Condensed sulfur-containing pyridine systems 3.*Construction of penta- and hexacyclic heterocyclic systems by the cascade reaction of 3-cyanopyridine-2(1H)-thiones and 3-cyano-pyridine-2(1H)-thiolates with 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene

Article abstract of DOI:10.1007/s10593-012-1149-1

The alkylation of 3-cyanopyridine-2(1H)-thiones with 8-chloromethyl-3- methyl-7-(2-oxo-2-phenylethyl)- xanthene in a KOH-H₂O-DMF system upon heating leads to the formation of pyrido-[3″,2″:4′,5′] thieno[3′,2′:5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-dione derivatives in good yields. Under milder conditions, the intermediates of the cascade reactions, namely, 2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3, 6,7-tetrahydro-1H-purin-8-yl]methyl}thio)pyridine-3-carbonitriles, can be isolated and characterized.

Full text of DOI:10.1007/s10593-012-1149-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
CONDENSED SULFUR-CONTAINING PYRIDINE SYSTEMS
3.* CONSTRUCTION OF PENTA- AND HEXACYCLIC
HETEROCYCLIC SYSTEMS BY THE CASCADE REACTION
OF 3-CYANOPYRIDINE-2(1H)-THIONES AND 3-CYANO-
PYRIDINE-2(1H)-THIOLATES WITH 8-CHLOROMETHYL-
3-METHYL-7-(2-OXO-2-PHENYLETHYL)XANTHENE
V. V. Dotsenko,1** D. V. Sventukh,2 and S. G. Krivokolysko1
The alkylation of 3-cyanopyridine-2(1H)-thiones with 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)-
xanthene in a KOH–H2O–DMF system upon heating leads to the formation of pyrido-
[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-dione derivatives in good yields.
Under milder conditions, the intermediates of the cascade reactions, namely, 2-({[3-methyl-2,6-dioxo-
7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)pyridine-3-carbonitriles, can be
isolated and characterized.
Keywords: 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene, 3-cyanopyridine-2(1H)-thiones,
thieno[2,3-b]pyridines, alkylation, cascade reaction, Thorpe-Ziegler reaction.
Cascade reactions, which are also termed tandem or domino reactions, are a current approach to the
synthesis of polycyclic structures. In comparison with multistep syntheses, cascade reactions are more efficient
and atom-economical, permitting the construction of complex molecules from simple low-molecular substrates
in a single step in much less time. Many such heterocyclization reactions have already been described (see
reviews of domino reactions [2-9]).
Some of the most rapidly developing areas in the chemistry of cascade reactions are heterocyclizations
using readily available 3-cyanopyridine-2(1H)-thiones (see reviews by Litvinov et al. [10-14]), leading to the
formation of condensed thieno[2,3-b]pyridine derivatives [15-18]. Thus, there have been many recent reports
concerning the reactions of substituted 3-cyanopyridine-2(1H)-thiones with various multifunctional alkylating
_______
*For Communication 2, see [1].
**To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1ChemEx Laboratory, Vladimir Dal' East Ukrainian National University, 20-A Molodezhnyi Kv., 91034
Lugansk, Ukraine.
2Zaporozh'e National Technical University, 64 Zhukovskogo St., 69063 Zaporozh'e, Ukraine; e-mail:
svyentukh@inbox.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1498-1512, September, 2012.
Original article submitted April 6, 2011.
0009-3122/12/4809-1397©2012 Springer Science+Business Media New York
1397

agents, leading to the formation of heterocyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidine [19-24], pyrido-
[2',3':4,5]thieno[2,3-b]pyridine [19, 25-39], pyrano[2,3-d]pyrido[3',2':4,5]thieno[3,2-b]pyridine [28], pyrido-
[3',2':4,5]thieno[3,2-e][1,4]diazepine [40], pyrido[3',2':4,5]thieno[3,2-c]isoquinoline [41], and pyrido[3',2':4,5]-
thieno[3,2-c][2,7]naphthyridine derivatives [42].
In a continuation of work on cascade reactions in the synthesis of condensed analogs of thieno[2,3-b]-
pyridine, we turned our attention to 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1) as a starting
compound for the construction of polycyclic systems based on 3-cyanopyridine-2(1H)-thione derivatives.
R2
R1
R
N
NH2
CN
R2
R2
N
R1
R
N
NH2
CN
N
S
R1
R
N
NH2
Ar
N
S
N
[19, 38,
39]
S
Me
[19–22]
R1
NH2
O
R2
[32–37]
H
R1
R
N
R2
N
R2
H
N
R1
O
N
[28]
Ar
N
S
S
[26–31]
O
R
S
R
N
S
CN
H
OH
[41]
NH2
R2
N
[42]
R2
N
R1
R
H
R1
R
N
O
N
NH2
[23–24]
S
R2
N
S
R1
N
O
R3
NH
NH
R2
R
[40]
R
S
[25]
R2
O
H
H
R1
N
O
R1
R
N
R4
N
R
N
S
N
S
R3
O
Chloromethylxanthene 1 may be readily obtained from 8-hydroxymethyl-3-methylxanthene [43] by consecutive
treatment with phenacyl bromide and SOCl2.
HO
HO
Cl
Ph
Ph
N
N
N
O
O
NH
N
N
Me
O
Me
O
Me
O
SOCl2
1) NaOH
N
N
N
2) PhCOCH2Br
, 2 h
N
O
O
O
N
N
DMF, , 2 h
H
H
H
1
It was found that the chloromethylxanthene 1 reacts under mild conditions (15°C, DMF) with
pyridinethiones 2a-h in the presence of one equivalent of 10% aqueous KOH to give sulfides 3a-h in 53-74%
1398

yield. Upon treatment with excess KOH, these sulfides are readily cyclized to give pyrido[3",2":4',5']-
thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-diones 4a-h in 72-90% yields (method A). We should
note that the Thorpe-Ziegler cyclization products formed in the first step of the cascade reaction, namely,
thieno[2,3-b]pyridines 5a-h, could not be isolated. An alternative method for the synthesis of diones 4 is based
on the direct reaction of chloromethylxanthene 1 and pyridinethione 2 in the presence of excess KOH in DMF at
reflux, without isolation of the S-alkylation products 3 (method B). This reaction gives polycyclic diones 4a-k
in 45-88% yield. Comparison of the results obtained using methods A and B indicates that the preferred
procedure is the one-pot method B, which eliminates the need to isolate the S-alkylation product and gives
higher yields of the desired polycyclic diones 4.
Ph
R2
R2
O
O
R1
CN
S
Method A
(from 2a–h)
NC
R1
N
1
+
KOH, DMF
15°C, 3–4 h
HN
O
S
R
N
H
2a–k
N
N
N
R
3a–h
Me
KOH, DMF
, 4–7 min
KOH, DMF
, 1–2 min
Method B
Ph
Me
R2
N
NH2
O
NH
R2
N
R1
R
N
O
N
K+
O
R1
N
N
N
S
S
N
O
O
N
R
N
Me
6a–k
Ph
5a–h
AcOH
Ph
7
R2
9
6
8 N
O
R1
N5
4
3
10
11
NH
2
S
N
N
R
13
N1
Me
12
O
4a–k
2–6 a R+R1 = (CH2)6, R2 = H; b R+R1 = (CH2)4, R2 = 2-ClC6H4; c R = Me, R1+R2 = (CH2)4;
d R = Me, R1+R2 = (CH2)3; e R+R1 = CH2CH2CH(t-Bu)CH2, R2 = H; f R = R2 = Me, R1 = H;
g R+R1 = (CH2)4, R2 = 4-ClC6H4; h R = R2 = Ph, R1 = H; i R+R1 = (CH2)3CO, R2 = H;
j R+R1 = (CH2)5, R2 = 2-ClC6H4; k R+R1 = (CH2)4, R2 = 2-thienyl
The products of the cascade cyclization are formed as potassium salts 6a-k, which convert to diones
4a-k upon mild acidification of the reaction mixture by adding a slight excess of acetic or hydrochloric acid. In
the case of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2f), we isolated and characterized the
corresponding potassium salt 6f (R = R2 = Me, R1 = H).
Sulfides 3a-h are white or light-yellow fine crystalline powders, which are insoluble in ethanol, have
slight solubility in acetone, but are moderately soluble in DMSO and DMF. Polycyclic diones 4a-k are high-
melting, bright-yellow or brown fine crystalline powders, which are insoluble in ethanol and acetone but
moderately soluble in hot DMSO and DMF.
1399

It is interesting to note that triethylammonium 3-cyano-6-methyl-4-oxo-1,4-dihydropyridine-2-thiolate
(7) [44] upon reaction with chloromethylxanthene 1 under analogous conditions (DMF and then heating with
1.5 equivalents of KOH at reflux) gives only the S-alkylation product 8 in 76% yield. This behavior may be
attributed to the enhanced NH-acidity of both the purine and pyridine fragments of carbonitrile 8, which leads to
binding of the base required for the Thorpe-Ziegler reaction and initiation of the cascade reaction.
Ph
O
O
O
CN
O
KOH, DMF
, 2–3 min
CN
N
1
+
NH
Me
N
H
7
S
S
N
Me
N
N
Et3NH+
H
O
Me
8
As we have recently shown [45], the starting 1-methyl-3-thioxo-2,3,5,6,7,8-hexahydroisoquinoline-
4-carbonitrile (2c) and 1-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile (2d),
obtained by the procedure described in our previous work [46] and used for the synthesis of compounds 3c, 4c
and 3d, 4d, respectively, are actually mixtures with the regioisomeric quinoline-2-thione 2'c and
cyclopenta[b]pyridine-2-thione 2'd (Fig. 1). Thus, derivatives 3c, 4c and 3d, 4d are also regioisomer mixtures.
The ratio of isoquinoline derivative 3c to quinoline derivative 3'c in the mixture obtained in the reaction of
1
thione 2c with chloromethylxanthene 1, according to H NMR spectral data (500 MHz), is ~9:2. However, it
proved impossible to unequivocally establish the regioisomer ratio in the mixture of products of the Thorpe-
Ziegler cascade cyclization 4c + 4'c due to complete signal overlap in the spectrum.
1H NMR spectral data showed a ~5:3 ratio for the mixture of cyclopenta[c]- (3d) and cyclo-
penta[b]pyridine (3'd) regioisomers in the product of thione 2d reaction with chloromethylxanthene 1 and a
1
~9:4 4d:4'd ratio for the cascade reaction product 4d. The H NMR spectra of compounds 3a-h and 8 show
signals for the SCH2 methylene group as broad pseudo singlets or two doublets (4.97-4.74 ppm) and for the
NCH2CO methylene group as a pseudo singlet at 6.09-5.93 ppm. The signals for the NH protons appear as a
broad singlet at 11.35-10.95 ppm, while signals for the NCH3 protons appear as a sharp singlet at 3.42-3.21 ppm.
The 1H NMR spectra of polycyclic diones 4a-k lack signals for SCH2 and NCH2CO groups, but display signals
for NC(6)H2 as a broad pseudo singlet or two doublets at 5.54-5.23 ppm. The signals for the NH and NCH3
protons are shifted somewhat downfield in comparison with the analogous signals in the spectra of nitriles 3a-h
1
and appear at 11.46-11.04 and 3.45-3.38 ppm, respectively. The H NMR spectrum of salt 6f shows only a
slight shift in the signals relative to the spectrum of polycyclic dione 4f and also lacks the NH proton signal at
11.37 ppm. The IR spectra of nitriles 3a-h have absorption bands for a conjugated nitrile group at 2213-2230
cm-1 and carbonyl groups at 1665-1720 cm-1, while the IR spectra of polycyclic diones 4 lack CN group
absorption bands. The absorption band for the C(8)=N(7) fragment is most often observed at 1630-1660 cm-1 as a
shoulder on the strong C=O band. The spectral data for products 3 and 4 are given in Table 1.
Thus, the reaction of 3-cyanopyridine-2(1H)-thiones with 8-chloromethyl-3-methyl-7-(2-oxo-2-phenyl-
ethyl)xanthene in the presence of KOH proceeds as a cascade process to give polycyclic products, namely,
pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-dione derivatives. The intermediates
of this cascade reaction have been isolated and characterized.
EXPERIMENTAL
The IR spectra were recorded on an IKS-29 spectrophotometer for vaseline mulls. The 1H NMR spectra
were recorded on a Bruker DRX-500 spectrometer (500 MHz) for compounds 3a-c,e,f and 4a-d and a Varian
1400

Me
Me
CN
S
CN
S
CN
S
CN
S
Me
N
H
N
H
Me
N
H
N
H
2d
2'd
2'c
2c
Ph
Ph
O
O
Me
NC
NC
O
O
N
N
HN
O
HN
S
S
N
N
N
N
N
N
Me
O
Me
Me
3c
3'c
Ph
Ph
O
O
Me
NC
NC
O
O
N
N
HN
O
HN
O
S
S
N
N
N
N
N
N
Me
3d
3'd
Me
Me
Ph
Ph
Me
N
N
N
O
O
N
N
NH
NH
S
S
N
N
N
Me
N
N
O
O
4c
Ph
Me
Me
4'c
Ph
Me
N
N
O
O
N
N
NH
NH
S
S
N
N
N
Me
N
N
N
O
O
4d
4'd
Me
Me
Fig. 1. Structure of regioisomeric compounds 2c-4c, 2'c-4'c, 2d-4d, and 2'd-4'd.
Unity Plus spectrometer (400 MHz ) for the other compounds. The solvent was DMSO-d6 with TMS as internal
standard. The IR spectra of starting 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1) and its
hydroxymethyl precursor were recorded on a Specord M-80 spectrometer for KBr pellets. The 1H NMR spectra
for these compounds were recorded on a Varian Gemini 200 spectrometer (200 MHz) in DMSO-d6 with TMS as
internal standard. The elemental analyses were carried out on a Perkin Elmer CHN Analyzer. The melting points
were determined on a Koefler hot stage and not corrected. The purity of the products was checked by thin-layer
chromatography on Silufol UV-254 plates using 1:1 acetone–hexane as the eluent and visualization by UV light
and iodine vapor.
1401

1402

1403

8-Chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1). A solution of NaOH (8.0 g, 0.2 mol)
in water (50 ml) was added to 8-hydroxymethyl-3-methylxanthene [43] (39.2 g, 0.2 mol) in warm water
(150 ml) and heated until the solid dissolved. The solvent was removed in vacuum to give a solid residue, which
was washed on the filter with acetone and dried at 70-75°C to give the 8-hydroxymethyl-3-methyl-xanthene
sodium salt. Yield 43.0 g (98%); mp >360°C. This product was used without further purification.
A mixture of 8-hydroxymethyl-3-methylxanthene sodium salt (2.18 g, 10 mmol) and phenacyl bromide
(2.39 g, 12 mmol) in DMF (15 ml) was heated at reflux for 2 h. The reaction mixture was cooled and poured
into water (50 ml). The precipitate formed was filtered off and recrystallized from ethyl cellosolve to give
8-hydroxymethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene. Yield 2.14 g (68%). Mp 269-270°С. IR spectrum,
, cm-1: 1615-1550 (C=N), 1715-1696 (3C=O), 3120 (NH). 1Н NMR spectrum, , ppm (J, Hz): 11.09 (1Н, s, NH);
8.06-7.51 (5H, m, Н Ph); 5.95 (2H, s, NCH2); 5.62 (1Н, t, J = 6.0, СН2ОН); 4.54 (2H, br. pseudo d, J = 6.0,
СН2ОН); 3.42 (3Н, s, NCH3). Found, %: C 57.32; H 4.53; N 17.80. C15H14N4O4. Calculated, %: C 57.32; H 4.49;
N 17.83.
A mixture of 8-hydroxymethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (3.14 g, 0.01 mol) and
SOCl2 (35 ml) was heated for 6 h at reflux on an oil bath. Excess SOCl2 was removed in vacuum to give
8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1). Yield 3.23 g (97%); mp 255-257°С (dioxane).
1
IR spectrum, , cm-1: 1610-1555 (C=N), 1705-1690 (3C=O), 3100 (N–H). Н NMR spectrum, , ppm: 11.21
(1Н, s, NH); 8.12-7.56 (5H, m, Н Ph); 5.99 (2H, s, NCH2); 4.97 (2H, s, СН2Cl); 3.36 (3Н, s, NCH3). Found, %:
C 54.10; H 4.01; N 16.82. C15H13ClN4O3. Calculated, %: C 54.15; H 3.94; N 16.84.
2-Thioxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carbonitrile (2a) was obtained according to a
published procedure [47, 48]. 4-(2-Chlorophenyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile
(2b), 4-(4-chlorophenyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2g), 4-(2-chlorophenyl)-
2-thioxo-2,5,6,7,8,9-hexahydro-1H-cyclopenta[b]pyridine-3-carbonitrile (2j), and 4-(2-thienyl)-2-thioxo-
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2k) were synthesized by the reaction of N-(cyclohexen-
1-yl)morpholine or N-(cyclohepten-1-yl)morpholine with 3-aryl- or 3-hetaryl-2-cyanoprop-2-enethioamides
according Sharanin et al. [49-51]. 4,6-Dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2f) was
obtained quantitatively by the reaction of cyanothioacetamide with acetylacetone [52], 4,6-diphenyl-2-thioxo-
1,2-dihydropyridine-3-carbonitrile (2h) was synthesized according to Krauze et al. [53]. 5-Oxo-2-thioxo-
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2i) was synthesized by the reaction of 2-(N-phenyl-
aminomethylene)-1,3-cyclohexanedione with cyanothioacetamide [54]. 1-Methyl-3-thioxo-2,3,5,6,7,8-hexa-
hydroisoquinoline-4-carbonitrile (2c) and 1-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-
4-carbonitrile (2d) were synthesized by the reaction of the 2-acetylcycloalkanones with cyanothioacetamide
[46]. Refined data on the structure of these products were given in our previous work [45].
6-tert-Butyl-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (2e). A solution of 4-tert-
butylcyclohexanone (10.0 g, 64.8 mmol) and ethyl formate (dried over potassium carbonate) (7.0 ml, 87 mmol)
in absolute ether (50 ml) was added dropwise with vigorous stirring and cooling with ice and salt bath to a
suspension of potassium tert-butoxide (7.3 g, 65 mmol) in absolute ether (100 ml). An exothermic reaction was
observed, the mixture turned yellow and viscous. The reaction mixture was stirred for 6 h and then maintained
for 24 h at 4°C. The precipitate was filtered off, washed with ether and acetone, and dried at 20°C to give 12.3 g
(86%) of 4-tert-butyl-2-formylcyclohexanone potassium salt, which was used immediately in the following
reaction.
A mixture of 4-tert-butyl-2-formylcyclohexanone potassium salt (12.3 g, 55.8 mmol), cyanothio-
acetamide (5.6 g, 55.9 mmol), and acetic acid (4.0 ml, 70.0 mmol) in 96% ethanol (25 ml) was heated slowly to
reflux with stirring. The suspension formed was stirred for 6 h at 20°C. The precipitate was filtered off to give
carbonitrile 2e. Yield 8.4 g (61%). Bright-yellow powder, decomp. temp. 305-310°С. IR spectrum, , cm-1:
3195 (NH), 2227 (C≡N), 1605 (C=C). 1Н NMR spectrum (500 MHz), , ppm: 13.91 (1Н, br. s, NH); 7.89 (1H,
s, H-4); 2.91-2.83 (1Н, m, СН); 2.70-2.57 (2Н, m, СН2); 2.26-2.21 (1Н, m,CН); 1.96-1.93 (1Н, m, СН);
1404

1.39-1.23 (2Н, m, 7-СН2); 0.90 (9Н, s, С(СН3)3). Found, %: C 68.26; H 7.35; N 11.44. C14H18N2S. Calculated,
%: C 68.25; H 7.36; N 11.37.
2-({[3-Methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)pyri-
dine-3-carbonitriles 3a-h (General Method A). A suspension of 3-cyanopyridine-2(1H)-thione 2a-h
(1.50 mmol) in warm DMF (3.0 ml) was treated with 10% aqueous KOH solution (0.8 ml, 1.56 mmol). A
solution of 8-(chloromethyl)-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1) (0.5 g, 1.50 mmol) in DMF
(1.0 ml) was added to the obtained solution of the corresponding potassium pyridine-2-thiolate. A precipitate
formed after a few seconds. The reaction mixture was stirred for 3-4 h at 15°C and diluted by adding an equal
volume of ethanol. After 2 h, the precipitate formed was filtered off, washed consecutively with ethanol, water,
ethanol, and petroleum ether, and dried at 60°C to give carbonitriles 3a-h as analytically pure compounds.
2-({[3-Methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)-
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carbonitrile (3a). Yield 0.53 g (69%). Pale-yellow powder, mp
280-282°С. Found, %: C 62.77; H 5.09; N 16.40. C27H26N6О3S. Calculated, %: C 63.02; H 5.09; N 16.33.
4-(2-Chlorophenyl)-2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-
8-yl]methyl}thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (3b). Yield 0.63 g (70%). Beige powder, mp
285-287°С. Found, %: C 62.38; H 4.20; N 14.26. C31H25ClN6О3S. Calculated, %: C 62.36; H 4.22; N 14.07.
1-Methyl-3-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}-
thio)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (3c) and 4-Methyl-2-({[3-methyl-2,6-dioxo-7-(2-oxo-
2-phenylethyl-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)-5,6,7,8-tetrahydroisoquinoline-3-carbonitrile
(3'c) (~9:2 ratio). Yield 0.40 g (53%). Sand-colored powder, mp 249-260°С (decomp.). Found, %: C 62.13;
H 4.88; N 16.85. C26H24N6О3S. Calculated, %: C 62.39; H 4.83; N 16.79.
1-Methyl-3-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}-
thio)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (3d) and 4-Methyl-2-({[3-methyl-2,6-dioxo-
7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)-6,7-dihydro-5H-cyclopenta[b]pyri-
dine-3-carbonitrile (3'd) (~5:3 ratio). Yield 0.47 g (64%). Pale-brown powder, mp 263-268°С (decomp.).
Found, %: C 62.02; H 4.58; N 17.25. C25H22N6О3S. Calculated, %: C 61.72; H 4.56; N 17.27.
6-tert-Butyl-2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}-
thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (3e). Yield 0.51 g (63%). Fine, white crystalline powder, mp
263-265°С. Found, %: C 64.12; H 5.58; N 15.65. C29H30N6О3S. Calculated, %: C 64.19; H 5.57; N 15.49.
4,6-Dimethyl-2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}-
thio)nicotinonitrile (3f). Yield 0.46 g (66%). Yellow powder, mp 260-265°С (decomp., АсОН). Found, %:
C 60.22; H 4.40; N 18.33. C23H20N6О3S. Calculated, %: C 59.99; H 4.38; N 18.25.
4-(4-Chlorophenyl)-2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-
8-yl]methyl}thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (3g). Yield 0.49 g (55%). Flesh-colored
powder, mp 260-261°С. Found, %: C 62.20; H 4.25; N 14.30. C31H25ClN6О3S. Calculated, %: C 62.36; H 4.22;
N 14.07.
2-({[3-Methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}thio)-
4,6-diphenylnicotinonitrile (3h). Yield 0.65 g (74%). White powder, mp 286-288°С (decomp.). Found, %:
C 67.67; H 4.17; N 14.50. C33H24N6О3S. Calculated, %: C 67.79; H 4.14; N 14.37.
Pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-diones 4a-h (General
Method A). Carbonitrile 3a-h (1.00 mmol) was dissolved in DMF (3-4 ml) at reflux and 10% aqueous
potassium hydroxide solution (0.8 ml, 1.56 mmol) was added dropwise with stirring. The mixture darkened, and
a potassium salt 6a-h precipitated. The suspension was stirred and heated at reflux for 1-2 min and cooled.
Acetic acid (1-2 ml) was added, and the reaction mixture turned a lighter color. After 2 h, the precipitate was
filtered off, washed consecutively with ethanol, water, hot ethanol, and petroleum ether, and dried at 60°C to
give diones 4a-h as analytically pure samples.
Pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f[purine-2,4(3H,6H)-diones 4a-k (General
Method B). A suspension of 3-cyanopyridine-2-(1H)-thione 2a-k (0.80 mmol) in warm DMF (3-4 ml) was
1405

treated with 10% aqueous potassium hydroxide solution (0.5 ml, 0.97 mmol) and stirred until full dissolution.
Then, 8-chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene (1) (0.27 g, 0.81 mmol) was added to the
obtained solution. A precipitate of alkylation product 3a-k formed after several seconds. The reaction mixture
was carefully heated at reflux for 3-5 min with continuous stirring. Then, an excess of 10% aqueous potassium
hydroxide solution (1.0 ml, 1.95 mmol) was added dropwise. The precipitate of 3a-k dissolved, and a
precipitate of potassium salt 6a-k formed immediately. The mixture was heated carefully at reflux with stirring
for 1-2 min, stirred for 1 h at 25-30°C, treated with acetic acid (1.0-1.5 ml) or several drops of hydrochloric acid
to achieve pH 4-5. An equal volume of ethanol was added. After 2 h the precipitate was filtered off, washed
consecutively with ethanol, water, hot ethanol, acetone, and petroleum ether, and dried at 60°C to give products
4a-k as analytically pure samples.
1-Methyl-7-phenyl-10,11,12,13,14,15-hexahydro-1H-cycloocta[5",6"]pyrido[3",2":4',5']thieno-
[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-dione (4a). Yield 0.38 g (77%, method A), 0.27 g (69%,
method B). Bright-yellow powder, mp > 300°С. Found, %: C 65.22; H 4.89; N 16.90. C27H24N6О2S. Calculated,
%: C 65.30; H 4.87; N 16.92.
9-(2-Chlorophenyl)-1-methyl-7-phenyl-10,11,12,13-tetrahydro-1H-purino[7",8":1',7'][1,4]diazepino-
[5',6':4,5]thieno[2,3-b]quinoline-2,4(3H,6H)-dione (4b). Yield 0.42 g (72%, method A), 0.25 g (54%, method B).
Bright-yellow powder, mp > 300°С. Found, %: C 64.12; H 3.98; N 14.66. C31H23ClN6О2S. Calculated, %:
C 64.30; H 4.00; N 14.51.
2,14-Dimethyl-8-phenyl-3,4,5,6-tetrahydro-9H-purino[7",8":1',7'][1,4]diazepino[5',6':4,5]thieno-
[2,3-c]isoquinoline-11,13(12H,14H)-dione (4c) and 1,9-Dimethyl-7-phenyl-10,11,12,13-tetrahydro-1H-pu-
rino[7",8":1',7'][1,4]diazepino[5',6':4,5]thieno[2,3-b]quinoline-2,4(3H,6H)-dione (4'c) (the regioisomer
ratio was not determined). Yield 0.36 g (75%, method A), 0.26 g (61%, method B). Yellow powder, mp > 300°С.
Found, %: C 64.42; H 4.65; N 17.36. C26H22N6О2S. Calculated, %: C 64.71; H 4.60; N 17.42.
2,13-Dimethyl-7-phenyl-4,5-dihydro-3H,8H-cyclopenta[4",5"]pyrido[3",2":4',5']thieno[3',2':5,6]-
[1,4]diazepino[7,1-f]purine-10,12(11H,13H)-dione (4d) and 1,9-Dimethyl-7-phenyl-11,12-dihydro-
1H,6H-cyclopenta[5",6"]pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,10H)-dione
(4'd) (regioisomer ratio ~9:4). Yield 0.38 g (80%, method A), 0.24 g (65%, method B). Bright-yellow powder,
mp > 300°С. Found, %: C 64.01; H 4.32; N 18.06. C25H20N6О2S. Calculated, %: C 64.09; H 4.30; N 17.94.
11-tert-Butyl-1-methyl-7-phenyl-10,11,12,13-tetrahydro-1H-purino[7",8":1',7'][1,4]diazepino[5',6':4,5]-
thieno[2,3-b]quinoline-2,4(3H,6H)-dione (4e). Yield 0.42 g (79%, method A), 0.26 g (63%, method B).
Bright-yellow powder, mp > 300°С. Found, %: C 66.25; H 5.42; N 16.16. C29H28N6О2S. Calculated, %:
C 66.39; H 5.38; N 16.02.
1,9,11-Trimethyl-7-phenyl-1H-pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-
2,4(3H,6H)-dione (4f). Yield 0.40 g (90%, method A), 0.26 g (72%, method B). Bright-yellow powder,
mp > 300°С. Found, %: C 62.20; H 4.13; N 19.01. C23H18N6О2S. Calculated, %: C 62.43; H 4.10; N 18.99.
9-(4-Chlorophenyl)-1-methyl-7-phenyl-10,11,12,13-tetrahydro-1H-purino[7",8":1',7'][1,4]diazepino-
[5',6':4,5]thieno[2,3-b]quinoline-2,4(3H,6H)-dione (4g). Yield 0.42 g (73%, method A), 0.24 g (52%, method
B). Bright-yellow powder, mp > 300°С. Found, %: C 64.16; H 4.03; N 14.74. C31H23ClN6О2S. Calculated, %:
C 64.30; H 4.00; N 14.51.
1-Methyl-7,9,11-triphenyl-1H-pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,6H)-
dione (4h). Yield 0.42 g (74%, method A), 0.27 g (59%, method B). Bright-yellow powder, mp > 300°С.
Found, %: C 69.76; H 3.95; N 14.99. C33H22N6О2S. Calculated, %: C 69.95; H 3.91; N 14.83.
1-Methyl-7-phenyl-12,13-dihydro-1H-purino[7",8":1',7'][1,4]diazepino[5',6':4,5]thieno[2,3-b]quino-
line-2,4,10(3H,6H,11H)-trione (4i). Yield 0.23 g (59%, method B). Red-brown powder, mp > 300°С. Found,
%: C 62.05; H 3.78; N 17.59. C25H18N6О3S. Calculated, %: C 62.23; H 3.76; N 17.42.
9-(2-Chlorophenyl)-1-methyl-7-phenyl-11,12,13,14-tetrahydro-1H,6H-cyclohepta[5",6"]pyrido-
[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-2,4(3H,10H)-dione (4j). Yield 0.42 g (88%, method B).
1406

Bright-yellow powder, mp > 300°С. Found, %: C 64.45; H 4.29; N 14.39. C32H25СlN6О2S. Calculated, %:
C 64.80; H 4.25; N 14.17.
1-Methyl-7-phenyl-9-(2-thienyl)-10,11,12,13-tetrahydro-1H-purino[7",8":1',7'][1,4]diazepino[5',6':4,5]-
thieno[2,3-b]quinoline-2,4(3H,6H)-dione (4k). Yield 0.20 g (45%, method B). Bright-yellow powder,
mp > 300°С. Found, %: C 62.95; H 4.09; N 15.47. C29H22N6О2S2. Calculated, %: C 63.25; H 4.03; N 15.26.
1,9,11-Trimethyl-7-phenyl-1H-pyrido[3",2":4',5']thieno[3',2':5,6][1,4]diazepino[7,1-f]purine-
2,4(3H,6H)-dione Potassium Salt (6f). A suspension of 3-cyanopyridine-4,6-dimethyl-2(1H)thione (2f) [52]
(0.115 g, 0.70 mmol) in warm DMF (1.8 ml) was treated with 10% aqueous potassium hydroxide solution
(0.4 ml, 0.78 mmol) and stirred until full dissolution. 8-(Chloromethyl)-3-methyl-7-(2-oxo-2-phenylethyl)-
xanthene (1) (0.232 g, 0.70 mmol) was added to the solution formed. A precipitate of the alkylation product 3f
formed immediately. The reaction mixture was carefully heated at reflux for 3-5 min with continuous stirring,
and 10% aqueous potassium hydroxide solution (0.6 ml, 1.17 mmol) was added dropwise. The precipitate of
compound 3f dissolved, and a new precipitate of potassium salt 6f formed immediately. The mixture was heated
carefully at reflux with stirring for 1-2 min and stirred for 1 h at 15°C. An equal volume of ethanol was added.
After 2 h, the precipitate was filtered off, washed consecutively with ethanol, water, acetone, and petroleum
ether, and dried at 60°C to give salt 6f as an analytically pure sample. Yield 0.252 g (75%). Yellow powder, mp
1
> 300°С. IR spectrum, , cm-1: 1710, 1680, 1635, 1605. Н NMR spectrum, , ppm: 8.41-8.38 (2H, m, H-2,6
Ph); 7.60-7.58 (3H, m, H-3,5 Ph); 7.28 (1H, s, H-10); 5.52 (2H, br. pseudo s, NCH2); 3.40 (3Н, s, NCН3); 2.88
(3Н, s, СН3); 2.62 (3Н, s, СН3). Found, %: C 57.31; H 3.60; N 17.62. C23H17KN6О2S. Calculated, %: C 57.48;
H 3.57; N 17.49.
6-Methyl-2-({[3-methyl-2,6-dioxo-7-(2-oxo-2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}-
thio)-4-oxo-1,4-dihydropyridine-3-carbonitrile (8). 8-Chloromethyl-3-methyl-7-(2-oxo-2-phenylethyl)xanthene
(1) (0.196 g, 0.59 mmol) was added to a solution of triethylammonium 3-cyano-6-methyl-4-oxo-1,4-dihydro-
pyridine-2-thiolate (7) [44] (0.150 g, 0.56 mmol) in warm DMF (2.0 ml), and the mixture was heated to reflux
with stirring. Then, 10% aqueous potassium hydroxide solution (0.4 ml, 0.78 mmol) was added dropwise to the
dark solution formed, heated at reflux carefully for 2-3 min, and left for 24 h at 15°C. Several drops of
concentrated hydrochloric acid were added to the reaction mixture to achieve pH 3-4, and the mixture was
diluted by adding water (6 ml). After five days the precipitate was filtered off, washed consecutively with
ethanol, water, acetone, and petroleum ether, and dried at 60°C to give carbonitrile 8 as an analytically pure
sample. Yield 0.197 g (76%). Brown powder, mp 232-235°С (decomp.). IR spectrum, , cm-1: 3165 (NH); 2221
(C≡N); 1715-1680 (4C=O). 1Н NMR spectrum, , ppm (J, Hz): 11.03 (1Н, br. s, NH xanthene); 7.98 (2H, br. d,
J = 7.6, H-2,6 Ph); 7.75-7.71 (1H, m, H-4 Ph); 7.58 (2H, dd J = 7.6, J = 7.6, H-3,5 Ph); 6.53 (1H, s, H-5 Py);
6.01 (2H, br. pseudo s, NCH2CO); 4.72 (2H, br. pseudo s, SCH2); 3.38 (3Н, s, NCН3); 2.22 (3Н, s, СН3).
The pyridone fragment NH signal does not appear, presumably due to a tendency towards rapid
deuterium exchange with water contained in the sample of DMSO-d6 [44]. Found, %: C 57.29; H 3.96; N 18.27.
C22H18N6О4S. Calculated, %: C 57.14; H 3.92; N 18.17.
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