Direct access to variously substituted 2-imino-4-thiazolines

Article abstract of DOI:10.1055/s-0030-1258108

1,2-Diaza-1,3-dienes readily react as Michael acceptors with thiocyanic acid generated in situ from potassium thiocyanate. The acidic medium of the reaction promotes the intramolecular ring closure of the α-thiocyanato hydrazones allowing access to novel 2-imino-4-thiazolines functionalized at positions 3, 4, and 5 in a one-pot, high-yielding process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258108

LETTER
1859
Direct Access to Variously Substituted 2-Imino-4-thiazolines
V
ariously Substitu
r
ted 2-Im
a
ino-4-thia
z
z
olines io A. Attanasi, Gianfranco Favi, Paolino Filippone, Francesca R. Perrulli, Stefania Santeusanio*
Istituto di Chimica Organica della Facoltà di Scienze e Tecnologie, Università degli Studi di Urbino ‘Carlo Bo’,
Via I Maggetti 24, 61029 Urbino, Italy
E-mail: stefania.santeusanio@uniurb.it
Received 26 March 2010
condensation of a-haloketone with thiourea, or the reac-
tion of a-bromoketimines with potassium thiocyanate.9
This latter method is limited to substrates having an alkyl
substituent at the 3- and the 5-position, and an aromatic
Abstract: 1,2-Diaza-1,3-dienes readily react as Michael acceptors
with thiocyanic acid generated in situ from potassium thiocyanate.
The acidic medium of the reaction promotes the intramolecular ring
closure of the a-thiocyanato hydrazones allowing access to novel 2-
imino-4-thiazolines functionalized at positions 3, 4, and 5 in a one- substituent at the 4-position; whereas this letter reports an
pot, high-yielding process.
efficient and straightforward one-pot synthesis of 2-imi-
no-4-thiazolines variously functionalized at all the three
positions.
Key words: 1,2-diaza-1,3-dienes, thiocyanation, Michael addition,
ring closure, 2-imino-4-thiazoline, heterocycles
Based on our experience4,5,10 and on the results obtained
by Yadav on chalcones,11 we decided to investigate an ap-
proach based on conjugate hydrothiocyanation of suitable
heterodiene systems from which to drive an intramolecu-
lar ring closure and achieve our target.
The chemistry of 1,2-diaza-1,3-dienes has been under ac-
tive investigation by several groups for a number of
years.1 Depending on the nature of the substituents
present both at the olefinic moiety and at the azo group, as
well as on the reagent, this class of intermediates is capa-
ble of participating in cycloaddition reactions2 or nucleo-
philic additions.3 From our experience,3a,b electron-
withdrawing groups on the terminal carbon and/or nitro-
gen atom increase the electrophilic character of the het-
erodiene system making conjugated azoalkenes good
Michael acceptors. Since the resulting Michael adducts
bear suitable nucleophilic and electrophilic features, a cy-
clization reaction can follow the addition step to produce
functionalized heterocycles. In this context, by using var-
iously functionalized S-nucleophiles, we have previously
reported the synthesis of 2-phenylimino-4-thiazoline4 and
2-alkylimino-4-thiazoline derivatives.5
Since the reaction of in situ generated conjugated phenyl-
azoalkenes and thiocyanic acid is reported to give rise to
2,3-dihydro-1H-imidazole-2-thione derivatives by [3+2]
cycloaddition,12 we postulated that the introduction of
electron-withdrawing substituents, both on the olefinic
moiety and at the azo group of the azo–ene system, could
influence the outcome of that reaction (Scheme 1).
EWG
R
R
N
NH
EWG
S
EWG
N
N
EWG
NH
present work
AcOH
R
KSCN
In view of the fact that 2-imino-4-thiazolines demonstrate
a range of biological effects such as antimicrobial, anti-
inflammatory, antihistaminic, antihypertensive, and hyp-
notic activity, as well as positive myeloperoxidase reac-
tivity,6 we were interested in their synthesis.
N
R
N
Ar
N
NH
Ar
HN
S
Schantl et al.
In the literature, several strategies for the synthesis of 2-
iminothiazoline are known. The first reports on the syn-
thesis of 2-imino-4-thiazoline, published more than a cen-
tury ago, comprise a condensation reaction of a-
haloketones with thiourea, in neutral or basic medium
(Hantzsch synthesis) or with ammonium thiocyanate;
both methods suffering from the drawback isomer forma-
tion.7 The same condensation reactions under acidic con-
ditions give rise to 2-imino-4-thiazolines in addition to
variable amounts of aminothiazoles as side products.8 At
present the best entries to the 2-imino-4-thiazoline system
involve alkylation of 2-aminothiazoles obtained from the
Scheme 1
Indeed, the treatment of 1,2-diaza-1,3-dienes 1a–k with
KSCN (2), in glacial acetic acid at room temperature, im-
mediately produced Michael adducts 3. We predicted that
the acidic conditions could promote the activation of the
cyano functionality of the a-thiocyanato hydrazones 3 to-
wards ring closure and, in fact, 3 was completely convert-
ed into the desired 2-imino-4-thiazoline derivatives 4a–k
(67–93%)13 on standing in acidic medium for several
hours (Scheme 2, Table 1).
From a mechanistic point of view (Scheme 2) and in ac-
cordance with our previous results, we propose that the
formation of 4 arises from nucleophilic addition of the
sulfur atom of thiocyanate anion at the terminal carbon of
SYNLETT 2010, No. 12, pp 1859–1861
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258108; Art ID: D08010ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

1860
O. A. Attanasi et al.
LETTER
the activated olefinic moiety to produce 3 followed by in-
tramolecular nucleophilic attack of the hydrazone sp2-
nitrogen across the carbon–nitrogen triple bond. In sup-
port of this, using 1j allowed us to characterize 3j14 as a
stable a-thiocyanato hydrazone derivative and to follow
its conversion into 4j15 upon treatment with acetic acid.
Acknowledgment
This work was supported by financial assistance from the Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR), and the
Università degli Studi di Urbino ‘Carlo Bo’.
References and Notes
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(b) Sommer, S. Angew. Chem. 1979, 91, 756.
R2
O
R2
O
AcOH, r. t.
H
R1
N
R1
NH
(c) Boeckmann, R. K. Jr.; Reed, J. E.; Ge, P. Org. Lett. 2001,
3, 3647. (d) Attanasi, O. A.; De Crescentini, L.; Filippone,
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(2) (a) South, M.; Jakuboski, T. L. Tetrahedron Lett. 1995, 36,
5703. (b) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Fringuelli, F.; Mantellini, F.; Mattucci, M.; Piermatti, O.;
Pizzo, F. Helv. Chim. Acta 2001, 84, 513. (c) Abbiati, G.;
Attanasi, O. A.; Rizzato, S.; Rossi, E.; Santeusanio, S.
Tetrahedron 2007, 63, 11055. (d) Attanasi, O. A.; Favi, G.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Org. Lett. 2009,
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(3) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org.
Chem. 2009, 3109. (b) Attanasi, O. A.; Cotarca, L.; Favi, G.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Synlett 2009,
1583. (c) Polanc, S. In Targets in Heterocyclic Systems:
Chemistry and Properties, Vol. 3; Attanasi, O. A.; Spinelli,
D., Eds.; Società Chimica Italiana: Rome, 2000, 33–92.
(d) Banert, K. In Targets in Heterocyclic Systems:
Chemistry and Properties, Vol. 3; Attanasi, O. A.; Spinelli,
D., Eds.; Società Chimica Italiana: Rome, 2000, 1–32.
(4) Attanasi, O. A.; Filippone, P.; Foresti, E.; Guidi, B.;
Santeusanio, S. Tetrahedron 1999, 55, 13423.
R3
N
R3
N
N
O
S
O
1a–k
+
KSCN
3
2
O
R2
N
O
R1
R3
NH
S
NH
4a–k 67–93%
Scheme 2
Table 1 Results of the Synthesis of 2-Imino-4-thiazolines 4a–k
Entry 1,3-Diaza-
R1
R2
R3
2-Imino-
Yield
1,3-diene 1
4-thiazoline 4 (%)a
(5) Attanasi, O. A.; Carvoli, G.; Filippone, P.; Perrulli, F. R.;
Santeusanio, S. Synlett 2004, 1643.
1
2
1a
1b
1c
1d
1e
1f
Ot-Bu
Ot-Bu
OMe
NH2
Me
Me
Me
Me
Et
OEt
4a
91
93
91
72
78
74
84
85
92
72
67
(6) (a) Patel, P. B.; Trivedi, J. T. Indian Chem. Soc. 1987, 54,
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Chem. Pharm. Bull. 1998, 46, 863. (e) Turan-Zitouni, G.;
Sivaci, D. M.; Kaplancikli, Z. A.; Ozdemir, A. Farmaco
2002, 57, 569. (f) Bonde, C. G.; Gaikwad, N. J. Bioorg.
Med. Chem. 2004, 12, 2151. (g) Bodtke, A.; Pfeiffer, W.-
D.; Ahrens, N.; Langer, P. Bioorg. Med. Chem. Lett. 2004,
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(7) (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887,
20, 3118. (b) Traumann, V. Liebigs Ann. Chem. 1888, 31.
(c) Weitzberg, M.; Aizensthat, Z.; Blum, J. J. Heterocycl.
Chem. 1984, 21, 1597.
(8) Beyer, H.; Ruhling, G. Chem. Ber. 1956, 89, 107.
(9) De Kimpe, N.; Boelens, M.; Declercq, J. P. Tetrahedron
1993, 49, 3411.
(10) Arcadi, A.; Attanasi, O. A.; Giorgi, G.; Filippone, P.; Rossi,
E.; Santeusanio, S. Tetrahedron Lett. 2003, 44, 8391.
(11) Yadav, L. D. S.; Patel, R.; Rai, V. K.; Srivastava, V. P.
Tetrahedron Lett. 2007, 48, 7793.
(12) (a) Schantl, J. G.; Prean, M. Monatsh. Chem. 1993, 124,
299. (b) Schantl, J. G.; Lagoja, I. M. Heterocycles 1997, 45,
691. (c) Schantl, J. G.; Nádeník, P. Synlett 1998, 786.
(13) Typical One-Pot Procedure for the Preparation of
2-Imino-4-thiazoline Derivatives 4a–k
OMe 4b
OBn 4c
3
4
OEt
4d
5
Ot-Bu
NHPh
OBn
OMe 4e
NMe2 4f
OMe 4g
6
Me
Et
7
1g
1h
1i
8
OMe
OEt
Me
Me
Me
Me
OEt
OEt
4h
4i
9
10
11
1j
Ot-Bu
NH2
NMe2 4j
1k
OMe 4k
a Yield of pure isolated product in one-pot procedure.
In summary, conjugate hydrothiocyanation of 1,2-diaza-
1,3-dienes in acidic medium offers an efficient one-pot
synthetic approach to novel 2-imino-4-thiazolines vari-
ously substituted at 3-, 4-, and 5-position. The nature of
substituents at the 1- and 4-positions of the conjugate azo–
ene system plays a key role in driving the process through
nucleophilic interactions without any isomerization of the
a-thiocyanato hydrazone intermediate in contrast to re-
sults obtained by other groups for similar reactions.12
The requisite 1,2-diaza-1,3-butadiene 1a–k (1 mmol),
prepared and used as an E,E/E,Z isomer mixture,1c was
added to a solution of KSCN (106.7 mg, 1.1 mmol) in glacial
AcOH (2 mL) under magnetic stirring. The consumption of
Synlett 2010, No. 12, 1859–1861 © Thieme Stuttgart · New York

LETTER
1a–k was rapid and TLC analysis indicated the presence one
Variously Substituted 2-Imino-4-thiazolines
1861
(dec.). IR (KBr): 3467, 3331, 2153, 1746, 1650, 1503 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.45 (s, 9 H, Ot-Bu),
1.86 (s, 3 H, CH3), 2.86 and 2.97 [2 s, 6 H, N(CH3)2], 5.79
(s, 1 H, CH), 10.00 (s, 1 H, NH). 13C NMR (100 MHz
DMSO-d6): d = 12.3 (q), 28.0 (q), 35.9 (q), 37.1 (q), 61.0 (d),
79.8 (s), 112.4 (s), 144.9 (s), 152.6 (s), 164.7 (s). ESI-MS:
m/z calcd for C12H20N4O3S: 300.4; found: 301 [M + 1].
(15) Data for tert-Butyl {5-[(Dimethylamino)carbonyl]-2-
imino-4-methyl-1,3-thiazol-3 (2H)-yl}carbamate (4j)
White powder from EtOAc–cyclohexane; mp 159–160 °C
(dec.). IR (KBr): 3318, 3255, 3203, 1736, 1631, 1606 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.38 and 1.43 (2 s, 9 H,
Ot-Bu), 1.89 (s, 3 H, CH3), 2.93 [s, 6 H, N(CH3)2], 8.18 (br
s, 1 H, NH), 9.64 (br s, 1 H, NH). 13C NMR (100 MHz
DMSO-d6): d = 12.7 (q), 27.6 and 27.8 (2 q), 36.6 (q), 40.1
(q), 80.5 (s), 98.5 (s), 136.9 (s), 154.6 (s), 157.9 (s), 162.8
(s). ESI-MS: m/z calcd for C12H20N4O3S: 300.4; found: 301
[M + 1].
major product. The reaction mixture was allowed to stand at
r.t. overnight to allow complete conversion of the Michael
adduct into the corresponding 2-imino-4-thiazoline
derivative. AcOH was removed in vacuo, the residue was
dissolved in H2O, and the solution neutralized with sat.
Na2CO3. Compounds 4a–c,e,g–i were obtained by extraction
of the aqueous phase with Et2O. The dried organic layers
were filtered and evaporated, and the crude compounds were
isolated as powders or foams and purified by
recrystallization or by flash chromatography on silica.
Compounds 4d,f,j,k, precipitated from the aqueous medium
after addition of sat. Na2CO3 and were isolated by filtration
and recrystallized from an appropriate solvent mixture
(14) Data for tert-Butyl-2-[3-(dimethylamino)-1-methyl-3-
oxo-2-thiocyanatopropylidene]hydrazinecarboxylate
(3j)
White powder from EtOAc–cyclohexane; mp 139–140 °C
Synlett 2010, No. 12, 1859–1861 © Thieme Stuttgart · New York

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