Studies on the synthesis and some reactions of (S)-proline hydrazides

Article abstract of DOI:10.1016/j.tetasy.2012.05.010

A convenient synthesis of (S)-proline hydrazide 2a via the reaction of ethyl (S)-N-benzylprolinate with hydrazine hydrate and subsequent deprotection of (S)-N-benzyl proline hydrazide 5 is described. The latter, in methanolic solution, reacted with aromatic aldehydes as well as with cycloaliphatic ketones at room temperature to give the corresponding hydrazones of type 7 in good yields. The structure of the product with furan-2-carbaldehyde 7b, proving the (E)-configuration of the hydrazone, was established by X-ray crystallography. In the case of the unprotected (S)-proline hydrazide 2a, the analogous reaction with aromatic aldehydes led either to the expected hydrazones 7 or the 1H-pyrrolo[1,2-c]imidazol-1-one derivatives 8, depending on the reaction conditions. The latter were formed via a secondary cyclocondensation of the initially formed 7 with a second molecule of the aldehyde. Whereas the reaction of (S)-N-benzyl proline hydrazide 5 with butyl isocyanate and isothiocyanate gave the corresponding semicarbazide and thiosemicarbazide, respectively, of type 9, the unprotected (S)-proline hydrazide 2a yielded the 1:2 adducts 10. Thiosemicarbazide 9b underwent cyclization reactions under basic (NaOH) and acidic (H₂SO₄) conditions to yield (S)-prolinyl- substituted 1,2,4-triazole-3-thione 11 and 1,3,4-thiadiazole-2-amine 12, respectively.

Full text of DOI:10.1016/j.tetasy.2012.05.010

Tetrahedron: Asymmetry 23 (2012) 795–801
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies on the synthesis and some reactions of (S)-proline hydrazides q
Grzegorz Mloston , Adam M. Pieczonka a, Aneta Wróblewska a, Anthony Linden b, Heinz Heimgartner b
a,
⇑
´
a
´
´
University of Łódz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łódz, Poland
b Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2012
Accepted 15 May 2012
A convenient synthesis of (S)-proline hydrazide 2a via the reaction of ethyl (S)-N-benzylprolinate with
hydrazine hydrate and subsequent deprotection of (S)-N-benzyl proline hydrazide 5 is described. The lat-
ter, in methanolic solution, reacted with aromatic aldehydes as well as with cycloaliphatic ketones at
room temperature to give the corresponding hydrazones of type 7 in good yields. The structure of the
product with furan-2-carbaldehyde 7b, proving the (E)-configuration of the hydrazone, was established
by X-ray crystallography. In the case of the unprotected (S)-proline hydrazide 2a, the analogous reaction
with aromatic aldehydes led either to the expected hydrazones 7 or the 1H-pyrrolo[1,2-c]imidazol-1-one
derivatives 8, depending on the reaction conditions. The latter were formed via a secondary cycloconden-
sation of the initially formed 7 with a second molecule of the aldehyde. Whereas the reaction of (S)-N-
benzyl proline hydrazide 5 with butyl isocyanate and isothiocyanate gave the corresponding semicarb-
azide and thiosemicarbazide, respectively, of type 9, the unprotected (S)-proline hydrazide 2a yielded
the 1:2 adducts 10. Thiosemicarbazide 9b underwent cyclization reactions under basic (NaOH) and acidic
(H2SO4) conditions to yield (S)-prolinyl-substituted 1,2,4-triazole-3-thione 11 and 1,3,4-thiadiazole-2-
amine 12, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Treatment of (S)-proline with hydrazine hydrate (large excess)
at elevated temperatures led to 4-amino-3,5-bis(2-pyrrolidine)-
It is well documented that enantiopure (S)-proline 1a (R = H)
and its derivatives belong to privileged compounds widely applied
in the field of asymmetric synthesis and organocatalysis.2 On the
other hand, carbohydrazides form an important class of building
blocks for the preparation of diverse N-heterocycles3 with practical
applications as agrochemicals and pharmaceuticals.4 Moreover, a
variety of hydrazones derived from hydrazides are known for their
biological activities.5 Finally, some hydrazides are also used as
pharmaceuticals; isoniazid (isonicotinohydrazide), synthesized
for the first time at the beginning of the 20th century, is the best
known example of this class of compound.6
1,2,4-triazoles,9 and proline hydrazide 2a was proposed to be the
key intermediate in the reaction. A biologically active hydrazone
derived from proline hydrazide was prepared by using 2-chloroac-
etophenone.10 In a very recent report, proline hydrazide prepared
from methyl (S)-prolinate hydrochloride and excess hydrazine hy-
drate in methanolic solution was isolated and fully characterized.11
The hydrazine hydrochloride formed was removed from the crude
product via precipitation from methanol. In a recent study, the
preparation of N0-mono- and N0,N0-disubstituted (S)-proline hydra-
zides and their applications as catalysts for asymmetric aldol reac-
tions were reported.12
Whereas proline amides and thioamides are well known and
have been explored successfully as catalysts and ligands,7 the re-
lated proline hydrazides 2 are less well known. To the best of our
knowledge, hydrazides of the non-protected (S)-proline are scar-
cely described. The synthesis of (S)-proline hydrazide 2a
(R1 = R2 = H) by using anhydrous (absolute) hydrazine, as well as
some of its hydrazones 3 (Scheme 1), was published in 1993.8a In
another paper, the authors reported the formation of bicyclic 1:2
products, that is, 2,3-disubstituted 1,3-diazabicyclo[3.3.0]octan-
4-ones.8b
Due to our current interests in the synthesis and applications of
heterocyclic carbohydrazides13 as well as asymmetric synthesis,14
we herein report a convenient and efficient protocol for the prep-
aration of (S)-proline hydrazide 2a, which is a promising reagent
for further and diverse applications.
2. Results and discussion
A typical procedure for the synthesis of acid hydrazides is the
treatment of the corresponding esters with hydrazine hydrate.3,15
Using this method, ethyl (S)-N-benzyl prolinate 4 can be easily
transformed into (S)-N-benzyl proline hydrazide 5 in high yield
(Scheme 2).16
q
See Ref. 1.
⇑
Corresponding author.
E-mail address: gmloston@uni.lodz.pl (G. Mloston´ ).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.010

´
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G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
R3
R3
O
H
N
R4
NHNR1R2
R4
N
COOR
N
H
N
H
N
H
R1 = R2 = H
O
O
1
2
3
Scheme 1.
In our hands, the reaction of methyl (S)-prolinate 1b with a
also detected. Therefore, we believe that two distinct rotamers ex-
ist in solution in an equilibrium.
commercial aqueous solution of hydrazine (80%) at room temper-
ature, resulted in hydrolysis, and proline 1a was isolated as the sole
product. Following the protocol reported in the literature,11 we ob-
tained 2a contaminated with hydrazine hydrochloride, which
could not be removed completely by repeated treatment with
methanol. When the aqueous hydrazine solution was distilled over
KOH pellets and then used for the reaction with 1b, a crystalline
product was obtained, which was identified as the well known
diketopiperazine derivative 6 (Scheme 3).12 In another experiment,
the sequential treatment of 1a with thionyl chloride and hydrazine
hydrate also led to 6. Most likely in both cases, the hydrazine hy-
drate acted only as a base.
Having in hand the N-benzylated hydrazide 5, the non-pro-
tected 2a was prepared by standard hydrogenolysis over palladium
on charcoal. Alternatively, substrate 5 could be converted into 2a
using ammonium formate in boiling methanolic solution, in the
presence of Pd/C as a deprotecting reagent. The physicochemical
and spectroscopic properties of 2a fitted well with the data re-
ported in the literature.8a,11 Thus, the method presented in
Scheme 2 provides convenient access to pure 2a on a multigram
scale.
In the second part of our study, selected reactions with hydra-
zides 2a and 5 were performed using aldehydes, ketones, butyl iso-
cyanate, and butyl isothiocyanate. The N-benzylated proline
hydrazide 5 reacted smoothly with aldehydes at room temperature
to yield the expected hydrazones 7 as a single isomer in each case
(Scheme 4). The 1H NMR spectra showed that a single isomer was
also present in solution. In the case of the non-protected proline
hydrazide 2a, the reaction was dependent on the protocol applied
and a test reaction was carried out with 4-methoxybenzaldehyde.
Whereas slow addition of the aldehyde to a stirred solution of 2a at
room temperature led to the expected hydrazone 7e, the reversed
addition of both reagents (2a was added in small portions to a stir-
red solution of excess aldehyde) resulted in the exclusive forma-
Similar to aromatic aldehydes, the reactions of 2a and 5 with
less reactive cyclohexanone and adamantanone also occurred
smoothly at room temperature in MeOH solutions. In all cases,
the expected hydrazones were obtained in high yields as crystal-
line materials.
Hydrazone 7b was obtained as a crystalline material suitable for
X-ray crystal structure analysis (Fig. 1). The compound in the crys-
tal was enantiomerically pure and the absolute configuration of the
molecule has been determined independently by the diffraction
experiment. The molecule had the expected (S)-configuration and
the C@N bond was (E)-configured. The amide group forms an intra-
molecular hydrogen bond with the ring N-atom to give a loop with
a graph set motif18 of S(5).
Reactions of butyl isocyanate and butyl isothiocyanate with 5
occurred smoothly in boiling ethanol to yield the desired semicarb-
azide 9a and thiosemicarbazide 9b, respectively (Scheme 5). On
the other hand, treatment of the non-protected 2a with 1 M equiv
of butyl isocyanate and butyl isothiocyanate, respectively, resulted
in the formation of the 1:2 adducts 10a and 10b, that is, the prod-
ucts of a twofold addition, which were obtained along with uncon-
verted starting material 2a. In another experiment with 2 M equiv
of the heterocumulene, the conversion of 2a to the corresponding
compounds 10 was complete. These results show that these addi-
tions occur non-selectively and, remarkably, no 1:1 adduct was ob-
tained regardless of the reaction conditions applied.
It is well established that thiosemicarbazides derived from car-
bohydrazides are versatile starting materials for the preparation of
diverse heterocycles.13,15 Thus, heating of 9b in aqueous NaOH
gave the 1,2,4-triazole-3-thione 11, whereas the reaction in
H2SO4 at room temperature yielded the 1,3,4-thiadiazol-2-amine
derivative 12 (Scheme 6). Further studies aimed at the exploration
of proline hydrazides for the preparation of enantiomerically pure
bis-heterocyclic products are currently in progress.
tion of the corresponding 1:2 product of type
8 in a
diastereoselective manner (Scheme 4). In two earlier publica-
tions,8a,b both types of products, i.e. hydrazones 7 and 1:2 products
8, were obtained using the same protocol based on the addition of
the corresponding aldehyde in one portion to the solution of 2a at
room temperature. In our hands, upon application of this protocol,
the formation of both products in a ratio of approximately 1:1 was
observed.
It is worth mentioning that in contrast to hydrazones 7a–d, the
non-protected analogues 7e–i exist in solution as mixtures of two
stereoisomers or conformers (1H NMR evidence). On the basis of
the present data, it was not possible to formulate a convincing
explanation for this phenomenon. However in the case of 7h and
7i, in which no (E/Z)-isomers are possible, two sets of signals were
3. Conclusion
Herein we have shown that non-protected (S)-proline hydra-
zide 2a can be prepared conveniently by using aqueous hydrazine
and N-benzyl prolinate with subsequent deprotection of the N-
atom. Both optically active (S)-proline derived hydrazides 2a and
5 react with aldehydes and cyclic ketones to yield the correspond-
ing hydrazones 7. However, in the case of the reaction of 2a with
aldehydes, depending on the reaction conditions, a secondary pro-
cess leading to a product of type 8 competes with the formation of
the corresponding hydrazone. The formation of 8 is rationalized by
the cyclocondensation of the initially formed hydrazone 7 with a
second molecule of the aldehyde. Furthermore, the reactions of
aq. NH2NH2
NHNH2
H2, Pd/C
MeOH
NHNH2
(80%)
COOEt
N
N
N
H
O
MeOH
O
Ph
Ph
4
5
2a
Scheme 2.

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G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
NH2NH2·H2O
(dist. KOH)
aq. NH2NH2
(80%)
O
N
COOH
COOMe
N
N
H
N
H
MeOH
MeOH
O
6
1a
1b
1. SOCl2
2. NH2NH2·H2O (dist. KOH), MeOH
Scheme 3.
R1
R2
H
N
NHNH2
R1
MeOH
N
+
O
N
N
R2
O
O
R
R
R = Bn, R1 = H, R2 = 4-MeOC6H4
5
(R = Bn)
7a
2a (R = H)
7b R = Bn, R1 = H, R2 = 2-furyl
1
R = Bn, R -R2 = (CH2)5
7c
7d R = Bn, R1-R2 = adamantylidene
1
R = R = H, R2 = 4-MeOC6H4
7e
7f R = R1 = H, R2 = 4-NO2C6H4
R = R1 = H, R2 = 2-furyl
7g
7h R = H, R1-R2 = (CH2)5
1
R = H, R -R2 = adamantylidene
7i
MeOH
8a Ar = 4-MeOC6H4
8b Ar = 4-NO2C6H4
O
N
H
2a
+ 2 ArCHO
H
N
8c Ar = 2-furyl
Ar
N
Ar
Scheme 4.
X
the N-benzylated hydrazide 5 with butyl isocyanate and isothiocy-
anate afforded semicarbazides and thiosemicarbazides, respec-
tively, which are attractive building blocks for the preparation of
chiral bis-heterocycles, such as 1,3,4-thiadiazoles and 1,2,4-tria-
zol-2-thiones. These compounds, and other products derived from
2a and 5, are of interest as promising organocatalysts and ligands
for asymmetric synthesis. The addition of butyl isocyanate and bu-
tyl isothiocyanate with the non-protected 2a occur at both N-
atoms in a non-selective manner.
NHNH2
H
N
EtOH
reflux
NH
Bu
N
C
X
+
N
H
N
R
Bu
N
R
O
O
5
(R = Bn)
9a R = Bn, X = O
9b
2a (R = H)
R = Bn, X = S
10a
10b
R = BuNHCO, X = O
R = BuNHCS, X = S
Scheme 5.
4. Experimental
4.1. General
Melting points were determined in a capillary using a Melt-
Temp. II apparatus (Aldrich) or STUART SMP30 and are uncor-
rected. IR spectra were recorded on a NEXUS FT-IR spectrophotom-
eter in KBr; absorptions (m .
) in cmꢀ1 1H and 13C{1H} NMR spectra
were measured on a Bruker Avance III instrument (600 and
150 MHz, resp.) using solvent signals as a reference. Chemical
shifts (d) are given in ppm and coupling constants J in Hz. Assign-
ments of signals in 13C NMR spectra were made on the basis of
HMQC experiments. HR-MS: Bruker maXis spectrometer. Optical
rotations were determined on a PERKIN-ELMER 241 MC polarime-
ter for k = 589 nm.
4.2. Starting materials
Figure 1. ORTEP plot17 of the molecular structure of 7b (arbitrary numbering of the
All solvents and reagents are commercially available and used
as received. Ethyl (S)-N-benzylprolinate 4 and methyl (S)-prolinate
atoms; 50% probability ellipsoids).

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G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
S
Bu
N
H
H2SO4
aq. NaOH
NH
Bu
N
S
N
H
S
NHBu
N
N
N
r.t.
reflux
- H2O
N
NH
N
N
O
-H2O
Bn
Bn
Bn
11
9b
Scheme 6.
12
1b were prepared following a known protocol based on the treat-
ment of the corresponding amino acid, dissolved in ethanol or
methanol, with thionyl chloride.11
was added and the mixture heated at reflux for 1 h. Next, water
was added and the aqueous layer was extracted with CHCl3. The
organic layer was dried over Na2SO4, and the solvent was evapo-
rated. The residue was passed through a silica gel plug to give 6.
Yield: 0.524 g (27%). Colorless crystals. Mp 139–141 °C.
4.3. Synthesis of (S)-proline hydrazide 2a
Procedure A: To a magnetically stirred solution of (S)-N-ben-
zylproline hydrazide 5 (10 mmol) in MeOH (5 ml) was added 10%
Pd/C (300 mg). Then, H2 gas was bubbled through the solution
for 24 h; the progress of the reaction was followed by TLC (SiO2,
MeOH/CH2Cl2 1:4). After the starting hydrazide was consumed,
Pd/C was filtered and the resulting solution was concentrated un-
der reduced pressure. The obtained highly pure product 2a was
analyzed without further purification. Yield: 1.161 g (90%).
4.6. General procedure for the synthesis of hydrazones 7a–d
To a stirred solution of hydrazide 5 (1 mmol) in MeOH (5 ml) at
20 °C was slowly added an equimolar quantity of the carbonyl
component. The mixture was stirred for 16 h at rt, after which
the solution was concentrated, and the resulting solid was treated
with Et2O, filtered, and crystallized from an appropriate solvent.
Procedure B: To a magnetically stirred solution of (S)-N-ben-
zylproline hydrazide 5 (5 mmol) in MeOH (10 ml) were added
10% Pd/C (165 mg) and HCOONH4 (5 eq). The mixture was heated
at reflux for 1 h. After cooling to rt, Pd/C was filtered and the result-
ing solution was concentrated under reduced pressure. The highly
pure product 2a obtained was analyzed without further purifica-
4.6.1. (2S)-1-Benzyl-N-[(E)-(4-methoxyphenyl)methylidene]
pyrrolidine-2-carbohydrazide 7a
Yield: 0.250 g (74%). Colorless crystals. Mp 94–96 °C (EtOH). IR
(KBr):
m 3255s (HN), 2973 m, 1676vs (C@O), 1603s, 1506 m,
1255 m. 1H NMR (CDCl3): d 10.21 (br s, HN); 7.99 (s, HC@N);
7.71, 6.93 (AA0BB0, JAB = 8.3, 4 arom. H); 7.39–7.28 (m, 5 arom. H);
3.93, 3.65 (AB, JAB = 13.2, CH2Ph); 3.86 (s, MeO); 3.45–3.42 (m,
CH); 3.16–3.14 (m, 1H); 2.52–2.47 (m, 1H); 2.35–2.31 (m, 1H);
2.10–1.77 (m, 3H). 13C NMR (CDCl3): d 170.4 (C@O); 148.1
(C@N); 138.4, 130.1, 126.3 (3 arom C); 129.3, 128.7, 128.6, 127.5,
114.1 (9 arom. CH); 67.1 (CH); 60.1 (CH2Ph); 55.4 (MeO); 54.3,
30.8, 24.3 (3 CH2). HR-ESI-MS: 338.1865 (calcd 338.1863 for
tion. Yield: 0.121 g (94%). IR (film):
m 3328s (HN), 2976 m,
1659vs (C@O), 1541 m, 1410 m. 1H NMR (CDCl3): d 8.50 (br s,
HN); 3.74–3.71 (m, CH); 2.95–2.80 (m, 2H); 2.61 (br s, NH2);
2.10–2.03 (m, 1H); 1.87–1.82 (m, 1H); 1.70–1.60 (m, 2H). 13C
NMR (CDCl3): d 175.1 (C@O); 59.9 (CH); 47.2, 30.6, 26.1 (3 CH2).
HR-ESI-MS: 130.0974 (calcd 130.0975 for C5H12N3O, [M+1]+).
½
a 2D5
ꢁ
¼ ꢀ38 (c 1.00, MeOH).
C
20H24N3O2, [M+1]+). ½a D25
¼ þ104 (c 1.00, MeOH).
ꢁ
4.4. Synthesis of (S)-N-benzylproline hydrazide 5
4.6.2. (2S)-1-Benzyl-N-[(E)-2-furylmethylidene]pyrrolidine-2-
carbohydrazide 7b
To a solution of freshly prepared (S)-N-benzylproline ethyl ester
4 (10 mmol) in MeOH (5 ml) was added NH2NH2ꢂH2O (20 mmol).
The mixture was stirred for 16 h at rt, after which the solvent
was evaporated under vacuum. The highly pure product 5 obtained
was analyzed without further purification. Yield: 2.102 g (96%).
Yield: 0.232 g (69%). Colorless crystals. Mp 135–136 °C (EtOH).
IR (KBr):
m 3250s (HN), 2977 m, 1679vs (C@O), 1515 m, 1470 m,
1346 m. 1H NMR (CDCl3): d 10.22 (br s, HN); 8.30 (s, HC@N);
7.50, 6.80, 6.47 (3d, J = 3.6, 3 furyl H); 7.35–7.25 (m, 5 arom. H);
3.89, 3.61 (AB, JAB = 13.2, CH2Ph); 3.40–3.37 (m, CH); 3.11–3.08
(m, 1H); 2.47–2.43 (m, 1H); 2.30–2.27 (m, 1H); 2.04–1.76 (m,
3H). 13C NMR (CDCl3): d 170.8 (C@O); 149.4, 138.2 (2 arom. C);
138.8 (C@N); 144.6, 128.7, 128.6, 127.6, 113.1, 111.9 (8 arom.
CH); 67.1 (CH); 60.1 (CH2Ph); 54.2, 30.8, 24.3 (3 CH2). HR-ESI-
Pale yellow oil. IR (film):
m 3316s (HN), 2969s, 1663vs (C@O),
1496s, 701 m. 1H NMR (CDCl3): d 8.26 (s, HN); 7.32–7.23 (m, 5
arom. H); 3.81, 3.51 (AB, JAB = 13.2, CH2Ph); 3.28–3.26 (m, CH);
3.02–2.99 (m, 1H); 2.36–2.32 (m, 1H); 2.22–2.18 (m, 1H); 1.89–
1.68 (m, 3H). 13C NMR (CDCl3): d 174.7 (C@O); 138.4 (1 arom. C);
128.7, 128.5, 127.3 (5 arom. CH); 66.5 (CH); 60.0 (CH2Ph); 54.0,
30.6, 24.1 (3 CH2). HR-ESI-MS: 220.1443 (calcd 220.1444 for
MS: 298.1550 (calcd 298.1550 for
¼ þ121 (c 1.00, MeOH).
C
17H20N3O2, [M+1]+).
½ ꢁ
a 2D5
C
12H18N3O, [M+1]+). ½a D25
¼ ꢀ70 (c 1.00, MeOH).
ꢁ
4.6.3. (2S)-1-Benzyl-N-(cyclohexylidene)pyrrolidine-2-carbo-
hydrazide 7c
4.5. Synthesis of diketopiperazine 6
Yield: 0.269 g (81%). Colorless crystals. Mp 85–87 °C (EtOH). IR
(KBr): m 3198s (HN), 2933s, 1678vs (C@O), 1550 m, 1209 m, 741 m.
Procedure A: To a solution of freshly prepared (S)-proline methyl
ester 1b (10 mmol) in MeOH (5 ml) was added NH2NH2ꢂH2O
(20 mmol) distilled over KOH pellets. The mixture was stirred for
16 h at rt, and the solvent was evaporated under vacuum to give
6. Yield: 1.223 g (63%). Colorless crystals. Mp 140–142 °C; lit.,12b
mp 144–145 °C.
Procedure B: A mixture of (S)-proline 1a (10 mmol) and thionyl
chloride (2.4 ml) was heated at reflux for 30 min. After cooling to
rt, an excess of NH2NH2ꢂH2O (1.18 ml) distilled over KOH pellets
1H NMR (CDCl3): d 10.15 (br s, HN); 7.33–7.27 (m, 5 arom. H); 3.91,
3.56 (AB, JAB = 13.2, CH2Ph); 3.41–3.39 (m, CH); 3.12–3.09 (m, 1
proline H); 2.44–1.62 (m, 5 proline H, 10 cyclohexyl H). 13C NMR
(CDCl3): d 170.2 (C@O); 161.0 (C@N); 138.6 (1 arom C); 128.7,
128.6, 127.4 (5 arom. CH); 67.4 (CH); 60.2 (CH2Ph); 54.3, 35.5,
30.8, 25.8, 26.7, 25.9, 25.6, 24.3 (3 proline CH2, 5 cyclohexyl
CH2). HR-ESI-MS: 300.2070 (calcd 300.2070 for C18H26N3O,
[M+1]+).). ½a 2D5
¼ ꢀ102 (c 1.00, MeOH).
ꢁ

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G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
4.6.4. (2S)-N-(2-Adamantylidene)-1-benzylpyrrolidine-2-carbo-
hydrazide 7d
or isomer: d 170.3 (C@O); 149.0 (1 arom. C); 144.8, 113.9, 112.0 (3
furyl CH); 139.3 (C@N); 59.5 (CH); 46.8, 30.4, 24.7 (3 CH2). HR-ESI-
Yield: 0.263 g (75%). Colorless crystals. Mp 169–171 °C (EtOH).
MS: 208.1077 (calcd 208.1081 for C10H14N3O2, [M+1]+). ½a D25
¼ ꢀ80
ꢁ
IR (KBr):
m
3203s (HN), 2912s, 1666vs (C@O), 1553 m, 1210 m,
(c 1.00, MeOH).
741 m. 1H NMR (CDCl3): d 10.17 (br s, HN); 7.33–7.24 (m, 5 arom.
H); 3.92, 3.53 (AB, JAB = 13.2, CH2Ph); 3.42–3.39 (m, CH); 3.10–3.08
(m, 1 proline H); 2.92, 2.82 (2 br. s, 2 adamantyl CH); 2.42–2.28 (m,
2 proline H); 2.05–1.73 (m, 3 proline H, 12 adamantyl H). 13C NMR
(CDCl3): d 170.3 (C@O); 167.4 (C@N); 138.7 (1 arom. C); 128.6,
128.4, 127.4 (5 arom. CH); 67.5 (CH); 60.2 (CH2Ph); 54.3, 39.5,
39.0, 37.8, 36.3, 31.5, 30.7, 27.8, 24.4 (3 proline CH2, 9 adamantyl
C). HR-ESI-MS: 352.2382 (calcd 352.2383 for C22H30N3O, [M+1]+).
4.7.4. (2S)-N-(Cyclohexylidene)pyrrolidine-2-carbohydrazide 7h
Yield: 0.082 g (39%). IR (film): 3261s (HN), 2935s, 1683vs
m
(C@O), 1534 m, 1221 m, 1043 m. 1H NMR ((D6)DMSO): major iso-
mer: d 10.96 (br s, HN); 4.09–4.06 (m, CH); 3.27–3.17 (m, 2 proline
H); 2.46–1.53 (m, 5 proline H, 10 cyclohexyl H); minor isomer: d
11.10 (br s, HN); 4.65–4.62 (m, CH); 3.27–3.17 (m, 2 proline H);
2.46–1.53 (m, 5 proline H, 10 cyclohexyl H). 13C NMR ((D6)DMSO):
major isomer: d 170.5, 167.7 (C@O, C@N); 58.2 (CH); 45.8, 35.4,
30.0, 29.2, 27.3, 26.1, 25.4, 24.0 (3 proline CH2, 5 cyclohexyl
CH2); minor isomer: d 170.5, 165.4 (C@O, C@N); 58.5 (CH); 46.0,
35.6, 30.4, 29.3, 27.4, 26.2, 25.5, 24.1 (3 proline CH2, 5 cyclohexyl
CH2). HR-ESI-MS: 210.1598 (calcd 210.1601 for C11H20N3O,
½
a 2D5
ꢁ
¼ ꢀ74 (c 1.00, CHCl3).
4.7. General procedure for the synthesis of hydrazones 7e–i
To a stirred solution of hydrazide 2a (1 mmol) in MeOH (5 ml)
at 20 °C, an equimolar quantity of the carbonyl component in
MeOH (10 ml) was added over 4 h. The mixture was then stirred
for 16 h at rt, after which the solution was concentrated, and the
resulting solid was treated with Et2O and filtered.
[M+1]+). ½a 2D5
¼ ꢀ88 (c 1.00, MeOH).
ꢁ
4.7.5. (2S)-N-(2-Adamantylidene)pyrrolidine-2-carbohydrazide
7i
Yield: 0.104 g (40%). Colorless crystals. Mp 95–97 °C (Et2O). IR
4.7.1. (2S)-N-[(E)-(4-Methoxyphenyl)methylidene]pyrrolidine-
2-carbohydrazide 7e
(KBr): m 3127s (HN), 2915s, 1686vs (C@O), 1542 m, 1450 m,
1226 m. 1H NMR ((D6)DMSO): major isomer: d 11.03 (br s, HN);
4.31–4.28 (m, CH); 3.25–3.13 (m, 2 proline H); 2.55, 2.49 (2 br.
s, 2 adamantyl CH); 2.00–1.65 (m, 4 proline H, 12 adamantyl H);
minor isomer: d 10.94 (br s, HN); 4.65–4.62 (m, CH); 2.55, 2.49 (2
br. s, 2 adamantyl CH); 2.41–2.25 (m, 2 proline H); 2.00–1.65
(m, 4 proline H, 12 adamantyl H). 13C NMR ((D6)DMSO): major
isomer: d 169.9, 166.1 (C@O, C@N); 58.7 (CH); 46.2, 39.2, 39.0,
37.8, 36.2, 31.9, 29.4, 27.6, 24.4 (3 proline CH2, 5 adamantyl CH2
and 4 adamantyl CH); minor isomer: d 170.6, 166.2 (C@O, C@N);
58.4 (CH); 46.0, 39.0, 38.8, 37.6, 36.1, 31.2, 29.3, 27.5, 24.3 (3 pro-
line CH2, 5 adamantyl CH2, 4 adamantyl CH). HR-ESI-MS: 262.1912
Yield: 0.188 g (76%). Colorless crystals. Mp 85–86 °C (Et2O). IR
(KBr):
m 3257s (HN), 2965 m, 1686vs (C@O), 1607s, 1513 m,
1253s. 1H NMR (CDCl3): major isomer: d 8.12 (s, HC@N); 7.35,
6.70 (AA0BB0, JAB = 8.3, 4 arom. H); 4.93–4.91 (m, CH); 3.76 (s,
MeO); 3.70–3.61 (m, 2 proline H); 2.49–2.08 (m, 4 proline H); min-
or isomer: d 8.18 (s, HC@N); 7.67 6.88 (AA0BB0, JAB = 8.3, 4 arom. H);
4.17–4.13 (m, CH); 3.82 (s, MeO); 3.20–3.06 (m, 2 proline H); 2.39–
1.80 (m, 4 proline H). 13C NMR (CDCl3): major isomer: d 161.3
(C@O); 146.7 (C@N); 142.4, 126.2, (2 arom. C); 129.3 114.0 (4
arom. CH); 58.6 (CH); 55.2 (MeO); 46.6, 30.7, 24.6 (3 CH2); minor
isomer: d 161.7 (C@O); 148.9 (C@N); 142.4, 126.2 (2 arom. C);
128.8, 114.1 (4 arom. CH); 59.9 (CH); 55.3 (MeO); 46.6, 29.8,
24.6 (3 CH2). HR-ESI-MS: 248.1392 (calcd 248.1394 for
(calcd 262.1914 for
MeOH).
C
15H24N3O, [M+1]+).
½
a 2D5
ꢁ
¼ ꢀ63 (c 1.00,
C
13H18N3O2, [M+1]+). ½a D25
ꢁ
¼ ꢀ65 (c 1.00, MeOH).
4.8. General procedure for the synthesis of compounds 8
4.7.2. (2S)-N-[(E)-(4-Nitrophenyl)methylidene]pyrrolidine-2-
carbohydrazide 7f
To a stirred solution of an aldehyde (2 mmol) in EtOH (5 ml), a
solution of 2a (1 mmol) in EtOH (5 ml) was added dropwise at
room temperature. The mixture was stirred overnight, and then
the solvent was removed under reduced pressure. The crude prod-
uct 8 was purified by crystallization or flash chromatography.
Yield: 0.233 g (89%). Yellow solid. Mp 264–268 °C (Et2O). IR
(KBr):
m
3074 m, 2965 m, 1694vs (C@O), 1518 m, 1342s. 1H NMR
((D6)DMSO): major isomer: d 8.21 (s, HC@N); 8.28, 8.00 (AA0BB0,
JAB = 8.6, 4 arom. H); 4.86–4.83 (m, CH); 3.37–3.17 (m, 2 proline
H); 2.55–1.91 (m, 4 proline H); minor isomer: d 8.44 (s, HC@N);
8.30, 7.97 (AA0BB0, JAB = 8.6, 4 arom. H); 4.21–4.19 (m, CH); 3.17–
3.07 (m, 2 proline H); 2.34–1.91 (m, 4 proline H). 13C NMR
((D6)DMSO): major isomer: d 170.7, (C@O); 143.7 (C@N); 148.5,
140.4 (2 arom. C); 128.6, 124.5 (4 arom. CH); 58.4 (CH); 46.2,
29.3, 24.1 (3 CH2); minor isomer: d 166.4 (C@O); 146.5 (C@N);
148.5, 140.6 (2 arom. C); 128.6, 124.4 (4 arom. CH); 59.0 (CH);
46.1, 30.0, 24.3 (3 CH2). HR-ESI-MS: 263.1137 (calcd 263.1139
4.8.1. (3R,7aS)-3-(4-Methoxyphenyl)-2-{[(E)-(4-methoxyphenyl)-
methyliden]amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-
one 8a
Yield: 0.186 g (72%). Colorless oil (flash chromatography, hex-
ane/AcOEt, 1:1) (lit.,8a mp 110–112 °C). IR (KBr):
m 3436br,
2963 m, 2936 m, 1713vs (C@O), 1608s, 1514s, 1251s. 1H NMR
(CDCl3): d 8.32 (s, 1H, CH@N); 7.61, 6.88 (AA0BB0, JAB = 8.82, 4 arom.
H); 7.30, 6.93 (AA0BB0, JAB = 8.67, 4 arom. H); 5.55 (s, 1H, HC(6));
4.04–4.00 (m, 1H, HC(5)); 3.46–3.40 (m, 1H, HC(2)); 2.90–2.85
(m, 1H, HC(2)); 2.24–2.16 (m, 2H, HC(4)); 1.95–1.86 (m, 2H,
HC(3)). 13C NMR (CDCl3): d 172.1 (C@O); 161.8, 160.1, 132.2,
127.1 (4 arom. C); 149.9 (C@N); 129.4, 127.7, 114.7, 114.2 (8 arom.
CH); 82.4 (C(6)); 63.3 (CH); 55.5 (2 MeO); 56.3, 27.7, 25.1 (3 pro-
line CH2). HR-ESI-MS: 366.1810 (calcd 366.1812 for C21H24N3O3,
for C12H15N4O3, [M+1]+). ½a D25
¼ ꢀ57 (c 1.00, MeOH).
ꢁ
4.7.3. (2S)-N-[(E)-2-Furylmethylidene]pyrrolidine-2-
carbohydrazide 7g
Yield: 0.164 g (79%). Colorless crystals. Mp 79–81 °C (Et2O). IR
(KBr):
m
3112s (HN), 2977 m, 1690vs (C@O), 1625 m, 1231 m. 1H
NMR (CDCl3): major isomer: d 8.13 (s, HC@N); 7.34, 6.54, 6.33
(3d, J = 3.7, 3 furyl H); 4.92–4.89, (m, CH); 3.70–3.46 (m, 2 proline
H); 2.25–2.09 (m, 4 proline H); minor isomer: d 8.31 (s, HC@N);
7.48, 6.68, 6.42 (3d, J = 3.7, 3 furyl H); 4.62–4.59 (m, CH); 3.57–
3.36 (m, 2 proline H); 2.55–1.90 (m, 4 proline H). 13C NMR (CDCl3):
major isomer: d 170.3 (C@O); 148.9 (1 arom. C); 144.4, 113.9, 111.7
(3 furyl CH); 136.5 (C@N); 58.8 (CH); 46.4, 29.5, 24.4 (3 CH2); min-
[M+1]+). ½a 2D5
¼ ꢀ75 (c 1.00, CH2Cl2).
ꢁ
4.8.2. (3R,7aS)-3-(4-Nitrophenyl)-2-{[(E)-(4-nitrophenyl) methyl-
iden]amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one 8b
Yield: 0.216 g (79%). Pale yellow crystals. Mp 144–145 °C
(Et2O). IR (KBr):
m 3421br, 2954w, 2877w, 1714vs (C@O),
1522s, 1344s. 1H NMR (CDCl3): d 9.27 (s, 1H, CH@N); 8.26, 7.77

´
G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
800
(AA0BB0, JAB = 9.00, 4 arom. H); 8.21, 7.62 (AA0BB0, JAB = 9.00, 4
arom. H); 5.63 (s, 1H, HC(6)); 4.04–4.00 (m, 1H, HC(5)); 3.46–
3.41 (m, 1H, HC(2)); 2.98–2.92 (m, 1H, HC(2)); 2.31–2.23 (m,
1H, HC(4)); 2.21–2.15 (m, 1H, HC(4)); 1.98–1.89 (m, 2H, HC(3)).
13C NMR (CDCl3): d 172.3 (C@O); 149.5 (C@N); 149.1, 148.4,
146.2, 140.4 (4 arom. C); 128.2, 128.0, 124.3, 124.2 (8 arom.
CH); 83.24 (C(6)); 63.99 (CH); 56.40, 28.29, 25.21 (3 proline
CH2). HR-ESI-MS: 396.1299 (calcd 396.1303 for C19H18N5O5,
product formed was then filtered off, washed with Et2O, and crys-
tallized from H2O.
4.10.1. 1-Butyl-3-{[(2S)-1-(butylcarbamoyl)pyrrolidine-2-
carbonyl]amino}urea 10a
Yield: 0.173 g (76%). Colorless crystals. Mp 80–82 °C (H2O). IR
(KBr):
m
3297s (HN), 2958s, 1674vs (C@O), 1550s, 1364 m. 1H
NMR ((D6)DMSO): d 9.64 (br s, HN); 7.62, 6.62, 6.28 (3s, 3 HN);
4.05–4.03 (m, CH); 3.34–3.24 (m, proline CH2); 3.04–2.95 (m, 2 bu-
tyl CH2); 2.01–1.74 (m, 2 proline CH2); 1.41–1.36, 1.29–1.24 (2 m,
4 butyl CH2); 0.88–0.84 (m, 2 butyl Me). 13C NMR ((D6)DMSO): d
173.4, 158.8, 157.2 (3 C@O); 59.2 (CH); 46.3, 29.6, 25.0 (3 proline
CH2); 40.6, 40.1, 32.6, 32.1, 20.1, 20.0 (6 butyl CH2); 14.2, 14.1
(2 butyl Me). HR-ESI-MS: 350.2162 (calcd 350.2163 for
[M+1]+). ½a 2D5
¼ ꢀ51 (c 1.00, CH2Cl2).
ꢁ
4.8.3. (3R,7aS)-3-(Furan-2-yl)-2-{[(E)-furan-2-ylmethyliden]
amino}hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one 8c
Yield: 0.151 g (69%). Colorless crystals. Mp 184–186 °C (Et2O);
lit.8b, mp 183–185 °C. IR (KBr):
m 3436br, 3112w, 2973w, 2880w,
1700vs (C@O), 1403 m, 1382 m, 1335 m. 1H NMR (CDCl3): d 8.85
(s, 1H, CH@N), 7.53–7.48 (m, 1 furyl H); 7.43–7.39 (m, 1 furyl H);
6.78–6.74 (m, 1 furyl H); 6.47–6.43 (m, 1 furyl H); 6.39–6.32 (m, 2
furyl H); 5.61 (s, 1H, HC(6)); 4.12–4.07 (m, 1H, HC(5)); 3.45–3.40
(m, 1H, HC(2)); 2.85–2.79 (m, 1H, HC(2)); 2.25–2.12 (m, 2H,
HC(4)); 1.92–1.86 (m, 2H, HC(3)). 13C NMR (CDCl3): d 172.1 (C@O);
151.4, 149.7 (2 furyl C); 145.1, 143.4 (2 furyl CH); 140.8 (C@N);
114.6, 112.2, 110.6, 108.4 (4 furyl CH); 77.3 (C(6)); 64.1 (CH);
55.76, 27.57, 25.09 (3 proline CH2). HR-ESI-MS: 286.1186 (calcd
C
15H29N5NaO3, [M+Na]+). ½a D25
¼ ꢀ11 (c 1.00, MeOH).
ꢁ
4.10.2. 1-Butyl-3-{[(2S)-1-(butylthiocarbamoyl)pyrrolidine-2-
carbonyl]amino}thiourea 10b
Yield: 0.289 g (78%). Colorless crystals. Mp 178–182 °C (H2O). IR
(KBr):
m 3254s (HN), 2956s, 1676vs (C@O), 1546s, 1377 m, 1189 m.
1H NMR ((D6)DMSO): d 9.97 (br s, HN); 9.18, 7.70, 7.53 (3s, 3 HN);
4.66–4.64 (m, CH); 3.60–3.34 (m, proline CH2, 2 butyl CH2); 2.15–
1.80 (m, 2 proline CH2); 1.55–1.46, 1.32–1.25 (2 m, 4 butyl CH2);
0.90–0.85 (m, 2 butyl Me). 13C NMR ((D6)DMSO): d 178.9, 173.8,
171.7 (2 C@S, C@O); 64.2 (CH); 48.6, 29.6, 24.5 (3 proline CH2);
45.2, 43.8, 31.5, 31.2, 20.0, 19.9 (6 butyl CH2); 14.3, 14.2 (2 butyl
Me). HR-ESI-MS: 382.1701 (calcd 382.1706 for C15H29N5NaOS2,
286.1186 for C15H16N3O3, [M+1]+). ½a D25
¼ ꢀ193 (c 0.44, CH2Cl2).
ꢁ
4.9. General procedure for the synthesis of compounds 9a,b
A mixture of 5 (1 mmol) and butyl isocyanate or isothiocyanate
(1.1 mmol) in EtOH (5 ml) was heated at reflux for 2 h. The product
formed was then filtered off and washed with Et2O.
[M+Na]+). ½a 2D5
¼ ꢀ54 (c 1.00, MeOH).
ꢁ
4.11. Synthesis of 1,2,4-triazole-3-thione 11
4.9.1. 1-{[(2S)-1-Benzylpyrrolidine-2-carbonyl]amino}-3-meth-
ylurea 9a
A mixture of 9b (1 mmol) and a 2% aqueous solution of NaOH
(5 ml) was heated at reflux for 2 h. The mixture was then neutral-
ized with AcOH, and the precipitate formed was filtered off and
crystallized from MeOH. Yield: 0.225 g (67%). Colorless crystals.
Yield: 0.312 g (98%). Colorless crystals. Mp 85–88 °C (MeOH). IR
(KBr):
m 3390s, 3277s (HN), 2958s, 1686vs (C@O), 1671vs (C@O),
1565s, 1254 m, 704 m. 1H NMR (CDCl3): d 9.04 (br s, HN); 7.34–
7.25 (m, 5 arom. H); 5.29 (br s, HN); 3.90, 3.58 (AB, JAB = 13.2,
CH2Ph); 3.34–3.31 (m, CH); 3.19–3.15 (m, butyl CH2); 3.08–3.06
(m, 1 proline H); 2.42–2.40 (m, 1 proline H); 2.22–2.20 (m, 1 pro-
line H); 1.97–1.78 (m, 3 proline H); 1.45–1.41, 1.33–1.30 (2 m, 2
butyl CH2); 0.90 (t, J = 7.8, butyl Me). 13C NMR (CDCl3): d 173.5,
157.6 (2 C@O); 138.2 (1 arom. C); 129.0, 128.6, 127.5 (5 arom.
CH); 66.4 (CH); 60.1 (CH2Ph); 54.2, 30.6, 24.2 (3 proline CH2);
39.9, 32.1, 19.9 (3 butyl CH2); 13.7 (butyl Me). HR-ESI-MS:
Mp 135–136 °C (MeOH). IR (KBr):
m 3258br. m (HN), 2964s,
2533br. m, 1569s, 1455 m, 1359 m, 1297 m. 1H NMR (CDCl3): d
10.31 (br s, HN); 7.30–7.21 (m, 5 arom. H); 4.23–3.81 (m, butyl
CH2); 3.81, 3.43 (AB, JAB = 13.2, CH2Ph); 3.80–3.72 (m, CH); 3.44–
3.13 (m, proline CH2); 2.41–1.85 (m, 2 proline CH2); 1.72–1.32
(m, 2 butyl CH2); 0.96 (t, J = 7.8, butyl Me). 13C NMR (CDCl3): d
161.2 (C@S); 142.6, 137.8 (triazole C(3), arom. C); 128.8, 128.3,
127.6 (5 arom. CH); 60.1 (CH); 58.2 (CH2Ph); 53.2, 30.2, 23.0 (3
proline CH2); 44.4, 33.2, 20.3 (3 butyl CH2); 13.6 (butyl Me). HR-
319.2131 (calcd 319.2129 for C17H27N4O2, [M+1]+). ½a D25
¼ ꢀ18 (c
ꢁ
1.00, CHCl3).
ESI-MS: 317.1794 (calcd 317.1794 for
¼ ꢀ126 (c 1.00, CHCl3).
C
17H25N4S, [M+1]+).
½ ꢁ
a 2D5
4.9.2. 1-{[(2S)-1-Benzylpyrrolidine-2-carbonyl]amino}-3-meth-
ylthiourea 9b
4.12. Synthesis of 1,3,4-thiadiazol-2-amine 12
Yield: 0.272 g (93%). Pale yellow oil. IR (film):
m 3307 br s (HN),
2930s, 1683vs (C@O), 1540s, 1455 m, 1273 m. 1H NMR (CDCl3): d
9.41 (br s, HN); 7.44–7.25 (m, 5 arom. H); 7.01 (br s, HN); 3.98,
3.59 (AB, JAB = 13.2, CH2Ph); 3.56–3.53 (m, butyl CH2); 3.35–3.32
(m, CH); 3.11–3.09 (m, 1 proline H); 2.44–2.41 (m, 1 proline H);
2.23–2.20 (m, 1 proline H); 2.00–1.80 (m, 3 proline H); 1.58–
1.53, 1.41–1.23 (2 m, 2 butyl CH2); 0.94 (t, J = 7.8, butyl Me). 13C
NMR (CDCl3): d 180.3 (C@S); 170.6 (C@O); 137.9 (1 arom. C);
129.2, 128.5, 127.5 (5 arom. CH); 66.2 (CH); 60.3 (CH2Ph); 54.1,
30.7, 24.2 (3 proline CH2); 44.6, 31.1, 20.1 (3 butyl CH2); 13.8
(butyl Me). HR-ESI-MS: 335.1899 (calcd 335.1900 for C17H27N4OS,
A solution of 9b (1 mmol) in 5 ml conc. H2SO4 was kept at rt for
1 day. After neutralization of the mixture with aqueous NH4OH,
the solid product was filtered off, dried, and crystallized from
MeOH. Yield: 0.177 g (56%). Yellowish crystals. Mp 99–100 °C
(MeOH). IR (KBr):
m
3242s (HN), 2953s, 1537s, 1478 m, 737 m. 1H
NMR (CDCl3): d 7.33–7.24 (m, 5 arom. H); 5.27 (br s, HN); 4.02,
3.95 (AB, JAB = 13.2, CH2Ph); 3.98–3.96 (m, CH); 3.34–3.31 (m, butyl
CH2); 3.07–3.04 (m, 1 proline H); 2.36–2.31 (m, 2 proline H); 1.92–
1.81 (m, 3 proline H); 1.68–1.63, 1.46–1.43 (2 m, 2 butyl CH2); 0.96
(t, J = 7.8, butyl Me). 13C NMR (CDC13): d 170.8, 144.9 (thiadiazol
C(2), C(5)); 139.2 (1 arom. C); 128.8, 128.3, 127.2 (5 arom. CH);
63.7 (CH); 58.0 (CH2Ph); 53.0, 33.3, 22.9 (3 proline CH2); 47.0,
31.5, 20.0 (3 butyl CH2); 13.7 (butyl Me). HR-ESI-MS: 317.1794
[M+1]+). ½a 2D5
¼ ꢀ68 (c 1.00, CHCl3).
ꢁ
4.10. General procedure for the synthesis of compounds 10a,b
(calcd 317.1794 for
CHCl3).
C
17H25N4S, [M+1]+).
½
a 2D5
ꢁ
¼ ꢀ92 (c 1.00,
A mixture of 2a (1 mmol) and butyl isocyanate or isothiocya-
nate (2.1 mmol) in EtOH (5 ml) was heated at reflux for 2 h. The

´
801
G. Mloston et al. / Tetrahedron: Asymmetry 23 (2012) 795–801
4.13. X-ray crystal-structure determination of 7b
References
1. Parts of the planned PhD theses of A. M. P and A. W., University of Lodz.
All measurements were made on an Agilent Technologies
2. (a) Zhang, S.; Wang, W. In ‘Privileged Chiral Ligands and Catalysts’; Zhou, Q.-L.,
Ed.; Wiley-VCH: Weinheim, 2011; pp 409–445; (b) List, B. Angew. Chem., Int. Ed.
2010, 49, 1730–1734.
SuperNova area-detector diffractometer19 using CuK radiation
a
(k = 1.54184 Å) from a micro-focus X-ray source and an Oxford
Instruments Cryojet XL cooler. The data collection and refinement
parameters are given below20 and a view of the molecule is shown
in Figure 1. Data reduction was performed with CrysAlisPro.19 The
intensities were corrected for Lorentz and polarization effects, and
an empirical absorption correction using spherical harmonics19
was applied. Equivalent reflections, other than Friedel pairs, were
merged. The structure was solved by direct methods using SHEL-
XS97,21 which revealed the positions of all non-hydrogen atoms.
The non-hydrogen atoms were refined anisotropically. The amine
H-atom was placed in the position indicated by a difference elec-
tron density map and its position was allowed to refine together
with an isotropic displacement parameter. 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 iso-
tropic displacement parameter with a value equal to 1.2 Ueq of its
parent C-atom. The refinement of the structure was carried out on
3. Hassan, A. A.; Shawky, A. M. J. Heterocycl. Chem. 2010, 47, 745–763.
4. Narasimhan, B.; Kumar, P.; Sharma, D. Acta Pharm. Sci. 2010, 52, 169–180.
5. Rollas, M.; Kuçukguzel, Sß. G. Molecules 2007, 12, 1910–1939.
6. Meyer, H.; Malley, J. Monatsh. Chem. 1912, 33, 393–414.
7. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-
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F2 by using full-matrix least-square procedures, which minimized
2
the function
R
wðF2o ꢀ F2c Þ . A correction for secondary extinction
was not applied. Refinement of the absolute structure parameter22
yielded a value of ꢀ0.0(2), while the Hooft analysis23 gave
y = 0.07(5), P2 = 1.000, and P3 = 0.000, which confidently confirms
that the refined coordinates represent the true enantiomorph. Neu-
tral atom scattering factors for non-H-atoms were taken from the
literature,24 and the scattering factors for H-atoms were also taken
from the literature.25 Anomalous dispersion effects were included
in Fc;26 the values for f0 and f00 were those of ref.27 The values of
the mass attenuation coefficients are those of the literature.28 All
calculations were performed using the SHELXL9721 program.
Crystal data for 7b: C17H19N3O2, M = 297.36, crystallized from
isopropanol, colorless, prism, crystal dimensions 0.15 ꢃ 0.22 ꢃ
0.25 mm, monoclinic, space group P21, Z = 2, reflections for cell
determination 6644, 2h range for cell determination 6–153°,
a = 5.54324(6) Å, b = 10.11476(12) Å, c = 14.24604(17) Å, b =
13. (a) Mloston´ , G.; Pieczonka, A. M.; Kowalczyk, E.; Linden, A.; Heimgartner, H.
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Helv. Chim. Acta 2011, 94, 1764–1777; (b) Pieczonka, A. M.; Mloston, G.;
Heimgartner, H. Helv. Chim. Acta 2012, 95, 404–414.
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14. (a) Kwiatkowski, P.; Mucha, P.; Mloston, G.; Jurczak, J. Synlett 2009, 1757–
1760; (b) Mloston´ , G.; Mucha, P.; Heimgartner, H. Lett. Org. Chem. 2012, 9, 89–
91.
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Pharma. – Drug Res. 2010, 67, 255–259.
16. Lloyd, J.; Finlay, H. J.; Vacarro, W.; Hyunh, T.; Kover, A.; Bhandura, R.; Yan, L.;
Atwal, K.; Conder, M. L.; Jenkins-West, T.; Shi, H.; Huang, C.; Li, D.; Sun, H.;
Levesque, P. Bioorg. Med. Chem. Lett. 2010, 20, 1436–1439.
17. Johnson, C. K. ‘ORTEP II, Report ORNL-5138’, Oak Ridge National Laboratory,
Oak Ridge, Tennessee, 1976.
18. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl.
1995, 34, 1555–1573.
19. CrysAlisPro, Version 1.171.35.21, Agilent Technologies, Yarnton, Oxfordshire,
England, 2012.
97.5394(11), V = 791.849(16) Å3, T = 160(1) K, DX = 1.247 g cmꢀ3
,
l
(CuK ) = 0.675 mmꢀ1, scan type
x
, 2h(max) = 153.5°, transmission
a
20. CCDC-879024 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
factors (min; max) = 0.887; 1.000, total reflections measured
8322, symmetry independent reflections 3035, reflections with I
21. Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, 64, 112–122.
22. (a) Flack, H. D.; Bernardinelli, G. Acta Crystallogr. Sect. A 1999, 55, 908–915; (b)
Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143–1148.
23. (a) Hooft, R. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96–103;
(b) Hooft, R. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2010, 43, 665–668.
24. Maslen, E. N.; Fox, A. G.; O’Keefe, M. A. In International Tables for
Crystallography; Wilson, A. J. C., Ed.; Kluwer Academic Publishers: Dordrecht,
1992; Vol. C, pp 477–486. Table 6.1.1.1.
>2r(I) 2996, reflections used in refinement 3035, parameters re-
fined 203, restraints 1; R(F) [I >2
r
(I) reflections] = 0.0286, wR(F2)
2
[all data] = 0.0800 (w ¼ ½r2ðFo2Þ þ ð0:0511PÞ þ 0:0771Pꢁꢀ1, where
P ¼ ðF2o þ 2Fc2Þ=3), goodness of fit 1.034, final Dmax
/r 0.001, Dq
(max; min) = 0.15; ꢀ0.10 e Åꢀ3
.
25. Creagh, D. C.; McAuley, W. J. In International Tables for Crystallography; Wilson,
A. J. C., Ed.; Kluwer Academic Publishers: Dordrecht, 1992; Vol. C, pp 219–222.
Table 4.2.6.8.
Acknowledgments
26. Creagh, D. C.; Hubbell, J. H. In International Tables for Crystallography; Wilson, A.
J. C., Ed.; Kluwer Academic Publishers: Dordrecht, 1992; Vol. C, pp 200–206.
Table 4.2.4.3.
27. Stewart, R. F.; Davidson, E. R.; Simpson, W. T. J. Chem. Phys. 1965, 42, 3175–
3187.
The authors thank PD Dr. L. Bigler, University of Zürich, for ESI-
HRMS. A.M.P. is grateful for financial support within the project
European Social Fund ‘HUMAN—BEST INVESTMENT!’, co-funded by
the European Union.
28. Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781–782.