Asymmetric induction in the reactions of azinones with C-nucleophiles

Article abstract of DOI:10.1007/s11172-010-0195-z

Effect of acylating agents on the course of addition of C-nucleophiles to 1,2,4- and 1,3,5-triazinones, as well as to quinoxalin-2(1H)-one, was studied. A series of new azinone derivatives was obtained. A method for the preparation of diastereomerically pure addition products of indoles to 1,2,4-triazinones and quinoxalin-2(1H)-one in the presence of N-Ts-L-amino acid acyl chlorides was suggested.

Full text of DOI:10.1007/s11172-010-0195-z

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 991—1001, May, 2010
991
Asymmetric induction in the reactions of azinones with Cꢀnucleophiles
O. N. Chupakhin,a,b I. N. Egorov,b V. L. Rusinov,b and P. A. Slepukhina
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Tel: +7 (343) 374 1189. Eꢀmail: chupakhin@ios.uran.ru
bB. N. Eltsyn Ural State Technical University — UPI,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Tel: +7 (343) 375 4501. Eꢀmail: i.n.egorov@gmail.com
Effect of acylating agents on the course of addition of Cꢀnucleophiles to 1,2,4ꢀ and
1,3,5ꢀtriazinones, as well as to quinoxalinꢀ2(1H)ꢀone, was studied. A series of new azinone
derivatives was obtained. A method for the preparation of diastereomerically pure addition
products of indoles to 1,2,4ꢀtriazinones and quinoxalinꢀ2(1H)ꢀone in the presence of
NꢀTsꢀLꢀamino acid acyl chlorides was suggested.
Key words: triazinones, 1,2,4ꢀtriazinꢀ5(4H)ꢀone, 1,2,4ꢀtriazinꢀ3(2H)ꢀone, 1,3,5ꢀtriazinꢀ
2,4(1H,3H)ꢀone, quinoxalinꢀ2(1H)ꢀone, diastereoselective synthesis, aromatic nucleophilic
addition, Cꢀnucleophiles, amino acid acyl chlorides, indoles.
H
Nucleophilic substitution reactions of hydrogen (SN
)
example, by in situ acylation), should determine stereꢀ
in the series of πꢀdeficient (hetero)aromatic compounds
are common for a wide class of twoꢀstep processes1
(Scheme 1), which are characterized by formation in the
first step of nucleophilic addition products, σHꢀadducts A
and В, due to the direct attack by nucleophiles on the
unsubstituted carbon atom of the azine ring.
ochemistry of the addition product formed, i.e., induce
stereoselective formation of new asymmetric center upon
attack by an achiral nucleophile. In the ideal case, an
individual stereoisomer can be the addition product. For
instance, known addition of the Grignard reagents and
allylsilanes to homochiral pyridinꢀ4ꢀone Nꢀacylium salts,
obtained in situ upon the action of optically active
chloroformates, allows one to reach a high degree of asymꢀ
metric induction (de = 88—98) and leads to substituted
pyridones in high yields.2,5 Stereoselective addition of
nucleophiles to quinolines or isoquinolines occurs when
amino acid acyl fluorides are used as auxilliary chiral
agents in the presence of Lewis acids.6 We have briefly
described a stereoselective reaction of indole with 3ꢀpheꢀ
nylꢀ1,2,4ꢀtriazinꢀ5ꢀone in the presence of amino acids
activated with DCC7 and with 6ꢀphenylꢀ1,2,4ꢀtriazinꢀ5ꢀ
one in the presence of mixed amino acid anhydrides.9
In the present work, we in details consider how the
nature of acylating agents and structure of the substrate
affect stereochemistry of the addition products of Cꢀnuꢀ
cleophiles to 1,2,4ꢀ and 1,3,5ꢀtriazinones 1—4, as well as
to quinoxalinꢀ2(1H)ꢀone 5.
Scheme 1
Initially, we studied nucleophilic addition reaction to
the azine ring in the presence of acetic anhydride. The
whole series of azinones 1—5 studied react with Cꢀnuꢀ
cleophiles under these conditions. Earlier, for 3ꢀphenylꢀ
1,2,4ꢀtriazinꢀ5ꢀone 1 we have already described addition
reactions of indoles and pyrroles in acetic anhydride with
the formation of the corresponding 6ꢀindolylꢀ or 3ꢀpheꢀ
Appearance of stereoisomers during formation of σHꢀ
adducts in the reactions of this type can be due to the
introduction of chiral catalysts into the reaction2—4 or
the use of an enantiomerically pure substrate2,5—7 and/or
nucleophile.2,8 An asymmetric carbon atom, directly
or indirectly incorporated into the substrate molecule (for
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 970—979, May, 2010.
1066ꢀ5285/10/5905ꢀ0991 © 2010 Springer Science+Business Media, Inc.

992
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Chupakhin et al.
Scheme 3
nylꢀ6ꢀpyrrolylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀones.10
In the present work, it was found that reflux of 6ꢀphenylꢀ
1,2,4ꢀtriazinꢀ5(2H)ꢀone (2) with indoles in acetic anhyꢀ
dride smoothly leads to 2,4ꢀdiacetylꢀ3ꢀindolylꢀ6ꢀphenylꢀ
1,2,4ꢀtriazinꢀ5(2H)ꢀones 6—8 (Scheme 2, Table 1). It is
noticeable that both nitrogen atoms placed in αꢀpositions
to the reaction center undergo acylation.
Scheme 2
Nu is the 3ꢀindole
–15÷–10 °C. Compounds 12 and 16 contain no tosyl
fragment, though the presence of tosyl chloride is necesꢀ
sary for the process to be successful, since no reaction
takes place if it is absent (see Scheme 4, Table 2).
6ꢀPhenylꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀone (2) and 6ꢀphenylꢀ
Table 1. Synthesis of compounds 6—8
Scheme 4
NuH
Product
Yield (%)
Indole
1ꢀМеꢀIndole
2ꢀМеꢀIndole
6
7
8
79
62
43
6ꢀPhenylꢀ1,2,4ꢀtriazinꢀ3(2H)ꢀone (3) behaves simiꢀ
larly in this reaction, which leads to 2,4ꢀdiacetylꢀ
5ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ2Hꢀ1,2,4ꢀtriazinꢀ
3ꢀone (9). The reaction of 1,3,5ꢀtriazineꢀ2,4(1H,3H)ꢀ
dione (4) with indole in acetic anhydride affords 1ꢀacetylꢀ
6ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ1,3,5ꢀtriazinaneꢀ2,4ꢀdione (10), whereas
4ꢀacetylꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀ
one (11) was obtained from quinoxalinꢀ2(1H)ꢀone 5
(Scheme 3).
Study of the possibility to carry out this reaction in the
presence of pꢀtoluenesulfonyl chloride as a compound
close in structure to amino acid acyl chlorides, which
were further used as the chiral acylating agents, showed
that in the case of 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (1)
and 1,3,5ꢀtriazineꢀ2,4(1H,3H)ꢀdione (4) formation of
the nucleophilic addition products of indoles, 12 and 16,
respectively, takes place in the temperature interval

Synthesis of asymmetric azinones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
993
Table 2. Synthesis of compounds 12—16
Scheme 5
Triazinone
NuH
Product T/°C
Yield (%)
1
2
Indole
Indole
Indole
1210
—
—
13
14
–15
–15
153
153
153
153
–15
65
—
—
92
80
95
85
3
4
Indole
1ꢀМеꢀIndole
2ꢀМеꢀIndole
Indole
15
1611
1,2,4ꢀtriazinꢀ3(2H)ꢀone (3) give no reaction at low temꢀ
peratures, however, when the reaction was performed
in boiling DMF, a number of nucleophilic addition prodꢀ
ucts were obtained for triazinone 3 both in the presence
and in the absence of paraꢀtoluenesulfonyl chloride.
In the reaction of quinoxalinꢀ2(1H)ꢀone (5) with inꢀ
dole, nucleophilic substitution product 17 was isolated.
This reaction proceeds similarly to the Reissert reaction,
that allows one to suggest that compound 5a is formed as
an intermediate product, possessing structure similar to
that of the Reissert compounds (Scheme 5).
i. TsCl, –15÷–10 °C.
To sum up, the experiments described showed a prinꢀ
cipal possibility of the formation of nucleophilic addition
products, as well as hydrogen substitution in the reaction
of a number of triazinones 1—4 and quinoxalinone 5 with
nucleophiles in the presence of acylating agents. These
data allowed us to suggest a possibility to use optically
active acylating agents in this reaction and obtain diaꢀ
stereomerically pure products. In the present work,
NꢀTsꢀLꢀvaline 18 and NꢀTsꢀLꢀleucine 19 were used as
such reagents.
of S,Sꢀisomers 21 and 24 in the reaction mixture reaches
90—95% (1H NMR data). After purification on a column,
1
the H NMR spectrum of the product exhibits only one
set of signals. Assignment of the signals was made based
1
on the H NMR spectrum of compound 24, the absolute
stereoconfiguration of which was determined by Xꢀray
diffraction (Fig. 1), as well as with allowance for the known
configuration of the chiral center in NꢀTsꢀLꢀvaline. In the
1
general case, the H NMR spectra of the reaction mixꢀ
3ꢀPhenylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (1). The reactions
of triazinone 1 with Cꢀnucleophiles in the presence of
acyl chlorides of NꢀTsꢀLꢀvaline 18 or NꢀTsꢀLꢀleucine 19
at temperatures of –15÷–10 °C leads to a number of
6ꢀsubstituted 1ꢀ(2ꢀtosylamino)acylꢀ6ꢀarylꢀ3,4ꢀdihydroꢀ
1,2,4ꢀtriazinꢀ5(4H)ꢀones 20—25 in the yield from 15 to
77% and in some cases with high diastereoselectivity
(Scheme 6). The use of NꢀTsꢀLꢀvaline as the acylating
agent produces higher diastereoselectivity. The content
tures exhibit two close sets of signals, whereas only one set
of signals is found in the spectra of isolated compounds.
Adducts 12 and 25b containing no acyl fragment are the
minor products at low temperatures in some cases, which
become predominant when the reaction temperature is
elevated to ambient. No reaction was observed at temꢀ
peratures below –15 °C (see Scheme 6, Table 3).
As an explanation of the asymmetric induction
observed, it can be suggested that formation of
Scheme 6
R´ = CHMe2 (18), CH2CHMe2 (19)

994
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Chupakhin et al.
Scheme 7
Table 3. Reactions of triazinone 1 with Cꢀnucleophiles in the presence of acyl chlorides 18 and 19
NuН
R´
T/°C
S,S : S,Ra
S,S : S,Rb
Product (yield (%))
Indole
CH2CHMe2
CH2CHMe2
–15
20
60 : 40
45 : 55
>95 : 5
>95 : 5
(S,S)ꢀ20 (15)b, 1210 (<5)
(S,S)ꢀ20 (10)b, 1210 (36),
(S,R)ꢀ20 (5)b
CHMe2
–15
–15
–15
–15
–15
90:10
55 : 45
65 : 35
>95 : 5
60 : 40
>95 : 5
>95 : 5
>95 : 5
>95 : 5
>95 : 5
(S,S)ꢀ21 (77)b
1ꢀMeꢀIndole
2ꢀMeꢀIndole
CH2CHMe2
CH2CHMe2
CHMe2
(S,S)ꢀ22 (65)b
(S,S)ꢀ23 (42)b
(S,S)ꢀ24 (32)b
1ꢀMeꢀPyrrole
CH2CHMe2
(S,S)ꢀ25a (15)b, 25b10 (7)
a dr in the reaction mixture.
b dr after separation on a chromatographic column.
Nꢀacylazinium salt takes place in the course of the reacꢀ
tion (Scheme 7, structure A), in which there is present a
dipoleꢀdipole interaction between the nitrogen atom of
the amino acid fragment and electrophilic carbon atom of
the heterocycle (structure В). As a result, one of the sides
of the heterocycle becomes sterically hindered for the
attack by a nucleophile (see Scheme 7). According to
the literature data,6 the amino group in NꢀTsꢀamino acids
is a strong enough nucleophile to form a covalent bond
with the carbon atom of the C=N bond of azaheterocycle
(isoquinoline), however, no formation of the corresponding
bicyclic product was observed in the reactions studied.
6ꢀPhenylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (2). The reaction
with Cꢀnucleophiles and amino acid acyl chlorides (18,
19) leads to the formation of a number of 3ꢀsubstituted
2ꢀ(2ꢀtosylamino)acylꢀ6ꢀarylꢀ3,4ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
5(4H)ꢀones (26—29) in moderate yields and low diastereoꢀ
selectivity. After separation on a chromatographic column,
diastereoisomers were isolated having only one set of
signals in their 1H NMR spectra (Scheme 8, Table 4).
The absolute configuration of compounds obtained
was determined based on the Xꢀray diffraction analysis
data for compound 27,13 as well as on the known configuꢀ
ration of the amino acid fragment, which showed that the
compound is a S,Sꢀdiastereomer.
It is obvious that Nꢀacyl derivative 2* is formed in the
course of the reaction, however, relatively low electrophiꢀ
licity of the carbon atom C(3) of the triazine ring leads to
the fact that no sterical hindrance arises for the attack by
nucleophile in contrast to position C(6) in triazinone 1
and the reaction results in the formation of diastereomers
in approximately equal proportion (Scheme 9).
6ꢀPhenylꢀ1,2,4ꢀtriazinꢀ3(2H)ꢀone (3) gives no reacꢀ
tion with Cꢀnucleophiles in the presence of amino acid
acyl chlorides in the temperature range from –15 to +25 °C.
The use of ester and carbodiimide methods for the activaꢀ
tion of amino acids did not result in obtaining amino acid
derivatives of triazinone 3.

Synthesis of asymmetric azinones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
995
Scheme 8
Table 4. Reactions of triazinone 2 with Cꢀnucleophiles in the presence of amino acid acyl chlorides 18 and 19
Compound
R´
NuН
Indole
Indole
1ꢀMeꢀPyrrol
1ꢀMeꢀIndole
S,S : S,Ra
S,S : S,Rb
Product
Yieldb (%)
19
18
19
18
CH2CHMe2
CHMe2
СН2CHMe2
CHMe2
55 : 45
65 : 35
—
>95 : 5
>95 : 5
>95 : 5
>95 : 5
26
27
28
29
52
23
15
32
50 : 50
a dr in the reaction mixture.
b dr after separation on a chromatographic column.
Scheme 9
1,3,5ꢀTriazinꢀ2,4(1H,3H)ꢀdione (4) forms no expected
acylated σHꢀadducts with Cꢀnucleophiles in the presence
of amino acid acyl chlorides 18 and 19 in the temperature
range from –15 to +25 °C either, nucleophilic addition
products 16 and 30 containing no amino acid fragment
were isolated instead, which are analogous to those deꢀ
scribed in the literature,11 rather obtained in higher yields
(Scheme 10, Table 5).
O(2)
N(4)
C(14)
C(23)
C(22)
S(1)
C(13)
O(1)
C(21)
C(15)
C(19)
C(24)
C(18)
C(16)
C(20)
O(3)
C(17)
N(1)
Scheme 10
C(12)
C(11)
N(2)
C(26)
C(3)
C(27)
C(4)
C(25)
N(5)
C(9)
C(1)
C(10)
C(5)
C(28)
C(2)
N(3)
C(30)
C(6)
C(7)
C(8)
C(29)
O(4)
Fig. 1. General view of molecule 24 (see Ref. 12).* Nonhydrogen
atoms are given as ellipsoids of thermal vibrations (p = 50 %).
Hydrogen atoms are not shown.
* These data are available at: www.ccdc.cam.ac.uk/data_request/cif.

996
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Chupakhin et al.
Quinoxalinꢀ2(1H)ꢀone (5). The reaction of quinoxalinꢀ
2(1H)ꢀone with indoles and amino acid acyl chlorides 18
and 19 in the temperature range from –40 to +25 °C gives
rise only to 3ꢀindolylquinoxalinꢀ2(1H)ꢀones 17 and 31
Table 5. Reactions of compound 4 with Cꢀnucleophiles
in the presence of amino acid acyl chlorides 18 and 19
Product
NuН
R´
Yield (%)
H
(Scheme 11, Table 6). Formation of the SN products in
1611
30
Indole
2ꢀMeꢀIndole
CHMe2
СН2CHMe2
43
35
this reaction allows us to suggest that amino acid acyl
chlorides play here the same role as the acylating agent in
the Reissert reaction.
Scheme 11
Table 6. Reactions of quinoxalinone 5 with Cꢀnucleophiles in the presence of amino acid
acyl chlorides 18 and 19
NuH
R´
Conditions
Solvent
Product
Yield
(%)
T/°C
–
–
–
–
–
–
15— 10
Indole
2ꢀMeꢀIndole
CHMe2
CH2CHMe2
CHMe2
CHMe2
CHMe2
THF
THF
THF
THF
DCM
1714,15
31
31
31
31
37
21
35
13
25
–
15— 10
–
15— 10
–
40— 10
–
15— 10
Scheme 12
i. THF, ClCO2R´, NEt3, 0 °C
R = CHMe2 (34), CH2CHMe2 (35)
Table 7. Reactions of quinoxalinone 5 with amino acid derivatives 34 and 35
NuН
R
R´
Et
Et
Et
Bui
Et
Et
Et
Solvent
Product (yield (%))
Indole
Indole
2ꢀMeꢀIndole
CHMe2
CHMe2
CH2CH(CH3)2
CH2CHMe2
CH2CHMe2
CHMe2
THF
DCM
THF
THF
THF
THF
THF
1712,13 (8), 36 (6)
17 (<5%), 36 (4)
31 (12)
31 (6), 37 (4)
32 (12)
1ꢀMeꢀIndole
Pyrrole
32 (15), 38 (3)
3316 (<5%)
CHMe2

Synthesis of asymmetric azinones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
997
Synthesis of compounds 6—8 (general procedure). A mixture
of 6ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀone (2) (1 mmol) and the
corresponding nucleophile (1.1 mmol) was refluxed in acetic
anhydride (3 mL) for 3 h. A precipitate was formed upon cooling
to room temperature. If no precipitate was formed immediately, the
reaction mixture was diluted with hot water. A precipitate formed
was filtered off and recrystallized from 50% aq. propanꢀ2ꢀol.
2,4ꢀDiacetylꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ2Hꢀ
[1,2,4]triazinꢀ5ꢀone (6). The yield was 79%, yellow crystalline
powder, m.p. 232—233 °C. 1H NMR (400 MHz, DMSOꢀd6), δ:
11.14 (br.s, 1 H, NH); 8.41 (d, 1 H, C(3)H, J = 0.6 Hz);
7.78—7.80 (m, 2 H, Ph); 7.54 (d, 1 H, C(4)Hindole, J = 8.1 Hz);
7.32 (d, 1 H, C(7)Hindole, J = 8.1 Hz); 7.31—7.42 (m, 3 H,
Ph); 7.17—7.18 (m, 1 H, indole); 7.06—7.10 (m, 1 H, indole);
6.97—7.01 (m, 1 H, indole); 2.63 (s, 3 H, CH3CO); 2.45 (s, 3 H,
CH3CO). Found (%): C, 67.30; H, 4.95; N, 14.82. C21H18N4O3.
Calculated (%): C, 67.37; H, 4.85; N, 14.96.
Replacement of amino acid acyl chlorides by NꢀAcꢀ
amino acid 34 and 35, activated due to the formation of
mixed anhydrides,9 leads to a decrease in the yields
of compounds 17, 31—33; expected acylated products
36—38 were isolated in low yields in some cases
(Scheme 12, Table 7).
The low yields of compounds 36—38 did not allow us
to carry out Xꢀray diffraction analysis to determine their
absolute stereochemical structures. The use of activation
method for the amino acids including formation of mixed
anhydrides leads to racemization of the asymmetric cenꢀ
ter in the amino acid.9 However, only one set of signals is
1
observed in the H NMR spectra of compounds 36—38,
this indicates that they are a single pare of diastereomers
(SS,RR or SR,RS).
2,4ꢀDiacetylꢀ3ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ
3,4ꢀdihydroꢀ2Hꢀ[1,2,4]triazinꢀ5ꢀone (7). The yield was 60%,
yellow crystalline powder, m.p. 203—205 °C. 1H NMR (250 MHz,
DMSOꢀd6), δ: 8.51 (d, 1 H, C(3)H, J = 0.8 Hz); 7.79—7.83 (m,
2 H, Ph); 7.58—7.63 (m, 1 H, indole, C(4)Hindole); 7.39—7.46
(m, 3 H, Ph); 7.32—7.46 (m, 1 H, C(7)Hindole); 7.19—7.26 (m,
1 H, indole); 7.07—7.13 (m, 2 H, indole); 3.69 (s, 3 H, NCH3);
2.62 (s, 3 H, CH3CO); 2.45 (s, 3 H, CH3CO). Found (%):
C, 68.24; H, 5.26; N, 14.53. C22H20N4O3. Calculated (%):
C, 68.03; H, 5.19; N, 14.42.
2,4ꢀDiacetylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ
3,4ꢀdihydroꢀ2Hꢀ[1,2,4]triazinꢀ5ꢀone (8). The yield was 40%,
yellow crystalline powder, m.p. 195—197 °C. 1H NMR (250 MHz,
DMSOꢀd6), δ: 8.32 (s, 1 H, C(3)H); 7.84—7.89 (m, 2 H, Ph);
7.43—7.49 (m, 3 H, Ph); 7.23—7.30 (m, 2 H, indole);
7.00—7.07 (m, 1 H, indole); 6.89—6.96 (m, 1 H, indole);
2.54 (s, 3 H, CH3); 2.46 (s, 3 H, CH3); 2.41 (s, 3 H, CH3).
Found (%): C, 68.18; H, 5.14; N, 14.51. C22H20N4O3. Calꢀ
culated (%): C, 68.03; H, 5.19; N, 14.42.
Synthesis of compounds 9 and 11 (general procedure).
A mixture of the corresponding azinone 3, 5 (1 mmol) and
indole (1.1 mmol) in acetic anhydride (3 mL) was refluxed for
60 min. Upon standing at room temperature, clusters of colorless
crystals grew from the solution. After 6 h a precipitate formed
was filtered off, washed with diethyl ether, and recrystallized
from ethanol.
2,4ꢀDiacetylꢀ5ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ2Hꢀ
[1,2,4]triazinꢀ3ꢀone (9). The yield was 51%, colorless crystalline
powder, m.p. 183—185 °C. 1H NMR (250 MHz, DMSOꢀd6), δ:
11.10 (br.s, 1 H, NH); 7.81—7.85 (m, 2 H); 7.67—7.70 (m,
1 H); 7.33—7.43 (m, 4 H); 7.03—7.14 (m, 4 H); 2.57 (s, 3 H,
CH3CO); 2.51 (s, 3 H, CH3CO). Found (%): C, 67.43; H, 4.88;
N, 14.87. C21H18N4O3. Calculated (%): C, 67.37; H, 4.85;
N, 14.96.
Experimental
Azinones 1,17 3,18 amino acid acyl chlorides 18, 19 used in
the work were synthesized according to the known procedures,
the rest of starting materials are commercially available. The
solvents were dried using standard procedures; TLC analysis was
performed on Merck silica gel 60F254 plates using the UV light
for visualization. Column chromatography was performed using
Merck 60 silica gel. 1H and 13C NMR spectra were recorded on
a Bruker DRXꢀ400 and Bruker WHꢀ250 spectrometers using
SiMe4 as an internal standard. Optical rotation was measured
on a Perkin Elmer model 341 polarimeter. Xꢀray diffraction
analysis for compound 24 (Table 8) was performed using Oxford
Diffraction Xcalibur S CCD diffractometer with the CrysAlisPro
soft ware. The structure was solved by the direct method using
the SHELXSꢀ97 program package and refined by the leastꢀ
squares fullꢀmatrix method on F2 using the SHELXLꢀ97 program.
6ꢀPhenylꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀone (2). A solution of 5ꢀcyanoꢀ
6ꢀphenylꢀ1,2,4ꢀtriazine19 (10 g, 0.055 mol) in dichloromethane
(100 mL) was added to aqueous NaOH (2 M, 200 mL). The
mixture was stirred for 3 h at room temperature, then the aqueous
layer was separated and washed with dichloromethane. Conꢀ
centrated hydrochloric acid was added with stirring to the aq.
solution obtained to pH 5. A precipitate formed was filtered off
and recrystallized from ethanol. The yield was 5.3 g (55%), cream
crystalline powder, m.p. 203—204 °C. 1H NMR (400 MHz,
DMSOꢀd6), δ: 13.73 (br.s, 1 H, NH); 8.56 (s, 1 H, CH); 8.10—8.13
(m, 2 H, Ph); 7.40—7.45 (m, 3 H, Ph). Found (%): C, 62.23;
H, 4.33; N, 24.52. C9H7N3O. Calculated (%): C, 62.42;
H, 4.07; N, 24.26.
Quinoxalinꢀ2(1H)ꢀone (5). A solution of glyoxalic acid
monohydrate (11.9 g, 0.13 mol) in water (10 mL) was slowly
added to a solution of orthoꢀphenylenediamine (14 g, 0.13 mol)
in methanol (50 mL) at 0 °C. The dense mass obtained was
stirred for 30 min, a precipitate formed was filtered off and
recrystallized from ethanol. The yield was 15.1 g (80%), colorless
crystalline powder, m.p. 268—269 °C. 1H NMR (400 MHz,
DMSOꢀd6), δ: 12.33 (br.s, 1 H, NH); 8.07 (s, 1 H, C(3)H);
7.72 (dd, 1 H, J = 8.0 Hz, J = 1.2 Hz); 7.44—7.48 (m, 1 H); 7.29
(dd, 1 H, J = 8.2 Hz, J = 1.0 Hz); 7.21—7.26 (m, 1 H, CH).
Found (%): C, 65.71; H, 4.09; N, 19.22. C9H7N3O. Calculꢀ
ated (%): C, 65.75; H, 4.14; N, 19.17. Physicoꢀchemical
characteristics and spectral data of compound obtained agree
with those reported in the literature.20
4ꢀAcetylꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ3,4ꢀdihydroꢀ1Hꢀquinoxalinꢀ
2ꢀone (11). The yield was 62%, colorless crystalline powder,
m.p.
>
260 °C. 1H NMR (400 MHz, DMSOꢀd6), δ:
10.78—10.80 (m, 2 H, 2 NH); 7.68 (d, 1 H, J = 7.9 Hz); 7.27 (d,
1 H, J = 8.0 Hz); 7.20—7.21 (m, 1 H); 7.11 (t, 1 H, J = 7.4 Hz);
7.03—7.06 (m, 2 H); 6.96—7.00 (m, 1 H); 6.92 (t, 1 H,
J = 7.2 Hz); 6.73 (d, 1 H, J = 1.5 Hz); 6.55 (s, 1 H); 2.26 (s, 3 H,
CH3CO). Found (%): C, 70.53; H, 4.97; N, 13.80. C18H15N3O2.
Calculated (%): C, 70.81; H, 4.95; N, 13.76.
1ꢀAcetylꢀ6ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ[1,3,5]triazinaneꢀ2,4ꢀdione (10).
A mixture of 1,3,5ꢀtriazineꢀ2(1H),4(3H)ꢀdione (4) (1 mmol)

998
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Chupakhin et al.
and indole (1.1 mmol) in acetic anhydride (3 mL) was refluxed
for 60 min. Then the reaction mixture was cooled and diluted
with water (50 mL). A precipitate formed was subjected to
chromatography on silica gel. The yield was 25%, colorless
crystalline powder, m.p. 215—216 °C, Rf = 0.6 (ethyl acetate).
1H NMR (400 MHz, DMSOꢀd6), δ: 11.02 (s, 1 H, NH); 10.17
(s, 1 H, NH); 8.80 (d, 1 H, N(5)H, J = 4.7 Hz); 7.61 (d, 1 H,
C(4)Hindole, J = 8.0 Hz); 7.35 (d, 1 H, C(7)Hindole, J = 8.1 Hz);
7.12—7.03 (m, 2 H, C(2)H+C(5)Hindole); 6.96—6.70 (m, 1 H,
C(6)Hindole); 6.84 (d, 1 H, C(6)H, J = 4.4 Hz); 2.49 (s, 3 H,
CH3CO). 13C NMR (75 MHz, DMSOꢀd6), δ: 170.35, 152.52,
151.20, 137.12, 124.90, 123.16, 122.13, 119.65, 119.33, 113.63,
112.37, 57.48, 26.01. Found (%): C, 57.03; H, 4.23; N, 20.24.
C13H12N4O3. Calculated (%): C, 57.35; H, 4.44; N, 20.58.
Synthesis of compounds 12,10 16,11 and 1712,13 (general
procedure). Indole (1.2 mmol) was added to a suspension of the
corresponding azinone (1, 4, 5) (1.2 mmol) and pꢀtolueneꢀ
sulfonyl chloride (1.2 mmol) in THF (5 mL) at –15 °C. The
mixture was stirred for 1 h at –15 °C, then the temperature was
raised to ambient over 1 h. A precipitate formed was filtered off,
washed with THF and diethyl ether, and recrystallized from
ethanol.
with silica gel using the ethyl acetate—chloroform (1 : 1) mixture
as an eluent.
(S)ꢀ1ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ6ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (S,Sꢀ20).
The yield was 15%, colorless crystalline powder, m.p. 244—245 °C,
20
Rf = 0.9 (ethyl acetate), [α]D = +309.2 (c = 1.0, DMF).
1H NMR (400 MHz, DMSOꢀd6), δ: 11.51 (s, 1 H, NH); 10.98
(d, 1 H, NH, J = 2.1 Hz); 7.90—7.92 (m, 2 H, Ph); 7.81 (d, 1 H,
NH, J = 9.1 Hz); 7.73 (d, 1 H, C(4)Hindole, J = 8.0 Hz); 7.54 (d,
2 H, Ts, J = 8.2 Hz); 7.44—7.50 (m, 3 H, Ph); 7.35 (d, 1 H,
C(7)Hindole, J = 8.1 Hz); 7.07—7.11 (m, 1 H, C(6)Hindole);
6.99—7.02 (m, 1 H, C(5)Hindole); 6.93—6.96 (m, 3 H,
Ts+C(2)Hindole); 6.07 (s, 1 H, C(6)H); 5.11 (dt, 1 H, CH,
J = 10.3 Hz, J = 3.8 Hz); 2.21 (s, 3 H, Ts); 1.81—1.62 (m, 1 H,
CH); 1.55—1.42 (m, 1 H, CH2); 1.31—1.38 (m, 1 H, CH2); 0.83
(d, 3 H, CH3, J = 6.6 Hz); 0.75 (d, 3 H, CH3, J = 6.6 Hz).
Found (%): C, 64.55; H, 5.56; N, 12.53. C30H31N5O4S.
Calculated (%): C, 64.61; H, 5.60; N, 12.56.
(R)ꢀ1ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ6ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (S,Rꢀ20).
The yield was 5%, colorless crystalline powder, m.p. 270—272 °C,
25
Rf = 0.8 (ethyl acetate), [α]D = –127.6 (c = 0.5, DMF).
1H NMR (400 MHz, DMSOꢀd6), δ: 11.48 (s, 1 H, NH); 10.90
(d, 1 H, NH, J = 1.5 Hz); 7.91—7.93 (m, 2 H, Ph); 7.79 (d,
1 H, NH, J = 10.3 Hz); 7.59 (d, 1 H, C(4)Hindole, J = 7.9 Hz);
7.47—7.50 (m, 5 H, Ts+Ph); 7.28 (d, 1 H C(7)Hindole, J = 8.1 Hz);
7.17 (d, 2 H, Ts, J = 8.2 Hz); 7.04 (t, 1 H, C(6)Hindole, J = 7.3 Hz);
Synthesis of compounds 13—15 (general procedure).
A solution of 6ꢀarylꢀ1,2,4ꢀtriazinꢀ3(2H)ꢀone (1.2 mmol) and
the corresponding nucleophile (1.2 mmol) in DMF (3 mL) was
refluxed for 60 min and concentrated in vacuo, A resinꢀlike
residue obtained was stirred with water, a precipitate formed
was filtered off, dried, and recrystallized from ethanol.
6.95 (t, 1 H, C(5)Hindole, J = 7.5 Hz); 6.89 (d, 1 H, C(2)Hindole
,
J = 2.5 Hz); 5.69 (s, 1 H, C(6)H); 4.95 (dt, 1 H, CH, J = 5.3 Hz,
J = 9.7 Hz); 2.41 (s, 3 H, Ts); 1.62—1.72 (m, 1 H, CH);
1.27—1.42 (m, 1 H, CH2); 1.31—1.38 (m, 1 H, CH2); 0.85 (d,
6 H, 2 CH3, J = 6.5 Hz). Found (%): C, 64.49; H, 5.58;
N, 12.52. C30H31N5O4S. Calculated (%): C, 64.61; H, 5.60;
N, 12.56.
5ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
3(2H)ꢀone (13). The yield was 92%, colorless crystalline powder,
m.p. 272—273 °C. 1H NMR (250 MHz, DMSOꢀd6), δ: 11.04
(br.s, 1 H, NH, indole); 10.26 (br.s, 1 H, N(2)H); 7.81 (d, 1 H,
N(4)H, J = 3.0 Hz); 7.68—7.33 (m, 3 H); 7.28—7.35 (m, 4 H,
Ph); 7.21—7.22 (m, 1 H); 7.08—7.09 (m, 1 H); 7.01—7.03 (m,
1 H); 5.97 (d, 1 H, C(5)H, J = 3.0 Hz). Found (%): C, 70.21;
H, 4.80. C17H14N4O. Calculated (%): C, 70.33; H, 4.86.
5ꢀ(1ꢀMethylindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
3(2H)ꢀone (14). The yield was 95%, colorless crystalline powder,
m.p. 265—267 °C. 1H NMR (250 MHz, DMSOꢀd6), δ: 10.22
(br.s, 1 H, N(2)H); 7.69—7.79 (m, 2 H); 7.50 (br.s, 1 H, N(4)H);
7.28—7.38 (m, 5 H); 7.06—7.18 (m, 2 H); 5.95 (d, 1 H, C(5)H,
J = 1.9 Hz); 3.69 (s, 3 H, CH3). Found (%): C, 71.02; H, 5.35.
C18H16N4O. Calculated (%): C, 71.04; H, 5.30.
5ꢀ(2ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ4,5ꢀdihydroꢀ1,2,4ꢀ
triazinꢀ3(2H)ꢀone (15). The yield was 80%, colorless crystalline
powder, m.p. 275—276 °C. 1H NMR (250 MHz, DMSOꢀd6), δ:
10.25 (br.s, 1 H, N(2)H); 7.58—7.61 (m, 2 H); 7.45—7.51 (m,
2 H); 7.20—7.27 (m, 4 H); 6.92—6.98 (m, 2 H); 5.97 (d, 1 H,
C(5)H, J = 2.2 Hz); 2.46 (s, 3 H, CH3). Found (%): C, 71.30;
H, 5.06. C18H16N4O. Calculated (%): C, 71.04; H, 5.30.
Synthesis of compounds 20—25 (general procedure). Triazinꢀ
one 1 (1.2 mmol) was added to a solution of (S)ꢀNꢀTsꢀamino
acid acyl chloride (18 or 19) (1.2 mmol) in THF (3 mL) at
–15 °C, after 5 min the corresponding nucleophile (1.2 mmol)
was added to the solution. The mixture was stirred for 1 h at
–15 °C, then the temperature was raised to ambient over 2 h.
Then the reaction mixture was poured into cold water and
extracted with ethyl acetate (2×20 mL). The organic layer was
washed with water and brine, dried with calcined Na2SO4. The
solution was concentrated, the residue was dissolved in chloroꢀ
form and subjected to chromatographic separation on a column
(R/S)ꢀ1ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ6ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (S,RSꢀ20).
The yield was 25%, colorless crystalline powder, m.p. 244—245 °C.
20
[α]D = +179.3 (c = 1.0, DMF). Found (%): C, 64.51;
H, 5.47; N, 12.42. C30H31N5O4S. Calculated (%): C, 64.61;
H, 5.60; N, 12.56.
(S)ꢀ1ꢀ[(S)ꢀ3ꢀMethylꢀ2ꢀtosylaminobutanoyl]ꢀ6ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (21). The
yield was 77%, pink crystalline powder, m.p. 248 °C, Rf = 0.9
(ethyl acetate), [α]D = +329.8 (c = 1.0, DMF). 1H NMR
20
(400 MHz, DMSOꢀd6), δ: 11.65 (s, 1 H, NH); 11.11 (d, 1 H,
NH, J = 1.8 Hz); 7.92 (d, 1 H, NH, J = 9.4 Hz); 7.82—7.90 (m,
2 H, Ph); 7.70 (d, 1 H, C(4)Hindole, J = 8.0 Hz); 7.52—7.62
(m, 3 H, Ph); 7.48 (d, 2 H, Ts, J = 8.2 Hz); 7.40 (d, 1 H,
C(7)Hindole, J = 8.1 Hz); 7.13—7.16 (m, 1 H, C(6)Hindole);
7.01—7.05 (m, 1 H, C(5)Hindole); 6.97 (d, 1 H, C(2)Hindole
,
J = 2.3 Hz); 6.88 (d, 2 H, Ts, J = 8.0 Hz); 6.12 (s, 1 H, C(6)H);
4.88—4.92 (m, 1 H, CH); 2.14 (s, 3 H, Ts); 1.94—2.05 (m,
1 H, CH); 0.87 (d, 3 H, CH3, J = 6.8 Hz); 0.80 (d, 3 H, CH3,
J = 6.8 Hz). Found (%): C, 63.95; H, 5.41; N, 12.77.
C29H29N5O4S. Calculated (%): C, 64.07; H, 5.38; N, 12.88.
(S)ꢀ1ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ6ꢀ(1ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀ
one (22). The yield was 65%, colorless crystalline powder,
25
m.p. 252—253 °C, Rf = 0.9 (ethyl acetate), [α]D = +262.7
1
(c = 1.0, DMF). H NMR (400 MHz, DMSOꢀd6), δ: 11.55 (s,
1 H, NH); 7.88—7.92 (m, 3 H, Ph, NH); 7.76 (d, 1 H, C(4)Hindole
,

Synthesis of asymmetric azinones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
999
J = 8.0 Hz); 7.57 (d, 2 H, Ts, J = 8.1 Hz); 7.44—7.52 (m, 3 H,
Ph); 7.34 (d, 1 H, C(7)Hindole, J = 8.2 Hz); 7.18 (t, 1 H,
DMSOꢀd6), δ: 11.64 (s, 1 H, NH); 10.96 (s, 1 H, NH);
7.96—7.99 (m, 2 H, Ph); 7.51—7.63 (m, 3 H, Ph); 7.27—7.31
(m, 2 H, C(4)Hindole+NH); 7.20 (d, 2 H, Ts, J = 8.2 Hz); 7.15
C(6)Hindole, J = 7.6 Hz); 7.04—7.08 (m, 2 H, C(5)Hindole
+
C(2)Hindole); 6.96 (d, 2 H, Ts, J = 8.1 Hz); 6.08 (s, 1 H, C(6)H);
5.10 (dt, 1 H, CH, J = 10.4 Hz, J = 3.6 Hz); 3.74 (s, 3 H,
NCH3); 2.23 (s, 3 H, Ts); 1.74—1.59 (m, 1 H, CH); 1.58—1.43
(m, 1 H, CH2); 1.30—1.37 (m, 1 H, CH2); 0.82 (d, 1 H,
J = 6.6 Hz); 0.70 (d, 1 H, J = 6.5 Hz). Found (%): C, 65.14;
H, 5.86; N, 12.47. C31H33N5O4S. Calculated (%): C, 65.13;
H, 5.82; N, 12.25.
(S)ꢀ1ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ6ꢀ(2ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
5(4H)ꢀone (23). The yield was 42%, colorless crystalline powder,
m.p. 274—275 °C, Rf = 0.9 (ethyl acetate). 1H NMR (400 MHz,
DMSOꢀd6), δ: 11.59 (s, 1 H, NH); 10.96 (s, 1 H, NH);
8.08—7.96 (m, 2 H, Ph); 7.47—7.61 (m, 4 H, Ph+NH); 7.29 (d,
1 H, C(4)Hindole, J = 8.0 Hz); 7.20 (d, 2 H, Ts, J = 8.2 Hz); 7.16
(d, 1 H, C(7)Hindole, J = 8.1 Hz); 6.99 (t, 1 H, C(6)Hindole,
J = 7.3 Hz); 6.81 (t, 1 H, C(5)Hindole, J = 7.3 Hz); 6.37 (d,
2 H, Ts, J = 8.0 Hz); 5.96 (s, 1 H, C(6)H); 4.89 (dd, 1 H, CH,
J = 9.0 Hz, J = 3.5 Hz); 2.39 (s, 3 H, CH3); 2.01—2.19 (m, 4 H,
CH+CH3); 0.99 (d, 3 H, CH3, J = 6.70 Hz); 0.85 (d, 3 H, CH3,
J = 6.81 Hz). Found (%): C, 64.75; H, 5.43; N, 12.85.
C30H31N5O4S. Calculated (%): C, 64.61; H, 5.60; N, 12.56.
(S)ꢀ1ꢀ[(S)ꢀ3ꢀMethylꢀ2ꢀtosylaminobutanoyl]ꢀ6ꢀ(1ꢀmethylꢀ
1Hꢀpyrrolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀ
one (25). The yield was 15%, colorless crystalline powder,
m.p. 177—178 °C, Rf = 0.9 (ethyl acetate). 1H NMR (400 MHz,
DMSOꢀd6), δ: 11.65 (s, 1 H, NH); 7.99—7.89 (m, 2 H, Ph);
7.75 (d, 1 H, NH, J = 9.5 Hz); 7.57—7.43 (m, 5 H, Ph+Ts);
7.01 (d, 2 H, Ts, J = 8.1 Hz); 6.60—6.67 (m, 1 H, pyrrole);
5.84—5.88 (m, 1 H, pyrrole); 5.81 (s, 1 H, C(6)H); 5.72—5.75
(m, 1 H, pyrrole); 5.01 (dt, 1 H, CH, J = 10.6 Hz, J = 3.6 Hz);
3.57 (s, 3 H, NCH3); 2.35 (s, 3 H, Ts); 1.67—1.87 (m, 1 H,
CH); 1.38—1.53 (m, 1 H, CH2); 1.24—1.31 (m, 1 H, CH2);
0.80—0.84 (m, 6 H, 2 CH3). Found (%): C, 61.97; H, 6.00;
N, 13.41. C27H31N5O4S. Calculated (%): C, 62.17; H, 5.99;
N, 13.43.
Synthesis of compounds 26—29 (general procedure). Triꢀ
azinone 2 (1.2 mmol) was added to a solution of (S)ꢀNꢀTsꢀ
amino acid acyl chloride (18 or 19) (1.2 mmol) in THF (3 mL)
at –15 °C, after 5 min the corresponding nucleophile (1.2 mmol)
was added to the solution. The mixture was stirred for 1 h at
–15 °C, then the temperature was raised to ambient over 2 h.
The reaction mixture was filtered off the unreacted residue of
triazine, the filtrate was poured into cold water and extracted
with ethyl acetate (2×20 mL). The organic layer was washed
with water and brine, dried with calcined Na2SO4. The solution
was concentrated, the residue was dissolved in chloroform and
subjected to chromatographic separation on a column with silica
gel using the ethyl acetate—chloroform (1 : 1) mixture as an
eluent.
(d, 1 H, C(7)Hindole, J = 8.0 Hz); 6.99 (t, 1 H, C(6)Hindole
,
J = 7.5 Hz); 6.81 (t, 1 H, C(5)Hindole, J = 7.5 Hz); 6.44 (d, 2 H,
Ts, J = 8.1 Hz); 5.92 (s, 1 H, C(6)H); 5.08 (dt, 1 H, CH,
J = 10.0 Hz, J = 3.8 Hz); 2.36 (s, 3 H, CH3); 2.15 (s, 3 H, CH3);
1.90—1.73 (m, 1 H, CH); 1.53—1.32 (m, 2 H); 0.87 (t, 6 H,
2 CH3, J = 7.2 Hz). Found (%): C, 64.85; H, 5.90; N, 12.20.
C31H33N5O4S. Calculated (%): C, 65.13; H, 5.82; N, 12.25.
(S)ꢀ1ꢀ[(S)ꢀ3ꢀMethylꢀ2ꢀtosylaminobutanoyl]ꢀ6ꢀ(2ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀ
one (24). The yield was 32%, colorless crystalline powder,
m.p. > 300 °C, Rf = 0.9 (ethyl acetate). 1H NMR (400 MHz,
Table 8. Crystallographic data and parameters of Xꢀray diffracꢀ
tion experiment for compound 24
Parameter
Value
Molecular formula
Molecular weight
C30H31N5O4S
557.66
Crystal system
Space group
a/Å
b/Å
c/Å
Orthorhombic
P2(1)2(1)2(1)
11.9669(9)
14.1290(15)
18.1570(14)
90.00
90.00
90.00
3070.0(5)
4
1.207
(S)ꢀ2ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ3ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀone (26). The
yield was 52%, colorless crystalline powder, m.p. 134—135 °C,
25
Rf = 0.8 (ethyl acetate), [α]D = +444.8 (c = 1.0, DMF).
α/deg
β/deg
γ/deg
1H NMR (400 MHz, DMSOꢀd6), δ: 11.04 (d, 1 H, NH, J = 1.8 Hz);
9.71 (d, 1 H, NH, J = 5.3 Hz); 8.10 (d, 1 H, NH, J = 8.7 Hz);
7.86—7.90 (m, 2 H, Ph); 7.75 (d, 1 H, C(4)Hindole, J = 8.0 Hz);
7.54 (d, 2 H, Ts, J = 8.2 Hz); 7.33—7.46 (m, 4 H, Ph+C(7)Hindole);
V/Å3
Z
ρ
7.08—7.11 (m, 1 H, C(6)Hindole); 6.98—7.05 (m, 5 H, C(5)Hindole
+
calc/g cm–3
+ C(2)Hindole, Ts, C(3)H); 5.02 (dt, 1 H, CH, J = 10.1 Hz,
J = 4.1 Hz); 2.27 (s, 3 H, Ts); 1.72—1.48 (m, 2 H, CH+CH2);
1.35—1.42 (m, 1 H, CH2); 0.82 (d, 3 H, CH3, J = 6.6 Hz); 0.65 (d,
3 H, CH3, J = 6.5 Hz). Found (%): C, 64.72; H, 5.71; N, 12.48.
C30H31N5O4S. Calculated (%): C, 64.61; H, 5.60; N, 12.56.
(S)ꢀ2ꢀ[(S)ꢀ3ꢀMethylꢀ2ꢀtosylaminobutanoyl]ꢀ3ꢀ(1Hꢀindolꢀ
3ꢀyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀone (27). The
yield was 23%, colorless crystalline powder, m.p. 210—211 °C,
μ/mm–1
0.146
F(000)
1176
Crystal size/mm
θ/deg
0.47×0.31×0.26
2.67—33.29
Total number of reflections
measured/independent
Rint
11075/5228
0.0386
Number of observed reflections
with I > 2σ(I)
R1 (I > 2σ(I))
2029
20
Rf = 0.8 (ethyl acetate), [α]D = +616.4 (c = 1.0, DMF).
1H NMR (400 MHz, DMSOꢀd6), δ: 11.03 (d, 1 H, NH, J = 2.1 Hz);
9.70 (d, 1 H, NH, J = 5.3 Hz); 7.97 (d, 1 H, NH, J = 9.1 Hz);
7.89—7.81 (m, 2 H, Ph); 7.75 (d, 1 H, C(4)Hindole, J = 8.0 Hz);
7.50 (d, 2 H, Ts, J = 8.2 Hz); 7.46—7.38 (m, 3 H, Ph); 7.36 (d,
1 H, C(7)Hindole, J = 8.1 Hz); 7.07—7.12 (m, 2 H); 6.97—7.00
0.0402
0.0490
0.196/–0.230
wR2 (I > 2σ(I))
Residual electron
density/e Å–3, ρmax/ρ
min

1000
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Chupakhin et al.
(m, 2 H); 6.87 (d, 2 H, Ts, J = 8.1 Hz); 4.80 (dd, 1 H, CH,
J = 8.9 Hz, J = 6.2 Hz); 2.21 (s, 3 H, CH3); 1.99—2.08 (m,
1 H, CH); 0.88 (d, 3 H, CH3, J = 6.7 Hz); 0.84 (d, 3 H, CH3,
J = 6.7 Hz). Found (%): C, 64.28; H, 5.42; N, 12.85.
C29H29N5O4S. Calculated (%): C, 64.07; H, 5.38; N, 12.88.
(S)ꢀ2ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminopentanoyl]ꢀ3ꢀ(1ꢀmethylꢀ
1Hꢀpyrrolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀ
one (28). The yield was 15%, colorless crystalline powder,
m.p. 196—197 °C, Rf = 0.8 (ethyl acetate). 1H NMR (400 MHz,
DMSOꢀd6), δ: 9.41 (d, 1 H, N(4)H, J = 5.2 Hz); 8.11 (d, 1 H,
NH, J = 8.8 Hz); 7.82—7.85 (m, 2 H, Ph); 7.62 (d, 1 H, Ts,
J = 8.2 Hz); 7.30—7.47 (m, 3 H, Ph); 7.21 (d, 2 H, Ts, J = 8.1 Hz);
6.63 (d, 1 H, C(3)H, J = 5.2 Hz); 6.54 (br.s, 1 H, pyrrole); 6.50
(t, 1 H, pyrrole, J = 2.4 Hz); 5.60—5.69 (m, 1 H, pyrrole);
4.98—4.82 (m, 1 H, CH); 3.58 (s, 3 H, NCH3); 2.40 (s, 3 H,
CH3CO); 1.78—1.61 (m, 1 H, CH); 1.59—1.47 (m, 1 H, CH2);
1.30—1.38 (m, 1 H, CH2); 0.82 (d, 3 H, CH3, J = 6.6 Hz); 0.66
(d, 3 H, CH3, J = 6.5 Hz). Found (%): C, 62.08; H, 5.95; N, 13.36.
C27H31N5O4S. Calculated (%): C, 62.17; H, 5.99; N, 13.43.
(S)ꢀ2ꢀ[(S)ꢀ4ꢀMethylꢀ2ꢀtosylaminobutanoyl]ꢀ3ꢀ(1ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀphenylꢀ3,4ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(2H)ꢀ
one (29). The yield was 32%, colorless crystalline powder,
m.p. 236—237 °C, Rf = 0.8 (ethyl acetate). 1H NMR (400 MHz,
DMSOꢀd6), δ: 9.28 (d, 1 H, NH, J = 5.2 Hz); 7.91—7.94 (m,
3 H, NH+Ph); 7.62 (d, 1 H, C(4)Hindole, J = 8.0 Hz); 7.56 (d,
2 H, Ts, J = 8.2 Hz); 7.44—7.46 (m, 3 H, Ph); 7.28 (d, 1 H,
3ꢀ(1HꢀIndolꢀ3ꢀyl)quinoxalinꢀ2(1H)ꢀone (17). Yellow crysꢀ
talline powder, m.p. > 300 °C (Refs 14 and 15: m.p. >300 °C),
Rf = 0.7 (ethyl acetate). 1H NMR (400 MHz, DMSOꢀd6), δ:
12.27 (br.s, 1 H, NH); 11.54 (br.s, 1 H, NH); 8.90 (d, 1 H,
C(2)Hindole, J = 3.0 Hz); 8.83—8.85 (m, 1 H); 7.82 (d, 1 H,
J = 7.8 Hz); 7.43—7.46 (m, 1 H); 7.28—7.35 (m, 2 H);
7.21—7.26 (m, 1 H); 7.14—7.19 (m, 2 H); 2.59 (s, 3 H, CH3).
Physicoꢀchemical characteristics and spectral data for the
compound obtained agree with those given in Refs 14 and 15.
3ꢀ(2ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)quinoxalinꢀ2(1H)ꢀone (31).
Yellow crystalline powder, m.p. 282—283 °C, Rf = 0.7 (ethyl
1
acetate). H NMR (400 MHz, DMSOꢀd6), δ: 12.17 (br.s, 1 H,
NH); 11.23 (s, 1 H, NH); 7.75 (dd, 2 H, J = 16.6 Hz, J = 7.8 Hz);
7.38 (t, 1 H, J = 7.6 Hz); 7.31 (dd, 2 H, J = 7.7 Hz, J = 4.4 Hz);
7.22 (t, 1 H, J = 7.4 Hz); 7.03 (t, 1 H, J = 7.4 Hz); 6.98 (t, 1 H,
J = 7.4 Hz); 2.59 (s, 3 H, CH3). Found (%): C, 74.05; H, 4.67;
N, 15.18. C17H13N3O. Calculated (%): C, 74.17; H, 4.76; N, 15.26.
Synthesis of compounds 17, 31—33, 36—38 (general proceꢀ
dure). Triethylamine (1.2 mmol) was added to a magnetically
stirred suspension of Nꢀsubstituted amino acid 34 or 35 (1 mmol)
in THF (3 mL) at room temperature. The solution was cooled to
0 °C in an iceꢀwater bath, followed by addition of the correꢀ
sponding chloroformate (1.1 mmol). After 5 min, quinoxalinone
5 (1 mmol) and the corresponding nucleophile (1.1 mmol) were
added. The iceꢀwater bath was removed in 30 min and the
reaction mixture was stirred for 12—18 h at room temperature
(TLC monitoring). A precipitate of unreacted starting comꢀ
pounds was filtered off, the filtrate was concentrated, the residue
was dissolved in chloroform and subjected to chromatographic
separation on a column with silica gel using the ethyl acetate—
chloroform (1 : 1) mixture as an eluent.
C(7)Hindole, J = 8.2 Hz); 7.21—7.07 (m, 4 H, Ts+C(6)Hindole
+
C(2)Hindole); 6.97 (t, 1 H, C(5)Hindole, J = 7.2 Hz); 6.83 (d, 1 H,
J = 5.1 Hz); 4.62 (dd, 1 H, J = 10.0 Hz, J = 7.1 Hz); 3.73 (s, 3 H,
CH3); 2.40 (s, 3 H, CH3); 1.81—1.90 (m, 1 H); 0.81 (d, 3 H,
CH3, J = 6.7 Hz); 0.58 (d, 3 H, CH3, J = 6.7 Hz). Found (%):
C, 64.52; H, 5.55; N, 12.61. C30H31N5O4S. Calculated (%):
C, 64.61; H, 5.60; N, 12.56.
Synthesis of compounds 16 and 30 (general procedure).
1,3,5ꢀTriazinꢀ2,4ꢀdione (4) (1.2 mmol) was added to a solution
of (S)ꢀNꢀTsꢀamino acid acyl chloride (18 and 19) (1.2 mmol)
in THF at –15 °C, after 5 min the corresponding nucleophile
(1.2 mmol) was added to the solution. The mixture was stirred
for 1 h at –15 °C, then the temperature was raised to ambient
over 2 h. A precipitate formed was filtered off, washed with THF
and diethyl ether, and recrystallized from ethanol.
6ꢀ(2ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ[1,3,5]triazinaneꢀ2,4ꢀdione
(30). The yield was 32%, pink crystalline powder, m.p. 188—190 °C.
1H NMR (400 MHz, DMSOꢀd6), δ: 10.86 (s, 1 H, NH); 9.15 (s,
1 H, NH); 7.56—7.58 (m, 3 H); 7.24—7.26 (m, 1 H); 6.92—7.01
(m, 2 H); 5.89 (s, 1 H, C(6)H); 2.40 (s, 3 H, CH3). Found (%):
C, 59.12; H, 5.05; N, 22.98. C12H12N4O2. Calculated (%):
C, 59.01; H, 4.95; N, 22.94.
Synthesis of compounds 17 and 31 (general procedure). The
corresponding quinoxalinꢀ2(1H)ꢀone (5) (1.2 mmol) was added
to a solution of (S)ꢀNꢀTsꢀamino acid acyl chloride (18 and 19)
(1.2 mmol) in THF (10 mL) at –15 °C, after 5 min the corꢀ
responding nucleophile (1.2 mmol) was added to the solution.
The mixture was stirred for 1 h at –15 °C, then the temperature
was raised to ambient over 2 h. The reaction mixture was poured
into cold water and extracted with ethyl acetate (2×20 mL). The
organic layer was washed with water and brine, dried with
calcined Na2SO4. The solution was concentrated, the residue
was dissolved in ethyl acetate and subjected to chromatographic
separation on a column with silica gel using ethyl acetate as
an eluent.
3ꢀ(1ꢀMethylꢀ1Hꢀindolꢀ3ꢀyl)quinoxalinꢀ2(1H)ꢀone (32).
Yellow crystalline powder, m.p. 289—290 °C, Rf = 0.7 (ethyl
1
acetate). H NMR (400 MHz, DMSOꢀd6), δ: 12.34 (br.s, 1 H,
NH); 8.86—8.89 (m, 2 H); 7.82 (d, 1 H, J = 7.9 Hz); 7.45 (d,
1 H, J = 7.3 Hz); 7.21—7.36 (m, 5 H); 3.94 (s, 3 H, CH3).
Found (%): C, 74.12; H, 4.71; N, 15.20. C17H13N3O. Calculꢀ
ated (%): C, 74.17; H, 4.76; N, 15.26.
3ꢀ(1Hꢀ2ꢀPyrrolꢀ2ꢀyl)quinoxalinꢀ2(1H)ꢀone (33). Yellow
crystalline powder, m.p. 242—243 °C, Rf = 0.8 (ethyl acetate).
1H NMR (400 MHz, DMSOꢀd6), δ: 12.39 (s, 1 H, NH); 11.44
(s, 1 H, NH); 7.69 (d, 1 H, J = 7.8 Hz); 7.26—7.40 (m, 3 H);
7.19—7.25 (m, 1 H); 6.99 (dd, 1 H, J = 3.9 Hz, J = 2.5 Hz); 6.19
(dd, 1 H, J = 5.8 Hz, J = 2.4 Hz). Physicoꢀchemical characꢀ
teristics and spectral data of the compound obtained agree with
those given in Ref. 16.
4ꢀ[2ꢀAcetylaminoꢀ4ꢀmethylpentanoyl]ꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ
3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (36). The yield was 6%, colorꢀ
less crystalline powder, m.p. 187—188 °C, Rf = 0.4 (ethyl
1
25
acetate), [α]D = +14.9 (c = 1.0, DMF). H NMR (250 MHz,
DMSOꢀd6), δ: 10.80 (br.s, 1 H, NH); 10.78 (br.s, 1 H, NH);
8.19 (d, 1 H, NH, J = 8.3 Hz); 7.70 (d, 2 H, J = 7.8 Hz);
7.25—7.27 (m, 1 H); 7.13—7.17 (m, 1 H); 7.02—7.06 (m, 2 H);
6.95—6.99 (m, 2 H); 6.69 (d, 1 H, J = 2.0 Hz); 6.50 (s, 1 H);
4.92 (t, 1 H, CH, J = 8.1 Hz); 1.94 (s, 3 H, CH3CO); 1.75—1.83
(m, 1 H, CH); 0.79 (d, 3 H, CH3, J = 6.7 Hz); 0.66 (d, 3 H,
CH3, J = 6.7 Hz).
4ꢀ[2ꢀAcetylaminoꢀ4ꢀmethylpentanoyl]ꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (37). The yield was 4%,
colorless crystalline powder, m.p. >260 °C, Rf = 0.5 (ethyl
acetate). 1H NMR (400 MHz, DMSOꢀd6), δ: 10.91 (s, 1 H,

Synthesis of asymmetric azinones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1001
NH); 10.80 (s, 1 H, NH); 8.13 (d, 1 H, J = 7.6 Hz); 7.53 (d, 1 H,
J = 7.9 Hz); 7.13—7.16 (m, 3 H); 6.94—6.97 (m, 2 H); 6.87 (t,
1 H, J = 7.5 Hz); 6.72 (t, 1 H, J = 7.5 Hz); 6.42 (s, 1 H, C(3)H);
5.05—5.10 (m, 1 H, CH); 2.30 (s, 3 H, CH3); 1.88 (s, 3 H,
CH3); 1.35—1.44 (m, 2 H, CH2); 0.94—1.01 (m, 1 H, CH); 0.61
(d, 3 H, CH3, J = 6.3 Hz); 0.41 (d, 3 H, CH3, J = 6.3 Hz).
4ꢀ[2ꢀAcetylaminoꢀ3ꢀmethylbutanoyl]ꢀ3ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (38). The yield was 4%,
colorless crystalline powder, m.p. >260 °C, Rf = 0.5 (ethyl
acetate). 1H NMR (250 MHz, DMSOꢀd6), δ: 10.76 (s, 1 H,
NH); 8.11 (d, 1 H, NH, J = 7.5 Hz); 7.68—7.72 (m, 2 H);
6.93—7.25 (m, 6 H); 6.84 (s, 1 H); 6.49 (s, 1 H); 4.90—4.97
(m, 1 H, CH); 3.61 (s, 3 H, NCH3); 1.94 (s, 3 H, CH3CO);
1.67—1.87 (m, 1 H, CH); 0.78 (d, 3 H, CH3, J = 6.5 Hz); 0.65
(d, 3 H, CH3, J = 6.5 Hz).
8. G. V. Zyryanov, V. L. Rusinov, O. N. Chupakhin, V. P.
Krasnov, G. L. Levit, M. I. Kodess, T. S. Shtukina, Izv.
Akad. Nauk, Ser. Khim., 2004, 1238 [Russ. Chem. Bull., Int.
Ed., 2004, 53, 1290].
9. I. N. Egorov, B. König, V. L. Rusinov, O. N. Chupakhin,
Mendeleev Commun., 2008, 18, 99.
10. V. L. Rusinov, G. V. Zyryanov, T. L. Pilitcheva, O. N.
Chupakhin, H. Neunhoeffer, J. Heterocycl. Chem., 1997, 34,
1013.
11. Y. A. Azev, Mendeleev Commun., 1997, 7, 164.
12. Cambridge Crystallographic Data Centre (CCDC 724365).
www.ccdc.cam.ac.uk/data_request/cif
13. I. N. Egorov, V. L. Rusinov, P. A. Slepukhin, O. N.
Chupakhin, J. Chem. Cryst., 2010, 40, 387 (CCDC 724265).
14. O. N. Chupakhin, E. O. Sidorov, I. Ya. Postovskii, Khim.
Geterotsikl. Soedin., 1975, 1433 [Chem. Heterocycl. Comp.
(Engl. Transl.), 1975, 10, 1224].
15. K. Aoki, J. Koseki, S. Takeda, M. Aburada, K. Miyamoto,
Chem. Pharm. Bull., 2007, 55, 922.
16. F. Szydlo, B. Andrioletti, E. Rose, C. Duhayon, Tetrahedron
Lett., 2008, 49, 3749.
This work was financially supported by the Ministry of
Science and Education of the Russian Federation (State
Contract 02.512.11.2237).
References
17. V. Uchutilova, P. Fiedler, M. Prystas, J. Gut, Collect. Czech.
Chem. Commun., 1971, 36, 1955.
1. O. N. Chupakhin, V. N. Charushin, H. C. van der Plas,
Nucleophilic Aromatic Substitution of Hydrogen, Academic
Press, SanꢀDiego, 1994, P. 367.
2. I. N. Egorov, G. V. Zyryanov, V. L. Rusinov, O. N.
Chupakhin, Usp. Khim., 2005, 74, 12, 1176 [Russ. Chem.
Rev. (Engl. Transl.), 2005, 74, 1073].
18. I. Lalezari, N. Sharghi, A. Shafiee, M. Yalpani, J. Heterocycl.
Chem., 1969, 403.
19. D. N. Kozhevnikov, V. N. Kozhevnikov, I. S. Kovalev, V. L.
Rusinov, O. N. Chupakhin, G. G. Aleksandrov, Zh. Org.
Khim., 2002, 38, 780 [Russ. J. Org. Chem. (Engl. Transl.),
2002, 780].
3. M. Takamura, K. Funabashi, M. Kanai, M. Shibasaki,
J. Am. Chem. Soc., 2000, 122, 6327.
20. D. G. Beckerman, M. I. Abasolo, B. M. Fernandez,
J. Heterocycl. Chem., 1992, 29, 129.
4. K. Funabashi, H. Ratni, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc., 2001, 123, 10784.
5. D. L. Comins, J. Heterocycl. Chem., 1999, 36, 1491.
6. O. Sieck, M. Ehwald, J. Liebscher, Eur. J. Org. Chem., 2005,
663.
7. I. N. Egorov, G. V. Zyryanov, E. N. Ulomsky, V. L. Rusinov,
O. N. Chupakhin, Tetrahedron Lett., 2006, 47, 7485.
Received June 11, 2009;
in revised form March 23, 2010