Selenation/thionation of α-amino acids: Formation and x-ray structures of diselenopiperazine and dithiopiperazine and related compounds

Article abstract of DOI:10.1002/ejoc.201100226

N-Phenylglycine reacts with an equivalent of 2,4-bis(phenyl)-1,3- diselenadiphosphetane 2,4-diselenide (Woollins' reagent, WR to generate as the major product 1,4-diphenylpiperazine-2,5-diselenone and as the minor product 1,4-diphenyl-5-selenoxopiperazin-

Full text of DOI:10.1002/ejoc.201100226

FULL PAPER
DOI: 10.1002/ejoc.201100226
Selenation/Thionation of α-Amino Acids: Formation and X-ray Structures of
Diselenopiperazine and Dithiopiperazine and Related Compounds
Guoxiong Hua,[a] Amy L. Fuller,[a] Michael Bühl,[a] Alexandra M. Z. Slawin,[a] and
J. Derek Woollins*[a]
Keywords: Selenium / Selenation / Amino acids / Heterocycles
N-Phenylglycine reacts with an equivalent of 2,4-bis-
(phenyl)-1,3-diselenadiphosphetane 2,4-diselenide (Wool-
lins’ reagent, WR) to generate as the major product 1,4-di-
phenylpiperazine-2,5-diselenone and as the minor product
1,4-diphenyl-5-selenoxopiperazin-2-one. Whereas, reacting
N-phenylglycine with an equivalent of 2,4-bis(4-methoxy-
phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawes-
son’s reagent, LR) affords 1,4-diphenylpiperazine-2,5-di-
thione and N-phenyl-2-(phenylamino)ethanethioamide. 2-
Phenylglycine treated with an equivalent of Woollins’ rea-
gent under identical reaction conditions leads to only the for-
mation of 2,5-diphenylpyrazine. Six X-ray structures are re-
ported. DFT-B3LYP calculations suggest that the planar con-
formation is around 2 kcal/mol less stable than the puckered
conformation for the bis-seleno derivative.
structures are also provided. The X-ray structures reveal
that the central piperazine ring can adopt planar or puck-
ered conformations and DFT calculations have been per-
formed to estimate the barriers between these two conform-
erations.
Introduction
2,5-Dioxopiperazines are an important class of biological
active natural peptide derivatives.[1,2] Their derivatives have
been used widely in the inhibition of the cell growth cycles
of mammals,[3] the inhibition of glutathione-S-transferase,[4]
the inhibition of the activated factor of thrombocytes,[5] and
as inhibitors of various enzymes including topoisomerases
and collagenase-1.[6,7] The effect of introduction of a sulfur
or selenium atom into these molecules has not been tested.
Furthermore, to the best of our knowledge, the synthesis of
the sulfur or selenium counterparts of 2,5-dioxopiperazines
from α-amino acids has not been reported.
2,4-Bis(4-methoxylphenyl)-1,3-dithia-2,4-diphosphetane
2,4-disulfide, Lawesson’s reagent (LR), is best known as a
versatile and effective thionation reagent[8] because of its
applications on the conversion of a wide variety of carbonyl
into thiocarbonyl compounds and the synthesis of phos-
phorus- and sulfur-containing heterocycles[9] and many
other reactions.[10] 2,4-Bis(phenyl)-1,3-diselenadiphosphet-
ane 2,4-diselenide [{PhP(Se)(μ-Se)}2] (Woollins’ reagent,
WR, the selenium counterpart of Lawesson’s reagent) is be-
coming an efficient selenation reagent in synthetic chemis-
try[11] due to its relatively pleasant chemical properties and
ready preparation.[12] Herein, we report the synthesis of new
sulfur and selenium counterparts of 2,5-dioxopiperazines
and the related compounds by the intermolecular cyclocon-
densation reaction of α-amino acids with Lawesson’s rea-
gent or Woollins’ Reagent. Six related single-crystal X-ray
Results and Discussion
The synthesis of diketopiperazine-2,5-dione has pre-
viously been accomplished by intermolecular cyclization of
α-halocarboxamide in a mixture of dichloromethane and
50% aqueous sodium hydroxide in the presence of strong
basic ion exchange resin in good yields.[13] However, we had
no success in attempts to synthesize diketopiperazine-2,5-
dithiones or diketopiperazine-2,5-diselenones from α-halo-
thiocarboxamide or α-haloselenocarboxamide.
Fortunately, treating N-phenylglycine with equimolar
quantities of Woollins’ reagent in refluxing toluene gave rise
to, upon work up in air, the coupling adduct 1,4-diphenyl-
piperazine-2,5-diselenone (1) in 31% yield and a tiny amount
of product 1,4-diphenyl-5-selenoxopiperazin-2-one (2)
(Scheme 1). The result can be explained through the follow-
ing two step reactions: the selenation of C=O by Woollins’
reagent generates the corresponding C=Se intermediate;
and subsequent cyclization of two unstable α-amino selena-
acid by loss of two molecules of H2O gives rise to the major
product 1,4-diphenylpiperazine-2,5-diselenone (1) or subse-
quent cyclization of one unstable molecule of α-amino se-
lena-acid with one moleculae of the starting N-phenyl-
glycine by loss of two molecules of H2O gives rise to the
minor product 1,4-diphenyl-5-selenoxopiperazin-2-one (2).
Reacting N-phenylglycine with one molar equivalent of
Lawesson’s reagent under identical reaction conditions led
[a] School of Chemistry, University of St Andrews,
St Andrews, Fife, KY16 9ST, U.K
Fax: +44-1334-463834
E-mail: jdw3@st-and.ac.uk
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G. Hua, A. L. Fuller, M. Bühl, A. M. Z. Slawin, J. D. Woollins
FULL PAPER
Scheme 1. Synthesis of 1 and 2 via the selenation and condensation of N-phenylglycine.
Scheme 2. Synthesis of 3 and 4 via the thionation and condensation of N-phenylglycine.
to two products, 1,4-diphenylpiperazine-2,5-dithione (3) in
For comparison, 1,4-bis(4-chlorophenyl)piperazine-2,5-
17% yield and N-phenyl-2-(phenylamino)ethanethioamide dione (6) was prepared according to a modified pro-
(4) in 25% yield (Scheme 2). The production of 1,4-di- cedure[14] from the reaction of 2-chloro-N-(4-chlorophenyl)-
phenylpiperazine-2,5-dithione (3) would follow a similar acetamide[15] and sodium hydroxide in the presence of so-
mechanism to the above selenium counterparts. However, dium oxide in 45% yield (Scheme 4). However, attempts to
the mechanism for the formation of N-phenyl-2-(phen- convert (6) into the corresponding dithione (7) or dis-
ylamino)ethanethioamide (4) is unclear.
elenone (8) by thionation/selenation using Lawesson’s rea-
Treating 2-phenylglycine, with one molar equivalent of gent/Woollins’ reagent were unsuccessful, suggesting high
Woollins’ reagent in refluxing toluene generated only 2,5- stability of the secondary amide.
diphenylpyrazine (5) in 31% yield rather than 2,5-diseleno-
Compounds 1, 3 and 4 are stable in air for several
piperazine (Scheme 3) suggesting that the formation of 5 months at room temperature without appreciable decompo-
follows the same initial pathway as in the formation of 1; sition. All compounds are soluble in common chlorinated
but in the second step, not only two molecules of water but solvents. The microanalyses of 1, 3 and 4 were satisfactory,
also two molecules of hydrogen selenide are eliminated.
and all compounds showed the anticipated [M]+ or [M +
Scheme 3. Synthesis of 5 from the selenation of 2-phenylglycine.
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Selenation/Thionation of α-Amino Acids
Scheme 4. Attempt to synthesize 7 or 8 from the thiation/selenation of 1,4-bis(4-chlorophenyl)piperazine-2,5-dione (6).
H]+ peak in their mass spectra. The chemical shift for C=Se
double bond (δSe = 668.2 ppm) in 1 is significantly higher
than that in primary aryl-substituted selenoamides (average
value is ca. 631 ppm)[16] and considerably higher than that
in methyl dimethyldiselenocarbamate (δSe = 602 ppm),[17]
however, it is drastically shifted to high-field, compared to
that in the similar six-membered systems such as 1-thia-
3,3,5,5-tetramethyl-4-cyclohexanselenone (δSe = 2131 ppm)
and selenofenchone (δSe = 1613 ppm).[18] The 13C chemical
shift for C=Se (δC = 197 ppm) in 1 is considerably lower
than that in the similar five- or six-membered cyclic com-
pounds containing C=Se double bonds (δC = 287–
294 ppm)[19] and is marginally lower, compared to that in
selenoamides (δC = 202–218 ppm).[19,20]
Figure 2. Single crystal X-ray structure of 2 (hydrogen atoms omit-
ted for clarity). Selected bond lengths [Å] and angles [°] (esd values
in parentheses): Se(2)–C(2) 1.818(4), O(5)–C(5) 1.225(5), N(1)–C(2)
1.330(5), N(1)–C(6) 1.481(5), N(4)–C(3) 1.476(5), N(4)–C(5)
1.357(6); C(2)–N(1)–C(6) 119.2(4), C(3)–N(4)–C(5) 118.4(3), Se(2)–
C(2)–N(1) 126.4(3), Se(2)–C(2)–C(3) 120.3(3), N(1)–C(2)–C(3)
113.2(3), N(4)–C(3)–C(2) 111.0(4), O(5)–C(5)–N(4) 125.4(2), O(5)–
C(5)–C(6) 122.1(4), N(4)–C(5)–C(6) 112.7(3), N(1)–C(6)–C(5)
111.2(3).
Recrystallization from chloromethane/hexane solution
gave crystals of 1–3 suitable for X-ray diffraction studies
(Figures 1, 2, and 3 and Table 1). 1 and 3 are the first struc-
turally characterized 2,5-piperazinediselenone and 2,5-pip-
erazinedithione; in both compounds the structural unit con-
tains a crystallographic center of symmetry at the center of
the six-membered N2C4 ring, and the eight heavy atoms N–
C(X)–C–N–C(X)–C (X = Se or S) are essentially coplanar.
Surprisingly, the structure of 2, in contrast to the structures
of 1 and 3, is appreciably puckered into a boat conforma-
tion. Similar boat conformations have also been found for
the parent 2,5-piperazinedione system in the gas phase[21a]
and, for 1,4-bis(2-methylphenyl)-2,5-piperazinedione (9b),
in the solid.[21b] In order to probe for the intrinsic structural
preferences of the seleno derivatives, density functional
Figure 3. Single crystal X-ray structure of 3 (hydrogen atoms omit-
ted for clarity). Selected bond lengths [Å] and angles [°] (esd values
in parentheses): S(2)–C(2) 1.663(3), N(1)–C(2) 1.328(3), N(1)–
C(3A) 1.474(3), C(2)–C(3) 1.499(5); C(2)–N(1)–C(3A) 124.8(3),
S(2)–C(2)–N(1) 125.6(3), S(2)–C(2)–C(3) 116.89(18), N(1)–C(2)–
C(3) 117.5(3), N(1A)–C(3)–C(2) 117.7(2).
theory (DFT) calculations were performed at the B3LYP
level for the dione 1,4-bis(2-methylphenyl)-2,5-piperazine-
dione (9a in Scheme 5), the diselenone 1 and the mixed Se/
O derivative 2. In all cases, the planar forms in C2h or Cs
symmetry are transition states connecting two degenerate
minima in boat conformation. The planar form is com-
puted to be less stable than the puckered one by 1.1, 1.6 and
2.0 kcal/mol for 9a, 2, and 1, respectively. This energetic
difference is thus indicated to increase with the Se content,
but to remain small enough in all cases to be overriden by
intermolecular interactions in the solid.
Figure 1. Single crystal X-ray structure of 1 (hydrogen atoms omit-
ted for clarity). Selected bond lengths [Å] and angles [°] (esd values
in parentheses): Se(2)–C(2) 1.822(7), Se(5)–C(5) 1.815(7), N(1)–
C(2) 1.317(9), N(1)–C(6) 1.469(10), N(4)–C(3) 1.478(9), N(4)–C(5)
1.322(8); C(2)–N(1)–C(6) 124.6(7), C(3)–N(4)–C(5) 123.3(6), Se(2)–
C(2)–N(1) 125.8(6), Se(2)–C(2)–C(3) 116.7(5), N(1)–C(2)–C(3)
117.4(7), N(4)–C(3)–C(2) 118.1(6), Se(5)–C(5)–N(4) 125.6(6),
Se(5)–C(5)–C(6) 116.5(6), N(4)–C(5)–C(6) 117.9(6), N(1)–C(6)–
C(5) 117.9(6).
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G. Hua, A. L. Fuller, M. Bühl, A. M. Z. Slawin, J. D. Woollins
Table 1. Details of the X-ray data collections and refinements for 1, 2 and 3.
FULL PAPER
1
2
3
Formula
M
C16H14N2Se2
392.22
C16H14N2OSe
329.26
C16H14N2S2
298.42
Crystal size /mm; crystal system 0.3ϫ0.15ϫ0.03; triclinic
0.09ϫ0.09ϫ0.03; triclinic
P1
0.09ϫ0.09ϫ0.06; monoclinic
P21/n
¯
¯
Space group
P1
a /Å
b /Å
c /Å
α
7.053(4)
9.998(5)
11.277(6)
107.697(14)
92.283(4)
103.980(14)
729.6(7)
2
4.9903(9)
11.6672(16)
12.945(2)
70.153(14)
82.324(16)
78.543(17)
693.01(19)
2
5.5306(15)
21.964(5)
6.2566(17)
90
111.047(6)
90
709.3(3)
2
1.379
β
γ
U /A3
Z
d /gcm–3
1.785
1.578
Reflections collected
Independent reflections
Rint
7507
2517
0.055
0.0608; 0.1140
7201
2379
0.051
0.0443; 0.0883
4127
1421
0.049
0.0603; 0.1115
R1; wR2 [IϾ2σ(I)]
try in C(1) adopts a highly distorted tetrahedral with angles
of S(1)–C(1)–N(1) [129.0(7) Å] and S(1)–C(1)–C(2)
[118.0(6) Å].
Scheme 5. Targets for DFT computations.
To probe for such intermolecular interactions, a simple
dimer of 1 was optimised imposing Ci symmetry and fixing
the nonbonded C(2)···Se(2Ј) and C(2Ј)···Se(2) distances to
the value observed in the solid (3.717 Å), see structure 10 in
Scheme 5. A significant driving force for this dimerisation is
predicted, ΔE = –21.6 kcal/mol, two thirds of which are due
to dispersion. The piperazine moieties optimise to the same
boat conformation as in monomeric 1. Interestingly, enforc-
ing a planar conformation in this dimer (by fixing the nec-
essary dihedral angles in the C4N2 ring to zero and optimis-
ing all other parameters) costs only 1.0 kcal/mol per mono-
mer, i.e. half the amount as in pristine 1. Additional interac-
tions in the fully periodic crystal may further reduce this
value, ultimately producing the observed planar strusture.
The molecular structure of 4 (Figure 4 and Table 2) re-
veals an intramolecular hydrogen bonding interaction be-
tween the sulfur atom in C=S double bond and the H atom
of the amine nitrogen leading to a polymeric structure.
Within the hydrogen bonded pairs the S(1)···H(3N) distance
of 2.704 Å with N(3)–H(3N)···S(1) angle of 170° is con-
siderably bigger than that in primary selenoamides [H···Se
2.527(7) and 2.535(8) Å; N–H···Se 164(3) and 165(4)°].[20]
The C=S distance 1.673(9) Å is slightly shorter that in N-
thioamide thiosemicarbazone derivatives [1.692(2) and
1.694(2) Å],[21] while the shortness of the C(1)–N(1) length
1.336(11) Å, compared to other N(1)–C(9) [1.427(11) Å],
N(3)–C(2) [1.439(11) Å] and N(3)–C(3) [1.403(11) Å] single
Figure 4. Top: Single crystal X-ray structure of 4 (hydrogen atoms
on carbon atoms omitted for clarity). Bottom: hydrogen bonding
interaction leading to chains of polymer. Selected bond lengths [Å]
and angles [°] (esd values in parentheses): S(1)–C(1) 1.673(9), N(1)–
C(1) 1.336(11), N(1)–C(9) 1.427(11), N(3)–C(2) 1.439(11), N(3)–
C(3) 1.403(11), C(1)–C(2) 1.531(12); C(1)–N(1)–C(9) 133.1(7),
S(1)–C(1)–N(1) 129.0(7), N(1)–C(1)–C(2) 113.0(7), C(2)–N(3)–C(3)
bonds, suggests some multiple bond character. The geome- 119.1(6), S(1)–C(1)–C(2) 118.0(6), N(3)–C(2)–C(1) 113.2(7).
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Selenation/Thionation of α-Amino Acids
Table 2. Details of the X-ray data collections and refinements for 4, 5 and 6.
4
5
6
Formula
M
C14H14N2S
242.34
C16H12N2
232.28
C16H12Cl2N2O2
335.19
Crystal size /mm; crystal system 0.15ϫ0.09ϫ0.03; monoclinic 0.09ϫ0.09ϫ0.09; monoclinic
0.21ϫ0.12ϫ0.12; orthorhombic
Space group
P21/n
P21/c
Cmca
6.754(8)
15.116(17)
14.086(15)
90
a /Å
b /Å
c /Å
α
11.118(5)
11.604(5)
9.640(4)
90
13.391(7)
5.727(3)
7.530(4)
90
β
γ
95.828(11)
90
1237.3(9)
4
93.652(15)
90
576.3(5)
2
90
90
1438(3)
4
1.548
U /A3
Z
d /gcm–3
1.301
1.339
Reflections collected
Independent reflections
Rint
6942
2158
0.0136
0.1745; 0.2468
3460
1000
0.065
0.0851; 0.1795
2092
672
0.046
0.0760; 0.1633
R1; wR2 [IϾ2σ(I)]
The crystal structure of 5 (Figure 5 and Table 2) reveals ure 6 and Table 2) consists of discrete C16H12Cl2N2O2 unit.
a similar conformational motif to 1 and 3, though the C– The structure reveals a crystallographically imposed sym-
N bond lengths within the C4N2 ring are significantly metry centre at the centre of the piperazinedione ring and
shorter in 5. The structure is built around a central six- the central six-membered ring C4N2 is essentially planar
membered ring with two phenyl ring wings. The six-mem- with two wing phenyl rings being also essentially coplanar
bered C4N2 ring is essentially planar, the dihedral angle be- with a N(1)–N(1A) axial. With the sterically hindered effect
tween the central plane and two phenyl rings is 21°. The of the p-Cl atom attached to the phenyl ring causes the
N(1)–C(2) and N(1A)–C(2A) distances are identical since whole molecule being not coplanar. The dihedral angle be-
they are symmetry related [1.339(3) Å]. The shortness of the tween the entre ring and each of the two phenyl rings is
C–N [N(1)–C(3A) 1.337(4) Å] and C–C [C(2)–C(3) 90.0°, significantly broader than that (74.7°) in 1,4-bis(2-
1.396(4) Å] suggests delocalisation in the six-membered
C4N2 ring.
Figure 5. Single crystal X-ray structure of 5 (hydrogen atoms omit-
ted for clarity). Selected bond lengths [Å] and angles [°] (esd values
in parentheses): N(1)–C(2) 1.339(3), N(1)–C(3A) 1.337(4), C(2)–
C(3) 1.396(4); C(2)–N(1)–C(3A) 117.7(2), N(1)–C(2)–C(3) 119.7(2),
N(1A)–C(3)–C(2) 122.6(2).
Compound 6 was first synthesized here. Previously, four
similar derivatives of N-substituted phenyl-2,5-piperazine-
dione, 1,4-bis(4-methoxyphenyl)-2,5-piperazinedione, 1,4-
bis(2-methylphenyl)-2,5-piperazinedione, 1,4-bis(1-naphth-
yl)-2,5-piperazinedione, and 1,4-bis(2-methoxyphenyl)-2,5-
piperazinedione have been synthesized by the cycloconden-
sation reaction of two molecules of the corresponding N-
Figure 6. Single crystal X-ray structure of 6 (hydrogen atoms omit-
ted for clarity). Upper diagram, single molecular structure with
substituted chloroacetamides in acetone solution under so-
dium carbonate basic condition with potassium iodide used
as a catalyst.[21b,23–25] Compound 6 is soluble in DMSO
rather than in common chlorinated solvents. Its microanal-
ysis was satisfactory, and showed the anticipated [M + H]+
oxygen atoms are at 50% occupancy; lower diagram, interaction
forming polymeric structure with oxygen atoms are at 50% occu-
pancy. Selected bond lengths [Å] and angles [°] (esd values in paren-
theses): O(1)–C(1) 1.233(7), N(1)–C(1) 1.404(4), N(1)–C(1A)
1.404(4), C(1), C(1B) 1.528(5); C(1)–N(1)–C(1A) 126.0(3), O(1)–
C(1)–N(1) 122.9(4), O(1)–C(1)–C(1B) 120.0(4), N(1)–C(1)–C(1B)
peak in its mass spectrum. The crystal structure of 6 (Fig- 117.0(3).
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G. Hua, A. L. Fuller, M. Bühl, A. M. Z. Slawin, J. D. Woollins
FULL PAPER
methoxyphenyl)-2,5-piperazinedione.[25] All bond lengths
and angles are within normal ranges. In addition, the dis-
tance of C=O double bonds [1.233(7) Å] in 6 are compar-
able with those [1.223–1.228 Å] in related com-
pounds.[21b,22–25]
from dichloromethane solution to hexane under aerobic condition.
No full characterisation is given due to lack of substance.
1,4-Diphenylpiperazine-2,5-diselenone (1): Pale yellow solid (0.12 g),
31% yield. IR (KBr, selected data): ν = 3045 (w), 2920 (w), 2849
˜
(w), 1686 (m), 1595 (m), 1531 (vs), 1490 (m), 1316 (m), 1258 (m),
1105 (s), 1027 (m), 754 (m), 692 (s), 553 (m) cm–1. 1H NMR
(CD2Cl2): δ = 7.53–6.64 (m, 10 H, Ar-H), 3.08 (s, 4 H, CH2) ppm.
13C NMR (CD2Cl2): δ = 197.4 (C=Se), 145.8 (Ar-C), 130.0 (Ar-
C), 129.4 (Ar-C), 125.9 (Ar-C), 58.4 (C-N) ppm. 77Se NMR
(CD2Cl2): δ = 68.2 ppm. Mass spectrum (EI+, m/z), 394 [M]+.
C16H14N2Se2 (392.22): calcd. C 49.00, H 3.60, N 7.14; found C
48.94, H 3.86, N 7.47.
Conclusions
We have developed new methods to synthesize 1,4-di-
phenylpiperazine-2,5-dithione and 1,4-diphenylpiperazine-
2,5-diselenone via the thionation or selenation of α-amino
acids. The structures of all new compounds have been eluci-
dated by using 1H, 31P, 77Se NMR spectroscopy and micro-
analysis in conjunction with single-crystal X-ray crystal-
lography. The diselenone shows an unusual planar structure
of the piperazine moiety in the crystal, which, according
to DFT computations, is probably due to intermolecular
interactions in the solid.
Synthesis of Compounds 3 and 4: A mixture of N-phenylglycine
(0.31 g, 2.0 mmol) and Lawesson’s reagent (0.41 g, 1.0 mmol) in
30 mL of dry toluene was refluxed for 7 h. The white suspension
disappeared and pale grey solution was formed. Upon cooling to
room temperature and removing solvent the residue was purified
by silica gel column (eluented by dichloromethane) to afford 3 and
4.
1,4-Diphenylpiperazine-2,5-dithione (3): Yellow solid (0.05 g), 17%
yield. IR (KBr, selected data): ν = 3062 (w), 2922 (w), 1706 (m),
˜
1595 (m), 1515 (vs), 1452 (m), 1410 (m), 1319 (s), 1268 (s), 1144
1
(vs), 1072 (m), 760 (m), 718 (m), 692 (s), 628 (s) cm–1. H NMR
Experimental Section
(CD2Cl2): δ = 7.52 (m, 4 H, Ar-H), 7.44 (m, 2 H, Ar-H), 7.39 (m,
4 H, Ar-H), 5.02 (s, 4 H, CH2) ppm. 13C NMR (CD2Cl2): δ = 191.5
(C=S), 143.3 (Ar-C), 129.8 (Ar-C), 128.9 (Ar-C), 126.2 (Ar-C), 65.6
(C-N) ppm. Mass spectrum (CI+, m/z), 299 [M + H]+. C16H14N2S2
(298.43): calcd. C 64.39, H 4.73, N 9.39; found C 64.21, H 4.56, N
9.47.
General: Unless otherwise stated, all reactions were carried out un-
der on oxygen free nitrogen atmosphere using pre-dried solvents
and standard Schlenk techniques, subsequent chromatographic and
work up procedures were performed in air. 1H (270 MHz), 13C
(67.9 MHz), 31P{1H} (109 MHz) and 77Se-{1H} (51.4 MHz refer-
enced to external Me2Se) NMR spectra were recorded at 25 °C
(unless stated otherwise) on a JEOL GSX 270. IR spectra were
recorded as KBr pellets in the range of 4000–250 cm–1 on a Perkin–
Elmer 2000 FTIR/Raman spectrometer. Microanalysis was per-
formed by the University of St-Andrews microanalysis service.
Mass spectrometry was performed by the EPSRC National Mass
Spectrometry Service Centre, Swansea and the University of St An-
drews Mass Spectrometry Service. X-ray crystal data for com-
pounds 1–6 were collected using the St Andrews Robotic dif-
fractometer (Saturn724 CCD) at 125 K with graphite monochro-
mated Mo-Kα radiation (λ = 0.71073 Å).[26–28] Intensity data were
collected using ω steps accumulating area detector images spanning
at least a hemisphere of reciprocal space. All data were corrected
for Lorentz polarization effects. Absorption effects were corrected
on the basis of multiple equivalent reflections or by semi-empirical
methods. Structures were solved by direct methods and refined by
full-matrix least-squares against F2 by using the program
SHELXTL.[29,30] Hydrogen atoms were assigned riding isotropic
displacement parameters and constrained to idealized geometries.
N-Phenyl-2-(phenylamino)ethanethioamide (4): Grey solid (0.06 g),
25% yield. IR (KBr, selected data): ν = 1565 (m), 1525 (s), 1452
˜
(m), 1415 (m), 1320 (m), 1268 (m), 1144 (s), 1082 (m), 760 (m), 720
1
(m), 620 (m) cm–1. H NMR (CD2Cl2): δ = 10.32 (s, 1 H, N-H),
7.76–7.19 (m, 10 H, Ar-H), 6.84 [t, J(H,H) = 7.4 Hz, 1 H, N-H],
5.01 [d, J(H,H) = 7.4 Hz, 2 H, CH2] ppm. 13C NMR (CD2Cl2): δ
= 191.5 (C=S), 147.0 (Ar-C), 143.3 (Ar-C), 129.9 (Ar-C), 129.7
(Ar-C), 128.6 (Ar-C), 126.8 (Ar-C), 126.2 (Ar-C), 123.2 (Ar-C),
65.7 (C-N) ppm. Mass spectrum (CI+, m/z), 243 [M + H]+.
C14H14N2S (242.34): calcd. C 69.39, H 5.82, N 11.56; found C
69.70, H 5.66, N 11.47.
2,5-Diphenylpyrazine (5): A suspension of 2-phenylglycine (0.302 g,
2.9 mmol) and Woollins’ reagent (0.54 g, 1.0 mmol) in 20 mL of
toluene was refluxed for 7 h. Upon cooling to room temperature
and removing solvent the residue was purified by silica gel column
(eluented by 1:4 ethyl acetate/dichloromethane) to afford 5. A white
solid (0.073 g) in 31% yield. IR (KBr, selected data): ν = 1565 (m),
˜
1505 (s), 1352 (m), 1319 (s), 1268 (m), 1172 (m), 769 (m), 620 (m)
1
CCDC-782915 (for 1), -782196 (for 2), -78197 (for 3), -78198 (for
4), -78199 (for 5) and -782920 (for 6) contain 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.
cm–1. H NMR (CD2Cl2): δ = 9.10 (s, 2 H, Pyr-H), 8.08–7.14 (m,
10 H, Ar-H) ppm. 13C NMR (CD2Cl2): δ = 150.6 (Pyr-C), 148.3
(Pyr-C), 141.2 (Ar-C), 129.1 (Ar-C), 128.6 (Ar-C), 126.8 (Ar-C)
ppm. Mass spectrum (CI+, m/z), 233 [M + H]+. C16H12N2 (232.28):
calcd. C 82.73, H 5.21, N 12.06; found C 82.09, H 6.16, N 12.07.
Synthesis of Compounds 1 and 2: A toluene solution of N-phenyl-
glycine (0.31 g, 2.0 mmol) and Woollins’ reagent (0.54 g, 1.0 mmol)
was refluxed for 7 h. The red suspension disappeared and pale
brown solution was formed along with small amount of elemental
selenium. Upon cooling to room temperature and removing solvent
the residue was purified by silica gel column (eluented by 1:4 ethyl
acetate/dichloromethane) to give the major product, 1,4-diphenyl-
piperazine-2,5-diselenone (1) and a tiny amount of 1,4-diphenyl-5-
selenoxopiperazin-2-one (2) that was found during crystallization
1,4-Bis(4-chlorophenyl)piperazine-2,5-dione (6): A mixture of 2-
chloro-N-(4-chlorophenyl)acetamide (0.41 g, 2.0 mmol) and so-
dium hydroxide (0.18 g, 4.5 mmol) in 30 mL of dry acetonitrile was
refluxed for 6 h. A white resulting suspension was formed. Upon
cooling to room temperature and removing the solvent the residue
was extracted by the mixture of water/ethyl acetate (30/30 mL). The
organic layer was washed three times with water (30 mLϫ3) and
was dried with MgSO4 overnight. The organic residue was purified
by silica gel column (eluented by dichloromethane) to give 6. A
3072
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3067–3073

Selenation/Thionation of α-Amino Acids
T. A. Perry, D. K. Lahiri, A. Brossi, N. H. Greig, J. Med.
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white solid (0.15 g) in 45% yield. IR (KBr, selected data): ν = 1666
˜
(s), 1488 (s), 1451 (m), 1321 (m), 1260 (m), 1144 (m), 1087 (m), 812
(s), 522 (m), 418 (m) cm–1. 1H NMR ([D6]DMSO): δ = 7.51 [d,
J(H,H) = 8.8 Hz, 4 H, Ar-H], 7.46 [d, J(H,H) = 8.8 Hz, 4 H, Ar-
H], 4.52 (s, 4 H, CH2) ppm. 13C NMR ([D6]DMSO): δ = 164.6
(C=O), 139.4 (Ar-C), 131.4 (Ar-C), 129.4 (Ar-C), 127.5 (Ar-C),
53.0 (CH2) ppm. Mass spectrum (CI+, m/z), 335 [M + H]+, 337 [M
+ H]+. C16H12Cl2N2O2 (335.18): calcd. C 57.33, H 3.61, N 8.36;
found C 57.25, H 3.76, N 8.47.
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Acknowledgments
The authors are grateful to the University of St Andrews and the
Engineering and Physical Science Research Council (EPSRC) for
financial support. Michael Bühl wishes to thank EaStCHEM for
support and for access to the EaStCHEM Research Computing
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Received: February 20, 2011
Published Online: April 14, 2011
Eur. J. Org. Chem. 2011, 3067–3073
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3073