Conformational properties, chiroptical spectra, and molecular self-assembly of 2,3-piperazinodiones and their dithiono analogues

Article abstract of DOI:10.1021/jo800037w

(Figure Presented) A family of chiral cyclic oxamides was prepared by the condensation of optically active 1,2-diamines with diethyl oxalate. Thionation of the products with Lawesson's reagent afforded a series of chiral 2,3-piperazinedithiones. Molecular

Full text of DOI:10.1021/jo800037w

Conformational Properties, Chiroptical Spectra, and Molecular
Self-Assembly of 2,3-Piperazinodiones and Their Dithiono Analogues
Barbara Piotrkowska,† Małgorzata Mys´lin´ska,† Maria Gdaniec,‡ Aleksander Herman,† and
Tadeusz Połon´ski*,†
Department of Chemistry, Technical UniVersity, 80-952 Gdan´sk, Poland, and Faculty of Chemistry,
A. Mickiewicz UniVersity, 60-780 Poznan´, Poland
tadpol@chem.pg.gda.pl
ReceiVed January 7, 2008
A family of chiral cyclic oxamides was prepared by the condensation of optically active 1,2-diamines
with diethyl oxalate. Thionation of the products with Lawesson’s reagent afforded a series of chiral
2,3-piperazinedithiones. Molecular geometries of the title compounds were studied with the use of quantum
mechanical DFT calculations and were compared to the X-ray crystallographic results. The heterocyclic
six-membered ring adopted a half-chair conformation with the C-5 substituent preferably at the equatorial
position, whereas a substitution at the nitrogen atoms resulted in domination of the axial form in the
conformational equilibrium. The opposite helicity of the twisted oxamide chromophore in the axial and
equatorial conformers led to the opposite signs of the Cotton effects corresponding to two π-π* electronic
transitions. The CD signs can be predicted by a simple helicity rule. The same rule is valid for 2,3-
piperazinodithiones, where a substitution of sulfur for oxygen in the carbonyl groups results in
bathochromic shifts of the absorption and CD bands. The crystal packing analysis of several
2,3-piperazinodiones revealed that strong NH‚‚‚OdC intermolecular hydrogen-bonding interactions
generating the chain motif resulted in the formation of 3-D networks as well as with the use of the cyclic
hydrogen-bond motif tape structures.
Introduction
gained considerable importance in the design of modified
peptide and protein structures. It has been shown that the
selective substitution of one or more amide groups by oxamide
units changes the folding properties of the peptide backbone
and thus can be envisaged as a potential strategy in protein
engineering.4 The most familiar application of dithiooxamides
is their use as reagents for the detection and determination of
Oxamides and dithioxamides represent an important class of
compounds with relevance in many areas of chemistry. Simple
oxamides, due to their ability of self-complementary hydrogen-
bonding interactions, have been used successfully in materials
science as supramolecular building blocks for the construction
of ordered solid state assemblies,1 helicate structures,2 and
gelators yielding thermo-reversible gels.3 The oxamide unit has
(2) (a) Blay, G.; Fernandez, I.; Pedro, J. R.; Ruiz-Garcia, R.; Carmen-
Munoz, M.; Cano, J.; Carrasco, R. Eur. J. Org. Chem. 2003, 1627. (b)
Piotrkowska, B.; Milewska, M. J.; Gdaniec, M.; Połon´ski, T. Tetrahedron:
Asymmetry 2007, 18, 1486.
(3) (a) Makarevic´, J.; Jokic´, M.; Peric´, B.; Tomisic´, V.; Kojic´-Prodic´,
B.; Zinic´, M. Chem.sEur. J. 2001, 7, 3328. (b) Makarevic´, J.; Jokic´, M.;
Frkanec, L.; Katalenic´, D.; Zinic´, M. Chem. Commun. (Cambridge, U.K.)
2002, 2238. (c) Makarevic´, J.; Jokic´, M.; Raza, Z.; Stefanic´, Z.; Kojic´-
Prodic´, B.; Zinic´, M. Chem.sEur. J. 2003, 9, 5567.
* Corresponding author. Fax: (48)-58-3472694.
† Technical University.
‡ A. Mickiewicz University.
(1) (a) Coe, S.; Kane, J. J.; Nguyen, T. L.; Toledo, L. M.; Wininger, E.;
Fowler, F. W.; Lauher, J. W. J. Am. Chem. Soc. 1997, 119, 86. (b) Nguyen,
T. L.; Scott, A.; Dinkelmeyer, B.; Fowler, F. W.; Lauher, J. W. New. J.
Chem. 1998, 129. (c) Nguyen, T. L.; Fowler, F. W.; Lauher, J. W. J. Am.
Chem. Soc. 2001, 123, 11057.
10.1021/jo800037w CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/12/2008
2852
J. Org. Chem. 2008, 73, 2852-2861

2,3-Piperazinodiones and Their Dithiono Analogues
various metals.5 On the other hand, N,N′-disubstituted oxamides
have played a key role in the design of polymetallic and
heterobimetallic complexes.6
Oxamides and dithiooxamides have been a subject of interest
to photochemists and spectroscopists for the last four decades,
and they have been investigated by various spectroscopic
methods.7 These chromophores are composed of two amide or
thioamide subunits, and their interaction lifts degeneracy
between pairs of the n, π, and π* levels. The interaction between
the carbonyl or the thiocarbonyl groups and thus splitting of
these levels is strongly influenced by the geometry of the
oxamide or dithiooxamide chromophore. According to X-ray
crystallographic studies, unsubstituted and N,N′-disubstituted
oxamides and dithiooxamides assume a planar s-trans conforma-
tion,8a-d whereas tetrasubstituted compounds, due to steric
interactions, prefer twisted conformations.8e,f However, the
oxamide unit incorporated in some cyclic systems is forced to
adopt an s-cis or twisted s-cis conformation.9 The twisted
oxamide and dithioxamide chromophores are inherently chiral,
and in the case of N,N,N′,N′-tetramethyldithiooxamide, the
energy barrier to racemization is sufficiently high to separate
to enantiomers at ambient temperature.10 It has been shown that
the six- and seven-membered cyclic oxamides and their dithio
analogues also contain the twisted chromophores.8e,f We focused
our interest on the conformational and chiroptical properties of
2,3-piperazinodiones and their dithio analogues. Attractive
characteristics of these compounds are their ease of preparation,
crystallinity, and restricted conformational flexibility. Further-
more, a long wavelength absorption of 2,3-piperazinodithiones
resulting from the substitution of sulfur for oxygen in the
carbonyl groups makes these compound particularly useful as
models for spectroscopic studies.11
DFT12 calculations, and the results were compared with those
obtained from X-ray crystallographic analysis. In addition, we
examined the crystal packing of several 2,3-piperazinediones
to establish their self-assembly mode in the solid state.
Results and Discussion
1,3-Piperazinediones 1a-6a were obtained in high yields by
the condensation of optically active 1,2-diamines with diethyl
oxalate in ethanol following a literature method.13 Methylation
of the products 4a-6a with methyl iodide gave the N,N′-
dimethyl derivatives 4b-6b. Since this procedure failed in the
case of 1a and 3a with a poor solubility, their N,N′-dimethyl
derivatives 1b and 3b were prepared from the corresponding
N,N′-dimethylamines by condensation with diethyl oxalate.
Thionation of these compounds with Lawesson’s reagent14 in
boiling toluene afforded 1,3-piperazinedithiones 1c-6c (Scheme
1) as dark red crystals.
Molecular Geometry. The 2,3-piperazinedione system may
exist in two enantiomeric half-chair conformations with C2
symmetry and identical energies. Our primary interest was to
learn about the influence of substituents on the ring and
chromophore geometry that determines the CE sign in the
chiroptical spectra. We investigated the structures with the aid
of quantum mechanical calculations and X-ray crystallography.
In this paper, we describe the synthesis, structure, and CD
spectra of several model compounds, including those with rigid
bicyclic skeletons (1 and 2) and more flexible ones (3-6). Our
aim was to examine their CD spectra to correlate the observed
Cotton effect (CE) signs with the molecular geometries. The
conformational preferences of the molecules were studied with
(4) (a) Karle, I. L.; Ranganathan, D. Biopolymers 1995, 46, 18. (b)
Padilla-Martinez, I. I.; Martinez-Martinez, F. J.; Garcia-Baez, E. V.; Rojas-
Lima, S.; Ho¨pfl, H. J. Chem. Soc., Perkin Trans. 2 2001, 1817.
(5) (a) Feigel, F. Spot Tests; Elsevier: New York, 1954; Vol. 1, pp 83,
139, 145. (b) Welcher, F. J. Organic Analytical Reagents; Van Nostrand:
New York, 1948; p 148.
(6) (a) Lloret, F.; Sletten, J.; Ruiz, R.; Julve, M.; Faus, J. Inorg. Chem.
1992, 31, 3778. (b) Sanada, T.; Suzuki, T.; Kaizaki, S. J. Chem. Soc., Dalton
Trans. 1998, 959.
(7) (a) Persson, B.; Sandstro¨m, J. Acta Chem. Scand. 1981, 35, 489. (b)
Henriksen, L.; Isaksson, R.; Liliefors, T.; Sandstro¨m, J. Acta Chem. Scand.
1963, 17, 1380. (c) Larson, D. B.; McGlynn, S. P. J. Mol. Spectrosc. 1973,
47, 469. (d) Larson, D. B.; Arnett, J. F.; McGlynn, S. P. Chem. Phys. Lett.
1973, 23, 322. (e) Isaksson, R.; Liliefors, T. J. Chem. Soc., Perkin Trans.
2 1980, 1815. (f) Green, M. R.; Jubran, N.; Bursten, B. E.; Bush, D. H.
Inorg. Chem. 1987, 26, 2326. (g) Servaas, P. C.; Stufkens, D. J.; Oskam,
A.; Vernooijs, P.; Baerends, E. J.; De Ridder, D. J. A.; Stam, C. H. Inorg.
Chem. 1989, 28, 4104.
(8) (a) Romers, C. Acta Crystallogr. 1953, 6, 429. (b) Ayerst, E. N.;
Duke, J. R. C. Acta Crystallogr. 1954, 7, 588. (c) Wheatley, P. J. J. Chem.
Soc. 1965, 396. (d) de With, G.; Harkema, S. Acta Crystallogr., Sect. B:
Struct. Sci. 1977, 33, 2367. (e) Adiwidjaja, G.; Voss, J. Chem. Ber. 1977,
110, 1159. (f) Lanza, S.; Bruno, G.; Scolaro, L. M.; Nicolo, F.; Rosace, G.
Tetrahedron: Asymmetry 1993, 4, 2311.
(12) (a) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.;
Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem.
1993, 1347. (b) Gordon, M. S.; Schmidt, M. W. Advances in Electronic
Structure Theory: GAMESS a Decade Later; In Theory and Applications
of Computational Chemistry; Dykstra, G. E., Frenking, G., Kim, K. S.,
Scuseria, G. E., Eds.; Elsevier: Amsterdam, 2005 and references therein.
(c) Granovsky, A. A. PC GAMESS version 7.1, http://classic.chem.msu.su/
gran/gamess/index.html.
(13) Isaksson, R.; Liliefors, T.; Sandstro¨m, J. J. Chem. Res., Synop. 1981,
43.
(9) Isaksson, R.; Liliefors, T. J. Chem. Soc., Perkin Trans. 2 1981, 1344.
(10) Mannschreck, A.; Talvitie, A.; Fischer, W.; Snatzke, G. Monatsh.
Chem. 1983, 114, 101.
(11) For a preliminary communication, see: Połon´ski, T. Tetrahedron:
Asymmetry 1994, 5, 149.
(14) (a) Yde, B.; Yousif, N. M.; Pedersen, V.; Thomsen, J. Lawesson,
S.-O. Tetrahedron 1984, 40, 2047. For a review, see: (b) Cava, M. P.;
Levinson, M. J. Tetrahedron 1985, 41, 5061. (c) Jesberger, M.; Davis, T.
P.; Barner, L. Synthesis 2003, 1929. (d) Ozturk, T.; Elas, E.; Mert, O. Chem.
ReV. 2007, 107, 5210.
J. Org. Chem, Vol. 73, No. 7, 2008 2853

Piotrkowska et al.
SCHEME 1
TABLE 1. Selected Torsional Angles and Relative Energies
Calculated by DFT12
SCHEME 2
structurea
7-2-3-8 1-6-5-4 1-2-3-4 rel energy (kJ/mol)
1a
-20.43
-18.7(4)
-9.85
-37.03
-15.23
16.47
-20.5(2)
-16.00
18.15
16.0(2)
-42.62
35.00
42.1(2)
-16.65
16.69
-13.48
15.84
-55.30
-56.6(2)
-43.51
-47.63
-51.83
52.37
-51.43(16) -21.0(2)
-53.81
54.44
52.79(17) 16.1(2)
-57.43
56.78
56.9(2)
-52.15
49.94
-54.92
53.16
-19.87
-20.0(4)
-10.49
-35.69
-14.09
15.28
in Scheme 2, they have an opposite helicity of the oxamide
unit. Crystal structure analysis revealed that the methyl group
in 3a prefers an equatorial orientation in the solid state (Figure
1a). The six-membered ring is twisted with a N-C5-C6-N
torsion angle of -51.43(16)°, and the oxamide chromophore
exhibits M-helicity [OdCsCdO is-20.5(2)°]. According to
our DFT calculations, the equatorial conformer is 2.5 kJ/mol
more stable than the axial conformer and should predominate
in solution. However, upon N-alkylation, the situation is
reversed, and the calculations predicted that the axial conformer
of 3b is preferred over the equatorial conformer by 5.9 kJ/mol.
This is apparently due to a destabilizing steric interaction
between the equatorial methyl group at C-5 and the nearly
coplanar neighboring N-methyl substituent. Also, the X-ray
structure of 3b showed that that this compound crystallizes
preferably in the axial conformation with the oxamide unit
twisted in the P-sense (Figure 1b). An analogous conformational
preference was predicted for 4a,b and 5a,b (i.e., a domination
of the equatorial form in the case of the NH derivatives and the
axial form in the case of the N-methyl derivatives), whereas
the benzyl group in both derivatives 6a,b prefers an axial
orientation. However, in the case of 6a, the calculated energy
difference between two conformers is rather small (1.6 kJ/mol).
The X-ray structure of 6b confirmed an axial orientation of the
benzyl substituent. The case of 5a shows that the energy
difference between the axial and the equatorial forms is small
and that the packing forces in the crystal can influence the
conformation adopted by the 2,3-piperazinedione system in the
solid state. This compound was obtained in two crystalline
forms, as a solvate with tetrahydrofuran 5a‚THF and as a
cocrystal with pentafluorobenzoic acid (pfb) 5a‚pfb‚H2O. X-ray
crystallography revealed that the diaxial form of 5a is preferred
in the solvate, whereas the diequatorial form is observed in the
cocrystal with pfb. The CD spectra pointed to a predominance
of the diequatorial form in solution (vide infra).
1ab
1b
1c
3a(eq)
3a(ax)
3ab
3b(eq)
3b(ax)
3bb
3c(eq)
3c(ax)
3cb
4a(eq)
4a(ax)
4b(eq)
4b(ax)
4c(eq)
4c(ax)
5a(eq)
5a(ax)
5a‚THFb
0
2.5
-16.70
18.62
5.9
0
-39.25
32.49
40.2(3)
-15.69
16.01
-13.90
15.95
-34.05
34.27
14.02
-17.49
-11.4(7)
16.2(4)
8.72
-20.39
-10.0(3)
-13.1(4)
12.18
13.1
0
0
6.8
5.0
0
7.9
0
-35.67
36.80
15.31
-17.60
-12.4(8)
-56.44
55.43
49.86
0
10.5
-51.01
-57.1(6)
52.9(3)
47.26
-54.85
-58.8(2)
-59.3(2)
50.90
-51.80
53.89
-55.77
-52.59(19) -13.2(3)
5a‚fba‚H2Ob 16.3(4)
5b(eq)
5b(ax)
5bb
8.30
15.8
0
-19.36
-9.4(3)
-12.7(4)
14.03
-15.18
15.83
6a(eq)
6a(ax)
6b(eq)
6b(ax)
6bb
1.6
0
15.8
0
-13.99
16.46
-22.15
-21.62
-13.9(3)
6c(I)b,c
6c(II)b,d
-38.52(17) -57.30(15) -36.24(19)
-35.4(4)
-30.9(4)
-56.5(4)
-56.5(4)
-32.3(5)
-30.8(4)
a DFT calculations [B3LYP RHF GAMESS (version 22) with 6-311G(d,p)
basis set]. b X-ray analysis. c Orthorhombic crystals. d Monoclinic crystals.
The calculated and observed geometries of some compounds
are compared in Table 1.
A substitution of the heterocyclic ring at C-5 led to two
different conformers: one with the substituent at the equatorial
position and the other with the axial substituent, and as shown
2854 J. Org. Chem., Vol. 73, No. 7, 2008

2,3-Piperazinodiones and Their Dithiono Analogues
and according to the ab initio calculations and photoelectron
spectra, the ordering of the highest occupied molecular orbitals
is π-, n+, π+, and n-, where the + and - subscripts indicate
the bonding/antibonding combination of the parent amide
orbitals.7e Besides two allowed π-π* transitions, the CNDO/
s-CI calculations predict an additional forbidden n-π* excitation
at slightly lower energies.7b It easily can be identified as a weak
absorption at 272 nm in the UV spectrum of oxamide in aqueous
solution. However, in the case of 2,3-piperazinodiones, this weak
absorption band is buried under the tail of the much stronger
π-π* transition and cannot be detected in the UV spectrum.
Fortunately, the chiroptical spectra are very useful for the
detection of hidden electronic transitions, and for example, the
CD spectrum of 1b taken in nonpolar solvents revealed the
n-π* excitation as a very weak negative CE at 310 nm (see
Figure 13S in the Supporting Information).
The CD spectra of cyclic oxamides 1a,b-6a,b collected in
Table 2 feature two strong CEs of opposite signs in accordance
with the opposite symmetry of the excited states involved in
two π-π* electronic transitions. In the case of skewed π
electron systems, usually the inherent chirality of the chro-
mophores controls the sign and magnitude of the CEs.15
Examples are provided by cisoidal dienes,16 helicenes,17 skewed
R-diketones,18 or dithiooxalates.19 Hug and Wagniere20 postu-
lated that the chromophores with C2 symmetry and P-helicity
produce negative CEs associated with the transitions of A
symmetry and positive CEs for transitions of B symmetry, and
the opposite signs are expected for the M-helicity. The rigid
bicyclic skeleton of the C2 symmetric molecules 1a and 1b
implies the M-helicity of the twisted oxamide chromophore [Od
CsCdO is-18.7(4)° in the crystals of 1a], and thus, a sequence
of the observed negative and positive CEs corresponding to the
lower and higher energy π-π* transitions suggests their B and
A symmetries, respectively. Similarly, the P-chirality of the
chromophore in the bicyclic system 2b results in reversed signs
of two π-π* CEs. Thus, a simple helicity rule can be proposed
for predictions of the CD sign of twisted oxamides: the right-
handed chirality of the chromophore should lead to sequence
positive and negative CEs corresponding to the lower and higher
energy π-π* electronic transitions (Scheme 3). This explains
correctly the observed CE signs for all of the compounds
studied. Whereas the CD sign and magnitude of the conforma-
tionally rigid compounds 1a,b largely are insensitive to substitu-
tion at the nitrogen atoms, the CD curves of oxamide 3a and
its N,N′-dimethyl derivative 3b show opposite CE signs (Figure
3).
FIGURE 1. Conformation of (a) 3a and (b) 3b in their crystal
structures.
FIGURE 2. CD and UV (lower curves) spectra of 1a and 1b taken in
methanol.
The calculated and experimental ring geometries of 2,3-
piperazinedithiones 1c-6c are generally similar to those of their
parent dioxo derivatives (Table 1). The only difference is a much
stronger twisting of the dithionooxamide unit as shown by the
SdCsCdS torsion angles of ca. 40°, which reflect the relative
steric size of oxygen and sulfur.
Since the inherent chirality of the skewed oxamide unit is
primarily responsible for the CE sign and a contribution from
the dissymmetrically located substituents is less important, the
observed CD signs point to an opposite helicity of the
chromophores in these compounds: the left-handed in 3a and
Chiroptical Spectra. The electronic absorption spectra of
2,3-piperazinediones 1a,b-3a,b resemble those reported for
other oxamides and are characterized by two absorption bands
in the near-UV region: one intense band appearing as a
maximum near 225 nm with a marked vibronic fine structure
and the second of moderate intensity appearing as a shoulder
near 250 nm (Figure 2). According to Larson and McGlynn,7c
both these bands can be assigned to two allowed π-π*
electronic transitions as supported by their large molecular
extinction and the solvent red shift exhibited in highly polar
media. In all cases, N-alkylation produces a considerable red
shifting of the absorption bands. The spectra of 4a,b-6a,b
containing phenyl substituents are influenced by a contribution
from the strong aromatic ring excitations. The oxamide chro-
mophore can be viewed as being composed of two interacting
amide units that results in splitting of the n, π, and π* levels,
(15) (a) Snatzke, G.; Snatzke, F. In Fundamental Aspects and Recent
DeVelopments in Optical Rotatory Dispersion and Circular Dichroism;
Ciardelli, F., Salvadori, P., Eds.; Heyden: London, 1973, pp 109-125 and
173-195. (b) Snatzke, G. Angew. Chem., Int. Ed. Engl. 1979, 18, 363.
(16) Gawronski, J. K.; Walborsky, H. M. In Circular Dichroism,
Principles and Applications; Nakanishi, K., Berova, N., Woody, R. W.,
Eds.; Wiley-VCH: New York, 1994; pp 301-304.
(17) Lightner, D. A.; Gurst, J. E. Organic Conformational Analysis and
Stereochemistry from Circular Dichroism Spectroscopy; Wiley-VCH: New
York, 2000; pp 409-421.
(18) Ibid, pp 305-335.
(19) Falth, L.; Hakansson, U.; Sandstro¨m, J. J. Mol. Struct. 1989, 186,
239.
(20) Hug, W.; Wagniere, G. Tetrahedron 1972, 28, 1241.
J. Org. Chem, Vol. 73, No. 7, 2008 2855

Piotrkowska et al.
TABLE 2. Electronic Absorption (UV-vis) and CD Data
compd
solventa
λ, nm (ꢀ)
λ, nm (10-3 [Θ])c
1a
1b
MeOH
CD
MeOH
CD
MeOH
CM
H2O
248 (1190shb), 221 (7710)
245 (-31.3), 214 (29.7)
246 ((3350shb), 226 (8900)
310 (-0.031), 253 (-25.5), 218 (20.4)
253 (-30.0), 215 (16.4)
253 (2520shb), 232 (7830)
1c
2a
2b
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
480 (98), 422 (840), 315 (11800), 280 (3700shb)
250 (2900shb), 222 (11870)
509 (6.1), 424 (-16.5), 308 (-32.3), 270 (15.2), 250 (-3.7), 228 (31.9)
249 (48.2), 217 (-25.3)
509 (80), 424 (406), 316 (7893), 280 (2530shb)
244 (1800shb), 218 (10800)
517 (-5.9), 424 (20.8), 308 (27.7), 259 (-22.0)
242 (-10.9), 210 (7.1)
249 (29.1), 220 (-16.6)
H2O
CD
250 (2530shb), 222 (10260)
470 (80), 418 (725), 312 (12370), 275 (2770shb)
244 (2200shb), 211 (12050)
495 (-7.6), 418 (20.8), 307 (35.8), 263 (-19.1), 243 (9.2), 225 (-28.7)
234 (-8.8), 225 (-9.3)
MeOH
MeOH
CM
MeOH
MeOH
CM
MeOH
MeOH
CD
248 (3150shb), 218 (11930)
253 (17.6), 222 (-31.9)
495 (128), 426 (732), 319 (11045)
513 (-8.1), 425 (28.6), 306 (32.0), 266 (-24.6), 246 (17.2), 227 (-32.3)
248 (11.9), 218 (-33.3)
247 (4020shb), 209 (22100)
253 (3650shb), 209 (23230)
254 (-49.2), 225 (34.9)
504 (73), 424 (690), 320 (1640)
510 (15.9), 426 (-38.7), 316 (-25.7), 270 (19.3), 245 (-68.1)
254 (1040shb), 208 (8850)
253 (-1.6), 228 (+)d
253 (2470shb), 213 (13330)
254 (-39.0), 224 (28.4)
504 (92), 422 (810), 316 (15080)
503 (24.9), 422 (-67.8), 307 (-102.7), 264 (77.2), 244 (-23.3), 228 (125)
a CD, cyclohexane/dioxane (4:1) and CM, cyclohexane/dichloromethane (4:1). b sh: Shoulder. c Molar ellipticity in deg cm2 dmol-1
.
d CD sign only was
determined.
SCHEME 3
chromophores, there is a close correspondence between their
lowest energy transitions.
However, a substitution of sulfur for oxygen carbonyls results
in bathochromic shifts and a better resolution of the absorption
and CD bands in the spectra of dithiooxamides 1c-6c. The
UV-vis spectrum of 1c reveals a weak absorption at 480 nm
(ꢀ 98) and a moderate intensity band at 422 nm (ꢀ 840) in
hydrocarbon solvents, and the absorptions shift to shorter
wavelengths (470 and 395 nm, respectively) after the solvent
is changed to methanol. Both these bands can be attributed to
two forbidden n-π* electronic transitions. A strong absorption
at 315 nm (ꢀ 11 800), a position of which is almost independent
of solvent polarity according to the energy-level diagram for
the excited states proposed by Sandstro¨m and co-workers, can
be attributed to two overlapping π-π* transitions,7b whereas a
shoulder at 275 nm (ꢀ 3700) is of less clear origin. A mutual
correspondence between the CE signs of the third and fourth
bands in the CD spectrum of 1c and two π-π* bands in 1a,b
points to a similar origin of the corresponding excitations in
both classes of compounds. Thus, exactly the same helicity rule
as that for oxamides (Scheme 3) also can be used for the
correlation of configuration of dithiooxamides. Indeed, the CE
signs of the analogous CD bands in dithiooxamides 1c-6c are
the same as those of the π-π* CEs in their parent oxo com-
pounds 1b-6b (Table 2). This means that the conformational
preferences of the dithionocarbonyl compounds 1c-6c resemble
those of their oxo analogues and, particularly, a predominance
of the axial conformations in the case of 3c-6c as confirmed
by the crystal structures of 3c and 6c. In contrast to oxamides,
where the weak n-π* CE can be observed with difficulty, their
dithiono analogues show two relatively strong n-π* bands: one
diffuse near 500 nm and the second of the opposite sign near
420 nm. The opposite sequence of the CEs to those of the π-π*
bands suggests that the corresponding excited states have B and
A symmetry, respectively. These CD bands have generally the
same diagnostic value for stereochemical predictions as the CEs
corresponding to the π-π* excitations.
the right-handed in 3b. This means that 3a prefers the equatorial
conformation in solution and 3b the axial one, similar to the
solid state. Furthermore, the magnitudes of the CEs in the
spectrum of 3b are roughly 3 times stronger than those in the
spectrum of 3a and comparable to those in the conformationally
rigid compound 1b, which suggests an overwhelming contribu-
tion of the axial form of 3b to the conformational equilibrium.
Analogous conformational preferences were observed for 4a,b
and 5a,b (i.e., a predominance of the equatorial form in the
case of the NH derivatives and the axial one for the N-methyl
derivatives). As was already mentioned, a strong steric interac-
tion between the N-methyl groups and the bulky equatorial
substituents at C-5 and C-6 is primarily responsible for
destabilization of the equatorial form. Particularly, a predomi-
nance of the diequatorial form of the diphenyl derivative 5a
observed in solution remains in variance with the solid state
structure of the solvate 5a‚THF. However, the diaxial orienta-
tion of substituents is apparently due to the crystal packing of
the solvate, and the crystals of the complex with pentafluo-
robenzoic acid (pfb) contain the diequatorial conformer of 5a.
Oxamide 6a behaves exceptionally, where the CD spectrum
suggests the axial orientation of the benzyl substituent in
solution; however, the magnitudes of both CEs are rather small,
which points to only a slight predominance of the axial form
over the equatorial one in the conformational equilibrium.
The CD spectrum of 1c (Figure 4) and the remaining
dithiooxamides show at least six bands with alternating signs
at the visible and near-UV region. Because of a similarity of
the electronic structures of the oxamide and dithiooxamide
Molecular Self-Assembly. Oxamides are superb hydrogen-
bonding compounds21 and have found a broad application in
the design and synthesis of new molecular solids. The majority
of the investigated structures contain a trans-oxamide function-
2856 J. Org. Chem., Vol. 73, No. 7, 2008

2,3-Piperazinodiones and Their Dithiono Analogues
FIGURE 3. CD and UV (lower curves) spectra of 3a and 3b taken in water.
FIGURE 5. Left-handed helical structures extending along the 43 screw
axis in the tetragonal crystals of (a) 1a and (b) 3b. Each oxalamide
molecule takes part in two C(5) hydrogen-bond motifs: one extending
along the helix axis and the second indicated by the arrows.
FIGURE 4. CD and UV-vis (lower curve) spectra of 1c taken in
cyclohexane-dioxane (4:1).
hydrogen bonds create a C(5) hydrogen-bond motif,24 as-
sembling molecules into a 3-D network (Figure 5). This motif
is generated by the hydrogen bonds between two different amide
units of the cyclic oxamide system: one acting as a donor and
the second as an acceptor. In the crystals of 1a, each constituent
molecule of C2 symmetry belongs to two 43 helices that leads
to a 3-D hydrogen-bond network (see Figures 11aS and 12aS
in the Supporting Information). In contrast, the molecules of
3a are asymmetric, and two different types of the C(5) hydrogen-
bond motifs are generated, one helical as shown in Figure 5
and the second extended perpendicularly to it, along the 2-fold
screw axes, running parallel to the ab-diagonals (see Figures
11bS and 12bS in the Supporting Information). This helical
assembly mode seems to be the preferred one for homochiral
cyclic oxalamides with relatively small substituents located at
C-5 and C-6. A completely different crystal packing was
observed in the solvated crystal of 5a, where the oxalamide
ality, and only a few structures containing cis-oxamide functions
have been reported.22 Cyclic oxamides are noncentrosymmetric
units, and their hydrogen-bonded crystalline aggregates having
a polar order are potentially useful because of their important
physical properties.23 Obtaining optically active 2,3-pipera-
zinediones prompted us to take a closer look at their assembly
mode in their homochiral crystals.
Compounds 1a and 4a crystallize in the space group P43212,
which may suggest the formation of hydrogen-bonded helical
structures running along a 4-fold screw axis. Indeed, the
common feature of these two structures is left-handed helices
extended along the c-axis. In both crystals, the NH‚‚‚OdC
(21) (a) Coe, S.; Kane, J. J.; Nguyen, T. L.; Toledo, L. M.; Wininger,
E.; Fowler, F. W.; Lauher, J. W. J. Am. Chem. Soc. 1997, 119, 86. (b)
Nguyen, T. L.; Scott, A.; Dinkelmeyer, B.; Fowler, F. W.; Lauher, J. W.
New J. Chem. 1998, 129. (c) Nguyen, T. L.; Fowler, F. W.; Lauher, J. W.
J. Am. Chem. Soc. 2001, 123, 11057.
(22) MacDonald, J. C.; Whitesides, G. M. Chem. ReV. 1994, 94, 2383.
(23) (a) Velsko, S. P. In Materials for Nonlinear Optics. Chemical
PerspectiVes; Marder, S. R., Sohn, J. E., Stucky, G. D., Eds.; ACS Symposia
Series 455; American Chemical Society: Washington, DC, 1991; pp 343-
359. (b) Evans, O. R.; Lin, W. Acc. Chem. Res. 2002, 35, 511.
(24) For details of the definition, terminology, and notation in the graph
set approach, see: (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120. (b)
Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1555.
J. Org. Chem, Vol. 73, No. 7, 2008 2857

Piotrkowska et al.
FIGURE 7. Molecular 1-D assemblies via CsH‚‚‚OdC (gray dashed
lines) interactions in 5b. The crystal contains two such polymeric
structures that are symmetry independent. Notice the similarity with
5a‚THF, where the analogue assemblies via CsH‚‚‚OdC interactions
are formed.
FIGURE 8. Hydrogen-bonded 1-D assembly of component molecules
in 5a‚fba2‚H2O; view along the b-axis.
FIGURE 6. (a) Layer-type assemblies via NsH‚‚‚OdC (black dashed
lines) and CsH‚‚‚OdC (gray dashed lines) interactions in 5a‚THF
and (b) side view of the layers showing channels filled with the solvent
molecules.
rophenyl rings,25 which we considered to be a potential driving
force for the complex formation, are absent since the centroid-
to-centroid distances between phenyl and pentafluorophenyl
rings are longer than 4.2 Å.
molecule of the crystallographic C2 symmetry assumed a diaxial
conformation. In this case, the NH‚‚‚OdC hydrogen bonds
2
generate the cyclic motif R2 (8), which assembles the molecules
In conclusion, 2,3-piperazinodiones being simple models of
cis-oxamides can be prepared easily by the condensation of 1,2-
diamines with diethyl oxalate. The heterocyclic six-membered
ring may assume two enantiomeric half-chair conformations
with the twisted oxamide chromophore. Substitution at C-5 shifts
the conformational equilibrium toward the equatorial conformer,
whereas substitution at the nitrogen atoms results in domination
of the axial form. Since the axial and equatorial conformers
are characterized by the opposite helicity of the twisted oxamide
chromophore, the changes in conformational equilibrium can
be easily monitored by CD spectroscopy. Particularly, the CE
signs corresponding to two allowed π-π* transitions were
determined by the inherent chirality of the chromophore and
can be predicted by the helicity rule. The same rule is also valid
for 2,3-piperazinodithiones, where the substitution of sulfur for
oxygen in the carbonyl groups results in bathochromic shifts
and better resolution of the absorption and CD bands.
into tapes running parallel to the c-axis (Figure 6a). The tapes
are further connected by a set of weaker CsH‚‚‚OdC interac-
tions into layers arranged parallel to (100). There are deep
grooves formed between the phenyl rings protruding on both
sides of the layer, which are, however, too narrow to accom-
modate the bumps from the adjacent layers. Since a closely
packed structure cannot be formed, the layers of 5a create a
host matrix with channels extended along the b-axis that are
filled with the THF molecules (Figure 6b). Interestingly, in the
crystals of the N,N′-dimethyl derivative 5b, where classical
hydrogen bonds cannot be formed, weak CsH‚‚‚OdC interac-
tions assemble the molecules in a manner analogous to that
observed in the crystal structure of 5a‚THF (Figure 7). It
appeared that oxamide 5a easily formed a hydrated complex
5a‚pfb2‚H2O upon cocrystallization with pentafluorobenzoic
acid from CH2Cl2. As mentioned earlier, in this case, the
molecules of 5a adopt a diequatorial conformation, in contrast
to 5a‚THF, where the phenyl substituents are axially oriented.
In this complex, the constituent molecules are connected via
NH‚‚‚O and OH‚‚‚O hydrogen bonds into a 1-D polymeric
structure extending along the b-axis (Figure 8). In this case,
the oxalamide molecule acts simultaneously as a hydrogen-bond
donor and acceptor to the pfb unit, whereas the water molecule
binds only to the carboxyl group. Surprisingly, the π-π stacking
interactions between phenyl and electron deficient pentafluo-
The crystal packing analysis of several homochiral 2,3-
piperazinodiones revealed that strong NH‚‚‚OdC intermolecular
hydrogen-bonding interactions generating the C(5) chain motif
resulted in the formation of supramolecular hydrogen-bonded
helices as in the case of homochiral compounds with small
(25) (a) Gdaniec, M.; Jankowski, W.; Milewska, M. J.; Po-lon´ski, T.
Angew. Chem., Int. Ed. 2003, 42, 3903. (b) Piotrkowska, B.; Gdaniec, M.;
Połon´ski, T. CrystEngComm 2007, 9, 868.
2858 J. Org. Chem., Vol. 73, No. 7, 2008

2,3-Piperazinodiones and Their Dithiono Analogues
δ 186.7, 182.9, 57.5, 55.6, 54.1, 45.4, 30.8, 23.2; νmax (KBr)/cm-1
1487, 1374. Anal. calcd for C8H12N2S2: C, 47.97; H, 6.04; N, 13.98;
S, 32.01. Found: C, 47.96; H, 6.00; N, 13.97; S, 32.09.
(R)-5-Methyl-2,3-piperazinodione (3a). Compound 3a was
prepared from (R)-1,2-diaminopropane29 in a similar manner to that
of 1a in 92% yield; mp 205-209 °C; [R]D25 -78.8 (c 1, MeOH);1H
NMR (DMSO-d6) δ 8.55 (s, 1H), 8.48 (s, 1H), 3.70 (m, 1H), 3.28
(m, 1H), 3.08 (m, 1H), 1.11 (d, J ) 6.9 Hz, 3H); 13C NMR (DMSO-
d6) δ 162.1, 49.6, 49.3, 22.0; νmax (KBr)/cm-1 3210, 1657. Anal.
calcd for C5H8N2O2 (128): C, 46.87; H, 6.29; N, 21.86. Found:
C, 46.93; H, 6.27; N, 22.06.
equatorially placed substituents or as in the case of the
compounds with larger axially oriented substituent polymeric
tapes with the use of the cyclic R2 (8) hydrogen-bond motif.
2
Experimental Section
1H and 13C NMR spectra were obtained at 300 and 50 MHz,
respectively, and the deuterated solvents were used as an internal
lock.
(9R,10R)-2,3-Decahydrobenzopyrazinodione (1a). To a solu-
tion of (1R,2R)-(-)-1,2-diaminocyclohexane (1.8 g, 15 mmol) in
EtOH (200 mL), diethyl oxalate (2.1 mL, 15 mmol) was added,
and the mixture was refluxed for 3 h. The reaction mixture was
filtered, the solvent was evaporated, and the product was crystallized
from ethanol-water, 1.57 g (75%), mp >300 °C (lit.26 racemate
(R)-1,4,5-Trimethyl-2,3-piperazinodione (3b). Compound 3b
was prepared from (R)-N,N′-dimethyl-1,2-diaminopropane27,30 in
20
a similar manner to that of 1b in 79% yield; mp 115-116 °C; [R]D
+100 (c 0.4, CHCl3); 1H NMR (CDCl3) δ 3.92 (dd, J ) 12.8 and
4.4 Hz, 1H), 3.59 (m, 1H), 3.13 (dd, J ) 12.8 and 2.9 Hz, 1H),
3.11 (s, 3H), 3.07 (s, 3H), 1.38 (d, J ) 6.8 Hz, 3H); 13C NMR
(CDCl3) δ 155.9, 155.7, 50.5, 50.3, 33.9, 31.7, 15.6; νmax (KBr)/
cm-1 1685, 1492. Anal. calcd for C7H12N2O2 (156): C, 53.83; H,
7.74; N, 17.94. Found: C, 53.63; H, 7.78; N, 18.04.
22
mp 301-303 °C); [R]D -87.3 (c 2, 50% EtOH); 1H NMR
(DMSO-d6) δ 8.58 (s, 2H), 3.19 (m, 2H), 1.84 (m, 2H), 1.64 (m,
2H), 1.22 (m, 4H); 13C NMR (DMSO-d6) δ 158.6, 54.9, 28.7, 23.0;
νmax (KBr)/cm-1 3251, 1703, 1672. Anal. calcd for C8H12N2O2
(168): C, 57.13; H, 7.19; N, 16.66. Found: C, 57.10; H, 7.28; N,
16.83.
(R)-1,4,5-Trimethyl-2,3-piperazinodithione (3c). Thionation of
3b with Lawesson’s reagent in toluene afforded the product in 85%
(9R,10R)-1,4-Dimethyl-2,3-decahydrobenzopyrazinodione (1b).
A mixture of (1R,2R)-(-)-N,N′-dimethyl-1,2-diaminocyclohexane27
(1.47 g, 15 mmol) and diethyl oxalate (1.5 mL, 10 mmol) in toluene
(50 mL) was refluxed for 5 h. After the addition of heptane
20
1
yield; mp 148 °C; [R]D -886 (c 0.2, CHCl3); H NMR (CDCl3)
δ 4.04 (dd, J ) 13.8 and 3.9 Hz, 1H), 3.82 (m, 1H), 3.61 (s, 3H),
3.55 (s, 3H), 3.41 (dd, J ) 13.8 and 1.9 Hz, 1H), 1.38 (d, J ) 6.8
Hz, 3H); 13C NMR (CDCl3) δ 184.8, 184.7, 54.0, 53.7, 44.3, 42.0,
14.4, νmax (KBr)/cm-1 1495, 1313. Anal. calcd for C7H12N2S2
(188): C, 44.65; H, 6.43; N, 14.88; S, 34.05. Found: C, 44.68; H,
6.62; N, 15.04; S, 34.25.
22
crystallized the product, 1.6 g (82%), mp 154 °C; [R]D -150.7
(c 2, CHCl3); 1H NMR (CDCl3) δ 3.38 (m, 2H), 3.06 (s, 6H), 2.32
(m, 2H), 1.92 (m, 2H), 1.45-1.30 (complex m, 4H); 13C NMR
(CDCl3) δ 157.9, 58.4, 28.6, 28.4, 23.4; νmax (KBr)/cm-1 1703,
1672. Anal. calcd for C10H16N2O2‚H2O (205): C, 58.53; H, 8.29;
N, 13.65. Found: C, 58.58; H, 8.35; N, 13.56.
(R)-5-Phenyl-2,3-piperazinedione (4a). Compound 4a was
prepared from (R)-1,2-diamino-1-phenylethane31 in a similar manner
22
to that of 1a in 92% yield; mp >220 °C (dec); [R]D -87.7 (c
(9R,10R)-1,4-Dimethyl-2,3-decahydrobenzopyrazinodithione
(1c). Oxamide 1b (1.0 g, 5 mmol) and Lawesson’s reagent (2.4 g,
6 mmol) were refluxed in toluene (20 mL) for 90 min. After
evaporation of the solvent, the residue was subjected to column
chromatography on silica gel, and elution with CDCl3 gave 0.95 g
0.114, DMSO); 1H NMR (DMSO-d6) δ 8.97 (s, 1H, NH), 8.45 (s,
1H, NH), 7.40 (t, J ) 7.5 Hz, 2H), 7.33 (m, 3H), 4.78 (s, 1H),
3.66 (m, 1H), 3.39 (m, 1H); νmax (KBr)/cm-1 3296, 1656. Anal.
calcd for C10H10N2O2 (190): C, 63.15; H, 5.30; N, 14.73. Found:
C, 63.39; H, 5.52; N, 14.93.
20
(83%) of the product; mp 236-238 °C; [R]D +812.5 (c 0.2,
(R)-1,4-Dimethyl-5-phenyl-2,3-piperazinedione (4b). To a
stirred suspension of 4a (2.5 g, 13.15 mmol) in anhydrous THF
(120 mL), sodium hydride (1.5 g, 37.5 mmol, 60% dispersion in
mineral oil) was added. After being stirred for 15 min, methyl iodide
(2.46 mL, 39.5 mmol) was added in one portion, and the reaction
mixture was stirred overnight. The excess of NaH was quenched
by the slow addition of water, and the product was extracted with
ethyl acetate. The organic layer was dried (MgSO4), and the solvent
was removed under reduced pressure. The residue was crystallized
from ethyl acetate-diethyl ether: yield 1.5 g, (52%); mp 197-200
1
CHCl3). H NMR (CDCl3) δ 3.57 (s, 6H), 3.43 (m, 2H), 2.48 (m,
2H), 1.95 (m, 2H), 1.55 (m, 2H), 1.37 (m, 2H); 13C NMR (CDCl3)
δ 188.5, 61.1, 37.8, 28.9, 23.6; νmax (KBr)/cm-1 1469, 1358, 1235.
Anal. calcd for C10H16N2S2 (228): C, 52.59; H, 7.06; N, 12.27; S,
28.08. Found: C, 52.66; H, 7.18; N, 12.18; S, 28.09.
(S)-2-Methylhexahydropyrrolo[1,2-a]pyrazine-3,4-dione (2b).
Bicyclic oxamide 2b was prepared from (S)-2-[N-methyl(aminom-
ethyl)]pyrrolidine28 in the same manner as compound 1b; yield 75%;
25
mp 178-180 °C, [R]D +154.5 (c 0.662, CHCl3); 1H NMR
(CDCl3) δ 4.02 (m, 1H), 3.66-3.58 (m, 2H), 3.46 (d, J ) 5.2 Hz,
1H), 3.06 (s, 3H), 2.26-2.02 (m, 2H), 2.0-1.8 (m, 2H), 1.68-
1.56, m, 1H); 13C NMR (CDCl3) δ 158.7, 155.7, 55.1, 52.8, 45.5,
35.4, 30.5, 23.6; νmax (KBr)/cm-1 1674. Anal. calcd for C8H12N2O2
(168): C, 57.13; H, 7.19; N, 16.66. Found: C, 57.04; H, 7.13; N,
16.48.
22
1
°C, [R]D -42.9 (c 0.14, CHCl3); H NMR (CDCl3) δ 7.39 (m,
3H), 7.23 (d, J ) 6.8 Hz, 2H), 4.61 (t, J ) 3.9 Hz, 1H), 4.07 (dd,
J ) 12.9 and 4.6 Hz, 1H), 3.41 (dd, J ) 13.2 and 3.4 Hz, 1H), 3.0
(s, 3H), 2.92 (s, 3H); 13C NMR (CDCl3) δ 158.2, 157.6, 136.9,
129.5, 129.1, 126.6, 60.3, 53.2, 35.4, 34.2; νmax (KBr)/cm-1 1681.
Anal. calcd for C12H14N2O2 (218): C, 66.04; H, 6.47; N, 12.84.
Found: C, 65.93; H, 6.42; N, 12.76.
(S)-2-Methylhexahydropyrrolo[1,2-a]pyrazine-3,4-dithione (2c).
The previous oxamide (1.0 g, 5.95 mmol) and Lawesson’s reagent
(2.64 g, 6.54 mmol) were refluxed in toluene (70 mL) for 2 h. The
reaction mixture was allowed to cool to room temperature, and the
brown precipitate was removed by filtration to give the title
(R)-1,4-Dimethyl-5-phenyl-2,3-piperazinedithione (4c). Thion-
ation of 4b with Lawesson’s reagent in toluene afforded brown
needles of the product in 68% yield; mp 152-154 °C (ethanol);
22
1
[R]D -677 (c 0.096, CHCl3); H NMR (CDCl3) δ 7.38 (d, J )
6.8 Hz, 3H), 7.19 (d, J ) 6.3 Hz, 2H), 4.85 (br s, 1H), 4.36 (dd,
J ) 13.7 and 3.4 Hz, 1H), 3.73 (d, J ) 12.2 Hz, 1H), 3.53 (s, 3H),
3.34 (s, 3H); 13C NMR (CDCl3) δ 187.7, 186.4, 135.0, 129.7, 129.4,
25
compound. Yield 0.91 g (76.5%); mp 209-211 °C (ethanol), [R]D
1
-480 (c 0.136, CHCl3); H NMR (CDCl3) δ 4.0 (br s, 1H), 3.89
(m, 2H), 3.8-3.64 (m, 2H), 3.58 (s, 3H), 2.33 (br s, 1H), 2.21 (br
s, 1H), 2.04 (br s, 1H), 1.78 (br s, 1H); 13C NMR (CDCl3)
(29) Dwyer, F. P.; Garvan, F. L.; Shulman, A. J. Am. Chem. Soc. 1959,
81, 290.
(26) Brill, E.; Schultz, H. P. J. Org. Chem. 1963, 28, 1135.
(27) Kashiwabara, K.; Hanaki, K.; Fujita, J. Bull. Chem. Soc. Jpn. 1980,
53, 2275.
(28) (a) Betschart, C.; Schmidt, B.; Seebach, D. HelV. Chim. Acta 1988,
71, 1999. (b) Bose, D. S.; Lakshminarayana, V. Tetrahedron Lett. 1998,
39, 5631. (c) Trotter, N.; Brimble, M. A.; Harris, P. W. R.; Callis, D. J.;
Sieg, F. Bioorg. Med. Chem. 2005, 13, 501.
(30) Trethof, J. A.; Cooke, D. W. Inorg. Nucl. Chem. Lett. 1972, 8, 1013.
(31) (a) Belokon, Y. N.; Pritula, L. K.; Tararov, V. I.; Bakhmutov, V.
I.; Struchkov, Y. T. J. Chem. Soc., Dalton Trans. 1990, 6, 1867. (b)
Lagriffoul, P.-H.; Tadros, Z.; Taillades, J.; Commeyras, A. J. Chem. Soc.,
Perkin Trans 2 1992, 1279. (c) Wang, M.-X.; Lin, S.-J. J. Org. Chem.
2002, 67, 6542.
J. Org. Chem, Vol. 73, No. 7, 2008 2859

Piotrkowska et al.
126.5, 62.9, 56.2, 45.6, 44.2; νmax (KBr)/cm-1 1491, 1344, 1297.
Anal. calcd for C12H14N2S2 (250): C, 57.56; H, 5.64; N, 11.19; S,
25.61. Found: C, 57.66; H, 5.72; N, 11.09; S, 25.56.
(5S,6S)-5,6-Diphenyl-2,3-piperazinedione (5a). The title com-
pound was prepared from (1S,2S)-(-)-1,2-diamino-1,2-diphenyle-
thane following the procedure analogous to that of 1a; yield 82%;
mp 222-224 °C, [R]D22 -58.3 (c 0.24, DMSO); 1H NMR (DMSO-
d6) δ 8.85 (br s, 2H, NH), 7.32 (m, 10H), 4.80 (t, J ) 2.4 Hz, 2H);
13C NMR (DMSO-d6) δ 158.4, 139.6, 128.5, 127.9, 126.8, 59.6;
νmax (KBr)/cm-1 3368, 1708. Anal. calcd for C16H14N2O2 (266):
C, 72.17; H, 5.30; N, 10.52. Found: C, 72.11; H, 5.35; N, 10.44.
and refined by full-matrix least-squares SHELXL97.34 All structural
drawings were prepared with the program Mercury, version 1.4.2.35
Crystal Data for C8H12N2O2 (1a). M ) 168.20, tetragonal, space
group P43212, a ) b ) 6.6090(3) Å, c ) 18.8339(15) Å, V )
822.64(8) Å3, T ) 293 K, Z ) 4, Fx ) 1.358 g cm-3, µ(Mo-KR)
) 0.099 mm-1, λ ) 0.71073 Å, 3290 reflections measured, 584
unique (Rint ) 0.0206). Final residuals for 56 parameters were R1
) 0.0367, wR2 ) 0.0865 for 483 reflections with I > 2σ(I), and R1
) 0.0471, wR2 ) 0.0962 for all data.
Crystal Data for C5H8N2O2 (3a). M ) 128.13, tetragonal, space
group P43212, a ) b ) 6.9810(1) Å, c ) 24.2018(7) Å, V )
1179.46(4) Å3, T ) 293 K, Z ) 8, Fx ) 1.443 g cm-3, µ(Mo-
KR) ) 0.113 mm-1, λ ) 0.71073 Å, 7224 reflections measured,
781 unique (Rint ) 0.0141). Final residuals for 82 parameters were
R1 ) 0.0282, wR2 ) 0.0702 for 719 reflections with I > 2σ(I), and
R1 ) 0.0316, wR2 ) 0.0736 for all data.
Crystal Data for C7H12N2O2 (3b). M ) 156.19, orthorhombic,
space group P212121, a ) 7.8934(2) Å, b ) 9.0440(2) Å, c )
11.2187(3) Å, V ) 800.88(3) Å3, T ) 120 K, Z ) 4, Fx ) 1.295
g cm-3, µ(Mo-KR) ) 0.096 mm-1, λ ) 0.71073 Å, 10 437
reflections measured, 959 unique (Rint ) 0.0229). Final residuals
for 103 parameters were R1 ) 0.0304, wR2 ) 0.0793 for 881
reflections with I > 2σ(I), and R1 ) 0.0338, wR2 ) 0.0828 for all
data.
Crystal Data for C7H12N2S2 (3c). M ) 188.31, orthorhombic,
space group P212121, a ) 6.4030(12) Å, b ) 11.526(2) Å, c )
12.735(3) Å, V ) 939.9(3) Å3, T ) 140 K, Z ) 4, Fx ) 1.331 g
cm-3, µ(Mo-KR) ) 0.507 mm-1, λ ) 0.71073 Å, 7126 reflections
measured, 1902 unique (Rint ) 0.0820). Final residuals for 102
parameters were R1 ) 0.0402, wR2 ) 0.0936 for 1833 reflections
with I > 2σ(I), and R1 ) 0.0422, wR2 ) 0.0949 for all data.
Crystal Data for C16H14N2O2‚C4H8O(5a‚THF). M ) 338.40,
orthorhombic, space group P2221, a ) 12.405(2) Å, b ) 6.9058-
(10) Å, c ) 11.0030(12) Å, V ) 942.6(2) Å3, T ) 200 K, Z ) 2,
Fx ) 1.192 g cm-3, µ(Mo- KR) ) 0.081 mm-1, λ ) 0.71073 Å,
4202 reflections measured, 988 unique (Rint ) 0.0390). Final
residuals for 116 parameters were R1 ) 0.0590, wR2 ) 0.1558 for
635 reflections with I > 2σ(I), and R1 ) 0.0942, wR2 ) 0.1846 for
all data. The solvent molecule is strongly disordered. At 195 K,
the crystal exhibited a phase transition to a triclinic twinned phase.
Crystal Data for C16H14N2O2‚2(C7HF5O2)‚H2O(5a‚fba2‚H2O).
M ) 708.46, monoclinic, space group P21, a ) 14.4997(15) Å, b
) 5.9482(7) Å, c ) 16.7914(17) Å, â ) 94.631(9)°, V ) 1443.5-
(3) Å3, T ) 100 K, Z ) 2, Fx ) 1.630 g cm-3, µ(Mo- KR) )
0.158 mm-1, λ ) 0.71073 Å, 12062 reflections measured, 3228
unique (Rint ) 0.0356). Final residuals for 460 parameters were R1
) 0.0297, wR2 ) 0.0526 for 2256 reflections with I > 2σ(I), and
R1 ) 0. 0.0600, wR2 ) 0.0633 for all data.
Crystal Data for C18H18N2O2 (5b). M ) 294.34, monoclinic,
space group C2, a ) 23.6192(10) Å, b ) 6.7822(3) Å, c ) 16.8873-
(6) Å, â ) 119.234(4)°, V ) 2360.63(19) Å3, T ) 200 K, Z ) 6,
Fx ) 1.242 g cm-3, µ(Mo-KR) ) 0.082 mm-1, λ ) 0.71073 Å,
6125 reflections measured, 2600 unique (Rint ) 0.0390). Final
residuals for 302 parameters were R1 ) 0.0314, wR2 ) 0.0794 for
2134 reflections with I > 2σ(I), and R1 ) 0. 0.0415, wR2 ) 0.0867
for all data.
Crystal Data for C13H16N2O2 (6b). M ) 232.28, orthorhombic,
space group P212121, a ) 7.3532(5) Å, b ) 8.6308(6) Å, c )
18.8901(13) Å, V ) 1198.84(14) Å3, T ) 140 K, Z ) 4, Fx )
1.287 g cm-3, µ(Mo-KR) ) 0.088 mm-1, λ ) 0.71073 Å, 9998
reflections measured, 1594 unique (Rint ) 0.0378). Final residuals
(5S,6S)-1,4-Dimethyl-5,6-diphenyl-2,3-piperazinedione (5b).
N-Methylation of 5a following the procedure analogous to that of
4b afforded the title product in 68% yield; mp 262-264 °C
(methanol-diethyl ether), [R]D22 -84.8 (c 0.33, CHCl3); 1H NMR
(CDCl3) δ 7.42 (m, 6H), 7.28 (m, 4H), 4.55 (s, 2H), 2.86 (s, 6H);
13C NMR (CDCl3) δ 157.4, 137.4, 129.4, 128.9, 125.9, 67.4, 34.5;
ν
max (KBr)/cm-1 1668. Anal. calcd for C18H18N2O2 (294): C, 73.45;
H, 6.16; N, 9.52. Found: C, 73.24; H, 6.15; N, 9.46.
(5S,6S)-1,4-Dimethyl-5,6-diphenyl-2,3-piperazinedithione (5c).
Thionation of 5b with Lawesson’s reagent in toluene afforded the
title product in 65% yield; mp 231-233 °C (toluene-hexane);
[R]D22 +685 (c 0.054, CHCl3); 1H NMR (CDCl3) δ 7.40 (m, 6H),
7.30 (m, 4H), 4.87 (s, 2H), 3.34 (s, 6H); 13C NMR (CDCl3) δ 186.7,
135.6, 129.6, 129.2, 126.0, 69.9, 44.8; νmax (KBr)/cm-1 1492, 1394,
1287. Anal. calcd for C18H18N2S2 (326): C, 66.22; H, 5.56; N, 8.58;
S, 19.64. Found: C, 66.28; H, 5.39; N, 8.57; S, 19.60.
(S)-5-Benzyl-2,3-piperazinedione (6a). The oxamide 6a was
prepared from (S)-1,2-diamino-3-phenylpropane32 in a manner
similar to that of 1a and had a mp >250 °C (dec), [R]D22 -82.2 (c
0.073, DMSO); 1H NMR (DMSO-d6) δ 8.71 (br s, 1H, NH), 8.45
(br s, 1H, NH), 7.18-7.38 (m,5H), 3.76 (br s, 1H), 3.16 (m, 1H),
3.08 (m, 1H), 2.93 (m, 1H), 2.73 (m, 1H); 13C NMR (DMSO-d6)
δ 158.9, 158.7, 137.7, 129.9, 129.2, 127.3, 51.7, 43.0, 39.0; νmax
(KBr)/cm-1 3287, 1654. Anal. calcd for C11H12N2O2 (204): C,
64.69; H, 5.92; N, 13.72. Found: C, 64.33; H, 6.04; N, 13.44.
(S)-1,4-Dimethyl-5-benzyl-2,3-piperazinedione (6b). N-Me-
thylation of 6a following the procedure analogous to that of 4b
22
afforded the title product in 70% yield; mp 126-129 °C; [R]D
-78.6 (c 0.458, CHCl3); 1H NMR (CDCl3) δ 7.36 (t, J ) 7.3 Hz,
2H), 7.29 (t, J ) 7.3 Hz, 1H), 7.15 (d, J ) 7.3 Hz, 2H), 3.81 (dd,
J ) 13.2 and 4.4 Hz, 1H), 3.55 (m, 1H), 3.12 (dd, J ) 13.7 and
5.4 Hz, 1H), 3.08 (d, J ) 1.5 Hz, 1H), 3.06 (s, 6H), 2.88 (dd, J )
13.7 and 10.5 Hz, 1H); 13C NMR (CDCl3) δ 157.6, 157.2, 136.6,
129.4, 129.3, 127.6, 58.6, 48.2, 37.5, 35.3, 34.4; νmax (KBr)/cm-1
1685. Anal. calcd for C13H16N2O2 (232): C, 67.22; H, 6.94; N,
12.06. Found: C, 67.25; H, 6.93; N, 11.95.
(S)-1,4-Dimethyl-5-benzyl-2,3-piperazinedithione (6c). Thion-
ation of 6b with Lawesson’s reagent in toluene afforded the title
product in 66% yield; mp 148-151 °C (toluene-hexane);
22
1
[R]D +800 (c 0.08, CHCl3); H NMR (CDCl3) δ 7.37 (t, J )
7.3 Hz, 2H), 7.29 (t, J ) 7.3 Hz, 1H), 7.16 (d, J ) 7.6 Hz, 2H),
3.79 (dd, J ) 14.2 and 3.9 Hz, 1H), 3.83 (m, 1H), 3.57 (s, 3H),
3.38 (s, 3H), 3.38 (dd, J ) 14.2 and 1.5 Hz, 1H), 3.09 (dd, J )
13.7 and 6.8 Hz, 1H), 2.82 (dd, J ) 13.7 and 9.03 Hz, 1H); 13C
NMR (CDCl3) δ 186.5, 186.3, 135.8, 129.5, 129.3, 127.9, 61.7,
51.9, 45.5, 44.5, 36.4; νmax (KBr)/cm-1 1493, 1392, 1330. Anal.
calcd for C13H16N2S2 (264): C, 59.05; H, 6.10; N, 10.59; S, 24.25.
Found: C, 59.21; H, 6.11; N, 10.67; S, 24.11.
X-ray data were collected with a KM4CCD diffractometer. The
crystal structures were solved by direct methods with SHELXS9733
(33) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
1990, 46, 467.
(34) Sheldrick, G. M. SHELXL-97: Program for the Refinement of a
Crystal Structure from Diffraction Data; University of Go¨ttingen: Go¨ttingen,
Germany, 1997.
(35) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields,
G. P.; Taylor, R.; Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006,
39, 453-457.
(32) (a) Brunner, H.; Schmidt, M.; Unger, G.; Schoenenberger, H. Eur.
J. Med. Chem. 1985, 20, 509. (b) Taillades, J.; Boussac, P.; Collet, H.;
Brugidou, J.; Commeyras, A. Bull. Soc. Chim. Fr. 1991, 3, 423. (c) Tandon,
V. K.; Yadav, D. B.; Singh, R. V.; Chaturvedi, A. K.; Shukla, P. K. Bioorg.
Med. Chem. Lett. 2005, 15, 5324.
2860 J. Org. Chem., Vol. 73, No. 7, 2008

2,3-Piperazinodiones and Their Dithiono Analogues
for 156 parameters were R1 ) 0.0365, wR2 ) 0.0811 for 1368
reflections with I > 2σ(I), and R1 ) 0.0485, wR2 ) 0.0862 for all
data.
9236 reflections measured, 4272 unique (Rint ) 0.0360). Final
residuals for 311 parameters were R1 ) 0.0438, wR2 ) 0.0784 for
3396 reflections with I > 2σ(I), and R1 ) 0.0625, wR2 ) 0.0849
for all data.
Crystal Data for C13H16N2S2 [6c(I)]. M ) 264.40, orthorhombic,
space group P21212, a ) 10.2156(11) Å, b ) 14.1494(12) Å, c )
9.4788(8) Å, V ) 1370.1(2) Å3, T ) 130 K, Z ) 4, Fx ) 1.282 g
cm-3, µ(Mo-KR) ) 0.369 mm-1, λ ) 0.71073 Å, 13 976
reflections measured, 2421 unique (Rint ) 0.0344). Final residuals
for 156 parameters were R1 ) 0.0288, wR2 ) 0.0591 for 2226
reflections with I > 2σ(I), and R1 ) 0.0376, wR2 ) 0.0616 for all
data. These crystals (red prisms) and crystals of 6c(II) (orange
needles) appeared as concomitant polymorphs. Recrystallization
from toluene-hexane mixture afforded only crystals of the form
6c(I).
Acknowledgment. We are indebted to Dr. J. Frelek (IChO
PAN, Warsaw) for CD measurements with use of her JASCO
J-715 instrument. Financial support from the Committee of
Scientific Research (Project 3 T09A 030 29) is gratefully
acknowledged.
Supporting Information Available: 1H and 13C NMR spectra
for all new compounds, ORTEP plots, crystal packing diagrams
for 1a, 3a, 6c(I), and 6c(II), and atomic coordinates for computed
structures. This material is available free of charge via the Internet
at http://pubs.acs.org.
Crystal Data for C13H16N2S2 [6c(II)]. M ) 264.40, monoclinic,
space group P21, a ) 7.2071(18) Å, b ) 15.029(3) Å, c ) 13.526-
(4) Å, â ) 104.71(2)°, V ) 1417.0(6) Å3, T ) 130 K, Z ) 4, Fx
) 1.239 g cm-3, µ(Mo- KR) ) 0.356 mm-1, λ ) 0.71073 Å,
JO800037W
J. Org. Chem, Vol. 73, No. 7, 2008 2861