Acetyl chloride - Silver nitrate - Acetonitrile: A reagent system for the synthesis of 2-nitroglycals and 2-nitro-1-acetamido sugars from glycals

Article abstract of DOI:10.1021/jo200475h

A new reagent system comprising acetyl chloride, silver nitrate, and acetonitrile has been developed for the synthesis of 2-nitroglycals from the corresponding glycals. Under certain conditions, the formation of 2-nitro-1-acetamido sugars has also been observed. In addition, a few other non-carbohydrate-derived olefins also gave the corrresponding conjugated nitroolefins.

Full text of DOI:10.1021/jo200475h

NOTE
pubs.acs.org/joc
Acetyl ChlorideꢀSilver NitrateꢀAcetonitrile: A Reagent System
for the Synthesis of 2-Nitroglycals and 2-Nitro-1-Acetamido Sugars
from Glycals
Pavan K. Kancharla, Y. Suman Reddy, Suresh Dharuman, and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
S Supporting Information
b
ABSTRACT: A new reagent system comprising acetyl chloride,
silver nitrate, and acetonitrile has been developed for the
synthesis of 2-nitroglycals from the corresponding glycals.
Under certain conditions, the formation of 2-nitro-1-acetamido
sugars has also been observed. In addition, a few other non-carbohydrate-derived olefins also gave the corrresponding conjugated
nitroolefins.
itroalkenes are of great importance in organic synthesis1
because of their ability to behave as excellent Michael
workup besides performing the reactions at low temperatures
(∼ ꢀ35 °C). The other method using nitronium tetra-
fluoroborate16 is also carried out at low temperature (ꢀ40 °C)
involving a two-step process. Thus, there is a need for the develop-
ment of a new, experimentally simple, and efficient method for the
nitration of glycals that works under neutral conditions.
We have been interested in the chemistry of aliphatic nitro
compounds for a long time17 and also have been involved in the
functionalization of glycals18,19 toward the synthesis of biologi-
cally important molecules. At the same time, we also have been
interested in developing a new method for the synthesis of
2-nitro-1-amino sugars which could be useful substrates for the
synthesis of biologically significant 2-amino-β-glycosylamines
that form the core in N-linked glycoproteins and glycopeptides,20
molecules that play a crucial role in cell recognition and signal
transduction.
In light of the fact that N-acetamido groups of the natural
glycopeptides (GlcNAc-β-GlcNAc-β-) introduce a unique con-
formational effect into the interglycosidic and glycopeptide
linkages,21 synthesis of 1,2-differentially protected amines22
could be of great significance. 2-Nitro-1-amino sugars can also
act as precursors for the synthesis of 2-deoxy-1-amino sugar
derivatives. Recently, we introduced a new reagent system
comprising oxalyl chlorideꢀAgNO3ꢀCH3CN for the vicinal-
chloroacetamidation of olefins.19 This reagent system was
anticipated to be the source of the nitronium ion but was
proven to be the source of the chloronium ion as shown in
Scheme 1, resulting in the vicinal-chloroacetamidation of
olefins. With the same idea of producing a nitronium ion
source, we presumed that a new and somewhat similar reagent
system acetyl chlorideꢀAgNO3ꢀCH3CN would introduce the
nitro group providing the expected vicinal nitroacetamide.
Thus, we discovered the combination of acetyl chloride and
N
acceptors,1,2 as dienophiles,3 and even as dienes4 in (4 þ 2)
cycloadditions leading to useful synthons carrying a nitro
functionality. The nitro group containing compounds are also
of enormous importance as the nitro group could be easily
trnsformed into a variety of other functionalities.1,5 Thus, for
example, a primary or a secondary nitro group can be converted
to a carbonyl group via the well-known Nef reaction.6 The nitro
group can also be converted to amines by reduction and
also into the corresponding oximes, hydroxyl amines, and nitroso
compounds.7 The nitro group, and especially the tertiary nitro
group, is also susceptible to both inter- and intramolecular CꢀC
bond formation in the presence of n-Bu3SnH via radical
pathways.8,9 Conjugated nitroalkenes are also good substrates
for asymmetric Michael reactions10 owing to the binding cap-
ability of the nitro group with the catalysts.
In the domain of carbohydrate chemistry, 2-nitroglycals have
gained attention in recent years as versatile synthetic intermediates
for the synthesis of various O-, C-, and N-glycosides because they
permit easy conjugate addition of a variety of nucleophiles at the
anomeric center.11,12 The 2-nitro glycosides, in turn, are valuable
precursors for the synthesis of biologically important 2-deoxy-2-
amino glycosides which are constituents of various nucleoside and
aminoglycosidic antibiotics.13 In addition, many other biologically
important monocyclic and bicyclic molecules have been procured
from 2-nitro glycosides and 2-nitroglycals. More recently, we have
also shown the utility of 2-nitroglycals in the synthesis of 2-C-
branched O-galactosides and related compounds.9
Although the nitration of aromatic compounds is extensively
studied,14 not many reports are available in the literature for the
conversion of olefins to conjugated nitroolefins.15 Moreover,
only two methods are available for the synthesis of 2-nitrogly-
cals from glycals, one of which requires the combination of
concentrated nitric acid and acetic anhydride.11 This method,
although useful, is a two-step process which involves tedious
Received: March 9, 2011
Published: May 25, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
NOTE
Scheme 1. Tentative Mechanism for the Formation of
Nitroolefins and Nitroacetamide
Table 2. Nitration of Various Glycals Using the New Reagent
System
Table 1. Reaction of Tri-O-benzylated Glucal with AgNO3
and Acetyl Chloride in CH3CN
entry no.
acetonitrile
temp.
time
ratio 2/3/4
% yield
1
2
3
4
5
0.5 mL
3 mL
3 mL
7 mL
7 mL
35 °C
15 °C
55 °C
15 °C
55 °C
0.5 h
6 h
0:1:2.4
1.3:1:0
8:1:0
82
68
75
72
79
1 h
12 h
2 h
0:1:0
1:3.1:0
silver nitrate, a new source of acetyl nitrate which behaves as an
excellent source of nitronium ion.
In our initial experiments, 0.24 mmol of tri-O-benzylated
glucal 1 was treated with 1 equiv of silver nitrate and 1 equiv
of acetyl chloride in 0.5 mL of acetonitrile at 35 °C. We observed
the formation of a complex mixture of nitroacetamides 3
1
(Table 1) and nitroacetates 4 by analysis of the H NMR
spectrum of the crude reaction mixture. We carried out our
study on tri-O-benzylated glucal 1 under different temperatures
and different dilutions of the reagent in acetonitrile, the results of
which are summarized in Table 1. The reaction was observed to
be sensitive to both the temperature as well as the dilution. We
obtained nitroolefin as a major product under one set of reaction
conditions and nitroacetamide under another set of reaction
conditions with the same reagent system. Thus, the reaction
when performed at 55 °C facilitates the elimination providing
2-nitroglucal as the major product, whereas it gives the vicinal-
nitroacetamide without any eliminated product at 15 °C, albeit
the reaction takes a long time for completion. However, to our
displeasure, formation of a mixture of all four diastereomers of
nitroacetamides that are chromatographically inseparable is
observed under all the different conditions suggesting that the
reaction proceeds through the formaton of an oxonium ion.
Besides, the nitronium ion can attack the double bond of the tri-
O-benzylated glucal 1 from either side since there is no steric
demand in this case. Although there is a competitive nucleophi-
licity between the acetate group and the acetonitrile, the forma-
tion of the nitroacetates 4 is observed only under less diluted
conditions (entry 1, Table 1), and the possibility of the attack
of the acetate ion is diminished by the larger dilution. Therefore,
we carried out our study for the conversion of glycals into
2-nitroglycals and performed the reaction on different benzyls
and acetyl-protected glycals, the results of which are summarized
in Table 2. All the acetylated glycals (5, 7, 11, 17) were converted
to the corresponding acetylated 2-nitroglycals (6, 8, 12, 18) in
very high yields with no nitroacetamide side products. On the
other hand, the benzylated glycals (1, 9, 13, 15, 19) showed a
somewhat poor conversion to the corresponding 2-nitroglycals
(2, 10, 14, 16, 20) and gave an inseparable mixture of vicinal-
nitroacetamides as the side products in each case even under
heating conditions. The proton R to the nitro group in the
intermediate oxonium ion species being more acidic in the case of
acetylated glycals facilitates the elimination faster under the
heating conditions before the solvent molecule (acetonitrile)
attacks. Although acetylated 2-nitroglycals were unstable on silica
gel column chromatography,16 all the reactions on acetylated
glycals gave the corresponding 2-nitroglycals in high purity after
the workup without the need of chromatograhic purification.
The reaction on peracetylated lactal 17 also yielded the corre-
sponding 2-nitrolactal 18 in good yield without affecting the
glycosidic linkage, thus affirming the utility of the reagent system
as a mild nitrating agent. We performed the nitration reaction on
methyl cinnamate 21 (Table 3), styrene 23, and trans-stilbene 25
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NOTE
Table 3. Reaction of Non-Carbohydrate Olefins with the
New Reagent System
Scheme 2. Synthesis of 2-Nitro-1-acetamido Sugars from the
Corresponding Glycal
Figure 1. NOE correlation for 2-nitro-1-acetamido sugars.
formation of the Ritter type of products was not observed, the
reasons for which are not clear at this stage.
The reagent has also been tested on simple olefins like
cyclohexene 32 and 1-methyl cyclohexene 35. Cyclohexene,
when reacted with the reagent system using general procedure
B (see Experimental Section), resulted in an inseparable complex
mixture of products. However, treating cyclohexene with the
reagent system under less diluted conditions, at room tempera-
ture, provided a mixture of nitroacetates and vicinal nitroaceta-
midates which on further treatment with triethylamine gave
nitrocyclohexene in 33% yield and a 1:1 mixture of vicinal
nitroacetamides 34 in 42% yield, and the data of the compounds
are in absolute match with the literature data.23,24 1-Methylcy-
clohexene when treated with the reagent system under the
nitration conditions gave the rearranged nitrated product 36
along with an inseparable mixture of a 4:1 mixture of vicinal
nitroacetamides 37. Compound 37 has been confirmed using all
the spectral data including DEPT-135 which predicted the
presence of a quartenary amine.
To our delight, unlike tri-O-benzylated glucal, tri-O-benzy-
lated galactal 9 when subjected to the reaction conditions to form
the nitroacetamide provided a mixture of chromatographically
separable two diastereomers 38 and 39 (Scheme 2) in 9:1 ratio in
good yields which could serve as valuable synthons for the
synthesis of biologically significant 2-amino-N-glycopeptides.
The major isomer 38 was confirmed to exist in a 4C1 conforma-
tion as analyzed by the NOE experiments (Figure 1). Thus,
irradiation of the signal for the ꢀNH proton results in the
enhancement of the signals for the protons H-4 and H-6, whereas
there was no enhancement in the signal for H-3 suggesting that
the acetamido group and the nitro group are cis to each other and
the acetamido group at the anomeric position is R-oriented. The
to assess the reactivity of the reagent system other than that on
enol ethers. It is clear that it works on all activated olefins. The
spectral data of all the known compounds were in absolute match
with the data reported in the literature.15,23 Surprisingly, reac-
tions on methyl acrylate 27 as well as methyl crotonate 29
produced the corresponding nitro alcohols as the sole products
and did not yield the nitroolefins under the reaction conditions.
It is likely that in these cases the β-carbons of the corresponding
nitroalkenes, when formed, being highly electrophilic in nature,
are trapped by water during workup leading to the nitro alcohols
28 and 30. The formation of nitroacetamides (cf. entries 6ꢀ8,
Table 3 and Scheme 2) occurs in a Ritter-type reaction, whereby
the carbocation is first trapped by acetonitrile to form the
corresponding nitrilium ions which subsequently react with
water. Surprisingly, however, in reactions with 27 and 29,
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NOTE
NOE experiments on the minor isomer 39 suggested it to be in
1C4 conformation. Irradiation of the anomeric proton resulted in
the enhancement of one of the C-7 protons which is only possible
when the compound exists in a 1C4 conformaton, and the
acetamido group is equatorially oriented. Besides, irradiation of
H-3 resulted in the enhancement of the signals for the protons H-4
and H-5 suggesting the equatorial orientation of the nitro group.
Likewise, di-O-benzylated arabinal 19 also gave a mixture of
two diastereomeric nitroacetamides 40 and 41 in 3:2 ratio which
were chromatographically separable in 82% yield. Irradiation of
the signal for H-2 in both the isomers resulted in the enhance-
ment of the corresponding signals for H-4 and H-6 suggesting
the 4C1 conformation and the equatorial orientation of ꢀNHAc.
Irradiation of the signal for ꢀNH in the major isomer 40 resulted
in the enhancement of the signal for H-3 showing the trans
relation of ꢀNHAc with the nitro group, whereas it resulted in
no enhancement of H-3 in the minor isomer 41 suggesting the
axial orientation of the nitro group. These observations clearly
suggest that the reaction proceeds via an oxonium ion inter-
mediate, and the diastereoselectivity can be obtained only on
sterically demanding substrates like galactal and arabinal.
Stilbene 25 was also subjected to the same conditions to obtain
the threo isomer of the corresponding nitroacetamide 3124 in
66% yield. Studies are under progress for the development of
improved conditions to obtain the 2-nitro-1-acetamido sugars
with this new reagent system and will be published in due
course.
was further diluted with 20 mL of dichloromethane and washed with
saturated brine solution. The organic phase was dried with Na2SO4 and
evaporated to obtain a crude product whose column chromatographic
purification led to pure 2-nitroglycal.
(B). General Procedure for the Nitration of Non-Carbohydrate
Olefins. To a stirred solution of an olefin (0.25 mmol) and AgNO3
(42 mg, 0.25 mmol) in acetonitrile (3.0 mL, 57.5 mmol) at 0 °C was
added dropwise acetyl chloride (19.0 μL, 0.25 mmol). After the
completion of the addition, the reaction vessel was transferred to an
oil bath maintained at 65 °C, and the reaction mixture was stirred for 1 h.
After the consumption of the starting material (TLC monitoring), the
reaction mixture was neutralized to pH 7 by the addition of solid sodium
bicarbonate. The reaction mixture was filtered off using sintered funnel,
and the filtrate was concentrated which was further diluted with 20 mL of
dichloromethane and washed with saturated brine solution. The organic
phase was dried with Na2SO4 and then evaporated to obtain a crude
product which was purified by column chromatography.
(C). Reaction of Cyclohexene for the Preparation of 1-Nitrocyclo-
hexene. To a stirred solution of an olefin (3.65 mmol) and AgNO3
(613 mg, 3.65 mmol) in acetonitrile (1.0 mL, 18.9 mmol) at 0 °C was
added dropwise acetyl chloride (281.0 μL, 3.65 mmol). After the
completion of the addition, the reaction mixture was stirred at room
temperature for 24 h. The reaction mixture was then neutralized to pH
7 by the addition of solid sodium bicarbonate. The reaction mixture
was filtered off using a sintered funnel, and the filtrate was concen-
trated which was further diluted with 20 mL of dichloromethane and
washed with saturated brine solution. The organic phase was dried with
Na2SO4 and then evaporated to obtain a crude product which was
treated with triethylamine for another 24 h. The reaction mixture was
diluted with 20 mL of dichloromethane, washed with 3 N HCL,
followed by saturated brine solution. The organic phase was dried with
Na2SO4 and then evaporated. The crude product was purified by
column chromatography which provided the 1-nitrocyclohexene 33
and the mixture of vicinal nitroacetamides 34 in 32% and 42% yields,
respectively.
(D). Procedure for the Synthesis of Nitroacetamides. To a stirred
solution of a glycal (0.25 mmol) and AgNO3 (42 mg, 0.25 mmol) in
acetonitrile (7.0 mL, 134.1 mmol) at 15 °C was added dropwise acetyl
chloride (19 μL, 0.25 mmol). The reaction mixture was stirred for 12 h at
the same temperature, and after the consumption of the starting material
(TLC consumption), the reaction mixture was neutralized to pH 7 by
the addition of a saturated sodium bicarbonate solution. The reaction
mixture was filtered off using a sintered funnel, and the filtrate was
concentrated, which was further diluted with 20 mL of dichloromethane
and washed with saturated brine solution. The organic phase was dried
with Na2SO4 and then evaporated. The crude product was purified by
column chromatography which provided the pure product.
(3R,4R)-5-Nitro-3,4-dihydro-2H-pyran-3,4-diyl Diacetate (12). Yield:
82%. Rf: 0.45 (hexane:ethyl acetate, 7:3), [R]2D8 = þ77.2 (c 0.25, CH2Cl2).
IR (neat) νmax: 2926, 2854, 1751, 1642, 1510, 1371, 1222, 1045 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 5.98 (s, 1H), 5.10 (s, 1H), 4.53
(d, J = 12.6 Hz, 1H), 4.04 (d, J = 12.9 Hz, 1H), 2.08 (brs, 6H, 2-OCOCH3).
13C NMR (125 MHz, CDCl3):δ169.1, 168.8, 157.3, 128.3, 65.5, 64.8, 60.8,
20.6(2). HRMS calcd for C9H12NO7 [M þ H]þ 246.0614. Found:
246.0617.
In summary, we have developed a new reagent system for the
conversion of olefins to nitroolefins. It is an excellent method for
the conversion of acetylated glucals to their 2-nitroglucals than
their benzyl-protected counterparts. Further, a new method has
been developed for the conversion of benzylated glycals to the
corresponding 2-nitro-1-acetamido sugars for the first time in
good yields which can serve as precursors for the synthesis of
2-amino N-glycopeptides.
’ EXPERIMENTAL SECTION
General Experimental Methods. IR spectra were recorded with
FT-IR as a thin film and are expressed in cmꢀ1. 1H (400 or 500 MHz)
and 13C (100 or 125 MHz) NMR spectra were recorded using CDCl3
and sometimes D2O as a solvent. The stereochemistry of the com-
pounds is assigned with the help of NOE experiments. Chemical shifts
are reported in parts per million downfield to tetramethylsilane.
Coupling constants are reported and expressed in Hz; splitting patterns
are designated as br (broad), s (singlet), d (doublet), dd (double
doublet), and m (multiplet). Optical rotations were measured using a
polarimeter at 28 °C. All reactions were carried out using freshly distilled
and dry solvents. The visualization of spots on TLC plates was effected
by exposure to iodine or spraying with 10% H2SO4 and charring.
Column chromatography was performed over silica gel (100ꢀ200
Mesh) using hexane and ethyl acetate as eluent. Mass spectra were
obtained on a high-resolution ESI mass spectrometer.
(A). General Procedure for the Synthesis of 2-Nitroglycals. To a
stirred solution of a glycal (0.25 mmol) and AgNO3 (42 mg, 0.25 mmol)
in acetonitrile (3.0 mL, 57.5 mmol) at 0 °C was added dropwise acetyl
chloride (19.0 μL, 0.25 mmol). After the completion of the addition, the
reaction vessel was transferred to an oil bath maintained at 55 °C, and
the reaction mixture was stirred for 1 h. After the consumption of the
starting material (TLC monitoring), the reaction mixture was brought to
room temperature and was neutralized to pH 7 by the addition of solid
sodium bicarbonate by checking the pH regularly. The reaction mixture
was filtered off using sintered funnel, and the filtrate was concentrated. It
(3R,4R)-3,4-Bis(benzyloxy)-5-nitro-3,4-dihydro-2H-pyran (14). Yield:
33%. Rf: 0.45 (hexane:ethyl acetate, 4:1), [R]2D8 = ꢀ27.7 (c 0.25, CH2Cl2).
IR (neat) νmax: 3070, 2921, 1686, 1637, 1499, 1292, 1240, 1128, 1072, 935,
707 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 8.28 (s, 1H), 7.35ꢀ7.23 (m,
10H, ArꢀH), 4.74ꢀ4.70 (m, 2H), 4.65 (d, J = 11.0 Hz, 1H), 4.49 (m, 2H),
4.37 (dt, J = 1.8 Hz, J = 10.1 Hz, 1H), 4.06 (d, J = 11.9 Hz, 1H), 3.70 (d, J =
2.7 Hz, 1H. 13C NMR (125 MHz, CDCl3): δ 156.3, 137.3, 136.7, 131.1,
128.6ꢀ127.7 (m, ArꢀC), 72.7, 71.3, 70.1, 66.6, 65.8. HRMS calcd for
C19H19NO5Na [M þ Na]þ 364.1161. Found: 364.1165.
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NOTE
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-methyl-5-nitro-3,4-dihydro-2H-pyran
(16). Yield: 39%. Rf: 0.60 (hexane:ethyl acetate, 9:1), [R]2D8 = þ86.0
(c 0.25, CH2Cl2). IR (neat) νmax: 3031, 2918, 1638, 1498, 1342, 1208,
1073, 1027, 739 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 8.20 (s, 1H),
7.34ꢀ7.21 (m, 10H, ArꢀH), 4.76 (d, J = 11.4 Hz, 1H), 4.71 (t, J =
2.2 Hz, 1H), 4.64ꢀ4.61 (m, 2H), 4.51 (d, J = 12.2 Hz, 1H), 4.43 (d, J =
11.9 Hz, 1H), 3.64 (d, J = 1.9 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 154.5, 137.6, 136.8, 134.5, 128.8ꢀ127.6
(m, ArꢀC), 76.0, 74.3, 73.0, 71.6, 68.2, 16.01. HRMS calcd for
C20H21NO5Na [M þ Na]þ 378.1268. Found: 378.1267.
major diastereomer), 2.02ꢀ1.97 (m, 2H, both diastereomers), 1.94 (s,
3H, ꢀNHCOCH3, minor diastereomer), 1.91 (s, 3H, -NHCOCH3,
major diastereomer), 1.82ꢀ1.59 (m, 6H, both diastereomers), 1.40 (s,
3H, ꢀCH3, minor diastereomer), 1.35 (m, 4H, both diastereomers),
1.20 (s, 3H, ꢀCH3, major diastereomer). 13C NMR (125 MHz, CDCl3),
both diastereomers: δ 170.6, 170.0, 92.4, 86.1, 56.4, 55.1, 35.4, 33.5,
26.9, 26.7, 24.5, 23.6, 23.3, 21.8, 21.8, 20.4, 19.9, 19.9. HRMS calcd for
C9H17N2O3 [M þ H]þ 201.1241. Found: 201.1244.
DEPT-135 Positive peaks: δ 92.4, 86.1, 24.5, 23.6, 19.6, 19.6.
Negative peaks: δ 35.4, 33.6, 26.9, 26.7, 23.3, 21.8, 21.8, 20.4.
(2S,3R,4S,5S,6R)-2-((2R,3S,4S)-4-Acetoxy-2-(acetoxymethyl)-5-nitro-
3,4-dihydro-2H-pyran-3-yloxy)-6-(acetoxymethyl)tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (18). Yield: 74%. Rf: 0.45 (hexane:ethyl acetate,
1:4), [R]2D8 = ꢀ54.4 (c 0.25, CH2Cl2). IR (neat) νmax: 2927, 2856, 1749,
1640, 1508, 1365, 1220, 1042 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
8.27 (s, 1H), 6.30 (s, 1H), 5.36 (d, J = 3.1 Hz, 1H), 5.11 (s, 1H), 5.01 (d,
J = 3.4 Hz, J = 10.6 Hz, 1H), 4.73 (d, J = 7.7 Hz, 1H), 4.58 (m, 1H), 4.29
(d, J = 8.6 Hz, J = 12.3 Hz, 1H), 4.16ꢀ4.07 (m, 4H), 4.02 (t, J = 6.3 Hz,
1H), 2.13 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.96
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 170.7, 170.3, 170.2, 170.1,
169.5, 169.2, 155.0, 127.5, 102.0, 73.3, 71.4, 70.7, 68.8, 66.9, 61.9, 61.3,
60.6. HRMS calcd for C24H31NO17Na [M þ Na]þ 628.1490. Found:
628.1494.
N-((2S,3R,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxy methyl)-3-
nitrotetrahydro-2H-pyran-2-yl)acetamide (38). Yield: 70%. Rf: 0.50
(hexane:ethyl acetate, 3:2), [R]2D8 = þ24.6 (c 0.25, CH2Cl2). IR (neat)
νmax: 3293, 3061, 3032, 2922, 2869, 1663, 1552, 1374, 1273, 1096, 1064,
738, 699 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.34ꢀ7.23 (m, 15H,
ArꢀH), 6.73 (d, J = 8.4 Hz, 1H, ꢀNH), 6.14 (dd, J = 5.8 Hz, J = 8.6 Hz,
1H, H-2), 5.30 (dd, J = 5.5 Hz, J = 11.0 Hz, 1H, H-3), 4.82 (d, J = 11.3
Hz, 1H, ꢀOCHPh), 4.71 (d, J = 11.0 Hz, 1H, ꢀOCHPh), 4.59 (d, J =
11.0 Hz, 1H, ꢀOCHPh), 4.51 (d, J = 11.0 Hz, 1H, ꢀOCHPh), 4.46 (d,
J = 11.6 Hz, 1H, ꢀOCHPh), 4.40 (d, J = 11.6 Hz, 1H, ꢀOCHPh), 4.30
(brd, J = 11.1 Hz, 1H, H-4), 4.13 (s, 1H, H-5), 3.89 (t, J = 7.3 Hz, 1H,
H-6), 3.60 (t, J = 8.5 Hz, 1H, H-7), 3.51 (dd, J = 5.2 Hz, J = 8.8 Hz, 1H,
H-70), 1.97 (s, 3H, ꢀNHCOCH3). 13C NMR (125 MHz, CDCl3): δ
170.5, 137.8, 137.6, 136.7, 128.6ꢀ128.0 (m, ArꢀC), 83.8, 75.7, 75.1,
74.1, 73.7, 72.6, 72.5, 70.6, 67.7, 23.4. HRMS calcd for C29H33N2O7 [M þ
H]þ 521.2288. Found: 521.2283.
(3S,4R)-3,4-Bis(benzyloxy)-5-nitro-3,4-dihydro-2H-pyran (20). Yield:
42%. Rf: 0.52 (hexane:ethyl acetate, 9:1), [R]2D8 = ꢀ69.9 (c 0.25, CH2Cl2).
IR (neat) νmax: 3032, 2915, 1636, 1498, 1340, 1210, 1070, 1028, 739 cmꢀ1
.
1H NMR (500 MHz, CDCl3):δ8.12 (s, 1H), 7.38ꢀ7.25 (m, 10H, ArꢀH),
4.99 (d, J = 2.15 Hz, 1H), 4.93 (d, J = 10.7 Hz, 1H), 4.81 (d, J = 11.0 Hz,
1H), 4.71 (d, J = 12.2 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.21ꢀ4.17 (m,
2H), 3.78 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 156.6, 138.0, 137.1,
131.9, 128.8ꢀ127.7 (m, ArꢀC), 74.6, 72.3, 71.8, 67.2, 64.3. HRMS calcd
for C19H19NO5Na [M þ Na]þ 364.1161. Found: 364.1164.
N-((2S,3S,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxy methyl)-3-
nitrotetrahydro-2H-pyran-2-yl)acetamide (39). Yield: 8%. Rf: 0.52
(hexane:ethyl acetate, 3:2), [R]2D8 = þ45.0 (c 0.25, CH2Cl2). IR (neat)
νmax: 3296, 3063, 3031, 2923, 2870, 1672, 1554, 1372, 1091, 1027, 738,
698 cmꢀ1
.
1H NMR (500 MHz, CDCl3): δ 7.35ꢀ7.13 (m, 15H,
ArꢀH), 6.73 (brd, J = 8.5 Hz, 1H, ꢀNH), 5.87 (t, J = 9.1 Hz, 1H,
H-2), 4.80 (dd, J = 3.3 Hz, J = 9.4 Hz, 1H, H-3), 4.72 (d, J = 11.0 Hz, 1H,
ꢀOCHPh), 4.63 (d, J = 12.2 Hz, 1H, ꢀOCHPh), 4.56 (m, 3H, H-4,
2-OCHPh), 4.48 (m, 3H, 3-OCHPh), 4.34 (t, J = 6.7 Hz, 1H, H-6), 4.17
(dd, J = 9.1 Hz, J = 12.2 Hz, 1H, H-7), 3.78 (m, 2H, H-70, H-5), 1.97
(s, 3H, -NHCOCH3). 13C NMR (125 MHz, CDCl3): δ 170.6, 138.2,
137.2, 136.9, 128.7ꢀ127.6 (m, ArꢀC), 82.5, 75.6, 75.4, 75.1, 73.6, 72.0,
69.8, 65.7, 23.6. HRMS calcd for C29H33N2O7 [M þ H]þ 521.2288.
Found: 521.2287.
Methyl 3-Hydroxy-2-nitropropanoate (28). Yield: 51%. Rf: 0.45
(hexane:ethyl acetate, 4:1). IR (neat) νmax: 3472, 2960, 2925, 1748,
1
1560, 1441,1420, 1227, 1126 cmꢀ1. H NMR (500 MHz, CDCl3): δ
4.75 (dd, J = 2.6 Hz, J = 3.8 Hz, 2H), 4.65 (t, J = 4.2 Hz, 1H), 3.85
(s, 3H), 3.55 (brs, 1H). 13C NMR (125 MHz, CDCl3): δ 171.2, 77.3,
67.6, 53. HRMS calcd for C4H7NO5 [M]þ 149.0324. Found: 149.0323.
Methyl 3-Hydroxy-2-nitrobutanoate (30). Yield: 73%. Rf: 0.55
(hexane:ethyl acetate, 4:1). IR (neat) νmax: 3475, 2968, 2928, 1749,
1
1559, 1438, 1422, 1227, 1125 cmꢀ1. H NMR (500 MHz, CDCl3)
N-((2R,3R,4R,5S)-4,5-Bis(benzyloxy)-3-nitrotetrahydro-2H-pyran-
2-yl)acetamide (40). Yield: 59%. Rf: 0.35 (hexane:ethyl acetate, 4:1),
[R]2D8 = þ66.3 (c 0.25, CH2Cl2). IR (neat) νmax: 3292, 3064, 3029, 2920,
diastereomeric mixture, 1.4:1: δ 4.92 (m, 1H, major diastereomer), 4.86
(brs, 1H, minor diastereomer), 4.82 (m, 1H, minor diastereomer), 4.35
(brs, 1H, major diastereomer), 3.85 (s, 6H, both diastereomers,
ꢀOCH3), 3.32 (brs, 2H, both diastereomers). 13C NMR (125 MHz,
CDCl3), both diastereomers: δ 171.6, 171.3, 83.4, 83.1, 71.9, 71.5, 53.6,
53.5, 15.1, 12.6. HRMS calcd for C5H9NO5Na [M þ Na]þ 186.0378.
Found: 186.0379.
1
2870, 1670, 1550, 1369, 1095, 1063, 739, 698 cmꢀ1. H NMR (400
MHz, CDCl3): δ 7.28ꢀ7.41 (m, 10H, ArꢀH), 6.61 (d, J = 8.5 Hz,
1H, ꢀNH), 5.24 (t, J = 8.0 Hz, 1H, H-2), 4.72ꢀ4.58 (m, 4H), 4.10 (t, J =
8.2 Hz, 1H, H-3), 3.96 (dd, J = 3.8 Hz, J = 12.6 Hz, 1H, H-6), 3.79 (s, 1H,
H-5), 3.65 (dd, J = 2.9 Hz, J = 8.8 Hz, 1H, H-4), 3.54 (dd, J = 1.6 Hz, J =
12.6 Hz, 1H, H-60), 1.98(s, 3H, ꢀNHCOCH3). 13C NMR (125 MHz,
CDCl3): δ 170.2, 137.6, 137.2, 128.5ꢀ127.4 (m, ArꢀC), 80.5, 79.7, 72.9,
71.8, 71.6, 64.3, 58.3, 29.6, 29.3, 23.2 calcd for C21H25N2O6 [M þ H]þ
401.1713. Found: 401.1716.
1-Methyl-6-nitrocyclohex-1-ene (36). Yield: 48%. Rf: 0.85 (hexane:
ethyl acetate, 99:1). IR (neat) νmax: 2946, 2866, 1639, 1549, 1333, 1278,
1
822 cmꢀ1. H NMR (400 MHz, CDCl3) δ 5.88 (brs, 1H), 4.88 (brs,
1H), 2.29ꢀ2.32 (m, 2H), 2.03ꢀ2.16 (m, 2H), 1.73 (s, 3H), 1.59ꢀ1.69
(m, 2H). 13C NMR (125 MHz, CDCl3): δ 131.2, 126.5, 85.8, 28.5, 24.7,
20.9, 17.8. HRMS calcd for C7H12NO2 [M þ Ha]þ 142.0868. Found:
142.0869.
DEPT-135 Positive peaks: δ 131.2, 85.8, 20.9. Negative peaks: δ 28.5,
14.7, 17.8.
N-((2R,3S,4R,5S)-4,5-Bis(benzyloxy)-3-nitrotetrahydro-2H-pyran-
2-yl)acetamide (41). Yield: 23%. Rf: 0.38 (hexane:ethyl acetate, 4:1),
[R]2D8 = ꢀ36.7 (c 0.25, CH2Cl2). IR (neat) νmax: 3064, 3029, 2920, 2870,
1
1670, 1550, 1369, 1095, 1063, 739, 698 cmꢀ1. H NMR (500 MHz,
CDCl3): δ 7.34ꢀ7.25 (m, 10H, ArꢀH), 6.20 (d, J = 9.5 Hz, 1H, ꢀNH),
5.77 (d, J = 9.7 Hz, 1H, H-2), 4.78 (d, J = 11.9 Hz, 1H, ꢀOCHPh), 4.69
(d, J = 11.9 Hz, 1H, ꢀOCHPh), 4.52 (s, 2H, ꢀOCH2Ph), 4.07 (brs,
1 H), 4.02 (m, 2H), 3.96 (t, J = 10.4 Hz, 1H, H-6), 3.83 (dd, J = 3.0 Hz,
J = 10.7 Hz, 1H, H-7), 2.01 (s, 3H, ꢀNHCOCH3). 13C NMR (125
MHz, CDCl3): δ 169.6, 137.7, 137.5, 128.4ꢀ127.5 (m, ArꢀC), 75.7,
73.7, 73.3, 71.6, 70.4, 64.0, 59.3, 29.6, 23.3. HRMS calcd for
C21H25N2O6 [M þ H]þ 401.1713. Found: 401.1718.
N-(1-Methyl-2-nitrocyclohexyl)acetamide (37). Yield: 73%. Rf:
0.55 (hexane:ethyl acetate, 4:1). IR (neat) νmax: 2947, 2868, 1657,
1
1547, 1278, 821 cmꢀ1. H NMR (500 MHz, CDCl3) diastereomeric
mixture, 4:1: δ 6.24 (brs, 1H, ꢀNH, minor diastereomer), 5.80 (brs,
1H, ꢀNH, major diastereomer), 5.56 (dd, J = 5.1 Hz, J = 11.1 Hz, 1H,
major diastereomer), 4.49 (brd, J = 14.8 Hz, 1H, minor diastereomer),
2.97 (m, 1H, minor diastereomer), 2.52 (td, J = 4.0 Hz, J = 12.8 Hz, 1H,
5836
dx.doi.org/10.1021/jo200475h |J. Org. Chem. 2011, 76, 5832–5837

The Journal of Organic Chemistry
NOTE
’ ASSOCIATED CONTENT
131, 12898 and references cited therein. (c) Olah, G. A.; Malhotra, R.;
Narang, S. C. Nitration: Methods and Mechanisms; VCH: New York,
1989. (d) Surya Prakash, G. K.; Mathew, T. Angew. Chem., Int. Ed. 2010,
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Supporting Information. Copies of H NMR and 13C
1
S
b
NMR spectra of all the new compounds, DEPT-135 spectra of
compounds 36 and 37, COSY and NOE spectra of compounds
38, 39, 40, and 41, and Homo nuclear decoupled spectra of the
compounds 40 and 41. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Holzapfel, C. W.; Marais, C. F.; Van Dyk, M. S. Synth. Commun.
1988, 18, 97.
’ AUTHOR INFORMATION
(17) (a) Gupta, A.; Haque, A.; Vankar, Y. D. J. Chem. Soc., Chem.
Commun. 1996, 1653. (b) Jayakanthan, K.; Madhusudanan, K. P.;
Vankar, Y. D. Tetrahedron 2004, 60, 397. (c) Jayakanthan, K.; Vankar,
Y. D. Org. Lett. 2005, 7, 5441.
Corresponding Author
*E-mail: vankar@iitk.ac.in.
(18) (a) Rawal, G. K.; Rani, S.; Madhusudanan, K. P.; Vankar, Y. D.
Synthesis 2007, 294. (b) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem.
2004, 69, 6137. (c) Reddy, B. G.; Madhusudanan, K. P.; Vankar, Y. D.
J. Org. Chem. 2004, 69, 2630. (d) Pachamuthu, K.; Vankar, Y. D. J. Org.
Chem. 2001, 66, 7511.
(19) Rawal, G. K.; Kumar, A.; Tawar, U.; Vankar, Y. D. Org. Lett.
2007, 9, 5171.
(20) (a) Liu, L.; Bannett, C. S.; Wong, C.-H. Chem. Commun.
2006, 21. (b) Kaneshiro, C. M.; Michael, K. Angew. Chem., Int. Ed.
2006, 45, 1077.
’ ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research,
New Delhi, for financial support (Grant No. 01(2298)/09/
EMR-II) and the Department of Science and Technology,
New Delhi, for the J. C. Bose National Fellowship to YDV
(JCB/SR/S2/JCB-26/2010). P.K.K. thanks the UGC, and Y.S.R.
and S.D. thank the CSIR, New Delhi for senior research
fellowships.
(21) Bosques, C. J.; Tschampel, S. M.; Woods, R. J.; Impariali, B.
J. Am. Chem. Soc. 2004, 126, 8421.
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