Thiols in Ugi- and passerini-smiles-type couplings

Article abstract of DOI:10.1002/ejoc.200800859

The use of the Smiles rearrangement in Ugi-type couplings with aromatic mercaptans allows for the straightforward, multicomponent formation of α-arylamino thiocarboxamides. The scope of this new four-component coupling is further broadened with the use of

Full text of DOI:10.1002/ejoc.200800859

FULL PAPER
DOI: 10.1002/ejoc.200800859
Thiols in Ugi- and Passerini–Smiles-Type Couplings
Anaëlle Barthelon,[a] Laurent El Kaïm,*[a] Marie Gizolme,[b] and Laurence Grimaud*[b]
Keywords: Ugi reaction / Smiles reaction / Isocyanides / Rearrangement / Thiols / Multicomponent reactions
The use of the Smiles rearrangement in Ugi-type couplings
with aromatic mercaptans allows for the straightforward,
multicomponent formation of α-arylamino thiocarboxamides.
The scope of this new four-component coupling is further
broadened with the use of heterocyclic mercapto derivatives
that afford thioamides of high biological interest in one step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
or hydrazones.[4] These modifications may slightly alter the
classical mechanism of the Ugi reaction, which involves a
series of equilibria displaced by an irreversible Mumm-type
rearrangement (Scheme 1, X = O).[1c,j] In order to be suc-
cessful, the replacement of the acidic derivative requires
new rearrangements of the imidoyl intermediate resulting
from the nitrilium trapping. The most significant alterations
were proposed by Ugi shortly after his first publication on
this coupling. In the case of hydrazoic,[5] isocyanic[6] or iso-
thiocyanic acid,[7] the last step involves a cyclization into
tetrazole or hydantoin derivatives. Coupling with sulfur de-
rivatives such as H2S2O3 were reported early on by Ugi.[8]
More recently, Dömling and coworkers described the use of
thiocarboxylic acids to form thioamides by a Mumm-type
conversion of the thioimidate intermediate (Scheme 1, X =
S).[9]
Introduction
Stimulated by the development of high-throughput
screening in the pharmaceutical industry, the use of isocya-
nide-based multicomponent reactions (IMCR)[1] has in-
creased dramatically over the last few years due to the
growing demand for new scaffolds. The interest in IMCRs
is mainly due to the efficiency of the Ugi reaction.[2] First
described in 1959, this reaction affords peptide derivatives
by a four-component coupling involving an isocyanide, an
amine, a carbonyl compound and a carboxylic acid. Al-
though it was discovered more than thirty years ago, this
reaction has become increasingly popular since the begin-
ning of the 1990s thanks to the publication of numerous
post-condensation transformations that provide heterocy-
cles.[1c,j] In addition to these post-condensation reactions,
the most significant development of this reaction lies in the
modification of the partners involved in the coupling. For
instance, imines have been successfully replaced by oximes[3]
We have recently been able to increase the synthetic scope
of these Ugi couplings by introducing Smiles rearrange-
ments of the nitrilium manifold.[10] If electron-poor phenols
Scheme 1. Mechanism of the Ugi and thio-Ugi reaction.
[a] E.N.S.T.A.,
are introduced as acidic partners, an N-arylation occurs
with overall transfer of the aryl moiety onto the nitrogen
of the starting amine (Scheme 2). The success of this new
coupling is combined with an irreversible Smiles rearrange-
ment of the imidate resulting from the trapping of the nitril-
ium by the phenolate (Scheme 2). The greater thermo-
32, Bd. Victor, 75015 Paris, France
Fax: +33-1-45525537
E-mail: laurent.elkaim@ensta.fr
[b] E.N.S.T.A.,
32, Bd. Victor, 75015 Paris, France
Fax: +33-1-45526565
E-mail: laurence.grimaud@ensta.fr
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Thiols in Ugi- and Passerini–Smiles-Type Couplings
dynamic stability of the final amide in comparison to that
of the phenolate intermediate vouches for the irreversibility
of the process.
Scheme 4. Ugi–Smiles coupling of o-nitrothiophenol.
Table 1. Ugi–Smiles couplings using 2-nitro-4-(trifluoromethyl)-
thiophenol (Cy = cyclohexyl).
Scheme 2. Ugi–Smiles coupling of o-nitrophenol.
Considering the successful substitution of carboxylic ac-
ids by thiocarboxylic acids in the Ugi coupling, we assumed
that similar modifications with phenols could give rise to a
new pathway to N-aryl-substituted thioamides. In that
coupling, the higher nucleophilicity of the thiolate com-
pared to that of the phenolate should favour the first steps.
However, a less efficient Smiles rearrangement could be ex-
pected, since the conversion of the thioimidate to the thio-
carbonyl derivative would bring less stabilization to the sys-
tem. Following our first communications on the Ugi–Smiles
reactions of thiophenols,[11] we now wish to give a full re-
port on the subject.
Results and Discussion
When 4-nitrobenzenethiol was stirred with a stoichio-
metric amount of cyclohexyl isocyanide, isovaleraldehyde
and p-chlorobenzylamine in MeOH at 60 °C, or in toluene
at 90 °C, or even neat at 120 °C, only a trace of the desired
adduct could be isolated (Scheme 3). No improvement was
observed upon preforming the imine or adding Lewis acids
such as magnesium perchlorate.[12]
Surprisingly, the less-activated methyl mercaptosalicylate
reacted in MeOH at 60 °C to form a four-component ad-
duct. The examination of the 13C NMR spectra clearly
showed the formation of the thioimidates instead of the de-
sired thioamides. The latter were obtained in good yields
whatever carbonyl compound, amine and isocyanide sub-
Scheme 3. Ugi–Smiles coupling with p-nitrothiophenol.
The best results were obtained with the more activated strates were used (Table 2).
2-nitro-4-(trifluoromethyl)benzenethiol in toluene at 90 °C.
The isolation of this non-rearranged product seemed to
After 2 d, the expected thioamide was isolated in 30% yield contradict the mechanism we proposed for the phenol de-
(Scheme 4). Varying the other three partners gave very dis- rivatives. Indeed, we had postulated that the final Smiles
appointing results, as yields were very low (Table 1).
rearrangement insured the efficiency of the four-component
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A. Barthelon, L. El Kaïm, M. Gizolme, L. Grimaud
Table 3. Mercaptopyridine in Ugi–Smiles couplings.
FULL PAPER
Table 2. Mercaptosalicylate as acidic inputs.
coupling by displacing all the equilibria. The driving force
of the whole process is probably the creation of the particu-
larly energetic C=O bond. In the thiocoupling, the higher
nucleophilicity of the thiolate compared to that of the phe-
nolate is probably sufficient to allow the formation of
thioimidates in good yields. They turned out to be very
stable and failed to rearrange in 1,2-dichloroethane at
120 °C, in 1:1 EtOH/H2O at reflux or under basic condi-
tions (LiOH, DMF, 80 °C). Acidic hydrolysis [Hg(OAc)2 in
1:1 EtOH/H2O at reflux or TFA in CH2Cl2 at 40 °C] did
not affect these compounds either. The peculiar stability of
such derivatives could be explained by a possible intramo-
lecular hydrogen bond between the NH of the amine and
one oxygen of the ester group. This assumption is based
upon the dramatic ortho substituent effect observed with
nitrophenol.[10,13]
To further explore the scope of this mercapto coupling,
we envisioned the use of heterocyclic systems known to eas-
ily undergo the Smiles rearrangement. As observed with the
hydroxy derivatives, mercaptopyridine did not react when
treated with a stoichiometric amount of an aldehyde, an
amine and an isocyanide in MeOH at 45 °C, or in toluene
at 90 °C or neat at 90 °C. However, when activated with an
Scheme 5. Ugi–Smiles coupling of 2-mercaptopyrimidine; Cy = cy-
electron-withdrawing substituent such as the trifluoro- clohexyl.
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Thiols in Ugi- and Passerini–Smiles-Type Couplings
methyl group, mercaptopyridine provided the expected time, as is usually observed. Unfortunately, no aromatic or
four-component coupling. The best yields were obtained in α,β-unsaturated aldehydes reacted under these experimental
toluene at 90 °C. Under these conditions, the desired conditions.
thioamides were obtained in moderate to good yields with
As previously reported in the Ugi–Smiles coupling,[13]
aliphatic aldehydes (Table 3, Entries 1–5) as well as with hydroxypyrimidines do not require further activation to
ketones (Table 3, Entry 6), which required a longer reaction provide the desired adducts. However, mercaptopyrimidine
Table 4. Mercaptopyrimidine in Ugi–Smiles couplings.
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FULL PAPER
analogues do not form any adduct unless the experimental
Mercaptopyrazines and quinoxalines were then submit-
conditions are modified. Indeed, in MeOH (1–3 ) at 60 °C ted to the coupling conditions. Unfortunately, these sub-
or in toluene (1–3 ) at 90 °C with or without additives strates turned out to be less efficient than the corresponding
(such as magnesium perchlorate or lithium chloride), the hydroxy derivatives, and the corresponding thioamides were
reaction was sluggish, and small amounts of the corre- isolated in rather low yields (Table 5).[16]
sponding thioamides were isolated (less than 25%). The use
Table 5. Mercaptopyrazines and related in Ugi–Smiles couplings.
of DMF or TFA as the solvent did not improve these re-
sults either. However, when 2-mercaptopyrimidine was
stirred neat at 90 °C with a stoichiometric amount of me-
thoxyethylamine, isovaleraldehyde and cyclohexyl isocya-
nide, the desired thioamide was isolated in 77% yield
(Scheme 5).
The reaction works with a wide range of partners and
various 2-aminopyrimidines have been prepared efficiently
from aliphatic aldehydes (Table 4, Entries 1–5). Most inter-
estingly, when using ethyl β-(dimethylamino)-α-isocyano-
acrylate,[9,14] the pyrimidothiazole was isolated in 35% yield
in one step (Table 4, Entry 6). As previously observed, aro-
matic aldehydes, α,β-unsaturated aldehydes and ketones did
not react under these conditions. Tosylmethyl isocyanide
failed to react as well.
4-Mercaptopyrimidines, easily prepared from the corre-
sponding 4-hydroxypyrimidines by treatment with P2S5,[15]
provide the desired 4-aminopyrimidines in moderate to
good yields as well (Table 4, Entries 7–9).
Table 6. Mercaptotriazoles in Ugi–Smiles couplings.
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Thiols in Ugi- and Passerini–Smiles-Type Couplings
We next investigated heterocyclic five-membered rings. (Table 7, Entries 9–18). When the reaction was performed
We were not able to perform a coupling with 2-mercapto- with ethyl β-(dimethylamino)-α-isocyanoacrylate, the bis-
imidazoles or thiazoles or with 5-mercaptopyrazoles or thiazole was isolated in 32% yield in one step (Table 7, En-
isoxazoles, whatever the reaction conditions tested (MeOH, try 16).
toluene or neat at different temperatures, Figure 1). These
In connection with this new thio coupling, we next ex-
results are consistent with the electron-rich nature of these amined the feasibility of a thio Passerini–Smiles reaction.
heterocyclic cores.
Given that the three-component coupling generally re-
quires stronger acidic conditions than Ugi couplings (as
the carbonyl is less reactive than the corresponding imin-
ium), we wondered whether mercaptans would perform
such a coupling. We subsequently tested a wide range of
thio derivatives, with a stoichiometric amount of aldehyde
and isocyanide, varying the experimental conditions (sol-
vents and temperatures). 4-Nitrothiophenol failed to react
with propionaldehyde and cyclohexyl isocyanide in MeOH
at 45 °C, in toluene at 80 °C, in 1:3 toluene/water at 80 °C
or in the presence of a Lewis acid such as diethylalumin-
ium chloride in dichloromethane. With mercaptopyridines,
propionaldehyde and cyclohexyl isocyanide, the yields did
not exceed 15% either in toluene at 80 °C or in MeOH
at 45 °C. Mercaptobenzo-fused compounds failed to react
under both conditions as well. Finally, 2-mercaptopyrim-
idine gave the desired adduct in 31% yield in MeOH at
45 °C within 3 d (Scheme 7). This coupling could be im-
proved slightly if performed in 1:3 toluene/water at 80 °C
for 2 d (56%), but Lewis acids [ZnCl2, TiCl4, SiCl4,
Mg(ClO4)2 in toluene, or Et2AlCl in CH2Cl2] seemed to
have no effect. However, the efficiency of the reaction was
restricted by the narrow range of reactive aldehydes (iBu-
CHO, PrCHO). Disappointed by these preliminary results,
we did not study the thio-Passerini–Smiles coupling fur-
ther.
Figure 1. Unefficient acidic partners in Ugi–Smiles couplings.
Similarly, 3-mercapto-4H-1,2,4-triazole failed the coup-
ling, but 3-mercapto-4-alkyl-1,2,4-triazoles reacted in tolu-
ene at 90 °C with cyclohexyl isocyanide, propionaldehyde
and p-chlorobenzylamine to form the corresponding
thioimidate in 47% yield (Table 6, Entry 1). As for the
thiosalicylate, the reasons why the Smiles rearrangement
did not occur are still unclear at the moment. Several
thioimidates bearing a triazole core have been prepared in
modest yields (Table 6).
Among those heterocyclic five-membered rings, the most
promising were the ones classically involved in the Julia–
Kocienski olefination such as tetrazoles or benzo-fused
heterocycles. Unfortunately, mercaptotetrazoles did not un-
dergo coupling (Scheme 6).
Scheme 7. Passerini–Smiles coupling with mercaptans (Cy = cyclo-
hexyl).
Scheme 6. Failed couplings with mercaptotetrazoles (Cy = cyclo-
hexyl).
Nonetheless, when mixing 2-mercaptobenzoxazole with
an amine, an aldehyde and an isocyanide, the reaction pro-
ceeded smoothly in toluene at 50 °C within 2 d.[17] The
Conclusions
The use of thiols in Ugi reactions combined the advan-
scope of the reaction was examined with various substrates. tages of the classical Ugi reaction with the selective synthe-
The desired thioamides were isolated in good yields with sis of thioamides, which would otherwise be difficult to ob-
aliphatic aldehydes (Table 7, Entries 1–6) as well as with tain. The application of the Ugi–Smiles approach to thiols
ketones (Table 7, Entry 8). The reaction was less efficient allowed for the formation of α-arylamino-thiocarboxam-
with aromatic aldehydes (Table 7, Entry 7). The use of 2- ides, but a different reactivity pattern was observed when
mercaptobenzothiazole required a slight increase in tem- compared with hydroxy derivatives. The reactions with thio-
perature to obtain similar results. Various aldehydes, amines phenol derivatives were poorly efficient. In the case of sali-
and isocyanides were tested successfully in this coupling cylic acid derivatives, the Smiles rearrangement was not ob-
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A. Barthelon, L. El Kaïm, M. Gizolme, L. Grimaud
FULL PAPER
Table 7. Mercaptobenzooxazoles and -benzothiazoles in Ugi–Smiles couplings.
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Thiols in Ugi- and Passerini–Smiles-Type Couplings
5.15 (d, J = 17.9 Hz, 1 H), 4.40–4.31 (m, 1 H), 4.17 (t, J = 6.5 Hz,
1 H), 3.89 (dd, J = 16.2, 5.7 Hz, 1 H), 3.55 (dd, J = 16.2, 5.7 Hz,
1 H), 2.22–2.15 (m, 1 H), 2.02–1.96 (m, 2 H), 1.77–1.72 (m, 2 H),
1.67–1.63 (m, 1 H), 1.58–1.51 (m, 1 H), 1.46–1.35 (m, 2 H), 1.30–
1.17 (m, 4 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.79 (d, J = 6.5 Hz, 3 H)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 199.1, 145.8, 144.7,
132.1, 129.8 (q, JC,F = 3.5 Hz), 125.7 (q, JC,F = 34.6 Hz), 125.5,
123.5 (q, JC,F = 3.8 Hz), 123.3 (q, JC,F = 271.9 Hz), 120.1, 72.3,
54.3, 52.3, 42.1, 31.8, 31.2, 26.0, 25.8, 24.9, 22.9 ppm. MS (DI, CI
served, and thioimidates were the only isolated adducts. The
behaviour of heteroaromatic thiols was much more
satisfying, and good yields were obtained for nitrogen-con-
taining, six-membered-ring systems. More interestingly,
five-membered ring-fused systems such as benzoxazoles
gave adducts when they were thiol-substituted, whereas the
corresponding hydroxy analogue failed to give any coup-
ling. Thus, hydroxy and thiol derivatives seemed comple-
mentary in the Ugi–Smiles system. We are further exploring
the reactivity of more complex heterocyclic thiols.
NH ): m/z = 458. IR (thin film): ν = 2360, 1323, 1159, 1127, 1090
˜
3
cm–1. HRMS: calcd. for C22H30F3N3O2S 457.2011; found
457.2010.
Methyl 2-[1-(Cyclohexylimino)-2-(4-methoxybenzylamino)-4-meth-
ylpentylthio]benzoate: See Table 2, Entry 1; yield (60 °C in MeOH
for 2 d): 82% (395 mg). 1H NMR (CDCl3, 400 MHz): δ = 7.83–
7.81 (m, 1 H), 7.40–7.37 (m, 1 H), 7.34–7.31 (m, 2 H), 7.23 (d, J
= 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 3.90 (s, 3 H), 3.85–3.80
(m, 1 H), 3.79 (s, 3 H), 3.40 (d, J = 12.5 Hz, 2 H), 3.12 (dd, J =
10.1, 3.1 Hz, 1 H), 2.23 (br. s, 1 H), 1.91–1.78 (m, 3 H), 1.74–1.59
(m, 2 H), 1.51–1.35 (m, 5 H), 1.30–1.19 (m, 3 H), 0.81 (d, J =
6.6 Hz, 3 H), 0.39 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 167.4, 161.5, 158.9, 136.4, 134.9, 133.6, 132.8,
132.0, 131.1, 129.7, 128.4, 114.0, 61.9, 60.5, 55.6, 52.7, 51.3, 45.1,
34.0, 33.4, 26.2, 25.1, 24.9, 24.2, 21.3 ppm. MS (DI, CI NH3): m/z
Experimental Section
General: 1H NMR spectra were recorded with a Bruker Avance 400
spectrometer, with CDCl3 as the solvent. 13C NMR spectra were
recorded with a Bruker Avance 400 (100.6 MHz) spectrometer.
Two-dimensional NMR spectroscopy [H-H COSY spectra, H-C
COSY spectra (HSQC) and long-range H-C COSY spectra
(HMBC)], were carried out to determine the correlation between
H and C. The chemical shifts for all NMR spectra are expressed
in parts per million (ppm) downfield from the TMS reference.
Coupling constants (J) are quoted in Hz and are recorded to the
nearest 0.1 Hz. The IR spectra were obtained with a Bruker IFS
66 or a Perkin–Elmer FT 1600 spectrometer. Low-resolution mass
spectral analysis (EI and CI) were recorded with a Hewlett–Pack-
ard HP5989 mass spectrometer by either direct injection or GC/MS
coupling with a Hewlett–Packard HP5890 chromatograph. High-
resolution (HR) mass spectra were performed with a JEOL JMS-
Gcmate II, GC/MS system spectrometer. TLC was carried out with
precoated plates of silica gel 60F254. All the reactions were per-
formed under a nitrogen atmosphere with reagent-grade solvents
and starting materials without further purification. These reactions
were not moisture-sensitive.
= 483. IR (thin film): ν = 1709, 1512, 1434, 1247, 1174, 1106 cm–1.
˜
HRMS: calcd. for C28H38N2O3S 482.2603; found 482.2612.
Methyl 2-[1-(tert-Butylimino)-2-(2-methoxyethylamino)-4-methyl-
pentylthio]benzoate: See Table 2, Entry 2; yield (60 °C in MeOH for
2 d): 84% (331 mg). 1H NMR (CDCl3, 400 MHz): δ = 7.81 (d, J =
7.5 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.43 (td, J = 7.5, 1.0 Hz, 1
H), 7.37 (t, J = 7.5 Hz, 1 H), 3.89 (s, 3 H), 3.38–3.31 (m, 2 H), 3.30
(s, 3 H), 2.94 (d, J = 8.6 Hz, 1 H), 2.82–2.75 (m, 1 H), 2.34–2.28
(m, 1 H), 2.20 (br. s, 1 H), 1.73–1.65 (m, 1 H), 1.42 (s, 9 H), 1.36–
1.24 (m, 1 H), 1.15–1.08 (m, 1 H), 0.75 (d, J = 6.4 Hz, 3 H), 0.38
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
167.5, 158.4, 136.8, 135.4, 133.1, 132.0, 131.0, 128.6, 73.1, 61.7,
58.9, 56.6, 52.7, 47.0, 45.4, 29.9, 25.1, 24.1, 21.2 ppm. MS (DI, CI
General Procedure for the Ugi–Smiles Coupling: To a solution of
the carbonyl compound (1 , 1 mmol) in the indicated solvent was
added successively 1.0 equiv. of amine, 1.0 equiv. of isocyanide and
1.0 equiv. of the acidic partner under an inert atmosphere. The re-
sulting mixture was stirred at the indicated temperature for the
indicated time. The mixture was then concentrated in vacuo, and
the crude product was purified by flash chromatography on silica
gel.
NH ): m/z = 395. IR (thin film): ν = 1709, 1653, 1459, 1252, 1105
˜
3
cm–1. HRMS: calcd. for C21H34N2O3S 394.2290; found 394.2278.
Methyl 2-[1-(Cyclohexylimino)-2-(2-methoxyethylamino)-4-methyl-
pentylthio]benzoate: See Table 2, Entry 3; yield (60 °C in MeOH for
2 d): 65% (273 mg). 1H NMR (CDCl3, 400 MHz): δ = 7.86 (d, J =
7.5 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H),
7.37 (t, J = 7.5 Hz, 1 H), 3.91 (s, 3 H), 3.78–3.72 (m, 1 H), 3.42–
3.33 (m, 2 H), 3.31 (s, 3 H), 3.08 (dd, J = 9.5, 3.3 Hz, 1 H), 2.86–
2.80 (m, 1 H), 2.44–2.38 (m, 1 H), 2.08 (br. s, 1 H), 1.81–1.73 (m,
3 H), 1.69–1.61 (m, 2 H), 1.44–1.36 (m, 3 H), 1.35–1.29 (m, 2 H),
1.28–1.19 (m, 3 H), 0.79 (d, J = 6.3 Hz, 3 H), 0.49 (d, J = 6.3 Hz,
3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 167.3, 158.5, 136.0,
135.2, 133.5, 132.1, 131.2, 128.2, 73.0, 62.1, 61.6, 58.9, 52.7, 46.9,
44.8, 33.8, 33.3, 26.1, 25.1, 24.9, 24.8, 24.0, 21.5 ppm. MS (DI, CI
2-{(4-Chlorobenzyl)[2-nitro-4-(trifluoromethyl)phenyl]amino}-N-cy-
clohexyl-4-methylpentanethioamide: See Scheme 4; yield (90 °C in
toluene for 2 d) 30% (163 mg). H NMR (CDCl3, 400 MHz): δ =
1
8.35 (br. s, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.52 (dd, J = 8.6, 2.0 Hz,
1 H), 7.15–7.10 (m, 3 H), 6.94 (d, J = 8.4 Hz, 2 H), 4.29–4.20 (m,
2 H), 4.06 (d, J = 15.5 Hz, 1 H), 3.98 (dd, J = 8.5, 5.0 Hz, 1 H),
2.00–1.90 (m, 2 H), 1.81–1.76 (m, 1 H), 1.68–1.62 (m, 1 H), 1.59–
1.48 (m, 3 H), 1.34–1.24 (m, 2 H), 1.18–1.01 (m, 4 H), 0.69 (d, J
= 6.5 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 199.1,
145.9, 145.4, 134.4, 134.1, 129.8 (q, JC,F = 3.4 Hz), 129.6, 129.4,
128.7 (q, JC,F = 6.7 Hz), 126.7, 125.5 (q, JC,F = 204.5 Hz), 123.4
(q, JC,F = 3.7 Hz), 72.6, 54.1, 53.2, 41.7, 31.6, 31.4, 25.9, 25.8, 24.9,
NH ): m/z = 421. IR (thin film): ν = 1709, 1653, 1436, 1291, 1106
˜
3
cm–1. HRMS: calcd. for C23H36N2O3S 420.2447; found 420.2443.
Methyl 2-[1-(3,4-Dimethoxyphenethylimino)-2-(2-methoxyethyl-
amino)-4-methylpentylthio]benzoate: See Table 2, Entry 4; yield
(60 °C in MeOH for 2 d): 45 % (226 mg). 1H NMR (CDCl3,
400 MHz): δ = 7.88 (dd, J = 7.9, 1.8 Hz, 1 H), 7.39 (t, J = 7.9 Hz,
2 H), 7.30–7.28 (m, 1 H), 6.80 (s, 3 H), 3.90–3.84 (m, 10 H), 3.79–
3.71 (m, 1 H), 3.38–3.33 (m, 2 H), 3.32 (s, 3 H), 3.14 (dd, J = 9.4,
3.8 Hz, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.76–2.71 (m, 1 H), 2.41–
2.35 (m, 1 H), 1.91 (br. s, 1 H), 1.75–1.67 (m, 1 H), 1.41–1.36 (m,
23.4, 22.4 ppm. MS (DI, CI NH ): m/z = 542. IR (thin film): ν =
˜
3
2359, 1539, 1322, 1157, 1087 cm– 1 . HRMS: calcd. for
C26H31ClF3N3O2S: 541.1778, found: 541.1778.
2-{Allyl[2-nitro-4-(trifluoromethyl)phenyl]amino}-N-cyclohexyl-4-
methylpentanethioamide: See Table 1, Entry 1; yield (90 °C in tolu-
1
ene for 2 d): 26% (118 mg). H NMR (CDCl3, 400 MHz): δ = 8.60
(br. s, 1 H), 8.00 (s, 1 H), 7.73 (dd, J = 8.7, 1.9 Hz, 1 H), 7.38 (d,
J = 8.7 Hz, 1 H), 5.72–5.62 (m, 1 H), 5.19 (d, J = 11.2 Hz, 1 H), 1 H), 1.30–1.23 (m, 1 H), 0.80 (d, J = 6.6 Hz, 3 H), 0.52 (d, J =
Eur. J. Org. Chem. 2008, 5974–5987
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5981

A. Barthelon, L. El Kaïm, M. Gizolme, L. Grimaud
FULL PAPER
6.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 167.4,
158.2, 149.3, 140.8, 135.4, 134.5, 133.5, 132.2, 131.9, 131.4, 128.2,
121.3, 112.6, 111.5, 72.9, 62.3, 59.0, 56.3, 56.2, 55.7, 52.7, 47.1,
44.6, 36.8, 25.1, 23.9, 21.5 ppm. MS (DI, CI NH3): m/z = 503. IR
63.1, 55.7, 49.1, 40.4, 27.9, 25.5, 23.3, 23.1 ppm. MS (DI, CI NH3):
m/z = 472. IR (thin film): ν = 2359, 1612, 1502, 1320, 1293, 1160,
˜
1115 cm–1. HRMS: calcd. for C23H29ClF3N3S 471.1723; found
471.1735.
(thin film): ν = 1709, 1622, 1436, 1237, 1141 cm–1. HRMS: calcd.
˜
N-(4-Chlorobenzyl)-2-{(2-methoxyethyl)[5-(trifluoromethyl)pyridin-
2-yl]amino}octanethioamide: See Table 3, Entry 5; yield (90 °C in
toluene for 16 h): 26% (130 mg). 1H NMR (CDCl3, 400 MHz): δ
= 10.23 (br. s, 1 H), 8.36 (d, J = 2.4 Hz, 1 H), 7.68 (dd, J = 9.0,
2.4 Hz, 1 H), 7.26 (d, J = 8.3 Hz, 2 H), 7.09 (d, J = 8.3 Hz, 2 H),
6.83 (d, J = 9.0 Hz, 1 H), 4.84–4.71 (m, 3 H), 3.98–3.91 (m, 1 H),
3.78–3.72 (m, 2 H), 3.61–3.56 (m, 1 H), 3.02 (s, 3 H), 2.51–2.43 (m,
1 H), 2.10–2.00 (m, 1 H), 1.37–1.24 (m, 8 H), 0.87 (t, J = 6.7 Hz,
3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 204.7, 160.1, 145.3
(q, JC,F = 4.3 Hz), 135.3, 135.0 (q, JC,F = 3.1 Hz), 134.0, 129.6,
129.3, 124.8 (q, JC,F = 270.7 Hz), 116.5 (q, JC,F = 32.2 Hz), 108.7,
71.0, 70.7, 58.9, 49.5, 32.4, 32.0, 29.4, 27.5, 22.9, 14.5 ppm. MS
for C27H38N2O5S 502.2501; found 502.2504.
2-{(4-Chlorobenzyl)[5-(trifluoromethyl)pyridin-2-yl]amino}-N-cyclo-
hexyl-4-methylpentanethioamide: See Table 3, Entry 1; yield (90 °C
1
in toluene for 16 h): 60% (298 mg). H NMR (CDCl3, 400 MHz):
δ = 9.22 (br. s, 1 H), 8.42 (d, J = 2.3 Hz, 1 H), 7.55 (dd, J = 9.0,
2.3 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 2 H), 7.10 (d, J = 8.3 Hz, 2 H),
6.35 (d, J = 9.0 Hz, 1 H), 5.62 (br. s, 1 H), 5.02 (d, J = 17.8 Hz, 1
H), 4.60 (d, J = 17.8 Hz, 1 H), 4.38–4.29 (m, 1 H), 2.26–2.18 (m,
1 H), 2.09–2.03 (m, 1 H), 1.88–1.82 (m, 1 H), 1.77–1.68 (m, 2 H),
1.63–1.54 (m, 2 H), 1.48–1.26 (m, 4 H), 1.22–1.17 (m, 2 H), 0.90
(d, J = 6.8 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
(DI, CI NH ): m/z = 502. IR (thin film): ν = 1612, 1503, 1320,
˜
200.7, 160.3, 144.9 (q, JC,F = 4.3 Hz), 136.5, 135.3 (q, JC,F
=
3
1116 cm–1. HRMS: calcd. for C24H31ClF3N3OS 501.1828; found
3.0 Hz), 133.2, 129.3, 128.1, 124.7 (q, JC,F = 270.3 Hz), 116.6 (q,
JC,F = 33.1 Hz), 108.7, 61.0, 53.6, 49.1, 40.5, 31.6, 31.2, 25.8, 25.5,
24.6, 23.3, 23.0 ppm. MS (DI, CI NH3): m/z = 498. IR (thin film):
501.1828.
1-{(4-Chlorobenzyl)[5-(trifluoromethyl)pyridin-2-yl]amino}-N-cyclo-
hexylcyclopentanecarbothioamide: See Table 3, Entry 6; yield (90 °C
ν = 2363, 1612, 1502, 1320, 1159, 1115, 1093 cm–1. HRMS: calcd.
˜
for C25H31ClF3N3S: 497.1879, found: 497.1892.
1
in toluene for 16 h): 42% (208 mg). H NMR (CDCl3, 400 MHz):
δ = 8.99 (br. s, 1 H), 8.41 (d, J = 2.5 Hz, 1 H), 7.59 (dd, J = 9.0,
2.5 Hz, 1 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H),
6.56 (d, J = 9.0 Hz, 1 H), 4.98 (br. s, 2 H), 4.36–4.27 (m, 1 H),
3.09–2.97 (m, 2 H), 2.13–2.05 (m, 2 H), 1.99–0.92 (m, 2 H), 1.90–
1.85 (m, 2 H), 1.84–1.79 (m, 2 H), 1.75–1.70 (m, 2 H), 1.66–1.58
(m, 3 H), 1.43–1.32 (m, 2 H), 1.25–1.17 (m, 1 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 204.3, 160.5, 144.5 (q, JC,F = 4.3 Hz),
138.7, 134.6 (q, JC,F = 3.1 Hz), 133.5, 129.5, 128.4, 124.7 (q, JC,F
= 270.7 Hz), 117.3 (q, JC,F = 33.0 Hz), 110.2, 79.3, 54.5, 51.8, 39.8,
31.3, 25.8, 24.7, 24.5 ppm. MS (DI, CI NH3): m/z = 496. IR (thin
2-{Allyl[5-(trifluoromethyl)pyridin-2-yl]amino}-N-(4-chlorobenzyl)-
4-methylpentanethioamide: See Table 3, Entry 2; yield (90 °C in tol-
uene for 16 h): 46% (209 mg). 1H NMR (CDCl3, 400 MHz): δ =
9.59 (br. s, 1 H), 8.21 (d, J = 2.3 Hz, 1 H), 7.66 (dd, J = 9.0, 2.3 Hz,
1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 6.61 (d,
J = 9.0 Hz, 1 H), 5.82–5.73 (m, 1 H), 5.69–5.63 (m, 1 H), 5.21 (d,
J = 10.2 Hz, 1 H), 5.18 (d, J = 17.1 Hz, 1 H), 4.80 (dd, J = 15.2,
4.9 Hz, 1 H), 4.71 (dd, J = 15.2, 4.9 Hz, 1 H), 4.44 (d, J = 18.1 Hz,
1 H), 3.92 (d, J = 18.1 Hz, 1 H), 2.24–2.16 (m, 1 H), 1.91–1.83 (m,
1 H), 1.65–1.57 (m, 1 H), 0.94 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 203.5, 160.4, 144.8 (q, JC,F = 4.3 Hz),
135.2, 134.1, 129.6, 129.3, 124.7 (q, JC,F = 270.3 Hz), 117.5, 116.2
(q, JC,F = 33.2 Hz), 108.6, 60.6, 49.1, 48.5, 40.4, 25.4, 23.2, 23.0
ppm. MS (DI, CI NH3 ): m/z = 456. HRMS: calcd. for
C22H25ClF3N3S 455.1410; found 455.1423.
film): ν = 1611, 1503, 1491, 1325, 1294, 1148, 1114 cm–1. HRMS:
˜
calcd. for C25H29ClF3N3S 495.1723; found 495.1728.
N-Cyclohexyl-2-[(2-methoxyethyl)pyrimidin-2-yl-amino]-4-methyl-
pentanethioamide: See Scheme 5; yield (90 °C neat for 12 h): 77%
1
(280 mg). H NMR (CDCl3, 400 MHz): δ = 9.36 (br. s, 1 H), 8.35
(d, J = 4.8 Hz, 2 H), 6.61 (t, J = 4.8 Hz, 1 H), 5.21 (br. s, 1 H),
4.41–4.31 (m, 1 H), 3.92–3.85 (m, 1 H), 3.78–3.75 (m, 2 H), 3.61–
3.57 (m, 1 H), 3.36 (s, 3 H), 2.32–2.25 (m, 1 H), 2.04–1.90 (m, 3
H), 1.68–1.56 (m, 2 H), 1.52–1.48 (m, 1 H), 1.42–1.35 (m, 2 H),
1.28–1.08 (m, 4 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 202.4, 162.5, 157.8,
111.4, 70.6, 59.1, 53.9, 40.7, 31.5, 31.2, 26.0, 25.5, 27.7, 24.8, 23.6,
N-tert-Butyl-2-{(2-methoxyethyl)[5-(trifluoromethyl)pyridin-2-
yl]amino}-4-methylpentanethioamide: See Table 3, Entry 3; yield
(90 °C in toluene for 16 h): 66 % (267 mg). 1H NMR (CDCl3,
400 MHz): δ = 9.52 (br. s, 1 H), 8.36 (d, J = 2.4 Hz, 1 H), 7.67 (dd,
J = 9.0, 2.4 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 5.10–5.02 (m, 1
H), 3.86–3.79 (m, 1 H), 3.76–3.70 (m, 1 H), 3.67–3.62 (m, 1 H),
3.60–3.54 (m, 1 H), 3.35 (s, 3 H), 2.14–2.07 (m, 1 H), 2.00–1.93 (m,
1 H), 1.55–1.50 (m, 1 H), 1.47 (s, 9 H), 0.94 (d, J = 6.6 Hz, 3 H),
0.90 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ
= 202.1, 160.4, 144.7 (q, JC,F = 4.4 Hz), 135.1 (q, JC,F = 3.1 Hz),
124.8 (q, JC,F = 270.2 Hz), 116.5 (q, JC,F = 33.1 Hz), 108.7, 71.1,
65.7, 59.3, 55.6, 46.2, 40.5, 27.7, 25.5, 23.6, 22.5 ppm. MS (DI, CI
22.4 ppm. MS (DI, CI NH ): m/z = 365. IR (thin film): ν = 2929,
˜
3
2854, 1585, 1507, 1477, 1359, 1116 cm–1. HRMS: calcd. for
C19H32N4OS 364.2297; found 364.2304.
N-tert-Butyl-2-[(2-methoxyethyl)pyrimidin-2-yl-amino]thiobutyr-
amide: See Table 4, Entry 1; yield (80 °C neat for 12 h): 42 %
NH ): m/z = 406. IR (thin film): ν = 1612, 1326, 1113, 1078 cm–1.
1
˜
(130 mg). H NMR (CDCl3, 400 MHz): δ = 9.52 (br. s, 1 H), 8.33
3
HRMS: calcd. for C19H30F3N3OS 405.2062; found 405.2051.
(d, J = 4.8 Hz, 2 H), 6.59 (t, J = 4.8 Hz, 1 H), 4.80 (br. s, 1 H),
3.86 (t, J = 6.0 Hz, 2 H), 3.69–3.63 (m, 1 H), 3.62–3.56 (m, 1 H),
3.34 (s, 3 H), 2.45–2.34 (m, 1 H), 2.14–2.03 (m, 1 H), 1.46 (s, 9 H),
0.87 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ
= 202.1, 162.2, 157.7, 111.3, 70.6, 59.1, 55.3, 46.2, 25.8, 24.5, 11.6
N-tert-Butyl-2-{(4-chlorobenzyl)[5-(trifluoromethyl)pyridin-2-
yl]amino}-4-methylpentanethioamide: See Table 3, Entry 4; yield
(90 °C in toluene for 16 h): 52 % (245 mg). 1H NMR (CDCl3,
400 MHz): δ = 9.41 (br. s, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 7.55 (dd,
J = 9.0, 2.4 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.12 (d, J = 8.3 Hz,
2 H), 6.35 (d, J = 9.0 Hz, 1 H), 5.54 (br. s, 1 H), 4.93 (d, J =
17.7 Hz, 1 H), 4.66 (d, J = 17.7 Hz, 1 H), 2.20–2.13 (m, 1 H), 1.81–
ppm. MS (DI, CI NH ): m/z = 311. IR (thin film): ν = 2964, 2360,
˜
3
2341, 1585, 1476, 1116 cm–1. HRMS: calcd. for C15H26N4OS
310.1827; found 310.1823.
1.73 (m, 1 H), 1.60–1.54 (m, 1 H), 1.52 (s, 9 H), 0.90 (d, J = 6.6 Hz, N-Cyclohexyl-2-cyclopropyl-2-[(4-methoxybenzyl)pyrimidin-2-yl-
6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 200.9, 160.2, 144.8
(q, JC,F = 4.4 Hz), 136.4, 135.3 (q, JC,F = 4.4 Hz), 133.2, 129.2,
128.2, 124.7 (q, JC,F = 270.7 Hz), 116.6 (q, JC,F = 33.2 Hz), 108.7,
amino]thioacetamide: See Table 4, Entry 2; yield (80 °C neat for
12 h): 71% (291 mg). H NMR (CDCl3, 400 MHz): δ = 9.30 (br. s,
1 H), 8.35 (d, J = 4.8 Hz, 2 H), 7.30 (d, J = 8.8 Hz, 2 H), 6.84 (d,
1
5982
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5974–5987

Thiols in Ugi- and Passerini–Smiles-Type Couplings
J = 8.8 Hz, 2 H), 6.61 (t, J = 4.8 Hz, 1 H), 5.22 (d, J = 16.0 Hz, 1
H), 4.90 (d, J = 16.0 Hz, 1 H), 4.38–4.29 (m, 1 H), 4.18 (br. s, 1
H), 3.81 (s, 3 H), 2.01–1.95 (m, 1 H), 1.92–1.86 (m, 1 H), 1.82–1.74
(m, 1 H), 1.67–1.55 (m, 2 H), 1.47–1.35 (m, 2 H), 1.28–1.14 (m, 4
H), 0.74–0.66 (m, 1 H), 0.45–0.39 (m, 1 H), 0.27–0.20 (m, 1 H),
0.14–0.04 (m, 1 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 200.8,
162.4, 158.9, 157.9, 132.0, 129.3, 114.0, 111.2, 73.0, 55.7, 53.6, 49.6,
31.5, 31.2, 25.9, 24.6, 13.3, 6.8, 5.7 ppm. MS (DI, CI NH3): m/z =
ν = 2955, 1582, 1550, 1469, 1203 cm–1. HRMS: calcd. for
C22H25ClN4O2S 444.1387; found 444.1383.
˜
2-[(4-Chlorobenzyl)(6-methyl-2-phenylpyrimidin-4-yl)amino]-N-cy-
clohexyl-4-methylpentanethioamide: See Table 4, Entry 7; yield
(80 °C neat for 12 h): 33% (172 mg). 1H NMR (CDCl3, 400 MHz):
δ = 9.30 (br. s, 1 H), 8.40–8.31 (m, 2 H), 7.54–7.51 (m, 3 H), 7.31
(d, J = 8.3 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 2 H), 6.06 (s, 1 H), 5.88
(br. s, 1 H), 4.99 (d, J = 17.9 Hz, 1 H), 4.59 (d, J = 17.9 Hz, 1 H),
4.30–4.21 (m, 1 H), 2.39 (s, 3 H), 2.28–2.19 (m, 2 H), 1.93–1.87 (m,
2 H), 1.76–1.69 (m, 2 H), 1.65–1.58 (m, 1 H), 1.52–1.42 (m, 2 H),
1.29–1.20 (m, 4 H), 0.92 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 200.9, 167.2, 163.2, 138.5, 136.4, 131.0,
129.3, 129.0, 128.2, 102.3, 53.0, 40.3, 31.5, 31.1, 25.7, 25.5, 25.1,
410. IR (thin film): ν = 2927, 2852, 2360, 2341, 1583, 1478, 1174
˜
cm–1.
N-(4-Chlorobenzyl)-2-[(2-methoxyethyl)(pyrimidin-2-yl)amino]-4-
methylpentanethioamide: See Table 4, Entry 3; yield (80 °C neat for
1
12 h): 33% (134 mg). H NMR (CDCl3, 400 MHz): δ = 9.98 (br. s,
24.5, 23.1 ppm. MS (DI, CI NH ): m/z = 521. IR (thin film): ν =
˜
1 H), 8.33 (d, J = 4.8 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 2 H), 7.12 (d,
J = 8.3 Hz, 2 H), 6.63 (t, J = 4.8 Hz, 1 H), 5.35 (br. s, 1 H), 4.85
(dd, J = 15.3, 5.2 Hz, 1 H), 4.78 (dd, J = 15.3, 5.2 Hz, 2 H), 3.93–
3.53 (m, 4 H), 3.10 (s, 3 H), 2.43–2.35 (m, 1 H), 2.08–1.99 (m, 1
H), 1.57–1.47 (m, 1 H), 0.95 (d, J = 6.5 Hz, 3 H), 0.91 (d, J =
6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 205.4,
161.8, 157.9, 135.6, 133.7, 129.5, 129.1, 111.7, 70.5, 58.9, 49.3, 41.1,
25.6, 23.7, 22.2 ppm. MS (DI, CI NH3): m/z = 407. IR (thin film):
3
1590, 1529, 1442, 1173, 1092 cm–1. HRMS: calcd. for C30H37ClN4S
520.2427; found 520.2422.
2-[Allyl(6-methyl-2-phenylpyrimidin-4-yl)amino]-N-(4-chlorobenzyl)-
4-methylpentanethioamide: See Table 4, Entry 8; yield (80 °C neat
for 16 h): 57% (273 mg). 1H NMR (CDCl3, 400 MHz): δ = 9.59
(br. s, 1 H), 8.12 (d, J = 7.4 Hz, 2 H), 7.46 (tt, J = 7.4, 1.2 Hz, 1
H), 7.36 (t, J = 7.4 Hz, 2 H), 6.96 (d, J = 8.4 Hz, 2 H), 6.88 (d, J
= 8.4 Hz, 2 H), 6.27 (s, 1 H), 5.96 (br. s, 1 H), 5.87–5.77 (m, 1 H),
5.26 (d, J = 17.2 Hz, 1 H), 5.22 (d, J = 10.4 Hz, 1 H), 4.61 (td, J
= 15.0, 4.9 Hz, 2 H), 4.39 (d, J = 14.1 Hz, 1 H), 3.92 (br. s, 1 H),
2.47 (s, 3 H), 2.26–2.17 (m, 1 H), 2.05–1.91 (m, 1 H), 1.71–1.61 (m,
1 H), 0.98 (d, J = 6.6 Hz, 6 H) ppm. 1 3C NMR (CDCl3,
100.6 MHz): δ = 203.3, 166.9, 163.1, 138.2, 134.5, 133.9, 130.8,
129.7, 129.1, 128.9, 127.9, 117.6, 102.2, 49.6, 47.7, 40.1, 25.4, 25.1,
ν = 1584, 1498, 1386, 1186, 1089 cm–1. HRMS: calcd. for
˜
C20H17ClN4OS 406.1594; found 406.1589.
2-[Allyl(pyrimidin-2-yl)amino]-N-(4-chlorobenzyl)-4-methylpentane-
thioamide: See Table 4, Entry 4; yield (80 °C neat for 12 h): 52%
1
(202 mg). H NMR (CDCl3, 400 MHz): δ = 9.64 (br. s, 1 H), 8.28
(d, J = 4.7 Hz, 2 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.12 (d, J = 8.2 Hz,
2 H), 6.58 (t, J = 4.7 Hz, 1 H), 6.01–5.91 (m, 1 H), 5.40 (br. s, 1
H), 5.20 (d, J = 17.2 Hz, 2 H), 5.12 (d, J = 10.2 Hz, 2 H), 4.80 (dd,
J = 15.3, 5.0 Hz, 1 H), 4.71 (dd, J = 15.3, 5.0 Hz, 1 H), 4.39 (dd,
J = 16.1, 6.0 Hz, 1 H), 4.21 (dd, J = 16.1, 6.0 Hz, 1 H), 2.19–2.13
(m, 1 H), 2.04–1.96 (m, 1 H), 1.62–1.54 (m, 1 H), 0.93 (d, J =
6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 204.4,
162.2, 158.0, 135.4, 135.2, 133.9, 129.6, 129.3, 116.9, 111.2, 49.3,
48.2, 40.5, 25.3, 23.1, 22.9 ppm. MS (DI, CI NH3): m/z = 389. IR
23.1 ppm. MS (DI, CI NH ): m/z = 479. IR (thin film): ν = 1590,
˜
3
1528, 1472, 1378 cm–1. HRMS: calcd. for C27H31ClN4S 478.1958;
found 478.1946.
2-[(4-Chlorobenzyl)(2-isopropyl-6-methylpyrimidin-4-yl)amino]-N-cy-
clohexyl-4-methylpentanethioamide: See Table 4, Entry 9; yield
(80 °C neat for 16 h): 69% (336 mg). 1H NMR (CDCl3, 400 MHz):
δ = 8.95 (br. s, 1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.09 (d, J = 8.3 Hz,
2 H), 5.93 (s, 1 H), 5.84 (br. s, 1 H), 4.86 (d, J = 17.6 Hz, 1 H),
4.55 (d, J = 17.6 Hz, 1 H), 4.38–4.29 (m, 1 H), 3.07 (sept, J =
6.9 Hz, 1 H), 2.27 (s, 3 H), 2.12–2.03 (m, 2 H), 1.96–1.90 (m, 1 H),
1.84–1.72 (m, 2 H), 1.69–1.62 (m, 1 H), 1.54–1.47 (m, 1 H), 1.39–
1.34 (m, 8 H), 1.26–1.13 (m, 2 H), 1.06–0.95 (m, 2 H), 0.86 (d, J
= 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 201.6,
173.9, 166.5, 163.2, 136.4, 133.1, 129.1, 128.2, 101.5, 54.2, 47.7,
40.3, 38.0, 32.1, 31.8, 25.8, 25.4, 25.2, 25.1, 24.9, 23.1, 22.9, 22.3
(thin film): ν = 2366, 2350, 1583, 1490, 1385, 1089 cm–1. HRMS:
˜
calcd. for C20H25ClN4S 388.1488; found 388.1504.
2-[(2-Methoxyethyl)pyrimidin-2-yl-amino]-4-methylpentanethioic
Acid [2-(3,4-dimethoxyphenyl)ethyl]amide: See Table 4, Entry 5;
yield (80 °C neat for 12 h): 75 % (335 mg). 1H NMR (CDCl3,
400 MHz): δ = 9.53 (br. s, 1 H), 8.22 (d, J = 4.8 Hz, 2 H), 6.66–
6.63 (m, 2 H), 6.60–6.55 (m, 2 H), 5.32 (br. s, 1 H), 3.97–3.88 (m,
4 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.77–3.71 (m, 1 H), 3.53–3.47 (m,
1 H), 3.28 (s, 3 H), 2.86 (t, J = 6.8 Hz, 2 H), 2.31–2.24 (m, 1 H),
2.00–1.92 (m, 1 H), 1.51–1.43 (m, 1 H), 0.92 (d, J = 6.8 Hz, 3 H),
0.87 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ
= 204.6, 162.4, 157.7, 149.3, 147.9, 131.5, 121.0, 112.0, 111.5, 111.3,
70.5, 59.1, 56.3, 56.2, 47.0, 40.9, 33.6, 25.5, 23.6, 22.3 ppm. MS
ppm. MS (DI, CI NH ): m/z = 487. IR (thin film): ν = 2361, 1469,
˜
3
1582, 1431, 1092 cm–1. HRMS: calcd. for C27H39ClN4S 486.2584;
found 486.2579.
2-[Allyl(5,6-diphenylpyrazin-2-yl)amino]-N-(4-methoxybenzyl)-4-
methylpentanethioamide: See Table 5, Entry 1; yield (110 °C in tolu-
ene for 12 h): 76% (408 mg). 1H NMR (400 MHz, CDCl3): δ =
9.36 (br. s, 1 H), 8.13 (s, 1 H), 7.35–7.17 (m, 10 H), 6.86 (d, J =
8.6 Hz, 1 H), 6.62 (d, J = 8.6 Hz, 1 H), 5.92–5.82 (m, 1 H), 5.61 (s
br, 1 H), 5.32–5.26 (m, 2 H), 4.64 (dd, J = 15.2, 5.3 Hz, 1 H), 4.56–
4.46 (m, 2 H), 4.11 (dd, J = 17.9, 2.5 Hz, 1 H), 3.75 (s, 3 H), 2.22–
2.14 (m, 1 H), 2.05–1.98 (m, 1 H), 1.69–1.63 (m, 1 H), 1.00–0.96
(m, 6 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 203.0, 152.1,
152.1, 143.5, 141.6, 139.1, 139.0, 134.3, 129.8, 129.7, 129.6, 128.8,
128.6, 128.5, 117.9, 114.3, 66.3, 55.6, 49.8, 48.5, 40.3, 25.3, 23.3,
23.1 ppm.
(DI, CI NH ): m/z = 447. IR (thin film): ν = 2927, 2360, 2342,
˜
3
1515, 1114 cm–1. HRMS: calcd. for C23H34N4O3S 446.2352; found
446.2358.
Ethyl 2-{1-[(4-Chlorobenzyl)(pyrimidin-2-yl)amino]-3-methyl-
butyl}thiazole-4-carboxylate: See Table 4, Entry 6; yield (80 °C in
toluene for 16 h): 35% (155 mg). 1H NMR (CDCl3, 400 MHz): δ
= 8.40 (d, J = 4.7 Hz, 2 H), 8.02 (s, 1 H), 7.15 (br. s, 4 H), 6.64 (t,
J = 4.7 Hz, 1 H), 6.42 (br. s, 1 H), 4.90 (d, J = 16.2 Hz, 1 H), 4.68
(d, J = 16.2 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.23–2.15 (m, 1
H), 2.12–2.05 (m, 1 H), 1.52–1.46 (m, 1 H), 1.40 (t, J = 7.1 Hz, 3
H), 0.90 (d, J = 6.7 Hz, 3 H), 0.76 (d, J = 6.7 Hz, 3 H) ppm. 13C
2-[Allyl(5,6-diphenylpyrazin-2-yl)amino]-N-cyclohexylbutanethio-
NMR (CDCl3, 100.6 MHz): δ = 172.2, 162.4, 161.7, 158.3, 146.8, amide: See Table 5, Entry 2; yield (110 °C in toluene for 3 d): 36%
1
138.3, 132.6, 129.2, 128.5, 128.3, 111.6, 61.7, 55.8, 47.5, 40.4, 25.3,
23.2, 22.5, 14.8 ppm. MS (DI, CI NH3): m/z = 445. IR (thin film):
(169 mg). H NMR (400 MHz, CDCl3): δ = 9.40 (br. s, 1 H), 8.13
(s, 1 H), 7.40–7.26 (m, 10 H), 5.96–5.87 (m, 1 H), 5.33–5.27 (m, 2
Eur. J. Org. Chem. 2008, 5974–5987
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5983

A. Barthelon, L. El Kaïm, M. Gizolme, L. Grimaud
FULL PAPER
H), 5.08 (br. s, 1 H), 4.52 (dd, J = 18.2, 4.8 Hz, 1 H), 4.20–4.07
H), 1.90–1.77 (m, 6 H), 1.63–1.49 (m, 4 H), 1.37 (t, J = 7.1 Hz, 3
(m, 2 H), 2.47–2.37 (m, 1 H), 2.15–2.04 (m, 1 H) 1.78–1.60 (m, 2 H), 1.31–1.26 (m, 2 H), 0.99 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
H), 1.43–1.27 (m, 3 H), 1.20–1.10 (m, 2 H) 1.00 (dd, J = 7.6, 7.0 Hz,
(CDCl3, 100.6 MHz): δ = 167.6, 151.9, 146.9, 140.0, 132.6, 131.7,
3 H), 0.86–0.77 (m, 1 H), 0.70–0.60 (m, 1 H), 0.52–0.43 (m, 1 H) 130.4, 129.7, 128.9, 128.7, 126.0, 62.9, 60.2, 51.3, 41.0, 33.8, 33.6,
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 200.5, 152.1, 148.1,
141.4, 139.8, 138.9, 134.3, 130.5, 129.9, 129.8, 129.0, 128.8, 128.5,
127.9, 117.7, 67.3, 53.6, 49.0, 31.3, 30.8, 25.4, 24.8, 24.4, 11.7 ppm.
HRMS: calcd. for C29H34N4S 470.2504; found 470.2509.
26.5, 24.7, 24.6, 14.2, 10.2 ppm. MS (DI, CI NH3): m/z = 496.
HRMS: calcd. for C27H34ClN5S 495.2223; found 495.2239.
2-[Benzo[d]oxazol-2-yl(4-chlorobenzyl)amino]-N-cyclohexyl-4-meth-
ylpentanethioamide: See Table 7, Entry 1; yield (50 °C in toluene
N-Cyclohexyl-2-[(2-methoxyethyl)(3-methylquinoxalin-2-yl)amino]- for 2 d): 61% (286 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.00
4-methylpentanethioamide: See Table 5, Entry 3; yield (110 °C in
toluene for 12 h): 31% (89 mg). H NMR (400 MHz, CDCl3): δ =
(br. s, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.36–7.28 (m, 5 H), 7.25 (td,
J = 7.8, 1.0 Hz, 1 H), 7.12 (td, J = 7.8, 1.0 Hz, 1 H), 4.95 (d, J =
1
7.95 (d, J = 7.8 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.66–7.5 (m, 2 16.2 Hz, 1 H), 4.81 (t, J = 6.8 Hz, 1 H), 4.75 (d, J = 16.2 Hz, 1 H),
H), 5.56–5.49 (m, 2 H), 4.08 (d, J = 13.1 Hz, 1 H), 3.67–3.65 (m, 4.36–4.28 (m, 1 H), 2.12–1.87 (m, 4 H), 1.70–1.54 (m, 2 H), 1.48–
1 H), 3.58–3.53 (m, 1 H), 3.35–3.27 (m, 1 H), 3.25 (s, 3 H), 2.65 (s, 1.39 (m, 3 H), 1.38–1.27 (m, 4 H), 0.81 (d, J = 5.6 Hz, 6 H) ppm.
3 H), 2.36–2.28 (m, 1 H), 2.16 (d, J = 11.6 Hz, 2 H), 2.02–1.96 (m, 13C NMR (CDCl3, 100.6 MHz): δ = 199.3, 163.0, 148.9, 142.3,
1 H), 1.84–1.72 (m, 3 H), 1.50–1.24 (m, 6 H), 0.80 (d, J = 6.6 Hz, 136.5, 133.9, 129.7, 129.1, 124.8, 121.8, 116.5, 109.7, 77.7, 54.0,
3 H), 0.53 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100.6 MHz, 51.5, 39.9, 31.2, 30.9, 25.9, 25.3, 24.3, 23.0, 22.7 ppm. MS (DI, CI
CDCl3): δ = 201.2, 154.3, 150.6, 139.2, 139.0, 129.6, 128.4, 127.5,
NH ): m/z = 470. IR (thin film): ν = 2359, 1458, 1625, 1569, 1245,
˜
3
127.0, 70.5, 70.2, 59.1, 55.0, 46.4, 42.3, 31.8, 31.7, 26.1, 25.4, 25.2, 1091 cm–1. HRMS: calcd. for C26H32ClN3OS 469.1955; found
24.0, 23.6, 20.7 ppm. HRMS: calcd. for C24H36N4OS – C9H6N2 469.1945.
286.2079; found 286.2069.
2-[Benzoxazol-2-yl(4-chlorobenzyl)amino]-N-cyclohexylthiobutyr-
2-[Allyl(3-methylquinoxalin-2-yl)amino]-N-(4-chlorobenzyl)-4-meth-
ylpentanethioamide: See Table 5, Entry 4; yield (110 °C in toluene
amide: See Table 7, Entry 2; yield (50 °C in toluene for 2 d): 59%
(221 mg). 1H NMR (CDCl3, 400 MHz): δ = 9.95 (br. s, 1 H), 7.39–
for 12 h): 9% (41 mg). 1H NMR (400 MHz, CDCl3): δ = 7.93–7.88 7.37 (m, 1 H), 7.35–7.30 (m, 5 H), 7.24 (td, J = 7.8, 1.3 Hz, 1 H),
(m, 2 H), 7.70–7.59 (m, 1 H), 7.58–7.53 (m, 1 H), 7.19–7.45 (m, 1
H), 7.32 (s, 2 H), 6.77 (d, J = 8.1 Hz, 1 H), 5.89–5.79 (m, 1 H),
7.11 (td, J = 7.8, 1.3 Hz, 1 H), 4.98 (d, J = 16.2 Hz, 1 H), 4.75 (d,
J = 16.2 Hz, 1 H), 4.62 (t, J = 7.6 Hz, 1 H), 4.37–4.28 (m, 1 H),
5.37 (d, J = 16.9 Hz, 1 H), 5.27 (d, J = 10.3 Hz, 1 H), 4.91–4.84 2.35–2.24 (m, 1 H), 2.12–2.03 (m, 1 H), 1.97–1.86 (m, 2 H), 1.68–
(m, 2 H), 4.73 (dd, J = 14.9, 4.3 Hz, 1 H), 4.05–3.94 (m, 2 H), 2.72
1.53 (m, 2 H), 1.47–1.25 (m, 6 H), 0.81 (t, J = 7.3 Hz, 3 H) ppm.
(s, 3 H), 2.14–2.08 (m, 1 H), 1.86–1.79 (m, 2 H), 0.88 (d, J = 6.5 Hz, 13C NMR (CDCl3, 100.6 MHz): δ = 198.9, 162.9, 148.9, 142.3,
3 H), 0.76 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (100.6 MHz, 136.5, 133.9, 129.7, 129.1, 124.8, 121.8, 116.5, 109.7, 71.8, 54.0,
CDCl3): δ = 205.6, 158.0, 153.2, 151.6, 142.1, 139.2, 143.3, 133.3,
130.6, 129.8, 129.6, 129.0, 128.4, 128.3, 128.0, 126.0, 120.7, 70.1,
53.9, 50.7, 40.4, 27.1, 24.1, 23.8, 21.6 ppm. HRMS: calcd. for
C25H29ClN4S 452.1801; found 452.1789.
51.5, 31.2, 30.9, 25.9, 24.3, 24.2, 11.3 ppm. MS (DI, CI NH3): m/z
= 442. IR (thin film): ν = 2360, 2341, 1627, 1572, 1360, 1240, 1091
˜
cm–1. HRMS: calcd. for C24H28ClN3OS 441.1642; found 441.1662.
2-[Benzo[d]oxazol-2-yl(4-chlorobenzyl)amino]-N-tert-butyl-4-meth-
4-Methyl-4H-1,2,4-triazol-3-yl-2-(4-chlorobenzylamino)-N-cyclo- ylpentanethioamide: See Table 7, Entry 3; yield (50 °C in toluene
hexylbutanimidothioate: See Table 6, Entry 1; yield (90 °C in tolu-
ene for 2 d): 47%. H NMR (CDCl3, 400 MHz): δ = 7.87 (s, 1 H),
for 2 d): 61% (270 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.10
(br. s, 1 H), 7.39–7.30 (m, 6 H), 7.24 (td, J = 7.7, 1.2 Hz, 1 H),
1
7.37 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 4.00 (d, J = 7.12 (td, J = 7.7, 1.2 Hz, 1 H), 4.92 (d, J = 16.0 Hz, 1 H), 4.80–
13.1 Hz, 1 H), 3.78 (d, J = 13.1 Hz, 1 H), 3.67 (dd, J = 6.9, 4.7 Hz,
1 H), 3.61 (s, 3 H), 3.24–3.17 (m, 1 H), 1.81–1.71 (m, 6 H), 1.58–
4.67 (m, 2 H), 2.08–2.01 (m, 2 H), 1.50 (s, 9 H), 1.48–1.41 (m, 1
H), 0.81 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz):
1.41 (m, 4 H), 1.30–1.20 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H) ppm. δ = 199.6, 162.9, 148.9, 142.0, 136.4, 133.8, 129.8, 129.1, 124.8,
13C NMR (CDCl3, 100.6 MHz): δ = 167.4, 149.3, 141.2, 139.7, 121.8, 116.6, 109.7, 70.6, 56.0, 51.7, 39.8, 27.6, 25.3, 23.1, 22.6 ppm.
132.7, 130.3, 128.7, 62.8, 60.0, 51.3, 33.8, 33.6, 33.0, 26.3, 26.0,
24.5, 10.0 ppm. MS (DI, CI NH3): m/z = 406. HRMS: calcd. for
C20H28ClN5S 405.1754; found 405.1734.
MS (DI, CI NH ): m/z = 444. IR (thin film): ν = 2357, 1625, 1569,
˜
3
1458, 1245, 1091 cm–1. HRMS: calcd. for C24H30ClN3OS 443.1798;
found 443.1778.
4-Methyl-4H-1,2,4-triazol-3-yl-2-(allylamino)-N-(4-chlorobenzyl)-4- 2-[Benzo[d]oxazol-2-yl(2-methoxyethyl)amino]-N-tert-butyl-4-meth-
methylpentanimidothioate: See Table 6, Entry 2; yield (90 °C in tolu-
ene for 2 d): 32% (125 mg). H NMR (CDCl3, 400 MHz): δ = 7.92
(s, 1 H), 7.29 (s, 4 H), 5.95–5.85 (m, 1 H), 5.19 (d, J = 17.2 Hz, 1
H), 5.07 (d, J = 10.1 Hz, 1 H), 4.66 (d, J = 16.6 Hz, 1 H), 4.45 (d,
ylpentanethioamide: See Table 7, Entry 4; yield (50 °C in toluene
for 2 d): 66% (249 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.26
(br. s, 1 H), 7.37–7.32 (m, 2 H), 7.22 (td, J = 7.9, 1.0 Hz, 1 H),
7.10 (td, J = 7.9, 1.0 Hz, 1 H), 4.66 (dd, J = 8.9, 6.6 Hz, 1 H),
1
J = 16.6 Hz, 1 H), 3.84 (q, J = 4.7 Hz, 1 H), 3.63 (s, 3 H), 3.30– 3.94–3.85 (m, 1 H), 3.79–3.71 (m, 2 H), 3.68–3.63 (m, 1 H), 3.36
3.16 (m, 2 H), 1.96–1.87 (m, 1 H), 1.72–1.60 (m, 1 H), 1.46–1.39
(s, 3 H), 2.26–2.18 (m, 1 H), 2.16–2.09 (m, 1 H), 1.63–1.55 (m, 1
(m, 1 H), 0.90 (t, J = 6.6 Hz, 3 H), 0.84 (t, J = 6.6 Hz, 3 H) ppm. H), 1.52 (s, 9 H), 0.96 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3,
13C NMR (CDCl3, 100.6 MHz): δ = 167.4, 153.5, 137.9, 137.3, 100.6 MHz): δ = 200.7, 163.0, 148.9, 142.3, 124.6, 121.6, 116.4,
132.9, 128.9, 116.6, 60.8, 54.8, 50.6, 41.0, 33.1, 25.3, 23.7, 22.4 ppm.
109.6, 71.5, 70.8, 59.2, 55.9, 48.7, 39.9, 27.4, 25.4, 23.5, 22.7 ppm.
MS (DI, CI NH3): m/z = 392.
MS (DI, CI NH ): m/z = 378. IR (thin film): ν = 2360, 1626, 1570,
˜
3
1459, 1362, 1246, 1116 cm–1. HRMS: calcd. for C20H31N3O2S
4-Ethyl-5-phenyl-4H-1,2,4-triazol-3-yl 2-(4-chlorobenzylamino)-N-
cyclohexylbutanimidothioate: See Table 6, Entry 3; yield (90 °C in
toluene for 2 d): 41% (203 mg). H NMR (CDCl3, 400 MHz): δ =
377.2137; found 377.2145.
1
2-[Benzoxazol-2-yl(4-chlorobenzyl)amino]-N-tert-butylthiobutyr-
7.61–7.56 (m, 5 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.4 Hz, amide: See Table 7, Entry 5; yield (50 °C in toluene for 2 d): 61%
2 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.04 (d, J = 13.1 Hz, 1 H), 3.82 (d,
J = 13.1 Hz, 1 H), 3.77 (dd, J = 6.9, 4.8 Hz, 1 H), 3.41–3.24 (m, 1
(253 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.0 (br. s, 1 H), 7.38–
7.28 (m, 6 H), 7.24 (td, J = 7.8, 1.3 Hz, 1 H), 7.12 (td, J = 7.8,
5984
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5974–5987

Thiols in Ugi- and Passerini–Smiles-Type Couplings
1.3 Hz, 1 H), 4.96 (d, J = 16.2 Hz, 1 H), 4.76 (d, J = 16.2 Hz, 1
H), 4.53 (t, J = 7.6 Hz, 1 H), 2.36–2.24 (m, 1 H), 2.12–2.02 (m, 1
2-[Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino]-N-cyclohexyl-4-meth-
ylpentanethioamide: See Table 7, Entry 10; yield (90 °C in toluene
1
H), 1.52 (s, 9 H), 0.82 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (CDCl3, for 16 h): 77% (371 mg). H NMR (CDCl3, 400 MHz): δ = 10.08
100.6 MHz): δ = 199.2, 162.8, 148.9, 142.3, 136.5, 133.9, 129.7,
(br. s, 1 H), 7.59 (d, J = 7.4 Hz, 2 H), 7.37 (d, J = 7.4 Hz, 1 H),
129.1, 124.8, 121.8, 116.5, 109.7, 74.1, 56.0, 51.7, 27.5, 24.2, 11.3 7.31 (br. s, 4 H), 7.15 (t, J = 7.4 Hz, 1 H), 5.20 (br. s, 1 H), 4.93
ppm. MS (DI, CI NH ): m/z = 416. IR (thin film): ν = 2965, 2930,
(d, J = 17.2 Hz, 1 H), 4.62 (d, J = 17.2 Hz, 1 H), 4.37–4.30 (m, 1
H), 2.25–2.17 (m, 1 H), 2.03–1.97 (m, 2 H), 1.90–1.85 (m, 1 H),
1.71–1.65 (m, 1 H), 1.60–1.53 (m, 3 H), 1.46–1.22 (m, 5 H), 0.89
(d, J = 6.4 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
199.2, 169.9, 151.3, 135.5, 133.9, 131.0, 129.1, 126.7, 122.5, 121.3,
119.3, 68.3, 54.7, 53.9, 40.0, 31.3, 31.0, 25.9, 25.5, 24.4, 23.1 ppm.
˜
3
2349, 1625, 1563, 1458, 1362, 1245, 1210, 1014 cm–1. HRMS: calcd.
for C22H26ClN3OS 415.1485; found 415.1471.
2-[Benzo[d]oxazol-2-yl(4-chlorobenzyl)amino]-N-cyclohexyloctane-
thioamide: See Table 7, Entry 6; yield (50 °C in toluene for 2 d):
1
44% (279 mg). H NMR (CDCl3, 400 MHz): δ = 9.99 (br. s, 1 H),
MS (DI, CI NH ): m/z = 486. IR (thin film): ν = 2359, 1513, 1490,
˜
3
7.39 (t, J = 7.6 Hz, 1 H), 7.34–7.31 (m, 5 H), 7.24 (td, J = 7.6,
1.2 Hz, 1 H), 7.11 (td, J = 7.6, 1.2 Hz, 1 H), 4.97 (d, J = 16.2 Hz,
1 H), 4.74 (d, J = 16.2 Hz, 1 H), 4.69 (t, J = 7.6 Hz, 1 H), 4.36–
4.28 (m, 1 H), 2.26–2.17 (m, 1 H), 2.11–2.01 (m, 1 H), 1.96–1.87
1093 cm–1. HRMS: calcd. for C26H32ClN3S2 485.1726; found
485.1728.
2-[Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino]-N-cyclohexyloctane-
(m, 2 H), 1.66–1.55 (m, 2 H), 1.45–1.28 (m, 6 H), 1.23–1.11 (m, 8 thioamide: See Table 7, Entry 11; yield (90 °C in toluene for 16 h):
H), 0.84 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz):
δ = 199.1, 162.9, 148.9, 142.3, 136.5, 133.9, 129.7, 129.1, 124.8,
121.8, 116.6, 109.7, 70.3, 54.0, 51.5, 31.9, 31.2, 30.9, 29.2, 26.6,
25.9, 24.4, 24.3, 22.9, 14.4 ppm. MS (DI, CI NH3): m/z = 498. IR
60% (308 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.03 (br. s, 1 H),
7.59 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.37 (dt, J =
7.6, 1.0 Hz, 1 H), 7.31 (br. s, 4 H), 7.15 (t, J = 7.6 Hz, 1 H), 5.06
(br. s, 1 H), 4.95 (d, J = 17.3 Hz, 1 H), 4.60 (d, J = 17.3 Hz, 1 H),
(thin film): ν = 1925, 1626, 1570, 1459, 1244, 1092 cm–1. HRMS: 4.37–4.28 (m, 1 H), 2.35–2.27 (m, 1 H), 2.08–1.97 (m, 2 H), 1.90–
˜
calcd. for C28H36ClN3OS 497.2268; found 497.2263.
1.85 (m, 1 H), 1.70–1.65 (m, 2 H), 1.58–1.53 (m, 2 H), 1.45–1.20
(m, 12 H), 0.85 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 199.1, 169.8, 151.4, 135.5, 133.9, 131.0, 129.3,
129.1, 126.7, 122.5, 121.3, 119.2, 54.7, 53.9, 31.9, 31.4, 31.0, 29.4,
26.8, 25.9, 24.4, 24.3, 22.9, 14.5 ppm. MS (DI, CI NH3): m/z =
2-[Benzoxazol-2-yl(2-methoxy-ethyl)amino]-N-tert-butyl-2-(4-chloro-
phenyl)thioacetamide: See Table 7, Entry 7; yield (50 °C in toluene
1
for 2 d): 22% (95 mg). H NMR (CDCl3, 400 MHz): δ = 9.94 (br.
s, 1 H), 7.38–7.28 (m, 6 H), 7.20 (td, J = 7.8, 1.3 Hz, 1 H), 7.11
(td, J = 7.8, 1.3 Hz, 1 H), 6.02 (s, 1 H), 3.97 (ddd, J = 10.0, 7.6,
4.3 Hz, 1 H), 3.75 (dt, J = 15.0, 4.3 Hz, 1 H), 3.61 (ddd, J = 15.0,
7.6, 4.3 Hz, 1 H), 3.47 (dt, J = 10.0, 4.3 Hz, 1 H), 3.35 (s, 3 H),
514. IR (thin film): ν = 1515, 1490, 1442, 1093 cm–1. HRMS: calcd.
˜
for C28H36ClN3S2 513.2039; found 513.2042.
2-[Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino]-N-tert-butyl-4-meth-
1.59 (s, 9 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 198.0, ylpentanethioamide: See Table 7, Entry 12; yield (90 °C in toluene
1
161.9, 149.3, 142.2, 135.0, 134.6, 130.4, 129.3, 124.7, 121.9, 117.1,
109.8, 77.2, 70.4, 59.2, 56.4, 49.4, 27.8 ppm. MS (DI, CI NH3): m/z
for 16 h): 45% (207 mg). H NMR (CDCl3, 400 MHz): δ = 10.24
(br. s, 1 H), 7.58 (d, J = 7.5 Hz, 2 H), 7.36 (td, J = 7.5, 1.0 Hz, 1
= 432. IR (thin film): ν = 2360, 2341, 1625, 1570, 1458, 1243, 1090 H), 7.31 (s, 4 H), 7.15 (td, J = 7.5, 1.0 Hz, 1 H), 5.15–5.06 (m, 1
˜
cm–1. HRMS: calcd. for C22H26ClN3O2S 431.1434; found H), 4.87 (d, J = 17.2 Hz, 1 H), 4.65 (d, J = 17.2 Hz, 1 H), 2.22–
431.1405.
2.12 (m, 1 H), 2.06–1.97 (m, 1 H), 1.61–1.65 (m, 1 H), 1.52 (s, 9
H), 0.90 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz):
δ = 199.9, 169.7, 151.2, 135.5, 133.9, 131.1, 129.2, 126.7, 122.5,
121.3, 119.2, 70.2, 55.8, 54.9, 39.9, 27.7, 25.5, 23.2, 23.0 ppm. MS
(DI, CI NH3): m/z = 460. HRMS: calcd. for C24H30ClN3S2
459.1570; found 459.1556.
1-[Benzo[d]oxazol-2-yl(2-methoxyethyl)amino]-N-cyclohexylcyclo-
pentanecarbothioamide: See Table 7, Entry 8; yield (50 °C in toluene
for 2 d): 45% (181 mg). 1H NMR (CDCl3, 400 MHz): δ = 6.95 (m,
2 H), 6.82 (td, J = 7.4, 2.2 Hz, 1 H), 6.73 (dd, J = 7.4, 1.0 Hz, 1
H), 5.06–4.89 (m, 1 H), 3.32 (t, J = 6.2 Hz, 2 H), 3.08 (s, 3 H), 3.00
(t, J = 6.2 Hz, 2 H), 2.74–2.54 (m, 2 H), 2.33–2.27 (m, 2 H), 2.07–
1.99 (m, 2 H), 1.88–1.80 (m, 4 H), 1.76–1.71 (m, 2 H), 1.68–1.62
(m, 2 H), 1.43–1.30 (m, 2 H), 1.28–1.15 (m, 2 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 209.9, 148.8, 147.7, 133.3, 123.7, 121.3,
119.8, 114.5, 82.7, 69.5, 59.1, 57.8, 43.2, 41.3, 27.6, 26.6, 25.6 ppm.
2-[Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino]-N-tert-butyloctane-
thioamide: See Table 7, Entry 13; yield (90 °C in toluene for 16 h):
43% (210 mg). 1H NMR (CDCl3, 400 MHz): δ = 10.20 (br. s, 1 H),
7.60 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.36 (td, J =
8.0, 1.0 Hz, 1 H), 7.31 (s, 4 H), 7.15 (td, J = 8.0, 1.0 Hz, 1 H),
5.00–4.95 (m, 1 H), 4.90 (d, J = 17.2 Hz, 1 H), 4.63 (d, J = 17.2 Hz,
1 H), 2.33–2.24 (m, 1 H), 2.11–2.03 (m, 1 H), 1.52 (s, 9 H), 1.28–
1.20 (m, 8 H), 0.86 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 199.2, 169.6, 151.3, 144.2, 135.5, 133.9, 129.2,
126.7, 122.5, 121.3, 119.1, 72.1, 55.8, 55.3, 32.0, 27.7, 31.0, 29.4,
26.8, 22.9, 14.5 ppm. MS (DI, CI NH3): m/z = 488. IR (thin film):
MS (DI, CI NH ): m/z = 402. IR (thin film): ν = 1653, 1489, 1414,
˜
3
1391, 1358, 1295, 1231, 1172, 1148, 1116 cm–1. HRMS: calcd. for
C22H31N3O2S 401.2137; found 401.2129.
2-[Benzo[d]thiazol-2-yl(2-methoxyethyl)amino]-N-cyclohexyl-4-meth-
ylpentanethioamide: See Table 7, Entry 9; yield (90 °C in toluene
for 16 h): 59% (247 mg). H NMR (CDCl3, 400 MHz): δ = 10.28
(br. s, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.8 Hz, 1 H),
7.35 (t, J = 7.8 Hz, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 4.90 (br. s, 1
1
ν = 1590, 1437, 1362, 1213, 1093, 1014 cm–1. HRMS: calcd. for
˜
C26H34ClN3S2 487.1883; found 487.1886.
H), 4.39–4.31 (m, 1 H), 3.91–3.85 (m, 1 H), 3.83–3.78 (m, 1 H), 2-[Allyl(benzo[d]thiazol-2-yl)amino]-N-(4-chlorobenzyl)-4-methyl-
3.74–3.69 (m, 1 H), 3.68–3.63 (m, 1 H), 3.38 (s, 3 H), 2.24–2.18 (m, pentanethioamide: See Table 7, Entry 14; yield (90 °C in toluene for
2 H), 1.99–1.94 (m, 2 H), 1.67–1.56 (m, 3 H), 1.44–1.34 (m, 2 H), 16 h): 46% (205 mg). H NMR (CDCl3, 400 MHz): δ = 10.50 (br.
1
1.29–1.18 (m, 4 H), 0.96 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 200.6, 169.8, 151.7, 131.1, 126.5, 122.3,
121.2, 119.3, 70.5 (C4, C10), 59.3, 54.3, 51.3, 40.4, 31.3, 31.1, 25.9,
25.5, 24.6, 23.5, 22.5 ppm. MS (DI, CI NH3): m/z = 416. IR (thin
s, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.35–7.27 (m, 2 H), 7.20 (d, J =
8.4 Hz, 2 H), 7.17–7.10 (m, 3 H), 5.92–5.82 (m, 1 H), 5.37 (d, J =
17.2 Hz, 1 H), 5.28 (d, J = 10.2 Hz, 2 H), 4.81 (dd, J = 15.4, 4.7 Hz,
1 H), 4.67 (dd, J = 15.4, 4.7 Hz, 1 H), 3.99 (dd, J = 17.2, 4.9 Hz,
1 H), 3.34 (dd, J = 17.2, 4.9 Hz, 1 H), 2.23–2.16 (m, 1 H), 2.13–
2.05 (m, 1 H), 1.70–1.61 (m, 1 H), 0.97 (d, J = 6.6 Hz, 6 H) ppm.
film): ν = 2928, 1534, 1444, 1115 cm–1. HRMS: calcd. for
˜
C26H32ClN3S2 419.2065; found 419.2055.
Eur. J. Org. Chem. 2008, 5974–5987
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5985

A. Barthelon, L. El Kaïm, M. Gizolme, L. Grimaud
FULL PAPER
13C NMR (CDCl3, 100.6 MHz): δ = 201.9, 169.8, 151.1, 135.0, N-Cyclohexyl-2-(pyrimidin-2-yloxy)butanethioamide: See Scheme 7;
1
133.9, 132.9, 130.9, 129.8, 129.3, 126.5, 122.4, 121.2, 119.2, 77.7,
yield 58% (162 mg). H NMR (CDCl3, 400 MHz): δ = 8.55 (d, J
= 4.8 Hz, 2 H), 7.99 (br. s, 1 H), 7.02 (t, J = 4.8 Hz, 1 H), 5.89
(dd, J = 6.5, 3.9 Hz, 1 H), 4.45–4.36 (m, 1 H), 2.28–2.21 (m, 1 H),
2.19–2.12 (m, 1 H), 2.10–2.03 (m, 1 H), 1.89–1.82 (m, 1 H), 1.76–
1.70 (m, 1 H), 1.66–1.59 (m, 1 H), 1.46–1.06 (m, 6 H), 1.00 (t, J =
7.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 198.9,
164.2, 160.0, 116.0, 84.3, 53.7, 31.8, 31.6, 28.4, 25.8, 25.0, 24.9, 9.0
53.5, 49.8, 39.9, 25.4, 23.1 ppm. MS (DI, CI NH3): m/z = 444. IR
(thin film): ν = 2350, 1512, 1491, 1444, 1309, 1216, 1092, 1015
˜
cm–1. HRMS: calcd. for C23H26ClN3S2 443.1257; found 443.1263.
Ethyl 2-(2-(Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino)-4-methyl-
pentylthiocarbonylamino)ethanoate: See Table 7, Entry 15; yield
(90 °C in toluene for 16 h): 65 % (318 mg). 1H NMR (CDCl3,
400 MHz): δ = 10.52 (br. s, 1 H), 7.72 (d, J = 7.4 Hz, 1 H), 7.58
(d, J = 7.4 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.31 (br. s, 4 H),
7.15 (t, J = 7.4 Hz, 1 H), 5.38 (br. s, 1 H), 4.92 (d, J = 17.3 Hz, 1
H), 4.58 (d, J = 17.3 Hz, 1 H), 4.36 (d, J = 4.7 Hz, 2 H), 4.22 (q,
J = 7.1 Hz, 2 H), 2.26–2.19 (m, 1 H), 2.01–1.93 (m, 1 H), 1.62–
1.54 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 6 H)
ppm. MS (DI, CI NH ): m/z = 280. IR (thin film): ν = 2939, 1580,
˜
3
1530, 1300, 1042 cm–1. HRMS: calcd. for C14H21N3OS 279.1405;
found 279.1405.
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 202.2, 169.8, 168.7, Acknowledgments
151.1, 135.5, 133.9, 131.1, 129.3, 129.1, 126.7, 122.5, 121.2, 120.0,
66.3, 62.1, 54.0, 48.0, 40.2, 25.4, 23.1, 22.9, 14.5 ppm. MS (DI, CI
Financial support was provided by the Ecole Nationale des Tech-
NH ): m/z = 490. IR (thin film): ν = 1550, 1340, 1200, 1091 cm–1.
˜
3
niques Avancées. M. G. and A. B. thank the Ministère de l’Enseig-
nement Supérieur et de la Recherche for a fellowship, and A. B.
thanks the Ecole Normale de Cachan for an additional fellowship.
HRMS: calcd. for C24H28ClN3O2S2 489.1311; found 489.1315.
Ethyl 2-(1-(Benzo[d]thiazol-2-yl(4-chlorobenzyl)amino)-3-methylbu-
tyl)thiazole-4-carboxylate: See Table 7, Entry 16; yield (90 °C in tol-
uene for 16 h): 32% (160 mg). 1H NMR (CDCl3, 400 MHz): δ =
8.07 (s, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.60 (dd, J = 7.8, 1.1 Hz,
1 H), 7.36 (td, J = 7.8, 1.1 Hz, 1 H), 7.22 (s, 4 H), 7.13 (td, J =
7.8, 1.1 Hz, 1 H), 6.00 (t, J = 8.1 Hz, 1 H), 4.71 (d, J = 8.5 Hz, 2
H), 4.42 (q, J = 7.1 Hz, 2 H), 2.26–2.20 (m, 2 H), 1.66–1.57 (m, 1
H), 1.42 (t, J = 7.1 Hz, 3 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.88 (d, J
= 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 169.9,
168.8, 161.6, 152.6, 147.0, 135.9, 133.5, 131.4, 129.1, 128.9, 128.6,
126.5, 122.2, 121.2, 120.0, 61.8, 60.3, 51.7, 40.5, 25.4, 23.2, 22.7,
14.8 ppm. MS (DI, CI NH3): m/z = 500. HRMS: calcd. for
C25H26ClN3O2S2 499.1155; found 499.1166.
[1]
For recent reviews, see: a) R. W. Armstrong, A. P. Combs, P. A.
Tempest, S. D. Brown, T. A. Keating, Acc. Chem. Res. 1996,
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2003, 36, 899–907; g) I. Ugi, B. Werner, A. Dömling, Molecules
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A. Dömling, Chem. Rev. 2006, 106, 17–89.
2-[Allyl(6-ethoxybenzo[d]thiazol-2-yl)amino]-N-(4-chlorobenzyl)-4-
methylpentanethioamide: See Table 7, Entry 17; yield (90 °C in tolu-
ene for 16 h): 66% (322 mg). 1H NMR (CDCl3, 400 MHz): δ =
10.44 (br. s, 1 H), 7.21–7.10 (m, 6 H), 6.91 (dd, J = 8.8, 2.5 Hz, 2
H), 5.89–5.82 (m, 1 H), 5.35 (d, J = 17.1 Hz, 1 H), 5.27 (d, J =
10.2 Hz, 1 H), 5.20 (br. s, 1 H), 4.81 (dd, J = 15.4, 4.7 Hz, 1 H),
4.65 (dd, J = 15.4, 4.7 Hz, 1 H), 4.31 (dd, J = 17.2, 5.4 Hz, 1 H),
4.06 (q, J = 7.0 Hz, 2 H), 3.96 (dd, J = 17.2, 5.4 Hz, 1 H), 2.21–
2.13 (m, 1 H), 2.12–2.03 (m, 1 H), 1.71–1.61 (m, 1 H), 1.46 (t, J =
7.0 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 202.0, 168.2, 155.1, 145.2, 135.1, 133.9, 133.2,
131.9, 129.8, 129.3, 119.7, 119.0, 114.8, 106.2, 66.7, 64.9, 53.6, 49.8,
39.9, 25.4, 23.2, 23.1, 15.4 ppm. MS (DI, CI NH3): m/z = 488. IR
[2]
a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbrückner, Angew. Chem.
1959, 71, 386; b) I. Ugi, C. Steinbrückner, Angew. Chem. 1960,
72, 267–268. For recent applications of Ugi reactions, see: c)
M. C. Pirrung, K. D. Sarma, J. Am. Chem. Soc. 2004, 126,
444–445; d) F. Bonnaterre, M. Bois-Choussy, J. Zhu, Org. Lett.
2006, 8, 4351–4354; e) A. Ilyin, V. Kysil, M. Krasavin, I. Kur-
ashvili, A. V. Ivachtchenko, J. Org. Chem. 2006, 71, 9544–9547;
f) Q. Lin, J. C. O’Neill, H. E. Blackwell, Org. Lett. 2005, 7,
4455–4458; g) M. Sanudo, S. Marcaccini, S. Basurto, T. Tor-
roba, J. Org. Chem. 2006, 71, 4578–4584; h) Z. Ma, Z. Xiang,
T. Luo, K. Lu, Z. Xu, J. Chen, Z. Yang, J. Comb. Chem. 2006,
8, 696–704.
G. Zinner, D. Moderhack, W. Kliegel, Chem. Ber. 1969, 102,
2536; D. Moderhack, Justus Liebigs Ann. Chem. 1973, 359; G.
Zinner, D. Moderhack, O. Hantelmann, W. Bock, Chem. Ber.
1974, 107, 2947; A. Basso, L. Banfi, G. Guanti, R. Riva, Tetra-
hedron Lett. 2005, 46, 8003–8006.
I. Ugi, F. Bodesheim, Justus Liebigs Ann. Chem. 1963, 666, 61;
T. Torroba, G. Zinner, W. Bock, Arch. Pharm. 1973, 306, 94–
96; S. Zinner, W. Bock, Arch. Pharm., Ber. Dtsch. Pharm. Ges.
1971, 304, 933–935; S. Marcaccini, R. Pepino, C. Polo, M.
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cini, R. Pepino, C. Polo, T. Torroba, Synthesis 2003, 5, 691–
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71, 4578–4584.
[3]
[4]
(thin film): ν = 2356, 1520, 1463, 1224 cm–1. HRMS: calcd. for
˜
C25H30ClN3OS2 487.1519; found 487.1498.
2-[(4-Chlorobenzyl)(6-ethoxybenzo[d]thiazol-2-yl)amino]-N-cyclo-
hexyl-4-methylpentanethioamide: See Table 7, Entry 18; yield (90 °C
1
in toluene for 16 h): 32% (169 mg). H NMR (CDCl3, 400 MHz):
δ = 9.97 (br. s, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.30 (s, 4 H), 7.10
(d, J = 2.5 Hz, 1 H), 6.95 (dd, J = 8.8, 2.5 Hz, 1 H), 5.13 (br. s, 1
H), 4.89 (d, J = 17.2 Hz, 1 H), 4.57 (d, J = 17.2 Hz, 1 H), 5.28–
4.38 (m, 1 H), 4.04 (d, J = 7.0 Hz, 2 H), 2.21–2.14 (m, 1 H), 2.01–
1.95 (m, 2 H), 1.88–1.83 (m, 1 H), 1.69–1.64 (m, 1 H), 1.59–1.53
(m, 2 H), 1.44 (t, J = 7.0 Hz, 3 H), 1.39–1.21 (m, 6 H), 0.88 (d, J
= 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 199.4,
168.2, 155.2, 145.3, 135.8, 133.8, 132.0, 129.1, 119.7, 115.2, 106.1,
68.5, 64.6, 54.8, 53.8, 40.0, 31.3, 30.9, 25.9, 25.5, 24.3, 23.1, 23.0,
[5]
I. Ugi, Angew. Chem. 1960, 72, 639; I. Ugi, C. Steinbruckner,
Chem. Ber. 1961, 94, 734–742.
[6]
[7]
I. Ugi, K. Offermann, Chem. Ber. 1964, 97, 2276–2281.
I. Ugi, F. K. Rosendahl, Justus Liebigs Ann. Chem. 1963, 670,
80–82; I. Ugi, F. K. Rosendahl, F. Bodensheim, Justus Liebigs
Ann. Chem. 1963, 666, 54–57.
I. Ugi, C. Steinbruckner, Angew. Chem. 1960, 72, 267.
S. Heck, A. Doemling, Synlett 2000, 424–426.
15.3 ppm. MS (DI, CI NH ): m/z = 530. IR (thin film): ν = 2361,
˜
3
1521, 1463, 1224 cm–1. HRMS: calcd. for C28H36ClN3OS2
[8]
[9]
529.1988; found 529.1984.
5986
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5974–5987

Thiols in Ugi- and Passerini–Smiles-Type Couplings
[10] L. El Kaim, L. Grimaud, J. Oble, Angew. Chem. Int. Ed. 2005,
44, 7961–7964; L. El Kaim, M. Gizolme, L. Grimaud, J. Oble,
J. Org. Chem. 2007, 72, 4169–4180.
[11] L. El Kaim, M. Gizolme, L. Grimaud, J. Oble, Org. Lett. 2006,
8, 4019–4021; L. El Kaim, M. Gizolme, L. Grimaud, J. Oble,
Synlett 2007, 465–469.
[12] We have already observed improvements in Ugi–Smiles coup-
lings between nitrophenols, isocyanides, amines and aromatic
aldehyde by adding Lewis acids such as magnesium perchlo-
rate. For previous examples, see ref.[9]
[13] L. El Kaim, M. Gizolme, L. Grimaud, J. Oble, J. Org. Chem.
2007, 72, 5835–5838.
[14]
[15]
J. Kolb, B. Beck, A. Dömling, Tetrahedron Lett. 2002, 43,
6897–6901; U. Schöllkopf, H. Porsch, H. H. Lau, Liebigs Ann.
Chem. 1979, 95.
H. C. Koppel, R. H. Springer, R. K. Robins, C. C. Cheng, J.
Org. Chem. 1961, 26, 792–803.
[16] A. Barthelon, A. Dos Santos, L. El Kaïm, L. Grimaud, Tetra-
hedron Lett. 2008, 49, 3208–3211.
[17] L. El Kaim, M. Gizolme, L. Grimaud, J. Oble, Synlett 2007,
465–469.
Received: September 5, 2008
Published Online: October 31, 2008
Eur. J. Org. Chem. 2008, 5974–5987
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5987