Synthesis and study of the properties of 7,8-polymethyleneimidazo[4,5-d]-1, 3,2-diazaphosphorev-2-thiones

Article abstract of DOI:10.1023/B:COHC.0000023777.35950.cd

In thionation of cyclic N-cyanoamidines, a four-step process occurs that leads to derivatives of novel heterocyclic systems: 7,8-polymethyleneimidazo[4, 5-d]-1,3,2-diazaphosphorin-2-thiones. We have studied the chemical and spectral properties of the compounds obtained.

Full text of DOI:10.1023/B:COHC.0000023777.35950.cd

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
SYNTHESIS AND STUDY OF THE PROPERTIES
OF 7,8-POLYMETHYLENEIMIDAZO[4,5-d]-
1,3,2-DIAZAPHOSPHORIN-2-THIONES
D. B. Nilov1, A. V. Kadushkin2, N. P. Solov'eva1, Yu. N. Sheinker1, and V. G. Granik2
In thionation of cyclic N-cyanoamidines, a four-step process occurs that leads to derivatives of novel
heterocyclic systems: 7,8-polymethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones. We have
studied the chemical and spectral properties of the compounds obtained.
Keywords: imidazo[4,5-d]-1,3,2-diazaphosphorins, phosphorus pentasulfide, N-cyanoamidines,
thionation, Thorpe–Ziegler cyclization.
In the course of studying the chemical and biological properties of derivatives of 1-carbamidomethyl-2-
pyrrolidone (piracetam) and its analogs [1-3], it has been established that converting the amide groups to
thioamide groups leads to a sharp enhancement of the antihypoxic and nootropic activity of the compounds
[4, 5]. Continuing this research, we attempted to convert the carbamoyl group of 1-carbamidomethyl-2-
cyanoiminopyrrolidine (1a), which also exhibits nootropic and anticonvulsive action [6] to thiocarbamoyl group.
However, in a study of the reaction product of carbamide 1a and phosphorus pentasulfide in pyridine, we found
that the reaction did not stop at the thionation step but rather proceeded all the way to formation of a tricyclic
system containing annelated pyrrole, imidazole, and 1,3,2-diazaphosphorin rings. In fact, in the IR spectrum of
the product 2a obtained (isolated as a pyridine solvate), there was no absorption band from the CN group. In the
1H NMR spectrum of compound 2a in DMSO-d6, we observed the following proton signals at δ, ppm (J, Hz):
2.50 (2H, m, 7-CH2); 2.84 (2H, t, 8-CH2); 4.30 (2H, t, 6-CH2); 9.30 (1H, br. d, 2J = 15.3, NH, NH–P), and 9.38
(1H, br. s, NH), and pyridine protons at 7.79 (2H, t, β-H); 8.26 (1H, t, γ-H); 8.79 (2H, d, α-H).* In the mass
spectrum of tricycle 2a, we observe a molecular ion peak (m/z) [M]+ 276 and ion peaks 243 [M+ - SH], 184
+
[M+ - SH, - CSNH2], 148 [M+ - SH, - PS2], 123 [M+ - CS - NH - PS2], 95 [PS2 ]. An SH proton signal is not
1
clearly seen in the H NMR spectrum, which is consistent with the data in [8] concerning a study of the spectra
for such compounds.
Based on all the results obtained, the isolated compound was assigned the structure of
7,8-trimethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione (2a). Similarly, 1-carbamidomethyl-2-cyano-
iminopiperidine (1b) and 1-carbamidomethyl-2-cyanoiminohexahydroazepine (1c), when reacted with P2S5 in
pyridine, are converted to 7,8-tetra- and 7,8-pentamethyleneimidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones
2b,c. The proposed scheme for these irreversible conversions is shown below:
_______
* The tendency of 1,3,2-diazaphosphorin derivatives to form pyridine solvates of variable composition has been
described in [7-12].
__________________________________________________________________________________________
1
Drug Chemistry Center/All-Russian Scientific Research Pharmaceutical Chemistry Institute, Moscow
2
119815; e-mail: nilov22@hotmail.com. Federal State Unitary Enterprises. "The State Scientific Center
NIOPIK", Moscow 103787, Russia; e-mail: alex111x@orc.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 1, pp. 113-121, January, 2004. Original article submitted July 19, 2001.
106
0009-3122/04/4001-0106©2004 Plenum Publishing Corporation

NCN
P2S5/Py
n(CH2)
N
CH2CONH2
1a–c
SH
P
H
N
S
N
N
NH2
NCN
n(CH2)
n(CH2)
n(CH2)
SH
N
N
N
CSNH2
CSNH2
3
CH2CSNH2
4
H
γ
N
N
S
SH
.
P
n(CH2)
β
.
N
NH
α
N
x
2a–c
S
1a, 2a n = 1; 1b, 2b n = 2; 1c, 2c n = 3
In the first step, conversion of amide to thioamide occurs (as is usual under these conditions), where
significant activation of the methylene unit occurs [14], making possible a Thorpe–Ziegler cyclization [15] with
participation of this unit and the N-cyano group. 1,2-Polymethylene-4-amino-5-carbamidoimidazoles 3 formed
in this case are acylated by the phosphorus pentasulfide at the primary 4-amino group, followed by cyclization of
the derivative 4 obtained to tricyclic diazaphosphorins 2.
We carried out an analogous cyclization within this work based on 1,2-trimethylene-4-amino-5-
cyanoimidazole (5) [16, 17]. In this case, as the reaction product we isolated the tricycle 2a (the reaction
probably occurs via intermediate 4).
N
NH2
CN
P2S5/Py
N
5
H
SH
N P
SH
CN
N
S
H2S
2a
4
N
We must reiterate that in this work, as in the papers cited above [7-12], depending on the conditions
under which the reaction products are isolated and the conditions under which the solvent is removed, the
pyridine content (%) in the solvates fluctuates in rather broad limits (from 6 to 50 mole %, according to 1H NMR
spectral data). Nevertheless, a stable compound was obtained upon heating pyridine solvate 2a with
benzylamine. The high basicity of the latter makes it possible to synthesize a stable compound 6, for which we
obtained not only clear spectral data but also satisfactory elemental analysis results (see Experimental).
The presence of thiol and thiocarbamoyl moieties in compounds 2a-c makes possible alkylation of their
anions by both alkyl halides and dialkyl sulfates. In this case, using alkyl halides we can obtain dialkyl
derivatives 7a-d. When compound 2a reacts with dimethyl and diethyl sulfates, the alkylation occurs not only at
the sulfur atoms but also at the NH group in the position 1, and as a result tris-alkyl derivatives 8a,b are formed:
107

H
N
S
N
P
n(CH2)
RHal
SR
N
N
EtONa/EtOH
2a–c
7a–d
SR
R2SO4/NaOH
(for 2a)
a–c n = 1–3, R =
d n = 1, R = Me
CH2Ph
PhCH2NH2
(for 2a)
R
S
N
N
P
H
SR
S
N
N
N
N
P
n(CH2)
PhCH2NH2
SH
NH
8a,b
N
SR
S
R = Me, Et
6
The next step in this work was to study the reactions of compounds 7 and 8 with nucleophilic reagents,
as which we selected various amino derivatives. When compounds 7d and 8a reacted with amines, we observed
an interesting fact: while diallyl derivative 7d yields 2-morpholide 9a as the major product when reacted with
morpholine (the other bis-alkyl substituted derivative 7a reacts analogously, to form the derivative 9b), the
reaction of tris-alkyl derivative 8a with morpholine leads to substitution at the position 4 and formation of
1
compound 10. To refine these results using H NMR spectroscopy, we studied the reaction mixtures (after
driving off the excess morpholine) obtained as a result of the indicated reactions. We found that after reaction of
compounds 7d and morpholine, the mixture contained morpholide 9a, the starting compound 7d, and
4-morpholino derivative 11 (~6:2:1). Only 4-morpholino derivative 10 and starting 8a (24:1) were present in the
reaction mass obtained when compound 8a was heated with morpholine.
H
H
N
N
N
S
HN
O
N
S
P
P
N
+
7d
SMe
N
N
N
N
O
N
SMe
N
O
9a
11
Me
HN
O
N
S
P
8a
SMe
N
N
N
O
10
The compounds 9a,b and 10 were isolated in pure form. A series of reactions carried out with other
amines, including aromatic amines (the mixtures thus obtained were analyzed using 1H NMR spectra) shows that
for reaction of 1-unsubstituted 2,4-dialkylthiodiazophosphorins 7a,d with amines, formation of 2-phosphamides
is typical (upon reaction with amines under harsher conditions (180-190°C), a mixture of 2,4-diamino
derivatives is formed), while for the 1-substituted compounds 8 the process of substitution at the position 4
predominates (this tendency has already been noted in the literature [18]). From our standpoint, such a direction
for the change in the course of the reaction with amines is due to the fact that the presence of the
108

substituent in the position 1 of the diazaphosphorin ring leads to steric hindrances in the transition state upon
attack at the phosphorus atom in the position 2, which in this case promotes the substitution process occurring
exclusively at the position 4.
1
The structure of all the synthesized compounds was studied in detail using H and 13C NMR spectra
13
(most of them are given in Experimental). Here we compare the C NMR spectra (in DMSO-d6) of compound
2a [δ, ppm (J, Hz): 24.1 (C(7)); 24.6 (C(8)); 49.8 (C(6)); 113.2 (C(4a), 3J = 7.6, C(4a)–P); 141.8 (C(9a)); 177.1 (C(4), d,
4
2J = 11.4, C–P)] and compound 7a [δ, ppm (J, Hz): 23.8 (C(7)); 25.0 (C(8)); 32.2 (4-C–S–CH2, J = 1.8, C–P);
2
37.7 (P–S–CH2, J = 4.4, C–P); 46.9 (C(6)); 108.9 (C(4a), 4J = 33.0, C–P); 155.4 (C(9a)); 159.4 (C(8a)); 160.9 (C(4),
4J = 17.0, C–P)].* Comparison of the chemical shifts for the C(4) atom of both compounds allows us to say that
tricycle 2a exists in the thione tautomeric form. For compounds 2a, 7a, 9b, and 12 (isolated from reaction of
31
compound 7a and benzylamine at 180-190°C, see Experimental), we also obtained data from P NMR spectra
(DMSO-d6, external standard 85% H3PO4). In diazaphosphorin 2a, the 31P signal is observed at 75 ppm; in
31
2-S- and 4-S-dibenzyl derivative 7a, the P signal is shifted upfield to 63.3 ppm, while for compound 11 we
observe further shift of the signal to 55.8 ppm. These results also are evidence in favor of thione structure for
compound 2a.
In conclusion, we need to focus on some features of the 1H NMR spectra of the synthesized compounds.
1. The signals from protons of the 2-S–CH2Ph group in compounds 8a-c are nonequivalent, which is due
to their spatial proximity to the asymmetric phosphorus atom: ∆δ = δSCHaPh – δSCHbPh = 0.07-0.08 ppm. These
protons are represented by two triplets of equal intensity at 3.74-3.79 ppm and 3.83-3.88 ppm (2JHaHb = 3JCHa-P
~
14 Hz).
2. The protons of the 4-thiobenzyl moiety in compounds 7a-c are spatially distant from the P atom (no
spin–spin coupling with the phosphorus atom appears) and form two doublets of equal intensity in the
4.26-4.35 ppm region with 2JHaHb ~ 13.5 Hz.
3. The most unexpected feature was the appearance of nonequivalence of the cyclic methylene protons in
the position 6, which formally are quite distant from the phosphorus atom. This nonequivalence is even observed
for the seven-membered compound 7c and is ~0.1 ppm. For compounds 9b and 8, the nonequivalence of the 6-H
protons is 0.04 ppm and 0.10 ppm respectively (two symmetric 1H multiplets each). For these compounds, the
nonequivalence of the 4-S–CH2Ph protons is ∆δ = 0.06 ppm and 0.18 ppm respectively, while for the diamino
derivative 12 that was isolated in pure form we have ∆δ6-CHa,CHb = 0.20 ppm (two symmetric 1H multiplets each
that are far apart from each other). For this compound, we also observe nonequivalence for the methylene
protons of the 4-S–CH2Ph moiety (∆δCH2 = 0.11 ppm).
The observed nonequivalence of the 4-S–CH2Ph and 6-CH2 protons undoubtedly is connected with the
spatial structure of the studied systems. It has been shown [8] that when benzo-1,3,2-diazaphosphorin-4-thiones
are converted to S,S-dialkyl derivatives, the heterocycle becomes markedly flatter.
H
H
N
S
S
N
P
P
SH
SR'
N
NH
SR'
S
In the case of the studied compounds, the transition of the heterocycle to a more planar structure also
should lead to the substituent at the 4 position coming appreciably closer to the 6-CH2 group. In order to assess
to what extent such flattening may affect the appearance of nonequivalence of the protons of this methylene
_______
* The signals from the carbon atoms of the two phenyl rings were: 127.4, 127.6, 128.7 (2C), 128.8 (4C), 129.5
(2C), 137.4, 137.7 ppm.
109

group, we studied the spectra of compound 9a in DMSO in the presence of NaOD. This transition of the
heterocyclic system to a flatter state, connected with formation of the anion, led to appreciable divergence of the
signals for the 6-CHa and 6-CHb protons, and ∆δ6-CHa,CHb (before addition of the base, ~0.02 ppm) increased up
to 0.1 ppm.
+NaOD
8
SH
N
S
N
N
N
N
P
O
O
P
N
7
Hb
Ha
N
N
N
N
6
+
Na
SMe
SMe
9a
Thus we can conclude that namely specifically spatial and conformational effects are responsible for the
appreciable nonequivalence of the 4-S–CH2R and 6-CH2 protons observed in the 1H NMR spectra of the studied
compounds.
EXPERIMENTAL
The NMR spectra were recorded on XL-200 and Unity 400+ (Varian) spectrometers (400 MHz for 13C,
163 MHz for 31P), internal standard TMS. The mass spectra were recorded on a MAT-112 (Varian) and an
SSQ-710 (Finnigan) spectrometer with electron impact ionization energy 70 eV. The IR spectra were recorded
on a Perkin-Elmer 599 spectrometer. The melting points were determined on a Boetius heating stage. Thin layer
chromatography was run on Silufol UV-254 plates, methanol as the eluent, visualization in iodine vapors.
1-Carbamidomethyl-2-cyanoiminopiperidine (1b). A stream of dry ammonia was passed through
suspension of 2-cyanoimino-1-ethoxycarbonylmethylpiperidine (2.1 g, 10 mmol) in methanol (30 ml) for 2 h at
room temperature. Then the reaction mass was cooled down to 0-5°C and the precipitate was filtered off.
Yield 1.3 g (72%); mp 222-224°C (EtOH–water, 5:1). Found, %: C 53.31; H 6.69: N 31.27. C18H12N4O.
Calculated, %: C 53.31; H 6.71; N 31.09.
Compound 1c was obtained similarly. Yield 79%; mp 215-217°C (EtOH–water, 5:1). Found, %:
C 55.79; H 7.48; N 28.66. C9H14N4O. Calculated, %: C 55.65; H 7.27; N 28.85.
7,8-Trimethylene-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-mercapto-2,4-dithione, Pyridine
Solvate (2a). A. Dry pyridine (30 ml) was added slowly and carefully with stirring to carefully ground and
stirred mixture of 1-carbamidomethyl-2-cyanoiminopyrrolidine 1a (10 g, 60 mmol) and phosphorus pentasulfide
(20 g, 90 mmol). The mixture was heated and changed to an oil. After addition of pyridine, the mixture was
boiled for 5 min and then washed with boiling benzene (2 × 100 ml); water (200 ml) was added and this was
boiled for 2 min and then cooled down. The precipitate was filtered off and carefully washed with water and
1
ethanol. Yield 12.4 g (63%)*; mp > 300°C (DMF–water, 3:1). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.50 (2H, m, 7-CH2); 2.84 (2H, t, 8-CH2); 4.30 (2H, t, 6-CH2); 9.30 (1H, br. d, 2J = 15.3, NH-P), and 9.38 (1H,
13
br. s, NH); pyridine: 7.85 (2H, m, β-H); 8.26 (1H, t, γ-H), 8.79 (2H, d, α-H); SH does not appear; C NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 24.1 (C(7)); 24.6 (C(8)); 49.8 (C(6)); 113.2 (C(4a)), d, 3J = 7.6, C(4a)–P); 141.8
2
(C(9a)); 153.1 (C(8a)); 177.1 (C(4), d, J = 11.4, C(4)–P). Mass spectrum: [M]+· 276, 243 [M+ - SH], 184 [M+ - SH,
+
- CSNH2], 148 [M+ - SH, –PS2], 123 [M+ - CS–NH–PS2], 95 (PS2 ).
_______
* Here and in other cases, to calculate the product yields we assumed that the average pyridine content in the
solvates was 2/3 mol/liter of pyridine per 1 mol/liter of diazaphosphorin.
110

B. Dry pyridine (3 ml) was added slowly with stirring to mixture of 1,2-trimethylene-4-amino-5-
cyanoimidazole 5 (1.48 g, 10 mmol) and phosphorus pentasulfide (3.33 g, 15 mmol), then the procedure was
continued as in Method A. Yield 1.02 g (31%).
Homologs of Compound 2a were obtained similarly.
Compound 2b. Yield 45%; mp > 300°C (DMF–water, 3:1), [M]+ · 374.
Compound 2c. Yield 54%; mp > 300°C (DMF–water, 3:1), [M]+ · 388.
7,8-Trimethylene-2,4-dibenzylthio-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione (7a). Pyridine
solvate 2a (1.65 g, 5 mmol) was dissolved in sodium ethoxide solution prepared from Na (0.28 g, 12 mmol) and
ethanol (20 ml). Then benzyl chloride (1.5 ml, 12 mmol) was added; this was boiled for 5 min and then poured
into cold water (40 ml). The mixture obtained was acidified with HCl down to pH 2-3, the precipitate was
filtered off and then washed with water and ethanol. Yield 1.73 g (76%); mp 187-189°C (DMF–water, 3:1). 1H
NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.49 (2H, m, 7-CH2); 2.78 (2H, t, 8-CH2); 4.07 (2H, t, 6-CH2); 3.77
(1H, t, 2JCHaCHb = 14.0, 3JCHa-P = 14.0, 2-CHaPh), and 3.85 (1H, t, 3JCHb-P = 14.0, 2-CHbPh); 4-CH2 protons: 4.30
2
2
13
(1H, d, JCHaCHb = 13.5, CHa) and 4.31 (1H, d, CHb); 10.26 (1H, d, J1NH-P = 8.5, 1-NH). C NMR spectrum
4
2
(DMSO-d6), δ, ppm (J, Hz); 23.8 (C(7)); 25.0 (C(8)); 32.2 (C(4)–S–CH2, Javg = 1.8); 37.7 (P–S–CH2, Javg
=
4.6); 46.9 (C(6)); 108.9 (C(4a), Javg = 33.0); 155.4 (C(9a)); 159.4 (C(8a)); 160.9 (C(4), 4Javg = 16.7), signals from the
4
two phenyl rings are observed at 127.4 (1C), 127.6 (1C), 128.7 (2C), 128.8 (4C), 129.5 (2C), 137.4 (1C, 3Javg
=
5.1), 137.7 (1C), mass spectrum: [M]+ 456, fragmentation: 333 [M+ - SCH2Ph], 301 [M+ - SCH2Ph, - S], 211 [M+
- SCH2Ph - SCH2Ph], 124 [HSCH2Ph+], 91 [CH2Ph+]. Found, %: C 55.00; H 4.65; N 12.25. C21H21N4PS3.
Calculated, %: C 55.25; H 4.64; N 12.27.
Compound 7b was obtained similarly. Yield 62%; mp 214-218°C (DMF–water). [M]+ · 470. H NMR
1
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.77, 1.90 (4H, m, 7-CH2, 8-CH2); 2.71 (2H, t, 9-CH2); 4.07 (2H, t,
6-CH2); 3.74, 3.83 (2H, t, 2JCHaCHb = 14.1, 3JCHa-P = 14.1, 3JCHb-P = 14.1, P–CHaHb); 4.26, 4.35 (2H, d, 2JCHaCHb
=
2
13.6, 4-C–S–CHaHb); 7.15-7.45 (10H, m, 2Ph); 10.16 (1H, d, JNH-P = 8.8, 1-NH). Found, %: C 55.73; H 5.07;
N 11.95; S 19.98. C22H23N4PS3. Calculated, %: C 56.15; H 4.93; N 11.91; S 20.44.
Compound 7c was obtained similarly. Yield 38%; mp 182-186°C (DMF–water, 3:1), [M]+ · 484.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.45-1.85 (6H, m, 7-, 8-, 9-CH2); 2.82 (2H, m, 10-CH2); 4.22,
4.32 (2H, m, 6-CH2); 3.79 (1H, t, 2JCHaCHb = 14.0, 3JCHa-P = 14.0, P–SCHa); 3.88 (1H, br. t, 3JCHb-P = 14.4, P–
2
2
SCHb); 4.27, 4.35 (2H, d, JH-H = 13.6, 4-C–S–CH2–Ph); 7.15-7.50 (10H, m, 2Ph); 10.20 (1H, d, J1-NH-P = 9.1,
1-NH). Found, %: C 56.72; H 5.14; N 11.50; S 19.68. C23H25N4PS3. Calculated, %: C 57.00; H 5.20; N 11.56; S
19.85.
1
Compound 7d was obtained similarly. Yield 47%; mp 249-251°C (DMF), [M]+ · 304. H NMR
3
spectrum (DMSO-d6, 90°C), δ, ppm (J, Hz): 2.11 (3H, d, JMe-P = 15.7, P–S–Me); 2.51 (3H, s, 4-C–SMe); 2.54
(2H, m, 7-CH2); 2.80 (2H, t, 8-CH2); 4.14 (2H, t, 6-CH2); ~10 (1H, br. s, 1-NH). Found, %: C 35.65; H 4.38;
N 18.47; S 31.35. C9H13N4PS3. Calculated, %: C 35.52; H 4.31; N 18.41; S 31.61.
1-Methyl-7,8-trimethylene-2,4-dimethylthio-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thione
(8a). Pyridine solvate 2a (3.29 g, 10 mmol) was dissolved in aqueous (1 mol/l) solution of NaOH (80 ml). The
solution obtained was washed twice with benzene and cooled down to 0-5°C, and then dimethyl sulfate (5 ml)
was added. The reaction mixture was stirred for 30 min, the precipitate was filtered off and washed with water
and ethanol. Yield 1.96 g (62%); mp 144-147°C (DMF–water, 3:1). [M]+ · 318, fragments 271 [M+ - SCH3], 255
+
1
[M+ - PS], 239 [M+ - SCH3 - SCH3], 198 [M+ - N=C–CH3 - CH3], 79 (P–SCH3 ), 63 (PS+). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.99 (3H, d, 3JMe-P = 15.7, P–SCH3); 2.52 (2H, m, 7-CH2); 2.52 (3H, s, 4-C–SCH3);
2.83 (2H, t, 8-CH2); 3.22 (3H, d, JMe-P = 10.1, 1-N–CH3), 4.16 (2H, m, 6-CH2). Found, %: C 37.65; H 4.94; N
3
17.46; S 30.12. C10H15N4PS3. Calculated, %: C 37.72; H 4.75; N 17.60; S 30.21.
Compound 8b was obtained similarly. Yield 54%; mp 131-134°C (DMF–water, 3:1). Found, %:
C 43.13; H 6.24; N 15.54; S 26.77. C13H21N4PS3. Calculated, %: C 43.32; H 5.87; N 15.54; S 26.69.
111

Reaction of 7,8-Trimethylene-1H-imidazo[4,5-d]-1,3,2-diazaphosphorin-2-thiones with Amines.
General Method. Mixture of diazaphosphorin 2a, 8a, or 7d (10 mmol) and 5-fold excess of the corresponding
amine was boiled for 10-30 min. 2-Propanol (50 ml) was added, the mixture was boiled for 1 min and cooled
down. The precipitate was filtered off and washed with 2-propanol and hexane.
1
Compound 6. Yield 37%; mp 236-239°C (decomp., DMF–water, 3:1), [M]+ · 276. H NMR spectrum
(DMS-d6), δ, ppm (J, Hz): 2.43 (2H, m, 7-CH2); 2.70 (2H, t, 8-CH2); 4.19 (2H, t, 6-CH2); 8.66 (2H, br. d,
2
2JNH-P = 16.4, NH); 8.92 (1H, br. d, JNH-P = 13.6, NH); 4.05 (2H, s, CH2Ph); 7.43 (5H, m, Ph); 8.13 (2H, br. s,
NH2). 13C NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 23.9 (C(7)); 24.9 (C(8)); 47.1 (C(6)); 115.5 (C(4a)
,
2
3JC4a-P = 6.8); 151.2 (C(9a)); 158.8 (C(8a)); 175.8 (C(4), JC4-P = 12.5); 42.7 (CH2Ph); 128.8, 129.0, 129.2, 134.3
(Ph). Found, %: C 43.85; H 4.80; N 18.17; S 25.50. C14H18N5PS3. Calculated, %: C 43.85; H 4.73; N 18.27;
S 25.09.
1
Compound 9a. Yield 74%; mp 243-246°C (DMF), [M]+ · 343. H NMR spectrum (DMSO-d6), δ, ppm
3
(J, Hz): 2.44 (3H, s, 4-C–SCH3); 2.50 (2H, m, 7-CH2); 2.76 (2H, t, 8-CH2); 3.10 (4H, m, JCH2-P = 8.3, α,α'-N–
CH2); 3.52 (4H, t, β,β'-OCH2); 4.10 (2H, m, 6-CH2); 9.36 (1H, d, 3JNH-P = 6.8, NH). Found, %: C 41.98; H 5.36;
N 20.40; S 18.64. C12H18N5OPS2. Calculated, %: C 41.97; H 5.28; N 20.40; S 18.68.
1
Compound 9b. Yield 36%; mp 240-242°C (DMF–water, 3:1). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.49 (2H, m, 7-CH2); 2.75 (2H, t, 8-CH2); 4.07 (2H, m, 6-CH2); 3.08 (4H, m, 3JCH2-P = 8.5, α,α'-NCH2);
2
2
3.51 (4H, m, β,β'-OCH2); 4.32 and 4.42 (2H, d, JCHaCHb = 13.6, S–CH2); 9.45 (1H, d, J1-NH-P = 6.8, NH);
7.15-7.45 (5H, m, Ph). Found, %: C 51.23; H 5.32; N 16.69; S 15.52. C18H22N5OPS2. Calculated, %: C 51.54;
H 5.29; N 16.70; S 15.29.
1
Compound 10. Yield 46%; mp 194-197°C (DMF–water, 2:1), [M]+ · 357. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.98 (3H, d, 2JMe-P = 14.9, P–S–Me); 2.47 (2H, m, 7-CH2); 2.83 (2H, t, 8-CH2); 3.15
3
(3H, d, JMe-P = 10.7, 1-N–Me); 3.53 (4H, t, α,α'-N–CH2); 3.65 (4H, t, β,β'-OCH2); 4.09 (2H, m, 6-CH2).
2
13C NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 23.7 (C(7)); 25.1 (C(8)); 31.7 (S–CH2); 45.4 (2C, JNCH2-P ~ 1,
3
3
N–CH2); 46.8 (C(6)); 66.7 (2C, JOCH2-P = 6.4, OCH2); 108.3 (C(4a), JC4a-P = 23.9); 155.4 (C(9a)); 158.4 (C(4),
3JC4-P = 10.9); 158.7 (C(8a)); aromatic carbon atoms of the SCH2Ph moiety give signals at 127.4 (1C), 128.7 (2C),
129.4 (2C), 138.3 (1C). Found, %: C 43.31; H 5.71; N 19.43; S 18.13. C13H20N5OPS2. Calculated, %: C 43.69; H
5.64; N 19.60; S 17.94.
1
Compound 12. Yield 69%; mp 225-227°C (DMF–water, 3:1). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.48 (2H, m, 7-CH2); 2.71 (2H, t, 8-CH2), and 4.05 and 4.25 (two symmetric multiplets 1H each, 6-CH2,
Σ2J6-CHa,6-CHb + 3J6-CH2,7-CH2 = 24); 8.55 (1H, d, NH, 2JNH-P = 6.0); 3.75 (Ha) and 3.83 (Hb) (two doublets 1H each,
2
3
3
P–NH–CH2Ph, JCHaCHb = 14.3, JNH-CHa = JCHb-NH = 7.4); 5.11 (1H, m, JNH-P = 14.2); 4.46 (Ha) and 4.58 (Hb)
2
3
13
(two q 1H each, 4-C–NH–CH2-Ph, JHaHb = 15.2, JNHCHb = 6.2); 7.12-7.36 (10H, m, 2Ph). C NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 23.4 (C(7)); 25.1 (C(8)); 43.1 (C(4)–NCH2–Ph); 45.5 (P–NH–CH2–Ph, 3J = 2.7); 46.0
(C(6)); 100.8 (C(4a), 3JC4b,P = 19.9); 151.1 (C(9a)); 155.6 (C(4), 2JC4,P = 4.4); 155.7 (C(8a)); 126.5, 126.8, 127.4 (C(4));
128.1 (C(2)); 128.4 (C(2)); 140.2, 141.3 (3Javg = 6.2, 2Ph). Found, %: C 59.52; H 5.66; N 19.78; S 7.38.
C21H23N6PS. Calculated, %: C 59.70; H 5.49; N 19.89; S 7.32.
REFERENCES
1.
2.
T. M. Bargar and C. M. Riley, Synth. Commun., 479 (1980).
T. V. Stezhko, V. G. Granik, R. G. Glushkov, L. E. Roshchina, A. I. Polezhaeva, and
M. D. Mashkovskii, Khim.-Farm. Zh., 290 (1984).
3.
4.
T. A. Gudasheva, R. I. Ostrovskaya, F. V. Maksimova, A. V. Chupin, S. S. Trofimov, V. P. Lezina,
T. A. Voronina, and A. P. Skoldinov, Khim.-Farm. Zh., 276 (1989).
V. G. Granik, T. V. Golovko, R. G. Glushkov, M. D. Mashkovskii, L. E. Roshchina, A. I. Polezhaeva,
R. B. Parimbetova, Yu. G. Bobkov, A. S. Losev, and I. A. Ivanova, Khim.-Farm. Zh., 1186 (1989).
112

5.
6.
A. V. Kadushkin, T. V. Golovko, V. G. Granik, R. G. Glushkov, R. B. Parimbetova, V. A. Parshin, and
M. D. Mashkovskii, Khim.-Farm. Zh., 1193 (1989).
D. B. Nilov, A. V. Kadushkin, V. G. Granik, N. P. Solov'eva, V. V. Asnina, R. B. Parimbetova,
V. A. Parshin, and M. D. Mashkovskii, Khim.-Farm. Zh., No. 1, 35 (1993).
W. Walter, T. Fleck, J. Voss, and M. Gerwin, Liebigs Ann. Chem., 275 (1975).
R. M. Acheson, C. T. Lines, M. R. Bryce, Z. Dauter, C. D. Reynolds, and A. Schmidpeter, J. Chem.
Soc., Perkin Trans. 2, 1913 (1985).
7.
8.
9.
10.
11.
K. Nagarajan, S. J. Shenoy, H. Fritz, O. Hosang, and W. J. Richter, Helv. Chim. Acta, 68, 900 (1985).
B. R. Shinde, S. J. Shenoy, and N. R. Pai, Indian J. Chem., 29B, 711 (1990).
R. Chen and J. Wang, Gaodeng Xuexiao Huaxue Xuebao, 923 (1992); Chem. Abstr., 118, 102089
(1992).
12.
D. B. Nilov, N. P. Solov'eva, I. S. Nikolaeva, V. V. Peters, L. Yu. Krylova, T. A. Gus'kova, and
V. G. Granik, Khim.-Farm. Zh., No. 7, 16 (1998).
13.
14.
15.
16.
D. B. Nilov, A. V. Kadushkin, N. P. Solov'eva, and V. G. Granik, Mendeleev Commun., 67 (1995).
A. S. Fissyuk, M. A. Vorontsova, and D. V. Temnikov, Tetrahedron Lett., 37, 5203 (1996).
V. G. Granik, A. V. Kadushkin, and J. Liebsher, Adv. Het. Chem., 72, 79 (1998).
D. B. Nilov, A. V. Kadushkin, S. G. Kalistratov, A. S. Sokolova, I. S. Nikolaeva, V. V. Peters,
L. Yu. Krylova, and V. G. Granik, Khim.-Farm. Zh., No. 9-10, 63 (1992).
E. N. Dozorova, A. V. Kadushkin, G. A. Bogdanova, N. P. Solov'eva, and V. G. Granik, Khim.
Geterotsikl. Soedin., 754 (1991).
17.
18.
B. R. Shinde, S. J. Shenoy, and N. R. Pai, Indian J. Chem., 29B, 721 (1990).
113