A selective and convenient method for the synthesis of 2- phenylaminothiazolines

Article abstract of DOI:10.1021/ol102428m

A series of 2-phenylaminothiazolines have been prepared from the corresponding N-(2-hydroxyethyl)-N'-phenylthioureas under mild reaction conditions using either thio-CDI (1,1'-thiocarbonyldiimidazole) or CDI (1,1'-carbonyldiimidazole) to promote the cycli

Full text of DOI:10.1021/ol102428m

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5526-5529
A Selective and Convenient Method for
the Synthesis of
2-Phenylaminothiazolines
April L. Bernacki,* Lingyang Zhu, and D. David Hennings
Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States
april.bernacki@arraybiopharma.com
Received October 7, 2010
ABSTRACT
A series of 2-phenylaminothiazolines have been prepared from the corresponding N-(2-hydroxyethyl)-N′-phenylthioureas under mild
reaction conditions using either thio-CDI (1,1′-thiocarbonyldiimidazole) or CDI (1,1′-carbonyldiimidazole) to promote the cyclization.
This protocol provides the desired cyclization products in good yield with excellent selectivity. The scope and selectivity of this
methodology are also described.
The 2-aminothiazoline ring system is a moiety that can
be found in biologically relevant compounds including
neuronal nicotinic acetylcholine receptor modulators,1
nitric oxide-synthase inhibitors,2 antimicrobial agents,3 and
antimicotic agents.4 Although there are several methods
reported for the conversion of 2-hydroxyethyl-thioureas
to the corresponding 2-aminothiazolines, most have
significant liabilities. One common method is acid-
promoted dehydrative cyclization5 which employs harsh
reaction conditions that are not compatible with acid-labile
substrates or materials prone to acid-catalyzed racemiza-
tion. Mitsunobu conditions6 are milder but tend to give
mixtures of N and S cyclization products (formation of
2-imidazolidinethiones and 2-aminothiazolines). The use
of sulfonyl chlorides as activating agents preferentially
forms the 2-aminooxazoline in most cases.7 In the course
of our research, we found that treatment of N-(2-
hydroxyethyl)-N′-phenylthioureas with either thio-CDI
(1,1′-thiocarbonyldiimidazole) or CDI (1,1′-carbonyldi-
imidazole) will form 2-aminothiazolines in good yield and
with excellent selectivity.
During the preparation of thiourea 1 from 3-aminoben-
zonitrile, it was discovered that although the desired
unsymmetrical thiourea was the major product a small
(6) (a) Kim, T. H.; Cha, M.-H. Tetrahedron Lett. 1999, 40, 3125–3128.
(b) Long, K.; Boyce, M.; Lin, H.; Yuan, J.; Ma, D. Bioorg. Med. Chem.
Lett. 2005, 15, 3849–3852.
(1) Faghih, R.; Gfesser, G. A.; Lynch, C. L.; Gopalakrishnan, M.;
Gopalakrishnan, S.; Malysz, J.; Gubbins, E. J.; El Kouhen, R.; Li, J.; Sarris,
K. A.; Michmerhuizen, M. J.; Wang, Y. Thiazoline and oxazoline derivatives
as nAChR modulators and their preparation and use in the treatment of
diseases. WO 2008002956.
(7) (a) It was originally reported by Kim et al. that treatment of N-(2-
hydroxyethyl)-N′-phenylthioureas with TsCl and NaOH produced the
corresponding 2-phenylaminothiazolines. Further analysis of the cy-
clization products, as described in their subsequent corrigendum, revealed
that no sulfur was present and that the products were indeed the
2-phenylamino-2-oxazolines when N1 was not substituted. Kim, T. H.;
Min, J. K.; Lee, G.-J. Tetrahedron Lett. 1999, 40, 8201-8204; Tetrahedron
Lett. 2001, 42, 2413. (b) Lee, G.-J.; Kim, J. N.; Kim, T. H. Bull. Korean
Chem. Soc. 2002, 23 (1), 19–20. (c) Heinelt, U.; Schultheis, D.; Jager, S.;
Lindenmaier, M.; Pollex, A.; Beckmann, H. S. g. Tetrahedron 2004, 60,
9883–9888.
(2) Bigot; Carry, J.-C.; Mignani, S. 2 - aminothiazoline derivatives and
their use as inhibitors of inducible NO-synthase. WO 2003040115.
(3) Bonde, C.; Gaikwad, G. Bioorg. Med. Chem. 2004, 12, 2151–2161.
(4) Baumann, R. J.; Mayer, G. D.; Fite, L. D.; Gill, L. M.; Harrison,
B. L. Chemotherapy 1991, 37, 157–165.
(5) (a) Xu, X.; Qian, X.; Li, Z.; Song, G.; Chen, W. J. Fluorine Chem.
2005, 126, 297–300. (b) Klayman, D. L.; Woods, T. S. J. Org. Chem. 1975,
40, 2000–2002.
10.1021/ol102428m  2010 American Chemical Society
Published on Web 11/01/2010

amount of the thiazoline cyclization product was observed
(Scheme 1). To confirm that thio-CDI was indeed promot-
With the initial proof of concept in hand, we looked at
optimizing the reaction with the addition of an auxiliary base.
Bases such as KOtBu, Cs2CO3, K2CO3, Et3N, imidazole, and
DBU were screened, all at 2 equiv in relation to the thiourea
starting material (5). We found that, in general, the inorganic
bases were detrimental to the reaction (low assay yields with
the balance of the material being unidentified impurities as
well as residual starting material), whereas the weaker amine
bases had little to no effect on the yield. The performance
of the reaction was also assessed using solvents other than
THF. Acetone, toluene, CH2Cl2, and EtOAc perform com-
parably to THF, while more polar solvents (DMF, NMP,
and acetonitrile) gave lower yields. On the basis of these
results, it was determined that our preferred conditions for
this transformation are to use THF at ambient temperature
with no additional base.
Scheme 1
.
Discovery of Thiazoline Formation under Novel
Conditions
Although the reaction conditions described above were
successful in converting hydroxyethyl-thioureas to the cor-
responding thiazolines under mild conditions, the use of thio-
CDI on a larger scale can be problematic. Thio-CDI is fairly
expensive compared to other activating reagents and has
limited availability in large batch sizes. It is a foul-smelling
solid that is unstable to moisture, which leads to storage
problems. For these reasons, we decided to investigate
alternative reagents to promote the cyclization.
Several common activating agents were screened using
compound 5 as a test substrate to evaluate their reactivity
and selectivity compared to the results using thio-CDI.
Several cyclization products (6-9) as well as a substitution
product (10) were observed as detailed in Table 1.9 The
use of diethylazodicarboxylate (Mitsunobu conditions,
entry 1) gave a mixture of S and N cyclization products,
with imidazolidinethione 9 being favored 3:1 over thia-
zoline 6. Activation of the thiourea using MeI or tosyl
chloride exclusively gave cyclization to oxazoline 7, and
although mesyl chloride was also selective for oxazoline
7, 10% of thiazoline 6 was observed (entries 2-4). The
results in entries 1-4 all corroborate the chemoselectivi-
ties reported in the literature for similar substrates.6,7,10
Other activating agents that are novel to this type of
transformation were also examined with mixed results. Both
triphosgene and thiophosgene produced multiple cyclization
products; however, the major product with these reagents
was alkyl chloride 10.
ing cyclization, thiourea 1 was purified and resubjected
to the reaction conditions with a full equivalent of thio-
CDI. The reaction proceeded readily at room temperature,
and phenylaminothiazoline 2 was isolated in 54% yield.
This serendipitous result led us to further explore the scope
and general utility of this novel transformation.
We chose N-phenylthioureas with simple alkyl-substi-
tuted amino alcohol side chains to study this transforma-
tion. These substrates can be easily prepared by reaction
of phenylisothiocyanate (3) with the appropriate amino
alcohol in THF at ambient temperature.8 The model
substrate used for optimization of the methodology
(thiourea 5, Scheme 2) was prepared in 93% yield from
Scheme 2. Synthesis of a Model System Using Thio-CDI
Performing the reaction using Vilsmeier reagent gave
60% of thiazoline 6 with the remaining 40% being comprised
of multiple unidentified impurities. As expected, thio-CDI
gave thiazoline 6 as the major product with only 3% of
oxazoline 7, but we were pleased to see that CDI gave
exclusively thiazoline 6. As the reaction profile for CDI is
equal to or superior to thio-CDI, and CDI is not hampered
by the limitations previously listed for thio-CDI, this reagent
was chosen for further examination.
phenylisothiocyanate (3) and valinol (4). To confirm the
result observed with compound 1, thiourea 5 was treated
with thio-CDI which gave the desired product, thiazoline
6, in 61% isolated yield.
(9) The products were characterized using 1H NMR and LC-MS
analysis, and the product ratios were generated from the 1H NMR
integrations of the crude reaction mixtures.
(8) (a) Kruse, L. I.; Kaiser, C.; DeWolf, W. E., Jr.; Frazee, J. S.; Garvey,
E.; Hilbert, E. L.; Faulkner, W. A.; Flaim, K. E.; Sawyer, J. L.; Berkowitz,
B. A. J. Med. Chem. 1986, 29, 2465–2472. (b) Lattanzi, A. Synlett 2007,
13, 2106–2110.
(10) (a) Perez, E. M.; Oliva, A. I.; Hernandez, J. V.; Simon, L.; Moran,
J. R.; Sanz, F. Tetrahedron Lett. 2001, 42, 5853–5856. (b) Hetenyi, A.;
Szakonyi, Z.; Klika, K.; Pihlaja, K.; Fulop, F. J. Org. Chem. 2003, 68,
2175
.
Org. Lett., Vol. 12, No. 23, 2010
5527

Table 1. Evaluation of Activating Agents for Thiazoline Formationa
entry
activating agent
% 6
% 7
% 8
% 9
% 10
1
2
3
4
5
6
7
8
9
Mitsunobu (DEAD)b
20
-
10
-
10
20
60
97
>99
-
>99
85
>99
20
-
-
3
<1
-
-
-
-
-
25
-
-
60
-
-
-
-
-
-
-
-
-
-
-
MeI
MsClc
TsCl
-
thiophosgene
triphosgene
Vilsmeier-Haackc
Thio-CDI
CDI
70
55
-
-
-
-
Product ratios were determined by H NMR. b 20% of compound 5 observed. c Unknown impurities comprise the balance of the material.
a
1
To probe the generality of this methodology, a series of
thioureas with substitution R to the amine of the amino
alcohol was treated with CDI in THF (11a-f, Table 2).
lar acylation (path b, Scheme 3). In these two examples,
formation of the thiazoline product may have been
Table 3. Synthesis of 5-Substituted Thiazolines
Table 2. Scope of Synthesis of 4-Substituted Thiazolines
entry
starting material
R1
R2
yielda
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
H
Me
Me
Et
iPr
(R)Ph
H
H
Me
H
H
71%
74%
75%
78%
82%
88%
entry starting material
R1
yield of 14a yield of 15a
1
2
3
4
5
13a
13b
13c
13d
13e
Et
CF3
ndb
ndb
99%
88%
4%
4-OMe-Ph 81%
Ph 67%
4-CF3-Ph 62%
H
29%
27%
a Yields determined after isolation by column chromatography.
a Isolated yield after column chromatography. b nd ) not detected.
In each case, the substrate was cleanly converted to the
desired thiazoline product with isolated yields ranging from
71 to 88% (12a-f).
disfavored due to increased steric hindrance around the
electrophilic site (path a, Scheme 3). An electronic effect
was also observed within the substrates examined. The
more electron-rich p-methoxy analog (13c) highly favored
formation of the desired thiazoline (14c), whereas the
simple phenyl and p-CF3 analogs gave both cyclization
products in ∼2:1 ratio favoring the thiazoline. Presumably,
the chemoselectivity observed with the phenyl substituents
is a result of benzylic stabilization of the electrophilic site
favoring path a (Scheme 3).
Continuing to evaluate the scope of this reaction, a
series of thioureas with substitution R to the hydroxyl
group of the amino alcohol (13a-e) were prepared and
subjected to CDI in THF (Table 3). In this series of
substrates, an interesting difference in chemoselectivity
was observed. When R1 is alkyl (ethyl and trifluorometh-
yl), the only isolable product was the corresponding
oxazolidinone (15a,b), which is the result of intramolecu-
5528
Org. Lett., Vol. 12, No. 23, 2010

hydroxyethyl)-N′-phenylthioureas to form 2-aminothiazolines
under very mild conditions. The cyclization tolerates sub-
stitutions of the ethyl group R to N1 or on the carbon bearing
the hydroxyl group provided the substituent is an aryl moiety.
Furthermore, the use of CDI, which is a stable, inexpensive,
and easily handled activating agent, makes this methodology
preparatively useful.
Scheme 3. Proposed Reaction Pathways
Acknowledgment. The authors wish to thank Phil Ander-
son, Cale Bibb, and Carman Bryant from Array BioPharma,
Inc. for providing HRMS and IR data.
Supporting Information Available: Experimental details
and characterization data are available for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have demonstrated that CDI can be used
to promote a selective dehydrative cyclization of N-(2-
OL102428M
Org. Lett., Vol. 12, No. 23, 2010
5529