The reaction of 4-amino-2-oxazolines with isocyanates and isothiocyanates. Synthesis and X-ray structures of polysubstituted 2-imidazolidinones, 1,3-oxazolidines and 1,3-thiazolidines

Article abstract of DOI:10.1016/j.tet.2006.04.058

Reactions of 4-alkylamino-2-phenyl-2-oxazolines 1 with isocyanates and isothiocyanates provide unprecedented efficient and regioselective heterocycle-heterocycle transformations. Compounds 1 reacted rapidly with tosyl isocyanate yielding directly 3-alkyl-

Full text of DOI:10.1016/j.tet.2006.04.058

Tetrahedron 62 (2006) 6172–6181
The reaction of 4-amino-2-oxazolines with isocyanates and
isothiocyanates. Synthesis and X-ray structures of polysubstituted
2-imidazolidinones, 1,3-oxazolidines and 1,3-thiazolidines
a
a
a
Antonio Guirado,a, Raquel Andreu, Bruno Martiz, Delia Bautista,
*
b
Carmen Ramırez de Arellano and Peter G. Jones
c
´
a
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Murcia, Campus de Espinardo, 30071 Murcia,
´
Apartado 4021, Spain
b
´
´
Departamento de Quımica Organica, Universidad de Valencia, 46100 Valencia, Spain
cInstitut fu€r Anorganische und Analytische Chemie, Technische Universita€t Braunschweig, Postfach 3329,
38023 Braunschweig, Germany
Received 14 March 2006; revised 10 April 2006; accepted 20 April 2006
Available online 11 May 2006
Abstract—Reactions of 4-alkylamino-2-phenyl-2-oxazolines 1 with isocyanates and isothiocyanates provide unprecedented efficient and
regioselective heterocycle–heterocycle transformations. Compounds 1 reacted rapidly with tosyl isocyanate yielding directly 3-alkyl-4-benz-
amido-1-tosyl-2-imidazolidinones 4 in almost quantitative yields. The corresponding ureido intermediates 2 were not isolable species.
However, the reactions with non-sulfonylated isocyanates or isothiocyanates were slower, leading to the expected ureido and thioureido
derivatives 5, which were easily and efficiently transformed to either polysubstituted 2-imino-1,3-oxazolidine or 2-imino-1,3-thiazolidine
hydrochlorides 7, respectively, by treatment with hydrochloric acid. The possible reasons for this disparity in chemical behaviour are discussed.
X-raycrystallographicstructuresfor4-benzamido-3-methyl-1-tosyl-2-imidazolidinone4b, 4-[1-isopropyl-3-(4-nitrophenyl)ureido]-2-phenyl-
2-oxazoline 5e, (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-oxazolidine hydrochloride 7a and (Z)-3-benzyl-4-benzamido-2-phenylimino-
1,3-thiazolidine hydrochloride 7b have been determined.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
thioureido derivatives, it was considered that these reactions
could be the starting point for attractive approaches to novel
heterocyclic compounds. In preliminary communication7,8
we reported the successful application of this synthetic meth-
odology for preparing novel 2-imidazolidinones, 1,3-oxazo-
lidines and 1,3-thiazolidines. In this paper we describe full
details of this work and new results of the preparative proce-
dures, together with spectral and X-ray crystallographic data
for the hitherto unknown classes of compounds newly
accessed. Differences in chemical behaviour observed for
ureido and thioureido intermediates may be attributed to
crucial electronic effects associated with the presence or
absence of the sulfonyl group.
2-Oxazolines are remarkably versatile synthetic intermedi-
ates.1–4 The vast number of transformations1 reported over
the last few years have led to a renewed interest in the chem-
istry of these compounds. However, only a few examples of
transformations of 2-oxazolines into other heterocycles have
been described; most work on this subject has been focused
on either hydrogenation or dehydrogenation processes to
give products retaining the original ring system.1
As a result of our research project on new methods for the
synthesis of heterocyclic compounds, based on using chloral
as a key starting material, we developed an efficient and gen-
eral preparative procedure that provided novel 4-amino-2-
aryl-2-oxazolines5,6 1 from chloralamides. Continuing this
project, we focused the work on the reactions of these com-
pounds with isocyanates and isothiocyanates. Given the
peculiar structural arrangement of the expected ureido and
2. Results and discussion
4-Alkylamino-2-aryl-2-oxazolines 1 were treated with p-
toluenesulfonyl isocyanate in ether solution at room tem-
perature (Scheme 1). The reactions occurred quickly under
such mild experimental conditions. The instantaneous for-
mation of a white solid precipitate was observed in all cases.
The resulting voluminous crude solid products were isolated
by filtration and identified by the usual analytical methods
Keywords: Oxazolines; Ureas; Thioureas; Imidazolidinones; Oxazolidines;
Thiazolidines.
* Corresponding author. Tel.: +34 968367490; fax: +34 968364148; e-mail:
anguir@um.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.058

A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
6173
R
R
N
N
H
ArCONH
O
N
4-MeC6H4SO2-N=C=O
N
Ar
O
1
Me
SO2
4
4-MeC6H4SO2-N=C=O
R
R
N
N
O
H
N
O
N
HN
Ar
O
2
Me
N
SO2
Ar
O
Me
SO2
3
R
Ar
C6H5
C6H5
C6H5
3-ClC6H4
a
b
c
d
e
C6H5CH2
CH3
(CH3)2CH
C6H5CH2
C6H5CH2
3,4,5-(CH3O)3C6H2
Scheme 1.
as highly pure 3-alkyl-4-benzamido-1-tosyl-2-imidazolidi-
nones 4. Yields were nearly quantitative. IR and NMR spec-
tra for crude and recrystallized products showed negligible
differences.
this analysis were obtained from hexane/chloroform and
contained one molecule of chloroform per molecule of 4b.
A thermogravimetric analysis of this compound showed a
sharp peak at 106.2 ꢀC, corresponding to quantitative loss
of chloroform. The crystallographic analysis showed the
crystal packing to be determined by N–H/O and Cl/O
interactions.
The structural assignment of these compounds was corrobo-
rated by X-ray crystallographic analysis of 4-benzamido-
3-methyl-1-tosyl-2-imidazolidinone 4b. The molecular
structure is illustrated in Figure 1. Selected intramolecular
distances(crystallographic numberingofatoms) and selected
bond angles are given in Table 1. Suitable single crystals for
A particularly facile rearrangement of the ureido intermedi-
ates 2 to imidazolidinones 4 appears as a key step in this
transformation (Scheme 1). However, ureido derivatives
are, in general, stable crystalline compounds that can be
used for the separation and characterization of amines. In
contrast, 2-oxazolines are characterized by a high reluctance
to undergo alteration of the ring system by nucleophilic at-
tacks, and are indeed commonly used as protecting or activat-
ing groups in strongly nucleophilic media.9 Therefore, the
pronounced lability evidenced by intermediates 2 indicates
the existence of some special factors that promote a remark-
able enhancement of electrophilic activity at C-5. A reason-
able explanation for this might be a protonic autoactivation
induced by the sulfonyl group, which would generate an
internal acidic centre. In conjunction with the cogeneration
of a benzamido group, this would strongly facilitate an
Figure 1. Molecular structure of product 4b, showing the crystallographic
numbering system used.
Table 1. Selected bond lengths and bond angles in crystal structure of 4b
Lengths (Å)
O(3)−C(1) 1.213(2)
N(1)−C(1) 1.418(2)
N(2)−C(1) 1.349(2)
N(2)−C(2) 1.458(2)
N(3)−C(2) 1.449(2)
O(4)−C(4) 1.229(2)
N(1)−C(3) 1.474(2)
N(2)−C(5) 1.453(2)
N(3)−C(4) 1.351(2)
C(2)−C(3) 1.537(2)
Angles (°)
C(3)−N(1)−S 120.49(11)
O(3)−C(1)−N(2) 127.28(16)
C(1)−N(1)−C(3) 110.l9(13)
C(4)−N(3)−C(2) 122.79(14)
N(2)−C(2)−C(3) 102.29(12)
C(5)−N(2)−C(2) 123.46(14)
N(3)−C(2)−C(3) 112.11(13)
C(1)−N(2)−C(2) 113.88(13)
N(3)−C(2)−N(2) 112.19(13)
C(1)−N(2)−C(5) 121.19(14)
N(2)−C(1)−N(1) 106.57(13)
C(1)−N(1)−S
122.86(11)
O(3)−C(1)−N(2) 127.3(2)
N(1)−C(3)−C(2) 102.25(13)

6174
A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
intramolecular attack at that site. Therefore, a rearrangement
process involving a ring opening of the oxazolinic intermedi-
ates 3 with simultaneous ring closure to form the correspond-
ing imidazolidinones 4 could take place easily in this way.
This type of rearrangement is as yet unknown in the litera-
ture. A paper containing a remotely related process reported
the conversion of 5-aryl(or benzyl)-3-(2-bromoethyl)1,3,4-
oxadiazol-2(3H)ones to 1-acylamino-3-alkylimidazolin-2-
ones by treatment with primary alkylamines.10c
(crystallographic numbering of atoms) and selected bond
angles are given in Table 2.
R1
R1
Y
N
H
N
R2
N
N
R2-N=C=Y
Y= O,S
NH
Ph
Ph
O
1
O
5
The isolation of the presumably labile sulfonylureido inter-
mediates 2 was attempted by carrying out the reactions at
subambient temperature. Thus, oxazolines 1d,e reacted
with tosyl isocyanate at 0 ꢀC yielding the targeted ureido de-
rivatives 2d,e instead of imidazolines 4d,e. These products
demonstrated a great tendency towards the postulated rear-
rangement to give the corresponding imidazolidinones 4d,e.
In agreement with this discussion, compounds 2d,e showed
mass spectra and melting points fully coincident with those
of 4d,e. However, they were clearly distinguishable by
analyzing the samples with non-aggressive low-temperature
analytical techniques such as IR and NMR spectroscopy.
HCl
R1
R2
R1
HN
H
N
H
N
PhCONH
N
Cl
N
Y
R2
Cl
Y
Ph
O
6
7
R1
R2
Y
entry
C6H5
C6H5
4-CH3OC6H5
4-ClC6H4
4-NO2C6H4
C6H5CH2
(CH3)2CH
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)2CH
C6H5CH2
C6H5CH2
(CH3)2CH
C6H5CH2
a
b
c
d
e
f
O
S
S
O
O
O
O
O
O
2-Imidazolidinones11 are compounds of great interest. As far
as we know, direct conversion of 2-oxazolines into 2-imida-
zolidinones has not yet been reported. The wide variety of
2-oxazolines 1 available5,6 confers a high versatility on this
new approach to specifically polysubstituted 2-imidazolidi-
nones. The most extended methodology for preparing 2-
imidazolidinones involves carbonylation of diamines with
various reagents12 and reactions of diols,12a aminols12a and
1,2-dicarbonyl compounds13 with urea. In general, the limi-
tations found for these procedures are caused by lack of mild-
ness in the required experimental conditions or a deficient
regiocontrol in the formation of more complex products. It
should be noted that the synthesis of specifically substituted
2-imidazolidinones has received significant attention.10 It is
also worth considering that certain polysubstituted 2-imida-
zolidinones exhibit a wide range of therapeutic14 and other
important properties and applications.15,16 Of special impor-
tance is the anticancer activity14c,17 found in several N-aryl-
sulfonyl-4-phenyl-2-imidazolidinones whose structure is
closely related to that of the products 4 described here.
g
h
i
CH3CH2CH2
Scheme 2.
The above results strongly favoured the study of the behav-
iour of the oxazolines 1 in reactions with simple aryl iso-
cyanates instead of tosyl isocyanate, since the role as
activator agent presumed for the sulfonyl group of ureides
2 would be evidenced by these experiments. Thus, amino-
oxazolines 1 were treated with aryl isocyanates in dry ether
at room temperature (Scheme 2). In contrast to the reactions
with p-toluenesulfonyl isocyanate, which occurred almost
instantaneously, a longer reaction time was necessary,
although solid precipitates were also formed. These were
easily isolated by filtration, and were identified as highly
pure4-[1-alkyl-3-arylureido]-2-phenyl-2-oxazolines5rather
than products analogous to compounds 4. IR and NMR spec-
tra for crude and crystallized products showed negligible dif-
ferences. Yields were almost quantitative. The molecular
structure of one of these novel compounds, 4-[1-isopropyl-
3-(4-nitrophenyl)ureido]-2-phenyl-2-oxazoline 5e, was de-
termined by X-ray crystallography. The molecular structure
is illustrated in Figure 2. Selected intramolecular distances
Figure 2. Molecular structure of product 5e, showing the crystallographic
numbering system used.
Compounds 5 were much more stable than the tosylated
intermediates 2. In contrast to the lability exhibited by
compounds 2d,e, the non-sulfonylated ureido derivatives 5
were stable enough to be handled in solution and to permit
prolonged storage without need of any special care. Given
the absence of the sulfonyl group, this relative stability ap-
pears to be attributable to the lack of the protonic autoactiva-
tion postulated above. In order to seek a firm support to this

A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
Table 2. Selected bond lengths and bond angles in crystal structure of 5e
Lengths (Å)
6175
O(1)–C(1) 1.3515(18)
N(1)–C(3) 1.4697(19)
C(2)–C(3) 1.541(2)
N(1)–C(1) 1.2796(19)
N(2)–C(3) 1.4608(18)
O(1)–C(2) 1.4485(19)
Angles (°)
C(1)–O(1)–C(2) 106.00(11)
C(1)–N(1)–C(3) 106.96(13)
N(2)–C(3)–N(1) 111.33(12)
N(1)–C(1)–C(11) 125.60(14)
N(1)–C(1)–O(1) 118.39(14)
N(1)–C(3)–C(2) 104.10(12)
O(1)–C(2)–C(3) 104.31(12)
O(1)–C(1)–C(11) 116.01(13)
hypothesis, it was considered that the treatment of ureides 5
with a mineral acid would circumvent the non-presence of
the sulfonyl group. Consequently, solutions of compounds
5 in ether were treated with concentrated hydrochloric acid
resulting in almost instantaneous reactions with formation
of solid precipitates. The products were crystallized and
characterized as the corresponding 2-arylimino-1,3-oxazoli-
dine or 2-arylimino-1,3-thiazolidine hydrochlorides 7. Crude
and crystallized products showed negligible spectroscopic
differences. Yields were almost quantitative. The molecular
structure of one of these compounds, (Z)-3-benzyl-4-benz-
amido-2-phenylimino-1,3-oxazolidine hydrochloride 7a, was
corroborated by X-ray crystallography. The structure is illus-
trated in Figure 3. Selected intramolecular distances (crystal-
lographic numbering of atoms) and selected bond angles are
given in Table 3. It is of significant interest that similar
treatment of ureides 2d,e with hydrochloric acid provided
the corresponding imidazolidinones 4d,e instead of oxazoli-
dine hydrochloride products.
phenyl-2-oxazolines 5 were isolated in high yields. Such
compounds are also indefinitely stable, but were quickly
and quantitatively convertible to (Z)-3-alkyl-4-benzamido-
2-phenylimino-1,3-thiazolidine hydrochlorides 7 by treat-
ment with hydrochloric acid. The molecular structure of one
of these compounds, (Z)-3-benzyl-4-benzamido-2-phenyl-
imino-1,3-thiazolidine hydrochloride 7b, was determined
by X-ray crystallography. The structure is illustrated in
Figure 4. Selected intramolecular distances (crystallographic
numbering of atoms) and selected bond angles are given in
Table 4.
There are no precedents for compounds of type 7. As far as
we know, this is the first time that direct conversions of 2-
oxazoline rings to either 1,3-oxazolidine or 1,3-thiazolidine
ring systems have been reported. The high versatility of
the reactions5,6 involved in preparing the starting materials
1 implies a concomitantly wide versatility for these synthetic
approaches. The described preparative procedures in sepa-
rate steps could also be carried out in a one-pot process,
which allows quick and highly efficient preparations of
the same compounds. It should be noted that the synthesis
of either 2-iminooxazolidines or 2-iminothiazolidines has
Analogous reactions of aminooxazolines 1 with isothiocya-
nates instead of isocyanates were carried out, providing
parallel results. Highly pure 4-[1-alkyl-3-arylthioureido]-2-
Figure 4. Molecular structure of product 7b, showing the crystallographic
numbering system used.
Figure 3. Molecular structure of product 7a, showing the crystallographic
numbering system used.
Table 3. Selected bond lengths and bond angles in crystal structure of 7a
Lengths (Å)
C(1)–O(1) 1.3182(14)
C(1)–N(2) 1.3241(15)
C(2)–N(1) 1.4776(14)
C(3)–O(1) 1.4632(14)
C(1)–N(1) 1.3204(14)
C(2)–N(3) 1.4350(14)
C(2)–C(3) 1.5331(17)
Angles (°)
N(1)–C(2)–C(3) 100.70(9)
O(1)–C(3)–C(2) 105.66(9)
C(4)–N(1)–C(2) 120.73(9)
C(5)–N(3)–C(2) 122.28(9)
N(1)–C(1)–N(2) 126.08(10)
C(1)–N(1)–C(4) 128.23(10)
C(1)–N(2)–C(11) 126.77(10)
O(1)–C(1)–N(1) 113.88(10)
N(3)–C(2)–N(1) 111.29(9)
C(1)–N(1)–C(2) 110.87(9)
C(1)–O(1)–C(3) 108.24(9)
O(1)–C(1)–N(2) 120.03(10)
N(3)–C(2)–C(3) 113.76(9)

6176
A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
Table 4. Selected bond lengths and bond angles in crystal structure of 7b
Lengths (Å)
S–C(5) 1.8135(12)
S–C(2) 1.7448(13)
C(2)–N(2') 1.323(7)
N(3)–C(4) 1.4635(15)
C(4)–N(1) 1.4518(16)
C(10)–C(11)1.5047(19)
C(30)–O(1) 1.2331(16)
C(30)–C(31)1.4988(19)
C(2)–N(3) 1.3338(16)
N(3)–C(10) 1.4802(16)
C(4)–C(5) 1.5226(17)
N(2')–C(21')1.427(7)
C(30)–N(1) 1.3557(16)
Angles (°)
C(2)–S–C(5)
N(3)–C(2)–S
90.45(6)
N(2')–C(2)–N(3) 129.5(3)
C(2)–N(3)–C(4) 114.62(10)
N(1)–C(4)–N(3) 109.57(9)
N(2')–C(2)–S
116.7(3)
113.75(9)
C(2)–N(3)–C(10) 125.97(10)
N(1)–C(4)–C(5) 115.03(11)
N(3)–C(10)–C(11) 110.64(10)
O(1)–C(30)–C(31) 120.88(12)
C(4)–N(3)–C(10) 117.41(10)
N(3)–C(4)–C(5) 105.64(10)
C(2)–N(2')–C(21') 127.7(6)
N(1)–C(30)–C(31) 118.42(12)
C(4)–C(5)–S
106.30(8)
O(1)–C(30)–N(1) 120.70(13)
special interest because certain members of these types
of compound exhibit important therapeutic and biological
activities.18
materials, mildness and simple experimental procedure
are noteworthy advantages of these approaches, which
provide potential access to previously unattainable com-
pounds. It seems feasible to extend the described synthetic
methodology to prepare a wide variety of heterocyclic
compounds.
2-Imino-1,3-oxazolidines have usually been prepared by
either dehydration of N-(b-hydroxyethyl)-N,N0-diaryl-
ureas19 or reaction of oxiranes with carbodiimides,20
whereas syntheses of 2-iminothiazolidines are based on reac-
tions of 1,2-dihaloalkanes with thioureas,21 treatment of
2-haloamines or g-halocrotonic acid derivatives with isothio-
cyanates,22 cycloaddition between aziridines and isothiocya-
nates23 and treatment of a-haloketone imines with potassium
thiocyanate.24
3. Experimental
3.1. General
NMR spectra were determined on Bruker AC-200 or Varian
Unity 300 Unity instruments with tetramethylsilane as inter-
nal reference. Electron-impact mass spectra were obtained
on Hewlett–Packard 5995 and Autospect 5000 VG spec-
trometers under an ionizing voltage of 70 eV. IR spectra
(Nujol emulsions) were recorded on a Nicolet Impact 400
spectrophotometer. Microanalyses were performed on
a Carlo Erba EA-1108 analyzer. Melting points were deter-
mined on a Kofler hot-plate melting point apparatus, and are
uncorrected.
With regard to the relatively high electrophilic activity of the
oxazoline moieties (Schemes 1 and 2), the evidence de-
scribed above clearly shows that both protonation and gener-
ation of a benzamido group would be the main factors
operating to facilitate the unusual nucleophilic attacks
occurring at C-5. Consequently, in each type of rearrange-
ment, analogous activated intermediates (3 or 6) would be
involved. However, this primary assumption needs to be con-
sidered in conjunction with the participation of either
nitrogen or oxygen and sulfur as nucleophilic active centres.
From this perspective it can be concluded that nucleophilic-
ities of the ureido moieties are crucially influenced by
electronic differences substantial enough to cause a total dis-
parity in the results. The different reaction modalities may
thus be explained taking into consideration that ureas and
thioureas are attacked25 by electrophilic agents, preferen-
tially at the oxygen or sulfur atoms, respectively; this seems
mainly attributable to a relatively high electron density at
such heteroatoms. This is the case for the formation of prod-
ucts 7 via intermediates 6. The formation of products 4 via
intermediates 3, however, would be a consequence of the
strong electron withdrawing effect of the sulfonyl group,
which would substantially decrease the nucleophilicity at the
oxygen.
X-ray crystallographic data were collected using Mo Ka
˚
radiation (l¼0.71073 A). For compounds 4b and 5e a
Siemens P4 diffractometer was used (u-scans, 2qmax 55ꢀ
and 50ꢀ, respectively); for 7a and 7b a Bruker SMART
1000 CCD (u- and ø-scans, 2qmax 60ꢀ). Structures were re-
fined anisotropically on F2 using the program SHELXL-97
(G.M. Sheldrick, University of Gottingen). Hydrogen atoms
¨
were included using rigid methyl groups or a riding model,
except for compound 4b C-5 methyl group which is disor-
dered over two sites. Crystal data are given below for each
compound individually.
3.2. Preparation of 4-benzamido-3-alkyl-1-tosyl-2-
imidazolidinones (4) and 4-(1-alkyl-3-tosylureido)-
2-aryl-2-oxazolines (2)
In conclusion, the first direct conversions of 2-oxazolines
into either 2-imidazolidinones or 1,3-oxazolidines
A solution of p-toluenesulfonyl isocyanate (1 mmol) in dry
ether (3 mL) was added dropwise at room temperature to
a stirred solution of the appropriate aminooxazoline 1
(1 mmol) in dry ether (5 mL). A white precipitate formed
almost instantaneously. The solid products 4 were filtered
off, washed with cold ether and crystallized from a mixture
of hexane/chloroform or hexane/dichloromethane. The reac-
tions carried out at 0 ꢀC yielded the ureido intermediates 2
instead of the final products 4.
7
(Y¼O) or 1,3-thiazolidines 7 (Y¼S) derivatives are
reported. The formation of these products involves hitherto
unknown rearrangement processes. The preparative methods
described here are of significant synthetic utility, providing
directly polysubstituted heterocyclic products of potential
biological interest with a full control of the substitution
pattern. Versatility, good yields, easy availability of starting

A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
6177
3.2.1. 4-(1-Benzyl-3-tosylureido)-2-(3-chlorophenyl)-2-
oxazoline (2d). Yield 88%; crystallization from petroleum
ether/dichloromethane gave white powder; mp 222–
223 ꢀC; 1H NMR (CDCl3, 300 MHz) d (ppm): 2.43 (s, 3H),
4.20 (dd, 1H, J¼10.0 Hz, J¼6.3 Hz), 4.28 (d, 1H,
J¼17.1 Hz), 4.39 (d, 1H, J¼17.1 Hz), 4.49 (t, 1H,
J¼10.0 Hz), 6.35–6.37 (m, 1H), 7.26–7.49 (m, 11H), 7.75–
7.87 (m, 3H); 13C NMR (CDCl3, 75.4 MHz) d (ppm): 21.73
(CH3), 46.49 (CH2), 71.66 (CH2), 77.83 (CH), 126.87
(CH), 126.99 (CH), 128.22 (C), 128.34 (CH), 128.44 (CH),
128.84 (CH), 129.41 (CH), 129.50 (CH), 129.93 (CH),
132.50 (CH), 134.71 (C), 136.14 (C), 136.28 (C), 144.63
(C), 151.99 (CO), 166.30 (C]N); MS (EI, 70 eV) m/z (rel
intensity, %): 483 [M+] (1), 392 (23), 328 (94), 173 (66),
155 (15), 139 (86), 131 (43), 111 (44), 106 (48), 91 (100),
77 (9), 65 (31); IR (Nujol) nmax/cmꢁ1 3321, 1678, 1647,
1462, 1349, 1246, 1165, 1088, 1069, 967, 713, 664; Anal.
Calcd for C24H22ClN3O4S (483.97): C, 59.56; H, 4.58; N,
8.68; S, 6.63. Found: C, 59.43; H, 4.61; N, 8.72; S, 6.51.
J¼10.2 Hz, J¼8.4 Hz), 4.05 (dd, 1H, J¼10.3 Hz,
J¼2.4 Hz), 5.87 (td, 1H, J¼8.4 Hz, J¼2.4 Hz), 7.29 (d, 2H,
J¼8.1 Hz), 7.42 (t, 2H, J¼7.8 Hz), 7.55 (t, 1H, J¼5.1 Hz),
7.83 (d, 2H, J¼8.4 Hz), 7.97–8.03 (m, 3H); 13C NMR
(CDCl3, 75.4 MHz) d (ppm): 21.68 (CH3), 28.00 (CH3),
48.72 (CH2), 59.69 (CH), 127.68 (CH), 127.92 (CH),
128.50 (CH), 129.82 (CH), 132.05 (CH), 133.31 (C),
134.50 (C), 145.04 (C), 153.41 (CO), 168.00 (CO); MS
(EI, 70 eV) m/z (rel intensity, %): 373 [M+] (1), 252 (19),
218 (20), 155 (13), 105 (100), 91 (47), 77 (41); IR (Nujol)
nmax/cmꢁ1 3310, 1732, 1667, 1537, 1464, 1366, 1265,
1171, 1134, 857, 814, 760, 666; Anal. Calcd for
C19H20Cl3N3O4ShC18H19N3O4S(CHCl3) (492.80): C,
46.31; H, 4.09; N, 8.53; S, 6.51. Found: C, 46.24; H, 4.11;
N, 8.49; S, 6.58.
Crystallographic data for 4b. CHCl3: C19H20Cl3N3O4S,
triclinic, space group P(ꢁ1), a¼5.9314(6), b¼13.013(2),
˚
c¼15.650(2) A, a¼109.983(8), b¼99.405(10), g¼
3
ꢀ
˚
96.709(10) , V¼1100.4 A , Z¼2. A colourless prism
0.60ꢂ0.38ꢂ0.28 mm was used to measure 5540 reflections
at T¼173 K, of which 4945 were unique (Rint¼0.010).
Refinement proceeded to wR2¼0.0948 (all data),
R1¼0.0351 and GOF¼1.07 [I>2s(I)]. Maximum residual
3.2.2. 4-(1-Benzyl-3-tosylureido)-2-(3,4,5-trimethoxy-
phenyl)-2-oxazoline (2e). Yield 96%; crystallization from
petroleum ether/dichloromethane gave white powder; mp
247–250 ꢀC; 1H NMR (CDCl3, 300 MHz) d (ppm): 2.43 (s,
3H), 3.85 (s, 6H), 3.88 (s, 3H), 4.20 (dd, 1H, J¼10.0 Hz,
J¼6.0 Hz), 4.29 (d, 1H, J¼15.9 Hz), 4.39 (d, 1H,
J¼16.0 Hz), 4.45 (t, 1H, J¼10.0 Hz), 6.29–6.32 (m, 1H),
7.15 (s, 2H), 7.24–7.36 (m, 7H), 7.78 (d, 2H, J¼8.0 Hz);
13C NMR (CDCl3, 75.4 MHz) d (ppm): 21.69 (CH3), 46.67
(CH2), 56.32 (CH3O), 60.99 (CH3O), 71.66 (CH2), 77.88
(CH), 106.08 (CH), 121.33 (CH), 127.02 (CH), 128.17
(CH), 128.40 (CH), 129.24 (CH), 129.44 (CH), 136.30 (C),
136.45 (C), 141.92 (C), 144.51 (C), 152.07 (C), 153.18 (C),
167.34 (C]N); MS (EI, 70 eV) m/z (rel intensity, %): 539
[M+] (7), 384 (2), 328 (51), 211 (26), 195 (69), 173 (38),
106 (5), 91 (100), 77 (4), 65 (9); IR (Nujol) nmax/cmꢁ1
1692, 1630, 1586, 1467, 1382, 1345, 1228, 1165, 1129,
1084, 1013, 819, 724, 681; Anal. Calcd for C27H29N3O7S
(539.60): C, 60.10; H, 5.42; N, 7.79; S, 5.94. Found: C,
59.98; H, 5.46; N, 9.84; S, 5.89.
ꢁ3
˚
electron density was 0.82 eA
.
3.2.5. 4-Benzamido-3-isopropyl-1-tosyl-2-imidazolidi-
none (4c). Yield 96%; crystallization from petroleum
ether/chloroform gave white micro needles; mp 222–
1
224 ꢀC; H NMR (CDCl3, 300 MHz) d (ppm): 1.22 (m,
6H), 2.45 (s, 3H), 3.84–4.03 (m, 3H), 5.98 (t, 1H,
J¼8.4 Hz), 7.26–7.56 (m, 6H), 7.84–7.90 (m, 4H); 13C
NMR (CDCl3, 75.4 MHz) d (ppm): 19.23 (CH3), 21.34
(CH3), 21.78 (CH3), 45.47 (CH), 50.40 (CH2), 57.05 (CH),
127.39 (CH), 128.24 (CH), 128.80 (CH), 129.84 (CH),
132.31 (CH), 133.33 (C), 134.60 (C), 145.09 (C), 152.78
(CO), 166.93 (CO); MS (EI, 70 eV) m/z (rel intensity, %):
401 [M+] (1), 358 (31), 280 (75), 265 (24), 216 (8), 155
(6), 125 (87), 105 (100), 91 (90), 83 (70), 77 (61); IR
(Nujol) nmax/cmꢁ1 3405, 1723, 1667, 1526, 1464, 1351,
1240, 1225, 1171, 1138, 1108, 716, 669; Anal. Calcd for
C20H23N3O4S (401.48): C, 59.83; H, 5.77; N, 10.47; S,
7.99. Found: C, 59.90; H, 5.81; N, 10.41; S, 8.05.
3.2.3. 3-Benzyl-4-benzamido-1-tosyl-2-imidazolidinone
(4a). Yield 95%; crystallization from petroleum ether/chlo-
roform gave white needles; mp 215–216 ꢀC; 1H NMR
(CDCl3, 300 MHz) d (ppm): 2.47 (s, 3H), 3.90–3.98 (m,
2H), 4.23 (d, 1H, J¼15.0 Hz), 4.53 (d, 1H, J¼15.3 Hz), 5.80
(m, 1H), 7.18–7.53 (m, 11H), 7.77 (d, 2H, J¼7.8 Hz), 7.88 (d,
2H, J¼8.1 Hz); 13C NMR (CDCl3, 75.4 MHz) d (ppm):
21.80 (CH3), 45.48 (CH2), 49.53 (CH2), 58.69 (CH), 127.49
(CH), 127.95 (CH), 128.15 (CH), 128.48 (CH), 128.59
(CH), 128.82 (CH), 129.89 (CH), 132.22 (CH), 133.15 (C),
134.55 (C), 136.24 (C), 145.23 (C), 153.49 (CO), 167.59
(CO); MS (EI, 70 eV) m/z (rel intensity, %): 449 [M+] (2),
358 (6), 328 (55), 294 (11), 173 (37), 155 (5), 131 (27),
105 (95), 91 (100), 77 (40); IR (Nujol) nmax/cmꢁ1 3311,
3.2.6. 3-Benzyl-4-(3-chlorobenzamido)-1-tosyl-2-imida-
zolidinone (4d). Yield 98%; crystallization from petroleum
ether/dichloromethane gave white needles; mp 220–221 ꢀC;
1H NMR (CDCl3, 300 MHz) d (ppm): 2.47 (s, 3H), 3.85 (dd,
1H, J¼10.5 Hz, J¼8.1 Hz), 3.99 (dd, 1H, J¼10.0 Hz,
J¼2.1 Hz), 4.23 (d, 1H, J¼15.0 Hz), 4.56 (d, 1H,
J¼15.0 Hz), 5.78 (td, 1H, J¼8.7 Hz, J¼2.1 Hz), 7.16–7.36
(m, 8H), 7.50 (d, 1H, J¼8.1 Hz), 7.70–7.88 (m, 5H); 13C
NMR (CDCl3, 75.4 MHz) d (ppm): 21.79 (CH3), 45.44
(CH2), 49.37 (CH2), 58.56 (CH), 125.92 (CH), 127.80
(CH), 128.09 (CH), 128.49 (CH), 128.85 (CH), 129.88
(CH), 132.17 (CH), 134.29 (C), 134.75 (C), 135.09 (C),
136.13 (C), 145.34 (C), 153.68 (CO), 166.39 (CO); MS
(EI, 70 eV) m/z (rel intensity, %): 483 [M+] (1), 328 (34),
173 (30), 155 (6), 139 (68), 106 (20), 91 (100), 77 (5); IR
(Nujol) nmax/cmꢁ1 3297, 1745, 1639, 1529, 1466, 1365,
1254, 1165, 1106, 810, 747, 703; Anal. Calcd for
C24H22ClN3O4S (483.97): C, 59.56; H, 4.58; N, 8.68; S,
6.63. Found: C, 59.38; H, 4.63; N, 8.61; S, 6.61.
1743, 1640, 1523, 1464, 1377, 1166, 1123, 1098 cmꢁ1
;
Anal. Calcd for C24H23N3O4S (449.52): C, 64.13; H, 5.16;
N, 9.35; S, 7.13. Found: C, 64.23; H, 5.20; N, 9.39; S, 7.09.
3.2.4. 4-Benzamido-3-methyl-1-tosyl-2-imidazolidinone
(4b). Yield 97%; crystallization from hexane/chloroform
gave colourless prisms; mp 216–218 ꢀC; 1H NMR (CDCl3,
300 MHz) d (ppm): 2.45 (s, 3H), 2.79 (s, 3H), 3.90 (dd, 1H,

6178
A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
3.2.7. 3-Benzyl-4-(3,4,5-trimethoxybenzamido)-1-tosyl-
2-imidazolidinone (4e). Yield 94%; crystallization from
hexane/dichloromethane gave white needles; mp 250 ꢀC;
1H NMR (DMSO-d6, 300 MHz) d (ppm): 2.44 (s, 3H),
3.71 (s, 3H), 3.82 (m, 7H), 4.17 (d, 1H, J¼15.3 Hz), 4.22
(t, 1H, J¼9.3 Hz), 4.38 (d, 1H, J¼15.0 Hz), 5.69 (td, 1H,
J¼8.5 Hz, J¼3.3 Hz), 7.09–7.12 (m, 4H), 7.22–7.24 (m,
3H), 7.48 (d, 2H, J¼8.0 Hz), 7.90 (d, 2H, J¼8.0 Hz), 9.10
(d, 1H, J¼8.5 Hz); 13C NMR (DMSO-d6, 75.4 MHz)
d (ppm): 21.11 (CH3), 44.33 (CH2), 48.10 (CH2), 56.15
(CH3O), 58.49 (CH), 60.13 (CH3O), 105.28 (CH), 127.31
(CH), 127.54 (CH), 127.78 (CH), 128.34 (CH), 128.40
(C), 129.74 (CH), 134.90 (C), 136.56 (C), 140.64 (C),
144.76 (C), 152.57 (C), 152.72 (C), 166.24 (CO); MS (EI,
70 eV) m/z (rel intensity, %): 539 [M+] (8), 384 (3), 328
(66), 211 (34), 195 (84), 173 (53), 155 (7), 131 (25), 106
(8), 91 (100), 77 (6), 65 (13); IR (Nujol) nmax/cmꢁ1 3304,
1744, 1637, 1584, 1525, 1501, 1465, 1378, 1331, 1239,
1174, 1130, 1002, 844, 813, 740, 670; Anal. Calcd for
C27H29N3O7S (539.60): C, 60.10; H, 5.42; N, 7.79; S,
5.94. Found: C, 60.02; H, 5.37; N, 8.85; S, 6.01.
(C]N), 182.94 (C]S); MS (EI, 70 eV) m/z (rel intensity,
%): 387 [M+] (16), 266 (43), 240 (58), 207 (8), 182 (26),
175 (32), 167 (70), 148 (32), 137 (23), 121 (24), 105 (69),
91 (100), 77 (70), 65 (22); IR (Nujol) nmax/cmꢁ1 3313,
1637, 1524, 1463, 1378, 1347, 1321, 1144, 1094, 1051,
967, 697; Anal. Calcd for C23H21N3OS (387.50): C, 71.29;
H, 5.46; N, 10.84; S, 8.28. Found: C, 71.33; H, 5.49; N,
10.95; S, 8.25.
3.3.3. 4-[1-Benzyl-3-(4-methoxyphenyl)thioureido]-2-
phenyl-2-oxazoline (5c). Yield 86%; crystallization from
hexane/dichloromethane gave white needles; mp 118–
120 ꢀC; 1H NMR (CDCl3, 300 MHz) d (ppm): 3.76 (s,
3H), 4.37 (dd, 1H, J¼10.2 Hz, J¼6.3 Hz), 4.63 (d, 1H,
J¼17.1 Hz), 4.77 (d, 1H, J¼17.1 Hz), 4.84 (t, 1H, J¼
9.9 Hz), 6.81 (d, 2H, J¼8.7 Hz), 7.03 (d, 2H, J¼9.0 Hz),
7.25–7.53 (m, 10H), 7.97 (d, 2H, J¼7.2 Hz); 13C NMR
(CDCl3, 75.4 MHz) d (ppm): 48.87 (CH2), 55.48 (CH3O),
72.94 (CH2), 82.28 (CH), 114.01 (CH), 126.80 (CH),
127.09 (C), 127.46 (CH), 128.25 (CH), 128.52 (CH),
128.80 (CH), 129.39 (CH), 132.24 (CH), 136.30 (C),
157.96 (C), 167.32 (C]N), 183.49 (C]S); MS (EI,
70 eV) m/z (rel intensity, %): 417 [M+] (30), 296 (85), 270
(230), 237 (36), 212 (58), 197 (69), 165 (75), 148 (27),
121 (28), 105 (73), 91 (100), 77 (68), 65 (21); IR (Nujol)
nmax/cmꢁ1 3314, 1639, 1519, 1467, 1346, 1280, 1093,
1052, 967, 826, 727, 703, 670; Anal. Calcd for
C24H23N3O2S (417.52): C, 69.04; H, 5.55; N, 10.06; S,
7.68. Found: C, 68.97; H, 5.47; N, 9.98; S, 7.74.
3.3. Preparation of 4-[1-alkyl-3-arylureido]-2-phenyl-2-
oxazolines and 4-[1-alkyl-3-arylthioureido]-2-phenyl-2-
oxazolines (5)
A solution of the appropriate isocyanate or isothiocyanate
(1.8 mmol) in dry ether (9 mL) was added dropwise at
room temperature to a stirred solution of the corresponding
aminooxazoline 1 (1.2 mmol) in dry ether (9 mL). After 1 h
the solid precipitate was filtered off and crystallized from
a suitable solvent.
3.3.4. 4-[1-Benzyl-3-(4-chlorophenyl)ureido]-2-phenyl-
2-oxazoline (5d). Yield 90%; crystallization from THF/
hexane gave white powder; mp 169–172 ꢀC; 1H NMR
(CDCl3, 200 MHz) d (ppm): 4.29 (dd, 1H, J¼10.0 Hz,
J¼6.3 Hz), 4.39 (d, 1H, J¼16.7 Hz), 4.51 (d, 1H, J¼
16.7 Hz), 4.61 (t, 1H, J¼10.0 Hz), 6.62 (dd, 1H,
J¼9.2 Hz, J¼6.4 Hz), 6.68 (s, 1H), 6.58–7.53 (m, 12H),
7.98 (d, 2H, J¼6.8 Hz); 13C NMR d (CDCl3, 50.4 MHz)
d (ppm): 46.93 (CH2), 71.61 (CH2), 78.07 (CH), 121.03
(CH), 126.87 (C), 127.05 (CH), 128.22 (CH), 128.59
(CH), 128.78 (CH), 128.87 (CH), 129.39 (CH), 132.32
(CH), 137.36 (C), 137.53 (C), 155.58 (CO), 166.97
(C]N); MS (EI, 70 eV) m/z (rel intensity, %): 405 [M+]
(6), 284 (53), 258 (11), 251 (16), 161 (8), 153 (46), 146
(37), 131 (53), 118 (39), 105 (48), 91 (100), 77 (38); IR
(Nujol) nmax/cmꢁ1 3378, 1676, 1633, 1593, 1526, 1494,
1455, 1374, 1337, 1226, 1106, 1011, 828, 706; Anal.
Calcd for C23H20ClN3O2 (405.88): C, 68.06; H, 4.97; N,
10.35. Found: C, 67.94; H, 4.99; N, 10.42.
3.3.1. 4-(1-Benzyl-3-phenylureido)-2-phenyl-2-oxazoline
(5a). Yield 81%; crystallization from petroleum ether/
1
dichloromethane gave white needles; mp 122–125 ꢀC; H
NMR (CDCl3, 200 MHz)
d (ppm): 4.30 (dd, 1H,
J¼10.1 Hz, J¼6.3 Hz), 4.40 (d, 1H, J¼17.4 Hz), 4.52 (d,
1H, J¼17.4 Hz), 4.63 (t, 1H, J¼9.8 Hz), 6.61 (br s, 1H),
6.67 (dd, 1H, J¼9.3 Hz, J¼6.3 Hz), 6.95–7.53 (m, 13H),
7.99 (d, 2H, J¼7.5 Hz); 13C NMR (CDCl3, 50.4 MHz)
d (ppm): 46.86 (CH2), 71.72 (CH2), 77.96 (CH), 119.84
(CH), 123.30 (CH), 126.94 (C), 127.07 (CH), 128.14
(CH), 128.57 (CH), 128.77 (CH), 128.90 (CH), 129.35
(CH), 132.24 (CH), 137.67 (C), 138.68 (C), 155.71 (CO),
166.87 (C]N); MS (EI, 70 eV) m/z (rel intensity, %): 371
[M+] (1), 250 (5), 146 (15), 131 (19), 119 (19), 105 (25),
91 (100), 77 (28); IR (Nujol) nmax/cmꢁ1 3295, 1632, 1532,
1446, 1377, 1315, 1173, 965, 756, 700; Anal. Calcd for
C23H21N3O2 (371.43): C, 74.37; H, 5.70; N, 11.31. Found:
C, 74.28; H, 5.71; N, 11.21.
3.3.5. 4-[1-Isopropyl-3-(4-nitrophenyl)ureido]-2-phenyl-
2-oxazoline (5e). Yield 89%; crystallization from petroleum
1
3.3.2. 4-(1-Benzyl-3-phenylthioureido)-2-phenyl-2-oxa-
zoline (5b). Yield 92%; crystallization from hexane/
ether/chloroform gave yellow prisms; mp 160–164 ꢀC; H
NMR (CDCl3, 300 MHz) d (ppm): 1.28 (d, 3H, J¼6.6 Hz),
1.36 (d, 3H, J¼6.6 Hz), 4.29 (t, 1H, J¼9.6 Hz), 4.47
(sept., 1H, J¼6.6 Hz), 4.64 (t, 1H, J¼9.6 Hz), 5.82 (t, 1H,
J¼9.6 Hz), 7.28 (d, 2H, J¼9.3 Hz), 7.51 (t, 2H,
J¼7.8 Hz), 7.62 (t, 1H, J¼7.8 Hz), 7.68 (br s, 1H), 8.03–
8.07 (m, 4H); 13C NMR (CDCl3, 75.4 MHz) d (ppm):
21.09 (CH3), 21.89 (CH3), 46.58 (CH), 71.81 (CH2), 76.57
(CH), 118.14 (CH), 125.11 (CH), 126.24 (C), 128.70
(CH), 128.90 (CH), 132.97 (CH), 142.38 (C), 145.15 (C),
154.73 (CO), 167.51 (C]N); MS (EI, 70 eV) m/z (rel
1
dichloromethane gave white needles; mp 99–102 ꢀC; H
NMR (CDCl3, 200 MHz)
d (ppm): 4.38 (dd, 1H,
J¼10.3 Hz, J¼6.3 Hz), 4.62 (d, 1H, J¼17.0 Hz), 4.79 (d,
1H, J¼17.0 Hz), 4.85 (t, 1H, J¼10.0 Hz), 7.13–7.52 (m,
15H), 7.98 (d, 2H, J¼7.0 Hz); 13C NMR (CDCl3,
50.4 MHz) d (ppm): 49.10 (CH2), 72.98 (CH2), 82.16
(CH), 125.28 (CH), 126.01 (CH), 126.90 (CH), 128.34
(CH), 128.54 (CH), 128.72 (CH), 128.80 (CH), 129.45
(CH), 132.29 (CH), 136.25 (C), 139.23 (C), 167.40

A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
6179
intensity, %): 368 [M+] (5), 247 (25), 217 (14), 203 (51), 189
(18), 175 (11), 164 (45), 146 (100), 134 (51), 118 (43), 105
(94), 90 (60), 83 (53), 77 (57); IR (Nujol) nmax/cmꢁ1 3235,
3281, 3131, 1680, 1635, 1598, 1545, 1505, 1463, 1371,
1307, 1113, 1079, 1028, 848, 704; Anal. Calcd for
C19H20N4O4 (368.39): C, 61.95; H, 5.47; N, 15.21. Found:
C, 62.02; H, 5.56; N, 15.15.
J¼7.8 Hz), 4.71 (d, 1H, J¼15.9 Hz), 5.49 (d, 1H, J¼
15.9 Hz), 6.17 (td, 1H, J¼8.0 Hz, J¼2.8 Hz), 7.33–7.63 (m,
14H), 7.91 (d, 2H, J¼7.1 Hz), 9.75 (d, 1H, J¼8.0 Hz); 13C
NMR (DMSO-d6 50.4 MHz) d (ppm): 33.85 (CH2), 48.81
(CH2), 70.35 (CH), 125.33 (CH), 127.86 (CH), 127.99
(CH), 128.37 (CH), 128.78 (CH), 129.64 (CH), 132.10
(CH), 133.09 (C), 134.64 (C), 166.74 (CO); MS (EI, 70 eV)
m/z (rel intensity, %): 387 [M+ꢁ36] (11), 266 (44), 240
(45), 182 (20), 167 (76), 148 (24), 121 (27), 105 (63), 91
(100), 77 (68), 65 (22); IR (Nujol) nmax/cmꢁ1 3146, 2692,
1650, 1626, 1587, 1519, 1487, 1463, 1378, 1181, 766, 700;
Anal. Calcd for C23H22ClN3OS (423.96): C, 65.16; H, 5.23;
N, 9.91; S, 7.56. Found: C, 65.23; H, 5.19; N, 9.87; S, 7.60.
Crystallographic data for 5e: C19H20N4O4, monoclinic,
˚
space group P21/n, a¼12.3880(12), b¼11.5752(12) A, c¼
3
ꢀ
˚
˚
13.6715(12) A, b¼110.444(4) , V¼1836.9(3) A , Z¼4. A
colourless prism 0.42ꢂ0.22ꢂ0.20 mm was used to measure
3736 reflections at T¼173 K, of which 3234 were unique
(Rint¼0.013). Refinement proceeded to wR2¼0.0803 (all
data), R1¼0.0344 and GOF¼0.901 [I>2s(I)]. Maximum
Crystallographic data for 7b: C23H22ClN3OS, orthorhom-
ꢁ3
˚
residual electron density was 0.12 eA
.
bic, space group Pbca, a¼16.8839(16), b¼10.7096(10),
3
˚
˚
c¼23.290(2) A, V¼4211.2 A , Z¼8. A colourless prism
0.38ꢂ0.21ꢂ0.21 mm was used to measure 33 360 reflec-
tions at T¼143 K, of which 6161 were unique (Rint¼
0.058). The phenyl group at N2 is disordered over two posi-
tions. Refinement proceeded to wR2¼0.0928 (all data),
R1¼0.0357 and GOF¼1.03 [I>2s(I)]. Maximum residual
3.4. One-pot synthesis of (Z)-3-alkyl-4-benzamido-2-
arylimino-1,3-oxazolidine and (Z)-3-alkyl-4-benzamido-
2-arylimino-1,3-thiazolidine hydrochlorides (7)
To a well-stirred solution of aminooxazoline 1 (1 mmol) in
dry ether (10 mL) a solution of the corresponding isocyanate
or isothiocyanate (1 mmol) in dry ether (10 mL) was added
dropwise, and the reaction mixture was stirred at room tem-
perature for 1 h. Then, hydrochloric acid (0.15 mL; 35%)
was added and the solid product was filtered off and crystal-
lized from the appropriate solvent.
ꢁ3
˚
electron density was 0.32 eA
.
3.4.3. (Z)-3-Benzyl-4-benzamido-2-(4-methoxyphenyl)-
imino-1,3-thiazolidine hydrochloride (7c). Yield 90%;
crystallization from ethanol gave white powder; mp 173–
1
182 ꢀC dec; H NMR (DMSO-d6, 200 MHz) d (ppm): 3.48
(dd, 1H, J¼8.0 Hz, J¼2.7 Hz), 3.80 (s, 3H), 3.92 (dd, 1H,
J¼7.9 Hz, J¼7.8 Hz), 4.68 (d, 1H, J¼16.0 Hz), 5.50 (d,
1H, J¼16.0 Hz), 6.19 (td, 1H, J¼8.0 Hz, J¼2.7 Hz), 7.05
(d, 2H, J¼8.7 Hz), 7.36–7.59 (m, 11H), 7.92 (d, 2H,
J¼7.9 Hz), 9.82 (d, 1H, J¼8.0 Hz); 13C NMR (DMSO-d6,
50.4 MHz) d (ppm): 33.88 (CH2), 48.88 (CH2), 55.56
(CH3O), 70.84 (CH), 114.76 (CH), 127.20 (CH), 127.87
(CH), 127.99 (CH), 128.04 (CH), 128.35 (CH), 128.78
(CH), 131.43 (C), 132.10 (CH), 133.03 (C), 134.32 (C),
159.10 (C), 166.72 (CO); FAB+, 418 (100); IR (Nujol)
nmax/cmꢁ1 3198, 2732, 2650, 1626, 1519, 1459, 1376,
1247, 1177, 1032, 828, 710; Anal. Calcd for
C24H24ClN3O2S (453.99): C, 63.49; H, 5.33; N, 9.26; S,
7.06. Found: C, 63.73; H, 5.47; N, 9.16; S, 7.03.
3.4.1. (Z)-3-Benzyl-4-benzamido-2-phenylimino-1,3-oxa-
zolidine hydrochloride (7a). Yield 92%; crystallization
1
from ethanol gave colourless prisms; mp 164–165 ꢀC; H
NMR (DMSO-d6, 200 MHz) d (ppm): 4.63 (d, 1H,
J¼16.1 Hz), 4.84 (dd, 1H, J¼9.6 Hz, J¼3.6 Hz), 5.10 (t,
1H, J¼9.3 Hz), 5.52 (d, 1H, J¼16.0 Hz), 6.00 (td, 1H,
J¼9.4 Hz, J¼3.3 Hz), 7.23–7.60 (m, 13H), 7.90 (d, 2H,
J¼7.0 Hz), 9.82 (d, 1H, J¼8.1 Hz); 13C NMR (DMSO-d6,
50.4 MHz) d (ppm): 45.46 (CH2), 64.87 (CH), 74.02
(CH2), 119.58 (CH), 124.07 (CH), 126.51 (C), 126.95
(CH), 127.68 (CH), 128.10 (CH), 128.47 (CH), 128.68
(CH), 129.23 (CH), 132.26 (CH), 132.87 (C), 134.07 (C),
158.71 (C]N), 166.90 (CO); MS (EI, 70 eV) m/z (rel inten-
sity, %): 371 [M+ꢁ36] (1), 250 (1), 226 (2), 181 (2), 145
(77), 117 (63), 105 (43), 90 (100), 77 (61); IR (Nujol)
nmax/cmꢁ1 3212, 3185, 1682, 1665, 1596, 1531, 1462,
1378, 1278, 1153, 1070, 997, 944, 839, 767; Anal. Calcd
for C23H22ClN3O2 (407.89): C, 67.73; H, 5.44; N, 10.30.
Found: C, 67.46; H, 5.31; N, 10.24.
3.4.4. (Z)-3-Benzyl-4-benzamido-2-(4-chlorophenyl)-
imino-1,3-oxazolidine hydrochloride (7d). Yield 94%;
crystallization from methanol gave white powder; mp
1
167 ꢀC; H NMR (DMSO-d6, 200 MHz) d (ppm): 4.60 (d,
1H, J¼16.1 Hz), 4.81 (dd, 1H, J¼8.0 Hz, J¼3.4 Hz), 5.07
(t, 1H, J¼8.1 Hz), 5.44 (d, 1H, J¼16.1 Hz), 5.98 (td, 1H,
J¼8.2 Hz, J¼3.3 Hz), 7.12–7.65 (m, 12 H), 7.87 (d, 2H,
J¼6.9 Hz), 9.70 (d, 1H, J¼8.1 Hz); 13C NMR d (DMSO-
d6, 50.4 MHz) d (ppm): 45.53 (CH2), 64.64 (CH), 73.68
(CH2), 121.13 (CH), 125.59 (CH), 127.61 (CH), 128.03
(CH), 128.48 (CH), 128.67 (CH), 129.17 (CH), 132.23
(CH), 132.97 (C), 134.35 (C), 139.13 (C), 139.26 (C),
154.88 (C]N), 166.95 (CO); FAB+, 406 (100); IR (Nujol)
nmax/cmꢁ1 3166, 2670, 1684, 1660, 1531, 1490, 1464,
1377, 1284, 1152, 1095, 1004, 959, 837, 809, 705; Anal.
Calcd for C23H21Cl2N3O2 (442.34): C, 62.45; H, 4.79; N,
9.50. Found: C, 62.13; H, 4.88; N, 9.43.
Crystallographic data for 7a: C23H22ClN3O2, triclinic, space
˚
group P(ꢁ1), a¼9.7195(8), b¼9.9757(8), c¼11.2373(10) A,
3
ꢀ
˚
a¼90.287(3), b¼112.816(3), g¼98.369(3) , V¼991.35 A ,
Z¼2. A colourless prism 0.35ꢂ0.18ꢂ0.15 mm was used to
measure 15 487 reflections at T¼143 K, of which 5751
were unique (Rint¼0.047). Refinement proceeded to wR2¼
0.0992 (all data), R1¼0.0373 and GOF¼1.05ꢁ3[I>2s(I)].
˚
Maximum residual electron density was 0.39 eA
.
3.4.2. (Z)-3-Benzyl-4-benzamido-2-phenylimino-1,3-
thiazolidine hydrochloride (7b). Yield 88%; crystallization
from acetonitrile gave colourless prisms; mp 172–174 ꢀC;
1H NMR (DMSO-d6, 200 MHz) d (ppm): 3.46 (dd,
1H, J¼11.9 Hz, J¼2.8 Hz), 3.91 (dd, 1H, J¼11.9 Hz,
3.4.5. (Z)-4-Benzamido-3-isopropyl-2-(4-nitrophenyl)-
imino-1,3-oxazolidine hydrochloride (7e). Yield 97%;

6180
A. Guirado et al. / Tetrahedron 62 (2006) 6172–6181
crystallization from ethanol/pentane gave white needles; mp
119–121 ꢀC; 1H NMR (DMSO-d6, 200 MHz) d (ppm): 1.23
(d, 3H, J¼6.2 Hz), 1.43 (d, 3H, J¼6.2 Hz), 4.36–4.39 (m,
1H), 4.97–5.07 (m, 2H), 6.17–6.19 (m, 1H), 7.62–7.82 (m,
5H), 8.11 (d, 2H, J¼9.1 Hz), 8.28 (d, 2H, J¼7.4 Hz), 9.69
(s, 1H); 13C NMR d (DMSO-d6, 50.4 MHz) d (ppm):
21.57 (CH3), 47.98 (CH), 69.49 (CH), 74.14 (CH2), 119.35
(CH), 124.52 (CH), 129.47 (CH), 129.92 (CH), 135.71
(CH), 141.34 (C), 146.77 (C), 153.78 (C]N), 170.02
(CO); MS (EI, 70 eV) m/z (rel intensity, %): 247 (2), 223
(4), 203 (5), 164 (18), 145 (80), 138 (69), 117 (76), 108
(62), 90 (100), 77 (26); IR (Nujol) nmax/cmꢁ1 3258, 2576,
1677, 1613, 1502, 1464, 1376, 1312, 1244, 1077, 855,
703; Anal. Calcd for C19H21ClN4O4 (404.85): C, 56.37; H,
5.23; N, 13.84. Found: C, 56.14; H, 5.57; N, 13.86.
J¼8.5 Hz), 6.06 (td, 1H, J¼8.0 Hz, J¼3.1 Hz), 7.30–7.65
(m, 8H), 7.91 (d, 2H, J¼6.8 Hz), 9.76 (d, 1H, J¼7.8 Hz),
10.71 (s, 1H); 13C NMR (DMSO-d6, 50.4 MHz) d (ppm):
18.83 (CH3), 20.90 (CH3), 45.71 (CH2), 46.51 (CH), 63.04
(CH), 73.80 (CH2), 127.51 (CH), 127.59 (CH), 127.71
(CH), 128.66 (CH), 132.27 (CH), 133.27 (C), 137.09 (C),
158.09 (C]N), 166.48 (CO); MS (EI, 70 eV) m/z (rel inten-
sity, %): 337 (1), 252 (7), 216 (39), 192 (45), 191 (43), 174
(19), 146 (37), 145 (38), 121 (19), 105 (79), 91 (100), 77
(61); IR (Nujol) nmax/cmꢁ1 3175, 1683, 1539, 1456, 1364,
1298, 1281, 1215, 1081, 1038, 710; Anal. Calcd for
C20H24ClN3O2 (373.88): C, 64.25; H, 6.47; N, 11.24.
Found: C, 64.13; H, 6.49; N, 11.06.
3.4.9. (Z)-3-Benzyl-4-benzamido-2-propylimino-1,3-oxa-
zolidine hydrochloride (7i). Yield 92%; crystallization
from ethanol/pentane gave colourless prisms; mp 170 ꢀC;
1H NMR (DMSO-d6, 300 MHz) d (ppm): 0.93 (t, 3H,
J¼7.5 Hz), 1.58–1.70 (m, 2H), 3.32 (m, 2H), 4.48 (d, 1H,
J¼16.2 Hz), 4.80 (dd, 1H, J¼8.7 Hz, J¼3.9 Hz), 5.05 (t,
1H, J¼8.7 Hz), 5.13 (d, 1H, J¼16.2 Hz), 5.91 (td, 1H,
J¼8.1 Hz, J¼3.3 Hz), 7.30–7.61 (m, 8H), 7.86 (d, 2H,
J¼8.1 Hz), 9.70 (d, 1H, J¼8.0 Hz), 10.59 (s, 1H); 13C
NMR (DMSO-d6, 75.4 MHz) d (ppm): 11.00 (CH3), 22.08
(CH2), 44.01 (CH2), 44.87 (CH2), 64.90 (CH), 73.42
(CH2), 127.58 (CH), 127.95 (CH), 128.37 (CH), 128.59
(CH), 132.13 (CH), 132.89 (C), 134.19 (C), 159.62
(C]N), 166.94 (CO); MS (EI, 70 eV) m/z (rel intensity,
%): 337 (3), 252 (64), 192 (36), 146 (49), 106 (53), 90
(100), 77 (68); IR (Nujol) nmax/cmꢁ1 3217, 3185, 1695,
1666, 1537, 1465, 1275, 1113, 996, 807, 712; Anal. Calcd
for C20H24ClN3O2 (373.88): C, 64.25; H, 6.47; N, 11.24.
Found: C, 63.86; H, 7.12; N, 11.37.
3.4.6. (Z)-3-Benzyl-2-benzylimino-4-benzamido-1,3-oxa-
zolidine hydrochloride (7f). Yield 90%; crystallization
from ethanol/hexane gave colourless prisms; mp 164 ꢀC;
1H NMR (DMSO-d6, 200 MHz) d (ppm): 4.53 (d, 1H,
J¼11.5 Hz), 4.58 (s, 2H), 4.83 (dd, 1H, J¼9.3 Hz, J¼
3.7 Hz), 5.06 (t, 1H, J¼8.8 Hz), 5.14 (d, 1H, J¼11.5 Hz),
5.97 (td, 1H, J¼8.0 Hz, J¼3.6 Hz), 7.28–7.63 (m, 13H),
7.88 (d, 2H, J¼7.1 Hz), 9.82 (d, 1H, J¼7.9 Hz), 11.34 (t,
1H, J¼5.9 Hz); 13C NMR (DMSO-d6, 50.4 MHz) d (ppm):
45.06 (CH2), 45.43 (CH2), 65.10 (CH), 73.66 (CH2),
127.71 (CH), 127.72 (CH), 127.83 (CH), 128.07 (CH),
128.16 (CH), 128.26 (CH), 128.45 (CH), 128.65 (CH),
132.24 (CH), 132.91 (C), 134.18 (C), 136.71 (C), 159.79
(C]N), 167.01 (CO); MS (EI, 70 eV) m/z (rel intensity,
%): 264 (17), 240 (75), 145 (43), 117 (22), 106 (100), 91
(90), 77 (47); IR (Nujol) nmax/cmꢁ1 3168, 1689, 1658,
1536, 1466, 1378, 1276, 1125, 1020, 952, 714; Anal. Calcd
for C24H24ClN3O2 (421.92): C, 68.32; H, 5.73; N, 9.96.
Found: C, 67.03; H, 5.88; N, 9.84.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC-299402 (4b), CCDC-298631
(5e), CCDC-243016 (7a) and CCDC-243018 (7b). Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
3.4.7. (Z)-3-Benzyl-4-benzamido-2-isopropylimino-1,3-
oxazolidine hydrochloride (7g). Yield 89%; crystallization
1
from THF gave colourless prisms; mp 171 ꢀC; H NMR
(DMSO-d6, 200 MHz) d (ppm): 1.30 (t, 6H, J¼6.7 Hz),
3.99 (sept., 1H, J¼6.6 Hz), 4.46 (d, 1H, J¼16.3 Hz), 4.79
(dd, 1H, J¼8.0 Hz, J¼3.6 Hz), 5.04 (t, 1H, J¼8.8 Hz), 5.09
(d, 1H, J¼16.3 Hz), 5.89 (td, 1H, J¼8.0 Hz, J¼3.5 Hz),
7.29–7.58 (m, 8H), 7.83 (d, 2H, J¼7.0 Hz), 9.62 (d, 1H,
J¼7.9 Hz), 10.10 (d, 1H, J¼7.4 Hz); 13C NMR d (DMSO-
d6, 50.4 MHz) d (ppm): 19.31 (CH3), 19.62 (CH3), 42.16
(CH2), 43.75 (CH), 62.15 (CH), 70.82 (CH2), 124.89 (CH),
125.11 (CH), 125.29 (CH), 125.73 (CH), 125.98 (CH),
129.50 (CH), 130.23 (C), 131.55 (C), 156.26 (C]N),
164.26 (CO); MS (EI, 70 eV) m/z (rel intensity, %): 337
(6), 322 (12), 252 (61), 216 (16), 201 (24), 191 (51), 146
Acknowledgements
We gratefully acknowledge the financial support of the
´
Ministerio de Educacion y Ciencia (project CTQ2004-
06427) and the Consejerıa de Economıa, Industria e
´
´
´
Innovacion of the Comunidad Autonoma de la Region de
Murcia (project 2I04SU005). B.M. thanks the Fundacion
´
´
´
(55), 131 (29), 106 (85), 91 (100), 77 (45); IR (Nujol) nmax
/
cmꢁ1 3130, 1695, 1657, 1531, 1460, 1379, 1287, 1157,
1101, 1081, 716; Anal. Calcd for C20H24ClN3O2 (373.88):
C, 64.25; H, 6.47; N, 11.24. Found: C, 63.79; H, 6.51; N,
11.05.
Cajamurcia for a grant.
References and notes
3.4.8. (Z)-2-Benzylimino-4-benzamido-3-isopropyl-1,3-
oxazolidine hydrochloride (7h). Yield 95%; crystallization
from THF/pentane gave white needles; mp 171 ꢀC; 1H NMR
(DMSO-d6, 200 MHz) d (ppm): 1.15 (d, 3H, J¼6.6 Hz),
1.39 (d, 3H, J¼6.6 Hz), 4.22 (sept., 1H, J¼6.6 Hz), 4.54
(s, 2H), 4.65 (dd, 1H, J¼8.5 Hz, J¼3.0 Hz), 4.89 (t, 1H,
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