Synthesis of novel spiro[indole-3,3'-pyrrolidin]-2(1H)-ones

Article abstract of DOI:10.1007/s11172-014-0449-2

Diastereoselective [3+2] cycloaddition of azomethine ylide to 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-[1,2,4]triazine-2,7(1H,6H)-dione yields hitherto unknown 1,1',3-trimethyl-

Full text of DOI:10.1007/s11172-014-0449-2

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 431—434, February, 2014
431
Synthesis of novel spiro[indoleꢀ3,3´ꢀpyrrolidin]ꢀ2(1H)ꢀones*
G. A. Gazieva, N. G. Kolotyrkina, A. N. Kravchenko, and N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: gaz@ioc.ac.ru
Diastereoselective [3+2] cycloaddition of azomethine ylide to 1,3ꢀdimethylꢀ6ꢀ(2ꢀoxoꢀ1,2ꢀ
dihydroꢀ3Hꢀindolꢀ3ꢀylidene)ꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydroimidazo[4,5ꢀe]thiazolo[3,2ꢀb]ꢀ
[1,2,4]triazineꢀ2,7(1H,6H)ꢀdione yields hitherto unknown 1,1´,3ꢀtrimethylꢀ3a,9aꢀdiphenylꢀ
3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ
4´,3ꢀindole)ꢀ2,2,7(1H,1H)ꢀtriones.
Key words: [3+2] cycloaddition, azomethine ylides, 3,3a,9,9aꢀtetrahydroimidazo[4,5ꢀe]thiꢀ
azolo[3,2ꢀb][1,2,4]triazines, tetrahydrodispiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀ
pyrrolidineꢀ4´,3ꢀindoles), spiro[indoleꢀ3,3´ꢀpyrrolidin]ꢀ2(1H)ꢀones, threeꢀcomponent reaction.
Scheme 1
Isatin and its derivatives exhibit wide range of biologiꢀ
cal activity, e.g., they affect the central nervous system,
inhibit tumor growth, exert anticonvulsant, antiviral, anꢀ
tibacterial, and antifungal effects.1 These compounds are
extensively used in the syntheses of different heterocycles
including analogs of natural alkaloids bearing spiro[indoleꢀ
3,´3ꢀpyrrolidin]ꢀ2(1H)ꢀone fragment (horsfiline, coerꢀ
ulescine, and ets.).2—7 One of the most efficient methods
to access spiroindolepyrrolidine derivatives is [3+2] dipoꢀ
lar cycloaddition of azomethine ylides to isatinꢀ3ꢀylidene
derivatives.3—7
The present work is devoted to the synthesis of novel
fused polycyclic dispiroheterocycles containing the oxoꢀ
indole, pyrrolidine, thiazolidine, imidazolidine, and triꢀ
azine moieties. Earlier, we demonstrated the principal posꢀ
sibility of cycloaddition of azomethine ylide generated
in situ from paraformaldehyde and sarcosine to 6ꢀ(2ꢀoxoꢀ
1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀylidene)ꢀ3a,9aꢀdiphenylꢀ
3,3a,9,9aꢀtetrahydroimidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]ꢀ
triazineꢀ2,7(1H,6H)ꢀdiones 1.8 It should be emphasized
that these dipolarophiles are the fused polycyclic comꢀ
pounds bearing bulky substituents.
Compounds 1a—h were synthesized in 61—89% yields
by either acidꢀ (1a—d)9a or baseꢀ (1e—h)9b catalyzed conꢀ
densation of 1,3ꢀdimethylꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀ
tetrahydroimidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ
2,7(1H,6H)ꢀdione (2) with the corresponding isatins 3a—h
following the previously developed procedures (Scheme 1).
The reactions diastereoselectively give Zꢀisomers.
1, 3: R = H (a), Me (b), Et (c), Bu (d), All (e), 4ꢀClC6H4CH2 (f),
H2COOEt (g), CH(Me)COOEt (h)
Reagents and conditions: AcOH (for 1a—d) or KOH, MeOH
(for 1e—h), heating.
reaction between compounds 1a—h, sarcosine (4 equiv.),
and paraformaldehyde (4 equiv.). Azomethine ylide 55—8,10
generated in situ from sarcosine and paraformaldehyde
upon refluxing in toluene undergoes subsequent [3+2]ꢀ
dipolar cycloaddition to dipolarophiles 1a—h (Scheme 2).
The completeness of the reaction is monitored by
both the complete discoloration of the reaction mixture
(initially, the toluene solutions of compounds 1a—h are
redꢀorange) and precipitation of the target products 4 obꢀ
tained in 52—74% isolated yields (Scheme 2).
Compounds 4a—h bearing spiro[indoleꢀ3,3´ꢀpyrrolidin]ꢀ
2(1H)ꢀone moiety are synthesized by threeꢀcomponent
Similar reaction of compound 1a bearing no substituꢀ
ent at the indole nitrogen atom unexpectedly gives comꢀ
pound 4a. In this case, not only cycloaddition of azomeꢀ
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of
Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0431—0434, February, 2014.
1066ꢀ5285/14/6302ꢀ0431 © 2014 Springer Science+Business Media, Inc.

432
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Gazieva et al.
Scheme 2
1: R = H (a),
4: R = CH2NMe2 (a),
1, 4: R = Me (b), Et (c), Bu (d), All (e), 4ꢀClC6H4CH2 (f), CH2COOEt (g), CH(Me)COOEt (h)
Reagents and conditions: toluene, reflux.
thine ylide at the double bond but also aminomethylation
at the indole nitrogen occur. 1H NMR spectrum of comꢀ
pound 4a contains no signal of the NH indole proton but
exhibits singlet signal of the NMe2 group at  2.29 and two
doublets of the NCH2 group at  4.36 and 4.45. Apparently,
azomethine ylide first undergoes aminomethylation folꢀ
lowed by the addition at the double bond, since prolonged
time is required for the discoloration of the reaction mixꢀ
ture (10 h vs. 1—3 h for other derivatives).
Compounds 4 are obtained as nearly one diastereomer.
Taking into account that no Z,Eꢀisomerization around
the double bond of reactants 1 occurs and considering
possible endo and exo approaches of azomethine ylide to
the plane of the dipolarophile double bond from the side
opposite to the phenyl groups as well as from the phenyl
group side, two cycloaddition diastereomers 4 and 4´ difꢀ
fering by chemical shifts can be predicted.
(compounds 4e—h). The highest content of the minor
diastereomer 4´e (17% according to the H NMR specꢀ
1
trum of the concentrated reaction mixture) is observed in
the reaction of azomethine ylide with N´ꢀallyl derivative 1e.
Fractional crystallization of a mixture of diastereomers 4e
and 4´e (obtained by concentration of the filtrates) from
benzene affords compound 4´e (R = All) in 8% yield.
According to Xꢀray diffraction of 4b,9a azomethine ylide
adds at the double bond of 1b from the side opposite the
one in which the phenyl substituents are directed (Fig. 1).
In summary, we elaborated versatile and efficient diaꢀ
stereoselective procedure to access dispiro heterocyclic
compounds bearing the spiro[iodoleꢀ3,3´ꢀpyrrolidin]ꢀ
2(1H)ꢀone fragment.
C(43)
N(41)
C(40)
C(42)
S(27)
O(38)
C(39)
N(31)
C(28)
C(26)
O(37)
C(30)
C(36)
C(25)
C(29)
C(33)
N(7)
C(8)
C(23)
O(24)
C(34)
N(6)
C(2)
C(35)
N(1)
N(9)
C(3)
C(5)
C(10)
C(17)
N(4)
C(22)
C(15)
C(16)
C(21)
C(18)
C(11)
1H and 13C NMR spectra of precipitated crystalline
products 4a—h contain only one set of the signals. In
1H NMR spectra of the concentrated filtrates of the reacꢀ
tion mixtures, the signals of other diastereomers are either
almost absent (compounds 4a—d) or of low intensity
C(12)
C(14)
C(13)
C(19)
C(20)
Fig. 1. Geometry of compound 4b.

Spiro[indoleꢀ3,3´ꢀpyrrolidines]
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
433
(ESI), m/z: [M + H]+, found 609.1919, calculated 609.1915.
C32H28N6O5S.
Experimental
NMR spectra were recorded on a Bruker AMꢀ300 spectromꢀ
eter (1H, 300.13 MHz and 13C, 75.5 MHz) in DMSOꢀd6, the
chemical shifts are given in the ꢀscale relative to Me4Si (interꢀ
nal standard). High resolution electrospray ionization mass specꢀ
tra were recorded on a Bruker micrOTOF II instrument11 operꢀ
ating in the positive ion mode (capillary voltage is 4500 V). The
massꢀtoꢀcharge (m/z) ratio ranges from 50 to 3000 Da. Both
internal and external calibrations were accomplished with Elecꢀ
trospray Calibrant Solution (Fluka). A solution of the sample in
MeCN or MeOH was injected via syringe, injection rate was
3 L min–1, nebulizing gas was nitrogen (4 L min–1), inlet temꢀ
perature was 180 C.
Ethyl (Z)ꢀ2ꢀ[3ꢀ(1,3ꢀdimethylꢀ2,7ꢀdioxoꢀ3a,9aꢀdiphenylꢀ
1,2,3,3a,9,9aꢀhexahydroimidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]ꢀ
triazinꢀ6(7H)ꢀylidene)ꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ1ꢀyl]propꢀ
ionate (1h). Yield 55%, m.p. 263—266 C. 1H NMR, : 1.15
(t, 3 H, CH3, J = 6.9 Hz); 1.60 (d, 3 H, CH3, J = 7.0 Hz); 2.64
(s, 3 H, N(3)CH3); 2.65 (s, 3 H, N(1)CH3); 4.16 (q, 2 H, OCH2,
J = 6.9 Hz); 5.33 (q, 1 H, NCH, J = 7.0 Hz); 6.76 (d, 2 H,
J = 7.1 Hz); 6.83 (d, 2 H, J = 7.1 Hz); 7.05—7.23 (m, 8 H); 7.49
(t, 1 H, H(6´) of indole, J = 7.6 Hz); 7.87 (d, 1 H, NH, J = 5.1 Hz);
8.95 (d, 1 H, H(4´) of indole, J = 7.9 Hz). MS (ESI), m/z:
[M + H]+, found 623.2066, calculated 623.2071. C33H30N6O5S.
1,1´,3ꢀTrimethylꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydrodiꢀ
spiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidꢀ
ineꢀ4´,3ꢀindole)ꢀ2,2,7(1H,1H)ꢀtriones 4a—h and 4´e (general
procedure). A suspension of the corresponding compound 1a—h
(0.5 mmol), sarcosine (0.18 g, 2 mmol), and paraformaldehyde
(0.06 g, 2 mmol) in toluene (10 mL) was refluxed for 1—3 h (10 h
for 4a) until clear solution was formed and initial orangeꢀred
color disappeared. For compounds 4b,c, the precipitate formed
1.5—2 h after reaction onset. For compounds 4a,d—h, the reacꢀ
tion mixture was cooled down, filtered to remove the fine preꢀ
cipitate, and kept at room temperature for 1—2 days. Then, the
precipitate formed was filtered, washed with toluene and water,
and dried. For compound 4e, the filtrate was concentrated
in vacuo until precipitation, the precipitate was recrystallized
from benzene. The first precipitate obtained by recrystallization
from benzene was a mixture of isomers 4e and 4´e in an 1 : 2
ratio, the second precipitate was a pure compound 4´e.
Melting points were determined on a GALLENKAMP apꢀ
paratus (Sanyo).
Compound 2 was synthesized from bromoacetic acid and
5,7ꢀdimethylꢀ4a,7aꢀdiphenylꢀ3ꢀthioxoperhydroimidazo[4,5ꢀe]ꢀ
[1,2,4]triazinꢀ6ꢀone,12 which, in turn, was obtained from 1,3ꢀ
dimethylꢀ4,5ꢀdihydroxyꢀ4,5ꢀdiphenylimidazolidinꢀ2ꢀone and thioꢀ
semicarbazide.13 1,3ꢀDimethylꢀ4,5ꢀdihydroxyꢀ4,5ꢀdiphenylꢀ
imidazolidinꢀ2ꢀone was synthesized according to the known procedꢀ
ure from commercially available 1,3ꢀdimethylurea and benzyl.14
(Z)ꢀ1,3ꢀDimethylꢀ6ꢀ(2ꢀoxoꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀylidꢀ
ene)ꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydroimidazo[4,5ꢀe]thiazoloꢀ
[3,2ꢀb][1,2,4]triazineꢀ2,7(1H,6H)ꢀdiones 1e—h (general proceꢀ
dure). To a solution (or suspension) of imidazothiazolotriazine 2
(0.39 g, 1 mmol) and the corresponding isatin 3e—h (1 mmol) in refꢀ
luxing MeOH (20 mL), 40% aqueous KOH (0.05 mL) was addꢀ
ed. The stirred reaction mixture was refluxed for 1—2 h and then
kept at room temperature for 16 h. Filtration of the precipitate
formed followed by recrystallization from ethyl acetate—proꢀ
paneꢀ2ꢀol, 3 : 2 (if required), affords the target products 1e—h.
(Z)ꢀ6ꢀ(1ꢀAllylꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ3ꢀylidene)ꢀ1,3ꢀ
dimethylꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydroimidazo[4,5ꢀe]ꢀ
thiazolo[3,2ꢀb][1,2,4]triazineꢀ2,7(1H,6H)ꢀdione (1e). Yield
(3aR*,4´S*,6R*,9aS*)ꢀ1ꢀDimethylaminomethylꢀ1,1´,3ꢀtriꢀ
methylꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazoꢀ
[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀinꢀ
dole)ꢀ2,2,7(1H,1H)ꢀtrione (4a). Yield 69%, m.p. 249—251 C.
1H and 13C NMR spectra and a high resolution mass spectrum
were published earlier.8
1
66%, m.p. 321—323 C. H NMR, : 2.64 (s, 3 H, N(3)CH3);
(3aR*,4´S*,6R*,9aS*)ꢀ1,1´,1,3ꢀTetramethylꢀ3a,9aꢀdipheꢀ
nylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb]ꢀ
[1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ2,2,7(1H,1H)ꢀ
2.66 (s, 3 H, N(1)CH3); 4.49 (d, 2 H, NCH2, J = 4.1 Hz); 5.19
(m, 2 H, CH2); 5.87—5.96 (m, 1 H, CH); 6.77 (d, 2 H, J = 7.2 Hz);
6.84 (d, 2 H, J = 7.3 Hz); 7.06—7.20 (m, 8 H); 7.47 (t, 1 H,
H(6´) of indole, J = 7.6 Hz); 7.84 (s, 1 H, NH); 8.91 (d, 1 H,
H(4´) of indole, J = 7.8 Hz). MS (ESI), m/z: [M + H]+, found
563.1848, calculated: 563.1860. C31H26N6O3S.
(Z)ꢀ1,3ꢀDimethylꢀ6ꢀ[2ꢀoxoꢀ1ꢀ(4ꢀchlorobenzyl)ꢀ1,2ꢀdihydroꢀ
3Hꢀindolꢀ3ꢀylidene]ꢀ3a,9aꢀdiphenylꢀ3,3a,9,9aꢀtetrahydroimidꢀ
azo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ2,7(1H,6H)ꢀdione (1f).
Yield 67%, m.p. 320—322 C. 1H NMR, : 2.64 (s, 3 H,
N(3)CH3); 2.65 (s, 3 H, N(1)CH3); 5.08 (dd, 2 H, NCH2,
J = 19.4 Hz, J = 16.2 Hz); 6.76 (d, 2 H, J = 6.9 Hz); 6.84 (d, 2 H,
J = 7.2 Hz); 7.06—7.18 (m, 8 H,); 7.37—7.44 (m, 5 H, H(6´) of
indole, 4ꢀClC6H4); 7.87 (s, 1 H, NH); 8.91 (d, 1 H, H(4´) of
indole, J = 7.8 Hz). MS (ESI), m/z: [M + H]+, found 647.1625,
calculated 647.1627. C35H27ClN6O3S.
1
trione (4b). Yield 67%, m.p. 280—282 C. H and 13C NMR
spectra and a high resolution mass spectrum were published earlier.8
(3aR*,4´S*,6R*,9aS*)ꢀ1ꢀEthylꢀ1,1´,3ꢀtrimethylꢀ3a,9aꢀ
diphenylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazoloꢀ
[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ2,2,7ꢀ
(1H,1H)ꢀtrione (4c). Yield 52%, m.p. 180—182 C. 1H and
13C NMR spectra and a high resolution mass spectrum were
published earlier.8
(3aR*,4´S*,6R*,9aS*)ꢀ1ꢀButylꢀ1,1´,3ꢀtrimethylꢀ3a,9aꢀ
diphenylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazoloꢀ
[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ2,2,7ꢀ
(1H,1H)ꢀtrione (4d). Yield 59%, m.p. 240—242 C. 1H and
13C NMR spectra and a high resolution mass spectrum were
published earlier.8
Ethyl (Z)ꢀ2ꢀ[3ꢀ(1,3ꢀdimethylꢀ2,7ꢀdioxoꢀ3a,9aꢀdiphenylꢀ
1,2,3,3a,9,9aꢀhexahydroimidazo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]ꢀ
triazinꢀ6(7H)ꢀylidene)ꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ3Hꢀindolꢀ1ꢀyl]acetate
(3aR*,4´S*,6R*,9aS*)ꢀ1ꢀAllylꢀ1,1´,3ꢀtrimethylꢀ3a,9aꢀdiꢀ
phenylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb]ꢀ
[1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ2,2,7(1H,1H)ꢀ
trione (4e). Yield 64%, m.p. 263—265 C. 1H NMR, : 2.49 (s, 3 H,
NCH3); 2.56 (s, 3 H, NCH3); 2.64 (s, 3 H, NCH3); 3.23 (d, 1 H,
N(1´)CH2, J = 10.3 Hz); 3.49—3.59 (m, 2 H, N(1´)CH2); 3.80
(d, 1 H, N(1´)CH2, J = 10.6 Hz); 4.29—4.49 (m, 2 H, N(1)CH2);
5.17—5.30 (m, 2 H, CH2); 5.82—5.95 (m, 1 H, CH); 6.11 (d, 2 H,
J = 7.7 Hz); 6.63 (d, 2 H, J = 7.5 Hz); 6.91 (t, 2 H, J = 7.7 Hz);
1
(1g). Yield 61%, m.p. 262—265 C. H NMR, : 1.23 (t, 3 H,
CH3, J = 7.0 Hz); 2.64 (s, 3 H, N(3)CH3); 2.66 (s, 3 H,
N(1)CH3); 4.18 (q, 2 H, OCH2, J = 7.0 Hz); 4.75 (s, 2 H,
NCH2); 6.77 (d, 2 H, J = 7.1 Hz); 6.84 (d, 2 H, J = 7.4 Hz);
7.05—7.21 (m, 8 H); 7.47 (t, 1 H, H(6´) of indole, J = 7.4 Hz);
7.79 (s, 1 H, NH); 8.91 (d, 1 H, H(4´) of indole, J = 7.9 Hz). MS

434
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Gazieva et al.
7.03—7.25 (m, 6 H); 7.37 (d, 1 H, J = 7.5 Hz); 7.58 (t, 1 H,
J = 7.7 Hz); 8.04 (s, 1 H, NH). 13C NMR, : 25.23, 25.89
(N(1,3)CH3); 41.64 (N(1)CH2); 41.97 (N(1´)CH3); 60.76,
60.94, 61.16, 61.76, (N(1´)CH2, C(4´), C(6)); 78.93, 83.02
(C(3a), C(9a)); 109.52, 117.07, 122.62, 124.41, 126.81, 127.00,
127.11, 127.53, 128.08, 128.79, 129.66, 131.49, 133.72, 134.53,
143.88 (indole, Ph); 145.94 (C=N); 159.20, 166.08, 175.74
(C=O). MS (ESI), m/z: [M + H]+, found 620.2443, calculated
620.2438. C34H33N7O3S.
(3aR*,4´R*,6S*,9aS*)ꢀ1ꢀAllylꢀ1,1´,3ꢀtrimethylꢀ3a,9aꢀdiꢀ
phenylꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]thiazolo[3,2ꢀb]ꢀ
[1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ2,2,7(1H,1H)ꢀ
trione (4´e). Yield 17%, m.p. 194—196 C. 1H NMR, : 2.36 (s, 3 H,
NCH3); 2.44 (s, 3 H, NCH3); 2.55 (s, 3 H, NCH3); 3.21 (d, 1 H,
N(1´)CH2, J = 9.9 Hz); 3.56—3.65 (m, 2 H, N(1´)CH2); 3.87
(d, 1 H, N(1´)CH2, J = 10.9 Hz); 4.38 (br.s, 2 H, N(1)CH2);
5.19 (d, 2 H, CH2, J = 13.0 Hz); 5.85—5.93 (m, 1 H, CH); 6.64
(d, 2 H, J = 6.9 Hz); 6.71 (d, 2 H, J = 7.0 Hz); 7.03—7.19 (m, 8 H);
7.27 (d, 1 H, J = 6.5 Hz); 7.38 (t, 1 H, J = 7.4 Hz); 7.49 (s, 1 H,
NH). 13C NMR, : 25.18, 25.67 (N(1,3)CH3); 41.58 (N(1)CH2);
41.95 (N(1´)CH3); 59.90, 61.54, 62.65, 65.14, (N(1´)CH2, C(4´),
C(6)); 79.09, 80.99 (C(3a), C(9a)); 109.69, 117.08, 122.76,
123.68, 124.79, 126.04, 127.17, 127.61, 127.71, 127.90, 128.10,
129.56, 131.45, 134.06, 134.89, 143.56 (indole, Ph); 147.74
(C=N); 158.79, 167.42, 176.11 (C=O). MS (ESI), m/z: [M + H]+,
found 620.2441, calculated 620.2438. C34H33N7O3S.
(3aR*,4´S*,6R*,9aS*)ꢀ1,1´,3ꢀTrimethylꢀ3a,9aꢀdiphenylꢀ1ꢀ
(1ꢀoxoꢀ1ꢀethoxypropꢀ2ꢀyl)ꢀ3,3a,9,9aꢀtetrahydrodispiro(imidꢀ
azo[4,5ꢀe]thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀ
indole)ꢀ2,2,7(1H,1H)trione (4h). Yield 74%, m.p. 183—185 C.
1H NMR, : 1.15 (t, 3 H, CH3, J = 7.0 Hz); 1.54 (d, 3 H, CH3,
J = 7.0 Hz); 2.49 (s, 3 H, NCH3); 2.56 (s, 3 H, NCH3); 2.65
(s, 3 H, NCH3); 3.17 (d, 1 H, N(1´)CH2, J = 10.1 Hz); 3.51 (d, 1 H,
N(1´)CH2, J = 10.6 Hz); 3.59 (d, 1 H, N(1´)CH2, J = 10.1 Hz);
3.78 (d, 1 H, N(1´)CH2, J = 10.6 Hz); 4.16 (q, 2 H, OCH2,
J = 7.0 Hz); 5.22 (q, 1 H, NCH, J = 7.0 Hz); 6.14 (d, 2 H,
J = 7.6 Hz); 6.64 (d, 2 H, J = 7.6 Hz); 6.93 (t, 2 H, J = 7.6 Hz);
7.06—7.19 (m, 6 H); 7.38 (d, 1 H, J = 7.5 Hz); 7.59 (t, 1 H,
J = 7.6 Hz); 8.02 (s, 1 H, NH). 13C NMR, : 13.96, 21.07 (CH3);
25.36, 25.98, 42.02 (N(1,3,1´)CH3); 48.77 (N(1)CH); 60.61,
60.87, 61.25, 61.38, 61.99 (N(1´)CH2, C(4´), C(6), OCH2);
79.08, 83.05 (C(3a), C(9a)); 109.72, 122.86, 122.93, 124.82,
125.34, 126.93, 127.14, 127.26, 127.68, 127.75, 128.23, 128.93,
129.84, 133.85, 134.67, 142.86 (indole, Ph); 146.17 (C=N);
159.33, 166.19, 169.48, 175.66 (C=O). MS (ESI), m/z: [M + H]+,
found 680.2651, calculated 680.2650. C36H37N7O5S.
This work was financially supported by the Division of
Chemistry and Materials Science of the Russian Academy
of Sciences (Basic Research Program "Medicinal Chemꢀ
istry" OKhNMꢀ9).
References
(3aR*,4´S*,6R*,9aS*)ꢀ1,1´,3ꢀTrimethylꢀ3a,9aꢀdiphenylꢀ1ꢀ
(4ꢀchlorobenzyl)ꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]ꢀ
thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ
2,2,7(1H,1H)trione (4f). Yield 68%, m.p. 255—257 C. 1H NMR,
: 2.51 (s, 3 H, NCH3); 2.57 (s, 3 H, NCH3); 2.65 (s, 3 H,
NCH3); 3.27 (d, 1 H, N(1´)CH2, J = 10.0 Hz); 3.52—3.59 (m, 2 H,
N(1´)CH2); 3.82 (d, 1 H, N(1´)CH2, J = 10.6 Hz); 4.99 (s, 2 H,
N(1)CH2); 6.11 (d, 2 H, J = 7.7 Hz); 6.63 (d, 2 H, J = 7.6 Hz);
6.89 (t, 2 H, J = 7.6 Hz); 7.04—7.18 (m, 6 H); 7.34—7.45 (m, 5 H);
7.52 (t, 1 H, J = 7.7 Hz); 8.03 (s, 1 H, NH). 13C NMR, : 25.26,
25.88, 41.95 (N(1,3,1´)CH3); 42.24 (N(1)CH2); 60.96, 61.07,
61.38, 61.82 (N(1´)CH2, C(4´), C(6)); 78.97, 83.00 (C(3a),
C(9a)); 109.57, 122.79, 122.87, 124.65, 125.21, 126.81, 127.02,
127.11, 127.56, 128.10, 128.53, 128.80, 129.20, 129.75, 132.05,
133.72, 134.49, 134.94, 143.64 (Carom); 145.94 (C=N); 159.19,
166.06, 176.21 (C=O). MS (ESI), m/z: [M + H]+, found
704.2198, calculated 704.2205. C38H34ClN7O3S.
(3aR*,4´S*,6R*,9aS*)ꢀ1,1´,3ꢀTrimethylꢀ3a,9aꢀdiphenylꢀ1ꢀ
(2ꢀoxoꢀ2ꢀethoxyethyl)ꢀ3,3a,9,9aꢀtetrahydrodispiro(imidazo[4,5ꢀe]ꢀ
thiazolo[3,2ꢀb][1,2,4]triazineꢀ6,3´ꢀpyrrolidineꢀ4´,3ꢀindole)ꢀ
2,2,7(1H,1H)ꢀtrione (4g). Yield 53%, m.p. 241—243 C.
1H NMR, : 1.17 (t, 3 H, CH3, J = 7.0 Hz); 2.49 (s, 3 H, NCH3);
2.56 (s, 3 H, NCH3); 2.64 (s, 3 H, NCH3); 3.17 (d, 1 H,
N(1´)CH2, J = 10.1 Hz); 3.50 (d, 1 H, N(1´)CH2, J = 10.6 Hz);
3.59 (d, 1 H, N(1´)CH2, J = 10.1 Hz); 3.78 (d, 1 H, N(1´)CH2,
J = 10.6 Hz); 4.14 (q, 2 H, OCH2, J = 7.0 Hz); 4.62 (m, 2 H,
NCH2); 6.15 (d, 2 H, J = 7.6 Hz); 6.64 (d, 2 H, J = 7.6 Hz); 6.90
(t, 2 H, J = 7.6 Hz); 7.04—7.19 (m, 6 H); 7.38 (d, 1 H, J = 7.5 Hz);
7.56 (t, 1 H, J = 7.6 Hz); 7.85 (s, 1 H, NH). 13C NMR, : 13.94
(CH3); 25.29, 25.88 (N(1,3)CH3); 41.21 (N(1)CH2); 41.98
(N(1´)CH3); 60.90, 60.96, 61.16, 61.22, 61.57 (N(1´)CH2, C(4´),
C(6), OCH2); 78.96, 83.01 (C(3a), C(9a)); 109.33, 122.46,
122.96, 124.47, 126.85, 127.08, 127.17, 127.62, 127.68, 128.17,
129.76, 133.73, 134.50, 143.81 (indole, Ph); 146.09 (C=N);
159.29, 166.12, 167.46, 176.18 (C=O). MS (ESI), m/z: [M + H]+,
found 666.2491, calculated 666.2493. C35H35N7O5S.
1. A. Medvedev, O. Buneeva, V. Glover, Biol.: Targets Ther.,
2007, 1, 151.
2. M. G.ꢀA. Shvekhgeimer, Chem. Heterocycl. Compd. (Engl. Transl.),
2004, 40, 257 [Khim. Geterotsikl. Soedin., 2004, 323].
3. C. Marti, E. M. Carreira, Eur. J. Org. Chem., 2003, 2209.
4. C. V. Galliford, K. A. Scheidt, Angew. Chem., Int. Ed., 2007,
46, 8748.
5. A. A. Shvets, S. V. Kurbatov, Russ. Chem. Bull. (Int. Ed.),
2010, 59, 1979 [Izv. Akad. Nauk, Ser. Khim., 2010, 1928].
6. A. A. Shvets, S. V. Kurbatov, Russ. J. Org. Chem.
(Engl. Transl.), 2010, 46, 306 [Zh. Org. Khim., 2010, 46, 309].
7. A. A. Shvets, S. V. Kurbatov, Chem. Heterocycl. Compd.
(Engl. Transl.), 2009, 45, 866 [Khim. Geterotsikl. Soedin.,
2009, 1087].
8. A. N. Kravchenko, P. A. Poluboyarov, S. V. Vasilevskii, G. A.
Gazieva, Yu. V. Nelyubina, Mendeleev Commun., 2012, 22, 90.
9. (a) S. V. Vasilevskii, Yu. V. Nelyubina, N. G. Kolotyirkina,
P. A. Belyakov, L. B. Kulikova, A. N. Kravchenko, Menꢀ
deleev Commun., 2010, 20, 285; (b) G. A. Gazieva, E. A.
Shishkova, L. B. Kulikova, N. G. Kolotyrkina, N. V. Sigay,
A. N. Kravchenko, J. Heterocycl. Chem., 2014, 51, 921.
10. V. Nair, K. C. Sheela, N. P. Rath, Chem. Lett., 2000, 29, 980.
11. P. A. Belyakov, V. I. Kadentsev, A. O. Chizhov, N. G. Koloꢀ
tyrkina, A. S. Shashkov, V. P. Ananikov, Mendeleev Comꢀ
mun., 2010, 20, 125.
12. S. V. Vasilevskii, P. A. Belyakov, G. A. Gazieva, Yu. V.
Nelyubina, N. G. Kolotyrkina, A. N. Kravchenko, Menꢀ
deleev Commun., 2010, 20, 47.
13. A. S. Sigachev, A. N. Kravchenko, K. A. Lyssenko, P. A.
Belyakov, O. V. Lebedev, N. N. Makhova, Mendeleev Comꢀ
mun., 2003, 13, 190.
14. R. G. Neville, J. Org. Chem., 1958, 23, 1588.
Received October 28, 2013;
in revised form December 5, 2013