Synthesis and reactions of 5-methylthieno[2′,3′:5,6]pyrimido- [2,1-a]isoindol-4(5h)-one

Article abstract of DOI:10.1135/cccc20080247

The reaction of 2-(bromomethyl)benzonitrile with methyl 3-aminothiophene-2-carboxylate results in two tautomeric thienopyrimidoisoindolones. Their methylation yields 5-methylthieno[2′, 3′:5,6]pyrimido[2,1-a]isoindol-4(5H)-one which reacts with N-substituted maleimides and dimethyl acetylenedicarboxylate.

Full text of DOI:10.1135/cccc20080247

Thienopyrimidoisoindolones
247
SYNTHESIS AND REACTIONS OF 5-METHYLTHIENO[2′,3′:5,6]PYRIMIDO-
[2,1-a ]ISOINDOL-4(5H)-ONE
a2
b
Andriy I. KYSILa1,*, Zoia V. VOITENKO and Jean-Gérard WOLF
a
Taras Shevchenko National University, 64 Volodymyrska Str., 01033 Kiev, Ukraine;
e-mail: kysil425@mail.ru, z_voitenko@mail.univ.kiev.ua
Université Paul Sabatier, SPCMIB UMR CNRS No. 5068, 118 route de Narbonne,
31062 Toulouse cedex 9, France; e-mail: wolf@chimie.ups-tls.fr
1
2
b
Received Decem ber 1, 2007
Accepted February 15, 2008
Publish ed on lin e March 7, 2008
Th e reaction of 2-(brom om eth yl)ben zon itrile with m eth yl 3-am in oth ioph en e-2-carboxylate
results in two tautom eric th ien opyrim idoisoin dolon es. Th eir m eth ylation yields 5-m eth yl-
th ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e wh ich reacts with N-substituted m ale-
im ides an d dim eth yl acetylen edicarboxylate.
Keyw ord s: Cycloaddition s; Heterocycles; Th ien opyrim idoisoin dolon e; Isoin dols, Maleim ides;
Isoin dolin es tautom ers; 7-Azan orborn en es.
Fused isoin doles are less in vestigated th an sim ple isoin dole system s1–3 an d
followin g th e literature data4–7, th ey are scarcely studied. Num erous practi-
cal application s of th eir derivatives as an tidepressan ts, an algesics, an ti-
in flam m atory agen ts, an tifun gals, an tipyretics, an orexigen ics, an tih yper-
ten sives8,9, an tim alarials10 an d h erbicides11,12 are kn own . From th e syn -
th etic poin t of view, th e m ost in terestin g an d ch allen gin g properties of
arom atic 10π-electron ic system s of sim ple isoin doles is th eir ability to react
with th e dien oph iles1–3,13,14 leadin g to th e endo- or exo-Diels–Alder adducts.
Moreover, com petitive Mich ael addition products are form ed un der sim ilar
con dition s15,16. Th e products of th ese reaction s are eith er 1:1 Diels–Alder
adducts or 1:2 Mich ael–Diels–Alder adducts, wh ich h ave n ot been obtain ed
so far from sim ple isoin dole system s7,17–20
.
Herein we wish to report th e syn th esis of 5-m eth ylth ien o[2′,3′:5,6]-
pyrim ido[2,1-a]isoin dol-4(5H)-on e an d its reaction s with m aleim ide deriva-
tives an d dim eth yl acetylen edicarboxylate.
It is kn own 4,21 th at th e com m on m eth od of buildin g th e pyrim ido[2,1-a]-
isoin dol-2(6H)-on e m oiety is based on th e reaction of 2-(brom om eth yl)-
ben zon itrile 1 with com poun ds possessin g an o-am in oaren ecarboxylate
fragm en t. Furth er alkylation of pyrim ido[2,1-a]isoin dol-2(6H)-on e with
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© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20080247

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Kysil, Voitenko, Wolf:
alkyl tosylates leads to th e form ation of N-alkyl salts, wh ich can be tran s-
form ed to isoin doles by base treatm en t22–24
.
RESULTS AND DISCUSSION
Synthesis and Structure Determination
Th e reaction of 1 with m eth yl 3-am in oth ioph en e-2-carboxylate (2) was car-
ried out followin g th e literature procedures described for an alogous tran s-
form ation s22–24 (Sch em e 1). Th e reaction yields th ien o[2′,3′:5,6]pyrim ido-
[2,1-a]isoin dol-4(10H)-on e (3) togeth er with its tautom er 4. Com poun ds 3
an d 4 were isolated an d ch aracterized. Such type of tautom erism was n ot
observed for th e pyrim ido[2,1-a]isoin dol-2(6H)-on e25
.
SCHEME 1
Th e m ass spectra of com poun ds 3 an d 4 exh ibit in ten sive peaks at m/z
241 (MH+).
Th e IR spectrum of 3 displays an in ten sive absorption ban d of th e pyrim i-
din e carbon yl group νC=O = 1597 cm –1 in addition to νC=N = 1500 cm –1. In
con trast, th e carbon yl group of com poun d 4 of th e pyrim idin e m oiety ab-
sorbs at 1691 cm –1
.
Com plete assign m en t of th e 13C NMR sign als was provided with DEPT
spectra. Th e 13C NMR-DEPT spectrum of 3 sh ows a ch aracteristic m eth ylen e
carbon atom (C10) at 58.63 ppm , wh ereas in th e spectrum of 4, th e
m eth in e carbon atom (C10) is observed at 83.20 ppm an d th e sign al at
158.39 ppm is attributed to th e carbon atom of th e C=O group.
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Thienopyrimidoisoindolones
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Reactivity
Th ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (4) reacts with alde-
h ydes at position 10 to give derivatives 7a–7c. Th is reaction is sim ilar to
Eh rlich reaction of pyrroles an d fused isoin doles with 4-dim eth ylam in o-
ben zaldeh yde26. Com poun d 4 reacts with th e N-substituted m aleim ides
8a–8c at th e sam e position in th e 1:1 ratio to form Mich ael adducts 9a–9c
(Sch em e 2).
SCHEME 2
Meth ylation of com poun ds 3 an d 4 or th eir m ixture with m eth yl
tosylate, followed by treatm en t of th e resultin g salt 5 with alkali led to th e
expected 5-m eth ylth ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (6)
(Sch em e 1).
It is kn own th at isoin doles are usually oxidized in air an d sh ould be kept
in in ert atm osph ere or stored as salts. However, isoin doles 4 an d 6 are sta-
ble to air for a lon g tim e.
An oth er in terestin g aspect of th e reactivity of 5-m eth ylth ien o[2′,3′:5,6]-
pyrim ido[2,1-a]isoin dol-4(5H)-on e (6) is its reaction with N-substituted
m aleim ides in th e 1:1 or 1:2 ratio as well as with dim eth yl acetylen e-
dicarboxylate.
Th e reaction of 5-m eth ylth ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-
on e (6) with 1 equivalen t of m aleim ide derivatives 8a–8e gives endo-Diels–
Alder adducts 10a–10e (Sch em e 3). Th eir structure was con firm ed by NMR
an d m ass spectra.
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Kysil, Voitenko, Wolf:
Fragm en tation of adducts 10 proceeds via th e retro Diels–Alder reaction ,
wh ich is con firm ed by th e in ten sive peaks correspon din g to isoin dole 6 an d
m aleim ide 8.
SCHEME 3
IR spectra of adduct 10d exhibit two characteristic bands of the pyrrolidine-
2,5-dione m oiety (νC=O = 1770–1775 an d 1705–1710 cm –1) an d a ban d of th e
carbon yl groups of th e pyrim idon e (νC=O = 1620–1643 cm –1).
1H NMR spectra of com poun ds 10a–10e allowed to determ in e th eir spa-
tial structure. Th e sign al from proton s of m eth yl groups of th e quin azolin e
rin gs is observed as a th ree-proton sin glet at 3.69–3.75 ppm . Th e sign al of
th e bridgeh ead proton Ha appears as a on e-proton doublet at 4.35–4.58 ppm
with a couplin g con stan t of 8.2–8.4 Hz. Th e sign al of th e bridge proton Hc
is observed as a on e-proton doublet at 6.28–6.71 ppm with a couplin g con -
stan t of 5.2 Hz. Th e sign al of th e bridge proton Hb is observed as on e-
proton doublet of doublets at 4.05–4.20 ppm with couplin g con stan t of
JHbHa = 8.2–8.8 Hz an d JHbHc = 5.2 Hz. Th ese values are in accordan ce with
th e th eoretically expected on es for endo-Diels–Alder adducts13–15
.
Th e reaction of isoin dole 6 with 2 equivalen t of m aleim ide 8a un der
th erm odyn am ic con trol yielded on ly th e Diels–Alder adduct 10a; th e excess
of th e startin g m aleim ide was recovered.
Th e Mich ael adduct 12 was obtain ed by h eatin g 5-m eth ylth ien o-
[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (6) with dim eth yl acetylen e-
dicarboxylate (11) in dioxan e (Sch em e 4).
We also tried to vary th e substituen t at C-10 of com poun d 6 in order to
in vestigate th e reaction of th e com poun ds obtain ed with dien oph iles.
Acylation of 5-m eth ylth ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (6)
with acyl ch lorides 13 led to com poun ds 14a–14c (Sch em e 5). IR spectra
of com poun d 14b sh owed an in ten sive ch aracteristic ban d correspon din g
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Thienopyrimidoisoindolones
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to pyrim idin e 1665 cm –1 an d to th e (4-m eth oxyph en yl)acetyl fragm en t
1593 cm –1
.
SCHEME 4
SCHEME 5
Heatin g of com poun d 6 with trifluoroacetic an h ydride in dioxan e af-
forded com poun d 14d (R = CF3). IR spectra of com poun d 14d exh ibit an in -
ten sive ban d correspon din g to pyrim idin e at 1683 cm –1 an d an oth er on e of
th e acyl group at 1601 cm –1. Attem pts to carry out th e reaction of 14 with
m aleim ide derivatives 8 failed. We recovered on ly th e startin g m aterial.
Th e explan ation of th is fact is an alogous to th at for th e acyl tetra-
soloisoin doles27. Th e latter exh ibit a stron g in teraction of th e carbon yl
group with arom atic fragm en t; th eir structure was con sidered to be zwitter-
ion ic, bearin g n o isoin dole m oiety.
Conclusions
Th e reaction of 2-(brom om eth yl)ben zon itrile (1) with m eth yl-3-am in oth io-
ph en e-2-carboxylate (2) resulted in th e form ation of th ien opyrim idoiso-
in dolon e existin g in two tautom eric form s: isoin dolin e 3 an d isoin dole 4.
Meth ylation of com poun ds 3 or 4 or th eir m ixtures with m eth yl tosylate,
followed by furth er treatm en t of salt 5 with alkali gave 5-m eth ylth ien o-
[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (6), wh ich reacted with m ale-
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Kysil, Voitenko, Wolf:
im ide derivatives 8 to form n ovel stable tricyclic 7-azan orborn en es 10.
Isoin dole 6 reacted with dim eth yl acetylen edicarboxylate (11), yieldin g th e
Mich ael adduct 12. Acylation of 12 leads to acyl derivatives 14, wh ich do
n ot react with dien oph iles.
EXPERIMENTAL
Ch em ical-ion ization m ass spectra were recorded on a Nerm ag R10 in strum en t. NMR spectra
(δ, ppm ; J, Hz) were obtain ed on a Mercury 400 Varian spectrom eter at 400 MHz (1H NMR)
or 100 MHz (13C NMR) in DMSO-d6 an d CF3COOD as th e solven t. UV-VIS spectra (λ, n m )
were recorded in th e solid state (KBr pellets) on a Perkin –Elm er-Lam bda-19 spectroph oto-
m eter equipped with a 60 m m in tegration sph ere for solid m easurem en ts. Th e electrospray
m ass spectra were recorded on an API-365 Perkin –Elm er Sciex in strum en t at th e Service
Com m un de Spectrom étrie de Masse of th e Paul Sabatier Un iversity, Toulouse. Elem en tal
an alyses were determ in ed with a Carlo Erba Strum en tazion e apparatus at th e ENSIACET
Toulouse.
Preparation of Com poun ds 3 an d 4. Gen eral Procedure
2-(Brom om eth yl)ben zon itrile (0.2 g, 1 m m ol) an d th e correspon din g 3-am in oth ioph en e-
2-carboxylate (0.24 g, 1.5 m m ol) were h eated un der reflux in dry DMF (4 m l) for 10 m in . Af-
ter coolin g, th e product was collected by filtration an d recrystallized from DMF. Com poun d
3 is little soluble in h ot DMF in con trast to com poun d 4.
Thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-one (3). Yield 0.21 g (80%) of a ligh t yellow
powder. M.p. 85 °C. For C13H8N2OS (240.3) calculated: 64.98% C, 3.36% H, 11.66% N;
foun d: 65.00% C, 3.42% H, 11.70% N. 1H NMR (DMSO-d6): 5.39 s, 2 H (CH2); 7.30 d, 1 H,
J = 5.2; 7.57 t, 1 H, J = 8.0; 7.66 d, 1 H, J = 8.0; 7.72 d, 1 H, J = 4.0; 7.98 d, 1 H, J = 8.0;
8.06 d, 1 H, J = 4.0. 13C NMR (DMSO-d6): 58.63, 119.31, 122.98, 126.14, 126.34, 126.53,
132.80, 139.42, 143.93, 144.37, 146.47, 157.97, 159.61. UV: λm ax = 340 n m . [MH]+ 241.
Thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(5H)-one (4). Yield 24 m g (10%) of ligh t yellow
crystals. M.p. 185 °C. For C13H8N2OS (240.3) calculated: 64.98% C, 3.36% H, 11.66% N;
foun d: 65.02% C, 3.41% H, 11.68% N. 1H NMR (DMSO-d6): 6.77 s, 1 H (CH); 7.49 d, 1 H,
J = 8.0; 7.63–7.72 m , 3 H; 7.97 d, 1 H, J = 8.0; 8.23 d, 1 H, J = 8.0. 13C NMR (DMSO-d6):
83.20, 122.63, 122.75, 125.07, 125.65, 130.72, 131.26, 133.12, 135.76, 143.73, 155.87,
156.40, 158.39. UV: λm ax = 370 n m . [MH]+ 241.
5-Meth yl-4-oxo-4,10-dih ydroth ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-5-ium Tosylate (5)
Com poun d 3 or 4 (2.4 g, 10 m m ol) an d m eth yl tosylate (3.4 g, 20 m m ol) were h eated to
100 °C for 1 h . Th e product was collected by filtration , an d wash ed twice with eth an ol.
Yield 4.0 g (93%). M.p. 237 °C. 1H NMR (DMSO-d6): 2.31 s, 3 H (CH3); 4.09 s, 3 H (CH3);
6.15 s, 2 H; 6.98 s, 2 H, J = 7.6; 7.33 d, 2 H, J = 8.0; 7.62 d, 1 H, J = 8.4; 7.93–8.07 m , 4 H;
8.31 d, 1 H, J = 5.2. [MH]+ 255.
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Thienopyrimidoisoindolones
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5-Meth ylth ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4(5H)-on e (6)
Furth er treatm en t of th e salt 5 with alkali led to th e expected com poun d 6. Th e product was
collected by filtration an d wash ed twice with water an d eth an ol or DMF. Yield 2.3 g (98%).
M.p. 115 °C. For C14H10N2OS (254.3) calculated: 66.12% C, 3.96% H, 11.02% N; foun d:
66.30% C, 4.00% H, 11.12% N. 1H NMR (DMSO-d6): 3.88 s, 3 H (CH3); 6.77 t, 1 H, J = 7.4;
6.93 t, 1 H, J = 7.4; 7.43 d, 1 H, J = 8.4; 7.85–7.95 m , 3 H; 8.26 d, 1 H, J = 5.2. 13C NMR
(DMSO-d6): 31.06, 99.08, 107.70, 118.13, 118.42, 119.28, 119.55, 120.56, 122.80, 123.02,
124.92, 136.21, 140.40, 154.30. [MH]+ 255.
Preparation of Com poun ds 7. Gen eral Procedure
Com poun d 4 was suspen ded in dry DMF con tain in g 1 equivalen t of R1CHO an d h eated un -
der reflux for 10 m in . After coolin g, th e product was recovered by filtration an d crystallized
from DMF.
10-[(2,3-Dihydro-1,4-benzodioxin-6-y)lmethylidene]thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-
4(10H)-one (7a). From 4 (0.24 g, 1 m m ol) an d 2,3-dih ydro-1,4-ben zodioxin e-6-carbaldeh yde
(0.25 g, 1.5 m m ol). Yield 0.31 g (82%) of yellow crystals. M.p. 230 °C. 1H NMR (CF3COOD):
4.42–4.43 m , 2 H; 4.45–4.46 m , 2 H; 7.14–7.16 d, 1 H, J = 8.0; 7.21–7.31 m , 2 H; 7.74–7.79 d,
1 H, J = 20.0; 7.81–7.88 m , 3 H; 8.10–8.12 d, 1 H, J = 8.0; 8.33–8.39 m , 2 H. [MH]+ 387.
10-(Pyridin-3-ylmethylidene)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-one (7b). From
4
(0.24 g, 1 m m ol) an d n icotin aldeh yde (0.16 g, 1.5 m m ol). Yield 0.3 g (93%) of yellow crys-
tals. M.p. 246 °C. 1H NMR (CF3COOD): 7.54 d, 1 H, J = 8.0; 7.98 t, 1 H, J = 7.2; 8.06 t, 1 H,
J = 7.6; 8.38 d, 1 H, J = 4.8; 8.52 t, 1 H, J = 7.2; 8.62–8.68 m , 2 H; 8.71 d, 1 H; 9.15 d, 1 H,
J = 8.0; 9.22 d, 1 H, J = 5.6; 9.48 s, 1 H. [MH]+ 330.
10-(Pyridin-2-ylmethylidene)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-one (7c). From
4
(0.24 g, 1 m m ol) an d pyridin e-2-carbaldeh yde (0.16 g, 1.5 m m ol). Yield 0.28 g (87%) of yel-
low crystals. M.p. 253 °C. For C19H11N3OS (329.4) calculated: 69.28% C, 3.37% H, 12.76% N;
foun d: 70.00% C, 3.48% H, 12.90% N. 1H NMR (CF3COOD): 7.44 d, 1 H, J = 8.0; 7.91 t, 1 H,
J = 7.6; 7.99 t, 1 H, J = 7.6; 8.29 d, 1 H, J = 6.0; 8.38 t, 1 H, J = 6.6; 8.52–8.68 m , 4 H; 9.93 t,
1 H, J = 8.0; 9.19 d, 1 H, J = 5.2. [MH]+ 330.
Preparation of Com poun ds 9. Gen eral Procedure
Com poun d 4 was suspen ded in m eth an ol con tain in g 1 equivalen t of derivatives of m ale-
im ide 8 an d h eated un der reflux for 1 h . After coolin g, th e product was recovered by filtra-
tion an d recrystallized from m eth an ol.
10-(1-Methyl-2,5-dioxopyrrolidin-3-yl)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-one (9a).
From 4 (0.24 g, 1 m m ol) an d N-m eth ylm aleim ide (0.11 g, 1 m m ol). Yield 0.29 g (83%) of a
wh ite powder. M.p. 222 °C. 1H NMR (DMSO-d6): 1.33 dd, 1 H, Hc, J = 17.6, 7.9; 2.23 s, 3 H
(CH3); 2.37 dd, 1 H, Hd, J = 18.4, 8.0; 3.96–3.99 m , 1 H, Hb; 6.17 d, 1 H, Ha, J = 4.0;
7.65–7.73 m , 3 H; 7.80 d, 1 H, J = 6.8; 8.07 d, 1 H, J = 7.6; 8.20 d, 1 H, J = 5.6. [MH]+ 352.
10-[1-(4-Methylphenyl)-2,5-dioxopyrrolidin-3-yl]thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-
one (9b). From 4 (0.24 g, 1 m m ol) an d N-(4-m eth ylph en yl)m aleim ide (0.19 g, 1 m m ol).
Yield 0.32 g (66%) of a wh ite powder. M.p. 231 °C. 1H NMR (DMSO-d6): 1.38 dd, 1 H, Hc,
J = 17.6, 7.6; 2.28 s, 3 H (CH3); 2.39 dd, 1 H, Hd, J = 18.4, 8.0; 4.00–4.32 m , 1 H, Hb; 6.17 d,
1 H, Ha, J = 4.0; 7.10 d, 2 H, J = 8.0; 7.30 d, 2 H, J = 8.0; 7.60–7.68 m , 3 H; 7.83 d, 1 H, J =
6.8; 8.15 d, 1 H, J = 7.6; 8.23 d, 1 H, J = 5.6. [MH]+ 428.
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10-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(10H)-one (9c).
From 4 (0.24 g, 1 m m ol) an d N-ben zylm aleim ide (0.19 g, 1 m m ol). Yield 0.31 g (73%) of a
wh ite powder. M.p. 228 °C. 1H NMR (DMSO-d6): 1.34 dd, 1 H, Hc, J = 17.6, 7.6; 2.39 dd,
1 H, Hd, J = 18.4, 8.0; 4.00 s, 2 H (CH2); 4.09–4.32 m , 1 H, Hb; 6.15 d, 1 H, Ha, J = 4.0;
7.32–7.80 m , 9 H; 8.17 d, 1 H, J = 7.6; 8.20 d, 1 H, J = 5.6. [MH]+ 428.
Preparation of Com poun ds 10. Gen eral Procedure
Com poun d 6 was suspen ded in m eth an ol con tain in g 1 equivalen t of m aleim ide derivative 8
an d h eated un der reflux for 1 h . After coolin g, th e product was recovered by filtration , ob-
tain ed product residue was separated by colum n ch rom atograph y (silica gel L 100/250 m esh ;
eth yl acetate–toluen e 8:2).
2,19-Dimethyl-5-thia-2,9,19-triazahexacyclo[8.6.5.01,9.04,8.011,16.017,21]henicosa-4(8),6,11,13,15-
pentaene-3,18,20-trione (10a). From 6 (0.25 g, 1 m m ol) an d N-m eth ylm aleim ide (0.11 g,
1 m m ol or 0.22 g, 2 m m ol). Yield 0.12 g (35%) of a wh ite powder. M.p. 217 °C. 1H NMR
(DMSO-d6): 2.27 s, 3 H (CH3); 3.70 s, 3 H (CH3-N); 4.21 dd, 1 H, Hb, JHbHa = 8.2, JHbHc = 5.2;
4.35 d, 1 H, J = 8.2, Ha; 6.28 d, 1 H, J = 5.2, Hc; 7.25 d, 1 H, J = 5.2; 7.60 t, 1 H, J = 8.0;
7.64 d, 1 H, J = 8.0; 7.75 d, 1 H, J = 4.0; 7.93 d, 1 H, J = 8.0; 8.00 d, 1 H, J = 4.0. [MH]+ 366.
2-Methyl-19-phenyl-5-thia -2,9,19-tria za hexa cyclo[8.6.5.01 ,9 .04 ,8 .01 1 ,1 6 .01 7 ,2 1 ]henicosa -
4(8),6,11,13,15-pentaene-3,18,20-trione (10b ). From
m aleim ide (0.17 g, 1 m m ol or 0.34 g, 2 m m ol). Yield 0.24 g (57%) of a wh ite powder.
M.p. 205 °C. 1H NMR (DMSO-d6): 3.72 s, 3 H (CH3-N); 4.26 dd, 1 H, Hb, JHbHa = 8.8, JHbHc
6 (0.25 g, 1 m m ol) an d N-ph en yl-
=
5.2; 4.55 d, 1 H, J = 8.8, Ha; 6.61 d, 1 H, J = 5.2, Hc; 7.42–7.88 m , 10 H; 7.95 d, 1 H, J = 4.0.
[MH]+ 428.
2-Methyl-19-(4-methylphenyl)-5-thia-2,9,19-triazahexacyclo[8.6.5.01,9.04,8.011,16.017,21]-
henicosa-4(8),6,11,13,15-pentaene-3,18,20-trione (10c). From 6 (0.25 g, 1 m m ol) an d N-
(4-m eth ylph en yl)m aleim ide (0.19 g, 1 m m ol or 0.38 g, 2 m m ol). Yield 0.26 g (60%) of a
ligh t yellow powder. M.p. 213 °C. 1H NMR (DMSO-d6): 2.96 s, 3 H (CH3); 3.75 s, 3 H
(CH3-N); 4.29 dd, 1 H, Hb, JHbHa = 8.8, JHbHc = 5.2; 4.41 d, 1 H, J = 8.8, Ha; 6.26 d, 2 H, J =
8.4; 6.71 d, 1 H, J = 5.2, Hc; 7.00 d, 2 H, J = 8.4; 7.30–7.71 m , 4 H; 7.90 d, 1 H, J = 8.0; 7.98
d, 1 H, J = 4.0. 13C NMR (DMSO-d6): 25.67, 38.10, 51.88, 55.11, 66.82, 91.31, 119.38,
120.30, 127.26, 128.01, 128.05, 133.69, 135.04, 135.19, 135.73, 135.84, 135.78, 143.08,
143.77, 145.81, 146.58, 147.90, 160.12, 178.28, 178.24. [MH]+ 442.
2-Methyl-19-(4-methoxyphenyl)-5-thia-2,9,19-triazahexacyclo[8.6.5.01,9.04,8.011,16.017,21]-
henicosa-4(8),6,11,13,15-pentaene-3,18,20-trione (10d ). From 6 (0.25 g, 1 m m ol) an d N-
(4-m eth oxyph en yl)m aleim ide (0.2 g, 1 m m ol or 0.4 g, 2 m m ol). Yield 0.2 g (44%) of a wh ite
powder. M.p. 209 °C. 1H NMR (DMSO-d6): 3.70 s, 3 H (CH3); 3.73 s, 3 H (CH3-N); 4.22 dd,
1 H, Hb, JHbHa = 8.4, JHbHc = 5.3; 4.55 d, 1 H, J = 8.4, Ha; 6.38 d, 2 H, J = 8.9; 6.70 d, 1 H, J =
5.2, Hc; 6.80 d, 2 H, J = 8.9; 7.44–7.75 m , 4 H; 7.88 d, 1 H, J = 8.0; 7.95 d, 1 H, J = 4.0.
IR (KBr): 1706 (CO), 1774 (CO), 1655 (CO). [MH]+ 458.
2-Methyl-19-(1-naphthyl)-5-thia-2,9,19-triazahexacyclo[8.6.5.01,9.04,8.011,16.017,21]henicosa-
4(8),6,11,13,15-pentaene-3,18,20-trione (10e). From 6 (0.25 g, 1 m m ol) an d N-(1-n aph th yl)-
m aleim ide (0.22 g, 1 m m ol or 0.44 g, 2 m m ol). Yield 0.24 g (51%) of a ligh t yellow powder.
M.p. 216 °C. 1H NMR (DMSO-d6): 3.74 s, 3 H (CH3-N); 4.29 dd, 1 H, Hb, JHbHa = 8.4, JHbHc
=
5.2; 4.58 d, 1 H, J = 8.4, Ha; 6.68 d, 1 H, J = 5.2, Hc; 7.42–7.79 m , 12 H; 7.99 d, 1 H, J = 4.1.
[MH]+ 478.
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255
Dim eth yl (2E)-2-(5-Meth yl-4-oxo-4,5-dih ydroth ien o[2′,3′:5,6]pyrim ido-
[2,1-a]isoin dol-10-yl)but-2-en edioate (12)
Com poun d 6 (0.5 g 2 m m ol) an d dim eth yl acetylen edicarboxylate (11; 0.35 g, 2.5 m m ol) in
a dioxan e were h eated un der reflux for 30 m in . Th e solution was evaporated un der reduced
pressure an d th e residue was separated by ch rom atograph y (silica gel L 100/250 m esh ;
dich lorom eth an e–aceton e 3:1). Yield 0.72 g (92%) of a red powder. M.p. 211 °C. 1H NMR
(DMSO-d6): 3.54 s, 3 H (CH3); 3.61 s, 3 H (CH3); 4.09 s, 3 H (CH3); 6.93 t, 1 H, J = 7.6;
7.03 s, 1 H; 7.07–7.11 m , 2 H, J = 7.8; 7.36 d, 1 H, J = 5.2; 8.07 d, 1 H, J = 8.8; 8.18 d, 1 H,
J = 5.2. [MH]+ 397.
Preparation of Acyl Derivatives 14a–14c. Gen eral Procedure
On e equivalen t of an acyl ch loride an d 1.5 equivalen t of trieth ylam in e were added to a solu-
tion of 6 in 15 m l of dioxan e. Th e m ixture was h eated at 100 °C for 1 h . After coolin g, th e
product was recovered by filtration an d recrystallized from eth an ol.
5-Methyl-10-(2-methyl-3-furoyl)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(5H)-one (14a). From
6 (0.25 g, 1 m m ol), 2-m eth yl-3-furoyl ch loride (0.17 g, 1.2 m m ol) an d trieth ylam in e (0.15 g,
1.5 m m ol). Yield 0.34 g (95%) of yellow crystals. M.p. 251 °C. For C20H14N2O3S (362.4) cal-
culated: 66.28% C, 3.89% H, 7.73% N; foun d: 66.31% C, 3.94% H, 7.75% N. 1H NMR
(DMSO-d6): 2.46 s, 3 H (CH3); 4.12 s, 3 H (CH3); 6.65 s, 1 H; 7.00–7.04 t, 1 H, J = 7.6;
7.17–7.21 t, 1 H, J = 7.8; 7.26–7.28 d, 1 H, J = 8.4; 7.56–7.59 m , 2 H; 8.10–8.11 d, 1 H, J =
3.6; 8.18–8.20 d, 1 H, J = 8.8. [MH]+ 363.
10-(4-Methoxybenzoyl)-5-methylthieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(5H)-one (14b). From
6 (0.25 g, 1 m m ol), 4-m eth oxyben zoyl ch loride (0.2 g, 1.2 m m ol) an d trieth ylam in e (0.15 g,
1.5 m m ol). Yield 0.37 g (97%) of yellow crystals. M.p. 234 °C. 1H NMR (DMSO-d6): 3.92 s,
3 H (OCH3); 4.11 s, 3 H (CH3); 6.90–7.01 m , 5 H; 7.53–7.55 d, 1 H, J = 8.0; 7.83–7.86 m ,
2 H; 8.08–8.10 m , 1 H; 8.15–8.17 d, 1 H, J = 8.0. 13C NMR (CF3COOD): 17.21, 36.02, 112.44,
122.55, 121.24, 124.50, 128.10, 129.55, 132.08, 135.63, 141.06, 144.06, 144.61, 146.60,
147.24, 160.33, 163.29, 163.55, 171.46, 188.18. [MH]+ 389.
5-Methyl-10-(2-phenylbutanoyl)thieno[2′,3′:5,6]pyrimido[2,1-a]isoindol-4(5H)-one (14c). From
6 (0.25 g, 1 m m ol), 2-ph en ylbutan oyl ch loride (0.21 g, 1.2 m m ol) an d trieth ylam in e (0.15 g,
1.5 m m ol). Yield 0.39 g (98%) of yellow crystals. M.p. 222 °C. 1H NMR (DMSO-d6): 0.99 t,
3 H, J = 7.2 (CH2CH3); 1.91–1.94 m , 1 H; 2.24–2.30 m , 1 H; 4.04 s, 3 H (CH3); 4.61 t, 1 H,
J = 7.2; 7.03 t, 1 H, J = 7.6; 7.16–7.23 m , 2 H; 7.27–7.23 m , 2 H; 7.37 t, 1 H, J = 7.6;
7.44–7.46 m , 2 H; 8.01 d, 1 H, J = 5.2; 8.04 d, 1 H, J = 9.2; 8.16 d, 1 H, J = 8.8. [MH]+ 401.
5-Meth yl-10-(trifluoroacetyl)th ien o[2′,3′:5,6]pyrim ido[2,1-a]isoin dol-4-(5H)-on e (14d )
Trifluoroacetic an h ydride (0.31 g, 1.5 m m ol) an d trieth ylam in e (0.15 g, 1.5 m m ol) were
added to a solution of 6 (0.25 g, 1 m m ol) in 15 m l of dioxan e. Th e m ixture was h eated to
60 °C for 1 h . After coolin g, th e product was recovered by filtration an d recrystallized from
eth an ol. Yield 0.33 g (96%) of yellow crystals. M.p. 236 °C. For C16H9F3N2O2S (350.3) calcu-
lated: 54.86% C, 2.59% H, 8.00% N; foun d: 54.90% C, 2.61% H, 7.97% N. 1H NMR
(DMSO-d6): 4.12 s, 3 H (CH3); 7.25 t, 1 H, J = 7.8; 7.59 d, 1 H, J = 5.6; 7.57 t, 1 H, J = 7.6;
7.88 d, 1 H, J = 8.8; 8.19 d, 1 H, J = 5.2; 8.36 d, 1 H, J = 8.8. [MH]+ 351.
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256
Kysil, Voitenko, Wolf:
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