A New Simple One-Pot Regioselective Preparation of Mixed Diesters of Carbonic Acid

Full text of DOI:10.1021/jo980286e

J . Org. Chem. 1998, 63, 6031-6034
6031
Sch em e 1
A New Sim p le On e-P ot Regioselective
P r ep a r a tion of Mixed Diester s of Ca r bon ic
Acid
Giorgio Bertolini,*,† Gianfranco Pavich, and
Barbara Vergani
Italfarmaco Research Center, via dei Lavoratori 54,
I-20092 Cinisello Balsamo, Milan, Italy
Received February 17, 1998
In tr od u ction
Diesters of carbonic acid (1) are frequently used in
organic synthesis for the protection of sensitive func-
tions.1 Two of the most commonly used carbonates are
the benzyl carbonate and the allyl carbonate which are
removed under neutral conditions. In addition to protec-
tion, carbonates are also used for the reversible introduc-
tion of either hydrophobic moieties2 or specific carrier
systems for the targeting of drugs.3 Recently it was
reported that mixed carbonates of carbohydrates are
useful starting materials for a novel intramolecular
decarboxylative glycosylation reaction.4 In general the
acylation reaction of substrates containing primary and
secondary hydroxy groups proceeds with low regioselec-
tivity when using the most common methods for the
synthesis of carbonates.
Sch em e 2
Improved regioselectivity is obtained when enzyme-
based reactions are carried out.5-8,14 Alternatively a two-
step procedure can be used which involves the separate
preparation of carbamates 2b-c from the desired alkyl-
chloroformates 2a prior to their use as acylating agents9,10
(Scheme 1). This approach however requires the puri-
fication of the intermediate 2b-c and, in the case of
carbohydrates, the use of dry pyridine as solvent to
improve the yields.9 Furthermore, alkyl chloroformates
of unusual alcohols are not generally commercially avail-
able and a three-step procedure, which includes chloro-
formylation of the desired alcohol with either phosgene
or phosgene substitutes, such as bis(trichloromethyl)-
carbonates (Triphosgene),11 is required. This further step
may be aggravated by incompatibility between the chlo-
roformylation conditions and functional groups present
on the alcoholic residue. For this reason, only the
synthesis of mixed carbonates with simple alkyl alcohols
has been described using this method.
In this paper we report a general and efficient one-pot
method for the selective preparation of mixed diesters of
carbonic acid of primary alcohols.
Resu lts a n d Discu ssion
It is well established that the selectivity of the acyla-
tion reactions toward primary alcohols increases with
increasing the bulkiness of the R′ group (e.g., tBu) of the
acylating agent (Scheme 1). Consequently the prepara-
tion of mixed carbonates having a non steric demanding
R′ groups such as benzyl and allyl groups proceeds with
low selectivity if both primary and secondary hydroxy
groups are present. To develop a general and highly
selective method for the synthesis of mixed carbonates,
we decided to explore the role played by the nature of
the leaving group X in the modulation of selectivity.
In the first experiment we used acylating agents
characterized by X groups of different size such as
N-hydroxysuccinimidyl ester 3a , acyl chloride 3b, and the
imidazolide derivative 3c. Their reactivity and selectivity
were tested on a 1:1 mixture of simple primary and
secondary alcohols (Scheme 2, Table 1). As described for
other types of acylating agents,12 increasing the steric
hindrance of the carbonyl system, as it occurs in the
series described here passing from N-hydroxysuccinimide
ester, to chloride to the imidazolide derivative, the
† Address correspondence to Dr. Giorgio Bertolini, Italfarmaco
Research Centre, Via Dei Lavoratori 54, 20092 Cinisello Balsamo,
Milan, Italy. Phone: (39) 2-64.43.3022. Fax: (39) 2-66.011.579. E-
mail: bertog@edith.sublink.org.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991: Vol. 2, pp 104-111.
(2) Tortolani, D. R.; Russel, J . W.; Whiterock, V. J .; Hitchcock, M.
J . M.; Ghazzouli, I.; Martin, J . C.; Mansuri, M. M.; Starrett, J . E., J r.
J . Pharm. Sci. 1994, 83, 339-343.
(3) Pochet, S.; Kansal, V.; Destouesse, F.; Sarfati, S. R. Tetrahedron
Lett. 1990, 31, 6021-6024.
(4) Iimori, T.; Shibazaki, T.; Ikegami, S. Tetrahedron Lett. 1996, 37,
2267-2270.
(5) Moris, F.; Gotor, V. Tetrahedron 1992, 48, 9869-9876.
(6) Moris, F.; Gotor, V. Tetrahedron 1993, 49, 10089-10098.
(7) Garcia-Alles, L. F.; Moris, F.; Gotor, V. Tetrahedron Lett. 1993,
34, 6337-6338.
(8) Pulido, R.; Gotor, V. J . Chem. Soc., Perkin Trans. I 1993, 589-
592.
(9) Allainmat, M.; L′Haridon, P.; Toupet, L.; Plusquellec, D. Syn-
thesis 1990, 27-32.
(10) Allainmat, M.; Plusquellec, D. Tetrahedron Lett. 1991, 32,
2751-2754.
(11) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26,
894-895.
(12) Katritzky, A. R.; Yang, B.; Semenzin, D. J . Org. Chem. 1997,
62, 726-728.
S0022-3263(98)00286-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/25/1998

6032 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Ta ble 1. Selective Acyla tion of a 1:1 Mixtu r e of P r im a r y
a n d Secon d a r y Alcoh ols Usin g Differ en t Acyla tin g
Agen ts 3a -c
Sch em e 4
acylating
agent
ratio
yield,b
%
entry
X
T, °C
6/7a
1
2
3
4
3a
3b
3c
3c
succinimidyloxy
Cl
1-imidazolyl
1-imidazolyl
rt
rt
rt
0
2.4
3.7
7.8
72
75
68
74
11.3
a
b
Products ratios are based on analysis by HPLC. Yields refer
to isolated mixtures of the two carbonates and are the average of
two runs.
Sch em e 3
Sch em e 5
Ta ble 2. Selective Acyla tion of a 1:1 Mixtu r e of P r im a r y
a n d Secon d a r y Alcoh ols Usin g Im id a zolid es 8a -d
acylating
agent
ratio
yield,b
%
entry
R′′
9/10a
1
2
3
4
5
6
8a
8b
8c
8d
PhCH2CH2
allyl
3-pyCH2
CH3OCH2CH2
PhCH2CH2
PhCH2CH2
6.5
9.4
7.3
8.9
7.4
79
81
62
73
8a
83c
46e
11-12d
11.7
a
b
Products ratios are based on analysis by HPLC. Yields refer
to isolated mixtures of the two carbonates and are the average of
two runs. c Acylation reaction without isolating the intermediate
system is shielded by two imidazolyl moieties (Scheme
4). Consistent with our hypothesis, imidazolide 11 and
12 were formed with high selectivity (ratio 11/12 ) 12.1).
Direct condensation without purification of the mixture
of imidazolides with activated phenethyl alcohol gave 9a
and 10a with higher selectivity compared to the previous
sequence of reactions (entry 6 vs entry 5). However, in
this case, yields were lower due to the presence in the
mixture of unreacted alcohols 4 and 5 which reacted with
11 and 12 causing the formation of 6 (yield 18%) and 7
(yield 10%).
Using this simple method we synthesized with high
regioselectivity the benzyl carbonate of the primary
hydroxy of methyl R-D-glucopyranoside (Scheme 5) with
yields comparable13 with those obtained with 2b9 but
using DMF as reaction solvent instead of dry pyridine.
In conclusion, we have identified a selective method
for the synthesis of a primary diester of carbonic acid.
This method seems to be general and gives good selectiv-
ity for primary alcohols even when the acylating agent
contains a nonsterically demanding alcoholic group.
imidazolide 8a . See Scheme 4. e 18% of symmetric 6 and 10% of
d
asymmetric 7 were observed.
selectivity of the acylating reaction toward the primary
alcohol was improved (Table 1, entries 1-3), although a
non steric demanding R′ such as a benzyl group was used.
As expected the reaction temperature played a crucial
role in this reaction (Table 1, entries 3 and 4).
To investigate whether this approach can be applied
to an acylating intermediate having an R′ group other
than benzyl, the reactivity and selectivity of the imida-
zolides 8a -d were tested (Scheme 3). These compounds
were prepared by reacting the appropriate alcohol with
1,1-carbonyldiimidazole in THF for 1-2 h. After a simple
workup procedure (see Experimental Section) the pure
acylating agent was used in the next reaction without
further purification. The results (Table 2) were similar
to those of the previous reaction, suggesting therefore
that the selectivity achieved was independent of the R′
group. Furthermore, when the same acylating reaction
was repeated without isolating the intermediate imida-
zolide 8a the yields were unaffected (Table 2, entry 5 vs
entry 1) and the regioselectivity improved slightly.
Therefore, under the above conditions the regioselective
derivatization of primary alcohols in the presence of
secondary alcohols can be carried out by a one-pot
reaction.
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded respectively
at 200 and 50.3 MHz. The solutions were dried over Na2SO4,
and the solvent was removed under reduced pressure. The
(13) Isolated yield of primary carbonate 14 was 49%, and the
remaining 51% of the starting glycoside was lost as both unreacted
starting material and the six-membered cyclic carbonate between the
primary hydroxy group and the secondary alcohol in position 4 of
methyl R-D-glucopyranoside. Only traces of carbonates on secondary
hydroxy groups of the glycoside were detected.
To verify whether steric hindrance by the imidazolyl
moiety is a factor governing the observed regioselectivity,
an equimolar mixture of alcohols 4 and 5 was reacted at
0 °C with 1,1-carbonyldiimidazole where the carbonyl
(14) Bisht, K. S.; Deng, F.; Gross, R. A.; Kaplan, D. L.; Swift, G. J .
Am. Chem. Soc. 1998, 120, 1363-1367.

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6033
mixture of carbonates was purified by flash chromatography on
silica gel 60 (230-400 mesh ASTM) (E. Merck & Co) using
n-hexanes-ethyl acetate (for 6, 7, 9a -d , and 10a -d ) or
chloroform-methanol (for 14) as the eluent system. HPLC
analysis was performed using a Supelcosil LC8DB (25 cm × 4.6
mm, 5 µm) column, acetonitrile-water 6:4, flow 1 mL/min, UV
detector 220 nm.
Gen er a l P r oced u r e for th e Syn th esis of Im id a zolid e (3c,
8a -d ). A solution of the desired alcohol (4.5 mmol) in THF (5
mL) was slowly added at 0 °C to a solution of 1,1-carbonyldi-
imidazole (730 mg, 4.5 mmol) in THF (5 mL). The solution was
stirred at room temperature for 1 h; then the solvent was
removed under reduced pressure and the crude product was
dissolved in Et2O and washed with a phosphate buffer solution
pH 7. The solvent was removed to give pure imidazolide.
Ben zyl ca r bon ylim id a zolid e (3c): yield 84%; tR ) 4.58
min; 1H NMR (DMSO-d6) δ 8.32 (s, 1H), 7.64 (s, 1H), 7.51-7.32
(m, 5H), 7.10 (s, 1H), 5.46 (s, 2H); 13C NMR (DMSO-d6) δ 148.58,
137.55, 134.97, 130.66, 128.89 (3C), 128.60 (2C), 117.84, 69.50.
Anal. Calcd for C11H10N2O2: C, 65.33; H, 4.98; N, 13.86.
Found: C, 64.98; H, 4.87; N, 13.64.
5.10 (s, 2H), 4.30 (t, 2H, J ) 6.8 Hz), 2.90 (t, 2H, J ) 6.8 Hz);
13C NMR (DMSO-d6) δ 154.68, 137.82, 135.75, 129.09 (2C),
128.72 (2C), 128.61 (3H), 128.40 (2C), 126.67, 69.05, 68.28, 75.60.
r-Meth ylben zyl (2-p h en yleth yl) ca r bon a te (10a ): tR
)
11.93 min; IR (cm-1, KBr) 1735, 1050; 1H NMR (DMSO-d6) δ
7.40-7.22 (m, 10H), 5.66 (q, 1H, J ) 6.6 Hz), 4.28 (t, 2H, J )
6.9 Hz), 2.91 (t, 2H, J ) 6.9 Hz), 1.50 (d, 3H, J ) 6.6 Hz); 13C
NMR (DMSO-d6) δ 154.09, 141.36, 137.85, 129.11 (2C), 128.75
(2C), 128.65 (2C), 128.26, 126.70, 126.11 (2C), 75.92, 68.11, 34.53,
22.32.
Ben zyl a llyl ca r bon a te (9b): tR ) 6.79 min; IR (cm-1, KBr)
1740, 1640, 955; 1H NMR (DMSO-d6) δ 7.42-7.39 (m, 5H), 5.95
(m, 1H), 5.34 (dd, 1H, J ) 17.5 and 1.7 Hz), 5.26 (dd, 1H, J )
10.6 and 1.4 Hz), 5.17 (s, 2H), 4.64 (d, 2H, J ) 5.5 Hz); 13C NMR
(DMSO-d6) δ 154.57, 135.77, 132.42, 128.77 (2C), 128.65, 128.45
(2C), 118.67, 69.24, 68.22.
r-Meth ylben zyl a llyl ca r bon a te (10b): tR ) 7.82 min; IR
(cm-1, KBr) 1740, 1645, 1055, 955; 1H NMR (DMSO-d6) δ 7.42-
7.34 (m, 5H), 5.95 (m, 1H), 5.70 (q, 1H, J ) 6.6 Hz), 5.31 (m,
2H), 4.59 (d, 2H, J ) 5.5 Hz), 1.53 (d, 3H, J ) 6.6 Hz); 13C NMR
(DMSO-d6) δ 153.94, 141.34, 132.45, 128.77 (2C), 128.29, 126.12
(2C), 118.60, 76.10, 68.03, 22.36.
Ben zyl (p yr id -3-ylm eth yl) ca r bon a te (9c): tR ) 5.03 min;
IR (cm-1, KBr) 1740, 1590, 1425; 1H NMR (DMSO-d6) δ 8.63 (d,
1H, J ) 2.2 Hz), 8.57 (dd, 1H, J ) 4.9 and 1.8 Hz), 7.84 (m, 1H),
7.46-7.38 (m, 6H), 5.23 (s, 2H), 5.18 (s, 2H); 13C NMR (DMSO-
d6) δ 154.57, 149.91, 149.78, 136.49, 135.63, 131.36, 128.77 (2C),
128.69, 128.50 (2C), 123.89, 69.46, 67.01.
2-P h en yleth yl ca r bon ylim id a zolid e (8a ): yield 74%; tR
)
4.93 min; 1H NMR (DMSO-d6) δ 8.22 (s, 1H), 7.56 (s, 1H), 7.56-
7.29 (m, 5H), 7.09 (s, 1H), 4.59 (t, 2H, J ) 6.7 Hz), 3.08 (t, 2H,
J ) 6.7 Hz); 13C NMR (DMSO-d6) δ 148.49, 138.02, 137.39,
130.62, 129.26 (2C), 128.72 (2C), 126.86, 117.68, 68.70, 34.33.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.60; N, 12.96.
Found: C, 66.47; H, 5.51; N, 12.76.
Allyl ca r bon ylim id a zolid e (8b): yield 79%; tR ) 3.70 min;
1H NMR (DMSO-d6) δ 8.31 (s, 1H), 7.64 (s, 1H), 7.10 (s, 1H),
6.13-5.96 (m, 1H), 5.48 (dt, 1H, J ) 17.3 and 1.4 Hz), 5.34 (dd,
r-Meth ylben zyl (p yr id -3-ylm eth yl) ca r bon a te (10c): tR
) 5.54 min; IR (cm-1, KBr) 1740, 1595, 1425, 1050; 1H NMR
(DMSO-d6) δ 8.57 (d, 1H, J ) 2.0 Hz), 8.54 (dd, 1H, J ) 4.8 and
1.7 Hz), 7.79 (m, 1H), 7.42-7.30 (m, 6H), 5.68 (q, 1H, J ) 6.6
Hz), 5.15 (s, 2H), 1.49 (d, 3H, J ) 6.6 Hz); 13C NMR (DMSO-d6)
δ 153.92, 149.85, 149.71, 141.19, 136.43, 131.35, 128.74 (2C),
128.31, 126.12 (2C), 123.85, 76.37, 66.81, 22.32.
1H, J ) 10.5 and 1.4 Hz), 4.91 (dd, 2H, J ) 5.5 and 1.4 Hz); 13
C
NMR (DMSO-d6) δ 148.40, 137.54, 131.64, 130.64, 119.43,
117.81, 68.42. Anal. Calcd for C7H8N2O2: C, 55.25; H, 5.30; N,
18.42. Found: C, 55.13; H, 5.34; N, 18.15.
P yr id -3-ylm eth yl ca r bon ylim id a zolid e (8c): yield 91%;
tR ) 3.22 min; 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.58 (dd, 1H,
J ) 4.8 and 1.7 Hz), 8.30 (s, 1H), 7.93 (dd, 1H, J ) 7.9 and 1.7
Hz), 7.62 (s, 1H), 7.44 (dd, 1H, J ) 7.9 and 4.8 Hz), 7.06 (s, 1H),
5.48 (s, 2H); 13C NMR (DMSO-d6) δ 150.04, 149.79, 148.48,
137.60, 136.57, 135.39, 130.62, 123.92, 117.85, 67.17. Anal.
Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found: C,
58.93; H, 4.42; N, 20.55.
2-Meth oxyeth yl ca r bon ylim id a zolid e (8d ): yield 70%; tR
) 3.24 min; 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.62 (s, 1H),
7.10 (s, 1H), 4.53 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H); 13C NMR
(DMSO-d6) δ 148.65, 137.49, 130.65, 117.79, 69.59, 67.26, 58.40.
Anal. Calcd for C7H10N2O3: C, 49.40; H, 5.92; N, 16.47.
Found: C, 49.51; H, 5.79; N, 16.27.
Ben zyl (2-m eth oxyeth yl) ca r bon a te (9d ): tR ) 5.01 min;
IR (cm-1, KBr) 1735, 1115; 1H NMR (DMSO-d6) δ 7.40-7.32 (m,
5H), 5.16 (s, 2H), 4.22 (m, 2H), 3.54 (m, 2H), 3.27 (s, 3H); 13C
NMR (DMSO-d6) δ 154.80, 135.77, 128.77 (2C), 128.64, 128.45
(2C), 69.85, 69.16, 66.95, 58.27.
r-Meth ylben zyl (2-m eth oxyeth yl) ca r bon a te (10d ): tR
)
5.71 min; IR (cm-1, KBr) 1735, 1115, 1050; 1H NMR (DMSO-d6)
δ 7.40-7.32 (m, 5H), 5.69 (q, 1H, J ) 6.6 Hz), 4.20 (m, 2H), 3.53
(m, 2H), 3.26 (s, 3H), 1.52 (d, 3H, J ) 6.6 Hz); 13C NMR (DMSO-
d6) δ 154.18, 141.34, 128.75 (2C), 128.28, 126.15 (2C), 76.00,
69.83 66.76, 58.27, 22.36.
On e-P ot Syn th esis of Ca r bon a tes 9a a n d 10a . A solution
of 2-phenylethanol (358 µL, 3 mmol) in THF (10 mL) was slowly
added to solution of 1,1-carbonyldiimidazole (486 mg, 3 mmol)
in THF (5 mL) at 0 °C. The solution was stirred at 0 °C for 2 h
and then was added without any further purification to an
equimolar solution of 4 (311 µL, 3 mmol) and 5 (362 µL, 3 mmol)
in THF (15 mL) at 0 °C, previously treated with NaH (9 mg, 0.3
mmol). The mixture was stirred at 0 °C for 30 min and then
was diluted with Et2O (50 mL) and washed with a saturated
aqueous solution of NH4Cl. The solvents were removed, and the
ratio 9a /10a , determined on the crude product by HPLC, was
7.4. The product was purified by flash chromatography giving
640 mg of mixture of the two carbonates (yield 83%).
On e-P ot Syn th esis of Ca r bon a tes 9a a n d 10a by In -
ver ted Ad d ition . An equimolar solution of 4 (311 µL, 3 mmol)
and 5 (362 µL, 3 mmol) in THF (10 mL) was slowly added to
solution of 1,1-carbonyldiimidazole (486 mg, 3 mmol) in THF (5
mL) at 0 °C. The solution was stirred at 0 °C for 2 h with the
selective formation of the primary carbonylimidazolide (ratio 11/
12 by HPLC ) 12.1). Then a solution of 2-phenylethanol (358
µL, 3 mmol) in THF (15 mL) previously treated with NaH (9
mg, 0.3 mmol) was added at 0 °C. The mixture was stirred at
at this temperature for 30 min and then was diluted with Et2O
(50 mL) and washed with a saturated aqueous solution of NH4-
Cl. The solvents were removed, and the ratio 9a /10a , deter-
mined on the crude product by HPLC, was 11.7. The product
was purified by flash chromatography giving 571 mg of mixture
of carbonates. Using the ratio among the carbonates determined
by both 1H NMR and HPLC the yields of carbonates were 46%
of the mixture of 9a and 10a , 18% of symmetric carbonate 6,
and 10% of asymmetric carbonate 7.
Gen er a l P r oced u r e for th e Syn th esis of Ca r bon a tes (6/7
a n d 9a -d /10a -d ). An equimolar solution of 4 (207 µL, 2 mmol)
and 5 (242 µL, 2 mmol) in THF (6 mL) was added to a suspension
of NaH (6 mg, 0.2 mmol) in THF (6 mL). The reaction mixture
was cooled to 0 °C; then
a solution of the desired alkyl
carbonylimidazolide (2 mmol) in THF (12 mL) was slowly added.
The mixture was stirred at 0 °C for 30 min and then was diluted
with Et2O (50 mL) and washed with a saturated aqueous
solution of NH4Cl. The solvents were removed, and the ratio
between primary and secondary carbonates was determined on
the crude product by HPLC by comparison with authentic
samples of pure compounds. The crude product was purified
by flash chromatography giving the mixture of the two carbon-
ates. The amount of the obtained mixture was used for the
determination of the yield of the reaction (Tables 1 and 2).
Analytical data of pure compounds used as authentic samples
are reported.
Diben zyl ca r bon a te (6): tR ) 9.33 min; IR (cm-1, KBr) 1735;
1H NMR (DMSO-d6) δ 7.41-7.38 (m, 5H), 5.18 (s, 2H); 13C NMR
(DMSO-d6) δ 154.70, 135.73, 128.77 (2C), 128.66, 128.47 (2C),
69.32.
Ben zyl (r-m eth ylben zyl) ca r bon a te (7): tR ) 10.95 min;
IR (cm-1, KBr) 1735, 1050; 1H NMR (DMSO-d6) δ 7.41-7.34 (m,
10H), 5.71 (q, 1H, J ) 6.6 Hz), 5.13 (s, 2H), 1.52 (d, 3H, J ) 6.6
Hz); 13C NMR (DMSO-d6) δ 154.07, 141.34, 135.74, 128.76 (4C),
128.63, 128.42 (2C), 128.30, 126.14 (2C), 76.21, 69.13, 22.40.
Ben zyl (2-p h en yleth yl) ca r bon a te (9a ): tR ) 10.31 min;
IR (cm-1, KBr) 1735; 1H NMR (DMSO-d6) δ 7.34-7.23 (m, 10H),

6034 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Syn t h esis of 6 a n d 7 Usin g Ben zyl Ch lor ofor m a t e or
N-(Ben zyloxyca r bon yloxy)su ccin im id e. An equimolar so-
lution of 4 (207 µL, 2 mmol) and 5 (242 µL, 2 mmol) in THF (6
mL) was added to a suspension of NaH (6 mg, 0.2 mmol) in THF
(6 mL). The reaction mixture was cooled to 0 °C; then a solution
of benzyl chloroformate or N-(benzyloxycarbonyloxy)succinimide
(2 mmol) in THF (12 mL) was slowly added. The mixture was
stirred either overnight (in the case of benzyl chloroformate) or
for 48 h (in the case of benzyl succinimidyl carbonate) at room
temperature and then was diluted with Et2O (50 mL) and
washed with a saturated aqueous solution of NH4Cl. The
solvents were removed, and the ratio between 6 and 7 was
determined on the crude product by HPLC.
Syn th esis of Ben zyl Ca r bon a te of Meth yl r-D-glu cop y-
r a n osid e (14). A solution of benzyl alcohol (373 µL, 3.6 mmol)
in THF (6 mL) was slowly added to solution of 1,1-carbonyldi-
imidazole (583 mg, 3.6 mmol) in THF (3 mL) at 0 °C. The
solution was stirred at room temperature for 1 h; then the
solution was added without any further purification to a solution
of 13 (582 mg, 3 mmol) in DMF (15 mL) at 0 °C, previously
treated with NaH (9 mg, 0.3 mmol). The mixture was stirred
at 0 °C for 30 min; then the solvents were removed under high
vacuum. The crude product was dissolved in THF (200 mL) and
washed with a saturated aqueous solution of NH 4Cl (3 mL). The
organic phase was dried, and the solvent was removed. The
crude product was purified by flash chromatography (eluent
chloroform-methanol 90:10) giving 480 mg of pure 14 (yield
1
49%): HPLC tR ) 4.01 min; IR (cm-1, KBr) 1740, 740, 695; H
NMR (DMSO-d6) δ 7.37 (s, 5H), 5.12 (s, 2H),, 4.51 (d, 1H, J )
3.7 Hz), 4.23 (m, 2H), 3.53 (m, 1H), 3.39 (dd, 1H, J ) 9.4 and
8.8 Hz), 3.22 (m, 1H), 3.20, (s, 3H), 3.09 (dd, 1H, J ) 10.0 and
8.8 Hz); 13C NMR (DMSO-d6) δ 154.80, 135.78, 128.77 (2C),
128.66, 128.51 (2C), 100.00, 73.37, 72.01, 70.34, 69.64, 69.17,
54.68. Anal. Calcd for C15H20O8: C, 54.87; H, 6.14. Found: C,
54.63; H, 6.12.
J O980286E