New methods for the synthesis of 2-aminothiazolones

Article abstract of DOI:10.1021/jo702369f

(Chemical Equation Presented) Two new methods for the synthesis of 2-aminothiazolones from 2-(4-methoxybenzylthio)acetic acids are described. A single reagent and simple experimental conditions are used in the key tandem deprotection-cyclization process. In the first approach 2-aminothiazolones are directly accessed via cyclization of the corresponding N-acylisothioureas. The second complementary approach provides access to a variety of 2-thiomethylthiazolones via cyclization of N-acyldithioimidates. The product 2-thiomethylthiazolones are then efficiently converted to 2-aminothiazolones via amine displacement.

Full text of DOI:10.1021/jo702369f

New Methods for the Synthesis of
2-Aminothiazolones
Seb Caille,* Eric A. Bercot,* Sheng Cui, and
Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320
scaille@amgen.com; ebercot@amgen.com
FIGURE 1. Biologically active 2-aminothiazolones.
ReceiVed NoVember 8, 2007
Given the prominence of the 2-aminothiazolone core structure
in biologically relevant molecules, a multitude of methods for
their assembly have been reported.6 The majority of approaches
rely on the condensation of substituted thioureas and R-halo
acid derivatives in the presence of an exogenous base.7 However,
this approach tends to be inefficient when tertiary R-halo acid
derivatives are employed in the reaction. Several reports have
appeared detailing the reaction of R-mercaptoacid derivatives
and cyanamides to access the 2-aminothiazolone ring system,
although the reactions generally proceed in moderate to low
yields with a limited substrate scope.8 Addition of amines to
2-thiothiazolone derivatives has also been reported.9
During the course of a recent development program, our group
became focused on the discovery of an efficient and modular
approach to C-5 mono- and disubstituted 2-aminothiazolones.
Considering that C-5 disubstituted 2-aminothiazolones (and C-5
disubstituted 2-thiothiazolones) are difficult to access from the
corresponding R-halo acid derivatives, we were interested in
the design of alternative methods to synthesize these compounds.
We envisioned two complementary cyclization manifolds that
would allow ready access to the target, both proceeding via a
tandem deprotection-cyclization process (Scheme 1). The first
approach (Route A) would emanate from an activated N-
acylisothiourea derivative 3 (Y ) NR3R4, X ) LG), which upon
deprotection and cyclization would supply 5 directly. The second
route (Route B) would involve the intermediacy of an activated
thiazolone derivative bearing a leaving group in the 2-position
(4), which would be accessed by the cyclization of N-acylimidate
3 (Y ) X ) LG). Reaction of activated intermediate 4 with the
appropriate amine coupling partner would then provide the target
2-aminothiazolones 5.
Two new methods for the synthesis of 2-aminothiazolones
from 2-(4-methoxybenzylthio)acetic acids are described. A
single reagent and simple experimental conditions are used
in the key tandem deprotection-cyclization process. In the
first approach 2-aminothiazolones are directly accessed via
cyclization of the corresponding N-acylisothioureas. The
second complementary approach provides access to a variety
of 2-thiomethylthiazolones via cyclization of N-acyldithio-
imidates. The product 2-thiomethylthiazolones are then
efficiently converted to 2-aminothiazolones via amine dis-
placement.
The 2-aminothiazolone core structure represents a widely
exploited pharmacophore in medicinal chemistry.1 Compounds
containing the 2-aminothiazolone subunit have demonstrated a
wide range of biological activity (Figure 1). For example 5-(2,4-
dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT)
is a potential therapeutic agent for colorectal cancer,2 thiazolone
1 is an antagonist of the Rvâ3 receptor,3 and 2 has shown potent
herbicidal activity.4 The majority of biologically active 2-ami-
nothiazolones display a C-5 alkylidene group while alternative
substitution at this position is less common.5
SCHEME 1. Proposed Intramolecular Cyclization Strategy
(1) Pulici, M.; Quartieri, F. Tetrahedron Lett. 2005, 46, 2387-2391.
(2) Teraishi, F.; Wu, S.; Zhang, L.; Guo, W.; Davis, J. J.; Dong, F.;
Fang, B. Cancer Res. 2005, 65, 6380-6387.
(3) Dayam, R.; Aiello, F.; Deng, J.; Wu, Y.; Garofalo, A.; Chen, X.;
Neamati, N. J. Med. Chem. 2006, 49, 4526-4534.
(4) Suzuki, M.; Morita, K.; Yukioka, H.; Miki, N.; Mizutani, A. J.
Pesticide Sci. 2003, 28, 37-43.
(5) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. ReV.
1981, 81, 175-203 and references cited therein.
(6) For an in-depth review, see: Barrett, G. C. Tetrahedron 1980, 36,
2023-2058. For a recent example, see: Blanchet, J.; Zhu, J. Tetrahedron
Lett. 2004, 45, 4449-4452.
(7) Example using R-bromoester: (a) Mahboobi, S.; Sellmer, A.; Hocher,
H.; Eichhorn, E.; Bar, T.; Schmidt, M.; Maier, T.; Stadlwieser, J. F.; Beckers,
T. L. J. Med. Chem. 2006, 49, 5769-5776. Example using R-bromocar-
boxylic acid: (b) St. Jean, D. J.; Yuan, C.; Bercot, E. A.; Cupples, R.;
Chen, M.; Fretland, J.; Hale, C.; Hungate, R. W.; Komorowski, R.; Veniant,
M.; Wang, M.; Zhang, X.; Fotsch, C. J. Med. Chem. 2007, 50, 429-432.
The success of our proposed approaches would rely heavily
on judicious choice of the leaving group resident on the
N-acylimine and the sulfur protecting group. Previous reports
10.1021/jo702369f CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/01/2008
J. Org. Chem. 2008, 73, 2003-2006
2003

of amine displacements with use of 2-thiomethylthiazolones (4,
X ) SMe)9 as electrophilic coupling partners and the acces-
sibility of the required isothioureas starting materials led us to
investigate the use of thiols as leaving groups. Our synthetic
approach to carboxylic acid 9 necessitated introduction of the
mercapto moiety as a 4-methoxybenzyl thioether (Scheme 2).
Utilization of this functionality bears several advantages: (i)
the acid-catalyzed deprotection is followed by in situ acid-
promoted cyclization to 4 or 5 and (ii) the 4-methoxybenzyl
thioether group can be introduced directly by sulfenylation of
the anion of 610 rather than an SN2 displacement of the
corresponding bromide that may be difficult depending on the
nature of R1 and R2. With mercaptoester 8 in hand, saponifica-
tion followed by coupling with imine salts11 10 provides the
desired cyclization substrates (11).
8, 9, and 10). With use of 1 equiv of TfOH, no reaction was
observed at 23 °C (4 h), with 1.5 equiv the reaction was very
sluggish (19% assay yield after 4 h at 23 °C). Increasing the
amount of TfOH to 2.0 equiv resulted in a 77% yield of 5a
(entry 10, 23 °C for 4 h).13
TABLE 1. Optimization of Cyclization To Generate 5aa
entry
acid (equiv)
additive (equiv)
solvent
TFA
yield, %
1
2
3
4
5
6
7
8
9
TfOH (1)
None
anisole (1)
anisole (1)
anisole (1)
anisole (1)
none
none
none
none
none
71
NR
81
TFA
TfOH (3)
TfOH (3)
TfOH (3)
TfOH (3)
MsOH (10)
TfOH (1)
TfOH (1.5)
TfOH (2)
toluene
CH2Cl2
toluene
Cl(CH2)2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
SCHEME 2. N-Acylimine Substrate Preparation
73
69
64b
28
NR
19b
77
10
none
a Reaction conditions: Substrate 12a was treated with the indicated
reagents in 10 mL of solvent per g of substrate at 23 °C for 5 h unless
otherwise indicated. Yields are isolated unless otherwise indicated. b Assay
yields determined by HPLC versus an authentic standard.
Having identified the optimum reaction conditions, the
substrate scope of this method was examined (Table 2). After
evaluation of the cyclization with substrates 12b and 12c (Table
2, entries 2 and 3), CH2Cl2 was selected as the preferred solvent
since use of toluene resulted in a biphasic reaction mixture14
thereby decreasing the reaction rates. A study of the substitution
at C-5 revealed that unsubstituted, dialkyl-substituted, and
monoalkyl-substituted starting materials undergo the cyclization
uneventfully (entries 1, 2, and 3). Additionally, a monoaryl-
substituted substrate (12d) was competent in the cyclization
reaction (60% yield, entry 4). Isourea 12e, synthesized from
4-fluorobenzylamine, successfully underwent the desired trans-
formation to generate 5e (57%, entry 5). Finally, by using
substrate 12f in which R3 and R4 are methyl and phenyl the
desired cyclic adduct 5f was produced in modest yield (49%,
entry 6).
With optimized cyclization conditions for N-acylisothioureas
in hand, we sought to expand the method to the cyclization of
N-acyldithoimidates to provide 2-thiomethythiazolones (Table
3). The cyclization reactions with substrates 13a-e were studied
by using the same reaction conditions described in Table 2,
except that 1.5 equiv of TfOH was found to be sufficient.
Examination of the substitution at C-5 revealed that unsubsti-
tuted, mono- and dialkyl-substituted starting materials are
equally competent in undergoing the desired transformation
(entries 1, 2, and 3). The reaction conditions allowed the
incorporation of other functional groups at the C-5 position.
Acyldithioimidates bearing an ester substituent (substrates 13d
and 13e) underwent the cyclization process efficiently (entries
4 and 5).
The deprotection-cyclization was first examined by using
N-acylisothiourea 12a (Table 1). N-Acylisothiourea 12a was
reacted with 1 equiv of trifluoromethane sulfonic acid (TfOH)
and 1 equiv of anisole in trifluoroacetic acid (TFA) at 23 °C
for 5 h to afford 2-aminothiazolone 5a in 71% yield (Table 1,
entry 1). The experimental conditions for this transformation
were examined in detail. As expected no reaction was observed
in the absence of TfOH (entry 2). TFA could be replaced by
either toluene (entry 3) or CH2Cl2 (entry 4) as the reaction
solvent, with toluene affording a higher yield (81%) of 5a. It
was determined that anisole was not required for a clean reaction
profile and further evaluation of the reaction parameters in the
absence of anisole was performed. A comprehensive solvent
survey revealed that Cl(CH2)2Cl was also suitable for the
reaction, affording a 64% yield of 5a (entry 6).12 A number of
acids were surveyed as a replacement for TfOH but only
methanesulfonic acid (MsOH) gave 5a albeit in low yield (entry
7). The number of equivalents of TfOH was investigated (entries
(8) Example using R-mercaptoester: (a) Ried, W.; Kuhnt, D. Liebigs
Ann. Chem. 1986, 4, 780-784. Example using R-mercaptocarboxylic
acid: (b) Kretov, A. E.; Bespalyi, A. S. Zh. Obshch. Khim. 1963, 33, 3323-
3325.
(9) For coupling of 2-thiothiazolones and amines, see: (a) Unangst, P.
C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J.; Kostlan, C. R.; Sircar,
J. C.; Wright, C. D.; Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1994, 37,
322-328. (b) Khodair, A. I. J. Heterocycl. Chem. 2002, 39, 1153-1160.
(10) For the electrophilic sulfenylation of esters and ketones, see: (a)
Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887-
4902. (b) Trost, B. M.; Massiot, G. S. J. Am. Chem. Soc. 1977, 99, 4405-
4412. (c) Shibata, N.; Baldwin, J. E.; Jacobs, A.; Wood, M. E. Tetrahedron
1996, 52, 12839-12852. (d) Bischoff, L.; David, C.; Martin, L.; Meudal,
H.; Roques, B.-P.; Faournie-Zaluski, M.-C. J. Org. Chem. 1997, 62, 4848-
4850. (e) Hayashi, S.; Furukawa, M.; Yamamoto, J.; Kunihiro, N. Chem.
Pharm. Bull. 1967, 15, 1188-1192.
Having successfully expanded the scope of the cyclization
to include N-acyl dithioimidate acceptors in the context of
(11) See the Supporting Information for the preparation of imine salts.
(12) Other solvents examined (MTBE, THF, MeOH, acetone, 2-butanone,
CH3CN, DMF, EtOAc) were not effective.
(13) No starting material 12a remained under these conditions.
(14) We postulate that these insoluble oils are trifluoromethanesulfonic
acid salts of the starting materials and products.
2004 J. Org. Chem., Vol. 73, No. 5, 2008

TABLE 2. Scope of Cyclization To Form 2-Aminothiazolonesa
TABLE 3. Scope of Cyclization To Form 2-Thiothiazolonesa
a Reaction conditions: Substrates were treated with the indicated reagents
in 10 mL of CH2Cl2 per g of substrate at 23 °C for 6-44 h unless otherwise
stated. Isolated yields are reported. b TFA was used as solvent to simplify
sample purification.
displacement reaction occurred smoothly at ambient temperature
in methanol without the requirement of an exogenous base. The
coupling of 2-thiomethylthiazolone 4c with aromatic, benzylic,
and secondary amines provided the desired 2-aminothiazolones
in uniformly high yield.
In summary, two novel, complementary methods to synthesize
2-aminothiazolones (5) have been developed. In the first protocol
heterocycles 5a-f were prepared directly from 4-methoxyben-
zylthioethers (12a-f) under mild conditions, avoiding the need
to perform a bromination-SN2 displacement sequence to
a Reaction conditions: Substrates were treated with TfOH (2.0 equiv)
in 10 mL of CH2Cl2 per g of substrate at 23 °C for 4 h unless otherwise
indicated. Isolated yields are reported. Yields represent averages of duplicate
experiments. No starting material N-acylisothioureas (or N-acylisourea) was
recovered in these experiments. b 2.5 equiv of TfOH was used.
TABLE 4. 2-Aminothiazolones via Amine Displacementa
5-membered heterocycle construction, we sought to expand the
reaction manifold to the formation of larger rings (eq 1).
N-acyldithioimidate 14 was prepared and subjected to the
prescribed reaction conditions for an extended amount of time
providing the desired cyclization adduct 15 in 44% yield.15
With ready access to a variety of substituted 2-thiomethylthi-
azolones, we next examined their reaction with amine coupling
partners (Table 4). A variety of conditions have been reported
to effect the desired transformation, many of which require
rigorous conditions.1,9 It was quickly established that the amine
a Reaction conditions: Substrates were treated with the indicated
reagents in 10 mL of MeOH per g of substrate at 23 °C. Isolated yields are
reported.
(15) The corresponding homologated N-acylisothiourea did not provide
cyclized product upon subjection to the optimized conditions.
J. Org. Chem, Vol. 73, No. 5, 2008 2005

partitioned between saturated aqueous NaHCO3 (30 mL) and CH2-
Cl2 (10 mL). The phases were separated and the aqueous phase
extracted with use of CH2Cl2 (1 × 25 mL) and the combined
organic phases were washed with brine, dried (MgSO4), filtered,
and concentrated. Chromatography of the residue on silica gel (5%
to 40% EtOAc/hexanes) afforded the thiazolone 4c (0.482 g, 95%)
as a colorless low-melting solid: 1H NMR (400 MHz, CDCl3) δ
2.73 (s, 3H), 1.65 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 199.9,
192.3, 61.6, 27.3, 16.1; IR (neat) 2972, 2930, 1708, 1440, 1229,
1144, 1119, 988 cm-1; exact mass (C6H9NOS2 + H) calculated
176.0198, measured 176.0197.
introduce the thiol functional group. The second more conver-
gent strategy involves cyclizations of N-acyldithioimidates
(13a-e) followed by displacement of the thiomethyl leaving
group with amines to produce the desired 2-aminothiazolones
(5b,g,h). We anticipate that these methods will find application
in the synthesis of enantiomerically enriched C5-disubstituted
2-aminothiazolones and 2-thiothiazolones from enantiomerically
enriched carboxylic acids (9). Examples of such transformations
will be reported in due course.
Experimental Section
Representative Procedure for the Preparation of 2-Ami-
nothiazolones via Amine Displacement: 5,5-Dimethyl-2-mor-
pholinothiazol-4(5H)-one (5h). To a solution of 2-thiomethylth-
iazolone 4c (103 mg, 0.59 mmol, 1.0 equiv) in dry MeOH (2 mL)
was added morpholine (70 µL, 0.80 mmol, 1.4 equiv). The
homogeneous mixture was stirred at ambient temperature for 2 h.
The reaction mixture was partitioned between EtOAc (10 mL) and
DI H2O (10 mL). The phases were separated and the aqueous phase
was extracted with use of EtOAc (1 × 10 mL). The combined
organic phases were washed with brine, dried (MgSO4), and
concentrated providing 117 mg (93%) of the title compound as a
white solid: 1H NMR (400 MHz, CDCl3) δ 3.81-4.01 (m, 2H),
3.77-3.79 (m, 4H), 3.47-3.50 (m, 2H), 1.66 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 192.3, 178.7, 66.3, 66.1, 48.5, 48.2, 27.9; IR
(neat) 2962, 2925, 2862, 1696, 1537, 1347, 1284, 1239, 1111, 1027,
892 cm-1; exact mass (C9H14N2O2S + H) calculated 215.0848,
measured 215.0852; mp 128-130 °C.
Representative Procedure for the Preparation of 2-Ami-
nothiazolones: 5,5-Dimethyl-2-(phenylamino)thiazol-4-(5H)-one
(5b). To a solution of isothiourea 12b (0.4 g, 0.001 mol) in CH2-
Cl2 (5 mL) was added TfOH (0.175 mL, 0.002 mol) via syringe
under a N2 atmosphere. The homogeneous mixture was stirred at
23 °C for 4 h during which time its color became deep red. After
4 h, an aliquot of the reaction mixture indicated complete conversion
(no starting material 12b was visible by LC). The reaction mixture
was treated with saturated aqueous NaHCO3 (10 mL) and the phases
separated. The aqueous phase was extracted with use of EtOAc (3
× 10 mL) and the combined organic phases were washed with
brine, dried (Na2SO4), and concentrated. Chromatography of the
residue on silica gel (10 to 40% EtOAc/hexanes) afforded the
thiazolone 5b (0.205 g, 94%) as a white solid: 1H NMR (400
MHz, CDCl3) δ 11.21 (br s, 1H), 7.35-7.43 (m, 2H), 7.16-7.28
(m, 3H), 1.66 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 184.1, 166.1,
142.6, 129.2, 125.9, 122.5, 56.2, 27.9; IR (neat) 2927, 2833, 1698,
1608, 1573, 1458, 1424, 1260, 1169, 772 cm-1; exact mass
(C11H12N2OS + H) calculated 221.0743, measured 221.0750; mp
128-130 °C.
Acknowledgment. We would like to thank Drs. Tiffany
Correll and Kevin Turney for their assistance with DSC and
HRMS measurements.
Representative Procedure for the Preparation of 2-Thiothia-
zolones: 5,5-Dimethyl-2-(thiomethyl)thiazol-4-(5H)-one (4c). To
a solution of N-acylimidate 13c (0.994 g, 2.89 mmol) in CH2Cl2
(15 mL) was added TfOH (0.390 mL, 4.41 mmol) via syringe under
a N2 atmosphere. The homogeneous mixture was stirred at 23 °C
for 6 h during which time its color became deep red. After 6 h, an
aliquot of the reaction mixture indicated complete conversion (no
starting material 13c was visible by LC). The reaction mixture was
Supporting Information Available: Experimental procedures
and spectral data for all new compounds described in the paper
are provided [1H and 13C NMR, FTIR, HRMS, melting points if
applicable]. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702369F
2006 J. Org. Chem., Vol. 73, No. 5, 2008