[3+2]-cycloadditions of 2-aminothioisomunchnones to alkynes: Synthetic scope and mechanistic insights

Article abstract of DOI:10.1016/S0040-4020(00)00022-3

This manuscript describes the regiospecific 1,3-dipolar cycloadditions of 2-aminothioisomunchnones (1-3) with methyl propiolate. The structure of compound 4 has been unequivocally determined by X-ray crystallography. Based on these experimental arguments and a theoretical rationale that supports the regiochemistry observed, a mechanistic pathway is discussed to account for the formation of pyridone or thiophene derivatives. The protocol has also been extended to the cycloadditions of aminothioisomunchnones derived from carbohydrates with dimethyl acetylenedicarboxylate to afford interesting glycosylaminoheterocycles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00022-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1247–1255
¨
[3ϩ2]-Cycloadditions of 2-Aminothioisomunchnones to Alkynes:
Synthetic Scope and Mechanistic Insights
a
a
a
a
b
´
´
´
Marıa J. Arevalo, Martın Avalos, Reyes Babiano, Pedro Cintas, Michael B. Hursthouse,
a
b
a
a,
*
´
´
´
Jose L. Jimenez, Mark E. Light, Ignacio Lopez and Juan C. Palacios
a
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Dedicated to Prof. J. Elguero on the occasion of his 65th birthday
Received 4 November 1999; revised 8 December 1999; accepted 23 December 1999
Abstract—This manuscript describes the regiospecific 1,3-dipolar cycloadditions of 2-aminothioisomu¨nchnones (1–3) with methyl
propiolate. The structure of compound 4 has been unequivocally determined by X-ray crystallography. Based on these experimental
arguments and a theoretical rationale that supports the regiochemistry observed, a mechanistic pathway is discussed to account for the
formation of pyridone or thiophene derivatives. The protocol has also been extended to the cycloadditions of aminothioisomu¨nchnones
derived from carbohydrates with dimethyl acetylenedicarboxylate to afford interesting glycosylaminoheterocycles. ᭧ 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
reactivity towards alkenes4,5 and carbonyls.6 The presence
of such a dialkylamino substituent constitutes a key stereo-
controlling factor and largely dictates the subsequent
fragmentation pathway of cycloadducts. With these premises,
it would be interesting to explore the dipolar cycloadditions
of these 2-amino-substituted thioisomu¨nchnones with
alkynes. This full account describes our results in this area,
which have also been extended to enantiomerically pure
thioisomu¨nchnones derived from carbohydrates. In addition,
a mechanistic rationale of the steric course is also provided.
In recent years considerable attention has been focused on
the formation of functionalized heterocyclic skeleta through
[3ϩ2]-cycloadditions of mesoionic rings.1 Thus, 1-3-thia-
zolium-4-olates (commonly named thioisomu¨nchnones),2
which can easily be prepared from simple thioamides,
contain a masked thiocarbonyl ylide dipole in their structure
capable of undergoing 1,3-dipolar cycloadditions. Despite
the considerable amount of research dealing with the
chemistry of thioisomu¨nchnones, the range of products
accessible by means of cycloaddition reactions has
remained somewhat narrow. In general, most thioisomu¨nch-
nones react with electron-deficient alkenes to give stable
cycloadducts which can further fragment to produce 2-pyri-
dones after extrusion of hydrogen sulfide, while the reaction
with acetylenic dipolarophiles gives rise to either thio-
phenes or 2-pyridones.1 In previous studies concerning the
preparation of optically active heterocycles, we have shown
that bulky and rather rigid carbohydrate-appended thio-
isomu¨nchnones react with acetylenic dipolarophiles to
afford exclusively 2-pyridone derivatives.3
Results and Discussion
Synthetic studies
The reaction of thioisomu¨nchnone 1, having an electron-
withdrawing substituent at C-3, with methyl propiolate in
CH2Cl2 solution at room temperature for 3 h gave a mixture
of pyridone and thiophene derivatives in 75 and 10% yield,
respectively. However, cycloadditions of thioisomu¨nchnones
2 and 3, conducted under the same reaction conditions,
afforded 2-pyridones in a regiospecific fashion (Scheme 1).
The formation of thiophenes could not be observed at all after
an inspection of crude samples by 400-MHz analysis.
Nevertheless, during the course of our recent research we
have also disclosed that thioisomu¨nchnones 1–3 bearing an
N-benzyl-N-methylamino group at C-2 exhibit a particular
The structures attributed to pyridones 4, 6 and 7 are con-
sistent with their spectroscopic data. The only proton
present at the heterocyclic nucleus, H-4, exhibits downfield
resonances (d 8.09–8.12, singlet signals). This large
deshielding should be caused by ring currents of the
Keywords: dipolar cycloadditions; mesoionic compounds; pyridones; thio-
phenes; thioisomu¨nchnones.
* Corresponding author. Tel.: ϩ34-924-289-380; fax: ϩ34-924-271-149;
e-mail: palacios@unex.es
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00022-3

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1248
Scheme 1.
adjacent methoxycarbonyl and phenyl groups at C-5 and
C-3, respectively. Similar chemical shifts have been found
in other pyridones with the same substitution pattern.3
The 13C DEPT spectrum7 also suggests that resonances
assigned to C-4 (dϳ140) should correspond to a carbon
atom with an attached hydrogen atom. Moreover, the struc-
ture of 4 was unequivocally established by X-ray diffraction
analysis, thereby confirming the regiochemistry and atom
connectivity (Fig. 1, see Experimental for diffraction details).
The structure of thiophene 5 was assigned on the basis of its
1H and 13C NMR spectra, and assuming that a common
cycloadduct led to both reaction products 4 and 5 (vide infra).
Although methyl propiolate is an unsymmetrically substi-
tuted dipolarophile, other regioisomers could not be
detected. This fact excludes the alternative structures
8–10 in which a small anisotropic effect would otherwise
be expected for H-5. On the other hand, aromatic protons of
4, 6 and 7 at C-3 appear as multiplet signals, in agreement
with a coplanar arrangement between that phenyl group and
the heterocyclic moiety, which is only possible in the
absence of substituents at C-4.
Next, we were interested in exploring the reactivity of thio-
isomu¨nchnones derived from carbohydrates by employing
N-methyl-d-glucamine (11) as a template. The sequential
preparation of such mesoionics comprises three steps: (a)
intermolecular coupling with an appropriate aryl isothiocya-
nate, (b) O-protection of the acyclic carbohydrate moiety,
and (c) mesoionization of the resulting aryl thioureas with
2-chloro-2-phenylacetyl chloride in the presence of
triethylamine.
The condensation of 11 with aromatic isothiocyanates was
conducted in pyridine at room temperature for 1 h. Further
Figure 1. Solid-state structure of pyridone 4.

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1249
Scheme 2.
addition of diethyl ether led to crystallization of the corre-
sponding thioureas in high yields (Ͼ85%), which could
easily be purified by recrystallization from 96% aqueous
ethanol. Conventional acetylation of hydroxyl groups at
the acyclic side chain was accomplished by dissolving the
aryl thioureas 15–17 in acetic anhydride and using melt
sodium acetate as catalyst. Although the acetylation
proceeded slowly at room temperature and required 7 days
for completion, the O-protected derivatives 18–20 were
isolated in good yields as crystalline materials and without
competing side products (Scheme 2).
days without appreciable decomposition. Alternatively,
homogeneous solutions of these substances were reacted
in situ with alkynes. Reactions with methyl propiolate
were sluggish and we then turned our attention to a more
reactive dipolarophile, dimethyl acetylenedicarboxylate
(Scheme 4).
As expected, thioisomu¨nchnones 21 and 22 afforded
exclusively pyridone derivatives, 24 and 25, respectively,
and no trace of thiophenes could be detected by inspection
of the reaction mixtures. Compounds 24 and 25 gave a
negative sulfur test and their structures are consistent with
their spectroscopic and analytical data. In particular, the
presence of two aromatic rings and a diagnostic 13C peak
at dϳ102, attributable to C-5,3,10 could easily be identified
in their NMR spectra.
The unprotected thioureas 15–17 were fully characterized
through their spectroscopic data and elemental analyses.
Having demonstrated the identity of such intermediates,
the formation of compounds 18–20 could also be carried
out in a one-step protocol starting from 11 (see Experi-
mental). The conversion of thioureas into mesoionic hetero-
cycles can successfully be accomplished by means of two
general procedures. On the one hand, the condensation of
thioureas with 2-bromophenyl acetic acid under basic
conditions followed by further cyclodehydration in hot
acetic anhydride to afford 1,3-thiazolium-4-olate systems.8
On the other hand, the direct coupling of an N-monosubsti-
tuted thioamide (e.g. thioureas 18–20) with an a-haloacyl
chloride in the presence of triethylamine causes the forma-
tion of 21–23 (Scheme 3).9 The latter procedure is preferred
since it avoids the chromatographic purification and isola-
tion of intermediates, which in the present case are in fact
diastereomeric mixtures, and the overall transformation can
be achieved in a shorter reaction time.
However, the coupling of 23 with dimethyl acetylene-
dicarboxylate under the same reaction conditions gave rise
to a thiophene derivative (26) as the sole product, albeit it
was isolated in moderate yield. This product gave a positive
sulfur test and 4-nitrophenyl isocyanate could be identified
as byproduct, in agreement with the accepted mechanistic
hypothesis that accounts for the formation of thiophenes.
Notably, all attempts to isolate or detect the transient
cycloadducts during the cycloadditions of 21–23 failed,
even when the reactions were conducted at 0ЊC.
Regioselectivity
We have investigated the reactions of thioisomu¨nchnones
1–3 with methyl propiolate at the PM3 level11 using the
Gaussian94 package,12 to clarify the nature of this cyclo-
addition and the regiochemistry observed experimentally.
Employing the background provided by the frontier orbital
theory,13 Table 1 depicts the energies and coefficients of the
frontier orbitals.
Although compounds 21–23 can be isolated as solids or oily
materials, they are not stable enough to be stored for several
We immediately learn from such data that the inter-
action
HOMOdipole–LUMOdipolarophile
ꢀ7:64 Ͻ DE Ͻ
8:02 eV† is more favorable than the opposite energy gap
between HOMOdipolarophile and LUMOdipole ꢀ9:76 Ͻ DE Ͻ
10:18 eV†: Accordingly, the above cycloadditions are called
dipole-HOMO controlled reactions or Sustmann’s type I
cycloadditions,14 which look a little bit like a normal
Diels–Alder reaction.
The HOMOs of 2 and 3 are brought closer in energy (Ϫ7.50
and Ϫ7.47 eV, respectively), whereas the HOMO of 1 is
Scheme 3.

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1250
Scheme 4.
Table 1. Energies and coefficients of the frontier orbitals for compounds 1–3 and methyl propiolate
Compound
Orbital
Energy (eV)
c1
c2
c3
c4
c5
1
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
Ϫ7.85
Ϫ1.81
Ϫ7.50
Ϫ1.39
Ϫ7.47
Ϫ1.81
Ϫ11.57
0.17
Ϫ0.19
Ϫ0.36
Ϫ0.18
Ϫ0.40
Ϫ0.21
Ϫ0.39
0.00
Ϫ0.28
0.58
Ϫ0.26
0.63
Ϫ0.26
0.64
0.00
0.15
Ϫ0.30
0.15
Ϫ0.37
0.15
Ϫ0.38
0.00
0.14
Ϫ0.01
0.14
Ϫ0.02
0.14
Ϫ0.02
0.51
0.29
0.51
0.29
0.53
0.30
2
3
Methyl propiolate
Ϫ0.60
Ϫ0.42
0.61
lowered to Ϫ7.85 eV. This small difference, however,
accounts for the higher reactivity of thioisomu¨nchnones 2
and 3, whose cycloadditions are complete within 1 h, while
the reaction of 1 and methyl propiolate required 3 h for
completion.
orbital symmetry conservation, together with experimental
considerations of reactivity and regioselectivity, and small
solvent effects, all suggest a highly ordered transition state
consistent with a concerted mechanism.15,16 Nevertheless,
the determination of transition states might be expected to
provide a definite answer, although only calculations at a
sufficiently high level will be a truly fair test of the energies
of concerted, zwitterionic or diradical transition states.17
Next, the coefficients of the atomic orbitals were examined
since they largely influence the regioselectivity.13 Fig. 2
shows the two possible orientations of the cycloaddition
of 1 with methyl propiolate. We have looked at the coeffi-
cients of the HOMO of the dipole and of the LUMO of the
dipolarophile on the atoms at which bonding is to take place
(C-5 of 1 and C-3 of methyl propiolate). Assuming that the
predicted regioselection arises from the interaction between
the larger coefficient on one component with the larger on
the other, we need to look only at the left-hand combination
in Fig. 2. Such an approach gives rise to an intermediate
cycloadduct, which upon sulfur extrusion, effectively leads
to the observed regioisomer. The other interaction disagrees
with the experiment (Scheme 5).
In principle, the formation of pyridones may take place
either by a cheletropic process or a stepwise mechanism
(Scheme 6). In both cases, the nature of the aryl substituent
at the endocyclic nitrogen atom should be a prime factor
controlling the stability of a concerted transition state or of a
Mechanistic considerations
The 1,3-dipolar cycloaddition of mesoionics with dipolaro-
philes should be occurring via the corresponding cyclo-
adducts as intermediates, even though the latter substances
could not be detected in the present study. The principles of
Figure 2.

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1251
Scheme 5.
Scheme 6.
dipolar intermediate. Electron-donating groups will increase
delocalization in a concerted mechanism or will spread the
positive charge over more atoms.
resonance, however, might disfavor a concerted cleavage.
Further studies, including the search of transition structures
for these cycloadditions with acetylenic and olefinic
dipolarophiles are currently in progress.
In stark contrast, an electron-withdrawing substituent (e.g.
4-nitrophenyl) will stabilize a different dipolar intermediate
or transition state, in which elimination of aryl isocyanate
will compete favorably with the alternative carbon–sulfur
scission (Scheme 7). Thus, the aryl substituent at C-3 of
thioisomu¨nchnones seems to be an important factor for
cycloadduct cleavage. On the other hand, the stereo-
electronic effect provided by the lone pair of the exocyclic
N,N-dialkylamino substituent will spread the charge at the
bridgehead carbon. The extended conjugation due to
Experimental
General methods
Melting points were determined on a capillary apparatus
and are uncorrected. Optical rotations were measured
at the sodium line at 18^2ЊC with a Perkin–Elmer 241
polarimeter. Analytical and preparative TLC were
Scheme 7.

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1252
performed on Merck 60 GF254 silica gel with monitoring by
means of UV at 254 and 360 nm and iodine vapors. Flash
chromatography18 was performed with Merck 60 silica gel
(400–230 mesh). IR spectra were recorded on a Perkin–
C, 76.39; H, 5.70; N, 6.60. Found: C, 76.74; H, 5.50; N,
6.62.
6-(N-Methyl)benzylamino-5-methoxycarbonyl-1-(4-
methoxyphenyl)-3-phenylpyridin-2-one (7). To a solution
of 2-(N-methyl)benzylamino-3-(4-methoxyphenyl)-5-phenyl-
1,3-thiazolium-4-olate (3, 0.50 g, 1.2 mmol) in dry CH2Cl2
(6.5 mL) was added methyl propiolate (0.12 g, 1.4 mmol)
and the reaction mixture was stirred at room temperature for
1 h. The solvent was evaporated to dryness and the further
addition of Et2O gave the title compound as yellow crystals
(0.20 g, 44%). Mp 176ЊC (Et2O); IR (KBr) nmax 1700, 1640,
1500, 1230, 900, 690 cmϪ1; 1H NMR (CDCl3) d 8.09 (s, 1H,
H-4), 7.72 (d, 2H, aryl), 7.38–6.88 (m, 12H, aryl), 3.96 (s,
2H, CH2Ph), 3.86 (s, 3H, CO2CH3), 3.82 (s, 3H, CH3O),
2.48 (s, 3H, CH3N); 13C NMR (CDCl3) d 165.6
(CO2CH3), 163.0 (C-2), 159.2 (aryl), 157.7 (C-6), 139.6
(C-4), 136.3, 136.1, 131.1, 129.8, 128.7, 128.5, 128.1,
128.0, 127.5, 127.4, 114.4 (aryl), 125.9 (C-3), 104.5
(C-5), 58.9 (CH2), 55.5 (CH3O), 52.0 (CO2CH3), 40.0
(CH3N). Anal. Calcd for C28H26N2O4: C, 73.99; H, 5.77;
N, 6.16. Found: C, 73.84; H, 5.73; N, 6.14.
1
Elmer 399 or a FT-IR Midac spectrometers. H and 13C
NMR spectra were obtained with a Bruker AM 400 instru-
ment at 400 and 100 MHz, respectively, in CDCl3 (Me4Si as
internal standard) unless otherwise specified. Elemental
analyses were recorded on a Lecco 932 analyzer at the
Universidad de Extremadura, and by the Servei de
`
Microanalisi del CSIC at Barcelona, and the Instituto de
´
Investigaciones Quımicas del CSIC at Sevilla. High-
resolution mass spectra (HRMS/CIϩ) were carried out at
´
the Universidad de Cordoba, Spain.
6-(N-Methyl)benzylamino-5-methoxycarbonyl-1-(4-nitro-
phenyl)-3-phenylpyridin-2-one (4) and 2-(N-methyl)-
benzylamino-3-methoxycarbonyl-5-phenylthiophene (5).
To a solution of 2-(N-methyl)benzylamino-3-(4-nitro-
phenyl)-5-phenyl-1,3-thiazolium-4-olate (1, 1.00 g, 2.4 mmol)
in dry CH2Cl2 (13 mL) was added methyl propiolate (0.24 g,
2.8 mmol) and the reaction mixture was stirred at room
temperature for 3 h. The solvent was evaporated under
reduced pressure and the resulting crude was purified by
flash chromatography (ethyl acetate–hexane, 1:3) to afford
4 (0.85 g, 75%) and 5 (0.03 g, 10%).
General procedure for the preparation of N0-aryl-N-
(2S,3R,4S,5S)-2,3,4,5,6-pentahydroxyhexyl-1-yl-N-
methylthioureas (15–17)
Compound 4: yellow crystals; mp 149ЊC (Et2O); IR (KBr)
To a suspension of N-methyl-d-glucamine (11, 1.0 g,
5.13 mmol) in pyridine (4.5 mL) was added the correspond-
ing aryl isothiocyanate (5.13 mmol) and the reaction
mixture was stirred at ambient temperature for 1 h. The
resulting thioureas were isolated by addition of Et2O and
further purification by recrystallization from 96% aqueous
EtOH.
1
nmax 1710, 1660, 1530, 1240, 900, 700 cmϪ1; H NMR
(CDCl3) d 8.23 (d, 2H, aryl), 8.12 (s, 1H, H-4), 7.69–6.82
(m, 12H, aryl), 3.98 (s, 2H, CH2Ph), 3.89 (s, 3H, CH3O),
2.49 (s, 3H, CH3N); 13C NMR (CDCl3) d(165.2 (CO2CH3),
162.3 (C-2), 156.8 (C-6), 147.2, 144.3, 135.7, 135.4, 130.2,
128.6, 128.4, 128.3, 128.2, 128.0, 127.8, 124.2 (aryl), 140.0
(C-4), 126.9 (C-3), 105.5 (C-5), 59.2 (CH2), 52.3 (CO2CH3),
40.0 (CH3N). Anal. Calcd for C27H23N3O5: C, 69.07; H,
4.94; N, 8.95. Found: C, 69.11; H, 4.80; N, 8.94.
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentahydroxyhexyl-1-yl-N-
methyl-N0-phenylthiourea (15). White crystals were
obtained in 87% yield, mp 100ЊC; [a]Dˆϩ12.5 (c 0.5,
H2O); IR (KBr) nmax 3300, 1510, 1320, 1050 cmϪ1 13C
;
Compound 5: yellow oil; IR (CHCl3) nmax 2940, 1700, 1510,
1
1430, 1350, 1200 cmϪ1; H NMR (CDCl3) d 7.52–7.21
NMR (DMSO-d6) d 181.9 (CyS), 141.2, 128.2 (2C),
124.6, 124.1 (phenyl), 72.1, 71.7, 71.6, 69.8 (CHOH),
63.2 (CH2OH), 56.1 (NCH2), 40.1 (NCH3). Anal. Calcd
for C14H22N2O5S: C, 50.89; H, 6.71; N, 8.48; S, 9.70.
Found: C, 50.74; H, 6.78; N, 8.56; S, 9.60.
(11H, H-4, aryl), 4.54 (CH2), 3.81 (CH3O), 2.90 (CH3N);
13C NMR (CDCl3) d 166.1 (CO2CH3), 163.2 (C-2), 136.9,
134.0, 128.8, 128.5, 128.2, 127.5, 126.8, 124.8 (aryl), 124.4
(C-4), 128.8 (C-3), 113.4 (C-5), 62.1 (CH2), 51.3 (CO2CH3),
42.4 (CH3N). Anal. Calcd for C20H19NO2S: C, 71.22; H,
5.64; N, 4.15. Found: C, 71.11; H, 5.80; N, 3.94.
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentahydroxyhexyl-1-yl-N-
methyl-N0-(4-methoxy)phenylthiourea (16). White crystals
were obtained in 92% yield, mp 120ЊC; [a]Dˆϩ9.0 (c 0.5,
6-(N-Methyl)benzylamino-5-methoxycarbonyl-1,3-di-
phenylpyridin-2-one (6). To a solution of 2-(N-methyl)-
benzylamino-3,5-diphenyl-1,3-thiazolium-4-olate (2, 0.50 g,
1.3 mmol) in dry CH2Cl2 (7 mL) was added methyl propio-
late (0.13 g, 1.5 mmol) and the reaction mixture was stirred
at room temperature for 1 h. The solvent was evaporated
and the residue was treated with Et2O to give the title
compound as yellow crystals (0.50 g, 93%). Mp 123ЊC
(Et2O); IR (KBr) nmax 1700, 1660, 1520, 1240, 900,
H2O); IR (KBr) nmax 3300, 1500, 1325 cmϪ1 13C NMR
;
(DMSO-d6) d 182.1 (CyS), 156.4, 134.1, 126.9, 113.4
(phenyl), 72.1, 71.9, 71.5, 69.7 (CHOH), 63.4 (CH2OH),
56.1 (NCH2), 55.4 (OCH3), 40.1 (NCH3). Anal. Calcd for
C15H24N2O6S: C, 49.99; H, 6.71; N, 7.77; S, 8.89. Found: C,
49.87; H, 6.69; N, 7.84; S, 8.82.
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentahydroxyhexyl-1-yl-N-
methyl-N0-(4-nitro)phenylthiourea (17). White crystals
were collected in 83% yield, mp 155ЊC; [a]Dˆϩ15.5
(c 0.5, MeOH); IR (KBr) nmax 3300, 1590, 1540, 1500,
1
700 cmϪ1; H NMR (CDCl3) d 8.10 (s, 1H, H-4), 7.74–
6.78 (m, 15H, aryl), 3.96 (s, 2H, CH2), 3.87 (s, 3H,
CH3O), 2.46 (s, 3H, CH3N); 13C NMR (CDCl3) d 165.5
(CO2CH3), 162.7 (C-2), 157.5 (C-6), 139.6 (C-4), 138.6,
136.1, 135.9, 129.1, 128.6, 128.4, 128.0, 127.9, 127.5,
127.3 (aryl), 126.2 (C-3), 104.8 (C-5), 58.7 (CH2), 52.0
(CO2CH3), 39.7 (CH3N). Anal. Calcd for C27H24N2O3:
1320 cmϪ1 13C NMR (DMSO-d6) d 181.1 (CyS), 147.8,
;
142.0, 124.3 (2C), 122.1 (2C) (phenyl), 71.8, 71.5 (2C),
69.9 (CHOH), 63.4 (CH2OH), 56.2 (NCH2), 41.02
(NCH3). Anal. Calcd for C14H21N3O7S: C, 44.79; H, 5.63;

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1253
N, 11.19; S, 8.54. Found: C, 44.73; H, 5.78; N, 11.24; S,
8.38.
(A or B) gave the title compound in 85% yield with mp
140ЊC; [a]DˆϪ45.5 (c 0.5, CHCl3); IR (KBr) nmax 1750,
1210 cmϪ1; 1H NMR (CDCl3) d 8.27–7.53 (m, 4H, phenyl),
5.80 (m, 1H, H-20), 5.46 (m, 1H, H-40), 5.40 (m, 1H, H-30),
5.06 (m, 1H, H-50), 4.30 (m, 2H, H-10, H-60), 4.11 (m, 2H,
H-100, H-600), 3.22 (s, 3H, NCH3), 2.13 (s, 3H, OAc), 2.10 (s,
3H, OAc), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.04 (s, 3H,
OAc); 13C NMR (CDCl3) d 185.3 (CyS), 170.5, 170.1,
169.8 (2C), 168.4 (CyO), 146.1, 144.9, 126.9 (2C), 124.6
(2C) (phenyl), 69.7, 68.9, 68.7, 68.3 (CHOAc), 61.3
(CH2OAc), 56.3 (CH2N), 41.6 (CH3N), 20.8, 20.8, 20.7
(2C), 20.5 (CH3CO). Anal. Calcd for C24H31N3O12S: C,
49.23; H, 5.34; N, 7.18; S, 5.47. Found: C, 49.36; H, 5.36;
N, 6.77; S, 4.79.
General procedures for the preparation of N-(2S,3R,4S,5S)-
2,3,4,5,6-pentaacetoxyhexyl-1-yl-N0-aryl-N-methyl-
thioureas (18–20)
Method A: To a suspension of the corresponding aryl
thiourea (15–17, 1.0 g) in acetic anhydride (14 mL), cooled
at 0ЊC (external bath), was added a catalytic amount of melt
sodium acetate (3 mg). The reaction mixture was allowed to
warm to room temperature and then it was kept under such
conditions till TLC analysis (ethyl acetate–hexane 3:2)
revealed the disappearance of the starting material and the
formation of a single product (ϳ7 days). The mixture was
poured into ice-water and the resulting solid was recrystal-
lized from 96% aqueous EtOH.
6-[N-Methyl-N-(2S,3R,4S,5S)-20,30,40,50,60-pentaacetoxy-
hexyl-1-yl]amino-4,5-dimethoxycarbonyl-1,3-diphenyl-
pyridin-2-one (24). To a solution of N-(2S,3R,4S,5S)-
2,3,4,5,6-pentaacetoxyhexyl-N-methyl-N0-phenylthiourea
(18, 1.0 g, 1.85 mmol) in dry CHCl3 (20 mL) was added
2-chloro-2-phenylacetyl chloride (0.88 mL, 5.5 mmol).
The reaction mixture was refluxed for 3 h, evaporated
under reduced pressure, and the residue was washed with
Et2O. The latter was dissolved in CHCl3 (40 mL), Et3N
(0.5 mL) was added, and the mixture was refluxed for
10 min. The resulting orange solution was washed repeat-
edly with distilled water, dried over anhydrous MgSO4, and
evaporated to dryness to give an oil. This substance was
dissolved in dry CHCl3 (10 mL), dimethyl acetylene-
dicarboxylate (0.25 mL, 2.0 mmol) was added, and the
reaction mixture was kept at room temperature for 1 h.
TLC analysis (Et2O–hexane 4:1) revealed the formation
of a new compound, which could be isolated after addition
of n-hexane, filtration, and recrystallization from CHCl3–
ethyl acetate (0.85 g, 60%). Mp 200ЊC; [a]Dˆϩ6.0 (c 0.5,
Method B: To a suspension of N-methyl-d-glucamine (11,
1.0 g, 5.13 mmol) in pyridine (5 mL) was added an aryl
isothiocyanate (5.13 mmol) and the mixture was stirred at
room temperature for 1 h. Then, acetic anhydride (25 mL)
and a catalytic amount of sodium acetate (3 mg) and the
reaction mixture was kept for 7 days under these conditions.
It was poured into ice-water, the white solids were collected
by filtration and recrystallized from 96% aqueous EtOH.
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentaacetoxyhexyl-1-yl-N-
methyl-N0-phenylthiourea (18). Either method gave the
title compound in 65% yield as white crystals with mp
105ЊC; [a]DˆϪ39.0 (c 0.5, CHCl3); IR (KBr) nmax 1750,
1370 cmϪ1; 1H NMR (CDCl3) d 7.43–7.30 (m, 5H, phenyl),
5.78 (m, 1H, H-20), 5.43 (m, 1H, H-40), 5.39 (m, 1H, H-30),
5.06 (m, 1H, H-50), 4.29–4.08 (m, 4H, H-10, H-100, H-60,
H-600), 3.29 (s, 3H, N–CH3), 2.14 (s, 3H, OAc), 2.10 (s, 3H,
OAc), 2.08 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.03 (s, 3H,
OAc); 13C NMR (CDCl3) d 186.4 (CyS), 170.4, 169.8,
169.7, 169.7, 169.5, 168.6 (CyO), 140.0, 129.2, 129.0,
128.0 (phenyl), 69.5, 68.9, 68.4, 67.9 (CHOAc), 61.3
(CH2OAc), 55.6 (CH2N), 41.2 (CH3N), 20.7, 20.7, 20.6,
20.4, 20.2 (CH3CO). Anal. Calcd for C24H32N2O10S: C,
53.33; H, 5.92; N, 5.18; S, 5.92. Found: C, 53.42; H, 5.87;
N, 4.93; S, 5.39.
1
CHCl3); IR (KBr) nmax 1745, 1650, 1370, 1210 cmϪ1; H
NMR (CDCl3) d 7.50–7.26 (m, 10H, phenyl), 5.29 (m, 2H,
H-30, H-40), 5.04–5.02 (m, 2H, H-20, H-50), 4.27 (m, 1H,
H-60), 4.12 (dd, 1H, Jˆ5.8, 12.5 Hz, H-600), 3.83 (s, 3H,
COOCH3), 3.56 (s, 3H, COOCH3), 2.75 (s, 4H, H-10,
NCH3), 2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.05 (s, 3H,
OAc), 2.03 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.57 (s, 1H,
H-100); 13C NMR (CDCl3) d 170.5, 170.0, 169.8, 169.7,
167.2, 165.1, 162.4, 155.1, 142.9, 137.7, 133.9, 129.6,
129.2, 129.0, 128.4, 128.2, 128.0, 127.8, 125.8, 102.7
(C-5), 69.5, 68.9, 68.8, 68.6 (CHOAc), 61.6 (CH2OAc),
53.5 (CH2N), 52.6 (COOCH3), 52.2 (COOCH3), 42.1
(CH3N), 20.9, 20.7 (2C), 20.6, 20.5. Anal. Calcd for
C38H42N2O15: C, 59.53; H, 5.48; N, 3.65. Found: C, 59.76;
H, 5.62; N, 3.73.
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentaacetoxyhexyl-1-yl-N-
methyl-N0-(4-methoxy)phenylthiourea (19). White crystals
were obtained in 75% (Method A) and in 86% yield
(Method B), having mp 120ЊC; [a]DˆϪ29.0 (c 0.5,
;
CHCl3); IR (KBr) nmax 1750, 1210 cmϪ1 1H NMR
(CDCl3) d 7.26–6.89 (m, 4H, phenyl), 5.75 (m, 1H, H-20),
5.42–5.36 (m, 2H, H-40, H-30), 5.03 (m, 1H, H-50), 4.28–
4.08 (m, 4H, H-10, H-100, H-60, H-600), 3.81 (s, 3H, OCH3),
3.28 (s, 3H, NCH3), 2.13 (s, 3H, OAc), 2.09 (s, 3H, OAc),
2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.02 (s, 3H, OAc); 13C
NMR (CDCl3) d 186.8 (CyS), 170.5, 169.9, 169.8 (2C), 168.9
(CyO), 159.2, 133.0, 129.3 (2C), 114.4 (2C) (phenyl), 69.6,
68.7, 68.5, 68.0 (CHOAc), 61.3 (CH2OAc), 55.5 (CH2N), 55.4
(OCH3), 41.1 (CH3N), 20.8 (2C), 20.7 (2C), 20.4 (CH3CO).
Anal. Calcd for C25H34N2O11S: C, 52.62; H, 6.01; N, 4.91; S,
5.62. Found: C, 52.64; H, 5.91; N, 4.65; S, 5.18.
0
6-[N-Methyl-N-(2S,3R,4S,5S)-20,30,4, 50,60-pentaacetoxy-
hexyl-1-yl]amino-4,5-dimethoxycarbonyl-1-(4-methoxy)-
phenyl-3-phenylpyridin-2-one (25). The title compound
was prepared from N-(2S,3R,4S,5S)-2,3,4,5,6-pentaacetoxy-
hexyl-N-methyl-N0-(4-methoxy)phenylthiourea (19) in 22%
yield in following the procedure described above for the
preparation of 24. Mp 130ЊC (Et2O); [a]Dˆϩ13.0 (c 0.5,
1
CHCl3); IR (KBr) nmax 1740, 1340, 1200 cmϪ1; H NMR
(CDCl3) d 7.31–6.95 (m, 9H, phenyl), 5.30 (m, 2H, H-40,
H-30), 5.07–5.01 (m, 2H, H-20, H-50), 4.27 (m, 1H, H-60),
4.11 (dd, 1H, Jˆ5.7, 12.4 Hz, H-600), 3.81 (s, 3H, COOCH3),
3.80 (s, 3H, OCH3), 3.53 (s, 3H, COOCH3), 2.75 (s, 3H,
N-(2S,3R,4S,5S)-2,3,4,5,6-Pentaacetoxyhexyl-1-yl-N-
methyl-N0-(4-nitro)phenylthiourea (20). Either procedure

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1254
NCH3), 2.07–2.01 (m, 16H, H-10, 5 OAc), 1.71 (m,
1H, H-100); 13C NMR (CDCl3) d 170.5, 170.0, 169.8,
169.7, 167.2, 165.1, 162.6, 159.2, 155.2, 142.7, 134.0,
130.1, 129.6, 128.0, 127.8, 125.6, 102.7 (C-5), 69.5, 68.9,
68.8, 68.6 (CHOAc), 61.6 (CH2OAc), 55.4 (OCH3),
53.3 (NCH2), 52.5 (COOCH3), 52.2 (COOCH3), 42.1
(CH3N), 23.0, 20.9, 20.7, 20.6, 20.4. HRMS (CIϩ)
found: 796.269084 (C39H44N2O16 requires 796.268062),
Dˆ1.3 ppm.
Acknowledgements
´
´
´
We thank the Spanish Direccion de Investigacion Cientıfica
´
y Tecnica (Project No. PB95-0259) and the Junta de
Extremadura-Fondo Social Europeo (Projects IPR98-
A064 and IPR98-C040) for generous support of this work.
We also thank Prof. F. Lafont (Servicio Espectrometrıa
´
´
Masas, Universidad de Cordoba), for kindly recording the
HRMS spectra for compounds 25 and 26.
3,4-Dimethoxycarbonyl-5-[N-(2S,3R,4S,5S)-20,30,40,50,
60-pentaacetoxyhexyl-1-yl]methylamino-2-phenylthiophene
(26). This substance was obtained from N-(2S,3R,4S,5S)-
2,3,4,5,6-pentaacetoxyhexyl-N-methyl-N0-(4-nitro)phenyl-
thiourea (20) in 43% yield as an oil, in following the above-
mentioned procedures for 24 and 25, and after purification
of the final residue by flash chromatography (Et2O–hexane
4:1). IR (neat) nmax 1740–1700, 1500, 1430, 1360,
1210 cmϪ1; 1H NMR (CDCl3) d 7.40–7.27 (m, 5H, phenyl),
5.36 (m, 3H, H-20, H-30, H-40), 5.05 (m, 1H, H-50), 4.27 (dd,
1H, Jˆ2.5, 12.5 Hz, H-60), 4.13 (dd, 1H, Jˆ5.2, 12.5 Hz,
H-600), 3.82 (s, 3H, COOCH3), 3.78 (m, 1H, H-10), 3.74 (s,
3H, COOCH3), 3.47 (dd, 1H, Jˆ2.6, 15.2 Hz, H-100), 2.99 (s,
3H, NCH3), 2.17 (s, 3H, OAc), 2.13 (s, 3H, OAc), 2.06 (s,
3H, OAc), 2.05 (s, 3H, OAc), 1.97 (s, 3H, OAc); 13C NMR
(CDCl3) d 170.5, 170.1, 169.8, 169.7, 166.1, 163.1, 132.5,
130.8, 129.3, 128.6, 128.2, 114.5, 69.1, 68.7 (2C), 68.5, 61.4
(CH2OAc), 57.2 (CH2N), 52.3 (COOCH3), 51.8 (COOCH3),
43.9 (CH3N), 30.9, 20.6 (3C), 20.4. HRMS (CIϩ)
found: 679.193665 (C31H37NO14S requires 679.193477),
DˆϪ0.3 ppm.
References
1. (a) Potts, K. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 2, pp 1–82. (b) Ollis, W. D.;
Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985, 41, 2239–
2329. (c) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis
1994, 123–141.
2. The term 1,3-thiazolium-4-olate system has been accepted as
IUPAC nomenclature. These substances are also indexed (CAS) as
anhydro-4-hydroxy-1,3-thiazolium hydroxides.
´
´
3. Areces, P.; Avalos, M.; Babiano, R.; Gonzalez, L.; Jimenez,
J. L.; Palacios, J. C.; Pilo, M. D. Carbohydr. Res. 1991, 222,
99–112.
´
4. (a) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Dianez,
´
´
M. J.; Estrada, M. D.; Jimenez, J. L.; Lopez-Castro, A.; Palacios,
J. C.; Garrido, S. P. J. Chem. Soc., Chem. Commun. 1995, 2213–
2214. (b) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.;
´
Higes, F. J.; Jimenez, J. L.; Palacios, J. C. J. Org. Chem. 1996,
61, 3738–3748.
´
5. Arevalo, M. J.; Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse,
M. B.; Jimenez, J. L.; Light, M. E.; Lopez, I.; Palacios, J. C.
´
´
Tetrahedron Lett. 1999, 40, 8675–8678.
6. Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.;
X-Ray crystallographic data for compound 419
´
´
Jimenez, J. L.; Light, M. E.; Lopez, I.; Palacios, J. C. Chem.
Yellow prisms from Et2O, FWˆ469.48 for C27H23N3O5;
data and diffraction parameters were obtained for a crystal
with dimensions 0.40×0.30×0.20 mm3 using MoKa
Commun. 1999, 1589–1590.
7. Silverstein, R. M.; Webster, F. X. Spectrometric Identification
of Organic Compounds; 6th ed.; Wiley: New York, 1998, p 236.
8. Potts, K. T.; Houghton, E.; Singh, U. P. J. Org. Chem. 1974, 39,
3627–3631.
9. Potts, K. T.; Chen, S. J.; Kane, J.; Marshall, J. L. J. Org. Chem.
1977, 42, 1633–1638.
˚
(lˆ0.71073 A) at 150(2) K. Crystal system: triclinic,
˚
space group: P-1; unit cell dimensions: aˆ10.0971(4) A,
˚
˚
bˆ10.3866(3) A, cˆ13.1345(5) A, aˆ99.618(2)Њ, bˆ
3
˚
101.5257(16)Њ, gˆ116.2341(18)Њ; Vˆ1158.45(7) A ; Z
(molecules/unit cell)ˆ2; density (calcd): 1.346 Mg mϪ3; m
(absorption coefficient): 0.094 mmϪ1; F(000)ˆ492; u range
for data collection: 3.19–25.03Њ; index ranges: Ϫ12 Յ h Յ
11; Ϫ12 Յ k Յ 12; Ϫ15 Յ l Յ 15; collected reflections:
11 909, independent reflections: 4086 [Rintˆ0.0348];
completeness to uˆ25.03Њ: 99.6%; maximum and minimum
transmission: 0.9814 and 0.9633; data/restraints/para-
meters: 4086/0/409; GOF (goodness-of-fit on F2): 1.040;
final R indices ‰F2 Ͼ 2sꢀF2†Š : R1ˆ0.0439, wR2ˆ0.1177;
final R indices (all data): R1ˆ0.0567, wR2ˆ0.1254;
extinction coefficient: 0.018(4); Drmax and Drmin (largest
´
10. (a) Avalos, M.; Babiano, R.; Dianez, M. J.; Espinosa, J.;
´
´
´
Estrada, M. D.; Jimenez, J. L.; Lopez-Castro, A.; Mendez, M.
M.; Palacios, J. C. Tetrahedron 1992, 48, 4193–4208. (b) Areces,
´
´
´
P.; Avalos, M.; Babiano, R.; Gonzalez, L.; Jimenez, J. L.; Mendez,
M. M.; Palacios, J. C. Tetrahedron Lett. 1993, 34, 2999–3002.
11. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220.
12. (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M.
W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.;
Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham,
M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.;
Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A.; Challacombe,
M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. M.; Andres,
J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.;
Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, Revision
D.1; Gaussian, Inc.: Pittsburgh, PA, 1995. (b) Frisch, M. J.; Frisch,
Æ.; Foresman, J. B. Gaussian 94 User’s Reference; Gaussian, Inc.:
Pittsburgh, PA, 1994–1996.
diff. peak and hole): 0.834 and Ϫ0.220 e AϪ3; refinement
˚
method: full-matrix least-squares on F2.
Data collection was performed using a Enraf Nonius
KappaCCD diffractometer. The structure was solved by
direct methods with the shelxs97 program,20 while refine-
ment was carried out on F2 by application of the shelxl97
program.21 Absorption correction was accomplished by
means of sortav.22 All hydrogen atoms were located from
the difference map and fully refined.
13. Fleming, I. Frontier Orbitals and Organic Chemical Reac-
tions; Wiley: Chichester, 1976, pp 121–161.
14. Sustmann, R. Tetrahedron Lett. 1971, 2717–2720.

´
M. J. Arevalo et al. / Tetrahedron 56 (2000) 1247–1255
1255
15. Woodward, R. B.; Hoffman, R. The Conservation of Orbital
Symmetry; Academic Press: New York, 1970, pp 87–89.
16. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 1–176. (b)
Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1–173.
17. Houk, K. N.; Yamaguchi, K. In 1,3-Dipolar Cycloaddition
Chemistry, Padwa, A. Ed.; Wiley: New York, 1984; Vol. 2,
pp 407–450.
CCDC-136057, and are available on request from the Director of
the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Any request
should be accompanied by the full literature citation for this
publication.
20. (a) Sheldrick, G. M. SHELXS97: Program for the Solution of
¨
¨
Crystal Structures; University of Gottingen: Gottingen, Germany,
1997. (b) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46,
467–473.
18. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
21. Sheldrick, G. M. SHELXL97: Program for the Refinement of
¨
¨
Crystal Structures; University of Gottingen: Gottingen, Germany,
19. The atomic coordinates and anisotropic displacement coeffi-
cients for this structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
1997.
22. (a) Blessing, R. H. Acta Crystallogr., Sect. A 1995, 51, 33–37.
(b) Blessing, R. H. J. Appl. Crystallogr. 1997, 30, 421–426.