Four-component synthesis of imidazolinium-fused heterocycles from Ugi-smiles couplings

Article abstract of DOI:10.1055/s-0029-1218550

New imidazolinium-fused scaffolds are synthesized via a one-pot, two-step procedure involving a Ugi-Smiles coupling of mercaptotriazine derivatives with an isocyanide, an aldehyde, and a primary amine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218550

LETTER
153
Four-Component Synthesis of Imidazolinium-Fused Heterocycles from
Ugi–Smiles Couplings
S
ynthesis of Imida
n
zolinium-F
u
a
sedHeteroc
ë
ycles lle Barthelon,a Xavier-Frédéric Legoff,b Laurent El Kaim,*a Laurence Grimaud*a
a
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
Laboratoire Hétéroéléments et Coordination, Ecole Polytechnique, CNRS, Route de Saclay, 91128 Palaiseau Cedex, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
b
Received 8 October 2009
under similar conditions).6 Following our study on pyri-
dine and pyrimidine derivatives, we now wish to report
our results on the behavior of triazines, as well as the
transformation of the resulting thioamides into new im-
idazolinium-fused heterocycles in a one-pot process.
Abstract: New imidazolinium-fused scaffolds are synthesized via
a one-pot, two-step procedure involving a Ugi–Smiles coupling of
mercaptotriazine derivatives with an isocyanide, an aldehyde, and a
primary amine.
Key words: triazine, mercaptan, Ugi–Smiles, multicomponent
reaction, thioamide
Thiopyridines and thiopyrimidines being prone to interact
in a Ugi–Smiles reaction, we assumed that the introduc-
tion of an additional nitrogen atom in the cycle would fa-
vor the process by lowering the electron density on the
aromatic carbon atom. To our delight, 3-mercapto-1,2,4-
triazines turned out to be among the most efficient acidic
partners in Ugi–Smiles couplings. The four-component
reaction (4-CR) proceeded smoothly at 50 °C in methanol
using stoichiometric amounts of each component. The
reaction seems to be quite general, as various aldehydes;
aliphatic aldehydes, even hindered ones (Table 1, entries
1–9), as well as aromatic aldehydes (Table 1, entry 10)
gave good results. Most noteworthy, the Ugi–Smiles cou-
plings of ketones whose reaction times traditionally range
from 1–10 days are much faster with the triazine 1a as a
surrogate acidic input for the Ugi reaction and give the
corresponding adducts in good yields (Table 1, entry 11–
13).
Compared to their related amides, thioamides show an in-
creased reactivity due to the heightened nucleophilicity of
the sulfur atom, enhanced by a rather weak carbon–sulfur
double bond. Their extensive use as synthetic intermedi-
ates for the preparation of various heterocycles,1 as well as
their interesting biological activities as peptidomimetics,2
have spurred chemists on to seek new methods for their
preparation.3 Following our interest on multicomponent
reactions involving isocyanides,4 we have recently dis-
closed a four-component access to complex thioamides
based on the Ugi–Smiles coupling of heteroaromatic mer-
captans (Scheme 1).5
SH
R2
S
X
Y
N
Y
R2NH2
R3NC
O
R3HN
The efficiency of the triazine 1a in triggering the process
is further demonstrated by the use of the Schöllkopf iso-
cyanide, which forms thiazoles through an Ugi–Smiles–
cyclocondensation cascade (Scheme 2).7
+
R1
X
R1
X, Y = N, CH
Scheme 1 Ugi–Smiles multicomponent thioamide synthesis
In order to assess the scope of this coupling, two addition-
The couplings with mercaptans give rather contrasting re- al mercaptotriazines were prepared by condensing a thio-
sults. Indeed, whereas ortho- and para-nitrothiophenols semicarbazide and a dicarbonyl compound.8 With the
fail to give any coupling with an isocyanide, an aldehyde, monosubstituted triazine compound 1b, the 4-CR occurs
and an amine, heteroaromatic mercaptans such as 2-mer- with similar yields to those obtained with the triazine 1a,
captobenzooxazoles or benzothiazoles give the expected even in the case of ketones (Table 2, entries 1–4). Howev-
adducts in fair to good yields (it is interesting to note that er, the bis(2-pyridinyl)mercaptotriazine (1c) is less effi-
the corresponding hydroxy derivatives are not reactive cient in this coupling, as the yields do not exceed 50%
EtOOC
NC
Ph
S
EtO2C
Ph
N
N
N
Ph
Ph
N
N
N
i-BuCHO
NMe2
NH2
+
N
MeOH, 50 °C
12 h
i-Bu
58%
N
1a
SH
Scheme 2 Ugi–Smiles–cyclocondensation cascade
SYNLETT 2010, No. 1, pp 0153–0157
x
x.
x
x.
2
0
0
9
Advanced online publication: 14.12.2009
DOI: 10.1055/s-0029-1218550; Art ID: D28409ST
© Georg Thieme Verlag Stuttgart · New York

154
A. Barthelon et al.
LETTER
Table 1 Ugi–Smiles Couplings with Triazine 1a
O
Ph
S
R3
N
Ph
N
R1
R2
R4NC
N
N
R4HN
N
+
R2 R1
MeOH, 50 °C
12 h
N
N
R3NH2
Ph
SH
Ph
1a
2
Entry
R1COR2
R3NH2
R4NC
CyNC
CyNC
Product
2a
Yield (%)
1
2
i-BuCHO
i-BuCHO
93
98
NH2
NH2
MeO
O
2b
3
4
i-BuCHO
i-BuCHO
CyNC
2c
79
21
NH2
CyNC
2d
NH2
Ar
MeO
5
6
7
i-BuCHO
i-BuCHO
i-BuCHO
2e
2f
86
84
93
NH2
NC
EtOOC
Cl
NC
NH2
MeO
2g
NH2
NC
MeO
8
9
i-BuCHO
2h
2i
95
42
NH2
NH2
MeO
NC
CHO
CyNC
10
11
CyNC
2j
47
95
Cl
CHO
NH2
NH2
CyNC
2k
O
Cl
12
13
2l
76
78
O
O
NH2
NH2
NC
NC
Cl
2m
(Table 2, entries 5 and 6). This method constitutes an easy complex heterocycles. Triazines are known to undergo in-
path to functionalized thioamides that would otherwise be tramolecular [4+2] cycloadditions with the elimination of
difficult to obtain.
nitrogen,9 these reactions having been recently exploited
with Ugi adducts by the Zanze group.10 The initial trials
with the thioamide 2d in toluene at reflux, or even at high-
er temperatures under microwave irradiation, failed to
give any cyclized product. During several attempted acti-
The high-yielding couplings observed with some of these
triazines prompted us to examine the chemistry of these
adducts in order to establish further one-pot syntheses of
Cy
Ph
Ph
i-Bu
N
Ar
HN
Cu(OTf)2
(1 equiv)
TfO
N
N
OMe
N
N
S
toluene, 110 °C
18%
N
3
N
N
CyHN
Ph
3
3a
i-Bu
Ph
Scheme 3 Triazolino imidazolinium formation
Synlett 2010, No. 1, 153–157 © Thieme Stuttgart · New York

LETTER
Synthesis of Imidazolinium-Fused Heterocycles
155
vations of the heterocycle with copper salts, traces of a of copper(II) trifluoromethanesulfonate was used in tolu-
highly colored product involving a cyclization with the ene at 110 °C, the triazolino imidazolinium salt 3a was
thioamide function were observed. When one equivalent obtained in a 18% isolated yield (Scheme 3).
Table 2 Couplings with Different Triazines
O
R'
S
R1
R2
R
R4NC
N
N
N
N
R
+
R4HN
N
N
MeOH, 50 °C
12 h
NH2
R2 R1
N
R'
SH
Entry
1
ArSH
R1COR2
R4NC
CyNC
Product and yield (%)
Ph
H
N
Ph
N
N
N
N
N
S
i-BuCHO
i-BuCHO
N
N
H
SH
i-Bu
1b
1b
2n 74
Ph
S
N
N
N
EtOOC
NC
EtO
O
2
3
N
N
NMe2
i-Bu
2o 45
Ph
S
N
N
N
Cl
1b
1b
O
N
N
H
NC
Cl
2p 53
Ph
N
N
N
S
4
CyNC
O
N
N
H
2q 72
N
N
N
N
N
N
N
Cl
5
i-BuCHO
N
N
N
S
NC
N
i-Bu
N
H
SH
1c
Cl
2r 43
N
N
N
N
N
6
1c
i-BuCHO
CyNC
S
N
N
H
i-Bu
2s 45
Synlett 2010, No. 1, 153–157 © Thieme Stuttgart · New York

156
A. Barthelon et al.
LETTER
As this cyclization involves two new functionalities intro-
duced in the Ugi–Smiles step, we decided to focus on this
reaction and to optimize the formation of this fused sys-
tem in a one-pot sequence starting directly from the four
components involved in the Ugi coupling. With the tri-
azine 1b, isovaleraldehyde, allylamine, and cyclohexyl-
isocyanide (Table 2, entry 1), we devised conditions in
which the Ugi–Smiles step is performed in refluxing tolu-
ene (1 M) for two hours followed by dilution of the medi-
um with toluene to a concentration of 0.1 M and addition
of the copper salt. The final imidazolinium salt 3b was ob-
tained in 69% isolated yield after refluxing the mixture for
three hours (Table 3, entry 1). The presence of the triflate
counterion was confirmed by an X-ray crystal structure
analysis performed on this imidazolinium salt
(Figure 1).11
Figure 1 X-ray crystal structure of compound 3b
The diphenyl-substituted triazine 1a behaved similarly,
giving the fused imidazolinium triflate 3c (Table 3, entry
Table 3 Formation of Different Imidazolinium Salts
Cy
HN
R1
Z
SH
i-Bu
TfO
X
i-BuCHO
CyNC
R2
Y
1. toluene
110 °C
X
N
R3
Y
X,Y,Z = N, CH
R3NH2
+
2. Cu(OTf)2
(1 equiv)
Z
R2
R1
3
Entry
ArSH
R2NH2
Time (step 1)
Time (step 2)
Product and yield
H
H
Ph
N
Ph
N
TfO
N
N
N
N
1
2 h
1 h
CyHN
NH2
N
SH
Ph
i-Bu
1b
3b 69%
Ph
Ph
N
N
Ph
N
TfO
N
N
N
N
MeO
2
2 h
4 d
2 h
36 h
CyHN
NH2
N
SH
i-Bu
OMe
1a
3c 63%
TfO
N
CyHN
3a
2 h
N
N
NH2
N
i-Bu
SH
3d 85%
CF3
CF3
TfO
N
MeO
4
12 h
CyHN
NH2
N
N
i-Bu
SH
OMe
3e 95%
a The first step was performed neat at 90 °C, followed by the copper addition in toluene (to a concentration of 0.1 M).
Synlett 2010, No. 1, 153–157 © Thieme Stuttgart · New York

LETTER
Synthesis of Imidazolinium-Fused Heterocycles
157
29.0, 25.7, 25.2, 22.9. IR (thin film): 3309, 2930, 2857, 1631, 1602,
1565, 1252, 1158 cm–1. MS: m/z calcd for C24H32N5: 390; found:
390.
2). Such a process can be extended to other nitrogenated
heterocycles. For instance, when submitted to a neat four-
component coupling – with allylamine, isovaleraldehyde,
and cyclohexylisocyanide – followed by a copper-
induced cyclization, 2-mercaptopyrimidine gave the cor-
responding pyrimidinyl imidazolinium salt in a 85% yield
(Table 3, entry 3), whilst the pyridinyl analogue was ob-
tained in excellent yields as well (Table 3, entry 4).
Acknowledgment
A.B. thanks the MENR for a fellowship. Financial support was pro-
vided by the ENSTA and the ANR (CP2D, Muse project).
In conclusion, we have disclosed a new family of highly
efficient acidic inputs in Ugi–Smiles reactions. Mercap-
totriazines, the diphenyl-substituted 1a in particular, al-
low the formation of Ugi–Smiles thioamides with short
reaction times and with better yields than the related reac-
tions with mercapto- or hydroxypyridines and pyrim-
idines. The synthetic value of these thioamides12 has been
further demonstrated in a one-pot preparation of fused im-
idazolinium salts.
References and Notes
(1) (a) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197. (b) Du,
W.; Curran, D. P. Org. Lett. 2003, 5, 1765. (c) Narender,
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68, 5792. (c) Zbruyev, O. I.; Stiasni, N.; Kappe, C. O.
J. Comb. Chem. 2003, 5, 145.
Typical Procedure for the Synthesis of Thioamide 2a (Table 1,
Entry 1)
To a solution of 265 mg (1.0 mmol, 1.0 equiv) of 5,6-diphenyl-
1,2,4-triazine-3-thiol in MeOH (1 mL) were added allylamine (75
mL, 1.0 mmol, 1.0 equiv), isovaleraldehyde (108 mL, 1.0 mmol, 1.0
equiv), cyclohexylisocyanide (110 mL, 1.0 mmol, 1.0 equiv). The
resulting mixture was stirred at 55 °C for 12 h. The solvent was then
removed in vacuo. The crude product was purified by flash chroma-
tography on silica gel (Et2O–PE = 10:90) to give 464 mg (93%) of
2a. Mp 110 °C. 1H NMR (400 MHz, CDCl3): d = 9.12 (br s, 1 H),
7.56–7.48 (m, 4 H), 7.47–7.41 (m, 1 H), 7.39–7.32 (m, 5 H), 6.08–
5.96 (m, 1 H), 5.53 (br s, 1 H), 5.33 (d, J = 17.4 Hz, 1 H), 5.21 (dd,
J = 10.1, 1.0 Hz, 1 H), 4.59 (dd, J = 16.0, 6.3 Hz, 1 H), 4.47–4.40
(m, 1 H), 4.39–4.30 (m, 1 H), 2.23–2.30 (m, 1 H), 2.07–1.93 (m, 2
H), 1.92–1.81 (m, 1 H), 1.69–1.47 (m, 5 H), 1.41–1.26 (m, 2 H),
1.18–1.07 (m, 2 H), 0.97 (d, J = 6.7 Hz, 6 H). 13C NMR (100.6
MHz, CDCl3): d = 200.7, 149.6, 136.5, 136.3, 134.4, 131.0, 133.1,
129.4, 129.0, 128.9, 128.8, 117.7, 66.7, 53.9, 48.3, 40.1, 31.5, 31.2,
25.8, 25.3, 23.2, 23.0. IR (thin film): 3705, 3602, 3029, 2854, 2341,
1581, 1564, 1426 cm–1. HRMS: m/z calcd for C30H37N5S: 499.2770;
found: 499.2769.
(4) (a) Dumestre, P.; El Kaim, L.; Grégoire, A. Chem. Commun.
1999, 775. (b) Atlan, V.; El Kaim, L.; Grimaud, L.; Jana,
N. K. Synlett 2002, 352. (c) El Kaim, L.; Grimaud, L.; Oble,
J. Angew. Chem. Int. Ed. 2005, 117, 7961. (d) El Kaim, L.;
Grimaud, L.; Oble, J. Org. Biomol. Chem. 2006, 4, 3410.
(e) El Kaim, L.; Gizolme, M.; Grimaud, L. Org. Lett. 2006,
8, 5021. (f) El Kaim, L.; Gageat, M.; Gaultier, L. Synlett
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Lett. 2009, 11, 995. (h) El Kaim, L.; Grimaud, L.; Schiltz,
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(7) For a related use of the Schollkopf isocyanide with
thiocarboxylic acid, see: Heck, S.; Dömling, A. Synlett
2000, 424.
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(11) The crystallographic data can be obtained free of charge
under the reference CCDC 730687 at the Cambridge
Crystallographic Data Centre (www.ccdc.cam.ac.uk/
data_request_cif).
(12) For related cyclization of thioamides with the formation
of fused nitrogen heterocycles, see: (a) Shibahara, F.;
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Typical Procedure for the Synthesis of Imidazolinium 3b (Table
3, entry 1)
To a solution of 189 mg (1.0 mmol, 1.0 equiv) of 5-phenyl-1,2,4-
triazine-3-thiol in toluene (1 mL) were added allylamine (75 mL, 1.0
mmol, 1.0 equiv), isovaleraldehyde (108 mL, 1.0 mmol, 1.0 equiv),
and cyclohexylisocyanide (110 mL, 1.0 mmol, 1.0 equiv). The re-
sulting mixture was stirred at 110 °C for 2 h and was then diluted to
a 0.1 M concentration. Copper triflate (362 mg, 1.0 mmol, 1.0
equiv) was added, and the resulting mixture was stirred at 110 °C
for 1 h. The solvent was removed in vacuo. The crude product was
purified by flash chromatography on silica gel (Et2O) to give 374
mg (69%) of 3b. 1H NMR (400 MHz, CDCl3): d = 9.31 (s, 1 H), 8.24
(d, J = 8.1 Hz, 2 H), 7.68–7.59 (m, 3 H), 6.13–6.04 (m, 1 H), 5.40
(d, J = 10.4 Hz, 1 H), 5.29 (d, J = 17.2 Hz, 1 H), 5.20 (d, J = 5.8 Hz,
2 H), 4.02 (d, J = 7.6 Hz, 1 H), 3.45 (br s, 1 H), 2.84 (d, J = 7.3 Hz,
2 H), 2.21–2.14 (m, 1 H), 2.01 (br s, 2 H), 1.79 (br s, 2 H), 1.65 (d,
J = 11.6 Hz, 1 H), 1.37–1.30 (m, 5 H), 1.06 (d, J = 6.6 Hz, 6 H). 13
C
NMR (100.6 MHz, CDCl3): d = 153.2, 140.6, 134.9, 134.0, 132.7,
130.9, 130.7, 130.2, 128.9, 127.2, 120.2, 55.8, 46.9, 34.6, 32.8,
Synlett 2010, No. 1, 153–157 © Thieme Stuttgart · New York

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