One-pot synthesis of N-glycooxazolines, N-glycoaminooxazolines, and N-glycothiazolines from glycals

Article abstract of DOI:10.1002/ejoc.201200130

Novel one-pot syntheses of N-glycooxazolines (N at C-1), N-glycoaminooxazolines, and N-glycothiazolines have been developed. Thus, the reaction of tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal with aryl amides, heteroaryl amides, thioamides, and substi

Full text of DOI:10.1002/ejoc.201200130

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FULL PAPER
DOI: 10.1002/ejoc.201200130
One-Pot Synthesis of N-Glycooxazolines, N-Glycoaminooxazolines, and
N-Glycothiazolines from Glycals
Erica M. Reid,[a] Edward S. Vigneau,[a] Synthia S. Gratia,[a] Cecilia H. Marzabadi,*[b] and
Michael De Castro*[a]
Dedicated to the memory of Dr. Frank Pellegrini
Keywords: Carbohydrates / Heterocycles / Natural products / Synthetic methods
Novel one-pot syntheses of N-glycooxazolines (N at C-1), N-
glycoaminooxazolines, and N-glycothiazolines have been
glycosylamide was isolated instead. Treatment of this newly
formed glycosylamide with an anhydrous base afforded the
O-glycooxazoline (O at C-1) in high to moderate yields. Prod-
uct outcomes and the overall stereoselectivity of the reactions
developed. Thus, the reaction of tri-O-benzyl-
D-glucal or tri-
O-benzyl- -galactal with aryl amides, heteroaryl amides,
D
thioamides, and substituted ureas in the presence of N-iodos- were found to be highly dependent on the nature of the sugar
uccinimide (NIS) in dry propionitrile at 45 °C afforded the
cyclized products in good yields. When tris(O-tert-butyldi-
protecting group, the nature of the substituent on the amide,
and the reaction temperature.
methylsilyl)-D-glucal was employed, the 2-deoxy-2-iodo-
are produced by human white blood cells and have been
linked to inflammation and airway constriction during
asthma attacks.[8] Thus, it has been proposed that chitinase
inhibitors may also be useful as chemotherapeutics in the
treatment of asthma.[9] Allosamidin is a pseudotrisac-
charide featuring an aminooxazoline fused to a cyclopent-
itol. Several analogues of Allosamidin have been isolated
from nature, and all of them contain the aminoxazoline
moiety.[10–12] X-ray crystal structures of Allosamidin bound
to hevamine, a plant chitinase/lysozyme, have shown that
the aminooxazoline moiety interacts directly with the cata-
lytic machinery of the enzyme, and it has been proposed to
play a crucial role in the inhibition of chitinase.[13] This sug-
gests that the aminooxazoline may be the minimal subunit
Introduction
The use and applications of carbohydrate-based oxazol-
ines cannot be understated. Carbohydrate-fused oxazolines
have been prepared with the oxygen atom at the C-1 posi-
tion (O-glycooxazolines), and these molecules have been
used as glycosyl donors in the synthesis of oligosaccha-
rides,[1] as activated donor substrates in the enzymatic syn-
thesis of glycoconjugates,[2] and as protecting groups of the
anomeric center.[3] However, recently there has been interest
in the preparation of carbohydrate-based oxazolines due to
their occurrence in natural products such as the chitinase
inhibitor Allosamidin (1)[4] and the trehalase inhibitor Tre-
hazolin (2) (Figure 1).[5] Chitinases are enzymes that hy-
drolyze chitin, a polysaccharide that consists of repeating
β-(1–4)-linked N-acetyl-d-glucosamine units. Chitin is the
second most abundant polysaccharide in nature and is com-
monly found in insects, plants, bacteria, and fungi.[6] Allos-
amidin can inhibit the biosynthesis of chitin, and as such it
has been used as an antifungal agent and as a pesticide.[7]
Although chitin is not synthesized by humans, chitinases
[a] Chemistry Department, Farmingdale State College – SUNY,
2350 Broadhollow Rd, Farmingdale, NY 11735, USA
Fax: +1-631-420-2759
E-mail: michael.decastro@farmingdale.edu
[b] Department of Chemistry and Biochemistry, Seton Hall
University,
400 South Orange Ave, NJ 07079, USA
Fax: +1-973-761-9772
E-mail: cecilia.marzabadi@shu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200130.
Figure 1. Carbohydrate-based heterocyclic compounds.
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required for binding to the enzyme. Trehazolin is a pseudo- ture of Ag salts and collidine[3] or NaHCO3.[22] On the
disaccharide that also features an aminooxazoline fused to other hand, only a few reports exist for the preparation of
a cyclopentitol. It is a powerful inhibitor of trehalases, N-glycooxazolines. Common approaches include Ritter-like
which are widespread in nature, including in inverte- addition reactions of acetonitrile to anhydrosugars in the
[23]
brates.[14] Just as with Allosamidin, the aminooxazoline presence of ZnCl2
and of fructopyranose and furanose
moiety found in Trehazolin binds directly to the active site 1,2-O-acetonide derivatives with various nitriles and triflic
of the enzyme and is capable of mimicking the high-energy acid.[24] Glycosyl azides have also been treated with trialkyl-
intermediate implicated in the hydrolysis of the native sub- phosphanes to prepare N-glycooxazolines.[25] In general, N-
strate trehalose.[15]
glycooxazolines have been used as precursors in the prepa-
ration of β-glycosyl isothiocyanates[26] and as a way of con-
structing glycosylamides for the preparation of N-glyco-
peptides. Therefore, there is still a need for a convergent
approach that will allow the preparation of a small library
of carbohydrate-fused oxazolines, thiazolines, and amino-
oxazolines. Having access to these constructs will facilitate
their rapid screening against various glycosidases, including
the all important chitinases.
As part of our ongoing research aimed at the generation
of carbohydrate-fused heterocyclic compounds, we became
interested in the development of a convergent approach to
the synthesis of a small library of carbohydrate-fused sub-
stituted oxazolines. Compounds of this kind have the po-
tential to be powerful glycosidase inhibitors. Our study tar-
geted the less common N-glycooxazolines 6 (N at C-1), N-
glycothiazolines 7, and N-glycoaminooxazolines
8
We herein report a novel one-pot procedure for the direct
preparation of N-glycooxazolines and the extension of this
methodology to the preparation of N-glycoaminooxazol-
ines and N-glycothiazolines by the iodonium-mediated ad-
dition of heteroaryl amides, thioamides, and substituted
ureas to glycals. The effects of the sugar protecting group,
the nature of the substituent on the amide, and the reaction
temperature on the product outcomes will also be dis-
cussed.
(Scheme 1) based on the frameworks of Allosamidin and
Trehazolin. We envisioned being able to access the latter
constructs by using 2-deoxy-2-iodoglycosylthioamides 5a
and 2-deoxy-2-iodoglycosylureas 5b as precursors. Cycliza-
tion under basic conditions by deprotonation of the nitro-
gen atom of the amide followed by O- or S-alkylation and
displacement of the iodine atom at the C-2 position of the
sugar should furnish our targeted compounds.
Results and Discussion
We have previously reported the preparation of 2-deoxy-
2-iodoglycosylamides from glycals as well as their use as
precursors in the preparation of both O- and N-glycooxaz-
olines by basic cyclization.[27,28] In this two-step procedure,
the product outcome of the initial addition reaction was
found to be highly dependent on different factors, including
the nature of the protecting group on the sugar hydroxy
moieties, the substituent on the amide, and the reaction
temperature. In the preparation of 2-deoxy-2-iodoglycosyl-
amides, the best overall yields and stereoselectivities were
obtained when the bulky tert-butyldimethylsilyl ether
(TBDMS) and benzyl ether were used as protecting groups
Scheme 1. Targeted N-glycooxazoline, N-glycothiazoline, and N-
glycoaminooxazoline.
1
on the sugar. Analysis of the H NMR coupling constants
of adjacent protons suggested that the TBDMS-protected
Although the total syntheses of Allosamidin and Tre- glycosylamides exist in the 1C4 chair conformation, whereas
hazolin are well documented,[16–19] the preparation of the benzyl-protected glycosylamide exists in the 4C1 confor-
monosaccharides bearing a fused aminooxazoline or -thiaz- mation. The trans-2-deoxy-2-iodoglycosylamide was ob-
oline based on the same frameworks remains relatively un- tained as the major addition product in both cases. Alkyl,
explored. Knapp and co-workers prepared glucothiazoline aryl, and heteroaryl amides gave the best yields, whereas
3 and aminothiazoline 4 (Figure 1), derivatives based on the the less nucleophilic trichloroacetamide and acetamide gave
structure of Allosamidin. These constructs were found to poor yields and mixtures of diastereomers. The best overall
competitively inhibit jack bean N-acetylhexoaminid- stereoselectivity was obtained when the reactions were car-
ase.[20,21] In contrast, several methods exist for the prepara- ried out at –78 °C in dry propionitrile or at 0 °C in dry
tion of O-glycooxazolines. Access to these constructs has DMF.[29] In our previous study we did not explore the ad-
been achieved by using haloglycosides as starting materials. dition of thioamides and substituted ureas. However, we en-
Their preparation has been accomplished by the displace- visioned the construction of N-glycoaminooxazolines and
ment of the halogen atom at the anomeric center followed N-glycothiazolines by using glycosylthioamides and glycos-
by O-alkylation of the neighboring acetamide using a mix- ylureas as precursors. Cyclization under basic conditions
2
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N-Glycooxazolines and N-Glycothiazolines from Glycals
Table 1. Proportions of diastereomeric iodoamides obtained from the glucals.[a]
Entry
Sugar RЈ
Amide
α-Manno
β-Manno
α-Gluco
β-Gluco
Yield [%][b]
1
2
3
4
5
6
7
8
9
TBDMS
TBDMS
Bn
NH2CSCH3
NH2CSPh
NH2CSCH3
1
0
1
1
1
1
1
–
–
traces
1
traces
traces
0
0
0
–
–
1
1
1
2
0
0
0
–
–
10
8
2
4
0
0
0
–
–
46
53
55
52
80
88
95
–
Bn
NH2CSPh
TBDMS
TBDMS
TBDMS
Bn
NH2CONHPh
NH2CON(CH3)2
1-(trimethylsilyl)pyrrolidin-2-one
NH2COOBn
TBDMS
NH2COOBn
–
[a] Dry propionitrile was used as solvent. The reaction was performed at –78 °C for 8 h and then at room temp. for 48 h. The proportions
1
of products were determined by integration of the signals of the anomeric protons in the H NMR spectrum. [b] Yields of product after
recovery by extractive workup and subsequent chromatographic purification on SiO2.
should furnish our targeted compounds. The addition of Entries 5 and 6). The TBDMS glucal was also treated
other amides, including benzyl carbamates and secondary with the secondary amide 1-(trimethylsilyl)-2-pyrrolidinone
silylated amides, was also examined.
to yield 1-[3,4,6-tris(O-tert-butyldimethylsilyl)-2-deoxy-2-
We began our studies by attempting the addition of thio- iodo-α-d-mannopyranosyl]-2-pyrrolidinone (11c) in 95%
acetamide and thiobenzamide to both tri-O-benzyl-d-glucal yield (Table 1, Entry 7). This is not a surprise, because N-
(9) and tris(O-tert-butyldimethylsilyl)-d-glucal (10) in the silylated amides have been used before in the direct addition
presence of NIS and dry propionitrile at –78 °C (Scheme 2). of amides to 1-hydroxyglycosyl donors in the presence of
Consistent with our previous results with acetamide and trifluoromethanesulfonic anhydride and diphenyl sulf-
benzamide, we anticipated the formation of the glycos- oxide.[31]
ylamides 11 and 12 (Scheme 2), but instead the reaction
proceeded very sluggishly, and poor yields and mixtures of
diastereoisomers were obtained (Table 1, Entries 1–4).
We noted that thioamides, ureas, and heteroaryl amides
(previous study) are only partially soluble in propionitrile
at –78 °C resulting in heterogeneous mixtures. We reasoned
that such a lack of solubility may lead to lengthy reaction
times and in some cases poor yields and stereoselectivity.
To optimize the reaction conditions and improve the reac-
tion times we decided to carry out the addition reaction
at a higher temperature. Therefore, a new procedure was
developed that involved the mixing of the glucal in dry pro-
pionitrile followed by the addition of the amide (6 equiv.).
The reaction mixture was heated at 45 °C until the amide
had completely dissolved. This was followed by the addition
of pre-activated molecular sieves (4 Å) to the reaction mix-
ture as a scavenger of water to prevent the formation of the
halohydrin byproduct.
Scheme 2. Preparation of 2-deoxy-2-iodoglycosylamides.
Furthermore, the halohydrin byproduct that can result
Finally, NIS (2 equiv.) was added to the reaction mixture
from the addition of adventitious water found in the system at 45 °C, and the reaction was monitored by TLC until
was isolated after flash column chromatography (data not complete disappearance of the starting material (Scheme 3).
shown) as a minor product. These results were rather sur- Under these new reaction conditions we did not observe
prising, because thioamides have quite a high nucleophilic- any improvement in the addition of both thioacetamide and
ity and have been used extensively in the synthesis of a wide thiobenzamide to the TBDMS-protected glucal (data not
variety of heterocycles.[30] We also attempted the addition shown). However, when benzamide, heteroaryl amides,
of benzyl carbamate to both the benzyl- and TBDMS-pro- phenylurea, and 1,1-dimethylurea were added to the
tected glucals (Table 1, Entries 8 and 9). Unfortunately, this TBDMS-protected glucal 10, the 2-deoxy-2-iodoglycosyl-
addition reaction failed, and starting material was isolated amides 14 were isolated exclusively (Scheme 3; Table 2, En-
exclusively.
tries 1–6). 1H NMR analysis suggests that all the newly pre-
1
However, in spite of the poor results obtained with the pared 2-deoxy-2-iodoglycosylamides exist in the C4 chair
thioamides and benzyl carbamate, other functionalities conformation due to the large values of J obtained for the
3
added quite readily under these reaction conditions. Mono- protons at C-1 and C-2, ranging from 10 to 12 Hz, and the
3
substituted phenylurea and disubstituted 1,1-dimethylurea medium to small values of J observed for the rest of the
added to the TBDMS-protected glucal 10, and 1-(2-deoxy- protons in the pyranose ring, ranging from 1 to 5 Hz. The
2-iodo-α-d-mannopyranosyl)-3-phenylurea 11a and 1-(2- total time for the completion of the reaction was just 2 h.
deoxy-2-iodo-α-d-mannopyranosyl)-3,3-dimethylurea 11b This represents a major improvement over our previously
were obtained exclusively in good yields (Scheme 2; Table 1, reported methodology in which a total of 48 h was required
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Scheme 3. Addition of various amides to glycals in the presence of N-iodosuccinimide at 45 °C.
Table 2. One-pot preparation of N-glycooxazolines, N-glycoamino- for the reaction to be completed. One can reason that such
oxazolines, and N-thiazolines.
an improvement must be correlated to the increased solubil-
ity of the amides at 45 °C, which results in a homogeneous
reaction mixture.
To our surprise, when benzamide was added to the
benzyl-protected glucal 9 and galactal derivatives, N-glyco-
oxazolines 13a and 13b were isolated exclusively in just one
step (Scheme 3; Table 2, Entries 7 and 8). Heteroaryl
amides, thiobenzamide, phenylurea, and 1,1-dimethylurea
were also added to 9 to yield the corresponding heteroaryl
N-glycooxazolines 13c and 13d (Table 2, Entries 9 and 10),
N-glycothiazoline 13e (entry 11), and N-glycoaminooxazol-
ines 13f and 13g (Entries 12 and 13). The direct formation
of O-glycooxazoline was never observed with the TBDMS-
protected glucal, instead the glycosylamide or dia-
stereomeric mixtures of the glycosylthioamide (data not
shown) were isolated exclusively.
The results obtained indicate that the temperature and
nature of the protecting group on the sugar may play a
crucial role in the outcomes of the reaction. It seems that
at high temperatures the in situ formation of N-glycooxaz-
oline is favored with the benzyl-protected glucal. We rea-
soned that a combination of the reverse anomeric effect and
the preference for the 4C1 chair conformation by the benzyl-
protected glycosylamide will favor the formation of 1,2-cis-
N-glycooxazoline. In previous studies, 1H NMR analysis of
15 indicated that the 4C1 chair conformation is preferred by
the benzyl-protected glycosylamide (Scheme 4).[27]
It is our hypothesis that the initial formation of the trans-
2-deoxy-2-iodoglycosylamide 15 takes place at 45 °C. In the
Scheme 4. Product outcomes for the addition of amides at 45 °C to various protected glucals.
4
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N-Glycooxazolines and N-Glycothiazolines from Glycals
Scheme 5. O- and N-glycooxazolines from 2-deoxy-2-iodoglycosylamides.
4C1 chair conformation the amide group at C-1 and the ureas, and thiobenzamide to tri-O-benzyl-d-glucal in the
iodine atom at C-2 will have the anti coplanar conformation presence of NIS and dry propionitrile at 45 °C. When
required for ring-closure through O-alkylation leading to tris(O-tert-butyldimethylsilyl)-d-glucal was used the 2-de-
the formation of the oxazoline 16. One can envision that oxy-2-iodoglycosylamides were isolated instead. Cyclization
cyclization may also be favored due to the preference of the by using a suspension of NaH in CH2Cl2 at –78 °C fur-
amide to occupy the equatorial position rather than the ax- nished some N-glycooxazoline with O-glycooxazoline as the
ial position attained in 15 due in part to the reverse anom- major product. The preparation of glycosylureas and glycos-
eric effect.[32] That is not true for the TBDMS-protected ylamides through the use of secondary silylated amides
glycosylamide 17 (Scheme 4). In this case the 1C4 chair con- in the presence of NIS and propionitrile at –78 °C has also
formation is favored due to the preference of the bulky silyl- been reported. Further mechanistic studies are in progress
oxy protecting groups to occupy the axial position.[33] In to validate the proposed pathway. In addition, the final de-
this particular chair conformation the amide group at C-1 protection and biological screening of the compounds de-
and the iodine atom at C-2 will not be able to assume the scribed in this paper are underway, and the results will be
anti coplanar conformation observed in compound 15 reported in due course.
thereby preventing the in situ formation of the oxazoline.
Note that the TBDMS-protected glycosylamides 14 were
subjected to cyclization through the use of a heterogeneous
Experimental Section
mixture of NaH in DCM and 15-crown-5 ether at –78 °C
General Synthetic Methods: Column chromatography was per-
(Scheme 5). The O-glycooxazolines 18 were obtained in
formed on silica gel 60 (EM Science, 70–230 mesh). Reactions were
monitored by TLC on Kieselgel 60 F254 (EM Science), and the
compounds were detected by examination under UV light and by
charring with 10% sulfuric acid in MeOH. Solvents were removed
good to excellent yields along with the N-glycooxazolines
19 as minor products (Table 3, Entries 1–4). As previously
reported, the latter is formed by the migration of the nitro-
gen atom from C-1 to C-2 through an N-acylaziridino sugar
intermediate.[27] The aziridine rearranges by nucleophilic
ring-opening at the anomeric center by the amide carbonyl
oxygen atom to form the O-glycooxazoline. To rule out the
possibility of an equilibrium between the N- and O-glyco-
oxazolines, the latter was stirred in a suspension of NaH
and CH2Cl2 at room temperature, but this did not lead to
equilibration.
under reduced pressure at Ͻ40 °C. CH2Cl2 was distilled from CaH2
and stored over molecular sieves (3 Å). Molecular sieves (4 Å) used
in the reactions were crushed and activated in vacuo at 390 °C for
8 h in the first instance and then at 390 °C for 2–3 h directly prior
1
to application. H and 13C NMR spectra were recorded with Var-
ian spectrometers (models Inova 300 and 500) equipped with Sun
workstations and an ECS 400 MHz JEOL spectrometer. 1H NMR
spectra were recorded in [D6]acetone and are referenced to residual
CH3COCH3 at δ = 2.04 ppm, and 13C NMR spectra are referenced
1
to the peak at δ = 205 ppm. H NMR spectra recorded in CDCl3
Table 3. Preparation of O-glycooxazolines.
are referenced to residual CHCl3 at δ = 7.24 ppm, and 13C NMR
spectra are referenced to the central peak of CDCl3 at δ =
77.0 ppm. Assignments were made by standard gCOSY and
gHSQC experiments. HRMS data were obtained with a Bruker
Ultraflex MALDI-TOF mass spectrometer. Tri-O-benzyl-d-glucal,
tri-O-benzyl-d-galactal,
3,4,6-tris(O-tert-butyldimethylsilyl)-d-
glucal, and N-iodosuccinimide (NIS) were purchased from Aldrich.
Amides, heteroaryl amides, and thiobenzamide were also pur-
chased from Aldrich Chemical Co., whereas phenylurea and 1,1-
dimethylurea were purchased from TCI America.
General Procedure for the Preparation of N-[3,4,6-Tris(O-tert-butyl-
dimethylsilyl)-2-deoxy-2-iodo-α-D-mannopyranosyl]amides at –78 °C:
3,4,6-Tris(O-tert-butyldimethylsilyl)-d-glucal
(10) (0.150 g,
Conclusions
0.30 mmol) was diluted in freshly distilled propionitrile (3.0 mL)
and mixed under N2. The amide (0.615 mmol) was added to the
reaction flask followed by N-iodosuccinimide (0.138 g, 0.61 mmol).
The reaction mixture was stirred at –78 °C for 8 h and then warmed
to room temp. and mixed for 48 h. The reaction was monitored
by TLC until complete disappearance of the starting material was
We have reported herein a practical one-pot synthesis of
various carbohydrate-based heterocycles, including N-glyco-
oxazolines, N-glycoaminooxazolines, and N-glycothiazol-
ines. Direct access to these constructs was achieved by the
addition of various aryl and heteroaryl amides, substituted observed. The reaction was quenched with distilled water and the
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mixture diluted in DCM (50 mL). The crude mixture was washed
with a saturated solution of Na2S2O3 (100 mL) and distilled water
succinimide (0.138 g, 0.61 mmol) was added to the flask, which was
then wrapped in aluminium foil, and the reaction mixture was
(3ϫ100 mL). The organic layer was dried with MgSO4 and the stirred at 45 °C for 2 h. The reaction was monitored by TLC, and
solvent removed in vacuo.
upon disappearance of the starting material the following workup
was carried out to isolate the crude product. The reaction was
quenched with distilled water, and the mixture was diluted in
CH2Cl2 (50 mL). The crude mixture was filtered and washed with
a saturated aqueous solution of Na2S2O3 (100 mL) and distilled
water (3ϫ100 mL). The organic layer was dried with MgSO4, and
the solvent was removed in vacuo.
1-Phenyl-3-[3,4,6-tris(O-tert-butyldimethylsilyl)-2-deoxy-2-iodo-α-
D
-mannopyranosyl]urea (11a): The crude mixture (0.250 g) was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 3:1, v/v), to give a colorless solid (0.184 g, 80%). Rf
= 0.40. 1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H, NH-Ph),
7.29 (d, J = 7.6 Hz, 2 H, Ar), 7.20 (t, J = 7.8 Hz, 2 H, Ar), 6.98
(t, J = 7.08 Hz,1 H, Ar), 5.92 (d, JNH-1 = 8.24 Hz, 1 H, NH), 5.56
N-[3,4,6-Tris(O-tert-butyldimethylsilyl)-2-deoxy-2-iodo-α-D-manno-
(dd, J1-NH = 9.16, J1-2 = 9.1 Hz, 1 H, 1-H), 4.61 (br. d, J2-1
=
pyranosyl]pyridine-2-carboxamide (14a): The crude mixture
12.8 Hz, 1 H, 2-H), 4.18 (dd, J5-4 = 11.0, J5-6 = 10.8 Hz, 1 H, 5-
(0.235 g) was purified by flash column chromatography on silica
H), 4.04 (s, 1 H, 4-H), 3.93–3.89 (m, 3 H, 3-H, 6-H), 0.97–0.84 gel (hexane/ethyl acetate, 8:1, v/v) to give a clear oil (0.197 g, 88%).
[m, 27 H, (CH3)3C], 0.15–0.1 (m, 18 H, CH3Si) ppm. 13C NMR Rf = 0.29. 1H NMR (400 MHz, [D6]acetone): δ = 8.59 (dd, J =
(100 MHz, CDCl3): δ = 156.99 (C=O), 138.33, 129.11, 128.95, 2.52, J = 0.92 Hz, 1 H, Ar), 8.09 (d, J = 0.56 Hz, 1 H, Ar), 7.98
128.59, 126.28, 123.57 (Ar), 81.85 (C-3), 76.86 (C-5), 76.47 (C-1),
69.18 (C-4), 61.38 (C-6), 33.99 (C-2), 32.04, 32.03, 29.81, 29.80,
(dd, J = 2.32, J = 1.36 Hz, 1 H, Ar), 7.57 (dd, J = 2.76, J = 2.06 Hz,
1 H, Ar), 5.86 (t, JN-H1 = 6.88, JNH-2 = 5.04 Hz, 1 H, NH), 5.10
26.37, 26.36, 26.08, 26.04, 22.80, 18.42, 18.19, 14.27 [(CH3)3C], (dd, J1-NH = 6.16, J1-2 = 2.88 Hz, 1 H, 1-H), 3.96 (dd, J2-3 = 5.04,
–3.46, –4.47, 4.56 (CH3Si) ppm. HRMS (MALDI-TOF): calcd. for
J2-1 = 2.28 Hz, 1 H, 2-H), 4.14 (s, 1 H, 5-H), 3.97 (dd, J4-3 = 2.08,
J4-5 = 1.72 Hz, 1 H, 4-H), 3.92 (dd, J3-2 = 5.96, J3-4 = 4.78 Hz, 1
H, 3-H), 3.90–3.85 (m, 2 H, 6-H), 0.90–0.86 [m, 27 H, (CH3)3C],
0.13–0.07 (m, 18 H, CH3Si) ppm. 13C NMR (100 MHz, [D6]ace-
tone): δ = 149.22, 138.42, 127.49, 123.0 (Ar), 81.90 (C-3), 77.27 (C-
5), 70.02 (C-1), 62.16 (C-6), 34.98 (C-2), 26.69, 26.27, 26.06, 18.85,
18.73, 18.45 [(CH3)3C], –3.14, –4.50, –5.07 (CH3Si) ppm. HRMS
(MALDI-TOF): calcd. for C30H57IN2O5Si3 736.2620 [M + H]+;
found 737.2698.
C31H59IN2O5Si3 750.2776 [M + H]+; found 751.2855.
1,1-Dimethyl-3-[3,4,6-tris(O-tert-butyldimethylsilyl)-2-deoxy-2-
iodo-α-D-mannopyranosyl]urea (11b): The crude mixture (0.240 g)
was purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 4:1, v/v) to give a white solid (0.189 g, 88%). Rf =
0.41. 1H NMR (500 MHz, [D6]acetone): δ = 5.86 (d, JN-H1
=
9.60 Hz, 1 H, NH), 5.49 (dd, J1-NH = 9.90, J1-2 = 9.75 Hz, 1 H, 1-
H), 4.69 (dd, J2-1 = 5.10, J2-3 = 2.41 Hz, 1 H, 2-H), 4.22–4.14 (m,
1 H, 5-H), 4.02 (s, 1 H, 4-H), 3.86 (dd, J3-2 = 1.80, J3-4 = 1.80 Hz, N-[3,4,6-Tris(O-tert-butyldimethylsilyl-2-deoxy-2-iodo-α-D-manno-
1 H, 3-H), 3.74–3.66 (m, 2 H, 6-H), 2.76 (s, 3 H, CH3), 2.71 (s, 3 pyranosyl]pyrazincarboxamide (14b): The crude mixture (0.240 g)
H, CH3), 0.91–0.88 [m, 7 H, (CH3)3C], 0.82–0.78 [m, 20 H, was purified by flash column chromatography on silica gel (hexane/
(CH3)3C], 0.16–0.12 (m, 9 H, CH3Si), 0.03–0.00 (m, 9 H, CH3Si)
ethyl acetate, 7:1, v/v) to give a yellowish oil (0.210 g, 93%). Rf =
0.34. H NMR (400 MHz, [D6]acetone): δ = 9.22 (s,1 H, Ar), 8.22
1
ppm. 13C NMR (125 MHz, [D6]acetone): δ = 156.79 (C=O), 81.18
(C-3), 77.45 (C-5), 75.27 (C-1), 69.61 (C-4), 61.80 (C-6), 35.78 (C- (d, J = 2.28 Hz, 1 H, Ar), 8.63 (d, J = 1.84 Hz,1 H, Ar), 5.87 (d,
2), 29.42, 29.17, 28.91, 28.65, 28.40, 26.11, 25.71, 25.51, 25.40, JNH-1 = 10.0 Hz, 1 H, NH), 5.13 (dd, J1-NH = 10.0, J1-2 = 6.2 Hz,
18.28, 18.18, 17.91 [(CH3)3C], –3.71, –5.02, –5.07, –5.14, –5.64, 1 H, 1-H), 4.20 (br. d, J2-1 = 7.8 Hz, 1 H, 2-H), 4.14 (s, 1 H, 5-H),
–5.66 (CH3Si) ppm. HRMS (MALDI-TOF): calcd. for C27H59
-
3.97 (dd, J4-3 = 1.6, J4-5 = 1.3 Hz, 1 H, 4-H), 3.93–3.90 (m, 3 H,
3-H, 6-H), 0.90–0.86 [m, 27 H, (CH3)3C], 0.26–0.07 (m, 18 H,
CH3Si) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 160.75
(C=O), 148.03, 144.42, 144.31, 143.35 (Ar), 81.29 (C-3), 76.63 (C-
1), 69.32 (C-4), 61.43 (C-6), 32.0 (C-2), 29.28, 29.09, 28.90, 28.70,
28.50, 25.54, 19.0, 18.80, 14.0 [(CH3)3C], –3.86, –5.27, –5.80
(CH3Si) ppm. HRMS (MALDI-TOF): calcd. for C29H56IN3O5Si3
737.2572 [M + H]+; found 738.2659.
IN2O5Si3 702.2776 [M + Na]+; found 725.2546.
1-[3,4,6-Tris(O-tert-butyldimethylsilyl)-2-deoxy-2-iodo-α-D-manno-
pyranosyl]-2-pyrrolidinone (11c): The crude mixture (0.220 g) was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 3:1, v/v) to give a clear oil (0.20 g, 95%). Rf = 0.38.
1H NMR (400 MHz, [D6]acetone): δ = 5.65 (d, JNH-1 = 10.5 Hz, 1
H, NH), 4.69 (br. d, J1-NH = 11.0 Hz, 1 H, 1-H), 4.14 (dd, J2-1
=
2.62, J2-3 = 1.34 Hz, 2 H, 2-H, 5-H), 3.91 (d, J3-2 = 3.2 Hz, 1 H,
N-[3,4,6-Tris(O-tert-butyldimethylsilyl)-2-deoxy-2-iodo-α-D-manno-
3-H), 3.86–3.85 (m, 3 H, 4-H, 6-H), 3.41–3.36 (m, 2 H, pyranosyl]thiophenecarboxamide (14c): The crude mixture (0.245 g)
COCH2CH2CH2), 2.24–2.22 (m, 2 H, COCH2CH2CH2), 2.02–2.01 was purified by flash column chromatography on silica gel (hexane/
(m, 2 H, COCH2CH2CH2), 0.91–0.87 [m, 27 H, (CH3)3C], 0.24–
ethyl acetate, 9:1, v/v) to give a white solid (0.197 g, 86%). Rf =
0.0 (m, 18 H, CH3Si) ppm. 13C NMR (100 MHz, [D6]acetone): δ 0.25. 1H NMR (400 MHz, [D6]acetone): δ = 7.54–7.48 (m, 2 H,
= 175.09 (C=O), 82.24 (C-3), 77.11 (C-5), 74.01 (C-1), 69.70 (C-4),
61.93 (C-6), 41.38 (C-2), 32.55, 31.59, 26.62, 26.26, 26.01, 18.78,
18.38 [(CH3)3C], –3.25, –4.59, –5.10 (CH3Si) ppm. HRMS
(MALDI-TOF): calcd. for C27H59IN2O5Si3 699.2667 [M + H]+;
found 700.2746.
Ar), 7.06 (d, J = 9.2 Hz, 1 H, Ar), 6.37 (d, JNH-1 = 9.2 Hz, 1 H,
NH), 5.77 (dd, J1-NH = 10.0, J1-2 = 9.84 Hz, 1 H, 1-H), 4.64 (dd,
J2-1 = 10.0, J2-3 = 2.4 Hz, 1 H, 2-H), 4.25 (m, 1 H, 5-H), 4.07 (s, 1
H, 4-H), 3.92 (dd, J3-2 = 2.76, J3-4 = 1.2 Hz, 1 H, 3-H), 3.85–3.83
(m, 2 H, 6-H), 0.97–0.76 [m, 27 H, (CH3)3C], 0.22–0.04 (m, 18 H,
CH3Si) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.16 (C=O),
138.24, 130.99, 128.82, 127.72 (Ar), 81.83 (C-3), 73.17 (C-1), 68.81
(C-4), 61.18 (C-6), 33.96 (C-2), 29.79, 26.30, 26.01, 25.90, 25.73,
25.66, 18.37, 18.28, 18.09, 14.23, 13.90 [(CH3)3C], –4.58, –4.65,
General Procedure for the Preparation of 3,4,6-Tris(O-tert-butyldi-
methylsilyl)-2-deoxy-2-iodo-α-D-mannopyranosyl Amides at 45 °C:
3,4,6-Tris(O-tert-butyldimethylsilyl)-d-glucal (10) (0.150 g,
0.30 mmol) was diluted in freshly distilled propionitrile (3.0 mL)
and stirred under N2. The amide (0.615 mmol) was added to the
reaction flask, and the reaction mixture was heated at 45 °C until
–5.17 (CH3Si) ppm. HRMS (MALDI-TOF): calcd. for C29H56
-
INO5Si3 741.2232 [M + Na]+; found 764.2234.
it became a homogeneous solution. Activated molecular sieves N-[3,4,6-Tris(O-tert-butyldimethylsilyl-2-deoxy-2-iodo-α-
D-manno-
(4 Å) in powder form (0.100 g) were added. After 10 min, N-iodo- pyranosyl]benzamide (14d): The crude mixture (0.250 g) was puri-
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20130
/KAP1
Date: 02-05-12 18:49:28
Pages: 10
N-Glycooxazolines and N-Glycothiazolines from Glycals
fied by flash column chromatography on silica gel (hexane/ethyl
acetate, 10:1, v/v) to give a clear oil (0.200 g, 88%). Rf = 0.35. H
NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 6.88 Hz, 2 H, Ar), 7.49
(t, J = 6.88 Hz, 1 H, Ar), 7.41 (t, J = 6.88 Hz, 2 H, Ar), 6.51 (d, J
= 9.16 Hz, 1 H, NH), 5.81 (dd, J1-NH = 10.0, J1-2 = 9.76 Hz, 1 H,
2-(2-Thienyl)-1,3-oxazoline 13c: The crude mixture (0.280 g) was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 6:1–3:1, v/v) to give a white solid (0.190 g, 73%). Rf
= 0.34. H NMR (500 MHz, [D6]acetone): δ = 7.78–7.72 (m, 2 H,
Ar), 7.44 (d, J = 7.0 Hz, 1 H, Ar), 7.37–7.71 (m, 15 H, Ar), 5.98
1
1
1-H), 4.67 (dd, J2-1 = 5.24, J2-3 = 2.76 Hz, 1 H, 2-H), 4.29 (dd, (d, J1-2 = 7.5 Hz, 1 H, 1-H), 4.81–4.75 (m, 3 H, Ph-CH2, 2-H), 4.69
J5-4 = 11.6, J5-6 = 11.4 Hz, 1 H, 5-H), 4.08 (s, 1 H, 4-H), 3.95 (dd, (d, J = 11.5 Hz, 2 H, Ph-CH2), 4.57–4.49 (m, 2 H, Ph-CH2), 3.98
J3-2 = 3.24, J3-4 = 1.20 Hz, 1 H, 3-H), 3.87 (m, 2 H, 6-H), 0.98–
0.84 [m, 27 H, (CH3)3C], 0.23–0.04 (m, 18 H, CH3Si) ppm. 13C 5-H, 6-H), 3.56–3.55 (m, 1 H, 6-H) ppm. 13C NMR (125 MHz,
NMR (100 MHz, CDCl3): δ = 166.75 (C=O), 133.93, 132.00, [D6]acetone): δ = 161.25 (C=N), 138.65, 138.52, 138.31, 131.69,
128.66, 127.32 (Ar), 81.76 (C-3), 73.15 (C-1), 68.85 (C-4), 61.22 (C- 129.45, 128.31, 128.19, 128.14, 128.02, 128.00, 127.74, 127.68,
(dd, J3-2 = 4.5, J3-4 = 4.5 Hz, 1 H, 3-H), 3.73–3.66 (m, 3 H, 4-H,
6), 34.26 (C-2), 26.02, 25.89, 18.39, 18.07 [(CH3)3C], –4.58, –4.65,
–5.17 (CH3Si) ppm. HRMS (MALDI-TOF): calcd. for C31H58I-
NO5Si3 735.2784 [M + Na]+; found 758.2786.
127.65, 127.43, 127.36, 127.77 (Ar), 93.33 (C-1), 78.98 (C-2), 78.72
(C-3), 74.92 (C-5), 72.82 (C-4), 72.56 (C-6), 71.82, 71.30,
70.04 ppm. HRMS (MALDI-TOF): calcd. for C32H31NO5S
541.1923 [M + H]+; found 542.2001.
Compounds 11a and 11b are identical to compounds 14e and 14f
found in Table 2.
2-(2-Pyridyl)-1,3-oxazoline 13d: The crude mixture (0.290 g) was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 6:1–3:1, v/v) to give a clear oil (0.185 g, 71%). Rf =
General Procedure for the Preparation of the α-
[1,3]oxazolines: 3,4,6-Tri-O-benzyl-d-glucal
D
-Glucopyrano[1,2-d]-
(9) (0.200 g,
1
0.30. H NMR (500 MHz, [D6]acetone): δ = 8.62 (d, J = 4.0 Hz, 1
0.48 mmol) was diluted in freshly distilled propionitrile (3.0 mL)
and stirred under N2. The amide (2.88 mmol) was added to the
reaction flask, and the reaction mixture was heated at 45 °C until
it became a homogeneous solution. Then preactivated molecular
sieves (4 Å) in powder form (0.100 g) were added. After 10 min, N-
iodosuccinimide (0.216 g, 0.96 mmol) was added to the reaction
flask while heating at 45 °C. The reaction was monitored by TLC,
and complete disappearance of the starting material was detected
after 2 h. The reaction was quenched with distilled water, and the
mixture was diluted in DCM (50.0 mL). The crude mixture was
filtered and washed with a saturated aqueous solution of Na2S2O3
(100 mL) and distilled water (3ϫ100 mL). The organic layer was
dried with MgSO4, and the solvent was removed in vacuo.
H, Ar), 8.14 (d, J = 7.5 Hz, 1 H, Ar), 8.03–8.0 (m, 1 H, Ar), 7.63–
7.60 (m, 1 H, Ar), 7.44 (d, J = 7.5 Hz, 1 H, Ar), 7.33–7.25 (m, 14
H, Ar), 6.05 (d, J1-2 = 6 Hz, 1 H, 1-H), 5.13–5.11 (m, 1 H, 2-H),
4.76–4.73 (m, 2 H, Ph-CH2), 4.68–4.53 (m, 4 H, Ph-CH2), 3.91 (dd,
J3-2 = 5.5, J3-4 = 5.5 Hz, 1 H, 3-H), 3.87–3.80 (m, 3 H, 4-H, 5-H,
6-H), 3.79–3.76 (m, 1 H, 6-H) ppm. 13C NMR (125 MHz, [D6]-
acetone): δ = 163.71 (C=N), 148.48, 138.82, 138.53, 137.93, 137.75,
128.26, 128.21, 128.16, 128.08, 127.86, 127.83, 127.70, 127.53,
127.51, 127.26, 126.93, 122.36 (Ar), 86.24 (C-1), 78.34 (C-2), 77.31
(C-3), 74.87 (C-5), 74.65 (C-4), 72.93 (C-6), 72.90, 71.66,
68.69 ppm. HRMS (MALDI-TOF): calcd. for C33H32N2O5
536.2311 [M + H]+; found 537.2389.
2-Phenyl-1,3-thiazoline 13e: The crude mixture (0.300 g) was puri-
fied by flash column chromatography on silica gel (hexane/ethyl
acetate, 3:1, v/v) to give a yellowish oil (0.190 g, 72%). Rf = 0.38.
1H NMR (500 MHz, CDCl3): δ = 8.00–7.26 (m, 20 H, Ar), 6.05 (s,
1 H, 1-H), 4.88–4.42 (m, 6 H, Ph-CH2), 4.11 (d, J2-1 = 7.5 Hz, 1
H, 2-H), 3.99 (d, J3-2 = 8.5 Hz, 1 H, 3-H), 3.77 (d, J4-5 = 11 Hz, 1
H, 5-H), 3.68–3.64 (m, 3 H, 4-H, 6-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 138.06, 137.70, 128.61, 128.47, 128.04, 128.01 (Ar),
88.25 (C-1), 73.52 (C-2), 72.78 (C-3), 71.48 (C-5), 60.54 (C-4), 52.10
(C-6), 69.0, 60.54, 52.10 ppm. HRMS (MALDI-TOF): calcd. for
C34H33NO4S 551.2130 [M + H]+; found 552.2209.
2-Phenyl-1,3-oxazoline 13a: The crude mixture (0.355 g) was puri-
fied by flash column chromatography on silica gel (hexane/ethyl
acetate, 6:1–3:1, v/v) to give a clear oil (0.180 g, 70%). Rf = 0.35.
1H NMR (500 MHz, [D6]acetone): δ = 7.99 (d, J = 7.0 Hz, 2 H,
Ar), 7.57 (t, J = 6.5 Hz, 1 H, Ar), 7.50–7.43 (m, 5 H, Ar), 7.39–
7.24 (m, 12 H, Ar), 6.01 (d, J1-2 = 7.0 Hz, 1 H, 1-H), 4.87 (dd,
J2-1 = 5.5, J2-3 = 4.75 Hz, 1 H, 2-H), 4.83–4.77 (m, 2 H, Ph-CH2),
4.75–4.50 (m, 4 H, Ph-CH2), 3.99 (dd, J3-2 = 5.0, J3-4 = 4.5 Hz, 1
H, 3-H), 3.80 (dd, J5-4 = 9.5, J5-6 = 9.0 Hz, 1 H, 5-H), 3.74–3.54
(m, 3 H, 4-H, 6-H) ppm. 13C NMR (125 MHz, [D6]acetone): δ =
165.47 (C=N), 138.90, 138.66, 138.53, 138.37, 132.20, 128.54,
128.45, 128.31, 128.22, 128.20, 128.16, 128.14, 128.00, 127.87,
127.79, 127.77, 127.67, 127.64, 127.58, 127.51, 127.44, 127.36,
2-(Phenylamino)-1,3-oxazoline 13f: The crude mixture (0.315 g) was
purified by flash column chromatography on silica gel (ethyl acet-
127.27, 127.15 (Ar), 93.35 (C-1), 79.05 (C-2), 78.74 (C-3), 76.61 (C- ate/hexane, 2:1, v/v) to give a clear oil (0.183 g, 71%). Rf = 0.44.
5), 76.25 (C-4), 74.97 (C-6), 74.58, 72.90, 72.84, 72.63, 71.86, 71.33,
1H NMR (400 MHz, CDCl3): δ = 11.74 (s, 1 H, NH-Ph), 7.60 (d,
70.12, 70.05, 69.43 ppm. HRMS (MALDI-TOF): calcd. for J = 4.5 Hz, 1 H, Ar), 7.35–7.24 (m, 19 H, Ar), 6.43 (d, J1-2
=
C34H33NO5 535.2359 [M + H]+; found 536.2437.
5.96 Hz, 1 H, 1-H), 4.67–4.63 (m, 3 H, Ph-CH2, 2-H), 4.54 (dd, J
= 11.5, J = 11.0 Hz, 2 H, Ph-CH2), 4.38 (d, J = 14.5 Hz, 1 H, Ph-
CH2), 4.06 (dd, J3-2 = 3.6, J3-4 = 3.2 Hz, 1 H, 3-H), 3.83–3.68 (m,
4 H, 4-H, 5-H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.71, 143.57, 138.21, 137.88, 137.75, 137.29, 128.56, 128.46,
128.14, 128.11, 128.00 (Ar), 119.9 (C-1), 80.21 (C-2), 75.62 (C-3),
74.20 (C-5), 73.72 (C-4), 72.77 (C-6), 72.64, 72.45, 70.0 ppm.
HRMS (MALDI-TOF): calcd. for C34H34N2O5 550.2468 [M +
H]+; found 551.2546.
2-Phenyl-1,3-oxazoline 13b: The crude mixture (0.300 g) was puri-
fied by flash column chromatography on silica gel (hexane/ethyl
acetate, 6:1–3:1, v/v) to give a clear oil (0.150 g, 58%). Rf = 0.37.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 11.0 Hz, 2 H, Ar),
7.40–7.27 (m, 18 H, Ar), 5.97 (d, J1-2 = 5.0 Hz, 1 H, 1-H), 4.82
(dd, J2-1 = 9.15, J2-3 = 8.8 Hz, 1 H, 2-H), 4.93 (dd, J = 14.0, J =
13.5 Hz, 2 H, Ph-CH2), 4.66 (dd, J = 14.1, J = 14.0 Hz, 2 H, Ph-
CH2), 4.45 (dd, J = 13.5, J = 13.0 Hz, 2 H, Ph-CH2), 4.08 (dd,
J3-2 = 6.8, J3-4 = 5.76 Hz, 1 H, 3-H), 4.00 (s, 1 H, 5-H), 3.74–3.67 2-(Dimethylamino)-1,3-oxazoline 13g: The crude mixture (0.300 g)
(m, 3 H, 4-H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.61
was purified by flash column chromatography on silica gel (ethyl
(C=N), 138.48, 137.98, 128.57, 128.48, 128.41, 127.66 (Ar), 93.94 acetate/hexane, 3:1, v/v) to give a white solid (0.180 g, 75%). Rf =
1
(C-1), 79.93 (C-2), 74.73 (C-3), 73.57 (C-5), 73.40 (C-4), 72.86 (C- 0.48. H NMR (400 MHz, CDCl3): δ = 7.31–7.23 (m, 15 H, Ar),
6), 71.56, 68.04, 60.5, 29.80, 21.17, 14.30 ppm. HRMS (MALDI-
6.70 (s, 1 H, 1-H), 4.62–4.32 (m, 8 H, Ph-CH2, 2-H, 3-H), 3.93 (s,
1 H, 5-H), 3.84 (dd, J4-5 = 5.84, J4-3 = 5.52 Hz, 1 H, 4-H), 3.54–
TOF): calcd. for C34H33NO5 535.2359 [M + H]+; found 536.2437.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20130
/KAP1
Date: 02-05-12 18:49:28
Pages: 10
C. H. Marzabadi, M. De Castro et al.
3.48 (m, 2 H, 6-H), 3.00 [s, 6 H, (CH3)2] ppm. 13C NMR (100 MHz, mixture from white to yellow. The reaction was monitored by TLC,
FULL PAPER
CDCl3): δ = 162.37 (C=O), 141.32, 138.29, 138.02, 137.65, 128.49,
127.94 (Ar), 81.0 (C-1), 74.00 (C-2), 73.45 (C-3), 70.76 (C-5), 70.54
and upon disappearance of the starting material the reaction was
quenched with distilled water. The reaction mixture was diluted in
(C-4), 69.00 (C-6), 37.83 (CH3) ppm. HRMS (MALDI-TOF): DCM (50.0 mL) and washed with distilled water (3ϫ100 mL). The
calcd. for C30H34N2O5 502.2468 [M + H]+; found 503.2546.
organic layer was dried with MgSO4, and the solvent was removed
in vacuo. The crude mixture (0.180 g) was purified by flash column
chromatography on silica gel (hexane/ethyl acetate, 7:1, v/v) to give
a white solid (0.140 g, 88%). Rf = 0.41. 1H NMR (400 MHz,
CDCl3): δ = 7.61 (d, J = 3.68 Hz, 1 H, Ar), 7.44 (dd, J = 3.68, J
= 2.58 Hz, 1 H, Ar), 7.06 (dd, J = 3.68, J = 2.55 Hz, 1 H, Ar), 6.11
(d, J1-2 = 6.84 Hz, 1 H, 1-H), 4.19 (dd, J2-1 = 6.88, J2-3 = 1.36 Hz,
1 H, 2-H), 3.73–3.69 (m, 4 H, 3-H, 4-H, 6-H), 3.31 (m, 1 H, 5-H),
0.88–0.81 [m, 27 H, (CH3)3C], 0.11–0.03 (m, 18 H, CH3Si) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.99 (C=N), 130.55, 130.12,
129.90, 127.46 (Ar), 100.00 (C-1), 74.37 (C-2), 70.23 (C-3), 67.46
(C-5), 63.84 (C-4), 25.91, 25.66, 18.36, 17.83, 17.68 [(CH3)3C],
–4.03, –4.55, –4.99, –5.22 (CH3Si) ppm. HRMS (MALDI-TOF):
calcd. for C29H55NO5SSi3 613.3109 [M + H]+; found 614.3187.
2-(2-Pyridyl)-1,3-oxazoline 18a: Compound 14a (0.197 g,
0.26 mmol) was added to a heterogeneous solution of NaH
(14.0 mg, 0.42 mmol) in dry DCM (2.0 mL) under N2. 15-Crown-
5 ether (0.1 mL) was subsequently added, and the mixture was al-
lowed to react at –78 °C for 2 h. Upon addition of the crown ether
fizzing was observed along with a change in color of the reaction
mixture from white to yellow. The reaction mixture was monitored
by TLC, and upon disappearance of the starting material the reac-
tion was quenched with distilled water. The reaction mixture was
diluted in DCM (50.0 mL) and washed with distilled water
(3ϫ100 mL). The organic layer was dried with MgSO4, and the
solvent was removed in vacuo. The crude mixture (0.175 g) was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate, 7:1, v/v) to give a white solid (0.150 g, 91%). Rf =
2-Phenyl-1,3-oxazoline 18d: Compound 14d (0.200 g, 0.27 mmol)
1
was added to
a heterogeneous solution of NaH (14.0 mg,
0.34. H NMR (500 MHz, [D6]acetone): δ = 8.66 (d, J = 4.5 Hz, 1
0.41 mmol) in dry DCM (2.0 mL) under N2. 15-Crown-5 ether
(0.1 mL) was subsequently added, and the mixture was allowed to
react at –78 °C for 2 h. Upon addition of the crown ether fizzing
was observed along with a change in color of the reaction mixture
from white to yellow. The reaction was monitored by TLC, and
upon disappearance of the starting material the reaction was
quenched with distilled water. The reaction mixture was diluted in
DCM (50 mL) and washed with distilled water (3ϫ100 mL). The
organic layer was dried with MgSO4, and the solvent was removed
in vacuo. The crude mixture (0.180 g) was purified by flash column
chromatography on silica gel (hexane/ethyl acetate, 10:1, v/v) to
H, Ar), 8.08 (d, J = 8.0 Hz, 1 H, Ar), 7.91 (dd, J = 4.5, J = 4.0 Hz,
1 H, Ar), 7.52 (dd, J = 3.5, J = 3.2 Hz,1 H, Ar), 6.25 (d, J1-2
=
8.0 Hz, 1 H, 1-H), 4.34 (dd, J2-1 = 2.50, J2-3 = 1.50 Hz, 1 H, 2-H),
4.30 (dd, J3-2 = 1.25, J3-4 = 1.0 Hz, 1 H, 3-H), 3.92 (d, J4-5 = 7.0 Hz,
1 H, 5-H), 3.78–3.73 (m, 3 H, 4-H, 6-H), 0.95–0.82 [m, 27 H,
(CH3)3C], 0.23–0.06 (m, 18 H, CH3Si) ppm. 13C NMR (125 MHz,
[D6]acetone): δ = 161.99 (C=N), 146.64, 143.02, 139.45, 126.23,
122.36 (Ar), 100.17 (C-1), 74.44 (C-2), 72.64 (C-3), 71.32 (C-5),
69.52 (C-4), 68.47 (C-6), 23.0, 22.0, 17.69, 17.46 [(CH3)3C], –5.13,
–5.77, –5.86 (CH3Si) ppm. HRMS (MALDI-TOF): calcd. for
C30H56N2O5Si3 608.3497 [M + H]+; found 609.3575.
1
give a white solid (0.120 g, 73%). Rf = 0.40. H NMR (400 MHz,
CDCl3): δ = 7.95 (d, J = 6.84 Hz, 2 H, Ar), 7.42 (t, J = 6.58, J =
2-Pyrazinyl-1,3-oxazoline 18b: Compound 14b (0.210 g, 0.28 mmol)
was added to
a heterogeneous solution of NaH (14.0 mg,
4.50 Hz, 1 H, Ar), 7.39 (d, J = 7.0 Hz, 2 H, Ar), 6.14 (d, J1-2
=
0.42 mmol) in dry DCM (2.0 mL) under N2. 15-Crown-5 ether
(0.1 mL) was subsequently added, and the mixture was allowed to
react at –78 °C for 2 h. Upon addition of the crown ether fizzing
was observed along with a change in color of the reaction mixture
from white to yellow. The reaction mixture was monitored by TLC,
and upon disappearance of the starting material the reaction was
quenched with distilled water. The reaction mixture was diluted in
DCM (50.0 mL) and washed with distilled water (3ϫ100 mL). The
organic layer was dried with MgSO4, and the solvent was removed
in vacuo. The crude mixture (0.200 g) was purified by flash column
chromatography on silica gel (hexane/ethyl acetate, 6:1, v/v) to give
3.68 Hz, 1 H, 1-H), 4.22 (dd, J2-1 = 1.40, J2-3 = 1.36 Hz, 1 H, 2-
H), 3.74–3.70 (m, 1 H, 3-H), 3.67 (d, J3-4 = 2.72 Hz, 1 H, 4-H)
3.68–3.61 (m, 1 H, 5-H), 3.29–3.25 (m, 2 H, 6-H), 0.98–0.84 [m, 27
H, (CH3)3C], 0.23–0.04 (m, 18 H, CH3Si) ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.32 (C=N), 131.54, 127.29 (Ar), 100.60
(C-1), 74.30 (C-2), 71.85 (C-3), 70.47 (C-5), 67.67 (C-4), 63.91 (C-
6), 18.46, 17.95, 17.78 [(CH3)3C], –3.93, –4.86, –5.08, –5.12 (CH3Si)
ppm. HRMS (MALDI-TOF): calcd. for C31H57NO5Si3 607.3545
[M + H]+; found 608.2984.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of the compounds synthesized.
1
a white solid (0.155 g, 92%). Rf = 0.35. H NMR (400 MHz, [D6]-
acetone): δ = 9.18 (s, 1 H, Ar), 8.72 (d, J = 2.28 Hz, 1 H, Ar), 8.70
(d, J = 2.32 Hz, 1 H, Ar), 6.27 (d, J1-2 = 7.80 Hz, 1 H, 1-H), 4.37
(dd, J2-1 = 1.40, J2-3 = 1.36 Hz, 1 H, 2-H), 4.26 (dd, J3-4 = 6.0,
J3-2 = 1.36 Hz, 1 H, 3-H), 3.72–3.68 (m, 2 H, 4-H, 5-H), 3.35–3.28
(m, 2 H, 6-H), 0.86–0.77 [m, 27 H, (CH3)3C], 0.22–0.01 (m, 18 H,
CH3Si) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 161.83
(C=N), 146.64, 145.02, 144.45, 142.47 (Ar), 101.17 (C-1), 74.44 (C-
2), 71.64 (C-3), 70.32 (C-5), 69.52 (C-4), 67.47 (C-6), 25.50, 25.33,
25.14, 17.69, 17.46 [(CH3)3C], –5.13, –5.77, –5.86 (CH3Si) ppm.
HRMS (MALDI-TOF): calcd. for C29H55N3O5Si3 609.3450 [M +
Na]+; found 632.3455.
Acknowledgments
We thank Dr. Nannette Wachter of the Chemistry Department at
Hofstra University for performing 1D and 2D NMR experiments.
Financial support was provided by Farmingdale State College.
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8
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Date: 02-05-12 18:49:28
Pages: 10
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Received: February 5, 2012
Published Online: ᭿
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9

Job/Unit: O20130
/KAP1
Date: 02-05-12 18:49:28
Pages: 10
C. H. Marzabadi, M. De Castro et al.
FULL PAPER
Carbohydrate Heterocycles
A novel one-pot synthesis of N-glycoox-
azolines, N-glycothiazolines, and N-glyco-
aminooxazolines has been developed based
on the frameworks of the natural products
Allosamidin and Trehazolin. Access to
these constructs was possible by the ad-
dition of heteroaryl amides, thiobenzamide,
and substituted ureas to glycals in the pres-
ence of N-iodosuccinimide and propio-
nitrile at high temperatures.
E. M. Reid, E. S. Vigneau, S. S. Gratia,
C. H. Marzabadi,*
M. De Castro* ................................ 1–10
One-Pot Synthesis of N-Glycooxazolines,
N-Glycoaminooxazolines, and N-Glycothi-
azolines from Glycals
Keywords: Carbohydrates / Heterocycles /
Natural products / Synthetic methods
10
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