200 mesh) was used for column chromatography.
IR spectra were recorded on Shimadzu model 8400 series FT-IR instrument.
1
13
H and C NMR spectra (ppm, TMS as internal standard) in CDCl were
3
recorded on Varian Mercury 300-MHZ instrument. Optical rotations were
measured on JASCO-181 digital polarimeter under standard condition.
Mass spectra were recorded on Shimadzu GCMS instrument and mass values
are expressed as (m/z). All melting points are uncorrected and obtained with
paraffin oil bath. The elemental analysis was obtained on HOSLI semiauto-
matic C, H analyzer. Satisfactory analytical (combustion) and spectral (IR,
NMR, and MS) data were obtained for all the new compounds. Yields refer
to purification by chromatography on silica gel.
General Procedure for Alkylation of
5,6-O-Isopropylidene-L-ascorbic Acid
A mixture of 5,6-O-isopropylidene-L-ascorbic acid 1 (1 mmol), CsF
2 mmol), and the corresponding alkyl halide or tosylate 2 (2 mmol) in dry
(
DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere
till the starting material was consumed completely (tlc check, 48–72 hr).
Then the reaction mixture was diluted with water and was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried over anhy-
drous sodium sulfate, and evaporated under reduced pressure. The crude product
was purified on silica gel column using hexane–ethyl acetate solvent system.
5
,6-O-Isopropylidene-3-O-methyl-L-ascorbic acid (3a). Yield: 61%.
2
5
[8a–c]
M.p.: 116–1178C. [a]D þ 14.008 (c ¼ 2.0, MeOH).

2
368
Kulkarni and Kate
5
,6-O-Isopropylidene-3-O-ethyl-L-ascorbic acid (3b). Yield: 62%.
2
0
21
M.p.: 98–1008C. [a]D þ 21.448 (c ¼ 0.3, CHCl ). IR (Nujol, n, cm ):
3
1
320 (OH), 1755 (C 55 O), 1695 (C 55 C). H NMR (CDCl , 300 MHz): d
3
1
3
.33–1.40 (m, 9H, H , H , H ), 4.03 (dd, 1H, J 6.8, 8.5 Hz, H ), 4.13
0
2 6a
8
a
8b
(
dd, 1H, J 6.6, 8.5 Hz, H ), 4.25 (ddd, 1H, J 3.5, 6.5, 6.5 Hz, H ), 4.47–
6b 5
0
.55 (m, 3H, H , H ), 5.06 (bs, 1H, OH). C NMR (CDCl , 75 MHz): d
4 1 3
1
3
4
1
7
5.42 (C2
5.65 (C ), 110.17 (C ), 118.82 (C ), 148.85 (C ), 171.27 (C ). MS: m/z
0
), 25.60 (C ), 25.94 (C ), 65.29 (C ), 68.08 (C ), 74.27 (C ),
0
8a 8b 6 5 1
4
7
2
3
1
þ
(
%): 244 (M , 6), 230 (3), 229 (22), 200 (1), 187 (5), 169 (12), 157 (4),
41 (18), 129 (4), 113 (5), 101 (100), 85 (12), 83 (12), 73 (30), 61 (12).
Anal. calcd for C H O : C, 54.09; H, 6.55. Found: C, 54.12; H, 6.41.
1
1
1 16 6
5
,6-O-Isopropylidene-3-O-propyl-L-ascorbic acid (3c). Yield: 60%.
2
0
21
Thick liquid. [a] þ 9.928 (c ¼ 0.5, CHCl ). IR (Neat, n, cm ): 3320
D
3
1
(
(
(
OH), 1766 (C 55 O), 1693 (C 55 C). H NMR (CDCl , 300 MHz): d 0.98
3
t, 3H, J 7.4 Hz, H3
m, 2H, H2 ), 4.02 (dd, 1H, J 6.8, 8.5 Hz, H ), 4.13 (dd, 1H, J 6.6, 8.5 Hz,
0
), 1.36 (s, 3H, H ), 1.40 (s, 3H, H ), 1.70–1.82
8a 8b
0
6a
H ), 4.24 (ddd, 1H, J 3.8, 6.5, 6.5 Hz, H ), 4.40–4.44 (m, 2H, H ), 4.54
0
1
6
b
5
1
3
d, 1H, J 3.6 Hz, H ), 5.36 (bs, 1H, OH). C NMR (CDCl , 75 MHz): d
(
4
3
1
0.03 (C3
3.66 (C1
0
), 23.01 (C2
), 76.57 (C ), 110.18 (C ), 118.63 (C ), 148.20 (C ), 172.15 (C ).
4 7 2 3 1
0
), 25.59 (C ), 25.96 (C ), 63.36 (C ), 70.03 (C ),
8a
8b
6
5
7
0
þ
MS: m/z (%): 258 (M , 5), 243 (22), 183 (9), 159 (6), 141 (15), 129 (4),
13 (5), 101 (100), 85 (10), 83 (8), 73 (26), 61 (11). Anal. calcd for
C H O : C, 55.81; H, 6.97. Found: C, 55.80; H, 6.98.
1
1
2 18 6
5
,6-O-Isopropylidene-3-O-butyl-L-ascorbic acid (3d). Yield: 63%. Thick
2
0
21
liquid. [a] þ 4.168 (c ¼ 0.42, CHCl ). IR (Neat, n, cm ): 3320 (OH), 1762
D
3
1
C 55 O), 1695 (C 55 C). H NMR (CDCl , 300 MHz): d 0.95 (t, 3H, J 7.4 Hz,
(
3
H4 ), 1.36–1.47 (m, 8H, H , H , H ), 1.62–1.76 (m, 2H, H2 ), 4.04 (dd,
0 0 0
8a 8b 3
1
6
1
H, J 6.8, 8.5 Hz, H ), 4.17 (dd, 1H, J 6.8, 8.5 Hz, H ), 4.23 (dt, 1H, J 2.8,
6a 6b
.5 Hz, H ), 4.46 (t, 2H, J 6.3 Hz, H
5
0
), 4.53 (d, 1H, J 3.5 Hz, H ), 5.38 (bs,
4
1
1
3
H, OH). C NMR (CDCl , 75 MHz): d 13.78 (C4
0
), 18.80 (C3 ), 25.39
0
), 65.30 (C ), 71.10 (C ), 74.36 (C ), 75.60
1
0
3
(
(
(
C ), 25.63 (C ), 31.65 (C
0
8
a
8b
2
6
5
C ), 110.15 (C ), 118.79 (C ), 148.95 (C ), 172.25 (C ). MS: m/z (%): 272
4
7
2
3
1
þ
M , not observed), 257 (3), 245 (28), 191 (6), 189 (42), 161 (15), 159 (8),
47 (15), 129 (5), 116 (8), 113 (7), 101 (100), 85 (8), 83 (6), 73 (10), 61 (7).
Anal. calcd for C H O : C, 57.35; H, 7.35. Found: C, 57.32; H, 7.37.
1
1
3 20 6
5
,6-O-Isopropylidene-3-O-octyl-L-ascorbic acid (3e). Yield: 60%. Thick
2
0
21
liquid. [a] þ 15.058 (c ¼ 0.55, CHCl ). IR (Neat, n, cm ): 3321 (OH), 1762
D
3
1
C 55 O), 1695 (C 55 C). H NMR (CDCl , 300 MHz): d 0.88 (t, 3H, J 7.0 Hz,
(
3
H8
0
), 1.22–1.34 (m, 10H, H3
.67–1.76 (m, 2H, H2 ), 4.02 (dd, 1H, J 6.6, 8.4 Hz, H ), 4.13 (dd, 1H, J 6.6,
.5 Hz, H ), 4.24 (ddd, 1H, J 3.8, 6.5, 6.6 Hz, H ), 4.45 (t, 2H, J 6.3 Hz,
0
–H7
0
), 1.36 (s, 3H, H ), 1.39 (s, 3H, H ),
8a
8b
1
0
6a
8
6
b
5
1
3
H1 ), 4.53 (d, 1H, J 3.8 Hz, H ), 5.80 (bs, 1H, OH). C NMR (CDCl3,
0
4

Chemistry of L-Ascorbic Acid. IV
2369
7
5MHz): d 14.19 (C8
C5 ), 29.66 (C4 ), 31.00 (C2
5.61 (C ), 110.17 (C ), 118.67 (C ), 148.47 (C ), 171.13 (C ). MS: m/z (%):
0
), 22.71 (C7
0
), 25.57 (C3
0
), 25.65 (C ), 25.99 (C ), 29.25
8a
8b
(
0
0
0
), 31.82 (C6
), 65.82 (C ), 72.31 (C ), 74.34 (C ),
0 0
6 5 1
7
3
1
4
þ
7
2
3
1
28 (M , not observed), 313 (11), 207 (2), 159 (4), 143 (4), 141 (3), 129 (3),
17 (2), 113 (3), 101 (100), 85 (11), 83 (7), 76 (7), 60 (3). Anal. calcd for
C H O : C, 62.19; H, 8.53. Found: C, 62.22; H, 8.51.
1
7 28 6
5
,6-O-Isopropylidene-3-O-tetradecyl-L-ascorbic acid (3f ). Yield:
21
2
0
5
3
0
1
4
8%. Faint yellow oil. [a]D þ 28.618 (c ¼ 1.0, MeOH). IR (Neat, n, cm ):
1
323 (OH), 1762 (C 55 O), 1697 (C 55 C). H NMR (CDCl , 300 MHz): d
3
.88 (t, 3H, J 7.0 Hz, H14
.68–1.76 (m, 2H, H2
.23–4.28 (m, 1H, H ), 4.47 (t, 2H, J 6.3 Hz, H
0
), 1.27–1.45 (m, 28H, H3 to H13 , H , H ),
0
0
8a 8b
0
), 4.01–4.06 (m, 1H, H ), 4.11–4.17 (m, 1H, H ),
6a 6b
0
), 4.54 (d, 1H, J 3.8 Hz,
1
5
1
3
H4). C NMR (CDCl , 75 MHz): d 14.10 (C ), 22.65 (C13 ), 25.25 (C3 ),
0 0 0
14
3
2
2
5.42 (C ), 25.47 (C ), 25.52, 25.88, 26.10, 29.21, 29.33, 29.51, 29.53,
8
a
8b
9.58 (C4
0
–C11
0
), 29.62 (C2 ), 31.88 (C12 ), 65.29 (C ), 72.29 (C ), 74.35
0 0
6 5
(
C1
m/z (%): 412 (M , not observed), 357 (6), 281 (5), 207 (6), 161 (36), 131
4), 119 (12), 101 (100), 85 (14), 73 (18), 69 (13). Anal. calcd for
C H O : C, 66.99; H, 9.71. Found: C, 66.93; H, 9.73.
0
), 75.62 (C ), 110.35 (C ), 118.32 (C ), 149.01 (C ), 171.39 (C ). MS:
4 7 2 3 1
þ
(
2
3 40 6
5
,6-O-Isopropylidene-3-O-methoxymethyl-L-ascorbic
2
acid
(3g).
5
[8b,9]
Yield: 56%. M.p.: 95–968C. [a]D þ 13.008 (c ¼ 2.0, MeOH).
5
,6-O-Isopropylidene-3-O-allyl-L-ascorbic acid (3h). Yield: 47%.
2
5
[4,8a,b]
Thick liquid. [a]D þ 32.408 (c ¼ 2.0, MeOH).
5
,6-O-Isopropylidene-3-O-benzyl-L-ascorbic acid (3i). Yield: 62%.
[8a,b,9,10]
2
5
M.p.: 109–1108C. [a]D þ 36.208 (c ¼ 1.0, MeOH).
5
,6-O-Isopropylidene-3-O-isopropyl-L-ascorbic acid (3j). Yield: 10%.
21
2
0
M.p.: 74–768C. [a]D þ 7.668 (c ¼ 0.06, CHCl ). IR (Nujol, n, cm ): 3334
3
1
OH), 1755 (C 55 O), 1691 (C 55 C). H NMR (CDCl , 300 MHz): d 1.25–
(
3
1
.51 (m, 12H, H , H , H , H2b ), 3.94–4.34 (m, 3H, H , H , H ), 4.51
0 0
8a 8b 2a 6a 6b 5
1
3
(d, 1H, J 4.1 Hz, H ), 5.00–5.20 (m, 1H, H ), 5.50 (bs, 1H, OH). C NMR
0
4 1
(
CDCl , 75 MHz): d 22.90 (C
3
0
), 22.99 (C2b
0
0
), 25.95 (C ), 26.32 (C ),
8a 8b
2a
6
1
1
5.65 (C ), 74.82 (C ), 75.45 (C
6
), 76.10 (C ), 110.39 (C ), 118.09 (C ),
4
5
1
7
2
þ
47.97 (C ), 171.32 (C ). MS: m/z (%): 258 (M , not observed), 243 (22),
59 (9), 141 (28), 129 (8), 113 (12), 102 (6), 101 (100), 85 (25), 83 (12), 73
3
1
(34), 69 (6), 61 (11). Anal. calcd for C H O : C, 55.81; H, 6.97. Found:
C, 55.41; H, 6.94.
12 18 6
ACKNOWLEDGMENT
The authors thank CSIR, New Delhi, India for financial support as well as
assistantship to SDK.

2
370
Kulkarni and Kate
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Received in India March 3, 2004