Non-biaryl atropisomers derived from carbohydrates. Part 3: Rotational isomerism of sterically hindered heteroaryl imidazolidine-2-ones and 2-thiones

Article abstract of DOI:10.1016/j.tet.2005.06.017

The present work describes in detail the preparation and structural characterization of a series of heteroaryls in which an o,o′-disubstituted phenyl ring is connected through a single C-N bond to a heterocyclic fragment of a chiral imidazolidine-2-one or

Full text of DOI:10.1016/j.tet.2005.06.017

Tetrahedron 61 (2005) 7931–7944
Non-biaryl atropisomers derived from carbohydrates. Part 3:
Rotational isomerism of sterically hindered heteroaryl
imidazolidine-2-ones and 2-thiones*
a,
Martın Avalos, Reyes Babiano, Pedro Cintas, Michael B. Hursthouse, Jose L. Jimenez,
a
a
b
a
´
*
´
´
´
Mark E. Light,b Juan C. Palaciosa and Guadalupe Silveroa
a
´
´
Departamento de Quımica Organica, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 23 December 2004; revised 3 June 2005; accepted 7 June 2005
Available online 5 July 2005
Abstract—The present work describes in detail the preparation and structural characterization of a series of heteroaryls in which an
o,o0-disubstituted phenyl ring is connected through a single C–N bond to a heterocyclic fragment of a chiral imidazolidine-2-one or 2-thione.
As a consequence of hindered rotation, some of these substances exist as stable rotamers at room temperature and can easily be separated and
characterized. Molecular mechanic calculations have also been carried out to evaluate the barriers to rotation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
however, requires the easy preparation, isolation, and
characterization of single molecules, together with an
in-depth understanding of their physical properties.
It is now unnecessary to emphasize the importance of biaryl
atropisomers with a well-defined sense of helicity, as these
substances have found numerous applications in asym-
metric catalysis and materials chemistry.3
A few years ago we introduced a new family of heteroaryl
atropisomers that combine both central and axial chirality.2,8,9
Thus, 1-naphtylimidazolidine-2-thiones appended to an
acyclic sugar fragment with different configurations (1),
exhibit atropisomerism due to hindered rotation around the
C–N bond between the aryl group and the heterocyclic ring.
Compounds 1 can easily be converted into more rigid
structures such as 2 by acid-catalyzed cyclization. However,
the barriers to rotation for compounds 1 and 2 were too low
to allow us their separation at room temperature.
In stark contrast, non-biaryl atropisomers still represent an
underestimated family of chiral conveyors. This concept,
however, is hardly new. Atropisomerism in heterocycles
bearing naphtyl and o-substituted phenyl groups have been
previously reported.4 Anyhow, atroposelective reactions
with this kind of substances are a rather unexplored domain
and offer promising perspectives.5
More recent challenges involving atropisomerism and
conformational control include the design of chiral motors
or switches, which can eventually be incorporated into parts
of data storage units or electronic circuits,6 as well as
the mimicing of allosteric functions characteristic of
biological systems.7
Controlling molecular motion in axially chiral systems,
* See Refs. 1,2.
We have also synthesized a large variety of compounds
featuring structures 3–5 (XZS or O) which bear and ortho-
substituted benzene ring. In all cases and, like 1 and 2, their
barriers to rotation are low and cannot be separated.2 The
Keywords: Atropisomerism; Carbohydrates; Imidazolidines; Molecular
mechanics; Rotational isomers.
*
Corresponding author. Tel.: C34 924 289 382; fax: C34 924 271 149;
e-mail: mavalos@unex.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.017

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7932
Scheme 1. (i) H2O; (ii) 7.
presence of a C]S bond is specially noticeable as this
structural feature largely increases the barrier to rotation,
whereas lower barriers were observed for their oxoanalogs.
The MM2 calculations support these experimental results.
therefore the diastereomeric rotamers could be isolated by
chromatography and/or crystallization, and unequivocally
identified by NMR and X-ray diffraction analyses.
2. Results
2.1. Synthesis of o,o0-disubstituted 1-aryl-(1,2-dideoxy-a-
D-glucofurano)[2,1-d]imidazolidine-2-ones
Our first attempts to prepare o,o0-disubstituted 1-aryl-(1,2-
dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-ones
involved the well-established reaction between 2-amino-2-
deoxy-D-glucopyranose (6) and aryl isocyanates in aqueous
media, followed by acid-catalyzed cyclization of the ureido
derivative.2b,11 Nevertheless, aryl isocyanates bearing large
groups at their ortho positions failed to react with
aminosugars in an aqueous medium owing to steric
hindrance. Under such circumstances, hydrolysis of the
isocyanate occurs leading to the unwanted N,N0-diarylurea.
Thus, for example, the reaction of 6 with 2,6-diisopropyl-
phenyl isocyanate (7) afforded exclusively 1,3-bis(2,6-
diisopropylphenyl)urea (10), through the intermediate
carbamic acid 8, and not the expected ureidosugar
derivative (Scheme 1).
In two consecutive papers we now extend these previous
results to imidazolidine-2-one and 2-thione derivatives
linked to o,o0-disubstituted phenyl rings. Such rotational
isomers10 are stable entities at room temperature, and
Scheme 2. (i) NH3/MeOH; (ii) AcOH 30%, 6; (iii) Ac2O/C5H5N, K20 8C.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7933
Conversely, it is possible to accomplish successfully the
synthesis of o,o0-disubstituted derivatives starting from
1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-a-D-glucopyra-
nose12 (11), thereby facilitating the condensation with aryl
isocyanates in an aprotic solvent and avoiding hydrolysis
side reactions. Following this procedure and using 2,6-
dimethylphenyl, 2,6-dichlorophenyl and 2-chloro-6-methyl-
phenyl isocyanates (13–15), the corresponding arylureido
derivatives 16–18 were obtained (Scheme 2). Although
symmetrically substituted isocyanates 13 and 14 cannot
induce atropisomerism, such derivatives are useful in
determining experimental rotational barriers and have
been employed to optimize the synthetic procedure.
methanol at room temperature provided, after complete
deacetylation, mixtures of the unprotected ureido deriva-
tives 19–21 and the corresponding 5-hydroxyimidazolidine-
2-ones 22–24. The later substances are generated in
different ratios by easy cyclization of ureas 19–21.11 Such
mixtures could not be separated, although were identified by
their spectroscopic data and used in subsequent steps
without purification.
The subsequent treatment of these mixtures with hot
aqueous acetic acid leads to a high-yielding preparation of
the corresponding 1-aryl-(1,2-dideoxy-a-D-glucofurano)
[2,1-d]imidazolidine-2-ones 25–27. The structures of these
compounds are consistent with their elemental analyses,
polarimetric and spectroscopic data, analogous to similar
bicycles.2b,11 The small value of J2,3 (w0 Hz) rules out a
pyranose structure and confirms that 25–27 are glycofura-
noses in which H-2 and H-3 display a trans arrangement. On
the contrary, J1,2 values (O6.2 Hz) show the existence of
cis-fused rings. The 13C NMR spectra show that C-4 (and
not C-5) is the most deshielded signal, a fact also accounting
for the furanoid character of the sugar moiety.
Compounds 16–18 were prepared in good to excellent
yields; however variable amounts of 2-acetamido-3,4,6-tri-
O-acetyl-2-deoxy-D-glucopyranose (12) were often
obtained as by-product. This substance was unequivocally
identified by comparison of its physical properties
and spectroscopic data with an authentic sample13
(see Section 3).
The structures attributed to 16–18 are supported by their
physical, spectroscopic, and polarimetric data, analogous to
those of other per-O-acetylated sugar ureas previously
described.2b,11 IR spectra show both the stretching (3400–
3300 cmK1) and deformation (w1500 cmK1) bands of the
NH group as well as the carbonyl stretching band
(w1690 cmK1), different from the ester carbonyl absorption
(w1750 cmK1). The a-anomeric configuration agrees with
the small value of J1,2 (!4 Hz) and the high values of
optical rotation.
As expected, 1H and 13C NMR spectra for 27 show
duplicated and close signals corresponding to a mixture of
two atropisomers in w2:1 (P:M) ratio,14 which could not be
separated by crystallization. Isolation of these rotamers was
attempted by preparing their per-O-acetyl derivatives. In
this way, treatment of 25–27 with acetic anhydride and
pyridine at K20 8C provided the corresponding 28–30 in
high yields.
1H NMR spectra show the absence of N-acetylation and IR
data for 28 show absorption bands at 3500–3000 cmK1 due
Further treatment of compounds 16–18 with ammonia in
Scheme 3. (i) CH2Cl2, 6; (ii) NH3/MeOH; (iii) Ac2O/C5H5N, K20 8C; (iv) KHCO3/C6H6, 6.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7934
to the presence of water in the crystal lattice.15 Again, NMR
spectra show 30 as a mixture of M and P atropisomers, each
separated by preparative chromatography (benzene–acetone
3:1) and crystallized from ethanol. The absolute configura-
tion of 30P was determined by X-ray diffraction analysis.1,16
by treatment of compound 34 with a saturated solution of
ammonia in methanol at room temperature. The H NMR
1
spectrum of a crude sample of 35 showed a mixture of two
M:P rotamers in a 70:30 ratio.16 Both of them presented R
absolute configuration at C-5 as it could be inferred from the
small values of J4,5 (w0 Hz) upon the addition of D2O.2b,8,11
Compound 35 could be characterized by treatment with
acetic anhydride and pyridine at low temperature to afford
the per-O-acetyl derivative 36 in almost quantitative yield
and, as mixture of two atropisomers again. The major
rotamer 36P could be isolated by fractional crystalliza-
tion.16 The small value of J4,5 (1.4 Hz) reveals that
configuration at C-5 should be R.
2.2. Synthesis of o,o0-disubstituted 1-aryl-(1,2-dideoxy-a-
D-glucofurano)[2,1-d]imidazolidine-2-thiones
Initially we followed a synthetic pathway analogous to that
described for aryl ureido derivatives, but using the protected
amino sugar 31 as starting material,17 in order to avoid the
formation of compound 12. Condensation at room tempera-
ture with 2-chloro-6-methylphenyl isothiocyanate (33)
allowed the preparation of thioureido derivative 34 (Scheme
3). When the reaction was carried out under reflux,
significant amounts of 2-acetamido-1,3,4,6-tetra-O-acetyl-
2-deoxy-b-D-glucopyranose (32) were formed. This sub-
stance was identified by comparison of its physical and
spectroscopic properties with an authentic sample.18
Following the procedure previously described in one of our
former works2a and starting from the atropisomeric mixture
of 36M and 36P, compound 37 was obtained by acetic acid
elimination as a mixture of two rotamers (85:15). The major
rotamer 37P16 was isolated by fractional crystallization in
42% yield. Treatment of this atropisomer with a saturated
solution of ammonia in methanol gave the corresponding
deprotected P rotamer 3816 (Scheme 4). Again, the
structures assigned to 36–38 are supported by their spectral
data and elemental analyses.
Pure imidazolidine-2-thione 35 was obtained in high yield
Since compound 35 represents a salient precursor en route
to the bicyclic imidazolidine-2-thiones we are aiming
to obtain, a more direct synthetic route was attempted.
o,o0-Disubstituted aryl isocyanates with large groups failed
to react with aminosugars in an aqueous medium due to the
hydrolysis of isocyanate. However, reactions with aryl
isothiocyanates can advantageously be conducted in the
presence of water because the competing hydrolysis
proceeds slowly. The direct condensation between
o,o0-disubstituted aryl isothiocyanates and 6 in ethanol–
water proved to be completely satisfactory. Thus,
Scheme 4. (i) NH3/MeOH.
Scheme 5. (i) 2-Cl-6-RC6H3NCS; (ii) Ac2O, C5H5N, K20 8C; (iii) AcOH 30%, 6, (iv) Ac2O, C5H5N, 40 8C.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7935
compounds 35 and 40 were obtained in high yields when
reaction between 6 and 2-chloro-6-methylphenyl isothio-
cyanate (33) or 2,6-dichlorophenyl isothiocyanate (39) took
place (Scheme 5). Although the symmetrically disubstituted
derivative 40 does not allow atropisomerism, this conden-
sation was carried out to test the feasibility of the process.
The structure attributed to 40 was further characterized as its
per-O-acetyl counterpart 41.
chromatography (ethyl acetate- n-hexane 1:2), followed by
treatment with saturated solution of ammonia in methanol
at room temperature, afforded the corresponding pure
1
atropisomers 42M and 42P. H and 13C NMR spectra for
these two rotamers showed a single signal set, thereby
evidencing that the axial chirality in atropisomers of
compound 44 remained unaffected by deacetylation. The
absolute configurations of 42M and 42P could be
unambiguously determined by single-crystal X-ray diffrac-
tometry as depicted in their ORTEP diagrams with the
crystallographic numbering (Figs. 1 and 2).19
Treatment of 35 or 40 with hot aqueous acetic acid resulted
in high yields of the corresponding 1-aryl-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]imidazolidine-2-thiones 42 or 43,
respectively. The structure assigned to these compounds is
consistent with their spectroscopic data and elemental
analyse. Compound 42 was found to be an unequal mixture
of two atropisomers as revealed by NMR analyses. The
major atropisomer 42P was isolated after several crystal-
lizations from 96% aqueous ethanol.16 Compounds 42 and
43 could be characterized as their acetylated derivatives 44
and 45, which were prepared by reaction with acetic
anhydride and pyridine at K20 8C.
Since all attempts to crystallize 45 were unsuccessful, this
product was transformed into the N-acyl derivative 46
running the acetylation at 40 8C.20 The IR spectra of 46
1
exhibits the amide band at 1675 cmK1 and its H and 13C
NMR spectra show the characteristic chemical shifts at 2.92
and 27.1 ppm, respectively, due to the N-Ac methyl group.
A comparison of the optical rotations of compounds 45 and
46 indicates that N-acetylation causes a significant decrease
of w288.20
Isolation of M and P rotamers of 44 by flash
3. Discussion
As mentioned, condensation of 2-amino-2-deoxy-D-gluco-
pyranose (6) with o,o0-disubstituted aryl isocyanates is more
difficult than when monosubstituted aryl isocyanates are
employed. On the other hand, with less reactive isothio-
cyanates, the direct condensation between 6 and o,o0-
disubstituted aryl isothiocyanates was successfully carried
out in aqueous media.
When 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-a-D-gluco-
pyranose12 (11) is used in an aprotic solvent, hydrolysis of
isocyanate is avoided and the expected ureidosugars are
formed. However, 2-acetamido-3,4,6-tri-O-acetyl-D-gluco-
pyranose (12) is often obtained from 11, probably due to an
intramolecular migration of the acetyl group located at the
anomeric position to the free amine group at C-2, through
the intermediate 47 (Scheme 6). The rationale appears to be
plausible as reactions employing the b-anomer 31 were not
contaminated with 12. The trans relationship between the
anomeric acetate and the amino group at C-2 avoids the
rearrangement because intermediate 48 is more strained and
therefore less stable than 47.21
Figure 1. X-ray diffraction analysis of compound 42P.
These results along with the extensive formation of
2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-b-D-gluco-
pyranose (32) in reactions at reflux, show that steric effects
play a key role and undesirable reactions such as the
rearrangement of 11 to 12 or the formation of 32 from 31 are
favored.
Figure 2. X-ray diffraction analysis of compound 42M.
It is interesting to point out that the thioureido derivative 34
Scheme 6.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7936
Figure 3. (A) 1H NMR spectrum of 34 at K30 8C. (B) Amplified area of anomeric protons in the 1H NMR spectrum. (C) D2O exchange experiment. (D), (E)
and (F) Amplified area of urea carbonyl groups, some aromatic carbons and anomeric carbons peaks, respectively, in the 13C NMR spectrum of 34 at K23 8C.
Table 1. Selected spectroscopic data and population for rotamers of 34a
Rotamer
NH
H-1
J1,2
C-1
C]O
Population (%)b
a
b
c
8.65
8.56
7.94
7.78
5.65
5.59
5.87
5.88
7.6
8.4
8.8
8.8
91.88
91.53
92.79
92.66
139.93
139.36
139.16
139.60
38.9
42.2
7.6
d
11.4
a In CDCl3.
b From digital integration of 1H NMR signals at 250 K.
has an important barrier to rotation. The 1H NMR spectrum
at room temperature showed broad signal sets. When this
spectrum was recorded at 60 8C all signals coalesced, while
at K30 8C they were split into four, corresponding to a
complex conformational equilibrium (Fig. 3). Some
spectroscopic data as well as the relative populations
observed at K30 8C for the four rotamers are showed in
Table 1.
possible conversion among the different conformers are
reduced to eight (Fig. 4).
Of such conformers, the more stable ones are depicted in
Scheme 7 and show a less steric hindrance. Rotamers a and
b should correspond to ZZM and ZZP geometries, as these
would show similar chemical shifts for NH, H-1 and C-1.
On the same way, geometries ZEM and ZEP would
correspond to rotamers c and d. In addition, NHc and NHd
peaks collapse at 9 8C (TcZ282 K) and NHa and NHb at
19 8C (TcZ292 K). The barriers to rotation calculated from
these data and the difference in frequency units (Hz)
between the NH signals for c and d (DnZ61.20 Hz) and for
a and b (DnZ35.20 Hz) in the spectrum recorded at low
temperature are 13.7 and 14.6 kcal molK1, respectively.23
Both barriers are of the same order and should correspond to
conversion between M and P atropisomers. A more accurate
study on these equilibria lie beyond the scope of the present
study and will be subject of future research.
Considering that H-2 and the NH bonded to C-2 always
show an antiperiplanar disposition, as it has been previously
described for other sugar-based ureas and thioureas,22 the
Both ureido and thioureido compounds (49, XZO or S)
were deacetyled by treatment with a saturated solution of
ammonia in methanol to give the unprotected derivatives 50
(XZO or S) and hence the corresponding imidazolidine-2-
ones and 2-thiones 51 (XZO or S). These substances were
Figure 4. Diagram showing the interconversion of ureido and thioureido
conformers.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7937
carbohydrate moiety, and nature of substituents at the ortho
position of the aromatic ring.
Free rotation around a single bond converts the M (aR)
isomer into its P (aS) counterpart and vice versa.14 Such
an interconversion takes place by rotation around the
N–C(aryl) single bond and the corresponding transition
states are the peaks of highest potential energy through a
3608 rotation. The potential energy was determined by
means of molecular mechanics (MM2) calculations.25,26
Starting from the P isomer, which is a conformation of low
potential energy, rotation of the dihedral angle q [C(sp3)
N
–
(sp2)–C(sp2)–C(sp2)] at 308 intervals gives rise to a
conformational energy diagram for the interconversion of
atropisomers. A further refinement was also accomplished
to determine the conformations when the energy is at a
maximum, simply by rotation of the angle of torsion every
58 within the interval between K30 and C308 around the
maxima previously reached. It was found that the
conformations of lower potential energy corresponded to
dihedral angles of w908 (EP) and w2708 (EM). The points
of higher potential energy are observed at w08 (Esmin) and
w1808 (Esmax) due to coplanarity of both the aromatic ring
and the heterocyclic moiety. All of the studied cases showed
barriers to rotation too low to make it possible to isolate
rotational isomers at room temperature.2
Scheme 7. Stable rotamers of (thio)ureido derivatives (priority order
according to Cahn–Ingold–Prelog rules: YOZ).
later transformed into bicyclic structures 52, under mild acid
catalysis (Scheme 8). These results support the mechanism
previously proposed for these transformations.9,11
Structures 51 and 52 with different substituents at both ortho
positions could be resolved as stable atropisomers and fully
characterized. The same fact happens with the imidazoline-
2-thione derivatives 37 and 38, suggesting that the
substituent at C-5 does not affect markedly the magnitude
of the barrier to rotation. This value is due exclusively to the
interactions between an ortho substituent and either O or S
atoms at C-2.2 When both ortho substituents have different
sizes, one should expect a large atropisomeric ratio, as it
happens with Cl and methyl group, a fact in agreement with
the magnitude of their steric parameters: EsZK0.97 for
chlorine and EsZK1.24 for the methyl group.24
However, molecular mechanics calculations predicted that
o,o0-disubstitution will cause high enough barriers to
rotation to allow isolation of atropisomers. According to
our theoretical results for compounds 25–27 and their
thioanalogous 42, 43 and 53, it will be possible to have
barriers to rotation higher than 23 kcal molK1 and hence
rotamer separation at room temperature,27 when the
aromatic ring bears two substituents at the ortho positions.
In this situation there will always be an important steric
interaction between either substituent and the C]X group
in both transition structures, 54 or 55 (Table 2).
However, the presence of two substituents at the ortho
positions moved the peaks of higher potential energy from
qZ0 and 1808 to qZ30 and 2108, respectively. As an
example, the potential energy diagram (MM2) for 53 is
shown in Figure 5.
In previous papers we have described an experimental and
theoretical study on several heteroaryl imidazolidine-2-
one(thione) and imidazoline-2-thione derivatives with
hindered rotation around a single bond.2 Some structural
variations were evaluated such as length of bond types,
C]O versus C]S; nature of substituents at C-5; cis or
trans stereochemistry between the heterocyclic ring and the
In order to confirm the above-mentioned predictions we
have studied the thermal stability of the isolated
Scheme 8. (i) ArNCX; (ii) NH3/MeOH; (iii) pH R7; (iv) AcOH 30%, 6.

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7938
Barriers to rotation (kcal molK1 a,b
)
for 25–27, 42, 43 and 53
Table 2.
Compound
EM
EP
DH‡min
DH‡max
DDH‡
DH8
25
26
27
42
43
53
23.60
25.36
36.48
34.85
0.00
0.00
4.38
5.18
0.00
0.00
0.00
0.00
0.13
0.10
0.00
0.00
24.39
24.87
24.52
24.74
30.31
37.91
34.69
43.09
25.73
23.94
42.36
50.35
a Determined by MM2.
b EM or EP denotes the potential energy of M or P conformers; Em‡ in (Em‡ ax) is the potential energy for the transition structure of the lowest (highest) energy;
DHm‡ in (DHm‡ ax)ZE‡ (E‡max)KEP; DDH‡ZDH‡max-DH‡min; DH8ZjEMKEPj; 1 kcalZ4.18 kJ.
min
predictions were found to be correct by a successful
synthesis and isolation of these sort of compounds.
4. Experimental
4.1. General methods
All solvents were purchased from commercial sources and
used as received unless otherwise stated. Melting points
were determined on Gallenkamp and Electrothermal
apparatus and are uncorrected. Analytical and preparative
TLC were performed on precoated Merck 60 GF254 silica
gel plates with a fluorescent indicator, and detection by
means of UV light at 254 and 360 nm and iodine vapors.
Flash chromatography29 was performed on Merck 60 silica
Figure 5. Plot of potential energy versus the angle of torsion for 53 (MM2
gel (230–400 mesh). Optical rotations were measured at the
calculations).
sodium line (589 nm) at 20G2 8C on a Perkin–Elmer 241
polarimeter. IR spectra were recorded in the range 4000–
600 cmK1 on Perkin–Elmer 399 or a FT-IR MIDAC
spectrophotometers. Solid samples were recorded on KBr
(Merck) pellets. 1H and 13C NMR spectra were recorded on
a Bruker 400 AC/PC instrument at 400 and 100 MHz,
respectively, or with a Bruker AC 200-E instrument at 200
and 50.3 MHz, respectively, in different solvent systems.
Assignments were confirmed by homo- and hetero-nuclear
double-resonance, DEPT (distortionless enhancement by
polarization transfer), and variable temperature experi-
ments. TMS was used as the internal standard (dZ
0.00 ppm) and all J values are given in Hz. Microanalyses
were determined on a Leco 932 analyser at the Universidad
atropisomers, using NMR techniques. All atropisomers are
stable at room temperature as they did not show any change
for a period of three weeks in DMSO-d6. Furthermore,
imidazolidine-2-thione derivatives 36P, 42P, 42M, 44P and
44M were heated for 4 h in DMSO-d6 at 160 8C, and in
some cases decomposition was observed but not the
interconversion between atropisomers.
Experiments of dynamic NMR were conducted for some
atropisomeric mixtures of 27, 30, 35, 42 and 44. Neither of
such mixtures coalesced under heating up to 150 8C. This
temperature (TcO423 K) and the chemical shifts for
analogous signals in each pair of atropisomers at room
temperature, allowed us to establish a threshold value of
20–22 kcal molK1 for their barriers to rotation,23,28 in total
agreement with our theoretical data obtained by MM2.
`
de Extremadura (Spain), and by the Servei de Microanalisi
del CSIC at Barcelona (Spain), and the Instituto de Investi-
´
gaciones Quımicas del CSIC at Sevilla (Spain). High
resolution mass spectra (chemical ionization) were recorded
on a VG Autospec spectrometer by the Servicio de Espectro-
´ ´
metrıa de Masas de la Universidad de Cordoba (Spain).
In conclusion, we have reported that MM2 calculations
predict the possibility of obtaining room-temperature stable
non-biaryl rotamers derived from carbohydrates. These
4.1.1. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2,6-dimethyl-
phenyl)ureido]-a-D-glucopyranose (16). To a solution of

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7939
1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-a-D-glucopyra-
nose12 (11) (0.35 g, 1.0 mmol) in dichloromethane (5 mL)
was added 2,6-dimethylphenyl isocyanate, 13 (1.0 mmol).
The reaction was controlled by TLC (benzene–methanol
3:1). After three days the mixture was evaporated to dryness
and the residue was crystallized from ethanol 96% giving 16
(83%), mp 196–198 8C, [a]D C108.5 (c 0.5, CHCl3); nmax
3600–3200 (H2O, NH)15, 1540 (NH), 1740 (C]O), 1220
(C–O–C), 1630 (NC]O), 1030, 1000 (C–O), 755 cmK1
CO), 18.3 (CH3). Anal. Calcd for C22H27ClN2O10: C, 51.32;
H, 5.29; N, 5.44. Found: C, 51.35; H, 5.36; N, 5.59.
4.1.4. 1-(2,6-Dimethylphenyl)-(1,2-dideoxy-a-D-gluco-
furano)[2,1-d]imidazolidine-2-one (25). To a solution of
1,3,4,6-tetra-O-acetyl-2-deoxy-2-[3-(2,6-dimethylphenyl)-
ureido]-a-D-glucopyranose, 16, (0.5 g, 1.0 mmol) in metha-
nol (16 mL), was added a saturated solution of ammonia in
methanol (16 mL). The reaction was controlled by TLC
(chloroform–methanol 3:1). After ten hours at room
temperature the mixture was evaporated to dryness and
the residue treated with acetic acid (15 mL), and heated at
w100 8C (external bath) for 30 min. The solution was
evaporated to dryness and the resulting solid was crystal-
lized from 96% aqueous ethanol affording 25 (0.17 g, 55%),
mp 245–247 8C, [a]D C96.5 (c 0.5, DMF); nmax 3480, 3380,
3250 (OH, NH), 1470 (NH), 1660 (C]O), 1080, 1030 (C–
O), 1580, 790, 780 cmK1 (aromatics); 1H NMR (400 MHz,
DMSO-d6) d 7.21 (d, J2,NHZ1.2 Hz, 1H, NH), 7.15–7.07
(m, 3H, Ar), 5.65 (d, J1,2Z6.2 Hz, 1H, H-1), 5.21 (d,
J3,OHZ4.8 Hz, 1H, C3–OH), 4.72 (d, J5,OHZ6.0 Hz, 1H,
1
(aromatics); H NMR (400 MHz, CDCl3) d 7.30–7.10 (m,
3H, Ar), 6.98 (bs, 1H, Ar–NH), 6.15 (d, J1,2Z2.8 Hz, 1H,
H-1), 5.15–5.04 (m, 3H, NH, H-3, H-4), 4.34 (m, 1H, H-2),
0
4.20 (dd, J5,6Z4.1 Hz, J6,6 Z12.5 Hz0, 1H, H-6), 4.01 (dd,
0
0
J5,6 Z2.0 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 3.90 (m, 1H, H-5),
2.19 (s, 6H, CH3), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc),
2.02 (s, 3H, OAc), 1.99 (s, 3H, OAc); 13C NMR (100 MHz,
CDCl3) d 170.8 (CH3–CO), 170.5 (CH3–CO), 169.0 (CH3–
CO), 168.4 (CH3–CO), 156.0 (NH–CO–NH), 137.0 (2C),
133.2 (2C), 128.5 (2C) (aromatics), 90.7 (C-1), 70.4 (C-3),
69.5 (C-5), 67.5 (C-4), 61.4 (C-6), 51.3 (C-2), 20.5 (2C,
CH3–CO), 20.4 (2C, CH3–CO), 17.8 (2C, CH3). Anal. Calcd
for C23H30N2O10$1/2 H2O: C, 54.87; H, 6.20; N, 5,56.
Found: C, 54.98; H, 6.15; N, 5.62.
0
C5–OH), 4.45 (t, J6,OHZJ6 ,OHZ5.6 Hz, 1H, C6–OH),
4.10–4.07 (m, 2H, H-2, H-3), 3.86 (dd, J3,4Z2.2 Hz,
J4,5Z8.6 Hz, 1H, H-4), 3.72 (m, 1H, H-5), 3.55 (m, 1H,
H-6), 3.34 (m, 1H, H-60), 2.18 (s, 3H, CH3), 2.12 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) d 158.3 (C]O),
139.0, 136.7, 135.5, 128.2, 128.1, 127.8 (aromatics), 91.1
(C-1), 79.7 (C-4), 74.5 (C-3), 68.8 (C-5), 64.1 (C-6), 61.8
(C-2), 18.4 (CH3), 17.7 (CH3). Anal. Calcd for C15H20N2O5:
C, 58.43; H, 6.54; N, 9.09. Found: C, 58.09; H, 6.64; N,
9.19.
4.1.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2,6-dichloro-
phenyl)ureido]-a-D-glucopyranose (17). From 2,6-
dichlorophenyl isocyanate (14) and following the above
procedure, 17 was obtained (87%), mp 172–175 8C, [a]D
C77 (c 0.5, CHCl3); nmax 3320, 1540 (NH), 1730 (C]O),
1210 (C–O–C), 1635 (NC]O), 1030, 1000 (C–O),
760 cmK1 (aromatics); 1H NMR (400 MHz, CDCl3) d
7.30–7.06 (m, 4H, Ar, Ar–NH), 6.24 (d, J1,2Z3.7 Hz, 1H,
H-1), 5.40 (bs, 1H, NH), 5.22 (m, 2H, H-3, H-4), 4.41 (ddd,
J1,2Z3.7, J2,NH Z10.2 Hz, J2,3Z9.1 Hz, 1H, H-2), 4.24
4.1.5. 1-(2,6-Dichlorophenyl)-(1,2-dideoxy-a-D-gluco-
furano)[2,1-d]-imidazolidine-2-one (26). From 17 and
following the procedure described for 25, compound 26
was obtained (95%), mp 255–257 8C, [a]D C89.0 (c 0.5,
DMF); nmax 3300 (OH, NH), 1470 (NH), 1695 (C]O),
0
(dd, J5,6Z4.4 Hz, J6,6 Z12.4 Hz, 1H, H-6), 4.05 (m, 1H,
H-60), 3.99 (m, 1H, H-5), 2.18 (s, 3H, OAc), 2.07 (s, 3H,
OAc), 2.03 (s, 3H, OAc), 2.02 (s, 3H, OAc); 13C NMR
(100 MHz, CDCl3) d 171.4 (CH3–CO), 170.7 (CH3–CO),
169.1 (CH3–CO), 168.7 (CH3–CO), 154.7 (NH–CO–NH),
134.3, 131.9, 128.4 (4C) (aromatics), 90.9 (C-1), 70.5 (C-3),
69.6 (C-5), 67.6 (C-4), 61.8 (C-6), 51.7 (C-2), 20.7 (CH3–
CO), 20.6 (2C, CH3–CO), 20.4 (CH3–CO). Anal. Calcd for
C21H24Cl2N2O10: C, 47.12; H, 4.52; N, 5.23. Found: C,
47.00; H, 4.55; N, 5.15.
1
1080, 1020, 1010 (C–O), 775 cmK1 (aromatics); H NMR
(400 MHz, DMSO-d6) d 7.59–7.40 (m, 4H, Ar, NH), 5.79
(d, J1,2Z6.4 Hz, 1H, H-1), 5.23 (d, J3,OHZ5.1 Hz, 1H, C3–
OH), 4.74 (d, J5,OHZ5.9 Hz, 1H, C5–OH), 4.41 (t, J6,OH
J6 ,OHZ5.6 Hz, 1H, C6–OH), 4.11 (d, J1,2Z6.5 Hz, 1H,
Z
0
H-2), 4.07 (m, 1H, H-3), 3.93 (dd, J3,4Z2.0 Hz, J4,5
Z
8.7 Hz, 1H, H-4), 3.78 (m, 1H, H-5), 3.53 (m, 1H, H-6),
3.33 (m, 1H, H-60); 13C NMR (100 MHz, DMSO-d6) d
157.0 (C]O), 137.1, 134.9, 132.7, 130.6, 129.2, 128.9
(aromatics), 89.9 (C-1), 80.2 (C-4), 74.6 (C-3), 68.9 (C-5),
64.5 (C-6), 62.2 (C-2). Anal. Calcd for C13H14Cl2N2O5: C,
44.72; H, 4.04; N, 8.02. Found: C, 44.59; H, 4.10; N, 7.87.
4.1.3. 1,3,4,6-Tetra-O-acetyl-2-[3-(2-chloro-6-methyl-
phenyl)ureido]-2-deoxy-a-D-glucopyranose (18). From
2-chloro-6-methylphenyl isocyanate (15) and following
the described procedure, 18 was obtained (99%), mp 162–
165 8C, [a]D C100 (c 0.5, CHCl3); nmax 3340, 3270, 1550
(NH), 1740 (C]O), 1230 (C–O–C), 1645 (NC]O), 1050,
4.1.6. 1-(2-Chloro-6-methylphenyl)-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]-imidazolidine-2-one (27). From 18
and following the procedure described for 25, compound 27
was obtained (83%) as mixture of rotamers with a 35:65
(M:P) ratio, mp 252–254 8C, [a]D C87.5 (c 0.5, DMF); nmax
3480, 3380, 3250 (OH, NH), 1475 (NH), 1660 (C]O),
1
1015 (C–O), 770 cmK1 (aromatics); H NMR (400 MHz,
CDCl3) d 7.31–7.10 (m, 3H, Ar), 7.01 (s, 1H, ArNH), 6.21
(d, J1,2Z3.6 Hz, 1H, H-1), 5.22–5.14 (m, 3H, NH, H-3,
0
H-4), 4.39 (m, 1H, H-2), 4.22 (dd, J5,6Z4.3 Hz, J6,6
Z
0
0
12.5 Hz, 1H, H-6), 4.04 (dd, J5,6 Z2.1 Hz, J6,6 Z12.4 Hz,
1H, H-60), 3.96 (m, 1H, H-5), 2.23 (s, 3H, CH3), 2.11 (s, 3H,
OAc), 2.07 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.01 (s, 3H,
OAc); 13C NMR (100 MHz, CDCl3) d 171.2 (CH3–CO),
170.6 (CH3–CO), 169.0 (CH3–CO), 168.5 (CH3–CO), 155.4
(NH–CO–NH), 139.0, 133.0, 132.3, 129.3, 128.3, 127.3
(aromatics), 90.8 (C-1), 70.4 (C-3), 69.5 (C-5), 67.5 (C-4),
61.6 (C-6), 51.7 (C-2), 20.5 (2C, CH3–CO), 20.4 (2C, CH3–
1
1080, 1030, (C–O), 1585, 790, 780 cmK1 (aromatics); H
NMR (400 MHz, DMSO-d6) d 7.40–7.16 (m, 8H, Ar, NH,
M and P), 5.73 (d, J1,2Z6.4 Hz, 1H, H-1, M), 5.71 (d, J1,2
Z
6.3 Hz, 1H, H-1, P), 5.24 (d, J3,OHZ5.2 Hz, 1H, C3–OH,
M), 5.19 (d, J3,OHZ4.8 Hz, 1H, C3–OH, P), 4.73 (d,
J5,OHZ6.2 Hz, 1H, C5–OH, M), 4.70 (d, J5,OHZ5.8 Hz, 1H,
0
C5–OH, P), 4.46 (t, J6,OHZJ6 ,OHZ5.6 Hz, 1H, C6–OH,

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7940
0
M), 4.38 (t, J6,OHZJ6 ,OHZ5.7 Hz, 1H, C6–OH, P), 4.08
(m, 4H, H-2, H-3, M and P), 3.94 (dd, J3,4Z2.2 Hz, J4,5
1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-one
(30). From 27 and following the procedure described for 28,
the titled compound 30 was obtained as a mixture of
rotamers in a w1:3 (M: P) ratio (88%). Both rotamers were
isolated by preparative TLC (benzene–acetone 3:1). After
extracting silica-gel with ethyl acetate and evaporating to
dryness, they were crystallized from 96% aqueous ethanol.
Z
8.7 Hz, 1H, H-4, P), 3.87 (dd, J3,4Z2.2 Hz, J4,5Z8.7 Hz,
1H, H-4, M), 3.72 (m, 2H, H-5, M and P), 3.55 (m, 2H, H-6,
M and P), 3.33 (m, 2H, H-60, M and P), 2.24 (s, 3H, CH3,
M), 2.20 (s, 3H, CH3, P); 13C NMR (100 MHz, DMSO-d6) d
157.9 C]O, (M), 157.6 C]O, (P), 141.9, 139.8, 135.6,
133.7, 133.2, 129.6, 129.5, 129.3, 127.6, 127.5 (aromatics),
90.7 C-1 (M), 90.2 C-1 (P), 80.2 C-4 (P), 79.8 C-4 (M), 74.7
C-3 (P), 74.4 C-3 (M), 69.0 C-5 (P), 68.6 C-5 (M), 64.7 C-6
(P), 64.1 C-6 (M), 62.1 C-2 (M), 62.0 C-2 (P), 18.5 CH3
(M), 18.0 CH3 (P). Anal. Calcd for C14H17ClN2O5: C,
51.15; H, 5.21; N, 8.52. Found: C, 51.00; H, 5.24; N, 8.45.
Compound 30P. Cubic transparent crystals, mp 193–196 8C,
[a]D C93.5 (c 0.5, CHCl3), RfZ0.3 (benzene–acetone 3:1);
nmax 3390 (NH), 1740 (C]O), 1690 (NC]O), 1220 (C–O–
C), 1070, 1045, 1030 (C–O), 1590, 1560, 1470, 780, 750,
710 cmK1 (aromatics); 1H NMR (400 MHz, CDCl3) d 7.35–
7.18 (m, 3H, Ar), 5.85 (d, J1,2Z6.4 Hz, 1H, H-1), 5.80 (d,
J2,NH Z1.6 Hz, 1H, NH), 5.33 (d, J3,4Z2.8 Hz, 1H, H-3),
5.24 (m, 1H, H-5), 4.74 (dd, J3,4Z2.8 Hz, J4,5Z9.4 Hz, 1H,
4.1.7. 1-(2,6-Dimethylphenyl)-(3,5,6-tri-O-acetyl-1,2-
dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-one
(28). To a solution of 1-(2,6-dimethylphenyl)-(1,2-dideoxy-
a-D-glucofurano)[2,1-d]imidazolidine-2-one, 25 (0.8 g,
2.6 mmol) in pyridine (10.0 mL), cooled at K20 8C, was
added acetic anhydride (8.0 mL) and the reaction mixture
was kept at that temperature for 12 h. Then it was poured
into ice-water and the resulting solid was filtered and
washed with cold water and identified as 28 (0.8 g, 71%).
Recrystallized from 96% aqueous ethanol it had mp 230–
232 8C, [a]D C116.0 (c 0.5, CHCl3); nmax 3600–3100 (H2O,
NH),15 1435 (NH), 1750 (C]O), 1710 (NC]O), 1230
0
H-4), 4.56 (dd, J5,6Z2.4 Hz, J6,6 Z12.3 Hz, 1H, H-6), 4.29
(dd, J2,NH Z2.2 Hz, J1,2Z6.4 Hz, 1H, H-2), 4.04 (dd,
0
0
0
J5,6 Z5.6 Hz, J6,6 Z12.3 Hz, 1H, H-6 ), 2.27 (s, 3H, CH3),
2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.03 (s, 3H, OAc); 13C
NMR (100 MHz, CDCl3) d 170.7 (CH3–CO), 169.9 (CH3–
CO), 169.7 (CH3–CO), 157.7 (C]O), 138.8, 135.8, 132.1,
129.6, 129.5, 128.2 (aromatics), 90.9 (C-1), 76.3 (C-3), 76.0
(C-4), 67.7 (C-5), 63.2 (C-6), 60.5 (C-2), 20.8 (2C, CH3–
CO), 20.7 (CH3–CO), 18.2 (CH3). Anal. Calcd for
C20H23ClN2O8: C, 52.81; H, 5.10; N, 6.16. Found: C,
52.80; H, 5.06; N, 6.19.
(C–O–C), 1030, (C–O), 1580, 1470, 770 cmK1; H NMR
1
(200 MHz, CDCl3) d 7.20–7.10 (m, 3H, Ar), 6.13 (d,
J2,NHZ1.8 Hz, 1H, NH), 5.80 (d, J1,2Z6.4 Hz, 1H, H-1),
5.36 (d, J3,4Z2.8 Hz, 1H, H-3), 5.20 (m, 1H, H-5), 4.59 (m,
Compound 30M. Needle shaped crystals, mp 170 8C, [a]D
C109 (c 0.5, CHCl3), RfZ0.4 (benzene- acetone 3:1), nmax
3300 (NH), 1730 (C]O), 1690 (NC]O), 1230 (C–O–C),
2H, H-4, H-6), 4.29 (dd, J1,2Z6.4, J2,NHZ2.3 Hz, 1H, H-2),
1
1040 (C–O), 1590, 1570, 1480, 750 cmK1 (aromatics); H
0
0
0
4.04 (dd, J5,6 Z4.3 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.32 (s,
3H, CH3), 2.20 (s, 3H, CH3), 2.08 (s, 3H, OAc), 2.07 (s, 3H,
OAc), 2.03 (s, 3H, OAc); 13C NMR (100 MHz, CDCl3) d
170.6 (CH3–CO), 169.8 (CH3–CO), 169.7 (CH3–CO), 158.9
(C]O), 138.8, 136.2, 133.8, 128.9, 128.7 (2C) (aromatics),
92.1 (C-1), 75.8 (C-3), 75.7 (C-4), 67.6 (C-5), 62.9 (C-6),
60.5 (C-2), 20.8 (2C, CH3–CO), 20.7 (CH3–CO), 18.4
(CH3), 18.0 (CH3). Anal. Calcd for C21H26N2O8$1⁄2H2O: C,
56.88; H, 6.14; N, 6.32. Found: C, 56.56; H, 5.98; N, 5.92.
NMR (400 MHz, CDCl3) d 7.33–7.19 (m, 3H, Ar), 6.35 (s,
1H, NH), 5.99 (d, J1,2Z6.4 Hz, 1H, H-1), 5.35 (d, J3,4
2.7 Hz, 1H, H-3), 5.21 (m, 1H, H-5), 4.58 (m, 2H, H-4,
Z
H-6), 4.33 (dd, J2,NHZ2.1 Hz, J1,2Z6.4 Hz,0 1H, H-2), 4.04
0
0
(dd, J5,6 Z4.4 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.36 (s, 3H,
CH3), 2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.03 (s, 3H,
OAc); 13C NMR (100 MHz, CDCl3) d 170.5 (CH3–CO),
169.8 (CH3–CO), 169.7 (CH3–CO), 158.7 (C]O), 141.3,
133.6, 132.8, 129.6 (2C), 127.8 (aromatics), 91.9 (C-1), 75.9
(C-3), 75.6 (C-4), 67.6 (C-5), 63.0 (C-6), 60.7 (C-2), 20.7
(3C, CH3–CO), 18.6 (CH3). HRMS: m/z found 455.1225.
MCHC required for C20H23ClN2O8: 455.1221.
4.1.8. 1-(2,6-Dichlorophenyl)-(3,5,6-tri-O-acetyl-1,2-
dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-one
(29). From 26 and following the procedure described for 28,
compound 29 was obtained (96%), mp 214–216 8C, [a]D
C102.0 (c 0.5, CHCl3), nmax 3380 (NH), 1740 (C]O),
1690 (NC]O), 1220 (C–O–C), 1055, 1030, (C–O), 1560,
1470, 785, 770 cmK1(aromatics); 1H NMR (400 MHz,
CDCl3) d 7.44–7.26 (m, 3H, Ar), 6.17 (d, J2,NHZ1.7 Hz,
4.1.10. 1,3,4,6-Tetra-O-acetyl-2-[3-(2-chloro-6-methyl-
phenyl)thioureido]-2-deoxy-b-D-glucopyranose (34). To
a solution of NaHCO3 (2.74 g, 32.6 mmol) in water
(130 mL) was added under stirring 1,3,4,6-tetra-O-acetyl-
2-amino-2-deoxy-b-D-glucopyranose hydrochloride 31,17
(10.4 g, 27.1 mmol) and dichloromethane (130 mL), keep-
ing the stirring for 30 min. The organic layer was separated
and the aqueous extracted with dichloromethane (50 mL).
The combined organic fractions were washed with water
and dried over anhydrous magnesium sulfate and concen-
trated to approx. 50 mL. 2-Chloro-6-methylphenyl isothio-
cyanate, 33, (5.0 g, 27.2 mmol) was then added and the
reaction mixture was left at room temperature for 48 h.
Compound 34 separated spontaneously as a white solid,
which was filtered and washed with cold diethyl ether
(75%), mp 174–176 8C, [a]D K15.0 (c 1.0, CHCl3); nmax
3300, 2940, 1530 (NH), 1730 (C]O), 1230 (C–O–C),
1070, 1030 (C–O), 770 cmK1 (aromatics); 1H NMR
1H, NH), 6.06 (d, J1,2Z6.5 Hz, 1H, H-1), 5.34 (d, J3,4
Z
2.8 Hz, 1H, H-3), 5.24 (m, 1H, H-5), 4.70 (dd, J3,4Z2.8 Hz,
0
J4,5Z9.4 Hz, 1H, H-4), 4.55 (dd, J5,6Z2.4 Hz, J6,6
Z
12.3 Hz, 1H, H-6), 4.31 (dd, J2,NHZ2.2 Hz, J1,2Z6.5 Hz,
0
0
0
1H, H-2), 4.03 (dd, J5,6 Z5.4 Hz, J6,6 Z12.3 Hz, 1H, H-6 ),
2.07 (s, 6H, OAc), 2.03 (s, 3H, OAc); 13C NMR (100 MHz,
CDCl3) d 170.6 (CH3–CO), 169.8 (CH3–CO), 169.7 (CH3–
CO), 157.4 (C]O), 137.2, 135.1, 131.4, 130.2, 129.1, 128.7
(aromatics), 90.5 (C-1), 76.2 (C-3), 75.7 (C-4), 67.5 (C-5),
63.1 (C-6), 60.7 (C-2), 20.8 (3C, CH3–CO). Anal. Calcd for
C19H20Cl2N2O8: C, 48.02; H, 4.24; N, 5.89. Found: C,
47.82; H, 4.21; N, 5.90.
4.1.9. 1-(2-Chloro-6-methylphenyl)-(3,5,6-tri-O-acetyl-

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M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7941
(400 MHz, CDCl3, TZ333 K) d 7.50 (d, J2,NHZ6.4 Hz, 1H,
NH), 7.34–7.19 (m, 3H, Ar), 5.64 (m, 2H, H-1, NH), 5.10
reaction mixture was kept at this temperature for 24 h. The
mixture was then poured into ice-water and the resulting
solid was filtered and washed with cold water affording 36
(94%) as a rotamer mixture in a w6:1 (P:M) ratio.
Fractional crystallization from 96% aqueous ethanol
allowed the major rotamer 36P to be isolated, mp 181–
183 8C, [a]D C28.0 (c 0.5, CHCl3), nmax 3320 (NH), 1760,
1730 (C]O), 1240, 1220, 1200 (C–O–C), 1500, 780 cmK1
0
(m, 3H, H-2, H-3, H-4), 4.21 (dd, J5,6Z4.7, J6,6 Z12.4 Hz,
0
0
0
1H, H-6), 4.12 (dd, J5,6 Z2.5, J6,6 Z12.4 Hz, 1H, H-6 ),
3.77 (m, 1H, H-5), 2.24 (s, 3H, CH3), 2.11 (s, 3H, OAc),
2.05 (s, 6H, OAc), 1.98 (s, 3H, OAc); 13C NMR (100 MHz,
CDCl3, TZ295 K) d 182.3 (C]S), 171.1 (CH3–CO), 170.7
(2C, CH3–CO), 169.4 (CH3–CO), 139.5, 133.9, 129.7 (2C),
128.1 (2C) (aromatics), 92.5 (C-1), 72.6 (C-3, C-5), 68.1
(C-4), 61.6 (C-6), 57.8 (C-2), 20.9 (CH3–CO), 20.8 (CH3–
CO), 20.7 (CH3–CO), 20.5 (CH3–CO) 18.0 (CH3). Anal.
Calcd for C22H27ClN2O9S: C, 49.77; H, 5.13; N, 5.28; S,
6.04. Found: C, 49.66; H, 5.16; N, 5.28; S, 5.80.
1
(aromatics); H NMR (400 MHz, CDCl3) d 7.96 (s, 1H,
NH), 7.35–7.19 (m, 3H, Ar), 6.58 (d, J4,5Z1.4 Hz, 1H,
0
0
0
0
H-5), 5.65 (dd, J4,1 Z8.8, J1 ,2 Z1.6 Hz, 1H, H-1 ), 5.32
0
0
0
0
0
(dd, J1 ,2 Z1.5 Hz, J2 ,3 Z9.0 Hz, 1H, H-2 ), 5.00 (m, 1H,
H-30), 4.21 (m, 2H, H-40, H-400), 3.93 (dd, J4,5Z1.4 Hz,
0
J4,1 Z8.7 Hz, 1H, H-4), 2.37 (s, 3H, CH3), 2.16 (s, 3H,
OAc), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.03 (s, 6H,
OAc); 13C NMR (100 MHz, CDCl3) d 182.7 (C]S), 170.6
(CH3–CO), 169.8 (CH3–CO), 169.7 (2C, CH3–CO), 169.3
(CH3–CO), 141.3, 133.5, 132.8, 130.1, 129.5, 127.7,
(aromatics), 85.6 (C-5), 68.7 (C-20), 68.3 (C-10), 67.6
(C-30), 61.2 (C-40), 61.1 (C-4), 20.8 (CH3–CO), 20.7 (CH3–
CO), 20.6 (3C, CH3–CO), 18.7 (CH3). Anal. Calcd for
C24H29ClN2O10S: C, 50.31; H, 5.10; N, 4.89; S, 5.59.
Found: C, 50.58; H, 5.05; N, 4.96; S, 5.14.
4.1.11. (4R,5R)-1-(2-Chloro-6-methylphenyl)-5-hydroxy-
4-(D-arabino-tetritol-1-yl)imidazolidine-2-thione (35).
Procedure A. To a solution of 2-amino-2-deoxy-a-D-
glucopyranose hydrochloride, 6, (10.8 g, 50.0 mmol) in
water (60.0 mL) was added NaHCO3 (4.6 g, 55.0 mmol)
and 2-chloro-6-methylphenyl isothiocyanate (50.0 mmol)
under stirring. The mixture was diluted with ethanol
(90.0 mL) to obtain a homogeneous solution that was then
heated at 45 8C (external bath) for 30 min. When the
mixture was left to room temperature, 35 spontaneously
crystallized as a white solid, mixture of two rotamers (72%)
in a w3:1(P:M) ratio, mp 173–175 8C (ethanol 96%), [a]D
K23.5 (c 1.0, DMF), nmax 3500–3000 (OH, NH), 1450
(NH), 1470 and 780 cmK1 (aromatics); 1H NMR (400 MHz,
DMSO-d6) d 8.43 (s, 1H, NH, P), 8.17 (s, 1H, NH, M), 7.37–
7.25 (m, 6H, Ar, P and M), 6.80 (d, J5,OHZ7.4 Hz, 1H, C5–
OH, P), 6.62 (d, J5,OHZ7.9 Hz, 1H, C5–OH, M), 5.26 (d,
4.1.13. Transformation of (4R,5R)-4-(1,2,3,4-tetra-O-
acetyl-D-arabino-tetritol-1-yl)-5-acetoxy-1-(2-chloro-6-
methylphenyl)imidazolidine-2-thione (36) into 4-(1,2,3,
4-tetra-O-acetyl-D-arabino-tetritol-1-yl)-1-(2-chloro-6-
methylphenyl)imidazoline-2-thione (37). A solution of 36
(0.08 g) in DMSO-d6 (0.5 mL) was heated at 80 8C and the
1
transformation was monitored by H NMR. Compound 37
was characterized by NMR spectroscopy. 1H NMR
(400 MHz, DMSO-d6, 295 K) d 9.92 (s, 1H, NH), 7.46–
7.32 (m, 6H, Ar, P and M), 7.09 (s, 1H, H-5,0P), 7.07 (s, 1H,
0
J5,OHZ7.2 Hz, 2H, H-5, P and M), 4.85 (d, J1 ,OHZ6.9 Hz,
1H, C10–OH, M), 4.74 (d, J1 ,OHZ6.5 Hz, 1H, C10–OH, P),
0
4.59 (d, J2 ,OHZ5.6 Hz, 1H, C20–OH, P), 4.47 (d, J3 ,OH
Z
0
0
8.3 Hz, 1H, C30–OH, P), 4.40 (t, J4 ,OHZJ4 ,OHZ5.7 Hz,
1H, 0C40–OH, P), 3.80–3.31 (m, 12H, H-4, H-10, H-20, H-30,
H-4 , H-400, P and M), 2.36 (s, 3H, CH3, P), 2.18 (s, 3H,
CH3, M); 13C NMR (100 MHz, DMSO-d6) d 180.6 (C]S,
M), 180.2 (C]S, P), 142.7, 139.8, 136.1, 134.8, 134.6,
133.2, 129.4 (3C), 129.3, 127.6, 127.3 (aromatics, P and M),
87.7 (C-5, M), 87.0 (C-5, P), 71.4 (C-10, M), 71.2 (C-10, P),
70.2 (C-20, P and M), 70.0 (C-30,0 P), 69.7 (C-300, M), 66.1
(C-4, M), 65.7 (C-4, P), 63.6 (C-4 , P), 63.4 (C-4 , M), 19.3
(CH3, P), 18.1 (CH3, M). Anal. Calcd for C14H19ClN2O5S:
C, 46.35; H, 5.28; N, 7.78; S, 8.84. Found: C, 46.08; H, 5.34;
N, 7.55; S, 8.63.
H-5, M), 5.90 (d, J1 ,2 Z2.7 Hz, 1H, H-1 , M), 5.89 (d,
0
00
0
0
0
0
0
0
0
0
0
J1 ,2 Z3.5 Hz, 1H, H-1 , P), 5.47 (dd, J1 ,2 Z3.4 Hz, J2 ,3
Z
8.1 Hz, 1H, H-20, P), 5.46 (dd, J1 ,2 Z3.3 Hz, J2 ,3 Z8.0 Hz,
0
0
0
0
1H, H-20, M), 5.16 (m, 2H, H-30, P 0and M), 4.21 (dd, J3 ,4
Z
0
0
0
00
2.7 Hz, J4 ,4 Z12.5 Hz, 2H, H-4 , P and M), 4.15 (dd,
00
0
0
0
00
J3 ,4 Z5.0 Hz, J4 ,4 Z12.4 Hz, 1H, H-4 , M), 4.14 (dd,
00
0
00
0
00
J3 ,4 Z5.1 Hz, J4 ,4 Z12.4 Hz, 1H, H-4 , P), 2.07 (s, 3H,
CH3), 2.02 (s, 6H, OAc), 2.01 (s, 3H, OAc), 1.99 (s, 3H,
OAc), 1.98 (s, 3H, OAc), 1.97 (s, 3H, OAc), 1.95 (s, 6H,
OAc).
4.1.14. 4-(1,2,3,4-Tetra-O-acetyl-D-arabino-tetritol-1-yl)-
1-(2-chloro-6-methylphenyl)imidazoline-2-thione (37P).
To a solution of 36 (0.6 g, 1.05 mmol) in benzene (23 mL)
was added KHCO3 (0.2 g) and heated at reflux under stirring
for 20 h. The reaction was followed by TLC (benzene–
acetone, 3:1). The salt was filtered and the organic phase
washed twice with water, dried over magnesium sulphate
and evaporated to dryness. The crude was crystallized from
96% aqueous ethanol, affording a mixture of both rotamers
(0.32 g, 60%). Recrystallization from 96% aqueous ethanol
afforded the major rotamer P (0.08 g, 42%), mp 176–
178 8C, [a]D K89.4 (c 0.5, CHCl3), nmax 3200 (NH), 1750
Procedure B. To a solution of 1,3,4,6-tetra-O-acetyl-2-
deoxy-2-[3-(2-chloro-6-methylphenyl)thioureido]-b-D-glu-
copyranose (34) (5.4 g, 10.2 mmol) in methanol (160 mL),
was added under vigorous stirring a saturated solution of
ammonia in methanol (160 mL). The process was followed
by TLC (chloroform–methanol, 3:1) and after 6 h at room
temperature the reaction mixture was evaporated to dryness.
The crude was crystallized from 96% aqueous ethanol. The
title compound was filtered and washed with cold 96%
aqueous ethanol and diethyl ether (3.5 g, 94%).
1
(C]O), 1270, 1210 (C–O–C), 780 cmK1 (aromatics); H
4.1.12. (4R,5R)-4-(1,2,3,4-Tetra-O-acetyl-D-arabino-
tetritol-1-yl)-5-acetoxy-1-(2-chloro-6-methylphenyl)-
imidazolidine-2-thione (36P). To a solution of 35
(2.4 mmol) in pyridine (10.0 mL), cooled at K20 8C for
15 min, was added acetic anhydride (6.0 mL) and the
NMR (400 MHz, CDCl3) d 11.84 (s, 1H, NH), 7.38–7.25
0
0
(m, 3H, Ar), 6.64 (s, 1H, H-5), 6.07 (d, J1 ,2 Z3.1 Hz, 1H,
0
H-10), 5.48 (dd, J1 ,2 Z3.1 Hz, J2 ,3 Z8.6 Hz, 1H, H-2 ),
0
0
0
0
5.20 (m, 1H, H-30), 4.23 (dd, J3 ,4 Z2.7 Hz, J4 ,4 Z12.6 Hz,
0
0
0
00
1H, H-40), 4.13 (dd, J3 ,4 Z4.3 Hz, J4 ,4 Z12.5 Hz, 1H,
0
00
0
00

´
M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7942
0
H-400), 2.18 (s, 3H, CH3), 2.17 (s, 3H, OAc), 2.14 (s, 3H,
OAc), 2.06 (s, 3H, OAc), 2.03 (s, 3H, OAc); 13C NMR
(100 MHz, CDCl3) d 170.5 (CH3–CO), 169.9 (CH3–CO),
169.7 (CH3–CO), 169.5 (CH3–CO), 163.3 (C]S), 139.2,
133.6, 132.7, 130.5, 129.4, 127.7 (aromatics), 124.5 (C-4),
116.1 (C-5), 70.6 (C-20), 68.2 (C-30), 64.4 (C-10), 61.5
(C-40), 20.8 (CH3–CO), 20.7 (CH3–CO), 20.6 (2C, CH3–
CO), 18.3 (CH3). Anal. Calcd for C22H25ClN2O8S: C;
51.51, H; 4.91, N; 5.46, S; 6.25. Found: C; 51.14, H; 5.00,
N; 5.60, S; 6.18.
J4,1 Z9.5 Hz, J1 ,2 Z1.6 Hz, 1H, H-1 ), 5.34 (dd, J1 ,2
Z
0
0
0
0
0
0
0
0
0
1.6 Hz, J2 ,3 Z9.2 Hz, 1H, H-2 ), 5.00 (m, 1H, H-3 ), 4.20
(m, 2H, H-40, H-400), 3.93 (d, J4,1 Z9.4 Hz, 1H, H-4), 2.17
0
(s, 3H, OAc), 2.12 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.06 (s,
3H, OAc), 2.03 (s, 3H, OAc); 13C NMR (100 MHz, CDCl3)
d 182.4 (C]S), 170.6 (CH3–CO), 169.8 (2C, CH3–CO),
169.5 (2C, CH3–CO), 137.1, 135.4, 132.8, 130.7, 129.0,
128.7 (aromatics), 84.4 (C-5), 68.5 (C-10), 68.1 (C-20), 67.1
(C-30), 61.1 (C-40), 61.0 (C-4), 20.8 (CH3–CO), 20.7 (CH3–
CO), 20.6 (CH3–CO), 20.5 (CH3–CO), 20.4 (CH3–CO).
Anal. Calcd for C23H26Cl2N2O10S: C, 46.55; H, 4.42; N,
4.72; S, 5.40. Found: C, 46.40; H, 4.60; N, 4.79; S, 5.53.
4.1.15. 1-(2-Chloro-6-methylphenyl)-4-(D-arabino-tetri-
tol-1-yl)imidazoline-2-thione (38P). Compound 37P
(0.11 g, 0.21 mmol) was dissolved in methanol (3 mL), a
saturated solution of ammonia in methanol (5.5 mL) was
added and the mixture kept at room temperature overnight.
The reaction was controlled by TLC (chloroform–methanol,
3:1). The mixture was then evaporated to dryness and
crystallized from 96% aqueous ethanol, affording pure
compound 38P (0.05 g, 62%), mp 207–209 8C, [a]D K73.4
(c 0.5, DMF), nmax 3530, 3500 (NH, OH), 1610 (C]C),
1120–1000 (C–O), 780 cmK1 (aromatics); 1H NMR
(400 MHz, DMSO-d6) d 12.13 (bs, 1H, NH), 7.47–7.34
4.1.18. 1-(2-Chloro-6-methylphenyl)-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]imidazolidine-2-thione (42). A solu-
tion of 35 (1.5 g, 4.13 mmol) in aqueous acetic acid
(53.0 mL) was heated at w100 8C (external bath) for
30 min. The mixture was then evaporated to dryness and
the residue crystallized from 96% aqueous ethanol,
affording a crystalline product that was filtered and washed
with cold ethanol, being a mixture of both rotamers of 42
(1.1 g, 75%).
0
(m, 3H, Ar), 6.82 (s, 1H, H-5), 5.09 (d, J1 ,OHZ6.9 Hz, 1H,
Compound 42P. From a mixture of atropisomers of 42
(1.8 g, 5.12 mmol) the major rotamer was separated by
fractional crystallization from 96% aqueous ethanol
(0.342 g, 19%). An analytic sample showed RfZ0.6, mp
238–240 8C, [a]D C92 (c 0.5, DMF), nmax 3480, 3320, 3200
(OH, NH), 1475 (NH), 1040 (C–O), 790 cmK1 (aromatics);
1H NMR (400 MHz, DMSO-d6) d 9.17 (s, 1H, NH), 7.36–
7.27 (m, 3H, Ar), 5.88 (d, J1,2Z6.6 Hz, 1H, H-1), 5.34 (d,
J3,OHZ4.7 Hz, 1H, C3–OH), 4.74 (d, J5,OHZ6.1 Hz, 1H,
C10–OH), 4.71(d, J1 ,OHZ5.9 Hz, 1H, H-10), 4.66 (s, 1H,
0
C20–OH), 4.60 (s, 1H, C30–OH), 4.39 (t, J4 ,OHZJ4 ,OH
Z
0
00
5.3 Hz, 1H, C40–OH), 3.62–3.35 (m, 4H, H-20, H-30, H-40,
H-400), 2.08 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) d
161.7 (C]S), 139.2, 134.8, 132.2, 132.1, 130.30, 129.5
(aromatics), 1270.6 (C-4), 115.2 (C-5), 73.5 (C-2 ), 71.4
(C-30), 64.4 (C-1 ), 63.4 (C-40), 18.3 (CH3). Anal. Calcd for
C14H17ClN2O4S: C; 48.77, H; 4.97, N; 8.12, S; 9.30. Found:
C; 48.31, H; 5.00, N; 8.12, S; 9.18.
0
C5–OH), 4.42 (t, J6,OHZJ6 -OHZ5.6 Hz, 1H, C6–OH), 4.27
(d, J1,2Z6.7 Hz, 1H, H-2), 4.13 (m, 1H, H-3), 3.85 (dd,
J3,4Z2.3 Hz, J4,5Z8.7 Hz, 1H, H-4), 3.75 (m, 1H, H-5),
3.62 (m, 1H, H-6), 3.31 (m, 1H, H-60), 2.17 (s, 3H, CH3);
13C NMR (100 MHz, DMSO-d6) d 181.5 (C]S), 139.6,
135.4, 134.8, 129.6, 129.5, 127.6 (aromatics), 94.1 (C-1),
80.5 (C-4), 74.1 (C-3), 68.8 (C-5), 66.3 (C-2), 64.5 (C-6),
17.9 (CH3). Anal. Calcd for C14H17ClN2O4S: C, 48.77; H,
4.97; N, 8.12; S, 9.30. Found: C, 49.07; H, 5.14; N, 8.23; S,
8.99.
4.1.16. (4R,5R)-1-(2,6-Dichlorophenyl)-5-hydroxy-4-(D-
arabino-tetritol-1-yl)imidazolidine-2-thione (40). From
2,6-dichlorophenyl isothiocyanate (39) and following the
procedure described for 35, compound 40 was obtained
(71%) by spontaneous crystallization when the mixture was
cooled to room temperature: mp 201–202 8C (96% aqueous
ethanol), [a]D K20.5 (c 1.0, DMF), nmax 3460–3000 (OH,
NH), 1470 (NH), 1550 and 780 cmK1 (aromatics); 1H NMR
(400 MHz, DMSO-d6) d 8.51 (s, 1H, NH), 7.56–7.39 (m,
3H, Ar), 6.75 (d, J5,OHZ7.3 Hz, 1H, C5–OH), 5.30 (dd,
0
Rotamer 42P was also obtained by the following procedure:
to a solution of 44P (0.47 g, 0.99 mmol) in methanol
(16 mL), was added a saturated solution of ammonia in
methanol (16 mL) and the mixture kept at room temperature
overnight. The reaction was followed by TLC (chloroform–
methanol, 3:1). After that time it was evaporated to dryness
and the residue crystallized from 96% aqueous ethanol,
affording 42P (0.28 g, 81%).
J4,5Z3.5 Hz, J5,OHZ7.3 Hz, 1H, H-5), 4.76 (d, J1 ,OH
Z
6.7 Hz, 1H, C10–OH), 4.59 (d, J2 ,OHZ5.1 Hz, 1H,
0
C20–OH), 4.50 (d, J3 ,OHZ8.0 Hz, 1H, C30–OH), 4.40 (t,
0
J4 ,OHZJ4 ,OHZ4.9 Hz, 1H, C40–OH), 3.83–3.39 (m, 6H,
H-4, H-10, H-20, H-30, H-40, H-400); 13C NMR (100 MHz,
DMSO-d6) d 180.3 (C]S), 137.9, 135.0, 133.8, 130.6,
129.1, 128.7 (aromatics), 87.0 (C-5), 71.2 (C-10), 70.4
(C-20), 69.9 (C-30), 65.9 (C-4), 63.6 (C-40). Anal. Calcd for
C13H16Cl2N2O5S: C, 40.74; H, 4.21; N, 7.31; S, 8.37.
Found: C, 40.49; H, 4.02; N, 7.35; S, 8.61.
0
00
Compound 42M. To a solution of 44M (0.15 g, 0.31 mmol)
in methanol (5 mL) was added a saturated solution of
ammonia in methanol (5 mL) and the mixture was kept at
room temperature overnight. The reaction was controlled by
TLC (chloroform–methanol, 3:1). After that time it was
evaporated to dryness and the residue crystallized from 96%
aqueous ethanol, affording 42M (0.07g, 64%), RfZ0.7, mp
209–211 8C, [a]D C193.0 (c 0.7, DMF), nmax 3500–3000
(OH, NH), 1500 (NH), 1030 (C–O), 780 cmK1 (aromatics);
1H NMR (400 MHz, DMSO-d6) d 9.26 (s, 1H, NH), 7.42–
7.27 (m, 3H, Ar), 5.85 (d, J1,2Z6.6 Hz, 1H, H-1), 5.40 (d,
4.1.17. (4R,5R)-4-(1,2,3,4-Tetra-O-acetyl-D-arabino-
tetritol-1-yl)-5-acetoxy-1-(2,6-dichlorophenyl)imidazoli-
dine-2-thione (41). From 40 and following the procedure
described for 36, compound 41 was obtained (97%), mp
191–193 8C, [a]D C63.5 (c 0.5, CHCl3), nmax 3300 (NH),
1750, 1720 (C]O), 1260, 1200 (C–O–C), 780 cmK1
1
(aromatics); H NMR (400 MHz, CDCl3) d 8.24 (s, 1H,
NH), 7.46–7.27 (m, 3H, Ar), 6.50 (s, 1H, H-5), 5.60 (dd,

´
M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7943
J3,OHZ5.3 Hz, 1H, C3–OH), 4.78 (d, J5,OHZ6.0 Hz, 1H,
C5–OH), 4.50 (t, J6,OHZJ6 ,OHZ5.5 Hz, 1H, C6–OH), 4.28
Compound 44M. RfZ0.7, (0.20 g, 16%), mp 88 8C, [a]D
C182 (c 0.5, CHCl3), nmax 3320 (NH), 1740 (C]O), 1230
(C–O–C), 1030, (C–O), 1470, 770, 730 cmK1 (aromatics);
1H NMR (400 MHz, CDCl3) d 7.42–7.28 (m, 4H, Ar and
NH), 6.18 (d, J1,2Z6.7 Hz, 1H, H-1), 5.44 (d, J3,4Z2.9 Hz,
0
0
(d, J1,2Z6.6 Hz, 1H, H-2), 4.15 (dd, J3,4Z2.1 Hz, J3,OH
Z
5.2 Hz, 1H, H-3), 3.78 (dd, J3,4Z2.1 Hz, J4,5Z8.7 Hz, 1H,
H-4), 3.75–3.53 (m, 3H, H-5, H-6, H-60), 2.29 (s, 3H, CH3);
13C NMR (100 MHz, DMSO-d6) d 181.6 (C]S), 141.9,
134.8, 132.8, 129.8, 129.6, 127.4 (aromatics), 94.4 (C-1),
80.3 (C-4), 73.9 (C-3), 68.3 (C-5), 66.3 (C-2), 63.9 (C-6),
18.8 (CH3). Anal. Calcd for C14H17ClN2O4S: C, 48.77; H,
4.97; N, 8.12; S, 9.30. Found: C, 48.98; H, 5.11; N, 7.99; S,
8.93.
1H, H-3), 5.31 (m, 1H, H-5), 4.68 (dd, J5,6Z2.3 Hz, J6,6
Z
12.4 Hz, 1H, H-6), 4.61 (dd, J3,4Z2.9 Hz, J4,5Z9.2 Hz, 1H,
0
H-4), 4.55 (d, J1,2Z6.7 Hz, 1H, H-2), 4.09 (dd, J5,6
Z
0
0
4.3 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.45 (s, 3H, CH3), 2.15 (s,
3H, OAc), 2.14 (s, 3H, OAc), 2.09 (s, 3H, OAc); 13C NMR
(100 MHz, CDCl3) d 183.6 (C]S), 170.5 (CH3–CO), 169.7
(CH3–CO), 169.5 (CH3–CO), 141.2, 133.9, 133.0, 129.9,
129.5, 127.7 (aromatics), 95.4 (C-1), 76.4 (C-3), 75.1 (C-4),
67.4 (C-5), 64.5 (C-2), 62.7 (C-6), 20.6 (2C, CH3–CO),
20.5 (CH3–CO), 18.6 (CH3). HRMS: m/z found 471.0987.
MCHC required for C20H23ClN2O7S 471.0993.
4.1.19. 1-(2,6-Dichlorophenyl)-(1,2-dideoxy-a-D-gluco-
furano)[2,1-d]imidazolidine-2-thione (43). A solution of
40 (1.0 g, 2.61 mmol) in aqueous acetic acid (30%, 33 mL),
was heated at 100 8C (external bath) for 30 min. The
solution was then evaporated to dryness and the white
residue obtained was crystallized from 96% aqueous
ethanol (0.67 g, 70%). An analytic sample obtained by
recrystallization from 96% aqueous ethanol showed mp
245–246 8C, [a]D C151.2 (c 0.5, DMF), nmax 3400–3000
(OH, NH), 1560, 1295 (thioamide), 1440 (NH), 1500,
4.1.21. 3,5,6-Tri-O-acetyl-1-(2,6-dichlorophenyl)-(1,2-
dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-thione
(45). From 43 and following the procedure described for 28,
compound 45 was obtained (100%), mp 102–105 8C, [a]D
C152.6 (c 0.5, CHCl3), nmax 3300 (NH), 1740 (C]O),
1230 (C–O–C), 1040 (C–O), 1470, 1440, 780 cmK1
1
770 cmK1 (aromatics); H NMR (400 MHz, DMSO-d6) d
1
9.38 (s, 1H, NH), 7.61–7.42 (m, 3H, Ar), 5.91 (d, J1,2
Z
(aromatics); H NMR (400 MHz, CDCl3) d 7.47–7.27 (m,
4H, Ar, NH), 6.17 (d, J1,2Z6.8 Hz, 1H, H-1), 5.35 (d, J3,4Z
6.6 Hz, 1H, H-1), 5.38 (d, J3,OHZ5.0 Hz, 1H, C3–OH), 4.77
0
(d, J5,OHZ5.9 Hz, 1H, C5–OH), 4.45 (t, J6,OHZJ6 -OH
Z
3.0 Hz, 1H, H-3), 5.30 (m, 1H, H-5), 4.68 (dd, J3,4Z3.0 Hz,
0
5.5 Hz, 1H, C6–OH), 4.29 (d, J1,2Z6.7 Hz, 1H, H-2), 4.14
(d, J3,4Z2.4 Hz, 1H, H-3), 3.86–3.30 (m, 4H, H-4, H-5,
H-6, H-60); 13C NMR (50.33 MHz, DMSO-d6) d 181.4
(C]S), 137.3, 134.8, 133.6, 131.0, 129.2, 128.9
(aromatics), 93.8 (C-1), 80.6 (C-4), 74.1 (C-3), 68.7 (C-5),
66.5 (C-2), 64.4 (C-6). Anal. Calcd for C13H14Cl2N2O4S: C,
42.75; H, 3.86; N, 7.67; S, 8.78. Found: C, 42.68; H, 3.75;
N, 7.74; S, 8.72.
J4,5Z9.3 Hz, 1H, H-4), 4.60 (dd, J5,6Z2.4 Hz, J6,6
Z
12.4 Hz, 1H, H-6), 4.47 (dd, J2,NHZ1.5 Hz, J1,2Z6.9 Hz,
0
0
0
1H, H-2), 4.02 (dd, J5,6 Z5.5 Hz, J6,6 Z12.4 Hz, 1H, H-6 ),
2.10 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.03 (s, 3H, OAc);
13C NMR (50.33 MHz, CDCl3) d 182.6 (C]S), 170.6
(CH3–CO), 169.8 (CH3–CO), 169.6 (CH3–CO), 137.3,
134.8, 132.6, 130.6, 129.0, 128.7 (aromatics), 94.4 (C-1),
76.6 (C-3), 76.3 (C-4), 67.4 (C-5), 64.6 (C-2), 62.9 (C-6),
20.8 (CH3–CO), 20.7 (CH3–CO), 20.6 (CH3–CO). Anal.
Calcd for C19H20Cl2N2O7S: C, 46.45; H, 4.10; N, 5.70; S,
6.52. Found: C, 46.25; H, 3.96; N, 5.63; S, 6.38.
4.1.20. 3,5,6-Tri-O-acetyl-1-(2-chloro-6-methylphenyl)-
(1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-
thione (44). From 42 and following the procedure described
for 28, compound 44 was obtained (85%) as a mixture of
rotamers in a w1:4 (M:P) ratio. From a fraction of this
mixture (1.3 g) both rotamers were separated by flash
chromatography (ethyl acetate–hexane 1:2).
4.1.22. 1-Acetyl-3-(2,6-dichlorophenyl)-(3,5,6-tri-O-
acetyl-1,2-dideoxy-a-D-glucofurano)[1,2-d]imidazoli-
dine-2-thione (46). A solution of 45 (0.13 g, 0.27 mmol) in
pyridine (0.8 mL) and acetic anhydride (0.8 mL) was heated
at 40 8C for 2 h. The reaction mixture was then poured over
ice-water and a white solid was formed. This product was
filtered and washed with cold water, (0.12 g, 86%), and then
recrystallized from 96% aqueous ethanol, mp 202–204 8C,
[a]D C124.4 (c 0.5, CHCl3), nmax 3600–3100 (crystal-
lization H2O)15, 1735, 1715 (C]O), 1675 (C]O), 1240,
1220 (C–O–C), 775 cmK1 (aromatics); 1H NMR (400 MHz,
CDCl3) d 7.49–7.27 (m, 3H, Ar), 6.06 (d, J1,2Z7.0 Hz, 1H,
H-1), 5.79 (d, J3,4Z3.1 Hz, 1H, H-3), 5.21 (m, 1H, H-5),
Compound 44P. RfZ0.6, (1.0 g, 78%). Recrystallized from
96% aqueous ethanol, mp 173–175 8C, [a]D C125.4 (c 0.5,
CHCl3), nmax 3310 (NH), 1740 (C]O), 1230 (C–O–C),
1
1050, 1030 (C–O), 1480, 780 cmK1 (aromatics); H NMR
(400 MHz, CDCl3) d 7.38–7.21 (m, 4H, Ar and NH), 5.97
(d, J1,2Z6.7 Hz, 1H, H-1), 5.36 (d, J3,4Z2.9 Hz, 1H, H-3),
5.27 (m, 1H, H-5), 4.72 (dd, J3,4Z2.9, J4,5Z9.3 Hz, 1H,
0
H-4), 4.60 (dd, J5,6Z2.4 Hz, J6,6 Z12.3 Hz, 1H, H-6), 4.44
0
(dd, J1,2Z6.6 Hz, J2,3Z1.0 Hz, 01H, H-2), 4.03 (dd, J5,6
Z
4.96 (d, J1,2Z7.0 Hz, 1H, H-2), 4.55 (m, 2H, H-4, H-6),
0
0
0
5.5 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.25 (s, 3H, CH3), 2.08
(s, 3H, OAc), 2.07 (s, 3H, OAc), 2.03 (s, 3H, OAc); 13C
NMR (100 MHz, CDCl3) d 182.9 (C]S), 170.6 (CH3–CO),
169.8 (CH3–CO), 169.6 (CH3–CO), 138.5, 135.6, 133.4,
129.9, 129.5, 128.2 (aromatics), 94.7 (C-1), 76.7 (C-3),
75.4 (C-4), 67.5 (C-5), 64.3 (C-2), 62.9 (C-6), 20.7 (2C,
CH3–CO), 20.6 (CH3–CO), 18.1 (CH3). Anal. Calcd for
C20H23ClN2O7S: C, 51.01; H, 4.92; N, 5.95; S, 6.81. Found:
C, 51.33; H, 4.81; N, 5.96; S, 6.86. HRMS: m/z found
471.1001. MCHC for C20H23ClN2O7S required 471.0993.
3.99 (dd, J5,6Z5.5 Hz, J6,6 Z12.3 Hz, 1H, H-6 ), 2.92 (s,
3H, N–Ac), 2.10 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.01 (s,
3H, OAc), 1.65 (bs, crystallization H2O); 13C NMR
(100 MHz, CDCl3) d 178.6 (C]S), 171.5 (CH3–CO),
170.6 (CH3–CO), 169.8 (CH3–CO), 168.5 (CH3–CO),
136.9, 134.2, 132.6, 130.9, 129.2, 129.0 (aromatics), 90.0
(C-1), 76.9 (C-4), 73.9 (C-3), 67.0 (2C, C-2, C-5), 63.0
(C-6), 27.1 (N–Ac), 20.8 (2C, CH3–CO), 20.7 (CH3–CO).
Anal. Calcd for C21H22Cl2N2O8S$2H2O: C, 44.30; H, 4.60;
N, 4.92; S, 5.63. Found: C, 44.29; H, 4.41; N, 4.67; S, 5.92.

´
M. Avalos et al. / Tetrahedron 61 (2005) 7931–7944
7944
E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 1119–1122.
Acknowledgements
This work was made possible by the financial support from
15. (a) Nakanishi, K.; Solomon, P. H. Infrared Absorption
Spectroscopy, 2nd ed.; Holden-Day: San Francisco, 1977; p
25. (b) Nakamoto, K. Infrared and Raman Spectra of
Inorganic and Coordination Compounds, 3rd ed.; Wiley:
New York, 1978; p 227.
´
Ministerio de Ciencia y Tecnologıa (BQU2002-00015 and
BQU2003-05946) and Junta de Extremadura-Fondo Social
Europeo (2PR02-A016). Special thanks to Dr. J. L. Bravo
for his valuable help in NMR studies.
16. Stereochemical assignment of M and P rotamers will be
discussed in the next article.
17. Bergmann, M.; Zervas, L. Ber. 1931, 64, 975.
18. Tejima, S.; Ness, R. K.; Kaufman, R. L.; Fletcher, H. G., Jr.
Carbohydr. Res. 1968, 7, 485.
References and notes
19. The authors have deposited the atomic coordinates for these
structures with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, upon request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK. Crystal data for 42M,
(CCDC-239943), C14H17ClN2O4S, MrZ344.81, monoclinic,
´
´
1. Avalos, M.; Babiano, R.; Cintas, P.; Higes, F. J.; Jimenez,
J. L.; Palacios, J. C.; Silvero, G. Tetrahedron: Asymmetry
1999, 10, 4071.
´
2. For previous studies, see Parts 1 and 2: (a) Avalos, M.;
´
Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C.; Silvero,
´
G.; Valencia, C. Tetrahedron 1999, 55, 4377. (b) Avalos, M.;
´
Babiano, R.; Cintas, P.; Higes, F. J.; Jimenez, J. L.; Palacios,
˚
˚
˚
P21, aZ7.7947(3) A, bZ7.5324(2) A, cZ13.4087(5) A,
3
VZ783.93(5) A , ZZ2, DcalcdZ1.461 g cmK3, l(Mo Ka)Z
˚
J. C.; Silvero, G.; Valencia, C. Tetrahedron 1999, 55, 4401.
3. (a) Pu, L. Chem. Rev. 1998, 98, 2405. (b) Bringmann, G.;
Breuning, M.; Tasler, S. Synthesis 1999, 525.
0.71073 A, mZ3.96 cmK1
,
F(000)Z360, TZ293(2) K,
˚
GooF2Z1.073, independent reflectionsZ2748 [RintZ0.0660]
of a total of 9490 collected reflections, R(F) obeying F2O
2s(F2)Z0.0347, wR(F2)Z0.0890, R(all data)Z0.0385,
wR(F2)Z0.0914. Crystal data for 42P, (CCDC-239942),
C14H17ClN2O4S, Mr Z344.81, orthorhombic, P212121,
4. For some examples of atropisomerism in heterocycles with
naphthyl or ortho-substituted phenyl groups, see: (a) Bock,
L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53, 374 see also p
3519. (b) Jochims, J. C.; Voithenberg, H.; Wegner, G. Chem.
Ber. 1978, 111, 2745. (c) Fujiwara, H.; Bose, A. K.; Manhas,
M. S.; van der Veen, J. M. J. Chem. Soc., Perkin Trans. 2 1979,
653. (d) Kashima, C.; Katoh, A. J. Chem. Soc., Perkin Trans. 1
1980, 1599. (e) Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri,
A. J. Org. Chem. 1988, 53, 5076. (f) Rubiralta, M.; Jaime, C.;
Feliz, M.; Giralt, E. J. Org. Chem. 1990, 55, 2307. (g) Saito,
K.; Yamamoto, M.; Yamada, K. Tetrahedron 1993, 49, 4549.
5. (a) Clayden, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 949.
(b) Clayden, J. Synlett 1998, 810.
˚
˚
˚
aZ9.7765(3) A, bZ12.2006(6) A, cZ13.1541(6) A, VZ
3
1569.01(12) A , ZZ4, DcalcdZ1.460 g cmK3, l(MoKa)Z
˚
0.71073 A, mZ3.95 cmK1
, F(000)Z720, TZ293(2) K,
˚
GooF2Z1.029, independent reflectionsZ2672 [RintZ0.0381]
of a total of 6126 collected reflections, R(F) obeying F2O
2s(F2)Z0.0362, wR(F2)Z0.0792, R(all data)Z0.0482,
wR(F2)Z0.0843.
´
´
20. Avalos, M.; Jimenez, J. L.; Palacios, J. C.; Ramos, M. D.;
Galbis, J. A. Carbohydr. Res. 1987, 161, 49.
´
´
´
21. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Lopez, I.;
Palacios, J. C.; Silvero, G. Stability of cis and trans-fused
tetrahydroglycopyranoso[2,1-d]imidazol-2-(thi)ones. VI Jor-
6. (a) Feringa, B. L.; van Delden, R. A.; Koumura, N.;
Geertsema, E. M. Chem. Rev. 2000, 100, 1789. (b) Molecular
Switches; Feringa, B. L., Ed.; Wiley-VCH: New York, 2001.
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nadas de Carbohidratos. Reunion del Grupo Especializado de
Hidratos de Carbono de la Real Sociedad Espan˜ola de
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7. Clayden, J.; Lund, A.; Vallverdu, L.; Helliwell, M. Nature
2004, 431, 966.
8. Valencia, C. MA Thesis, University of Extremadura, Badajoz,
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Quımica. II Encuentro Iberico de Carbohidratos. Ronda,
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Malaga, Spain, 2002. Book of Abstracts, p 101.
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1990.
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22. Avalos, M.; Babiano, R.; Duran, C. J.; Jimenez, J. L.; Palacios,
J. C. J. Chem. Soc., Perkin Trans. 2 1992, 2205.
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9. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
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23. The following equation was used: DG‡(cal molK1)Z
¯
10. (a) Oki, M. In Hafner, K., Lehn, J. M., Rees, C. W., Rague
´
¨
1.987Tc[22.961Cln(Tc/Dn)]: Sandstrom, J. Dynamic NMR
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Schleyer, P. V., Trost, B. M., Zahradnık, R., Eds.; The
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¯
30. (b) Oki, M.; Toyota, S. Eur. J. Org. Chem. 2004, 255.
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11. (a) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
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DC, 1982.
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Palacios, J. C.; Valencia, C. Tetrahedron 1993, 49, 2655.
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(b) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
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Palacios, J. C.; Valencia, C. Tetrahedron 1993, 49, 2676.
´ ´
12. Gomez, A.; Gomez, M.; Scheidegger, U. Carbohydr. Res.
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21.4 kcal molK1), 35 (DGsO22.8 kcal molK1), 42 (DGsO
21.1 kcal molK1), and 44 (DGsO20.7 kcal molK1).
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13. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
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J. C.; Valencia, C. Tetrahedron Lett. 1993, 34, 1359.
14. For further information about M and P descriptors, see: Eliel,