Synthesis and crystal structure of (S)-2-((S)-2-(N-Ts-Amino)-3- methylbutanoyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-1,2,4-triazin-5(2H)-one

Article abstract of DOI:10.1007/s10870-010-9741-7

The diastereoselective synthesis, NMR and X-ray structure of (S)-2-((S)-2-(N-Ts-amino)-3-methylbutanoyl)-3-(1H-indol-3-yl)-6-phenyl-3, 4-dihydro-1,2,4-triazin-5(2H)-one-a potential antivirus agent are reported. The compound crystallizes in the triclinic space group P1 with unit cell parameters: a = 5.9259(6) A, b = 9.6370(12) A, c = 12.9541(9) A, α = 109.210(9)°, β = 90.804(7)°, γ = 105.074(10)° and Z = 1.

Full text of DOI:10.1007/s10870-010-9741-7

J Chem Crystallogr (2010) 40:387–390
DOI 10.1007/s10870-010-9741-7
COMMUNICATION
Synthesis and Crystal Structure of (S)-2-((S)-2-(N-Ts-Amino)-
3
1
-methylbutanoyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-
,2,4-triazin-5(2H)-one
Ilya N. Egorov
Pavel A. Slepukhin
•
Vladimir L. Rusinov
Oleg N. Chupakhin
•
•
Received: 2 April 2009 / Accepted: 12 February 2010 / Published online: 24 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The diastereoselective synthesis, NMR and X-ray
structure of (S)-2-((S)-2-(N-Ts-amino)-3-methylbutanoyl)-3-
shown fluoroanhydrides of amino acids [8], free amino
acids activated by DCC [9], by ethylchloroformate [10] can
be used as chiral auxiliaries in the reactions of this type.
We report here the crystal structure of a new amino acid
derivative of 1,2,4-triazin-5(4H)-one formed with use of
N-Ts-L-valine chloroanhydride.
(
1H-indol-3-yl)-6-phenyl-3,4-dihydro-1,2,4-triazin-5(2H)-
one—a potential antivirus agent are reported. The
compound crystallizes in the triclinic space group P1 with
˚
unit cell parameters: a = 5.9259(6) A, b = 9.6370(12) A,
˚
˚
c =12.9541(9) A, a = 109.210(9)°, b = 90.804(7)°, c =
1
05.074(10)° and Z = 1.
Experimental
Keywords Antivirus agent Á Crystal structure Á
,2,4-Triazinone Á Asymmetric synthesis Á Amino acid
1
Preparation of (S)-2-((S)-2-(N-Ts-Amino)-3-methylbuta-
noyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-1,2,4-triazin-5
(2H)-one (4).
Triazinone 1 (1.2 mmol) was added to a magnetically
Introduction
,2,4-Triazine nuclei is associated with a high biological
stirred solution of (S)-N-Ts-valine chloride (3) (1.2 mmol) in
3 ml of THF at the temperature -15 °C, after 5 min indole
(2) (1.2 mmol) was added. The mixture was stirred at
-15 °C for a 1 h. Then temperature was allowed to reach
20 °C during 2 h. Then unreacted residue of the triazinone
1 was filtered from the mixture, the filtrate was poured in the
cooled water (15 mL) and was extracted by ethylacetate
(2*20 mL). The organic layer was washed out by water,
brine and was dried over Na SO . The solution was evapo-
1
activity, particularly antiviral activity, [1–5] therefore
synthesis of its derivatives especially of amino acid
derivatives represents a notable interest in the pharmaco-
logical field. It is known, the addition of C-nucleophiles to
a prochiral C=N double bond in azines in the presence of
optically active acylation reagents results in formation of
the addition products with a high diastereoselectivity [6, 7]
Use of amino acids in the capacity of chiral auxiliarities
can also leads to the high diastereoselectivity. Earlier it was
2
4
rated; the gummy residue was dissolved in ethylacetate and
purified on silicagel column with ethylacetate as an eluent
(R = 0.7). The product was dissolved in ethanol. An
f
evaporation of the solution in open flask at the room tem-
I. N. Egorov (&) Á V. L. Rusinov Á O. N. Chupakhin
Department of Organic Chemistry, Urals State Technical
University, 19, Ul. Mira, Ekaterinburg 620002,
Russian Federation
perature results in formation of the colorless crystals of 4.
Yield 23%, mp = 221–222 °C, [a] = ? 570.8 (c = 1.0,
DMF). H NMR (400 MHz, DMSO-d6) d: 11.03 (d,
J = 2.1 Hz, 1H, NH), 9.70 (d, J = 5.3 Hz, 1H, NH), 7.97
D
1
e-mail: i.n.egorov@gmail.com
(
d, J = 9.1 Hz, 1H, NH), 7.89–7.81 (m, 2H, Ph), 7.75 (d,
J = 8.0 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H, Ts), 7.46–7.38
m, 3H, Ph), 7.36 (d, J = 8.1 Hz, 1H), 7.07–7.12 (m, 2H),
6.97–7.00 (m, 2H), 6.87 (d, J = 8.1 Hz, 2H, Ts), 4.80 (dd,
P. A. Slepukhin Á O. N. Chupakhin
Institute of Organic Synthesis, Ural Branch of the Russian
Academy of Sciences, 20, Ul. S. Kovalevskaya,
Ekaterinburg 620219, Russian Federation
(
123

3
88
J Chem Crystallogr (2010) 40:387–390
J = 8.9, 6.2 Hz, 1H, CH), 2.21 (s, 3H, CH ), 1.99–2.08
3
then refined independently. The restraints were generated
automatically.
(
m, 1H, CH), 0.88 (d, J = 6.7 Hz, 3H, CH ), 0.84 (d, J =
3
6
.7 Hz, 3H, CH3).
Results and Discussion
Structure Determination and Refinement
Crystal Structure of (S)-2-((S)-2-(N-Ts-Amino)-3-meth-
ylbutanoyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-1,2,4-
triazin-5(2H)-one (4).
X-Ray analysis including data collection, cell refinement
and data reduction was carried out with an Oxford Dif-
fraction Xcalibur S CCD diffractometer using CrysAlisPro
software package [11]. The X-ray data collection was
carried out at 295(2) K with graphite monochromatized
The chemical diagram of the title compound, 4, is
illustrated in Scheme 1 and experimental conditions are
summarized in Table 1. Selected bond distances and bond
angles are listed in Table 2. Weak interactions geometry is
presented in Table 3. The data for publication were pre-
pared with WinGX [13], ORTEP [14], and Mercury [15]
program packages.
˚
Mo–Ka radiation (a = 0.71073 A). The structure was
solved by direct methods using SHELXS-97 [12] and
2
refined by full-marix least-squares procedure on F with
SHELXL-97 [12]. Non-H atoms were refined anisotropi-
cally, hydrogen atoms were placed in idealized positions
and were constrained to ride on their parent atoms with
U (H) = 1.5 Ueq(C) for CH groups and U (H) = 1.2
1
X-ray and NMR H data shows the reaction results in
formation of the diastereomerically pure compound (S)-2-
((S)-2-(N-Ts-Amino)-3-methylbutanoyl)-3-(1H-indol-3-yl)-
6-phenyl-3,4-dihydro-1,2,4-triazin-5(2H)-one (4) (Fig. 1).
The absolute stereochemistry of the synthesized compound is
iso
3
iso
Ueq(C) for all other C–H (Table 1). H-atoms of N–H
groups (H3, H4, H5) were located in a difference map and
Table 1 Crystal data and
Empirical formula
29 29 5 4
C H N O S
structure solution methods and
refinement results for 4
Formula weight
543.63
Crystal system
Space group
Triclinic
P1
˚
a(A)
5.9259(6)
˚
b(A)
9.6370(12)
12.9541(9)
109.210(9)
90.804(7)
˚
c(A)
a(°)
b(°)
c(°)
105.074(10)
670.51(12)
1
3
˚
Volume (A )
Z
3
Calculated density (g/cm )
1.346
-
1
)
Absorption coefficient (mm
F (000)
0.166
286
Crystal size (mm)
Crystal color/shape
0.45 9 0.41 9 0.34
Colorless/prismatic
3.35–28.28
h Range for data collection (°)
Reflections collected/independent (Rint
Observed reflections [I [ 2r(I)]
Completeness (%)
)
7142/3703 (0.0241)
2571
97.1 (to h = 28.28°)
Full matrix least-squares procedure on F
2
Refinement method
2
2
2
2
2
Weight, w
o o c
1/[r (F )] ? (0.0262P) ? 0.00P] where P = (F ? 2F )/3
Data/restraints/parameters
2
Goodness of fit on F
3703/3/364
1.000
Final R indices [I [ [2r(I)]
Absolute structure parameter
R
1
= 0.0325, wR
-0.02(5)
0.159 and -0.190
2
= 0.0573
-
3
˚
Largest peak and hole (eA
)
1
23

J Chem Crystallogr (2010) 40:387–390
389
O
˚
Table 3 Hydrogen bonds and weak interactions for 4 (A and °)
Ph
O
N
NHTs
N
THF
Cl
D–HÁÁÁA
d(D–H)
d(HÁÁÁA) d(DÁÁÁA) \(DHA) Symmetry
+
+
t = -15 o
operation
C
N
N
H
H
H C
CH3
3
1
2
3
N3–H3ÁÁÁO2
N3–H3ÁÁÁO1
N3–H3ÁÁÁS1
N4–H4ÁÁÁO3
C22–H22ÁÁÁO3 0.960
C21–H21ÁÁÁO3 0.961
C10–H10ÁÁÁO4 0.930
0.86(3)
0.86(3)
0.86(3)
0.85(3)
2.30(3)
2.60(3)
2.84(3)
2.33(3)
3.148(4) 170.0(17) x, -1 ? y, z
CH3
CH3
3.213(4) 129.4(17) x, -1 ? y, z
3.651(4) 159.6(17) x, -1 ? y, z
3.032(4) 140.4(18) 1 ? x, 1 ? y, z
TsNH
Ph
N
N
O
2.480(4) 3.356(4) 7.7(2)
2.651(4) 3.458(4) 142.0(2)
2.425(4) 3.069(4) 126.4(2)
1 ? x, 1 ? y, z
1 ? x, 1 ? y, z
-1 ? x, y, z
O
N
H
SS
N
4
H
Scheme 1 Synthesis of (S)-2-((S)-2-(N-Ts-amino)-3-methylbutanoyl)-
3
-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-1,2,4-triazin-5(2H)-one (4)
˚
Table 2 Selected geometrical parameters for 4 (A and °)
N1–N2
1.372(3)
1.463(4)
1.439(3)
1.332(3)
1.489(4)
1.294(3)
117.8(2)
110.7(2)
117.6(2)
110.9(2)
N1–N2–C1
120.7(2)
107.4(2)
122.8(2)
114.4(2)
122.8(2)
80.3(2)
N2–C1
N3–C1–N2
C1–N3
C1–N3–C2
N3–C2
N3–C2–C3
C2–C3
N1–C3–C2
C3–N1
C18–N2–C1–C11
N1–N2–C18–O4
O4–C18–C19–C20
O4–C18–C19–N4
N1–C3–C4–C9
N1–N2–C18
N2–C1–C11
N2–C18–C19
C18–C19–N4
176.2(2)
105.6(3)
-17.4(3)
37.6(3)
assigned on the base of known stereochemistry of starting
material (S)-N-Ts-valine chloride (3). In CCDC [16] the
structures of hundreds compounds with C–SO –N-group are
Fig. 1 View of the structure of 4, drawn with 50% probability
displacement ellipsoids and showing the atom labeling scheme.
H-atoms are shown as small spheres of arbitrary radii
2
presented and only six of them have C–SO –NH–CH(i-Pr)–
2
˚
1.428(2) A) and S–N bond lengths (1.597(2)) are near to the
CO-fragment (as in the structure 4). The measured bond
lengthsandanglesare typicalforthisclassof compounds. For
example, the measured S–O bond lengths (1.439(2) and
medium bond lengths for C–SO N-group from CCDC [16].
2
The measured torsion angles S1N4C19C20 156.2(3)° and
Fig. 2 Packing diagram with
H-bonds of 4. Dotted lines
indicate intermolecular
hydrogen-bonding interactions
123

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J Chem Crystallogr (2010) 40:387–390
N4C18C18O4-17.2(3)° also are typical for Ts-amines
with polar substituents [16]. The triazine ring has a
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Acknowledgments This work was supported by the program of the
Russian Federation President for government support of young
scientists, MK-1157.2009.3.
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