Multicomponent synthesis of bicyclic thiazolidinethiones and oxazolidinones in water

Article abstract of DOI:10.1002/ejoc.201301213

A powerful three-component reaction for the synthesis of bicyclic thiazolidinethiones and oxazolidinones at room temp. in water, starting from readily available amines, chloroacetaldehyde, and CS₂/CO₂, is described. A simple one-pot pro-cedure allows the construction of two new cyclic systems and four new bonds, with all reactants being efficiently utilized in this transformation. KHCO₃ is used as a productive source of CO₂. Broad potential for derivatization is demonstrated.

Full text of DOI:10.1002/ejoc.201301213

FULL PAPER
DOI: 10.1002/ejoc.201301213
Multicomponent Synthesis of Bicyclic Thiazolidinethiones and Oxazolidinones
in Water
Timo Stalling,[a] Jan Pauly,[a] Marc Schmidtmann,[a] and Jürgen Martens*[a]
Keywords: Synthetic methods / Multicomponent reactions / Water chemistry / Carbon dioxide / Heterocycles
A powerful three-component reaction for the synthesis of bi-
cyclic thiazolidinethiones and oxazolidinones at room temp.
in water, starting from readily available amines, chloroacet-
aldehyde, and CS2/CO2, is described. A simple one-pot pro-
cedure allows the construction of two new cyclic systems and
four new bonds, with all reactants being efficiently utilized
in this transformation. KHCO3 is used as a productive source
of CO2. Broad potential for derivatization is demonstrated.
of CO2, while also generating harmless waste, and therefore
provided the essential C1 building block. Besides this inno-
vation, we also observed the direct substitution of the hy-
droxy group by amino compounds to give N,N-acetals as
byproducts as part of these investigations.
As a consequence, we considered the possibility that bi-
cyclic compounds might be directly accessible by use of a
variety of bifunctional amines, chloroacetaldehyde, and
either CS2 (X = S) or CO2 (X = O) in a three-component
water-mediated reaction protocol (Scheme 1). The ready ap-
proach to these compounds, combined with the synthetic
utility of the amino functional group, would make this pro-
ject particularly attractive.
Introduction
Modern chemistry requires attributes such as simple and
rapidly available starting materials, experimental simplicity,
very high versatility, beneficial (atom-) economic factors,
and environmentally friendly conditions.[1] This is the
reason why both academic and industrial groups all over
the world are investigating and developing absorbing pro-
cesses that allow the rapid and straightforward creation of
several bonds in single operations. One-pot syntheses stand
out, due to their clean and atom- and step-efficient pro-
cesses and so are classifiable in the area of sustainable de-
velopment in the interests of green chemistry.[2] In the same
vein, multicomponent reactions (MCRs) are among the
most multifaceted and efficient synthetic methods for
smooth elaboration of highly substituted and diverse het-
erocyclic systems, in particular bioactive substances.[3]
MCRs are also privileged reactions because of their facility
for increasing molecular complexity while reducing a series
of reactions into one synthetic operation. Accordingly, the
design and development of new MCRs that proceed in a
green and experimentally simple fashion are attractive goals
in various fields of research, such as drug discovery, organic
synthesis, and materials science.
Scheme 1. Retrosynthetic analysis of the target bicyclic compounds.
In the course of our ongoing research into multicompo-
nent reactions,[4] we recently reported an efficient one-pot
synthesis of ring-fused hydroxy thiazolidinethiones and ox-
azolidinones.[5] These compounds served as starting materi-
als for the preparation of unsaturated bicyclic compounds
through ring-closing metathesis. In the oxazolidinone case
we had been pleased to find conditions that did not need a
CO2 atmosphere. KHCO3 proved to be an efficient source
In this research area, the thiazolidinethione and oxazol-
idinone subunits are of wide interest. Thiazolidinethione
derivatives, for example, are useful tools for biological
applications,[6] whereas the oxazolidinone substructure oc-
curs in diverse antibiotics[7] or in an array of different chiral
auxiliaries for stereoselective operations.[8]
Surprisingly, in spite of their remarkable potential syn-
thetic value, no practical and flexible direct method to ob-
tain such bicyclic compounds is currently available. Only
rare examples have so far been described in the literature.[9]
Along similar lines, however, a four-component cascade re-
action based on aliphatic diamines has recently been dis-
cussed in carbonyl chemistry.[10] This notwithstanding, in
[a] Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg, Germany
E-mail: juergen.martens@uni-oldenburg.de
www.martens.chemie.uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301213.
Eur. J. Org. Chem. 2014, 833–843
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
833

T. Stalling, J. Pauly, M. Schmidtmann, J. Martens
FULL PAPER
the context of thiazolidinethiones aromatic diamines have Table 1. Thiazolidinethiones 1 and oxazolidinones 2. Variables n,
X, Y, R1, and R2, together with yields.
commonly led to dimeric compounds in multi-step pro-
cesses.[11]
Entry
n
X
Y
R1
R2
GP[a] Product
(yield)[b]
1
2
3
4
5
6
7
8
0
0
1
1
1
2
1
0
0
1
1
1
1
1
1
2
1
1
S
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
O
O
NH
O
NH
NH
O
NH
NCH3
NH
O
NH
NH
NH
NH
NH
O
H
H
H
H
H
H
A
A
A
A
A
A
A
B
B
B
C
B
B
C
B
B
B
B
1a (63%)[c]
1b (11%)
1c (50%)[d]
1d (19%)
1e (9%)
Results and Discussion
CH3 CH3
In continuation of our very recently described multicom-
ponent reactions,[5] we next focused on establishing a rapid
and effective protocol for the direct formation of bicyclic
thiazolidinethiones and oxazolidinones without isolation of
any intermediates. We envisioned that the use of various
types of bifunctional primary amines should provide access
to the desired products 1 and 2 (Scheme 2).
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1f (3%)[e]
1g (7%)
2a (6%)
[f]
9
–
10
11
12
13
14
15
16
17
18
2b (94%)
2b (13%)
2c (96%)
2d (2%)
CH3 CH3
OH
OH
H
H
H
H
H
H
H
H
H
2d[g] (93%)
2e (73%)
2f (13%)
2g (97%)
NH
NCH3
NCH(CH2)5
[f]
H
–
[a] GP = General Procedure (see Exp. Sect. for details). [b] Isolated
yields after column chromatography (no purification was necessary
for compounds 2b, 2c, 2d, 2e, and 2g). [c] Starting at room temp.:
9% yield. [d] Starting at room temp.: 35%. [e] THF as solvent,
starting at room temp. [f] No main product isolated. [g] Dia-
stereomeric ratio according to the H NMR of the crude product:
dr = 67:33.
Scheme 2. Synthesis of fused-ring thiazolidinethiones 1 (X = S) and
oxazolidinones 2 (X = O). (i) Compounds 1: 1 equiv. amine,
4 equiv. CS2, 1.33 equiv. aldehyde, 1.33 equiv. K2CO3, H2O, 0 °C to
room temp., 2 h. (ii) Compounds 2: 3 equiv. amine, 10 equiv.
KHCO3, 1 equiv. aldehyde, H2O, room temp., 10 h.
1
Applying a varied series of bifunctional amines, chloro- GP B, CH2Cl2). Considering the method of extraction in
acetaldehyde, and a C1 building block – namely either CS2 more detail, we came to the conclusion that the use of
(X = S) or CO2 (X = O) – in H2O, we set out to screen CH2Cl2 provided on average 50% more product than the
the scope and limitations of this method. In the case of use of ethyl acetate in the case of oxazolidinones 2. Surpris-
thiazolidinethiones 1, acceptable yields were achieved with ingly, when starting from aminoethanol (Table 1, Entry 9)
1,2- and 1,3-diamines (up to 63%, Table 1, Entries 1, 3, and the reaction failed, which was hard to understand in view
4). Gratifyingly, a change of solvent (THF instead of water) of the fact that that aminoethanol had been successfully
also allowed the preparation of 1f. Surprisingly, the forma- converted to give bicyclic thiazolidinethione 1b. In an at-
tion of 1f could only be achieved by starting at room temp., tempt to amplify the scope of potential bifunctional amines
which is not readily understandable in view of the fact that we examined a sterically demanding secondary amine [Y =
all of the other reactions were optimally carried out at 0– NCH(CH2)5; Table 1, Entry 18], but no unique product was
5 °C. Although the yield of 1g is rather low (7%), it can isolated.
nevertheless be seen that secondary bifunctional amines are
As illustrated by the formation of 2a, 2b, and 2f, the
also suitable components for this reaction.
chain length of the amine had a noticeable impact on the
The strategy was then transferred to the synthesis of bi- yield of the reaction. The best results were achieved in cases
cyclic oxazolidinones 2. As mentioned above, the corre- of six-membered rings (Table 1, Entries 10, 12, 14, 15, and
sponding procedure for efficient generation of CO2 from 17). Ethyl- and butylamine derivatives, however, partici-
readily available KHCO3 has been reported by us pre- pated less efficiently in the reaction (Table 1, Entries 8, 9,
viously.[5] The new multicomponent reaction provides the and 16). The synthesis of compound 2d (Table 1, Entry 14;
oxazolidinones in often very good yields of up to 97% R1 = OH, R2 = H), containing two stereogenic centers, led
(Table 1, Entries 8–18). It is worth mentioning that the to the formation of two racemic diastereomers (dr = 67:33).
products 2b, 2c, 2d, 2e, and 2g were obtained in pure form Unfortunately, these diastereomers could not be separated
after extraction without any need for further purification. by column chromatography. It should be mentioned that
Otherwise, standard purification by column chromatog- the excellent isolated yield in the case of compound 2d
raphy on silica gel was sufficient. Fortunately, we found af- (93%) was achieved by changing the extracting agent from
ter additional experiments that the use of CH2Cl2 instead CH2Cl2 (Table 1, Entry 13; GP B) to ethyl acetate (Table 1,
of ethyl acetate as extracting agent for the clear solutions Entry 14; GP C). This observation could be explained in
improved the isolated yields significantly. To give an exam- terms of better solubility of 2d in ethyl acetate.
ple: in the case of the formation of 2b the isolated yield
A change in the C1 source (CS2 or CO2) influenced the
could be appreciably improved from 13% (Table 1, En- performance of the new multicomponent reaction consider-
try 11; GP C, ethyl acetate) to 94% (Table 1, Entry 10; ably. The decreased reactivity of CS2 is not a novelty. As
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MCR Synthesis of Heterocycles in Water
reported previously, the appearance of this phenomenon
has led to surprising products.[12]
In order to examine its potential as an aza-Michael do-
nator, oxazolidinone 2b was treated with acrylates in the
With regard to green chemistry, the new multicomponent presence of silica gel as low-cost, reclaimable, resource-con-
reaction furthermore utilizes chloroacetaldehyde as a com- serving, and readily reclaimable catalyst[15] to yield com-
ponent. This is a very interesting chemical, due to its ready pounds 7.
availability as a waste product of the Wacker process.[13]
Furthermore, KMnO4, use of which has been established
To examine the accessible ranges of bicyclic compounds for similar reactions,[16] was used for oxidation to give the
1 and 2, we set out to address the amino functions in some corresponding ketimines 8 in moderate yields (up to 48%).
thiazolidinethiones 1 and oxazolidinones 2 synthetically. The new C=N bond could provide great opportunity for
From a strategic perspective, the secondary amino function functionalizations.
is a very important element for building up complex molec-
These reactions illustrate the enormous potential of
ular structures. The potential was representatively revealed derivatization of the bicyclic thiazolidinethiones 1 and ox-
by selected reactions under mild conditions with both thi- azolidinones 2.
azolidinethione 1c and oxazolidinone 2b.[14] As expected,
Fortunately, we were able to obtain single crystals of
treatment with a series of various carboxylic acid and sulf- compound 4c (Figure 1). By comparing the NMR spectro-
onyl chlorides in the presence of Et3N gave carboxamides scopic data for 4c with the data for compounds 1 and 2, it
and sulfonamides 3 and 4 (Scheme 3) in good yields (up to was possible, thanks to this X-ray structure,[17] to verify the
93%). Treatment with different types of isocyanates pro- proposed constitutions of all thiazolidinethiones 1 and ox-
vided urea derivatives 5 in predominantly high yields (up to azolidinones 2 unequivocally. The comparison of the NMR
91%).
spectroscopic data is reasonable because characteristic spec-
Of course, the treatment with alkyl halides has to be con- troscopic features [e.g., similar shifts and coupling patterns
sidered from two different perspectives. On the one hand, of the CH2–CH2–CH2 unit (established by 1H,1H-COSY,
1
the potential for derivatization by nucleophilic substitution HMQC, and HMBC)] were found in the corresponding H
is demonstrated. On the other hand, it is easily conceivable and 13C spectra both of thiazolidinethiones 1 and of oxaz-
that compounds 6a and 6c might also be directly accessible olidinones 2. There is no question that the values for the
by the new multicomponent reaction described above, by CH2 unit next to the CX2 building block (X = S, O) are
use of the corresponding amines, although the small selec- somewhat different, due to unequal electron-withdrawing
tion of suitable secondary bifunctional amines correlates effects of the heteroatoms. Different shifts were also ob-
with relatively high prices.
served for the NCH fragment, this also being influenced by
Scheme 3. Diversification at NH. Reagents and conditions: (a) 1 equiv. halogenated compound, 1.75 equiv. Et3N, CH2Cl2, 0 °C to room
temp., overnight; (b) 1 equiv. isocyanate, CH2Cl2, 0 °C to room temp., overnight; (c) 1 equiv. acrylate, cat. silica gel, acetonitrile, reflux,
15–45 h; (d) 2.5 equiv. KMnO4, acetone, reflux, 2 h.
Eur. J. Org. Chem. 2014, 833–843
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T. Stalling, J. Pauly, M. Schmidtmann, J. Martens
FULL PAPER
77.16 ppm (13C NMR). [D6]DMSO: 2.50 ppm (1H NMR),
39.52 ppm (13C NMR). CD3OD: 3.31 ppm (1H NMR), 49.00 ppm
(13C NMR)].[18] Signal assignments were supported by measure-
ments with application of DEPT and COSY techniques. Mass spec-
tra were obtained with Finnigan MAT 95 (CI) and Waters Q-TOF
Premier (ESI) spectrometers. IR spectra were recorded with a
Bruker Tensor 27 spectrometer fitted with a “Golden Gate” dia-
mond-ATR (attenuated total reflection) unit. CH2Cl2 was dried
and distilled from CaH2. Acetonitrile was dried with molecular si-
eves and freshly distilled prior to use. Et3N was dried with molecu-
lar sieves and freshly distilled prior to use.
the adjacent CX2 function (X = S, O). Nevertheless, charac-
teristic ABX spin systems were noted for these groups in
the five-membered heterocyclic systems in all cases.
Furthermore, the X-ray structure confirms the successful
derivatization of bicyclic compounds 1c and 2b.
General Procedure A: The appropriate bifunctional amine
(1 equiv.), dissolved in distilled H2O (8 mL per mmol amine), was
treated at 0–5 °C with CS2 (4 equiv.), chloroacetaldehyde
(1.33 equiv.), and K2CO3 (1.33 equiv.). After the system had been
stirred for 2 h at room temp., ethyl acetate (10 mL per mmol amine)
was added. The phases were separated and the aqueous phase was
extracted with ethyl acetate (3ϫ 10 mL per mmol amine). The
combined organic phases were dried (MgSO4). The solvent was
removed (rotary evaporator). The crude product was purified by
column chromatography.
Figure 1. X-ray crystal structure of oxazolidinone derivative 4c
(only one enantiomer is shown.).[17] The atom numbering does not
follow IUPAC nomenclature.
(RS)-Tetrahydroimidazo[1,2-c][1,3]thiazole-5-thione (1a): Ethylene-
1,2-diamine (90 mg, 1.50 mmol), CS2 (457 mg, 6.00 mmol), chloro-
acetaldehyde (157 mg, 2.00 mmol, 45% in H2O), and K2CO3
(276 mg, 2.00 mmol) were used as described in GP A. The crude
product was purified by column chromatography on silica gel (ethyl
acetate; Rf = 0.09) to provide the title compound as a colorless
Conclusions
In conclusion, we have developed a new water-mediated
protocol for the synthesis of bicyclic thiazolidinethiones
and oxazolidinones of different ring sizes and containing
different functional groups under extremely mild condi-
tions. An efficient, facile, and environmentally benign three-
component reaction protocol with high scaffold diversity
based on bifunctional amines, CS2/CO2, and chloroacetal-
1
solid (151 mg, 63%), m.p. 108 °C. H NMR (500.1 MHz, CDCl3):
δ = 2.23 (br. s, 1 H, NH), 3.32 (dd, 2J = 11.1, 3J = 9.4 Hz, 1 H,
SCH2), 3.33–3.37 (m, 1 H, NHCH2), 3.43–3.50 (m, 2 H, SCH2,
NCH2), 3.62–3.66 (m, 1 H, NCH2), 3.70–3.76 (m, 1 H, NHCH2),
dehyde is presented. In some cases the workups were very 5.27 (dd, 3J = 7.4, 9.1 Hz, 1 H, NCH) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 35.29 (SCH2), 47.13 (NHCH2), 50.20 (NCH2), 85.79
easy and the products were obtained by simple extraction
in excellent yields of up to 97%. The green methodology is
particularly attractive due to the sustainable utilization of
KHCO3 as source of CO2. Because of the secondary amino
functions in these molecules, these thiazolidinethiones and
oxazolidinones appear ideally suited for diverse subsequent
functionalization and to offer great opportunities as unique
building blocks in the elaboration of chemical libraries. For
this purpose, an array of various derivatives was success-
fully prepared by using typical reactions of secondary
amines.
(NCH), 192.31 (CS) ppm. IR (ATR): ν = 3233, 2990, 2952, 2930,
˜
2877, 2855, 1486, 1449, 1295, 1173, 1090, 1033, 918, 894 cm–1. MS
(CI, isobutane): m/z (%) = 161.0 (100) [M + H]+. HRMS (CI, iso-
butane): calcd. for C5H9N2S2 [M + H]+ 161.0207; found 161.0205.
(RS)-Tetrahydro[1,3]thiazolo[4,3-b][1,3]oxazole-5-thione (1b): 2-
Aminoethanol (183 mg, 3.00 mmol), CS2 (914 mg, 12.00 mmol),
chloroacetaldehyde (314 mg, 4.00 mmol, 45% in H2O), and K2CO3
(552 mg, 4.00 mmol) were used as described in GP A. The crude
product was purified by column chromatography on silica gel twice
(1. ethyl acetate; 2. n-hexane/ethyl acetate 1:1; Rf = 0.55) to provide
the title compound as a yellow oil (55 mg, 11%). 1H NMR
(500.1 MHz, CDCl3): δ = 3.46 (dd, 2J = 11.7, 3J = 5.6 Hz, 1 H,
SCH2), 3.47–3.53 (m, 1 H, NCH2), 3.55 (dd, 2J = 11.7, 3J = 6.9 Hz,
1 H, SCH2), 4.12–4.20 (m, 2 H, NCH2, OCH2), 4.32–4.37 (m, 1 H,
OCH2), 5.65–5.67 (m, 1 H, NCH) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 34.32 (SCH2), 46.85 (NCH2), 68.61 (OCH2), 97.62
Experimental Section
General: Synthetic procedures under argon were performed on a
vacuum line with use of standard Schlenk techniques. Preparative
column chromatography was carried out with Grace SiO2 (0.035–
0.070 mm, type KG 60) and CH2Cl2, ethyl acetate, n-hexane,
MTBE (tert-butyl methyl ether), and ethanol as eluents. CH2Cl2,
ethyl acetate, and n-hexane were distilled prior to use. TLC was
performed with Machery–Nagel SiO2 F254 plates on aluminum
sheets. Melting points were obtained with a melting point appara-
(NCH), 198.51 (CS) ppm. IR (ATR): ν = 2949, 2887, 1471, 1446,
˜
1426, 1308, 1277, 1190, 1159, 1108, 1085, 1028, 974, 944, 907,
676 cm–1. MS (CI, isobutane): m/z (%) = 162.2 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C5H8NOS2 [M + H]+ 162.0047;
found 162.0050.
(RS)-Hexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione (1c): 1,3-Di-
aminopropane (111 mg, 1.50 mmol), CS2 (457 mg, 6.00 mmol),
chloroacetaldehyde (157 mg, 2.00 mmol, 45% in H2O), and K2CO3
(276 mg, 2.00 mmol) were used as described in GP A. The crude
product was purified by column chromatography on silica gel (ethyl
acetate; Rf = 0.18) to provide the title compound as a colorless
solid (130 mg, 50%), m.p. 144–146 °C. 1H NMR (500.1 MHz,
CDCl3): δ = 1.63–1.74 (m, 3 H, NH, NCH2CH2), 2.86–2.99 (m,
1
tus (Laboratory Devices) and are uncorrected. H and 13C NMR
spectra were recorded with Bruker AMX R 500 (measuring fre-
quency: 1H NMR = 500.1 MHz, 13C NMR = 125.8 MHz) or
Bruker Avance III 500 (measuring frequency: 1H NMR
=
499.9 MHz, 13C NMR = 125.7 MHz) spectrometers in CDCl3,
[D6]DMSO, or CD3OD solution. Chemical shifts are referenced to
the residual peaks of the solvent [CDCl3: 7.26 ppm (1H NMR),
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MCR Synthesis of Heterocycles in Water
2 H, NHCH2, SCH2), 3.12–3.18 (m, 1 H, NCH2), 3.23–3.26 (m, 998, 705, 666 cm–1. MS (CI, isobutane): m/z (%) = 189.1 (100) [M
1 H, NHCH2), 3.52–3.56 (m, 1 H, SCH2), 4.81–4.84 (m, 1 H,
NCH2), 4.93–4.96 (m, 1 H, NCH) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 25.72 (NCH2CH2), 33.31 (SCH2), 44.04 (NHCH2),
+ H]+. HRMS (CI, isobutane): calcd. for C7H13N2S2 [M + H]+
189.0520; found 189.0519.
(RS)-1-Methylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione (1g):
N-Methylpropylene-1,3-diamine (132 mg, 1.50 mmol), CS2
(457 mg, 6.00 mmol), chloroacetaldehyde (157 mg, 2.00 mmol, 45%
in H2O), and K2CO3 (276 mg, 2.00 mmol) were used as described
in GP A. The crude product was purified by column chromatog-
raphy on silica gel (ethyl acetate/n-hexane 4:1; Rf = 0.16) to provide
the title compound as a colorless oil (21 mg, 7%). 1H NMR
46.73 (NCH ), 81.26 (NCH), 194.13 (CS) ppm. IR (ATR): ν =
˜
2
3253, 2946, 2925, 2855, 1471, 1433, 1306, 1268, 1185, 1104, 1034,
1012, 915, 878, 837, 797, 745 cm–1. MS (CI, isobutane): m/z (%) =
175.1 (100) [M
+
H]+. HRMS (CI, isobutane): calcd. for
C6H11N2S2 [M + H]+ 175.0364; found 175.0360.
(RS)-3,3-Dimethylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione
(1d): 2,2-Dimethylpropylene-1,3-diamine (153 mg, 1.50 mmol), CS2
(457 mg, 6.00 mmol), chloroacetaldehyde (157 mg, 2.00 mmol, 45%
in H2O), and K2CO3 (276 mg, 2.00 mmol) were used as described
in GP A. The crude product was purified by column chromatog-
raphy on silica gel (ethyl acetate/n-hexane 9:1; Rf = 0.26) to provide
the title compound as a yellowish solid (58 mg, 19%), m.p. 194–
(499.9 MHz, CDCl3):
δ = 1.68–1.71, 1.87–1.95 (2ϫm, 2 H,
NCH2CH2), 2.33 (s, 3 H, CH3), 2.38–2.43 (m, 1 H, CH3NCH2),
2
3
3
2.88 (ddd, J = 16.0, J = 13.2, J = 2.8 Hz, 1 H, CNCH2), 3.02–
3.04 (m, 1 H, CH3NCH2), 3.19 (dd, 2J = 10.9, 3J = 7.8 Hz, 1 H,
SCH2), 3.40 (dd, 2J = 10.9, 3J = 7.9 Hz, 1 H, SCH2), 4.25–4.28 (m,
1 H, NCH), 4.79–4.82 (m, 1 H, CNCH2) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 22.74 (NCH2CH2), 32.34 (SCH2), 39.83
(CH3), 46.14 (CNCH2), 53.89 (CH3NCH2), 86.35 (NCH), 195.75
1
196 °C. H NMR (500.1 MHz, CDCl3): δ = 0.95, 1.02 (2ϫs, 6 H,
2ϫ CH3), 2.02–2.29 (m, 1 H, NH), 2.73–2.73 (m, 2 H, NHCH2),
2.83 (d, 2J = 13.2 Hz, 1 H, NCH2), 2.98 (dd, 2J = 11.7, 3J = 6.9 Hz,
(CS) ppm. IR (ATR): ν = 2986, 2952, 2926, 2856, 2793, 1455, 1300,
˜
1277, 1225, 1163, 1122, 1039, 1021, 900, 888 cm–1. MS (ESI): m/z
2
3
1 H, SCH2), 3.57 (dd, J = 11.8, J = 8.2 Hz, 1 H, SCH2), 4.51 (d,
2J = 13.2 Hz, 1 H, NCH2), 4.86–4.89 (m, 1 H, NCH) ppm. 13C
NMR (125.8 MHz, CDCl3): δ = 22.60, 25.21 (2ϫ CH3), 31.65
[C(CH3)2], 32.84 (SCH2), 56.19 (NHCH2), 56.95 (NCH2), 80.98
(%)
= 211.0 (100) [M +
Na]+. HRMS (ESI): calcd. for
C7H12N2NaS2 [M + Na]+ 211.0340; found 211.0336.
General Procedure B: The appropriate bifunctional amine
(3 equiv.), dissolved in distilled H2O (4 mL per mmol amine), was
treated with KHCO3 (10 equiv.) and chloroacetaldehyde (1 equiv.).
After the system had been stirred for 10 h at room temp., CH2Cl2
(2 mL per mmol amine) was added. The phases were separated and
the aqueous phase was extracted with CH2Cl2 (13ϫ 2 mL per
mmol amine). The combined organic phases were dried (MgSO4).
The solvent was removed (rotary evaporator). The crude product
was purified by column chromatography.
(NCH), 194.24 (CS) ppm. IR (ATR): ν = 3265, 2958, 2935, 2890,
˜
2871, 2850, 1485, 1467, 1439, 1310, 1294, 1214, 1173, 1107, 1052,
1009, 969, 900, 845, 821, 747 cm–1. MS (CI, isobutane): m/z (%) =
203.1 (100) [M
+
H]+. HRMS (CI, isobutane): calcd. for
C8H15N2S2 [M + H]+ 203.0677; found 203.0675.
(RS)-Tetrahydro[1,3]thiazolo[4,3-b][1,3]oxazine-6-thione (1e): 1-
Aminopropan-3-ol (113 mg, 1.50 mmol), CS2 (457 mg, 6.00 mmol),
chloroacetaldehyde (157 mg, 2.00 mmol, 45% in H2O), and K2CO3
(276 mg, 2.00 mmol) were used as described in GP A. The crude
product was purified by column chromatography on silica gel twice
(1. n-hexane/ethyl acetate 7:3; 2. CH2Cl2/n-hexane 7:3; Rf = 0.31)
to provide the title compound as a colorless oil (23 mg, 9%). 1H
NMR (499.9 MHz, CD3OD): δ = 1.62–1.64, 1.86–1.95 (2ϫm, 2 H,
NCH2CH2), 3.10–3.13 (m, 1 H, SCH2), 3.33–3.38 (m, 1 H, NCH2),
3.60–3.63 (m, 1 H, SCH2), 3.86–3.91 (m, 1 H, OCH2), 4.12–4.14
(m, 1 H, OCH2), 4.75–4.75 (m, 1 H, NCH2), 5.56–5.57 (m, 1 H,
General Procedure C: The appropriate bifunctional amine
(3 equiv.), dissolved in distilled H2O (4 mL per mmol amine), was
treated with KHCO3 (10 equiv.) and chloroacetaldehyde (1 equiv.).
After the system had been stirred for 10 h at room temp., ethyl
acetate (2 mL per mmol amine) was added. The phases were sepa-
rated and the aqueous phase was extracted with ethyl acetate (13ϫ
2 mL per mmol amine). The combined organic phases were dried
(MgSO4). The solvent was removed (rotary evaporator). The crude
product was purified by column chromatography.
NCH) ppm. 13C NMR (125.7 MHz, CD3OD):
(NCH2CH2), 33.48 (SCH2), 46.60 (NCH2), 68.35 (OCH2), 96.36
δ = 25.81
(RS)-Tetrahydroimidazo[1,2-c][1,3]oxazol-5-one (2a): Ethylene-1,2-
diamine (541 mg, 9.00 mmol), KHCO3 (3.004 g, 30.00 mmol), and
chloroacetaldehyde (235 mg, 3.00 mmol, 45% in H2O) were used
as described in GP B. The crude product was purified by column
chromatography on silica gel (EtOH; Rf = 0.23) to provide the title
compound as a yellowish solid (22 mg, 6%), m.p. 50–52 °C. 1H
NMR (500.1 MHz, CDCl3): δ = 1.93 (br. s, 1 H, NH), 3.04–3.09
(m, 1 H, NHCH2), 3.11–3.15 (m, 1 H, NCH2), 3.18–3.23 (m, 1 H,
NHCH2), 3.63–3.68 (m, 1 H, NCH2), 4.19 (dd, 2J = 9.8, 3J =
(NCH), 197.95 (CS) ppm. IR (ATR): ν = 2953, 2858, 1467, 1424,
˜
1299, 1268, 1232, 1184, 1117, 1077, 1043, 1003, 963, 906, 879, 857,
674 cm–1. MS (CI, isobutane): m/z (%) = 176.3 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C6H10NOS2 [M + H]+ 176.0204;
found 176.0201.
(RS)-Hexahydro[1,3]thiazolo[3,4-a][1,3]diazepine-7-thione (1f): Pu-
trescine (132 mg, 1.50 mmol), CS2 (457 mg, 6.00 mmol), chloro-
acetaldehyde (157 mg, 2.00 mmol, 45% in H2O), and K2CO3
(276 mg, 2.00 mmol) were used as described in GP A. The reaction
was performed at room temp. in THF. The crude product was puri-
fied by column chromatography on silica gel (ethyl acetate/n-hex-
ane 9:1; Rf = 0.27) to provide the title compound as a colorless
solid (8 mg, 3%), m.p. 107–108 °C. 1H NMR (499.9 MHz, CDCl3):
δ = 1.62–1.81 (m, 3 H, NCH2CH2, NHCH2CH2), 1.85–1.94 (m,
1 H, NCH2CH2), 2.05 (br. s, 1 H, NH), 2.88–2.97 (m, 2 H,
2
3
2.2 Hz, 1 H, OCH2), 4.51 (dd, J = 9.8, J = 6.4 Hz, 1 H, OCH2),
4.62 (dd, 3J = 2.1, 3J = 6.4 Hz, 1 H, NCH) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 46.07 (NHCH2), 46.64 (NCH2), 68.47
(OCH ), 74.89 (NCH), 162.20 (CO) ppm. IR (ATR): ν = 3273,
˜
2
2984, 2970, 2956, 2907, 2885, 1725, 1483, 1470, 1454, 1393, 1229,
1212, 1115, 1089, 1058 cm–1. MS (CI, isobutane): m/z (%) = 129.2
(100) [M + H]+. HRMS (CI, isobutane): calcd. for C5H9N2O2 [M
+ H]+ 129.0664; found 129.0661.
2
3
NHCH2), 3.11 (dd, J = 11.7, J = 7.7 Hz, 1 H, SCH2), 3.35–3.42
(m, 2 H, NCH2, SCH2), 4.44–4.49 (m, 1 H, NCH2), 5.18–5.22 (m,
1 H, NCH) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 26.15
(RS)-Hexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (2b): 1,3-Di-
aminopropane
(667 mg,
9.00 mmol),
KHCO3
(3.004 g,
(NHCH2CH2), 32.57 (NCH2CH2), 33.89 (SCH2), 44.46 (NHCH2), 30.00 mmol), and chloroacetaldehyde (235 mg, 3.00 mmol, 45% in
48.35 (NCH ), 82.98 (NCH), 193.84 (CS) ppm. IR (ATR): ν = H2O) were used as described in GP B. Purification was not neces-
˜
2
3294, 2926, 2852, 1471, 1446, 1417, 1283, 1218, 1178, 1150, 1121,
sary. The title compound was obtained as a colorless solid (400 mg,
Eur. J. Org. Chem. 2014, 833–843
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
837

T. Stalling, J. Pauly, M. Schmidtmann, J. Martens
94%), m.p. 63–65 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.49– 1.46, 1.84–1.94 (2ϫm, 2 H, NCH2CH2), 3.20 (ddd, 2J = 16.8, 3J =
FULL PAPER
3
2
3
3
1.51, 1.54–1.63 (2ϫm, 2 H, NCH2CH2), 1.72 (s, 1 H, NH), 2.77–
3.7, J = 13.2 Hz, 1 H, NCH2), 3.71 (ddd, J = 14.0, J = 1.9, J
= 12.3 Hz, 1 H, OCH2CH2), 3.90–3.93 (m, 1 H, NCH2), 4.06–4.09
2.83 (m, 1 H, NHCH2), 3.12 (ddd, 2J = 16.9, 3J = 3.8, 3J = 13.0 Hz,
2
3
2
3
1 H, NCH2), 3.15–3.19 (m, 1 H, NHCH2), 3.86 (dd, J = 9.6, J =
(m, 2 H, OCH2CH, OCH2CH2), 4.28 (dd, J = 10.1, J = 5.6 Hz,
3.4 Hz, 1 H, OCH2), 3.88–3.92 (m, 1 H, NCH2), 4.33–4.37 (m, 1 H, 1 H, OCH2CH), 5.07–5.08 (m, 1 H, NCH) ppm. 13C NMR
OCH2), 4.58 (dd, 3J = 3.4, 7.3 Hz, 1 H, NCH) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 25.58 (NCH2CH2), 40.81 (NCH2), 43.70
(NHCH2), 67.66 (OCH2), 68.90 (NCH), 156.36 (CO) ppm. IR
(125.8 MHz, CDCl3): δ = 24.47 (NCH2CH2), 40.09 (NCH2), 66.16
(OCH2CH2), 67.96 (OCH2CH), 84.06 (NCH), 157.16 (CO) ppm.
IR (ATR): ν = 2976, 2942, 2909, 2859, 1733, 1474, 1464, 1452,
˜
(ATR): ν = 3287, 2974, 2945, 2929, 2868, 1736, 1492, 1475, 1468,
1438, 1416, 1259, 1234, 1217, 1094, 1070, 1044, 1030 cm–1. MS (CI,
isobutane): m/z (%) = 144.3 (100) [M + H]+. HRMS (CI, isobut-
ane): calcd. for C6H10NO3 [M + H]+ 144.0661; found 144.0656.
˜
1458, 1418, 1375, 1357, 1271, 1255, 1239, 1221, 1203, 1096, 1081,
1060, 1026, 1020 cm–1. MS (CI, isobutane): m/z (%) = 143.2 (100)
[M + H]+. HRMS (CI, isobutane): calcd. for C6H11N2O2 [M +
H]+ 143.0821; found 143.0819.
(RS)-Hexahydro[1,3]oxazolo[3,4-a][1,3]diazepine-7-one (2f): Pu-
trescine (793 mg, 9.00 mmol), KHCO3 (3.004 g, 30.00 mmol), and
chloroacetaldehyde (235 mg, 3.00 mmol, 45% in H2O) were used
as described in GP B. The crude product was purified by column
chromatography on silica gel (EtOH; Rf = 0.40) to provide the title
compound as a yellow solid (59 mg, 13%), m.p. 58–62 °C. 1H
(RS)-3,3-Dimethylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (2c):
2,2-Dimethylpropylene-1,3-diamine (920 mg, 9.00 mmol), KHCO3
(3.004 g, 30.00 mmol), and chloroacetaldehyde (235 mg,
3.00 mmol, 45% in H2O) were used as described in GP B. Purifica-
tion was not necessary. The title compound was obtained as a col-
NMR (499.9 MHz, CDCl3):
δ = 1.68–1.83 (m, 5 H, NH,
1
NCH2CH2, NHCH2CH2), 2.72–2.75 (m, 1 H, NHCH2), 2.88–2.91
(m, 1 H, NHCH2), 3.18–3.22 (m, 1 H, NCH2), 3.54–3.59 (m, 1 H,
NCH2), 3.84 (dd, 2J = 9.2, 3J = 5.7 Hz, 1 H, OCH2), 4.37–4.41 (m,
orless solid (492 mg, 96%), m.p. 67–68 °C. H NMR (499.9 MHz,
CDCl3): δ = 0.88, 1.03 (2ϫs, 6 H, 2 ϫ CH3), 1.69 (s, 1 H, NH),
2
2.68 (d, 2J = 13.9 Hz, 1 H, NHCH2), 2.73 (d, J = 14.0 Hz, 1 H,
1 H, OCH2), 4.77 (dd, J = 6.3, J = 7.5 Hz, 1 H, NCH) ppm. 13C
NMR (125.7 MHz, CDCl3): δ = 26.46 (NHCH2CH2), 33.66
(NCH2CH2), 43.80 (NCH2), 45.55 (NHCH2), 68.83 (OCH2), 71.04
3
3
NHCH2), 2.87, 3.59 (2ϫd, 2J = 13.3 Hz, 2 H, NCH2), 3.94 (dd, 2J
= 9.7, 3J = 3.3 Hz, 1 H, OCH2), 4.43 (dd, 2J = 9.4, 3J = 7.7 Hz,
1 H, OCH2), 4.54 (dd, 3J = 3.1, 7.3 Hz, 1 H, NCH) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 22.55, 25.63 (2ϫ CH3), 30.18 [C(CH3)2],
51.86 (NCH2), 56.05 (NHCH2), 67.56 (OCH2), 68.78 (NCH),
(NCH), 157.22 (CO) ppm. IR (ATR): ν = 3304, 2940, 2917, 2859,
˜
1727, 1497, 1478, 1424, 1392, 1272, 1174, 1133, 1096, 1063,
1014 cm–1. MS (CI, isobutane): m/z (%) = 157.1 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C7H13N2O2 [M + H]+ 157.0977;
found 157.0979.
156.75 (CO) ppm. IR (ATR): ν = 3292, 2981, 2949, 2919, 2890,
˜
2865, 1724, 1492, 1463, 1450, 1429, 1370, 1255, 1155, 1117, 1098,
1073, 1065, 1004 cm–1. MS (CI, isobutane): m/z (%) = 171.3 (100)
[M + H]+. HRMS (CI, isobutane): calcd. for C8H15N2O2 [M +
H]+ 171.1134; found 171.1138.
(RS)-1-Methylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (2g): N-
Methylpropylene-1,3-diamine (793 mg, 9.00 mmol), KHCO3
(3.004 g, 30.00 mmol), and chloroacetaldehyde (235 mg,
3.00 mmol, 45% in H2O) were used as described in GP B. Purifica-
tion was not necessary. The title compound was obtained as a yel-
(3R*,8aR*)-and(3S*,8aR*)-3-Hydroxyhexahydro[1,3]oxazolo[3,4-a]-
pyrimidin-6-one
(2d):
1,3-Diaminopropan-2-ol
(811 mg,
9.00 mmol), KHCO3 (3.004 g, 30.00 mmol), and chloroacetalde-
hyde (235 mg, 3.00 mmol, 45% in H2O) were used as described in
GP C. Analysis of the crude product by 1H NMR spectroscopy
revealed a 67:33 mixture of diastereomers (A: major diastereomer;
B: minor diastereomer). The diastereomers could not separated by
column chromatography. Purification was not necessary. The title
compound was obtained as a colorless solid (440 mg, 93%). 1H
NMR (499.9 MHz, CD3OD, mixture of diastereomers): δ = 2.54–
2.58 (m, 1 H, ANHCH2), 2.83–2.88 (m, 1 H, ANCH2), 2.99–3.06
(m, 2 H, BNHCH2), 3.17–3.20 (m, 1 H, ANHCH2), 3.36–3.39 (m,
1 H, BNCH2), 3.51–3.57 (m, 1 H, ACHOH), 3.68–3.69 (m, 1 H,
BCHOH), 3.78–3.81 (m, 1 H, BNCH2), 3.96–4.04 (m, 3 H, ANCH2,
AOCH2, BOCH2), 4.43–4.50 (m, 2 H, AOCH2, BOCH2), 4.57–4.58
(m, 1 H, ANCH), 4.72–4.73 (m, 1 H, BNCH) ppm. 13C NMR
1
low oil (454 mg, 97%). H NMR (500.1 MHz, CDCl3): δ = 1.53–
1.55, 1.72–1.82 (2ϫm, 2 H, NCH2CH2), 2.11–2.11 (m, 3 H, CH3),
2.12–2.18 (m, 1 H, CH3NCH2), 2.81–2.88 (m, 1 H, CNCH2), 2.93–
2.96 (m, 1 H, CH3NCH2), 3.71–3.73 (m, 1 H, NCH), 3.82–3.85 (m,
1 H, CNCH2), 4.08–4.11, 4.20–4.23 (2ϫm, 2 H, OCH2) ppm. 13C
NMR (125.8 MHz, CDCl3):
(CNCH2), 40.33 (CH3), 53.89 (CH3NCH2), 66.51 (OCH2), 75.05
δ = 23.98 (NCH2CH2), 39.96
(NCH), 156.75 (CO) ppm. IR (ATR): ν = 2952, 2927, 2855, 2792,
˜
2712, 1745, 1453, 1418, 1381, 1283, 1249, 1229, 1177, 1134, 1107,
1069, 1045 cm–1. MS (CI, isobutane): m/z (%) = 157.3 (100) [M +
H]+. HRMS (CI, isobutane): calcd. for C7H13N2O2 [M + H]+
157.0977; found 157.0978.
General Procedure C: The appropriate halogenated compound
(1 equiv.), dissolved in anhydrous CH2Cl2 (60 mL per mmol thiaz-
olidinethione/oxazolidinone), was treated dropwise under argon at
0–5 °C with a solution of the appropriate thiazolidinethione/oxaz-
olidinone (1 equiv.) and anhydrous Et3N (1.75 equiv.) in anhydrous
CH2Cl2 (30 mL per mmol thiazolidinethione/oxazolidinone). After
having been stirred overnight at room temp., the solution was
washed with a saturated aqueous solution of NaHCO3 (1ϫ 60 mL
per mmol thiazolidinethione/oxazolidinone) and H2O (1ϫ 60 mL
per mmol thiazolidinethione/oxazolidinone). The combined aque-
ous phases were extracted with CH2Cl2 (3ϫ 60 mL per mmol thi-
azolidinethione/oxazolidinone) and dried (MgSO4). The solvent
was removed (rotary evaporator). The crude product was purified
by column chromatography.
(125.7 MHz, CD3OD, mixture of diastereomers):
δ = 47.77
(BNCH2), 48.09 (ANCH2), 49.62 (BNHCH2), 51.30 (ANHCH2),
63.19 (BCHOH), 64.17 (ACHOH), 68.69 (AOCH2), 68.80 (BOCH2),
69.15 (ANCH), 69.56 (BNCH), 158.76 (ACO), 159.57 (BCO) ppm.
IR (ATR): ν = 3429, 3283, 2989, 2964, 2925, 2881, 1736, 1477,
˜
1452, 1440, 1259, 1138, 1104, 1077, 1049 cm–1. MS (CI, isobutane):
m/z (%) = 159.1 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C6H10N2NaO2 [M + H]+ 181.0589; found 181.0586.
(RS)-Tetrahydro[1,3]oxazolo[4,3-b][1,3]oxazine-6-one
(2e):
1-
Aminopropan-3-ol (676 mg, 9.00 mmol), KHCO3 (3.004 g,
30.00 mmol), and chloroacetaldehyde (235 mg, 3.00 mmol, 45% in
H2O) were used as described in GP B. The crude product was puri-
fied by column chromatography on silica gel (ethyl acetate; Rf =
0.57) to provide the title compound as a colorless solid (314 mg,
73%), m.p. 44–47 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.43–
(RS)-1-Acetylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione (3a):
Thiazolidinethione 1c (25 mg, 0.14 mmol), acetyl chloride (11 mg,
838
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 833–843

MCR Synthesis of Heterocycles in Water
0.14 mmol), and anhydrous Et3N (25 mg, 0.25 mmol) were used m.p. 126–127 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.73–1.80,
as described in GP C. The crude product was purified by column
chromatography on silica gel (ethyl acetate; Rf = 0.21) to provide
the title compound as a colorless solid (27 mg, 93%), m.p. 63–
64 °C. 1H NMR (499.9 MHz, CDCl3): δ = 1.95–2.04 (m, 1 H,
1.90–1.97 (2 ϫ m, 2 H, NCH2 CH2 ), 3.13–3.18 (m, 1 H,
OOCNCH2), 3.31–3.36 (m, 1 H, CArCNCH2), 3.64–3.68 (m, 1 H,
CArCNCH2), 3.90–3.95 (m, 1 H, OOCNCH2), 4.33–4.36 (m, 1 H,
OCH2), 4.73–4.77 (m, 1 H, OCH2), 5.38–5.40 (m, 1 H, NCH),
NCH2CH2), 2.09–2.13 (m, 1 H, NCH2CH2), 2.15 (s, 3 H, CH3), 7.40–7.48 (m, 5 H, 5 ϫ CHAr) ppm. 13C NMR (125.8 MHz,
3.10–3.16 (m, 1 H, SCNCH2), 3.19 (dd, 2J = 11.6, 3J = 7.8 Hz, 1 H,
SCH2), 3.26–3.27 (m, 1 H, OCNCH2), 3.73–3.76 (m, 2 H, SCH2, (CArCNCH2), 66.82 (NCH), 69.14 (OCH2), 127.93, 128.77 (2ϫ m-
OCNCH2), 4.79–4.85 (m, 1 H, SCNCH2), 6.00–6.03 (m, 1 H, CHAr, 2ϫ o-CHAr), 131.35 (p-CHAr), 134.07 (CAr), 157.14 (COO),
NCH) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 22.18 (CH3), 173.44 (COCAr) ppm. IR (ATR): ν = 2978, 2958, 2891, 1738, 1610,
CDCl3): δ = 23.46 (NCH2CH2), 38.93 (OOCNCH2), 45.76
˜
22.82 (NCH2CH2), 33.24 (SCH2), 40.09 (OCNCH2), 41.60
(SCNCH2), 77.29 (NCH), 169.92 (CO), 197.04 (CS) ppm. IR
1573, 1468, 1449, 1437, 1412, 1379, 1366, 1336, 1259, 1236, 1221,
1176, 1150, 1104, 1088, 1038, 1022, 1012, 798, 759, 734, 723,
707 cm–1. MS (CI, isobutane): m/z (%) = 247.4 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C13H15N2O3 [M + H]+ 247.1083;
found 247.1086.
(ATR): ν = 3013, 2960, 2925, 2859, 1626, 1462, 1412, 1396, 1319,
˜
1255, 1236, 1218, 1188, 1165, 1148, 1103, 1063, 1047, 1014, 955,
925, 897, 888 cm–1. MS (CI, isobutane): m/z (%) = 217.3 (100) [M
+ H]+. HRMS (CI, isobutane): calcd. for C8H13N2OS2 [M + H]+
217.0469; found 217.0464.
(RS)-1-Methylsulfonylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-
thione (4a): Thiazolidinethione 1c (25 mg, 0.14 mmol), meth-
anesulfonyl chloride (16 mg, 0.14 mmol), and anhydrous Et3N
(25 mg, 0.25 mmol) were used as described in GP C. The crude
product was purified by column chromatography on silica gel (ethyl
acetate/n-hexane 7:3; Rf = 0.46) to provide the title compound as
a colorless solid (14 mg, 43 %), m.p. 111–114 °C. 1H NMR
(499.9 MHz, CDCl3): δ = 1.97–2.01 (m, 2 H, NCH2CH2), 3.02 (s,
3 H, CH3), 3.10–3.15 (m, 1 H, CNCH2), 3.38–3.43 (m, 1 H,
(RS)-1-Benzoylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione
(3b): Thiazolidinethione 1c (25 mg, 0.14 mmol), benzoyl chloride
(20 mg, 0.14 mmol), and anhydrous Et3N (25 mg, 0.25 mmol) were
used as described in GP C. The crude product was purified by col-
umn chromatography on silica gel (n-hexane/MTBE, 1:1; Rf = 0.15)
to provide the title compound as a colorless solid (18 mg, 43%),
m.p. 167–168 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.93–2.09 (m,
2 H, NCH2CH2), 3.24–3.29 (m, 1 H, SCNCH2), 3.33–3.40 (m, 2 H, SNCH2), 3.62–3.76 (m, 3 H, SCH2, SNCH2), 4.86–4.91 (m, 1 H,
3
3
OCNCH2, SCH2), 3.74 (ddd, 2J = 13.7, J = 3.4, J = 5.3 Hz, 1 H, CNCH2), 5.49–5.51 (m, 1 H, NCH) ppm. 13C NMR (125.7 MHz,
OCNCH2), 3.93 (dd, 2J = 12.0, 3J = 7.3 Hz, 1 H, SCH2), 4.81 (ddd, CDCl3): δ = 22.78 (NCH2CH2), 33.20 (SCH2), 40.74 (CH3), 43.84
2J = 14.3, 3J = 9.2, 3J = 5.5 Hz, 1 H, SCNCH2), 6.04–6.07 (m, 1 H,
(SNCH2), 44.07 (CNCH2), 79.22 (NCH), 196.96 (CS) ppm. IR
NCH), 7.44–7.52 (m, 5 H, 5ϫ CHAr) ppm. 13C NMR (125.8 MHz, (ATR): ν = 2960, 2927, 2889, 2867, 1469, 1447, 1425, 1413, 1334,
˜
CDCl3): δ = 23.02 (NCH2CH2), 33.59 (SCH2), 42.59 (OCNCH2), 1318, 1303, 1276, 1258, 1238, 1200, 1145, 1109, 1053, 1034, 1016,
42.68 (SCNCH2), 77.66 (NCH), 127.60, 128.94 (2ϫ m-CHAr, 2ϫ 980, 971, 915, 875, 839, 780, 759 cm–1. MS (CI, isobutane): m/z
o-CHAr), 131.27 (p-CHAr), 134.53 (CAr), 172.00 (CO), 197.38 (%) = 253.3 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
(CS) ppm. IR (ATR): ν = 3060, 3006, 2960, 2936, 2926, 2876, 2866,
C7H13N2O3S3 [M + H]+ 253.0139; found 253.0135.
˜
1622, 1598, 1578, 1439, 1397, 1342, 1292, 1265, 1220, 1169, 1134,
1096, 1060, 931, 902, 862, 795, 737, 717, 696, 684, 626 cm–1. MS
(CI, isobutane): m/z (%) = 279.3 (100) [M + H]+. HRMS (CI, iso-
butane): calcd. for C13H15N2OS2 [M + H]+ 279.0626; found
279.0632.
(RS)-1-(4-Methylphenylsulfonyl)hexahydro[1,3]thiazolo[3,4-a]pyr-
imidine-6-thione (4b): Thiazolidinethione 1c (25 mg, 0.14 mmol),
toluene-4-sulfonyl chloride (27 mg, 0.14 mmol), and anhydrous
Et3N (25 mg, 0.25 mmol) were used as described in GP C. The
crude product was purified by column chromatography on silica
gel (n-hexane/ethyl acetate 1:1; Rf = 0.60) to provide the title com-
pound as a colorless solid (39 mg, 86%), m.p. 127 °C. 1H NMR
(RS)-1-Acetylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (3c): Ox-
azolidinone 2b (50 mg, 0.35 mmol), acetyl chloride (27 mg,
0.35 mmol), and anhydrous Et3N (62 mg, 0.61 mmol) were used (500.1 MHz, CDCl3): δ = 1.70–1.77 (m, 1 H, NCH2CH2), 1.80–
as described in GP C. The crude product was purified by column
chromatography on silica gel (EtOH; Rf = 0.43) to provide the title
compound as a colorless solid (39 mg, 60%), m.p. 63–65 °C. 1H
1.89 (m, 1 H, NCH2CH2), 2.46 (s, 3 H, CH3), 2.66 (ddd, 2J = 13.7,
3
3J = 10.3, J = 6.0 Hz, 1 H, CNCH2), 3.21 (ddd, 2J = 12.4, 3J =
7.1, 3J = 5.0 Hz, 1 H, SNCH2), 3.60–3.66 (m, 2 H, SCH2, SNCH2),
2
3
2
NMR (500.1 MHz, CDCl3): δ = 1.77–1.85, 1.90–1.98 (2ϫm, 2 H, 3.69 (dd, J = 12.0, J = 8.0 Hz, 1 H, SCH2), 4.69 (ddd, J = 13.7,
NCH2CH2), 2.05 (s, 3 H, CH3), 3.05–3.11 (m, 1 H, OOCNCH2), 3J = 7.3, 3J = 2.9 Hz, 1 H, CNCH2), 5.15–5.18 (m, 1 H, NCH),
3.41–3.53 (m, 2 H, CH3CNCH2), 3.84–3.89 (m, 1 H, OOCNCH2), 7.37–7.39 (m, 2 H, 2 ϫ m-CHArS), 7.72–7.73 (m, 2 H, 2 ϫ o-
4.20 (dd, 2J = 10.3, 3J = 4.7 Hz, 1 H, OCH2), 4.65 (dd, 2J = 10.2, 3J
CHArS) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 21.77 (CH3),
22.12 (NCH2CH2), 33.99 (SCH2), 43.23 (SNCH2), 43.65 (CNCH2),
= 6.8 Hz, 1 H, OCH2), 5.23–5.25 (m, 1 H, NCH) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 21.96 (CH3), 23.35 (NCH2CH2), 38.10 78.97 (NCH), 127.55 (2ϫ o-CHArS), 130.42 (2ϫ m-CHArS), 134.76
(OOCNCH2), 42.98 (CH3CNCH2), 66.17 (NCH), 69.63 (OCH2), (CArS), 145.08 (CArCH ), 196.76 (CS) ppm. IR (ATR): ν = 3063,
˜
3
157.17 (COO), 171.84 (COCH ) ppm. IR (ATR): ν = 3000, 2968, 3031, 2962, 2924, 2875, 2852, 1657, 1598, 1493, 1468, 1456, 1430,
˜
3
2939, 2893, 2867, 1741, 1648, 1438, 1374, 1359, 1321, 1259, 1234,
1158, 1125, 1103, 1056, 1025, 1002 cm–1. MS (CI, isobutane): m/z
(%) = 185.4 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C8H13N2O3 [M + H]+ 185.0926; found 185.0931.
1341, 1333, 1305, 1283, 1262, 1200, 1187, 1160, 1110, 1089, 1051,
1035, 982, 935, 881, 812, 803, 776, 738, 657 cm–1. MS (CI, isobut-
ane): m/z (%) = 329.2 (100) [M + H]+. HRMS (CI, isobutane):
calcd. for C13H17N2O2S3 [M + H]+ 329.0452; found 329.0459.
(RS)-1-Benzoylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (3d): (RS)-1-Methylsulfonylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one
Oxazolidinone 2b (50 mg, 0.35 mmol), benzoyl chloride (49 mg, (4c): Oxazolidinone 2b (50 mg, 0.35 mmol), methanesulfonyl chlor-
0.35 mmol), and anhydrous Et3N (62 mg, 0.61 mmol) were used ide (40 mg, 0.35 mmol), and anhydrous Et3N (62 mg, 0.61 mmol)
as described in GP C. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate 1:1; Rf = 0.18)
to provide the title compound as a colorless solid (75 mg, 86%),
were used as described in GP C. The crude product was purified
by column chromatography on silica gel (ethyl acetate/n-hexane 4:1;
Rf = 0.33) to provide the title compound as a colorless solid (38 mg,
Eur. J. Org. Chem. 2014, 833–843
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
839

T. Stalling, J. Pauly, M. Schmidtmann, J. Martens
FULL PAPER
49%), m.p. 130 °C. H NMR (499.9 MHz, CDCl3): δ = 1.80–1.90
1
2858, 2842, 1636, 1598, 1543, 1503, 1466, 1440, 1366, 1338, 1321,
(m, 2 H, NCH2CH2), 2.94 (s, 3 H, CH3), 2.94–2.98 (m, 1 H, 1288, 1247, 1218, 1186, 1161, 1145, 1037, 1027, 903, 750, 690,
CNCH2), 3.03–3.09, 3.66–3.70 (2ϫm, 2 H, SNCH2), 3.93–3.96 (m, 668 cm–1. MS (CI, isobutane): m/z (%) = 294.2 (9) [M + H]+, 175.1
2
3
1 H, CNCH2), 4.50 (dd, J = 10.5, J = 6.5 Hz, 1 H, OCH2), 4.65
(100) [M + H – C7H7NO]+. HRMS (CI, isobutane): calcd. for
(dd, 2J = 10.6, 3J = 4.1 Hz, 1 H, OCH2), 4.96–4.99 (m, 1 H, C13H16N3OS2 [M + H]+ 294.0735; found 294.0738.
NCH) ppm. 1 3 C NMR (125.7 MHz, CDCl3 ): δ = 23.67
(NCH2CH2), 39.15 (CH3), 39.47 (CNCH2), 45.88 (SNCH2), 68.19
(RS)-1-(3-Trifluoromethyl)phenylcarbamoylhexahydro[1,3]thiazolo-
[3,4-a]pyrimidine-6-thione (5b): Thiazolidinethione 1c (25 mg,
(OCH ), 68.66 (NCH), 156.29 (CO) ppm. IR (ATR): ν = 3017,
˜
2
0.14 mmol) and 3-(trifluoromethyl)phenyl isocyanate (27 mg,
0.14 mmol) were used as described in GP D. The title compound
was obtained as a colorless solid (37 mg, 71%), m.p. 174–176 °C.
1H NMR (499.9 MHz, [D6]DMSO): δ = 1.81–1.89 (m, 1 H,
NCH2CH2), 1.95–2.03 (m, 1 H, NCH2CH2), 3.19–3.25 (m, 1 H,
SCNCH2), 3.38–3.44 (m, 2 H, OCNCH2, SCH2), 3.74–3.81 (m,
2972, 2939, 2876, 1739, 1467, 1437, 1409, 1397, 1330, 1288, 1269,
1152, 1127, 1091, 1012, 969, 890, 814, 778, 759, 734 cm–1. MS (CI,
isobutane): m/z (%) = 221.3 (100) [M + H]+. HRMS (CI, isobut-
ane): calcd. for C7H13N2O4S [M + H]+ 221.0596; found 221.0594.
(RS)-1-(4-Methylphenylsulfonyl)hexahydro[1,3]oxazolo[3,4-a]pyr-
imidin-6-one (4d): Oxazolidinone 2b (50 mg, 0.35 mmol), toluene-4-
sulfonyl chloride (67 mg, 0.35 mmol), and anhydrous Et3N (62 mg,
0.61 mmol) were used as described in GP C. The crude product
was purified by column chromatography on silica gel (n-hexane/
ethyl acetate 1:1; Rf = 0.32) to provide the title compound as a
3
3
2 H, SCH2, OCNCH2), 4.57 (ddd, 2J = 12.6, J = 8.1, J = 3.6 Hz,
1 H, SCNCH2), 5.89–5.92 (m, 1 H, NCH), 7.32–7.33 (m, 1 H, p-
CHArNH), 7.49–7.52 (m, 1 H, m-CHAr), 7.74–7.75 (m, 1 H, p-
CHArCF3), 7.93–7.94 (m, 1 H, o-CHAr), 9.27 (s, 1 H, NH) ppm.
13C NMR (125.7 MHz, [D6]DMSO): δ = 22.21 (NCH2CH2), 32.62
colorless solid (57 mg, 54 %), m.p. 145–150 °C. 1H NMR (SCH2), 41.32 (OCNCH2), 42.65 (SCNCH2), 77.80 (NCH), 115.58
(500.1 MHz, CDCl3): δ = 1.64–1.67, 1.76–1.85 (2 ϫ m, 2 H,
(q, 3JC,F = 3.9 Hz, o-CHAr), 118.58 (q, 3JC,F = 3.6 Hz, p-CHArNH),
3
1
NCH2CH2), 2.45 (s, 3 H, CH3), 2.55 (ddd, J = 14.0, 2.2, 11.9 Hz,
122.99 (p-CHArCF3), 124.18 (q, JC,F = 272.3 Hz, CF3), 129.23 (q,
1 H, SNCH2), 2.72 (ddd, 3J = 15.5, 3.8, 13.5 Hz, 1 H, CNCH2),
2JC,F = 31.5 Hz, CArCF3), 129.60 (m-CHAr), 140.57 (CArNH),
3.68–3.72 (m, 1 H, SNCH2), 3.84–3.87 (m, 1 H, CNCH2), 4.54– 155.39 (CO), 194.58 (CS) ppm. IR (ATR): ν = 3334, 3006, 2944,
˜
4.58 (m, 2 H, OCH2), 4.86 (dd, 3J = 7.8, 13.0 Hz, 1 H, NCH), 7.37–
7.39 (m, 2 H, 2 ϫ m-CHA r S), 7.63–7.64 (m, 2 H, 2 ϫ o-
CHArS) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 21.71 (CH3),
2903, 2871, 1638, 1597, 1551, 1484, 1476, 1440, 1396, 1323, 1255,
1172, 1155, 1110, 1058, 904, 887, 799, 700 cm–1. MS (CI, isobut-
ane): m/z (%) = 362.3 (20) [M + H]+, 175.2 (100) [M + H –
23.40 (NCH2CH2), 39.31 (CNCH2), 46.07 (SNCH2), 68.38 C8H4F3NO]+. HRMS (CI, isobutane): calcd. for C14H15F3N3OS2
(OCH2), 68.67 (NCH), 128.09 (2 ϫ o-CHArS), 130.24 (2 ϫ m- [M + H]+ 362.0609; found 362.0606.
CHArS), 132.41 (CArS), 145.15 (CArCH3), 156.11 (CO) ppm. IR
(RS)-1-Phenylcarbamoylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-
(ATR): ν = 3067, 3027, 2993, 2938, 2857, 1760, 1596, 1459, 1431,
˜
one (5c): Oxazolidinone 2b (50 mg, 0.35 mmol) and phenyl isocyan-
ate (42 mg, 0.35 mmol) were used as described in GP D. The crude
product was purified by column chromatography on silica gel (ethyl
acetate/n-hexane 9:1; Rf = 0.59) to provide the title compound as
a colorless solid (82 mg, 89%), m.p. 156 °C. 1H NMR (500.1 MHz,
[D6]DMSO): δ = 1.64–1.77 (m, 2 H, NCH2CH2), 2.97–3.03 (m,
1 H, OOCNCH2), 3.14–3.19 (m, 1 H, NHCNCH2), 3.68–3.71 (m,
1396, 1363, 1345, 1335, 1281, 1163, 1088, 1032, 1014, 980, 811,
769, 750, 680, 652 cm–1. MS (CI, isobutane): m/z (%) = 297.4 (15)
[M + H]+, 143.2 (100) [M + H – C7H6O2S]+. HRMS (CI, isobut-
ane): calcd. for C13H17N2O4S [M + H]+ 297.0909; found 297.0915.
General Procedure D: The appropriate isocyanate (1 equiv.), dis-
solved in anhydrous CH2Cl2 (60 mL per mmol oxazolidinone), was
treated dropwise under argon at 0–5 °C with 1 equiv. of the appro-
priate oxazolidinone solved in CH2Cl2 (30 mL per mmol oxazolidi-
none). The reaction mixture was stirred for 30 min at 0 °C and then
overnight at room temp. In the case of thiazolidinethione deriva-
tives the product was filtered off, washed with cold n-hexane, and
dried in vacuo. The mother liquor was put in a freezer for quantifi-
cation. In the case of oxazolidinone derivatives the solvent was re-
moved (rotary evaporator) and the crude product was purified by
column chromatography.
2
1 H, OOCNCH2), 3.91–3.95 (m, 1 H, NHCNCH2), 4.16 (dd, J =
10.0, 3J = 4.3 Hz, 1 H, OCH2), 4.59 (dd, 2J = 10.0, 3J = 6.8 Hz,
1 H, OCH2), 5.07 (dd, 3J = 4.9, 3J = 6.3 Hz, 1 H, NCH), 6.96–6.99
(m, 1 H, p-CHAr), 7.24–7.27 (m, 2 H, 2ϫ m-CHAr), 7.44–7.46 (m,
2 H, 2ϫ o-CHAr), 9.06 (s, 1 H, NH) ppm. 13C NMR (125.8 MHz,
[D6]DMSO): δ = 23.31 (NCH2CH2), 38.78 (OOCNCH2), 45.22
(NHCNCH2), 66.81 (NCH), 68.60 (OCH2), 119.49 (2ϫ o-CHAr),
122.46 (p-CHAr), 128.52 (2 ϫ m-CHAr), 139.58 (CAr), 156.10
(COO), 157.73 (CONH) ppm. IR (ATR): ν = 3298, 3204, 3142,
˜
3085, 2966, 2939, 2850, 1743, 1638, 1599, 1544, 1504, 1462, 1440,
1360, 1323, 1297, 1252, 1179, 1110, 1022, 1009, 775, 750, 717, 691,
650 cm–1. MS (CI, isobutane): m/z (%) = 262.2 (40) [M + H]+,
218.2 (100) [M + H – CO2]+. HRMS (CI, isobutane): calcd. for
C13H16N3O3 [M + H]+ 262.1192; found 262.1186.
(RS)-1-Phenylcarbamoylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-
thione (5a): Thiazolidinethione 1c (50 mg, 0.29 mmol) and phenyl
isocyanate (34 mg, 0.29 mmol) were used as described in GP D. The
title compound was obtained as a colorless solid (68 mg, 79%),
m.p. 185–188 °C. 1H NMR (500.1 MHz, [D6]DMSO): δ = 1.77–
1.85 (m, 1 H, NCH2CH2), 1.92–1.99 (m, 1 H, NCH2CH2), 3.19 (RS)-1-(3-Trifluoromethyl)phenylcarbamoylhexahydro[1,3]oxazolo-
2
3
3
(ddd, J = 13.5, J = 9.1, J = 6.7 Hz, 1 H, SCNCH2), 3.38 (dd, 2J [3,4-a]pyrimidin-6-one (5d): Oxazolidinone 2b (50 mg, 0.35 mmol)
= 11.8, 3J = 7.6 Hz, 1 H, SCH2), 3.39–3.47 (m, 1 H, OCNCH2),
3.66–3.71 (m, 1 H, OCNCH2), 3.77 (dd, 2J = 11.8, 3J = 7.5 Hz,
and 3-(trifluoromethyl)phenyl isocyanate (65 mg, 0.35 mmol) were
used as described in GP D. The crude product was purified by col-
1 H, SCH2), 4.57 (ddd, 2J = 11.5, 3J = 3.5, 3J = 7.8 Hz, 1 H, umn chromatography on silica gel (ethyl acetate/n-hexane 7:3; Rf =
SCNCH2), 5.83–5.86 (m, 1 H, NCH), 6.97–7.00 (m, 1 H, p-CHAr), 0.23) to provide the title compound as a colorless solid (104 mg,
1
7.25–7.28 (m, 2 H, 2ϫ m-CHAr), 7.46–7.48 (m, 2 H, 2ϫ o-CHAr),
9.03 (s, 1 H, NH) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ =
22.38 (NCH2CH2), 32.73 (SCH2), 42.03 (OCNCH2), 42.92
91%), m.p. 146 °C. H NMR (500.1 MHz, [D6]DMSO): δ = 1.66–
1.81 (m, 2 H, NCH2CH2), 2.99–3.05 (m, 1 H, OOCNCH2), 3.21–
3.27 (m, 1 H, NHCNCH2), 3.68–3.72 (m, 1 H, OOCNCH2), 3.89–
2
3
(SCNCH2), 78.03 (NCH), 119.72 (2ϫ o-CHAr), 122.50 (p-CHAr), 3.93 (m, 1 H, NHCNCH2), 4.19 (dd, J = 10.1, J = 4.4 Hz, 1 H,
128.50 (2ϫ m-CHAr), 139.63 (CAr), 155.96 (CO), 194.52 (CS) ppm.
IR (ATR): ν = 3275, 3198, 3135, 3076, 3024, 2953, 2928, 2875,
OCH2), 4.61 (dd, 2J = 10.1, 3J = 6.8 Hz, 1 H, OCH2), 5.11–5.13
(m, 1 H, NCH), 7.30–7.32 (m, 1 H, p-CHArNH), 7.47–7.51 (m, 1 H,
˜
840
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 833–843

MCR Synthesis of Heterocycles in Water
m-CHAr), 7.69–7.70 (m, 1 H, p-CHArCF3), 7.93–7.93 (m, 1 H, o-
CHAr), 9.37 (s, 1 H, NH) ppm. 13C NMR (125.8 MHz, [D6]-
as described in GP C. The crude product was purified by column
chromatography on silica gel (ethyl acetate/n-hexane 4:1; Rf = 0.53)
DMSO): δ = 23.18 (NCH2CH2), 38.70 (OOCNCH2), 44.89 to provide the title compound as a colorless solid (13 mg, 17%),
3
1
(NHCNCH2), 66.69 (NCH), 68.57 (OCH2), 115.37 (q, JC,F
=
m.p. 102 °C. H NMR (499.9 MHz, CDCl3): δ = 1.51–1.54, 1.72–
3.9 Hz, o-CHAr), 118.61 (q, 3JC,F = 3.6 Hz, p-CHArNH), 122.79 (p-
1.81 (2ϫm, 2 H, NCH2CH2), 2.09–2.13 (m, 1 H, CH2NCH2CH2),
2.90 (ddd, 3J = 15.8, 2.9, 13.0 Hz, 1 H, CNCH2), 2.98–3.01 (m,
1 H, CH2NCH2CH2), 3.15 (d, 2J = 13.5 Hz, 1 H, CH2CAr), 3.68
(d, 2J = 13.5 Hz, 1 H, CH2CAr), 3.91–3.95 (m, 1 H, CNCH2), 4.08–
1
2
CHArCF3), 124.23 (q, JC,F = 272.2 Hz, CF3), 129.33 (q, JC,F
=
31.4 Hz, CArCF3), 129.71 (m-CHAr), 140.57 (CArNH), 156.13
(COO), 157.40 (CONH) ppm. IR (ATR): ν = 3305, 3210, 3153,
˜
2
3
3091, 3037, 2982, 2950, 2877, 1745, 1660, 1601, 1551, 1468, 1444,
1320, 1302, 1289, 1256, 1179, 1159, 1119, 1063, 1012, 900, 889,
794, 794, 775, 753, 696 cm–1. MS (CI, isobutane): m/z (%) = 330.4
(23) [M + H]+, 286.4 (100) [M + H – CO2]+. HRMS (CI, isobut-
ane): calcd. for C14H15F3N3O3 [M + H]+ 330.1066; found 330.1056.
4.08 (m, 1 H, NCH), 4.20 (dd, J = 8.9, J = 2.7 Hz, 1 H, OCH2),
4.28–4.31 (m, 1 H, OCH2), 7.28–7.35 (m, 5 H, 5ϫ CHAr) ppm. 13
C
NMR (125.7 MHz, CDCl3): δ = 24.06 (NCH2CH2), 40.49
(CNCH2), 50.88 (CH2NCH2CH2), 57.15 (CH2CAr), 67.15 (OCH2),
73.95 (NCH), 127.75 (p-CHAr), 128.69, 128.91 (2ϫ m-CHAr, 2ϫ
o-CHAr), 136.89 (CAr), 156.90 (CO) ppm. IR (ATR): ν = 3083,
˜
(RS)-1-Benzylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione (6a):
Thiazolidinethione 1c (25 mg, 0.14 mmol), benzyl bromide (25 mg,
0.14 mmol), and anhydrous Et3N (25 mg, 0.25 mmol) were used
as described in GP C. The crude product was purified by column
chromatography on silica gel (CH2Cl2; Rf = 0.28) to provide the
title compound as a colorless solid (11 mg, 29%), m.p. 109–110 °C.
1H NMR (499.9 MHz, CDCl3): δ = 1.62–1.64, 1.85–1.94 (2ϫm,
3060, 3028, 3008, 2976, 2954, 2928, 2918, 2833, 2817, 2791, 1744,
1493, 1454, 1423, 1390, 1241, 1128, 1107, 1042, 1024, 1000, 967,
901, 877, 792, 765, 743, 699 cm–1. MS (CI, isobutane): m/z (%) =
233.4 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C13H17N2O2 [M + H]+ 233.1290; found 233.1285.
(RS)-1-(2-Nitrobenzyl)hexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one
2 H, NCH2CH2), 2.35–2.40 (m, 1 H, CH2NCH2CH2), 2.95 (ddd, (6d): Oxazolidinone 2b (100 mg, 0.70 mmol), 2-nitrobenzyl brom-
2J = 16.2, 3J = 3.0, 3J = 13.2 Hz, 1 H, CNCH2), 3.01–3.04 (m, 1 H,
ide (151 mg, 0.70 mmol), and anhydrous Et3N (123 mg, 1.22 mmol)
CH2NCH2CH2), 3.29 (dd, 2J = 10.8, 3J = 8.1 Hz, 1 H, SCH2), were used as described in GP C. The crude product was purified
3.48–3.53 (m, 2 H, CH2CAr, SCH2), 3.88 (d, 2J = 13.7 Hz, 1 H, by column chromatography on silica gel (CH2Cl2/ethyl acetate 19:1;
CH2CAr), 4.65–4.67 (m, 1 H, NCH), 4.85–4.88 (m, 1 H, CNCH2),
Rf = 0.36) to provide the title compound as a colorless solid (66 mg,
34%), m.p. 121 °C. H NMR (500.1 MHz, CDCl3): δ = 1.49–1.52,
1
7.29–7.36 (m, 5 H, 5 ϫ CHAr) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 22.41 (NCH2CH2), 32.66 (SCH2), 46.49 (CNCH2), 1.69–1.79 (2 ϫ m, 2 H, NCH2 CH2 ), 2.15–2.20 (m, 1 H,
50.27 (CH2NCH2CH2), 55.33 (CH2CAr), 85.46 (NCH), 127.77 (p- CH2NCH2CH2), 2.83–2.85 (m, 1 H, CH2NCH2CH2), 2.89–2.95
CHAr), 128.71, 128.76 (2ϫ m-CHAr, 2ϫ o-CHAr), 137.26 (CAr), (m, 1 H, CNCH2), 3.46 (d, J = 15.6 Hz, 1 H, CH2CAr), 3.87–3.91
2
2
195.52 (CS) ppm. IR (ATR): ν = 3083, 3060, 3028, 2974, 2954, (m, 1 H, CNCH2), 4.00 (d, J = 15.6 Hz, 1 H, CH2CAr), 4.14 (dd,
˜
3
3
2927, 2900, 2836, 2818, 2797, 2749, 2726, 1493, 1471, 1456, 1441,
1300, 1268, 1231, 1209, 1194, 1108, 1095, 1045, 1029, 963, 899,
886, 805, 759, 744, 736, 697 cm–1. MS (CI, isobutane): m/z (%) =
265.3 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C13H17N2S2 [M + H]+ 265.0833; found 265.0826.
2J = 9.0, J = 2.9 Hz, 1 H, OCH2), 4.18 (dd, 2J = 6.1, J = 2.9 Hz,
1 H, NCH), 4.29 (dd, 2J = 8.9, 3J = 6.1 Hz, 1 H, OCH2), 7.41–7.44
(m, 1 H, p-CHArCH2), 7.57–7.60 (m, 1 H, p-CHArNO2), 7.71–7.73
(m, 1 H, o-CHArCH2), 7.88–7.89 (m, 1 H, o-CHArNO2) ppm. 13C
NMR (125.8 MHz, CDCl3): δ = 23.86 (NCH2CH2), 40.33
(CNCH2), 51.30 (CH2NCH2CH2), 53.32 (CH2CAr), 66.58 (OCH2),
73.70 (NCH), 124.83 (o-CHArNO2), 128.47 (p-CHArCH2), 130.66
(o-CHArCH2), 132.72 (CArCH2), 133.29 (p-CHArNO2), 149.21
(RS)-1-Allylhexahydro[1,3]thiazolo[3,4-a]pyrimidine-6-thione (6b):
Thiazolidinethione 1c (25 mg, 0.14 mmol), allyl bromide (17 mg,
0.14 mmol), and anhydrous Et3N (25 mg, 0.25 mmol) were used
as described in GP C. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate 3:2; Rf = 0.36)
to provide the title compound as a colorless solid (12 mg, 43%),
m.p. 157–160 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.66–1.71 (m,
(CArNO ), 156.95 (CO) ppm. IR (ATR): ν = 2962, 2936, 2878,
˜
2
2850, 2830, 1523, 1471, 1460, 1434, 1364, 1302, 1261, 1128, 1049,
1038, 1013, 783, 756, 737 cm–1. MS (CI, isobutane): m/z (%) =
278.4 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C13H16N3O4 [M + H]+ 278.1141; found 278.1138.
2
1 H, NCH2CH2), 1.83–1.92 (m, 1 H, NCH2CH2), 2.40 (ddd, J =
3
3
2
15.3, J = 12.5, J = 2.7 Hz, 1 H, CHCH2NCH2), 2.91 (ddd, J =
General Procedure E: The appropriate oxazolidinone (1 equiv.), dis-
solved in anhydrous acetonitrile (10 mL per mmol oxazolidinone),
CH2CH=CH2), 3.16–3.19 (m, 1 H, CHCH2NCH2), 3.24 (dd, J = was treated under argon with the appropriate acrylate (1 equiv.)
17.1, 3J = 13.2, 3J = 3.8 Hz, 1 H, CNCH2), 3.02–3.06 (m, 1 H,
2
3
11.2, J = 7.6 Hz, 1 H, SCH2), 3.31–3.35 (m, 1 H, CH2CH=CH2),
dissolved in anhydrous acetonitrile (10 mL per mmol oxazolidi-
none) and with silica gel (1.000 g per mmol oxazolidinone). The
3.44 (dd, 2J = 11.1, 3J = 7.5 Hz, 1 H, SCH2), 4.52–4.55 (m, 1 H,
NCH), 4.81–4.84 (m, 1 H, CNCH2 ), 5.21–5.23 (m, 1 H, suspension was heated under reflux and the reaction was monitored
CH=CH2trans), 5.25–5.29 (m, 1 H, CH=CH2cis), 5.83 (dddd, 3J =
by TLC. The solvent was removed (rotary evaporator), the crude
5.5, J = 7.3, Jcis = 10.1, Jtrans = 17.3 Hz, 1 H, CH=CH2) ppm. product was suspended in ethyl acetate, and the silica gel was fil-
13C NMR (125.8 MHz, CDCl3): δ = 22.51 (NCH2CH2), 32.42
tered off. The silica gel was washed with a mixture (9:1) of ethyl
3
3
3
(SCH2 ), 46.40 (SCNCH2 ), 50.07 (CHCH2NCH2), 54.29 acetate/MeOH (100 mL per mmol oxazolidinone). The solvent was
(CH2CH=CH2), 85.01 (NCH), 119.02 (CH=CH2), 133.62 removed (rotary evaporator) and the crude product was purified by
(CH=CH ), 195.49 (CS) ppm. IR (ATR): ν = 3066, 2956, 2931,
column chromatography.
˜
2
2856, 2817, 2728, 1643, 1467, 1438, 1296, 1260, 1195, 1163, 1108,
1095, 1034, 969, 934, 896, 882, 800 cm–1. MS (CI, isobutane): m/z
(%) = 215.3 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C9H15N2S2 [M + H]+ 215.0677; found 215.0675.
(RS)-1-(3-Oxo-4-oxapentyl)hexahydro[1,3]oxazolo[3,4-a]pyrimidin-
6-one (7a): Oxazolidinone 2b (50 mg, 0.35 mmol), methyl acrylate
(30 mg, 0.35 mmol), and silica gel (350 mg) were used as described
in GP E. The reaction time was 15 h. The crude product was puri-
fied by column chromatography on silica gel (n-hexane/ethyl acet-
ate 1:1; Rf = 0.11) to provide the title compound as a colorless
(RS)-1-Benzylhexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (6c): Ox-
azolidinone 2b (50 mg, 0.35 mmol), benzyl bromide (60 mg,
0.35 mmol), and anhydrous Et3N (62 mg, 0.61 mmol) were used solid (48 mg, 60%), m.p. 83–85 °C. 1H NMR (500.1 MHz, CDCl3):
Eur. J. Org. Chem. 2014, 833–843
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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841

T. Stalling, J. Pauly, M. Schmidtmann, J. Martens
FULL PAPER
2
δ = 1.54–1.57, 1.69–1.78 (2ϫm, 2 H, NCH2CH2), 2.11 (ddd, J = to provide the title compound as a colorless solid (77 mg, 46%),
1
14.4, 3J = 2.3, 3J = 12.2 Hz, 1 H, COCH2CH2NCH2), 2.23–2.28 m.p. 60–62 °C. H NMR (499.9 MHz, CD3OD): δ = 1.03 (s, 6 H,
(m, 1 H, COCH2CH2), 2.40–2.53 (m, 2 H, COCH2), 2.72–2.78 (m,
2ϫ CH3), 3.17–3.17 (m, 2 H, C=NCH2), 3.26–3.26 (m, 2 H,
1 H, COCH2CH2), 2.86 (ddd, 2J = 16.5, 3J = 3.5, 3J = 13.0 Hz,
OCNCH2), 4.77–4.77 (m, 2 H, OCH2) ppm. 13C NMR
1 H, CNCH2), 3.11–3.13 (m, 1 H, COCH2CH2NCH2), 3.67 (s, 3 H, (125.7 MHz, CD3OD): δ = 24.68 (2ϫ CH3), 27.46 [C(CH3)2], 50.44
OCH3), 3.84–3.88 (m, 1 H, CNCH2), 3.93–3.95 (m, 1 H, NCH),
(OCNCH2), 57.34 (C=NCH2), 68.39 (OCH2), 154.04 (N=C),
157.63 (CO) ppm. IR (ATR): ν = 2953, 2919, 2851, 1774, 1688,
4.25–4.26 (m, 2 H, OCH2) ppm. 13C NMR (125.8 MHz, CDCl3): δ
˜
= 23.91 (NCH2CH2), 32.01 (COCH2), 40.32 (CNCH2), 47.51 1476, 1465, 1423, 1355, 1266, 1250, 1166, 1073, 1040 cm–1. MS (CI,
(COCH2CH2), 50.45 (COCH2CH2NCH2), 51.93 (OCH3), 66.87
(OCH2), 73.35 (NCH), 156.97 (CON), 172.46 (COOCH2) ppm. IR
isobutane): m/z (%) = 169.1 (96) [M + H]+. HRMS (CI, isobutane):
calcd. for C8H13N2O2 [M + H]+ 169.0977; found 169.0981.
(ATR): ν = 2991, 2969, 2959, 2946, 2930, 2843, 1750, 1720, 1469,
˜
Supporting Information (see footnote on the first page of this arti-
1456, 1440, 1416, 1360, 1226, 1218, 1187, 1133, 1117, 1059,
1044 cm–1. MS (CI, isobutane): m/z (%) = 229.3 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C10H17N2O4 [M + H]+ 229.1188;
found 229.1186.
1
cle): H and 13C NMR spectra of all products.
Acknowledgments
(RS)-1-(3-Oxo-4-oxahexyl)hexahydro[1,3]oxazolo[3,4-a]pyrimidin-6-
one (7b): Oxazolidinone 2b (995 mg, 7.00 mmol), ethyl acrylate
(701 mg, 7.00 mmol), and silica gel (7.000 g) were used as described
in GP E. The reaction time was 45 h. The crude product was puri-
fied by column chromatography on silica gel (CH2Cl2/ethyl acetate
4:1; Rf = 0.21) to provide the title compound as a colorless solid
(628 mg, 37%), m.p. 55 °C. 1H NMR (500.1 MHz, CDCl3): δ =
1.22–1.25 (m, 3 H, CH3), 1.54–1.57, 1.68–1.77 (2 ϫ m, 2 H,
NCH2CH2), 2.07–2.12 (m, 1 H, COCH2CH2NCH2), 2.22–2.27 (m,
1 H, COCH2CH2), 2.38–2.50 (m, 2 H, COCH2), 2.72–2.78 (m, 1 H,
CH2CH2CO), 2.86 (ddd, 2J = 16.3, 3J = 3.3, 3J = 13.3 Hz, 1 H,
CNCH2), 3.11–3.14 (m, 1 H, COCH2CH2NCH2), 3.84–3.87 (m,
1 H, CNCH2), 3.92–3.94 (m, 1 H, NCH), 4.12 (q, 3J = 7.0 Hz, 1 H,
CH2CH3), 4.22–4.27 (m, 2 H, OCH2CH) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 14.25 (CH3), 23.91 (NCH2CH2), 32.22
(COCH2 ), 40.32 (CNCH2 ), 47.52 (COCH2 CH2 ), 50.40
(COCH2CH2NCH2), 60.81 (CH2CH3), 66.82 (OCH2CH), 73.34
The silica gel was generously supplied by Grace GmbH & Co. KG.
T. S. gratefully acknowledges the Heinz Neumüller Stiftung for a
doctoral fellowship.
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˜
2
3
= 2989, 2969, 2960, 2925, 2873, 2832, 2795, 1753, 1727, 1474, 1450,
1428, 1384, 1369, 1249, 1216, 1193, 1132, 1119, 1064, 1045, 1026,
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2 h and filtered. The solvent was removed (rotary evaporator). The
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2,3,4,8-Tetrahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one (8a): Oxazol-
idinone 2b (142 mg, 1.00 mmol) and KMnO4 (395 mg, 2.50 mmol)
were used as described in GP F. The crude product was purified by
column chromatography on silica gel (EtOH; Rf = 0.60) to provide
the title compound as a colorless solid (67 mg, 48 %), m.p. 85–
87 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.79–1.83 (m, 2 H,
NCH2CH2), 3.42–3.44 (m, 2 H, C=NCH2), 3.55–3.57 (m, 2 H,
OCNCH2 ), 4. 71–4.72 (m, 2 H, OCH2 ) ppm. 1 3 C NMR
(125.8 MHz, CDCl3): δ = 18.87 (NCH2CH2), 38.72 (OCNCH2),
44.07 (C=NCH2), 67.39 (OCH2), 150.76 (N=C), 155.77 (CO) ppm.
IR (ATR): ν = 2997, 2966, 2948, 2918, 2862, 1778, 1691, 1472,
˜
1455, 1423, 1364, 1286, 1248, 1183, 1154, 1099, 1073, 1049,
1010 cm–1. MS (CI, isobutane): m/z (%) = 141.1 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C6H9N2O2 [M + H]+ 141.0664;
found 141.0660.
3,3-Dimethyl-2,3,4,8-tetrahydro[1,3]oxazolo[3,4-a]pyrimidin-6-one
(8b): Oxazolidinone 2c (170 mg, 1.00 mmol) and KMnO4 (395 mg,
2.50 mmol) were used as described in GP F. The crude product was
purified by column chromatography on silica gel (EtOH; Rf = 0.61)
842
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 833–843

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Received: August 12, 2013
Published Online: November 22, 2013
Eur. J. Org. Chem. 2014, 833–843
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
843