Microwave-assisted regioselective benzylation: An access to glycal derivatives with a free hydroxyl group at C4

Article abstract of DOI:10.1080/07328303.2012.698438

D-glucal, D-galactal, and their 6-O-TBDMS derivatives were benzylated in a two-step procedure under microwave conditions. In the first step glycals were converted into dibutylstannylene acetal or tributyltin ether intermediates, which were next alkylated with benzyl bromide in the presence of Bu ₄NBr. In all cases the 4-OH group stayed unsubstituted. Microwave-assisted benzylation contributes to a significant reduction of the reaction time in comparison with the classical synthesis, which requires several hours of heating. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Carbohydrate Chemistry to view the free supplemental file.

Full text of DOI:10.1080/07328303.2012.698438

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Microwave-Assisted Regioselective
Benzylation: An Access to Glycal
Derivatives with a Free Hydroxyl Group
at C4
Tadeusz Bieg a , Katarzyna Kral a , Jadwiga Paszkowska a , Wiesław
Szeja a & Ilona Wandzik a
a Silesian University of Technology, Faculty of Chemistry,
Department of Organic Chemistry, Bioorganic Chemistry and
Biotechnology, 44-100 Gliwice, Poland
Version of record first published: 30 Aug 2012.
To cite this article: Tadeusz Bieg , Katarzyna Kral , Jadwiga Paszkowska , Wiesław Szeja & Ilona
Wandzik (2012): Microwave-Assisted Regioselective Benzylation: An Access to Glycal Derivatives with a
Free Hydroxyl Group at C4, Journal of Carbohydrate Chemistry, 31:7, 593-601
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Journal of Carbohydrate Chemistry, 31:593–601, 2012
ꢀ
C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2012.698438
Microwave-Assisted
Regioselective Benzylation:
An Access to Glycal
Derivatives with a Free
Hydroxyl Group at C4
Tadeusz Bieg, Katarzyna Kral, Jadwiga Paszkowska,
Wiesław Szeja, and Ilona Wandzik
Silesian University of Technology, Faculty of Chemistry, Department of Organic
Chemistry, Bioorganic Chemistry and Biotechnology, 44-100 Gliwice, Poland
D-glucal, D-galactal, and their 6-O-TBDMS derivatives were benzylated in a two-step
procedure under microwave conditions. In the first step glycals were converted into
dibutylstannylene acetal or tributyltin ether intermediates, which were next alkylated
with benzyl bromide in the presence of Bu4NBr. In all cases the 4-OH group stayed
unsubstituted. Microwave-assisted benzylation contributes to a significant reduction
of the reaction time in comparison with the classical synthesis, which requires sev-
eral hours of heating. Supplemental materials are available for this article. Go to the
publisher’s online edition of Journal of Carbohydrate Chemistry to view the free supple-
mental file.
Keywords Glycals; Regioselective benzylation; Microwave irradiation
INTRODUCTION
Glycals are versatile synthetic intermediates for the preparation of 2-
deoxyglycosides and 2,3-unsaturated glycosides that can be easily function-
alized at the C-2 and C-3 positions.[1–4] The utilization of glycals as the
building blocks for the total synthesis of various natural products is of great in-
terest in bioorganic and medicinal chemistry. Perbenzylated glycals are readily
Received April 1, 2012; accepted May 27, 2012.
Address correspondence to Ilona Wandzik, Silesian University of Technology, Faculty of
Chemistry, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnol-
ogy, 44-100 Gliwice, Krzywoustego 4, Poland. E-mail: ilona.wandzik@polsl.pl
593

T. Bieg et al.
594
available substrates[5] that can be employed as glycosyl donors. More com-
plex is the regioselective functionalization of the hydroxyl groups in glycals
affording valuable glycosyl acceptors. Among them, the derivatives of D-glucal
and D-galactal possessing a free hydroxyl group at C-4 are important sub-
strates. The synthesis of di-O-benzylated D-glucal and D-galactal derivatives
in a direct benzylation with BnBr in DMF/NaH leads preferentially to 4,6-
di-O-benzyl products and per-O-benzylated glycals. For example, the yield of
3,6-di-O-benzyl-D-galactal as a minor product is in the range 8%–20%.[6] The
synthesis of 3,6-di-O-benzyl-D-glucal has recently been accomplished via 4,6-
O-p-methoxybenzylidene acetal in 61% yield in four steps.[7] In order to elimi-
nate the multistep synthesis and improve the yield of 3,6-substituted glycals,
a selective enhancement of the nucleophilicity of the 3-OH over the 4-OH
group is necessary. It is possible to differentiate the reactivity of hydroxyl
groups via organotin derivatives: dibutylstannylene acetals[8] and tributyltin
ethers.[9] Both strategies have had several successful applications in carbohy-
drate chemistry. Many examples of regioselective benzylation of hexopyranoses
and hexopyranosides after prior conversion to dibutylstannylene acetal[10] and
tributyltin ether[11] intermediates have been reported. Among many success-
ful regioselective benzylations, a preparative utilization of stannyl ethers and
dibutylstannylene acetals of D-glucal[12–14] and D-galactal[15] derivatives and
their subsequent benzylation have been reported. Both steps—the regioselec-
tive O-stannylation and benzylation—require several hours of heating in re-
flux to afford mono- or disubstituted D-glucal derivatives as major products.
The purpose of the present work is to compare the classical reaction condi-
tions with the microwave irradiation, which has become an emerging tech-
nique in organic chemistry and has recently been frequently used in the field
of carbohydrate chemistry for protecting group manipulations and glycosida-
tions.[16] Although the microwave-assisted one-pot protocol for the preparation
of 3-O-alkylated galactosides using stannylene acetal chemistry has been de-
scribed,[17] no report on microwave-assisted alkylation of glycals is available.
In this study, we used microwave irradiation in the tin-mediated
two-step synthesis of mono- and dibenzylated glycals (Sch. 1). In our ini-
tial microwave-assisted experiments D-glucal (1) was transformed into
R2
R3
R2
R3
Step I
Step II
O
R1
HO
O
R1
BnO
(Bu3Sn)2O or Bu2SnO
BnBr, Bu4NBr
toluene, 125 oC
30 min, MW
toluene, 125 oC
10 min, MW
1: R1 = OH, R2 = H, R3 = OH
2: R1 = H, R2 = OH, R3 = OH
3: R1 = OH, R2 = H, R3 = OTBDMS
4: R1 = H, R2 = OH, R3 = OTBDMS
5: R1 = OH, R2 = H, R3 = OBn
6: R1 = H, R2 = OH, R3 = OBn
7: R1 = OH, R2 = H, R3 = OTBDMS
8: R1 = H, R2 = OH, R3 = OTBDMS
Scheme 1: Microwave-assisted regioselective benzylation of glycals 1–4.

Microwave-Assisted Regioselective Benzylation
595
Table 1: Microwave-assisted regioselective dibenzylation of D-glucal (1) upon
activation with (Bu3Sn)2O
Step I
Step II
Temp. Power Time∗
Program
type
Temp. Power Time∗
Program
type
Yield
(%)
Entry (◦C)
(W) (min)
(◦C)
(W) (min)
1
2
3
4
5
6
125
125
125
125
80
17
100
150
150
150
150
30 Conventional 125
60 Power cycling 125
1–2
60
100
100
100
100
20 Conventional
0
30 Power cycling 38
15 Power cycling 41
10 Power cycling 51∗∗
10 Power cycling 10
10 Power cycling 27
30 Power cycling
80
30 Power cycling 125
30 Power cycling 125
15 Power cycling 125
125
∗
Effective time of specified microwave energy.
∗∗59% in the classical synthesis.[13a]
3,6-di-O-benzyl-D-glucal (5) (Table 1). Thus, stannylation of D-glucal 1 with
1.05 equiv. of bis(tributyltin)oxide and subsequent treatment of the stan-
nylated intermediate with 3.4 equiv. of benzyl bromide in the presence of
Bu4NBr gave dibenzyl ether 5 as a main product. Reactions were carried
out with controlled microwave irradiation under sealed vessel conditions by
using the CEM Discover microwave synthesizer in 10 mL glass vessels with
stirring in toluene as solvent. The preferred concentration of glycal substrate
was 0.5–1.0 mmol/2 mL of toluene. It was found that the microwave-assisted
benzylation cannot be carried out in a solvent-free manner or in more con-
centrated solutions. In both cases 2-(1ꢁ-hydroxy-2ꢁ-benzyloxyethyl)furan was
formed as a major product (1H NMR[18a,b] and 13C NMR[18b] spectral data
matched those reported).
Based on the results presented in Table 1, it can be concluded that the yield
of the reaction depends both on the power level and the reaction time. The typ-
ical conventional program based on the reaction temperature was initially ap-
plied and the temperature was set to 125◦C (Table 1, entry 1). The microwave
power levels—17 W in step I and 2 W in step II—were automatically adjusted
to maintain the reaction temperature of 125◦C. The set values of 150 W in step
I and 100 W in step II were never reached. Under these conditions no product
was observed. In the following experiments, in order to ensure the required
level of microwave power, instead of a conventional program, another power
cycling control program was used (Table 1, entries 2–6). It was observed that
the repeating cycles of strong microwave could enhance the reaction yields.
This observation suggests that microwave is not just a simple heating source
and that the power level is the most important parameter. The described in-
crease of the reaction yield with the microwave power level under a controlled
temperature indicates a possibility of the existence of a nonthermal microwave
effect, which is in accordance with published reports.[19] The reaction time de-
pended on the applied microwave power and temperature, and in the optimal

T. Bieg et al.
596
Table 2: Microwave-assisted regioselective benzylation of glycal derivatives 1–4
Entry
1
Substrate
Product
Organotin compound
(Bu3Sn)2O
Yield (%)
51
2
3
1
5
Bu2SnO
44
59
(Bu3Sn)2O
4
5
2
3
6
7
Bu2SnO
52
54
(Bu3Sn)2O
6
7
Bu2SnO
50
71
(Bu3Sn)2O
8
4
8
Bu2SnO
61
case was set to 30 min in the O-stannylation step (150 W, 125◦C) and 10 min
in the benzylation step (100 W, 125◦C). The yield of 3,6-di-O-benzyl-D-glucal
(5) was comparable to the classical method[13a] (Table 1, entry 4) and was cho-
sen for further experiments on regioselective benzylation of glycals 2–4. The
overall yields obtained are presented in Table 2.
Benzylated glycals 5–8 were purified by column chromatography and their
structures were elucidated with the aid of 1H and 13C NMR spectroscopy
data (including two-dimensional HSQC, HMBC experiments, and simulation
analysis) and mass spectrometry analysis (for details see the experimental
section). In all cases 4-OH groups stayed unsubstituted, which was confirmed
by the acetylation of glycals 5–8 and the comparison of chemical shifts of
H-4 protons. The H-4 protons of 4-O-acetylated products resonated at lower
1
fields than the H-4 protons in glycals with free 4-OH groups. H NMR spec-
tral data for 4-O-acetyl-3,6-di-O-benzyl-D-glucal[20] and 4-O-acetyl-3,6-di-O-
benzyl-D-galactal[21] matched those reported.
EXPERIMENTAL
General Methods
NMR spectra were recorded for solutions in CDCl3 (internal Me4Si) with
a Varian spectrometer at a frequency of 600 MHz. NMR simulation analysis

Microwave-Assisted Regioselective Benzylation
597
was performed using MestReNova software.[22] Optical rotations were mea-
sured with a P-2000 Jasco polarimeter using a sodium lamp (589 nm) at rt.
Mass spectra were recorded in the positive mode on a Mariner (Perseptive
Biosystem) detector using the electrospray-ionization (ESI) technique. The
experiments were performed in 10 mL vessels in a CEM Discover mi-
crowave synthesizer interfaced with a personal computer. The synthesizer was
connected to an air compressor system (1.5 atm) that automatically provided
cooling and assisted the microwave power tuning in order to not significantly
overcome the maximum set temperature. TLC was performed on precoated
plates of silica gel G (Merck); components were detected by charring with 10%
sulfuric acid in ethanol. Column chromatography was performed on silica gel
60 (70–230 mesh, E. Merck) developed with hexane/EtOAc solvent systems. All
evaporations were performed under diminished pressure at 50◦C.
General Procedure for Microwave-Assisted Benzylation
General Procedure for Dibenzylation
Glycal 1 or 2 (0.68 mmol) was suspended in toluene (2 mL) and Bu2SnO
or (Bu3Sn)2O was added (1.05 equiv). The mixture was exposed to microwave
irradiation at 125◦C and 30 min (power cycling, 150 W, 60 cycles) was required
to obtain a homogenous light yellow solution (Table 1, Step I, entry 4). Then
benzyl bromide (3.4 equiv.) and Bu4NBr (2 equiv.) were added and the mix-
ture was irradiated again at 125◦C and 10 min (power cycling, 100 W, 30 cy-
cles) (Table 1, Step II, entry 4). The reaction mixture was diluted with toluene
(50 mL), washed with water (3 × 50 mL), dried over anhydrous MgSO4, and
concentrated to give crude products. Crude products were purified by column
chromatography on silica gel with the hexane/ethyl acetate system 10:1 → 6:1
and yielded 5 or 6 as colorless oils in the amounts presented in Table 2.
General Procedure for Monobenzylation
Glycal 3 or 4 (0.68 mmol) was suspended in toluene (2 mL) and Bu2SnO
or (Bu3Sn)2O was added (1.05 equiv). The mixture was exposed to microwave
irradiation at 125◦C and 30 min (power cycling, 150 W, 60 cycles) was re-
quired to obtain a homogenous light yellow solution (Table 1, Step I, en-
try 4). Then benzyl bromide (1.7 equiv.) and Bu4NBr (1 equiv.) were added
and the mixture was irradiated again at 125◦C and 10 min (power cycling,
100 W, 30 cycles) (Table 1, Step II, entry 4). The reaction mixture was diluted
with toluene (50 mL), washed with water (3 × 50 mL), dried over anhydrous
MgSO4, and concentrated to give crude products. Crude products were pu-
rified by column chromatography on silica gel with the hexane/ethyl acetate

T. Bieg et al.
598
system 20:1 → 10:1 and yielded 7 or 8 as colorless oils in yields presented in
Table 2.
1,5-Anhydro-3,6-di-O-benzyl-2-deoxy-D-arabino-hex-1-
enopyranose (3,6-di-O-benzyl-D-glucal) (5)
[α]D −22.7 (c 1.0, CHCl3), lit.[13a] [α]D −25.0 (c 5.7, CHCl3), lit.[12a] [α]D
22
23
−32.2 (c 2.5, CHCl3). H NMR and 13C NMR (CDCl3) spectral data matched
1
those reported.[12a,13a]
1,5-Anhydro-3,6-di-O-benzyl-2-deoxy-D-lyxo-hex-1-enopyranose
(3,6-di-O-benzyl-D-galactal) (6)
[α]D −14.9 (c 1.3, CHCl3), lit.[15] [α]D −21.5 (c 2.6, CHCl3). 1H NMR and
22
23
13C NMR (CDCl3) spectral data matched those reported.[15]
1,5-Anhydro-3-O-benzyl-6-O-tert-butyldimetylsilyl-2-deoxy-D-
arabino-hex-1-enopyranose (3-O-benzyl-6-O-tert-
butyldimetylsilyl-D-glucal) (7)
[α]D −9.9 (c 1.0, CHCl3). 1H NMR: δ 7.374 (ddd, 2H, J = 7.5, 1.7, 1.7 Hz,
25
CH2Ph, Horto), 7.342 (ddd, 2H, J = 7.5, 7.2, 1.7 Hz, CH2Ph, Hmeta), 7.279 (dddd,
J = 7.2, 7.2, 1.7, 1.7 Hz, 1H, CH2Ph, Hpara), 6.339 (dd, J = 6.1, 1.6 Hz, 1H,
H-1), 4.805 (dd, J = 6.1, 2.2 Hz, 1H, H-2), 4.701, 4.661 (ABq, J = 11.8 Hz,
2H, CH2Ph), 4.106 (ddd, J = 6.9, 2.2, 1.6 Hz, 1H, H-3), 3.983 (ddd, J = 9.4,
6.9, 2.8 Hz, 1H, H-4 ), 3.973 (dd, J = 11.1, 4.5 Hz, 1H, H-6a), 3.900 (dd, J =
11.1, 4.7 Hz, 1H, H-6b), 3.802 (ddd, J = 9.4, 4.7, 4.5 Hz, 1H, H-5), 2.855
(d, 1H, J = 2.8 Hz, 4-OH), 0.905 (s, 9H, Si[C(CH3)3(CH3)2]), 0.089 (s, 6H,
Si[C(CH3)3(CH3)2]). 13C NMR: δ 144.524 (C-1), 138.516 (CH2Phq), 128.441,
127.792, 127.669 (5C, CH2Ph), 100.151 (C-2), 77.323 (C-5), 76.402 (C-3), 71.014
(CH2Ph), 69.839 (C-4), 63.373 (C-6), 25.891 (3C, Si[C(CH3)3(CH3)2]), 18.338
(Si[C(CH3)3(CH3)2]), −5.373, −5.427 (2C, Si[C(CH3)3(CH3)2]). ESI-HRMS:
Calcd for C19H30O4SiNa ([M+Na]+): m/z 373.1811, found: m/z 373.1802.
Acetylation of 7 (0.2 mmol) with acetic anhydride (40 µL) in pyridine
1
(0.5 mL) for 18 h at rt gave the 4-O-acetyl derivative as an oil. H NMR:
δ 7.400–7.270 (m, 5H, CH2Ph), 6.440 (dd, J = 6.3, 1.2 Hz, 1H, H-1), 5.307
(ddd, J = 5.2, 4.2, 1.0 Hz, 1H, H-4), 4.863 (ddd, J = 6.3, 3.9, 1.0 Hz, 1H, H-
2), 4.620, 4.600 (ABq, J = 11.8 Hz, 2H, CH2Ph), 4.126 (dddd, J = 6.3, 5.2,
4.9, 1.3 Hz, 1H, H-5), 3.916 (dddd, J = 4.2, 3.9, 1.3, 1.2 Hz, 1H, H-3), 3.861
(dd, J = 11.2, 6.35 Hz, 1H, H-6b), 3.832 (dd, J = 11.2, 4.9 Hz, 1H, H-6a),
2.061 (s, 3H, CH3CO), 0.890 (s, 9H, Si[C(CH3)3(CH3)2]), 0.052, 0.043 (2 s, 6H,
Si[C(CH3)3(CH3)2]).

Microwave-Assisted Regioselective Benzylation
599
1,5-Anhydro-3-O-benzyl-6-O-tert-butyldimetylsilyl-2-deoxy-D-
lyxo-hex-1-enopyranose (3-O-benzyl-6-O-tert-
butyldimetylsilyl-D-galactal) (8)
[α]D −10.3 (c 2.0, CHCl3). 1H NMR: δ 7.380–7.288 (m, 5H, CH2Ph), 6.396
25
(dd, J = 6.3, 1.8 Hz, 1H, H-1), 4.701 (ddd, J = 6.3, 2.0, 2.0 Hz, 1H, H-2),
4.664, 4.622 (ABq, J = 11.81 Hz, 2H, CH2Ph), 4.209 (dddd, J = 4.4, 2.0, 1.8,
0.4 Hz, 1H, H-3), 4.128 (dddd, J = 4.4, 3.5, 3.0, 2.0 Hz, 1H, H-4), 3.950 (dddd,
J = 6.6, 6.4, 3.5, 0.4 Hz, 1H, H-5), 3.851 (dd, J = 11.0, 6.4 Hz, 1H, H-6a),
3.828 (dd, J = 11.0, 6.6 Hz, 1H, H-6b ), 2.538 (d, 1H, J = 3.0 Hz , 4-OH),
0.907 (s, 9H, Si[C(CH3)3(CH3)2]), 0.095, 0.090 (2 s, 6H, Si[C(CH3)3(CH3)2]).
13C NMR: δ 145.004 (C-1), 137.792 (CH2Phq), 128.531, 127.931, 127.807, (5C,
CH2Ph), 99.558 (C-2), 76.643, 71.057, 70,477, 62,447, 62,111 (5C, C-3, C-4, C-
5, C-6, CH2Ph), 25.919 (3C, Si[C(CH3)3(CH3)2]), 18.377 (Si[C(CH3)3(CH3)2]),
−5.371, −5.397 (2C, Si[C(CH3)3(CH3)2]). ESI-HRMS: Calcd for C19H30O4SiNa
([M+Na]+): m/z 373.1811, found: m/z 373.1780.
Acetylation of 8 (0.2 mmol) with acetic anhydride (40 µL) in pyridine
1
(0.5 mL) for 18 h at rt gave the 4-O-acetyl derivative as an oil. H NMR: δ
7.345–7.250 (m, 5H, CH2Ph), 6.375 (dd, J = 6.3, 2.0 Hz, 1H, H-1), 5.606 (ddd,
J = 4.2, 1.7, 1.3 Hz, 1H, H-4), 4.696, 4.502 (ABq, J = 11.8 Hz, 2H, CH2Ph),
4.737 (ddd, J = 6.3, 1.9, 1.7 Hz, 1H, H-2), 4.253 (ddd, J = 4.2, 2.0, 1.9 Hz,
1H, H-3), 4.033 (dddd, J = 7.1, 6.2, 1.3, 0.9 Hz, 1H, H-5), 3.766 (dd, J = 10.2,
6.2 Hz, 1H, H-6a), 3.684 (dd, J = 10.2, 7.1, 1H, H-6b), 2.134 (s, 3H, CH3CO),
0.901 (s, 9H, Si[C(CH3)3(CH3)2]), 0.066, 0.062 (2 s, 6H, Si[C(CH3)3(CH3)2]).
ACKNOWLEDGEMENTS
Publication partly financed by the European Union within the European Re-
gional Development Fund (POIG. 01.01.02-14-102/09).
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