New optically active bis-heterocycles derived from (S)-proline

Article abstract of DOI:10.1002/hlca.201200400

Enantiomerically pure bis-heterocycles containing a (S)-proline moiety have been prepared starting from (S)-N-benzylprolinehydrazide (2b). The reactions with isothiocyanates or butyl isocyanate in refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N-benzylprolinoyl residue. The structure of the tert-butyl derivative 5d was established by X-ray crystallography. Base-catalyzed cyclization of 5 and 9 led to (S)-3-(pyrrolidin-2-yl)-1H-1,2,4-triazole-5(4H)-thiones 6 and the corresponding 5(4H)-one 8, respectively, whereas, in concentrated H₂SO₄, compounds 5 undergo cyclization to give (S)-5-amino-2-(pyrrolidin-2-yl)-1,3,4- thiadiazoles 7. Furthermore, 2b reacted with hexane-2,5-dione in boiling ⁱPrOH to yield the (S)-N-(2,5-dimethylpyrrol-1-yl)prolinamide 10. In the case of the bis-heterocycle 8, treatment with HCOONH₄ and Pd/C in MeOH gave the debenzylated product 12.

Full text of DOI:10.1002/hlca.201200400

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New Optically Active Bis-Heterocycles Derived from (S)-Proline
by Adam M. Pieczonka1) and Grzegorz Mloston´*
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łodz
(phone: þ 48426355761; fax: þ 48426655162; e-mail: gmloston@uni.lodz.pl)
and Anthony Linden and Heinz Heimgartner*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
Enantiomerically pure bis-heterocycles containing a (S)-proline moiety have been prepared starting
from (S)-N-benzylprolinehydrazide (2b). The reactions with isothiocyanates or butyl isocyanate in
refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N-
benzylprolinoyl residue. The structure of the tert-butyl derivative 5d was established by X-ray
crystallography. Base-catalyzed cyclization of 5 and 9 led to (S)-3-(pyrrolidin-2-yl)-1H-1,2,4-triazole-
5(4H)-thiones 6 and the corresponding 5(4H)-one 8, respectively, whereas, in concentrated H2SO4,
compounds 5 undergo cyclization to give (S)-5-amino-2-(pyrrolidin-2-yl)-1,3,4-thiadiazoles 7. Further-
i
more, 2b reacted with hexane-2,5-dione in boiling PrOH to yield the (S)-N-(2,5-dimethylpyrrol-1-
yl)prolinamide 10. In the case of the bis-heterocycle 8, treatment with HCOONH4 and Pd/C in MeOH
gave the debenzylated product 12.
1. Introduction. – The importance of (S)-proline and its derivatives for organo-
catalysis and asymmetric synthesis is well-documented [1 – 3]. Acccordingly, the
preparation of diverse compounds via functionalization of proline is of current interest.
To the best of our knowledge, prolinehydrazide was only scarcely studied for this
purpose. On the other hand, carbohydrazides are known as versatile starting materials
for the synthesis of five- and six-membered heterocycles containing N-, O-, and S-atoms
[4]. In our recent publications, the preparation and reactivity of 3-oxidoimidazole-4-
carbohydrazides 1 as well as prolinehydrazides 2 were described [5 – 8]. Semicarbazides
and thiosemicarbazides obtained from hydrazides by treatment with isocyanates and
isothiocyanates, respectively, are starting materials for cyclocondensations leading to
pyrazolones, 1,3,4-oxadiazoles, 1,2,4-triazole-3-thiones, and 1,3,4-thiadiazoles. In a
previous study, the non-protected prolinehydrazide 2a (R ¼ H) was shown to react with
butyl isocyanate (BuNCO), as well as with butyl isothiocyanate (BuNCS), to yield bis-
adducts of type 3 irrespective of the molar ratio of the reagents [7]. Therefore, for the
present study aimed at the preparation of new bis-heterocycles derived from (S)-
proline, the N-benzylprolinehydrazide (2b) was selected as the key substrate.
2. Results and Discussion. – The starting hydrazide 2b was conveniently prepared
by treatment of methyl (S)-N-benzylprolinate with NH2NH2 · H2O [7]. Subsequent
1
´
´
)
Part of the planned Ph.D. thesis of A. M. P., University of Łodz.
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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reaction of 2b with isothiocyanates 4a – 4d in boiling MeOH afforded the correspond-
ing thiosemicarbazides 5a – 5d in good yields (Scheme 1).
Scheme 1
The structures of the products were confirmed from their spectroscopic data. For
example, the 13C-NMR spectrum of 5a exhibited the signals for C¼O and C¼S at 182.5
and 172.6 ppm, respectively. Finally, the structure of 5d was established by X-ray
crystallography (Fig. 1).
The compound in the crystal is enantiomerically pure, and the absolute config-
uration of the molecule has been determined independently by the diffraction
experiment. The molecule has the expected (S)-configuration. There are two
symmetry-independent molecules in the asymmetric unit. In one of them, the (tert-
butylamino)thiocarbonyl group is disordered over two nearly equally occupied
positions. Intermolecular H-bonds between the NꢀH groups on either side of the S-
atom and the amide O-atom of the other molecule form a ring with a graph set motif
[10] of R12(6) and link the two independent molecules into discrete pairs. These two
opposing sets of interactions create another ring with a graph set motif of R22(10). The
amide group forms an intramolecular H-bond with the heterocyclic ring N-atom to give
a loop with a graph set motif of S(5).
After purification, the obtained thiosemicarbazides 5 were treated with 5%
aqueous NaOH under reflux conditions, and the corresponding 1,2,4-triazole-3-thione
derivatives 6a – 6c were obtained as crystalline products. However, in the case of 5d
t
with the bulky Bu substituent, the attempted cyclization failed (Scheme 2).
The triazole-3-thiones 6 are optically active compounds and the enantiomeric purity
1
of 6a was tested by recording the H-NMR spectrum in the presence of equimolar
amounts of the chiral solvating agent (ꢀ)-(SP)-(tert-butyl)(phenyl)phosphinothioic

Helvetica Chimica Acta – Vol. 95 (2012)
1523
Fig. 1. ORTEP Plot [9] of the molecular structure of one conformation of one of the two symmetry-
independent molecules of 5d (50% probability ellipsoids; arbitrary numbering of the atoms)
Scheme 2
acid (MOD reagent) [11] (Fig. 2). For comparison, racemic triazole-3-thione rac-6a
was synthesized starting with racemic N-benzylprolinehydrazide (rac-2b; Schemes 1
1
and 2). The H-NMR spectrum of rac-6a obtained thereby was also recorded in the
presence of MOD reagent. The registered spectra with diagnostic AB systems of the
PhCH2 groups are depicted in Fig. 2, and, in the case of rac-6a, two well-separated sets
of AB signals were detected (8 lines). On the other hand, the spectrum of optically
active 6a, prepared from (S)-2b, showed only four lines typical for the AB system. Thus,
the obtained results evidenced that the cyclization of (S)-5a under basic conditions
gave the enantiomerically pure product, i.e., occurred without racemization. Based on
this result, enantiomeric purity was also attributed to the optically active triazole-3-
thiones 6b and 6c, which were also tested with MOD reagent giving only one set of
signals for the diagnostic AB system in each case.

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1
Fig. 2. Selected H-NMR signals of rac-6a and (S)-6a in CDCl3 in the presence of 1 equiv. of (ꢀ)-(SP)-
(tert-butyl)(phenyl)phosphinothioic acid
An alternative cyclization of thiosemicarbazides 5 was observed under acidic
conditions. Thus, the reactions of 5a – 5c in concentrated H2SO4 at room temperature
furnished 1,3,4-thiadiazol-2-amines 7a – 7c in fair yields (Scheme 2). Interestingly,
under these conditions, 5c was converted into 7c, which contains a sulfonic acid group in
the para-position of the phenyl ring. An analogous result was observed in the earlier
described series of 1,3,4-thiadiazole-2-anilines derived from 3-oxidoimidazole carbo-
hydrazides 1 [6]. Again, an important question was the enantiomeric purity of the
obtained products 7. In the case of 7a, the 1H-NMR spectrum recorded after addition of
1 mole-quiv. of (ꢀ)-(SP)-(tert-butyl)(phenyl)phosphinothioic acid evidenced that no
racemization occurred.
In an extension of the experiments described above, the synthesis of a 1,2,4-triazol-
3-one 8, the O-analogue of 6b, was achieved. In the first step, the reaction of 2b with
BuNCO gave semicarbazide 9 [7], which subsequently was heated in aqeous NaOH, to
yield the desired product 8 (Scheme 3). The isolated crystalline product was optically
active ([a]2D5 ¼ ꢀ39, c ¼ 1.00, CHCl3).
In another case, a derivative of a pyrrol-1-yl-substituted (S)-proline fragment was
prepared by reacting 2b with hexane-2,5-dione. The reaction was performed in boiling

Helvetica Chimica Acta – Vol. 95 (2012)
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Scheme 3
iPrOH in the presence of a small amount of concentrated HCl. The formation of the
final product 10 (Scheme 3) results from the cyclocondensation of the in situ formed
hydrazone 11. The product displayed optical activity, thus confirming that its formation
did not lead to racemization.
In view of the potential application of bis-heterocycles derived from (S)-proline in
the field of amino catalysis, the availability of the non-protected proline moiety is of
great importance. For this reason, the debenzylation of selected products obtained in
this study was attempted. In a typical procedure, a methanolic solution of 8 and 5 equiv.
of HCO2NH4 in the presence of catalytic amounts of Pd/C was heated to reflux for 1 h
[12]. After usual workup, 12 was obtained in 95% yield (Scheme 4).
Scheme 4
Unfortunately, the attempted hydrogenolytic deprotections (HCO2NH4, Pd/C,
heating or H2, Pd/C) of 1,2,4-triazole-3-thione 6b and 1,3,4-thiadiazole 7b failed.
3. Conclusions. – This study revealed that the (S)-N-benzylprolinehydrazide (2b)
smoothly undergoes reaction with butyl isocyanate and isothiocyanates to yield the
desired semicarbazide 9 and thiosemicarbazides 5, respectively, in good-to-excellent
yields. These derivatives were used for cyclization reactions, which afforded bis-
heterocycles such as (S)-pyrrolidin-2-yl-1,2,4-triazole-3-one 8 or (S)-pyrrolidin-2-yl-

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1,2,4-triazole-3-thiones 6, respectively, upon treatment with aqueous NaOH. On the
other hand, cyclizations of thiosemicarbazides 5 performed in concentrated H2SO4 led
to (S)-pyrrolidin-2-yl-1,3,4-thiadiazol-2-amines 7. However, the analogous reaction of
semicarbazide 9 with H2SO4, expected to yield a 1,3,4-oxadiazol-2-amine, was
unsuccessful. Furthermore, the presence of the bulky tBu group in thiosemicarbazides
or in semicarbazides prevents the cyclization step, and in these cases no expected bis-
heterocyclic products could be obtained. Another cyclization leading to (S)-pyrrolidin-
2-yl-pyrrole derivative 10 was successfully carried out using hexane-2,5-dione as the
substrate. All bis-heterocyclic products were isolated as optically active compounds,
1
and the H-NMR experiments performed with (ꢀ)-(SP)-(tert-butyl)(phenyl)phosphi-
nothioic acid (MOD reagent) established that they are enantiomerically pure
substances. In addition, it was demonstrated that, in the case of N-benzylated
pyrrolidin-2-yl-1,2,4-triazole-3-one 8, debenzylation can be efficiently performed by
treatment of the desired substrate with HCO2NH4/Pd,C. The enantiomerically pure
semicarbazide, thiosemicarbazides, and bis-heterocycles described in these study
constitute a new group of (S)-proline derivatives, which are of potential importance for
new applications as ligands and organocatalysts for asymmetric synthesis.
The authors thank PD Dr. L. Bigler, University of Zurich, for recording of the HR-ESI-MS. A. M. P.
thanks for financial support within the project co-funded by the European Union under the European
Social Fund ꢀ HUMAN – BEST INVESTMENT!ꢁ.
Experimental Part
1. General. M.p.: Melt-Temp. II (Aldrich) or STUART SMP30 apparatus; uncorrected. Optical
rotations: Perkin-Elmer 241 MC polarimeter for l 589 nm. IR Spectra: NEXUS FT-IR spectropho-
.
tometer; in KBr; absorptions in cmꢀ1 1H- and 13C{1H}-NMR spectra: Bruker Avance III (600 and
150 MHz, resp.), in CDCl3, using solvent signal as reference; d in ppm; coupling constants J in Hz;
assignments of signals in 13C-NMR spectra accomplished by HMQC experiments. HR-ESI-MS: Bruker
maXis spectrometer.
2. Starting Materials. All solvents are commercially available and used as received. (S)-N-
Benzylprolinehydrazide (2b) [7] was prepared according to known procedures.
3. Synthesis of Thiosemicarbazides 5a – 5d and Semicarbazide 9. General Procedure. A mixture of 2b
(1 mmol) and the corresponding isothiocyanate (1.1 mmol) or isocyanate (1.1 mmol) in EtOH (5 ml) was
heated to reflux for 2 h. Then, the formed product was filtered off, washed with Et2O and crystallized
from MeOH.
1-({[(2S)-1-Benzylpyrrolidine-2-yl]carbonyl}amino)-3-methylthiourea (5a). Yield: 0.263 g (90%).
Pale yellow oil. [a]2D5 ¼ ꢀ79 (c ¼ 1.00, CHCl3). IR (film): 3262s (br., NH), 2969s, 1684vs (C¼O), 1551s,
1
1495m, 1277m, 702m. H-NMR (CDCl3): 8.99 (br. s, NH); 7.44 – 7.30 (m, 5 arom. H); 6.66 (br. s, NH);
3.97, 3.66 (AB, JAB ¼ 13.2, PhCH2); 3.40 – 3.37 (m, CH); 3.16 – 3.13 (m, 1 H, Pro); 3.06 (d, J ¼ 3.0, Me);
2.50 – 2.46 (m, 1 H, Pro); 2.28 – 2.22 (m, 1 H, Pro); 2.05 – 1.86 (m, 3 H, Pro). 13C-NMR (CDCl3): 182.5,
172.6 (C¼O, C¼S); 138.2 (1 arom. C); 129.2, 128.6, 127.5 (5 arom. CH); 66.2 (CH); 60.4 (PhCH2); 54.5,
30.8, 24.3 (3 CH2); 31.4 (Me). HR-ESI-MS: 293.1432 ([M þ 1]þ, C14H21N4OSþ; calc. 293.1431).
1-({[(2S)-1-Benzylpyrrolidine-2-yl]carbonyl}amino)-3-butylthiourea (5b). See [7].
1-({[(2S)-1-Benzylpyrrolidine-2-yl]carbonyl}amino)-3-phenylthiourea (5c). Yield: 0.336 g (95%).
Pale yellow oil. [a]2D5 ¼ ꢀ59 (c ¼ 1.00, CHCl3). IR (film): 3243s (br., NH), 2971s, 1662vs (C¼O), 1600s,
1
1497s, 1450m, 1320m, 698m. H-NMR (CDCl3): 9.93, 8.83 (2 br. s, 2 NH); 7.52 – 7.22 (m, 10 arom. H);
4.04, 3.58 (AB, JAB ¼ 13.2, PhCH2); 3.41 – 3.38 (m, CH); 3.12 – 3.08 (m, 1 H, Pro); 2.43 – 2.38 (m, 1 H,
Pro); 2.25 – 2.20 (m, 1 H, Pro); 2.04 – 1.79 (m, 3 H, Pro). 13C-NMR (CDCl3): 177.2, 170.6 (C¼O, C¼S);

Helvetica Chimica Acta – Vol. 95 (2012)
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137.7, 129.6 (2 arom. C); 129.2, 128.5, 128.4, 127.5, 126.0, 123.9 (10 arom. CH); 66.2 (CH); 60.2 (PhCH2);
54.0, 30.7, 24.2 (3 CH2). HR-ESI-MS: 355.1592 ([M þ 1]þ, C19H23N4OSþ; calc. 355.1587).
1-({[(2S)-1-Benzylpyrrolidine-2-yl]carbonyl}amino)-3-(tert-butyl)thiourea (5d). Yield: 0.321 g
(96%). Colorless crystals. M.p. 154 – 1568 (iPrOH). [a]D25 ¼ ꢀ63 (c ¼ 1.00, CHCl3). IR (KBr): 3306s
1
(NH), 3228s (NH), 2962s, 1652vs (C¼O), 1558s, 1482m, 1362m, 1277m. H-NMR (CDCl3): 9.25 (br. s,
NH); 7.46 – 7.25 (m, 5 arom. H); 6.97 (br. s, NH); 4.01, 3.55 (AB, JAB ¼ 13.2, PhCH2); 3.34 – 3.31 (m, CH);
3.08 – 3.05 (m, 1 H, Pro); 2.39 – 2.35 (m, 1 H, Pro); 2.25 – 2.18 (m, 1 H, Pro); 2.00 – 1.81 (m, 3 H, Pro); 1.51
(s, 3 Me). 13C-NMR (CDCl3): 178.1, 169.6 (C¼O, C¼S); 137.9 (1 arom. C); 129.1, 128.5, 127.5 (5 arom.
CH); 66.2 (CH); 60.2 (PhCH2); 53.9, 30.8, 24.2 (3 CH2); 53.7 (Me3C); 29.0 (Me3C). HR-ESI-MS:
335.1906 ([M þ 1]þ, C17H27N4OSþ; calc. 335.1900).
Suitable crystals of 5d for the X-ray crystal-structure determination were grown from iPrOH.
1-({[(2S)-1-Benzylpyrrolidine-2-yl]carbonyl}amino)-3-butylurea (9). See [7].
4. Synthesis of Optically Active 1,2,4-Triazole-3-thiones 6 and 1,2,4-Triazole-3-one 8. General
Procedure. A mixture of 5 (1 mmol) or 9 [7] (1 mmol), and a 2% aq. soln. of NaOH (5 ml) was heated to
reflux for 2 h. Then, the soln. was neutralized with AcOH, and the formed precipitate was filtered off and
crystallized from H2O.
Racemic 6a was obtained from rac-5a by the same procedure.
5-[(2S)-1-Benzylpyrrolidin-2-yl]-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (6a). Yield:
0.219 g (80%). Colorless crystals. M.p. 130 – 1328 (H2O). [a]2D5 ¼ ꢀ42 (c ¼ 1.00, CHCl3). IR (KBr):
3142m, 2941s, 2552m (br.), 1571s, 1453m, 1333m, 1071m. 1H-NMR (CDCl3): 11.36 (br. s, HN); 7.29 – 7.18
(m, 5 arom. H); 3.76, 3.41 (AB, JAB ¼ 13.2, PhCH2); 3.71 (s, Me); 3.75 – 3.72 (m, CH); 3.14 – 3.11 (m, 1 H);
2.36 – 2.22 (m, 2 H); 1.99 – 1.89 (m, 3 H). 13C-NMR (CDCl3): 168.9 (C¼S); 152.6, 137.7 (1 arom. C, C(3));
128.7, 128.3, 127.6 (5 arom. CH); 60.8 (CH); 58.5 (PhCH2); 53.6, 29.1, 22.9 (3 CH2); 31.3 (Me). HR-ESI-
MS: 275.1327 ([M þ 1]þ, C17H27N4OSþ; calc. 275.1325).
rac-5-(1-Benzylpyrrolidin-2-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (rac-6a). Yield:
0.222 g (81%). Colorless crystals. M.p. 166 – 1678 (H2O).
5-[(2S)-1-Benzylpyrrolidin-2-yl]-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (6b). See [7].
5-[(2S)-1-Benzylpyrrolidin-2-yl]-2,4-dihydro-4-phenyl-3H-1,2,4-triazole-3-thione (6c). Yield:
0.286 g (85%). Colorless crystals. M.p. 129 – 1318 (H2O). [a]2D5 ¼ ꢀ55 (c ¼ 1.00, CHCl3). IR (KBr):
1
3223m (NH), 3029m, 2934m (br.), 1560m, 1497s, 1312m, 695m. H-NMR (CDCl3): 11.03 (br. s, NH);
7.52 – 7.20 (m, 10 arom. H); 3.86, 3.47 (AB, JAB ¼ 13.2, PhCH2); 3.55 – 3.53 (m, CH); 3.01 – 2.97 (m, 1 H);
2.36 – 2.31 (m, 1 H); 1.98 – 1.61 (m, 4 H). 13C-NMR (CDCl3): 169.5 (C¼S); 154.4, 137.9, 133.6 (2 arom. C,
C(3)); 130.0, 129.6, 128.9, 128.5, 128.3, 127.2 (10 arom. CH); 59.0 (CH); 58.0 (PhCH2); 52.9, 30.7, 22.9
(3 CH2). HR-ESI-MS: 337.1487 ([M þ 1]þ, C19H21N4Sþ; calc. 337.1481).
5-[(2S)-1-Benzylpyrrolidin-2-yl]-4-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (8). Yield: 0.165 g
(55%). Colorless oil. [a]2D5 ¼ ꢀ39 (c ¼ 1.00, CHCl3). IR (film): 3197m (br., NH), 2959s, 1701vs
1
(C¼O), 1468m, 1102m. H-NMR (CDCl3): 9.63 (br. s, NH); 7.30 – 7.22 (m, 5 arom. H); 3.95 – 3.91 (m,
1 H, CH2 of Bu); 3.86, 3.37 (AB, JAB ¼ 13.2, PhCH2); 3.66 – 3.62 (m, 1 H, CH2 of Bu); 3.57 – 3.54 (m, CH);
3.09 – 3.07 (m, 1 H); 2.30 – 2.20 (m, 2 H); 1.97 – 1.87 (m, 3 H); 1.72 – 1.36 (m, 2 CH2, Bu); 0.94 (t, J ¼ 7.8,
Me). 13C-NMR (CDCl3): 156.4 (C¼O); 148.4, 138.0 (1 arom. C, C(3)); 128.8, 128.2, 127.1 (5 arom. CH);
61.3 (CH); 58.2 (PhCH2); 53.2, 29.5, 22.8 (3 CH2); 41.7, 31.0, 20.1 (3 CH2, Bu); 13.7 (Me). HR-ESI-MS:
301.2026 ([M þ 1]þ, C17H25N4Oþ; calc. 301.2023).
5. Synthesis of 1,3,4-Thiadiazoles 7. General Procedure. A soln. of 5 (1 mmol) in conc. H2SO4 (5 ml)
was kept at r.t. for 1 d. After neutralization of the soln. with dil. NH4OH, the solid product was filtered
off, dried i.v., and crystallized from H2O.
Racemic 7a was obtained from rac-5a by the same procedure.
5-[(2S)-1-Benzylpyrrolidin-2-yl]-N-methyl-1,3,4-thiadiazol-2-amine (7a). Yield: 0.241 g (88%).
Yellowish crystals. M.p. 128 – 1308 (H2O). [a]2D5 ¼ ꢀ78 (c ¼ 1.00, CHCl3). IR (KBr): 3250s (HN),
3024m, 1546s, 1520m, 1153m, 1113m. 1H-NMR (CDCl3): 7.33 – 7.25 (m, 5 arom. H); 5.43 (br. s, NH); 4.02,
3.38 (AB, JAB ¼ 13.2, PhCH2); 3.99 – 3.96 (m, CH); 3.07 – 3.04 (m, 1 H, Me); 2.36 – 2.30 (m, 2 H); 1.96 –
1.80 (m, 3 H). 13C-NMR (CDC13): 171.7, 142.7 (thiadiazol C(2), C(5)); 138.4 (1 arom. C); 128.8, 128.3,
127.2 (5 arom. CH); 63.7 (CH); 58.0 (PhCH2); 53.0, 33.3, 22.9 (3 CH2); 33.2 (Me). HR-ESI-MS: 275.1326
([M þ 1]þ, C14H19N4Sþ; calc. 275.1325).

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rac-5-(1-Benzylpyrrolidin-2-yl)-N-methyl-1,3,4-thiadiazol-2-amine (rac-7a). Yield: 0.247 g (90%).
Yellowish crystals. M.p. 158 – 1598 (H2O).
5-[(2S)-1-Benzylpyrrolidin-2-yl]-N-butyl-1,3,4-thiadiazol-2-amine (7b). See [7].
4-({5-[(2S)-1-Benzylpyrrolidin-2-yl]-1,3,4-thiadiazol-2-yl}amino)benzenesulfonic Acid (7c). Yield:
0.225 g (54%). Yellowish crystals. M.p. 262 – 2648 (H2O). [a]2D5 ¼ ꢀ89 (c ¼ 1.00, CHCl3). IR (KBr):
3550 – 3100m (br.), 3266s (NH), 2979m, 1603m, 1508s, 1220m (br.), 1132m. 1H-NMR (CDCl3): 10.32 (br.
s, NH); 7.53 – 7.24 (m, 9 arom. H); 3.96 – 3.94 (m, CH); 3.91, 3.39 (AB, JAB ¼ 13.2, PhCH2); 2.92 – 2.89 (m,
1 H, Me); 2.38 – 2.28 (m, 2 H); 1.83 – 1.79 (m, 3 H). 13C-NMR (CDC13): 171.1, 142.5 (thiadiazol C(2),
C(5)); 139.1, 128.9, 127.0 (3 arom. C); 128.7, 127.4, 127.1, 116.6, 112.7 (9 arom. CH); 63.4 (CH); 58.0
(PhCH2); 53.1, 33.6, 23.2 (3 CH2). HR-ESI-MS: 415.0909 ([M ꢀ 1]þ, C19H19N4O3S2þ ; calc. 415.0904).
6. Synthesis of (2S)-1-Benzyl-N-(2,5-dimethylpyrrol-1-yl)pyrrolidine-2-carboxamide (¼1-Benzyl-N-
(2,5-dimethyl-1H-pyrrol-1-yl)-l-prolinamide; 10). A mixture of 2b (1 mmol), hexane-2,5-dione
i
(3 mmol), PrOH (15 ml), and conc. HCl (0.5 ml) was heated to reflux for 4 h, then cooled, and H2O
(15 ml) was added. The mixture was extracted with CHCl3, the org. layer was dried (Na2SO4), and the
solvent was evaporated. The crude product 10 was purified by flash chromatography and crystallization.
Yield: 0.199 g (67%). Colorless crystals. M.p. 131 – 1328 (MeOH). [a]2D5 ¼ ꢀ69 (c ¼ 1.00, CHCl3). IR
1
(KBr): 3250s (br.), (NH), 2973m, 1678vs (C¼O), 1473m, 1416m, 699m. H-NMR (CDCl3): 9.45 (br. s,
NH); 7.36 – 7.28 (m, 5 arom. H); 5.80 (s, 2 pyrrol CH¼); 4.05, 3.60 (AB, JAB ¼ 13.2, PhCH2); 3.52 – 3.50 (m,
CH); 3.12 – 3.10 (m, 1 H); 2.48 – 2.32 (m, 2 H); 2.10 – 1.84 (m, 3 H, 2 Me). 13C-NMR (CDC13): 173.2
(C¼O); 138.1 (1 arom. C); 128.8, 128.7, 127.7, 127.6 (5 arom. CH and 2 pyrrole C); 104.1 (2 CH¼); 66.9
(CH); 60.3 (PhCH2); 54.1, 31.1, 24.4 (3 CH2); 11.1 (2 Me). HR-ESI-MS: 298.1914 ([M þ 1]þ,
C18H24N3Oþ; calc. 298.1914).
7. Synthesis of 4-Butyl-2,4-dihydro-5-[(2S)-pyrrolidin-2-yl]-3H-1,2,4-triazol-3-one; 12). To a mag-
netically stirred soln. of 8 (1 mmol) in MeOH (2 ml) were added 10% Pd/C (165 mg) and HCO2NH4
(5 mmol). The mixture was heated at reflux for 1 h. After cooling to r.t., Pd/C was filtered, and the
resulting soln. was concentrated under reduced pressure. The crude product 12 was purified by short flash
chromatography. Yield: 0.199 g (95%). Colorless oil. [a]2D5 ¼ ꢀ87 (c ¼ 1.00, CHCl3). IR (film): 3169m
(br., NH), 2963s, 1702vs (C¼O), 1652m, 1393m, 743m. 1H-NMR ((D6)DMSO): 8.34 (br. s, NH); 4.07 –
4.05 (m, CH); 3.60 – 3.56 (m, 1 CH2, Bu); 2.85 – 2.70 (m, 2 H); 2.08 – 2.04 (m, 1 H); 1.91 – 1.74 (m, 2 H);
1.67 – 1.56 (m, 1 H, 1 CH2 of Bu); 1.30 – 1.25 (m, 1 CH2, Bu); 0.89 (t, J ¼ 7.8, Me). 13C-NMR
((D6)DMSO): 165.2 (C¼O); 149.3 (C(3)); 53.8 (CH); 46.9, 28.7, 23.7 (3 CH2); 41.7, 31.1, 19.9 (3 CH2,
Bu); 14.0 (Me). HR-ESI-MS: 211.1554 ([M þ 1]þ, C10H19N4Oþ; calc. 211.1553).
8. X-Ray Crystal-Structure Determination of 5d (Table and Fig. 1)2). All measurements were made
on an Agilent Technologies SuperNova area-detector diffractometer [13] using CuKa radiation (l ¼
1.54184 ꢃ) from a micro-focus X-ray source and an Oxford Instruments Cryojet XL cooler. Data
reduction was performed with CrysAlisPro [13]. The intensities were corrected for Lorentz and
polarization effects, and an empirical absorption correction using spherical harmonics [13] was applied.
The space group was determined from packing considerations, a statistical analysis of intensity
distribution, and the successful solution and refinement of the structure. Equivalent reflections, other
than Friedel pairs, were merged. The data collection and refinement parameters are compiled in the
Table. A view of the molecule is shown in Fig. 1. The structure was solved by direct methods using
SHELXS97 [14], which revealed the positions of all non-H-atoms. There are two symmetry-independent
molecules in the asymmetric unit. The atomic coordinates of the two molecules were tested carefully for a
relationship from a higher symmetry space group using the program PLATON [15], but none could be
found. In one of them, the (tert-butylamino)thiocarbonyl group is disordered over two nearly equally
occupied positions. Two sets of positions were defined for the atoms of the tBu group and the neighboring
N-atom, and the site occupation factor of the major conformation of these groups was refined to 0.564(7).
Similarity restraints were applied to the chemically equivalent bond lengths and angles involving all
disordered atoms, while neighboring atoms within and between each conformation of the disordered
2
)
CCDC-897913 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.

Helvetica Chimica Acta – Vol. 95 (2012)
1529
Table 1. Crystallographic Data for Compound 5d
Crystallized from
iPrOH
Empirical formula
Formula weight [g molꢀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C17H26N4OS
334.48
Colorless, prism
0.18 ꢁ 0.20 ꢁ 0.25
160(1)
]
Crystal system
Space group
Z
monoclinic
P21
4
Reflections for cell determination
13773
2q Range for cell determination [8]
6 – 15
Unit cell parameters a [ꢃ]
11.72165(12)
11.54445(12)
14.70502(17)
105.5398(11)
1917.14(4)
1.159
b [ꢃ]
c [ꢃ]
b [8]
V [ꢃ3]
Dx [g cmꢀ3
]
m(CuKa) [mmꢀ1
Scan type
]
1.567
w
2q(max) [8]
153.3
Transmission factors (min; max)
Total reflections measured
0.722; 1.000
20475
Symmetry independent reflections
Reflections with I > 2s(I)
7676
7427
Reflections used in refinement
Parameters refined; restraints
7676
492; 120
0.0241
Final
R(F) [I > 2s(I) reflections]
wR(F2) (all data)
0.0654
Weights: w ¼ [s2(Fo2) þ (0.0370P)2 þ 0.1103P]ꢀ1 where P ¼ (Fo2 þ 2F2c )/3
Goodness-of-fit
1.019
Secondary extinction coefficient
Final Dmax/s
0.0009(2)
0.001
0.15; ꢀ 0.13
D1 (max; min) [e ꢃꢀ3
]
region were restrained to have similar atomic displacement parameters. The non-H-atoms were refined
anisotropically. Except for the disordered group, the amide H-atoms were placed in the positions
indicated by a difference electron-density map and their positions were allowed to refine together with
individual isotropic displacement parameters. All remaining H-atoms were placed in geometrically
calculated positions and refined by using a riding model where each H-atom was assigned a fixed
isotropic displacement parameter with a value equal to 1.2 Ueq of its parent C-atom (1.5 Ueq for Me
groups). The refinement of the structure was carried out on F2 by using full-matrix least-squares
procedures, which minimized the function Sw(F2o ꢀ Fc2 )2. A correction for secondary extinction was
applied. Refinement of the absolute structure parameter [16] yielded a value of 0.001(8), which
confidently confirms that the refined coordinates represent the true enantiomorph. Neutral atom
scattering factors for non-H-atoms were taken from [17a], and the scattering factors for H-atoms were
taken from [18]. Anomalous dispersion effects were included in Fc [19]; the values for f’ and f’’ were
those of [17b]. The values of the mass attenuation coefficients are those of [17c]. The SHELXL97
program [14] was used for all calculations.

1530
Helvetica Chimica Acta – Vol. 95 (2012)
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Received July 30, 2012