Direct conversion of 4-amino-2-phenyl-2-oxazolines into either 2-arylimino-1,3-oxazolidine or 2-arylimino-1,3-thiazolidine hydrochlorides

Article abstract of DOI:10.1016/S0040-4039(03)00783-4

A novel heterocycle-heterocycle inter-conversion is reported. It enables direct and efficient syntheses of either polysubstituted 2-arylimino-1,3-oxazolidine or 2-arylimino-1,3-thiazolidine hydrochlorides by a one-pot treatment of 4-amino-2-phenyl-2-oxazolines with arylisocyanates or arylisothiocyanates, respectively, followed by addition of hydrochloric acid.

Full text of DOI:10.1016/S0040-4039(03)00783-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3809–3812
Direct conversion of 4-amino-2-phenyl-2-oxazolines into either
2-arylimino-1,3-oxazolidine or 2-arylimino-1,3-thiazolidine
hydrochlorides
Antonio Guirado,a,* Raquel Andreua and Jesu´s Ga´lvezb
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Murcia, Campus de Espinardo, 30071-Murcia,
Apartado 4021, Spain
bDepartamento de Qu´ımica F´ısica, Facultad de Qu´ımica, Universidad de Murcia, Campus de Espinardo, 30071-Murcia,
Apartado 4021, Spain
Received 14 January 2003; accepted 14 March 2003
Abstract—A novel heterocycle–heterocycle inter-conversion is reported. It enables direct and efficient syntheses of either
polysubstituted 2-arylimino-1,3-oxazolidine or 2-arylimino-1,3-thiazolidine hydrochlorides by a one-pot treatment of 4-amino-2-
phenyl-2-oxazolines with arylisocyanates or arylisothiocyanates, respectively, followed by addition of hydrochloric acid. © 2003
Elsevier Science Ltd. All rights reserved.
We recently developed an efficient new preparative
procedure for 2-oxazolines1 that provided the first syn-
thesis of 4-amino-2-aryl-2-oxazolines 1. On exploring
the reactivity of these compounds, we found that they
undergo direct and remarkably fast conversions to imi-
dazolidinones 4 by reaction with p-toluenesulfonyl iso-
cyanate at room temperature2 (Scheme 1). It was taken
into account that the first generated arylsulfonylureido
derivatives 2, which have a relatively highly acidic
centre, were not detected. The participation in this
transformation of the reactive intermediate 3 was pos-
tulated. A protonic autoactivation of 2 would lead to 3.
Hence, a ring opening of the normally stable 2-oxazo-
line system with a simultaneous ring closure to give the
corresponding imidazolidinones 4 would occur easily in
this way. By working at low temperature, two of these
labile ureido compounds 2 were recently isolated3 and
consistently showed a remarkable proclivity to undergo
a quantitative conversion to the corresponding prod-
ucts 4. The chemistry of 2-oxazolines has been exten-
sively studied,4 with there being few examples of
transformation into other heterocycles. The reported
work on this subject mainly corresponds to either
hydrogenation or dehydrogenation of starting com-
pounds to give products retaining the original ring
system.4e
In view of the high interest of the above results, we
have directed our attention to the study of reactions of
4-alkylamino-2-phenyl-2-oxazolines 1a–e with aryliso-
cyanates and arylisothiocyanates in order to clarify the
action of the sulfonyl group in the isomerisation pro-
cess. This paper deals with the dramatic change found
between the behaviour of sulfonylated ureido deriva-
tives 2 and the corresponding non-sulfonylated ureido
and thioureido compounds 5 which also exhibit a high
potential for the synthesis of previously unattainable
heterocyclic compounds.
In contrast to the reactions with p-toluenesulfonyl iso-
cyanate, which occurred almost instantaneously it was
observed that compounds 1 reacted with both iso-
cyanates or isothiocyanates over a longer time. The
crude products formed were easily isolated in a high
purity state5 by simple filtration, and were crystallized
and identified by IR, MS, NMR spectroscopy and
elemental analysis as the corresponding ureido or
thioureido derivatives 5. Yields were near to quantita-
tive. The molecular structure of one of these com-
pounds:
4-[1-isopropyl-3-(4-nitrophenyl)ureido]-2-
phenyl-2-oxazoline 5e, was confirmed by X-ray crystal-
lography.7
Contrary to the lability of the N-sulfonylureido inter-
mediates 2, it was found that the ureido analogs 5 were
stable enough to be handled in solution and also to
permit a prolonged storage without need of any special
Keywords: oxazolines; ureas; thioureas; oxazolidines; thiazolidines.
* Corresponding author. Fax +34-968364148; e-mail: anguir@um.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00783-4

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A. Guirado et al. / Tetrahedron Letters 44 (2003) 3809–3812
Scheme 1.
care. This is on excellent agreement with that expected
for the case of a non-favoured rearrangement moti-
vated by the absence of the postulated protonic
autoactivation.
There are no precedents for the families of compounds
7 and 8. As far as we know, this is the first time that
direct conversions of 2-oxazolines into 1,3-oxazolidines
or 1,3-thiazolidines have been reported. The wide vari-
ety of oxazolines 1 available1,8 determines a high ver-
satility in these new synthetic approaches. The
preparative procedures in separate steps described
could also be carried out in a one-pot process, which
allows a quick and very efficient preparation of the
same heterocyclic compounds (Table 1). It should be
noted that the synthesis of either 2-iminooxazolidines
or 2-iminothiazolidines has an especial interest because
they show a range of important therapeutic and biolog-
ical activities.9
The above facts strongly suggested that a mineral acid
would have the ability to circumvent the non-presence
of the sulfonyl group and, therefore, provoke a rear-
rangement process. This hypothesis was fully confirmed
by treatment of compounds 5 with hydrochloric acid,
which gave almost instantaneous reactions with the
formation of solid products in high purity state5 which
were, in turn, crystallized and characterised by IR, MS,
NMR spectroscopy and elemental analysis as the corre-
sponding hydrochlorides of 2-arylimino-1,3-oxazo-
lidines6 7 (Y=O) and 2-arylimino-1,3-thiazolidines6 7
(Y=S). Yields were almost quantitative. The molecular
structure of these compounds was corroborated by
X-ray crystallography of (Z)-3-benzyl-4-benzamido-2-
phenylimino-1,3-oxazolidine hydrochloride7 7a and
(Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-thiazoli-
dine hydrochloride7 7b. It was proved that this hydro-
chloride liberates hydrogen chloride quantitatively by
treatment with an equivalent amount of thiethylamine
to give the corresponding free aryliminothiazolidine 8b.
Both the relatively highly reactivity of the sulfonylated
ureides 2 and the entire change of selectivity towards
each reaction mode observed can be explained on the
basis of a crucial electronic effect of the sulfonyl group.
Thus, it seems reasonable to postulate that in each
transformation the reactive intermediates—either 3 or
6—would participate. An internal electrophilic attack
on one of the alternative heteroatoms (N or O,S) would
subsequently operate.

A. Guirado et al. / Tetrahedron Letters 44 (2003) 3809–3812
Table 1. One-pot synthesis of compounds 7
3811
Entry
Y
R
Ar
Yield (%)
Mp (°C)
7a
7b
7c
7d
7e
O
S
S
S
O
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)2CH
C6H5
C6H5
4-CH3OC6H4
4-ClC6H4
4-O2NC6H4
92
88
90
94
97
164–165
172–174
173 (dec.)
167
119–121
The reasons for the difference in behaviour between
intermediates 2 and 5 can be explained if we consider
that ureas and thioureas are attacked10 by electrophilic
agents preferentially at the oxygen or sulfur atoms,
respectively. This is mainly attributable to a high elec-
tron density on such heteroatoms. This is the case for
the formation of products 7 from intermediates 5. The
formation of products 4 from intermediates 2, however,
seems to be in agreement with the strong electron
withdrawing effect of the sulfonyl group, which would
substantially decrease the nucleophilicity of those reac-
tive centres.
2. Guirado, A.; Andreu, R.; Ga´lvez, J. Tetrahedron Lett.
1999, 40, 8163.
3. Unpublished results.
4. For reviews, see: (a) Wiley, R. H.; Bennett, L. L. Chem.
Rev. 1949, 44, 447; (b) Seeliger, W.; Aufderhaar, E.;
Diepers, W.; Feinauer, R.; Nehring, R.; Their, W.; Hell-
mann, H. Angew. Chem., Int. Ed. Engl. 1966, 5, 875; (c)
Frump, J. A. Chem. Rev. 1971, 71, 483; (d) Meyers, A. I.;
Mihelich, E. D. Angew. Chem., Int. Ed. Engl. 1976, 15,
270; (e) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41,
837; (f) Maryanoff, B. E. In Chemistry of Heterocyclic
Compounds; Turchi, I., Ed. Oxazoles. John Wiley & Sons:
Chichester, 1986; Vol. 45, p. 963; (g) Gant, T. G.;
Meyers, A. I. Tetrahedron 1994, 50, 2297.
In summary, the first direct conversion of 2-oxazolines
into either 1,3-oxazolidines 7 (Y=O) or 1,3-thiazolidi-
nes 7 (Y=S) is reported. Versatility, good yields, easy
availability of starting materials, mildness and simple
experimental procedure are noteworthy advantages of
this approach, which has high prospects in the access to
previously unattainable compounds. In this work a new
reaction mode has been found which is associated to a
peculiar molecular arrangement of 4-amino-2-oxazoline
ureido derivatives. It seems feasible to extend the
described synthetic methodology for preparing a wide
variety of heterocyclic compounds.
1
5. IR and H NMR spectra for crude and crystalline prod-
ucts were recorded showing negligible differences.
6. All compounds gave satisfactory microanalyses. Spectral
data for 7a and 7b are reported as examples of spectro-
scopic properties of these classes of compound. Com-
pound 7a: 1H NMR l (DMSO-d6, 200 MHz): 4.63 (d,
1H, J=16.1 Hz), 4.84 (dd, 1H, J=9.6 Hz, J=3.6 Hz),
5.10 (t, 1H, J=9.3 Hz), 5.52 (d, 1H, J=16.0 Hz), 6.00
(td, 1H, J=9.4 Hz, J=3.3 Hz), 7.23–7.60 (m, 13H), 7.90
(d, 2H, J=7.0 Hz), 9.82 (d, 1H, J=8.1 Hz); 13C NMR l
(DMSO-d6, 50.4 MHz): 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 (CꢀN), 166.90 (CO); MS; m/z (%): 371 (M+−HCl,
1), 250 (1), 226 (2), 181 (2), 145 (77), 117 (63), 105 (43),
90 (100), 77 (61); IR (Nujol): 3212, 3185, 1682, 1665,
1596, 1531, 1462, 1378, 1278, 1153, 1070, 997, 944, 839,
767 cm−1. Compound 7b: 1H NMR l (DMSO-d6, 200
MHz): 3.46 (dd, 1H, J=11.9 Hz, J=2.8 Hz), 3.91 (dd,
1H, J=11.9 Hz, J=7.8 Hz), 4.71 (d, 1H, J=15.9 Hz),
5.49 (d, 1H, J=15.9 Hz), 6.17 (td, 1H, J=8.0 Hz, J=2.8
Hz), 7.33–7.63 (m, 14H), 7.91 (d, 2H, J=7.1 Hz), 9.75 (d,
1H, J=8.0 Hz); 13C NMR l (DMSO-d6 50.4 MHz):
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; m/z (%): 387 (M+−HCl, 11), 266 (44), 240
(45), 182 (20), 167 (76), 148 (24), 121 (27), 105 (63), 91
(100), 77 (68), 65 (22); IR (Nujol): 3146, 2692, 1650, 1626,
One-pot synthesis of compounds 7. Typical procedure:
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 temperature for 1 h. Then, hydrochlorid
acid (0.15 mL; 35%) was added and the solid product
was filtered off and crystallized from the appropriate
solvent: compound 7a (ethanol), 7b (acetonitrile), 7c
(ethanol), 7d (methanol), 7e (ethanol–pentane).
Acknowledgements
This work was supported by the Ministerio de Ciencia
y Tecnolog´ıa (Project BQU2000-0222). We are grateful
to Professor Peter G. Jones at Technische Universita¨t
Braunschweig for the X-ray crystallographic analyses.
1587, 1519, 1487, 1463, 1378, 1181, 766, 700 cm−1
.
7. Details of the structure determination will be reported in
a future full paper.
8. Guirado, A.; Andreu, R.; Cerezo, A.; Ga´lvez, J. Tetra-
hedron 2001, 39, 4925.
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1998, 39, 1071; (b) Guirado, A.; Andreu, R.; Ga´lvez, J.;
Jones, P. G. Tetrahedron 2002, 58, 9853.

3812
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