SN2 substitution reaction of 2-C-acetoxymethyl glycals catalyzed by iodine: A novel synthesis of 2-C-N-arylamidomethyl glycals

Article abstract of DOI:10.1016/j.tetlet.2012.11.106

The reaction of 2-C-acetoxymethyl glycals with N-aryl amides such as N-aryltosyl amine, p-toluenesulfonamide, and t-butoxycarbonyl amine in the presence of a catalytic amount of iodine affords a novel class of 2-C-N-arylamidomethyl glycals through direct attack at the C-2 position bearing the acetyl group under mild reaction conditions. The use of iodine makes this method simple, convenient, and cost-effective. This is the first report on nucleophilic substitution of 2-C-acetoxymethyl glycals with N-aryl amides using molecular iodine as a catalyst.

Full text of DOI:10.1016/j.tetlet.2012.11.106

Tetrahedron Letters 54 (2013) 871–873
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Tetrahedron Letters
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SN2 substitution reaction of 2-C-acetoxymethyl glycals catalyzed by iodine:
a novel synthesis of 2-C-N-arylamidomethyl glycals
⇑
J. S. Yadav, G. Narasimhulu, N. Umadevi, Y. Vikram Reddy, B. V. Subba Reddy
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2-C-acetoxymethyl glycals with N-aryl amides such as N-aryltosyl amine, p-toluenesul-
fonamide, and t-butoxycarbonyl amine in the presence of a catalytic amount of iodine affords a novel
class of 2-C-N-arylamidomethyl glycals through direct attack at the C-2 position bearing the acetyl group
under mild reaction conditions. The use of iodine makes this method simple, convenient, and cost-effec-
tive. This is the first report on nucleophilic substitution of 2-C-acetoxymethyl glycals with N-aryl amides
using molecular iodine as a catalyst.
Received 10 September 2012
Revised 23 November 2012
Accepted 24 November 2012
Available online 10 December 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Nucleophilic substitution
2-C-Acetoxymethyl glycals
2-C-N-Arylamidomethyl glycals
Molecular iodine
Lewis acid catalyzed organic transformations are of great
importance in organic synthesis because of their high reactivity,
selectivity, and mild reaction conditions.1 In particular, acid cata-
lyzed nucleophilic substitution reactions are very useful for car-
bon–carbon2 and carbon–heteroatom bond formation.3,4 The
allylic acetates are well-known carbon electrophiles capable of
reacting with various nucleophiles and their ability to undergo
nucleophilic substitution reactions contributes largely to their syn-
thetic value.5 Of various allylic acetates, glycals (1,5-anhydro-hex-
1-enitols) are attractive chiral building blocks in organic synthe-
sis.6 In most cases, the glycals undergo allylic rearrangement with
nucleophiles in the presence of acid catalysts.7 However, 2-C-acet-
oxymethyl glycals behave differently depending upon the reactiv-
ity of nucleophiles. In the case of alcohols, they are known to
undergo allylic rearrangement by preferential attack of nucleophile
at anomeric carbon to give 2-C-methylene-O-aryl/alkyl glyco-
sides.8 In the case of thiols, they undergo nucleophilic substitution
by direct attack of thiol at the C-2 position bearing the leaving
group to furnish 2-C-arylthiomethyl glycals.9
Recently, molecular iodine catalyzed or mediated reactions
have gained importance in organic synthesis because of its low
cost and ready availability. The mild Lewis acidity associated with
molecular iodine has enhanced its use in organic synthesis to per-
form several organic transformations using stoichiometric levels to
catalytic amounts.10 To the best of our knowledge, there are no re-
ports on nucleophilic substitution of 2-C-acetoxymethyl glycals
with aryl amides.
Following our interest on catalytic application of molecular io-
dine,11 we herein report a novel strategy for the preparation of
2-C-N-arylamidomethyl glycals from 2-C-acetoxymethyl glycals
and N-aryltosyl amines via nucleophilic substitution. Initially, we
attempted the aminoglycosidation of 3,4,6-tri-O-benzyl-2-C-acet-
oxymethyl glycal (1) with aniline in the presence of 10 mol % of
InCl3 in acetonitrile. To our surprise, the reaction did not proceed
even under reflux conditions. In this reaction, we anticipated the
formation of sugar annulated tetrahydroquinolines from 3,4,6-tri-
O-benzyl-2-C-acetoxymethyl glycal and aryl amine as has been de-
scribed in our earlier work.12 The above reaction also did not pro-
ceed with 5 mol % of iodine in acetonitrile. Next, we performed the
reaction of 3,4,6-tri-O-benzyl-2-C-acetoxymethylglycal (1) with N-
phenyltosyl amine (2) using 5 mol % of iodine in acetonitrile.
Though, the reaction proceeded smoothly at 25 °C, the desired 2-
C-N-phenyltosylaminomethyl glycal 3a was obtained only in 70%
yield. To improve the conversion, we carried out the above reaction
in various solvents such as CH2Cl2 and THF. Of these, CH2Cl2 gave
the best results. Therefore, the reaction was successful only with
amides and not with amines due to their intrinsic basic nature
and low reactivity. Under optimized conditions, treatment of
3,4,6-tri-O-benzyl-2-C-acetoxymethyl glycal (1) with N-phenylto-
syl amine (2) in the presence of 5 mol % of iodine in CH2Cl2 at
25 °C gave the 2-C-N-phenyltosylaminomethyl glycal 3a with high
regioselectivity (Scheme 1).
This result provides the incentive to extend this method for
other glycals and amides. Other glycals such as 3,4,6-tri-O-benzyl-
and 3,4,6-tri-O-ethyl-2-C-acetoxymethyl glycals reacted smoothly
with N-aryl sulfonamides to produce the corresponding 2-C-N-ary-
lamidomethyl glycals in good yields (Table 1, entries b, c, f, g, and
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.106

872
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 871–873
H
EtO
H
O
O
BnO
BnO
O
BnO
BnO
5 mol% I2
H
+
EtO
EtO
N
CH2Cl2, r.t.
Ts
H
H
H
H
OBn OAc
1
NHTs
2
OBn
3a; Yield : 83%
N
Ts
Scheme 1. SN2 substitution of 2-C-acetoxymethyl glycal with N-phenyltosyl amine.
Me
h). The structure of 3g was thoroughly studied by NMR techniques.
The characteristic NOEs of 3g are shown in Figure 1.
Under similar conditions, 3,4,6-tri-O-benzyl-2-C-acetoxymethyl
galactal also underwent a smooth nucleophilic substitution to pro-
duce 2-C-N-aryltosylaminomethyl galactal in good yields (entries d
and e, Table 1).
Figure 1. Characteristic NOE cross peaks of product 3g.
observed even after an extended reaction time (12 h). As solvent,
dichloromethane gave the best results. In all the cases, the reac-
tions proceeded rapidly at 25 °C under mild conditions. The reac-
tions were clean and no side products were detected under these
conditions as determined from the NMR spectra of the crude
The products were characterized by 1H, 13C NMR, IR spectra, and
mass spectrometry. In the absence of catalyst, no reaction was
Table 1
Iodine-catalyzed synthesis of 2-C-N-arylamidomethyl glycals
Entry
Substrate (1)
Nucleophile (2)
Product (3)a
Time (h)
3.0
Yieldb (%)
83
O
NHTs
O
BnO
BnO
BnO
BnO
Ts
N
OAc
OAc
a
OBn
O
OBn
O
NHTs
BnO
BnO
BnO
BnO
Ts
N
b
c
3.5
4.3
3.2
86
81
89
Me
OBn
O
OBn
O
Me
NHTs
BnO
BnO
BnO
BnO
Ts
N
OAc
OAc
OAc
MeO
Me
OBn
O
OBn
O
OMe
Me
NHTs
BnO
BnO
BnO
BnO
Ts
N
d
OBn
O
OBn
O
NHTs
BnO
BnO
BnO
BnO
Ts
N
e
f
4.0
3.5
3.0
75
86
83
MeO
OBn
OBn
OMe
O
NHTs
O
EtO
EtO
EtO
EtO
Ts
N
OAc
OAc
OEt
O
OEt
O
NHTs
EtO
EtO
EtO
EtO
Ts
N
g
Me
OEt
O
OEt
O
Me
NHTs
Br
EtO
EtO
EtO
EtO
Ts Br
N
OAc
OAc
OAc
h
i
3.5
5.1
4.6
80
73
65
OEt
O
OEt
O
SO2NH2
BnO
BnO
BnO
BnO
NHTs
H
Me
OBn
O
OBn
O
O
BnO
BnO
BnO
BnO
NH2
O
N
O
j
OBn
OBn
O
a
The products were characterized by NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 871–873
873
..
References and notes
O
O
RO
RO
I2
RO
RO
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OAc
a
OR
O
I2
OR
-OAc
Ts
N
O
RO
Ar
O
a
RO
RO
H
+
b
N
X
-H
RO
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Ar
Ts
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OR
OR
O
RO
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R = benzyl or ethyl
Ar
OR
Scheme 2. A plausible reaction pathway.
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products. The efficiency of various metal halides such as FeCl3,
InCl3, GaCl3, YCl3, and YbCl3 was studied for this transformation.
Among them, 5 mol % of iodine was found to be superior to other
catalysts tested. For instance, treatment of 3,4,6-tri-O-benzyl-2-
C-acetoxymethyl glycal (1) with N-p-tolyltosyl amine (2) in the
presence of 5 mol % of iodine and 5 mol % of InCl3 gave the desired
product 3b in 86% and 75% yields, respectively.
The reaction likely proceeds via the activation of allylic acetate
by molecular iodine thereby generating the oxocarbenium ion as
shown in Scheme 2. Due to intrinsic low reactivity of oxocarbeni-
um ion toward amide, the nucleophile is attacked preferentially
at C-2-methylene position via path ‘b’ to give the desired 2-C-N-
arylamidomethyl glycals (Scheme 2).
The scope and generality of this process are illustrated with re-
spect to various 2-C-acetoxymethyl glycals and N-arylsulfon-
amides and the results are presented in Table 1.13
In summary, we have described a novel method for the synthe-
sis of 2-C-N-arylamidomethyl glycals from 2-C-acetoxymethyl gly-
cals and N-arylamides using a catalytic amount of molecular iodine
under mild reaction conditions. This method provides various 2-C-
N-arylamidomethyl glycals in good yields in short reaction times
with high regioselectivity, which makes it a useful and attractive
process.
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13. General procedure: A mixture of 2-C-acetoxymethyl glycals (1, 1.0 mmol), N-
arylamide (2, 1.1 mmol) in DCM (3 mL) and I2 (12 mg, 5 mol %) was stirred at
25 °C for a specified time as required to complete the reaction (see Table 1).
After complete conversion, as indicated by TLC, the mixture was quenched
with 15% solution of sodium thiosulfate and extracted with dichloromethane
(3 Â 10 mL). The combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo and purified by column chromatography on silica gel
(Merck, 60–120 mesh, ethyl acetate/hexane, 2:8) to afford the pure 2-C-N-
arylamidomethyl glycals.
Acknowledgments
G.N.L. thanks CSIR, N.U. thanks UGC, New Delhi for the award of
fellowships.
Supplementary data
Supplementary data (experimental procedures and compound
characterization) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.106.