Synthesis of pyrido[3',2':4,5]thieno[3,2-d]-[1,3,2]diazaphosphorine derivatives

Article abstract of DOI:10.1007/s10593-013-1220-6

Refluxing 3-aminothieno[2,3-b]pyridine-2-carboxamides with P ₄S₁₀ in dry pyridine gave the substituted 2-mercapto-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorin-4(1H) -one-2-thiones and/or -2,4(1H)-dithiones as 1:1 c

Full text of DOI:10.1007/s10593-013-1220-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS OF PYRIDO[3',2':4,5]THIENO[3,2-d]-
[1,3,2]DIAZAPHOSPHORINE DERIVATIVES
V. V. Dotsenko1* and S. G. Krivokolysko1
Refluxing 3-aminothieno[2,3-b]pyridine-2-carboxamides with P4S10 in dry pyridine gave the substituted
2-mercapto-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorin-4(1H)-one-2-thiones
and/or -2,4(1H)-dithiones as 1:1 complexes with pyridine.
Keywords: 1,3,25-diazaphosphorines, tetraphosphorus decasulfide, thieno[2,3-b]pyridines, thiophos-
phorylation.
Thieno[2,3-b]pyridines form a very numerous and accessible group of compounds with a broad
spectrum of useful properties [1-4], which includes anti-inflammatory, antibacterial, anticancer and other types
of activity. In recent times, thieno[2,3-b]pyridines have been actively used in the preparation of condensed
analogs and of different functionalized derivatives [1-4]. 1,3,25-Diazaphosphorines are a relatively little
studied class of compounds [5, 6]. They principally attract interest as aza analogs of known 1,3,2-oxaza-
phosphorine series anticancer drugs (cyclophosphamide, trofosfamide and its derivatives [7-9]). The data
concerning the antitumor activity of 1,3,2-diazaphosphorines [9, 10] points to the possibility of promising
developments in this area. In addition, condensed 1,3,2-diazaphosphorines have been seldom reported in the
literature. Accessible 3-aminothieno[2,3-b]pyridine-2-carboxamides are convenient substrates for
phosphorylation reactions, but similar reactions of thienopyridines have not been described, and phosphorus
containing thieno[2,3-b]pyridine derivatives have not been reported to the current time.
R2
R2
SH
P
R1
R1
· Py
H
NH2
N
S
0.25–2.00 equiv. P4S10
NH
NH2
Py, 
R
R
N
N
S
1a–d
S
X
O
2, 3 a–d
1–3 a R+R1 = (CH2)3, R2 = 2-furyl; b R+R1 = (CH2)4, R2 = 4-BnOC6H4;
c R+R1 = (CH2)4, R2 = H; d R = R2 = Me, R1 = H; 2a–d X = O, 3a–d X = S
_______
*To whom correspondence should be addressed, e-mail: victor_dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A/7 Molodyozhnyi Kv, Lugansk
91034, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1987-1991, December, 2012.
Original article submitted June 25, 2012.
0009-3122/13/4812-1863©2013 Springer Science+Business Media New York
1863

We have found that the 3-aminothienopyridine-2-carboxamides 1a,b,d are readily thiophosphorylated
using 0.25 equivalents of P4S10 in refluxing absolute pyridine, to form the tetrahydropyrido[3',2':4,5]thieno-
[3,2-d][1,3,2]diazaphosphorines 2a,b,d, representing a novel heterocyclic system. The reaction was not
conducted with compound 1c under these conditions.
Using an excess of P4S10 led to a mixture of compounds 2a-d and the thionation products 3a-d in
variable proportions. It should be noted that the thiophosphorylation of ortho-aminocarboxamides with excess
P4S10 was almost always accompanied by full thionation, and products with a carbonyl function were very rarely
found [11]. Full thionation in this case clearly required the use of at least equimolar amount of P4S10.
Compounds 2, 3a-d form stable 1:1 solvates with pyridine, which agrees well with known data for
benzo[1,3,2]diazaphosphorine derivatives [12]. Compounds 2, 3a-d are insoluble in ether and acetone, poorly
soluble in pyridine, cold water, and ethanol, but soluble in DMSO and in hot water.
Hence treatment of 3-aminothieno[2,3-b]pyridine-2-carboxamides with P4S10 in pyridine opens up
possibilities for preparing pyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorine derivatives. The use of an
excess of P4S10 also provides an option for thionation of the substrate carbonyl group.
EXPERIMENTAL
1
The H NMR spectra were recorded on Bruker DPX-400 (400 MHz) and DRX-500 (500 MHz)
instruments using DMSO-d6 with TMS as internal standard. The 13C NMR spectra were recorded in
heteronuclear decoupling mode on a Bruker DRX-500 (125 MHz) instrument using DMSO-d6 with TMS as
31
internal standard. The P NMR spectra were recorded on a Varian VXR-300 (121 MHz) using 85% H3PO4 as
external standard. HPLC-MS analysis was performed for compounds 2a and 3c using an Agilent 1100
chromato-mass spectrometer with diode array (UV, 215, 254, and 265 nm) and Agilent LC/MSD SL mass
selective detectors with a Zorbax SB-C18 analytical column and with electrospray ionization at atmospheric
pressure. HPLC-MS analysis of compounds 2b,d and the mixtures of compounds 2b+3b and 2d+3d was
performed on a Shimadzu LC-10AD liquid chromatograph with Shimadzu SP D-10A UV-Vis (254 nm) and
Sedex 75 ELSD detectors combined with a PE SCIEX API 150EX mass spectrometer. Elemental analysis was
carried out using a Carlo-Erba 1106 Elemental Analyzer. Melting points were determined on a Kofler hot stage
apparatus, and were not corrected. The purity of the obtained compounds was monitored on Silufol UV-254
plates with acetone–hexane (1:1) as eluent and visualized using UV light and iodine vapor. Compounds 1c,d
have been reported in the literature [13, 14] and were prepared by alkylation of the corresponding 3-cyano-
pyridine-2(1H)-thiones with 2-chloroacetamide with subsequent Thorpe–Ziegler cyclization of the S-alkyl
derivatives using KOH in DMF.
3-Amino-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxamide (1a). A 10%
aqueous KOH solution (2.3 ml, 4.40 mmol) was added to a suspension of the 4-(2-furyl)-2-thioxo-2,5,6,7-tetra-
hydro-1H-cyclopenta[b]pyridine-3-carbonitrile [15] (1.0 g, 4.13 mmol) in DMF (5 ml) and stirred at 70-80°C to
full dissolution. 2-Chloroacetamide (0.4 g, 4.28 mmol) was added as a single aliquot to this solution, stirred for
30 min at 25°C, and heated to reflux. A further amount of the 10% aqueous KOH (2.3 ml, 4.40 mmol) was
added, and the obtained mixture was refluxed with stirring for 2-3 min, cooled, diluted with EtOH (10 ml), and
left overnight. The precipitate that formed was filtered off and washed with EtOH and water. Yield 0.8 g (65%).
1
Fine, yellow-brown crystals. Mp >260ºC (decomp.). H NMR spectrum (400 MHz), , ppm (J, Hz): 2.07-2.12
(2Н, m, СН2); 2.90-2.94 (2Н, m, СН2); 3.04-3.08 (2Н, m, СН2); 6.34 (2H, br. s, NН2); 6.77-6.80 (1H, m, Н-4
Fur); 6.91 (1Н, br. d, J = 2.5, Н-3 Fur); 7.20 (2H, br. s, CONH2); 7.98 (1H, m, Н-5 Fur). Found, %: C 60.34;
H 4.30; N 14.19. C15H13N3O2S. Calculated, %: C 60.19; H 4.38; N 14.04.
3-Amino-4-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide
(1b)
was prepared by modification of method [16]. A suspension of the 4-[4-(benzyloxy)phenyl]-2-thioxo-
1,2,5,6,7,8-tetrahydroquinoline-3-carbonitrile (1.00 g, 2.69 mmol) in DMF (6 ml) was treated with 10%
1864

aqueous KOH (1.5 ml, 2.89 mmol), and 2-chloroacetamide (0.26 g, 2.78 mmol) was added to the solution
obtained. The suspension of the S-alkylated derivative was stirred for 1 h at 40°C, a further 10% aqueous KOH
(1.5 ml) was added, and the mixture was refluxed with stirring for 3 min. The reaction mixture was maintained
for 24 h at 20°C, the precipitate formed was filtered off and washed successively with EtOH, water, EtOH, and
Et2O. Yield 1.06 g (93%). Light-yellow powder. Mp 248-250°C. 1H NMR spectrum (400 MHz), , ppm (J, Hz):
1.65-1.69 (2Н, m, СН2); 1.77-1.84 (2Н, m, СН2); 2.34-2.37 (2Н, m, СН2); 2.95-2.99 (2Н, m, СН2); 5.18 (2H,
br. s, OCH2); 5.62 (2H, br. s, NH2); 7.07 (2H, br. s, CONH2); 7.20 (2H, d, J = 8.7, H Ar); 7.26 (2H, d, J = 8.7,
H Ar); 7.34-7.38 (1H, m, Н-4 Ph); 7.42 (2H, dd, J = 7.3, J = 7.3, Н-3,5 Ph); 7.50 (2H, d, J = 7.3, Н-2,6 Ph).
Found, %: C 70.04; H 5.47; N 9.89. C25H23N3O2S. Calculated, %: C 69.91; H 5.40; N 9.78.
Synthesis of Tetrahydropyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorines 2, 3 (General
Method). Finely powdered thienopyridine 1a-d (1-3 mmol) was dissolved with heating in absolute pyridine
(4-5 ml). The indicated amount of P4S10 was added in one aliquot to the solution obtained. The reaction mixture
was refluxed for 1 h. Generally, even after 5-7 min a yellow, crystalline product began to precipitate. The
suspension was cooled, poured into EtOH (15-20 ml), stirred for 3 h, filtered, and repeatedly washed with EtOH
and acetone.
10-(2-Furyl)-2-mercapto-2-thioxo-2,3,8,9-tetrahydrocyclopenta[5',6']pyrido[3',2':4,5]thieno[3,2-d]-
[1,3,2]diazaphosphorin-4(1H)-one, 1:1 Complex with Pyridine (2a). Obtained from the thienopyridine 1a
(563 mg, 1.88 mmol) and P4S10 (210 mg, 0.47 mmol). Yield 443 mg (50%). Yellow-brown, fine crystalline
1
powder. Mp >250ºC (decomp.). H NMR spectrum (500 MHz), , ppm (J, Hz): 2.08-2.18 (2Н, m, СН2);
2.98-3.12 (4Н, m, 2СН2); 6.86-6.91 (1H, m, Н-4 Fur); 7.03-7.08 (2Н, m, Н-3 Fur, 1-NН); 7.73 (2Н, dd, J = 7.5,
J = 5.0, H-3,5 Py); 8.04-8.10 (1H, m, Н-5 Fur); 8.20 (1Н, dt, J = 7.5, J = 1.7, H-4 Py); 8.75 (2H, br. d, J = 5.0, H-2,6
Py); 9.97 (1H, d, JH–P = 13.1, 3-NН). Signals for the SH protons were not observed, probably because of
deuterium exchange. 13C NMR spectrum, , ppm: 23.4 (С-8); 30.8 (С-9); 34.5 (С-7); 108.8 (C Ar); 113.8
(C Ar); 114.8 (C Ar); 127.3 (C-3,5 Py); 130.0 (C Ar); 133.4 (C-4 Py); 138.8 (C Ar); 143.6 (C-2,6 Py); 145.2
(C Ar); 145.6 (C Ar); 147.4 (C Ar); 150.8 (C Ar); 160.4 (C Ar); 161.5 (C Ar); 167.5 (C=O). 31P NMR spectrum
(DMSO-d6), , ppm (J, Hz): 78.9 (dd, JP–H = 8.9, JP–H = 13.1). Mass spectrum, m/z: 394.0 [М-Py+H]+, 392.0
[М-Py-H]-. Found, %: C 51.06; H 3.70; N 11.99. C20H17N4O2PS3. Calculated, %: C 50.84; H 3.63; N 11.86.
According to the HPLC-MS data, the purity was 94.5%. The product contained an impurity of the
starting compound 1a (m/z 300.2 [M+H]+) and the thionation product 10-(2-furyl)-2-mercapto-2,3,8,9-tetra-
hydrocyclopenta[5',6']pyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorine-2,4(1H)-dithione (3a) (1:1
complex with pyridine) (m/z 410.0 [M-Py+H]+, 407.8 [M-Py-H]-).
11-[4-Benzyloxy)phenyl]-2-mercapto-2-thioxo-2,3,7,8,9,10-hexahydro[1,3,2]diazaphosphorino-
[4',5':4,5]thieno[2,3-b]quinolin-4(1H)-one, 1:1 Complex with Pyridine (2b). Obtained from the thieno-
pyridine 1b (421 mg, 1.02 mmol) and P4S10 (113 mg, 0.26 mmol). Yield 213 mg (38%). Yellow crystals. Mp
1
225-240°C (decomp.). H NMR spectrum (500 MHz), , ppm (J, Hz): 1.66-1.70 (2Н, m, СН2); 1.79-1.84 (2Н,
m, СН2); 2.39-2.42 (2Н, m, СН2); 2.98-3.01 (2Н, m, СН2); 5.06 (1H, d, JH–P = 12.6, NН-1); 5.22 (2H, br. s,
3
3
OCH2); 7.26 (2H, d, J = 8.7, H Ar); 7.30 (2H, d, J = 8.7, H Ar); 7.36 (1H, t, 3J = 7.3, H-4 Ph); 7.43 (2Н, dd,
3J = 7.3, J = 7.3, H-3,5 Ph); 7.52 (2H, d, J = 7.3, H-2,6 Ph); 8.00 (2Н, dd, J = 7.9, J = 6.7, H-3,5 Py); 8.52
(1H, t, J = 7.9, H-4 Py); 8.89-8.93 (3H, m, 3-NН, H-2,6 Py). Signals for the SH protons were not observed,
probably because of deuterium exchange. 13C NMR spectrum, , ppm: 22.7, 22.8 (С-8,9); 26.7 (С-10); 33.6
(С-7); 70.1 (OCH2); 108.4 (C Ar); 115.8 (C Ar); 116.2 (C Ar); 126.4 (C-3,5 Py); 126.6 (C Ar); 128.2 (C Ar);
128.3 (C Ar); 128.4 (2C Ar); 129.0 (C Ar); 130.2 (C Ar); 130.4 (C-4 Py); 137.2 (C Ar); 142.6 (C Ar); 145.6
(C Ar); 145.7 (C-2,6 Py); 157.9 (C Ar); 159.4 (C Ar); 161.2 (C=O). 31P NMR spectrum (DMSO-d6), , ppm
3
3
(J, Hz): 80.1 (dd, JP–H = 12.6, JP–H = 13.4). Mass spectrum, m/z: 524.3 [M-Py+H]+, 1046.8 [2M-2Py+H]+.
3
3
Found, %: C 60.06; H 4.60; N 9.49. C30H27N4O2PS3. Calculated, %: C 59.78; H 4.52; N 9.30.
Using a 1.5-fold excess of P4S10 (170 mg, 0.38 mmol) gave a mixture (288 mg), which according to
1
HPLC-MS and H NMR spectroscopy contains compounds 2b and 11-[4-(benzyloxy)phenyl]-2-mercapto-
2,3,7,8,9,10-hexahydro[1,3,2]diazaphosphorino[4',5':4,5]thieno[2,3-b]quinoline-2,4(1H)-dithione (3b) in
1865

~4:1 ratio. Compound 3b (as 1:1 complex with pyridine) was identified from the minor peaks in the 1H, 13C, and
31P NMR spectra. 1H NMR spectrum (500 MHz), , ppm (J, Hz): 5.38 (1H, d, 3JH–P = 13.1, 1-NH); 10.47 (1H, d,
3JH–P = 15.6, 3-NH). 13C NMR spectrum, , ppm: 194.6 (C=S). 31P NMR spectrum (DMSO-d6), , ppm (J, Hz):
73.7 (dd, 3JP–H = 13.1, 3JP–H = 15.6). Mass spectrum, m/z: 540.0 [M-Py+H]+.
2-Mercapto-7,9-dimethyl-2-thioxo-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorin-
4(1H)-one, 1:1 Complex with Pyridine (2d). Obtained from the thienopyridine 1d (625 mg, 2.82 mmol) and
P4S10 (314 mg, 0.71 mmol). Yield 591 mg (53%). Yellow-green, fine crystalline powder. Mp >300°C (decomp.).
1H NMR spectrum (400 MHz), , ppm (J, Hz): 2.54 (3Н, s, СН3); 2.76 (3Н, s, СН3); 7.13 (1Н, s, Н-8); 7.53 (2Н,
ddd, J = 7.5, J = 5.8, J = 1.7, H-3,5 Py); 7.95 (1Н, dt, J = 7.5, J = 1.3, H-4 Py); 8.56 (1H, d, JH–P = 12.1, 1-NН);
8.61 (2H, dd, J = 5.8, J = 1.3, H-2,6 Py); 10.04 (1H, d, JH–P = 15.8, 3-NН). Signals for the SH protons were not
observed, probably because of deuterium exchange. 31P NMR spectrum (D2O), , ppm (J, Hz): 79.7 (dd, JP–H = 11.1,
JP–H = 15.8). Mass spectrum, m/z: 316.0 [M-Py+H]+, 631.0 [2M-2Py+H]+, 945.8 [3M-3Py+H]+. Found, %:
C 45.96; H 3.80; N 14.48. C15H15N4OPS3. Calculated, %: C 45.67; H 3.83; N 14.20.
The use of 2.0 equivalents of P4S10 (625 mg, 1.41 mmol) gave a mixture (490 mg), which according to
1
HPLC-MS and H NMR spectroscopy consisted of compound 2d and 2-mercapto-7,9-dimethyl-2,3-dihydro-
pyrido[3',2':4,5]thieno[3,2-d][1,3,2]diazaphosphorine-2,4(1H)-dithione (3d) in a ~6:1 ratio. Compound 3d
(as a 1:1 pyridine complex) was identified from the minor peaks. 1H NMR spectrum (400 MHz), , ppm (J, Hz):
2.73 (3H, s, CH3); 7.11 (1H, s, H-8); 8.15 (1H, br. pseudo-s, 1-NH); 11.10 (1H, br. pseudo-s, 3 NH). Mass
spectrum, m/z: 332.0 [M-Py+H]+, 665.3 [2M-2Py+H]+.
2-Mercapto-2,3,7,8,9,10-hexahydro[1,3,2]diazaphosphorino[4',5':4,5]thieno[2,3-b]quinoline-
2,4(1H)-dithione, 1:1 Complex with Pyridine (3c). Obtained from the thienopyridine 1c (340 mg,
1.38 mmol) and P4S10 (611 mg, 1.38 mmol). Yield 455 mg (79%). Dark-yellow, fine crystalline powder. Mp
>250°C (decomp.). 1H NMR spectrum (500 MHz), , ppm (J, Hz): 1.78-1.94 (4Н, m, 8,9-СН2); 2.86-2.98 (4Н, m,
7,10-СН2); 7.39-7.50 (3H, m, H-11, H-3,5 Py); 7.87 (1H, t, 3J = 8.3, H-4 Py); 8.23 (1H, d, JH–P = 13.2, 1-NН); 8.61
(2H, br. d, H-2,6 Py). Signals for the SH and 3-NH protons were not observed, probably because of deuterium
exchange. 13C NMR spectrum, , ppm: 22.7, 22.8 (С-8,9); 28.8 (С-10); 30.1 (С-7); 125.2 (C-3,5 Py); 126.0 (C Ar);
129.3 (C Ar); 132.5 (C Ar); 134.8 (C Ar); 137.4 (C Ar); 138.9 (C-4 Py); 148.3 (C-2,6 Py); 151.4 (C Ar); 159.8
(C Ar); 215.6 (C=S). 31P NMR spectrum (DMSO-d6), , ppm (J, Hz): 73.7 (dd, JP–H = 13.2, JP–H = 15.6). Mass
spectrum, m/z: 358.0 [М-Py+H]+, 356.0 [М-Py-H]-. Found, %: C 47.03; H 4.01; N 12.98. C17H17N4PS4.
(M 436.58). Calculated, %: C 46.77; H 3.92; N 12.83.
According to HPLC-MS data, the purity of the obtained compound 3c was ~96%. The product
contained an impurity (~4%) of the 2-mercapto-2-thioxo-2,3,7,8,9,10-hexahydro[1,3,2]diazaphosphorino-
[4',5':4,5]thieno[2,3-b]quinolin-4(1H)-one (2c) (1:1 complex with pyridine). Mass spectrum, m/z: 342.0
[M-Py+H]+, 339.8 [M-Py-H]+.
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