Convenient synthesis of novel N-substituted-5-aminothiazole derivatives

Full text of DOI:10.1021/jo000653y

J . Org. Chem. 2000, 65, 8077-8079
8077
Notes
Sch em e 1
Con ven ien t Syn th esis of Novel
N-Su bstitu ted -5-a m in oth ia zole Der iva tives
Alan R. Katritzky,* Xiaojing Wang, and Rexiat Maimait
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received April 27, 2000
In tr od u ction
Many thiazoles are important pharmaceuticals,1a-d
dyes, and photographic chemicals.2 Simple 2,4-diarylthi-
azoles, readily synthesized by Hantzsch reactions,3 in-
clude 2,4-bis(3-indolyl)thiazoles, which are potent cyto-
toxic agents.4 Less is known about efficient syntheses of
2,4-diarylthiazoles functionalized at the 5 position. Lit-
erature syntheses of 2,4-diaryl-5-aminothiazoles (1)
(Scheme 1) include: (i) the photoconversion of unstable
azirene 2 into 1 (where Ar ) R1 ) Ph, R2 ) H) in a 20%
yield;5 (ii) the condensation of unstable ω-chloro-ω-
acylamidoacetophenones (3) with benzothioamide to gen-
erate 1 (where Ar ) Ph, R1 ) COR3, R2 ) H) in 64-94%
yields,6 which is limited by the need to access of 3, via
condensation of phenylglyoxal with acid amides and
thionyl chloride; (iii) a general method of synthesizing
5-(arylidenamino)-2-aryl-4-phenylthiazoles in 25-75%
yields, as presented by Gewald et al.7 In these syntheses,
phenyl was the only 4-substituent and yields were low
for the thiazoles bearing electron-withdrawing groups in
the 2 position (25%).
dipolar cyclizations with alkenes or alkynes to prepare
pyrroles and dihydropyrroles.10 We now report the con-
venient synthesis of N-substituted-2,4-diaryl-5-aminothi-
azoles from such 1,3-dipolar synthons.
Resu lts a n d Discu ssion
N-Ar ylm et h ylen e[(ben zot r ia zol-1-yl)a r ylm et h yl]-
amines 6a-c,e (Scheme 2) were previously reported to
be obtained in high yields by stirring a mixture of
benzotriazole, the appropriate arylaldehyde, and ethan-
olic ammonia at room temperature (route b).9 Compound
6e was prepared cleanly in 90% yield using the published
procedure. However, in the present study, application of
this procedure gave products 6a -d mixed with varying
amounts of trimers 5a -d . In a general two-step synthesis
(route a), intermediate trimers 5a -d were readily ob-
tained in 75-90% yields by stirring the corresponding
aldehydes and excess (10-fold) aqueous NH3 solution (or
methanolic NH3 solution) at 20 °C for ca. 10 h.11a-c
Subsequent refluxing of 5a -d with benzotriazole in
toluene or 1,4-dioxane then gave 6a -d in 80-92% yields.
This procedure was particularly suitable for compound
6c with an electron-withdrawing group: 6c was obtained
in 90% yield. Novel compound 6d functionalized with a
thiophene moiety was prepared in 80% yield. Purification
on silica gel is not suitable for compounds 6a -e due to
the acid-sensitive imine functionality. However, if the
imine is solid, recrystallization or removal of excess
benzotriazole by washing with saturated Na2CO3 solution
after reactions provided the pure imines 6a -e.
Existing synthetic routes for 5-aminothiazoles8a-f ap-
pear not to have been used for 2,4-diaryl-5-aminothi-
azoles. In our group, readily available9 N-arylmethylene-
[(benzotriazol-1-yl)arylmethyl]amines were used in 1,3-
(1) (a) Tsuruoka, A.; Kaku, Y.; Kakinuma, H.; Tsukada, I.; Yanag-
isawa, M.; Nara, K.; Naito, T. Chem. Pharm. Bull. 1998, 46 (4), 623.
(b) Roy, R. S.; Kelleher, N. L.; Milne, J . C.; Walsh, C. T. Chem. Biol.
1999, 6, 305. (c) Geronikaki, A. A.; Hadjipavlou-Litina, D. J . Arzneim.-
Forsch. 1998, 48 (I), 263. (d) Wei, P. H. L.; Bell, S. C. U.S. Pat.
3,704,239, 1972 (Chem. Abstr. 1973, 78, 43482m).
(2) Barone, R.; Chanon, M.; Gallo, R. Aminothiazoles and Their
Derivatives in Thiazole and Its Derivatives; Metzger, J . V., Ed.; J ohn
Wiley & Sons: New York, 1979; Part 2, p 154.
(3) Hantzsch, A.; Weber, J . H. Chem. Ber. 1887, 20, 3118.
(4) Gu, X.-H.; Wan, X.-Z.; J iang, B. Bioorg .Med. Chem. Lett. 1999,
9, 569.
(5) J ackson, B.; Gakis, N.; Marky, M.; Hansen, H.-J .; von Philips-
born, W.; Schmid, H. Helv. Chim. Acta 1972, 55, 916.
(6) Drach, B. S.; Dolgushina, I. Y.; Sinitsa, A. D. Chem. Heterocycl.
Compd. (Engl. Transl.) 1974, 10, 810.
(7) Gewald, K.; Schonfelder, H.; Hain, U. J . Prakt. Chem. 1974, 361,
299.
Treatment of 6a -e with 1 equiv of n-BuLi in dry THF
at -78 °C resulted in a dark solution within seconds,
typical of carbanions stabilized by a benzotriazole
group.12a,b Presumably the resonance-stabilized lithiated
(8) (a) Barrett, G. C. Tetrahedron 1978, 34, 611. (b) Rahman, A.;
Ila, H.; J unjappa, H. J . Chem. Soc., Chem. Commun. 1984, 430. (c)
Suda, K.; Fuke, H.; Hino, F.; Yijima, C. Chem. Lett. 1985, 1115. (d)
Alvarez-Ibarra, C.; Gil, M.; Ortiz, P.; Quiroga, M. L. Heterocycles 1988,
27, 2177. (e) Freeman, F.; Kim, D. S. H. L. J . Org. Chem. 1991, 56,
4645. (f) Uchikawa, O.; Fukatsu, K.; Aono, T. J . Heterocycl. Chem.
1994, 31, 877.
(10) Katritzky, A. R.; Hitchings, G. J .; Zhao, X. Synthesis 1991, 863.
(11) (a) Laurent, M. A. Liebigs Ann. Chem. 1837, 21, 130. (b) Ogata,
Y.; Kawasaki, A.; Okumura, N. J . Org. Chem. 1964, 29, 1985. (c)
Hunter, D. H.; Sim, S. K. Can. J . Chem. 1972, 50, 669.
(12) (a) Katritzky, A. R.; Lang, H. J . Org. Chem. 1995, 60, 7612. (b)
Katritzky, A. R.; Oniciu, D. C.; Ghiviriga, I.; Soti, F. J . Org. Chem.
1998, 63, 2110.
(9) Katritzky, A. R.; Zhao, X.; Hitchings, G. J . Synthesis 1991, 703.
10.1021/jo000653y CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

8078 J . Org. Chem., Vol. 65, No. 23, 2000
Notes
Sch em e 2a
Ta ble 1. Syn th esis of Th ia zole Der iva tives 15a -m
flash chromatography starting from electron-deficient
phenyl isothiocyanates 8b-d . A lower yield (35%) was
observed for 15e starting with 2-chlorophenyl isothio-
cyanate (8e) compared with 15d starting with 4-chloro-
phenyl isothiocyanate (8d , 56%), possibly due to the steric
hindrance of the ortho-chloro atom substituted. For the
electron-rich isothiocyanates (8f,g, R2 ) p-Me, p-MeO),
the precipitates took longer to form than in reactions with
electron-deficient isothiocyanates, but 15f,g were ob-
tained as expected (44%, 55% yield). The 1H NMR spectra
of 15a -g all show signals from phenyl rings directly
attached to the thiazole ring appearing between 7.2 and
8.0 ppm. Proton signals from the N-phenyl rings occur
between 6.7 and 7.3 ppm. The NH-proton signals typi-
cally show around 5.5 ppm (for 15a -d ,f,g), except that
for 15e which is shifted downfield to 6.1 ppm, perhaps
by a steric effect.
SMa
R1
R2
product
yield (%)
6a , 8a
6a , 8b
6a , 8c
6a , 8d
6a , 8e
6a , 8f
6a , 8g
6b, 8a
6c, 8a
6c, 8d
6e, 8a
6e, 8d
6d , 8a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
4-ClC6H4
Ph
15a
15b
15c
15d
15e
15f
15g
15h
15i
81
65
60
56
35
44
55
60
61
80
55
70
47
3-FC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
Ph
4-ClC6H4
Ph
15j
15k
15l
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
thien-2-yl
4-ClC6H4
Ph
15m
Starting Material: 6a -d , R1CH(Bt)N=CHR1; 8a -g, R2NCS.
a
azomethine ylide 7 (Scheme 2) was formed. After 5-10
min, the appropriate isothiocyanate (R2NCS, 1.1 equiv)
was added dropwise while stirring at -78 °C. The color
of the solution changed to dark red ca. 5 min after the
complete addition of the electrophile. Any lack of regio-
selectivity in providing a mixture of intermediates 9 and
10 is immaterial since isomers 9 and 10 both cyclize and
then aromatize to the same thiazole 15. Consistent with
the hypothesis of azomethine ylide 7 is the observation
of precipitates only 15 min after the addition of isothio-
cyanate at -78 °C. The precipitates were tentatively
During the one-pot reaction starting from 6a, self-
condensation of 6a gave 16a as a side product (<10%),
as suggested by the two doublets [4.79 (d, J ) 6.6 Hz,
1H), 5.09 (d, J ) 6.3 Hz, 1H)] from the 1H NMR spectrum
of the crude sample (Scheme 2). Self-condensation reac-
tion of 6a indeed gave 16a , in 50% yield as a single
isomer (which isomerized during flash column chroma-
1
tography on silica gel). The H NMR spectra of isomers,
each characterized by CHN analysis, show the same
pattern of double doublet peaks (see Supporting Informa-
tion).
1
identified by the H NMR spectra as possibly complexes
of the benzotriazole lithium salt with THF. The reaction
was monitored by TLC and found to produce mainly the
desired 15a -m . Only thiazoles were isolated as final
products which reflects the nucleophilicity of sulfur: no
imidazoles were formed by cyclization of intermediates
9 and 10 from nitrogen anion to the ylides.
Products 15a -g (Table 1) were obtained in 35-81%
yields as stable solids (except 15g which is an oil) starting
from imine 6a . Product 15a was easily obtained in high
yield with no substituent on N-phenyl ring. Products
15b-d were isolated in reasonable yields of 56-65% after
The reaction of 6b with phenyl isothiocyanate (8a ) gave
the expected thiazole 15h (60%) as yellow needles. A self-
condensation product of 6b was observed as a minor side
reaction (<10%).
When there was an electron-withdrawing group such
as a chlorine atom in 6c, the reaction went smoothly with
both phenyl (8a ) and 4-chlorophenyl isothiocyanate (8d ).
The fact that the self-condensation products were hardly
1
observed from the H NMR spectra of crude mixtures is
consistent with the relatively stable ylide 7 compared
with the ylide formed from 6a .

Notes
Products with strong electron-donating moieties, like
J . Org. Chem., Vol. 65, No. 23, 2000 8079
Gen er a l P r oced u r e for t h e Syn t h esis of Com p ou n d s
15a -m . n-BuLi (1.6 M in hexane, 2.5 mL, 4 mmol) was added
to a solution of the corresponding N-arylmethylene[(benzotri-
azole-1-yl)arylmethyl]amines 6 (4 mmol) in THF (50 mL) at -78
°C under argon. After 5 min of stirring, isothiocyanate (4.1 mmol)
was added. If precipitates were observed after around 15 min
and TLC showed the desired product, the reaction mixture was
quenched at -78 °C by the addition of 2 M NaOH solution (30
mL). Otherwise the reaction mixture was allowed to warm to
room temperature overnight, before being washed with 2 M
NaOH or brine solution (30 mL). After separation, the aqueous
layer was extracted by Et2O (2 × 20 mL). The combined organic
layer was dried (Na2SO4), and the solvent was removed under
reduced pressure. The products were purified by flash chroma-
tography with the combination of pentane and ethyl ether as
eluent to give the product.
methoxy groups in 15k ,l, were obtained in 55% and 70%
yields, respectively. There are significant changes in the
1H NMR spectra for the phenyl rings directly attached
to the thiazole ring. The protons on these phenyl rings
show signals in a broader range 6.9-8.3 ppm. The peak
for the proton attached to the nitrogen shifts downfield
to 6.4-6.5 ppm. In the 1H NMR spectra of crude
mixtures, there were no peaks at 4.00-6.00 ppm for the
suggested self-condensation product; possibly, these peaks
were also shifted downfield because of the strong electron-
donating moieties in the molecule.
1H-1,2,3-Benzotriazol-1-yl(2-thienyl)-N-[(E)-2-thienyl-
methylidene]methanamine (6d ) was successfully depro-
tonated and further reacted with phenyl isothiocyanate
8a to result in the final product 15m in 47% yield. During
workup, brine solution was used instead, as aqueous 2
M NaOH solution seemed to decompose 15m signifi-
cantly. A minor self-condensation product observed from
N-P h en yl-2,4-d ip h en yl-1,3-th ia zol-5-a m in e (15a ): yellow
microcrystals (yield 81%); mp 125.0-125.7 °C (lit.5 mp 122.5-
1
124.0 °C); H NMR δ 5.48 (br s, 1H), 6.84-6.91 (m, 3H), 7.19-
7.39 (m, 8H), 7.92-7.94 (m, 4H); 13C NMR δ 114.8, 120.4, 126.1,
127.7, 127.8, 128.6, 128.8, 129.5, 129.7, 133.9, 134.0, 135.6, 145.3,
146.7, 160.6. Anal. Calcd for C21H16N2S: C, 76.80; H, 4.91; N,
8.53. Found: C, 77.09; H, 5.03; N, 8.61.
1
the H NMR spectrum of the crude product was repre-
sented by two doublet-doublet peaks at 5.28 and 5.53
ppm.
N-[2,4-Bis(4-m et h ylp h en yl)-1,3-t h ia zol-5-yl]-N-p h en yl-
a m in e (15h ): yellow needles (yield 60%); mp 143.2-143.3 °C;1H
NMR δ 2.34 (s, 3H), 2.37 (s, 3H), 5.45 (s, 1H), 6.86-6.90 (m,
3H), 7.17-7.27(m, 6H), 7.81-7.85 (m, 4H); 13C NMR δ 21.3, 21.4,
114.6, 120.2, 126.0, 127.7, 129.2, 129.5, 131.3, 131.4, 134.4, 137.6,
139.9, 145.5, 147.0, 161.1. Anal. Calcd for C23H20N2S: C, 77.49;
H, 5.65; N, 7.86. Found: C, 77.43; H, 5.71; N, 7.84.
2,4-Bis(4-ch lor op h en yl)-N-p h en yl-1,3-t h ia zol-5-a m in e
(15i): yellow microcrystals (yield 61%); mp 44.5-45.5 °C; 1H
NMR δ 5.50 (s, 1H), 6.86-6.96 (m, 3H), 7.24-7.29 (m, 2H), 7.32-
7.41 (m, 4H), 7.83-7.93 (m, 4H); 13C NMR δ 114.9, 120.9, 127.3,
128.8, 129.0, 129.1, 129.6, 132.3, 133.7, 135.9, 136.3, 144.9, 145.8,
159.6. Anal. Calcd for C21H14Cl2N2S: C, 63.48; H, 3.55; N, 7.05.
Found: C, 63.31; H, 3.65; N, 6.84.
In conclusion, this paper describes a practical and facile
way to make 2,4-diaryl-N-substituted-5-aminothiazoles
in moderate to good yields. Compared to literature
procedures, this method has the advantages of easily
available stable starting materials and simple reaction
procedures.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
5a -d . Aldehydes (0.1 mol) were added to aqueous NH3 (1 mol,
30%) or methanolic NH3 (for 5d , 38 mL) solution and stirred
vigorously for 10 h (or until precipitates formed) at room
temperature. The crude products were filtered out, washed with
water and recrystallized from ethanol to give products 5a -d .
P h e n yl-N ,N -b is[(E )-p h e n ylm e t h ylid e n e ]m e t h a n e d i-
a m in e (5a ): white solid; mp 99.0-99.9 °C (lit.13 mp 102 °C).
Gen er a l P r oced u r e for t h e Syn t h esis of Com p ou n d s
6a -d . Compounds 5a -d (20 mmol) and benzotriazole (37 mmol,
1.5 equiv) were dissolved in 1,4-dioxane (for 6a ) or toluene (for
6b-d ) (100 mL), and the solution was refluxed for 12 h. The
reaction mixture was cooled to room temperature, and the
solvent was removed. The crude mixture was recrystallized from
ethyl acetate/hexane, to give pure product 6a ,d . Otherwise, the
crude mixture was dissolved in ether and washed with saturated
aqueous Na2CO3 solution to remove excess BtH. The organic
layer was dried over MgSO4. Upon removal of the MgSO4 and
solvent, oily products 6b,c were obtained and can be used further
without any purification.
2,4-Bis(2,4-d im et h oxyp h en yl)-N-p h en yl-1,3-t h ia zol-5-
a m in e (15k ): yellow microcrystals (yield 55%); mp 141.7-144.3
°C; 1H NMR δ 3.81 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 3.92 (s,
3H), 6.48-6.64 (m, 5H), 6.80 (t, J ) 7.2 Hz, 1H), 6.98 (d, J )
8.4 Hz, 2H), 7.19 (t, J ) 7.5 Hz, 2H), 7.63 (d, J ) 8.4 Hz, 1H),
8.32 (d, J ) 9.0 Hz, 1H); 13C NMR δ 55.3, 55.4, 55.5, 56.1, 98.2,
99.3, 105.5, 105.9, 114.7, 116.3, 117.1, 119.6, 128.8, 129.1, 132.3,
136.6, 139.2, 145.2, 152.4, 156.9, 157.0, 160.7, 161.3. Anal. Calcd
for C25H24N2O4S: C, 66.94; H, 5.39; N, 6.25. Found: C, 66.56;
H, 5.21; N, 6.16.
N-P h en yl-2,4-b is(2-t h ien yl)-1,3-t h ia zol-5-a m in e (15m ):
1
yellow microcrystals (yield 47%); mp 141.1-143.1 °C; H NMR
δ 5.39 (s, 1H), 6.83-6.88 (m, 2H), 6.91 (d, J ) 7.5 Hz, 1H), 7.01-
7.06 (m, 2H), 7.22-7.27 (m, 3H), 7.37-7.42 (m, 1H), 7.43 (d, J
) 2.4 Hz, 1H), 7.60 (d, J ) 3.6 Hz, 1H); 13C NMR δ 114.7, 120.6,
125.7, 125.8, 126.4, 127.3, 127.8, 129.5, 132.3, 136.1, 137.7, 143.0,
144.9, 156.0. Anal. Calcd for C17H12N2S3: C, 59.97; H, 3.55; N,
8.23. Found: C, 59.94; H, 3.64; N, 8.12.
1H -1,2,3-Ben zot r ia zol-1-yl(2-t h ien yl)-N-[(E)-2-t h ien yl-
m eth ylid en e]m eth a n - a m in e (6d ): brown powder; mp 101.0-
102.2 °C; 1H NMR δ 6.90-7.10 (m, 1H), 7.05-7.10 (m, 2H),
7.30-7.39 (m, 4H), 7.50-7.52 (m, 2H), 7.75 (s, 1H), 8.04-8.07
(m, 1H), 8.37 (s, 1H); 13C NMR δ 79.6, 112.1, 119.8, 124.1, 126.2,
126.6, 127.2, 127.5, 127.8, 131.3, 131.5, 133.3, 140.7, 140.8, 146.7,
156.9. Anal. Calcd for C16H12N4S2: C, 59.23; H, 3.73; N, 17.27.
Found: C, 59.26; H, 3.72; N, 17.17.
Ack n ow led gm en t. We thank Dr. Sergey Denisenko
for his contributions to this project.
Su p p or tin g In for m a tion Ava ila ble: Text providing 1H
and 13C NMR spectral data and elemental analyses for
compounds 5b-d , 6a -c,e, 15b-g,j,l, and 16a . This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Fu¨rth, A. Monatsh Chem. 1906, 27, 839 (Chem. Abstr. 1907, 1,
323).
J O000653Y