Diversity-oriented synthesis of N-aryl-N-thiazolyl compounds

Article abstract of DOI:10.1016/j.tetlet.2010.06.117

An efficient approach toward the parallel solid-phase synthesis of highly diversified N-aryl-N-thiazolyl compounds is presented. The treatment of resin-bound aniline derivatives with Fmoc-isothiocyanate generated aryl thioureas which, following Hantzsch's reaction with a variety of α-haloketones and cleavage of the solid support, led to the desired N-aryl-N-thiazolyl compounds in good yield and high purity.

Full text of DOI:10.1016/j.tetlet.2010.06.117

Tetrahedron Letters 51 (2010) 4797–4800
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diversity-oriented synthesis of N-aryl-N-thiazolyl compounds
*
Adel Nefzi , Sergey Arutyunyan
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach toward the parallel solid-phase synthesis of highly diversified N-aryl-N-thiazolyl
Received 3 June 2010
Revised 21 June 2010
Accepted 23 June 2010
Available online 30 June 2010
compounds is presented. The treatment of resin-bound aniline derivatives with Fmoc-isothiocyanate
generated aryl thioureas which, following Hantzsch’s reaction with a variety of a-haloketones and cleav-
age of the solid support, led to the desired N-aryl-N-thiazolyl compounds in good yield and high purity.
Ó 2010 Elsevier Ltd. All rights reserved.
The thiazole ring is an important heterocycle which plays a
prominent role in nature and has broad applications in agricultural
and medicinal chemistry.1 Specifically, 2-aminothiazoles present
an important class of heterocycles found in numerous biologically
active compounds. They have been reported to possess antiviral,2
antibacterial,3 antiprion,4 and psychotropic activities.5 Compounds
containing the aminothiazole moiety are also known to be a ligand
of estrogen receptors,1h adenosine receptor antagonists,1i while
other analogs exhibit antitumor properties.1j 2-Aminothiazoles
were successfully employed as heterocyclic bioisosteres of the
phenol moiety on dopamine agonists and the widely used anti-Par-
kinsonian agent, pramipexole. These resulted in improved pharma-
cological properties including longer duration of action and
improved bioavailability.6 Conjugated polyaminothiazole films
were reported to display electrochemical properties with high
thermal stability.7 A number of biologically important aminothia-
zole analogs have been disclosed. For example, MTIP inhibits the
binding of corticotrophin-releasing factor (CRF) to the CRF1 recep-
tor8, and MB06322 is an orally bioavailable phosphoramidase sen-
sitive-prodrug for the treatment of type 2 diabetes (Fig. 1).9
2-Aminothiazoles are readily obtained by Hantzsch’s cyclocon-
reaction of ketones with a mixture of N-bromosuccinimide, thiourea,
and benzoyl peroxide.12
Herein, we describe an efficient approach for the parallel solid-
phase diversity-oriented synthesis13 of N-aryl-N-thiazolyl deriva-
tives. Starting from p-methylbenzhydrylamine hydrochloride
Table 1
Synthesized N-aryl-N-thiazolyl compounds 4
Entry R1
R2
X
MW obtaineda (MH+) Purityb (%)
4a
4b
4c
–CH3
–CH3
–(CH2)4–
–H
–CH3 NH
NH
NH
318 (MH+)
332 (MH+)
358 (MH+)
90
95
70c
OH
4d
4e
–H
–H
NH
396 (MH+)
85
93
NH
437 (MH+)
4f
4g
4h
–CH3
–CH3
–(CH2)4–
–H
–CH3
O
O
O
319 (MH+)
333 (MH+)
359 (MH+)
95
95
92
OH
397 (MH+)
88
densation of thiourea with a a-
-haloketones,10 or by the reaction of
4i
–H
O
O
thiocyanate carbonyl compounds with aromatic or aliphatic amine
hydrochlorides.11 They can also be obtained by following the one-pot
4j
–H
–H
438 (MH+)
95
4k
4l
4m
–CH3
–CH3
–(CH2)4–
CH2 317 (MH+)
89
91
88
–CH3 CH2 331 (MH+)
CH2 357 (MH+)
EtO2C
O
NH
OH
N
H2N
P
4n
4o
–H
–H
CH2 395 (MH+)
90
89
N
O
NH
CO2Et
N
N
S
S
N
O
CH2 436 (MH+)
N
iBu
MB06322
MTIB
a
Determined by ESI-MS.
The products were run on a Vydac column, gradients 5– 95% (1% formic acid in
Figure 1.
b
ACN) in 7 min. The purity was estimated on analytical traces at k = 214 nm and
254 nm.
* Corresponding author. Tel.: +1 772 345 47396; fax: +1 772 345 3649.
E-mail address: adeln@tpims.org (A. Nefzi).
c
Incomplete cyclization was observed.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.117

4798
A. Nefzi, S. Arutyunyan / Tetrahedron Letters 51 (2010) 4797–4800
O
O
O
a
b
NO2
F
NO2
N
NH2
N
N
H
N
N
H
H
X
2
1
X
R1
R2
N
S
S
NH2
c, d
O
O
e, f
NH
NH
N
H2N
N
H
N
X
X
3
4
Scheme 1. Reagents and conditions: (a) 20 equiv of amine in DMF (0.3 M), 20 equiv DIEA in DMF, rt, 20 h; (b) 10 equiv SnCl2Á2H2O in DMF (2 M), rt, overnight; (c) 6 equiv
Fmoc-NCS in DMF (0.3 M), rt, overnight; (d) 20% piperidine/DMF; (e) 20 equiv a-halogenoketones in DMF (0.3 M), 70 °C, overnight; (f) HF/anisole (95:5), 0 °C, 90 min.
Table 2
Synthesized N-aryl-N-thiazolyl compounds 6
Entry
R1
R2
R3
MW obtaineda (MH+)
466
Purityb (%)
91
6a
–CH3
–H
O
O
O
O
6b
6c
–CH3
–CH3
480
506
85
78
–(CH2)4–
OH
6d
–H
544
83
O
6e
6f
–H
586
494
508
534
93
86
81
75
–CH3
–H
6g
6h
–CH3
–CH3
–(CH2)4–
OH
6i
6j
–H
–H
572
614
82
81
6k
6l
–CH3
–H
437
451
477
68
72
68
HN
HN
HN
HN
–CH3
–CH3
6m
–(CH2)4–
OH
6n
6o
–H
–H
515
557
70
65
HN
a
Determined by ESI-MS.
b
The products were run on a Vydac column, gradients 5–95% (1% formic acid in ACN) in 7 min. The purity was estimated on analytical traces at k = 214 nm and 254 nm.

A. Nefzi, S. Arutyunyan / Tetrahedron Letters 51 (2010) 4797–4800
4799
R2
N
R3
S
O
O
O
a, b
c, d, e, f
NO2
N
NH2
N
NH
N
H
N
H
H2N
N
NH
R1
O
N
R1
N
5
6
O
c, d, e
R3
R4
N
S
O
S
NH2
O
O
b, c, d
e, f
NH
H2N
NO2
NH
N
N
H
N
H
N
N
N
N
N
N
N
R1
N
R1
R1
8
9
7
S
S
S
R2
R2
R2
Scheme 2. Reagents and conditions: (a) 10 equiv carboxylic acids or isocyanate in DMF (0.3 M), 10 equiv DIC, rt, 3 h; (b) 10 equiv SnCl2Á2H2O in DMF (2 M), rt, overnight;
(c) 6 equiv Fmoc-NCS in DMF (0.3 M), rt, overnight; (d) 20% piperidine/DMF; (e) 20 equiv a-haloketone in DMF (0.3 M), 70 °C, overnight; (f) HF/anisole (95:5), 0 °C, 90 min.
Table 3
Synthesized piperazino aryl bis-thiazole compounds 9
Entry
R1
R2
R3
R4
MW obtaineda (MH+)
Purityb (%)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
Methyl
Methyl
–(CH2)4–
3-Hydroxyphenyl
1-Adamantyl
Methyl
Methyl
–(CH2)4–
3-Hydroxyphenyl
1-Adamantyl
Methyl
Methyl
–(CH2)4–
3-Hydroxyphenyl
1-Adamantyl
Methyl
Methyl
–(CH2)4–
–H
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
3-Hydroxyphenyl
3-Hydroxyphenyl
3-Hydroxyphenyl
3-Hydroxyphenyl
3-Hydroxyphenyl
1-Adamantyl
1-Adamantyl
1-Adamantyl
1-Adamantyl
–H
–H
–H
–H
415
429
455
493
535
429
443
469
507
549
455
469
495
533
575
493
507
533
571
613
535
549
575
613
76
71
50
70
75
77
80
56
85
89
74
65
58
65
83
79
59
56
75
56
76
76
53
51
–H
–H
–H
Methyl
–H
Methyl
Methyl
Methyl
Methyl
Methyl
–H
–H
–H
Methyl
–H
–H
–H
Methyl
–H
–H
–H
–H
–H
–H
–H
–H
–H
9s
9t
9u
9v
9w
9x
3-Hydroxyphenyl
1-Adamantyl
Methyl
Methyl
–(CH2)4–
–H
–H
–H
Methyl
3-Hydroxyphenyl
–H
a
Determined by ESI-MS.
b
The products were run on a Vydac column, gradients 5–95% (1% formic acid in ACN) in 7 min. The purity was estimated on analytical traces at k = 214 nm and 254 nm.
(MBHAÁHCl) resin, 3-nitro-4-fluoro benzoic acid was coupled in the
presence of diisopropylcarbodiimide (DIC). The fluoro group was
displaced with a variety of secondary cyclic amines such as piper-
idine, morpholine, and piperazine. The nitro group was reduced in
the presence of tin chloride and the generated amine was treated
with Fmoc-isothiocyanate to provide the corresponding thiourea
3. Following Fmoc deprotection, the resin-bound aryl thiourea
was treated with a variety of a-haloketones to generate the corre-
sponding resin-bound N-aryl-N-thiazolyl compounds (Scheme 1).
The final compounds were obtained following the cleavage of the
solid support with HF/anisole (95:5). All the expected N-aryl-N-
thiazolyl compounds 4 were obtained in high purity and good
yields (Table 1), and the selected compounds were characterized
by 1H NMR.14
In order to generate more diversity around the N-aryl-thiazole,
the piperazine was acylated with a variety of carboxylic acids and
isocyanates (Scheme 2). Thus, following the displacement of the
fluoro group with Boc piperazine, the Boc group was deprotected
with trifluoroacetic acid and the generated resin-bound aryl-piper-
azine was treated with various acylating reagents. The nitro group

4800
A. Nefzi, S. Arutyunyan / Tetrahedron Letters 51 (2010) 4797–4800
Carter, G. W. J. Med. Chem. 1988, 31, 1719; (d) Clemence, F.; Marter, O. L.;
Delevalle, F.; Benzoni, J.; Jouanen, A.; Jouquey, S.; Mouren, M.; Deraedt, R. J.
Med. Chem. 1988, 31, 1453; (e) Jaen, J. C.; Wise, L. D.; Caprathe, B. W.; Tecle,
H.; Bergmeier, S.; Humblet, C. C.; Heffner, T. G.; Meltzner, L. T.; Pugsley, T. A. J.
Med. Chem. 1990, 33, 311; (f) Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan,
M. J.; Taylor, D. G., Jr.; Connolly, C. J. C.; Doharty, A. M.; Klutchko, S. R.; Sircar,
I.; Steinbaugh, B. A.; Bately, B. L.; Painchand, C. A.; Rapundalo, S. T.;
Michniewicz, B. M.; Olzon, S. C. J. J. Med. Chem. 1992, 35, 2562; (g) Tsuji,
K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601; (h) Fink, B. A.;
Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol.
1999, 6, 205; (i) Van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R. C.;
Von Drabbe Kunzel, J. F.; De Groote, M.; Visser, S.; Ijzerman, A. P. J. Med. Chem.
2001, 44, 749; (j) Komar, Y.; Green, R.; Wise, D.; Worting, L. L. J. Med. Chem.
1988, 23, 501.
was reduced and the resin-bound piperazine aniline 5 was treated
with Fmoc-NCS. Following Fmoc deprotection, the thiazole was
formed using the same procedure described above. The desired
N-aryl-N-thiazolyl compounds 6 were generated following the
cleavage of the solid support. We selected adamantyl acetic acid,
4-methoxyphenyl acetic acid, and phenylisocyanate for the diver-
sity R1, and five different commercially available
a-haloketones
for the position of diversity R2. Fifteen compounds were extracted,
lyophilized, and analyzed by LC–MS (Table 2). Starting materials
were consumed to completion leading to good yields and good to
high purities of the target compound.
Similarly, the same approach was applied for the parallel syn-
thesis11 of a variety of piperazino aryl bis-thiazole derivatives 9
(Scheme 2). Following deprotection of the Boc group from the
piperazine, the generated amine was treated with Fmoc-isothiocy-
anate and the resin-bound piperazine thiazole 7 was formed using
the same Hantzsch’s cyclocondensation reaction as described
above. Following nitro reduction, the second thiazole was gener-
ated and the final aryl-dithiazolyl compounds 9 were obtained
following the cleavage of the solid support. Five different commer-
2. (a) Liu, C.; Phadke, A.; Wang, X.; Zhang, S. PCT Int. Appl., WO 2009149436 A1
20091210, 2009.; (b) Liebig, H.; Pfetzing, H.; Grafe, A. Arzneimittel-Forschung
1974, 24, 887.
3. (a) Thomas, K. K.; Reshmy, R. Asian J. Chem. 2008, 20, 1457; (b) More, P. G.;
Bhalvankar, R. B. J. Indian Chem. Soc. 2006, 83, 113; (c) Ming, Z.; Zhen-Feng, C.;
Hong, L.; Shao-Ming, S. Guangxi Shifan Daxue Xuebao, Ziran Kexueban 2002,
20, 42.
4. Ghaemmaghami, S.; May, B. C. H.; Renslo, A. R.; Prusiner, S. B. J. Virol. 2010, 84,
3408.
5. Zablotskaya, A.; Segal, I.; Germane, S.; Shestakova, I.; Domracheva, I.;
Nesterova, A.; Geronikaki, A.; Lukevies, E. Chem. Heterocycl. Compd. (New
York, NY, United States) (Translation of Khimiya Geterotsiklicheskikh
Soedinenii) 2002, 38, 859.
6. Zhang, A.; Xiong, W.; Hilbert, J. E.; DeVita, E. K.; Bidlack, J. M.; Neumeyer, J. L. J.
Med. Chem. 2004, 47, 1886.
7. Solmaz, R.; Kardas, G. Prog. Org. Coat. 2009, 64, 81.
8. Gehlert, D. R.; Cipiletti, A.; Thorsell, A.; Le, A. D.; Hipskind, P. A.; Hamdouchi, C.;
Lu, J.; Hember, E. J.; Cramer, J.; Song, M.; McKinzie, D.; Morin, M.; Ciccocioppo,
R.; Heilig, M. J. Neuroscience 2007, 27, 397.
9. Erion, M. D.; van Poelje, P. D.; Dang, Q.; Kasibhatla, S. R.; Potter, S. C.; Reddy,
M. R.; Reddy, K. R.; Jiang, T.; Lipscomb, W. N. Proc. Natl. Acad. Sci. 2005, 102,
7970.
10. (a) Hantzsch, A. R.; Weber, J. H. Ber. 1887, 20, 3118; (b) Garcia-Egido, E.; Wong,
S. Y. F.; Warrington, B. H. Lab Chip 2002, 2, 31; (c) Lin, P. Y.; Hou, R. S.; Wang, H.
M.; Kang, I. J.; Chen, L. C. J. Chin. Chem. Soc. 2009, 56, 455; (d) Kearney, P. C.;
Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998, 63, 196; (e) Arutyunyan, S.;
Nefzi, A. J. Comb. Chem. 2010, 12, 315.
11. (a) Baily, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.; Storer, R.; Watson, S. P.
Bioorg. Med. Chem. Lett. 1996, 6, 1409; (b) Kearney, P. C.; Fernandez, M. J. Org.
Chem. 1998, 63, 196; (c) Rudolp, J. Tetrahedron 2000, 56, 3161; (d) Schantl, J. G.;
Lagoja, I. M. Synth. Commun. 1998, 28, 1451.
cially available a-haloketones were selected for both the cyclocon-
densation reactions. We performed the parallel synthesis of 25
piperazino aryl bis-thiazole compounds 9. All the desired com-
pounds were obtained in good yields and purities (Table 3).
We presented a high yielding approach for the parallel diver-
sity-oriented synthesis of a variety of N-aryl-N-thiazolyl com-
pounds. Taking advantage of the wide variety of commercially
available secondary amines,
a-halogenoketones, and different
acylating reagents such as carboxylic acids, sulfonyl chlorides, iso-
cyanates, and isothiocyanates, large libraries of highly diversified
aminoarylthiazoles can be prepared and screened for the identifi-
cation of new therapeutics.
Acknowledgments
12. Dahiya, R.; Pujari, H. K. Indian J. Chem. 1986, 25B, 966.
13. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
14. Compound 4k: 1H NMR (500 MHz, DMSO-d6): 8.19 (s, 1H), 7.83 (dd, J = 1.8 Hz,
J = 8.2 Hz), 6.50 (s, 1H), 2.84 (t, J = 5.0 Hz, 4H), 2.19 (s, 3H), 1.62 (m, 4H), 1.52
(m, 2H). 13C (125 MHz, DMSO-d6): 167.5, 164.4, 146.8, 133.3, 129.2, 123.1,
120.2, 119.3, 102.9, 52.0, 25.5, 23.6, 16.5. Compound 4h: 1H NMR (500 MHz,
DMSO-d6): 8.17 (s, 1H), 7.84 (s, 1H), 7.60 (dd, J = 1.8 Hz, J = 8.3 Hz, 1H), 7.24 (s,
1H), 7.14 (d, J = 8.3 Hz, 1H), 7.04 (9s, 1H), 4.2 (m, 2H), 3.72 (t, J = 4.2 Hz, 4H),
2.88 (t, J = 3.4 Hz, 4H), 2.56 (br s, 2H), 1.75 (br s, 4H). 13C (125 MHz, DMSO-d6):
167.4, 162.3, 145.8, 133.2, 129.5, 123.3, 120.8, 119.1, 117.7, 116.9, 66.0, 50.9,
25.4, 22.8, 22.4, 22.2.
The authors would like to thank the State of Florida Funding, NIH
(1R03DA025850-01A1, Nefzi), NIH (5P41GM081261-03, Houghten)
and NIH (3P41GM079590-03S1, Houghten) for their financial
support.
References and notes
1. (a) Lewis, J. R. Nat. Prod. Rep. 1999, 16, 389–416; (b) Hargrave, K. D.; Hess, F. K.;
Oliver, J. T. J. Med. Chem. 1983, 26, 1158; (c) Haviv, F.; Ratajczyk, J. D.; DeNet, R.
W.; Kerdesky, F. A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young, P. R.;