Highly diastereoselective 1,2-dichlorination of glycals using NCS/PPh 3: Study of substituent and solvent effects

Article abstract of DOI:10.1016/j.tet.2013.12.088

Highly diastereoselective 1,2-dichlorination of glycals has been achieved at room temperature conditions in good to excellent yields using a milder, more convenient, less hazardous reagent combination NCS/PPh₃ giving only one major product out of four possible diastereomers [either α-gluco (2) or α-manno (4)] depending upon the substituents. The diastereoselectivity is maximum (100% α/β-selectivity as well as cis/trans selectivity) for d-galactal and l-rhamnal derivatives. Detailed studies showed that solvent and substituent effects play a significant role in determining the product distribution.

Full text of DOI:10.1016/j.tet.2013.12.088

Tetrahedron xxx (2014) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly diastereoselective 1,2-dichlorination of glycals using
NCS/PPh3: study of substituent and solvent effects
,
,b,
Altaf Hussain a b, Debaraj Mukherjee a
*
a Academy of Scientific and Innovative Research (AcSIR), India
b CSIR e IIIM (Indian Institute of Integrative Medicine), Canal Road, Jammu (J & K) 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly diastereoselective 1,2-dichlorination of glycals has been achieved at room temperature conditions
in good to excellent yields using a milder, more convenient, less hazardous reagent combination NCS/
Received 10 September 2013
Received in revised form 27 December 2013
Accepted 28 December 2013
Available online xxx
PPh3 giving only one major product out of four possible diastereomers [either
depending upon the substituents. The diastereoselectivity is maximum (100%
cis/trans selectivity) for -galactal and -rhamnal derivatives. Detailed studies showed that solvent and
substituent effects play a significant role in determining the product distribution.
Ó 2014 Elsevier Ltd. All rights reserved.
a
-gluco (2) or
a-manno (4)]
a/b
-selectivity as well as
D
L
Keywords:
1,2-Dichlorination
Glycals
Diastereoselectivity
Chlorophosphonium ion
Solvent effects
1. Introduction
and Horton et al.9 in 1986 established that product formation is
under kinetic, not thermodynamic control; the product distribution
is dependent on the polarity of the solvent and even on the
electron-withdrawing or -donating effect of the substituent at C-6
as well as stereochemistry of substituent at C-4 of sugar moiety.
Kent et al.10 and Hall et al.11 reported the reaction of glycals with
NCS/HCl system instead of molecular chlorine to obtain the prod-
ucts 2, 3, 4, and 5 in 15.7, 4.4, 1.4, and 10.7% yields, respectively.
Thus, the NCS/HCl method lacked the stereoselectivity achieved
even with molecular chlorine. A detailed description of product
distributions achieved under different reaction conditions is given
in Table 1. The above methods suffer from either or both of the
following drawbacks: (i) handling of gaseous molecular chlorine is
hazardous (Hathaway et al. 1991), (ii) lack of stereoselectivity as an
inseparable mixture of diastereomers results (Fig. 1). Although
Halogeno sugars are valuable starting materials for the synthesis
of amino-sugars, deoxy sugars, and deoxy nucleosides, which are
not easily obtainable. Due to the polar nature of CeX bonds, halo-
geno sugars are easily attacked by a wide range of nucleophiles
giving biologically significant molecules. Halogeno sugars specially
1- or/and 2-halogenated ones are of particular interest because 1-
halogeno sugars have become the most frequently used glycosyl
donor in O-glycosylation of both sugar and non-sugar compounds
(aglycones),1 whereas 2-halogeno sugars can be used for the gen-
eration of 2-deoxy glycosides. Further, the anomeric carbon of
sugar shows electrophilic reactivity in most of the reactions but
halogeno sugars have been successfully exploited in the generation
of the corresponding anomeric carbanions2 and radicals.3
First report on 1,2-dichlorination of glycals dates back to 1920
when Fischer et al. investigated the addition of molecular chlorine
to D
-glucal triacetate in carbon tetrachloride at 0e2 ꢀC and obtained
a mixture of diastereomers because 1,2-dichlorination of glycals
may generate four possible diastereomers (2e5 in Fig. 1).4 Lemieux
and Fraser-Reid studied the addition of halogens to glycals and
proposed a mechanism, which leads to products of thermodynamic
control.5,6 Later, Igarashi et al.7 in 1970, Boullanger et al.8 in 1976,
* Corresponding author. Tel.: þ91 191 2569000; fax: þ91 191 2569111; e-mail
Fig. 1. Possible diastereomers in the 1,2-dichlorination of glycals 2 (
manno), 4 ( -manno), 5 ( -gluco).
a-gluco), 3 (b-
addresses: dmukherjee@iiim.ac.in, debarajrrl@gmail.com (D. Mukherjee).
a
b
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.088
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

2
A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
when the NCS/PPh3 reagent combination was used in the ratios of
Table 1
2:1 and 3:1 (entries 2 and 3, Table 2). Thus, 2:1 (NCS:PPh3) was the
ratio of choice for 1,2-dichlorination reaction.
Literature methods on 1,2-dichlorination of glycals using different reaction
conditions
Under the optimized conditions the reaction was found to be
Entry Reaction
conditions
Nature of Product distribution (%)
solvent
diastereoselective (
because only two of the four possible diastereomers were ob-
tained, i.e., only 2a ( -gluco) and 4a ( -manno) were obtained in
a/b-selectivity as well as cis/trans selectivity)
a
-gluco
b
-manno
a
-manno
b-gluco
(5)
a
a
(2)
(3)
(4)
the ratio of 1:0.23 with excellent yield (entry 2, Table 2). On car-
rying out the 1,2-dichlorination reaction at 1.0 gram scale
showed similar results. Further, in order to see the effect of tem-
perature on the stereochemical outcome and rate of reaction, 1,2-
dichlorination was carried out at lower (upto 0 ꢀC) or higher
(upto 60 ꢀC) temperatures. Decreasing the temperature had no
effect on the stereochemical outcome of the reaction except that
the reaction proceeded at a slower rate. At higher temperatures the
reaction mixture got charred giving only small amount of the
1
2
3
4
5
Cl2, 0 ꢀC
Non-polar 76%
3%
4%
17%
18%
1.6%
39.1%
10.7%
d
(Horton et al.)9
Cl2, 0 ꢀC
Polar
Non-polar 85.3%
Polar 9.4%
Non-polar 15.7%
Polar
Non-polar 80%
35%
23%
3.8%
6.4%
4.4%
d
24%
4.5%
45.1%
1.4%
d
(Igarashi et al.)7
NCS/HCl
(Kent, et al.)10
Cl2, 0 ꢀC
d
Traces
d
Traces
d
Traces
d
(Lemieux et al.)5,6 Polar
d
Cl2, 0e2 ꢀC
Non-polar A mixture of isomers, which were not
only separated
(Fischer et al.)4
products. The structure and stereochemistry of products 2a (
gluco as major product) and 4a ( -manno as minor product) were
determined by 1H NMR by comparing the chemical shifts (
value)
and coupling constants (J1,2 value) of products obtained using the
present methodology with spectroscopic data available in litera-
ture (Table 3). In the 1H NMR spectrum, appearance of two distinct
a-
a
Colovic et al.12 in 2008 achieved considerably higher selectivity
under milder conditions for the bromination of glycals using qua-
ternary ammonium bromide, there is no such stereoselective
method for the chlorination of glycals. Keeping in mind the above
mentioned facts a milder, less hazardous, and more selective
method is highly needed for the 1,2-dichlorination of glycals. Re-
cently, Yoshimitsu et al. successfully exploited the NCS/PPh3 system
for the dichlorination of olefins giving products of anti-addition.13
This prompted us to examine whether the NCS/PPh3 system was
suitable to perform the chlorination of glycals. With our interest in
halogeno-sugars and glycals,14,15 herein we report a convenient
method for the chlorination of glycals using NCS/PPh3 system with
better diastereoselectivity than the existing methods. The stereo-
chemical outcome is interestingly quite different in glycals from
that of simple olefins. The superiority of the present methodology
over already existing methods (Table 1) lies in the use of lesser
hazardous reagents and higher diastereoselectivity.
d
doublet signals for anomeric protons, one at
(J1,2¼3.5 Hz) and the other at ¼6.23 ppm (J1,2¼1.3 Hz), corre-
sponding to diastereoisomers 2a ( -gluco diastereomer) and 4a (
d¼6.14 ppm
d
a
a-
manno diastereomer) respectively, are consistent with NMR data
available in the literature (entries 1 and 3, Table 3). When tri-O-
acetyl-
the results showed a contrasting feature. Here 4b [
astereomer,
¼6.17 ppm (J1,2¼1.3 Hz)] was the major product and
2b [( -gluco diastereomer,
¼6.15 ppm (J1,2¼3.5 Hz)] was the mi-
nor product (entry 2, Table 4). Gratifyingly, we obtained 100% se-
lectivity ( -selectivity as well as cis/trans selectivity) when tri-O-
benzoyl- -glucal (1c) was subjected to 1,2-dichlorination reaction
under similar conditions, i.e., only -manno diastereomer was
D
-glucal (1b) was subjected to similar reaction conditions,
a
-manno di-
d
a
d
a/b
D
a
formed in this case (entry 3, Table 4).
2. Results and discussion
Table 3
Chemical shifts of H-1 and coupling constants (J1,2) of diastereomers expected from
dichlorination of glycals reported in literature
In order to test our hypothesis, we chose tri-O-benzyl-D-glucal
(1a) for 1,2-dichlorination using NCS/PPh3 system (Scheme 1).
Initially, we carried out the reaction of 1a in DCM using different
ratios of NCS and PPh3 at room temperature. The results are sum-
marized in Table 2 and it has been found that the reaction does not
occur at all when NCS/PPh3 system was used in the ratios of 1:1,1:2,
and 1:3 (entries 1, 4, and 5, Table 2). The reaction occurred best
a
Entry
Compound
dH-1
J1,2 (Hz)a
1
2
3
4
2
3
4
5
6.16
5.60
6.17
5.31
3.5e3.7
1.2
1.0e1.5
9.3
a
For chemical shifts
(dH-1) and coupling constants (J1,2 value) of 1,2-
dichlorination products of protected glucal see Ref. 7.
After getting promising results using the NCS/PPh3 reagent
combination in case of different glucals (1aec), we applied this
reagent system to different galactals. All the galactals (1eeg)
showed 100% selectivity (
tivity), i.e., only -galacto diastereomer was formed out of the four
possible diastereomers (entries 5,6, and 7, Table 4). This method
was next extended to 2,3,4,6-tetra-O-acetyl- -glucal (1d), which
a/b-selectivity as well as cis/trans selec-
Scheme 1. 1,2-Dichlorination of glycals (1aec) using NCS/PPh3 reagent combination as
chlorinating agent.
a
D
was prepared from the easily available starting material glucose
penta-acetate.16 Compound 1d was subjected to NCS/PPh3 condi-
tions leading to the formation of 2d and 4d in the ratio of 1:0.32 in
3e4 h (Scheme 2). The 1H NMR spectrum of the purified product
Table 2
Standardization of reaction conditions for 1,2-dichlorination of tri-O-benzyl-
D
-glucal
Entry
NCS/PPh3 (mmol)
Yield%
Product distribution 2a:4a (%)
1
2
3
4
5
1:1
2:1
3:1
1:2
1:3
05%
90%
90%
No reaction
No reaction
d
showed two sharp singlets for H-1 at
d
¼6.20 and 6.33 ppm in the
1:0.23 (81:19%)
1:0.23 (81:19%)
d
ratio of 1:0.32 (76:24%). From the chemical shift values it can be
concluded17 that1,2-cis-dichloro diastereomer (2d) is the major
product (76%) and 1,2-trans-dichloro diastereomer (4d) is the mi-
nor product (24%) as shown in Scheme 2. Our next target was to
carry out 1,2-dichlorination of silyl protected glycals. Unfortunately,
d
Reagents & conditions: substrate 1a (100 mg, 0.24 mmol), NCS (3 equiv, 96 mg),
PPh3 (1.5 equiv, 94 mg), dichloromethane (4 mL), room temperature, 3e4 h.
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
3
Table 4
Diastereoselective 1,2-dichlorination of glycals using NCS/PPh3 reagent combination as chlorinating agent
Entry
1
Substratea
Product
cis/trans Selectivity 2:4 (%)
a
/
b
Selectivity
Yield(%)b
1:0.23 (81:19%)
100%
90
2
3
1:1.46 (41:59%)
100%
100%
88
88
0:1 (100% trans)
4
5
1:0.32 (76:24%)
100%
100%
90
89
1:0 (100% cis)
6
7
1:0 (100% cis)
1:0 (100% cis)
100%
100%
88
88
8
1:0 (100% cis)
100%
90
a
Reagents & conditions: substrate (100 mg), NCS (3 equiv), PPh3 (1.5 equiv), DCM (3 mL), room temperature, 3e4 h, stir.
b
For entries 1, 2, and 4 overall yields of inseparable mixtures (
a
-gluco/
a
-manno) whereas for entries 3, 5, 6, and 7 isolated yields after column chromatography are mention.
silyl protecting groups (eOTMS, eOTBDMS and eOTBDPS groups)
do not survive the NCS/PPh3 reagent system and get decomposed
within 1 h under the standardized conditions.
Finally, the deoxy sugar 3,4-di-O-acetyl- -rhamnal (1h) was
L
subjected to NCS/PPh3 reagent conditions to see what happens to
product distribution. Rhamnal acetate (1h) was synthesized from
Scheme 2. 1,2-Dichlorination of 2,3,4,6-tetra-O-acetyl-D-glucal (1d).
easily available starting material
L-rhamnal (A) in three steps
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

4
A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
namely (1) acetylation, (2) bromination, and (3) elimination
(Scheme 3). On carrying out 1,2-dichlorination of 1h it was found
that the reaction proceeds with 100% diastereoselectivity (Scheme
3, entry 8, Table 4). The appearance of a doublet for H-1 at
d
¼6.09 ppm with J1,2 value of 3.7 Hz in 1H NMR spectrum confirms
the formation of syn addition product 2h. The 1H NMR data exactly
matches with the literature data (Horton et al., reported H-1 at
Fig. 3. a. Ground state conformations of 1,2-glycal
b. Conformations of oxocarbenium ion C (4H3) and D (3H4).
A B
(4H5) and (5H4).
d¼6.08 ppm with J1,2¼3.7, see Ref. 9).
conformer A (5H4) (Fig. 3a) giving the mannose-derived oxocarbe-
nium ion (II). Thus, the electrophilic attack in the step 1 is governed
by the ground state conformations of 1,2-glycals A (4H5) or B (5H4)
depending upon the substituents.18 In the second step the nucle-
ophilic attack onto the oxocarbenium ions (I and II, Fig. 2) occurs
preferentially to a conformer in which the C-5 substituent is
equatorial (conformer C, Fig. 3b) to avoid powerfully destabilizing
interactions in the transition state when this substituent is axial
(conformer D, Fig. 3b).19 The stereoselectivity of the nucleophilic
attack of Clꢁ (step 2, Fig. 2) will depend on the relative energies of
the transition states for nucleophilic attack.20 Therefore, regardless
of the position of the equilibrium of Fig. 3 the two conformers of the
oxocarbenium ion (C & D, Fig. 3b) do not react with nucleophiles at
Scheme 3. Preparation of L-rhamnal (1h) and its 1,2-dichlorination using NCS/PPh3
reagent combination.
the same rate. The a-selective reaction thus appears to be a result of
2.1. Mechanism
an interconverting mixture of conformers, arguably favoring the
3H4 conformer D, reacting through the lowest-energy transition
state20 (namely, via conformer C), in accord with the Cur-
tineHammett kinetic scenario.20 Thus, substituent effect plays
1,2-Dichlorination of glycals involves a two-step mechanism.
First step is an electrophilic attack of the chlorophosphonium ion
generated in situ from NCS/PPh3 (as shown in Scheme 4) at C-2 of
glycal double bond while the second step involves nucleophilic
attack of Clꢁ (present in the medium) at the anomeric center.13
a role in the electrophilic attack (step 1) while step 2 is
irrespective of the substituents.
a-selective
2.2. Solvent effects in the 1,2-dichlorination of glycals
In order to see the effect of solvent polarity on product distri-
bution we have selected 1a and 1b as model substrates. We have
carried out the chlorination in polar and non-polar solvents, such as
CCl4, CH2Cl2, CH3CN or CH3NO2 using NCS/PPh3 in the ratio of 2:1
under optimized conditions. 1,2-Dichlorination of 1a and tri-O-
Scheme 4. Generation of chlorophosphonium ion from NCS/PPh3.
acetyl-
zyl- -glucal (1a), increasing the polarity of solvent from CCl4 to
CH3NO2 decreased the percentage of the product 2a ( -gluco) from
85% to 73% while that of 4a ( -manno) increased from 15% to 27%
though the major product was always the same, i.e., 2a ( -gluco) as
shown in Fig. 4a. On carrying out similar studies on 1b we found
that the percentage of 2b ( -gluco, minor product) increased from
39% to 49% while that of 4b ( -manno, major product) decreased
from 61% to 51% as shown in Fig. 4b. The only common feature was
that in both the cases (1a and 1b), the percentage of major product
always decreased with increase in solvent polarity from CCl4 to
CH3NO2 while that of the minor product increased though the
D
-glucal (1b) showed opposite trends. In case of tri-O-ben-
In the first step the electrophile (chlorophosphonium ion) at-
tacks C-2 of the glycal double bond with assistance from the lone
pair on the ring oxygen giving oxocarbenium ions I or II (step 1,
Fig. 2) depending upon the substituents, e.g., in the case of tri-O-
D
a
a
a
benzyl-
face of conformer B (5H4) (Fig. 3a) giving the glucose-derived
oxocarbenium ion (I) while in the case of tri-O-acetyl- -glucal
(1b) the preferred attack takes place mainly from the -face of
D-glucal (1a) preferred attack takes place mainly from the a-
a
D
a
b
major product was always the same in different solvents (
case of 1a and -manno in case of 1b).
a-gluco in
a
1,2-Dihalo-pyranosides can easily be converted to 2-haloglycals
using literature methods.21 2-Haloglycals contain vinylic halide
moiety, which may find applications in organic synthesis especially
Pd-catalyzed CeC coupling reactions. Although there are
several examples of CeC bond formations using 2-iodo or
2-bromoglycals,22 transition metal-catalyzed CeC bond formation
reactions of 2-chloroglycals has not been reported to date. In order
to demonstrate the application of 2-chloroglycals in CeC bond
formation reactions, we carried out the reaction of 3,4,6-tri-O-
benzyl-2-chloro-2-deoxy-a-glucopyranosyl chloride (2a/4a mix-
ture) with potassium tert-butoxide in diethyl ether to give
2-chloroglycal (6),21 which was subsequently subjected to modified
Suzuki conditions to produce the coupled product 8 (Scheme 5) in
Fig. 2. Plausible mechanism for 1,2-dichlorination of glycals using NCS/PPh3 as chlo-
rinating agent.
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
5
installed at CSIR-IIIM, Jammu, India-180001). Reagents and sol-
vents used were mostly of LR grade. Optical rotation measurements
were carried out on PerkineElmer 241 polarimeter.
4.2. General procedure for 1,2-dichlorination of glycals
To a solution of the glycal (100 mg) in CH2Cl2 (3 mL) was added
PPh3 (1.5 equiv) followed by NCS (3.0 equiv) over a period of 5 min.
After stirring for 3e4 h at room temperature, the completion of
reaction was checked by TLC. Then the mixture was treated with
saturated NaHCO3, poured into a separatory funnel, and extracted
with DCM. The separated organic phase was washed with sodium
thiosulphate to remove Cl2, dried over Na2SO4, filtered, and con-
centrated. The residue was purified by 60e120 silica gel column
chromatography (EtOAc/hexane) to yield the chlorinated products
(88e90%) as colorless syrups.
4.3. Preparation and spectral data of compounds 2a and 4a
Prepared by the general procedure for the dichlorination of
glycals by using 1a (100 mg, 0.24 mmol), NCS (96 mg, 3 equiv.), and
Fig. 4. a. 1,2-Dichlorination of tri-O-benzyl-D-glucal in different solvents; b. 1,2-
dichlorination of tri-O-acetyl-D-glucal in different solvents.
PPh3 (94 mg, 1.5 equiv) to yield
a-gluco/a-manno mixture (2a/4a in
the ratio of 1:0.23) as semisolid (90% yield).
4.3.1. 3,4,6-Tri-O-benzyl-2-chloro-2-deoxy-
ride (2a). Rf (10% EtOAc/hexane) 0.5; IR (CHCl3) 1635, 1219,
772 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.38e7.28 (m, 15H), 6.14 (d,
a-glucopyranosyl chlo-
d
J¼3.5 Hz, 1H), 4.96 (d, J¼10.4 Hz, 1H), 4.53 (m, 6H), 4.12 (dd, J¼10.2,
3.5 Hz, 1H), 4.02 (dd, J¼10.0, 8.9 Hz, 1H), 3.81e3.75 (m, 2H), 3.66
(dd, J¼11.1, 1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 138.3, 137.9,
137.8, 137.7, 137.5, 137.3, 128.5, 128.5, 128.5, 128.4, 128.4, 128.2,
127.9, 127.9,127.8,127.8,127.8,127.6, 94.4, 81.5, 76.7, 76.3, 75.3, 73.9,
73.5, 67.5, 60.5, ESI MS (m/z): 486 [M]þ.
4.3.2. 3,4,6-Tri-O-benzyl-2-chloro-2-deoxy-
ride (4a). Rf (10% EtOAc/hexane) 0.6; IR (CHCl3) 1635, 1219,
772 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.38e7.28 (m, 15H), 6.23 (d,
a-mannopyranosyl chlo-
d
Scheme 5. Conversion of 1,2-dichloropyranoside (2a/4a) into 2-chloroglycal (6) and
subsequent Suzuki coupling.
J¼1.3 Hz, 1H), 4.86 (d, J¼10.6 Hz, 1H), 4.74e4.63 (m, 6H), 4.18 (d,
J¼2.4 Hz, 1H), 4.09 (d, J¼1.2 Hz, 1H), 3.81e3.75 (m, 2H), 3.69 (d,
J¼0.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 129.4, 128.5, 128.5,
somewhat low yield (30%) considering the low reactivity of vinylic
chlorides.23 The coupled product 8 was confirmed by comparing
the NMR data with literature reports.22
128.4, 128.4, 128.3, 128.1, 128.1, 128.1, 128.1, 128.0, 127.9, 127.9, 127.9,
127.8, 127.8, 127.7, 126.3, 92.5, 75.5, 74.9, 73.4, 73.1, 72.1, 71.9, 67.9,
60.9, ESI MS (m/z): 486 [M]þ.
3. Conclusions
4.4. Preparation and spectral data of compounds 2b and 4b
In conclusion our investigation showed that diastereoselective
1,2-dichlorination of different protected glycals can be achieved by
using NCS/PPh3 reagent combination. Improved stereoselectivity,
less hazardous reagent combination, and room temperature con-
ditions are the advantages of the present method over the existing
methods available in the literature. Finally, the downstream prod-
uct, i.e., 2-chloroglycal has been utilized for Pd-catalyzed Suzuki
coupling.
Prepared by the general procedure for dichlorination of glycals
by using 1b (100 mg, 0.37 mmol), NCS (147 mg, 3 equiv), and PPh3
(145 mg, 1.5 equiv) to yield a-gluco/a-manno mixture (2b/4b in the
ratio of 1:1.46) as semisolid (88% yield).
4.4.1. 3,4,6-Tri-O-acetyl-2-chloro-2-deoxy-a-glucopyranosyl chloride
(2b). Rf (20% EtOAc/hexane) 0.6; ½a D25
ꢂ
þ227 (c 1.0, CHCl3);7 IR
(CHCl3) 1744, 772 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.17 (d,
J¼0.9 Hz, 1H), 5.61 (dd, J¼9.9, 3.7 Hz, 2H), 5.11 (dd, J¼10.1, 9.5 Hz,
4. Experimental section
4.1. General information
1H), 4.35e4.29 (m, 2H), 4.20 (m, 1H), 2.12 (s, 6H), 2.09 (s, 3H); 13C
NMR (125 MHz, CDCl3)
d 170.6, 169.9, 169.3, 90.9, 71.9, 68.5, 64.6,
61.4, 59.8, 20.7, 20.7, 20.7; ESI MS (m/z): 342 [M]þ.
1H and 13C NMR spectra were recorded on Bruker 200, 400 and
500 MHz spectrometers with TMS as the internal standard.
4.4.2. 3,4,6-Tri-O-acetyl-2-chloro-2-deoxy-a-mannopyranosyl chlo-
ride (4b, major product). Rf (30% EtOAc/hexane) 0.6; ½a D25
ꢁ44 (c 1.0,
ꢂ
Chemical shifts are expressed in parts per million (
d
ppm). MS were
CHCl3);7 IR (CHCl3) 1744, 772 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
recorded on Waters LC Mass spectrometer (Model No. Symapt MS).
Silica gel coated aluminum plates were used for TLC. Elemental
analyses were performed on Vario Elementar (Model No. EL-III,
d
6.15 (d, J¼3.7 Hz, 1H), 5.49 (m, 2H), 4.65 (dd, J¼3.7, 1.4 Hz, 1H),
4.28 (m, 2H), 4.13 (dd, J¼12.6, 2.1 Hz, 1H), 2.09 (s, 6H), 2.06 (s, 3H).
13C NMR (125 MHz, CDCl3)
170.5,169.7, 169.5, 92.5, 71.4, 70.8, 68.1,
d
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

6
A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
61.1, 57.7, 20.6, 20.5, 20.5, ESI MS (m/z): 342 [M]þ. Anal. Calcd for
12H16Cl2O7: C, 42.00; H, 4.70. Found C, 41.87; H, 4.59.
yield); Rf (20% EtOAc/hexane) 0.6; ½a D25
ꢂ
þ154 (c 1.0, CHCl3); IR
C
(CHCl3) 1744, 772 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.21 (d,
J¼3.6 Hz, 1H), 5.50 (d, J¼3.0 Hz, 1H), 5.38 (dd, J¼11.1, 3.2 Hz, 1H),
4.61 (t, J¼6.4 Hz, 1H), 4.44 (dd, J¼11.0, 3.6 Hz, 1H), 4.18e4.06 (m,
4.5. Preparation and spectral data of 3,4,6-tri-O-benzoyl-2-
chloro-2-deoxy- -mannopyranosyl chloride (4c)
a
2H), 2.15 (s, 3H), 2.06 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 170.4,
169.8, 169.6, 93.6, 69.8, 69.2, 67.5, 60.9, 55.4, 20.7, 20.6, 20.5, ESI MS
(m/z): 342 [M]þ. Anal. Calcd for C12H16Cl2O7: C, 42.00; H, 4.70.
Found C, 41.92; H, 4.67.
Prepared by the general procedure for dichlorination of glycals
by using 1c (100 mg, 0.22 mmol), NCS (88 mg, 3 equiv), and PPh3
(86 mg, 1.5 equiv) to yield the desired product 4c as semisolid (90%
yield); Rf (10% EtOAc/hexane) 0.5; ½a D25
ꢂ
þ2.7 (c 1.0, CHCl3); IR
4.9. Preparation and spectral data of 3,4,6-tri-O-benzoyl-2-
chloro-2-deoxy-a-galactopyranosyl chloride (2g)
(CHCl3) 1727, 1601, 771 cmꢁ1; 1H NMR (125 MHz, CDCl3)
d
8.10 (dd,
J¼16.3, 8.0 Hz, 3H), 7.99 (dd, J¼9.6, 8.6 Hz, 4H), 7.58e7.51 (m, 2H),
7.44 (m, 3H), 7.41e7.37 (m, 4H), 6.30 (d, 1H), 6.15 (t, J¼9.9 Hz, 1H),
6.06 (dd, J¼10.1, 3.4 Hz, 1H), 4.89 (d, J¼3.4 Hz, 1H), 4.70e4.64 (m,
Prepared by the general procedure for dichlorination of glycals by
using 1g (100 mg, 0.22 mmol), NCS (88 mg, 3 equiv.), and PPh3
(86 mg, 1.5 equiv) to yield the desired product 2g as semisolid (88%
2H), 4.48 (dd, J¼12.1, 3.7 Hz,1H); 13C NMR (125 MHz, CDCl3)
d 165.9,
165.3, 164.9, 133.5, 133.5, 133.4, 132.9, 129.9, 129.7, 129.6, 129.5,
129.2, 129.1, 128.4, 128.4, 128.3, 128.3, 128.3, 128.2, 128.2, 128.2,
90.9, 71.8, 69.0, 65.1, 61.9, 59.9, ESI MS (m/z): 528 [M]þ. Anal. Calcd
for C27H22Cl2O7: C, 61.26; H, 4.19. Found C, 61.22; H, 4.15.
yield); Rf (10% EtOAc/hexane) 0.5; ½a D25
ꢂ
þ80.3 (c 1.0, CHCl3); IR
(CHCl3) 1728, 1601, 772 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
8.02e7.98
(m, 4H), 7.90e7.86 (m, 2H), 7.56e7.39 (m, 7H), 7.32 (d, J¼7.8 Hz, 2H),
6.39 (d, J¼3.6 Hz, 1H), 6.05 (d, J¼2.1 Hz, 1H), 5.82 (dd, J¼11.0, 3.2 Hz,
1H), 4.97 (t, J¼6.5 Hz, 1H), 4.76 (dd, J¼11.0, 3.6 Hz, 1H), 4.61 (dd,
J¼11.5, 6.8 Hz, 1H), 4.40 (dd, J¼11.5, 6.1 Hz, 1H); 13C NMR (125 MHz,
4.6. Preparation and spectral data of compounds 2d and 4d
CDCl3)
d 165.9, 165.2, 165.2, 133.8, 133.4, 133.5, 130.3, 129.9, 129.9,
Prepared by the general procedure for dichlorination of glycals
by using 1d (100 mg, 0.30 mmol), NCS (121 mg, 3 equiv.), and PPh3
(119 mg, 1.5 equiv) to yield the a-gluco/a-manno mixture (2d/4d in
129.9, 129.8, 129.8, 129.2, 128.9, 128.8, 128.7, 128.6, 128.5, 128.5, 128.4,
127.8, 93.8, 70.4, 69.9, 68.5, 61.7, 56.1, ESI MS (m/z): 528 [M]þ. Anal.
Calcd for C27H22Cl2O7: C, 61.26; H, 4.19. Found C, 61.19; H, 4.11.
the ratio of 1:0.32) as semisolid (90% yield).
4.10. 3,4-Di-O-acetyl-2-chloro-2,6-dideoxy-a-glucopyranosyl
4.6.1. 2,3,4,6-Tetra-O-acetyl-2-chloro-2-deoxy-
a
-glucopyranosyl
chloride (2h)
chloride (2d). Rf (30% EtOAc/hexane) 0.5; IR (CHCl3) 1744,
771 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
6.20 (s, 1H), 5.97 (d,
Prepared by the general procedure for dichlorination of glycals
by using 1h (100 mg, 0.47 mmol), NCS (187 mg, 3 equiv.), and PPh3
(185 mg, 1.5 equiv) to yield the desired product 2h as white solid
J¼8.8 Hz, 1H), 5.10e5.07 (m, 1H), 4.41 (dt, J¼8.3, 5.4 Hz, 2H), 4.23
(dd, J¼9.5, 4.7 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.06 (s,
3H); 13C NMR (125 MHz, CDCl3)
d
170.5, 169.2, 169.1, 168.8, 108.7,
(88% yield); mp135e136 ꢀC, Rf (10% EtOAc/hexane) 0.6; ½a D25
ꢂ
71.9, 71.9, 65.3, 61.6, 20.7, 20.7, 20.6, 20.5, ESI MS (m/z): 400 [M]þ.
ꢁ214 (c 1.0, CHCl3); IR (CHCl3) 1728, 772 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
d
6.09 (d, J¼3.7 Hz, 1H), 5.47 (dd, J¼10.4, 9.5 Hz, 1H), 4.83 (t,
4.6.2. 2,3,4,6-Tetra-O-acetyl-2-chloro-2-deoxy-
chloride (4d). Rf (30% EtOAc/hexane) 0.5; IR (CHCl3) 1744,
771 cmꢁ1 1H NMR (400 MHz, CDCl3)
6.33 (s, 1H), 5.74 (d,
a
-mannopyranosyl
J¼9.7 Hz, 1H), 4.31 (dq, J¼10.1, 6.2 Hz, 1H), 4.14 (dd, J¼10.5, 3.7 Hz,
1H), 2.07 (d, J¼7.8 Hz, 6H), 1.25 (d, J¼6.2 Hz, 3H); 13C NMR
;
d
(125 MHz, CDCl3) d 169.8, 169.78, 92.7, 73.6, 71.4, 68.9, 58.2, 20.7,
J¼9.0 Hz, 1H), 5.12e5.10 (m, 1H), 4.41 (dt, J¼8.3, 5.4 Hz, 2H), 4.23
20.6, 17.1, ESI MS (m/z): 242 [M]þ. Anal. Calcd for C8H12Cl2O4: C,
(dd, J¼9.5, 4.7 Hz, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09 (s,
39.53; H, 4.98. Found C, 39.49; H, 4.4.93.
3H); 13C NMR (125 MHz, CDCl3)
d 170.4, 169.3, 169.2, 168.8, 107.9,
72.7, 72.1, 65.0, 61.5, 20.7, 20.6, 20.5, 20.4, ESI MS (m/z): 400 [M]þ.
4.11. 3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-chloro-3,4-
dihydro-2H-pyran (6)
4.7. Preparation and spectral data of 3,4,6-tri-O-benzyl-2-
chloro-2-deoxy-
a
-galactopyranosyl chloride (2e)
To a solution of 1,2-dichloropyranoside 2a/4a mixture (200 mg,
0.41 mmol) in diethyl ether (3 mL) was added KOt-Bu (92 mg,
2 equiv). The reaction mixture was allowed to stir for 3 h. Completion
of reaction was checked by TLC. The reaction mixture was extracted
with ethyl acetate, dried over Na2SO4, and concentrated. The residue
was purified by 60e120 silica gel column chromatography (EtOAc/
hexane) to yield the product 6 (85%) as white solid. M.p 30e35 ꢀC; Rf
(20% EtOAc/hexane) 0.55; IR (CHCl3) 3064, 3031, 2906, 2867, 1649,
Prepared by the general procedure for dichlorination of glycals
by using 1e (100 mg, 0.24 mmol), NCS (96 mg, 3 equiv), and PPh3
(94 mg, 1.5 equiv) to yield a-gluco isomer (2e) as semisolid (89%
yield); Rf (10% EtOAc/hexane) 0.6; ½a D25
ꢂ
þ10 (c 1.0, CHCl3); IR (CHCl3)
1618, 1113, 771 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.43e7.25 (m,
15H), 6.18 (d, J¼3.5 Hz, 1H), 4.91 (d, J¼11.1 Hz, 1H), 4.80 (d,
J¼11.4 Hz, 1H), 4.73 (d, J¼11.4 Hz, 1H), 4.64 (dd, J¼10.5, 3.5 Hz, 1H),
4.54e4.41 (m, 3H), 4.32 (t, J¼6.5 Hz, 1H), 4.01 (s, 1H), 3.94 (dd,
J¼10.5, 2.6 Hz, 1H), 3.61e3.52 (m, 2H); 13C NMR (125 MHz, CDCl3)
1496, 1454, 1364, 698 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.41e7.18
(m, 15H), 6.64 (s, 1H), 4.60 (m, 6H), 4.27 (dd, J¼10.1, 5.2 Hz, 1H), 4.10
(d, J¼4.3 Hz, 1H), 3.95 (dd, J¼5.5, 4.4 Hz, 1H), 3.79 (dd, J¼10.7, 6.1 Hz,
d
137.9, 137.6, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3,
1H), 3.66 (dd, J¼10.7, 4.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 142.5,
128.2, 128.1, 128.0, 127.9, 127.9, 127.9, 127.9, 127.7, 95.6, 78.4, 75.3,
74.5, 73.6, 73.6, 72.9, 67.8, 58.8; ESI MS (m/z): 486 [M]þ. Anal. Calcd
for C27H28Cl2O4: C, 66.53; H, 5.79. Found C, 66.45; H, 5.69.
137.9, 137.8, 137.6, 128.6, 128.5, 128.0, 127.9, 127.8, 110.0, 76.5, 76.4,
73.8, 73.5, 72.8, 72.5, 67.8; ESI MS (m/z): 450 [M]þ. Anal. Calcd for
C27H27ClO4: C, 71.91; H, 6.03. Found C, 71.83; H, 6.00.
4.8. Preparation and spectral data of 3,4,6-tri-O-acetyl-2-
4.12. 3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-
chloro-2-deoxy-
a
-glalactopyranosyl chloride (2f)
5-phenyl-2H-pyran (8)
Prepared by the general procedure for dichlorination of glycals
by using 1f (100 mg, 0.37 mmol), NCS (147 mg, 3 equiv.), and PPh3
(145 mg, 1.5 equiv) to yield the desired product 2f as semisolid (89%
The compound 6 (100 mg, 0.22 mmol) was dissolved in toluene
(3 mL) phenylboronic acid 7 (27 mg, 1 equiv) was added to it fol-
lowed by the addition of Cs2CO3 (101 mg, 1.4 equiv) and SPhos
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088

A. Hussain, D. Mukherjee / Tetrahedron xxx (2014) 1e7
7
(10 mol %). The reaction mixture was allowed to stir at 130 ꢀC for
12 h. After standard workup the crude was purified by column
chromatography (EtOAc/petrol) to afford 8 (48%) as semisolid. Rf
3. (a) Praly, J. P. Adv. Carbohydr. Chem. Biochem. 2001, 56, 65e151; (b) Togo, H.; He,
W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700e717.
4. Fischer, E.; Bergmann, M.; Schotte, H. Bcr. 1920, 68, 509e547.
5. Lemieux, R. U.; Fraser-Reid, B. Can. J. Chem. 1964, 42, 532e538.
6. Lemieux, R. U.; Fraser-Reid, B. Can. J. Chem. 1965, 43, 1460e1478.
7. Igarashi, K.; Honma, T.; Imagawa, T. J. Org. Chem. 1970, 35, 610e616.
8. Boullanger, P.; Descotes, G. Carbohydr. Res. 1976, 51, 55e63.
9. Horton, D.; Priebe, W.; Varela, O. J. Org. Chem. 1986, 51, 3479e3485.
10. (a) Kent, P. W.; Robson, F. O.; Welch, V. A. J. Chem. Soc. 1963, 3273e3276; (b)
Campbell, J. C.; Dwex, R. A.; Kent, P. W.; Prout, C. K. Chem. Commun. 1968,
34e35.
(20% EtOAc/petrol): 0.45; ½a D25
ꢁ6.6 (c 1.0, CHCl3); IR (CHCl3) 3083,
ꢂ
3071, 3038, 2929, 2871, 1627, 1613, 1488, 1455, 1399, 1344, 1288,
849, 800, 735, 691, 681; 1H NMR (400 MHz, CDCl3)
d 7.27 (m, 19H),
6.83 (s, 1H), 4.71e4.56 (m, 4H), 4.51 (s, 2H), 4.27 (dd, J¼10.0, 5.2 Hz,
1H), 4.08 (d, J¼4.2 Hz, 1H), 3.93 (dd, J¼5.4, 4.6 Hz, 1H), 3.77 (dd,
J¼10.6, 6.1 Hz, 1H), 3.67 (dd, J¼10.6, 4.0 Hz,1H); 13C NMR (125 MHz,
11. Hall, L. D.; Manville, J. F. J. Chem. Soc., Chem. Commun. 1968, 35e36.
12. Colovic, M.; Vukicevic, M.; Segan, D.; Manojlovic, D.; Sojic, N.; Somsak, L.;
Vukicevic, R. D. Adv. Synth. Catal. 2008, 350, 29e34.
CDCl3)
d 143.5, 137.8, 137.7, 137.6, 137.5, 128.6, 128.5, 128.5, 128.6,
128.5, 128.4, 128.3, 128.3, 128.3, 128.3, 128.3, 128.2, 128.2, 128.2,
128.1, 128.1, 128.0, 127.9, 127.8, 127.8, 112.9, 76.5, 76.5, 73.7, 73.5,
72.8, 72.4, 67.7; ESI MS (m/z): 492 [M]þ. Anal. Calcd for C33H32O4: C,
80.46; H, 6.55. Found C, 80.40; H, 6.51.
13. Kamada, Y.; Kitamura, Y.; Tanaka, T.; Yoshimitsu, T. Org. Biomol. Chem. 2013, 11,
1598e1601.
14. (a) Thota, N.; Mukherjee, D.; Reddy, M. V.; Yousuf, S. K.; Koul, S.; Taneja, S. C.
Org. Biomol. Chem. 2009, 7, 1280e1283; (b) Yousuf, S. K.; Hussain, A.; Sharma,
D. K.; Wani, A. H.; Singh, B.; Mukherjee, D.; Taneja, S. C. J. Carbohydr. Chem. 2011,
30, 61e74.
15. (a) Yousuf, S. K.; Taneja, S. C.; Mukherjee, D. J. Org. Chem. 2011, 75, 3097e3100;
(b) Mukherjee, D.; Yousuf, S. K.; Taneja, S. C. Org. Lett. 2008, 10, 483e4834.
16. Iriarte Capaccio, C. A.; Varela, O. J. Org. Chem. 2001, 66, 8859e8866.
17. (a) Lichtenthaler, F. W. Pure Appl. Chem. 1978, 50, 1343e1362; (b) Lichtenthaler,
F. W.; Kraska, U. Carbohydr. Res. 1977, 58, 363e377; (c) Lichtenthaler, F. W.;
Sakakibara, T.; Oeser, E. Carbohydr. Res. 1977, 59, 47e56.
18. (a) Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287e313; (b) Yousuf, S. K.;
Mukherjee, D.; Rao, L. M.; Taneja, S. C. Org. Lett. 2011, 13, 576e579.
19. (a) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641e2647; (b) Beaver,
M. G.; Woerpel, K. A. J. Org. Chem. 2010, 75, 1107e1118; (c) Yang, M. T.; Woerpel,
K. A. J. Org. Chem. 2009, 74, 545e553; (d) Krumper, J. R.; Salamant, W. A.;
Woerpel, K. A. J. Org. Chem. 2010, 74, 8039e8050; (e) Beaver, M. G.; Billings, S.
B.; Woerpel, K. A. J. Am. Chem. Soc. 2008, 130, 2082e2086.
Acknowledgements
Authors are highly thankful to director CSIR-IIIM for necessary
facilities and DST (Project GAP 1145) for funding. A.H. is thankful to
University Grants Commission, New Delhi for fellowship (UGC-SRF).
Supplementary data
Supplementary data contains the copies of 1H NMR and 13C NMR
data of products. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.12.088.
20. Seeman, J. I. Chem. Rev. 1983, 83, 83e134.
21. Boyd, E.; Hallett, M. R.; Jones, R. V. H.; Painter, J. E.; Patel, P.; Quayleb, P.; Waring,
A. J. Tetrahedron Lett. 2006, 47, 8337e8341 and references therein.
ꢀ
22. (a) Cobo, I.; Isabel, M.; Castillon, S.; Boutureira, O.; Davis, B. G. Org. Lett. 2012, 14,
References and notes
1728e1731; (b) Leibeling, M.; Werz, D. B. Beilstein J. Org. Chem. 2013, 9,
2194e2201.
23. Thakur, A.; Zhang, K.; Louie, J. Chem. Commun. 2012, 203e205.
1. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503e1531.
ꢀ
2. Somsak, L. Chem. Rev. 2001, 101, 81e135.
Please cite this article in press as: Hussain, A.; Mukherjee, D., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2013.12.088