Two sequential multicomponent reactions: Synthesis of thiazolidin-4-yl-1,3, 4-oxadiazoles under mild conditions

Article abstract of DOI:10.1055/s-0033-1341043

This work describes the synthesis of compounds including both thiazolidine and 1,3,4-oxadiazole heterocyclic systems. The preparation is realized following a new synthesis route consisting of two multicomponent reactions. First 3-thiazolines are formed by an Asinger four-component reaction. Conversion of these cyclic imines into α-amino-1,3,4-oxadiazoles is subsequently achieved by a three-component reaction involving (isocyanoimino) triphenylphosphorane and a carboxylic acid. The synthesis route is characterized by mild reaction conditions and it tolerates many functional groups. As shown by the conversion into urea derivatives the prepared α-amino-1,3,4- oxadiazoles are marked by their potential in subsequent reactions.

Full text of DOI:10.1055/s-0033-1341043

PAPER
▌1603
paper
Two Sequential Multicomponent Reactions: Synthesis of Thiazolidin-4-yl-
1,3,4-oxadiazoles under Mild Conditions
Thiazolidin-4-yl-1,3,4-oxadiazoles
Fabian Brockmeyer, David van Gerven, Wolfgang Saak, Jürgen Martens*
Institut für Chemie, Carl von Ossietzky Universität Oldenburg, P.O. Box 2503, 26111 Oldenburg, Germany
E-mail: juergen.martens@uni-oldenburg.de
Received: 29.01.2013; Accepted after revision: 26.02.2014
nent reactions (MCR) are a feasible and efficient way to
Abstract: This work describes the synthesis of compounds includ-
synthesize various heterocyclic compounds by the simul-
ing both thiazolidine and 1,3,4-oxadiazole heterocyclic systems.
taneous formation of two or more bonds.16 Processes that
involve two or more consecutive multicomponent reac-
The preparation is realized following a new synthesis route consist-
ing of two multicomponent reactions. First 3-thiazolines are formed
by an Asinger four-component reaction. Conversion of these cyclic tions construct complex products with enormous diversity
in only a few steps, and they are particularly convenient.17
imines into α-amino-1,3,4-oxadiazoles is subsequently achieved by
a three-component reaction involving (isocyanoimino)triphenyl-
phosphorane and a carboxylic acid. The synthesis route is character-
Accordingly, we performed the described synthesis of α-
amino-1,3,4-oxadiazoles for the first time as a 3-CR with
imines that were preformed by a MCR (Scheme 1). The
Asinger reaction is a well-known and commonly used 4-
CR for the construction of heterocyclic imines.18 Follow-
ing the modified Asinger reaction, 2,5-dihydrothiazoles
(3-thiazolines) are prepared by the treatment of α-chloro
aldehydes with a carbonyl compound, ammonia, and so-
dium hydrosulfide.19
ized by mild reaction conditions and it tolerates many functional
groups. As shown by the conversion into urea derivatives the pre-
pared α-amino-1,3,4-oxadiazoles are marked by their potential in
subsequent reactions.
Key words: heterocycles, imines, multicomponent reaction, ring
closure, polycycles
In the last two decades interest has grown distinctly in
compounds that contain the heterocyclic 1,3,4-oxadiazole
skeleton. This is reflected in the number of reports ap-
proaching the synthesis of novel 1,3,4-oxadiazole deriva-
tives and the investigation of their chemical and biological
behavior.1 1,3,4-Oxadiazole-containing substrates are
known for their antimicrobial,2 anti-inflammatory,3 anti-
convulsant,4 analgesic,3b,c,5 diuretic,6 antitumor,7 antivi-
ral,2d,8 and antihypertensive9 activities. Raltegravir,
commonly used as antiretroviral drug for the treatment of
HIV infection, is one example of the application of 1,3,4-
oxadiazole derivatives.10 The substructure of 1,3,4-oxadi-
azole is often used as bioisostere of carboxylic acids, es-
ters, and carboxamides in pharmaceuticals; thereby,
bioavailability and binding selectivity and strength are
amplified.1,11 Beyond that, 1,3,4-oxadiazole derivatives
are valuable as scintillators12 or in the development of
light-emitting diodes13 and optical brighteners14 due to
their electron properties and fluorescence behavior.
N
R5
N
O
MCR
MCR
N
NH
O
R1
R2
R1
R2
R3
R4
R1
R2
R3
R4
S
S
Cl
Scheme 1 Retrosynthetic consideration of the target structures
In addition to this handy synthesis, we selected 3-thiazo-
lines as preformed imines due to the pharmacological rel-
evance of their corresponding cyclic amines (i.e., 3-
thiazolidines).20–22 3-Thiazolidine derivatives are sub-
structures of penicillins20 and diabetes mellitus drugs,21
among other bioactive compounds.22 One similar com-
pound bearing the 1,3,4-oxadiazole substructure was pre-
viously synthesized in several steps via
a
cyclodehydration of an diacyl hydrazide.23 There are ex-
amples of potential pharmacological useful 3-thiazoli-
dines bearing a carboxamido group in the α-position to the
amine, e.g. antimalarial 4-{N-[2-(quinolin-4-ylami-
no)ethyl]carbamoyl}thiazolidines.22a By utilizing the bio-
isosterism concept, the 1,3,4-oxadiazole-based structural
analogues may be more advantageous.
Ramazani and co-workers reported a four-component re-
action (4-CR) for the preparation of 2,5-disubstituted
α-amino-1,3,4-oxadiazoles.15 An amine and a carbonyl
compound, forming an imine, are treated with a carboxyl-
ic acid and the bifunctional (isocyanoimino)triphe-
nylphosphorane to construct the α-amino-1,3,4-
oxadiazole skeleton. Aside from the formation of the im-
ine, the Ramazani 4-CR is composed of an Ugi 4-CR and
an intramolecular aza-Wittig cyclization.15 Multicompo-
Hence, novel products of the synthesis route containing
both the 3-thiazolidine and the 1,3,4-oxadiazole substruc-
ture are characterized by a high chemical diversity and a
potential pharmacological activity.
By means of the modified Asinger reaction19 five different
3-thiazolines 1 were prepared as preformed imines for
synthesis of 1,3,4-oxadiazoles by a 3-CR. Analogous to
the common procedure,19 the imines 1 were synthesized in
moderate to very good yields (up to 88%) by the reaction
SYNTHESIS 2014, 46, 1603–1612
Advanced online publication: 26.03.2014
DOI: 10.1055/s-0033-1341043; Art ID: SS-2014-T0076-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1604
F. Brockmeyer et al.
PAPER
of α-chloro aldehydes with the respective ketone, aqueous
ammonia solution, and sodium hydrosulfide in dichloro-
methane. α-Chloro aldehydes are readily available start-
ing from the respective aldehydes.27
Table 2 Optimization of Reaction Conditions To Prepare 2a
PPh3
N
O
N
N
C
N
OH
Besides the previously reported 3-thiazolines 1a–c,e,
herein we report the synthesis of the novel compound 1d
(Table 1).
O
NH
N
S
S
1a
2a
Table 1 Synthesis of 3-Thiazolines 1
NH3
Entry
Solvent
Ratio 1a/acid/ Temp
Time
(h)
Yielda
(%)
R3
R4
N
isocyanide
(°C)
O
CH2Cl2
R1
R2
R1
R2
R3
R4
O
Cl
S
5 °C to r.t., 16 h
1
2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeOH
THF
1:1:1
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
reflux
0
36
36
36
36
36
36
60
15
6
27
46
45
46
–
NaSH
1
1:1.2:1.2
1:1.4:1.4
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
Entry
R1
R2
R3
R4
Product Yielda
(%)
3
4
1
2
3
4
5
Me
Me
Me
Me
Me
Me
Me
1a
1b
1c
1d
1e
8824
6625
5719d
60
5
Me
(CH2)5
6
60
61
65
49
27
60
62
Me
(CH2)2O(CH2)2
(CH2)2S(CH2)2
(CH2)5
7
THF
Me
8
THF
(CH2)5
6826
9
THF
a All yields are isolated yields.
10
11
12
THF
15
72
We began our investigation of the conversion of the cyclic
imines 1 into 1,3,4-oxadiazole derivatives 2 via a 3-CR by
choosing the reaction of 3-thiazoline 1a with benzoic acid
and (isocyanoimino)triphenylphosphorane as a model re-
action (Table 2). Initially, we examined reaction condi-
tions based on those used by Ramazani15 and co-workers.
To our delight, the conversion of 3-thiazoline 1a in di-
chloromethane at room temperature using a reaction time
of 36 hours led to the desired 1,3,4-oxadiazole 2a (entry
1). Raising the number of molar equivalents of the acid
and the isocyanide to 1.2 improved the yield from 27% to
46% (entry 2).
THF
THF
r.t.
5, 10b
a All yields are isolated yields.
b Imine 1a and (isocyanoimino)triphenylphosphorane were stirred for
5 h before the addition of benzoic acid.
yield gained without a pre-reaction time. Thus, the opti-
mal reaction conditions are as follows: 1a (1.0 equiv),
benzoic acid (1.2 equiv), (isocyanoimino)triphenyl-
phosphorane (1.2 equiv), tetrahydrofuran, room tempera-
ture, 15 hours.
Next, the effect of the solvent on the yield was studied. Of
the solvents examined, tetrahydrofuran was found to give
highest yield (60%) of 1,3,4-oxadiazole 2a (entry 6). Fur-
ther screening of the reaction time revealed that 15 hours
are ideal (entry 8); longer or shorter reaction times led to
lower yields (entries 7 and 9). Utilizing the optimal reac-
tion time, the yield of 2a increased to 65%. Examining
various reaction temperatures (entries 8, 10, and 11)
showed that the reaction takes place best at room temper-
ature; increasing or decreasing the temperature did not im-
prove the yield. Due to the observed formation of the
known28 byproduct 2-phenyl-1,3,4-oxadiazole in all ex-
periments run during the optimization period, we stirred
3-thiazoline 1a and (isocyanoimino)triphenylphospho-
rane in tetrahydrofuran for five hours before the addition
of benzoic acid (entry 12) in an additional experiment.
However, it transpired that the conversion of the 3-thiazo-
line 1a does not begin before addition of the acid, with the
result that the yield was comparatively identical with the
After having identified the optimal reaction conditions
(Table 2, entry 8), we applied this method to various 3-thi-
azolines 1 and carboxylic acids. The results are summa-
rized in Table 3. All five different 3-thiazolines 1 could be
converted into the desired 1,3,4-oxadiazoles 2 using ben-
zoic acid (entries 1–5). This underlines the feasibility of
the preparation of α-amino-1,3,4-oxadiazoles 2 by a 3-CR
applying preformed imines, which has not been previous-
ly reported. Concomitantly, cyclic imines were converted
in this MCR for the first time, so that polycyclic 1,3,4-
oxadiazoles 2 were obtained.
The scope of the carboxylic acid was expanded likewise.
Both electron-rich and electron-poor aromatic acids led to
the formation of 1,3,4-oxadiazoles 2 (entries 7 and 8). It
was found that the aromatic acid bearing an electron-
donating group was more reactive than those without a
substituent or with an electron-withdrawing group, so that
the use of 2-methoxybenzoic acid led to a relatively high
yield (entry 7, 71%). Above and beyond aromatic acids,
Synthesis 2014, 46, 1603–1612
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolidin-4-yl-1,3,4-oxadiazoles
1605
Table 3 Three-Component Reaction To Give 1,3,4-Oxadiazole Derivatives 2
PPh3
N
R5
O
N
N
R5
C
N
OH
O
THF
NH
N
R3
R4
R1
R2
R3
R4
R1
R2
r.t., 15 h
S
S
1
2
Entry
Substrate
R1
R2
R3
R4
R5
Product
Yielda (%)
1
2
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1d
1a
1a
1a
1a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
65
95
58
80
70
52
71
41
28
32
27
65
54
41
(CH2)5
Ph
3
(CH2)2O(CH2)2
Ph
4
(CH2)2S(CH2)2
Ph
5
(CH2)5
(CH2)5
Ph
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH=CHPh
2-MeOC6H4
2-O2NC6H4
Me
7
Me
2g
2h
2i
8
Me
9
Me
10
11
12
13
14
15
16
17
Me
(CH2)2SH
CH=CH2
(CH2)8CH=CH2
3-MeOC6H4CH2
CH2Br
2j
Me
2k
2l
Me
(CH2)2S(CH2)2
2m
2n
–
Me
Me
Me
Me
Me
Me
Me
Me
b
(CH2)2NH2
(CH2)2NH2·HCl
(CH2)2NHFmoc
–
b
–
–
2o
62
a All yields are isolated yields.
b No product was observed.
alkanecarboxylic acids were converted into the respective come by protecting the primary amino group with
1,3,4-oxadiazoles
using (isocyanoimino)triphe- FmocCl29 (entry 17). After deprotection the 1,3,4-oxadi-
2
nylphosphorane for the first time (entries 9–17). This re- azole 2p bearing a primary amino group is accessible
sult expands the diversity of the described 3-CR based on (Scheme 2).
the Ramazani 4-CR tremendously. Due to the fact that
Lee11 and co-workers reported in the context of the devel-
NHFmoc
NH2
opment of new potent drugs for the treatment of obesity
that alkyl-substituted 1,3,4-oxadiazoles are characterized
by a much higher receptor binding affinity than aryl-
substituted 1,3,4-oxadiazoles, the applicability of alkane-
carboxylic acids seems to be valuable.
N
N
N
N
N
H
O
O
NH
NH
CH2Cl2
r.t., 70 h
S
S
2o
2p 84%
Furthermore, several functional groups, e.g. thiol, alke-
nyl, ether, and alkyl halides, were tolerated in this reac-
tion. As a result, the prepared 1,3,4-oxadiazoles 2 may act
as scaffolds for subsequent reactions.
Scheme 2 Deprotection of 1,3,4-oxadiazole 2o to access primary
amine 2p
However, the desired product 2 was not observed when
using the amino acid β-alanine or its hydrochloride (en-
tries 15 and 16). Fortunately, this limitation can be over-
In addition to functional groups introduced by the carbox-
ylic acid, the prepared 1,3,4-oxadiazoles 2 bear a reactive
amino group in the α-position. With reference to potential
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1603–1612

1606
F. Brockmeyer et al.
PAPER
pharmaceuticals featuring a urea group in the α-position
to an amide or its bioisostere,30 we converted the α-amino-
1,3,4-oxadiazoles 2 into urea derivatives 3. Treatment of
the α-amino-1,3,4-oxadiazoles 2 with isocyanates31 in di-
chloromethane gave the respective urea derivatives 3 (Ta-
ble 4).
Table 4 Formation of Urea Derivatives 3
F3C
CF3
N
N
R5
R5
N
HN
N
N
OCN
O
O
O
NH
R3
R4
R3
R4
R1
R2
R1
R2
CH2Cl2
r.t., 72 h
S
S
2
3
Figure 1 X-ray crystal structure of racemic α-carbamido-1,3,4-oxa-
diazole 3b (only one enantiomer is shown);32 the atom numbering
does not follow IUPAC nomenclature
Entry Substrate R1–R4 R5
Product Yield (%)a
1b
2b
3c
2a
2j
2j
Me
Me
Me
Ph
3a
3b
85
76
91
vices) and are uncorrected. 1H and 13C NMR spectra were recorded
with Bruker AM 300 [300.1 MHz (1H), 75.5 MHz (13C)], Bruker
AMX R 500 [500.1 MHz (1H), 125.8 MHz (13C)], or Bruker Avance
III 500 [499.9 MHz (1H), 125.7 MHz (13C)] spectrometers in CDCl3
solution; the signal of the residual non-deuterated solvent was used
[δ = 7.26 (1H), 77.16 (13C)] as internal standard.33 Assignments of
the signals were supported by measurements applying DEPT and
COSY techniques. Mass spectra were obtained on Waters Q-TOF
Premier (ESI) or Finnigan MAT 95 (CI) spectrometers. IR spectra
were recorded with a Bruker Tensor 27 spectrophotometer
equipped with a Golden Gate diamond-ATR (attenuated total re-
flection) unit. 2-Chloro-2-methylpropanal,27 1-chlorocyclohexane-
carbaldehyde,34 and (isocyanoimino)triphenylphosphorane35 were
prepared according to published procedures. CH2Cl2 was refluxed
with CaH and freshly distilled prior to use. THF was refluxed with
Na and freshly distilled prior to use.
(CH2)2SH
(CH2)2S(C=O)NH 3c
(3-CF3C6H4)
a All yields are isolated yields.
b The reaction was performed with an amine/isocyanate ratio of 1:1.
c The reaction was performed with an amine/isocyanate ratio of 1:2.
Conversion of 1,3,4-oxadiazole 2j bearing a thiol moiety
with one equivalent of isocyanate results in a regioselec-
tive reaction at the amino nitrogen (product 3b). An in-
crease to two equivalents of isocyanate led to the
conversion of both reactive groups (i.e., amino and thiol
group), with the result that compound 3c was formed.
3-Thiazolines 1; General Procedure (GP A)
Gratifyingly, we were able to obtain single crystals of 3b
to verify the proposed structure of the urea derivatives and
as a consequence thereof the structure of the α-amino-
1,3,4-oxadiazoles 2 by X-ray crystal structure analysis
(Figure 1) in addition to NMR, IR, and mass analysis.
The ketone and NaSH·H2O were dissolved in 25% aq NH3 solution.
The α-chloro aldehyde was added dropwise at 5–10 °C. The solu-
tion was diluted with CH2Cl2 (0.25 mL per mmol α-chloro alde-
hyde) and then it was stirred for 16 h at r.t. The phases were
separated and the aqueous phase was extracted with CH2Cl2 (2 × 5
mL per mmol α-chloro aldehyde). The recombined organic phases
were dried (MgSO4) and the solvent was removed on a rotary evap-
orator. The crude product was purified by column chromatography
(silica gel), recrystallization, or distillation.
In conclusion, we succeeded in the synthesis of new α-
amino-1,3,4-oxadiazoles applying preformed cyclic im-
ines in a 3-CR. The preparation of the cyclic imines was
achieved by a 4-CR. Due to the mild reaction conditions
and the toleration of many functional groups, the reported
novel multicomponent reaction sequence allows the prep-
aration of manifold products. We also presented the po-
tential of these new α-amino-1,3,4-oxadiazoles in
subsequent reactions. Based on the pharmacological rele-
vance of their structural elements, all products of the de-
veloped synthesis route could be useful in medicinal
research.
2,2,5,5-Tetramethyl-2,5-dihydrothiazole (1a)24
Following GP A using acetone (21.84 g, 0.376 mol), NaSH·H2O
(13.92 g, 0.188 mol), 25% aq NH3 solution (25.61 g, 0.376 mol),
and 2-chloro-2-methylpropanal (20.03 g, 0.188 mol). The crude
product was purified by recrystallization (n-hexane) to give a
colorless solid; yield: 23.62 g (88%); mp 52 °C; Rf = 0.56 (EtOAc–
n-hexane, 1:1).
1H NMR (500.1 MHz, CDCl3): δ = 1.56, 1.68 [2 s, 12 H, C(CH3)2],
6.89 (s, 1 H, NCH).
2,2-Dimethyl-1-thia-4-azaspiro[4.5]dec-3-ene (1b)25
Following GP A using cyclohexanone (29.45 g, 0.300 mol),
NaSH·H2O (22.21 g, 0.300 mol), 25% aq NH3 solution (21.80 g,
0.320 mol), and 2-chloro-2-methylpropanal (21.31 g, 0.200 mol).
The crude product was purified by fractional distillation (76 °C/
1 mbar) to give a colorless oil; yield: 24.18 g (66%); Rf = 0.61
(EtOAc–n-hexane, 1:1).
Synthetic procedures, performed under an argon atmosphere, were
performed on a vacuum line using standard Schlenk techniques.
Preparative column chromatography was carried out using Grace
silica gel (0.035–0.070 mm, type KG 60). TLC was performed on
Machery-Nagel silica gel F254 plates on aluminum sheets. Melting
points were obtained on a melting point apparatus (Laboratory De-
Synthesis 2014, 46, 1603–1612
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolidin-4-yl-1,3,4-oxadiazoles
1607
1H NMR (500.1 MHz, CDCl3): δ = 1.22–1.35 (m, 1 H, CH2), 1.40–
1.66 (m, 3 H, CH2), 1.52 [s, 6 H, C(CH3)2], 1.73–1.83 (m, 4 H, CH2),
1.96–2.06 (m, 2 H, CH2), 6.96 (s, 1 H, NCH).
13C NMR (125.8 MHz, CDCl3): δ = 27.8, 28.1, 32.5, 33.5 [2
C(CH3)2], 61.3 [SC(CH3)2CH], 67.2 (NCH), 73.2 [SC(CH3)2N],
123.6 (CArC=N), 127.1 (2 o-CHArC), 129.3 (2 m-CHArC), 132.1 (p-
CHArC), 163.1 (CHC=N), 165.1 (CArC=N).
MS (CI, isobutane): m/z (%) = 290.2 (100) [M + H]+.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C15H20N3OS:
2,2-Dimethyl-8-oxa-1-thia-3-azaspiro[4.5]dec-3-ene (1c)19d
Following GP A using tetrahydro-4H-pyran-4-one (4.380 g, 43.75
mmol), NaSH·H2O (3.240 g, 43.75 mmol), 25% aq NH3 solution
(3.725 g, 54.69 mmol), and 2-chloro-2-methylpropanal (3.885 g,
36.46 mmol). The crude product was purified by recrystallization
(n-hexane) to give a colorless solid; yield: 3.856 g (57%); mp 45 °C;
Rf = 0.30 (EtOAc–n-hexane, 1:1).
1H NMR (500.1 MHz, CDCl3): δ = 1.55 [s, 6 H, C(CH3)2], 1.80–
1.83 [m, 2 H, C(CH2)2], 2.20–2.26 [m, 2 H, C(CH2)2], 3.59–3.63 [m,
2 H, O(CH2)2], 3.98–4.02 [m, 2 H, O(CH2)2], 7.03 (s, 1 H, NCH).
290.1327; found: 290.1331.
(RS)-2-(2,2-Dimethyl-1-thia-4-azaspiro[4.5]decan-3-yl)-5-phe-
nyl-1,3,4-oxadiazole (2b)
Following GP B using 1b (367 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and benzoic acid (293
mg, 2.40 mmol). The crude product was purified by column chro-
matography (CH2Cl2–EtOAc, 19:1) to give a colorless solid; yield:
622 mg (95%); mp 123 °C; Rf = 0.34 (CH2Cl2–EtOAc, 19:1).
2,2-Dimethyl-1,8-dithia-4-azaspiro[4.5]dec-3-ene (1d)
Following GP A using tetrahydro-4H-thiopyran-4-one (3.000 g,
25.82 mmol), NaSH·H2O (1.912 g, 25.82 mmol), 25% aq NH3 so-
lution (2.199 g, 32.28 mmol), and 2-chloro-2-methylpropanal
(2.476 g, 23.24 mmol). The crude product was purified by column
chromatography (CH2Cl2–EtOAc, 14:1) to give a colorless solid;
yield: 3.143 g (60%); mp 48 °C; Rf = 0.42 (CH2Cl2–EtOAc, 14:1).
IR (ATR): 3314, 3054, 2960, 2927, 2849, 1608, 1588, 1565, 1551,
1515, 1484, 1462, 1450, 1390, 1369, 1148, 1137, 1109, 1087, 1069,
894, 864, 851, 829 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.17 [s, 3 H, C(CH3)2], 1.25–
1.33 (m, 1 H, CH2,Cy), 1.42–1.52 (m, 2 H, CH2,Cy), 1.53–1.58 (m, 1
H, CH2,Cy), 1.67 [s, 3 H, C(CH3)2], 1.74–1.85 (m, 3 H, CH2,Cy),
1.91–2.00 (m, 2 H, CH2,Cy), 2.02–2.07 (m, 1 H, CH2,Cy), 3.84 (br s,
1 H, NH), 4.60 (s, 1 H, NCH), 7.50–7.57 (m, 3 H, 2 m-CHArC, p-
CHArC), 8.05–8.06 (m, 2 H, 2 o-CHArC).
13C NMR (125.8 MHz, CDCl3): δ = 23.7, 25.3, 25.5 (CH2,Cy), 28.0,
28.0 [C(CH3)2], 41.8, 41.8 (CH2,Cy), 58.7 [SC(CH3)2CH], 66.3
(NCH), 79.0 [SC(CH2)2N], 123.7 (CArC=N), 127.1 (2 o-CHArC),
129.3 (2 m-CHArC), 132.1 (p-CHArC), 163.4 (CHC=N), 165.1
(CArC=N).
IR (ATR): 2947, 2913, 1693, 1436, 1422, 1410, 1319, 1294, 1278,
1214, 1127, 987, 976, 937, 751 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.54 [s, 6 H, C(CH3)2], 2.01–
2.05 [m, 2 H, C(CH2)2], 2.31–2.36 [m, 2 H, C(CH2)2], 2.76–2.78 [m,
4 H, S(CH2)2], 7.00 (s, 1 H, NCH).
13C NMR (125.8 MHz, CDCl3): δ = 26.7 [S(CH2)2], 30.3 [C(CH3)2],
42.9 [2 C(CH2)2], 63.8 [SC(CH3)2CH], 94.6 [SC(CH2)2N], 166.5
(NCH).
MS (ESI): m/z (%) = 330.2 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N3OS: 330.1640;
MS (ESI): m/z (%) = 202.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C9H16NS2: 202.0724; found:
found: 330.1632.
202.0726.
(RS)-2-(2,2-Dimethyl-8-oxa-1-thia-4-azaspiro[4.5]decan-3-yl)-
5-phenyl-1,3,4-oxadiazole (2c)
7-Thia-14-azadispiro[5.1.5.2]pentadec-14-ene (1e)26
Following GP A using cyclohexanone (29.45 g, 0.300 mol),
NaSH·H2O (11.11 g, 0.150 mol), 25% aq NH3 solution (20.44 g,
0.300 mol), and 1-chlorocyclohexanecarbaldehyde (21.99 g, 0.150
mol). The crude product was purified by fractional distillation
(110 °C, 0.07 mbar) to give a colorless oil; yield: 22.78 g (68%);
Rf = 0.67 (EtOAc–n-hexane, 1:1).
Following GP B using 1c (371 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and benzoic acid (293
mg, 2.40 mmol). The crude product was purified by column chro-
matography (n-hexane–EtOAc, 4:1) to give a colorless solid; yield:
384 mg (58%); mp 143 °C; Rf = 0.17 (n-hexane–EtOAc, 4:1).
IR (ATR): 3296, 3065, 2960, 2922, 2850, 1963, 1610, 1588, 1567,
1553, 1483, 1450, 1417, 1371, 1262, 1248, 1147, 1138, 1121, 1099,
1081, 1069, 993, 862, 846, 822, 748, 733 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.17–1.33 (m, 2 H, CH2), 1.48–
1.85 (m, 16 H, CH2), 1.97–2.02 (m, 2 H, CH2), 6.99 (s, 1 H, NCH).
1H NMR (500.1 MHz, CDCl3): δ = 1.17, 1.67 [2 s, 6 H, C(CH3)2],
1.95–1.99 [m, 1 H, C(CH2)2], 2.01–2.03 [m, 2 H, C(CH2)2], 2.12–
2.17 [m, 1 H, C(CH2)2], 3.37 (br s, 1 H, NH), 3.54–3.59 [m, 2 H, 2
O(CH2)2], 3.92–3.99 [m, 2 H, 2 O(CH2)2], 4.56 (s, 1 H, NCH), 7.49–
7.56 (m, 3 H, 2 m-CHArC, p-CHArC), 8.03–8.04 (m, 2 H, 2 o-
CHArC).
13C NMR (125.8 MHz, CDCl3): δ = 27.9 [C(CH3)2], 41.4, 42.1
[C(CH2)2], 59.4 [SC(CH3)2CH], 65.6 (OCH2), 66.1 (NCH), 66.6
(OCH2), 75.5 [SC(CH2)2N], 123.5 (CArC=N), 127.0 (2 o-CHArC),
129.2 (2 m-CHArC), 132.1 (p-CHArC), 162.9 (CHC=N), 165.1
(CArC=N).
1,3,4-Oxadiazoles 2; General Procedure (GP B)
Under an argon atmosphere, the 3-thiazoline 1 (1 equiv) and (isocy-
anoimino)triphenylphosphorane (1.2 equiv) were dissolved in an-
hyd THF (5 mL per mmol 3-thiazoline). A solution of the
carboxylic acid (1.2 equiv) in anhyd THF (5 mL per mmol 3-thia-
zoline) was added dropwise. The mixture was stirred for 15 h at r.t.,
and then the solvent was removed on a rotary evaporator. The crude
product was purified by column chromatography (silica gel).
(RS)-2-Phenyl-5-(2,2,5,5-tetramethylthiazolidin-4-yl)-1,3,4-
oxadiazole (2a)
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and benzoic acid (293
mg, 2.40 mmol). The crude product was purified by column chro-
matography (CH2Cl2–EtOAc, 19:1) to give a colorless solid; yield:
376 mg (65%); colorless solid; mp 84 °C; Rf = 0.32 (CH2Cl2–
EtOAc, 19:1).
MS (ESI): m/z (%) = 354.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21N3NaO2S: 354.1252;
found: 354.1241.
(RS)-2-(2,2-Dimethyl-1,8-dithia-4-azaspiro[4.5]decan-3-yl)-5-
phenyl-1,3,4-oxadiazole (2d)
IR (ATR): 3328, 2963, 2929, 1611, 1561, 1552, 1485, 1454, 1429,
1328, 1229, 809, 740, 713 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.18, 1.66, 1.69, 1.75 [4 s, 12 H,
2 C(CH3)2], 3.78 (br s, 1 H, NH), 4.60 (s, 1 H, NCH), 7.50–7.57 (m,
3 H, 2 m-CHArC, p-CHArC), 8.04–8.06 (m, 2 H, 2 o-CHArC).
Following GP B using 1d (604 mg, 3.00 mmol), (isocyanoimino)tri-
phenylphosphorane (1.088 g, 3.60 mmol), and benzoic acid (440
mg, 3.60 mmol). The crude product was purified by column chro-
matography (CH2Cl2–EtOAc, 9:1) to give a colorless solid; yield:
834 mg (80%); mp 139 °C; Rf = 0.48 (CH2Cl2–EtOAc, 9:1).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1603–1612

1608
F. Brockmeyer et al.
PAPER
IR (ATR): 3318, 2956, 2927, 2898, 2863, 1606, 1568, 1556, 1491,
1453, 1391, 1328, 1246, 1195, 1133, 1072, 1024, 876, 846, 820,
756, 694 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.17, 1.66 [2 s, 6 H, C(CH3)2],
2.12–2.17 [m, 1 H, C(CH2)2], 2.19–2.23 [m, 1 H, C(CH2)2], 2.28–
2.33 [m, 2 H, C(CH2)2], 2.68–2.84 [m, 4 H, S(CH2)2], 3.33 (br s, 1
H, NH), 4.58 (s, 1 H, NCH), 7.49–7.57 (m, 3 H, 2 m-CHArC, p-
CHArC), 8.03–8.05 (m, 2 H, 2 o-CHArC).
13C NMR (125.8 MHz, CDCl3): δ = 26.4, 27.7 [S(CH2)2], 27.8, 28.0
[C(CH3)2], 42.6, 42.7 [C(CH2)2], 59.3 [SC(CH3)2CH], 66.2 (NCH),
77.4 [SC(CH2)2N], 123.5 (CArC=N), 127.1 (2 o-CHArC), 129.3 (2
m-CHArC), 132.1 (p-CHArC), 162.9 (CHC=N), 165.1 (CArC=N).
(RS)-2-(2-Methoxyphenyl)-5-(2,2,5,5-tetramethylthiazolidin-4-
yl)-1,3,4-oxadiazole (2g)
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and 2-methoxybenzoic
acid (265 mg, 2.40 mmol). The crude product was purified by col-
umn chromatography (n-hexane–acetone, 9:1) to give a yellow oil;
yield: 454 mg (71%); Rf = 0.50 (n-hexane–acetone, 9:1).
IR (ATR): 3283, 3079, 2968, 2926, 2866, 2841, 1734, 1662, 1607,
1591, 1547, 1480, 1458, 1371, 1286, 1262, 1234, 1143, 1116, 1023,
855, 816, 800, 751, 673 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.15, 1.63, 1.67, 1.72 [4 s, 12 H,
2 C(CH3)2], 3.46 (br s, 1 H, NH), 3.91 (s, 3 H, OCH3), 4.58 (s, 1 H,
NCH), 7.02–7.06 (m, 2 H, 2 m-CHArO), 7.47–7.51 (m, 1 H,
p-CHArO), 7.87–7.89 (m, 1 H, o-CHArO).
13C NMR (125.8 MHz, CDCl3): δ = 27.7, 28.0, 32.5, 33.5 [2
C(CH3)2], 56.0 (OCH3), 61.5 [SC(CH3)2CH], 67.1 (NCH), 73.2
[SC(CH3)2N], 111.9 (p-CHArC), 112.7 (CArC=N), 120.8 (o-CHArC),
130.6 (o-CHArO), 133.4 (p-CHArO), 157.9 (CArO), 162.8 (CHC=N),
163.8 (CArC=N).
MS (ESI): m/z (%) = 370.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21N3NaOS2: 370.1024;
found: 370.1034.
(RS)-2-Phenyl-5-(7-thia-14-azadispiro[5.1.5.2]pentadecan-15-
yl)-1,3,4-oxadiazole (2e)
Following GP B using 1e (447 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and benzoic acid (293
mg, 2.40 mmol). The crude product was purified by column chro-
matography (CH2Cl2–EtOAc, 19:1) to give a colorless solid; yield:
513 mg (70%); mp 177 °C; Rf = 0.48 (CH2Cl2–EtOAc, 19:1).
MS (ESI): m/z (%) = 342.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C16H21N3NaO2S: 342.1252;
found: 342.1257.
IR (ATR): 3312, 3056, 2930, 2858, 2842, 2164, 1609, 1488, 1465,
1450, 1440, 1361, 1326, 1309, 1249, 995, 979, 962, 925 cm–1.
(RS)-2-(2-Nitrophenyl)-5-(2,2,5,5-tetramethyl-1,3-thiazolidin-
4-yl)-1,3,4-oxadiazole (2h)
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and 2-nitrobenzoic acid
(401 mg, 2.40 mmol). The crude product was purified by column
chromatography (CH2Cl2–EtOAc, 9:1) to give a colorless solid;
yield: 274 mg (41%); mp 115 °C; Rf = 0.34 (CH2Cl2–EtOAc, 9:1).
1H NMR (499.9 MHz, CDCl3): δ = 0.82–0.86 (m, 1 H, CH2,Cy),
0.95–1.02 (m, 1 H, CH2,Cy), 1.25–1.32 (m, 1 H, CH2,Cy), 1.36–1.43
(m, 1 H, CH2,Cy), 1.49–1.67 (m, 7 H, 4 CH2,Cy), 1.73–1.85 (m, 4 H,
2 CH2,Cy), 1.87–1.97 (m, 4 H, 2 CH2,Cy), 2.01–2.03 (m, 1 H, CH2,Cy),
4.29 (br s, 1 H, NH), 4.53 (s, 1 H, NCH), 7.49–7.57 (m, 3 H, 2 m-
CHArC, p-CHArC), 8.05–8.06 (m, 2 H, 2 o-CHArC).
13C NMR (125.7 MHz, CDCl3): δ = 23.2, 23.6, 25.3, 25.4, 25.6,
27.0, 35.7, 38.4, 41.5, 41.8 (10 CH2,Cy), 66.3 [SC(CH2)2CH], 66.5
(NCH), 78.00 [SC(CH2)2N], 123.7 (CArC=N), 127.1 (2 o-CHArC),
129.2 (2 m-CHArC), 132.0 (p-CHArC), 163.6 (CHC=N), 165.0
(CArC=N).
IR (ATR): 3309, 3069, 2978, 2929, 2865, 1564, 1524, 1477, 1455,
1434, 1349, 1231, 1101, 1067, 868, 820, 753, 732, 692, 648 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.22, 1.64, 1.65, 1.74 [4 s, 12 H,
2 C(CH3)2], 3.63 (br s, 1 H, NH), 4.56 (s, 1 H, NCH), 7.76–7.82 (m,
2 H, p-CHArC, p-CHArN), 7.94–7.95 (m, 1 H, o-CHArC), 8.11–8.13
(m, 1 H, o-CHArN).
13C NMR (125.8 MHz, CDCl3): δ = 27.7, 27.9, 32.5, 33.5 [2
C(CH3)2], 61.4 [SC(CH3)2CH], 67.1 (NCH), 73.1 [SC(CH3)2N],
118.9 (CArC=N), 125.1 (o-CHArN), 132.3 (o-CHArC), 132.9, 133.6
(p-CHArC, p-CHArN), 148.2 (CArNO2), 162.1 (CHC=N), 164.5
(CArC=N).
MS (ESI): m/z (%) = 392.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H28N3OS: 370.1953;
found: 370.1949.
(RS)-(E)-2-Styryl-5-(2,2,5,5-tetramethylthiazolidin-4-yl)-1,3,4-
oxadiazole (2f)
MS (ESI): m/z (%) = 357.2 (100) [M + Na]+.
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and cinnamic acid (356
mg, 2.40 mmol). The crude product was purified by column chro-
matography (CH2Cl2–EtOAc, 19:1) to give a colorless solid; yield:
324 mg (52%); mp 84 °C; Rf = 0.20 (CH2Cl2–EtOAc, 19:1).
HRMS (ESI): m/z [M + Na]+ calcd for C15H18N4NaO3S: 357.0997;
found: 357.0997.
(RS)-2-Methyl-5-(2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl)-
1,3,4-oxadiazole (2i)
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and acetic acid (144 mg,
2.40 mmol). The crude product was purified by column chromatog-
raphy (n-hexane–THF, 3:2) to give a colorless solid; yield: 125 mg
(28%); mp 66 °C; Rf = 0.37 (n-hexane–THF, 3:2).
IR (ATR): 3440, 3283, 3060, 2967, 2925, 2863, 1644, 1567, 1529,
1450, 1369, 1229, 1183, 1141, 1113, 966, 852, 817, 756, 735, 702,
686, 640 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.16, 1.63, 1.66, 1.72 [4 s, 12 H,
2 C(CH3)2], 3.45 (br s, 1 H, NH), 4.54 (s, 1 H, NCH), 7.00 (d, 3J =
16.5 Hz, 1 H, CHC=N), 7.36–7.41 (m, 3 H, 2 m-CHArC, p-CHArC),
7.50–7.54 (m, 2 H, 2 o-CHArC, CHCAr).
13C NMR (125.8 MHz, CDCl3): δ = 27.7, 28.0, 32.4, 33.4 [2
C(CH3)2], 61.2 [SC(CH3)2CH], 67.0 (NCH), 73.1 [SC(CH3)2N],
109.6 (CHC=N), 127.6 (2 o-CHArC), 129.1 (2 m-CHArC), 130.2 (p-
CHArC), 134.5 (CArC), 139.5 (CHCAr), 162.5 (NCHC=N), 164.5
(C=CHC=N).
IR (ATR): 3276, 2967, 2923, 2864, 1592, 1568, 1453, 1381, 1368,
1343, 1291, 1225, 1199, 1143, 1045, 859, 820, 758, 724, 643, 619
cm–1.
1H NMR (499.9 MHz, CDCl3): δ = 1.09, 1.58, 1.58, 1.67 [4 s, 12 H,
2 C(CH3)2], 2.50 (s, 3 H, CH3C=N), 3.31 (br s, 1 H, NH), 4.44 (s, 1
H, NCH).
13C NMR (125.7 MHz, CDCl3): δ = 11.0 (CH3C=N), 27.6, 27.9,
32.4, 33.4 [2 C(CH3)2], 61.1 [SC(CH3)2CH], 67.0 (NCH), 72.9
[SC(CH3)2N], 163.3 (CHC=N), 163.9 (CH3C=N).
MS (ESI): m/z (%) = 338.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21N3NaOS: 338.1303;
MS (ESI,): m/z (%) = 228.1 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C10H17N3NaOS: 250.0990;
found: 338.1305.
found: 250.0992.
Synthesis 2014, 46, 1603–1612
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Thiazolidin-4-yl-1,3,4-oxadiazoles
MS (ESI): m/z (%) = 374.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H33N3NaOS: 374.2242;
found: 374.2240.
1609
(RS)-2-(2-Sulfanylethyl)-5-(2,2,5,5-tetramethyl-1,3-thiazolidin-
4-yl)-1,3,4-oxadiazole (2j)
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and 3-mercaptopropano-
ic acid (255 mg, 2.40 mmol). The crude product was purified by
column chromatography (CH2Cl2–EtOAc, 4:1) to give a colorless
solid; yield: 171 mg (32%); mp 63 °C; Rf = 0.28 (CH2Cl2–EtOAc,
4:1).
(RS)-2-(2,2-Dimethyl-1,8-dithia-3-azaspiro[4.5]decan-4-yl)-5-
(3-methoxybenzyl)-1,3,4-oxadiazole (2m)
Following GP B using 1d (604 mg, 3.00 mmol), (isocyanoimino)tri-
phenylphosphorane (1.088 g, 3.60 mmol), and 2-(4-methoxyphe-
nyl)acetic acid (598 mg, 3.60 mmol). The crude product was
purified by column chromatography (CH2Cl2–EtOAc, 9:1) to give a
yellow oil; yield: 639 mg (54%); Rf = 0.48 (CH2Cl2–EtOAc, 9:1).
IR (ATR): 3313, 2962, 2924, 2853, 2545, 1588, 1562, 1454, 1396,
1381, 1369, 1228, 1142, 1113, 852, 820, 759, 733, 704, 688, 635
cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.12, 1.62, 1.62 [3 s, 9 H, 2
C(CH3)2], 1.67 (t, 3J = 8.5 Hz, 1 H, SH), 1.72 [s, 3 H, C(CH3)2], 2.96
(td, 3J = 6.9 Hz, 3J = 8.5 Hz, 2 H, CH2SH), 3.19 (t, 3J = 6.9 Hz, 2 H,
CH2C=N), 3.80 (br s, 1 H, NH), 4.50 (s, 1 H, NCH).
13C NMR (125.8 MHz, CDCl3): δ = 21.3 (CH2SH), 27.8, 28.1
[C(CH3)2], 30.1 (CH2C=N), 32.5, 33.4 [C(CH3)2], 61.2
[SC(CH3)2CH], 67.0 (NCH), 73.1 [SC(CH3)2N], 163.5 (CHC=N),
165.3 (CH2C=N).
IR (ATR): 3277, 2960, 2927, 2835, 1600, 1585, 1562, 1491, 1455,
1369, 1259, 1149, 1133, 1042, 962, 910, 768, 730, 691 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.06, 1.56 [2 s, 6 H, C(CH3)2],
2.09–2.14 [m, 1 H, C(CH2)2], 2.16–2.20 [m, 1 H, C(CH2)2], 2.25–
2.30 [m, 2 H, C(CH2)2], 2.67–2.84 [m, 4 H, S(CH2)2], 3.21 (d, 3J =
12.6 Hz, 1 H, NH), 3.81 (s, 3 H, OCH3), 4.18 (d, 2J = 15.7 Hz, 1 H,
CH2CAr), 4.24 (d, 2J = 15.6 Hz, 1 H, CH2CAr), 4.47 (d, 3J = 12.6 Hz,
1 H, NCH), 6.82–6.87 (m, 3 H, 2 o-CHArO, p-CHArO), 7.28–7.29
(m, 1 H, m-CHArO).
13C NMR (125.8 MHz, CDCl3): δ = 26.3, 27.7 [S(CH2)2], 27.7, 27.9
[C(CH3)2], 31.8 (CH2CAr), 42.6, 42.6 [C(CH2)2], 55.4 (OCH3), 59.3
[SC(CH3)2CH], 66.1 (NCH), 77.3 [SC(CH2)2N], 113.2 (p-CHArC),
114.4, 121.0 (2 o-CHArC), 130.1 (m-CHArO), 135.1 (CArCH2), 160.1
(CArO), 163.6 (CHC=N), 165.7 (CH2C=N).
MS (ESI): m/z (%) = 296.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19N3NaOS2: 296.0867;
found: 296.0859.
(RS)-2-(2,2,5,5-Tetramethyl-1,3-thiazolidin-4-yl)-5-vinyl-1,3,4-
oxadiazole (2k)
MS (ESI): m/z (%) = 414.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25N3NaO2S2: 414.1286;
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and acrylic acid (173 mg,
2.40 mmol). The crude product was purified by column chromatog-
raphy (n-hexane–THF, 7:3) to give a colorless solid; yield: 129 mg
(27%); mp 52 °C; Rf = 0.47 (n-hexane–THF, 7:3).
found: 414.1285.
(RS)-2-(Bromomethyl)-5-(2,2,5,5-tetramethylthiazolidin-4-yl)-
1,3,4-oxadiazole (2n)
IR (ATR): 3326, 3072, 3027, 2970, 2926, 2866, 1689, 1647, 1563,
1532, 1451, 1390, 1370, 1146, 1117, 999, 987, 942, 890, 772, 745,
706, 675 cm–1.
1H NMR (499.9 MHz, CDCl3): δ = 1.15, 1.64, 1.65, 1.73 [4 s, 12 H,
2 C(CH3)2], 3.52 (br s, 1 H, NH), 4.53 (s, 1 H, NCH), 5.83–5.85 (m,
1 H, CH2), 6.25–6.28 (m, 1 H, CH2), 6.72 (dd, 3Jtrans = 17.7 Hz, 3Jcis
= 11.3 Hz, 1 H, CH2CH).
13C NMR (125.7 MHz, CDCl3): δ = 27.8, 28.1, 32.5, 33.5 [2
C(CH3)2], 61.3 [SC(CH3)2CH], 67.1 (NCH), 73.2 [SC(CH3)2N],
119.8 (CH2CH), 125.6 (CH2), 162.9 (CH2CHC=N), 164.0
(NCHC=N).
Following GP B using 1a (287 mg, 2.00 mmol), (isocyanoimino)tri-
phenylphosphorane (726 mg, 2.40 mmol), and 2-bromoacetic acid
(333 mg, 2.40 mmol). The crude product was purified by column
chromatography (MTBE–n-hexane, 7:3) to give a colorless solid;
yield: 274 mg (41%); mp 94 °C; Rf = 0.39 (MTBE–n-hexane, 7:3).
IR (ATR): 3309, 2967, 2925, 2863, 1584, 1557, 1466, 1453, 1427,
1395, 1372, 1233, 1189, 1113, 855, 817, 762, 751, 684, 602 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.12, 1.63, 1.64, 1.73 [4 s, 12 H,
2 C(CH3)2], 3.34 (br s, 1 H, NH), 4.52 (s, 2 H, CH2), 4.53 (s, 1 H,
NCH).
13C NMR (125.8 MHz, CDCl3): δ = 16.4 (CH2), 27.7, 28.0, 32.5,
33.4 [2 C(CH3)2], 61.3 [SC(CH3)2CH], 67.0 (NCH), 73.2
[SC(CH3)2N], 163.0 (CH2C=N), 164.6 (CHC=N).
MS (ESI): m/z (%) = 262.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H17N3NaOS: 262.0990;
found: 262.0983.
MS (ESI): m/z (%) = 328.0 (100) [M + Na]+.
(RS)-2-(Dec-9-enyl)-5-(2,2,5,5-tetramethylthiazolidin-4-yl)-
1,3,4-oxadiazole (2l)
HRMS (ESI): m/z [M + Na]+ calcd for C10H16BrN3NaOS: 328.0095;
found: 328.0101.
Following GP B using 1a (500 mg, 3.49 mmol), (isocyanoimino)tri-
phenylphosphorane (1.267 g, 4.19 mmol), and undec-9-enic acid
(772 mg, 4.19 mmol). The crude product was purified by column
chromatography (n-hexane–EtOAc, 3:2) to give a light yellow oil;
yield: 796 mg (65%); Rf = 0.37 (n-hexane–EtOAc, 3:2).
(RS)-2-{2-[(9H-Fluoren-9-ylmethoxycarbonyl)amino]ethyl}-5-
(2,2,5,5-tetramethylthiazolidin-4-yl)-1,3,4-oxadiazole (2o)
Following GP B using 1a (400 mg, 2.79 mmol), (isocyanoimino)tri-
phenylphosphorane (1.013 g, 3.35 mmol), and 2-bromoacetic acid
(1.043 g, 3.35 mmol). The crude product was purified by column
chromatography (EtOAc–CHCl3–toluene–n-hexane, 5:2:2:1) to
give a colorless solid; yield: 829 mg (62%); mp 74 °C; Rf = 0.16
(EtOAc–CHCl3–toluene–n-hexane, 5:2:2:1).
IR (ATR): 3279, 3075, 2969, 2925, 2855, 1640, 1586, 1565, 1457,
1382, 1369, 1228, 1142, 1114, 991, 909, 814 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.04 [s, 3 H, C(CH3)2], 1.22–
1.31 [m, 10 H, CH2(CH2)5CH2], 1.56, 1.56, 1.66 [s, 9 H, 2 C(CH3)2],
IR (ATR): 3315, 3065, 3041, 2967, 2925, 1715, 1563, 1519, 1450,
1370, 1248, 1141, 1113, 1010, 909, 817, 759, 729, 646 cm–1.
1.68–1.74 (m,
2 H, CH2CH2C=N), 1.94–1.98 (m, 2 H,
CH2CH=CH2), 2.77–2.80 (m, 2 H, CH2C=N), 3.47 (br s, 1 H, NH),
4.43 (s, 1 H, NCH), 4.84–4.93 (m, 2 H, CH=CH2), 5.69–5.77 (m, 1
H, CH=CH2).
13C NMR (125.8 MHz, CDCl3): δ = 25.2 (CH2C=N), 26.5
(CH2CH2C=N), 27.6, 27.9 [C(CH3)2], 28.8, 28.9, 28.95, 28.97, 29.2
[CH2(CH2)5CH2], 32.33, 33.3 [C(CH3)2], 33.7 (CH2CH=CH2), 61.1
[SC(CH3)2CH], 66.9 (NCH), 72.9 [SC(CH3)2N], 114.2 (CH=CH2),
139.0 (CH=CH2), 163.0 (CHC=N), 167.2 (CH2C=N).
1H NMR (500.1 MHz, CDCl3): δ = 1.12, 1.62, 1.62, 1.71 [4 s, 12 H,
3
2 C(CH3)2], 3.07 (t, J = 6.0 Hz, 2 H, CH2C=N), 3.44 (br s, 1 H,
NHCH), 3.68 (dt, 3J = 6.2 Hz, 3J = 6.0 Hz, 2 H, CH2N), 4.18 (t, 3J =
6.9 Hz, 1 H, CHCH2), 4.36 (d, 3J = 7.0 Hz, 1 H, CHCH2), 4.50 (s, 1
H, NCH), 5.48 (t, 3J = 6.2 Hz, 1 H, NHC=O), 7.28–7.31 (m, 2 H, 2
p-CHArC), 7.37–7.40 (m, 2 H, 2 p-CHArC), 7.55–7.57 (m, 2 H, 2
CArCHAr), 7.74–7.76 (m, 2 H, 2 CArCHAr).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1603–1612

1610
F. Brockmeyer et al.
PAPER
13C NMR (125.8 MHz, CDCl3): δ = 26.4 (CH2C=N), 27.7, 27.9,
32.4, 33.4 [2 C(CH3)2], 37.5 (CH2N), 47.2 (CHCH2), 61.2
[SC(CH3)2CH], 66.9 (NCH), 67.0 (CHCH2), 73.0 [SC(CH3)2N],
120.1, 125.1 (4 CArCHAr), 127.1, 127.8 (4 p-CHArC), 141.4 (2
CHCArCAr), 143.9 (2 CHCAr), 156.4 (C=O), 163.6 (CHC=N), 165.3
(CH2C=N).
MS (ESI): m/z (%) = 501.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H30N4NaO3S: 501.1936;
1JCF = 272.4 Hz, CF3), 127.2 [o-CHAr(C=N)], 129.4 (m-CHArNH),
129.4 [m-CHAr(C=N)], 131.3 (q, 2JCF = 32.4 Hz, CArCF3), 132.6
[p-CHAr(C=N)], 139.0 (CArN), 152.0 (C=O), 164.3 (CHC=N),
166.3 (CArC=N).
MS (ESI): m/z (%) = 499.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H23F3N4NaO2S:
499.1392; found: 499.1378.
(RS)-2-(2-Sulfanylethyl)-5-(2,2,5,5-tetramethyl-3-{[3-(trifluo-
romethyl)phenyl]carbamoyl}thiazolidin-4-yl)-1,3,4-oxadiazole
(3b)
Following GP C using 3-(trifluoromethyl)phenyl isocyanate (62
mg, 0.33 mmol) and 2j (90 mg, 0.33 mmol) with stirring for 72 h to
give a colorless oil; yield: 113 mg (76%); mp 155 °C; Rf = 0.32
(CH2Cl2–EtOAc, 19:1).
found: 501.1937.
(RS)-2-(2-Aminoethyl)-5-(2,2,5,5-tetramethylthiazolidin-4-yl)-
1,3,4-oxadiazole (2p)
α-Amino-1,3,4-oxadiazole 2o (446 mg, 0.93 mmol) and piperidine
(158 mg, 1.86 mmol) were dissolved in CH2Cl2 (15 mL). The mix-
ture was stirred for 70 h at r.t., and then the solvent was removed on
a rotary evaporator. The crude product was purified by column
chromatography (CH2Cl2–EtOH–Et3N, 11:8:1) to give a yellow oil;
yield: 201 mg (84%); Rf = 0.33 (CH2Cl2–EtOH–Et3N, 11:8:1).
IR (ATR): 3336, 3018, 2972, 2931, 2856, 1665, 1601, 1588, 1539,
1439, 1374, 1329, 1319, 1268, 1235, 1216, 1123, 1099, 1073, 1099,
1073, 889, 796, 702, 674 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.22 [s, 3 H, C(CH3)2], 1.72 (t,
IR (ATR): 3272, 2967, 2926, 1656, 1586, 1563, 1457, 1383, 1369,
1227, 1141, 1113, 984, 913, 860, 818, 729, 645 cm–1.
1H NMR (500.1 MHz, CDCl3): δ = 1.06, 1.55, 1.55, 1.65 [4 s, 12 H,
2 C(CH3)2], 3.16–3.21 (m, 2 H, CH2C=N), 3.29–3.32 (m, 2 H,
CH2N), 4.43 (s, 1 H, NCH), 5.30 (m, 3 H, NH, NCH2).
13C NMR (125.8 MHz, CDCl3): δ = 26.6 (CH2C=N), 27.6, 27.9,
32.3, 33.3 [2 C(CH3)2], 37.6 (CH2N), 61.0 [SC(CH3)2CH], 66.8
(NCH), 72.9 [SC(CH3)2N], 163.6 (CH2C=N), 164.9 (CHC=N).
3J = 8.5 Hz, SH), 1.83, 1.96, 2.15 [3 s, 9 H, 2 C(CH3)2], 2.99 (td,
3
3
3J = 6.9 Hz, J = 8.4 Hz, 2 H, CH2SH), 3.26 (t, J = 6.9 Hz, 2 H,
CH2C), 5.42 (s, 1 H, NCH), 7.05 (s, 1 H, NH), 7.27–7.28 (m, 1 H,
p-CHArN), 7.34–7.37 (m, 1 H, m-CHArN), 7.43–7.45 (m, 1 H, p-
CHArC), 7.64–7.65 (m, 1 H, CArCHArCAr).
13C NMR (125.8 MHz, CDCl3): δ = 21.1 (CH2SH), 24.9, 29.7
[C(CH3)2], 30.1 (CH2C=N), 32.9, 33.1 [C(CH3)2], 50.0
[SC(CH3)2CH], 68.1 (NCH), 73.8 [SC(CH3)2N], 116.9 (q, 3JCF = 3.7
MS (ESI): m/z (%) = 257.1 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H21N4OS: 257.1436;
3
Hz, CArCHArCAr), 120.2 (q, JCF = 3.7 Hz, p-CHArN), 123.4 (p-
CHArC), 123.9 (q, 1JCF = 272.5 Hz, CF3), 129.3 (m-CHArN), 131.2
1
found: 257.1434.
(q, J = 32.2 Hz, CArCF3), 139.0 (CArNH), 152.1 (C=O), 164.82
(CHC=N), 166.54 (CH2C=N).
MS (ESI): m/z (%) = 483.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H23F3N4NaO2S2:
483.1112; found: 483.1115.
Urea Derivatives 3; General Procedure (GP C)
Under argon atmosphere 3-(trifluoromethyl)phenyl isocyanate (1
equiv; 2 equiv for the preparation of 3c), dissolved in anhyd CH2Cl2
(5 mL per mmol α-amino-1,3,4-oxadiazole), was cooled to 0–2 °C.
A solution of the α-amino-1,3,4-oxadiazole 2 (1 equiv) dissolved in
anhyd CH2Cl2 (2 mL per mmol α-amino-1,3,4-oxadiazole) was add-
ed dropwise. The mixture was stirred at r.t. for given time, and then
the solution was poured into sat. aq NaHCO3 solution (5 mL per
mmol α-amino-1,3,4-oxadiazole). The phases were separated and
the organic phase was washed with H2O (2 × 10 mL per mmol α-
amino-1,3,4-oxadiazole). The recombined aqueous phases were ex-
tracted with CH2Cl2 (5 × 20 mL per mmol α-amino-1,3,4-oxadia-
zole). The recombined organic phases were dried (MgSO4) and the
solvent was removed on a rotary evaporator. The crude product was
purified by column chromatography (silica gel, CH2Cl2–EtOAc,
19:1).
X-ray Crystal Structure Determination of (RS)-3b
Single crystals were obtained by recrystallization (CH2Cl2–
n-hexane, 1:1, r.t.). Data collection was performed at 120(2) K on a
Bruker Kappa Apex II CCD diffractometer, using MoKα radiation
(λ = 0.71073 Ǻ). C19H23F3N4O2S2, M = 460.53 g mol–1, monoclinic,
P21/n, unit cell dimensions: a = 10.8435(5) Å, b = 10.1567(4) Å,
c = 19.8956(8) Å, β = 99.333(2)°, V = 2162.18(16) Å3, z = 4, DC =
1.415 mg/m3, absorption μ = 0.295 mm–1, F(000) = 960, θ range for
data collection 2.07–29.02°, reflections collected 29691, indepen-
dent reflections 5664 (Rint = 0.0712), index ranges: –14 < h < 14;
–13 < k < 12; –27 < l < 26, completeness to θ = 29.02° is 98.2%. For
solution of crystal structure SHELXS-97 program was used and for
least-squares refinement on F2 SHELXL-97 program respectively.
Non-hydrogen atoms were refined with anisotropic displacement
parameters. All H atoms were placed in calculated positions and re-
fined using a riding model. 5664 reflections were included in calcu-
lation, giving final standard residual R1 value of 0.0488 (wR2 =
0.0921) for observed data [I > 2σ(I)] and 0.1127 for all data (wR2 =
0.1110) (data/restraints/parameters = 5664:0:310). Goodness-of-fit
on F2 was 1.012, largest diff. peak hole 0.319 and –0.364 e Ǻ–3.28
(RS)-2-Phenyl-5-(2,2,5,5-tetramethyl-3-{[3-(trifluorometh-
yl)phenyl]carbamoyl}thiazolidin-4-yl)-1,3,4-oxadiazole (3a)
Following GP C using 3-(trifluoromethyl)phenyl isocyanate (73
mg, 0.39 mmol) and 2a (101 mg, 0.35 mmol) with stirring for 36 h
to give a colorless oil; yield: 142 mg (85%); Rf = 0.32 (CH2Cl2–
EtOAc, 19:1).
IR (ATR): 3430, 2987, 2930, 1674, 1611, 1546, 1495, 1450, 1378,
1318, 1283, 1227, 1204, 1158, 1139, 1114, 1100, 1073, 1049, 964,
883, 847, 801, 779, 743, 714, 699, 690, 652 cm–1.
(RS)-2-[2-({[3-(Trifluoromethyl)phenyl]carbamoyl}sulfa-
nyl)ethyl]-5-(2,2,5,5-tetramethyl-3-{[3-(trifluoromethyl)phe-
nyl]carbamoyl}thiazolidin-4-yl)-1,3,4-oxadiazole (3c)
Following GP C using 3-(trifluoromethyl)phenyl isocyanate (82
mg, 0.44 mmol) and 2j (60 mg, 0.22 mmol) with stirring for 72 h to
give a colorless solid; yield: 129 mg (91%); mp 125 °C; Rf = 0.38
(CH2Cl2–EtOAc, 19:1).
1H NMR (500.1 MHz, CDCl3): δ = 1.27, 1.87, 2.01, 2.19 [4 s, 12 H,
2 C(CH3)2], 5.41 (s, 1 H, NCH), 7.03 (s, 1 H, NH), 7.25–7.26 (m, 1
H, p-CHArN), 7.32–7.35 (m, 1 H, m-CHArN), 7.43–7.45 [m, 1 H, p-
CHAr(CF3)], 7.51–7.59 [m, 3 H, m-CHAr(C=N), p-CHAr(C=N)],
7.68–7.69 (m, 1 H, CArCHArCAr), 8.05–8.07 [m, 2 H, o-
CHAr(C=N)].
13C NMR (125.8 MHz, CDCl3): δ = 24.9, 29.6, 33.2, 33.4 [2
C(CH3)2], 50.1 [SC(CH3)2CH], 68.3 (NCH), 74.1 [SC(CH3)2N],
117.0 (q, JCF = 3.9 Hz, CArCHArCAr), 120.2 [q, JCF = 3.8 Hz,
p-CHAr(C=N)], 122.9 (CArC=N), 123.2 [p-CHAr(CF3)], 124.0 (q,
IR (ATR): 3263, 3086, 2984, 1686, 1642, 1604, 1585, 1542, 1492,
1445, 1326, 1231, 1155, 1119, 1097, 1070, 885, 860, 843, 721, 657
cm–1.
3
3
Synthesis 2014, 46, 1603–1612
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolidin-4-yl-1,3,4-oxadiazoles
1611
1H NMR (500.1 MHz, CDCl3): δ = 1.23, 1.82, 1.93, 2.14 [4 s, 12 H,
2 C(CH3)2], 3.30–3.33 (m, 2 H, CH2C=N), 3.36–3.39 (m, 2 H,
CH2S), 5.36 (s, 1 H, NCH), 6.94 (s, 1 H, NHC=ON), 7.23–7.25 (m,
1 H, p-CHArN), 7.30–7.34 (m, 3 H, p-CHArN, m-CHArN, NHC=OS),
7.37–7.39 (m, 2 H, m-CHArN, p-CHArC), 7.51–7.52 (m, 1 H, p-
CHArC), 7.63–7.64, 7.69–7.70 (m, 2 H, 2 CArCHArCAr).
L.; Melancon, B. J.; Mi, D.; Lewis, L. M.; Zou, B.; Yang, L.;
Morrison, R. ACS Chem. Neurosci. 2011, 2, 730.
(10) Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.;
Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Paz, O. G.;
Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.;
Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.;
Pescatore, G.; Scarpelli, R.; Strillmock, K.; Witmer, M. V.;
Rowley, M. J. Med. Chem. 2008, 51, 5843.
13C NMR (125.8 MHz, CDCl3): δ = 24.9 [C(CH3)2], 26.8, 27.0 (2
CH2), 29.7, 29.8, 33.0, 33.3 [2 C(CH3)2], 50.0 [SC(CH3)2CH], 68.4
4
(11) Lee, S. H.; Seo, H. J.; Lee, S.-H.; Jung, M. E.; Park, J.-H.;
Yoo, J.; Yun, H.; Na, J.; Kang, Y.; Song, K.-S.; Kim, M.;
Chang, C.-H.; Kim, J.; Lee, J. J. Med. Chem. 2008, 51, 7216.
(12) (a) Taber, R. L.; Binkley, E. S. J. Heterocycl. Chem. 1972,
9, 199. (b) Hill, J. In Comprehensive Heterocyclic
Chemistry; Vol. 6; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 427.
(NCH), 73.8 [SC(CH3)2N], 116.4 (q, JCF = 2.9 Hz, CArCHArCAr),
4
3
117.1 (q, JCF = 2.9 Hz, CArCHArCAr), 120.3 (q, JCF = 3.8 Hz, p-
CHArNH), 121.1 (q, 3JCF = 2.7 Hz, p-CHArNH), 123.5 (2 p-CHArC),
1
1
123.8 (q, JCF = 272.4 Hz, CF3), 124.0 (q, JCF = 271.5 Hz, CF3),
129.4, 129.8 (2 m-CHArN), 131.4 (q, 2JCF = 28.2 Hz, CArCF3), 131.6
2
(q, JCF = 27.9 Hz, CArCF3), 138.2, 138.9 (2 CArNH), 152.3
(NC=ON), 164.8 (SC=ON), 165.1 (CHC=N), 166.6 (CH2C=N).
(13) (a) Thelakkat, M.; Schmidt, H.-W. Polym. Adv. Technol.
1998, 9, 429. (b) Mikroyannidis, J. A.; Spiliopoulos, I. K.;
Kasimis, T. S. Macromolecules 2003, 36, 9295. (c) Schulz,
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(14) Zhu, Y.-C.; Lu, H.-X.; He, D.-H.; Yang, Z.-R. J. Photochem.
Photobiol. B. 2013, 125, 8.
(15) (a) Ramazani, A.; Rezaei, A. Org. Lett. 2010, 12, 2852.
(b) Ramazani, A.; Nasrabadi, F. Z.; Ahmadi, Y. Helv. Chim.
Acta 2011, 94, 1024. (c) Ramazani, A.; Nasrabadi, F. Z.;
Karimi, Z.; Rouhani, M. Bull. Korean Chem. Soc. 2011, 32,
2700. (d) Holagh, M. V.; Maharramov, A. M.;
MS (ESI): m/z (%) = 670.2 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C27H27F6N5NaO3S2:
670.1357; found: 670.1347.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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