Diastereoselective synthesis of 3-substituted acylamino-3,4-dihydro-1,2,4-triazinones

Article abstract of DOI:10.1016/j.mencom.2008.03.017

6-Phenyl-1,2,4-triazin-5(4H)-one 1 reacts with C-nucleophiles, such as indole, in the presence of N-acetylamino acids, to yield 2-acyl-3-indolyl-6-phenyl-3,4-dihydro-1,2,4-triazin-5(4H)-ones 2-6 with high diastereoselectivity.

Full text of DOI:10.1016/j.mencom.2008.03.017

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 99–101
Diastereoselective synthesis of 3-substituted
acylamino-3,4-dihydro-1,2,4-triazinones
Ilya N. Egorov,*a Burkhard König,b Vladimir L. Rusinova and Oleg N. Chupakhina,c
a Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian
Federation. Fax: +7 343 374 0458; e-mail: i.n.egorov@googlemail.com
b Institüt für Organische Chemie, Universität Regensburg, 93040 Regensburg, Germany
c I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620219
Ekaterinburg, Russian Federation
DOI: 10.1016/j.mencom.2008.03.017
6-Phenyl-1,2,4-triazin-5(4H)-one 1 reacts with C-nucleophiles, such as indole, in the presence of N-acetylamino acids, to yield
2-acyl-3-indolyl-6-phenyl-3,4-dihydro-1,2,4-triazin-5(4H)-ones 2–6 with high diastereoselectivity.
In the presence of optically active acylation reagents, the
N-acetyl-
-amino acid
Ph
O
N
addition of C-nucleophiles to a prochiral C=N double bond in
azines results in the formation of addition products with high
diastereoselectivity.1,2 Comins2 found the asymmetric induction
in the reactions of nucleophiles to 4-methoxypyridines, which
are acylated by chiral chloroformates. Such reactions are useful
in the synthesis of alkaloid structures.1,2 Amino acid fluorides
can also be used as chiral auxiliaries in reactions of this type.3–5
We reported previously that 3-aryl-1,2,4-triazin-5(4H)-ones can
give asymmetric products with high diastereoselectivity in
reactions with C-nucleophiles in the presence of DCC-activated
amino acids.6
NH
NuH, ClCO2Et,
NEt3, THF, 0 °C
N
1
O
O
H
N
H
Ph
O
N
Ph
O
N
N
N
N
R'
R'
+
R
R
H
H
N
H
N
H
Nu
Nu
(SS), (RR)
major
2–6
(RS), (SR)
minor
6-Phenyl-1,2,4-triazin-5(4H)-one 1 was acylated by N-sub-
stituted L-amino acids in the presence of ethyl chloroformate and
reacted with C-nucleophiles yielding 3-substituted 2-(2-acyl-
amino)acyl-6-aryl-3,4-dihydro-1,2,4-triazin-5(4H)-ones 2–6 in
moderate yields but with high diastereoselectivity (Scheme 1,
Table 1).†,‡
diastereomer
diastereomer
Scheme 1
Table 1 Reactions of triazinone 1 with amino acids.
Nucleophile NuH
N-acetyl- -amino acid
Producta Yield (%)
Indole
Indole
N-Acetyl-L-leucine
N-Acetyl-L-valine
N-Acetyl-L-valine
N-Acetyl-L-tryptophane
N-Acetyl-L-valine
2
3
4
5
6
49
76
40
32
30
In attempts to optimise the synthesis of compounds 2–6,
reaction conditions were varied for valine-derived product 3.
We observed that the replacement of a THF solvent by acetonitrile
or dichloromethane and the use of a higher dilution decreased
the yield. Changing the ratio of reactants and the reaction
temperature did not increase the yield.
1-Methylindole
Indole
Pyrrole
aDiastereomeric ratio > 95:5 for products 2–6 (from 1H NMR).
determine the relative stereochemistry, the X-ray analysis of
compounds 3 and 6 was performed (Figures 1 and 2).§ The
analysis established that the compounds represent a pair of
SS- and RR-enantiomers.
The initial stereoinformation of the natural amino acids used
as starting materials in the synthesis of 2–6 is lost most likely
during activation by ethyl chloroformate. Racemization via the
well-known azlacton mechanism and reaction with 1 lead to
The 1H NMR analysis of compounds 2–6 indicates the forma-
tion of only one pair of diastereomers in each case. In order to
†
Acetylamino acids and starting triazinone 1 were synthesised by known
procedures. TLC analysis was performed on Merck silica gel 60F254
plates and visualised by exposure to UV light. Column chromatography
was conducted with Merck silica gel 60. 1H and 13C NMR spectra were
recorded with Bruker WH-250, AC-300 and AC-600 instruments. Melting
points were measured on a Boetius apparatus and are uncorrected. Optical
rotations were measured on a Perkin Elmer model 341 polarimeter.
General procedure for the synthesis of 2–6: to a magnetically stirred
suspension of the N-acetylamino acid (1 mmol) in 3 ml of THF at room
temperature NEt3 (1.2 mmol) was added. The solution was cooled to
0 °C in an ice bath and ClCO2Et (1.1 mmol) was added. After 5 min,
triazinone 1 (1 mmol) and indole (1.1 mmol) were added. After 30 min,
the ice bath was removed and the reaction mixture was stirred for 12–18 h
at room temperature (control by TLC). The precipitate formed was filtered
off anf then, in case of 2–4, washed with THF and water, recrystallised
from DMF and dried. In case of 5 and 6, the mother liquid was evaporated
and the residue oil purified by column chromatography on silica gel with
ethyl acetate as a solvent. Then the solution was evaporated, the residue
oil crystallised from diethyl ether and the resulting solid was dried.
H(11)
C(17)
C(18)
N(2)
N(3)
C(3)
C(1)
N(1)
C(2)
H(8)
Figure 1 ORTEP diagram of the X-ray crystal structure of product 3.§
– 99 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 99–101
racemic acyltriazinones as reaction intermediates. The reaction
proceeds equally in the absence of amino acids as acylation
reagents; ethyl chloroformate and 1 yield an intermediate ethyl
carbamate, which subsequently reacts with the nucleophile
leading to 7 (Scheme 2).¶
We supposed the use of naproxen 8 as an acylation agent
would allow to avoid racemization of the stereo centre in the
starting material in the course of the reaction. The observed
optical rotation ([a]D20 –590, c 0.7) of reaction product 9
indicated that this assumption was valid (Scheme 3). The HPLC
analysis of 9 showed a 98:2 ratio between SS and SR.††
H(15)
C(15)
N(3)
N(4)
C(7)
C(14)
C(6)
N(2)
C(5)
H(5)
Figure 2 ORTEP diagram of the X-ray crystal structure of product 6.§
X-ray diffraction data for 3. C24H24N5O3, M = 430.48, triclinic, space
‡
2-(2-Acetamido-4-methylpentanoyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-
dihydro-2H-[1,2,4]triazin-5-one 2: yield, 49%; white solid; mp 256–257 °C;
Rf 0.6 (ethyl acetate). 1H NMR (600 MHz, [2H6]DMSO) d: 0.89 (d, 3H,
Me, J 6.6 Hz), 0.92 (d, 3H, Me, J 6.6 Hz), 1.47–1.52 (m, 1H, CH2),
1.61–1.66 (m, 1H, CH2), 1.72–1.79 (m, 1H, CH), 1.88 (s, 3H, COMe),
5.52–5.62 (m, 1H, CH), 6.96 (t, 1H, indole, J 7.3 Hz), 7.04 (t, 1H,
indole, J 7.3 Hz), 7.13 (d, 1H, indole, J 2.1 Hz), 7.17 [d, 1H, C(3)H,
J 5.4 Hz], 7.28 (d, 1H, indole, J 8.1 Hz), 7.29–7.36 (m, 3H, Ph), 7.72 (d,
1H, indole, J 8.1 Hz), 7.89–7.90 (m, 2H, Ph), 8.03 (d, 1H, NH, J 8.1 Hz),
9.74 [d, 1H, N(4)H, J 5.4 Hz], 10.87 (d, 1H, NH, indole, J 1.6 Hz).
13C NMR (150 MHz, [2H6]DMSO) d: 21.01, 22.22, 23.05, 24.44, 48.01,
59.01, 111.47, 111.70, 119.02, 119.05, 121.52, 124.00, 124.46, 127.64,
127.99, 129.36, 132.25, 136.66, 144.01, 155.41, 169.48, 172.46. Found
(%): C, 67.14; H, 5.90; N, 15.87. Calc. for C25H27N5O3 (%): C, 67.40;
H, 6.11; N, 15.72.
§
group P1, a = 8.881(2), b = 11.0359(18) and c = 11.5092(16) Å, V =
= 1080.2(4) Å3, Z = 2, dcalc = 1.324 g cm–3, m = 0.832 mm–1, F(000) = 454.
Data collection was performed at 295 K within the q range from 2.62 to
31.77°; a total of 14931 reflections (of which 2063 were unique) were
collected [R(int) = 0.0547] and used to refine 337 parameters. The structure
was solved with the SHELXS-97 program and refined using SHELXL-97.
X-ray diffraction data for 6. C20H22N5O3, M = 380.43, monoclinic, space
group P21/a, a = 9.62160(10), b = 19.08220(10) and c = 10.78380(10) Å,
V
= 1974.54(3) Å3, = 4, dcalc = 1.280 g cm–3, = 0.727 mm–1,
Z m F(000) = 804.
Data collection was performed at 123 K within the q range from 2.3119 to
62.1351°; a total of 28335 reflections (of which 3103 were unique) were
collected [R(int) = 0.0253] and used to refine 256 parameters. The structure
was solved with the SIR-97 program and refined using SHELXL-97.
CCDC 672106 and 649200 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. For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2008.
2-(2-Acetamido-3-methylbutanoyl)-3-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-
2H-[1,2,4]triazin-5-one 3: yield, 76%; yellow solid; mp 276 °C; Rf 0.6
1
(ethyl acetate). H NMR (300 MHz, [2H6]DMSO) d: 0.97 (t, 6H, 2Me,
J 6.4 Hz), 1.89 (s, 3H, COMe), 2.07–2.18 (m, 1H, CH), 5.41 (dd, 1H,
CH, J 8.4 and 6.4 Hz), 6.95–7.05 (m, 1H, indole), 7.06–7.16 (m, 1H,
indole), 7.22 [d, 1H, C(3)H, J 5.5 Hz], 7.24 (d, 1H, indole, J 2.6 Hz),
7.35 (d, 1H, indole, J 8.0 Hz), 7.41–7.53 (m, 3H, Ph), 7.71 (d, 1H,
indole, J 8.0 Hz), 7.94–7.80 (m, 2H, Ph), 8.23 (d, 1H, NH, J 8.4 Hz),
9.86 [d, 1H, N(4)H, J 5.5 Hz], 11.19 (d, 1H, NH, indole, J 2.2 Hz).
13C NMR (150 MHz, [2H6]DMSO) d: 17.79, 19.27, 22.14, 30.44, 45.59,
53.87, 58.69, 111.54, 111.72, 118.97, 121.53, 124.22, 124.33, 127.80,
128.01, 129.44, 132.20, 136.60, 144.05, 155.21, 169.51, 171.31. Found
(%): C, 66.99; H, 5.88; N, 16.13. Calc. for C24H25N5O3 (%): C, 66.81;
H, 5.84; N, 16.23.
¶
Procedure for the synthesis of ethyl 3-(1H-indol-3-yl)-5-oxo-6-phenyl-
4,5-dihydro-3H-[1,2,4]triazine-2-carboxylate 7. To a magnetically stirred
suspension of triazinone 1 (1 mmol) in 3 ml THF cooled to 0 °C,
ClCO2Et (1.1 mmol) and NEt3 (1.2 mmol) were added. Then indole
(1.1 mmol) was added. After 30 min the ice bath was removed and the
reaction mixture was stirred at room temperature for 12–18 h (monitoring
by TLC). The formed precipitate was filtered off, washed with THF. The
resulting solution was evaporated, the residue oil purified by column
chromatography on silica gel with CHCl3 (Rf 0.1) and ethyl acetate
(Rf 0.7) as eluents and recrystallised from diethyl ether. Yield, 41%;
white solid; mp 168–169 °C. 1H NMR (300 MHz, CDCl3) d: 1.05 (t, 3H,
Me, J 7.1 Hz), 4.05 (dq, 2H, CH2, J 7.1 and 1.0 Hz), 6.68–6.84 (m, 4H),
6.98–7.04 (m, 4H), 7.47 (d, 1H, J 7.9 Hz), 7.53–7.69 (m, 2H, Ph), 9.07
[d, 1H, N(4)H, J 5.4 Hz], 10.25 (s, 1H, NH, indole). Found (%): C,
66.31; H, 4.98; N, 15.55. Calc. for C20H18N4O3 (%): C, 66.29; H, 5.01;
N, 15.46.
†† Procedure for the synthesis of 3-(1H-indol-3-yl)-2-[2-(6-methoxy-
naphthalen-2-yl)propionyl]-6-phenyl-3,4-dihydro-2H-[1,2,4]triazin-5-one
9. To a magnetically stirred solution of naproxen (1 mmol) in 3 ml THF
at room temperature NEt3 (1.2 mmol) was added. The solution was cooled
to 0 °C and ClCO2Et (1.1 mmol) was added. After 5 min, triazinone 1
(1 mmol) and indole (1.1 mmol) were added. After 30 min, the ice bath
was removed and the reaction mixture was stirred for 12–18 h at room
temperature (monitoring by TLC). The precipitate formed was filtered
off, washed with THF. The mother liquid was evaporated, dissolved in
CHCl3 and purified using a silica gel column with CHCl3 (Rf 0.1) and
ethyl acetate (Rf 0.8) as eluents. Yield, 33%; white solid; mp 235–236 °C;
[a]D20 –590 (c 0.7, MeCN); diastereomeric ratio of 98:2 (HPLC:
Lichrosorb S, hexane/isopropil alcohol, 16:1, 1.0 cm3 min–1, l = 254 nm).
1H NMR (300 MHz, CDCl3) d: 1.55 (d, 3H, CMe, J 7.0 Hz), 3.82 (s,
3H, OMe), 4.82 (q, 1H, CH, J 6.9 Hz), 6.73–6.74 (m, 1H), 6.87–7.06
(m, 4H), 7.22–7.34 (m, 7H), 7.44 (s, 1H), 7.51–7.54 (m, 1H), 7.67–7.70
(m, 1H), 7.80–7.84 (m, 2H, Ph), 9.52 (d, 1H, NH, J 5.2 Hz), 10.81 (s,
1H, NH). 13C NMR (150 MHz, CDCl3) d: 18.92, 41.31, 54.68, 58.09,
104.88, 111.20, 112.37, 118.13, 118.93, 119.24, 121.59, 123.68, 124.03,
125.23, 126.24, 126.39, 127.48, 128.03, 128.09, 128.45, 129.11, 132.37,
132.66, 135.66, 136.35, 143.37, 155.41, 156.80, 172.65. Found (%):
C, 74.15; H, 5.16; N, 11.33. Calc. for C31H26N4O3 (%): C, 74.09; H, 5.21;
N, 11.15.
2-(2-Acetamido-3-methylbutanoyl)-3-(1-methylindol-3-yl)-6-phenyl-3,4-di-
hydro-2H-[1,2,4]triazin-5-one 4: yield, 40%; yellow solid; mp 246–247 °C;
1
Rf = 0.6 (ethyl acetate). H NMR (300 MHz, [2H6]DMSO) d: 1.00 (d,
6H, 2Me, J 6.8 Hz), 1.90 (s, 3H, COMe), 2.09–2.23 (m, 1H, CH), 3.72
(s, 3H, NMe), 5.41 (dd, 1H, CH, J 8.4 and 6.2 Hz), 6.99–7.04 (m, 1H),
7.10–7.17 (m, 3H), 7.27–7.30 (m, 1H), 7.37–7.39 (m, 3H, Ph), 7.75
(m, 1H), 7.92–7.99 (m, 3H), 9.69 (d, 1H, NH, J 5.6 Hz). Found (%):
C, 67.61; H, 6.04; N, 15.88. Calc. for C25H27N5O3 (%): C, 67.40;
H, 6.11; N, 15.72.
2-[2-Acetamido-3-(1H-indol-3-yl)propanoyl]-3-(1H-indol-3-yl)-6-phenyl-
3,4-dihydro-2H-[1,2,4]triazin-5-one 5: yield, 32%; white solid; mp 173–
174 °C; Rf 0.4 (ethyl acetate). 1H NMR (250 MHz, [2H6]DMSO) d: 1.87
(s, 3H, MeCO), 3.10–3.29 (m, 2H, CH2), 5.71–5.80 (m, 1H, CH),
6.74–6.79 (m, 1H), 6.96–7.11 (m, 3H), 7.15–7.18 (m, 3H), 7.25–7.46
(m, 6H), 7.76–7.81 (m, 3H), 8.18 (d, 1H, NH, J 5.6 Hz), 9.62 (d, 1H,
NH, J 5.3 Hz), 10.63 (br. s, 1H, NH), 10.98 (br. s, 1H, NH). Found (%):
C, 69.55; H, 5.07; N, 16.33. Calc. for C30H26N6O3 (%): C, 69.48; H, 5.05;
N, 16.21.
2-(2-Amino-3-methylbutanoyl)-6-phenyl-3-(1H-pyrrol-2-yl)-3,4-dihydro-
2H-[1,2,4]triazin-5-one 6: yield, 30%; white solid; mp 224–225 °C; Rf 0.6
(ethyl acetate). 1H NMR (600 MHz, CD3OD) d: 1.05 (d, 3H, Me, J 6.88 Hz),
1.06 (d, 3H, Me, J 6.88 Hz), 2.06 (s, 3H, COMe), 2.26 (dqq, 1H, CH,
J 5.67, 6.87 and 6.86 Hz), 5.45 (d, 1H, CH, J 5.69 Hz), 6.02 [dd, 1H,
C(4')H, pyrrole, J 3.51 and 2.73 Hz], 6.15 [ddd, 1H, C(3')H, pyrrole,
J 3.51, 1.58 and 0.94 Hz], 6.75 [ddd, 1H, C(5')H, pyrrole, J 2.73, 1.58
and 0.48 Hz], 7.08 [dd, 1H, C(3)H, J 0.94 and 0.48 Hz], 7.39–7.45 (m,
3H, Ph), 7.88–7.90 (m, 2H, Ph). 13C NMR (150 MHz, CD3OD) d: 18.16,
19.84, 22.29, 32.07, 56.82, 60.54, 108.72, 109.79, 120.82, 128.67, 129.17,
129.66, 131.09, 133.69, 146.06, 157.92, 173.69, 173.90. Found (%):
C, 62.73; H, 6.06; N, 18.43. Calc. for C20H23N5O3 (%): C, 62.98; H, 6.08;
N, 18.36.
– 100 –

Mendeleev Commun., 2008, 18, 99–101
OMe
O
O
HO
Ph
O
N
Ph
O
N
Ph
N
ClCO2Et, NEt3
NuH, THF, 0 °C
NH
N
O
NH
8
N
N
H
Nu
NuH, ClCO2Et, NEt3, THF, 0 °C
O
N
1
7
(41%)
1
ClCO2Et,
NEt3
OMe
NuH
O
Ph
O
N
O
N
Ph
N
N
N
O
N
H
Nu
9
(SS) (33%)
NuH = indole
O
Scheme 3
Scheme 2
References
In summary, we have extended the use of triazinones as
starting materials in heterocylic synthesis. Activation of the
triazinone by natural amino acids or naproxen and subsequent
addition of a nucleophile lead to 2-acyl-3-indolyl-6-phenyl-
3,4-dihydro-1,2,4-triazin-5(4H)-ones in diastereomerically pure
form. The relative stereochemistry was determined by an X-ray
analysis.
1 I. N. Egorov, G. V. Zyryanov, V. L. Rusinov and O. N. Chupakhin, Usp.
Khim., 2005, 74, 1176 (Russ. Chem. Rev., 2005, 74, 1073).
2 D. L. Comins, J. Heterocycl. Chem., 1999, 36, 1491.
3 O. Surigina, M. Ehwald and J. Liebscher, Tetrahedron Lett., 2000, 41,
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4 O. Sieck, S. Schaller, S. Grimme and J. Liebscher, Synlett, 2003, 3, 337.
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6 I. N. Egorov, G. V. Zyryanov, E. N. Ulomsky, V. L. Rusinov and O. N.
Chupakhin, Tetrahedron Lett., 2006, 47, 7485.
This work was supported by the German Academic Exchange
Service (DAAD).
Received: 20th September 2007; Com. 07/3017
– 101 –