M. Lasalle et al. / Tetrahedron Letters 56 (2015) 1011–1014
1013
Table 2
was investigated (entries 14, 16, and 17 for 10 min reaction and 15
and 18 for 20 min reaction). An increase in temperature led to
improved conversion and 150 °C was chosen for further optimiza-
tion. At this temperature, a decrease of the amount of DIEA (entries
20 and 21) or in T3P (entry 22) was detrimental for the conversion.
T3P (3 equiv), DIEA (6 equiv) under microwave heating at
150 °C during 10 min appeared optimal for the conversion of the
reaction (entry 19).
Scope of the 5-amino-2-thioimidazole synthesis
O
H
N
R4
R2
R2
N
N
N
S
N
R3
N
R3
R1
R1
S
R4
Compd R1
R2
R3
R4
Yield
(%)
The optimized conditions (Table 1, entry 19) were then used to
explore the scope of the reaction. We investigated the effect of
each substituent (R1–R4, Table 2).14
1
2
CH3
CH3
58
71
In R3, both aryl (1–4) and alkyl groups (5) were compatible with
the reaction. Hindered aromatic rings in R3 were well tolerated (4,
98% yield). The presence of electron withdrawing or donating
groups on the aromatic ring in R3 position (2–3) had no impact
on the yield of the reaction. Influence of the sulfur component
(R4) was assessed using aliphatic (6–8) or benzylic (1) groups.
An ether function (8) as well as a protected amine (phthalimide
protection, 7) did not impact the reaction. Finally, the influence
of the substitution on the nitrogen atom (R1, R2) was evaluated.
N-Methylaniline bearing electron withdrawing or donating groups
were tested. The yield was better (70%) in the case of para-CF3 sub-
stitution (9) compared to para-OMe (10, 50%) or the unsubstituted
aromatic ring (1, 58%). The electron withdrawing effect of the CF3
group is likely to enhance the electrophilicity of the carbonyl of the
amide function thereby facilitating the nucleophilic attack by the
nitrogen of the isothiourea moiety. Conversely, the methoxy elec-
tron donating group decreases the reactivity of the carbonyl com-
pared to the unsubstituted aromatic ring. The piperidine was
evaluated as an aliphatic amine and gave the desired compound
in a moderate yield of 31%. In this case, the elimination of the
piperidine instead of the dehydration was also observed leading
to the side product 10 (60% yield).
O
3
CH3
75
CF3
4
5
6
CH3
CH3
CH3
98
51
77
–CH3
O
N
7
CH3
61
O
O
In summary, a method for the synthesis of original 5-amino-2-
thioimidazoles has been developed. This method takes advantage
of a highly selective T3P-mediated microwave cyclodehydration
of N-acetamidoisothiourea and yields the target imidazoles in good
to excellent yields. This novel access to an underrepresented class
of imidazoles could be of high interest in medicinal chemistry.
8
CH3
CH3
CH3
92
70
50
31
CF3
O
9
10
11
Acknowledgments
(CH2)5
We are grateful to the institutions that support our laboratory:
INSERM, Université de Lille, Institut Pasteur de Lille. This project
was supported by Conseil Régional Nord-Pas de Calais, EDFR (con-
vention 11003609), Etat DRRT, PRIM and Université Lille 2 (Appel à
projets «orientations stratégiques»: convention A007). Manuel Las-
alle is a recipient of a doctoral fellowship of the French Ministere
de la Recherche. NMR acquisitions were done at the Laboratoire
d’Application de Résonance Magnétique Nucléaire (LARMN), Lille,
France.
instead of aniline elimination. The effect of the stoichiometry of
T3P was further investigated. As shown in Table 1 (entries 6–9),
increasing the amount of T3P to 3 equiv allowed a marked increase
in 1:10 ratio (63:6 after 24 h, entry 9). The addition of T3P (3 equiv)
and DIEA (6 equiv) after 8 h of reaction (entry 10) led to a 80%
conversion rate (after 24 h) without detection of the undesired
compound 10.
Supplementary data
Eventually, in order to validate that the cyclization was mediated
by T3P and not just by a thermal process in basic media, a control
experiment without T3P (entry 5) was undertaken. No conversion
was observed, confirming the importance of T3P in the reaction.
Moreover, experiments using dehydrating agents like acetic
anhydride and trifluoroacetic anhydride failed to provide the target
compound (data not shown).
With the aim to reduce reaction time, we then carried out the
reaction under microwave irradiation. Comparable to classical
heating, the conversion of 1c into 1 increased with the amount of
T3P (entry 11 vs 13, 12 vs 14). Then the effect of the temperature
Crystallographic data (including structure factors) for the
structure in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication No.
CCDC1029533. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Supplementary data (detailed synthesis, spectral data for all
compounds and RX data) associated with this article can be found,