One-Pot 2-o-alkylation of l -ascorbic acid

Article abstract of DOI:10.1055/s-0033-1338858

One-pot 2-O-alkylation of l-ascorbic acid involving an in situ 3-O-silylation and desilylation sequence was investigated. Initially the 3-OH group was masked with a t-butyldimethylsilyl (TBDMS) group followed by alkylation of the 2-OH group. Removal of the TBDMS group using 20% sulfuric acid also resulted in hydrolysis of the 5,6-O-isopropylidene to give 2-O-alkyl derivatives of l-ascorbic acid. Selective removal of the 3-O-TBDMS with tetrabutylammonium fluoride (TBAF) gave 5,6-O-isopropylidene-2-O-alkyl derivatives of l-ascorbic acid in good overall yields. Through the application of this protocol, 5,6-O-isopropylidene 2-O-alkyl derivatives of l-ascorbic acid as well as 2-O-alkyl derivatives of l-ascorbic acid may be easily accessed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338858

LETTER
▌1555
letter
One-Pot 2-O-Alkylation of L-Ascorbic Acid
One-Pot 2-O-Alkylation of L-Ascorbic Acid
Shankar R. Thopate,*a Rohit A. Dengale,a Mukund G. Kulkarnib
a
Department of Chemistry, Dr. John Barnabas Post Graduate School for Biological Studies, Ahmednagar College, Ahmednagar, Maharashtra,
414 001, India
Fax +91(241)2322415; E-mail: srthopate@gmail.com
b
Department of Chemistry, University of Pune, Ganeshkhind, Pune, Maharashtra, 411 007, India
Received: 29.04.2013; Accepted after revision: 01.05.2013
which the 3-OH group is protected with either methoxy-
methyl (MOM) or benzyl (Bn) group, followed by alkyl-
ation of the 2-OH group and finally the MOM or benzyl
group is removed to give 2-O-alkyl derivatives.7b Howev-
Abstract: One-pot 2-O-alkylation of L-ascorbic acid involving an
in situ 3-O-silylation and desilylation sequence was investigated.
Initially the 3-OH group was masked with a t-butyldimethylsilyl
(TBDMS) group followed by alkylation of the 2-OH group. Re-
moval of the TBDMS group using 20% sulfuric acid also resulted er, there is only a single report on direct 2-O-alkylation of
L-ascorbic acid using t-BuOK in DMSO–THF.9 As part of
in hydrolysis of the 5,6-O-isopropylidene to give 2-O-alkyl deriva-
tives of L-ascorbic acid. Selective removal of the 3-O-TBDMS with
tetrabutylammonium fluoride (TBAF) gave 5,6-O-isopropylidene-
acid in organic synthesis, we required both 5,6-O-protect-
2-O-alkyl derivatives of L-ascorbic acid in good overall yields.
an ongoing program to explore the utility of L-ascorbic
ed as well as unprotected 2-O-alkyl derivatives of L-ascor-
Through the application of this protocol, 5,6-O-isopropylidene
bic acid. Our attempts to prepare these derivatives by a
reported method9 were unsuccessful. In our hands, meth-
ylation using t-BuOK (2.0 equiv) and methyl iodide (1.0
equiv) in DMSO–THF at –10 °C for more than ten hours,
furnished the 2,3-di-O-methyl derivative of 5,6-O-isopro-
pylidene L-ascorbic acid in low yield (25%) with recovery
of starting material. An alternative route involving a
three-step 3-OH protection, 2-OH alkylation, and 3-OH
deprotection sequence is also available, however, this ap-
proach has drawbacks because it requires purification at
each step, which makes it a somewhat tedious process. In
this paper we wish to report an efficient one-pot synthesis
of 2-O-alkyl derivatives of L-ascorbic acid.
2-O-alkyl derivatives of L-ascorbic acid as well as 2-O-alkyl deriv-
atives of L-ascorbic acid may be easily accessed.
Key words: L-ascorbic acid, alkylation, one-pot synthesis, si-
lylation, desilylation
L-Ascorbic acid (Vitamin C) exhibits an array of biologi-
cal activities. It acts as an antioxidant, radical scavenger
and protects cellular components against oxidative dam-
age by free radicals and oxidants;1 furthermore, the com-
pound serves as a reductant in many important enzymatic
transformations.2,3 In addition, L-ascorbic acid appears to
play preventive roles in chronic diseases such as cancer,
cerebral apoplexy, diabetes, atopic dermatitis, myocardial
infarction, and AIDS.4 L-Ascorbic acid is susceptible to
thermal and oxidative degradation and therefore consider-
able efforts have been made in recent years to develop
more stable derivatives. For example, 5,6-O-modified L-
ascorbic acid derivatives are known to be effective anti-
tumor agents for various human cancers, and induce apop-
tosis in tumor cells,5 2-C-alkyl derivatives have immuno-
stimulant activity,6 and 2-O- and 3-O-alkylated deriva-
tives are known to protect against peroxidation of lipids in
biomembranes.7
The tert-butyldimethysilyl (TBDMS) group was chosen
for 3-OH protection due to the ease of preparation of TB-
DMS ethers, their stability, and because they can be selec-
tively deprotected under specific reaction conditions. It
was conceived that treatment of L-ascorbic acid with TB-
DMSCl in the presence of an amine could give the 3-O-
TBDMS derivative selectively, which, upon subsequent
treatment with alkyl halides in the same reaction pot,
could undergo 2-O-alkylation. The deprotection of both
the TBDMS ether and 5,6-O-isopropylidene acetal under
acidic conditions could thus deliver 5,6-O-unprotected, 2-
O-alkyl derivatives of L-ascorbic acid. On the other hand,
selective removal of the TBDMS group with tetrabutyl-
ammonium fluoride (TBAF) could yield 5,6-O-protected
2-O-alkyl derivatives of L-ascorbic acid.
Most reports of O-alkylation of L-ascorbic acid are cen-
tered on selective 3-O-alkylation because the 3-OH group
is more reactive towards electrophiles under mildly basic
conditions as compared to the 2-OH group. As a result,
many reaction conditions have been developed for selec-
tive 3-O-alkylation of L-ascorbic acid.8 We have recently
shown that selective 3-O-alkylation of L-ascorbic acid can
be achieved by using phase-transfer catalysis in aqueous
medium.8 2-O-Alkylation of L-ascorbic acid has been
achieved indirectly through a three-step sequence in
Initially, 5,6-O-isopropylidene L-ascorbic acid 1 was
treated with triethylamine (1.2 equiv) in anhydrous
CH2Cl2 at 0 °C, followed by addition of TBDMSCl (1.1
equiv) and the reaction mixture was allowed to warm to
room temperature. After completion of the reaction (reac-
tion monitored by TLC; 2 h), triethylamine (1.2 equiv),
and dimethyl sulfate (1.1 equiv) were added to the same
reaction vessel, the mixture was stirred at room tempera-
ture for 1.5 h and then treated with 20% aq. H2SO4 to de-
SYNLETT 2013, 24, 1555–1557
Advanced online publication: 10.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338858; Art ID: ST-2013-D0394-L
© Georg Thieme Verlag Stuttgart · New York

1556
S. R. Thopate et al.
LETTER
liver 2-O-methyl L-ascorbic acid (2a)10 in an overall yield
of 51% (over three steps).
Table 2 Synthesis of 2-O-Alkyl Derivatives of 5,6-O-Isopropyli-
dene L-Ascorbic Acid
Having established a successful one-pot 2-O-methylation,
we next explored the scope of this methodology. A variety
of alkyl halides underwent smooth alkylation under these
reaction conditions and delivered 2-O-alkyl derivatives
2b–h10 in good yields (Table 1).11 Minor modification of
the above procedure provided an efficient synthesis of the
5,6-O-protected 2-O-alkyl derivatives. Thus, use of
TBAF (1.00 equiv, 9.25 mmol) instead of H2SO4 in the
last step of the sequence selectively removed the TBDMS
group and gave various 2-O-alkyl derivatives of 5,6-O-
isopropylidene L-ascorbic acid 3a–h10 in good overall
yields (Table 2).12
O
O
1. TBDMSCl (1.1 equiv)
Et3N (1.2 equiv)
CH2Cl2, 0 °C to r.t., 2 h
O
O
O
O
O
O
2. RX (1.1 equiv),
Et3N (1.2 equiv), r.t., 1.5 h
3. TBAF (1 equiv), r.t., 30 min
HO
OH
HO
OR
1
3
Entry
3
R
Yield (%)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Me
55
50
48
42
46
45
41
44
Et
Bn
2-ClC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
3-O2NC6H4CH2
4-O2NC6H4CH2
Table 1 One-Pot Synthesis of 2-O-Alkyl Derivatives of L-Ascorbic
Acid
HO
O
1. TBDMSCl (1.1 equiv)
Et3N (1.2 equiv)
CH2Cl2, 0 °C to r.t., 2 h
HO
O
O
O
O
O
3g
3h
2. RX (1.1 equiv),
Et3N (1.2 equiv)
r.t., 1.5 h
HO
OR
HO
OH
1
a Isolated yields for the three-step, one-pot reaction.
2
3. H2SO4 (20% aq)
r.t., 1.5 h
Yield (%)a
Supporting Information for this article is available online at
Entry
2
R
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Me
51
48
45
48
50
52
40
43
References and Notes
Et
(1) Bielski, B. H. J. In Ascorbic Acid: Chemistry, Metabolism,
and Uses; Seib, P. A.; Tolbert, B. M., Eds.; American
Chemical Society: Washington DC, 1982, 81–100.
(2) Tolbert, B. M.; Downing, M.; Carlson, R. W.; Knight, M. K.;
Baker, E. M. Ann. N. Y. Acad. Sci. 1975, 258, 48.
(3) Bielski, B. H. J.; Richter, H. W.; Chan, P. C. Ann. N. Y. Acad.
Sci. 1975, 258, 231.
(4) (a) Rose, R. C.; Bode, A. M. FASEB J. 1993, 7, 1135.
(b) Ames, B. N.; Shigenaga, M. K.; Hagen, T. M. Proc. Nat.
Acad. Sci. U. S. A. 1993, 90, 7915.
i-Pr
Bn
4-ClC6H4CH2
4-BrC6H4CH2
2g
2h
3-O2NC6H4CH2
4-O2NC6H4CH2
(5) (a) Tanuma, S.; Shiokawa, D.; Tanimoto, Y.; Ikekita, M.;
Sakagami, H.; Takeda, M.; Fukuda, S.; Kochi, M. Biochem.
Biophys. Res. Commun. 1993, 194, 29. (b) Gazivoda, T.;
Raić-Malić, S.; Marjanović, M.; Kralj, M.; Pavelić, K.;
Balzarini, J.; De Clercq, E.; Mintas, M. Bioorg. Med. Chem.
2007, 15, 749. (c) Wittine, K.; Babić, M. S.; Makuc, D.;
Plavec, J.; Pavelić, S. K.; Sedić, M.; Pavelić, K.; Leyssen, P.;
Neyts, J.; Balzarini, J.; Mintas, M. Bioorg. Med. Chem.
2012, 20, 3675.
a Isolated yields for the three-step, one-pot reaction.
To conclude, we report an efficient procedure for 2-O-al-
kylation of L-ascorbic acid through a three-step, one-pot
protocol, using a 3-O-silylation and desilylation se-
quence, under mild reaction conditions. This strategy al-
lowed a wide variety of both 5,6-O-protected and
unprotected 2-O-alkyl derivatives of L-ascorbic acid to be
synthesized in good yields. Further studies are in progress
to expand the scope of this protocol.
(6) (a) Veltri, R. W.; Fodor, G.; Liu, C. M.; Woolverton, C. J.;
Baseler, M. W. J. Biol. Res. Mod. 1986, 5, 444.
(b) Woolverton, C. J.; Veltri, R. W.; Snyder, I. S. J. Biol.
Res. Mod. 1986, 5, 527. (c) Sakagami, H.; Takeda, M.;
Utsumi, A.; Fujinaga, S.; Tsunoda, A.; Yasuda, N.;
Shibusawa, M.; Koike, T.; Ota, H.; Kazama, K.; Shiokawa,
D.; Tanuma, S.; Kochi, M. Anticancer Res. 1993, 13, 65.
(7) (a) Nihro, Y.; Miyataka, H.; Sudo, T.; Matsumoto, H.;
Satoh, T. J. J. Med. Chem. 1991, 34, 2152. (b) Kato, K.;
Terao, S.; Shimamoto, N.; Hirata, M. J. Med. Chem. 1988,
31, 793. (c) El-Demerdash, F. M.; Yousef, M. I.; Zoheir, M.
A. Food Chem. Toxicol. 2005, 43, 1743.
Acknowledgment
This work was supported by the Council of Scientific and Industrial
Research (CSIR), New Delhi (No: 02(0001)/11/EMR-II). R.A.D.
thanks CSIR, New Delhi for a fellowship. We wish to thank Dr. R.
J. Barnabas (Ahmednagar College, Ahmednagar) for helpful
discussions and suggestions.
(8) Thopate, S. R.; Kote, S. R. African J. Pure Appl. Chem.
2012, 6, 50; and references therein.
Synlett 2013, 24, 1555–1557
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot 2-O-Alkylation of L-Ascorbic Acid
1557
(9) Olabisi, A. O.; Wimalasena, K. J. Org. Chem. 2004, 69,
7026.
8.4, 6.4 Hz, 1 H), 4.22 (dt, J = 6.4, 3.3 Hz, 1 H), 4.64 (m,
1 H), 5.44 (s, 2 H), 7.32 (m, J = 8.2 Hz, 2 H), 7.51 (m, 2 H),
9.05 (br s, 1 H); 13C NMR (100 MHz, CDCl3): δ = 25.2,
25.6, 64.7, 71.2, 73.5, 74.4, 109.1, 120.1, 121.6, 129.4,
130.8, 135.5, 148.3, 169.7; MS: m/z = 385.0 [M + H]+.
Compound 3g: Viscous liquid; IR: 3502, 2987, 1745, 1687,
1529, 1346, 1115, 729 cm–1; 1H NMR (400 MHz, CDCl3): δ
= 1.32 (s, 3 H), 1.34 (s, 3 H), 4.03 (m, J = 8.6, 6.8 Hz, 1 H),
4.15 (dd, J = 8.6, 6.8 Hz, 1 H), 4.31–4.35 (m, 1 H), 4.61 (d,
J = 3 Hz 1 H), 5.56–5.63 (AB q, J = 12.6 Hz, 2 H), 7.56 (m,
1 H), 7.73 (d, J = 7.6 Hz, 1 H), 8.20 (m, 1 H), 8.25 (d, J =
1.5 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 25.4, 25.8,
65.3, 71.8, 73.6, 75.5, 110.5, 120.1, 122.6, 123.5, 124.7,
129.7, 133.7, 137.9, 148.0, 171.0.
(10) Selected analytical data of novel compounds:
Compound 2a: Viscous liquid; [α]D25 +21.60 (c 0.5,
MeOH); IR: 3400, 2951, 1770, 1675, 1352, 1145, 759 cm–1;
1H NMR (400 MHz, DMSO-d6): δ = 3.47–3.57 (m, 2 H),
3.71–3.76 (m, 1 H), 4.12 (s, 3 H), 4.73–4.85 (br m, 3 H); 13
NMR (100 MHz, DMSO-d6): δ = 58.9, 61.9, 68.6, 74.6,
119.5, 150.8, 170.7; MS: m/z = 213.2 [M + Na]+.
C
Compound 2b: Viscous liquid; 1H NMR (400 MHz,
DMSO-d6): δ = 1.30 (t, J = 3.2 Hz, 3 H), 3.47–3.57 (m, 2 H),
3.72–3.76 (m, 1 H), 4.18 (m, 3 H), 4.43–4.49 (m, 3 H); 13
NMR (100 MHz, DMSO-d6): δ = 15.2, 61.7, 66.5, 68.8,
74.70, 118.8, 150.0, 170.7.
C
Compound 2c: White solid; mp 100–102 °C; [α]D25 +69.72
(c 0.5, MeOH); IR: 3423, 2987, 1749, 1681, 1373, 1074,
910 cm–1; 1H NMR (300 MHz, CDCl3): δ = 1.28 (m, 6 H),
2.90 (br s, 3 H), 3.79–3.85 (m, 2 H), 3.96 (dd, J = 6.2,
2.4 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 5.10–5.18 (m, J =
5.7 Hz, 1 H); 13C NMR (75 MHz, DMSO-d6): δ = 23.3, 23.4,
62.1, 68.7, 73.1, 74.8, 118.1, 149.2, 170.8.
Compound 2g: Viscous liquid; IR: 3332, 3155, 2949, 1739,
1681, 1537, 1340, 1161, 731 cm–1; 1H NMR (400 MHz,
DMSO-d6): δ = 3.47 (m, 2 H), 3.75 (dd, J = 13, 6.4 Hz, 1 H),
4.86 (s, 2 H), 5.05 (d, J = 6.2 Hz, 1 H), 5.98 (AB q, J =
12.6 Hz, 2 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.90 (d, J = 7.6 Hz,
1 H), 8.21 (d, J = 7.6, 1.5 Hz, 1 H), 8.31 (s, 1 H), 9.02 (br s,
1 H); 13C NMR (100 MHz, DMSO-d6): δ = 61.7, 68.5, 70.5,
74.6, 119.9, 122.1, 122.9, 129.7, 134.0, 138.8, 147.8, 149.5,
170.2; MS: m/z = 333.8 [M + Na]+.
Compound 3h: Yellow solid; mp 152 °C; [α]D25 +59.96
(c 0.5, MeOH); IR: 3266, 2996, 1758, 1701, 1523, 1339,
1164 cm–1; 1H NMR (300 MHz, CDCl3): δ = 1.36 (s, 3 H),
1.37 (s, 3 H), 4.06 (dd, J = 8.5, 6.7 Hz, 1 H), 4.14 (dd, J =
8.5, 6.7 Hz, 1 H), 4.33 (dt, J = 6.7, 3.3 Hz, 1 H), 4.64 (d, J =
3.3 Hz, 1 H), 5.60 (AB q, J = 13 Hz, 2 H), 6.37 (br s, 1 H),
7.58 (d, J = 8.6 Hz, 2 H), 8.25 (d, J = 8.6 Hz, 2 H); 13C NMR
(75 MHz, CDCl3): δ = 25.5, 25.8, 65.2, 71.8, 73.7, 75.4,
110.4, 119.8, 123.8, 128.1, 142.9, 147.8, 147.9, 170.8; MS:
m/z = 373.9 [M + Na]+ .
(11) One-Pot Synthesis of 2-O-Alkyl Derivatives of L-
Ascorbic Acid; General Procedure: A solution of 5,6-O-
isopropylidene-L-ascorbic acid (1; 2.00 g, 9.25 mmol) and
Et3N (1.2 equiv, 11.12 mmol) in anhydrous CH2Cl2 (10.0
mL) was cooled to 0 °C. To this reaction mixture was added
a solution of TBDMSCl (1.53 g, 10.18 mmol) in anhydrous
CH2Cl2 (5.0 mL). The reaction mixture was allowed to warm
to r.t. and stirred for 2 h. After completion of the reaction
(TLC), Et3N (1.2 mL, 11.12 mmol) was added followed by
the requisite alkylating agent (1.1 equiv 10.18 mmol) and the
mixture was stirred for a further 1–2 h at r.t. The reaction
mixture was then treated with 20% aq H2SO4 (10.0 mL) and
stirred at r.t. for 1.5 h. After completion of the reaction as
indicated by TLC, the reaction mixture was neutralized with
solid NaHCO3 and the product was extracted with EtOAc
(3 × 10 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered, and the solvent was removed
under vacuum. The crude product was purified by silica gel
column chromatography (hexane–EtOAc).
Compound 2h: Yellow solid; mp 118–120 °C; IR: 3385,
3238, 2960, 1743, 1685, 1543, 1336, 1163, 732 cm–1; 1H
NMR (400 MHz, DMSO-d6): δ = 3.50 (m, 2 H), 3.78 (m,
1 H), 4.20–4.35 (br s, 2 H), 4.73 (s, 1 H), 5.6 (m, 2 H), 7.72
(m, 2 H), 8.20–8.27 (m, 2 H), 9.04 (br s, 1 H); 13C NMR
(100 MHz, DMSO-d6): δ = 61.7, 68.5, 70.5, 74.6, 119.9,
122.9, 129.8, 138.8, 147.7, 149.4, 170.2; MS: m/z = 333.9
[M + Na]+.
Compound 3b: White solid; mp 92–93 °C; [α]D25 +15.52 (c
0.5, MeOH); IR: 3348, 2928, 1775, 1602, 1411, 1390,
707 cm–1; 1H NMR (300 MHz, CDCl3): δ = 1.35–1.40 (m,
9 H), 4.03 (dd, J = 8.5, 6.7 Hz, 1 H), 4.15 (dd, J = 8.5,
6.7 Hz, 1 H), 4.24–4.28 (m, 1 H), 4.51–4.58 (m, 3 H); 13
C
NMR (75 MHz, CDCl3): δ = 15.3, 25.5, 25.8, 65.2, 68.1,
74.2, 75.6, 110.7, 118.8, 148.8, 171.3.
(12) One-Pot Synthesis of 2-O-Alkyl Derivatives of 5,6-O-
Isopropylidene L-Ascorbic Acid; General Procedure:
The same experimental procedure as described in ref. 11 was
employed with minor modifications. Selective deprotection
of TBDMS group was achieved by the addition of TBAF
(1.0 equiv, 9.25 mmol) instead of H2SO4. The reaction
mixture was stirred at r.t. for 0.5 h. After completion of
reaction (monitored by TLC), the mixture was diluted with
H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined extracts were dried over anhydrous Na2SO4,
filtered, and the solvent was removed under vacuum. The
crude product was purified by silica gel column
Compound 3e: White solid; mp 122–124 °C; [α]D25 +12.56
(c 0.5, MeOH); IR: 3289, 2988, 1757, 1697, 1757, 1697,
1372, 1117, 810 cm–1; 1H NMR (300 MHz, CDCl3): δ = 1.35
(s, 3 H), 1.37 (s, 3 H), 3.99–4.14 (m, 2 H), 4.27 (m, 1 H),
4.58 (d, J = 2.9 Hz, 1 H), 5.48 (s, 2 H), 6.51 (s, 1 H), 7.35 (m,
4 H); 13C NMR (75 MHz, CDCl3): δ = 25.5, 25.8, 65.2, 72.5,
73.9, 75.6, 110.3, 119.7, 128.8, 129.5, 134.1, 134.6, 148.4,
171.2; MS: m/z = 341.3 [M + H]+.
Compound 3f: White solid; mp 136–138 °C; [α]D25 +82.84
(c 0.5, MeOH); IR: 3981, 2987, 1753, 1678, 1334, 1038,
806 cm–1; 1H NMR (400 MHz, CDCl3): δ = 1.29 (s, 3 H),
1.30 (s, 3 H), 3.93 (dd, J = 8.4, 6.4 Hz, 1 H), 4.08 (dd, J =
chromatography (hexane–EtOAc).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1555–1557

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.