Synthesis of thiazolines by the reaction of aryl ketonitriles with cysteamine via microwave irradiation

Article abstract of DOI:10.1002/jhet.5570440220

(Chemical Equation Presented) Thiazolines were synthesized in a one-pot reaction in excellent yield using a newly developed methodology. Ketonitriles were directly condensed with cysteamine (2-amino-thioalcohol) via microwave irradiation at 210°C for 10 m

Full text of DOI:10.1002/jhet.5570440220

Mar-Apr 2007
407
Synthesis of Thiazolines by the Reaction of Aryl Ketonitriles with
Cysteamine via Microwave Irradiation
Sukanta Kamila and Edward R. Biehl*
Department of Chemistry, Southern Methodist University, Dallas, Texas-75275, USA
E-mail- ebiehl@smu.edu
Received July 19, 2006
NH2
SH
microwave
O
N
Ar
+
CN
210 oC, 10 minutes
150 psi
S
Ar
1
2
3
Thiazolines were synthesized in a one-pot reaction in excellent yield using a newly developed
methodology. Ketonitriles were directly condensed with cysteamine (2-amino-thioalcohol) via microwave
irradiation at 210°C for 10 minutes under solvent free conditions and without any solid support. All the
compounds were characterized by 1H nmr, 13C nmr spectroscopy and elemental analyses.
J. Heterocyclic Chem., 44, 407 (2007).
RESULTS AND DISCUSSION
INTRODUCTION
The use of thiazolines building blocks in pharma-
ceutical drug discovery is continually increasing [1].
Thiazolines are found in numerous interesting
biologically active natural products such as Curacin A,
Thiangazole, Mirabazole B, and Lissoclinamides [2].
As shown in Scheme 1, the thiazolines 3 were
synthesized in a one pot reaction by the microwave
irradiation of a 1:1 mixture of cysteamine (2) and the
Scheme 1
Moreover, thiazolines constitute
a
family of
compounds known for their application in flavor
chemistry [3]. More than 30 thiazoline structures have
been identified from natural sources [4], particularly in
cooked meat [3] and in certain exotic fruits such as
litchis [5]. Some thiazolines derivatives present
interesting anti-HIV [6] and anti-cancer [7,8] activities
and can inhibit cell division [9].
microwave
NH2
SH
O
N
Ar
+
CN
Ar
210 oC, 10 minutes
150 psi
S
3
2
1
appropriate aryl ketonitrile 1 at 210 °C for 10 minutes.
The crude reaction mixtures were purified by column
chromatography on silica gel using 40% ethyl acetate-
hexane as eluent to give, as shown in Table 1, the
corresponding thiazoline 3 in good to excellent yields.
Irradiation of the reaction mixture above 210 °C or for
longer periods of time (> 10 minutes) afforded
intractable mixtures. The procedure used was simple;
Consequently, a variety of methods have been reported
for the synthesis of thiazoline building blocks, for
example (i) the condensation of aminothiols with nitriles
[10], esters [11], iminoethers [12], or imino triflates [13],
(ii) from N-acyl-2-aminoethanols [14] and (R)-hydroxy
thioamides [15], (iii) by the multi-step conversion from
oxazolines [16] and (iv) by the microwave irradiation of
N-acylbenzotriazoles with 2-aminoethanethiol hydro-
chloride [17]. However, these reactions generally require
drastic reaction conditions, such as the use of triisobutyl
aluminium. Furthermore when nitriles are employed, a
Lewis acid is required along with higher temperatures for
the elimination of ammonia [10]. Other methods employ
complex reagents [15b] or strongly acidic conditions. For
example, the preparation of N-acyl-benzotriazoles [17]
requires triethylamine along with hazardous chemicals
such as thionyl chloride. Herein, we report a solvent-free
direct synthesis of thiazolines by irradiation of a 1:1
mixture of commercially available cysteamine and an aryl
ketonitrile without the use of a solid support or hazardous
chemicals.
one mixes the two reagents in 1:1 ratio in
a
microwaveable test tube that is then irradiated at 210
°C for 10 minutes. For comparison, when we carried
out the reaction of 1a with 2 using conventional oil
bath heating at 210 °C for 10 minutes, thiazoline 3a
was obtained in a significantly lower yield of 55%. The
difference in the thiazoline yields most probably
reflects the rapid and volumetric heating in the
microwave procedure as compared to the slow
superficial heating in the conventional method [18].
The most plausible mechanism (Scheme 2) involves
either nucleophilic attack by the thiol group of cystamine
onto the carbonyl carbon of ketonitrile forming adduct 4.
The elimination of water from 4 yields the aminonitrile

408
S. Kamila and E. R. Biehl
Vol 44
General Procedure for the Synthesis of Compounds 3a- 3l
via Microwave Irradiation: A mixture of cystamine (200 mg,
1.6 mmol) and aryl ketonitrile (1 equivalent, 1.6 mmol) were
taken in a sealed microwavable test tube and irradiate the
mixture at 210 °C for 10 minutes at 150 W output. The reaction
mixture was purified by column chromatography using 40%
ethyl acetate-hexane as eluent. The results are shown below.
2-Phenylthizoline (3a). This compound was isolated as a
yellow gummy liquid [20]. 1H nmr (deuteriochloroform): 3.41 (t,
J= 8.3 Hz, 2H, CH2), 4.46 (t, J = 8.2 Hz, 2H, CH2), 7.40-7.46
(m, 3H, phenyl hydrogens), 7.85 (d, J = 7.0 Hz, 2H, phenyl
hydrogens). 13C nmr (deuteriochloroform): 34.0 (CH2),
65.6(CH2), 128.7 (CH), 128.8(CH), 131.5(CH), 133.6 (C),
168.8(C). Anal. Calcd for C9H9NS: C, 66.22; H, 5.56; N, 8.58.
Found: C, 66.25; H, 5.58; N, 8.59.
Table 1
Synthesis of Thiazolines
Entry
1
Ar
3
Yield, %
[a]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
C6H5
4-F-C6H4
4-Cl-C6H4
4-Me-C6H4
a
b
c
d
e
f
g
h
i
93
93
98
89
98
96
91
96
92
85
97
4-MeO-C6H4
Naphth-1-yl
2,4-diMeO-C6H3
2,4-di-Cl-C6H3
3,4,5-tri-MeO-C6H3
4-CN-C6H4
9
10
11
j
k
j
k
4-Br-C6H4
2-(4-Fluorophenyl)thiazoline (3b). This compound was
isolated as a yellow oil. H nmr (deuteriochloroform): 3.42 (t, J
1
[a] Isolated yield
= 8.2 Hz, 2H, CH2), 4.44 (t, J = 8.2 Hz, 2H, CH2), 7.09 (d, J =
8.1 Hz, 2H, phenyl hydrogens), 7.83 (d, J = 8.1 Hz, 2H, phenyl
hydrogens). 13C nmr (deuteriochloroform): 34.3(CH2),
65.6(CH2), 115.8(CH), 116.0(CH), 129.9(CH), 130.7(CH),
130.8(CH), 163.6(C), 166.1(C). Anal. Calcd for C9H8FNS: C,
59.65; H, 4.45; N, 7.73. Found: C, 60.01; H, 4.48; N, 7.76.
5 which undergoes intra-molecular conjugate addition of
the amino group onto the nitrile 5 to give 6. Compound 6
then loses acetonitrile to give the product 3. The
Scheme 2
NH2
S
NH2
SH
O
NH2
N
-CH CN
N
OH
-HOH
3
R
CN
R
CN
R
R
S
S
CN
S
R
CN
2
1
4
5
6
3
2-(4-Chlorophenyl)thiazoline (3c). This compound was
formation of acetonitrile was confirmed by GC/MS
analysis of the crude reaction mixture. The proposed
mechanism is consistent with that reported previously
[19].
isolated as a yellow solid, mp 51-52 °C (Lit [21] mp 50-51°C).
1H nmr (deuteriochloroform): 3.42 (t, J = 8.3 Hz, 2H, CH2),
4.45 (t, J = 8.3 Hz, 2H, CH2), 7.38 (d, J = 8.5 Hz, 2H, phenyl
hydrogens), 7.77 (d, J = 8.5 Hz, 2H, phenyl hydrogens). 13C nmr
In conclusion, we have developed a new high yield
solvent-free one-pot synthesis of biologically
important thiazolines that are otherwise not possible
by previous methods described in the literature. This
successful use of microwave irradiation provides a
good example of green synthesis for biologically
important organic molecule.
(deuteriochloroform):
34.3(CH2), 65.6(CH2), 129.1(CH),
130.0(CH), 132.1(C), 137.5(C), 167.6(C). Anal. Calcd for C9H8
ClNS: C, 54.68; H, 4.08; N, 7.09. Found: C, 54.69; H, 4.09; N,
7.10.
2-(4-Methylphenyl)thiazoline (3d). This compound was
isolated as a yellow solid, mp 40°C (Lit [21] mp 39.5-40.5°C).
1H nmr (deuteriochloroform); 2.39 (s, 3H, CH3), 3.40 (t, J = 8.3
Hz, 2H, CH2), 4.45 (t, J = 8.3 Hz, 2H, CH2), 7.22 (d, J = 8.2 Hz,
2H, phenyl hydrogens), 7.74 (d, J = 8.2 Hz, 2H, phenyl
hydrogens). nmr (deuteriochloroform): 21.8(CH3), 33.9(CH2),
65.5 (CH2), 128.7(CH), 129.5(CH), 131.0(C), 141.8(C),
168.7(C). Anal. Calcd for C10H11NS: C, 67.76; H, 6.25; N, 7.90.
Found: C, 67.77; H, 6.25; N, 8.01.
EXPERIMENTAL
Melting points were taken on a Mel-Temp capillary apparatus
1
and are uncorrected with respect to stem correction. H and 13C
2-(4-Methoxyphenyl)thiazoline (3e). This compound was
isolated as a light yellow solid, mp 55-56 °C (Lit [21] mp 53.5-
1
54.5 °C). H nmr (deuteriochloroform): 3.40 (t, J = 8.3 Hz, 2H,
nmr spectra were recorded on a 400 MHz Bruker ADVANCE
DRX-400 Multinuclear nmr spectrometer. Chemical shifts are
reported in reference to TMS as internal standard. GC/MS
experiment was done in HP Gas Chromatograph Electron
Ionization Detector (GCD System, G1800C). Elemental analysis
was obtained from Southern Methodist University Analytical
Service Laboratories. All chemicals were purchased from Fisher
Scientific or Aldrich chemicals. Microwave experiment was
done in CEM-Discover (From CEM Corporation, POB 200)
instrument at 150 W output power.
CH2), 3.85 (s, 3H, -OMe), 4.43 (t, J = 8.3 Hz, 2H, CH2), 6.92 (d,
J = 7.9 Hz, 2H, phenyl hydrogens), 7.79 (d, J = 7.9 Hz, 2H,
phenyl hydrogens). 13C nmr (deuteriochloro-form): 34.1(CH2),
55.7 (OMe), 65.4(CH2), 114.1(CH), 126.4, 130.4(CH), 162.2(C),
168.1(C).
2-Naphthalenethiazoline (3f). This compound was isolated
as a yellow gummy liquid. 1H nmr (deuteriochloroform): 3.47 (t,
J = 8.3 Hz, 2H, CH2), 4.53 (t, J = 8.2 Hz, 2H, CH2), 7.52-7.58

Mar-Apr 2007
Synthesis of Thiazolines by the Reaction of Aryl Ketonitriles with Cysteamine
409
(m, 2H, phenyl hydrogens), 7.87 (d, J = 8.4 Hz, 2H, phenyl
hydrogens), 7.93 (d, J = 7.8 Hz, 1H, phenyl hydrogen), 8.03 (d, J
= 8.4 Hz, 1H, phenyl hydrogen), 8.28 (s, 1H, phenyl hydrogens).
13C nmr (deuteriochloroform): 34.1 (CH2), 65.7(CH2),
125.1(CH), 127.0(CH), 127.8(CH), 128.1(CH), 128.6(CH),
129.2(CH), 129.8(CH), 131.1(C), 133.2(C), 135.0(C), 168.8(C).
Anal. Calcd for C13H11NS: C, 73.20; H, 5.20; N, 6.57. Found: C,
73.22; H, 5.21; N, 6.58.
131.8(CH), 131.9(CH), 136.5(C), 163.5(C). Anal. Calcd for
C9H8BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.66; H, 3.34;
N, 5.58.
Acknowledgments. We thank the Robert Welch Foundation,
Houston, Texas, for partial financial support of this work.
REFERENCES
2-(2,4-Dimethoxyphenyl)thiazoline (3g). This compound
1
was isolated as a yellow gummy liquid. H nmr (deuteriochloro-
[1] For recent lead references, see the following: [a] Li, Q;
Woods, K. W.; Claiborne, A.; Gwaltney, S. L.; Barr, K. J.; Liu, G.;
Gehrke, L.; R. Credo, R. B.; Hui,Y. H.; Lee, J.; Warner, R. B.; Kovar,
P.; Nukkala, M. A.; Zielinski, N. A.; Tahir S. K.; Fitzgerald, Kim, K.;
Marsh, D.; Frost, D.; Ng, S.-C.; Rosenberg, S.; Sham, H. L. Bioorg.
Med. Chem. Lett. 2002, 12, 465; [b] Einsiedel, J.; Hubner, H.; Gmeiner,
P. Bioorg. Med. Chem. Lett. 2001, 11, 2533; [c] Campiani, G.; De
Angelis, M.; Armaroli, S.; Fattorusso, C.; Catalanotti, B.; Ramunno, A.;
Nacci, V.; Novellino, E.; Grewer, C.; Ionescu, D.; Rauen, T.; Griffiths,
R.; Sinclair, C.; Fumagalli, E.; Mennini, T. J. Med. Chem. 2001, 44,
2507; [d] Wipf, P.; Reeves, J. T.; Balachandran, R.; Day, B. W. J. Med.
Chem. 2002, 45, 1901.
form): 3.35 (t, J = 8.3 Hz, 2H, CH2), 3.83 (s, 6H, -OMe X 2),
4.44 (t, J = 8.2 Hz, 2H, CH2). 6.46 (d, J = 8.3 Hz, 1H, phenyl
hydrogens), 6.51 (s, 1H, phenyl hydrogen), 7.32 (d, J = 8.3 Hz,
1H, phenyl hydrogen). 13C nmr (deuteriochloroform): 32.1
(CH2), 55.7 (-OMe), 55.8 (-OMe), 63.3(CH2), 101.1(CH),
106.0(CH), 116.1(C), 132.3(CH), 161.6(C), 163.5(C), 164.5(C).
Anal. Calcd for C11H13NO2S: C, 59.17; H, 5.87; N, 6.27. Found:
C, 59.18; H, 5.88; N, 6.28.
2-(2,4-Dichlorophenyl)thiazoline (3h). This compound was
isolated as a yellow gummy liquid. 1H nmr (deuteriochloro-
form): 3.26 (t, J = 8.1 Hz, 2H, CH2), 4.25 (t, J = 8.1 Hz, 2H,
CH2), 7.13 (d, J = 7.9 Hz, 1H, phenyl hydrogen), 7.30 (s, 1H,
phenyl hydrogen), 7.55 (d, J = 7.9 Hz, 1H, phenyl hydrogen).
13C nmr (deuteriochloroform): 32.5(CH2), 61.5(CH2),
126.9(CH), 128.5(CH), 131.3(CH), 135.6(C), 135.8(C),
137.2(C), 164.1(C). Anal. Calcd for C9H7Cl2NS: C, 46.57; H,
3.04; N, 6.03. Found: C, 46.57; H, 3.09; N, 6.06.
[2a] Wipf. P.
Chem.Rev. 1995, 95, 2115; [b] Wipf, P.;
Venkatraman, S. Synlett 1997, 1. (c) Wipf. P. In Alkaloids: Chemical
and Biological Perspectives, S. W. Pelletier, ed, Pergamon Press, New
York, 1988, p 187.
[3] MacLeod, G.; Ames, J. J. Food Sci. 1987, 52, 42.
[4] MacLeod, G.; Ames, J. Flavour Fragr. J. 1986, 1, 91.
[5] Ong, P.; Acree, T. J. Agric. Food. Chem. 1998, 46, 2282.
[6] Boyce, R. J.; Mulqueen, G. C.; Pattenden, G. Tetrahedron
Lett. 1994, 35, 5705.
2-(3,4,5-Trimethoxyphenyl)thiazoline (3i). This compound
1
was isolated as a yellow gummy liquid. H nmr (deuteriochloro-
form): 3.29 (t, J = 8.4 Hz, 2H, CH2), 4.41 (t, J = 8.4 Hz, 2H,
CH2), 3.83 (s, 3H, -OMe), 3.85 (s, 6H, -OMe X 2), 6.65 (s, 2H,
phenyl hydrogens). 13C nmr (deuteriochloroform): 33.4(CH2),
[7] Wipf, P.; Fritch, P. Tetrahedron Lett. 1994, 35, 5377.
[8] Pattenden, G.; Boden, C.; Ye, T.; Synlett 417. 1995.
[9] Lai, J. –H.; Yu, J.; Makennen, B.; Falck J. R. Tetrahedron
Lett. 1996, 37, 7167.
[10] Mulqueen G.; Pattenden, G.; Whiting, D, Tetrahedran 1993,
49, 5359.
[11] Busacca, C. A.; Dong, Y.; Spinelli, E. M. Tetrahedron Lett.
1996, 37, 2935.
[12] Boden, C.; Pattenden, G.; Ye, T. Synlett 417 (1995).
[13] Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908.
[14a] Wenker, H. J. Am. Chem. Soc. 1935, 57, 9; [b] Nishio, T.
Tetrahedron Lett. 1994, 35. 5397.
[15a] Lafargue, P.; Guenot, P.; Lellouche, J.-P. Synlett, 1995, 171;
[b] Mahler, S. G.; Serra, G. L.; Antonow, D.; Manta, E. Tetrahedron
Lett. 2001, 42, 8143.
[16] Wipf, P.; Miller, C. P.; Venkatraman, S.; Fritch, P. C.
Tetrahedron Lett. 1995, 36, 6395.
[17] Katritzky, A. R.; Cai, C.; Suzuki, K.; Singh, S. K. J. Org.
Chem. 2004, 69, 811.
[18] de la Hoz, A,; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev.
2005, 34, 164.
56.3(-OMe), 56.5(-OMe
X
2), 63.1(CH2), 106.1(CH),
106.5(CH), 131.6(C), 135.5(C), 150.1(C), 150.3(C), 163(C).
Anal. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N, 5.53. Found:
C, 56.95; H, 6.01; N, 5.56.
2-(4-Cyanophenyl)thiazoline (3j). This compound was
isolated as a brownish solid, mp 128-130 °C. 1H nmr
(deuteriochloroform): 3.25 (t, J = 8.3 Hz, 2H, CH2), 4.24 (t, J =
8.3 Hz, 2H, CH2), 7.51 (d, J = 8.3 Hz, 2H, phenyl hydrogens),
7.84 (d, J = 8.3 Hz, 2H, phenyl hydrogens). 13C nmr (deuterio-
chloroform): 33.2 (CH2), 61.5 (CH2), 113.5(C), 117.1(CN),
129.3(CH), 129.4(CH), 132.1(CH), 132.2(CH), 141.5 (C),
164.5(C). Anal. Calcd for C10H8N2S: C, 63.80; H, 4.28; N,
14.88. Found C, 63.83; H, 4.29; N, 14.90.
2-(4-Bromophenyl)thiazoline (3k). This compound was
isolated as a yellow gummy liquid. 1H nmr (deuteriochloro-
form): 3.35 (t, J= 8.1 Hz, 2H, CH2), 4.24 (t, J=8.2 Hz, 2H,
CH2), 7.31 (d, J=8.2 Hz, 2H, phenyl hydrogens), 7.55 (d, J =8.2
Hz, 2H, phenyl hydrogens). 13C nmr (deuteriochloroform):
33.1(CH2), 63.2(CH2), 124.1(C), 131.1(CH), 131.3 (CH),
[19] Landor, S. R.; Landor, P. D.; Seliki-Muruumu, J.; Fomum, Z.
T.; Mbafor, J. T. J. Chem. Soc. Perkin Trans 1, 1988, 1759.
[20] Kodama, Y.; Ori, M; Nishio, T. Helv. Chem. Acta. 2005, 88,
187.
[21] George, B.; Papadopoulos, E. P. J. Org. Chem. 1977. 42,
441.