Unprecedented one-pot chemocontrolled entry to thioxoimidazolidinones and aminoimidazolones: Synthesis of kinase inhibitor Leucettamine B

Article abstract of DOI:10.1021/co500152s

A novel and highly chemoselective protocol for the construction of thioxoimidazolidinone and aminoimidazolone frameworks was explored, and the influence of the reaction conditions on product formation was studied to establish two distinct approaches for their selective formation. In this one-pot reaction, ambient temperature generally resulted in the formation of thioxoimidazolidinones, whereas microwave irradiation provided aminoimidazolones exclusively. An attempt to elucidate the observed chemoselectivity is described, and the products were confirmed by X-ray studies. One-pot synthesis toward Leucettamine B, a marine alkaloid, was achieved on the basis of this protocol.

Full text of DOI:10.1021/co500152s

Research Article
pubs.acs.org/acscombsci
Unprecedented One-Pot Chemocontrolled Entry to
Thioxoimidazolidinones and Aminoimidazolones: Synthesis of
Kinase Inhibitor Leucettamine B
Manikandan Selvaraju† and Chung-Ming Sun*,†,‡
†Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan
‡Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807-08,
Taiwan
S
* Supporting Information
ABSTRACT: A novel and highly chemoselective protocol for
the construction of thioxoimidazolidinone and aminoimidazo-
lone frameworks was explored, and the influence of the
reaction conditions on product formation was studied to
establish two distinct approaches for their selective formation.
In this one-pot reaction, ambient temperature generally
resulted in the formation of thioxoimidazolidinones, whereas
microwave irradiation provided aminoimidazolones exclu-
sively. An attempt to elucidate the observed chemoselectivity
is described, and the products were confirmed by X-ray
studies. One-pot synthesis toward Leucettamine B, a marine alkaloid, was achieved on the basis of this protocol.
KEYWORDS: chemoselectivity, one-pot protocol, domino reactions, microwave chemistry, total synthesis
inhibitors derived from the marine sponge Leucettamine B,
were investigated as potential therapeutics for Alzheimer’s
disease and in diseases involving abnormal pre-mRNA
splicing.10 Aminoimidazolones constitute an attractive template
to exploit the chemical diversity of a broad drug-like library. A
structure−activity relationship study on a diversified small
molecule library of aminoheterocycle (III) provided a novel
series of γ-secretase modulators.11,12
Normally, 4-benzylidene-substituted aminoimidazolones are
synthesized by the condensation of 2-thioxoimidazolidinone
(or 2-alkylthio-imidazolones) with aldehydes followed by
reaction with alkylamines.13 Ding et al. assembled an
aminoimidazolone ring system by the reaction of aliphatic
primary amines with carbodiimides, which were generated from
aza-Wittig reactions of vinylimino-phosphorane with isocya-
nates.14 Similarly, Houghten reported the solid-phase synthesis
of 5-substituted aminoimidazolones through guanidine deriva-
tives.15,16 All of these reports involved the reaction of primary
amines with thiourea in the presence of guanylating agents to
furnish aminoimidazolones. There are two possible pathways
that can be postulated for this reaction, as depicted in Scheme
1. Nucleophilic attack of amines in the presence of mercuric
chloride leads to the generation of a guanidine intermediate
that subsequently undergoes intramolecular amidation (Scheme
1, route 1). In view of the equal spatial proximity and
INTRODUCTION
■
Diversity-oriented synthesis is recognized as being a powerful
synthetic strategy owing to its great potential to produce
chemically and skeletally diversified molecular scaffolds from
the same or commonly used precursors; this strategy is
continuously aimed at developing high levels of efficiency in
organic synthesis.1 A challenging task encountered with
diversified synthesis from a common intermediate is the precise
control of chemo-, regio-, and stereoselectivities through fine
tuning the reaction conditions. In recent years, many groups
have reported the control of chemoselectivity with metal
catalysts and solvents, whereas reaction conditions (temper-
ature, microwave, and reflux) dependent selectivity has been
relatively less explored.2,3 Consequently, the development of
reaction conditions-based chemoselective transformation is a
worthy and challenging goal.4 In this context, we disclose a
novel domino reaction leading to the selective synthesis of
thioxoimidazolidinones at room temperature and amino-
imidazolones under microwave irradiation in a straightforward
manner, which is normally difficult to achieve in a single
operation.
A conformationally strained small molecule, aminoimidazo-
lone, represents an attractive motif in the quest for new drug
development.5 It is envisioned as a combination of two
important pharmacophores, guanidine and imidazole, which
appear in many bioactive molecular scaffolds and therapeutic
agents (Figure 1).6,7 Among these, aplysinopsin (I), a marine
natural product, was identified as an anticancer agent against
the HT 29 cell line.8,9 Leucettines (II), a family of kinase
Received: October 7, 2014
Revised: January 3, 2015
© XXXX American Chemical Society
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Figure 1. Bioactive heterocycles containing an aminoimidazolone framework.
Scheme 1. Synthetic Strategy for Aminoimidazolones and Thioxoimidazolidinones
comparable nucleophilicities of nitrogens N1 and N3 of the
guanidine intermediate, two regioisomeric imidazolones (A and
B) through pathway a or b are possible, in principle, and their
formation has been reported in the literature.17 In both
pathways, thioureas may undergo guanylation by an in situ
formation of carbodimides followed by a nucleophilic addition
with amines.
interest to develop a robust method for the effective synthesis
of 2-aminoimidazolone and 4-amino thioxoimidazolidinone
from the common intermediate by tuning the reaction
conditions. Hence, the reaction conditions play a crucial role
in the product outcome, and the application of microwave
irradiation not only increases the reaction rate but also switches
the selectivity of the product distribution.
The present synthetic strategy makes use of the tunable
reactivity of thiohydantoin generated from disubstituted
thioureas (Scheme 1, route 2). In our novel approach, the
initial formation of a thiohydantoin by a base-induced
intramolecular amidation affords a suitable intermediate for a
subsequent regioselective guanylation with primary amines
promoted by mercuric chloride. The formation of thioxoimi-
dazolidinones 5 involves the initial in situ oxidation of the
thiohydantoin to a cyclic imine followed by a nucleophilic
attack of a primary amine at room temperature to the imine. In
contrast, under microwave irradiation, thiohydantoin 3 delivers
a cyclic enamine intermediate that subsequently undergoes
guanylation to furnish aminoimidazolones 6. The in situ
generation of thiohydantoin effectively prevents the formation
of regioisomeric products from the acyclic guanidine
intermediate.18 Hence, the need to specifically functionalize
substrates and the regioisomeric issues associated with
carbodimide intermediates were setbacks encountered in earlier
reports. The synthesis and biological evolution of 4-amino-
substituted thioxoimidazolidinone have been little-explored.
Previously, amino-substituted thioxoimidazolidinone 5 was
accomplished only intramolecularly by using DDQ as an
oxidant.19 In light of the above observations, it would be of
RESULTS AND DISCUSSIONS
■
At the outset of our studies, we intended to probe the reactivity
and chemoselectivity of thiohydantoins under guanylation
conditions to generate the first ever guanidine derivative of
thiohydantoin. Initial reaction of phenyl alanine methyl ester
with butyl isothiocyanate in the presence of triethylamine in
dichloromethane furnished thiohydantoin 3{1,1}. The obtained
intermediate was treated with isobutylamine 4{1}, mercuric
chloride, and triethylamine in DMF at room temperature
(Table 1). To our surprise, the anticipated guanidine product
was not observed, and an unexpected 4-amino thioxoimidazo-
lidinone 5{1,1,1} possessing a quaternary carbon was isolated
instead. Careful scrutinization of the analytical data revealed the
participation of all of the starting materials in the obtained
product, and the exact structure was confirmed by single-crystal
X-ray analysis (Figure 2). We reasoned that, in the presence of
base and HgCl2, 3{1,1} underwent oxidation followed by
nucleophilic addition of the amine to deliver the product,
5{1,1,1}. Although the envisioned product was not obtained by
the reaction of thiohydantoin, this unexpected formation of
5{1,1,1} might be more rewarding, as there are no earlier
B
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temperature to 100 °C did not improve the reaction yield. In
the absence of either the base or HgCl2, the final products were
not produced. However, compound 5{1,1,1} was obtained in
the absence of HgCl2 at room temperature with 30% yield
(entry 8), whereas the addition of HgCl2 furnished product
5{1,1,1} in 2 h with 85% yield.
Still, the actual role of mercuric chloride was not ascertained;
we assume that it may act as an oxidant as well as a
desulfurizing agent for this transformation. In general, the
oxidation of an amine to an imine is demonstrated with various
metal catalysts in combination with oxygen.21 However, the
reported mercuric chloride-mediated oxidation of thiohydan-
toins to imines and enamines is a new addition to such a
transformation. The diversity of amino esters, isothiocyanates,
and various amines is depicted in Figure 3.
Figure 2. ORTEP representation of 4-amino thioxoimidazolidinone
5{1,1,1}.
reports on such a convenient one-pot synthesis from these
readily available reagents.
Having established two selective protocols for the formation
of 5{1,1,1} and 6{1,1,1}, the scope of the reaction was
investigated, as shown in Tables 2 and 3, respectively. All of the
amino ester substituents as well as various isothiocyanates were
well-tolerated under these reaction conditions, delivering the
final products with satisfactory yields. Next, we focused on the
wider utility of primary and secondary amines for the current
transformations.
All of the primary amines 4 afforded satisfactory yields,
whereas the secondary amines 4 (Table 3, entries 10 and 12)
resulted in lower yields. During the course of the substrate
scope studies, we explored the reactivity of thiohydantoin from
phenyl glycine having no hydrogen on its beta carbon, which
cannot undergo oxidation, to provide an enamine intermediate.
As shown in Table 4, we observed the formation of
iminoimidazolone 7 under the optimized conditions, and a
possible explanation for this observation is illustrated in Scheme
3.
In order to study the formation of 5{1,1,1}, the reaction
conditions were fine-tuned with various solvents at different
temperatures (Table 1). Switching the solvent to dichloro-
methane leads to complete conversion to compound 5{1,1,1}
with a yield of 85% (entry 4). The reaction did not afford
complete conversion in DMF, THF, acetone, acetonitrile, or
toluene under the same conditions (entries 1−3 & 5−6). As
part of our interest in developing microwave-assisted
reactions,20 the same reaction was powered by microwave
irradiation at 60 °C for 10 min in dichloromethane. A
serendipitous outcome was discovered here when compound
5{1,1,1} was obtained in only 20% yield while the major
product was identified as compound 6{1,1,1} with 65% yield
(entry 9). The use of microwave irradiation altered the
reactivity of hydantoin 3{1,1} by the predominant formation
of enamine rather than imine to deliver compound 6{1,1,1}.
Finally, the optimized conditions to deliver compound
6{1,1,1} exclusively were identified as Et3N (1.5 equiv) and
HgCl2 (1.5 equiv) in dichloromethane at 80 °C for 10 min
(entry 10). With the same stoichiometry, increasing the
To gain insight into the reaction mechanism, we carried out a
few control experiments (shown in Scheme 2). When the
a
Table 1. Influence of the Reaction Conditions on the Reactivity of 3{1,1} with Butyl Amine 4{1}
b
yields (%)
entry
catalyst
solvent
DMF
conditions temperature (° C)/time
5{1,1,1}
6{1,1,1}
1
2
3
4
5
6
7
8
9
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
none
rt/16 h
60
20
30
85
15
35
10
30
20
0
0
THF
rt/16 h
0
acetone
DCM
rt/16 h
0
rt/2 h
0
acetonitrile
toluene
DCM
rt/16 h
0
rt/16 h
0
rt/16 h
0
Et3N
DCM
rt/24 h
0
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
HgCl2/Et3N
DCM
60(MW)/10 m
80(MW)/10 m
100(MW)/10 m
40/16 h
65
85
85
15
c
10
DCM
c
11
DCM
0
c
12
DCM
60
a
b
c
Reaction conditions: 1{1} (1.0 equiv), 2{1} (1.2 equiv), 4{1} (1.5 equiv), HgCl2 (1.0 equiv), Et3N (1.0 equiv). Isolated yields. HgCl2 (1.5 equiv)
and Et3N (1.5 equiv).
C
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Figure 3. Diversity of amino esters 1{1−5}, isothiocyanates 2{1−7}, and amines 4{1−13}.
The isolated enamine 9{4,7} was converted smoothly to
product 6{4,7,3} in 80% yield under the optimized reaction
conditions. These results clearly demonstrate that oxidation
occurred before guanylation and that the oxidized product
9{4,7} is an intermediate in the cascade reaction. Furthermore,
compound 6{1,7,9} possesses a cis ring junction and Z
configuration at the alkene (Figure 4), and its absolute
structure was unequivocally confirmed by X-ray analysis.22
In a similar way, we tried to isolate the cyclic imine
intermediate 8 for the formation of 5 (Scheme 3), but the
efforts were not fruitful, suggesting that under basic conditions
the oxidation and nucleophilic addition are rapid. Although
mechanistic details are not clear at this point, on the basis of
experimental observations and literature precedent,23 we
propose a possible mechanism for the exclusive formation of
these products based on the reaction conditions (Scheme 3). At
room temperature, thiohydantoin 3 underwent oxidation to
cyclic imine 8, which underwent subsequent nucleophilic attack
by an amine on the α carbon to deliver 4-amino-substituted
thioxoimidazolidinone 5. Under microwave irradiation, how-
ever, formation of enamine 9 through H+ elimination is favored
over the addition of an amine on imine 8. Subsequently, the
activation of the thio-carbonyl group by mercury(II) chloride to
furnish the thio-mercury conjugate and the nucleophilic
displacement of mercury-coordinated sulfur by amines could
deliver cyclic guanidine 6 by an addition−elimination pathway.
The thiohydantoin derived from phenyl glycine may deliver
Table 2. Oxidation/Addition Reaction of Thiohydantoins
with Amines
a
entry
product
isolated yield (%)
1
2
3
4
5
6
7
8
9
5{1,1,1}
5{2,2,2}
5{5,2,2}
5{5,4,3}
5{5,3,3}
5{3,2,2}
5{4,2,3}
5{4,3,4}
5{4,3,5}
85
87
89
87
88
90
85
84
86
a
Isolated yields.
reaction of 3{4,7} with methoxypropyl amine in DCM at 80 °C
was heated only to the halfway point (5 min), the oxidized
enamine 9{4,7} together with the desired product 6{4,7,3} was
observed.
D
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isolate compound 10 were unsuccessful, which demonstrated
that conversion to final product 7 was very rapid. Thus,
thiohydantoin can be treated as a suitable substrate for
mercury-induced desulfurization without functionalizing the
thione, facilitating nucleophilic attack of an amine at the C-2
and C-4 positions.
Table 3. Oxidation/Guanylation Reaction of Thiohydantoins
with Amines
To further demonstrate the synthetic importance of our
protocol, we applied this method to the synthesis of biologically
active kinase inhibitor Leucettamine B. This marine alkaloid
exerts selective inhibition toward protein kinases that are
potential targets for the treatment of Alzheimer’s disease.
Although several methods were reported earlier, we disclosed
herein a telescoped, rapid synthesis of Leucettamine B.13b,24
Reaction of 11 with methyl isothiocyante in the presence of
base provided the corresponding thiohydantoin, which was
treated with ammonia(aq) under our unique reaction strategy
to provide Leucettamine B, 12, in 76% yield (Scheme 4).
Hence, the interesting results obtained from our synthetic
approach indicate that the reaction conditions play a crucial
role in controlling the reaction pathways, allowing the same
starting materials to generate different types of products
selectively.
a
entry
product
isolated yield (%)
1
6{1,1,1}
6{1,1,13}
6{1,1,6}
6{1,1,7}
6{1,1,2}
6{1,1,8}
6{1,7,9}
6{1,5,10}
6{5,2,2}
6{5,2,9}
6{5,6,11}
6{5,6,12}
6{5,3,3}
6{5,4,3}
6{4,7,3}
6{4,2,3}
85
83
82
80
88
79
77
85
70
61
69
65
73
69
64
68
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CONCLUSIONS
■
In summary, the unique reactivity of thiohydantoins, which can
be switched by the reaction conditions, was explored for the
one-pot formation of thioxoimidazolidinones and amino-
imidazolones. At room temperature, oxidation is followed by
nucleophilic addition of amines to furnish 4-amino thioxoimi-
dazolidinones, whereas under microwave irradiation, the
sequential oxidation followed by guanylation delivers amino-
imidazolones. The developed method was successfully applied
to a concise synthesis of a kinase inhibitor, Leucettamine B.
These results provide new insights into the divergent
functionalization of thiohydantoins. Further studies on the
detailed reaction mechanisms and their utility on other
heterocycles for biological applications are underway by our
group.
a
Isolated yields.
Table 4. Oxidation/Guanylation Reaction of Thiohydantoins
with Amines
a
entry
product
isolated yield (%)
EXPERIMENTAL PROCEDURES
1
2
3
7{2,2,1}
7{2,2,13}
7{2,2,8}
80
79
77
■
General Procedure for the Synthesis of 5-Benzyl-3-
butyl-5-(isobutylamino)-2-thioxoimidazolidin-4-one
(5{1,1,1}). To phenylalanine methyl ester hydrochloride 1{1}
(0.1 g, 0.46 mmol) in dichloromethane was added triethyl-
amine (0.093 g, 0.92 mmol) followed by butyl isothiocyante
2{1} (0.063 g, 0.55 mmol), and the resulting reaction mixture
was subjected to microwave irradiation at 80 °C for 10 min to
furnish thiohydantoin 3{1,1}. To the same reaction mixture
were added mercuric chloride (0.125 g, 0.46 mmol) and
triethylamine (0.047 g, 0.46 mmol) followed by isobutyl amine
4{1} (0.04 g, 0.55 mmol), and the mixture was allowed to stir
at room temperature for 2 h. After completion of the reaction,
the reaction mixture was filtered through a Celite pad and
washed with dichloromethane (10 mL). The filtrate was
concentrated, and the residue was purified by silica-gel column
chromatography (20% ethyl acetate/hexane) to afford the
desired product 5{1,1,1} in 85% yield.
a
Isolated yields.
Scheme 2. Control Experiments for the Formation of
6{4,7,3}
new intermediate 10, which preferably undergoes an in situ
auto-oxidation to provide iminoimidazolones 7. It is believed
that intermediate 10 is very unstable and undergoes
dehydrogenation to the more stable conjugated iminoimidazo-
lones 7. A possible driving force could be the formation of the
more stable product, which has a double bond in conjugation
with the exocyclic carbonyl and the imine. All of the efforts to
5-Benzyl-3-butyl-5-(isobutylamino)-2-thioxoimidazo-
lidin-4-one, 5{1,1,1}. 1H NMR (300 MHz, CDCl3) δ 7.97 (s,
1H), 7.34−7.24 (m, 3H), 7.21−7.19 (m, 3H), 3.72−3.49 (m,
2H), 3.12 (s, 2H), 2.23 (d, J = 6.4 Hz, 2H), 1.92 (s, 1H), 1.76−
1.59 (m, 1H), 1.36−1.22 (m, 2H), 1.21−1.07 (m, 2H), 0.90 (d,
E
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Figure 4. ORTEP representation of compound 6{1,7,9}.
Scheme 3. Possible Mechanism for the Formation of 5−7
added triethylamine (0.093 g, 0.92 mmol) followed by butyl
isothiocyante 2{1} (0.063 g, 0.55 mmol), and the resulting
reaction mixture was subjected to microwave irradiation at 80
°C for 10 min to furnish thiohydantoin 3{1,1}. To the same
reaction mixture were added mercuric chloride (0.188 g, 0.69
mmol) and triethylamine (0.070 g, 0.69 mmol) followed by
isobutyl amine 4{1} (0.06 g, 0.69 mmol), and the mixture was
subjected to microwave irradiation at 80 °C for 10 min. After
completion of the reaction, the reaction mixture was filtered
through a pad of Celite and washed with dichloromethane (10
mL). The filtrate was concentrated, and the residue was purified
by silica-gel column chromatography (35% ethyl acetate/
hexane) to afford the desired product 6{1,1,1} in 85% yield.
(Z)-4-Benzylidene-1-butyl-2-(isobutylamino)-1H-imi-
Scheme 4. Telescoped Synthesis of Leucettamine B
J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 182.9, 174.2, 132.5, 130.3,
128.5, 127.7, 79.4, 50.3, 43.3, 40.1, 29.4, 28.6, 20.4, 19.8, 13.6;
MS (ESI) m/z: 334 (MH+); HRMS (ESI, m/z) calcd for
C18H27N3OS [MH+], 334.1948; found, 334.1955 (M+H).
General Procedure for the Synthesis of (Z)-4-
Benzylidene-1-butyl-2-(isobutylamino)-1H-imidazol-
5(4H)-one (6{1,1,1}). To phenylalanine methyl ester hydro-
chloride 1{1} (0.1 g, 0.46 mmol) in dichloromethane was
1
dazol-5(4H)-one, 6{1,1,1}. H NMR (300 MHz, CDCl3) δ
8.08 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.26−7.23
(m, 1H), 6.7 (s, 1H), 4.57 (s, 1H), 3.58 (t, J = 7.2 Hz, 2H),
F
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2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxa-
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3.43 (d, J = 6.3 Hz, 2H), 2.04 (sep, J = 6.6 Hz, 1H), 1.62
(quint, J = 6.6 Hz, 2H), 1.38 (sext, J = 7.2 Hz, 2H), 1.04 (d, J =
6.6 Hz, 6H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.4, 157.4, 139.3, 135.7, 130.8, 128.4, 128.0, 116.7,
49.4, 39.0, 31.0, 28.5, 20.2, 20.1, 13.7; MS (FB+): m/z 300;
HRMS (EI): calcd for C18H25N3O, 299.1998; found, 299.2021.
(5) Scala, F.; Fattorusso, E.; Menna, M.; Scafati, O. T.; Tierney, M.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H and 13C NMR, LRMS, HRMS) of
compounds 5−7 and X-ray data of compounds 5{1,1,1} and
6{1,7,9}. This material is available free of charge via the
Internet at http://pubs.acs.org.
(6) (a) Rodriguez, F.; Rozas, I.; Ortega, J. E.; Erdozain, A. M.; Meana,
J. J.; Callado, L. F. Guanidine and 2-aminoimidazoline aromatic
derivatives as alpha2-adrenoceptor ligands: searching for structure-
activity relationships. J. Med. Chem. 2009, 52, 601. (b) Keller, K.; Pop,
N.; Hutzler, C.; Sickinger, A. G. B.; Bernhardt, G.; Buschauer, A.
Guanidine-acylguanidine bioisosteric approach in the design of
radioligands: synthesis of a tritium-labeled N(G)-propionylarginina-
mide ([3H]-UR-MK114) as a highly potent and selective neuropeptide
Y Y1 receptor antagonist. J. Med. Chem. 2008, 51, 8168.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
■
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Science Council of Taiwan for
financial assistance and the authorities of the National Chiao
Tung University for providing the laboratory facilities. This
work was particularly supported by “Aim for the Top University
Plan” of the National Chiao Tung University and Ministry of
Education, Taiwan.
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