Full text of DOI:10.1007/s10593-018-2237-7

DOI 10.1007/s10593-018-2237-7
Chemistry of Heterocyclic Compounds 2018, 54(1), 93–95
Reactions of 5-mesyl-2-phenyl-4-tosyloxazole
with N-, C-, and S-nucleophiles
1
1
Vladimir S. Zyabrev *, Sergey B. Babii
1
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences
of Ukraine, 1 Murman'ska St., Kyiv 02660, Ukraine; е-mail: zyabrev@bpci.kiev.ua
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
Submitted July 5, 2017
Accepted after revision January 16, 2018
2
018, 54(1), 93–95
The reaction of 5-mesyl-2-phenyl-4-tosyloxazole with N-, C-, and S-nucleophiles led to products arising from substitution of the mesyl
group at the С-5 position, while the tosyl group at the С-4 position was not affected.
Keywords: amines, Fischer's base, oxazoles, thiols, nucleophilic substitution.
–
The sulfinate anion RSO
2
is known as a good leaving
In the current work, we studied the reactions of 5-mesyl-
2-phenyl-4-tosyloxazole (1) with amines, thiols, and the
Fischer's base. All of these reactions proceeded under
relatively mild conditions with cleavage of the mesyl
group and gave high yields of substitution products 2–4
(Scheme 1).
It should be noted that transformation 1→2 is more of
theoretical interest than preparative value: compounds 2
can be obtained more conveniently by cyclocondensation of
N-(2,2-dichloro-1-tosylethenyl)benzamide with amines.12
The reaction of oxazole 1 with the Fischer's base provided
product 3, which exists in the form of only one of the two
possible geometric isomers according to NMR analysis.
The reactions with thiols were more important and led to
oxazoles 4a,b containing a tosyl group at position 4 and a
cyclohexyl or p-tolylsulfanyl group at position 5. Such
compounds are difficult to obtain by using the known
group, which has been used for nucleophilic substitution
reactions in oxazoles in the synthesis of promising pharma-
1,2
3,4
ceutical agents, plant growth regulators, and natural
5
compounds. Despite the fact that such applications of a
sulfonyl group do not follow the atom economy principles,
they are justified in the cases when the respective
6
halogenated oxazoles are difficult to obtain.
The earlier examples of such nucleophilic substitution
reactions used oxazoles with one sulfonyl group, which
1
–5,7,8
was bonded either to the С-2 atom
or to the С-5
atom.6
,9,10
Later, in 2001 we reported the preparation of
oxazoles containing two sulfonyl groups: one at the С-4
11
atom and the other at С-5 atom. Each of these groups, on
one hand, activates the respective β-carbon atom in the
oxazole ring, making this ring highly electron-deficient,
and on the other hand may act as a leaving group.
Scheme 1
0
009-3122/18/54(1)-0093©2018 Springer Science+Business Media, LLC
93

Chemistry of Heterocyclic Compounds 2018, 54(1), 93–95
methods for the synthesis of 4,5-dimercaptooxazole
(5H, m, H Ph); 7.80 (4H, d, J = 6.9, H Ar). Mass spectrum, m/z
derivatives.11
(Irel, %): 343 [М+Н] (100). Found, %: C 63.00; H 5.44;
+
The direction of our discovered transformations was in
agreement with previously reported experimental data.
Thus, a research group from Japan studied the reactivity of
N 8.26. C18
N 8.18.
H
18
N
2
3
O S. Calculated, %: C 63.14; H 5.30;
4-[(4-Methylphenyl)sulfonyl]-5-[(1,3,3-trimethylindo-
lin-2-ylidene)methyl]-2-phenyl-1,3-oxazole (3). 1,3,3-Tri-
methyl-2-methyleneindoline (Fischer's base) (0.39 ml,
2.0 mmol) was added to a suspension of compound 1
(0.38 g, 1.0 mmol) in EtOH (5 ml), and the reaction
mixture was refluxed for 5 h. The resulting solution was
cooled to room temperature, the precipitated compound 3
was filtered off. Yield 0.44 g (94%), yellow crystals, mp 188–
isomeric halodiphenyloxazoles toward
a
carbanion
7
generated from phenylacetonitrile and demonstrated, in
particular, that 5-bromo- and 5-chloro-2,4-diphenyl-
oxazoles gave substitution products in significantly higher
yields compared to the respective 4-halooxazoles. On the
basis of these considerations, the authors concluded that the
С-5 atom of the oxazole ring is more preferrable for
nucleophilic attack compared to the С-4 atom.
1
191°С. Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.69
Thus, the reactions of the 5-mesyl-2-phenyl-4-tosyl-
oxazole with N-, C-, and S-nucleophiles do not involve the
tosyl group and may provide a new regioselective method
for the functionalization of a 4-arylsulfonyl-substituted
oxazole ring.
(6H, s, CH
3
); 2.37 (3H, s, CH
3
); 3.31 (3H, s, CH ); 6.14
3
(1H, s, CH); 6.90–7.04 (2H, m, H Ar); 7.22 (1H, t, J = 7.6,
H Ar); 7.33 (1H, d, J = 7.2, H Ar); 7.44 (2H, d, J = 7.9,
H Ar); 7.49–7.62 (3H, m, H Ar); 7.84–7.97 (4H, m, H Ar).
1
3
C NMR spectrum (101 MHz), δ, ppm: 21.3; 24.7; 29.7;
6.4; 78.4; 107.9; 121.4; 122.0; 125.8; 125.9; 127.1; 128.1;
29.0; 129.6; 130.3; 131.2; 138.6; 139.1; 143.7; 144.4;
4
1
Experimental
1H and 13C NMR spectra were acquired on Bruker
Avance DRX 500 (500 and 126 MHz, respectively) and
Varian Unity Plus 400 (400 and 101 MHz, respectively)
152.8; 156.6; 162.9. Mass spectrum, m/z (Irel, %): 471
+
[М+Н] (100). Found, %: C 71.14; H 5.85; N 5.87.
C
28
H
26
N
2
O S. Calculated, %: C 71.47; H 5.57; N 5.95.
3
spectrometers in DMSO-d
6
using the residual solvent
5-Cyclohexylsulfanyl-4-[(4-methylphenyl)sulfonyl]-
signals as standards. LC-MS analysis was performed on an
Agilent 1200 chromatograph with a G6130A mass
spectrometer using electrospray ionization at atmospheric
pressure, capillary voltage 4000 V. The carbon and
hydrogen content was determined by the Pregl gravimetric
method, nitrogen – by the Dumas gasometric method, and
sulfur – by the Schöniger titration method. Melting points
were determined on a Fisher-Johns apparatus.
2-phenyl-1,3-oxazole (4а). Triethylamine (0.13 ml,
1.0 mmol) was added to a mixture of compound 1 (0.30 g,
0.8 mmol) and cyclohexanethiol (0.12 ml, 1.0 mmol) in
EtOH (4 ml), and the reaction mixture was refluxed for 4 h.
The volatile compounds were removed by evaporation at
reduced pressure, the oily residue was diluted with EtOH
and, after the crystallization was complete, compound 4а
was filtered off. Yield 0.24 g (72%), colorless crystals,
1
5-Mesyl-2-phenyl-4-tosyloxazole (1) was obtained
mp 94–95°С (EtOH). H NMR spectrum (400 MHz), δ, ppm
1
1
according to a previously described procedure.
(J, Hz): 1.16–1.61 (6H, m, C H11); 1.70 (2H, d, J = 9.1,
6
N-Benzyl-4-[(4-methylphenyl)sulfonyl]-2-phenyl-1,3-
oxazol-5-amine (2a). Benzylamine (0.40 ml, 3.66 mmol)
was added to a suspension of oxazole 1 (0.33 g, 0.87 mmol)
in EtOH (5 ml), and the reaction mixture was refluxed
with stirring for 4 h. The resulting solution was cooled to
room temperature, the precipitated compound 2a was
filtered off. Yield 0.32 g (91%), colorless crystals, mp 185–
C
6
H
11); 1.94 (2H, d, J = 9.6, C
6
H
11); 2.39 (3H, s, CH ); 3.59
3
(1H, t, J = 9.9, C H11); 7.41–7.64 (5H, m, H Ph); 7.81–7.99
6
(4H, m, H Ar). 1 C NMR spectrum (101 MHz), δ, ppm:
21.1; 24.8; 25.2; 33.0; 47.2; 125.2; 126.3; 127.4; 129.3;
130.1; 131.8; 137.1; 140.0; 145.1; 149.4; 161.5. Mass
spectrum, m/z (Irel, %): 414 [М+Н] (100). Found, %:
C 63.92; H 5.22; N 3.16. C22
C 63.90; H 5.61; N 3.39.
3
+
H
23NO
3
2
S . Calculated, %:
1
2
1
1
86°С (mp 186–188°С ). H NMR spectrum (500 MHz),
δ, ppm (J, Hz): 2.35 (3H, s, CH ); 4.58 (2H, d, J = 6.2, СH );
.25 (1H, t, J = 7.3, H Ph); 7.30–7.52 (9H, m, H Ar and
H Ph); 7.66–7.75 (2H, m, H Ph); 7.79 (2H, d, J = 8.1,
3
2
5-[(4-Methylphenyl)sulfanyl]-4-[(4-methylphenyl)sul-
fonyl]-2-phenyl-1,3-oxazole (4b). Triethylamine (0.17 ml,
1.2 mmol) was added to a mixture of compound 1 (0.46 g,
1.2 mmol) and p-thiocresol (0.15 g, 1.2 mmol) in EtOH
(4 ml), and the reaction mixture was refluxed for 2 h. The
resulting solution was cooled to room temperature, the
precipitated compound 4b was filtered off. Yield 0.50 g
7
1
3
H Ar); 8.19 (1H, t, J = 6.2, NH). C NMR spectrum
(
126 MHz), δ, ppm: 21.0; 46.3; 108.8; 124.9; 125.7; 126.2;
1
1
27.2; 127.4; 128.4; 129.0; 129.8; 130.1; 139.0; 139.5;
43.5; 149.4; 156.6. Mass spectrum, m/z (Irel, %): 405
+
–
1
[
М+Н] (50), 403 [М–Н] (100). Found, %: C 68.07;
(98%), colorless crystals, mp 116–117°С (EtOH). H NMR
H 5.36; N 6.82. C23
H
20
N
2
O
3
S. Calculated, %: C 68.30;
spectrum (400 MHz), δ, ppm (J, Hz): 2.32 (3H, s, CH );
3
H 4.98; N 6.93.
2.39 (3H, s, CH
3
); 7.25 (2H, d, J = 7.8, H Ar); 7.34–7.61
N,N-Dimethyl-[(4-methylphenyl)sulfonyl]-2-phenyl-1,3-
oxazol-5-amine (2b) was obtained analogously to
compound 2a from compound 1 (0.38 g, 1.0 mmol) and
aqueous 7.8 М dimethylamine solution (1.0 ml). Yield 0.28 g
(7H, m, H Ar and H Ph); 7.77 (2H, d, J = 7.1, H Ar); 7.86
13
(2H, d, J = 8.1, H Ar). C NMR spectrum (126 MHz),
δ, ppm: 20.7; 21.1; 124.9; 125.5; 126.3; 127.6; 129.3;
130.2; 130.4; 132.0; 136.6; 139.2; 140.3; 145.3; 147.8;
161.9. Mass spectrum, m/z (Irel, %): 422 [М+Н] (100).
Found, %: C 65.68; H 4.78; S 15.31. C23
Calculated, %: C 65.54; H 4.54; S 15.21.
+
(
82%), colorless crystals, mp 160–161°С (EtOH) (mp 174–
12
1
1
76°С (EtOH) ). H NMR spectrum (400 MHz), δ, ppm
H
19NO
3 2
S .
(
J, Hz): 2.37 (3H, s, CH ); 3.18 (6H, s, N(CH ); 7.36–7.55
3
)
3 2
9
4

Chemistry of Heterocyclic Compounds 2018, 54(1), 93–95
References
. Harrison, R. G. US Patent 4143047.
. Yamamoto, H.; Ohkawa, T.; Nakamura, K.; Imamura, K.;
Sawada, Yu.; Ishida, J.; Tanabe, D.; Satoh, S. WO Patent
6. Golovchenko, A. V.; Brovarets, V. S.; Drach, B. S. Russ. J.
Gen. Chem. 2004, 74, 1414. [Zh. Obsch. Khim. 2004, 74, 1524.]
. Yamanaka, H.; Ohba, S.; Sakamoto, T. Heterocycles 1990,
1
2
7
3
1, 1115.
8
9
. Williams, D. R.; Fu, L. Org. Lett. 2010, 12, 808.
2
00465374.
. Pil'o, S. G.; Brovarets, V. S.; Vinogradova, T. K.;
Golovchenko, A. V.; Drach, B. S. Russ. J. Gen. Chem. 2002,
3
4
5
. Kehne, H.; Dietrich, H.; Feucht, D.; Schmutzler, D.; Hauser-
Hahn, I.; Paulitz, C.; Dittgen, J.; Marteletti, A.; Rosinger, C. H.
US Patent 201139696.
. Rosinger, C. H.; Feucht, D.; Schmutzler, D.; Haeuser-Hahn, I.;
Dittgen, J.; Martelletti, A.; Dietrich, H. US Patent
7
2, 1714. [Zh. Obshch. Khim. 2002, 72, 1818.]
10. Misra, N. C.; Ila, H. J. Org. Chem. 2010, 75, 5195.
11. Babii, S. B.; Zyabrev, V. S.; Drach, B. S. Russ. J. Org. Chem.
2001, 37, 1149. [Zh. Org. Khim. 2001, 37, 1208.]
12. Chervoniy, V. A.; Kharchenko, A. V.; Drach, B. S. Ukr.
Khim. Zh. 1991, 57, 415.
2011190125.
. Schäckermann, J.-N.; Lindel, T. Org. Lett. 2017, 19, 2306.
9
5