Synthesis of spiro-2-oxazolines

Article abstract of DOI:10.1055/s-1998-1830

Several spiro-2-oxazolines were synthesized by treatment of 2-benzoylamino-3-chloropropenoic acid with a series of aromatic and heteroaromatic diamines. Alkylation of these compounds took place on the lactam nitrogen of the 3,4-dihydropyrazin-2(1H)-one part of the spiro systems.

Full text of DOI:10.1055/s-1998-1830

September 1998
SYNLETT
983
Synthesis of Spiro-2-oxazolines
I. Mušic, A. Golobic, B. Vercek*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerceva 5, 1000 Ljubljana, Slovenia
Fax: 386 1258 220; E-mail: Bojan.Vercek@uni-lj.si
Received 7 May 1998
Abstract: Several spiro-2-oxazolines were synthesized by treatment of
2-benzoylamino-3-chloropropenoic acid with a series of aromatic and
heteroaromatic diamines. Alkylation of these compounds took place on
the lactam nitrogen of the 3,4-dihydropyrazin-2(1H)-one part of the
spiro systems.
It is well-known that 2-oxazolines are important compounds in organic
1
chemistry due to their synthetic utility. An interesting class of
2-oxazolines are spiro-2-oxazolines having spiro connection at position
4. For example, 4,5-dihydro-1,3-oxazole-4-spiro-2’-thiiranes are
2
reported to be intermediates in the synthesis of thietanes. A spiro-2-
oxazoline derivative containing the penicillin system was formed as
a
by-product in an attempt to prepare fluoromethyl substituted
3
penicillin derivative. Some other spiro-2-oxazolines having protected
D-psicofuranose were prepared in attempts of C-glycosidation. They
were also synthesized as α-adrenergic agonists and parasitic
insecticides.
4
5
6
In continuation of our investigations on the reactivity and synthetic
7
utility of functionalized amino acid derivatives, we designed a general
one-pot approach to spiro-2-phenyl-2-oxazolines having 3,4-
dihydroquinoxalin-2(1H)-one, 3,4-dihydrobenzoquinoxalin-2(1H)-one
system,
1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one
or
5,6-
dihydropteridin-7(8H)-one system. The spiro compounds
2
were
8
prepared by heating of 2-benzoylamino-3-chloropropenoic acid 1 with
equimolar amounts of vicinal aromatic or heteroaromatic diamines in
ethanol in the presence of triethylamine for 6.5 h in 17-50 % yields
9
(Scheme 1, Table 1).
Scheme 1
Alkylation of spirooxazolines in the presence of excess MeI or EtBr in
acetonitrile using 0.2-0.4 equivalent of Bu NHSO as a catalyst and
4
4
o
excess K CO at 80 C for 2-7.5 h resulted in the introduction of methyl
2
3
or ethyl groups on the lactam nitrogen in the pyrazinone ring giving
compounds 3 or 4 in 19-88 % yields. Alkylation of the nitro compound
10
2b failed (Table 2).
The structures of the spiro compounds 2-4 were elucidated on the basis
1
13
of H, C and 2D (COSY, HMQC, HMBC) NMR spectroscopy and
11
confirmed by X-ray analysis of the ethyl derivative 4a. The main
1
characteristic feature of their H NMR spectra are two doublets at 4.24-
4.36 ppm and 5.11-5.22 ppm for two nonequivalent 5-CH protons with
2
13
coupling constants of 9.0-9.8 Hz. C NMR spectra show the spiro
carbons at 84-85 ppm. The structures of compounds obtained in
reactions with unsymmetrical diamines were determined on the basis of
HMBC correlations betweeen NH groups in the dihydropyrazin-2(1H)-
one system and carbon atoms in the adjacent fused ring.

984
LETTERS
SYNLETT
The intimate mechanistic details of the formation of spiro-2-oxazolines
remain to be clarified. The structures of products of the reactions with
unsymmetrical diamines suggest that the diamine predominantly reacts
via the more basic amino group with the tautomeric form of the starting
acid giving rise to the formation of 2-oxazoline and pyrazinone rings.
The possible pathways of this transformation are outlined in Scheme 2.
(5) Cordi, A. A.; Lacoste, J.-M.; Descombes, J.-J.; Courchay, C.;
Vanhoutte, P. M.; Laubie, M.; Verbeuren, T. J. J. Med. Chem.
1995, 38, 4056.
(6) Mencke, N.; Turberg, A.; Kraatz, U.; Kraemer, W.; Lantzsch, R.;
Marhold, A. Ger. Offen. DE 19,520,936, 1996; Chem. Abstr. 1997,
126, 117963c.
(7) a) ucek K.; Verèek, B. Synlett 1994, 667. b) Cucek, K.; Mušiè, I.;
Vercek, B. Synth. Commun. 1996, 26, 1135. c) Mušic, I.; Golobic,
A.; Vercek, B. Heterocycles 1998, 48, 353.
(8) Strukov, I. T. Zh Obshch. Khim. 1957, 27, 432; Chem. Abstr. 1957,
51, 15500b.
(9) Typical procedure for the preparation of spiro-2-oxazolines 2:
A mixture of acid 1 (451 mg, 2 mmol), o-phenylenediamine (220
mg, 2 mmol, 98%), ethanol (8 ml), and triethylamine (320 mg, 3.2
mmol) was heated under reflux for 6.5 h. Upon cooling, the
precipitate was filtered and washed with ethanol giving the crude
o
1
product 2a (131 mg, 23%). Mp 227-228 C dec. (methanol).
H
NMR (300 MHz, DMSO-d ) δ 4.24 (d, 1H, J=9.2 Hz, 1H of 5-
6
CH ), 5.11 (d, 1H, J=9.2 Hz, 1H of 5-CH ), 6.73 (m, 2H, 6’-H and
2
2
8’-H), 6.86 (m, 2H, 5’-H and 7’-H), 7.14 (s, 1H, 1’-NH), 7.46 (m,
2H, Ph), 7.57 (m, 1H, Ph), 7.85 (m, 2H, Ph), 10.73 (s, 1H, 4’-NH).
13
C NMR (75.5 MHz, DMSO-d ) δ 72.9, 84.8, 113.9, 114.8,
6
118.6, 122.8, 125.6, 126.6, 128.1, 128.6, 132.1, 132.1, 163.1,
+
164.3. MS m/z 279 (M , 90%). Anal. Calcd for C
H N O : C,
16 13 3 2
68.81; H, 4.69; N, 15.04; Found: C, 68.52; H, 4.65; N, 15.23.
Scheme 2
Typical procedure for the preparation of N-ethyl spiro-2-
oxazolines 4:
To a suspension of 2a (558 mg, 2 mmol) in acetonitrile (10 ml)
In summary, we have elaborated a short route for the synthesis of some
new spiro-2-oxazoline systems containing fused pyrazinone rings. It is
of interest to note that the 3,4-dihydroquinoxalin-2(1H)-one system is
structurally related to the widely used benzodiazepine nucleus and as
such has become the focus of recent research interests. The synthetic
applications of the above mentioned spiro-2-oxazolines are the subject
of current investigations.
K CO (4.14 g, 30 mmol) and a solution of Bu NHSO (203 mg,
2
3
4
4
0.6 mmol) in ethyl bromide (0.9 ml, 12 mmol, 99%) were added.
o
The reaction mixture was then stirred at 80 C for 3 h. Upon
12
cooling to room temperature, the solid was filtered and washed
with acetonitrile (2 x 5 ml). The collected filtrate was evaporated
under reduced pressure, the solid residue was suspended in
ethanol (2-3 ml) and washed with ethanol to give the crude
o
1
Acknowledgement
We would like to thank The Ministry of Science and Technology of
Slovenia for financial support.
product 4a (542 mg, 88%). Mp 182-185 C (ethanol). H NMR
(300 MHz, DMSO-d ) δ 1.15 (t, 3H, J=7.0 Hz, CH CH ), 4.01 (q,
6
2
3
2H, J=7 Hz, CH CH ), 4.27 (d, 1H, J= 9.2 Hz, 1H of 5-CH ),
2
3
2
5.19 (d, 1H, J= 9.2 Hz, 1H of 5-CH ), 6.89 (m, 3H, 6’-H, 7’-H, 8’-
2
H), 7.14 (m, 1H, 5’-H), 7.23 (s, 1H, 1’-NH), 7.45 (m 2H, Ph), 7.56
References and Notes
13
(m, 1H, Ph), 7.83 (m, 2H, Ph). C NMR (75.5 MHz, DMSO-d )
6
(1) See for example: a) Grant, T. G.; Meyers, A. I. Tetrahedron 1994,
50, 2297.
12.3, 36.6, 73.4, 85.0, 114.4, 114.6, 119.0, 123.2, 126.3, 126.6,
+
128.2, 128.7, 132.2, 133.5, 163.4, 163.5. MS m/z 307 (M , 91%).
(2) L’abbe, G.; Francis, A.; Dehaen, W.; Bosman, J. Bull. Soc. Chim.
Belg. 1996, 105, 253.
Anal. Calcd for C
H N O : C, 70,34; H, 5.58; N, 13.67; Found:
18 17 3 2
C, 70.10; H, 5.59; N, 13.52.
(3) Guest, A. W.; Milner, P. H.; Southgate, R. Tetrahedron Lett. 1989,
30, 5791.
(11) Detailed data of X-ray crystal structure analysis will be reported
elsewhere.
(4) a) Sano, H.; Mio, S.; Tsukaguchi, N.; Sugai, S. Tetrahedron 1995,
51, 1387. b) Dillon, M. P.; Maag, H.; Muszynski, D. M.
Tetrahedron Lett. 1995, 36, 5469.
(12) See for example: Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J.
Org. Chem. 1998, 63, 1172.